Digestive Pathology Lecture 7 - School of Medicine - LSU ...medschool.lsuhsc.edu/pathology/cytopathology/digestive/PP_lecture_7... · Digestive Pathology Lecture 7 ... Acute and chronic

Digestive Pathology Lecture 7

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Last updated October 1, 2015

Gallbladder, extrahepatic biliary tract

1. Congenital abnormalities2. Cholelithiasis

3. Cholesterolosis

4. Acute and chronic cholecystitis

5. Choledocholithiasis

6. Cholangitis

7. Neoplasms

Duplicated/accessory gallbladder

Septate/bilobed, diverticular, malplaced gallbladder

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Biliary atresia

Complete obstruction

Manifest within the first 3 months of life

One-third of infants with neonatal cholestasis

If untreated, secondary biliary cirrhosis develops within 3-6 months

Accounts for 50-60% of children referred for liver transplantation

Is the most common cause of death from liver disease in early childhood

Biliary atresia, two forms

Fetal (aberrant development), 20%

Perinatal (normal development, secondary injury), the most common– Viral infection

– Apoptosis of bile duct epithelium

– Abnormal inflammatory response

– Genetic predisposition

Biliary atresia etiologyPre- or perinatal viral infection (rotavirus, reovirus, cytomegalovirus), apoptosis of bile duct epithelium with aberrant MHC class II antigens expression, eliciting an abnormal inflammatory response in a genetically-predisposed host, resulting in fibrosis and complete bile duct obstruction

Semin Liver Dis 2012; 32(04): 307-316

Biliary atresia, Three types

Type I:– Common bile duct involved

– Patent proximal ducts

Type II:– Hepatic duct involved

– Patent (IIa) OR obliterated (IIb) cystic and common bile ducts

Type III (majority of cases):– Complete extrahepatic biliary atresia (including

right and left hepatic ducts)

Biliary atresia, types

Common bile duct

Hepatic duct

Hepatic duct,cystic duct &common bile duct

Complete

Biliary-enteric anastomosis (A, B and C)Hepatoportoenterostomy (Kasai procedure, E, F)

Hepatoportoenterostomy (Kasai procedure)

View of porta hepatis after transection. Gallbladder and all extrahepatic ducts have been removed from patient with type 3 biliary atresia. Several scattered small ducts are visible on the portal plate (arrows show portal plate). The Lancet, 374, 9702, 2009:1704–1713

Choledochal cysts

Congenital cystic dilatations or diverticula of the bile ducts

Most manifest before age 10

More common in females, 4:1

Choledochal cysts

Choledochocele

Multiple Dilatations

Single Dilatations(80-90%)

Diverticulum

Caroli’s

Choledochocele

ERCP image of a choledochocele, or type III choledochal cyst (arrow) Radiographics.rsna.org

Choledochocele

31-year-old man with recurrent pancreatitis and choledochocele. ERCP demonstrates choledochocele (white arrow), dilated common bile duct (black arrow) and pancreatic duct (arrowhead) Intraoperative photograph shows open duodenum with cyst bulging into the lumen. Radiology Case Reports, Vol 3, No 3 (2008)

Choledochal cysts

May cause:

– Neonatal cholestasis

– Recurrent biliary colic and/or jaundice

– Pancreatitis

Predispose to:

– Stones

– Inflammation

– Stenosis

– Pancreatitis

– Cholangiocarcinoma

Choledochal cyst, type IExcision, biliary-enteric anastomosis

Odze, Surgical Pathology of the GI Tract, Liver Biliary Tract and Pancreas


1. Congenital abnormalities

2. Cholelithiasis3. Cholesterolosis



6. Cholangitis

7. Neoplasms

Cholelithiasis

Calculi (stones) in the gallbladder (gallstones)

Present in 10-20% of the population

Most are silent May cause RUQ/epigastric pain

– constant or

– postprandial (after fat-rich meals)• Subsides gradually in 1 to 5 hours

– may radiate to the right scapular region

– may associate nausea and vomit

Gallstones, shape, size

When solitary or few: large, round or oval

When multiple: faceted (molded)

Size decreases in proportion to their number

Very small stones, called “gravel”, are more likely to escape the gallbladder and produce biliary obstruction

Thick bile is called “sludge”, may also cause obstruction

Gallstones, rounded, faceted

Gallstones, composition

Different amounts of:

– Cholesterol (yellow)

– Calcium bilirubinate (green-black)

