Soft Tissue Sarcomas

Introduction

Soft tissue sarcomas are rare mesenchymal tumors that originate from the mesoderm, with the notable exceptions of those arising from primitive neuroectodermal tissue and those with unknown cell derivation, such as Ewing sarcoma or synovial sarcoma. Because more than 50 clinically and molecularly distinct sarcoma subtypes exist, there is tremendous clinical variation that leads to marked heterogeneity in their respective clinical behavior, prognosis, metastatic risk, and chemotherapy responsiveness. For this reason, clinicians must be aware of the subtype-dependent nuances, even though many soft tissue sarcomas are treated similarly. Despite having nearly the same incidence as multiple myeloma or thyroid carcinoma, soft tissue sarcomas are responsible for more deaths than from testicular tumors, Hodgkin disease, and thyroid cancer combined. They are two to three times more common than primary malignant bone tumors, and, despite apparently complete surgical resection, they often metastasize to the lungs.

Epidemiology and Etiologic Considerations

Soft tissue sarcomas account for approximately 1% of all primary adult malignancies and 7% to 15% of pediatric neoplasms. The general incidence of these tumors is 1.4 per 100, 000, but rises to 8 per 100, 000 in people older than 80 years. Roughly 40% of all soft tissue sarcomas occur in people older than 50 years. The American Cancer Society estimates a combined incidence of soft tissue (including heart) sarcomas in adults and children of approximately 13, 460 new cases (7720 males and 5740 females) and approximately 5270 deaths (2840 males and 2510 females) for the year 2021. The overall incidence has been gradually increasing, in part because of better diagnosis. A male to female ratio of approximately 1.2 to 1 has been reported, although this varies considerably depending upon the sarcoma subtype. The relative frequency of each subtype of soft tissue sarcoma varies according to age. For instance, rhabdomyosarcoma mostly occurs in children, synovial sarcoma in young adults, and undifferentiated pleomorphic sarcoma (MFH) in the older population. Benign soft tissue tumors are approximately 100 times more common than malignant soft tissue tumors. Soft tissue sarcomas are most often seen in the extremities (59%), the trunk (19%), the retroperitoneum (15%), and the head and neck (9%).

The vast majority of soft tissue malignancies occur sporadically without any predisposing cause. However, secondary soft tissue sarcomas may be seen 3 to 15 years following irradiation for lymphoma, cervical cancer, breast cancer, or testicular cancer. Viruses have also been implicated with some soft tissue sarcomas, such as leiomyosarcoma, and with Kaposi sarcoma in patients with acquired immunodeficiency syndrome. Chronic lymphedema-associated angiosarcoma (Stewart–Treves syndrome) occurs as a rare complication of breast cancer treatment. An increased incidence of soft tissue sarcomas has been reported in several genetic disorders, such as neurofibromatosis, hereditary retinoblastoma, and Li–Fraumeni syndrome. Chemicals, such as Agent Orange (a dioxin-containing herbicide) and immunosuppressive drugs, are an uncommon cause of soft tissue sarcoma.

Histopathologic Considerations

The World Health Organization (WHO) classifies various histologic subtypes of soft tissue sarcomas. This classification is based on the presence of predominant constituent mesenchymal tissue of malignant soft tissue tumor, as well as whether a malignant soft tissue sarcoma is low-, intermediate-, or high-grade on histopathology. Thus, a malignant soft tissue tumor consisting of mostly malignant adipocytic cells is termed as liposarcoma. A less aggressive well-differentiated liposarcoma (atypical lipomatous tumor) may recur locally, but rarely it has distant metastases, whereas high-grade dedifferentiated liposarcoma often has distant metastases, usually to the lungs. Similarly, fibrosarcoma is named after its constituent malignant fibrous tissue. At times, a soft tissue tumor may have admixture of constituent malignant cells, as in case of myxoinflammatory fibroblastic sarcoma, which not only contains malignant fibroblasts and myxoid tissue, but also inflammatory cells. Similarly, highly malignant dedifferentiated/pleomorphic soft tissue sarcoma (malignant fibrous histiocytoma) is composed mostly of malignant fibrous and histiocytic tissues. It is therefore imperative that histopathologic diagnosis of a soft tissue mass be made before treatment to establish its tissue composition and to know whether it is benign or malignant. Also, in case of a malignant tumor, it is essential to determine whether it is low-, intermediate-, or high-grade. This histopathologic diagnosis will ultimately decide treatment, management, and patient prognosis, as different soft tissue tumors vary greatly in their clinical behavior and outcome. In general, biopsy should be performed on any symptomatic or enlarging soft tissue mass that persists longer than 4 weeks or is larger than 5 cm in diameter.

