Diseases of the liver and pancreas

Fibro-lamellar Carcinoma

• 
  A distinctive variant of HCC
  
• 
  Occurs in young men and women (20 to 40 years of age)
  
• 
  Equal incidence
  
• 
  No association with HBV or cirrhosis risk factors
  
• 
  Has a distinctly better prognosis
  
• 
  It usually constitutes a single large, hard “scirrhous” tumor with fibrous bands coursing through it.
  
• 
  Histologically composed of well-differentiated polygonal cells growing in nests or cords and separated by parallel lamellae of dense collagen bundles hence the name “fibrolamellar.”
  

Microscopic Appearance (See D above)

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  Nests and cords of malignant-appearing hepatocytes
  
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  Separated by dense bundles of collagen
  

Cholangiocarcinoma

Morphology -

• 
  Cholangiocarcinomas are rarely bile stained because differentiated bile duct epithelium does not synthesize pigmented bile.
  
• 
  Cholangiocarcinoma are more firm and gritty as compared with HCC
  

• 
  Resemble adenocarcinomas arising in other parts of the body and may exhibit the full range of morphologic variation.
  
• 
  Most are well-differentiated sclerosing adenocarcinomas with clearly defined glandular and tubular structures lined by anaplastic cuboidal-to-low columnar epithelial cells.
  
• 
  Mucus present within cells & lumina but not bile
  
• 
  There is no reliable histologic feature distinguishing intrahepatic cholangiocarcinoma from metastatic adenocarcinoma
  
• 
  Diagnosis depends on reasonable exclusion of an extrahepatic primary
  
• 
  Vascular invasion is less common with cholangiocarcinomas than with HCC.
  

• 
  Glandular appearance (on the left) Gross Appearance
  
• 
  Mucin production
  
• 
  No bile production
  

Primary Carcinoma of the Liver-Clinical Course

• 
  Clinical manifestations are seldom characteristic
  
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  Most patients have ill-defined upper abdominal pain, malaise, fatigue, weight loss, and sometimes awareness of an abdominal mass or abdominal fullness.
  
• 
  In many cases, the enlarged liver can be felt on palpation, with sufficient irregularity or nodularity to permit differentiation from cirrhosis. Jaundice, fever, and gastrointestinal or esophageal variceal bleeding are inconstant findings.
  
• 
  Laboratory studies may be helpful but are rarely conclusive
  

• 
  Elevated levels of serum alpha-fetoprotein (in 60 to 75% )
  
• 
  Elevated levels of Carcinoembryonic antigen
  

• 
  These biochemical tests fail to detect small lesions, when curative resection might be possible.
  

• 
  Most valuable for small tumors are ultrasonography, hepatic angiography, computed tomography, and magnetic resonance imaging scans.
  

• 
  False-positive results of elevated alpha fetoprotein are encountered with :
  

• 
  yolk-sac tumors
  
• 
  Non-neoplastic conditions
  
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  Cirrhosis
  
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  Massive liver necrosis
  
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  Chronic hepatitis
  
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  Normal pregnancy
  
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  Fetal distress or death
  
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  Fetal neural tube defects such as anencephaly and spina bifida
  

Prognosis

• 
  The natural course of primary liver cancer is progressive enlargement of the primary mass until it encroaches on hepatic function or metastasizes, generally first to the lungs and then to other sites
  
• 
  Overall death usually occurs within 6 months of diagnosis from:
  

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  Cachexia
  
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  Gastrointestinal or esophageal variceal bleeding
  
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  Liver failure with hepatic coma
  
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  Rupture of the tumor with fatal hemorrhage
  

• 
  Possibility of significantly reducing the global mortality from HCC by immunization of high-risk populations against HBV, in whom infections are commonly acquired in early life.
  
• 
  Such public-health measures provide the extraordinary opportunity to eradicate a major cancer by a vaccination program.
  

• 
  Fibrolamellar variant of HCC is associated with a far more favorable outlook.
  
• 
  It arises in otherwise healthy young adults and may be discovered while still amenable to surgical resection.
  
• 
  About 60% of patients are alive at 5 years
  
• 
  Cholangiocellular carcinoma is not usually detected until late in its course
  
• 
  Clinical outlook is dismal
  
• 
  Death characteristically ensuing within 6 months.
  

Metastatic Tumors

• 
  Metastatic involvement of the liver is far more common than primary neoplasia.
  
