Lymphoepithelioma-like carcinoma of head and neck skin: a systematic analysis of 11 cases and review of literature
2010; Elsevier BV; Volume: 111; Issue: 1 Linguagem: Inglês
10.1016/j.tripleo.2010.05.075
ISSN1528-395X
AutoresPreston Q. Welch, Stephen B. Williams, Robert D. Foss, Maria-Magdalena Tomaszewski, Anish Gupta, Junu Ojha,
Tópico(s)Ear and Head Tumors
ResumoLymphoepithelioma-like carcinoma of the skin (LELCS) is a rare tumor of unknown etiology, low malignant potential, and microscopic resemblance to undifferentiated nasopharyngeal carcinoma. Clinically, it presents as a flesh-colored firm nodule or plaque on the face, scalp, or shoulder of middle-aged to elderly individuals. Histologically, LELCS is composed of islands of enlarged epithelial cells with large vesicular nuclei surrounded and permeated by a dense lymphoplasmacytic infiltrate. LELCS exhibits immunoreactivity with high-molecular-weight cytokeratins and epithelial membrane antigen, indicating the epithelial origin. The differential diagnosis includes basal cell carcinoma, squamous cell carcinoma, lymphoma, pseudolymphoma, and Merkel cell carcinoma. We report 11 cases of LELCS of the head and neck region with discussion of the clinical, histopathologic, immunohistochemical, and therapeutic aspects of this rare cutaneous neoplasm. In addition, we systematically review and compare the findings with the previously published cases of LELCS. This study is the largest case series of LELCS reported in the English-language literature. It attempts to more clearly define the diagnostic criteria for LELCS. Its histomorphologic and immunophenotypic features help distinguish this tumor from similar-appearing malignancies, including metastatic nasopharyngeal carcinoma. Lymphoepithelioma-like carcinoma of the skin (LELCS) is a rare tumor of unknown etiology, low malignant potential, and microscopic resemblance to undifferentiated nasopharyngeal carcinoma. Clinically, it presents as a flesh-colored firm nodule or plaque on the face, scalp, or shoulder of middle-aged to elderly individuals. Histologically, LELCS is composed of islands of enlarged epithelial cells with large vesicular nuclei surrounded and permeated by a dense lymphoplasmacytic infiltrate. LELCS exhibits immunoreactivity with high-molecular-weight cytokeratins and epithelial membrane antigen, indicating the epithelial origin. The differential diagnosis includes basal cell carcinoma, squamous cell carcinoma, lymphoma, pseudolymphoma, and Merkel cell carcinoma. We report 11 cases of LELCS of the head and neck region with discussion of the clinical, histopathologic, immunohistochemical, and therapeutic aspects of this rare cutaneous neoplasm. In addition, we systematically review and compare the findings with the previously published cases of LELCS. This study is the largest case series of LELCS reported in the English-language literature. It attempts to more clearly define the diagnostic criteria for LELCS. Its histomorphologic and immunophenotypic features help distinguish this tumor from similar-appearing malignancies, including metastatic nasopharyngeal carcinoma. Undifferentiated carcinoma of the lymphoepithelial type is a well defined epithelial malignancy of the nasopharynx. Histologically and immunophenotypically identical neoplasms have been described in the salivary glands, larynx, thymus, stomach, uterine cervix, and skin.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 2Lind A.C. Breer W.A. Wick M.R. Lymphoepithelioma-like carcinoma of the skin with apparent origin in the epidermis—a pattern or an entity? A case report.Cancer. 1999; 15: 884-890Google Scholar Lymphoepithelioma-like carcinoma of the skin (LELCS) was first described by Swanson et al.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar in 1988 as a distinctive primary malignant neoplasm with remarkable microscopic similarity to undifferentiated carcinoma of the nasopharynx. There have been only 54 reported cases of primary LELCS of the head and neck in the English-language literature (Table I). Clinically, LELCS has a predilection for sun-exposed skin of the head and neck in elderly individuals. There is a tendency toward local recurrence and very limited metastatic potential.3Shek T.W. Leung E.Y. Luk I.S. Loong F. Chan A.C. Yik Y.H. et al.Lymphoepithelioma-like carcinoma of the skin.Am J Dermatopathol. 1996; 6: 637-644Google Scholar The clinical appearance of LELCS is varied and ranges from a solitary flesh-colored nodule or plaque to an erythematous or indurated lesion with a keratotic center.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 4Sagatys E. Kirk J.F. Morgan M.B. Lymphoid lost and found.Am J Dermatopathol. 2003; 2: 159-161Google Scholar Histologically, LELCS is composed of a neoplastic epithelial component associated with a reactive lymphoid infiltrate.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 5Carr K.A. Bulengo-Ransby S.M. Weiss L.M. Nickoloff B.J. Lymphoepithelioma like carcinoma of the skin A case report with immunophenotypic analysis and in situ hybridization for Epstein-Barr viral genome.Am J Surg Pathol. 