Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico

Abstract

Gallbladder cancer is a rare malignancy of the biliary tract with a poor prognosis, frequently presenting at an advanced stage. While rare in the United States overall, gallbladder cancer has an elevated incidence in geographically distinct locations of the globe including Chile, North India, Korea, Japan and the state of New Mexico in the United States. People with Native American ancestry have a much elevated incidence of gallbladder cancer compared to Hispanic and non-Hispanic white populations of New Mexico. Gallbladder cancer is also one of the few bi-gendered cancers with an elevated female incidence compared to men. Similar to other gastrointestinal cancers, gallbladder cancer etiology is likely multi-factorial involving a combination of genomic, immunological, and environmental factors. Understanding the interplay of these unique epidemiological factors is crucial in improving the prevention, early detection, and treatment of this lethal disease. Previous studies have failed to identify a distinct genomic mutational profile in gallbladder cancers, however, work to identify promising clinically actionable targets is this form of cancer is ongoing. Examples include, interest in the HER2/Neu signaling pathway and the recognition that chronic inflammation plays a crucial role in gallbladder cancer pathogenesis. In this review, we provide a comprehensive overview of gallbladder cancer epidemiology, risk factors, pathogenesis, and treatment with a specific focus on the rural and Native American populations of New Mexico. We conclude this review by discussing future research directions with the goal of improving clinical outcomes for patients of this lethal malignancy.

Keywords: Chronic Inflammation; Gallbladder Cancer; Gallstones; HER2/Neu; Heavy Metals; New Mexico; Personalized medicine.

Fig. 1

Age-adjusted GBC incidence among women (left) and men (right) of New Mexico from 2000 to 2014. Native American women and men show highly elevated incidence of GBC relative to Hispanics and Caucasians of New Mexico. The wide variation (gray) seen in Native American GBC incidence is due to the smaller population size and the number of annual GBC cases relative to Hispanics and Caucasians of New Mexico. Data is age-adjusted to the 2000 U.S standard population

Fig. 2

Age-adjusted GBC incidence data (2000–2014) mapped to the 33 counties of New Mexico. Darker color intensity represents elevated GBC incidence. Native American populations who live predominantly in the north-west portion of New Mexico (e.g., Navajo reservation) show the highest GBC incidence

Fig. 3

A hematoxylin and eosin stained image of gallbladder cancer histomorphology. The four panels (clockwise from top left) shows the differing degrees of differentiation commonly observed in gallbladder cancer pathology specimens (dysplasia, well differentiated, poorly differentiated, and moderately differentiated)

Fig. 4

HER2 positivity in New Mexican cases of gallbladder cancer by immunohistochemistry. The panels (clockwise from top left) represent HER2 staining status of 0, 1+, 3+ and 2+ grades. Gallbladder cancer HER2 staining is axial, similar to the staining pattern seen in gastric cancers. In contrast, HER2 staining in breast cancers is more circumferential and evenly distributed around the tumor cell periphery

Fig. 5

HER2 gene amplification detected by Fluorescence In-Situ Hybridization (FISH) method. This case had approximately nine HER2 gene copies per cell and showed a concordant 3+ staining for HER2 protein expression by IHC