A 70-year-old man with diplopia
Mehenaz Hanbazazh, MD, Ryan Okal, MD, and Jeffrey A. Vos, MD
A 70-year-old man is referred from outside hospital with the chief complaint of double vision. Ophthalmologic evaluation revealed no decrease in visual acuity and no pain or tenderness associated with eye movement. An infraorbital mass was noted on the left side, while the right eye appeared unremarkable. The patient otherwise had a single enlarged neck lymph node along the left cervical chain. He underwent a left orbitotomy with excision of mass.
The periorbital tissue biopsy shows a diffuse infiltrate of monomorphic cells with scattered tingible-body macrophages (Figures 1). The lymphoid cells are medium to large in size with irregular nuclei, vesicular chromatin and distinct nucleoli (Figure 2). Occasional mitotic figures and apoptotic cells are present, imparting an overall high-grade appearance. By immunohistochemistry, the atypical lymphoid infiltrate is composed of CD20-positve B-cells (Figure 3) which co-express bcl-2 (Figure 4) and bcl-6 (weak) (Figure 5). These cells are also positive for MUM-1 and CD5 (weak), while negative for CD10 (Figure 6). Epstein Barr virus by encoded RNA (EBER) is negative by in-situ hybridization. The tumor proliferative activity is high with Ki-67 staining approximately 90% of the neoplastic cells (Figure 7). CD3 highlights few by-standing T-cells in the background. Flow cytometric analysis confirmed an atypical lymphoid population expressing CD19, CD20, CD22, CD5 (dim) and kappa surface immunoglobulin light chains.
Figure 1. H&E, 200X: Atypical lymphoid infiltrate composed of sheets of monomorphic medium to large cells with scattered tingible-body macrophages.
Figure 2. H&E, 400X: The cells are pleomorphic with irregular nuclei, vesicular chromatin and prominent nucleoli.
Figure 3. IHC, 400X: The infiltrate is strongly and diffusely positive for CD20.
Figure 4. IHC, 400X: Essentially all of the malignant cells, as well as the background T-cells, express bcl-2.
Figure 5. IHC, 400X: Bcl-6 is variably positive in the majority of tumor cells.
Figure 6. IHC, 400X: The atypical large cells are negative for CD10.
Figure 7. IHC, 200X: The proliferation index is high. Ki-67 highlights approximately 90% of the neoplastic cells.
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Primary orbital lymphoproliferative disorders are a heterogeneous group of conditions ranging from benign lymphoid hyperplasia to high-grade malignant lymphomas, such as diffuse large B-cell lymphoma (DLBCL).1,2 Most orbital lymphoproliferative disorders occur between the ages of 50-70 years with a slight female predominance. The clinical presentation is nonspecific and depends on the location of the lymphoma. Orbital lymphoma is a hematopoietic tumor arising in the conjunctiva, lacrimal gland, soft tissues of the eyelid, or extraocular muscles.3 It is the most common primary malignancy of the orbit/ocular adnexae in adults, yet they constitute only about 2% of all lymphomas.4 Patients usually present with a painless, slowly growing mass with gradual eye proptosis. Vision is usually preserved, as infiltration of the globe or optic nerve is rare.3,5 The patient in the current case presented with diplopia secondary to mass effect on the left eye.
