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.
A, Computed tomographic scan of
the left orbit shows a large mass occupying the lacrimal fossa and lateral
orbit. B, Magnetic resonance imaging scan of the left orbit shows a large
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.
The orbital mass shows fibrous
septa, with islands of malignant epithelial cells surrounded by lymphoid cells
(hemotoxylin-eosin, original magnification ×63). Note the presence of
lacrimal gland acini with lymphocytic infiltration in the lower part of the
illustration. Inset, Abnormal mitotic figure (hemotoxylin-eosin, original
An island of carcinoma cells surrounded
and permeated by lymphocytes. Note the presence of fibrous strands partly
surrounding the carcinoma island (hemotoxylin-eosin, original magnification
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.
A, Carcinoma cells stain positive
with Pan keratin. B, Lymphoid infiltrate showing positive staining with common
leukocyte antigen (immunoperoxidase, original magnification ×220).
Immunohistochemical staining shows
many T lymphocytes (A) and many macrophages encircling the tumor cells (B)
(original magnification ×220).
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
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
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: firstname.lastname@example.org).
Rao NA, Kaiser E, Quiros PA, Sadun AA, See RF. Lymphoepithelial Carcinoma of the Lacrimal Gland. Arch Ophthalmol. 2002;120(12):1745-1748. doi: