Elderly Woman With Progressive Eyelid Ptosis

An 84-year-old woman presents with progressive ptosis of her right upper eyelid and blurred vision in the right eye (Figure 1). The eyelid started to droop 1 month earlier. She denies recent ocular injury or diplopia. Her history includes bilateral pseudophakia and a trabeculectomy. The patient takes atenolol (for systemic hypertension), aspirin (for prevention of cardiovascular events), acetaminophen, and a multivitamin daily. She uses artificial tears in her right eye as needed. Corrected visual acuity is 20/60 in the right eye and 20/20 in the left eye. There is no afferent pupillary defect. Extraocular muscle movements are full with no restrictions, and there are no visual field defects. Intraocular pressures are normal. Hertel exophthalmometry shows a 2-mm proptosis in the left eye, when compared with the right eye. Further evaluation reveals a palpable mass within the left lower lid. The mass feels rubbery and is tender. Slit lamp examination helps identify a “salmon patch” on the conjunctiva of the right lower eyelid (Figure 2). An MRI scan of the head shows a small, asymmetric density in the left inferior lateral aspect of the extraorbital soft tissues. The mass is better defined after gadolinium contrast enhancement (Figure 3). Signal changes in the right ethmoidal sinus are suggestive of sinusitis. Results of a biopsy of the mass show a low-grade B-cell lymphoma, consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). Figure 3 – A coronal MRI scan with gadolinium contrast enhancement shows the tumor infiltrating the infratemporal orbit. Immunoperoxidase studies are performed using antibodies directed against the following antigens: CD3, CD20, CD43, CD5, cyclin-D1, CD10, bcl-6, and CD23 and   and   immunoglobulin light chains. The neoplastic cells are positive for CD20 and express monoclonal   immunoglobulin light chains (Figure 4). The cells are negative for the remaining tested stains. These findings support the diagnosis of B-cell lymphoma. A CT scan of the chest, abdomen, and pelvis is obtained. An exophytic mass is found in the stomach. Gastric biopsy results are positive for MALT lymphoma. The patient refuses further surgery and declines radiation and intravenous chemotherapy. She is given oral chlorambucil, 4 mg/d, and oral prednisone, 60 mg/d, for 5 days. At 2- week follow-up, her right upper eyelid is no longer ptotic and the mass in her abdomen has decreased minimally. The 5-day regimen is repeated every 4 weeks for 4 months. The therapy is tolerated well and discontinued after the 4 months. The patient’s condition has remained stable for 7 months since her initial diagnosis. She is being monitored by her oncologist. OCULAR ADNEXAL LYMPHOID TUMORS: HISTOPATHOLOGY These tumors are divided into 2 broad categories: reactive lymphoid hyperplasia and malignant lymphoma.1 The latter is composed of cytologically malignant and immature lymphocytic cells.2  Most ocular adnexal lymphomas contain B lymphocytes; T-cell lymphomas are extremely rare.3 The extranodal marginal zone B-cell lymphoma is the most common subtype of B-cell lymphomas in the ocular adnexa.4 According to the International Lymphoma Study Group, this subtype includes MALT lymphomas with and without mucosal involvement.5 In MALT lymphomas, the mucosal epithelial architecture is recognizable, but it is infiltrated and overrun by neoplastic cells.6 MALT lymphoma occurs most commonly in the GI tract; however, it can affect any mucosal surface, including the conjunctiva.7  The orbit has no natural reservoir of lymphoid tissue.8  The conjunctiva has a natural, submucosal reservoir of lymphoid tissue within the substantia propria, which is similar to MALT elsewhere in the body.9  When arising in tissues associated with the epithelium, such as the conjunctiva, lacrimal gland, and retinal pigment epithelium, nests of extranodal B-cell lymphoma cells may infiltrate the neighboring structures and form lymphoepithelial lesions. The cell nests of neoplastic tissue are further evidence of the neoplastic nature of MALT lymphomas and aid in differentiating between extranodal marginal zone B-cell lymphoma and reactive lymphoid hyperplasia.4,10 Morphologically, extranodal marginal zone B-cell lymphomas are characterized by an expansion of a heterogeneous cell population, which consists of centrocyte-like monocytoid and plasmacytoid tumor cells with occasional blasts in the marginal zone surrounding reactive follicles.4  On immunophenotypic analysis, extranodal marginal zone B-cell lymphomas characteristically test positive for CD20, CD 79a, bcl-2, and CD43 and test negative for CD5, CD10, CD23, bcl-6, and cyclin-D1.4 Monotypic expression of immunoglobulin light and heavy chains can usually be demonstrated.4 CLINICAL PRESENTATION A typical orbital lymphoma presents as a slowly growing, painless mass. It has a firm, rubbery feel and is usually freely mobile. Progressive proptosis of usually less than 5 mm is also evident.11  Orbital lymphomas can cause ptosis of the eyelid when they involve the dermis of the orbicularis