B-Cell Acute Lymphoblastic Leukemia Relapse Presenting as Choroidal Infiltration Confirmed by Choroidal Biopsy Along with Ipsilateral Optic Nerve Involvement

ABSTRACT

We report a case that describes the relapse of histopathologically confirmed B-cell acute lymphoblastic leukaemia (B-ALL) in a 21-year-old male who presented with monocular subacute vision loss, photopsia, and floaters. His exam was notable for optic disc oedema and peripapillary choroidal thickening. He underwent trans-retinal choroidal biopsy where B-ALL recurrence was confirmed, and external beam radiation was initiated. This case demonstrates how choroidal biopsy can assist with establishing the diagnosis of ALL relapse in clinically atypical cases. ALL relapse isolated to the optic nerve and choroid is rare but should be considered in patients with appropriate medical history. Prompt diagnosis and initiation of treatment can yield excellent visual recovery, prevent irreversible vision loss, and potentially avert systemic relapse.

Introduction

Acute Lymphoblastic Leukaemia (ALL) is a malignant proliferation of lymphoid cells halted at an early stage of differentiation.^1,2 This disease typically originates in the bone marrow but can spill into the bloodstream with potential to invade lymphatics, extramedullary sites, as well as sanctuary sites such as the central nervous system (CNS) and testes. In the United States, the incidence of ALL is approximately 1.57 per 100,000 people, with the highest incidence in children aged 1–4 years old.^1,2 Outcomes have improved remarkably with new therapies. The 5-year survival of ALL was 31% in 1975 but has risen to 90% in 2009.^1,2 Unfortunately, relapses still occur in 15–20% of ALL patients and typically yield a poor prognosis.² Relapse of ALL isolated to the optic nerve and choroid is rare but should be considered by ophthalmologists and oncologists. Early identification of suspected ALL ocular relapse can prompt initiation of vision and lifesaving therapies.

Case report

The patient presented at 18 years of age with National Cancer Institute high risk precursor B cell acute lymphoblastic leukaemia. His initial symptoms were fever, headache, and intermittent blurry vision. He was found to have bilateral retinal hemorrhages at that time and markedly abnormal blood count, with white blood cell count (WBC) 254 k/uL. Peripheral blood smears showed the blasts were CD34+ with co-expression of CD19 (variable), CD22 (variable), cCD79a, CD7, CD13 and CD33. These were enumerated at 94% of leukocytes. A myeloperoxidase (MPO) stain was negative in the blasts. The patient subsequently underwent bone marrow biopsy. Cytogenetic studies revealed an apparently balanced t (X;10)(p11.2;p12) in 15 of 20 metaphases. B-ALL fluorescent in situ hybridization (FISH) studies identified three copies of the mixed lineage leukaemia translocated to 10 (MLLT10) gene region. Chromosomal microarray analysis detected loss of 2p22.2p21 and loss of 6q25.2q25.3. Pertinent negatives in the patient’s specimen included: no breakpoint cluster region/Abelson murine leukaemia (BCR/ABL1) fusion, no deletions of the IKAROS family zinc finger 1 (IKZF1) or ETS-related gene (ERG) gene regions and no genome-wide copy neutral loss of heterozygosity (cnLOH) that would indicate a doubled near-haploid or low-hypodiploid subtype. In addition, these results do not indicate intrachromosomal amplification of chromosome 21 (iAMP21). There were leukaemic blasts present in the initial diagnostic cerebrospinal fluid, which cleared with subsequent intrathecal and systemic chemotherapy (Figure 1). The patient was treated with chemotherapy according to modified Berlin-Frankfurt-Munich protocol, as per the standard of care at that time. The patient achieved remission (minimal residual disease) at the end of the first month of therapy (induction). However, nearing the end of his planned treatment, at age 21, the patient developed intermittent flashes, floaters, and decreased vision in the left eye, prompting concern for relapse and further medical evaluation.

Figure 1.

(a) Peripheral blood smear review shows numerous circulating blasts, characterized by large size, scant cytoplasm without granules and nuclei with smooth chromatin. (b) Bone marrow aspirate smears show an abnormal population (comprising approximately 90% of marrow cellularity) of variably sized blasts characterized by scant, agranular cytoplasm, occasional nuclear clefts and smooth chromatin. There is a proportional reduction in maturing myeloid and erythroid precursors, neither of which displays dysplastic changes. (c) Sections of the bone marrow core biopsies show markedly hypercellular marrow spaces. The marrow cellularity consists of sheets of immature blasts, characterized by variable size, scant cytoplasm and irregular nuclear outlines. Residual maturing myeloid and erythroid precursors are very few and are isolated. (d) Cytospin preparations of cerebrospinal fluid consist of frequent blasts, characterized by high nuclear to cytoplasmic ratios and scant cytoplasm. These findings are consistent with CSF involvement by the patient’s B-cell lymphoblastic leukemia.

