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Tissue Tumors
eMedicine, Last Updated: June 28, 2002
INTRODUCTION
1
Though most soft tissue tumors of various histogenetic types are
classified as either benign or malignant, many are of an intermediate
nature, which typically implies aggressive local behavior with a low-
to-moderate propensity to metastasize.
Etiology:
Genetic conditions
2
cytologic specimen from fine-needle aspiration biopsy (FNAB),
histological material from paraffin block, or from frozen material.
Radiation
Chronic lymphedema
Environmental carcinogens
Infection
Trauma
3
of tissue called the reactive zone surrounds the compression zone,
especially in higher-grade tumors. Together, the compression and
reactive zones form a pseudocapsule that encloses the tumor and is
useful in defining the extent of surgical resection.
Local recurrence
Distant metastasis
Many patients with high-grade and a few with low-grade soft tissue
sarcomas progress to metastatic disease, even following adequate
local control of the primary tumor. Although at the time of
presentation, most patients do not have clinically evident
metastases, patients may have occult micrometastases that eventually
manifest clinically. This is the impetus to develop effective methods
of chemotherapy to control systemic disease. The lung is by far the
most common site of metastasis, which occurs in up to 52% of patients
4
with high-grade lesions. At present, this is a controversial area of
investigation and it is not certain that systemic chemotherapy offers
any improvement in long-term survival for patients with high-grade
sarcomas.
WORKUP
Lab Studies:
Imaging Studies:
5
As prognosis is primarily dependent on the disease stage
rather than the histologic tumor type, evaluation of local and
distant extent is pivotal in the ultimate management of soft
tissue sarcoma. Imaging methods commonly used for this purpose
include plain radiographs, CT, MRI, and bone scintigraphy
(bone scan). Positron emission tomography (PET) is being used
more frequently to assess the metabolic activity and
presumably the biologic aggressiveness of a lesion.
Angiography to evaluate any vascular involvement by soft
tissue tumors has essentially been replaced by MRI.
o CT scan
Check for presence and number of pulmonary
metastases.
Consider CT scan of the liver in cases of
intra-abdominal or retroperitoneal tumors.
o MRI
In contrast to CT scan, MRI is not limited to
the transverse (axial) plane. Coronal,
sagittal, and oblique planes may be imaged.
MRI best defines the relationship between tumor
and adjacent anatomic structures such as
compartment boundaries, nerves, vessels, and
muscle.
Though for most patients MRI alone suffices,
the information obtained from CT scan and MRI
of the primary tumor occasionally may be
complementary. Evaluation of bony involvement
may be better assessed with a CT scan. The
boundary between normal muscle and fibromatosis
may be better delineated with a CT scan.
Diagnostic Procedures:
6
o FNAB
This is a cytological technique involving the
use of a fine-gauge (usually 21- to 25-gauge)
needle to aspirate individual tumor cells and
microfragments from the mass. The aspirated
material then can be examined as a cytology
smear with immediate evaluation of specimen
adequacy. Depending on the initial
cytomorphological features observed during the
onsite adequacy evaluation, additional passes
may be performed at the same time to obtain
more material for cell-block preparation (for
histomorphology and immunocytochemical
evaluation), cytogenetics (see Table 1),
electron microscopy, and microbiology cultures.
Deletion of 5q 10%
Rearrangement of
Lipoblastoma >25%
8q
Rearrangement of
Lipoma, solitary 75%
bands 12q14-15
Rearrangement of
10%
6p
7
Uterine leiomyoma t(12;14)(q15;q24) 20%
Deletion of 7q 15%
Trisomy 12 10%
Dermatofibrosarcoma
Ring chromosome 17 >75%
protuberans
Extraskeletal
myxoid t(9;22)(q31;q12) 50%
chondrosarcoma
Liposarcoma, well
Ring chromosome 12 80%
differentiated
Alveolar
t(2;13)(q35;q14) 80%
rhabdomyosarcoma
95%
Synovial sarcoma t(X;18)
8
is minimally invasive and relatively
atraumatic.
Published literature highlights the rarity of
needle track seeding with FNAB. Core biopsy, on
the other hand, has a higher rate of needle
track seeding.
o Incisional biopsy
Open incisional biopsy is used for most soft
tissue masses. A generous wedge of tissue is
removed with minimal manipulation of tissue at
the time of surgery. Several important
technical factors must be considered while
performing an incisional biopsy. The incision
should be oriented along the long axis in the
case of extremity lesions. Any biopsy incision
and tract should be oriented so that it can be
resected at the time of definitive surgery.
The sample obtained may be evaluated for
adequacy using intraoperative cytology or a
frozen section at the time of biopsy.
Meticulous hemostasis minimizes local
dissemination of tumor cells.
o Excisional biopsy
With this method, the entire lesion is
surgically removed. Many sarcomas appear to be
well demarcated grossly. However,
microscopically, this usually is a
pseudocapsule with foci of infiltrating tumor.
Removal of the tumor along this apparent plane
may leave gross or microscopic sarcoma behind.
Excisional biopsy may be safely performed for
small superficial tumors (< approximately 5 cm
in diameter) or those known to be benign.
9
Frozen section and intraoperative cytology are
extremely helpful tools for the management of
soft tissue tumors. Proper communication with a
musculoskeletal oncopathologist preoperatively
and intraoperatively is essential for proper
evaluation. Frozen section can guide retrieval
of adequate diagnostic material, and, depending
on the initial evaluation, it is an important
triage mechanism to direct further pathologic
workup.
Depending on the availability of FNAB support,
most advantages achieved by frozen sectioning
for diagnostic biopsy can be achieved using
FNAB. However, open biopsy (with the help of
frozen sectioning support) may be indicated in
situations when FNAB result is equivocal or for
other clinical reasons.
Fatty lesions are not suitable for frozen
section evaluation. In addition to the loss of
diagnostic material during frozen sectioning
and other technical difficulties due to fatty
nature, freezing also compromises the final
interpretation on permanent sections.
I. Fibrous tumors
o IA. Benign tumors
10
1. Nodular fasciitis (including intravascular and
cranial types)
2. Proliferative fasciitis and myositis
3. Atypical decubital fibroplasia (ischemic
fasciitis)
4. Fibroma (dermal, tendon sheath, nuchal)
5. Elastofibroma
6. Keloid
7. Calcifying aponeurotic fibroma
8. Fibrous hamartoma of infancy
9. Fibromatosis colli
10. Infantile digital fibromatosis
11. Myofibromatosis (solitary, multicentric)
12. Hyalin fibromatosis
13. Calcifying fibrous pseudotumor
o IB. Fibromatoses
1. Superficial fibromatoses
11
d. Xanthomatous (inflammatory type)
fibrous histiocytoma
III. Lipomatous tumors
o IIIA. Benign tumors
1. Lipoma
a. Cutaneous lipoma
b. Deep lipoma
i. Intramuscular lipoma
ii. Tendon sheath lipoma
iii. Lumbosacral lipoma
iv. Intraneural and perineural
fibrolipoma
c. Multiple lipomas
2. Angiolipoma
3. Spindle cell or pleomorphic lipoma
4. Myolipoma
5. Angiomyolipoma
6. Myelolipoma
7. Chondroid lipoma
8. Hibernoma
9. Lipoblastoma or lipoblastomatosis
10. Lipomatosis
a. Diffuse lipomatosis
b. Cervical symmetrical lipomatosis
(Madelung disease)
11. Atypical lipoma
o IIIB. Malignant tumors
1. Liposarcoma
a. Well-differentiated liposarcoma
i. Lipomalike liposarcoma
ii. Sclerosing liposarcoma
iii. Inflammatory liposarcoma
b. Myxoid liposarcoma
c. Round cell (poorly differentiated
myxoid) liposarcoma
d. Pleomorphic liposarcoma
e. Dedifferentiated liposarcoma
IV. Smooth muscle tumors
o IVA. Benign tumors
1. Leiomyoma (cutaneous, deep, pleomorphic)
2. Angiomyoma (vascular leiomyoma)
3. Epithelioid leiomyoma
4. Intravenous leiomyomatosis
5. Leiomyomatosis peritonealis disseminata
o IVB. Malignant tumors
1. Leiomyosarcoma
2. Epithelioid leiomyosarcoma
V. Skeletal muscle tumors
o VA. Benign tumors
1. Adult rhabdomyoma
2. Genital rhabdomyoma
3. Fetal rhabdomyoma
4. Intermediate (cellular) rhabdomyoma
o VB. Malignant tumors
12
1. Rhabdomyosarcoma
a. Embryonal rhabdomyosarcoma
b. Botryoid rhabdomyosarcoma
c. Spindle cell rhabdomyosarcoma
d. Alveolar rhabdomyosarcoma
e. Pleomorphic rhabdomyosarcoma
f. Rhabdomyosarcoma with ganglionic
differentiation (ectomesenchymoma)
VI. Tumors of blood and lymph vessels
o VIA. Benign tumors
1. Papillary endothelial hyperplasia
2. Hemangioma
a. Capillary (including juvenile)
hemangioma
b. Cavernous hemangioma
c. Venous hemangioma
d. Epithelioid hemangioma (angiolymphoid
hyperplasia, histiocytoid hemangioma)
e. Granulation-type hemangioma (pyogenic
granuloma)
f. Tufted hemangioma
3. Deep hemangioma (intramuscular, synovial,
perineural)
4. Lymphangioma
5. Lymphangiomyoma and lymphangiomyomatosis
6. Angiomatosis
7. Lymphangiomatosis
o VIB. Intermediate tumors
1. Hemangioendothelioma
a. Epithelioid hemangioendothelioma
b. Endovascular papillary angioendothelioma
(Dabska tumor)
c. Spindle cell hemangioendothelioma
o VIC. Malignant tumors
1. Angiosarcoma and lymphangiosarcoma
2. Kaposi sarcoma
VII. Perivascular tumors
o VIIA. Benign tumors
1. Glomus tumor
2. Glomangiomyoma
3. Hemangiopericytoma
o VIIB. Malignant tumors
1. Malignant glomus tumor
2. Malignant hemangiopericytoma
VIII. Synovial tumors
o VIIIA. Benign tumors
1. Tenosynovial giant cell tumor
a. Localized tenosynovial giant cell tumor
b. Diffuse tenosynovial giant cell tumor
(extraarticular pigmented villonodular
synovitis, florid tenosynovitis)
o VIIIB. Malignant tumors
1. Synovial sarcoma
a. Biphasic (fibrous and epithelial)
synovial sarcoma
b. Monophasic (fibrous or epithelial)
synovial sarcoma
2. Malignant giant cell tumor of tendon sheath
IX. Mesothelial tumors
o IXA. Benign tumors
13
1. Solitary fibrous tumor of pleura and peritoneum
(localized fibrous mesothelioma)
2. Multicystic mesothelioma
