Gallbladder and Extrahepatic Bile Ducts - Printer Friendly Version

Regional lymph nodes: lymph node present at gallbladder neck or cystic duct drains to hepatic hilar nodes (along common bile duct, hepatic artery, portal vein, cystic duct); also celiac, periduodenal, peripancreatic and superior mesenteric nodes

Normal histology-Gallbladder

Has mucosa, muscularis propria and serosa on free surface; no muscularis mucosa or submucosa is present

Mucosa: variable branching folds, more prominent if gallbladder not distended

Surface epithelium: composed of single layer of uniform, tall columnar cells with basal nuclei, indistinct nucleoli, pale cytoplasm due to sulfomucins; also pencil cells (small, darkly staining columnar cells), inconspicuous basal epithelial cells, T lymphocytes; no goblet cells, myoepithelial cells or melanocytes; neck region has tubuloalveolar mucus glands that secrete sulfo-, sialo- and neutral mucin and contain neuroendocrine cells; true glands are not present outside the neck

Lamina propria: loose connective tissue with blood vessels, lymphatics, occasional chronic inflammatory cells (IgA secreting plasma cells), no neutrophils

Muscular layer: circular, longitudinal and oblique smooth muscle fibers without distinct layers, resembles muscularis mucosa; adjacent to lamina propria without an intervening submucosa

Adventitia: perimuscular connective tissue composed of collagen, elastic tissue, fat, vessels, lymphatics, nerves, paraganglia

Peritoneum: lines gallbladder that is not directly attached to liver, is continuous with that of liver

Aberrant bile ducts (ducts of Lushka): present in 10% of cholecystectomy specimens, often buried in gallbladder wall adjacent to liver, may contain collar of fibrous tissue, may communicate with intrahepatic bile ducts

Rokitansky-Aschoff sinuses: outpouchings of gallbladder mucosa that penetrate into muscle wall; may be acquired herniations

Larger accessory bile ducts: join with cystic or hepatic ducts, may be present within gallbladder bed

Mucin-secreting accessory glands: prominent near terminus of common bile duct

Positive stains (surface epithelium): EMA, low molecular weight keratin, alpha-1-antitrypsin, alpha-1-antichymotrypsin, polyclonal CEA

Embryology

Develops with bile duct and liver during week 4 as ventral bud (hepatic diverticulum) from caudal foregut

Hepatic diverticulum has two components: pars hepatica and pars cystica

Parts hepatica gives rise to liver, common hepatic duct and intrahepatic bile ducts

Pars cystica gives rise to cystic diverticulum, which gives rise to gallbladder and cystic duct

Hepatic diverticulum elongates to form common bile duct

Above structures begin as solid cords, but at 8 weeks have lumina

Normal physiology

Bile excretion is normally 500-1000 ml/day

Bile is concentrated 5-10x via active absorption of electrolytes accompanied by passive movement of water

Cholecystokinin causes gallbladder contraction and release of stored bile into gut

Bile is critical for intestinal absorption of dietary fat, but the gallbladder is not

Bile is 2/3 bile salts, bicarbonate rich, has 3% organic solutes

Bile salts: cholates, chenodeoxycholates, deoxycholates, lithocholates, ursodeoxycholates; major hepatic products of cholesterol metabolism; a family of water-soluble sterols with carboxylated side chains; are highly effective detergents, solubilize water-insoluble lipids secreted by the liver (usually lecithin) into the biliary tree and promote dietary lipid absorption within the gut

Lecithin (phosphatidylcholine): hydrophobic, non-aqueous; has minimal solubility in water

95% of secreted bile salts is reabsorbed in ileum and returned to liver via portal blood, called enterohepatic circulation of bile salts

Cholesterol is eliminated by loss of 0.5 g of bile salts per day

Congenital anomalies-Gallbladder

Includes duplication, bilobed gallbladder due to longitudinal or transverse septum, agenesis of hepatic or common bile duct, hypoplastic narrowing of biliary channels (true biliary atresia), and topics below

Abnormal position

Rare

Left sided (with or without situs inversus), intrahepatic (5%), retroperitoneal, suprahepatic; also within falciform ligament, lesser sac or abdominal wall

Agenesis (absence)

Rare; 50% discovered at autopsy

Usually no cystic duct either

Associated with choledocholithiasis, duodenal atresia and other congenital anomalies

No clinical significance

Cysts

May begin as pseudodiverticula (Rokitansky-Aschoff sinuses) with progressive occlusion of communication with gallbladder

Diverticula

Solitary, 6 mm to 8 cm

Rarely are congenital anomalies with all 3 layers of gallbladder wall

Usually pseudodiverticula (Rokitansky-Aschoff sinuses) with incomplete muscular wall; due to cholelithiasis or cholecystitis

Heterotopia

Also called ectopia or choristoma

Normal tissue in abnormal location

Usually incidental

Includes liver parenchymal nodules, usually 2.5 cm or less, suspended to gallbladder by mesenteric stalk (DD: accessory lobe); gastric heterotopia arising as intramural nodules, plaques or polyps, in neck or cystic duct, rarely with peptic ulceration; pancreatic heterotopia with acinar tissue, rarely islets, that may cause acute pancreatitis in gallbladder

Hourglass gallbladder

Divided by central constriction

Variant of transverse septate gallbladder

Usually acquired, due to septum of inflamed fibrous tissue or adenomyomatous hyperplasia

Hypoplasia

Associated with extrahepatic biliary atresia

Micro: compressed epithelium-lined structures, fibrous tissue, smooth muscle strands, inflammatory cells in gallbladder fossa and porta hepatis

Micro gallbladder

Defined as less than 2-3 cm long, 0.5 -1.5 cm wide

Associated with idiopathic neonatal hepatitis, alpha-1-antitrypsin disease, cystic fibrosis

Multiseptate gallbladder

Congenital or acquired

3-10 communicating compartments lined by columnar epithelium

Stones often present in adults

Phrygian cap

Inversion of distal fundus into body, to which it may become adherent

Either anatomic variant or acquired abnormality

Present in 5% of cholecystograms

Micro: may have small mucosal fold with disorganized muscle layer; may have focal adenomyoma at apex of inverted fundus

Wandering gallbladder

Long mesentery or no firm attachment to liver

At risk for torsion

Cholecystitis

Acute cholecystitis

Present in 5-10% of cholecystectomy specimens

Either gallstone associated (acute calculous cholecystitis) or not (acute acalculous cholecystitis)

10% perforate without treatment

Treatment: cholecystectomy

Gross: enlarged, distended gallbladder; congested vessels (“angry red color”), serosal and mucosal exudate, thickened wall with edema and hemorrhage; ulcers with blood clot, pus and bile

Micro: initially edema, congestion, hemorrhage, fibrin deposition in and around muscular layer; later mucosal and mural necrosis with neutrophils; variable reactive epithelial changes resembling dysplasia; finally myofibroblastic proliferation with chronic inflammatory infiltrate; also fresh thrombi within small veins

