J Cutan Pathol 2014 doi: 10.1111/cup.12340 John Wiley & Sons. Printed in Singapore

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Journal of Cutaneous Pathology

Primary cutaneous epithelioid rhabdomyosarcoma: a rare, recently described entity with review of the literature We report a case of a primary cutaneous epithelioid rhabdomyosarcoma that presented as a single raised pink-purple lesion (3.3 × 2.2 cm) on the left base of neck in a 75-year-old man. Histopathologic examination revealed an exophytic, nodular tumor within the dermis and superficial subcutis with overlying ulceration. The tumor exhibited sheet-like growth, infiltration of adjacent structures, and was composed of uniform epithelioid cells with abundant eosinophilic cytoplasm and eccentrically placed vesicular nuclei with irregular nuclear contours and prominent central nucleoli. Numerous mitotic figures were present [28/10 high power fields (HPF)] but only mild cytologic pleomorphism was identified. By immunohistochemistry, tumor cells were diffusely and strongly positive for desmin and MYOD1. Focal positive staining for myogenin and cytokeratin CK903 was identified. Stains for Melan-A, S-100, SOX10, p63 and CK5/6 were negative. These histopathologic and immunophenotypic features support a diagnosis of epithelioid rhabdomyosarcoma. No evidence of a deep soft tissue primary lesion was identified. In summary, epithelioid rhabdomyosarcoma can present as a primary cutaneous lesion and dermatopathologists should be aware of this entity. Keywords: cutaneous neoplasm, immunohistochemistry, soft tissue tumors Feasel PC, Marburger TB, Billings SD. Primary cutaneous epithelioid rhabdomyosarcoma: a rare, recently described entity with review of the literature. J Cutan Pathol 2014. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Rhabdomyosarcoma is a malignant mesenchymal neoplasm with skeletal muscle differentiation that can occur in any anatomic location. It is the most common soft tissue sarcoma in children and adolescents, accounting for approximately 8% of all pediatric tumors1 but is rare in persons older than 45 years; accounting for less

Patrick C. Feasel1∗ , Trent B. Marburger1,2∗ and Steven D. Billings1,2 1

Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA, and 2 Department of Dermatology, Cleveland Clinic, Cleveland, OH, USA ∗ These authors contributed equally to this work and are considered as co-first authors.

Steven D. Billings, Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA Tel: 216-444-2826 Fax: 216-445-6967 e-mail: [email protected] Accepted for publication March 12, 2014

than 3% of adult sarcomas.2 Epithelioid rhabdomyosarcoma is a recently proposed and morphologically distinct variant of rhabdomyosarcoma seen predominantly in adults.3 It is characterized by sheet-like growth of uniformly sized epithelioid cells with abundant amphophilic to eosinophilic cytoplasm, large vesicular nuclei

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Feasel et al. and prominent nucleoli.3 The differential diagnosis of epithelioid rhabdomyosarcoma includes aggressive epithelioid neoplasms such as poorly differentiated carcinoma, melanoma and other mesenchymal neoplasms with epithelioid morphology. Herein, we present a case of cutaneous epithelioid rhabdomyosarcoma in an elderly man and review the current literature on cutaneous presentations in this tumor. Report of a patient A75-year-old man presented with a single raised pink-purple nodule (3.3 × 2.2 cm) located on the left base of neck. Microscopic sections demonstrated diffuse replacement of the dermis by a sheet-like growth of epithelioid cells with overlying ulceration (Fig. 1). On high power, the tumor is predominantly composed of uniformly sized epithelioid cells with eccentric nuclei, prominent central nucleoli and abundant eosinophilic cytoplasm (Fig. 2). Multiple mitotic figures, including atypical forms are scattered throughout the tumor (Fig. 2). In areas the tumor cells were suspended in a myxoid matrix (Fig. 3). The tumor infiltrated through the collagen bundles of the reticular dermis (Fig. 4, left) and subcutaneous fibroadipose tissue (Fig. 4, right). Multiple foci of tumoral necrosis were identified (Fig. 5). Immunohistochemical stains in our case demonstrated tumor cells with strong and diffuse positive immunohistochemical staining for desmin (Fig. 6, left) and MyoD1 (Fig. 6, right). Tumor cells were focally positive for myogenin and cytokeratin CK903 (Fig. 7). Stains for Melan-A, S-100, SOX10, p63 and CK5/6 were negative in tumor cells. This case was received in consultation from an outside institution and despite our best efforts no clinical follow up or information regarding treatment was available. Discussion Epithelioid rhabdomyosarcoma is a recently described and potentially under-recognized variant of rhabdomyosarcoma characterized by sheet like growth of uniform epithelioid cells with abundant eosinophilic cytoplasm, large vesicular nuclei and prominent nucleoli. Our case represents the fourth cutaneous epithelioid rhabdomyosarcoma reported in the English language literature to date. In the original description by Jo et al., two subcutaneous tumors were described among the 16 cases reviewed.3

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Fig. 1. Epithelioid rhabdomyosarcoma with overlying ulceration (×6).

