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Benign and Malignant Soft

Tissue Tumors
eMedicine, Last Updated: June 28, 2002

Synonyms and related keywords: sarcoma, fibrosarcoma, liposarcoma,


lipoma, head and neck cancer, retroperitoneal cancer, visceral
sarcoma, neurofibromatosis, neurofibroma, synovial sarcoma, Kaposi
sarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma,
liposarcoma, intramuscular lipoma, Ewing sarcoma, primitive
neuroectodermal tumors.

Author: Vinod B Shidham, MD, FIAC, MRCPath, Director of Fellowship


Training Program, Associate Professor, Department of Pathology,
Medical College of Wisconsin

INTRODUCTION

History of the Procedure: Present achievements in the field of soft


tissue tumors are the result of advances in molecular biology,
oncogenetics, imaging techniques, immunochemistry, diagnosis by
fine-needle aspiration, surgical reconstruction, radiation
therapy, and tissue banking. Benign soft tissue tumors are
fairly common and are treated with surgery alone. Prior to
1970, surgery was the primary therapy for malignant soft tissue
tumors, and most patients with high-grade tumors had a poor
prognosis with a significant mortality rate. Since the mid
1970s, radiation therapy, chemotherapy, and advanced surgical
techniques have improved the ability to achieve long-term
survival while decreasing the need for ablative surgery. Future
advances in molecular oncology may improve diagnostic,
prognostic, and treatment protocols for patients with soft
tissue sarcomas.

Problem: Soft tissue is defined as the supportive tissue of various


organs and the nonepithelial extraskeletal structures exclusive of
lympho-hematopoietic tissues. It includes fibrous connective tissue,
adipose tissue, skeletal muscle, blood/lymph vessels, and the
peripheral nervous system. Embryologically, most of it is derived
from mesoderm, with a neuroectodermal contribution in the case of
peripheral nerves.

Soft tissue tumors are a large and heterogenous group of neoplasms.


Traditionally, tumors have been classified according to histogenetic
features (eg, fibrosarcoma classified as a tumor arising from
fibroblasts). However, histomorphologic, immunohistochemical, and
experimental data suggest that most, if not all, sarcomas arise from
primitive multipotential mesenchymal cells, which in the course of
neoplastic transformation, differentiate along one or more lines. A
liposarcoma appears to arise from a lipoblast but may in fact
actually arise by lipoblastic differentiation of a precursor
multipotent mesenchymal cell. At the clinical level, soft tissue
tumors are classified according to various parameters including
location, growth pattern, likelihood of recurrence, presence and
distribution of metastases, patient age, and prognosis.

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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.

Frequency: True incidence of soft tissue tumors is not well


documented. In general, benign tumors occur at least 10 times more
frequently than malignant soft tissue tumors.

Data from the National Cancer Institute, Surveillance, Epidemiology,


and End Results Program (SEER) from 1973-1983 comprising 6883 soft
tissue sarcomas offer some insight. Overall age-adjusted annual
incidence ranges from 15-35 sarcomas per 1,000,000 population. The
rate increases steadily with age and is slightly higher in men than
in women.

Malignant soft tissue tumors occur twice as often as primary bone


sarcomas.

Approximately 45% of sarcomas occur in the lower extremity, 15% in


the upper extremity, 10% in the head and neck region, 15% in the
retroperitoneum, and the remaining 15% in the abdominal and chest
wall. Visceral sarcomas, arising from the connective tissue stroma in
parenchymal organs, constitute a small minority of cases.

The different types of soft tissue tumors have distinct age


distributions. Rhabdomyosarcoma is seen more frequently in children
and young adults. Synovial sarcoma arises in young adults. Malignant
fibrous histiocytoma and liposarcoma generally arise in older adults.
Benign deep masses in adults usually are due to intramuscular lipoma.
In general, the prognosis in older patients with a diagnosis of high-
grade sarcoma is poor.

The incidence of soft tissue tumors is slightly higher in males than


in females.

Etiology:

Genetic conditions

Good evidence exists suggesting that certain genetic disorders and


gene mutations are predisposing factors for some benign and malignant
soft tissue tumors. The NF1 gene in neurofibromatosis is a classic
example, predisposing patients to multiple neurofibromas with
proclivity for malignant transformation. Many tumor suppressor genes,
oncogenes, and cytogenetic defects are now associated with various
soft tissue sarcomas. Other clinical risk factors account for a small
proportion of soft tissue malignancies.

A partial list of reported cytogenetic abnormalities is shown in


Table 1. These cytogenic abnormalities have a significant role in
diagnosis. In the future, some of these abnormalities may be of
therapeutic significance. Specific translocations involving selected
genes have been observed. One of these is the t(X;18) translocation
in synovial sarcoma, resulting in fusion of the SYT gene from
chromosome 18 to either of 2 highly homologous genes at Xp11, SSX1 or
SSX2. SYT-SSX fusion transcript may be detected by reverse
transcriptase-polymerase chain reaction (RT-PCR) assay using a

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cytologic specimen from fine-needle aspiration biopsy (FNAB),
histological material from paraffin block, or from frozen material.

Radiation

Similar to postirradiation bone tumors, postirradiation fibrosarcomas


have been described. The pathogenetic mechanism is the emergence of
radiation-induced genetic mutations leading to neoplastic
transformation.

Chronic lymphedema

As observed in patients with late-stage breast carcinoma, chronic


lymphedema may predispose patients to the development of
lymphangiosarcoma.

Environmental carcinogens

Various carcinogens have been reported in association with an


increased incidence of soft tissue tumors. Examples include arsenic,
thorium dioxide, and vinyl chloride exposure in relation to hepatic
angiosarcoma.

Infection

Kaposi sarcoma due to human herpesvirus 8 (HHV 8) in patients with


human immunodeficiency virus (HIV) is a classic example of an
infection-induced soft tissue tumor. Infection with Epstein-Barr
virus in an immunocompromised host also increases the likelihood of
the patient developing soft tissue tumors.

Trauma

The relationship between trauma and soft tissue tumors appears to be


coincidental. Trauma probably draws attention to a preexisting
lesion.

Pathophysiology: Generally, soft tissue tumors grow centripetally,


although some benign tumors, such as fibromatosis, may grow
longitudinally along tissue planes. Most soft tissue tumors respect
fascial boundaries and hence remain confined to the compartment of
origin until later stages of disease. Once the tumor reaches the
anatomic limits of the compartment, the tumor is more likely to
breach compartmental boundaries. Major neurovascular structures
usually are displaced as opposed to being enveloped or invaded by
tumor. Tumors arising in extracompartmental locations such as the
popliteal fossa may expand more quickly due to lack of fascial
boundaries and are also more likely to involve neurovascular
structures.

The peripheral portion of the tumor compresses surrounding normal


soft tissue due to centripetal expansile growth and results in the
formation of a more or less well-defined zone of compressed fibrous
tissue potentially containing scattered tumor cells. This zone may
also consist of inflammatory cells and neovascularity. A thin layer

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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.

Some extremely aggressive lesions with infiltrative growth patterns,


such as childhood rhabdomyosarcoma, may not respect anatomic
compartmental boundaries and frequently may invade fascial planes.

Local recurrence

Soft tissue sarcomas have the propensity to recur locally, and


recurrences are more difficult to treat than the primary lesion;
thus, complete resection and appropriate use of radiation therapy are
critical during the initial treatment. The pseudocapsule provides
surgeons with a more or less obvious plane of dissection; however,
such an excision may leave behind microscopic or occasionally gross
tumor. Such marginal excisions may lead to local recurrences in up to
80% of patients. The addition of postoperative radiation therapy
decreases the risk of recurrence associated with a marginal
resection.

Technical ease of resectability and thus the likelihood of local


control may be affected by the location of a soft tissue sarcoma. For
example, lesions of the head and neck are more likely to involve or
abut vital structures and, thus, are often more difficult to resect
than lesions of the extremities. Even in the extremity, the tumor
site may have prognostic implications. For proximal tumors, local
control is more difficult to achieve than in tumors located more
distally. Retroperitoneal sarcomas have higher proclivity for local
recurrence and intra-abdominal dissemination and, in general, have a
poor prognosis.

The pattern of recurrence generally is predictable, and most tumors


destined to recur do so within the first 2-3 years. Adjuvant
radiation therapy clearly minimizes local recurrence, although its
impact on increasing overall chances for survival is likely but less
certain. Adjuvant chemotherapy may decrease the risk of local
recurrence of high-grade tumors, presumably due to a reduction in the
size of the tumor and an increase in the reactive zone, but this
notion is very controversial.

Distant metastasis

Regional lymph node involvement is rare in soft tissue sarcomas;


fewer than 4% of cases have nodal metastases at presentation. Lymph
node involvement is more frequent in epithelioid sarcoma,
rhabdomyosarcoma, synovial sarcoma and clear cell sarcoma. Carcinoma
and melanoma should be included in the differential diagnosis for any
mass presenting with lymph node metastases.

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

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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.

Clinical: A mass is the most common symptom of a soft tissue tumor.


It usually is painless and does not cause limb dysfunction. However,

depending on the anatomic location of the tumor, it may cause pain or


neurologic symptoms by compression or stretching of nerves,
irritation of overlying bursae, or expansion of sensitive structures.
A rapid rate of increase in the size of a mass should arouse
suspicion that the lesion is malignant.

Physical examination can be used to determine the location and size


of a mass and to exclude other more common causes of pain. Whether
the mass is deep or subcutaneous, whether it transilluminates
(cysts), and whether it is adherent to underlying structures can also
be gleaned from physical examination. Regional lymph nodes should
also be examined. Neurovascular examination is useful to detect
either a primary or secondary involvement by a tumor.

Extremity masses larger than 5-7 cm and deeper than subcutaneous


tissue favor a diagnosis of a malignant soft tissue tumor. However,
up to 30% of soft tissue sarcomas occur in subcutaneous tissue and
exhibit relatively less aggressive behavior.