When he first presented to the neuro-ophthalmology clinic, his left eye (OS) vision was markedly reduced: 20/400. There was also a left relative afferent pupillary defect. Dilated fundus exam demonstrated significant optic disc oedema, choroidal thickening, and peripapillary subretinal fluid OS (Figure 2). The fundus exam of the right eye (OD) was normal. Fluorescein angiography (FA) revealed early and late phase optic disc leakage with faint peripapillary leakage OS. Optical coherence tomography (OCT) showed peripapillary choroidal thickening, subretinal fluid, and disc oedema OS. B-scan ultrasonography demonstrated choroidal thickening superior (~3.3 mm), inferior (~3.5 mm), nasal (~3.8 mm), and temporal (~3.0 mm) to the nerve OS. Given his history of ALL, the clinical picture was concerning for isolated leukemia infiltration of the left optic nerve and choroid (as his recent cerebrospinal fluid (CSF) analysis was disease-free).

Figure 2.

(a) Fundus photograph of normal appearing OD. (b) Fundus photographs OS at initial presentation demonstrating optic disc oedema, choroidal thickening, and subretinal fluid in the left eye. (c) Late phase fluorescein angiogram illustrating normal appearance of disc and retinal vessels OD. (d) Initial and late phase fluorescein angiography demonstrating optic disc leakage with faint peripapillary leakage OS. (e) Spectral domain OCT OD showing normal appearing macula. (f) Initial spectral domain OCT OS. Left eye demonstrates intraretinal fluid nasal to fovea with a large area of subretinal fluid and disruption of the photoreceptor layer and fovea contour. Initial b-scan ultrasonography with nasal (g) and superior (h) transverse sections. These show choroidal thickening superior, inferior, nasal, and temporal to the optic nerve OS.

Laboratory workup then was notable for a WBC of 2.5 k/uL/UL (reference range 3.5–11.0 k/uL) with negative or non-reactive testing for syphilis, bartonella, toxoplasma, sarcoidosis, toxocara, and tuberculosis. Magnetic resonance imaging (MRI) of the orbits demonstrated a thin curvilinear lesion along the left posterior globe with associated enhancement (Figure 3). There was no clear optic nerve enhancement. No other concerning lesion or abnormality was noted on the MRI brain imaging. Repeated cytological analysis of the CSF did not show any abnormal cells or blasts. Bone marrow biopsy also did not show evidence of recurrent disease.

Figure 3.

Axial MRI images of the patient’s orbits. At 1 month after symptom onset, MRI imaging showed thin curvilinear T2 isointensity along the left posterior globe (a, white arrowhead) along with associated enhancement on T1 with contrast sequence (b, white arrow). At 3 months after symptoms onset, there was interval increase of the T2 lesion (c, white arrowhead) along with thickening enhancement (d, white arrow).

At this point, we had an extensive discussion with the patient and his medical oncologist regarding proceeding with empiric radiation treatment for presumed leukaemic relapse in the choroid and optic nerve. However, given that the systemic workup was negative, the patient’s oncologist felt strongly that pathologic confirmation should be obtained before initiating radiation treatment as this finding would be the first documented evidence of relapse. Since the patient had extensive choroidal thickening without evidence of vitreous cell, the decision was made to perform a trans-retinal choroidal biopsy. The biopsy was performed via a standard three-port pars plana vitrectomy, during which the 25-gauge vitreous cutter was used to obtain a trans-retinal choroidal biopsy at three sites nasal and superior to the optic nerve. Biopsy from those sites then revealed atypical cells that were CD34-positive, subset positive for cytoplasmic CD3, and negative for B-cell markers (CD19, CD10, cytoplasmic CD79a, cytoplasmic CD22), nuclear terminal deoxynucleotidyl transferase (TdT), and cytoplasmic MPO. FISH studies detected trisomy 8, which is not a lineage-specific finding and can be seen in myeloid neoplasms and some lymphoid neoplasms (Figure 4). These overall findings most likely represented recurrence of patient’s B-ALL with a change in blast immunophenotype or evolution of a treatment-resistant subclone.

Figure 4.

Cytospin preparations of the choroidal mass and vitreous fluid specimens show scattered atypical cells with high nuclear to cytoplasmic ratio, irregular nuclear contours, prominent nucleoli, and scant basophilic cytoplasm. The atypical cells are morphologically consistent with blasts.

