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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e31828625bf
Review Articles

Cutaneous Neoplasms Showing EWSR1 Rearrangement

Boland, Jennifer M. MD; Folpe, Andrew L. MD

Free Access
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Author Information

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

The authors have no funding or conflicts of interest to disclose.

All figures can be viewed online in color at http://www.anatomicpathology.com.

Reprints: Andrew L. Folpe, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905 (e-mail: folpe.andrew@mayo.edu).

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Abstract

Rearrangements of the EWSR1 gene are found in an increasing number of human neoplasms, including several tumors that can involve the skin: Ewing sarcoma/primitive neuroectodermal tumor, angiomatoid (malignant) fibrous histiocytoma, myoepithelioma of soft tissue, and clear cell sarcoma. Although these tumors share this common genetic link, they have very different clinical features, morphology, immunophenotype, and sometimes fusion gene partners; these will be the subjects of this review.

The Ewing sarcoma breakpoint region 1 gene (EWSR1, chromosome 22q12) encodes a ubiquitously expressed RNA-binding protein.1,2 Although the exact function of the EWSR1 protein is unknown, the universal nature of its expression makes it likely that it has important housekeeping functions within the cell. EWSR1 is a member of the TET gene family, which includes other related genes such as FUS and TAF15.1,2

As is apparent from its name, rearrangements involving EWSR1 were first described in Ewing sarcoma.3–5 However, it has become increasingly clear that EWSR1 is a “promiscuous” gene, with rearrangements (involving a number of different partner genes) identified in a variety of morphologically distinct soft tissue tumors including extraskeletal myxoid chondrosarcoma, desmoplastic small round cell tumor, clear cell sarcoma (CCS), angiomatoid (malignant) fibrous histiocytoma (AMFH), soft tissue myoepitheliomas, primary pulmonary myxoid sarcoma, CCS-like gastrointestinal tumor, and a subset of myxoid liposarcomas.6–13 EWSR1 rearrangements have also been identified in a nonmesenchymal tumor, hyalinizing clear cell carcinoma of the salivary gland.14 This review article will highlight the unique clinicopathologic features of these genetically related entities, particularly in their cutaneous manifestations.

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EWING SARCOMA/PRIMITIVE NEUROECTODERMAL TUMOR

Historical and Clinical Features

Ewing sarcoma (ES) was first described as “malignant endothelioma of bone” by Ewing in 1921.15 Angervall and Enzinger16 recognized in 1975 that an identical tumor could occur in the deep soft tissue, and rarely in the skin. Originally described as distinct entities, ES and primitive neuroectodermal tumor (PNET) are now known to represent slightly different morphologic variants of the same entity, sometimes referred to as the “Ewing family of tumors”.3,4 ES/PNET is a rare sarcoma that most frequently occurs in the bone or deep soft tissues.17,18 ES/PNET can occur at any age but is most common in male patients younger than 30 years, and for unknown reasons, is very rare in African Americans.17 They are high-grade sarcomas, and survival rates seem to depend heavily on the presence or absence of metastatic disease at presentation (around 75% survival for localized disease versus 30% with systemic disease).17,18

Cutaneous ES/PNET is extremely rare, with fewer than 100 cases reported in the literature.19,20 As in osseous and soft tissue forms of this disease, most tumors present in teenagers and young adults, although cutaneous ES/PNET seem to be more common in women.19,21–23 Cutaneous tumors can occur at any body site, with the extremities being the most common location, followed by the trunk and head and neck region.19,21,22 Primary tumors are usually small (<2.5 cm) and localized to the dermis/subcutis at presentation. Cutaneous ES/PNET seem to metastasize less frequently than do their bone and soft tissue counterparts and may represent a favorable prognostic group, although only a small number of cases with limited clinical follow-up have been reported.19–25 Clinical information and radiographical studies may be necessary to distinguish primary cutaneous ES/PNET from metastasis from a previously treated or occult deeply situated primary tumor, which is a critical distinction.26