WORKUP

Lab Studies:

Other than histologic and cytogenetic analysis, no specific


laboratory tests exist for diagnosing soft tissue tumors.
However, ancillary studies may be indicated as part of the
general workup in patients with other systemic conditions.

Imaging Studies:

In the last 2 decades, imaging studies have contributed


greatly to the management of soft tissue tumors. Though
imaging studies cannot themselves yield a specific diagnosis
(except in a few conditions, eg, lipoma or liposarcoma), they
are extremely useful to define anatomic location, tumor
extent, and involvement of vital structures.

Imaging studies should be obtained prior to biopsy to ensure


that a biopsy of a potentially malignant lesion is taken in a
manner that will not preclude limb salvage surgery. In
addition, the biopsy tract can adversely affect the anatomic
detail seen on an MRI. Evaluate the relationship of the tumor
and surrounding normal structures to the planned biopsy site.
Evaluate functional status of the involved limb, signs of
lymph node involvement, and any other factors that could
compromise optimal surgical or radiation therapy.

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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:

Biopsy usually is indicated for a soft tissue mass arising in


a patient without a history of trauma or for a mass that
persists more than 6 weeks following local trauma. Biopsy all
soft tissue masses larger than 5 cm, as well as any enlarging
or symptomatic lesions. Small subcutaneous lesions that
persist unchanged for years may be considered for observation
rather than biopsy. A high level of suspicion is necessary to
ensure early treatment.

Early tissue diagnosis is the most important component of


multimodality treatment for soft tissue tumor. Proper and
timely biopsy is critical. An inadequately performed biopsy
may complicate patient care and result in loss of limb or
life. Several biopsy techniques are available, including FNAB,
core needle biopsy, incisional biopsy, and excisional biopsy.
The choice of biopsy is based on the size and location of the
mass and the experience of the surgeon. Excisional biopsy is
indicated only for small superficial masses (<3-5 cm in
greatest dimension). The probability of malignancy in these
cases is low. Effective reexcision is more likely for smaller
malignant lesions that are unintentionally treated as benign
initially.

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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.

Table 1. Characteristic Cytogenetic Aberrations


in Soft Tissue Tumors

Benign Soft Tissue Characteristic


Tumors Cytogenetic Events Frequency

Benign schwannoma Monosomy 22 50%

Desmoid tumor Trisomy 8 25%

Deletion of 5q 10%

Rearrangement of
Lipoblastoma >25%
8q

Rearrangement of
Lipoma, solitary 75%
bands 12q14-15

Rearrangement of
10%
6p

Deletion of 13q 10%

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Uterine leiomyoma t(12;14)(q15;q24) 20%

Deletion of 7q 15%

Trisomy 12 10%

Malignant Soft Characteristic


Frequency
Tissue Tumors Cytogenetic Events

Clear cell sarcoma t(12;22)(q13;q12) >75%

Dermatofibrosarcoma
Ring chromosome 17 >75%
protuberans

Ewing sarcoma t(11;22)(q24;q12) 95%

Extraskeletal
myxoid t(9;22)(q31;q12) 50%
chondrosarcoma

Liposarcoma, myxoid t(12;16)(q13;p11) 75%

Liposarcoma, well
Ring chromosome 12 80%
differentiated

Alveolar
t(2;13)(q35;q14) 80%
rhabdomyosarcoma

95%
Synovial sarcoma t(X;18)

With the help of relevant ancillary techniques,


diagnostic accuracy with FNAB is very high, and
soft tissue tumors can be graded. This method

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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 Core needle biopsy


This technique retrieves a thin core of tissue
(approximately 1X10 mm). The procedure may be
performed using various needles (most commonly
a Tru-Cut needle). The core may not be
representative of the entire tumor, so
nonrepresentative grading is possible. FNAB
samples a larger area of the tumor with more
cellular material for proper evaluation than
core needle biopsy.
Concern has been expressed about possible
dissemination of tumor cells beyond the
confines of the primary site; however, this
appears to be uncommon. Both core needle and
open biopsies can result in histological
diagnosis and grading of a sarcoma in more than
90% of cases. Similar to FNAB, biopsy may be
taken of deeper lesions under image guidance
(eg, CT scan, ultrasound, MRI).

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.

o Frozen section and intraoperative cytology

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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.

Histologic Findings: The outline below comprises the histological


classification of soft tissue tumors. The histopathological
evaluation of soft tissue tumors with categorization into one of the
types listed in Table 1 is performed on permanent sections. This may
require results from immunochemistry and other tests, such as
cytogenetics, electron microscopy, and molecular studies.

Once the diagnosis of sarcoma has been established, the most


important consideration in determining the treatment strategy is the
histological grade of the tumor. Sarcomas usually are assigned a
grade; low-grade sarcomas rarely metastasize, although they can be
locally aggressive, and high-grade sarcomas pose a significant threat
of metastasis with higher risk of local recurrence. The pathological
grade assigned to an individual tumor is subjective. Assigning these
grades can be a difficult task. The clinical importance of the tumor
grade cannot be overemphasized, and an ideal biopsy should allow a
confident grade assignment with proper sampling of the lesion.

Grading systems are based on evaluation of various histomorphological


features. Many systems exist and generally are based on evaluation of
cellularity, cellular pleomorphism, mitotic activity, and necrosis,
in addition to histological category. The grading system with 3
grades (grade 1, 2, 3) may be simplified further by lumping them into
low-grade (grade 1) and high-grade (grade 2).

More recently, other markers have been investigated as potential


indicators of proliferation activity of soft tissue tumors. They
include Ki-67, argyrophilic stain for nucleolar organizer regions
(AgNOR), mast cell counts, and DNA flow cytometry.

A histological classification of soft tissue tumors is as follows:

I. Fibrous tumors
o IA. Benign tumors

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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

a. Palmar and plantar fibromatosis


b. Penile (Peyronie) fibromatosis
c. Knuckle pads
2. Deep fibromatoses (desmoid tumor)
a. Abdominal fibromatosis (abdominal
desmoid)
b. Extra-abdominal fibromatosis (extra-
abdominal desmoid)
c. Intra-abdominal fibromatosis (intra-
abdominal desmoid)
d. Mesenteric fibromatosis (including
Gardner syndrome)
e. Infantile (desmoid-type) fibromatosis
o IC. Malignant tumors
1. Fibrosarcoma
a. Adult fibrosarcoma
b. Congential or infantile fibrosarcoma
c. Inflammatory fibrosarcoma (inflammatory
myofibroblastic tumor)
II. Fibrohistiocytic tumors
o IIA. Benign tumors
1. Fibrous histiocytoma
a. Cutaneous fibrous histiocytoma
(dermatofibroma)
b. Deep fibrous histiocytoma
2. Juvenile xanthogranuloma
3. Reticulohistiocytoma
4. Xanthoma
o IIB. Intermediate tumors
1. Atypical fibroxanthoma
2. Dermatofibrosarcoma protuberans (including
pigmented form Bednar tumor)
3. Giant cell fibroblastoma
4. Plexiform fibrohistiocytic tumor
5. Angiomatoid fibrous histiocytoma
o IIC. Malignant tumors
1. Malignant fibrous histiocytoma
a. Storiform-pleomorphic fibrous
histiocytoma
b. Myxoid fibrous histiocytoma
c. Giant cell fibrous histiocytoma
(malignant giant cell tumor of soft
parts)

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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

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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

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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

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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

Staging: The grading, tumor, node, metastases (GTNM) staging system


is used in staging benign and malignant soft tissue tumors.

The usual tumor, node, metastases (TNM) classification is modified to


a GTNM system for soft tissue sarcomas (see Table 2). Histologic
grading is an important prognostic factor in sarcomas, so it is
incorporated into the TNM classification, resulting in a modified
GTNM system. This staging system is very useful clinically and
stratifies patients into groups with distinct prognostic patterns.

In addition to tumor grade, size of the tumor also is of prognostic


significance. The risk of metastasis and death is higher with larger
primary sarcomas. According to the current American Joint Commission

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.

Site also is a significant prognostic factor. Superficially located


tumors (those situated entirely superficial to the deep or muscular
fascia) have a relatively better prognosis. Alternative staging
systems incorporate this factor.

GTNM staging system definitions are as follows:

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

Table 2. AJCC GTNM Classification and Stage Grouping of Soft Tissue


Sarcomas

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

Stage IVA Any G Any T N1 M0

Stage IVB Any G Any T Any N M1

TREATMENT

Medical therapy: High-grade soft tissue sarcomas are often treated


with ifosfamide- and Adriamycin-based chemotherapy. This is
controversial, as no definitive studies exist proving that adjuvant
chemotherapy contributes to prolonged overall survival.

Surgical therapy:

Localized tumors: Complete local excision is adequate treatment for


benign soft tissue tumors. Treatment of localized primary and
recurrent sarcomas, however, may involve various treatment
approaches, including surgery alone or surgery combined with
radiation therapy or chemotherapy.

Extremity sarcoma

Extremity sarcomas may be treated surgically, with or without


radiation therapy and adjuvant chemotherapy.

Surgery is the most important component of any treatment plan for a


clinically localized primary or recurrent soft tissue sarcoma. Based
on the achievable margin, 4 types of excisions may be performed.

Intracapsular excisions and amputation: The excision or


amputation passes within the tumor itself. The tumor inside
the pseudocapsule is removed (often piecemeal). Incidence of
local recurrence with these types of excisions is virtually
100%; these procedures are performed only in unusual
circumstances.
Marginal excisions and amputation: The excision is performed
through the pseudocapsule surrounding the tumor. Shelling-out
procedures and most excisional biopsies belong to this
category. The chance of local recurrence is 20-75% depending
upon the nature of the tumor and whether radiotherapy is used.
Wide excisions and amputation: The tumor is excised with a
wide margin of surrounding normal tissue but within the
muscular compartment. Incidence of local recurrence following
wide excision without adjuvant therapy varies and may be up to
30%. The incidence of local recurrence depends on the
selection criteria used and the adequacy of the histologically
assessed surgical margin. A wide amputation is performed

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.

Small, superficial, or low-grade tumors with wide local excision


alone have a very low risk of local recurrence. For better local
control, many patients undergoing surgical excision receive radiation
therapy. In patients who refuse or cannot tolerate surgery, radiation
alone has been shown to be effective therapy for certain extremity
sarcomas.

Postoperative radiation therapy: Following wide surgical


excision, radiation therapy enhances local control for primary
extremity sarcomas. The concept of limb-sparing surgery with
postoperative radiation has been validated by randomized
trials of amputation versus wide local excision. Usually, a
total dose of about 60 grays (Gy) is adequate.
Brachytherapy: Postoperative radiation also can be delivered
to the tumor bed by means of brachytherapy (implanted
radioactive sources). The advantage of this approach is a much
shorter time for initiation and completion of therapy than
with external radiation. External beam radiation is used for 6
weeks beginning a month or more following surgery;
brachytherapy usually is started within a week of surgery and
completed in 4 or 5 days. Due to its technical complexity,
brachytherapy requires an experienced radiation oncologist
during the operating procedure. Brachytherapy and external
beam radiation appear to be equally effective when properly
administered.
Preoperative radiation therapy: Preoperative radiation therapy
may permit less radical surgery in cases with large tumors
that otherwise may compromise limb-sparing procedures. When
tumors respond to radiation therapy, tumor size is reduced,
thereby decreasing the magnitude of resection needed and
reducing the risk of seeding by viable tumor cells. Local
fibrosis may make the resection more challenging.

Even following local control, the risk of metastatic disease


following multimodality treatments without amputation in patients
with intermediate-grade and high-grade soft tissue sarcomas is up to
50%. The risk is even higher if stage IIIB tumors are included. Thus,
effective systemic adjuvant chemotherapy is desirable following
definitive treatment of local disease. However, conclusive evidence
that adjuvant chemotherapy for extremity sarcomas increases overall
survival rates is lacking. Randomized trials have not demonstrated
improvement in overall survival rates following adjuvant doxorubicin
therapy compared to overall survival rates following surgery alone.

In randomized clinical trials, multiagent chemotherapy with


doxorubicin, cyclophosphamide, and methotrexate following surgery
improved disease-free survival rates for patients with high-grade
extremity sarcomas (but not those of the trunk or retroperitoneum).
However, the toxicity of this regimen was substantial.

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.

A significant hypothetical advantage of neoadjuvant chemotherapy is


that it allows for monitoring of treatment effectiveness by
evaluating the degree of necrosis in the resected primary tumor.
However, no evidence that this results in improved clinical prognosis
exists.

Nonextremity sarcoma

Similar to that of sarcomas of extremities, therapeutic management of


nonextremity sarcomas includes surgery, radiation, and chemotherapy.
Sarcomas arising in the head and neck, thoracic or abdominal wall,
mediastinum, and retroperitoneum are difficult to treat. Most of
these tumors arise in areas where surrounding normal tissue limits
the maximum dosage of radiation that can safely be delivered to the
tumor bed. In general, the risk of local recurrence is high. For
retroperitoneal tumors, the patient usually succumbs due to local
complications before metastases are evident.

Recurrent and metastatic disease

As many as 35% of patients develop local recurrence or distant


metastases following surgical resection in addition to adjuvant
therapy. Eighty percent of local recurrences and disseminated
metastases were observed within 5 years.

Though removal of normal lymph nodes generally has no role in the


treatment of soft tissue sarcomas, dissection of biopsy-proven tumor-
positive lymph nodes is recommended in the absence of metastatic
disease elsewhere. Radical lymphadenectomy in patients with nodal
involvement without pulmonary metastases may yield better 5-year
survival rates.

Whenever technically amenable, surgical removal of pulmonary


metastases is recommended following thorough evaluation for
extrapulmonary tumor. In one study, resection of isolated pulmonary
metastases achieved an actuarial 3-year survival rate of 38%. Fewer
than 3 or 4 metastatic nodules as observed with the preoperative CT
scans is a favorable prognostic factor.

Since some clinical response has been achieved with neoadjuvant


chemotherapy in soft tissue sarcomas, studies to evaluate high dose
therapy with autologous stem cell transplant have been conducted.
These have been pursued for patients with a high risk of metastatic
disease at the time of diagnosis and as salvage therapy at the time
of disease relapse. Most of these studies have been conducted in
children with small blue cell tumors (Ewing sarcoma, primitive
neuroectodermal tumors). The results of these studies have been
mixed. Randomized trials have not been reported. Some studies showed
improvement in survival compared to control patients treated with
conventional therapy. Other studies have failed to show any
improvement in outcomes. Thus, the use of high dose therapy in

19
sarcomas remains controversial. This approach should be investigated
further in well-designed randomized clinical trials.

Postoperative details: Compressive bandages and suction drains should


be used to minimize seroma formation that can result in delayed
administration of chemotherapy or radiation therapy. Physical therapy
and rehabilitation support may be required.

Follow-up care: General follow-up care includes surveillance studies


to evaluate local recurrence and distant metastasis of malignant and
intermediate tumors. The precise interval and duration for obtaining
various follow-up studies is not well defined. In general, vigorous
surveillance continues for 3-5 years after treatment. Benign tumors
generally do not require such surveillance.

COMPLICATIONS

Complications can be divided into those that occur before completion


of therapy and those that occur after completion of therapy.

Before completion of therapy

Related to the tumor: Depending on histopathological category


and anatomical site, the tumor may cause complications such as
skin ulceration, thrombocytopenia, hemorrhage, and fracture.
Related to operative procedures: Infection and wound
dehiscence are possible.

After completion of therapy

Related to the tumor: Complications include local recurrence


and distant metastasis.
Related to chemotherapy and radiation therapy: Infections may
occur due to immunosuppression. Postirradiation sarcomas may
occur, usually 10 years or longer after radiation therapy.

OUTCOME AND PROGNOSIS

Outcome and prognosis depend on several often-interrelated factors.

Tumor size: Similar to tumors of other tissues, a direct


relationship exists between tumor size and outcome. Larger
soft tissue tumors confer a worse prognosis.
Depth of tumor: Superficially located tumors (dermis and
subcutaneous tissue) have a relatively better prognosis than
the deep-seated lesions (intermuscular/intramuscular,
retroperitoneal) of similar histologic type. This difference
is likely due to the fact that superficial lesions are
considerably smaller at the time of excision.
Histologic type: With few exceptions, most sarcomas of the
same stage and grade behave the same regardless of histologic
subtype. Some soft tissue tumors (eg, atypical lipomatous
tumors) are low-grade without any ability to metastasize.
Others such as pleomorphic liposarcoma are highly aggressive
with a tendency for distant metastases.

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.

FUTURE AND CONTROVERSIES

Management of soft tissue tumors may evolve due to the advent of


molecular diagnostics and antitumor therapies. One problem inherent
to soft tissue tumors is the small number of many different
histologic subtypes seen at any one institution. More
multiinstitutional studies are necessary.

Soft tissue sarcomas are challenging lesions demanding a


multidisciplinary and multimodality approach for proper clinical
evaluation and treatment. Limb-sparing therapies for high-grade
extremity sarcomas, which were treated by amputation in the past, are
well established today. The multidisciplinary team of surgeons,
radiologists, pathologists, medical oncologists, radiation
oncologists, oncology nurses, rehabilitation therapists, and social
workers is the backbone for successful management of these tumors.

Due to the relative rarity of these tumors and general lack of


expertise, patients with soft tissue sarcomas should be considered
for referral to medical centers experienced in sarcoma management,
preferably during the initial evaluation phase.

21
MEDICAL ONCOLOGY: A COMPREHENSIVE REVIEW

Soft-Tissue and Bone Sarcomas


Danai Daliani, MD
Division of Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
S.R. Patel, MD
Section of Sarcoma, Department of Melanoma/Sarcoma, Division of Medicine, M.D. Anderson
Cancer Center, Houston, Texas

Sarcomas are a heterogenous group of tumors originating from mesenchymal tissues.


According to American Cancer Society estimates, approxiately 8,070 new cases will be
diagnosed in 1995, including 6,000 cases of soft-tissue sarcomas and 2,070 cases of bone
tumors.

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.

Soft-tissue sarcomas represent a histologically heterogeneous group of malignant tumors


arising in the soft tissues. The majority of soft-tissue sarcomas are of mesodermal origin, but
some sarcomas are derived from the ectoderm (eg, tumors of the connective tissues of the
face and tumors composed of neurons). Although sarcomas are often thought to be exclusively
mesenchymal in origin, some histologic subtypes (eg, synovial sarcoma and epithelioid
sarcoma) share some epithelial features, and it is even speculated that they may be derived
from epithelial tissue containing the cytokeratin type of intermediate filament.

Epidemiology and Pathogenesis

The pathogenesis of soft-tissue sarcomas is not completely understood. Exposure to


environmental toxins has been linked with the development of two specific sarcomas:
mesothelioma (asbestos) and hepatic angiosarcoma (thorotrast and vinyl chloride). In 1979, a
Swedish report linked exposure to phenoxyacetic acids (herbicides) and chlorophenols (wood
preservatives) to an increased risk of developing soft-tissue sarcomas, but this was not
confirmed in later studies. Ionizing radiation has been implicated as a cause of sarcomas
arising in soft tissue and bone. The latent period averages approximately 10 years but ranges
between 2 and 30 years, and the prognosis is usually poor. The association of lymphedema
and lymphangiosarcoma is well recognized, as in Stewart-Treves syndrome, and carries a
very poor prognosis.

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.

Biopsy: The biopsy of soft-tissue sarcomas is an important aspect of disease management.


Needle biopsy is the preferred method because it is less invasive, less expensive, and easy to
perform; however, a needle biopsy requires expertise in cytopathology for interpretation. Core
biopsies can provide enough tissue for morphologic details, electron microscopy, DNA flow
cytometry, cytogenetics, immunohistochemistry, and molecular studies, if necessary, without
compromising the definitive surgery.

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.

Botryoid sarcoma is a subtype of embryonal sarcoma that has a polypoid or grapelike


appearance. This tumor is commonly found in the urogenital tract of infants and children and
rarely in the oral and nasal pharynges. The alveolar typethe second most common type of
rhabdomyosarcomaoccurs in patients who are 10 to 25 years older and more frequently in
the extremities. It is an aggressive tumor and has a poorer prognosis than the embryonal type.
Pleomorphic rhabdomyosarcoma is the least common subtype. It occurs in adults, more
commonly in the extremities, and should be differentiated from other pleomorphic sarcomas,
pleomorphic lymphomas, pleomorphic melanomas, and carcinomas. Here again, electron
microscopy and immunohistochemistry are very helpful.

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.

Angiosarcomas include hemangiosarcomas and lymphangiosarcomas, which arise from blood


vessels and lymphatic vessels, respectively. Although they are rare, representing only 2% of all
soft-tissue sarcomas, they are almost always high-grade tumors, and the 5-year survival rate
of patients is only 12% despite multimodality therapy.

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.

Disease Grade and Staging

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%).

TABLE 1: Staging System

T Primary tumor

T1 Tumor smaller than 5 cm

T2 Tumor 5 cm or larger

G Histologic grade of malignancy

25
G1 Low

G2 Moderate

G3 High

N Regional lymph nodes

N0 No histologically proven regional lymph-node metastasis

N1 Histologically verified regional lymph-node metastasis

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.

Investigators at the University of California at Los Angeles, used intra-arterial chemotherapy


with doxorubicin (Adriamycin, Rubex), 30 mg/d for 3 days as a continuous infusion, followed by
preoperative XRT and wide resection, in patients with soft-tissue sarcoma. This strategy
produced a local recurrence rate of less than 10%, which included an amputation rate of 5%.
These results are comparable to those from more conventional surgery and radiation
schemes.

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).

Adjuvant Chemotherapy: Adjuvant chemotherapy is considered standard therapy for


rhabdomyosarcomas and extraskeletal Ewing's sarcoma. These two tumors are highly
responsive to systemic chemotherapy, have a high incidence of systemic micrometastases,
and are associated with a 5-year disease-free survival rate of less than 20%. The role of
adjuvant chemotherapy in all other soft-tissue sarcomas remains controversial.

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.

TABLE 2: Randomized Adjuvant Studeis in Soft-Tissue Sarcomas

Number of % %
Study Regimen Follow-up patients % DFS DFS* % OS OS*

EORTC CVAD 44 468 61 61 68 71


[105]

Bordeau CVAD 40 59 37 65 43 93
[106]

MDA [107] CVAAd > 120 47 83 76

NCI [108] ACM 85

Extremity 60 67 28 54 60 54

Trunk 36 22 47 77 61 82

Retroperitoneum 24 15 49 92 100 47

Mayo [109] AVCAd 64 61 68 65 70 70

GOG [110] A 60 156 45 60 47 60

Scandi [111] A 22 139 44 40 55 52

UCLA [112] A 28 119 52 56 70 80

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

ECOG [116] A 105 36 55 68 53 65

C = cyclophosphamide, V = vincristine, D = dacarbazine, M = methotrexate, Ad = actinomycin


Observation arm
* Chemotherapy arm

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.

Staging of Bone Tumors

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.

TABLE 3: Surgical Staging of Bone Sarcomas

Stage Grade Site

IA Low (G1) Intracompartmental (T1)

IB Low (G1) Extracompartmental (T2)

IIA High (G2) Intracompartmental (T1)

IIB High (G2) Extracompartmental (T2)

III Any G + regional or Any T


distant metastases

Osteosarcoma

Epidemiology and Clinical Presentation: Osteosarcoma is the most common primary


malignant bone tumor. It affects men more than women (ratio, 1.5:1). There is a bimodal age
distribution; the first peak occurs during childhood and adolescence and the second peak
occurs during the sixth decade of life. It is a high-grade, malignant, spindle-cell tumor of the
bone characterized by the production of osteoid by the malignant spindle-cell stroma.

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.

Treatment of Localized Disease: Prior to the 1970s, treatment of localized osteosarcoma


consisted of amputation one joint above the tumor-containing bone or transmedullary
amputation, with an overall survival rate of 5% to 20% at 2 years. Pulmonary metastases
usually occurred within 9 months and were responsible for the patient's death at 18 to 24
months after diagnosis. The introduction of effective chemotherapeutic agentshigh-dose
methotrexate with leucovorin rescue, doxorubicin, cisplatin (Platinol), and the alkylating agents
ifosfamide and high-dose cyclophosphamide (Cytoxan, Neosar)allowed a change in the
approach to treatment of osteosarcomas.

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.

Currently, limb-salvage surgery is preferred for a significant number of patients with


osteosarcoma and other high-grade sarcomas. The risk of local recurrence (less than 5%) was
shown to be the same or lower than that of patients treated with amputation in a carefully
selected group of patients. Contraindications for limb-salvage surgery include major
neurovascular involvement, an inappropriate biopsy site, infection, a pathologic fracture with
spread of tumor cells via hematoma, extensive muscle involvement, and immature skeletal

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.

Treatment of Metastatic Disease: Metastatic osteosarcoma is a treatable and potentially


curable disease when combined modality therapy is administered. The most frequent sites of
metastasis are the lungs. Whether pulmonary metastasis is present at diagnosis or occurs
after the primary tumor is treated, if the lungs are the only sites of metastatic disease, it should
be resected aggressively. A 5-year postthoracotomy survival rate of nearly 40% has been
reported by Putnam et al, and similar results were reported by Skinner et al for patients treated
with combined-modality therapy. The number of nodules on preoperative lung tomograms, the
disease-free interval, the resectability of the tumor, and the number of metastases resected at
thoracotomy are prognostic factors influencing survival. The completeness of the surgical
resection is crucial to prolonged survival. Variables such as preoperative chemotherapy vs
immediate surgery, serum lactic dehydrogenase (LDH) level, alkaline phosphatase level, or the
site of primary tumor did not affect the survival of patients who presented with metastatic
disease [194]. Patients with unresectable metastatic disease have a poor prognosis.
Ifosfamide (with mesna for urothelial protection), alone or in combination with etoposide, has
shown activity in up to one third of patients with recurrent osteosarcoma.

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%.

Radiographically, parosteal osteosarcoma is characterized by a large, dense, lobulated mass


broadly attached to the underlying bone without involvement of the medullary canal. However,
such involvement can be present without being radiographically apparent. Parosteal
osteosarcoma is treated surgically with wide excision alone. Dedifferentiated parosteal
osteosarcoma and high-grade surface osteosarcoma have a much poorer prognosis and are
treated with chemotherapy and surgery.

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.

Chondrosarcomas are pathologically classified as grade I to grade III tumors. High-grade


(grade III) tumors have the worst prognosis, with a risk of metastasis of 75%. Surgical removal
of the tumor is the treatment for chondrosarcoma. There is no effective chemotherapy for the
central and peripheral types of the disease. Dedifferentiated chondrosarcoma, on the other
hand, does respond to standard chemotherapy used against osteosarcoma, and such
treatment should be employed.

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.

Mesenchymal chondrosarcoma is a rare, aggressive tumor that affects younger patients. It


shows a predilection for flat bones and has high metastatic potential. Treatment is wide
surgical excision with adjuvant chemotherapy. XRT is used when the tumor cannot be
completely excised.

Malignant Fibrous Histiocytoma of Bone

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.

A careful review of light microscopy studies by an experienced pathologist is extremely


important for the diagnosis of ES. Morphologic features may be indistinguishable from those of
the peripheral primitive neuroectodermal tumors (pPNETs). Immunocytochemical staining is
often positive for neuron-specific enolase (NSE), although others believe that NSE is specific
for pPNET and might be used to distinguish between the two entities. The monoclonal
antibody 5C11 has been reported to react exclusively with ES and not with pPNET, whereas
expression of the MIC2 gene has been reported in both entities. Electron microscopy studies
may also assist the diagnosis, revealing dense core granules, neurites, neurotubules, and
neurofilaments in prominent Golgi's complexes. A chromosomal translocation t(11;22)(q24;q12)
is a characteristic abnormality of ES, but it has also been reported in pPNET.

ES is associated with skeletal abnormalities (such as enchondroma and aneurysmal bone


cyst) and genitourinary anomalies (hypospadias and duplicate collecting system).

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.

Treatment: ES is considered a systemic disease; even when a tumor is apparently localized,


approximately 90% of the cases include occult metastatic disease. Before treatment with
chemotherapy was available, local control was achieved in 50% to 85% of patients by means
of surgery or radiation doses of more than 40 Gy to 50 Gy. However, only 10% of these

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

Although no definite information regarding causation, soft tissue


sarcomas have been etiologically related to several factors. These
include various chemical (i.e vinyl chloride gas), radiation injury, chronic
lymphedema that associated with irradiation (lymphangiosarcoma) and
other causes, such as von Recklinghausens disease that inherited
factors play a role.

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

Striated Rhabdomyoma Rhabdomyosarco


muscle ma
Smooth Leiomyoma Leiomyosarcoma
Muscle Angiomyoma
Blood vessels Haemangioma Haemangiosarco Intermediate-
ma haemangioendothe
Malignant lioma
haemangiopericy
toma
Glomus tumour
Lymph Lymphangioma Lymphangiosarc
vessels oma
Synovial Giant cell tumour of Synovial PVNS
tissue tendon sheath sarcoma
Malignant giant
Ganglia
cell tumour of
tendon sheath
Synovial
osteochondromatos
is
Peripheral Traumatic neuroma Malignant
nerves schwannoma
Mortons neuroma
Peripheral
tumours of
Neurilemmoma
primitiveneuroec
(benign
todermal tissue
schwannoma)

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.

