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Pathogenetic factors in soft tissue and bone sarcomas

Pathogenetic factors in soft tissue and bone sarcomas
Literature review current through: May 2024.
This topic last updated: Jun 26, 2023.

INTRODUCTION — Sarcomas are malignant tumors arising from skeletal and extraskeletal connective tissues, including the peripheral nervous system. Approximately 76 percent arise in soft tissue, the remainder in bone.

There is no clearly defined etiology in most cases of soft tissue sarcoma, but a number of associated or predisposing factors have been identified [1]. These include a genetic predisposition, gene mutations, radiation therapy (RT), chemotherapy, chemical carcinogens, chronic irritation, and lymphedema. In addition, an association between viral infection and sarcoma has been shown for human herpesvirus 8 (HHV-8) in Kaposi sarcoma, and for Epstein-Barr virus (EBV) and smooth muscle tumors in immunocompromised patients.

GENETIC PREDISPOSITION — Some patients with bone and soft tissue sarcomas, particularly children, have a genetic predisposition to cancer [1-5]. In some cases, individuals are from families with a defined inherited predisposing condition, such as Li-Fraumeni syndrome (LFS) or retinoblastoma, but many cases do not fit recognized inherited cancer syndromes. One analysis, in which 1162 patients with sarcoma, unselected for family history, underwent targeted exon sequencing of 72 genes selected for their association with cancer risk, concluded that approximately one-half of the patients had putatively pathogenic, monogenic, and polygenic variation in known and novel cancer genes [6]. In a pooled analysis of all sarcoma probands, 240 carried multiple variants, suggesting a polygenic contribution to sarcoma risk. Only 155 (17 percent) of the 911 families with informative pedigrees fit recognizable cancer syndromes.

The major genetic syndromes are briefly outlined below.

Li-Fraumeni syndrome — Mutations in TP53 are the most common germline mutations that predispose to pediatric sarcomas, including osteosarcoma, undifferentiated pleomorphic sarcoma, rhabdomyosarcoma, leiomyosarcoma, and liposarcoma [5]. As many as 7 percent of children with soft tissue sarcomas may have LFS [7]. In a series of 151 children with soft tissue sarcomas, for example, five of the families (3.3 percent) manifested the classic LFS familial cancer syndrome, 10 (6.6 percent) had features consistent with the syndrome, and 16 (10.5 percent) had one parent with a possible hereditary cancer syndrome or with cancer before the age of 60 [4].

The LFS is inherited as an autosomal dominant trait, and a germline mutation in the TP53 tumor suppressor gene is found in most affected families [8-10]. LFS is primarily characterized by soft tissue and bone sarcomas and breast cancer; other features include brain tumors, leukemia, and adrenocortical carcinoma occurring before the age of 45. The cumulative case risk among affected individuals is 100 percent by age 70 [11]. Sarcomas account for 25 to 33 percent of tumors in affected individuals, and they arise at a younger age than those unassociated with LFS [11,12]. In one series of individuals from the International Agency for Research on Cancer (IARC) database, 96 percent of the sarcomas arising in individuals with LFS arose before the age of 50, compared with 38 percent before 50 years of age in the general population [12]. (See 'TP53 gene' below and "Li-Fraumeni syndrome".)

Familial adenomatous polyposis and Gardner syndrome — There is a high frequency of intra-abdominal desmoid fibromatosis (also called desmoid tumors) among patients with familial adenomatous polyposis (FAP); this combination is also known as Gardner syndrome (see "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy") [13]. This disorder is characterized by mutations in the APC (adenomatous polyposis coli) gene. (See "Gardner syndrome".)

Retinoblastoma — Sarcomas of soft tissue and bone, particularly osteosarcoma, develop later in life in surviving patients with retinoblastoma (RB), particularly of the familial or bilateral type, in which individuals inherit a mutant copy of the RB gene [14-16]. The gene itself appears to predispose to second cancers of bone and soft tissue, with radiation therapy (RT) shortening the latent period and increasing the risk [16,17].

These relationships were illustrated in a longitudinal study of 1601 patients with RB (963 with the inherited type) [15,17,18]. The cumulative frequency of a second cancer at 50 years after diagnosis was significantly different based on whether the patient had the genetic form of RB (bilateral tumors or unilateral disease with a positive family history) versus nongenetic form of RB (ie, unilateral disease in the absence of a positive family history, due to a somatic mutation; 36 versus 6 percent), and whether the second tumor was associated with RT or not (38 versus 21 percent, respectively) [15]. More than 60 percent of the cancers were sarcomas.

A later publication provided a detailed description of 69 secondary soft tissue sarcomas among 68 children with hereditary RB [17]. Almost all of the sarcomas (n = 66) developed in children who had received orbital RT, but 18 did not arise within the irradiated field. The predominant histology was leiomyosarcoma (33 percent), followed by fibrosarcoma, undifferentiated pleomorphic sarcoma (UPS), soft tissue tumors/sarcomas not otherwise specified, rhabdomyosarcoma, and liposarcoma (19, 17, 15, 12, and 4 percent of cases, respectively).

