Gallbladder cancer pathophysiology

Overview

It is thought that gallbladder cancer (GBC) is the result of 2 different biological pathways based on morphological, genetic, and molecular evidence.

Pathophysiology

Pathogenesis

• It is understood that GBC is the result of persistent irritation of the gallbladder mucosa over a period of years which predispose to malignant transformation or act as a enhancer for carcinogenic exposure.
• The primary mechanism involves cholelithiasis and resultant cholecystitis and appears to be the driving force in most areas of the arena
• Where as GBC is strongly related to gallstone disease, female gender bias, and age over 65

Theory #1:

• In the setting of chronically inflamed gallbladder, metaplasia is not unusual.
• Much like metaplasia of the stomach, gallbladder metaplasia happens in two forms
  • 1) Gastric form
  • 2) Intestinal form
• Chronically inflamed gallbladder may additionally express both pyloric gland and intestinal metaplasia
• But, fluke-infested gallbladders more commonly shows intestinal metaplasia and p53 mutations than sporadic gallbladder cancers .
• The right relationship among metaplasia and dysplasia remains unwell-established.
• The first concept indicates that dysplasia progresses to carcinoma in situ (CIS) which will become invasive.
• This concept is supported via the finding that over 80% of invasive gallbladder cancers have adjoining areas of CIS and epithelial dysplasia .
• One study validated the presence of metaplasia, dysplasia, and CIS adjoining to the cancer in 66%, 81.3%, and 69%, respectively.
• Dysplastic lesions have molecular genetic proof that supports progression towards CIS.
• It is well recognized that gallbladder dysplasia progresses to invasive most cancers normally over a path of 15 to 19 years

Theory #2

• There are also histologic and molecular differences in GBCs related to anomalous pancreaticobiliary duct junction and in the ones related to gallstones, Providing further proof that two different pathogenetic pathways are involved .
• GBCs arising in Japan within the setting of an anomalous pancreaticobiliary duct junction are characterized by means of KRAS mutations and relatively late onset of p53 mutations
• By means of comparison, as a minimum in Chilean patients with cholelithiasis and chronic cholecystitis, KRAS mutations are uncommon, while p53 mutations rise up early at some stage in multistage pathogensis

• Less than 3% of early gallbladder carcinomas have adenomatous remnants, indicating this mechanism has less importance within the carcinogenic pathway
• It's hard to predict which of those will go through malignant transformation
• In contrast to properly-established carcinogenic pathways in colorectal most cancers , it remains debated within the literature whether or not or not adenomas are actual precursors of invasive gallbladder carcinomas
• Only 1% of cholecystectomy specimens have adenomatous polyps as preneoplastic lesions