Adipocytic Tumors

No major changes in the category of adipocytic tumors were effected, with the exception of the removal of the terms round cell liposarcoma and mixed-type liposarcoma. Myxoid liposarcoma is graded based on cellularity using a 3-tier system (low, intermediate, and high); transition between different grades is often seen within a tumor. Histologic grade is prognostic and high-grade tumors show greater risk for recurrence, metastasis, and tumor-related death, thus tumors are classified according to the highest grade present. Although some high-grade myxoid liposarcomas show a predominance of round cell morphology (hence previously classified as round cell liposarcoma), the hypercellular high-grade areas more commonly show a spindle cell morphology. All myxoid liposarcomas, regardless of grade, harbor FUS-DDIT3 gene fusion, or rarely an alternate EWSR1-DDIT3 fusion.

Most tumors previously classified as mixed-type liposarcoma are now considered to represent unusual examples of dedifferentiated liposarcoma, based on currently available immunohistochemical and molecular studies that confirm the presence of amplification of chromosome 12q13-15. Amplification of 12q13-15 (via supernumerary ring or giant marker chromosomes) results in overexpression of the encoded gene products, MDM2 and CDK4. Since 2002, MDM2 and CDK4 immunohistochemistry and/or fluorescence in situ hybridization for MDM2 gene amplification have come into widespread use for the diagnosis of atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). In addition to enabling accurate reclassification of mixed-type liposarcoma, these immunohistochemical and molecular studies also facilitate the diagnosis of retroperitoneal lipoma and exclude the more likely possibility of WDLPS at this anatomic site; the former follows a benign clinical course, unlike WDLPS, which requires surgical resection given its risk for recurrence and dedifferentiation.

Note that although the 2013 WHO classification lists the term ALT as the section heading, it is pointed out that the retention of WDLPS in practice is still appropriate for tumors in sites at which complete resection is often not feasible, such as the mediastinum and retroperitoneum, and there is associated significant morbidity by locally aggressive growth, recurrence, and extensive surgical resections that often requires removal of multiple organs.

DDLPS, previously defined as a nonlipogenic sarcoma, is now known to occasionally show homologous lipoblastic differentiation by having morphologic features indistinguishable from pleomorphic liposarcoma. Since publication of the 2013 WHO classification, a subset of such lipogenic DDLPS have been reported to show low nuclear grade. It has also recently been suggested that the histologic grade of DDLPS is prognostically significant, with one study showing 5-year survival rates of 93%, 57%, and 21% associated with grade 1, 2, and 3, respectively, of retroperitoneal liposarcoma graded according to the French National Federation of the Centers for the Fight Against Cancer grading system, as well as worse survival for tumors with heterologous myogenic and rhabdomyoblastic differentiation.

In addition, the benign tumor chondroid lipoma is now known to harbor the recurrent translocation t(11;16) (q13;p13), resulting in C11orf95-MKL2 fusion, which was confirmed in a larger study of 8 cases after the 2013 publication.

Fibroblastic/Myofibroblastic Tumors

The pathobiology of many neoplasms in this category has been updated to reflect significant genetic and molecular discoveries. Two entities are no longer included here: myofibroma/myofibromatosis (now described under pericytic tumors) and giant cell angiofibroma, which is now listed as a synonym for extrapleural solitary fibrous tumor (SFT).

The 2013 WHO classification includes giant cell fibroblastoma and dermatofibrosarcoma protuberans (DFSP), which were formerly classified in the WHO skin tumor volume. Both giant cell fibroblastoma and DFSP are characterized by the translocation t(17;22) (q21;q13) (resulting in PDGFB-COL1A1 fusion), and occasionally occur together as hybrid tumors. Giant cell fibroblastoma shows frequent local recurrence but has no metastatic potential; DFSP also shows locally aggressive behavior and can metastasize if it undergoes fibrosarcomatous transformation.

