Soft Tissue Sarcomas

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Ovid: Oncology and Basic Science

Editors: Tornetta, Paul; Einhorn, Thomas A.; Damron, Timothy A.

Title: Oncology and Basic Science, 7th Edition

> Table of Contents > Section III – Specific Soft Tissue Neoplasms and Simulators > 12 – Soft Tissue Sarcomas

Soft Tissue Sarcomas

Carol D. Morris

Soft tissue sarcomas are malignant neoplasms that arise
in nonepithelial extraskeletal tissue (e.g., fat, muscle, fibrous
structures, etc.) of mesenchymal origin. They account for less than 1%
of all cancers, with approximately 8,000 to 9,000 diagnosed annually in
the United States. Benign soft tissue tumors outnumber malignant ones
by a factor of at least 100. More than 50 histologic subtypes of soft
tissue sarcoma are recognized (Table 12-1).

Soft tissue sarcomas can occur anywhere in the body,
though the majority occur in the extremities (50% to 75%). Ten percent
occur on the trunk. As with other malignancies, soft tissue sarcoma
tends to occur in older individuals, with a median age of 65, although
there are subtype-related variations in peak age. For example,
embryonal rhabdomyosarcoma occurs almost exclusively in children
(<10 years old), synovial sarcoma occurs in young adults (20 to 40
years old), and pleomorphic sarcoma and liposarcoma occur in older
adults (>60 years old). Approximately 10% of patients have
clinically detectable metastases at presentation, usually in the lung.

The management of soft tissue sarcoma requires a
multidisciplinary approach that includes surgery, radiation therapy,
and chemotherapy. Treatment plans are best coordinated and administered
when possible by specialty centers with expertise in treating the
disease. The overall 5-year survival for patients with soft tissue
sarcoma is largely dependent on the stage of disease. This, in turn, is
determined by a combination of factors that include the grade, size,
and location of the tumor. Using the four-tiered staging system of the
American Joint Committee on Cancer (AJCC), 5-year survival rates are
approximately 90% for stage I, 70% for stage II, 50% for stage III, and
10% to 20% for stage IV.

This chapter will review the rationale and outcomes for
the management of soft tissue sarcoma with current treatment paradigms.
In addition, the clinical and histopathologic presentation of the more
common soft tissue sarcomas likely to be encountered in practice and on
examinations will be discussed.

Pathogenesis

The etiology of soft tissue sarcoma is largely unknown.
While numerous genetic aberrations continue to be identified, the
clinical significance of these is still being elucidated. The more
consistent genetic findings are outlined in connection with individual
tumor types.

Etiology

Largely unknown
Chemical carcinogens
- Increased incidence reported after exposure to dioxins (herbicides)
- Controversial

Radiation

Termed “post-radiation” or “radiation-induced” sarcoma
More common in women, reflecting the
distribution of conditions for which radiation is widely used: breast
cancer, genitourinary cancers

Risk increases with dose, with most patients having received at least 50 Gy.

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Table 12-1 Who Classification of Malignant Soft Tissue Tumors

Adipocytic tumors	Atypical lipomatous tumor/well-differentiated liposarcoma Dedifferentiated liposarcoma Myxoid liposarcoma Round cell liposarcoma Pleomorphic liposarcoma Mixed-type liposarcoma Liposarcoma, not otherwise specified
Fibroblastic/myofibroblastic	Solitary fibrous tumor and hemangiopericytoma Inflammatory myofibroblastic tumor Low-grade myofibroblastic sarcoma Myxoinflammatory fibroblastic sarcoma Infantile fibrosarcoma Adult fibrosarcoma Myxofibrosarcoma Low-grade fibromyxoid sarcoma Hyalinizing spindle cell tumor Sclerosing epithelioid fibrosarcoma
Fibrohistiocytic tumors	Undifferentiated pleomorphic sarcoma Pleomorphic malignant fibrous histiocytoma (MFH) Giant cell MFH Inflammatory MFH Not otherwise specified
Smooth muscle tumors	Leiomyosarcoma
Skeletal muscle tumors	Embryonal rhabdomyosarcoma (including spindle cell, botryoid, anaplastic) Alveolar rhabdomyosarcoma (including solid, anaplastic) Pleomorphic rhabdomyosarcoma
Vascular tumors	Retiform hemangioendothelioma Papillary intralymphatic angioendothelioma Composite hemangioendothelioma Kaposi sarcoma Epithelioid hemangioendothelioma Angiosarcoma of soft tissue
Chondro-osseous tumors	Mesenchymal chondrosarcoma Extraskeletal osteosarcoma
Tumors of peripheral nerves	Malignant peripheral nerve sheath tumor (MSNST)
Tumors of uncertain differentiation	Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma (“chordoid” type) Primitive neuroectodermal tumor/extraskeletal Ewing tumor Desmoplastic small round cell tumor Extrarenal rhabdoid tumor Malignant mesenchymoma Neoplasms with perivascular epithelioid cell differentiation (PEComa) Clear cell myomelanocytic tumor Intimal sarcoma

