Lymphoepithelioma-like Carcinoma of the Skin: A Case of One Patient Presenting with Two Primary Cutaneous Neoplasms

Jacqueline C. Fisher, DO,* Rachel M. White, BA,** Daniel S. Hurd, DO, FAOCD***

*Dermatology Resident, PGY-2, VCOM/LewisGale Hospital Montgomery, Blacksburg, VA **Medical Student, OMS IV, Philadelphia College of Osteopathic Medicine, Philadelphia, PA ***Dermatology Residency Program Director, VCOM/LewisGale Hospital Montgomery, Blacksburg, VA

Abstract Lymphoepithelioma-like carcinoma of the skin (LELCS) is a rare cutaneous neoplasm most frequently found on the head and neck of elderly patients. Debate exists regarding its histogenesis, but it’s believed to be of epithelial origin. Histologically, LELCS is remarkably similar to undifferentiated nasopharyngeal carcinoma, a neoplasm associated with Epstein-Barr virus (EBV) infection. EBV reactivity is the main distinguishing factor between these two cutaneous neoplasms, with LELCS rarely documented to test positive for EBV. In general, those diagnosed with LELCS are advised to undergo evaluation of the nasopharynx as well as other internal organ systems that may harbor a lymphoepithelioma-like carcinoma to exclude cutaneous metastasis. Current treatment guidelines recommend wide local excision or Mohs micrographic surgery to prevent local recurrence of LELCS. To the best of the authors’ knowledge, this case is the first to report a patient with two separate lymphoepithelioma-like carcinomas of the skin presenting simultaneously. Introduction Case Report neck and left parietal scalp neoplasms showed Lymphoepithelioma-like carcinoma of the skin An 83-year-old Caucasian female was referred a dermal proliferation of atypical epithelioid (LELCS) is a rare cutaneous neoplasm with low to our dermatology clinic for surgical excision cells forming well-defined nests invested by malignant potential. It is currently classified as of a previously biopsied lesion on her left a dense lymphocytic infiltrate (Figure 2). a variant of squamous-cell carcinoma (SCC), neck reported initially as a nodular basal-cell The atypical epithelioid cells were basophilic although historically, its etiology has been debated. carcinoma with focal morpheaform features. The and featured enlarged nuclei with prominent LELCS demonstrates nearly identical histologic patient also complained of an asymptomatic, nucleoli. A central ulceration was present under features to undifferentiated nasopharyngeal slowly enlarging lesion to her left parietal scalp microscopic examination of the cutaneous carcinoma, also known as metastatic believed to be present for at least three months. biopsy on the patient’s left parietal scalp. The lymphoepithelioma of the nasopharynx, classically The patient’s past medical history was non- overlying epidermis appeared uninvolved in differentiated from LELCS by positive reactivity contributory, and she denied any constitutional both samples. Each specimen stained positive for an associated infection with Epstein-Barr symptoms at the time of clinical presentation. for cytokeratin (CK) 5/6 and epithelial 1,2 Therefore, an evaluation of the virus (EBV). Clinical examination revealed a solitary, 2.0 cm x nasopharynx with an ear, nose, and throat (ENT) 2.2 cm, tan to pink, indurated ulcerative plaque examination is advised to exclude undifferentiated (Figure 1). There were no naso-oropharyngeal nasopharyngeal carcinoma.2-4 LELCS generally abnormalities or regional lymphadenopathy. A is a slow-growing neoplasm with a good overall shave biopsy was performed to the left parietal prognosis. However, due to multiple cases of scalp to exclude both basal-cell carcinoma and recurrence after initial surgical excision, the gold squamous-cell carcinoma. standard of treatment for LELCS is wide local excision or Mohs micrographic surgery.2,5 The histopathological findings for both the left

Figure 2. H&E staining of LELCS (20x).

Figure 3. In situ hybridization Epstein-Barr virus encoded RNA (ISH/EBER) of LELCS on parietal scalp. Demonstrates absence of blue staining; determined to be EBV negative Figure 1. Lymphoepithelioma-like carcinoma of the skin on parietal scalp. (20x).