3. Adenomatoid tumor
4. Well-differentiated papillary mesothelioma
o IXB. Malignant tumors
1. Malignant solitary fibrous tumor of pleura and
peritoneum
2. Diffuse mesothelioma
a. Epithelial diffuse mesothelioma
b. Fibrous (spindled, sarcomatoid) diffuse
mesothelioma
c. Biphasic diffuse mesothelioma
X. Neural tumors
o XA. Benign tumors
1. Traumatic neuroma
2. Morton neuroma
3. Multiple mucosal neuromas
4. Neuromuscular hamartoma (benign Triton tumor)
5. Nerve sheath ganglion
6. Schwannoma (neurilemoma)
a. Cellular schwannoma
b. Plexiform schwannoma
c. Degenerated (ancient) schwannoma
d. Schwannomatosis
7. Neurothekeoma (nerve sheath myxoma)
8. Neurofibroma
a. Diffuse neurofibroma
b. Plexiform neurofibroma
c. Pacinian neurofibroma
d. Epithelioid neurofibroma
9. Granular cell tumor
10. Melanocytic schwannoma
11. Ectopic meningioma
12. Ectopic ependymoma
13. Ganglioneuroma
14. Pigmented neuroectodermal tumor of infancy
(retinal anlage tumor, melanotic progonoma)
o XB. Malignant tumors
1. Malignant peripheral nerve sheath tumor (MPNST)
(malignant schwannoma, neurofibrosarcoma)
a. Malignant Triton tumor (MPNST with
rhabdomyosarcoma)
b. Glandular MPNST (malignant glandular
schwannoma)
c. Epithelioid MPNST (malignant
epithelioid schwannoma)
2. Malignant granular cell tumor
3. Clear cell sarcoma (malignant melanoma of soft
parts)
4. Malignant melanocytic schwannoma
5. Gastrointestinal autonomous nerve tumor
(plexosarcoma)
6. Primitive neuroectodermal tumor
a. Neuroblastoma
b. Ganglioneuroblastoma
c. Neuroepithelioma (peripheral
neuroectodermal tumor)
d. Extraskeletal Ewing sarcoma
XI. Paraganglionic tumors
o XIA. Benign tumor
1. Paraganglioma
14
o XIB. Malignant tumors
1. Malignant paraganglioma
XII. Extraskeletal cartilaginous and osseous tumors
o XIIA. Benign tumors
1. Panniculitis ossificans and myositis ossificans
2. Fibroosseous pseudotumor of the digits
3. Fibrodysplasia (myositis) ossificans
progressiva
4. Extraskeletal chondroma or osteochondroma
5. Extraskeletal osteoma
o XIIB. Malignant tumors
1. Extraskeletal chondrosarcoma
a. Well-differentiated chondrosarcoma
b. Myxoid chondrosarcoma
c. Mesenchymal chondrosarcoma
2. Extraskeletal osteosarcoma
XIII. Pluripotential mesenchymal tumors
o XIIIA. Benign tumors
1. Mesenchymoma
o XIIIB. Malignant tumors
1. Malignant mesenchymoma
XIV. Miscellaneous tumors
o XIVA. Benign tumors
1. Congenital granular cell tumor
2. Tumoral calcinosis
3. Myxoma
a. Cutaneous myxoma
b. Intramuscular myxoma
c. Juxta-articular myxoma
4. Angiomyxoma
5. Amyloid tumor
6. Parachordoma
7. Ossifying and nonossifying fibromyxoid tumors
8. Palisaded myofibroblastoma of lymph node
o XIVB. Malignant tumors
1. Alveolar soft part sarcoma
2. Epithelioid sarcoma
3. Malignant extrarenal rhabdoid tumor
4. Desmoplastic small cut tumor
XV. Unclassified tumors
15
on Cancer (AJCC) system, tumors of 5 cm or less in greatest dimension
are T1, and tumors exceeding 5 cm are T2. Though not a part of the
AJCC system, tumors larger than 10 cm have a worse prognosis than do
those larger than 5 cm.
G - Tumor grade
o G1 - Well differentiated
o G2 - Moderately differentiated
o G3 - Poorly differentiated
T - Primary tumor
o T1 - Tumor less than 5 cm in greatest diameter
o T2 - Tumor more than 5 cm in greatest diameter
N - Regional lymph node involvement
o N0 - No known metastasis to lymph nodes
o N1 - Verified metastasis to lymph nodes
M - Distant metastasis
o M0 - No known distant metastasis
o M1 - Known distant metastasis
Regional
Stage Tumor Primary Distant
Lymph Node
Groupings Grade Tumor Metastasis
Involvement
Stage IA G1 T1 N0 M0
Stage IB G1 T2 N0 M0
Stage II A G2 T1 N0 M0
Stage IIB G2 T2 N0 M0
Stage IIIA G3 T1 N0 M0
16
Stage IIIB G3 T2 N0 M0
TREATMENT
Surgical therapy:
Extremity sarcoma
17
through the normal tissue proximal to the reactive zone around
the tumor but remains within the involved compartment. Limb-
sparing procedures belong to this category.
Radical excisions and amputation: These are en bloc excisions
of the tumor along with the entire muscle compartment.
Amputation with disarticulation of the joint proximal to the
involved compartment is called radical amputation. The risk of
local recurrence is lowest with this procedure.
18
Preoperative chemotherapy is also called neoadjuvant chemotherapy.
This treatment is an option for most patients with osteosarcomas of
the extremity. However, it is not established as a superior approach
compared to conventional chemotherapy for soft tissue tumors. It may
be used alone or with preoperative or postoperative radiation
therapy.
Nonextremity sarcoma
19
sarcomas remains controversial. This approach should be investigated
further in well-designed randomized clinical trials.
COMPLICATIONS
20
Surgical margins: Adequacy of surgical margins is directly
related to local relapse. However, development of distant
metastases may not be related to the development of local
recurrence.
Histologic grade: A relationship exists between various
microscopic grading systems and outcome.
Clinical stage: Clinical stage is the most important predictor
of clinical outcome. The GTNM staging system, which
incorporates microscopic grading, is described in Table 2.
DNA ploidy: DNA ploidy can be evaluated by flow-cytometric
studies performed on formalin-fixed paraffin-embedded tissue
sections or by image analysis using cytology smears.
Aneuploidy is observed in tumors with a higher microscopic
grade and a higher rate of cell proliferation. However, its
role as an independent prognostic factor has not been
established.
Cell proliferation: The number of mitotic figures stratifies
the tumors into benign, intermediate, and malignant categories
and is incorporated into most grading systems. Proliferation
markers like Ki-67 and p105 are useful for evaluation of
proliferative activity and its relationship to prognosis.
However, similar to ploidy, it remains to be established as an
independent prognostic factor.
Oncogene mutations: Mutations of TP53, overexpression of MDM2,
or altered expression of the retinoblastoma gene have been
reported to be associated with a worse prognosis.
21
MEDICAL ONCOLOGY: A COMPREHENSIVE REVIEW
Soft-Tissue Sarcomas
Soft-tissue sarcomas are extremely rare tumors. They represent 0.7% of adult malignancies; it
is estimated that in the United States 6,000 new cases and 3,600 deaths will occur from this
disease in 1995. Soft-tissue sarcomas occur more frequently in children; they represent 6.5%
of all cancers in children younger than 15 years of age and are the fifth leading cause of
cancer death in this age group.
Soft tissues are the extraskeletal tissues of the body that support, connect, and surround other
discrete anatomic structures. These tissues contribute more than 50% of the body weight and
include muscles and tendons as well as fibrous, adipose, and synovial tissues.
Despite anecdotal reports about clusters of sarcomas in some families, there is no clear
genetic predisposition except in the Li-Fraumeni syndrome. On the other hand, soft-tissue
tumors are thought to occur more frequently in patients with a variety of genetically transmitted
diseases, such as the basal cell nevus syndrome, tuberous sclerosis, Werner syndrome,
intestinal polyposis, and Gardner's syndrome. Sarcomas rarely develop from preexisting
benign soft-tissue tumors. The exceptions are neurofibromas in type-I Recklinghausen's
disease, which have an increased risk for degeneration into malignant schwannomas. Patients
22
with this disease have a 15% risk of developing neurofibrosarcoma and should be carefully
monitored.
Recent advances in molecular biology indicate that genetic mutations in mesenchymal stem
cells within the soft tissues may be responsible for the development of sarcomas. Alterations in
the retinoblastoma gene and p53 gene have been found in a variety of soft-tissue sarcomas.
Germline mutations of these genes have been identified in familial retinoblastoma cases and in
the Li-Fraumeni syndrome, with soft-tissue sarcomas as manifestations of these disorders. In
sarcomas, mutations of p53 have been associated with specific tumor subtypes, high histologic
grade, and a poor prognosis.
Specific cytogenetic alterations have been associated with some sarcomas and appear
to be pathognomonic. For example, t(11;22) is present in 90% of patients with extraskeletal
Ewing's sarcomas, and 50% of alveolar rhabdomyosarcomas show a t(2;13) translocation.
Myxoid liposarcomas have been found to have a t(12;16) translocation, clear-cell sarcoma a
t(12;22) translocation, extraskeletal myxoid chondrosarcoma a t(9;22) translocation, and
synovial sarcoma a t(x;18) translocation. Neuroblastoma has been associated with structural
abnormalities of chromosome 1p in 70% to 80% of cases, and these abnormalities appear to
confer a poor prognosis. The increasing availability of molecular biology techniques and the
identification of specific DNA and RNA gene sequences as expressions of the gene product
Myo D1 and oncogenes will help in the diagnosis of sarcomas.
Clinical Presentation
Soft-tissue sarcomas can occur in any anatomic region of the body because of the ubiquitous
nature of connective tissue, but most sarcomas (60%) develop in the extremities. Three times
as many sarcomas develop in the legs as in the arms. Other sites include the trunk (31%) and
head and neck region (9%). The most common manifestations of sarcomas of the extremity
are swelling and pain. Pain is usually mild and occurs later in the course of the disease. Thus,
a patient might delay seeking medical attention, and a definitive diagnosis also might be
delayed. In children, the majority of soft-tissue sarcomas are rhabdomyosarcomas, arising in
20% of the cases in the extremities, in 37% in the head and neck region, and in 25% in
genitourinary sites. Patients with pelvic sarcomas might present with swelling of the leg that
simulates primary iliofemoral thrombosis or with pain in the distribution of the femoral or sciatic
nerve. Hypoglycemia is rare and is usually associated with large retroperitoneal sarcomas.