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Median time between exposure and tumor development is ~10 years.
More common in patients with germline mutations

Viral and immunological factors
- Increased incidence of sarcomas in immunocompromised individuals
  - Immunodeficiency syndromes
  - Therapeutic immunosuppression associated with organ transplantation
  - Stewart-Treves syndrome: an acquired
    “regional” immunodeficiency of the edematous upper extremity in breast
    cancer patients following radical mastectomy associated with
    lymphangiosarcoma
- Oncogenic viruses
  - Human herpes virus 8 associated with Kaposi sarcoma
  - Epstein-Barr virus associated with leiomyosarcomas
Genetic predisposition
- Neurofibromatosis-1 associated with malignant peripheral nerve sheath tumors (MPNST)
- Li-Fraumeni syndrome: germline mutation in p53 suppressor gene
- Hereditary retinoblastoma: germline mutation of RB1 locus

Epidemiology

Approximately 8,700 new cases diagnosed annually in the United States
Annual incidence is 1.5 per 100,000 individuals
- 8 per 100,000 in individuals greater than 80 years old
Slight male predominance
No proven racial variation

Classification

Soft tissue sarcomas are a highly heterogeneous group of
tumors that are most commonly classified on a histological basis
according to the tissue they most resemble. The most widely recognized
classification system is that of the World Health Organization (WHO),
which was first published in 1969 and most recently updated in 2002
(see Table 12-1).

Staging

Staging systems incorporate histological and clinical information for prognostic value.
The staging system used throughout this chapter is the AJCC staging system (Table 12-2).
- 75% of soft tissue sarcomas are high grade.
- One third of soft tissue sarcomas are superficial and two thirds are deep.

Table 12-2 American Joint Committee on Cancer (Ajcc) Staging System for Soft Tissue Sarcoma

Stage	Size	Depth*	Grade	Metastases
I	Any	Any	Low	No
II	<5 cm, any depth or >5 cm, superficial		High	No
III	>5 cm	Deep	High	No
IV	Any	Any	Any	Yes
*Depth is termed superficial (above the deep fascia) or deep (deep to the deep fascia). Retroperitoneal tumors are considered deep. From American Joint Committee on Cancer (AJCC) Staging System for Soft Tissue Sarcoma, 6th ed.

Diagnosis

The diagnosis of soft tissue sarcoma is
made with a combination of a good history and physical examination,
appropriate radiology imaging, and biopsy.
The pertinent components of the history
and physical examination as well as the clinical and radiologic
features are detailed in Chapter 2.

Clinical Findings

Summary of clinical features and examination findings:
- Most soft tissue sarcomas are painless.
- Masses that are suspicious for sarcoma:
  - >5 cm regardless of location
  - Deep to fascia
  - Firm or fixed
  - Enlarging
- Clinical features of tumors with advanced size
  - Distal edema
  - Nerve compression
  - Bladder symptoms (pelvic sarcomas)
- Metastatic disease
  - 10% of patients present with metastatic disease.
  - Lung is the most common metastatic site.
  - Bone (6%) and lymph node (3%) metastases are less common.

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Radiologic Findings

Necessary imaging
- Chest x-ray
- Computed tomography (CT) of chest: preferred for detection of metastases
- Magnetic resonance imaging (MRI) of primary site
  - CT with contrast substituted in patients with contraindication for MRI
  - CT often preferred for intra-abdominal tumors
- Role of positron emission tomography (PET) scan unclear

Other Diagnostic Tests

Histologic analysis of tissue is required
for staging and should be performed prior to initiating any treatment,
with rare exceptions.
A good biopsy is the first step in a successful limb salvage operation.
Diagnostic tissue can be obtained by the following methods:
- Needle
  - Fine-needle aspiration (FNA)
  - Core
- Open incision
- Open excisional
The advantages and disadvantages of each type of biopsy are discussed in Chapter 3, Biopsy of Musculoskeletal Tumors.