Page 40 LYMPHOEPITHELIOMA-LIKE CARCINOMA OF THE SKIN: A CASE OF ONE PATIENT PRESENTING WITH TWO PRIMARY CUTANEOUS NEOPLASMS incidence is equal in men and women.8 LELCS the spindle-cell variant of melanoma.23 often presents as a solitary, flesh-colored to red, However, unlike LELCS, melanoma is positive firm papule, plaque, or nodule.2 The average size for S100 and other neuroectodermal markers is fairly large, measuring about 2 cm to 3 cm in such as HMB-45 and melan-A. LELCS should diameter.3 Typically, LELSC is asymptomatic be distinguished from malignant lymphoma and slowly enlarges over a period of months to by the absence of atypical lymphocytes in years.8 LELCS.1 Epithelial markers such as epithelial- membrane antigen and cytokeratins will react Histology positive in LELCS and negative in malignant On histology, LELCS presents as a dermal lymphoma. LELCS has shown the presence of proliferation of atypical polygonal epithelioid occasional binucleated cells resembling Reed- cells arranged in nests, cords, or sheets surrounded Sternberg cells; however, Hodgkin lymphoma is by a peripheral dense lymphocytic infiltrate.6 negative for cytokeratins and positive for CD30 Figure 4. Control slide demonstrating positive 1,2,21,23 Cellular atypia includes vesicular hyperchromatic and CD15. Basal-cell carcinoma will reaction to ISH/EBER immunohistochemical nuclei and prominent nucleoli with scant demonstrate neoplastic basophilic cells extending stain (20x). amphophilic-to-eosinophilic cytoplasm.2 The downward from the epidermis, whereas LELCS reactive lymphoid stroma is comprised of small does not typically have an epidermal connection membrane antigen (EMA), suggesting tumors B- and T-lymphocytes, staining positive for and lacks peripheral palisading. Inflamed, poorly differentiated squamous-cell carcinoma (SCC) of epithelial origin. Staining for CK7 and CD3 and CD20, with an occasional plasma cell 1,19 CK20 yielded negative results, excluding Paget’s present.2,8 LELCS generally extends into the strongly resembles LELCS. However, LELCS disease and Merkel-cell carcinoma (MCC), reticular dermis with occasional involvement into typically does not involve overlying epidermis, respectively, from the differential diagnosis. Due the subcutis and even skeletal muscle.6,10 LELCS and poorly differentiated SCC usually has an area of well-differentiated carcinoma or overlying to the concern for an underlying metastatic stains positively for pancytokeratin, CK5, CK6, 1,3,5 undifferentiated nasopharyngeal carcinoma or p63 and EMA reactivity, likely indicating a SCC in situ. Cutaneous lymphadenoma lymphoepithelioma-like carcinoma (LELC) of neoplasm of epithelial origin.2,7 These markers demonstrates a similar dense lymphocytic infiltrate as LELCS, but these lymphocytes another internal organ, an in situ hybridization also indicate that LELCS may derive from an 1,2 for Epstein-Barr virus-encoded RNA (ISH/ epidermal, follicular, glandular, sudoriferous appear benign and monomorphic. Follicular EBER) was performed for detection of an active origin.2,5,7,11-14 In fact, the histogenesis of LELCS dendritic-cell tumor (FDCT) is similar to or latent EBV infection (Figure 3). The patient’s is controversial. Historically, LELCS was thought LELCS by way of syncytial-appearing plump cells surrounded by reactive lymphoid cells, but histologic slides were compared to a control ISH/ to derive from adnexal origin, supported by the 2 EBER immunohistochemical stain (Figure 4). fact that LELCS is located in the dermis and FDCT stains negative for cytokeratin markers. 6,15 FDCT will demonstrate positive reactivity to Ki- The negative ISH/EBER stain for both lesions usually lacks a connection with the epidermis. 