Patterns of spread of soft-tissue sarcomas


Soft-tissue sarcomas spread via direct local invasion,
lymphatics, and hematogenous dissemination. Locally these tumors
spread within tissue planes and along nerve sheaths, vessels, and fascial
compartments. The incidence of metastatic soft-tissue sarcoma depends
upon the primary site, histology, and most importantly the degree of
differentiation.

Plain Xray findings


Every soft tissue mass that is going to undergo intervention
should have a plain radiograph
Fat density lesion (lipoma)
Punctate calcifications (synovial cell sarcoma, soft tissue
chondrosarcoma or hemangioma)

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

1. Stage of the patient

(Ennekings stage: I:inactive, II:growing & symptomatic,


III:aggressive)

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.

SPECIFIC SOFT TISSUE TUMOURS

Fibrous benign

1. Calcifying aponeurotic fibroma

Slow Growing, painless mass, ages 3-30


Xrays show faint mass with stippling
Histology shows fibrous tumour with some calcification and
cartilage formation
50 % recurrence after excision
Resolves with maturity

2. Nodular fasciitis

Painful reactive rapidly enlarging lesion in a young person


50% in upper limbs
Histology- short irregular bundles and fascicles, only small
amounts of mature collagen
Treat with excision with marginal resection

3. Palmar (Dupuytrens) and plantar (Ledderhosen) fibromatoses

4. Extraabdominal Desmoid tumour

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

Enlarging painless mass


Age group 30-80
Usually 10 cm in size before symptoms
Plain Xray usually normal unless encroaching on bone
MRI deepseated inhomogenous mass
Histology- fasciculated growth pattern with fusiform or spindle
shaped cells, scanty cytoplasm, indistinct borders separated by
interwoven collagen, or herringbbone appearance.
Metastasize range from very well-differentiated tumors, which
rarely metastasize to poorly differentiated, bizarre tumors with a
paucity of collagen and frequent evidence of hematogenous
metastasis.
Treatment- Wide local excision. If > 5cm add radiation therapy,
preop/postop/periop

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

Similar to malignant fibrosarcoma


Histology slightly different with cartwheel pattern to the spindle
and histiocytic cells
Treat as for fibrosarcoma

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.

Benign fatty tumours

1. Lipomas

Subcutaneous/intramuscular or intermuscular tumours of mature


fat
Most are not painful
Plain xrays may show a radioluscent region in the soft tissues
MR or CT scan show a well demarcated lesion with exactly the
same signal as fat
If no symptoms and definite radiological diagnosis, leave alone
If mass growing or causing symptoms excise with a marginal line
of resection
Recurrence uncommon
Subgroups are spindle cell cell lipoma and pleomorphic lipoma
A rare benign tumor in infants and children, the lipoblastomas, is
a lobulated encapsulated tumor which is also treated adequately
by simple enucleation.

Malignant fatty tumours

1. Liposarcomas

Malignant tumours with differentiation towards fatty tissue


Heterogenous group of tumours with the presence of signet ring
type cells(lipoblasts) in common
In contrast to most sarcomas, which usually arise in the
extremities, liposarcomas often arise in the retroperitoneum as
well.
Extremity liposarcomas have a generally good prognosis after
operative treatment retroperitoneal liposarcomas have a
poor prognosis for the anatomic reason.
Recurrences of liposarcomas often tend to be more
undifferentiated than the primary lesion and may cause
diagnostic difficulties.
Range from low grade and myxoid varieties to high grade

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

Benign peripheral nerve tumours

1. Neurilemmoma (benign schwannoma)

Benign nerve sheath tumour


Young to middle aged patients
Usually asymptomatic apart from the mass
Neoplasms of nerve cell sheaths are virtually never
malignant when located centrally, i.e in the spinal cord, but
may become malignantaelsewhere in the body.
MR scan shows eccentric mass arising from a peripheral nerve
Histologically contains:
o Antoni A- compact spindle cells, twisted nuclei, indistinct
cytoplasm, clear vacuoles
o Antoni B-less cellular
Treat by excision leaving the nerve intact

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

Malignant peripheral nerve tumours


Malignant nerve cell sheath tumors(malignant Schwannoma, malignant
neurilemmoma, neurobrosarcoma) are most commonly found on the
extremities. They tend to be poorly differentiated tumors with their
origin usually from the sheath surrounding small nerve rather than from
major nerves. Prognosis tends to be poor, they rarely metastazise to
lymph nodes but hematogenous metastasis, primarily pulmonary, is
common.

46
Neurobrosarcom
Rare
Can arise de novo or in neurofibromatosis
Tend to be high grade, therefore treated with wide surgical
resection +/- radiotherapy

Benign tumours of muscle tissue

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.

Malignant tumours of muscle tissue

1. Leiomyosarcoma

Can be high or low grade


Are the most common sarcoma arising from GIT, stomach &
small bowel sites being the most frequent.
Sarcomas that originate in the bowel, with it portal drainage,
distant metastases tend to be hepatic rather than pulmonary.
Wide/radical surgical excision and radiotherapy
Long-term survival of patient with GIT leiomyosarcoma: 30-40%.

2. Rhabdomyosarcoma

The most common sarcoma in young patients


Highly malignant
Grows rapidly
Spindle cells in parallel bundles, multinucleated giant cells and
racquet shaped cells, cross striations within the tumour cells
(rhabdomyoblasts)
The histologic subtypes: embryonal, alveolar, and pleomorphic.
In adult the pleomorphic variety are commonly type and
prognosis tends to be poor.
The lungs are the major metastatic site
Sensitive to multiagent chemotherapy
Treat with preop chemo, followed by wide surgical excision and
radiotherapy

47
Benign vascular tumours

1. Haemangioma

Seen in children and adults


Can be cutaneous, subcutaneous, intramuscular
If large, patients complain due to symptoms of venous
engorgement (aching)
Plain Xray can show small pleboliths
MR scan shows a heterogenous lesion with many small blood
vessels
Treat nonoperatively if possible
Wide surgical resection if symptomatic, local recurrence rate
high

Malignant vascular tumours

1. Haemangiopericytoma

Rare tumour of the pericytes of blood vessels


Can be benign or malignant and from intermediate to high grade
Slowly enlarging painless mass
Treatment based on grade of lesion

2. Angiosarcoma

Rare

Tumour resembles the endothelium of blood vessels


Most commonly arise on the scalp, face, breast, or extremities.
Treatment depends on grade and location of lesion

Benign synovial tumours

1. Ganglia (see Hand Tumours)

Malignant Synovial disorders

1. Synovial sarcoma(tendosynovial sarcoma)

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

Synovial proliferative disorders

1. Pigmented Villonodular synovitis

Not a true neoplasm


Exuberant proliferation of synovial villi and nodules
Most common in the knee, followed by hip and shoulder
Symptoms include painful swollen joint
Aspiration reveals a bloody effusion
Xray may show cystic
Histologically, highly vascular villi lined with plump hyperplastic
synovial cells, hemosiderin stained multinucleated giant cells
and chronic inflammatory cells
Treat with complete synovectomy
Local recurrence common

2. Giant cell tumour of the tendon sheath

Benign but highly recurrent lesion originating in the tendon


sheaths or joint synovium
Usually seen on the palmar surface of the digits especially the
PIP joint of the index and middle fingers
Recurrence rate of 10%
Second most common hand mass

3. Synovial chondromatosis

Typically affects young adults complaining of pain, stiffness and


swelling
Xrays show fine stippled calcification
Histologically varies between metaplasia of synovial tissue to
firm nodules of cartilage
Treat with synovectomy and removal of loose bodies

49
Other rare Sarcomas

1. Epitheloid Sarcoma

Nodular tumour occuring in the hands of young adults, buttock


thigh, knee or foot
May ulcerate and mimic a granuloma or rheumatoid nodule
Lymph node metastases may occur
Histologically ovoid to polygonal with eosinophilic cytoplasm
Wide surgical excision required

2. Clear cell sarcoma

Slow growing painless mass in young adults


In region of tendons or aponeuroses
Treat with wide surgical resecion with adjuvant radiotherapy

3. Alveolar Cell Sarcoma

Most common in the anterior thigh


Treat with wide surgical excision and radiotherapy

STAGE INFORMATION

Staging has an important role in determining the most effective


treatment of soft tissue sarcomas. The stage is determined by the size of
the tumor, the histologic grade, and whether it has spread to lymph
nodes or distant sites. Intracompartmental or extracompartmental
extension of extremity sarcomas is also important for surgical decision
making.

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.

Grade and TNM definitions

Tumor grade (G)


GX: Grade cannot be assessed
G1: Well differentiated
G2: Moderately differentiated
G3: Poorly differentiated
G4: Undifferentiated
Primary tumor (T)
TX: Primary tumor cannot be assessed

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

TREATMENT OPTION OVERVIEW

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.

For patients with lesions amenable to a combined approach, i.e.,


preoperative or postoperative radiation in conjunction with
nonamputative conservative excision, 5-year survival rates are roughly
equivalent to those achieved in the past with more radical surgical
procedures.

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.

High-grade soft tissue sarcomas of the extremities can often be


effectively treated while preserving the limb; preoperative or
postoperative radiation therapy frequently has a beneficial role.
Preoperative chemotherapy is also under evaluation. In adults, local
control of soft tissue sarcomas of the trunk and the head and neck can
be achieved with surgery, often in combination with radiation therapy.
However, the role of adjuvant chemotherapy in all of these sites remains
to be determined. The prognosis for retroperitoneal sarcomas is
less favorable than for other sites because of the difficulty in
completely resecting these tumors and the limitations placed on high-
dose radiation therapy. Patients with retroperitoneal sarcomas should be
treated with adjuvant chemotherapy only on prospective controlled
adjuvant trials. Adjuvant chemotherapy for extremity sarcomas has
generated conflicting reports of benefit.

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.

