Man referred for repair of progressive left-sided ptosis of uncertain etiology
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A 67-year-old man was referred to the oculoplastic service at Beth Israel Lahey Medical Center by an outside eye care provider for surgical evaluation of worsening left upper eyelid ptosis for about 7 months.
His symptoms began with unilateral left-sided upper lid ptosis 7 months prior, associated with morning epiphora and blurriness that seemed to resolve shortly after awakening. He denied any diplopia, pain, headaches or neurologic symptoms, and he reported no problems in the opposite eye. Ocular history was significant for acute iritis in both eyes that was successfully treated with steroid drops 8 years prior, for which the etiology was unclear as the patient had declined lab workup at the time. Surgical history was significant for otoplasty as a child.
Source: Daniel Azzam, MD, and Susan Tucker, MD
Examination
Uncorrected visual acuity was 20/25 in the right eye and 20/50 in the left eye, stable compared to 8 years prior. Pupil exam was normal with no relative afferent pupillary defect. IOP was normal, measuring 15 mm Hg in both eyes. Visual fields to confrontation showed a superotemporal deficit in the left eye.
Hertel exophthalmometer measurements showed 16 mm in the right eye and 18 mm in the left eye. External exam demonstrated 3+ ptosis of the right upper eyelid and 3 to 4+ ptosis of the left upper eyelid, with a margin-reflex distance 1 measuring 2 mm in the right eye and 0.5 mm in the left eye (Figure 1a). Furthermore, elevation of the upper lids revealed bilateral (left greater than right) superior orbital masses that were smooth, salmon-pink, non-pigmented and non-hypervascular (Figure 1b). Extraocular movements were full. Anterior segment examination was unremarkable; the conjunctiva was white and quiet, and there was no anterior chamber reaction.
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Bilateral superior orbital masses
The presence of bilateral superior orbital masses, more prominent on the left, prompted further investigation into the patient’s medical history. His medical history revealed prior mantle cell lymphoma, initially diagnosed from a colon biopsy 9 years ago followed by bone marrow biopsy. He was treated with three cycles of R-CHOP and three cycles of R-DHAP and achieved cancer remission. At the time, he declined autologous stem cell transplant and therefore received maintenance rituximab for 2 years. He remained in remission during his last hematology/oncology visit 6 months prior.
Based on the clinical history, ocular adnexal lymphoma was highest on the differential, with the provisional diagnosis being recurrent mantle cell lymphoma. This was further supported by the superior palpebral conjunctival location, the bilaterality, and the salmon-colored smooth appearance without significant pigmentation, nodularity/follicles or feeder vessels. Other types of lymphoma on the differential included extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, although this typically would be more common in an elderly woman and is often unilateral. Follicular and lymphoblastic lymphomas are also on the differential, but these often have a multinodular follicular appearance. Benign etiologies such as lymphoid hyperplasia were less likely given the patient’s older age and the aggressive bilateral spread. The appearance of the mass was also uncharacteristic of ocular surface squamous neoplasia, which typically has a gray, gelatinous, pearly appearance with feeder vessels, often located at the sun-exposed interpalpebral fissure.
Workup and management
Interdisciplinary discussion with oncology resulted in a systemic workup including tissue biopsy and restaging. Tissue biopsy was performed in the oculoplastic clinic without any complications. Histopathology and flow cytometry of the superior orbital mass were consistent with mantle cell lymphoma, showing abnormal lymphoid infiltrate of CD20+ monoclonal B lymphocytes, which were positive for CD5, CD19, cyclin D1 and BCL02, with lambda light chains. The abnormal lymphoid infiltrate was negative for the remaining markers tested and showed a Ki-67 proliferation index of approximately 10% to 20%.
PET-CT scan demonstrated fullness of the superior and medial aspects of the globes, as well as multiple subcutaneous nodules in the body, which were concerning for lymphoma (Figures 2a and 2b).
The clinical picture was consistent with ocular adnexal mantle cell lymphoma as the primary manifestation of relapsed malignancy, with multiple sites of apparent extranodal involvement.
Given the proximity of the lesions to the optic nerve and central nervous system (CNS) on PET imaging, an MRI of the brain and orbits with and without contrast was ordered for further evaluation of leptomeningeal disease or cranial nerve involvement and oncologic treatment planning. MRI revealed bilateral superior extraconal orbital masses and left medial wall extraconal and intraconal masses surrounding the medial rectus and extending to the posterior orbit without clear involvement of the cranial nerves or CNS (Figure 3).
