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Principles of
Pediatric Oncology,
Genetics of Cancer,
and Radiation
Therapy
Matthew J. Krasin and Andrew M. Davidoff
398
PART III
TABLE 28-1
Frequency of Cancer Diagnoses in Childhood
Type of Cancer
Percentage of Total
Leukemia
Brain tumors
Lymphoma
Neuroblastoma
Sarcoma
Wilms tumor
Osteosarcoma
Retinoblastoma
Liver tumors
30
25
15
8
7
6
5
3
1
CHAPTER 28
399
400
PART III
TABLE 28-2
Proto-oncogenes and Tumor Suppressor Genes in Pediatric Malignancies
Oncogene Family
Proto-oncogene
Chromosome Location
Tumors
ERBB2
TRK
SRC
17q21
9q22
7p11
Signal transducers
Transcription factors
H-RAS
c-MYC
MYCN
11p15.1
18q24
2p24
Glioblastoma
Neuroblastoma
Rhabdomyosarcoma,
Osteosarcoma, Ewing sarcoma
Neuroblastoma
Burkitt lymphoma
Neuroblastoma
Syndrome
Chromosome Location
Tumors
APC
5q21
Familial retinoblastoma
RB
13q24
WAGR*
Denys-Drash{
Beckwith-Weidemann{
WT1
WT1
WT2 (?)
11p13
11p13
11p15
Li-Fraumeni
Neurofibromatosis type 1
Neurofibromatosis type 2
TP53
NF1
NF2
17q13
17q11.2
22q12
von Hippel-Lindau
VHL
3p25-26
Protein kinase
CHAPTER 28
401
TABLE 28-3
Common, Recurrent Translocations in Soft Tissue Tumors
Tumor
Ewing sarcoma/primitive
neuroectodermal tumor
Alveolar rhabdomyosarcoma
Malignant melanoma of
soft part (clear cell sarcoma)
Myxoid liposarcoma
Extraskeletal myxoid
chondrosarcoma
Dermatofibrosarcoma
protuberans and giant cell
fibroblastoma
Congenital fibrosarcoma and
mesoblastic nephroma
Lipoblastoma
Genetic
Abnormality
Fusion
Transcript
t(11;22)(q24;q12)
t(21;22)(q22;q12)
t(7;22)(p22;q12)
t(17;22)(q12;q12)
t(2;22)(q33;q12)
t(11;22)(p13;q12)
t(11;22)(q24;q12)
t(X;18)(p11.23;
q11)
t(X;18)(p11.21;
q11)
t(2;13)(q35;q14)
t(1;13)(p36;q14)
t(12;22)(q13;q12)
FLI1-EWS
ERG-EWS
ETV1-EWS
E1AF-EWS
FEV-EWS
WT1-EWS
FLI1-EWS
SSX1-SYT
SSX2-SYT
t(12;16)(q13;p11)
t(12;22)(q13;q12)
t(9;22)(q22;q12)
CHOP-TLS(FUS)
CHOP-EWS
CHN-EWS
t(17;22)(q22;q13)
COL1A1-PDGFB
t(12;15)(p13;q25)
ETV6-NTRK3
t(3;8)(q12;q11.2)
t(7;8)(q31;q13)
?
?
PAX3-FKHR
PAX7-FKHR
ATF1-EWS
From Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors in
childhood. Semin Pediatr Surg 2001;10:106-118.
402
PART III
methylation resulting in silencing of caspase 8, a protein involved in apoptosis, likely contributes to the pathogenesis of
MYCN-amplified neuroblastoma37 as well as Ewing sarcoma.23
Histone Modification Histones are the proteins that give
structure to DNA and, together with the DNA, form the major
components of chromatin. The functions of histones are
to package DNA into a smaller volume to fit in the cell, to
strengthen the DNA to allow replication, and to serve as a
mechanism to control gene expression. Alterations in histones
can mediate changes in chromatin structure. The compacted
form of DNA, termed heterochromatin, is largely inaccessible
to transcription factors and therefore genes in the affected
regions are silent. Other modifications of histones can cause
DNA to take a more open or extended configuration (euchromatin), allowing for gene transcription. The N-terminal tails of
histones can be modified by a number of different processes
including methylation and acetylation, mediated by histone
acetyl transferases (HAT) and deacetylases (HDAC), and
histone methyltransferases (HMT). Each of these processes
alters histone function, which, in turn, alters the structure
of chromatin and therefore the accessibility of DNA to transcription factors. Methylation of the DNA itself can also effect
changes in chromatin structure.
MicroRNA As stated above, miRNAs are a group of small,
regulatory noncoding RNAs that appear to function in gene
regulation. These miRNAs are single-stranded RNA fragments
of 21 to 23 nucleotides that are complementary to encoding
mRNAs.25 Their function is to down-regulate expression of
target mRNAs; it is estimated that miRNAs regulate the expression of about 30% of all human genes.38 These miRNAs regulate gene expression primarily by incorporating into
silencing machinery called RNA-induced silencing complexes
(RISC). MiRNAs are involved in a number of fundamental
biological processes, including development, differentiation,
cell-cycle regulation, and senescence. However, broad analyses of miRNA expression levels have demonstrated that
many miRNAs are dysregulated in a variety of different cancer
types, including neuroblastoma and other pediatric tumors,39
frequently losing their function as gene silencers/tumor suppressors. The activity of miRNAs, like gene expression, is also
under epigenetic regulation.
METASTASIS
Metastasis is the spread of cancer cells from a primary tumor to
distant sites and is the hallmark of malignancy. The development of tumor metastases is the main cause of treatment
failure and a significant contributing factor to morbidity
and mortality resulting from cancer. Although the dissemination of tumor cells through the circulation is probably a
frequent occurrence, the establishment of metastatic disease
is a very inefficient process. It requires several events, including the entry of the neoplastic cells into the blood or lymphatic
system, the survival of those cells in the circulation, their
avoidance of immune surveillance, their invasion of foreign
(heterotopic) tissues, and the establishment of a blood supply
to permit expansion of the tumor at the distant site. Simple,
dysregulated cell growth is not sufficient for tumor invasion
and metastasis. Many tumors progress through distinct stages
CHAPTER 28
403
that can be identified by histopathologic examination, including hyperplasia, dysplasia, carcinoma in situ, invasive cancer,
and disseminated cancer. Genetic analysis of these different
stages of tumor progression suggests that uncontrolled growth
results from progressive alteration in cellular oncogenes and
inactivation of tumor suppressor genes, but these genetic
changes driving tumorigenicity are clearly distinct from those
that determine the metastatic phenotype.
Histologically, invasive carcinoma is characterized by a lack
of basement membrane around an expanding mass of tumor
cells. Matrix proteolysis appears to be a key part of the mechanism of invasion by tumor cells, which must be able to move
through connective tissue barriers, such as the basement
membrane, to spread from their site of origin. The proteases
involved in this process include the matrix metalloproteinases
and their tissue inhibitors. The local environment of the target
organ may profoundly influence the growth potential of
extravasated tumor cells.40 The various cell surface receptors
that mediate interactions between tumor cells and between
tumor cells and the extracellular matrix include cadherins,
integrins (transmembrane proteins formed by the noncovalent
association of alpha and beta subunits), and CD44, a transmembrane glycoprotein involved in cell adhesion to hyaluronan.41 Tumor cells must decrease their adhesiveness to escape
from the primary tumor, but at later stages of metastasis, the
same tumor cells need to increase their adhesiveness during
arrest and intravasation to distant sites.
ANGIOGENESIS
------------------------------------------------------------------------------------------------------------------------------------------------
Molecular Diagnostics
The explosion of information about the human genome has led
not only to an improved understanding of the molecular
genetic basis of tumorigenesis but also to the development of
a new discipline: the translation of these molecular events
into diagnostic assays. The field of molecular diagnostics has
developed from the need to identify abnormalities of gene or
chromosome structure in patient tissues and as a means of
supporting standard histopathologic and immunohistochemical diagnostic methods. In most instances, the result
of genetic testing confirms light microscopic- and immunohistochemistry-based diagnosis. In some instances, however
(e.g., primitive, malignant, small round cell tumor; poorly
differentiated synovial sarcoma; lipoblastic tumor), molecular
analysis is required to make a definitive diagnosis.
The molecular genetic methods most commonly used to
analyze patient tumor material include direct metaphase
cytogenetics or karyotyping, fluorescence in situ hybridization
(FISH), and reverse transcriptase polymerase chain reaction
(RT-PCR). Additional methods, such as comparative genomic
hybridization, loss of heterozygosity analysis, and complementary DNA (cDNA) microarray analysis, may eventually
become part of the routine diagnostic repertoire but are
currently used as research tools at referral centers and academic institutions. Each standard method is summarized in
Table 28-4. As with any method, molecular genetic assays
have advantages and disadvantages, and it is important to
understand and recognize their limitations.
The value of molecular genetic analysis of patient tissue
is not limited to aiding histopathologic diagnosis. Many of
the most important markers provide prognostic information
as well. MYCN amplification in neuroblastomas,13 for example, is strongly associated with biologically aggressive behavior. Amplification of this gene can be detected by routine
404
PART III
TABLE 28-4
Comparison of the Cytogenetic and Molecular Methods Routinely Used as Aids in Pathologic Diagnosis of Soft Tissue Tumors
Method
Purpose
Advantages
Disadvantages
Cytogenetics
In situ
hybridization
From Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors in childhood. Semin Pediatr Surg 10: 2001;106-118.
PCR, polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction.
metaphase cytogenetics or by FISH, and current neuroblastoma protocols include the presence or absence of MYCN
amplification in their stratification schema. Some fusion gene
variants are also thought to influence prognosis. In initial
studies, two examples noted to confer relatively favorable
prognoses are the type 1 variant fusion of EWS-FLI1 in Ewing
sarcoma or primitive neuroectodermal tumor20 and the
PAX7-FKHR fusion in alveolar rhabdomyosarcoma.19
New technologies are emerging that permit accurate,
high-throughput analysis or profiling of tumor tissue: Gene
expression can be analyzed by using RNA microarrays, and
proteins by using proteomics. These approaches identify a
unique fingerprint of a given tumor that can provide diagnostic or prognostic information. Proteomic analysis can also
identify unique proteins in patients serum or urine; such a
profile can be used for early tumor detection, to distinguish
risk categories, and to monitor for recurrence. Additional
types of omics that are currently being used to evaluate
tumor or patient specimens include transcriptomics (RNA
and gene expression), metabolomics (metabolites and metabolic networks), and pharmacogenomics (how genetics affects
host drug responses). Information from each of these areas of
investigation provides an increasingly precise and unique
perspective on the biology, clinical behavior, and responsiveness to specific therapeutic interventions of individual patient
tumors. It is through these analyses that personalized therapy
is likely to be realized. In addition, it is anticipated that with
the identification of new, critical components of oncogenesis
and tumor progression will come new druggable targets
for cancer therapy. Drugs that act on these targets will not
CHAPTER 28
405
Genetic Screening
------------------------------------------------------------------------------------------------------------------------------------------------
General Principles
of Chemotherapy
------------------------------------------------------------------------------------------------------------------------------------------------
Cytotoxic agents were first noted to be effective in the treatment of cancer in the 1960s, after alkylating agents, such as
nitrogen mustard gas, used during World War II, were observed to cause bone marrow hypoplasia. Chemotherapy is
now an integral part of nearly all cancer treatment regimens.
The overriding goal of cancer chemotherapy is to maximize
the tumoricidal effect (efficacy) while minimizing adverse side
effects (toxicity). This goal can be difficult to achieve, however,
because the dose at which tumor cells are affected is often similar to the dose that affects normal proliferating cells, such as
those in the bone marrow and gastrointestinal tract. Despite
the early promise of chemotherapy and the observation that
most tumor types are initially sensitive to chemotherapy, often
406
PART III
RISK STRATIFICATION
Major advances in the variety of chemotherapeutic agents and
dosing strategies used to treat pediatric cancers in the past
30 years are reflected in improved patient survival rates.
Regimen toxicity (including late effects, which are particularly
important in the pediatric population) and therapeutic
resistance are the two main hurdles preventing further advancement. As more information about diagnostically and
prognostically useful genetic markers becomes available,
therapeutic strategies will change accordingly. With molecular
profiling, patients can be categorized to receive a particular
treatment on the basis of not only the tumors histopathologic
and staging characteristics but also its genetic composition.
Some patients whose tumors show a more aggressive biological profile may require dose intensification to increase their
chances of survival. Patients whose tumors do not have an
aggressive biological profile may benefit from the lower
toxicity of less intensive therapy. Such an approach may allow
the maintenance of high survival rates while minimizing longterm complications of therapy in these patient populations.
The paradigm for the use of different therapeutic intensities
on the basis of risk stratification drives the management of
pediatric neuroblastoma. There is increasing evidence that
the molecular features of neuroblastoma are highly predictive
of its clinical behavior. Most current studies of the treatment of
neuroblastoma are based on risk groups that take into account
both clinical and biological variables. The most important
clinical variables appear to be age and stage at diagnosis,
and the most powerful biological factors appear to be MYCN
status, ploidy (for patients younger than 1 year), and histopathologic classification. These variables currently define
the Childrens Oncology Group risk strata and therapeutic
approach, which are further refined by determining whether
there is 1p/11q LOH. At one extreme, patients with low-risk
disease are treated with surgery alone; at the other extreme,
patients at high risk for relapse are treated with intensive
multimodality therapy that includes multiagent doseintensive chemotherapy, radiation therapy, and stem cell
transplantation. Other factors, such as 17q gain, caspase
8 inactivation, and TRKA/B expression, are currently being
evaluated and may help further refine risk assessment in the
future. The management of other solid pediatric tumors is also
shifting to risk-defined treatment. For example, the current
protocol for the management of patients with Wilms tumor
includes risk stratification and therapy adjustment based
on molecular analysis of the primary tumor for 16q and 1p
deletions.
TARGETED THERAPY
Another major change in the approach to the treatment of cancer has been the concept of targeted therapy. Until recently, the
development of anticancer agents was based on the empirical
screening of a large variety of cytotoxic compounds without
particular regard to disease specificity or mechanism of action.
Now, one of the most exciting prospects for improving the
TABLE 28-5
Common Chemotherapeutic Agents
Synonyms
Alkylating
agents
Carboplatin
CBCDCA
Paraplatin
Cisplatin
CDDC
Platinol
Cyclophosphamide
CTX
Cytoxan
Ifosfamide
IFOS
Ifex
Dacarbazine
Temozolomide
Nitrogen Mustard
TMZ
Mechlorethamine
DTIC
Temodar
Mustargen
Melphalan
L-PAM
Alkeran
Busulfan
Antimetabolites
Busulfex
Cytarabine
Ara-C
Cytosar
Fluorouracil
5-FU
(Several)
Method of
Elimination
Susceptible
Solid
Tumors
Mechanism of Action
Platination,
intrastrand and
interstrand DNA
cross-linking
Platination,
intrastrand and
interstrand DNA
cross-linking
Alkylation,
intrastrand and
interstrand DNA
cross-linking
Alkylation,
intrastrand and
interstrand DNA
cross-linking
Methylation
Methylation
Alkylation,
intrastrand and
interstrand DNA
cross-linking
Alkylation,
intrastrand and
interstrand DNA,
cross-linking
Alkylation,
intrastrand and
interstrand DNA
cross-linking
Inhibits DNA
polymerase,
incorporated into
DNA
Inhibits thymidine
synthesis,
incorporated into
DNA/RNA
BT, GCT,
NBL, STS
BT, GCT,
NBL, OS
Liver
H, R (minor)
Broad, BMT
Liver
H, R (minor)
Broad
Liver
Spontaneous
R
R
Spontaneous
hydrolysis
NBL, STS
BT
BT
Spontaneous
hydrolysis
NBL, RMS,
BMT
A, H, M, N/V, P, mucositis
BMT
Target cell
Biotransformation
Limited
Target cell
Biotransformation,
renal (minor)
GI
carcinomas,
liver tumors
Continued
Agent
Site of
Activation
CHAPTER 28
Class of Drug
Brand
Name
407
408
PART III
MAJOR TUMORS OF CHILDHOOD
TABLE 28-5
Common Chemotherapeutic Agentscontd
Class of Drug
Antibiotics
Plant Alkaloids
Agent
Synonyms
Brand
Name
Mercaptopurine
6-MP
Purinethol
Methotrexate
MTX
Trexall
Dactinomycin
Actinomycin-D
Cosmegen
Bleomycin
BLEO
Blenoxane
Anthracyclines
Daunomycin
Daunorubicin
Cerubidine
Adriamycin
Doxorubicin
Adriamycin
Epipodophyllotoxins
Etoposide
VP-16
VePesid
Teniposide
VM-26
Vumon
Vinca alkaloids
Vincristine
VCR
Oncovin
Mechanism of Action
Site of
Activation
Inhibits thymidine
synthesis,
incorporated into
DNA/RNA
Blocks folate
metabolism, inhibits
purine synthesis
DNA intercalation,
strand breaks
DNA intercalation,
strand breaks
H, M, mucositis
Target cell
Susceptible
Solid
Tumors
Method of
Elimination
Biotransformation,
renal (minor)
Limited
R, H (minor)
OS
RMS, Wilms
P, skin, mucositis
H, R
GCT
Limited
Broad
Topoisomerase II
inhibitor, DNA strand
breaks
Topoisomerase II
inhibitor, DNA strand
breaks
Broad
Degraded
Broad
Inhibits tubulin
polymerization,
blocks mitosis
H
H
Broad
DNA intercalation,
strand breaks, free
radical formation
DNA intercalation,
strand breaks, free
radical formation
Vinblastine
Velban
Inhibits tubulin
polymerization,
blocks mitosis
A, M, mucositis, vesicant
Taxanes
Paclitaxel
Taxol
Docetaxel
Taxotere
Interferes with
microtubule
formation
Interferes with
microtubule
formation
Topoisomerase I
inhibitor, DNA strand
breaks
Topoisomerase I
inhibitor, DNA strand
breaks
L-Asparagine
depletion, inhibits
protein synthesis
Nuclear receptor
mediated apoptosis
TPT
Hycamtin
Irinotecan
CPT-11
Camptosar
L-Asparaginase
Erwinia
Elspar
Corticosteroids
GCT
NBL, RMS
H, R (minor)
NBL, RMS
degraded
Limited
H, R (minor)
BT
A, H, M, N/V, diarrhea
H, GI
Toxic effects: A, alopecia; CNS, central nervous system toxicity; H, hepatotoxicity; M, myelosuppression; N/V, nausea and vomiting; P, pulmonary toxicity;
R, renal toxicity; SIADH, syndrome of inappropriate antidiuretic hormone; XRT, x-ray therapy.
Solid tumors: BMT, conditioning for bone marrow transplantation; BT, brain tumor; EWS, Ewing sarcoma; GCT, germ cell tumors; NBL, neuroblastoma; OS, osteosarcoma; RMS, rhabdomyosarcoma; STS, soft tissue
sarcoma; W, Wilms tumor.
Camptothecins
Topotecan
CHAPTER 28
Miscellaneous
VLB
409
410
PART III
pediatric malignancies. Finally, cells with alterations in programmed cell death as a result of the persistence or reactivation of telomerase activity, which somatic cells normally lose
after birth, can be targeted by various telomerase inhibitors.
Several methods of targeting tumor cell differentiation are
being used for the treatment of neuroblastoma. Treatment
with 13-cis-retinoic acid, a vitamin A derivative that signals
through receptors that mediate transcription of different sets
of genes of cell differentiation, including HOX genes, is now
standard of care for maintenance therapy in patients with
high-risk neuroblastoma.82,83 Also, different neurotrophin receptor pathways appear to mediate the signal for both cellular
differentiation and malignant transformation of sympathetic
neuroblasts to neuroblastoma cells. Neurotrophins are
expressed in a wide variety of neuronal tissues and other
tissues that require innervation. They stimulate the survival,
maturation, and differentiation of neurons and exhibit a
developmentally regulated pattern of expression.84,85 Neurotrophins and their TRK tyrosine kinase receptors are particularly important in the development of the sympathetic nervous
system and have been implicated in the pathogenesis of neuroblastoma. Three receptorligand pairs have been identified:
TRKA, TRKB, and TRKC, which are the primary receptors for
nerve growth factor, brain-derived neurotrophic factor
(BDNF), and neurotrophin 3 (NT-3), respectively.84 TRKA
appears to mediate the differentiation of developing neurons
or neuroblastoma in the presence of nerve growth factor ligand and to mediate apoptosis in the absence of nerve growth
factor.85 Conversely, the TRKB-BDNF pathway appears to
promote neuroblastoma cell survival through autocrine or
paracrine signaling, especially in MYCN-amplified tumors.86
TRKC is expressed in approximately 25% of neuroblastomas
and is strongly associated with TRKA expression.87 Studies are
ongoing to test agonists of TRKA in an attempt to induce
cellular differentiation. Conversely, blocking the TRKB-BDNF
signaling pathway with TRK-specific tyrosine kinase inhibitors such as CEP-751 may induce apoptosis by blocking
crucial survival pathways.66,86 This targeted approach has
the attractive potential for increased specificity and lower
toxicity than conventional cytotoxic chemotherapy.
Inhibition of Angiogenesis
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 28
411
Immunotherapy
------------------------------------------------------------------------------------------------------------------------------------------------
CLINICAL CONSIDERATIONS
Radiation therapy for the management of pediatric cancer is
most frequently combined with surgery and chemotherapy
as part of a multidisciplinary treatment plan. The sensitive
nature of pediatric tumors requires the use of a combined
therapy approach to maximize tumor control while minimizing the long-term side effects of treatment. Radiation may be
delivered preoperatively, postoperatively (relative to a definitive surgical resection), or definitively without surgical
management. Systemic therapy may also be integrated into
this management approach.
Definitive Irradiation
Definitive radiation therapy is an alternative local approach to
surgical resection of primary solid tumors. It is often the only
local therapeutic approach for children and adolescents with
leukemia or lymphoma.96,97 Definitive radiation therapy for
rhabdomyosarcoma has been used as an alternative to surgical
resection, which has potentially greater morbidity; it has
achieved high rates of local tumor control while allowing preservation of function.38 The Ewing sarcoma family of tumors
may also be considered candidates for definitive radiation
therapy as an alternative to surgery. With careful patient selection, excellent local tumor control rates can be maintained
while reducing or avoiding the morbidity associated with
difficult surgical resections.98,99
Preoperative Irradiation
Targeting of a localized tumor is straightforward in the preoperative setting; the tumor has clearly defined margins undisturbed by a surgical procedure. The volume of normal,
healthy tissues receiving high doses of radiation may be
412
PART III
CHAPTER 28
413
heavy charged particle beams is the capacity to end the radiation beam at a specific and controllable depth. This may
allow the protection of healthy, normal tissues directly adjacent to tumor-bearing tissues.114 However, the use of proton
therapy has been limited because of the expense of constructing a suitable treatment facility. Several new facilities have
opened in the United States, and pediatric malignancies are
always noted as one of the tumors systems on which the
centers will focus their research efforts. With appropriately
designed studies and comparisons with current state-ofthe-art focal radiation therapy delivered with photon beams,
a determination of the potential benefits of this treatment
modality may be made.
Brachytherapy
Brachytherapy is a method of delivering radiation to a
tumor or tumor bed by placing radioactive sources within
or adjacent to the target volume, usually at the time of surgical
resection and under direct vision. Planning of the dose to be
delivered to the target volume is accomplished after resection
and may use CTor MRI studies; the appropriate strength of the
radioactive source is determined prospectively. Sources
commonly used in children include iridium 192 and iodine 125.
Brachytherapy may consist of either low dose-rate treatments
(approximately 40 to 80 cGy per hour) or high dose-rate treatments (approximately 60 to 100 cGy per minute). Low dose-rate
treatments are delivered during a period of days, often while the
patient remains hospitalized, whereas high dose-rate treatments
are divided into fractions and delivered on several days during 1
to 2 weeks. The primary advantage of brachytherapy is that a radiation source can be placed into or adjacent to the tumor, often
at the time of resection. Preoperative planning and cooperation
between the surgical and radiation oncology teams are necessary
to ensure the appropriate and accurate implementation of
brachytherapy. Nonrhabdomyosarcoma soft tissue sarcomas
and some rhabdomyosarcomas are the pediatric tumors most
commonly treated with brachytherapy.115,116 Most other pediatric solid tumors are not amenable to brachytherapy, however,
because of the tumors behavior (e.g., radioresistance) or its
anatomic location (e.g., retroperitoneal).
Intraoperative radiation therapy has been used intermittently after resection in the management of localized tumors.117 Although of limited availability in the United
States, intraoperative radiation therapy has the distinct advantage of allowing the operative tumor bed to be visible in the
operating theater while radiation is delivered, thereby enhancing the accuracy of delivery and providing the opportunity
to displace or temporarily move mobile crucial structures
(e.g., bowel, bladder) from the field of delivery. The primary
limitation of intraoperative radiation therapy is that it can
deliver only a single fraction of radiation, usually in the 10
to 20 Gy range. Radiation tolerances of normal tissues that
cannot be removed from the treatment field must be respected
and may limit the ability to deliver an effective treatment dose.
414
PART III
TABLE 28-6
Radiation-Related Adverse Events in Children and the Associated Radiation Doses
Organ/Site
Acute
Chronic
Dose Relation
Reference
Skin
Atrophy
Hyperpigmentation
Fibrosis
Ulceration
Necrosis
Myelitis
Decline in cognition
Eye
Conjunctivitis
Thyroid
Heart
Lung
Pneumonitis
Cataract
Retinopathy
Dry eye
Hypothyroidism
Pericarditis
Myocarditis
Valvular disease
Pulmonary fibrosis
121
Subcutaneous tissue
Mucosa
Central nervous
system
Erythema
Desquamation
Edema
Mucositis
Headache
Edema
Bowel
Nausea
Diarrhea
Kidney
Bladder
Muscle
Dysuria
Urgency
Frequency
Edema
Bone
Necrosis
Nephritis
Renal insufficiency
Hemorrhagic cystitis
Fibrosis
Hypoplasia
Hypoplasia
Fracture
Premature physis
closure
122, 123
124
125
126, 127
128
129
130132
CHAPTER 28
415
Clinical Trials
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416
PART III
Conclusion
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CHAPTER 29
Biopsy Techniques
for Children
with Cancer
James D. Geiger and Douglas C. Barnhart
Handling of Specimens
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418
PART III
aberrations, which has both diagnostic and prognostic significance.69 Techniques used to detect these changes include reverse transcriptasepolymerase chain reaction (rt-PCR),10
fluorescence in situ hybridization (FISH), microarray analysis,
and flow cytometry. Inappropriate specimen handling can
preclude these analyses. For example, phenotypic classification of lymphoma cannot be performed using flow cytometry
on formalin-fixed lymph nodes. Given the rapidly evolving
field of molecular diagnosis, it is essential that the surgeon
consult with the pathologist regarding specimen handling
prior to performing the biopsy. Additionally, if the patient is
eligible for a research protocol, care must be taken to assure
the specimen is handled in accordance with the protocol requirements. This requires a coordinated effort by the surgeon,
medical oncologist, and pathologist.
Fine-needle aspiration was first introduced as a technique to obtain specimens for cytopathology by Grieg and Gray in 1904.
Jereb and colleagues reported success with the use of needle biopsy for the diagnosis of pediatric solid tumors in 1978.11 Subsequently, extensive experience from multiple institutions has
confirmed the accuracy and safety of both needle aspiration
and core needle biopsy techniques. The appeal of these techniques is that they both may provide diagnosis without requiring a significant delay in therapy and can be performed as
outpatient procedures. Needle biopsies are often performed under either general anesthesia or sedation. In selected older children, some sites may be biopsied under local anesthesia alone.12
Percutaneous needle biopsies may be performed by palpation in the extremities and other superficial locations such as
lymph nodes. However, deeper biopsies require guidance with
either ultrasonography or CTscan. Ultrasonography that can be
supplemented with Doppler mode allows clear identification of
large vessels and other structures and provides real-time visualization as the needle is advanced.13 Some core needle devices
also deposit a small air bubble that allows verification of the site
that was biopsied. CT scan, on the other hand, allows clear visualization of aerated lung and is not obscured by bowel gas.14
It also allows measurement and planning of depth of biopsy.1
Decision making regarding image guidance is made in conjunction with the radiologist, and ideally, biopsies should be performed with both modalities available if required.
is dependent upon the availability of an experienced cytopathologist. In adult patients with the higher prevalence of carcinomas, FNA is a popular method for confirming the
presence of malignancy in suspicious lesions. Often, in these
adult cases, a diagnosis of carcinoma and primary site are sufficient to make initial treatment decisions. However, given the
fact that multimodality therapy is histiotype-specific in pediatric patients, FNAB has been used less frequently in children.
Recent application of molecular techniques and electron microscopy to supplement light microscopy has increased the
histiotype specificity of FNAB and may lead to increased application in pediatric solid malignancies.18,19 FNAB has been
used in several pediatric settings with sufficient data reported
for consideration.
The use of FNAB in the evaluation of thyroid nodules in
adults is well-established. Although thyroid nodules are less
common in children, the techniques and interpretation of
FNAB are similar to those used in adults.20 Given the good degree of specificity, FNAB may be considered a standard component of evaluation of thyroid nodules in children.21
Another relatively straight forward application and interpretation of fine-needle aspirate biopsy is in the verification
of metastatic or recurrent disease in the setting of a previously
characterized primary tumor.22 In this context, the verification
of the presence of malignant cells may be sufficient to guide
further clinical decisions. This least invasive biopsy method
is particularly appealing in these patients who may already
be immunologically or physiologically compromised.
There is a limited body of literature on the use of FNAB in
the diagnosis of sarcomas. Osteosarcoma has been diagnosed
by the use of fine-needle aspirates, with definitive diagnosis
being obtained in 65% to 92% of patients. The technique is
as accurate in children as it is in adults.23 The use of FNAB
in soft tissue tumors has been facilitated by the recognition
of cytogenetic abnormalities and fusion proteins that are specific to these tumor types.17,19,24 However, caution should be
exercised in the use of FNAB in this setting, because the reported
series come from a limited number of institutions with extensive
experience in cytologic interpretation. The use of FNAB in diagnosing sarcoma has not gained widespread use.
Fine-needle aspiration has not been widely used for the diagnosis of small, round, blue cell tumors of childhood. However, with the increasing availability of ancillary studies, such
as electron microscopy, immunocytochemistry, DNA ploidy,
cytogenetics, and fluorescent in situ hybridization, its use
may become more common.25 Use of FNAB for the evaluation
of head and neck masses in children has been reported to have
good sensitivity and specificity.26,27 The results of these series,
however, should be interpreted with caution, because the majority of aspirates diagnosed as reactive lymphadenopathy and
the number of new malignant diagnoses was small. In addition, false-negative FNAB diagnosis occurred frequently in patients ultimately diagnosed with lymphoma in other series
(not specifically isolated to the head and neck).15
The advantage of core needle biopsy versus fine-needle aspiration is that it provides a sample sufficient in size to allow histologic examination rather than only cytologic examination.
In addition, it can provide sufficient tissue for molecular
CHAPTER 29
FIGURE 29-1 Two commonly used core needle biopsy devices. The upper device is a 14-gauge Tru-Cut needle (Allegiance, Cardinal Health). It is
advanced into the region of interest, and then the inner needle is advanced. The outer sheath is manually advanced over the inner needle to
obtain a core. The lower device is a 16-gauge Monopty biopsy device
(Bard). It is spring-loaded and is activated after the tip is advanced into
the region of interest. The spring-loaded mechanism automatically
sequentially advances the obturator and the cannula.
419
has been demonstrated in pediatric kidney biopsies. Regardless of the system used, visual inspection of the core biopsy is
necessary to verify adequate sampling. The number of passes
required with a core needle is dependent upon the purpose of
the biopsy and the consistency of the tissue being biopsied.
For primary tumor diagnosis, multiple cores are typically required to obtain sufficient tissue for biological studies. Alternatively, in pulmonary lesions evaluated for metastatic disease,
a single pass was usually sufficient in most series.
Several large series have demonstrated the utility of core
needle biopsies in children. The larger, more recent series
are summarized on Table 29-1. The three most common
scenarios for which percutaneous biopsies in children with
malignancies are used are diagnosis of primary tumors,
evaluation for possible recurrent disease, and evaluation of
pulmonary lesions.
Success with core needle biopsy has been demonstrated in
a wide variety of anatomic locations. These include neck, mediastinum, lung, peritoneal cavity, liver, retroperitoneum,
kidney, adrenal, pelvis, and extremities.1,2,12,13,28 Core needle
biopsies have been demonstrated to be effective in obtaining
adequate tissue for both primary diagnoses and confirmation
of recurrence in these series. In the largest series of pediatric
oncologic core needle biopsies, multiple passes were typically
performed (median 6 and maximum 17). With this repetitive sampling, adequate diagnostic tissue was obtained for
histologic and biological studies, obviating the need for operative biopsy in a wide variety of pediatric cancers. No patients
in these series suffered procedure-related deaths or required
operative therapy for procedural complications.28
The other common use of percutaneous core biopsies in
pediatric oncology patients is in the evaluation of pulmonary
nodules. Pulmonary nodules can be biopsied under either CT
scan29 or ultrasound guidance, often determined by the size
and location of the lesions.30 These procedures may be performed under either sedation or general anesthesia with
TABLE 29-1
Series of Percutaneous Biopsies in Children
Number of
Children
Number of
Biopsies (Total/
Malignancy)
Skoldenberg
(2002)13
110
147/84
HayesJordan
(2003)52
32
35/23
Cahill
(2004)29
64
75/24
Fontalvo
(2005)30
33
38/32
Author (Year)
Garrett
(2005)28
202/202
Method
Diagnostic
Yield
89%
85%
93% overall
98% initial
diagnosis 88%
suspected
recurrence
80%
84%
Comments
420
PART III
LAPAROSCOPY
Laparoscopy affords several advantages for the evaluation of
the abdominal cavity in children with childhood cancer. First,
it provides the opportunity to completely examine the peritoneal cavity. A systematic examination of all peritoneal surfaces
can be performed. The entire length of the bowel may be examined along with mesenteric lymph nodes. Multiple biopsies
can easily be obtained. The second chief advantage of laparoscopy is decreased physiologic stress in children who may
already be critically ill. Finally, as in all minimally invasive
procedures, postoperative pain is reduced and recovery is
hastened.35 The main disadvantages of laparoscopy are the
limited ability to assess retroperitoneal structures and the loss
of tactile evaluation of deep lesions.
Diagnostic laparoscopy with biopsy has been used in several settings in the management of children with solid malignancies.3,35 Biopsies obtained using laparoscopic techniques
have a high rate of success in yielding diagnostic tissue.3,36
Laparoscopy allows the surgeon to obtain larger tissue samples than may be obtained with core needle biopsy. This is particularly relevant if larger samples are required for biological
studies. In the initial diagnosis, laparoscopy aids in the identification of site of origin of large abdominal masses. Laparoscopy has been shown to be superior to computerized
tomography in assessing intraperitoneal neoplasms and for
the evaluation of ascites. For example, laparoscopy allows direct assessment of whether a pelvic mass arises from the ovary
or bladder neck, which may be difficult to distinguish by
Thoracoscopy
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CHAPTER 29
421
FIGURE 29-2 Computed tomography (CT) scans obtained at the time of diagnosis of a new abdominal mass in a 5-year-old boy. A, Abdominal and pelvic
CT scan shows a large left-sided renal mass. B, Chest CT scan demonstrates a single 8-mm pulmonary nodule in the left upper lobe. No other pulmonary
lesions were identified. At the time of nephrectomy, a thoracoscopic excisional biopsy of the lung lesion was performed. Final pathology of the kidney
demonstrated a stage II-favorable-histology Wilms tumor, and the lung pathology showed a hyalinized granuloma.
422
PART III
Conclusion
------------------------------------------------------------------------------------------------------------------------------------------------
Prior to performing a biopsy of a potential malignancy, the surgeon should consider the likely possible diagnoses. The biopsy should then be planned so that adequate tissue is
obtained and preserved to determine not only diagnosis but
also risk stratification. Percutaneous, minimal access surgical,
and open surgical techniques each have an appropriate place
in the evaluation of potential pediatric malignancies. The use
of these techniques in a systematic, stepwise fashion is appropriate in some patients. The selection of the appropriate biopsy technique should be driven by both the specific
question to be answered by the biopsy and individual institutional experience and resources. Planning an operative biopsy
must account for the anticipated operative approach for definitive resection.
The complete reference list is available online at www.
expertconsult.com.
Wilms Tumor
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 30
Wilms Tumor
Peter F. Ehrlich and Robert C. Shamberger
History
------------------------------------------------------------------------------------------------------------------------------------------------
Renal tumors account for 6.3% of cancer diagnoses for children younger than 15 years of age, with a reported incidence
of 7.9 per million. Including adolescents younger than
20 years of age, this drops slightly to 4.4% of cancer diagnoses, with an incidence of 6.2 per million.1 Renal tumors
include Wilms tumor (WT) (also referred to as nephroblastoma or renal embryoma), renal cell carcinoma (RCC), clear
cell sarcoma of the kidney (CCSK), rhabdoid tumor of the
kidney (RTK), congenital mesoblastic nephroma, cystic renal
tumor, and angiomyolipoma.2,3 WT is by far the most common, accounting for approximately 91% of all renal tumors in
childhood. CCSK and RTK were originally considered subtypes of WT, but are now recognized as separate tumors.
RCC comprises 5.9% of renal malignancies in children and
adolescents.1,4
The treatment strategy for children with renal tumors
evolved in conjunction with the definition of these pathologic
subtypes. Treatment is based on traditional risk factors, stage
and histology, and, more recently, on genetic markers. The
goal of risk-based management is to maintain excellent outcomes but at the same time spare children with low-risk tumors intensive chemotherapy and radiation, with their
long-term side-effects, and to intensify therapy for children
with high-risk tumors in an effort to increase their survival.
Despite these advances, children with rhabdoid, renal cell carcinoma, and anaplastic tumors still do poorly. This chapter
WT is named after Carl Max Wilhelm Wilms, a German pathologist and surgeon. He was one of the first to propose that
tumor cells originate during the development of the embryo.
He published his findings in 1897 and 1899 in an influential
monograph titled Die Mischgeschwulste der Niere, which
described seven children with nephroblastoma as part of a
monograph on mixed tumors.9,10 Although reports of successful excision of renal tumors in children appeared in the
end of the 19th century, his name has been indelibly applied
to them. Dr. Thomas Jessop (1837 to 1903), probably performed the first successful nephrectomy at the General Infirmary in Leeds, England, on June 7, 1877, on a 2-year-old child
with hematuria and a tumor of the kidney.11,12
At the beginning of the 20th century, survival for a child
with WT was 5%. Surgery was the first effective treatment
for nephroblastoma and continues to be a critical component
of successful multimodality therapy. Although surgery at that
time was the only option for cure, it carried a significant operative mortality. In 1916, radiation therapy was added by
Friedlander.13 In the late 1930s, Ladd described removing
renal tumors in selected children. His technique included a
large transverse transabdominal approach with early ligation
of the renal vessels and removal of the surrounding Gerota
fat and fascia. This modification improved the outcome in
children with nonmetastatic nephroblastoma to a 32.2% survival at 3 years, with an operative mortality reduced from 23%
to 7%. The basic tenets of this operative procedure described
by Ladd are used today, with the exception of early ligation of
the renal vessels.1215
423
424
PART III
Percent
5-YEAR WT SURVIVAL
100
90
80
70
60
50
40
30
20
10
0
87
92
92
92
73
60
47
WT
20
5
1899
1938
1954
1960
1975
Year
1981
1987
1995
2003
FIGURE 30-1 This graph shows the improved survival of children with
Wilms tumor (WT) over time.
Epidemiology
------------------------------------------------------------------------------------------------------------------------------------------------
In the United States, there are 500 to 550 cases of WT per year.
It is the second most common malignant abdominal tumor in
childhood after neuroblastoma. The risk of developing WT in
the general population is 1:10,000.16 The incidence is slightly
elevated for American and African blacks compared with
whites and is significantly lower in Asians. The mean age at
diagnosis is 36 months, with most children presenting between the ages of 12 and 48 months. Tumors tend to occur
about 6 months later in girls than in boys. WT is rare at greater
than 10 years and at less than 6 months of age. Tumors can be
unilateral or bilateral (Figs. 30-2 and 30-3). Bilateral Wilms
tumors (BWT) occur in 4% to 13% of patients.5,1719 Children
with congenital syndromes associated with WT, such as Beckwith-Wiedemann, have a higher risk of developing BWT.
Congenital anomalies, either isolated or as part of a congenital syndrome, occur in about 10% of children with
WT.20 WAGR syndrome (WT, aniridia, genitourinary malformation, mental retardation) is a rare genetic syndrome associated with a chromosomal defect in 11p13. Children with
WAGR syndrome are at a 30% higher risk of developing
WT than a normal child. Because of the presence of aniridia,
most children with WAGR syndrome are diagnosed at birth.
Children with WAGR account for about 0.75% of all children
with WT.21
Beckwith-Wiedemann syndrome (BWS) is a congenital disorder of growth regulation, affecting 1 in 14,000 children.
Children with BWS have visceromegaly, macroglossia,
omphalocele, and hyperinsulinemic hypoglycemia at birth.
They also have an increased risk of tumor development.
The risk is greatest in the first decade of life and thereafter approaches that of the general population. Three large studies
of children with BWS reported tumor frequencies of 7.1%
(13/183), 7.5% (29/388), and 14% (22/159).2225 The most
frequently observed tumors in BWS are WT and hepatoblastoma, which comprise 43% and 12% of reported cancers, respectively.22,26 Denys-Drash syndrome (DDS) (nephropathy,
renal failure, male pseudohermaphroditism, and WT) is also
associated with an increased risk of WT. Some investigators
have recommended prophylactic nephrectomy in children
with this syndrome once they develop renal failure.27,28 Other
TABLE 30-1
Childrens Oncology Group (COG) and Societe Internationale dOncologie Pediatrique (SIOP) Staging Systems
COG Wilms Tumor Staging
Stage
I
II
III
IV
V
Criteria
The tumor is limited to the kidney and has been completely resected.
The tumor was not ruptured or biopsied prior to removal.
There is no penetration of the renal capsule or involvement of renal sinus vessels.
The tumor extends beyond the capsule of the kidney but was completely resected with no evidence of tumor at or beyond the margins
of resection.
There is penetration of the renal capsule or invasion of the renal sinus vessels.
Gross or microscopic residual tumor remains postoperatively, including inoperable tumor, positive surgical margins, tumor spillage surfaces,
regional lymph node metastases, positive peritoneal cytology, or transected tumor thrombus.
The tumor was ruptured or biopsied prior to removal.
Hematogenous metastases or lymph node metastases outside the abdomen (e.g., lung, liver, bone, brain).
Bilateral renal involvement is present at diagnosis, and each side may be considered to have a stage.
SIOP Staging
Stage
I
II
III
IV
V
Criteria
The tumor is limited to the kidney or surrounded with a fibrous pseudocapsule, if outside the normal contours of the kidney. The renal capsule
or pseudocapsule may be infiltrated with the tumor, but it does not reach the outer surface, and it is completely resected. The tumor may be
protruding (bulging) into the pelvic system and dipping into the ureter, but it is not infiltrating the walls. The vessels of the renal sinus are not
involved. Intrarenal vessels may be involved.
The tumor extends beyond the kidney or penetrates through the renal capsule and/or fibrous pseudocapsule into the perirenal fat, but it
is completely resected. The tumor infiltrates the renal sinus and/or invades blood and lymphatic vessels outside the renal parenchyma, but
it is completely resected. The tumor infiltrates adjacent organs or vena cava, but it is completely resected. The tumor has been surgically
biopsied (wedge biopsy) prior to preoperative chemotherapy or surgery.
There is incomplete excision of the tumor, which extends beyond resection margins (gross or microscopic tumor remains postoperatively).
Any positive lymph nodes are involved. Tumor ruptures before or during surgery (irrespective of other criteria for staging). The tumor has
penetrated the peritoneal surface. Tumor implants are found on the peritoneal surface. The tumor thrombi present at resection, margins of
vessels or ureter are transected or removed piecemeal by surgeon.
Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases are outside the abdominopelvic region.
Bilateral renal tumors present at diagnosis. Each side has to be substaged according to above classifications.
CHAPTER 30
WILMS TUMOR
425
are several candidate genes that are been investigated and evaluated or are being evaluated in the clinical setting. These are
described later.
LOSS OF HETEROZYGOSITY
AND DNA PLOIDY
A number of important advances in WT development have occurred since the early 1990s. A detailed description is beyond
the scope of this chapter. Table 30-2 summarizes some of the
key genes and more detailed references are cited.2956 There
FIGURE 30-3 Two computed tomography (CT) scans of bilateral Wilms tumor at presentation and after 6 weeks of chemotherapy.
426
PART III
TABLE 30-2
Summary of Current Genes Being Investigated in Wilms Tumor
Gene(s)
Location
Function
Clinical Relevance
WT1
11.13
WT2
11p15.5
Cadherin-associated
protein b1 gene4
3p21
WTX
Xq11.1
Unknown
Unknown
BWS, Beckwith-Wiedemann syndrome; IGF, insulin growth factor; WAGR, Wilms tumor, aniridia, genitourinary malformation, mental retardation.
1.0
1.0
0.9
0.8
No LOH
LOH 1p only
LOH 16q only
LOH both loci
0.7
0.6
0.9
0.8
No LOH
LOH 1p only
LOH 16q only
LOH both loci
0.7
0.6
0
2
3
Time since diagnosis (years)
Clinical Presentation
TP53 GENE
The TP53 gene is located on chromosome 17. The Tp53 protein is a negative regulator of cell proliferation and a positive
regulator of apoptosis in response to DNA damaging agents.
TP53 is the most common mutated gene associated with
human cancer. Li-Fraumeni syndrome is a multicancer predisposition syndrome that has constitutional TP53 mutations.61
However, WT rarely develops in Li-Fraumeni syndrome,
and the majority of WT develop in the presence of wild-type
TP53.62 TP53 mutations in WT are almost exclusively found in
tumors with anaplastic histology. Seventy-five percent of
------------------------------------------------------------------------------------------------------------------------------------------------
Most children with WT present with an asymptomatic abdominal mass, often discovered by either a parent or pediatrician.
Nonpalpable tumors are typically discovered by ultrasonography during evaluation for abdominal pain. Gross hematuria
has been reported in 18.2% of patients and microscopic
hematuria in 24.4%. Ten percent of children with WT have
coagulopathy, and 20% to 25% present with hypertension
because of activation of the renin-angiotensin system.63 Fever,
anorexia, and weight loss occur in 10%. Extension of tumor
thrombus into the renal vein can obstruct the spermatic vein
and result in a left varicocele and, in rare cases, tumor
CHAPTER 30
Diagnosis
------------------------------------------------------------------------------------------------------------------------------------------------
Screening
------------------------------------------------------------------------------------------------------------------------------------------------
WILMS TUMOR
427
Pathology
------------------------------------------------------------------------------------------------------------------------------------------------
Tumor histology is a major determinant of therapeutic stratification for children with WT. The diagnostic classification of
pediatric renal tumors has benefited from central review of tumors from patients treated in the cooperative group trials.77
This success has enabled the introduction of disease-specific
and risk-based therapy. For example, clear cell sarcoma of
the kidney (CCSK) and malignant rhabdoid tumor (MRT)
were initially considered to be variants of WT and were
428
PART III
Risk
Histology
Low
II
Intermediate
III
High
Mesoblastic nephroma
Cystic partially differentiated
nephroblastoma
Nephroblastoma epithelial type
Nephroblastoma stromal type
Nephroblastoma mixed type
Nephroblastoma regressive type
Nephroblastoma focal anaplasia type
Nephroblastoma blastemal type
Nephroblastoma diffuse anaplasia type
Clear cell sarcoma of the kidney
Rhabdoid tumor of the kidney
CHAPTER 30
WILMS TUMOR
429
Staging
------------------------------------------------------------------------------------------------------------------------------------------------
Hyperplastic
Wilms
tumor
Incipient
or dormant
Regressing
Obsolete
FIGURE 30-6 Computed tomography (CT) scans showing diffuse hyperplastic perilobar nephrogenic rests.
430
PART III
only, whereas disease stage considers both the local and distant hematogenous metastatic disease. Both factors determine
therapy; the use of local radiation therapy to the tumor bed is
based on the local stage, and the use of additional chemotherapy is based on both stage III local disease or distant metastasis.95 The current COG and SIOP staging systems are shown in
Table 30-1.
Treatment
------------------------------------------------------------------------------------------------------------------------------------------------
PROGNOSTIC FACTORS
The current prognostic factors used in COG trials are histology, stage, age, tumor weight, response to therapy, and loss of
heterozygosity at 1p and 16q. The two most important continue to be the histology and the stage of the tumor.7,8,96
Histology: The details and prognostic significance of tumor
pathology have been previously discussed in the Pathology section.
Stage: The tumor stage is determined by the results of the
imaging studies and both the surgical and pathologic
findings at nephrectomy (see Table 30-1).
Rapid response: This is a prognostic category being evaluated in patients who have stage IV disease that is based
on lung metastasis alone. The goal in these patients is to
avoid lung radiation. Response to therapy is also being
assessed in bilateral disease.
Loss of heterozygosity: LOH (described previously) at both
1p and 16q are now used as determinants of therapy
on the current COG renal tumor studies.96
OPERATIVE THERAPY
Surgical therapy is a primary component in the multidisciplinary treatment of WTor other neoplastic renal lesions. Irrespective of whether surgery is performed as a primary therapy or in
a delayed fashion after chemotherapy, there are a number of
fundamental tasks that are required of the surgeon. These are
(1) safe resection of the tumor, (2) accurate staging of the tumor,
(3) avoidance of complications that will upstage the tumor
(rupture or unnecessary biopsy), and (4) accurate documentation of operative findings and details of the procedure in the
operative note. Intraoperative events that negatively affect
patient survival include tumor spill, failure to biopsy lymph
nodes, incomplete tumor removal, failure to assess for extrarenal tumor extension and surgical complications.9799
Technical Concerns: Unilateral Tumors
Ladd and Gross established the basic principles for resection
of a presumed malignant tumor of the kidney, including wide
abdominal exposure, resection of the surrounding Gerota fat
CHAPTER 30
WILMS TUMOR
431
the only means of removing the kidney tumor requires removal of the other structures (e.g., spleen, pancreas, and colon
but excluding the adrenal gland); (3) there are bilateral
tumors; (4) the tumor is in a solitary kidney; or (5) there is
pulmonary compromise resulting from extensive pulmonary
metastases. Studies conducted by the cooperative groups have
shown that pretreatment with chemotherapy almost always
reduces the bulk of the tumor.113116 This makes tumor
removal easier and may reduce the incidence of surgical complications.117 Preoperative chemotherapy does not result in
improved survival rates, and it may result in the loss of staging
information and changes the histology of the tumor as noted
previously.118,119
SPECIAL CONSIDERATIONS
Management of Tumor Extension in the Renal
Vein, Inferior Vena Cava, and Atrium
WT patients may present with tumor extension through the
renal vein to the IVC and even up to the right atrium. This
is found in 4% to 11% of children. Surgical treatment is dependent on the extent of vascular invasion. Extension is usually asymptomatic, and many are detected preoperatively by
US, CT, and/or MRI scans. However, those that extend just
into the renal vein may only be detected at operation because
of compression and distortion of the veins by the tumor, reinforcing the need to palpate the renal vein and IVC at the start
of nephrectomy before any mobilization of the kidney that
might dislodge the thrombus.106,120,121 As noted previously,
a primary resection when tumor thrombus extends into the
inferior vena cava at the level of the liver or higher is discouraged. COG protocols recommend that these patients be managed initially with preoperative chemotherapy. This approach
will often achieve significant shrinkage and regression of the
intravascular thrombus, facilitating subsequent surgical removal.106,122 The severity and number of operative complications are reduced with preoperative chemotherapy for those
with vascular extension above the hepatic veins. Alternatively,
if the tumor extends only into the renal vein or renal vein and
IVC below the level of the liver, the tumor and thrombus can,
in most cases, be removed en bloc with the kidney.
Control of renal veins and cava above and below the tumor
with vessel loops is necessary, using standard vascular surgery
techniques. The tumor should not be transected, if possible,
because this will result in spill and upstaging of the patient.
In some cases, the tumor may be adherent to the vessel wall.
A similar technique used for removing plaque for a carotid
endarterectomy is helpful to lift the tumor off the vein wall.
It must be stated in the operative report if the intravascular tumor extension was removed en bloc or if tumor was transected, as well as if the tumor thrombus is removed
completely and if there is evidence of either adherence to or
invasion of the vein wall. If, after preoperative chemotherapy,
the tumor still extends above the hepatic veins, cardiopulmonary bypass is generally needed to remove the vascular extension of the tumor.
Management of Tumor Extension in the Ureter
Extension of WT into the ureter is a rare event.107 In NWTS-5,
the incidence of ureteral extension was 2%. Preoperative imaging detected ureteral extension in only 30% of these
432
PART III
patients; the rest were discovered at operation. Clinical presentations included gross hematuria, passage of tissue per urethra, hydronephrosis, and a urethral mass. The diagnosis
should be suspected in these patients, and cystoscopy with
retrograde ureterogram may aid in preoperative diagnosis. If
extension of tumor into the ureter is detected or suspected,
the ureter should be resected with clear margins.
Horseshoe Kidney, Single Kidney,
and Nonfunctioning Kidney
A WT in a horseshoe kidney presents unique challenges.
Children with a tumor in a horseshoe kidney are treated as
unilateral tumors, NOT as bilateral tumors. Children with
horseshoe kidneys and WT must be carefully imaged prior to
any surgery.123 The blood supply to horseshoe kidneys is
quite variable and must be carefully imaged prior to surgery.123
At the time of operation, the blood supply to the kidney as well
as the location of the ureters must be identified and isolated. Exposure and mobilization of the kidney on the side of the tumor
is carried out as in unilateral resection. The side of the kidney
containing the tumor, the isthmus, and the ipsilateral ureter
are resected. As with other unilateral procedures, the lymph
nodes are sampled for staging purposes. Children with a single
kidney, or a situation where a tumor occurs in one kidney but
the second kidney is nonfunctioning, should be managed using
a renal-sparing approach, with preoperative chemotherapy to
facilitate surgery and preserve more renal tissue.
Patients with Wilms Tumor Treated Only
with Surgery
NWTS-5 evaluated a subset of very-low-risk patients with
favorable-histology tumors who might be treated without
chemotherapy. The criteria for this arm of the study was stage
I FH in patients who had lymph nodes biopsied, had a specimen weight of less than 550 g, and who were less than 2 years
of age. Seventy-five patients were enrolled before closure of
the study, and 8 developed recurrent disease (lung involvement in 5 and the operative bed in 3). Three other patients
developed metachronous contralateral WT. Stringent stopping rules for the study were designed to ensure closure of this
arm of the study if the 2-year EFS was 90% or less based on the
expectation that approximately 50% of the surgery-only children would be salvaged after recurrence, thus attaining the
95% predicted survival of these children treated with vincristine and dactinomycin (EE-4A). This limit was exceeded on
June 14th, 1998, and this arm of the study was closed when
the 2-year disease-free survival estimate reached 86.5%.124
Subsequent patients were treated with EE-4A. A recent
long-term follow-up study of the surgery-only cohort and
the EE-4A group, with a median follow-up of 8.2 years,
reported the estimated 5-year EFS for surgery only was 84%
(95% confidence interval [CI]: 73% to 91%); for the EE-4A
patients it was 97% (95% CI: 92% to 99%, P 0.002).
One death was observed in each treatment group. The estimated 5-year overall survival (OS) was 98% (95% CI: 87%
to 99%) for surgery only and 99% (95% CI: 94% to 99%)
for EE-4A (P 0.70).125 The surgery-only EFS was less than
for EE-4A, consistent with the earlier report. The salvage rate
for the surgery-only cohort, however, exceeded that seen with
children who had received two-drug chemotherapy, which
had been predicted to be 50%. Thus 85% of the infants
avoided any chemotherapy, while those who did receive it
CHAPTER 30
WILMS TUMOR
433
chemotherapy and radiation, and the potential for hyperfiltration injury to the remaining renal parenchyma. Ritchey
defined the incidence and etiology of renal failure in patients
treated on NWTS-1 to NWTS-4. BWT was the greatest risk
factor for renal failure (16.4% for NWTS-1 and NWTS-2,
9.9% for NWTS-3, and 3.8% for NWTS-4). Other risk factors
identified were Denys-Drash syndrome, metachronous tumor, progressive disease in patients with bilateral tumors requiring bilateral nephrectomies and radiation nephritis.144
Breslow reported the 20-year end-stage renal disease (ESRD)
outcomes in children treated for WT (see Figs. 30-7 and
30-8).142 The major risk factors he identified for renal failure
were BWT and congenital syndromesDenys-Drash, WAGR,
and genital urinary anomalies (hypospadias or cryptorchidism). Thus preservation of renal tissue without sacrificing
long-term survival is of particular importance for those
with BWT.
Despite 40 years of clinical trials for WT, it was not until
2009 that a formal BWT trial was opened by COG. Several
prior reports contributed to the development of this protocol.
Shamberger and colleagues examined 38 of 188 patients with
BWT with progressive or nonresponsive disease (PNRD).145
The mean duration of chemotherapy was 7 months; 36 patients were treated with two regimens of chemotherapy, and
21 patients received three. Patients with PNRD fell into two
categories: first, patients with anaplasia whose tumors were
not sensitive to the therapy administered (4 patients); second,
patients who had tumors with very mature rhabdomyomatous
or differentiated stromal elements (14 patients) and 1 with
complete necrosis. A second study from Anderson looked
at the histologic changes in BWT patients who did not respond to chemotherapy and the relationship between these
changes and prognosis.146 Their results mirrored those of
the NWTS study. Fifteen patients whose tumors did not respond were evaluated. One had complete necrosis, 4 had
rhabdomyomatous differentiation, and 10 had mature stromal
differentiation. Despite not radiographically responding
to chemotherapy, these patients had favorable outcomes.
Patients in these studies fell into two categories. First, there
were patients with anaplasia whose tumors were not sensitive
to the therapy administered. Anaplastic tumors respond poorly
to chemotherapy and, once the diagnosis of anaplasia is
made, a complete resection is needed.84,140,147,148 Second,
DDS (12/17)
60
WAGR (11/37)
40
20
GU (5/125)
Other (28/5, 347)
0
0
10
15
20
Time since diagnosis of
unilateral Wilms tumor (years)
25
100
Cumulative incidence of
ESRD (%)
Cumulative incidence of
ESRD (%)
80
WAGR (5/10)
80
GU (8/25)
60
DDS (3/6)
40
20
Other (44/409)
0
0
5
10
15
20
25
Time since diagnosis of bilateral Wilms tumor (years)
FIGURE 30-9 Kaplan-Meier plot of renal failure rates at 20 years of age in
children with bilateral Wilms tumor (BWT). DDS, Denys-Drash syndrome;
ESRD, end-stage renal disease; GU, genitourinary; WAGR (syndrome),
Wilms tumor, aniridia, genitourinary malformation, mental retardation.
434
PART III
there were patients who had tumors with very mature rhabdomyomatous or differentiated stromal elements and complete
necrosis, all of whom had an excellent outcome. Again these
patients are best served with resection.146 Therefore if the bilateral lesions do not respond radiographically to therapy, it is critical to establish whether this is due to anaplasia or mature
histology.
Hamilton and colleagues have demonstrated the difficulty
in identifying anaplasia in patients with BWT.148 Twentyseven patients with anaplasia were reviewed from NWTS-4.
Discordant pathology between the kidneys was seen in 20 patients, highlighting the importance of obtaining tissue from
both kidneys. Seven children who were eventually found to
have diffuse anaplasia had core needle biopsies, which failed
to establish the diagnosis in all of these cases. Anaplasia was
identified in only three of nine patients who had an open
wedge biopsy and in seven of nine patients by partial or complete nephrectomy. Thus percutaneous biopsies rarely
establish the diagnosis, and open biopsies were successful
in only a third of the cases.
An important question is to determine how long to treat a
child who has BWT with chemotherapy before intervening
surgically. In SIOP-9, patients with unilateral tumors were
randomized to receive either 4 or 8 weeks of dactinomycin
and vincristine preoperatively. There was an average 48% reduction in tumor volume after 4 weeks that increased to 62%
after 8 weeks of chemotherapy.116,149 A review by the German
Pediatric Hematology Group (GPOH) of their patients with
BWT reported that maximum tumor shrinkage occurred in
the first 12 weeks of chemotherapy.150
The two principal aims of the COG BWT study are to
improve 4-year event-free survival and to prevent complete
removal of at least one kidney in 50% of patients with BWT
by using preoperative chemotherapy. This is a response-based
protocol starting with chemotherapy, followed by evaluation
at 6 and 12 weeks with definitive surgical therapy in all patients by 12 weeks (see Fig. 30-3). This protocol does not
mandate an initial tissue diagnosis because bilateral renal tumors in children are invariably WT; biopsy does not change
the therapy in most cases; anaplasia is hard to diagnose,
and the biopsy will effectively increase the stage of the tumor
and its risk for local recurrence.148 In the current COG protocol, local spill of the tumor is designated as stage III. This classification was changed because of the finding of an increased
incidence of abdominal recurrences in NWTS-4 patients with
tumor spill.99 First, for patients with BWT, the initial regimen
will consist of regimen vincristine, actinomycin D, doxorubicin
(VAD) (vincristine [VCR], dactinomycin [DACT], doxorubicin
[DOX]), a more intensive combination of drugs based on regimens used with good results and minimal toxicities by both
SIOP and the UKCCSG WT groups, which enables patients
to receive two doses of DOX, in addition to six of VCR and
two of DACT, during the first 6 weeks of therapy.151 It differs
from the standard three-drug regimen, DD-4A, in which
the DOX and DACT are administered in separate cycles.152
The three-drug chemotherapy regimen of VAD was chosen to
give an enhanced therapy for possible stage III disease, because
patients rarely have a lymph node biopsy before initiation of
therapy. Second, it was elected to enhance the chemotherapy
rather than administer radiotherapy, which might increase
the occurrence of radiation nephritis in the remaining kidney.
Third, a more intensive therapy was selected for treatment
CHEMOTHERAPY
In 1963, Farber first reported that dactinomycin had activity
against WT.153 Today, dactinomycin continues to be part of
the backbone of therapy for children with WT. Other active
chemotherapeutic agents have been identified subsequently,
including vincristine, doxorubicin, and cyclophosphamide.
Clinical trials conducted by NWTSG and SIOP have evaluated, stage by stage, different chemotherapeutic protocols to
assess the efficacy of various combinations and duration of
therapy.105,154159 In NWTS-4, 4-year event-free survival
and overall survival averaged 90% for patients with favorable
histology.154,159 Therefore NWTS-5 focused on evaluating
biologic markers of prognosis, such as LOH, developing more
effective therapy for recurrent disease, and reducing therapy
in children with low-risk tumors.
Treatment on the current COG protocols for favorablehistology WT is determined by stage, histology, and LOH.
For children with favorable-histology stage I and II tumors
without LOH, 18 weeks of vincristine and dactinomycin (regimen EE-4A) is recommended. Results from NWTS-5 showed
these children had an overall survival of 98.4% and 98.7%,
respectively. For children with FH stage III and IV tumors
without LOH, 24 weeks of vincristine, dactinomycin, and
doxorubicin is recommended (regimen DD-4A). For those
patients who have positive LOH at both loci (1p and 17q),
treatment will be intensified. If they are stage I or II and
LOH positive, they will receive DD-4A, and if they are stage
III and IV LOH positive, they will receive vincristine, dactinomycin, and doxorubicin with alternating cycles of cyclophosphamide versus etoposide (regimen M). Dosing modifications
are made for children less than 12 months of age.
Anaplastic tumors have been less successfully treated.
NWTS-3 and NWTS-4 were the first studies to prospectively
evaluate the benefit of additional/different chemotherapy
therapy for these tumors. One randomized arm compared
15 months of vincristine, dactinomycin, and doxorubicin,
with or without cyclophosphamide. For patients with stage
II to IV diffuse anaplastic histology, the addition of cyclophosphamide resulted in a 4-year relapse-free survival estimate of
54.8% when treated with cyclophosphamide compared with
27.2% when treated without it (P 0.02).160 In NWTS-5,
patients with focal anaplasia or diffuse stage I were treated
with EE-4A. This was based on prior historical data, with a
goal of reducing therapy. Unfortunately, the 4-year event-free
and overall survival estimates for stage I (focal or diffuse)
anaplastic WT were lower than previous studies (EFS 69.5%
and OS 82.6%). Thus therapy with EE-4A is inadequate.
Patients with focal anaplasia stage II to IV were treated with
DD-4A. Children with stage II to IV diffuse anaplastic WTwere
treated with vincristine, doxorubicin, and cyclophosphamide
(VDC) alternating with cyclophosphamide and etoposide
(CyE) (regimen I). The 4-year event-free survival estimates
for stage II to IV diffuse anaplastic WT on NWTS-5 were
82.6%, 64.7%, and 33.3%, respectively, with similar overall
survival.84 The current protocols and chemotherapy agents
for unilateral tumors are shown in Table 30-4.
CHAPTER 30
TABLE 30-4
Current Childrens Oncology Group Chemotherapy Regimens
for Unilateral Wilms Tumor
Regimen
Agents
EE-4A
DD-4A
Regimen I
Regimen M
Revised UH-1
Revised UH-2
Vincristine/irinotecan
window therapy
Recurrent Tumor
Treatment of recurrent disease in children with WT is challenging. Recurrence occurs in 15% of patients with favorable
histology tumors and in 50% with anaplastic histology. Recurrence is most frequent within 2 years of the initial diagnosis and
most common in the lungs, tumor bed, and liver.161 Less common sites are bone, brain, and distant lymph nodes.
Recurrent disease is treated by chemotherapy, surgery, and
radiotherapy. NWTS-5 evaluated two protocols for recurrent
disease, avoiding use of agents included in the primary protocols. Stratum B was for patients with stage I and II disease initially treated with EE-4A. The chemotherapy for this relapse
protocol was regimen I (alternating courses of vincristine/
doxorubicin with cyclophosphamide), in addition to surgical
resection and radiation therapy. Event-free survival at 4 years
was 71.1%, and 4-year overall survival was 81.8% for all patients and was 67.8% and 81.0%, respectively, for those who
relapsed only to their lungs.162 Stratum C was for patients initially treated with DD-4A.163 The chemotherapy protocol for
this group was alternating cycles of cyclophosphamide versus
etoposide and carboplatin versus etoposide. Four-year eventfree survival and overall survival were 42.3% and 48.0%,
respectively, for all patients and were 48.9% and 52.8% for
those who relapsed in the lungs only. Bone marrow transplantations have been performed for patients with recurrent disease,
with reported event-free or disease-free survival rates of 36% to
60% in these small series.164166 At present, there is no open
relapsed study in SIOP or COG, because the groups are awaiting new and more effective agents for treatment of this disease.
RADIOTHERAPY
Analogous to surgery and chemotherapy, the cooperative
group trials have refined the indications for radiotherapy. In
addition, technologic advances have helped to deliver irradiation with increased efficacy and less toxicity to surrounding
tissues. The three principle fields for radiotherapy for renal tumors are whole abdominal, flank, and lung (metastatic lung
WILMS TUMOR
435
disease). All five NWTSG studies and the current COG studies
use radiotherapy as part of the multimodality treatment for
advanced-stage tumors.
In 1950, Gross and colleagues demonstrated the efficacy
of radiotherapy as an adjuvant therapy prior to the advent
of chemotherapy. In this series, nephrectomy with postoperative radiation improved survival to 47%.167 Favorable histology tumors are generally very radiosensitive. NWTS-1 to
NWTS-3 helped define the indications, timing, and dose of
radiotherapy. NWTS-1 established that irradiation provided
no advantage in children younger than 24 months with stage
I FH tumors who also received 15 months of dactinomycin.168
That study also demonstrated that in stage III tumors with local tumor spill or previous biopsy, there was no need for irradiation of the whole abdomen, thus sparing patients the
associated toxicity.169 NWTS-2 showed that radiotherapy
could be avoided in all children with stage I WT if they received vincristine and dactinomycin.170 NWTS-3 established
that radiotherapy could be avoided in children with stage II
tumors given vincristine and dactinomycin and also demonstrated that children with stage III favorable-histology tumors
who received 10.8 Gy radiotherapy and vincristine, dactinomycin, and doxorubicin had similar tumor control to those
who received 20 Gy with vincristine and dactinomycin. This
was an important finding, because it eliminated the need for
an age-adjusted dose schedule and significantly reduced the
recommended dose of radiation.157
Timing of radiation following nephrectomy was assessed
on NWTS-2, where a delay of 10 days or more before initiation of radiotherapy was associated with a higher rate of
abdominal relapse, particularly among patients with unfavorable-histology tumors and a small radiation field.157,168,169 A
recent review of this issue from NWTS-3 and NWTS-4 data
confirmed this observation.171 Thus, in the COG protocols, it
is recommended that abdominal irradiation be delivered as
soon as practical after nephrectomy and not later than 14
days after surgery. The current recommendation for radiation
therapy for COG protocols is shown in Table 30-5.
In contrast to FH tumors, the ideal dose for patients with
anaplastic tumors is unknown. Anaplastic tumors are more
resistant to chemotherapy and seem to be more resistant to
radiotherapy as well. Anaplastic tumors have not demonstrated a radiation dose response between 10 Gy and 40 Gy.160
The radiotherapy strategy for patients with anaplastic histology (AH) on NWTS-5 included no irradiation for stage I AH
tumors and 10-Gy radiotherapy for AH stage II and III in conjunction with nephrectomy and regimen I. The outcomes for
both of these treatment strategies were suboptimal. Stage 1 patients had a 4-year EFS and overall survival of only 69.5% and
82.6%, respectively. Stage II, III, and IV patients had a 4-year
OS after immediate nephrectomy, irradiation, and regimen I
chemotherapy of 82.6%, 64.7%, and 33.3%, respectively.84
EFS was similar to OS in all groups. Fifty percent of stage
III recurrences were local, suggesting that the dose of 10 Gy
was not adequate. These results form the basis for the current
COG study that recommends the addition of irradiation for
patients with stage I anaplasia and augmentation of irradiation
for patients with stage III anaplasia.
For liver metastases, only those that are unresectable at diagnosis are irradiated. The treatment portal includes that portion of
the liver known to be involved as identified by CTor MRI studies.
The whole liver is treated in children with diffuse metastases.
436
PART III
TABLE 30-5
Radiotherapy for Favorable-Histology Wilms Tumor
Treatment Site
Flank irradiation
All instances of soilage
will be classified as Stage
III and require abdominal
radiation. Flank radiation
is given to all Stage III
patients with three
exceptions (the patients
meeting any of these
exceptions requiring
whole abdominal
radiation).
Whole abdomen irradiation
(WAI)
10.8
10.8
10.5
Liver irradiation
Patients with residual
tumor will receive
supplemental irradiation
with 5.4 to 10.8 Gy.
21
19.8
19.8
LATE EFFECTS
The increasing numbers of survivors of WT have led to a
better understanding of adverse medical conditions related
to treatment of their disease that can develop over time.182
Treatment for WT impacts renal function (discussed earlier),
pregnancy, cardiac and pulmonary function, and second
malignancies may develop.178,183187
Lung Radiotherapy
Pregnancy
CHAPTER 30
WILMS TUMOR
437
438
PART III
0.1
Wilms tumora
Renal cell carcinoma
15
18.3
10
5.6
0.4
0.8
<5
0.7
0.4
5 to 9
10 to 14
15 to 19
Age at diagnosis (years)
CHAPTER 30
WILMS TUMOR
439
CYSTIC NEPHROMA
CN is an uncommon benign renal lesion that occurs most
commonly in children younger than 24 months of age, with
a male to female ratio close to 2:1. A second peak incidence
occurs in adults around 30 years of age, with an 8:1 female
to male predominance.255258 Grossly, these masses are
440
PART III
well-encapsulated multilocular tumors composed of varioussized cysts with thin septations that compress the normal kidney. Microscopically, the identifying feature is that of mature
well-differentiated cell types within the septa of the cyst wall.
There are no blastemal or embryonal elements.254,255 Most
cases are unilateral, but some are bilateral.259 Although CN
is benign, cases have been reported with pleuropulmonary
blastoma as well. The relationship between these two entities
is undefined.260,261
CHAPTER 31
Neuroblastoma
Barrie S. Rich and Michael P. La Quaglia
442
PART III
Mediastinal 20%
Neck <5%
Paraspinal 25%
Pelvic <5%
Adrenal 50%
FIGURE 31-1 Distribution of cases of neuroblastoma at each of the primary tumor sites. Primary tumors most commonly occur in the adrenal
gland.
Mass Screening
------------------------------------------------------------------------------------------------------------------------------------------------
Clinical Presentation
------------------------------------------------------------------------------------------------------------------------------------------------
Neuroblastoma is a tumor with multiple clinical manifestations related to the site of the primary tumor, the presence
of metastases, and the production of certain metabolic tumor
byproducts. In 50% to 75% of reported cases, patients present
with an abdominal mass. The tumor may be hard, nodular,
fixed, and painful on palpation. Generalized symptoms include weight loss, failure to thrive, abdominal pain and distention, fever, and anemia.1,5,10,14 Hypertension is found in 25%
of cases and is related to the production of catecholamines
by the tumor. Instances of hypercalcemia have been observed
in association with neuroblastoma, and hemoperitoneum
caused by sudden spontaneous rupture of the neoplasm
has also been reported.53,54
Neoplasms arising in the upper mediastinum or neck may
involve the stellate ganglion and cause Horner syndrome,
which is characterized by ptosis, miosis, enophthalmos,
anhydrosis, and heterochromia of the iris on the affected
side.5,10,14 Metastases to the bony orbit may produce proptosis or bilateral orbital ecchymosisoften referred to as panda
eyes or raccoon eyes (Fig. 31-2). The latter finding in a child
CHAPTER 31
NEUROBLASTOMA
443
FIGURE 31-3 A, Plain chest radiograph shows the presence of a left upper thoracic tumor. B, Computed tomography scan documents a mass in the
posterior mediastinum that contains calcium, suggestive of a neuroblastoma.
444
PART III
older children with headaches and seizures.8,82 Lung metastases are found on chest radiographs in only 4% of patients.83
This may be the result of direct extension to the lung from
mediastinal lymph nodes or diffuse hematogenous spread,
presenting with a radiographic pattern that may be confused
with pulmonary edema or interstitial pneumonia.83 Lung
involvement by intralymphatic metastases (not seen on chest
radiographs) may be noted at autopsy. Occasionally, patients
with advanced disease present with a bleeding diathesis
related to thrombocytopenia from extensive involvement of
bone marrow and interference with hepatic production of
clotting factors by liver metastases. Multiple subcutaneous
skin nodules and hepatomegaly may occur in infants with
stage IV-S neuroblastoma.
Diagnosis of neuroblastoma is made through a variety of imaging and isotopic studies, serum and urine determinations,
and histologic and genetic evaluation of tumor tissue. On
the plain abdominal radiograph, approximately 50% of cases
may show finely stippled tumor calcification.10,11,14 Radiographs also may show displacement of bowel gas by a mass.
Paraspinal widening is commonly found with celiac axis
tumors. Chest radiographs may show a posterior mediastinal
tumor, a paraspinal widening above the diaphragm from
extension of an abdominal tumor, or a primary thoracic tumor. The diagnostic workup of patients with retroperitoneal
tumors includes an initial upright radiograph of the abdomen,
an ultrasound examination to distinguish a cystic from a solid
lesion, and an evaluation for potential obstruction or compression of the inferior vena cava. As a rule, obstruction of
the inferior vena cava in patients with neuroblastoma suggests
the presence of an initially unresectable lesion.10,84 Computed
tomography (CT) can demonstrate tumor calcification in approximately 80% of cases (Fig. 31-4).14,85 With CT studies
using contrast enhancement, one can often distinguish kidney
and liver from adrenal and paraspinal lesions and evaluate for
FIGURE 31-4 Abdominal computed tomography shows a retroperitoneal mass with stippled calcification, consistent with neuroblastoma.
FIGURE 31-5 123I-MIBG scintiscan shows the presence of bone metastases and uptake of the isotope in a primary tumor in the adrenal gland.
Diagnosis
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 31
NEUROBLASTOMA
445
FIGURE 31-6 Helical computed tomography scan with three-dimensional reconstruction of a neuroblastoma arising near the celiac axis. A, Anterior view
indicates that the tumor does not involve the branches of the celiac axis. B, Lateral view demonstrates that the superior mesenteric artery passes through
the tumor.