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Histopathology and Immunohistochemistry

The histopathologic features of cutaneous ES/PNET are similar to those of ES/PNET elsewhere, with a sheet-like to vaguely lobular proliferation of uniform “small blue round cells” and a well-developed capillary network (Fig. 1A).15,16,23 The neoplastic cells are typically monomorphic, with clear to lightly eosinophilic cytoplasm, finely dispersed chromatin and small nucleoli (Fig. 1B).15,16,23 Areas of geographic and individual cell necrosis are common.15,27 Tumors falling closer to the PNET end of this spectrum may show pseudorosette formation and a modest degree of cellular spindling. Rare morphologic variants of ES/PNET include large cell (“atypical” ES), adamantinoma-like, and sclerosing and spindled tumors.27,28

Figure 1
Figure 1
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Immunohistochemistry (IHC) can be quite helpful in the diagnosis of ES/PNET, as essentially 100% of these tumors express CD99 (MIC2, p30/32) in a strong membranous pattern (Fig. 1C).27 CD99 expression is, of course, not at all specific for ES/PNET, and may be seen in lymphoblastic lymphoma, poorly differentiated synovial sarcoma, and a subset of rhabdomyosarcomas, among others.29,30 IHC for FLI-131,32 and ERG proteins33,34 may also be of some value in the diagnosis of cutaneous ES/PNET, although the need for these additional markers has been greatly reduced with the increased availability of molecular genetic testing, as described below. A significant minority of ES/PNET (around 25%) show anomalous expression of low–molecular-weight cytokeratins, with only very rare cases (<3%) showing limited anomalous desmin expression.25,27,35 It is important to remember that expression of “neuroendocrine” or “neuroectodermal” markers, such as S100 protein, synaptophysin, chromogranin, and CD56, is uncommon and usually limited in extent in ES/PNET; in our experience cases showing more robust expression of these markers usually prove to represent other tumor types, such as small cell carcinoma and Merkel cell carcinoma.

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Genetics

Genetically, ES/PNET is characterized by t(11;22)(q24;q12) in over 90% of cases, resulting in the classic EWSR1-FLI1 fusion gene.3–5,36 Most of the remaining cases (∼5%) contain the variant t(21;22) (q22;q12), fusing the EWSR1 gene with ERG.37 Additional alternative fusion partners for EWSR1 have been described, each accounting for <1% of cases, including ETV1, ETV4 (E1AF), FEV, and unknown partners.38–40 Identification of any of these specific translocations is considered highly specific for the diagnosis of ES/PNET. These translocations can be identified by traditional cytogenetics, although RT-PCR based assays on formalin-fixed paraffin-embedded tissue have become fast, reliable, and relatively easy alternatives.41,42 In general, however, RT-PCR assays are only designed to detect the EWSR1-FLI1 and EWSR1-ERG fusions, and not the less common ones. FISH for EWSR1 should detect all EWSR1 rearranged cases, although this finding is by no means specific for ES/PNET.43 Extremely rare cases of ES/PNET may show FUS, rather than EWSR1, rearrangement, most often reflecting the presence of the variant t(16;21) (p11;q22)(FUS-ERG).44

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Differential Diagnosis

The differential diagnosis of cutaneous ES/PNET includes other “round blue cell tumors”, especially those which more regularly involve the skin, either primarily, by direct extension from the underlying soft tissue, or as metastatic disease. These include lymphoblastic lymphoma, small cell carcinoma, Merkel cell carcinoma, small cell melanoma, poorly differentiated synovial sarcoma, and rhabdomyosarcoma.21,30 In general, an approach that integrates clinical, morphologic, immunohistochemical and (when necessary) molecular genetic data should allow for the ready distinction of these tumors.

