Long-term management of orbital and systemic reactive lymphoid hyperplasia with rituximab.

Rituximab, a monoclonal antibody to the B cell marker CD20, is becoming increasingly popular in the treatment of various orbital disorders. In this university-based interventional case series, we describe two patients with bilateral orbital and extra-orbital reactive lymphoid hyperplasia (RLH) treated with rituximab. Initially both had favorable responses; but roughly a year later recurrent disease necessitated maintenance therapy in both cases. Both again responded to additional courses of rituximab. Although recalcitrant disease may persist after treatment, rituxmab may play a role in the management of RLH with widespread involvement.

INTRODUCTION

Reactive lymphoid hyperplasia (RLH) is characterized by the proliferation of a polymorphic lymphocytic infiltrate without an identifiable monoclonal subpopulation or other markers of malignancy.1 RLH is distinguished from orbital inflammatory syndrome clinically and histologically.2 RLH is a proliferation of lymphocytes within a structure as opposed to an inflammatory response. Accordingly it usually presents more indolently with less pain, discomfort, and other inflammatory associates.2

Traditional treatment modalities for RLH include corticosteroids and external beam radiation therapy (EBRT).3 Rituximab is a chimeric humanized monoclonal antibody directed against CD20 receptors, found on B lymphocytes.4 Variably successful treatment of orbital RLH has been described with rituximab.5–7 In the largest series, 10 out of 11 patients (91%) with orbital RLH refractory to steroids were reported to have responded favorably.5 Disease recurrence was seen in six patients, between 4 and 70 months after initial treatment.

In this manuscript, we present our experience with two patients with widespread multisystem RLH who presented with orbital involvement.

CASE REPORTS

Case 1

A 63-year-old man was referred for the management of bilateral orbital infiltrates. He reported a 7 year history of steadily progressive bilateral painless proptosis and visual loss. He had no additional complaints and an unremarkable past medical history. Best corrected visual acuity (BCVA) was 20/40 oculus uterque (OU). He had a mild relative afferent pupillary defect on the right and mild optic disk pallor bilaterally. Anterior and posterior segment examinations were otherwise unremarkable. Extraocular motility was mildly limited in all direction of gaze OU. Exophthalmometry measured 20 mm oculus dexter (OD) and 17.5 mm oculus sinister (OS) [Figure 1a].

Figure 1

Patient #1, pretreatment: (a) External photograph demonstrating bilateral proptosis (b) Humphrey visual field demonstrating a superior arcuate defect and general constriction OD; normal field OS (c) Axial (left) and coronal (right) MRI of the orbits demonstrating bilateral diffuse infiltration involving the extraocular muscles and lacrimal glands (d) Pretreatment positron emission tomography (PET) demonstrating increased metabolic activity in the orbits (left) and paraspinal region (right)

Visual field testing was abnormal in the right and normal in the left eye [Figure 1b]. Magnetic resonance imaging (MRI) demonstrated diffuse infiltration of both orbits. [Figure 1c] Several extraorbital sites of involvement were detected on positron emission tomography (PET). [Figure 1d] Biopsies of both the orbital and paraspinal masses were consistent with RLH. [Figure 2]

Figure 2

Patient #1: Orbital biopsies demonstrating lymphoid hyperplasia (a) Hematoxylin and eosin stain showing lymphoid follicles with well-formed germinal centers surrounded by mantle zones composed of a polymorphous mixture of small lymphocytes (b) CD20 immunohistochemical stain: CD20 positive B-cells are prominent in scattered follicles (c) CD21 immunohistochemical stain: highlighted dendritic cells underlie the follicles (d) CD3 immunohistochemical stain: T-cells are seen in both follicles and inter-follicular areas

Following failed treatment with steroids (roughly 1 mg/kg for 1 month) and doxycycline, two cycles of rituximab (370 mg/m2 weekly for 4 weeks) were given. The patient improved with little clinical evidence of persistent disease. His visual acuity improved to 20/20 OU. Exophthalmometry measurements decreased to 13 mm OD and 14 mm OS. The visual field resolved with the exception of a slight depression OD [Figure 3a]. Much improved but persistent abnormality was detected on MRI. [Figure 3b].

Figure 3

Patient #1, post treatment: (a) Humphrey visual field demonstrating a normal field OS and near complete normalization OD (b) MRI demonstrating improved but persistent areas of abnormality

Ten months after the last rituximab treatment returned with periocular discomfort. Exophthalmometry measurements had increased to 15 mm OU and progression of disease was seen on MRI. Following repeat rituximab therapy using a similar dosing regimen, the patient was again asymptomatic and remains so 11 months following treatment.

Case 2

A 66-year-old man was referred with a 3 month history of progressive proptosis [Figure 4a]. A right submandibular mass had progressively enlarged since detection several years prior. BCVA was 20/40 OU. Extraocular motility was full with the exception of limited supraduction OU. Anterior and posterior segment examinations were unremarkable with the exception of early nuclear sclerosis. He had bilateral blepharoptosis with a margin reflex distance (MRD) of 1 mm OD and 3 mm OS. Exophthalmometry measurements were 17 mm OU. Visual field testing was normal. MRI showed bilateral lacrimal gland and extraocular muscle enlargement. [Figure 4b] PET scan demonstrated abnormalities in both orbits and the right submandibular area. Multiple abnormal areas were also identified in the chest, most densely within the right hilum. [Figure 4c] Biopsies of the right orbital and submandibular masses were consistent with RLH.

Figure 4

Patient #2, pretreatment: (a) External photograph demonstrating bilateral proptosis (b) Pretreatment axial (left) and coronal (right) orbital MRI demonstrating bilateral infiltration involving the lacrimal glands (c) PET scan demonstrating increased metabolic activity of the right submandibular space (left) and at multiple focal areas in the chest (right). Multiple bilateral mediastinal foci are seen and likely represent lymph node involvement

Two cycles of rituximab (370 mg/m2) were given. The patient responded promptly with normalization of most findings: proptosis improved to 14 mm OD and 13 mm OS, supraduction returned to normal, and blepharoptosis improved with MRD of 2.5 OD and 3.5 OS. MRI showed marked reduction in the soft tissue infiltrate of the lacrimal glands and extraocular muscles. PET scan no longer demonstrated any abnormal uptake.

Sixteen months following initial treatment, the patient returned with recurrent symptoms. MRI demonstrated increased orbital infiltration and PET scan identified increased activity within the submandibular, hilar, and mediastinal lymph nodes. Following repeat rituximab therapy, the patient was again asymptomatic and remains so 9 months following treatment.

DISCUSSION

Although variable success has been reported in the management of orbital RLH;5–7 this is the first report specifically addressing orbital involvement in widespread RLH. In this study we present two patients with systemic with orbital involvement. Although clinical resolution was achieved with rituximab, in both patients, recurrent disease necessitated maintenance therapy. This recalcitrant disease emphasizes the limitations of rituximab therapy and could arguably be interpreted as failure. However, both of our patients responded to subsequent rituximab therapy and remain clinically asymptomatic years after presentation. Until definitive treatment of widespread RLH is available, rituximab remains a viable option for such patients.