Sarcoma Classification: An Update Based on the 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone

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1 Sarcoma Classification: An Update Based on the 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone Leona A. Doyle, MD The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone incorporates changes in tumor classification, as well as new genetic insights into the pathogenesis of many different tumor types that have emerged over the 11 years since the publication of the prior volume. This article reviews changes in the classification of soft tissue and bone sarcomas as well as tumors of intermediate biologic potential in the 2013 World Health Organization volume, new molecular insights into these tumors, and associated surgical and clinical implications. Cancer 2014;120: VC 2014 American Cancer Society. KEYWORDS: soft tissue, bone, tumor, sarcoma, World Health Organization, tumor classification. INTRODUCTION The current 2013 World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone 1 was published 11 years after the prior volume. 2 During that period, many changes have taken place in soft tissue and bone tumor classification, predominantly based on the identification of new genetic findings in different tumor types. In addition, several new morphologically distinct tumor types have been described, often along with their novel genetic changes. The advances in classifying and understanding the pathogenesis of soft tissue and bone tumors based on the correlation of histologic and genetic findings have been particularly significant in the field of soft tissue and bone oncopathology, perhaps more so than in many other areas of pathology, with the exception of hematolymphoid neoplasia. Although many interesting molecular genetic findings have been described in benign soft tissue and bone tumors, this article will focus on changes in the classification of soft tissue and bone sarcomas as well as soft tissue and bone tumors of intermediate biologic potential (ie, locally aggressive or rarely metastasizing tumors), new molecular insights into these tumors, and associated surgical and clinical implications. The changes are reviewed according to the categorization of tumors in the WHO volume. These changes, along with those in benign soft tissue and bone tumors, are summarized in Tables 1 and 2. TUMORS OF SOFT TISSUES Adipocytic Tumors The most notable change in this category of tumors was the deletion of the term round cell liposarcoma, which describes a morphologic appearance present in a subset of high-grade myxoid liposarcoma. Myxoid liposarcoma is graded using a 3-tier system as low, intermediate, or high grade, based on the degree of cellularity. Transition between different grades may be observed in a given tumor, and the highest grade should be reported. High-grade myxoid liposarcoma most often demonstrates spindle cell morphology, but occasionally a round cell appearance predominates, which accounted for the previous designation of round cell liposarcoma ; the same genetic findings ie, FUS-DDIT3 [fused in sarcoma-dna damage inducible transcript 3] or, less commonly, EWSR1-DDIT3 fusion genes are present in both histologic types. Regardless of round cell or spindle cell tumor cell morphology, high-grade myxoid liposarcoma carries the same prognostic information, with a greater frequency of metastasis and worse survival compared with low-grade tumors. 3-5 The category of mixed-type liposarcoma was removed for the 2013 classification. This category had previously been reserved for those tumors demonstrating apparently combined histologic features of myxoid and/or well- Corresponding author: Leona A. Doyle, MD, Department of Pathology, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115; Fax: (617) ; ladoyle@partners.org Department of Pathology, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts. DOI: /cncr.28657, Received: January 21, 2014; Accepted: February 10, 2014, Published online March 19, 2014 in Wiley Online Library (wileyonlinelibrary. com) Cancer June 15,

2 TABLE 1. Key Changes and Updates in the 2013 WHO Classification of Tumors of Soft Tissue Tumor Category Major Changes and Updates Adipocytic Classification changes Round cell liposarcoma removed as a synonym for high-grade myxoid liposarcoma. Mixed-type liposarcoma removed. Recurrent translocation t(11;16)(q13;p13) in chondroid lipoma. Fibroblastic/ myofibroblastic Classification changes DFSP and giant cell fibroblastoma included for first time. Hemangiopericytoma removed as a synonym for SFT. MYH9-USP6 fusion gene in nodular fasciitis. NAB2-STAT6 fusion gene in SFT. Recognition of molecular and morphologic overlap of LGFMS and SEF; MUC4 overexpression in LGFMS and SEF. So-called fibrohistiocytic Classification changes Malignant fibrous