Case Report: Isolated leptomeningeal relapse after systemic control in PALB2-altered pancreatic cancer

Leptomeningeal metastasis (LM) is an uncommon manifestation of pancreatic ductal adenocarcinoma (PDAC) and has a median survival of only 1-2 months after diagnosis. Isolated LM after prolonged extracranial disease control is particularly rare and may be overlooked when systemic imaging results look stable.

We describe a 51-year-old man with metastatic PDAC who initially received a treatment regimen comprising KN046 and gemcitabine and nab-paclitaxel, followed by a prolonged course of folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), and subsequently underwent conversion surgery with a pathological complete response (ypT0N0, R0). Several months after completing adjuvant FOLFIRINOX, the patient developed a new right lower limb weakness. Brain MRI and cerebrospinal fluid (CSF) cytology results confirmed the presence of isolated LM, but there was no evidence of active extracranial disease. CSF sequencing identified Kirsten rat sarcoma viral oncogene homolog G12D, an AT-rich interaction domain 1A frameshift alteration, and a truncating partner and localizer of BRCA2 p.L920* alteration involving the homologous recombination repair (HRR) pathway. Then, the patient underwent ventriculoperitoneal shunt and Ommaya reservoir placement, followed by treatment with serial intrathecal methotrexate plus dexamethasone and systemic toripalimab with bevacizumab. This multimodal approach was followed by temporary neurological stabilization, but the disease eventually progressed. He survived approximately 30 months since the initial PDAC diagnosis and 3.5 months after LM diagnosis.

Together with our review of 29 published PDAC-LM cases, this report suggests two recurring clinical patterns: fulminant presentation at/or near initial diagnosis and delayed central nervous system (CNS) relapse after prolonged systemic disease control. The repeated detection of Fanconi anemia/homologous recombination repair pathway alterations in several genomically characterized cases gives rise to the possibility that treatment-responsive, HRR pathway-altered PDAC may survive long enough for CNS sanctuary relapse to become clinically apparent. CSF genomic profiling may help characterize rare CNS relapse in molecularly defined PDAC, and new neurological symptoms in long-surviving patients warrant prompt evaluation even when extracranial disease appears controlled.