Radiation Oncology/Sarcoma/Overview

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Soft Tissue Sarcoma

Described originally by ancient Greek physicians, the term comes from sarx, meaning “flesh”

Incidence

0.66% of adult cancer cases (8100 cases/yr)
- 15% of patients are <16 years old, 40% are >40
- 6.5% of pediatric cancers
Deaths: 4,600 cases/yr, about 50%
- 5th most common cause of death in children under 15 yrs
Distribution: 60% in extremities, 30% in the trunk, 9% head and neck
- Extremity: 75% lower extremity; of these 75% are at or above the knee.
- Trunk: 40% are in the retroperitoneum. The rest are abdominal wall, chest wall, mediastinum, breast, etc.

Etiology

Arise from primitive mesenchyme of the mesoderm, which gives rise to muscle, fat, fibrous tissues, blood vessels, and supporting cells of the peripheral nervous system
Most are sporadic. Familial inheritance pattern may be found in:
- Familial polyposis - desmoid tumors
- Retinoblastoma - bone and soft tissue sarcomas
- Neurofibromatosis type 1 - benign neurofibromas and malignant neurofibrosarcomas
- Li-Fraumeni syndrome - bone and soft tissue sarcomas
May be radiation induced; in breast the actuarial risk of developing radiation-induced sarcoma after breast RT is ~0.5% at 15-20 years
- Most common types are malignant fibrous histiocytoma, fibrosarcoma, and malignant nerve sheath tumor
Environmental: vinyl chloride, phenoxyacetic acid, arsenic - hepatic angiosarcomas. Increased incidence found in gardeners (phenoxy herbicides), railroad workers, construction workers exposed to impregnating agents
May be observed in the setting of chronic massive edema (e.g. Stewart-Treves Syndrome)
Rare cases have also been observed in scar tissues after surgery, burn, or foreign body implants

Pathologic types

Tissue	Sarcoma
Fibrous	Fibrosarcoma
Fibrohistiocytic	Malignant fibrous histiocytoma
Lipomatous	Liposarcoma
Smooth muscle	Leiomyosarcoma
Skeletal muscle	Rhabdomyosarcoma
Vascular/lymphatic	1) Angiosarcoma; 2) Lymphangiosarcoma; 3) Kaposi's sarcoma
Perivascular	1) Malignant Glomus Tumor; 2) Malignant hemangiopericytoma
Synovial	1) Synovial sarcoma; 2) Malignant giant cell tumor of tendon sheath
Mesothelial	1) Fibrous tumor of pleura/peritoneum; 2) Diffuse mesothelioma
Neural	1) Malignant peripheral nerve sheath tumor; 2) Malignant granular cell tumor; 3) Clear cell sarcoma; 4) Malignant melanocytic schwannoma; 5) Gastrointestinal autonomous nerve tumor; 6) Primitive neuroectodermal tumors
Paraganglionic	Malignant paraganglioma
Extraskeletal cartilagenous/osseous	1) Extraskeletal chondrosarcoma; 2) Extraskeletal osteosarcoma
Pluripotent	Malignant mesenchymoma
Miscellaneous	1) Alveolar soft part sarcoma; 2) Epithelioid sarcoma; 3) Malignant extrarenal rhabdoid tumor; 4) Desmoplastic small cell tumor

Comment: MFH is the most heterogenous group of sarcomas. A hypothesis proposes that MFH, as a poorly differentiated sarcoma, may represent a common endpoint for various other sarcomas (PMID 11408500, PMID 11965276)

Diagnosis by immunostains

The following immunostains are useful in excluding or ruling in certain sarcomas (the stains listed are positive for the tumor type listed). Those listed below are not all sarcomas but some are useful diagnoses to exclude.

