Histopathology 2014, 64, 2–11. DOI: 10.1111/his.12267

REVIEW

The evolving classification of soft tissue tumours – an update based on the new 2013 WHO classification Christopher D M Fletcher1,2 1

Department of Pathology, Brigham and Women’s Hospital, and 2Department of Pathology, Harvard Medical School, Boston, MA, USA

Fletcher C D M (2014) Histopathology 64, 2–11

The evolving classification of soft tissue tumours – an update based on the new 2013 WHO classification The new World Health Organization (WHO) classification of soft tissue tumours was published in early 2013, almost 11 years after the previous edition. While the number of newly recognized entities included for the first time is fewer than that in 2002, there have instead been substantial steps forward in molecular genetic and cytogenetic characterization of this family of tumours, leading to more reproducible diagnosis, a more meaningful classification scheme

and providing new insights regarding pathogenesis, which previously has been obscure in most of these lesions. This brief overview summarizes changes in the classification in each of the broad categories of soft tissue tumour (adipocytic, fibroblastic, etc.) and also provides a short summary of newer genetic data which have been incorporated in the WHO classification.

Keywords: sarcoma, soft tissue, tumour, WHO

Introduction The previous WHO classification of tumors of soft tissue and bone was published in 20021 when, for the first time, extensive genetic data were incorporated, the concepts of so-called ‘malignant fibrous histiocytoma’ and ‘haemangiopericytoma’ began to be dismantled, and a very striking array of newly recognized ‘entities’ were included for the first time. The quite dramatic changes in the 2002 edition reflected the ever-increasing influence of immunohistochemistry, cytogenetics and molecular genetics in our better understanding and classification of this group of tumours. The changes in the 2013 classification2 are somewhat less dramatic, but nevertheless very significant, and these represent important steps forward in our understanding of the biology as well as the reproAddress for correspondence: C D M Fletcher MD, FRCPath, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. e-mail: [email protected] © 2013 John Wiley & Sons Ltd.

ducible diagnosis of this complex group of tumour types. The new classification also now incorporates gastrointestinal stromal tumours (formerly included in ‘Tumours of digestive system’) and peripheral nerve sheath tumours (some of which were included previously in ‘Tumours of the nervous system’ and Tumours of the skin’). Overall, the WHO felt that these groups of lesions fitted better under the heading of ‘Soft tissue tumours’, and this allows a more comprehensive classification. This brief overview deals with each broad group of tumours, focusing on major and minor changes in each category. ADIPOCYTIC TUMOURS

There have been minimal changes in this group of soft tissue tumours, principal among which has been deletion of the term ‘round cell liposarcoma’, which is nowadays fully understood to simply represent high-grade myxoid liposarcoma. Only a subset of these tumours truly has round cell morphology and,

WHO classification 2013

instead, high-grade myxoid liposarcoma is characterized more often by substantially increased cellularity of either spindle or round cell shape. The other minor change was deletion of the category of ‘mixed-type liposarcoma’ – the consensus view is that such lesions probably do not exist, but instead represent unusual morphological patterns of de-differentiated liposarcoma. At least for coding purposes, a category of liposarcoma NOS is retained for the rare cases that cannot be subclassified otherwise. FIBROBLASTIC/MYOFIBROBLASTIC TUMOURS

An important step forward in the category of benign fibroblastic/myofibroblastic lesions has been the recognition that nodular fasciitis (Figure 1), and therefore by analogy its variants proliferative fasciitis and proliferative myositis, are in fact neoplastic. Prior to this 2013 edition, the nosological status of these lesions was uncertain, and many people had believed that they were reactive, despite the usual absence of any history of local trauma. However, it is appreciated nowadays that these lesions have a consistent gene fusion, MYH9–USP6, indicating that they are clonal neoplasms.3 Identification of this fusion gene allowed the allocation of an ICD-O code for these tumours for the very first time. Interestingly, structurally related USP6 fusion genes have been identified previously in aneurysmal bone cyst,4 also long viewed as a reactive process by many bone pathologists. Other changes in the fibroblastic/myofibroblastic category were the inclusion of the closely related enti-

Figure 1. Typical example of nodular fasciitis, long thought to be a reactive process despite any evident predisposing cause, now known to be a true neoplasm. © 2013 John Wiley & Sons Ltd, Histopathology, 64, 2–11.

