The soft-tissue sarcomas are a group of rare but anatomically and histologically diverse neoplasms. This is due to the ubiquitous location of the soft tissues and the nearly three dozen recognized histologic subtypes of soft-tissue sarcomas. It is estimated that in 2014, approximately 12,020 new cases of soft-tissue sarcoma will be identified in the United States, and 4,740 patients will die of the disease. The age-adjusted incidence is 3.3 cases per 100,000 persons.
In late February 2013, the US Food and Drug Administration (FDA) expanded approved use of the multi-kinase inhibitor regorafenib (Stivarga, approved in 2012 to treat colorectal cancer), to treat patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed or are metastatic, and which no longer respond to treatment with imatinib (Gleevec) and sunitinib (Sutent). It was also granted orphan drug status because it is intended to treat a rare disease. The pivotal study leading to approval of regorafenib was a randomized trial of 199 patients with GIST that could not be surgically removed and progressed after treatment with imatinib or sunitinib. Patients were randomly assigned to receive either regorafenib or placebo, plus best supportive care, until disease progression or unacceptable toxicity, with the option to crossover from placebo to regorafenib at progression. Progression-free survival was a median of 3.9 months longer with regorafenib compared with placebo. The most common side effects reported with regorafenib were weakness and fatigue, hand-foot syndrome, diarrhea, and hypertension. Serious side effects, which occurred in less than 1% of patients, were liver damage, severe bleeding, skin blistering and peeling, hypertension requiring emergency treatment, heart attacks, and intestinal perforation.
In early February 2013, the FDA granted imatinib (Gleevec) full approval as an adjuvant treatment following surgical removal of CD117-positive gastrointestinal stromal tumors (GIST) in adult patients. Imatinib was first approved in 2001 for the treatment of chronic myeloid leukemia for Philadelphia chromosome–positive patients. In 2002, imatinib was granted approval for the treatment of advanced or metastatic GIST. The accelerated approval for adjuvant use of imatinib in patients with resectable GIST was granted in 2008. The pivotal phase III study that led to the current approval of imatinib in adjuvant treatment of GIST showed patients taking imatinib for 36 months had a 5-year overall survival of 92%, compared with 82% for those who received the standard 12 months of treatment with imatinib. Data regarding cancer-specific survival were not provided. Imatinib given for 36 months compared to the standard 12 months of treatment resulted in a 54% reduction in the risk of recurrence (P < .0001) and a 55% reduction in the risk of death (P < .02). The most common adverse events observed in patients receiving imatinib include edema, bone or muscle pain, diarrhea, rash, nausea, vomiting, muscle cramps, fatigue, and abdominal pain.
In April 2012, the FDA approved the oral multitargeted angiogenesis inhibitor pazopanib (Votrient) for treatment of patients with metastatic soft-tissue sarcoma who previously received chemotherapy. While over 20 sarcoma subtypes were included in the clinical trial that led to the approval, GISTs and adipocytic sarcomas (liposarcomas) were not among them, and so are excluded from this indication. Safety and effectiveness of pazopanib as a second- or later-line treatment for soft-tissue sarcoma were evaluated in the international multicenter PALETTE trial, a double-blind phase III study in 369 patients (median age, 56 years) with metastatic soft-tissue sarcoma who had had failed to respond to treatment with at least one anthracycline-containing regimen. Patients were randomized to receive either pazopanib at 800 mg once daily (n = 246) or placebo (n = 123) until tumor progression. Pazopanib significantly prolonged progression-free survival, with a median progression-free survival of 4.6 months vs 1.6 months in patients randomized to placebo (hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.24–0.4; P < .0001). An interim analysis of overall survival, reported at the 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO), showed a statistically nonsignificant overall survival improvement with pazopanib vs placebo (median overall survival, 11.9 vs 10.4 months; HR = 0.83; 95% CI, 0.62–1.09; P value not significant). In an update, overall survival outcomes with pazopanib vs placebo were still found to be nonsignificant, at 12.6 vs 10.7 months, respectively. The most common side effects with pazopanib were fatigue, diarrhea, nausea, weight loss, headache, dysgeusia, shortness of breath, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, and skin discoloration. Pazopanib carries a boxed warning alerting patients and healthcare professionals to the potential risk of fatal hepatotoxicity, advising that patients should be monitored for liver function and treatment should be discontinued if liver function declines.
Sarcomas constitute less than 1% of all cancers, but 15% of cancers in children, although bone tumors predominate in children. There are familial syndromes in which sarcomas are common, but such genetic conditions are rare.
There is a slight male predominance, with a male-to-female ratio of 1.1:1. Some sarcomas demonstrate a distinct male predominance, such as desmoplastic small round cell tumor.
The age distribution in adult soft-tissue sarcoma studies is < 40 years, 20.7% of patients; 40 to 60 years, 27.6% of patients; and > 60 years, 51.7% of patients.
Studies in large cohorts of patients demonstrate that the race distribution of soft-tissue sarcomas mirrors that of the American population (86% Caucasian, 10% African American, 1% Asian American, and 3% other). Some sarcomas are distinctly unusual in African-American and Asian populations, such as Ewing sarcoma.
Besides issues of ethnicity and the frequency of specific cancers, there are not strong data to indicate a geographical bias in the development of sarcomas.
