Clinical presentation, diagnostic evaluation, and staging of soft tissue sarcoma

INTRODUCTION — 

Sarcomas are a rare and heterogeneous group of malignant tumors of mesenchymal origin that comprise less than 1 percent of all adult malignancies and approximately 10 percent of pediatric cancers. Approximately 80 percent of all new cases of sarcoma originate from soft tissue, and the rest originate from bone.

The histopathologic spectrum of sarcomas is broad, presumably because the embryonic mesenchymal cells from which they arise have the capacity to mature into striated skeletal and smooth muscle, adipose and fibrous tissue, bone, and cartilage, among other tissues. Although ectodermal in origin, malignant tumors affecting peripheral nerves are included because of similarities in their clinical behavior, management, and outcome.

This topic review will cover the clinical presentation, diagnostic evaluation, and staging of soft tissue sarcoma.

The clinical presentation, diagnosis, and treatment of gastrointestinal stromal tumors (GIST) are discussed separately. While previously categorized with soft tissue sarcoma, the clinical behavior and treatment of GIST is different from soft tissue sarcomas discussed in this topic.

●(See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".)

A discussion of issues unique to sarcomas arising in distinct anatomic areas is located elsewhere.

●(See "Head and neck sarcomas".)

●(See "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma".)

●(See "Breast sarcoma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging".)

A discussion of specific sarcoma subtypes is also located elsewhere.

●(See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment".)

●(See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)

●(See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma".)

●(See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis".)

ETIOLOGY AND PATHOGENESIS — 

In nearly all instances, sarcomas are thought to arise de novo and not from a pre-existing benign lesion. Most cases have no clearly defined etiology, but several genetic syndromes have been identified such as Li-Fraumeni syndrome, neurofibromatosis type I, hereditary retinoblastoma, and others. Additional predisposing factors include exposure to radiation therapy or chemotherapy, chemical carcinogens, chronic irritation, and lymphedema. (See "Pathogenetic factors in soft tissue and bone sarcomas".)

Viral infections are rarely associated with the development of sarcomas except for Kaposi sarcoma. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis" and "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment".)

MOST COMMON SUBTYPES — 

The most common subtypes of soft tissue sarcoma are different between adults and children. In a tertiary referral population, the most common soft tissue sarcoma subtypes in adults are liposarcoma (which has three distinct subtypes), leiomyosarcoma, and undifferentiated pleomorphic sarcoma (UPS) (figure 1) [1,2]. However, among children rhabdomyosarcoma is the most common soft tissue sarcoma. Other types include the "small round blue cell" sarcomas, such as Ewing sarcoma and related tumors (sometimes called peripheral primitive neuroectodermal tumor), including rare versions of these tumors with CIC-DUX4 or other unique translocations (table 1) [3]. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma" and "Epidemiology, pathology, and molecular genetics of Ewing sarcoma" and "Rhabdomyosarcoma in childhood and adolescence: Clinical presentation, diagnostic evaluation, and staging" and "Uncommon brain tumors", section on 'Embryonal tumors'.)

A brief description of some of the common soft tissue sarcoma subtypes follows:

●Liposarcoma – Liposarcomas appear to arise from precursors of adipocytes (fat cells) and are commonly found in the extremities and retroperitoneum. The three main morphologic subgroups are well-differentiated/dedifferentiated, myxoid, pleomorphic, and the extremely rare myxoid pleomorphic liposarcomas [4,5]. There is a great range of biologic behavior amongst these subtypes, spanning from well-differentiated liposarcomas with minimal metastatic potential to the high-risk pleomorphic and myxoid pleomorphic types, which are higher grade and are associated with a high rate of distant metastases [6]. (See 'Histologic grade' below.)

Some well-differentiated liposarcomas arising on the extremities and trunk are referred to as "atypical lipomas" or atypical lipomatous tumors to denote the fact that, at these sites, excision is usually curative and that there is no potential for metastases, as compared with sites in the retroperitoneum, mediastinum, and spermatic cord [7]. However, in our view, this is a confusing name that underestimates the risk of local recurrence of such tumors; atypical lipomatous tumors have MDM2 and CDK4 amplifications like other well-differentiated liposarcomas and are essentially synonymous histologically.

The metastatic pattern of the various subtypes of liposarcomas is also unique. In myxoid liposarcoma metastases to other soft tissue sites and bone marrow are more common than lung metastases. By contrast, metastases to lung are often seen in pleomorphic liposarcomas or other common soft tissue sarcomas such as synovial sarcoma or UPS. (See 'Pattern of recurrence' below.)

Myxoid and round cell liposarcomas share the same reciprocal translocation t(12;16)(q13;p11), in which the DNA damage inducible transcript 3 (DDIT3) gene (also called CHOP in older literature) is inserted adjacent to a novel gene called fused in sarcoma (FUS) or translocated in liposarcoma (TLS). While no specific chromosomal translocations have been identified in well-differentiated/dedifferentiated liposarcomas, amplification of MDM2 and CDK4 is very frequent in these subtypes, and their identification may be useful diagnostically. Furthermore, overexpression of the MDM2 and CDK4 genes is also being exploited for therapeutic gain [4,8]. Pleomorphic liposarcomas genetically most closely resemble the pleomorphic variant of undifferentiated/unclassified sarcomas. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Myxoid liposarcomas' and "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Somatic gene mutations'.)

●Leiomyosarcoma – Leiomyosarcomas, which are characterized by smooth muscle differentiation, can be found throughout the body. In addition to presentation in the extremities, they can arise from a branch of the inferior vena cava, the gastrointestinal tract, or the uterus. Leiomyosarcomas that originate in the uterus may be a distinct subgroup of tumors as they have different gene expression patterns when compared with nonuterine leiomyosarcomas [9]. However, the same therapeutics are used for leiomyosarcomas, regardless of the primary site. Uterine leiomyosarcomas are discussed in detail separately. (See "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis", section on 'Leiomyosarcoma'.)

Unlike superficial and deep tumors, cutaneous leiomyosarcomas typically have a more indolent course and rarely metastasize [10].

●Undifferentiated pleomorphic sarcoma/unclassified soft tissue sarcoma – This subgroup was formerly included in a broad category of soft tissue sarcomas that included sarcomas that were termed malignant fibrous histiocytoma (MFH), which historically was the most common subtype of soft tissue sarcoma [2]. However, many sarcomas that were previously identified as MFH have been reclassified to other subtypes when reanalyzed using histology, immunohistochemical staining (IHC), or next generation sequencing [11]. The term undifferentiated/unclassified soft tissue sarcoma is now reserved specifically for sarcomas that lack specific lines of differentiation [5], although some pathologists use the term "sarcoma, not otherwise specified (NOS)" for these sarcomas. Not surprisingly, such sarcomas are more monotonous on microscopic examination than UPS, as the name implies.

Subsets of undifferentiated/unclassified soft tissue sarcomas simply describe the predominant cell types on microscopic examination and do not connote a specific subtype. Such descriptions may include pleomorphic (UPS), round cell, and spindle cell variants. One version of what was formerly termed myxoid MFH is now classified as a distinct sarcoma subtype, myxofibrosarcoma. In comparison with undifferentiated/unclassified soft tissue sarcoma, myxofibrosarcomas may be associated with a greater local recurrence risk than other histologies, but they cluster genetically with UPS [12-14].

●Synovial sarcoma – Synovial sarcoma initially derived its name from a histologic resemblance to synovial cells, but its cell of origin is unknown. There are two morphologic subtypes, monophasic and biphasic. The most common presentation is a soft tissue tumor of the extremities in young adults.

The majority of synovial sarcomas are characterized by the chromosomal translocation t(X;18)(p11;q11). The breakpoint of this translocation fuses the SS18 (previously called SYT) gene from chromosome 18 to one of three homologous genes, SSX1, SSX2, and SSX4 on the X chromosome. SS18-SSX1 is associated with biphasic tumors (glandular epithelial differentiation on a background of spindle tumor cells), while SS18-SSX2 is associated with monophasic tumors that lack glandular epithelial differentiation.

Cytogenetic analysis, fluorescence in situ hybridization, or reverse transcriptase polymerase chain reaction can be used to detect the translocation or the protein product of the fusion gene, thus aiding in the diagnosis of synovial sarcoma. The specific SS18-SSX fusion type may have prognostic importance, with better outcomes reported for patients with the SS18-SSX2 fusion in many, but not all, reports. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Synovial sarcoma'.)

●Malignant peripheral nerve sheath tumor (MPNST) – MPNSTs are of neuroectodermal origin and originate from peripheral nerves. Approximately 50 percent of these tumors occur in patients with neurofibromatosis type I and often result from degeneration of plexiform neurofibromas. (See "Peripheral nerve tumors", section on 'Malignant peripheral nerve sheath tumors' and "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Neurofibromatosis' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Soft tissue sarcomas'.)

MPNSTs are commonly found in the trunk, extremities (image 1), and head and neck. The diagnosis of an MPNST can be difficult due to variable histomorphology. There are no characteristic chromosomal translocations. The presence of S100 protein can aid in the diagnosis of lower grade versions of these sarcomas, but it is not uniformly expressed in these tumors, since the line of differentiation appears to be lost in many high-grade MPNSTs.

●Angiosarcoma – Angiosarcomas arise from endothelial cells. The disease has several distinct clinical presentations including development on the:

•Scalp in older adults

•Breast or chest wall after therapeutic radiation for breast cancer

•An extremity in conjunction with chronic lymphedema

•Deep soft tissues

•Liver or spleen

•Heart or large vessels

It is one of the most common tumors caused by therapeutic radiation, often after treatment of breast cancer or Hodgkin lymphoma, with a median time of development of 8 to 10 years. (See "Breast sarcoma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Ionizing radiation' and "Head and neck sarcomas", section on 'Angiosarcoma'.)

In IHC, the tumor cells stain positive for vascular markers such as CD31 and factor VIII. Mutations in the vascular endothelial growth factor receptor-2 (VEGFR2; also called Flk1/KDR) are seen in a subset of these patients, with unclear clinical implications. (See "Overview of angiogenesis inhibitors", section on 'VEGF receptors'.)

●Solitary fibrous tumor (SFT) – SFTs are slow-growing tumors that arise most commonly in the pleura, pelvis, or dura, where they can reach a very large size before detection due to their slow change over time. Previously, many of these tumors were named hemangiopericytomas. (See "Solitary fibrous tumor" and "Uncommon brain tumors", section on 'Solitary fibrous tumor'.)

While many SFTs are classified as benign tumors with a very low risk of metastasis, others are classified as malignant because of hypercellularity, at least focal cytologic atypia, tumor necrosis, numerous mitoses, and/or infiltrative borders [15]. These lesions have a greater ability to metastasize, usually at an interval of several years, most commonly to bone, liver, and lung, so they can never truly be called benign. Tumor cells stain positive for stem cell marker CD34.

Less than 5 percent of the time patients present with hypoglycemia related to overexpression of a form of insulin-like growth factor 2 (IGF-2). This finding resolves with resection of the tumor [16].

These tumors are characterized by an NAB2-STAT6 fusion gene, which functions as a chimeric transcription factor [17]. (See "Solitary fibrous tumor", section on 'Molecular pathogenesis and molecular diagnostics'.)

●Rhabdomyosarcoma (RMS) – RMS is the most common soft tissue sarcoma of childhood [18,19]. In children, the most common location is the head and neck region followed by the genitourinary tract and extremities. However, it can also be diagnosed in adults. The presenting signs and symptoms are variable and dependent on the site of origin, age of the patients, and presence of metastases.