1992; 9: 909-913Google Scholar Tumor cells are arranged in nodules, isolated or anastomosing islands, trabeculae, narrow cords, or round to oval nests. The epithelial component of the tumor is represented by atypical polygonal cells with vesicular nuclei and prominent nucleoli.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 6Chen K.T. Cytology of lymphoepithelioma-like carcinoma of the skin.Diagn Cytopathol. 1999; 21: 230-232Google Scholar The histologic diagnosis of LELCS may be complicated by the variable architectural and cytologic appearance of the epithelial cells and the dense lymphoplasmacytic infiltrate which may obscure the epithelial component.7Clarke L.E. Ioffreda M.D. Lymphoepithelioma-like carcinoma of the skin with spindle cell differentiation.J Cutan Pathol. 2005; 6: 419-423Google Scholar Immunohistochemical evaluation may serve to exclude other histologically similar lesions. Owing to the close histologic similarity to nasopharyngeal lymphoepithelioma, patients with suspected LELCS should have a thorough otolaryngologic examination, including indirect laryngoscopy to rule out a metastatic nasopharyngeal lymphoepithelioma. Although the skin metastasis of nasopharyngeal lymphoepithelioma is extremely rare, with only 16 cases documented in the literature, they are associated with a worse prognosis, with patients succumbing within a year.8Luk N.M. Yu K.H. Choi C.L. Yeung W.K. Skin metastasis from nasopharyngeal carcinoma in four Chinese patients.Clin Exp Dermatol. 2004; 29: 28-31Google ScholarTable ISummary of the literature review of head and neck lymphoepithelioma-like carcinoma of the skin (LELCS)StudyNo. of patientsGenderAge, yLocationClinical presentationTreatmentSwanson et al.,1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar 19884M50ScalpLumpLocal excisionM62ForeheadNoduleSurgical excisionM68CheekNoduleSurgical excision, radiotherapyF81CheekNoduleSurgical excisionMalhotra et al.,32Malhotra R. Woda B. Bhawan J. Lymphoepithelioma-like carcinoma of the skin The microscopic and immunohistochemical findings of two patients.J Cutan Pathol. 1989; 16: 317Google Scholar 19892M67NosePapuleN/AM71ScalpNoduleN/AWalker et al.,28Walker A.N. Kent D. Mitchell A.R. Lymphoepitheloma-like carcinoma of the skin.J Am Acad Dermatol. 1990; 22: 691-693Google Scholar 19901F83ZygomaNoduleRadiotherapyKutzner et al.,19Kutzner H. Schwenzer G. Embacher G. Kutzner U. Schroder J. Lymphoepithelioma-like carcinoma of the skin.Hautarzt. 1991; 42: 575-579Google Scholar 19911F56Upper lipPearly papuleSurgical excisionWick et al.,18Wick M.R. Swanson P.E. LeBoit P.E. Strickler J.G. Cooper P.H. Lymphoepithelioma-like carcinoma of the skin with adnexal differentiation.J Cutan Pathol. 1991; 18: 93-102Google Scholar 19913F51ForeheadPapuleElectrodissectionM52FaceNoduleLocal excisionF71EyelidNoduleLocal excisionCarr et al.,5Carr K.A. Bulengo-Ransby S.M. Weiss L.M. Nickoloff B.J. Lymphoepithelioma like carcinoma of the skin A case report with immunophenotypic analysis and in situ hybridization for Epstein-Barr viral genome.Am J Surg Pathol. 1992; 9: 909-913Google Scholar 19921F84CheekNoduleSurgical excisionOrtiz-Frutos et al.,33Ortiz-Frutos F.J. Zarco C. Gil R. Ballestin C. Iglesias L. Lymphoepithelioma-like carcinoma of the skin.Clin Exp Dermatol. 1993; 18: 83-86Google Scholar19931M70NoseNoduleSurgical excision, radiotherapy on recurrenceStahr,34Stahr B.J. Self assessment.J Cutan Pathol. 1993; 20: 513-524Google Scholar 19931M63ForeheadN/AN/ARequena et al.,20Requena L. Sanchez Yus E. Jimenez E. Roo E. Lymphoepithelioma-like carcinoma of the skin: a light-microscopic and immunohistochemical study.J Cutan Pathol. 1994; 21: 541Google Scholar 19941F83TempleNoduleSurgical excisionClarke and Ioffreda,7Clarke L.E. Ioffreda M.D. Lymphoepithelioma-like carcinoma of the skin with spindle cell differentiation.J Cutan Pathol. 2005; 6: 419-423Google Scholar 19951M72ForeheadNoduleSurgical excisionDozier et al.,35Dozier S.E. Jones T.R. Nelson-Adesokan P. Hruza G.J. Lymphoepithelioma-like carcinoma of the skin treated by Mohs micrographic surgery.Dermatol Surg. 1995; 8: 690-694Google Scholar19951F91NoseNoduleElectrodissection, curettage; Moh's surgery at recurrenceJimenez et al.,11Jimenez F. Clark R.E. Buchanan M.D. Kamino H. Lymphoepithelioma-like carcinoma of the skin treated with Mohs micrographic surgery in combination with immune staining for cytokeratins.J Am Acad Dermatol. 1995; 32: 878-881Google Scholar 19951M68Nasal alaPlaqueMoh's surgeryLeung et al.,25Leung E.Y. Yik Y.H. Chan J.K. Lack of demonstrable EBV in Asian lymphoepithelioma-like carcinoma of skin.Am J Surg Pathol. 1995; 8: 974-976Google Scholar 19951M78Orbit angleNoduleSurgical excisionMaruyama et al.,36Maruyama M. Miyauchi S. Ohtsuka H. Miki Y. Lymphoepithelioma- \like carcinoma originating on the eyelid.J Dermatol. 1995; 22: 218-222Google Scholar 19951F89EyelidPapuleSurgical excisionRobins and Perez,10Robins P. Perez M.I. Lymphoepithelioma like carcinoma of the skin treated by Mohs micrographic surgery.J Am Acad Dermatol. 