胃と腸51巻12号

2016年11月発行

今月の主題 十二指腸の上皮性腫瘍 主題研究

十二指腸の腫瘍様病変と上皮性腫瘍におけるGNAS遺伝子解析

著者： 松原亜季子¹ 九嶋亮治² 鈴木晴久³ 小田一郎³ 津田均¹ 関根茂樹⁴

所属機関： ¹防衛医科大学校病態病理学講座 ²滋賀医科大学医学部臨床検査医学講座（附属病院病理診断科） ³国立がん研究センター中央病院内視鏡科 ⁴国立がん研究センター中央病院病理科

ページ範囲：P.1603 - P.1612

要旨●十二指腸に発生する良性上皮性病変と腫瘍に対して，GNAS，KRAS，BRAF遺伝子変異検索を行った．良性病変については臨床病理学的事項についても検討した．胃腺窩上皮化生，異所性胃粘膜，幽門腺腺腫，腸型腺腫，腺癌はGNAS変異をそれぞれ41％，28％，92％，0％，17％に認め，KRAS変異をそれぞれ26％，2％，42％，20％，37％に認めた．BRAFは胃腺窩上皮化生の1例のみ変異を認めた．異所性胃粘膜3例で，胃腺窩上皮化生部分と胃底腺部分で共通のGNAS変異が認められた．腺癌に対する免疫染色では，GNAS変異陽性例ではMUC5ACが有意に強陽性を示し，CDX2が陰性もしくは弱陽性となる傾向を示した．以上より，十二指腸の胃腺窩上皮化生や異所性胃粘膜が幽門腺腺腫や腺癌の前駆病変である可能性が改めて示唆された．

参考文献

1）Shepherd NA, Carr NJ, Howe JR, et al. Carcinoma of the small intestine. Bosman FT, Carneiro F, Hruban RH（eds）. WHO classification of tumours of the digestive system 4th ed. International Agency for Research on Cancer, Lyon, pp96-101, 2010

2）九嶋亮治．十二指腸・小腸．中村眞一（編）．消化管病理標本の読み方，改訂2版．日本メディカルセンター，pp81-104, 2008

3）Genta RM, Kinsey RS, Singhal A, et al. Gastric foveolar metaplasia and gastric heterotopia in the duodenum：no evidence of an etiologic role for Helicobacter pylori. Hum Pathol 41：1593-1600, 2010

4）Montgomery EA, Voltaggio L. Biopsy interpretation of the gastrointestinal tract mucosa Volume 1：Non-neoplastic, 2nd ed. Lippincott Williams & Wilkins, Philadelphia, pp119-120, 2011

5）岩下明德．腸管─非腫瘍性疾患．向井清，真鍋俊明，深山正久（編）．外科病理学，4版．文光堂，p507, 2006

6）Terada T. Heterotopic gastric mucosa of the gastrointestinal tract：a histopathologic study of 158 cases. Pathol Res Pract 207：148-150, 2011

7）田中三千雄，岩井久和．胃上皮化生によるポリープと異所性胃粘膜によるポリープ─その鑑別を中心に．消内視鏡 27：124-132, 2015

8）Wolf EM, Kushima R, Vieth M, et al. Adenocarcinoma with eosinophilic cells with non-overlapping low-grade nuclei arising from heterotopic gastric mucosa in the duodenal bulb：a new tumour entity? Virchows Arch 456：723-725, 2010

9）Sakurai T, Sakashita H, Honjo G, et al. Gastric foveolar metaplasia with dysplastic changes in Brunner gland hyperplasia：possible precursor lesions for Brunner gland adenocarcinoma. Am J Surg Pathol 29：1442-1448, 2005

10）Kushima R, Stolte M, Dirks K, et al. Gastric-type adenocarcinoma of the duodenal second portion histogenetically associated with hyperplasia and gastric-foveolar metaplasia of Brunner's glands. Virchows Arch 440：655-659, 2002

11）Kushima R, Rüthlein HJ, Stolte M, et al.‘Pyloric gland-type adenoma'arising in heterotopic gastric mucosa of the duodenum, with dysplastic progression of the gastric type. Virchows Arch 435：452-457, 1999

12）Landis CA, Masters SB, Spada A, et al. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340：692-696, 1989

13）Lyons J, Landis CA, Harsh G, et al. Two G protein oncogenes in human endocrine tumors. Science 249：655-659, 1990

14）Freda PU, Chung WK, Matsuoka N, et al. Analysis of GNAS mutations in 60 growth hormone secreting pituitary tumors：correlation with clinical and pathological characteristics and surgical outcome based on highly sensitive GH and IGF-I criteria for remission. Pituitary 10：275-282, 2007

15）Riminucci M, Liu B, Corsi A, et al. The histopathology of fibrous dysplasia of bone in patients with activating mutations of the Gs alpha gene：site-specific patterns and recurrent histological hallmarks. J Pathol 187：249-258, 1999

16）Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med 3：92ra66, 2011

17）Furukawa T, Kuboki Y, Tanji E, et al. Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. Sci Rep 1：161, 2011

18）Matsubara A, Sekine S, Kushima R, et al. Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum. J Pathol 229：579-587, 2013

19）Matsubara A, Ogawa R, Suzuki H, et al. Activating GNAS and KRAS mutations in gastric foveolar metaplasia, gastric heterotopia, and adenocarcinoma of the duodenum. Br J Cancer 112：1398-1404, 2015

20）Yamada M, Sekine S, Ogawa R, et al. Frequent activating GNAS mutations in villous adenoma of the colorectum. J Pathol 228：113-118, 2012

21）Nishikawa G, Sekine S, Ogawa R, et al. Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms. Br J Cancer 108：951-958, 2013

22）Nomura R, Saito T, Mitomi H, et al. GNAS mutation as an alternative mechanism of activation of the Wnt/β-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type. Hum Pathol 45：2488-2496, 2014

23）Matsubara A, Sekine S, Ogawa R, et al. Lobular endocervical glandular hyperplasia is a neoplastic entity with frequent activating GNAS mutation. Am J Surg Pathol 38：370-376, 2014

24）Ushiku T, Amason T, Fukayama M, et al. Extra-ampullary duodenal adenocarcinoma. Am J Surg Pathol 38：1484-1493, 2014

25）Lessells AM, Martin DF. Heterotopic gastric mucosa in the duodenum. J Clin Pathol 35：591-595, 1982

26）Sarbia M, Sauer G, Karimi D, et al. Foveolar Gastric Metaplasia of the Duodenum：A Frequent, so far Neglected Type of Duodenal Polyp. Z Gastroenterol 52：348-350, 2014

27）Hashimoto T, Sekine S, Matsubara A, et al. Frequent presence of gastric-type epithelial cells in the duodenal bulb：an immunohistochemical study. Pathol Int 64：631-633, 2014