Regional differences in gallbladder cancer pathogenesis: Insights from a multi-institutional comparison of tumor mutations.

BACKGROUND: Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens. METHODS: Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations. RESULTS: A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors. CONCLUSIONS: Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials.

Colonic adenosquamous carcinoma and mucinous adenocarcinoma with microsatellite instability.

A 43-year-old man presented with two-month history of fatigue, weakness, paleness, rectal bleeding, sweating, and weight loss of 10 kg in the past one month. A complete blood count revealed anaemia. The patient underwent a right hemicolectomy. The microscopic examination revealed an adenosquamous carcinoma associated with a mucinous adenocarcinoma in a patient with microsatellite instability due to loss of MLH1 and PMS2 expression and retention of MSH2 and MSH6 expression in both the squamous and glandular components. We also observed an atypical immunohistochemical phenotype in the adenocarcinoma component showing CK7 expression and reduced CK20 and CDX2 expression.

The value of p53 protein expression in gallbladder carcinoma: analysis of 60 cases.

BACKGROUND/AIMS: Few studies, with small samples and diverging results, have been performed to evaluate the p53 protein expression in gallbladder carcinoma and its relationship to different clinicopathological parameters. Based on these facts, we performed a study for the purpose of assessing p53 expression in this disease and its association to prognostic factors. METHODOLOGY: Samples of 141 gallbladders, with 60 cases of carcinoma, 62 cholelithiasis and 19 without gallstones were assessed using an immunohistochemical technique for the expression of p53 protein, and analyzed for prognosis, survival and other clinicopathological parameters. RESULTS: p53 expression was positive in 58.3% of carcinomas of the gallbladder, 9.7% of the chronic cholecystitis and 10.5% of the gallbladders not associated to stones. In cases of carcinoma of the gallbladder there was no statistically significant association between the expression of this protein, the prognostic factors, histological type or grade, presence of gallstones and survival. CONCLUSIONS: The mutation of gene p53 is involved in the pathogenesis of carcinoma of the gallbladder, and the intense chronic inflammatory process associated or not with cholelithiasis, appears to be one of the factors involved in the genesis of this process. Our data do not show an association between p53 protein expression and patient's survival prognosis.

Detection of oncogenic HPV DNA by a consensus polymerase chain reaction method in genital carcinomas in twenty women in Barbados.

Paraffinized tissue from Barbadian women with histologically proven genital carcinoma was subjected to a consensus polymerase chain reaction method. Nineteen patients had cervical and one, vaginal carcinoma. The histological types were 17 squamous cell carcinoma, 2 adenocarcinoma and 1 adenosquamous carcinoma. HPV DNA was detected in 18/20 (90%). HPV DNA type 16 in 13 (65%), type 33 and type 45 in 1 (5%) each and 3 (15%) could not be typed. HPV DNA, type 16, was detected in one (50%) of the two cases of adenocarcinoma and 12/17 (71%) cases of squamous cell carcinoma. DNA HPV, type 33, and type 45 were each detected in 1/17 (6%) cases of squamous cell carcinoma. No HPV DNA, type 18, was detected.