Conjunctival lymphoma masquerading as chronic conjunctivitis

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Conjunctival Lymphoma Masquerading as Chronic Conjunctivitis Esen Karamursel Akpek, MD,1 Wasee Polcharoen, MD,2 Judith Ann Ferry, MD,3 C. Stephen Foster, MD1 Objective: Malignant lesions of the conjunctiva may present with slowly evolving signs resembling inflammation. The authors describe the clinical and histopathologic findings of two patients with bilateral conjunctival lymphoma who presented with a history of chronic conjunctivitis without clinically noticeable subconjunctival nodules. Design: Case report. Participants: Two patients. Intervention: Both patients underwent conjunctival biopsy for evaluation of persistent conjunctival inflammation that did not respond to various medical treatment methods. Results: Histopathologic examination revealed extranodal marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue type) in one patient and follicle center lymphoma in the other patient. Both patients subsequently received radiation therapy and achieved a complete remission with no evidence of recurrence in the follow-up period of 20 and 16 months, respectively. Conclusions: Conjunctival lymphoma should be included in the differential diagnoses of chronic conjunctivitis. Persisting signs and symptoms of conjunctivitis not responding to standard treatment should prompt biopsy. Ophthalmology 1999;106:757–760 Primary lymphoma of the ocular adnexa is rare, constituting 2% to 28% of extranodal lymphomas1,2 and 10% of all ocular tumors.3 Although the orbit represents the most frequent ophthalmic location,4 the most common conjunctival subepithelial tumor in one large series was lymphoma, constituting 1.5% of all conjunctival tumors.5 Lymphoid lesions of the conjunctiva usually present as painless, mobile, salmon–pink or flesh-colored patches of the lower fornix or bulbar conjunctiva in patients in their fifth or sixth decade of life. The lesions often form a sausage-shaped mass with a nodular surface, especially at the borders of the lesion. These lesions normally present either in an isolated fashion in the conjunctiva or in association with anteriorly located orbital lymphoid tumors. The clinical, radiologic, and histopathologic differentiation of benign reactive lymphoid hyperplasia from malignant lymphoid proliferations is challenging. The most accurate means of making the diagnosis and predicting the eventual clinical outcome is by studying the pathologic features of the lesion. Immunohistochemical studies are helpful in dis-

Originally received: June 2, 1998. Revision accepted: November 25, 1998. Manuscript no. 98287. 1 Ocular Immunology Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts. 2 Ocular Pathology Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts. 3 James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Address correspondence to C. Stephen Foster, MD, Immunology Service, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.

tinguishing benign from malignant lymphoid infiltrates and in subclassifying lymphomas. The diagnosis of conjunctival lymphoid tumors is straightforward when they present with a characteristic salmon–pink, pebbly multinodular appearance, particularly if they are located in the inferior fornices. However, rarely a diffuse clinical presentation is encountered, and this may mimic chronic conjunctivitis of other etiologies. In these cases, a high index of suspicion is required if one is to avoid a delay in diagnosis, and the importance of correct early diagnosis is obvious. We report herein the clinical and histopathologic features of two patients with conjunctival lymphoma who underwent conjunctival biopsy for evaluation of chronic conjunctivitis of unknown etiology, unresponsive to various medical treatment methods.

Materials and Methods Two patients with persistent ocular surface inflammation were referred to the Ocular Immunology Service at the Massachusetts Eye and Ear Infirmary for further diagnosis and management of a disorder of possible immunologic etiology. Histopathologic examination of the biopsy specimens disclosed conjunctival lymphoma in both patients. The lymphomas were classified according to the R.E.A.L. (Revised European–American Lymphoma) Classification6 and the International Working Formulation.7

Case 1 A 39-year-old woman was evaluated and treated elsewhere in June 1996 with a complaint of ingrowing eyelashes in both eyes. The

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Figure 1. Case 1, left eye. Slit-lamp photograph showing conjunctival injection, subepithelial fibrosis with fornix foreshortening, and several conjunctival follicles without a noticeable mass in the inferior forniceal area.

patient’s visual acuity was 20/20 in both eyes without correction. Keratoconjunctivitis sicca was diagnosed, and punctum plugs were placed in both inferior puncti. The patient developed conjunctival cicatrization and fornix foreshortening along with lid thickening bilaterally. A conjunctival biopsy was performed in September 1996 to determine whether the patient had ocular cicatricial pemphigoid. Light microscopy disclosed focal dense lymphoid infiltrates. Immunofluorescence studies were negative for ocular cicatricial pemphigoid. The patient was referred to Massachusetts Eye and Ear Infirmary Ocular Immunology Service for further evaluation in October 1996. Her visual acuity was 20/30 in the right eye and 20/20 in the left eye. Slit-lamp biomicroscopy disclosed thickened conjunctiva with an Arlt’s line on the upper palpebral conjunctiva of the right eye. The conjunctiva of the inferior fornix was injected and thickened, with subepithelial fibrosis and fornix foreshortening, significant mucus discharge, and a few follicles (Fig 1). Two areas of conjunctival thickening were noted in the bulbar conjunctiva. Subconjunctival cicatrization, mild injection, and fornix foreshortening with a few subconjunctival follicles but no tarsal conjunctival thickening were noticed in the left eye. Super-

