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Duodenal Neoplasms of Gastric Phenotype: An Immunohistochemical and Genetic Study With a Practical Approach to the Classification.

胃表型十二指肠肿瘤:免疫组织化学和遗传学研究及可操作性分类方案

Hida R,Yamamoto H,Hirahashi M,Kumagai R,Nishiyama K,Gi T,Esaki M,Kitazono T,Oda Y

Abstract

Duodenal neoplasm of gastric phenotype (DNGP) is very rare, and details of its histopathologic, genetic, and biological features are still unclear. Frequent gene mutations in GNAS, KRAS, and APC have been reported in pyloric gland adenomas and fundic gland-type neoplasms (initially reported as low-grade adenocarcinomas) of the stomach. Here we retrospectively analyzed 16 cases of extra-ampullary DNGP (benign to malignant), and we examined the mucin immunoprofile and oncogene mutations (GNAS, KRAS, APC, BRAF, and CTNNB1). The 16 DNGPs were histologically classified into adenomas (5 pyloric gland adenomas and 2 foveolar-type adenomas), neoplasms of uncertain malignant potential (NUMPs, n=6), and invasive adenocarcinomas (n=3). NUMPs consisted of slightly atypical epithelial cells with pale, eosinophilic, or basophilic cytoplasm growing in an anastomosing or branching glandular pattern, often with expansive submucosal extension. In contrast to invasive adenocarcinomas, NUMPs lacked significant nuclear irregularity, desmoplastic stromal reaction, lymphovascular invasion, and metastasis; their features were reminiscent of fundic gland-type neoplasms of the stomach. Immunophenotypically, most of NUMPs were predominantly positive for MUC6 with variable expressions of pepsinogen-I, HKATPase, human gastric mucin, and MUC5AC. Molecular analyses revealed the gene mutations of GNAS in 6 (38%) of 16 DNGPs (4 [57%] adenomas, 1 [16%] NUMP, and 1 [33%] invasive adenocarcinoma) and APC in 4 of 15 (27%) DNGPs: no adenomas, 2 (33%) NUMPs, and 2 (67%) invasive adenocarcinomas. BRAF mutation was present in only 1 (16%) NUMP, and KRAS and CTNNB1 mutations were absent. In conclusion, gastric-phenotype adenomas and NUMPs of the duodenum are similar to their counterparts of the stomach, in terms of histologic, genetic, and clinicopathologic features. We propose the term "NUMP" as an intermediate category between adenoma and definitely invasive adenocarcinoma. Our findings may provide novel insights into the classification of undescribed but distinctive duodenal tumors showing similarity to gastric-phenotype neoplasms of the stomach.

摘要

胃表型十二指肠肿瘤(DNGP)是非常罕见的,其详细的组织病理学、遗传和生物学特征仍不清楚。GNAS、KRAS及APC的基因突变在胃幽门腺腺瘤和胃底腺型肿瘤(起初被称为低级别腺癌)中均有报道。

此处,我们回顾性地分析了16例壶腹外DNGP(良性到恶性),并研究了粘蛋白的免疫表型和癌基因突变(GNAS、KRAS、BRAF、APC和CTNNB1)。这16例DNGPS在组织学上分为腺瘤(5例幽门腺腺瘤和2例小凹型腺瘤),恶性潜能不确定性肿瘤(NUMPS,n =6),浸润性腺癌(n=3)。NUMPS由具有淡染、嗜酸性或嗜碱性胞质的轻度非典型上皮细胞组成,此细胞呈现出吻合状或者分支状腺样生长,常向黏膜下扩展。与浸润性腺癌相比,NUMPS缺乏明显的核不规则、促结缔组织增生性间质反应、淋巴管及血管浸润以及转移;其特征与胃内胃底腺型肿瘤相似。免疫表型方面,大多数NUMPS主要为MUC-6阳性,部分地表达胃蛋白酶原-I,氢钾ATP酶、人胃粘蛋白,以及MUC5AC。分子生物学研究表明,16例DNGPS中6例出现GNAS基因突变(38%)(4例腺瘤[57%],1例NUMP[16%],1例浸润性腺癌[33%]);15例DNGP中APC基因突变的有4例(27%):腺瘤无突变,2例NUMPS(33%)和2例浸润性腺癌(67%);BRAF基因突变仅在1例NUMP(16%)中发现,而KRAS和CTNNB1突变并未发现。总之,十二指肠中胃表型腺瘤和NUMPS从组织学、遗传学和临床病理特征三方面均类似于胃中相应的肿瘤。我们提出,NUMP可以认为是腺瘤和确定性浸润腺癌之间的一个中间类别。有一些尚未描述的独特的十二指肠肿瘤与胃内胃表型肿瘤相似,我们的研究结果可能为这些肿瘤的分类提供新见解。

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