Introduction

Intravascular large B-cell lymphoma (IVLBCL), formally known as “angiotrophic large cell lymphoma” and “malignant angioendotheliomatosis” [1, 2], is a rare B-cell lymphoma subtype characterized by the growth of tumor cells exclusively within vascular lumina. IVLBCL is most common in older adults (median age, 67 years) and is clinically aggressive with a mean survival of 18 months [3]. The poor clinical outcome is partially attributed to the late stage of diagnosis due to the lack of lymph node involvement or a mass to biopsy. Most cases are widely disseminated at the time of diagnosis or autopsy. Although tumor involvement has been reported in nearly every organ system, the most frequently involved sites are the central nervous system (CNS) and skin. Two distinct clinical variants have been recognized, Asian and Western. The Asian variant is characterized by multi-organ failure, hepatosplenomegaly, pancytopenia, and hemophagocytic syndrome. In the Western form, the symptoms are related to the organ or organs infiltrated by the neoplastic cells [3].

Only very rarely does IVLBCL present with ophthalmologic signs and symptoms. All reported cases of ophthalmologic IVLBCL have involved other organ systems or were not completely staged to rule out systemic involvement [4–11]. Most cases of ophthalmologic IVLBCL were not diagnosed by biopsy of an ophthalmologic structure, but at either autopsy or the patient’s ophthalmologic signs and symptoms were correlated with eye involvement after a biopsy of another organ system established the diagnosis. Only three cases have been diagnosed by an ophthalmologic procedure [4, 6, 8]. We present an unusual case of an ophthalmologic IVLBCL diagnosed by a biopsy of an orbital mass with no evidence of systemic involvement.

Report of a case

An 88-year-old woman presented with an 8-day history of pain, proptosis, loss of vision in her left eye, and a 30-pound weight loss over the preceding 3 months. Visual acuity was no light perception in the affected left eye with 5 mm of proptosis and limited ductions in all fields of gaze. Magnetic resonance imaging and computed tomography scanning revealed a 2.8 × 2.1 × 1.9 cm avidly enhancing intraconal mass in her left orbit (Fig. 1). A fine needle aspiration of the mass was unsatisfactory due to scant cellularity. An incisional biopsy was performed, and on histologic examination, large atypical lymphoid cells were identified in the blood vessel lumina of the intraorbital adipose tissue (Fig. 2). No extravascular tumor cells were present in the surrounding tissue. By immunohistochemistry, the tumor cells expressed CD20 (Fig. 3a), Bcl-2, Bcl-6 (Fig. 3b), and CD5 (Fig. 3c). CD10, CD3 (Fig. 3d), and cyclin D1 were negative. Ki-67 (MIB1) revealed a proliferation rate of approximately 80–90% (Fig. 3e), and CD31 highlighted the vascular endothelium (Fig. 3f). Flow cytometric immunophenotyping did not reveal a monoclonal proliferation. The presence of malignant B-cells within vascular lumina and no evidence of lymphoma cells outside of vessels were diagnostic for intravascular large B-cell lymphoma. The bone marrow was negative for involvement by morphology and immunohistochemical studies. Cerebrospinal fluid examination was normal. Magnetic resonance imaging (MRI) of the brain revealed mild cerebral atrophy with scattered white matter lesions interpreted as chronic small vessel ischemic changes. The patient received systemic treatment with 1 cycle of etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (R-EPOCH). The patient also received intrathecal methotrexate. The chemotherapy was discontinued after 1 cycle secondary to neutropenia; however, the patient had complete resolution of her intraorbital mass with no radiographic or clinical evidence of lymphoma 2 years since diagnosis. There was no change in the white matter lesions. Her eye pain, proptosis, and motility disturbance resolved, but there was no improvement in her vision.