2 strongly favors two primary LELSC in our patient Also, within LELCS, there is often sebaceous, M4, CD21, and CD35. and does not favor a metastatic disease related to eccrine and trichilemmal differentiation.8 In Histologically, LELCS is remarkably similar an EBV-driven undifferentiated nasopharyngeal more recent literature, some consider LELCS to metastatic lymphoepithelioma of the carcinoma or internal LELC. to be a variant of squamous-cell carcinoma nasopharynx, also known as undifferentiated (SCC).2,4,16-20 For instance, Wang et al. presented 1,3,22 Our patient was referred to an oncologist for nasopharyngeal carcinoma. Epstein-Barr a case of LELCS occurring below a scar from medical evaluation to exclude cutaneous metastasis virus (EBV) reactivity is the main distinguishing removal of multiple recurrent, well-differentiated of an undifferentiated nasopharyngeal carcinoma factor between LELCS and undifferentiated and subsequent moderately differentiated 1,2,4,24 or lymphoepithelioma-like carcinoma of other nasopharyngeal carcinoma. In general, SCC.19 However, SCC is typically located in internal organs. Given the patient’s advanced LELCS is negative for EBV reactivity, whereas the superficial dermis and maintains connectivity age and frail status, the patient refused oncologic undifferentiated nasopharyngeal carcinoma will with the epidermis.4 Finally, others believe that 1,2,4,24 examination as she planned to decline systemic test positive for EBV. There has been only LELCS is a morphologic pattern as opposed to a treatment if an underlying internal malignancy one reported case, that of a Japanese woman, of distinct clinicopathologic entity.17,21,22 was discovered. Per initial consultation with LELCS in a patient who tested EBV positive, but no related neoplasms were found elsewhere the patient, the oncologist remarked that it was 22 highly unlikely that an internal carcinoma was Differential in the patient’s body. In situ hybridization for metastasizing to her skin. She was also referred The differential diagnosis is fairly extensive EBER, the most reliable, specific, and highly to a plastic surgeon for evaluation and surgical and includes cutaneous metastasis of sensitive method for detecting latent EBV, was used in this case report and yielded a negative removal of both LELCS. undifferentiated nasopharyngeal carcinoma, a 22,25 lymphoepithelioma-like carcinoma of another result for EBV in our patient. Metastatic Our patient plans to undergo surgical excision internal organ, basal-cell carcinoma, squamous- lymphoepithelioma of the nasopharynx is rare, of both cutaneous neoplasms and remains free 2,4,6 cell carcinoma, keratoacanthoma, Merkel-cell but aggressive when it does occur. LELCS from systemic symptoms, which supports the carcinoma, melanoma, malignant lymphoma, secondary to metastasis of undifferentiated diagnosis of two primary lymphoepithelioma- Hodgkin’s lymphoma, cutaneous lymphadenoma, nasopharyngeal carcinoma appears to be very rare, like carcinomas of the skin. 2,4 as there are fewer than 20 cases currently reported and follicular dendritic cell tumor. Histologic 2,6,11 features and immunohistochemical staining in the literature. Nonetheless, it is highly Discussion distinguish LELCS from the possible differential recommended to evaluate the patient for possible Lymphoepithelioma-like carcinoma of the skin diagnosis. undifferentiated nasopharyngeal carcinoma (LELCS) is a rare primary cutaneous neoplasm by a complete otolaryngologic exam including 6 Merkel-cell carcinoma (MCC) can present 4,26 initially described in 1988 by Swanson et al. indirect laryngoscopy of the nasopharynx. clinically similar to LELCS but will stain Since this first report, close to 80 cases have A review of symptoms is recommended when positive for neuroendocrine markers such as been described in the English literature. LELCS LELCS is confirmed to exclude metastasis synaptophysin, neuron-specific enolase, and from a variety of internal organ systems.2,4,5,22 occurs most often in elderly individuals on sun- 1 2 CK20. In addition, peripheral lymphocytic exposed areas, primarily the head and neck. Lymphoepithelioma-like carcinoma