Diagnostic Tools

Numerous investigative tools are available to the pathologist to assist in the diagnosis of specific sarcoma subtypes (Tables 12-3 and 12-4).

Table 12-3 Common Immunohistochemistry Stains and Tissue Distribution

Tissue	Representative Sarcomas	Antigen Stains
Mesenchymal tissue	All soft tissue sarcomas	Vimentin
Skeletal muscle	Rhabdomyosarcoma	Actin Desmin Myosin Myogenin MyoD
Smooth muscle	Leiomyosarcoma	Smooth muscle antigen (SMA) Desmin
Epithelium	Synovial sarcoma Epithelioid sarcoma	Epithelial membrane antigen (EMA) Cytokeratin
Neural, uncertain differentiation	Malignant peripheral nerve sheath tumor Clear cell sarcoma Extraskeletal myxoid chondrosarcoma (variable)	S-100
Endothelium	Angiosarcoma (all) Epithelioid Hemangioendothelioma (CD31, CD34) Hemangiopericytoma (CD34)	CD34 CD31 Factor VIII (von Willebrand’s factor)

Treatment

Soft tissue sarcoma is treated with an interdisciplinary
approach that incorporates surgery, radiation, and chemotherapy. The
details, rationale, and outcomes for each of these modalities are
reviewed in Chapter 4, Treatment Principles. The following is a summary.

Surgery

Complete surgical excision is the main cornerstone of treatment.
Often curative for localized disease
Limb salvage is the preferred method.
Amputation is ultimately required in 5% to 10% of patients.

Radiation

Methods of delivery

External beam (pre-, post-, and intraoperation)
Brachytherapy

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Table 12-4 CHROMOSOMAL TRANSLOCATIONS IN SOFT TISSUE SARCOMA

Tumor Type	Translocation	Involved Genes
Ewing/primitive neuroectodermal tumor	11;22	FLI1, EWS
Clear cell sarcoma	12;22	ATF1, EWS
Extraskeletal myxoid chondrosarcoma	9;22	CHN, EWS
Synovial sarcoma	X;18	SSX1 or SSX2, SYT
Myxoid liposarcoma	12;16	CHOP, TLS
Alveolar rhabdomyosarcoma	2;13	PAX3, FKHR
Alveolar soft part sarcoma	X;17	TFE3, ASPL
Dermatofibrosarcoma protuberans (DFSP)	17;22	COL1A1, PDGFB1

Typical dose ~6,000 cGy
Primarily indicated for:
- High-grade tumors (unless margins are very wide)
- Intermediate-grade tumors with close margins
- Large tumors
- Recurrent disease
Improves local control by 20% to 35%

Chemotherapy

Indicated for patients at the highest risk of developing metastatic disease or patients with metastatic disease
Best administered in the setting of a clinical trial
Doxorubicin-based therapy is associated with a minimal improvement in overall survival (<10%).
Ifosfamide-based therapy is associated
with moderately improved survival at intermediate follow-up; long-term
results are unknown.

Results and Outcome

The outcome of patients with soft tissue sarcoma is
multifactorial but largely dependent on the stage of disease. The
overall survival for all patients with soft tissue sarcoma is
approximately 70%. Using the four-tiered staging system of the AJCC,
5-year survival rates are approximately 90% for stage I, 70% for stage
II, 50% for stage III, and 10% to 20% for stage IV.

