Xu Bing, Yoshimoto Katsuhiko, Miyauchi Akira, Kuma Seiji, Mizusawa Noriko, Hirokawa Mitsuyoshi, Sano Toshiaki
Department of Pathology, University of Tokushima School of Medicine, Tokushima 770-8503, Japan.
J Pathol. 2003 Jan;199(1):58-67. doi: 10.1002/path.1225.
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.
筛状桑葚样变异型（C-MV）是甲状腺乳头状癌（PTC）一种罕见且特殊的亚型，在家族性腺瘤性息肉病（FAP）相关的甲状腺癌以及散发性甲状腺癌中均有频繁发现。本文报道了5例诊断为PTC的C-MV的年轻女性，癌症诊断时年龄为22 - 34岁；其中2例患有轻度FAP。大体上，1例FAP相关肿瘤和1例散发性肿瘤为多中心性，其他为单发性。组织学上，肿瘤有包膜，呈现筛状、滤泡状、小梁状、实性和乳头状生长模式的组合，并伴有桑葚样区域。免疫组化方面，肿瘤细胞显示甲状腺球蛋白、神经元特异性烯醇化酶、上皮膜抗原、高分子量和低分子量细胞角蛋白、波形蛋白和bcl-2蛋白的细胞质表达；雌激素和孕激素受体以及视网膜母细胞瘤蛋白的核表达；以及β-连环蛋白的细胞质和核内积聚。在4例受试者（包括2例FAP个体）中使用蛋白质截短试验研究了腺瘤性息肉病 coli（APC）基因的胚系突变。仅在1例患有多中心性PTC的C-MV的FAP患者中鉴定出胚系APC突变，该患者第512密码子处有一个胸腺嘧啶缺失，导致移码，产生一个过早的终止密码子。在这4例患者的肿瘤组织中未检测到靠近APC基因位点的杂合性缺失。β-连环蛋白基因（CTNNB1）第3外显子的体细胞突变分析显示，所有5例个体的7个肿瘤中存在改变：1个在丝氨酸残基（第29密码子），3个在与丝氨酸或苏氨酸残基相邻的氨基酸处（第22、39和44密码子），3个在其他氨基酸处（第49、54和56密码子）。此外，从2例患有多中心性PTC的C-MV的患者中检查的2个不同肿瘤，每个都有CTNNB1基因的不同体细胞突变。综上所述，这些数据表明突变型β-连环蛋白的积累有助于PTC的C-MV的发生发展。