Evaluation
Imaging Techniques: Radiologic evaluation should include a chest x-ray and a computed
tomography (CT) scan of the lungs, the most common sites of metastasis, and a CT scan or,
preferably, a magnetic resonance imaging (MRI) scan of the primary tumor-bearing area. MRI
examination of the affected area using T1-weighted images, proton-density-weighted images,
and T2-weighted images can maximize the contrast among soft-tissue neoplasm, muscle, fat,
and vessels and almost eliminates the need for an arteriogram.
If the lesion abuts bone, a bone scan should be obtained to help determine whether there is
periosteal invasion or reaction. A positive bone scan does not document bone involvement by
the tumor, but it may represent periosteal reaction. The bone scan can serve as a guide to
wide resection near the bone or to removal of the periosteum and/or part of the bone in
patients treated with surgery alone.
23
If an open biopsy must be performed, the biopsy site should be removed at the time of
definitive resection. Therefore, it is important for the biopsy incision not to compromise
subsequent surgical excision. An excisional biopsy may be used for small or superficial lesions
smaller than 2 cm in diameter. The tissues surrounding the tumor form a pseudocapsule that
always contains invasive prongs of malignant tissue. Therefore, shelling out soft-tissue
sarcomas is never curative. Local recurrence following such procedures occurs in
approximately 80% of cases.
Pathology
There are approximately 70 different histologic types of soft-tissue sarcomas. Most sarcomas
are classified according to the normal cell type they mimic, based on the system proposed by
Enzinger and Weiss. Even among experienced pathologists, significant disagreement often
arises as to the cell of origin of an individual tumor. The relative frequency of the various types
of sarcomas differs according to a patient's age. In children, for example, the most common
sarcoma is rhabdomyosarcoma, which represents 5% to 8% of all childhood cancers. It occurs
primarily in infants and children and has a predilection for the head and neck region, urinary
bladder, vagina, prostate, and retroperitoneum. In older children, it can also occur in the
extremities.
Rhabdomyosarcoma may present as one of four subtypes: embryonal, botryoid, alveolar, and
pleomorphic. Immunohistochemistry is very helpful in the differential diagnosis;
rhabdomyosarcoma stains positive with antibodies to actin, desmin, myoglobulin, S-100
protein, vimentin, and Myo-D. Electron microscopy can also help by showing the characteristic
Z-band pattern of skeletal muscle differentiation. Along with the synovial, epithelioid, and clear-
cell sarcomas, rhabdomyosarcoma has a higher tendency toward lymphatic dissemination to
the regional lymph nodes, in contrast to the generally low incidence (5%) of regional lymph-
node metastases found in soft-tissue sarcomas.
The embryonal subtype is the most frequent and constitutes 75% of all rhabdomyosarcomas.
The differential diagnosis of this particular type includes some of the small-cell tumors, such
as lymphoma, neuroblastoma, oat-cell carcinoma of the lungs, Ewing's sarcoma, small-cell
osteosarcoma, and mesenchymal chondrosarcoma.
In adolescents and young adults, the most common soft-tissue tumors are synovial sarcoma,
epithelioid sarcoma, clear-cell sarcoma, and primitive neuroectodermal tumors. Synovial
sarcoma occurs usually near the large joints of the lower extremities in patients 15 to 40 years
of age and has a slightly higher incidence of lymph-node metastases. Synovial sarcomas
frequently calcify, which is rare for soft-tissue tumors; calcification may also occur in
extraskeletal osteosarcoma, mesenchymal chondrosarcoma, and myositis ossificans.
In adults, the most common sarcoma is malignant fibrous histiocytoma (MFH), which accounts
for 10% to 20% of all soft-tissue sarcomas. This type of tumor is believed to be composed of
neoplastic fibroblasts with acquired histiocytic features. MFH usually occurs in the thigh and
retroperitoneum of adults 40 to 80 years old. In general, the term refers to a high-grade
sarcoma, with the exception of myxoid MFH, which is usually regarded as an intermediate-
grade sarcoma.
24
Liposarcomas are the second most common adult sarcoma. They usually occur in the deep
soft tissue of the extremities and retroperitoneum, rarely in the subcutaneous tissue, and
almost never metastasize to the regional lymph nodes. Liposarcomas occur slightly more
frequently in men than in women (1.5:1) and can vary in behavior, ranging from low-grade,
well-differentiated disease (also called atypical lipomatous tumor) to intermediate-grade
myxoid liposarcoma to high-grade pleomorphic liposarcoma.
Leiomyosarcomas arise from smooth muscle and can occur anywhere in the body. They
commonly arise in the retroperitoneum, where they behave very aggressively.
Neurofibrosarcomas originate from the neural sheath. They are frequently associated with
Recklinghausen's disease, where patients have a 15% risk of developing neurofibrosarcomas,
either de novo or from malignant transformation of preexisting benign soft-tissue tumors.
Alveolar soft-part sarcomas have no benign counterpart. These tumors evolve slowly, with
most patients developing metastases that progress gradually over 5 to 15 years before death
occurs. Five-year survival rates of 60% are common. This subtype has a higher incidence of
brain metastases.
Epithelioid sarcomas are very aggressive tumors of unknown origin. They occur almost
exclusively in the extremities and have a tendency to spread to noncontiguous areas, including
the skin, subcutaneous tissue, fat, bone, and draining lymph nodes, which are the most
common sites of metastases for these tumors; the lungs are the second most common sites of
metastases.
Sarcomas are classified according to their grade, which represents the most important
prognostic factor. Grade 1 describes well-differentiated disease, and, at the other extreme,
grade 3 refers to poorly differentiated disease. The histopathologic grade of sarcomas is based
on the degree of differentiation, cellularity, number of mitoses, pleormorphism, and amount of
necrosis.
In multivariate analysis, necrosis has been shown to be the best parameter for predicting
prognosis. The next important prognostic factors are the size and location of the tumor.
Sarcomas located in extremities generally have a better prognosis than those not in
extremities, probably because they are diagnosed earlier, are more likely to be completely
resected, and have a lower risk of dissemination. The staging system of the American Joint
Committee on Cancer depends largely on grade and tumor-node-metastasis (TNM)
classification (Table 1). The lungs are the most frequent sites of metastasis (33%), followed by
bone (23%) and the liver (15%).
T Primary tumor
T2 Tumor 5 cm or larger
25
G1 Low
G2 Moderate
G3 High
M Distant metastases
M0 No distant metastasis
M1 Distant metastasis
Stage I
IA G1T1N0M0
IB G1T2N0M0
Stage II
IIA G2T1N0M0
IIB G2T2N0M0
Stage III
IIIA G3T1N0M0
IIIB G3T2N0M0
Stage IV
IVA G1-3T1-2N1M0
IVB G1-3T1-2N0-1M1
Adapted, with permission, from Bears OH, Henson DE, Hutter RVP, et al
(eds): Manual for Staging of Cancer, American Joint Committee on
Cancer, 4th ed, pp 145-149. Philadelphia, JB Lippincott Co, 1992.
Treatment
Local Disease: Most soft-tissue sarcomas are treated according to their grade, size, and
location, except for Kaposi's sarcoma, extraskeletal Ewing's sarcoma, and
rhabdomyosarcoma. In all grades of soft-tissue sarcomas, despite the presence of a
pseudocapsule surrounding the tumor, extrusions of tumor extend through the capsule and
form micro- and macronodules called satellites. High-grade sarcomas also have a significant
incidence (almost 20%) of nodules found in normal tissue beyond the capsuleskip
metastasesthat are usually confined to the compartment of origin of the tumor. The goal of
the treatment of local disease is local control followed by the preservation of optimal function.
26
The surgical margin achieved has a direct influence on the local recurrence rate. Marginal en
bloc excision through the pseudocapsule carries a risk of local recurrence of 70% to 90%.
Wide en bloc excision through normal tissue has a local recurrence rate of 20% to 30% for
low-grade lesions and as high as 50% for high-grade lesions. Radical resection involving
removal of an entire compartment or amputation is associated with a risk of local recurrence of
less than 50% but obvious limitations in function.
The results of combination radiotherapy (XRT) can influence decisions about proposed
surgery. When properly designed XRT is coupled with surgery, narrow surgical margins with
XRT have equivalent prognoses to those for wide surgical margins alone, and wide surgical
margins coupled with XRT are equivalent to radical surgical margins for local control and
survival. Limb salvage should be considered when the oncologic margin is not compromised
and the functional result is preferable to a prosthesis. Lymph-node dissection is not routinely
recommended, even for the histologic types at high risk for lymph-node dissemination, unless
clinical findings indicate that it should be performed.
Pre- and postoperative XRT has been used in conjunction with surgery to improve local control
of the tumor. If used postoperatively, a dose of 60 to 65 Gy is required to achieve local control.
If XRT is used preoperatively, the dose required is lower (ie, 50 to 54 Gy), and the radiation
field is usually smaller. This is because the postoperative radiation field should include the
tumor site and all tissues handled during surgery, including the stab wound and drain tube
sites. Also, preoperative XRT usually causes tumor shrinkage, so the tumor is smaller at the
time of surgery and has significantly fewer viable cells. Thus, the surgical margins can be
safely reduced and the likelihood of reseeding tumor cells during surgery is almost eliminated.
The advantages of postoperative radiation include the feasibility of immediate surgery and the
avoidance of delay in wound healing caused by prior XRT. A study conducted at The University
of Texas M.D. Anderson Cancer Center showed a local failure rate of 22% for patients
receiving XRT postoperatively for grades 2 and 3 tumors larger than 5 cm vs a local failure rate
of 10% for patients who received preoperative treatment. Comparable results are reported by
other investigators. Wound morbidity after surgery and XRT is adversely affected by disease
located in the lower extremity, advanced patient age, and a postoperative XRT boost with an
interstitial implant, as shown by multivariate analysis. Accelerated fractionation was of
borderline significance, whereas high pathologic grade and a resection volume of more than
200 cm were significant only on univariate analysis. Preoperative XRT is associated with more
wound morbidity than postoperative XRT. Gentle handling of tissues during surgery with
adequate hemostasis and drainage, sufficient immobilization, and omission of a postoperative
boost XRT dose when possible (ie, negative histologic margins) can reduce wound morbidity.
Retroperitoneal sarcomas pose a complex problem, because complete resection is not often
possible due to anatomic constraints. In many cases, partial resection of a major organ is
required, and even in completely resected sarcomas, a local recurrence rate of 50% to 70% is
common. XRT has been used as adjuvant therapy and in unresectable disease. Harrison et al
reported the outcome of Yale University's experience with XRT in retroperitoneal sarcomas. All
three patients who underwent a complete excision with negative margins and adjuvant XRT
with more than 40 Gy survived free of disease for longer than 5 years. Among the 10 patients
who underwent only a biopsy for unresectable retroperitoneal sarcomas, only 4 survived longer
than 1 year, and the average radiation dose was 44 Gy. The remaining 6 patients received only
an average of 27 Gy and did not survive for 1 year.
