ORIGINAL ARTICLE

Epithelioid Malignant Peripheral Nerve Sheath Tumor Clinicopathologic Analysis of 63 Cases Vickie Y. Jo, MD and Christopher D.M. Fletcher, MD, FRCPath

Abstract: Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is rare and differs from conventional malignant peripheral nerve sheath tumor by showing diffuse S-100 protein positivity, infrequent association with NF1, and occasional origin in a schwannoma. Loss of INI1 expression is seen in a subset of tumors. The purpose of this study was to further define clinicopathologic features and outcome data in a large series of EMPNST. Sixty-three cases were identified in consultation files. The patient group consisted of 33 men and 30 women; the median age was 44 years (range, 6 to 80 y). One patient was reported to have NF1. One patient had 3 seemingly separate primary EMPNSTs during his 12-year clinical course. The median tumor size was 3.0 cm (range, 0.4 to 20 cm), and tumors were located most frequently on the lower extremity (30/63; 48%) and trunk (16/63; 25%). Most tumors were superficial (5 dermal, 38 subcutaneous); 15 were subfascial, and 5 were visceral. Microscopically, tumors comprised a relatively uniform but clearly atypical population of epithelioid cells. The majority of tumors demonstrated a multilobular growth pattern, with lobules and nests surrounded by myxoid and/or fibrous stroma. Tumor cells were round, polygonal, or ovoid and had round vesicular nuclei and abundant amphophilic to palely eosinophilic cytoplasm. Focal spindled morphology was seen in one third of cases. Most tumors (55/63; 87%) showed marked cytologic atypia with irregular vesicular nuclei and prominent nucleoli. Mitotic rate ranged from 1 to 46/10 HPF (median, 5/ 10 HPF); atypical mitotic figures were seen in 7 cases. Necrosis was present in 17 tumors. Twelve tumors were associated with a nerve. Nine tumors arose in a schwannoma (6 conventional type, 3 epithelioid) and 1 in a neurofibroma (in the NF1 patient). All tumors expressed S-100 protein, and the majority showed strong and diffuse staining (87%; 55/63). There was no expression of the melanocytic markers Mart-1/Melan-A (0/58), HMB-45 (0/57), and MiTF (0/9). Other immunohistochemical results included variable staining for GFAP (24/40; 60%) and EMA (4/29; 14%), whereas keratin was consistently negative From the Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Presented in part at the 103rd Annual Meeting of the US-Canadian Academy of Pathology, San Diego, March 2014. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Christopher D.M. Fletcher, MD, FRCPath, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: cfl[email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

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(0/33). INI1 expression was lost in 67% of tumors examined (35/ 52). Most tumors were treated by surgical resection; 13 also received chemotherapy and/or radiation. Follow-up data were available for 31 cases and ranged in duration from 3 months to 20 years (median, 36 mo). Twenty-two patients have no evidence of disease at the time of follow-up. Nine patients developed local recurrence, 3 of whom were reported to be disease-free at the time of latest follow-up (44 mo, 19 y, and 20 y). Five patients developed distant metastases, and 4 patients died of disease (including 2 with unresectable recurrent tumors). Recurrence, metastasis, and disease-related death were observed independent of anatomic site or depth. In summary, EMPNST is a morphologically distinct variant that most commonly affects adults on the lower extremity or trunk, although a wide age range and site distribution are seen. Most tumors arise in superficial soft tissue, are diffusely S-100 positive, and two thirds show INI1 loss. On the basis of available follow-up information there is a comparatively low risk for recurrence and metastasis, irrespective of tumor depth. Key Words: malignant peripheral nerve sheath tumor, epithelioid, soft tissue, INI1, sarcoma (Am J Surg Pathol 2015;39:673–682)

irst described in 1954,1 the epithelioid variant of malignant peripheral nerve sheath tumor (MPNST) is rare and is characterized by predominantly epithelioid cytomorphology and a frequently multinodular growth pattern. Epithelioid MPNST (EMPNST) is strikingly different from conventional spindle cell MPNST by showing strong and diffuse S-100 protein staining,2 infrequent association with neurofibromatosis type 1,2,3 and occasional origin in a schwannoma.4,5 Published data are limited, but earlier reports suggested that patients with “superficial” EMPNST (dermal or subcutaneous) have a better prognosis2 compared with “deep” (subfascial) EMPNST, which are believed to behave similarly to conventional MPNST with a significant risk for recurrence, metastasis, and death.2,3 Given its typically strong and diffuse S-100 protein positivity, EMPNST must be distinguished from malignant melanoma, particularly in adult patients. Immunohistochemical analysis for the tumor-suppressor gene product SMARCB1/INI1 may be helpful, as loss of SMARCB1/ INI1 expression has been observed in a subset of EMPNST (around 50% of cases6) but not in melanoma. The

