➢ Many sarcomas such as osteosarcoma have complex molecular compositions and behaviors that make standardized treatment difficult for patients with these tumors.
➢ Chromosomal translocations are noted in specific bone and soft-tissue sarcomas, and there are molecular tests (polymerase chain reaction [PCR] and fluorescence in situ hybridization [FISH]) used for accurate diagnosis.
➢ The translocations noted in sarcomas may allow future therapeutic targeting.
Sarcomas are rare tumors of mesenchymal origin and account for about 20% of pediatric solid tumors and <1% of solid tumors in adults. Approximately 15,000 new sarcomas (12,000 soft tissue and 3,000 bone) were diagnosed in the United States in 20141. Sarcomas are a diverse group of malignancies derived from connective tissues including bone, cartilage, fat, muscle, and neural and fibrous tissue. Historically, sarcomas were classified on the basis of histologic phenotypes and differentiation of a mesenchymal phenotype. This was done on the basis of morphology and immunohistochemical markers that could identify specific cells. For example, markers of smooth muscle origin were used to identify leiomyosarcomas and markers for fat cells were used to identify liposarcomas. However, benign and malignant mesenchymal tumors may share histologic features, making it challenging to obtain an accurate diagnosis on the basis of morphology alone. Additionally, there has been a discrepancy rate of up to 27% in the diagnosis of sarcomas between primary institutions and tertiary centers2.
Advances in diagnostics, specifically in cytogenetics and molecular markers, have made it possible to better classify this heterogeneous group of tumors. As a result of identifying correlations between genetic and histologic changes, the current (2013) World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone has eliminated previous diagnoses such as malignant fibrous histiocytoma and has added several newly described entities such as hemosiderotic fibrolipomatous tumor and pseudomyogenic or epithelioid sarcoma-like hemangioendothelioma3. Although the term malignant fibrous histiocytoma can still be found in historical articles, moving forward, this diagnostic category is no longer used. Molecular markers have become critically important in the diagnosis and prognosis of sarcomas and may, in the future, be used as therapeutic targets. For example, the genetic translocations of Ewing sarcoma are well defined and are thought to be oncogenic. Currently, much research is aimed toward targeting the fusion products and stopping the oncogenic process. Figure 1 is a graph based on recognized sarcoma subtypes reported in the literature4-10. Although the overall incidence per year of sarcomas has remained relatively constant over time, there has been an expansion of sarcoma classifications and subtypes leading to new, more specific diagnoses due to new cytogenetic and molecular diagnostic methods. However, some of these newer biomarkers have not been found to be reproducible and have yet to be validated11. This article will discuss only commonly used molecular markers that aid in the diagnosis and differentiation of sarcoma from benign bone and soft-tissue tumors.
Molecular Pathology Techniques
Immunohistochemistry combines morphological, immunologic, and biochemical techniques to identify targeted epitopes in tissue sections using a specific antibody-antigen reaction labeled with a visible reporter molecule. This binding reaction is then visualized through the use of various enzymes that are conjugated to the antibodies being used. The enzyme acts on chromogenic substrate to cause deposition of a tinctorial material at the site of the antibody-antigen bindings. This latter reaction then permits visualization and localization of specific cellular elements within a cell or tissue section. Importantly, immunohistochemistry preserves the overall morphology and structure of the tissue section for immunologic and morphological correlation. In standard immunohistochemistry, these slides are viewed with routine bright field microscopy, and all immunohistochemistry and fluorescence in situ hybridization (FISH) testing is performed on formalin-fixed, paraffin-embedded tissue blocks or sections. Major improvements in protein conjugation, antigen preservation, and antigen retrieval methodology, along with enhanced immunodetection systems, have enshrined immunohistochemistry as a major adjunctive investigative tool for both surgical pathology and cytopathology. Immunohistochemistry not only is critical for the accurate diagnosis of sarcomas but also plays a pivotal role in prognostication and targeted treatment strategies (e.g., c-kit protein for gastrointestinal stroma tumors). Lung adenocarcinomas are quite easily identified with a combined immunohistochemistry panel of p63, TTF-1 (thyroid transcription factor 1), and Mapsin-A; similarly, breast cancers can be identified with mammoglobin, GCDFP (gross cystic disease fluid protein)-15 (also known as BREST-2), and GATA-3. In addition to the use of immunohistochemistry for the detection of differentiation markers for accurate diagnoses, this technique is increasingly being applied to the detection of nuclear transcription factors that are often dysregulated and overexpressed because of genetic alterations (e.g., FLI1 [friend leukemia integration 1] overexpression caused by fusion transcripts in Ewing sarcoma and MDM2 and/or CDK4 overexpression in subtypes of liposarcoma and osteosarcoma). Hence, it is critical not only to choose antibodies targeted toward a morphological differential diagnosis but also to immunohistochemically detect underlying genetic mutations. Furthermore, caution is advised in the interpretation of immunohistochemistry because of the importance not only of the chromogenic reaction (positive compared with negative) but also of the localization of the reaction (e.g., nuclear immunostaining for beta-catenin in desmoid-type fibromatosis and nuclear or cytoplasmic staining for S100 in nerve sheath tumors). A final word of caution is that immunohistochemistry detects physiological protein expression in entirely normal cells as well as in neoplastic cells. Cytokeratin (an intermediate filament), typically useful for the diagnosis of synovial and epithelioid sarcomas, also stains normal and neoplastic epithelial cells. Lastly, the incorporation of appropriate adequate tissue and reagent controls (both positive and negative) in every daily run of immunohistochemistry cannot be overemphasized, this being the highest form of quality control of the immunohistochemistry assay.
