Research Article: Clinicopathological characteristics and outcomes of rare histologic subtypes of gallbladder cancer over two decades: A population-based study

Date Published: June 11, 2018

Publisher: Public Library of Science

Author(s): Sandeep Samuel, Sarbajit Mukherjee, Nischala Ammannagari, Venkata K. Pokuri, Boris Kuvshinoff, Adrienne Groman, Charles M. LeVea, Renuka Iyer, John Green.


There is limited literature about the clinicopathological characteristics and outcomes of rare histologic variants of gallbladder cancer (GBC).

Using SEER database, surgically managed GBC patients with microscopically confirmed adenocarcinoma, adenosquamous/squamous cell carcinoma and papillary carcinoma were identified from 1988 to 2009. Patients with second primary cancer and distant metastasis at presentation were excluded. The effect of clinicopathological variables on overall survival (OS) and disease specific survival (DSS) were analyzed using univariate and multivariate proportional hazards modeling. All associations were considered statistically significant at an alpha error of 0.01.

Out of 4738 cases, 217 adenosquamous/squamous (4.6%), 367 papillary (7.7%), and 4154 adenocarcinomas (87.7%) were identified. Median age was 72 years. Higher tumor grade (grade 2, 3, 4 versus grade 1), higher T stage (T2, T3, T4 versus T1), lymph node positivity (N1 versus N0) and adenosquamous/squamous histology (versus adenocarcinoma) had worse OS and DSS (p < .001). Papillary GBC had better OS and DSS than adenocarcinoma (HR = 0.7; p < .001). Radical surgery (versus simple cholecystectomy) had better OS (HR = 0.83, p = 0.002) in multivariate analysis. OS rates at 3 and 5 years were 0.56 and 0.44 for papillary, 0.3 and 0.22 for adenocarcinoma, and 0.14 and 0.12 for adenosquamous/squamous histology, while DSS rates at 3 and 5 years were 0.67 and 0.61 for papillary, 0.38 and 0.31 for adenocarcinoma, and 0.17 and 0.16 for adenosquamous/squamous subtypes respectively. Papillary GBC had better survival outcomes while adenosquamous/squamous GBC had worse survival outcomes compared to gallbladder adenocarcinoma.

Partial Text

Gall bladder cancer (GBC) is the most common biliary tract malignancy and the fifth most common gastrointestinal cancer [1, 2]. GBC and nearby large bile duct cancers accounted for an estimated 11,420 new cases and 3710 deaths in the United States in 2016. GBC has a dismal prognosis and majority of the cases are asymptomatic and are incidentally diagnosed during gall stone exploration or after cholecystectomy performed for a non-malignant indication[3]. Therefore, the index surgical procedure is often a simple resection of the gallbladder and a revision surgery is planned based on the staging results [4]. According to the National Comprehensive Cancer Network (NCCN) guidelines [2], a simple cholecystectomy is an adequate treatment for T1a tumors. While there is some controversy over T1b tumors [2], a complete surgical resection consisting of cholecystectomy with a limited hepatic resection and portal lymphadenectomy is the only curative treatment for T2 or greater tumors. It is performed either as an index procedure or as a revised procedure at a later date.

14,349 patients with GBC were identified between 1988-and 2009. Of these, 6004 patients belonged to the three histological subtypes of interest; adenocarcinoma (n = 5321; 88.6%), adenosquamous/squamous (n = 284; 4.7%) and papillary (n = 399; 6.6%). Among the adenosquamous/squamous GBC patients, 157 (55%) were adenosquamous, while most of the papillary GBC group (n = 382; 96%) included papillary adenocarcinoma.

The rarity of adenosquamous/squamous and papillary histologic types of GBC in the general population precludes the description of their clinicopathological characteristics, survival outcomes and treatment responses [10, 11]. A national cancer registry like SEER database samples tumor data from approximately 26 percent of the US population and is an ideal tool for quality and outcome studies on rare cancer histology. To the best of our knowledge, our study is the largest in showing the clinicopathological characteristics and survival outcomes of the papillary, adenosquamous/squamous variants of GBC and comparing them with pure adenocarcinoma of gallbladder.




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