Leptomeningeal relapse in primary cutaneous DLBCL: Implications for a prophylactic CNS therapy

Abstract Background Isolated leptomeningeal relapse in a case of cutaneous lymphoma is an uncommon event more so in a case of primary cutaneous diffuse large B‐cell lymphoma (PCDLBCL). This phenomenon is of great significance as the subsequent prognosis becomes poor and the prophylactic central nervous system (CNS) therapy if administered, can reduce the chances of relapse, however, the survival benefit remains uncertain. The role of prophylactic CNS therapy is not well defined in the case of PCDLBCL. Case We report a case of PCDLBCL leg type with a low CNS International Prognostic Index (CNS‐IPI) risk, who developed isolated leptomeningeal relapse in the form of bilateral facial nerve palsy. He was managed by 2nd line chemotherapy and CNS directed therapy and achieved complete remission. Conclusion PCDLBCL leg type is an aggressive malignancy. Molecular/genomic mechanism likely responsible for CNS dissemination should be identified by prospective multi‐centric studies that can better define the subsets of patients eligible for prophylactic therapy in the absence of a high CNS‐IPI risk.

The disease is rapidly progressive, and the outcomes are poor with the standard treatment protocols. We present a case of PCDLBCL leg type, who developed isolated leptomeningeal relapse during the course of treatment. The patient was planned for R-CHOP protocol chemo-immunotherapy. CNS prophylaxis was not given because of low CNS-IPI risk.

| CASE
He received 4 cycles of chemotherapy without any untoward incident.
A PET-CT done on day 14 post fourth cycle, was suggestive of partial metabolic as well as a morphological response. Further, 2 cycles were advised.
He reported to us 2 days before the 5th cycle with a 3-days history of headache, inability to close the eyes, and drooling of liquids from both angles of the mouth ( Figure 1). On examination, he had bilateral lower motor neuron facial nerve palsy. Zubrod PS was preserved. The rest of the clinical examination was non-contributory.
Contrast-enhanced magnetic resonance imaging of the brain was negative for any intra-cranial lesion and leptomeningeal enhancement.
Complete blood counts, metabolic panel, liver function, kidney function, and coagulation studies were normal. He was admitted to the day-care and a diagnostic lumbar puncture was done, and cerebrospinal fluid examination (CSF) was ordered. CSF examination revealed elevated proteins (139 mg/dL) and increased total cell count (140/μL) with a lymphocytic predominance. Infiltration by atypical lymphoid cells was seen, ruling a diagnosis of leptomeningeal metastasis from PCDLBCL, leg type ( Figure 2).  Among the specific extranodal sites, only the kidney or adrenal gland involvement was significantly associated with CNS relapse or relapse.

| OUTCOME
Skin involvement was not included in the analysis as only a few events were reported, and details were missing. 5 An international multicentre study of 1532 patients treated with chemoimmunotherapy identified secondary CNS involvement in only 62(4%) patients. In this study, disease stage III/IV, elevated serum LDH, kidney/adrenal, and uterine/ testicular involvement were independently associated with secondary CNS involvement. 6 However, the Involvement of the skin significantly increased the risk of CNS disease in the German High-Grader Non-Hodgkin Lymphoma Study Group and the MAbThera International Trial (DSHNHL/MInT) data. 7,8 British Committee for the standards in hematology recommend prophylaxis for those with elevated LDH and >1 extranodal site, or with testicular, breast, or epidural involvement. 9 Similarly, the Spanish Lymphoma Group recommends CNS prophylaxis for high CNS-IPI, double-hit lymphoma, and the involvement of the kidney or adrenal gland without mentioning cutaneous lymphoma. 10 PCDLBCL leg type is an uncommon, aggressive malignancy, and CNS relapse has been a rare event. Gardette et al and Bekkenk et al identified CNS relapse only in 3.7% and 4.5% of the cases of PCDLBCL leg type, respectively. Patients with PCDLBCL leg type died more frequently due to the involvement of non-CNS organ systems. CNS prophylaxis is hence, not recommended due to the paucity of data and rarity of CNS involvement. 11,12 5 | CONCLUSION PCDLBCL leg type is an aggressive malignancy. CNS relapse is a rare event and currently, it is debatable to recommend prophylactic CNS therapy in the absence of a high CNS-IPI score. Since it is an uncommon malignancy, molecular/genomic mechanism likely responsible for CNS dissemination should be identified by prospective multi-centric studies that can better define the subsets of patients eligible for prophylactic therapy as well as the survival benefit.

CONFLICT OF INTEREST
The authors declare that they do not have any conflicts of interest.

AUTHOR CONTRIBUTIONS
D.S. and L.A. collected and interpreted the data. D.S., A.S., and M.W. prepared the manuscript. A.S. and L.A. were involved in patient management. All authors read and approved the final manuscript.

ETHICS STATEMENT
Approval was taken from the Institutional Ethics Committee and the patient for publication of this report.

DATA AVAILABILITY STATEMENT
Data available on request from the authors.