There are four major histologic subtypes: embryonal RMS, alveolar RMS, pleomorphic RMS, and spindle cell/sclerosing RMS [20]. The embryonal subtype is the most common. Both embryonal and alveolar RMS are more susceptible to chemotherapy and carry a better prognosis than many types of adult soft tissue sarcomas. Pleomorphic RMS has a relatively poor prognosis compared with other RMS subtypes and predominates in adults, and outcomes are worse than in children. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Histologic classification' and "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)

CLINICAL FEATURES

Presenting symptoms — The most common presenting complaint for a soft tissue sarcoma is a gradually enlarging, painless mass. These tumors can become quite large, especially in the thigh and retroperitoneum. Some patients may develop pain or symptoms associated with compression by the mass, including paresthesias or edema in an extremity. Rarely, a patient may present with constitutional symptoms, such as fever and/or weight loss or with hypoglycemia.

Distribution — Soft tissue sarcomas occur at all anatomic body sites, but the majority are in the extremities. The anatomic distribution of soft tissue sarcomas in 4550 adults reviewed by the American College of Surgeons was as follows [21]:

●Thigh, buttock, and groin – 46 percent

●Upper extremity – 13 percent

●Torso – 18 percent

●Retroperitoneum – 13 percent

●Head and neck – 9 percent

Some histologic types of soft tissue sarcoma have a predilection for certain anatomic sites. As examples:

●While only 14 percent of all soft tissue sarcomas present in the upper extremity, 40 to 50 percent of all epithelioid sarcomas arise on the forearm and finger [22-24].

●Desmoplastic small round cell tumors, which have a predilection for adolescent and young adult males, primarily involve the abdominal cavity and pelvis [25,26].

The anatomic distribution of histologic subtypes is not a simple function of abundance of the tissue type. Liposarcomas are not common in the large fatty deposits of the abdominal wall, while in the thigh, a frequent site, they often arise deep in the muscle mass, rather than in the subcutaneous fat.

A discussion of soft tissue sarcomas presenting in a specific region such as the retroperitoneum, uterus, or head and neck area is presented elsewhere. (See "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma" and "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis" and "Head and neck sarcomas".)

Pattern of growth — Soft tissue sarcomas grow at various rates depending on the aggressiveness of the tumor. Tumors tend to grow along tissue planes and only rarely traverse or violate major fascial planes or bone. The growing tumor compresses surrounding normal tissue, leading to the formation of a so-called pseudocapsule that is comprised of compressed normal tissue with poorly defined margins and fingerlike tumor projections that infiltrate adjacent tissues. Dissection along the pseudocapsule plane will invariably leave residual disease and should be avoided. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Resection'.)

Pattern of spread — The most common pattern of spread is hematogenous, predominantly to the lung, though metastatic patterns are also linked to specific sarcoma histology. Spread to the regional nodes is not common.

●Metastatic disease – The presence of distant metastatic disease at the time of initial diagnosis is uncommon, but is more likely in large, deep, high-grade sarcomas and with specific histologies. In a retrospective review of 1170 patients over a 7.5-year period, the following were noted [27]:

•The incidence of distant metastatic disease at the time of diagnosis was 10 percent, and 83 percent of metastases were located in the lungs.

•There was a higher risk of lung metastases in tumors that were deep to the fascia (9 versus 4 percent).

•The risk of having lung metastases at diagnosis also increased with higher histologic grade of differentiation (12, 7, and 1.2 percent for high-grade, intermediate-grade, and low-grade tumors, respectively).

•The histologic subtypes most likely to present with lung metastases were soft tissue Ewing sarcoma, malignant peripheral nerve sheath tumor, and extraskeletal chondrosarcoma (25, 16.2, and 13.6 percent respectively). (See "Chondrosarcoma".)

●Regional nodes – Overall, spread to regional nodes is infrequent for soft tissue sarcomas [28-32]. An analysis of 1772 sarcoma patients in a prospective database identified 46 (2.6 percent) with lymph node metastases [33]. However, the risk of nodal metastases is related to the specific sarcoma subtype. The histologies with the greatest risk of lymph node metastases are rhabdomyosarcoma, synovial sarcoma, epithelioid sarcoma, clear cell sarcoma, and the vascular sarcomas (including angiosarcomas) [22-24,28-31,33-36].

The staging of nodal metastases in soft tissue sarcoma has evolved over time and is discussed separately. (See 'Staging' below.)

Management of the regional lymph nodes, including the role of sentinel node biopsy, is discussed separately. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Lymphadenectomy'.)

Pattern of recurrence — Recurrent disease after treatment of a soft tissue sarcoma can present as a local recurrence or metastatic disease [37,38]. The incidence of local recurrence depends on anatomic location, extent of resection, use of perioperative radiation therapy, and histology. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Recurrence' and "Initial management of retroperitoneal soft tissue sarcoma".)

Overall, approximately 25 percent of patients will develop distant metastatic disease after successful treatment of their primary tumor; the incidence increases to 40 to 50 percent with tumors that are >5 cm in size, deep to the fascia, and intermediate or high grade [39,40].

In 70 to 80 percent of cases, metastatic disease is to the lungs [27,38,41,42]. Rare sites of metastatic disease spread include the skin, soft tissues, bone, liver, and brain [37,38,43,44].

There are some exceptions to the typical pattern of metastatic disease:

●In myxoid liposarcomas, where extrapulmonary metastases to the retroperitoneum, abdomen, bone (particularly the spine and pelvis), and paraspinal soft tissue are common [45,46].

●Retroperitoneal sarcomas, in particular leiomyosarcomas, also commonly metastasize to the liver as well as the lung. Conversely, for retroperitoneal liposarcomas, most of the well-differentiated/dedifferentiated subtype recur local-regionally instead of with metastatic disease. (See "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma".)