Lymphoblastic lymphoma can involve the skin and may closely resemble ES/PNET at the light microscopic level. This mimicry may be enhanced by IHC, as lymphoblastic lymphomas are typically diffusely positive for CD99 and FLI-1 protein,31 and often CD45 negative. ERG is less often positive in lymphoblastic lymphoma, but may be expressed by myeloid leukemias.33 Thus, particularly in a child, one should always include markers such as TdT, CD10, and CD43 in the workup of any cutaneous “small blue round cell tumor.” Metastatic small cell carcinoma to the skin typically lacks CD99 expression and shows much more extensive immunoreactivity for cytokeratins, synaptophysin, chromogranin, and CD56. Similarly, Merkel cell carcinomas usually lack CD99 expression, diffusely express neuroendocrine markers, and express more specific markers such as cytokeratin 20 and Merkel cell polyoma virus large T antigen.45 Small cell melanomas, which may be S100 protein negative, are typically strongly positive for HMB45 and Melan-A.46 Poorly differentiated synovial sarcoma can extend to involve the skin, and shows some morphologic overlap with ES/PNET, but typically contains more classic areas of monophasic or biphasic synovial sarcoma.18 Synovial sarcomas also express high–molecular-weight keratins, and are positive for TLE-1 and negative for for FLI-1/ERG.30,31 Alveolar rhabdomyosarcoma shows a greater degree of nuclear variability than does ES/PNET and expresses markers of skeletal muscle differentiation, including desmin, myogenin, and myoD1.18

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ANGIOMATOID (MALIGNANT) FIBROUS HISTIOCYTOMA

Historical and Clinical Features

AMFH was first described by Enzinger in 1979.47 It is a very rare soft tissue tumor that typically occurs in children and young adults.47,48 It has a predilection for the extremities, trunk and head and neck, where it typically forms a small mass in the deep dermis and subcutis.48,49 AMFH can be associated with systemic symptoms including fever, weight loss, lymphadenopathy, and anemia,47,48 thought to be due to cytokine production by the tumor itself.50 Local recurrence of AMFH is common, so complete surgical excision is critical to achieve a cure.47,48 Lymph node and pulmonary metastases are rare (2% to 5%), but can occur, although long-term survival and even cure are still possible in the presence of metastatic disease.47,48 Adverse prognostic features include head and neck location, infiltrative margins and skeletal muscle involvement.48

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Histopathology and Immunohistochemistry

AMFH is characterized by a fibrous pseudocapsule with pericapsular lymphocytic infiltrate, often leading to the false impression that the tumor is arising within or secondarily involving a lymph node (Fig. 2A).47 The tumor cells grow in a fascicular and whorling growth pattern, and generally have a bland histiocytoid to spindled appearance (Fig. 2B).47–49 Cellular atypia and increased mitotic activity are present in a minority of cases, but have not been found to portend a worse outcome.48 Pseudovascular blood-filled spaces are often present, and can be associated with hemosiderin deposition within the tumor cells (Fig. 2C).47,48 Myxoid change can occur in a minority of tumors.48 In long-standing or traumatized tumors, dense fibrosis and hemorrhage can largely obscure the underlying tumor. Such cases often present as “recurrent hematomas,” and this clinical scenario should always prompt careful examination for small nests of AMFH tumor cells. AMFH have an unusual, distinctive immunophenotype, typically showing some combination of CD99, EMA, desmin, and CD68 expression (Figs. 2D–F), in the absence of expression of other myoid (eg, myogenin and MyoD1), endothelial, or histiocytic markers.49,51–53

Figure 2
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Genetics

AMFH are characterized at the molecular genetic level most often by rearrangements of the EWSR1 locus, with FUS rearrangements seen in a smaller percentage of cases.12,54,55 In 80% to 90% of AMFH EWSR1 is fused with the CREB1 gene (located on 2q34), with most of the remaining 10% to 20% of cases showing rearrangements of EWSR1 with ATF1 (located on 12q13); identical EWSR1-CREB1 and EWSR1-ATF1 gene fusions may also seen in CCS of soft parts,56–59 malignant gastrointestinal neuroectodermal tumor (CCS-like tumor of the gastrointestinal tract),60,61 hyalinizing clear cell carcinoma of salivary gland,14 and soft tissue myoepithelioma.62 For unclear reasons, EWSR1 rearrangements in AMFH do not cause downstream activation of the MiTF pathway and melanogenesis, as seen in CCS.54,57