Staging
------------------------------------------------------------------------------------------------------------------------------------------------
The pathologic classification of neuroblastoma has been revised, and histologic features of the tumor that have important prognostic value have been established.9799 Previously,
the Shimada classification system was used. The Shimada
446
PART III
TABLE 31-1
International Neuroblastoma Staging System
Stage
Description
IIA
IIB
III
IV
IV-S
Description
L1
L2
M
MS
TABLE 31-3
Modified Shimada Pathologic Classification of Neuroblastic
Tumors
Age
Stroma-rich
appearance
All
Stroma-poor
Age < 18
appearance (i.e., months
neuroblastoma)
Age 18-60
months
Age > 5
years
Favorable
Histology
Unfavorable
Histology
None
histology. Stroma-poor tumors often have MYCN amplification, a high MKI, and a dismal outcome. A report by
Shimada and colleagues99 documented that both histology
and MYCN amplification provided prognostic information that was independent of staging. Neuroblastomas with
MYCN amplification have a characteristic histopathologic
phenotype and a rapidly progressive clinical course.
The International Neuroblastoma Pathology Classification
(INPC) adopted the Shimada classification with some minor
modifications.90,100102 This age-linked classification is both
prognostically significant and biologically relevant. The current system subdivides the undifferentiated subtype into
undifferentiated and poorly differentiated tumors; changes the
name of stroma-rich, well-differentiated tumors to ganglioneuroma intermixed; and adds a descriptive Schwannian,
stroma-dominant character to ganglioneuroma.103 There is
also a ganglioneuroblastoma nodular (GNBn) group that is
both Schwannian stroma rich/stroma dominant and stroma
poor. Age remains a critical prognostic factor, and the grade
of differentiation and MKI have different prognostic effects,
depending on the patients age at diagnosis. Favorable tumors
are those that are poorly differentiated in children younger
than 1.5 years of age, differentiating in children younger than
5 years of age, ganglioneuroblastoma intermixed, and ganglioneuroma. MKI is low (in those less than 5 years of age) or intermediate (in those less than 1.5 years of age) in this group as
well. Unfavorable tumors are those that are undifferentiated or
poorly differentiated in children older than 1.5 years, or any
subtype of neuroblastoma in children older than 5 years. Patients with high MKI, or patients older than 1.5 years with an
intermediate MKI, also have an unfavorable prognosis.101 Although the presence of calcification was thought to favorably
influence survival, further studies demonstrated that calcification does not have an independent prognostic impact.97,103
Favorable Shimada histology was associated with an 85% survival rate, compared with 41% for unfavorable histologic
CHAPTER 31
NEUROBLASTOMA
AbsentGanglioneuroma
maturing subtype
FH
PresentGanglioneuroblastoma
intermixed
FH
447
AbsentMicroscopic
neuroblastic foci
Macroscopically
visible
50%
nodules
Present
Schwannian
development
0 or 50%
Undifferentiated
Neuroblastoma
Poorly
differentiated
Ganglioneuroblastoma
nodular classic*
UH/FH
UH/FH
%MKC**
Age
Any MKI
Any age
UH
4%
Any age
UH
Any MKI
1.5 yr
UH
4%
1.5 yr
FH
5 yr
UH
4%
1.5 yr
FH
4%
1.5 yr
UH
2%
1.5-5.0 yr
FH
2%
1.5-5.0 yr
UH
Any MKI
Differentiating
Histology
FIGURE 31-7 International Neuroblastoma Pathology Classification. FH, favorable histology; GNBn, ganglioneuroblastoma nodular; MKI, mitotic
karyorrhexis index; %MKC, mitotic and karyorrhectic cells; UH, unfavorable histology; *classic GNBn (single, macroscopically visible, usually hemorrhagic
nodule in stroma-rich, stroma-dominant tissue background; **MKC 2%, 100 of 5,000 cells; MKC 4%, 200 of 5,000 cells. (From Peuchmaur M, dAmore ES,
Joshi VV, et al: Revision of the International Neuroblastoma Pathology Classification: Confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 2003;98:2274-2281.)
operative manipulation. The tumor is often necrotic, especially the undifferentiated form. Mature tumors (ganglioneuromas) have a more solid consistency and frequently have a
fleshy white color. The histologic pattern may be quite variable. Primitive stroma-poor neuroblastomas may be indistinguishable from other small, blue round cell tumors, such as
Ewing tumor, rhabdomyosarcoma, or primitive neuroectodermal tumors. The neuroblast is a small round cell consisting
predominantly of the nucleus without much cytoplasm. Immature, undifferentiated tumors are characterized by closely
packed small spheroid cells without any special arrangement
or differentiation.108 Nuclei may appear cone shaped and are
hyperchromic. Rosette formation may be observed and is considered a sign of early tumor differentiation (Fig. 31-8). The
center of each rosette is formed by a tangle of fine nerve fibers.
More mature-appearing, stroma-rich tumors may contain cells
that resemble normal ganglion cells, with an admixture of histologic components characterized by abundant nerve filaments, neuroblastic rosettes, and ganglion cells all seen in a
single microscopic field.28,109 On electron microscopy, neurofibrils and electron-dense, membrane-bound neurosecretory
granules may be observed. The neurosecretory granules may
be the site of conversion of dopamine to norepinephrine.
448
PART III
TABLE 31-4
Genetic Alterations in Neuroblastoma
Genetic Feature
Associated Factor
Risk Group
MYCN amplification
High
Variable
Beckwith-Weidemann syndrome
Low
High
Risk related to MYCN status
High
Intermediate decreased survival in patients
without MYCN amplification
Intermediate
Low
Note: This table does not include changes in the genetic expression of TRK-A, TRK-B, and TRK-C; the multidrug-resistant protein gene; telomerase; or others that are
covered elsewhere in this chapter.
LOH, loss of heterozygosity.
CHAPTER 31
NEUROBLASTOMA
449
Neuroblastoma in Infancy
------------------------------------------------------------------------------------------------------------------------------------------------
For many years, the age of the patient and the stage of disease
at the time of diagnosis were the two key independent variables determining prognosis in children with neuroblastoma.
Evans and colleagues3 and others found that infants younger
than 1 year and those with stage I, II, or IV-S disease had
a significantly better outcome.5,11,34,151,152 Historically,
patients older than 1 year and those with advanced disease
(stages III and IV) did poorly. The worst survival data
were observed in patients older than 1 year with stage
IV disease and metastases to cortical bone.1,5,11,14,153
450
PART III
Percent survival
Age
Over 1 yr
Under 1 yr
10
20
30
40
50
60
70
80
Percent
FIGURE 31-9 Bar graph demonstrates the improved survival in infants with neuroblastoma who are younger than 1 year.
Stage IV-S
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 31
NEUROBLASTOMA
451
FIGURE 31-10 A, Six-week-old infant presented with abdominal distention and hepatomegaly. B, Appearance of the liver at laparotomy. There were
multiple metastatic nodules, and the biopsy confirmed the diagnosis of stage IV-S neuroblastoma.
Cystic Neuroblastoma
------------------------------------------------------------------------------------------------------------------------------------------------
Cystic neuroblastomas are relatively rare and are often identified on prenatal ultrasound examinations.168 They characteristically occur in the adrenal gland, and almost all are
diagnosed in early infancy (Fig. 31-11). Few are calcified,
and only 10% are associated with elevation of urinary VMA
and HVA levels.169 They display a benign behavior and a
favorable outcome. Some evidence suggests that they often
regress and undergo spontaneous involution.26 Some investigators have recommended observation alone, with close serial
sonographic monitoring during the first few months of life.
Operative resection should be reserved for tumors that fail
to regress or that increase in size. Adjuvant chemotherapy is
rarely required after resection. The Childrens Oncology
Group (COG) has performed a prospective study of observation alone for cases of perinatal neuroblastoma, with strict criteria for enrollment, including tumor volume (< 16 mL, if
solid, or < 65 mL, if cystic). Results from the study are not
yet available.
452
PART III
CHAPTER 31
NEUROBLASTOMA
453
TABLE 31-5
Neuroblastoma Risk Groups*
Risk group
Low
Low
High
Intermediate
Intermediate
High
High
High
Intermediate
High
High
High
Intermediate
High
Low
Intermediate
Intermediate
High
INSS Stage
1
2a/2b
2a/2b
3
3
3
3
4
4
4
4
4
4
4
4s
4s
4s
4s
Age
Any
Any
Any
< 547 days
547 days
Any
547 days
< 365 days
< 365 days
365 to <547 days
365 to <547 days
365 to <547 days
365 to <547 days
547 days
< 365 days
< 365 days
< 365 days
< 365 days
Any
Not amplified
Amplified
Not amplified
Not amplified
Amplified
Not amplified
Amplified
Not amplified
Amplified
Any
Any
Not amplified
Any
Not amplified
Not amplified
Not amplified
Amplified
DNA Ploidy{
Any
Any
Any
Any
Any
Any
Any
Any
Any
Any
DI 1
Any
DI > 1
Any
DI > 1
DI 1
Any
Any
Any
Any
Any
Any
FH
Any
UH
Any
Any
Any
Any
UH
FH
Any
FH
Any
UH
Any
*Courtesy Childrens Oncology GroupTable 109.4 Childrens Oncology Group Neuroblastoma Risk Stratification.
{
MYCN nonamplified 1 copy, amplified greater than 1 copy.
{
DNA index > 1 (aneuploid) or 1 (diploid).
DI, DNA index; FH, favorable histology; INPC, International Neuroblastoma Pathology Classification; INSS, International Neuroblastoma Staging System;
UH, unfavorable histology.
rapidly progressive disease, and a dismal outcome. Although attempts to stimulate tumor maturation with nerve growth factor,
adrenergic agonists, papaverine, prostaglandins, exogenous cyclic adenosine monophosphate, and hyperthermia were successful in the laboratory setting, there was minimal clinical
evidence of their usefulness.14,109,174177 The use of retinoids
as a promoter of differentiation, however, has rekindled interest
in this concept and has been successful in prolonging survival in
advanced cases during clinical trials.174 The addition of cis-retinoic acid to the treatment protocol for high-risk cases of neuroblastoma following BMTor peripheral stem cell transplantation is
now standard practice.1
A new pretreatment classification system based on
13 prognostic factors has recently been developed by the
INRG, aiming to create international consensus for risk stratification. These factors include age, INRG stage, histology,
DNA index, MYCN amplification status, and presence of
11q abnormality; they classify patients into 1 of 16 groups.
Each group is categorized as very low, low, intermediate,
and high risk, based on event-free survival rates of more than
85%, more than 75% to less than or equal to 85%, greater than
or equal to 50% to less than or equal to 75%, or less than 50%,
respectively.178
For low-risk patients, surgical excision of the tumor is
usually curative and avoids the risks associated with chemotherapy. Intermediate-risk patients are usually treated with
surgery and chemotherapy. Studies aimed at minimizing
treatment regimens for this group of patients are ongoing.
The poor prognosis in high-risk patients justifies a much
more intense treatment regimen, including combination
chemotherapy followed by complete surgical excision
(if possible), radiotherapy to achieve local control, myeloablative treatments with bone marrow rescue, and biologic
therapy.
Operative Management
------------------------------------------------------------------------------------------------------------------------------------------------
454
PART III
subdiaphragmatic vessels on the left. Inferiorly located paraspinal and primary pelvic tumors often require careful dissection to separate the lesion from the bifurcation of the aorta and
inferior vena cava. The tumor frequently extends into the
intervertebral foramina (Fig. 31-12).
Minimally invasive surgical techniques have also been
employed for selected cases of neuroblastoma.180 Adrenal
tumors initially detected by mass screening have been
excised laparoscopically by a number of investigators.181,182
Yamamoto and colleagues49 described three cases of
adrenal neuroblastoma in which the lesions were less than
20 mm in diameter. They used a 5-trocar technique and kept
the intra-abdominal pressure for the pneumoperitoneum
less than 4 mm Hg. The well-encapsulated tumors were
completely excised; they were placed in a plastic bag and
removed through the 10-mm trocar site. All had favorable
Tumor
Adrenal
blood supply
Tumor
Duodenum
Ureter
Le
ft i
Right iliac
vein
lia
ca
rte
ry
ry
rte
ht
Rig
a
iac
il
C
FIGURE 31-12 A, Lower retroperitoneal paraspinal neuroblastoma and its relationship to the bifurcation of the aorta and ureter. B, Tumor may extend
into the vertebral foramina. C, Photograph of the operative field after resection of a right-sided pelvic neuroblastoma. Note the vascular loops placed
around the iliac arteries, right iliac vein, and ureter to facilitate a safe dissection.
CHAPTER 31
NEUROBLASTOMA
455
Rib space
Esophagus
Azygos vein
Latissimus
dorsi m.
Sympathetic
chain
Intercostal vessels
Tumor
extensions
C
FIGURE 31-13 A, Right posterolateral thoracotomy incision used for the excision of a posterior mediastinal neuroblastoma. B, Relationship of the tumor
to surrounding tissues. C, The tumor is mobilized and retracted anteriorly, exposing numerous intervertebral extensions. The tumor extensions are divided
at the vertebral foramina, leaving small remnants of residual tumor behind. This does not adversely influence the outcome.
456
PART III
Chemotherapy
------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------------
Radiotherapy
Neuroblastoma is a radiosensitive tumor, so radiotherapy remains an important part of the treatment regimen for patients
with neuroblastoma. In general, in the management of neuroblastoma, radiotherapy is administered after both induction
therapy and surgery, when minimal disease remains. It has
also been used for bulky metastatic disease after a response
is seen with chemotherapy, and for palliation in patients
with refractory end-stage disease or painful metastases.193195
At our institution, a regimen that includes dose-intensive chemotherapy, surgery, and a dose of 2100 cGy of hyperfractionated
radiotherapy to the primary site in patients with stage IV neuroblastoma resulted in a local control rate of greater than 90%.46
Although it is useful, external-beam radiotherapy is associated with considerable toxicity in growing children, resulting
in growth disturbance, bony deformity, endocrine deficiency,
hypoplastic soft tissue changes, skin atrophy, and, of greater
concern, secondary malignancies in the radiation portal. Techniques used to decrease radiation-induced toxicity include
hyperfractionation of the radiation dose, which usually does
not reduce the desired antitumor effect, and avoiding the simultaneous administration of chemotherapy agents that
may enhance the radiation effect. Brachytherapy and intraoperative radiotherapy can better confine the radiation
effect to the target tissue and spare surrounding normal tissues.196,197 Although early local control can be achieved, only
38% of patients with stage IV disease given intraoperative radiotherapy survived after 3 years. Some patients still require
supplemental external-beam radiotherapy; postoperative
ureteral stricture, renal artery stenosis, and neuropathies have
been described.5 Haas-Kogan and colleagues196 described an
experience using intraoperative radiotherapy in 23 cases of
high-risk neuroblastoma and noted that this technique was
effective only in patients who had gross total resection of
the primary tumor.196 All patients with partial tumor resection
had recurrence, despite radiotherapy, and subsequently died.
There are few data to support the efficacy of this therapy.
Intraoperative radiotherapy is sometimes cumbersome to perform, especially in institutions that do not have an operative
suite in the radiotherapy department or radiotherapy
CHAPTER 31
Myeloablative Therapy
------------------------------------------------------------------------------------------------------------------------------------------------
Myeloablative therapy, using near-lethal doses of phenylalanine mustard (melphalan) with autologous bone marrow
rescue, has been shown to improve the tumor response rate.
A combination of melphalan, doxorubicin, teniposide, and
low-dose total-body irradiation followed by autologous
BMTresulted in a relapse-free rate of 40% and, if deaths resulting from toxicity were excluded, there was a 2-year survival
rate of 34% in patients with stage IV disease.198 An alternative
treatment was developed that relies on myeloablative chemotherapy using escalating doses of drugs given by constant
infusion, followed by autologous (purged) bone marrow
infusion but without total-body irradiation.199
Currently, stem cells are harvested during the induction
phase of treatment, and stored for later use during the consolidation phase of treatment.200 Chemotherapeutic agents used
for this phase of treatment include carboplatin, etoposide, and
melphalan. Peripheral blood stem cell infusion is used to reconstitute the marrow after myeloablative treatment. Immunoglobulin G levels are monitored and replaced with
gamma globulin. Sulfamethoxazole and fluconazole are given
prophylactically to avoid opportunistic Pneumocystis carinii
and fungal infection.
The use of purged, peripheral blood hematopoietic stem cells
has shown to have survival benefits over the use of allogeneic
cells, mainly because of a higher toxic death rate and an increased
incidence of graft-versus-host disease in the latter group.94,201
Patients with high-risk stage IV disease have a better outcome
with BMT, especially if they have amplification of the
MYCN oncogene.37,94,124 Preliminary reports are demonstrating improved event-free survival with rapid sequential
tandem transplant consolidation therapy. This has initiated
the ongoing COG phase III trial testing single versus tandem
transplant as consolidation therapy.201 However, to date, there
NEUROBLASTOMA
457
are no prospective studies examining the use of myeloablative therapy in addition to dose-intensive induction
therapy.190 At our institution, the addition of myeloablative
chemotherapy to dose-intensive chemotherapy did not
decrease the rate of systemic or central nervous system
recurrence.202
The addition of 13-cis-retinoic acid (isotretinoin), a biologic response modifier that causes tumor differentiation
and decreases bone marrow tumor involvement, was shown
to be useful.199 Retinoids serve as multistep modulators
of the MHC class I presentation pathway and sensitize
neuroblastomas to cytotoxic lymphocytes.202204 In a phase
III randomized trial in high-risk patients, Reynolds and
colleagues203,204 showed that high-dose pulse therapy with
13-cis-retinoic acid given after completion of intensive chemoradiation (with or without autologous BMT) significantly
improved event-free survival. A CCG phase III randomized
trial showed the use of 13-cis-retinoic acid after myeloablative
chemotherapy had superior event-free survival in patients
with remission, and this protocol is now commonly used
for these particular patients.199 A newly developed retinoid,
fenretinide, has completed a COG phase I trial, and different
oral formulations are being tested in the hopes of improving
its bioavailability.189,205
Immunotherapy
------------------------------------------------------------------------------------------------------------------------------------------------
458
PART III
were in remission. Five of the seven patients remained in remission between 4 and 8 years later.214 The same group
reported that high-dose cyclophosphamide, irinotecan, and
topotecan were effective in achieving remission and inducing
an immunologic state conducive to antibody-based passive
immunotherapy (using 3F8 antibody) in resistant neuroblastoma.215 Further studies have been completed that continue
to show improved outcomes with the use of this antibody.
In contrast to 3F8, which is a mouse-derived monoclonal antibody, ch14.18 is a chimeric human/murine anti-GD2 antibody,
and it has shown positive results in both phase I and II clinical
trials (German NB90 and NB97 studies). Preliminary results
from the COG randomized phase III trial using ch14.18 plus cytokines after autologous stem cell transplant versus control
showed improved survival in the treatment group.216
Dendritic cells are potential targets for immunotherapy.
They can enhance growth and differentiation of CD40activated B lymphocytes, directly affect natural killer cell
function, and act as antigen presenters.217,218 Redlinger and
colleagues218 noted that advanced neuroblastoma impairs
dendritic cell differentiation and function in adoptive immunotherapy. It has been shown that neuroblastoma-derived
gangliosides inhibit dendritic cell function. Interleukin-12
(IL-12) is a potent proinflammatory cytokine that enhances
the cytotoxic activity of T lymphocytes and resting natural
killer cells.217 In a murine model of neuroblastoma, Shimizu
and colleagues219 demonstrated that IL-12transduced dendritic cell vaccine (with an adenoviral vector expressing
IL-12) led to a complete and sustained antitumor response.
Tumor regression was associated with a high infiltration of
dendritic cells and viable T cells.
Additional Therapies
------------------------------------------------------------------------------------------------------------------------------------------------
131I-MIBG
infusion provides a way to specifically deliver radiotherapy to neuroblastoma cells, because it is taken up by more
than 90% of neuroblastomas. The use of this treatment alone
results in a response in 18% to 37% of patients with refractory
or relapsed disease.220 Rapamycin (mTOR) plays a significant
role in cell growth and persistence of neuroblastomas, and
phase II trials investigating rapamycin (mTOR) inhibitors are
ongoing. Early results reveal a benefit in patients with recurrent
neuroblastoma.221 Additionally, trials are examining targeted
therapies for the AKT pathway, as activation of AKT correlates
with worse event-free and overall survival.222224 Biologic
agents, such as histone deacetylase inhibitors, tyrosine kinase
inhibitors, IGF-1 receptor inhibitors, N-myc inhibitors, ALK
inhibitors, and various antiangiogenic agents, are also being investigated in ongoing clinical trials. The use of bisphosphonates
is being explored as a possible treatment for bone metastases.
Tumor vaccines and techniques of adoptive immunotherapy
are also being evaluated in clinical trials.
Diagnosis
------------------------------------------------------------------------------------------------------------------------------------------------
LABORATORY TESTS
CHAPTER 32
Nonmalignant
Tumors of the Liver
Wolfgang Stehr and Philip C. Guzzetta, Jr.
Clinical Presentation
------------------------------------------------------------------------------------------------------------------------------------------------
Serum alpha fetoprotein (AFP) is present in very high concentrations at birth (48,000 35,000 ng/mL) and rapidly
declines to adult levels of less than 10 ng/mL by 8 months of
age (Table 32-1).10 Thus in infants younger than 8 months,
AFP levels must be interpreted in the context of this dramatic
change. Markedly elevated AFP levels in a child with a liver
mass almost certainly means that the mass is malignant,
although milder elevation may be encountered with some
benign lesions, such as mesenchymal hamartoma11 or teratoma.12 As mentioned previously, significant thrombocytopenia
associated with a liver mass is usually part of the KasabachMerritt syndrome resulting from a liver hemangioma. Hypothyroidism may also occur in multiple or diffuse forms of liver
hemangioma13; thyroid function tests should be done routinely
in these children, because hypothyroidism significantly impacts
their management.14
IMAGING TECHNIQUES
The initial imaging study in a child presenting with an
abdominal mass should be a supine radiograph of the abdomen, looking for calcifications within the mass. The next imaging study should be an abdominal ultrasonogram with
Doppler spectral analysis, followed by computed tomography (CT) with intravenous contrast (Fig. 32-1).15 Magnetic
resonance imaging (MRI) may be indicated, depending on
the sonogram and CT scan results, especially when surgical
resection is planned and more detailed information about the
vascular anatomy relative to the tumor is desired or in infants
with hemangiomas in whom another diagnosis is being considered because the MRI appearance may be diagnostic.
Arteriography is reserved for children with a liver hemangioma, an AVM, or, rarely, a mesenchymal hamartoma with
CHF, when embolization of the blood supply to the tumor
is needed for treatment. The use of percutaneous biopsy
under sonogram or CT guidance in children with benign tumors is generally discouraged, unless excision of the tumor
would pose a major risk to the child, because establishing a
diagnosis on the basis of a small sample may be problematic
for the pathologist and because resection is the proper
459
460
PART III
TABLE 32-1
Normal Serum Alpha Fetoprotein (AFP) Levels of Infants by Age
Age
Premature
Newborn
Newborn to 2 weeks
2 weeks to 1 month
1 month
2 months
3 months
4 months
5 months
6 months
7 months
8 months
No. of Patients
11
55
16
43
12
40
5
31
6
9
5
3
138,734 41,444
48,406 34,718
33,113 32,503
9452 12,610
2645 3080
323 278
88 87
74 56
46.5 19
12.5 9.8
9.7 ?7.1
8.5 5.5
From Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal
infants. Pediatr Res 1981;5:50.
DIFFUSE LESIONS
ARTERIOVENOUS MALFORMATION
Hepatic Hemangioma
------------------------------------------------------------------------------------------------------------------------------------------------
Hepatic hemangiomas are the most common benign liver tumor in children and are more common than all other benign
liver tumors combined. Most of these lesions are identified in
the newborn period or during prenatal ultrasound screening.8
To facilitate discussion about treatment and prognosis, a
new subtype classification was delineated in 2007.4 This classification designates the hemangioma as either focal, multiple,
or diffuse and eliminates confusing terms such as infantile
hepatic hemangioendothelioma.
CHAPTER 32
MESENCHYMAL HAMARTOMA
Mesenchymal hamartoma (MH) usually presents as a painless
right upper quadrant abdominal mass in a child younger than
2 years.20,26,27 Some patients may have evidence of CHF,7 and,
similar to liver hemangiomas, MH has been diagnosed prenatally.20,9 Edmondson28 proposed that MH arises from a mesenchymal rest that becomes isolated from the normal portal
triad architecture and differentiates independently. The tumor
grows along bile ducts and may incorporate normal liver tissue. Because the blood vessels and bile ducts are components
of the mesenchymal rest, the biologic behavior of the tumor
varies with the relative predominance of these tissues within
the loose connective tissue stroma (mesenchyma) that surrounds them. Thus the tumor may present as a predominantly
cystic structure (Fig. 32-2) that enlarges rapidly because of
fluid accumulation,29 or it may be predominantly vascular
and present with CHF.7 Von Schweinitz and colleagues30 suggested that fat-storing (Ito) cells of the immature liver may be
involved in the development of MH. There are reports of chromosomal translocations within mesenchymal hamartomas.31
Serum AFP levels are usually normal in children with MH,
but they may be mildly elevated.20,11,32 The radiographic features of these tumors are consistent and distinguishing; abdominal sonography and CT demonstrate a single, usually
large, fluid-filled mass with fine internal septations and no
calcifications.33
Management must be tempered by the understanding that
MH usually follows a benign course,34 although there have
been reports of malignant transformation.35,36 In general,
complete operative resection is the procedure of choice, if it
can be accomplished safely. Huge lesions or those that involve
461
HEPATOCELLULAR ADENOMA
Although isolated lesions are encountered in childhood, hepatocellular adenoma (HCA) is most commonly observed in
adults in association with the use of anabolic corticosteroids
or estrogen. HCA has been described in children treated
with anabolic steroids and multiple blood transfusions for
chronic anemia,38 and it is expected in children with type I
glycogen storage disease.39 Bianchi40 proposed several mechanisms for the development of HCA in patients with type I
glycogen storage disease, including (1) regional imbalance
in insulin and glucagon metabolism, because these hormones
are important in the regulation of hepatocyte proliferation
and regeneration; (2) response to glycogen overload; and
(3) oncogene activation. A giant hepatocellular adenoma has
also been reported in a child treated with oxcarbazepine for
a seizure disorder.41
Microscopic examination of adenomas reveals hepatocytes
in sheets and cords oriented along sinusoids without a ductal
component. The cells have glycogen-filled cytoplasm and
small nuclei without mitoses. Adjacent liver and vessels are
compressed but not invaded. Children usually do not have
coexisting cirrhosis.38 The histologic pattern is similar to that
of a well-differentiated hepatocellular carcinoma, and development of hepatocellular carcinoma within an unresected
HCA has been reported.42,43
In children, HCA generally presents as an asymptomatic
hepatic mass. The mass is solid on ultrasonography and CT.
Liver enzyme and AFP levels are normal. A feature unique
to this lesion is its propensity for intraperitoneal hemorrhage
from spontaneous rupture. In adults, intraperitoneal bleeding
is almost always seen in patients receiving estrogen therapy,
and tumor regression may occur with the cessation of hormone administration. In patients with glycogen storage disease and HCA, tumor regression may occur with the
correction of metabolic disturbances.40 Because of the known
association between HCA and hepatocellular carcinoma,
resection of HCA is recommended when it occurs in a child
who is not receiving steroids and does not have glycogen storage disease. If resection cannot be accomplished without substantial risk, observation of the lesion while monitoring the
serum AFP level may be appropriate. If the AFP level begins
to increase or the lesion is significantly symptomatic, and if
the risk of resection is unacceptably high, liver transplantation
may be the best alternative.
462
PART III
comparison with the levels seen with hepatoblastoma. Resection is the procedure of choice for a teratoma because of the
risk of malignancy in any immature elements of the tumor.
INFLAMMATORY PSEUDOTUMOR
Inflammatory pseudotumor of the liver is rare and generally
seen in children older than 3 years but has been reported in
younger children as well. Because this lesion is predominantly solid, it is difficult to differentiate it from other
benign or malignant tumors by imaging studies. Invariably,
the serum AFP level is normal. Fever, leukocytosis, and high
C-reactive protein level in a child with a solid liver mass and
normal AFP level are suggestive of an inflammatory pseudotumor of the liver thought to be an inflammatory reaction
to some insult, although the instigating cause is usually
unknown. It is difficult to diagnose this lesion without
a large biopsy. Most children undergo resection, which is
curative.52,53
NONPARASITIC CYSTS
FIGURE 32-3 Surgical view of focal nodular hyperplasia within the left
lobe of the liver in a 2-year-old child treated by left lateral lobectomy.
TERATOMA
There have been fewer than 25 case reports of hepatic teratoma in children invariably younger than 1 year.12,50 Calcification is usually present within the teratoma, helping to
differentiate it from other tumors. Some have met the criteria
for an intrahepatic fetus in fetu.51 Serum AFP levels may be
elevated with a teratoma, but only mildly elevated in
Nonparasitic cysts of the liver are rare and occur more commonly in adults than in children. Although they may be present and symptomatic at birth, most are asymptomatic and are
identified incidentally at autopsy or laparotomy. Symptoms
are related to abdominal distention or displacement of adjacent structures. Nonparasitic cysts occur with equal frequency
in males and females54 and are generally unilocular lined by
cuboidal or columnar epithelium characteristic of bile ducts.
The cyst fluid is typically clear or brown, and bile is rarely
present. Pathologic studies suggest that nonparasitic cysts
arise from congenital or secondary obstruction of peribiliary
glands. These glands normally arise from the ductal plate at
the hepatic hilum around the 7th week of gestation and continue to proliferate until adolescence.54 Symptomatic cysts can
be effectively treated by simple unroofing, marsupialization,55
or sclerotherapy.56 If biliary communication is suspected,
cholangiography may identify the source and allow the communicating ductule to be oversewn.
Cystic dilatation of the intrahepatic ducts may also present as
a mass, although jaundice and cholangitis are often associated
with this problem. Resection of the affected lobe is the preferred
therapy.57 If mesenchymal hamartoma appears to be completely
cystic on imaging, it may be misdiagnosed as a nonparasitic cyst.
Post-traumatic bile cysts result from ductal disruption and intrahepatic accumulation of bile. These lesions can be treated by
percutaneous drainage or, in some cases, by biliary sphincterotomy to reduce the bile duct pressure and lessen the biliary
leak.58 Resection is rarely necessary for post-traumatic cysts.
Multiple parenchymal cysts associated with hereditary polycystic kidney disease are generally asymptomatic and so small that
they do not require intervention.
Epidermoid cysts differ from other nonparasitic cysts, in
that the lining epithelium is squamous rather than cuboidal.
This histologic characteristic has led to the theory that these
lesions may be foregut bud anomalies trapped in the hepatic
substance. Although they are rare, there has been a report of
malignant degeneration. Thus resection is the appropriate
management.59
The complete reference list is available online at www.
expertconsult.com.
CHAPTER 33
Malignant Liver
Tumors
Rebecka L. Meyers, Daniel C. Aronson,
and Arthur Zimmermann
Historical Context
------------------------------------------------------------------------------------------------------------------------------------------------
One hundred and thirteen years ago, the first case report of a
hepatoblastoma (HB) was published in the English literature
in 1898 by Misick in Prague.1 He reports A Case of Teratoma
Hepatis in a 6-week-old boy who died of respiratory problems. Autopsy showed a large tumor that occupied the lower
half of the right liver lobe. Cysts, cartilaginous, and bony deposits were seen, as well as venous tumor infiltration. It was
therefore not surprising that the tumor was described as a teratoma, with tissue representatives of the three embryonic
germ cell layers. More than 60 years later in 1962, Willis
introduced the term hepatoblastoma for this type of tumor
that he defined as an embryonic tumor that contains hepatic
epithelial parenchyma.2 At that time, hepatoblastoma usually
was not distinguished from hepatocellular carcinoma (HCC).
Through the work of Ishak and Glunz in 1967, morphologic
criteria were defined for HB and HCC that were refined in the
decennia that followed.3,4
Modern treatment dates to 1975 when Exelby published
a landmark paper that has been cited in most reviews dealing with liver tumors in children. He reports the results of
a survey of the American Academy of Pediatrics Surgical
Section documenting the 1974 treatment practices and outcomes for liver tumors in children.5 Through questionnaires
sent to the members of the Surgical Section of the American
Academy of Pediatrics (AAP), data on liver tumors in children
operated upon during the previous 10 years were requested.
From 110 replies, 375 liver tumors were reported, of which
252 were malignant (129 HB, 98 HCC), and 123 were benign.
All patients with HB underwent primary surgical exploration,
with biopsy only in 43 children and a subsequent attempt at
definitive resection in 86. Seventy-eight of the 86 children in
whom resection was attempted had complete excision of the
tumor and 45 (60% of those resected) survived. Excessive blood
loss was the most common complication during and immediately after operation, after which cardiac arrest occurred in
9 patients. There were 8 deaths in the operating room and
17 deaths in the immediate postoperative period attributable
to the operation. Fifteen HB patients had irradiation of the liver;
53 patients had chemotherapy using a wide variety of agents.
It was apparent that no cures were obtained from irradiation
and/or chemotherapy in the absence of complete surgical resection. The overall survival for HB was 35%; for HCC it was 13%.
With incomplete surgical excision no patient survived. There
was no evidence that radiation therapy or chemotherapy controlled disease that could not be completely excised surgically.
At this time, before the introduction of cisplatin-based chemotherapy and modern surgical techniques, it seemed that complete operative excision carried a high risk of morbidity, even
mortality, but offered the only chance of cure.
The field has progressed considerably since Exelbys 1975
survey. With the introduction of cisplatin-based chemotherapy
regimens in the 1980s, overall survival for HB increased from
35% to 70%6 and has increased further to nearly 80% in the
most recent trials.7 Although our sophistication with chemotherapy and antiangiogenic regimens for both HB and HCC
continues to evolve, the primary advantage of chemotherapy
has been in a neoadjuvant setting to shrink the tumor and
enable surgical resection. Although pediatric HCC is more
likely to respond to chemotherapy than its adult counterpart,
most HCC remains largely chemoresistant, and treatment
efforts often focus on slowing tumor progression with the
newest antiangiogenic agents. Complete surgical excision
remains the cornerstone for cure in both HB and HCC as
evidenced by the recent improvements in survival achieved
with complete hepatectomy and liver transplantation.810
Diagnosis
------------------------------------------------------------------------------------------------------------------------------------------------
CLINICAL PRESENTATION
Most liver tumors present with an asymptomatic abdominal
mass palpated either by a parent or pediatrician.11 In the
youngest children (infants and toddlers) the most common
malignant tumor is hepatoblastoma, which presents as an
asymptomatic right upper quadrant or epigastric abdominal
mass. Some children may have fatigue, fever, pain, anorexia,
and weight loss. Rarely, HB may present with abdominal pain
and hemorrhage after post-traumatic or spontaneous rupture of a previously occult tumor. Hepatocellular carcinoma
and hepatic sarcomas are more common in older children
and are more likely to present at an advanced stage. Nonspecific symptoms of inanition or respiratory failure may appear
insidiously. As the cancer grows, the pain in the abdomen may
463
464
PART III
progress to shoulder or back pain and becomes more pronounced. The child may develop progressive anorexia and
vomiting and appear thin and sickly. Tumor growth may compress or obstruct the normal hepatic architecture causing
(1) ascites secondary to occlusion of the portal or hepatic
veins, (2) gastrointestinal (GI) bleeding or splenomegaly from
the portal hypertension of portal vein occlusion, or (3) jaundice, scleral icterus, and pruritus from obstruction of the
biliary tree.12 Symptoms of biliary obstruction are most
common with biliary rhabdomyosarcoma.13
DIFFERENTIAL DIAGNOSIS
Differential diagnosis of a pediatric liver mass includes malignant tumors, benign tumors, and a wide assortment of congenital and acquired lesions of the liver, listed as other
masses in Table 33-1. For many of the other masses listed
in Table 33-1, the key to the diagnosis might lie in the underlying medical condition. For example, one might expect to see
a bacterial hepatic abscess in a child with chronic granulomatous disease, a fatty deposit in the liver of a child with hyperlipidemia, or perhaps an inspissated bile lake in a child with
biliary atresia as shown in Figure 33-1. Organizing intrahepatic hematoma should be suspected in any child with a history
of hepatic trauma or in newborns with sepsis and coagulopathy, especially if there is a history of perinatal birth trauma or
hemodynamic collapse requiring cardiopulmonary resuscitation. Congenital liver cysts are rare and represent a spectrum
ranging from large simple cysts, intrahepatic choledochal
cyst, and ciliated hepatic foregut cyst. Acquired cysts might
be due to a bacterial, hydatid, or amoebic abscess. A simple,
asymptomatic congenital liver cyst may be safely observed.14
If infectious or large and symptomatic, cyst drainage, marsupialization, or excision may be needed to relieve pain and
prevent risk of rupture. Recent literature suggests a risk of
squamous cell carcinoma arising later in life in those congenital hepatic cysts with a ciliated epithelial lining (ciliated
hepatic foregut cyst), and therefore these should probably
be excised rather than observed or marsupialized.15,16
Neoplastic liver masses, including benign and malignant
tumors, account for about 1.0% to 1.5% of all pediatric
tumors.17 Age at presentation is often the key to differential
diagnosis (Table 33-2).18 In newborns, the most common
LABORATORY EVALUATION
Routine laboratory investigation should include complete blood
count; many children with a malignant liver tumor will exhibit
some degree of anemia and thrombocytosis.22 In HB, the thrombocytosis is thought to be caused by tumor production of
thrombopoietin, interleukin-6, and interleukin-1B.2325 Additional laboratory tests include a liver panel (albumin, transaminases, glutamyl transferase, alkaline phosphatase, total and
conjugated bilirubin), lactate dehydrogenase, tumor markers
(alpha-fetoprotein [AFP], beta-human chorionic gonadotropin
[beta-HCG], ferritin, carcinoembryonic antigen [CEA], catecholamines), and viral titers (hepatitis A, B, and C, Epstein-Barr
virus).18
The most important tumor marker is the serum AFP. AFP
will be elevated in 90% of children with hepatoblastoma and
in 50% of children with HCC.26 Although AFP is elevated in
most children with hepatoblastoma, increased AFP is not
pathognomonic for a malignant liver tumor. European,
German, and American multicenter trials have all concluded
that hepatoblastomas that fail to express AFP at diagnosis
(diagnosis AFP level less than 100) are biologically more
aggressive with a worse prognosis.2731 Rarely, the opposite
has been reporteda case of well-differentiated, fetal-type,
favorable prognosis hepatoblastoma that did not express
AFP.32 AFP levels must be interpreted with caution in neonates,
because AFP is the major protein produced by the fetal liver
TABLE 33-1
Differential Diagnosis of Pediatric Liver Masses
Malignant Tumors
Benign Tumors
Other Masses
Hepatoblastoma
Hepatocellular carcinoma
Sarcoma
Biliary rhabdomyosarcoma
Angiosarcoma
Rhabdoid
Undifferentiated
Metastatic/other
Wilms tumor
Neuroblastoma
Colorectal
Carcinoid tumor
Kaposiform hemangioendothelioma
Hemophagocytic lymphohistiocytosis
Langerhans cell histiocytosis
Megakaryoblastic leukemia
Mesenchymal hamartoma
Biliary cystadenoma
Focal nodular hyperplasia
Infantile hemangioma
Hepatic adenoma
Nodular regenerative hyperplasia
Teratoma
Inflammatory myofibroblastic tumor
Vascular malformations
Arteriovenous malformation
Blue rubber nevus syndrome
Congenital/acquired cysts
Simple
Ciliated foregut cyst
Polycystic liver disease
Choledochal cyst
Inspissated bile lake/biliary atresia
Parasitic cysts
Amoebic
Abscess
Bacterial
Chronic granulomatous disease
Hematoma
Fatty liver
CHAPTER 33
465
FIGURE 33-1 Differential diagnosis: examples of non-neoplastic liver masses and cysts. A, Multiple small bacterial abscesses in a child with chronic
granulomatous disease. B, Inspissated bile lake in a child with biliary atresia and cholangitis. C, Organizing hematoma in a newborn with sepsis and
coagulopathy. D, Infarction of right lobe liver and hepatic abscess (with air fluid level) in a premature baby with necrotizing enterocolitis. E, Acquired cyst
is an amoebic abscess in a toddler with fever. F, Congenital cyst is a ciliated foregut cyst in an infant with abdominal distension and feeding difficulties.
TABLE 33-2
Age at Presentation, Most Common Liver Tumors of Childhood
Age Group
Malignant
Benign
Infant/toddler
Hepatoblastoma 43%
Rhabdoid tumor 1%
Malignant germ cell 1%
Hepatocellular (including transitional cell tumors) 23%
Sarcomas 7%
Hemangioma/vascular 14%
Mesenchymal hamartoma 6%
Teratoma 1%
Focal nodular hyperplasia 3%
Hepatic adenoma 1%
School age/adolescent
From Von Schweinitz D: Management of liver tumors in childhood. Semin Pediatr Surg 2006;15:17-24.
RADIOLOGY
The radiographic appearance of the most common benign and
malignant liver tumors is shown in Figure 33-2. Mesenchymal
hamartoma is classically multicystic with the complex
cysts separated by thick vascular septae. Focal nodular
466
PART III
FIGURE 33-2 Radiographic appearance of the most common hepatic benign and malignant neoplastic masses of the liver in children. A, Mesenchymal
hamartoma, a complex multicystic mass with solid septae. B, Focal nodular hyperplasia with arrow pointing to classic stellate central scar. C, Diffuse infantile
hepatic hemangioma with multiple nodules showing peripheral contrast enhancement. D, PRETEXT 2 hepatoblastoma. E, PRETEXT 4 P hepatocellular
carcinoma with involvement of main portal vein. F, Metastatic tumor, two nodules of metastatic colorectal carcinoma in right anterior and posterior sections.
HEPATOBLASTOMA
Epidemiology, Biology, and Genetics
Hepatoblastoma accounts for about 80% of the malignant
liver tumors in children.12,44 In the United States, the incidence of HB has increased from 0.6 to 1.2 cases per million
population in the last 2 decades.44 It comprises 1% of all
CHAPTER 33
POSTTEXT
= Extent of tumor after
neoadjuvant chemotherapy
...
...
...
...
467
PRETEXT
= Extent of tumor at diagnosis
I
II
III
IV
II
III
b
a
In addition, any group may have:
V ... ingrowth vena cava, all 3 hepatic veins
P ... ingrowth portal vein, portal bifurcation
E ... extrahepatic
C ... caudate
M ... metastasis
IV
Diagram courtesy of SIOPEL liver tumor study group
seen in those with hemihyperplasia.53 In addition to BeckwithWeidemann syndrome, a number of other genetic syndromes
have been associated with an increased risk of HB, including familial adenomatous polyposis (FAP), Li-Fraumeni syndrome,
trisomy 18, and others as shown in Table 33-3.5468 Familial case
reports of HB with familial adenomatous polyposis are striking
and suggest a role in the pathogenesis of HB for chromosomes 5
and 11.56,69 Additional screening for cases in familial adenomatous polyposis kindred families is recommended by testing for
germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene.55,70 Germline APC mutations are not
commonly seen in children with sporadic HB.71 The association
between Beckwith-Weidemann syndrome and HB is so strong
that experts recommend that children with Beckwith-Weidemann syndrome be screened with abdominal ultrasonography
and AFP at regular intervals until they reach the age of 7 years.72
The genetic abnormality in HB patients with Beckwith-Weidemann syndrome is mapped to the 11p15.15 locus and suggests
the presence of a tumor suppressor gene at this location.73 Additional biological markers may include trisomy 2, 8, 18, 20, and
translocation of the NOTCH2 gene on chromosome 1q12-21.61
Up-regulation of insulin-like growth factor 2 may be mediated
by overexpression of PLGA1 oncogene, a transcriptional activator on the 8q chromosome.74
One of the most provocative genetic findings has been the
association between HB and mutations of beta-catenin and
activation of the WNT/beta-catenin signaling.7577 Microarray
analysis of WNT/beta-catenin and MYC signaling has defined
two tumor subclasses resembling distinct phases of liver
development and characterized by a discriminating 16-gene
signature. The highly proliferating tumor subclass showed
gains of chromosome 8q and 2p and up-regulated MYC signaling.78,79 Histologic subtypes of hepatoblastoma have also
468
PART III
TABLE 33-3
Genetic Syndromes Associated with Pediatric Liver Tumors
Disease
Tumor
Chromosome
Gene
Reference
Familial adenomatous
polyposis (FAP)
Beckwith-Wiedemann
syndrome (BWS)
Li-Fraumeni syndrome
5q21.22
APC
11p15.5
17p13
TP53, others
Trisomy 18
HB, undifferentiated
sarcoma
HB
Thomas 200354
Hirschman 200555
Steenman 200056
Fukuzawa 200357
Fraumeni 196958
18
Other trisomies
Glycogen storage disease type I-IV
Hereditary tyrosinemia
HB
HB, HCC, adenoma
HCC
2, 8, 20
Several
15q23-25
Alagille syndrome
Progressive familial intrahepatic
cholestasis (PFIC)
Neurofibromatosis
HCC
HCC
20p12
18q21-22, 2q24
Fumarylaceto-acetate
hydrolase
JAG1
F1C1, BSEP
HCC, schwannoma,
angiosarcoma
HCC
17q11.2
NF-1
Kanai 199566
11q22-23
ATM
Geoffroy-Perez67
HCC, adenoma
FAA, FAC
Touraine 199368
Ataxia telangiectasia
Hepatocellular carcinoma
Fanconi anemia
Bove 199659
Maruyama 200160
Tomlinson 200661
Siciliano 200062
Demers 200363
Keefe 199364
Alonso 199465
TABLE 33-4
Classification of Hepatoblastoma Histologic Subtype*
Hepatoblastoma, Wholly Epithelial Type
Fetal
Embryonal/mixed fetal and embryonal
Macrotrabecular (MT)
Small cell undifferentiated (SCU; formerly anaplastic)
Hepatoblastoma Mixed Epithelial and Mesenchymal Type (HB-MEM)
Without teratoid features
With teratoid features
Hepatoblastoma, Not Otherwise Specified (HB-NOS)
*This is the classification used by the SIOPEL (International Society of Pediatric
Oncology [epithelial] liver tumor study group). Classification systems used
by American, German, and Japanese study groups vary.
CHAPTER 33
Right
posterior
section
(VI and VII)
469
Right
anterior
Left medial Left lateral
section
section
section
(V and VIII)
(IV)
(II and II)
VIII
IV
VII
II
I
III
Risk Group stratification determines treatment for hepatoblastoma (HB) in current multicenter group trials. As shown
in Table 33-5, The Childrens Oncology Group (COG) has
low, intermediate, and high-risk treatment groups, whereas
SIOPEL defines a standard-risk and a high-risk group. COG
continues to use traditional COG (Evans) stage I to IV, and
prognostic factors (pure fetal and small cell undifferentiated
histology and AFP < 100) to assign risk groups. Although
COG does not currently use PRETEXT to assign risk group,
it does use PRETEXT to define surgical guidelines, where it
determines whether or not a tumor should be resected at
diagnosis. The timing of resection will determine the tumor
stage for all nonmetastatic tumors. In contrast, SIOPEL uses
PRETEXT and prognostic factors to define risk groups.
PRETEXT (see Fig. 33-3) was devised by SIOPEL 1.93 Subsequent SIOPEL trials (SIOPEL 2, and SIOPEL 3) have used
PRETEXT as a tool to stratify treatment, define risk categories,
and report outcomes in HB. Although the risk stratification
schema differs somewhat between groups, the three other major multicenter pediatric liver tumor study groups, Childrens
Oncology Group (COG), German Pediatric Oncology Hematology (GPOH), and the Japanese Pediatric Liver Tumor (JPLT)
have all chosen to adopt PRETEXT in their current and future
protocols. Although PRETEXT has been found to have a slight
tendency to overstage patients, it is postulated to show good
interobserver agreement (reproducibility.) PRETEXT may also
be used to monitor the effect of preoperative therapy when it is
applied serially to assess tumor response to neoadjuvant
chemotherapy.28 In North America, COG uses PRETEXT to
define surgical resectability (i.e., surgical resection guidelines)
V
VI
Umbilical fissure/ligamentum teres
Right hepatic vein
TABLE 33-5
Hepatoblastoma Staging and Risk Stratification
Traditional COG (Evans) Staging System
*COG surgical guidelines recommend resection of tumors at diagnosis (stage I/II) based upon PRETEXT. PRETEXT I and PRETEXT II resected at diagnosis if there is an
anticipated greater than 1-cm surgical margin based upon preoperative imaging.
AFP, alpha-fetoprotein; COG, Childrens Oncology Group; PRETEXT, pretreatment extent (of tumor) staging system; SCU, small cell undifferentiated; SIOPEL,
International Society of Pediatric Oncology (epithelial) liver tumor study group.
470
PART III
+V
+V
FIGURE 33-5 Examples of PRETEXT for hepatoblastoma risk stratification. A, PRETEXT I, left lateral section. B, PRETEXT II, right anterior and right posterior
sections. C, PRETEXT III, V: left lateral section, left medial section, and right anterior section with invasion of all three hepatic veins (V). D, PRETEXT IV, V,
P: tumor involves all four sections and invades vena cava and portal bifurcation.
chemotherapy not only makes the tumor smaller and consequently more likely to be completely resected, but also more
solid, less prone to bleeding, and better demarcated from the
remaining healthy liver parenchyma.101,102 Also, when chemotherapy is given as soon as possible after diagnosis, occult
(micro)metastases in the lung have no delay in treatment. No
matter how small the primary tumor, SIOPEL recommends
preoperative chemotherapy in ALL patients as shown in
Figure 33-6. This approach is hypothesized to increase the
number of patients for whom complete surgical resection will
be feasible, to reduce the surgical morbidity of resection, and to
provide more time for making definitive surgical plans, including liver transplantation when indicated.103,104 Because of
the large number of countries participating in the SIOPEL
studies, standardization of both sophisticated surgical approaches and supportive care measures has been difficult;
therefore the use of preoperative chemotherapy in every case
has permitted patients from countries with limited resources
to participate in these studies.
In contrast to the SIOPEL approach, the North American
legacy groups Childrens Cancer Group (CCG) and Pediatric
Oncology Group (POG) (now COG) and the German Study
Group (GPOH) have historically recommended primary surgery, whenever prudently possible, as the initial treatment. The
decision about which tumors are resectable, and which ones
are not, has been subjectively made by the treating surgeon;
hence, the approach has been criticized for being highly
variable. Because traditional Evans staging relies on the surgical resection decision at diagnosis (see Table 33-5), and
because this is a surgeon-initiated subjective decision, the
stage has often depended more on the surgeon than on the
tumor. Figure 33-6 shows the North American strategy in
COG study AHEP0731, which recommends tumor resection
CHAPTER 33
471
Benign
Treatment based
on tumor type
No,
Biopsy
Neoadjuvant
chemotherapy
+ V,P,E,M
Resection
(Transplant POSTTEXT III+V+PM
or POSTTEXT IVM)
Metastatic
workup
Adjuvant
chemotherapy
+ V,P,E,M
Hepatoblastoma (HB)
Hepatocellular carcinoma (HCC)
PRETEXT
I or II
(COG)
Resection
at diagnosis
POSTTEXT II, III
Resection
PRETEXT
III, IV, or
(COG)
Neoadjuvant
chemotherapy
PRETEXT
I, II, III, IV
(SIOPEL/GPOH)
Neoadjuvant
chemotherapy
POSTTEXT III+V+PM
POSTTEXT IVM
Transplant
POSTTEXT I, II, III
Resection
POSTTEXT III+V+PM
POSTTEXT IVM
Transplant
472
PART III
FIGURE 33-7 Central PRETEXT IIId hepatoblastoma: resection with mesohepatectomy versus complete hepatectomy and transplantation, depends upon
extent of macroscopic vessel involvement. A, Central hepatoblastoma involving left medial and right anterior sections (PRETEXT IIId). B, Resection with right
or left trisegmentectomy would leave very little residual normal liver. C, Much of the normal liver can be saved by mesohepatectomy if the portal vessels
are not encased and a good margin can be obtained. If tumor encases or invades the portal vessels, complete hepatectomy and transplantation is recommended. D, Frozen section shows negative margins.
CHAPTER 33
473
TABLE 33-6
Summary Results Recent Hepatoblastoma Cooperative Trials
Study
Chemotherapy
No. of Patients
Outcomes
INT0098 (CCSG,
POG)96
Stage I/II: 50
Stage III: 83
Stage IV: 40
P9645 (COG)97
HB94 (GPOH)31
SIOPEL 295
SR: PLADO
HR: CDDP/CARBO/DOXO
SIOPEL 37,99
JPLT-1100
4-Year EFS/OS
Stage I/II: 88%/100% vs. 96%/96%
Stage III: 60%/68% vs. 68%/71%
Stage IV: 14%/33% vs. 37%/42%
1-Year EFS*
Stage III/IV C5V: 51%; CDDP/CARBO: 37%
*Study closed early due to inferior results
CDDP/CARBO arm
4-Year EFS/OS
Stage I: 89%/96%; II: 100%/100%; III: 68%/76%;
IV: 21%/36%
3-Year EFS/OS
SR: 90%/88%
HR: 52%/55%
3-Year EFS/OS
SR: 73%/91%
HR: IV: 48%/61%
HR mets: 36%/44%
3-Year EFS/OS
SR: CDDP 83%/95%; PLADO 85%/93%
HR: overall 65%/69%; mets 57%/63%
5-Year EFS/OS
Stage I: ?/100%; II: ?/76%; IIa: ?/50%; IIIb:
?/64%; IV: ?/77%
HB99 (GPOH)98
SR: 58
HR: 42
C5V, cisplatin; CARBO, carboplatin; fluorouracil and vincristine; CCSG, Childrens Cancer Study Group; CDDP, cisplatin; COG, Childrens Oncology Group; DOXO,
doxorubicin; EFS, event-free survival; GPOH, German Pediatric Oncology Hematology; JPLT, Japanese Pediatric Liver Tumor (study); IFOS, ifosfamide; HR, high
risk; IPA, ifosfamide, cisplatin, Adriamycin; mets, metastatic disease; OS, overall survival; POG, Pediatric Oncology Group; PRETEXT, pretreatment extent (of tumor)
staging system; SIOPEL, International Society of Pediatric Oncology (epithelial) liver tumor study group; SR, standard risk; SUPERPLADO, CDDP/CARBO/DOXO;
THPA, THP-adriamycin; VP, etoposide; VPE mets, Vena Cava, Portal vein, Extrahepatic metastatic disease.
474
PART III
TABLE 33-7
Contemporary Outcomes Transplantation for Hepatoblastoma
114
No. of Patients
Survival (%)
Follow-up (years)
8
12
12
9
13
4
7
75
83
83
55
85
75
57
0.1-15.4
0.1-9.2
0.5-16
0.1-9
1.1-2
0.2-9
106
41
9
10
14
7
11
135
8
15
25
14
6
82
30
80
70
71
85
82
69
75
86
78
71
66
3.7-18
3.5 ?
0.6-18
1-14
0.6-4.4
3.3 3.5
0.9-14.9
3.8 ?
SIOPEL, International Society of Pediatric Oncology (epithelial) liver tumor study group; UNOS, United Network for Organ Sharing.
FIGURE 33-8 PRETEXT IV multifocal hepatoblastoma. In the presence of extensive multifocal tumors, microscopic satellites should be assumed, and no
distance of surgical margin can ensure complete surgical excision. Extensive multifocal tumors are best treated by complete hepatectomy and liver
transplantation.
results from rescue transplantation.116,120,124,126,129 In a recent series from Padova, predictors of failed conservative therapy included multifocality.132
Major Venous Involvement: Transplantation versus
Extreme Resection Aggressive resections, less than total
hepatectomy, may be successful in select patients with tumor
encroachment on the vena cava or main portal vein. Complex
extensive resection, with vascular reconstruction if necessary,
depends upon surgical expertise and a careful evaluation of
the degree of vascular involvement and realistic ability to
achieve complete, and safe, resection.133,134 Poorly planned
or executed operations risk excessive bleeding, inflow or outflow vascular obstruction, biliary leakage or stricture, cholangitis, and/or hepatic failure. Although most agree that extreme
resection of tumors without liver transplantation will avoid the
need for long-term immunosuppression,102,113,132,133,135137
outcomes with these techniques have not been rigorously
reported. Current recommendations for referral of high-risk
CHAPTER 33
475
TABLE 33-8
Liver Transplantation in Children with Hepatoblastoma and Pulmonary Metastasis at Diagnosis, Review of Literature (Meyers and Otte,9 2010)
Pulmonary Metastasis at
Diagnosis
Lung lesions disappeared
with chemotherapy
Pretransplantation
pulmonary metastasectomy
TOTAL
No. of
Patients
Post-transplantation
Pulmonary Relapse
Alive without
Evidence of Tumor
Died of
Other Causes
24
9 (38%)
14 (58%)
1 (4%)
3 (38%)
5 (62%)
32
12 (37%)
19 (60%)
1 (3%)
*Patients listed in table have been separately reported in the following series during the past 10 years: Perilongo, 200495; Casanova, 200999; Schnater, 2002101; AlQabandi et al, 1999114; Reyes et al, 2000115; Avila et al, 2006124; Cassas-Medley, 2007126; Superina et al, 1996139; Nathan 2009140; Otte, 2009.141
476
PART III
HEPATOCELLULAR CARCINOMA
Epidemiology, Biology, and Genetics
In Western countries, hepatocellular carcinoma occurs approximately half as often as hepatoblastoma (HB) or in 23% of all
primary pediatric liver tumor cases, most often in school-age
children and adolescents. Although described previously, it
was not until 1967 that childhood HCC was identified by Ishak
and Glunz3 as an entity to be distinguished from HB. In 1974,
Exelby and colleagues5 analyzed the clinical course of childhood HCC and found an overall dismal outcome.
HCC occurs predominantly in the setting of underlying liver
disease and cirrhosis. Compared with adults, in children cirrhosis is less commonly part of the antecedent process, while congenital or acquired disorders of the liver, such as metabolic
disease, are common.17 Table 33-9 shows the conditions that
are associated with HCC in children.43,66,160175 Patients with
tyrosinemia seem to be a particularly high risk and should be
vigilantly screened with serial AFP and imaging.174 In East Asia
and Africa, HCC is more common than HB because of the widespread prevalence of hepatitis B and C.43 In Taiwan, where HCC
is most often seen in carriers of the hepatitis B virus, vaccination
TABLE 33-9
Conditions Associated with Hepatocellular Carcinoma
in Children
Alpha-1 antitrypsin deficiency160
Anomalous abdominal venous drainage161
Alagille syndrome162
Biliary atresia163
Congenital hepatic fibrosis164
Familial polyposis/Gardner syndrome165
Focal nodular hyperplasia166
Hemochromatosis167
Hepatic adenoma168
Hepatitis B and C43
Glycogen storage disease (type I and III)169
Methotrexate therapy166
Neurofibromatosis66
Oral contraceptives170
Parenteral nutritionassociated liver disease (PNALD); total parenteral
nutrition (TPN) cholestatic liver failure171
Progressive familial intrahepatic cholestasis (PFIC)172,173
Tyrosinemia174
Wilms tumor/Bloom syndrome175
CHAPTER 33
477
478
PART III
TABLE 33-10
Summary Results Hepatocellular Carcinoma Cooperative Trials
Study
Chemotherapy
No. of Patients
Outcomes
CDDP/DOXO
HB89 (GPOH)26
CDDP/DOXO
HB94 (GPOH)26
CDDP/DOXO
HB99 (GPOH)26
CDDP/DOXO
SIOPEL 1182
CDDP/DOXO
Stage I: 8
Stage II: 0
Stage III: 25
Stage IV: 13
Stage I/II/IIIa: 6
Stage IIIb, IV: 6
Stage: I/II/IIIa: 5
Stage IIIb, IV: 20
Stage: I/II/IIIa: 14
Stage IIIb, IV: 27
PRETEXT: I, 1; II, 14; III, 11; IV, 13, VPEM, 8
SIOPEL 2182
CDDP/DOXO
SIOPEL 3183
CDDP/DOXO
5-Year EFS/OS
Stage I/II: 88%/88%;
III: 8%/23%;
IV: 19%/34%
5-Year DFS
Stage I/II/IIIa: 50%; IIIb, IV: 17%
5-Year DFS
Stage I/II/IIIa: 60%; IIIb, IV: 25%
5-Year DFS
Stage I/II/IIIa: 71%; IIIb, IV: 15%
5-Year EFS/OS
17%/28%
5-Year EFS/OS
23%/23%
3-Year EFS/OS 10%/16%
181
CARBO, carboplatin; CCSG, Childrens Cancer Study Group; CDDP, cisplatin; DFS, disease-free survival; DOXO, doxorubicin; EFS, event-free survival; GPOH, German
Pediatric Oncology Hematology (study); IFOS, ifosfamide; IPA, ifosfamide, cisplatin, Adriamycin; OS, overall survival; POG, Pediatric Oncology Group; PRETEXT,
pretreatment extent (of tumor) staging system; SIOPEL, International Society of Pediatric Oncology (epithelial) liver tumor study group; VP, etoposide; VPEM,
Vena cava, Portal vein, Extrahepatic, Metastatic disease.
CHAPTER 33
479
TABLE 33-11
Literature, Transplantation for Pediatric Hepatocellular Carcinoma
No. of
Patients
{Olthoff et al, 1990, Arch Surg, UCLA
{Penn et al, 1991, Surgery, Transplant Registry187
Tagge et al, 1992, J Pediatr Surg, Pittsburgh, Pa188
Yandza et al, 1993, Transplant Int, Paris189
Broughan et al, 1994, J Pediatr Surg, multicenter190
Otte et al, 1996, Transplant Proc, Brussels191
Achilleos, et al 1996, J Pediatr Surg, Birmingham, UK192
Superina et al, 1996, J Pediatr Surg, Toronto139
Reyes et al, 2000, J Pediatr, Pittsburgh, Pa115
Tatekawa et al, 2001, J Pediatr Surg, Kyoto193
Czaudema et al, 2002, J Clin Oncol, SIOPEL 1182
Avila et al, 2006, Eur J Ped Surg, Madrid124
Austin et al, 2006, J Pediatr Surg, UNOS database125
Beaunoyer et al, 2007, Pediatr Transplant, Stanford,
Calif127
Kalicinski et al, 2008, Ann Transplant, Warsaw130
Ismail et al, 2009, Pediatr Transplant, Warsaw194
186
Survival (%)
Tumor Recurrence
Small Incidental*{
10
22
44
100
75
60
0
100
63
100
100
41
83
8/16
158/429
3/9
2/5
0/3
6/19
0
63%
1/10
31/429
0
0
3/3
7/19
12/41
4/10
4/16
1/9
0
0
0
2/12
0
2/10
8
11
75
72
1/8
1/11
3/11
1/8
2/11
16
429
9
2
4
5
2
3
19
2
2
1
*Most are patients with tyrosinemia, other metabolic liver disease, familial intrahepatic cholestasis, hepatitis, or biliary atresia.
{
Died as a result of complications of orthoptic liver transplantation.
{
Did not separately analyze pediatric cohort.
Comp, complications; OLT, orthotopic liver transplantation; SIOPEL, International Society of Pediatric Oncology (epithelial) liver tumor study group; UCLA,
University of CaliforniaLos Angeles; UNOS, United Network for Organ Sharing.
three foci of tumor, each one not exceeding 3 cm; (3) no angioinvasion; (4) no extrahepatic involvement. Since the introduction
of these criteria, long-term recurrence-free survival after liver
transplantation in adults with HCC improved from 30% to
75%.195198 The problem with the Milan criteria in children
is that 50% to 70% of children present with large de novo
tumors and a large tumor burden in otherwise healthy livers,
and the Milan criteria were developed in adults with small tumors
and underlying cirrhotic liver disease. In children, the number
of nodules, as stipulated by the Milan criteria, is usually not
considered a contraindication to transplantation as long as
the disease is confined to the liver. Furthermore, de novo pediatric HCC often shows features on a continuum with pediatric
HB, and these transitional liver tumors may have a more favorable biology.92200 In view of the lack of improvement in results
of conventional treatment of pediatric HCC during the past 2
decades, most clinicians treating pediatric HCC do NOT
recommend adherence to Milan criteria in children who present
with large de novo tumors, no cirrhosis, and no evidence of
extrahepatic disease.201
Metastatic Disease Metastatic disease is considered an
absolute contraindication to liver transplantation in HCC,
and a very careful and thorough evaluation to exclude metastatic microdeposits is essential.
Post-transplantation Chemotherapy Guidelines for posttransplantation immunosuppression in HCC are the same as
with transplantation for HB with one possible difference.
Many centers would consider post-transplantation adjuvant
antiangiogenic therapy with sorafenib in HCC. Experience
in the transplantation population of patients is limited, but
in any patient considered to be at high risk for tumor relapse,
options for possible antiangiogenic therapy should be
480
PART III
Rhabdoid Tumor
Although pediatric rhabdoid tumors are most common in the
kidney and brain, they do occur at other sites, including the
mediastinum and liver. When primary to the liver, rhabdoid
tumor is difficult to distinguish from the small cell undifferentiated (SCU) variant of hepatoblastoma. Given the aggressive
biological behavior and poor prognosis seen with the SCU variant of HB, it has been suggested that some tumors previously
classified as HB-SCU may actually have been hepatic rhabdoid
tumors. The differentiation of an HB-SCU from a rhabdoid
tumor is challenging and is important in terms of research,
but possibly clinically irrelevant at present because both are
biologically aggressive with poor response to chemotherapy.
Malignant rhabdoid tumor of the liver is a rare and aggressive
tumor of toddlers and school-age children that may present
with spontaneous rupture.216,217 These rare tumors are often
chemoresistant and fatal,216 although a recent case report
documents the potential for cure with multimodal therapy,
including ifosfamide, vincristine, and actinomycin D.217 As
with all locally aggressive liver tumors that respond poorly
to chemotherapy, the most important treatment goal is
complete surgical excision.
Undifferentiated Sarcomas
Undifferentiated (embryonal) sarcoma of the liver is a rare
childhood hepatic tumor that has historically been considered
an aggressive neoplasm with an unfavorable prognosis. These
tumors may arise in a solitary liver cyst.218 Survival has
improved in recent multimodal approaches, designed for
patients with soft tissue sarcomas at other sites, including
conservative surgery at diagnosis, multiagent chemotherapy,
and second-look operation in cases of residual disease. Using
these techniques several small series have reported survival in
up to 70% of children.219221
Angiosarcoma
Primary hepatic sarcomas are rare. Outcome depends primarily on tumor histology, sensitivity to chemotherapy and/
or radiotherapy, and the ability to achieve complete tumor
resection.215
Biliary Rhabdomyosarcoma
Hepatic Sarcomas
CHAPTER 33
481
antibodies to thyroid-stimulating hormone (TSH), and screening to rule out secondary hypothyroidism is recommended.232,233 Most recently, propranolol has been shown
to inhibit the growth of infantile hemangioma.234 Although
rare, malignant transformation to angiosarcoma has been
reported, and close follow-up is recommended.223,224,235,236
In infants who fail medical management, symptomatic
solitary tumors may be treated by excision, hepatic arterial
ligation, or selective angiographic embolization.237 Treatment
algorithms may stratify treatment based upon whether or
not the tumor is solitary, multifocal, or diffuse.238,239 About
65% of tumors are solitary or unifocal with a survival of
86% and death usually not caused by the tumor but by a
comorbidity.19 Thirty-five percent of tumors are multifocal
or diffuse, with a survival somewhere between 60% to
100%, with death usually secondary to cardiorespiratory
compromise caused by tumors refractory to medical and
interventional management.19,237,238
Metastatic and Other Liver Tumors
Metastatic Liver Tumors Unlike the large body of literature
concerning liver resection for metastatic colorectal tumors in
adults, there is little published data that addresses the treatment of metastatic tumors in the liver following from abdominal solid tumors in childhood. A recent series from a large
metropolitan childrens cancer center reported only 15 such
patients during a 17-year period, including neuroblastoma
(7), Wilms tumor (3), osteogenic sarcoma (2), gastric epithelial (1), and desmoplastic small round cell tumor (2).240
Eleven of the 15 patients died of progressive disease; 4 had
a local recurrence. These results lead the authors to conclude
that the overall prognosis in these patients remains poor, and
the decision to perform hepatic metastasectomy should be
made with caution. The treatment approach should not, however, be uniformly nihilistic, because not all liver lesions in
children with abdominal solid tumors turn out to be metastatic disease. Both nodular regenerative hyperplasia and focal
nodular hyperplasia have been reported to mimic hepatic metastasis in children241; definitive diagnosis requires biopsy
and/or resection.
Occasionally, a pancreatoblastoma may present with extensive hepatic metastasis (Fig. 33-10). Despite the alarming radiographic appearance at diagnosis, this tumor was, in fact,
FIGURE 33-9 Symptomatic multifocal/diffuse infantile hepatic hemangioma. These tumors are benign but occasionally will be refractory to aggressive
attempts at medical and percutaneous management. This tumor showed progressive growth despite chemotherapy and percutaneous embolization of
largest nodules. The baby developed abdominal compartment syndrome and vena cava obstruction. Treated with temporizing abdominal decompressive
laparotomy and, definitively, with hepatectomy and live-donor liver transplantation.
482
PART III
FIGURE 33-10 Metastatic pancreatoblastoma. A, Infant with extensive metastatic tumor in the liver at diagnosis. B and C, Appearance at laparoscopic
biopsy. Primary tumor is a pancreatoblastoma involving the body of the pancreas. Although the tumor metastases were extensive at diagnosis, they prove
to be exquisitely chemosensitive with cisplatin/doxorubicin chemotherapy.
exquisitely chemosensitive, and the child did well after neoadjuvant chemotherapy, subtotal pancreatectomy, hepatectomy,
and live-donor liver transplantation. Pancreatoblastomas are
treated with multiagent chemotherapy analogous to hepatoblastoma and have a fair prognosis if chemosensitive.
Liver Tumors as Secondary Malignancies
We recently saw a case of multiple lesions of focal nodular
hyperplasia in the liver of a 10-year-old boy 9 years after treatment for stage IV neuroblastoma with double autologous stem
cell transplantations. Given the history, we initially suspected
metastatic neuroblastoma, but diagnostic laparoscopy and
laparoscopic biopsy of multiple lesions showed focal nodular
hyperplasia (FNH). Another case report of FNH in a child with
a history of stage IV neuroblastoma showed foci of small cell
undifferentiated hepatoblastoma in the resection specimen;
so, very close follow-up is necessary if treatment of the
FNH is nonoperative.242 Liver tumors have been recognized
as potential late effects and/or secondary malignancies in
children who have previously undergone chemotherapy and
radiation as toddlers.
Hemophagocytic Lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) may occasionally present as an abnormal liver mass in a newborn with
coagulopathy. Predisposing factors include familial, herpes
simplex virus, and severe combined immunodeficiency.243
Diagnostic criteria according to HLH-2004 include fever,
splenomegaly, bicytopenia, hypotriglyceridemia, hypofibrinogenemia, hemophagocytosis, low natural killer (NK) cell
activity, hyperferritinemia, and high interleukin-2 (IL-2)
receptor levels.244 Treatment is with combination chemoimmunotherapy, including etoposide, dexamethasone, cyclo-
CHAPTER 34
Pediatric
Gastrointestinal
Tumors
Joseph T. Murphy and Robert P. Foglia
484
PART III
EPIDEMIOLOGY
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal
tumors whose classification is hindered by anecdotal reports,
failure to distinguish between primary and secondary GISTs,
and the mixing of benign and malignant tumors in the
reports.17 In addition, GISTs arising from various anatomic
sites have been reported together, making prediction of their
clinical behavior difficult.18 The most common site is the
stomach (50% to 70%), followed by the small intestine
(20% to 30%), colon or rectum (10%), and esophagus (5%).19
CLINICAL PRESENTATION
Patients with GIST tumors present with nonspecific symptoms, often generalized abdominal pain, dyspepsia, and occult
GI bleeding. Iron-deficiency anemia should prompt an investigation to exclude a GI tract malignancy as the cause.1 Less
commonly, patients present with a palpable abdominal mass
or intestinal obstruction.20 Standard imaging studies may
assist in the diagnosis (plain radiographs and computed
tomography [CT]). Endoscopy can identify a tumor mass in
the stomach, duodenum, or colon.21
PATHOLOGY
GISTs are classified as mesenchymal tumors of the GI tract
thought to originate from the intestinal cell of Cajal, an
intestinal pacemaker cell.22 Historically, smooth muscle tumors, such as leiomyomas and leiomyosarcomas, and neural
tumors, such as nerve sheath tumors, have been categorized as
GISTs. GISTs are now defined as cellular spindle cell, epithelioid, or occasional pleomorphic mesenchymal tumors that
express the KIT (CD117, stem cell factor receptor) protein,
as detected by immunohistochemistry. Additional cell type
markers, such as CD34, smooth muscle actin, desmin, and
S-100 protein, are also used to establish a diagnosis of
GIST. These histologic and immunohistochemical features
now distinguish GISTs from leiomyomas, leiomyosarcomas,
neural tumors, and other tumors of smooth muscle origin.23
Prognosis relies on traditional pathologic staging criteria, such
as size, extent of tumor invasion into mucosa or surrounding organs, mitotic index, and nuclear pleomorphism. However, no single feature is consistently reliable in predicting
outcome.24
Determining prognosis of pediatric patients with GIST
tumors can be controversial. The usual criteria for assessing
risk of malignancy (i.e., tumor size, mitotic activity, anatomic
location) are not reliable in pediatric GIST. Children frequently present with multiple gastric nodules, making identification of a dominant mass difficult. Secondly, there exists a
wide variation in proliferation index between patients and
even among multiple tumors within the same patient. Furthermore, some pediatric patients develop GIST metastasis despite
being classified as low risk by adult criteria, and others with
low proliferation indices develop recurrent disease in perigastric nodal basins, the peritoneum, or liver.25 Pediatric GIST
is distinguished as a separate clinical, pathologic, and molecular subset with a predisposition for females, multifocal gastric tumors, and wild-type KIT/PDGRA genotype. This is in
ASSOCIATED CONDITIONS
The Carney triad consists of a gastric leiomyosarcoma, functioning extraadrenal paraganglioma, and pulmonary chondroma. The gastric stromal tumors are usually located along
the lesser curve or antrum and produce few symptoms; however, continued growth leading to mucosal ulceration, GI
bleeding, and serosal involvement is common. Despite the
possible development of additional gastric tumors in the
remaining stomach, if feasible, partial gastrectomy is recommended as the initial operation, to avoid the complications
of more extensive gastric resection, particularly in teenaged
patients. Because the multifocal nature of the tumor can lead
to local recurrence, regular follow-up is mandatory to assess
for new gastric tumors. Adjuvant therapy has been unsuccessful in treating metastatic disease. Evaluation for adrenal tumors in patients with gastric stromal sarcomas and
pulmonary chondromas should be considered, and a family
history should be obtained from patients with the Carney
triad. Recently, an autosomal dominant inheritance of paragangliomas and gastric GIST, called the Carney-Stratakis syndrome, has been identified, representing a separate condition
affecting both males and females. Succinate dehydrogenase
subunit gene mutations, typically associated with familial
paragangliomas, have been implicated in the pathogenesis
of Carney-Stratakis syndrome.2730
An uncommon, histologically distinct subset of GIST,
called a GI autonomic nerve tumor (GANT), has been described in children. Pediatric GANTs have a female prevalence
and symptoms that may include anemia, abdominal pain, fullness, emesis, and a palpable abdominal mass. Although adult
GANTs are found predominantly in the small intestine, pediatric GANT lesions are primarily gastric tumors. The majority
of pediatric patients have localized disease at the time of diagnosis. Younger age, localized disease, gastric location, and
small tumor size at diagnosis are associated with favorable
prognosis. Immunocytochemical and ultrastructural evaluation is required to differentiate these tumors from GIST. Established pathologic criteria for malignancy are not well defined
for the pediatric GANT because of the low incidence of these
tumors. Surgical resection of the tumor is the treatment of
choice, because there appears to be no definite role for chemotherapy or radiation.10
TREATMENT
Complete surgical excision of GISTs, along with the pseudocapsule, is the treatment of choice. Achieving negative pathologic
margins is frequently possible, because GISTs tend to hang from
and do not diffusely infiltrate the structure from which they
arise. Consequently, wedge resection of the stomach or segmental resection of the intestine provides adequate therapy; wide
resection is not necessary.17 In addition, because the status of
microscopic margins does not appear to be important for survival, vital structures should not be sacrificed if gross tumor
clearance has been attained. GIST rarely metastasizes to lymph
nodes; so, lymphadenectomy is seldom warranted.19
CHAPTER 34
SURVIVAL
The long-term survival following surgical resection of pediatric GIST is difficult to determine, because most reports contain
small numbers of children or include adults. Moreover, given
recent changes in the recognition and pathologic identification of these tumors, many older series contain tumors that
are actually not GISTs. Factors associated with long-term
survival following surgical resection include small tumor size,
low mitotic index, genotype, and gastric primary location.20
Pediatric GISTs present with a higher incidence of metastasis
than comparable adult gastric tumors. However, the biology of
pediatric lesions appears more indolent than adult disease
with significant long-term survival, despite the presence of
metastatic disease and with or without effective adjuvant
chemotherapy.25
Intestinal Tumors
------------------------------------------------------------------------------------------------------------------------------------------------
MYOFIBROMATOSIS
Infantile myofibromatosis is a mesenchymal tumor that can
arise in the skin, muscle, bone, subcutaneous tissue, or
viscera. It is the most common fibrous tumor of infancy. Myofibromatosis presents with either solitary or generalized
lesions, with or without visceral involvement. Most lesions
spontaneously regress; however, extensive intestinal myofibromatosis is associated with significant morbidity and
mortality.37,38 Various chemotherapeutic interventions have
485
LYMPHOMA
Lymphoma is the most common small bowel malignancy in
children, with high-grade non-Hodgkin lymphoma comprising 74% of these tumors. Burkitt lymphoma constitutes the
most common histologic subtype. The majority of patients
(50% to 93%) present with lymphoma localized to the distal
small bowel, although tumor may occur anywhere from the
stomach to the rectum.41
Patients may present with chronic GI distress, occult blood
per rectum, hematochezia, and/or an abdominal mass. An
acute worsening of symptoms may result in emergency
surgery for treatment of ileocolic intussusception, with lymphoma creating the lead point (46%), acute appendicitis
(22%), perforation (11%), or obstruction (8%). Higher mortality is associated with advanced disease stage, intestinal
perforation, high-grade histology, and T-cell lymphomas.42
Surgical management depends on disease presentation, as
well as extent of disease at presentation. Bulky disease is
usually not completely resectable. Extensive resection of bulky
retroperitoneal or mesenteric disease does not enhance survival; nevertheless, complete surgical resection (including
bowel resection), if possible, significantly enhances the prognosis of patients with intestinal lymphoma, especially when
included in a multimodality treatment approach. Tumor
downstaging by complete resection allows for decreased
duration and intensity of post-operative chemotherapy. When
operating for a complication of intraperitoneal disease, the
extent of the procedure should be limited to resolution of
the complication and resection of sufficient tissue to ensure
an accurate diagnosis. If limited disease is encountered, complete resection and an evaluation of mesenteric, perihepatic,
and periaortic nodes should be undertaken to assess for
regional metastatic spread. Two-year cumulative survival for
intestinal B-cell lymphoma is 94% and 28% for intestinal
T-cell lymphoma. The overall 5- and 10-year survival rates
for all intestinal lymphoma patients treated with multimodality therapy (surgery, radiation, chemotherapy) are 52% and
44%, respectively. The corresponding disease-free survival
rates are 43% and 38%, respectively.4348
Carcinoid Tumors
------------------------------------------------------------------------------------------------------------------------------------------------
EPIDEMIOLOGY
Carcinoid tumors originate from neuroendocrine cells within
the GI tract. These neoplasms derive from GI epithelial and
subepithelial endocrine progenitor cells that function as part
of the amine precursor uptake and decarboxylation (APUD)
system.49 Carcinoids can also be found in the lungs, mediastinum, thymus, liver, pancreas, bronchus, ovaries, prostate,
testes, and kidneys.50 Pediatric carcinoid tumors typically
occur in the GI tractstomach, small intestine, appendix
(most common), and rectum. Carcinoid tumors of the appendix occur with an estimated incidence of 1 case per million
children per year, with a slight female predominance.5153
486
PART III
DIAGNOSIS
Carcinoid tumors are classified according to the location of
origin in the primitive gut (foregut, midgut, and hindgut).
