Gallbladder and Biliary System Pathology

Pathology of Gallbladder and Biliary System; Pathology of Pancreas

• Gallbladder and biliary system anatomy includes the right and left hepatic ducts, liver, common hepatic duct, common bile duct, pancreas, gallbladder, cystic duct, pancreatic duct, duodenum, and sphincter of Oddi.

Classification

• Congenital anomalies include gallbladder agenesis, duplication, and heterotopic tissue.
• Biliary atresia is a congenital anomaly
• Congenital cystic lesions of the bile ducts and liver, such as Caroli's disease, choledochal cysts, polycystic liver disease, and congenital hepatic fibrosis, are congenital anomalies
• Cholelithiasis refers to gallstones
• Cholecystitis refers to inflammation of the gallbladder
• Tumors can occur in the gallbladder and biliary system

Cholelithiasis (Gallstones)

• The gallbladder is where gallstones usually form, but they can sometimes form in biliary passages.
• Gallstones are composed of cholesterol, bile pigment (bilirubin), and calcium carbonate in varying proportions.

Gallstone Types

• Pure gallstones account for 10% of cases and are usually asymptomatic or associated with cholesterolosis.
• These can be pure cholesterol (solitary, oval, large, yellow-white), pure pigment (multiple, jet-black), or pure calcium carbonate.
• Mixed gallstones are the most common (80%), often multiple, multifaceted, and of variable size, accompanied by chronic cholecystitis.
• These are different combinations of cholesterol, bilirubin, and calcium salts laid down in layers.
• Combined gallstones account for 10% of cases, usually solitary, and associated with chronic cholecystitis.
• These have a pure gallstone nucleus with a mixed gallstone shell, or vice versa.

Strawberry Gallbladder (Cholesterolosis)

• The gross appearance of the gallbladder mucosa resembles a strawberry
• This results from abnormal deposits of cholesterol esters in macrophages within the lamina propria (foamy cells)
• Is usually asymptomatic

Cholelithiasis Prevalence

• Cholesterol stones account for 80-85% of gallstones
• Pigment (bilirubin calcium salts) stones account for 15-20% of gallstones.

Cholesterol Stone Etiology and Risk Factors

• Forty: Incidence increases above the age of 40.
• Female: Female to male ratio is 2:1.
• Fatty: Increased cholesterol synthesis and excretion into the bile.
• Fertile: Incidence is higher in multiparous females, and the gallbladder empties more slowly in the last trimester
• Estrogen therapy/birth control pills lead to increased cholesterol levels in bile, decreasing gallbladder movement

Pigment (Bilirubin Calcium Salts) Stones Etiology

• Increased content of unconjugated bilirubin in the bile
• Hemolytic anemias cause the stones.
• Bacterial or parasitic biliary tract infections can cause stones via microbial beta-glucuronidases hydrolyzing bilirubin glucuronides.

Cholelithiasis Symptoms and Complications

• 70-80% of gallstones are "silent" and cause no symptoms.
• Stones may pass distally into other parts of the biliary tract.
• Complications include acute or chronic cholecystitis, perforation, choledocholithiasis leading to obstructive jaundice, pancreatitis, and gallstone ileus.
• Gallstone ileus involves adhesion of the gallbladder to the small bowel (usually the duodenum), which occurs after repeated bouts of cholecystitis with eventual erosion by a stone and passage of gallstones into the bowel
• Inflammation of the biliary tree (ascending cholangitis)

Summary of Cholelithiasis

• Cholesterol and mixed stones are linked to dietary cholesterol, obesity, oral contraceptives, and diabetes mellitus.
• Pigment stones are related to hemolytic anemias and parasitic infections.
• Cholelithiasis can lead to several complications, including obstruction of the cystic duct, mucocele of the gallbladder, acute cholecystitis, empyema of the gallbladder, and rupture of the gallbladder leading to peritonitis.
• Chronic cholecystitis increases the risk of carcinoma and can lead to calcification of the wall (porcelain gallbladder).
• Other complications include postinflammatory fibrosis, stricture, obstruction of the common bile duct, biliary colic (pain), pancreatitis, cholangitis, obstructive jaundice, acute pancreatitis, chronic pancreatitis, and gallstone ileus.

Cholecystitis

• Acute cholecystitis is a surgical emergency (acute abdomen)
• Can be chronic
• Can be acute superimposed on chronic

Acute Cholecystitis: Forms

• Calculous accounts for 90% of cases

• This is caused by obstruction of the neck of the gallbladder or cystic duct by a gallstone, leading to obstruction of bile outflow, chemical irritation by bile salts, increased intraluminal pressure, compromised mucosal blood flow, and prostaglandins release.

• Acute inflammation in the absence of bacterial infection can lead to secondary bacterial contamination, particularly with E. coli and Streptococcus faecalis.

• Acalculous accounts for 10% of cases

• This can be caused by surgery, trauma, burns, multiorgan failure, sepsis, recent childbirth, diabetes mellitus, and immunosuppression.

• Pathogenesis involves ischemia, dehydration, bile stasis, viscous bile, and bacterial contamination.

Acute Cholecystitis: Clinical Features

• Ranges from mild symptoms resolved without medical intervention to acute medical emergency with features of peritoneal irritation.
• Right upper quadrant or epigastric pain may radiate to the back
• Other symptoms include nausea, vomiting, fat intolerance, abdominal distention, fever, leucocytosis, and slight jaundice.

Chronic Cholecystitis

• More than 90% of cases are associated with cholelithiasis.
• Conditions can be primary chronic or result from repeated bouts of acute cholecystitis
• Symptoms are vague, including nausea, flatulence (abdominal distension), intolerance of fatty foods, epigastric discomfort, and recurrent attacks of pain.

Complications of Cholecystitis

• Bacterial superinfection can lead to cholangitis or sepsis
• Gallbladder perforation can lead to local abscess.
• Gallbladder rupture can lead to diffuse peritonitis
• Cholecystenteric fistula can lead to the entry of air and bacteria into the biliary tree and gallstone-induced intestinal obstruction (ileus)
• Aggravation of a preexisting medical illness can lead to cardiac, pulmonary, renal, or liver decompensation.
• Porcelain gallbladder increases the risk of cancer.

Hyalinizing Cholecystitis/Porcelain Gallbladder

• A morphological variant of chronic cholecystitis
• This involves inflammatory scarring of the wall, combined with dystrophic calcification within the wall.
• The gallbladder is transformed into a porcelain-like vessel.
• There is approximately a 6% increase in incidence of gallbladder carcinoma.
• Treatment involves removal of the gallbladder (cholecystectomy).

Tumors

• Benign tumors are exceedingly rare: papilloma, adenoma, fibroma, lipoma, and hemangioma.

Malignant Tumor Regions

• Gallbladder
• Ampulla of Vater
• Common bile duct (lower)
• Hepatic duct
• Junction of hepatic ducts

Carcinoma of the Gallbladder

• 90% is adenocarcinoma.
• The female to male ratio is 3:1, and it commonly occurs in the 6th and 7th decade
• Risk factors include cholelithiasis, hyalinizing cholecystitis/porcelain gallbladder, obesity, infections, and primary sclerosing cholangitis
• 30% are the fungating type, and 70% are the infiltrating type.

Carcinoma of the Gallbladder: Clinical Manifestations

• Longstanding cholelithiasis and cholecystitis can lead to metaplastic changes (intestinal or pseudopyloric) in the gallbladder mucosa.
• Metaplasia, especially intestinal type, gives rise to epithelial dysplasia and carcinoma in situ (biliary intraepithelial neoplasia).
• Progression from dysplasia to advanced gallbladder carcinoma takes around 15 years.
• Most patients are asymptomatic.
• Symptoms, when present, are often vague, including:
• Right upper quadrant pain
• Weight loss
• Fever
• Jaundice and vomiting
• The disease is usually advanced by the time the patient develops symptoms.
• It is an aggressive cancer with an overall 5-year survival rate of less than 10%.
• Often metastasizes to the liver

Cholangiocarcinoma

• Malignancy of biliary tree arising from bile ducts within or outside the liver
• 80-90% of cases are extrahepatic bile duct cancers.
• These arise from precursor lesions, namely biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile ducts.
• Risk factors include chronic parasitic infections (Opisthorchis viverrini, Clonorchis sinensis) of the biliary tract, congenital fibropolycystic diseases of the biliary system, primary sclerosing cholangitis, cholelithiasis, chronic pancreatitis, and ulcerative colitis.

Cholangiocarcinoma: Prognosis and Symptoms

• Relatively rare and occurs in the 6th and 7th decade.
• Poor prognosis comes with a mean survival of 6-18 months
• Higher prevalence in southeast Asia, attributed to endemic chronic parasitic infestation.
• Obstructive jaundice, itching, acholic stools, dark urine, fever, abdominal pain, and weight loss.

Pathology of Pancreas

• The pancreas has a head, tail, and lobules, and includes common bile duct and pancreatic duct.
• Acinar cells secrete digestive enzymes, and exocrine cells secrete pancreatic juice
• Pancreatic islet cells secrete hormones.

Pancreas: Classification

• Congenital Anomalies
• Pancreatitis
• Acute
• Chronic
• Cystic Fibrosis
• Tumors

Congenital Anomalies of Pancreas

• Ectopic pancreatic tissue can be found in the stomach, duodenum, and Meckel's diverticulum.
• Annular pancreas completely encircles the duodenum.
• Pancreas divisum is a failure of fusion of the ventral and dorsal pancreatic ducts, causing the bulk of pancreatic secretions to pass through the minor papilla, predisposing to chronic pancreatitis.

Acute Pancreatitis: Types

• Acute interstitial: Milder and self-limiting, with mild inflammation, interstitial edema, and focal areas of fat necrosis.
• Acute hemorrhagic: More severe with acute abdomen, necrosis of pancreatic tissue, fat tissue, arteries, and arterioles with areas of hemorrhage.
• Has a high mortality rate (20-30%).

Acute Pancreatitis: Etiology and Symptoms

• May occur after a bout of alcohol or a heavy meal
• Alcoholism (M>F)
• Cholelithiasis (F>M)
• Less common are trauma, ischemia, shock, bloodborne infections, hypercalcemia (hyperparathyroidism), hyperlipoproteinemia, medications, and familial hereditary pancreatitis.
• Clinical features include constant and intense abdominal pain and vomiting.
• Elevated serum amylase (first 24 hours).
• Elevated serum lipase (after 3-4 days) are indicators
• Complications include peritonitis and the release of enzymes and cytokines into the circulation, leading to the activation of systemic inflammatory response (DIC, ARDS, shock, acute renal failure).

Acute Pancreatitis: Pathogenesis

• Liberation and activation of intracellular pancreatic enzymes due to acinar cell damage (alcohol, viruses, drugs, ischemia, trauma). OR
• Pancreatic duct obstruction (gallstones in the region of the ampulla of Vater, neoplasms, parasites, chronic alcoholism) leads to increased intrapancreatic ductal pressure. Leakage of enzymes from the ductules into the interstitium causes lipase-mediated local fat necrosis and release of proinflammatory cytokines. OR
• Defective intracellular transport of pancreatic proenzymes, leading to delivery of digestive proenzymes to the lysosomal compartment

Pancreatic Enzymes

• Amylase
• Proteases (trypsin, chymotrypsin) - proteolysis
• Lipases and phospholipases
• Elastases – destruction of the elastic tissue of the blood vessels
• Nucleases

Acute Hemorrhagic Pancreatitis

• Gland displays Edematous or hemorrhagic / necrotic appearance
• Usually presence of white nodules representing fat necrosis in pancreas

Chronic Pancreatitis

• Occurs after repeated mild and subclinical attacks of acute pancreatitis
• The inflammation of the pancreas is accompanied by progressive irreversible destruction of the exocrine parenchyma (+ endocrine in the late stages) and fibrosis.
• Etiology is most commonly associated with chronic alcoholism (middle-aged males), which has a direct toxic effect on acinar cells.

