Immunohistochemical and Genetic Analysis of Non–Small Cell and Small Cell Gallbladder Carcinoma and Their Precursor Lesions

Abstract

Gallbladder carcinomas can be highly lethal neoplasms. Relatively little is known about the genetic abnormalities that underlie these tumors, particularly with respect to their timing in neoplastic progression. The authors evaluated 5 noninvasive dysplasias and 33 invasive gallbladder carcinomas (6 small cell carcinomas, 27 non-small cell carcinomas, of which 16 were accompanied by an in situ carcinoma component) for expression of the protein products of the p16, p53, Dpc4, and pRB tumor suppressor genes by immunohistochemistry. Neoplasms were also evaluated for the presence of activating K-ras oncogene mutations. Seventy-five percent of non-small cell gallbladder carcinomas demonstrated loss of p16 expression, whereas 63% accumulated high levels of p53. Loss of Dpc4 and pRB expression was less frequent, seen in 19% and 4% of the neoplasms, respectively. Thirty percent of neoplasms harbored activating K-ras mutations. In contrast, 100% of the small cell carcinomas of the gallbladder demonstrated inactivation of the pRB/ p16 pathway; 67% showed loss of pRB expression, and the other 33% lost p16 expression. Eighty-three percent of small cell carcinomas accumulated high levels of p53, whereas loss of Dpc4 expression and activating K-ras mutations were not found. Among 15 evaluable in situ components, 13 harbored the same alterations found in the invasive component.Inactivation of p16 and p53 occur in the majority of non-small cell gallbladder carcinomas. Dpc4 inactivation and K-ras mutations occur in a significant minority of cases. pRB loss is uncommon in nonsmall cell gallbladder carcinoma, but virtually all small cell carcinomas inactivate the p16/pRB pathway, usually by retinoblastoma protein loss. It is noteworthy that all of these alterations occur at the level of carcinoma in situ.

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

“…29,34,35 Mutations in the TP53 gene have been implicated in tumor progression, and these mutations are frequent in invasive biliary tract cancers. 8 Interestingly, molecular alterations in TP53 have been identified in the majority of carcinoma in situ of the gallbladder, 7,36 which suggests that shortened telomeres within this epithelium may promote tumor progression, rather than senescence or apoptosis.…”

Genetic alterations in Japanese extrahepatic biliary tract cancer

“…The data suggest that disrupted cell cycle regulation at the G 1 -S transition is involved in the tumorigenesis of Japanese BTC. Furthermore, immunohistochemical staining demonstrated loss of p16 (CDKN2A) expression in 74.1% (20/27) of GBC tissues, and loss of pRB expression in 3.7% (1/27) of GBC tissues (50). Recently, the FDA approved palbociclib, an inhibitor of CDK4/6, for the treatment of patients with HR-negative and HER2-negative metastatic breast cancer (51).…”

Two distinct pathways of p16 gene inactivation in gallbladder cancer

“…We examined p16 protein expression by immunohistochemistry in 51 cases of gallbladder cancer. Loss of p16 protein expression has been reported to range between 24 and 76% in gallbladder cancer [14,[18][19][20]23] . In our study, the loss of p16 expression was detected in 32 of 51 (62.7%) patients with gallbladder cancer.…”