Figure 2. Case 1. Dense subconjunctival lymphoplasmacytic infiltrate (stain, hematoxylin– eosin; original magnification, ⫻320) (Inset) Dutcher body; an intranuclear invagination of cytoplasmic immunoglobulin (stain, periodic acid-Schiff; original magnification, ⫻1600).

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Figure 3. Case 2. Slit-lamp photograph showing tarsal conjunctival injection, subepithelial fibrosis, and several small follicles without any apparent mass.

ficial epithelial keratitis in the right eye was noted; the left cornea was normal. The patient was diagnosed with probable chlamydial conjunctivitis and doxycycline 100 mg twice daily in the left eye was begun. The conjunctival inflammation still persisted after a 3-week course of therapy. In January 1997, a full-thickness lid biopsy was performed in the right lower lid because of the suspicion of a “masquerade” cause (e.g., sebaceous carcinoma) of chronic conjunctivitis. The histopathologic examination showed a dense but relatively superficial subconjunctival infiltrate of small lymphoid cells and plasma cells, with plasma cells found in a layer immediately beneath the conjunctival epithelium, and the lymphoid cells deep to the plasma cells. Also present were scattered reactive germinal centers, some with infiltration by the small lymphoid cells, consistent with “follicular colonization.” Occasional polykaryocytes were identified. Several Dutcher bodies were identified on a periodic acid-Schiff-stained section (Fig 2). Immunohistochemical staining on paraffin sections showed that most lymphoid cells were B cells (L26⫹) with an admixture of moderate numbers of T cells (CD3⫹, CD43⫹). There appeared to be an excess of plasma cells expressing IgM kappa, although

Figure 4. Case 2. Histopathology demonstrating several large, poorly circumscribed lymphoid follicles in the substantia propria (stain, hematoxylin– eosin; original magnification, ⫻50). (Inset) The atypical lymphoid cells in a follicle (left side of the field) are larger and paler than the normal lymphocytes outside the follicle (right) (stain, hematoxylin– eosin; original magnification, ⫻320).

Akpek et al 䡠 Conjunctival Lymphoma Posing as Chronic Conjunctivitis scattered lambda⫹ plasma cells were also present. Although kappa⫹ cells outnumbered lambda⫹ cells, the difference was not striking enough to be sufficient evidence for definite identification of a monotypic population. However, the kappa excess, in conjunction with the appearance on routine sections, and the presence of Dutcher bodies, was interpreted as supporting a diagnosis of extranodal marginal zone B-cell lymphoma (MALT-type) (small lymphocytic lymphoma, plasmacytoid). The patient underwent a systemic evaluation, including a bone marrow aspiration biopsy, which revealed no abnormal findings. Radiation therapy with a total dosage of 3500 cGy was administered bilaterally. The patient presented to the emergency department with a corneal ulcer of the right eye in April 1997. The cultures from the ulcer scrapings were negative. Despite maximal medical treatment for this neurotrophic ulcer, the ulcer persisted, necessitating performance of a central tarsorrhaphy in May 1997. In September 1997, the cornea healed with dense scarring and neovascularization. The tarsorrhaphy was opened, and a penetrating keratoplasty was performed. At the time of last evaluation in February 1998, the patient’s anterior segment findings were normal, with a clear corneal graft in her right eye and moderate subconjunctival fibrosis bilaterally with no evidence of disease recurrence.