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Differential Diagnosis

The differential diagnosis of AMFH often includes lymph node metastases, as the tumor can so closely resemble a lymph node.47 Careful inspection, however, reveals the absence of normal lymph node structures, such as afferent or efferent sinuses, in AMFH. Particularly in pediatric patients, desmin-positive AMFH may be confused with rhabdomyosarcomas. In general, rhabdomyosarcomas present as larger, more deeply situated masses composed of obviously malignant spindled and round cells, with a variable degree of rhabdomyoblastic differentiation in the form of strap cells and tumor giant cells. In difficult cases, the diagnosis of rhabdomyosarcoma should always be confirmed with immunostains to myogenin and/or MyoD1, which are not expressed by AMFH. Some AMFH may show principally “small cell” morphology, and mimic ES/PNET, a potential pitfall heightened by CD99 expression and EWSR1 rearrangement in both tumors. Again, attention to the characteristic morphologic features of AMFH and the finding of expression of other markers such as EMA, CD68 and desmin should allow this distinction in most cases. Follicular dendritic cell tumors may show considerable morphologic overlap with AMFH, but are extremely uncommon in the skin and superficial soft tissues, and express CD21, CD35 and clusterin, markers negative in AMFH.49,63 Finally, the similar sounding aneurysmal benign fibrous histiocytoma lacks a pseudocapsule and lymphoid aggregates and show typical features of fibrous histiocytoma, including epidermal hyperplasia, collagen trapping, multinucleated giant cells, and foamy macrophages.18 EWSR1 and FUS rearrangements are not seen in any variant of benign fibrous histiocytoma.

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MYOEPITHELIOMA (PARACHORDOMA)

Historical Aspects and Terminology

Parachordoma, first described as “chordoma periphericum” by Laskowski in 1951,64 was more fully described by Dabska in 1977.65 Initially believed to represent chordomas arising in a paramidline or peripheral location, it has subsequently become apparent that these tumors are distinct from true chordomas. Fewer than 60 cases of parachordoma have been reported, reflecting both the rarity of these tumors and the rise of the term “myoepithelioma.”66–74

The term “myoepithelioma/mixed tumor of soft tissue” was first applied to these lesions by Kilpatrick and Fletcher in 1997.75 Subsequently, 4 large series of soft tissue myoepithelial tumors and a large number of case reports have been published, totalling over 200 cases.13,76–78 The most recent WHO classification of soft tissue tumors considers parachordoma and myoepithelioma to be essentially synonymous, with myoepithelioma the preferred term.17

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Clinical Features

Myoepithelioma of soft tissue (MST) typically occurs in adults in the second to fourth decades of life, most often involving the subcutis or deep soft tissues of the thigh, calf, arms, and head/neck.66,75,76 Both primary cutaneous myoepitheliomas and subcutaneous tumors with dermal involvement have been reported.78–81 Although most MST are histologically and clinically benign, some cases locally recur, and others are either histologically malignant, clinically malignant, or both.82,83 The largest series to date by Hornick and Fletcher showed local recurrences and distant metastases in 18% and 0%, respectively, of histologically benign tumors, as compared with 42% and 32% of histologically malignant MST.76 Most cases previously reported as “parachordoma” have behaved in an indolent fashion, although metastasizing examples have been reported.66,84,85 It is unclear whether cutaneous/superficial MST behave in a more indolent fashion than do deeply situated tumors.

