Ocular post-transplant lymphoproliferative disorder.

We report a case of an iris tumor with muttonfat keratic precipitates in a young patient after liver transplantation surgery. A 6yearold girl underwent liver transplantation for congenital biliary atresia and was subsequently immunosuppressed with oral cyclosporine. We examined her 5 years after transplantation because of a "white nodule in her left eye," which had been detected by her father one day before visiting our clinic. Ophthalmological examinations revealed symmetric visual acuity and normal afferent papillary reflex. Slitlamp examination revealed a depigmented iris nodule approximately3 × 2 mm with muttonfat keratic precipitates in the anterior chamber. Fundus examination was unremarkable, and computed tomography (CT) of the head, neck, and abdomen showed normal findings. Based on the suspicion of post-transplant lymphoproliferative disorder (PTLD), therapy was initiated, which included tapering cyclosporine and topical mydriatics. After 2.5 months, the lesion resolved and no more muttonfat keratic precipitates were identified in the anterior chamber. In this PTLD case, the patient presented with an iris nodule and muttonfat keratic precipitates, and the ocular PTLD presentation resolved spontaneously after tapering cyclosporine.

1. Introduction

Post-transplant lymphoproliferative disorders (PTLDs) are a spectrum of diseases caused by lymphoplasmacytic proliferations that occur as a result of immunosuppression following solid organ or allogeneic hematopoietic cell transplantation.1 The spectrum of PTLDs ranges from polymorphic, polyclonal proliferations with features of viral infection, to monomorphic, monoclonal proliferations, usually of the Bcell type.2 Primary ocular PTLDs represent a distinct, late-onset, polyclonal lymphoproliferation primarily affecting pediatric transplant patients.3 The uveal tract becomes infiltrated by a mixture of lymphocytes and plasma cells, and is often associated with the presence of Epstein-Barr virus (EBV).4 In this case report, we present a patient who underwent liver transplantation and subsequently developed presumed ocular PTLD complications, which resolved after adjusting immunosuppression therapy.

2. Case Report

A 6-year-old girl underwent liver transplantation for congenital biliary atresia and was placed on immunosuppression therapy with oral cyclosporine (30 mg/day), with a mean cyclosporine level of 524 ng/mL in her blood during the 5th post-transplant year. Five years after liver transplantation, she presented with a “white nodule in her left eye”, which had been detected by her father the day before attending our clinic. There was no previous history of traumatic injury to the eye, and she denied any systemic discomfort. Visual acuity was 20/50 in both eyes, eye movements were full and free and intraocular pressures were within normal limits. The patient had normal light reflex in both eyes, but the examination of the anterior segment revealed a highly vascularized, hypopigmented iris nodule situated on the peripheral iris in her left eye (Fig. 1). Multiple mutton-fat keratic precipitates were noted, but there were no cells in the anterior chamber (standardization of uveitis nomenclature, SUN grade 0). The vitreous cavity was clear with no other mass lesions detected on B-scan ultrasonography or dilated fundus examination. Examination of the right eye was un remarkable. Physical examination and systemic surveys including computed tomography (CT) of the head, neck, chest, and abdomen were performed and were within normal limits. Laboratory investigation of the patient's blood was positive for EBV DNA, Epstein-Barr nuclear antigenantibody (EBNAAb) (>1.640), and EBViral Capsid Antigen IgG antibody (EBVCAG) (>750 U/mL), and was negative for EBViral Capsid Antigen IgM antibody (EBVCAM).

Fig. 1

Hypopigmented neoplasm located between 7:00 and 8:00. Multiple mutton-fat keratic precipitates noted.

On suspicion of ocular PTLD without systemic involvement, topical steroid and cycloplegic eye drops were given, along with the adjustment of systemic cyclosporine dosage to 15 mg/day. Cyclosporine levels in the blood and liver function tests were monitored regularly. Six weeks after adjustment of the systemic cyclosporine dosage, her blood cyclosporine levels dropped to 211 ng/mL, and the iris nodule resolved spontaneously (Fig. 2). The patient is currently maintained on oral cyclosporine 15 mg/day, without additional immunosuppressive agents needed, and shows no signs of graft rejection so far.

Fig. 2

Resolved iris neoplasm and clear anterior chamber. Mutton-fat keratic precipitates have almost disappeared.

