What's New in Soft Tissue Tumor Pathology?

2021-02-15 病理維基百科

SPECIAL ARTICLE

The 2020 WHO Classification

What’s New in Soft Tissue Tumor Pathology?

Michael E. Kallen, MD* and Jason L. Hornick, MD, PhD†

Abstract: The ﬁfth edition of the World Health Organization Classiﬁcation of Tumors of Soft Tissue and Bone was published in early 2020. The revisions reﬂect a consensus among an inter- national expert editorial board composed of soft tissue and bone pathologists, geneticists, a medical oncologist, surgeon, and ra- diologist. The changes in the soft tissue tumor chapter notably include diverse, recently described tumor types (eg, atypical spindle cell/pleomorphic lipomatous tumor, angioﬁbroma of soft tissue, and CIC-rearranged sarcoma), new clinically signiﬁcant prognostic information for a variety of existing entities (eg, de- differentiated liposarcoma and solitary ﬁbrous tumor), and a plethora of novel genetic alterations, some of practical diagnostic relevance (eg, NAB2-STAT6 in solitary ﬁbrous tumor, FOSB rearrangements in epithelioid hemangioma and pseudomyogenic hemangioendothelioma, and SUZ12 or EED mutations in ma- lignant peripheral nerve sheath tumor, leading to loss of H3K27 trimethylation). In this review, we highlight the major changes to the soft tissue chapter in the 2020 World Health Organization Classiﬁcation, as well as the new chapter on undifferentiated small round cell sarcomas, with a focus on updates in diagnostic categories, prognostication, and novel markers. Recent discov- eries in molecular genetics are also discussed, particularly those of immediate utility in differential diagnosis, including protein correlates detectable using immunohistochemistry.

Key Words: sarcoma, soft tissue tumors, solitary ﬁbrous tumor,

NAB2-STAT6 fusion, malignant peripheral nerve sheath tumor,

H3K27me3

(Am J Surg Pathol 2020;00:000–000)

he new ﬁfth edition of the World Health Organization (WHO) Classiﬁcation of Tumors of Soft Tissue and Bone was published in early 2020,1 7 years following publication of the fourth edition.2 The revisions reﬂect a consensus among an international expert editorial board composed of soft tissue and bone pathologists, geneticists,

a medical oncologist, surgeon, and radiologist. Updates to the classiﬁcation reﬂect extensive new genetic data, prompting expansion and reorganization of several categories. The soft tissue tumor chapter in particular in- cludes the addition of recently described tumor types; in some cases, increasing outcome data and comparative genetic studies argued for splitting into separate tumor types or changes in nomenclature and managerial categories. Despite the expanding contribution of genetics to our understanding of the molecular pathogenetic basis for soft tissue tumors, the new classiﬁcation empha- sizes the continued central diagnostic importance of morphology.

In addition to a discussion of 「new」 soft tissue tu- mor entities, this review will highlight updated prognostic information for familiar tumor types, such as dediffer- entiated liposarcoma (DDLPS) and solitary ﬁbrous tumor (SFT). Finally, we will include a focused discussion of the dizzying array of recently described genetic alterations in soft tissue tumors. The past decade has seen a plethora of novel gene fusions in rare soft tissue tumor types; a comprehensive and in depth examination of these alter- ations is beyond the scope of this review. Instead, we will focus on selected genetic alterations with practical diag- nostic relevance. An example is the undifferentiated small round cell sarcoma chapter; detection of novel gene fu- sions has led to subclassiﬁcation of the former wastebasket of 「Ewing-like」 sarcomas into new categories with distinct presentations, clinical behavior, and morphologic and immunohistochemical (IHC) features. Additional prac- tical examples include the identiﬁcation of recurrent ge- netic alterations in SFT and malignant peripheral nerve sheath tumor (MPNST), leading to the introduction of highly sensitive and speciﬁc IHC markers, which are now in routine use in surgical pathology.

NEW SOFT TISSUE TUMOR TYPES

The ﬁfth edition of the WHO Classiﬁcation features

「new」 soft tissue tumor types that were not found in the

From the *Department of Pathology, University of Maryland School of Medicine, Baltimore, MD; and †Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Conﬂicts of Interest and Source of Funding: J.L.H. is a consultant to Epizyme, Aadi Biosciences, and TRACON Pharmaceuticals. For

M.E.K. none was declared.

Correspondence: Jason L. Hornick, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: jhornick@bwh.harvard.edu).

fourth edition (Table 1). As was the case for prior editions, tumors are organized by line of differentiation, such as adipocytic, ﬁbroblastic/myoﬁbroblastic, vascular, and smooth muscle neoplasms. Several emerging tumor types, including the morphologically heterogenous NTRK-rearranged spindle cell neoplasms, are contained within the section on tumors of uncertain differentiation. Epithelioid hemangioendothelioma (EHE) with YAP1-TFE3 fusion will be discussed in the novel

Am J Surg Pathol • Volume 00, Number 00, 』』 2020 www.ajsp.com | 1

TABLE 1. 2020 WHO Classification: New Soft Tissue Tumor Types

Section/Chapter Tumor Type

Adipocytic tumors Atypical spindle cell/pleomorphic

lipomatous tumor

differential diagnosis includes spindle cell/pleomorphic lipoma and ALT/WDLPS. Spindle cell/pleomorphic lipomas have a different anatomic distribution, are well circumscribed, and contain characteristic brightly eosinophilic, coarse 「ropy」 collagen ﬁbers. ALT/WDLPS

rarely involves the subcutaneous compartment but shows

Fibroblastic/myoﬁbr- oblastic tumors

Vascular tumors Smooth muscle tumors Tumors of uncertain

differentiation Undifferentiated small

round cell sarcomas of bone and soft tissue

Myxoid pleomorphic liposarcoma Angioﬁbroma of soft tissue

EWSR1-SMAD3-positive ﬁbroblastic tumor (emerging)

Superﬁcial CD34-positive ﬁbroblastic tumor

EHE with YAP1-TFE3

Inﬂammatory leiomyosarcoma*

NTRK-rearranged spindle cell neoplasm (emerging)

CIC-rearranged sarcoma

Sarcomas with BCOR genetic alterations Round cell sarcomas with EWSR1-non-

ETS fusions

similar histologic appearances as atypical spindle cell lipomatous tumors, although a prominent spindle cell component is uncommon; IHC or ﬂuorescence in situ hybridization (FISH) can be helpful to make this distinction. By IHC, the tumor cells in atypical spindle cell lip- omatous tumors show variable expression of CD34, S100 protein, and desmin, whereas MDM2 and CDK4 are gen- erally negative (rarely, weak or focal staining for the latter markers may be seen). Spindle cell lipomas show diffuse CD34 expression, but by contrast are usually negative for desmin and S100 protein.10 Notably, loss of nuclear RB1 expression is observed in 50% to 70% of atypical spindle cell

*Formerly included as variant of (conventional) leiomyosarcoma; now separate

section.

lipomatous tumors, in keeping with chromosome 13q14

deletion, including the RB1 locus, which is also a consistent

ﬁnding in spindle cell/pleomorphic lipomas.11,12 MDM2

genetic changes section below. Also discussed here are 「new」 tumor types within the undifferentiated small round cell sarcoma chapter.