• 
  Most common primaries producing hepatic metastases are those of
  
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  Breast
  
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  Lung
  
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  Colon
  
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  However, any cancer in any site of the body may spread to the liver, including leukemias and lymphomas.
  
• 
  Often the only clinical telltale sign is hepatomegaly, sometimes with nodularity of the free edge.
  
• 
  With massive or strategic involvement (obstruction of major ducts), however, jaundice and abnormal elevations of liver enzymes may appear
  
• 
  Typically multiple nodular implants are found that often cause striking hepatomegaly and may replace more than 80% of existent hepatic parenchyma
  
• 
  There is a tendency for metastatic nodules to outgrow their blood supply, producing central necrosis and umbilication
  

Cholelithiasis (Gallstones)

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  Gallstones afflict 10 to 20% of adult populations in developed countries
  
• 
  There are two main types of gallstones.
  

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  Cholesterol stones - containing more than 50% of crystalline cholesterol monohydrate.
  
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  Pigment stones - composed predominantly of bilirubin calcium salts
  

Cholesterol stones

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  Arise exclusively in the gallbladder
  
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  Consist of 100% down to around 50% cholesterol
  
• 
  Pure cholesterol stones are pale yellow and round to ovoid and have a finely granular, hard external surface
  

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  On transection reveals a glistening radiating crystalline palisade.
  

• 
  With increasing proportions of calcium carbonate, phosphates, and bilirubin, the stones exhibit discoloration and may be lamellated and gray-white to black on transection.
  
• 
  Most often, multiple stones are present
  
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  Rarely there is a single, much larger stone that may virtually fill the fundus.
  
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  Surfaces of multiple stones may be rounded or faceted, owing to tight apposition.
  
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  Stones composed largely of cholesterol are radiolucent
  
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  Sufficient calcium carbonate is found in 10 to 20% of cholesterol stones to render them radiopaque.
  

Pigment gallstones

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  Black pigment stones
  
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  Are found in sterile gallbladder bile
  
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  Are composed of oxidized polymers of the calcium salts of unconjugated bilirubin, calcium carbonate, calcium phosphate, and mucin glycoprotein
  
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  < 1.5 cm in diameter
  
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  Present in great number (with an inverse relationship between size and number)
  
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  May crumble to the touch.
  
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  Contours are usually spiculated and molded
  
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  ~ 50 to 75% of black stones are radiopaque
  
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  Brown stones
  
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  Are found in infected intrahepatic or extrahepatic ducts.
  
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  Contain pure calcium salts of unconjugated bilirubin, mucin glycoprotein, a substantial cholesterol fraction, and calcium salts of palmitate and stearate.
  
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  Tend to be laminated and soft and may have a greasy consistency
  
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  Are radiolucent
  

Stages in Cholesterol Stone Formation


-exam: biliary infection

A.Cholesterol Stones

B.Black pigment stones
Cholecystitis

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  Acute Calculous Cholecystitis
  
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  Acute Acalculous Cholecystitis
  
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  Chronic Cholecystitis
  

Acute Calculous Cholecystitis

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  Acute calculous cholecystitis is an acute inflammation of the gallbladder, precipitated 90% of the time by obstruction of the neck or cystic duct.
  
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  It is the primary complication of gallstones
  
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  Is the most common reason for emergency cholecystectomy.
  
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  May appear with remarkable suddenness and constitute an acute surgical emergency or may present with mild symptoms that resolve without medical intervention
  

An attack of acute cholecystitis

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  Begins with progressive right upper quadrant or epigastric pain
  
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  Associated with mild fever, anorexia, tachycardia, diaphoresis, and nausea and vomiting
  
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  Upper abdomen is tender
  
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  Most patients are free of jaundice; the presence of hyperbilirubinemia suggests obstruction of the common bile duct.
  
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  Mild-to-moderate leukocytosis may be accompanied by mild elevations in serum alkaline phosphatase values.
  
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  In the absence of medical attention, the attack usually subsides over 7 to 10 days and frequently within 24 hours.
  
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  Up to 25% of patients, however, develop progressively more severe symptoms, requiring immediate medical intervention. In those patients that recover, recurrence is common.
  