Note: diagnosis of dysplasia should be made cautiously if extensive ulceration or acute inflammation

DD: leptospirosis

Acute calculous cholecystitis

90% of cases

Mean age 60 years, 60% women

Abdominal pain, right upper quadrant tenderness, nausea, vomiting, fever, leukocytosis, mild jaundice

50% of those with jaundice have coexisting choledocholithiasis

Due to stone impaction, versus biliary colic, which is due to intermittent obstruction

50% have bacterial infection (E. coli, Enterobacter, Enterococcus, Klebsiella, Clostridium, Peptostreptococcus, Bacteroides)

1% mortality; perforation unlikely if early operation

Pathophysiology: chronic obstruction causes increased intraluminal pressure, vascular compromise, stasis and concentration of bile within lumen, mucosal damage, release of cellular enzymes, release of inflammatory mediators

Acute acalculous cholecystitis

10% of cases

2/3 male, mean age 50+ years

Often only fever or hyperamylasemia

Patients usually severely debilitated, due to severe trauma, sepsis, shock, burns, cancer, diabetes, multiple blood transfusions, surgery, torsion, cystic duct obstruction from various causes

May be associated with infection by CMV, cryptosporidia or microsporidia in AIDS patients

10-50% mortality

Case reports of leptospirosis in athletes swimming in freshwater lake mimicking acute cholecystitis, Hum Path 2001;32:750

Cocaine related acute cholecystitis

Young, otherwise healthy patients

Vascular thrombi present

Other parts of GI tract also affected

Chronic cholecystitis

Most cholecystectomies are performed for intermittent obstruction of gallbladder neck / cystic duct by gallstones, causing biliary colic

95% are associated with cholelithiasis

75% women, ages 40+

Complications: acute cholecystitis, choledocholithiasis, acute pancreatitis, gallstone ileus, biliary fistulas

Bacteria present in 11-30%, similar organisms as in acute cholecystitis

Giardia lamblia: associated with IgA deficiency, achlorhydria, malabsorption

Salmonella typhi: associated with chronic carrier states

Chronic active cholecystitis: with intraepithelial neutrophils

Rokitansky-Aschoff sinuses: tubular structures present within the wall in 90%, likely herniations or diverticula due to increased intraluminal pressure; called Luschka’s ducts if subserosal

Gross: variable thickening of gallbladder wall, variable adhesions

Micro: mild chronic inflammation with Rokitansky-Aschoff sinuses, granulomas (from ruptured Rokitansky-Aschoff sinuses), smooth muscle hypertrophy; neuromatous hyperplasia, hyalinized collagen, dystrophic calcification, lymphoid aggregates (5%); variable mucosal changes (normal, atrophic, ulcerated); variable metaplastic change

DD: normal gallbladder (if minimal inflammation), primary sclerosing cholangitis or extrahepatic bile duct obstruction (if abundant plasma cells and no gallstones),

Diffuse lymphoplasmacytic acalculous cholecystitis

Relatively sensitive for primary sclerosing cholangitis, but does not distinguish between primary and secondary cholangiopathies

Associated with lymphoplasmacytic sclerosing pancreatitis

Micro: diffuse, mucosal based, dense lymphoplasmacytic infiltrate without cholelithiasis

References: AJSP 2003;27:1313, AJSP 2003;27:441

AIDS related cholecystitis

Often acalculous

40% have opportunistic infections (cryptosporidia, CMV, microsporidia), which are usually also present at other sites

Cryptosporidia: small, round, basophilic organisms at luminal epithelial border

CMV: usually erosions and deep ulcers; marked microscopic changes

Microsporidia: Enterocytozoon bieneusi, less often Septata intestinalis; S. intestinalis within epithelium and lamina propria; can identify with H&E stain, but often missed

Usually no opportunistic infections if HIV+ but not classified as AIDS

Emphysematous cholecystitis

Rare form of acute cholecystitis

2/3 men, usually 50-70 years old

Associated with diabetes and peripheral atherosclerotic disease

May be due to vascular compromise of cystic artery

Associated with acalculous disease, gallbladder perforation, Clostridium welchii and E. coli infection

References: Radiographics 2002;22:543

Eosinophilic cholecystitis

Restrict usage to inflammatory infiltrates composed almost entirely of eosinophils, since eosinophils are common in subacute cholecystitis

1-5% of resected gallbladders

Often involves muscular layer, but may be transmural or mucosal

Associated with gallstones, fibroblasts

Causes: idiosyncratic reaction to biliary contents; less commonly due to erythromycin, ampicillin, cephalosporin, interleukin 2 and lymphokine activated killer cells, peripheral eosinophilia, hypereosinophilic syndrome, atopy, eosinophilic enterocolitis or appendicitis, parasitic infection, eosinophilic cholangitis, lymphoplasmacytic sclerosing pancreatitis (AJSP 2003;27:334)

Churg-Strauss syndrome: granulomatous angiitis with eosinophilia

Follicular cholecystitis

Also called lymphoid polyp

Well formed germinal centers throughout gallbladder wall

May grossly resemble polyps up to several mm in size

Associated with typhoid fever, primary sclerosing cholangitis

Gangrenous cholecystitis

Occurs in 15% of acute cholecystitis cases

Mural infarction, with perforation in 25%

Associated with Clostridium perfringes and air in gallbladder (pneumobilia)

Granulomatous cholecystitis

Causes: Mycobacterium tuberculosis, fungi, Crohn’s disease, primary biliary cirrhosis, parasites

DD: xanthogranulomatous cholecystitis (below)

Malakoplakia

Rare

Iron and calcium positive calcospherites (Michaelis-Guttmann bodies) in cytoplasm of histiocytes

Porcelain gallbladder

0.5% of cholecystectomies

20% of cases associated with gallbladder carcinoma

Gross: pearly white appearance due to dystrophic calcification

Xanthogranulomatous cholecystitis

1-2% of surgically excised gallbladders

Usually women ages 60-70 years

Due to rupture of Rokitansky-Aschoff sinuses with extravasation of bile, or ulceration of gallbladder mucosa

Complications include perforation, abscess formation, fistulous tracts, extension to liver, colon or soft tissue

Associated with malignancy

Gross: yellow-brown, poor to well-demarcated foci of wall thickening with variable ulceration, simulates neoplasm

Micro: foamy macrophages or macrophages with ceroid, bile or iron; also cholesterol clefts and multinucleated giant cells; may be focal, nodular or diffuse; may contain lymphocytes, plasma cells, foreign body giant cells and neutrophils

DD: carcinoma, sarcoma, inflammatory myofibroblastic tumor, other granulomatous cholecystitis

Miscellaneous non-tumor disorders

Adenomyomatous hyperplasia

Also called adenomyomatosis, diverticular disease of gallbladder

Benign; usually asymptomatic; relatively common (9% of cholecystectomy specimens)

Generalized, segmental or localized types

Generalized: diffuse wall thickening (up to 5x normal) with intramural diverticula resembling cystic spaces within the wall

Segmental: focal thickening in gallbladder wall, usually body, giving it an hourglass configuration

Localized: fundus has nodules from 0.5 to 2.5 cm with gray-white cut surface containing multiple cysts; may cause gallbladder inversion; also called adenomyoma

80% associated with chronic cholecystitis; rarely associated with dysplasia and carcinoma

Micro: circumscribed lesion of Rokitansky-Aschoff sinuses, often containing inspissated bile concretions, lined by columnar to cuboidal epithelium, within hyperplastic smooth muscle; surface epithelium may be papillary; may have reactive epithelial changes and metaplasia; rarely has perineural and intraneural invasion

DD: chronic cholecystitis

Choledocholithiasis

Stones in common bile duct

Primary: originate in common bile duct

Secondary: originate in gallbladder

40% of common bile duct stones are brown stones, usually associated with recurrence pyogenic cholangitis

Diagnosis: ERCP (95% sensitive and specific), ultrasound is only 50% sensitive

Cholelithiasis

Also called gallstones

Accounts for 1% of national heath care budget

Affects 10% of adults in developed countries (80% are silent) vs. <1% of children

80% of gallstones in West are cholesterol stones with 50% or more crystalline cholesterol monohydrate

20% of gallstones in West are pigment stones composed of bilirubin calcium salts

Gallstones impact at neck just proximal to cystic duct; typically within lumen but may be intramural

Risk factors: Pima, Hopi or Navajo (75% of stones are pure cholesterol vs. 25% in industrialized vs. minimal in developing countries), also Scandinavians, Chileans, Mexican-Americans, increasing age (>50% risk by age 80); “fat, fertile [multiple pregnancies], 40, female”, obesity, rapid weight loss, gallbladder stasis, genetic disorders that impair bile salt synthesis/secretion or increase cholesterol levels (serum or biliary), low HDL levels

Biliary sludge typically occurs before gallstones

Estrogens from birth control pills or pregnancy increase expression of hepatic LDL receptors, which increase cholesterol uptake, which stimulate HMG CoA reductase, which synthesizes cholesterol

Pigment stone risk factors are increased unconjugated bilirubin (from hemolytic syndromes, ileal dysfunction/bypass, bacterial contamination of biliary tree)

Clofibrate: anti-cholesterol drug that increases HMG CoA reductase activity and decreases conversion of cholesterol to bile acids by reducing cholesterol 7 alpha hydroxylase activity, causes excess biliary secretion of cholesterol

Symptoms: usually none, but may have biliary colic (severe, right upper quadrant pain)

Diagnosis: ultrasound (95% sensitive and specific for gallstones 2 mm or larger or gallbladder sludge), Xrays detect 10-25% of gallstones that are radiopaque due to calcium

Treatment: laparoscopic cholecystectomy if symptomatic or in children, Native Americans, patients with sickle cell disease or porcelain gallbladder, stones 3 cm or larger

Complications: 1-2% have acute or chronic cholecystitis, choledocholithiasis, cholangitis, empyema, gallstone ileus, acute pancreatitis

Mirizzi’s syndrome: rare; stone impacting in cystic duct or gallbladder neck causes extrinsic compression or obstruction of common bile duct, causing jaundice

Report: presence of biliary sludge, number, size and type of gallstones

Gross: 85% are 2 cm or less

Micro: minimal/mild lymphocytic mucosal inflammation, Rokitansky-Aschoff sinuses, fibrosis, thickening of muscularis propria, cholesterolosis, focal epithelial metaplasia (pyloric/gastric mucin cell metaplasia or intestinal metaplasia)

References: AJSP 2003;27:1313

Cholesterolosis

Present in 20% of cholecystectomy specimens, usually adult multiparous women

Asymptomatic

Associated with bile supersaturation with cholesterol, but not with increased serum cholesterol

Due to accumulation of cholesterol esters and triglycerides in subepithelial macrophages and gallbladder epithelium

Gross: yellow, flat deposits on mucosal surface, focal or diffuse; may have speckled appearance (“strawberry gallbladder”), 20% are associated with cholesterol polyps

Micro: foamy macrophages in lamina propria and epithelium; villous mucosal hyperplasia with macrophages at tips of villi; usually no or minimal cholecystitis; may be polypoid, rarely with heterotopic bone (AJSP 2000;24:895); usually changes are restricted to gallbladder and don’t involve extrahepatic bile ducts

Positive stains: Oil red O / Sudan black (on frozen tissue)

Fistula

Biliary-enteric fistulas found in 0.2 to 5.0% of patients with biliary tract surgery for non-malignant disease

90% due to cholelithiasis, 10% due to penetrating peptic ulcers of stomach or duodenum

Pathophysiology: gallstones cause inflammation and necrosis of gallbladder or bile duct wall, leading to intestinal adhesions, leading to fistula

Sites: from gallbladder in 90%, biliary tract in 10%; usually to duodenum, also colon

Diagnosis: air within biliary tree by Xray, vomiting or passing a large gallstone

Mortality: 15%

Complications: gallstone ileus

Gallbladder in extrahepatic bile duct obstruction

Diffuse, bandlike, superficial chronic inflammatory infiltrate of predominantly plasma cells suggests primary sclerosing cholangitis, ulcerative colitis

Chronic active cholecystitis and chronic acalculous cholecystitis suggests primary sclerosing cholangitis, choledocholithiasis or other extrahepatic bile duct obstruction

Gallstone classification

Gallstones composed of insoluble bile components: cholesterol, calcium bilirubinate, calcium salts (organic and inorganic), bile salts, mucin glycoproteins

In U.S., 75-85% are cholesterol stones, 15-25% are pigment stones

Calcium stones are gray-white and amorphous; very uncommon

Calcium carbonate may fill lumen as thick, inspissated, cream-gray to yellow-green putty-like material

Cholesterol stones

75-85% of all gallstones

Only 10% are pure (at least 90% cholesterol), the remainder are mixtures with at least 60% cholesterol by weight

Cholesterol monohydrate precipitates when no longer soluble in bile; initially bile supersaturation with cholesterol occurs; then nucleation (initial crystallization), then stone growth facilitated by bile stasis and mucin hypersecretion

Pure and mixed occur predominantly in women; also associated with increasing age, obesity, rapid weight loss, diabetes, ileal disease, multiple pregnancies, total parenteral nutrition, various drugs, specific ethnic groups

Gross: less than 1 cm to 4 cm; single or multiple; white-yellow, round/oval with crystalline cut surface

Pigment stones

15-25% of all gallstones

Associated with increasing age

Less than 25-35% cholesterol

Brown (not black) stones associated with infected bile (usually E. coli) due to acute cholecystitis or choledocholithiasis with cholangitis

Black stones associated with older age, chronic hemolysis, cirrhosis, sclerosing cholangitis (increased unconjugated bilirubin in bile)

Composed of calcium bilirubinate, calcium salts, mucin glycoprotein

Gross: multiple shiny black stones, 0.2 to 5 cm, rarely brown in US (more commonly brown in Japan)

Gallstone ileus

Bowel obstruction due to gallstone entering intestine through cholecystoenteric fistula

Occurs in 20% of cases of gallstones passing into intestine

Usually single stones, 3-4 cm

Involves distal ileum (65-80%), also jejunum (20%), colon (3%), rarely appendix

Gallbladder usually small, fibrotic with adhesions

DD: enterolith (bile acid stones that form in situ within the bowel)

Hydrops / mucocele

Distended gallbladder containing clear and watery (hydrops) or mucoid secretions (mucocele), instead of bile

Adult cases almost always due to impacted stones in ampulla or cystic duct; rarely due to regional tumors causing compression

Pediatric cases associated with Kawasaki syndrome or other inflammatory narrowing of cystic duct

Mucoceles that perforate may cause pseudomyxoma peritonei

Gross: thickened gallbladder wall

Micro: adults - fibrous replacement of muscular wall; rarely muciphages simulating signet ring adenocarcinoma; children - thin wall with flattened epithelium and sparse inflammation

Metaplasia

Usually gastric or intestinal, rarely squamous

Associated with older age, gallstones

Gastric gland metaplasia

66-84% of cholecystectomy specimens

Pyloric, antral or mucous glands

Glands usually scattered in lamina propria but may extend into muscular layer

May form polyps

Don’t call adenoma unless dysplasia present

Intestinal metaplasia

12-52% of cholecystectomy specimens

Goblet cells, endocrine cells, Paneth cells, absorptive cells; also pyloric gland metaplasia

Rarely forms polyps

Papillary hyperplasia

Usually secondary to inflammatory disorders (chronic cholecystitis [5-20%] or cholelithiasis, adenomyomatous hyperplasia, primary sclerosing cholangitis, ulcerative colitis), cholesterolosis (up to 100%) or anomalous arrangement of pancreaticobiliary duct (40-90%)

Diffuse or focal

Micro: single layer of columnar epithelium in papillary mucosal folds, may be villiform; basal nuclei, no atypia

Vasculitis

Rare

Associated with cholecystitis, but only 20% have gallstones or sludge

Vasculitis often due to polyarteritis nodosa (involves gallbladder at autopsy in 10-40%)

Benign gallbladder tumors

Adenoma of gallbladder

By definition, contains at least low grade dysplastic epithelium

Found in 0.5% of cholecystectomy specimens, usually asymptomatic

Increased prevalence found with familial adenomatous polyposis or Peutz-Jeghers syndrome

70% women

Invasive carcinoma rare if < 1 cm

Entire lesion should be submitted for microscopic examination

Not a premalignant lesion since different molecular abnormalities from carcinoma, Hum Path 1999;30:21

Treatment: total excision

Gross: 3-25 mm polypoid structure projecting into lumen; may be sessile; 90% are single

Micro: usually tubular with pyloric gland features; papillary or intestinal types associated with high grade dysplasia; may have squamous morules

Positive stains: estrogen receptors (50%)

Adenomyosis

15-25% of benign polyps

See also adenomyomatous hyperplasia

Gross: 5-25 mm, usually in fundus in muscular layer; gray-white

Micro: hyperplasia of muscularis propria with intramural hyperplastic or cystically dilated glands

Cholesterol polyp

Most common benign polyp (50-90%)

Morphologic variation of cholesterolosis

Usually women (75%), 40-50 years old

Gross: 4-15 mm, yellow, soft, pedunculated, often multiple

Micro: mucosal projections with lipid-laden macrophages covered by normal gallbladder epithelium

Granular cell tumor

Often associated with similar lesions in extrahepatic bile ducts

Gross: nodules in gallbladder wall

Micro: large cells with abundant, eosinophilic, granular cytoplasm

Positive stains: S100, PAS+ granules, inhibin-alpha

References: AJSP 2001;25:1200 (inhibin-alpha staining)

Hyperplastic / metaplastic polyp

Common (25% of benign polyps)

Gross: < 5 mm, brown-gray, granular or villiform, sessile or pedunculated, usually multiple

Micro: usually nodules of pyloric-type glands

DD: gastric heterotopia (also parietal and chief cells)

Inflammatory polyp

15% of benign polyps

Associated with chronic cholecystitis

Gross: 3-15 mm, red-gray-brown, usually sessile and single

Micro: sessile mucosal projections with a surface of columnar epithelial cells covering a fibrous stroma with chronic inflammatory cells and lipid-laden macrophages in granulation-type tissue

Villous papilloma

Associated with metachromatic leukodystrophy in children and adults

May cause massive hemobilia

Dysplasia

Dysplasia-general

Neoplastic intraepithelial proliferation

Present in 1-34% of cholecystectomy specimens (severe dysplasia in 1-3%)

May be associated with invasive carcinoma

Diagnose with caution if extensive ulceration or acute inflammation

Extensive sampling recommended after diagnosis (can use jelly roll technique used for placentas)

Gross: granular mucosal patches or no gross findings

Micro: involves flat mucosa, papillae, Rokitansky-Aschoff sinuses, metaplastic pyloric glands; abrupt transition from normal mucosa; may resemble carcinoma but no desmoplasia; often goblet cells

Low grade: crowding and hyperchromatic and elongated nuclei

High grade: low grade features plus stratification; includes carcinoma in situ

DD: reactive epithelial changes (no abrupt transition from normal mucosa, prominent nucleoli, epithelial atypia proportional to stromal atypia)

Dysplasia-carcinoma sequence

Major pathway to invasive gallbladder carcinoma

Adenomas do not appear to be important precursors

Hyperplasia may not be part of this sequence

Malignant gallbladder tumors

Gallbladder carcinoma

Relatively uncommon; age 60+ years (mean 72 years), 75% women, usually not resectable

Incidence: 2.5 per 100,000 population; 6500 annual deaths in US vs. largest cause of cancer death for women in Chile

Often invades liver, common bile duct, stomach, duodenum and transverse colon; 70% involve liver at diagnosis, 50% involve regional lymph nodes

Metastases to peritoneum and liver, pericholedochal lymph nodes of lesser omentum, occasionally to lungs and pleura

5 year survival: overall 1%; 85-100% for T1, 30-40% for T2; median survival 6 months

Associated with gallstones (2/3), American Indians, Hispanics, cholecystoenteric fistula, porcelain gallbladder, ulcerative colitis, adenomyomatosis, polyposis coli / Gardner’s syndrome, Peutz-Jeghers syndrome, anomalous connection between common bile duct and pancreatic duct; lower incidence in Asia, where pyogenic and parasitic disease of biliary tree are more common; very rare in blacks

