Soft Tissue Tumors & Sarcomas
Size, depth and genetic fingerprints: telling benign lumps from sarcomas
Approach to a soft tissue mass
Benign far outnumbers malignant. Benign soft tissue tumors outnumber sarcomas by roughly 100 to 1. Sarcomas are malignant tumors of mesenchymal tissues such as fat, muscle, fibrous tissue, vessels and nerve sheath. A mass deserves suspicion when it lies deep to the fascia, exceeds 5 cm, is enlarging, or recurs after excision; pain is an unreliable guide.
Pattern of spread. Sarcomas metastasize hematogenously, and the lung is the usual first site; lymph node spread is uncommon. Exceptions that do reach nodes include rhabdomyosarcoma, synovial sarcoma, angiosarcoma, clear cell sarcoma and epithelioid sarcoma. Grade (differentiation, mitotic rate, necrosis) and size predict behavior.
Adipocytic and smooth muscle tumors
Lipoma. The most common soft tissue tumor: a soft, mobile, painless, thinly encapsulated subcutaneous mass of mature fat cells, cured by simple excision.
Liposarcoma. A sarcoma of adults, typically in the deep thigh or retroperitoneum, where it can grow very large before detection. The diagnostic cell is the lipoblast, whose lipid vacuoles indent and scallop the nucleus. Well-differentiated and dedifferentiated liposarcomas carry amplification of MDM2 on 12q15; myxoid liposarcoma has t(12;16) FUS-DDIT3 and a delicate "chicken-wire" capillary network.
MDM2 is the E3 ubiquitin ligase that targets p53 for proteasomal degradation, so amplifying it disables p53 without any TP53 mutation.
Leiomyoma versus leiomyosarcoma. Uterine leiomyomas (fibroids), the most common tumor in women, are whorled, well-circumscribed, estrogen-responsive and mitotically quiet, and they essentially never transform. Leiomyosarcoma arises de novo in older adults, in the uterus, the retroperitoneum or the wall of large veins such as the inferior vena cava. It is diagnosed by cytologic atypia, brisk mitoses and tumor cell necrosis, not by size or number of masses, and stains for smooth muscle actin and desmin.
Rhabdomyosarcoma
Overview. The most common soft tissue sarcoma of children. Tumor cells recapitulate primitive skeletal muscle: rhabdomyoblasts have eosinophilic cytoplasm and occasional cross-striations, and they stain for desmin and the nuclear myogenic transcription factors myogenin and MyoD1. Favored sites are the head and neck (orbit, parameningeal), the genitourinary tract and the extremities.
| Feature | Embryonal | Alveolar |
|---|---|---|
| Frequency | Most common subtype | Less common |
| Typical patient and site | Young children; head and neck, GU tract | Adolescents; extremities, trunk |
| Genetics | No fusion gene | t(2;13) PAX3-FOXO1 or t(1;13) PAX7-FOXO1 |
| Prognosis | Better | Worse |
Sarcoma botryoides. This embryonal variant forms a grape-like polypoid mass protruding from the vagina of girls under 5, or from the bladder, often with bleeding. Beneath the surface epithelium lies a dense band of tumor cells, the cambium layer.
Orbital rhabdomyosarcoma declares itself early with proptosis and has one of the best prognoses of any site.
Other signature sarcomas
Desmoid fibromatosis. A clonal proliferation of bland fibroblasts that infiltrates muscle and recurs after excision but never metastasizes. Sporadic tumors carry CTNNB1 (β-catenin) mutations; familial adenomatous polyposis, especially Gardner syndrome (APC; with osteomas, epidermoid cysts and dental anomalies), predisposes to mesenteric desmoids, often after surgery. Abdominal wall desmoids arise in pregnant or postpartum women. Nuclear β-catenin staining supports the diagnosis.
Synovial sarcoma. Despite its name it does not arise from synovium. It is a deep soft tissue sarcoma of adolescents and young adults (15–40) near large joints, especially the knee, driven by the SS18-SSX fusion of t(X;18). Histology is biphasic (epithelial glands plus spindle cells) or monophasic spindle; cells are cytokeratin, EMA and TLE1 positive, and imaging often shows calcification.
Undifferentiated pleomorphic sarcoma. One of the most common sarcomas of late adulthood, usually in the deep thigh or retroperitoneum. Bizarre pleomorphic spindle and giant cells, often in a storiform pattern, show no identifiable line of differentiation, so it is a diagnosis of exclusion (formerly malignant fibrous histiocytoma). It is also a classic post-radiation sarcoma.
| Tumor | Genetic lesion | Typical patient and site |
|---|---|---|
| Synovial sarcoma | t(X;18) SS18-SSX | Young adult, near the knee |
| Alveolar rhabdomyosarcoma | t(2;13) PAX3-FOXO1 | Adolescent extremity |
| Myxoid liposarcoma | t(12;16) FUS-DDIT3 | Adult thigh |
| Well-differentiated/dedifferentiated liposarcoma | MDM2 amplification (12q15) | Older adult retroperitoneum or thigh |
| Desmoid fibromatosis | CTNNB1 or APC | Abdominal wall, mesentery |
Predisposing conditions
- Li-Fraumeni syndrome: autosomal dominant germline TP53 loss; soft tissue sarcomas and osteosarcoma, early breast cancer, brain tumors, adrenocortical carcinoma and leukemia, often multiple primaries at young ages.
- Hereditary retinoblastoma: germline RB1 loss raises the risk of osteosarcoma and soft tissue sarcoma, especially in irradiated fields.
- Neurofibromatosis type 1: loss of neurofibromin, a Ras GTPase-activating protein, gives an estimated 8–13% lifetime risk of malignant peripheral nerve sheath tumor, usually arising in a plexiform neurofibroma that suddenly enlarges or becomes painful; the high-grade spindle cells show patchy or absent S-100.
- Prior radiation: sarcomas arise in the treated field years later, such as breast angiosarcoma after lumpectomy and radiation, or undifferentiated pleomorphic sarcoma.
- Chronic lymphedema: Stewart-Treves syndrome is angiosarcoma in a lymphedematous limb, classically the arm after mastectomy with axillary dissection. It appears as violaceous nodules; tumor cells line anastomosing vascular channels, stain for CD31 and ERG, and carry a poor prognosis.
Hepatic angiosarcoma has its own exposures: vinyl chloride, arsenic and Thorotrast.