Lymphoepithelial Carcinoma of the Lacrimal Gland

The association of benign lymphoepithelial lesions with Sjögren syndrome is well recognized; however, such lesions can also develop in patients without clinical features of this syndrome.¹ The lymphoid infiltrate or the epithelial component of the lymphoepithelilal lesions can undergo malignant transformation, resulting in B-cell lymphomas or lymphoepithelial carcinoma. The development of such carcinomas in the salivary glands and other sites has been amply documented.^2-5 Recently, Bloching et al⁶ briefly described a lacrimal gland tumor, which they called "lymhoepithelioma-like carcinoma." The tumor they described could be the first reported case of lymphoepithelial carcinoma. In the present article, we describe in detail the clinical and histopathologic features of a primary lacrimal gland lymphoepithelial carcinoma with immunohistochemical and molecular analysis.

A 63-year-old white woman visited an ophthalmologist with a history of dry eyes, "fullness" around the superotemporal aspect of the left eye, proptosis, and binocular horizontal diplopia on left gaze, during the past several months. She gave no reports of pain, local tenderness, or headache. Her medical history was significant for obesity and hypothyroidism; the latter was being treated with levothyroxine sodium. On examination, visual acuity was 20/25 OU. There was no afferent pupillary defect, and color vision was normal. The left eye was proptotic, and Hertel exophthalmometry measurements were 14 mm OD and 20 mm OS across a base of 100 mm. There was mild-to-moderate resistance to retropulsion of the left globe. The patient was orthophoric in all gaze positions except for left gaze, where she had a 15-diopter esotropia. Ductions were full except for a 20% limitation of left eye abduction. Visual field and funduscopy findings were unremarkable. The clinical impression was a benign mixed tumor of the lacrimal gland. Computed tomographic scans of the orbit showed an enlarged left lacrimal gland without bone involvement, and magnetic resonance imaging scans revealed a solid, 3-cm mass in the region of the lacrimal fossa. The mass was somewhat homogenous with respect to signal, and enhanced with gadolinium (Figure 1). The patient underwent en bloc excision via Kronlein lateral orbitotomy, and the entire mass was removed with care to avoid rupture of the pseudocapsule of the presumed benign mixed-cell tumor. However, there was adherence to the posterior lateral scleral wall that required shaving off the sclera. The patient subsequently received 3500 rad (35 Gy) rad) of radiotherapy to the left orbit. Six months following the treatment, she had full levator function and 20/25 visual acuity without recurrence or metastasis.

The orbital tumor was roughly oval and measured 31 × 29 × 28 mm. The mass appeared partially encapsulated, and the cut surface was tan-white. Histologic examination of the tumor revealed a circumscribed mass containing irregularly shaped nests of epithelial cells, dense lymphocytic infiltrates, lymphoid follicles containing germinal centers, and fibrous tissue stroma (Figure 2). The epithelial nests were frequently permeated by lymphocytes, and small islands of these epithelial cells were widely separated by the lymphoid infiltrates and fibrous septae (Figure 3). The undifferentiated epithelial cells showed indistinct cell boundaries and eosinophilic cytoplasm containing large vesicular nuclei and prominent nucleoli. There were frequent abnormal mitotic figures (Figure 2, inset). The carcinoma cells formed cords, small irregular nests, and syncytial aggregates, distinctly surrounded by lymphoid-rich stroma (Figure 3). The lymphoid infiltrate was primarily made up of small lymphocytes admixed with a few plasma cells and occasional polymorphonuclear leukocytes and eosinophils.

On immunohistochemical analysis, the epithelial component stained positive with Pan-keratin (Ventana Medical Systems Inc, Tucson, Ariz), and the lymphoid infiltrate was positive for common leukocyte antigen (Figure 4). These stains confirmed the presence of permeated leukocytes in the nests of epithelial cells. The lymphoid-rich stroma were mainly stained with CD-3 (Pan T-cell marker; Figure 5 A). The CD-68–positive (macrophage marker) cells were seen encircling the lobules and cords of neoplastic cells (Figure 5B). The CD-20–positive (B-cell marker) cells were present mainly in the lymphoid follicles, whereas the CD-3–positive cells were widely distributed. This heterogeneous lymphoid and mononuclear cell infiltration was also noted in the lacrimal gland tissue present at the periphery of the tumor (Figure 2). The morphologic features, in addition to the immunohistochemical results, were supportive of the diagnosis of lymphoepithelial carcinoma of the lacrimal gland.