Fig. 2. Epithelioid rhabdomyosarcoma demonstrating a sheet-like growth of uniformly sized epithelioid cells with eccentric nuclei, prominent central nucleoli and multiple mitotic figures (×400).

Marburger et al. identified one case of cutaneous epithelioid rhabdomyosarcoma arising within the dermis in their review of primary cutaneous rhabdomyosarcoma.4 Thus, including the case presented herein, 16% of reported cases of epithelioid rhabdomyosarcoma to date have presented as superficial lesions.3 – 7 This suggests that superficial presentation of this rhabdomyosarcoma subtype is more common in comparison to other rhabdomyosarcoma subtypes.

Epithelioid rhabdomyosaroma

Fig. 3. Epithelioid rhabdomyosarcoma with epithelioid neoplastic cells suspended in a myxoid stroma (×200).

Fig. 6. Epithelioid rhabdomyosarcoma demonstrating immunohistochemical staining with desmin (left, ×200) and MYOD1 (right, ×200).

Fig. 4. Epithelioid rhabdomyosarcoma exhibiting an infiltrative growth pattern with epithelioid tumor cells coursing through collagen bundles (left, ×100) and subcutaneous fibroadipose tissue (right, ×100).

Fig. 5. Epithelioid rhabdomyosarcoma with prominent tumor cell necrosis (×200).

Within these four cases of superficial epithelioid rhabdomyosarcoma, all patients were adults ranging in age from 60 to 78 years (mean 69.5 years). The tumors presented in two men and two women (male : female ratio of 1 : 1) in the anterior abdominal wall, scalp, shoulder and base of neck, respectively and measured from 1.2

Fig. 7. Epithelioid rhabdomyosarcoma cytokeratin CK903 (×400).

focally

expressing

to 4.5 cm in greatest dimension (mean 3.75 cm). With respect to the depth of tumor involvement, one case was centered in the dermis without involvement of the underlying subcutis, one case involved both the dermis and subcutis and two cases solely involved the subcutis. One case in the series by Marburger et al. demonstrated bilateral lymph node metastasis 24 months after initial diagnosis but the patient was alive with disease at the time of publication.4 One of the cases from the Jo et al. article died of an unrelated disease 4 months after diagnosis.3 The outcomes of the remaining cases, including this case, were not available. The clinical features of the four cases are outlined in Table 1. Histopathologically, cutaneous epithelioid rhabdomyosarcoma may be mistaken for melanoma, epithelioid angiosarcoma, poorly differentiated myoepithelial carcinoma, proximal-type epithelioid sarcoma, extrarenal rhabdoid tumor and poorly differentiated squamous cell carcinoma. Absence of S-100 and other melanocytic markers (Melan-A,

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Feasel et al. Table 1. Clinical features of reported cases of cutaneous epithelioid rhabdomyosarcoma Case Case 93 Case 163 Case 64 Present case

Age/sex 65/F 78/F 60/M 75/M

Site

Size (cm)

Depth

Follow up

Recurrence/metastasis

4.5 6 1.2 3.3

SC SC D D/SC

NA 4 months 24 months NA

NA Died of unrelated cause Met, axillary LN (bilateral) NA

Anterior abdominal wall Scalp Shoulder Base of neck

F, female; M, male; SC, subcutaneous; D, dermal; LN, lymph node; Met, metastasis; NA, not available.