Magnetic resonance imaging (MR) is considered the most useful modality for detecting local recurrences while computed tomography (CT) is typically used for evaluation at distant sites [47]. However, positron emission tomography (PET)/CT may have a role in patients with a clinical suspicion of recurrent sarcoma. In one study, the sensitivity of fludeoxyglucose (FDG)-PET for recurrence of soft tissue sarcoma was higher than that of contrast-enhanced CT (83 versus 50 percent), though specificity was equally good (100 percent with both tests) [48]. However, this is likely histology dependent.

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of a soft tissue mass includes both benign and malignant tumors. Some examples include:

●Lipoma – Lipomas often present as painless subcutaneous nodules that can range in size from 1 to >10 centimeters. Typically, these are diagnosed based on clinical exam. Symptoms such as pain, rapid enlargement, or firmness are atypical for a lipoma and should prompt imaging and/or a biopsy. (See "Overview of benign lesions of the skin", section on 'Lipoma'.)

●Epidermoid cysts – These present as asymptomatic dermal nodules located anywhere on the body. They typically contain a visible central punctum. (See "Overview of benign lesions of the skin", section on 'Epidermoid cyst'.)

●Schwannomas – Schwannomas, a neoplastic proliferation of Schwann cells, can arise from any peripheral nerve. They often have an insidious onset as a slow growing mass but can present with neurologic deficits. Further evaluation with imaging is needed to establish a diagnosis. (See "Peripheral nerve tumors", section on 'Schwannoma'.)

●Lymphoma – Lymphoma presents with lymphadenopathy and should be suspected especially in patients with fever, night sweats, and chills. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Clinical presentation' and "Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults", section on 'Clinical presentation'.)

●Metastatic disease – A soft tissue mass can develop as a manifestation of distant metastatic disease. Examples of primary malignancies include melanoma, Merkel cell carcinoma, and head and neck carcinomas.

DIAGNOSTIC EVALUATION

Indications for urgent referral — Once there is a suspicion for soft tissue sarcoma, a patient should be offered a referral to a tertiary center, if available, as studies have shown improved outcomes in patients treated at a specialist sarcoma center [49,50].

Given that benign soft tissue masses are at least 100 times more common than malignant soft tissue sarcomas [5], it can be difficult to determine which soft tissue masses warrant further evaluation. The United Kingdom Department of Health has published criteria for urgent referral of a patient with a soft tissue lesion [51]:

●Soft tissue mass >5 cm (golf ball size or larger)

●Painful lump

●Lump that is increasing in size

●A lump of any size that is deep to the muscle fascia

●Recurrence of a lump after previous excision

In a prospective review of 365 patients with confirmed soft tissue sarcoma, tumor depth was found to be the most sensitive marker of malignancy, followed by size >5 cm and a history of rapid growth [52].

Initial steps in evaluation — We perform the following evaluation in patients with a suspected soft tissue sarcoma:

●Clinical history and exam – Questions to ask at the initial evaluation include when the mass was first noticed, how quickly it has been growing, and whether there are symptoms to suggest distal neurovascular compromise. The physical examination should focus on the size and depth of the mass, fixation to adjacent structures, and associated edema or signs of nerve impingement.

●Radiographic imaging – Radiographic imaging is used to assist in defining the etiology of a soft tissue mass, determining the extent of a primary tumor for surgical planning, and establishing the presence or absence of metastatic disease. Ideally, imaging should be performed prior to a biopsy. (See 'Imaging of the primary tumor' below and 'Evaluation for metastatic disease' below.)

●Biopsy – Histologic examination of a soft tissue mass is essential for diagnosis and treatment planning. We typically obtain a core biopsy. (See 'Biopsy' below.)

Delay in diagnosis of soft tissue sarcomas is common [53]. Patients frequently do not seek prompt medical attention due to the painless nature of the tumor, and delays on the part of the physician are likewise common due to assumptions that the lesion is benign [54].

Imaging of the primary tumor — Our diagnostic workup of a soft tissue mass suspicious for soft tissue sarcoma includes cross-sectional imaging of the primary tumor. The preferred modality depends on the site of the mass.

●We obtain MRI without and with contrast for patients with soft tissue masses of the extremities, trunk, and head and neck. MRI is better than CT at defining the primary tumor at these sites.

●We obtain CT with intravenous and oral contrast for patients with primary abdominal, visceral, and retroperitoneal lesions. MRI is unlikely to improve accuracy of preoperative assessment in this population.

Positron emission tomography (PET)/CT is not routinely recommended for the initial workup of a soft tissue mass, although it may be useful later in the workup, in certain circumstances.

●MRI and CT – We obtain an MRI for the evaluation of soft tissue masses of the extremities, trunk, and head and neck and a CT for retroperitoneal and visceral sarcomas. While studies have had mixed results, MRI appears to be superior to CT in evaluating soft tissue sarcomas of the extremity, trunk, and head and neck. MRI provides multiplanar images with better spatial orientation, and is better able to delineate the extent of the neoplasm and the relation to surrounding structures, especially individual muscle involvement (image 2) [55-57]. By contrast, CT appears to perform as well as MRI for soft tissue masses primarily in the abdomen, viscera, or retroperitoneum. A multicenter prospective study that included 133 patients who underwent both CT (image 3) and MRI within four weeks of surgery for a soft tissue sarcoma of the arm, shoulder, pelvis, hip, or lower extremity found no significant difference between the two modalities in determining tumor involvement of muscle, bone, joints, or neurovascular structures [58]. Combined interpretation of CT and MRI did not improve accuracy of preoperative assessment.

●Plain radiography – Plain films of the primary site do not provide as much detail as a CT or MRI and are not sufficient for initial imaging of suspected soft tissue sarcoma. However, they can be useful to rule out soft tissue masses that arise from bone and to detect intratumoral calcifications such as those that appear within soft tissue (extraskeletal) osteosarcomas and synovial sarcomas.