In situ hybridization enables the direct visualization of nucleic acid targets in relation to cytological, histologic, or karyotypic features. In situ hybridization was first developed in 1969 with the use of radiolabeled probes but was subsequently replaced by chromogenic in situ hybridization techniques using biotin, digoxigenin, or fluorescein hapten-labeled probes (FISH) in the 1980s. Similar to immunohistochemistry, labels are detected using enzyme (e.g., horseradish peroxidase or alkaline phosphatase)-linked reagents followed by a chromogenic substrate. The FISH technique can be performed using fluorophore-labeled nucleic acid probes or using fluorophore-labeled secondary reagents against hapten-labeled probes. FISH uses these labeled DNA probes to specifically hybridize with chromosomal regions involved in or adjacent to areas of gene fusion or gene amplification. The main disadvantage of FISH is that the tissue morphology has to be interpreted on the basis of fluorescent counterstains. FISH is applicable to all pathology sample preparations including cytology, frozen-section preparations, and formalin-fixed, paraffin-embedded specimens.
For sarcoma diagnosis, FISH is widely used for the detection of gene amplification (e.g., MDM2 in well-differentiated or dedifferentiated liposarcoma) and chromosomal rearrangements (e.g., EWSR1 in Ewing sarcoma). For the latter, two probes complementary to the DNA regions flanking the anticipated breakpoint are labeled with two different colored fluorochromes. This results in two distant signals in the presence of a chromosomal break involved in the translocation (break-apart FISH). In contrast, the construction of probes complementary to the fused chromosomal region will result in fluorescent signals being fused or in proximity (fused or combination FISH). Amplification of chromosomal regions may be detected with different colored fluorescent probes complementary to the centromere and the amplified region. Thus, a high ratio of these signals detects amplification (amplification FISH).
Certain genes are promiscuous (e.g., EWSR1), being associated with a variety of translocations and tumor subtypes. Hence, in these instances, further consideration of a more refined morphological differential diagnosis is warranted with the complementary use of immunohistochemistry (e.g., Ewing sarcoma compared with clear cell sarcoma).
Reverse Transcription Polymerase Chain Reaction (RT-PCR)
The precise identification of fusion transcripts is best accomplished with RT-PCR following extraction of genetic material from fresh-frozen or formalin-fixed, paraffin-embedded sarcoma material. The majority of pathological translocations transcribe into novel messenger RNA (mRNA) encoding a pathogenic fusion protein with potential oncogenic properties. Technically, the transcribed new mRNA is reverse-transcribed to complementary DNA (cDNA). This step is followed by PCR with the use of primers specifically designed toward the exons flanking the fusion site. The resultant amplicons may be visualized on electrophoretic gels or restriction fragment analysis or may be subject to direct Sanger sequencing for confirmation of the amplified product. Although RT-PCR remains a highly specific and useful diagnostic technique, the sensitivity of PCR incurs the potential defect of false-positive data due to the amplification of cross-contamination from exogenous sources. Therefore, strict measures are necessary from patient sample collection to the PCR assay to ensure authentic results and to avoid false-positive data.