Foregut tumors include carcinoids of the lung, bronchus,
stomach, proximal duodenum, and pancreas. Midgut tumors
arise from the distal duodenum, jejunum, ileum, and right
colon, including the appendix. These account for 60% to
80% of all carcinoids in adults and children.5456 Hindgut
tumors arise in the transverse and distal colon and rectum.
Tumors can also arise from a Meckel diverticulum, enteric
duplications, and the mesentery. Appendiceal carcinoids are
the most common, with more than 70% of these tumors
developing at the appendiceal tip. Pediatric carcinoid tumors
are often discovered incidentally during an operation for presumed appendicitis or another unrelated diagnosis. Although
clinical signs of acute appendicitis or gynecologic pathology
may prompt exploration, true inflammatory changes of acute
appendicitis are not often induced by the carcinoid, possibly
because of the distal location of the tumor and absence of
proximal luminal obstruction.51,53,55
The most serious complication of carcinoid tumors is a carcinoid crisis, which is most often associated with foregut tumors,
larger tumors, and high serum/urine 5-hydroxyindoleacetic
acid (5-HIAA) levels. Although pediatric carcinoids vary in
size, carcinoid syndrome (flushing, diarrhea, abdominal
pain, tachycardia, hypertension, hypotension, altered mental
status, and coma) has not been typically associated with tumors
confined to the appendix.53,54 In contrast, pediatric patients
with extra-appendiceal carcinoid tumors, such as in the
lung or liver, are often symptomatic. Biologically active
amines (serotonin, catecholamines, histamine) and metabolites
(5-HIAA) are characteristically elevated in the plasma and urine
of patients with symptomatic carcinoid tumors.57 Patients with
extra-appendiceal carcinoids frequently present with disseminated disease at the time of diagnosis and have a higher
incidence of recurrent tumor following the initial diagnosis
and resection.58
TREATMENT
Tumor size at presentation dictates surgical decision making
for carcinoid tumors of the appendix. For appendiceal carcinoid
tumors less than 2 cm in diameter, surgical resection of the
appendix and mesoappendix is considered curative. Long-term
follow-up demonstrates minimal disease recurrence and a rare
likelihood of metastatic disease.51,52,58,59 Carcinoid tumors
greater than 2 cm, those with cecal involvement, lymphatic
invasion, lymph node involvement, mesoappendix infiltration,
positive resection margins, goblet cell malignancy, or cellular
pleomorphism with a high mitotic index require a more
extensive resection (i.e., a right hemicolectomy with associated
resection of the mesocolon).55,60,61
SURVIVAL
Complete resection of localized appendiceal carcinoid tumors
can result in cure, with greater than a 90% survival rate.
Diminished disease-free and overall survival is associated with
carcinoids larger than 2 cm, older age, positive lymph nodes,
extra-appendiceal spread, distant metastatic disease, and
tumors with atypical histologic features.62
Colorectal Adenocarcinoma
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 34
These patients and their families require long-term endoscopic surveillance (semiannual panendoscopy) with subsequent total abdominal colectomy if mucosal dysplasia,
persistent bleeding, or rapid increase in polyp number is
detected. Depending on individual circumstance, there also
appears to be a role for prophylactic total colectomy and rectal
mucosectomy with an endorectal pull-through procedure.
Diffuse juvenile polyposis of infancy is a nearly universally
fatal disease typically diagnosed within the first few months
of life. Patients present with diarrhea, lower GI bleeding, intussusception, prolapse, obstruction, protein-wasting enteropathy, macrocephaly, and hypotonia. Despite involvement
of the entire GI tract, bowel rest and total parenteral nutrition
(TPN) permit selective surgical resection. However, survival
beyond 2 years of age is rare.
Diffuse juvenile polyposis presents with hematochezia, abdominal pain, and prolapse from hamartomatous polyps in
the colon and rectum in infancy to 5 years of age. Although
hamartomas typically do not have premalignant potential,
chronic polyp inflammation is thought to result in reactive
hyperplasia that then progresses to dysplasia or adenomatous
changes.
Several genetic disorders carry significant risk for the
subsequent development of colon carcinoma and are characterized as polyposis syndromes. They include Gardner syndrome (adenomatous polyposis and soft tissue and bone
tumors), Turcot syndrome (familial adenomatous polyps
and central nervous system tumors), and familial polyposis
coli. Both Gardner syndrome and familial polyposis are
autosomal dominant disorders and are associated with adenomatous polyps in the colon and the small intestine. Because
the entire surface of the colon can be carpeted with thousands
of polyps, the ability to carry out effective surveillance and
identify suspicious lesions is low. Recommendations for and
the timing of colon resection are based on the likelihood of
the development of malignancy. There is little question that
colectomy is the appropriate treatment for patients with
familial polyposis coli (familial adenomatous polyposis),
Gardner syndrome, and Turcot syndrome.
Peutz-Jeghers syndrome is defined by polyposis of the intestinal tract and melanotic skin lesions. It is inherited as an
autosomal dominant trait. Germline mutations in LKB1,
STK11, and ENG genes may have a causative role in the pathogenesis of this syndrome.73,74 Despite equal sex distribution,
symptoms appear earlier in males. Brown and black melanotic
spots occur in the rectum, around the mouth, lips, buccal
mucosa, feet, nasal mucosa, and conjunctivae, typically presenting at puberty. Adolescents characteristically complain
of frequent defecation, rectal bleeding, abdominal pain,
vomiting, and may present with anemia or recurrent episodes
of intussusception. Polyps are found in the small intestine
(55%), stomach and duodenum (30%), and the colorectal
bowel (15%). The risk of death because of cancer for those
with Peutz-Jeghers syndrome is 50% by 60 years of age. There
is a 13-fold increased risk of death because of GI cancer and
a 9-fold increased risk for all other malignancies. Rapid
growth, severe dysplasia, villous changes, or larger polyps
(greater than 15 mm) may indicate GI malignancy and necessitate aggressive surgical intervention. However, repeated,
extensive intestinal resections may result in short-bowel syndrome resulting from the multifocal and recurrent nature of
these polyps.
487
Hereditary Associations
------------------------------------------------------------------------------------------------------------------------------------------------
488
PART III
CHAPTER 34
Other Associations
------------------------------------------------------------------------------------------------------------------------------------------------
489
Diagnosis
------------------------------------------------------------------------------------------------------------------------------------------------
490
PART III
Treatment
------------------------------------------------------------------------------------------------------------------------------------------------
Summary
------------------------------------------------------------------------------------------------------------------------------------------------
Rhabdomyosarcoma Patient
Demographics
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 35
Diagnosis and
Treatment of
Rhabdomyosarcoma
Kevin P. Mollen and David A. Rodeberg
Rhabdomyosarcoma Tumor
Biology
------------------------------------------------------------------------------------------------------------------------------------------------
492
PART III
80
IRS-III
5-year survival
70
60
IRS-IV
IRS-II
IRS-I
50
40
Pre30 cooperative
20
10
0
FIGURE 35-1 Improvement in survival for RMS during the past 40 years.
precursor cells, and the TP53 proto-oncogene, which is responsible for tumor suppression.10,11 At the chromosomal level,
ERMS is characterized by a loss of heterozygosity at the
11p15 locus, with a loss of maternal information and duplication of paternal genetic information. Within this locus lies the
insulin growth factor II (IGF-II) gene.1214 Both ERMS and
ARMS overproduce IGF-II, which has been shown to stimulate
RMS tumor growth, suggesting that IGF-II plays a role in unregulated growth of these tumors.15 Although the significance is
unclear, ARMS is frequently tetraploid, whereas ERMS lesions
are generally diploid. Translocations of the FKHR transcription
factor gene from chromosome 13 with either the PAX3 (chromosome 2) or PAX7 (chromosome 1) transcription factor genes
occur frequently in ARMS.1618 In these PAX/FKHR fusions,
the DNA binding domain of PAX is combined with the regulatory domain of FKHR. This results in increased PAX activity
leading to the de-differentiation and proliferation of myogenic
cells. Understanding the role of these fusion proteins in tumor
development may provide insight into treatment strategies and
potential biomarkers for the diagnosis of RMS.8 For example, it
has been demonstrated that approximately 25% of ARMS
tumors are translocation negative. By gene array analysis, these
fusion negative ARMS tumors more closely resemble ERMS
overall and have a similar prognosis to ERMS. It has therefore
been proposed that tumors should be divided into PAX/FKHR
fusionpositive and negative tumors rather than the more
ambiguous alveolar and embryonal histologies.
Although most cases of RMS occur sporadically, the disease
is associated with familial syndromes, including Li-Fraumeni
and neurofibromatosis I. Li-Fraumeni is an autosomal dominant disorder and is usually associated with a germline mutation of TP53. Patients with this syndrome present with RMS
at an early age and have a family history of other carcinomas,
especially premenopausal breast carcinoma.1922 Neurofibromatosis is an autosomal dominant genetic disorder characterized by optic gliomas, cafe-au-lait spots, and neurofibromas.23
The association of RMS with Li-Fraumeni and neurofibromatosis appears to involve malignant transformation through
the inactivation of the TP53 tumor suppressor gene and
hyperactivation of the RAS oncogene.24,25 Nevoid basal cell
carcinoma (Gorlin syndrome) is an autosomal dominant
disorder caused by mutations in the PTCH tumor suppressor
gene mapping to chromosome 9q22.3.26 Animals with
mutations in the PTCH gene have elevated levels of the tumor growthpromoting IGF-II and develop spontaneous
RMS.27,28 The association of mutations in the PTCH gene in
human disease with spontaneous development of RMS is supported by the finding that up to 30% of sporadic cases of
ERMS demonstrate molecular abnormalities at the 9q22.3
Presentation of
Rhabdomyosarcoma
------------------------------------------------------------------------------------------------------------------------------------------------
Preoperative Workup
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 35
Surgical Principles
------------------------------------------------------------------------------------------------------------------------------------------------
BIOPSY
Open biopsy of a mass suspected to be RMS should be
performed to confirm the diagnosis. Care should be taken to
obtain adequate specimens for pathologic, biological, and treatment protocol studies. For small lesions in areas that will
be treated with chemotherapy and radiation or for metastatic
disease, core needle biopsy may be appropriate for diagnosis.44,45 Although less invasive than open biopsy, core needle
biopsy obtains a smaller tissue sample, which increases sampling error and the number of inconclusive findings. This
smaller volume of tissue may prevent the performance of
adequate molecular biology studies. Image guidance with
ultrasonography may increase the accuracy of sampling while
helping to avoid inadvertent puncture of surrounding structures.46 Clinical and radiographic positive lymph nodes should
be confirmed pathologically. Open biopsy is recommended;
however, fine-needle aspiration or core needle biopsy of lymph
nodes may be performed at the discretion of the surgeons
judgment and pathologists recommendations.44,47 Sentinel
Sites
Size
Orbit
Head and neck (excluding
parameningeal)
GU nonbladder/
nonprostate
T1 or T2
a or b
N0 or N1 or Nx
Bladder/prostate,
extremity, cranial
parameningeal, other
(includes trunk,
retroperitoneum, etc.)
T1 or T2
Bladder/prostate,
extremity, cranial
parameningeal, other
(includes trunk,
retroperitoneum, etc.)
T1 or T2
a
b
All
T1 or T2
a or b
Definitions:
Tumor T(site)1
T(site)2
Regional nodes
N0
N1
Nx
Metastasis
M0
M1
493
physical examination and preoperative imaging. Several investigators have validated the modified TNM staging system as a
reliable predictor of patient outcome.43
It is unclear what role FDG PET will have in the clinical evaluation of RMS, although there are several settings in which this
imaging modality may improve our pretreatment staging and
thus alter treatment for patients. FDG PET may enhance the
evaluation of regional adenopathy versus traditional modalities.
Similarly, FDG PET may offer improved detection of occult
metastases, helping to differentiate them from normal structures. Finally, this modality may offer a guide to the diagnosis
and treatment of recurrent disease. The diagnosis of a recurrence in a previously operated field is often difficult to obtain
with conventional imaging methods. FDG PET/CT may offer
an enhanced diagnostic tool and, more important, may offer
tumor viability information which will guide further surgical
therapy. One of the goals of ongoing trials will be to investigate
the role of FDG PET in RMS.
Stage
N0 or NX
N1
N0 or N1 or Nx
N0 or N1
FIGURE 35-2 TNM Pretreatment Staging Classification. Staging before treatment requires thorough clinical, laboratory, and imaging examinations.
Biopsy is required to establish histologic diagnosis. Pretreatment tumor size is determined by external measurement or MRI or CT, depending on anatomic
location. For less accessible primary sites, CT also will be used for lymph node assessment. Metastatic sites will require some form of imaging confirmation
(but not histologic confirmation, except for bone marrow examination). CT, computed tomography; GU, genitourinary; MRI, magnetic resonance imaging.
494
PART III
node biopsy may offer a safe and less invasive means of lymph
node evaluation for extremity and truncal lesions, although its
role in RMS is yet to be determined but will soon become the
focus of a clinical trial.4851
CLINICAL GROUP
The extent of residual disease after resection is one of the most
important prognostic factors in RMS. For this reason, a clinical
grouping system was developed in 1972 to stratify patients
into groups that would more accurately reflect their prognosis
and treatment options. Currently, patients are assigned to a
clinical group based on the completeness of tumor excision
and the evidence of tumor metastasis to the lymph nodes or
distant organs after pathologic examination of surgical specimens (Fig. 35-3). This system differs from TNM staging in that
determination of each patients clinical group is based on the
extent of the surgical resection instead of tumor size and site.
Group
Criteria
II
III
IV
CHAPTER 35
100
Group II
60
Group III
40
Group IV
20
0
0
495
Group I
80
Years
FIGURE 35-4 Rhabdomyosarcoma survival based on completeness of
surgical resection (clinical group).
Chemotherapy
------------------------------------------------------------------------------------------------------------------------------------------------
Risk group
Pretreatment
stage*
Low 1
1 or 2
I or II
Favorable or unfavorable
EMB
III
Orbit only
EMB
III
Favorable
EMB
I or II
Unfavorable
EMB
III
Unfavorable
EMB
13
IIII
Favorable or unfavorable
ALV
IV
Favorable or unfavorable
EMB
IV
Favorable or unfavorable
ALV
Low 2
Intermediate 2 or 3
High
Clinical
group#
Site#
Histology
496
PART III
Radiation Therapy
------------------------------------------------------------------------------------------------------------------------------------------------
Assessment of Response
to Treatment
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 35
497
498
PART III
Metastatic Disease
------------------------------------------------------------------------------------------------------------------------------------------------
Rhabdomyosarcoma metastasizes both through hematogenous and lymphatic routes. Children with metastatic RMS
have very poor survival rates. For the IRS studies I through
III, children with metastatic disease had a 5-year disease-free
survival of 20%, 27%, and 32%, respectively, in each of the
successive studies. Recently studies have employed the use
of upfront window studies to address potential chemotherapeutic regimens that would improve the disease-free survival
period when given to patients with newly diagnosed metastatic RMS. One such study evaluated the combination of
ifosfamide and doxorubicin for the treatment of children
with metastatic disease who are less than 10 years of age,
have embryonal histology, and lack nodal, bone, or bone
marrow involvement. This treatment strategy increased 5-year
failure-free survival to 28% and 5-year overall survival to
34%.68 Despite these improvements, more intensive research
into chemotherapeutic regimens for group IV disease should
be investigated to improve overall outcome.
Prognosis
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 35
499
CHAPTER 36
Nonrhabdomyosarcoma Soft
Tissue Sarcoma in Children:
Background and Overview
------------------------------------------------------------------------------------------------------------------------------------------------
intermediate, or high risk based on criteria previously ascertained in a thorough review of 121 patients by Spunt.2,3
In patients with surgically resected NRSTS, univariate analysis
revealed clear risk factors. Positive surgical margins (P
0.004), tumor size greater than or equal to 5 cm (P < 0.001),
invasiveness (P 0.002), high grade (P 0.028), and intraabdominal primary site (P 0.055) had a negative impact on
event-free survival (EFS). Multivariate analysis confirmed all
of these risk factors, except for invasiveness. Local recurrence
was predicted by intra-abdominal primary site (P 0.028),
positive surgical margins (P 0.003), and the omission of
radiation therapy (P 0.043). As expected, the biology of the
tumor, assessed by tumor size greater than 5 cm, invasiveness,
and high grade, predicted distant recurrences. Children and
adolescents with initially unresectable NRSTSs are a subgroup
with pediatric NRSTSs that is particularly high risk. These are
large tumors, greater than 5 cm, which involve critical neurovascular structures of the extremity, trunk, abdomen, or pelvis.
In these patients, the 5-year estimated overall survival and EFS
were 56% and 33%, respectively, and postrelapse survival was
poor, 19% despite multimodality therapy.4
In addition to the tumor being unresectable, age is a prognostic indicator in pediatric NRSTS. Patients less than 1 year of
age have an excellent prognosis, whereas the adolescents and
young adults have the worse prognosis compared with younger patients or older adults.2 A 34-year review of patients
treated at St. Jude Childrens Research Hospital (SJCRH)
revealed the overall 5-year survival estimate for children less
than 1 year of age was 92% compared with 36% in those
15 to 21 years of age. Patients between 1 and 15 years of
age had an intermediate survival of approximately 60%.
Survival after relapse was poor in all age groups less than
18 years, except those less than 1 year of age. The 5-year
estimate of postrelapse survival in patients less than 1 year
of age was 80% compared with the 15- to 25-years cohort
in which survival was 21%. The type of chemotherapy used
in these patients was variable; surgical excision was generally
completed for lesions less than or equal to 5 cm, and for most
patients, incisional biopsy was performed for lesions greater
than 5 cm, followed by chemotherapy, reexcision, and
radiation therapy or amputation.5
INFANTILE FIBROSARCOMA
Patients in the study above who were less than 1 year of age
had infantile fibrosarcoma (IF). This is a very rare form of
NRSTS that occurs primarily during the first year of life, but
can appear up to year 4. IF presents as a rapidly growing mass
in the trunk or extremities. It can erode bone and usually
reaches a large size.
Most cases of IF have a specific translocation t(12;15)
(p13;q25)68 leading to fusion of ETV6 (TEL), a member of
the ETS family of transcription factors, on chromosome
12p13, and NTRK3 (TRKC), which encodes a tyrosine kinase
receptor for neurotropin-39,10 on chromosome 15q25. Other
cytogenetic abnormalities include trisomy 11; random gains of
chromosomes 8, 11, 17, and 2011; deletion of the long arm of
chromosome 1712; and a t(12;13) translocation.13 The helixloop-helix dimerization domain of ETV6 fuses to the protein
tyrosine kinase domain of NTRK3. The fusion protein results
in ligand-independent chimeric protein tyrosine kinase activity with autophosphorylation. This leads to constitutive
501
502
PART III
SYNOVIAL SARCOMA
Synovial sarcoma (SS) and malignant peripheral nerve sheath
tumor (MPNST) are the most common pediatric NRSTSs. SS
is characterized by a very specific fusion gene 18[t(X;18)
(p11.2;g11.2)]. Its etiology is unknown.23 In evaluating the
three largest reviews of pediatric SS, common principles are evident. For children 0 to 16 years old and tumors less than 5 cm in
size, overall 5-year survival (OS) is 71% to 88%. In this group,
the addition of chemotherapy did not improve survival.
In patients 17 to 30 years old, the addition of chemotherapy does
improve metastasis-free survival. In patients with SS tumors
greater than 5 cm that are deep and invasive and without metastasis, OS is 50% to 75%, and chemotherapy responsiveness is
50% to 60%.24 It is clear that for SS survival does not depend
on surgical margins but depends on size (>5 cm) and local
invasiveness. Brecht and colleagues found event-free survival
was 92% and 56%, respectively, when SS tumors were less than
or equal to 5 cm or greater than 5 cm.24 Figure 36-1 shows the
leg of a child with synovial sarcoma that was not responsive
to chemotherapy and required resection down to the periosteum
of the tibia. Radiotherapy does have a role in this disease and
is recommended after marginal resection or before anticipated
marginal resection, such as the one pictured.23
Surgical Approach
and Presentation
of Nonrhabdomyosarcoma
Soft Tissue Sarcoma
------------------------------------------------------------------------------------------------------------------------------------------------
Unlike rhabdomyosarcomas, NRSTSs are relatively chemoinsensitive. In the above pediatric studies and in adult multiinstitutional studies, the impact of chemotherapy on outcome
is minimal. In large American Joint Commission on Cancer
(AJCC) stage 3 tumors, overall survival was no different
whether or not chemotherapy was added to surgery and also
if neoadjuvant or adjuvant radiation therapy was added.27
Complete surgical excision provides the best outcome.
Patients usually present with a painless mass, sometimes
identified after a recent episode of trauma. Pediatric patients
who have an extremity or trunk mass that is greater than
5 cm, should have a magnetic resonance imaging (MRI)
examination, followed by core needle or open biopsy. If
NRSTS is identified and no mutilating limb-sparing surgical
excision is feasible, resection should be completed. If margins
are microscopically positive, postoperative radiotherapy
should be given in high-grade tumors and tumors larger than
5 cm. Low-grade tumors that are less than 5 cm can be reexcised or just watched closely. If surgical excision is not feasible
without amputation or severe morbidity, whether less than or
greater than 5 cm, preoperative chemotherapy and radiotherapy should be administered. If surgical excision is feasible, but
R1 resection is anticipated, the type of radiotherapy, whether
FIGURE 36-1 A-C, Magnetic resonance (MR) image of a child with synovial sarcoma abutting the tibia. Neoadjuvant chemotherapy was not successful in
reducing the size of the tumor. Marginal resection with postoperative radiation or brachytherapy is a preferred alternative to amputation.
CHAPTER 36
503
DSRCTwas multimodality therapy with the P6 regimen: cyclophosphamide, doxorubicin, and vincristine, alternating with
ifosfamide and etoposide for seven total courses,31 followed
by aggressive debulking surgery to remove all visible
disease.32 It is clear that without complete resection of all visible disease survival is poor.32 Hyperthermic intraperitoneal
chemotherapy (HIPEC) is a new therapeutic modality recently
used in children; its results are promising, but studies are
ongoing. Hyperthermia and chemotherapy have synergistic
cytotoxicity that is of value in the treatment of microscopic
disease in adult carcinomas. HIPEC has been applied
successfully in adults with extensive peritoneal disease,
commonly observed with mesothelioma, appendiceal, colon,
and gastric carcinoma.3337 A recent publication shows that
DSRCT can now be treated safely with aggressive cytoreductive surgery followed by (HIPEC) in children.38 The study
included 23 pediatric adolescent and young adult patients
with DSRCT. HIPEC was compared with standard chemotherapy, radiation therapy, and surgical debulking. The patients
were mostly males (96%). The age of the HIPEC patients
ranged from 5 to 25 years of age. Complete resection (CR0)
to less than 1.0-cm tumor size was achieved in all 8 patients
who underwent HIPEC. Operative times ranged from 7 to 16
hours. Figure 36-3 shows the setup used in the operating
room to deliver HIPEC. In the pediatric patients, the estimated
12-month disease-free survival (DFS) rate was 53% for the
HIPEC group, compared with 14% for the non-HIPEC group.
Median 3-year survival in this small group of patients was 29%
with chemotherapy and radiotherapy alone, compared with
71% in the HIPEC with cytoreductive surgery group. The
severe morbidities that occurred were partial bowel obstruction managed nonoperatively, prolonged ileus/gastroparesis,
transient renal insufficiency, and one patient developed
cardiomyopathy secondary to resection of more than 3 kg of
tumor, causing release of tumor necrosis factor. HIPEC is an
option in treating this rare tumor.38
Desmoid Tumors
------------------------------------------------------------------------------------------------------------------------------------------------
504
PART III
Drugs
Thermistor
Cardiotomy
Reservoir
Heat
Exchanger
Monitor
FIGURE 36-3 Setup for hyperthermic intraperitoneal chemotherapy (HIPEC) therapy for children with
sarcomatosis after cytoreductive surgery.
Water Heater
Roller
Pump
Positive
Observation
Margin
assessment
(microscopic)
Resection
Significant
morbidity?
Adequate
response
Yes
Primary/
recurrent
desmoid
Yes
*Radiation
therapy
Resectable?
No
Extraabdominal
Negative
Observation
No
Resectable
without
morbidity?
Resection
Yes
Inadequate
response
*Systemic
therapy
Adequate
response
Location
Intraabdominal
Observation
Systemic
therapy
Inadequate
response
No
Radiation
therapy
?Radiation
therapy
FIGURE 36-4 General treatment protocol for desmoid tumors at the University of Texas M.D. Anderson Cancer Center. The route of initial observation for
certain cases, to avoid overtreatment advocated by some, is depicted in gray. Given the propensity for progression on treatment and local recurrence, all
treatment pathways ultimately end in observation. *Radiation therapy can be preceded, and even precluded, by systemic therapy in certain cases of initially
unresectable extraabdominal desmoid tumors.
CHAPTER 36
Dermatofibrosarcoma
Protuberans
------------------------------------------------------------------------------------------------------------------------------------------------
Dermatofibrosarcoma protuberans (DFSP) is a relatively common soft tissue tumor. Its peak age is in young adulthood,
but it is frequently present in children and at birth. DFSP occurs
primarily on the trunk and extremities. It can present as a plaque on the skin or in a more diffuse multinodular pattern.52,53
The latter is more common in children. Pigmented dermatofibrosarcoma, giant cell fibroblastoma, and fibrosarcoma can
arise in DFSP.54,55
Dermatofibrosarcoma protuberans has a reciprocal translocation, t(17;22)(q22;q13.1), resulting in fusion of the genes
COL1A (encoding the alpha 1 chain of collagen type 1, a heterotrimer) on 17q21-22 and PDGFB1 (encoding the beta
chain of platelet-derived growth factor, a homodimer) at
22q13.55,56 The same fusion is also seen in supernumerary
ring chromosomes derived from t(17;22),57 which are found
in adult cases of dermatofibrosarcoma. Fusion gene transcripts can be detected by reverse transcriptasepolymerase
chain reaction (RT-PCR).53,58 This is not usually required
for diagnosis but might be useful in guiding therapy, especially
for superficial fibrosarcomas.
Dermatofibrosarcoma protuberans has a high local
recurrence rate, especially if incompletely excised, and can
metastasize in 5% of cases, usually after multiple local
505
recurrences. Therefore complete excision with negative margins is crucial, and 2- to 3-cm margins are recommended. However, in areas such as the head and neck, lesser margins are
acceptable.
Platelet-derived growth factor receptor (PDGFR) is a receptor
tyrosine kinase, which in dermatofibrosarcoma protuberans is
constitutively activated by autocrine or paracrine mechanisms
as a result of overproduction of its ligand platelet-derived growth
factor-beta (PDGFB),59 leading to cellular proliferation.60 This
has suggested the use of the tyrosine kinase inhibitors imatinib61
and, more recently, sunitinib or sorafenib in locally advanced or
metastatic disease,6263 but fibrosarcomatous variants without
the translocation do not respond64,65 so that genetic analysis
is indicated before targeted therapy. In the only multicenter
Phase 2 study published to date, imatinib was found to be effective preoperative therapy in 36% of patients (n 25) by reducing
tumor size by an average of 20%. Response was measured by
physical exam, ultrasonography, and MRI. Decrease in average
diameter by 1 cm on physical exam, 1 cm by ultrasonography,
and 2 cm by MRI were observed, respectively. In 21 of 25
patients, the fusion gene COL1A1-PDGFB was detected. Therefore when DFSP is located in places where a decrease in size provides a significant advantage in wound closure, neoadjuvant
imatinib is a viable option.
The complete reference list is available online at www.
expertconsult.com.
CHAPTER 37
Teratomas and
Other Germ Cell
Tumors
Frederick J. Rescorla
Pediatric germ cell tumors are rare tumors that are unique due
to their varied clinical presentation and locations. Approximately 20% of pediatric germ cell tumors are malignant,
and they represent 1% to 3% of all malignant tumors in childhood and adolescence.1,2 Three features distinguish these
childhood tumors from many other malignancies as well as
their counterparts: In children, the extragonadal tumor site
is more common than the gonadal site, whereas in adults, only
10% are at extragonadal sites; yolk sac tumor is the predominant malignant histology, and a serum marker (alpha fetoprotein, AFP) exists to follow response to therapy and monitor for
recurrent disease; and the introduction of modern chemotherapy with cisplatin and bleomycin significantly increased
survival for affected children and has allowed neoadjuvant
therapy with vital organ preservation in initially unresectable
cases.
Abnormal or arrested migration of primordial germ cells
results in deposition of cells in the sacrococcygeal region,
retroperitoneum, mediastinum, and pineal gland of the brain,
resulting in the potential of extragonadal germ cell tumors
at these sites. Whereas in adults 90% of germ cell tumors are
at gonadal locations, in childhood, the extragonadal site is
CLASSIFICATION
Teilum6 proposed the germ cell origin of gonadal tumors, and
the pathway of differentiation is listed in Figure 37-1. Seminoma (or dysgerminoma) is a primitive germ cell tumor that
lacks the ability for further differentiation. It is unusual in
childhood and occurs most frequently in the mediastinum,
pineal gland, and at the gonadal sites during the adolescent
years. Embryonal carcinoma is composed of cells capable of
further differentiation into embryonic or extraembryonic tumors. Teratomas are the most common germ cell tumor and
are composed of elements from one or more of the embryonic
germ layers and contain tissue foreign to the anatomic site of
origin.7,8
Mature and immature teratomas are considered benign
lesions. It is, however, imperative to have a thorough and
accurate pathologic review, because 25% of germ cell tumors
in childhood are mixed tumors with more than one histologic
507
508
PART III
Gonads
Abnormal
Suppressed
differentiation
Seminoma/
Dysgerminoma
Differentiation
Embryonal carcinoma
Embryonic
Mature or
immature teratoma
Extraembryonic
Choriocarcinoma
Yolk sac tumor
(endodermal sinus tumor)
noted in malignant ovarian germ cell tumors but not in ovarian immature teratomas.19
The presence of intersex disorders is a known risk factor for
gonadoblastoma, an in-situ germ cell tumor with the ability to
differentiate into dysgerminoma, immature teratoma, yolk
sac tumor, or choriocarcinoma.20 One risk group includes
testosterone deficiency, androgen insensitivity syndromes,
and 5-alpha-reductase deficiency, which are androgendeficient males. The presence of any portion of a Y chromosome is considered a risk factor in these children.21 Risk of
malignancy in androgen insensitivity is 3.6% at age 20 and
22% at age 3022; in view of this, gonadectomy usually in adolescence, is recommended. Gonadal dysgenesis is associated
with a risk of malignancy of 10% at age 20 and 19% at age 30.
Undescended testes have an increased risk of malignancy,
with the rate highest for intraabdominal testes. Approximately
0.4% of all males have undescended testes, however, it is observed in 3.5 to 12% of the testicular cancer population.23
One study noted that although intraabdominal testes only account for 14% of undescended testes, they account for nearly
50% of tumors in the undescended testes group. The effect of
orchiopexy on the risk of testes cancer is not known, and 20%
of the tumors in patients with undescended testis occur in the
descended testis.24 Seminomas occur in a higher percentage of
undescended testes (60%) compared with the descended
testes tumors (30% to 40%),25 and one study observed that
orchiopexy decreases the incidence of seminoma.26 The early
identification of these children is important, because a recent
report noted a 2-year-old boy with a large yolk sac tumor in
an intraabdominal testis with lymph node involvement.27
Surgery and chemotherapy yielded a successful outcome.
Risk-Based Therapy
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 37
testes and 88.9% for stage III-IV gonadal and stage I-IV
extragonadal.3133 The higher-risk group (stage III-IV gonadal
and stage I-IV extragonadal) were stratified to either standard
or high-dose cisplatin, and the overall survival was not different between the groups, but the toxicity was higher with the
high-dose cisplatin, and it has therefore not been incorporated
in the current study.
Based on these past studies, the current COG protocol for
malignant germ cell tumors is risk based (Fig. 37-2). The overall goal is to maintain the excellent survival from the past
intergroup study while decreasing the toxicity of the chemotherapy. Mature teratoma is considered to be a benign lesion,
and these tumors are not entered on the current protocol.
Immature teratomas at all sites are treated with surgery and
observation. The 3-year survival for immature teratomas on
the last study was 93% among 73 patients with immature teratoma, and four of the five recurrences were salvaged with
platinum-based chemotherapy.13,34 Stage I ovarian and testes
tumors are treated with surgery and observation, although this
portion of the protocol is currently suspended (see Ovary section). Stage II-III ovary and stage II-IV testes currently receive
three cycles of PEB administered during 3 days compared with
four cycles during 5 days on the prior study, thus resulting in
significantly less total chemotherapy. Higher-risk tumors
(stage IV ovary and stage III-IV extragonadal), are currently
not a part of a protocol but would received PEB.
Testes
------------------------------------------------------------------------------------------------------------------------------------------------
Low risk
Stage 1 ovary
Stage 1 testes
Immature teratoma
Intermediate risk
Stage IIIII ovary
Stage IIIV testes
509
Surgery alone
COG, AGCT 0132
Surgery and
Chemo-PEB x 3
COG, AGCT 132
High risk
Stage IIIIV extragonadal
Stage IV ovary
Surgery and
PEB
OPERATIVE MANAGEMENT
The standard approach consists of an inguinal incision, with
initial control of the vessels at the level of the internal inguinal
ring with subsequent mobilization of the testes. A preoperative elevation of AFP indicates the presence of yolk sac tumor
and thus precludes consideration of testes-sparing surgery,
and a radical orchiectomy is performed with ligation of the
cord at the internal ring. If the AFP is normal, there is a much
greater chance that the mass represents a benign lesion, and in
these instances, the field can be draped off and the tunica
opened. Enucleation is often possible, leaving a large amount
of residual normal testes.40 If frozen section analysis reveals a
benign lesion, the tunica is closed, and if malignant, an orchiectomy is completed. Unfortunately, this is not always possible, and in a recent review from the U.K. Childrens Cancer
Group, 48 of 53 boys with mature or immature teratoma
had radical orchiectomy.41 There were no recurrences in the
five treated with enucleation. Bilateral testes-sparing surgery
510
PART III
Stage
Extent of disease
II
III
IV
POSTSURGICAL TREATMENT
Testicular teratomas are benign lesions and are treated with
enucleation, if possible, and then postoperative observation.
Testicular immature teratomas are also benign germ cell tumors, and surgery alone (enucleation if possible) is definitive
treatment. Higher-grade immature teratomas are, however, associated with yolk sac tumors. In a (CCG/POG) review, grade
1 and 2 immature teratomas were not associated with yolk sac
tumors, whereas 2 of 3 grade 3 lesions were associated with
yolk sac tumors.13
Yolk sac tumor is the primary malignant prepubertal testes
cancer. The current staging is noted in Fig. 37-3. The role of
surgery alone for stage I testes tumors was reported in the
1980s44 and confirmed in an initial small series.45 The U.K.
Childrens Cancer Study Group46 and the Testicular Tumor
Registry of the Section of Urology of the American Academy
of Pediatrics,47 in larger series (73 and 181 children, respectively), confirmed the safety of surgery alone for stage I malignant testes tumors.
The intergroup trial of testes cancer (CCG/POG; 1990
1996)31 confirmed the excellent outcome with stage 1 testes
tumors treated with surgery alone (Table 37-1). This study
of 63 boys (median age 16 months) reported AFP elevation
in 98%. In patients with the preoperative diagnosis of tumor,
the surgical guidelines were followed in 84% of boys but were
followed in only 27% with a nontumor diagnosis. Although
overall adherence to surgical guidelines did not affect outcome, scrotal violation was associated with a 75% recurrence
rate compared with 15.5% in those without scrotal violation.
All recurrences were successfully treated with surgery and
chemotherapy.
Stage 2 boys on the CCG/POG study included only 17 patients, and 11 were stage II because of a transcrotal procedure.32 Survival was excellent (see Table 37-1) with surgery
and chemotherapy. Higher-stage 3 and 4 boys received surgery
and were then randomized to standard or high-dose cisplatin,
both with etoposide and bleomycin.33 Sixteen were recurrences from stage 1 disease (median age 3.1 years), and the
rest were newly diagnosed and much older (median age
16 years). Despite the advanced disease, outcome was
TABLE 37-1
Survival for Testes Cancer, POG/CCG 9048/8891; 9049/8882,
1990-1996
Stage
Treatment
6-Year
EFS (%)
I
II
III
IV
63 S
17
17
43
78.5
S PEB 4
S HDP/EB vs. PEB
S HDP/EB vs. PEB
100
100
94.1
88.3
6-Year
Survival (%)
100
100
90.6
excellent (see Table 37-1). The toxicity with high-dose cisplatin was significant without added benefit, and it has therefore been eliminated from current protocols.
The current protocol of the Childrens Oncology Group is
designed to reduce the total dose and days of chemotherapy
(Fig. 37-2). As noted in the staging, if the retroperitoneal
nodes are greater than 4 cm in size, it is assumed to be due
to tumor, whereas nodes between 2 and 4 cm require biopsy
to confirm status. There is no role for retroperitoneal lymph
node dissection in prepubertal yolk sac tumors at diagnosis
and simple biopsy is adequate.
Ovary
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 37
511
TABLE 37-2
Event-free Survival (EFS) and Survival in Pediatric Ovarian Germ
Cell Tumors, POG/COG Intergroup Study 1990-1996
Stage
Treatment
I
II
III
IV
41
16
58
16
S
S
S
S
PEB
PEB
HDP/EB vs. PEB
HDP/EB vs. PEB
6-Year
EFS (%)
6-Year
Survival (%)
95
87.5
96.6
86.7
95.1
93.8
97.3
93.3
Sacrococcygeal Tumors
------------------------------------------------------------------------------------------------------------------------------------------------
512
PART III
B
FIGURE 37-7 A, Three-month-old boy with a small external mass noted
since birth. B, Underlying presacral mass noted on magnetic resonance
imaging.
SURGICAL MANAGEMENT
In neonates presenting with large external masses, the degree
of pelvic and abdominal involvement should be assessed
preoperatively with either ultrasonography, CT, or magnetic
resonance imaging (MRI), and these studies may also offer a
clue as to the characteristics of the vascular supply. An open
or laparoscopic abdominal exploration may be required to mobilize the pelvic portion and to divide the middle sacral artery.
The neonatal type I and II lesions can usually be
approached with the child in the prone position (Fig. 37-9).
Removal of the coccyx is an essential step, because Gross
and colleagues70 reported a 37% recurrence rate if it was
not removed. In view of the anterior displacement caused
by the large mass, the rectum is often brought back to a more
posterior location at the time of closure. Fishman and colleagues71 described a buttocks contouring closure bringing
CHAPTER 37
Type I
Type III
513
Type II
Type IV
FIGURE 37-8 Classification of sacrococcygeal teratomas based on Altmans study: Type I (46.7% of reported cases) predominantly external, type II
(34.7%) external with intrapelvic extension, type III (8.8%) visible externally but predominantly pelvic and abdominal, type IV (9.8%) entirely presacral.
(Adapted from Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatric Surgical Section Survey1973. J Pediatr Surg
1974;9:389-398.)
the ventral portion of the lateral flaps to a more central posterior location, thus resulting in a transverse posterior incision
and two vertical incisions in the midportion of each buttock.
The operative approach in older infants and children is similar; however, due to the presence of malignancy in many of
these cases with invasion of adjacent structures or massive
size, initial resection is not possible, and an initial biopsy
followed by neoadjuvant chemotherapy is the best mode of
management (Fig. 37-10). In the CCG/POG Intergroup study,
there was no survival difference between initial and delayed
rejections, supporting surgical delay in these cases.72
POSTOPERATIVE MANAGEMENT
The staging system for extragonadal tumors is noted in
Figure 37-11. Most neonatal tumors are mature or immature
teratomas that can be managed by surgery and postoperative
observation. Recurrent tumors are noted in 10% to 20% of
initially benign tumors, and 50% of these are malignant
recurrences.65,73 The recurrence may be due to a sampling
error of the original tumor, incomplete resection of a malignant focus, or transformation of a small benign remnant into
a malignant lesion. The large size of the neonatal tumors and
frequent cystic components can often result in rupture during resection. Follow-up of these neonates should include
514
PART III
D
FIGURE 37-9 A and B, Operative excision of sacrococcygeal teratoma in a neonate with an inverted-V incision. C and D, The tumor along with the coccyx
is excised with careful preservation of the rectum.
CHAPTER 37
515
A
Diagnosis
B
Postchemotherapy
FIGURE 37-10 A, Appearance of a large unresectable malignant yolk sac
tumor treated with biopsy and neoadjuvant chemotherapy. B, Residual
postchemotherapy tumor.
B
leading to further compression with loss of spontaneous ventilation. An early report suggested increased risk of respiratory
collapse upon induction of anesthesia if the trachea was compressed by one third of the cross-sectional area.79 Shamberger
and colleagues,80 added pulmonary function tests and observed that general anesthesia was well tolerated if both the
tracheal area and the peak expiratory flow rate were greater
than 50% of predicted. Alternatives to general anesthesia for
diagnostic procedures in children in these situations include
aspiration of pleural fluid and needle biopsy or open biopsy
Extent of disease
II
III
IV
516
PART III
in the patients with yolk sac tumors, and all of the tumor
deaths were noted in adolescent boys with mixed germ cell
tumors.
Genital lesions are rare and most commonly involve the vagina
in girls. Although early reports of surgery alone reported survival rates of 50%, survival has improved with the addition
of platinum-based adjuvant chemotherapy.91,92 Vaginal lesions
generally occur in girls less than 3 years of age who usually present with vaginal bleeding. A mass is typically identified within
and often protruding from the vagina and uterus, and the actual
site of origin may be difficult to ascertain. The CCG/POG report
of 13 genital lesions (12 vaginal, 1 penile) confirmed the efficacy of platinum-based chemotherapy administered in a neoadjuvant fashion, with ultimate preservation of the vagina in 10 of
12 girls.93 This is best accomplished by initial biopsy, followed
by chemotherapy, and subsequent excision of the residual tumor, with the goal of partial vaginectomy. Although there is
no role for initial total vaginectomy or hysterectomy, this rarely
may be required in chemoresistant cases.
Cervicofacial Teratomas
------------------------------------------------------------------------------------------------------------------------------------------------
Gastric Teratomas
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 38
Hodgkin
Lymphoma and
Non-Hodgkin
Lymphoma
Peter F. Ehrlich
Hodgkin Lymphoma
------------------------------------------------------------------------------------------------------------------------------------------------
518
PART III
Percent
5-YEAR SURVIVAL
100
95
90
85
80
75
70
65
60
55
50
1975
1981
1987
1995
2003
Year
Bone
HD
Wilms
Neuroblastoma
ALL
FIGURE 38-1 Graph shows survival statistics of different pediatric cancers
from 1975 to 2003.
B
FIGURE 38-3 A, Chest radiograph demonstrating a large anterior mediastinal mass. B, Computed tomography scan demonstrating a large anterior mediastinal mass.
FIGURE 38-2 High-power hematoxylin and eosinstained slide of a
patient with nodular sclerosis Hodgkin lymphoma with typical Reed-Sternberg cells.
CLINICAL PRESENTATION
Hodgkin lymphoma must be considered in any child with
lymphadenopathy. Involved nodes are described as firm, nodular, and painless. Children and adolescents most frequently
present with cervical and or supraclavicular lymphadenopathy (80%). Patients presenting primarily with enlarged axillary
nodes (25% of all cases) or inguinal nodes (5%) are far less
common. Associated mediastinal disease is found in up to
75% of adolescents and 33% of children.13,2527 Mediastinal
involvement must be assessed prior to any operative intervention; involvement may be extensive and produce major complications upon the induction of anesthesia (Fig. 38-3)
Patients may also present with B symptoms, including fever
greater than 38 C, soaking night sweats, and weight loss of
10% or more. These symptoms are not specific to HL and
can occur in non-Hodgkin lymphoma. The presence or absence of B symptoms, which occur in up to a third of children,
has prognostic significance and is reflected in the staging of
HL.13,25 Respiratory symptoms may also result from large mediastinal masses, including dyspnea on exertion or orthopnea.
Itching or pruritus is a frequent finding but is nonspecific.28
DIAGNOSIS
A full history and physical examination focusing on nodal
areas and the abdomen should be performed. At present there
is no specific laboratory test for HL. An excisional biopsy of a
suspicious lymph node should be the initial step to diagnosis
CHAPTER 38
519
TABLE 38-1
Hodgkin Lymphoma Staging: Ann Arbor Classification
with Cotswolds Modification
Stage 1
Stage II
Stage III III1 III2
Stage IV
Modifiers:
A or B: The absence of constitutional (B-type) symptoms is denoted by adding
an A to the stage; the presence is denoted by adding a B to the stage.
E: Used if the disease is extranodal (not in the lymph nodes) or has spread
from lymph nodes to adjacent tissue.
X: Used if the largest deposit is greater than 10 cm large (bulky disease),
or whether the mediastinum is wider than one third of the chest on a
chest x-ray.
S: Used if the disease has spread to the spleen.
The nature of the staging is (occasionally) expressed with:
CS: Clinical stage as obtained by doctors examinations and tests.
PS: Pathologic stage as obtained by exploratory laparotomy (surgery
performed through an abdominal incision) with splenectomy (surgical
removal of the spleen). Note: Exploratory laparotomy has fallen out of favor
for lymphoma staging.
HISTOPATHOLOGY
Reed-Sternberg cells are the pathognomonic cells of HD (see
Fig. 38-2). The classification systems for HL have evolved over
time from the Rye classification to the Ann Arbor Classification and the Cotswolds modification (Table 38-1).3032 The
current World Health Organization classification system separates HL into two broad categories: classical and lymphocyte
predominant. Classical has four subtypes: lymphocyte depleted, nodular sclerosing, mixed cellularity, and classical
lymphocyte rich. Classical HL accounts for 90% of all cases.
For children, nodular sclerosis is the most common subtype,
accounting for 65% of cases. Immunohistochemical studies
STAGING
Staging has both clinical and pathologic features. The Ann
Arbor staging system and its Cotswolds modification
remain the standard for adult and pediatric HL (see
Table 38-1).30,33,34 The original Ann Arbor staging system developed in 1974 was based principally upon the use of staging
laparotomy and lymphangiogram, both of which have been
abandoned.
Clinical staging requires a complete history and physical
examination. Basic tests should include a complete blood cell
count with differential, lactate dehydrogenase, alkaline phosphatase, erythrocyte sedimentation rate, or C-reactive protein
(CRP), baseline hepatic and renal function tests, and electrolytes. Radiographic studies include a chest radiograph and a
computed tomography (CT) scan of the neck, chest, abdomen, and pelvis. Chest radiographs often reveal the presence
of a mediastinal mass, and the ratio of its maximal diameter to
that of the thoracic cavity on a posteroanterior view is important prognostically. A mass with a ratio greater than 1:3 places
520
PART III
number of involved nodal regions, and extranodal involvement of disease. High-risk patients are those with stage IIIB
and IVA/B disease.3840 LPHD is considered a low-risk disease
but is often separated from the classical HL studies.
Surgery
the patient in the subcategory of bulky mediastinal disease associated with a worse prognosis. Bone marrow biopsy is reserved for those patients with B symptoms or stage III-IV
disease. (18F)-2 fluoro-D-2-deoxyglucose positron emission
tomography (FDG PET) is replacing gallium scans, and recent
studies have assessed the ability of PET scans to replace CT
scans and as possible prognostic indicators for response to
therapy.25,28,3537 Magnetic resonance imaging (MRI) provides a more accurate evaluation of disease in the abdomen
compared with CT, with better visualization of fat-encased retroperitoneal nodes, but whether or not this provides clinically
significant information has yet to be established.
TREATMENT
Risk Classification
Children and adolescents with HL are divided into three risk
categorieslow-, intermediate-, and high-risk disease
based on clinical and pathologic staging data, histology, stage
at presentation, presence or absence of B symptoms, number
of involved sites, and/or presence of bulky disease (>10 cm).
The exact definitions of each stage will often change between
studies and clinical trial consortiums, such as the Childrens
Oncology Group (COG).34 In general, low-risk disease is
defined as classical Hodgkin lymphoma patients, with clinical
stage I or II disease showing no B symptoms or bulky nodal
involvement and disease in fewer than three nodal regions.
Intermediate-risk disease includes stage I, II, and sometimes
IIIA disease with criteria that vary from trial to trial.26,30 Some
trials have included B symptoms, bulky disease, a large
CHAPTER 38
521
522
PART III
radiation therapy. Also reported in females is a high risk of prematurity and premature menopause.75
Second Cancers (SC) The risk of second cancers is significantly increased in the long-term survivors of HL treated with
full-dose RT.7680 The Late Effects Study Group estimated the
30-year cumulative incidence of SC to be 26.3% among survivors diagnosed before age 16. The two most frequent cancers are breast cancer (20% risk at 45 years of age),
followed by thyroid carcinoma (36-fold increased rate).80 Exposure to alkylating agents, particularly in conjunction with
extended-field RT, is associated with an increased risk of leukemia. Leukemias tend to arise 2 to 10 years after therapy. The
risk of SC after modern treatment is not yet known, because
reduction in exposure to alkylating agents and the use of lowdose IFRT became standard practice within the last 15 to 20
years. The transition from extended-field RT to IFRT significantly reduces the radiation dose to breast and lung tissue.81
It is thought that modern IFRT should lead to lower SC rates
than have been documented in the past.
Non-Hodgkin Lymphoma
------------------------------------------------------------------------------------------------------------------------------------------------
INCIDENCE EPIDEMIOLOGY
AND CLASSIFICATION
There are 750 to 800 new cases of non-Hodgkin lymphoma
each year in the United States.82 Non-Hodgkin lymphoma
(NHL) accounts for 7% of cancer in children and adolescents,
with an incidence of 10 per 1 million population annually in
the United States.83 NHL is rare at less than 5 years of age, with
an incidence of 2.8 per million cases but increases dramatically after age 20. NHL is more common in males (1.1 to
1.4:1), with a higher frequency in whites than in blacks or
Asians. Certain NHL types cluster according to race, for example, the natural killer (NK) T-cell lymphomas are most frequently encountered in Asian populations. A family history
of a hematologic malignancy produces an increased risk,
but it is not NHL-disease specific.82
DNA and RNA viruses are thought to play an important role
in the pathogenesis of NHL.17,82 The Epstein-Barr virus (EBV)
CHAPTER 38
523
TABLE 38-2
World Health Organization and Clinical Classification of Selected Subtypes of Non-Hodgkin Lymphoma
Clinical Behavior
WHO Pathologic
Category
Mature B-cell
neoplasms
Mature T-cell
and NK-cell
neoplasms
Indolent
Aggressive
Highly
Aggressive
Follicular lymphoma
Chronic lymphocytic leukemia/small
lymphocytic lymphoma
Hairy cell leukemia
Extranodal marginal zone lymphoma
Lymphoplasmacytic lymphoma/Waldenstrom
macroglobulinemia
Splenic B-cell marginal zone lymphoma
Mycosis fungoides
Sezary syndrome
Burkitt
lymphoma
Adapted from Jaffe E, Harris NL, Stein H, et al: Introduction and overview of the classification of lymphoid neoplasms. In Swerdlow SH, Campo E, Harris NL,
et al (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2008, p 158-166.
ALK, anaplastic lymphoma kinase; NK, natural killer; NOS, not otherwise specified; WHO, World Health Organization.
Staging laparotomy is not performed in non-Hodgkin lymphoma, because all patients require systemic chemotherapy.
However, patients may require surgical intervention because
of abdominal complications, such as intussusception or bleeding or to obtain diagnostic tissue. In some cases, the disease is
localized and a total resection can be performed, in others the
524
PART III
TABLE 38-3
St. Judes Murphy Staging System for Non-Hodgkin Lymphoma
Stage
I
II
III
IV
Description
A single extranodal tumor or single anatomic nodal area with
exclusion of mediastinum and abdomen
A single extranodal tumor with regional nodal Involvement
greater than or equal to two involved nodal regions or
localized involvement of extranodal disease on the same side
of diaphragm
A primary gastrointestinal tract tumor that is completely
resected
Greater than or equal to two nodal or extranodal tumors on
opposite sides of the diaphragm
Any primary intrathoracic tumor
Unresectable primary intraabdominal disease
Any paraspinal or epidural disease
Involvement of central nervous system and/or bone marrow
T cell lineage
B cell lineage
Stage I
CD2, CD7, CD38, CD71
Pre-B cell
Stage II
CD1, CD2, CD4, CD7,
CD8, CD38
Pre-B cells
Stage III
CD2, CD3, TCR, CD4/8,
CD5, CD7, CD 38
Mature B
cell with
surface IGM
Activated
mature
B cell
FIGURE 38-6 A schematic of B-cell and T-cell lineages.
equatorial Africa, it usually arises in the mandible, but abdominal lymphoma is also noted in up to 20% of these patients. BL
can also be found in the central nervous system and bone marrow. BL of the anterior mediastinum is extremely rare.95,96 The
gold standard for the diagnosis of BL is c-MYC rearrangement.97 This is based on a characteristic chromosomal translocation, usually involving chromosomes 8 and 14, that was
discovered in BL in 1976.98 In 80% of the translocations, this
involves the locus at 14q32, in 15% of cases it is 2p11, and in
5% it is 22q11. BL is the most rapidly growing tumor in
CHAPTER 38
525
526
PART III
Initial surgical management includes incisional biopsy for diagnosis, followed by intense, multiagent chemotherapy, except for small, easily resectable lesions.119 Resection of
massive retroperitoneal or mediastinal masses is not indicated.
In abdominal BL, the extent of disease is a more significant
predictive variable than is completeness of surgical resection.
The surgical committee of the Childrens Cancer Group (CCG)
evaluated the role of surgical therapy in 68 patients with nonHodgkin lymphoma in the CCG-551 study.60 Tumor burden
was the most important prognostic factor. However, in disease
that can be completely resected, it may improve EFS and prevent complications such as bowel perforation. In the setting of
localized disease, data do support a role for complete resection.120122
Radiation Therapy
In the treatment of localized non-Hodgkin lymphoma, radiation therapy has been shown to add toxicity with no therapeutic benefit. Several studies continue to show that radiotherapy
Surgery
CHAPTER 38
in mature B-cell NHL reporting overall survival of 93%. Children and adolescents with disseminated ALCL have a poorer
survival of 60% to 75%. It is unclear which strategy is best
for the treatment of disseminated ALCL. COG is testing the
replacement of vincristine with vinblastine in the maintenance
phase of the APO regimen (doxorubicin, vincristine, and
prednisone.)
527
TOXICITIES
The long-term toxicity profile for patients with NHL is very
similar to HL. Acutely, the NHL regimens, because of their intensity, tend to be more toxic as described previously.
The complete reference list is available online at www.
expertconsult.com.
Epidemiology
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 39
Ovarian Tumors
Daniel Von Allmen and Mary E. Fallat
530
PART III
Clinical Presentation
------------------------------------------------------------------------------------------------------------------------------------------------
Diagnosis
------------------------------------------------------------------------------------------------------------------------------------------------
LABORATORY TESTS
Many ovarian neoplasms are associated with the secretion of
specific tumor markers or hormones. These are outlined in
Tables 39-1 and 39-2 and are discussed further in the sections
on individual tumors.
TABLE 39-1
Ovarian Tumor Markers
CA 125
AFP
hCG
Inhibin
/
/
/
/
/
/
/
/
/
/
/
/
Epithelial-Stromal Tumors
Serous carcinoma
Mucinous carcinoma
Endometrioid carcinoma
/
/
/
/
/
Tumor Markers
Germ cell tumors are associated with various biologic markers
that are useful in identifying and managing this group of tumors.26 Protein markers, including alpha fetoprotein (AFP),
beta-human chorionic gonadotropin (beta-hCG), and lactate
dehydrogenase (LDH), are the most readily available. They
are measured with serum assays or immunohistochemical
staining of paraffin-fixed or frozen tumor.
Alpha Fetoprotein
Because the fetal yolk sac is the source of AFP early in human
embryogenesis, elevations of the marker occur with yolk sac
tumors.27 This is also true with hepatoblastoma, hepatocellular carcinoma, and teratocarcinoma.28 The elevation reflects
the presence of fetal tissue from which normal progenitor cells
arise. There is wide variability in normal levels of AFP from
birth through the first year of life,29 and AFP is significantly
elevated in premature and normal newborns. Its usefulness
in the diagnosis of yolk sac tumor or embryonal carcinoma
in the first month of life is limited. Its value in tumor identification begins when the AFP level is significantly elevated
over the normal range at any particular age. The normal serum
half-life of AFP is 5 to 7 days. Its decline after removal of an
AFP-producing tumor signifies a response to treatment. The
goal of any treatment is to return AFP to normal levels. Tumor
recurrence is marked by a sudden elevation of the AFP level.
Beta-Human Chorionic Gonadotropin
Beta-hCG is a glycoprotein produced by placental syncytiotrophoblasts. It comprises two subunits, alpha and beta; the
latter can be reliably assayed.30 Beta-hCG elevation in a patient
with a germ cell tumor suggests the presence of syncytiotrophoblasts, as seen in seminoma, dysgerminoma, choriocarcinoma,
CHAPTER 39
OVARIAN TUMORS
531
TABLE 39-2
Ovarian Tumors and Hormones
Histologic Subtype
Ovarian cyst
Simple
Follicular
Luteal
Sex cordstromal
Juvenile granulosa
Sertoli-Leydig
Luteinized thecomas
Sex cord tumors with annular tubules
Steroid cell tumor
Gonadoblastoma
Choriocarcinoma
Estradiol
Testosterone
Urinary 17-ketosteroid
Gonadotropin
MIS
#
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IMMUNOHISTOCHEMISTRY
Immunohistochemistry (IHC) has had a major impact in
recent years as an aid to diagnosis in ovarian neoplasia. From
a practical standpoint, the time-honored approaches, including gross and microscopic features, thorough sampling, and
consideration of patient age and presence or absence of coexisting endometriosis, still take precedence. In general, IHC
panels should include markers which are expected to be positive (and negative) in the various tumors in the differential
diagnosis. Virtually no antibody is specific for any given tumor, and unexpected positive and negative immunoreactions
may occasionally occur. In ovarian pathology, IHC seems to be
most valuable in the evaluation of tumors with follicles or
other patterns that bring a sex cordstromal tumor into the
differential. The two most useful markers are alpha inhibin
and calretinin. Calretinin is a slightly more sensitive marker
of ovarian sex cordstromal tumors as a group, but alpha inhibin, produced by granulosa cells, is a more specific marker,
because most other ovarian neoplasms are negative.37,38
CANCER GENETICS
Benign, borderline, and malignant lesions have been identified within the same surgical specimen, suggesting evolution
from dysplasia to cancer in some cases, although frequency
and speed of this process remain unknown. A quantitative
systematic review performed to estimate the diagnostic
accuracy of frozen sections compared with paraffin sections,
including specimens from 3,659 women aged 1 to 95 years
532
PART III
IMAGING TECHNIQUES
Various radiographic studies play an important role in the
clinical evaluation of pediatric ovarian lesions. Prenatal US
can usually differentiate ovarian lesions from intestinal duplication, hydronephrosis, duodenal atresia, choledochal cyst,
urachal remnants, hydrometrocolpos, and intestinal obstruction (Fig. 39-1). Mesenteric and omental cysts are more difficult to distinguish from simple ovarian cysts, because the
ovary is an abdominal rather than a pelvic organ in an infant.
US is the diagnostic study of choice for the initial evaluation
of potential ovarian pathology in all age groups. Adequate
urinary bladder distention is mandatory to displace gas-filled
intestinal loops out of the pelvis and to ensure adequate
sound wave transmission through the ovaries. Ovarian volume changes with age from less than 0.7 cm3 in girls younger
than 2 years to 1.8 to 5.7 cm3 in postpubertal patients.52 Morphologic characteristics also change. In children younger than
8 years, the ovaries are generally solid, ovoid structures with a
homogeneous echogenic texture. During and after puberty,
the ultrasonographic spectrum of the gonad undergoes cystic
changes that parallel ovulatory follicle activity in the organ.
Ovarian cysts are generally anechoic, thin-walled masses with
through transmission. With torsion, fluid debris or septation
may be present.53 Most benign tumors are complex masses
that are hypoechoic with peripheral echogenic mural nodules,
which may exhibit acoustic shadowing. Malignant tumors are
Axial view
Spleen
Coronal view
Amniotic fluid
Colon
Spleen
Ribs
Colon
Spine
Stomach
Liver
Umbilical vein
Small
bowel
Liver Stomach
FIGURE 39-1 A and B, Two views of an ultrasonogram of a fetus in the third trimester. A large, complex ovarian cyst containing fluid debris, internal
septation, and solid components can be seen (arrowheads). An ovarian neoplasm was identified during surgery after birth. (Courtesy Gary A. Thieme, MD,
Prenatal Diagnosis Center, University of Colorado School of Medicine.)
CHAPTER 39
OVARIAN TUMORS
533
Disease Classification
and Staging
------------------------------------------------------------------------------------------------------------------------------------------------
A
FIGURE 39-2 A, Plain abdominal radiograph of a 16-year-old girl with a unilateral ovarian teratoma; the pelvic mass contains toothlike calcifications.
B, Computed tomography scan of a large, calcified abdominal mass. The mass has a large cystic component, with solid, thickened walls that are eccentric
in appearance. The tumor was a thin-walled fibrous cyst with extensive hemorrhagic infarction throughout the entire cyst wall. Histology was consistent
with a benign cystic teratoma.
534
PART III
TABLE 39-3
World Health Organization Histologic Classification
of Nonneoplastic Ovarian Lesions
TABLE 39-4
World Health Organization Classification of Tumors
of the Ovary
CHAPTER 39
TABLE 39-5
Staging of Carcinoma of the Ovary: International Federation
of Gynecology and Obstetrics (FIGO)
Stage
0
I
IA
IB
IC
II
IIA
IIB
IIC
III
IIIA
IIIB
IIIC
IV
Extent of Disease
Primary tumor cannot be assessed
No evidence of primary tumor
Tumor confined to ovaries
Tumor limited to one ovary, capsule intact
No tumor on ovarian surface
No malignant cells in ascites or peritoneal washings
Tumor limited to both ovaries, capsule intact
No tumor on ovarian surface
No malignant cells in ascites or peritoneal washings
Tumor limited to one or both ovaries, with any of the
following:
capsule ruptured, tumor on ovarian surface, malignant cells in
ascites or peritoneal washings
Tumor involves one or both ovaries with pelvic extension
Extension to or implants on uterus or tubes or both
No malignant cells in ascites or peritoneal washings
Extension to other pelvic organs
No malignant cells in ascites or peritoneal washings
IIA or IIB with positive malignant cells in ascites or peritoneal
washings
Tumor involves one or both ovaries with microscopically
confirmed peritoneal metastasis outside the pelvis or regional
lymph nodes metastasis
Microscopic peritoneal metastasis beyond the pelvis
Macroscopic peritoneal metastasis beyond the pelvis 2 cm or
less in greatest dimension
Peritoneal metastasis beyond the pelvis more than 2 cm in
greatest dimension or regional lymph nodes metastasis
Distant metastasis beyond the peritoneal cavity
TABLE 39-6
Clinicopathologic Staging of Ovarian Germ Cell Tumors:
Childrens Oncology Group (COG)
Stage
Extent of Disease
II
III
IV
inspection of the contralateral ovary are appropriate in the initial management of benign lesions or tumors of low malignant
potential. Pelvic washings are part of the staging system for
ovarian tumors and should be performed immediately on
entry into the abdomen (by either laparoscopy or laparotomy)
in an attempt to avoid contamination in the event of intraoperative tumor rupture. Because the final pathology will not
be known until either frozen section or histologic evaluation
of paraffin-embedded tissue, peritoneal washings should be
OVARIAN TUMORS
535
Treatment
------------------------------------------------------------------------------------------------------------------------------------------------
536
PART III
Follicular Cysts
Follicular cysts represent about half of nonneoplastic ovarian
lesions. They are unilateral, unilocular, and histologically
benign and often have a thin, yellowish, clear liquid content.
Cohen and associates83 detected cysts in 84% of all imaged
ovaries in 77 patients from birth to 24 months of age. The
prevalence was similar in each 3-month age bracket. Parallel
findings were noted in premenarchal girls between 2 and
12 years of age,84 with a generally equal distribution across
the age spectrum. Occasionally, ovarian cysts persist and
enlarge and are capable of secreting estrogen, thereby leading
to precocious isosexual development.85
The size of an ovarian lesion has been a major factor in
determining clinical management.80 Simple cysts, regardless
of size, are more likely to regress. Larger cysts (>5 cm) have
a greater risk of torsion. Larger cysts in children have a greater
association with sexual precocity. Complex cysts may already
have torsed or may be neoplastic. Complex cysts should
be resected, rather than observed, in prepubertal children.
Complex cysts in adolescents are most often due to hemorrhage
into a functional cyst and can be managed conservatively with
symptom control. Operation is indicated for persistent cysts or
persistent symptoms despite conservative management.
Ovarian cysts noted in the prenatal period can be expected
to spontaneously regress during the first year of life, and in
utero therapy is seldom justified.86,87 Cysts that develop in
utero are most often lined by luteinized cells, whereas those
in older children are more often lined by granulosa cells.32
These lesions may occasionally be complicated by torsion, intestinal obstruction, or perforation and cyst rupture.80,88
Bagolan and colleagues89 and Giorlandino and colleagues90
confirmed that echogenic cysts with fluid debris, retracting
clot, or septation were associated with torsion and hemorrhage. In newborns, torsion is often a prenatal event, and viable ovarian tissue may not be identified, even with the most
expeditious neonatal surgical intervention (Fig. 39-3). Most
authors now advocate increasingly conservative measures
for neonatal ovarian lesions.80 Small, asymptomatic cysts are
generally observed for regression with serial US. Cysts 5 cm in
True functioning corpus luteum cysts develop only in adolescents who are actively ovulating. Although these cysts may be
bilateral and become quite large, they usually regress spontaneously with the cyclic decline in serum progesterone. The
gross appearance of the external surface is often bright yellow,
although it may take on a hemorrhagic appearance when filled
with bloody fluid. The cyst lining is composed of luteinized
granulosa and theca cells and is capable of actively producing
estrogen and progesterone. These cysts may cause acute pelvic
pain if they rupture or undergo torsion. Failure of the corpus
luteum to involute may cause menstrual irregularity and dysfunctional uterine bleeding. Surgical goals for corpus luteum
cysts parallel those for other follicular lesions. Surgical intervention is indicated in the presence of cyst accident or persistence, demonstrated by repeat pelvic US performed 4 to 6
weeks after the initial assessment. Hasson96 was able to treat
17 of 19 patients who had corpus luteum cysts with laparoscopic aspiration, fenestration, or cyst wall excision. Clinical
symptoms resolved in all but one patient. Cyst recurrence
was rare.
CHAPTER 39
OVARIAN TUMORS
537
Endometriosis
Parovarian Cysts
538
PART III
C
FIGURE 39-4 A, Ovarian tumor from a 17-year-old girl with massive bilateral ovarian lesions. The opened specimen shows a cavity filled with clear fluid,
and the wall is lined by numerous nodules and papillary protuberances. B, Histologic section of the lesion shows serous papillary tumor of low malignant
potential (hematoxylin-eosin stain). C, Higher-power photomicrograph of a section of the lesion shows mucinous tumor of low malignant potential
(hematoxylin-eosin stain).
CHAPTER 39
OVARIAN TUMORS
539
FIGURE 39-5 A, Three-year-old girl demonstrating isosexual pseudoprecocious puberty. B, Surgery revealed a benign juvenile granulosa cell tumor.
Unilateral salpingo-oophorectomy was performed to remove the tumor.
540
PART III
CHAPTER 39
OVARIAN TUMORS
541
542
PART III
C
FIGURE 39-6 A, This encapsulated mass from a 5-year-old girl with acute abdominal pain proved to be a dysgerminoma. The childs contralateral tube
and ovary are seen to the left of the tumor. A small portion of the ipsilateral tube and uterus were in the surgical specimen but uninvolved with tumor.
B, The cut surface of the tumor is characterized by lobules divided by thin, fibrous septae. C, Micrograph of a dysgerminoma demonstrating polygonal,
clear tumor cells divided into small lobules by fibrous septae that contain scattered lymphocytes.
CHAPTER 39
multiagent chemotherapeutic programs that include platinum, etoposide, and bleomycin, which is now standard
therapy.146,151,152
Endodermal Sinus Tumors Endodermal sinus or yolk sac
tumors are aggressive malignant neoplasms that, either alone
or as a component of a mixed germ cell tumor, are the second
most common histologic subtype of malignant ovarian germ
cell tumors in children and adolescents.32,153 In neonates
and young children the primary location of these tumors is
in the sacrococcygeal area. In older children and adolescents,
it is found most frequently in the ovary. The origin of this
particular tumor has been debated, and many microscopic
patterns of this tumor have now been described. Nogales suggested that this tumor originates from the primary yolk sac, a
structure that develops very early in embryogenesis and
consists of multipotential primitive endoderm.154 This tissue
is capable of differentiating epithelial somatic tissues as well as
secondary yolk sac tissue (a terminal, temporary structure
with limited differentiating capacity) and mesenchyme. Yolk
sac tumors with pure endodermal sinus subtypes are less
mature than the differentiated glandular or hepatoid subtypes.155 Symptoms are generally present for less than a
month and are related to the presence of an intra-abdominal
mass. Sixty-three percent of patients present with abdominal
pain and/or abdominal distention.156 Elevation of the biologic
marker AFP is the hallmark of this tumor.
The gross appearance of these tumors during surgery is pale
yellow-tan and slimy, with foci of cystic areas and necrosis.157
The tumors are soft and friable when handled. Most tumors
show a distinct histologic subtype with differentiation toward
vitelline or yolk sac structures.158 Microscopically, the most
common papillary pattern has the so-called endodermal sinus
structures (Schiller-Duval bodies) or perivascular sheaths of
cells. Most well-differentiated yolk sac tumors also contain
extracellular and intracellular droplets that are resistant to
periodic acidSchiff diastase staining and positive for AFP.
Embryonal Carcinomas A relatively uncommon isolated
germ cell tumor is embryonal carcinoma, which may resemble
an anaplastic carcinoma with extensive necrosis. Embryonal
carcinoma is more often found in association with other germ
cell tumors and is referred to as a mixed germ cell tumor. One
subtype of this tumor, the polyembryoma, is capable of
producing both AFP and beta-hCG, resulting in clinical endocrinopathies, including menstrual irregularities and isosexual
precocious puberty. The histologic appearance is characterized by bodies that resemble tiny embryos.159
The workup and surgical approach to this tumor is similar
to that for an endodermal sinus tumor. Isolated, unilateral
disease is managed by unilateral salpingo-oophorectomy.
Advanced local disease necessitates hysterectomy for local
control along with multiagent chemotherapy.160
Choriocarcinomas Choriocarcinomas are extremely rare in
the pure form but may be present in mixed germ cell tumors
as well. They are endocrinologically active, highly malignant
germ cell tumors that occur in girls and women. Estrogen is
produced both by the tumor and by the ovary itself in response
to release of gonadotropin by the neoplastic chorionic tissue.
The beta-hCG level is elevated, and AFP is normal. The clinical
presentation is influenced by the age of the patient. In a review
OVARIAN TUMORS
543
544
PART III
response with the development of a mass of intestine and omentum adhering to the anterior abdominal wall; this condition is
associated with pelvic adenopathy, which mimics a malignant
tumor.168 On examination, findings are primarily related to
the mass itself. These tumors are located in the abdomen in
infants and young children. They are found in the pelvis of
adolescents, although large tumors may be palpated in the
abdomen, and there may be associated tenderness.