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ties giant cell fibroblastoma and dermatofibrosarcoma protuberans (DFSP), formerly included in the skin volume. Giant cell fibroblastoma was included in the intermediate (locally aggressive) category, while dermatofibrosarcoma protuberans was included in the intermediate (rarely metastasizing) category. Such metastasis, for practical purposes, occurs only after transformation to the higher-grade fibrosarcomatous variant. One additional small change, forced mainly on the basis of ICD coding considerations, given the extreme rarity of metastasis in tumours of this type, was introduction of the synonym ‘atypical myxoinflammatory fibroblastic tumour’ for lesions known most often as myxoinflammatory fibroblastic sarcoma. It is recognized nowadays that distant metastasis in these tumours is vanishingly rare, as is also the case in conventional DFSP. An important new conceptual shift has been the realization that, at least in a substantial proportion of cases, there is a close relationship between low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF), the majority of which share FUS gene rearrangement.5,6 It has also been appreciated that one may see tumours showing hybrid morphological features of SEF and LGFMS (Figure 2). The precise nosological status of cases of SEF which lack FUS gene rearrangement remains to be determined.6,7 SO-CALLED FIBROHISTIOCYTIC TUMOURS

The major but not unexpected change here has been the final removal of the term ‘malignant fibrous histiocytoma’ which, in the 2002 edition, was admitted

Figure 2. This thigh mass from an adult patient shows hybrid morphological features of sclerosing epithelioid fibrosarcoma (left) and low-grade fibromyxoid sarcoma (right).

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to be a diagnosis of exclusion, synonymous with undifferentiated pleomorphic sarcoma. Such lesions, without using the outdated terminology, are now included in the quite separate and new category of undifferentiated/unclassified sarcomas (see below).

A

SMOOTH MUSCLE TUMOURS

There were no major changes in this category, except for the fact that angioleiomyoma (vascular leiomyoma) was reallocated to the category of pericytic (perivascular) tumours (see below). PERICYTIC (PERIVASCULAR) TUMOURS

In the 2002 classification, the group of myopericytomas had been incorporated under this heading for the first time (at the same time as haemangiopericytoma had been removed and listed as a synonym for solitary fibrous tumour). In the new classification, it is now acknowledged that myofibroma/myofibromatosis also represent morphological points along the spectrum of myopericytic neoplasms, while the term ‘myofibroma’ can still prove to be useful in describing that subset of perivascular lesions which show predominantly myofibroblastic-like cytomorphology and prominent stromal hyalinization. Included for the first time under this general heading are the common angioleiomyomas (vascular leiomyomas), occurring typically as painful lesions in the distal extremities of middle-aged adults. These lesions are characterized by smooth muscle cells proliferating concentrically around vascular channels, and they also form a morphological continuum with the myoid end of the spectrum of myopericytomas. As yet there are only very limited molecular genetic data concerning the family of pericytic (perivascular) tumours, but this gap is already beginning to be filled, even since the conclusion of the new classification, with increasing data emerging regarding the role(s) of mutations in BRAF, NF1, NOTCH2 and NOTCH3.8–10 Ultimately, this group of tumours may end up being renamed ‘haemangiopericytoma’ – but the latter can only happen once the loosely used understanding of haemangiopericytoma (which was a wastebasket diagnosis for many years) has been overcome. SKELETAL MUSCLE TUMOURS

The one principal change in this group of lesions has been the recognition that spindle cell rhabdomyosarcoma is related very closely to sclerosing rhabdomyosarcoma (Figure 3) and that neither of these lesions

B

Figure 3. Spindle cell rhabdomyosarcoma often mimics other types of fascicular spindle cell sarcoma (A). This lesion shows areas of transition to sclerosing rhabdomyosarcoma (B), underlining the close relationship between these two variants of rhabdomyosarcoma.

is truly related to embryonal rhabdomyosarcoma. Spindle cell rhabdomyosarcoma had been regarded previously as a variant of embryonal rhabdomyosarcoma, based on its generally very good prognosis. However, neither spindle cell nor sclerosing rhabdomyosarcoma shows any genetic overlap with either embryonal or alveolar rhabdomyosarcoma; in fact, most recently, rearrangements of the NCOA2 gene have been identified in infantile cases of spindle cell rhabdomyosarcoma.11 There are as yet no good data regarding similar lesions in adults nor in the sclerosing variant. In adult patients, such tumours are identified more often in the head and neck region, in contrast to their propensity to arise in the paratesticular region in children. These tumours appear to be less chemosensitive than other rhabdomyosarcomas, at least in adults, and need to be treated more often © 2013 John Wiley & Sons Ltd, Histopathology, 64, 2–11.