histiocytoma removed from WHO classification. Smooth muscle Classification changes Angioleiomyoma moved to pericytic category. Pericytic Classification changes Angioleiomyoma now classified as a pericytic tumor. Myofibroma now classified as a pericytic tumor, on a spectrum with myopericytoma. NOTCH2/3 mutations in a subset of glomus tumors. Skeletal muscle Classification changes Spindle cell/sclerosing rhabdomyosarcoma now classified together and separate from other subtypes. Rearrangement of NCOA2 gene in pediatric cases of spindle cell rhabdomyosarcoma. MYOD1 mutations in a subset of adult spindle cell rhabdomyosarcoma. Vascular Classification changes New entity: pseudomyogenic/epithelioid sarcoma-like hemangioendothelioma, with recurrent translocation t(7;19) resulting in SERPINE1-FOSB fusion gene. Recurrent fusion genes in epithelioid hemangioendothelioma: WWTR1-CAMTA1 and YAP1-TFE3. Amplification of MYC in postradiation angiosarcoma. Chondroosseous Classification changes/ None. new genetics Gastrointestinal stromal Classification changes GIST included in soft tissue volume for first time. Recognition of the clinicopathologically and genetically distinct group of succinate dehydrogenase-deficient GIST. Nerve sheath Classification changes Peripheral nerve sheath tumors included in soft tissue volume for first time. Newly described hybrid benign nerve sheath tumors included (eg, hybrid schwannoma/perineurioma). Tumors of uncertain differentiation Undifferentiated/ unclassified sarcoma Classification changes Classification changes Newly described entities: acral/digital fibromyxoma, hemosiderotic fibrolipomatous tumor, phosphaturic mesenchymal tumor. Atypical fibroxanthoma now included in soft tissue volume. PNET removed as a synonym for Ewing sarcoma. EWSR1 gene rearrangement in myoepithelial carcinoma. PHF1 gene rearrangement in ossifying fibromyxoid tumor. This new category recognizes tumors that cannot be classified into any of the other categories. A subset of undifferentiated round cell (non-ewing) sarcomas harbor CIC-DUX4 or BCOR-CCNB3 fusion genes. Abbreviations: BCOR, BCL6 corepressor; CAMTA1, calmodulin-binding transcription activator 1; CCNB3, cyclin B1; CIC, capicua transcriptional repressor; DFSP, dermatofibrosarcoma protuberans; DUX4, double homeobox, 4; EWSR1, EWS RNA-binding protein 1; FOSB, FBJ murine osteosarcoma viral oncogene homolog B; GIST, gastrointestinal stromal tumor; LGFMS, low-grade fibromyxoid sarcoma; MUC4, mucin-4; MYH9, myosin, heavy chain 9, non-muscle; MYOD1, myogenic differentiation 1; NAB2, NGFI-A binding protein 2; NCOA2, nuclear receptor coactivator 2; NOTCH, neurogenic locus notch homolog protein; PHF1, PHD finger protein 1; PNET, primitive neuroectodermal tumor; SEF, sclerosing epithelioid fibrosarcoma; SERPINE1, serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1); SFT, solitary fibrous tumor; STAT6; signal transducer and activator of transcription 6; TFE3, transcription factor binding to IGHM enhancer 3; USP6, ubiquitin carboxyl-terminal hydrolase 6; WHO, World Health Organization; WWTR1, WW domain containing transcription regulator 1; YAP1, yes-associated protein 1. differentiated/dedifferentiated and/or pleomorphic liposarcoma. However, consensus opinion acknowledges that tumors showing such a mixed pattern most likely represent dedifferentiated liposarcoma. For those rare cases of liposarcoma that cannot be subclassified, the term liposarcoma not otherwise specified is retained as an International Classification of Diseases code. The definition of dedifferentiated liposarcoma has been modified slightly from its prior definition as a nonlipogenic sarcoma arising in association with welldifferentiated liposarcoma/atypical lipomatous tumor, to recognize that a small subset of cases may in fact demonstrate lipoblastic differentiation within the dedifferentiated component (ie, rare cases may be lipogenic ). This 1764 Cancer June 15, 2014

3 WHO Update of Sarcoma Classification/Doyle TABLE 2. Key Changes and Updates in the 2013 WHO Classification of Tumors of Bone Tumor Category Major Changes and Updates Chondrogenic Classification changes New entity: osteochondromyxoma (associated with Carney complex) included. Atypical cartilaginous tumor introduced as synonym for grade 1 chondrosarcoma. IDH1/2 mutations in enchondroma, periosteal chondroma and chondrosarcoma. HEY1-NCOA2 fusion gene in mesenchymal chondrosarcoma. Osteogenic Classification changes Osteoma separated from osteoid osteoma. Amplification of MDM2 and CDK4 in low-grade central and paraosteal osteosarcomas, and less often in conventional osteosarcoma. Fibrogenic Classification changes Fibrosarcoma strictly defined to exclude cases demonstrating any recognizable line of differentiation other than fibroblastic. Fibrohistiocytic Classification changes Malignant fibrous