Ruemmele Petra, Dietmaier Wolfgang, Terracciano Luigi, Tornillo Luigi, Bataille Frauke, Kaiser Annette, Wuensch Peter-Heinz, Heinmoeller Ernst, Homayounfar Kia, Luettges Jutta, Kloeppel Guenter, Sessa Fausto, Edmonston Tina Bocker, Schneider-Stock Regine, Klinkhammer-Schalke Monika, Pauer Armin, Schick Stefan, Hofstaedter Ferdinand, Baumhoer Daniel, Hartmann Arndt
Institute of Pathology, University of Regensburg, Regensburg, Germany.
Am J Surg Pathol. 2009 May;33(5):691-704. doi: 10.1097/PAS.0b013e3181983ef7.
The prevalence and development of microsatellite instability (MSI) and underlying mismatch repair (MMR) deficiency in the carcinogenesis of adenocarcinomas of the papilla of Vater and their precursor lesions are not well established. We analyzed 120 ampullary adenomas (31 pure adenomas and 89 carcinoma-associated adenomas) and 170 pure adenocarcinomas for MSI, immunohistochemical expression of MMR proteins and specific histopathologic features. The most common histologic subtype was intestinal (46.5%), followed by pancreatobiliary (23.5%), poorly differentiated adenocarcinomas (12.9%), intestinal-mucinous (8.2%), and invasive papillary carcinomas (5.3%). Eight of 89 adenomas (9%) and 15/144 carcinomas (10%) showed high microsatellite instability (MSI-H), 10/89 adenomas (11%) and 5/144 carcinomas (4%) showed low microsatellite instability (MSI-L), and 71/89 adenomas (80%) and 124/144 carcinomas (86%) were microsatellite stable (MSS). MSI analysis from carcinomas contiguous with an adenomatous component (n=54) exhibited concordant results in 6/8 (75%) MSI-H and 42/46 (91.3%) MSS tumors. Of 14 carcinomas with MSI-H, 7 showed loss of MLH1 and 5/6 (83%) MLH1 promoter methylation, and 2 carcinomas showed simultaneous loss of MSH2 and MSH6. Two carcinomas and 3 adenomas with MSI-H revealed exclusive loss of MSH6. MSI-H cancers were significantly associated with intestinal mucinous subtype (P<0.001), high tumor grade (P=0.003), expansive growth pattern (P=0.044), and marked lymphoid host response (P=0.004). Patients with MSI-H carcinoma had a significantly longer overall survival (P=0.0082) than those with MSI-L or MSS tumors. Our findings indicate that the MSI-phenotype is an early event, which develops at the stage of adenoma and is reliably detectable in the precursor lesion. The MMR deficient molecular pathway of carcinogenesis is associated with a histopathologic phenotype in ampullary cancer, similar to the one that has been well described in colon cancer.
在 Vater 壶腹腺癌及其前驱病变的致癌过程中，微卫星不稳定性（MSI）和潜在错配修复（MMR）缺陷的发生率及发展情况尚未完全明确。我们分析了 120 例壶腹腺瘤（31 例纯腺瘤和 89 例癌相关腺瘤）以及 170 例纯腺癌的 MSI、MMR 蛋白的免疫组化表达和特定组织病理学特征。最常见的组织学亚型为肠型（46.5%），其次是胰胆管型（23.5%）、低分化腺癌（12.9%）、肠黏液型（8.2%）和浸润性乳头状癌（5.3%）。89 例腺瘤中有 8 例（9%）和 144 例癌中有 15 例（10%）显示高微卫星不稳定性（MSI-H），89 例腺瘤中有 10 例（11%）和 144 例癌中有 5 例（4%）显示低微卫星不稳定性（MSI-L），89 例腺瘤中有 71 例（80%）和 144 例癌中有 124 例（86%）为微卫星稳定（MSS）。对与腺瘤成分相邻的癌（n = 54）进行的 MSI 分析显示，在 6/8（75%）MSI-H 和 42/46（91.3%）MSS 肿瘤中结果一致。在 14 例 MSI-H 的癌中，7 例显示 MLH1 缺失，5/6（83%）显示 MLH1 启动子甲基化，2 例癌显示 MSH2 和 MSH6 同时缺失。2 例癌和 3 例 MSI-H 的腺瘤显示 MSH6 单独缺失。MSI-H 癌与肠黏液亚型（P < 0.001）、高肿瘤分级（P = 0.003）、膨胀性生长模式（P = 0.044）和显著的淋巴细胞宿主反应（P = 0.004）显著相关。MSI-H 癌患者的总生存期明显长于 MSI-L 或 MSS 肿瘤患者（P = 0.0082）。我们的研究结果表明，MSI 表型是一个早期事件，在腺瘤阶段就已出现，并且在前驱病变中可可靠检测到。壶腹癌的 MMR 缺陷致癌分子途径与一种组织病理学表型相关，类似于在结肠癌中已得到充分描述的表型。