Nodular fasciitis was long considered to be a reactive process, because of self-limited presentation of rapid growth with spontaneous regression over the course of months. On histology, some cases may be worrisome for sarcoma, especially if biopsied during the active growth phase when abundant mitotic activity is present. Nodular fasciitis is now understood to represent a transient neoplasia with the discovery of a recurrent MYH9-USP6 gene fusion resulting from translocation t(17p;22q) (p13;q13.1).

Mammary-type myofibroblastoma, cellular angiofibroma, and the adipocytic tumor spindle cell lipoma/pleomorphic lipoma (all benign tumors), have long been appreciated to share morphologic features and are now known to share the genetic features of consistent 13q and 16q rearrangements or deletions. Aberrations involving the 13q14 locus include the region encoding the tumor suppressor gene Retinoblastoma (Rb); after publication of the 2013 WHO classification it has been reported that immunohistochemical detection of loss of Rb expression secondary to 13q14 rearrangement is characteristic of mammary-type myofibroblastoma, cellular angiofibroma, and spindle cell lipoma/pleomorphic lipoma. In addition, a subset of cellular angiofibroma is now known to show severe cytologic atypia or sarcomatous transformation; despite the worrisome histologic features, such tumors do not show increased recurrence risk compared with conventional cellular angiofibroma.

For extrapleural SFT, the prior synonym hemangiopericytoma has now been omitted. Since publication of the WHO volume, there have been several significant advances in the understanding of SFT. SFTs are characterized by the NAB2-STAT6 fusion oncogene resulting from inversion of 2 genes located on chromosome 12q13 ; this intrachromosomal fusion cannot be detected by conventional cytogenetic methods. NAB2-STAT6 fusion results in overexpression of STAT6, immunohistochemistry for which is highly sensitive and specific for SFT.

Myxoinflammatory fibroblastic sarcoma is now known to harbor the translocation t(1;10) (p22–31;q24–25); this is also a feature of the newly described entity hemosiderotic fibrolipomatous tumor (classified under tumors or uncertain differentiation). Myxoinflammatory fibroblastic sarcoma may recur but rarely metastasizes, hence the introduction of the synonym atypical myxoinflammatory fibroblastic tumor. Tumors with hybrid features of both myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor are now recognized.

Low-grade fibromyxoid sarcoma (LGFMS) is characterized by the translocation t(7;16) (q33;p11) resulting in the FUS-CREB3L2 fusion gene. Some cases have alternate fusions with EWSR1 in lieu of FUS and in such instances CREB3L1 (encoded on 11p11) is the fusion partner; this occurs more frequently in tumors with hybrid LGFMS and sclerosing epithelioid fibrosarcoma (SEF) or in pure SEF. MUC4 is a newly described immunohistochemical marker that was shown to have high sensitivity and specificity for LGFMS and SEF after overexpression in LGFMS was identified by gene expression studies. LGFMS shows low recurrence and metastatic rates within the first 5 years, but rates increase (up to 50%) over the course of decades after initial diagnosis. In contrast, SEF shows high rates of recurrence, and metastases occur in up to 80% of patients.

Recognition of distinct morphologic variants of existing tumor types has also been facilitated by the increased understanding of defining immunohistochemical and genetic features. One such example is the epithelioid variant of inflammatory myofibroblastic tumor (IMT), which has a characteristic ALK-RANBP2 gene fusion that results in a characteristic nuclear membrane staining pattern for ALK immunohistochemistry, because RANBP2 localizes ALK to the nuclear membrane. This epithelioid variant is important to recognize because it shows far more aggressive biological behavior than conventional IMT, and is considered by some investigators to be better designated as epithelioid inflammatory myofibroblastoma sarcoma because of its high rate of metastasis and death from disease.

So-Called Fibrohistiocytic Tumors

The most significant change in this category is the abandonment of the outdated (and largely meaningless) term malignant fibrous histiocytoma (MFH). Most tumors previously classified as MFH can now be classified as specific sarcoma types with currently available immunohistochemical and genetic/molecular tests. Some sarcomas remain unclassified or undifferentiated, and are discussed in the newly introduced section on undifferentiated/unclassified sarcomas (discussed later in this article).