In the majority of cases of patients with soft-tissue sarcoma, no specific etiologic agent is identifiable. However, a number of predisposing factors have been recognized, which are discussed below.
Soft-tissue sarcomas are recognized to originate in radiation fields following therapeutic irradiation for a variety of malignancies. Frequently, they are seen in the lower-dose regions at the edge of the radiation target volume. By definition, radiation-induced sarcomas arise no sooner than 3 years after radiation therapy and often develop decades later; the median time from radiation to development of a soft tissue sarcoma is 8 to 10 years. The majority of these sarcomas are high-grade lesions (90%), and high-grade undifferentiated pleomorphic sarcoma (formerly termed MFH, malignant fibrous histiocytoma) is a predominant histology. Osteosarcoma, angiosarcoma, and other histologic subtypes have also been reported.
Exposure to various chemicals in specific occupations or situations has been linked with the development of soft-tissue sarcoma. These chemicals include the phenoxyacetic acids (forestry and agriculture workers), chlorophenols (sawmill workers), vinyl chloride (individuals working with this gas, used in making plastics and as a refrigerant), and arsenic (vineyard workers).
Soft-tissue sarcomas have been reported after previous exposure to alkylating chemotherapeutic agents, most commonly after treatment of pediatric acute lymphocytic leukemia. The drugs implicated include cyclophosphamide, melphalan (Alkeran), procarbazine (Matulane), nitrosoureas, and chlorambucil (Leukeran). The relative risk of sarcoma appears to increase with cumulative drug exposure.
Soft-tissue sarcomas have been noted to arise in the chronically lymphedematous arms of women treated with radical mastectomy for breast cancer (Stewart-Treves syndrome). Lower-extremity lymphangiosarcomas have also been observed in patients with congenital lymphedema or filariasis complicated by chronic lymphedema.
Trauma and Foreign Bodies
Although a recent history of trauma is often elicited from patients presenting with soft-tissue sarcoma, the interval between the traumatic event and diagnosis is often short; thus, a causal relationship is highly unlikely. Chronic inflammatory processes, however, may be a risk factor for sarcoma. Foreign bodies, such as shrapnel, bullets, and implants, have also been implicated.
Signs and symptoms of soft-tissue sarcoma depend, in large part, on the anatomic site of origin. Due to the ubiquitous location of the soft tissues, these malignancies may arise at any site in the body where soft tissues are located. Since 50% of soft-tissue sarcomas arise in an extremity, the majority of patients present with a palpable soft-tissue mass. Pain at presentation is noted in only one-third of cases.
Extremity and Superficial Trunk
Extremity and superficial trunk sarcomas account for 60% of all soft-tissue sarcomas. The majority of patients present with a painless primary soft-tissue mass. Lipomas are at least 100 times more common than soft-tissue sarcomas; however, any growing lesion or even a deep-seated fatty lesion should be biopsied to rule out a sarcoma.
Retroperitoneal sarcomas account for 15% of all soft-tissue sarcomas. Most patients (80%) present with an abdominal mass, with 50% of patients reporting pain at presentation. Due to the considerable size of the retroperitoneum and the relative mobility of the anterior intra-abdominal organs, these tumors often grow to substantial size before the patient's nonspecific complaints are evaluated or even before an abdominal mass is noted on physical examination.
Visceral soft-tissue sarcomas, which comprise 15% of all soft-tissue sarcomas, present with signs and symptoms unique to their viscus of origin. For example, GISTs present with GI symptoms that are usually indistinguishable from those of the more common adenocarcinomas, such as anemia, melena, abdominal pain, or weight loss. Similarly, uterine leiomyosarcomas frequently present with painless vaginal bleeding, such as that often noted in patients with more common uterine malignancies.
Head and Neck
Head and neck sarcomas comprise 10% of all soft-tissue sarcomas. Although generally smaller than sarcomas in other sites, they may present as a palpable mass or with important mechanical problems related to compression or invasion of adjacent anatomy (eg, orbital contents, airway, or pharynx). In addition, their proximity to critical anatomy can pose management difficulties due to compromise in the delivery of both surgery and radiotherapy.
As a consequence of the wide spectrum of soft tissues, a variety of histologically distinct neoplasms have been characterized. The current histopathologic classification is based on the putative cell of origin of each lesion. Such classification based on histogenesis is reproducible for the more differentiated tumors. However, as the degree of histologic differentiation declines, it becomes increasingly difficult to determine a potential cellular origin, and such tumors are usually described by their architecture or cellular morphology, for example, clear cell sarcoma.
In addition, many of these tumors appear to have the ability to dedifferentiate. This process results in a variety of overlapping patterns, making uniform classification difficult. Experienced soft-tissue pathologists frequently disagree as to the cell of origin of an individual tumor. Comparative studies have demonstrated concordance in histopathologic diagnosis in only two-thirds of cases. Malignant fibrous histiocytoma (MFH) used to be the most common histologic subtype of soft-tissue sarcoma. However, in one study, reanalysis histologically, immunohistochemically, and ultrastructurally allowed reclassification of most tumors to a specific line of differentiation. As a result, the term "malignant fibrous histiocytoma" is increasingly being replaced by the term "high-grade undifferentiated pleomorphic sarcoma" (UPS). GIST is now recognized as the most common form of soft-tissue sarcoma, if all small and relatively inconsequential lesions removed as very early tumors are counted.