●PET/CT – PET and PET/CT are not routinely recommended for the initial workup of a soft tissue mass as it has poor sensitivity for some soft tissue sarcoma subtypes and does not provide adequate imaging for surgical planning. However, it may be useful in certain circumstances. For instance, a number of studies report that PET and integrated PET/CT using fluorodeoxyglucose (FDG) can distinguish benign soft tissue tumors from sarcomas with the greatest sensitivity for high-grade sarcomas [59-61]. However, the ability to differentiate benign soft tissue tumors from low- or intermediate-grade sarcomas is limited [62-64].

PET/CT may have a role in distinguishing well-differentiated from dedifferentiated retroperitoneal liposarcomas [65]. However, since management is the same for either diagnosis, it is unclear what FDG PET/CT adds to CT imaging alone. More importantly, FDG PET/CT may also have a role in characterization of a suspected peripheral nerve sheath tumor in a patient with neurofibromatosis; in this scenario, PET imaging can be helpful in distinguishing a malignant peripheral nerve sheath tumor from a neurofibroma [66-68]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Soft tissue sarcomas'.)

Consensus guidelines for workup of a soft tissue sarcoma of the extremity and trunk issued by the National Comprehensive Cancer Network (NCCN) suggest that PET scan may be useful in prognostication, grading, and determining response to neoadjuvant chemotherapy in patients with soft tissue sarcoma [69]. However, this recommendation is based upon a single study demonstrating that FDG-PET was useful to predict the outcomes of patients with high-grade extremity soft tissue sarcomas who were treated initially with chemotherapy [70]. Patients with a baseline tumor standard uptake value maximum ≥6 who had a <40 percent decrease in FDG uptake after neoadjuvant chemotherapy were found to be at high risk of systemic disease recurrence. The clinical utility of having this information prior to surgical treatment is unclear. At present, the use of PET for prognostication or assessment of treatment response is not considered routine at most institutions. [47,48].

Biopsy — The diagnostic biopsy must be carefully planned to ensure that adequate tissue is obtained to ascertain the histologic subtype and grade of the tumor while not compromising options for definitive therapy [71]. Our preferred method for obtaining tissue is with a core needle biopsy, if technically feasible. Ideally, the biopsy should be performed after an MRI has been obtained, as postprocedural edema may make the MRI difficult to interpret.

Because the diagnosis of soft tissue sarcoma is often unsuspected, unplanned and inappropriate excisions of these tumors frequently occur before a proper pathologic diagnosis has been made [72]. Partial excision of the tumor before referral to a tertiary center does not appear to compromise limb preservation, local control, or in most series, survival. However, a higher incidence of distant metastatic disease has been reported in such patients [73], and reresection may entail a larger procedure than a de novo procedure and impact the functional result. These data underscore the importance of transferring patients with soft tissue masses of uncertain identity to centers that specialize in treating sarcomas so that they can undergo adequate initial resection. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Inadequate initial resection'.)

The options for biopsy are as follows:

●Core needle biopsy – Core needle biopsy is considered the preferred method to achieve an initial biopsy in most cases due to its low incidence of complications and high diagnostic accuracy [74-77]. In a study of 530 patients with suspected soft tissue tumors, core needle biopsy differentiated malignant soft tissue sarcomas from benign soft tissue tumors in 98 percent of patients. Histologic grade was accurately determined in 86 percent of patients, and the subtype was accurately identified in 88 percent [75].

CT or ultrasound guidance can assist in the biopsy of deep lesions and improve the diagnostic accuracy in lesions with cystic areas and necrosis by allowing the operator to select the site to be biopsied [78,79]. In cases where core needle biopsy is unsuccessful in obtaining adequate material for diagnosis, a subsequent incisional biopsy is usually considered. The incidence of follow-up biopsy has been reported as high as 20 percent [80].

●Incisional biopsy – Although incisional biopsy was the historic gold standard procedure for obtaining diagnostic tissue for a suspicious soft tissue mass, core needle biopsy has become the most common procedure used for diagnosis. However, the larger sample size in an incisional biopsy provides the pathologist with more tissue and a greater degree of confidence in the diagnosis, in part because of the degree of morphologic heterogeneity throughout the tumor. If several additional tests such as flow cytometry, cytogenetics, or molecular analysis for chromosomal translocations are needed, an incisional biopsy may be preferred.

If needed, incisional biopsy should ideally be performed by the surgeon planning the definitive resection. A poorly placed initial biopsy may preclude subsequent surgical resection, preparation of flaps, and/or cosmetic repair, or result in the need for a more extensive surgery to encompass the biopsy site at the time of definitive resection. Errors, complications, and changes in patient outcome occur more frequently when an incisional biopsy is performed in a referring institution instead of a treatment center [81,82]. Open biopsy incisions should be placed longitudinally along the extremity so that the scar can be resected along with the tumor at the time of definitive surgical resection. Adequate hemostasis is important to prevent dissemination of tumor cells.

●Fine needle aspiration – Fine needle aspiration (FNA) is not recommended in the initial diagnostic evaluation of a suspicious soft tissue mass as it has a lower diagnostic accuracy than core needle biopsy [83,84]. In addition, FNA may not provide the histologic subtype or grade of the sarcoma, which are both important for treatment planning. FNA can be useful in confirming disease recurrence, however [85].

Evaluation for metastatic disease — Imaging studies to evaluate for metastatic disease are typically influenced by tumor histology and patterns of disease spread. Since sarcomas are a rare and heterogenous group of cancers, clinicians may consult with an expert center to define the most appropriate imaging. (See 'Pattern of spread' above.)

Our general approach to evaluating for metastatic disease is presented in the following sections.