Osteosarcoma is the most common primary malignant bone tumor in adults and children. The incidence per year is 4.4 per 1,000,000 individuals12. Although it is a rare tumor overall, osteosarcoma is the second most common malignancy noted in adolescents after lymphoma. Marked advances in survival in patients with osteosarcoma have occurred over the past 50 years. Prior to the advent of chemotherapy, the 5-year overall survival for patients with isolated extremity osteosarcoma was 20%13; currently, the 5-year survival is 70%. However, there has been little improvement in survival over the past 30 years14, and the prognosis is still poor for patients who present with metastatic osteosarcoma or primary disease in an axial location.
The immunoprofile of osteosarcoma is broad and lacks diagnostic specificity15. Table I shows commonly expressed antigens in osteosarcoma. Recently, a new marker, SATB2, has been found to be sensitive for identifying osteoblasts and can be used in osteosarcoma with little osteoid production16. However, it has been shown to lack specificity17. Certain markers such as Her2/Neu, Cox2, and p53 are believed to be associated with a worse prognosis18. Osteosarcoma is a genetically complex tumor with an elevated rate of gain or loss of chromosomes or sections of chromosomes19. This high level of chromosomal instability leads to heterogeneity between osteosarcomas and even within a single osteosarcoma. Genomic profiling of tumor DNA in osteosarcoma has shown recurrent amplification and DNA copy number gains at distinct chromosomal regions and DNA copy loss at other regions19-21. Candidate genes have been identified that may play a role in the genesis of osteosarcomas or metastasis22. However, a better understanding of these molecular changes is required before these findings can be translated for diagnostic or treatment purposes.
Ewing sarcoma is the second most common primary bone malignancy in children. The incidence per year is 1 per 1,000,000 individuals23. Many consider Ewing sarcoma the prototypical translocation sarcoma. It was one of the first sarcomas to be defined cytogenetically by a signature translocation24. It is believed that the pathogenesis of Ewing sarcoma is driven by a recurrent balanced translocation that causes fusion oncogenes to act as aberrant transcription factors. They may activate or may repress certain target genes that give rise to Ewing sarcoma15. The most common translocation in Ewing sarcoma, present in 85% of tumors, is t(11;22) generating the EWSR1-FLI1 fusion gene. The FLI1 gene found on chromosome 11 is part of the ETS family of transcription factors. Another 10% of cases involve alternative translocations between EWSR1 and other members of the ETS family. Fourteen translocations have been found in Ewing sarcoma or Ewing-like sarcoma and are recognized by the WHO (Table II). These fusion proteins are the presumed oncogenic triggers required for proliferation and tumorigenesis24. Currently, research is being done to elucidate this pathway and to identify potential therapeutic targets. The presence of these translocations identified by either RT-PCR or FISH is routinely used to confirm the diagnosis of Ewing sarcoma.
Chondrosarcoma is the second most common primary malignant bone tumor and primarily found in adults. More than 40% of primary bone sarcomas in adults are chondrosarcoma. Chondrosarcomas are a genetically diverse group of tumors with a wide range of clinical behavior from relatively indolent to extremely aggressive. Recently, mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have been identified in primary and secondary central chondrosarcomas, enchondromas, and periosteal cartilaginous tumors but not in peripheral chondrosarcoma, osteochondromas, mesenchymal chondrosarcoma, and clear-cell sarcoma or other mesenchymal tumors including osteosarcoma. They are the first common genetic abnormalities identified in central cartilaginous neoplasms. It is thought that the mutation occurs early in tumorigenesis25,26. Identification of these mutations may lead to targeted therapies for this group of tumors.
Mesenchymal chondrosarcoma is a small, round, blue cell tumor with focal cartilaginous differentiation. Unlike conventional chondrosarcoma, it affects teenagers and young adults. In 2011, a novel fusion protein, HEY1-NCOA2, was identified consistently in mesenchymal chondrosarcoma and found to be absent in other chondrosarcomas. The action of this fusion protein has not been definitively elucidated, but it may cause ectopic activation of Notch target genes27.
Benign Bone Tumors
Fibrous dysplasia is a benign fibro-osseous lesion confined to the medullary canal in long bones or craniofacial bones. It can either be monostotic or, less commonly, polyostotic. Although these lesions do not metastasize, they can cause considerable deformity and can lead to lower extremity-length discrepancies, pain, and disability. Fibrous dysplasia can be a component of syndromes such as McCune-Albright syndrome (fibrous dysplasia, skin pigmentation abnormalities, and endocrinopathies) or Mazabraud syndrome (fibrous dysplasia and intramuscular myxomas), but it usually presents as an isolated bone lesion. All forms of fibrous dysplasia are caused by a postzygotic, activating missense mutation in the GNAS gene, which encodes the alpha-subunit of the GTP-binding protein Gs. These mutations have been found in up to 93% of cases15.
Soft-tissue sarcomas are more common than primary bone sarcomas and can affect patients of any age. Several common soft-tissue sarcomas have recognized translocations and specific antigens that can be identified by FISH, RT-PCR, and immunohistochemistry (Table III). The most common of these soft-tissue sarcomas will be discussed in further detail.
Rhabdomyosarcoma is the most common soft-tissue sarcoma among children and adolescents, with an incidence per year of 4.5 per 1,000,000 among patients from birth to 20 years of age. Embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma are the two most common subtypes28. Rhabdomyosarcoma is a sarcoma with skeletal muscle differentiation. Embryonal rhabdomyosarcoma contains primitive mesenchymal cells in various stages of myogenesis. Alveolar rhabdomyosarcoma is highly cellular and contains primitive cells with features of arrested myogenesis15. Although antibodies against MyoD1 and myogenin are sensitive and specific for rhabdomyosarcoma, embryonal rhabdomyosarcoma shows negative, weak focal, or moderate staining for myogenin, which is in contrast to alveolar rhabdomyosarcoma, which is diffusely strongly positive29. Unlike embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma has recurrent translocations (Table III). The t(2;13) translocation occurs in most cases; t(1;13) is less common. The t(2;13) translocation generates fusion protein PAX3-FOXO1, and the t(1;13) translocation generates fusion protein PAX7-FOXO130. These proteins act as transcription factors essential in oncogenesis. It has been noted that alveolar rhabdomyosarcoma is more aggressive than embryonal rhabdomyosarcoma, which is thought to be due to the PAX-FOXO1 fusions. Additionally, genes involved in the receptor tyrosine kinase/RAS/PIK3CA pathway are often altered31.
By further elucidating these receptor tyrosine kinase mutations, there may be an opportunity for therapeutic intervention. Currently, several specific tyrosine kinase inhibitors are available for anticancer treatment with promising results, such as imatinib for gastrointestinal stromal tumor, sunitinib for renal cell carcinoma, and erlotinib for lung and pancreatic cancers.
Infantile fibrosarcoma is a rare form of fibrosarcoma that occurs in infants and has a more benign course compared with adult fibrosarcoma. Up to 80% of cases are congenital. Although local recurrences are common following positive margins, metastases are rare, and a mortality rate of <5% to 20% has been reported15,32,33. Unique to infantile fibrosarcoma is the ETV6-NTRK3 gene fusion34. The resulting oncoprotein can be detected by FISH and RT-PCR and distinguishes infantile fibrosarcoma from benign entities such as infantile myofibromatosis and infantile fibrosis as well as from the adult form of fibrosarcoma that can occasionally occur in infants35.
The WHO recognizes 4 different categories of liposarcoma: atypical lipomatous tumor or well-differentiated liposarcoma, dedifferentiated liposarcoma, myxoid liposarcoma (including round cell liposarcoma), and pleomorphic liposarcoma.
Atypical lipomatous tumor or well-differentiated liposarcoma is an adipocyte tumor that can recur locally in the extremities or retroperitoneum more commonly than a simple lipoma. The same histologic tumor is considered benign atypical lipomatous tumor in the extremities and a low-grade malignant well-differentiated liposarcoma in the retroperitoneum. Neither entity has metastatic potential unless dedifferentiation occurs. Both show amplification of MDM236,37 and CDK438. Supernumerary ring or giant marker chromosomes involving the 12q14-15 regions characterize atypical lipomatous tumor. This region includes both MDM2 and CDK4. Amplification of MDM2 protein inactivates TP53, a tumor suppressor39. Detection of MDM2 by FISH, PCR, or immunohistochemistry can differentiate atypical lipomatous tumor from a benign lipoma.
Dedifferentiated liposarcoma is a high-grade tumor and often has increased amplification of MDM2 and CDK4, also due to supernumerary ring or giant marker chromosomes. Diffuse nuclear expression of MDM2 and/or CDK4 can distinguish dedifferentiated liposarcoma from pleomorphic liposarcoma. Dedifferentiated liposarcoma appears to have coamplifications of other regions besides 12q14-15, suggesting that other activated pathways are involved in progression from atypical lipomatous tumor or well-differentiated liposarcoma to dedifferentiated liposarcoma40. High levels of CDK4 have been shown to be a marker of poor prognosis in well-differentiated liposarcoma and dedifferentiated liposarcoma41, and inhibition of CDK4 has been studied in a phase-II trial. Dickson et al. showed 66% progression-free survival at 12 weeks among 29 patients with either well-differentiated liposarcoma or dedifferentiated liposarcoma who had experienced progression on systemic therapy. Although promising, the authors were investigating different dosing regimens to reduce systemic toxicity42.