Discussion
Lymphomas of the ocular adnexa are rare and represent only 1% to 2% of lymphomas overall. Ocular adnexal mantle cell lymphoma (MCL) is a particularly scarce neoplasm comprising only 5% of ocular adnexal lymphomas, with high frequency of dissemination, poor survival rates and frequent recurrences. Originally described in the mid-20th century, MCL is an aggressive, malignant subtype of B-cell non-Hodgkin lymphoma, which approximates to roughly one to two cases of MCL per 100,000 people. MCL originates in the mantle zone of a lymph node follicle followed by dissemination to other organs, commonly the bone marrow, liver and gastrointestinal tract. MCL can be distinguished by the overexpression of the protein cyclin D1, which stimulates cell growth, due to upregulation of BCL1 caused by a translocation between chromosomes 11 and 14.
Clinical presentation of ocular adnexal MCL typically occurs in older individuals (median age, 60 to 71 years) with a 3:1 male predominance, which is among the most striking gender difference seen in contrast to the female predominance in ocular adnexal lymphoma as a whole. Ocular MCL typically appears as bilateral orbital masses. Additionally, the patient may demonstrate proptosis, diplopia, salmon-pink conjunctival swelling, conjunctival erythema and ptosis due to involvement of either the orbicularis muscle or the dermis of the upper eyelid. Systemically, MCL usually appears as stage IV disease with extensive lymphadenopathy, splenomegaly and bone marrow involvement, along with either pancytopenia or a leukemic picture of leukocytosis.
The diagnosis of ocular MCL involves examination of the involved tissue and is confirmed by surgical biopsy with histopathological examination. MCL characteristically has surface markers of B cells (such as CD20), overexpression of cyclin D1 protein, expression of monoclonal B surface light chains and heavy chains, and is positive for CD5, CD45, BCL1 and BCL2. Staging MCL includes various laboratory tests, such as complete blood counts and bone marrow aspiration with biopsy, and imaging studies, such as pan-CT scan and PET scan.
Management of ocular MCL was historically limited to irradiation, followed by the development of palliative therapy, which consisted of anthracycline-based chemotherapy. However, advances in recent decades have resulted in the development of the current standard treatment guideline of R-CHOP, which includes the anti-CD20 drug rituximab combined with the chemotherapy agents cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone. R-CHOP regimens have demonstrated significant improvements in survival rates. Additional options include ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor approved for relapsed MCL. Intrathecal therapy may be considered for CNS involvement. If there is truly no systemic involvement, external beam radiation therapy can be considered. In cases of unilateral disease without systemic involvement, an intralesional injection of rituximab can also be considered; excisional biopsy alone for isolated unilateral disease is an alternative option, although less preferred. For MCL in first complete remission, autologous stem cell transplantation can be used for treatment, or allogeneic stem cell transplantation may be considered based on availability of a matched donor. Numerous clinical trials are in the works to investigate additional novel treatment approaches.
Case resolution
At oculoplastic follow-up, the biopsy site was healing well. The oncology team discussed standard treatment options for relapsed MCL, including BTK inhibitors such as acalabrutinib or zanubrutinib, the latter of which demonstrated effectiveness for CNS disease in some case reports. Furthermore, more aggressive treatment options were considered, such as bendamustine-rituximab with cytarabine regimen followed by autologous stem cell transplantation. However, the patient had previously declined and continued to decline autologous stem cell transplantation. Lumbar puncture was considered; however, the oncology team felt that this would not significantly change the plan for a BTK inhibitor. Treatment was started with zanubrutinib 160 mg orally twice per day given its preferred side effect profile and coverage of any possible CNS activity. The patient was scheduled for a 2-week follow-up with laboratory workup, as well as repeat PET-CT and MRI 3 to 4 months after starting treatment for response assessment.
- References:
- Bou Ghanem GO, et al. Hemasphere. 2021;doi:10.1097/HS9.0000000000000599.
- Ejima Y. Ocular adnexal lymphoma. In: Sasai K, et al, eds. Radiation Therapy for Extranodal Lymphomas. Springer; 2017:15–28.
- Knudsen MKH, et al. JAMA Ophthalmol. 2017;doi:10.1001/jamaophthalmol.2017.4810.
- Tanenbaum RE, et al. Eye Vis (Lond). 2019;doi:10.1186/s40662-019-0146-1.
- Vali Khojeini E, et al. Case Rep Pathol. 2013;doi:10.1155/2013/581856.
- For more information:
- Daniel Azzam, MD, and Susan Tucker, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Yi Ling Dai, MD, and Teresa P. Horan, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.