Atypical Spindle Cell/Pleomorphic Lipomatous Tumor

Atypical spindle cell/pleomorphic lipomatous tumor is a benign adipocytic neoplasm, distinct from atypical lipomatous tumor/well-differentiated liposarcoma (ALT/ WDLPS) and spindle cell/pleomorphic lipoma, although it shares some histologic features with both of these other tumor types.3–5 The largest series of atypical spindle cell lipomatous tumors reported a male-to-female ratio of 3:2 and a median age of 54 years.6 Approximately two thirds of tumors occur in the limbs and limb girdles, with a predilection for the hands and feet, and an approximately equal distribution between superﬁcial and deep sites. Less commonly involved are the head and neck, genitals, and trunk, with very rare retroperitoneal involvement. By contrast, ALT/WDLPS occurs equally commonly in the retroperitoneum and limbs, less commonly in the sper- matic cord, mediastinum, and head and neck. Spindle cell/ pleomorphic lipomas characteristically occur in the pos- terior aspect of the neck or upper back, less often the face, orbital region, and oral cavity, with few reports of deep- seated lesions in a broader anatomic distribution.

Histologically, atypical spindle cell lipomatous tumor shows inﬁltrative margins and demonstrates a range of appearances, with varying proportions of spindle cells, adi- pocytes, and lipoblasts, including hyperchromatic and sometimes pleomorphic cells (atypical pleomorphic lip- omatous tumor).7 The histology may be viewed as a spec- trum ﬂanked by 2 morphologic extremes: a paucicellular pattern with bland spindle cells, minimal nuclear atypia, adipocytes, and abundant (often myxoid) matrix, and a hy- percellular pattern at the other end of the spectrum with mild-to-moderate cytologic atypia, easily identiﬁable lipoblasts, and less abundant matrix (Fig. 1).6,8,9 The

ampliﬁcation is absent in atypical spindle cell lipomatous tumor, in distinction from ALT/WDLPS.

Importantly, atypical spindle cell/pleomorphic lip- omatous tumors pursue a benign clinical course with a low rate of nondestructive local recurrence (10% to 15%), lower than the risk for ALT/WDLPS; in contrast to ALT/ WDLPS, atypical spindle cell lipomatous tumor has no potential to dedifferentiate.6

Myxoid Pleomorphic Liposarcoma

Another 「new」 adipocytic tumor type, myxoid pleomorphic liposarcoma is an exceptionally rare and aggressive neoplasm occurring in children and young adults with a predilection for the mediastinum.13 Some cases are associated with Li-Fraumeni syndrome (ie, germline TP53 mutation).14–16 Histologic features include an admixture of bland zones resembling conventional myxoid liposarcoma (including scattered lipoblasts, a delicate capillary vascular network, and myxoid pools) and cellular areas resembling pleomorphic liposarcoma with marked nuclear atypia and pleomorphic lipoblasts (Fig. 2).17 These tumors lack both FUS/EWSR1- DDIT3 fusions (of conventional myxoid liposarcoma) and MDM2 ampliﬁcation (of well-differentiated and DDLPS).18,19 Myxoid pleomorphic liposarcomas are clinically aggressive, with a high rate of local recurrence and distant metastasis and poor outcomes.

Angiofibroma of Soft Tissue

Angioﬁbroma of soft tissue is a benign ﬁbroblastic neoplasm that typically arises in the lower extremities, often involving or adjacent to large joints, uncommonly in the back, abdominal wall, pelvic cavity, and breast. A series of 37 cases reported a male predominance, a median age of 49 years, and a slightly more frequent subcutaneous rather than deep/subfascial situation.20 Histologically, angioﬁbroma of soft tissue contains uniform bland spindle cells, variably myxoid and collagenous stroma, and

FIGURE 1. Atypical spindle cell lipomatous tumor. A, This tumor shows a variably collagenous to myxoid stroma and is dominated by spindle cells, in areas admixed with adipocytes. B, The tumor cells are relatively uniform, whereas the adipocytes show marked variation in size, including occasional lipoblasts. C, This tumor contains abundant myxoid stroma with prominent adipocytes and scattered spindle cells with hyperchromatic nuclei. D, This example shows dense collagenous stroma, notably pleomorphic and multinucleated cells, and occasional lipoblasts.

a prominent vascular network comprised of small thin-walled branching blood vessels, similar to (although thicker in caliber than) those in myxoid liposarcoma (Fig. 3). Cytologic atypia is generally absent, other than degenerative atypia in occasional cases.

Angioﬁbroma of soft tissue features the recurrent translocation t(5;8)(p15;q13), resulting in the fusion of aryl hydrocarbon receptor repressor (AHRR) at 5p15 with nuclear receptor coactivator 2 (NCOA2) at 8q13 in most

cases.21 AHRR had not previously been implicated in gene fusions, whereas NCOA2 is the 3′ partner in fusions with MYST3 and ETV6 in leukemias, and with PAX3 and HEY1 in sarcomas.21 The AHRR-NCOA2 fusion is found in 60% to 80% of angioﬁbromas of soft tissue. Variant GTF2I-NCOA2 and GAB1-ABL1 fusions have been re- ported in few cases.22,23

Of note, the similarly named cellular angioﬁbroma is entirely different from angioﬁbroma of soft tissue, in its inguinoscrotal/vulvar location and distinct and less

uniform histologic features.24,25 Genetic ﬁndings in cel- lular angioﬁbroma include losses of RB1, also seen in spindle cell/pleomorphic lipoma, atypical spindle cell/ pleomorphic lipomatous tumor (discussed above), and myoﬁbroblastoma, with overlapping morphologic features shared among these tumor types in the so-called 13q/RB1 family of tumors.26

EWSR1-SMAD3-positive Fibroblastic Tumor (Emerging)

This provisional entity is a benign ﬁbroblastic neoplasm, with recent reports describing a wide age range, female predilection, and distribution largely in the hands and feet, in superﬁcial (dermal or subcutaneous) locations.27,28 Histologic features include nodular growth, a pattern of zonation dem- onstrating peripheral areas of intersecting cellular fascicles comprised of bland spindle cells (Fig. 4), and sometimes central areas of hyalinization and infarction.27 IHC reveals diffuse ERG expression, whereas SMA and CD34 are

FIGURE 2. Myxoid pleomorphic liposarcoma. A, The tumor contains abundant myxoid stroma and 「crow’s feet」 blood vessels, mimicking myxoid liposarcoma; the presence of tumor cells with large, hyperchromatic nuclei would not fit with myxoid liposarcoma. B, In other areas, markedly pleomorphic cells and atypical lipoblasts resemble pleomorphic liposarcoma.

typically negative. This tumor type is deﬁned by fusion of exon 7 of EWSR1 with exon 5 of SMAD3; SMAD3 is an important signal transducer in the TGF-β/SMAD pathway, involved in extracellular matrix synthesis by ﬁbroblasts. This benign neoplasm may recur locally following incomplete excision.