Mucocele/Empyema of the gall bladder Chronic cholecystitis

Thickening and fibrosis of gall bladder wall

Variable chronic inflammatory infilterate in the mucosa and submucosa

Disorders of the Extrahepatic Bile Ducts

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  Biliary Atresia
  
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  Choledocholithiasis and Ascending Cholangitis
  

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  Stone in the bile duct
  

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  Choledochal Cysts
  

Biliary Atresia

• 
  A major contributor to neonatal cholestasis is extrahepatic biliary atresia (EHBA)
  
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  Representing 30% of infants with neonatal cholestasis
  
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  EHBA is defined as a complete obstruction of bile flow owing to destruction or absence of all or part of the extrahepatic bile ducts
  
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  It is the single most frequent cause of death from liver disease in early childhood
  
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  Accounts for 50-60% of children referred for liver transplantation,
  

owing to the rapidly progressing secondary biliary cirrhosis

Pathogenesis

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  Most infants with EHBA are born with an intact biliary tree
  
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  In the weeks following birth, the biliary tree undergoes
  

progressive inflammatory destruction

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  Cause remains unknown
  
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  Possibly:
  

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  Viral infection
  

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  Reovirus 3
  
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  Cytomegalovirus
  
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  Rubella virus
  

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  Genetic inheritance
  
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  Anomalous embryologic development
  

Morphology

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  The salient features of EHBA include
  

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  Inflammation and fibrosing stricture of the
  

hepatic or common bile ducts

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  Periductular inflammation of intrahepatic bile ducts
  
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  Progressive destruction of the intrahepatic biliary tree
  

• 
  Biliary atresia can be of three types:
  

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  Type I: Disease is limited to the common duct
  
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  Type II: Disease is limited to hepatic bile ducts with patent proximal branches
  
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  Type III: Obstruction of bile ducts at or above the porta hepatis (most common – 90%)
  

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  Surgically correctible lesions are type I and II
  
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  Noncorrectable – type III because there are no patent extrahepatic ducts amenable to surgical anastomosis
  

Clinical Course

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  Infants with EHBA present with neonatal cholestasis,
  
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  These infants exhibit normal birth weight and postnatal weight gain
  
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  Slight female preponderance
  
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  Progression of initially normal stools to acholic stools as the disease evolves.
  

Treatment:

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  Liver transplantation with accompanying donor bile ducts
  
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  Without surgical intervention, death usually occurs within 2 years of birth.
  

Choledochal Cysts

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  Are congenital dilatations of the common bile duct
  
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  In children < age 10
  
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  Nonspecific symptoms of jaundice or recurrent abdominal pain typical of biliary colic, or both.
  
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  ~ 20% of patients become symptomatic only in adulthood
  

• 
  sometimes occur in conjunction with cystic dilatation of the intrahepatic biliary tree (Caroli’s disease).
  

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  Female-to-male ratio is 4:1
  
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  Choledochal cysts predispose to stone formation, stenosis and stricture, pancreatitis, and obstructive biliary complications within the liver
  
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  In the older patient, the risk of bile duct carcinoma is elevated
  

Tumors

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  Adenomas are benign epithelial tumors, representing localized neoplastic growth of the lining epithelium.
  
• 
  Adenomas are classified as
  

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  Tubular
  
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  Papillary
  
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  Tubulopapillary
  

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  Histologically indistinguishable from intestinal adenomas
  
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  In the gallbladder, they may be sessile or pedunculated and are generally under 1 cm in size and are visualized as immobile translucent lesions on imaging studies or found incidentally on cholecystectomy.
  
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  Adenomas of the bile ducts are even less common and frequently present with obstructive symptoms.
  
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  As with alimentary tract adenomas, a close relationship appears to exist with the development of carcinoma; some 10% of adenomas show evidence of carcinoma in situ.
  

Carcinoma of the Gallbladder

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  Carcinoma of the gallbladder is the fifth most common cancer of the digestive tract
  
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  Is slightly more common in women
  
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  Occurs most frequently in the seventh decade of life.
  
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  Mean 5-year survival has remained for many years at about 1%, despite surgical intervention
  
• 
  Gallstones present in 60-90% cases, not 100%
  

Morphology

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  Infiltrating
  

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  Is more common
  
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  Usually appears as a poorly defined area of diffuse thickening and induration of the gallbladder wall that may cover several square centimeters or may involve the entire gallbladder
  
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  Tumors are scirrhous and have a firm consistency
  

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  Fungating
  

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  Grows into the lumen as an irregular, cauliflower-like mass
  

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  May be necrotic, hemorrhagic, and ulcerated
  

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  At the same time invades the underlying wall
  
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  Most common sites of involvement are the fundus and neck
  
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  ~ 20% involve the lateral walls
  
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  Direct penetration of the gallbladder wall into the liver bed
  
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  Fistula formation to adjacent viscera may occur.
  