STAGE I ADULT SOFT TISSUE SARCOMA

Stage I soft tissue sarcomas have little or no metastatic potential, but


they may recur locally if inadequately treated. Accordingly, surgical
excision with negative tissue margins of at least 2 centimeters or more
in all directions is the treatment of choice for stage I sarcomas. Carefully
executed high-dose radiation therapy using a shrinking field
technique may be beneficial for unresectable tumors or for resectable
tumors in which a high likelihood of residual disease is thought to be
present, when margins are known to be less than 2 centimeters in
diameter, and when wider resection would require either an amputation
or the removal of a vital organ. Because of the low metastatic potential
of these tumors, adjuvant chemotherapy should not be administered
outside of clinical trials. 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.

52
Treatment options:

Standard:

1. Surgical excision with negative tissue margins of several centimeters


in all directions.

2. Conservative surgical excision with preoperative or postoperative


radiation therapy.

3. If the tumor is unresectable, high-dose preoperative radiation therapy


may be used, followed by surgical resection and postoperative
irradiation. If it is still unresectable, high-dose radiation therapy alone
should be considered.

4. For tumors of the retroperitoneum, trunk, and head and neck:

a. Surgical resection with the option of postoperative radiation


therapy if negative margins cannot be obtained. Wide margins
are unusual in these sites, and radiation therapy is usually
required. It may also be helpful in managing high-grade tumors,
which tend to recur locally even when they have been completely
resected.
b. Preoperative radiation therapy followed by maximal surgical
resection. Radiation therapy is usually used to maximize local
control because of the inability to obtain wide surgical margins.

STAGE II & III ADULT SOFT TISSUE SARCOMA

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.

Several prospective randomized trials have examined the role of


adjuvant chemotherapy with doxorubicin either as a single agent or in
combination with other cytotoxic drugs. The majority of these studies
accrued small numbers of patients and did not demonstrate either a

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:

Surgery with or without radiation therapy.

a. Surgical excision with negative tissue margins of several


centimeters in all directions. In many cases, amputation will be
required. Mohs surgical technique may be considered as an
alternative to wide surgical excision.
b. If the tumor is resectable but wide margins cannot be obtained,
or if wide margins would produce significant morbidity, radiation
therapy is added.
c. If the tumor is unresectable, high-dose radiation therapy alone
may be used, but poor local control is likely to result.
d. In some situations, radiation therapy may be used prior to
surgery to convert a marginally resectable tumor to one that can
be adequately resected with limb preservation; this treatment is
followed by postoperative irradiation.

Retroperitoneum, trunk, and head and neck


Stage II soft tissue sarcomas of the trunk, retroperitoneum, and head
and neck are most effectively treated by surgical resection with wide
margins of negative tissue and high-dose postoperative radiation therapy
or by preoperative radiation combined with conservative resection and
additional postoperative irradiation. For tumors in these areas that
cannot be completely resected, palliation may be obtained with high-
dose radiation therapy and chemotherapy. Intraoperative radiation
therapy is under evaluation for the treatment of retroperitoneal
sarcomas.

Treatment options:

Standard:

1. Wide surgical excision of the primary tumor to obtain negative


margins (for tumors of the retroperitoneum, this may involve
resection of adjacent structures), with or without
postoperative external-beam radiation therapy (delivered
with supervoltage equipment).
2. Preoperative irradiation followed by surgical resection and
postoperative irradiation.

54
STAGE IVA ADULT SOFT TISSUE SARCOMA

Stage IVA sarcomas are tumors that have metastatic involvement of


regional lymph nodes but have not spread to distant organs. Soft
tissue sarcomas that more commonly spread to lymph nodes include
synovial cell sarcomas, epithelioid sarcomas, and rhabdomyosarcomas.
For stage IVA sarcomas, local control of the primary tumor probably is
best obtained by resection with negative margins, lymphadenectomy,
and postoperative external-beam radiation therapy.

Treatment options:

Standard:

1. Surgical resection and lymphadenectomy with or without


postoperative radiation to the primary site. This may require
amputation in some patients who have extremity lesions.
2. In some centers, radiation therapy may be used prior to and
following surgical extirpation.

STAGE IVB ADULT SOFT TISSUE SARCOMA

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:

1. Surgical resection of the primary tumor with radiation therapy.


Resection of pulmonary lesions may be performed following definitive
therapy of the primary tumor.

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.

2. Radiation therapy to the primary sarcoma if unresectable.

3.For palliation of patients with unresectable stage IVB disease,


chemotherapy with the following agents: doxorubicin [2,6-8] doxorubicin
+ dacarbazine [2,3,9,10] ifosfamide with or without other agents.

RECURRENT ADULT SOFT TISSUE SARCOMA


Treatment of recurrent soft tissue sarcomas depends on the type of
initial presentation and treatment. Patients who develop a local
recurrence often can only be salvaged by aggressive local therapy: local
excision plus radiation therapy after previous minimal therapy or
amputation after previous aggressive treatment. For selected patients,
preoperative radiation therapy and wide local excision may avoid the
need for amputation in previously irradiated patients. Metastases to the
lung as first recurrence should be treated as described under treatment
stage IV disease. Tumor-cell heterogeneity may be an important
determinant of therapy and respons

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.

Whats new in soft


tissue sarcoma

Yondelis, or ET-743 (ecteinascidin-743)


A very new drug, is still in trial. Ectenaiscidia is a
tetrahydroisoquinolone alkaloid isolated from the tunicate
Ecteinascidia turbinate. Physiologically relevant concentrations of
ET-743 abrogate transcriptional activation of both the endogenous
MDR1 gene and MDR1 reporter construct by the histone deacetylase
inhibitors. Its a type of biological therapy that interferes with the
cancer cells ability to copy itself and reproduce. Recommended dose
was 1300 mcg/mq in 3 hours every 21 days.

Gilvec, or STI-571 (Imatinib Mesylate)


It gives in patient with GIST expressing the KIT receptor tyrosine
kinase(CD117) at 2 doses levels (400 or 800 mg). Gilvec is licenced
in the UK for people who have GIST that: cannot be completely
removed, had already spread, and has come back since it was first
treated.

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.

Nonrhabdomyosarcoma Soft Tissue


Sarcomas
eMedicine, Last Updated: March 21, 2003
Synonyms and related keywords: NRSTS, tumor, fibrosarcomas, malignant peripheral nerve sheath
tumors, malignant fibrous histiocytomas, synovial sarcomas, alveolar soft part sarcomas,
leiomyosarcomas, liposarcomas

Author: Gary D Crouch, MD, Program Director of Pediatric Hematology-


Oncology Fellowship, Associate Professor, Department of Pediatrics, Uniformed
Services University of the Health Sciences

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).

NRSTS are a heterogenous set of tumors, sharing some biologic characteristics


but differing in histology. The most common types are the synovial cell sarcomas,
malignant fibrous histiocytomas, fibrosarcomas, and malignant peripheral nerve
sheath tumors. Other histologies include the hemangiopericytomas, alveolar soft
part sarcomas, leiomyosarcomas, liposarcomas, and desmoplastic small cell
tumors. Because soft tissue sarcomas are more common in adults, many of the
treatment modalities are extrapolated from the adult experience. In many cases,
the pediatric counterparts have a different clinical behavior and outcome. Infants
and young children with these tumors tend to have a better prognosis than
adolescents and adults with similar diagnoses.

Pathophysiology: Soft tissues comprise a variety of structural and supportive


tissues in the body, including muscle, connective tissues, endothelium, synovium,
fat, lymphatics, and fascia. Soft tissue sarcomas may arise in any part of the body.
The most common sites are the trunk and the extremities. Approximately 15-30%
of patients have metastatic disease at presentation. The most common metastatic
site is the lung. Other common sites for metastatic disease are skin, bone, liver,
and lymph nodes. Spread to omentum/peritoneum and brain has been described
as well. A brief discussion of the more common NRSTS follows.

Fibrosarcoma

The most common of the NRSTS in children, fibrosarcoma has 2 peaks in


incidence in children, which occur in children younger than 5 years and in
individuals aged 10-15 years. Congenital fibrosarcoma is usually observed in
children younger than 2 years, it occurs in the extremity 70% of the time, it rarely
is metastatic, and it is associated with trisomy 11 chromosomal abnormality. The
adult form of fibrosarcoma usually occurs in individuals aged 10-15 years, occurs
most often in the extremity, has high metastatic potential (usually to the lung),
and is genetically associated with clonal chromosomal translocations.

Histologically, fibrosarcoma is a spindle-shaped tumor with a characteristic


herringbone pattern. Aggressive fibromatosis, nodular fasciitis, myositis
ossificans, and inflammatory pseudotumor are included as the most important
differentials. Congenital fibrosarcoma is usually treated with surgery alone, with
survival rates of more than 90% in some series. The adult form of fibrosarcoma is
treated with aggressive surgical resection with consideration for chemotherapy in
some patients. Overall, the survival rate is approximately 60%.

Malignant peripheral nerve sheath tumor

Accounting for approximately 5-10% of NRSTS in children, malignant peripheral


nerve sheath tumors are associated with neurofibromatosis type I, and they have
a common chromosome abnormality in region 17q11. These tumors occur most
frequently on the extremity. They have a similar pathologic appearance to the
fibrosarcoma but are a more aggressive malignancy. Surgery and radiation
therapy are major modalities for treatment. Malignant peripheral nerve sheath
tumors are considered chemoresponsive; however, the role of chemotherapy in
ultimate outcome of these patients is still under study.

Malignant fibrous histiocytoma

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.

Chemotherapy may have a role in unresectable and metastatic disease. Series


have demonstrated efficacy with the use of cisplatin, doxorubicin, and high-dose
ifosfamide in combination with surgery and radiation therapy. Advanced-stage
disease has been treated with regimens including cytoxan and doxorubicin, as
well as the combination of vincristine, dactinomycin, and cyclophosphamide. Low-
stage disease has a 70% survival rate. Higher-stage disease has a poor prognosis.