There were some major differences between histologic types. Leiomyosarcomas were diagnosed more often outside of the RT field than within it (14 of 23), suggesting that genetic predisposition may have played a more important role than RT. Leiomyosarcoma was also the only histology for which risk was significantly higher among patients receiving chemotherapy plus RT versus RT alone. Furthermore, these were also late developing tumors; 18 were diagnosed more than 30 years after diagnosis (ie, at the same age as individuals in the general population).

In contrast, seven of eight secondary rhabdomyosarcomas occurred within the RT field, and seven developed within 20 years of treatment, during a normal growth period.

These data underscore the need for long-term surveillance for second cancers in RB survivors, particularly for those with the bilateral or inherited form of the disease. (See "Retinoblastoma: Treatment and outcome", section on 'Long-term follow-up'.)

Neurofibromatosis — Some of the multiple benign neurofibromas of von Recklinghausen disease (type 1 neurofibromatosis, NF1) can undergo malignant change to malignant peripheral nerve sheath tumors (MPNSTs (image 1)). The karyotypic changes seen in MPNSTs are typically complex [19,20].

NF1 is associated with a mutation in the NF1 gene; it has been proposed that malignant degeneration reflects the two-hit hypothesis in which one allele is constitutionally inactivated in the germline while the other allele undergoes somatic inactivation (the second hit). (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

Among nonneurogenic sarcomas, rhabdomyosarcomas also tend to arise more often in NF1 patients than in the general population. In one series, the risk of developing a malignant peripheral nerve sheath tumor among patients with NF1 was 4.6 percent, compared with 0.001 percent among the general population [21]. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Inherited syndromes'.)

Other — Rothmund-Thomson syndrome (poikiloderma congenitale) is an autosomal recessive condition characterized by a distinctive skin finding (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, skeletal anomalies, and a significantly increased risk for osteosarcoma. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Genetic conditions'.)

GENETICS AND MOLECULAR PATHOGENESIS — The genetics of sarcomas segregate into two major types: those with specific genetic alterations and usually simple karyotypes, including fusion genes due to reciprocal translocations (eg, PAX3-FOXO1A in alveolar rhabdomyosarcomas (table 1)) or specific point mutations (eg, KIT mutations in gastrointestinal stromal tumors [GIST]), and those with nonspecific genetic alterations and complex, unbalanced karyotypes, reflected by numerous genetic losses and gains (eg, osteosarcoma, undifferentiated pleomorphic sarcoma [UPS], angiosarcoma, leiomyosarcoma).

Fusion gene-related sarcomas account for approximately one-third of all sarcomas [22]. In many cases, the aberrant protein product of the fused gene acts as an abnormal transcriptional regulator, thus providing the molecular basis for oncogenesis. Just as specific mutations in KIT impact the diagnosis and response to therapy in GIST, for many fusion gene-related sarcomas, molecular testing to identify specific translocations that are unique to certain subtypes of sarcoma can be used for diagnostic refinement, prognostic assessment, or both [23]. (See 'Chromosomal translocations' below and "Epidemiology, pathology, and molecular genetics of Ewing sarcoma", section on 'Molecular diagnostics' and "Dermatofibrosarcoma protuberans: Epidemiology, pathogenesis, clinical presentation, diagnosis, and staging", section on 'Molecular diagnostics' and "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'Pathogenesis'.)

In contrast, the molecular pathogenesis of sarcomas with unbalanced karyotypic complexity has not been definitively proven, but inactivation of the p53 pathway appears to be a main differentiating feature between these tumors and those with simple genetic alterations [24]. Among the mechanisms for p53 pathway inactivation are TP53 point mutations, homozygous deletion in CDKN2A, and MDM2 amplification. (See 'Somatic gene mutations' below.)

Somatic gene mutations — There is a high incidence of acquired (somatic) gene alterations in soft tissue and bone sarcomas. In one study of tumor biopsies of soft tissue sarcomas, for example, the concurrent application of standard cytogenetics and DNA ploidy by flow cytometry identified an abnormal cell population by one or both methods in 84 percent of the tumors [25]. This discussion will focus on those mutations that are seen in soft tissue sarcomas. The degree to which mutations affect prognosis in soft tissue sarcomas, and the molecular pathogenesis of bone sarcomas, are discussed elsewhere. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Risk factors' and "Epidemiology, pathology, and molecular genetics of Ewing sarcoma", section on 'Molecular genetics' and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

Somatic mutations in specific genes vary across the histologic subtypes of soft tissue sarcoma. One study performed DNA sequencing of 722 protein-coding genes that have been implicated in cancer in 200 samples of soft tissue sarcomas encompassing seven distinct histologic subtypes [26]. Frequently mutated genes included the TP53 tumor suppressor gene (17 percent of pleomorphic liposarcomas), type 1 NF1 (10.5 percent of myxofibrosarcomas and 8 percent of pleomorphic liposarcomas), and PIK3CA (18 percent of myxoid liposarcomas). The retinoblastoma (RB1) gene was mutated in 4 percent of pleomorphic liposarcomas. DNA amplifications of chromosome 12q were observed in 90 percent of patients with dedifferentiated liposarcomas. Genes amplified in the 12q13-15 amplicon in well differentiated and dedifferentiated liposarcomas include MDM2, HMGA2, YEATS4, CDK4, and SAS [27].