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Histopathology and Immunohistochemistry

MST are typically 3 to 7 cm in size, and are generally well-circumscribed masses with a glistening, myxoid cut surface.76 Although grossly well circumscribed, the periphery of MST typically contain small nests of cells that are separated from the main tumor and trail off into the surrounding soft tissue (Fig. 3A), sometimes evoking a desmoplastic reaction. MST show essentially the same range of histologic features as their salivary gland counterparts, most often with chains and cords of epithelioid, ovoid, or spindled cells deposited in a variably collagenous or chondromyxoid stroma (Fig. 3B). The cells of MST may be predominantly spindled, glomoid, or vacuolated (physaliferous-like). Metaplastic cartilage, bone, or both can be seen in a small percentage of cases.

Figure 3
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Most MST show only a mild degree of nuclear atypia, and have mitotic activity less than 1MF/20 HPF.66,75,76,78 However, some are cytologically malignant, being composed of larger cells with vesicular or coarse chromatin and prominent nucleoli.76,77 Some histologically malignant tumors show small benign-appearing foci, whereas others have heterologous chondrosarcomatous or osteosarcomatous differentiation.76 MST occurring in children more often show atypical features.77

Immunohistochemically, MST consistently co-express epithelial markers (low–molecular-weight cytokeratins and/or EMA) and S-100 protein (Figs. 3C, D).66,76,78,86 Cytokeratin expression may, however, be very limited in extent. Expression of other myoepithelial markers, including muscle actins, GFAP, calponin, and p63 is seen in a minority of cases.66,76 The notochordal marker brachyury is negative.87 Loss of expression of SMARCB1 (INI1) may be seen in malignant myoepitheliomas.88

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Genetics

MST are characterized most often by the presence of EWSR1 rearrangements, with a variety of different fusion partners, including PBX1,89 ZNF444,90 POU5F113 and ATF1.62 The EWSR1-POU5F1 fusion seems to be the most common genetic event in MST.13 As with other EWSR1 rearranged tumors, rare MST show FUS rearrangements instead.13 EWSR1 rearrangements have been documented in cutaneous myoepitheliomas (Fig. 3E).79,91 Myoepithelial tumors of soft tissue and skin showing true ductal differentiation (mixed tumors) lack EWSR1 rearrangements, showing instead PLAG1 rearrangements, similar to their salivary gland counterparts.13,92

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Differential Diagnosis

The differential diagnosis of MST is broad and depends upon the predominant cell type and stromal component. If ducts are present, the diagnosis of mixed tumor is straightforward. Dermal mixed tumors also tend to be smaller, more clearly cutaneous in origin,93 and show PLAG1 rearrangements.92 Extra-axial chordomas, which may occur in cutaneous locations, are exceedingly rare, morphologically identical to their axial counterparts, and brachyury positive.87,94 Extraskeletal myxoid chondrosarcomas typically occur as large, deeply situated soft tissue masses, lack expression of cytokeratins, and are usually S100 protein negative. Importantly, both extraskeletal myxoid chondrosarcoma and MST commonly show rearrangements involving the EWSR1 locus. Unlike extraskeletal myxoid chondrosarcoma, however, MST lack rearrangements of NR4A3.91 Ossifying fibromyxoid tumors are often partially surrounded by a shell of bone, typically co-express S100 protein, desmin, and neurofilament protein,95 lack EWSR1 rearrangements,13 and often contain PHF1 rearrangements.96 Myoepithelial carcinoma (malignant myoepithelioma) may be confused with metastatic carcinoma, metastatic melanoma, and even epithelioid sarcoma. Clinical history may obviously be very valuable in making these distinctions, as is IHC for primary site-directed epithelial markers (eg, TTF-1, CDX2) and melanocytic markers (eg, HMB45, Melan-A).