These results agree with the results reported by Tepper et al from Massachusetts General
Hospital. Of the 13 patients who had a primary tumor treated with curative intent, seven
patients underwent incomplete surgical resections, three of whom had a relapse of local
27
disease when treated with radiation doses of less than 50 Gy; the four patients with good local
disease control received radiation doses varying from 4,990 to 6,070 cGy. Of the three
patients with unresectable disease, one treated with 62 Gy had good local control, whereas the
other two treated with less than 50 Gy had local relapses. Due to the retrospective nature of
the studies and the small number of patients, adjuvant XRT for retroperitoneal sarcomas
remains controversial. XRT for unresectable disease, however, does have some potential for
local control and palliation.
XRT has also been used with good results in the management of desmoid tumors. Desmoid
tumors lack the capacity to metastasize, but they aggressively infiltrate locally and can be fatal.
Abdominal desmoid tumors usually occur in women postpartum. Patients in whom a complete
resection is possible have a good prognosis. Extra-abdominal desmoid tumors usually occur in
the head and neck area, shoulder girdle, and inguinal region. Wide resection is often difficult or
impossible in these areas, and the recurrence rate ranges between 50% and 75% for cases
involving close or positive margins.
XRT has been used by different investigators as an alternative treatment; it provided good
local control in approximately 80% of cases when 60 Gy was given over 6 to 8 weeks. A review
of a 20-year experience at M.D. Anderson Cancer Center using XRT doses of 50 to 76 Gy to
treat desmoid tumors revealed no evidence of a dose-control relationship, but a clear dose-
complication relationship was seen. Therefore, the current recommended XRT dose at M.D.
Anderson is 50 to 55 Gy at 1.8 Gy per fraction. At the time of a patient's initial surgery, XRT is
not routinely recommended.
A review of the M.D. Anderson experience with chemotherapy for desmoid tumors identified 12
patients so treated; 10 with unresectable primary or recurrent disease and 2 treated
preoperatively in an attempt to shrink the tumor and decrease surgical morbidity. Eleven
patients received doxorubicin-plus-dacarbazine-based regimens; six of the nine patients
whose responses could be evaluated had objective responses (two complete responses [CR]
and four partial responses [PR]). With a response rate of more than 60%, chemotherapy is
now recommended as primary therapy for inoperable/unresectable tumors.
Hormonal therapy with tamoxifen, toremifene (Estrinex), and progesterone has been reported
to achieve long-term remission of desmoid tumors. Indomethacin and ascorbic acid have been
reported to cause regression of some desmoid tumors. In addition, good responses have
recently been reported with a combination of methotrexate and oral etoposide (VePesid).
The most active single agents for soft-tissue-sarcomas are ifosfamide (Ifex, 30%), doxorubicin
(26%), dactinomycin (Cosmegen, 17%), and dacarbazine (16%). The combination of
dacarbazine and doxorubicin resulted in a response rate of 42% and has been found to be
superior to doxorubicin alone. There was a dose-response relationship for doxorubicin, with
regimens including doses of greater than 70 mg/m having higher response rates than
regimens using lower doses; significantly less cardiotoxicity was seen when doxorubicin was
administered as a prolonged infusion. Ifosfamide (with mesna [Mesnex] for urothelial
protection) resulted in a response rate of 25% to 30% in patients who did not respond to
doxorubicin-based regimens. A dose-response relationship was documented for ifosfamide in
subsequent trials.
Several prospective, randomized studies were conducted to evaluate the role of adjuvant
chemotherapy in localized soft-tissue sarcomas (Table 2). Several studies show a statistically
significant improvement in disease-free survival; however, only one study (Bordeaux) showed
a statistically significant difference in the rate of overall survival in favor of the adjuvant
chemotherapy group. Despite criticism of the use of single-agent suboptimal-dose doxorubicin
28
as adjuvant treatment in most of these cases and the inclusion of low-risk patients in some of
the studies, results of a recent meta-analysis of 11 published prospective, randomized,
adjuvant studies (that took into account only published information) revealed a disease-free
survival advantage (68% vs 53%, P < .00001) and an overall survival advantage (81% vs 71%,
P = .0005) for adjuvant chemotherapy for soft-tissue sarcomas. A preferred approach is to
provide preoperative chemotherapy to patients in a high-risk subset. This would help to identify
patients who are more likely to benefit from aggressive systemic treatment while sparing the
nonresponders from the morbidity of prolonged chemotherapy.
Number of % %
Study Regimen Follow-up patients % DFS DFS* % OS OS*
Bordeau CVAD 40 59 37 65 43 93
[106]
Extremity 60 67 28 54 60 54
Trunk 36 22 47 77 61 82
Retroperitoneum 24 15 49 92 100 47
ISC [113] A 47 86 54 71 55 65
Rizzoli [114] A 28 77 45 73 70 91
DFCI [115] A 73 46 62 66 72 71
Recurrent Disease: The two most common types of disease recurrence are local recurrence
and hematogenous spread that most commonly involves the lungs. Local recurrence should be
treated with aggressive surgical resection or as a high-risk primary tumor, with preoperative
chemotherapy followed by local therapy depending on the clinical situation. Eighty percent of
local recurrences occur in the first 2 years after initial surgery, and all recurrences develop by 3
years. Patients with isolated local recurrences have a 5-year survival rate of 45% to 85% when
treated with aggressive local therapy.
29
Resection of pulmonary metastases is indicated for patients with favorable prognostic factors
a tumor-doubling time of longer than 40 days, a disease-free interval of more than 1 year,
fewer than three nodules, unilateral disease, and MFH tumor histology (rather than other
histologies)yielding a 5-year survival rate of 10% to 30%, with little morbidity and very low
mortality.
For patients with less favorable prognostic factors, chemotherapy is the only available
treatment option, although CR rates range between 10% and 15% and only one third of
patients achieve long-term disease-free survival. Doxorubicin and ifosfamide are the most
active single agents, with response rates ranging from 15% to 40%. The combination of
ifosfamide and doxorubicin with or without dacarbazine yielded variable results, with a CR rate
of 5% to 10% and a PR rate of 25% to 48%. Two prospective, randomized, cooperative group
trials indicated better overall response rates with the ifosfamide/doxorubicin combination with
or without dacarbazine but no significant improvement in CR rate or survival time.
Attempts to use high-dose chemotherapy with or without total-body irradiation (TBI) have been
disappointing. Responses were of short duration, and substantial treatment-related morbidity
and mortality without improvement in the survival rate were seen. The use of growth factors,
such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-
stimulating factor (GM-CSF) allows intensification of the chemotherapeutic regimens and
reduces the morbidity related to neutropenia. The multilineage growth factor PIXY 321 (a
fusion protein of GM-CSF and interleukin-3) or thrombopoietin with G-CSF or GM-CSF may
allow an increase in the dose intensity by counteracting dose-limiting thrombocytopenia, which
currently remains a significant consideration.
Bone Sarcomas
Bone sarcomas account for 0.2% of all primary cancers in adults and approximately 5% of
childhood malignancies. It is estimated that 2,070 new cases will be diagnosed in the United
States in 1995 and that 1,280 deaths will be caused by bone sarcomas in the same year.
Bone sarcomas are classified according to the tissue of origin: I, bone-forming tumors; II,
cartilage-forming tumors; III, giant-cell tumors; IV, mesenchymal tumors; and V, vascular
tumors. The four most common types of bone sarcomas are osteosarcoma, chondrosarcoma,
MFH of bone, and Ewing's sarcoma. A team at a specialized center, including an orthopedic
surgeon with experience with bone tumors, a radiologist, an experienced pathologist, and a
medical oncologist, is essential for the appropriate management of these tumors. As in the
case of soft-tissue sarcomas, careful preoperative evaluation is necessary for patients with
bone sarcomas.
Evaluation
Imaging Techniques: Staging requires plain films and CT scans of the involved area and the
lungs. CT scanning of the area, including the entire bone and adjacent joint, helps to determine
intraosseous and extraosseous extension. CT scans of the lungs are required to evaluate for
metastatic disease because the lungs are the most common sites of metastasis via
hematogenous spread. Bone scans can detect bone metastases and occasional multicentric
primary lesions or skip metastases. MRI films of the area are very helpful in evaluating the
extent of bone-marrow involvement and in detecting skip lesions. MRI can also help to
evaluate a positive bone scan when findings on the corresponding plain radiograph are
normal. Some authors believe that MRI is the best single technique to use for preoperative
evaluation, whereas others prefer a baseline CT scan for better bony details and a
preoperative MRI scan for surgical planning. As in the case of soft-tissue sarcomas,
arteriograms are rarely necessary for surgical planning for bone sarcomas. However, they are
very helpful in assessing the vasculature of the tumor preoperatively and in determining
chemotherapy response that manifests as a decrease in vascularity of the tumor. After careful
staging, a biopsy is performed, preferably by the same physician who will be involved in the
patient's definitive treatment. The same principles apply for biopsy of bone sarcomas as for
biopsy of soft-tissue sarcomas. The biopsy site should be removed during definitive resection.
30
Biopsy: Trephine or core biopsy under fluoroscopic visualization is recommended and in most
cases (as with 89% of patients with suspected osteosarcoma at M D. Anderson) yields
adequate material for diagnosis. Needle biopsy has the advantage of less tissue contamination
than open biopsy. If the lesion extends to the extraosseous soft tissues, a biopsy of these
components should be obtained. Intraosseous lesions require perforation of the cortex. In
blastic lesions, tissue should be obtained from the least dense area.
A surgical staging system proposed by the Musculoskeletal Tumor Society in 1980 is used for
bone sarcomas (Table 3). The system is based on the fact that bone sarcomas, regardless of
their histologic type, behave similarly according to grade (G), location (T), and lymph-node
involvement or distant metastases (M). Bone tumors metastasize almost exclusively through
hematogenous spread, with pulmonary metastases usually occurring first followed by bony
involvement . Lymphatic involvement occurs rarely; it is found in 10% of cases at autopsy and
in 3% of patients with osteosarcoma undergoing amputation. Lymphatic involvement is
considered a poor prognostic sign.
Osteosarcoma
Genetic alterations of the retinoblastoma (Rb) gene have been identified in cases of
osteosarcoma in patients with hereditary retinoblastoma, who carry a risk for osteosarcoma of
7% in radiation ports and in nonirradiated long bones, as well as in patients with sporadic
osteosarcoma. Loss of heterozygosity (LOH) and DNA alterations of the Rb gene in sporadic
osteosarcomas indicate a poor prognosis. During childhood and adolescence, 80% to 90% of
osteosarcomas occur in a lower limb. The disease's peak incidence during
childhood/adolescence and the predominance of the distal femur and proximal tibia as first
sites of presentation in that age group indicate that osteosarcoma is associated with rapid
growth of weight-bearing long bones.