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significance of SMARCB1/INI1 loss of expression is currently unknown but is perhaps secondary to functional loss of material on chromosome 22q11.3 (which encodes the SMARCB1/INI locus), adjacent to the NF2 gene encoded on 22q12. Recently, a novel germline SMARCB1/INI1 mutation (c,245_246insAT) was reported in a patient with “neuroblastoma-like schwannomatosis” who suffered malignant transformation of a schwannoma to EMPNST.7 Given that only limited data have been reported for EMPNST, the clinicopathologic features remain incompletely defined. In this series, we describe the clinical, histopathologic, and immunohistochemical features of 63 cases of EMPNST, with attention to clinical outcome and differential diagnoses.



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Institutional Review Board at the Brigham and Women’s Hospital, Boston, MA.

RESULTS Clinical Features The patient group consisted of 33 men and 30 women, with a median age of 44 years (range 6 to 80 y). One patient was reported to have NF1. Affected anatomic sites were lower extremity (30; 4 on foot), upper extremity (6; 1 on hand), trunk (16), neck (4), lip (2), and visceral locations (5; 1 each in ileum, prostate, pleura, mediastinum, and retroperitoneum, respectively). For tumors in somatic sites, 5 were dermal, 38 subcutaneous, and 15 subfascial. Most patients presented with a slowly enlarging mass, described in a subset as painful. Reported preoperative duration ranged from 1 month to 20 years. No patient was known or reported to have a history of melanoma. Suggested clinical diagnoses included lipoma, hemangioma, schwannoma, neurofibroma, and low-grade sarcoma. Proposed diagnoses by referring pathologists included malignant melanoma (13), clear cell sarcoma (6), extraskeletal myxoid chondrosarcoma (EMCS) (5), epithelioid sarcoma (2), myoepithelioma (4), myoepithelial carcinoma (2), schwannoma (6; 3 suggested to be epithelioid), and nerve sheath tumor, not otherwise specified (3). MPNST was the suggested diagnosis in 22 cases, 12 of which were suggested to be the epithelioid variant and sent in consultation for confirmation.

MATERIALS AND METHODS Sixty-three cases identified as EMPNST between 1993 and 2013 were retrieved from consultation files of one of the authors (C.D.M.F). Three of these cases have been reported previously.5,8,9 Hematoxylin and eosin– stained sections were evaluated for the following histologic features: growth pattern, presence of a capsule, nuclear and cytoplasmic features, cytologic atypia, the presence of necrosis, mitotic rate (recorded as number of mitotic figures per 10 high-power fields [HPF]; field size 0.25 mm2), stromal features, and association with a preexisting nerve, schwannoma, or neurofibroma. Immunohistochemical analysis was performed in our laboratory on 4-mm-thick formalin-fixed paraffin-embedded tissue sections (when available) using the antibodies and conditions listed in Table 1. The Envision Plus detection system (Dako, Carpinteria, CA) was used for all antibodies. Appropriate positive and negative controls were used throughout. Immunoreactivity was recorded according to the percentage of positive tumor cells (0/ negative, no staining; 1+/focal, 75%) and intensity of staining (graded as weak, moderate, and strong). Clinical and follow-up data were obtained from medical records and referring pathologists using a standardized data sheet (see the Acknowledgments section). This study was performed with the approval of the

Gross and Microscopic Features Tumor size ranged from 0.4 to 20 cm (median 3.0 cm). Most tumors were well circumscribed and described as having cystic, firm, or lobular cut surfaces. Hemorrhage and necrosis were observed grossly in 9 tumors. Microscopically, tumors comprised a relatively uniform but clearly atypical population of epithelioid cells. The majority of tumors (0/59) demonstrated a multilobular growth pattern (Fig. 1); however, 4 tumors were circumscribed nodules, and 2 showed solid sheet-like growth of tumor cells (Fig. 2). Among superficially located tumors, 1/5 dermal lesions and 11/38 subcutaneous lesions appeared to be encapsulated. Tumors were characterized by myxoid and/or fibrous stroma (often prominent), in

TABLE 1. Immunohistochemistry: Sources, Clones, Dilutions, and Pretreatment Conditions Antibody S-100 protein Mart-1 Melan-A HMB-45 MiTF INI1 GFAP EMA CK (Pan-keratin) CK (AE1/AE3) CK (CAM5.2)

