Biotin-rich intranuclear inclusions in morule-lacking adenocarcinoma of the gallbladder: a new category of “neoplastic/non-morular” lesions

Biotin-rich intranuclear inclusions, also called “optically clear nuclei,” are observed in various neoplastic and non-neoplastic lesions, including pregnancy-related endometrium and benign and malignant neoplasms with morular structures. A recent study reported that lesions with biotin-rich intranuclear inclusions can be classified as “(non-neoplastic) pregnancy-related endometrial” and as “(neoplastic) morular” category. In the present report, we describe two cases of well-differentiated adenocarcinoma of the gallbladder in which biotin-rich intranuclear inclusions were found without morular structures. Immunohistochemically, as reported previously, the intranuclear inclusions were positive for biotin and two biotin-binding enzymes (pyruvic acid carboxylase and propionyl CoA carboxylase). Intranuclear expression of β-catenin was also observed in neoplastic cells with and without intranuclear inclusion. We also detected a frame shift mutation of APC gene in one case but no mutation of β-catenin gene in both cases. Although intranuclear expression of β-catenin by mutation of APC gene might contribute to carcinogenesis in our cases, the relationships among intranuclear expressions of β-catenin, biotin, biotin-binding enzymes and intranuclear inclusions remain unclear. Our cases are the first neoplastic lesions with biotin-rich intranuclear inclusions that lacked morular structures. We propose a new “neoplastic/non-morular” category for lesions with biotin-rich intranuclear inclusions.