I. NORMAL ANATOMY. The gallbladder, comprised by the fundus, body, and neck, is covered by serosa, except the portion in the liver fossa which merges with liver parenchyma. The lining mucosa, a layer of folded columnar epithelium and lamina propria of loose connective tissue, directly rests on muscularis propria which consists of longitudinally oriented, to irregularly arranged bundles of smooth muscle with overlying subserosa and serosa. No muscularis mucosae or submucosa are present. Secretory mucous glands in the neck and extrahepatic bile ducts are arranged in a lobular pattern (e-Fig. 16.1).*
The extrahepatic ducts include the right and left hepatic ducts, which join to form the common hepatic duct in the porta hepatis; when the common hepatic duct is joined by the cystic duct, the common bile duct is formed. A single layer of columnar cells lines the ducts and rests directly on dense connective tissue; from proximal to distal, there is a variable periductal smooth muscle fiber investment, intermingled with collagen bundles.
II. GROSS EXAMINATION
A. Cholecystectomy is most commonly performed for cholelithiasis. After the gallbladder is measured and opened longitudinally, the following should be described: serosal, mural, and mucosal appearances; cystic duct integrity; and consistency, quantity, and color of stones. Full-thickness sections should be submitted from the fundus, body, neck, and duct; the cystic duct margin should also be submitted, as well as any lymph nodes. For a suspicious lesion, the overlying serosal surface or hepatic bed should be inked, the lesion breadloafed, and sections taken to demonstrate relevant anatomic relationships.
The gross finding that the gallbladder wall is uniformly firm with an associated flattened mucosal surface suggests the diagnosis of a so-called porcelain gallbladder. After the specimen is photographed, at least one section per cm should be submitted (if not the entire specimen) to exclude adenocarcinoma (e-Figs. 16.2 and 16.3).
B. Biopsy of the common bile duct is performed for stricture or overt neoplasm during endoscopic retrograde cholangiopancreatography (ERCP). The number and dimensions of specimens should be recorded to ensure that the biopsy fragments are adequately represented; inking is not needed. At the time of initial histologic sectioning, preparation of three hematoxylin and eosin (H&E) stained slides together with six additional unstained slides avoids resurfacing the block if subsequent deeper levels or special stains are required for diagnosis.
C. Frozen section. Evaluation of bile duct margins by frozen section during pancreatoduodenectomy, or liver resections for bile duct adenocarcinoma, is often performed. The tissue should be frozen in its entirety, oriented in the frozen section block to obtain enface sections, and cut deeply to obtain sections that
represent the entire margin so that small foci of tumor are not missed by inadequate sampling. The tissue that remains after frozen section should be submitted for evaluation by permanent sections, which helps assure adequate sampling.
III. DIAGNOSTIC FEATURES OF COMMON NONNEOPLASTIC CONDITIONS
A. Cholecystitis is associated with cholelithiasis in >90% of the cases. Acute cholecystitis is characterized by full thickness edema, congestion, and an associated fibrinopurulent serosal exudate. Hemorrhage, transmural necrosis (gangrenous cholecystitis), and/or perforation may occur (e-Figs. 16.4 and 16.5).
Chronic cholecystitis is variably characterized by mural hypertrophy or atrophy with fibrosis and chronic inflammation (e-Fig. 16.6). Intestinal, pyloric, or foveolar surface metaplasia may occur. Rokitansky-Aschoff sinuses, which are herniations of the lining mucosa into the muscle layers, are common. Adenomyoma represents exaggerated herniations in the fundus accompanied by muscular hypertrophy and may appear as a gross deformity (e-Figs. 16.7 to 16.9). Both xanthogranulomatous cholecystitis (due to rupture of Rokitansky-Aschoff sinuses) or mucosal ulceration from stones may be transmural with associated bile extravasation and accumulation of foamy macrophages. Acalculous cholecystitis may be acute or chronic. Follicular cholecystitis may be associated with primary sclerosing cholangitis (PSC) (e-Fig. 16.10).