Whole-genome sequencing has been performed on childhood rhabdomyosarcomas. One study analyzed 16 rhabdomyosarcoma tumors from 13 patients and compared the results with matched normal tissue [28]. Another study analyzed 44 rhabdomyosarcoma tumors and matched normal leukocyte DNA [29]. These studies provide a comprehensive genomic analysis that reveals the landscape of gene mutations in rhabdomyosarcoma. These studies show that rhabdomyosarcomas fall into two broad categories. The first group includes alveolar rhabdomyosarcomas that contain a PAX3 or PAX7 translocation without other recurrent cancer mutations. The second group is embryonal rhabdomyosarcomas, which are characterized by mutations in the receptor tyrosine kinase, RAS, PIK3CA axis. Interestingly, mutations in RAS or NF1, which negatively regulates Ras, were significantly associated with more aggressive tumors (ie, intermediate and high-risk rhabdomyosarcoma). Therefore, the RAS is a critical driver mutation for embryonal rhabdomyosarcoma and a potential therapeutic target [30].

Mutations in the KIT protooncogene, which are associated with GISTs, are discussed elsewhere. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis" and "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".)

NF1 gene — The NF1 gene encodes the neurofibromin protein that functions as a Ras-GTPase to suppress the Ras pathway [31,32]. Loss of NF1 expression, which occurs in malignant peripheral nerve sheath tumors (MPNSTs) in patients with neurofibromatosis type I and in a variety of other sporadic soft tissue sarcomas [26], activates Ras signaling. Most MPNSTs also have loss-of-function mutations in subunits of the histone-modifying PRC2 complex (SUZ12 or EED), which amplify Ras-driven transcription [33,34].

PIKC3A gene — The PI3KCA gene encodes for the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which phosphorylates lipids to create second messengers that regulate cell proliferation, survival, and motility. Mutations of PIK3CA in myxoid liposarcomas are associated with a shorter duration of disease-specific survival [26].

TP53 gene — The p53 protein is a transcriptional activator that plays a key role in the integration of signals inducing cell division, arrest of DNA synthesis following DNA damage, and programmed cell death (apoptosis). DNA damage results in increased levels of p53 protein, which induces cell cycle arrest at the G1/S interface, thereby permitting the cell to repair genomic damage or to initiate apoptosis [35-37]. The TP53 gene also functions as a tumor suppressor gene, and alterations are the most commonly detected mutations in a diverse group of malignancies. The wild-type p53 in normal tissue has a short half-life and is not detectable by immunohistochemical methods; in comparison, mutations of the gene result in a stabilized p53 protein, which accumulates in the cell and often becomes detectable by immunohistochemistry.

As noted above, germline mutations in the TP53 gene are present in most families with the Li-Fraumeni syndrome [8-10]. (See "Li-Fraumeni syndrome".)

Germline mutations in this gene also may occur in other patients with soft tissue sarcoma, particularly those with other cancers that are not considered indicative of the Li-Fraumeni syndrome [38-40]. In one study of patients with sarcoma, for example, germline TP53 mutations were relatively common (5 of 15) in those with multiple primary cancers or a positive family history of cancer but rare (3 of 185) in those without such a history [38]. Germline mutations in TP53 also may predispose to sarcoma formation in NF1 [41].

Somatic mutations in the TP53 gene are the most frequently detected molecular alteration in sporadic soft tissue sarcomas. These mutations have been detected in a variety of soft tissue sarcomas including UPS, leiomyosarcoma, liposarcoma, and rhabdomyosarcoma [42-51].

TP53 gene mutations are present in approximately one-third of tumors [42,44,45]. In one series of 127 bone and soft tissue sarcomas, 42 had somatic alterations in the TP53 gene: one-half were gross rearrangements and one-half were subtle missense or nonsense mutations [42]. Nearly all of the rearrangements and nonsense mutations showed no immunostaining for p53 (the "null pattern"), in contrast to the strong and diffuse pattern observed with pathogenic missense mutations (indicative of increased protein half-life) [43]. Furthermore, there was staining (usually weak) in 29 percent of the cases without detectable alterations in the TP53 gene.

Somatic loss of the TP53 gene appears to be quite variable in soft tissue sarcomas. Some tumors show a loss of both alleles or a loss of one allele with the remaining allele being either normal or with a point mutation [47]. In a case report, a synovial sarcoma metastasis was composed exclusively of cells bearing a distinct TP53 mutation. This same mutation was found as a small clone within the primary tumor, indicating that the metastasis resulted from expansion of a mutant TP53 clone [52].

