Genetic Predisposition

Germline mutations can play an important role in the development of STSs (Table 93-2). These genetic changes are identified with or similar to the genetic changes that are seen in corresponding sporadic sarcomas (Table 93-3). Mechanistically, the proteins encoded by the altered genes are involved in maintenance of the genome through DNA repair and the cell cycle.

The epidemiological relationship between the development of STS and inherited syndromes associated with a predisposition to neoplasia (e.g., neurofibromatosis and Li-Fraumeni syndrome) has been appreciated for decades.39,40 For example, patients with neurofibromatosis have a 7% to 10% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST).⁴¹ A sudden increase in the size of any neurofibroma suggests malignant transformation.^42,43 The mechanisms underlying the transformation from a benign neurofibroma to MPNST are not well understood.

However, loss-of-function mutations in the NF1 gene, which are found in patients with neurofibromatosis, result in activation of one of the ras signaling pathways, a well-known mechanism that has been identified in a variety of cancers.⁴⁴ It has been observed that secondary MPNSTs (arising from a prior neurofibroma) have deletions of 17p (particularly 17p12–17p13.1) and mutations at the region of the TP53 tumor suppressor gene.^47–47 Thus it is postulated that an initial alteration in the NF1 gene contributes to the formation of a benign neurofibroma through activation of the ras pathway and that secondary mutations in the TP53 gene allow the transformation into MPNST. Because mutations in TP53 lead to an inability to control DNA damage via the cell cycle, they also enable rapid accumulation of other mutations, which encode mutant proteins that undoubtedly play an important role in sarcomagenesis.

Li-Fraumeni syndrome was identified when relatives of pediatric STS patients were noted to have an increased frequency of diverse and often multiple primary cancers.39,48 The neoplasms that were noted in relatives included some STSs, premenopausal breast cancers, brain tumors, adrenocortical carcinomas, leukemias, and occasional germ cell tumors.⁴⁹ Follow-up of Li-Fraumeni kindreds over 2 decades has revealed that the majority of individuals have cancer at young ages, with 79% of those affected younger than age 45 years at the time of diagnosis of malignancy.⁵⁰ The observed cancer distribution in families is believed to fit a rare autosomal dominant mode of genetic transmission with high penetrance.⁵¹ Recent molecular genetic studies have identified germline TP53 mutations in the majority of patients with Li-Fraumeni syndrome.⁵² Germline mutations in CHK2, another component of the cell-cycle checkpoint machinery encoded by a gene located on 22q11, are responsible for another subgroup of patients with Li-Fraumeni syndrome, and other Li-Fraumeni–like patients’ kindreds without TP53 alteration have been described.⁵³

Pediatric patients with familial retinoblastoma have a 13q chromosomal deletion⁵⁴ and an increased incidence of osteosarcoma and other neoplasms, including STS.^15,55,56 The retinoblastoma (Rb1) protein is expressed ubiquitously in normal cells and is a well-known tumor suppressor, involved in maintaining the integrity of the genome through control of the cell cycle. Interestingly, not only is the Rb1 gene that is mutated in osteosarcomas associated with retinoblastoma, but abnormality or absence of the Rb1 gene product has also been observed in multiple other malignancies, including sporadic osteosarcomas, breast cancer,⁵⁷ small cell lung cancer,⁵⁸ and STSs.⁵⁹

Familial adenomatous polyposis, a subset of which includes Gardner syndrome with its desmoid tumors, is caused by germline mutations in the APC gene.62–62 Patients with Gardner syndrome experience desmoid fibromatosis at a younger age than do patients with sporadic desmoids.⁶³ With the use of prophylactic colectomy, progressive mesenteric desmoid tumor is now a significant cause of death of patients who have familial adenomatous polyposis,⁶⁴ as are second neoplasms such as ampullary and duodenal cancers. The APC gene is involved in the Wnt cell-signaling pathway. One of the normal functions of the APC protein is to bind β-catenin.⁶⁵ Thus loss-of-function mutations of APC result in the activation of transcription of oncogenes by β-catenin. Consistent with the importance of this pathway in desmoid tumors, APC loss and CTNNB1 (encoding β-catenin) mutations are also identified in sporadic desmoid fibromatosis.^68–68

