Pathology of the Gallbladder and Extrahepatic Bile Ducts

Clinical Features

Cholecystitis presents with intermittent postprandial epigastric or right upper quadrant pain. By far the most common underlying cause is cholelithiasis, which in some cases may also lead to obstruction of the bile duct (choledocholithiasis). Acute cholecystitis is also associated with fever and leukocytosis. Clinical examination is supported by a positive “Murphy sign” in which pain is elicited when the inflamed gallbladder descends during inspiration. The clinical impression may be confirmed by ultrasound, which demonstrates choleliths, gallbladder wall thickening, and pericholecystic fluid. Xanthogranulomatous cholecystitis may show mural nodularity and dense adhesions to adjacent organs, which may cause clinical concern for malignancy.

In 0.5% to 1% of cases, a porcelain gallbladder, characterized by diffuse calcification of the wall, is seen radiographically and intraoperatively. This finding correlates with the pathologic diagnosis of hyalinizing cholecystitis (HC) and has classically been associated with an increased risk of gallbladder carcinoma. This risk has traditionally been considered sufficient to warrant prophylactic cholecystectomy, but recent studies have shown the risk to be lower than previously reported.

Sterile acalculous cholecystitis is much less common, and most patients present with multiple other comorbidities, especially in the hospital setting. It is most commonly associated with ischemia and dysmotility. Infectious cholecystitis is rare, occurring predominantly in immunocompromised patients. The most common infections are Cryptosporidium parvum and cytomegalovirus. Rare cases of cholecystitis represent manifestations of systemic diseases, including eosinophilic cholecystitis, presenting as a component of eosinophilic gastroenteritis, primary sclerosing cholangitis (PSC)–associated cholecystitis, and immunoglobulin (Ig) G4–associated sclerosing cholecystitis, which is present in almost all patients with IgG4 sclerosing cholangitis of the bile duct.

Gross Findings

Acute cholecystitis is characterized by mucosal erythema, friability, and ulceration. The gallbladder wall may be thickened and edematous. In severe cases, serositis may be present with a fibrinous exudate on the serosal surface. Chronic cholecystitis most often exhibits mural fibrosis with a thick and firm gallbladder wall. Extensive hyalinization and calcification (>80% of the circumferential wall) is classified as porcelain gallbladder. Xanthogranulomatous cholecystitis may be associated with mural nodules that can grossly mimic malignancy ( Fig. 15.1A ). Cholesterolosis, which is found in approximately 20% of cholecystectomy specimens, results in a stippled mucosal surface, often described as “strawberry gallbladder” ( Figs. 15.1B and C ). Choleliths or choledocholiths may be present. Cholesterol gallstones, the most common type, are yellow-green, whereas gallstones composed of abundant bilirubin (“pigment stones”) are black or brown. Black pigment stones are sometimes associated with hereditary hemolytic conditions, although the majority of cases are sporadic.

Microscopic Findings

Features of acute cholecystitis include neutrophilic or eosinophilic infiltration, mucosal erosion or ulceration, hemorrhage, gangrenous necrosis, and reactive epithelial changes ( Fig. 15.2 ). The predominant findings in chronic cholecystitis are mural fibrosis, muscular hypertrophy, and a variable degree of mononuclear cell infiltration ( Fig. 15.3 ). Mucosal invaginations through the muscularis propria, known as Rokitansky-Aschoff sinuses, are frequently seen in chronic cholecystitis and are usually associated with muscular hypertrophy. The sinuses may undergo striking cystic change because of outflow obstruction and can mimic a neoplastic process ( Fig. 15.4 ). Inflammatory polyps may also be present. In cases of both acute and chronic cholecystitis, these polyps may have associated reactive epithelial changes and must be distinguished from the polypoid dysplastic lesions. Pyloric gland and intestinal metaplasia may also be present as a consequence of chronic injury and repair ( Fig. 15.5 ). Less frequently, squamous metaplasia may be seen. Xanthogranulomatous cholecystitis is caused by extravasation of bile into the gallbladder wall, eliciting a florid histiocytic response ( Fig. 15.6 ). Reactive fibroblasts are present, which can be so cellular as to mimic a mesenchymal neoplasm. Clues to a benign diagnosis include bland histology, abundant foamy macrophages, and admixed cholesterol clefts and bile pigment. Cholesterolosis is characterized by clusters of cholesterol-laden macrophages that accumulate under the epithelial surface. It is generally considered an incidental finding and does not necessitate further work-up.

Hyalinizing cholecystitis is defined by paucicellular hyaline sclerosis that obliterates all of the layers of the gallbladder wall ( Fig. 15.7 ). It is typically seen, on average, in patients one decade older than other variants of cholecystitis and in those with long-standing gallbladder inflammation. Focal or diffuse dystrophic calcification may be present in the gallbladder wall. HC cases with diffuse (>80%) calcification correlate with porcelain gallbladder, but all cases of radiographically identified porcelain gallbladder show HC histologically. However, the converse is not always true. Paucicellular hyalinizing sclerosis of HC may be present in some patients with only minimal or no mural calcification. HC, and in particular cases with minimal or no calcification, is associated with an increased (10%–20%) risk for gallbladder carcinoma. Given this risk, complete histologic examination of gallbladder specimens with HC is warranted. Carcinomas associated with HC are generally very well differentiated and may be paucicellular with only scattered neoplastic glands present in the wall. An overt desmoplastic response is not always present.

Gross Findings

As expected, flat dysplasia or BilIN is invisible on gross examination and is detected in random sections from a cholecystectomy. However, ICPN, by definition, is a grossly visible lesion, typically 1 cm or larger, with a median size around 2 cm. Some ICPNs are friable and may be present as detached fragments within the gallbladder lumen. They can be mistaken for luminal debris if this possibility is not considered. Mild thickening of the gallbladder wall may be seen in early invasive carcinomas, but this is often too subtle to be of practical utility, especially because most inflamed gallbladders are edematous. Adequate sampling is key to ensure an accurate diagnosis. Although there is some variation in “optimal practice” based on expert opinion, most agree on the general principle that more sections should be taken with increasing degrees of atypia or dysplasia. The cystic duct margin and one to three sections of representative mucosa are sampled routinely in all cholecystectomy specimens. When low-grade dysplasia or epithelial atypia insufficient for a definite diagnosis of dysplasia is found, submission of extra random sections is useful to exclude high-grade dysplasia or to detect more easily diagnosed foci of neoplasia, respectively. When high-grade dysplasia is seen, thorough sampling is mandatory to rule out an invasive carcinoma. Similarly, multiple additional sections should be submitted in T1a or T1b carcinomas to exclude a more advanced tumor. Areas grossly suspicious for invasive carcinoma should be entirely examined. ICPNs should be submitted entirely along with generous sampling of adjacent mucosa because they are commonly associated with high-grade dysplasia or invasive carcinoma away from the grossly apparent lesion.