Negative prognostic factors
- Metastatic disease
- High histologic grade
- Size >10 cm
- Bone and neurovascular invasion
- Advanced age
- Retroperitoneal and visceral location
- Positive microscopic surgical margins
- Presentation with locally recurrent disease

Adipocytic Tumors

Well-Differentiated Liposarcoma

Synonym: atypical lipomatous tumor

Pathogenesis

No potential for metastasis unless it undergoes dedifferentiation (<2% in the extremity, ~20% in retroperitoneum)
Locally aggressive nature can cause
symptoms and even death when complete excision is not possible, as in
the retroperitoneum and mediastinum.
Genetics: ring chromosome 12 with amplification of the MDM2 gene

Epidemiology

Frequency: accounts for 40% to 45% of all liposarcomas
Age: incidence peaks during sixth decade of life
Site: most commonly occurs in the thigh

Classification

Subtypes: lipoma-like, sclerosing, inflammatory, and spindle cell

Diagnosis

Histology: mature adipocytic tissue with slight atypia and scattered to rare lipoblasts (Fig. 12-1)

Myxoid Liposarcoma

Synonyms: round cell liposarcoma, myxoid/round cell liposarcoma

Pathogenesis

Tendency for extrapulmonary metastases (soft tissue and bone, especially the spine)
Multifocal presentation not uncommon
Genetics: >90% of cases associated with t(12:16)(q13;p11) leading to the TLS/CHOP fusion protein; t(12;22) has been described less frequently

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Figure 12-1
Well differentiated liposarcoma; relatively mature adipocytic tissue
with varying cell size admixed with hyperchromatic and multinucleated
stromal cells.

Epidemiology

Frequency: accounts for about one third of all liposarcomas
Age: incidence peaks during the fourth and fifth decades of life
Site: most commonly arises in the deep tissues of the thigh

Classification

Grade is often equated to the size of the
round cell component, usually expressed as a percentage (>5% round
cells = high grade).

Diagnosis

Myxoid component is characterized
histologically by mixture of lipoblasts and uniform nonlipogenic
mesenchymal cells in prominent myxoid stroma associated with a fine
capillary network (Fig. 12-2).
Round cell component is characterized histologically by more cellular regions of round cells (see Fig. 12-2).

Figure 12-2 (A)
Myxoid liposarcoma. Mixture of lipoblasts and uniform nonlipogenic
mesenchymal cells in prominent myxoid stroma associated with a fine
capillary network. (B) High-grade myxoid liposarcoma with a predominant round cell component.

Fibroblastic/Myofibroblastic Tumors

Hemangiopericytoma

Historically evolving term used to refer
to neoplasms with a thin-walled branching vascular pattern; its current
status as a discrete entity is controversial, as the pattern appears
within numerous other types of tumors
Synonym: extrapleural solitary fibrous tumor

Pathogenesis

Genetics: breakpoints in chromosomes 12 and 19 reported but sporadic
May cause hypoglycemia due to secretion of insulin-like growth factor

Epidemiology

Age: occurs in middle-aged adults, most often in the pelvic retroperitoneum

Diagnosis

Characterized histologically by
monomorphic, evenly distributed cellularity arranged around thin-walled
vessels with a staghorn pattern (Fig. 12-3)
Immunohistochemistry: positive for CD34

Adult Fibrosarcoma

Pathogenesis

Genetics: inconsistent aberrations

Epidemiology

Frequency: accounts for 1% to 3% of all soft tissue sarcomas
Age: occurs in middle-aged and older adults
Site: most commonly affects the trunk, head, and neck

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Figure 12-3 Hemangiopericytoma. Monomorphic evenly distributed cellularity arranged around thin-walled vessels with a staghorn pattern.

Classification

Termed “infantile fibrosarcoma” when it occurs in children

Diagnosis

Fibroblasts with variable collagen
production arranged in long intersecting fascicles classically with a
herringbone architecture (Fig. 12-4)

Myxofibrosarcoma

Synonym: myxoid malignant fibrous histiocytoma

Pathogenesis

Local recurrence is notoriously high at >50%, independent of grade.
Low-grade tumors may acquire a higher grade in recurrence, thereby increasing their metastatic potential.
Genetics: inconsistent aberrations

Figure 12-4
Adult fibrosarcoma. Fibroblasts with variable collagen production
arranged in long intersecting fascicles with a classic herringbone
architecture.

Figure 12-5
Low-grade myxofibrosarcoma. Nodular growth pattern of spindle cells in
a myxoid stroma composed of hyaluronic acid with characteristic
elongated, curvilinear blood vessels surrounded by a condensation of
tumor cells.