histiocytoma removed. Ewing sarcoma Classification changes PNET removed as a synonym for Ewing sarcoma. A subset of undifferentiated round cell (non-ewing) sarcomas harbor CIC-DUX4 or BCOR-CCNB3 fusion genes. Osteoclastic giant cell-rich Classification changes Giant cell tumor of bone is separated from giant cell lesion of the small bones. Notochordal Classification changes Benign notochordal cell tumor added. Copy number gain of brachyury in chordoma. Vascular Classification changes Epithelioid hemangioma added as a new entity and distinguished from hemangioma. Epithelioid hemangioendothelioma now included. Recurrent fusion genes in epithelioid hemangioendothelioma: WWTR1-CAMTA1 and YAP1-TFE3. Myogenic, lipogenic, Classification changes Leiomyoma and schwannoma removed. and epithelial Tumors of undefined neoplastic nature Classification changes Chondromesenchymal hamartoma is new designation for tumors previously classified as chest wall hamartoma. USP6 gene rearrangement in 70% of primary aneurysmal bone cyst, usually due to t(16;17)(q22;p13), and not present in secondary aneurysmal bone cyst. Undifferentiated high-grade pleomorphic sarcoma Classification changes This new category recognizes pleomorphic sarcomas that cannot be classified into any of the other categories. Abbreviations: BCOR, BCL6 corepressor; CAMTA1, calmodulin-binding transcription activator 1; CCNB3, cyclin B1; CDK4; cyclin-dependent kinase 4; CIC, capicua transcriptional repressor; DUX4, double homeobox, 4; HEY1, hairy/enhancer-of-split related with YRPW motif 1; IDH, isocitrate dehydrogenase; MDM2, mouse double minute 2 homolog; NCOA2, nuclear receptor coactivator 2; PNET, primitive neuroectodermal tumor; TFE3, transcription factor binding to IGHM enhancer 3; USP6, ubiquitin carboxyl-terminal hydrolase 6; WHO, World Health Organization; WWTR1, WW domain containing transcription regulator 1; YAP1, yes-associated protein 1. finding is referred to as dedifferentiated liposarcoma with homologous lipoblastic differentiation or pleomorphic liposarcoma-like features. 6,7 Fibroblastic/Myofibroblastic Tumors Dermatofibrosarcoma protuberans and the closely related giant cell fibroblastoma were included in the 2013 classification; they were previously described in the WHO volume on skin tumors. Both these tumors harbor rearrangements of chromosomes 17 and 22, which result in the formation of the chimeric gene PDGFB-COL1A1 (platelet-derived growth factor beta polypeptide-collagen, type I, alpha 1). Hybrid tumors demonstrating histologic features of each exist, confirming their shared biologic origin. Dermatofibrosarcoma protuberans is categorized as a rarely metastasizing (intermediate) tumor, although it should be noted that metastatic potential is gained only when a component of fibrosarcomatous change is present. Giant cell fibroblastoma is classified in the locally aggressive (intermediate) category because it recurs in approximately 50% of cases, but does not metastasize. The subcategory of hemangiopericytoma has been removed from the classification of extrapleural solitary fibrous tumor (SFT) because it is now well established that this outdated term included tumors that represented cellular examples of SFT, as well as other distinct tumor types that may histologically resemble SFT. A recurrent intrachromosomal rearrangement on chromosome 12q that leads to the formation of a NAB2-STAT6 (NGFI-A binding protein 2-signal transducer and activator of transcription 6) fusion oncogene was identified in SFT (including malignant and dedifferentiated tumors, and tumors at various anatomic locations) in 2013, just after the publication of the current WHO volume This finding has led to the recognition that so-called meningeal hemangiopericytoma is in fact SFT arising in the meninges. 11 Nuclear expression of STAT6, a transcription factor and one of the Cancer June 15,

4 Figure 1. Sclerosing rhabdomyosarcoma composed of round tumor cells with minimal cytoplasm embedded within a densely sclerotic stroma; dyshesion between tumor cells may result in a pseudovascular growth pattern. fusion gene partners, has proven to be an extremely useful immunohistochemical marker for SFT. 12 The synonym atypical myxoinflammatory fibroblastic tumor was introduced for myxoinflammatory fibroblastic sarcoma. This is to reflect the extremely low risk of metastasis for this tumor type. The 2013 WHO classification recognizes the close relationship between low-grade fibromyxoid sarcoma (LGFMS) and a subset of sclerosing epithelioid fibrosarcoma (SEF). Both are malignant neoplasms that demonstrate fibroblastic differentiation and that show overlapping immunohistochemical and molecular genetic features. Hybrid tumors that demonstrate histologic features of both tumor types exist. The t(7;16)(q33;p11) that results in a FUS-CREB3L2 (camp responsive