Animal models are consistent with a pathogenetic role for TP53 defects in sarcoma development, as suggested by the observations:

Mice deficient for p53 expression develop a variety of neoplasms including bone and soft tissue sarcomas [53].

Irradiated transgenic mice harboring mutant TP53 show higher frequencies of sarcomas [54].

Transduction of wild type TP53 genes into soft tissue sarcomas bearing mutated p53 genes restores enhanced cell cycle control and suppresses sarcoma growth [55].

Restoring p53 function in primary sarcomas in mice lacking p53 expression causes sarcoma regression [56].

ATRX gene — Alpha-thalassemia/mental retardation syndrome X-linked (ATRX) is one of the most commonly mutated genes after TP53 in several types of sarcoma, including leiomyosarcoma [57] and osteosarcoma [58]. Loss of expression of ATRX frequently occurs in a number of complex karyotype sarcomas, including angiosarcoma, UPS, and dedifferentiated liposarcoma, which correlates with tumors utilizing the alternative lengthening of telomeres (ALT) as a mechanism to maintain telomeres [59]. ATRX binds to death-associated protein 6 (DAXX) to remodel chromatin. Cells lacking ATRX may be sensitive to inhibitors of the ATR kinase [60].

Retinoblastoma gene — Deletions or mutations of the tumor suppressor RB1 gene are critical in the pathogenesis of retinoblastoma and a variety of solid tumors. Even before the RB1 gene had been identified, it was recognized that some sporadic sarcomas had deletions on chromosome 13 similar to those observed in some patients with retinoblastoma. Alterations in the RB1 gene are common in soft tissue sarcoma, occurring in up to 70 percent of tumors in some series [61-63]. It has been proposed that RB1 alterations are primary events in human sarcomas and may be involved in tumorigenesis or the early phases of tumor progression [62]. The RB1 gene is critical for proper entry into DNA replication and transition through the cell cycle, and mutations are believed to perturb normal cell cycle function. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Pathogenesis'.)

MDM2 gene — The MDM2 (murine double minute 2 homolog) gene, located at 12q15, is overexpressed in a variety of human tumors including soft tissue sarcomas [64-67]. Its gene product localizes predominantly to the nucleus, where it acts as an inhibitor of the TP53 tumor suppressor gene product. The MDM2 product functions by concealing the activation domain of the p53 protein, thereby inhibiting TP53 transcriptional activity [68,69].

In a series of 24 soft tissue sarcomas, an alteration in p53 was found in eight tumors and MDM2 amplification in another eight [70]. No tumor contained alterations in both genes, which is consistent with the hypothesis that TP53 and MDM2 genetic alterations are alternative mechanisms for inactivating the same regulatory pathway for suppressing cell growth. In another study, 22 of 211 soft tissue sarcomas showed increased immunoreactivity to both MDM2 and p53 [71]. However, the overexpression of p53 and MDM2 proteins in the nuclei of these cells did not always correlate well with gene amplification at the MDM2 locus or mutation at the TP53 gene.

CDK4 gene — The CDK4 gene, which encodes a cyclin dependent kinase, occurs in an adjacent amplicon at 12q14. Amplification of CDK4 has been found in a variety of sarcomas including well-differentiated and dedifferentiated liposarcomas [27,72,73]. The frequent association with MDM2 has suggested a synergistic effect in opposing p53 function [73]. A role for CDK4 amplification in the pathogenesis of soft tissue sarcomas is suggested by the fact that knockdown of CDK4 in liposarcoma cell lines or treatment of these cells with a CDK4/6 inhibitor inhibits proliferation [27].

Detection of MDM2 and CDK4 overexpression by immunohistochemical staining may be helpful in diagnosing well-differentiated and dedifferentiated liposarcomas [74].

YEATS4 gene — The YEATS4 gene, which is adjacent to MDM2 at 12q15, is amplified along with MDM2 in well-differentiated and dedifferentiated liposarcomas [27]. YEATS4 functions as a transcription factor and negatively regulates p53 function [75]. Therefore, overexpressed YEATS4 may act in concert with amplified MDM2 to block p53 function.

HMGA2 gene — The HMGA2 (high mobility group-AT hook 2) gene is not only amplified with MDM2 in liposarcomas, but also frequently undergoes intragenic or close extragenic rearrangements [27]. The product of the HMGA2 gene is a high-mobility group protein that can accumulate on the chromatin of senescent cells to form senescent associated heterochromatic foci [76]. The ability of HMGA2 to promote senescence (permanent cell cycle arrest) is cancelled by overexpression of MDM2 and CDK4. Overexpression of HMGA2 has been shown to promote anchorage independent growth, a feature of oncogenic transformation [77].

SAS gene — A gene originally called SAS (sarcoma amplified sequence), designated tetraspanin 31 (TSPAN31), is also located at 12q14 and often coamplified with CDK4 in some soft tissue sarcomas [27,78]. SAS encodes a new member of the transmembrane 4 superfamily of proteins that may function in signal transduction and growth control [79]. One study of 12q13-14 amplification in 98 sarcomas found, among others, SAS amplification in 10, MDM2 in nine (eight of which had amplification of SAS), and the DDIT3 gene (formerly known as CHOP or GADD153) in four; it was suggested that the target of these amplifications may be an unidentified gene [80]. (See 'Myxoid liposarcomas' below.)

