Tumors of the Gallbladder

Benign and pseudotumors of the gallbladder

• Most benign tumors of the gallbladder are detected as polypoid lesions.
  
• In 1970, Christensen and Ishak proposed a simplified classification scheme of benign gallbladder lesions, which are classified as either tumors or pseudotumors.
  
• Benign tumors are further classified into
  • epithelial (adenoma) and
    
  • mesenchymal (hemangioma, lipoma, etc.) variants.
• Pseudotumors include such lesions as
  • cholesterol and inflammatory polyps,
    
  • adenomatous hyperplasia, and
    
  • heterotopic tissues.

The prevalence of polypoid lesions of the gallbladder (PLG) in healthy subjects varies from 3 to 7% on ultrasound in up to 10% in cholecystectomy specimens.

The most common type of PLG is the cholesterol polyp, comprising 63% of 172 cases in the largest series of PLG reported in the literature.

• Cholesterol polyps are characteristically small (10 mm), multiple, and appear as yellow spots on the surface of the gallbladder mucosa, giving rise to the term “strawberry gallbladder.”
  
• They are formed by the proliferation of lipid-laden macrophages in the lamina propria and have no malignant potential.
  

Inflammatory polyps of the gallbladder are reactive lesions without malignant potential that are usually discovered at the time of cholecystectomy performed for chronic cholecystitis.

• Microscopically, there is evidence of focal epithelial hyperplasia associated with a marked infiltration of chronic inflammatory cells.
  

Adenomyomatous hyperplasia of the gallbladder is characterized by extensions of the mucosa into and through a thickened muscular wall, typically in the fundus of the gallbladder.

• These lesions have long been thought to have no malignant potential, though there are case reports of gallbladder carcinoma developing in areas of adenomyomatosis.
  

Simplified classification of benign tumors and pseudotumors of the gallbladder.

Benign tumors

• Epithelial
  • Adenoma, papillary
  • Adenoma, nonpapillary

• Supporting tissue
  • Hemangioma
  • Lipoma
  • Leiomyoma
  • Granular cell tumor
    

Benign pseudotumors

• Hyperplasia
  • Adenomatous
  • Adenomyomatous (adenomyoma)
    

• Heterotopia
  • Gastric mucosa
  • Intestinal mucosa
  • Pancreas
  • Liver
• Polyp
  • Inflammatory
  • Cholesterol
    

• Miscellaneous
  • Fibroxanthogranulomatous inflammation
  • Parasitic infection
  • Other
    

The incidence of adenoma of the gallbladder is approximately 1% in cholecystectomy specimens, and these lesions can be papillary or sessile.

• It is unclear whether a gallbladder adenoma represents a premalignant lesion.
  
• Evidence in support of the adenoma to adenocarcinoma sequence comes from a study by Kozuka et al., in which the histology of 1605 gallbladders was reviewed.
  
• Adenomatous components were identified in all of the in situ carcinomas and in 19% of the invasive carcinomas.
  
• There was a distinct correlation between the size of the lesion and malignant change, with all benign adenomas measuring less than 12 mm in diameter, all adenomas with malignant change measuring greater than 12 mm in diameter, and most of the invasive cancers measuring greater than 30 mm in diameter.
  
• Similarly, Koga et al. performed a comparative analysis between benign and malignant gallbladder lesions and found that 94% of benign lesions were smaller than 10 mm, whereas 88% of malignant lesions were greater than 10 mm.
  
• Yang et al. provided further evidence in support of the malignant potential of large PLG in a clinicopathologic review of 182 patients with PLG. All 138 PLG less than 10 mm in diameter were benign, whereas all 13 malignant PLG measured greater than 10 mm in diameter, and most of these (11/13) were greater than 15 mm.

Others refute the polyp-to-cancer sequence and believe that gallbladder carcinomas arise in situ from flat, dysplastic epithelium.

Wistuba et al. extracted DNA from gallbladder adenomas and screened for mutations in the p53, Kras, and N-ras genes and five different chromosomal regions that had previously been shown to be frequently deleted in dysplasia, carcinoma in situ, and gallbladder carcinoma.

• They found no mutations of the p53 gene in 16 gallbladder adenomas but did identify K-ras mutations in 25% of the adenomas.
  
• K-ras mutations are rare in gallbladder carcinomas.
  
• They concluded that gallbladder adenomas lack the molecular changes frequently seen in gallbladder cancers, arguing against a proposed adenoma–carcinoma pathway.
  
• Other investigators have followed the natural history of PLG.
  

Moriguchi et al. followed 109 asymptomatic patients with PLG (94% <1>

• Only one gallbladder carcinoma was identified, at a site distinct from that of the pre-existing polyp, and 88% of the PLG were unchanged in size.
  
• The authors concluded that most PLG detected by ultrasound are benign.
  

Csendes et al. followed 111 patients with PLG smaller than 10 mm by clinical examination and ultrasound for a mean time of 71 months.

• No patient developed symptoms of biliary disease, gallstones, or gallbladder carcinoma.
  

Collectively, these studies confirm that the most significant risk factor for malignancy in a PLG is a diameter greater than 10 mm.

Other risk factors include solitary PLG, symptomatic PLG, concurrent gallstones, and patient age greater than 50 years.

• These factors then allow for the proper selection of patients with PLG who would most likely benefit from cholecystectomy.