1995; 32: 814-816Google Scholar 19951F74CheekNoduleMohs surgeryGillum et al.,22Gillum P.S. Morgan M.B. Naylor M.F. Everett M.A. Absence of Epstein-Barr virus in lymphoepitheliomalike carcinoma of the skin Polymerase chain reaction evidence and review of five cases.Am J Dermatopathol. 1996; 5: 478-482Google Scholar 19964F64ChinN/AN/AF74CheekN/AN/AM39ForeheadN/AN/AM69CheekN/AN/AShek et al.,3Shek T.W. Leung E.Y. Luk I.S. Loong F. Chan A.C. Yik Y.H. et al.Lymphoepithelioma-like carcinoma of the skin.Am J Dermatopathol. 1996; 6: 637-644Google Scholar 19962F81ForeheadNoduleSurgical excisionM78External orbital angleNoduleSurgical excisionTakayasu et al.,24Takayasu S. Yoshiyama M. Kurata S. Terashi H. Lymphoepithelioma-like carcinoma of the skin.J Dermatol. 1996; 23: 472-475Google Scholar 19961F62Nasal alaNoduleSurgical excision, radiotherapyKo et al.,23Ko T. Muramatsu T. Shirai T. Lymphoepithelioma-like carcinoma of the skin.J Dermatol. 1997; 2: 104-109Google Scholar 19971M67CheekNoduleSurgical excisionDudley et al.,13Dudley C.M. Snow S.N. Voytovich M.C. Warner T.F. Hartig G.K. Enlarging facial nodule on an elderly patient Lymphoepithelioma-like carcinoma of the skin (LELCS).Arch Dermatol. 1998; 12: 1628-1629Google Scholar 19981M81MandibleNoduleMoh's surgeryBornhövd et al.,26Bornhövd E.C. Schmid-Wendtner M.H. Volkenandt M. Wendtner C.M. Sander C.A. Malignant skin lesions Case 2: lymphoepithelioma-like carcinoma of the skin.J Clin Oncol. 1999; 12: 3853-3855Google Scholar 19991F87CheekNoduleSurgical excisionChen,6Chen K.T. Cytology of lymphoepithelioma-like carcinoma of the skin.Diagn Cytopathol. 1999; 21: 230-232Google Scholar 19991M71ForeheadNoduleSurgical excisionLind et al.,2Lind A.C. Breer W.A. Wick M.R. Lymphoepithelioma-like carcinoma of the skin with apparent origin in the epidermis—a pattern or an entity? A case report.Cancer. 1999; 15: 884-890Google Scholar 19991F96Nasal alaNoduleSurgical excisionFerlicot et al.,17Ferlicot S. Plantier F. Rethers L. Bui A.D. Wechsler J. Lymphoepithelioma-like carcinoma of the skin: a report of 3 Epstein-Barr virus (EBV)–negative additional cases Immunohistochemical study of the stroma reaction.J Cutan Pathol. 2000; 6: 306-311Google Scholar 20003M61Nasal alaNoduleSurgical excisionM88EarNoduleSurgical excisionM87CheekNoduleSurgical excisionAhmadi et al.,30Ahmadi M.A. Prieto V.G. Clayman G.L. Ginsberg L.E. Esmaeli B. Lymphoepitheliomalike carcinoma of the orbit.Arch Ophthalmol. 2001; 8: 1206-1208Google Scholar 20011M45ForeheadNoduleSurgical excision, radiotherapyHo et al.,37Ho W. Taylor A. Kemp E. Roberts F. Lymphoepithelioma-like carcinoma of the eyelid: a report of two cases.Br J Ophthalmol. 2005; 9: 1222-1223Google Scholar 20052M79Lower eyelidNoduleSurgical excisionM67Lower eyelidN/ASurgical excisionOtsuki et al.,38Otsuki T. Watanabe D. Yano K. Tamada Y. Matsumoto Y. Yokoo K. Lymphoepithelioma-like carcinoma of the skin with potential for sweat glandular differentiation.J Dermatol. 2005; 32: 393-396Google Scholar 20051M77CheekNoduleSurgical excisionFenniche et al.,39Fenniche S. Zidi Y. Tekaya N.B. Ammar F.B. Yaacoub K. Mokni M. et al.Lymphoepithelioma-like carcinoma of the skin in a Tunisian patient.Am J Dermatopathol. 2006; 1: 40-44Google Scholar 20061F78CheekNoduleSurgical excisionGlaich et al.,12Glaich A.S. Behroozan D.S. Cohen J.L. Goldberg L.H. Lymphoepithelioma-like carcinoma of the skin: a report of two cases treated with complete microscopic margin control and review of the literature.Dermatol Surg. 2006; 2: 316-319Google Scholar 20061F97CheekNoduleMoh's surgeryCavalieri et al.,9Cavalieri S. Feliciani C. Massi G. et al.Lymphoepithelioma-like carcinoma of the skin.Int J Immunopathol Pharmacol. 2007; 20: 851-854Google Scholar 20071F92CheekViolaceous noduleSurgical excisionKazakov et al.,31Kazakov D.V. Nemcova J. Mikyskova I. Michal M. Absence of Epstein-Barr virus, human papillomavirus, and simian virus 40 in patients of central european origin with lymphoepithelioma-like carcinoma of the skin.Am J Dermatopathol. 2007; 4: 365-369Google Scholar 200774 M57-86FaceN/AN/A2 FFaceN/AN/A1 N/AFaceN/AN/AFaceN/AN/AScalpN/AN/AScalpN/AN/AAuricleN/AN/AArsenovic et al.,40Arsenovic N. Lymphoepithelioma-like carcinoma of the skin: new case of an exceedingly rare primary skin tumor.Dermatol Online J. 2008; 8: 12Google Scholar 20081F89CheekBrown beige plaque like non ulcerated lesionSurgical excisionLyle et al.,41Lyle P. Nakamura K. Togerson S. Lymphoepithelioma-like carcinoma arising in the scar from a previously excised basal cell carcinoma.J Cutan Pathol. 2008; 6: 594-598Google Scholar 20081F68ForeheadPapuleMohs surgeryMahomed et al.,42Mahomed F. Grayson W. A rare case of lymphoepithelial carcinoma of the lip.Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008; 105: e49-e52Google Scholar 20081M73Lower lipUlcer with indurated edgesSurgical excisionHinz et al.,43Hinz T. Wiechert A. Bieber T. Bauer R. Schmid-Wendtner M.H. Lymphoepithelioma-like carcinoma of the skin mimicking a basal cell carcinoma.Eur J Dermatol. 