90% are adenocarcinoma, 5% squamous cell or adenosquamous, 5% undifferentiated

Prognostic factors: favorable - papillary histology, low stage; unfavorable - small cell or undifferentiated types, angiolymphatic invasion, poorly differentiated, high stage

Treatment: cholecystectomy (T1 tumors), uncertain for more advanced tumors; tumor may recur at trochar site after laparoscopic cholecystectomy

Case reports: poorly differentiated adenocarcinoma presenting as meningeal carcinomatosis (Archives 2001;125:1120)

Gross: fibrosis and thickening of wall, may be papillary and diffuse; often associated with gallstones > 3 cm; tumor may not be obvious, although liver spread is usually evident at time of diagnosis

Micro: infiltrative (diffuse thickening and induration of wall with possible fistula formation due to deep ulceration) or exophytic (irregular, cauliflower mass that grows into lumen and invades wall); well formed glands in papillary architecture with wide lumina, atypical cuboidal cells, high grade; may extend to Rokitansky-Aschoff sinuses (but this does not signify deep invasion); superficial portion is often better differentiated than deeper portion; may have foci of intestinal differentiation

Positive stains: keratin, CEA, P504S

References: AJSP 2002;26:758 (beta catenin expression), Mod Path 2003;16:299 (oncogenes), Radiographics 2001;21:295 (review with numerous images)

Carcinoma in situ

Often an incidental finding after cholecystectomy for cholecystitis or cholelithiasis

Not associated with tumor related death

Micro: may extend into Rokitansky-Aschoff sinuses resembling invasive carcinoma, but is connected to surface epithelium, has mixture of benign and neoplastic epithelium, has inspissated bile in long dilated spaces, and lacks invasion into smooth muscle bundles; may arise in adenomyomatous hyperplasia; no perineurial invasion

References: AJSP 2004;28:621

Clear cell carcinoid tumor

Rare; carcinoid tumors in general are rare in gallbladder and may be associated with MEN syndromes and Zollinger-Ellison syndrome

Case reports: 38 year old man with von Hippel-Lindau disease (AJSP 2001;25:1334), 64 year old man without von Hippel-Lindau disease (Archives 2003;127:745)

Micro: nests and tubules of clear cells containing lipid; may have pagetoid spread into biliary epithelium; resembles clear cell endocrine pancreatic neoplasm associated with von Hippel-Lindau disease

Positive stains: AE1-AE3, CK7, chromogranin, synaptophysin; inhibin in von Hippel Lindau patients

Negative stains: serotonin

DD: metastatic renal cell carcinoma

Ewings/PNET

Initial case report in 53 year old woman, Archives 2004;128:571

Micro: monotonous small round cells with Homer-Wright rosettes

Positive stains: CD99/MIC2, NSE, synaptophysin

Negative stains: CD45/LCA, desmin, S100

Gastrointestinal stromal tumor

Very rare (<10 cases reported)

Benign or malignant behavior

Case reports: 69 year old woman (AJSP 2000;24:1420), 34 year old woman (Archives 2002;126:481)

Micro: bland spindle cells with hyperchromatic nuclei

Positive stains: CD117, vimentin, variable CD34

Negative stains: smooth muscle actin, desmin, myoglobin, cytokeratin, S100

Large cell neuroendocrine carcinoma

Very rare (<10 cases reported)

Similar to pulmonary counterpart

Micro: organoid growth pattern with rosettes and necrosis; large cells, prominent nucleoli, coarse chromatin, high mitotic rate; may have intestinal metaplasia of tumor cells or adjacent mucosa

Positive stains: endocrine markers

Negative stains: high molecular weight cytokeratin

References: AJSP 2000;24:1424 (report of 2 cases)

Metastases to gallbladder

6% of patients dying of carcinoma at any site have metastases to gallbladder

Most common are melanoma and lung cancer

Mucinous tumor

Very uncommon

Case report in 83 year old Japanese man with separate nodule of anaplastic carcinoma, Archives 1999;123:1280

Sarcomatoid carcinoma

Also called spindle cell carcinoma, carcinosarcoma

< 50 cases reported in gallbladder

Usually elderly women

Both components (spindled and epithelial) appear to be derived from single clone, Hum Path 2004;35:418

Usually death within 6 months of diagnosis

Case report of 61 year old woman with tumor containing rhabdoid component, Archives 2003;127:e406

Gross: polypoid, firm, solid, yellow-gray, granular with necrosis

Micro: malignant epithelial and sarcomatous components; neoplastic glands contain mucin or rarely include squamous cell carcinoma; sarcomatous component consists of pleomorphic or spindle cells, sometimes with heterologous osteosarcoma, chondrosarcoma or rhabdomyosarcoma

Positive stains: cytokeratin and EMA in both components; CEA in epithelial component

Small cell carcinoma

Rare

High grade neuroendocrine carcinoma resembling tumor of lung

Mean age 69 years, slight female predominance

75% had local extension or metastasis at surgery

50% had other coexisting neoplasms, usually adenocarcinoma

Mean survival 11 months, range 3-25 months

No systemic endocrine symptoms

Gross: mean 3 cm

Micro: sheets of small cells with hyperchromatic nuclei, finely stippled chromatin, inconspicuous nucleoli, nuclear molding, Azzopardi phenomenon (basophilic staining of blood vessel walls by DNA deposition), scant cytoplasm; may have minor component of tumor cells in trabeculae, nests or ribbons; frequent mitotic activity, necrosis and apoptosis; invasion of muscularis propria and perimuscular connective tissue in 90%

Positive stains: AE1-AE3, CAM5.2, chromogranin, NSE, Leu7, CEA (25%)

Molecular: p53 (75%), p16 INK4a (33%), K-ras codon 12 abnormalities (17%); no DPC4 mutations

EM: dense core secretory granules

References: AJSP 2001;25:595

Squamous cell carcinoma

Micro: cords,islands, sheets of malignant squamous cells separated bydense fibrous stroma; anaplastic to well-differentiated, keratinizingtumors

Miscellaneous

TNM staging for Gallbladder carcinoma

Classification excludes sarcomas and carcinoid tumors

Primary tumor (T)

TX: primary tumor cannot be assessed

T0: no evidence of primary tumor

Tis: carcinoma in situ (high grade dysplasia)

T1: tumor invades lamina propria or muscle layer

T1a: tumor invades lamina propria

T1b: tumor invades muscle layer

T2: tumor invades perimuscular connective tissue; no extension beyond serosa or into liver

T3: tumor perforates the serosa (visceral peritoneum) or directly invades the liver or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum or extrahepatic bile ducts

T4: tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures

Regional lymph nodes (N)

NX: regional lymph nodes cannot be assessed

N0: no regional lymph node metastasis

N1: regional lymph node metastasis

Distant metastasis (M)