Immunohistochemical (DAKO, Carpinteria, Calif) and in situ hybridization tests to detect Epstein-Barr viral antigen and the viral genome gave negative results (Enzo Diagnostics, Farmingdale, NY). The polymerase chain reaction (PCR) using paraffin-embedded sections of the tumor, and primers specific for Epstein-Barr virus (forward primer L1 [5′-GTTAGATCTTACCAAGTAAGCA-3′] and reverse primer L2 [5′-TTATGAGTGACTGGACTGGAGGA-3′])⁷ showed the absence of amplified products.

The present case shows the typical histopathologic features of lymphoepithelial carcinoma, characterized by islands of undifferentiated large carcinoma cells permeated and enveloped by an admixture of T lymphocytes, macrophages, and a few B lymphocytes (Figure 2 and Figure 5). These histologic features are virtually identical to those seen in lymphoepithelial carcinomas occurring in the salivary glands and other sites.^2-4 Under low magnification, the lacrimal gland carcinoma showed indistinct epithelial components and distinct heavy infiltration of lymphoid cells, simulating a lymphoma. Higher magnification disclosed nests of malignant epithelial cells, exhibiting eosinophilic cytoplasm with ill-defined cell borders and frequent abnormal mitotic figures (Figure 2, inset). Although lacrimal gland acini were seen juxtaposed to the malignant epithelial lobules, the lacrimal gland acini did not show epimyoepithelial proliferation, but focal lymphocytic infiltration was present. These features, as well as the gross appearance of the lacrimal gland, suggest that the tumor arose de novo from the lacrimal gland rather than from a preexisting benign lymphoepithelial lesion. Although the patient was not given a workup for Sjögren syndrome, her history of unilateral dry eye in the involved eye, unaccompanied by dryness in any other body part, makes the diagnosis of Sjögren syndrome less likely, and accordingly supports a de novo origin of the tumor.

There is a proclivity for the occurrence of nasopharyngeal and salivary gland lymphoepithelial carcinomas in individuals with Mongolian ancestry. The carcinoma can also develop in individuals with non-Mongolian ancestry, but this group constitutes less than 15% of such carcinomas.² The tumor affects both sexes, with a female-male ratio of 1.5:1.0. Familial clustering of nasopharyngeal lymphoepithelial carcinomas has been previously reported.² The age at diagnosis ranges from 10 to 86 years, with a median age of approximately 40 years.² Although the present patient with the lacrimal gland lymphoepithelial carcinoma was a 63-year-old woman, she has no known Mongolian lineage, and there is no history of the occurrence of such tumors in her family.

Lymphoepithelial carcinomas, in particular those occurring in the nasopharynx, are often associated with Epstein-Barr virus infection.^2,8,9 Such an association is present in a significant number of individuals with Mongolian ancestry, but it is rarely seen in non-Mongolian people.² The tumor samples from this patient were negative for Epstein-Barr virus infection when examined by the immunohistochemical stain, in situ hybridization, and PCR methods.

The characteristic lymphoid infiltration seen in lacrimal gland carcinoma consists primarily of T lymphocytes, followed by CD-68–positive macrophages and B lymphocytes (Figure 5). The predominant presence of T-lineage cells suggests that cell-mediated immunity may play a role in the tumor progression and metastasis. Overall, irrespective of their site of origin, lymphoepithelial carcinomas carry a better prognosis than similar carcinomas that are devoid of such lymphoid infiltration. It has been proposed that the T-cell–mediated immunity and the cytokines generated by these cells may contribute to long-term survival.²

Lymphoepithelial carcinoma shows histopathologic features similar to those noted in benign lymphoepithelial lesions; however, the former is distinguished by the presence of malignant cytologic features in the epithelial structures and by the invasion of adjacent tissues. Large-cell lymphomas, histiocytic neoplasms, and amelanotic melanoma need to be considered in the differential diagnosis, but immunohistochemical methods can distinguish these tumors from lymphoepithelial carcinoma.

Because of the rarity of lymphoepithelial carcinomas of the lacrimal gland, optimal therapy is unknown. The rationale for therapy in our patient was based on the clinical experience with the more common lesion in the salivary gland, which shows improved survival with surgical excision of the mass, followed by irradiation.² Although lymphoepithelial carcinoma rarely occurs in the lacrimal gland, our immunohistochemical and molecular studies suggest that its pathogenesis at this site may be independent of previous Epstein-Barr virus infection.

This study was supported in part by grant EY03040 from the National Eye Institute, Bethesda, Md, and by a grant from Research to Prevent Blindness, New York, NY.

Corresponding author and reprints: Narsing A. Rao, MD, Doheny Eye Institute, 1450 San Pablo St, DVR-211, Los Angeles, CA 90033 (e-mail: nrao@hsc.usc.edu).