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  Most carcinomas of the gallbladder are adenocarcinomas.
  
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  Some are papillary and others are infiltrative and poorly differentiated to
  

undifferentiated

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  About 5% are squamous cell carcinomas or have adenosquamous differentiation
  
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  By the time these neoplasms are discovered, most have spread locally and invaded the liver, and many have extended to the cystic duct and adjacent bile ducts and portahepatic lymph nodes.
  
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  The peritoneum, gastrointestinal tract, and lungs are common sites of seeding; distant metastasis is uncommon
  

Carcinoma of the Extrahepatic Bile Ducts

• 
  Refers to malignancies of the extrahepatic biliary tree, down to the level of the ampulla of Vater
  
• 
  Cancers arising in the immediate vicinity of the ampulla are known as periampullary carcinomas and include
  

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  Pancreatic carcinoma
  
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  Adenomas of the ampullary orifice
  

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  Bile duct carcinoma
  
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  Are uncommon
  
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  Age range as in carcinoma of the gallbladder
  
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  Slightly more frequent in males
  
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  The role of gallstones is unconvincing because they are present in only 35 to 50% of cases. Choledochal cysts, ulcerative colitis, and chronic biliary infection with Clonorchis sinensis and Giardia lamblia impart an increased risk for bile duct carcinoma, but such cases represent a minority of patients.
  

Morphology

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  Are generally small lesions at the time of diagnosis
  
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  Most appear as firm, gray nodules within the bile duct wall
  
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  Some may be diffusely infiltrative lesions, and others are papillary, polypoid lesions
  
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  Vast majority of bile duct tumors are adenocarcinomas
  

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  May or may not be mucin secreting
  

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  Uncommonly squamous features are present. For the most part, an abundant fibrous stroma accompanies the epithelial proliferation.
  
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  Tumors arising from the part of the common bile duct between the cystic duct junction and the confluence of the right and left hepatic ducts at the liver hilus are called Klatskin tumors
  
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  These tumors are notable for their slow-growing behavior, marked sclerosing characteristics, and the infrequent occurrence of distal metastases.
  

Clinical Course

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  Jaundice generally arises owing to obstruction, often preceded by decolorization of the stools, nausea and vomiting, and weight loss.
  
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  Hepatomegaly is present in about 50%
  
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  Palpable gallbladder in about 25%
  
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  Associated changes are elevated levels of serum alkaline phosphatase and transaminases and bile-stained urine.
  
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  Differentiation of obstructive jaundice owing to calculous disease or other benign conditions from neoplasia is a major clinical problem because the presence of stones does not preclude the existence of concomitant malignancy
  
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  Majority of ductal cancers are not surgically resectable at the time of diagnosis, despite their small size
  
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  Mean survival times range from 6 to 18 months, regardless of whether aggressive resections or palliative surgery are performed
  
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  Metastatic spread is uncommon because death comes so soon.
  

PANCREAS

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  Exocrine
  

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  Inflammation – Pancreatitis
  

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  Acute
  
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  Chronic
  

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  Tumors
  

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  Benign
  

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  Cysts
  
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  Pseudocysts
  

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  Malignant
  

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  Carcinoma
  

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  Endocrine
  

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  Diabetes Mellitus
  
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  Islet cell tumors
  

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  Insulinoma
  
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  Gastrinoma
  

Pancreatitis

• 
  Inflammation of the pancreas
  
• 
  Almost always associated with acinar cell injury
  
• 
  Types:
  
• 
  Acute pancreatitis
  

• 
  Acute hemorrhagic pancreatitis
  

• 
  Chonic pancreatitis
  

Acute pancreatitis

• 
  Condition characterized by an acute onset of abdominal pain due to enzymatic necrosis and inflammation of the pancreas
  
• 
  80% of cases are associated with two conditions:
  

• 
  Biliary tract disease
  
• 
  Alcoholism
  

• 
  Acute hemorrhagic pancreatitis:
  

• 
  Is a severe form of acute pancreatitis
  
• 
  There is extensive fat necrosis in and about the pancreas and in other intra-abdominal fatty depots
  
• 
  Hemorrhage into the parenchyma of the pancreas
  

• 
  The morphology of acute pancreatic necrosis stems directly from the action of activated pancreatic enzymes that are released into the pancreatic substance.
  