2009; 2: 179-180Google Scholar 20091F91TempleErythematous with central erosion, peripheral telengectasiaSurgical excisionM, male; F, female; N/A, not available. Open table in a new tab M, male; F, female; N/A, not available. Eleven new LELCS cases are reviewed along with previously reported cases from the English-language literature. Eleven cases of LELCS of head and neck were identified in the Armed Forces Institute of Pathology (AFIP) files. The clinical findings, including presentation, patient age, gender, location, and clinical differential diagnosis, were reviewed. Histomorphologic features were evaluated regarding architecture, cellular and nuclear atypia, mitotic rate, growth pattern, and lymphoid stroma. The immunophenotypic features were evaluated with a panel of antibodies on the paraffin-embedded sections by using a modified avidin-biotin complex technique with appropriate controls. When necessary, the contributors were contacted for additional material and follow-up information. Additionally, a review of the available English-language literature was performed. Eight patients (72%) were male and 3 (28%) female (Table II). Patients ranged in age from 47 to 84 years, with a median of 79 years and a mean of 74 years, which is similar to the previously reported cases (Table I). As in the previously reported cases, all lesions were located on sun-exposed areas of head and neck, involving forehead (2), cheek (2), ear (2), zygoma (1), scalp (1), temple (1), eyebrow (1), and upper lip (1). Most cases presented as a solitary flesh-colored pearlescent or erythematous firm nodule or plaque, often roughened or hypopigmented with or without telangiactasia and ulceration. The most commonly offered clinical differential diagnosis was basal cell carcinoma. The treatment modalities for the cases included local surgical excision, reexcision of residual tumor after incomplete removal, and deep shave followed by electrocautery (Table II). The clinical follow-up was available for 8 patients: 5 patients were alive without evidence of recurrent disease, and 3 died of unrelated causes with no evidence of disease.Table IISummary of the findings of the present cases of LELCSCase no.Age, yGenderLocationClinical appearanceClinical impressionContributor's microscopic differentialTreatment184MCheekIrregular noduleBCCMalignant adnexal tumorSurgical excision274FZygomaFlesh colored nodule with telangiactasiaSarcoidosisGranulomatous rosaceaSurgical excision378MForeheadRed nodule with ulcerationAtypical fibroxanthomaAtypical lymphoid proliferation/lymphomaSurgical excision480MForeheadIrregular noduleH/O carcinoma of hypopharynx, R/O metastasisALHESurgical excision579MScalpIrregular ulcerated white plaqueN/ATrichilemmal carcinomaSurgical excision647FCheekPearlescent noduleBCCLymphoid hyperplasiaSurgical excision760MEarRaised pale brown nodule with ulcerationCystSquamous cell carcinoma(poorly differentiated)Surgical excision870MTempleRed-purple scaly noduleBCCLELCSSurgical excision982MEyebrowIrregular ulcerated noduleBCCAtypical lymphoid proliferation/lymphomaSurgical excision1080FEarPearly papuleBCCLELCSSurgical excision1180MUpper lipRed firm noduleCalcified cystAtypical lymphoid & squamous epithelial proliferationElectrocautery with deep shaveBCC, basal cell carcinoma; H/O, history of; R/O, rule out; ALHE, angiolymphoid hyperplasia with eosinophilia; other abbreviations as in Table I. Open table in a new tab BCC, basal cell carcinoma; H/O, history of; R/O, rule out; ALHE, angiolymphoid hyperplasia with eosinophilia; other abbreviations as in Table I. The 11 cases revealed 2 distinct histologic growth patterns. Seven cases were characterized by nodular growth of syncytial sheets, islands, and/or nests of atypical epithelioid cells in the middle and deep dermis associated with a dense lymphoid infiltrate with a variable plasma cell component (Fig. 1, A and B). Four cases exhibited diffuse growth of a cohesive more sheet-like atypical epithelioid cells with scant lymphoid component approximating surface epidermis (Fig. 1, C and D). The tumor cells appeared to be of moderate size with vesicular, monotonous, and polymorphic nuclei, 1-2 nucleoli, and variable amount of eosinophilic cytoplasm. Mitotic figures ranged from 1 to 8 per high-power field (Fig. 2, A and B). The borders of the atypical epithelioid component were often indistinct, blending with the lymphoid stroma (Fig. 2, C). No connection to the overlying epidermis was evident in any of the cases (Fig. 3). Two of the present cases displayed evidence of squamous differentiation (Fig. 4, A), and a sebaceous differentiation was independently observed in another (Fig. 4, B). Reed-Sternberg–like cells were noted in 1 case (Fig. 5, A). The stromal fibrosis was not uniform, and 1 case demonstrated prominent collagenized fibroblastic stroma dividing the tumor cells into compartments (Fig. 5, B). "Pseudorosettes" were observed on rare occasion (Fig. 5, C).Fig. 2Composite histologic images. A, B, Dense neoplastic proliferation of moderately sized cells with polymorphic nuclei, 1-2 nucleoli, eosinophilic cytoplasm, and atypical mitotic figures (hematoxylin-eosin [HE], ×40). C, Indistinct borders of the tumor nests owing to heavy lymphocytic infiltrate (HE, ×40).