Lymphoepithelioma-like carcinoma of head and neck skin:
a systematic analysis of 11 cases and review of literature
Preston Q. Welch, DMD, MS,aStephen B. Williams, DDS,bRobert D. Foss, DDS, MS,c Maria-Magdalena Tomaszewski, MD,dAnish Gupta, MS,eand Junu Ojha, BDS,fWiesbaden, Germany; Honolulu, Hawaii; Washington, D.C.; and Detroit, Michigan
WIESBADEN DENTAL CLINIC COMMAND, TRIPLER ARMY MEDICAL CENTER, ARMED FORCES INSTITUTE OF PATHOLOGY, AND UNIVERSITY OF DETROIT
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. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:78-86)
Undifferentiated carcinoma of the lymphoepithelial type is a well defined epithelial malignancy of the nasopharynx. Histologically and immunophenotypi- cally identical neoplasms have been described in the salivary glands, larynx, thymus, stomach, uterine cer- vix, and skin.1,2Lymphoepithelioma-like carcinoma of the skin (LELCS) was first described by Swanson et al.1 in 1988 as a distinctive primary malignant neo-
plasm with remarkable microscopic similarity to undif- ferentiated 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-ex- posed skin of the head and neck in elderly individuals.
There is a tendency toward local recurrence and very limited metastatic potential.3The clinical appearance of LELCS is varied and ranges from a solitary flesh- colored nodule or plaque to an erythematous or indu- rated lesion with a keratotic center.1,4 Histologically, LELCS is composed of a neoplastic epithelial compo- nent associated with a reactive lymphoid infiltrate.1,5 Tumor cells are arranged in nodules, isolated or anas- tomosing 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.1,6The histologic diag- nosis of LELCS may be complicated by the variable architectural and cytologic appearance of the epithelial
aCommander, Wiesbaden Dental Clinic Command.
bChief, Oral and Maxillofacial Pathology, Tripler Army Medical Center.
cChairman, Department of Oral and Maxillofacial Pathology, Armed Forces Institute of Pathology.
dDepartment of Dermatopathology, Armed Forces Institute of Pathology.
eSenior dental student, College of Dentistry, University of Detroit Mercy.
fAssistant Professor, Department of Biomedical and Diagnostic Sci- ences, College of Dentistry, University of Detroit Mercy.
Received for publication Apr 17, 2010; returned for revision May 12, 2010; accepted for publication May 31, 2010.
1079-2104/$ - see front matter
© 2011 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2010.05.075
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ORAL AND MAXILLOFACIAL PATHOLOGY Editor: Mark W. Lingen
Table I. Summary of the literature review of head and neck lymphoepithelioma-like carcinoma of the skin (LELCS)
Study
No. of
patients Gender Age, y Location Clinical presentation Treatment
Swanson et al.,11988 4 M 50 Scalp Lump Local excision
M 62 Forehead Nodule Surgical excision
M 68 Cheek Nodule Surgical excision, radiotherapy
F 81 Cheek Nodule Surgical excision
Malhotra et al.,321989 2 M 67 Nose Papule N/A
M 71 Scalp Nodule N/A
Walker et al.,281990 1 F 83 Zygoma Nodule Radiotherapy
Kutzner et al.,191991 1 F 56 Upper lip Pearly papule Surgical excision
Wick et al.,181991 3 F 51 Forehead Papule Electrodissection
M 52 Face Nodule Local excision
F 71 Eyelid Nodule Local excision
Carr et al.,51992 1 F 84 Cheek Nodule Surgical excision
Ortiz-Frutos et al.,331993 1 M 70 Nose Nodule Surgical excision, radiotherapy
on recurrence
Stahr,341993 1 M 63 Forehead N/A N/A