can be infiltrate is usually absent in MCC.2,14 Clarke However, there has been a report of LELCS found in many organs besides the skin, including 7-9 and Ioffreda report a case in which LELCS occurring on the trunk and upper extremity. The salivary glands, thyroid, thymus, lungs, stomach, demonstrates spindle-shaped cells that resemble FISHER, WHITE, HURD Page 41 kidney, breasts, uterine cervix, prostate, vagina, 2. Welch PQ, Williams SB, Foss RD, et al. of the skin. A case report with immunophenotypic and urinary bladder..6,7,16,17,23,27 Histologically, Lymphoepithelioma-like carcinoma of head and analysis and in situ hybridization for Epstein-Barr EBV reactivity has been associated only with neck shin: a systemic analysis of 11 cases and viral genome. Am J Surg Pathol. 1992;9:909-13. review of literature. Oral Surg Oral Med Oral lymphoepithelioma-like carcinoma of the 17. Lind AC, Breer WA, Wick MR. 4,7,22,24 Pathol Oral Radiol Endod. 2011;111:78-86. stomach, salivary glands, lungs, and thymus. Lymphoepithelioma-like carcinoma of the skin 3. Abedi SM, Salama S, Alowami S. with apparent origin in the epidermis-a pattern Treatment Lymphoepithelioma-like carcinoma of the skin: or an entity? A case report. Cancer. 1999;15:884- The prognosis for patients with LELCS is case report and approach to surgical sign out. 90. generally good despite its categorization as a Rare Tumors. 2013;5:157-9 18. Cassarino DS, DeRienzo DP, Barr R. poorly differentiated neoplasm.2,5,6,22,27 It is a low 4. Lassen CB, Lock-Anderson J. Cutaneous squamous cell carcinoma: a malignant tumor with rare reports of metastasis Lymphoepithelioma-like carcinoma of the skin: comprehensive clinicopathologic classification. J to lymph nodes at presentation and to internal a case with perineural invasion. Plast Reconstr Cutan Pathol. 2006;33:191-206. organs such as, liver, lung, and bone.9,27 There Surg Glob Open. 2014 Dec 5;2(11):e252 are only two reported deaths from metastatic 19. Wang G, Bordeaux JS, Rowe DJ, Honda KS. LELCS.4,6 There are multiple reports of local 5. Gille TM, Miles EF, Mitchell AO. Lymphoepithelioma-like carcinoma vs inflamed recurrence after incomplete excision.6 Therefore, Lymphoepithelioma-like carcinoma of the squamous cell carcinoma of the skin. JAMA most LELCS are treated by wide local excision skin treated with wide local excision and Dermatol. 2014;150:1367-8. chemoradiation therapy: A case report and or Mohs micrographic surgery to lower the risk 20. Bolognia JL, Jorizzo JL, Rapini RP, eds. 2,28 review of the literature. Case Rep Oncol Med. of recurrence. LELCS and undifferentiated Dermatology. Edinburgh: Mosby, Inc; 2008. p. 2012;2012:241816. nasopharyngeal carcinoma are both radiosensitive, 1782-1783. Print. and this treatment modality should be used for 6. Swanson SA, Cooper PH, Mills SE, Wick 21. Shek, TW, Leung EY, Luk IS, Loong F, recurrent cases, nonsurgical candidates, and MR. Lymphoepithelioma-like carcinoma of the 3,8 Chan AC, Yik YH, et al. Lymphoepithelioma- those with lymph-node metastasis. There skin. Mod Pathol. 1988;1:359-65. are also a few reports of perineural invasion, in like carcinoma of the skin. Am J Dermatopathol. which Mohs micrographic surgery, radiation, and 7. Robins P, Perez MI. Lymphoepithelioma 1996;6:637-44. like carcinoma of the skin treated by Mohs chemotherapy were used in combination therapy 22. Aoki R, Mitsui H, Karada K, et al. A case micrographic surgery. J Am Acad Dermatol. without evidence of recurrence on follow-up of lymphoepithelioma-like carcinoma of the skin 3-5,7 1995;32:814-16. evaluation. associated with Epstein-Barr virus infection. J 8. Glaich AS, Behroozan DS, Cohen JL, Goldberg Am Acad Dermatol. 2010;62(4):681-84. LH. Lymphoepithelioma-like carcinoma of the 23. Clarke LE, Ioffreda MD. Lymphoepithelioma- Conclusion skin: a report of two cases treated with complete In conclusion, lymphoepithelioma-like like carcinoma of the skin with spindle cell microscopic margin control and review of the carcinoma of the skin is a rare, slowly growing differentiation. J Cutan Pathol. 