The patient underwent orbital radiation with a dose of 24 Gy in 16 fractions.³ Two weeks after completing radiotherapy, his vision improved to 20/70 OS with dramatic improvement in his optic disc oedema and choroidal thickening. Six months after completing radiotherapy, his vision continued to improve to 20/40 OS. There was complete resolution of the optic disc oedema, subretinal fluid, and choroidal thickening with residual subretinal retinal pigment epithelium (RPE) irregularities (Figure 5). Unfortunately, approximately six months after concerning vision symptoms and negative marrow evaluation, repeat CSF analysis and bone marrow biopsy revealed systemic relapse. At the time of this fulminant relapse, the patient developed back pain and had WBC of 74 k/uL. The character of the relapse clone was identical to that which was present at initial diagnosis at age 18. Therapy was initiated with mini hyper- cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (CVAD), with inclusion of targeted immunotherapy agents blinatumomab and inotuzumab. As of this writing, the patient has achieved a second complete remission and has been scheduled for allogeneic marrow transplantation.

Figure 5.

(a) Post treatment fundus photo OS demonstrating resolution of optic disc oedema and subretinal fluid. The three chorioretinal scars observed represent sites of choroidal biopsy. (b) Spectral domain OCT OS showing resolution of subretinal and intraretinal fluid. There is mild thinning of the nasal half of the interdigitation zone with disruption of the photoreceptor layer. Post treatment b-scan ultrasonography with nasal (c) and superior (d) transverse sections revealing resolution of the peripapillary choroidal thickening.

Discussion

Primary (direct infiltration) and secondary ophthalmic manifestations of ALL demonstrate involvement of nearly all ocular structures.^4–7 Several studies reported ocular findings in 32–80% of patients newly diagnosed with ALL.^4–7 “Leukaemic retinopathy” is most commonly seen, which can present as isolated or a combination of retinal vascular tortuosity, intraretinal haemorrhages (often accompanied by a white center), and cotton wool spots.^4–7 Neuro-ophthalmic manifestations are rare with reported incidences between 2.1% and 5% at time of ALL diagnosis.^6,7 Less is known regarding the incidence of ophthalmic manifestations in ALL recurrence. As modern therapies continue to improve survival rates, the incidence of CNS recurrence has increased.^8,9 Ocular ALL recurrence is reported at 2.2% of all ALL relapses.¹⁰ ALL recurrence isolated to the optic nerve and choroid is even more rare with discussions limited to several case reports and series.^8,9 This finding is indicative of CNS involvement.

In a patient with a history of leukaemia, new onset optic neuropathy yields a broad differential. This includes direct infiltration, infections, compression, vasculitis, radiotherapy-induced complications, and/or adverse effects from chemotherapeutic agents.¹¹ This differential must be carefully worked through with a combination of history, laboratory evaluation, and imaging. A lumbar puncture should be performed in every case as malignant cells can be identified in the CSF in most patients with leukaemic infiltration of the optic nerve.¹⁰

In this case, we felt that the optic nerve oedema and choroidal thickening were due to leukaemic infiltration, although it is also possible that this could be secondary optic nerve swelling due to congestion from circumpapillary choroidal involvement. Therefore, we pursued trans-choroidal biopsy, which led to pathologic confirmation. To our knowledge, we present the first case of histologically confirmed ALL infiltration with change in blast immunophenotype or evolution of a treatment-resistant subclone. Although not entirely ruled out, we think it is unlikely that this tumor represents a novel lineage. Classically, the ophthalmic system is considered a “sanctuary” for lymphoblastic blast cells that provides shelter from chemotherapeutics.¹⁰ This unique attribute in addition to altered cellular immunophenotype may explain why our patient experienced optic nerve and choroidal recurrence with repeatedly normal CSF cytology. Furthermore, it is interesting that our patient developed a systemic relapse seven months after presenting with isolated ocular findings.

At times, establishing a diagnosis of leukaemic infiltration of the optic nerve and choroid can be difficult and will likely change the course of treatment. In cases with choroidal thickening or vitritis, one can consider vitreous or choroidal sampling. If the infiltration is posterior to the globe and involves the optic nerve, biopsy of this site may also be reasonable.¹⁰

Conclusion

This case demonstrates the possibility of ALL relapse isolated to the optic nerve and choroid in the absence of CNS involvement. To our knowledge, this represents the first case where the diagnosis of ALL recurrence was proven by choroidal biopsy, even though CSF and bone marrow analysis were unremarkable. The characteristics of the relapse clone were similar to the clone present initially at diagnosis at age 18, though with some immunophenotype alterations. ALL relapse isolated to the optic nerve and choroid is rare but should be considered in patients with histories of hematological malignancies. Prompt diagnosis and initiation of treatment can yield excellent visual recovery, prevent irreversible vision loss, and delay systemic relapse.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical approval

This case report was conducted in accordance with the Declaration of Helsinki. The collection and evaluation of all protected patient health information was performed in a Health Insurance Portability and Accountability Act (HIPAA)-compliant manner.

Statement of informed consent

Written informed consent was obtained from the subject included in our report, including permission for publication of all photographs and images included herein.