Plain abdominal radiographs demonstrate calcifications in
up to 67% of cases.169 Ultrasonography is a commonly used
diagnostic test. The positive predictive ability of ultrasonography approaches 100% when two or more characteristic findings for mature cystic teratoma (MCT), such as shadowing
echodensity and regionally bright echodensity, are present.170
Magnetic resonance imaging has been reported to be more
useful than CT scan in the diagnosis of mature cystic teratoma
due to its ability to clearly define soft tissue components.171
Conservative ovarian surgery in childhood and adolescence is important for the development of normal puberty
and future fertility. This must be balanced with complete removal of the mature cystic teratoma. Traditional management
of children with mature cystic teratomas has been oophorectomy by laparotomy. However, laparoscopic removal, either by
cystectomy or oophorectomy affords a safe alternative option
when done by an experienced laparoscopist.73 Campo and
colleagues, in a randomized controlled trial, demonstrated
that the use of an endobag in the removal a mature cystic
teratoma at the time of laparoscopy decreased spillage from
46% to 3.7% of cases.172 Aspiration of a giant predominantly
cystic lesion in order to facilitate removal through a smaller
incision runs the risk of upstaging the patient by spillage
of the cyst contents if malignant components are identified.
Techniques have been described to minimize this risk while
allowing a less invasive approach to large cystic lesions.173,174
Every effort should be made to spare the ovary when a
teratoma is suspected based on radiographic findings and normal tumor markers. Very large or bilateral teratomas can be
successfully enucleated in an attempt to preserve hormonal
and reproductive functions (Fig. 39-7).165,175, If this is not
possible, the gonad and tumor alone should be removed, leaving the ipsilateral fallopian tube in place.
Miliary, intraperitoneal glial implants (gliomatosis peritonei) are occasionally encountered in association with mature
teratomas.176 These implants are rarely suspected before
surgery. They appear as white or gray nodules, usually 1 to
3 mm in diameter, and are usually confined to the omentum,
pelvic peritoneum, or adjacent or adherent to the tumor itself.
Several explanations have been offered for the development of
these implants.177 The most recent data using microsatellite
DNA analysis suggest that the glial implants arise from subperitoneal cells, presumably pluripotent mullerian stem cells and
not from the teratoma.178,179 Implants can have a disturbing
appearance and biopsy is necessary, but no specific treatment
is indicated when they are well differentiated, and their presence does not change management of the primary tumor.
However, if adjacent components are immature, the lesions
may progress and require adjuvant therapy.
Immature Teratomas Immature teratomas are germ cell
neoplasms that are composed of tissue derived from the three
germ cell layers. These teratomas are clinically distinct from
benign or malignant teratomas, because they also contain
immature, neuroepithelial elements (see Fig. 39-7). Immature
CHAPTER 39
OVARIAN TUMORS
545
FIGURE 39-7 A, Large ovarian dermoid tumor in a 14-year-old girl with acute severe abdominal pain upon awakening. The fallopian tube is seen below
the tumor. B, Opened gross specimen of ovarian dermoid showing multiple tooth- and jawlike calcifications. C, Characteristic gross appearance of an
immature teratoma in a 5-year-old girl who presented with a left ovarian mass. The tumor is a solid and cystic globoid mass with a smooth, shiny surface.
D, Cut section of an immature teratoma shows a variegated, solid, cystic appearance with focal areas of hemorrhage.
Gonadoblastomas
Gonadoblastoma, a tumor first described by Scully188 in 1953,
is relatively rare and occurs most commonly in patients with
dysgenetic gonads. Most patients are virilized or nonvirilized
phenotypic females. In the only large series reported, Scully189
reviewed 74 cases and found that 89% were chromatin negative
and the most common karyotype was 46XY or 45X/46XY.
Troche, in a literature review of 140 cases of neoplasms arising
in dysgenetic gonads, found that 80% also had these karyotypes.190 Patients are usually older adolescents or in the third
decade of life with a history of primary amenorrhea. Androgen
production by the tumor causes virilization. When a workup
for amenorrhea or virilization is undertaken, an abnormal
karyotype with a Y chromosome or chromosome fragment
can be found in as many as 90% of patients.190 These often
546
PART III
malignant component and other changes, including calcification, fibrosis, or both. In fact, calcification may be the only
remnant of the gonadoblastoma, and the presence of calcification in a dysgerminoma should raise the suspicion of an underlying gonadoblastoma. The malignant potential of this
tumor is determined by the underlying malignant component
and should be treated accordingly. The outcome for patients
with these tumors may be improved, because abnormal sexual
development prompts early evaluation of the patient and
subsequent diagnosis of the tumor. The prognosis of nongerminomatous germ cell tumors has improved with the advent
of bleomycin, etoposide, and cisplatin protocols, and survival
rates of 70% to 90% have been reported.32
Mixed Germ Cell Tumors
Germ cell tumors in children are often composed of more than
one pure histologic type. Benign but questionably malignant tumors (i.e., immature teratomas) and frankly malignant tumors
(germinomas, choriocarcinomas, endodermal sinus tumors,
and embryonal carcinomas) may be present. Management of
mixed tumors is geared toward the most malignant component
of the mass.
CHAPTER 39
Group (COG-AGCT0132) stratified malignant germ cell tumors into three risk groups (low, intermediate, and high risk)
defined by stage and primary site. Based on data from the POG
9048/CCG 8891 study, demonstrating that patients with stage
I ovarian and extragonadal immature teratoma with malignant
elements appeared to do well following complete surgical resection,69 all patients with stage I ovarian tumors were categorized as low risk and were initially treated with surgery,
followed by close observation and monitoring. That arm of
the study has subsequently been amended to include stage I
ovarian tumors in the intermediate-risk group because of a
higher-than-expected failure rate with observation alone.
Overall survival remains greater than 95%. The intermediaterisk group will consist of patients with stage I to III gonadal
tumors. Such patients have been shown to have a 3-year EFS
of about 90% with standard-dose PEB.49,71 These patients will
be treated with a modified standard PEB regimen, consisting of
three cycles of compressed PEB every 21 days. Saxman and
colleagues203 reported that long-term survival was equivalent
for men treated with germ cell cancer for three or four cycles
of PEB. Patients who are partial responders (PR) may then
have surgical resection of residual tumor. Therapy is discontinued upon pathologic complete response and normal
markers, or continued for an additional three cycles in children
who remain PR. High-risk patients, defined as those with stage
IV disease, showed some improvement in survival with a highdose platinum regimen that was offset by increased toxicity.
Patients with recurring germ cell tumors may be salvaged
using high-dose chemotherapy with autologous stem cell
transplantation.
Miscellaneous Tumors
------------------------------------------------------------------------------------------------------------------------------------------------
Small cell carcinoma of the ovary is an extremely rare condition with a very poor prognosis.204 These tumors are very aggressive and are the most common undifferentiated ovarian
carcinoma in young patients. They have been encountered
in patients from 9 to 44 years of age, with a mean age of
23 years.205 Paraendocrine hypercalcemia occurs in two
thirds of cases, but patients rarely have clinical manifestations
of this abnormality. Serum parathormone levels are normal.
Virtually all tumors are unilateral, although only 40% have
been detected at stage 1A. Only one third of patients with stage
1A tumors survive long-term, and survival of patients with
more widespread disease is rare.13 Unilateral salpingooophorectomy has been associated with long-term survival in
some patients with stage 1A tumors. Asynchronous appearance
of tumor in a contralateral conserved ovary has been encountered, and bilateral adnexectomy may be a more appropriate surgical option. Despite various treatment modalities including
resection, radiation therapy, and intensive chemotherapy, the
average life expectancy remains low at 18 months.205
Primary ovarian sarcomas are a heterogenous group of aggressive tumors associated with poor survival. Most cases occur in older women; however, a recent review of 151 cases
described 10 of 29 patients with rhabdomyosarcoma who
were younger than 20 years of age.206 These patients presented with nonspecific symptoms of abdominal discomfort
or swelling with occasional urinary or gastrointestinal complaints secondary to mass effect. Accurate staging is critical.
Hysterectomy with bilateral salpingo-oophorectomy and
OVARIAN TUMORS
547
debulking of as much diseased intra-abdominal tissue as possible has been done. Radiation therapy was administered for
residual pelvic disease, and several chemotherapeutic regimens have been used. In contrast to rhabdomyosarcomas arising at other sites, the outcome for patients with ovarian lesions
has generally been poor, perhaps because of the advanced
stage of disease at diagnosis. Nevertheless, the most recent
chemotherapeutic regimens used in cooperative group studies
have been highly effective, and it is reasonable to assume that
more conservative surgical resection will provide adequate
treatment for these rare tumors.
Stromal sarcomas and low-grade endometrial stromal sarcomas of the ovary have been occasionally reported in the second decade of life. These lesions are believed to arise from
ovarian endometriosis, coelomic mesenchyme, or neometaplasia of stromal cells. Lesions are usually discovered because
of nonspecific pelvic discomfort, although early infiltration
into adjacent tissues may cause intestinal or ureteral obstruction. Tumor infiltration may not be grossly apparent, so initial
surgical resection should be aggressive with total hysterectomy and bilateral salpingo-oophorectomy. Progesterone administration may provide effective adjunctive therapy,
although this has to be continued indefinitely because stromal
sarcomas have been reported to reappear and spread dramatically when the medication is stopped. Radiation therapy has
been used for local residual disease, although recurrence is
common. The role of chemotherapy for these tumors has
not been defined.
Cases of genuine ovarian fibrosarcoma in children are extremely rare. Patients present with pelvic pain and a palpable
mass. Fibrosarcoma has been associated with Maffucci syndrome.8 Although the outcome has been uniformly poor in
older patients, survival of younger patients who have undergone aggressive surgical resection, including hysterectomy
and bilateral salpingo-oophorectomy, has been reported.
Success with subsequent radiation or chemotherapy has not
been reported.
Primary leiomyosarcoma of the ovary is extremely rare in
children. These tumors may arise de novo from any of the
smooth muscle sites in the ovary or may represent malignant
degeneration of leiomyoma, a benign counterpart.207 As with
most of these rare tumors, presenting symptoms are nonspecific and discovery may occur in the advanced stage of disease.
Aggressive surgical therapy is recommended, because no
adjuvant therapy has proven to be effective.
Secondary Tumors
------------------------------------------------------------------------------------------------------------------------------------------------
548
PART III
TABLE 39-7
Secondary (Metastatic) Tumors Occurring in the Ovary
in Children
Colorectal
Breast
Gastric carcinoma
Carcinoid tumors (liver, lung)
Malignant melanoma
Burkitt lymphoma
Rhabdomyosarcoma
Wilms tumor
Neuroblastoma
Retinoblastoma
Ewing sarcoma
Rhabdoid tumor of the kidney
Medulloblastoma
Osteogenic sarcoma
Chondrosarcoma
Leukemia
Although the ovary is highly vascularized, hemangiomas are extremely rare; a recent review found only 40 published cases.214
Their occurrence is relatively evenly distributed between infancy
and postmenopausal age groups. The lesions are usually quite
small, asymptomatic, and discovered incidentally. Bilateral
occurrence is rare, and the tumors are almost always cavernous.
Benign-appearing ultrasonographic features have been described.215 When the tumors are large, associated symptoms
include abdominal pain, distention, and bloody ascites. Torsion
or rupture may cause an acute surgical emergency. No malignant
Summary
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 40
Testicular Tumors
Bryan J. Dicken and Deborah F. Billmire
Although a number of risk factors have been proposed regarding the occurrence of testicular tumors, to date only a few may
be considered as established based upon a sufficient level of
evidence.16 Other associations that have historically been considered important etiologically have since been refuted. Only
four factors have sufficient evidence that links them highly
with testicular cancer: (1) undescended testis (cryptorchidism), (2) contralateral testicular germ cell tumor (GCT),
(3) familial testicular germ cell tumor, and (4) gonadal dysgenesis.16,17 Associations that may be considered likely include
infertility, twin-ship, and testicular atrophy. Clinical factors
with equivocal/low association include scrotal trauma, inguinal hernia, mumps orchitis, testicular torsion, maternal estrogen exposure, and occupational exposure. Parameters that
have historically drawn attention but have since been shown
to be irrelevant include obesity, vasectomy, smoking, hydrocele, varicocele, alcohol, and circumcision.16
Cryptorchidism occurs in 2% to 5% of term infant males;
however, by 12 months of age, this number is reduced to
1%.18 To date, cryptorchidism is the only factor that has level
I evidence linking it with testicular cancer. A meta-analysis of
20 case control studies showed a strong association between
undescended testis (UDT) and testicular cancer, with an overall relative risk of 4.8.16 Similarly, Walsh and colleagues19
showed boys who underwent orchiopexy after 10 years of
age had a 3.5-fold increased risk of testicular cancer, compared with those that had the procedure at an earlier age.
In a population-based prospective observational study, Pettersson and colleagues followed 16,983 men treated for
UDT for a mean period of 12.4 7.4 years.20 This study demonstrated two important findings. There was an increased risk
of testicular cancer for the entire cohort (relative risk [RR]
2.23) versus normal population figures, and the incidence of
cancer was significantly higher (RR 5.4) in those who were
549
550
PART III
Clinical Presentation
------------------------------------------------------------------------------------------------------------------------------------------------
Diagnosis
Tumor Markers
------------------------------------------------------------------------------------------------------------------------------------------------
Serum tumor markers are essential in the workup and postoperative monitoring of children with testicular tumors. Human
chorionic gonadotropin (HCG) and a-fetoprotein (AFP) are
important markers for certain malignant germ cell histologies.2 AFP is secreted by yolk sac tumors in up to 90% of cases,
and b-HCG is secreted by choriocarcinoma. HCG has a halflife of 24 hours, whereas AFP has a half-life of 5 days. In the
prepubertal age group yolk sac tumors are the most common
malignant histology, and AFP is very important, whereas HCG
is rarely elevated. An important consideration is that AFP is
normally very high in infancy, and remains elevated for up
to 8 months, decreasing to adult levels around 1 year of
age.2,23 Older boys are more likely to have malignant germ cell
tumors of mixed histology, and both AFP and HCG may be
elevated. For those patients with elevated tumor markers at
diagnosis, serial AFP and HCG should be monitored monthly
in the first postoperative year, then every other month in the
second year to follow current recommendations.25 Patients
presenting with precocious puberty and a testicular mass
should prompt assessment of a urinary 17-ketosteroid, serum
luteinizing hormone (LH), follicle-stimulating hormone
(FSH), and testosterone. Unlike precocious puberty induced
by a pituitary lesion, in which the LH, FSH, and testosterone
are high, testicular tumors display a low LH and FSH and a
high testosterone.
Table 40-1 lists the histologic diagnoses for prepubertal testicular tumors from several institutions, and the diagnoses are
compared with the 2002 AAP tumor registry.1,13,26 This table
demonstrates the reporting bias of the national tumor registry
and the population-based distribution of all testicular tumors.
Table 40-2 outlines the Childrens Oncology Group (COG)
testicular tumor staging system.7
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 40
TABLE 40-1
Differences in Distribution of Testicular Tumors Based on
Tumor Histology among Study Sites
Tumor Type
Benign
Teratoma
Epidermoid cyst
Leydig cell
Sertoli cell
Juvenile granulosa
cell
2002
Registry %
(N 395)
Pohl %
(N 98)
Metcalfe %
(N 51)
Ciftci %
(N 51)
23
3
1
3
3
48
14
4
3
5
43
10
0
4
0
18
6
6
0
N/A
Malignant
Yolk sac
62
Mixed germ cell
0
Rhabdomyosarcoma
4
Gonadoblastoma
1
15
8
0
8
Excluded 25
2
2
45
6
19
0
TABLE 40-2
Staging of Testicular Malignant Germ Cell Tumors
Testicular
Stage
I
II
III
IV
TESTICULAR TUMORS
551
552
PART III
of the risk of degeneration into an invasive seminoma. However, the recognized role of testosterone in gender differentiation has led to a more conservative approach to the
contralateral gonad, which may involve a contralateral orchiopexy to allow gender development, followed by annual scrotal
examinations and ultrasonography after age 10 years until puberty. At puberty, testicular biopsy should be carried out to
evaluate for CIS in the remaining testicle.38 If no evidence
of CIS is identified, annual follow-up with testicular ultrasonography until age 20 is recommended. If CIS is identified
at puberty, orchiectomy should be considered.38
Choriocarcinoma Choriocarcinoma is among the rarest of
the gonadal germ cell tumors, representing 0.3% of testicular
tumors.29 These tumors elaborate b-HCG, and may be associated with a number of hormonal manifestations. These include precocious puberty from b-HCGinduced Leydig cell
stimulation, gynecomastia, and hyperthyroidism because of
the similarity of the b-HCG subunits to thyroid-stimulating
hormone.29 Testicular choriocarcinomas frequently have
distant metastasis at the time of presentation rather than a
scrotal mass. Histologically, they are composed of syncytiotrophoblastic cells with mononucleated cells around foci
of hemorrhage. They stain positive for b-HCG and placental
lactogen.32
Rhabdomyosarcoma
Although technically a paratesticular tumor, rhabdomyosarcoma should be included in the differential diagnosis of
scrotal tumors. It is the most frequent tumor of paratesticular origin, accounting for 4% to 25% of scrotal masses.13 The
tumor has a bimodal distribution, peaking between 3 to
4 months of age and 15 to 19 years of age. The infant tumor
has a more indolent behavior than the tumor presenting in
the adolescent age group (90% vs. 63% failure-free survival).39 Despite its aggressive behavior, the prognosis of
paratesticular rhabdomyosarcoma has improved dramatically from 10% to 77% overall survival with the introduction
of vincristine, dactinomycin, and cyclophosphamide (VAC)
chemotherapy.39,40 The most common subtype is embryonal
rhabdomyosarcoma, which accounts for 97% of paratesticular tumors.
The tumor consists of small round blue cells and presents
as a scrotal mass in 80% of patients. Ultrasonography is highly
effective in demonstrating its paratesticular location and distinguishing it from the tumors of testicular origin.13 CT or
MRI of the retroperitoneum should be performed prior to surgery for staging purposes. Thirty to 40 percent of boys will
have micrometastasis to the retroperitoneum. The tumor
should be resected by a radical inguinal orchiectomy. A retroperitoneal lymph node dissection (RPLND) is recommended
for all patients 10 years of age or older for accurate staging,
and in patients less than 10 years with radiologic evidence
of retroperitoneal involvement.39 A metastatic workup should
include a chest CT, liver function tests, bone scan, and bone
marrow biopsy.
CHAPTER 40
TESTICULAR TUMORS
553
Surgical Management
------------------------------------------------------------------------------------------------------------------------------------------------
TESTIS-SPARING SURGERY
In the last 2 decades, multiple reports have confirmed that many
testicular tumors in the prepubertal population can be managed
more conservatively than in adults, because the distribution of
prepubertal tumors favors a benign histology. This realization
has confirmed the safety and feasibility of testis-sparing surgery,
especially when the lesion is evaluated preoperatively by
ultrasonography and serum AFP and intraoperatively by frozen
section analysis. Metcalfe and colleagues13 have provided a
practical treatment algorithm incorporating the common benign
tumors for nonradical surgery (Fig. 40-1).
In general, before puberty, teratoma, gonadal stromal tumors (Leydig cell and Sertoli cell) and epidermoid cyst can
be managed with a testis-sparing approach (Fig. 40-2). Postpubertal patients with teratoma or stromal tumors should be
treated as adults, with radical orchiectomy because of their
more malignant behavior.
Testis-sparing surgery is carried out through an inguinal incision. The cord is mobilized after opening the external oblique aponeurosis to the level of the internal ring. The
cremasteric fibers are dissected from the cord structures to
allow circumferential control of the cord. The cord should
be occluded at the level of the internal ring with a noncrushing
clamp. The testis is then delivered through the inguinal incision, and the wound is protected. The tunica vaginalis is
opened directly over the mass, and an excisional biopsy of
Paratesticular
rhabdomyosarcoma
Normal AFP
Confirms/suggests
malignancy
Elevated AFP
Radical orchiectomy
No to either
FIGURE 40-1 Proposed treatment algorithm for prepubertal patients presenting with a painless scrotal mass. AFP, a-fetoprotein. (From Metcalfe PD,
Farivar-Mohseni H, Farhat W, et al: Pediatric testicular tumors: Contemporary incidence and efficacy of testicular preserving surgery. J Urol 2003;170:24122415; discussion 2415-2416.)
554
PART III
than 90% of cases. These cells are the precursors for germ cell
tumors and are felt to represent a risk for recurrent neoplasia
if the residual testicular parenchyma is left in situ. The progression through puberty evolves over a period of time and
sequential histologic changes. The testes go through a maturation process starting from simple tubules without lumen
and with interstitial Leydig cells in the neonate. The Leydig
cells then regress and the tubules become more tortuous.
As puberty begins, the Leydig cells become more prominent,
and the basal germ cells begin to divide. There are multiple
layers of spermatocytes and the tubule lumens form, followed
by the appearance of mature sperm. The appearance of mature
sperm or ITGCN would be indicative of completion of pubertal changes.
C
FIGURE 40-2 A, Intraoperative photograph of a child with painless
swelling of testicle. B, Wedge resection of epidermoid cyst. C, Suture closure of testicular capsule. (Courtesy Dr. P. Metcalfe, personal file.)
A radical inguinal orchiectomy is performed through a standard inguinal incision, with clear demarcation of the external
oblique aponeurosis and external ring and opening of the external ring back to the level of the internal ring. The cremasteric fibers are once again dissected from the cord, and the
cord is fully mobilized from the inguinal canal, followed by
vascular control at the internal ring. The cord is then clamped
and divided at the level of the internal ring, after which the
stump is suture ligated. After ligation, dissection proceeds distally with mobilization of the testis from the scrotum and division of the gubernaculum. If the tumor is too large to deliver
through the scrotal canal, the incision may be carried onto the
superior aspect of the scrotum.42,43 Once the tumor is excised,
the wound is closed in standard fashion.
Current pediatric testicular tumor protocols do not include
a RPLND. Postchemotherapy masses are treated with local resection. Postpubertal patients will often be managed with
adult protocols, although data regarding adolescents is lacking. The indications for and the extent of RPLND are a matter
of some controversy even in adults. Prechemotherapy RPLND
is no longer employed, and postchemotherapy RPLND is eliminated in some centers if residual disease is less than 1 cm in
dimension by imaging.44 In the event that a RPLND is required, a midline abdominal incision is made and a thorough
laparotomy performed to identify retroperitoneal low-volume
metastasis not appreciated on preoperative imaging. There is
also controversy regarding the extent of dissection. Because of
the morbidity of bilateral RPLND (40%), a variety of unilateral
templates have been developed in addition to the concept of
nerve-sparing dissection.45,46 In low-stage disease, lymphatic
spread is typically unilateral, and therefore a full bilateral
RPLND is not used in some centers.47 For the unilateral template, dissection for patients with right-sided disease involves
removal of the lymphatics in the interaortocaval, precaval, and
right paracaval distribution (Fig. 40-3, A).43 For left-sided lesions, this includes the left paraortic and preaortic lymphatics
(Fig. 40-3, B). This dissection strategy is important, because it
preserves the contralateral sympathetics important for emission and ejaculation.48 Preservation of efferent sympathetic
fibers maintains emission and ejaculation rates at 99%.48
The finding of viable tumor outside of the template distribution has led to the recommendation for bilateral dissection
C
FIGURE 40-3 A, Right modified nerve-sparing retroperitoneal lymph node dissection. B, Left modified nerve-sparing retroperitoneal lymph node
dissection. C, A full retroperitoneal dissection involves left and right combined. (From Marshall FF [ed]: Operative Urology. Philadelphia, WB Saunders,
1996, p 368-369.)
556
PART III
in all patients undergoing RPLND in other centers.46 In advanced-stage/high-volume disease bilateral RPLND is always
used, as shown in Figure 40-3, C.45 With either technique,
the nodal packets are split at the 12 oclock position over
the vessels and rolled laterally away. The sympathetic fibers
are carefully identified and preserved as they cross the iliac
bifurcation.
CHEMOTHERAPEUTIC STRATEGIES
AND SURVIVAL IN CHILDREN WITH
MALIGNANT GERM CELL TUMORS
Prior to effective chemotherapy, children with malignant
germ cell tumors (MGCT) had 3-year survival rates of 15%
to 20% with surgery and radiation.7,49 The introduction of
cisplatin-based regimens has dramatically improved outcomes
(Table 40-3).11 In patients with low- and intermediate-risk
(<15 years of age) MGCT, the 6-year overall survival rates
for advanced gonadal tumors (stages III and IV) are now
greater than 94%.7 Standard chemotherapy for children
with MGCT of the testes includes standard-dose cisplatin, etoposide, and bleomycin (PEB) for 4 to 6 courses.2 The current
protocol under investigation examines stages II to IV with
three courses of chemotherapy. Management of patients
is based upon risk groups as proposed by the Childrens
Oncology Group (COG) as follows (see Table 40-3)11:
1. Low risk: Stage I immature teratoma and MGCT of the
testis. Recommend surgery and close follow-up observation to document normalization of tumor markers following resection
TABLE 40-3
Standard Treatment for Children Younger Than 15 Years
with Testicular Germ Cell Tumors by Histology and Stage
Histology
Stage
Treatment
Overall
Survival
(6-Year)
Mature
teratoma
Immature
teratoma
MGCT
Localized
Surgery observation
100%
Localized
Surgery observation
100%
Stage I
Stage II-IV*
Surgery observation
Surgery PEB
100%
94%
2. Intermediate risk: Stages II-IV gonadal tumors (excluding patients >15 years with stage IV testicular
tumors).
The complete reference list is available online at www.
expertconsult.com.
Embryology
CHAPTER 41
Adrenal Tumors
Michael G. Caty and Mauricio A. Escobar, Jr.
Anatomy
------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------------
558
PART III
Physiology
------------------------------------------------------------------------------------------------------------------------------------------------
PHEOCHROMOCYTOMA
In 1886, Frankel of Freiburg, Germany, published the first description of bilateral pheochromocytomas found during the
postmortem examination of an 18-year-old woman who had
presented with symptoms of anxiety, palpitations, and headache.2 In 1912, Pick named the tumor for its predominant cell
type, the pheochromocyte, but it was not until 1922 that
Labbe and colleagues first described a clear relationship
between pheochromocytoma and paroxysmal hypertension.
In 1927, Mayo performed the first successful removal of a
pheochromocytoma in a patient with paroxysmal hypertension who underwent surgical exploration without a preoperative diagnosis. In 1929, Pincoffs made the first correct
preoperative diagnosis, and the successful operation was
performed by Shipley.3 Since that time, the behavior of
pheochromocytomas has become better understood, particularly with respect to children.
Pheochromocytoma is an uncommon tumor of childhood,
and there are several characteristics that distinguish its presentation between adults and children. The incidence of
pheochromocytoma in childhood is 10% of the adult incidence, occurring in approximately 1 in 500,000 children compared with 1 in 50,000 adults.4 Approximately 10% of
childhood pheochromocytomas are familial, which is about
4 times the frequency in adults. Whereas only 7% of pheochromocytomas are bilateral in adults, the reported incidence of
CHAPTER 41
TABLE 41-1
Comparison of Pheochromocytoma in Children and Adults
Incidence
Familial pattern (%)
Bilateral (%)
Extraadrenal site (%)
Malignant (%)
Pediatric
Adult
1:500,000
10
24-70
30
3
1:50,000
2-3
10
10
10
SYMPTOMS
In children with pheochromocytoma, the average age at presentation is 11 years, although the tumor can occur at any age.
Over half the children present with headaches, fever, palpitations, thirst, polyuria, sweating, nausea, and weight loss, but
the most common presentation is sustained hypertension.4,6,7
In children, most causes of hypertension are secondary, with
renal abnormalities being most common (78%), followed by
renal artery disease (12%), and coarctation of the aorta
(2%).8 Pheochromocytoma accounts for 0.5% of children
with hypertension and must be considered once other causes
are eliminated. In children with pheochromocytoma, hypertension is sustained in up to 70% to 90% of cases, with only
a small minority presenting with paroxysmal hypertension.
In contrast, up to 50% of adults with pheochromocytoma have
paroxysmal hypertension.6
ADRENAL TUMORS
559
After establishing the chemical diagnosis of pheochromocytoma, the tumor must be localized. Although large masses
such as a neuroblastoma can be seen on plain abdominal films,
most adrenal masses cannot be visualized without the use
of other imaging methods. Almost all pheochromocytomas
occur in the abdomen or pelvis, and although the adrenal
gland is the most common site, up to 43% of children may
have multifocal disease.6 The initial study in infants and
children is often US, which can be useful in distinguishing
between solid and cystic masses while determining their vascularity and avoiding ionizing radiation, but it may not
visualize small adrenal lesions. Additionally, it may be difficult
to identify the adrenal gland as the organ of origin for large
masses, because of compression from adjacent organs such
as the kidney. Computed tomography (CT) and magnetic
resonance imaging (MRI) offer the advantage of much better
resolution and sensitivity (Fig. 41-1). Although CT is an accurate method of diagnosing adrenal lesions, it is less accurate
in younger children because of the absence of retroperitoneal
fat. Other disadvantages of CT are the need for intravenous
contrast material and exposure to ionizing radiation. Simultaneous scanning of the chest to rule out pulmonary metastases in patients suspected of having adrenal carcinoma is a
benefit of CT. Currently, both CT and MRI offer multiplanar
imaging. Coronal imaging is a useful modality to distinguish
DIAGNOSIS
The diagnosis of pheochromocytoma relies on the demonstration of elevated levels of blood and urinary catecholamines
and their metabolites. A 24-hour urine measurement of
catecholamines, metanephrine, and vanillylmandelic acid
is the best diagnostic test.9,10 Urinary metanephrine levels
are increased in about 95% of patients, and urinary vanillylmandelic acid and catecholamine levels are increased in
approximately 90% of patients.10 There is also a linear relationship between the amount of vanillylmandelic acid and
the size of the pheochromocytoma.11 The normal 24-hour
urinary secretion is less than 100 mg for free catecholamines,
less than 7 mg for vanillylmandelic acid, and less than 1.3 mg
for metanephrine. Plasma catecholamines can also be measured by radioenzyme assay. However, patients must remain
supine and calm during the blood draws, which can be difficult in children. Patients with normal plasma catecholamine
levels during a hypertensive episode probably do not have
pheochromocytoma, but levels greater than 2000 pg/mL
are diagnostic of pheochromocytoma. Plasma catecholamine
levels between 500 and 1000 pg/mL are suspicious for a
pheochromocytoma, and further testing is indicated.6 It must
be remembered, however, that neuroblastoma can in some
cases secrete significant levels of catecholamines.
B
FIGURE 41-1 A, Computed tomography of the abdomen in a 10-yearold girl with a left adrenal mass associated with hypertension. B, Magnetic
resonance image demonstrates a left adrenal pheochromocytoma. No
other masses were noted. No contrast agent was required.
560
PART III
TREATMENT
The treatment of pheochromocytoma is surgical excision,
although medical management of the hypertension is an
essential part of the preoperative preparation. The high levels
of catecholamines increase the risk of sudden and severe
intraoperative hypertension, as well as profound hypotension
once the tumor is removed and catecholamine release has
ceased. In fact, these complications accounted for the
high mortality rate associated with surgical resection in the
past.6 Improvements in preoperative and intraoperative
management have reduced the operative mortality of 24% to
45% in the past to less than 10% today.20 Preoperative use of
alpha-adrenergic blockers, such as oral phenoxybenzamine
and phentolamine, reduces the effects of epinephrine and norepinephrine by blocking the alpha-adrenergic receptors. These
agents should be started at least 3 to 7 days before the procedure
and the dose increased until the pressures are well controlled to
minimize the intraoperative risks. Replacement of intravascular volume is often required as alpha blockade is achieved,
because patients with pheochromocytomas tend to be hypovolemic at baseline, with an average 15% reduction in plasma
volume. This volume re-expansion also helps minimize intraoperative blood pressure fluctuations and cardiac arrhythmias.
Beta-adrenergic blockade with agents such as propranolol
and labetalol may be used once an alpha-adrenergic blockade
is achieved, particularly if a resting tachycardia develops despite adequate volume replacement. If these agents are used,
it is crucial that alpha blockade be established first. Administration of a beta blocker before an alpha blockade can worsen
hypertension secondary to unopposed vasoconstriction.
Methyl-para-tyrosine (metyrosine) competitively inhibits
tyrosine hydroxylase, the rate-limiting step in catecholamine
biosynthesis. Treatment with metyrosine reduces tumor stores
of catecholamines, decreases the need for intraoperative antihypertensive drugs, lowers intraoperative fluid requirements, and
attenuates blood loss. It has not been tested in children less than
12 years of age. Metyrosine may not be necessary for patients
with minimal or no symptoms from a minimally functioning
pheochromocytoma.21
Despite good preoperative normalization of blood pressure, the anesthesiologist must be prepared for sudden fluctuations. The times of significant intraoperative risk are during
anesthetic induction and intubation, during surgical manipulation of the tumor, and immediately following ligation of the
tumors venous drainage.22 An arterial catheter and a central
venous line are crucial for monitoring intraoperative blood
pressure and fluid status. The anesthesiologist must also be
prepared to use fast-acting agents to raise or lower blood
pressure as needed. Sodium nitroprusside and nitroglycerin
are useful agents, as are vasopressors and intravenous fluids.
Cardiac arrhythmias can be managed with the use of propranolol, esmolol, and lidocaine. Adrenalectomy is described later.
An adrenal pheochromocytoma is typically encapsulated,
and although there may be small amounts of normal adrenal
tissue, the entire adrenal gland should be removed. It is rarely
necessary to perform a nephrectomy, because the tumor is
rarely adherent to the kidney.
As previously mentioned, once the adrenal vein is ligated
and the tumor is removed, the patient may become hypotensive because of the removal of the catecholamine excess. In
fact, it may be several days before the blood pressure normalizes. If hypertension returns postoperatively, one should
suspect a second pheochromocytoma. All patients should undergo follow-up to confirm normalization of catecholamine
levels. Long-term follow-up is indicated because of the
possibility of a metachronous occurrence of a multifocal pheochromocytoma or occult metastasis.6,22
ASSOCIATED DISORDERS
Familial pheochromocytomas may occur in the setting of
several syndromes. The most common syndromes are multiple endocrine neoplasia type 2 (MEN-2) and von HippelLindau disease. There is a smaller incidence of familial
CHAPTER 41
ADRENAL TUMORS
561
CUSHING SYNDROME
In 1932, Cushing first described the syndrome that bears his
name in a patient with a pituitary adenoma. Since that time,
the understanding of the pathophysiology and cause has
expanded considerably. Endogenous Cushing syndrome is a
rare condition in the pediatric population. In general, the
incidence of spontaneous Cushing syndrome is approximately
5 per million persons; it occurs primarily in young adult
women, with a female to male ratio of 9:1. Ten percent of cases
occur in children and adolescents.31
The typical manifestation of Cushing syndrome in children
is generalized obesity and long bone growth retardation.31
Other symptoms include hypertension, weakness, thin skin
with striae and easy bruising, acne, menstrual irregularity,
osteoporosis, and glucose intolerance. Unlike in adults with
Cushing syndrome, muscle weakness, sleep disturbances,
and mental changes, such as emotional lability, irritability,
or depression, are rare in children.31 Cushing syndrome can
be divided into ACTH-dependent and ACTH-independent
types. In the former condition, the inappropriately high
ACTH levels stimulate the adrenal cortex to produce excessive cortisol. In the ACTH-independent type, abnormal
adrenal tissue produces excessive cortisol irrespective of
ACTH levels.
Cushing disease refers to Cushing syndrome caused by
pituitary tumors that lead to excessive ACTH production.
Typically, these tumors are microadenomas and are less than
1 cm in diameter; however, large, invasive pituitary adenomas
may develop. These tumors lead to bilateral adrenocortical
hyperplasia, with a corresponding glucocorticoid excess. As
the age of the patient increases, there is a greater likelihood
of a pituitary cause of the syndrome. In patients younger
than 6 years, the most likely cause of endogenous Cushing
syndrome is an adrenal tumor. Although adrenocortical carcinomas represent only 0.2% of all childhood malignancies
and 6% of adrenal cancers, approximately 60% to 80% of pediatric Cushing syndrome cases are caused by adrenocortical
carcinomas.28
The clinical diagnosis of hypercortisolism must be
confirmed biochemically to diagnose Cushing syndrome. In addition, the specific source of the syndrome must be localized
(Fig. 41-2). Cortisol production is normally suppressed at
night, but in Cushing syndrome, this suppression does not
occur. The normal circadian rhythm of cortisol secretion is lost
in Cushing syndrome. Random serum cortisol levels are of limited value. The three most common tests used to diagnose
Cushing syndrome are the 24-hour urinary free cortisol test,
562
PART III
<100 g/day
24-hour
urinary free
cortisol
Repeat test
>100 g/day
>5 pg/mL
<5 pg/mL
ACTH
ACTH-independent
causes
ACTH-dependent
causes
Ratio < 2
(No suppression)
Ectopic ACTH-secretion
Inferior petrosal
sinus
sampling
or
High-dose
dexamethasone
suppression
Ratio >2
(Suppression)
Cushing disease
CT of
adrenal
glands
No
mass
or
nodules
Nodular
hyperplasia
Dominant
mass
Adenoma
Adenocarcinoma
FIGURE 41-2 Algorithm to localize the cause of hypercortisolism in children with suspected Cushing syndrome. ACTH, adrenocorticotropic hormone;
CT, computed tomography.
CHAPTER 41
ADRENAL TUMORS
563
Hyperaldosteronism
------------------------------------------------------------------------------------------------------------------------------------------------
564
PART III
Addison Disease
------------------------------------------------------------------------------------------------------------------------------------------------
Insufficient production of steroid hormones (either glucocorticoids or mineralocorticoids) can lead to Addison disease.
Children with Addison disease present with a variety of symptoms, including weakness, anorexia, weight loss, fatigue, nausea, vomiting, and diarrhea. If the child has an elevated ACTH
level, hyperpigmentation will develop, because melanocytes
are stimulated by ACTH. Seizures may also occur in the setting
of the hypoglycemia, which occurs with adrenal crisis.
There are many causes of adrenal insufficiency in children.
Congenital adrenal hypoplasia can result from either an autosomal recessive disorder or an X-linked disorder that occurs in
boys. Errors in steroid metabolism can also lead to adrenal
insufficiency. The most common group of inborn errors involves defects in glucocorticoid synthesis and is collectively
known as congenital adrenal hyperplasia. Acquired lesions
involving the hypothalamus or pituitary can also lead to adrenal
insufficiency through a reduction in CRH or ACTH secretion.
Destruction of the adrenal glands can also lead to adrenal
insufficiency. Conditions causing adrenal demise include
hemorrhage, infection, adrenoleukodystrophy, and autoimmune diseases. In older patients, overwhelming infection
can lead to adrenal hemorrhage. Tuberculosis used to be a
common cause of infectious destruction of the adrenal; however, the incidence of this condition has fallen in modern
times. One of the more common causes of acute adrenal insufficiency is cessation of chronic exogenous glucocorticoid
administration.
In newborns, adrenal hemorrhage is not an uncommon
event. In fact, the adrenal gland is the second most common
source of hemoperitoneum in the newborn period.38 The
pathogenesis of adrenal hemorrhage in newborns is not
fully understood. Associated factors include traumatic delivery,
asphyxia, maternal hypotension, overwhelming infection, or
hemorrhagic disorders.35,39 The incidence of adrenal hemorrhage is almost 2 cases per 1000 live births,1 but as the
sensitivity of imaging technology improves, this number may
increase. Adrenal hemorrhage occurs 3 to 4 times more frequently in the right adrenal gland than the left and is bilateral
in 8% to 10% of patients.39 This bias toward the right
side may be due to the direct drainage of the right adrenal gland
into the inferior vena cava, making the right gland more
susceptible to changes in venous pressure. The left gland
remains somewhat protected by its drainage into the left renal
vein. The fetal cortex contributes to fetal and neonatal adrenal
hemorrhage because of both its size and its later involution.
The large size of the fetal cortex makes the adrenal glands
relatively large, increasing their vulnerability to trauma. The
normal adrenal gland is easily visualized by US during
the first week of life. The adrenal soon involutes, and the distinction between the cortex and the medulla is lost. The physiologic
involution of the fetal cortex may occur quite rapidly, tearing the
unsupported central adrenal gland vessels.38
On prenatal US, adrenal hemorrhage appears as an echogenic mass. This mass becomes increasingly hypoechoic
Adrenalectomy
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 41
ADRENAL TUMORS
565
the right adrenal vein and the greater risk of tearing this vessel.
Multiple veins may be present and should be identified to prevent accidental avulsion. During the anterior approach to the
left adrenal gland, the initial maneuver is to mobilize the
splenic flexure of the colon. The pancreas and spleen are
retracted superiorly, and the Gerota fascia is opened, exposing
the left adrenal gland. Alternatively, the surgeon can divide the
gastrocolic ligament, mobilizing the stomach superiorly and
the transverse colon inferiorly. The posterior peritoneum
along the inferior pancreatic border can then be incised,
allowing mobilization of the pancreatic tail and exposure of
the adrenal vein. The left adrenal vein enters the renal vein superiorly and can be ligated in this plane. Several arteries enter
the medial surface of the adrenal gland from the lateral side of
the aorta; these arteries need to be divided before adrenal
Early control and ligation of the adrenal vein limit the release
of catecholamines as the tumor is removed.
During the anterior approach to right adrenalectomy,
the duodenum is mobilized by the Kocher maneuver
(Fig. 41-3) by reflecting the transverse colon inferiorly and
mobilizing the duodenum medially. This exposes the upper
portion of the right kidney as well as the right adrenal gland.
The Gerota fascia is opened, and the right lobe of the liver is
retracted in a cephalad direction. The most important element
of the procedure is the dissection between the medial border
of the adrenal mass and the lateral wall of the inferior vena
cava. This plane is developed in a cephalad direction until
the relatively short right adrenal vein is identified entering
the vena cava. There is a greater risk of hemorrhage on the
right side than on the left, because of the shorter length of
Live
r
Adrenal gland
Duodenum
Sto m
ac
o
col
Tran s
vers e
Rt. kidney
Vena cava
Adrenal tumor
Spleen
Stomach
and
pancreas
L. kidney
B
FIGURE 41-3 Transabdominal approach to tumors of the adrenal glands. A, The right adrenal gland is exposed by reflecting the transverse mesocolon
inferiorly, mobilizing the duodenum medially with a Kocher maneuver, and incising the posterior fascia to expose the diaphragm, adrenal gland, and
superior pole of the right kidney. B, The left adrenal gland is exposed by dividing the gastrocolic ligament and elevating the stomach. The colon is retracted
inferiorly, and the pancreas is elevated, exposing the adrenal gland and left adrenal vein that enters the renal vein.
566
PART III
removal. The posterior approach to the adrenal gland is accomplished most commonly through the bed of the 11th
rib. This strategy avoids intraperitoneal dissection, eliminates
postoperative adhesions, and decreases postoperative ileus.
The posterior approach is not useful for bilateral adrenal
lesions, malignancies, or large vascular tumors. The thoracoabdominal approach to adrenalectomy is best applied to
very large unilateral lesions. Although this approach provides
optimal exposure of large vascular tumors; postoperative pain
and impairment of ventilation limit its application.
The first laparoscopic adrenalectomy was reported in
an adult in 1991.44 Since then, a number of studies involving laparoscopic adrenalectomy in children have been
published,45,46 demonstrating the feasibility and safety of this
approach. Most commonly, laparoscopic adrenalectomy is
performed with the patient in the lateral position. A kidney
rest elevates the flank opposite the adrenal lesion. Four
or five trocars are placed in a subcostal position on the side
of the adrenal gland to be resected. Exposure is improved
on the right side by dividing the right triangular ligament of
the liver. Division of the lienocolic ligament on the left
improves exposure of the left adrenal gland. When possible,
CHAPTER 42
HAMARTOMA
Pulmonary hamartoma is the second most frequent benign lesion seen in children. These lesions usually present as parenchymal lesions and can be quite large. Approximately one
quarter are calcified, and popcorn-like calcification is pathognomonic.11 Two endobronchial lesions have been reported.
Four tumors occurring in the neonatal period were quite large
and were associated with significant respiratory distress; all
were fatal. An interesting triad is the combination of pulmonary hamartoma, extraadrenal paraganglioma, and gastric
smooth muscle tumors; the majority of these patients are
young women. Carney triad, in addition to its female predilection, is seen in young patients, is associated with multifocal
gastrointestinal stromal tumors (GISTs) and has an unpredictable biological behavior.12 Conservative pulmonary resection
is the treatment of choice; however, lobectomy, or even pneumonectomy, may be required, especially for large lesions and
endobronchial lesions when sleeve resection is not possible.
------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------------
BRONCHIAL ADENOMA
The most frequently encountered malignant primary pulmonary tumor is bronchial adenoma. These tumors are a heterogeneous group of primary endobronchial lesions. Although
adenoma implies a benign process, all varieties of bronchial
567
568
PART III
Benign (n 92)
Plasma cell granuloma
Hamartoma
Neurogenic tumor
Leiomyoma
Mucous gland adenoma
Myoblastoma
Benign teratoma
48 (52.2)
22 (23.9)
9 (9.8)
6 (6.5)
3 (3.3)
3 (3.3)
1 (1.1)
Malignant (n 291)
Bronchial adenoma
Bronchioalveolar carcinoma
Pulmonary blastoma
Fibrosarcoma
Rhabdomyosarcoma
Leiomyosarcoma
Sarcoma
Hemangiopericytoma
Plasmacytoma
Lymphoma
Teratoma
Mesenchymoma
Myxosarcoma
118 (40.5)
49 (16.8)
45 (15.5)
28 (9.6)
17 (5.8)
11 (3.8)
6 (2.1)
4 (1.4)
4 (1.4)
3 (1.0)
3 (1.0)
2 (1.7)
1 (0.3)
BRONCHOGENIC CARCINOMA
Although bronchogenic carcinoma is rare in children, this tumor was the second most common malignant lesion reported
by Hancock and colleagues.2 Interestingly, squamous cell carcinoma was rare, with the majority of tumors being either
undifferentiated carcinoma or adenocarcinomas. The term
bronchioalveolar carcinoma has been used in most cases.21
These tumors are associated with both cystic adenomatoid
malformations and intrapulmonary bronchogenic cysts
(Table 42-2).4,11,2138 Only rare survivors have been reported,
TABLE 42-2
Bronchioalveolar Carcinoma Associated with Congenital Cystic Lung Malformations
Year of
Publication
Type of Lung
Cyst
Age at Diagnosis
(Year)
Author Comments
Prichard22
Hurley23
Benjamin24
1984
1985
1991
CCAM type 1
CCAM type 1
CCAM type 1
30
19
Morresi21
Ribet26
Kaslovsky27
Granata28
Endo29
1995
1995
1997
1998
1982
20
42
11
11
37
De Perrot30
2001
MacSweeney31
2003
Sudou32
2003
CCAM type 1
CCAM type 1
CCAM type 1
CCAM type 1
Bronchogenic
(intrapulmonary)
Bronchogenic
(intrapulmonary)
CCAM type 1, 0.5,
13, 18, 30, 36
CCAM type 1
79
17
Adapted from LaBerge JM, Puligandla P, Flageole H: Asymptomatic congenital lung malformations. Semin Pediatr Surg 2005;14:16-33.
BAC, bronchioalveolar carcinoma; CCAM, congenital cystic adenomatoid malformation; CXR, chest radiograph.
CHAPTER 42
569
PULMONARY BLASTOMA
Pulmonary blastoma is a rare malignant tumor that occurs
primarily in adults and arises from mesenchymal blastema.
This tumor is an aggressive lesion, with metastatic disease at
presentation in approximately 20% of cases.40,2 They may
arise from the lung, pleura, and mediastinum.41 These tumors
are classified into three types: type I (purely cystic), type II
(cystic and solid), and type III (completely solid).42 Type I
tumors may be difficult to distinguish from cystic adenomatoid malformation.43 Occasionally, these tumors may arise
in an extralobar sequestration or in a previous lung cyst
(Table 42-3).22,25,29,36,41,4473 The majority of cases occur in
the right hemithorax (Fig. 42-2). Frequent sites of metastases
TABLE 42-3
Mesenchymal Malignancy and Cystic Lung Malformations
Author
Year
Type of Malignancy
Stephanopoulos44
Ueda45
Martinez46
Valderrama47
Sumner48
Weinberg49
Krous50
Weinblatt51
Holland-Moritz36
Morales25
Williams52
Allan53
1963
1977
1978
1978
1979
1980
1980
1982
1984
1986
1986
1987
Myxosarcoma
RMS
Pulmonary blastoma
Pulmonary blastoma
Pulmonary blastoma
Mixed mesenchymal sarcoma
Embryonal RMS
Pulmonary blastoma
PPB
Pulmonary blastoma
Embryonal RMS
RMS
Hedlund54
Cairoli55
Domizio56
Senac57
Murphy58
Bogers59
Calabria60
McDermott61
Seballos62
Tagge63
Adirim64
DAgostino65
Federici66
Ozcan67
Papagiannopoulos68
Stocker69
1989
1990
1990
1991
1992
1993
1993
1993
1994
1996
1997
1997
2001
2001
2001
2002
Cystic hamartoma
CCAM
Polycystic disease
Extralobar sequestration
Peripheral cyst
Congenital lung cyst
Bronchogenic cyst (intrapulmonary)
Cystic lung disease
Pneumatocele
Congenital cyst
CCAM
Congenital origin of cysts not
confirmed
Cystic hamartoma
CCAM
Congenital cyst
Bronchogenic cyst, CCAM (2)
Lobar emphysema
Pneumatoceles
Congenital cyst
CCAM
Bilateral pneumatocele
CCAM type 1
CCAM type 2
CCAM type 1
CCAM
CCAM type 4
CCAM type 4
RMS
RMS
Malignant mesenchymoma
PPB
Embryonal RMS
RMS
Pulmonary blastoma
Embryonal RMS
Pulmonary blastoma
PPB
Pulmonary blastoma
Embryonal RMS
PPB
Embryonal RMS
PPB
PPB
Adapted from LaBerge JM, Puligandla P, Flageole H: Asymptomatic congenital lung malformations. Semin Pediatr Surg 2005;14:16-33.
CCAM, congenital cystic adenomatoid malformation; CPAM congenital pulmonary airway malformation; PPB, pleuropulmonary blastoma;
RMS, rhabdomyosarcoma.
Age at Diagnosis
(Months)
18
24
48
108
30
30
48
21
21, 30
18, 22
36
48
24, 36, 42
18
36
22
45
22
36
13
30
48
570
PART III
FIGURE 42-2 A, Computed tomography scan of the chest shows a cystic lesion in the right hemithorax. B, The tumor was resected (lobectomy), and the
histology showed findings consistent with a pleuropulmonary blastoma. (Courtesy Jay L. Grosfeld, MD.)
Although children with primary lung tumors represent a heterogeneous group of patients, analysis of the reported cases suggests
that evaluation and treatment are similar in the majority of
patients. Many children are asymptomatic, especially those with
benign tumors; however, cough, recurrent pneumonitis, and
symptoms of atypical bronchial asthma may be the initial presentation. Radiographic findings usually indicate a solitary mass lesion or evidence of airway obstruction with resultant atelectasis
and pneumonitis. Because many of these tumors can be visualized by bronchoscopy, a bronchoscopic examination should be
performed. Flexible bronchoscopic techniques may be helpful
for diagnosis, but the use of rigid bronchoscopy with modern
magnification, along with general anesthesia, is necessary if endoscopic biopsy is contemplated. Preparation for emergency
thoracotomy should be made at the time of bronchoscopy in
the event of life-threatening hemorrhage.
Bronchoscopic removal of some isolated lesions may be
attempted, but because of the high incidence of recurrence
and the possibility of severe hemorrhage, this technique should
be used selectively. Conservative surgical resection is the procedure of choice for benign pulmonary tumors to achieve histologic diagnosis and preserve maximum functioning lung
tissue. Thoracoscopic resection is an option in these children.83
CT and magnetic resonance imaging should be performed in
children with large space-occupying lesions to determine resectability. Fine-needle aspiration for cytology or core needle biopsy
may be performed as the initial procedure for diagnosis in selected cases. Treatment of malignant lesions varies, depending
on location and histology. Sleeve resections should be considered for bronchial adenomas. Resection of involved lymphatics
should be considered with malignant lesions. Combinedmodality therapy with adjuvant chemotherapy and possibly radiation therapy may be helpful in children with large primary
malignancies or dissemination.
An important consideration is the association of primary
lung tumors with congenital cystic pulmonary malformations.
These lesions may be asymptomatic and are often discovered
incidentally. In some instances, the natural history of the lung
cyst is unknown, and a few may regress.80 Although some authors recommend simple observation, most pediatric surgeons argue against prolonged observation of cystic lesions
because of an increased risk of infection, pneumothorax,
sudden cyst enlargement with potential respiratory compromise, and associated malignancy.* As mentioned previously,
are the liver, brain, and spinal cord. Local recurrences are frequent, and the mortality rate is approximately 40%.2,7476 The
majority of children present before 4 years of age, and symptoms include persistent cough, chest pain, episodes of pneumonia that are refractory to antibiotics, and hemoptysis.
Diagnosis is achieved by CT of the chest, bronchoscopy, and
biopsy. Because most of these tumors are located peripherally,
resection is usually possible by segmental or lobar resection.
The use of multimodal neoadjuvant chemotherapy and radiation following surgical resection has shown promising results
in a few patients with extensive disease and dissemination.41,75
Chemotherapeutic agents that have been used include actinomycin D, vincristine, cyclophosphamide alternating with
courses of doxorubicin, and cisplatin. Histologic evaluation
of the tumor shows an exclusive mesenchymal composition,
including primitive tubules, immature blastema, and spindle
cell stroma. Some demonstrate elements of embryonal rhabdomyosarcoma (RMS) arising within a multicystic lesion.
RHABDOMYOSARCOMA
RMSs of the lung are rare and account for only 0.5% of all
childhood RMSs (see Chapter 35).45,77 Many of the lesions
are endobronchial in origin (Fig. 42-3); however, several
cases apparently originated in congenital cystic anomalies.
(see Table 42-3).* This is an important issue because 4% of benign tumors and 8.6% of malignant tumors enumerated in
Table 42-1 were associated with previously documented cystic
malformations.2 Tumors that developed in these malformations included 11 sarcomas, 9 pulmonary blastomas, 3 bronchogenic carcinomas, and 2 mesenchymomas.
COMMENTS
CHAPTER 42
571
FIGURE 42-3 Patient with complete atelectasis of the left lung (A) and obstruction of the left main bronchus secondary to rhabdomyosarcoma (B).
Pulmonary metastases occur much more frequently than primary tumors in children, and the surgical approach depends
on the histology of the primary tumor and the response of the
primary site to combined-modality therapy.72,85 Pulmonary
metastases should not be considered for resection until the
primary tumor is eradicated, without evidence of recurrence
and other sites of metastatic disease ruled out. Tumors most
frequently considered for pulmonary metastasectomy are
osteosarcoma (OS), soft tissue sarcoma, and Wilms tumor.86
OSTEOSARCOMA
Children with OS should be considered for resection of pulmonary metastases once the primary lesion is controlled. The
overall disease-free survival is approximately 40% in children
who develop metachronous pulmonary metastases. Multiple
factors, such as number of pulmonary nodules and time of recurrence, play an important role in children with OS and
572
PART III
TABLE 42-4
Pulmonary Metastasectomy for Osteogenic Sarcoma
Martini92
Spanos93
Telander82
Giritsky34
Rosenberg94
Marion70
Schaller38
Goorin89
Carter95
Average Interval
to Relapse
No. of Procedures
(Months) (Range)
Disease-Free Survival,
(No. of Lesions)
No. of Patients
(Range)
22
29
28
12
18
12
17
32
43
10 (2-25)
15.7 (4-30)
9/6 (2-34)
9 (1-21)
13 (2-20)
12.5 (4-59)
13 (1-83)
59 (113)
52 (124)
60 (173)
19
9
34
26 (>63)
7 (32)
11 (37)
13 (46)
6 (50)
7 (39)
5 (42)
7 (41)
9 (28)
4 (10)
33 (15-234)
36 (9-234)
25 (6-48)
17 (9-39)
(36-72)
(12-192)
55 (19-101)
69 (59-80)
From LaQuaglia MP: The surgical management of metastases in pediatric cancer. Semin Pediatr Surg 1993;2:75-82.
is not responsive to chemotherapy or radiation.97 Musclesparing techniques are available in those children requiring
posterolateral thoracotomies, and thoracoscopy may be appropriate in certain cases.37 New localization techniques
are being developed to aid in the thoracoscopic resection of
lung lesions.81 However, port site recurrences have been
reported following thoracoscopic resection of pulmonary
metastatic disease.98,99
WILMS TUMOR
EPIDEMIOLOGY
Tumors of the chest wall are rare entities in the pediatric population with an incidence of no more than 2%,100,101 and up
to two thirds of these lesions are malignant.102 The majority
arise from the bony structures of the chest wall (55%), as
opposed to soft tissue (45%).103 Collectively, a 60% 5-year
overall survival rate for all tumors has been reported, with a
recurrence rate of 50% (local and distant) and subsequent
5-year survival rate of only 17%.104
COMMENTS
Operation for pulmonary metastases in children depends on
the histology of the primary tumor, the extent of the metastatic
disease, and whether the metastatic disease is responsive to
chemotherapy. The surgical approach varies, depending on
the disease process and the age of the patient. No difference
in survival has been demonstrated with sequential lateral thoracotomy versus sternotomy, but the latter is preferable in
older patients with OS. Complete resection of all metastatic
disease is an important consideration, and the use of
automatic stapling devices can be helpful. Wedge resection
is usually possible in children with OS. However, formal lobectomy or segmentectomy may be required to remove all
of the tumor completely, especially when the primary tumor
PRESENTATION
Masses of the chest wall typically present as lumps bulging underneath the skin, and the majority of malignant lesions have
pain as a presenting symptom as well. In young children and
infants, they are often found incidentally by caregivers, while
older children and young adults may present with larger
masses that have been present and growing for some time. Incidental discovery on routine chest imaging has been reported
to be as high as 20%.105 They can be found anywhere on the
thorax, and the tissue of origin is generally mesenchymal in
nature, regardless of whether the tumors are malignant or
benign. Hence, sarcomatous variants are the most common
malignant tumors, while carcinomas are almost nonexistent.
The minority of patients present with nonspecific symptoms
of respiratory compromise or dysfunction (tachypnea,
hypoxia, cough, dyspnea on exertion), and these symptoms
may have been present for quite a while before seeking
medical advice. Symptoms stem from parenchymal compression from the mass intruding into the pleural space and onto
the lung or from malignant effusions, both of which interfere
with normal respiratory mechanics. Regardless of the presentation, a full history and physical exam, including a family
CHAPTER 42
DIAGNOSTIC ADJUNCTS
Once the initial evaluation has been performed in the office,
basic laboratory evaluations for complete blood count, coagulation profile, and baseline chemistries are needed. Imaging
studies should consist first of erect, posterior-anterior, and lateral chest radiographs to evaluate the location, size, presence
of calcifications, osseous involvement, and the presence of
pulmonary parenchymal disease. Next, an ultrasound exam
to determine the echo features (solid versus cystic, degree of
homogeneity) and vascularity of the mass is recommended.
Axial imaging (computed tomography or magnetic resonance
imaging [MRI]) is performed afterward. The advantages of CT
reside in its ability to clearly define the lung parenchyma and
pleural space in relation to the osseous, vascular, and soft
tissue components of the thorax (and hence mass), and the fact
that it is a fast technique requiring minimal to no sedation even
in the youngest of patients. The negative aspects of CT are the
radiation exposure with subsequent risk of a secondary malignancy.106 The benefits of MRI include better definition of the
soft tissue components versus CT, as well as enhanced evaluation of the osseous and neural structures to determine the extent of central or peripheral nerve involvement and/or the
presence of skip lesions or metastases. Unfortunately, this
technique is time consuming and generally requires sedation
or even general anesthesia to adequately acquire the data. Motion artifact from the heart and lungs can also interfere with
this technique, limiting its utility, but this obstacle is being
overcome with the use of cardiac-gated, respiratory-triggered
protocols.107,108 Determination of the precise entity from
radiology studies alone is impossible, but the accurate construction of a differential diagnosis is readily possible, including the differentiation of malignant versus benign
lesions.107,108 Finally, other imaging studies may also be
indicated to determine the presence of metastases (brain and
abdominal CT, bone scan, positron emission tomogram [PET]
scan) depending on the type of lesion, especially if malignant.
Recent reports have suggested that the combination of PET
and CT scans yields more accurate data in assessing the primary tumor, local and regional lymph node basins, evidence
of recurrence, and for response to ongoing therapies.109,110
Once initial studies have been performed, retrieval of tissue
for histopathologic evaluation and diagnosis is warranted.
DIAGNOSIS
Biopsy options include small or large specimen approaches. If
a mass is small (less than 3 centimeters) or thought to be benign, then an upfront excisional biopsy may be warranted.
However, the incision should be oriented so that a future reexcision, if needed, can be performed without compromising
oncologic principles. Excising a normal rim of tissue circumferentially around the mass is also something for which the
surgeon should opt. If the mass is large (greater than 4 to 5
centimeters), fixed to surrounding structures, involving many
structures in the thorax, or if it is considered malignant by
573
THERAPEUTIC PRINCIPLES
Though treatment regimens are tumor specific, there are certain general principles that apply. For malignant lesions, multimodality therapy is the accepted paradigm for the majority of
lesions, while simple extirpation is the rule with benign entities. With surgery, the most important concept to emphasize is
that of the need for negative margins to decrease the risk of
recurrence and subsequent therapy. Surgical extirpation also
mandates wound reconstruction, which must be considered
prior to the initiation of operative therapy. Large defects
(greater than 5 centimeters, except for posterior and superior
lesions where the defect will be buttressed by the scapula) will
require the use of prosthetic materialsrigid (silicone, Teflon
[DuPont, Wilmington, Del.], methyl methacrylate) or flexible
(Prolene mesh [Ethicon, Cincinnati, Ohio], PTFE mesh, Marlex mesh [Chevron Phillips Chemical, Bartlesville, Okla.],
Gore-Tex [WL Gore & Associates, Newark, Del.])and/or autologous tissues (pedicle or free flaps [latissimus dorsi, rectus
abdominis, or pectoralis major]) to reconstruct the chest wall
and thus ensure normal chest wall mechanics and prevent respiratory embarrassment.
TUMOR TYPES
Chest wall tumors are separated into benign and malignant cohorts (Table 42-5), as well as primary and secondary lesions.
Specific tumors and their treatment will be outlined in the
subsequent sections, but a discussion concerning secondary
tumors is beyond the scope of this work.
Benign Chest Wall Tumors
Aneurysmal Bone Cyst Aneurysmal bone cysts (ABCs) can
be found anywhere on the chest wall, and they generally
arise in the ribs. They have characteristic patterns of appearance
on both chest radiographs and MRI,107 and they can grow to be
quite large, producing local destruction to the adjacent tissues.
Surgical extirpation with complete excision is the treatment of
choice, and recurrence is rare. Histologically, the lesions are
blood-filled cysts composed of fibrous tissue and giant cells.
Chondroma Chondromas are slow growing, painless masses
that usually arise in the costal cartilages. On imaging studies,
they are lytic lesions with sclerotic margins, and unfortunately,
they are difficult to distinguish radiographically from their malignant brethren, chondrosarcomas. Hence, complete resection
with a wide margin of normal tissue is advocated.112
Desmoid Desmoid tumors are fibrous neoplasms that can be
found anywhere in the body. They are thought to be benign,
but they have also been reported to undergo malignant degeneration.112 Desmoid tumors infiltrate adjacent and surrounding tissues, and they are known to travel down fascial planes
and to encase neurovascular structures in the mediastinum or
574
PART III
TABLE 42-5
Pediatric Chest Wall Tumors
Benign
Aneurysmal bone cyst
Chondroma
Desmoid
Fibroma
Fibrous dysplasia
Lipoblastoma
Lipoma
Mesenchymal hamartoma
Osteochondroma
Osteoma
Vascular malformations
Malignant
Chondrosarcoma
Ewing sarcoma family
Fibrosarcoma
Langerhans cell histiocytosis
Leiomyosarcoma
Leukemia
Liposarcoma
Lymphoma
Neuroblastoma
Rhabdomyosarcoma
Osteosarcoma
B
FIGURE 42-4 Axial (A) and coronal (B) images of a computed tomography scan of the chest in an infant with a mesenchymal hamartoma.
Osteochondroma Osteochondromas are tumors composed of bony and cartilaginous elements more commonly
found in males (3:1 ratio).112 The lesion can present
with pain from a pathologic fracture or compression of
nearby nerves, or it can be asymptomatic if it grows inward
into the thoracic cavity. The lesion is well characterized on plain radiographs, and it arises from the cortex
of the rib at the metaphysis and has a cartilage cap.120
Malignant degeneration has been documented,107 and resection
is warranted in all postpubertal patients, with symptoms, or if
the mass is growing.
CHAPTER 42
575
B
FIGURE 42-5 Axial images of a computed tomography scan of the chest
in a child with a Ewing sarcoma family/primitive neuroectodermal tumor
(EWS/PNET) of the chest wall before (A) and after (B) neoadjuvant
chemotherapy.
irradiation in all cases.134 Five-year survival using the previously mentioned protocol was around 70% for nonmetastatic
disease,135 and the 8-year survival was roughly 30% with
metastatic disease.136 In patients presenting with metastatic
disease, the European Intergroup Cooperative Ewings
Sarcoma Studies Group demonstrated improved survival
with the use of myeloablative chemotherapy followed by stem
cell rescue at the conclusion of conventional treatment
protocols.137
Fibrosarcoma Fibrosarcoma (FS) (also known as infantile
or congenital fibrosarcoma) are malignant tumors found
throughout the body in infants who present with large masses
that often involve, invade, and surround adjacent structures.
FS have been found in the chest wall, and several reports have
documented the success of multimodality therapy in combating these tumors.138,139 FS can be distinguished from other
myofibrous and sarcomatous lesions by the presence of a
unique gene rearrangement between the TEL gene (12q13)
and TRKC gene (15q25).138 FSs are chemotherapy sensitive,
and reports demonstrating the effectiveness of neoadjuvant
chemotherapy with vincristine, actinomycin, cyclophosphamide, and Adriamycin, followed by surgical extirpation, are
well accepted.138,139 A recent report139 from Europe
576
PART III
and presence of metastatic disease (including lymph node metastases).143,145 Despite advances in the treatment of RMS over
the last 40 years, unfavorable sites carry an overall survival of
only 55% (versus 90% for favorable sites),143 and those with
truncal RMS have been reported to have a failure-free survival
rate of no greater than 67%.146 These tumors require multimodality therapy, and neoadjuvant chemotherapy followed
by surgical extirpation is the norm. Radiation is reserved for
lesions with positive margins following surgery, or in unresectable tumors. A report from Saenz and colleagues documented
the utility of radiation (median dose of 44 Gy) to salvage some
patients with residual disease.146 However, the necessity for
complete surgical resection has been called into question by
a recent report from the Childrens Oncology Group
(COG),147 where the outcome of patients enrolled in IRS
I-IV with chest wall RMS were analyzed. The report documents that regardless of clinical group (I-III) and other
tumor-specific factors (histologic subtype, tumor size), the
only critical factor to influence failure-free and overall survival
was the presence of metastatic disease. In the face of metastases, patients with chest wall RMS had an overall and failurefree survival of 7% and 7% versus 49% and 61%, respectively,
in the cohort without metastases (P < 0.001). Therefore the
authors suggest where gross total surgical resection will
produce significant morbidity or physical debilitation, less
aggressive operative approaches should be entertained.
The complete reference list is available online at www.
expertconsult.com.
General Considerations
------------------------------------------------------------------------------------------------------------------------------------------------
PATHOPHYSIOLOGY
CHAPTER 43
Bone Tumors
Saminathan S. Nathan and John H. Healey
Bone tumors are rare. In the United States, there were 166,487
cases of breast cancer and 164,753 cases1 of prostate cancer in
2000. By comparison, there were only 2,051 cases of all types
of bone sarcomas that year. A large proportion of these tumors,
26.8% in one published database, occur in the pediatric population. There are no population-based benign bone tumor
registries; so, it would be impossible to establish their true
incidence. Most databases of this nature derive from tertiary
referral institutions, and so, benign conditions, which are
often asymptomatic, would be grossly underrepresented.
Nevertheless, one study has shown that up to 43% of children
have a bone lesion that mimics or is a true neoplasm during
skeletal development.2 This implies that the overwhelming
majority of lesions are benign.
The pediatric surgeon will often be called into the management of the patient with bone tumors for a number of
reasons. The very young child on follow-up for an unrelated
condition may manifest with a bone lesion secondary to
osteomyelitis or leukemia. The older child with a metastatic
osteogenic sarcoma may require the expertise of the pediatric thoracic surgeon for the resection of pulmonary nodules.
The teenager with a pathologic fracture through a unicameral bone cyst or nonossifying fibroma may present first to
the pediatric surgeon on call in the pediatric emergency
department.
The diagnosis of these rare conditions is readily attained
through a careful clinical evaluation. In that regard, the utility
578
PART III
TABLE 43-1
Commonly Occurring Tumors by Age Group
Age
Benign Tumors
Birth to
5 years
Eosinophilic
granuloma
5 to 15
years
Unicameral bone
cyst
Osteochondroma
Aneurysmal bone
cyst
Osteoid osteoma
Enchondroma
Nonossifying
fibroma
Chondromyxoid
fibroma
Chondroblastoma
Unicameral bone
cyst
Osteochondroma
Osteoid osteoma
Aneurysmal bone
cyst
Nonossifying
fibroma
Giant cell tumor
Enchondroma
Chondroblastoma
Chondromyxoid
fibroma
15 to 20
years
TABLE 43-2
Incidence of the More Commonly Diagnosed Bone Tumors
Malignant
Tumors
Tumor-like
Conditions
Leukemia
Metastatic
neuroblastoma
Ewing sarcoma
Osteogenic
sarcoma
Osteomyelitis
Nonaccidental
injury
Fibrous
dysplasia
Osteomyelitis
Osteofibrous
dysplasia
Stress fracture
Osteogenic
sarcoma
Ewing sarcoma
Fibrous
dysplasia
Stress fracture
Bone Tumors
All Bone
Tumors (%)
7.86
2.60
2.99
1.13
3.02
5.10
1.07
0.41
4.69
1.96
1.94
0.99
0.98
0.80
0.66
0.14
Unknown
Unknown
14.9
4.6
7.53
3.50
Benign
Osteochondroma
Aneurysmal bone cyst
Osteoid osteoma
Nonossifying fibroma
Enchondroma
Giant cell tumor
Chondroblastoma
Chondromyxoid
fibroma
Unicameral bone cyst
Malignant
Osteogenic sarcoma
Ewing sarcoma
By considering the factors of age, frequency, and location in the long bones
(see Fig. 43-3), a diagnosis can be proposed in the majority of cases. The
possibility of trauma should always be borne in mind, and in the
noncommunicative child younger than 5 years old, nonaccidental injury
may be the cause.
FIGURE 43-1 A, Chondrosarcoma in the proximal humerus of a 13-yearold boy. This is an exceedingly rare diagnosis in this age group.
B, A proximal humeral resection with allograft reconstruction was performed. In children, the available prostheses may be too large, and hence
bulk allografts may be the only choice.
CHAPTER 43
Benign lesions
BONE TUMORS
579
Malignant lesions
Enchondroma
Aneurysmal
bone cyst
Osteogenic
sarcoma
Osteochondroma
Unicameral
bone cyst
Non-ossifying fibroma
chondromyxoid fibroma
Ewings
sarcoma
Chondroblastoma
Osteoid osteoma
osteoblastoma
FIGURE 43-3 The location of lesions in relation to the physis gives a clue
to the diagnosis. In most cases, the diagnosis can be made on radiographs,
leaving further imaging to plan for surgery.
580
PART III
MALIGNANT LESIONS
Epidemiology
The main histologic types of bone tumors are osteogenic
sarcoma, Ewing family tumor, chondrosarcoma, and other sarcomas. They affect children at a rate of 6:3:2:1, respectively.1,5
Osteogenic sarcomas (also known as osteosarcomas) are
malignant bone-forming tumors of the bone. They occur at
any age but most frequently present in an extremity in the
middle teenage years. There are various subtypes with varying
implications for survival. In general, the subtypes behave
similarly, except perhaps for telangiectatic osteogenic sarcoma, which bears special mention. In the prechemotherapy
era this was regarded as the tumor with the worst prognosis.20
Presently, however, it has the best prognosis.21 The lytic nature of these sarcomas weakens bone, resulting in the highest
rate of pathologic fracture. Increasingly, rarer forms of osteogenic sarcoma are described. Two variants of note are the small
cell sarcoma and giant cell-rich osteogenic sarcoma. The
former can be confused with a Ewing family tumor and thus
is often treated by similar chemotherapy protocols.22,23
The latter can be confused, in the appropriate setting, with a
giant cell tumor of the bone, which is a benign condition.2426
The Ewing sarcoma occurs at a younger age (see
Table 43-1) and may affect any bone, particularly, the femur,
pelvis, and humerus. It is the most common cancer in the
pelvis, ribs, foot, and fibula. It was once considered to be distinct from peripheral neuroectodermal tumors but has been
shown to be genetically identical to this entity. It is presently
considered to be in the same family of neoplasms also known
as Ewing family tumors.3,6
Chondrosarcoma is less prevalent in the pediatric age
group. It is more widely distributed in the body compared
with its occurrence in adults.
Genetics There have been few consistent genetic or syndromic associations with osteogenic sarcoma. Patients with the
Li-Fraumeni syndrome27 have a TP53 germline mutation28,29
on 9p21 and are predisposed to osteogenic sarcoma, breast
cancer, and leukemia (Fig. 43-4). Two to 3 percent of patients
with osteogenic sarcoma will be the proband for Li-Fraumeni
families.30 Another germline mutation of 13q14, hereditary
retinoblastoma (RB), predisposes to osteogenic sarcoma.31
Children who received radiation therapy for retinoblastoma,
B
FIGURE 43-4 A, Osteogenic sarcoma in the left scapula of a female
patient with Li-Fraumeni syndrome. This patient had a family history of
osteogenic sarcoma in a first-degree relative. At the time of staging for
the osteogenic sarcoma in the scapula, a lesion in the breast was
discovered on computed tomography (CT) of the chest. This was subsequently found to be an adenocarcinoma. B, The patient underwent
a scapular replacement. A latissimus dorsi flap was used for skin cover.
CHAPTER 43
translocation. These rarer variants have not been as well studied but appear to confer a poorer prognosis.32 Further additive
mutations involving cell-cycle genes reduce the prognosis of
these tumors still more. The Ewing family tumor is the most
common solid tumor to metastasize to the brain.33
BONE TUMORS
581
Radiology
The minimal radiologic assessment at the first visit should be
two orthogonal radiographic views of the area in question.
A radiograph remains the most specific diagnostic imaging test
and is the only one that gives the gestalt of overall assessment
of skeletal biology and mechanics. By analyzing the location
of the tumor (see Fig. 43-3), as well as whether it is benign
or malignant, the diagnosis can be made in the majority of
cases.36
Benign lesions are well circumscribed, with a good sclerotic
border, and produce no soft tissue edema. Malignant lesions
have lucent or variegated matrices and permeative borders.
Edema is often apparent with the presence of fat lines.
The often-quoted eponymous phrases are not specific to
distinct malignancies. The Codman triangle refers to the lifting
and ossification of periosteum at the periphery of an osteogenic sarcoma. The sunburst appearance is due to the ossification of fibers and vessels subperiosteally, as the tumor
expands out of the cortex. Onion skinning refers to the periodic ossification and expansion of periosteum from the cortex.
Any of these conditions can be seen in tumors or infections
that are sufficiently fast growing.
In Figure 43-3, epiphyseal lesions are typical of chondroblastoma or giant cell tumors; physeal lesions are typical of
osteochondromas; metaphyseal lesions are typical of osteogenic sarcomas, unicameral bone cysts, aneurysmal bone
cysts, and nonossifying fibromas; and diaphyseal lesions
are typical of Ewing family tumor, fibrous dysplasia, or
enchondromas.
Laboratory Evaluation
The main blood parameters of importance are lactate dehydrogenase and alkaline phosphatase.3638 Lactate dehydrogenase
levels have been used as a surrogate for tumor load and have
been correlated with survival in the case of Ewing family tumor.36 Serum alkaline phosphatase elevation is characteristic
of osteogenic sarcoma and is correlated with poor survival in
this condition.37,38 Glucose intolerance is associated with
chondrosarcoma of the bone.39,40 Erythrocyte sedimentation
rates, C-reactive protein, and white blood cell and differential
counts should be sought to rule out infection.
Preoperative Planning
Magnetic resonance imaging (MRI) of the lesion offers an assessment of compartmentalization of the tumor. A compartment is an abstract concept and refers to any plane that
offers a fascial or cortical bone barrier to contiguous spread.