WHO classification 2013

in the same way as other adult-types of soft tissue sarcoma. The prognosis is worse in adults than in children. VASCULAR TUMOURS

The only substantive change in this group of lesions has been the introduction of a new entity pseudomyogenic haemangioendothelioma12 (also sometimes known as epithelioid sarcoma-like haemangioendothelioma13). This is a very distinctive tumour type, arising mainly in the extremities of adolescents and young adults and characteristically being multicentric in more than 50% of patients. Multicentric lesions often involve multiple tissue planes including skin, skeletal muscle and bone. Despite such a worrisome presentation, these lesions seem to give rise to distant

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metastasis only very rarely and in an indolent fashion. Morphologically, these tumours have a remarkably pseudomyogenic appearance which would not, at first, suggest endothelial differentiation, but immunohistochemistry and electron microscopy support their vascular nature (Figure 4). These tumours also harbour a distinctive t(7;19)(q22;q13) chromosomal translocation.14 A variety of other important new insights concerning the molecular genetics of malignant and intermediate vascular tumours have emerged in recent years; see section New Genetics below. GASTROINTESTINAL STROMAL TUMOURS

As mentioned above, this was the first occasion on which gastrointestinal stromal tumour (GIST) was

A

B

C

D

Figure 4. Pseudomyogenic haemangioendothelioma may develop in any tissue plane, here involving skin (A), and most often has strikingly rhabdomyoblast-like cytomorphology (B). These tumours are very often positive for CD31 (C) and ERG, and virtually all cases also show positivity for AE1/AE3 (D). © 2013 John Wiley & Sons Ltd, Histopathology, 64, 2–11.

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included in the soft tissue volume. Since the time of previous ‘Soft tissue’ and ‘Digestive system’ classifications, there is now a much better-established and validated set of prognostic criteria for these lesions (based largely on the work of Miettinen), allowing more reliable assessment of metastatic risk.2,15 In addition, a biologically important new group of GISTs has been recognized in recent years, being characterized by loss of function of the succinate dehydrogenase (SDH) complex, a key component of the Krebs cycle.16–18 These tumours, which are now known as SDH-deficient GISTs, lack mutations in either KIT or PDGFRA and account for the important subset of tumours known as paediatric-type GIST, which are often multinodular (Figure 5) and clinically very indolent, as well as the GISTs occurring in (the inherited) Carney–Stratakis syndrome and (the sporadic)

Carney triad. The mechanism of SDH deficiency in the majority of these lesions is poorly understood, but seems likely to be epigenetic (perhaps related to A

A

B

B

C

Figure 5. SDH-deficient gastrointestinal stromal tumour (GIST) characteristically shows a multinodular pattern of infiltration through stomach wall (A) and is essentially the only subset of GIST which gives rise to lymph node metastasis (B), although this does not necessarily portend an aggressive clinical course.

Figure 6. Hybrid schwannoma/perineurioma has a mixed fascicular and whorled growth pattern (A) with mostly schwannian-type cytomorphology (B), but dual immunostaining helps to highlight the presence of both schwannian (S-100 protein, red) and perineurial (EMA, brown) components (C). © 2013 John Wiley & Sons Ltd, Histopathology, 64, 2–11.

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methylation status). Only a small subset harbour a mutation in one of the SDH genes, most often SDHA.19,20 Germline mutations may be associated with the additional development of paragangliomas.

any neurocristopathy and typically arises in somatic soft tissue or, less often, the gastrointestinal tract. Hybrid nerve sheath tumours of either type show little or no tendency for local recurrence.

NERVE SHEATH TUMOURS

TUMOURS OF UNCERTAIN DIFFERENTIATION

As mentioned above, this was the first time nerve sheath tumours have been included in the soft tissue volume. One distinct group of newly recognized tumours included in the category of benign nerve sheath tumours were hybrid nerve sheath tumours, by far the most common among which is hybrid schwannoma/perineurioma21 (Figure 6). However, rare examples of hybrid neurofibroma/schwannoma are also recognized.22 While the latter may be associated with NF-2, NF-1 or schwannomatosis,23 hybrid schwannoma/perineurioma shows no association with

In this category, the principal changes have been the addition of several recently recognized ‘entities’. In the benign category, acral fibromyxoma,24 also known as digital fibromyxoma,25 is now included. These tumours arise almost exclusively in the periungual region of digits, mainly in adults, and have bland fibroblastic cytomorphology with a myxoid matrix (Figure 7). These lesions may recur locally if excised incompletely. Added into the intermediate (locally

A A

B B

Figure 7. Digital fibromyxoma characteristically arises in the periungual region and has a variably myxoid or collagenous stroma (A). Cytologically, these tumours have bland fibroblastic morphology (B). © 2013 John Wiley & Sons Ltd, Histopathology, 64, 2–11.

