Re-evaluating archival specimens as a pathologic diagnostic resource for neuronal intranuclear inclusion disease.

Abstract

Neuronal intranuclear inclusion disease (NIID) is a multisystem neurodegenerative disorder caused by GGC repeat expansions in the NOTCH2NLC gene. Although genetic testing has improved diagnostic efficiency, histopathologic confirmation remains essential. We investigated whether routine archival surgical specimens could serve as an alternative pathologic resource for NIID diagnosis. We retrospectively analyzed archival formalin-fixed, paraffin-embedded specimens from patients with genetically confirmed NIID, including gastric antrum, colon, gallbladder, prostate, and kidney tissues. Hematoxylin-eosin staining and immunofluorescence for p62 and uN2CpolyG were performed to identify characteristic intranuclear inclusions. Histopathologic evaluation was conducted in a blinded manner and compared with non-neurologic control tissues. Characteristic eosinophilic intranuclear inclusions positive for p62 and uN2CpolyG were detected in all NIID archival specimens but not in control tissues. These inclusions were consistently identified across gastrointestinal and urogenital tissues, including small endoscopic biopsy samples. Ultrastructural examination further demonstrated dense filamentous intranuclear material in gastric tissue. Notably, inclusions were preferentially localized to fibroblasts and smooth muscle cells within the lamina propria and muscularis mucosae, whereas epithelial cells were consistently spared. Detection was not apparently affected by tissue type or storage duration. Routine archival surgical specimens may provide a readily available pathologic resource that avoids additional invasive biopsy for confirming NIID. Their consistent cellular distribution pattern may also facilitate recognition of diagnostic inclusions in routine pathology practice.