– Calcium carbonate (gray-white)

Classified as:

– Pure

– Mixed (80%)

– Combined (nucleus, shell)

Mix

ed s

tones

Combined stones

Gallstones, also classified as

Cholesterol stones (80%)

– When made predominantly of cholesterol

– Pale-yellow, yellow-green, yellow-gray

Pigmented

– When made predominantly of calcium bilirubinate

– Brown or jet black

Chole

stero

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ones

Pig

mente

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tones

Gallstones, radiology

Pure cholesterol stones are radiolucent

Mixed/combined stones are radiopaque depending on their concentration of calcium

Gallstones, plain film

Gallstones, ultrasound

Cholesterol stones, nucleation

In the bile, cholesterol is kept soluble by aggregation with phospholipids and bile acids (lithogenic index)

Nucleation (crystallization) of cholesterol is promoted by

– Supersaturation of bile with cholesterol

– Microprecipitates of inorganic or organic calcium salts

Cholesterol, lecithin, bile acids balanceOnly below the solid line cholesterol is kept in solution (micelles)

Risk factors, cholesterol stones

Native Americans, Hispanics, Northern European Age > 55 Female sex, oral contraceptives, estrogen

replacement therapy, pregnancy Obesity Rapid weight reduction (gastric bypass) Hyperlipidemia Some cholesterol-lowering medications (fibrates) may

increase the risk, others (statins) may decrease the risk

Ileal dysfunction or bypass Gallbladder stasis Family history

Genetic mechanisms

Cholesterol transporter ABCG5/G8 mutation:

– Cholesterol hypersecretion

CYP7A1 mutation:

– Deficiency in the synthesis of bile acids

MDR3 mutation:

– Defective phospholipid export pump in the canalicular membrane

Risk factors, pigmented stones

Asian populations

Hemolytic disorders (hyperbilirubinemia)

Bacterial colonization of the biliary tree (bacterial glucuronidases)

Parasitic colonization of the biliary tree (Ascaris lumbricoides, trematodes)

Pigmented gallstones

Faceted pigmented gallstones in a gallbladder from a patient with a mechanical mitral valve prosthesis, leading to chronic intravascular hemolysis.

Robbins Cotran



2. Cholelithiasis

3. Cholesterolosis4. Acute and chronic cholecystitis


6. Cholangitis

7. Neoplasms

Cholesterolosis

Accumulation of cholesterol esters in foamy histiocytes within the lamina propria

Related to “cholesterol hypersecretion”

Grossly: “strawberry” gallbladder

Chole

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Chole

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2. Cholelithiasis

3. Cholesterolosis

4. Acute and chronic cholecystitis5. Choledocholithiasis

6. Cholangitis

7. Neoplasms

Cholecystitis

Inflammation of the gallbladder

– Acute vs. chronic

– Calculus (majority) vs. acalculous

Acute cholecystitis

Obstruction of gallbladder neck or cystic duct, by stones, gravel or sludge (90%)

Acute acalculous cholecystitis

– Postpartum, postoperative, trauma, sepsis, shock

• Ischemia/shock (cystic artery is an end-artery with no collateral circulation)

– Prolonged restriction of oral feeding (lack cholecystokinin-induced contraction)

– Primary bacterial infection (diabetes, immunosuppression, HIV/AIDS)

Acute cholecystitis

Symptoms:

– Nausea, vomiting

– Right upper quadrant, epigastric pain > 6 hours

– Murphy’s sign

– Mild fever

– Mild to moderate leukocytosis

– Absence of high fever, chills, jaundice or hyperbilirubinemia

Usually subsides within days

May require immediate surgery

Recurrence is common

Acalculous cholecystitis is masked by underlying condition, high risk of gangrene and perforation

Acute cholecystitis

Chronic cholecystitis

Cholelithiasis >90%

Obstruction not always found

Clinically

– Recurrent attacks of RUQ/epigastric pain as described for cholelithiasis

Microscopically

– Chronic inflammation and fibrosis

– Outpouchings of the mucosa (Rokitansky-Aschoff sinuses)

Rokitansk

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Cholecystitis, complications

Choledocholithiasis, cholangitis

Sepsis

Perforation, abscess, peritonitis

Cholecystenteric fistula

– Gallstone ileus

Cholecystenteric fistulaGallstone ileus



2. Cholelithiasis

3. Cholesterolosis


5. Choledocholithiasis6. Cholangitis

7. Neoplasms

Choledocholithiasis

Stones within the common bile duct

– Most originate in the gallbladder

– May also form within the bile duct with cysts, bacterial and parasitic infections

Obstruction may cause:

– Pain and jaundice

– Cholangitis

– Secondary biliary cirrhosis

– Pancreatitis



2. Cholelithiasis

3. Cholesterolosis



6. Cholangitis7. Neoplasms

Cholangitis

Inflammation of the biliary tract

Results most commonly from

– Choledocholithiasis

– Other sources of obstruction

• Indwelling catheters

• Strictures

• Tumors

• Parasites

• Acute pancreatitis

Cholangitis, clinical findings

The Charcot triad:

– RUQ pain

– Fever, chills

– Jaundice/hyperbilirubinemia

Cholangitis, complications

Is a medical emergency, requires

– Prompt antibiotic therapy

– Endoscopic biliary drainage

– Surgical evacuation

May cause:

– Hepatic abscesses

– Sepsis

Pyogenic abscesses, acute cholangitis



2. Cholelithiasis

3. Cholesterolosis



6. Cholangitis

7. Neoplasms

– Gallbladder adenomas

– Gallbladder carcinomas

– Carcinomas of the extrahepatic bile ducts

Gallbladder adenomas

Rare

Similar to colonic adenomatous polyps may have a tubular, tubulovillous or villousarchitecture

But are lined by gastric-type, intestinal-type or biliary-type epithelium

Have malignant potential

Gallbladder adenomas

J. A

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Adenom

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Gallbladder cancer

Infrequent

Most are adenocarcinomas

Risk factors:

– Gallstones (the strongest risk factor)

– Obesity

– Female sex, multiparity

– Old age

– In the US, higher rates in: Native Americans, Hispanics, Korean and Chinese

– Salmonella typhi/paratyphi, Helicobacter bilis, Helicobacter pylori, trematodes

– Anomalous pancreatobiliary junction

Gallbladder cancer

Gallbladder cancer

Gallbladder cancer

Preoperative diagnosis is exceptional

Symptoms are those associated with cholelithiasis

Dismal survival

Carcinoma of extrahepatic bile ducts

Most are adenocarcinomas

Slightly more frequent in men

Association with:

– Primary sclerosing cholangitis, IBD

– Choledochal cysts

– Trematodes

Carcinoma of extrahepatic bile ducts

Signs (Courvoisier’s sign):

– Progressive jaundice

– Painless, palpable gallbladder

Most are not resectable

Short survival

Ampullary, periampullary carcinoma

Klatskin’s tumor

Pancreas

1. Congenital malformations

– Pancreas divisum

– Annular pancreas

– Ectopic pancreas

– Congenital cysts2. Pancreatitis

3. Pancreatic cystic neoplasms

4. Pancreatic ductal adenocarcinoma

5. Pancreatic endocrine neoplasms

Pancreas divisumDorsal and ventral duct systems fail to fuse

Accessory duct

Primordia fail to fuse

Main duct

Main duct → major papilla

Accessory duct → minor papilla

A. Dorsal and ventral primordia at about 4 weeks of development. B. Tethering of the ventral bud tip to the duodenum and rotation lead to a ring of pancreatic tissue encircling the duodenum. C. annular pancreas with pancreas divisum; this combination is present in 29% of adult patients. Journal of the American College of Surgeons Volume 206, issue 5, 2008:1019 -1025

Annular pancreasTethering of the ventral primordium as it rotates

Ectopic/accessory pancreas

Stomach

Duodenum

Jejunum

Ileum

Meckel diverticulum

Mesentery

May cause:

– Inflammation, bleeding

– Tumors

Congenital pancreatic cystsAutosomal dominant polycystic kidney disease

Von Hippel–Lindau disease. (a) Contrast material–enhanced CT scan shows enhancing septa separating congenital pancreatic cysts. (b) Axial T2-weighted MR image shows cystic replacement of the pancreas and a serous microcystic pancreatic adenoma (arrow). RadioGraphics, 2006, 26:715

Pancreas1. Congenital malformations

2. Pancreatitis

– Acute pancreatitis

Pancreatic pseudocyst

– Chronic pancreatitis

– Autoimmune pancreatitis3. Pancreatic cystic neoplasms



Acute pancreatitis, main causes

80% of cases:– Alcohol (males)

– Biliary obstruction by gallstones (females)

Cryptogenic: 10-20% (biliary sludge)

Acute pancreatitis, other causes

Pancreas divisum, annular pancreas, choledochocele

Periampullary tumors

Hypertriglyceridemia

Hypercalcemia, hyperparathyroidism

Drugs (thiazide diuretics)

Trauma (blunt, surgical)

Ischemia (shock, vasculitis)

Infections (Mumps)

Mutations in trypsinogen

Mutations in serine protease inhibitor

Mutations causing abnormal bicarbonate secretion

Defense mechanisms

Most pancreatic enzymes are secreted as proenzymes

Proenzymes are activated by trypsin

Trypsinogen is activated in the duodenum by enteropeptidase, avoiding intrapancreatic activation of other proenzymes

Pancreatic acinar and ductal cells secrete trypsin inhibitors (serine protease inhibitor Kazal type 1)

Lipase is secreted in its active form; however, for optimal function it requires colipase that does require activation by trypsin in the intestinal lumen

Acute pancreatitis, pathogenesis

Pancreatitis occurs when normal defenses are deranged mostly by abnormal intrapancreatic activation of trypsin

Alcohol– Direct toxic effect

– Protein-rich secretion, protein plugs

– Contraction of sphincter of Oddi

Obstruction by stones, gravel, sludge, choledochocele, tumors

Viruses, drugs, trauma… (direct acinar injury)

Hereditary pancreatitis

Cationic trypsinogen gene mutation: – Cleavage-resistant trypsin

Serine protease inhibitor Kazal type 1 mutation:– Inactive serine protease, an essential trypsin

inhibitor

Cystic fibrosis CFTR gene mutation: – Abnormal bicarbonate secretion, inspissated

secretions

Acute pancreatitis, morphology

Inflammation

Fat necrosis

Released fatty acids combine with calcium to form dark precipitates

Destruction of the parenchyma and vessels, hemorrhage

Acute pancreatitis

Acute pancreatitis

Acute pancreatitis

Precipitated by:

– Alcoholic binge

– Overeating

– Drugs (opiates)

Epigastric pain

– Stabbing, severe, referred to the upper back

Jaundice

– If there is concomitant obstruction of the bile duct

Hemorrhagic exudates:

– Periumbilical ecchymosis

– Flank ecchymosis

– Nodules of subcutaneous fat necrosis

Cullen’s sign

Cullen’s signPeriumbilical

Turner’s signFlank

Subcutaneous fat necrosis

Acute pancreatitis, laboratory

Elevation of amylase

Elevation of lipase

Hypocalcemia

Hyperglycemia

Leukocytosis

Electrolyte disturbances

Acute pancreatitis, complications

Disseminated intravascular coagulation

Acute respiratory distress syndrome

Shock, acute renal failure

Abscess (sterile or infected)

Splenic/portal venous thrombosis



Walled-off collection of debris and fluid rich in pancreatic enzymes

Wall lacks epithelial lining

Usually solitary

Arise after episodes of acute pancreatitis, chronic pancreatitis with acute exacerbation

May be caused by trauma (blunt, penetrating or operative)

May retain a communication with the ductal system



May

– Resolve spontaneously

– Become infected

– Compress adjacent structures

– Erode into adjacent vessels causing abundant bleeding

– Rupture

Chronic pancreatitis, causes

Repeated bouts of acute pancreatitis

Alcoholism, the most common cause

Long-standing pancreatic duct obstruction (gallstones, neoplasms)

Pancreas divisum


Tropical pancreatitis

Autoimmune pancreatitis

Idiopathic, up to 40%

Chronic pancreatitis, fibrosis, atrophy, dilated ducts with calcified concretions

Chronic pancreatitis calcifications

Chronic pancreatitis

Fibrosis, chronic inflammation, acinar loss, fusion of islets, ductal dilatation with calcified concretions

Chronic pancreatitis, outcome

Atrophy:

– With repeated attacks of acute pancreatitis amylase and lipase may fail to elevate after a substantial portion of the acinar parenchyma is lost

– Malabsorption (pancreatic insufficiency)

– Diabetes

Chronic pain

Pancreatic cancer

– With hereditary pancreatitis, 40% risk


Periductal inflammation with abundant IgG4-secreting plasma cells

Periductal fibrosis with ductal narrowing

Response to steroid treatment

Older men

Involvement of bile ducts and gallbladder and many other organ systems (IgG4-related disease)

Often presents with obstructive jaundice, mimicking pancreatic cancer



2. Pancreatitis


– Serous

– Mucinous

– Intraductal papillary mucinous



Serous cystadenomas

More common in women

Microcystic (numerous small cysts)

Clear, thin, straw-colored fluid

Low cuboidal epithelium

Almost always benign

Serous cystadenoma

Mucinous cystic neoplasm

Arise almost exclusively in women

Macrocystic (few large cysts)

Thick, mucinous fluid

Tall columnar epithelium

Can be benign or malignant

Mucinous cystic neoplasm

Intraductal papillary mucinous neoplasm

More common in men

Arise in the main pancreatic ducts

Intraductal proliferation of mucinous cells in papillary arrangements

Mucin accumulation leads to cystic dilatation

May be multifocal

Can be benign or malignant




2. Pancreatitis


4. Pancreatic ductal adenocarcinoma5. Pancreatic endocrine neoplasms

Pancreatic (ductal) adenocarcinoma

Incidence and mortality

– Greater in men than in women

– Greater in blacks than in whites

– Greater in Acadiana

5-year survival rate < 5%

Pancreatic cancer, incidence rate

Pancreatic adenocarcinoma, risk factors

Smoking

High-protein, high-fat diets

Chronic pancreatitis, diabetes


Alcohol

Exposure to gasoline products, pesticides

Hereditary nonpolyposis colorectal cancer

BRCA2, hereditary breast and ovarian cancer

Peutz-Jeghers syndrome

p16 mutation, 95%

KRAS mutation, 80-90%

Genetic progression

Annual Review of Pathology: Mechanisms of Disease. 2008;3:157–188

www.annualreviews.org

http://www.annualreviews.org/

Pancreatic intraepithelial neoplasia

Pancreatic adenocarcinoma, morphology

Location:

– 60% arise in the head

– 20% diffusely

– 15% in the body

– 5% in the tail

Microscopically:

– High invasiveness (perineural invasion, lymphatic invasion)

– Desmoplastic (scirrhous, fibrous)

Pancreatic ductal carcinoma, desmoplasia

Pancreatic ductal carcinomaDesmoplasia, perineural invasion

Clinical findings

Pain

Obstructive jaundice, palpable non-tender gallbladder (Courvoisier’s sign)

Migratory thrombophlebitis (Trousseau sign)

– Tumor procoagulants

Tumor marker:

– CA19-9

Fewer than 20% are resectable


2. Pancreatitis




– Insulinoma

– Gastrinoma

– Glucagonoma

– Other

Pancreatic endocrine neoplasms

Only 2% of all pancreatic neoplasms May elaborate hormones

– Some are non-functional

Morphologically similar to carcinoids May be associated with MEN I syndrome,

hyperplasia or adenomas in:– Pancreatic islets– Adrenal cortex– Parathyroid– Pituitary

Pancreatic neuroendocrine tumor

Beta-cell tumors (insulinomas)

The most common type

May cause severe hypoglycemia

Whipple triad:

– Fatigue, confusion, stupor, coma, convulsions

– Glucose < 50 mg/dL

– Attacks precipitated by fasting/exercise and relieved by feeding/glucose

Usually small and encapsulated

Only about 10% metastasize

G-cell tumors (gastrinomas)

Located in the “gastrinoma triangle”: duodenum, pancreas and peripancreatic soft tissues

Zollinger-Ellison syndrome

– Hypergastrinemia

– Multiple peptic ulcers (gastric, duodenal, jejunal), unresponsive to therapy

– Diarrhea

Over half locally invasive or have metastasized at the time of diagnosis

Alpha-cell tumors (glucagonoma)

Cause the glucagonoma syndrome:

– Mild diabetes

– Necrolytic migratory erythema

– Deep vein thrombosis

– Anemia

– Tendency to develop overwhelming infections

Seen mostly perimenopausal and postmenopausal women

Approximately 50% have metastases at the time of diagnosis

Necrolytic migratory erythema

Other endocrine neoplasms

Somatostatinoma (Delta-cell tumors), may present with diabetes

VIPomas (vasoactive intestinal peptide), may present with secretory diarrhea

Carcinoids

Tumors producing more than one hormone

Documents

Digestive Pathology Lecture 7 - School of Medicine - LSU ...medschool.lsuhsc.edu/pathology/cytopathology/digestive/PP_lecture_7... · Digestive Pathology Lecture 7 ... Acute and chronic