element binding protein 3-like 2) fusion gene in approximately 90% of LGFMS cases is also found in a subset of SEF. 13,14 In some cases, EWSR1 acts as an alternate fusion partner to FUS; this is more common in SEF or hybrid tumors than in pure LGFMS, and CREB3L1 is usually the fusion partner with EWSR1 in these cases MUC4 (mucin-4) is a newly described immunohistochemical marker identified through gene expression profiling that has proven to be highly sensitive and specific for LGFMS and SEF. 15,19,20 Despite histologic and genetic similarities, the clinical course of LGFMS and SEF differ somewhat. Early recurrence of LGFMS is uncommon, and metastasis of LGFMS often occurs many years after the initial diagnosis, with long-term follow-up metastatic rates of approximately 50%. Multiple recurrences of SEF are common and occur in approximately 50% of patients. Metastasis of SEF is frequent, developing in up to 80% of patients, typically to the lung, bone, and brain, and usually occurs earlier than in patients with LGFMS. Finally, although a benign tumor, the recent identification of a recurrent MYH9-USP6 (myosin, heavy chain 9, non-muscle ubiquitin carboxyl-terminal hydrolase 6) fusion gene in nodular fasciitis due to a translocation between chromosomes 17p13 and 22q13.1 is of particular interest. 21 Nodular fasciitis was previously believed to be a reactive process, but the finding of this recurrent translocation supports the theory that it is in fact an example of a self-limiting neoplasm, given that the natural history of nodular fasciitis is spontaneous regression. So-Called Fibrohistiocytic Tumors The category of malignant fibrous histiocytoma was deleted from the 2013 WHO classification, reflecting the outdated terminology that formerly included many tumors that can now be accurately classified as specific sarcoma types. Unclassified/undifferentiated sarcomas are now classified separately (see below). Smooth Muscle Tumors The only change in this group was the removal of angioleiomyoma, which is now included in the category of pericytic tumors. Skeletal Muscle Tumors The category of spindle cell/sclerosing rhabdomyosarcoma was separated from embryonal rhabdomyosarcoma, with the recognition that the spindle cell and sclerosing subtypes share a spectrum of morphologic appearances and lack genetic changes typically observed in either embryonal or alveolar rhabdomyosarcoma (Fig. 1). Even since the publication of the 2013 WHO classification, new insights into the biology of these tumors has emerged. Rearrangement of the NCOA2 (nuclear receptor coactivator 2) gene has been identified in pediatric cases of spindle cell rhabdomyosarcoma, but not in adult cases. 25 Mutations in MYOD1 (myogenic differentiation 1), a transcription factor involved in skeletal muscle differentiation,havebeenidentifiedin40%ofadultspindlecell rhabdomyosarcomas. 26 The prognosis of spindle cell rhabdomyosarcoma in adults is worse than in children, and recent insights into the genetics of this tumor suggest that there may be underlying genetic differences between pediatric and adult cases Cancer June 15, 2014

5 WHO Update of Sarcoma Classification/Doyle Figure 2. Pseudomyogenic hemangioendothelioma often presents with multiple discontiguous nodules and may involve bone. (A) This coronal T2 fat-suppressed magnetic resonance image of the left arm shows a T2 hyperintense enhancing lesion in the distal radius with cortical disruption and a soft tissue component (white arrow); additional lesions are observed in the radial head and proximal ulna (black arrows). (B) The tumor is composed of spindled-shaped tumor cells with abundant eosinophilic cytoplasm reminiscent of smooth muscle differentiation. (C) ERG, a marker of endothelial differentiation, is positive in tumor cells. Magnetic resonance image courtesy of Dr. Jyothi Jagannathan of the Dana-Farber Cancer Institute, Boston, Massachusetts. Vascular Tumors A newly recognized entity designated pseudomyogenic hemangioendothelioma (and also known as epithelioid sarcoma-like hemangioendothelioma ) was included in this category. 27,28 This tumor is classified as a rarely metastasizing endothelial neoplasm. The name reflects the histologic appearance of spindle-shaped cells with bright eosinophilic cytoplasm that appear myoid, but the tumor cells express endothelial markers and are consistently negative for desmin (Fig. 2). This tumor most commonly arises in young adult males, and often presents as multiple discontiguous nodules in different tissue planes of a limb, and may involve the skin as well as deep soft tissues and bone. Pseudomyogenic hemangioendothelioma tends to be highly [ 18 F]fluorodeoxyglucose (FDG)-avid, and therefore positron emission tomography scan is useful for the detection of deep lesions. A recurrent translocation t(7;19)(q22;q13) is present in this tumor type and results in the formation of the very recently recognized fusion gene SERPINE1-FOSB (serpin peptidase inhibitor, clade E [nexin, plasminogen activator inhibitor type 1]-FBJ murine osteosarcoma viral oncogene homolog B). 