Source

Clone

Dilution

Pretreatment

Dako Covance Dako Dako Dako BD Biosciences Dako Dako Dako Dako Dako

Polyclonal M2-7C10 A103 HMB-45 34CA5 Mo25 Polyclonal E29 MNF-116 AE1+AE3 CAM5.2

1:1000 1:100 1:200 1:400 1:4 1:200 1:15,000 1:200 1:700 1:200 1:50

None Citrate buffer, pressure cook Citrate buffer, pressure cook None Citrate buffer, pressure cook Citrate buffer, EDTA Citrate buffer, pressure cooker None 10 min protease digestion 10 min protease digestion 10 min protease digestion

CK indicates cytokeratin; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; SMA, smooth muscle actin.

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FIGURE 1. Most EMPNSTs showed a multilobulated growth pattern.

FIGURE 3. Tumor cells were arranged in nests or cords associated with a fibromyxoid stroma in most cases.

which lobules, nests, and cords of single cells were embedded (Fig. 3). Tumor cells were round, polygonal, or ovoid in shape and had round nuclei and abundant amphophilic to palely eosinophilic cytoplasm (Fig. 4). Most tumors showed moderate to severe cytologic atypia with irregular vesicular nuclei and prominent nucleoli (Fig. 5). Eight tumors showed milder atypia with vesicular round nuclei and small nucleoli but had greater atypia and pleomorphism than expected for epithelioid schwannoma (Fig. 6). Among these 8 lesions, only 2 were encapsulated and both of these showed frequent mitotic figures. One third of tumors exhibited focally spindled morphology (Fig. 7). Mitotic rates ranged from 1 to 46/10 HPF (median 5/10 HPF) (Fig. 8A); atypical mitotic figures were seen in 7 cases (Fig. 8B). Seventeen tumors exhibited necrosis, all of which were characterized by at least moderate atypia and frequent mitoses (median rate 10/10 HPF). No necrosis was seen in the 8 tumors with milder cytologic atypia, which also showed a generally lower mitotic rate (median rate

1/10 HPF, range 1 to7/HPF); 7 of these tumors were subcutaneous in depth, and 1 was dermal. Other notable histologic features included rhabdoid cytomorphology (2 cases), prominent multinucleate giant cells (1 case), nuclear inclusions (2 cases), clear cell morphology (1 case), and perivascular whorling (2 cases). Heterologous chondroosseous differentiation was observed in 1 case (Fig. 9). Overall, 12 tumors arose in clear association with a nerve. Nine tumors arose in a schwannoma (6 conventional, 3 epithelioid) (Fig. 10) and 1 in a neurofibroma (in the NF1 patient). Table 2 summarizes the clinicopathologic data of the study group.

FIGURE 2. Areas of solid sheet-like growth in EMPNST were occasionally observed. Copyright

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Immunohistochemical Findings All tumors expressed S-100 protein (63/63): the majority of cases (88%; 55/63) showed strong and diffuse staining (Fig. 11A), whereas there was multifocal staining in 7 cases

FIGURE 4. Tumors were composed of a uniform population of cells with round, vesicular nuclei and abundant amphophilic cytoplasm. www.ajsp.com |

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FIGURE 5. Most tumors were showed moderate to severe atypia with irregular nuclei and prominent nucleoli.

FIGURE 7. Spindled foci with myxoid matrix were occasionally present.

and focal positivity in 1 case. There was no expression of the melanocytic markers Mart-1/Melan-A (0/58) (Fig. 11B), HMB-45 (0/57), and MiTF (0/9). GFAP was positive in 60% (24/40) of cases, with staining ranging from diffuse (2), to multifocal (10), to focal (12). Four cases (4/29; 14%) showed rare cells positive for EMA, which also highlighted a capsule in 7 cases (2 of which were tumors arising in schwannoma). INI1 expression was lost in 67% of tumors (35/52) (Fig. 11C). Keratin (1 or more: pan-keratin, AE1/AE3, CAM5.2) was consistently negative in all cases tested (0/33).