The most common lymphoma associated with the orbit/ocular adnexa is extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), which comprises approximately 50% of lymphomas in the region.2,5 Occasionally, a history of a chronic inflammatory process (infectious or autoimmune disease) is associated with these lesions. Studies have shown an association of ocular MALT lymphoma with Chlamydia psittaci infections. Due to the association with these precursor chronic inflammatory disorders, a diagnosis of ocular MALT lymphoma can be challenging. Cytogenetic studies, particularly t(14;18)(q32;q21) and trisomy 3, are frequently seen in ocular MALT lymphomas.6
Diffuse large B-cell lymphoma (DLBCL)1,7 is the often considered the next most common lymphoma arising in the orbit, although this is somewhat controversial as follicular lymphoma shows a similar incidence2. In general, DLBCL is the most common adult non-Hodgkin lymphoma,6 and in the orbit, it more commonly presents as secondary involvement of a systemic process.7 Unlike other orbital lymphomas, DLBCL is more commonly seen in men. The median age of presentation is similar, but it may also occur in younger patients.6 However, it rarely occurs before the age of 20 within the orbit.5 DLBCL can arise de novo or as transformation of an underlying low-grade lymphoma.6,7 On morphologic evaluation, a diffuse growth pattern is seen. The lymphocytes have large, irregular nuclei with vesicular chromatin and single to multiple nucleoli. As in the current case, mitotic figures and apoptotic cells are prominent.6,7
Immunohistochemistry is essential in the diagnosis of DLBCL. B-cell biomarkers such as CD19, CD20, CD22, and CD79a, by way of immunohistochemistry or flow cytometric immunophenotyping, are usually positive. Sub-groups of DLBCL can be established based on the co-expression of other markers, such as CD5, CD10, bcl-6, and MUM-1. Co-expression of CD5 is usually not present, but approximately 10% of cases may be positive; CD5+ DLBCL in general is associated with a worse prognosis. Expression of CD10 or, when CD10 is negative, a combination of bcl-6 without co-expression of MUM-1 is associated with the germinal center-like subgroup. Ki-67 proliferation index is frequently high (between 40 – 90%). This subset of cases has a favorable prognosis with better response to chemotherapy. Non-germinal center phenotypes and those positive for Epstein-Barr virus, in contrast, are associated with worse prognoses.6,7 The current case demonstrated a non-germinal center B-cell-like phenotype (CD10-/bcl-6+/MUM-1+) and additionally showed aberrant expression of CD5.
Orbital radiation, in conjunction with systemic chemotherapy and immunotherapies such as anti-CD20 (rituximab), have increased the survival rate in purely localized cases.7-9 The overall 5-year survival rate for all types of primary orbital lymphoma is approximately 76%; however, when compared by subtype, diffuse large B-cell lymphoma shows a worse overall survival.10
MYC, BCL2, and BCL6 chromosomal rearrangements have been reported in DLBCL of the orbit. BCL6 rearrangements are the most frequent cytogenetic abnormality. While less commonly detected, MYC translocations have an adverse prognosis with high proliferation rates (Ki-67 > 80%), chemoresistance and shortened survival. For these reasons, evaluation by fluorescence in-situ hybridization (FISH) for these rearrangements is performed on most cases of DLBCL. Furthermore, DLBCL with MYC in addition to BCL2 and/or BCL6 rearrangements, have been termed ‘double hit’ or ‘triple hit’ lymphomas, which are characterized by aggressive clinical behavior and poor prognosis, likely related to the combined effects of MYC-growth promotion and BCL2-anti-apoptosis. 11 In the current case, BCL6 translocation and no rearrangements of MYC or BCL2 were detected by the FISH.
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- Stacy RC, Jakobiec FA, Herwig MC, Schoenfield L, Singh A, Grossniklaus HE. Diffuse large B-cell lymphoma of the orbit: Clinicopathologic, immunohistochemical, and prognostic features of 20 cases. Am J Ophthalmol. 2012;154(1):87-98. e1.
- Madge SN, McCormick A, Patel I, et al. Ocular adnexal diffuse large B-cell lymphoma: local disease correlates with better outcomes. Eye. 2010 Jun 1;24(6):954-61.
- Munch-Petersen HD, Rasmussen PK, Coupland SE, et al. Ocular adnexal diffuse large B-cell lymphoma: a multicenter international study. JAMA ophthalmology. 2015 Feb 1;133(2):165-73.
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- Akyurek N, Uner A, Benekli M, Barista I. Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B‐cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Cancer. 2012 Sep 1;118(17):4173-83.