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 3Composite histologic images. No evidence of connection to the overlying epidermis (HE, ×20).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 4Composite histologic images. A, Evidence of squamous differentiation (hematoxylin-eosin [HE], ×40). B, Evidence of sebaceous differentiation (HE, ×40).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 5Composite histologic images. A, Binucleated tumor cells resembling Reed-Sternberg cells (hematoxylin-eosin [HE], ×40). B, Collagenized fibroblastic stroma dividing the tumor cells into compartments (HE, ×20). C, Evidence of pseudorosettes formation (HE, ×20).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The neoplastic cells showed strong positive reaction with pancytokeratin (Fig. 6, A). The surrounding lymphoid infiltrate exhibited a positive reaction with the T-cell and B-cell markers CD3 and CD20, respectively (CD3 > CD20; Fig. 6, B and C). All tumors exhibited strong p63 protein reactivity (Fig. 6, D). Stains for Epstein-Barr virus (EBV) latent membrane protein 1 (Fig. 6, E) cytokeratin (CK) 7, CK-20, neuron-specific enolase, and carcinoembryonic antigen were negative in all of the cases studied (Table III).Table IIIImmunohistochemical reagents⁎Source: Dako Corp., Carpinteria, CA. and their reactivity in the present casesAntibodyCloneDilutionReactivityCD3F7.2.381:400+CD20L261:100+PancytokeratinAE1/AE31:200+EBV LMP-1CS12341:300−p634A41:400+EBV LMP-1, Epstein-Barr virus latent membrane protein 1. Source: Dako Corp., Carpinteria, CA. Open table in a new tab EBV LMP-1, Epstein-Barr virus latent membrane protein 1. LELCS is a distinctive tumor of low malignant potential that is morphologically similar to undifferentiated nasopharyngeal carcinoma and lymphoepithelioma-like carcinoma occurring in other anatomic sites, such as salivary glands, tonsils, larynx, thyroid, thymus, lungs, stomach, breasts, and uterine cervix.2Lind A.C. Breer W.A. Wick M.R. Lymphoepithelioma-like carcinoma of the skin with apparent origin in the epidermis—a pattern or an entity? A case report.Cancer. 1999; 15: 884-890Google Scholar, 5Carr K.A. Bulengo-Ransby S.M. Weiss L.M. Nickoloff B.J. Lymphoepithelioma like carcinoma of the skin A case report with immunophenotypic analysis and in situ hybridization for Epstein-Barr viral genome.Am J Surg Pathol. 1992; 9: 909-913Google Scholar LELCS is usually seen in older individuals and has a male predilection.9Cavalieri S. Feliciani C. Massi G. et al.Lymphoepithelioma-like carcinoma of the skin.Int J Immunopathol Pharmacol. 2007; 20: 851-854Google Scholar Our study of 11 cases demonstrated a definite male bias similarly to the data collected from the published literature (Table II). The most frequent location for LELCS is sun-exposed skin of the head and neck region, although it has also been reported to occur on the trunk.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 10Robins P. Perez M.I. Lymphoepithelioma like carcinoma of the skin treated by Mohs micrographic surgery.J Am Acad Dermatol. 1995; 32: 814-816Google Scholar Clinically, LELCS appears as an asymptomatic, slowly enlarging, solitary, flesh- or red-colored, firm nodule or plaque.11Jimenez F. Clark R.E. Buchanan M.D. Kamino H. Lymphoepithelioma-like carcinoma of the skin treated with Mohs micrographic surgery in combination with immune staining for cytokeratins.J Am Acad Dermatol. 1995; 32: 878-881Google Scholar, 12Glaich A.S. Behroozan D.S. Cohen J.L. Goldberg L.H. Lymphoepithelioma-like carcinoma of the skin: a report of two cases treated with complete microscopic margin control and review of the literature.Dermatol Surg. 2006; 2: 316-319Google Scholar, 13Dudley C.M. Snow S.N. Voytovich M.C. Warner T.F. Hartig G.K. Enlarging facial nodule on an elderly patient Lymphoepithelioma-like carcinoma of the skin (LELCS).Arch Dermatol. 1998; 12: 1628-1629Google Scholar The clinical differential diagnosis of LELCS includes basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, and Merkel cell carcinoma (MCC). Histomorphologically, LELCS is characterized by nests, cords, or sheets of mitotically active polygonal epithelioid cells with scant amphophilic to eosinophilic cytoplasm, hyperchromatic nuclei, coarse chromatin granules, and 1 or 2 prominent nucleoli.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 4Sagatys E. Kirk J.F. Morgan M.B. Lymphoid lost and found.Am J Dermatopathol. 2003; 2: 159-161Google Scholar, 11Jimenez F. Clark R.E. Buchanan M.D. Kamino H. Lymphoepithelioma-like carcinoma of the skin treated with Mohs micrographic surgery in combination with immune staining for cytokeratins.J Am Acad Dermatol. 1995; 32: 878-881Google Scholar, 14Rosso R. Paulli M. Carnevali L. Neuroendocrine carcinoma of the skin with lymphoepithelioma-like features.Am J Dermatopathol. 1998; 5: 483-486Google Scholar The tumor cells display a syncytial or cohesive growth pattern surrounded by variable amounts of a lymphoid stroma composed predominantly of small lymphocytes with occasional plasma cells.7Clarke L.E. Ioffreda M.D. Lymphoepithelioma-like carcinoma of the skin with spindle cell differentiation.J Cutan Pathol. 