Soft-tissue sarcomas arise from mesenchymal tissue. Aside from this presumed common tissue of origin, these types of tumors display an exceedingly wide range of clinical behavior, anatomic location, and histologic findings. Some of the challenges of treating patients with soft-tissue sarcoma arise from this wide degree of variability. For most patients and clinicians, the notion of cancer brings to mind a painful, rapidly growing mass. Some soft-tissue sarcomas, however, can display indolent clinical characteristics that contrast with their histology and potential for metastasis. This counterintuitive behavior can lead to a delay in seeking medical attention and to unplanned, inadequate initial surgical resections.

Soft-tissue sarcomas often cause few local symptoms, and many patients have no pain. For this reason, proximal lesions, especially around the thigh, shoulder girdle, and pelvis, can reach significant size before patients seek medical attention (Figure 1). Although osseous sarcomas frequently spread into adjacent soft tissues, soft-tissue sarcomas rarely invade bone.¹ Although 25% to 30% of soft-tissue sarcomas occur superficially, most occur deep to investing fascia. The relationship between duration of symptoms and survival is not clearly defined.² Despite their malignant nature, sarcomas often remain within fascial boundaries. Evidence exists that fascial invasion can portend worse prognosis.³ Superficial fungating masses can also have a worse outcome.⁴

As discussed in a 2024 study, approximately 13,000 new cases of soft-tissue sarcoma occur in the United States each year.⁵ Compared with other malignancies, these tumors are exceedingly uncommon, comprising less than 1% of all cancers in the United States.

Commensurate with the wide array of histologic subtypes, soft-tissue sarcoma affects patients throughout life. Most soft-tissue sarcomas develop during adulthood, but 15% to 20% of tumors develop in patients younger than 15 years. Some types of sarcomas occur more frequently in different age groups. Synovial sarcoma is more commonly seen in younger patients; angiosarcomas and pleomorphic undifferentiated sarcomas are more typically seen in older adults. Data from one study suggest that older patients may have a greater propensity for the development of larger, higher-grade tumors than their younger counterparts.⁶

Despite improved molecular characterization of soft-tissue sarcomas, their pathogenesis is largely unknown. Although some data correlate the risk of soft-tissue sarcoma with genetic conditions, there is much that remains unknown.^7,8 Definitive tissue diagnosis is possible through percutaneous or open techniques.^9,10 Given the infrequent occurrence of these tumors, there is no clear consensus on screening for higher-risk populations.¹¹

Given the heterogeneity of soft-tissue sarcomas and ongoing advances in molecular diagnostics, the classification of soft-tissue sarcomas is an ongoing process. For example, the World Health Organization recently added 11 new tumor types in 6 chapters of its recently updated (2020) classification.^12,13

As with any tumor, appropriate treatment involves coordinated multidisciplinary care to manage local and systemic issues. Local management of soft-tissue sarcoma is largely successful, with a recurrence rate of 10% to 15%. Local recurrence is multifactorial, with some data suggesting that margin status, tumor size, and primary versus recurrent status all are contributing factors.¹⁴ Evidence also suggests that older patients may be more likely to experience a local disease relapse.¹⁵ For instances in which the tumor is large and deep, neoadjuvant or adjuvant radiation therapy should be strongly considered. According to a 2022 study, there is growing interest in novel, hypofractionated treatment regimens for neoadjuvant treatment of soft-tissue sarcomas.¹⁶ Systemic therapy is usually reserved for large, deep, high-grade extremity sarcomas, for which meta-analysis has shown an improvement in survival.¹⁷ Although some data suggest a possible role for chemotherapy in patients undergoing neoadjuvant radiation therapy for soft-tissue sarcoma, there are no clear indications at this time.¹⁸ No established role exists for stem cell transplants.¹⁹ Because of the intensity of the doxorubicin-based regimens, greater consideration is given to chemotherapy in younger patients with large, high-grade tumors. Local recurrence is a challenging clinical problem that can affect prognosis.²⁰ Although local recurrence can portend a worse clinical outcome, the relationship between recurrence and survival is uncertain.²¹ Given the heterogeneous nature of soft-tissue sarcomas, predicting prognosis remains an ongoing clinical challenge.²² The most recent American Joint Committee on Cancer staging system for soft-tissue
sarcoma emphasizes size as an important prognostic factor relevant in decision making.²³ In the United States, there are also data suggestive of improved clinical outcomes in patients with commercial insurance as opposed to Medicaid or no insurance.²⁴