3. Discussion

Making a correct diagnosis is the essential first step in managing a pediatric patient with uveitis, which requires detailed history taking thorough ophthalmic examination and selected laboratory tests. Examination under general anesthesia may be needed in young pa tients should they be incapable of cooperating during the examina tion. For patients with suspected PTLD, differential diagnosis that needed to be ruled out include, iris melanoma, retinoblastoma, ju venile xanthogranuloma, and intraocular foreign bodies.15

PTLDs are characterized by an uncontrolled proliferation of Bcells as a result of immunosuppression following solid organ or allogeneic hematopoietic cell transplantation. Immunosuppressive therapy inhibits Tcell function, which leads to a reduction in Bcell growth suppression. Diagnosis of PTLD is based on both clinical and histological criteria. Children were considered to have clinical evidence suggestive of PTLD when there was evidence of lymphadenopathy, tonsillar hypertrophy, or extranodal masses on physical examination.6 In ocular PTLD, a mixture of lymphocytes and plasma cells diffusely infiltrates the uveal tissue. Cho et al7 reported that anterior uveitis and iris nodules are the most common ocular manifestations of PTLDs, but the posterior segment can also be involved.

In young patients who have received organ or bone marrow transplantation, it is reported that the 1-year post-transplantation ocular complication rate is 16% (including cataract, keratoconjunctivitis sicca secondary to Graft-versus-host-disease (GVHD), cytomegalovirus retinitis, PTLD, strabismus, transient visual loss, preseptal cellulitis, allergic periorbital edema, and conjunctivitis) in USA,4 whereas PTLDs occurs in 3% of all liver transplantation recipients.4 The prevalence of PTLD in adult patients following liver transplantation was reported to be 1.1% in a separate study.8 The incidence of PTLD is significantly higher in children (9.7%) than in adults (2.9%), with an overall average incidence of 4.3%.9 Persistent monoclonal immunoglobulins in liver transplantation recipients was also associated with a 23% incidence of PTLD.10 The average time interval between transplantation to PTLDs diagnosis is 50 months with a range of 5–140 months.8 In our patient, a 6-year-old girl, the interval between transplantation and PTLD diagnosis was 60 months.

The majority of PTLD cases are associated with EBV infection.1112 EBV induces uncontrolled proliferation of B-cells, which are normally regulated by cytotoxic T-cells and natural killer cells.11 Treatments for PTLD include prophylactic high-titer anti-EBV intravenous immunoglobulin13 in high-risk (donor was EBV positive, recipient was EBV negative) pediatric recipients, intravenous ganciclovir in high-risk EBV-positive donors to EBV-negative recipients,14 and immunosuppressive therapy reduction.7 In previous studies, EBV monitoring has been shown to be useful in high-risk transplant recipients.6 In the study by Ho cyclosporine was reduced to one-half of the original dosages after PTLD was diagnosed.15 In our patient, tapering the dosage of cyclosporine (from 30 mg/day to 15 mg/day) led to the resolution of the iris nodule presumed to be due to PTLD.

Our patient's laboratory test for EB-VCAG was positive, but the EB-VCAM was negative, indicating that she had a history of EBV infection, but the infection was not in the acute phase. Parker et al16 suggested that patients must be monitored for EBV seroconversion at the initial presentation of PTLD and then monthly (IgM to IgG against VCAs) until the stable appearance of IgG EBNA-1. If the lymph node or tonsillar enlargement does not improve, or worsens, a biopsy should be performed. In our patient, EBV seroconversion to IgG was present in the beginning of her clinical course. For the evaluation of PTLD, Dhillon et al8 reported an investigation protocol which included biopsy of the tumor/lymph node mass for histology, CT scans for staging (head, neck, chest, and abdomen), and analysis of peripheral blood (full blood count, flow cytometry for monoclonal B cells, EBV serology, and EBV load).

In the present case, the patient showed no signs of systemic involvement and neurological symptoms. Because of the young age of this patient and the family's concerns regarding the risk of general anesthesia and complications of biopsy, including infection, bleeding, and loss of vision, biopsy of the iris nodule was not performed. However, our patient was followed up closely, with progressive regression of the iris tumor noted after reduction of cyclosporine levels, and complete resolution of the tumor by 6 weeks. Nevertheless, in a patient with mass lesions or lymphadenopathy due to suspected PTLD, where no documented improvements have been noted after the reduction of immunosuppressive therapy, a low threshold for biopsy is warranted to confirm diagnosis.

In conclusion, the incidence of PTLD is higher in children than in adults, and the majority of cases appear to be related to the presence of EBV. In our case, the diagnosis of PTLD was made based on her history after having had a liver transplantation, the presence of past EBV infection, and the regression of the iris tumor after adjusting the immunosuppressant dose. When a patient is suspected of having PTLDs, adjunctive evaluations may include staging with CT of major organs, bone marrow aspiration, and peripheral blood measurements and analysis including titers for EBV anti-bodies. The patients should undergo frequent and careful monitoring, and biopsy of the tumor lesion whenever possible to provide adefinite pathological diagnosis.