Figure 8. Haemosiderotic fibrolipomatous tumour is characterized by a complex admixture of spindle cells and mature adipocytes in varying proportions (A). These spindle cells show uniform fibroblastic morphology. Note prominent haemosiderin deposition and a patchy lymphocytic infiltrate (B).

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aggressive) category is haemosiderotic fibrolipomatous tumour,26,27 an uncommon lesion which arises principally on the dorsum of the hands or feet in middleaged adults, and which is characterized by a complex admixture of mature adipose tissue and uniform fibroblastic cells associated with haemosiderin deposition (Figure 8). These lesions have been shown to harbour the same chromosome translocation t(1;10)(p22;q24) as identified in myxoinflammatory fibroblastic sarcoma (also known as atypical myxoinflammatory fibroblastic tumour) (see above),28,29 and tumours showing hybrid morphology have been recognized. These lesions very often recur locally unless excised with clear margins. A new addition in the intermediate (rarely metastasizing) category is phosphaturic mesenchymal tumour, a tumour type which has been

recognized for many years30 but which had not been defined clearly until more recently.31 These lesions, which very often have myofibroblastic or myopericytic-like morphology with the addition of a chondroid or calcified matrix, are characterized by overexpression of FGF 23,31,32 which leads directly to the phosphaturia and hence associated bony abnormalities. Also included into this category is atypical fibroxanthoma, which was formerly included in the skin volume. Metastasis from these lesions is now recognized to be exceedingly rare, and there is no longer believed to be any relationship with those pleomorphic sarcomas known as so-called ‘MFH’ in the past. Among the group of malignant lesions, PNET has been dropped as a synonym for Ewing sarcoma in order to minimize confusion with similarly named lesions in the CNS

Table 1. Recently identified cytogenetic and molecular genetic aberrations in soft tissue tumours t(12;22)(q13;q12)

ATF1–EWSR1

t(2;22)(q33;q12)

CREB1-EWSR1

inv(12)(q13q13)

NAB2-STAT6

t(7;16)(q33;p11)

FUS–CREB3L2

t(11;16)(p13;p11)

FUS-CREB3L1

Myxoinflammatory fibroblastic sarcoma/ hemosiderotic fibrolipomatous tumour28,29

t(1;10)(p22;q24)

TGFBR3-MGEA5

Myoepithelial carcinoma44

t(6;22)(p22;q12)

EWSR1-POU5F1

t(1;22)(q23;q12)

EWSR1-PBX1

t(19;22)(q13;q12)

EWSR1-ZNF444

t(1;3)(p36.3;q25)

WWTR1-CAMTA1

Mesenchymal chondrosarcoma47

t(8;8)(q21.1;q13.3)

HEY1-NCOA2

Undifferentiated (Ewing-like) sarcoma35,36

t(4;19)(q35;q13.1)

CIC-DUX4

t(10;19)(q35;q26)

CIC-DUX4

t(17;22)(p13;q12.3)

USP6-MYH9

t(7;19)(q22;q13)

???

Angiomatoid ‘MFH’41,42

Solitary fibrous tumour37,38 Low-grade fibromyxoid sarcoma/ epithelioid fibrosarcoma (subset)

5,6,43

Epithelioid hemangioendothelioma

sclerosing

45,46

Nodular fasciitis3 Pseudomyogenic hemangioendothelioma

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Ossifying fibromyxoid tumour48

Rearrangement of PHF1 at 6p21

PEComa

TSC2 deletion49,50 TFE3 rearrangement (small subset)51,52

Angiosarcoma (mammary)

KDR mutation53

Angiosarcoma (secondary)

MYC amplification*54,55 FLT4 co-amplification (25%)55

*Also now known to occur in a subset of primary (sporadic) angiosarcomas.56 © 2013 John Wiley & Sons Ltd, Histopathology, 64, 2–11.