Epidemiology

One of the more common soft tissue sarcomas of adulthood
Frequency: incidence peaks in sixth to eighth decades of life
Site: two thirds occur in the subcutaneous tissue, usually in the limbs

Diagnosis

Characterized histologically by nodular
growth pattern of spindle cells in a myxoid stroma composed of
hyaluronic acid with characteristic elongated, curvilinear blood
vessels surrounded by a condensation of tumor cells (Fig. 12-5)

Fibrohistiocytic Tumors

Undifferentiated High-Grade Pleomorphic Sarcoma, Not Otherwise Specified

Formerly termed pleomorphic malignant fibrous histiocytoma (MFH)
Definition: Once considered the most
common soft tissue sarcoma of adulthood, MFH has been declassified as a
distinct diagnostic entity; it is now thought to represent a variety of
poorly differentiated or dedifferentiated neoplasms and has been
renamed “undifferentiated pleomorphic sarcoma.”

Pathogenesis

Genetics: extensive heterogeneity

Etiology

2% to 3% arise in a previously radiated field (radiation-induced sarcoma).

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Figure 12-6
Undifferentiated pleomorphic sarcoma. Marked cellularity and nuclear
pleomorphism with bizarre tumor giant cells admixed with spindle and
histiocyte-type cells.

Epidemiology

Frequency and age: The pleomorphic
sarcomas are the most common soft tissue sarcomas in patients >40
years of age, with an increasing incidence with increasing age, peaking
during the sixth and seventh decades of life.
Site: most commonly arise in the deep tissues of the lower limbs

Diagnosis

Considered a diagnosis of exclusion
Characterized histologically by marked
cellularity and nuclear pleomorphism with a storiform pattern and often
bizarre tumor giant cells admixed with spindle cells and
histiocyte-type cells (Fig. 12-6)

Smooth Muscle Tumors

Leiomyosarcoma

Pathogenesis

Genetics: heterogeneous, though losses on chromosomes 3, 8, and 13 are common; the latter is associated with an RB1 mutation

Epidemiology

Frequency: accounts for 10% to 15% of limb sarcomas
Age: may occur in any age, though more common in middle-aged adults
Site: commonly arise primarily in the pelvis from the uterus and large blood vessels (inferior vena cava)

Diagnosis

Characterized histologically by elongated cigar-shaped spindle cells with blunt-ended nuclei interspersed with myxoid changes (Fig. 12-7)
Immunohistochemistry: positive for smooth muscle antigen (SMA) and desmin

Figure 12-7 Leiomyosarcoma. Spindle cells with blunt-ended nuclei interspersed with myxoid changes.

Skeletal Muscle Tumors

Embryonal Rhabdomyosarcoma

Synonyms: myosarcoma, rhabdomyosarcoma, rhabdosarcoma

Pathogenesis

Genetics: losses on chromosome 11

Epidemiology

Frequency: most common soft tissue sarcoma in children and adolescents, with 4.6 cases per million persons <15 years of age
Site: Most arise in the head and neck, followed by the genitourinary tract; limb and trunk involvement is less common (<10%).
- Spindle cell variant most commonly arises in the scrotum.
- Botryoid variant arises beneath mucosal epithelial surfaces (e.g., bladder, biliary tract, pharynx).
Age: ~45% occur in children <5 years of age.

Classification

Embryonal is the most common subtype of rhabdomyosarcoma and encompasses the spindle cell, botryoid, and anaplastic variants.

Diagnosis

Immunohistochemistry: desmin and actin positivity variable; MyoD1 and myogenin highly specific
Histologically characterized by a
constellation of rhabdomyoblasts in various stages of differentiation,
with the more primitive cells possessing oval nuclei and more
differentiated cells demonstrating elongated nuclei (“tadpole” cells)
with eosinophilic cytoplasm (Fig. 12-8)

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Figure 12-8
Embryonal rhabdomyosarcoma. A constellation of rhabdomyoblasts in
various stages of differentiation. The more primitive cells possess
oval nuclei, while more differentiated cells demonstrate elongated
nuclei (“tadpole” cells) with eosinophilic cytoplasm.

