Pathology of Gallbladder and Extrahepatic Biliary Tract, with Clinical Correlations

1
Pathology of Gallbladder and Extrahepatic Biliary
Tract,with Clinical Correlations

• Paul G. Koles, M.D.
• Assoc. Professor of Pathology and Surgery
• Boonshoft School of Medicine at Wright State
  University
• paul.koles_at_wright.edu

2
Content outline

• Normal histology and physiology
• Congenital abnormalities
• Gallstones
• Acute and chronic cholecystitis
• Ascending cholangitis
• Selected non-neoplastic disorders
• Neoplasms of gallbladder and extrahepatic bile
  ducts

3
Gallbladder normal histology
Mucosa tall columnar epithelium
Lamina propria normally with few lymphocytes no
muscularis mucosa
Fibromuscular layer mixed fascicles of smooth
muscle and fibrous tissue
Immunohistochemical stain for actin smooth
muscle in FM layer
4
Composition of Bile Solutes
lecithin
Bile secreted by hepatocytes 97 water, 3
solutes
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Gallbladder and Bile Physiology

• Gallbladder function
• concentrates bile 5-10 fold by active sodium
  transport in epithelial cells water follows
  sodium
• After cholecystectomy, normal absorption and
  digestion of nutrients (bile necessary, not
  gallbladder)
• Bile salts conjugation of bile acids with
  taurine or glycine
• Bile acids catabolic products of cholesterol
  (cholic acid and chenodeoxycholic acid) that
  solubilize lipids in bile and enhance absorption
  of lipids in gut lumen
• Enterohepatic recirculation 95 of secreted bile
  salts are reabsorbed in ileum
• Cholecystokinin (CCK) causes contraction
  gallbladder and release of stored bile. CCK is
  produced by duodenal and jejunal
  ________________________ cells when
  ________________ or ______________________
  are present in the small intestinal lumen.

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Congenital Anomalies

• anatomic variants common
• Mainly of concern to surgeons, who must avoid
  cutting, ligating, or removing the wrong thing
• disease-causing anomalies are rare

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Cystic Diseases of Bile Ducts

• Congenital lesions
• Clinical presentation in childhood jaundice,
  recurrent episodes of pain
• classification
• choledochal cyst dilations of common bile duct
  
• choledochal diverticulum of common bile duct
• choledochocele of intraduodenal bile duct
  (cyst protrudes into duodenum)
• fusiform cysts (intra- and extra-hepatic)
• multiple intrahepatic cysts
  (Caroli disease)

Fig. 14-65, Rubins Pathology, 4th ed,
Lippincott, Williams Wilkins
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Cystic Diseases of Bile Ducts Complications

• Size of cysts few ml. -- 10 liters
• Complications of cystic disease
• obstruction
• perforation, leading to bile peritonitis
• ascending cholangitis (esp. with Caroli disease)
• hepatic abscess
• secondary biliary cirrhosis
• bile duct carcinoma (adults, rare)

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Extrahepatic Biliary Atresia

• Definition complete or partial obstruction of
  the lumen of extrahepatic bile ducts within first
  3 months of life
• Clinical neonatal jaundice (conjugated
  bilirubin)
• Pathology progressive inflammation, fibrosis,
  and stenosis of bile duct lumina
• Early dx essential if not corrected, chronic
  obstruction leads to biliary cirrhosis and death
  by age 2
• Treatment 10 surgically correctable (disease
  limited to common or hepatic bile ducts) most
  children referred for liver and bile duct
  transplantation because of advancing biliary
  cirrhosis

Fig. 22-13, Lack, Pathology of the Pancreas,
Gallbladder, Extrahepatic Biliary Tree, and
Ampullary Region Oxford University Press, 2003.
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Biliary System other congenital lesions

• Folded fundus fundus invaginated into lumen
• Aberrant locations of gallbladder (5 population)
• Hurglass gallbladder
• Double and bilobed gallbladder
• Bile ducts
• abnormally long
• accessory hepatic ducts
• low fusion of hepatic ducts, resulting in double
  common bile ducts

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Gallbladder anomalies
Hourglass g.b. with stones
Folded fundus PBD 8th ed, fig. 18-50
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Gallstones

• Definition concretions of bile constituents
• Stones in gallbladder cholelithiasis
• Stones in common duct choledocholithiasis
• sequelae obstruction (conjugated
  hyperbilirubinemia, potential for acute
  cholangitis) pancreatitis (obstructed pancreatic
  duct)
• Range of size grains of sand to boulders
• Three major varieties
• Pure cholesterol 10
• Pure pigment (calcium bilirubinate) 10
• Mixed 80 cholesterol calcium carbonate or
  cholesterol calcium
  bilirubinate