Chromosomal translocations — As noted above, a number of soft tissue sarcomas display recurrent nonrandom chromosomal translocations, which serve as definitive diagnostic criteria for the tumors in which they occur (table 1) [23].

Furthermore, these chromosomal abnormalities have been characterized at the molecular level, and many of the chimeric genes have been identified as being important to the biology of these tumors, acting as abnormal transcription factors that deregulate the transcription of multiple downstream genes and pathways [24]. Thus, the identification of these molecular signatures has provided clues as to the molecular alterations that are fundamental for the development and often maintenance of sarcoma. Because these translocations generate fusion proteins that are specific to the sarcoma cell, they are attractive targets for sarcoma therapy. A Surveillance, Epidemiology, and End Results (SEER) database study noted an increased subsequent malignant neoplasm (SMN) risk experienced by survivors of sarcoma and demonstrated higher SMN rates in survivors of fusion-negative sarcomas compared with those with a history of fusion-associated sarcomas.

Ewing sarcoma — Approximately 85 to 90 percent of Ewing sarcomas (EWS) display a reciprocal exchange t(11;22)(q24;q12) [81-83]. In this translocation, the EWSR1 gene from chromosome 22q12 is covalently linked to the ETS family member, FLI1 [84]. A less common translocation t(21;22)(q22;q12) has also been identified and links EWSR1 to a different ETS family member, ERG [85]. In one study, t(11;22)(q24;q12) fusion transcripts were identified in 83 of 87 of EWS [83]. In this series, 6 of 15 tumors classified as undifferentiated (ie, not EWS) showed fusion transcripts indicating that they might have to be reclassified as EWS.

Undifferentiated round cell sarcoma that lack an EWSR1-FLI1 or EWSR1-ERG translocation may harbor other translocations that do not include the EWSR1 gene. As an example, a t(4;19)(q35;q13) or t(10;19)(q26;q13) translocation results in fusion of the transcriptional repressor CIC with DUX4, a double homeobox transcription factor [86]. These tumors, which are classified as CIC-rearranged sarcomas [87], characteristically express ETV family transcription factors such as ETV4, along with WT1 [88,89]. CIC-rearranged sarcomas can also result from a t(X;19)(q13;q13.3) translocation that leads to the fusion of CIC and the transcription factor FOXO4 [90].

Furthermore, an intrachromosomal X-chromosome fusion of the BCL6 corepressor (BCOR) gene and CCNB3, which encodes the testis-specific cyclin B3, has been found in a distinct undifferentiated bone and soft tissue tumor (table 1) [91-95].

It is thought that the chimeric proteins that result from these translocations act as transcriptional regulators. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma".)

Desmoplastic small round cell tumor — The rare desmoplastic small round cell tumor contains a characteristic translocation t(11;22) EWSR1-WT1, in which the breakpoints are between the Ewing sarcoma breakpoint region 1 (EWSR1) and a second gene on chromosome 11, WT1. This specific translocation differentiates these tumors from Ewing sarcoma and other small round blue cell tumors.

Myxoid liposarcomas — Myxoid liposarcoma (including high-grade examples formerly known as "round cell" liposarcoma) usually harbors the reciprocal translocation t(12;16)(q13;p11) [96,97]. In this translocation, the DDIT3 (DNA damage inducible transcript 3) gene (formerly known as CHOP) is inserted adjacent to an FUS (fused in sarcoma; also known as TLS, translocated in liposarcoma). The fusion gene FUS-DDIT3 is found in 95 percent of myxoid liposarcomas; around 5 percent of tumors harbor an alternate EWSR1-DDIT3 fusion [96-99]. These fusions fail to induce G1/S arrest, which is one of the functions of the nononcogenic form of DDIT3 [100]. Identification of the fusion gene has been used as a diagnostic aid for this type of liposarcoma; immunohistochemistry using an antibody directed against DDIT3 has been developed as a diagnostic tool [98,101,102].

Synovial sarcoma — Synovial sarcomas is characterized by the translocation t(X;18)(p11.2;q11.2) [103]. The breakpoint of this translocation fuses the SS18 (synovial sarcoma translocation, chromosome 18, previously called SYT) gene from chromosome 18 to one of three homologous genes, SSX1, SSX2, and SSX4, on the X chromosome [104-106]. An SS18-SSX fusion-specific antibody has been developed for immunohistochemistry; this antibody is highly sensitive and specific for synovial sarcoma [107].

The SS18 gene encodes for a protein subunit of the mSWI/SNF (BAF) chromatin remodeling complex. The SS18-SSX fusion gene product competes with the endogenous SS18 protein, forming an altered complex lacking the tumor suppressor BAF47 (hSNF5). The altered protein complex binds the SOX2 locus and reverses polycomb-mediated repression, resulting in activation of the transcription factor SOX2, which promotes self-renewal and a stem cell phenotype [108].