disease at the time of follow-up; of these, 13 tumors were dermal/subcutaneous in depth, 7 were deep, and 2 tumors were in visceral locations. Nine patients developed local recurrence (2 to 180 mo after surgery, median 7 mo), including 1 histologically low-grade primary tumor and 4 cases with negative resection margins. Of the patients with local recurrence, 3 were reported to have no evidence of disease at the time of subsequent follow-up (44 mo, 19 y, and 20 y). One patient with a neck primary died secondary to an unresectable recurrent tumor extending into the skull, and another patient with a leg primary died due to complications of local recurrence. The distribution of anatomic depth of tumors that recurred was dermal/ subcutaneous (5), deep (3), and visceral (1). Five patients had metastases to distant sites; all primary tumors (3 subcutaneous, 1 deep, 1 visceral) showed moderate to severe cytologic atypia, and 2 showed necrosis; 2 had been resected with negative margins. Metastatic sites included lung, bone, brain, and lymph node; 1 patient had multiple metastases to lung, bone, and lymph node. The 2 tumors associated with lymph node metastasis were subcutaneous primaries, 1 with a prominent myxoid stroma and 1 arising in a schwannoma; in neither case was melanoma a diagnostic consideration. Four patients died of disease (including the previously mentioned case), all having tumors with moderate to severe cytologic atypia and necrosis; 2 were subcutaneous, 1 was deep, and 1 was visceral. Two patients suffered local recurrence (neck and leg primary sites, both locally unresectable), 1 patient had distant metastases, and the fourth patient had both local recurrence and lung metastasis. Interestingly, 1 patient had 3 clinically distinct and separate primary EMPNSTs over a 12-year period in the absence of any evident metastasis; tumors were in the subclavian region, thigh, and axilla. All 3 primary tumors were examined and demonstrated INI1 loss; no genetic data for the patient were available at the time of latest follow-up. The clinicopathologic features of the cases with available follow-up data are summarized in Table 3.

Treatment and Outcome Most patients were treated by surgical resection (9 with positive margins, 15 marginal, 26 with wide margins); 13 received chemotherapy and/or radiation (either preoperative or postoperative). Follow-up data were available for 31 cases (range 3 mo to 20 y; median duration 36 mo). Twenty-two patients had no evidence of

FIGURE 6. Eight tumors showed milder cytologic atypia with vesicular round nuclei and small nucleoli, but most were unencapsulated and notably mitotic.

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FIGURE 8. Mitoses were readily found in most cases (A), and atypical mitotic figures were seen in a subset of cases (B).

DISCUSSION The epithelioid variant of MPNST is a distinct subtype that is characterized by predominantly epithelioid cytomorphology and a frequently multilobular

FIGURE 9. One tumor showed heterologous chondro-osseous differentiation. Copyright

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growth pattern. Its immunophenotype is distinctive, with diffuse S-100 positivity and INI1 loss in two thirds of cases (67%). Similar to prior reports, these tumors most commonly affect adult patients (median 44 y) and are most frequently located on the lower extremity (30/63; 48%), although a wide age range (6 to 80 y) and site distribution was observed. Men and women were equally affected. Tumors can show somewhat aggressive biological behavior (recurrence, metastasis, disease-related death) regardless of histologic grade and anatomic depth of tumor, although this seems to be relatively infrequent. Whereas conventional MPNST may sometimes show focally epithelioid morphology, EMPNST is characterized by a predominance of epithelioid tumor cells showing a multilobular growth pattern with myxoid and/or fibrous stroma, with foci of spindled morphology only being observed in a subset of cases. Most tumors showed moderate to severe cytologic atypia, with a median mitotic rate of 5/ 10 HPF. One tumor showed heterologous chondro-osseous differentiation; heterologous differentiation is well known to occur in MPNST, and there is 1 previously reported EMPNST that showed cartilaginous differentiation.10 In contrast to conventional MPNST, association with a neurofibroma or type 1 neurofibromatosis seems rare, with www.ajsp.com |

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FIGURE 10. Nine tumors arose in a benign schwannoma (A, conventional schwannoma; B, epithelioid schwannoma).

only 1 patient known to have type 1 neurofibromatosis in this series. Nine cases (14%) of EMPNST arose in association with a schwannoma, a rare occurrence that has been TABLE 2. Clinicopathologic Features of the Study Group (n = 63) Feature Age, median (range) (y) Sex Male Female Anatomic site Lower extremity Upper extremity Neck Trunk Lip Visceral Anatomic depth Dermal Subcutaneous Deep (subfascial) Visceral Tumor size, median (range) (cm)

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N/Total (%) 44 (6-80) 33/63 (52) 30/63 (48) 30/63 6/63 4/63 16/63 2/63 5/63

(48) (10) (6) (25) (3) (8)

5/63 (8) 38/63 (60) 15/63 (24) 5/63 (8) 3.0 (0.4-20.0)

reported occasionally in the past,2,4,5,7–9,11 some cases being preceded by epithelioid malignant change in the schwannoma.5 By contrast, “conventional” MPNST with spindle cell morphology arising in schwannoma is a truly exceptional occurrence.12 Although it has been demonstrated quite recently that EMPNST lacks expression of the tumor suppressor INI1 in around 50% of cases,6 the mechanism of loss/deletion is currently unknown. However, insights are emerging, as Carter et al7 reported a novel germline mutation (c,245_246insAT) in a patient with “neuroblastoma-like schwannomatosis” who suffered malignant transformation of a schwannoma to EMPNST. “Mosaic” or “partial” loss of INI1 has been reported in the majority of schwannomas arising in familial schwannomatosis and approximately half of the tumors associated with sporadic schwannomatosis but in only 5% of sporadic schwannomas (histologic subtype not indicated by the authors).13 Interestingly, 1 patient in our series had 3 separate primary EMPNST tumors during his clinical course, first presenting with a subclavian mass at 18 years of age, followed by a thigh primary at age 25 years, and finally an axillary tumor at age 30 years. All tumors demonstrated absent INI1 immunoreactivity, raising the possibility of a SMARCB1/INI1 germline Copyright

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Epithelioid MPNST

FIGURE 11. EMPNST was consistently positive for S-100 protein, most frequently in a strong and diffuse pattern (A). All tumors tested were negative for the melanocytic markers Mart-1/Melan-A (B), HMB-45, and MiTF. C, INI1 expression was absent/lost in 67% of cases.

mutation. Genetic testing data had not been performed for this patient at the time of most recent available follow-up. Similar to prior reports, there is a risk for local recurrence and metastasis in EMPNST. Although the majority of EMPNSTs in our series showed moderate to severe cytologic atypia, 1 recurrent tumor had only mild atypia, showed low mitotic activity, and lacked necrosis. However, the histologic grade of EMPNST appears not to correlate reliably with prognosis, similar to conventional MPNST.14,15 In 1986, Lodding et al3 reported that 7 of 14 patients with EMPNST developed metastatic disease; a total of 9 patients in the cohort died, which is a noticeably poorer outcome than that described in other series. In a series of 26 EMPNSTs reported 5 years later, Laskin et al2 reported that 3 of 10 patients with deepseated EMPNST developed metastatic disease, but only 2 of 16 patients with superficial tumors developed metastases. However, we found that among the 43 patients with superficially located tumors, 5 developed recurrence, 3 developed metastases, and 2 died of disease. Our findings support that EMPNST in superficial locations exhibits the same potentially aggressive biological Copyright

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behavior as its deep-seated counterparts. It is perhaps possible that some of the superficially located tumors studied by Laskin et al2 were epithelioid schwannomas, which were not well characterized until more recently and which may show worrisome nuclear features. Distinction between EMPNST and epithelioid schwannoma may be difficult, especially in cases of EMPNST showing milder cytologic atypia—in fact, as yet, there are no clearly agreed or validated criteria to help underpin this distinction. Both entities show diffuse S-100 protein positivity. Epithelioid schwannoma is rare and has been described only in reports and small series.16–19 In our experience, tumors are well circumscribed and typically encapsulated, mostly dermal or subcutaneous, and lack significant cytologic atypia. Tumor cells are epithelioid with variable amounts of amphophilic to eosinophilic cytoplasm and can resemble EMPNST at low-power magnification with a multilobular growth pattern and a frequently fibrous and myxoid stroma. Although all schwannomas (conventional and epithelioid) can show degenerative nuclear atypia, EMPNST should be favored when there is diffuse nuclear atypia and www.ajsp.com |

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TABLE 3. Clinicopathologic Features for Cases With Outcome Data (n = 31) Feature Sex Male Female Age, median (y) Tumor depth Dermal Subcutaneous Deep Visceral Tumor size, median (cm) Necrosis Mitotic count (per 10 HPF) Atypical mitoses Cytologic atypia Mild Moderate to severe Margin status Negative Positive NA

A/NED (n = 22)

Recurrence (n = 9)

Metastasis (n = 5)

Death (n = 4)

11 11 44

7 2 48

4 1 48

4 — 41

1 12 7 2 3.0 8/22 3.5 2/22

1 4 3 1 4.5 6/9 4.5 1/9

— 3 1 1 6.0 2/5 14 2/5

— 2 1 1 5.0 4/4 12.5 1/4

3 19

1 8

— 5

— 4

18 4 —

4 3 2

2 1 2

2 1 1

A/NED indicates alive and/or no evidence of disease; NA, not available.