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and female genital tract, which consistently lack EWSR1 gene rearrangement. UNDIFFERENTIATED/UNCLASSIFIED SARCOMAS

This is an entirely new category of tumours, introduced for the first time in the 2013 classification in acknowledgment of the fact that a small, but significant, subset of sarcomas cannot be classified into any presently defined categories. Such undifferentiated tumours may have spindle cell, pleomorphic, round cell or epithelioid cytomorphology.33,34 A significant subset of radiation-associated sarcomas fall into this category. These lesions show no definable line of differentiation using currently available technologies. However, at least within the round cell category, genetic subsets which almost certainly represent discrete entities are already beginning to be recognized, most notably those characterized by CIC–DUX4 gene fusion,35,36 which results from either a t(4;19) or a t (10;19) chromosome translocation. Interestingly, this translocation results in up-regulation of a group of genes in the ETS family, similar to the genes up-regulated in conventional Ewing sarcoma, suggesting that there may prove to be a very close molecular biological relationship. Undoubtedly, this entire group of tumours will continue to pose a challenge both in terms of understanding their pathogenesis, their classification and optimal methods of treatment, at least in the near future, until their underlying biology is better understood. Genomic data may be informative in this regard. NEW GENETICS

One of the most striking features of the new WHO classification is the remarkable expansion in our understanding of the molecular pathogenesis of many soft tissue tumours, in a significant subset of which specific chromosome translocations continue to be identified. In addition, characteristic patterns of gene rearrangement are also increasingly recognized. Some of the new aberrations are mentioned in the text above, but a comprehensive list of the newer findings which are included in the new classification is provided in Table 1. This work continues at an impressive pace and most recently, in the short time since this new WHO classification was finalized, a distinctive and specific gene fusion, NAB2–STAT6, has been identified in solitary fibrous tumour.37,38 The same gene fusion has been identified more recently in socalled meningeal ‘haemagiopericytoma’,39 confirming this author’s long-held personal belief that the latter © 2013 John Wiley & Sons Ltd, Histopathology, 64, 2–11.

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tumours simply represent cellular or malignant examples of solitary fibrous tumour, rather than a separate or distinct entity. The gene fusion results in notable overexpression of STAT6, which proves to be an impressively specific immunohistochemical marker for solitary fibrous tumour.39,40 A remarkable finding of as yet undetermined significance is the increasing recognition of identical gene fusions in different tumour types, some of which are clearly related (e.g. DFSP and giant cell fibroblastoma) and some not (e.g. clear cell sarcoma and so-called angiomatoid ‘MFH’).

Conclusion The latest WHO classification of soft tissue tumours reflects substantial conceptual evolution since the previous 2002 volume and also demonstrates the expanding importance of cytogenetic and molecular genetic characterization of these lesions in underpinning a meaningful classification system. It is clear that, over the past 20 years, diagnosis of soft tissue tumours has become impressively more reproducible and, as such, treatment strategies are more likely to succeed. Based upon experience to date, it seems likely that new ‘entities’ will continue to be recognized in the years to come, and these will further facilitate more accurate subclassification of this large and complex group of consistently fascinating tumours.

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43. Mertens F, Fletcher CD, Antonescu CR et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma and cloning of a novel FUS/CREB3L1 fusion gene. Lab. Invest. 2005; 85; 408–415. 44. Antonescu CR, Zhang L, Chang NE et al. EWSR1–POU5F1 fusion in soft tissue myoepithelial tumours. A molecular analysis of sixty-six cases, including soft tissue, bone and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromosom. Cancer 2010; 49; 1114–1124. 45. Errani C, Zhang L, Sung YS et al. A novel WWTR1–CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosom. Cancer 2011; 50; 644–653. 46. Tanas MR, Sboner A, Oliveira AM et al. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci. Transl. Med. 2011; 3; 98ra82. 47. Wang L, Motoi T, Khanin R et al. Identification of a novel, recurrent HEY1–NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes Chromosom. Cancer 2012; 51; 127–139. 48. Gebre-Medhin S, Nord KH, M€oller E et al. Recurrent rearrangement of the PHF1 gene in ossifying fibromyxoid tumours. Am. J. Pathol. 2012; 181; 1069–1077. 49. Pan CC, Chung MY, Ng KF et al. Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma. J. Pathol. 2008; 214; 387–393.

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