Requena et al.,201994 1 F 83 Temple Nodule Surgical excision
Clarke and Ioffreda,71995 1 M 72 Forehead Nodule Surgical excision
Dozier et al.,351995 1 F 91 Nose Nodule Electrodissection, curettage;
Moh’s surgery at recurrence
Jimenez et al.,111995 1 M 68 Nasal ala Plaque Moh’s surgery
Leung et al.,251995 1 M 78 Orbit angle Nodule Surgical excision
Maruyama et al.,361995 1 F 89 Eyelid Papule Surgical excision
Robins and Perez,101995 1 F 74 Cheek Nodule Mohs surgery
Gillum et al.,221996 4 F 64 Chin N/A N/A
F 74 Cheek N/A N/A
M 39 Forehead N/A N/A
M 69 Cheek N/A N/A
Shek et al.,31996 2 F 81 Forehead Nodule Surgical excision
M 78 External orbital angle
Nodule Surgical excision
Takayasu et al.,241996 1 F 62 Nasal ala Nodule Surgical excision, radiotherapy
Ko et al.,231997 1 M 67 Cheek Nodule Surgical excision
Dudley et al.,131998 1 M 81 Mandible Nodule Moh’s surgery
Bornhövd et al.,261999 1 F 87 Cheek Nodule Surgical excision
Chen,61999 1 M 71 Forehead Nodule Surgical excision
Lind et al.,21999 1 F 96 Nasal ala Nodule Surgical excision
Ferlicot et al.,172000 3 M 61 Nasal ala Nodule Surgical excision
M 88 Ear Nodule Surgical excision
M 87 Cheek Nodule Surgical excision
Ahmadi et al.,302001 1 M 45 Forehead Nodule Surgical excision, radiotherapy
Ho et al.,372005 2 M 79 Lower eyelid Nodule Surgical excision
M 67 Lower eyelid N/A Surgical excision
Otsuki et al.,382005 1 M 77 Cheek Nodule Surgical excision
Fenniche et al.,392006 1 F 78 Cheek Nodule Surgical excision
Glaich et al.,122006 1 F 97 Cheek Nodule Moh’s surgery
Cavalieri et al.,92007 1 F 92 Cheek Violaceous nodule Surgical excision
Kazakov et al.,312007 7 4 M 57-86 Face N/A N/A
2 F Face N/A N/A
1 N/A Face N/A N/A
Face N/A N/A
Scalp N/A N/A
Scalp N/A N/A
Auricle N/A N/A
Arsenovic et al.,402008 1 F 89 Cheek Brown beige plaque like non ulcerated lesion
Surgical excision
Lyle et al.,412008 1 F 68 Forehead Papule Mohs surgery
Mahomed et al.,422008 1 M 73 Lower lip Ulcer with indurated edges Surgical excision Hinz et al.,432009 1 F 91 Temple Erythematous with central erosion,
peripheral telengectasia
Surgical excision
M, male; F, female; N/A, not available.
cells and the dense lymphoplasmacytic infiltrate which may obscure the epithelial component.7Immunohisto- chemical evaluation may serve to exclude other histo- logically similar lesions. Owing to the close histologic similarity to nasopharyngeal lymphoepithelioma, pa- tients with suspected LELCS should have a thorough otolaryngologic examination, including indirect laryn- goscopy to rule out a metastatic nasopharyngeal lym- phoepithelioma. Although the skin metastasis of naso- pharyngeal lymphoepithelioma is extremely rare, with only 16 cases documented in the literature, they are associated with a worse prognosis, with patients suc- cumbing within a year.8
Eleven new LELCS cases are reviewed along with previously reported cases from the English-language literature.
MATERIALS AND METHODS
Eleven cases of LELCS of head and neck were identified in the Armed Forces Institute of Pathology (AFIP) files. The clinical findings, including presenta- tion, patient age, gender, location, and clinical differ- ential diagnosis, were reviewed. Histomorphologic features were evaluated regarding architecture, cel- lular and nuclear atypia, mitotic rate, growth pattern, and lymphoid stroma. The immunophenotypic fea- tures 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. Addi- tionally, a review of the available English-language literature was performed.