Abdominal pelvic sarcoma: MART-1
Desmoplastic small round cell tumor: WT1, perinuclear dot-like desmin
Rhabdomyosarcoma: myogenin, myo-D1, myoglobin
Leiomyosarcoma: Desmin, caldesmin
Peripheral neuroectodermal tumor (PNET): CD-99, synaptophysin, chromogranin A
Pleomorphic liposarcoma: S-100
Neuroblastoma: neurofilament, chromogranin A, synaptophysin
Angiosarcoma: CD31, CD34
Follicular dendritic cell sarcoma: CD21, CD35
GIST: CD117 (c-kit)
Melanoma: S-100, MART-1
Poorly differentiated carcinoma: pancytokeratin, EMA
High grade lymphoma: CD45 (leukocyte common antigen), CD4, nuclear TdT
Mesothelioma: WT1, pancytokeratin
Poorly differentiated germ cell tumor: PLAP, pancytokeratin, CD117 (c-kit)
Synovial sarcoma: translocation t(X;18)

Others to be classified: vimentin, CD56, CD57, collagen type 4 immunostaining -- peripheral nerve sheath tumor or synovial sarcoma

See also:

Clear cell sarcoma of kidney (see Wilms' tumor)

Fibrous Tumors

Please see the Fibrosarcoma page for more detail

Fibrohistiocytic Tumors

Historically believed to come from histiocytes, but likely fibroblastic in origin
Fibrous histiocytoma: benign, typically solitary, slow-growing nodules. Fibroblasts and histiocytes. In skin called dermatofibroma. Treated by simple excision or wide local excision to prevent local recurrence
Xanthoma: histiocytes full of lipid; associated with hyperlipidemia, and usually manifested in skin though may involved deep tissues as well
Dermatofibrosarcoma protuberans: low-grade cutaneous sarcoma
High-grade undifferentiated pleomorphic sarcoma:
- Historically called Malignant Fibrous Histiocytoma (MFH)
- Group of malignant soft tissue tumors, with several subtypes. There is some evidence MFH may be the final undifferentiated stage for sarcoma of various differentiation lines.
- Most commonly diagnosed extremity sarcoma
- Presents as painless mass
- Please see below for treatment approaches

Adipose Tumors

Lipoma: most common benign soft tissue neoplasm. Subcutaneous tissues of trunk and proximal limbs (thighs). Frequently solitary, slow-growing, and painless. Local excision, with recurrence <2%
Angiomyolipoma: renal tumor composed of fat, smooth muscle, and blood vessel. Presents with pain or hematuria. Does not metastasise. May be associated with tuberous sclerosis. Wide local excision
Liposarcoma:
- Mostly in adults. ~20% of soft tissue sarcomas
- May occur anywhere, though most common locations are retroperitoneum and thigh
- Three primary histologies:
  - Atypical lipomatous tumor: Deep-seated, painless, enlarging mass. Typically mature adipocytes, although ~10% can become dedifferentiated. The low grade mature adipocyte lesions have a low rate of lymph node involvement and distant metastases. The dedifferentiated lesions are more aggressive (5-year DSS 20%, local failure 80%, and distant mets 30%), especially if located in the retroperitoneum
  - Myxoid liposarcoma: ~40% of liposarcomas. Typically extremities, particularly thigh. t(12;16) translocation resulting in fusion protein TLS-CHOP in >90%. Proportion of tumor containing round cells determines grade, which has impact on survival (5-year OS <5% round cell 90% vs >5% round cell 50%). Respond well to RT
  - Pleomorphic liposarcoma: highly undifferentiated, high metastatic potential, rapid death

Smooth Muscle Tumors

Leiomyoma: Mostly in uterus, GI tract, and extensor surfaces of extremities. Painful, frequently multiple. Histologically benign. May have high recurrence rate after surgery
Leiomyosarcoma:
- Smooth muscle cells staining for desmin and actin. Grading can be difficult, and mitotic activity is used
- Mostly arise as uterine sarcoma or as retroperitoneal sarcoma, though can arise in any location
- Subcutaneous LMS presents as small nodules, and has much better prognosis

Skeletal Muscle Tumors

Please see the Rhabdomyosarcoma page

Vascular Tumors

Hemangioma: Most present at birth, and regress spontaneously. If rapid growth occurs, intralesional injection with interferon
Lymphangioleiomyomatosis (LAM): Progressive infiltration of lungs by smooth muscle cells. Predominately in younger women. Efforts to treat it with lung transplant
Kaposi's Sarcoma
Angiosarcoma
Hemangiopericytoma
Hemangioendothelioma

Synovial Tumors

Nodular Tenosynovitis: Giant cell tumor, commonly seen in women, age 30-50. Frequently in hand, but also ankles and knees. Slow-growing tumors. Due to location, excision often has close margins, and local recurrence 10-20%
Pigmented Villonodular Synovitis
Synovial sarcoma