2005; 6: 419-423Google Scholar, 11Jimenez F. Clark R.E. Buchanan M.D. Kamino H. Lymphoepithelioma-like carcinoma of the skin treated with Mohs micrographic surgery in combination with immune staining for cytokeratins.J Am Acad Dermatol. 1995; 32: 878-881Google Scholar The cytologic features of LELCS are similar to those found in the fine-needle aspirations of metastatic nasopharyngeal carcinoma in cervical lymph nodes15Jayaram G. Swain M. Khanijow V. Jalaludin M.A.B. Fine-needle aspiration cytology of metastatic nasopharyngeal carcinoma.Diagn Cytopathol. 1998; 19: 168-172Google Scholar and lymphoepithelial carcinomas of the lung.16Chow L.T.C. Chow W.H. Tsui W.M.S. Chan S.K. Lee J.C.K. Fine-needle aspiration cytologic diagnosis of lymphoepithelioma-like carcinoma of the lung; report of two cases with immunohistochemical study.Am J Clin Pathol. 1995; 103: 35-40Google Scholar The most frequent submitted microscopic differential diagnoses for the present cases were LELCS and atypical lymphoid proliferation (Table I). The histologic differential diagnosis of LELCS is wide, including entities such as cutaneous lymphadenoma, metastatic nasopharyngeal carcinoma, metastatic lymphoepithelial carcinoma from other organs, follicular dendritic cell tumor, MCC, melanoma, Hodgkin disease, and lymphoma.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 4Sagatys E. Kirk J.F. Morgan M.B. Lymphoid lost and found.Am J Dermatopathol. 2003; 2: 159-161Google Scholar, 13Dudley C.M. Snow S.N. Voytovich M.C. Warner T.F. Hartig G.K. Enlarging facial nodule on an elderly patient Lymphoepithelioma-like carcinoma of the skin (LELCS).Arch Dermatol. 1998; 12: 1628-1629Google Scholar, 17Ferlicot S. Plantier F. Rethers L. Bui A.D. Wechsler J. Lymphoepithelioma-like carcinoma of the skin: a report of 3 Epstein-Barr virus (EBV)–negative additional cases Immunohistochemical study of the stroma reaction.J Cutan Pathol. 2000; 6: 306-311Google Scholar, 18Wick M.R. Swanson P.E. LeBoit P.E. Strickler J.G. Cooper P.H. Lymphoepithelioma-like carcinoma of the skin with adnexal differentiation.J Cutan Pathol. 1991; 18: 93-102Google Scholar, 19Kutzner H. Schwenzer G. Embacher G. Kutzner U. Schroder J. Lymphoepithelioma-like carcinoma of the skin.Hautarzt. 1991; 42: 575-579Google Scholar, 20Requena L. Sanchez Yus E. Jimenez E. Roo E. Lymphoepithelioma-like carcinoma of the skin: a light-microscopic and immunohistochemical study.J Cutan Pathol. 1994; 21: 541Google Scholar The immunohistochemical profile of LELCS aids in differentiating it from other histologic mimics. LELCS expresses high-molecular-weight cytokeratins and epithelial membrane antigen reactivity, favoring an epidermal, follicular, or sudoriferous differentiation. The tumor cells are negative for carcinoembryonic antigen, S-100 protein, CK-20, CK-7, and neuron-specific enolase.10Robins P. Perez M.I. Lymphoepithelioma like carcinoma of the skin treated by Mohs micrographic surgery.J Am Acad Dermatol. 1995; 32: 814-816Google Scholar Surrounding lymphoid cells show reactivity with T-cell and B-cell markers.12Glaich A.S. Behroozan D.S. Cohen J.L. Goldberg L.H. Lymphoepithelioma-like carcinoma of the skin: a report of two cases treated with complete microscopic margin control and review of the literature.Dermatol Surg. 2006; 2: 316-319Google Scholar Cutaneous lymphadenoma also exhibits a dense lymphocytic infiltrate similar to that of LELCS which surrounds the neoplastic lobules. But unlike LELCS, the neoplastic cells of cutaneous lymphadenoma are monomorphous, there is no mitotic activity, and a peripheral layer of basal-like cells is generally observed.17Ferlicot S. Plantier F. Rethers L. Bui A.D. Wechsler J. Lymphoepithelioma-like carcinoma of the skin: a report of 3 Epstein-Barr virus (EBV)–negative additional cases Immunohistochemical study of the stroma reaction.J Cutan Pathol. 2000; 6: 306-311Google Scholar The most complex differential diagnosis of LELCS is a metastatic nasopharyngeal carcinoma. The histopathologic features of metastatic nasopharyngeal carcinoma are akin to those of LELCS, and the only reliable method to differentiate the two lesions is by testing for EBV. LELCS stains negative to EBV, in contrast to the EBV-positive staining of nasopharyngeal carcinoma.17Ferlicot S. Plantier F. Rethers L. Bui A.D. Wechsler J. Lymphoepithelioma-like carcinoma of the skin: a report of 3 Epstein-Barr virus (EBV)–negative additional cases Immunohistochemical study of the stroma reaction.J Cutan Pathol. 2000; 6: 306-311Google Scholar Follicular dendritic cell tumor (FDCT) is histologically characterized by the presence of syncytial-appearing plump cells in a background of reactive lymphoid cells similar to LELCS. The diagnosis of FDCT is confirmed by immunohistochemical studies. In contrast to LELCS, the tumor cells of FDCT stain negative for cytokeratins. FDCT stains positive for FDC markers, namely Ki-M4, CD21, and CD35.3Shek T.W. Leung E.Y. Luk I.S. Loong F. Chan A.C. Yik Y.H. et al.Lymphoepithelioma-like carcinoma of the skin.Am J Dermatopathol. 