Rhabdoid predisposition syndrome is due to inactivating germline mutations in the INI1 gene.⁶⁹ Patients with this syndrome experience one or more extrarenal and/or renal rhabdoid tumors. INI1 is a member of the SWI/SNF protein complex, which controls gene expression globally through its ability to alter chromatin structure.⁷⁰ Thus loss of INI1 gene expression results in other changes in gene expression, specifically activation of oncogenes. Rhabdoid tumors have loss-of-function mutations in both copies of the INI1 gene.⁷¹

Werner syndrome is a rare genetic instability syndrome caused by mutations in the WRN gene.72,73 Affected patients age prematurely and are at greatly increased risk for a variety of cancers, including STSs. The WRN gene encodes a protein involved in DNA repair⁷⁴ and loss of WRN protein function leads to genetic instability, accumulation of genetic mutations, and, ultimately, predisposition to rapid aging and cancer.

Germline mutations in the KIT oncogene are found in patients with familial gastrointestinal stromal tumor (GIST) syndrome.75,76 Activating KIT or PDGFRA mutations are also identified in over 90% of sporadic gastrointestinal stromal tumors (GISTs).⁷⁷ Patients with the familial syndrome experience, to varying degrees, skin hyperpigmentation, urticaria pigmentosa, and cutaneous mast cell disease in addition to one or more GISTs.⁷⁸ Activating KIT mutations have been shown to lead to ligand-independent activation of the KIT receptor tyrosine kinase pathway, which results in dysregulated cell growth, and are thought to be the first step in the pathogenesis of GISTs.⁷⁵ Interestingly, the identification of the important role of KIT in the pathogenesis of GISTs has led to treatment with imatinib,⁷⁹ the oral multitargeted receptor tyrosine kinase inhibitor (see “Prognostic Factors as Therapeutic Targets” and “Gastrointestinal Stromal Tumors” below).

Genetics of Sporadic Soft-Tissue Sarcomas

Sarcomas tend to fall into two major subsets. In one group, the tumors are cytogenetically simple and are characterized by near diploid karyotypes with few chromosomal rearrangements, resulting in the formation of fusion proteins. These translocations are highly diagnostic of specific histologic subtypes of STSs. Also included within the cytogenetically simple STSs are GISTs, which are characterized by a specific activating mutation of KIT or PDGFRA genes, but otherwise have relatively limited genetic abnormalities.

Chromosomal Rearrangements

A large number of sarcomas have been found to have consistent chromosomal abnormalities (see Table 93-3).⁸⁰ These chromosomal rearrangements are important diagnostically, may be important prognostically (see “Potential Molecular Prognostic Factors” below), and have shed light on the pathogenesis of sarcomas. Some of the specific translocations, such as those seen in dermatofibrosarcoma protuberans or tenosynovial giant cell tumor provide targets for pharmacologic therapy (see the section on treatment of GISTs). Benign soft-tissue neoplasms also harbor chromosomal rearrangements.

Chromosomal translocations are the most common cytogenetic abnormality in soft-tissue neoplasms and are likely responsible for the initiation of tumorigenesis in most cases.⁸⁰ Deletions and trisomies have also been reported and are thought to represent secondary changes involved in tumor progression. Deletions tend to represent loss of tumor suppressor genes, whereas trisomies suggest the presence of an oncogene. Although we know much about the principal tumorigenic events in many sarcomas, defining the secondary changes has been much more problematic and is an area of intense study with the advent of large-scale tumor DNA and RNA sequencing and related genomic techniques.

Cloning and molecular analysis of the various genetic aberrations that characterize different sarcomas have revealed the different pathogenetic mechanisms that underlie these tumors. Translocations typically create chimeric transcription factors or growth factors that result in deregulation of transcription or growth control. A typical example of a chimeric transcription factor is the PAX3-FOXO1 fusion protein, which has been shown to activate a complex myogenic transcriptional program when the protein is expressed in a fibroblast cell line.⁸¹ Infantile fibrosarcoma is characterized by a translocation involving chromosomes 12 and 15 that encodes a chimeric ETV6-NTRK3 constitutively activated growth factor receptor, which remarkably is found in other cancers such as secretory breast cancer, a subset of acute myelogenous leukemia, and a form of salivary gland carcinoma.⁸² Other oncogenic proteins appear to act by a mechanism that remodels chromatin structure, which is known to have a profound influence on gene expression (e.g., INI1 mutations in rhabdoid tumors).⁷¹ Specific chromosomal rearrangements are very useful in the diagnosis of STSs. Beyond the obvious benefit of providing further objective proof of a diagnosis in morphologically typical cases, the detection of chromosomal aberrations may facilitate the diagnosis of lesions that are difficult to characterize by standard histopathological, ultrastructural, and immunohistochemical techniques.^83,84 For example, the presence of the translocation t(X;18)(p11;q11) has been used to confirm the diagnosis of synovial sarcoma in poorly differentiated cases that were diagnostically very challenging.^87–87 Similarly, the finding of the characteristic translocation t(11;22)(q24;q12) in a small round blue cell tumor supports the diagnosis of Ewing sarcoma/primitive neuroectodermal tumor (PNET).⁸⁸ By the same token, a morphologic sarcoma subtype without an expected translocation may suggest a variant translocation, as has been observed in Ewing sarcoma–like small round blue cell tumors that lack the EWSR1-FLI1 translocation but rather contain CIC-DUX4 or a pericentric X chromosome inversion.^91–91

Translocations may be identified by a variety of genetic analyses, spanning older techniques such as cytogenetic analysis to fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and RNA sequencing. A detailed description of these techniques is beyond the scope of this chapter, but each technique has its advantages and disadvantages. Cytogenetic analysis requires fresh (living) tissue, because the cells need to be cultured before karyotypic analysis, and it largely has been supplanted by newer techniques. Fluorescence in situ hybridization does not require fresh or frozen tissue and frequently may be used with paraffin-embedded material; it is a standard diagnostic tool in many pathology laboratories. It is noted that evidence of a translocation by fluorescence in situ hybridization is not absolutely diagnostic of a sarcoma subtype, because one gene, such as EWSR1, may be involved in many different types of sarcomas, and such data must be incorporated with other data regarding the tumor sample. Reverse transcriptase polymerase chain reaction is a more sensitive technique that may be performed on fresh, frozen, or paraffin-embedded tissues. The major drawback of reverse transcriptase polymerase chain reaction is the relatively high false-positive rate, which results from its sensitivity. Meticulous care is required to prevent problems from contamination. Sequencing of the RNA complement of the genome allows for detection of mutations, translocations, and, to some degree, gene amplification, and is expected to be used more frequently over time.⁹²

Many sarcomas are characterized by several different translocations, most of which are mutually exclusive (see Table 93-3). For instance, alveolar rhabdomyosarcoma is characterized by a translocation involving chromosomes 2 and 13, which results in fusion of the PAX3 and FOXO1 genes, or by a translocation involving chromosomes 1 and 13, which results in fusion of the PAX7 and FOXO1 genes.^93–96 Sarcomas within a subtype may also have differences in the specific exons that are involved in each of these different translocations. It has been proposed that this heterogeneity may result in differences in prognosis (see “Potential Molecular Prognostic Factors” below). For example, Ewing sarcoma/PNET and synovial sarcoma possess genetic variations that have been suggested to have prognostic significance, further underscored by the Ewing-like sarcomas that lack EWSR1 fusions but contain other translocations.^{89,91,97–102} Future research will hopefully establish whether cytogenetic and molecular factors may be used as a basis for therapeutic decisions and the prediction and evaluation of response to treatment.