29 The clinical course of patients with pseudomyogenic hemangioendothelioma is characterized by repeated local recurrences or the development of new tumor nodules within the same anatomical region, but metastasis is very rare. The relationship between margin status and risk of disease recurrence has not been established, and at this point conservative management is the treatment of choice. The classification of angiosarcoma and epithelioid hemangioendothelioma (EHE) has remained the same. However, new insights into the molecular genetics of these tumors warrant mention. Recurrent fusion genes have been identified in EHE, specifically WWTR1- Cancer June 15,

6 CAMTA1 (WW domain containing transcription regulator 1 calmodulin-binding transcription activator 1), which results from a t(1;3)(p36.3;q25) translocation and is the most common fusion gene in EHE, 30,31 and less commonly YAP1-TFE3 (yes-associated protein 1- transcription factor binding to IGHM enhancer 3), 32 which occurs in tumors from young adults and is associated with distinctive morphologic findings such as the formation of well-formed vascular channels and voluminous eosinophilic cytoplasm. Furthermore, by analyzing breakpoints in these genes, it has been shown that multifocal EHE most likely arises as a result of metastatic disease rather than representing synchronous primary tumors as previously thought. 33 The presence of MYC amplification in post-radiation angiosarcomas was described within the last few years, and the detection of MYC overexpression at the protein level has proved to be a useful immunohistochemical tool for distinguishing angiosarcoma from atypical postradiation vascular proliferations, which are negative for MYC. 34,35 Figure 3. (A) Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor demonstrating a characteristic multinodular growth pattern on low power. (B) Tumor cells are usually epithelioid, and lack expression of SDHB, in contrast to surrounding normal endothelial cells and lymphocytes, which show retained cytoplasmic expression of SDHB (C). Gastrointestinal Stromal Tumor For the first time, gastrointestinal stromal tumor (GIST) is now included in the WHO soft tissue classification; it previously was part of the volume of WHO Tumors of the Digestive System. The most notable change in the classification of GIST is the recognition of the category of succinate dehydrogenase (SDH)-deficient GIST. Tumors in this group are wild-type for KIT and PDGFRA mutations, and demonstrate loss of expression of the SDH complex, subunit B (SDHB) protein immunohistochemically, which reflects dysfunction of the SDH enzyme complex of the Krebs cycle This dysfunction may arise due to the presence of mutations in any of the 4 SDH subunit genes (namely SDHA, SDHB, SDHC, and SDHD) which can be detected by sequencing methods, but can also occur in the absence of demonstrable mutations due to as yet unknown mechanisms. Mutations in SDHA appear to be the most common mutation in SDHdeficient GIST in adults (present in 35% of cases), and can be confirmed by the additional loss of expression of SDHA protein by immunohistochemistry Clinically, these tumors always arise in the stomach, especially the antrum, where they may be multifocal, and often spread to lymph nodes, which is an extremely uncommon pattern of spread in KIT- or PDGFRA-mutant GIST. Histologically, SDH-deficient GISTs demonstrate a distinctive multinodular growth pattern and are usually purely epithelioid or mixed epithelioid and spindle cell type (Fig. 3). The clinical course tends to be 1768 Cancer June 15, 2014

7 WHO Update of Sarcoma Classification/Doyle indolent, even in the presence of metastatic disease. Standard risk stratification criteria for assessing the malignant potential of GISTs (ie, evaluation of mitotic activity and tumor size) do not predict the clinical behavior of this subtype. 37,43,44 It is important to note that SDHdeficient GISTs are imatinib-resistant, but may respond better to second-generation and third-generation tyrosine kinase inhibitors such as sunitinib, sorafenib, nilotinib, and dasatinib. 