It has implications for the extent of surgery, which by definition must be outside the compartment to be radical (see
later).41 Also, by forming a baseline assessment, one is able
to make an assessment of response to chemotherapy in the
case of neoadjuvant treatment.42 It has secondary importance
in providing the actual diagnosis. In specific examples it is
useful in histologic diagnosis. The aneurysmal bone cyst
shows fluid-fluid levels on an MR image. Pigmented villonodular synovitis is hypointense (dark) on T1- and T2-weighted
imaging because of hemosiderin deposition. Cartilaginous
lesions are hyperintense (light) on T2-weighted imaging.
Mineralized and dense fibrous tissues are dark on T1- and
T2-weighted imaging.43,44
582
PART III
Staging
Staging studies are meant to assess the degree of spread of
the disease. In the case of bone tumors two systems are used:
the Enneking system or surgical staging system (SSS),45
as adopted by the Musculoskeletal Tumor Society and the American Joint Committee on Cancer (AJCC) system, which at the
time of writing is in its sixth revision.46 In the case of Ewing
family tumor, a different classification than Enneking is used.47
In the SSS, tumors are designated G0, G1, and G2 for benign,
low-grade, and high-grade lesions, respectively. Benign lesions
(G0) are classified as latent, active, or aggressivedesignated by
Arabic numerals 1, 2, and 3, respectively. Malignant lesions are
designated with the Roman numeral I if low grade and II if high
grade. The further designation A or B denotes intracompartmental or extracompartmental disease. Stage III disease
is metastatic disease. Therefore in this classification, grade,
compartmentalization, and metastases are the fundamental
prognostic factors.
In the AJCC system, I and II similarly designate low- and
high-grade lesions. The letters A and B designate tumors
smaller or larger than 8 cm, respectively. The Roman numeral
III denotes multicentric disease, and IV denotes metastatic
disease. The designation IVA denotes pulmonary metastases,
and IVB denotes extrapulmonary metastases. Therefore
this classification considers grade, size, multicentricity, and
metastases as prognostic factors.
In the Enneking staging system of Ewing family tumor, stage
I tumors are solitary intraosseous lesions, stage II are solitary
lesions with extraosseous extension, stage III are multicentric
lesions, and stage IV are metastatic. It is unclear how to stage
patients who have independent sites of bone marrow involvement versus those who have circulating tumor cells identified by light microscopy (i.e., Enneking stage III or IV).
Modern pathology analysis extends these concepts to include
immunohistochemistry or reverse transcriptase polymerase
chain reaction (RT-PCR) of recombinant gene products.
The modalities used for staging are bone scans and computed tomography (CT) of the chest.45 Positron emission tomography scans are presently being evaluated, but have
fundamental utility in the management of recurrent or metastatic disease.48 In the case of Ewing family tumor, bone marrow
biopsies are obtained to try capturing cases that are multicentric
at presentation. The utility of this approach is being evaluated.49
BIOPSY
The biopsy is a critical procedure that can complicate management severely if not performed appropriately. Misplaced
incisions continue to be an important cause of resectable
tumors being rendered nonamenable to limb salvage surgery.41,50 A good pathologist who is comfortable handling
bony tissue is critical to this process. In the appropriate case,
extra tissue may be needed for cytogenetic studies. Ewing
family tumors are particularly fragile, and biopsy specimens
should be handled carefully to allow for processing.
Presurgical Considerations
As a general rule, all imaging and staging should be completed
before biopsy. The lesion that warrants biopsy should be given
consideration for a primary wide excision. This approach is
CHAPTER 43
BONE TUMORS
583
B
A
ADJUVANT THERAPY
This section concentrates on the use of radiation and chemotherapy. In general, these modalities are not used in the treatment of benign conditions. Up to 10% risk of malignant
transformation occurs when benign lesions are irradiated.36
Both chemotherapy and radiation therapy can be used in
the neoadjuvant (preoperative) or adjuvant (postoperative)
setting in the treatment of malignant conditions. The neoadjuvant approach has the advantage of shrinking the tumor
and provides a more discernible margin, theoretically improving local control of the disease. In the case of chemotherapy,
before the era of modular prostheses, the neoadjuvant route
was necessary while the custom prostheses were manufactured. This technique has been shown to be as efficacious
as primary surgery. Even so, the one randomized trial of preoperative and postoperative chemotherapy versus only
SURGERY
In bone tumors, resection and reconstruction are two aspects
of management that have largely complementary but occasionally conflicting goals (e.g., cryotherapy is good for extending the margins of resection of a tumor but results in
weakening of the bone). Therefore, while the goals of resection are generally quite clear (i.e., cure), the goals of reconstruction are often compromised, especially in malignant
conditions. In benign conditions, reconstruction usually
restores more function. In this section, we present a general
list of considerations that will be elaborated further in the
section on specific considerations.
584
PART III
Resections
Amputations
Radical
Radical
Wide
Wide
Marginal
Marginal
Intralesional
Intralesional
CHAPTER 43
BONE TUMORS
585
Linear accelerator
Celiotomy
with shielded
adjacent
organs
Electron
beam
applicator
586
PART III
Tumor
Acetabulum remodelling in
Winklemann procedure
Winklemann rotationplasty
FIGURE 43-10 A, Osteogenic sarcoma (arrow) with large soft tissue extension in an 8-year-old child. The small size of the child and high level of activity
precluded endoprosthetic reconstruction. B, A Van Nes rotationplasty was performed. C, Variants of the rotationplasty are compared with the above-knee
amputation. The bottom panel illustrates how the proximal tibia remodels and accommodates the acetabulum in the Winkelmann procedure.
CHAPTER 43
BONE TUMORS
587
resections, the ability to provide intercalary stability with overlying skin closure can be provided by a vascularized fibular
graft with a skin paddle. The skin paddle affords the additional advantage of monitoring the viability of the flap. Rotationplasties and their variants are remarkably functional
solutions to the problem but have poor acceptance among patients because of their appearance. Similarly, amputations are
often an instant solution to the problem, although, even here,
the occasional exception exists.82
Joint reconstruction is a challenging endeavor. Biologic
solutions include the use of bulk allograft (Fig. 43-11). They
have the advantage of becoming incorporated by the body. The
disadvantages89 are a high fracture rate of 19%, a nonunion
rate of 17%, and an infection rate of 11%. Osteoarticular allografts also become arthritic (16%) with time. Theoretically,
however, with good incorporation of the allograft, a conventional, less-constrained joint replacement can be performed
(Fig. 43-12). The endoprosthetic solution tends to be easier
C
FIGURE 43-11 A, Ewing sarcoma of the proximal tibia in an 11-year-old
child. B and C, This was widely resected and reconstructed with an osteoarticular tibial allograft. A gastrocnemius flap was raised to provide soft
tissue cover to the construct.
588
PART III
FIGURE 43-13 A, Osteogenic sarcoma in a 16-year-old girl. B, An endoprosthetic device was placed in the patient after resection of the lesion. C,
As a child grows, it occasionally becomes necessary to swap implants
with devices that can provide further extensibility.
FIGURE 43-15 A, Osteogenic sarcoma of the proximal femur in a 14-yearold girl. B, A wide resection and bipolar hemiarthroplasty with proximal
femoral replacement was performed. Of note, the femoral head matched
the acetabulum; so, an additional bipolar component was not added.
FIGURE 43-14 A, Osteogenic sarcoma in proximal humerus of a 16year-old boy. B, A proximal humeral
resection with allograft and prosthetic composite was used to reconstruct the defect.
FIGURE 43-16 Ewing sarcoma of the tibia. The patient underwent wide
resection and a planned bone transport procedure. The middle ring (arrow)
is secured to a segment of bone that has been osteotomized. This segment
of bone is allowed 5 days for a provisional callus to form. By progressively
advancing the ring distally at a rate of 1 mm/day, the segment of bone is
transported to fill the defect, while at the same time remaining connected
to the proximal tibia. This regenerate is weak and requires an equivalent
amount of time to consolidate. For example, an 80-mm defect would require 5 days to form a provisional callus, 80 days to lengthen, and 80 days
to consolidate before removal of the frame. This ungainly device needs to
be tolerated by the patient for the duration of the limb-lengthening
procedure.
590
PART III
The development of immunohistochemical staining techniques allows pediatric tumors to be classified by histology.
Tumors can arise from any of the cell types of the central
nervous system. The brain is composed of neurons and glial
cells. Glial cells far outnumber the neurons, and provide a
nourishing and supportive role. The three main types of glial
cells are astrocytes, oligodendrocytes, and ependymal cells,
and the neoplasms they give rise to are gliomas. More specifically, they form astrocytomas, oligodendrogliomas, and ependymomas, respectively. Tumors involving both neuronal and
glial cells are called ganglion cell tumors and consist of gangliogliomas, desmoplastic infantile gangliogliomas, and gangliocytomas. Another mixed neuronal and glial tumor is a
dysembryoplastic neuroepithelial tumor (DNET). Finally,
there are embryonal tumors, which include medulloblastoma,
primitive neuroectodermal tumors (PNETs), medulloepithelioma, neuroblastomas, melanotic neuroectodermal tumors
in infancy, and atypical teratoid/ rhabdoid tumors (ATRTs).4
Other primary brain tumors include germ cell tumors, choroid plexus tumors, craniopharyngiomas, and meningiomas.
CHAPTER 44
Brain Tumors
Eamon J. McLaughlin, Michael J. Fisher,
Leslie N. Sutton, and Phillip B. Storm
Clinical Features
------------------------------------------------------------------------------------------------------------------------------------------------
The signs and symptoms of brain tumors in children vary considerably based on tumor type, location, and age of the patient. In the absence of a seizure or a focal neurologic
deficit (e.g., diplopia caused by sixth nerve paresis), the vast
majority of the symptoms are nonspecific and easily attributable to many more common and less serious causes. Common
symptoms may include headache, nausea, vomiting, lethargy,
subtle changes in personality, and worsening school performance. This constellation of symptoms can often be attributed
to gastrointestinal problems, depression, school anxiety, migraines, sinusitis, or the need for prescription eyeglasses. Even
a long-standing seizure disorder may ultimately be diagnosed
as a supratentorial brain tumor. Infants typically present with
failure to thrive, decreased intake, macrocephaly, or lethargy.
Because of the nonspecific nature of these symptoms, it is
common for a patient to present for neurologic evaluation
after having visited numerous other specialists without establishing a diagnosis.
Most pediatric patients with brain tumors are between
the ages of 2 and 14 years and typically present with a few days
to weeks of headache, nausea/vomiting, gait ataxia, and/or
diplopia. This constellation of symptoms is caused by hydrocephalus resulting from obstruction of the ventricles by tumor,
commonly located in the midline posterior fossa. Headaches
are common in children with viral infections, whereas
frequent, daily morning headaches should raise the clinical
suspicion of an intracranial mass lesion. This is especially true
in the absence of a fever or other viral sequelae. Patients with
elevated intracranial pressure often have an exacerbation of
their symptoms in the morning. Both lying in the recumbent
position overnight and sleep-induced hypoventilation (which
leads to an increase in Pco2) cause an increase in intracranial
pressure. Elevated intracranial pressure can also cause the cerebellar tonsils to herniate into the foramen magnum and result
in occipital headaches and neck pain.
There are two instances in which tumors cause nausea and
vomiting. One is the elevation of intracranial pressure, and the
other is direct irritation/infiltration of the vomiting center. The
591
592
PART III
TABLE 44-1
Brain Tumors in Children
Age
Tumor Histology
0 to 2 years
Teratoma
Primitive neuroectodermal tumor
Astrocytoma (high grade)
Choroid plexus papilloma
Supratentorial tumors (50%)
Astrocytoma (low grade)
Craniopharyngioma
Hypothalamic glioma
Primitive neuroectodermal tumor
Ependymoma
Choroid plexus papilloma
Infratentorial (50%)
Primitive neuroectodermal tumor: medulloblastoma
Cerebellar astrocytoma
Ependymoma
Brainstem glioma
2 to 15 years
insipidus, short stature, truncal obesity, galactorrhea, and precocious or delayed puberty. These symptoms result from tumors affecting the hypothalamic-pituitary axis. Because of
the proximity of these tumors to the optic nerves and chiasm,
they often cause decreased vision and visual field deficits.
Radiographic Evaluation
------------------------------------------------------------------------------------------------------------------------------------------------
Patients suspected of having a brain tumor should be evaluated with an MRI with and without gadolinium. Although
MRI is the gold standard for evaluating tumors, many patients
presenting in the emergency department with progressive
clinical signs and symptoms of a brain tumor are evaluated
with a head computed tomography (CT) without instillation
of a contrast medium. CT is the ideal imaging modality to
use during emergent situations for a number of reasons. CT
is excellent in evaluating hydrocephalus and hemorrhage,
the two main causes of rapid neurological decline. Furthermore, CT can be performed in minutes, frequently does not
require sedation, gives excellent detail and information, and
is considerably less expensive. If the patients condition is rapidly deteriorating, a contrast agentenhanced head CT is occasionally performed to better characterize the lesion for the
radiologist and neurosurgeon when the patient requires emergent surgical intervention. If the patients condition is stable,
the contrast agent may be omitted, and MRI with and without
gadolinium should be performed, the timing of which is dictated by the clinical signs and symptoms.
Magnetic resonance imaging provides much better resolution of the brain and provides images in the sagittal, axial, and
coronal planes. Standard MR imaging combined with newer
imaging sequences and spectroscopy can even point to a
specific histologic diagnosis.7 Furthermore, it is difficult to
evaluate the lower brainstem with CT, because of the bony
artifact from the skull base. One limitation of MRI is that it
does not show intratumoral calcifications very well, and occasionally, patients require both studies to aid in establishing the
proper diagnosis.
Magnetic resonance imaging with and without gadolinium
can provide significantly more information about the patients
tumor. The bloodbrain barrier is made up of tight junctions
in the endothelial cells lining the capillaries in the brain,
which prevent most blood contents from entering the brain,
including gadolinium. However, certain brain tumors cause
breakdown of the bloodbrain barrier and permit the gadolinium to enter the tumor and then enhance the tissues (appear
bright on T1-weighted images). In general, in the adult population, enhancement in an intra-axial lesion means a more
aggressive brain tumor and a poorer prognosis. This is not
as consistent in pediatric tumors. There are many enhancing
pediatric brain tumors that are not aggressive and are curable
with total resection.
When viewing an MRI, the important factors to consider
are (1) the location of the tumor (e.g., supratentorial, infratentorial, pineal region, suprasellar), (2) whether the tumor is
intra-axial (within the brain tissue) or extra-axial (outside
the brain tissue), (3) the age of the patient, (4) whether the
tumor enhances, and (5) if there are single or multiple lesions.
By systematically assessing the scans and considering these
factors, the differential diagnosis can be narrowed considerably, which can be extremely helpful in preoperative planning.
CHAPTER 44
Surgical Intervention
------------------------------------------------------------------------------------------------------------------------------------------------
BRAIN TUMORS
593
594
PART III
Tumor Types
------------------------------------------------------------------------------------------------------------------------------------------------
CEREBELLAR ASTROCYTOMAS
These tumors are usually low-grade and curable with total surgical resection. The average age at presentation is 9 years, and
the patient normally presents with pernicious vomiting, intermittent morning headaches, and disturbances of balance, usually spanning a period of months. The classical CT appearance
of these tumors is a hypodense, cystic cerebellar mass (usually
around the vermis) with a brilliantly enhancing mural nodule.18 However, about one fourth will be entirely solid tumors. MRI is helpful in defining the surgical anatomy, such
as the relationship of the tumor to the brainstem, and the
nature of the cyst wall. Cerebellar astrocytomas are typically
of low signal intensity on T1-weighted MRI sequences, demonstrate increased intensity on T2-weighted sequences, and
show enhancement of the solid component with gadolinium
(Fig. 44-1). Because of their location and size, they cause
CHAPTER 44
BRAIN TUMORS
595
C
FIGURE 44-1 A, Axial T1WI postgadolinium image of a cerebellar pilocytic astrocytoma, in a 3-year-old boy, showing a large cyst (white asterisk)
and enhancing mural nodule (white arrowhead). B, Axial T2WI image showing markedly dilated lateral ventricles and transependymal flow of cerebral spinal
fluid (CSF) out of the ventricles into the surrounding brain parenchyma (black arrows). The obstructive hydrocephalus is a result of the cerebellar
astrocytoma. C, Sagittal T2WI postoperative image showing resection of tumor and flow through the floor of the third ventricle (white arrow) after the
endoscopic third ventriculostomy done at the time of tumor resection.
FIGURE 44-2 A, Axial T1WI postgadolinium image, in an 8-year-old boy, showing an enhancing primitive neuroectodermal tumor (PNET) arising from the
roof of the fourth ventricle and involving the cerebellar vermis (white arrow). B, Axial T1WI postoperative image showing resection of tumor and partial
splitting of the vermis (white arrowhead). The patient suffered severe postoperative mutism.
596
PART III
EPENDYMOMAS
CHAPTER 44
BRAIN TUMORS
597
BRAINSTEM GLIOMAS
HYPOTHALAMIC/CHIASMATIC
ASTROCYTOMAS
FIGURE 44-5 A, Sagittal T2WI image in a 4-year-old girl showing an infiltrative, hyperintense tumor in the pons (white arrow). B, Sagittal T1WI postgadolinium image showing that the tumor does not enhance (white arrowhead). This tumor is an intrinsic pontine glioma, and the diagnosis is made by MRI
alone, a biopsy is not required.
598
PART III
C
FIGURE 44-6 A, Axial T2WI image in a 3-month-old girl who has a hyperintense lesion (black asterisk) in the left optic nerve and into the optic chiasm.
B, Axial T1WI postgadolinium image showing an enhancing tumor (white arrowhead). The tumor causes stretch on the internal carotid artery and middle
cerebral artery, putting the patient at risk of a postoperative stroke when this chiasmatic/hypothalamic glioma is resected. C, Axial T2WI postoperative image
showing a large left internal carotid stroke (white arrows) that occurred on postoperative day 4 and was a result of vasospasm in the stretched arteries.
after administering contrast. Extension to the intraorbital optic nerves or along the optic radiations is diagnostic and rules
out craniopharyngiomas, germinomas, or other tumors in this
location (Fig. 44-6).
Because most of these tumors will not progress significantly
(especially in the setting of neurofibromatosis type 1), initial
management is usually observation with serial imaging and
ophthalmologic screening. Tumors that progress significantly
and/or cause worsening vision are treated with chemotherapy.
The most common regimen used is vincristine and carboplatin62,63; however, thioguanine, procarbazine, lomustine
(CCNU), and vincristine (TPCV) are also effective.64 Radiotherapy is avoided if possible because of the high risk of
secondary effects, such as endocrine dysfunction, stroke,
secondary malignant neoplasms, and neurocognitive deficits.
Although radical surgical resection results in prolonged
disease stability in the majority of patients, it carries a higher
risk of stroke and injury to the optic pathways and the hypothalamic/pituitary axis.65,66 Surgery is reserved for cases when
the diagnosis is unclear, there is a unilateral optic nerve tumor
with severe visual impairment or painful proptosis, and
tumors are causing obstruction of the third ventricle or exerting mass effect on surrounding areas of the brain.
CRANIOPHARYNGIOMA
Craniopharyngiomas are histologically benign masses believed to arise from embryonic rests derived from the hypophyseal-pharyngeal duct. Symptoms result from optic
chiasm or nerve compression, hypopituitarism, hypothalamic
dysfunction, or increased intracranial pressure in association
with hydrocephalus.67 They also occur in adults, but the
childhood form represents a distinct entity characterized by
large size and extensive calcification. There are two varieties
of craniopharyngiomas, the papillary and adamantinomatous
types, the latter being the most common in the pediatric population. Histologically, they typically are composed of a
squamous epithelial cyst wall, with cystic fluid composed of
cholesterol crystals, and calcifications. They tend to be inseparable from the pituitary stalk and may have an interdigitating
gliotic interface with the hypothalamus above. This makes
complete surgical removal challenging, because small rests
of tumor may reside in the brain. This is also the reason for
hypothalamic dysfunction that may be seen after surgical
excision.68
Computed tomography can reveal either a cystic mass
with basal calcifications or an entirely solid tumor. MRI shows
CHAPTER 44
BRAIN TUMORS
599
employed with cortical tumors, but simple removal of the tumor usually provides good seizure control, and the value of
these strategies is uncertain.9,80
The outcome of low-grade astrocytomas,9 gangliogliomas,81(Fig. 44-8), and DNETs (Fig. 44-9) that are completely
resected is favorable, although surveillance scanning is
LOW-GRADE SUPRATENTORIAL
ASTROCYTOMAS
Low-grade astrocytomas and gangliogliomas involving the
cortical regions and temporal lobes can often present with intractable seizures. CT may show masses of low density. MRI
usually shows a mass of decreased signal on T1-weighted images and increased signal on T2-weighted images that may or
may not enhance with gadolinium.
Complete resection is the goal of surgery, but this may
prove difficult because of problems in defining the tumor
margins and its proximity to eloquent areas. Adjuncts to aid
in this include language and motor mapping using implantable
grids or intraoperative electrophysiologic monitoring techniques,78 functional MRI techniques, and image-directed
tumor resection.79 Tumors of the temporal lobe are often
treated by formal temporal lobectomy to decrease the incidence of seizures. Seizure mapping techniques have also been
600
PART III
MALIGNANT SUPRATENTORIAL
ASTROCYTOMAS
Anaplastic astrocytomas and glioblastoma multiforme account
for roughly 9% of pediatric tumors, which is a smaller
incidence than in the adult population. Clinical signs and
symptoms are reflective of their location. Imaging features are
similar to those seen in adults, and the masses are often large,
with enhancing rings and necrotic centers (Fig. 44-10).
Dissemination occurs in about 10% of cases.86
Treatment includes maximal resection followed by radiation therapy. Unfortunately, the prognosis is still poor.
Although more extensive resection confers better outcome,
this may be due to the fact that more favorable tumors are
more amenable to aggressive surgery. Chemotherapy has a
modest impact on survival.87,88
CHAPTER 44
FIGURE 44-11 Axial T1WI postgadolinium image showing an avidly enhancing tumor in the atrium of the left ventricle in a 6-month-old girl with a
rapidly growing head circumference (black asterisk). The tumor was a choroid plexus papilloma.
MENINGIOMAS
Meningeal tumors are uncommon in childhood, accounting
for about 2% of intracranial tumors. Meningiomas can occur
in the orbit, sphenoid wing, or virtually any portion of the intracranial compartment, and do not necessarily need a dural
attachment. Radiographically, they typically enhance and
may be extremely large. Treatment is surgical resection. In
adults, a gross total resection is curative; however, in the pediatric population, it is less common to have a meningioma
with the typical benign histology seen in adults. Meningiomas
in pediatric patients are usually much more aggressive and
carry a worse prognosis than in adults.90
Tumor Genetics
------------------------------------------------------------------------------------------------------------------------------------------------
BRAIN TUMORS
601
developed empirically rather than as a branch of classic immunology. This occurred in four distinct phases, each lasting
more than a decade. Only at the end was it possible to explain
organ engraftment and thereby eliminate the mystique of
transplantation.
CHAPTER 45
Principles of
Transplantation
Jorge Reyes, Noriko Murase, and Thomas E. Starzl
The variable acquired tolerance on which transplantation depends has been one of the most enigmatic and controversial
issues in all of biology. This was caused, in part, by the unexpected achievement of organ engraftment (the kidney) at an
early time (a decade before successful bone marrow transplantation) and in ostensible violation of the very principles that
would shape the impending revolution in general immunology. As a consequence, clinical organ transplantation was
606
PART IV
TRANSPLANTATION
A
FIGURE 45-1 The mouse models of acquired tolerance described between 1953 and 1956. White cells (leukocytes) were isolated from the
spleen or bone marrow of adult donor mice (upper left) and injected into
the bloodstream of newborn mice (upper right) or of irradiated adult mice
(middle right). Under both circumstances, the recipient immune system
was too weak to reject the foreign cells (dark shaded). With engraftment
of the injected cells (i.e., donor leukocyte chimerism), the recipient mice
now could freely accept tissues and organs from the leukocyte donor
but from no other donor (bottom left).
TABLE 45-1
First Successful Transplantation of Human Allografts
(Survival >1 Year)
Physician/
Organ
City
Date
Surgeon
Reference
Kidney
Boston
42, 48
Liver
Heart
Lung
Pancreas
Denver
Cape Town
Ghent
Minneapolis
Merrill/
Murray
Starzl
Barnard
Derom
Lillehei
72
5
18
34
CHAPTER 45
Immunosuppression (1962-1963)
Azathioprine
Azathioprine
Serum creatinine
Prednisone
Serum creatinine
607
Prednisone
PRINCIPLES OF TRANSPLANTATION
Rejection
Tolerance
Pretreatment
Tx
Tx
FIGURE 45-3 A, Empirically developed immunosuppression used for kidney transplant recipients from 1962 to 1963. Note the reversal of rejection with
the addition of prednisone to azathioprine. More than a third of a century later, it was realized that the timing of drug administration had been in accord
with the tolerogenic principles of immunosuppression (see text). B, Treatment revisions in immunosuppression made at the University of Colorado in
December 1963, which unwittingly violated principles of tolerogenic immunosuppression. Pretreatment was de-emphasized or eliminated, and high doses
of prednisone were given prophylactically instead of as needed. Although the frequency of acute rejection was reduced, the drug-free tolerance shown in
Figure 45-4 was no longer seen. Tx, treatment.
Recipient
Immunosuppression
35 years passed before the long-term immunologic consequences of the modifications were realized.
No Immunosuppression
Donor
CR
Sister
<1.5
Brother <1.5
Mother <1.5
Mother <1.5
Mother 2.5-3
Sister
Father
Uncle
0
10
20
30
Years post transplantation
40
<1.5
608
PART IV
TRANSPLANTATION
Solid Organ
Bone Marrow
1959
1968
Nonessential
Tissue match
Essential
Acceptance
Graft take
Tolerance
Uncommon
GVHD
Common
Seed
FIGURE 45-6 Four years old at the time of liver replacement for biliary atresia and a hepatoma, but now in her 40th post-transplant year (shown here at
35 years post-transplant), the (former) patient is the longest-surviving recipient of an extrarenal organ.
CHAPTER 45
the time of surgery, the better drugs fueled the golden age of
transplantation of the 1980s and early 1990s. Acute rejection
had become almost a nonproblem. However, the unresolved
issues now were chronic rejection, risks of long-term immunosuppression (e.g., infections and de novo malignancies),
609
100
80
60
TAC (n=1391)
CYA (n=1835)
AZA (n=168)
40
PRINCIPLES OF TRANSPLANTATION
20
Historical Dogma
0
0
4
1
2
3
Time after transplantation (years)
Proliferation
of host
antigraft cells
Proliferation
of host
antigraft cells
Defenseless recipient
HVG (rejection)
B
Double response (organ)
Immunosuppression
GVH
GVH
Reciprocal clonal
deletion
Reciprocal clonal
deletion
Unconditioned recipient
Unaltered bone
marrow
HVG (rejection)
Conditioned recipient
HVG
FIGURE 45-8 Old (A and B) and new views (C and D) of transplantation recipients. A, The early conceptualization of immune mechanisms in organ transplantation in terms of a unidirectional host-versus-graft (HVG) response. Although this readily explained organ rejection, it limited possible explanations of
organ engraftment. B, Mirror image of A depicting the early understanding of successful bone marrow transplantation as a complete replacement of the
recipient immune system by that of the donor, with the potential complication of an unopposed lethal unidirectional graft-versus-host (GVH) response, that
is, rejection of the recipient by the graft. C, Our current view of bidirectional and reciprocally modulating immune responses of coexisting immune-competent
cell populations. Because of variable reciprocal induction of deletional tolerance, organ engraftment was feasible despite a usually dominant HVG reaction. The
bone silhouette in the graft represents passenger leukocytes of bone marrow origin. D, Our currently conceived mirror image of C after successful bone
marrow transplantation. Recipients cytoablation has caused a reversal of the size proportions of the donor and recipient populations of immune cells.
610
PART IV
TRANSPLANTATION
Seed
FIGURE 45-10 Unification of organ and bone marrow transplantation
(see text).
Immunosuppression
FIGURE 45-9 Contemporaneous HVG (upright
curves) and GVH (inverted curves) responses
after transplantation. In contrast to the usually
dominant HVG reaction of organ transplantation, the GVH reaction usually is dominant
after bone marrow cell transplantation to the
irradiated or otherwise immunodepressed recipient. Therapeutic failure with either type of
transplantation implies the inability to control
one, the other, or both of the contemporaneous responses with a protective umbrella of
immunosuppression.61
Failure
HVG
Immune
reaction
Recipient
Success
GVH
Donor
Failure
CHAPTER 45
PRINCIPLES OF TRANSPLANTATION
611
Therapeutic Implications
How could the new insight be exploited clinically? The window of opportunity for the donor leukocyte-induced clonal
deletion that corresponds with collapse of the antigraft
response (Fig. 45-14, left) is open only for the first few
FIGURE 45-12 Initial preferential migration of passenger leukocytes from organ allografts (here a liver) to host lymphoid organs (left), where they induce
a donor-specific immune response. After about 30 days, many of the surviving cells move on to nonlymphoid sites (right).
TRANSPLANTATION
es
sit
d
oi
on
lati
cu hymus
T
cir
es
sit
mus
Thy
lee
Sp
n
lee
Sp
No
nly
mp
h
Lym
ph
d
oi
No
nly
mp
circLymph
h
ula
tion
Blo
od
PART IV
Blo
od
612
h
mp
Ly odes
n
h
mp
Ly odes
n
ne
Bo rrow
ma
ne
Bo rrow
ma
FIGURE 45-13 The migration routes of passenger leukocytes of transplanted organs are similar to those of infused bone marrow cells. Left, Selective
migration at first to host lymphoid organs. After 15 to 30 days, surviving leukocytes begin to secondarily move to nonlymphoid sites. Right, Establishment of
reverse traffic by which the exhaustion-deletion induced at the outset can be maintained.
Time
Tx
Delayed
rejection
Time
Too little
treatment
Immune response
Tolerance
Too much
treatment
Immune response
Tx
tio
Activ
atio
n
Exhaustion
le
De
Immune response
Tolerogenic
immunosuppression
Tx
Graft
loss
1. Irradiation
2. Thoracic duct
drainage
Immune responses
post-transplant weeks.55,7274 It was apparent that the window could be closed by excessive postoperative immunosuppression (Fig. 45-14, middle). With later reduction of the
initial overimmunosuppression, recovery of the inefficiently
deleted clone would be expected, leading to the delayed acute
rejection, or the chronic rejection, that was being seen in
the transplant clinics. Even in the best-case scenario, the
patients would be predestined to lifetime dependence on immunosuppression. However, too little immunosuppression
would result in uncontrolled rejection (Fig. 45-14, right).
The problem faced by clinicians was how to find just the
right amount of post-transplant immunosuppression. In
2001, it was suggested that this dilemma could be addressed
by successively applying two historically rooted therapeutic
principles: recipient pretreatment, followed by minimalistic
post-transplant immunosuppression.75 With pretreatment,
the recipients immune responsiveness would be reduced before exposure to donor antigen, thereby lowering the anticipated donor-specific response to a more readily deletable
range (Fig. 45-15). Clonal deletion by the kidneys passenger
leukocytes undoubtedly is what had been accomplished after
sublethal irradiation alone in the ground-breaking fraternal
twin (i.e., sublethal total-body irradiation or myelotoxic
drugs) cases of 1959.8,12 In fact, radical pretreatment by recipient cytoablation ultimately became the essential therapeutic
step for conventional bone marrow transplantation. Because
Irreversible
rejection
3. Other drugs
4. Antilymphoid
antibodies
Donor
specific
clonal
deletion
Pretreatment
Tx
Time
FIGURE 45-15 Rather than producing rejection (thick dark arrow), the
donor-specific immune response to allografts may be exhausted and deleted, as depicted by the fall of the initially ascending continuous thin line,
when recipient immune responsiveness is weakened in advance of transplantation (the pretreatment principle). Tx, treatment.
CHAPTER 45
PRINCIPLES OF TRANSPLANTATION
Prednisone
Organ Preservation
Tacrolimus
PROCUREMENT
HVG
------------------------------------------------------------------------------------------------------------------------------------------------
GVH
Immune responses
Lymphoid-depleting
pretreatment
Irreversible
rejection
With pretreatment
With pretreatment
and minimal
immunosuppression
Tx
Every 2
weeks
2
613
Off immunosuppression
5
Daily multitherapy
1
EXTENDED PRESERVATION
Daily monotherapy
8
Every other
day
2
1 a week
10
2 a week
4
The breakthroughs of the early 1960s that made transplantation clinically practical were so unexpected that almost no
formal preparation had been made to preserve the transplanted
organs. Cardiac surgeons had used hypothermia for open-heart
operations from 1950 onward and knew that ischemic damage
below the level of aortic cross-clamping could be reduced
by cooling the subdiaphragmatic organs.83 In an early report,
Lillehei and colleagues84 immersed intestines in iced saline
before autotransplantation. In Boston, Sicular and Moore85
reported greatly slowed enzyme degradation in cold slices
of liver.
Despite this awareness, kidneys were routinely transplanted until 1963 with no protection from warm ischemia
during organ transfer. The only attempt to cool kidney
allografts until then was by the potentially dangerous practice
(used by thoracic surgeons for open-heart surgery) of
immersing the live donor in a bathtub of ice water (totalbody hypothermia).86 This cumbersome method of cooling
was quickly replaced by infusion of chilled solutions into
the renal artery after donor nephrectomy,87 exploiting a
principle of core (transvascular) cooling that had been
standardized several years earlier for experimental liver
transplantation.88
Core cooling in situ, the first critical step in the preservation of all cadaveric whole organs, is done today with variations of the technique described in 1963 by Marchioro and
coworkers,89 which permits in situ cooling to be undertaken90
(Fig. 45-18). Ackermann and Snell91 and Merkel and associates92 popularized in situ cooling of cadaveric kidneys with
simple infusion of cold electrolyte solutions into the donor
femoral artery or distal aorta. Procurement techniques were
eventually perfected that allowed removal of all thoracic
and abdominal organs, including the liver, without jeopardizing any of the individual organs (Fig. 45-19).93 Modifications
of this flexible procedure have been made for unstable donors
and even for donors whose hearts have stopped beating.94
During the 5 years between 1980 and 1985, such techniques
had become interchangeable in all parts of the world, setting
the stage for reliable organ sharing. After the chilled organs are
removed, subsequent preservation is possible with prototype
strategies: simple refrigeration or continuous perfusion (see
later).
3 a week
6
614
PART IV
TRANSPLANTATION
Arterial inflow
Portal v.
Re-circulation line
Heat exchanger
I.V.C
To
femoral
a. & v.
Aorta
Inf. mesentric
a.
Pump
Preservation fluid
through splenic v.
Preservation fluid
through terminal
aorta
Static Preservation
With these slush techniques, special solutions, such as those
described by Collins and coworkers,98 were instilled into the
renal vascular system of kidneys or the vascular system of other
organs after their preliminary chilling and separation. The original Collins solution or modifications of it were used for nearly
2 decades before they were replaced with the University of Wisconsin (UW) solution that was developed by the team of Folkert
Belzer. Although it was first used for the liver,99101 the UW
solution provides superior preservation of kidneys and other
organs.102,103 The UW preservation permitted longer and safer
preservation of kidneys (2 days) and livers (18 hours), a higher
rate of graft survival, and a lower rate of primary nonfunction.
With the UW solution, national organ sharing was made
economical and practical. This success has refocused efforts
on understanding the mechanisms involved in the ischemia/
reperfusion injury (deprivation and then restoration of tissue
oxygen) that impacts organ function, and has resulted in the
development of other preservation solutions (Celsior, HTK:
histidine-tryptophan-ketoglutarate) and the inclusion of drugs
that act on the mediators of injury.104
Tissue Typing
------------------------------------------------------------------------------------------------------------------------------------------------
ANTIGEN MATCHING
FIGURE 45-19 Principle of in situ cooling used for multiple organ
procurement. With limited preliminary dissection of the aorta and of the
great splanchnic veins (in this case, the splenic vein), cold infusates can
be used to chill organs in situ. In this case, the kidneys and liver were being
removed. Note the aortic cross-clamp above the celiac axis.
CHAPTER 45
Graft
Match
Rx
Host
PRINCIPLES OF TRANSPLANTATION
615
CROSSMATCHING
Partial
mismatch
Total
mismatch
Rx
Rx
Future Prospects
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 46
Renal
Transplantation
John C. Magee
uncommon in children, this rate is well below the overall national incidence of ESRD of 362 per million per year.
The etiology of renal disease in the pediatric transplantation population is summarized in Table 46-1. According to
these NAPRTCS data, the five most common diagnoses are
renal aplasia/hypoplasia/dysplasia, obstructive uropathy, focal
segmental glomerulosclerosis (FSGS), reflux nephropathy,
and chronic glomerulonephritis.1 These diagnoses account
for just over half the transplantations performed. The causes
of renal failure are distinctly different from those in adults;
specifically, congenital abnormalities and obstructive uropathy are the leading causes for transplantation. In addition,
FSGS is the most common acquired renal disease and is much
more common in children compared with adults.
Within the pediatric population, the prevalence of causes
varies by age, sex, and race.1 Congenital causes are more
prevalent in younger children, whereas acquired diseases tend
to become manifest in older children. Overall, 59.4% of the
recipients are male, and males represent the majority of
the recipients with obstructive uropathy (85.2%), aplasia/
hypoplasia/dysplasia (61.8%), and FSGS (57.8%). Reflux
nephropathy, chronic glomerulonephritis, and lupus nephritis
are more prevalent in females, with females accounting
for 56.7%, 57.0%, and 83.3%, respectively. Regarding race,
for black children, FSGS was the most prevalent diagnosis
(23.1%), followed by obstructive uropathy (15%) and
aplasia/hypoplasia/dysplasia (13.5%). In white recipients,
obstructive uropathy was the most prevalent etiology
(17.0%), followed by aplasia/hypoplasia/dysplasia (16.9%)
and FSGS (9.0%).
Recipient Evaluation
------------------------------------------------------------------------------------------------------------------------------------------------
Any child with ESRD should be considered for transplantation. Absolute contraindications are rare and include
untreated malignancy or systemic sepsis. Relative contraindications include severe systemic disease that profoundly limits
the patients life span or a social situation that makes follow-up
with post-transplantation care and immunosuppression regimen absolutely impossible. At times, the decision whether to
transplant a child with a poor quality of life or significant
impairment can be extremely difficult. In such situations, a
thorough discussion focused on the expectations and goals
for that child is helpful.
All children with progressive chronic renal insufficiency
should be evaluated by a multidisciplinary pediatric transplantation team, including a pediatric nephrologist, a
transplantation surgeon, social worker, and nutritionist. In
addition, many teams include pediatric urologists and clinical
psychologists, with other experts included as indicated.
Ideally, the child would be fully evaluated before initiating
dialysis. This can facilitate evaluation of potential living donors and permit preemptive transplantation, obviating the
need for dialysis. Regarding infant size, although it is often
stated that approaching 10.0 kg is ideal, it is clear that transplantation can be performed successfully in smaller infants at
experienced centers.68 The guiding principle should be to
optimize the situation as much as possible but not let an
arbitrary weight target compromise the health of the child.
Our standard evaluation process is summarized in
Table 46-2. Every effort should be made to optimize the
617
618
PART IV
TRANSPLANTATION
TABLE 46-1
Primary Diagnosis for Renal Transplantation Recipients
(N 9854) Age 20 Years and Younger
TABLE 46-2
Evaluation of Pediatric Kidney Transplantation Candidate
Disease
Aplasia/hypoplasia/dysplasia
Obstructive uropathy
Focal segmental glomerulosclerosis
Reflux nephropathy
Chronic glomerulonephritis
Polycystic disease
Medullary cystic disease
Hemolytic-uremic syndrome
Prune-belly syndrome
Congenital nephrotic syndrome
Familial nephritis
Cystinosis
Pyelointerstitial nephritis
Membranoproliferative glomerulonephritis type I
Idiopathic crescentic glomerulonephritis
Systemic lupus erythematosus nephritis
Renal infarct
Berger (IgA) nephritis
Henoch-Schonlein nephritis
Membranoproliferative glomerulonephritis type II
Wegener granulomatosis
Wilms tumor
Drash syndrome
Oxalosis
Membranous nephropathy
Other systemic immunologic disease
Sickle cell nephropathy
Diabetic glomerulonephritis
Other
Unknown
15.9
15.6
11.7
5.2
3.3
2.9
2.8
2.6
2.6
2.6
2.3
2.0
1.8
1.7
1.7
1.5
1.4
1.3
1.1
0.8
0.6
0.5
0.5
0.5
0.4
0.3
0.2
0.1
9.8
6.2
medical management of the child with ESRD, including management of bone disease, optimization of nutrition, and completing childhood immunizations. Several aspects of the
evaluation of the pediatric recipient are unique and deserve
special attention. One is the evaluation and management of
bladder function. Urologic anomalies are common, and many
will have also undergone previous urologic procedures.
Rarely, the bladder may be inadequate for transplantation.
Expertise in such issues, or a close working collaboration with
pediatric urology, is essential. Nutrition is also of paramount
importance to optimize growth and development. Finally, it
is important to evaluate and optimize issues related to the
psychological state of the child and caregivers.9 Adequate
social support is vital for all involved. The stress of a chronically ill child undergoing a complex procedure places a great
strain on all, and the need for ongoing education and reassurance is significant. In older children, it is important to ensure
they are actively involved. Adolescents can be particularly
challenging, because the risk of noncompliance appears to
be greatest in this group.
In addition to these factors, several other issues require special attention. One is the potential need to evaluate the patients
vasculature. As renal replacement therapy has improved, it is
CHAPTER 46
In addition to a rational consideration of the risks and benefits of native nephrectomy, the timing of the nephrectomy is
important. In children on renal replacement therapy, bilateral
native nephrectomies may be safer and easier to accomplish in
the weeks before transplantation. In children not on renal replacement therapy, the issue is more complex. We prefer not to
perform bilateral nephrectomies at transplantation because
this combines two major procedures. We also perform the
transplant through a retroperitoneal approach even in small
infants, which does not provide access to the contralateral native kidney. For children requiring bilateral native nephrectomy, and who are not yet on dialysis, some will have
sufficient renal reserve to tolerate a unilateral left nephrectomy
before transplantation and still not require dialysis. In this situation, at transplantation we extend the standard right retroperitoneal incision slightly cephalad and perform a right
native nephrectomy. In cases where unilateral native nephrectomy prior to transplantation would require initiation of renal
replacement therapy, we typically remove the ipsilateral native
kidney during the transplantation procedure. The remaining
contralateral native kidney can be removed several months after transplantation if still indicated.
In considering when to perform the transplantation, any
child currently on renal replacement therapy should undergo
transplantation as soon as a suitable living donor is identified
or a deceased donor organ becomes available. In children not
yet on dialysis, transplantation should be performed before
the onset of symptoms of uremia. It is important to be aware
of the impact of ESRD on growth and development. In patients
with FSGS or lupus nephritis, transplantation is typically
delayed until the disease is quiescent, which may preclude
preemptive transplantation. In most other situations, preemptive transplantation provides significant benefit by obviating
the need for dialysis. Unfortunately, only 33% of children
who receive a living donor transplant and only 13% of
deceased donor recipients are transplanted before initiation
of dialysis.13
Urologic Issues
------------------------------------------------------------------------------------------------------------------------------------------------
RENAL TRANSPLANTATION
619
function. Urologic procedures that preserve native renal function for many years are clearly prudent, but interventions
before transplantation should be planned by carefully
considering the risks and benefits of the procedure and being
mindful of the impact on subsequent transplantation and
long-term management.
Dialysis Access
------------------------------------------------------------------------------------------------------------------------------------------------
Donor Selection
------------------------------------------------------------------------------------------------------------------------------------------------
Living donor transplantation is the preferred option for all patients with ESRD. Living donor transplantation offers the best
outcomes, compared with deceased donor transplantation.4,16 In addition, living donor transplantation can be performed as soon as a suitable donor is identified, minimizing
exposure to ESRD. Living donors may be either genetically related or unrelated to the potential recipient. The results from
both types of living donors are equivalent, and both are superior to outcomes from deceased donors. Potential living donors should undergo a full evaluation by a transplant center
experienced in this process. The donor must be willing, be
in good health, and have two normal kidneys. In addition,
the donor and recipient must be ABO compatible. Although
there is a growing interest in strategies to cross this barrier,
efforts are relatively limited in the pediatric population.17
620
PART IV
TRANSPLANTATION
CHAPTER 46
The improved access to deceased donors has been associated with a decrease in the number of living donor transplantations performed in children. Prior to 2005, living donors
accounted for more than half of the pediatric transplantations.
This proportion has fallen to less than 40% in recent years and
is a source of concern. Although greater access to the best
deceased donors is appealing, it is important to note that
outcomes are significantly better with living donors compared
with deceased donors. Specifically, living donors up to
55 years of age provide greater long-term survival compared
with even the ideal deceased donor.16
Transplantation
------------------------------------------------------------------------------------------------------------------------------------------------
PREOPERATIVE PREPARATION
Deceased donor recipients are admitted once a kidney is
accepted. We typically also admit our living donor recipients,
although they can be admitted on the day of surgery if their
dialysis regimen is stable or if they are not on dialysis. On
admission, the need for dialysis is assessed. It is important
to ask about intervening health issues since the last visit, as
well as examining for any evidence of ongoing infection.
ANESTHESIA
Close coordination with the anesthesia team is vital to the conduct of any operation, and it is particularly important in kidney transplantation in small infants. Maintaining adequate
volume status is critical. Because a kidney from an adult donor
is typically used, blood flow to the graft often equals the entire
cardiac output of the recipient. Hypotension can be particularly problematic. Many children have an obligate polyuria
that can cause hypovolemia if not carefully monitored. After
reperfusion, the new kidney can also sequester several
hundred milliliters of blood, further aggravating hypovolemia.
OPERATIVE PROCEDURE
After induction of general anesthesia, adequate intravenous
access is established. In children larger than 20 kg, we do
not place a central venous line if adequate peripheral access
can be established. For smaller children, we find central
venous access useful, both for fluid administration as well
as for monitoring central venous pressure. In these smaller
children, we also place an arterial line to permit constant
blood pressure monitoring. The child is positioned supine.
A Foley catheter is inserted and connected to a three-way
irrigation system, using dilute providone-iodine (Betadine)
in saline. In other centers, an antibiotic solution may be preferred. This arrangement allows the bladder to be filled and
drained outside of the operative field as necessary. The childs
temperature should be monitored closely, especially with
small children who may become hypothermic with either
fluid resuscitation or the perfusion of the cold kidney. In
addition to routine monitoring, ongoing attention must be
directed to volume status. It is vital that the arterial blood
pressure and central venous pressure are adequate when
the kidney is reperfused. For infants and small children, the
central venous pressure is usually maintained in the range
of 12 to 18 cm H2O by administration of crystalloid and/or
RENAL TRANSPLANTATION
621
colloid as necessary. Near completion of the vascular anastomoses, we typically give 0.5 mg/kg of mannitol intravenously.
We do not routinely employ a loop diuretic.
OPERATIVE TECHNIQUES
Small Children (<20.0 kg)
Historically, many have performed kidney transplantations
intra-abdominally in infants and small children using a midline incision. Since 1998, we have used a retroperitoneal approach similar to that used in adults, even in infants. Placing
the kidney on the right side is preferable, because this gives
the easiest access to the vena cava. A curvilinear skin incision
is made in the lower quadrant. The abdominal wall musculature is divided, and the preperitoneal space is entered. Attempts are made to stay extraperitoneal. The spermatic cord
is mobilized and preserved in males, whereas the round ligament is routinely divided in females. The dissection is carried
medially until the common iliac vessels, the distal aorta, and
vena cava are visualized. If a right native nephrectomy is necessary, this is performed at this point.
The site of the vascular anastomosis depends on kidney
size as well as the size of the child. In general, in small children, the renal vein is anastomosed to the vena cava, and
the renal artery is anastomosed to either the distal aorta or
the common iliac artery. The lymphatics overlying these
vessels are divided between ties in an effort to minimize the
risk of a lymphocele. When an aortic anastomosis is planned,
the aorta is mobilized from below the inferior mesenteric
artery to the bifurcation. Lumbar branches are controlled with
Pott ties rather than ligated. The common iliac arteries are
controlled just distal to the aortic bifurcation. The vena cava
is mobilized to allow placement of a side-biting vascular
clamp, which can require ligation of several lumbar veins.
Once the recipients vessels have been exposed, the donor
kidney is brought into the operative field. The kidney should
be inspected for any evidence of unsuspected pathology. The
renal vessels are examined. After preparing the kidney,
thoughtful consideration needs to be given for the fit of the
kidney in the recipients body cavity. Particular attention must
be focused on the length of the renal vessels as well as their
orientation. It is important to consider the final resting
position of the kidney after it is perfused, the retractor is
removed, and the fascia closed.
The venous anastomosis is performed first. The vena cava
or iliac vein is controlled with a side-biting clamp. A longitudinal venotomy is made along the anterolateral or lateral
aspect of the vein. The renal vein is cut to length, again after
considering the ultimate lie of the kidney, and mindful that a
redundant renal vein may predispose to thrombosis. We place
two corner sutures of 5-0 Prolene. The anastomosis is
performed in a running manner. An end-to-side arterial anastomosis is then performed to the recipients distal aorta or
common iliac artery. The recipient vessels are controlled using
vessel loops or gentle spring clips. A longitudinal arteriotomy
is made, mindful of the final orientation of the renal artery. We
enlarge the arteriotomy using a 4.0-mm aortic punch.
The renal artery is then sewn end-to-side using a running
6-0 Prolene suture. We typically perform the procedure with
loupe magnification.
622
PART IV
TRANSPLANTATION
lie of the kidney once the retractor is removed. Careful planning and attention to detail before performing the anastomosis
is usually rewarded at this point. The fascia is closed in one
layer with a running suture. The skin is closed using a running
absorbable suture. The urinary catheter is flushed with saline
to remove any clots that might obstruct the catheter. For small
infants, the volume resuscitation required to ensure excellent
renal perfusion, combined with the size of the kidney decreasing respiratory excursion, may make ventilatory support in the
immediate postoperative period necessary. If the patients oxygen saturation and pulmonary mechanics are satisfactory, the
patient can be extubated in the operating room.
Larger Children (20.0 kg)
The technique for transplantation in larger children is similar
to that in adults. We prefer to put the kidney on the right side
when possible. An incision is made in the right lower quadrant, extending from one to two fingerbreadths above the pubis to just lateral of the rectus sheath. As in smaller children,
the placement of the arterial and venous anastomoses depends
on the size of the child and the renal vessels. The venous anastomosis can be done to the vena cava, the common iliac, or the
external iliac vein. The arterial anastomosis is performed to the
distal aorta, the common iliac, or the external iliac artery. After
revascularizing the kidney, the ureteroneocystostomy is performed using an extravesicular technique. At the completion
of the operation, these larger children are extubated.
Ureteral Reconstruction in Patients with Previous
Urologic Procedures
The ideal urinary reservoir stores a reasonable volume at a low
pressure, does not leak, and empties nearly completely with
voiding.14 In the majority of cases, the ideal reservoir is the
patients bladder. If the bladder functioned normally before
development of oliguria, it is likely to function adequately
after transplantation. Nonetheless, up to 30% of pediatric recipients will not have normal bladder function, and frequently
a surgical augmentation or other urologic procedure has been
performed before referral for transplantation.
Drainage into an augmented bladder or urinary conduit is
an appropriate management strategy when the native bladder
is unsuitable or absent.37,38 When indicated, we prefer to have
the intended urinary reservoir created and suitable for use before the transplant procedure. Intraoperatively, when planning the ureteroneocystostomy to an augmented bladder, it
is important to consider the blood supply to the augmented
section so as not to compromise it during the transplant. It
is preferable to perform the ureteroneocystostomy to the native bladder, and this can be accomplished in most situations.
An antireflux ureteroneocystostomy is essential, and it is most
readily performed with the bladder wall.
Patients with an augmented bladder or urinary conduit are
at increased risk for urine infection, but compared with historical controls, graft survival is not adversely affected.39 The rate
of surgical complications related to the ureteral anastomosis is
higher in these patients, approximately 20%.3941 Regardless
of the etiology of the bladder dysfunction, these patients require regular clean intermittent straight catheterization after
transplantation.
Children with obstructive uropathy from posterior urethral
valves will not have normal bladder function, and this can
contribute to renal dysfunction after transplantation.37
CHAPTER 46
Awareness of these issues is vital, and evaluation with followup urodynamic studies is frequently indicated in children
with voiding disorders. Bladder dysfunction, such as hypocompliance and/or hyper-reflexia, requires medical or surgical
treatment.
RENAL TRANSPLANTATION
623
Postoperative Care
------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------------
Attention to detail in the postoperative period is essential. Special care must be directed to the fluid and electrolyte status.
Many children are polyuric before transplant, and this obligate
urine loss will continue in the immediate postoperative period. Intravenous fluids are administered, taking into account
urine output as well as insensible losses. The composition of
these solutions is adjusted as needed, depending on regular
measurement of serum electrolytes. Serum sodium, potassium, and calcium levels are followed closely and replaced
as necessary. Heart rate, blood pressure, and central venous
pressure are carefully monitored. No single factor alone is
entirely reliable in assessing intravascular volume.
For patients who were oliguric or who had native nephrectomies before transplantation, monitoring urine output is an
excellent monitor of graft function. For patients who made significant urine before transplantation, evaluation of graft function is more difficult. The volume of urine production may be
suggestive. In addition, the serum creatinine concentration
should fall with time. Recipients with oliguria should be rapidly evaluated. The urinary catheter should be flushed with
small volumes of sterile saline. The volume status of the
patient should be carefully assessed. A fluid bolus is usually
warranted, both as a diagnostic test and as therapeutic intervention. Doppler ultrasonography will confirm adequate arterial flow and venous outflow. Ultrasonography will also show
evidence of fluid or blood around the kidney, as well as assess
for possible ureteral obstruction. In patients who appear to
be adequately volume loaded and hemodynamically stable,
a dose of diuretic can be given. It is important to do this
carefully, because sudden massive urine output can cause
significant intravascular volume depletion, which can then
lead to problems with renal perfusion. In patients who are
massively volume overloaded or have significant electrolyte
abnormalities, dialysis may be indicated.
If ventilated postoperatively, the smaller children are
weaned from the ventilator generally within the first 24 hours.
Enteral feedings can be started at a slow rate almost immediately after the extraperitoneal approach. Infants who were on
tube feedings before transplantation should resume these tube
feedings, because they usually will not feed orally in the
immediate post-transplantation period. Hypertension can be
problematic. The volume loading associated with the procedure as well as the use of calcineurin inhibitors (CNIs) for
immunosuppression can result in significant hypertension,
which can be severe and require aggressive therapy to prevent
seizures and other sequelae.
To monitor and replace urine output on an hourly basis, we
admit our children to the intensive care unit (ICU). If this can
be accomplished on a surgical floor unit, larger children could
be admitted to an area specializing in the care of renal transplant patients. Children who are admitted into the ICU are
typically transferred to the floor unit within 1 to 2 days. Most
624
PART IV
TRANSPLANTATION
Immunosuppression
------------------------------------------------------------------------------------------------------------------------------------------------
Significant advances have been made in understanding the immune response and several new immunosuppressive agents
have been developed. The introduction of new agents has permitted consideration of avoidance, conversion, and minimization strategies in an effort to minimize toxicities associated
with specific agents. There are several potential regimens,
but all require a balance between prevention of rejection
and unwanted side effects of immunosuppression. Most
centers use standardized protocols for recipients based on
immunologic risk. Immunosuppressive agents are used for
induction, maintenance, and treatment of rejection episodes.
ANTIBODY PREPARATIONS
Antilymphocyte Antibodies
Antilymphocyte antibodies include polyclonal preparations,
such as equine antithymocyte globulin (ATGAM) and rabbit
antithymocyte globulin (Thymoglobulin), and the monoclonal antibody preparations muromonab-CD3 (OKT3) and
anti-CD52 (Alemtuzumab). Of these antilymphocyte agents,
Thymoglobulin is currently predominant, and the use of the
others is either rare or of historic interest. Antilymphocyte
antibodies act by lymphodepletion, as well as by interactions
with cellular receptors. The use of antilymphocyte induction
regimens has declined precipitously with time.1,2 We
currently restrict the use of Thymoglobulin to recipients at
higher risk for immunologic graft loss, such as patients
requiring retransplantation, highly sensitized patients, or
black recipients. These agents are also effective in the
treatment of acute cellular rejection.
CALCINEURIN INHIBITORS
The introduction of cyclosporine after its FDA approval in
1983 was one of the most significant advances in transplantation. Tacrolimus received FDA approval in 1994. Both agents
act through inhibition of calcineurin activity. They first bind to
specific cytoplasmic proteins; cyclosporine binds to cyclophilin, and tacrolimus binds to tacrolimus binding protein (also
known as FK-binding protein). Both drug-protein complexes
then bind to calcineurin, a phosphatase that controls the
transport of transcriptional regulator factors across the nuclear
membrane. By inhibiting the translocation of these factors into
the nucleus, both drugs inhibit transcription of several early
T-cell activation genes, most significantly IL-2.
Both cyclosporine and tacrolimus are effective at preventing rejection. A randomized prospective open-label trial performed in Europe in pediatric renal recipients compared
tacrolimus with cyclosporine, along with azathioprine and
steroids. There was a significantly lower incidence of acute
rejection in the tacrolimus group (36.9%) compared with
cyclosporine therapy (59.1%).48 In contrast with this observation, a retrospective analysis of NAPRTCS data comparing
cyclosporine with tacrolimus, along with mycophenolate
mofetil and corticosteroids, showed equal rates of rejection
and graft survival. Although rejection rates were similar, tacrolimus therapy was associated with improved graft function at
1 and 2 years after transplant.49 Currently, approximately 70%
of pediatric recipients are reported as being discharged on
tacrolimus compared with 10% on cyclosporine.1,2
Cyclosporine side effects include hirsutism and gingival
hyperplasia, whereas tacrolimus is associated with increased
incidence of post-transplantation diabetes and neurotoxicity.
In children who develop a problematic side effect from one
agent, conversion to the other agent is appropriate. Both
calcineurin inhibitors have significant nephrotoxicity that
impact graft function with time.
MYCOPHENOLATE
Mycophenolate mofetil (MMF) (CellCept) and mycophenolic
acid (MPA) (Myfortic) inhibit purine synthesis. MMF is
converted in vivo to mycophenolic acid, a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH),
which is a key enzyme in de novo purine biosynthesis.
Although most cells can synthesize purines by either the de
novo or the salvage pathway, B and T lymphocytes lack the
CHAPTER 46
PREDNISONE
Glucocorticoids have played an integral role in immunosuppression regimens since the earliest days of transplantation.
They act primarily through transcriptional regulation, diffusing across the plasma membrane and binding to cytoplasmic
steroid receptors. This complex is translocated to the nucleus,
where it binds to specific gene promoters and other regulatory
regions, inhibiting cytokine synthesis. Corticosteroids are also
lymphocytotoxic and possess significant anti-inflammatory
activity, inhibiting macrophage function and other nonspecific
aspects of the inflammatory response.
Long-term corticosteroid therapy is associated with increased risk of hypertension, hyperlipidemia, diabetes, bone
loss, cosmetic disfigurement, and cataracts. Attempts at minimizing corticosteroids have not had a significant effect on
these side effects, and efforts are being directed to corticosteroid avoidance. Although it is appealing to consider withdrawal of corticosteroids with time, late corticosteroid
withdrawal appears associated with increased risk of acute
and chronic rejection. Early corticosteroid withdrawal and
corticosteroid-free regimens, with and without antibody
induction, have shown promise. Sarwal and associates, at
Stanford University, have reported excellent results in a
corticosteroid-free protocol using an extended induction with
daclizumab, tacrolimus, and MMF.54 In their recent report,
129 recipients have been treated with a mean follow-up of
5 years. One-year graft and patient survival were 93% and
96%, respectively. The rate of acute rejection was 12% during
the first year. Significant improvements in post-transplantation growth and avoidance of steroid side effects were noted.
This experience led to a prospective, multicenter randomized
study that has been completed, though the results have not yet
been published. Similar results have also been reported by the
Stanford group in 13 recipients using Thymoglobulin induction in place of daclizumab.55
Another large randomized multicenter international trial
with 196 pediatric kidney recipients compared rapid steroid
withdrawal in children treated with daclizumab, tacrolimus,
and MMF with recipients maintained on steroids along with
tacrolimus and mycophenolate.56 Early steroid withdrawal
was associated with improved growth and metabolic profiles,
with similar acute rejection rates (10.2% vs. 7.1%, respectively) and equivalent graft and patient survival during the first
6 months.
Although encouraging, efforts to withdraw steroids while
maintaining acceptable rejection rates have also resulted in
regimens with a greater rate of complications of immunosuppression. One multicenter randomized trial of steroid withdrawal after 6 months in recipients treated with basiliximab
induction, cyclosporine or tacrolimus, sirolimus, and steroids
was halted early because of a high rate of post-transplantation
lymphoproliferative disorder (PTLD).57
RENAL TRANSPLANTATION
625
TREATMENT OF REJECTION
Suspected rejection should be confirmed by biopsy. The
first-line therapy for acute cellular rejection is pulse corticosteroids. Typically, intravenous methylprednisolone is administered for 3 days, with doses ranging from 5.0 to
25.0 mg/kg/day (maximum dose, 1.0 g). We use 10.0 mg/kg
for children younger than aged 6 years and 5.0 mg/kg for children aged 6 years and older, with a maximum dose of 500 mg/
day. Severe rejection or rejection refractory to corticosteroids
is treated with Thymoglobulin. Treatment of acute rejection is
nearly always successful, although late episodes of rejection
are less likely to respond. After successful treatment, many
consider altering maintenance immunosuppression, including changing to the other calcineurin inhibitor, or substituting
sirolimus for MMF; however, there is little evidence to support
this approach. An assessment of adherence to the immunosuppression regimen should also be initiated. If the patients
creatinine level does not return to baseline, a follow-up biopsy
should be strongly considered. Although most acute rejection
episodes reflect primarily T-cellmediated processes, there is
growing recognition of the role of B cells and alloantibodies
in immunologically mediated graft injury.
Outcomes
------------------------------------------------------------------------------------------------------------------------------------------------
626
PART IV
TRANSPLANTATION
Living donor
1
5
year year
100%
98.7%
96.2%
100%
96.1%
96.0% 94.1%
Deceased donor
98.0% 96.7%
97.2% 93.9%
611
1217
91.6%
80%
Graft survival
75.6%
60%
Graft survival
85.4%
80%
60%
40%
20%
40%
0%
20%
0%
Recipient age
15
611
1217
Recipient age
1
5
year year
100%
94.9%
91.7%
Graft survival
80%
78.2%
74.5%
64.4%
60%
40%
0%
15
93.4%
20%
15
611
1217
Recipient age
FIGURE 46-1 A, One- and 5-year graft survival of living donor kidney
transplantations by recipient age. B, One- and 5-year graft survival of
deceased donor kidney transplantations by recipient age. (From Organ
Procurement Transplant Network/Scientific Registry of Transplant
Recipients: 2009 Organ Procurement Transplant Network/Scientific
Registry of Transplant Recipients Annual Report: Transplant data
1999-2008. Health and Human Services/Health Resources and Service
Administration/Special Pathogens Branch/Department of Transportation.
Available at www.ustransplant.org. Accessed September 29, 2010.)
Figure 46-1. Recipient survival stratified by age range is summarized in Figure 46-2. The leading causes of death are infection (28.9%), cardiopulmonary (15.7%), and malignancy
(11.0%).2 Although patient survival is good, it is important
to realize that even with transplantation, these children face
a significantly increased risk of mortality compared with the
general population.61
With time there has been improvement in outcomes for all
pediatric age ranges. This improvement is particularly noteworthy in children younger than 2 years of age who previously
had the worst graft survival but now have outcomes that equal
the outcomes of any age group.13,50 In fact, the longest transplant half-lives of all recipients are now the youngest recipients,
especially if the pediatric recipient receives an adult kidney that
functions immediately.62 These improvements likely reflect
better donor selection, improvement in surgical techniques,
better immunosuppression agents, and a better understanding
of immunosuppression management in children.
Although short-term graft survival in children is excellent, it
is important to appreciate that long-term graft survival in the
POST-TRANSPLANTATION OUTCOMES
AND RISK FACTORS ASSOCIATED
WITH GRAFT LOSS
Smith and coworkers reported that the most common causes of
allograft failure reported to NAPRTCS for transplantations performed between 2000 and 2005 are chronic rejection (41.3%),
vascular thrombosis (8.1%), recurrence of the primary disease
(7.9%), acute rejection (6.3%), and discontinuation of immunosuppression (6.3%).2 Analysis of large single-center experiences and registry data has revealed risk factors associated
with specific post-transplantation outcomes.2,13,64 For a given
child, some of these risk factors, such as their race, age, or
primary disease, are not modifiable. Other factors are potentially modifiable, and efforts should be made to mitigate risk.
The type and timing of the transplant affect outcomes.
Living donor transplantation is associated with better graft
survival compared with deceased donor transplantation.2,4
Preemptive transplantation is associated with better graft survival compared with patients on dialysis at the time of transplantation. For children on dialysis, the choice of dialysis
therapy does not impact graft survival, although graft loss
from vascular thrombosis is more common in children on
peritoneal dialysis compared with hemodialysis.65
CHAPTER 46
VASCULAR THROMBOSIS
Vascular thrombosis is currently the second most common
reported cause of graft loss.2 Risk factors include donor age
younger than 6 years, cold ischemic time greater than
24 hours, prior transplantation, and peritoneal dialysis before
transplantation.65 Careful consideration of donor quality,
along with efforts to ensure adequate perfusion to the graft,
may minimize the risk of thrombosis. Patients with ESRD have
a higher incidence of hypercoagulable conditions, and any
history of thrombosis, including recurrent or unexplained
thrombosis of hemodialysis access, should prompt further
evaluation.
ACUTE REJECTION
Acute rejection typically occurs between 1 week and 3 months
after transplantation, although it can happen at any time. A
rise in the serum creatinine level is frequently the first sign
of rejection. Findings such as low-grade fever, graft tenderness, hypertension, or decreased urine output are infrequent.
Any renal dysfunction should be promptly investigated. A
percutaneous biopsy should be obtained to confirm the diagnosis, because many other processes can lead to allograft dysfunction, including calcineurin inhibitor toxicity, ureteral
obstruction, infection, renal artery stenosis, and recurrence
of original disease. Acute rejection episodes are treated by
either pulse corticosteroids or antilymphocyte antibodies as
detailed previously.
Risk factors associated with acute rejection include AfricanAmerican race, delayed graft function, and a history of allosensitization. Acute rejection, and, in particular, late acute
rejection episodes occurring more than 1 year after transplant, are independent risk factors for graft loss because of
chronic rejection.67 One episode of acute rejection increases
the risk of graft loss from chronic rejection graft failure threefold, and two episodes of acute rejection increase the risk
12-fold. The incidence of acute rejection is decreasing with
time. In the 2003 to 2005 NAPRTCS cohort, 12.2% of living
donor recipients and 15.8% of deceased donor recipients
had a rejection episode in the first year after transplant.2
Acute rejection, even if successfully treated, impacts graft
survival and all efforts to minimize this risk are important.
Unfortunately, intensifying the immunosuppression regimen
is limited by the consequences of nonspecific systemic immunosuppression. Ensuring the patient remains on therapeutic
immunosuppression is vital, because noncompliance can
RENAL TRANSPLANTATION
627
NONADHERENCE
Adherence with the medical regimen is essential for the success of transplantation. Nonadherence is believed to be largely
responsible for the poorer long-term graft survival seen in adolescent recipients. Shaw and coworkers reviewed 112 pediatric renal transplant recipients and found one third had
clinically significant periods of medication nonadherence.69
Nonadherence was significantly more common in adolescents
compared with younger recipients. Nonadherence was associated with both acute and chronic rejection, as well as graft
loss. The relative lack of reliable measures of adherence and
effective interventions has focused research in the field.70,71
Improved parental involvement and discussion of the child
parent relationship may improve adherence.
RECURRENT DISEASE
The recurrence of the patients primary disease is variable, and
recurrence may or may not lead to graft loss. Recurrent disease
is a more significant issue in the pediatric population, because
of the diagnoses leading to ESRD and their association with
higher rates of graft loss after recurrence. FSGS is the most
prevalent and clinically significant disease to recur after renal
transplantation. In children, the recurrence rate can be as high
as 40% to 50%.72 It can recur almost immediately after
transplant, and most recurrences are within the first month.
Patients with FSGS should be followed closely after transplantation with urine protein measurements. Graft survival is often
worse in adolescents with recurrent FSGS, with up to a 38%
risk of graft loss.73 A circulating permeability factor is believed
to play a critical role in the pathogenesis of FSGS. Plasmapheresis is the most frequently used therapy for recurrence,
although controlled trials supporting its efficacy are lacking.
Some have proposed a role for preoperative plasmapheresis
to decrease the risk of recurrence.74 Others have suggested
a role for intensifying the immunosuppression and potentially
rituximab. In addition to FSGS, other primary renal causes
associated with recurrent disease include membranoproliferative glomerulonephritis types 1 and 2 and IgA nephropathy.75
628
PART IV
TRANSPLANTATION
MEDICAL COMPLICATIONS
Infection
Infection is a constant risk of immunosuppression and is
one clinical representation of the precarious balance between overimmunosuppression and underimmunosuppression.
Great vigilance should be maintained during periods of heaviest immunosuppression, as occurs immediately after transplantation or during treatment of rejection. Additional
prophylaxis is warranted during these periods of greatest risk.82
Post-transplantation infection accounts for more hospitalizations than acute rejection, even in the first 6 months after
transplantation.83 Post-transplantation infections are predominantly bacterial and viral. Fungal infections, although
accounting for 0.2% to 2.7% of infection-related hospitalizations, can be particularly dangerous. Pediatric recipients are
often at higher risk, reflecting the fact that they are more likely
to be nave to a particular pathogen than the general population. Younger age and the use of antibody induction immunosuppression are significant independent risk factors for
infectious complications.84
Cytomegalovirus
Cytomegalovirus (CMV) represents the most common viral infection after transplantation. CMV infection can occur in any
recipient, although the risk is highest when a seronegative recipient receives a kidney from a seropositive donor. Infection
occurs in seropositive recipients as well because of activation
of latent virus. The incidence and the severity of CMV have
declined with more effective prophylaxis. The severity of
CMV infection may range from asymptomatic to organ involvement and death. The typical presentation occurs 1 to
6 months after transplantation, with the patient feeling relatively well but having fevers or sometimes flulike symptoms.
CHAPTER 46
depends on the histology.90,93 Epstein-Barr virus (EBV) is believed to be the causative agent in the progression to PTLD,
especially in B-cell lymphomas. A wide variety of factors have
been proposed to be associated with an increased risk,
including the use of antilymphocyte induction therapy,
EBV-seronegative recipient, EBV infection, and era of transplant. Young white males appear to be at greatest risk.92 The
incidence of PTLD is associated with the overall intensity of
immunosuppression.91,92,94,95
The second most common cancer in pediatric recipients is
skin cancer. Squamous cell carcinoma accounts for the majority, followed by malignant melanoma and basal cell carcinoma.
The best strategy combines sunblock and sun avoidance. All
recipients should undergo regular dermatologic follow-up,
specifically focusing on this risk. Long-term immunosuppression is also associated with increased risks of cervical, vulvar,
and anal carcinoma.
Other Medical Issues
In addition to the risks of infection and malignancy, transplant
recipients face many other risks secondary to their history of
ESRD, their underlying renal disease, and the individual risks
associated with all their medications.
Renal transplant recipients are at high risk for cardiovascular disease.96 Preexisting renal insufficiency, time on dialysis,
and immunosuppressive medications after transplantation
all contribute to this risk. In addition, the prevalence of
hypertension in pediatric kidney recipients is 50% to
80%.97,98 The incidence of left ventricular hypertrophy at
initiation of renal replacement therapy ranges from 54% to
82%, though it generally improves after transplantation.99101
Many children and adolescents will have additional cardiovascular risk factors, including hyperlipidemia, hyperhomocysteinemia, anemia, malnutrition, and chronic inflammation.
Although there are few data examining the magnitude of
the risk in pediatric patients, young adult patients with ESRD
have a 1000-fold higher risk of cardiovascular death compared with the general population. Although the risk of cardiovascular death decreases after successful transplantation
RENAL TRANSPLANTATION
629
available in clinical practice,5 and be accompanied by an increased frequency of severe hypoglycemia.4 Currently, the only
way to restore sustained normoglycemia without the associated risk of hypoglycemia is to replace the patients glucosesensing and insulin-secreting pancreatic islet beta cells6,7
either by the transplantation of a vascularized pancreas8,9 or
by the infusion of isolated pancreatic islets.1012 The tradeoff is the need for immunosuppression to prevent rejection
of allogenic tissue, and for this reason, most pancreas or islet
transplant recipients have been adults. However, the potential
for application earlier in the course of the disease exists, particularly in diabetic children already on immunosuppression
for other indications.13 Of the nearly 24 million people
estimated to have diabetes mellitus in the United States, 5%
to 10% have type 1 diabetes mellitus,14 and the prevalence
in children is increasing.15
Pancreas Transplantation
------------------------------------------------------------------------------------------------------------------------------------------------
HISTORY
CHAPTER 47
Pancreas and
Islet Cell
Transplantation
David E. R. Sutherland, Angelika C. Gruessner,
Bernhard J. Hering, and Rainer W. G. Gruessner
Type 1 diabetes is an autoimmune disease in which the pancreatic islet insulin-producing beta cells are selectively
destroyed.1 It most commonly presents in childhood and continues to represent a therapeutic challenge. Secondary diabetes complications, observed in 30% to 50% of patients who
live more than 20 years after onset of the disease, result in poor
quality of life, premature death, and considerable health care
costs.2 The principal determinant of the risk of devastating
diabetes complications is the total lifetime exposure to
elevated blood glucose levels.3 Therefore establishing safe
and effective methods of achieving and maintaining normoglycemia will have substantial implications for the health
and the quality of life of individuals with diabetes.
The Diabetes Control and Complications Trial (DCCT)
demonstrated that, given a qualified diabetes care team and
intensive insulin treatment control, near-normalization of glycemia could be achieved and sustained for several years.4
However, such a near-perfect level of treatment would
increase a patients burden of day-to-day diabetes management, be difficult to implement for many patients, require
more attention and medical services than are routinely
632
PART IV
1600
1400
TRANSPLANTATION
U.S.
n = 23,850
Non-U.S. n = 11,365
1200
1000
800
600
400
200
Pr
e
-7
19 8
79
19
81
19
83
19
8
19 5
8
19 7
89
19
91
19
9
19 3
9
19 5
97
19
9
20 9
0
20 1
03
20
0
20 5
07
20
09
FIGURE 47-1 Annual number of U.S. and non-U.S. pancreas transplantations reported to the International Pancreas Transplant Registry (IPTR),
1978-2009.
leaving the common iliac artery segment of the Y-graft for anastomosis to the recipient arterial system, usually the right common iliac artery. The portal vein of the donor is usually divided
midway between the upper border of the pancreas and the liver,
leaving adequate length for transplantations of both organs, but
if necessary, an extension graft of donor iliac vein can be anastamosed to the pancreatic graft portal vein portion. In the recipient, the pancreas graft portal vein, with or without an
extension graft, can be anastomosed to the systemic venous system (usually the iliac vein or vena cava) or to the portal system
(usually the superior mesenteric vein).
When venous drainage is to the recipients iliac vein, the
whole pancreas graft can be oriented with the head directed
into either the pelvis or the upper abdomen. When directed cephalad, enteric drainage is the only option. When
directed caudad, the duodenum can be anastomosed to either
the bladder (Fig. 47-2) or bowel (Fig. 47-3). Figure 47-2
CHAPTER 47
40 to 80 cm
FIGURE 47-3 Pancreas-duodenal transplantation using a deceased donor with systemic venous drainage and enteric drainage of graft exocrine
secretions to a proximal loop of recipient jejunum. In this particular case, an
end-to-side two-layer duodenojejunostomy, using the distal end of the
graft duodenum, is illustrated, and the anastomosis is located 40 to
80 cm distal to the ligament of Treitz (inset). Alternatively, a side-to-side
stapled or handsewn duodenojejunostomy, with or without a Roux-en-Y
loop, can be done. (Reproduced from Gruessner RWG, Sutherland DER
[eds]: Transplantation of the Pancreas. New York, Springer-Verlag, 2004.)
shows the bladder-drainage technique and also depicts a kidney transplantation to the left iliac vessels, but, as mentioned,
with a kidney transplantation, enteric drainage is more common than bladder drainage.