MX: distant metastasis cannot be assessed

M0: no distant metastasis

M1: distant metastasis

Notes:

Direct extension into liver, colon, duodenum, stomach, common bile duct, abdominal wall or diaphragm is not considered a metastasis

Stage grouping

0 : Tis N0 M0

IA : T1 N0 M0

IB : T2 N0 M0

IIA : T3 N0 M0

IIB : T1-T3 N1 M0

III : T4 any N M0

IV : any T any N M1

Frozen section

Optimally should have clinical data and serum AFP levels available

Should know if specimen is from a mass

Grossing

Sample tumor thoroughly, margins, normal bile duct

Larger masses/carcinoma

Submit several full thickness sections, including areas of deepest penetration; cystic duct margin, hepatic margin, extent of penetration into liver (if applicable)

Features to report

Tumor size and location

Tumor histologic type and pattern

Depth of invasion

Number and size of tumor nodules

Tumor extension to adjacent structures

Status of resection margins (cystic duct, liver bed, other)

Cystic duct involvement

Liver bed involvement

Regional lymph nodes: number identified, number with tumor

Angiolymphatic invasion

Perineural invasion

Presence of carcinoma in situ or dysplasia

References: Archives 2000;124:37

Extrahepatic bile ducts

Normal anatomy

Right and left hepatic ducts: 3-4 mm in diameter, within hepatoduodenal ligament, join to form common hepatic duct in porta hepatis (hilum of liver) within 1 cm of their exit from liver

10-30% have variation of 2 right sided ducts that join separately with left hepatic duct, common hepatic duct or cystic duct

Common hepatic duct: 2-8 mm, 1-5 cm long, joins cystic duct (1-3 cm long) to form common bile duct

Common bile duct: 2-9 cm long, passes posterior to first portion of duodenum, traverses the head of pancreas, enters the second part of duodenum through the ampulla of Vater and discharges gallbladder contents into duodenal lumen; 60% have common channel for pancreatic duct and common bile duct; remainder have 2 ducts in parallel

Cystic duct: attaches gallbladder to extrahepatic bile duct, marks division between common hepatic duct and common bile duct; usually 2-4 cm; contains spiral valves of Heister

Sacculi of Beale: tiny pits that are infoldings of surface epithelium, and give mucosa a reticular macroscopic appearance

Spiral valves of Heister: folds in proximal mucosa of cystic duct, supported by underlying smooth muscle fibers; regulates degree of gallbladder distension

Normal histology-extrahepatic bile ducts

Surface epithelium: composed of tall, uniform, columnar cells; mucosa forms irregular pleats or small longitudinal folds

Peribiliary mucous glands: unevenly distributed within large intrahepatic ducts and all extrahepatic bile ducts; have lobular architecture and surrounded by fibroconnective tissue (important in differentiating from well differentiated carcinoma),

Subepithelial region: dense, hypocellular connective tissue, few lymphocytes; overlies loose connective tissue with elastic fibers and smooth muscle fibers that are most prominent distally but absent or sparse proximally

Muscle layer: not well defined until distal common bile duct (lower 1/3 of extrahepatic bile duct); upper 1/3 has no muscle layer or scattered muscle fibers

References: AJSP 2000;24:660

Grossing: may want to submit entire specimen; submit margins separately, including hepatic margin (if liver tissue present)

Positive stains: peribiliary glands - amylase, trypsin, lipase

Extrahepatic bile duct metaplasia

Pyloric gland metaplasia and less commonly intestinal metaplasia are associated with neoplasms and inflammation

References: Mod Path 2001;14:1119

Congenital anomalies-extrahepatic bile ducts

Choledochal cyst

Incidence: 1 per 13,000 live births in US vs. 1 per 1000 in Japan; 75% girls

Most common cause of obstructive jaundice in infants beyond infancy, but may be found at any age

Associated with other hepatobiliary tract abnormalities

May rupture spontaneously, be associated with reflux of pancreatic enzymes into bile duct

Associated with stones in 1-30% of cases

Not actually a cyst, but a dilation of common bile duct which may secondarily obstruct other biliary ducts or the duodenum

Type 1: segmental or diffuse fusiform dilation of common bile duct (50-90%)

Type 2: diverticulum of common bile duct

Type 3: dilation of intraduodenal common bile duct (choledochocele)

Type 4: multiple cysts of extrahepatic bile ducts with (4A) or without (4B) cysts of intrahepatic ducts

Type 5: one or more cysts of intrahepatic ducts (Caroli’s disease)

2-8% develop biliary tract carcinoma (20x normal risk) at mean age 34 years, lower risk if surgery earlier in life (age 10 years or less), carcinoma may develop within wall of cyst, within gallbladder or bile ducts

Treatment: complete cyst removal with biliary reconstruction, usually with Roux-en-Y hepaticojejunostomy

Case report: case associated with multilocular pancreatic cyst, Hum Path 2003;34:99

Gross: contain 1-2 liters of bile, up to 15 cm in diameter; wall is fibrous, variable calcification, 2-10 mm thick

Micro: focal columnar epithelium (more intact in infants); walls composed of dense fibrous tissue, scattered smooth muscle and elastic fibers; variable chronic inflammatory infiltrate (increases with age); variable hyperplasia, metaplasia, dysplasia

Extrahepatic biliary atresia

Most frequent extrahepatic cause of neonatal cholestasis, causes 1/3 of all neonatal cholestasis

1 per 10,000 live births worldwide, 70% girls, usually from uncomplicated pregnancies

Associated with cardiovascular defects and polysplenia (10-25%), small gallbladder

Acquired sclerosing inflammatory disorder that replaces bile ducts by threadlike cord embedded in fibrous tissue of porta hepatis; leads progressively to loss of intrahepatic ducts and biliary cirrhosis

Most common cause of childhood death from liver disease; reason for 50% of pediatric liver transplants

Laboratory: persistent conjugated hyperbilirubinemia

Treatment: Kasai procedure (portoenterostomy) before 10-12 weeks may be more helpful if hilar bile ductal structures are patent with lumina 1-4 mm or greater; frozen section useful to determine if bile ducts in hilum are present and what their caliber is; liver transplantation may be curative

Gross: total or focal complete fibrous obliteration of major hepatic duct lumina or common bile duct

Micro: early - obstructive changes with ductular proliferation, variable portal edema, lobular cholestasis; variable multinucleated giant hepatocytes; late - ductopenia

Positive stains: CD56 (helpful to differentiate from other causes, AJSP 2003;27:1454)

Primary sclerosing cholangitis

Chronic cholestatic disorder of unknown origin (possibly autoimmune) involving entire biliary tract from ampulla of Vater to small intrahepatic bile ducts or gallbladder

Much less common than secondary sclerosing cholangitis

Rule of 70’s: 70% men, 70% have chronic inflammatory bowel disease (particularly ulcerative colitis which is usually detected first; only 4% with ulcerative colitis have primary sclerosing cholangitis, which is unaffected by colectomy), 70% younger than age 45

Also associated with chronic pancreatitis (15-25%), Riedel’s thyroiditis, retroperitoneal and mediastinal fibrosis, orbital pseudotumor, Sjogren’s syndrome, angioimmunoblastic lymphadenopathy

Symptoms: fatigue, pruritis, jaundice

Complications: biliary cirrhosis and liver failure in all cases with median survival 9-12 years; cholangiocarcinoma (10-43%), colon carcinoma

End stage disease is associated with hyperplasia of glands of extrahepatic bile ducts, with low incidence of dysplasia and adenocarcinoma, AJSP 2003;27:349

Laboratory: elevated serum alkaline phosphatase, IgM, IgG; variable bilirubin; may be p-ANCA positive

Xray: beading of barium column in cholangiogram due to irregular strictures and dilations of affected bile ducts

Treatment: liver transplant since no effective medical therapy (associated with autoimmune liver disease in 42% and recurrence in 33%)

Gross: periductal portal tract fibrosis, segmental stenosis of extrahepatic and intrahepatic bile ducts

Micro: fibrosing cholangitis of intra- and extrahepatic bile ducts with lymphocytic infiltration; progressive atrophy of bile duct epithelium and obliteration of the lumen, diffuse bile ductular proliferation; “onion skin” fibrosis around affected ducts, which later disappear, leaving cord-like fibrous scar; remaining ducts are ectatic and inflamed; mild to florid hyperplasia often noted; recurrence after transplant exhibits bile duct structuring and nonspecific autoimmune hepatitis with variable fibrosis; variable portal eosinophils

Staging: 1-inflammation without expansion of portal tracts or piecemeal necrosis, 2-piecemeal necrosis or fibrosis without bridging, 3-bridging necrosis or fibrosis, 4-cirrhosis

DD: sclerosing, well differentiated adenocarcinoma

References: Hum Path 2003;34:1127 (transplants)

Secondary sclerosing cholangitis

Much more common than primary sclerosing cholangitis

Causes: biliary obstruction (choledocholithiasis, post-operative, chronic pancreatitis, choledochal cyst, extrahepatic biliary atresia), infection (immunodeficiency states), toxins, ischemia, malignancy, other (chronic graft vs. host disease, sarcoidosis, Langerhans cell histiocytosis, systemic mastocytosis)

Associated with hepatic lobar atrophy, bacterial infection

Micro: fibrosis, inflammation, ulceration, foreign body granulomas

DD: bile duct carcinoma (no lobular pattern of peribiliary glands, no concentric fibrosis around peribiliary glands, infiltrating glands, perineural invasion, often marked cytologic atypia)

Tumors of extrahepatic bile ducts

Adenoma

Incidence only 10% of carcinoma; more common in gallbladder than extrahepatic biliary tree

Treatment: total excision

Gross: 1-3 cm, usually in common bile duct; single or multiple; pedunculated or sessile

Micro: tubular, tubulovillous, villous; low to high grade dysplasia; usually lined by pseudostratified columnar epithelium and composed of intestinal type glands with goblet cells, endocrine cells, Paneth cells

Carcinoid tumor

0.3% of tumors in extrahepatic bile ducts

2/3 women, mean 50 years old, range 37-67 years

No systemic endocrine symptoms

Rarely associated with MEN1 and von Hippel-Lindau syndrome

Indolent course with long survival even if nodal or hepatic metastases

Micro: nests, cords or trabeculae of small cells with granular chromatin; perineural and vascular invasion is common

Positive stains: chromogranin, synaptophysin, serotonin, loss of DPC4

Negative stains: p53

EM: numerous membrane bound, round, neurosecretory granules

References: AJSP 2000;24:1501

Carcinoma of extrahepatic bile ducts

90-95% of extrahepatic bile duct malignancies are adenocarcinomas (bile duct carcinoma, cholangiocarcinoma)

Present in 0.5% of autopsies

Incidence: 1 per 100,000 in US; 2-3 times less common than gallbladder carcinoma

More common in Native Americans, Mexicans, Israelis, Japanese

Painless, progressive jaundice; 1/3 have gallstones (10% in bile ducts themselves), 20% had prior biliary tract surgery

Usually ages 60+; rare before age 40; younger age at diagnosis if risk factors below

Risk factors: Clonorchis sinensis and Opisthorchis viverrini infestations, primary sclerosing cholangitis, chronic ulcerative colitis, choledochal cysts, Caroli’s disease, congenital hepatic fibrosis; also cystic fibrosis, familial polyposis coli, chronic typhoid carriers, biliary giardiasis, Thorotrast exposure

Small at diagnosis because even small tumors cause obstruction and jaundice

Local extension to liver, pancreas, ampulla of Vater, duodenum, colon, omentum, stomach, gallbladder

Tumors from right or left hepatic duct usually extend proximally into liver or distally to common hepatic duct; tumors from cystic duct extend to gallbladder or common bile duct; tumors from distal common bile duct extend to pancreas, duodenum, stomach, colon, omentum

Metastases to regional lymph nodes, liver, lungs, peritoneum

Laboratory tests: elevated alkaline phosphatase but normal serum bilirubin suggests location above hepatic duct bifurcation or incomplete common bile obstruction

Diagnosis: tissue diagnosis is optimal because clinical diagnosis is often incorrect; also brushings, bile drainage cytology

Prognostic factors: favorable - low stage, papillary histology, distal tumors, unfavorable - high grade or high stage tumors, positive surgical margins, hilar tumors

Prognosis: mean survival 6-18 months, 2 years if resectable, 5 year survival is 5%

T1 tumors: rare, but 60% 5 year survival

Klatskin (hilar) tumors: 70% of tumors; arise at confluence of right and left hepatic ducts at liver hilus; slow growing with infrequent distant metastases, have marked sclerosing characteristics; poorer prognosis since difficult to resect; 28-89% have positive margins

Treatment: Klatskin tumors require resection of hepatic duct bifurcation; distal tumors may require Whipple procedure

Gross: either firm, gray nodules within bile duct wall or diffusely infiltrative (2%); often extends into adjacent structures; limits of tumor often difficult to detect due to desmoplasia; tumors may be papillary, multifocal and friable

Micro: nodular or diffusely infiltrative tumors with marked desmoplastic response; sclerosing, nodular, polypoid-papillary or mixed types; resembles gallbladder carcinoma; most are well or moderately differentiated with conspicuous glands, but have extensive perineural invasion; even well differentiated tumors may have poorly differentiated foci deep within wall; mucin always present within tumor cells and glandular lumina; tumor cells cuboidal or columnar, with vesicular nuclei and prominent nucleoli; usually angiolymphatic invasion, necrosis and chronic inflammatory infiltrate; often adjacent intestinal and pylori metaplasia; dysplasia usually present

