Soft Tissue Sarcoma: Diagnosis and Treatment




Soft tissue sarcomas (STSs) are rare adult tumors, with 3.4 new cases per 100,000 persons or 12,310 expected new cases in 2016.1 Sarcomas are a heterogeneous collection of tumors that affect fat, muscle, nerve, nerve sheath, vascular, and connective tissues. There are more than 50 histological subtypes that comprise this diverse category of tumors. Treatment varies by stage, with limb-sparing surgery representing the mainstay of curative-intent treatment. Radiation and chemotherapy may also be considered depending on the size, grade, and location of the tumor. Survival rates have been stagnant until recently, with a disease-specific survival hovering around 65%.1 Given the complexity of these cases, all patients ideally should be evaluated and treated by a multidisciplinary team at an institution with extensive experience treating STS.2

Epidemiology and Classification

The most common STS subtypes are gastrointestinal stromal tumor (GIST), undifferentiate pleomorphic sarcoma (previously referred to as malignant fibrous histiocytoma), liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, and unclassified sarcoma.3 Liposarcoma is one of the most common subtypes, comprising 20% of all STSs; it is subdivided into well-differentiated/dedifferentiated liposarcomas, myxoid/round cell liposarcomas, and pleomorphic liposarcomas. Well-differentiated liposarcomas tend to occur in the retroperitoneum and limbs, while both myxoid and round cell as well as pleomorphic liposarcomas more commonly originate on the limbs. Histology varies based on subtype and ranges from mature-appearing adipocytes and fibroblasts to undifferentiated cells with minimal lipogenic differentiation.4

Leiomyosarcomas are smooth muscle tumors and are usually located in the retroperitoneum, but have also been associated with peripheral soft tissue and vasculature. Typical histology ranges from well-defined areas of spindle-shaped cells to poorly differentiated anaplastic spindle cells.5,6 Synovial sarcomas are a distinct type of STS that can show epithelial differentiation and account for 5% of adult STSs. The extremities are the most common presenting location (90%).7

Rhabdomyosarcomas are skeletal muscle tumors and are further subdivided into embryonal, alveolar, and pleomorphic subtypes. Embryonal histology ranges from primitive mesenchymal-appearing cells to highly differentiated muscle cells. Alveolar rhabdomyosarcoma has the worst prognosis of the subtypes and consists of round cells with high nuclear-to-chromatin ratios that form “glandular-like” or “alveolar” spaces.8 Pleomorphic rhabdomyosarcomas are composed of rhabdomyoblasts that can affect many different locations, but most commonly present on the lower extremities.9

Malignant peripheral nerve sheath tumor (MPNST) comprises 5% to 10% of all STSs. These tumors are associated with neurofibromatosis type 1 (NF-1), with 25% to 50% of tumors occurring in NF-1 patients. Additionally, most patients have a truncating lesion in the NF1 gene on chromosome 17.10 Anghileri et al in their single institution analysis of 205 patients with MPNSTs found the 2 most common presenting sites were the trunk and extremities. Histologically, these tumors have dense fascicles of spindle cells.10

GISTs are the most common STS of the gastrointestinal (GI) tract. Previously, GISTs were classified as smooth muscle tumors and were not accounted for in the literature as a separate entity distinct from leiomyomas, leiomyoblastomas, and leiomyosarcomas.11 GISTs are found throughout the GI tract: the most common sites are the stomach (60%) and small intestine (30%). Less common sites include duodenum (4%–5%), esophagus (1%), rectum (1%–2%), and appendix (< 0.2%).12 GISTs can be spindle cell, epithelioid, or mesenchymal tumors. Immunohistochemically, GISTs are KIT (CD117) positive. Other cell markers that are also commonly positive include CD34 (60%–70%) and smooth muscle actin (SMA) (25%).11 The majority of GISTs (80%) have an activating c-KIT gene mutation. The most common mutation site is exon 11, with less common c-KIT gene mutations also occurring at exon 9 or 13. Not all GISTs have KIT mutations. The second most common mutation is the PDGFRA mutation (5%–10% of GISTs).2 A minority of GISTs are negative for both KIT and PDGFRA mutations. These tumors were previously called wild-type, but as the majority have either a succinate dehydrogenase (SDH) loss of function or loss of SDHB protein expression, they are now referred to as SDH-deficient GISTs.2 GISTs vary in aggressiveness from incidental to aggressive. Typically, small intestine and rectal GISTs are more aggressive than gastric GISTs. Both size and mitotic rate help to predict the metastatic potential of the tumor. Tumors less than 2 cm in size and having a mitotic rate of less than 5 per 50 high-power fields (hpf) have the lowest risk of metastases, while tumors greater than 5 cm and with more than 5 mitoses per 50 hpf have the highest rates of metastases.12

Angiosarcomas are rare tumors comprising 4% of all STSs. Although they can occur in any site, the majority are cutaneous and occur most frequently in the head and neck regions. These tumors are either of vascular or lymphatic origin and are comprised of abnormal, pleomorphic, malignant endothelial cells. The most useful immunohistochemical markers include von Willebrand factor, CD31, and Ulex europaeus agglutinin 1. The majority of these tumors occur sporadically; however, radiation exposure, chronic lymphedema, and certain toxins including vinyl chloride and thorium dioxide are known risk factors.13

Undifferentiated sarcomas have no specific features and typically consist of primitive mesenchymal cells.


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