With the bladder-drainage technique, the anastomosis may
be handsewn or performed with an end-to-end anastomosis
(EEA) stapler brought through the distal duodenum (which
is subsequently stapled closed) for connection to the post of
the anvil projected through the posterior bladder by an
anterior cystotomy (see Fig. 47-2). The inner layer is then
reinforced with a running absorbable suture for hemostasis
and for burying the staples under the mucosa.
With enteric drainage/systemic venous drainage, the anastomosis may be handsewn in an end-to-side fashion (see
Fig. 47-3), or it can be done in a side-to-side fashion by handsewing or by using an EEA stapler.34 The barrel of the EEA
stapler is inserted into the end of the graft duodenum, and
the post is projected through the side wall. The anvil is
inserted into the recipient bowel through an enterotomy
secured around the connecting post by a purse-string suture.
The two posts are connected and the stapler is fired, creating
the anastomosis. The end of the duodenum is then closed with
a simple stapler. The enteric anastomosis can be done directly
to the most convenient proximal small bowel loop of the
recipient or to a Roux-en-Y segment of recipient bowel that
is created at the time. Outcome analyses do not show any
statistical advantage of a Roux-en-Y loop.
For portal drainage of the pancreas graft venous effluent
(Fig. 47-4), the head and duodenum of the graft is oriented
633
40 to 80
cm
TRANSPLANTATION
1200
PTA
PAK
SPK
600
400
200
0
19
98
20
00
20
02
20
04
20
06
20
08
800
19
88
Number of transplants
1000
19
96
19
94
FIGURE 47-5 Living donor segmental (body and tail) pancreas transplantation to right iliac vessels (systemic venous drainage) and bladder
drainage of exocrine secretions through a ductocystostomy by means of
an intraperitoneal approach. The donor splenic artery and splenic vein
are anastomosed end to side to the recipient external iliac artery and vein
after ligation and division of all hypogastric veins to bring the main vein as
superficial as possible. The splenic artery anastomosis is lateral and proximal to the splenic vein anastomosis. A two-layer ductocystostomy is constructed: The pancreatic duct is approximated to the urothelial layer (inner
layer) using interrupted 7-0 absorbable sutures over a stent (inset). If the
kidney is transplanted simultaneously, the donor ureter is implanted into
the bladder using the extravesical ureteroneocystostomy (Lich) technique. (Reproduced from Gruessner RWG, Sutherland DER [eds]: Transplantation of the Pancreas. New York, Springer-Verlag, 2004.)
19
91
PART IV
19
90
634
CHAPTER 47
with antiT-cell monoclonal or polyclonal depleting or nondepleting agents may be used or reserved for rejection episodes.73 Maintenance immunosuppression usually consists
of a combination of a calcineurin inhibitor (cyclosporine or
tacrolimus), with the dose and blood levels adjusted to
minimize nephrotoxicity, and an antiproliferative agent
(mycophenolate mofetil or sirolimus), with or without prednisone. Corticosteroid-free regimens are now quite common
for all organ transplantations, including the pancreas.7483
Suspected pancreas allograft rejection episodes, based on
transient rise of serum amylase or lipase in enteric-drained
grafts or on a decline in urine amylase in bladder-drained
grafts, or by a rise in serum creatinine in SPK transplantations,
can be confirmed by biopsy of the graft.84,85
635
%
100
80
60
PAK
PTA
SPK
40
Category
20
1-yr fxn
SPK
4,146
85%
PAK
947
79%
PTA
465
78%
Current outcomes with deceased donor pancreas transplantations, according to recipient categories, surgical technique,
and immunosuppression protocol, for U.S. cases as reported
to UNOS from January 2005 to December 2009, are summarized here.55 During this period, 5567 primary deceased donor
pancreas transplantations were reported to UNOS, including
4155 SPK, 947 PAK, and 465 PTA transplantations.
The primary transplantation patient survival rates in the
three recipient categories are shown in Figure 47-7. At 1 year,
96% of the SPK, 97% of the PAK, and 97% of the PTA recipients were alive; at 3 years, 92%, 91%, and 92%, respectively,
were alive. The highest patient survival rate could be found in
PTA subgroups, presumably because this group had less
advanced complications before transplantation.
The primary pancreas graft survival rates in the three recipient categories are shown in Figure 47-8. At 1 year, 85% of the
SPK, 79% of the PAK, and 78% of the PTA recipients were
totally insulin-independent; at 3 years, 79%, 68%, and
62%, respectively, were insulin-independent (P < 0.001).
The highest pancreas graft survival rates are in the SPK category, presumably because the kidney graft (usually from the
same donor as the pancreas) can be used to detect rejection
episodes earlier than in the other categories, where only the
pancreas can be monitored. Support for this hypothesis comes
12
18
24
30
36
Months posttransplant
FIGURE 47-8 Pancreas graft functional survival rates (insulin independence) for 2005 to 2009 U.S. deceased donor primary transplantations
by recipient category. Fxn, function; PAK, pancreas after kidney transplantation; PTA, pancreas transplantation alone; SPK, simultaneous pancreas
and kidney transplantation.
%
100
Category
25
PTA
PAK
SPK
20
90
n
413
811
3,687
1-yr loss
PAK
PTA
SPK
6.0%
5.5%
2.1%
15
80
Category
n
465
PTA
947
PAK
4,155
SPK
70
PAK
PTA
SPK
1-yr surv.
97.4%
96.8%
95.5%
10
5
0
60
0
12
18
24
30
36
Months posttransplant
FIGURE 47-7 Patient survival rates for 2005 to 2009 U.S. deceased donor
primary transplantations by recipient category. PAK, pancreas after kidney
transplant; PTA, pancreas transplant alone; SPK, simultaneous pancreas
and kidney transplantation; surv., survival.
12
18
24
30
36
Months posttransplant
FIGURE 47-9 Technically successful pancreas graft immunologic failure
rates (return to exogenous insulin) for 2005 to 2009 U.S. deceased donor
primary transplants by recipient category. PAK, pancreas after kidney
transplantation; PTA, pancreas transplantation alone; SPK, simultaneous
pancreas and kidney transplantation.
636
PART IV
TRANSPLANTATION
for SPK transplants (91%); for PAK and PTA, the proportion
that were enteric drained was slightly lower (86% and 79%,
respectively). Overall, the technical failure rate was significantly
higher with enteric-drained SPK than with bladder-drained
SPK (7% vs. 4%) transplants. No difference was found for
solitary transplants. Pancreas graft survival rates, however, were
not significantly different for enteric-drained versus bladderdrained transplantations in any of the categories: At 1 year,
the rates were 85% (n 3665) versus 86% (n 366) for
SPK, 79% (n 790) versus 82% (n 130) for PAK, and
80% (n 366) versus 75% (n 99) for PTA cases. No difference in the failure rate from rejection for technically successful
grafts for enteric-drained versus bladder-drained transplantations could be found anymore.
In the SPK category, bladder drainage and enteric drainage
would be expected to give similar results: In most cases, both
grafts come from the same donor, and monitoring of serum
creatinine serves as a surrogate marker for rejection in the pancreas transplant, allowing easy detection and reversal by treatment. In contrast, for solitary pancreas transplants (PAK and
PTA), serum creatinine cannot be used as a marker of pancreas
rejection, hyperglycemia is a late manifestation of rejection,
and exocrine markers must be used. Although serum amylase
and lipase may elevate during a rejection episode, this does
not occur in all cases, but for bladder-drained grafts, a
decrease in urine amylase eventually always accompanies
rejection (100% sensitive, even though it is not specific)
and nearly always precedes hyperglycemia so that a rejection
episode is more likely to be diagnosed in a bladder-drained
graft and lead to treatment and reversal.
Approximately one quarter of enteric-drained pancreas
grafts reported to UNOS were done with a Roux-en-Y loop;
in the past, the outcomes were not improved by this procedural addition,45 and that is still the case.55
Another variation in surgical technique is portal drainage of
the venous effluent for enteric-drained grafts.30,86 It establishes normal physiology and a theoretic metabolic advantage
versus systemic venous drainage, and some groups have
reported that portal venous enteric-drainage grafts are less
prone to rejection than systemic venous enteric-drainage
grafts,87,88 although others have not.89 The latest Registry
analysis shows that portal venous drainage was used for one
fifth of enteric-drainage transplantations, but there were no
significant differences in pancreas graft survival versus
systemic venous enteric-drainage transplantations in any of
the categories: at 1 year, 84% (n 718) versus 86%
(n 2896) for SPK, 79% (n 130) versus 79% (n 651)
for PAK, and 78% (n 51) versus 80% (n 305) for PTA cases.
Regarding immunosuppression, according to the latest
Registry analysis, antiT-cell agents were used for induction
therapy for more than 80% of the 2005 to 2009 U.S. pancreas
recipients in each category.55 The most frequently used regimen for maintenance immunosuppression (more than two
thirds of the recipients in each category) was tacrolimus and
mycophenolate mofetil in combination, with or without prednisone. In recipients of primary deceased donor pancreas
grafts given antiT-cell agents for induction and tacrolimus
and mycophenolate mofetil for maintenance immunosuppression (Fig. 47-10), the 1-year graft survival rates in the SPK,
PAK, and PTA categories were 86% (n 2737), 81%
(n 544), and 86% (n 271), respectively. A sirolimus-based
regimen was used as a maintenance immunosuppressive drug
%
100
80
60
PAK
PTA
40
SPK
Category
20
PAK
PTA
SPK
1-yr fnx
544
271
2,737
81.3%
85.6%
86.3%
0
0
12
18
24
30
36
Months posttransplant
FIGURE 47-10 Pancreas graft functional survival rates (insulin independence) for 2005 to 2009 U.S. deceased donor primary transplantations by
category in diabetic recipients given antiT-cell agents for induction and
tacrolimus (TAC) and mycophenolate mofetil (MMF) for maintenance immunosuppression. Fxn, function; PAK, pancreas after kidney transplantation; PTA, pancreas transplantation alone; SPK, simultaneous pancreas
and kidney transplantation.
100
80
60
PAK
PTA
SPK
40
Category n
20
PAK
PTA
SPK
95
87
407
1-yr fnx
89.3%
90.2%
89.6%
0
0
12
18
24
30
36
Months posttransplant
FIGURE 47-11 Pancreas graft functional survival rates (insulin independence) for 2005 to 2009 U.S. deceased donor primary transplantations by
category in diabetic recipients given sirolimus-based maintenance immunosuppression. Fxn, function; PAK, pancreas after kidney transplantation;
PTA, pancreas transplantation alone; SPK, simultaneous pancreas and
kidney transplantation.
CHAPTER 47
failure rates and a decrease in graft survival rates with increasing preservation time. The relative risk (RR) to lose the graft
doubled for SPK grafts with a preservation time greater than
24 hours compared with a preservation time of 12 to 24 hours.
Shorter SPK preservation time showed a decreased risk of one
third. HLA matching had virtually no impact on SPK graft
survival rates, but matching at least at the class I loci had a
beneficial effect in the PAK and the PTA categories.
Regarding pancreas recipient age, the recent Registry analysis of the 2005 to 2009 cases showed an effect on outcome
mainly in solitary recipients, with rejection more likely in
younger patients. In the SPK category, only 3 patients were
younger than 15 years of age, and 312 recipients (7%)
were between 15 and 29 years of age. In PAK, 5% (n 60)
were between the age of 15 and 29 years of age, and 15%
(n 75) in PTA. The relative risk for graft loss was not significantly increased for younger SPK recipients (P 0.21) but
clearly higher for PAK recipients (RR 1.75, P 0.003)
and PTA recipients (RR 1.99, P 0.009) compared with
recipients 30 to 45 years of age. Thus the young nonuremic
diabetic is highly immunocompetent and more prone to reject
a pancreas graft, consistent with an earlier analysis of outcomes in U.S. pediatric pancreas transplantation recipients
from 1988 to 1999.90 In that analysis, of slightly more than
8000 pancreas transplantations, only 49 were in recipients
younger than 21 years of age (<1%), 34 in the SPK, 2 in
the PAK, and 13 in the PTA category; all were deceased donor
pancreas transplantations, except for two PTA segmental
grafts from living donors. Less than half of the pediatric pancreas recipients were younger than 19. In the PTA recipients,
the 1-year graft survival rate was only 15%, with all but one
loss being from rejection in less than 1 year. The Registry data
do not include the indications for a PTA in the pediatric recipients, but presumably they had extremely labile diabetes, justifying placement on immunosuppression in an attempt to
gain control. In the pediatric SPK recipients, however, the
1-year patient, pancreas, and kidney graft survival rates were
96%, 78%, and 71%, respectively, which were outcomes comparable to those of adult SPK recipients for the entire period.
Of the pediatric SPK recipients, most had a renal disease other
than diabetic nephropathy.
Thus pancreas transplantations in the pediatric age group
are uncommon, and most are in diabetic children who also
have renal failure and thus need a kidney transplantation, obligating them to immunosuppression. At least in this group,
the outcomes are such that it seems reasonable to recommend
the addition of the pancreas so that the child can become insulin independent as well as dialysis free for the price of immunosuppression.13 For nonuremic diabetic children with
extreme lability, in whom a successful pancreas transplantation would be appropriate treatment, the antirejection strategies need to be optimized to improve the graft survival rates
versus what has been achieved in the past.
With respect to outcome measures other than insulin independence, prevention and reversal of secondary complications, improvement in quality of life, extension of life span,
and reduction of health care costs per quality-adjusted lifeyear have all been positively demonstrated in type 1 diabetic
pancreas transplant recipients.9197 In patients with labile diabetes and hypoglycemic unawareness, a pancreas transplantation can resolve an otherwise intractable and life-threatening
course.98100
637
Whether a pancreas transplantation has an effect on survival probabilities for the diabetic population selected for
the procedure is controversial. Two separate analyses of U.S.
data from UNOS and the Organ Procurement Transplant Network (OPTN) for pancreas transplantation candidates and recipients between 1995 and 2000 compared the survival
probabilities for patients who remained on the waiting list
with those receiving a transplant by category.103,104 In the first
analysis,103 SPK recipients had a significantly higher probability of survival than those remaining on the waiting list for the
procedure, but, for solitary (PAK or PTA) recipients, just the
opposite was the case. In the second analysis,104 the higher
survival probability for SPK recipients was confirmed, and,
in addition, the overall survival probabilities of solitary pancreas transplant recipients compared with those waiting,
and even after 1 year, were favorable for transplantation. In
the second analysis, patients who listed at multiple centers
were identified and were counted only once from the time
of first listing, corrections were made for patients who
changed categories, and longer follow-up was available. Thus
pancreas transplantation does not entail a higher risk than
staying on exogenous insulin for those on the waiting list
and may improve survival probabilities for solitary as well
as SPK recipients.105
In regard to secondary complications of diabetes,106 numerous studies show a beneficial effect on neuropathy,94,107113 retinopathy114118 and nephropathy92,119122
as well as on cardiovascular disease,123128 and quality of
life.129,130 In regard to nephropathy, specifically in PTA recipients, even though the diabetic lesions in the native kidneys
can improve,131 this can be offset by the nephrotoxicity of
the calcineurin inhibitors given for immunosuppression.132
It should be noted that pancreas retransplantation can be
done if the first graft fails, with only slightly lower graft survival rates than for primary transplants.66,67,133,134 Indeed,
even third transplants can do well.134
Also of note, pancreas allografts are often procured by one
center and transplanted at another, and there are studies
showing no difference in outcomes compared with locally
procured organs.135
Surgical complications of pancreas transplantation are numerous and are the subject of an extensive review recently
published.136 The most frequent complication leading to graft
loss is venous or arterial thrombosis (5% to 10%). Anastomotic leaks are also common, but if diagnosed early, graft salvage is possible.
Islet Transplantation
------------------------------------------------------------------------------------------------------------------------------------------------
Human islet transplantation, the less invasive islet beta cell replacement alternative to transplantation of the vascularized
pancreas, has been investigated for more than 3
decades137140 after the first clinical islet allograft was performed
in 1974.141 Since then, nearly 1000 islet allotransplantations
have been performed worldwide.142,143
Islet autotransplantations have had a relatively high success
rate in preventing diabetes after total pancreatectomy for more
than 2 decades; so, they are briefly described before reviewing
the current status of islet allografts for type 1 as well as for
surgical diabetes.
638
PART IV
TRANSPLANTATION
FIGURE 47-12 Pylorus-sparing total pancreatectomy and partial duodenectomy technique for patients with chronic pancreatitis undergoing islet
autotransplantations. The bile duct is transected and reimplanted into the
duodenum, shown here proximal to a duodenoduodenostomy or duodenojejunostomy, but, more commonly, it is placed distal to the enteric anastomosis, with the site depending on the individual anatomy. When
possible, only the second portion of the duodenum is resected, and an
end-to-end duodenoduodenostomy is created; but if viability is not maintained, the entire distal duodenum must be resected and an end-to-end or
end-to-side duodenojejunostomy performed. The short gastric vessels are
preserved, as well as the gastroepiploic artery if possible, and the spleen is
not removed if its viability is maintained. (Reproduced from Gruessner
RWG, Sutherland DER [eds]: Transplantation of the Pancreas. New York,
Springer-Verlag, 2004.)
pancreas are removed, they should always be processed for islet isolation for an intraportal autotransplant (Fig. 47-13, A).
If a distal pancreatectomy is the primary procedure and a
Whipple (completion) pancreatectomy becomes necessary, diabetes will have been prophylactically prevented by the initial
islet autograft. If a Whipple procedure was the primary procedure, but pain persists and a distal (body and tail) completion
pancreatectomy is required, it should be done in an institution
capable of isolating islets from the excised gland for an
autotransplantation.158
ISLET ALLOTRANSPLANTATIONS
Islet allotransplantations have been performed for the treatment of surgical and type 1 diabetes. As with autotransplantations, islet allotransplantations are usually done with
embolization of the islets to the liver via the portal vein, where
at least some islets will survive by nutrient diffusion until
revascularization occurs (Fig. 47-13, B). A drawback of
islet allotransplantations, as compared with pancreas transplantations, is the reduced beta cell mass; much attention
has been given to compensating for the attrition that occurs.
Islet allografts in patients with surgical diabetes have been
associated with a very high success rate,159,160 possibly
because of the avoidance of diabetogenic steroids and the lack
of an autoimmunity.
Islet allograft transplantations in patients with autoimmune
type 1 diabetes have initially been performed simultaneously
with a kidney transplant or in patients with established kidney
transplants.142 Insulin independence in this recipient group,
even on an anecdotal basis, was not achieved until the early
1990s.161165
Islet allografts have also been performed in patients in
whom type 1 diabetes (T1D) is complicated by hypoglycemia
unawareness and defective hormonal glucose counter-regulation resulting in recurrent episodes of severe hypoglycemia.166 Today, the majority of human islet allografts are
performed in this recipient group.143 Acute complications
are frequent in the 12.5% of T1D patients who have become
aware of hypoglycemia 20 years after diabetes onset.167
Iatrogenic hypoglycemia is the most limiting factor in the
glycemic management of T1D;168 it causes recurrent physical
and psychological morbidity, including coma, seizures, and
significant social embarrassment, and 7% to 10% of all deaths
in patients with T1D are the result of hypoglycemia.169,170
Hypoglycemia-related problems have not abated during the
more than 18 years since they were first highlighted by the
landmark report of the DCCT in 1993.168,171 New glucose
monitoring technologies are being developed; however, continuous glucose monitoring did not lower the rate of severe
hypoglycemia in patients with T1D.173,174
A major milestone was reached in 2000 when Dr. Shapiro
and colleagues at the University of Alberta in Edmonton
achieved diabetes reversal in seven of seven recipients by
using islets from more than one donor pancreas and by using
corticosteroid-free, less diabetogenic immunosuppression.175
Since then, several groups around the world have reported
restoration of insulin independence after human islet allotransplantation in type 1 diabetic recipients.11,176194
Furthermore, remarkable additional progress has been
made in the past decade toward developing islet transplantation into a vital treatment option for T1D. First, new protocols
CHAPTER 47
639
Isolated native
islet of Langerhans
Liver
Islet isolation
Syringe
Pancreas
Pancreas
Islet isolation
Recipient
Liver
Isolated islet
of Langerhans
Syringe
Portal vein
Pancreas
B
Islet in pancreas
FIGURE 47-13 Islet transplantation using the portal vein for embolization to the liver where revascularization will occur, either as an autograft of islets
isolated from the excised specimen after pancreatectomy for benign disease (A) or as an allograft of cells isolated from a donor for treatment of a patient
with type 1 diabetes (B).
calcineurin inhibitorfree regimens may be an effective alternative to improve graft function and longevity while minimizing renal and islet beta cell toxicity. Third, Berney and
colleagues reported on the first type 1 diabetic patient who
remained insulin independent for more than 10 years after
islet allotransplantation.195 Preliminary data now suggest that
long-term insulin independence (>5 years) can be achieved in
50% of recipients given T-celldepleting induction immunotherapy, matching insulin independence rates of solitary pancreas transplantation.196 Early studies examining long-term
islet function suggested a rapid loss of insulin independence
beyond 1 year in many patients.183,197 One possible factor contributing to islet loss is recurrent beta cell autoimmunity.198,199
640
PART IV
TRANSPLANTATION
CHAPTER 47
incapacitating hypoglycemic unawareness and is also appropriate in children and adults who otherwise need immunosuppression, such as for a kidney transplantation. As antirejection
strategies become safer and with fewer side effects, the indications for pediatric beta cell replacement therapy can be
liberalized.
641
Acknowledgments
We are indebted to Christine Johnson and Heather Nelson for assistance in
preparing the manuscript.
CHAPTER 48
Liver
Transplantation
Bob H. Saggi, Douglas G. Farmer,
and Ronald W. Busuttil
------------------------------------------------------------------------------------------------------------------------------------------------
644
PART IV
TRANSPLANTATION
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Total #
2009
2008
2007
2006
2005
572
613
605
577
569
1117 years
610 years
15 years
<1 year
FIGURE 48-1 Distribution of pediatric liver transplantations by age.
Data obtained from www.unos.org.
Acute hepatic
necrosis
12%
Metabolic
disease
9%
Cholestatic liver
disease/cirrhosis
12%
Malignant
neoplasms
8%
Non-cholestatic
cirrhosis
8%
Other
14%
TPN liver
disease
8%
FIGURE 48-3 Decompensated cirrhosis after a Kasai portoenterosotomy. This 6-month-old, 5-kg child presented for liver transplant with the
advanced findings of hepatosplenomegaly, extensive abdominal wall venous collaterals, tense ascites, jaundice, and profound malnutrition.
NONCHOLESTATIC CIRRHOSIS
Noncholestatic cirrhosis is an uncommon indication for liver
replacement in children, accounting for less than 10% of all
procedures performed in 2008 (see Fig. 48-2).2 These children usually present later in life than the cholestatic disorders.
CHAPTER 48
Etiologies of cirrhosis and decompensated cirrhosis in these patients include chronic autoimmune hepatitis, neonatal hepatitis,
chronic viral (B or C) hepatitis, and cryptogenic cirrhosis.
TUMORS
The most common liver malignancy in children is hepatoblastoma.13,14 Although sporadic cases have been reported, hepatocellular carcinoma (HCC) is primarily seen in children with
viral hepatitis, tyrosinemia, some of the glycogen storage diseases, or in association with cirrhosis from other causes. Primary liver malignancies in pediatric patients are managed by
surgical resection unless tumor size and/or location preclude
resection. The benefit of neoadjuvant and/or adjuvant chemotherapy and radiation for hepatoblastoma has been well documented.1517 In HCC, multimodal therapy can be used to
LIVER TRANSPLANTATION
645
MISCELLANEOUS CONDITIONS
These conditions include diagnoses such as Budd-Chiari syndrome, trauma, biliary cirrhosis secondary to intestinal failure,
and long-term total parenteral nutrition (TPN) use. The latter
is detailed in Chapter 49.
646
PART IV
TRANSPLANTATION
HEPATOBILIARY ANATOMY
The performance of a donor hepatectomy or transplant operation requires a thorough understanding of foregut anatomy.
In addition, a very detailed understanding of this anatomy is
essential to the field of segmental liver transplantation and has
impacted hepatobiliary surgery. The blood supply to the liver
is based on a highly variable arterial and portal system. Venous
drainage is through the right, mid-, and left hepatic veins that
join the inferior vena cava, which traverses the dorsal surface
of the liver (the retrohepatic cava). The liver is composed of
the major right and left lobes that are separated by external
landmarks and further subdivided into the right anterior
and posterior sectors and left medial and lateral sectors. This
nomenclature is still used to describe major anatomic liver
resections. However, through the elegant anatomic techniques
of the pioneering surgical anatomist Claude Couinaud,
hepatic anatomy was found to be much more intricate
(Fig. 48-4). The Couinaud nomenclature describes nine
hepatic segments based on portal vein branching in relationship to the transverse plane (a cross-sectional plane located
at midpoints of the hepatic veins) and the longitudinal
planes of the individual hepatic veins (see Fig. 48-4). Each
of the segments is supplied by an independent portal and
Donor Operation
------------------------------------------------------------------------------------------------------------------------------------------------
2
7
8
1
4
FIGURE 48-4 Segmental liver anatomy. The division of the liver into independently vascularized and drained segments is based on the parallel
bifurcation of the portal vein and hepatic artery.
FIGURE 48-5 Cadaveric organ procurement. A wide exposure with median sternotomy extending to midline laparotomy is made for multiorgan
procurement. This harvest resulted in the procurement of six organ grafts
from a single recipient, benefiting six different recipients.
CHAPTER 48
Segmental Liver
Transplantation: Living Donor,
Reduced Size, and Split
------------------------------------------------------------------------------------------------------------------------------------------------
LLS: 2,3
RTS: 1,48
FIGURE 48-6 Cadaveric in-situ split-liver procedure. The liver is separated just to the left of the umbilical fissure into a right trisegment (RTS)
graft and a left-lateral segment (LLS) graft.
LIVER TRANSPLANTATION
647
648
PART IV
TRANSPLANTATION
Suprahepatic caval
anastomosis
Portal venous
anastomosis
Hepatic arterial
anastomosis
Roux-en-Y
choledochojejunostomy
FIGURE 48-7 Whole organ engraftment. Both the standard orthotopic and piggyback techniques are depicted.
IVC
PHA
SA
A
CA
IVC
PV
FIGURE 48-8 Left-lateral segment engraftment. A, aorta; CA, celiac artery; IVC, inferior vena cava; PHA, proper hepatic artery; PV, portal vein;
SA, splenic artery. (Reprinted with permission from Goss J, Yerziz H, Shackelton H, et al: In situ splitting of the cadaveric liver for transplantation.
Transplantation 1997;64:871-877.)
Post-transplant Care
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 48
Technical Complications
------------------------------------------------------------------------------------------------------------------------------------------------
VASCULAR COMPLICATIONS
Major vascular complications include hepatic artery thrombosis (HAT), portal vein thrombosis, and caval thrombosis or
stenosis. Intravenous low-dose unfractionated heparin with
or without low-molecular-weight dextran is routinely used
for prophylaxis against vascular thromboses. Duplex ultrasonography and computerized tomographic or conventional
angiography are accepted means of diagnosis. HAT is the
most common complication, and its incidence varies from
5% to 18% depending on patient age and type of
graft.7,8,23,24,27,28 Early vascular complications are usually
technical in nature, while immunologic and infectious
(e.g., cytomegalovirus [CMV]) etiologies have been ascribed
to those occurring months after transplantation. HAT occurring in the first week is commonly associated with graft nonfunction and biliary necrosis or leak, while those occurring
later do not necessarily affect graft function immediately,
but usually produce biliary complications. These include
intrahepatic biliary abscesses, biliary anastomotic stricture,
and sclerosing cholangitis with sepsis, all of which lead to
significant morbidity. If diagnosed early, some patients can
be managed by thrombectomy and surgical revision. However, most early HATs require urgent retransplantation. Late
HATs with preserved graft function can be managed by radiologic interventional techniques and retransplanted remote
from initial transplantation. Thrombosis of the portal vein
occurs in 2% to 4% of pediatric liver transplantations and
is usually associated with loss of the graft. Prompt retransplantation is required for patient salvage. Late portal vein
thrombosis usually presents with recurrent variceal bleeding
or ascites and can be managed medically, endoscopically, or
surgically with shunting or retransplantation. Vena caval or
hepatic vein thrombosis or stenosis occurs in 3% to 6% of
LIVER TRANSPLANTATION
649
BILIARY COMPLICATIONS
Biliary complications that are not associated with HAToccur in
3% to 20% of patients depending on the type of graft and
whether a choledochojejunostomy was used. These usually
result from technical factors, but occasionally warm ischemia
or immunologic and infectious factors can be implicated (e.g.,
CMV). Diagnosis is by cholangiography and treatment can
be by endoscopic or radiologic intervention or by surgical
revision.7,2325,27
Immunosuppressive Therapy
and Rejection
------------------------------------------------------------------------------------------------------------------------------------------------
650
PART IV
TRANSPLANTATION
TABLE 48-1
Modern Immunosuppressants Used in Liver Transplantation
Name
Mechanism of Action
Principal Use
Common Toxicities
Calcineurin
inhibitors (CNI)
cyclosporine
tacrolimus
Glucocorticoids
methylprednisolone
prednisone
Mycophenolate
mofetil
Shared: nephrotoxicity,
hypertension, hyperglycemia,
neurotoxicity (seizures, myoclonus,
essential tremors)
Cyclosporine: hirsutism, gingival
hyperplasia, more diabetes
Tacrolimus: diarrhea, anorexia, more
neurotoxicity, more hypertension
Hyperlipidemia, osteopenia,
hypertension, diabetes, impaired
wound healing, growth retardation,
Cushingoid features, striae, acne
Myelosuppression, diarrhea,
anorexia, nausea, vomiting, GI
mucosal ulceration
Hyperlipidemia, impaired wound
healing, pneumonitis, oral ulceration
Mammalian target
of rapamycin
inhibitors
rapamycin
OKT3 monoclonal
antibody
Antilymphocyte
globulin
(Thymoglobulin)
IL-2 receptor
antagonists
basiliximab
daclizumab
Induction of immunosuppression as an
adjunct to CNI; used to minimize other
immunosuppression (CNI, steroids)
SIRS and other infusional reactions, increased risk of viral infections and PTLD
Increased risk of viral infections and
PTLD, lower incidence of infusional
reactions than OKT3,
thrombocytopenia
Increased risk of viral infections,
possible PTLD, rare infusional
reactions
AR, acute rejection; GI, gastrointestinal; IL-1, IL-2, interleukin-1, interleukin-2; PTLD, post-transplant lymphoproliferative disorder; SIRS, systemic inflammatory
response syndrome.
vascular endothelium and biliary epithelium but not hepatocytes. This is based on the greater expression of donor human
leukocyte antigens on the former cell types. The histologic
hallmark of AR is a mixed cell inflammatory infiltrate (polymorphonuclear cells, lymphocytes, and eosinophils) in the
portal triad, with evidence of inflammation of the endothelium and/or biliary epithelial injury. Rejection can be graded
as mild, moderate, and severe depending on the proportion
of involved portal triads, the degree of infiltrate and injury,
and the presence of central vein endothelial inflammation,
which is a sign of severe AR. Treatment of AR is centered
on a high-dose methylprednisone bolus, but cases unresponsive to this may require use of antibody therapy (OKT3,
antithymocyte globulin [ATG], see Table 48-1). Mild AR can
often be treated by simply increasing the tacrolimus level,
though steroid bolus should be considered if there is not a
prompt response. AR does not influence long-term graft survival in adults or children, unless it occurs in multiple or steroid refractory episodes, or if it occurs beyond the first year
post-transplant.4,7,29 AR accounts for less than 3% of overall
patient and graft loss. However, treatment for AR is an important risk factor for the development of cytomegalovirus and
Epstein-Barr viral infections in children. The latter is a risk factor for the development of post-transplant lymphoproliferative disorder. Therefore a balance between adequate
immunosuppression to prevent AR and over-immunosuppression to avoid toxicity is necessary. Currently, long-term
morbidity from immunosuppressive drug therapy is the major
challenge facing long-term survival and quality of life in the pediatric population.
Infectious Complications
------------------------------------------------------------------------------------------------------------------------------------------------
Post-transplant infections are the most common cause of morbidity and mortality after liver transplantation (Table 48-2).
The highest incidence of bacterial and fungal infections is in
the first month after transplantation. Fungal infections occurring months to years after transplantation are unusual and are
more commonly the atypical or endemic organisms, such as
Cryptococcus spp., Mucormycosis spp., Blastomycosis spp., or
Coccidiomycosis spp. Viral infections are the most common infections after the early post-transplant period. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections account for
the vast majority of opportunistic viral infections. Overall
CHAPTER 48
LIVER TRANSPLANTATION
651
TABLE 48-2
Infectious Complications after Liver Transplantation
Organism
Presentation
Diagnosis
Antimicrobials
Cytomegalovirus
(CMV)
Quantitative CMV-DNA
PCR
pp65 antigen
Tissue cultures
Blood or fluid cultures
Biopsy with
immunostains
Quantitative EBV-DNA
PCR
Blood smear
Biopsy with
immunostains
CT scans of suspected
sites
HSV-1 and HSV-2
antibodies
Biopsy with viral cultures
BAL, lung biopsy
Epstein-Barr virus
(EBV)
Herpes simplex
virus (HSV)
Pneumocystis
Candida
Aspergillus
Bacteria
Acyclovir
BAL, bronchoalveolar lavage; CNS, central nervous system; CT, computed tomography; GI, gastrointestinal; IV, intravenous; PCR, polymerase chain reaction.
reduction and more selective immunosuppression and prophylaxis with ganciclovir have reduced the incidence and
morbidity of these infections. The other agents responsible
for infectious morbidity, their presentation, diagnosis, and
treatment are included in Table 48-2. Of particular importance in children is the prophylaxis and effective treatment
of EBV. This is associated with the development of numerous
malignant consequences. The most common of these is a diffuse proliferation of lymphoid tissue known as post-transplant
lymphoproliferative disorder (PTLD). PTLD can present as a
mononucleosis-like syndrome with diffuse lymphadenopathy
or as lymphoma involving any organ. A variety of other tumors
are also associated with EBV infections.29 The general therapy
for PTLD is reduction or elimination of immunosuppression,
and, occasionally, surgical intervention and/or chemotherapy.
The complete discussion of these disorders is beyond the
scope of this chapter but is extensively covered elsewhere.29
652
PART IV
TRANSPLANTATION
CHAPTER 49
Pediatric Intestinal
Transplantation
Yann Revillon and Christophe Chardot
654
PART IV
TRANSPLANTATION
FIGURE 49-1 Indications for intestinal transplantation. From the Intestine Transplant Registry 2003 report2: 606 grafts (223 isolated bowel,
306 liver and intestine, 77 multivisceral) in 563 children (age 18 years).
Transplantation Surgery
------------------------------------------------------------------------------------------------------------------------------------------------
The donor is usually a deceased donor, although a few livingrelated donations have been reported for isolated small bowel
transplants.14 The volume of the graft must correlate with the
abdominal cavity of the recipient; this depends on (1) the
donor to recipient weight ratio, (2) the native organs removed
and the type of graft implanted, and (3) whether the abdominal cavity is small (IT for short bowel) or distended (IT
for intestinal motility disorders with chronic intestinal
distention).
A wide variety of grafts can be implanted, from isolated
small bowel to multivisceral grafts, including stomach, pancreas and duodenum, small bowel, right colon, liver, and kidneys (Fig. 49-2). These grafts can be classified as
1. Isolated intestinal transplantation: small bowel right
colon. This type of graft is generally indicated for IF with
normal motility of the stomach and duodenum, and without significant liver disease. The native stomach, duodenum, pancreas, spleen, and liver are preserved. The
superior mesenteric artery of the graft is connected to
the recipient infrarenal aorta, and the mesentericoportal
axis of the graft is joined to the native infrarenal vena
cava. The proximal jejunum of the graft is connected to
the native jejunum.
CHAPTER 49
B
FIGURE 49-2 A, Multivisceral transplantation: the graft before implantation. The graft includes stomach, pancreas, duodenum, small bowel, right
colon, liver, and two kidneys. B, Multivisceral transplantation: the
graft after implantation and reperfusion.
655
Postoperative Care
------------------------------------------------------------------------------------------------------------------------------------------------
656
PART IV
TRANSPLANTATION
Results of Intestinal
Transplantation
------------------------------------------------------------------------------------------------------------------------------------------------
C
FIGURE 49-3 A, Intestinal transplantation, end of operation. The edema
of the graft after reperfusion prevents primary abdominal closure. A Silastic
silo is performed. B, Staged abdominal closure. The Silastic silo is covered
with a vacuum dressing. The silo is progressively tightened over the next
days at the bedside, as edema progressively resolves and graft reintegrates
the abdomen. C, Final abdominal closure. After 5 to 7 days, the edema of
the graft has diminished, and final abdominal closure can be achieved; the
musculoaponeurotic layer can be closed either completely or with a
wound prosthesis (for instance, a GORE-TEX sheet).
CHAPTER 49
657
Patient survival
1
.8
.6
.4
.2
0
0
10 12
14 16 18
1-year
Patient survival
73.0%
61.8% 48.6%
Standard error
4.5%
66
5.2%
43
43.7%
6%
6.3%
21
duodenum, and bowel in 1; liver, stomach, pancreas, duodenum, bowel, and two kidneys in 1 (see Fig. 49-2). In 63 of
97 transplants (65%), the graft included the right colon.
One-year, 5-year, 10-year, and 15-year patient survival rates
are 73.0%, 61.8%, 48.6%, and 43.7%, respectively, and
1-year, 5-year, 10-year, and 15-year graft survival rates are
59.5%, 45.0%, 33.6%, and 31.2%, respectively (Figs. 49-4
and 49-5). Early mortality is higher, but long-term graft survival is better after combined liver and intestine transplantation compared with isolated intestinal transplantation. This
is probably due to the protective effect of the liver against
intestinal rejection.19,20
In a study of 31 children treated by our group, and who
are alive with their graft 2 to 18 years after transplantation,21
FIGURE 49-4 Patient survival after intestinal transplantation in the tacrolimus era. Paris series from
November 1994 to March 2011: 90 patients.
1
Graft survival
.8
.6
.4
.2
0
0
10 12
14 16 18
1-year
Graft survival
59.5% 45%
Standard error
Number of grafts reaching considered follow-up
5%
53
5.3%
31
33.6%
31.2%
5.7%
5.8%
14
FIGURE 49-5 Graft survival after intestinal transplantation in the tacrolimus era. Paris series from November
1994 to July 2010: 97 grafts.
658
PART IV
TRANSPLANTATION
Conclusion
------------------------------------------------------------------------------------------------------------------------------------------------
Acknowledgments
The authors, Yann Revillon and Christophe Chardot, who are part of the surgical team, wish to thank the following pediatric multidisciplinary team
members*:
1. Current team members treating intestinal failure and performing
transplantations:
Surgery: Sabine Irtan, Sabine Sarnacki, and Yves Aigrain.
Gastroenterology, hepatology, and nutrition: Florence Lacaille, Virginie
Colomb, Cecile Talbotec, Franck Ruemmele, Muriel Girard, Dominique Debray, Jean-Pierre Hugot, and Olivier Goulet.
Pathology: Nicole Brousse, Virginie Verkarre, Danie`le Canioni, Julie
Bruneau, and Jean-Christophe Fournet.
Intensive care: Fabrice Lesage, Laurent Dupic, Jean Bergounioux, Olivier Bustaret, Sandrine Jean, and Philippe Hubert.
Radiology: Karen Lambot, Sophie Emond, Laureline Berteloot, and
Francis Brunelle.
Anesthesiology: Nade`ge Salvi, Nathalie Bourdeau, and Caroline Telion.
Research laboratory: Nadine Cerf-Bensoussan.
2. Former members of the team: Claude Ricour, Jean-Pierre Cezard, Dominique Jan, Jean-Luc Michel, Frederique Sauvat, Patrick Jouvet, and
Francis Jaubert.
Historical Notes
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 50
Heart
Transplantation
Stephanie M. P. Fuller and Thomas L. Spray
Thoracic organ transplantation has been successfully performed in pediatric patients since the mid-1980s and now
serves as an important option in the treatment of both congenital and end-stage heart and lung disease in children. Approximately 400 pediatric heart transplantations are
performed annually in the United States, or roughly 16%
of all pediatric solid organ transplantations.1 Despite the
clinical success of heart and lung transplantation in children,
limited donor availability has prevented broader application
of this therapy. Infants awaiting heart transplantation face the
highest wait-list mortality among all children and adults
listed for a heart transplantation in the United States, with
one in four infants dying before a donor heart can be identified.2 Complications, such as acute and chronic rejection,
graft coronary artery disease (CAD), and bronchiolitis obliterans, as well as the infectious and neoplastic complications
of current methods of immunosuppression, threaten cardiac
transplant longevity. This chapter focuses on the clinical
aspects of heart transplantation in infants and children,
including indications, preoperative evaluation, operative
techniques, postoperative management, complications, and
outcomes.
Indications
------------------------------------------------------------------------------------------------------------------------------------------------
659
Number of transplants
660
PART IV
500
450
400
350
300
250
200
150
100
50
0
TRANSPLANTATION
1117 years
110 years
<1 year
82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08
19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20
NOTE: This figure includes only the heart transplants that are reported
to the ISHLT Transplant Registry. As such, this should not be
construed as evidence that the number of hearts transplanted
worldwide has increased and/or decreased in recent years.
multiple previous palliative procedures do not preclude successful transplantation.11 In the current era, despite the need
for repeat sternotomy, the tendency toward diffuse coagulopathy and potentially prolonged ischemic times, patients undergoing transplantation for congenital heart disease experience
no actuarial difference in survival compared with those
patients undergoing transplantation for cardiomyopathy
who undergo first-time sternotomy and dissection of mediastinal structures.8,12
Cardiomyopathy is the other most common indication for
heart transplantation in infancy and childhood. Most pediatric
heart transplantations outside infancy are performed for dilated, idiopathic cardiomyopathy. Other causes of cardiomyopathy include viral, familial, and hypertrophic. Despite the
diverse causes of cardiomyopathy, several variables have been
associated with poor outcome, including a very high left
ventricular end-diastolic pressure, a left ventricular ejection
fraction less than 20%, ventricular arrhythmia, and a family
33%
Myopathy
17%
Congenital
0%
1%
Other
2%
80%
3%
ReTX
19881995
63%
1/19966/2009
% of cases
100
75
50
Myopathy
Congenital
25
0
86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09
19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20
FIGURE 50-2 Infant heart recipient diagnosis according to year of transplantation. ReTx, retransplant. (From Kirk K, Edwards LB, Kucheryavaya AY, et al:
The Registry of the International Society for Heart and Lung Transplantation: Thirteenth official pediatric heart transplantation report2010. J Heart Lung
Transplant 2010;29:1119-1128.)
CHAPTER 50
HEART TRANSPLANTATION
661
Myopathy
25%
27%
Congenital
68%
Other
65%
3%
3%
8%
ReTX
2%
1/19966/2009
19881995
% of cases
100
Myopathy
75
Congenital
50
25
0
86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09
19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20
FIGURE 50-3 Diagnosis of heart recipients aged 11 to 17 years according to year of transplantation. ReTx, retransplant. (From Kirk K, Edwards LB, Kucheryavaya AY, et al: The Registry of the International Society for Heart and Lung Transplantation: Thirteenth official pediatric heart transplantation report
2010. J Heart Lung Transplant 2010;29:1119-1128.)
% of Patients
176
58
49
38
38
39
37
53
488
36
12
10
8
8
8
8
11
100
Modified from Chen JM, Davies RR, Mital SR, et al: Trends and outcomes in
transplantation in complex congenital heart disease: 1984-2004. Ann
Thorac Surg 2004;78:1352-1361.
Preoperative Evaluation
------------------------------------------------------------------------------------------------------------------------------------------------
662
PART IV
TRANSPLANTATION
physical and psychosocial evaluation with careful examination of the cardiac, pulmonary, neurologic, renal, infectious,
and socioeconomic systems. The presence of an adequate family support system is of paramount importance to survival
postoperatively. Parents must demonstrate the ability and
resources to comply with the complex medical regimens
required and to cope with the potential for long or frequent
hospitalizations even years after transplantation. As part of
this multidisciplinary evaluation, patients undergo screening
laboratory tests, including a viral serology panel (e.g., human
immunodeficiency virus [HIV], cytomegalovirus [CMV], human Epstein-Barr virus [EBV], hepatitis).
Cardiac evaluation is performed mainly by echocardiography and cardiac catheterization in which the anatomy of the
systemic and pulmonary venous connections of the heart
and lungs are precisely identified. Important hemodynamic
data, including systemic cardiac output and pulmonary vascular resistance (PVR), both indexed to the patients body area,
are obtained at cardiac catheterization and used to screen candidates. These numbers become significant, because the major
contraindication to transplantation is fixed pulmonary hypertension unresponsive to pulmonary vasodilators. Patients with
elevated PVR (>4 to 6 Wood units) are tested with pulmonary
vasodilators, including sodium nitroprusside, oxygen (Fio2
100%), and inhaled nitric oxide, to establish whether the pulmonary vascular bed is reactive. In general, the presence of a
fixed PVR in excess of 6 to 8 Wood units is a contraindication
to orthotopic heart transplantation, because the donor heart is
unable to tolerate right-sided dilation caused by high pulmonary vascular resistance. Patients who demonstrate improvement with vasodilators may undergo transplantation with a
survival rate comparable to that in patients with normal
resistance.11 Although patients with fixed pulmonary hypertension have successfully undergone transplantation, they
have a much higher mortality rate, usually because of postoperative right ventricular failure. Other contraindications
to cardiac transplantation include multiple noncardiac congenital anomalies, active malignancy, infection, severe metabolic disease (i.e., diabetes mellitus), multiple organ failure,
multiple congenital anomalies, and the lack of an adequate
family support system, in addition to socioeconomic factors
that lead to noncompliance with drug regimen and followup care (Table 50-3).
TABLE 50-3
Potential Contraindications to Cardiac Transplantation
General
Specific
CHAPTER 50
The criteria for an ideal organ donor are as follows: meets requirements for brain death, consent from next of kin, ABO
compatibility in older children, weight compatibility (1 to
3 times that of the recipient), normal echocardiogram, age
younger than 35 years, and normal heart by visual inspection
at the time of harvest. A history of cardiopulmonary resuscitation is not an absolute contraindication to cardiac donation
for pediatric recipients. All potential donors are evaluated
carefully for the cause of death, including the presence of
HEART TRANSPLANTATION
663
664
PART IV
TRANSPLANTATION
access for femoral bypass. Once in the chest, the main pulmonary artery is dissected off the aorta past the bifurcation, and
the pericardial reflection is mobilized off the aortic arch. Normally, aortic and bicaval cannulation is used.
In the case of a neonatal recipient with HLHS, the aortic
arch vessels are mobilized proximally and controlled with
snares, and the descending thoracic aorta is dissected to a level
2 to 3 cm below the insertion of the ductus arteriosus. The
right and left pulmonary arteries are mobilized and controlled
with snares in preparation for cardiopulmonary bypass. After
heparinization, the main pulmonary artery is cannulated for
arterial inflow, and a single venous cannula is placed in the
right atrium, because circulatory arrest will be used. Immediately on instituting cardiopulmonary bypass, the pulmonary
arteries are snared tight and the body perfused though a patent
ductus arteriosus. The recipient is cooled to 18 C for circulatory arrest.
Once the donor organ is available in the operating room and
the patient has been adequately cooled, circulatory arrest is
established, the arch vessels are snared tightly, and the patient
is exsanguinated into the venous reservoir. The aorta is divided
just above the valve and incised longitudinally along the lesser
curve of the aortic arch to a level 1 to 2 cm below the ductal
insertion site on the descending aorta. The ductus is ligated
next to the pulmonary artery and divided, and then the main
pulmonary artery is transected just below the bifurcation.
The right atrial incision is started superiorly at the base of
the appendage. This incision is then carried down into the coronary sinus and across the atrial septum into the left atrium.
The superior aspect of the right atrial incision is next carried
across the septum to open the roof of the left atrium. The lateral
wall of he left atrium is incised above the left pulmonary veins
with the left atrial appendage included with the specimen.
The donor organ is prepared on the back table in cold saline solution. The right atrium is incised from the inferior vena
FIGURE 50-4 Standard heart transplantation using biatrial anastomosis. A, A recipient ventricular mass has been removed, and the left atrial anastomosis
has been started. B, Final appearance after all anastomoses are completed.
CHAPTER 50
Postoperative Management
------------------------------------------------------------------------------------------------------------------------------------------------
The recipient is returned from the operating room to an isolation room in the intensive care unit. Mechanical ventilation
is required initially but is weaned as rapidly as possible. Antibiotics are continued until all monitoring lines and chest
tubes have been removed.
HEART TRANSPLANTATION
665
Transplant Immunosuppression
------------------------------------------------------------------------------------------------------------------------------------------------
666
PART IV
TRANSPLANTATION
C
FIGURE 50-5 Technique for transplantation in hypoplastic left heart syndrome (with the use of bicaval anastomosis). A, Recipient anatomy before cardiectomy. B, Appearance of the recipient after cardiectomy. Note that the aortic incision must be extended into the descending aorta beyond the level of
the arterial duct. C, Final appearance after all anastomoses are completed.
differences in the average number of rejection episodes in patients treated for rejection regardless of the type of induction
used. In addition, there is no significant difference in survival
between the induction groups or between use of induction
versus no induction. Induction therapy does not increase
CHAPTER 50
HEART TRANSPLANTATION
667
TABLE 50-4
Heart Transplantation Immunosuppression Regimen at the Childrens Hospital of Philadelphia
Drug
Dosage
1.5 mg/kg IV given in operating room before transplantation for sensitized patients and once daily for 5 days;
titrated to CD3 count
2 mg/kg IV given in the operating room before transplantation
Then 2 mg/kg IV given once daily for 5 days (neonates), 7 days (infants), 9 days (adolescents)
Change to MMF 600 mg/m2 IV given twice daily
Change to MMF orally once intestinal function resumes
0.05 mg/kg every 12 hours orally
0.02 mg/kg/hr IV infusion beginning in the operating room before transplantation
Then 0.02 mg/kg/hr IV infusion for 24 hours
Change to ATG on postoperative day 3 and give 1.5 mg/kg IV once daily for 3 days (neonates), 5 days (infants),
or 7 days (adolescents)
Change back to cyclosporine orally once ATG course completed
Dosing should be carefully adjusted to maintain levels of 125-150 mg in neonates, 175-200 mg in children, 250 mg
in 6- to 12-year-olds, and 250-300 mg in adolescents
15 mg/kg in operating room before transplantation
3 mg/kg IV twice daily for 3 doses
0.5 mg/kg twice daily for sensitized patients followed by oral prednisone taper
Tacrolimus
Cyclosporine
Solumedrol
Early Complications
------------------------------------------------------------------------------------------------------------------------------------------------
Acute rejection and infection are the most common early complications after cardiac transplantation. Nearly 60% to 75% of
patients have at least one episode of rejection, and it should be
expected that about a third will have an episode in the first
3 months and 50% within the first year after transplantation.27
Some studies suggest that infants may be less prone to rejection than older children. Rejection surveillance is based on
clinical evaluation, echocardiography, and endomyocardial
biopsy. Clinical assessment includes observation of changes
in a patients activity or appetite. Atrial or ventricular ectopy,
including tachycardia, is suspicious for rejection and mandates evaluation. Echocardiography is particularly useful
in neonates, in whom biopsy is technically difficult and
carries significant risk because of patient size. Echocardiographic evaluation is typically performed weekly for the first
month and then monthly for the first year after transplantation. Echocardiography-guided transjugular endomyocardial biopsy has been shown to be an effective means of
monitoring pediatric transplant recipients for rejection and
remains the gold standard for detection of rejection.28 An
aggressive approach, consisting of routine endomyocardial
biopsy weekly for the first month after transplantation, every
second week for the second month, and then once monthly
for the remainder of the first year, has been adopted at the
Childrens Hospital of Philadelphia for rejection surveillance.
Subsequent biopsies are obtained twice annually or whenever
rejection is clinically suspected. Most biopsies are performed
on an outpatient basis. The international grading system for
cardiac transplant rejection is shown in Table 50-5.
Episodes of acute rejection are usually treated with a 3-day
course of intravenous methylprednisolone (10 mg/kg). OKT3
and antithymocyte globulin are reserved for an incomplete response or rejection refractory to steroids. Response is confirmed by follow-up biopsy 1 to 2 weeks after treatment.
TABLE 50-5
International Society of Heart and Lung Transplantation
Grading System for Evaluation of Cellular Rejection
2005 Classification
0
No acute rejection
1R
Interstitial and/or perivascular infiltrate with up to 1 focus of
myocyte damage
2R
Two or more foci of infiltrate with associated myocyte damage
3R
Diffuse infiltrate with multifocal myocyte damage, edema,
hemorrhage, vasculitis
1990 Classification
0
No acute rejection
1A
Focal, mild acute rejection
1B
Diffuse, mild acute rejection
2
Focal, moderate acute rejection
3A
Multifocal moderate rejection
3B
Diffuse, borderline severe rejection
4
Severe acute rejection
Modified from Billingham ME, Cary NRB, Hammond ME, et al: A working
formulation for the standardization of nomenclature in the diagnosis of
heart and lung rejection: Heart Rejection Study Group. J Heart Lung
Transplant 1990;9:587-593; Stewart S, Winters GL, Fishbein MC, et al:
Revision of the 1990 working formulation for the standardization of
nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant
2005;24:1710-1720.
668
PART IV
TRANSPLANTATION
Late Complications
------------------------------------------------------------------------------------------------------------------------------------------------
Results
------------------------------------------------------------------------------------------------------------------------------------------------
90
have been performed. Nearly 65% were for HLHS, and the
rest were for other complex congenital anomalies (29%) or
cardiomyopathy or tumor (8%). The operative (30-day) survival rate was 89%, with the primary causes of mortality being primary graft failure, technical problems, pneumonia, or
acute rejection. The overall 1-year survival rate was 84%,
with a 5- and 10-year actuarial survival rate of 73% and
68%, respectively. In addition, patients undergoing transplantation when younger than 30 days had a significantly
better outcome than did older infants, with an actuarial
survival rate of 80% and 77% at 5 and 10 years, respectively,
potentially related to improved immune tolerance in the
younger subgroup.
Stanford University reported its series of 72 patients younger than 18 years who have undergone heart transplantation
since 1977. Only 25% were younger than 1 year (mean of
9 years), and nearly two thirds had cardiomyopathy unrelated
to congenital heart disease. The operative survival rate was
87.5%, with deaths mainly caused by pulmonary hypertension/right ventricular failure and acute rejection. There were
20 late deaths, 24% were due to rejection, and 17% were
due to graft CAD. Actuarial survival rates at 1, 5, and 10 years
were 75%, 60%, and 50%, respectively.
At St. Louis Childrens Hospital, 45 heart transplants were
performed from 1983 to 1993, more than half in infants with
HLHS. The infant group had a survival rate (92%) similar to that
of the Loma Linda series, whereas the pediatric group (older
than 1 year) had an 80% early survival rate. Morales and colleagues published results of their experience spanning more
2 decades at Texas Childrens Hospital and reported no change
in mortality in survivors after the first post-transplant year.30
Results from the Registry of the International Society for
Heart and Lung Transplantation reveal a perioperative mortality rate higher for infants than for older children (Fig. 50-6).
Despite the much greater early mortality, however, the half-life
of 18.3 years is longer than that of the childhood or adolescent
survivors. For the childhood age group of 1 to 10 years, the
half-life was 17.5 years versus 11.3 years for the adolescent
age group, thus conferring the younger patients a significant
survival advantage. If those patients who died within the first
year after transplant were excluded, the median conditional
survival was 21.4 years for those who underwent transplantation in the first year of life, 19.3 years for those aged between 1 and 10 years, and 15.2 years for older children
(Fig. 50-7). Survival has been improving in relation to the
era of transplantation, with the median survival increased
Survival (%)
80
70
60
0<1 vs. 110: P <0.0001;
0<1 vs. 1117: P = 0.3284;
110 vs. 1117: P = 0.0003.
50
40
30
20
Half-life <1: 18.3 years; 110: 15.5 years; 1117: 11.3 years
10
0
0
9 10 11 12 13 14 15 16 17 18 19 20
Years
FIGURE 50-6 Survival analysis for transplantations performed January 1982 to June 2008. (From Kirk K, Edwards LB,
Kucheryavaya AY, et al: The Registry of the International Society
for Heart and Lung Transplantation: Thirteenth official pediatric
heart transplantation report2010. J Heart Lung Transplant
2010;29:1119-1128.)
CHAPTER 50
HEART TRANSPLANTATION
669
100
Half-life: <1: 21.4; 110: 19.3 years; 1117: 15.2 years
90
Survival (%)
80
70
0<1 vs. 110: P = 0.0138;
0<1 vs. 1117: P <0.0001;
110 vs. 1117: P <0.0001.
60
50
40
30
0
9 10 11 12 13 14 15 16 17 18 19 20
Years
acute rejection, lymphoma, graft failure, and infection. Retransplantations now account for 5% of all transplantation operations. Survival for retransplantation is decreased when the
intertransplantation interval was less than 3 years and is relative
to indication for primary transplantation (Fig. 50-10).31,32
Aside from survival, it has been demonstrated that transplanted hearts in children appear to grow normally, and the
left ventricle increases muscle mass to maintain the normal left
ventricular mass-to-volume ratio with time. Exercise testing in
older children has shown peak heart rate and oxygen
consumption to be consistently two thirds of that predicted
in heart transplant recipients. Somatic growth appears to be
normal in infants after heart transplantation, and neurologic
development is generally preserved, although some neuro-
from 9.5 years for the period 1982 to 1989, to 11.7 years for
the period 1990 to 1994, to 14.3 years for the period 1995 to
1999 (Fig. 50-8). Averaged over 15 years, an infant recipient
would have an approximate 2% per year risk of mortality,
whereas for older children, it remains approximately 4%,
again indicating a longer-term survival advantage for younger
cardiac transplant recipients.
The most predictive risk factors for 1-year mortality in the
pediatric population remain congenital heart disease, donor
age, pulmonary artery systolic pressure greater than 35 mm
Hg, and the need for mechanical ventilation and hospitalization
while awaiting transplantation. Among the most significant risk
factors for 5-year mortality are dialysis, congenital heart disease,
and female gender (Fig. 50-9). Causes of death include CAD,
100
19821989 (N = 846)
19901994 (N = 1,803)
19951999 (N = 1,846)
20006/2008 (N = 3,510)
Survival (%)
80
60
40
20
All P values significant at P = 0.01
0
0
Percentage of deaths
40
9 10 11 12 13 14 15 16 17 18 19 20
Years
CAV
Acute rejection
Primary failure
Graft failure
Infection
(non-CMV)
30
20
10
0
030 days
(N = 226)
31 days1
year
(N = 266)
>1 year3
years
(N = 173)
>3 years5
years
(N = 173)
>5 years10
years
(N = 306)
>10 years
(N = 190)
670
PART IV
TRANSPLANTATION
100
90
Survival (%)
80
70
60
50
40
0
Conclusion
------------------------------------------------------------------------------------------------------------------------------------------------
Despite further improvements in surgical technique, immunosuppression, perioperative management, and rejection surveillance, long-term results of pediatric heart transplantation
have shown little change, with a 15-year survival rate of approximately 50%. Chronic rejection, graft CAD, and the
FIGURE 50-10 Survival rates for retransplantations, stratified by intertransplantation interval, for retransplantations
performed January 1994 to June 2008. (From Kirk K, Edwards LB, Kucheryavaya AY, et al: The Registry of the International Society for Heart and Lung Transplantation:
Thirteenth official pediatric heart transplantation report
2010. J Heart Lung Transplant 2010;29:1119-1128.)
Organ Allocation
------------------------------------------------------------------------------------------------------------------------------------------------
Indications
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 51
Pediatric Lung
Transplantation
Sanjiv K. Gandhi, Albert Faro,
and Charles B. Huddleston
CYSTIC FIBROSIS
The first reported attempt at lung transplantation occurred
in 1963 and was performed by Dr. James Hardy at the University of Mississippi Medical Center.1 The patient did not
survive the hospitalization, dying 18 days after the transplant. There were a number of additional attempts at this
during the next few years, with most failures related to poor
healing of the airway anastomosis. Approximately 20 years
after Dr. Hardys ill-fated effort, the first truly successful lung
transplant was performed in Toronto, Canada, by a team led
by Dr. Joel Cooper. This patient had a single-lung transplant
for pulmonary fibrosis and survived for more than 6 years,
ultimately dying of renal failure.2 During the subsequent
years, and particularly in the late 1990s, pediatric lung
transplantation has emerged as a viable treatment option
for children with end-stage pulmonary parenchymal and
vascular diseases. However, the number of children undergoing transplantations throughout the world since 1989 remains relatively small, representing only 4% of all lung
transplantations performed.3 In this chapter, pediatric lung
transplantation is described as an isolated procedure, and
heart-lung transplantation is not included.
671
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TABLE 51-1
Indications for Lung Transplantation in Children
Cystic fibrosis
Pulmonary fibrosis
Pulmonary vascular disease
Primary pulmonary hypertension
Eisenmenger syndrome
Bronchiolitis obliterans
Retransplantation
Other
will die of progressive right-sided heart failure over a protracted period of time.18 In the past several years, a number
of somewhat selective pulmonary vasodilators have become
available for use in these patients. These include intravenous
prostacyclin,19 prostacyclin analogues iloprost (inhaled)20
and betaprost (oral),21 and bosentan,22 an endothelin receptor
antagonist. These drugs have enabled patients to delay the
need for transplantation for years. In fact, the number of
patients undergoing transplantation for pulmonary vascular
disease has significantly dropped in recent years. The timing
of transplantation for patients with pulmonary vascular disease is influenced significantly by the response to medical
therapy and the underlying cause of the pulmonary vascular
disease. Although primary pulmonary hypertension and
Eisenmenger syndrome result in identical histologic changes
in the pulmonary vascular bed, the latter of these two is
associated with a much more favorable long-term prognosis.
A retrospective analysis by Hopkins of 100 adults with severe
pulmonary hypertension resulting from either Eisenmenger
syndrome or PPH revealed that, in the former group, actuarial
survival without transplantation was 97% at 1 year, 89% at
2 years, and 77% at 3 years. In contrast, survival was 77%,
69%, and 35% during the same respective time intervals in
the PPH cohort.23 It is presumed that the intracardiac defect
allows the right ventricle to decompress via the defect when
the afterload in the pulmonary vascular bed becomes prohibitively high. On the basis of this and other observations, atrial
septostomy performed in the cardiac catheterization suite has
been demonstrated to provide clinical benefit in patients with
PPH.24 Results from a multicenter study of patients with PPH
performed before the advent of long-term intravenous prostacyclin therapy demonstrated a median survival from time of
diagnosis of 2.8 years. In that study, a formula was developed
incorporating hemodynamic variables to assist in predicting
the 2-year mortality,18 and it was recommended that patients
should be listed when this figure is less than or equal to 50%.
Studies regarding natural history in adults have been applied
to children, but it is unclear whether this disease behaves the
same in a younger population. Clabby and co-workers
reviewed 50 patients from many centers to provide a means
of estimating survival in children with PPH.25 There was a direct correlation of mortality with the product of the mean right
atrial pressure and the pulmonary vascular resistance.25 With
progress in the medical therapy of PPH to identify selective
pulmonary vasodilators as well as the underlying mechanisms
of this disease, these formulas predicting survival may be obsolete. The durability of medical therapy is unclear. How this
therapy might be applied to secondary pulmonary hypertension, such as Eisenmenger syndrome, is speculative.
The two main issues in considering patients with Eisenmenger syndrome or PH/CHD for lung transplantation are the timing of listing and the complexity of the cardiac lesion to be
repaired. As noted earlier, it is clear that, once the diagnosis
is made, these patients can live much longer than those with
PPH.23 The mode of death in these patients is by progressive
heart failure, pulmonary hemorrhage, stroke, or sudden death,
presumably due to arrhythmias.25 Patients should be listed
when symptoms develop, when there has been a single pulmonary hemorrhage, or perhaps arbitrarily when they reach their
late 30s. Most patients with PH/CHD have an atrial septal defect, ventricular septal defect, or patent ductus arteriosus. All of
these require relatively simple cardiac repairs. However, there
CHAPTER 51
673
PULMONARY FIBROSIS
These patients account for 5% to 10% of pediatric patients
undergoing lung transplantation.3 Placed in this category
are those patients with usual interstitial fibrosis, radiationinduced fibrosis, bronchopulmonary dysplasia, and pulmonary fibrosis secondary to chronic aspiration. The progression
of these disease processes is quite variable. Generally, patients
should be listed when normal activities are markedly limited
and minor viral illnesses lead to significant deterioration. Most
patients will be oxygen dependent and may well have evidence of coexistent pulmonary hypertension. For those in
whom aspiration is the underlying problem, the source of
the aspiration must be eliminated.
The prognosis of children with idiopathic pulmonary fibrosis is not altogether clear. This may be because there is not a
usual interstitial pulmonary fibrosis disease in children; the
underlying causes are frequently unique and unusual. Decisions regarding listing for transplantation are somewhat difficult because of this. Pulmonary fibrosis presenting during
infancy was once believed to have a poor prognosis; however,
some studies have demonstrated improved survival with high
doses of corticosteroid therapy.27 The prognosis for adults
with total lung capacity less than 60% predicted is still poor;
nearly all are dead within 2 years.28 It is difficult to translate
this information into the pediatric experience. Pulmonary
hypertension frequently accompanies this disease as it progresses. These patients should be evaluated and listed for
transplantation when they become symptomatic. If there is
a favorable response to corticosteroids, they can be followed
with standard (age > 5 years) or infant (length < 90 centimeters) pulmonary function tests. One problem with managing this disease is that patients with progression of their
disease tend to remain on relatively high doses of corticosteroids and come to transplantation in a rather cushingoid state.
This should not exclude them from transplantation.
BRONCHIOLITIS OBLITERANS
AND RETRANSPLANTATION
Bronchiolitis obliterans is not a specific disease but rather
a histologic description characterized by the obstruction
and destruction of the distal airways. It may occur as a
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TRANSPLANTATION
MISCELLANEOUS
A variety of diagnoses fall into this group. Congenitally based
pulmonary parenchymal diseases constitute one of the more
interesting broad categories. Typically, these full-term newborns present with severe respiratory distress and no obvious
cause, such as meconium aspiration, sepsis, or persistent fetal
circulation. The diagnoses falling into this category include
surfactant protein B deficiency, other forms of pulmonary
alveolar proteinosis, alveolar-capillary dysplasia, pulmonary
dysmaturity, congenital interstitial pneumonitis, and others.
These infants usually have severe respiratory failure and
require a high level of ventilatory support. Often extracorporeal membrane oxygenation has been or is currently being
used. An open-lung biopsy is often necessary to either make
the diagnosis or to exclude other diagnoses. Surfactant protein
(SP) B or C deficiency and the ABCA 3 mutation can now be
diagnosed by looking for the specific genetic mutation in
peripheral blood or cheek swabs and assaying tracheal effluent
for the presence of this surfactant protein.32 All children will
survive less than 3 months even with aggressive therapy.
Abnormalities in SP-C and ABCA3 can have more varied presentations. Additionally, because the surfactant proteins are
expressed only in the lungs, extrapulmonary organ dysfunction is rare.33 Until other therapies become available, lung
transplantation is the only viable therapeutic option. In general, the waiting time for an organ offer is relatively short in
infants. Therefore one might realistically believe that an infant
with a 3-month life expectancy could undergo transplantation
and survive. When an infant is on ECMO, every effort should
be made to wean from it, using whatever means possible,
including a high-frequency oscillating ventilator and/or nitric
oxide. Although ECMO is not an absolute contraindication to
transplantation, one should be very cautious in this setting
because of the relatively high incidence of other organ
dysfunction.
Contraindications
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 51
SPECIAL CIRCUMSTANCES
Some infants born extremely prematurely survive the early
days of their lives only to develop severe bronchopulmonary
dysplasia with respiratory failure within the first year of life.
The incidence of significant cerebral injury in this group is
high; approximately 50% of those surviving have some
disability.35 We can only assume that the incidence is higher
in those with severe residual lung disease requiring transplantation. It is often difficult to assess the neurologic status in
these infants because of their small size and often the need
for sedation and neuromuscular paralysis for maintenance
of satisfactory ventilation. It is probably unwise to submit
an infant born at less than 28 weeks estimated gestational
age to lung transplantation, unless there has been an opportunity for an accurate neurologic examination. Imaging studies
may offer some reassurance but are inconclusive. Another unusual situation that arises where lung transplantation may be
considered appropriate is the child with severe acute respiratory distress syndrome. Those children still in the acute phase
of this illness often have other organ dysfunction, and their
condition is too unstable for them to wait the obligatory time
once listed for transplantation, given the current organ allocation system for children less than 12 years of age. Those who
survive the early phase of acute respiratory distress syndrome
and are left with fibrotic lungs and stable ventilatory requirements should be evaluated. Finally, occasionally a patient with
a history of prior pneumonectomy will be referred for lung
transplantation. After pneumonectomy in children, the mediastinum shifts to the affected side. This distorts the hilar structures to the point that bilateral or single lung transplantation is
virtually impossible. When possible, a patient undergoing
675
Donor availability remains a major limitation to the applicability of transplantation for end-stage lung disease. Donors must
be matched by ABO blood type compatibility and within a reasonable size range of the recipient. Height is used as the most
accurate correlate to lung size. Height that falls within 15% to
20% of the recipient height is probably suitable. Extending
this range upward is certainly feasible, because it is not difficult to reduce the size of the lungs by trimming off the edge or
even using only the lower lobes. However, extending the lower
limit should be done with great caution, because the transplanted lungs may not fill the chest and may be more prone
to pulmonary edema. Donors are excluded in the presence
of positive HIV serology, active hepatitis, history of asthma, tuberculosis, or other significant pulmonary disease. A history of
limited cigarette smoking is probably acceptable if other parameters of the evaluation fall within the guidelines. In general, the upper limit of donor age is approximately 55 years.
The chest radiograph should be free of infiltrates, and the arterial oxygen tension should be more than 300 mm Hg on an
inspired oxygen fraction of 1.0 with an appropriate tidal volume and 5 cm H2O positive end-expiratory pressure. Mild
pulmonary contusions and subsegmental atelectasis would
not necessarily exclude a donor as long as these criteria are
met. Flexible bronchoscopy should be performed to examine
the airways for erythema suggestive of aspiration of gastric
contents. In addition, this provides an opportunity to assess
the nature and quantity of pulmonary secretions. The presence of purulent secretions that do not clear well with suctioning should exclude the donor even if the chest radiograph is
clear and the oxygenation is adequate.
The surgical part of the procurement process is performed
through a median sternotomy. Both pleural spaces are opened
widely to allow visual inspection of the lungs and also the topical application of cold saline and slush. The trachea is dissected
out between the superior vena cava and aorta. It may be helpful
to develop the interatrial groove, also, to allow a more accurate
division of the left atrial tissue that must be shared with the
cardiac donor team in most situations. The principles of the procurement process beyond this are (1) anticoagulation with
high-dose (300 units/kg) heparin; (2) bolus injection of prostaglandin E1 (50 to 70 mcg/kg) directly into the main pulmonary
artery; (3) decompressing the right side of the heart by incising
the inferior vena cava; (4) decompressing the left side of the
heart by amputating the left atrial appendage; (5) high-volume
(50 mL/kg), low-pressure flush of cold (4 C) pulmonary preservation solution of choice; (6) topical application of cold saline
and slush to the lungs; and (7) continued ventilation of the
lungs with low volumes and low pressures using an FiO2 of
0.4. When all the preservation solution has been administered,
the lungs are excised en bloc. The trachea is divided while the
lungs are held in gentle inflation (pressure of 20 cm H2O)
with the FiO2 at 0.4. The lungs are then extracted, placed in a
bag containing the preservation solution used for the flush,
and then placed in cold storage for transport.
676
PART IV
TRANSPLANTATION
Much research has been devoted to finding the ideal preservation solution to extend potential ischemic times and avoid
reperfusion injury.36 A full discussion of this complex topic
goes beyond the scope of this chapter. The most commonly
used preservation solutions at this time are modified EuroCollins solution, University of Wisconsin solution, Perfadex,
and Celsior. None of these is clearly superior to the others,
and all work reasonably well. However, none reliably allows
for preservation times greater than 8 hours, and none
completely avoids reperfusion injury.
Technique of Transplantation
------------------------------------------------------------------------------------------------------------------------------------------------
The surgical technique used for children is like that for adults,
except that virtually all children will require cardiopulmonary
bypass, whereas that is not always necessary in adults.
Transplantation without cardiopulmonary bypass would
require single-lung ventilation during the procedure. Maintaining single-lung ventilation in these small children is
extremely difficult, because the airways are too small to accommodate double-lumen endobronchial tubes. Bilateral
lung transplantation is performed for nearly all children
because of concerns over the growth potential of the transplanted lungs. Trans-sternal bilateral anterior thoracotomy
incision (the so-called clamshell incision) through the fourth
intercostal space provides excellent exposure of the heart and
hilar regions. Though absorbable suture theoretically provides
the greatest potential for growth, some surgeons use nonabsorbable suture material for the anastomoses.37 We recommend a simple end-to-end rather than a telescoping
anastomosis for the airway because of the high incidence of
stenosis in the latter.38,39 If the patient requires concomitant
repair of an intracardiac lesion (e.g., with Eisenmenger
syndrome), that is best performed after the recipient pneumonectomies and before implanting the donor lungs. Many of
these patients have significant aortopulmonary collaterals
resulting in significant pulmonary venous return to the heart
while on cardiopulmonary bypass. After the recipient lungs
have been removed, the absence of pulmonary venous return
to the heart from bronchial arteries and other collateral vessels
will allow for a bloodless operative field for the intracardiac
repair. The subsequent period during which allograft implantation is performed provides sufficient time for cardiac
reperfusion before weaning from cardiopulmonary bypass.
Living donor lobar transplantation and the use of cadaveric
lobes, has become less commonplace as an alternative to
standard cadaveric whole lung transplantation, since implementation of the LAS.40 Although the upper lobes have been
used, lower lobes seem better suited anatomically, with each
lobe serving as an entire lung. When lobes come from a living
donor, there is less bronchial and vascular tissue with which to
work and thus longer cuffs of the bronchus, pulmonary artery,
and pulmonary vein of the recipient will facilitate the procedure. A technique has been devised whereby a single left
lung can be partitioned such that the upper lobe is used on
the right and the lower lobe on the left.41 The circumstances
under which one might use this technique would be quite
unusuala single left lung from a large donor being made
available to a desperately ill child. Nonetheless, it is another
attempt at solving the ongoing problem of inadequate donor
organ supply.
Immunosuppression
------------------------------------------------------------------------------------------------------------------------------------------------
TABLE 51-3
Immunosuppressant Agents
Class of Drug
Side Effects
CHAPTER 51
Post-transplantation
Surveillance
------------------------------------------------------------------------------------------------------------------------------------------------
Surveillance after transplantation is based on periodic spirometry and bronchoscopy with biopsies and bronchoalveolar
lavage. Before discharge from the hospital, patients are
provided with a home spirometer and are asked to perform
spirometry at least once daily. A decrease in FEV1 of greater
than 10% from baseline is considered an indication for evaluation. All patients, regardless of size, undergo regularly
scheduled surveillance bronchoscopy to diagnose lower
respiratory infections, subclinical graft rejection, and airway
anastomotic complications. Virtually all episodes of suspected
rejection should be confirmed with transbronchial biopsies.
The main challenge occurs in small infants in whom a miniforceps is used through either the 2.8-mm or the 3.5-mm
pediatric flexible fiberoptic bronchoscope. However, obtaining an adequate specimen with these forceps can be challenging. Recently a 4.0 mm bronchoscope with a 2.2-mm suction
channel was introduced into clinical practice, thus allowing
the use of adult-sized forceps for many young children. At
our institution, bronchoscopy with biopsy is performed at
7 to 10 days and at 1, 2, 3, 6, 9, 12, and 18 months after transplantation as a surveillance procedure. Worsening pulmonary
function, infiltrates on a chest radiograph, or deterioration in
clinical status, such as fever or an oxygen requirement, also
prompt bronchoscopy and biopsy. Bronchoalveolar lavage is
performed at these procedures for quantitative bacterial,
routine viral, and fungal cultures.