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 [109].

Alveolar rhabdomyosarcoma — Alveolar rhabdomyosarcomas (ARMS) have a translocation t(2;13)(q35;q14) or less often t(1;13)(p36;q14); the corresponding chimeric genes are termed PAX3-FOXO1A and PAX7-FOXO1A (formerly known as FKHR) [110,111].

These translocations are associated with overexpression of a fusion product, which is thought to be involved in the pathogenesis of ARMS, although the specific mechanisms are incompletely understood [111-113].

Compared with PAX3-FOXO1A tumors, PAX7-FOXO1A tumors are more often extremity located and localized [114]. Molecular determination of minimal residual disease in ARMS is possible, but the clinical significance of this finding is uncertain [115].

Clear cell sarcoma — Clear cell sarcoma is a translocation-associated soft tissue sarcoma with melanocytic differentiation; this tumor type was previously also known as "melanoma of the soft parts." Although these tumors stain immunohistochemically for melanoma markers, the genetics is entirely different from melanoma.

Cytogenetically, most clear cell sarcomas exhibit a translocation at t(12;22)(q13-14;q12), which is not seen in melanoma [116,117]. This results in the fusion of the EWSR1 with ATF1, a gene encoding a member of the cyclic AMP-responsive element binding protein (CREB) family of transcription factors. A variant translocation (EWSR1-CREB1) is commonly found in clear cell sarcoma-like tumors of the gastrointestinal tract (also known as malignant gastrointestinal neuroectodermal tumor [GNET]); these tumors lack melanocytic differentiation [118]. (See "Uncommon sarcoma subtypes", section on 'Clear cell sarcoma'.)

Alveolar soft part sarcoma — Alveolar soft part sarcomas are highly vascular, rare malignant soft tissue tumors that tend to arise on the extremities of adolescents and young adults, with a female predilection [119]. A characteristic nonreciprocal translocation (derivative or der(17)t(X;17)(p11;q25)) is found in nearly all cases [120,121]. The translocation involves the ASPSCR1 (previously called ASPL) gene on chromosome 17 and the TFE3 gene on the X chromosome. The resulting ASPSCR1-TFE3 fusion gene is postulated to be involved in the pathogenesis of this tumor [122], possibly by upregulating angiogenesis-related genes [123]. It is hypothesized that the female predominance is due to their possession of an extra X chromosome, and the fusion gene not being subject to X-inactivation [119]. (See "Uncommon sarcoma subtypes", section on 'Alveolar soft part sarcoma'.)

Extraskeletal myxoid chondrosarcoma — Extraskeletal myxoid chondrosarcoma (EMC) is a tumor of uncertain histogenesis (despite its name suggesting cartilaginous differentiation) that is characterized by abundant myxoid matrix and often presents in the lower extremities [124,125]. (See "Uncommon sarcoma subtypes", section on 'Extraskeletal myxoid chondrosarcoma'.)

The majority are characterized by a unique reciprocal translocation t(9;22) that results in the fusion of the EWSR1 gene on chromosome 22 with a novel gene at 9q22 called NR4A3 (previously known as NOR1, CHN, or TEC) [126-129]. The biological function of the NR4A3 nuclear receptor is not yet fully elucidated. The fusion protein appears to function as a transcriptional activator and has been shown to induce cellular transformation [130-133].

A small proportion have a different translocation, either t(9;17), which results in a TAF15-NR4A3 fusion gene [134,135], or t(9;15), which results in an TCF12-NR4A3 fusion gene [136].

Dermatofibrosarcoma protuberans — DFSP is characterized by a specific nonreciprocal translocation t(17;22)(q22;q13), often within ring chromosomes. (See "Dermatofibrosarcoma protuberans: Epidemiology, pathogenesis, clinical presentation, diagnosis, and staging".)

Solitary fibrous tumor — Solitary fibrous tumors (SFTs) of all sites are characterized by a recurrent inversion of the long arm of chromosome 12 (12q13). This inversion results in a fusion of two genes, NAB2 (NGFIA-binding protein 2) and STAT6 (signal transducer and activator of transcription 6). The fusion of NAB2 and STAT6 creates a chimeric transcription factor in which the NAB2 repressor domain is substituted by a carboxy-terminal STAT6 transactivation domain or near-full-length STAT6. The NAB2-STAT6 chimeric transcription factor constitutively localizes to the nucleus, where it is thought to serve as a driver of tumorigenesis by constitutively activating NAB2 target genes [137]. The NAB2-STAT6 fusion gene is a distinct molecular feature of SFTs, present in up to 100 percent of cases, which has not been detected in other tumors. (See "Solitary fibrous tumor", section on 'Molecular pathogenesis and molecular diagnostics'.)