In patients older than 40 years, the skull, pelvis, and mandible are frequent sites of
osteosarcoma presentation. People with Paget's disease have a 10-fold risk of developing
bone cancer. Other conditions associated with an increased risk for bone sarcoma are
31
hereditary multiple exostoses, enchondromatosis (Ollier's disease), enchondromatosis with
skin hemangiomas (Maffucci's syndrome), polyostotic fibrous dysplasia, and osteogenesis
imperfecta. Ionizing radiation is the only environmental agent known to cause bone tumors.
People who were exposed to radium and patients receiving radiation therapy are at increased
risk for osteosarcoma. Such risk is expected to decrease with the use of megavoltage therapy,
which is not absorbed by bone as much as orthovoltage therapy is.
Fifty percent of all osteosarcomas occur in the knee joint area; the proximal humerus is the
next most common site, with 25% of the cases. The axial skeleton is rarely involved. The most
common presenting symptom is pain, with a firm, palpable, soft-tissue mass fixed to the
underlying bone with slight tenderness. There is no erythema or effusion in the adjacent joint,
and range of motion is normal. Fewer than 1% of patients will have a pathologic fracture.
There are different types of osteosarcoma. Radiologically, the classic osteosarcoma may
present as a lesion that can range from nearly normal to extremely dense or even involve
complete destruction of the bone. In one series, purely lytic osteosarcoma was described in
nearly 14% of patients. Radiographically, purely lytic disease cannot be distinguished from a
telangiectatic osteosarcoma, giant-cell tumor, aneurysmal bone cyst, or MFH of bone. The
periosteal reaction classically described as sunburst is an important diagnostic feature; this is
characteristically irregular and interrupted, which distinguishes malignancy from other benign
conditions. A soft-tissue mass immediately adjacent to the bone lesion is usually present.
Histologically, 75% of all osteosarcomas fall in the conventional category, which includes
osteoblastic, chondroblastic, and fibroblastic subtypes. The survival rate is similar for all
subtypes.
In patients treated with surgery alone, the size of the tumor, the age of the patient, and the
degree of malignancy did not correlate with the survival rate. The most significant variable was
anatomic site; patients with pelvic and axial lesions had lower survival rates than patients with
tumors of the extremities, probably because of incomplete resection in the former group. The
preoperative serum alkaline phosphatase level has been reported as a significant prognostic
factor of survival time. Tumor ploidy also has been shown to be a significant prognostic factor.
Disease-free survival and overall survival times are significantly longer in patients with near-
diploid cell lines. However, a recent review of the published data on prognostic factors in the
postadjuvant-chemotherapy era assessed age, anatomic location, tumor size, and tumor
necrosis following neoadjuvant chemotherapy; only tumor necrosis maintained its significance
as a predictor of disease-free survival in multivariate models.
The beneficial role of adjuvant chemotherapy in patients with osteosarcoma is now proven. A
large multi-institutional study showed a 2-year disease-free survival rate of 66% for patients
treated with surgery and adjuvant postoperative chemotherapy vs a 2-year disease-free
survival rate of less than 20% for patients treated with surgery alone. Moreover, the
introduction of neoadjuvant chemotherapy allowed more conservative limb-salvage surgery in
50% to 80% of patients without compromising a patient's chance of survival by delaying
surgery.
32
age, especially for anticipated significant discrepancies in leg length. The latter is far less
critical now with the development of expandable prostheses, but limb-sparing surgery is still
usually not an option for children younger than 10 years old.
A number of trials have evaluated the role of chemotherapy administered either preoperatively
or postoperatively. Most of the chemotherapeutic regimens included combinations of
doxorubicin, high-dose methotrexate, cyclophosphamide, cisplatin, and ifosfamide. Relapse-
free survival rates of 48% to 77% have been reported with different regimens. The
effectiveness of high-dose methotrexate, however, has not been universally accepted.
Response rates ranging from 0% and 80% have been reported; a dose-response relationship
has been proposed.
A study from the National Cancer Institute (NCI) evaluated the relationship of dose intensity to
more than 90% tumor necrosis following neoadjuvant chemotherapy and suggested that large,
highly concentrated doses of doxorubicin contribute to a favorable outcome in cases of
Ewing's sarcoma and osteosarcoma. Cisplatin and high-dose methotrexate also revealed
significant activity. Doxorubicin and cisplatin-based adjuvant chemotherapy are now
accepted as standard therapy for osteosarcoma in many institutions.
The role of chemotherapy prior to surgery (neoadjuvant) vs its role postoperatively (adjuvant)
has not yet been established in a randomized trial. The rationale for neoadjuvant
chemotherapy has been to institute early systemic therapy against micrometastases, to
increase the chances for successful limb-salvage surgery, to decrease the risk of viable tumor
cells being spread at the time of surgery, and, very importantly, to tailor treatment individually
according to the patient's response.
Several systems have been proposed for grading the tumor response to neoadjuvant
chemotherapy, all of which are based on the degree of cellularity and necrosis in the resected
specimen. Only grade 4 response, as determined by Huvos et al (absence of viable tumor
within the entire specimen), and more than 90% tumor necrosis, by the M.D. Anderson criteria,
predicted continuous disease-free survival.
Both intra-arterial (IA) and intravenous (IV) chemotherapy have been administered
preoperatively. A randomized trial using IA vs IV cisplatin combined with systemic doxorubicin
and high-dose methotrexate showed a significantly higher histologic response (more than 90%
tumor necrosis) in the group treated with IA cisplatin. No differences in the percentage of
clinical/radiologic response or in the percentage of limb-salvage procedures performed were
seen, and no differences in local or systemic side effects were observed. IA cisplatin was
compared with high-dose IV methotrexate at M.D. Anderson, and IA cisplatin was found to be
more efficacious. It should be noted that the IA technique requires excellent angiographic
support facilities and experienced personnel to minimize complications.
At the present time, preoperative chemotherapy is standard at M.D. Anderson, with four cycles
of systemic doxorubicin administered as a continuous infusion followed by cisplatin, preferably
given IA where feasible, followed by limb-salvage surgery and the tailoring of postoperative
therapy based on the tumor's response. Therapy is switched to ifosfamide and high-dose
methotrexate for patients with less than 90% tumor necrosis. Patients with more than 90%
tumor necrosis receive another six cycles of doxorubicin, with dacarbazine replacing cisplatin
due to dose-limiting peripheral neuropathy.
Mature data from patients treated between 1980 and 1982 (cisplatin, 120 mg/m) have shown
that patients with complete responses at the time of surgery had a 5-year continuous disease-
free survival rate of 86%, compared with 13% for patients with partial and/or poor responses.
Patients treated later with intensified cisplatin (160 mg/m) showed a slight improvement in the
overall survival rate, although this difference was not statistically significant. A significant
improvement in the overall survival rate was observed for patients with less than 90% tumor
necrosis (33%). Late relapses, although rare, can occur; 1 of 37 patients treated at M.D.
Anderson between 1980 and 1982 had a recurrence of disease more than 6 years after
surgery. Therefore, careful long-term follow-up and reports of mature data are very important.
33
Recent studies with muramyltripeptide phosphatidylethanolamine (MTP-PE), a synthetic,
lipophilic analog of muramyldipeptide (MDP), the smallest component of a mycobacterium
capable of stimulating the immune system, have shown that liposomes containing MTP-PE
localize to the pulmonary microvasculature, resulting in activation of pulmonary macrophages.
Animal studies revealed the efficacy of MTP-PE in canine osteosarcoma models. A phase II
study in humans documented histologic changes in the characteristics of the pulmonary
nodules that recurred after treatment with MTP-PE; peripheral fibrosis and inflammatory-cell
infiltration with neovascularization were demonstrated as well as a change from high- to low-
grade lesions after therapy. These changes indicated a potential role for MTP-PE in
conjunction with surgery and chemotherapy in the treatment of osteosarcomas. A phase II trial
of L-MTP-PE administered to patients with osteosarcoma who had pulmonary metastases that
either developed during adjuvant chemotherapy or persisted despite chemotherapy showed a
significant prolongation of disease-free survival in the patients who received treatment for 24
weeks.
XRT was used as primary therapy for osteosarcoma in the 1950s and early 1960s, without
good results. High doses of radiation were required to sterilize only a small subset of tumors
and were associated with significant necrosis of normal tissue. Preoperative XRT did not offer
any survival advantage either compared with surgery alone. XRT has been used successfully
in facial lesions; when followed by wide surgical excision, XRT promotes a 5-year survival rate
of 73%, compared with 35% to 45% with surgery alone. For palliation of metastatic bone
sarcomas and unresectable lesions in axial sites or the pelvis, XRT is useful, especially when
combined with IA or IV radiosensitizers (5-bromodeoxyuridine or idoxuridine).
Variants of Osteosarcoma
Parosteal and periosteal osteosarcomas are the most common variants of osteosarcoma.
Parosteal osteosarcoma accounts for 4% of all osteosarcomas. It usually occurs in older
people, with a slightly higher incidence in women. The distal femur is involved in 75% of cases.
Parosteal osteosarcoma arises from the cortex of bone. It presents as a mass that is
occasionally associated with pain and grows slowly over months or years with late metastases.
Overall survival rates range between 75% and 85%.
Periosteal osteosarcoma originates in the cortex, usually of the tibial shaft. A characteristic,
small, radiolucent lesion, evidence of bone spicules on a plain radiograph, and a Codman's
triangle are hallmarks of this disease. Pathologically, periosteal osteosarcoma is usually a
34
high-grade chondroblastic osteosarcoma. Treatment recommendations follow the same
concepts as those for high-grade classic osteosarcoma.
Chondrosarcoma of Bone
Chondrosarcoma is the second most common primary malignant spindle-cell tumor of the
bone, characterized by cartilaginous neoplastic tissue without direct osteoid formation.
Occasionally, bone formation occurs from differentiated cartilage. There are five types of
chondrosarcoma: central (arising within the bone), peripheral (arising from the bone surface),
mesenchymal, dedifferentiated, and clear cell. The most common variants are central and
peripheral chondrosarcomas, which may arise as primary tumors or may be secondary to
underlying benign neoplasms (multiple osteochondromas or enchondromas).
Chondrosarcomas usually present in patients older than 40 years of age. The most common
sites are the pelvis (30%), femur (20%), and shoulder girdle (15%). Chondrosarcomas usually
reach a significant size before symptoms, such as a palpable mass with pain or pressure and
occasionally urinary symptoms (sometimes noted with pelvic tumors), are noted.