The identification of genetic alterations with high specificity for different sarcomas will also identify specific therapeutic targets. This has already resulted in the successful treatment of a variety of sarcomas, for example, GISTs, dermatofibrosarcoma protuberans (DFSP), and tenosynovial giant cell tumor/pigmented villonodular synovitis (TGCT/PVNS), and to a lesser degree, angiosarcoma, desmoid tumor, and Ewing sarcoma.79,103–105 Approximately 90% of GISTs harbor activating mutations in the KIT oncogene, which result in ligand-independent activation of the KIT receptor tyrosine kinase pathway.⁷⁷ Imatinib, a small molecule drug that is administered orally and inhibits the KIT receptor tyrosine kinase, is highly efficacious in the treatment of GIST (see section of treatment of GISTs). DFSP is characterized by translocations involving the COL1A1 and PDGFB genes, which result in activation of the platelet-derived growth factor-β (PDGF-β) pathway in what is believe to be an autocrine fashion. Imatinib is active against the PDGF-β pathway and has been shown to be effective in the treatment of a small number of DFSPs. In a similar way, TGCT/PVNS with its t(1;2) involving COL6A3-CSF1 is responsive to imatinib by virtue of its inhibition of the CSF1 receptor.¹⁰⁶

It is noteworthy to mention two common benign soft-tissue tumors—leiomyomas and lipomas—that have a high frequency of chromosomal rearrangements of chromosome 12q that involves the high-mobility protein group gene HMGIC/HMGA2.107,108 These translocations are not seen in the corresponding leiomyosarcomas or liposarcomas, indicating that in these tumors, the benign form is not a precursor of the malignant counterpart. Other benign soft-tissue neoplasms contain specific translocations, such as nodular fasciitis [t(17;22)(p13;q13) MYH9-USP6] or angiomatoid fibrous histiocytoma [t(12;22)(q13;q12) EWSR1-ATF1], underscoring the idea that translocations can occur in tumors anywhere in the spectrum of connective tissue tumors from benign to malignant.^109,110

Sarcomas with Complex Karyotypes

A second major subset of STSs is characterized by aneuploidy and the lack of specific fusion genes. This group of sarcomas includes such tumors as leiomyosarcomas, MPNST, and fibrosarcomas (see Tables 93-3 and 93-4). These tumors tend to occur in older patients and appear to have a relatively high frequency of mutations in the p53 and retinoblastoma (Rb) signaling pathways.^111,112 These tumors are characterized by chromosomal gains and losses that presumably target tumor suppressor genes (in the event of losses) and oncogenes (in the event of gains). A special case appears to be well-differentiated/dedifferentiated liposarcoma, with amplifications of cell-cycle regulatory genes CDK4 and HDM2 and others on chromosome 12q. The cooperation of these genes to create a unique type of aneuploid sarcoma remains a current challenge in the field. Supporting the clinical data from syndromic sarcomas, alterations disrupting chromosomal mechanics and DNA repair appear to be involved in sarcomagenesis.

Classification

In broad terms, sarcomas may be classified into neoplasms that arise in bone and those that arise from the soft tissues. However, even this seemingly simple distinction is fraught with difficulty, as is illustrated by Ewing sarcoma. In childhood, Ewing sarcomas most commonly arise in close association with bone and are often classified as bone sarcomas. However, it is now clear that these tumors can also arise in soft tissues, more commonly in adults. So are Ewing sarcomas bone sarcomas or STSs, and does it really matter in terms of classification? Sarcomas of the soft tissues may be further grouped into those that arise from viscera (gastrointestinal, genitourinary, and gynecologic organs) and those that arise from nonvisceral soft tissues (muscle, tendon, adipose, pleura, and connective tissue).

An alternative way to index STSs is by their differentiation. Tumors may be grouped broadly into adipocytic tumors, fibroblastic/myofibroblastic tumors, so-called fibrohistiocytic tumors, smooth muscle tumors, pericytic (perivascular) tumors, PNETs, skeletal muscle tumors, vascular tumors, osseous tumors, and tumors of uncertain differentiation (Table 93-5).¹¹³ Classification is based on clinical, histologic, ultrastructural, immunohistochemical, and genetic features. Electron microscopic evidence of cellular substructures, neurofibrils, microfilaments, actin-myosin complexes, and dense bodies, has historically been used to define the tissue of origin.¹¹⁴ However, the widespread availability of commercial antibodies for immunohistochemical analysis has all but eliminated the need for electron microscopic examination. Immunohistochemical staining for proteins that are characteristic of smooth muscle (smooth muscle actin and desmin), skeletal muscle (muscle-specific actin, desmin, and myogenin), blood vessels (factor VIII, CD34, and CD31), and epithelial tissue (epithelial membrane antigen and cytokeratins) often facilitates reliable classification, with genetic proof of a sarcoma translocation considered to be iron-clad evidence of a specific sarcoma subtype.^115,116 However, because the identical translocation may be found in more than one type of cancer, such as the ASPL-TFE3 translocation of both alveolar soft part sarcoma and papillary renal cancer, translocation data cannot be used in isolation.