Post-transplantation
Complications
------------------------------------------------------------------------------------------------------------------------------------------------
677
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PART IV
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BLEEDING
A number of factors place these patients at increased risk for
bleeding after transplantation. Nearly all transplantations in
children require prolonged cardiopulmonary bypass for
recipient pneumonectomies and implantation of donor
organs. Additionally, many of these patients have undergone
prior thoracotomies or sternotomies. Patients with cyanotic
heart disease and a prior thoracotomy have the greatest risk
of serious bleeding, as mentioned earlier.
HOARSENESS
Vocal cord paralysis caused by recurrent laryngeal nerve injury
has an incidence of approximately 10%. This diagnosis is
made at the time of flexible fiberoptic bronchoscopy with
direct examination of the cords. In most cases, anatomic asymmetry improves without directed therapy within 6 months of
transplantation. The left vocal cord is nearly always the one
involved, and the injury presumably occurs as a result of
dissection of the left pulmonary artery in the region of the
ligamentum arteriosum.
GASTROINTESTINAL COMPLICATIONS
Many centers now routinely assess for the presence of gastroesophageal reflux because of its potential association with the
development of bronchiolitis obliterans (BO).52 Since instituting routine 24-hour pH probe monitoring at the 2-month
post-transplantation evaluation, we have found that almost
70% of our patients have evidence of acid reflux. The etiology
of this high incidence of gastroesophageal reflux is not clear
but may be due to injury to the vagus nerves bilaterally in
the process of performing the recipient pneumonectomies.
Decreased intestinal motility is also a common problem in
all age groups. Patients with CF are at risk for distal intestinal
obstruction syndrome. This can be avoided by aggressively
treating with osmotic cathartics after transplantation. Gastrografin enemas may be necessary if there is no response to oral
cathartics.
ATRIAL FLUTTER
Atrial arrhythmias are relatively common with significant
episodes of atrial flutter occurring in 10% of pediatric lung
transplantation recipients. Many require long-term treatment.53 Investigation into this entity using a model of lung
transplantation has shown that the suture lines for the left
atrial anastomoses provide sufficient substrate for the maintenance of atrial flutter when initiated by programmed extrastimulus.54
GRAFT COMPLICATIONS
Reperfusion injury manifesting as graft failure with diffuse
infiltrates on chest radiography, frothy sputum, and poor
oxygenation is the most common graft complication early after
lung transplantation, occurring in 20% to 30% of transplantation recipients.55 It is the most common cause of death
within the first 30 days after transplantation.3 The underlying
cause is probably multifactorial, with both donor and recipient conditions contributing to this problem. The best preventive measures include careful evaluation and procurement of
the donor organs as well as having a recipient free of active
infection or other acute problems. A well-conducted transplantation procedure is also of utmost importance. The treatment of reperfusion injury is mostly supportive, although
nitric oxide56 and prostaglandin E157 may be of some primary
benefit.
Rejection is a common occurrence after lung transplantation, perhaps more so than in other solid organ transplantations (Fig. 51-1). The lung has a much larger
endothelial surface than other organs. Because the major histocompatibility antigen expression on endothelial surfaces is
the primary signal for local immune recognition, the lung
would seem to be the least easily camouflaged organ in the
body. In addition, the lung graft comes with its own parenchymal bronchial lymphocytes and macrophages. Gradually,
these are replaced by the recipient lymphocytes and macrophages. This rather intense immunologic activity adds to
the risk of rejection. Acute graft rejection early after transplantation presents in such a nonspecific fashion that each suspected episode should be documented with histologic
evidence obtained by either transbronchial biopsy or openlung biopsy. The great majority of episodes of acute rejection
occur in the first 6 months after transplantation. Although
the incidence of acute rejection in all children is about the
same as that seen in adults, it appears that infants have a
much lower incidence.58,59 The precise reason for this is
unclear but may have to do with the relative immaturity of
the immunologic system in infants.
Antibody-mediated rejection (AMR) is now recognized as a
serious and relatively common complication of lung transplantation. With the advent of better detection assays, one
can now quantitate the amount of circulating donor-specific
antibody in the recipient. However, it is also becoming
increasingly clear that nonhuman leukocyte antigen (HLA)
antibodies may also be responsible and that, in fact, autoantibodies to previously sequestered antigens may play a vital role
CHAPTER 51
679
FIGURE 51-1 Acute rejection. Multiple lymphocytes are present in a perivascular position involving many blood vessels, which can be seen better on
higher power. This was interpreted as grade A2 acute rejection.
obliterans in the United States is to augment immunosuppression, usually beginning with antithymocyte globulin daily for
7 to 10 days; the clinical response has been variable. A change
in the maintenance immunosuppression may also be appropriate. Antiproliferative agents may provide a more effective
approach, but that has yet to be proved. Results from small
studies suggest that azithromycin may be effective in stabilizing and perhaps even improving lung function.64,65
Researchers at Duke University demonstrated that fundoplication in patients with BO and gastroesophageal reflux may
potentially improve BO grade if performed early.52 Total lymphoid irradiation and photopheresis are other modalities that
have been proposed.66 Patients not responding to these
measures may be suitable candidates for retransplantation.
As mentioned earlier, this is a somewhat controversial topic,
because there is a shortage of donor organs, and the results
with retransplantation overall are not quite as good as with
first-time transplantations. However, if the candidates are
ambulatory, not ventilator dependent, and at an experienced
lung transplantation center, the survival results are not
significantly different from first-time transplantations.30
Post-transplantation lymphoproliferative disease (PTLD)
occurs in 10% to 19% of pediatric patients undergoing lung
transplantation. PTLD occurs more frequently in association
with a primary Epstein-Barr virus (EBV) infection.67 Children
may be somewhat more prone to this complication, because
they are frequently seronegative for EBV infection at the time
of transplantation and are therefore likely to acquire a primary
EBV infection during their post-transplantation life. Reduction in immunosuppression is the mainstay of early therapy,
although this may be insufficient and not uncommonly
leads to the subsequent development of bronchiolitis obliterans. Rituximab, an anti-CD20 monoclonal antibody, has
been used effectively in the treatment of PTLD.60 Other
treatment modalities include conventional chemotherapy,68
irradiation, and infusion of human leukocyte antigen
matched T lymphocytes.69
680
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TRANSPLANTATION
FIGURE 51-2 Histologic slide taken from the lung of a patient undergoing retransplantation for bronchiolitis obliterans. Small airways are obliterated by
fibrous tissue.
INFECTION
Although infection is generally common after any solid organ
transplantation, lung transplantation recipients are at greater
risk. Donors are all on mechanical ventilation, resulting in
colonization of the airway with bacteria from an intensive care
unit. The lung is the only solid organ constantly in contact
with the nonsterile outside world. An endotracheal tube necessary early after the transplantation bypasses some of the
natural defenses available to the respiratory tract. Obligate
denervation of the lung that occurs with transplantation results in the cough reflex being markedly diminished or absent
altogether. These and numerous other factors demand that the
caregivers maintain constant vigilance in the diagnosis and
treatment of respiratory infections and also emphasize to
the recipient the importance of pulmonary toilet.
All potential candidates are screened for the presence of
organisms in the airway and evidence of previous infections.
Evidence of prior viral infections is evaluated by serologic
testing for antibodies to cytomegalovirus; herpes simplex
virus; varicella; EBV; hepatitis A, B, and C; and human immunodeficiency virus. Viral serologic screening is less informative in young infants whose immunoglobulin pool reflects
passively transferred maternal antibodies. The initial antimicrobial therapy given in the early post-transplantation period is directed in part by the results of pretransplantation
studies. Ganciclovir is given at a dose of 5 mg/kg/day for
6 weeks for any positive donor or recipient serology for
cytomegalovirus. If patients have evidence of present or past
Aspergillus infection, antifungal therapy with either intravenous anidulafungin or voriconazole followed by oral voriconazole is used, depending on the clinical situation.
A number of viral respiratory infections are quite common
in pediatric patients. Adenovirus and parainfluenza viruses
are particularly bothersome in children. As for cytomegalovirus,
primary disease is generally more likely to be severe than reactivation disease.2 As mentioned earlier, primary infection with
EBV is an important risk factor for the development of PTLD.
Fungal infections are uncommon but potentially devastating. Nystatin oral suspension is employed to reduce the risk of
infection from Candida species. Virtually all infections caused
by Candida species can be successfully treated with oral or
intravenous triazole antifungal agents. Invasive Aspergillus infections, however, are much more difficult to treat and may
result in widespread dissemination if appropriate antifungal
therapy is delayed.
Bacterial infections are common after lung transplantation.
Bacterial lower respiratory tract infections, which include both
purulent bronchitis and pneumonia, occur in most patients at
some point after transplantation. Patients with CF are more
likely to experience this complication, with the organism usually the same as that colonizing the airway before transplantation. Prophylaxis against lower respiratory tract infections in CF
lung transplantation recipients may be accomplished by administering aerosolized antibiotics (tobramycin or colistin) just as
one might for end-stage CF.
OTHER COMPLICATIONS
Hypertension is a common problem after transplantation and
is presumably due to treatment with the calcineurin inhibitors
cyclosporine and tacrolimus, as well as prednisone. Renal insufficiency occurs with increasing time after transplantation
and is also related to treatment with cyclosporine and tacrolimus. Diabetes mellitus occurs in approximately 15% of
patients after transplantation, primarily in patients with CF.2
Tacrolimus predictably increases the likelihood for the development of hyperglycemia.
Survival
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 51
681
100
1 year vs. 111 years: P = 0.3124
<1 year vs. 1217 years: P = 0.8387
111 years vs. 1217 years: P = 0.0395
Survival (%)
75
50
N at risk = 17
N at risk = 10
25
N at risk = 20
HALF-LIFE
<1 year: 6.4 years
111 years: 6.0 years
1217 years: 4.3 years
0
0
10
Years
It is unclear whether transplanted lungs grow in terms of number and size of alveoli, and experimental data are inconclusive.70,71 Measurement of lung growth is fraught with a
number of complicating factors. One cannot use pulmonary
function tests and lung volume size as measured by either
chest radiograph or computed tomography, because there are
a number of elements that affect these studies that would not
accurately reflect the number or size of alveoli. The impact of
lung growth is particularly critical in small infants, because their
transplanted lungs will have to grow substantially over the rest
of their lives to handle the physiologic load presented to them.
Those children in our series too young to undergo standard
pulmonary function testing underwent infant pulmonary function tests that provide a measurement of functional residual
capacity, a reasonable surrogate for lung volume. The average
functional residual capacity per centimeter in height at
3 months after transplantation was 2.3 mL/cm and remained
between 2.1 and 2.8 mL/cm through 15 months after transplantation. During this time, substantial somatic growth
occurred in these infants.72 Thus in the absence of central or
peripheral airway obstruction, these data suggest that lung
growth appropriate for size is occurring. However, we do not
11
12
Future Considerations
------------------------------------------------------------------------------------------------------------------------------------------------
Factors that limit the success of lung transplantation in children are similar to those in adults: donor shortage, balance
of immunosuppression and prevention of infection, and
development of bronchiolitis obliterans. Xenotransplantation
may eventually offer another solution, but realistically, this
is many years from application. Transplantation across ABO
blood groups, now commonplace in infant cardiac transplantation, is another possibility in small children, though the
overall impact of this would be minor. Newer immunosuppressive agents aimed at more specific areas of the immune
response involved with organ recognition are necessary. Bronchiolitis obliterans remains the Achilles heel of long-term
survival after lung transplantation. Although still not
completely characterized as to its precise cause, most investigators ascribe this development to airway injury leading to
chronic rejection. To that end, clinical and basic research
aimed at understanding the vectors of injury and disease
progression in bronchiolitis obliterans are of paramount importance to the field of lung transplantation. Because the
airway as the site of injury is accessible for assessment and
therapy, bronchiolitis obliterans may provide a model system
whereby chronic rejection, which also affects long-term
success in heart, kidney, and liver transplantation, can be
understood and overcome.
The complete reference list is available online at www.
expertconsult.com.
CHAPTER 52
Surgical
Implications
Associated with
Pediatric Bone
Marrow
Transplantation
------------------------------------------------------------------------------------------------------------------------------------------------
683
684
PART IV
TRANSPLANTATION
Complications of Immune
System Ablation and
Immunosuppression
TABLE 52-1
Neutropenic Enterocolitis: Criteria for Appropriate Surgical
Intervention
1. Persistent gastrointestinal bleeding after resolution of neutropenia
and thrombocytopenia and correction of clotting abnormalities
2. Evidence of free intraperitoneal perforation
3. Clinical deterioration requiring support with vasopressors or large
volumes of fluid, suggesting uncontrolled sepsis
4. Development of symptoms of an intra-abdominal process, in the
absence of neutropenia, which would normally require surgery
------------------------------------------------------------------------------------------------------------------------------------------------
INTESTINAL COMPLICATIONS
Abdominal pain and diarrhea are common post-HSCT. A substantial component of the initial inflammatory cascade is
thought to occur in the gastrointestinal tract, and patients with
higher volumes of diarrhea at the time of the preparative regimen have an increased risk of acute GVHD.5 Barker and
associates6 performed a retrospective study of 132 consecutive
pediatric HSCT patients, and diarrhea occurred in 67% of
patients. Common etiologic agents included GVHD (27%),
viral (6%), Clostridium difficile (8%), and unknown (28%).
When stool cultures are negative, endoscopy is considered
to differentiate infectious etiologies from GVHD. Gastric antral
biopsies and small bowel biopsies may be preferred, because
duodenal hematomas have been reported by Ramakrishna and
Treem.7 They recommended avoiding the duodenum if possible and maintaining platelet counts greater than 55,000/mm3
for 48 hours postbiopsy when a duodenal biopsy is necessary.
A prospective multicenter study of pediatric bone marrow
transplantation (BMT) patients who underwent 1120 small
bowel biopsies did not report hematoma as a complication.8,9
Silbermintz and co-workers10 reported successful identification of small bowel graft versus host disease by capsule endoscopy in a child with refractory hemorrhage, when upper and
lower endoscopies were nondiagnostic. Identification of small
intestinal cytomegalovirus (CMV) disease has also been
reported by capsule endoscopy.11 The future role for capsule
endoscopy is increasing as the intestinal complications after
HSCT predominate in the small intestine.12 Accurate visualization may help guide the need for more intensive immunosuppressive therapy or to avoid immunosuppressive therapy.
Neutropenic enterocolitis (typhlitis) is characterized by
necrotizing inflammation of the colon in a severely immunocompromised patient (Table 52-1). Clinically, fever, abdominal pain, tenderness, and neutropenia are present
(Fig. 52-1). The incidence is low in children after HSCT.
Barkers retrospective review of 132 consecutive pediatric
HSCT patients reported an incidence of 3.5%.6 Early experience with neutropenic enterocolitis was marked by controversy regarding the timing of surgical intervention, and
mortality exceeded 50%.1316 Delineation of the criteria for
surgical intervention reserved for clearly identified surgical
complications has contributed to a substantial decrease in
mortality and morbidity.15,17
Multiple contemporary series now report excellent outcomes using a strategy of bowel rest, prompt institution of
appropriate intravenous fluid resuscitation, broad-spectrum
antibiotics and antifungal therapy, nutritional support with
total parenteral nutrition (TPN), and the use of granulocyte
colony-stimulating factor (GCSF).1821 In 2002, Otaibi reported a series of 142 HSCT transplantations performed in
Alberta Childrens Hospital. Ninety-seven patients developed
abdominal pain, and only five developed radiographically
proven typhlitis. No patients required surgical intervention.20
Mullassery, from The Royal Liverpool Childrens Hospital reported a 5-year retrospective series in 2009 in which 18 of
596 patients had radiographically confirmed typhlitis and
three required surgical intervention. One child, each, had
extensive colonic necrosis, perforated gastric ulcer, and perforated appendix. A single mortality was also reported from
fulminant gram-negative sepsis without intervention.19
HEPATOBILIARY COMPLICATIONS
Abnormal liver function studies are commonly identified in
HSCT patients. An extensive 40-year review of hepatobiliary complications in HSCT has recently been published by
McDonald.22 Liver complications have become far less frequent as the understanding of how to prevent and treat severe
hepatobiliary problems has emerged. Surgeons are frequently
consulted to discern whether abnormal liver function studies
are secondary to obstruction or parenchymal dysfunction.
Biliary obstruction occurs secondary to calculous disease.
CHAPTER 52
685
HEMORRHAGIC CYSTITIS
Hemorrhagic cystitis (HC) occurs in 10% to 20% of pediatric
HSCT patients. Decker and colleagues32 have recently
reviewed the pediatric experience. HC is characterized by diffuse vesical bleeding which ranges from microscopic hematuria to gross hemorrhage with clot formation and urinary
obstruction requiring instrumentation for evacuation. With
severe HC, prolonged hospitalization with significant morbidity may occur. High-dose chemotherapy and immunosuppression that accompany HSCT make the pediatric patient
particularly susceptible. Investigations point to a multifactorial pathophysiology of HC. Damage to the transitional epithelium by radiation, chemotherapy, and infectious agents have
been postulated. BK virus is now a known pathogen with
increasing evidence for a major role in HC. High-dose cyclophosphamide and bisulfan are well studied alkylating agents
used in conditioning protocols for HSCT that are known to
cause HC. Three main strategies for HC prophylaxis include
mesna, hyperhydration with forced diuresis, and continuous
bladder irrigation (CBI). Three-way catheter drainage is often
difficult in pediatric populations and may require a suprapubic tube. Ultrasonography may underestimate the clot burden,
and cystoscopy provides visualization with the opportunity
for clot evacuation and fulguration of the bladder epithelium.
Escalation to more intensive therapies, such as instillation of
drugs into the bladder (intravesical therapy), carry increased
risk. Many agents, including aluminum potassium sulfate,
prostaglandins, and E-aminocaproic acid and cidofovir have
been used for intravesical therapy, but none are well studied
in a pediatric population. HC is a self-limiting condition
once engraftment and immune reconstitution occur, effective
defense barriers of the bladder mucosa are reconstituted,
and viral replication is controlled. More intensive therapies
should be undertaken under the auspices of a multidisciplinary team.33
PULMONARY COMPLICATIONS
Opportunistic infections are common in HSCT patients.
Pneumonia is the most common infectious complication but
must be distinguished from noninfectious causes, such as
bronchiolitis obliterans, diffuse alveolar hemorrhage (DAH),
and a constellation of noninfectious fever accompanied by
either skin rash, pulmonary infiltrates, or diarrheatermed
engraftment syndrome.34 Early recognition and treatment of
post-HSCT pneumonia favorably impacts survival.35,36 A
recent article from Shannon and co-workers37 from M.D.
Anderson Cancer Center has examined the utility of early versus late fiberoptic bronchoscopy (FOB) with bronchoalveolar
lavage (BAL) post-HSCT in 501 consecutive adult patients.
Five hundred and ninety-eight fiberoptic bronchoscopies
(FOB) with bronchoalveolar lavage (BAL) were performed
for the evaluation of pulmonary infiltrates. The overall diagnostic yield was 55%. The diagnostic yield was 2.5-fold
higher when the FOB was performed within the first 4 days
686
PART IV
TRANSPLANTATION
and highest (75%) when performed within 24 hours of clinical presentation. The rates of adjustment in antimicrobial
therapy were not different with early versus late treatment
(51%); however, late FOB-guided antibiotic adjustments were
associated with 30-day pulmonary-associated deaths that
were threefold higher (6% vs. 18%, P 0.035). The authors
conclude early referral for FOB may yield a higher diagnostic
yield and favorably impact survival in adult patients.
The utility of lung biopsy in pediatric patients post-HSCT is
controversial. Shorter and colleagues38 reported a 10-year experience of 126 HSCT patients from Childrens Hospital of
Philadelphia from 1976 to 1986. Twenty-one patients had open
lung biopsies; 14 showed no causative organisms. One patient
had CMV, and three patients had Pneumocystis carinii. Thirteen
patients died because of continued deterioration postbiopsy.
Hayes-Jordan and associates39 reported a retrospective series
of 528 patients post-HSCT from St. Judes Childrens Research
Center from 1991 to 1998. Eighty-three patients developed
pulmonary infiltrate within 6 months; 43 (52%) had BAL
and 19 (23%) had open lung biopsies, 6 (7%) underwent needle biopsy, and 5 (7%) underwent transbronchial biopsy.
Histology identified infections in 6 (30%), bronchiolitis obliterans organizing pneumonia (BOOP) in 5 (26%), interstitial
pneumonia in 4 (21%), gangliosidosis in 1, and lymphocytic
infiltrate in 1. Despite changing the clinical plan, based on histology in 17 of 19 (90%) patients, improvement in outcome
was only seen in 8 (47%). Postoperative morbidity at 30 days
was 47%, including prolonged intubation (7 patients), pneumothorax (2 patients), and pleural effusion (1 patient).
Thirty-day survival was 63.2%, and no patient with multiorgan
system failure, ventilator dependence, or postoperative complication survived postopen lung biopsy. Careful patient selection and consideration of less-invasive modalities should be
strongly considered in these extremely high-risk patients. Minimally invasive surgical techniques have been applied both
diagnostically and therapeutically in childhood cancer;40 however, the decrease in pulmonary compliance and increase in
cardiac afterload is often prohibitive for thoracoscopic techniques in the post-HSCT patient population.
Invasive pulmonary aspergillosis (IPA) is a common infection in the HSCT population. A potentially lethal complication
of HSCT is pulmonary hemorrhage secondary to the angioinvasive nature of this agent. IPA is one specific opportunistic
infection where surgical therapy remains beneficial. Gow and
colleagues41 reported on 43 patients with invasive pulmonary
aspergillosis, spanning 9 years, from St. Judes Childrens
Cancer Research Hospital. Eighteen patients had surgical
intervention, (16 thoracotomies [89%] and 2 thoracoscopies).
Fourteen had one operation; 4 patients had two. Surgical
resection of the affected parenchyma significantly improved
survival (P < 0.001). The four survivors had disease amenable
to wedge resection, the longest interval at the time of report
being 43.5 months. When feasible, a surgical approach should
be strongly considered, because, left untreated, invasive
pulmonary aspergillosis is almost always fatal.
Conclusion
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 52
687
The Craniosynostoses
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 53
Craniofacial
Anomalies
Jason J. Hall and H. Peter Lorenz
692
PART V
gene on chromosome 7p21 has been linked with SaethreChotzen syndrome.5,4 FGF receptor mutations causing constitutive activation of the receptor occur in many of the human
craniosynostosis syndromes, including Apert, Crouzon,
Muenke, and Pfeiffer syndromes.4 Interestingly, one mechanism of bony fusion across the suture occurring with the
FGF-R mutation is the loss of Noggin expression in the involved
suture mesenchyme. Noggin is a BMP-inhibitor that prevents
bony fusion in the mesenchyme. When Noggin is not present,
bone forms across the mesenchyme, and the suture fuses.6
Most incidences of craniosynostosis are the result of sporadic
genetic anomalies. Yet, a number of both autosomal dominant
and autosomal recessive syndromes, whose most striking phenotype is the pattern of craniosynostosis, are known. Patients
with a family history of craniosynostosis should thus be referred to a dedicated craniofacial team and be evaluated by
a skilled geneticist, as new genetic mutations linked to the
craniosynostosis syndromes are being discovered frequently.
The treatment for craniosynostosis is surgical calvarial vault
remodeling, which is performed to avoid future adverse
sequelae. Chief among these is the avoidance of intracranial
hypertension, which has been linked to brain damage, optic
nerve compression, and cognitive impairment.7 Early surgical
correction (between 3 to 6 months of age) has the advantages of prevention of elevated intracranial pressure and its
attendant consequences, improved reossification of calvarial
bone defects, and the need for a less extensive surgical correction. Correction at a more advanced age (6 to 9 months) is
reported to have more stable long-term results and lower rates
of reoperation. These factors are taken into account by the
craniofacial surgeon and pediatric neurosurgeon during the
treatment planning process.
The most common form of craniosynostosis is sagittal synostosis, with an incidence of approximately 2 per 10,000 live
births. In concordance with Virchows law, premature fusion
of the sagittal suture leads to compensatory growth in the anteroposterior dimension, resulting in scaphocephaly (Fig. 53-1).
Unilateral coronal synostosis is less common, with an incidence of approximately 0.9 per 10,000 live births. The growth
pattern in unicoronal synostosis is more complex, albeit leading to a stereotypical calvarial phenotype. Ipsilateral to the
fused coronal suture, the supraorbital rim is flattened and
recessed, and the forehead is flattened. As calvarial growth occurs, the contralateral forehead becomes bossed and the nasal
bridge starts to twist, producing a C-shaped facial deformity
(Fig. 53-2).
Premature fusion of the metopic suture results in constriction of growth in an axial plane centered on the caudal forehead.
A palpable bony ridge is present in the midline of the forehead
(described as a keel-shaped forehead or trigonocephaly). The
forehead is narrow and pointed. The medial orbital rims are
consequently closer to the midline, giving the appearance of
hypotelorism. Bilateral lateral brow recession and temporal
hollowing also occurs and exaggerates this appearance.
The least common form of single suture craniosynostosis
affects the lambdoid suture. Common findings are posterior
FIGURE 53-2 A child with left unicoronal synostosis. Characteristic findings include ipsilateral fronto-orbital retrusion, prominent contralateral
forehead bossing, and nasal root deviation toward the affected side.
The C-shaped facial deformity is notable here.
Syndromic Craniosynostosis
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 53
CRANIOFACIAL ANOMALIES
693
DIAGNOSIS
A thorough history and physical examination is the cornerstone of diagnosing synostosis of the calvarial sutures. Single
suture fusion results in the characteristic patterns of calvarial
morphology described previously and are readily diagnosed
by physical examination.
Measurement of head circumference with plotting on a
standard growth curve gives an indication of head growth relative to the childs body. Physical examination should accurately define asymmetries in the infant skull. Head shape
should be assessed from anterior, posterior, and top-down
views to identify areas of relative bossing or recession. Ear position in both anterior-posterior and craniocaudal planes
should be examined. Lateral examination of the forehead
and face will identify forehead bossing and the position of
the midface and orbits. Facial examination is especially important in identifying children with the craniofacial
syndromes that have midface retrusion as part of their phenotype. Stigmata of intracranial hypertension should be investigated. For infants, these include a history of irritability,
burrowing behavior, or repetitive head slapping.
Since the advent in the early 1990s of the American
Academy of Pediatrics Back to Sleep campaign, designed
to decrease the incidence of sudden infant death syndrome
(SIDS), a sharp increase in the incidence of positional plagiocephaly has occurred. Positional plagiocephaly is the deformation of the calvarium despite the presence of widely patent
cranial sutures. This condition may be difficult to differentiate
from unilateral coronal or lambdoid craniosynostosis, which
both result in forms of plagiocephaly. Usually, an experienced
craniofacial surgeon can make the correct diagnosis based on
physical examination findings alone. However, sometimes
computed tomography (CT) imaging is needed. The correct
diagnosis is critical, however, because children with positional
plagiocephaly are treated with changes in sleeping position or,
in more severe cases, a custom orthotic molding helmet.
Children who are suspected of having craniosynostosis
should be referred to a craniofacial team for evaluation. This
evaluation includes detailed cranial measurements and a thorough physical examination. CT scanning is rarely needed for
diagnosis, but is obtained by many craniofacial surgeons prior
to calvarial vault remodeling to assess for intracranial abnormalities. Given the additional cost, risks of sedation, and potential harmful effects of ionizing radiation on the growing
child, radiologic imaging should be undertaken on a caseby-case basis as determined by the craniofacial surgeon.12
694
PART V
In addition to findings of suture fusion, stigmata of intracranial hypertension, such as a moth-eaten appearance of the
calvarium on CT images or a copper-beaten appearance
on plain radiographs will be seen. Papilledema may be seen
on fundoscopic examination and is an indication for urgent
cranial vault expansion.
TREATMENT
The mainstay of treatment for premature fusion of cranial sutures is surgical cranial vault remodeling. The two goals of surgery are to release the involved suture through resection and
reconstruction of the cranial vault to a more normal shape.
Surgery is a combined procedure between a craniofacial plastic surgeon and a pediatric neurosurgeon. In general, the pediatric neurosurgeon performs the initial craniotomy, and the
craniofacial surgeon performs the bony reshaping. However,
the procedure is mainly bone surgery and not brain surgery. Cranial vault remodeling is accomplished by removing
the abnormally shaped calvarial bones and recontouring
them. The plasticity of the infant calvarium is utilized as the
bones are bent and shaped to a more anatomic contour. Barrel
stave osteotomies are commonly performed to expand the cranial vault. Wedge osteotomies are done to reduce the vault in
areas of bony excess or bossing. Except in cases of isolated sagittal or lambdoid synostosis, the orbits are deformed, which
necessitates advancement of the supraorbital rim in addition
to reshaping of the forehead and anterior cranial vault. Bones
are fixed into their new position with resorbable hardware
consisting of polyglactic/polyglycolic acid plates and screws.
This type of hardware undergoes degradation over the course
of a year, and is not prone to intracranial migration, which can
occur with traditional titanium hardware. After initial reconstruction in infants, bony defects remain after surgery. The
unique osteogenic potential of the dura and overlying periosteum in infants results in primary bone formation and complete healing of these large bone defects. Bone defects that
remain after 2 years of age typically require secondary bone
grafting. Endoscopic techniques have been described for correction of both sagittal and coronal synostosis.13,14 Although
resection of the involved suture is performed, these techniques rely on a long period of postoperative molding helmet
therapy to achieve final head shape. Despite their reported
benefit of reduced blood loss and transfusion requirements,
endoscopic techniques have not gained wide acceptance, primarily due to their poor head shape outcomes.
Timing of surgery is somewhat controversial among craniofacial surgeons. Some surgeons advocate early correction at
3 to 6 months of age, believing that the rapidly growing brain
will assist in remodeling the skull if the fused suture is released
and the calvarium reshaped. This theoretically reduces the
amount of correction that needs to be performed in the
operating room. Delaying surgery until 9 to 12 months of
age allows the infant skull growth to begin to plateau prior
to surgery. Although this reduces the amount of intrinsic bone
shape normalization resulting from brain growth, the thicker
calvarial bone may provide a more stable skeletal correction
with less relapse. In reality, a large window exists when the
surgery can be performed with acceptable risks and outcomes.
Children who present late for corrective surgery present
unique challenges to the craniofacial surgeon. Bone in these
children is typically thicker and more difficult to contour with
Orthognathic Surgery
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 53
CRANIOFACIAL ANOMALIES
695
lateral walls, frontonasal junction, and pterygomaxillary junction. The nasal septum is divided in the coronal plane. This
allows for complete separation of the facial skeleton from
the cranial base and subsequent advancement of the Le Fort
III segment to correct midface hypoplasia. The Le Fort III advancement is used to correct severe malocclusion or upper airway obstruction from overall midface growth restriction. The
majority of patients who undergo a Le Fort III osteotomy have
a named syndrome (Crouzon, Apert, and Pfeiffer being the
most common), and have their first midface advancement at
age 5 or 6 years. Because the growth of the midface is not complete until mid- to late adolescence, a second advancement is
frequently necessary. When midface retrusion is accompanied
by growth restriction of the supraorbital rim and forehead, a
monobloc frontofacial advancement may be necessary. This is an
intracranial and extracranial procedure and requires both a
pediatric neurosurgeon and a craniofacial surgeon for intracranial access. A monobloc advancement is similar to a Le Fort
III osteotomy, except that the supraorbital rim and forehead
are advanced along with the midface. This procedure has
fallen out of favor because of infectious complications arising
from difficulty obtaining adequate separation of the intracranial space and nasal cavities.17 Thus the monobloc is now
usually performed as a staged procedure (fronto-orbital advancement, followed by a Le Fort III osteotomy a few months
later) or is performed with the use of distraction osteogenesis
to allow the soft tissues to grow along with bony skeletal
expansion, which minimizes the risk of intracranial infectious
complications.
Distraction osteogenesis was pioneered by Ilizarov (a Russian
orthopedist) in 1958, and adapted for use in the mandible by
McCarthy in 1992.18,19 It is now commonly used for a number
of applications in craniofacial surgery. The principle behind
distraction osteogenesis is that gradual expansion of the bony
skeletal gap left by a surgically placed osteotomy will allow
lengthening of the bone by gradual osteoblastic activity and
ingrowth of new bone. This results in lengthening of the skeleton in the direction of the vector of expansion. Distraction is
useful in situations that would require extensive bone grafting
to obtain adequate bone length, or in cases in which opposing
soft tissue forces would result in skeletal relapse if the bone
was rapidly advanced and grafted. Clinically, maxillary distraction is most commonly applied when a large discrepancy
exists between the maxilla and mandible as a result of a complete cleft lip and palate and resultant maxillary hypoplasia.
Scarring from the numerous previous procedures makes maxillary advancement alone prone to relapse; by applying the
principle of distraction, the bone and soft tissue are gradually
expanded, and the cleft maxilla can be advanced into a normal
occlusal relationship (Angle class 1) with minimal chances of
relapse resulting from soft tissue resistance. Distraction is also
useful to correct severe mandibular hypoplasia accompanying
conditions such as hemifacial microsomia or Pierre Robin sequence, which will be discussed in subsequent sections of this
chapter.
Craniofacial Clefts
------------------------------------------------------------------------------------------------------------------------------------------------
696
PART V
14 131211
1 23
10
4 9
8
0 1
2
3
30
14 13 12
0 1 2 11 10
3 4
9
8
FIGURE 53-5 A child with a typical Tessier number 7 soft tissue cleft.
56
6
0
12 3
30
FIGURE 53-4 Tessiers pre-computed tomography classification system
of rare craniofacial clefts. The lower image represents the cleft location of
the bony skeleton, while the upper illustrates the cutaneous manifestations of the various bony clefts.
The Tessier system is based on specific anatomic derangements that fall along embryonic lines of fusion within the face
(although these were not known at the time they were initially
described) (Fig. 53-4). Tessiers classification system is notated
0 to 14, with clefts 0 to 7 describing facial clefts and clefts 8 to
14 describing cranial vault clefts. Each cleft has unique soft
tissue and bone lines of clefting. Also, the facial and cranial
clefts coincide such that the sum of the two components is
14 (i.e., 0 and 14 clefts coincide, as do 3/11 and 5/9, etc.).
A thorough search along the meridian of the cleft will usually
elucidate subtle (or not-so-subtle) findings.
The majority of craniofacial clefts are rare and will be seen
infrequently during an individual surgeons career. As such,
the remainder of this section of the chapter will be spent dealing with those more common Tessier clefts.
CLEFT NUMBER 7
A number 7 cleft can be protean in physical manifestation and
is known by a number of different names. Hemifacial microsomia, oculoauriculovertebral syndrome (OAV), first and second branchial arch syndrome, and otomandibular dysostosis
syndrome all refer to the physical findings associated with a
number 7 cleft. The number 7 cleft is thought to have an incidence of between 1 in 3000 and 1 in 564220 live births.
A number 7 cleft is usually unilateral, but approximately
CHAPTER 53
CRANIOFACIAL ANOMALIES
697
698
PART V
Acknowledgments
SELECTED READINGS
Special thanks to Henry K. Kawamoto, Jr., DDS, MD, for Figures 53-4 and
53-7.
Bentz ML, Bauer BS, Zucker RM, eds. Principles and Practice of Pediatric Plastic Surgery. St Louis: Quality Medical Publishing; 2007.
Mathes SJ, ed. Plastic Surgery. Pediatric Plastic Surgery. Vol 4. Philadelphia:
Saunders; 2005.
Posnick JC. Craniofacial and Maxillofacial Surgery in Children and Young
Adults. Philadelphia: Saunders; 2000.
Thaller SR, Bradley JP, Garri JI, eds. Craniofacial Surgery. New York: Informa
Healthcare; 2008.
workup and counseling is mandatory, as is heightened suspicion for other physical and physiologic anomalies.
Etiology
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 54
Understanding and
Caring for Children
with Cleft Lip
and Palate
James Y. Liau, John A. van Aalst, and
A. Michael Sadove
Epidemiology
------------------------------------------------------------------------------------------------------------------------------------------------
The incidence of orofacial clefting varies among racial backgrounds. Because of the close association between cleft lip
and palate, the presence of cleft lip is often described as being
with or without cleft palate. Worldwide prevalence of cleft lip
and palate is 1 per 700 live births.1 People of African descent
have the lowest incidence of cleft lip with/without cleft palate
at 0.5 per 1000 live births, followed by whites (1 per 1000 live
births), and Asians (1.3 per 1000 per live births). Overall, an
isolated cleft lip makes up approximately 21% of all patients
with cleft lip and palate. Unilateral clefts are roughly 9 times
more prevalent than bilateral cleft lips, and males are more
affected than females. The U.S. incidence of cleft palate alone
ranges from 0.3 to 0.5 per 1000 live births.2 A child with a
cleft lip with or without cleft palate has an approximately
30% chance of having an associated syndrome; interestingly,
a child with an isolated cleft palate has a 50% incidence of
an associated syndrome.2,3 Because of this association, genetic
Embryology
------------------------------------------------------------------------------------------------------------------------------------------------
Basic understanding of midface and palatal embryologic development helps elucidate the pathoanatomy of cleft lip with or
without palate. Orofacial clefting occurs when there is failure
of fusion of maxillofacial structures migrating from lateral to
medial during the initial 4 to 10 weeks of embryonic development. A key anteriorposterior embryologic and anatomic landmark in understanding clefts is the incisive foramen. The
structures that form anterior to the foramen ultimately develop
into the nose, lip, and alveolus; embryologically, these structures
form first and are designated as the primary palate. The structures
that form posterior to the foramen become the hard palate and
soft palate, and are referred to as the secondary palate, because
they fuse secondarily. Clefting of the lip (primary palate) occurs
when the nasomedial and nasolateral prominences of the frontonasal prominence do not meet with the maxillary prominence
(Fig. 54-1, A). Clefting of the palate (secondary palate) occurs
when the lateral palatine shelves do not elevate and fuse at the
midline to each other or to the primary palate (Fig. 54-1, B).
Because the development of this craniofacial area is complex, deformities can occur at multiple points along the embryologic time
line, resulting in a full spectrum or combination of anomalies.
Anatomy
------------------------------------------------------------------------------------------------------------------------------------------------
700
PART V
Primary palate
Nasolateral
Nasomedial
Incisor foramen
Secondary plate
Maxillary prominence
FIGURE 54-1 A, The nasolateral and nasomedial prominence fuse to make the lip and nose. Lack of fusion between the maxillary nasal prominence with
the nasomedial prominence will yield a cleft lip. B, The lateral palatine shelves fuse in the midline, thus forming the secondary palate. The primary palate
fuses posteriorly with the palatine shelves to form a complete palate.
C
FIGURE 54-2 A, Microform cleft can be seen with mild notching of the lips vermilion along with the minimal distortion of the nose. B, Incomplete cleft
has some webbing across the cleft with some retention of the lateral nose; however, the skin across the cleft is devoid of orbicularis oris muscle and is
functionless. This skin is also called a Simonart band. C, Complete cleft lip has lateralization of the lip and lateral nasal element. Notice the deviation of the
nasal columella and philtrum away from the cleft, and the flattened nose on the cleft side. This picture also demonstrates the clefting of the palate, which
allows an unobstructed view into the nasal airway.
CHAPTER 54
UNDERSTANDING AND CARING FOR CHILDREN WITH CLEFT LIP AND PALATE
701
CLEFT PALATE
B
FIGURE 54-3 A, Bilateral cleft lip with a Simonart band transversing both
clefts. B, Complete bilateral cleft lip. The midline protuberance is called
the premaxilla and is much more protruding than an incomplete bilateral
cleft; tethering of the Simonart bands help in keeping the premaxilla in a
more anatomic position. Absence, or shortening of the columella, widening of the alar bases, and anterior projection of the premaxilla are all trademarks of bilateral cleft lips.
elements of skin, mucosa and bone, which can be asymmetrically deviated to one side or the other, and can be anteriorly positioned, depending on the severity of the
deformity. Bilateral clefts can be incomplete with Simonart
bands (Fig. 54-3, A), or complete with defects that proceed
through the alveolar ridges (Fig. 54-3, B). A central feature
of the bilateral cleft lip deformity is depression of the nasal
tip, a shortened columella, and widely splayed alae.
Clefts of the palate can exist with clefts of the lip or may be
present alone. Anatomically, the hard palate begins immediately posterior to the incisive foramen, with embryologic
fusion of the palate from anterior to posterior. Hence, an isolated cleft of the soft palate may exist; however, an isolated
cleft of the hard palate cannot. A complete cleft of the secondary palate includes both the hard and soft palate, extending
anteriorly from the incisive foramen to the uvula, and this
can be bilateral as well (Fig. 54-4). The primary function of
the palate is to separate the oral cavity from the nasal cavity.
This function is lost in the presence of a cleft. The function
of the soft palate is primarily speech related and dependent
on five paired muscles, the two most important of which
are the levator veli palatini and the tensor veli palatini. Ordinarily, these muscles form a transverse sling enabling the palate to rise and move posteriorly to close the oropharynx from
the nasopharynx. In a cleft palate, these muscles abnormally
insert onto the posterior shelf of the hard palate, and as a consequence, the palate is deficient in its ability to seal off the oropharynx from the nasopharynx.
A submucous cleft is the most minor expression of the
clefting spectrum. The soft palate mucosa is actually intact,
but split posteriorly, resulting in a bifid uvula; there is a midline lucency in the soft palate, referred to as a zona pellucidum, which is a muscle diastasis, and a notch at the
midline, posterior edge of the hard palate.13 As in a full cleft,
the levator and tensor veli palatine abnormally insert onto the
posterior hard palate, preventing the soft palate from moving
appropriately during speech, potentially leading to nasal
sounding speech. The incidence of submucous clefts is
roughly 1 in 1,200 to 2,000; however, this is likely an underestimation, because many patients may not seek treatment or
even know of their submucous cleft unless there is functional
speech deficit.14
Treatment Protocols
------------------------------------------------------------------------------------------------------------------------------------------------
The timing for cleft lip repair in the United States is generally
between 3 to 6 months of age. Depending on the severity of the
deformity, various forms of presurgical orthopedics can be
used to prepare the child for lip surgery. In general, the goals
of these techniques are to improve the alignment of the alveolar segments, decrease the size of the soft tissue cleft, and to
FIGURE 54-4 The figure on the left depicts a cleft of the secondary palate only; there is an intact hard palate. The middle figure depicts a complete
unilateral cleft. The figure on the right depicts a complete bilateral cleft.
702
PART V
FIGURE 54-6
lip repair).
B
FIGURE 54-5 A, A unilateral cleft lip prior to nasoalveolar molding (NAM)
has a wide alveolar cleft, slumping of the nasal cartilage on the cleft side,
and lateralization of the alar base of the cleft side. B, Nasoalveolar molding
assists in realigning the alveolar segments, reshaping the slumping nasal
cartilage of the cleft side, and medializing the alar base of the cleft side.
improve the symmetry of the nose. The simplest form is a taping regimen (literally from cheek to cheek) that helps to pull
the two sides of the clefts together, with the goal of narrowing
the cleft and realigning the tissues in an anterior-posterior
dimension. Some centers also use a technique termed nasoalveolar molding (NAM) to address the three major components
of the cleft deformity (Fig. 54-5). NAM addresses the slumping of the nasal alar cartilage, helps realign the alveolar ridges,
and brings the soft tissue of the lips into closer proximity.15,16
CHAPTER 54
UNDERSTANDING AND CARING FOR CHILDREN WITH CLEFT LIP AND PALATE
703
cupids bow, reapproximation of the orbicularis oris, repositioning the nasal alar cartilages, lengthening the columella,
and closure of the nasal floor (Fig. 54-8). The absence of
the philtral column and cupids bow is especially problematic
since these structures are difficult to replicate in a repair. Postoperatively, these imperfections can be quite noticeable at
conversational distances.27 Realistically, patients with bilateral
cleft lips will ultimately require revisional surgeries to correct
the secondary stigmata of the repair, which include a shortened columella, blunted nasal tip, widened nasal ala, and a
widened philtrum.
FIGURE 54-8 Schematic of the steps involved with a bilateral cleft lip repair. Re-creation of the columella, dissection of the muscle in the lateral lip
elements, re-creation of the nasal floor, reapproximation of the lateral lip muscle, and insetting of the nasal alar bases with trimming of skin for final closure
are all integral parts of bilateral cleft lip repair.
704
PART V
FIGURE 54-9 The Bardach two-flap palatal reconstruction consists of elevating the palatal mucosa off the hard palate bone as a flap, elevation of the
nasal mucosa, and closure of these two layers separately for the hard palate. Pedicles for the mucosal flaps come from the greater palatine arteries posteriorly. Closure of the soft palate is a three-layer repair, including a nasal mucosal layer, muscle layer (levator veli palatini and tensor veli palatini
realignment), and oral mucosal layer.
FIGURE 54-10 The double opposing Z-plasty, (Furlow palatoplasty) of the soft palate includes realignment of the levator and tensor veli palatine muscles
in the form of Z-plasty. One flap has oral mucosa only, whereas the contralateral side has oral mucosa and muscle. The nasal layer consists of a separate nasal
mucosal layer, which is on the side with oral mucosa and muscle flap, and the contralateral side has nasal mucosa and muscle. Closure of both layers in a
double opposing Z-plasty assists in elongating the soft palate, which should subsequently improve palatal speech function.
FIGURE 54-11 The Veau-Ward-Kilner repair consists of advancing the oral mucosal flaps posteriorly to allow closure of the hard palate. Muscle realignment of the soft palate assists in palatal function.
Multidisciplinary Care
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 54
UNDERSTANDING AND CARING FOR CHILDREN WITH CLEFT LIP AND PALATE
705
FIGURE 54-12 The von Langenbeck repair consists of relaxing incisions on the lateral palate with subsequent advancement to midline, allowing a palatal
repair of both mucosa and muscle layers. Benefits include keeping a bipedicled flap; however, the advancement can be limited and inadequate with wider
cleft defects.
FIGURE 54-13 Closure of bilateral cleft palate follows in the same principles. Nasal mucosal layers are dissected off the vomer and palatine shelves and
closed. Dissection of the hard palate oral mucosa allows closure separately, thus providing a two-layer closure. The soft palatal muscles are dissected and
realigned to provide palatal function.
706
PART V
air escape through the nose during speech. The patient with
VPI has a nasal quality to his or her speech. Usually the most
affected sounds are plosives, /p/ and /b/, in words such a
papa and buggy. In a patient with VPI, the pressure is dissipated through the nose, making these sounds more nasal in
quality: mama and muggy. Depending on the severity of
the condition, VPI can range from being barely audible to rendering speech unintelligible. VPI usually occurs in patients
whose palates are short and scarred or who have an inadequately functioning soft palate muscle sling. The advent of
VPI is usually noticed as children become more verbal,
between 3 and 5 years of age. Another time period during
which VPI may arise is during tonsillar and adenoid regression. As these tissues atrophy, the nasopharyngeal and oropharyngeal spaces enlarge; a marginally functional soft palate may
no longer be able to seal the nasopharynx from the oropharynx, resulting in VPI. Because of these ongoing changes, vigilance for VPI must be maintained throughout a childs growth
and development.
In patients suspected of VPI, evaluation by a speech
therapist is vital in determining whether additional speech
Conclusions
------------------------------------------------------------------------------------------------------------------------------------------------
Cleft lip and palate can be visually and functionally devastating to a child. Multispecialty and interdisciplinary team care is
both ideal and necessary for the care of these children because
of the complexity of the anomalies and the longitudinal nature
of cleft care. Establishing rapport with patients and their
families, as well as among team specialists, can lead to lifechanging differences in patients with clefts, allowing them
to lead normal, productive lives, as well as making the formidable problems of cleft care rewarding to treat.
The complete reference list is available online at www.
expertconsult.com.
CHAPTER 55
Otolaryngologic
Disorders
Lisa M. Elden, Ralph F. Wetmore,
and William P. Potsic
Ear
------------------------------------------------------------------------------------------------------------------------------------------------
ANATOMY
The ear is divided into three anatomic and functional areas:
the external ear, the middle ear, and the inner ear. The external
ear consists of the auricle, external auditory canal, and the
lateral surface of the tympanic membrane. The auricle is a
complex fibroelastic skeleton that is covered by skin and subcutaneous tissue that directs sound into the external ear canal.
The external auditory canal is oval with the long axis in the
superior to inferior direction. In neonates, the external canal is
almost entirely supported by soft, collapsible cartilage. As the
temporal bone grows over several years, the bony portion of
the canal enlarges to comprise the inner one third, leaving the
outer two thirds supported by firm cartilage. Hair and cerumen
glands are present in the outer two thirds of the external canal.
The ear canal is lined by skin that is continuous with the lateral
surface of the tympanic membrane, and it is innervated by
cranial nerves V, VII, IX, and X and by the great auricular nerve.
The tympanic membrane separates the external ear canal
from the middle ear. It has three layers: an outer layer of squamous epithelium (skin); a middle layer of fibrous tissue that is
attached to the malleus, the most lateral middle ear ossicle;
and an inner layer of mucosa that is continuous with the
mucosa lining the middle ear. The fibrous layer is also attached
to a thick fibrous annulus that anchors the tympanic membrane to the temporal bone.
The middle ear is an air-filled space within the temporal
bone of the skull that is lined by ciliated, columnar respiratory
epithelium. The middle ear communicates with the mastoid
air cell system posteriorly and is lined by the same mucosa.
It also communicates with the nasopharynx anteriorly
through the eustachian tube. The mucociliary transport system of the middle ear moves mucus and debris into the nasopharynx, where it is swallowed. Secretory cells are not evenly
distributed throughout the middle ear and mastoid complex
and are more numerous anteriorly near the eustachian tube.
Three ossicles are present in the middle earthe malleus,
incus, and stapesthat transmit sound from the vibrating
tympanic membrane to the stapes footplate. Stapes movement
creates a fluid wave in the inner ear that travels to the round
window membrane and is dissipated by reciprocal motion to
the stapes.
There are two striated muscles in the middle ear. The tensor
tympani muscle lies parallel to the eustachian tube, and its
tendon attaches to the medial surface of the malleus. The stapedius muscle lies along the vertical portion of the facial nerve
in the posterosuperior part of the middle ear. Its tendon
attaches to the head of the stapes. These muscles stiffen the
ossicular chain in the presence of sustained loud noise.
The facial nerve traverses the middle ear with its horizontal
portion lying superior to the stapes. Posterior to the stapes, the
facial nerve turns inferiorly in a vertical fashion to exit the stylomastoid foramen deep to the tip of the mastoid. The chorda
tympani nerve is a branch of the facial nerve that innervates
taste to the anterior two thirds of the tongue. It exits the facial
nerve in the vertical segment and passes under the posterosuperior surface of the tympanic membrane, crossing the middle
ear lateral to the long process of the incus and medial to the
malleus. The facial nerve lies within a protective bony canal
throughout its course in the middle ear. However, the bony
canal may be absent (in the horizontal portion) in as many
as 8% to 30% of patients.1 Cranial nerve IX supplies sensation
to the floor of the middle ear.
The inner ear consists of the cochlea, semicircular canals,
and vestibule. The cochlea is a coiled fluid-filled tube consisting of 2 to 23/4 turns surrounded by dense bone. It
contains the membranes that support the organ of Corti and
has hair cells that detect the fluid wave from vibration of
the stapes footplate. The hair cells create the neural impulses
that are transmitted from the auditory nerve (cranial nerve
VIII) to the brain, providing the sensation of hearing.
The three paired semicircular canals (horizontal, superior,
and inferior) are also fluid-filled tubes surrounded by dense
bone. The semicircular canals each have a hair cellcontaining
structure (the ampulla) that detects motion. The utricle and
saccule of the vestibule also have hair cell structures that
detect acceleration.2
707
708
PART V
EMBRYOLOGY
The external ear develops during the sixth week of gestation
and is completely developed by the 20th week. Six hillocks
fuse to form the basic units of the pinna. Defects in the fusion
of the hillocks lead to preauricular tags and sinuses. The external auditory canal develops from the first branchial cleft.
A solid epithelial plug forms during the beginning of the third
month of gestation and canalizes in the seventh month to form
the external auditory canal.
The middle ear space develops from the first pharyngeal
pouch. The ossicles develop from the first and second pharyngeal arches. The inner ear arises from neuroectodermal tissue
within the otic placode that forms the otic pit.2
Any combination of anomalies may occur. Abnormalities of
the development of the ear may create anomalies of the pinna,
external auditory canal, middle ear structures, and inner ear.
One of the anomalies that involves the external and middle
ear is aural atresia (absence of the external auditory canal).
Absence of the external canal may occur with a deformed or
normal external ear. The ossicles may be deformed and are
usually fused to each other as well as the bony plate representing the undeveloped tympanic membrane. The facial nerve
may also be altered in its course through the temporal bone.
Reconstruction of the atretic canal, removal of the bony tympanic plate, release of the fused ossicles, and reconstruction of
a new eardrum is a complex surgical procedure that may
improve hearing. Rarely, there is incomplete development of
the inner ear structures. The most common of these is dysplasia of the cochlea, and it may vary in severity. Dysplasia
is associated with sensorineural hearing loss in most cases.3,4
EXAMINATION
The examination of the ear should always start with inspection
of the outer ear and surrounding structures. Deformities of the
outer ear structure may suggest the presence of other anomalies, such as a first branchial cleft sinus. A first branchial cleft
sinus usually presents below the ear lobe near the angle of
the jaw. The sinus tract may connect to the ear canal or, rarely,
the middle ear.
The external auditory canal and tympanic membrane are
best examined with a handheld otoscope that has a bright
fiberoptic light source and a pneumatic bulb attached to its
head. The largest speculum that comfortably fits in the external canal should be used to maximize visualization and minimize pain. A very small speculum may be inserted deeply, but
it might lacerate the ear canal as well as limit visibility of the
tympanic membrane. The otoscope permits visualization of
the ear canal and tympanic membrane. A translucent tympanic membrane will also permit visualization of the contents
of the middle ear.
A healthy middle ear contains air and is ventilated via the
eustachian tube that connects to the nasopharynx. Insufflation
of air into the ear canal via the pneumatic bulb should cause
the tympanic membrane to move if the middle ear is normal
(aerated) and fail to move if it is filled with effusion (mucus or
pus). Cerumen may be encountered in the ear canal that
obstructs the view of the tympanic membrane or fails to allow
insufflation to occur with pneumatic otoscopy. Removal of
cerumen may be performed by using an operating otoscope
head and an ear curette. However, the use of a headlight, such
CHAPTER 55
OTOLARYNGOLOGIC DISORDERS
709
Certain Diagnosis
Uncertain Diagnosis
Younger than
6 months
6 months to 2 years
Antibiotics
Antibiotics
Antibiotics
Antibiotic if severe
illness*; observe if
nonsevere illness{
Antibiotic if severe
illness*; observe if
nonsevere illness{
Observe
710
PART V
on appropriate treatment of the intracranial process, in addition to a wide-field myringotomy and tympanostomy tube
placement in the affected ear.9
CHAPTER 55
existing speech delay, autism, or neurocognitive delays). Adenoidectomy would be considered as well if the adenoids are
found to be enlarged, especially if the child has symptoms
of heavy snoring, sleep apnea, or chronic nasal congestion.10
Chronic suppurative otitis media occurs when otorrhea
(drainage of pus or mucous) persists for more than 3 months,
either through a perforation of the tympanic membrane or
through a tube in the tympanic membrane. A cholesteatoma
of the middle ear may also be present in patients who have
perforated tympanic membranes. A cholesteatoma is a squamous epithelial-lined cyst that may be congenital or acquired.
Congenital cholesteatomas are caused by epithelial rests that
persist in the middle ear during temporal bone development.
They present behind an intact tympanic membrane and
appear as a white, smooth mass, most often located in the
anterior superior quadrant of the middle ear. They expand
over time and are filled with squamous debris and may erode
the ossicular chain and extend into the mastoid.
Acquired cholesteatomas develop from skin entering the
middle ear after a tympanic membrane perforation or a retraction
pocket from eustachian tube dysfunction and are usually
located in the posterior-superior quadrant of the middle ear
space. Cholesteatomas are usually painless, cause a conductive
hearing loss, and, in acquired cases, often present as otorrhea.
The otorrhea should be treated with ototopical antibiotic
eardrops, but the only treatment of cholesteatomas is complete
surgical excision by tympanomastoid surgery and ossicular
reconstruction.11 The potential complications of cholesteatomas
are the same as those for acute suppurative otitis media (ASOM).
TRAUMA
Objects stuck deeply into the ear canal, such as a cottontipped applicator, may perforate the tympanic membrane.
This usually causes acute pain, bleeding, and a conductive
hearing loss. If the ossicular chain is not disrupted, the vast
OTOLARYNGOLOGIC DISORDERS
711
FIGURE 55-2 A, Longitudinal temporal bone fracture. These fractures run parallel to the petrous pyramid. The otic capsule is generally not affected by the
fracture lines. Balance, hearing, and facial function are generally preserved. B, Transverse temporal bone fracture. These fractures generally extend through
the cochlea and facial canal and result in deafness, vertigo, and facial nerve paralysis of immediate onset. Facial nerve exploration with repair should always
be considered in these cases.
712
PART V
TUMORS
Benign and malignant tumors of the ear are rare. Glomus tympanicum tumors and neuromas of the facial nerve may present
in the middle ear. Also, eosinophilic granuloma and rhabdomyosarcoma may involve the structures of the temporal
bone.12,13
Nose
------------------------------------------------------------------------------------------------------------------------------------------------
ANATOMY
The nose can be divided into three anatomic sections. The
bony vault is the immobile portion of the nose. It consists
of the paired nasal bones, the frontal process of the maxillary
bone, and the nasal process of the frontal bone. The cartilaginous vault is supported by the upper lateral cartilages and the
cartilaginous nasal septum. The nasal lobule is supported
by the lower lateral cartilages and the cartilaginous septum.
The nasal septum is formed by the quadrilateral cartilage
anteriorly. The posterior septum is composed of bone from
the vomer, perpendicular plate of the ethmoid, nasal crest
of the maxillary bone, and palatine bone.
Both the internal and external carotid artery systems supply
blood to the nose. The roof and lateral wall of the internal nasal cavity are supplied by the anterior and posterior ethmoidal
arteries, sphenopalatine artery, and greater palatine artery. The
septum is supplied by the anterior and posterior ethmoidal
arteries, palatine artery, and the superior labial artery. The
convergence of these vessels in the anterior segment of the
nose is referred to as the Kiesselbach plexus or the Little area.
Venous drainage is accomplished mainly by the ophthalmic,
anterior facial, and sphenopalatine veins.
The olfactory bulb is positioned high in the roof of the nasal
cavity and is responsible for the sense of smell. Sensory information is transported by nerves that penetrate the cribriform
plate and traverse cranial nerve I (the olfactory nerve) to
the brain. Smell is also an important component of what is
perceived as taste.
Bony projections, called turbinates, form the lateral nasal
wall and significantly increase the surface area of the nose,
allowing for more efficient humidification and warming
of the air to 36 C. Three turbinates are usually present
(i.e., inferior, middle, and superior). A supreme turbinate,
which is essentially a flap of mucosa, is occasionally present.
The turbinates contribute to the turbulent airflow that creates
approximately 50% of the total airflow resistance to the lungs.
Cleaning of air is accomplished through the nasal hairs
(vibrissae) and the mucosal surface. Anteriorly, the nose is
lined with stratified squamous epithelium, which changes
to respiratory epithelium immediately anterior to the turbinates. Trapped debris is transported in a posterior direction
into the nasopharynx by a mucociliary transport mechanism.
Speech is affected by nasal anatomy and pathologic conditions. Hyponasality from nasal obstruction or hypernasality
from an excessive air leak can affect voice quality and intelligibility of speech.
EMBRYOLOGY
The nose serves as a drainage port for the paranasal sinuses.
The meati are spaces between the lateral aspect of the nasal
turbinates and the medial aspects of the lateral nasal wall.
Each meatus is named for the turbinate that surrounds it.
The maxillary, frontal, and anterior ethmoidal sinuses drain
into the middle meatus. The posterior ethmoidal sinuses drain
into the superior meatus. The sphenoidal sinus drains into an
area known as the sphenoethmoidal recess that is located posterior and superior to the superior turbinate. The nasolacrimal
duct drains into the inferior meatus.
The nasal cavities develop from the nasal pits in the 4-week
embryo. These pits deepen and move medially to form the
nasal cavity. The oronasal membrane that separates the nose
from the mouth resolves in the seventh week to permit
communication between the nose and nasopharynx.
The paranasal sinuses develop from an outpouching of the
lateral nasal walls during the third and fourth months of
CHAPTER 55
INFLAMMATORY CONDITIONS
Viral rhinosinusitis (the common cold) accounts for the
majority of nose and sinus infections. It is caused by many
strains of viruses and is a self-limited infection. Symptoms
of fever, nasal congestion, headache, and clear rhinorrhea
usually resolve over 5 to 7 days. Treatment is symptomatic.
BACTERIAL RHINOSINUSITIS
Acute bacterial rhinosinusitis may often follow an acute viral
upper respiratory tract infection. The most common bacteria
causing rhinosinusitis are Streptococcus pneumoniae, Haemophilus
influenzae, and Moraxella catarrhalis. Acute rhinosinusitis causes
malaise, headache, and nasal congestion. There may also be
pain localized to the sinus region or pain on palpation over
the maxillary or frontal sinuses. Chronic sinus infection may
persist after the acute phase, and symptoms often last longer than
30 days.
The gold standard for diagnosing sinusitis is CT of the
sinuses, but a thorough history and nasal examination is
usually sufficient to diagnose acute rhinosinusitis. The nasal
cavity can be visualized by using a large speculum on an
otoscopic head. The posterior nasal cavity can be visualized
with either a straight-rod endoscope or a flexible fiberoptic
nasopharyngoscope.
The treatment of rhinosinusitis includes oral antibiotics,
short-term use of topical nasal decongestants (e.g., oxymetazoline), and saline nasal sprays. Topical nasal corticosteroid
sprays may be helpful for the treatment of both acute and
chronic sinusitis.
Chronic sinusitis in a child may be exacerbated by gastroesophageal reflux disease, immunodeficiencies, mucociliary
dysfunction, and, more commonly, upper respiratory allergy.
These predisposing conditions should be managed while
treating the sinus infection. If the signs and symptoms of
chronic sinus infection persist, a sinus CT is required to
evaluate the condition of the sinus mucosa and the drainage
pathways. Endoscopic sinus surgery may be necessary to open
the involved sinuses to provide drainage.
Chronic inflammation of the nasal and sinus mucosa may
lead to nasal and sinus polyp formation that chronically
obstructs the nose and sinuses. Antrochoanal polyps are large
polyps that originate from the walls of the maxillary sinus and
extend through the nasal cavity into the nasopharynx. Nasal
polyps may be removed endoscopically, but a large antrochoanal polyp may require removal through an open maxillary sinus procedure. Nasal polyps in a child should always
prompt an evaluation for cystic fibrosis.
COMPLICATIONS OF SINUSITIS
The sinuses surround the orbit so a common complication
of acute rhinosinusitis in children is orbital cellulitis with
erythema and edema of the eyelids. Chemosis (edema of the
ocular conjunctiva) is usually absent. However, if a periorbital
subperiosteal abscess forms adjacent to an infected sinus,
OTOLARYNGOLOGIC DISORDERS
713
FUNGAL SINUSITIS
Fungal sinusitis may occur in immunocompromised children,
specifically severe diabetics, children undergoing chemotherapy, and bone marrow transplant recipients. The more
common invasive fungi include Mucor and Aspergillus species.
The treatment of fungal sinusitis involves surgical drainage
and intravenous antifungal agents.
However, a chronic form of fungal sinusitis is allergic
fungal sinusitis. The presence of fungi causes inflammatory
cells to proliferate in the sinuses, causing symptoms of
nasal plugging and facial pain, along with discharge or
polyps. These patients usually have other signs of allergy,
such as asthma. The treatment of this condition is corticosteroids and debridement of the involved sinuses. The diagnosis
is made by sinus CT findings and the presence of eosinophils
as well as fungi in the sinus secretions that are removed at the
time of surgery.16
CONGENITAL MALFORMATIONS
Pyriform Aperture Stenosis
Congenital stenosis of the anterior bony aperture causes
partial nasal obstruction that may be severe enough to cause
difficulty feeding, respiratory distress, and failure to thrive.
Anterior rhinoscopy demonstrates a very constricted nasal
opening bilaterally. CT of the nose shows marked narrowing
of the pyriform aperture.
Neonates are obligate nasal breathers, and severe stenosis
must be surgically corrected. Because the stenotic segment
is very anterior and the remainder of the nasal cavity is normal,
removal of the constricting bone with drills is done through
a sublabial approach. The nasal openings are stented with
3.0-mm endotracheal tube stents that are sutured in place
and removed after a few days.
Choanal Atresia
Choanal atresia may be unilateral or bilateral. The obstructing
tissue is usually a bony plate, but a few cases will have only
membranous atresia. Unilateral choanal atresia presents as
chronic unilateral rhinorrhea. There is no significant respiratory distress. Because neonates are obligate nose breathers, bilateral choanal atresia is associated with severe respiratory
distress, difficulty feeding, and failure to thrive. The diagnosis
is suspected if catheters cannot be passed through the nose
and into the pharynx. The obstruction may be visualized with
a narrow flexible nasopharyngoscope after the nasal cavity has
714
PART V
been suctioned of mucus and the nasal mucosa has been constricted with a nasal decongestant (e.g., oxymetazoline). The
diagnosis is best made with CT of the nasal cavity. CTwill demonstrate the atresia, define the tissue (bony or membranous),
and show the configuration of the entire nasal cavity.
Choanal atresia may be successfully treated by removing the
obstructing tissue transnasally. Curettes, lasers, microdebriders,
bone punches, and drills may all be effective to remove the atresia plate. However, when the bony plate is very thick and there
is an extremely narrow posterior nasal cavity, a transpalatal
repair is more direct. A transpalatal repair provides better access
for more effective removal of the bony plate and posterior
septum (Fig. 55-3). Stents fashioned from endotracheal tubes
are placed and secured with sutures to the septum. They are
removed after several weeks. The stents must be moistened
with saline and suctioned several times daily to prevent mucus
plugging and acute respiratory distress. Transpalatal repair of
choanal atresia has a lower incidence of restenosis.11
Nasal Dermoid
FIGURE 55-3 Choanal atresia. This disorder frequently presents at birth
with respiratory distress.
FIGURE 55-5 Nasal dermoid. These lesions typically present on the nasal
dorsum as a single midline pit, often with a hair extruding from the depths
of the pit. The pits may also be found on the columella. The dermoid will
then tract through the septum toward the cranial base.
CHAPTER 55
OTOLARYNGOLOGIC DISORDERS
715
TRAUMA
Anosmia
Head trauma can lead to temporary or permanent anosmia
(lack of sense of smell). In one large study of head trauma
patients (n 190), 11% reported loss of sense of smell that
persisted after their initial recovery and later was confirmed
by smell tests. Those at higher risk had trauma that led to
intracranial hematoma and/or hemorrhages or injury near
the skull base.17
Nasal Fracture
An infant may be born with the soft nasal bones and the
septum deviated to one side either as a result of a difficult delivery or from persistent intrauterine compression of the nose.
The nasal structures can most often be returned to the midline
with digital manipulation. If the nasal deformity is partially
reduced, the nose usually straightens with growth during
the first 12 to 18 months of age.
Nasal bone and nasal septal fractures in older children
usually occur from a blow to the face during sports. There
is usually a brief period of epistaxis and deviation of the nasal
dorsum to one side. Swelling occurs rapidly, and the degree
of the cosmetic deformity or the need for fracture reduction
may not be easily determined. At the fourth to sixth day after
injury, the edema subsides and the need for reduction can be
determined. Nasal bone radiographs are of little help in making this judgment; so, the need for nasal fracture reduction is
usually based solely on clinical examination. Effective closed
nasal fracture reduction may be done up to 2 weeks after
the injury. Closed reduction under general anesthesia is the
method of choice. Oral antibiotics prevent infection and are
essential if nasal packing is used to support the nasal bone.
Although nasal fracture reduction is not urgent, a septal
hematoma from a fractured septum should be excluded by
the initial physician seeing the child. A septal hematoma that
remains untreated may cause cartilage necrosis and loss of nasal
support, with a resulting saddle-nose deformity. Treatment of a
septal hematoma is with incision and evacuation of the clot. The
mucoperichondrial flap should then be sutured in place by
bolster sutures through the septum. A small rubber band drain
may be required and, if used, should remain in place for 12 to
24 hours, and antibiotics be given for 10 to 14 days to prevent
secondary infection while a drain is in place.
NASAL/NASOPHARYNGEAL TUMORS
Rhabdomyosarcoma, lymphoma, squamous cell carcinoma,
and esthesioneuroblastoma may occur in the nose and sinuses
of children. Fortunately, these malignant tumors are very rare
in children. The treatment of children with malignant tumors
of the nose and sinuses usually involves a multidisciplinary,
multimodal approach.
Juvenile nasopharyngeal angiofibroma is a benign tumor of
adolescent males that originates from the lateral wall of the
nose and nasopharynx. The tumor may completely obstruct
the nose and fill the nasopharynx. This type of angiofibroma
may also extend intracranially through the base of the skull.
Patients with these tumors present with nasal obstruction,
recurrent epistaxis, and rhinorrhea.
The tumor may be seen with a flexible fiberoptic nasopharyngoscope or a rod lens telescope after decongesting the nasal
mucosa. It appears as a smooth reddish mass. Biopsy of the
mass should be avoided because of the potential for severe
bleeding. CT and MRI define the extent and location of the
tumor. On imaging, the mass originates in the pterygopalatine
716
PART V
Oral Cavity/Pharynx
------------------------------------------------------------------------------------------------------------------------------------------------
ANATOMY
ACUTE PHARYNGOTONSILLITIS
The boundaries of the oral cavity include the lips anteriorly, the
cheeks laterally, and the palate superiorly. The posterior boundary is a plane that extends from the soft palate to the junction of
the anterior two thirds and posterior one third of the
tongue. The oral cavity is composed of the vestibule, the space
between the lips and cheeks and alveolar ridges, and the oral cavity proper. The vestibule and oral cavity proper are separated by
the alveolar ridge and teeth. The vestibule is divided in the midline by the frenula of the upper and lower lips. The alveolar ridge
is contiguous superiorly with the hard palate. The parotid ducts
(Stensen ducts) enter the vestibule opposite the second maxillary
molars. The submandibular ducts (Wharton ducts) enter the
floor of mouth near the lingual frenulum.
The palate is formed by a fusion of the primary palate
anteriorly and medial growth of the palatal processes that form
the secondary palate. The hard palate divides the nasal and oral
cavities and is formed by the premaxilla and the horizontal
plates of the palatine bones. The soft palate is formed by a muscular aponeurosis of the tensor veli palatini tendon. Five muscles insert into this aponeurosis and include the tensor veli
palatini, levator veli palatini, palatoglossus, palatopharyngeus,
CHAPTER 55
OTOLARYNGOLOGIC DISORDERS
717
corticosteroids has been proven to reduce the lymphoid hypertrophy that can cause acute airway obstruction.
Group A beta-hemolytic streptococci (GABHS, i.e.,
S. pyogenes) commonly infect the pharynx. In addition to sore
throat, associated symptoms include fever, headache, and
abdominal pain. Associated signs include pharyngeal erythema,
halitosis, tonsillar exudates, and tender lymphadenopathy.
Lack of cough helps differentiate it from other upper respiratory
tract infections. Diagnosis may be confirmed initially with a
rapid streptococcal antigen test. Because rapid antigen testing
is more sensitive than formal plating on blood agar, a negative
test does not need confirmation, but positive rapid streptococcal
tests should be confirmed with formal plating. Other bacterial
pathogens that cause acute pharyngitis include Haemophilus
influenzae and groups C and G beta-hemolytic streptococci.
Occasionally, concurrent infection with penicillin-resistant
Staphylococcus aureus may interfere with treatment of a GABHS
infection.19 Although many cases of GABHS infections respond
to treatment with penicillin Vor amoxicillin, emerging resistance
to oropharyngeal pathogens mandates treatment of recalcitrant
cases with an antibiotic having known effectiveness against
beta-lactamaseproducing organisms. In cases in which a lack
of compliance is suspected, intramuscular benzathine penicillin
or ceftriaxone may be used.
Acute pharyngitis may also be associated with acute bacterial infections of the nose, nasopharynx, and sinuses. These
infections may be caused by a variety of viral and bacterial pathogens; in addition to a sore throat, symptoms include fever,
mucopurulent nasal drainage, nasal obstruction, and facial pain.
RECURRENT PHARYNGOTONSILLITIS
CHRONIC PHARYNGOTONSILLITIS
The pharynx and, specifically, the tonsils may be the target of
chronic infection. Affected children complain of chronic
throat pain, halitosis, and production of white particles or
ORAL TRAUMA
PERITONSILLAR CELLULITIS/ABSCESS
Localized extension of tonsillar infection may result in peritonsillar cellulitis. The same pathogens that cause acute
pharyngotonsillitis are responsible for peritonsillar cellulitis.
In addition to a severe sore throat, symptoms and signs include drooling, trismus, muffled voice, ipsilateral referred
otalgia, and tender lymphadenopathy. The affected tonsil is
usually displaced in a medial and inferior position. Peritonsillar cellulitis may progress to frank abscess formation (quinsy).
718
PART V
FIGURE 55-6 A, Retropharyngeal abscess. Computed tomography of the cervical area demonstrates fluid loculated in the retropharyngeal space.
The abscess is typically unilateral and frequently extends into the medial aspect of the peripharyngeal space. In the absence of associated complications,
drainage can be done intraorally (arrow). B, Lateral neck abscess on the left side (arrow).
RETROPHARYNGEAL/PARAPHARYNGEAL
SPACE INFECTIONS
Signs and symptoms of deep neck space (retropharyngeal/
parapharyngeal) infections that involve the pharynx typically
are as fever, drooling, irritability, decreased oral intake, torticollis, and/or trismus. Often there is a history of a preceding
viral illness. Stridor or symptoms of upper airway obstruction
may be seen in half of patients.25 A neck mass or enlarged cervical nodes may be present, depending on the location of the
infection. Usual pathogens include coagulase-positive staphylococci and GABHS. Anaerobic bacteria have been found in as
many as 50% of cases.25 Complications of deep neck space infections include airway obstruction, bacteremia, rupture of
the abscess into the pharynx with aspiration, mediastinal extension of infection, jugular thrombosis, and carotid artery
rupture.
In suspected cases, the diagnosis of a retropharyngeal/
parapharyngeal space infection is confirmed with either
contrast mediumenhanced CT or MRI. Widening of the retropharynx on a lateral neck radiograph suggests a retropharyngeal infection. Although ultrasonography can detect the
presence of an abscess cavity, CT or MRI are most helpful in
demonstrating the extent of infection and the location of
surrounding structures of importance, specifically the great
vessels. Contrast mediumenhanced CT is particularly useful
in distinguishing a phlegmon (cellulitis) from cases of frank
SLEEP-DISORDERED BREATHING
In the past decade, the impact of sleep-disordered breathing
(SDB) on the health of children has been well described,
beginning with the report of normative sleep data by Marcus
and colleagues.26 Children appear to have briefer but more
frequent episodes of partial (hypopnea) and complete (apnea)
obstruction. Because an apnea of less than 10 seconds may
represent several missed breaths in a child, an apnea of any
duration is abnormal. In most cases the site of obstruction
during sleep is in the pharynx. In contrast to adults with this
disorder, in whom the pharyngeal impingement is due to
CHAPTER 55
OTOLARYNGOLOGIC DISORDERS
719
on exertion. In contrast to adults, hypersomnolence is uncommon in children because of the lower incidence of gas exchange
abnormalities, specifically hypercarbia. Children may complain of headaches, seem irritable, and perform poorly in
school. Nighttime symptoms are more obvious and include
snoring, gasping, and choking respirations, apnea, coughing,
and a variety of other behaviors, including sleepwalking, sleeptalking, rocking, head banging, and bruxism. Enuresis may
appear in children with airway obstruction and then resolve
after surgical treatment. In addition to enlarged tonsils, signs
include the presence of a posterior pharyngeal flap in cleft
palate patients, a craniofacial disorder, adenoid facies, and,
rarely, evidence of right-sided heart failure.