Few reports document the efficacy of XRT in chondrosarcomas. Five-year local control rates
ranged between 45% and 82% and were directly related to the histology of the tumor. A review
of a 15-year XRT experience with chondrosarcoma of bone at M.D. Anderson revealed that
none of the four patients treated with a combination of neutron- and photon-beam XRT had
disease recurrence locally. One of the seven patients treated with conventional radiotherapy
alone experienced local disease recurrence, suggesting a benefit from the mixed-beam
technique.
Clear-cell chondrosarcoma is the rarest type. This tumor grows slowly and locally recurs with
some malignant potential. It is often confused with chondroblastoma. Treatment is wide
surgical excision; systemic therapy is not required, and metastases occur only after multiple
local recurrences.
MFH is a high-grade tumor in bone as well as in soft tissues. It usually occurs during adulthood
and commonly involves the metaphyseal ends of long bones, especially those of the knee
joint. MFH presents as a lytic, metaphyseal lesion with marked cortical disruption, minimal
cortical or periosteal reaction, and no evidence of bone formation. Pathologic fractures are
common. The patient's alkaline phosphatase level is normal. MFH of bone disseminates
rapidly to lung tissue, and lymph-node metastases have been reported in up to one third of
cases with lung metastases.
Although data are limited, it seems that MFH of bone is sensitive to chemotherapy. In one
study, patients treated with surgery and chemotherapy had a disease-free survival rate of 59%,
compared with only 5% of patients treated with surgery alone. In a recently updated study, 7 of
15 patients with MFH of bone treated with neoadjuvant chemotherapy at M.D. Anderson
showed more than 90% tumor necrosis. The median continuous disease-free survival for
patients who achieved more than 90% tumor necrosis was 43 months, compared with only 7
35
months for patients with less than 90% tumor necrosis (P < .05). A trend for better overall
survival was documented (66 months vs 20 months, respectively), although it was not
statistically significant. MFH of bone should be treated as is osteosarcoma, with chemotherapy
and surgery.
Ewing's Sarcoma
Ewing's sarcoma (ES) is a rare tumor that usually occurs in bone and presents most frequently
during the second decade of life; it is an unusual occurrence before 5 or after 30 years of age.
In patients up to 13 years old, ES occurs with equal frequency in girls and boys; after age 13,
the disease is more common in males. ES is extremely rare in African and American blacks
and Chinese populations but constitutes 12% of malignant primary tumors of bone in white
persons. It was originally thought to arise from endothelial cells, but mesenchymal, myeloid,
reticular, pericystic, neuroepithelial, and primitive multipotential cells have been suspected to
be the cells of origin. The most widely accepted belief is that ES is of neuroectodermal origin.
ES is an undifferentiated, small, round-cell tumor that may be confused with other small,
round, blue-cell tumors of childhood, among them small-cell osteosarcoma, mesenchymal and
myxoid chondrosarcoma, rhabdomyosarcoma, lymphoma, neuroblastoma, and peripheral
neuroepithelioma.
Clinical Presentation, Prognostic Factors, and Staging: ES can affect any bone, although it
most commonly presents in the femur and pelvis. The axial skeleton is often involved. In the
long bones, ES usually localizes in the diaphysis, with frequent extension through the bone
cortex into the soft tissues. It presents as a rapidly enlarging mass causing poorly localized
pain. Constitutional symptoms, such as fatigue, weight loss, and fever, may be present,
especially in metastatic disease. Leukocytosis and an elevated erythrocyte sedimentation rate
(ESR) may mimic osteomyelitis. Metastases are present at the time of initial diagnosis in 15%
to 50% of cases. The lungs are the most common sites of metastasis at presentation or
relapse, followed by bone and bone-marrow sites. Metastases to the central nervous system
occur in fewer than 1% of patients.
Diagnostic and staging evaluations should include plain radiographs of the involved area and
the lungs, CT or MRI scans of the primary tumor, a CT scan of the lungs, a bone scan, and
bone-marrow biopsy and aspirate studies. There is no uniformly accepted staging system for
ES, but a TNM system seems appropriate. Lymph-node (N) involvement is rare.
Central location of the tumor, systemic symptoms at diagnosis, elevated pretreatment LDH
levels, the presence of a gross extraosseous extension of the primary tumor, metastatic
disease at diagnosis, and less-than-complete response to preoperative chemotherapy are poor
prognostic factors.
36
patients survived for 5 years. Death was usually caused by distant metastatic disease.
Because XRT can establish good local control of Ewing's sarcoma, the role of surgery has
historically been limited to diagnostic biopsy and primary control of an expendable bone, such
as a rib or clavicle. Surgery can also be used to treat the primary tumor when XRT would
jeopardize function. However, the higher rate of local control achieved with surgery or surgery
plus XRT, compared with XRT alone, and the desire for prevention of long-term side effects of
XRT (growth failure, normal tissue damage, and development of second malignancies) may
broaden the indications for surgery.
The advent of chemotherapy significantly improved the disease-free survival rate (50% to
60%) at 2 to 3 years, compared with such rates when XRT or surgery was used alone. The
most active single agents are cyclophosphamide (50%), doxorubicin (40%), vincristine
(Oncovin, 30%), dactinomycin (33%), etoposide (30%), and high-dose melphalan (Alkeran,
80%). Adjuvant chemotherapy is now accepted as standard therapy for ES. The combination
of vincristine, dactinomycin, and cyclophosphamide has been evaluated alone or with
doxorubicin or bilateral pulmonary XRT in a large intergroup study. According to this study, the
addition of doxorubicin significantly improved relapse-free survival and overall survival. A dose-
intensity relationship exists between doxorubicin and ES. A high-dose, intermittent method of
chemotherapy delivery using the four drugs listed yielded significantly better disease-free
survival (68%) and overall survival (77%) rates than a moderate-dose, continuous method
(48% and 53%, respectively). The high-dose, intermittent schedule also improved the relapse-
free survival and overall survival rates of patients with ES of the pelvic or sacral bones, a group
with a generally poor outcome.
The combination of ifosfamide and etoposide has also shown activity in newly diagnosed and
previously treated cases of ES, with response rates of 96% and 50% to 60%, respectively.
Longer follow-up is needed to assess the duration of these responses and their effect on
survival rates.
The prognosis for patients with recurrent or metastatic disease is poor. Combination
chemotherapy using doxorubicin, vincristine, cyclophosphamide, and dactinomycin has been
the basis of treatment. Methotrexate, bleomycin (Blenoxane), and fluorouracil have been
incorporated into some protocols with 5-year survival rates in the 30% range. XRT to the sites
of metastatic disease (bone or soft tissue) in a dose of 45 to 50 Gy can be considered for
palliation. Myeloablative therapy with high-dose etoposide, fractionated high-dose melphalan
with or without carboplatin (Paraplatin), and total-body irradiation has yielded promising results
(a projected relapse-free survival rate of 45% at 6 years, compared with a relapse-free survival
rate of 2% in the historic control group). These patients have a poor prognosis (multifocal
primary tumor and early or multiple relapses), and the follow-up has been short.
In contrast, Horowitz et al treated poor-risk patients with TBI and autologous bone marrow
transplantation support after complete remission was reached with induction therapy. However,
this study failed to show any benefit over nontransplantation protocols. Therefore, the role of
high-dose chemotherapy with bone marrow transplantation support remains controversial.
37
SOFT TISSUE SARCOMAS
Reference:
1. The Newcaste Upon Tyne Hospitals (NHS Trust)
2. Manual of Soft-Tissue Tumor Surgery. W. Lawrence, J.P. Neifeld, Jose J
Terz. Springer-Verlag
3. Orthoteers
4. Whats new in soft tissue soft sarcoma.
Available on URL: http://www.ieo.it/inglese/clinical/med_02_c.htm
5. Enhanced apoptosis of soft tissue sarcoma cells with chemotherapy: A
potential new
approach using TRAIL. M Clayer, S Bouralexis, A Evdokiou, S Hay, GJ
Atkins and DM Findlay. J. of Orthopaedic Surgery 2001, 9(2): 1922
Address correspondence & reprint requests to: Dr Mark Clayer, Depart.
of Orthopaedics & Trauma, The Queen Elizabeth Hospital, Woodville
Road,Woodville, South Australia 5011,Australia. E-mail:
mark.clayer@nwahs.sa.gov.au.
INCIDENCE
1500 people are diagnosed with a soft tissue sarcoma each year in UK.
STS can occur at any age but are more common in people over 30 years.
Most lumps in soft tissue are not cancer only about one in 200 is
cancer.
DEFINITION
Sarcomas are rare cancers tumours. They originate in the bodys
connective tissue, which include: bone, fat, cartilage, blood
vessels, nerves, muscle and deep skin tisuue.
There are over 200 types of cancer, but all start in the same way. The
control signals in a normal cell in the body go wrong, resulting in an
abnormal cell. Cells normally divide in a controlled way, but abnormall
cells keep on dividing, which can form a lump.
ETIOLOGY
PATHOLOGICAL CLASSIFICATION
Tissue of Benign Malignant Reactive
origin tumour like
lesions
38
Fibrous Fibroma Fibrosarcoma Palmar and plantar
Postradiation superficial
fibrosarcoma fibromatoses
Nodular fasciitis
Deep
extraabdominal
Proliferative fasciitis fibromatoses
Fibrohistiocy Fibrous histiocytoma Malignant Intermediate-
tic Atypical fibrous dermatofibrosarco
fibroxanthoma histiocytoma maprotruberans
Fat Lipoma (cutaneous Liposarcoma
deep or multiple)
Angiolipoma
Spindle cell
/pleomorphic lipoma
Lipoblastoma
Intra and
intermuscular lipoma
Hibernoma
Neurofibroma
Neurofibromatosis
39
Extraosseous Myositis ossificans Extraskeletal
Bone and chondrosarcoma
cartilage Extraskeletal
Fibrodysplasia
osteosarcoma
Panniculitis
ossificans
Extraskeletal
chondroma
Extraskeletal
osteoma
Unce
Tumoral calcinosis Alveolar soft
Myxoma part sarcoma
rtai Epithelioid
sarcoma
n Clear cell
sarcoma of
tendons and
aponeuroses
Extra-skeletal
Ewings
DIAGNOSTIC CLUES
Characteristics
Size
A mass that is small (< 5 cm in its greatest dimension) is unlikely
to be malignant, while a mass that is greater than 5 cm has at
least a 20% chance of being a soft tissue sarcoma.
The size of the lesion can be determined by physical examination
if the lesion is subcutaneous and easily palpable, or by
ultrasound, computed tomography (CT) or magnetic resonance
imaging (MRI).
Superficial or deep?
Superficial lesions are more likely to be benign and, when
malignant, may have a better prognosis than deep lesions.
The depth of the lesion is best determined by physical exam,
ultrasound or MRI.