The tissue of origin classification scheme is the basis for the 2013 World Health Organization classification system for sarcomas.113,117 The World Health Organization classification system is reproducible for most sarcomas. As the degree of histologic differentiation declines, however, the determination of the tissue of origin becomes increasingly difficult. In particular, despite advanced immunohistochemical and molecular analyses, determining the tissue of origin for some soft-tissue tumors may be difficult, occasionally arbitrary, and sometimes impossible. This leads to significant disparities in diagnoses among pathologists. Discrepancies between the original histologic diagnosis and the subsequent diagnosis by an expert reviewer have been noted in as many as 25% of cases, although these data predate modern immunohistochemical and genetic analyses.^118,119 Review of suspicious tissue specimens at an expert center is therefore wise, because the degree of expertise in correctly diagnosing some of the 50 or more types of rare and unusual sarcoma is directly related to the number of sarcomas that a pathologist has seen, and, increasingly, the specific molecular diagnostic tools needed to identify rare sarcoma subtypes.

It is important to classify STSs as precisely as possible because of major differences in their clinical behavior and in their susceptibility to different therapies. For example, a few STSs, including epithelioid sarcoma, clear cell sarcoma, angiosarcoma, and rhabdomyosarcoma have a greater risk of regional lymph node metastasis.120,121 In one single-institution study, the overall rate of nodal metastasis at the time of sarcoma presentation was under 3%; however, the rate was much higher for angiosarcoma (13%), embryonal rhabdomyosarcoma (14%), and epithelioid sarcoma (17%).^120,121

Patterns of distant metastases also differ for subtypes of sarcoma. For example, myxoid/round cell liposarcoma tends to metastasize to soft-tissue sites, including the retroperitoneum as well as to the spine and pelvis and other bone marrow sites,122,123 and patients with myxoid/round cell liposarcoma often present with metastatic disease. If a myxoid/round cell liposarcoma is identified in the abdomen, the thighs should be examined for an occult primary tumor. The majority of what had been suspected to be primary myxoid liposarcomas of the abdomen and retroperitoneum are actually misdiagnosed well differentiated / dedifferentiated liposarcomas that have myxoid features (and usually metastasize far less often than myxoid/round cell liposarcoma).¹²⁴

Patterns of local spread also differ dramatically among subtypes of sarcoma. For example, DFSP has a propensity to infiltrate subcutaneous adipose tissue in a manner that is very difficult to detect; therefore, wide surgical excision of DFSP is essential. Mohs surgery has been used for DFSP, but the concern of recurrences 5 to 10 years after initial diagnosis make the authors wary about anything less than a wide excision. When planning a surgery for DFSP, the surgeon should regard the grossly observable lesion as the tip of the iceberg. Myxofibrosarcoma and, to an even greater extent, angiosarcoma, also spread very diffusely and may be very difficult to resect with negative margins because of microscopic tumor insinuation 2 cm or more from the gross tumor.

Histologic Grading

Histologic classification alone does not always provide enough information to predict the clinical behavior of STSs. For many sarcomas, histologic grading provides additional information that can aid in predicting biological behavior and planning treatment. The spectrum of grades varies among specific histologic subtypes (Fig. 93-2). For example, liposarcomas exhibit wide variations in grade, whereas Ewing sarcomas/PNETs are always considered high-grade. In careful comparative multivariate analyses, histologic grade has been the most important prognostic factor in assessing the risk for distant metastasis and tumor-related mortality.^127–127 Several grading systems have been proposed, but there is no consensus regarding the specific morphologic criteria that should be employed in the grading of STSs. The two most important criteria appear to be the mitotic index and the extent of tumor necrosis.

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