Isolated ocular relapse in pediatric acute lymphoblastic leukemia: a case report

Summary

A 5-year-old girl, previously in complete remission from common B-cell acute lymphoblastic leukemia (B-ALL), presented at the University Hospital of Leuven with a unilateral, painless red left eye. Over several weeks, the clinical picture evolved from common conjunctivitis into a painful red eye with iris heterochromia and increased iris vascularization unresponsive to topical and oral antibiotics. No signs of leukemic relapse were detected on comprehensive systemic work-up, including bone marrow and lumbar puncture. Aqueous sampling at this time could not confirm the clinical suspicion of isolated ocular relapse of ALL. Oral prednisolone was initiated, with good clinical response. After discontinuation of steroids, the affected eye developed a hypopyon-like mass in the anterior chamber. Urgent anterior chamber washout was performed. Cytology now confirmed the presence of a leukemic infiltrate, indicating an isolated ocular relapse of common B-ALL. Not only because this was the fourth relapse, but primarily because this patient had already undergone extensive prior treatments, including an allogeneic stem cell transplant just 6 months earlier, there were no systemic therapeutic options available. Palliative radiotherapy to the left orbit was therefore initiated. Two months later, the girl presented with similar symptoms in the right eye, which was also treated with radiotherapy.

Introduction

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children, representing approximately 25% of all childhood malignancies. Of pediatric cases, 85% are of B-cell origin (B-ALL); 15%, of T-cell origin (T-ALL).1,2 Treatment of ALL consists of intensive multiagent chemotherapy for about 2 years. Improved supportive care and optimization of therapy based on precise risk stratification have increased the long-term survival rate to 90%.1–3

Previous studies demonstrated that ophthalmic manifestations of childhood leukemia were associated with significantly worse survival rates.4,5 Recent studies, however, offer a more nuanced perspective. Whereas Mirshahi et al6 found evidence to support the association of ophthalmic involvement and poorer outcomes, Laimon et al7 found no statistically significant difference in survival between patients with and without ocular findings, suggesting that the prognostic significance of ophthalmic involvement may be less pronounced with modern risk-stratified treatment approaches.6,7 Although ocular infiltration in ALL is rare (0.5%–2.5% of cases), it presents a diagnostic challenge.4 A review of anterior segment infiltration in ALL delineated a diverse spectrum of presenting symptoms, including conjunctivitis, scleral hyperemia, corneal edema, iris heterochromia, thickened iris, rubeosis iridis, plastic iridocyclitis, anisocoria, mydriasis, glaucoma/elevated intraocular pressure (IOP), hyphema, hypopyon, uveitis, and panuveitis.8

The anterior uveitis seen in juvenile idiopathic arthritis (JIA) typically presents with a quiet white eye.8 A red eye in a child secondary to uveitis should therefore raise suspicion, especially when there is a history of ALL. We describe the possible clinical presentation and challenging diagnostic work up of this rare, isolated extramedullary relapse in a young girl.

Case Report

A 5-year-old girl presented to the ophthalmology clinic at the University Hospital of Leuven with painless red left eye. Her symptoms began with a red eye accompanied by mild rhinitis. Visual acuity measurement was not possible because of patient discomfort. IOP was normal (10 mm Hg) in each eye. Slit lamp examination revealed follicular conjunctival injection, with mild palpebral edema. Viral or allergic conjunctivitis was suspected. Polymerase chain reaction testing for viruses and bacteria were negative.

The patient’s medical history was significant for common B-ALL diagnosed at 20 months, with three bone marrow relapses. She was treated with chemotherapy, anti-CD19 CAR-T cell therapy, and inotuzumab ozogamicin. At 4 years and 9 months, she received an allogeneic hematopoietic stem cell transplantation (HSCT) following etoposide and total body irradiation (TBI) with eye protection. Six months post-HSCT, she was in molecular remission (measurable residual disease–negative), with complete donor chimerism.