1996; 6: 637-644Google Scholar Metastatic lymphoepithelial carcinoma from other organs and primary LELCS are identical both histogically and immunophenotypically, but are different in their association with EBV. Metastatic LELCS are positive for EBV.21Iezzoni J.C. Gaffey M.J. Weiss L.M. The role of Epstein-Barr virus in lymphoepithelioma-like carcinomas.Am J Clin Pathol. 1995; 103: 308Google Scholar Merkel cell carcinoma is histologically characterized by closely approximated hyperchromatic cells containing coarse chromatin. Unlike LELCS, MCC may demonstrate connection to the surface epithelium. The other important histologic criterion that separates these 2 entities is the absence of lymphocytic infiltrate in MCC. MCC shows negativity for cytokeratin and immunopositivity for neuroendocrine markers such as neuron-specific enolase, synaptophysin, and chromogranin.17Ferlicot S. Plantier F. Rethers L. Bui A.D. Wechsler J. Lymphoepithelioma-like carcinoma of the skin: a report of 3 Epstein-Barr virus (EBV)–negative additional cases Immunohistochemical study of the stroma reaction.J Cutan Pathol. 2000; 6: 306-311Google Scholar, 22Gillum P.S. Morgan M.B. Naylor M.F. Everett M.A. Absence of Epstein-Barr virus in lymphoepitheliomalike carcinoma of the skin Polymerase chain reaction evidence and review of five cases.Am J Dermatopathol. 1996; 5: 478-482Google Scholar Microscopically, LELCS may also bear resemblance to Hodgkin lymphoma owing to the presence of occasional binucleated cells resembling Reed-Sternberg cells. Negativity for cytokeratin and positivity for CD30 and CD15 support a diagnosis of Hodgkin lymphoma.3Shek T.W. Leung E.Y. Luk I.S. Loong F. Chan A.C. Yik Y.H. et al.Lymphoepithelioma-like carcinoma of the skin.Am J Dermatopathol. 1996; 6: 637-644Google Scholar, 7Clarke L.E. Ioffreda M.D. Lymphoepithelioma-like carcinoma of the skin with spindle cell differentiation.J Cutan Pathol. 2005; 6: 419-423Google Scholar Lymphoma also is considered to be a possible differential diagnosis of LELCS. The cells of malignant lymphoma exhibit unevenly shaped nuclei with coarser chromatin and smaller basophilic or amphophilic nucleoli, whereas the lymphocytes in LELCS show no cellular atypia. Additionally, depending on the type of lymphoma, the cells are either positive to CD20 (B-cell) or CD3 (T-cell) and negative for cytokeratins.22Gillum P.S. Morgan M.B. Naylor M.F. Everett M.A. Absence of Epstein-Barr virus in lymphoepitheliomalike carcinoma of the skin Polymerase chain reaction evidence and review of five cases.Am J Dermatopathol. 1996; 5: 478-482Google Scholar In addition to these entities, one of the cases reported by Clarke and Ioffreda7Clarke L.E. Ioffreda M.D. Lymphoepithelioma-like carcinoma of the skin with spindle cell differentiation.J Cutan Pathol. 2005; 6: 419-423Google Scholar displayed a spindle cell component, thereby including mesenchymal spindle cell lesions, especially the spindle cell variant of melanoma, in the spectrum of histologic differential diagnosis of LELCS. The immunohistochemical profile of melanoma is used to distinguish it from LELCS. The neoplastic cells of melanoma stain positively with S-100 and HMB-45 and negatively with cytokeratins.7Clarke L.E. Ioffreda M.D. Lymphoepithelioma-like carcinoma of the skin with spindle cell differentiation.J Cutan Pathol. 2005; 6: 419-423Google Scholar Although LELCS represents a distinct pathologic entity, its histogenesis still remains unclear.11Jimenez F. Clark R.E. Buchanan M.D. Kamino H. Lymphoepithelioma-like carcinoma of the skin treated with Mohs micrographic surgery in combination with immune staining for cytokeratins.J Am Acad Dermatol. 1995; 32: 878-881Google Scholar, 17Ferlicot S. Plantier F. Rethers L. Bui A.D. Wechsler J. Lymphoepithelioma-like carcinoma of the skin: a report of 3 Epstein-Barr virus (EBV)–negative additional cases Immunohistochemical study of the stroma reaction.J Cutan Pathol. 2000; 6: 306-311Google Scholar There have been competing opinions regarding the origin of LELCS among different reviewers. Adnexal origin is favored by many authors because of its location in the dermis, its lack of continuity with the surface epidermis, and the reported presence of cytoplasmic acid epithelial mucin vacuoles1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 23Ko T. Muramatsu T. Shirai T. Lymphoepithelioma-like carcinoma of the skin.J Dermatol. 1997; 2: 104-109Google Scholar with possible follicular,10Robins P. Perez M.I. Lymphoepithelioma like carcinoma of the skin treated by Mohs micrographic surgery.J Am Acad Dermatol. 1995; 32: 814-816Google Scholar, 11Jimenez F. Clark R.E. Buchanan M.D. Kamino H. Lymphoepithelioma-like carcinoma of the skin treated with Mohs micrographic surgery in combination with immune staining for cytokeratins.J Am Acad Dermatol. 1995; 32: 878-881Google Scholar, 18Wick M.R. Swanson P.E. LeBoit P.E. Strickler J.G. Cooper P.H. Lymphoepithelioma-like carcinoma of the skin with adnexal differentiation.J Cutan Pathol. 1991; 18: 93-102Google Scholar, 24Takayasu S. Yoshiyama M. Kurata S. Terashi H. Lymphoepithelioma-like carcinoma of the skin.J Dermatol. 