Computed tomography (CT)– or ultrasound (US)-guided percutaneous fine needle aspiration (FNA) biopsy is routinely performed under local anesthesia. An FNA biopsy has low risk of complications, but a greater probability of misdiagnosis; however, it is ideal for suspected recurrent soft tissue tumors or nodal metastases.

A core needle biopsy is often preferred for diagnosis, as it has relatively low (~1%) rate of complications and a much higher diagnostic yield than a FNA biopsy. Several specimens should be obtained from within a soft tissue tumor to ensure adequate tumor tissue for various pathologic stains, electron microscopic studies, cytogenetic analysis, and flow cytometric studies. US, CT, or gadolinium (Gd)-enhanced MRI is often used as a guide to determine the best area for biopsy. In addition, the biopsy site should be chosen so that it lays within the area of subsequent en bloc resection. Improper biopsy has been shown to be associated with greater morbidity, complications, and changes in clinical course and outcome. To prevent tumor seeding, biopsy can be obtained by using a coaxial needle with its tip at the outer margin of the tumor, through which the core biopsy needle can be placed within the tumor. An adequacy rate of 93% and an accuracy rate of 95% have been reported with FNA and core needle biopsies.

When a closed needle biopsy technique returns inadequate specimen, an open biopsy should be considered. For a small mass less than 3 cm in diameter, an excisional biopsy can be performed. However, for tumors larger than 5 cm in diameter, an incisional biopsy through a small longitudinal incision, preferably performed by the surgeon planning surgical resection, is recommended.

In case of a malignant retroperitoneal soft tissue tumor, needle biopsy should not be performed routinely, because of the potential danger of transperitoneal tumor spread and track seeding. Exceptions include suspected intraabdominal nodal involvement in lymphoma and germ cell tumors and for soft tissue tumors where preoperative chemotherapy or radiation is to be used.

The histologic grade of soft tissue sarcoma best predicts its biologic behavior and is determined by four factors: mitotic index, degree of cellularity, intratumoral necrosis, and degree of nuclear anaplasia. A soft tissue sarcoma is graded as low-grade or high-grade malignancy on histopathology. High-grade soft tissue sarcomas can be moderately differentiated, poorly differentiated, or undifferentiated.

Clinical Evaluation

Soft tissue sarcomas usually present clinically as gradually enlarging, painless masses. Diagnosis of soft tissue sarcoma relies on clinical examination, imaging, and histologic analysis. Clinical examination and imaging define tumor relationship with adjoining structures. Because they are more superficial, soft tissue tumors in distal limbs and in the head and neck tend to be small; those in the thighs, buttocks, and retroperitoneum, being deep-seated, can be huge.

When evaluating a patient with a soft tissue mass, one must ascertain how long the mass has been present; whether the mass is slow- or fast-growing; presence of local pain and tenderness; constitutional symptoms; history of prior surgery, radiation, or trauma to the area; and recent use of anticoagulants. The growth rate of a soft tissue sarcoma can often vary with aggressiveness of the tumor. However, slow growth does not always imply benignity. It is not uncommon for epithelioid sarcoma to be mistaken for a benign tumor because of its small size, thereby leading to improper management. Presence of local pain, seen in approximately one-third of patients with rapidly growing high-grade tumors, usually indicates poor prognosis. Discoloration of overlying skin or variation in size of the soft tissue mass with activity or palpation favors hemangioma. Regional lymph nodes should always be examined for metastatic spread, even though lymphangietic spread of a soft tissue sarcoma is uncommon.

Most soft tissue sarcomas expand centrifugally and tend to have a peripheral pseudocapsule of compressed normal soft tissue around them. However, this pseudocapsule is often infiltrated by tumor. As a soft tissue sarcoma grows, it follows the path of least resistance and tends to remain confined to the compartment of origin. Such an intracompartmental soft tissue tumor is bounded by natural anatomical barriers, such as fascial septa, tendon, ligament, cortical bone, articular cartilage, and joint capsule. Larger tumors can cause symptoms secondary to increased pressure/stretch on adjoining neurovascular structures. This can not only cause pain, but also produce paresthesias and regional soft tissue edema. With highly aggressive soft tissue tumors, satellite soft tissue tumor foci (skip metastases) may be found frequently beyond the peritumoral reactive zone within the compartment of origin.

The presence of a pseudocapsule at the periphery of a soft tissue sarcoma does not always confer benignity. A well-marginated soft tissue tumor with a pseudocapsule can be malignant, whereas an infiltrating soft tissue tumor with ill-defined borders, such as desmoid tumor, rarely metastasizes distally. The size of a soft tissue tumor does not always distinguish a benign from a malignant soft tissue tumor, as has been pointed out earlier. However, in general, a soft tissue mass smaller than 3 cm in diameter tends to be benign, with a positive predictive value of 88%, while a soft tissue mass larger than 5 cm in diameter indicates malignancy, with a sensitivity of 74%, a specificity of 59%, and an accuracy of 66%.

Extracompartmental extent, involvement of adjacent bone, and encasement of neurovascular bundle are insensitive signs of malignancy, as these can also be seen with benign soft tissue tumors, such as hemangioma or desmoid tumor. A benign soft tissue lesion, such as fibromatosis, can be aggressive in behavior, while a well-differentiated liposarcoma is usually slow-growing. In some cases, both benign and malignant soft tissue tumors may be seen in the same patient. For instance, in a patient with neurofibromatosis, numerous benign soft tissue neurofibromas may coexist with a neurofibrosarcoma, and sometimes it may be difficult to distinguish between the two.

Classification and Staging

Soft tissue is derived from mesenchyme and consists of skeletal muscle, fat, fibrous tissue, blood vessels, and neurovascular tissue. Soft tissue sarcomas (Greek, sarx means “flesh”) are designated on the basis of the adult tissue they resemble microscopically, and not necessarily the tissue in which they originate. For instance, the designation lipoma does not mean that the tumor arose from adipose tissue; instead, it means the tumor contains tissue resembling mature fat. Dedifferentiated soft tissue sarcoma contains poorly differentiated mesenchyme on microscopy, and thus lacks a specific histologic designation to the tumor. More sophisticated immunohistochemical stains and genetic markers are now available to further classify these differentiated soft tissue sarcomas. Only a few of the genetic aberrations that occur in soft tissue sarcomas are congenital; most are acquired spontaneously.

Staging refers to evaluation of local and distant spread of tumor and has multiple purposes. It provides a standardized method for determining extent of tumor, allows assessment of prognosis, and serves to guide initial treatment decisions. The French Federation of Cancer Centers Sarcoma Group (Federation Nationale des Centres de Lutte Contre le Cancer [FNCLCC]) system and the National Cancer Institution (NCI) system are most commonly used for grading soft tissue sarcomas. The FNCLCC system is based on tumor differentiation, tumor necrosis, and mitotic activity, while the NCI system uses histology, location, and tumor necrosis for grading. In comparison studies, the FNCLCC system has slightly greater ability to predict metastatic risk and mortality, as the NCI system does not directly take into consideration the histological subtype. Instead, the NCI system uses parameters such as tumor cellularity, differentiation, pleomorphism, mitotic rate, and necrosis to assign tumors to one of three possible tumor grades (low-, intermediate-, and high-grade) that indirectly predict a cancer phenotype (American Joint Committee on Cancer [AJCC] website).

The GTNM (Grade-Tumor-Node-Metastasis) system of the AJCC/Union for International Cancer Control for staging soft tissue sarcoma is based on grading, tumor, node, and metastases. However, these criteria do not apply to all soft tissue sarcomas, such as visceral, retroperitoneal, and Kaposi sarcomas. The recent staging classification has undergone several critical changes. For example, several soft tissue sarcomas subtypes previously included within the general soft tissue sarcoma staging system, such as gastrointestinal stromal tumor, desmoid fibromatosis, and uterine sarcoma, now have their own respective staging classification. Conversely, dermatofibrosarcoma protuberans, angiosarcoma, extraskeletal Ewing sarcoma, and neurogenic tumor are newly included with the soft tissue sarcoma staging system.

Another change is that tumor depth, previously described as superficial or deep, is no longer used within the current AJCC staging system, and the three-tiered grading method advocated by FNCLCC for tumor grading is now preferred over the GTNM system.