Fig. 1
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MRI study showing an avidly enhancing intraconal mass in her left orbit

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Fig. 2
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Lymphoma cells in the vessel lumina (hematoxylin and eosin stain, ×400)

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Fig. 3
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CD20 (a), BCL-6 (b), and CD5 (c) immunohistochemistry reveals strong expression in the lymphoma cells. CD3 immunohistochemistry is negative in the tumor cells and highlights background T-cells (d). The proliferation index is 80–90% by Ki-67 immunohistochemistry (e). CD31 highlights the vascular endothelium (f). All figures, 200×

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Discussion

IVLBCL is a rare form of B-cell non-Hodgkin lymphoma characterized by accumulation of neoplastic B-cells within blood vessels, especially capillaries. It is thought that aberrant expression or lack of surface adhesion molecules involved in lymphocyte migration and trafficking contribute to the tumor’s intravascular distribution [12]. IVLBCL most frequently involves the brain and skin, but any organ system can be involved. Sixty-eight percent of patients in one series showed involvement of at least the CNS and/or the skin [1]. Cutaneous lesions were the most common clinical presentation in this series. The Western variant is often diagnosed by skin biopsy, while the Asian variant is diagnosed by bone marrow biopsy [1]. Random skin biopsies have been advocated to help establish the diagnosis in patients suspected of having IVLBCL [13].

Primary ocular adnexal lymphomas comprise approximately 6–8% of all ophthalmologic tumors [14]. The majority of ocular adnexal lymphomas are B-cell non-Hodgkin lymphoma, with a smaller proportion being T-cell and NK-cell tumors. The most common B-cell lymphoma type is low-grade extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue. IVLBCL very rarely affects the eye and has been previously reported in only 10 patients (Table 1). Of the 10 cases, one was diagnosed by biopsy of the lacrimal gland and another from a biopsy of an orbital mass [4, 6]. One case of intraocular IVLBCL was diagnosed after enucleation due to concern for a malignant melanoma [8]. The remaining cases were either diagnosed through biopsy of non-ocular tissues (e.g., brain, skin, lung) in patients with associated ophthalmic findings or diagnosed in the ocular tissues at autopsy. The cases diagnosed at autopsy had extensive involvement of other organ systems. The majority of these patients presented with either blurred vision or other ophthalmic symptoms. Three of the ten patients had lower extremity weakness. The presentation of IVLBCL frequently involves neurological manifestation since the brain is the one of the most frequent sites of involvement. These findings are commonly non-specific and may be attributed to direct involvement of the vasculature in the central nervous system by the neoplastic cells. Interestingly, neuroimaging discloses CNS involvement only in half of patients with neurological symptoms [15]. When neuroimaging does reveal positive findings, ischemic foci are the most common presentation pattern [16].

Table 1 Previous cases of ophthalmological intravascular large B-cell lymphoma
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Patients with IVLBCL are typically considered to have disseminated disease at diagnosis. Anthracycline-based chemotherapy regimens are associated with a 60% response rate and a 3-year survival of approximately 30%. More intensive treatment in patients with CNS involvement is warranted due to the poorer outcomes, and intrathecal methotrexate may improve prognosis [3]. The use of anti-CD20 antibody rituximab with anthracycline-based regimens has improved clinical outcomes [17].

To our knowledge, this is the first reported case where the disease was confined to the orbit with no evidence of CNS or systemic involvement. However, it should be noted that radiographic staging procedures are associated with a high false-negative rate [1]. In this case, radiographic examination of the brain revealed white matter lesions suggestive of ischemia, which is seen in patients with IVLBCL; however, an MRI after chemotherapy revealed no change in the white matter lesions, while the orbital mass resolved. This finding, and the patient’s subsequent apparently disease-free clinical course, favors ischemic brain lesions over lymphoma. The presence of a mass lesion in IVLBCL is an atypical finding, but a mass was present in a case with a similar clinical presentation [4]. It is possible that the presence of intravascular tumor cells expanded the surrounding benign adipose tissue creating the appearance of a mass lesion.