Over several days after presentation, ocular pain and swelling increased, prompting antibiotic treatment. Magnetic resonance imaging (MRI) of the brain and orbit showed preseptal edema, scleritis, and dacryoadenitis. Despite topical tobramycin and dexamethasone and systemic (amoxicillin/clavulanic acid) antibiotics, symptoms worsened. Oral steroids were started to treat scleritis.

On follow-up, slit-lamp examination revealed follicular conjunctival injection, Altered iris pigmentation, and mild palpebral edema (Figure 1). Anterior segment paracentesis identified rare, large B-cell lymphocytes, although TdT (terminal deoxynucleotidyl transferase), a useful marker for the diagnosis of acute lymphoblastic leukemia and lymphoblastic lymphoma, was negative. Lumbar puncture and bone marrow biopsy showed no evidence of central nervous system (CNS) or systemic relapse, respectively.

Figure 1.

Altered iris pigmentation of the left eye.

After a month, redness and pain persisted despite steroid therapy. Steroids were stopped to perform a vitreal biopsy. After discontinuation of the steroids within 2 weeks a firm, white hypopyon-like infiltrate on the left inferior iris appeared (Figure 2). Vitreal biopsy and anterior chamber washout were subsequently performed and confirmed numerous atypical lymphocytes positive for TdT, CD10, and CD22, indicating anterior segment relapse of ALL.

Figure 2.

Hypopyon-like mass in the left eye, with increased vascularization of the iris.

Given prior extensive treatments, only palliative left orbital radiotherapy (24Gy in 12 fractions) was performed, resolving pain and iris heterochromia. Two months later, an isolated relapse in the right eye was diagnosed. MRI was performed after the patient presented with scleritis in the right eye and showed identical features as the left eye. It was treated similarly with radiotherapy. Thirty-six months after treatment, she remained in complete remission. As a consequence of the radiotherapy, bilateral cataracts developed. Due to decreased visual acuity, cataract surgery was performed on the left eye 27 months after completion of radiotherapy. The right eye showed a mild subcapsular plaque. Most recent visual acuity was logMAR 0.15 in both eyes.

Discussion

Diagnosis of an ocular relapse in ALL, often established via anterior chamber paracentesis, can be challenging.8 In our case, the initial anterior chamber paracentesis yielded ambiguous results, consistent with findings in existing literature. It is noteworthy that our patient was receiving oral corticosteroid therapy, which may have masked the diagnostic results. To improve the diagnostic yield of anterior chamber paracentesis, Yu et al8 have proposed the tap-refill-tap technique and recommended using needles with a lumen larger than 30 gauge to minimize cell damage. Ultimately, a vitreal biopsy confirmed the diagnosis in our patient, albeit through a more invasive procedure.

Initially considering the relapse as an innocent anterior chamber inflammation can lead to delay in appropriate treatment, increasing the chance of systemic relapse. Chocron et al.9 reported a case of an 11-year-old girl who developed anterior uveitis 17 months after remission of B-ALL CNS relapse with ocular involvement. Despite normal findings on extensive work-up, including bone marrow biopsy, cerebrospinal fluid analysis, and brain and orbits MRI, anterior chamber paracentesis failed to detect blast cells initially. After 8 months, the patient developed a hypopyon, and a subsequent paracentesis confirmed blast cells. Treatment for ocular relapse with chemotherapy, radiotherapy, and allogeneic HSCT was initiated, but the patient succumbed to recurrent bone marrow and CNS disease 2 years later, underscoring the challenges in diagnosis and management.9

We report a rare case of isolated extramedullary ocular relapse of B-cell ALL in a 5-year-old girl who achieved a third complete remission following extensive treatment, including multiagent chemotherapy, immunotherapy, and allogeneic HSCT. Remarkably, nearly 2 years after receiving only palliative radiation for the ocular relapse, she remains in remission. The lack of curative systemic options due to prior therapies underscores the significance of this outcome. Eye protection during prior TBI may have contributed to the eye serving as a sanctuary site for ALL.10,11 This case underscores the challenges and complexities associated with diagnosing and managing ocular relapse in pediatric patients with a history of ALL.