Q1) What percentage of all gallstones contain
cholesterol? _________ Q2) What percentage are
pure cholesterol? ______
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Gallstones 3 major types
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Lithogenesis (physical model)
Factors ? Cholesterol soluble when aggregated
with bile salts or lecithn (detergents) bile
deficient in bile salts or with excess
cholesterol ? cholesterol supersaturation ?
nucleates as solid cholesterol monohydrate
crystals hypomotility of gallbladder and
hypersecretion of mucus promote accretion of
crystals calcium salts crystallized
cholesterol ? stone
Fig. 18-51, Pathologic Basis of Disease, 8th ed,
Elsevier, 2010
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Gallstones clinical diagnosis

• 70-80 persons with gallstones remain
  asymptomatic throughout life
• Symptoms biliary colic spasmodic,
  intermittent RUQ or epigastric pain with nausea,
  often after meals constant pain less often
• Diagnostic imaging
• --ultrasound most reliable imaging method,
  sensitivity detects stones as small as 2-3 mm.
  diameter
• --flat plate abdominal x-ray only 10-20
  stones are radio-opaque, therefore visible (a
  fortuitous incidental finding in abdominal x-ray
  obtained for other reasons)
• Intraoperative considerations
• Not all stones may be contained in gallbladder
• MUST make sure extrahepatic bile ducts do not
  harbor any stones before operation is completed

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Ultrasound of gallbladder
Solitary gallstone in lumen of gallbladder
Screening test of choice for gallbladder
non-invasive, no radiation,
inexpensive, detects calculi gt 2-3 mm diameter
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Intraoperative cholangiogram gallstones in
common bile duct (must remove before closing)
T-tube for injecting dye
duodenum
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Gallstones risk factors for pure cholesterol or
mixed stones

• Demographic high incidence in western/northern
  Europe, U.S., very high in Native Americans
  Mexican-Americans uncommon third world
• Advancing Age under 40, lt5 have stones over
  80, gt30 stones
• Sex premenopausal females have 2-3x higher
  incidence than males of same age range
• Estrogen promotes uptake synthesis of
  cholesterol by hepatocytes (risk increased by
  oral contraceptives and pregnancy)
• Obesity and metabolic syndrome (risk increases
  with greater obesity)
• Rapid weight reduction
• ? Family history parents/siblings with stones
• Hypercholesterolemia
• Inborn errors of bile acid metabolism
• GI disorders or surgery that interfere with bile
  salt reabsorption in ileum (e.g., Crohn disease)

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Pigment Gallstones
Unconjugated bilirubin mixed with calcium salts
Patient with mechanical mitral valve prosthesis
that caused intravascular hemolysis fig. 18-53,
PBD 8th ed, 2010
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Gallstones risk factors for pure pigment stones
(black stones containing Ca bilirubinate)

• Disorders that present excess unconjugated
  bilirubin to hepatocytes ? excess conjugated
  bilirubin secreted in bile but about 1
  conjugated bili is deconjugated in bile ducts by
  glucuronidase ? unconjugated bili exceeds its
  solubility. (normal miniscule unconjugated
  bilirubin in bile)
• chronic hemolytic syndromes (all causes)
• disease or removal ileum (less bile salts)
• bacterial infection of biliary tract, esp.
  E.coli, which secretes ß-glucuronidase,
  converting conjugated bilirubin to unconjugated
  bilirubin
• parasitic infections of biliary tract, especially
  Clonorchis sinensis and Ascaris lumbricoides
  (frequent in Asia)

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Sequelae of Gallstones

• Gallstones may
• Intermittently obstruct orifice of cystic duct
  when gallbladder contracts ? partially restricted
  outflow of bile ? intermittent biliary colic
  pain
• be released from GB into bile ducts and small
  bowel
• possible complications
• common bile duct obstruction (/- cholangitis)
• acute cholecystitis with sepsis
• acute pancreatitis (due to obstruction of where
  it joins common bile duct pancreatic duct)
• fistula from gallbladder to small bowel ?
  gallstone ileus
• Mirizzi syndrome stone in bile ducts causing
  stricture

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Segmental resection for small intestinal
obstruction
Gallstone Ileus
Resected segment contains rather huge
barrel-shaped gallstone
23
Distribution of calculi in gallstone ileus (80
cases)
Fig. 19.50, EE Lack, Pathology of the Pancreas,
Gallbladder, Extrahepatic Biliary Tract, and
Ampullary Region (based on Raf Spangen
Gallstone Ileus, Acta Chir Scand 137665-675,
1971).
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Gallstones Treatment

• Medical restricted to pure cholesterol stones
• Approximately 50 recurrence rate after
  dissolution (unsatisfactory to most patients)
• Surgical
• standard of care
• prevents serious complications
• Laparoscopic vs. open cholecystectomy
• Elective surgery with low morbidity mortality lt
  0.5

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Endoscopic sphincterotomy for choledocholithiasis
Gastroenterologist retrieves gallstone in distal
common bile duct, avoiding need for surgery
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Cholecystitis

• A wide clinical spectrum of disease from
  life-threatening acute cholecystitis to
  asymptomatic chronic cholecystitis
• gt95 cases associated with gallstones
• Scenarios
• chronic symptoms gradually worsen over years
• chronic disease may be completely asymptomatic,
  or cause intermittent symptoms
• acute may be superimposed on chronic
• acute may progress to sepsis or ascending
  cholangitis, and thus pose a life-threatening risk

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Acute cholecystitis

• Clinical picture
• History intermittent pain, recently progressively
  worse RUQ pain
• Signs RUQ tenderness, fever, leukocytosis
• Variable signs palpable dilated gallbladder,
  jaundice suggests obstruction of common duct by
  gallstone
• Pathogenesis calculous 90, acalculous 10
• Calculous acute obstruction of cystic duct ?
  chemical irritation of mucosa by bile salts and
  toxic lysolecithin ? acute inflammation
• Acalculous probably ischemic risk factors are
  sepsis, major trauma or burns, diabetes mellitus,
  infections, immunosuppression
• Pathology
• GROSS edema, hemorrhage, mucosal necrosis
• MICRO transmural infiltrate of neutrophils, with
  associated hemorrhage, edema, and necrosis

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Acute calculous cholecystitis
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Acute cholecystitis histopathology
Ulcerated epithelium with dense infiltrate of
neutrophils extending through the fibromuscular
layer
Acute inflammation may produce severe transmural
congestion and hemorrhage
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Acute cholecystitis treatment

• Decision risky surgery vs. delaying surgery with
  medical therapy
• Emergency surgery during acute cholecystitis
  3-5 mortality rate, higher mortality
  rate in elderly
• Medical management 75 remission of acute
  symptoms, followed by less risky elective surgery
• However, 25 will require emergency surgery due
  to unremitting pain, obstruction of biliary tract
  by stone, or sepsis.

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Chronic cholecystitis

• Objective evidence gallstones !!!
• Pathogenesis unclear cholesterol
  supersaturation of bile contributes to both
  chronic inflammation and stones obstruction of
  cystic duct not required (cf. acute calculous
  cholecystitis)
• Pathology
• Gross stones plus variably thickened wall
• Micro some chronic inflammation (not always
  prominent) and hyperplasia of fibromuscular layer
  (more reliable feature)
• Clinical picture vague and various symptoms
• intermittent nausea, belching, discomfort
• Intermittent epigastric or RUQ pain
• symptoms worse after meals (flatulent
  dyspepsia)
• symptoms exacerbated by fatty foods or large meals

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Chronic cholecystitis pathology
A treasure chest of stones
Note (right) grossly thickened wall due to
marked fibromuscular hyperplasia
Marked fibromuscular hyperplasia
Fig. 14-71, Rubins Pathology, 4th ed,
Lippincott, Williams Wilkins 2005
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Chronic cholecystitis variants

• Porcelain Gallbladder
• Chronic inflammation and lithiasis gradually
  erode mucosa, leaving a leathery fibrous wall
• Hydrops and Mucocele
• Marked dilation up to 15 cm 1.5 liters fluid
• Mechanism stone obstructing the cystic duct (?
  why not acute cholecystitis)
• Hydrops fluid in lumen is watery
• Mucocele fluid in lumen is thick mucoid

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CC Variant porcelain gallbladder
Leathery thick wall and eroded mucosa stone
often found at orifice of cystic duct
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CC variants hydrops and mucocele
Hydrops
Mucocele
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Ascending Cholangitis

• Def bacterial infection of bile ducts
  (cholangitis) leading to infection of
  intrahepatic bile ducts (ascending c.)
• Clinical
• fever, abdominal pain, jaundice
• sepsis frequent early diagnosis needed
• Pathogenesis
• any lesion that obstructs bile flow (commonly
  bile duct strictures and choledocholithiasis)
• bacteria enter ducts through sphincter of Oddi
  gram-neg. bacilli, anaerobes
  (Clostridium, Bacteroides)

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Non-neoplastic disorders (1)

• Cholesterolosis accumulation of lipid-laden
  macrophages in lamina propria
• Cholesterol polyps (larger accumulations)
• Diverticular disease
• diffuse type adenomyomatosis
• localized type adenomyomatous hyperplasia
• pathogenesis pulsion diverticulum
• histopathologic differential diagnosis carcinoma

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Cholesterolosis
Pale-staining foamy macrophages filling lamina
propria (contain cholesterol in cytoplasm)
Diffuse linear yellow streaks in mucosa
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Cholesterol polyps gross
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Diverticular disease
diffuse adenomyomatosis
Diffuse mural thickening with cysts in wall
Cysts lined by normal columnar epithelium,
embedded within fibromuscular layer
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Non-neoplastic disorders (2)