37,45,46 The diagnosis of SDH-deficient GIST is important not only because of the prognostic and predictive information mentioned above, but also because of its syndromic associations. While SDH-deficient GISTs may arise sporadically in adults and represent the vast majority of pediatric GIST cases, they also occur in the setting of the Carney triad (GIST, paraganglioma/pheochromocytoma, and pulmonary chondroma) and Carney-Stratakis syndrome (GIST and paraganglioma/pheochromocytoma). For this reason, it is recommended that all patients with SDH-deficient GIST be referred for genetic counseling. In addition, in many cases, GIST is the sentinel tumor in these syndromes, and the time interval before the development of a second tumor may be delayed by many years; long-term clinical follow-up for the development of additional gastric GISTs or other tumor types is therefore warranted for all patients with SDH-deficient GIST. The frequency of SDH-deficient tumors among all gastric GISTs is estimated to be 7.5%. 43 Nerve Sheath Tumors For the first time, nerve sheath tumors (including both benign and malignant peripheral nerve sheath tumors) are now included in the WHO soft tissue classification. Although several newly described histological variants of benign peripheral nerve sheath tumors have been included, there have been no changes to the classification of malignant peripheral nerve sheath tumors. Tumors Of Uncertain Differentiation There were 2 new additions to this category. The first is hemosiderotic fibrolipomatous tumor (HFLT), a locally aggressive neoplasm that typically arises in middleaged women, most commonly around the ankle or wrist. HFLT is an unencapsulated lesion composed of adipocytes, hemosiderin-laden spindle cells, and chronic inflammatory cells, which impart a yellow-brown color grossly. These lesions may reach large sizes, and the rate of local recurrence approaches 50% if they are incompletely excised. 47,48 With complete excision, the recurrence rate is low. It is interesting to note that HFLT demonstrates the same translocation t(1;10)(p22;q24) noted in myxoinflammatory fibroblastic sarcoma (MIFS), a rarely metastasizing lesion that is included in the category of fibroblastic tumors Tumors demonstrating hybrid features of both these entities exist, suggesting a close biological relationship between HFLT and MIFS. The second addition to this category is phosphaturic mesenchymal tumor (PMT), which is classified as a rarely metastasizing lesion. PMT is an extremely rare but clinically and histologically distinctive tumor. The tumor produces fibroblast growth factor 23, a hormone that inhibits renal proximal tubule phosphate reuptake, resulting in phosphaturia and tumor-induced osteomalacia. 52 Clinically, elevated serum levels of fibroblast growth factor 23 can be demonstrated in the majority of patients with PMT. Although most of these lesions are benign, disease recurrence is common with incomplete excision, and rare malignant cases with metastasis occur. 53 Complete excision leads to the resolution of osteomalacia. The term primitive neuroectodermal tumor (PNET) has been removed as a synonym for Ewing sarcoma. This is to minimize confusion with the histologically and genetically different, but similarly named, PNET of the central nervous system and female genital tract. Undifferentiated/Unclassified Sarcoma This category of tumors is new to the 2013 WHO classification, and recognizes those tumors that cannot be classified into any of the other categories due to lack of a demonstrable line of differentiation or lack of distinguishing histologic, immunohistochemical, or genetic features. Tumors in this category may have spindled, epithelioid, pleomorphic, or round cell morphology. 54 Interestingly, it has been very recently recognized that a subset of otherwise undifferentiated round cell (non- Ewing) sarcomas harbor CIC-DUX4 or BCOR-CCNB3 fusion genes, suggesting that some of these undifferentiated/unclassified sarcomas will in time be recognized as genetically distinct tumor types. Although the number of reported cases is small, round cell sarcomas with the CIC-DUX4 fusion gene are more common in males, demonstrate variable expression of CD99, and arise in soft tissues more often than in bone (Fig. 4) Round cell sarcomas with the BCOR-CCNB3 fusion gene typically arise in bone, but may also arise in soft tissues and also demonstrate variable expression of CD Data regarding these tumor types are still emerging, but at this time it appears that they are best managed with systemic chemotherapy in addition to locoregional treatment, similar to Ewing sarcoma. Cancer June 15,

