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

Abstract

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 beta-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 beta-catenin gene in both cases. Although intranuclear expression of beta-catenin by mutation of APC gene might contribute to carcinogenesis in our cases, the relationships among intranuclear expressions of beta-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.

Anaplerosis in cancer: Another step beyond the warburg effect

“…A further link between Wnt and pyruvate carboxylase is also suggested elsewhere, as intranuclear biotin-enriched particles containing PC and propionyl-CoA carboxylase (PCC) were found in gallbladder adenocarcinomas [83]. These accumulations could be dependent on β-catenin activation, which is the main downstream effector of the Wnt signaling activation.…”

The metabolic advantage of tumor cells

“…This source of OAA is abnormal, since Pcarb, another biotin-requiring enzyme, should have provided OAA. Tumors may indeed contain "morule inclusions" of biotin-enzyme [14] suggesting an inhibition of Pcarb, presumably a consequence of the maintained citrate synthase activity, and decrease of ketone bodies that normally stimulate Pcarb. The OAA coming via PEP carboxykinase and OAA coming from aspartate transamination or via malate dehydrogenase condenses with acetyl CoA, feeding the elevated tumoral citric acid condensation starting the Krebs cycle.…”

CD10 is a characteristic marker of tumours forming morules with biotin‐rich, optically clear nuclei that occur in different organs

“…1,4,8,9,11,12,15,17,[23][24][25][26]28,29,31,[33][34][35] In contrast, biotin-rich intranuclear inclusions (optically clear nuclei) without morules appear in pregnancyrelated endometria 31 and have also been reported in two cases of morule-lacking adenocarcinoma of the gallbladder recently published as a new category of 'neoplastic ⁄ non-morular' lesions. 36 Although intranuclear expression of b-catenin by mutation of CTNNB1 and ⁄ or APC genes might contribute to carcinogenesis in these tumours, the relationship among intranuclear expression of b-catenin, biotin, biotin-binding enzymes and intranuclear inclusions remains unclear. 31,36 The C-MV of papillary thyroid carcinoma represents the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma.…”

“…36 Although intranuclear expression of b-catenin by mutation of CTNNB1 and ⁄ or APC genes might contribute to carcinogenesis in these tumours, the relationship among intranuclear expression of b-catenin, biotin, biotin-binding enzymes and intranuclear inclusions remains unclear. 31,36 The C-MV of papillary thyroid carcinoma represents the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma. In addition to the germ-line mutations of the APC gene in familial cases of the C-MV, somatic APC mutations and ⁄ or mutations in the b-catenin gene 4 have also been described in this type of tumour.…”