B. Cholesterolosis (strawberry gallbladder) is characterized by yellow mucosal specks grossly and lipid-laden macrophages in the lamina propria microscopically (e-Fig. 16.11). It is an incidental finding of no clinical significance.
C. Choledochal cyst, a form of fibropolycystic disease, results in fusiform or spherical dilatation of the common bile duct. Following photographic documentation, the entire lesion should be submitted for microscopic examination to exclude biliary intraepithelial neoplasia (BillN) or adenocarcinoma (e-Fig. 16.12).
D. Biliary atresia is a congenital process in which the extrahepatic ducts and gallbladder may be completely absent, or replaced by fibrous cords with no or only a very small lumen.
E. PSC involving the extrahepatic biliary system is an idiopathic disease diagnosed by cholangiography (discussed in more detail in Chap. 15).
F. Secondary sclerosing cholangitis, histologically indistinguishable from PSC, has a variety of obstructive and nonobstructive etiologies, including tumors, toxins, ischemia, and infections (including AIDS cholangiopathy).
IV. DIAGNOSTIC FEATURES OF COMMON NEOPLASMS AND PRECURSOR LESIONS (Table 16.1)
A. Adenoma is a single, small, and incidentally found polypoid lesion, and is characterized by a tubular, papillary, or tubulopapillary architecture. A pyloric or intestinal type epithelium is more common than a biliary type epithelium; squamous morules, Paneth cells, and neuroendocrine cells may be present. By definition, all adenomas are low grade, but larger adenomas may harbor foci of high-grade intraepithelial neoplasia or invasive carcinoma and thus should be entirely submitted for microscopic examination.
B. Biliary intraepithelial neoplasia (BilIN) is a classification nomenclature introduced in 2010 by the World Health Organization (WHO). BilIN-1 and BilIN-2 (low and intermediate grade lesions) are incidental and without established clinical significance. BilIN-3 may be associated with invasive carcinoma, and thus if present in the gallbladder, thorough sampling (including of the cystic duct and margin of excision) is necessary to exclude invasive carcinoma. If no invasive carcinoma is present, and the surgical margin of the cystic duct is not involved, cholecystectomy is considered curative. A distinguishing characteristic between BilIN-3 and reparative atypia is the abrupt transition noted in the former (e-Fig. 16.13) compared with the gradual alterations and heterogenous, widespread epithelial involvement of the latter. In addition, p53 expression is more extensive in BilIN than in reactive atypia.
TABLE 16.1 WHO Histologic Classification of Tumors of the Gallbladder and Extrahepatic Bile Ducts
Biliary intraepithelial neoplasia, grade 3 (BillN-3)
Intracystic (gallbladder) or intraductal (bile ducts) papillary neoplasm with low- or intermediate-grade intraepithelial neoplasia
Intracystic (gallbladder) or intraductal (bile ducts) papillary neoplasm with high-grade intraepithelial neoplasia
Mucinous cystic neoplasm with low- or intermediate-grade intraepithelial neoplasia
Mucinous cystic neoplasm with high-grade intraepithelial neoplasia
Adenocarcinoma, biliary type
Adenocarcinoma, gastric foveolar type
Adenocarcinoma, intestinal type
Clear cell adenocarcinoma
Signet-ring cell carcinoma
Intracystic (gallbladder) or intraductal (bile ducts) papillary neoplasm with an associated invasive carcinoma
Mucinous cystic neoplasm with an associated invasive carcinoma
Squamous cell carcinoma
Neuroendocrine tumor (NET)
NET G1 (carcinoid)
Neuroendocrine carcinoma (NEC)
Mixed adenoneuroendocrine carcinoma
Goblet cell carcinoid
Granular cell tumor
From: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. World Health Organization Classification of Tumours of the Digestive System. Lyon: IARC Press; 2010. Used with permission.
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