Superficial CD34-positive Fibroblastic Tumor

This distinctive low-grade neoplasm of the skin and subcutis is rare, with few reported cases. Most have oc- curred in middle-aged adults, with a slight male predom- inance, and a predilection for the lower extremities, followed by upper extremities, buttock, and shoulder. Histology demonstrates highly cellular fascicles and sheets of spindled to epithelioid cells with abundant eosinophilic, often glassy cytoplasm and moderate-to-marked pleo- morphism (Fig. 5). There is morphologic overlap reported with PRDM10-rearranged soft tissue tumors.29 By IHC, there is strong CD34 expression (Fig. 5B), and keratins are positive in 70% of cases. The prognosis in reported cases has been excellent.30,31

Inflammatory Leiomyosarcoma

Inﬂammatory leiomyosarcoma is a rare low-grade sarcoma that was originally buried within the 「inﬂammatory malignant ﬁbrous histiocytoma」 wastebasket, and previously included as a variant of leiomyosarcoma (in the fourth edition of the WHO Classiﬁcation); owing to marked differences in clinical behavior and genetics, inﬂammatory leiomyosarcoma has now been designated a separate entity in the ﬁfth edition. Inﬂammatory leiomyosarcoma has a peak incidence in young adults and occurs in the soft tissues of the extremities and trunk.32 The histologic features are notable for a prominent inﬂammatory inﬁltrate obscuring the neoplastic cells, com- prised of foamy histiocytes and prominent lymphocytes; the tumor cells are arranged in fascicles and are typically rela- tively uniform with mild atypia and eosinophilic cytoplasm (Fig. 6). Cytogenetic studies have identiﬁed a distinctive characteristic near-haploid genotype,33,34 with or without subsequent whole genome doubling. Gene expression studies have also identiﬁed a distinct signature with prominent expression of genes involved in muscle development and function.35

FIGURE 3. Angiofibroma of soft tissue. A, The tumor shows a hypocellular appearance with evenly distributed, branching blood vessels and a fine collagenous stroma. B, Some examples contain myxoid stroma. Note the prominent thin-walled blood vessels. C, The uniform ovoid to short spindle cells contain fine chromatin. D, The characteristic blood vessels are generally thicker in caliber than similarly shaped vessels of myxoid liposarcoma.

The differential diagnosis can present a challenge in these cases due to the striking inﬂammatory inﬁltrate, with some histologic resemblance to other tumors including inﬂammatory myoﬁbroblastic tumor and DDLPS, as well as idiopathic mass-forming disorders such as sclerosing mesenteritis, idiopathic retroperitoneal ﬁbrosis, and Ig- G4-related disease (depending upon the anatomic site).

Although only small numbers of cases have been reported, and follow-up data are limited, the prognosis appears to be favorable, in contrast to the high rate of metastasis and often poor prognosis of conventional leiomyosarcoma.36

NTRK-rearranged Spindle Cell Neoplasm (Emerging)

This provisional category includes a group of rare soft tissue tumors deﬁned by NTRK gene fusions, en- compassing a wide spectrum of histologies and clinical behavior (ranging from benign neoplasms to aggressive sarcomas); infantile ﬁbrosarcoma is excluded from this

category.37 These tumors frequently demonstrate monot- onous spindle cell morphology, inﬁltrative growth, and co- expression of CD34 and S100 protein by IHC.38 This category includes the recently described lipoﬁbromatosis- like neural tumor39 and tumors that resemble peripheral nerve sheath tumors; many of these tumor subsets most often affect children.40,41 The varied histologic features include haphazard and inﬁltrative monomorphic spindle cell morphology, a solid pattern with stromal bands and perivascular rings of keloid-like collagen (Fig. 7),42 a pattern with zonation resembling MPNST, and a particularly uncommon pattern with a myopericytoma- like architecture. In addition to CD34 and S100 protein co-expression, tumors retain H3K27me3 (in contrast to many MPNSTs), and the majority are reactive with a pan- TRK monoclonal antibody,43,44 although the latter shows imperfect speciﬁcity45; tumors with NTRK1 fusions show the most consistent and strong staining (Fig. 7D).

Most tumors in this category harbor NTRK1 fu- sions, with a variety of partners, although rare NTRK2

FIGURE 4. EWSR1-SMAD3-positive fibroblastic tumor. A, Intersecting fascicles of spindle cells show irregular margins with adjacent subcutaneous adipose tissue. B, The fibroblastic spindle cells contain uniform nuclei and pale eosinophilic cytoplasm.

and NTRK3 fusions have also been reported; those re- sembling peripheral nerve sheath tumors may instead harbor RAF1 or BRAF fusions. NTRK fusions form chi- meric proteins containing aberrant oncogenic receptor tyrosine kinases (TRK-A, TRK-B, or TRK-C), which are therapeutic targets; detection of NTRK fusions is currently mandatory for systemic therapy. The prognosis appears to be related to histologic grade, although many NTRK-rearranged spindle cell neoplasms are clinically benign, and ﬁrm criteria for malignancy have yet to be established.

Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue

Ewing sarcoma, and the growing family of un- differentiated, predominantly round cell sarcomas that lack EWSR1 (or FUS) rearrangements (formerly des- ignated 「Ewing-like」 sarcomas), are aggressive sarcomas that predominantly affect children and young adults but may also occur in older adults. Recent molecular genetic discoveries and clinicopathologic studies have allowed subclassiﬁcation of tumors within the former wastebasket

of undifferentiated/unclassiﬁed round cell sarcomas into new distinct entities in the 2020 WHO: round cell sarco- mas with EWSR1-non-erythroblast transformation spe- ciﬁc (ETS) fusions, CIC-rearranged sarcomas, and sarcomas with BCOR genetic alterations. In addition, the Ewing sarcoma section has been pulled out from the bone tumor chapter of the fourth edition of the WHO Classi- ﬁcation, and grouped with the other aforementioned sar- comas in a new chapter 「undifferentiated small round cell sarcomas of bone and soft tissue」 in the 2020 WHO Classiﬁcation, to reﬂect a more accurate biological un- derstanding of the complex genomic landscape of this updated category. Finally, there remains a small subset of round cell sarcomas that are as yet unclassiﬁable.

The substantial overlap in morphology and clinical features, but divergent biological behavior and very low incidence, present unique diagnostic problems for these sarcoma types, and mandate ancillary IHC and/or molecular testing and a multimodal approach that is challenging outside of specialized referral centers. The broad morphologic differential diagnosis for this group of tumors also includes rhabdomyosarcomas

FIGURE 5. Superficial CD34-positive fibroblastic tumor. A, The tumor is composed of sheets of variably pleomorphic and epithelioid cells with abundant, glassy eosinophilic cytoplasm. Mitotic activity is minimal, in contrast to undifferentiated pleomorphic sarcoma. B, IHC for CD34 is diffusely positive. Keratins are also often positive (not shown).