oculi muscle or infiltrate the conjunctiva, as in this patient. Extraocular motility disturbance and loss of vision are less common. Orbital lymphomas usually infiltrate the anterior and superior aspects of the orbit and mold themselves to the globe and orbital bones.12  The lesions rarely result in bony destruction or erosion. The most frequent ocular location of lymphoma is the orbit, followed by the conjunctiva, eyelid, and lacrimal gland.13  When localized to the conjunctiva, the lymphoma may present with a pink-white “salmon patch” in the subconjunctival extension.14  The lacrimal gland is enlarged in 30% of patients, because of the scattered population of lymphoid cells, which may be fertile ground for development of lymphoma.15 IMAGING WORKUP On CT evaluation, lymphomas are relatively high-density, homogeneous masses with definite, but mild, contrast enhancement; the imaging shadow has a soft, puttylike appearance.16  Because lymphomas lack a true capsule, the tumor margins often appear irregular.12  CT usually is sufficient to identify the lesion and define the extent of disease.16 On MRI, orbital lymphomas are homogeneous and show moderate to marked enhancement with gadolinium contrast dye.16  Order fatsuppressed, contrast-enhanced sequences because enhancing lesions may be obscured by their proximity to orbital fat.13 MANAGEMENT Further workup to detect dissemination. A complete physical examination is required for all patients with lymphoid lesions of the orbit. Recommended laboratory tests include a complete blood cell count, blood chemistries, and serum protein electrophoresis.2  In addition, order a chest radiograph; a CT scan of the chest, abdomen, and pelvis; and bone marrow studies.16 Treatment. External beam irradiation provides local control of all types of lymphoid orbital tumors.17 The use of low-dose radiation does not prevent progression to systemic lymphoma. Administration of cytotoxic agents by an oncologist is indicated when there is evidence of systemic lymphoma.16 Alternative treatment plans include “watchful waiting,” chemotherapy, combination chemotherapy and radiation, systemic corticosteroids, surgical excision, and immunotherapy using monoclonal antibodies. Surgery is used infrequently because tumor microinfiltration of surrounding tissue may be present.18 Systemic corticosteroids, which may initially reduce the size of the tumor, have proved to be ineffective for long-term control.4  Immunotherapy with rituximab—a genetically engineered chimeric (murine-human) monoclonal antibody directed against the CD20 antigen found on the surface of malignant B cells—also has been successful.19 PROGNOSIS Although prognosis is excellent for patients with nondisseminated orbital lymphomas, the overall survival rate depends on the tumor grade. In one study, the survival rate was 100% in patients with low-grade lymphoma, but only 57.1% in patients with intermediate-grade lymphoma because of progression and dissemination.20  Lifelong monitoring of patients (every 6 months) by both an ophthalmologist and an oncologist is necessary to detect ocular recurrence or systemic disease.16  REFERENCES: 1. Knowles DM 2nd, Jakobiec FA. Orbital lymphoid neoplasms: a clinicopathologic study of 60 patients. Cancer. 1980;46:576-589. 2. Skorin L. Malignant lymphoma of the orbit. J Osteo Col Ophthalmol Otorhino. 1997;9:12-14. 3. Lauer S. Ocular adnexal lymphoid tumors. Curr Opin Ophthalmol. 2000;11:361-366. 4. Coupland SE, Hummel M, Stein H. Ocular adnexal lymphomas: five case presentations and a review of the literature. Surv Ophthalmol. 2002;47:470-490. 5. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84:1361-1392. 6. Harris NL, Isaacson PG. What are the criteria for distinguishing MALT from non-MALT lymphoma at extranodal sites? Am J Clin Pathol. 1999;111(suppl 1): S126-S132. 7. Kurtin PJ. How do you distinguish benign from malignant extranodal small B-cell proliferations? Am J Clin Pathol. 1999;111(suppl 1):S119-S126. 8. Knowles DM 2nd, Jakobiec FA. 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Jakobiec FA, Nelson D. Lymphomatous, plasmacytic, histiocytic, and hematopoietic tumors of the orbit. In: Tasman W, Jaeger EA, eds. Duane’s Clinical Ophthalmology. Vol 2. Philadelphia: JB Lippincott Co; 1991:1-52. 15. Rhee D, Pyfer M. Lacrimal gland mass/chronic dacryoadenitis. In: Rhee D, Pyfer M, eds. The Wills Eye Manual. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1999:185. 16. Kennerdell JS, Cockerham KP, Maroon JC, Rothfus WE. Practical Diagnosis and Management of Orbital Disease. Boston: Butterworth-Heinemann; 2001:99-107. 17. Lutz S, Anderson S, Connie Y, et al. Non-Hodgkin’s orbital lymphoma. J Am Acad Optom. 2001;78: 639-645. 18. Baldini L, Blini M, Guffanti A, et al. Treatment and prognosis in a series of primary extranodal lymphomas of the ocular adnexa. Ann Oncol. 1998;9: 779-781. 19. Esmaeli B, Murray JL, Ahmadi MA, et al. Immunotherapy for low-grade non-hodgkin secondary lymphoma of the orbit. Arch Ophthalmol. 2002;120: 1225-1227. 20. 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