8 Figure 4. Round cell sarcoma with the CIC-DUX4 fusion gene is composed of round to ovoid tumor cells with amphophilic cytoplasm and variably prominent nucleoli. (B) CD99 may demonstrate patchy expression, in contrast to the diffuse membranous pattern characteristic of Ewing sarcoma. Case courtesy of Dr. Christopher Fletcher of Brigham and Women s Hospital, Boston, Massachusetts. BONE TUMORS Chondrogenic Tumors A new addition to this category is osteochondromyxoma, a benign but locally aggressive tumor that demonstrates both osteoid and chondroid production. 62 This rare tumor arises in approximately 1% of patients with Carney complex. Sites of involvement include the tibia and sinonasal bones, and destructive growth with extension into soft tissue can occur. Disease recurrence is more likely at sites where complete resection is difficult; metastases have not been reported. Chondrosarcoma is now separated into two International Classification of Diseases codes, which reflects the different prognosis of chondrosarcoma based on grade, with grade 1 distinguished from cases of grade 2 and grade 3 chondrosarcoma. In addition, the synonym atypical cartilaginous tumor was introduced for grade 1 chondrosarcoma. These tumors are locally aggressive but metastasize only extremely rarely; the 5-year survival rate is 83%, with death from disease occurring due to uncontrollable tumor growth, especially in patients with pelvic tumors. 63,64 Curettage/simple excision alone is considered adequate treatment. For those tumors that recur, approximately 10% demonstrate an increase in cellularity warranting a change in grade. In contrast, grade 2 and 3 chondrosarcomas frequently metastasize and have a 5-year survival rate of 53%; en bloc resection is recommended for this group of patients. Tumors should be graded based on the area of highest histologic grade in cases in which variable histologic grades exist within the same tumor. Minor clarifications and expansions to the definitions of chondrosarcoma were as follows: primary central chondrosarcoma (chondrosarcoma arising centrally in bone without a benign precursor); secondary central chondrosarcoma (chondrosarcoma arising centrally in bone in a preexisting enchondroma); and secondary peripheral chondrosarcoma (chondrosarcoma arising in association with the cartilaginous cap of osteochondroma). The classification of periosteal, dedifferentiated, clear cell, and mesenchymal chondrosarcoma remains unchanged. The most significant new genetic finding in chondrosarcoma is the recognition of mutations in the isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) genes, which code for the metabolic enzymes IDH1 and IDH2 that are now recognized to play a role in tumorigenesis. IDH1 and IDH2 mutations are present in up to 70% of primary central chondrosarcomas, 80% of secondary central chondrosarcomas, virtually all periosteal chondrosarcomas, and 50% of dedifferentiated chondrosarcomas. 65,66 These mutations also occur in enchondroma, both the sporadic type and those associated with Ollier disease and Maffucci syndrome. 67 A recurrent fusion gene, HEY1-NCOA2 (hairy/ enhancer-of-split related with YRPW motif 1-NCOA2), has been identified in mesenchymal chondrosarcoma. 68 Given the close proximity of these 2 genes on chromosome 8, this fusion most likely results from a small interstitial deletion between these loci. Osteogenic Tumors The only change in the classification of osteogenic tumors is the incorporation of secondary osteosarcoma into the category of conventional osteosarcoma for descriptive 1770 Cancer June 15, 2014

9 WHO Update of Sarcoma Classification/Doyle purposes. Conventional osteosarcoma is subclassified based on histologic features (eg, osteoblastic, chondroblastic), but there remains no relationship between the subtype of conventional osteosarcoma and treatment and prognosis, in contrast to other types of osteosarcoma. Amplification of mouse double minute 2 homolog (MDM2) and cyclin-dependent kinase 4 (CDK4) have now been well documented in low-grade central osteosarcoma and paraosteal osteosarcoma, and immunohistochemistry for these 2 markers can be a helpful tool, especially in those cases that have undergone dedifferentiation to a high-grade osteosarcoma and in which recognition of the precursor low-grade lesion is difficult clinically or pathologically. 69,70 Fibrogenic Tumors The definition of fibrosarcoma of bone is clarified as an intermediate- to high-grade spindle cell malignant neoplasm that lacks significant pleomorphism and lacks any line of differentiation other than fibroblastic. This clarification addresses several issues. First, although historically the classification of fibrosarcoma of bone was used relatively commonly, it is now recognized that a fascicular or herringbone pattern of growth may be observed in many different tumor types that can be classified in other specific diagnostic categories. 