Extranodal NK/T-cell lymphoma with isolated central nervous system relapse: A defiant disease and the role of flow cytometry in monitoring

Central nervous system (CNS) involvement in extranodal NK/T cell lymphoma (ENKTCL) is rare and confers a dismal prognosis. Though newer treatment modalities like L-asparaginase based chemotherapy, immunotherapy, and hematopoietic stem cell transplant (HSCT) have yielded encouraging results, treatment failure with relapse of primary disease continues to be a major a concern (Yamaguchi et al., 2018). Herein, we report a rare phenomenon of isolated CNS relapse in a patient with ENKTCL within 3 months of allogenic HSCT subsequent to SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) and nivolumab induced disease remission. Our patient, a 51-year-old male, was a known case of ENKTCL with simultaneous involvement of both nasal and right testes 1 year back. Initial diagnosis was made on histopathology and EBER in situ hybridization was positive on tissue sections. No signs or symptoms of CNS involvement was present at initial diagnosis and CSF was clear of any disease. He had undergone right sided orchiectomy and received six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with gemcitabine and prophylactic intrathecal methotrexate. He experienced a relapse 6 months into therapy with a left testicular hypoechoic mass lesion and required left sided orchiectomy. Subsequently, he was treated with low dose nivolumab and SMILE regimen for six cycles and achieved remission. This was followed by allo-HSCT after a 10/10 HLA match with his blood brother. The initial 2 months post-transplant time period was uneventful and chimerism was 100%. On day 62 of post allo-HSCT, he presented to our outpatient department with complaints of headache since last 4 days, blurring of vision in the right eye and difficulty in chewing solid food. Physical examination revealed diminished distant vision in the right eye, weakness in the left side of face, altered taste sensation and dysarthria in speech. MRI of brain and orbits showed borderline enhancement of bilateral optic nerves at optic disc level along with right facial and trigeminal nerve enhancement. Laboratory investigation showed normal complete blood counts with no atypical cells on peripheral smear. CSF cell count on was 15 cells/μL and biochemistry showed high protein (138 mg/dL) and low sugar (26 mg/dL) levels. Meningitis panel through multiplex PCR for viral, bacterial, and parasitic infection was negative; however, the panel did not include EBV target. Though CSF cytology was suspicious, a definite opinion could not be furnished due to scant number of cells and in the absence of obvious atypia. But, flow cytometry immunophenotyping (FCMI) through stain-no lyse-no wash technique on CSF revealed an abnormal NK cell population with CD45 bright, surfaceCD3 , CD7 , CD56 bright+, CD16 , CD2dim+, CD4 , CD8 , CD5 (Figure 1a–e) confirming CNS relapse of the primary disease. PET scan did not show any other lesion elsewhere in the body and bone marrow examination was unremarkable. On quantitative PCR on peripheral blood, target EBV DNA was detected, though the values were below the lower limit of linear range of the assay that is, <316 copies/mL. Finally, a diagnosis of isolated CNS relapse of NK cell lymphoma was provided and he was started on high-dose methotrexate. On day 45 follow-up of CNS relapse, there was mild improvement of vision in right eye, however bilateral facial weakness and speech dysarthria were still present. Though CSF cytology was negative for malignant cells, FCMI showed persistent disease (Figure 1f–m). The last follow up was on day 154 of posttransplant and our patient was alive with alleviating CNS symptoms. CSF examination was acellular on cytology and FCMI showed 11 viable events consisting of normal mature T cells only. ENKTCL is prevalent in Asian and South American populations with highest incidences in Southeast Asian countries. Though predominantly a locally invasive tumor through angiodestruction, disseminated disease at presentation or during the disease is not uncommon. CNS involvement is rare and mostly seen during relapse of the disease, though involvement at initial presentation has been reported in few cases (Yamaguchi et al., 2018). Factors like extra nasal involvement at diagnosis, Ann Arbor stage III/IV, and advanced NK cell lymphoma prognostic index have attributed to increase the risk of CNS involvement or relapse. The widely used scoring system prognostic index of natural killer lymphoma-EBV (PINK-E) includes age, Ann Arbor stage, nonnasal primary localization, distal lymph node involvement and detectable plasma EBV DNA as individual parameters. In the current case, the patient had unilateral testicular involvement at primary diagnosis, was Ann Arbor stage IV as well as EBV positive and belonged to PINK-E high risk category. Despite the fact that our patient's CSF biochemistry and pleocytosis initially mirrored the symptoms of bacterial or tubercular meningitis, both of them were disregarded by multiplex PCR. Furthermore, hypoglycorrhachia and increased CSF protein levels have been shown to be related to a significant proportion of primary as well as secondary CNS lymphomas. Particularly, a persistently low sugar level in the CSF should suggest a diagnosis other than an infectious etiology. Traditionally, Epstein Barr virus subtype A has been linked to pathogenesis of these lymphoma Received: 6 December 2022 Revised: 16 April 2023 Accepted: 25 April 2023