The thigh and buttocks are the two most common sites for soft tissue
sarcomas. Any large deep mass in the thigh or buttocks should be
considered at high risk for being a malignant lesion.
40
Consistency on physical examination
Soft tissue sarcomas tend to be firm and not very painful until they get
very large and compromise their vascular supply or adjacent neural
structures.
Lipomas are usually nontender and soft to palpation. A deep lipoma
(intramuscular or infiltrating) may feel firm to palpation when the
muscular compartment is flexed. However if that compartment is
relaxed, the mass will then seem to "change" to the more classic soft
consistency.
Pseudoaneurysm. These are unusual lesions that can get very large, look
like a sarcoma on imaging studies but on physical examination they
should be pulsatile and have an audible bruit with auscultation.
Cystic or solid
Most cystic lesions are inflammatory or benign lesions, such as
ganglion cysts or soft tissue abscesses.
If the lesion is solid, it could represent either a benign or
malignant neoplasm.
Attempt transillumination
If deep ultrasound or MR scan will determine this
Length of symptoms
A mass that has rapidly increased in size over two months is
more likely to be a sarcoma than the lesion that has slowly
enlarged over a 20-year.
A mass that increases and decreases in size is usually a cystic
lesion.
However, caution should be taken with masses that have been
present for a long time. Soft tissue sarcomas occasionally present with
a history of many years duration. The longest length of symptoms of a
mass before diagnosis of a soft tissue sarcoma in the author's experience
has been 30 years.
41
Ossification (soft tissue osteosarcoma or myositis ossificans),
and skeletal abnormalities (osteomyelitis, primary bone lesion or
periosteal reaction from the soft tissue tumor).
MR Scan findings
The MRI gives the most information of any radiographic study
but should be reserved for large lesions or those that are ill
defined.
It will clearly delineate whether the lesion is a bone lesion with a
very large soft tissue component (bone malignancy) or whether
the lesion is a primary soft tissue lesion.
A lesion can have a low Tl weighted and a low T2 weighted
sequence, which means that it is either an extra-abdominal
desmoid tumor, extensive scar tissue, cortical or dense bone or a
foreign material such as bone cement or air.
A lesion can have a high T1 and a high T2 weighted sequence
that means that it is most likely a lipoma. A low-grade
liposarcoma occasionally can present with the same imaging
characteristics of a low Tl and a high T2 sequence. This could
be any lesion, neoplastic or otherwise, benign or
malignant.
DIAGNOSTIC STEPS
History
Examination +/- transillumination
Ultrasound and plain radiography
If lesion< 5cm, cystic and subcutaneous, observe
(If patient keen on removal use a longitudinal incision with good
haemostasis, ensure the incision can be encorporated in any
later excision and perform an excisional biopsy)
If lesion >5cm,or not cystic, or painful, perform MR scan, then
refer to tumour specialist for an incisional biopsy / trucut needle
biopsy / FNA.
If a possibility of malignancy exists, perform isotope bone scan
for other lesions, FBC, ESR, Chest Xray, CT scan of chest, for
metastases
PROGNOSTIC FACTORS
42
o Metastatic disease from soft tissue sarcomas is most
frequently identified in the lungs, less frequently in the
draining lymphatics and the skeleton.
o The standard staging studies include a physical
examination of the lymph nodes, a chest radiograph, a
chest CT, a whole body bone scan and possibly a gallium
scan.
2. Histologic grade.
o Patients with high-grade lesions have a worse
prognosis than patients with low grade lesions.
3. Size of the lesion
o Although small lesions (less than 5 cm) are rarely
malignant, when they are, they have a better prognosis
than larger lesions. The size cut-off is somewhat
arbitrary, but small is considered less than 5 cm to 8 cm
in most studies. This is measured as the single largest
dimension of the mass.
4. Depth of the lesion
o Superficial (subcutaneous) soft tissue sarcomas
have a better prognosis than deep (below the muscle
fascia) lesions.
Fibrous benign
2. Nodular fasciitis
43
Most locally invasive of the benign soft tissue tumours
Most common in adolescents and young adults
Rock hard on palpation
May be multiple lesions
Histologically well differentiated fibroblasts and abundant
collagen
Infiltrates surrounding tissues
Surgery aims at excision with a wide margin
Local recurrence common
Fibrous malignant
1. Fibrosarcoma
2. Fibrohistiocytic
Dermatofibrosarcoma protruberans
Rare, nodular cutaneous tumour
Occurs in early adult life
Intermediate in grade
Recurs locally but only rarely metastasises
Treat with wide resection
3. Malignant fibrohistiocytoma
44
Malignant fibrous histiocytomas are sarcomas of uncertain
histogenesis which have been associated with a poor prognosis,
appearing to have both histiocytic and fibroblastic features.
Malignant fibrous histiocytomas may metastasize
hematogenously (usually to the lungs) or lymphatically; of all
the soft-tssue sarcomas in adults, they have the highest
incidence of lymph node metastases.
1. Lipomas
1. Liposarcomas
45
Low grade liposarcomas - can be difficult to differentiate
between a benign lipoma and a low grade liposarcoma
Low grade liposarcomas treated with wide local excision +/-
radiotherapy
High grade liposarcomas treated with wide local excision +
radiotherapy
2. Neurofibroma
Solitary or multiple
Most are superficial, grow slowly and are painless
When they involve a major nerve they can expand the nerve in a
fusiform fashion
Histologically, interlacing bundles of elongated cells with wavy
dark staining nuclei
Treatment- excision with a marginal margin
In neurofibromatosis, malignant change occurs in 5-30% of
patients
46
Neurobrosarcom
Rare
Can arise de novo or in neurofibromatosis
Tend to be high grade, therefore treated with wide surgical
resection +/- radiotherapy
Leiomyoma, Rhabdomyoma
Seldom occur in the extremities, leiomyoma often arise in the
wall of the GIT. Other sites include the retroperitoneal area, skin
and subcutaneous tissues, and rarely major veins.
1. Leiomyosarcoma
2. Rhabdomyosarcoma
47
Benign vascular tumours
1. Haemangioma
1. Haemangiopericytoma
2. Angiosarcoma
Rare
Highly malignant
48
Occurs in close proximity to joints but rarely from an
intraarticular lesion
Xrays may show mineraalisation within the lesion
Histologically, tumour is biphasic with a spindle cell component
and an epithelial component
Treat with wide excision and adjuvant radiotherapy
3. Synovial chondromatosis
49
Other rare Sarcomas
1. Epitheloid Sarcoma
STAGE INFORMATION
The staging classification that is currently used for adult soft tissue
sarcomas is that proposed by Russell et al. Additional staging systems
include that proposed by the Intergroup Rhabdomyosarcoma Study
group, which is applicable to the pediatric age group, and the sarcoma
staging system proposed by Enneking for bone and soft tissue
sarcomas.
50
T0: No evidence of primary tumor
T1: Tumor 5.0 cm or less in greatest dimension
T2: Tumor more than 5.0 cm in greatest dimension
Nodal involvement (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
Distant metastasis (M)
MX: Presence of distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
Stage I
Stage IA: G1, T1, N0, M0
Stage IB: G1, T2, N0, M0
Stage II
Stage IIA: G2, T1, N0, M0
Stage IIB: G2, T2, N0, M0
Stage III
Stage IIIA: G3, T1, N0, M0 and G4, T1, N0, M0
Stage IIIB: G3, T2, N0, M0 and G4, T2, N0, M0
Stage IV
Stage IVA: any G, any T, N1, M0
Stage IVB: any G, any T, any N, M1
GENERAL INFORMATION
At the time of diagnosis, these are highly treatable, often curable
tumors that are best treated by an experienced multimodality team.
These tumors may be histologically heterogeneous, and adequate tissue
should be available for microscopic examination. Because the treatment
options available will depend on the extent of involvement of adjacent
tissues, careful planning of the initial biopsy is important. Since the
selection of treatment is determined by the histology of the tumor, it is
essential to have a careful review of the biopsy tissue by a pathologist
who is experienced in diagnosing sarcomas. Complete staging and
treatment planning by a multidisciplinary team of cancer specialists is
required to determine optimal treatment of patients with this disease.
51
The prognosis for adult soft tissue sarcomas depends on several factors,
including the patient's age and the size, histologic grade, and stage
of the tumor. While low-grade tumors are usually curable by aggressive
surgery alone, higher grade sarcomas (as determined by the mitotic
index and the presence of hemorrhage and necrosis) are associated with
higher local treatment failure rates and increasing metastatic potential
and require an aggressive local treatment plan. This plan may include
radiation therapy in addition to wide surgical excision. Mohs surgical
technique may be considered as an alternative to wide surgical excision
for small, well-differentiated sarcomas when cosmetic results are
considered to be of paramount importance, as margins can be assured
with minimal normal tissue removal.
Soft tissue sarcomas that have spread to distant sites are often
treatable. Patients who have pulmonary metastases alone may be
curable with resection of these lesions.
52
Treatment options:
Standard:
Extremities
Stage II soft tissue sarcomas have an increased potential for
metastatic spread. For sarcomas of the extremities, local control
comparable to that obtained with amputation may be achieved with limb-
sparing surgery that involves wide local excision in combination with
preoperative or postoperative radiation therapy. Regional (intra-
arterial) chemotherapy has been used in some centers in combination
with reduced doses of radiation therapy and surgery in limb-sparing
treatment. Whether this approach is superior, equivalent, or inferior to
other multimodality treatment is not yet established. There is
controversy about the amount of surgery performed when postoperative
radiation therapy is planned, but these tumors are frequently
surrounded by a pseudocapsule containing viable tumor cells; therefore,
they should never be simply "shelled out." Where conservative resection
and radiation therapy are not feasible, amputation should be the primary
recommendation to avoid local recurrence rates of 40% or higher.
53
metastasis-free or an overall survival benefit for adjuvant
chemotherapy. There was wide interstudy variability among the
numerous trials, including differences in therapeutic regimens, drug
doses, sample size, tumor site, and histologic grade. Although a meta-
analysis of 15 prospective randomized trials suggests a treatment
benefit in favor of adjuvant chemotherapy, inherent flaws and biases in
analyzing published data from disparate studies render any conclusions
unreliable.