Chronic Pancreatitis: Pathogenesis

• Direct toxic effect on acinar cells
• Increase in protein concentration in the pancreatic juice, leading to obstruction of the ducts.
• Biliary tract obstruction
• Obstruction of the pancreatic duct is observed in neoplasms and trauma
• Familial hereditary: AD inherited, recurrent attacks of severe pancreatitis beginning in childhood, alteration in genes encoding pancreatic enzymes and their inhibitors
• Pancreas divisum

Chronic Pancreatitis: Symptoms

• Repeated attacks of moderately severe abdominal pain OR
• Recurrent attacks of mild pain and indigestion OR
• Persistent abdominal and back pain
• Irreversible impairment in pancreatic function: DM, pancreatic insufficiency with steatorrhea, and malabsorption.
• Histologically can identify fibrosis and chronic inflammation

Cystic Fibrosis

• Mucoviscidosis: Obstruction of the organ passages by viscid mucous secretions in all the exocrine glands of the body and respiratory, GIT, and reproductive tract
• Autosomal Recessive trait: genetic mutation in CFTR gene located on chromosome 7.
• Manifestations appear at any point from birth to adolescence.
• Pancreatic insufficiency with malnutrition, steatorrhea, male infertility, intestinal obstruction, hepatic cirrhosis, and respiratory complications with recurrent infections follow.

Tumors of Pancreas

• Exocrine (around 95% of tumors) – 85% ductal adenocarcinoma, 5% acinar cell adenocarcinoma
• Neuroendocrine: Arise from the hormone-producing cells of the pancreas
• Are generally less aggressive than pancreatic adenocarcinoma
• A diverse group of benign or malignant tumors
• Can be functional and nonfunctional types according to hormone production
• The functional types secrete hormones such as insulin, gastrin, and glucagon into the bloodstream, producing symptoms and favoring relatively early detection
• The most common functioning tumors are insulinomas and gastrinomas
• May find glucagonoma, VIPoma, stomatostatinoma, ACTH producing tumor, and serotonin producing tumor, etc.
• MINEN (mixed neuroendocrine-nonneuroendocrine neoplasms)

Carcinoma of Pancreas

• One of the highest mortality rates of any cancer
• Highly invasive
• Highly diagnosed in 80% age 60 - 80
• The most common is ductal adenocarcinoma.
• Frequency: 60-70% head, 5-15% body, and 10-15% tail
• Etiology is smoking, obesity, diet rich in fats, animal proteins, chronic pancreatitis, chemical carcinogens, DM, and hereditary syndromes.
• Clinical features include pain and obstructive jaundice.
• Cancer of the head of the pancreas causes pressure on the common bile duct, leading to marked distention of the biliary tree.
• Cancer of the body and tail remain silent for some time, most are widely disseminated by the time they are discovered.
• Has ductal adenocarcinoma or acinar cell carcinoma.
• Ductal adenocarcinoma involves infiltrating well to poorly formed glandular / ductal structures surrounded by remarkably desmoplastic stroma
• Mucin production is specific for ductal origin versus acinar or neuroendocrine differentiation.
• Prognosis is dismal with a median survival of 6 months from confirmed diagnosis 5-year survival rate is only 6% patients
• Metastasizes to the liver, lungs, and bones.

Note: Acute Medical Emergencies

• Acute cholecystitis
• Acute appendicitis
• Acute pancreatitis
• Perforated peptic ulcer
• Infarction of the intestine