(especially embryonal and alveolar), as well as poorly differentiated (round cell) synovial sarcoma, small cell osteosarcoma, mesenchymal chondrosarcoma, schwan- nian stroma-poor or undifferentiated neuroblastomas, Wilms tumor, and desmoplastic small round cell tumor.46 Here we will discuss the main subcategories of undifferentiated small round cell sarcomas, with a focus on novel genetic alterations and their histologic/ immunophenotypic differences, as well as clinical im- plications.

Ewing sarcoma is the second most common sarcoma in children, usually affecting young males aged 10 to 25 years, although it infrequently occurs in older adults. The entity now encompasses a spectrum of clinical presentations and morphologic appearances, including the now obsolete 「peripheral primitive neuroectodermal tumor」 (PNET; this designation was used when rosettes were apparent histolog- ically).47 Extraskeletal Ewing sarcoma usually occurs in the thigh, followed in descending frequency by pelvis, paraspinal area, and foot. The histology of conventional Ewing sarco- ma demonstrates sheets of closely packed though evenly spaced uniform small round cells, with ﬁnely granular

chromatin and inconspicuous nucleoli. The 「large cell」 or 「atypical」 variant of Ewing sarcoma has no im- munophenotypic differences or prognostic implications, al- though a subset of these cases have now been reclassiﬁed into CIC-DUX4 sarcomas, as will be further discussed. IHC features include CD99 and FLI1 expression, which are highly sensitive but not speciﬁc for Ewing sarcoma (FLI1 in particular is positive in a subset of a wide range of other tumor types); strong, diffuse membranous CD99 is almost invariably seen in Ewing sarcoma. Identiﬁcation of NKX2-2, a downstream target of EWSR1-FLI1 signaling, provided an IHC marker that is highly sensitive and relatively speciﬁc for Ewing sarcoma (although it also labels mesenchymal chon- drosarcoma and olfactory neuroblastoma).48–50

Approximately 85% of Ewing sarcomas have EWSR1-FLI1 fusions, with the remainder showing EWS- R1-ERG fusions (10%), and rare cases harboring fusions between EWSR1 and other members of the ETS tran- scription factor family.51 Rare Ewing sarcoma cases can instead harbor a FUS instead of EWSR1 rearrangement, with an ERG or FEV fusion partner.51 Establishment of one of these alterations by FISH (or alternative methodologies

FIGURE 6. Inflammatory leiomyosarcoma. A, The tumor is composed of relatively uniform, elongated spindle cells with eosinophilic cytoplasm, including scattered atypical forms, admixed with prominent lymphocytes and scattered foam cells. B, Desmin is typically strongly positive.

such as reverse transcription-polymerase chain reaction or next-generation sequencing) may be necessary for selection of appropriate therapy; the prognosis has improved with multimodality therapy to a near 80% 5-year overall survival. CIC rearrangements were identiﬁed in primitive mesen- chymal tumors as early as several decades ago52,53; these al- terations are the most common abnormalities in undifferen- tiated round cell sarcomas that lack EWSR1 fusions, com- prising at least 70% of such cases.54 By far the most common CIC rearrangement partner is DUX4 (95% of cases), followed by FOXO4, as well as rare cases with partners including LEUTX, NUTM1, and NUTM2A. Most CIC-rearranged sarcomas arise in young adults and are extraskeletal, favoring the deep soft tissues of the extremities and trunk, with rare tumors presenting in bone and visceral sites. Histologic distinctions from Ewing sarcoma include heterogeneity in nu- clear size and shape; prominent nucleoli; variably abundant, sometimes clear cytoplasm; focal spindle cell or epithelioid features; and focally myxoid stroma (Fig. 8). By IHC, the majority of cases show patchy CD99 staining; useful ﬁndings include extensive ETV4 and WT1 nuclear expression (Figs. 8E, F)50,55–57; these are particularly helpful given the

potential for false negativity with FISH testing using CIC break-apart probes (ie, 15% of cases show cryptic rearrangements).58,59 CIC-rearranged sarcomas pursue an aggressive clinical course,60 with a series of 115 cases reporting a 5-year overall survival of 43%, signiﬁcantly inferior to that of Ewing sarcoma.56

Sarcomas with BCOR genetic alterations were more recently reported61 and represent ∼5% of non- EWSR1 or FUS rearranged 「Ewing-like」 sarcomas. BCOR fusion partners include CCNB3 (by far the most common), as well as MAML3, ZC3H7B, and unknown

partners62; other cases show BCOR internal tandem du- plication. These tumors share a similar anatomic dis- tribution as Ewing sarcoma, predominantly affecting the long bones or pelvis of adolescents, but show a striking male predominance and appear to pursue a less ag- gressive clinical course than Ewing sarcoma.63,64 The histologic features include variably round to spindled cells, with some cases dominated by spindle cell mor- phology; the individual cells contain uniform nuclei with ﬁne chromatin and scant cytoplasm (Fig. 9). Focal areas of myxoid or collagenous stroma are commonly seen,

FIGURE 7. NTRK-rearranged spindle cell neoplasms. A, This group of tumors shows a range of histologic appearances and sometimes resembles nerve sheath tumors, ranging from (A) hypocellular tumors with bland spindle cells in a collagenous stroma to (B) more cellular examples with mitotically active, atypical spindle cells in a myxoid stroma. Note the perivascular hyalinized collagen, similar to the vascular pattern observed in schwannomas. C, Some tumors show a focally nodular or whorled appearance. D, IHC using a pan-TRK antibody is usually positive, most strongly and diffusely in tumors with NTRK1 rearrangements. Weak or moderate staining is not entirely specific for this tumor class.

often with a delicate capillary vasculature. By IHC, nuclear BCOR expression has been shown to be highly sensitive (though only moderately speciﬁc), regardless of fusion partner (Fig. 9D), with additional frequently positive markers including cyclin B3 (CCNB3), cyclin D1, SATB2, and CD99 (the latter with patchy staining).65 Notable pitfalls include histologic mimics that share BCOR expression such as poorly differentiated synovial sarcomas66 and SFT,67 as well as positivity in genetically similar tumors including clear cell sarcoma of the kidney and primitive myxoid mesenchymal tumor of infancy. Nuclear CCNB3 expression is seen in cases with BCOR-CCNB3 fusions. In a recent series of 36 cases, unsupervised clustering by RNAseq indicated that BCOR altered tumors form a tight genomic group distinct from Ewing sarcoma and CIC-rearranged sarcomas.68

A ﬁnal category is that of round cell sarcomas har- boring EWSR1 fusions partnered to non-ETS family

members; emerging categories are the EWSR1-PATZ1 and EWSR1-NFATC2 sarcomas.69 Limited numbers of cases have been reported. Features of EWSR1-PATZ1 sarcomas include an equal sex distribution, broad age range, predi- lection for deep soft tissues of the chest wall, abdomen, and limbs, and potentially aggressive behavior.69–71 Their histology shows rounded to spindle cells forming sheets and nests, with a dense ﬁbrous or myxohyaline stroma, which sometimes mimic myoepithelial tumors (Fig. 10), particularly given S100 protein and SOX10 expression, or nerve sheath tumors; other IHC ﬁndings include desmin, myogenin, and myoD1 positivity in some cases (such tumors have also been referred to as 「polyphenotypic sarcomas」), variable CD99 expression, and keratin negativity. EWSR1-NFATC2 sarcomas have a marked male predilection, affect both children and adults, and generally occur in the metaphysis or diaphysis of long bones72–76; histology demonstrates round, epithelioid, and/ or spindle cells forming cords, nests, and trabeculae, with