No other major changes were made in this section. Both localized and diffuse types of tenosynovial giant cell tumors are now known to harbor translocations involving the CSF1 gene (encoded on chromosome 1p13), most frequently with COL6A3 (encoded on chromosome 2q37).

Smooth Muscle Tumors

The only change in this tumor group is the removal of angioleiomyoma, which is now classified under pericytic (perivascular) tumors (discussed later).

Pericytic (Perivascular) Tumors

Several classification changes were made in this section. This category now includes angioleiomyoma, a benign tumor characterized by perivascular concentric arrangement of smooth muscle cells. Myopericytomas now include myofibromas (previously classified as a fibroblastic/myofibroblastic tumor) based on the morphologic continuum between these two tumors.

The 2013 WHO classification revised recommendations for the designation of glomus tumors as malignant and of uncertain malignant potential. Malignant glomus tumors applies to tumors having marked nuclear atypia and any mitotic activity, or if atypical mitotic figures are present. Tumor size greater than 2.0 cm and deep location are no longer criteria for malignancy, and tumors with these features (and without nuclear atypia) are now considered to be glomus tumors of uncertain malignant potential. Glomus tumors may be associated with type 1 neurofibromatosis, and BRAF (V600E) and KRAS (G12A) mutations occur in some sporadic cases. Since publication of the 2013 WHO classification, NOTCH mutations (of either NOTCH2 or NOTCH3 ) have also been described in glomus tumors.

Skeletal Muscle Tumors

The major change in this section is that spindle cell/sclerosing rhabdomyosarcoma (RMS) is now considered a distinct entity constituting a morphologic continuum; both spindle and sclerosing subtypes were previously considered to be variants of embryonal RMS ( Fig. 1 ). Clinicopathologic and genetic differences have been recognized in spindle cell/sclerosing RMS. In pediatric patients, spindle cell RMS most frequently arises in paratesticular sites, and is associated with a more favorable outcome compared with other RMS subtypes. In contrast, spindle cell RMS in adults more frequently arise in the head and neck, and are associated with a significantly worse outcome than in children, with up to 50% risk for recurrence and metastasis. Although many spindle cell/sclerosing RMSs harbor recurrent NCOA2 and VGLL2 rearrangements in congenital/infantile tumors, a separate subset in children and adults has recurrent MyoD1 mutations.

Sclerosing rhabdomyosarcoma is composed of small to medium-sized cells with variable amounts of eosinophilic cytoplasm, embedded in a densely sclerotic stroma, and often producing a pseudovascular appearance (H&E, 200×).

Vascular Tumors

The 2013 WHO classification includes updates in the molecular genetics of several entities, as well as the introduction of the newly recognized tumor, pseudomyogenic hemangioendothelioma.

Pseudomyogenic (epithelioid sarcomalike) hemangioendothelioma is a recently recognized entity with distinct clinicopathologic and genetic features. Tumors most frequently arise in the limbs of young adult men, and have a distinctive clinical presentation as multifocal discontiguous nodules involving multiple tissue planes (dermal, subcutaneous, subfascial, intramuscular, and intraosseous) ( Fig. 2 A ). Pseudomyogenic hemangioendothelioma has the microscopic appearance of uniform plump myoid-appearing spindle cells distributed singly or in sheets and loose fascicles ( Fig. 2 B, C), with the characteristic immunophenotype of positivity for cytokeratin AE1/AE3 ( Fig. 2 D) and expression of vascular markers ERG ( Fig. 2 E) and CD31; CD34 and desmin are negative. This tumor is characterized by the translocation t(7:19) (q22;q13), which results in a SERPINE-FOSB fusion gene. Despite the worrisome and dramatic clinical presentation as well as frequent local recurrences or regional development of new nodules, most cases seem to follow a fairly indolent course and distant metastasis is infrequent, although rare cases showing an aggressive clinical course and pulmonary metastases have been reported. Conservative management via local control by surgical resection or curettage of bone lesions is currently the mainstay of treatment.