2005;6:419-23. neoplasm with low malignant potential. LELCS literature. Dermatol Surg. 2006:2:316-19. 24. Iezzoni JC, Gaffey MJ, Weiss LM. The role is believed to be of epithelial origin based on 9. Hall G, Duncan A, Azurdia R, Leonard N. of Epstein-Barr virus in lymphoepithelioma-like immunohistochemical reactivity, although its Lymphoepithelioma-like carcinoma of the skin: a carcinomas. Am J Clin Pathol. 1995;103:308. exact histogenesis remains debatable. There case with lymph node metastases at presentation. are multiple dermatologic neoplasms that can Am J Dermatopathol. 2006;3:211-5. 25. Chang YL, Wu CT, Shih JY, Lee YC. New clinically resemble LELCS. Therefore, it is aspects in clinicopathologic and oncogene 10. Wick MR, Swanson PE, LeBoit PE, Strickler important to conduct a histologic examination studies of 23 pulmonary lymphoepithelioma-like JG, Cooper PH. Lymphoepithelioma-like from a biopsied specimen to exclude other carcinomas. Am J Surg Pathol. 2002;26:715-23. carcinoma of the skin with adnexal differentiation. dermatologic entities. Undifferentiated J Cutan Pathol. 1991;18:93-102. 26. Dudley CM, Snow SN, Voytovich MC, nasopharyngeal carcinoma demonstrates identical Warner TF, Hartig GK. Enlarging facial nodule 11. Luk NM, Yu KH, Choi CL, Yeung WK. histologic characteristics, and although it rarely on an elderly patient. Lymphoepithelioma-like Skin metastasis from nasopharyngeal carcinoma occurs, it is a very aggressive neoplasm that carcinoma of the skin (LELCS). Arch Dermatol. in four Chinese patients. Clin Exp Dermatol. requires a thorough otolaryngologic examination 1998;134:1628-9, 1631-2. and CT scans of the head and neck if suspected. 2004;29:28-31. 27. Kazakov DV, Nemcova J, Mikyskova I, A thorough review of systems is recommended 12. Ng KF, Chen TC, Chang PL. Michal M. Absence of Epstein-Barr virus, to exclude other possible organ systems that Lymphoepithelioma-like carcinoma of the ureter. human papillomavirus, and simian virus 40 may have a lymphoepithelioma-like carcinoma J Urol. 1999;161:1277-8. metastasizing to the skin. Wide surgical in patients of central European origin with excision or Mohs micrographic surgery are the 13. Gillum PS, Morgan MB, Naylor MF, lymphoepithelioma-like carcinoma of the skin. recommended treatments for non-aggressive Everett MA. Absence of Epstein-Barr virus in Am J Dermatopathol. 2007;4:365-9. lymphoepithelioma like carcinoma of the skin. forms of LELCS to prevent local recurrence. To 28. Jimenez F, Clark RE, Buchanan MD, Polymerase chain reaction evidence and review of the best of our knowledge, this is the first case Kamino H. Lymphoepithelioma-like carcinoma five cases. Am J Dermatopathol. 1996;5:478-82. demonstrating two primary lymphoepithelioma- of the skin treated with Mohs micrographic like carcinomas of the skin presenting in different 14. Abdelkrim SB, Dhouibi A, Moussa A, et al. surgery in combination with immune staining for anatomic locations on the same patient without Merkel cell carcinoma with lymphoepithelioma- cytokeratins. J Am Acad Dermatol. 1995;32:878- evidence of a metastatic source. like pattern: a case report of an exceedingly rare 81. variant of Merkel cell carcinoma with lymph References node metastases at presentation. Case Rep 1. Ferlicot S, Plantier F, Rethers L, Bui Pathol. 2011;2011:840575. Correspondence: Jacqueline C. Fisher, DO; [email protected] AD, Wechsler J. Lymphoepithelioma-like 15. Ko T, Muramatsu T, Shirai T. carcinoma of the skin: a report of 3 Epstein- Lymphoepithelioma-like carcinoma of the skin. Barr virus (EBV)-negative additional cases. J Dermatol. 1997;2:104-9. Immunohistochemical study of stroma reaction. J Cutan Pathol. 2000;6:306-11. 16. Carr KA, Bulengo-Ransby SM, Weiss LM, Nickoloff BJ. Lymphoepithelioma like carcinoma

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