Treatment options:
Standard:
Treatment options:
Standard:
54
STAGE IVA ADULT SOFT TISSUE SARCOMA
Treatment options:
Standard:
Stage IVB soft tissue sarcomas are those that have spread to distant
sites, most commonly to the lung. Stage IVB sarcomas with
metastases only to the lung may be curable (20%-30% of the cases) by
aggressive treatment of the primary tumor and resection of the
pulmonary metastases, even if multiple bilateral metastases are
present. The primary tumor in these cases should be treated as stage II
or III sarcomas, with wide excision followed by high-dose radiation
therapy or systemic chemotherapy. There are a number of active
combination chemotherapy regimens, including doxorubicin plus
ifosfamide, and CYVADIC (cyclophosphamide, vincristine, and
doxorubicin plus dacarbazine). However, none appears to be superior to
single-agent doxorubicin. For patients with multiple unresectable
pulmonary metastases or widespread disseminated disease, palliation
may be provided by radiation therapy to the primary tumor and systemic
chemotherapy. For patients with unresectable stage IVB disease,
standard therapy is not curative and is inadequate.
Treatment options:
Standard:
55
a. Surgical excision with negative tissue margins of several
centimeters in all directions.
b. If the tumor is resectable but wide margins cannot be obtained,
radiation therapy is added.
c. If the tumor is unresectable, high-dose radiation therapy may be
used.
d. For tumors of the retroperitoneum, trunk, and head and neck,
surgical resection with radiation therapy may be used.
e. In some centers, radiation therapy may be used prior to and
following surgical extirpation.
New
info!
!!
The poor sensitivity of most soft tissue sarcomas to traditional
chemotherapeutic agents, like doxorubicin, has been reported to have a
response rate of only 34% at best and most studies report approximately
26%. Recently, attention has been drawn to the potential use of the TNF
family member, tumor necrosis factor-related apoptosis-inducing ligand
(TRAIL/Apo2L), as a selective anti-tumour agent. The combination of
TRAIL and conventional
chemotherapeutic agents has been shown to be synergistic with respect
to inducing cell death in several cancer types in vitro. We tested this
approach, which has not previously been reported for freshly isolated
sarcoma cells, in a variety of soft tissue sarcomas in primary culture. We
found an increased sensitivity of sarcoma cells to chemotherapeutic
56
agents in the presence of TRAIL, suggesting that this combination may
be useful in the future treatment of sarcomas.
Thalidomide
Thalidomide is an anti-angiogenic drug. This means a
drug that blocks the growth of new blood vessels. Recommended
dose was 100 mg/12 hrs orally.
INTRODUCTION
57
Background: Soft tissue sarcomas, the fifth most common solid tumor in
children, are relatively rare, comprising about 6-7% of childhood malignancies.
Rhabdomyosarcomas account for about half of these tumors;
nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) account for the remainder
(ie, about 3% of childhood malignancies).
Fibrosarcoma
58
Rarely observed in young children, malignant fibrous histiocytoma is usually
observed in patients older than 10 years and occurs primarily in the extremity.
Cytogenetic analysis demonstrates chromosome 19p+ and ringed chromosomes.
Malignant fibrous histiocytoma has very similar histology to fibrosarcoma except
for the loss of a herringbone cellular pattern and more malignant phenotype.
These tumors are commonly observed in radiation-induced sarcomas. The most
common metastatic site is the lung. Surgical excision with irradiation to residual
local disease is the therapy of choice. Chemotherapy may be useful in select
cases. Chemotherapy regimens, including the agents vincristine, dactinomycin,
and cyclophosphamide, with and without radiation have been somewhat
successful in select pediatric and adult patients. Activity has also been observed
with ifosfamide and etoposide combinations. The optimal use of chemotherapy in
this tumor is yet to be determined.
Synovial sarcoma
One of the most common NRSTS, synovial sarcoma is rarely observed in children
younger than 10 years. One third of cases occur in individuals younger than 20
years. With synovial sarcoma, the most common chromosomal abnormality is
t(x;18)(p11.2,q11.2) and the genes involved are SYT-SSX. The tumors are usually
in the extremity, with lower extremity lesions more common than upper extremity
lesions. Pathologically, the 2 forms of tumor are a spindle cell fibrous form and a
glandular form with epithelial differentiation. The most common site for
metastasis is the lung. Surgical resection followed by radiation of residual disease
is the best therapy.
This NRSTS is rare, usually arising in individuals aged 15-35 years. The primary
site of occurrence in children is the head and neck; orbit and tongue tumors are
most common. Patients with alveolar soft part sarcoma usually present with an
indolent slow-growing mass. Short-term prognosis is good, with 80% of patients
alive at 2 years from diagnosis. However, the long-term survival rate is poor
regardless of initial stage of disease. In several cases, a chromosomal abnormality
at 17q25 has been demonstrated. Pathologic classification of this tumor is
uncertain, but some evidence of myogenic differentiation has been made. Alveolar
soft part sarcoma often arises in skeletal muscle tissue. The most common site of
metastasis is the lung, followed by the brain, bone, and lymph nodes. The primary
treatment modality is surgical, with radiation and chemotherapy reserved for
disease recurrence. Surgical resection is also indicated for select metastatic sites
as well.
Leiomyosarcoma
59
triad), which is most commonly found in young women. Surgical resection has
been the most common approach to treatment of this NRSTS. Generally, tumors
in the GI tract have a poor prognosis. Prognosis is good with complete resections
of tumors outside the GI tract. The role of radiation therapy and chemotherapy in
leiomyosarcoma is still unknown.
Liposarcoma
Frequency:
Race: Blacks have a slightly higher incidence than whites (14 cases versus 10
cases per 1 million population).
Sex: Males have a slightly higher incidence than females (12 cases versus 10
cases per 1 million population).
Age: Incidence rates for NRSTS among young children are highest in infancy,
affecting approximately 15 per 1 million infants. Incidence drops in the second
year of life to a fairly stable rate until about age 10 years when approximately 8-
10 per 1 million children are affected. For individuals older than 10 years, the
incidence rate increases to about 15 cases per 1 million population annually.
CLINICAL
60
Physical: Physical examination findings of patients with NRSTS depend on the
location of the mass. A palpable mass is noted in most cases. Specific tumors may
be associated with specific findings. Malignant peripheral nerve sheath tumors
may be associated with neurofibromatosis type I, which is characterized by caf
au lait spots, axillary freckling, neurofibromas, skeletal dysplasias, learning
disabilities, and a variety of neoplasms. CNS tumors may cause an abnormal
neurologic examination finding depending on the location of the mass and what
structures are affected.
DIFFERENTIALS
Liposarcoma
Lymphadenopathy
Neuroblastoma
Nonrhabdomyosarcoma Soft Tissue Sarcomas
Osteosarcoma
Rhabdomyosarcoma
Diagnosis can be confirmed only with biopsy of the mass. Other malignancies that
cause masses in children must be considered in the evaluation, such as
lymphomas, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and
neuroblastoma. Benign lesions, such as lipoma or rhabdomyoma should be
considered as well.
WORKUP
Lab Studies:
Imaging Studies:
61
CT and MRI scanning of the involved mass area are used to determine
the size of the mass and the extent of local involvement and impingement
on adjacent structures. These studies also define surgical resection
options. Contrast enhanced studies are most helpful. Abdominal CT
scanning is important for abdominal primaries and to determine liver
involvement.
Other Tests:
Procedures:
62
Consider long-term venous access. In most cases, placement of an
implanted or externalized central venous catheter is useful for
monitoring laboratory studies and delivering chemotherapy and
supportive care.
Staging:
Stages
Groups
63
o Gross residual disease (primary site or regional nodes)
o Distant metastases
TREATMENT
Brachytherapy has been used with some success in select centers for
pediatric cases of NRSTS.
Surgical Care:
Wide local excision is the primary form of therapy for NRSTS. Every
attempt is made to obtain negative tumor margins, which can be
accomplished in 50-80% of patients.
64
o New orthopedic limb lengthening procedures and prostheses
may make this a more viable option in select patients.
MEDICATIONS
The following chemotherapeutic agents are used in select cases of NRSTS. Doses
and schedules of treatment for an individual agent vary with the clinical
environment in a particular patient. General facts, representative pediatric doses,
and toxicities for each agent are noted.
The cell division rate varies for different tumors. Most common cancers increase
very slowly in size compared to normal tissues, and the rate may decrease further
in large tumors. This difference allows normal cells to recover more quickly than
malignant ones from chemotherapy, and it is the rationale behind current cyclic
dosage schedules.
Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle
specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not
phase specific. Cellular apoptosis (ie, programmed cell death) also is a potential
mechanism of many antineoplastic agents. Refer to specific protocol for duration
65
of therapy with each drug and timing of administration within each treatment
cycle.
66
Hemorrhagic cystitis can occur at higher doses if
adequate hydration and urine output are not maintained;
mesna used for bladder protection with
cyclophosphamide and ifosfamide; fluid retention
Precautions resolves with low doses of furosemide; renal output may
be compromised by fluid retention secondary to SIADH-
type effect; myelosuppression, nausea, vomiting,
alopecia, cystitis, water retention, decreased fertility,
and cardiac necrosis (in high doses)
67
Etoposide (Toposar, VePesid) -- VP-16 is a plant
alkaloid. Usually administered IV as slow or continuous
infusion. Use PO in certain diagnoses. Rapid infusion
Drug Name causes hypotension and allergic reactions.
It inhibits topoisomerase II and causes DNA strand
breakage, causing cell proliferation to arrest in the late
S or early G2 portion of the cell cycle.
Adult Dose 100 mg/m2 IV on days 1-5
Pediatric Dose Administer as in adults
Contraindication
Documented hypersensitivity
s
May prolong the effects of warfarin and increase the
Interactions clearance of methotrexate; cyclosporine and etoposide
have additive effects in the cytotoxicity of tumor cells
Pregnancy D - Unsafe in pregnancy
Infuse over 1 h to avoid hypotension; long-term concern
with high cumulative doses is secondary malignancy,
particularly acute myelogenous leukemia;
Precautions
myelosuppression, alopecia, nausea, vomiting, mucositis,
mild neurotoxicity, hepatic, hypotension, and allergic
reactions
68
0.045 mg/kg/dose for 1 d; alternate 0.015 mg/kg/dose for
Pediatric Dose
5d
Contraindication Documented hypersensitivity; chicken pox; herpes
s zoster; concomitant radiation
Increases risk of hepatotoxicity with enflurane or
Interactions
halothane
Pregnancy D - Unsafe in pregnancy
Myelosuppression, nausea, vomiting, alopecia, mucositis
Precautions
and hepatitis
Antineoplastic agents may cause nausea and vomiting so intolerable that patients
may refuse further treatment. Some antineoplastic agents are more emetogenic
than others. Prophylaxis with antiemetic agents before and after cancer treatment
often is essential to ensure administration of the entire chemotherapy regimen.
69
Ondansetron is discussed here, but other effective antiemetics include
granisetron, metoclopramide, diphenhydramine, lorazepam, perphenazine,
prochlorperazine, and trimethobenzamide.
In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol
groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite
considered responsible for urotoxicity.
FOLLOW UP
70
Further Inpatient Care:
o Disease recurrence
Prognosis:
71