RESULTS Clinical findings
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, involv- ing 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 differ- ential diagnosis was basal cell carcinoma. The treat- ment 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 II. Summary of the findings of the present cases of LELCS
Case no. Age, y Gender Location Clinical appearance
Clinical impression
Contributor’s
microscopic differential Treatment
1 84 M Cheek Irregular nodule BCC Malignant adnexal tumor Surgical excision
2 74 F Zygoma Flesh colored nodule with telangiactasia
Sarcoidosis Granulomatous rosacea Surgical excision
3 78 M Forehead Red nodule with ulceration Atypical fibroxanthoma
Atypical lymphoid proliferation/lymphoma
Surgical excision
4 80 M Forehead Irregular nodule H/O carcinoma of
hypopharynx, R/O metastasis
ALHE Surgical excision
5 79 M Scalp Irregular ulcerated white plaque
N/A Trichilemmal carcinoma Surgical excision
6 47 F Cheek Pearlescent nodule BCC Lymphoid hyperplasia Surgical excision
7 60 M Ear Raised pale brown nodule with
ulceration
Cyst Squamous cell
carcinoma(poorly differentiated)
Surgical excision
8 70 M Temple Red-purple scaly nodule BCC LELCS Surgical excision
9 82 M Eyebrow Irregular ulcerated nodule BCC Atypical lymphoid
proliferation/lymphoma
Surgical excision
10 80 F Ear Pearly papule BCC LELCS Surgical excision
11 80 M Upper lip Red firm nodule Calcified cyst Atypical lymphoid &
squamous epithelial proliferation
Electrocautery with deep shave
BCC, basal cell carcinoma; H/O, history of; R/O, rule out; ALHE, angiolymphoid hyperplasia with eosinophilia; other abbreviations as in Table I.
Histologic findings
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 epider- mis (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 com- ponent were often indistinct, blending with the lym- phoid stroma (Fig. 2, C). No connection to the over- lying 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 an-
other (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).
Immunohistochemical findings
The neoplastic cells showed strong positive reaction with pancytokeratin (Fig. 6, A). The surrounding lym- phoid 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).
DISCUSSION
LELCS is a distinctive tumor of low malignant poten- tial that is morphologically similar to undifferentiated Fig. 1. Composite histologic images. A, B, Nodular growth of neoplastic epithelial cells immersed in a dense lymphoid stroma (hematoxylin-eosin [HE],⫻10). C, D, Diffuse pattern exhibiting a cohesive arrangement of neoplastic cells with less lymphoid stroma and closer to the surface (HE,⫻10).
nasopharyngeal carcinoma and lymphoepithelioma-like carcinoma occurring in other anatomic sites, such as sal- ivary glands, tonsils, larynx, thyroid, thymus, lungs, stom- ach, breasts, and uterine cervix.2,5LELCS is usually seen in older individuals and has a male predilection.9 Our
study of 11 cases demonstrated a definite male bias sim- ilarly 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.1,10 Fig. 2. Composite 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).
Fig. 3. Composite histologic images. No evidence of connection to the overlying epidermis (HE,⫻20).
Clinically, LELCS appears as an asymptomatic, slowly enlarging, solitary, flesh- or red-colored, firm nodule or plaque.11-13 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 gran- ules, and 1 or 2 prominent nucleoli.1,4,11,14 The tumor Fig. 4. Composite histologic images. A, Evidence of squamous differentiation (hematoxylin-eosin [HE],⫻40). B, Evidence of sebaceous differentiation (HE,⫻40).
Fig. 5. Composite 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).
cells display a syncytial or cohesive growth pattern sur- rounded by variable amounts of a lymphoid stroma com- posed predominantly of small lymphocytes with occa- sional plasma cells.7,11 The cytologic features of LELCS are similar to those found in the fine-needle aspirations of metastatic nasopharyngeal carcinoma in cervical lymph nodes15 and lymphoepithelial carcino- mas of the lung.16
The most frequent submitted microscopic differential diagnoses for the present cases were LELCS and atypical lymphoid proliferation (Table I). The histologic differen- tial diagnosis of LELCS is wide, including entities such as cutaneous lymphadenoma, metastatic nasopharyngeal car-
cinoma, metastatic lymphoepithelial carcinoma from other organs, follicular dendritic cell tumor, MCC, mela- noma, Hodgkin disease, and lymphoma.1,4,13,17-20 The immunohistochemical profile of LELCS aids in differen- tiating it from other histologic mimics. LELCS expresses high-molecular-weight cytokeratins and epithelial mem- brane antigen reactivity, favoring an epidermal, follic- ular, or sudoriferous differentiation. The tumor cells are negative for carcinoembryonic antigen, S-100 protein, CK-20, CK-7, and neuron-specific enolase.10 Sur- rounding lymphoid cells show reactivity with T-cell and B-cell markers.12
Cutaneous lymphadenoma also exhibits a dense lym- phocytic infiltrate similar to that of LELCS which sur- rounds the neoplastic lobules. But unlike LELCS, the neoplastic cells of cutaneous lymphadenoma are mono- morphous, there is no mitotic activity, and a peripheral layer of basal-like cells is generally observed.17 The most complex differential diagnosis of LELCS is a metastatic nasopharyngeal carcinoma. The histopatho- logic 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.17 Fig. 6. Composite immunohistochemical photomicrographs. A, Strong positivity with pancytokeratins (⫻20). B, Positive staining with CD20 (⫻20). C, Strong positivity with CD3 (⫻20). D, Positive reactivity to p63 protein (⫻20). E, Negative reactivity to Epstein-Barr virus–associated antibodies (⫻20).