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CLEAR CELL SARCOMA

Historical Aspects

CCS was initially described by Enzinger97 in 1965, who regarded it as a neoplasm of uncertain histogenesis. Interestingly, although Enzinger noted the presence of Fontana-positive pigment in CCS, he regarded this as a potential diagnostic pitfall, rather than as a clue to its line of differentiation. Credit for the recognition of melanocytic differentiation in CCS thus belongs to Hoffman and Carter, who identified melanosomes in CCS cells by electron microscopy.98 In 1983, Chung and Enzinger99 proposed the term “malignant melanoma of soft parts” for this entity, recognizing, however, that the clinicopathologic features of CCS were quite different from those of conventional melanoma. It is now abundantly clear that CCS and conventional melanoma represent clinically and genetically distinct entities sharing melanocytic differentiation.

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Clinical Features

CCS is a very rare tumor that typically affects young to middle-aged adults.99,100 It has a propensity for the deep soft tissues of the foot/ankle, and frequently involves the tendons or aponeuroses.99 Cutaneous involvement is usually seen as secondary extension from large deep-seated lesions, although genetically confirmed primary cutaneous CCS have been reported.101 Lesions are often relatively small at the time of diagnosis (<5 cm) and patients will often give a long history of a slowly growing mass preceding the biopsy.102 Primary cutaneous CCS are usually quite small at the time of diagnosis (<1 cm), but otherwise seem to have similar clinical and pathologic features to more common deep-seated CCS.101

The natural history of CCS is frequently protracted, with multiple local recurrences followed by late metastases to lymph nodes, bone, or lung.97,99,100,102 The survival for patients with metastases is approximately 50% at 5 years, but drops to 33% at 10 years, and 10% at 20 years.99,100,102,103 Wide surgical excision with adjuvant radiation is the treatment of choice. There is an unclear role at this time for chemotherapy and immunotherapy. Some advocate sentinel lymph node biopsy/lymph node dissection,104 similar to conventional melanoma, but this practice has not been widely adopted at this time.

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Histopathology and Immunohistochemistry

CCS is typically centered in the deep soft tissues or subcutis, often in association with tendons or aponeuroses. Cutaneous involvement is typically a late event, although very rare primary cutaneous CCS have been reported, as noted above. Epidermal involvement by nest of tumor cells in cutaneous CCS may closely mimic the junctional component of a conventional melanoma.101 However, pagetoid spread and increased single melanocytes in the basal epidermis should not be present. The cells of CCS are classically arranged in nests, separated by bundles of hyalinized collagen, and may be both epithelioid and spindled in shape (Fig. 4A).97,99 The neoplastic cells tend to have amphophilic to lightly eosinophilic cytoplasm; despite its name, optically clear cell are unusual in CCS. The nuclei of CCS are typically round and regular, with prominent macronucleoli, similar to conventional melanoma (Fig. 4B). In general, CCS is a relatively monomorphic tumor, usually lacking the pleomorphism seen in large, advanced conventional melanomas. Recurrent and/or metastatic CCS may show multinucleated neoplastic Touton-type giant cells, a potentially valuable clue (Fig. 4C). Melanin pigment may be identified, but is usually not prominent. CCS shows an identical immunophenotype as do conventional melanomas, with expression of S100 protein, melan A, HMB45, tyrosinase, and MiTF (Figs. 4D, E).105–107

Figure 4
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Genetics

CCS was first characterized at the cytogenetic level as showing a recurrent t(12;22)(q13;q13).108 It was subsequently shown that translocation results in fusion of EWSR1 to ATF1,109 usually resulting in the creation of the EWSR1-ATF1 fusion gene (over 80% of cases), which is not found in conventional melanoma.56,59,102,103,110 A much smaller percentage of CCS contain the alternative EWSR1-CREB1 fusion, more commonly associated with malignant gastrointestinal neuroectodermal tumor (CCS-like tumor of the gastrointestinal tract)56,60,61,102 and AMFH.12,54 A small number of genetically confirmed CCS have been reported to show BRAF and NRAS mutations, although the frequency of these molecular genetic events seems to be much lower than in conventional malignant melanoma.111–114 EWSR1 rearrangements are not seen in melanomas, although we have seen a number of conventional melanomas that showed additional EWSR1 signals on FISH testing, most likely representing nonspecific gains in 22q.

