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 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.
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References
Brabletz T, Herrmann K, Jung A, Faller G, Kirchner T (2000) Expression of nuclear β-catenin and c-myc is correlated with tumor size but not with proliferative activity of colorectal adenomas. Am J Pathol 156:865–870
Cadigan KM, Nusse R (1997) Wnt signaling: a common theme in animal development. Genes Dev 11:3286–3305
Cameselle-Teijeiro J, Chan JKC (1999) Cribriform-morular variant of papillary carcinoma: a distinctive variant representing the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma? Mod Pathol 12:400–411
Cameselle-Teijierio J, Ruiz-Ponte C, Loidi L, Suarez-Penaranda J, Baltar J, Sobrinho-Simoes M (2001) Somatic but not germline mutation of the APC gene in a case of cribriform-morular variant of papillary thyroid carcinoma. Am J Clin Pathol 115:486–493
Dakshinamurti K, Mistry SP (1963) Tissue and intracellular distribution of biotin-COOH in rats and chicks. J Biol Chem 238:294–296
Gamachi A, Kashima K, Daa T, Nakatani Y, Tsujimoto M, Yokoyama S (2003) Aberrant intranuclear localization of Biotin, Biotin-binding enzymes and β-Catenin in pregnancy-related endometrium and morule-associated neoplastic lesions. Mod Pathol 16:1124–1131
Gamallo C, Palacios J, Moreno G, Calvo de Mora J, Suarez A, Armas A (1999) β-Catenin expression pattern in stage I and II ovarian carcinomas. Relationship with β-catenin gene mutations, clinicopathological features, and clinical outcome. Am J Pathol 155:527–536
Lu CS, Kashima K, Daa T, Yokoyama S, Yanagisawa S, Nakayama I (2000) Immunohistochemical study of the distribution of endogenous biotin and biotin-binding enzymes in ductal structures of salivary gland tumors. J Oral Pathol Med 29:445–451
Mazur MT, Hendrickson MR, Kempson RL (1983) Optically clear nuclei: an alteration of endometrial endometrium in the presence of trophoblast. Am J Surg Pathol 7:415–423
Nakatani Y, Kitamura H, Inayama Y, Ogawa N (1994) Pulmonary endodermal tumor resembling fetal lung: the optically clear nucleus is rich in biotin. Am J Surg Pathol 18:637–642
Nakatani Y, Masudo K, Miyagi Y, Inayama Y, Kawano N, Tanaka Y, Kato K, Ito T, Kitamura H, Nagashima Y, Yamanaka S, Nakamura N, Sano J, Ogawa N, Ishiwa N, Notohara K, Resl M, Mark EJ (2002) Aberrant nuclear localization and gene mutation of β-catenin in low-grade adenocarcinoma of fetal lung type: up-regulation of the Wnt signaling pathway may be a common dominator for the development of tumors that form morules. Mod Pathol 15:617–624
Nakatani Y, Masudo K, Nozawa A, Inayama Y, Yamanaka S, Ito T, Kitamura H, Notohara K, Kashima K, Yokoyama S, Tsujimoto M, Tamai S, Abe Y, Resl M, Mark EJ (2004) Biotin-rich, optically clear nuclei express estrogen receptor-β: tumors with morules may develop under the influence of estrogen and aberrant β-catenin expression. Hum Pathol 35:869–874
Okamoto Y, Kashima K, Daa T, Yokoyama S, Nakayama I, Noguchi S (1995) Morule with biotin-containing intranuclear inclusions in thyroid carcinoma. Pathol Int 45:573–579
Saegusa M, Okayasu I (2001) Frequent nuclear β-catenin accumulation and associated mutations in endometrioid-type endometrial and ovarian carcinomas with squamous differentiation. J Pathol 194:59–67
Sasaki A, Yokoyama S, Arita T, Inomata M, Kashima K, Nakayama I (1999) Morules with biotin-containing optically clear nuclei in colonic tubular adenoma. Am J Surg Pathol 23:336–341
Sato T, Kashima K, Gamachi A, Daa T, Nakayama I, Yokoyama S (2002) Immunohistochemical localization of pyruvate carboxylase and carbamyl-phosphate synthetase I in normal and neoplastic human pancreatic tissues. Pancreas 25:130–135
Sickel JZ, disant’Agenese PA (1994) Anomalous immunostaining of “optically clear” nuclei in gestational endometrium: a potential pitfall in the diagnosis of pregnancy-related herpes virus infection. Arch Pathol Lab Med 118:831–833
Tanaka Y, Ijiri R, Yamanaka S, Kato K, Nishihara H, Nishi T, Misugi K (1998) Pancreatoblastoma: optically clear nuclei in squamoid corpuscles are rich in biotin. Mod Pathol 11:945–949
Tanaka Y, Kato K, Notohara K, Nakatani Y, Miyake T, Ijiri R, Nishimata S, Ishida Y, Kigasawa H, Ohama Y, Tsukayama C, Kobayashi Y, Horie H (2003) Significance of aberrant (cytoplasmic/nuclear) expression of beta-catenin in pancreatoblastoma. J Pathol 199:185–190
Tetsu O, McCormick F (1999) β-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature (London) 398:422–426
Tujimoto M, Noguchi M, Taki I (1991) Immunohistochemical and electron microscopic study of the intranuclear inclusion bodies containing biotin in the ovarian endometrioid carcinoma. J Clin Electron Microsc 24:5–6
Yanagisawa N, Mikami T, Saegusa M, Okayasu I (2001) More frequent β-catenin exon 3 mutations in gallbladder adenoma than in carcinomas indicate different lineages. Cancer Res 61:19–22
Yokoyama S, Kashima K, Inoue S, Daa T, Nakayama I, Moriuchi A (1993) Biotin-containing intranuclear inclusions in endometrial glands during gestation and puerperium. Am J Clin Pathol 99:13–17
Wood GS, Warnke R (1981) Suppression of endogenous avidin-binding activity in tissues and its relevance to biotin-avidin detection systems. J Histochem Cytochem 29:1196–1204
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The authors thank Ms. M. Hisaka, Ms. F. Kawamura, Mr. S. Yano, Ms. T. Nakamatsu and Ms. E. Katsuki for their skilled technical assistance.
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Kimura, Y., Kashima, K., Daa, T. et al. Biotin-rich intranuclear inclusions in morule-lacking adenocarcinoma of the gallbladder: a new category of “neoplastic/non-morular” lesions. Virchows Arch 446, 194–199 (2005). https://doi.org/10.1007/s00428-004-1161-7
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DOI: https://doi.org/10.1007/s00428-004-1161-7