Department of Pathology Biliary Tract Kimiko Suzue MD, Ph.D. Department of Pathology

Biliary Tract Extrahepatic biliary tract Intrahepatic biliary tract Gallbladder Cystic duct Common hepatic duct Common bile duct Intrahepatic biliary tract

Biliary Disease Gallbladder Disorders Extrahepatic Bile Duct Disorders -Cholelithiasis -Cholesterolosis -Cholecystitis Extrahepatic Bile Duct Disorders -Choledocholithiasis -Cholangitis -Biliary Atresia -Choledochal cysts Tumors

GALLBLADDER Contraction of the muscle induced by cholecystokinin Storage and concentration of bile

Gallbladder Gallstones (cholelithiasis) Afflict 10% of adult population in Western countries Costs of management: $6 billion a year 20 million patients are estimated to have gallstones totalling several tons Made of cholesterol, bilirubin and calcium salts with different concentrations

Cholelithiasis In West, >90% are cholesterol stones Usually radiolucent (10% radiopaque due to calcium) Risk factors: -Native Americans -Women > Men -Advancing Age (25-30% of people over 80) -Estrogenic influence Pregnancy, Oral contraceptives -Clofibrate -Obesity -Gallbladder stasis (neurogenic or hormonal) -Hereditary (bile acid metabolism)

Cholelithiasis Pigmented bilirubin stones Usually radiopaque (calcium bilirubinate) Risk factors: -Chronic hemolytic states (increased bilirubin in bile) Sickle cell, hereditary spherocytosis, cardiac valve replacement, malaria) -Ileal disease (bile salt malabsorption) Crohn’s disease, bowel resection -Biliary tract infection/infestation Ascaris lumbricoides, Clonorchis sinensis -Liver disease (alcoholic cirrhosis)

Cholelithiasis Hepatolithiasis Choledocholithiasis

Cholelithiasis Asymptomatic: 70% Obstruction: Biliary Colic Spasmodic right upper quadrant pain Symptoms are relieved if stone passes Infection: Cholecystitis, cholangitis Acute Pancreatitis Gallbladder cancer Principal therapeutic modality: Laporascopic cholecystectomy (late 1980’s)

Cholesterolosis Aggregates of lipid-containing macrophages in lamina propria of gallbladder Debated clinical relevance “Strawberry gallbladder”

Cholesterolosis

Polypoid cholesterolosis Abundant foamy macrophages forming polypoid excrescences

Cholecystitis General Features Present in autopsy series in half of the population Female, obese, multiparous, 5th and 6th decades Acute (Chemical irritation and inflammation) Suppurative (Empyema, purulent contents) Emphysematous (clostridia and coliforms) Gangrenous (Necrotic) Chronic

Cholecystitis Clinical Picture Acute: RUQ pain referred to right shoulder Rigidity of abdominal wall (RUQ) Fever, nausea, vomiting, leukocytosis Jaundice (25% of cases) Increased WBC count Increased serum alkaline phosphatase (duct damage) Chronic: Fatty food intolerance Epigastric distress, nausea Vague RUQ pain Complications: Ca or obstructive jaundice

Acute Cholecystitis Gross Pathology The gallbladder is enlarged (x2 or x3) The gallbladder wall is thickened (x10) The serosa is covered by fibrin with subserosal hemorrhages The lumen is filled with turbid bile, fibrin or pus The mucosa is hyperemic, ulcerated or frankly necrotic Gallstones are present in 80% of cases

Acute Cholecystitis Histology Edema and neutrophilic inflammation Vascular congestion Abscess formation & gangrenous necrosis Later neutrophils → eosinophils (subacute) Ca++ deposition: “porcelain gallbladder”

Porcelain Gallbladder

Porcelain Gallbladder with Stones

Chronic Cholecystitis Gross Pathology The gallbladder wall thickened (about x5) It is contracted, enlarged or of normal size Serosa is smooth and glistening with subserosal fibrosis Lumen contains normal bile Stones are present in 90% of cases

Chronic Cholecystitis Histology Mucosa is preserved or atrophic Mononuclear cell infiltration Subepithelial and subserosal fibrosis Severe fibrosis with replacement of smooth muscle Outpouchings of mucosal epithelium through wall “Rokitansky-Aschoff sinuses”

Choledocholithiasis Passage of gallstones into common bile duct occurs in 10-15% of patients with cholelithiasis Majority are cholesterol stones formed in gallbladder Primary calculi arising de novo in ducts are typically pigmented stones in pts with: -Chronic recurrent cholangitis -Congenital anomalies of bile ducts (Caroli’s disease) -Dilated, sclerosed or strictured ducts -MDR3 gene defect leading to impaired biliary phospholipid secretion

Choledocholithiasis May remain asymptomatic May pass spontaneously into duodenum May present as biliary colic or complications -Cholangitis -Obstructive jaundice -Pancreatitis -Secondary biliary cirrhosis

Cholangitis Acute or chronic Bacteria present in 75% of pts with acute cholangitis Charcot’s triad Intermittent abdominal pain Spiking fevers with chills Jaundice

Biliary Atresia Complete or partial obstruction of lumen of extrahepatic biliary tree within first 3 months of life Perinatal type (80% to >90%) -Presumed normal biliary tree is destroyed at birth -Jaundice develops within 2 weeks -No associated congenital anomalies -Etiology unknown(?viral, ?autoimmunity) Fetal type (less common) -Jaundice at birth or within a day or 2 -Assoc cardiac and vascular malformations, sinus inversus, polysplenia, midgut malrotation -Presumed aberrant intrauterine development of extrahepatic biliary tree

Biliary Aresia Histologic features: Bile ductular proliferation Portal fibrosis Bile plugs in bile ducts/ductules Parenchymal cholestasis

Biliary Atresia Type I – Disease limited to common bile duct Type II – Disease limited to hepatic bile ducts Type III – Obstruction of ducts above porta hepatis

Biliary Atresia Normal birth weight and postnatal weight gain Initially normal stools but become acholic stools Present with neonatal cholestasis Timing of biopsy Liver biopsy shows nonspecific changes at less than 4 weeks Fairly good sensitivity/specificity at 6-8 weeks Diagnostic at >8 weeks Cirrhosis develops within 3 to 6 months if not recognized Kasai procedure for types I and II Liver transplantation for rest Without surgery, death within 2 years

Choledochal Cysts Congenital dilatations of bile duct

Choledochal Cysts Present most often before 10 yrs of age Jaundice, abdominal pain, abdominal mass Delayed diagnosis can lead to complications: Pancreatitis Spontaneous perforation Cholelithiasis Cholangitis Secondary biliary cirrhosis Portal hypertension Carcinoma

Carcinoma of Gallbladder Close to 50% of gallbladder carcinomas are diagnosed incidentally in cholecystectomy specimens for cholelithiasis Most important risk factor is cholelithiasis -Gallstones present in >80% of gallbladders with carcinomas -But low incidence of carcinoma in pts with gallstones, <0.2% Slightly more common in women Most frequent in seventh decade of life Mean 5 year survival of 5 to 12%

Carcinoma of the Gallbladder Clinical Symptoms Pain 70-80% Weight loss 60% Jaundice 50% Gallstones 50-80% Palpable mass 60% Ascites 20%

Carcinoma of the Gallbladder Histologic Types Adenocarcinoma Adenosquamous carcinoma Squamous cell carcinoma Intracystic or intraductal papillary neoplasm with an associated invasive carcinoma Mucinous cystic neoplasm with an associated invasive carcinoma Undifferentiated carcinoma Neuroendocrine neoplasms Mesenchymal tumors

Dysplasia

Adenoca. of Gallbladder

Adenoca of Gallbladder

Adenoca of Gallbladder

Adenoca of Gallbladder

Biliary Disease Gallbladder Disorders Extrahepatic Bile Duct Disorders -Cholelithiasis -Cholesterolosis -Cholecystitis Extrahepatic Bile Duct Disorders -Choledocholithiasis -Cholangitis -Biliary Atresia -Choledochal cysts Tumors