71 Second, this pattern of growth may also be seen in otherwise unclassified high-grade pleomorphic sarcomas, and if significant pleomorphism is present the tumor is best classified as the latter. Fibrosarcoma of bone is therefore a diagnosis of exclusion, and the diagnosis cannot be made on limited biopsy samples, because thorough sampling is needed to exclude other lines of differentiation. The incidence of fibrosarcoma is likely much less than the 5% documented in the prior WHO classification. Fibrohistiocytic Tumors Similar to soft tissue tumor classification, the category of malignant fibrous histiocytoma of bone has been removed from the 2013 classification of bone tumors. Ewing Sarcoma The term PNET has been removed as a synonym for Ewing sarcoma, as previously discussed. Of round cell sarcomas of bone that do not fulfill criteria for Ewing sarcoma, 2 genetically distinct groups of tumors have been recognized that harbor CIC-DUX4 (Fig. 4) or BCOR-CCNB3 fusion genes; these tumors are discussed in the section on undifferentiated sarcomas of soft tissues above. Osteoclastic Giant Cell-Rich Tumors In this category, giant cell tumor of bone is now separated from giant cell lesion of the small bones. Giant cell lesion of the small bones is a very rare tumor-like lesion that arises in the small bones of the hands and feet and commonly recurs after initial curettage, but is almost always cured after the second excision. Giant cell tumor of bone is a locally aggressive neoplasm that may very rarely metastasize or undergo malignant transformation into a high-grade sarcoma, either de novo or after radiotherapy. Notochordal Tumors Benign notochordal cell tumor was added to this category, which previously only included chordoma. This benign tumor may represent persistent notochord rather than a true neoplastic proliferation; benign notochordal cell tumor arises at the base of skull, vertebral bodies, and sacrococcygeal bones and is usually an incidental finding. Vascular Tumors Hemangioma (a benign tumor composed of capillary-like blood vessels most commonly involving vertebral bones, with a low rate of local recurrence) is separated from epithelioid hemangioma, a recently characterized locally aggressive neoplasm composed of small vessels lined by epithelioid endothelial cells. Epithelioid hemangioma most often arises in long tubular bones, followed by flat bones and vertebrae. 72 In contrast to conventional hemangioma, epithelioid hemangioma is locally aggressive: recurrence occurs in approximately 10% of cases. Treatment consists primarily of curettage, and less often local resection. Epithelioid hemangioma should also be distinguished from EHE, which is classified separately in this category. EHE is a malignant neoplasm that demonstrates endothelial differentiation, and the mainstay of treatment is wide resection. The mortality rate is approximately 20% and histologic features do not predict the development of metastases. As discussed in the section on soft tissue tumors, very recent work has identified recurrent fusion genes in EHE, namely WWTR1-CAMTA1 and YAP1-TFE3. These fusion genes are not present in angiosarcoma or benign vascular tumors. There are no significant updates to the classification of angiosarcoma of bone. Undifferentiated High-Grade Pleomorphic Sarcoma High-grade pleomorphic malignant tumors that lack a specific line of differentiation are classified as undifferentiated high-grade pleomorphic sarcoma. This diagnosis is one of exclusion, and thorough sampling is needed to exclude osteoid deposition, which would Cancer June 15,

10 necessitate a diagnosis of osteosarcoma, as well as other histologic features that may suggest a specific diagnosis. 71 Tumors in this category have a metastatic rate of at least 50%. Treatment generally involves neoadjuvant therapy followed by wide excision for potentially resectable lesions. Similar to osteosarcoma, the degree of tumor necrosis after neoadjuvant chemotherapy is an important prognostic factor. 73 Conclusions Since the publication of the prior WHO Classification of Tumors of Soft Tissue and Bone 11 years ago, new clinicopathologic and genetic features of many soft tissue and bone tumors have been characterized, which has led to more reproducible classifications of these tumors and therefore more effective treatment stratification. This has also allowed wastebasket diagnostic categories and obsolete tumor types such as hemangiopericytoma and socalled malignant fibrous histiocytoma to be removed from the 2013 WHO classification. In addition, several new entities have been included for the first time in this volume. Huge advances have been made, and continue to be made at an ever-increasing pace, in defining the genetic basis of both benign and malignant mesenchymal tumors; these findings and the major classification changes in the current 2013 WHO classification have been reviewed in this article, along with new genetic data that have emerged even since the publication of the current volume. FUNDING SUPPORT No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. REFERENCES 1. Fletcher CD, Hogendoorn P, Mertens F, Bridge J. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press; Fletcher CDM, Unni KK, Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. 3rd ed. Lyon, France: IARC Press; Antonescu CR, Tschernyavsky SJ, Decuseara R, et al. 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