Ocular adnexal reactive lymphoid hyperplasia in children.

AIM: To describe the clinical and histopathological features of ocular reactive lymphoid hyperplasia in children, and review the literature regarding this entity.
MATERIALS AND METHODS: In this retrospective, interventional case series, a chart review was performed of three patients diagnosed with reactive lymphoid hyperplasia. Details of clinical presentation, ocular and systemic examination findings, management and subsequent course were noted.
RESULTS: Three children, aged 9-14 years presented with ocular adnexal masses (two unilateral and one bilateral) with 7-12 months duration. Ocular examination revealed discrete nasal conjunctival masses in two patients, and bilateral eyelid fullness and conjunctival chemosis in the third patient. Systemic evaluation and laboratory tests were normal in all patients. Orbital imaging showed lacrimal gland enlargement in one patient. Histopathological evaluation with immunohistochemical markers established the diagnosis of reactive lymphoid hyperplasia. Two patients underwent surgical excision with complete resolution. All patients have remained stable and at their last follow-up have showed no evidence of recurrence, transformation, or systemic involvement.
CONCLUSION: Reactive lymphoid hyperplasia, though uncommon in children, can have a favorable outcome with timely intervention.

INTRODUCTION

Reactive lymphoid hyperplasia (RLH) of the ocular adnexa is part of a spectrum of ocular adnexal lymphocytic infiltrative disorders that has malignant lymphoma as the most aggressive end of the spectrum.1 These lesions frequently present a diagnostic challenge, due to considerable overlap between malignant and reactive processes.2 Patients can present with a constellation of symptoms, none pathognomonic, involving the conjunctiva, lacrimal gland or sac regions.3 RLH is commonly seen in adults in the sixth–seventh decade of life.4

We present three children with ocular adnexal benign RLH and the course of the disease over a follow-up period ranging from 9 to 15 months. The lesions involving the conjunctiva and lacrimal gland were diagnosed as RLH based on histopathological findings and immunophenotyping.

MATERIALS AND METHODS

The electronic medical records of three patients diagnosed with RLH, were retrospectively reviewed. Age, gender, best corrected Snellen visual acuity, intraocular pressure, slit-lamp, and fundus examination findings were recorded. Opinion from a pediatric oncologist was sought in all cases.

Laboratory investigations included full blood and reticulocyte count, serum electrolytes profile, liver function tests, bone profile, serum lactate dehydrogenase level, serum IgA, IgG, and IgM levels, auto-antibody screen, beta-2 microglobulin level, and serology for chlamydia trachomatis, chronic hepatitis, Epstein Barr virus, and Herpes simplex. Computerized tomography scan (CT) and/or magnetic resonance imaging (MRI) of the orbits was performed in all cases to determine the extent of ocular involvement. All patients had undergone surgical intervention. Excisional biopsy was performed in two patients (patients 1 and 3) while the second patient underwent incisional biopsy due to the diffuse nature of the disease process.

Histopathological examination included the use of immunohistochemical markers CD20, CD3, CD21, CD43, BCL-2, kappa, and lambda following standard protocols.5 The follow-up period ranged from 9 to 15 months.

RESULTS

The demographic and ocular findings on presentation are summarized in Table 1.

Table 1

Clinical characteristics of the study patients

Two patients (patients 1 and 3) had unilateral involvement with discrete, salmon colored nasal conjunctival masses in the region of the plica semilunaris [Figure 1], and one patient (patient 2) had bilateral eyelid fullness and conjunctival chemosis [Figure 2a]. The masses were painless, nontender, and were not associated with any other ocular complaints. The rest of the ocular examination was unremarkable. All patients were in good health systemically.

Figure 1

Patient 1. Nodular, pinkish conjunctival mass involving the medial canthal region in the right eye

Figure 2

Patient 2. (a) Diffuse involvement of temporal conjunctiva in left eye. Part of the involved lacrimal gland can also be seen. (b) MRI of patient 2: Bilateral lacrimal gland enlargement, more on the left side, involving the left upper eyelid

MRI of the orbits in patient 2 revealed bilateral lacrimal gland enlargement, greater on the left side, and involving the left upper eyelid [Figure 2b]. All laboratory tests were within normal limits.

Light microscopic examination of the biopsy specimens revealed a dense infiltrate of mature lymphocytes in the conjunctival substantia propria with multiple nests of lymphocytes (follicles) with germinal centers. Immunohistochemical staining with B-lymphocyte (anti-CD-20) and T-lymphocyte (anti-CD-3 and anti-CD-43) markers showed heavy staining of the cells [Figure 3a]. The B cells were located in the well-defined lymphoid follicles with reactive T cells interspersed in the peri- and interfollicular areas [Figure 3b]. Anti-CD-21 staining was also positive. Anti-BCL-2 staining was negative and kappa and lambda staining was polytypic with no evidence of restriction, confirming the benign nature of the follicles [Figure 3c]. These light microscopic, and immunohistochemical findings were consistent with a benign reactive process, and the patients were diagnosed with RLH [Table 2].

Figure 3

Immunohistopathology (Patient 1): (a) Dense lymphoid cell infiltrate in subepithelial tissue (haematoxylin and eosin). (b) B-lymphocytes present mainly within the follicles (arrow) (CD20 stain) with reactive germinal centre. The follicles are composed mainly of B-lymphocytes (CD20, original magnification, 20×). (c) The perifollicular lymphoid cells are T-lymphocytes (arrow; CD3, original magnification, 20×)

Table 2

Histopathology, Immunohistophenotypes and follow up

The patients have been followed up for a period of 9–15 months. There has been no evidence of recurrence or transformation of the ocular surface disease. Systemic evaluation by a pediatric oncologist has not revealed any abnormalities.

DISCUSSION

Lymphoproliferative disorders of the ocular adnexa (orbit, eyelid, and conjunctiva) include a group of diseases ranging from RLH and atypical lymphoid hyperplasia to lymphoma. RLH is believed to be a consequence of a chronic inflammatory response of lymphoid cells in the lacrimal gland, conjunctiva, or lacrimal drainage system to irritating or antigenic stimuli.67 Benign RLH in a myopic patient with extremely thin sclera, led the authors to hypothesize that choroidal antigens are able to perfuse through thin sclera and act as chronic irritants to the overlying conjunctiva resulting in a lymphoid response.8 RLH has been reported to account for 10% of all conjunctival lymphoid proliferative lesions.9

Histopathology, immunophenotyping, and molecular studies are helpful in the diagnosis of these lesions and establishing their benign nature. A unicentric, polyclonal lymphoproliferation favors a diagnosis of RLH as compared with multicentricity and monoclonality, which are hallmarks of lymphomas.10 Recently, a new entity of multifocal RLH with a more favorable prognosis than follicular lymphoma has been described.11

Patients with ocular adnexal RLH have an indolent clinical course. Some patients have a history of asthma, hypergammaglobulinemia, and systemic involvement.1213 Malignant transformation of conjunctival lesions is reportedly rare compared with eyelid or orbital lesions. Development of systemic lymphoma is significantly associated with extent of disease at presentation, and bilateral disease.14 One of our patients (patient 2) who had bilateral involvement had a residual conjunctival tumor after resection. The management of such patients is not well defined in literature; whether local irradiation prevents later transformation to a higher-grade lymphoma is not clear. Awareness of the substantial vision-threatening risks associated with radiation led to the decision of observation of our patient.

In conclusion, RLH in children tends to have a benign, self-limited course, but surgical excision may be necessary for complete resolution. A potential for recurrence and transformation necessitates periodic, long-term follow-up of patients.