Peripheral Nerve Tumors

Neurofibroma: Small, slowly growing, cutaneous or subcutaneous nodules. May be painful. Associated with NF1. Plexiform neurofibromas may affect larger segments of nerve, causing dysesthetic pain. Sometimes difficult to differentiate from MPNST
Benign schwannoma (neurilemoma): Slowly growing. Usually encapsulated, containing an ordered cellular region (Antoni A) and a myxoid component (Antoni B). Frequently a painless vertebral mass in the retroperitoneum, also in H&N, and flexor surfaces of the extremities. Treated with surgical resection
Malignant peripheral nerve sheet tumor

Uncertain Histogenesis

Myxoma: Typically occurs in large muscles of the extremities. Abundant mucoid material with few cells.
Alveolar soft part sarcoma: Slow-growing, painless mass, typically in lower extremities. Poorly circumscribed; alveolar spaces are areas of necrosis. Poor prognosis. Essentially no response to chemotherapy
Clear cell sarcoma of the tendons and aponeuroses (melanoma of soft parts): more common in young women. Poor prognosis. High grade. Appears morphologically and behaviorally similar to melanoma, but it has a distinct translocation
Desmoplastic small round cell tumor: Diffuse peritoneal implants. Small round blue cells, fibrosclerotic stroma. Co-express epithelial, mesenchymal, myogenic, and neural markers, with t(11;22) translocation. Poor prognosis (3-year OS 30%)
Follicular dendritic cell sarcoma: Follicular dendritic cells that present antigens to B-cells in a lymph node. Surgery primary approach. High rate of recurrence.

Patterns of spread

Lymph nodes
- ~5% have positive lymph nodes at presentation (PMID 3308055)
- Increased risk in clear cell sarcoma (28%), angiosarcoma (23%), epithelioid sarcoma (20%), rhabdomyosarcoma (15%), synovial sarcoma (14%). (Mnemonic: SCARE for synovial, clear cell, angio, rhabdo, epithel.)
- However, recent studies on synovial sarcoma show only 1-3% rate of LN failure, and radiation of regional LNs may no longer recommended
Distant metastases
- ~10% have distant mets at presentation
- Extremity sarcomas most commonly spread to lung (70-82% experience lung mets as first metastatic site); ~80% of distant mets appear within 2 years
- Retroperitoneal sarcomas spread frequently to liver (liposarcoma spreads to nonpulmonary sites in 59% of metastases)

Risk of Distant mets:

French Federation, 2001 (1980-94) - PMID 11346874 — "Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group." Coindre JM et al. Cancer. 2001 May 15;91(10):1914-26.
- Grade, tumor size, depth, and neurovascular bone involvement (NBI) are independent predictors of mets.
- Metastasis-free survival:
  - MFH: 88% (<5cm), 65% (5-9cm), 53% (10+cm). 90% (grade 1), 76% (gr 2), 48% (gr 3).
  - Liposarcoma: size - 92%, 94%, 78%, grade - 93%, 71%, 58%.
  - Leiomyosarcoma: size - 88%, 52%, 41%. grade - 92%, 66%, 44%.
  - Synovial sarcoma: size - 66%, 56%, 27%. grade - 74% (grade 2), 35% (gr 3).
  - MPNST: size - 61%, 57%, 44%. grade - 77%, 56%, 52%.

Prognostic factors

Increased risk for local recurrence
- Age > 50
- Recurrent disease
- Positive surgical margins
- Fibrosarcoma (including desmoid)
- Malignant peripheral nerve tumors

Increased risk of distant mets
- Size > 5cm
- High grade
- Deep location
- Recurrent disease
- Leiomyosarcoma

Risk of Death

MSKCC, 2002 PMID 11821462 -- "Postoperative nomogram for 12-year sarcoma-specific death." (Kattan MW, J Clin Oncol. 2002 Feb 1;20(3):791-6.)
- Nomogram developed for 12-year sarcoma-specific death
- Variables: age, size (<5, 5-10, >10), grade (high, low), histology (various types), depth (superficial, deep), site (UE, LE, visceral, thoracic/trunk, retroperitoneal, H&N)

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