Epithelioid hemangioendothelioma — Epithelioid hemangioendothelioma (EHE) is a malignant vascular neoplasm that is characterized by recurrent translocations involving chromosome regions 1p36.3 and 3q25; the resulting translocation between the WWTR1 (WW domain-containing transcription regulator 1; 3q25) and CAMTA1 (calmodulin-binding transcription activator 1; 1p36) genes results in the formation of a disease-defining WWTR1-CAMTA1 fusion gene [138,139]. The fusion gene is under the transcriptional control of the WWTR1 promoter and encodes a putative chimeric transcription factor that leads to overexpression of both genes. The fusion gene appears to be present in approximately 90 percent of EHEs tested, but not in other vascular neoplasms. Immunohistochemical staining for CAMTA1 protein expression is useful for distinguishing EHE from other epithelioid mesenchymal neoplasms, which are negative for expression of CAMTA1 [140].

A small subset of EHE have a different translocation, which results in a gene rearrangement between Yes-associated protein 1 (YAP1) and transcription factor for the immunoglobulin heavy chain enhancer 3 (TFE3) [141]. (See "Uncommon sarcoma subtypes", section on 'Epithelioid hemangioendothelioma'.)

Chromosomal instability — Although approximately one-third of all soft tissue sarcomas have a defining translocation as described above, the remaining sarcomas often have a complex karyotype. A positive correlation exists between the number of genomic alterations and the histologic grade of soft tissue sarcomas [142]. Because high-grade soft tissue sarcomas have worse outcome, genomic complexity is correlated with more aggressive sarcomas. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Histologic grade'.)

Molecular genetic testing for tumor classification — Immunohistochemistry, cytogenetics, and next-generation sequencing are important tools that aid in sarcoma classification. As an example, molecular assays for specific fusion genes can provide a genetic approach to the differential diagnosis of soft tissue sarcomas [143].

Gene expression profiling (GEP) by means of DNA microarrays has been applied to soft tissue sarcomas [144]. In one report, transcriptional profiling for 5520 different known genes was used to separate 41 soft tissue sarcomas into five distinct groups [145]:

GIST highly expressed a cluster of 125 genes, which separated them from other sarcomas.

Synovial sarcomas expressed a specific cluster of 104 genes, among them, molecules involved in retinoic acid pathways, and the epidermal growth factor receptor.

Neural tumors (eg, malignant peripheral nerve sheath tumors).

One-half of all leiomyosarcomas, in which 24 specific genes were highly expressed.

A broad group, containing all of the liposarcomas, UPS, and the remainder of the leiomyosarcomas, in which molecular profiles were not predicted by histologic features or immunohistochemistry.

The clinical utility of such a classification system has been realized only for the GISTs, in which tyrosine kinase-activating KIT mutations predict responsiveness to targeted therapy. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".)

However, the potential for future benefit of improved classification of soft tissue tumors includes better prediction of natural history and patient-tailored therapy based on the specific targets identified by microarray analysis [146]. For example, a prognostic gene expression signature termed the complexity index in sarcomas (CINSARC) has been developed that includes 67 genes related to mitosis and chromosome management [142]. In multivariate analysis, CINSARC predicted metastasis outcome in a training set and in a validation set of 127 independent soft tissue sarcomas. CINSARC was validated as a predictor of metastasis in patients with synovial sarcoma [147]. Interestingly, chromosomal complexity was more prevalent in adult patients with synovial sarcoma who had worse outcome than pediatric patients with synovial sarcoma. The CINSARC signature had already been shown to be a predictor of clinical outcomes in soft tissue sarcomas, GIST, and other cancers [142].

RADIATION THERAPY AND CHEMOTHERAPY

Epidemiology — Radiation therapy (RT) is recognized as a cause of sarcoma of bone and soft tissue; sarcomas were one of the first solid cancers to be linked to ionizing radiation exposure. The most frequent histopathologic type of radiation-induced soft tissue sarcoma arising in soft tissues is undifferentiated pleomorphic sarcoma (UPS). The most common type of bone sarcoma is osteosarcoma. Among females treated with RT for breast cancer, the most common secondary sarcoma is cutaneous angiosarcoma. (See "Radiation-associated sarcomas", section on 'Histologic distribution' and "Breast sarcoma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging".)

The frequency increases with the RT dose and with the post-RT observation period, and it decreases with age. Sarcoma is primarily a complication of high-dose therapy; it is rarely seen after low doses (<40 Gy). However, the actuarial frequency at 15 to 20 years is small, approximately 0.5 percent for RT of normal bone and soft tissue in the adult treated with RT alone to full doses and without chemotherapy. (See "Radiation-associated sarcomas", section on 'Radiation dose and age of exposure'.)

Childhood cancer survivors — The frequency of secondary sarcomas is even higher following RT in survivors of childhood cancer. The risk is highest in children who receive both RT and chemotherapy (particularly anthracyclines and alkylating agents) and in those who are treated for a primary sarcoma or retinoblastoma. (See "Radiation-associated sarcomas", section on 'Childhood RT' and "Radiation-associated sarcomas", section on 'Chemotherapy agents'.)