A B

C D

E F

FIGURE 8. CIC-rearranged sarcoma. A, This tumor is composed of sheets of round cells somewhat resembling Ewing sarcoma, although the amount of cytoplasm and uneven spacing of nuclei would be unusual. B, The tumor cells often contain prominent nucleoli and abundant pale cytoplasm, helpful clues to the diagnosis. C, Epithelioid tumor cells with clear cytoplasm are a focal finding in many cases. D, This example contains an admixture of rounded to epithelioid cells with amphophilic cytoplasm. Note the extensive necrosis. The combination of nuclear WT-1 (E) and ETV4 (F) is helpful to support the diagnosis.

hyalinized or myxohyaline stroma. IHC features include CD99 expression in 50% of cases, as well as variable NKX2-2 and PAX7, and focal, often dot-like keratin

expression. Limited outcome data describe some patients cured by resection, but with the potential for late metastasis.

FIGURE 9. Sarcomas with BCOR genetic alterations. A, This tumor is composed of uniform round cells with fine chromatin in a fibrillary collagenous stroma. B, Some examples contain myxoid stroma and thin-walled blood vessels. C, A component of short spindle cells is often seen. D, Diffuse nuclear staining for BCOR is a characteristic finding, albeit not entirely specific for tumors with BCOR gene alterations.

NEW CONCEPTS IN NOMENCLATURE, GRADING, AND RISK STRATIFICATION

In addition to the new additions to the classiﬁcation, recent information has also led to clinically signiﬁcant updates in familiar entities, with prognostic and ther- apeutic implications (Table 2). Examples span the spectrum from common to rare tumors. Although a comprehensive discussion is beyond the scope of this review, selected important examples are included below.

Malignant Melanotic Nerve Sheath Tumor

This tumor type had been widely known as melanotic schwannoma; however, new nomenclature has been in- troduced, given increasing evidence of aggressive clinical behavior. These rare lesions are comprised of Schwann cells with melanocytic differentiation and are frequently asso- ciated with Carney complex, an autosomal dominant tu- mor predisposition syndrome. Malignant melanotic nerve sheath tumor (MMNST) most often arises from spinal or autonomic nerves of adults, with an earlier age of onset

seen in patients with Carney complex. These tumors affect up to 8% of individuals with Carney complex; the majority harbor biallelic inactivating mutations in PRKAR1A on 17q24, which encodes a tumor suppressor. Gene expression analysis has shown a transcriptional signature distinct from both conventional schwannomas and melanomas.77

Histology demonstrates sheets of uniform plump spindled to polygonal or epithelioid cells with eosinophilic to amphophilic cytoplasm, round to ovoid nuclei, nuclear grooves and pseudoinclusions, and coarse to ﬁne melanin pigment which can be sufﬁciently abundant as to obscure the nuclear morphology; some tumors feature prominent nu- cleoli and a high mitotic rate (Fig. 11). Psammoma bodies are a common ﬁnding that impart no clinical signiﬁcance. By IHC, S100 protein, SOX10, and melanocytic markers including HMB45, melan A, and tyrosinase are positive; these immunophenotypic ﬁndings are indistinguishable from melanoma. PRKAR1A expression is often lost, in sporadic tumors and those from patients with Carney complex (Fig. 11D). Awareness of this lesion can facilitate

FIGURE 10. Round cell sarcomas with EWSR1-PATZ1 fusions. A, This tumor contains an admixture of round cells and epithelioid cells. Note the bland nuclei. B, Some tumors show a reticular growth pattern with short spindle cells in a more myxoid stroma. C, The histology of these tumors is often reminiscent of myoepithelial neoplasms. Note the perivascular hyalinization. D, IHC for S100 protein is often positive, further mimicking a myoepithelial tumor.

separation from melanoma, which despite the similar immunoproﬁle, is not generally as uniform cytologically; the typical anatomic sites of MMNST are also a helpful clue to the diagnosis.

The clinical behavior of MMNST cannot be pre- dicted based on morphologic features.78 Although in the past this tumor type was thought to be generally benign

with occasional cases pursuing an aggressive clinical course, recent evidence has shown a high rate of malignant behavior, including a large series of 40 cases with local recurrences in 35% and metastases in 44% of patients.79

Dedifferentiated Liposarcoma

DDLPS is a relatively common sarcoma type that arises most often in the retroperitoneum, with other sites

including spermatic cord, and more rarely the media-

TABLE 2. 2020 WHO Classification: New Concepts in Nomenclature, Grading, and Risk Stratification of Soft Tissue Tumors

Tumor Type What’s New?

MMNST Change in nomenclature (formerly melanotic

schwannoma) to reﬂect aggressive clinical behavior DDLPS Recognition of adverse prognostic impact of high

FNCLCC grade, as well as myogenic (particularly rhabdomyoblastic) differentiation

SFT Prognostic model predicting metastatic risk, using patient age, mitotic rate, tumor size, and necrosis

stinum, head and neck, and trunk. DDLPS shares ampliﬁcation of MDM2 and CDK4 with ALT/WDLPS, with additional abnormalities more frequently found in DDLPS than in ALT/WDLPS, including ampliﬁcation of JUN, TERT, CPM, and MAP3K5, and deletion of ATRX, ATM, CHEK1, ABTB16, PPP2R1B, and EI24.80

The histologic hallmark of DDLPS is transition from ALT/WDLPS to a nonlipogenic sarcoma, which is usually but not always high grade, and can be of variable extent within the tumor. The transition between well- differentiated and dedifferentiated areas is usually abrupt,

FIGURE 11. MMNST. A, Some examples contain abundant melanin pigment, obscuring the tumor cells. B, This tumor contains less prominent melanin. The uniform spindle cells show a fascicular architecture. C, Some tumors show a melanoma-like appearance with epithelioid cells with prominent nucleoli and a high mitotic rate. D, By IHC, many examples show loss of staining for PRKAR1A (red reaction product).

but can be more gradual, and rarely shows intermingling. A well-differentiated component is not always identiﬁable. Dedifferentiated areas most frequently resemble un- differentiated pleomorphic sarcoma, or less commonly an intermediate-to-high-grade myxoﬁbrosarcoma, although the histologic spectrum is broad, occasionally including an unusual meningothelial-like whorling pattern.