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Differential Diagnosis

As should be apparent from the above discussion, the most important and difficult differential diagnosis for CCS is with conventional melanoma, given the extensive morphologic and immunohistochemical overlap between these two tumors.102 The presence of a true junctional melanocytic component obviously supports a diagnosis of melanoma, although care should be taken not to mistake epidermal involvement by cutaneous CCS for junctional melanoma.93,101 A high degree of pleomorphism also generally supports conventional melanoma.18 In difficult cases in which the distinction between dermal melanoma and CCS cannot be made on clinical and morphologic grounds, FISH for EWSR1 rearrangement or PCR for the specific CCS-associated fusion genes noted above may be extremely useful.18,101 As noted above, rare cases of bona fide CCS have been reported to contain BRAF or NRAS mutations,111–114 and thus tests for these molecular genetic events must be interpreted with care. It is unclear what if any role recently described FISH panels for melanoma may have in this differential diagnosis.115–117

Other dermal tumors that should be distinguished from CCS include dermal perivascular epithelioid cell neoplasm (PEComa) and cellular blue nevus. PEComas typically show optically clear cytoplasm and lower nuclear grade with smaller nucleoli, and lack the hyalinized collagenous bands and the distinctly nested growth pattern of CCS.118 Although PEComas express melanocytic markers, they also typically express smooth muscle actins, and lack expression of S100 protein.119 Cellular blue nevi tend to involve the scalp and buttock region, uncommon locations for CCS, and show low nuclear grade as well as a component of conventional blue nevus, composed of bland, heavily pigmented spindled cells.18 EWSR1 rearrangements have not been reported in PEComas or cellular blue nevi.

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CONCLUSIONS

Over the past few decades, our understanding of the genetic events underlying many different types of human neoplasia has increased exponentially. This knowledge has revolutionized the diagnosis of certain tumor types, in particular tumors of hematopoietic and soft tissue origin. However, although it was initially hoped that the identification of specific genetic events would prove absolutely specific for individual tumor types, it has become increasingly obvious that this is not the case. Few areas exemplify this as well as the ever-expanding family of tumors characterized by ETS family (EWSR1 or FUS) rearrangements, including the 4 dermal tumors discussed in this article, as well as hyalinizing clear cell tumor of the salivary gland, malignant gastrointestinal neuroectodermal tumor, extraskeletal myxoid chondrosarcoma, desmoplastic small round cell tumor, myxoid liposarcoma, primary pulmonary myxoid sarcoma, low-grade fibromyxoid sarcoma, and sclerosing epithelioid sarcoma.7–10,14,60,61,120,121 It is perhaps even more striking that wholly identical gene fusions can be found in clinically, morphologically, and immunohistochemically entirely different tumors, exemplified by the EWSR1-ATF1 fusion now known to be present in CCS, AMFH, MST, malignant gastrointestinal neuroectodermal tumor, and hyalinizing clear cell tumor of the salivary gland,11,14,55 whereas EWSR1-CREB1 occurs in CCS, AMFH, primary pulmonary myxoid sarcoma, and CCS-like tumor of the gastrointestinal tract.7,54,56,61 As has been discussed by Barr and Zhang, this strongly suggests the importance of factors beyond fusion type in the development of specific tumor types, including the specific gene breakpoints, the cell type in which the fusion occurs, tissue site/microenvironment, epigenetic changes, and the other genetic alterations that occur in the tumor.122 Thus, while molecular genetic studies have contributed immensely to our understanding of soft tissue tumors, and are increasingly important in their diagnosis, they must for the time being remain adjunctive techniques, interpretable only in the context of traditional clinicopathologic analysis.

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Keywords:

Skin; cutaneous; soft tissue; sarcoma; EWSR1; florescence in situ hybridization

© 2013 Lippincott Williams & Wilkins, Inc.

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