In general, secondary sarcomas have a poorer prognosis than do de novo sarcomas. However, these patients warrant aggressive treatment, as secondary sarcomas are potentially curable. This subject is discussed in detail separately. (See "Radiation-associated sarcomas" and "Breast sarcoma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging" and "Breast sarcoma: Treatment" and "Head and neck sarcomas", section on 'Risk factors'.)

INDUSTRIAL CHEMICALS — There are a number of inherent problems in occupational epidemiology with small numbers of patients in any given series and the difficulty in isolating a single agent [148]. For these reasons, few associations can be considered established and causal [149]. As examples, there is a clear association between vinyl chloride or arsenic exposure and hepatic angiosarcoma [150,151] and a probable association between phenoxy herbicides and soft tissue sarcoma [152-154]. The last risk may be greater with exposure to phenoxy herbicides contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or higher chlorinated dioxins [155,156]. A role for dioxin per se is controversial. A population-based case control study, however, found no increased risk for soft tissue sarcoma among Vietnam veterans, including those exposed to Agent Orange, which contains dioxin [157].

High intensity chlorophenol exposure in jobs involving wood preservation, machinists and the use of cutting fluids may increase the risk of soft tissue sarcoma, independent of phenoxy herbicides [153,158]. However, some studies have not confirmed this association [152].

CHRONIC EDEMA, CHRONIC IRRITATION, AND TRAUMA — Sarcomas of soft tissue (primarily angiosarcomas) may be observed following massive and quite protracted edema. This has classically been seen in the postmastectomy lymphedematous arm (Stewart-Treves syndrome) [159,160]. It has also been described with chronic lymphedema due to filarial infection [161].

Chronic irritation secondary to foreign bodies also may be a factor in the induction of sarcomas. Trauma may also be a factor in the development of soft tissue sarcomas including desmoid tumors. In an occasional patient, there is a history of major trauma to the affected site many months prior to the appearance of local symptoms of tumor. The usual history is of a traumatic incident occurring shortly prior to the awareness of the mass. Clinicians often explain this sequence of events that the trauma merely brought the patient's attention to the presence of the mass. However, injury has been shown to promote sarcoma development in animal models [162,163]. Therefore, additional study is needed in patients to determine whether injury promotes sarcomagenesis.

VIRAL INFECTION — Viral infections are rarely associated with the development of sarcomas:

Human herpesvirus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi sarcoma. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis" and "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis", section on 'Anti-HHV-8 antibodies and viremia'.)

Epstein-Barr virus (EBV)-associated smooth muscle tumors have been described in patients with HIV/AIDS and in other immunocompromised hosts (eg, solid organ transplant, NK cell deficiency) [164-167]. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis".)

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".)

SUMMARY

There is no clearly defined etiology in most cases of soft tissue sarcoma, but a number of associated or predisposing factors have been identified. These include familial predisposition (Li-Fraumeni syndrome, familial adenomatous polyposis [FAP], retinoblastoma, and neurofibromatosis), gene mutations, radiation therapy (RT), chemotherapy, chemical carcinogens, chronic irritation, and lymphedema. In addition, viruses, including human herpesvirus 8 (HHV-8), have been implicated in the pathogenesis of Kaposi sarcoma. (See "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis" and "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)

There is a high incidence of acquired (somatic) gene alterations in soft tissue and bone sarcomas. Somatic mutations in specific genes vary across the histologic subtypes of soft tissue sarcoma. (See 'Somatic gene mutations' above.)

A number of soft tissue sarcomas display recurrent nonrandom chromosomal translocations, which serve as definitive diagnostic criteria for the tumors in which they occur (table 1). Furthermore, the identification of these molecular signatures has provided clues as to the molecular alterations that are fundamental for the development and often maintenance of sarcoma. (See 'Chromosomal translocations' above.)

RT is recognized as a cause of sarcomas of soft tissue and bone. The frequency increases with the RT dose and with the post-RT observation period, and it decreases with age. The risk of a radiation-induced sarcoma is particularly high in survivors of childhood cancer, and it is highest in children who receive both RT and chemotherapy (particularly anthracyclines and alkylating agents) and in those who are treated for a primary sarcoma. (See 'Radiation therapy and chemotherapy' above.)

Chronic edema has been linked to soft tissue sarcomas, particularly angiosarcoma in the setting of an edematous extremity. (See 'Chronic edema, chronic irritation, and trauma' above.)

Viral infections are associated with the development of specific sarcomas (Kaposi sarcoma and Epstein-Barr virus [EBV]-associated smooth muscle tumors). (See 'Viral infection' above.)

Sarcomas of soft tissue (primarily angiosarcomas) may be observed following massive and protracted edema. This has classically been seen in the postmastectomy lymphedematous arm and is termed Stewart-Treves syndrome. (See 'Chronic edema, chronic irritation, and trauma' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Thomas DeLaney, MD, and David G Kirsch, MD, PhD, who contributed to earlier versions of this topic review.

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Topic 7737 Version 46.0

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