胃と腸45巻11号

2010年10月発行

今月の主題 大腸低分化腺癌の初期像とその進展 主題

大腸低分化腺癌の腫瘍発生と分子異常

著者： 菅井有¹ 上杉憲幸¹ 幅野渉² 小西康弘¹ 無江良晴¹ 鈴木正通¹ 大塚幸喜³ 若林剛³ 千葉俊美⁴ 鈴木一幸⁴

所属機関： ¹岩手医科大学医学部病理学講座分子診断病理学分野 ²岩手医科大学薬学部薬物代謝動態学講座 ³岩手医科大学医学部外科学講座 ⁴岩手医科大学医学部内科学講座消化器肝臓内科分野

ページ範囲：P.1734 - P.1748

要旨　目的：大腸低分化腺癌の臨床病理学的，分子病理学的検討を行った．対象と方法：低分化腺癌42例，分化型腺癌57例を用いた．低分化腺癌は，大胞巣型，小胞巣型，索状型，に分類した．低分化腺癌は分化型成分と低分化成分に分けて解析を行った（32/42例）．腫瘍細胞の粘液形質，p53，Ki-67，β- catenin，MLH1およびMSH2の発現は免疫組織化学的に行った．Ki-rasおよびBRAF変異解析はパイロシークエンス法で解析した．MSIはPCR-microsatellite法を用いて行った．結果：各低分化腺癌はリンパ管侵襲像の頻度が高く，小胞巣型は静脈侵襲像の頻度が高かった．p53過剰発現は分化型腺癌と比較して差がなかった．大胞巣型ではKi-ras変異の頻度が低かったが，BRAF変異は高い傾向があった．MSIは大胞巣型で頻度が高かったが，索状型にはみられなかった．結語：低分化腺癌は分化型腺癌を経由して発生することが多いが，臨床病理学的，分子病理学的にも異なっていた．

参考文献

1）佐藤美信，丸田守人，前田耕太郎，他．大腸低分化腺癌の臨床病理学的検討．日臨外会誌 59 : 1214-1221, 1998

2）神野正博，坂本浩也，月岡雄治，他．大腸低分化腺癌の臨床病理学的検討．日本大腸肛門病会誌 45 : 244-247, 1992

3）田中千凱，木下裕夫，深田代造，他．大腸低分化腺癌の臨床病理学的検討．日臨外医会誌 53 : 313-317, 1992

4）Japanese Society for Cancer of the Colon and Rectum. Japanese Classification of Colorectal Carcinoma, First English Edition. Kanehara Co., pp 30-63, 1997

5）Arai T, Esaki Y, Sawabe M, et al. Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly. Mod Pathol 17 : 172-179, 2004

6）Hinoi T, Tani M, Lucas PC, et al. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol 159 : 2239-2248, 2001

7）Lanza G, Gaf・R, Maestri I, et al. Immunohistochemical pattern of MLH1/MSH2 expression is related to clinical and pathological features in colorectal adenocarcinomas with microsatellite instability. Mod Pathol 15 : 741-749, 2002

8）Winn B, Tavares R, Fanion J, et al. Differentiating the undifferentiated : immunohistochemical profile of medullary carcinoma of the colon with an emphasis on intestinal differentiation. Hum Pathol 40 : 398-404, 2009

9）Rüschoff J, Dietmaier W, Lüttges J, et al. Poorly differentiated colonic adenocarcinoma, medullary type : clinical, phenotypic, and molecular characteristics. Am J Pathol 150 : 1815-1825, 1997

10）Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature 386 : 623-627, 1997

11）Shen L, Toyota M, Kondo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A 104 : 18654-18659, 2007

12）Ogino S, Goel A. Molecular classification and correlates in colorectal cancer. J Mol Diagn 10 : 13-27, 2008

13）Jass JR, Whitehall VL, Young J, et al. Emerging concepts in colorectal neoplasia. Gastroenterology 123 : 862-876, 2002

14）Sugai T, Habano W, Uesugi N, et al. Three independent genetic profiles based on mucin expression in early differentiated-type gastric cancers - a new concept of genetic carcinogenesis of early differentiated-type adenocarcinomas. Mod Pathol 17 : 1223-1234, 2004

15）Sugai T, Tsukahara M, Endoh M, et al. Analysis of cell cycle-related proteins in gastric intramucosal differentiated-type cancers based on mucin phenotypes : a new concept of molecular carcinogenesis for early differentiated-type gastric cancers. BMC Gastroenterology, in press

16）Yao T, Tsutsumi S, Akaiwa Y, et al. Phenotypic expression of colorectal adenocarcinomas with reference to tumor development and biological behavior. Jpn J Cancer Res 92 : 755-761, 2001

17）Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition : development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58 : 5248-5257, 1998

18）Iacopetta B. Are there two sides to colorectal cancer ? Int J Cancer 101 : 403-408, 2002

19）Hawkins N, Norrie M, Cheong K, et al. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 122 : 1376-1387, 2002

20）Sugai T, Habano W, Jiao YF, et al. Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis : proposal for new molecular profile of colorectal carcinomas. J Mol Diagn 8 : 193-201, 2006

21）Shimaoka S, Niihara T, Tashiro K, et al. Signet-ring cell carcinoma of the colon 7mm in size with peritonitis carcinomatosa. J Gastroenterol 37 : 550-555, 2002

22）Bouzourene H, Gervaz P, Cerottini JP, et al. p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer. Eur J Cancer 36 : 1008-1015, 2000

23）Taniyama K, Sasaki N, Wada S, et al. Comparison of proliferative activities and metastases between two subtypes classified at the deeply infiltrating sites of colorectal moderately differentiated adenocarcinomas. Pathol Int 46 : 195-203, 1996

24）Sugai T, Nakamura S, Uesugi N, et al. Role of DNA aneuploidy, overexpression of p53 gene product, and cellular proliferation in the progression of gastric cancer. Cytometry 38 : 111-117, 1999

25）Pannequin J, Delaunay N, Buchert M, et al. Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Gastroenterology 133 : 1554-1568, 2007

26）Wong SC, Lo ES, Chan AK, et al. Nuclear beta catenin as a potential prognostic and diagnostic marker in patients with colorectal cancer from Hong Kong. Mol Pathol 56 : 347-352, 2003

27）Endoh Y, Tamura G, Ajioka Y, et al. Frequent hypermethylation of the hMLH1 gene promoter in differentiated-type tumors of the stomach with the gastric foveolar phenotype. Am J Pathol 157 : 717-722, 2000

28）Winn B, Tavares R, Matoso A, et al. Expression of the intestinal biomarkers Guanylyl cyclase C and CDX2 in poorly differentiated colorectal carcinomas. Hum Pathol 41 : 123-128, 2010

29）Morrin M, Kelly M, Barrett N, et al. Mutations of Ki-ras and p53 genes in colorectal cancer and their prognostic significance. Gut 35 : 1627-1631, 1994

30）Slattery ML, Curtin K, Anderson K, et al. Associations between dietary intake and Ki-ras mutations in colon tumors : a population-based study. Cancer Res 60 : 6935-6941, 2000

31）Siena S, Sartore-Bianchi A, Di Nicolantonio F, et al. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst 101 : 1308-1324, 2009

32）Spring KJ, Zhao ZZ, Karamatic R, et al. High prevalence of sessile serrated adenomas with BRAF mutations : a prospective study of patients undergoing colonoscopy. Gastroenterology 131 : 1400-1407, 2006