1996; 23: 472-475Google Scholar glandular,22Gillum P.S. Morgan M.B. Naylor M.F. Everett M.A. Absence of Epstein-Barr virus in lymphoepitheliomalike carcinoma of the skin Polymerase chain reaction evidence and review of five cases.Am J Dermatopathol. 1996; 5: 478-482Google Scholar or sebaceous differentiation.20Requena L. Sanchez Yus E. Jimenez E. Roo E. Lymphoepithelioma-like carcinoma of the skin: a light-microscopic and immunohistochemical study.J Cutan Pathol. 1994; 21: 541Google Scholar All of our cases exhibited strong p63 protein reactivity, supporting the epithelial origin with a putative adnexal histiogenesis. It is possible that newer isoforms of p63 may in the future reliably distinguish between basilar cells of the skin and basilar-myoepithelial cell of the adnexa. Some authors favor epidermal origin based on the presence of keratinocytic atypia and epidermal involvement.2Lind A.C. Breer W.A. Wick M.R. Lymphoepithelioma-like carcinoma of the skin with apparent origin in the epidermis—a pattern or an entity? A case report.Cancer. 1999; 15: 884-890Google Scholar, 3Shek T.W. Leung E.Y. Luk I.S. Loong F. Chan A.C. Yik Y.H. et al.Lymphoepithelioma-like carcinoma of the skin.Am J Dermatopathol. 1996; 6: 637-644Google Scholar, 13Dudley C.M. Snow S.N. Voytovich M.C. Warner T.F. Hartig G.K. Enlarging facial nodule on an elderly patient Lymphoepithelioma-like carcinoma of the skin (LELCS).Arch Dermatol. 1998; 12: 1628-1629Google Scholar, 23Ko T. Muramatsu T. Shirai T. Lymphoepithelioma-like carcinoma of the skin.J Dermatol. 1997; 2: 104-109Google Scholar, 25Leung E.Y. Yik Y.H. Chan J.K. Lack of demonstrable EBV in Asian lymphoepithelioma-like carcinoma of skin.Am J Surg Pathol. 1995; 8: 974-976Google Scholar, 26Bornhövd E.C. Schmid-Wendtner M.H. Volkenandt M. Wendtner C.M. Sander C.A. Malignant skin lesions Case 2: lymphoepithelioma-like carcinoma of the skin.J Clin Oncol. 1999; 12: 3853-3855Google Scholar None of the present 11 cases exhibited these features. Like undifferentiated nasopharyngeal carcinoma, LELCS may be a squamous cell carcinoma variant.2Lind A.C. Breer W.A. Wick M.R. Lymphoepithelioma-like carcinoma of the skin with apparent origin in the epidermis—a pattern or an entity? A case report.Cancer. 1999; 15: 884-890Google Scholar, 27Cassarino D.S. DeRienzo D.P. Barr R. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification.J Cutan Pathol. 2006; 33: 191-206Google Scholar In spite of the high-grade histologic features of LELCS, the prognosis is good. There have been reports of recurrences after incomplete excision.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar The treatment of choice is complete surgical removal. Radiotherapy is a useful adjunctive therapy for aggressive or unresectable tumors and for those patients who are not surgery candidates.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 12Glaich A.S. Behroozan D.S. Cohen J.L. Goldberg L.H. Lymphoepithelioma-like carcinoma of the skin: a report of two cases treated with complete microscopic margin control and review of the literature.Dermatol Surg. 2006; 2: 316-319Google Scholar, 28Walker A.N. Kent D. Mitchell A.R. Lymphoepitheloma-like carcinoma of the skin.J Am Acad Dermatol. 1990; 22: 691-693Google Scholar To prevent local recurrence, some reports also recommend Mohs micrographic surgery.11Jimenez F. Clark R.E. Buchanan M.D. Kamino H. Lymphoepithelioma-like carcinoma of the skin treated with Mohs micrographic surgery in combination with immune staining for cytokeratins.J Am Acad Dermatol. 1995; 32: 878-881Google Scholar, 23Ko T. Muramatsu T. Shirai T. Lymphoepithelioma-like carcinoma of the skin.J Dermatol. 1997; 2: 104-109Google Scholar It is imperative to properly diagnose and adequately treat this type of malignancy with complete excision of the tumor. Close clinical follow-up of the patient is recommended. Metastasis to lymph nodes and internal organs (liver, lungs, and bone), though exceptionally uncommon (only 5 cases), have been reported.1Swanson S.A. Cooper P.H. Mills S.E. Wick M.R. Lymphoepithelioma-like carcinoma of the skin.Mod Pathol. 1988; 1: 359-365Google Scholar, 29Hall G. Duncan A. Azurdia R. Leonard N. Lymphoepithelioma-like carcinoma of the skin: a case with lymph node metastases at presentation.Am J Dermatopathol. 2006; 3: 211-215Google Scholar, 30Ahmadi M.A. Prieto V.G. Clayman G.L. Ginsberg L.E. Esmaeli B. Lymphoepitheliomalike carcinoma of the orbit.Arch Ophthalmol. 2001; 8: 1206-1208Google Scholar, 31Kazakov D.V. Nemcova J. Mikyskova I. Michal M. Absence of Epstein-Barr virus, human papillomavirus, and simian virus 40 in patients of central european origin with lymphoepithelioma-like carcinoma of the skin.Am J Dermatopathol. 2007; 4: 365-369Google Scholar In conclusion, LELCS is an uncommon neoplasm that is rarely suspected at the time of presentation. It displays distinctive histologic features and similarities to nasopharyngeal carcinoma. Awareness can serve to prevent a diagnostic and therapeutic misadventure.
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