Cases of 「low-grade」 dedifferentiation have increas- ingly been recognized, most often with uniform spindle cells and mild cytologic atypia, and a cellularity intermediate between WDLPS and conventional DDLPS; in these cases, the distinction between WDLPS and DDLPS may be challenging.80 Although DDLPS is usually nonlipogenic, occasional cases contain scattered lipoblasts in the otherwise undifferentiated component, or sheets of pleomorphic lip- oblasts resembling a pleomorphic liposarcoma; this phe- nomenon is referred to as homologous lipoblastic differen- tiation.81 FISH demonstrating MDM2 ampliﬁcation (or IHC showing diffuse nuclear expression of MDM2 and CDK4) is useful in separating these rare cases of DDLPS

from pleomorphic liposarcoma; the latter is associated with much higher metastatic potential. Heterologous differ- entiation may also be seen in DDLPS, including rhabdo- myoblastic and chondro-osseous differentiation, and rarely foci of angiosarcoma.

The prognosis of DDLPS is better than that of other high-grade pleomorphic sarcomas, with an overall mor- tality of 28% to 30% at 5-year follow-up. As reported in the fourth edition of the WHO, the extent of dediffer- entiated areas does not seem to predict outcome. It was historically believed that the morphologic appearances and histologic grade of dedifferentiated areas did not im- pact prognosis; however, the ﬁfth edition includes updated information showing an adverse prognostic impact asso- ciated with high-grade tumors based on the French Féd- ération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system. In a retrospective review of 148 patients with retroperitoneal WDLPS and DDLPS, Mussi et al82 demonstrated a signiﬁcant negative prognostic impact of high FNCLCC grade on both

disease-speciﬁc and event-free survival. In a study of 119 primary retroperitoneal DDLPS cases, Keung et al83 found that FNCLCC grade predicted overall survival, as did extent of resection and tumor integrity. In addition, Jour et al84 identiﬁed FNCLCC grade as an independent prognostic factor predicting local recurrence in a study of 50 cases of DDLPS, with grade 3 tumors demonstrating worse local recurrence-free survival than grade 1 and 2 cases. Furthermore, recent studies have indicated that myogenic, particularly rhabdomyoblastic differentiation is associated with a worse outcome in DDLPS.85,86

Solitary Fibrous Tumor

SFT is an anatomically ubiquitous ﬁbroblastic neo- plasm; uniformly cellular examples were formerly known as hemangiopericytoma. SFT occurs most commonly in adults with no gender predilection and is most common in deep somatic soft tissue and at body cavity sites (especially pleura, pelvis, and retroperitoneum); 「extrapleural」 has been removed from the ofﬁcial designation in the 2020

WHO Classiﬁcation. The histopathology demonstrates a wide spectrum of ﬁndings, classically characterized by haphazardly arranged spindled to ovoid cells, with branching, thin-walled staghorn-shaped blood vessels and prominent stromal collagen (Fig. 12). Fat-forming, giant cell-rich, and dedifferentiated variants may be encountered. By IHC, diffuse nuclear STAT6 expression is characteristic of SFT (see below) (Fig. 12D).

A critical genetic update for SFT is the discovery of a pathognomonic NAB2-STAT6 fusion, resulting from a paracentric inversion within chromosome 12q.87–89 The fusion is thought to convert wildtype NAB2 from a transcriptional repressor of EGR1-mediated signaling into a transcriptional activator, via replacement of the C-ter- minal repression domain by the transcriptional activation domain of STAT6, resulting in constitutive activation of proliferation and survival-associated growth factors including IGF2 and FGFR1. The proximity of NAB2 and STAT6 makes detection of fusions difﬁcult by conventional cytogenetics or FISH testing; however,

FIGURE 12. SFT. A, The tumor contains prominent stromal collagen and shows a haphazard architecture. B, This tumor shows a more cellular appearance. Note the scattered dilated, thin-walled blood vessels. C, A highly cellular example with prominent staghorn vessels. This high-risk tumor had a high mitotic rate (not shown). D, Nuclear immunoreactivity for STAT6 is a consistent finding, reflecting the underlying NAB2-STAT6 fusion that defines this tumor type.

Am J Surg Pathol • Volume 00, Number 00, 』』 2020 2020 WHO Classification of Soft Tissue Tumors

STAT6 IHC is both a highly sensitive and speciﬁc surro- gate for fusions.90,91 Additional alterations in the TERT promoter and TP53 have been associated with aggressive behavior and dedifferentiation.92,93

The clinical course of SFT has been notoriously difﬁcult to predict based on histologic features.94 Although the majority of tumors pursue a benign course, 5% to 10% recur or metastasize, typically to lungs, liver, and bone, including occasional cases with benign- appearing histology. Traditional criteria for malignancy included large size, dissemination at presentation, pleo-

morphism, necrosis, and a mitotic rate of ≥ 4 per 10 high power ﬁelds, the latter being the most reliable criterion

for malignancy in the past. Overtly malignant SFTs demonstrate a 20% to 30% metastatic rate. The un- predictable relationship between histology and clinical

RECENTLY IDENTIFIED GENETIC ALTERATIONS

Recent years have seen an explosion of publications describing novel recurrent genetic alterations in soft tissue tumor types, including many that are included for the ﬁrst time in the 2020 WHO Classiﬁcation (Table 4). Abnormalities of particular interest are those with immediate practical diagnostic or clinical implications98; examples for endothelial neoplasms will be described here, including FOS and FOSB fusions in epithelioid hemangiomas, YAP1-TFE3 variant of EHE, and SERPINE-FOSB and ACTB-FOSB fusions in pseudomyogenic hemangioendothelioma. A major advance to improve the reproducibility of the diagnosis of MPNST is the discovery of SUZ12 and EED mutations, and resultant loss of H3K27 trimethylation (H3K27me3), which can be demonstrated by IHC, as detailed below. An important step

behavior has led in recent years to the development of

risk stratiﬁcation models. A 3-tiered model established by Demicco et al95 incorporated age (below 55 or 55 y and

above), tumor size (< 5 to ≥ 15 cm in increments of 5 cm), and mitotic count (0, 1 to 3, or ≥ 4/10 high power

TABLE 4. 2020 WHO Classification: Recently Identified Genetic Alterations in Soft Tissue Tumors

Section Tumor Type New Genetic Alterations

ﬁelds). This model was subsequently validated in 79 cases

of SFT; the addition of necrosis as a fourth criterion (<< span=""> 10% or ≥ 10%) increased the percentage of patients

Fibroblastic/

myoﬁbroblas- tic tumors

Fibrous hamartoma of

infancy Calcifying ﬁbrous

tumor

EGFR mutations

FN1-EGF

correctly deﬁned as low risk and more precisely identiﬁed

a high-risk group with rapid development of metastasis

Lipoﬁbromatosis FN1-EGF; other receptor

tyrosine kinase or EGFR

(Table 3).96 The French Sarcoma Group has also published a risk calculator, using patient age, tumor site, mitotic count, and history of radiotherapy to predict local and metastatic recurrences; their ﬁndings also conﬁrmed the not infrequent occurrence of delayed relapses 10 to 20 years following primary excision, highlighting the need for long-term follow-up of SFT.97

Pericytic/

ligand fusions Dermatoﬁbrosarcoma COL6A3-PDGFD,

protuberans EMILIN2-PDGFD

SFT NAB2-STAT6

Myxoinﬂammatory BRAF fusions

ﬁbroblastic sarcoma

Infantile ﬁbrosarcoma EML4-NTRK3; NTRK1,

NTRK2, BRAF, and MET

fusions

Glomus tumor MIR143-NOTCH1/2/3

TABLE 3. Risk Stratification of Solitary Fibrous Tumor for Development of Metastasis

