Ki-ras mutations and p53 protein expressions in intrahepatic cholangiocarcinomas: Relation to gross tumor morphology

Ohashi, Kazuhiko; Nakajima, Yoshiyuki; Kanehiro, Hiromichi; Tsutsumi, Masahiro; Taki, Junichiro; Aomatsu, Yukio; Yoshimura, Atsushi; Ko, Saiho; Kin, Tatsuya; Yagura, Kazuaki; Konishi, Yoichi; Nakano, Hirofumi

doi:10.1016/0016-5085(95)90650-9

Cited by 135 publications

(102 citation statements)

References 22 publications

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“…The reported frequencies of p53 over-expression in cholangiocarcinoma vary from 19% to 58%. [31][32][33][34] In this study, p53 over-expression was detected less in IG-ICC than in non- IG-ICC (6% vs. 37%, P Ͻ .01). Expression of MUC2 and CDX2 is characteristic of IPNL, whereas over-expression of MUC1, EGFR, and p53 is rare in IPNL.…”

Section: Discussionmentioning

confidence: 43%

“…1 Various predisposing factors, including liver fluke infestation, hepatolithiasis, primary sclerosing cholangitis, choledochocyst, and Caroli's disease, have been implicated. [1][2][3] In Taiwan, ICC was found in 5% to 10% of patients with hepatolithiasis. 3,4 Based on gross morphology, ICC can be divided into three types (mass-forming, periductalinfiltrating, and intraductal growth [IG]-type).…”

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confidence: 99%

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Characterization of Intrahepatic Cholangiocarcinoma of the Intraductal Growth-Type and Its Precursor Lesions *

et al. 2005

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A cohort of patients with intraductal growth-type intrahepatic cholangiocarcinoma (IG-ICC) and its precursor lesions, collectively termed intraductal papillary neoplasm of the liver (IPNL), was characterized with respect to demographics, clinical manifestations, perioperative management, long-term survival, and molecular features associated with carcinogenesis. A total of 122 patients with IPNL types 1 through 4, 108 patients with non-IG-ICC and 210 patients with hepatolithiasis alone were studied. Expression of CDX2, TFF1, MUC1, MUC2, MUC5AC, EGFR, and p53 was determined by using immunohistochemistry. Females predominated in those with hepatolithiasis alone and IPNL. The mean age of patients with hepatolithiasis alone was 6 to 8 years younger than that of those with IPNL. The association with hepatolithiasis in patients with IPNL types 1 and 2, IPNL types 3 and 4, and non-IG-ICC was 100%, 79%, and 64%, respectively. Mucobilia, anemia, and elevated serum carcinoembryonic antigen levels were helpful in distinguishing IG-ICC and its precursor lesions. The mean survival of patients with IPNL type 3, IPNL type 4, and non-IG-ICC was 55.5 months, 36.9 months, and 15.8 months, respectively. The incidence of expression of CDX2 and TFF1 was maximal in IPNL type 3. Expression and cellular distribution of MUC2 and CDX2 were similar. MUC5AC was strongly expressed in all patients with IPNL; EGFR and p53 were rarely expressed in patients with IPNL. In conclusion, hepatolithiasis appears to be a precipitating factor in the development of IPNL. Signs of mucobilia were specific for the diagnosis of IPNL. Expression of CDX2 and MUC2 are helpful in differentiating IPNL and non-IG-ICC. Significant differences in survival associated with the various lesions studied warrants a more aggressive surgical strategy in their management. ( I ntrahepatic cholangiocarcinoma (ICC) is a primary adenocarcinoma originating from the second or higher order branches of hepatic bile ducts. The incidence of ICC exhibits wide geographical variations that range from 5% to 30% of primary liver cancers. 1 Various predisposing factors, including liver fluke infestation, hepatolithiasis, primary sclerosing cholangitis, choledochocyst, and Caroli's disease, have been implicated. [1][2][3] In Taiwan, ICC was found in 5% to 10% of patients with hepatolithiasis. 3,4 Based on gross morphology, ICC can be divided into three types (mass-forming, periductalinfiltrating, and intraductal growth [IG]-type). 1 The IG-ICC is the least common type but is associated with the most favorable outcome. 1,5 Biliary papillomatosis, intraductal growth-type cholangiocarcinoma (IG-ICC), and mucin-producing ICC constitute essentially the same disease entity. [5][6][7] This category of papillary biliary neoplasm resembles intraductal papillary mucinous neoplasm of the pancreas histologically. 8 We recently proposed the term intraductal papillary neoplasm of the liver (IPNL) for such lesions, which include both IG-ICC and its precursor lesions. 6,9 Phenotypes of gastrointestinal meta...