Pseudomyogenic hemangioendothelioma typically arises as multiple nodules within different tissue planes; in this case nodules can be seen in skin, subcutaneous tissue, and soleus muscle ( A , arrows ). Skin lesions have a vaguely circumscribed nodular appearance but infiltrative edges (H&E, 40×) ( B ). The tumor cells grow in fascicles and are typically spindled with mild cytologic atypia and pleomorphism; the eosinophilic cytoplasm imparts a myoid appearance to the cells (H&E, 200×) ( C ). The characteristic immunoprofile is expression of cytokeratin AE1/AE3 (200×) ( D ) and endothelial markers such as ERG, which shows nuclear reactivity in tumor cells (400×) ( E ).

It is now known that epithelioid hemangioendothelioma (EHE) is characterized by the recurrent translocation t(1;3) (p36;q23–25), which results in the WWTR1-CAMTA1 fusion gene. It was further elucidated via breakpoint analysis that multifocal EHE likely represents monoclonal metastases rather than synchronous primary tumors. Since the 2013 WHO publication, CAMTA1 expression by immunohistochemistry has been shown to be a useful diagnostic marker for EHE. Another recent study found recurrent YAP1-TFE3 fusion genes in a distinct subset of epithelioid EHE that occurs most frequently in young adults and morphologically shows abundant eosinophilic cytoplasm and well-formed vascular channels. EHE shows overall indolent clinical behavior but up to 30% of tumors eventually metastasize. A risk stratification scheme for EHE has been proposed based on 1 large study that reported that tumors larger than 3.0 cm and having more than 3 mitoses per 50 high-power fields (HPF) were associated with 59% 5-year survival, in contrast with 100% 5-year disease-specific survival in patients with tumors lacking these features.

Some insights have been gained into the genetics of angiosarcomas in the past decade. Most secondary angiosarcomas associated with radiation treatment or preexisting lymphedema are associated with MYC gene amplification, and FLT4 coamplification is identified in 25% of cases ; MYC amplification can be shown by corresponding MYC protein expression using immunohistochemistry, and this is particularly helpful in distinguishing radiation-associated angiosarcoma from atypical postradiation vascular proliferation, which does not show MYC amplification or overexpression. However, MYC amplification is also present in a subset of primary angiosarcoma and therefore these methods cannot be used to determine whether a given angiosarcoma is radiation associated or not. KDR mutations are also present in up to 10% of primary and secondary angiosarcomas. CIC gene rearrangements have recently been reported in a subset of angiosarcomas, predominantly in young patients. Although angiosarcomas have a wide morphologic spectrum, the histologic grade is not predictive of biological behavior.

Chondro-Osseous Tumors

There were no major changes in this category.

Gastrointestinal Stromal Tumors

The 2013 WHO classification now includes gastrointestinal stromal tumors (GISTs), which had previously been part of the WHO volume on gastrointestinal tumors. The National Comprehensive Cancer Network (NCCN) guidelines for risk stratification are now widely used in reporting GISTs. The guidelines were first established in 2006 and then modified in 2010, and are based on anatomic site, tumor size, and mitotic count, features determined to be highly predictive of malignant behavior in several large retrospective studies.