Evaluation for pulmonary metastatic disease in all patients — We obtain chest imaging to evaluate for pulmonary metastatic disease for all newly diagnosed patients with soft tissue sarcoma, given the propensity for lung metastases [69]. We prefer a chest CT without contrast for all patients. However, a chest x-ray (CXR) is a reasonable alternative in patients with small, low-grade tumors.

However, we note that recommendations for chest imaging from expert groups differ:

●Consensus-based NCCN guidelines suggest chest imaging with either CXR or CT for soft tissue sarcoma of the extremity or trunk, but chest CT (not CXR) for retroperitoneal/abdominal soft tissue sarcoma [86].

●On the other hand, guidelines from the European Society of Medical Oncology recommend chest CT for all patients with newly diagnosed soft tissue sarcoma, regardless of site of origin [87].

●The eighth edition of the American Joint Committee on Cancer staging manual suggests the use of chest CT to assess for pulmonary metastases [88].

While CT scan is often preferred due to its greater sensitivity in detecting small lung nodules, it is unknown whether this provides benefit over CXR alone. Both modalities are considered highly appropriate for this purpose by the American College of Radiology [89]. A retrospective review performed in the United Kingdom found that CXR alone detected two-thirds of pulmonary metastases in patients with soft tissue sarcoma; when compared with CT as the "gold standard," the sensitivity, specificity, positive predictive value, and negative predictive value of CXR were 60.8, 99.6, 93.3, and 96.7 percent, respectively [27]. The use of CXR only to stage the lungs would have missed one-third of all patients with lung metastases, but because of the infrequency of lung metastases overall (96 of 1170 patients), the initial staging would have been inaccurate in only 3.1 percent of cases. A greater proportion (4.9 percent) would have been incorrectly staged if CXR alone had been used in patients with high-grade, large, deep tumors. As more tools become available to assess metastatic potential, it is appropriate to choose imaging based on metastatic risk factors.

Additional imaging in select histologies — A subset of patients also undergo imaging of the abdomen and pelvis, brain, and/or spine to evaluate for metastatic disease.

●Abdominal and pelvic imaging – We recommend CT imaging of the abdomen and pelvis with contrast in myxoid-round cell liposarcomas due to the common presentation of extrapulmonary metastases to the abdomen and retroperitoneum [90,91]. Some clinicians may also offer this approach to patients with select histologies involving the lower extremities (eg, angiosarcomas, epithelioid sarcoma, and clear cell sarcoma) who are at risk for lymph node or liver metastases [92-94].

We do not typically offer routine CT imaging of the abdomen and pelvis for other sarcomas of the extremities, as the risk of abdominal and retroperitoneal involvement for these other histologies is low overall [91,95].

●Brain imaging – We suggest imaging of the brain with MRI with and without contrast (with CT as an alternative if MRI is contraindicated) for patients with cardiac angiosarcoma and alveolar soft part sarcoma due to the high propensity of these tumors for central nervous system metastases [96,97]. For noncardiac angiosarcomas and other soft tissue sarcoma histologies, we do not pursue central nervous system imaging unless there are concerning neurologic signs or symptoms.

●Bone imaging – We do not routinely obtain bone imaging of patients with soft tissue sarcoma unless they have symptoms to suggest bone metastases (eg, pain) since bone metastases are uncommon. However, a notable exception is that in patients with myxoid-round cell liposarcomas, we often obtain an MRI of the spine and pelvis, given the risk of bony metastases in this histology and low sensitivity of bone scan [90,98].

Is there a role for PET/CT? — We do not routinely pursue positron emission tomography (PET) or integrated PET/CT as a component of the initial staging workup of soft tissue sarcoma for evaluation of either pulmonary or extrapulmonary metastatic disease.

PET scanning can achieve whole body imaging, and it is widely considered to be more sensitive than CT for the detection of occult distant metastases in a variety of solid tumors (image 4). However, the utility of PET alone or with integrated CT for staging of distant disease extent in soft tissue sarcoma is unclear.

In several reports, chest CT is more sensitive than PET for detection of thoracic metastases in patients with sarcoma [99-102]. In the largest report of 106 patients with bone or soft tissue sarcomas who had PET or integrated PET/CT, pulmonary metastases were found in 40 [100]. CT identified 17 lesions larger than 1 cm, while PET identified only 13 of them. These results suggest that subcentimeter CT lesions should not be considered false-positive if inactive on PET and that a negative PET scan in the presence of suspicious CT findings in the chest cannot reliably exclude pulmonary metastases.

One purported benefit of PET is its ability to detect additional sites of extrapulmonary metastatic disease [99,103]. However, the risk of extrapulmonary metastases is so low with most soft tissue sarcomas that the routine use of PET for this purpose is unlikely to change the therapeutic plan. This was illustrated in a report of 75 patients who underwent PET during staging evaluation for a soft tissue sarcoma [101]. Only one patient was upstaged as a result of PET imaging, and PET did not alter the management of patients already known to have metastatic disease (ie, no new organ sites were identified).

HISTOPATHOLOGY

Histology — We recommend that all pathology specimens of suspected soft tissue sarcoma be reviewed by a pathologist who specializes in the evaluation of soft tissue tumors. The differential diagnosis of a soft tissue mass includes benign soft tissue tumors, such as a lipoma, as well as malignant tumors, including sarcoma, metastatic carcinoma, melanoma, or lymphoma.

As classified by the World Health Organization (WHO), the group of soft tissue neoplasms includes over 70 different malignant histologic subtypes [5]. The most common subtypes that arise in adults are outlined in the figure (figure 1).

WHO classifies most soft tissue neoplasms according to the presumptive tissue of origin (ie, the normal tissues the tumor most closely resembles) [5]. Examples include liposarcoma, synovial sarcoma, leiomyosarcoma, rhabdomyosarcoma (RMS), fibrosarcoma, and angiosarcoma. In some cases, histogenesis is uncertain, and the designation reflects the architectural pattern (eg, alveolar soft part sarcoma, epithelioid sarcoma, clear cell sarcoma).