Case 2 In November 1996, a 54-year-old woman was referred to the Ocular Immunology Service at the Massachusetts Eye and Ear Infirmary with a 5-month history of irritation, contact lens intolerance, and unilateral follicular conjunctivitis unresponsive to prior medical treatment with topical steroids and antibiotics. The patient’s ocular history was remarkable for contact lens wear for more than 20 years. Her visual acuity was 20/25 in the right eye and 20/20 in the left eye. She was noted to have bilateral mild blepharitis and a chalazion in the left lower eyelid. Slit-lamp examination showed 2⫹ giant papillary conjunctivitis in the upper palpebral conjunctivae of both eyes and several small subconjunctival follicles in the lower fornix of the left eye only (Fig 3). Both corneas displayed a superficial epithelial keratitis. A conjunctival biopsy in the left eye was performed with a suspicion for conjunctival granulomata due to sarcoidosis. Light microscopic examination revealed multiple lymphoid follicles composed of a mixture of small cleaved cells (centrocytes) with large noncleaved cells (centroblasts) without tingible body macrophages and with infrequent mitotic figures (Fig 4). Immunohistochemical staining on paraffin sections showed that the follicles were composed of B cells (L26⫹) and small numbers of T cells (CD45RO⫹, CD43⫹). The B cells coexpressed bcl-2 protein, and there was a suggestion of monotypic kappa light chain expression. The findings were interpreted as follicle center lymphoma, follicular, grade 2 of 3 (follicular lymphoma, mixed small cleaved, and large cell type). Although the right lower fornix appeared clinically normal, histologic and immunohistochemical examination of a conjunctival biopsy from this area disclosed bilateral lymphomatous infiltration. Extensive systemic workup did not reveal any other organ involvement. The patient was treated with local radiation therapy with 3000 cGy, and a complete clinical response was achieved. In February 1998, there was no evidence of disease recurrence. The patient’s visual acuity was 20/20 in both eyes. Anterior segment examination showed trichiatic eyelashes in the left eye and subconjunctival fibrosis in both lower fornices.

Discussion Theodore8 and Irvine9 independently described the masquerade syndrome in 1967 as chronic blepharoconjunctivitis due to an underlying conjunctival carcinoma. Although the originally described neoplasms were squamous cell carcinomas, many of the tumors producing such clinical pictures are believed to be sebaceous in origin.10 Two cases of bilateral conjunctival lymphoma are described herein. One patient presented with signs of bilateral chronic inflammation and subconjunctival cicatrization without evidence of infiltrates or mass; the other patient presented with giant papillary conjunctivitis, unilateral small subconjunctival follicles, and a history of contact lens intolerance. Both patients were symptomatic, complaining of red eyes along with ocular irritation, photophobia, and foreign body sensation. They were treated for chronic conjunctivitis over several months and referred to our clinic for unresponsiveness to various treatment methods. In neither of the cases was the diagnosis of conjunctival lymphoma considered likely at the time of the referral or by us at the time of the biopsy. Conjunctival lymphomas are reported to be the most common acquired subepithelial lesions and most frequently of B-cell origin.5 They typically present as subepithelial, mobile, orange–pink infiltrates in the substantia propria; commonly are known as salmon patches11; and 20% of the patients have bilateral involvement.12 Subconjunctival vegetating, multinodular pink masses simulating amyloid deposits have also been recognized.13 In rare instances, however, lesions may be only minimally elevated mimicking chronic conjunctivitis. Diagnosis in these cases is more challenging. In a large series with 38 patients, none of the cases were documented to present with chronic conjunctivitis.5 In one series of seven patients with conjunctival lymphoma, five of which were bilateral, only one presented with chronic conjunctivitis without a noticeable mass.14 Only one previous report actually described a patient with conjunctival lymphoma masquerading as scleritis unresponsive to immunosuppressive treatment.15 We present two cases of bilateral conjunctival lymphoma without any presence of subconjunctival infiltration and with signs and symptoms of chronic conjunctivitis. One was diagnosed with MALT lymphoma, and the other was diagnosed with follicle center lymphoma. Both patients subsequently received radiation therapy, and the lesions did not recur in the follow-up period of 20 and 16 months, respectively. Lymphocytes normally reside in the substantia propria of the conjunctiva and lacrimal gland. The conjunctiva, similar to extranodal sites such as bowel and lung, may be a site of several lymphoproliferative lesions that may constitute a spectrum of disorders: reactive hyperplasia, atypical hyperplasia, and lymphoma. Benign and malignant lesions share similar characteristics and clinically cannot be differentiated. Occasionally, the reactive lymphoid hyperplasia is capable of malignant transformation to lymphoma.16 Because extra-adnexal involvement may be encountered in 27% to 46% of patients, depending on the histopathologic

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Ophthalmology Volume 106, Number 4, April 1999 subtype,17 the importance of correct early diagnosis and management by local radiation therapy is apparent. Our cases emphasize that although rare, conjunctival lymphoma may also present with a diffuse clinical involvement, without the classical conjunctival subepithelial infiltrates, clinically indistinguishable from chronic conjunctivitis. Therefore, we suggest that lymphoma along with other conjunctival malignancies should be included in the differential diagnoses of longstanding unusual conjunctivitis not responding to various medical treatment methods. In these cases, conjunctival biopsy should be performed for earlier detection and prompt treatment.

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