pleomorphism, vesicular nuclei, or atypical mitotic figures. Necrosis would also favor the diagnosis of EMPNST. Furthermore, foci resembling conventional schwannoma can sometimes be seen in the epithelioid variant. As discussed above, most sporadic (conventional) schwannomas retain INI1, but those associated with familial or sporadic schwannomatosis show partial or mosaic INI1 loss; whereas Patil et al13 did not specify whether their included cases were epithelioid or regulartype sporadic schwannoma, in our unpublished experience we have found that most epithelioid schwannomas are INI1 negative. Benign epithelioid peripheral nerve sheath tumors, including those that cannot be definitively classified as neurofibroma or schwannoma, follow a benign clinical course17,20; thus distinction from EMPNST is important where possible, given the propensity of the latter for recurrence and metastasis. The differential diagnosis of EMPNST also includes malignant melanoma, myoepithelial carcinoma, proximaltype epithelioid sarcoma, epithelioid myxofibrosarcoma, and less often EMCS and (on morphologic grounds) carcinoma. However, given the broad range of patient age and tumor sites of EMPNST, the differential diagnosis may be more extensive. An inclusive immunohistochemistry panel including keratins and S-100 will help to exclude carcinoma, and association with a nerve will favor EMPNST over other mesenchymal entities. Malignant melanoma (and its metastases) may occur at virtually any anatomic site and often shows strong and diffuse S-100 staining, a nested growth pattern, and epithelioid morphology. However, malignant melanoma typically shows greater cytologic atypia and pleomorphism, as well as intact INI1 positivity, whereas EMPNST lacks expression of the melanoma-associated markers Melan-A/Mart-1, HMB-45, and MiTF. Myxoid stroma is frequent in EMPNST but notably rare in ma-

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lignant melanoma. The presence of melanin pigment would strongly suggest malignant melanoma. Careful examination to confirm the absence of a junctional component, attention to clinical records to exclude a history of a prior melanocytic neoplasm, and application of immunohistochemistry should help distinguish EMPNST from malignant melanoma in most cases. Loss of INI1 also occurs in myoepithelial carcinoma and proximal-type epithelioid sarcoma,6 2 entities that share many demographic and morphologic features with EMPNST. Myoepithelial carcinoma is typically characterized by cytologic atypia in epithelioid, ovoid, or spindled cells, often arranged in nests, cords, or a reticular pattern. Similar to EMPNST, chondromyxoid stroma is frequent, and when myoepithelial carcinoma is dominated by epithelioid cells the distinction may be difficult. Myoepithelial carcinoma also demonstrates S-100 protein positivity (sometimes strong and multifocal) but, unlike EMPNST, shows expression of cytokeratin (pan-keratin, AE1/AE3, Cam5.2) and/or EMA. INI1 loss is reported in 10% of myoepithelial carcinomas in adult patients6 and in up to 41% of pediatric myoepithelial carcinomas of soft tissue.21 EWSR1 gene rearrangements are associated with a subset of myoepitheliomas and myoepithelial carcinomas of soft tissue.22–24 Proximal-type epithelioid sarcoma most frequently occurs in inguinal, pelvic, and perineal sites in young adults and is composed of sheets of epithelioid cells having copious eosinophilic cytoplasm, large, vesicular nuclei, and distinct nucleoli.25 Myxoid stroma is rare in epithelioid sarcoma, and a multilobular growth pattern favors EMPNST. Despite the fact that INI1 loss characterizes both EMPNST and epithelioid sarcoma, differential diagnosis should be straightforward with application of immunohistochemistry. Epithelioid sarcoma is negative for S-100 and positive for pan-keratin, EMA, and often CD34 (in around 50% of cases). INI1 loss and Copyright

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S-100 positivity (in some cases) is also shared with EMCS, but hematoxylin and eosin morphology usually allows ready distinction as EMCS consists of spindled or ovoid cells with limited amounts of eosinophilic cytoplasm, typically with delicate cytoplasmic processes arranged in a strikingly reticular manner. Epithelioid myxofibrosarcoma is another diagnostic consideration, especially given the shared propensity for lower limb location and multinodular growth pattern. However, epithelioid myxofibrosarcoma tends to occur in older adults, is usually much more pleomorphic, and is negative for S-100 protein.26 Most cases of epithelioid myxofibrosarcoma have focal areas of conventional myxofibrosarcoma, with alternating hypercellular and hypocellular areas, curvilinear vessels around which tumors cells are aggregated, and mucin-containing pseudolipoblasts. In summary, the epithelioid variant of MPNST comprises relatively uniform but atypical epithelioid tumor cells, typically showing a multilobular growth pattern in which nests, cords, and single cells are associated with a myxoid and/or fibrous stroma. Overall, EMPNST is often smaller and more superficial than conventional MPNST and is distinctive for only rare association with type 1 neurofibromatosis, occasional origin in a schwannoma, and a distinct immunophenotype. EMPNST is characterized by multifocal to diffuse and strong staining for S-100 protein, and INI-1expression is lost in up to two thirds of cases. On the basis of available follow-up information there is a risk for recurrence, metastasis, and disease-related death for both superficially located tumor and deep-seated tumors, but this risk seems lower than that for conventional MPNST. ACKNOWLEDGMENTS The authors thank the following pathologists who kindly submitted the cases and provided clinical follow-up information when available: Dr M. Afonso, Porto, Portugal; Dr M. A˚kerman, Lund, Sweden; Dr G. Amann, Vienna, Austria; Dr M. Arida, Greensboro, NC; Dr C. Bacchi, Botucatu, Brazil; Dr P. Bacchini, Bologna, Italy; Dr K. Balachandran, Kerala, India; Dr B. Bartlett, Fort Worth, TX; Prof. F. Bertoni, Bologna, Italy; Dr J. Chuah, Singapore; Dr R. Conrad, Indooroopilly, Australia; Dr K. Cooper, Philadelphia, PA; Dr A. Covert, Halifax, Canada; Dr K. Dakin-Hache´, Halifax, Canada; Dr H. Domanski, Lund, Sweden; Dr W. Duke, Springfield, MA; Dr F. Ellinger, Marilia, Brazil; Dr R. Factor, Salt Lake City, UT; Dr D. Ferber, Milwaukee, WI; Dr C. Galant, Bruxelles, Belgium; Dr M. Horton, Seattle, WA; Dr P. Jedlicka, Denver, CO; Dr H. Kalekou-Greka, Thessaloniki, Greece; Dr Z. Karanjawala, Sacramento, CA; Prof. D. Katenkamp, Jena, Germany; Dr R. Knierim, Seattle, WA; Dr U. Krishnamurti, Pittsburgh, PA; Dr M. Lapsley, Surrey, United Kingdom; Dr L. Layfield, Columbia, Missouri; Prof. M. Leader, Dublin, Ireland; Dr J.-C. Lee, Taipei, Taiwan; Dr H. Llewellyn, Victoria, Australia; Dr D. Lucas, Ann Arbor, MI; Dr A. Mansoor, Portland, OR; Dr V. McKane, Muskogee, OK; Dr T. Mentzel, Friedrichshafen, Copyright