Alveolar Rhabdomyosarcoma

Synonyms: rhabdomyoblastoma, rhabdomyopoetic sarcoma, monomorphous round cell rhabdomyosarcoma

Pathogenesis

Genetics: t(2;13)(q35;q14) leading to the PAX3/FKHR fusion protein; t(1;13) in rare cases

Epidemiology

Frequency: less common than embryonal rhabdomyosarcoma
Age: occurs most commonly in adolescents and young adults
Site: most commonly arises in the extremities, followed by paraspinal, perineal, and paranasal locations

Diagnosis

Histologically resembles lymphoma and
other small blue round cell tumors but characterized by alveolar
pattern similar to that in the lung, with cellular areas separated by
fibrovascular septa (Fig. 12-9)
Immunohistochemistry: positive for desmin, actin, myogenin, and MyoD

Vascular Tumors

Epithelioid Hemangioendothelioma

Synonyms: angioglomoid tumor, myxoid angioblastomatosis

Pathogenesis

Genetics: t(1;3) has been reported, though consistency is unknown.

Figure 12-9
Alveolar rhabdomyosarcoma. Nest of small blue round cells separated by
fibrovascular septa to produce a morphologic pattern similar to alveoli
in lung.

Epidemiology

Age: affects all ages
Site: usually arises in the extremity, often originating from a small vein
Often presents with a multifocal distribution in an entire limb bud involving both soft tissue and bone

Diagnosis

Clinical presentation: unlike other soft tissue sarcomas, typically presents as a painful mass
Characterized histologically by short
strands of eosinophilic epithelioid endothelial cells embedded in a
blue to pink acidic matrix (Fig. 12-10)
Immunohistochemistry: positive for CD31, CD34, and FLI1

Angiosarcoma

Synonyms: lymphangiosarcoma, malignant hemangioendothelioma, hemangiosarcoma, hemangioblastoma

Figure 12-10 Epithelioid hemangioendothelioma. Short strands of bland eosinophilic endothelial cells in a deep pink hyaline matrix.

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Figure 12-11
Angiosarcoma. Spindle and epithelial cells arranged morphologically in
loose, irregular vascular channels. Areas of hemorrhage are common.

Pathogenesis

Genetics: inconsistent chromosomal aberrations

Etiology

One third of tumors are associated with a
pre-existing condition such as chronic lymphedema, neurofibromatosis-1,
vascular implants, Klippel-Trenaunay syndrome, Maffucci syndrome, and
previous radiation.

Epidemiology

Age: Incidence peaks in the seventh decade of life, though may occur at any age.
Site: Most occur in the subcutaneous tissue; the majority of deep angiosarcomas occur in the thigh.

Diagnosis

Histologically characterized by nodular
hemorrhagic masses composed of epithelioid and spindle cells attempting
to form interconnecting rudimentary vascular channels (Fig. 12-11)
Immunohistochemistry: positive for von Willebrand factor, CD31, and CD34

Chondro-Osseous Tumors

Extraskeletal Osteogenic Sarcoma

Synonym: soft tissue osteosarcoma

Pathogenesis

~10% associated with previous radiation (radiation- induced sarcoma)
Genetics: inconsistent aberrations

Epidemiology

Frequency: accounts for <2% of all soft tissue sarcomas and 2% to 4% of all osteogenic sarcomas
Age: Incidence peaks during fifth to seventh decades of life.
Site: most commonly arises in the deep soft tissue of the lower extremity

Figure 12-12
Extraskeletal osteogenic sarcoma. Neoplastic bone in a lacy, sheet-like
pattern interspersed with atypical, mitotically active tumor cells.

Diagnosis

Histologically characterized by same features as skeletal osteosarcoma; lace-like osteoid produced by pleomorphic cells (Fig. 12-12)
Immunohistochemistry: variable positivity for many antigens, most specifically osteocalcin
Prognosis is worse than in skeletal osteogenic sarcoma (likely due to lack of chemotherapy response).

Tumors of Peripheral Nerves

Malignant Peripheral Nerve Sheath Tumor (MPNST)

Synonym: neurofibrosarcoma (generally abandoned)

Pathogenesis

Genetics: alterations at the NF-1 locus on chromosome 17; p53 mutations

Epidemiology

50% of cases occur in the setting of neurofibromatosis-1.
Two thirds arise from neurofibromas.
More common in large nerves
- Sciatic nerve most commonly affected

Diagnosis

Histologically characterized by elongated, tapered nuclei in a fibrosarcoma-type background (Fig. 12-13)
Herringbone pattern suggestive of fibrosarcoma arising within a major nerve is highly suggestive of MPNST.

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Immunohistochemistry: positive for S-100
Triton tumor: MPNST with rhabdomyosarcomatous differentiation; associated with a poor prognosis (5-year survival ~12%)

Figure 12-13 Malignant peripheral nerve sheath tumor. Elongated, tapered nuclei in a background of fibrosarcoma-like spindle cells.

