# Radiation Oncology/Sarcoma/Overview

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Soft Tissue Sarcoma

## 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)

## Other Resources

* ARRO Case - STS
* ASTRO/ARRO Journal Club Webinar 2011 - "IMRT vs. Brachy for STS" with Thomas Delaney, M.D.
* ASTRO/ARRO Journal Club Webinar 2012 - "RT for Extremity STS: Why, Where, and When?" with Thomas Delaney, M.D.