Myxoid liposarcoma represents 15% to 20% of liposarcomas and is more common in young adults. Histologically, it contains round to oval cells and small signet-ring cell lipoblasts in a prominent myxoid stroma. Tumors with a hypercellularity or round cell morphology (>5% of total cells) have a worse prognosis and used to be considered separately as round cell liposarcomas. Currently, the WHO recognizes these as a subset of myxoid liposarcoma. More than 95% of cases of myxoid liposarcoma have a t(12;16) translocation producing the FUS-DDIT3 gene. The remaining tumors have an EWSR1-DDIT3 fusion gene. These are highly specific for myxoid liposarcoma and are absent in other liposarcomas. A 2012 study identified NY-ESO-1, a potent stimulator of the immune system, in 100% of tested myxoid liposarcomas, suggesting the possibility of NY-ESO-1-directed therapies43.
Synovial sarcoma is a mesenchymal tumor characterized by purely spindled cells (monophasic) or both spindled and epithelial cells (biphasic). It is most common in adolescents and young adults. The epithelial cells in a biphasic pattern express epithelial membrane antigen (EMA) and keratin, but EMA is expressed more widely than keratin in the monophasic pattern. The expression of EMA and/or keratin can distinguish synovial sarcoma from other spindle cell neoplasms. The t(X;18) translocation, which is only found in synovial sarcoma, is present in >95% of cases. The fusion gene SS18-SSX can be detected by FISH or RT-PCR and is used to accurately diagnose synovial sarcoma. Interestingly, most biphasic tumors carry the SS18-SSX1 fusion, which was initially thought to predict a worse prognosis44. Both fusions have been detected in monophasic tumors45. A meta-analysis of 10 studies and more than 900 patients failed to find an effect of fusion type on overall survival; however, they did note a trend toward worse progression-free survival and metastasis-free survival among patients with SS18-SSX1 fusions (hazard ratio, 1.26 [95% confidence interval, 0.96 to 1.65]; p = 0.09)46.
Dermatofibrosarcoma protuberans is a low-grade, locally aggressive dermal sarcoma. Dermatofibrosarcoma protuberans carries the fusion gene COL1A1-PDGFB. This can be due to the presence of supernumerary ring chromosomes that contain the interspersed sequences from chromosomes 17 and 22 (adult cases) or from an unbalanced t(17;22) translocation (pediatric cases)47. The COL1A1-PDGFB fusion protein ultimately gets processed to a normal platelet-derived growth factor beta (PDGFB) ligand48. This causes overproduction of the PDGFB ligand, stimulates PDGFB receptors on the tumor cells themselves, and promotes tumorigenesis through an autocrine or paracrine loop15. Tyrosine kinase inhibitors such as imatinib have been used to disrupt the phosphorylation and activation of PDGFB, with a 50% response rate in unresectable or metastatic Dermatofibrosarcoma protuberans49,50.
Clear-cell sarcoma is a rare sarcoma usually involving deep tendons and aponeuroses of the extremities that affects young adults. More than 90% of cases have a reciprocal translocation resulting in the EWSR1-ATF1 fusion gene. The identification of this fusion is helpful in distinguishing clear-cell sarcoma from metastatic melanoma, as they share many histologic features51. Although the melanocyte-specific micropthlamia-associated transcription factor promoter has been identified as the target of the fusion protein, this has not yet led to novel therapies.
Vascular tumors are a group of benign or malignant tumors that are formed from blood vessels. The WHO recognizes 13 distinct soft-tissue vascular tumors, 2 of which are considered malignant (epithelioid hemangioendothelioma and angiosarcoma), 7 that are considered locally aggressive and rarely metastasizing, and 4 that are considered benign.