Histologically, the diagnosis of a soft tissue sarcoma is made on the basis of morphologic pattern. Immunohistochemical staining (IHC) often aids in the identification of the presumptive tissue of origin. Some IHC markers are more characteristic than others, and it is the spectrum of markers examined that determines the histological subtype. As examples:

●Desmin is particularly valuable in the identification of myogenic differentiation: RMS and, to a lesser degree, leiomyosarcoma. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Tissue diagnosis'.)

●The presence of S100 antigen and neurofilaments suggests cells arising from the neural sheath, but this is also found in tumors with melanocytic differentiation. Among sarcomas, these include clear cell sarcoma and perivascular epithelioid cell tumors (PEComa).

●Cytokeratin is rarely expressed in most sarcomas but can help distinguish between synovial or epithelioid sarcoma (which both contain cytokeratin) and fibrosarcomas (which do not).

●Factor VIII-related antigen and CD31 identify tumors of endothelial origin.

Molecular diagnostics — A number of histologic subtypes are associated with specific chromosomal translocations; several examples are provided in the table (table 1), and molecular techniques (including fluorescence in situ hybridization [FISH] and reverse transcriptase polymerase chain reaction to detect the protein products of these fusion genes) can aid in the diagnosis of these tumors. A prospective study has shown that molecular methods can modify expert histologic diagnoses in certain sarcomas, and argument has been made that such testing should be considered mandatory [104]. However, in our view, the decision of such testing should be made by an experienced sarcoma pathologist taking into account the clinical information provided by a multidisciplinary care team.

Cytogenetics on fresh sarcoma specimens have largely been supplanted by FISH probes that can be performed on paraffin-embedded material. FISH testing can be definitive in ruling-in a specific sarcoma subtype in certain cases when the differential diagnosis has been narrowed but histology and IHC staining remain equivocal (eg, synovial sarcoma). However, when a translocation-associated tumor is suspected based upon the clinical presentation, in consultation with a pathologist, it is reasonable to send tissue for a genomic fusion panel as a part of next generation sequencing. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Chromosomal translocations'.)

Histologic grade — The pathologic evaluation of most sarcomas includes an assignment of histologic grade using a three-tiered grading schema that incorporates differentiation (which is histology specific), mitotic rate, and the extent of necrosis (table 2):

●Grade 1 - well differentiated, low grade

●Grade 2 - moderately differentiated

●Grade 3 - poorly differentiated, high grade

Histologic grade is based on the resected tumor or pretreatment biopsy material. This approach to grading is consistent with guidelines from the College of American Pathologists [105,106], the 2017 American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) cancer staging manual [88], and the French Federation of Cancer Centers Sarcoma Group (FNCLCC) [107].

Grading is not applicable to all soft tissue sarcomas. It is of little prognostic value for malignant peripheral nerve sheath tumors (the majority of which are considered high grade [108,109]), and it is not recommended for angiosarcoma, alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, clear cell sarcoma, and epithelioid sarcoma [5,110]. The impact of histologic grade on prognosis is discussed below. (See 'Prognostic factors' below.)

STAGING — 

The most widely used staging system for soft tissue sarcomas is the Tumor, Node, Metastasis (TNM) system developed as a collaborative effort of the UICC and the AJCC. The AJCC TNM system uses tumor size (T), lymph node involvement (N), presence or absence of distant metastases (M), and histologic grade (G) to determine the stage grouping for soft tissue sarcomas.

The eighth edition of the TNM staging classification contains separate T staging criteria and prognostic stage groups for soft tissue sarcomas arising in the extremity/trunk (table 3) and retroperitoneum (table 4); there are also unique primary tumor definitions for soft tissue sarcoma of the viscera of the abdomen and thorax but no recommended prognostic stage groupings at this site (table 5) [111,112]. The eighth edition represent a change in prognostic stage groups for nodal metastases as these are now considered to be stage IV disease which reflects their poor prognostic implication.

The AJCC staging system has not been in widespread use for retroperitoneal sarcomas. It does not account for disease site or histology, two major prognostic indicators. In addition, its ability to discriminate outcome based on tumor size alone is limited [113,114]. Because of this, the AJCC specifically recommends the use of a prognostic nomogram to estimate the likelihood of postoperative survival (figure 2) [115]. Given that histologic grade, the presence or absence of metastatic disease, and achieving macroscopic total resection are the major determinants of survival for patients with retroperitoneal sarcoma, alternative staging systems have been proposed, but they are not in widespread use. (See "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma", section on 'Staging'.)

PROGNOSTIC FACTORS — 

A number of prognostic factors have been identified in patients with soft tissue sarcoma, the most important of which are histologic grade, tumor size [1,116-118], and pathologic stage at the time of diagnosis. These factors are the main determinants of the primary tumor (T) stage (see 'Staging' above). In a series derived from a single institution using the TNM stage groupings from the 2010 seventh edition, five-year rates disease-free survival for stage I, II, and III disease were 86, 72, and 52 percent, respectively [119]. The corresponding values for overall survival were 90, 81, and 56 percent.

Histologic grade — Histologic grading is an independent indicator of the degree of malignancy and the probability of distant metastases and death from sarcoma [1,2,5,120]. Histologic grade is included in many of the prognostic nomograms and other tools. By contrast, histologic grade is a poor predictor of local recurrence, which is mainly a function of surgical margins. (See 'Histologic grade' above.)

Tumor size — The risk of developing a local recurrence and distant metastases increases substantially as tumor size increases [116,121,122]. Examples include:

●The impact of tumor size category on local disease-free survival, overall recurrence-free interval, and disease-specific survival in a series of 5267 patients with soft tissue sarcoma of the extremities or trunk is illustrated in the figure (figure 3) [122].