Alveolar soft part sarcoma

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

A rare tumor in children, leiomyosarcoma occurs only about 2% of the time in


NRSTS. Pathologically, these tumors are derived from smooth muscle tissue.
Leiomyosarcomas are associated with human immunodeficiency virus (HIV)
disease, Epstein-Barr virus (EBV) infection, and immunosuppressive states. The
most common site for these tumors is the GI tract, particularly the stomach. An
important clinical presentation to recognize is the occurrence of leiomyosarcoma
with extrarenal or adrenal paraganglioma and pulmonary chondroma (ie, Carney

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

Primarily a disease of adults, liposarcoma may occur in older children. This


NRSTS rarely occurs in young children and infants and usually is benign in this
setting if completely removed. A consistent cytogenetic abnormality in myxoid
liposarcoma tumors is a t(12;16)(q13;p11) translocation; genes involved are FUS-
CHOP. The lower extremity and the trunk are the 2 most common sites of
presentation. Liposarcoma rarely metastasizes, and for this reason, the treatment
of choice is wide local excision. The role of radiation and chemotherapy in the
setting of gross residual disease is being investigated.

Frequency:

In the US: NRSTS accounts for approximately 3% of childhood


malignancies. The most frequent NRSTS is fibrosarcoma, which accounts
for 23.9% of cases. In individuals younger than 20 years, approximately
500-600 cases of NRSTS are diagnosed yearly.

Mortality/Morbidity: The two most important prognostic factors in children with


NRSTS are tumor invasiveness and histologic grade. Except for malignant fibrous
histiocytoma and fibrosarcoma, most NRSTS in children are immature and poorly
differentiated with a highly malignant histologic grade. Patients with low-grade
localized disease have survival rates of 90%, while those with high-grade,
invasive, or metastatic disease have survival rates of less than 15%.

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

History: Usually, patients with NRSTS present with painless asymptomatic


masses. These tumors may come to attention secondary to an episode of trauma
in the area. Mass effect from the tumor may cause specific signs or symptoms
depending on mass location. For instance, invasion of local neurovascular bundles
in the extremity may lead to pain, swelling, numbness, or loss of function. Large
chest wall masses may cause pulmonary dysfunction. If advanced metastatic
disease is present, systemic symptoms with fever, sweats, and weight loss may be
observed. Hemangiopericytomas have been associated with hypoglycemia and
hypophosphatemic rickets. Hyperglycemia has been observed with fibrosarcoma
of the lung.

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.

Causes: Genetic conditions (eg, Li-Fraumeni syndrome associated with P53


mutations, neurofibromatosis type I) are the only known risk factors for
developing NRSTS. Factors with an implied, but not proven, association with the
development of sarcomas are low socioeconomic status, in utero exposure to
ionizing radiation, and parental use of recreational drugs.

DIFFERENTIALS

Liposarcoma
Lymphadenopathy
Neuroblastoma
Nonrhabdomyosarcoma Soft Tissue Sarcomas
Osteosarcoma
Rhabdomyosarcoma

Other Problems to be Considered:

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:

CBC with differential provides baseline parameters prior to therapy and


evaluates for bone marrow involvement.

Renal function chemistries provide baseline parameters prior to further


testing.

Liver function testing provides baseline parameters prior to therapy and


evaluates for liver involvement.

Imaging Studies:

Chest radiography and chest CT scanning evaluate for lung involvement.


Perform these studies prior to general anesthesia, which can cause
pulmonary changes that might make interpretation difficult.

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.

Radionucleotide bone scanning is necessary to rule out bony


involvement.

Plain radiography of the involved areas may be useful in the initial


evaluation of a mass depending on its location and suspected
involvement of bony structures.

Other Tests:

Consultation with a cardiologist with cardiac ECG may be needed in


patients who will receive anthracycline-based chemotherapy regimens or
radiation therapy to the chest.

Renal glomerular filtration or creatinine clearance testing may be


necessary prior to administration of renal-toxic chemotherapy agents
(eg, cisplatin, ifosfamide).

Procedures:

A carefully planned and executed biopsy of the mass lesion is required


for diagnosis. Whatever technique is used, adequate tissue must be
obtained to yield the diagnosis. If possible, surgery should be
accomplished in a manner that does not compromise the chance for later
local surgical control of the tumor.

o A surgeon with expertise in oncologic surgery should perform


this procedure. The specific discipline depends on the mass
location.

o Small lesions in accessible areas may be best approached with


an excisional biopsy.

o Large masses involving critical organ structures may require an


incisional biopsy for diagnosis.

o Delay the definitive surgical procedure until after adjuvant


chemotherapy, radiation therapy, or both to induce tumor
shrinkage.

o Fine-needle aspiration biopsy may be possible in certain cases,


but an open procedure is required if nondiagnostic pathologic
material is obtained using this technique.

o Minimally invasive surgical techniques using fiberoptic surgical


procedures may be appropriate in certain biopsy situations.

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.

Bilateral bone marrow aspirates and biopsies should be performed in


most cases to rule out tumor involvement of the bone marrow. Strongly
consider performing a bone marrow examination in all cases of NRSTS.

o In children, these procedures are best performed from the


posterior iliac crests.

o They should be accomplished in conjunction with another


sedated procedure if possible.

Lumbar puncture for assessment of the cerebrospinal fluid (CSF) may be


necessary for parameningeal tumors or tumors involving the CNS to rule
out CSF contamination with tumor cells.

Histologic Findings: A wide range of histologies comprises the group of tumors


collectively considered as NRSTS. A tumor is classified as low- or high-grade on
the basis of its potential to metastasize. Low-grade lesions are unlikely to
metastasize. Certain tumor types are considered arbitrarily high-grade, such as
synovial cell sarcomas. Malignant and metastatic potential are interpreted by the
degree of anaplasia and mitotic activity exhibited by the tumor specimen.
Diagnosis of the specific tumor depends on which mesenchymal/support tissue it
most closely represents. Immunostaining, electron microscopy, cytogenetic
analysis, and molecular markers for gene rearrangements may all be used in the
final determination of diagnosis depending on the degree of differentiation of the
specific tumor.

Staging:

Stages

o Involvement of organ or tissue of origin (T1, N0, M0)

o Invasion of contiguous organs or tissues or adjacent malignant


effusion (T2, N0, M0)

o Regional node involvement (T1 or T2, N1, M0)

o Distant metastases (T1 or T2, N0 or N1, M1)

Groups

o Complete resection except regional disease (II)

o Excision with microscopic residual tumor (margins or regional


nodes)

63
o Gross residual disease (primary site or regional nodes)

o Distant metastases

TREATMENT

Medical Care: General treatment considerations for NRSTS vary somewhat


depending on the exact anatomic tumor site and extent of local and metastatic
disease. Traditionally, complete surgical resection is performed when possible,
followed by radiation therapy to provide local control. Metastatic disease, disease
of high metastatic potential, or large unresectable primary tumors may involve
chemotherapy as part of the treatment plan. In general, multimodality therapy
offers the greatest chance of survival.

Chemotherapeutic agents demonstrating the most activity against


NRSTS include ifosfamide, cyclophosphamide, and doxorubicin. Other
active agents include vincristine, etoposide, cisplatin, and actinomycin D.
Ongoing clinical trials are underway to prospectively evaluate the exact
role of chemotherapy in these tumors.

Although NRSTS are relatively radioresistant tumors, radiation therapy


is used for local control of incompletely excised tumors.

o Radiation therapy also has a role in control and palliative


treatment of certain metastatic disease.

o Radiation therapy in children causes concerns for long-term


development of irradiated tissues and secondary malignancies.

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.

o Tumors in the head and neck, mediastinum, or retroperitoneum


are difficult to remove with wide surgical margins.

o Extremity lesions usually are totally resectable.

Limb salvage procedures or amputation are the options with limb


tumors.

o Limb salvage procedures in rapidly growing young children are


not always the best functional option.

64
o New orthopedic limb lengthening procedures and prostheses
may make this a more viable option in select patients.

In cases of NRSTS, lymph node dissection is not always warranted


because of the infrequency of lymph node involvement with these tumors
(6-9% of pediatric cases, usually high-grade NRSTS).

Lymph node resection is warranted if lymph nodes are enlarged on


examination or scanning or if the tumor arises in a lymph node area.

Surgical staging is important in the treatment decisions made in NRSTS.


Appropriate staging also allows for establishing prognosis.

o The tumor, node, metastases (TNM) staging system is useful and


takes into account tumor size (>5 cm or <5 cm), lymph node
involvement, and the presence or absence of metastatic disease.

o Another staging system used by the Intergroup


Rhabdomyosarcoma Study (IRS) group is based on the extent of
disease after initial surgical resection. Tumors in group I have
complete resection, and group II tumors have microscopic
residual disease after resection. Group III tumors have gross
localized residual disease, and tumors in group IV have
metastatic disease.

Consultations: For limb salvage procedures or amputation, consultation with a


physical therapist and occupational therapist is essential to maximize functional
outcome and recovery. Use of these services in select other patients may be
necessary depending on the site and surgical procedure.

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.

Drug Category: Chemotherapeutic agents -- Cancer chemotherapy is based on an


understanding of tumor cell growth and how drugs affect this growth. After cells
divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis
(ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic
cell division (ie, phase M).

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.