The diagnosis of SDB is suggested by history and physical
examination. Confirmation of obstruction and apnea may be
made with overnight pulse oximetry and video or audio
monitoring of sleep. The gold standard in the diagnosis of
obstructive sleep apnea remains formal polysomnography,
including measures of nasal and oral airflow, transcutaneous
oxygen and carbon dioxide, chest wall movements, electrocardiography, extraocular muscle movements, electroencephalography, leg movements, and gastric pH monitoring in
selected cases. Depending on the suspected site of obstruction, adjuvant studies, such as a lateral neck radiograph,
MRI of the head and neck, and flexible upper airway
endoscopy, might be helpful.
The nonsurgical management of SDB consists of weight
loss in obese patients and treatment of underlying allergies
and gastroesophageal reflux. Nasal and dental appliances
to maintain airway patency that may be useful in adults are
usually poorly tolerated in children. Nasal continuous positive
airway pressure, the mainstay of treatment in adults, is tolerated in many children and should be considered as a treatment
option, especially in patients in whom other therapies have
been exhausted or proven ineffective.
720
PART V
The initial surgical treatment for most children with SDB remains a tonsillectomy and adenoidectomy, a therapy that is usually curative. In patients with documented sleep apnea or a sleep
disorder, both procedures should be used even if the tonsils appear small. Tonsillectomy and adenoidectomy techniques that
have been standard for decades have been supplanted in some
institutions by new technology, including use of coblation, harmonic scalpel, and the microdebrider. Efficacy of these newer
techniques versus established methods remains unproven.
Complications after tonsillectomy and adenoidectomy usually consist of respiratory compromise and acute or delayed
bleeding. Since the advent of modern pediatric anesthesia,
respiratory complications, such as aspiration with resultant
pneumonia and lung abscess, are rare. Humidification, intraoperative corticosteroids, and antibiotics have all been shown
to improve the postoperative course after tonsil and adenoid
surgery. Young children are most vulnerable to complications,
and, in most institutions, children younger than 3 to 4 years
of age are observed overnight for signs of dehydration and
respiratory compromise.
Adjuvant surgery in the management of SDB includes
craniofacial repair or posterior flap revision surgery in appropriate patients. Midface, mandibular, and hyoid advancement
have proved useful in selected patients, along with nasal
surgery such as septoplasty, partial inferior turbinectomy, or
nasal polypectomy. Tracheostomy remains the treatment of last
resort in patients who fail to respond to other forms of therapy.
ANKYLOGLOSSIA
Ankyloglossia or tongue-tie is a common congenital disorder
involving the lingual frenulum (Fig. 55-9). Neonates with
diminished tongue mobility resulting from a foreshortened
frenulum may have problems in sucking and feeding. Because
the frenulum is thin and relatively avascular in neonates and
young infants, it can often be incised as an office procedure.
In older children the greatest effect of ankyloglossia is on
speech and it can lead to dental caries because it may be difficult to clean the lower teeth. Because the tip of the tongue
MACROGLOSSIA
Macroglossia is uncommon. Generalized macroglossia, as seen
in association with Beckwith-Wiedemann syndrome, with
glycogen storage diseases (Hunter and Hurler syndromes)
or hypothyroidism, is rare. Relative macroglossia can be seen
normally on occasion but is most common in Down syndrome. The most serious complication of this condition is
airway obstruction. In infants, macroglossia should be distinguished from focal enlargement of the tongue seen in patients
with a lymphatic malformation or hemangioma. Glossoptosis,
posterior displacement of a normal-sized tongue, is seen in association with cleft palate and micrognathia in infants afflicted
with the Pierre Robin sequence. The airway symptoms in most
of these infants usually improve over the first year or two of
life; so, supportive care is most often recommended (including oral airways and upright positioning with feeding). Infants
with severe airway obstruction secondary to an enlarged or
displaced tongue may require tongue reduction or a temporary tongue-to-lower lip adhesion suture, respectively. Tracheostomy is reserved for the worst cases. Macroglossia in older
children that affects cosmesis, interferes with speech, or
causes drooling may be treated with a variety of other tongue
reduction techniques.
BENIGN LESIONS
Epulis is a congenital granular cell tumor that typically
presents as a soft, pink submucosal mass on the anterior
alveolar ridge of the maxilla (Fig. 55-10). Females are more
FIGURE 55-10 Congenital epulis. The congenital epulis is an unusual benign lesion that frequently arises from the anterior maxillary alveolar ridge.
Airway and feeding difficulties may develop secondary to large lesions.
Surgical excision is required.
CHAPTER 55
FIGURE 55-11 A ranula is a pseudocyst caused by obstruction of a sublingual gland. It generally presents as a unilateral, painless swelling in the
floor of the mouth.
OTOLARYNGOLOGIC DISORDERS
721
MALIGNANT LESIONS
Rhabdomyosarcoma, the most frequent soft tissue malignancy
of childhood, typically occurs in the 2- to 6-year-old group
and is derived from embryonic skeletal muscle.28,29 In the oral
cavity and oropharynx, it presents as a rapidly growing mass
in the tongue, palate, and uvula or cheek. These tumors metastasize early to local lymph nodes, lung, and bone. Surgical
therapy is limited to biopsy, excision of small lesions, or surgical salvage of treatment failures. The usual therapy includes
a combination of chemotherapy and radiation therapy.
Lymphoma of the oral cavity and oropharynx typically involves the lymphoid tissue of the Waldeyer ring and presents
722
PART V
Larynx
------------------------------------------------------------------------------------------------------------------------------------------------
ANATOMY
With the exception of the hyoid bone, the major structural
framework of the larynx consists of cartilage and soft tissue.
The hyoid bone lies superior to the larynx and is attached
to it by the thyrohyoid membrane and strap muscles. The
hyoid bone is derived from the second and third branchial
arches. The cartilaginous structures of the larynx are composed of hyaline cartilage, with the exception of the epiglottis,
which is composed of elastic cartilage. The cartilaginous structures of the larynx develop from the fourth, fifth, and sixth
branchial arches. There are nine laryngeal cartilages, three that
are single (thyroid, cricoid, and epiglottis) and six that are
paired (arytenoid, cuneiform, and corniculate). The thyroid
cartilage consists of two quadrilateral cartilages that form
the anterior framework of the larynx. The cricoid cartilage
is the only completely cartilaginous structure in the airway
and provides posterior stability and a base of support for
the cricoarytenoid and cricothyroid joints.
The cricothyroid muscles are paired extrinsic laryngeal
muscles that serve to tilt the larynx down and forward, tensing
the vocal folds. Paired intrinsic musclesthe thyroarytenoid,
thyroepiglottic, and aryepiglottic musclesact as a sphincter
to close the larynx. The vocalis muscle comprises the internal
fibers of the thyroarytenoid muscle and attaches to the vocal
ligament. Action of this muscle serves to regulate the pitch of
the vocal ligament. The other set of paired muscles includes
the posterior cricoarytenoid, lateral cricoarytenoid, and
interarytenoid muscles. The posterior cricoarytenoid muscles
serve to abduct the vocal folds, whereas the cricoarytenoid
and interarytenoid muscles adduct the vocal folds.
The quadrangular membrane is a connective tissue
covering of the superior larynx that ends in a free margin along
the vestibular ligament of the false cord. The conus elasticus is
a membrane of elastic tissue that extends superiorly from
the cricoid cartilage to form the paired vocal ligaments, the
supporting structures of the vocal folds.
The blood supply of the larynx arises from the superior and
inferior laryngeal arteries. The former is a branch of the
superior thyroid artery, whereas the latter is a branch from
the thyrocervical trunk. The intrinsic muscles of the larynx
are innervated by the recurrent laryngeal nerve, which also
supplies sensory branches to the inferior larynx. The superior
laryngeal nerve has two branches: The external branch innervates the cricothyroid muscle, while the internal branch
supplies sensation to the superior larynx.
CHAPTER 55
OTOLARYNGOLOGIC DISORDERS
723
density reduces air turbulence and gas resistance, allowing improved delivery of oxygen in patients with airway obstruction.
Nonsurgical airway management may include use of nasal
or oral airways, endotracheal intubation, and, rarely, transtracheal ventilation. Nasal airways of rubber or other synthetic
material can be easily inserted into the nose of most children
after adequate lubrication with a water-soluble lubricant.
Their best use is in cases where the pharynx is the site of obstruction. Oral airways are not as readily tolerated by children
and only serve as a brief solution to an airway problem. During
the 1970s, endotracheal intubation with polyvinyl chloride
tubes revolutionized the management of supraglottitis, and
even today intubation remains the mainstay of initial airway
therapy in most children with severe airway obstruction.
The size of the endotracheal tube used correlates with the
age of the child. The subglottis, the narrowest part of the infant
airway, typically admits a 3.5- or 4.0-mm inner-diameter tube.
The tube used in children older than 1 year can be roughly
estimated by using the following formula: tube size (age
in years/4) 4. Once the airway has been established, the tube
should be carefully secured and the child appropriately sedated and/or restrained, if necessary, to avoid accidental
self-extubation. Another method of airway management
should be considered in children with an unstable cervical
spine or in whom oral or neck trauma makes visualization
difficult. Transtracheal ventilation, insertion of a 16-gauge
needle through the cricothyroid membrane for the delivery
of oxygen, should be reserved for emergencies and used only
until a more stable airway can be obtained.
The surgical management of the child with acute airway
obstruction should begin with endoscopy. The larynx can
be visualized with one of a variety of pediatric laryngoscopes
and the airway secured with a rigid pediatric ventilating
bronchoscope of appropriate size. Once the airway is secured,
a more stable form of airway management can be used. Rarely,
in a child with acute airway obstruction, an airway cannot be
established, and a cricothyrotomy may need to be performed.
As in adults, this procedure avoids some of the risks of bleeding and pneumothorax inherent in a formal emergency tracheostomy. A small endotracheal or tracheostomy tube can be
inserted through the incision in the cricothyroid membrane,
but conversion should be made to a more stable airway as
soon as possible. Tracheostomy remains the preferred airway
in cases of acute obstruction in which a translaryngeal
approach is unsuccessful or must be avoided. The emergent
tracheostomy should be avoided if at all possible to lessen
complications of bleeding, pneumothorax, pneumomediastinum, subcutaneous emphysema, or damage to surrounding
structures. The incidence of these complications can be
reduced by careful attention to surgical technique, good lighting, and adequate assistance.
724
PART V
before they reach normal birth weights. Neonates with bilateral involvement typically present with high-pitched inspiratory or biphasic stridor but a good cry. Respiratory
compromise and feeding difficulties may accompany the stridor because the vocal cords cannot abduct and the resultant
airway is narrow. However, compensatory extralaryngeal muscles can help adduct the cords to produce a strong voice. In
infants with unilateral involvement, the airway may be adequate because the affected vocal cord remains partly lateralized at rest. Unlike the case of bilateral vocal cord
paralysis, the extralaryngeal muscles cannot cause the cord
to adduct upon vocalization or during a swallow. As a result,
these infants are at increased risk of aspiration and often have
breathy, weak voices. The diagnosis of unilateral or bilateral
vocal fold paralysis is confirmed with flexible or rigid endoscopy. Additional studies in the evaluation of patients with vocal fold paralysis include lateral neck and chest radiography,
barium swallow, and CT or MRI of the head and neck. Most
children with unilateral involvement can be observed. As they
grow, they may be candidates for vocal cord medialization procedures, whereby, agents such as Gelfoam or Teflon are
injected lateral to the cord to improve vocalization. Another
treatment option is ansa cervicalistorecurrent laryngeal
nerve anastomosis to reinnervate the affected cord. This increases the tone, bulk, and tension of the cord, but does
not restore normal mobility.34 Infants with bilateral vocal fold
paralysis often require a tracheostomy. In addition, infants
with associated feeding difficulties may need a gastrostomy.
In older children (4 or 5 years of age) with bilateral vocal cord
paralysis, a more permanent solution, such as a cordotomy or
arytenoidectomy, can be considered to improve the glottic airway and to allow for decannulation of the tracheotomy tube.
Congenital subglottic stenosis is the third most common
congenital laryngeal anomaly and is defined as a neonatal
larynx in a term baby without a history of prior instrumentation or intubation who fails to admit a 3.5-mm endotracheal
tube (Fig. 55-13). The underlying abnormality is a cricoid
cartilage that is either small or deformed. Children with Down
syndrome are at higher risk for this condition. Infants with
congenital subglottic stenosis present with inspiratory
CHAPTER 55
OTOLARYNGOLOGIC DISORDERS
725
INFLAMMATORY DISEASE
OF THE UPPER AIRWAY
FIGURE 55-14 Subglottic hemangiomas typically arise from the posterior lateral aspect of the larynx. Small lesions may be managed conservatively, whereas lesions with aggressive growth patterns that do not
respond to propranolol or steroids require tracheotomy to bypass the laryngeal obstruction.
726
PART V
FIGURE 55-15 Recurrent respiratory papillomatosis. Severe papillomatosis may completely obstruct the larynx. Papillomas are characterized
by malignant degeneration and aggressive growth patterns.
Neck
------------------------------------------------------------------------------------------------------------------------------------------------
ANATOMY
The surgical anatomy and embryology of the neck is discussed
in Chapter 59.
CLINICAL EVALUATION
The initial examination of a disease or disorder of the neck
begins with a thorough history. A detailed history can often
serve to focus the differential diagnosis of a neck disorder.
The age of the child is an important first consideration.
The appearance of a neck mass in an infant often suggests a
CHAPTER 55
OTOLARYNGOLOGIC DISORDERS
727
cytomegalovirus infection, toxoplasmosis, or cat-scratch disease may be diagnostic. Thyroid function testing is essential
in any child with a suspected thyroid disorder. Finally, collection of urine for catecholamine metabolites (vanillylmandelic
acid) may assist in the diagnosis of neuroblastoma.
If the diagnosis remains in doubt at this point, incisional or
excisional biopsy may be indicated. Biopsy provides material
for pathologic examination, culture, and other more sophisticated testing if necessary. Fine-needle aspiration of a neck
mass in children for suspected malignancy is not as reliable
as in adults.
728
PART V
neck include Kawasaki syndrome, sarcoidosis, sinus histiocytosis (Rosai-Dorfman disease), Kikuchi-Fujimoto disease, and
PFAPA syndrome (periodic recurrent fever).
MALIGNANT NEOPLASMS
Thyroid malignancies are discussed in Chapter 58, and
malignant lymphadenopathies in Chapters 38 and 57.
Neurofibromatosis is a benign disorder that in some forms
(plexiform) may infiltrate surrounding tissues. For this reason,
CT and/or MRI are vital in the preoperative evaluation of these
lesions. When the tumors are multiple and extensive, surgical
resection is reserved for symptomatic lesions, because complete excision is usually impossible without compromising
neurovascular structures. Neuroblastoma is a malignancy that
develops from neural crest cells and may present as a solitary
tumor or as lymphadenopathy. Clinical staging determines the
mode of therapy that includes surgery, chemotherapy, and
radiation therapy.
Rhabdomyosarcoma rarely presents as a primary tumor in
the neck, more often being found as a primary tumor in the
orbit, temporal bone, or nasopharynx. The diagnosis is made
by biopsy, and patients are staged according to involvement.
Treatment includes surgery, chemotherapy, and radiation
therapy.
Malignancies of almost any type and location in the body
can metastasize to the neck. The most common are thyroid
malignancies. In adolescents, carcinomas, especially those
arising in the nasopharynx, may spread to the neck lymphatics.
The complete reference list is available online at www.
expertconsult.com.
process is similar for all of the major salivary gland embryogenesis.2 During early gestation, the parotid ductules begin
to grow around the facial nerve and its branches. This is of
great clinical and surgical significance, because the facial nerve
may be compressed or invaded by parotid gland lesions, or its
branches may be injured during parotid gland surgery.3
CHAPTER 56
Salivary Glands
Douglas Sidell and Nina L. Shapiro
Salivary gland disorders are rare in children. They often present as a painful or, less commonly, a painless swelling in
the affected gland. Disease processes may be of infectious,
inflammatory, systemic, autoimmune, congenital, neoplastic,
or traumatic origin.1 Treatment is guided by the medical or
surgical nature of the specific disease process.
Classification
------------------------------------------------------------------------------------------------------------------------------------------------
Salivary glands may be divided into major and minor categories. The former category includes the parotid, submandibular, and sublingual glands, all of which are paired structures
with their own well-defined anatomy, including blood supply
and ductal drainage. Their function is augmented and facilitated by the minor salivary glands, which include the
mucus-secreting tissues in the buccal mucosa, palate, mucosal
surfaces of the lips, and floor of the mouth.
Embryology
------------------------------------------------------------------------------------------------------------------------------------------------
In the sixth week of gestation, solid epithelial buds of ectoderm from the developing mouth invaginate into the surrounding mesenchyme. A groove from this invagination
develops into a tunnel, which subsequently forms branches
of salivary ductal tissue. The mesenchymal tissue forms
the capsule and connective tissue of the salivary glands. This
Pathology
------------------------------------------------------------------------------------------------------------------------------------------------
Diagnosis
------------------------------------------------------------------------------------------------------------------------------------------------
HISTORY
A careful history should focus on the duration of the lesion, its
bilateral or unilateral presentation, and whether there is any
symptom fluctuation associated with eating. A complete
medical history is essential, because the salivary glands may
be involved in several systemic conditions.
PHYSICAL EXAMINATION
The physical examination should include careful inspection of
the overlying skin, both local and distant, to evaluate for any
cutaneous hemangiomas, as well as of the intraoral mucosa to
729
730
PART V
DIAGNOSTIC IMAGING
Plain radiographs of the salivary glands are helpful in detecting
salivary duct calculi or diffuse glandular calcification.1 Sialography is useful in identifying strictures, sialectasis, calculi, or saccular dilatation (Fig. 56-1).6 High-resolution ultrasonography
is a useful, noninvasive technique in the diagnosis of sialectasis
and salivary gland calculi.7 The addition of color-flow Doppler
imaging can provide accurate information regarding the consistency of the lesion and its vascular pattern (Fig. 56-2).8
Computed Tomography
Computed tomography (CT) is an excellent diagnostic modality for assessing both the pathology and anatomy of the
salivary glands. It can aid in distinguishing intrinsic or extrinsic lesions. Use of an intravenous contrast agent can help
detect an abscess or delineate the vascularity of congenital
and acquired vascular lesions.1 These features help in both
medical and surgical planning.9,10
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) provides the best soft tissue detail of the salivary glands, and it is the only imaging
technique that can delineate the facial nerve anatomy within
the parotid glands. Signal intensity variations (T1- and T2weighted images) provide additional valuable information
regarding the nature of the mass.11,12
BIOPSY
Fine-needle aspiration (FNA) biopsy is an excellent tool in the
diagnostic evaluation of salivary gland masses.13,14 The overall
diagnostic accuracy is 84%, with a sensitivity and specificity
approaching 92% for parotid lesions.1517 Obtaining an adequate needle biopsy specimen may preclude the necessity for
surgical therapy or aid in surgical planning. Understandably,
the accuracy and dependability of FNA rely heavily on the
expertise of the cytopathologist and may vary based on institution or clinical setting.13 For deeper salivary gland tumors,
fine-needle aspiration may be performed under image guidance. Open excisional biopsy is the definitive tool for investigation and may be curative. If the size and location of the
lesion are favorable, the entire tumor may be resected intact
with a clear surrounding cuff of normal tissue. The diagnosis
of Sjogren syndrome may be obtained by incisional biopsy of
the minor salivary glands of the labial mucosa, or, alternatively, of the parotid gland.18
SIALENDOSCOPY
Sialendoscopy involves semirigid endoscopy and microinstrumentation to evaluate and treat certain disorders of the parotid
and submandibular glands. Although relatively new, this technique is increasing in popularity and has been demonstrated to
effectively classify and treat ductal lesions, such as stricture and
calculi. Sialendoscopy has been reported to produce a greater
sensitivity in detecting salivary calculi than conventional radiography, MRI, or ultrasonography. Duct marsupialization and
intraductal calculi retrieval have been demonstrated, allowing
for the early treatment of some lesions without the requirement
for open surgery.19,20
CHAPTER 56
Inflammatory Disease
SALIVARY GLANDS
731
CHRONIC SIALADENITIS
------------------------------------------------------------------------------------------------------------------------------------------------
VIRAL SIALADENITIS
Acute inflammation of the salivary glands may be viral in up to
85% of cases, and the majority of viral sialadenitis involves the
parotid glands. Viral infections are characterized by a benign
self-limiting course over 2 to 3 weeks. Antipyretics, analgesics,
and anti-inflammatory agents may be given for relief of symptoms. Causative organisms include coxsackievirus A and
echovirus. Before the nearly universal implementation of the
mumps vaccine in 1967, mumps virus (paramyxovirus) was
the most common cause of acute parotid inflammation in
children.2124 Other potential causes include cytomegalovirus
(CMV), which is most commonly seen as a component of
disseminated CMV infection in infants and young children,25
and Epstein-Barr virus (EBV), which in healthy children is
associated with infectious mononucleosis and in chronically
ill children may be associated with human immunodeficiency
virus (HIV) infection.26,27
Chronic sialadenitis is the most common cause of inflammatory salivary gland disease in children and may lead to
structural changes in the gland and acinar destruction
(Fig. 56-3). There are obstructive and nonobstructive causes
of this condition. Obstruction is caused by ductal stenosis,
which may be congenital, caused by a stone, or result from
chewing or biting the ductal opening. In such cases, the duct
should be probed and stented for continuous drainage.
Nonobstructive chronic sialadenitis may occur in conjunction
with metabolic disorders, such as Sjogren syndrome, or
chronic granulomatous disease, such as sarcoidosis, tuberculosis, or atypical mycobacterial disease.
The treatment of obstructive sialadenitis is initially conservative, with warm compresses and anti-inflammatory medications. Ductal dilatation or marsupialization may be necessary
for recalcitrant disease. Gland excision is rarely required.
Sialolithiasis (salivary gland or duct calculi) is rare in children and occurs in the submandibular gland in 80% of cases.
When the stone is located at the distal salivary duct, it may be
excised by a simple incision at the ductal orifice. Temporary
stent placement may be necessary. Rarely, a large calculus will
be located in the proximal salivary duct or salivary gland
parenchyma and may require complete gland excision with
the stone-containing duct.
Cystic Disease
------------------------------------------------------------------------------------------------------------------------------------------------
Cystic disease may be acquired, congenital, or traumatic. Congenital cystic disease may occur in the salivary glands, but it is
not of salivary gland origin. Work type I and type II first branchial cleft cysts may present as parotid gland masses, and
depending on the orientation of the tract, may have accompanying otorrhea.31,32 Congenital lymphatic malformations may
also present in the parotid, submandibular, or sublingual
glands. Large, bilateral intraparotid lymphoepithelial cysts
are characteristic of HIV infection.1 Small mucous retention
cysts may present in the minor salivary glands of the labial
or buccal mucosa; these cysts usually result from single or
FIGURE 56-3 A, Sialogram of patient with history of recurrent parotid swelling. Note normal ductal system with early diffuse punctate sialectasis.
B, Parotid gland swelling between acute attacks of inflammation.
732
PART V
RANULA
A ranula is a mucus extravasation cyst of the sublingual gland.
Initial presentation is a bluish, cystic mass at the floor of mouth,
which may lead to lingual elevation or difficulty with deglutition.
They may extend to the neck through the mylohyoid (plunging
ranula) (Fig. 56-4). Surgical management is controversial and
ranges from simple transoral marsupialization to combination
transoral-transcervical approaches.33,34 Despite controversy,
recurrence rates as high as 67% have been described with marsupialization alone. Recent evidence, derived from the largest
review to date, suggests that the excision of the ipsilateral sublingual gland produces the lowest incidence of recurrence.35
During sublingual gland excision, care must be taken to avoid
Wharton duct injury, and it can be avoided by placing a lacrimal
probe in the duct intraoperatively. The lingual nerve must also be
meticulously dissected just deep to the sublingual gland.
Neoplasms
------------------------------------------------------------------------------------------------------------------------------------------------
BENIGN NEOPLASMS
AND MALFORMATIONS
Benign neoplasms account for 60% of salivary tumors in children and are most commonly vascular in origin.5 Vascular
lesions include hemangiomas and lymphatic malformations,
which are both congenital in origin (Fig. 56-5).
Hemangiomas
Hemangiomas are one of the most common salivary (primarily
intraparotid) neoplasms in children, with infantile hemangiomas comprising greater than 90% of all salivary lesions in children less than 1 year of age.4 Hemangiomas usually present in
infancy as a soft, nontender parotid swelling, with or without
associated pigmented cutaneous lesions.44 Diagnosis is usually
confirmed with ultrasonography, which demonstrates a lobulated, hypervascular mass, with arterial and venous signals visible on color-flow Doppler.4,45 MRI may also be useful but is
rarely required. Parotid hemangiomas often resolve spontaneously and do not require treatment. If they are rapidly growing
or are causing functional impairments, such as facial nerve
weakness, external auditory canal obstruction, or cutaneous
breakdown, systemic therapy such as corticosteroids, propranolol, or interferon alfa-2a or alfa-2b are viable options to inhibit
vascular growth and promote involution of the tumor.4649
Lymphatic Malformations
Lymphatic malformations are less common than hemangiomas.
They do not undergo spontaneous involution, are usually present at or soon after birth, and grow with the growth of the
child.44 They are not true salivary lesions, but they are commonly seen in the submandibular and parotid region in infants
and young children.50 Lymphatic malformations are susceptible
to infection, with potential for cellulitis, intralesional bleeding,
abscess formation, or lymphangiomatous extension to the floor
of mouth or trachea with airway compromise. Treatment modalities have been an area of much investigation. Surgical resection
must be complete to obviate recurrence. This is often difficult,
because of the fragility of the tumor lining, its infiltrative nature,
and its proximity to major vessels and branches of the facial
nerve.51,52 In an effort to avoid surgical morbidity, success with
intralesional sclerotherapy has been demonstrated, resulting in
reduction in tumor size and minimal scarring or recurrence.53
Pleomorphic Adenoma
Pleomorphic adenomas (benign mixed tumors) are the most
common nonvascular benign salivary tumors in children
(Fig. 56-6).42,54 They present as firm, rubbery masses, most
often in the parotid gland, with an average age at presentation
of 9.5 years within the pediatric population.54,55 The tumor
CHAPTER 56
SALIVARY GLANDS
733
involving the submandibular or minor salivary glands, concomitant neck dissection and adjuvant radiation therapy is
recommended by many institutions.36,64,65
Acinic Cell Carcinoma
Acinic cell carcinomas present in a similar fashion as mucoepidermoid carcinomas. They tend to be low grade, and treatment
is similar to that of mucoepidermoid carcinoma (Fig. 56-7).
Adenoid Cystic Carcinoma
Adenoid cystic carcinoma is a rare, high-grade salivary gland
tumor. Perineural invasion may result in cranial nerve deficits.
There is a high incidence of regional nodal metastases, as well
as distant metastases to the lungs, liver, and bone. Treatment
includes wide surgical resection, neck dissection, and adjuvant radiation therapy.61
FIGURE 56-6 Pleomorphic adenoma (mixed tumor) of the parotid gland.
Epithelial areas are mixed with myxomatoid and chondroid stroma.
(Hematoxylin-eosin stain, 50.)
presents as a painless, slowly growing mass and is rarely infiltrative.56 They have variable echogenicity on imaging, with increased heterogenicity seen in larger lesions secondary to
necrosis or cystic changes.4 Treatment of superficial lobe
tumors includes superficial parotidectomy with facial nerve
dissection and preservation. Recurrence rates have been
reported to be up to 40%; so, long-term follow-up is recommended.57,58 Simple excisional biopsy should be avoided,
because it is associated with a higher recurrence rate. Rarely,
recurrent pleomorphic adenomas may undergo malignant
degeneration.59
Rhabdomyosarcoma
Rhabdomyosarcoma may present as a parotid mass. Histologic
variants include undifferentiated and embryonal types
(Fig. 56-8). Treatment and outcomes depend on tumor stage
and may include wide local surgical resection with radiation
and chemotherapy.
Monomorphic Adenomas
Monomorphic adenomas are rare in children. Histologically,
they may resemble adenoid cystic carcinoma, a highly aggressive malignant salivary tumor.60 Treatment includes complete
surgical resection and close long-term follow-up.
Papillary Cystadenoma Lymphomatosum
(Warthin Tumor)
These tumors are most commonly seen in men and are often
bilateral parotid lesions. They may rarely present as benign
parotid tumors in children.1 Treatment is similar to that for
pleomorphic adenomas.
MALIGNANT NEOPLASMS
Malignant salivary neoplasms are rare in children. When present, they are often low-grade lesions, located most commonly
in the parotid gland, and have a female preponderance.54
Diagnostic evaluation should include CT or MRI and fineneedle aspiration biopsy. Treatment is surgical, with complete
tumor excision with clear margins. Invasive malignancies may
require sacrifice of the facial nerve branches. Postoperative
radiation therapy is recommended for high-grade lesions.61,62
Mucoepidermoid Carcinoma
Mucoepidermoid carcinoma is the most common pediatric
salivary malignancy and is most commonly low grade and
located in the parotid gland. Surgery is usually curative.39,63
For high-grade mucoepidermoid carcinomas, or those
734
PART V
Surgical Considerations
------------------------------------------------------------------------------------------------------------------------------------------------
PAROTID GLAND
An S-shaped incision is made, beginning in the preauricular
crease and extending in a curvilinear fashion to the postauricular region, followed by an inferior extension to 2 fingerbreadths below the angle of the mandible (Fig. 56-9). Skin
flaps are elevated, and the greater auricular nerve and posterior facial vein will be identified and may need to be sacrificed
to expose the posterior border of the parotid gland. Blunt dissection along the tragal pointer and mastoid process, following the posterior belly of the digastric muscle, will allow
visualization of the main trunk of the facial nerve as it emerges
from the stylomastoid foramen. Meticulous dissection along
the facial nerve branches in an anterior direction will elevate
FACIAL NERVE
Mastoid process
Gr. auricular ns.
Parotid gland deep lobe
Zygoma
Pterygoid fossa
Cartilage of external
auditory canal
Masseter m.
FACIAL NERVE
Mastoid process
CHAPTER 56
the superficial lobe of the parotid gland. Careful blunt dissection, with use of the bipolar cautery and facial nerve monitor, will maximize excellent surgical results with minimal
morbidity.64,67
SUBMANDIBULAR GLAND
For submandibular gland resection, a horizontal skin incision
is made in a natural skin crease approximately two fingerbreadths inferior to the body of the mandible. The dissection
plane is carried to the investing fascia of the submandibular
gland. Exposure should reveal the mylohyoid muscle anteriorly, the sternocleidomastoid muscle posteriorly, and the
digastric muscle inferiorly. Identification and division of
the anterior facial vein, just deep to this fascia, will facilitate
protection of the facial nerve. Anterior retraction of the
mylohyoid muscle and downward retraction on the submandibular gland will enable identification of the lingual nerve
and Wharton duct. Division of the duct will free the lingual
nerve from the gland and allow complete blunt dissection
of the gland.66
SALIVARY GLANDS
735
Conclusion
------------------------------------------------------------------------------------------------------------------------------------------------
Anatomy
------------------------------------------------------------------------------------------------------------------------------------------------
The regional lymph node groups of the head and neck are
shown in Figure 57-1. The precise borders for these groups
have been classified by the American Head and Neck Society
and are shown in Figure 57-2.4 Drainage to lymphatic basins
usually follows predictable, anatomic routes, with the nomenclature reflecting the site of the lymph nodes. The face and
oropharynx drain predominantly to the preauricular, submandibular, and submental nodes; the posterior scalp drains to the
occipital nodal group; and the mouth, tongue, tonsils, oropharynx, and nasopharynx drain to superficial and deep
chains of the anterior cervical nodes. Significant lymphatic
collateralization exists.
Differential Diagnosis
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 57
Lymph Node
Disorders
Faisal G. Qureshi and Kurt D. Newman
MALIGNANCY
Malignancy accounts for 11% to 24% of the diagnoses,
depending on the nature of the group reporting their result.
The higher rates are reported in series from oncology practices.5,6 Malignant processes are more common in the age
group of 2 to 12 years old and very rare in the age group of
less than 2 years old. Malignancy as a cause is also more common in children with chronic generalized lymphadenopathy,
nodes greater than 3 cm in diameter, and nodes in the supraclavicular region. Associated symptoms of night sweats,
weight loss, and hepatosplenomegaly also increase the chance
of malignancy. Finally abnormal laboratory and radiologic
evaluation are associated with increased malignancy rates.7
Soldes and colleagues reviewed predictors of malignancy in
children with peripheral lymphadenopathy and determined
that increasing node size, increasing number of sites of adenopathy, and age were associated with an increasing risk of
malignancy (P < 0.05).8 In addition, supraclavicular adenopathy, an abnormal chest radiograph, and fixed nodes were
all significantly associated with malignancy.
The most common malignancies as a cause of lymphadenopathy are Hodgkin and non-Hodgkin lymphomas, leukemia, and metastatic disease.
Evaluation
------------------------------------------------------------------------------------------------------------------------------------------------
A careful history, physical examination, appropriate laboratory evaluation, and targeted imaging will usually help in deciding the need for tissue sampling. Persistent or progressive
new-onset lymphadenopathy of greater than 4 to 6 weeks duration usually triggers a workup by the referring pediatrician.
Indeed, most children with acute lymphadenopathy are rarely
ever evaluated by pediatric surgeons. Most will improve with
antibiotic therapy initiated by their pediatrician or the lymphadenopathy will resolve spontaneously when related to viral
illnesses.
737
738
PART V
Retroauricular
II
Occipital
III
Parotid
VI
Submandibular
Superficial cervical
Supraclavicular
IV
Submental
Jugulodigastric
Deep cervical
FIGURE 57-1 Regional lymph node groups of the head and neck.
FIGURE 57-2 Lymphatic node levels of the neck. Level I: submental and
submandibular; level II: superior jugular; level III: middle jugular; level IV:
inferior jugular; level V: supraclavicular or posterior; and level VI: central
or anterior.
TABLE 57-1
Differential Diagnosis of Lymphadenopathy in Children
Generalized lymphadenopathy:
infectious
Generalized lymphadenopathy:
malignant
Generalized lymphadenopathy:
others
Localized lymphadenopathy:
infectious
Localized lymphadenopathy:
malignant
Localized lymphadenopathy:
site specific
CGD, chronic granulomatous disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; JRA, juvenile rheumatoid arthritis;
LCH, Langerhans cell histiocytosis; LGV, lymphogranuloma venereum; SLE: systemic lupus erythematosus; URI, upper respiratory infection.
CHAPTER 57
INVESTIGATION
Laboratory Studies
Most patients have had a laboratory evaluation prior to referral
to surgery. These tests usually include a complete blood
count (CBC) with manual differential, sedimentation rate,
and C-reactive protein. However, these are not always helpful
in determining the specific etiology of the disease process. Pancytopenia can be seen in leukemia; lymphocytosis is seen with
mononucleosis, cytomegalovirus (CMV), and toxoplasmosis.
Based on the history and physical examination, more specific tests for Epstein-Barr virus (EBV), CMV, toxoplasmosis,
brucellosis, histoplasmosis, syphilis, bartonellosis, and coccidioidomycosis should be considered. Tests for human immunodeficiency virus (HIV) should also be considered,
based on the history as well as the tuberculin skin test.
Serum lactate dehydrogenase should be assayed when
suspecting leukemia or lymphoma as a byproduct of high cell
turnover.
Radiologic Evaluation
Diagnostic imaging can be used to determine the characteristic
of the lymphadenopathy, identify potential sources of infection, identify mediastinal and abdominal masses, and to help
differentiate enlarged lymph nodes from other pathology.
Chest radiographs, ultrasonography with Doppler, and computer tomography have all been used in the evaluation of
adenopathy.
In children with long-term lymphadenopathy, a two-view
chest radiograph is helpful to rule out mediastinal masses that
may compress the airway with or without significant symptoms. A chest radiograph should be performed prior to any
operative intervention, including biopsies done under general
739
anesthesia. Patients with large mediastinal masses compressing the airway should not undergo general anesthesia,
because this could result in airway collapse (see Chapter 38).9
Ultrasonography (US) is helpful when the nodes are difficult to palpate and to help differentiate nodes from other
structures, such as thyroglossal duct cysts and dermoid cysts
in the neck, and undescended testis and inguinal hernias in
the groin, US may also be helpful in determining the characteristics of the node. Fluctuance and abscess formation will
help guide therapies such as needle aspiration or incision
and drainage.
Attempts have been made to use ultrasonography and
Doppler characteristics to differentiate neoplastic from nonneoplastic etiologies. Reactive lymphadenopathy is associated
with central necrosis, central hyperechogenicity, long to
shortaxis ratio (>2.0), hilar vascularity, and low pulsatility
index.1014 However, these modalities are not sensitive or
specific enough to primarily rule out neoplastic processes.
The decision to delay biopsy diagnosis should not be dependent on US/Doppler findings.
Computed tomography (CT) is useful in patients with mediastinal masses and suspected intra-abdominal malignancies.
Airway compromise may be best evaluated by chest CT. Interventional radiologists sometimes use CT scans to help guide
biopsies from mediastinal masses.
Diagnostic Procedures
The decision to proceed with obtaining tissue from the involved lymph node is made in conjunction with the referring
physician and after appropriate physical, laboratory, and radiologic evaluation as required. Often, the child has been observed for several weeks prior to referral to a surgeon. Small,
soft, mobile nodes should not undergo biopsy, because these
are most likely benign unless they are in the supraclavicular
region. Tissue diagnosis is helpful when lymph nodes persist
or enlarge after adequate antibiotic therapy, when they are associated with signs or symptoms of malignancy, and, finally, if
the diagnosis is questioned.
Most authors recommend waiting at least 4 to 6 weeks before obtaining tissue samples. Earlier biopsy should be considered for nodes in the supraclavicular or epitrochlear region,
nodes greater than 3 cm in diameter, and for children with
a history of malignancy, weight loss, night sweats, fever, or
hepatosplenomegaly. Similarly, physical characteristics of the
lymph node may also indicate earlier biopsy.15,16
Fine-Needle Aspiration Fine-needle aspiration (FNA) has
been used extensively in adults, with practical advantages, including its simplicity, speed in the outpatient setting without
sedation, as well as its cost effectiveness. In addition, the sensitivity and specificity reaches more than 90%.
The use of FNA in children has increased, especially in
countries where tuberculosis is prevalent.1720 Aspirates
should be sent for Gram stain, acid-fast stain, and cultures
for aerobic/anaerobic bacteria, mycobacteria, and fungi.
However, the use of FNA in children has not become universal, because the aspirate usually provides a small sample,
which limits the ability to perform flow cytometry, chromosomal analysis, and electron microscopy. Most pediatric hematologists and pathologists prefer excisional biopsy, because
it allows the assessment of nodal architecture and permits
740
PART V
Excisional Biopsy Excisional biopsy provides enough tissue to perform flow cytometry, chromosomal analysis, electron microscopy, and the use of special stains. Indications
for an excisional biopsy include
1. Lymph nodes that are hard/matted
2. Lymph nodes fixed to surrounding tissue
3. Progressively enlarging nodes without response to antibiotic therapy
4. Presence of abnormally enlarged nodes after 4 to 6 weeks
5. Supraclavicular, epitrochlear lymph nodes
6. Hepatosplenomegaly
7. Mediastinal or hilar masses
8. Laboratory anomalies, especially anemia, leukocytosis,
leucopenia, and thrombocytopenia
9. Symptoms such as fever, weight loss, and night sweats
10. Suspicion of atypical mycobacterial adenitis
11. Diagnostic dilemma
Most excisional biopsies are done under general anesthesia
or sedation and, very rarely, under local anesthesia. The biopsy
should be coordinated with pathology so that the lymph node
can be sent as a fresh specimen. The nodes should not be fixed
in formalin. As discussed earlier, a chest radiograph should be
obtained to rule out a mediastinal mass that may compromise
the airway prior to exposing children to general anesthesia or
sedation.
In a recent review, Oguz et al. reviewed their experience
with 457 children (2 months to 19 years old) with lymphadenopathy who were referred to their oncology group; 346
(75.7%) had benign processes, and 111 (24.3%) had malignant disease. Of these, 134 patients underwent excisional
biopsy for indications highlighted previously. Table 57-2
highlights the findings on excisional biopsy and compares
them to findings by other authors.7
------------------------------------------------------------------------------------------------------------------------------------------------
TABLE 57-2
Excisional Biopsy Results
Oguz
et al,
20067
(n = 134)
Moore
et al,
20035
(n = 1332)
Yaris
et al,
200621a
(n = 38)
79.8%
40.2%
29.1%
11.8%
6%
2.1%
50%
3.7%
2.2%
4.2%
20.1%
5.9%
5.9%
2.9%
2.2%
3.2%
3.9%
88.2%
11.3%
47.8%
25%
4.1%
50%
25%
15.7%
Management of Adenopathy
Darville and colleagues have suggested a helpful algorithm for
the management of cervical lymphadenopathy (Fig. 57-3).22
This algorithm is a useful tool to help surgeons determine their
role in the management of enlarged lymph nodes. As suggested elsewhere in this chapter, most of the medical evaluation and management has usually been performed by the
referring physician; however, it is the surgeons responsibility
to review each case prior to intervention.
SURGICAL MANAGEMENT
Surgical management is usually limited to diagnostic FNA,
excisional biopsy, incision and drainage, and total excision.
Further details are provided under the specific conditions discussed later.
ACUTE LYMPHADENITIS
The most common cause of self-limiting, acute, inflammatory
lymph node is a viral infection.23 Acute bilateral cervical adenopathy is most often caused by a viral respiratory tract infection
(rhinovirus, parainfluenza virus, influenza virus, respiratory
syncytial virus, coronavirus, adenovirus, reovirus) and is usually hyperplastic in nature.24 Viral-associated adenopathy does
not suppurate and usually resolves spontaneously.
Unilateral lymphadenitis is usually caused by streptococcal
or staphylococcal infection in 40% to 80% of the cases.25
These are usually large (>2 cm), solitary, and tender in the
preschool child.26 The submandibular, upper cervical, submental, occipital, and lower cervical nodes are affected in
decreasing order of frequency.27 Suppurative adenitis is
associated with group A streptococcal or penicillin-resistant
staphylococci. Staphylococcus infection leading to lymphadenitis seems to occur more commonly in infants.28 Other less
frequent causal organisms include Hemophilus influenzae type
B, group B streptococci, and anaerobic bacteria. Communityacquired methicillin-resistant Staphylococcus aureus (MRSA) is
now more commonly being isolated from superficial abscesses
and suppurative lymphadenitis in children. Clindamycin is an
appropriate agent to use under these circumstances.25,29
Suppurative lymphadenitis presents with local inflammatory
signs, including unilateral tender adenopathy involving the
submandibular or deep cervical nodes draining the oropharynx. Erythema, fever, malaise, and signs of systemic illness
may occur. The primary infection in the head and neck regions
should be looked for with careful attention to the oropharynx
and middle ear. Appropriate treatment should be started, usually an empirical 5- to 10-day course of an oral b-lactamase
resistant antibiotic. Intravenous antibiotics should be started
if systemic signs are present or in very young infants. A response
should be observable within 72 hours, and failure of therapy
usually necessitates additional diagnostic testing. This is usually
fine-needle aspiration or ultrasonography.
CHAPTER 57
741
Cervical lymphadenitis
Asymptomatic
Symptomatic
Small node (<3 cm)
Nonfluctuant
Fluctuant
Culture possible
primary focus
Culture possible
primary focus;
Needle aspirate
with stains and
cultures
Culture possible
primary focus;
Needle aspirate with
stains and cultures;
Blood culture;
Draw acute serum
Observe
Node size
persists or enlarges
within 46 weeks
Diagnosis in doubt;
Node persists, enlarges,
is fixed to underlying
tissues, or is hard
Therapeutic needle
aspiration/incision
and drainage of
abscess
Excisional biopsy
FIGURE 57-3 Evaluation and treatment algorithm. ASO, antistreptolysin titer; CBC, complete blood count; CMV, cytomegalovirus; CXR, chest radiograph;
EBV, Epstein-Barr virus; ESR, erythrocyte sedimentation rate; PPD, purified protein derivative; VDRL, Venereal Disease Research Laboratory. (Reprinted with
permission from Elsevier.22)
Aspirate culture by FNA can guide further organismspecific antibiotic treatment, including clindamycin if MRSA
is encountered. If no fluid is aspirated, sterile saline can be
injected and then aspirated to obtain material for culture.26
In addition, repeated aspiration together with antibiotics is
an effective treatment for fluctuant lymphadenitis.30 As stated
previously, however, FNA may require sedation or anesthesia
in young children.
Ultrasonography may help to differentiate between solid
and cystic masses and can identify fluid that may require operative drainage. Incision and drainage is a more definitive
surgical approach to suppurative fluctuant lymphadenitis.
Gauze packing has been used to prevent early skin closure
and achieve hemostasis; however, the use of minimal incisions, with vessel loops functioning as drains, has been gaining wider acceptance recently.31
PERSISTENT LYMPHADENITIS
Persistent lymphadenitis that does not resolve despite 2 to
4 weeks of appropriate therapy warrants additional diagnostic
workup. Some common causes of persistent lymphadenitis
are discussed in this section.
Atypical Mycobacterial Adenitis
The genus Mycobacterium is characterized on light microscopy
to be bacilli distinguished by their dense lipid capsules. The
lipid capsules resist decolorization by acid alcohol after
staining and thus are termed acid-fast bacilli. In the United
States, 70% to 95% of mycobacterial lymphadenitis cases
are caused by atypical mycobacteria (nontuberculous strains).
742
PART V
CAT-SCRATCH DISEASE
Cat-scratch disease is a common cause of lymphadenitis in
children, with an estimated incidence in the United States
of 9.3 per 100,000 ambulatory pediatric and adult patients
per year.48 The highest age-specific incidence is among children younger than 10 years of age.2 Current microbiologic
and PCR-directed DNA analysis demonstrates that the pleomorphic, gram-negative bacillus Bartonella henselae (formerly
Rochalimaea) is the causative organism of cat-scratch disease.49
Most cases can be directly related to contact with a cat, and the
usual site of inoculation is an extremity. Subsequent adenitis
occurs at regional lymphatic drainage basins (inguinal, axillary, epitrochlear nodes) 5 days to 2 months later.50 Similarly,
cervical lymphadenopathy is observed with scratches in the
head and neck region. Although the primary manifestation
of Bartonella henselae infection is lymphadenopathy, some
series report up to 25% of cases resulting in severe systemic
illnesses.51
Initial infection occurs at the portal of entry in the skin,
such as a scratch or bite. Papule formation may be observed
at the site of inoculation in 3 to 5 days, with development
of subacute lymphadenopathy at regional nodal drainage beginning within 1 to 2 weeks. Early systemic symptoms of fever,
malaise, myalgia, and anorexia are commonly reported.
Although most cases involve the lymph nodes of limbs,
approximately 25% of cases involve the cervical nodes.50
Diagnosis is based on a history of exposure to cats, presence
at a site of inoculation, and regional lymphadenopathy.
Identification of Bartonella henselae from involved lymph
nodes using Warthin-Starry silver impregnation stain has
CHAPTER 57
traditionally been used for diagnosis, but the stain has been
found to be unreliable and lacking specificity. PCR for Bartonella henselae using paraffin sections from lymph nodes or
other tissue is more reliable and specific.52 To confirm diagnosis without obtaining tissue, many centers use serologic testing, which has been available for several years; it has a low
sensitivity but is highly specific.53
Lymphadenitis associated with cat-scratch disease is usually benign, self-limiting, and resolves within 6 to 8 weeks
without specific treatment.54 Antibiotic treatment has thus
been controversial, although azithromycin has been associated with rapid resolution of the adenitis.55 Suppuration is
unusual; however, if it occurs, needle aspiration may provide
symptomatic relief. Excisional biopsy is generally unnecessary
but may be warranted if a draining sinus tract develops or if
the diagnosis is uncertain and the potential for malignancy
cannot be excluded.
MISCELLANEOUS LESIONS
Various other infectious and inflammatory conditions can produce lymphadenopathy in infants and children. Most patients
with these disorders do not require surgical management or,
in particular, excisional biopsy of the lesions. A systematic approach to evaluation of these patients, as outlined previously,
generally leads to the correct diagnosis. Surgical management
of these lesions should be directed to patients who present diagnostic dilemmas and have nodal disease in suspicious areas,
or have persistent adenopathy despite adequate medical therapy.
Infectious lymphadenopathy
Lymphadenopathy caused by infectious agents include toxoplasmosis (caused by Toxoplasma gondii), tularemia (caused by
Francisella tularensis), and mononucleosis (caused by EpsteinBarr virus). Infection with Actinomyces israelii in the head and
neck may lead to cervicofacial actinomycosis that is characterized by a woody indurated cervical mass and development of
chronic, draining fistulas. Direct involvement of the lymph
nodes is uncommon, but the induration can make the clinical
differentiation difficult.56 Infection with HIV can produce
general lymphadenopathy in infants and children.57
743
MALIGNANT DISORDERS
Although lymphoma is the most common malignant disorder
manifested by cervical adenopathy, neuroblastoma and thyroid carcinoma are other childhood cancers that can present
as enlarged cervical lymph nodes.
Lymphomas are one of the more common malignant conditions in children. They may present as primary neck adenopathy that does not resolve with antibiotics or is enlarging.
Patients with congenital or acquired immunodeficiency states,
including HIV infection, are at greater risk for developing
malignant lymphoproliferative conditions. Excisional biopsy
is often used to help diagnose lymphomas.
In neuroblastoma, adenopathy is usually bilateral. These
patients often have stage 4 disease, and if the primary is not
evident on examination and radiologic evaluation, excisional
biopsy is performed for initial diagnosis of neuroblastoma.
Metastatic thyroid carcinoma may present with unilateral
cervical lymph node enlargement that should not be mistaken for ectopic thyroid gland. If a thorough neck examination does not reveal a thyroid nodule, and a history of
neck irradiation or other high-risk factors is obtained, thyroid ultrasonography should be performed as part of the
evaluation of neck lymphadenopathy.
Inflammatory disorders
Inflammatory disorders include Kawasaki disease, Kikuchi
disease, Castleman disease, and Rosai-Dorfman disease.
Kawasaki disease, or mucocutaneous lymph node syndrome,
is a febrile disorder of childhood that is characterized in part
by the abrupt onset of erythematous changes in the oropharyngeal mucosa, acute vasculitis, and extensive nonsuppurative,
nontender cervical adenopathy.58 Diagnosis is made on clinical
grounds, and the resolution of the nodal disease occurs
relatively quickly in the course of the disease.
Kikuchi disease, or histiocytic necrotizing lymphadenitis,
may present as cervical lymphadenopathy that resolves spontaneously. It typically presents in the older child with bilateral,
painful cervical nodes. There are associated fevers, night
sweats, splenomegaly, leucopenia with atypical lymphocytosis, and elevated erythrocyte sedimentation rate (ESR). This
disease can be clinically confused with malignant disease,
and the patients often appropriately undergo excisional biopsy for definitive diagnosis.59
Summary
------------------------------------------------------------------------------------------------------------------------------------------------
Most adenopathy in children is nonpathologic and spontaneously resolves. Pathologic lymphadenopathy has a large differential diagnosis, with viral lymphadenitis being the most
common. Surgical consultation is often obtained when the
lymph nodes do not spontaneously resolve, if there is concern
for malignancy, or if there is a diagnostic dilemma. Most of the
investigation is usually performed prior to surgical consult,
but the surgeon must be aware of an adequate workup prior
to intervention. The surgeons role is usually limited to excisional biopsy, incision and drainage, and, rarely, aspiration
in children, depending on the pathology suspected. FNA
for diagnosis has a more limited role in children but may be
useful in selected cases.
The complete reference list is available online at www.
expertconsult.com.
CHAPTER 58
Childhood Diseases
of the Thyroid and
Parathyroid Glands
Hannah G. Piper and Michael A. Skinner
Thyroid Embryology
and Physiology
------------------------------------------------------------------------------------------------------------------------------------------------
Proper evaluation of a child with potential thyroid disease begins with a focused history inquiring about symptoms of hyperthyroidism or hypothyroidism as well as any family history
of thyroid disease or multiple endocrine neoplasia. This is followed by a detailed examination of the neck. The thyroid
should be palpated to evaluate size, consistency, symmetry,
and whether there are any nodules or associated enlarged
745
746
PART V
Lingual thyroid
Accessory
thyroid tissue
Hyoid bone
Pyramidal lobe
of thyroid gland
Normal position
of thyroid gland
FIGURE 58-1 Usual sites of ectopic thyroid tissue. The broken line demonstrates the path of normal thyroid descent. (Reprinted from The Pharyngeal (Branchial) Apparatus: In Moore K, Persaud TVN: The Developing
Human: Clinically Oriented Embryology, ed 6. Philadelphia, WB Saunders,
1998, p 233; with permission from WB Saunders.)
Non-neoplastic Thyroid
Conditions
------------------------------------------------------------------------------------------------------------------------------------------------
GOITER
A goiter is an enlargement of the thyroid gland that can be diffuse or nodular in nature, and patients can be euthyroid, hypothyroid, or hyperthyroid. The most common cause
worldwide is iodine deficiency, resulting in hypertrophy secondary to substrate deficiency. However, in locations with
FIGURE 58-2 SPECT/CT for nodal localization: cervical nodal metastasis in a 12-year-old girl. A, Planar image shows a single focus in the right upper neck
(arrowhead) and two foci of activity in the central neck. B and C, Computed tomography (CT) and fused single-photon emission computed tomography
(SPECT)/CT localizes the right upper neck focus to an enlarged lymph node (arrow). (Reprinted from Wong KK, Zarzhevsky N, Cahill JM, et al: Hybrid
SPECT-CT and PET-CT imaging of differentiated thyroid cancer. Br J Radiol 2009;82:860-876, 2009; with permission from the British Journal of Radiology.)
CHAPTER 58
THYROIDITIS
Inflammation of the thyroid gland can have several different
etiologies, including autoimmune, viral, bacterial, or an infiltrative fibrous process. The most common type of thyroiditis
in children is chronic lymphocytic or Hashimoto thyroiditis.
Hashimoto thyroiditis is an autoimmune process in which antibodies against thyroid antigen are produced, resulting in a
lymphocytic infiltrate within the gland. It often occurs in association with other autoimmune disorders, such as type I diabetes, Addison disease, systemic lupus and juvenile arthritis,
as well as in children with Down and Turner syndromes. Initially, patients may be euthyroid or hyperthyroid, but this can
be transient, and eventually hypothyroidism may ensue. Usually, the management is expectant with about 30% of patients,
demonstrating resolution over time. Exogenous thyroid hormone should be provided to patients who are hypothyroid
but does not seem to have any meaningful effect on reducing
the size of the goiter or decreasing progression of disease in
euthyroid patients.9
Other forms of thyroiditis, although rare, can also be seen
in children, as listed in Table 58-1. Subacute thyroiditis is
thought to be viral in nature, and patients often present with
fever and gland tenderness in the setting of a recent upper respiratory infection. Initially, there may be excessive hormone
release, followed by transient hypothyroidism. About 10%
of patients develop permanent hypothyroidism. In most cases,
nonsteroidal anti-inflammatory medication or low-dose corticosteroids is the only treatment required. Acute suppurative
thyroiditis is bacterial in origin, can present with hard nodules,
and be diagnosed on ultrasonography or with fine-needle aspiration (FNA). Treatment is with antibiotics, drainage if necessary, and, very rarely, thyroid lobectomy. Many cases
formerly called acute suppurative thyroiditis are the result of
a third or fourth branchial pouch remnant, also called pyriform sinus fistula. This should be suspected, especially when
the infection presents in the left superior pole (see
Chapter 59). Ideally, treatment is with antibiotics, followed
by excision of the fistula tract to the pyriform sinus.10
747
HYPOTHYROIDISM
The primary cause of congenital hypothyroidism is abnormal
thyroid gland development rather than from a problem with
the hypothalamic-pituitary-thyroid axis. Most commonly, it
is secondary to either thyroid dysgenesis or agenesis and, less
commonly, from defects in thyroid hormone synthesis or from
the transfer of maternal thyroid blocking antibodies. Dietary
iodine deficiency in utero can also lead to hypothyroidism,
and in those cases, a palpable goiter may be appreciated. T4
is essential for myelinization of the central nervous system
during the first 3 years of life. Deficiencies in T4 can lead to
intellectual disability, which is completely preventable if recognized.11 Newborn screening for hypothyroidism is essential
and involves measuring TSH. Some states also require measuring T4, which will allow for rare cases of central hypothyroidism to be detected. However, if these tests are normal but
symptoms persist, it is important to maintain a high index
of suspicion, because up to 50% of cases of central hypothyroidism will have a normal newborn screen.12 In older children with acquired hypothyroidism, presenting signs and
symptoms include a decline in linear growth, fatigue, constipation, and poor school performance. Preteens or teenagers
may complain of dry skin, thin hair, weight gain, and menstrual irregularities. The most common causes of pediatric
hypothyroidism can be seen in Table 58-2.
HYPERTHYROIDISM
Graves disease, or diffuse toxic goiter, is the most common
cause of hyperthyroidism in children, with an incidence of
0.02%,13 and it is approximately 5 times more common in
girls than in boys. Thyroid gland hypertrophy occurs because
antibodies against the TSH receptor bind and mimic the effect
of TSH. Patients usually present with a firm, smooth goiter and
symptoms of hyperthyroidism. Occasionally, there can be fibroblast deposition in the eyes, leading to exophthalmos, or
in the skin, leading to pretibial myxedema, although these
findings are less common in children. Severe hyperthyroidism
is sometimes seen with associated hyperthermia and tachycardia, referred to as thyroid storm, and initial treatment includes
active cooling and propanolol.
Usually, first-line therapy for Graves disease is antithyroid
medication (methimazole or propylthiouracil), and improvement in symptoms can occur within 1 month of treatment.
Treatment is maintained for 12 to 18 months, during which
time thyroid function is monitored routinely.14 Remission is
achieved in 30% of children after the first course of medication, and risk factors for relapse include young age and severe
TABLE 58-1
Types of Thyroiditis
Histopathology
Eponym
Etiology
Goiter
TSH
T4
Thyroid Function
Chronic lymphocytic
Subacute granulomatous
Subacute lymphocytic
Acute suppurative
Invasive fibrous
Hashimoto
De Quervain
Silent
Bacterial
Reidel
Autoimmune
Viral (mumps, Coxsackie virus, EBV)
Autoimmune
Bacterial, fungal, parasitic
Unknown
Yes
Variable
Yes
Variable
No
Variable
Low
Low
Normal
Normal or low
Variable
High
High
Normal
Normal or low
Hyper or hypo
Hyper then hypo
Hyper then hypo
Variable
Hypothyroid
748
PART V
TABLE 58-2
Pediatric Causes of Hypothyroidism
No
Goiter
Newborn to
childhood
Adolescence
Goiter
Newborn
Childhood to
adolescence
Gland dysgenesis
Deficiency of the hypothalamic/
pituitary axis
Postsurgical
Inborn error in hormone synthesis
Maternal ingestion (propylthiouracil,
methimazole, iodides)
Severe endemic iodine deficiency
Ingestion of goiter-inducing drugs
Inborn error in hormone synthesis
Hashimoto thyroiditis
Infiltrative disease (lymphoma)
biochemical hyperthyroidism at the time of diagnosis.15,16 Because of the relatively low remission rate, some advocate the
use of radioactive iodine (I131). The radioactive iodine is
ingested and then incorporated into the thyroid. The radiation
to thyroid cells leads to gland ablation over the following 6 to
18 weeks. However, this is not recommended for children less
than 5 years of age, and most patients will be made hypothyroid after treatment requiring hormone replacement therapy.
Surgery is also an option for some children with Graves
disease, usually for those who have very large goiters, are unable to take antithyroid medication, or cannot tolerate radioactive iodine. Surgery is also the treatment of choice if there is
any concern of underlying malignancy in the gland. The preferred operation continues to be debated. In a large metaanalysis looking at more than 7000 adult patients, there were
no cases of recurrent disease after total thyroidectomy versus
an 8% recurrence rate after subtotal thyroidectomy. The incidence of other complications, including injury to the recurrent laryngeal nerve or hypoparathyroidism, did not differ
between the two groups.17
WELL-DIFFERENTIATED THYROID
CARCINOMA
Well-differentiated thyroid cancer (WDTC) includes papillary
and follicular cell tumors, accounting for approximately 1%
of malignancies in prepubertal children and up to 7% in
TABLE 58-3
Sensitivity and Specificity of FNA in Children and Adolescents
Study
Type of Study
Retrospective
Retrospective
Prospective
Retrospective
Retrospective
Retrospective
2-21
10-21
Children
9-20
1-18
<17
No. of Patients
37
31
44
57
63
41
Minimum Follow-up
23
24
24
24
24
24
months
months
months
months
months
months
Sensitivity
100%
100%
100%
92.9%
88.9%
90%
Specificity
85.7%
64.7%
95%
81.4%
92.6%
96.8%
Data from Stevens C, Lee JK, Sadatsafavi M, Blair GK: Pediatric thyroid fine-needle aspiration cytology: A meta-analysis. J Pediatr Surg 2009;44:2184-2191; with
permission from Elsevier.
CHAPTER 58
749
750
PART V
TABLE 58-4
ATA Risk Category Guidelines for Prophylactic Thyroidectomy and Screening for Medullary Thyroid Cancer
ATA Risk Level
Age at First US
D
C
B
A
*Criteria for delay must be met: normal basal and stimulated calcitonin, normal annual neck US, less aggressive MTC family history.
ATA, American Thyroid Association; MTC, medullary thyroid cancer; RET, rearranged during transfection (proto-oncogene); US, ultrasonography.
Adapted from Kloos RT, Eng C, Evans DB, et al: Medullary thyroid cancer: Management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612;
with permission from Mary Ann Liebert, Inc.
Parathyroid Embryology
and Physiology
------------------------------------------------------------------------------------------------------------------------------------------------
The parathyroid glands arise from the third and fourth pharyngeal pouches, which are paired endoderm-lined structures
between the branchial arches. By the sixth week of gestation,
the dorsal aspects of the third and fourth pouches differentiate
into the inferior and superior parathyroids, respectively. The
ventral aspects of the third pouches form the thymus and
the ventral aspects of the fourth pouches develop into the ultimobranchial body, which eventually fuses with the thyroid to
supply the parafollicular cells that produce calcitonin. The
thymus and parathyroid glands then lose their connection
to the pharynx and descend into the neck. Typically the parathyroid glands migrate to the posterior aspect of the thyroid
gland, where they obtain their blood supply from the thyroid
capsule. However, there is significant variability in the
eventual location of the parathyroid glands, as seen in
Figure 58-3. They are variable in both location and number
and can be found anywhere in the vicinity of the thyroid or
thymus. The superior glands tend to be more consistent in
their location than the inferior glands.
CHAPTER 58
1.2%
14.8%
1.2%
82.7%
Normal position
n = 67 glands
Thymus
n = 12 glands
Carotid sheath
n = 1 gland
Paraesophageal
n = 1 gland
DiGEORGE SYNDROME
DiGeorge syndrome is a congenital disorder characterized by
athymia or thymic hypoplasia and absence of the parathyroid
glands due to failure of the third and fourth pharyngeal
pouches to differentiate. Infants are hypocalcemic and also
have increased susceptibility to infection. Additional associated characteristics can include shortened philtrum, low set
ears, nasal clefts, thyroid hypoplasia, and cardiac anomalies,
especially truncus arteriosum. Treatment is largely symptomatic and includes supplementation with calcium and vitamin
D. Emerging therapies include replacement with synthetic
PTH66 and thymus transplantation for children with severe
immunodeficiency.67
HYPERPARATHYROIDISM
There are several forms of hyperparathyroidism, all of which
lead to excessive PTH secretion. In the case of primary hyperparathyroidism, this results from one or more abnormal
751
parathyroid glands. In secondary hyperparathyroidism, elevated PTH is in response to hypocalcemia, and in tertiary hyperparathyroidism, PTH remains elevated despite correction
of the hypocalcemia. Both secondary and tertiary types are
seen in the setting of renal disease. Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder that presents with
severe hypercalcemia resulting from a homozygous loss-offunction mutation with four-gland hyperplasia. Treatment
has traditionally been with a three and one halfgland parathyroidectomy or total parathyroidectomy with autotransplantation. More recently, there has also been some success
with medical management with bisphosphonates.68
In general, hyperparathyroidism presents clinically with
symptoms related to elevated calcium or is suspected when
hypercalcemia is found incidentally. However, the differential
diagnosis of hypercalcemia in children is quite broad, and this
must be kept in mind during the initial evaluation, as outlined
in Table 58-5. For example, familial hypocalciuric hypercalcemia is an autosomal dominant condition resulting from a mutation in the calcium sensing receptor. Children have elevated
serum calcium but can be distinguished from having hyperparathyroidism by detecting decreased 24-hour urinary calcium levels. PTH levels are often within the normal range.
Usually these children are completely asymptomatic, and no
specific treatment is required. This condition should be
excluded prior to considering parathyroid resection for
hypercalcemia.
The incidence of primary hyperparathyroidism in children
is estimated to be 2 to 5 per 100,000.69 In contrast to adults,
children may present with more serious effects of hypercalcemia, including renal failure, cardiac arrhythmias, and osteopenia.2 When suspected, the diagnosis can be confirmed by
measuring serum calcium and PTH. Most commonly, there
will be a solitary parathyroid adenoma, and there are several
localization studies that can be used to identify the abnormal gland. The imaging options include ultrasonography,
TABLE 58-5
Causes of Hypercalcemia in Children
Endocrine
Primary hyperparathyroidism
Secondary hyperparathyroidism
Tertiary hyperparathyroidism
Thyrotoxicosis
Familial hypocalciuric hypercalcemia
Neonatal severe hyperparathyroidism
Ectopic parathyroid hormone production
Granulomatous disease
Sarcoidosis
Tuberculosis
Fungal infection
Pharmacologic
Vitamin D
Vitamin A
Thiazide diuretics
Theophylline
Milk alkali
Lithium
Immobilization
Subcutaneous fat necrosis
752
PART V
INTRAOPERATIVE PTH
800
700
600
500
400
Parathyroid
hormone
300
200
100
0
0
10
Time (minutes)
FIGURE 58-4 A, Parathyroid adenoma in the setting of hypercalcemia. The small arrow demonstrates the parathyroid adenoma, and the large arrow
demonstrates the retracted thyroid gland. B, Intraoperative PTH monitoring for the patient seen in A demonstrating the fall in PTH over 10 minutes after
removal of the parathyroid gland.
99m
Parathyroid Carcinoma
------------------------------------------------------------------------------------------------------------------------------------------------
lesions to minimize the risks of recurrence, infection, or malignancy. Knowledge of the relevant local anatomy and
adjacent structures is crucial to safe surgical dissection.
Embryology
------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 59
754
PART V
ARCH
Tuberculum impar
Branchial arch
Mandibular n.
Facial n.
Glossopharyngeal n.
Superior laryngeal
branch of vagus
Branchial cleft
FIGURE 59-1 Early development
of branchial apparatus. (From
Donegan JO: Congenital neck masses. In Cummings CW, Fredrickson
JM, Harker LA, et al [eds]:
OtolaryngologyHead and Neck
Surgery, ed 2. St Louis, Mosby-Year
Book, 1993.)
Branchial pouch
Foramen cecum
Branchial nerve
Arch 5 disappears
Branchial artery
6
Branchial cartilage
Recurrent laryngeal
branch of vagus
TABLE 59-1
Derivatives of Branchial Arches, Clefts, and Pouches
I
Arch
External maxillary artery
Nerve V
Cleft
Pouch
II
Arch
Stapedial artery
Dorsal
Ventral
Incus body
Malleus head
Pinna
External auditory canal
Eustachian tube
Middle ear cavity
Mastoid air cells
Meckel cartilage
Malleus
Body of tongue
Stapes
Styloid process
Hyoid (lesser horn and
part of body)
Root of tongue
Foramen cecum
Thyroid glands
median anlage
Palatine tonsil
Supratonsillar fossa
III
Arch
Internal carotid artery
Nerve IX
Pouch
IV
Arch
Arch of aorta (L)
Part of subclavian artery (R)
Nerve X
Pouch
V
Arch
Pouch
VI
Arch
Pulmonary artery
Ductus arteriosus (L)
Nerve X (recurrent laryngeal)
Thymus (inconstant)
From Skandalakis JE, Gray SW, Todd NW: The pharynx and its derivatives. In Skandalakis JE, Gray SW (eds): Embryology for Surgeons, ed 2. Baltimore, Williams &
Wilkins, 1994.
CHAPTER 59
755
Maxillary
process
Mandibular
process
Pharyngeal
pouches
Pharyngeal
clefts
1
I
External
auditory
meatus
1
II
Primitive
tympanic
cavity
Auditory
tube
II
Palatine
tonsil
Parathyroid
gland (inferior)
III
III
3
3
Thymus
IV
4
5
IV
Cervical
sinus
Ultimobranchial
body
Epicardial
ridge
Parathyroid gland
(superior)
Body of tongue
Auditory tube
Foramen cecum
Primitive
tympanic
cavity
Thyroglossal cyst
Ventral side of
pharynx
External
auditory
meatus
Epiglottis
Foramen
cecum
Hyoid bone
Palatine tonsil
Thyroglossal cysts
Thyroid cartilage
Thyroid
gland
Thyroid gland
Ultimobranchial body
Thymus
Cricoid cartilage
Foregut
Although the exact incidence varies between different pediatric series, thyroglossal duct remnants are typically the
more common etiology of congenital neck cysts or sinuses,
followed closely by branchial cleft remnants.35 In general,
thyroglossal duct lesions lie close to the midline, whereas
branchial remnants present more laterally in the neck,
although atypical locations have been described.6
FIGURE 59-4 Various locations of thyroglossal duct cysts. (From Sadler TW:
Head and neck. In Sadler TW (ed): Langmans Medical Embryology, ed 11.
Baltimore, Lippincott Williams & Wilkins, 2010.)
756
PART V
FIGURE 59-5 Sistrunk procedure: intraoperative photograph of resection of thyroglossal duct cyst in continuity with central hyoid bone (arrow).
SURGICAL MANAGEMENT
The primary indication for excision of thyroglossal duct remnants is to avoid problems with recurrent infection. However,
malignancy within thyroglossal duct remnants is also well described.11 Such tumors usually present as papillary carcinoma
in adults, but pediatric cases are reported, and multiple cell
types have been encountered.1214
Appropriate surgical management of uncomplicated thyroglossal duct disease involves complete resection of the cyst
and its tract in continuity with the central hyoid bone, as described by Sistrunk.15 One should be aware that in young children the hyoid bone may override the thyroid notch,
potentially placing the larynx at risk. The patient is positioned
supine with the head elevated and neck extended. A transverse
cervical incision is used to carefully mobilize the cyst along
with its tract. The underlying hyoid bone is divided about
1 cm from the midline on either side after dividing the attachments of the mylohyoid and hyoglossus muscles from its
superior border. En-bloc resection is completed with suture
ligation of the proximal tract, prior to removal of the specimen
(Fig. 59-5). Elegant studies of resected surgical specimens
by Horisawa and colleagues, as depicted in Figure 59-6, demonstrate the importance of this strategy to achieve complete excision, thereby reducing the likelihood of recurrence.16
In the setting of acute infection, initial efforts are aimed to
control the infection. If antibiotics alone are insufficient, aspiration or incision and drainage of the cyst/abscess may be required. Once the infection is well-controlled, the described
Sistrunk procedure can be performed using an elliptic skin
b
c
Hyoid bone
Hyoid bone
Cyst
Cyst
FIGURE 59-6 Diagram of the common running pattern of the thyroglossal duct based on anatomic reconstruction. a, Horizontal distance from
midline to the most distant thyroglossal duct; b, length of the single duct
above the hyoid bone; c, point where the diameter of the duct is measured. (From Horisawa M, Niinomi N, Ito T: What is the optimal depth
for core-out toward the foramen cecum in a thyroglossal duct cyst operation? J Pediatr Surg 1992;27:710-713.)
CHAPTER 59
757
Branchial Anomalies
------------------------------------------------------------------------------------------------------------------------------------------------
FIGURE 59-7 Child with bilateral second branchial cleft sinuses (arrows).
9
12
10
FIGURE 59-8 Second branchial cleft cyst and sinus tract. (From
Donegan JO: Congenital neck masses. In Cummings CW, Fredrickson JM,
Harker LA, et al [eds]: OtolaryngologyHead and Neck Surgery, ed 2. St
Louis, Mosby-Year Book, 1993.)
758
PART V
Type 1
Type 2
FIGURE 59-10 Type I and type II first branchial cleft abnormalities. (From
Donegan JO: Congenital neck masses. In Cummings CW, Fredrickson JM,
Harker LA, et al [eds]: OtolaryngologyHead and Neck Surgery, ed 2. St
Louis, Mosby-Year Book, 1993.)
in preauricular, infraauricular, or postauricular locations. Sinuses may present with external drainage below the angle of
the mandible or otorrhea, which may become infected. Cysts
present as soft tissue masses in this region which may also become secondarily infected. A communication with the external
auditory canal may be present. A careful otologic examination is
important to define the pathology.
Complete surgical excision is once again recommended,
but great care must be taken given the proximity of the facial
nerve. In infants and children, the nerve is probably even
more susceptible given that it is smaller and more superficial
without well-developed landmarks.32 Many authors recommend initial exposure of the main trunk of the facial nerve
and its peripheral branches with superficial parotidectomy
to reduce the risk of facial nerve injury.33,34 Prior infection
may distort accurate tissue dissection planes. It is necessary
to excise the involved skin and cartilage of the external auditory canal. Furthermore, if the tract extends medially to the
tympanic membrane a second operation may be required to
remove this segment.35,36
CHAPTER 59
12
759
12
12
10
10
FIGURE 59-11 Third branchial cleft cyst and sinus tract. Note that these occur much more frequently on the left side (approximately 90%); also, during
surgery the tract is often seen to go straight up from the left upper thyroid lobe
area toward the thyroid cartilage, without passing behind the carotid artery
as the embryologic development would suggest. (From Donegan JO: Congenital neck masses. In Cummings CW, Fredrickson JM, Harker LA, et al
[eds]: OtolaryngologyHead and Neck Surgery, ed 2. St Louis, Mosby-Year
Book, 1993.)
10
760
PART V
Once again, complete excision is necessary to avoid continued difficulties. Often several previous operations have
been performed before the correct pathology is recognized.41,42 Direct laryngoscopy or rigid pharyngoscopy, using
a Hopkins rod-lens telescope, is recommended for accurate
diagnosis as well as endoscopic cannulation of the opening into
the piriform sinus, if possible, to facilitate accurate dissection.37,43 A standard collar incision is used with identification
of the recurrent laryngeal nerve. Partial or total ipsilateral thyroid lobectomy with excision of the tract to the piriform sinus is
usually required. Partial resection of the thyroid cartilage may
also be necessary to remove the entire tract.44 Cauterization of
the internal opening has been described.45,46
Dermoid Cysts
------------------------------------------------------------------------------------------------------------------------------------------------
Congenital Midline
Cervical Clefts
------------------------------------------------------------------------------------------------------------------------------------------------
B
FIGURE 59-14 Photographs of infant with midline cervical cleft (A) and
Z-plasty reconstruction after excision (B).
Thymic cysts are usually seen within the chest and mediastinum. However, given that the thymus arises from the third,
and sometimes fourth, branchial pouches, one can appreciate
the possibility for a cervical location. Cervical thymic cysts
typically present in the anterior triangle, more commonly
on the left than the right. They occur more frequently in males,
with peak onset at age 5 to 7 years.53 They may be difficult to
distinguish preoperatively from more common cystic lesions,
such as branchial cleft cysts or lymphatic malformations. They
can be unilocular or multilocular. Extension into the mediastinum is common and accounts for the often-described physical
finding of enlargement with a Valsalva maneuver. The precise
diagnosis is usually made postoperatively when elements of
CHAPTER 59
thymus are identified within the cyst wall. The fluid within
these cysts is typically brownish in color. The lesions are almost always benign. Surgical excision is generally quite
straightforward, although one needs to be cognizant of potentially adherent vessels (e.g., carotid artery, jugular vein) or
nerves (e.g., phrenic, recurrent laryngeal). Although the aim
is to completely remove the cyst, one should be careful in very
young children, to avoid removing the entire thymus, which
might have untoward immunologic consequences.
Although the focus of this chapter has been congenital
lesions, the differential diagnosis for neck cysts and sinuses
761