Discussion
ALL is a hematologic malignancy that arises from lymphoid progenitor cells and results in the uncontrolled overproduction of immature cells called blasts. It is the most common malignancy affecting children under age 14 years, with 80% of all cases occurring in the pediatric population.1,2 ALL can arise from either immature B cells or T cells, with B-lymphoblastic leukemia accounting for approximately 90% of pediatric ALL. Further cytogenetic subclassification is important so that treatment can be adapted according to risk stratification. Clinical presentation of new-onset ALL is nonspecific, with symptoms such as fever, unexpected weight loss, easy bruising, fatigue and joint pain.1,2
The 5-year survival rate for pediatric patients with ALL is 90% and is much lower in the adult population at 30-40%.2 The high cure rate for pediatric ALL patients is in part due to the implementation of prophylactic CNS therapy to mitigate CNS relapse.3 Leukemia can also recur in other extramedullary sites like the testes (immunologically privileged like the CNS in that there is a blood-brain or blood-testis barrier), though other possible sites vary widely.4 One such location is the optic nerve, where relapse can manifest as blurred vision, photophobia and pain, eventually progressing to central retina artery occlusion (CRAO), central retinal vein occlusion (CRVO), neovascular glaucoma, and retinal detachment if not promptly addressed.5 It has been posited that the optic nerve is a pharmacologic sanctuary and especially susceptible to leukemia recurrence.6
We present a young male in which optic nerve invasion was the only manifestation of recurrent pre-B cell ALL, as evidenced by the negative CSF and BM analyses. Such isolated leukemic relapse is rare, since optic nerve involvement usually occurs simultaneously with CNS involvement.4-8 At one time, optic nerve invasion was even considered a “preterminal event” in the course of a child whose disease progresses to the point of CNS involvement, though we now know that not to be true.8 One study analyzed 5 cases of leukemic infiltration of the optic nerve and found only 1 of the cases to be positive for leukemia in both CSF and bone marrow. Three of the 5 cases were positive only in CSF studies and 1 case was positive in bone marrow.7 Another study reviewed cases of isolated optic neuropathy in the context of leukemia or lymphoma and found malignant cells in the CSF 64% of the time.5 There are a few cases such as ours reported in the literature of isolated optic nerve leukemic invasion in which both CSF and BM analyses are negative, but most of the cases were not confirmed via biopsy.4,6,9
The differential diagnosis for optic nerve impairment can present significant challenges to the clinician, given the limited access to the anatomic region, the proximity of vital structures, and similar presentation of many different medical concerns. Other diagnoses sharing comparable clinical features include inflammation, infections, medication effects, autoimmune disorders, ischemia and other neoplasms.5,8,10 The diagnostic process is sometimes compounded by the fact that systemic investigations including LP and BM analysis can be normal. For elusive diagnoses, the following process is often applied: 1) urgent ophthalmology consult, 2) MRI of the brain and orbits, and 3) optic nerve biopsy.
One additional reliable and relatively safe preliminary diagnostic tool before attempting any invasive procedure is (FNAB) of the optic nerve head, thoroughly discussed by Khan et. al.11 Though not reported for the diagnosis of leukemic infiltration, FNAB has been used for the diagnosis of other ophthalmologic issues. For example, Shields and group presented a young girl with suspected optic disk melanocytoma. They performed FNAB of the optic nerve head, which confirmed there was no malignant transformation and guided further treatment.12 In our case, cytopathology following FNAB revealed very rare atypical cells, further adding to the suspicion of ALL recurrence. Definitive diagnosis was ultimately achieved on transconjunctival optic nerve biopsy, which was essential in identifying antigens like CD19 that could serve as therapeutic targets for chimeric antigen receptor (CAR) T-cells, or monoclonal antibodies such as the bispecific T-cell engager, blinatumomab.
Various approaches to optic nerve biopsy have been described in the literature, such as the transconjunctival approach.10,13 However, only a few other groups of investigators have discussed the diagnosis of ALL optic nerve infiltration via transconjunctival biopsy.5,10 In our case, the transconjunctival approach yielded conclusive results that supported the suspected diagnosis.
Prompt diagnosis and treatment of leukemic optic nerve infiltration is crucial to optimizing patient outcomes by preventing blindness and promoting long-term survival.9 The process necessitates multiple diagnostic tools including clinical exam, MRI, LP, BM, FNAB, and transconjunctival optic nerve biopsy. All clinicians, especially ophthalmologists, should recognize the potential for leukemic recurrence, especially in rare locations such as the optic nerve. Diagnosis of optic nerve impairments can be difficult, especially if the patient has a confounding medical background.