Digestive Pathology Lecture 7

Transcription

1 Digestive Pathology Lecture 7 Reproduction Prohibited This file contains original text and images as well as materials adapted from copyrighted sources For use only as a temporary educational aid Partially or completely copying or distributing the contents of this file may constitute an infringement of the fair use exception for teaching faculty of the U.S. Copyright Law LSUHSC-New Orleans, 2015 Last updated October 1, 2015

2 Gallbladder, extrahepatic biliary tract 1. Congenital abnormalities 2. Cholelithiasis 3. Cholesterolosis 4. Acute and chronic cholecystitis 5. Choledocholithiasis 6. Cholangitis 7. Neoplasms

3 Duplicated/accessory gallbladder

4 Septate/bilobed, diverticular, malplaced gallbladder

5 Gallbladder, folded fundus, phrygian cap

6 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

7 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

8 Biliary atresia etiology Pre- 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 geneticallypredisposed host, resulting in fibrosis and complete bile duct obstruction Semin Liver Dis 2012; 32(04):

9 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)

10 Biliary atresia, types Hepatic duct Common bile duct Hepatic duct, cystic duct & common bile duct Complete

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

12 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:

13 Choledochal cysts Congenital cystic dilatations or diverticula of the bile ducts Most manifest before age 10 More common in females, 4:1

14 Choledochal cysts Single Dilatations (80-90%) Diverticulum Choledochocele Multiple Dilatations Caroli s

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

16 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)

17 Choledochal cysts May cause: Neonatal cholestasis Recurrent biliary colic and/or jaundice Pancreatitis Predispose to: Stones Inflammation Stenosis Pancreatitis Cholangiocarcinoma

18 Choledochal cyst, type I Excision, biliary-enteric anastomosis Odze, Surgical Pathology of the GI Tract, Liver Biliary Tract and Pancreas

19 Gallbladder, extrahepatic biliary tract 1. Congenital abnormalities 2. Cholelithiasis 3. Cholesterolosis 4. Acute and chronic cholecystitis 5. Choledocholithiasis 6. Cholangitis 7. Neoplasms

20 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

21 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

22 Gallstones, rounded, faceted

23 Gallstones, composition Different amounts of: Cholesterol (yellow) Calcium bilirubinate (green-black) Calcium carbonate (gray-white) Classified as: Pure Mixed (80%) Combined (nucleus, shell)

24 Mixed stones

25 Combined stones

26 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

27 Cholesterol stones

28 Pigmented stones

29 Gallstones, radiology Pure cholesterol stones are radiolucent Mixed/combined stones are radiopaque depending on their concentration of calcium

30 Gallstones, plain film

31 Gallstones, ultrasound

32 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

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

34 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

35 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

36

37 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)

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

39 Gallbladder, extrahepatic biliary tract 1. Congenital abnormalities 2. Cholelithiasis 3. Cholesterolosis 4. Acute and chronic cholecystitis 5. Choledocholithiasis 6. Cholangitis 7. Neoplasms

40 Cholesterolosis Accumulation of cholesterol esters in foamy histiocytes within the lamina propria Related to cholesterol hypersecretion Grossly: strawberry gallbladder

41 Cholesterolosis

42 Cholesterolosis, strawberry gallbladder

43 Gallbladder, extrahepatic biliary tract 1. Congenital abnormalities 2. Cholelithiasis 3. Cholesterolosis 4. Acute and chronic cholecystitis 5. Choledocholithiasis 6. Cholangitis 7. Neoplasms

44 Cholecystitis Inflammation of the gallbladder Acute vs. chronic Calculus (majority) vs. acalculous

45 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)

46 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

47 Acute cholecystitis

48 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)

49 Rokitansky-Aschoff sinuses

50 Porcelain gallbladder

51 Cholecystitis, complications Choledocholithiasis, cholangitis Sepsis Perforation, abscess, peritonitis Cholecystenteric fistula Gallstone ileus

52 Cholecystenteric fistula Gallstone ileus

53 Gallbladder, extrahepatic biliary tract 1. Congenital abnormalities 2. Cholelithiasis 3. Cholesterolosis 4. Acute and chronic cholecystitis 5. Choledocholithiasis 6. Cholangitis 7. Neoplasms

54 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

55 Gallbladder, extrahepatic biliary tract 1. Congenital abnormalities 2. Cholelithiasis 3. Cholesterolosis 4. Acute and chronic cholecystitis 5. Choledocholithiasis 6. Cholangitis 7. Neoplasms

56 Cholangitis Inflammation of the biliary tract Results most commonly from Choledocholithiasis Other sources of obstruction Indwelling catheters Strictures Tumors Parasites Acute pancreatitis

57 Cholangitis, clinical findings The Charcot triad: RUQ pain Fever, chills Jaundice/hyperbilirubinemia

58 Cholangitis, complications Is a medical emergency, requires Prompt antibiotic therapy Endoscopic biliary drainage Surgical evacuation May cause: Hepatic abscesses Sepsis

59 Pyogenic abscesses, acute cholangitis

60 Gallbladder, extrahepatic biliary tract 1. Congenital abnormalities 2. Cholelithiasis 3. Cholesterolosis 4. Acute and chronic cholecystitis 5. Choledocholithiasis 6. Cholangitis 7. Neoplasms Gallbladder adenomas Gallbladder carcinomas Carcinomas of the extrahepatic bile ducts

61 Gallbladder adenomas Rare Similar to colonic adenomatous polyps may have a tubular, tubulovillous or villous architecture But are lined by gastric-type, intestinal-type or biliary-type epithelium Have malignant potential