Risk Factor Score

Age (y)

<< span=""> 55 0

≥ 55 1

Tumor size (cm)

<< span=""> 5 0

5- << span=""> 10 1

10- << span=""> 15 2

≥ 15 3

Mitotic count (per 10 high power ﬁelds)

0 0

perivascular tumors

Vascular tumors

Skeletal muscle tumors

Myopericytoma/ myoﬁbroma

Epithelioid hemangioma

Pseudomyogenic hemangioendothelio- ma

Spindle cell/sclerosing rhabdomyosarcoma

PDGFRB mutations, SRF- RELA (cellular myoﬁbroma)

FOS and FOSB fusions

SERPINE1-FOSB, ACTB-FOSB

MYOD1 mutations (adolescents/adults)

SRF-NCOA2, TEAD1-NCOA2, VGLL2-NCOA2,

VGLL2-CITED2

(congenital/infantile)

EWSR1-TFCP2, FUS-

TFCP2 (intraosseous; spindle cell and epithelioid)

1-3 1

Peripheral nerve Epithelioid

SMARCB1 mutations

≥ 4 2

Tumor necrosis (%)

<< span=""> 10 0

sheath tumors

schwannoma

Granular cell tumor ATP6AP1 or ATP6AP2

mutations

≥ 10 1

Risk class Total score

Benign triton tumor (neuromuscular choristoma)

CTNNB1 mutations

Low risk 0-3

Intermediate risk 4-5

MPNST SUZ12 or EED mutations

(loss of H3K27me3)

High risk 6-7

Reprinted by permission from Springer Nature.96

Tumors of uncertain differentiation

Phosphaturic mesenchymal tumor

FN1-FGFR1, FN1-FGF1

(rare)

forward in our understanding of SFT was the identiﬁcation of NAB2-STAT6 fusions, and diagnostic utility of STAT6 IHC, as discussed above.

Additional novel genetic abnormalities included in the 2020 WHO are of less immediate practical diagnostic utility, but nevertheless improve our understanding of pathogenesis, and in some cases hold promise for potential tailored therapies. Examples include PDGFD fusions in a small subset of der- matoﬁbrosarcoma protuberans (in addition to the dominant PDGFB fusions),99,100 BRAF fusions in a subset of myxoin- ﬂammatory ﬁbroblastic sarcomas,101 and FN1 fusions in phosphaturic mesenchymal tumors.102,103 Rhabdomyosarco- mas are also undergoing subclassiﬁcation due to emerging molecular data, as the spindle cell/sclerosing rhabdomyo- sarcoma category has been revealed to harbor recurrent fusions and mutations and show distinct clinical features, analogous to reorganization of the formerly unclassiﬁable small round cell sarcoma category into new fusion-deﬁned entities.

Epithelioid Hemangioma

Epithelioid hemangioma is a benign vascular neo- plasm that occurs most commonly in young to middle-aged

adults, with a predilection for the head and neck region. Other sites include the distal extremities, as well as rarely the oral mucosa, bone, or penis. Must tumors arise in dermis or subcutaneous tissues. The designation angio- lymphoid hyperplasia with eosinophilia has been used to describe a subset of head and neck cases with obscuring inﬂammation, although neither prominent lymphocytes nor eosinophils are required for the diagnosis of epithelioid hemangioma.

The histology of epithelioid hemangioma is charac- terized by well-circumscribed lesions with often lobular growth, and vessels that sometimes show a pattern of zo- nation including well-deﬁned peripheral areas and com- pressed central areas; some examples are highly cellular with poorly canalized vascular channels (Fig. 13). The diagnostic cytologic ﬁnding is that of plump epithelioid endothelial cells with round nuclei, small nucleoli, and abundant eosinophilic cytoplasm containing occasional vacuoles (Fig. 13). Intimal or mural involvement of large blood vessels may be seen, and rare cases show purely intravascular growth, which is of no prognostic signiﬁcance.104 By IHC, the lesional cells are positive for vascular markers (CD31 and ERG), as well as

FIGURE 13. Epithelioid hemangioma. A, A cellular example with nests of epithelioid tumor cells with abundant eosinophilic cytoplasm and occasional vacuoles. B, Nuclear staining for FOSB is a helpful diagnostic finding, identified in around 50% of cases.

FIGURE 14. EHE. A, Conventional EHE composed of uniform epithelioid cells with glassy eosinophilic cytoplasm arranged in cords within a myxohyaline stroma. B, EHE with YAP1-TFE3 fusion often shows a nested appearance; the tumor cells contain abundant pale eosinophilic cytoplasm. C, A focally vasoformative architecture is usually seen, in contrast to conventional EHE. The degree of nuclear atypia in this case is notable. D, IHC for TFE3 shows strong nuclear staining.

FOSB in roughly half of cases (Fig. 13B), including the angiolymphoid hyperplasia with eosinophilia variant105 (although these cases appear to lack FOS family gene fusions; see below).

The 2020 WHO Classiﬁcation includes the novel genetic discovery of characteristic recurrent fusions in FOS or FOSB, involving as many as half of epithelioid hemangioma cases. FOS has a variety of fusion partners, including LMNA, MBNL1, VIM, and lincRNA, whereas FOSB is often fused to ZFP36, or rarely to WWTR1 or ACTB. The FOS family genes encode leucine zipper pro- teins regulating angiogenesis, differentiation, and cell proliferation. Dysregulation of FOS signaling occurs by fusion partners affecting the C-terminal end of the protein, preventing normal degradation by the 20S proteasome and therefore prolonged FOS activation. The fusion pos- itive tumors are more often found in the extremities, trunk, and bone, and are far less often cutaneous; addi- tionally, these fusions are more often identiﬁed in the cellular subtype of epithelioid hemangioma.106–108 Recent

data indicate that the angiolymphoid hyperplasia with eosinophilia variant lacks these gene fusions.106

EHE With YAP1-TFE3

EHE is a malignant vascular neoplasm composed of epithelioid endothelial cells, distinct from epithelioid angio- sarcoma. Although > 90% of cases harbor the translocation t(1;3)(p36;q23-25), resulting in a WWTR1-CAMTA1 gene fusion, a small subset of tumors instead have a novel YAP1-TFE3 fusion; this subset of tumors is reported to occur in younger patients and shows distinctive histology.109 YAP1, similar to WWTR1, is a downstream transcriptional regulator of the Hippo pathway; there is substantial sequence homology between the 2 proteins. The histology of the classic variant includes cords and nests of epithelioid cells with eosinophilic cytoplasm and occasional intracytoplasmic vacuoles in a characteristic myxohyaline stroma (Fig. 14); conventional EHE does not form vascular channels. In contrast, the YAP1-TFE3 variant is composed of large epithelioid cells with voluminous pale cytoplasm and often

