Sarcomas of Soft Tissue
Summary of Key Points
Incidence and Epidemiology
• In the United States, there are 11,280 new cases annually; fewer than 1% of cancer diagnoses.
• No specific etiologic agent is identifiable in the majority of cases.
• Occasional cases are related to previous radiation, chemical exposure, alkylating chemotherapeutic agents, or chronic lymphedema.
• Genetic conditions related to soft-tissue sarcoma include neurofibromatosis, tuberous sclerosis, basal cell nevus syndrome, Gardner syndrome, and Li-Fraumeni syndrome.
Diagnosis and Evaluation of Extent of Disease
• Core-needle biopsy (large lesions) or excisional biopsy (small lesions).
• Pathological review of histologic subtype, grade, and assessment of margins (excisional biopsies).
• Magnetic resonance imaging or computed tomography (CT) of primary site.
• Chest x-ray for low-grade tumors and high-grade T1 lesions, chest CT for high-grade T2 tumors.
Prognostic Factors
• High-grade histology, deep location, and T2 tumor size are independent adverse prognostic factors for distant metastasis and survival.
• Presentation with recurrent disease and positive surgical margin (gross or microscopic) are independent adverse prognostic factors for local recurrence.
• Individual patient prognosis may be estimated by using a nomogram or newer techniques.
Staging Systems
• The American Joint Committee on Cancer (International Union Against Cancer) system uses criteria that include grade, size, and location relative to the investing muscular fascia, nodal status, and distant metastases. Other means to characterize risk of recurrence of soft-tissue sarcomas include nomograms and Bayesian belief networks.
Primary Therapy
• Surgical resection with an adequate margin of normal tissue; for extremity lesions, a limb-sparing approach is possible in more than 90% of patients and offers survival comparable to amputation without the associated morbidity.
• For most patients, local control is improved with preoperative or postoperative radiotherapy, with size and primary site also impacting its use.
• The role of chemotherapy for high-risk patients remains controversial, but chemotherapy is used at several major centers for high-risk patients, especially for extremity tumors with known chemotherapy sensitivity, preoperatively when possible.
• In addition to surgery, 3 years of adjuvant imatinib is the standard of care for high-risk gastrointestinal stromal tumor (GIST).
Recurrent Disease
• Local recurrence rates vary depending on the anatomic primary site and the adequacy of local therapy; for extremity lesions, approximately 20% of patients experience locally recurrent disease.
• Systemic cytotoxic chemotherapy with selective use of surgery is the mainstay of therapy for patients with metastatic disease.
• Kinase-directed therapy is clinically beneficial for patients with GIST; pazopanib was shown active in patients with other types of sarcoma who failed to respond to other systemic therapies, but has comparatively limited benefit.
• For the small subset of patients who experience isolated (solitary) lung metastases, 20% to 50% 3-year survival rates have been reported with metastasis resection.
1. Identify the genetic alteration associated with each of these common sarcoma subtypes. Choose three answers in all.
2. What are the three most clearly identified clinical characteristics of high-risk nonmetastatic soft-tissue sarcoma (STS)? Choose two.
3. What is the best example of a soft-tissue sarcoma in which a specific genetic alteration has led to demonstration of clinical activity of a therapeutic agent?
A Leiomyosarcoma (vascular endothelial growth factor receptor [VEGFR]) and pazopanib
B Gastrointestinal stromal tumor (KIT) and imatinib
C Synovial sarcoma (SYT-SSX) and vorinostat
D Myxoid-round cell liposarcoma (FUS-DDIT3) and trabectedin
E Malignant peripheral nerve sheath tumor (NF1) and sorafenib
1. Answer: C, D, and H. Most soft-tissue sarcomas can be divided into those characterized by relatively normal cytogenetics except for a single translocation (examples include synovial sarcoma, extraskeletal Ewing sarcoma, alveolar rhabdomyosarcoma) and those without recurrent translocations but characterized by significant aneuploidy (malignant peripheral nerve sheath tumor [MPNST], leiomyosarcomas). Gastrointestinal stromal tumors (GISTs) are somewhat unusual in having one specific driving mutation in the most common form of that sarcoma subtype.
2. Answer: A and D. Several independent studies have shown that for localized STS, the most important markers of tumor more likely to recur include high grade and size greater than 5 cm, as well as a location deep to investing fascia (regardless of specific anatomic site).
3. Answer: B. The identification of KIT mutations most commonly and less frequently platelet-derived growth factor receptor A (PDGFRA) mutations rapidly led to the successful use of imatinib and other tyrosine kinase inhibitors in both the treatment of recurrent disease and the adjuvant setting for high-risk patients.