There is growing interest in using machine learning and other tools to predict survival in patients with soft-tissue sarcoma. Sarculator is an online nomogram that was based on an initial cohort of patients from Italy. Many clinicians use Sarculator and similar tools to guide discussions with patients. As discussed in a 2022 study, this particular tool and other nomograms will likely continue to be refined over the upcoming years.²⁵

Soft-tissue sarcomas typically spread hematogenously to the lungs. Although visceral and skeletal metastases do occur, these events are considerably less common than pulmonary involvement.²⁶ Nodal disease is also rare and occurs most commonly with certain histologic subtypes: epithelioid sarcoma, synovial sarcoma, clear cell sarcoma, and rhabdomyosarcoma. Staging evaluations typically include local imaging of the tumor with plain radiography and MRI as well as cross-sectional chest imaging with CT. Given the relatively low incidence of nodal and other nonpulmonary metastases, the role of positron emission tomography in systemic evaluation is not yet fully defined for sarcoma staging.²⁷ According to a 2020 study, there is no definitive evidence that sentinel node biopsy is indicated for patients without clinical or imaging evidence of possible nodal disease.²⁸ Often, sarcomas are more aggressive when they originate from preexisting tumors or other conditions. Malignant peripheral nerve sheath tumors (MPNSTs), for example, can be high grade even though they develop in neurofibromas. Similarly, postradiation sarcomas have a poor prognosis.^29,30,31

Malignant fibrous histiocytoma was previously a widely used term to describe many high-grade, pleomorphic sarcomas in adults. Over time, the histiocytic origin of these tumors was called into question. Therefore, the current preferred term for these tumors is undifferentiated pleomorphic sarcoma. Despite the changes in terminology and classification of these tumors, use of the term malignant fibrous histiocytoma largely persists in clinical practice. The molecular characteristics of these tumors are highly variable.^32,33 Some of these tumors also display lipogenic markers.³⁴

With a slight male predominance, these tumors tend to occur in patients older than 50 years. According to a 2023 study, tumor size and local lymphovascular invasion are adverse prognostic factors.³⁵ These tumors usually occur in a subfascial location in the proximal extremities, with a preponderance in the lower extremities. A nonspecific heterogeneous signal is seen on MRI (Figure 2).

Histologically, these tumors show significant pleomorphism and aggressive mitotic activity (Figure 3). Pleomorphic sarcomas do not show distinctive characteristics on immunostaining or karyotype analysis, and their negative histochemical staining patterns can help differentiate them from other histologic subtypes.

Myxofibrosarcoma, described for its light microscopic features, is distinctive for its propensity to be associated with deep fascia. These tumors can have extensive microscopic spreading. These tentacle-like extensions of tumor are likely responsible for the relatively higher local recurrence rate following conventional resections.³⁶ The propensity of these sarcomas to infiltrate adjacent tissue means that negative surgical margins are often more challenging to achieve than in resections for other soft-tissue sarcomas.

Liposarcomas represent a wide range of soft-tissue sarcomas and are the second most common histologic subtype following undifferentiated pleomorphic sarcoma. MDM2, an oncogene and a regulator of the P53 tumor suppressor gene, may be amplified in liposarcoma. The presence of MDM2 amplification increases the risk of transformation to dedifferentiated liposarcoma. Lower-grade tumors such as atypical lipomatous tumors and well-differentiated liposarcomas are predominantly fatty and are bland on MRI (Figure 4).