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.