title: Cribriform-morular variant of papillary thyroid carcinoma: a pathological and molecular genetic study with evidence of frequent somatic mutations in exon 3 of the beta-catenin gene.
abstract: The cribriform-morular variant (C-MV), an unusual and peculiar subtype of papillary thyroid carcinoma (PTC), has been observed frequently in familial adenomatous polyposis (FAP)-associated thyroid carcinoma and also in sporadic thyroid carcinoma. In this paper, five young women with the C-MV of PTC, aged 22-34 years at cancer diagnosis, are reported; two of them had attenuated FAP. Grossly, one FAP-associated tumour and one sporadic tumour were multicentric and the others were solitary. Histologically, the tumours were encapsulated and exhibited a combination of cribriform, follicular, trabecular, solid, and papillary patterns of growth, with morular areas. Immunohistochemically, the tumour cells showed cytoplasmic expression of thyroglobulin, neuron-specific enolase, epithelial membrane antigen, high- and low-molecular-weight cytokeratins, vimentin, and bcl-2 protein; nuclear expression of oestrogen and progesterone receptors, and retinoblastoma protein; and cytoplasmic and nuclear accumulation of beta-catenin. Germline mutations of the adenomatous polyposis coli (APC) gene were investigated using the protein truncation test in four subjects, including two FAP individuals. Germline APC mutation was identified in only one FAP patient with the multicentric C-MV of PTC, who had a thymidine deletion at codon 512, resulting in a frameshift leading to a premature stop codon. No loss of heterozygosity of loci close to the APC gene was detected in tumour tissues from these four patients. Somatic mutation analysis of exon 3 of the beta-catenin gene (CTNNB1) revealed alterations in seven tumours from all five individuals: one at a serine residue (codon 29), three at amino acids adjacent to serine or threonine residues (codons 22, 39, and 44), and three at other amino acids (codons 49, 54, and 56). Moreover, each of two different tumours examined from two patients with the multicentric C-MV of PTC, had different somatic mutations of the CTNNB1 gene. Taken together, these data suggest that accumulation of mutant beta-catenin contributes to the development of the C-MV of PTC.
authors.affiliation: Department of Pathology, University of Tokushima School of Medicine, Tokushima 770-8503, Japan. xubing@basic.med.tokushima-u.ac.jp
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Akira
authors.initials: A
authors.lastname: Miyauchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kuma
authors.forename: Noriko
authors.initials: N
authors.lastname: Mizusawa
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Hirokawa
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sano
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000150:complications / Q000235:genetics / Q000473:pathology*; D011125:Adenomatous Polyposis Coli / Q000150:complications / Q000473:pathology; D000328:Adult; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D013961:Thyroid Gland / Q000473:pathology; D013964:Thyroid Neoplasms / Q000150:complications / Q000235:genetics / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics*; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin