Soft-tissue and visceral sarcomas are a group of malignant diseases characterized by neoplastic proliferation of specialized or nonspecialized cells of mesenchymal tissues. Sarcomas represent about 1% to 2% of cancers in humans, with an incidence close to 5.9/105/year.¹,²,³,⁴

The four most frequent histologic subtypes—gastrointestinal stromal tumors (GISTs), liposarcomas (LPSs), leiomyosarcomas (LMSs), and undifferentiated pleomorphic sarcomas—have an incidence of 8 to 12/10⁶/year and represent about 50% of all sarcomas. All other histologic subtypes have an incidence of less than 5/10⁶/year, and are therefore very rare tumors.²

Few risk factors for the development of soft-tissue and visceral sarcomas have been identified. Previous radiotherapy is a well-identified risk factor for these tumors (e.g., after conservative surgery in breast cancer). The presence of tumor-suppressor gene loss in the germ line, such as TP53 (Li-Fraumeni syndrome), Rb, or NF1, significantly increases the risk of developing sarcoma over a lifetime.³,⁴

Despite their overall rarity, the histologic classification of soft-tissue and visceral sarcomas is complex, encompassing a large variety of histologic subtypes. This classification has been evolving substantially in the past 20 years: an increasing number of different histotypes and molecular subtypes have been progressively identified,and their nosology and histogenesis are being refined over time.³,⁴,⁵

Over 80 different histologic subtypes of sarcomas have been identified in the most recent World Health Organization (WHO) classification. Sarcomas are classified according to the lines of differentiation resembling that of normal tissues. For example, rhabdomyosarcomas show evidence of skeletal, striated, muscle fibers, LPSs show fat production, and GISTs resemble the interstitial cells of Cajal (the pacemaker cells of intestinal motility).⁴,⁵,⁶ Importantly, among these histologic subtypes, molecular subtypes are being identified, with different natural histories and treatment approaches, as illustrated here with LPSs. Some sarcomas lack a line of differentiation and are considered to be of “uncertain histogenesis” or within the “unclassified sarcoma” subgroup, often with pleomorphic features. Pleomorphic tumors
previously classified as malignant fibrous histiocytoma (MFH) are now frequently referred to as unclassified high-grade pleomorphic sarcomas. Of note, sarcomas similar to primary bone sarcoma may arise in soft tissue: extraskeletal osteosarcoma, extraskeletal Ewing sarcoma (30% of Ewing sarcomas), and extraskeletal chondrosarcoma.

In addition to immunohistochemistry, molecular characterization tools such as fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), or direct sequencing can be powerful to facilitate and refine the diagnosis of soft-tissue sarcoma, when morphologic analysis is insufficient to guide the final diagnosis. Different categories of sarcomas are now being identified on the basis of the presence of characteristic molecular hallmarks: sarcoma with translocations (e.g., Ewing sarcoma, synovial sarcoma, myxoid and round-cell LPS), sarcoma with kinase mutations (e.g., GIST with mutations of KIT or PDGFRA, angiosarcoma with mutations of VEGFR2), sarcoma with deletion of a key tumor-suppressor gene (malignant peripheral nerve sheath tumors [MPNSTs] with NF1 deletion), sarcoma with chromosome 12q13 amplification (e.g., well-differentiated LPS [WDLPS], dedifferentiated LPS [DDLPS], intimal sarcomas), and a group of sarcomas with complex genetic alteration not yet fully characterized, representing about 50% of all sarcomas (Table 17.1).³,⁴,⁵,⁶

LPSs are categorized into the following groups: WDLPS and DDLPS characterized by a specific amplification of 12q13 (along with additional genetic alterations for DDLPS), myxoid LPSs exhibiting specific translocations, and pleomorphic LPSs displaying complex genetic alterations. These distinct LPSs have a different natural history and prognosis, and require different treatment approaches. In GIST as well, the precise identification of the kinase mutation is an important parameter to decide on a specific treatment (e.g., imatinib—close to 20% of primary gastric GISTs express a PDGFRA mutation, and the majority of these mutations are missense mutations arising on codon 842 (D842V). The protein encoded by this mutated gene is resistant to the kinase inhibitory effects of imatinib, both in vitro and in vivo. These tumors have a limited risk of progression following definitive surgery. Surgery should be the preferred treatment option for these tumors whenever possible. GISTs with wild-type KIT and PDGFRA are often affected by NF1 mutations, BRAF mutations, or mutations of the SDHA,B,C,D genes, and also have specific natural histories. The clinical activity of imatinib in these subtypes is less important than in tumors bearing the classical mutations of the KIT exons 11 and 9.

Sarcomas can arise in any part of the body and from any tissue and organ. Most commonly, they arise from the soft tissue of the extremities (in particular the thigh), the trunk (in particular the retroperitoneal area), and more rarely from upper limb, trunk wall, or head and neck areas. Sex ratio is close to one, with heterogeneity across histologic subtypes. Age distribution varies considerably across histologic subtypes: rhabdomyosarcomas are most often diseases occurring in children and adolescents; synovial sarcomas occur at a median age in the third decade of life; and undifferentiated sarcomas or LPSs are diagnosed at a median age close to 60 years.³,⁴,⁵

A progressively growing lump, swelling, or pain is the usual revealing symptom of sarcomas. Sometimes the lump has been noticed for years by the patient and his or her family, and was mistakenly regarded as a benign lesion requiring no further exploration. The consultation is often triggered by a recent change in the clinical behavior of the tumor.