FIGURE 15. Pseudomyogenic hemangioendothelioma. A, The tumor shows a loose fascicular architecture with relatively uniform spindle cells with abundant eosinophilic cytoplasm, mimicking a myoid neoplasm. Note the scattered stromal neutrophils. B, This example infiltrates muscle and contains polygonal to spindle cells with amphophilic cytoplasm. C, By IHC, the tumor cells are diffusely positive for keratins using AE1/AE3 (but not MNF116). D, FOSB is strongly positive, reflecting an underlying FOSB gene rearrangement.

shows a nested growth pattern with a focally vasoformative architecture (Figs. 14B, C). By IHC, YAP1-TFE3 tumors show diffuse nuclear TFE3 expression (Fig. 14D). Recent data suggest that EHE with YAP1-TFE3 is associated with a more favorable outcome than conventional EHE.110

Pseudomyogenic Hemangioendothelioma

Pseudomyogenic hemangioendothelioma is an en- dothelial neoplasm of intermediate biologic potential that often presents as multiple discontiguous nodules in dif- ferent tissue planes, typically involving the limbs, espe- cially the lower extremities.111,112 Most patients present with skin lesions, roughly half have lesions within skeletal muscles, and a minority have bone lesions. This tumor type has a marked male predominance, a peak incidence in young adults, and is rare in adults older than 50 years. Histology demonstrates sheets and loose fascicles of plump spindled to polygonal cells with abundant brightly eosinophilic cytoplasm (Fig. 15), resembling a myoid tumor

or sometimes epithelioid sarcoma. A subset of cases demonstrates a prominent neutrophilic inﬁltrate. Additional features include inﬁltrative margins, and, for cutaneous lesi- ons, overlying epidermal hyperplasia. By IHC, pseudom- yogenic hemangioendothelioma is consistently positive for keratins (with AE1/AE3 but not MNF116) (Fig. 15C) and ERG; CD31 expression is less consistent, and CD34, EMA, desmin, and S100 protein are negative. FOSB shows diffuse nuclear expression in nearly all cases (Fig. 15D); this marker is useful to exclude histologic mimics including EHE and epithelioid sarcoma.113,114

The ﬁrst hallmark genetic ﬁnding described in pseu- domyogenic hemangioendothelioma was the balanced translocation t(7;19)(q22;q13), resulting in a SERPINE1- FOSB fusion.115,116 Recently, a recurrent ACTB-FOSB fusion has also been found, in roughly half of cases117,118; these cases appear to demonstrate similar histologic fea- tures and clinical behavior as tumors with SERPINE1- FOSB fusion, except for more common presentation as

FIGURE 16. MPNST. A, The tumor shows alternating highly cellular, fascicular areas and less cellular areas. B, The tumor cells show loss of nuclear staining for H3K27me3 (histone H3 with lysine 27 trimethylation).

solitary lesions. Both fusions lead to upregulation of FOSB; as mentioned, IHC for FOSB is a useful diagnostic marker. Approximately 60% of patients suffer local recurrences or develop new nodules in the same anatomic region, usually within several years of initial presentation. Lymph node and distant metastases are uncommon.

Malignant Peripheral Nerve Sheath Tumor

MPNST is an aggressive neoplasm showing variably schwannian differentiation; MPNST often arises from a peripheral nerve or from a pre-existing neuroﬁbroma, the latter most often in patients with neuroﬁbromatosis type 1 (NF1).119 Overall, around 50% of patients with MPNST have NF1, 10% arise following therapeutic radiation therapy, and the remainder are sporadic. These tumors usually arise in adults, occur in deep-seated locations, and most commonly affect the proximal lower extremities, the paraspinal region, and proximal upper extremities. NF1 patients carry a 5% to 10% lifetime risk of developing MPNST, with malignant transformation most common in deep plexiform neuroﬁbromas.120 Diagnosis in the spora- dic setting relies on distinctive histology and exclusion of mimics; the conventional Schwann cell markers S100

protein and SOX10 are only positive in 40% to 50% of cases, usually with limited, focal or patchy staining. The diagnosis has recently become more straightforward through the demonstration of loss of H3K27me3 by IHC, as detailed below.

The histology of MPNST is usually characterized by highly cellular fascicles of spindle cells, and often features al- ternating hypocellular/myxoid and hypercellular areas with perivascular accentuation of cellularity (Fig. 16). The spindle cells have hyperchromatic, tapering nuclei and are often relatively uniform, with some degree of nuclear pleomor- phism. Approximately 10% to 15% of tumors show heterologous mesenchymal differentiation, which can include rhabdomyoblastic, chondro-osseous, or rarely angiosarc- omatous elements; MPNST with rhabdomyoblastic differe- ntiation is widely known as malignant triton tumor. Rarely, epithelial (glandular) elements can be seen; glandular MPNST is highly associated with NF1.

In addition to mutations in NF1 and CDKN2A, recent genomic studies have identiﬁed inactivating mutations in genes that encode core components of the polycomb re- pressive complex 2 (PRC2), EED or SUZ12.121,122 Sporadic and radiotherapy-associated MPNST most often have

loss-of-function somatic alterations of PRC2 components, identiﬁed in the majority of such cases. PRC2 inactivation results in loss of trimethylation of lysine 27 of histone H3 (H3K27me3), and aberrant downstream transcriptional activation.123 Epithelioid MPNST, by contrast, is molecu- larly and immunophenotypically distinct from conventional MPNST, commonly showing SMARCB1 gene inactivation and loss of INI1 by IHC, as well as consistent diffuse ex- pression of S100 protein and SOX10.

These improvements in our understanding of the biol- ogy of MPNST have led to identiﬁcation of H3K27me3 as a diagnostically useful marker; it is otherwise often difﬁcult (or impossible) to support the diagnosis by IHC given the limited (or completely absent) expression of Schwann cell markers. Complete loss of H3K27me3 has been demonstrated

in ∼60% of intermediate-grade and 85% of high-grade MPNST (Fig. 16B); H3K27me3 loss is uncommon in low-

grade tumors.124–127 Loss of H3K27me3 is also relatively speciﬁc for MPNST in the differential diagnosis with morphologic mimics, including benign nerve sheath tumors (eg, cellular schwannoma and atypical neuroﬁbroma), monophasic synovial sarcoma, and high-risk SFT, among others, although a small subset of spindle cell melanomas and DDLPS also show loss of H3K27me3.128,129

CONCLUSIONS

The 2020 WHO Classiﬁcation of Tumors of Soft Tis- sue and Bone features 「new」 soft tissue tumor entities, as well as updates in prognostic information for both rare and common sarcomas, and a host of recently described re- current genetic alterations. Increased awareness of rare tu- mor subtypes will facilitate their distinction from more commonly encountered lesions. Despite the rapidly emerging novel molecular alterations that have been identiﬁed across a broad array of tumor types, histologic features remain cru- cial to accurate subclassiﬁcation. The WHO revision reﬂects the contemporary knowledge of the clinicopathologic fea- tures and molecular underpinnings of soft tissue tumors, updating classiﬁcation with the goal of an increased under- standing of their biology, accurate diagnosis, and ultimately reﬁned treatment regimens and improved patient outcomes.

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