• 
  The basic alterations are:
  

• 
  Proteolytic destruction of pancreatic substance
  
• 
  Necrosis of blood vessels with subsequent hemorrhage
  
• 
  Necrosis of fat - pancreatic and peripancreatic fat
  
• 
  Accompanying inflammatory reaction
  

Microscopic Pancreatitits Acute Hemmorhagic Pancreatitis

Central focus of necrotic fat

Surrounding leucocytic infiltrate

Clinical Features

• 
  Abdominal pain is the cardinal manifestation of acute pancreatitis.
  
• 
  Varies from mild and tolerable, to severe and incapacitating.
  
• 
  Localization in the epigastrium with radiation to the back is characteristic.
  
• 
  Mild acute pancreatitis is diagnosed primarily by the presence of elevated plasma levels of amylase and lipase and exclusion of other causes of abdominal pain.
  
• 
  Full-blown, acute pancreatic necrosis is a medical emergency of the first magnitude.
  
• 
  Differential Diagnosis of “acute abdomen”
  

• 
  Ruptured acute appendicitis
  
• 
  Perforated peptic ulcer
  
• 
  Acute cholecystitis with rupture
  
• 
  Occlusion of mesenteric vessels with infarction of the bowel.
  

• 
  Systemic features attributed to release of toxic enzymes into the systemic circulation:
  

• 
  Leukocytosis
  
• 
  Hemolysis
  
• 
  Disseminated intravascular coagulation
  
• 
  Fluid sequestration (due to a leaky vasculature)
  
• 
  Adult respiratory distress syndrome
  
• 
  Diffuse fat necrosis
  
• 
  Peripheral vascular collapse
  
• 
  Shock with acute renal tubular necrosis may occur due to:
  

• 
  loss of blood volume
  
• 
  electrolyte disturbances
  
• 
  Endotoxemia
  
• 
  release of vasodilatory agents, such as bradykinin and prostaglandins.
  

Laboratory findings

• 
  Marked elevation of the serum amylase during the first 24 hours,
  
• 
  Rising serum lipase level within 72 to 96 hours
  
• 
  Glycosuria occurs in 10% of cases.
  
• 
  Hypocalcemia may result from precipitation of calcium soaps in the fat necrosis
  

• 
  if persistent, it is a poor prognostic sign.
  

• 
  Direct visualization of the enlarged inflamed pancreas by radiographic means is useful in the diagnosis of pancreatitis.
  

Complications and Sequelae

• 
  About 5% die of shock during the first week
  
• 
  Complications:
  

• 
  Acute adult respiratory distress syndrome
  
• 
  Acute renal failure
  

• 
  Sequelae :
  

• 
  Pancreatic abscess
  
• 
  Pseudocyst
  
• 
  Duodenal obstruction
  

• 
  Also termed as chronic relapsing pancreatitis
  
• 
  Progressive destruction of the pancreas by repeated bouts of silent or mildly symptomatic acute pancreatitis.
  
• 
  As in acute pancreatitis most commonly the middle-aged, male alcoholic, and less frequently the patient with biliary tract disease
  
• 
  Hypercalcemia and hyperlipidemia also predispose
  

to chronic pancreatitis.

Morphology

• 
  Chronic pancreatitis is distinguished by
  

• 
  Irregularly distributed fibrosis
  
• 
  Reduced number and size of acini with relative
  

sparing of the islets of Langerhans

• 
  Variable obstruction of pancreatic ducts of all sizes
  

• 
  Grossly:
  

• 
  Gland is hard
  
• 
  Exhibits foci of calcification
  
• 
  Fully developed pancreatic calculi
  

• 
  Therefore the term “chronic calcifying pancreatitis.”
  

• 
  Pseudocyst formation is common.
  

Clinical Features

• 
  Can present as repeated attacks of abdominal pain, or persistent and intractable abdominal and back pain.
  
• 
  Entirely silent until pancreatic insufficiency and diabetes develop.
  
• 
  Recurrent episodes of mild jaundice or bouts of indigestion.
  
• 
  Diagnosis requires a high index of suspicion.
  
• 
  Attacks may be precipitated by alcohol abuse, overeating, or the use of opiates and other drugs.
  
• 
  Abdominal imaging may show calcification in of the pancreas.
  
• 
  Pancreatic pseudocysts occur frequently
  
• 
  Profound weight loss
  
• 
  Hypoalbuminemic edema
  
• 
  A modestly increased risk of pancreatic carcinoma.
  

Causes and Consequences of chronic pancreatitis