For deeply seated tumors, gastrointestinal or gynecologic bleeding is the initial symptom, and weight loss and fever are the constitutional symptoms.

Not unusually, sarcomas are detected incidentally at the occasion of an unrelated clinical or radiologic examination.

Sarcomas are rare tumors, and will be rarely encountered by any nonspecialized physician. An inappropriate initial biopsy or surgical removal can affect the risk of relapse, survival, and the
overall success of the final treatment.⁷,⁸ It is therefore important to remember, as proposed by the Scandinavian Sarcoma Group, that any tumor mass above 5 cm with no obvious cause should be considered as a sarcoma unless proven otherwise. Discussion with an expert team and then carefully planned biopsy should be advised at this stage.

Primary sarcoma tumors tend to grow progressively and invade the adjacent organ. This is particularly observed in tumors occurring in sites where symptoms are late, for example, in the retroperitoneal area.

Metastatic spread of all sarcomas tends to be through the blood rather than through the lymphatic system. The lungs are the most frequent site of metastatic disease. Liver metastases are observed mainly in abdominal sarcoma, such as GIST or peritoneal sarcomas. Metastases to soft tissue are observed selectively in a molecular subtype of myxoid LPSs and in some LMSs. Bone and central nervous system (CNS) metastases are rare except for certain histologic subtypes, such as alveolar soft-part sarcoma. Lymph node metastases are also observed in selected subtypes (e.g., epithelioid sarcomas, alveolar soft part sarcomas).

Sarcoma staging is based on the size of the primary tumor (T), the presence of invaded lymph nodes (N), the presence of metastasis (M), and the grade of the tumor.³,⁴

Tumor grade is an important parameter to be determined for an optimal staging of the tumor. The WHO classification is usually recommended, and it considers three grades (G1, G2, or G3) depending on mitotic rate, differentiation, and the presence of necrosis in the primary tumor. This grading is applied to most but not all histologic subtypes of sarcomas. When unknown, the grade is considered as GX.

The primary tumor (T) is T1 when the maximal size of the primary tumor is 5 cm (2 in.) or less, and T2 when above. T1a or T2a indicates a tumor above the superficial fascia, and T1b or T2b, beneath. When unknown, it is classified as TX.

The tumor is N0 when it has not spread to the regional lymph nodes, and N1 if the tumor has spread to the regional lymph nodes. When unknown, it is classified as NX.

The tumor is M0 if no distant metastases of sarcoma are found, and M1 otherwise. When unknown, it is classified as MX.

The clinical stage is determined by grouping the information on T, N, M, and G.

For specific histological subtypes, specific parameters and prognostic tools are applied. The prognostic classification of GIST, for example, can be made with different classification models that use 2 digits (size, mitotic rate; NIH Classification), 3 digits (the same, with organ origin; Miettinen Classification), 4 digits (the same, with tumor rupture, in the revised NIH classification/Joensuu), and 5 digits (same with the nature of the mutation).

A possible sarcoma should be suspected in the presence of a deepseated tumor over 5 cm, without a clear etiologic diagnosis. Obviously, tumors smaller than 5 cm can be sarcomas, but the frequency is much lower in this subgroup.

Ultrasound can be proposed for specific presentations. However, magnetic resonance imaging (MRI) for limb and pelvic tumors and computed tomography (CT) scan for any site should always be performed when a sarcoma is suspected, to establish the size and location of the tumor.

A careful biopsy should be first considered, either needle biopsy or open surgery, optimally after a multidisciplinary discussion with a team with experience in sarcoma management.³,⁴,⁷,⁸

Histologic diagnosis, as mentioned previously, is complex and often requires a review by a specialized sarcoma pathologist for optimal classification. It is sometimes difficult to distinguish a benign tumor (e.g., lipoma) from a very well differentiated liposarcoma—WDLPS—(aka atypical lipomatous tumor [ALT]). A molecular analysis to detect the presence of the 12q13 amplicon of ALT/WDLPS is needed. It has been shown that, even when unsolicited, secondary opinions resulted in modification of the definitive diagnosis of sarcoma in 20% to 30% of the cases, including major changes from benign to malignant tumors, sarcoma to carcinoma, and so on.⁷

Because sarcomas are rare, it is useful to manage them within a multidisciplinary team with greater collective experience.

Despite the heterogeneity of histologic and molecular subtypes, soft-tissue and visceral sarcomas are still treated according to clinical practice guidelines, which have traditionally proposed similar approaches of treatment across histotypes.³,⁴

However, specific treatment approaches are now more frequently adapted to the different histologic or molecular subtypes of sarcomas, in both localized-phase and metastatic settings. Specific surgical (re-resection) or adjuvant (radiotherapy or chemotherapy) strategies are proposed, depending on the nature of the primary treatment applied to the patient and the quality of histologic resection of the primary tumor.

The emergence of specific cytotoxic and targeted therapies has led to a rationally based, personalized management for subsets of sarcoma, with significant survival improvement. The rapid emergence of novel molecular subsets, within several sarcoma types, is now guiding the clinical development of novel agents.

Still, the quality of the initial diagnostic procedure and of the primary surgery remains the key predictive factor for the risk of relapse and death.

Surgery is the foundation of the treatment of primary tumor.³,⁴