• Torsion twisting of gallbladder on its blood
  supply ? ischemia followed by necrosis (urgent
  surgery to avoid rupture with bile peritonitis)

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Non-neoplastic disorders (3) metaplasia
dysplasia in setting of chronic inflammation
Metaplasia, gastric type
Dysplasia, high grade
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Neoplasms Overview

• all neoplasms of gallbladder are uncommon
• benign neoplasms are less frequent than malignant
• benign neoplasms and mass-like lesions of
  gallbladder
• papillary adenoma
• heterotopias gastric, pancreatic
• non-epithelial neoplasms lipoma, fibroma,
  others
• adenomyoma more properly a diverticulum (more
  accurately named localized adenomyomatous
  hyperplasia)

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Gallbladder papillary adenoma
Soft, polypoid, exophytic lesion protruding into
lumen
Papillary fronds of epithelium supported by
fibrovascular stroma no invasion of wall
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Carcinoma of gallbladder (1)

• Gross Appearance
• --70 diffusely infiltrating
• --30 polypoid or exophytic (better
  prognosis)
• Concepts
• most common site carcinoma in extrahepatic
  biliary tract
• 21 femalemale
• peak incidence 60-70 years
• 80-90 have gallstones, but only 0.5 of
  patients with stones develop carcinoma
• cholic acid (bile acid) is an experimental
  carcinogen
• presumed pathogenesis gallstones or chronic
  infection (Asia) ? chronic inflammation ?
  dysplasia ? carcinoma

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Carcinoma of gallbladder diffusely infiltrating
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Carcinoma of gallbladder localized exophytic
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Carcinoma of gallbladder (2)

• Microscopic features
• 5 adenocarcinoma-in-situ asymptomatic
  early lesions are discovered incidentally at
  elective cholecystectomy (VERY FORTUNATE
  PERSONS ! )
• 90 invasive adenocarcinomas
• 5 squamous cell carcinoma or mixed adenosquamous
  carcinoma

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Carcinoma of gallbladder histopathology
Carcinoma with glandular squamous features
Well-differentiated adenocarcinoma invading wall
Above Mixed adeno- (top) and squamous (lower)
carcinoma
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Carcinoma of gallbladder (3)

• Clinical presentation late, often invading
  liver, often with regional/distant metastases
• fewer than 25 of cancers are surgically
  resectable at time of diagnosis
• treatment surgery radiation/chemotherapy
• prognosis poor, mainly hinges on stage
• I 85 survival at 5 yrs
• II 25 survival at 5 yrs.
• III 10 survival at 5 yrs.
• IV 2 survival at 5 yrs.
• overall 5-10 survival at five years

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Gallbladder adenocarcinoma with massive hepatic
metastases
Gallbladder adenocarcinoma with regional lymph
node metastases
52
Carcinoma of bile ducts (1)

• Less common than gallbladder carcinoma
• Incidence by sites
• 1st ampullary (ampulla of Vater)
• 2nd common bile duct
• 3rd hepatic ducts (right and left)
• 4th junction hepatic and common ducts
  (Klatskin tumor)

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Carcinoma bile ducts (2)

• Clinical presentation obstructive jaundice
• Predispositions gallstones (35-50), parasitic
  infections, sclerosing cholangitis, chronic
  ulcerative colitis
• Clinical differential diagnosis
  choledocholithiasis or bile duct stricture
• Evaluation for surgical resectability
  ultrasound, endoscopy, CT scan, biopsies

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Surgically curable bile duct carcinoma
normal

• Whipple procedure for carcinoma at ampulla
  indicated if tumor is small (lt 2cm.) and
  localized to ampulla and periampullary mucosa
• Prognosis in this group 75 survival at 5
  years.
• More extensive tumors dismal prognosis

ampullary
periampullary
mixed
55
Ampullary invasive adenocarcinoma, treated by
Whipple procedure
Head of pancreas
CB Duct
Duodenum
56
References (books only)

• Kumar, Abbas, Fausto, Aster Pathologic Basis of
  Disease, 8th edition, Elsevier 2010.
• Lack, EE Pathology of the Pancreas, Gallbladder,
  Extrahepatic Biliary Tract, and Ampullary Region
  Oxford University Press, 2003.
• McGee, Isaacson, Wright eds. Oxford Textbook of
  Pathology, Oxford University Press, 1992.
• Owen Kelly Pathology of the Gallbladder,
  Biliary Tract, and Pancreas WB Saunders, 2001.
• Rubin, Gorstein, Rubin, Schwarting, Strayer
  Rubins Pathology, 4th edition, Lippincott,
  Williams Wilkins, 2005.
• Townsend, Beauchamp, Evers, Mattox Sabiston
  Textbook of Surgery, 17th edition,
  Elsevier-Saunders, 2004.