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Section: Discussionmentioning

confidence: 43%

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confidence: 99%

Characterization of Intrahepatic Cholangiocarcinoma of the Intraductal Growth-Type and Its Precursor Lesions *

et al. 2005

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“…There is now increasing evidence that the genetic alterations and phenotypic changes are different between papillary-CC and non-papillary-CC. [7][8][9][22][23][24] Among intrahepatic cholangiocarcinoma, the papillary type had a lower frequency of K-ras and p53 mutations compared to the periductal infiltrating or mass-forming types. 7 The aberrant nuclear expression of ␤-catenin, which is one of the key events during tumorigenesis of various malignant tumors, was closely related to the tumor-growth type of cholangiocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas

Zen¹,

Fujii²,

Itatsu³

et al. 2006

Hepatology

345

349

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Recently, attention has been drawn to papillary neoplasm of the pancreatobiliary systems. In the pancreas, the disease entity of intraductal papillary mucinous neoplasm (IPMN-P) is widely recognized. In contrast, the pathological characteristics of biliary papillary tumors, such as biliary papilloma(tosis) and papillary cholangiocarcinoma, have not yet been well documented. In this study, we compared the pathological features and post-operative prognosis among biliary papillary tumors (10 cases of biliary papilloma(tosis) and 22 cases of papillary cholangiocarcinoma), conventional non-papillary cholangiocarcinoma (15 cases), and IPMN-P (31 cases). Macroscopically, all biliary papillary tumors were characterized by the prominent intraductal papillary proliferation, and macroscopic mucin-hypersecretion was seen in 9 of 32 cases (28%). Histologically, biliary papillary tumors consisted of three types of tumor cells (pancreaticobiliary, intestinal and gastric types), whereas only the pancreaticobiliary type was observed in non-papillary cholangiocarcinoma. Immunohistochemically, biliary papillary tumors were characterized by the common expression of MUC2, CDX2 and cytokeratin 20. In addition, biliary papillary tumors could be associated with two types of invasive lesions: tubular adenocarcinoma (9 cases) and mucinous carcinoma (5 cases). Patients with tubular adenocarcinoma had a poor prognosis compared to non-invasive papillary tumor or papillary tumor with mucinous carcinoma. These pathological characteristics and the survival status of biliary papillary tumors were different from those of non-papillary cholangiocarcinoma, and rather closely resembled those of IPMN-P. C ertain types of papillary tumors with different malignant potentials are known to occur in the intrahepatic and extrahepatic bile ducts. 1 Biliary papilloma (papilloma adenoma) is a rare benign neoplasm composed of papillary proliferation of the dysplastic biliary epithelium with delicate fibrovascular stalks. 1 Multiple recurring biliary papillomas are known as biliary papillomatosis. Some cases of biliary papillomatosis have multiple tumors at the same time, and others manifest asynchronous tumors at different sites of the biliary tract. 1,2 Biliary papilloma and papillomatosis are now thought to be pre-malignant lesions, and they have the potential to progress to invasive lesions via an adenomacarcinoma sequence. 3 Some cholangiocarcinomas show mainly papillary proliferation in the bile duct lumen, and those cases are designated as papillary cholangiocarcinoma (papillary-CC)

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“…Immunohistochemical demonstration of p53 is thought to reflect mutations of the p53 gene. p53 expression or mutation has been studied in a variety of cancers, but there have been only a few studies investigating the expression of p53 in cholangiocarcinoma (CC) and primary sclerosing cholangitis (PSC; [1][2][3][4][5][6]. Such studies are particularly important because development of cholangiocarcinoma in PSC is common, varying from 7% in asymptomatic patients to 42% in necropsy series (7).…”

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confidence: 99%

Expression of p53 and PCNA in Cholangiocarcinoma and Primary Sclerosing Cholangitis

et al. 2000

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The aim of this study was to identify the pattern and significance of expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis. Histological sections from 18 patients with cholangiocarcinoma (3 of the cases were associated with primary sclerosing cholangitis), 10 patients with primary sclerosing cholangitis without cholangiocarcinoma, and 7 patients with cirrhosis without cholangiocarcinoma or primary sclerosing cholangitis were stained immunohistochemically for p53 and PCNA. Samples from 17 patients with cholangiocarcinoma (94%) stained positively for p53. Among these 17 cases, nontumorous bile duct epithelium was positive in 7 (including 3 cases with primary sclerosing cholangitis and 2 with carcinoma in situ), and were positive proliferating bile ductules in 4 cases. The single p53-negative cholangiocarcinoma did not show p53 positivity in either the bile duct epithelium or the proliferating bile ductules. Bile ductal and ductular cells in all 10 patients with primary sclerosing cholangitis without cholangiocarcinoma and in the 7 controls were not reactive for p53. All 18 samples from patients with cholangiocarcinoma (100%) were positive for PCNA protein. Bile duct epithelium was positive for PCNA in nine cases (90%) of primary sclerosing cholangitis without cholangiocarcinoma and in six (85%) controls. Our study showed a high rate of p53 expression (94%) in cholangiocarcinoma. The adjacent uninvolved bile duct epithelium was also immunoreactive for p53 in 7 of 17 patients (41%). These findings suggest an early p53 mutation in bile ductal cells in cholangiocarcinogenesis. Expression of p53 may potentially be used to identify or screen, by bile duct brushings, cases of primary sclerosing cholangitis suspected of harboring cholangiocarcinoma. Expression of PCNA was a universal feature in cholangiocarcinoma.

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Ki-ras mutations and p53 protein expressions in intrahepatic cholangiocarcinomas: Relation to gross tumor morphology

Cited by 135 publications

References 22 publications

Characterization of Intrahepatic Cholangiocarcinoma of the Intraductal Growth-Type and Its Precursor Lesions *

Characterization of Intrahepatic Cholangiocarcinoma of the Intraductal Growth-Type and Its Precursor Lesions *

Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas

Expression of p53 and PCNA in Cholangiocarcinoma and Primary Sclerosing Cholangitis

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