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Epithelioid MPNST

Germany; Dr T. Merrick, Denver, CO; Dr C. Mitchell, Victoria, Australia; Dr J. Morawski, Poughkeepsie, NY; Dr G. Niedt, New York, NY; Dr M. Nowacki, Louisville, KY; Dr J. O’Connell, Herndon, VA; Dr H. Qureshi, Herndon, VA; Dr M. Scarpelli, Ancona, Italy; Dr S. Schreiner, Orlando, FL; Dr K. Sirgi, Denver, CO; Dr H. Sonobe, Hiroshima, Japan; Dr C. Szpak, Raleigh, NC; Dr A. Talleyrand, Newark, NJ; Dr J.M.H.H. van Gorp, Utrecht, The Netherlands; Dr S. Warren, Indianapolis, IN; Dr D. Wilhyde, Tacoma, WA; Dr G.R. Williams, London, United Kingdom; Dr T.Zdunek, Chicago, IL; Dr T. Zhang, West Palm Beach, FL; Dr A. Zieske, Dallas, TX. REFERENCES 1. McCormack LJ, Hazard JB, Dickson JA. Malignant epithelioid neurilemoma (schwannoma). Cancer. 1954;7:725–728. 2. Laskin WB, Weiss SW, Bratthauer GL. Epithelioid variant of malignant peripheral nerve sheath tumor (malignant epithelioid schwannoma). Am J Surg Pathol. 1991;15:1136–1145. 3. Lodding P, Kindblom LG, Angervall L. Epithelioid malignant schwannoma. A study of 14 cases. Virchows Arch A Pathol Anat Histopathol. 1986;409:433–451. 4. Woodruff JM, Selig AM, Crowley K, et al. Schwannoma (neurilemoma) with malignant transformation. A rare, distinctive peripheral nerve tumor. Am J Surg Pathol. 1994;18:882–895. 5. McMenamin ME, Fletcher CD. Expanding the spectrum of malignant change in schwannomas: epithelioid malignant change, epithelioid malignant peripheral nerve sheath tumor, and epithelioid angiosarcoma: a study of 17 cases. Am J Surg Pathol. 2001;25:13–25. 6. Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol. 2009;33:542–550. 7. Carter JM, O’Hara C, Dundas G, et al. Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with “neuroblastoma-like” schwannomatosis and a novel germline SMARCB1 mutation. Am J Surg Pathol. 2012;36:154–160. 8. Rasbridge SA, Browse NL, Tighe JR, et al. Malignant nerve sheath tumour arising in a benign ancient schwannoma. Histopathology. 1989;14:525–528. 9. Mikami Y, Hidaka T, Akisada T, et al. Malignant peripheral nerve sheath tumor arising in benign ancient schwannoma: a case report with an immunohistochemical study. Pathol Int. 2000;50:156–161. 10. Yamamoto T, Minami R, Ohbayashi C. Subcutaneous malignant epithelioid schwannoma with cartilaginous differentiation. J Cutan Pathol. 2001;28:486–491. 11. Chen Y, Diamond AS, Vaheesan KR, et al. Retroperitoneal neurofibrosarcoma in a patient with neurofibromatosis. 2: a case report and review of the literature. Pediatr Pathol Mol Med. 2003; 22:375–381. 12. Endo M, Yamamoto H, Harimaya K, et al. Conventional spindle cell-type malignant peripheral nerve sheath tumor arising in a sporadic schwannoma. Hum Pathol. 2013;44:2845–2848. 13. Patil S, Perry A, Maccollin M, et al. Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas. Brain Pathol. 2008;18:517–519. 14. Coindre JM, Terrier P, Guillou L, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91: 1914–1926. 15. Hagel C, Zils U, Peiper M, et al. Histopathology and clinical outcome of NF1-associated vs. sporadic malignant peripheral nerve sheath tumors. J Neurooncol. 2007;82:187–192. 16. Smith K, Mezebish D, Williams JP, et al. Cutaneous epithelioid schwannomas: a rare variant of a benign peripheral nerve sheath tumor. J Cutan Pathol. 1998;25:50–55.

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17. Kindblom LG, Meis-Kindblom JM, Havel G, et al. Benign epithelioid schwannoma. Am J Surg Pathol. 1998;22:762–770. 18. Saad AG, Mutema GK, Mutasim DF. Benign cutaneous epithelioid Schwannoma: case report and review of the literature. Am J Dermatopathol. 2005;27:45–47. 19. Rezanko T, Sari AA, Tunakan M, et al. Epithelioid schwannoma of soft tissue: unusual morphological variant causing a diagnostic dilemma. Ann Diagn Pathol. 2012;16:521–526. 20. Laskin WB, Fetsch JF, Lasota J, et al. Benign epithelioid peripheral nerve sheath tumors of the soft tissues: clinicopathologic spectrum of 33 cases. Am J Surg Pathol. 2005;29:39–51. 21. Gleason BC, Fletcher CD. Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases. Am J Surg Pathol. 2007;31:1813–1824. 22. Antonescu CR, Zhang L, Chang NE, et al. EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing

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common involvement of the EWSR1 gene. Genes Chromosomes Cancer. 2010;49:1114–1124. Jo VY, Antonescu CR, Zhang L, et al. Cutaneous syncytial myoepithelioma: clinicopathologic characterization in a series of 38 cases. Am J Surg Pathol. 2013;37:710–718. Flucke U, Palmedo G, Blankenhorn N, et al. EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases. Mod Pathol. 2011;24:1444–1450. Guillou L, Wadden C, Coindre JM, et al. “Proximal-type” epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series. Am J Surg Pathol. 1997;21: 130–146. Nascimento AF, Bertoni F, Fletcher CD. Epithelioid variant of myxofibrosarcoma: expanding the clinicomorphologic spectrum of myxofibrosarcoma in a series of 17 cases. Am J Surg Pathol. 2007; 31:99–105.

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Epithelioid malignant peripheral nerve sheath tumor: clinicopathologic analysis of 63 cases.

Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is rare and differs from conventional malignant peripheral nerve sheath tumor by showing ...
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