GIST classification now reflects numerous advances in genetic characterization and subsequent phenotypic correlations. Most GISTs harbor oncogenic mutations in the tyrosine kinase receptor gene KIT , and a smaller subset have PDGFRA mutations; both result in constitutive activation of the type III receptor tyrosine kinase family. Most of these conventional GISTs have a spindle or mixed spindle and epithelioid morphology; epithelioid-predominant morphology is often associated with PDGFRA mutation or succinate dehydrogenase (SDH) deficiency. SDH-deficient GISTs are a newly recognized category of GIST and were first recognized among pediatric GISTs (and therefore initially known as pediatric-type GIST), having the distinct features of wild-type KIT and PDGFRA mutational status, exclusive location in the stomach with a typical multinodular growth pattern within the gastric wall ( Fig. 3 A ), epithelioid morphology ( Fig. 3 B), and frequent lymph node metastases. SDH deficiency results from dysfunction of the mitochondrial SDH complex of the Krebs cycle, secondary to inactivation of any of the SDH subunit genes ( SDHA , SDHB , SDHC , or SDHD ) by mutation or dysfunction by other mechanisms (such as SDHC promoter hypermethylation), and correlates with loss of expression of SDHB by immunohistochemistry ( Fig. 3 C). Immunohistochemical loss of SDHB is caused by mutations or dysfunction in any of the 4 subunits, whereas loss of both SDHB and SDHA is seen only in the presence of SDHA mutation. The behavior of SDH-deficient tumors cannot be predicted using conventional NCCN risk stratification; despite frequent lymph node metastases (which are exceptionally rare in conventional GIST) the overall clinical behavior is indolent. SDH-deficient GIST is also imatinib resistant, but in most cases shows clinical response to second-generation and third-generation tyrosine kinase inhibitors, such as sunitinib, sorafenib, and dasatinib. Most SDH-deficient GISTs are sporadic, but a subset arise in the setting of Carney triad (GIST, paraganglioma, pulmonary chondroma) or the autosomal dominant Carney-Stratakis syndrome (characterized by GIST and paraganglioma), which is caused by germline SDH mutations. Identification of SDH-deficient GIST thus has strong clinical implications with regard to prognostication and therapeutics, and patients should be referred for genetic counseling to assess for possible inherited disorders.

SDH-deficient GIST arises in the stomach and shows a characteristic multinodular or plexiform architecture (H&E, 40×) ( A ). The tumor cells are usually epithelioid, grow in a nested pattern, and have mild cytologic atypia and abundant palely eosinophilic cytoplasm (H&E, 100×) ( B ). Similar to most GIST, SDH-deficient GIST expresses KIT and DOG1, but is differentiated by loss of cytoplasmic expression of SDHB in tumor cells, which is normally expressed in all cells, including endothelium and inflammatory cells, as shown (100×) ( C ).

Nerve Sheath Tumors

Nerve sheath tumors are now included in the 2013 WHO volume, although no major changes in the classification of malignant peripheral nerve sheath tumors were introduced. Several new subtypes of benign tumors were added, including hybrid tumors that have features of more than 1 type of conventional nerve sheath tumor. The most common is hybrid schwannoma and perineurioma, which is typically sporadic, whereas hybrid neurofibroma/schwannoma is associated with type 1 neurofibromatosis.

Tumors of Uncertain Differentiation

There were 4 tumor types included for the first time in this category: acral fibromyxoma, atypical fibroxanthoma, hemosiderotic fibrolipomatous tumor (HFLT), and phosphaturic mesenchymal tumor. Many existing entities have been further characterized by immunohistochemical and molecular advances.

Acral fibromyxoma (or digital fibromyxoma) is a benign tumor that arises in subungual/periungual sites on the hands or feet. Atypical fibroxanthoma (AFX) is a benign dermal tumor that, when strictly defined by complete confinement to the dermis, has no risk for recurrence of metastasis. AFX often has microscopic features of a pleomorphic sarcoma caused by the presence of marked cytologic atypia and pleomorphism, and thus requires complete excision for thorough evaluation of the lesion base in order to exclude the presence of invasion of tumor into subcutaneous tissue, in which case the diagnosis of pleomorphic dermal sarcoma is applied.

HFLT is a locally aggressive tumor that frequently arises on the distal lower extremities of adult women and shares the same translocation t(1;10) as myxoinflammatory fibroblastic sarcoma; hybrid tumors of these entities may occur. HFLT is composed of an admixture of adipocytes and bland spindle cells with hemosiderin deposition and lymphocytic inflammation. HFLT has recurrence rates of 30% to 50%, often associated with incomplete excision.