●In a review of 220 patients the frequency of distant metastases in high-grade tumors as a function of tumor size was [121]:

•Tumors ≤2.5 cm – 6 percent

•Tumors 2.6 to 4.9 cm – 23 percent

•Tumors 5 to 10 cm – 38 percent

•Tumors 10.1 to 15 cm – 49 percent

•Tumors 15.1 to 20 cm – 58 percent

•Tumors >20 cm – 83 percent

●Another study grouped 316 patients with soft tissue sarcomas into four subgroups on the basis of tumor size (less than 5 cm, 5 to less than 10 cm, 10 to less than 15 cm, and greater than 15 cm). Each subgroup was found to have a different prognosis, with five-year survival rates of 84, 70, 50, and 33 percent, respectively [116].

These data form the basis of the primary tumor (T) stage classification in the 2017 American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) cancer staging manual for extremity/trunk (table 3) and retroperitoneal (table 4) primary soft tissue sarcomas.

Prognostic tools — Clinical nomograms can estimate the prognosis of patients with soft tissue sarcoma [123-128]. Estimating prognosis is important for individual patient counseling and therapeutic decision-making. Major clinical determinants of survival include stage, tumor size, grade, anatomic site, age, and histologic subtype. Other important prognostic factors include the presence or absence of metastatic disease and ability to achieve macroscopic total resection.

Several available prognostic nomograms are as follows:

●"Sarculator" nomograms – The "Sarculator" prognostic tool is available online and incorporates externally validated nomograms for overall survival and risk of distant metastases after resection of a primary extremity soft tissue sarcoma [128-130]. This prognostic tool was developed by the Istituto Nazionale Tumori, Mount Sinai Hospital (Toronto), Royal Marsden Hospital NHS Foundation Trust, and the Institute Gustave Roussy. In addition, there is an externally validated dynamic nomogram to predict five-year overall survival for soft tissue sarcoma survivors during the first three years after surgery and a nomogram for retroperitoneal sarcoma [115,130]. (See "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma".)

●Memorial Sloan Kettering Cancer Center (MSKCC) nomogram – The MSKCC postoperative nomogram for 12-year sarcoma-specific death applies to all anatomic sites (figure 4) [123,124], and is also available online [131]. This nomogram has been validated with an external cohort of patients who were treated at the University of California-Los Angeles [132]. Histologic grade in the MSKCC nomogram was defined as high or low according to previously published criteria [133]. A subsequent adapted nomogram has been published incorporating the FNCLCC three-grade classification [125].

●The Helsinki University sarcoma nomogram – This is an externally validated, web-based, prognostic tool for extremity and abdominal wall sarcomas to predict 10 year sarcoma specific survival [127].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Soft tissue sarcoma (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Soft tissue sarcomas most commonly present as an enlarging, painless mass in the extremities or trunk. Distant metastatic disease is uncommon at diagnosis, but more likely in large, deep, high-grade sarcomas. Approximately 80 percent of metastases are located in the lungs. (See 'Clinical features' above.)

●Diagnostic evaluation – Our diagnostic evaluation of a soft tissue mass includes a clinical exam, imaging, and biopsy. (See 'Diagnostic evaluation' above.)

•Imaging – We perform imaging to characterize the soft tissue mass, determine the extent of a primary tumor for surgical planning, and identify metastatic disease.

-To evaluate the primary lesion, we obtain MRI for a primary extremity, trunk, or head and neck lesion and contrast-enhanced CT for a primary abdominal, visceral, or retroperitoneal lesion. (See 'Imaging of the primary tumor' above.)

-For evaluation of metastatic disease we obtain chest imaging (CT or chest radiograph) for all patients with soft tissue sarcoma. We prefer a chest CT without contrast, but a chest x-ray is a reasonable alternative in patients with small, low-grade tumors. In addition, we obtain CT imaging of the abdomen and pelvis and an MRI of the spine and pelvis in myxoid-round cell liposarcomas. (See 'Evaluation for metastatic disease' above.)

•Biopsy – The diagnostic biopsy must be carefully planned to ensure that adequate tissue is obtained for determining the histologic subtype and tumor grade while not compromising options for definitive therapy. We obtain a core needle biopsy, if technically feasible. Ideally, the biopsy should be performed after an MRI has been obtained, as postprocedural edema may make the MRI difficult to interpret. (See 'Biopsy' above.)

●Histopathology – All pathology specimens of suspected soft tissue sarcoma should be reviewed by a pathologist who specializes in the evaluation of soft tissue tumors. The diagnosis of a soft tissue sarcoma is made based on morphologic pattern. The soft tissue subtype requires immunohistochemical staining with or without genetic testing (table 1). In addition, a histologic grade should be assigned to most sarcomas. (See 'Histopathology' above.)

●Staging

•Nonretroperitoneal soft tissue sarcoma – Nonretroperitoneal soft tissue sarcomas are staged according to the Tumor, Node, Metastasis (TNM) system, which is based on tumor size (T), lymph node involvement (N), distant metastases (M), and histologic grade (G).

There are separate T staging criteria and prognostic stage groups for soft tissue sarcoma arising in the extremity or trunk (table 3) and retroperitoneum (table 4); in addition, there are unique primary tumor definitions for sarcomas of the viscera of the abdomen and thorax but no defined prognostic stage groupings at this site (table 5). (See 'Staging' above.)

•Retroperitoneal soft tissue sarcoma – The TNM staging system is not in widespread use for retroperitoneal sarcomas. It does not account for disease site or histology, two major prognostic indicators. In addition, its ability to discriminate outcome is limited. Because of this, a prognostic nomogram is used to estimate the likelihood of postoperative survival (figure 2).

●Prognostic factors – In addition to tumor stage, other prognostic variables include anatomic site, patient age, and histologic subtype. Several nomograms are available online to aid in predicting survival and treatment decision-making for individual patients. (See 'Prognostic factors' above.)