Tumors of Uncertain Differentiation

Epithelioid Sarcoma

Pathogenesis

Genetics: inconsistent aberrations

Epidemiology

Age: occurs in young adults in the second to fourth decades of life
Site: commonly arises on the flexor surfaces of fingers, hands, wrist, and forearm

Diagnosis

Clinically, often associated with superficial ulceration
Histologically challenging: may be misdiagnosed as a benign granulomatous process (Fig. 12-14)
Immunohistochemistry: positive for cytokeratins and epithelial membrane antigen (EMA)

Alveolar Soft Part Sarcoma

Pathogenesis

Genetics: t(X;17)(p11;q25) resulting in the ASPL/TFE2 fusion protein
Associated with very high metastatic potential; brain and lung metastases are common

Epidemiology

Frequency: very rare, accounting for <1% of all soft tissue sarcomas
Age: Incidence peaks during the second to fourth decades of life.
Site: most commonly arises in deep tissues of the thigh
- In children, most commonly arises in the head and neck

Figure 12-14 Epithelioid sarcoma. Nodular mixture of eosinophilic epithelial cells and spindle cells.

Diagnosis

Histologically characterized by nests of
tumor cells separated by sinusoidal vascular partitions, resulting in a
pseudoalveolar architecture (Fig. 12-15)

Clear Cell Sarcoma

Synonym: malignant melanoma of soft parts

Pathogenesis

Genetics: t(12;22)(q13;q12) resulting in the EWS/ATF1 fusion protein
Associated with high metastatic potential, especially to lymph nodes

Figure 12-15
Alveolar soft part sarcoma. Nests of tumor cells separated by
sinusoidal vascular partitions resulting in a pseudoalveolar
architecture.

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Epidemiology

Age: Incidence peaks during the third and fourth decades of life.
Site: >90% arise in the extremities, with almost half of those cases involving the foot and ankle.
- Often attached to tendons and aponeuroses

Diagnosis

Histologically characterized by large cells with clear cytoplasm
Immunohistochemistry: positive for melanoma antigens and S100

Extraskeletal Myxoid Chondrosarcoma

Pathogenesis

Genetics: t(9:22) (q22;q12) resulting in the EWS/NR4A3 fusion protein is seen in ~50% of cases.
Despite the name, there is no evidence of cartilaginous differentiation.
Late disease recurrence is common.

Epidemiology

Frequency: accounts for <3% of soft tissue sarcomas
Age: Incidence peaks during sixth decade of life.
Site: most commonly arises in the deep tissues of the proximal limb girdles (thigh > arm)

Diagnosis

Histologically characterized by uniform round and oval cells in a blue chondromyxoid hypovascular stroma (Fig. 12-16)
No characteristic immunohistochemistry findings, although variable S100, cytokeratin, EMA

Synovial Sarcoma

Synonyms: malignant synovioma, tendosynovial sarcoma, synovial cell sarcoma (but all of these terms have been abandoned)

Figure 12-16 Extraskeletal myxoid chondrosarcoma. Uniform round and oval cells in a blue chondromyxoid hypovascular stroma.

Figure 12-17
Biphasic synovial sarcoma. Mixture of both spindle cells and epithelial
cells. The epithelial cells display ovoid nuclei and form
mucin-containing glands.

Pathogenesis

Can be deceptively slow-growing; not unusual to present as mass present for years without change
Genetics: t(x;18)(p11;q11) results in the SYT/SSX1, SYT/SSX2, or SYT/SSX4 fusion protein.
Monophasic synovial sarcoma with the SSX2 gene variant is associated with a better prognosis.

Epidemiology

Frequency: accounts for 5% to 10% of all soft tissue sarcomas
Age: may occur at any age but peaks during second to fourth decades of life
Site: 80% arise in the extremity.
- ~5% arise intra-articular.

Diagnosis

Histologically characterized by both mesenchymal background cells with nests of epithelial cells (biphasic) (Fig. 12-17)
or simply mesenchymal or epithelial tissue (monophasic), the latter
similar in appearance to the herringbone pattern of fibrosarcoma
Immunohistochemistry: for tumors with an epithelial component, positive for cytokeratins and EMA