Doxorubicin (Adriamycin) -- An anthracycline


antibiotic. A vesicant administered in a free-flowing
peripheral vein or central venous catheter.
Drug Name Multiple mechanisms of action: DNA intercalation,
topoisomerase-mediated DNA strand breaks, and
oxidative damage via free radical production.
Adult Dose 30 mg/m2/dose IV
Pediatric Dose Administer as in adults
Documented hypersensitivity; myocardial damage;
Contraindication
cumulative anthracycline dose >450 mg/m2 (relative
s
contraindication)
May decrease phenytoin and digoxin plasma levels;
phenobarbital may decrease plasma levels of
doxorubicin; cyclosporine may induce coma or seizures;
Interactions
mercaptopurine increases toxicity of doxorubicin;
cyclophosphamide increases cardiac toxicity of
doxorubicin
Pregnancy D - Unsafe in pregnancy
Extravasation leads to severe chemical burn; cardiac
toxicity (to point of cardiac failure) is dose-limiting in
cumulative fashion, monitoring cardiac function by ECG
Precautions
or MUGA scanning is required during therapy;
cardiotoxicity, myelosuppression, nausea, vomiting,
alopecia, and hepatic mucositis

Cyclophosphamide (Cytoxan, Neosar) -- An alkylating


agent. Usually administered IV. Available PO. Use with
higher doses in combination with aggressive fluid
hydration and monitoring of renal output.
Drug Name Chemically related to nitrogen mustards. As an
alkylating agent, the mechanism of action of the active
metabolites may involve cross-linking of DNA, which
may interfere with growth of normal and neoplastic
cells.
Adult Dose 2.2 g/m2/dose IV
Pediatric Dose Administer as in adults
Contraindication Documented hypersensitivity; severely depressed bone
s marrow function
Allopurinol may increase risk of bleeding or infection
and enhance myelosuppressive effects of
cyclophosphamide; may potentiate doxorubicin-induced
cardiotoxicity; may reduce digoxin serum levels and
antimicrobial effects of quinolones; chloramphenicol may
increase half-life of cyclophosphamide while decreasing
Interactions metabolite concentrations; may increase effect of
anticoagulants; coadministration with high doses of
phenobarbital may increase rate of metabolism and
leukopenic activity of cyclophosphamide; thiazide
diuretics may prolong cyclophosphamide-induced
leukopenia and neuromuscular blockade by inhibiting
cholinesterase activity
Pregnancy D - Unsafe in pregnancy

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)

Ifosfamide (Ifex) -- An alkylating agent. Inhibits DNA


and protein synthesis and, thus, cell-proliferation by
Drug Name causing DNA cross-linking and denaturation of double
helix.
Adult Dose 1.8 g/m2/d IV for 5 d
Pediatric Dose Administer as in adults
Contraindication Documented hypersensitivity; depressed bone marrow
s function
Phenobarbital, phenytoin, chloral hydrate, and other
Interactions drugs that interfere with CYP450 activity, may alter
effects of ifosfamide
Pregnancy D - Unsafe in pregnancy
Fluid hydration and vigorous renal output minimize
renal tubular damage; mesna and vigorous fluid
hydration minimize cystitis; high doses cause Fanconi
Precautions
syndrome of kidneys; myelosuppression, nausea,
vomiting, alopecia, cystitis, neurotoxicity, and renal
tubular damage

Cisplatin (Platinol) -- An alkylating agent. Forced


diuresis with IV fluids, mannitol, and furosemide is
necessary to minimize renal effects.
Drug Name Inhibits DNA synthesis and, thus, cell proliferation by
causing DNA crosslinks and denaturation of double
helix.
Adult Dose 60-120 mg/m2 IV
Pediatric Dose Administer as in adults
Contraindication Documented hypersensitivity; preexisting renal
s insufficiency; myelosuppression; hearing impairment
Interactions Increases toxicity of bleomycin and ethacrynic acid
Pregnancy D - Unsafe in pregnancy
During administration, consider forced diuresis with
mannitol; severe nausea and vomiting; renal toxicity
manifests as Fanconi syndrome of kidneys; ototoxicity,
Precautions particularly high-frequency hearing loss; audiology
testing is required during therapy; myelosuppression,
nausea, vomiting, alopecia, renal, neurotoxicity,
ototoxicity, and allergic reactions

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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

Vincristine (Oncovin, Vincasar PFS) -- A plant


alkaloid. Inhibits cellular mitosis by inhibition of
intracellular tubulin function, binding to microtubule
Drug Name and spindle proteins in the S phase.
Only administer IV in a free flowing vein or central
venous catheter. Pain from peripheral neuropathy
usually treated with acetaminophen or codeine.
Adult Dose 2 mg IV push
Pediatric Dose 1.5 mg/m2 IV push; not to exceed 2 mg/dose
Contraindication Documented hypersensitivity; IT administration (may
s cause death)
Acute pulmonary reaction may occur when taken
concurrently with mitomycin-C; asparaginase, CYP3A4
inhibitors (eg, itraconazole, quinupristin/dalfopristin,
Interactions sertraline, ritonavir), GM-CSF (eg, sargramostim,
filgrastim), or nifedipine increase toxicity; CYP3A4
inducers (eg, carbamazepine, phenytoin, phenobarbital,
rifampin) may decrease effects
Pregnancy D - Unsafe in pregnancy
Vesicant that causes severe chemical burns if
administered SC; accidental delivery to CNS causes
death; neurotoxicity usually manifests as pain
Precautions (particularly jaw, back, leg), constipation to the point of
ileus, foot drop, loss of reflexes, ptosis, and vocal cord
paralysis; neurotoxicity, alopecia, SIADH, hepatic, and
hypotension

Dactinomycin (Actinomycin D) -- Antibiotic derived


from Streptomyces bacterium. Apparently inhibits DNA
Drug Name synthesis.
A vesicant administered in a free-flowing vein or central
catheter.
Adult Dose 0.5 mg IV push qd for 5 d

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

Drug Category: Colony-stimulating factors -- Used for supportive care. Act as


hematopoietic growth factor that stimulates the development of granulocytes.
Used to treat or prevent neutropenia when receiving myelosuppressive cancer
chemotherapy and to reduce the period of neutropenia associated with bone
marrow transplantation. Also used to mobilize autologous peripheral blood
progenitor cells for bone marrow transplantation and in the management of
chronic neutropenia.

Filgrastim (Neupogen) -- Granulocyte colony-


stimulating factor (G-CSF) that activates and stimulates
Drug Name production, maturation, migration, and cytotoxicity of
neutrophils. Allows for more dose intensification of
chemotherapy and faster recovery from neutropenia.
Adult Dose 5 mcg/kg/d SC until ANC has reached 10,000/mm3
5-10 mcg/kg/d IV/SC; doses begun 24-48 h following a
Pediatric Dose course of myelosuppressive chemotherapy and
continued until recovery (past nadir)
Contraindication
Documented hypersensitivity
s
Interactions None reported
C - Safety for use during pregnancy has not been
Pregnancy
established.
Do not use 12-24 h before or 24 h after administering
cytotoxic chemotherapy because it increases sensitivity
Precautions
of rapidly dividing myeloid cells to cytotoxic
chemotherapy; may cause bone pain or headache

Drug Category: Antiemetic agents -- Antineoplastic-induced vomiting is stimulated


through the chemoreceptor trigger zone (CTZ), which then stimulates the
vomiting center (VC) in the brain. Increased activity of central neurotransmitters,
dopamine in CTZ or acetylcholine in VC, appears to be a major mediator for
inducing vomiting. Following administration of antineoplastic agents, serotonin
(5-HT) is released from enterochromaffin cells in the GI tract. With serotonin
release and subsequent binding to 5-HT3-receptors, vagal neurons are stimulated
and transmit signals to the VC, resulting in nausea and vomiting.

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.

Ondansetron (Zofran) -- Selective 5-HT3-receptor


antagonist that blocks serotonin both peripherally and
centrally. Prevents nausea and vomiting associated with
Drug Name emetogenic cancer chemotherapy. Sometimes used in
combination with dexamethasone to potentiate
antiemetic effect.
8 mg PO bid for chemotherapy prophylaxis
Adult Dose Alternatively, 0.15 mg/kg IV for 3 doses or 32 mg IV once
as a single dose
0.15 mg/kg/dose IV 30 min before chemotherapy for
Pediatric Dose prophylaxis and following chemotherapy q4h for 2 doses
Alternatively, 0.15 mg/kg/dose PO/IV q4-6h
Contraindication
Documented hypersensitivity
s
Although potential exists for CYP450 inducers (eg,
barbiturates, rifampin, carbamazepine, phenytoin) to
Interactions
change the half-life and clearance of ondansetron,
dosage adjustment is not usually required
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Commonly causes headache; may cause dizziness

Drug Category: Uroprotective antidotes -- Mesna is a prophylactic detoxifying


agent used to inhibit hemorrhagic cystitis caused by ifosfamide or
cyclophosphamide.

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.

Mesna (Mesnex) -- Inactivates acrolein and prevents


Drug Name urothelial toxicity without affecting cytostatic activity.
Dose dependent on dose of ifosfamide or
cyclophosphamide, typically 60-100% of the
antineoplastic agent used; may be administered as an
Adult Dose
initial bolus followed by IV continuous infusion or
intermittent IV infusions prior to and following
chemotherapy regimen
Pediatric Dose Administer as in adults
Contraindication
Documented hypersensitivity
s
May increase warfarin affect, adjust dose according to
Interactions
INR target
Pregnancy B - Usually safe but benefits must outweigh the risks.
Monitor morning urine for hematuria prior to ifosfamide
Precautions or cyclophosphamide dose; common adverse effects
include hypotension, headache, GI toxicity, and limb pain

FOLLOW UP

70
Further Inpatient Care:

Inpatient care involves admissions for chemotherapy as well as for


supportive care from therapy delivered. Patients must be hospitalized for
episodes of fever and neutropenia and started on broad-spectrum
antibiotic coverage while awaiting culture results or recovery from
illness.

Further Outpatient Care:

Frequent outpatient visits are required for monitoring the effectiveness


of therapy and the adverse effects of therapy.

o CBCs are required once to twice weekly for patients while on G-


CSF therapy.

o Periodically monitoring the toxic effects of chemotherapy on


liver and renal function is required with serum chemistry levels.

o Support with blood products, including packed RBCs and


platelets, may be necessary if on chemotherapy.

Long-term follow-up is required after therapy is completed to monitor for


the following:

o Disease recurrence

o Development of a secondary malignancy

o Assessment of growth and development issues

Prognosis:

By IRS grouping, group I patients have an 82% survival rate; group II


have a 67% survival rate; group III have a 12% survival rate; and group
IV have a 5% survival rate. These survival data emphasize the need for
further research and study to improve the prognosis for higher-risk
patients. Many factors contribute to survival, but the degree of
resectability at diagnosis is the most important to date

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