Erythroblast transformation-specific (ETS)-related gene (ERG) is a transcription factor within the ETS family and is expressed in endothelial cells. Additionally, oncogenic fusion products involving ERG are present in Ewing sarcoma, prostate carcinoma, and acute myeloid leukemia. Recently, a monoclonal antibody, CPDR ERG-MAb, was developed that is specific for detecting the ERG protein. This antibody was tested on 250 vascular endothelial tumors, 973 other mesenchymal tumors, and 657 epithelial tumors. ERG was expressed in all hemangiomas and lymphangiomas, 96% of angiosarcomas, 42 of 43 epithelioid hemangioendotheliomas, and all Kaposi sarcomas52. CD31 is a useful cell marker for vascular and lymphatic endothelial cells. CD31 has been shown to be positive in almost all benign vascular tumors, in normal vascular and lymphatic endothelial cells, and in most angiosarcomas. Unlike other vascular endothelial markers, however, CD31 is negative in all other sarcomas tested, making it a useful angiosarcoma marker53. Epithelioid hemangioendothelioma is a malignant angiocentric vascular tumor that is characterized by a WWTR1-CAMTA1 fusion. The translocation has been identified as t(1;3)(p36;q25) in almost all cases. This marker is both sensitive and specific for epithelioid hemangioendothelioma, as it has not been found in other vascular tumors, benign or malignant54,55.
Benign Soft-Tissue Tumors
Benign soft-tissue tumors can be difficult to distinguish from sarcomas using magnetic resonance imaging (MRI), positron emission tomography (PET) scans, and regular hematoxylin and eosin sections. Newly identified molecular events (Table IV) can now help to identify certain benign soft-tissue tumors.
Nodular fasciitis is a self-limiting, pseudosarcomatous neoplasm originally thought to be a reactive process. It can grow rapidly and occasionally is quite tender. Nodular fasciitis is typically slightly hyperintense to muscle on T1-weighted sequences and hyperintense on T2-weighted sequences. It has heterogeneous enhancement after gadolinium injection56. Histologically, it is composed of spindle-shaped fibroblasts. Although pleomorphic cells are absent, there can be a high number of mitotic figures15,57-59. Because of these clinical, imaging, and histologic features, it is often misdiagnosed as a sarcoma60. Recently, the amplification of USP6 was found in 92% of nodular fasciitis cases, and the fusion gene MYH9-USP6 was identified as a novel fusion gene in 65% of cases58. The identification of this sensitive and specific translocation can now aid in differentiation of nodular fasciitis from true sarcomas. Interestingly, USP6 overexpression has also been identified in aneurysmal bone cysts, a benign bone tumor with some histologic features similar to those of nodular fasciitis15.
Desmoid fibromatosis, an aggressive, benign soft-tissue tumor, is diagnosed by the use of nuclear staining of beta-catenin61,62. Beta-catenin plays a role in the formation of desmoid fibromatosis through the Wnt signaling pathway. Although nuclear staining is helpful for distinguishing a desmoid tumor from schwannomas, neurofibromas, nodular fasciitis, and leiomyosarcomas, it can be present in other tumors such as solitary fibrous tumors, infantile fibrosarcoma, and myofibroblastic tumors.
Tenosynovial Giant Cell Tumor
Tenosynovial giant cell tumor (formerly pigmented villonodular synovitis) is a family of tumors that arise from synovium of joints, bursa, and tendon sheaths. Similar to nodular fasciitis, tenosynovial giant cell tumors were originally thought to be inflammatory or reactive lesions ranging from the localized form commonly seen in digits to the more clinically aggressive diffuse form found in and around joints. Although benign, treatment of diffuse tenosynovial giant cell tumor or pigmented villonodular synovitis can be difficult. Many patients experience local recurrences that require multiple surgical procedures and occasionally radiation63. Cytogenetic analyses have demonstrated chromosome alterations in both localized and diffuse forms. Translocations involving CSF1 on chromosome 1 with COL6A3 on chromosome 2 leads to overexpression of CSF1 in a small subset of tumor cells, which attract large numbers of macrophages carrying the CSF1 receptor (CSF1R)64. Several clinical studies have evaluated the role of CSF1R inhibitors in the treatment of diffuse and recurrent tenosynovial giant cell tumor or pigmented villonodular synovitis and have had promising results65-67.
Cytogenetic analysis of bone and soft-tissue tumors has identified unique markers across subtypes that allow for more precise diagnosis, prognosis, and potential therapeutic targets. Future treatments of patients with sarcoma will ideally become more personalized to their own specific tumor biology. Targeted immunologic therapies or biologic inhibition with small molecules will become more prevalent as additional knowledge is gained about the unique molecular signatures of each tumor type.
Investigation performed at the University of California, San Francisco, San Francisco, California, and the University of Pennsylvania, Philadelphia, Pennsylvania
Disclosure: There was no source of external funding related to this manuscript. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and “yes” to indicate that the author had other relationships or activities that could be perceived to influence, or have the potential to influence, what was written in this work.
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