Variants include adenosquamous, clear cell, colloid, mucoepidermoid, small cell, squamous cell, undifferentiated (pleomorphic, sarcomatoid, giant cell) carcinomas

Difficult cases are extremely well differentiated, but still have thickened duct wall with prominent desmoplastic response and perineural invasion

Positive stains: mucin, CEA, CK7

Negative stains: CK20

DD: sclerosing cholangitis (no perineural invasion, no random glandular infiltration), metastatic carcinoma (breast, colon, ovary, kidney), primary tumors of adjacent sites (pancreas, liver, ampulla, duodenum, gallbladder, stomach, colon), intraductal spread (hepatocellular carcinoma, cholangiocarcinoma, metastatic carcinoma)

References: AJSP 2000;24:870 (CK7/CK20), Archives 2000;124:870

Papillary carcinoma

Usually biliary phenotype; also intestinal

Often extend into pancreas or liver

Often dedifferentiate

Papillary carcinomas confined to ductal wall have better 10 year survival than adenocarcinomas confined to ductal wall; better survival even if nodal metastases

References: Mod Path 2002;15:1309

Cystadenoma

More uncommon in extrahepatic biliary system than in liver; extremely rare in gallbladder

Usually women ages 42-55 years

Resembles pancreatic cystadenoma

Treatment: excision, may recur or become malignant

Gross: unilocular or multilocular; well defined cystic masses with serous, mucinous, bilious, hemorrhagic or mixed fluid; outer fibrous wall; inner surface is smooth, granular or trabeculated

Micro: multiple locules lined by biliary-type cuboidal or columnar epithelium; stroma is cellular, resembling ovarian stroma in 85%, surrounded by hyalinized fibrous tissue; 13% have dysplastic changes

Dysplasia of extrahepatic bile ducts

Spectrum from hyperplasia to high grade dysplasia to invasive adenocarcinoma exists, similar to intraductal papillary mucinous neoplasms

Micro: may have prominent subnuclear vacuoles

DD: papillary hyperplasia

References: Archives 2000;124:387 (cytology)

Granular cell tumor of extrahepatic bile ducts

Most common benign nonepithelial tumor of extrahepatic biliary tree

Usually young to middle-aged (mean 34 years) black (65%) women (91%)

Biliary tree sites: common bile duct or cystic duct; also gallbladder (4%), intrahepatic ducts (4%)

Gross: nonencapsulated, 85% solitary, < 3 cm, yellow-tan-white

Micro: large polygonal cells with abundant, eosinophilic, granular cytoplasm and central, small, dark, uniform nuclei

Positive stains: S100, PAS+ granules, inhibin-alpha

References: AJSP 2001;25:1200 (inhibin-alpha staining)

Intraductal papillary neoplasms of biliary tract

Uncommon

Solitary, or may spread along biliary tree to cystic duct or duodenal papilla

May resemble intrapapillary mucinous neoplasms of pancreas as both arise within a dilated duct system and demonstrate predominantly intraductal growth

Risk factor for cholangiocarcinoma, biliary obstruction, recurring ascending cholangitis

Are often carcinomas

Micro: papillary fronds with fine vascular cores; epithelial cells are either biliary type or have gastric or intestinal differentiation with goblet cells and Paneth cells; production of extracellular intraductal mucin less common than papillary IPMN

Borderline tumors: mild to moderate nuclear atypia and nuclear pseudostratification limited to basal 2/3 of the epithelium

Carcinomas: severe cytological atypia, loss of nuclear polarity, or architectural cribriforming/papillary fusion is present

Negative stains: p53, CK20

Molecular: Kras activating mutations (29%), 18q- (31%) but no loss of DPC4; often has microsatellite instability (Mod Path 2002;15:1309)

References: Hum Path 2003;34:902, Hum Path 2002;33:503 (stains)

Metastases to extrahepatic bile ducts

Various, including colon, stomach, pancreas, breast, kidney, lymphoma

Neurofibroma

Very rare

Micro: fascicles of spindle cells with wavy nuclei in loose myxoid stroma

Positive stains: S100

Papillomatosis

Also called adenomatosis

Rare; multiple and recurrent papillary adenomas in biliary tract, usually involving extrahepatic bile ducts

Usually ages 50-60 years, no gender preference

Treatment: complete excision, but local recurrence is common

Gross: dilated bile ducts with thick, fibrotic walls; entire mucosal surface may be replaced by papillary adenomas; intraluminal mucin common; adenomas tan, soft, friable polyps without gross invasion

Micro: columnar or cuboidal cells with basal nuclei overlying fibrovascular core

Rhabdomyosarcoma of extrahepatic bile ducts

<1% of bile duct malignancies are sarcomas; most common sarcoma is embryonal rhabdomyosarcoma

In children past infancy, #2 cause of obstructive jaundice (after choledochal cysts); usually 3-4 years old with fever, weight loss, jaundice

Usually embryonal or botyroid subtypes

40% have metastases, usually to regional lymph nodes, distal metastases less common

Often extends into liver or gallbladder

Sites: common bile duct (77%)

Treatment: surgery, chemotherapy, radiation therapy may produce long term survival

Gross: botyroid tumors have white-tan, edematous, polypoid grapelike features; tumor 3-14 cm

Micro: embryonal tumors have condensed (cambium) layer of primitive spindle cells just below surface epithelium; rhabdomyoblasts may be prominent with abundant eosinophilic cytoplasm; may have relatively acellular layer with myxoid stroma

Positive stains: desmin, muscle specific actin, MyoD1, variable myoglobin

EM: thick and thin filaments

Traumatic neuromas

Often post-operative, at stump of cystic duct

May cause postcholecystectomy pain or obstructive jaundice

TNM staging for extrahepatic bile duct carcinoma

Applies to carcinomas arising above ampulla of Vater, including carcinomas in congenital choledochal cysts and intrapancreatic portion of common bile duct

Classification excludes sarcomas and carcinoid tumors

Primary tumor (T)

TX: primary tumor cannot be assessed

T0: no evidence of primary tumor

Tis: carcinoma in situ

T1: tumor confined to the bile duct histologically

T2: tumor invades beyond the wall of the bile duct

T3: tumor invades the liver, gallbladder, pancreas or unilateral branches of the portal vein (right or left) or hepatic artery (right or left)

T4: tumor invades main portal vein or its branches bilaterally, common hepatic artery or other adjacent structures such as colon, stomach, duodenum or abdominal wall

Regional lymph nodes (N)

NX: regional lymph nodes cannot be assessed

N0: no regional lymph node metastasis

N1: regional lymph node metastasis

Note: at least three regional lymph nodes should be examined

Distant metastasis (M)

MX: distant metastasis cannot be assessed

M0: no distant metastasis

M1: distant metastasis

Notes:

Direct extension into liver, colon, duodenum, stomach, common bile duct, abdominal wall or diaphragm is not considered a metastasis

Stage grouping