HMB-45 and Sox10) allows reliable differentiation of epithelioid rhabdomyosarcoma from melanoma. However, S-100 expression in rhabdomyosarcoma8 and desmin expression in melanoma9 have been reported but are rare and usually only demonstrate focal positive staining. Epithelioid angiosarcoma will demonstrate strong and diffuse staining with endothelial markers (CD31 and ERG) which are negative in epithelioid rhabdomyosarcoma. Poorly differentiated myoepithelial carcinomas co-express myoepithelial markers and cytokeratins (calponin, smooth muscle actin and p63).10,11 Proximal-type epithelioid sarcoma and extrarenal rhabdoid tumor demonstrate loss of INI-1 which is retained in epithelioid rhabdomyosarcoma.7 Poorly differentiated squamous cell carcinoma can demonstrate an epithelioid appearance but will be negative for desmin and skeletal muscle specific markers. Focal positive immunohistochemical staining with cytokeratins, as seen in our case with focal CK903 positivity, is a well-documented potential pitfall in the differentiation of rhabdomyosarcoma from carcinomas.12,13

Co-expression of desmin and a specific marker of skeletal muscle differentiation such as myogenin and/or MYOD1 allow reliable differentiation of epithelioid rhabdomyosarcoma from its potential mimics with high sensitivity and specificity.8 Utilization of this combination of immunohistochemical stains in the proper histomorphologic context is paramount in establishing the diagnosis. In summary, epithelioid rhabdomyosarcoma is a recently described aggressive variant of rhabdomyosarcoma composed of uniformly sized epithelioid cells mimicking other malignancies with an epithelioid histopathologic appearance. This differential diagnosis can be complicated by the aberrant expression of cytokeratin seen in some cases of epithelioid rhabdomyosarcoma, including this case. Co-expression of desmin and a specific marker of skeletal muscle differentiation allow reliable differentiation of epithelioid rhabdomyosarcoma from its mimics with high sensitivity and specificity in the appropriate context. A significant subset of epithelioid rhabdomyosarcoma, including the case presented herein, arise within the dermis and/or subcutis.

References 1. Gurney JG, Ross JA, Wall DA, Bleyer WA, Severson RK, Robison LL. Infant cancer in the U.S.: histology-specific incidence and trends, 1973 to 1992. J Pediatr Hematol Oncol 1997; 19: 428. 2. Hawkins WH, Goos A, Antonescu CR, et al. Clinicopathologic analysis of patients with adult rhabdomyosarcoma. Cancer 2001; 91: 794. 3. Jo VY, Mariño-Enríquez A, Fletcher CD. Epithelioid rhabdomyosarcoma: clinicopathologic analysis of 16 cases of a morphologically distinct variant of rhabdomyosarcoma. Am J Surg Pathol 2011; 35: 1523. 4. Marburger TB, Gardner JM, Billings SD. Primary cutaneous rhabdomyosarcoma: a clinicopathologic review of 11 cases. J Clin Pathol 2012; 39: 987.

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5. Fujiwaki R, Miura H, Endo A, Yoshino N, Iwanari O, Sawada K. Primary rhabdomyosarcoma with an epithelioid appearance of the fallopian tube: an adult case. Eur J Obstet Gynecol Reprod Biol 2008; 140: 289. 6. Seidal T, Kindblom LG, Angervall L. Rhabdomyosarcoma in middle-aged and elderly individuals. APMIS 1989; 97: 236. 7. Zin A, Bertorelle R, Dall’igna P, et al. Epithelioid rhabdomyosarcoma: a clinicopathologic and molecular study. Am J Surg Pathol 2014; 38: 273. 8. Cessna MH, Zhou H, Perkins SL, et al. Are myogenin and Myo-D1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics. Am J Surg Pathol 2001; 25: 1150. 9. Banarjee SS, Harris M. Morphologic and immunophenotypic variations in malignant melanoma. Histopathology 2000; 36: 387.

10. Ren J, Liu Z, Liu X, et al. Primary myoepithelial carcinoma of palate. World J Surg Oncol 2011; 9: 104. 11. He DQ, Hua CG, Tang XF, Feng Y. Cutaneous metastasis from a parotid myoepithelial carcinoma: a case report and review of the literature. J Cutan Pathol 2008; 35: 1138. 12. Scatena C, Massi D, Franchi A, De Paoli A, Canzonieri V. Rhabdomyosarcoma of the skin resembling carcinosarcoma: report of a case and literature review. Am J Dermatopathol 2012; 34: e1. 13. Miettinen M, Rapoala J. Immunohistochemical spectrum of rhabdomyosarcoma and rhabdomyosarcoma-like tumors. Expression of cytokeratin and the 68-kD neurofilament protein. Am J Surg Pathol 1989; 13: 120.

Primary cutaneous epithelioid rhabdomyosarcoma: a rare, recently described entity with review of the literature.

We report a case of a primary cutaneous epithelioid rhabdomyosarcoma that presented as a single raised pink-purple lesion (3.3 × 2.2 cm) on the left b...
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