Phosphaturic mesenchymal tumor most commonly affects adults and arises over a wide anatomic distribution. It is associated with a distinct clinical picture of tumor-associated osteomalacia and phosphaturia secondary to overexpression of FGF23, which is also at increased levels in serum and inhibits renal tubule phosphate reabsorption. FN1-FGFR1 fusion gene has recently been identified as a recurrent finding that drives the formation of these tumors. Tumors are composed of bland spindle and stellate cells with admixed thin-walled slitlike vessels and so-called grungy stromal calcifications. Most tumors follow a benign clinical course with recurrence secondary to incomplete excision; malignant examples that metastasize are rare. Osteomalacia resolves after resection.

Since the 2002 WHO publication, myoepithelial tumors of soft tissues have been further characterized. Tumors are now known to affect patients over a wide age range and can arise at all anatomic sites (including visceral locations). Mixed tumors are related to their salivary gland counterparts, and show ductal differentiation and similarly harbor PLAG1 gene rearrangement. Myoepithelioma is composed of benign myoepithelial cells; malignant tumors (myoepithelial carcinoma) are defined by the presence of cytologic atypia and are often associated with high mitotic rate and necrosis. Mixed tumors and myoepithelioma are benign tumors; however; myoepithelial carcinoma follows an aggressive clinical course. A subset of myoepitheliomas and myoepithelial carcinomas are associated with EWSR1 rearrangement, and a small subset have alternate FUS rearrangement. SMARCB1/INI1 protein expression is lost in a subset of myoepitheliomas and myoepithelial carcinomas, likely secondary to functional loss of material on chromosome 22q.

Recurrent rearrangements of PHF1 (on chromosome 6p21) have been identified in ossifying fibromyxoid tumor (OFMT), including atypical and malignant examples. Criteria for atypical and malignant OFMT remain to be well defined, but some investigators suggest that high nuclear grade, hypercellularity, mitotic activity greater than 2 mitoses per 50 HPF, and atypical ossification within tumor nodules are features of malignancy.

Criteria for malignancy in PEComa also remain to be clearly defined and validated, but the features of mitotic activity, necrosis, marked atypia, pleomorphism, large tumor size, and infiltrative growth seem predictive of malignant behavior. Sclerosing PEComa is a recently recognized variant that occurs most frequently at retroperitoneal sites in adult women and is typically benign. Although most PEComas show both myoid and melanocytic differentiation, a subset is negative for melanocytic markers (HMB-45, Mart-1, and MiTF) and instead harbor TFE3 gene fusions and show nuclear expression for TFE3 by immunohistochemistry.

Undifferentiated/Unclassified Sarcomas

This newly introduced section encompasses unclassified tumors that have no distinct histologic, immunohistochemical, or genetic features, which comprise 20% to 25% of all soft tissue sarcomas. Tumors in this category are subclassified according to the predominant morphologic patterns of round cell, spindled, epithelioid, or pleomorphic. Many pleomorphic tumors are high grade and associated with poor prognosis, and would have been classified as MFH in the past. Distinct genetic subsets of round cell sarcomas have been increasingly recognized, including round cell sarcomas having EWSR1 translocations involving non- ETS fusion partners, CIC-DUX4 fusion, and BCOR-CCNB3 fusion. Many of these tumors may have been classified as atypical Ewing sarcoma in the past given the variable staining pattern for CD99 within these molecularly distinct groups ( Fig. 4 ). CIC-DUX4 sarcoma shows nuclear WT1 immunoreactivity, and immunohistochemistry for CCNB3 is a useful marker for sarcomas with BCOR-CCNB3 fusion. Tumors with BCOR-CCNB3 gene fusion are more common in bone than in soft tissue and usually occur in young adult male patients, whereas those with CIC-DUX4 fusion most often arise in soft tissue and show a slight male predominance. These tumors have generally been treated similarly to Ewing sarcoma, but to date data have shown limited or poor responses to Ewing sarcoma treatment regimens.

Round cell sarcoma with CIC-DUX4 fusion gene. In contrast with Ewing sarcoma, the tumor cells have amphophilic cytoplasm, greater cytologic pleomorphism, and often show areas with spindle cell morphology (H&E, 400×) ( A ). In addition, CD99 staining is often multifocal or patchy in distribution (200×) ( B ), unlike the diffuse pattern seen in Ewing sarcoma.

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