Table III. Immunohistochemical reagents* and their reactivity in the present cases
Antibody Clone Dilution Reactivity
CD3 F7.2.38 1:400 ⫹
CD20 L26 1:100 ⫹
Pancytokeratin AE1/AE3 1:200 ⫹
EBV LMP-1 CS1234 1:300 ⫺
p63 4A4 1:400 ⫹
EBV LMP-1, Epstein-Barr virus latent membrane protein 1.
*Source: Dako Corp., Carpinteria, CA.
Follicular dendritic cell tumor (FDCT) is histologi- cally characterized by the presence of syncytial-appear- ing 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 CD35.3
Metastatic lymphoepithelial carcinoma from other organs and primary LELCS are identical both histogi- cally and immunophenotypically, but are different in their association with EBV. Metastatic LELCS are pos- itive for EBV.21
Merkel cell carcinoma is histologically characterized by closely approximated hyperchromatic cells contain- ing coarse chromatin. Unlike LELCS, MCC may dem- onstrate 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 immuno- positivity for neuroendocrine markers such as neuron- specific enolase, synaptophysin, and chromogranin.17,22 Microscopically, LELCS may also bear resemblance to Hodgkin lymphoma owing to the presence of occa- sional binucleated cells resembling Reed-Sternberg cells.
Negativity for cytokeratin and positivity for CD30 and CD15 support a diagnosis of Hodgkin lymphoma.3,7 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. Ad- ditionally, depending on the type of lymphoma, the cells are either positive to CD20 (B-cell) or CD3 (T-cell) and negative for cytokeratins.22
In addition to these entities, one of the cases reported by Clarke and Ioffreda7displayed a spindle cell com- ponent, 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 mela- noma is used to distinguish it from LELCS. The neo- plastic cells of melanoma stain positively with S-100 and HMB-45 and negatively with cytokeratins.7
Although LELCS represents a distinct pathologic entity, its histogenesis still remains unclear.11,17There 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 epider- mis, and the reported presence of cytoplasmic acid epithelial mucin vacuoles1,23 with possible follicu- lar,10,11,18,24
glandular,22or sebaceous differentiation.20 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 in- volvement.2,3,13,23,25,26
None of the present 11 cases exhibited these features. Like undifferentiated nasopha- ryngeal carcinoma, LELCS may be a squamous cell carcinoma variant.2,27
In spite of the high-grade histologic features of LELCS, the prognosis is good. There have been reports of recurrences after incomplete excision.1 The treat- ment of choice is complete surgical removal. Radio- therapy is a useful adjunctive therapy for aggressive or unresectable tumors and for those patients who are not surgery candidates.1,12,28 To prevent local recurrence, some reports also recommend Mohs micrographic sur- gery.11,23It is imperative to properly diagnose and ade- quately treat this type of malignancy with complete exci- sion 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 un- common (only 5 cases), have been reported.1,29-31
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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Reprint requests:
Junu Ojha, BDS Assistant Professor
Department of Diagnostic Sciences College of Dentistry
University of Detroit Mercy 2700 Martin Luther King Jr. Blvd.
Detroit, MI 48208 ojhaj@udmercy.edu