62 Gallbladder adenomas J. Albores-Saavedra et al. Adenomas of the gallbladder. Human Pathology, 43:1506, 2012

63 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

64 Gallbladder cancer

65 Gallbladder cancer

66 Gallbladder cancer Preoperative diagnosis is exceptional Symptoms are those associated with cholelithiasis Dismal survival

67 Carcinoma of extrahepatic bile ducts Most are adenocarcinomas Slightly more frequent in men Association with: Primary sclerosing cholangitis, IBD Choledochal cysts Trematodes

68 Carcinoma of extrahepatic bile ducts Signs (Courvoisier s sign): Progressive jaundice Painless, palpable gallbladder Most are not resectable Short survival

69 Ampullary, periampullary carcinoma

70 Klatskin s tumor

71 Pancreas 1. Congenital malformations Pancreas divisum Annular pancreas Ectopic pancreas Congenital cysts 2. Pancreatitis 3. Pancreatic cystic neoplasms 4. Pancreatic ductal adenocarcinoma 5. Pancreatic endocrine neoplasms

72 Pancreas divisum Dorsal and ventral duct systems fail to fuse Accessory duct Main duct Primordia fail to fuse Accessory duct minor papilla Main duct major papilla

73 Annular pancreas Tethering of the ventral primordium as it rotates 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:

74 Ectopic/accessory pancreas Stomach Duodenum Jejunum Ileum Meckel diverticulum Mesentery May cause: Inflammation, bleeding Tumors

75 Congenital pancreatic cysts Autosomal 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

76 Pancreas 1. Congenital malformations 2. Pancreatitis Acute pancreatitis Pancreatic pseudocyst Chronic pancreatitis Autoimmune pancreatitis 3. Pancreatic cystic neoplasms 4. Pancreatic ductal adenocarcinoma 5. Pancreatic endocrine neoplasms

77 Acute pancreatitis, main causes 80% of cases: Alcohol (males) Biliary obstruction by gallstones (females) Cryptogenic: 10-20% (biliary sludge)

78 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

79 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

80 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)

81 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

82 Acute pancreatitis, morphology Inflammation Fat necrosis Released fatty acids combine with calcium to form dark precipitates Destruction of the parenchyma and vessels, hemorrhage

83 Acute pancreatitis

84 Acute pancreatitis

85 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

86 Cullen s sign

87 Cullen s sign Periumbilical Turner s sign Flank

88 Subcutaneous fat necrosis

89 Acute pancreatitis, laboratory Elevation of amylase Elevation of lipase Hypocalcemia Hyperglycemia Leukocytosis Electrolyte disturbances

90 Acute pancreatitis, complications Disseminated intravascular coagulation Acute respiratory distress syndrome Shock, acute renal failure Abscess (sterile or infected) Splenic/portal venous thrombosis Pancreatic pseudocyst

91 Pancreatic pseudocyst 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

92 Pancreatic pseudocyst

93 Pancreatic pseudocyst May Resolve spontaneously Become infected Compress adjacent structures Erode into adjacent vessels causing abundant bleeding Rupture

94 Chronic pancreatitis, causes Repeated bouts of acute pancreatitis Alcoholism, the most common cause Long-standing pancreatic duct obstruction (gallstones, neoplasms) Pancreas divisum Hereditary pancreatitis Tropical pancreatitis Autoimmune pancreatitis Idiopathic, up to 40%

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

96 Chronic pancreatitis calcifications

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

98 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

99 Autoimmune pancreatitis 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

100 Autoimmune pancreatitis

101 Pancreas 1. Congenital malformations 2. Pancreatitis 3. Pancreatic cystic neoplasms Serous Mucinous Intraductal papillary mucinous 4. Pancreatic ductal adenocarcinoma 5. Pancreatic endocrine neoplasms

102 Serous cystadenomas More common in women Microcystic (numerous small cysts) Clear, thin, straw-colored fluid Low cuboidal epithelium Almost always benign

103 Serous cystadenoma

104 Mucinous cystic neoplasm Arise almost exclusively in women Macrocystic (few large cysts) Thick, mucinous fluid Tall columnar epithelium Can be benign or malignant

105 Mucinous cystic neoplasm

106 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

107 Intraductal papillary mucinous neoplasm

108 Intraductal papillary mucinous neoplasm

109 Pancreas 1. Congenital malformations 2. Pancreatitis 3. Pancreatic cystic neoplasms 4. Pancreatic ductal adenocarcinoma 5. Pancreatic endocrine neoplasms

110 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%

111 Pancreatic cancer, incidence rate

112

113 Pancreatic adenocarcinoma, risk factors Smoking High-protein, high-fat diets Chronic pancreatitis, diabetes Hereditary pancreatitis 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%

114 Genetic progression Annual Review of Pathology: Mechanisms of Disease. 2008;3:

115 Pancreatic intraepithelial neoplasia

116 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)

117 Pancreatic ductal carcinoma, desmoplasia

118 Pancreatic ductal carcinoma Desmoplasia, perineural invasion

119 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

120 Pancreas 1. Congenital malformations 2. Pancreatitis 3. Pancreatic cystic neoplasms 4. Pancreatic ductal adenocarcinoma 5. Pancreatic endocrine neoplasms Insulinoma Gastrinoma Glucagonoma Other

121 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

122 Pancreatic neuroendocrine tumor

123 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

124 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

125 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

126 Necrolytic migratory erythema

127 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