A, Clinical photograph shows bilateral eyelid erythema with lacrimal gland enlargement producing an S-shaped upper eyelid configuration. B, Several days later, a fine, flaky scaling was observed in the skin, signifying rapid epidermal turnover due to inflammatory stimulation. C and D, Computed tomographic studies show bilateral lacrimal gland enlargement. C, Axial view demonstrates oblong enlargement of the lacrimal glands with involvement of the palpebral lobes anterior to the orbital rim (arrowhead) with molding to the globe and absence of bone destruction. D, Coronal view displays intact orbital bones and elongated enlargement of the lacrimal glands (arrowhead), without indentation of the globe, rather than the oval shape of an epithelial tumor. E, Histopathologic studies show enlarged lobules without spillover of inflammation into surrounding connective tissue. The pale-staining small foci correspond to surviving parenchyma (hematoxylin-eosin, original magnification ×40). Inset, The acini of the gland are separated by intermediate-sized, mildly atypical lymphoplasmacytic cells (hematoxylin-eosin, original magnification ×400).
A, Ki-67 immunostains the nuclei of 70% of the infiltrating cells (original magnification ×200). B, CD3+ T lymphocytes are diffusely distributed between the pale-staining acini (original magnification ×100). C, Inflammatory cells with Epstein-Barr virus–positive nuclei surround pale-staining acini (original magnification ×200). In situ hybridization discloses a polyclonal population of B lymphocytes with roughly equal numbers of cells staining for κ (D) and λ (E) cytoplasmic light chains (original magnification ×200).
Rashid A, Lee NG, Jakobiec FA, Freitag SK. Epstein-Barr Virus–Positive Polymorphous Lymphoplasmacytic Infiltrate of the Lacrimal Glands in a Patient With Acute Lymphoblastic Leukemia. JAMA Ophthalmol. 2014;132(7):892-894. doi:10.1001/jamaophthalmol.2014.382
An atypical inflammatory infiltrate of the orbital tissues in the setting of a patient with a known history of treated leukemia presents the clinician with the daunting task of having to establish whether a relapse of the leukemia has occurred, which would necessitate reintroduction of toxic chemotherapeutic agents. Herein, we report such a case.
A boy in his early teens presented to the hospital with a 3-day history of painless swelling and erythema of bilateral upper and lower eyelids. He had had very high-risk acute lymphoblastic leukemia that was in remission with maintenance chemotherapy. The upper eyelids exhibited temporal fullness (Figure 1A and B). Computed tomography revealed preseptal edema with bilaterally enlarged lacrimal glands and no bony destruction or globe compression (Figure 1C and D).
After admission to the hospital, blood cultures and viral cultures were obtained and were negative for cytomegalovirus, influenza, respiratory syncytial virus, and adenovirus. Of note, Epstein-Barr virus (EBV) IgG was positive and IgM was negative, with a serum viral load greater than 100 000 copies/mL. Lacrimal gland biopsies revealed that the lacrimal gland lobules were preserved (Figure 1E). The acini and ducts were splayed apart by polymorphous lymphoplasmacytic cells displaying mildly enlarged and irregularly shaped nuclei with modest amphophilic cytoplasm (Figure 1E, inset). There was no fibrosis of the lacrimal gland or spillover of the infiltrate into the adjacent orbital connective tissues.
Immunohistochemical staining revealed the following results: CD10− and CD20+ lymphocytes; a small focus of CD21+ and CD23− dendritic cells; CD56 predominantly negative except for some natural killer cells; CD138 strongly positive for plasma cells; BCL2 dimly positive; BCL6 negative; terminal deoxynucleotidyl transferase negative for leukemic cells; and Ki-67 positive in 70% of cells (Figure 2A). Immunoglobulin staining disclosed IgG greater than IgA greater than IgM. Many CD3+ and CD5+ T cells were dispersed throughout the lesion (Figure 2B). Flow cytometry did not reveal any abnormal B-, T-, or plasma-cell populations. The T cells showed an inverted CD4 to CD8 ratio, which would most likely represent a T-cell response to EBV-infected B cells. In situ hybridization to test for EBV-associated RNA expression was strongly positive in lymphocytes but was negative in the acini (Figure 2C). In situ hybridization for κ immunoglobulin light chain (Figure 2D) was slightly more positive than that for λ immunoglobulin light chain (Figure 2E). Polymerase chain reaction testing revealed a clonal heavy-chain gene rearrangement, indicating the presence of a small clonal B-cell population considered to be of no clinical significance.
The central dilemma in this case was to determine whether the lacrimal gland infiltrates represented a relapse of the acute lymphoblastic leukemia, an inflammatory infiltrate, or a B- or T-cell neoplasm caused by EBV-positive lymphocytes. The clinical picture was confusing because the patient was receiving maintenance chemotherapy. The bilaterality of the process and its rapid evolution appeared ominous, as did the infiltrates composed of intermediate lymphocytes with somewhat irregular nuclei displaying a high Ki-67 proliferative index of 70%. Immunohistochemical studies, however, disclosed EBV infection of B lymphocytes with in situ hybridization and showed approximately equal κ and λ light-chain expression. Polymerase chain reaction disclosed a small clonal immunoglobulin heavy-chain gene rearrangement, which was not interpreted as evidence of a malignant cell population.1,2
In light of the absence of peripheral blood and bone marrow abnormalities of leukemia and the results of the lacrimal gland biopsy, it was decided not to treat the patient for a relapse of leukemia. The patient’s routine prednisone dose was discontinued. During the ensuing 3 months, the lacrimal gland swellings subsided spontaneously and the serum EBV viral load fell to less than 300 copies/mL from greater than 100 000 copies/mL.
Epstein-Barr virus has been implicated in the pathogenesis of a number of orbital conditions, including Burkitt B-cell lymphoma, CD57+ natural killer cell lymphoma, and EBV-positive T-cell lymphoma as well as immunodeficiency and autoimmune disorders.3- 6
Corresponding Author: Frederick A. Jakobiec, MD, DSc, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Ste 328, 243 Charles St, Boston, MA 02114 (firstname.lastname@example.org).
Author Contributions: Drs Rashid and Jakobiec had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Rashid, Lee, Jakobiec.
Critical revision of the manuscript for important intellectual content: Jakobiec, Freitag.
Statistical analysis: Jakobiec.
Administrative, technical, or material support: Rashid, Jakobiec.
Study supervision: All authors.
Conflict of Interest Disclosures: None reported.