liver Flashcards
Give the numbering system for liver lobes
8 lobes total
1- caudate
2-3-left lobe upper/lower
4-right adjacent to falciform
5,6-right lobe lower
7,8-right lobe upper
Name the finding, condition where it is seen, mutation
- Kayser-Fleisher ring
- Wilson’s disease
- ATP7B- mutation in copper transport protein
What are features to report in hepatocellular carcinoma synoptic report?
- Specimen/procedure
- tumor size
- tumor focality
- histologic type (HCC, fibrolamellar, undifferentiated)
- histologic grade (G1-G4)
- tumor extension (within iver, portal vein, peritoneum, gallbladder)
- margins (parenchymal)
- macroscopic venous extension, microscopic venous extension
- TNM (T1-solitary tumor no vascular invasion, T2-solitary with vascular, or multiple tumors each less than 5cm, T3-multiple tumors more than 5cm, any size with portal vein involvement, T4-direct invasion other organs)
- additional pathologic findings (fibrosis, clinical history)
What virus is most implicated in transfusion-acquired hepatitis?
HCV
Give four clinico-pathologic findings possible in a patient with Wilson’s disease
Low serum copper level
Kayser-Fleisher rings
Increased urine copper
Elevated liver enzymes
What histologic finding is seen in Reye’s syndrome
Microvesicular fatty change with panacinar distribution
List 5 clinicopathologic findings in A-1 antitrypsin disease
- Possible emphysema and pulmonary dysfunction
- Spectrum of liver abnormalities in adults includling chronic hepatitis, cirrhosis, HCC
- Infants/neonates with giant cell hepatitis
- micro featurs including eosinophilic globules in periportal hepatocytes, PASD+
- intracellular inclusions are positive for a-1-antitrypsin antibody on IHC
What histologic feature is needed on bio;sy to establish a diagnosis of extrahepatic biliary atresia in a neonate?
Ductular proliferation
LIver biopsy: what is minimum length?
minimum 1.5cm and 6 portal tracts, doesn’t matter for mass lesion as long as you get it
Needle stick injuries: what is the risk of becoming infected with HBV or HCV?
- 1.8% for both
- HIV is 0.3%
What is the risk of chronic hepatitis from HBV and HCV?
- HBV is 10%
- HCV is 80%
What is a carrier in the setting of viral hepatitis?
Carrrier is an individual who harbours and can transmit an organism, but who has no manifest symptoms
- IN HBV, healthy carrier is positive for HBsAg for >6months, without HBeAg but with anti-Hbe antibody, normal aminotransferases, low or undetectable serum HBV DNA, liver biopsy showing ack of significant inflammation and necrosis
What is chronic hepatitis (viral)?
- Symptomatic, biochemical, serologic evidence of continuing or relapsing hepatic disease for >6months
What is the role of pathologist in the diagnosis of viral hepatitis in liver biopsies
- Confirm diagnosis
- Ascertain etiology
- Grading of activity
- Staging of fibrosis
- Rule out other superimposed disease processes
Describe the positive histology that can aid in the diagnosis of Hep A, Hep B, Hep C
Hep A:
acute: anti-HAV IgM
immunity: anti- HAV IgG
Hep B
acute: HBsAg, anti-HbsAg, anti-HBc IgM, anti-HBc IgG
chronic without replication: HBsAg, anti-HBc IgG
Chronic with replication: HBsAg, anti HBc-IgG, HBV DNA
Reactivation: HBsAg, HBV DNA, anti HBc IgM, anti-HBc IgG
Past exposure immunity: anti HBsAg, anti- HBc IgG
vaccination immunity: anti HBsAg
List the histologic clues in the ddx of viral infections in the liver
In Immunocompetent:
HAV: abundant plasma cells and cholestasis
HBV: prominent central ballooning degeneration
HCV: dense lymphoid aggregates, bile duct damage, sinusoidal lymphocytes
CMV/EBV: portal/sinusoidal lymphocytes, with granulomas and minimal hepatocyte damage
HEV: confluent necrosis and cholangitis
Immunocompromised:
CMV: nuclear/cytoplasmic inclusions and microabcesses
EBV: portal infiltration with alrge lymphocytes
Herpes or adenovirus: randomly distributed coagualitve necrosis and nuclear inclusions
HCV: extensive hepatocyte necrosis, prominent cholestasis and pericellular fibrosis (fibrosing cholestatic hcv)
What is the significance of steatosis/steatohepatitis in a patient with HCV?
- Likely genotype 3
- Steatosis favours viral replication
- may represent superimposed disease process
- usually associated with more inflammation and increased fibrosis
What is the Ddx of lymphoma in the liver
HCV
EBV/CMV
Toxoplasmosis
Hemophagocytic syndrome
Small cell carcinoma
Extramedullary hematopoesis, tropical splenomegally, myeloid metaplasia
Classify viral hepatitis based on mode of transmission
- Fecal oral: Hep A/Hep E
Parenteral/sexual: Hep B, C, D
Parenteral: Hep G
List biochemical tests for the liver and their significance
Liver cell necrosis: AST, ALT
cholestasis: GGT, ALP, bilirubin
Hepatocyte dysfunction: low albumen, high PTT INR and ammonia
autoimmune hepatitis: ANA, ASMA
Primary biliary cirrhosis: IgM, AMA-PBV
HCC: AFP
What is the ddx of ground-glass hepatocytes in the non-neoplastic setting?
- Drug induced hypertrophy of smooth endoplasmic reticulum, centrolobular and PASD neg
- Fibrinogen storage disease, random location, PASD+
- alcohol aversion drug (cyanamide): lysosomal accumulations, periportal, PAS+/PASD-
- Glycogen storage disease (type 4 ) or abnormal glycogen metabolism; periportal, pAS+, PASD-
- Lafora disease (myoclonal epilepsy), periportal, PAS+ colloidal iron+
- HBsAg
Name 3 subtypes of autoimmune hepatitis and their characteristic autoimmune markers
Type 1: antinuclear antibody, anti-smooth muscle antibody (ASMA)
Type 2: anti-liver-kidney-microsomal antibody (anti-LKM)
Type 3: antisoluble liver antigen/antisoluble liver-pancreas antigen anti SLA
Liver: ddx for central zone necrosis with inflammation
- Drug toxicity
- Autoimmune hepatitis
- Ischemia
What is the pathogenesis of autoimmune hepatitis?
- Chronic and progressive hepatitis of presumed autoimmune origin
- hepatocyte injury caused by CD4+ and CD8+ IFN-gamma and CD8+ T-cell mediated cytoxicity
- May be triggered by viral infection, drugs (minocycline, statins, methyldopa, herbal prodcuts)
- Commonly associated with other autoimmune disease
Name some clinicopathologic features of autoimmune hepatitis
- Variable course (indolent–>fulminant)
- female predominance
- White northern europeans
- serum markers include elevated serum IgG and -gamma globulin levels, high autoantibody levels (ANA, Anti-Smooth muscle, anti-actin, SLA-LP
- 3 types; type 1 most common in North America and associted wth HLA-DR3
- prominent lymphocytes and plasma cells at interface of portal tracts/hepatic lobules
- treated with steroids, azathioprine, etc.
- May need liver transplant
What is the definition of liver cirrhosis?
- Criteria needed for diagnosis of cirrhosis include bridging fibrous septa, parenchymal nodules, architectural distortion throughout the liver
What is the role of liver biopsy in a cirrhotic liver?
- Confirm diagnosis
- Possible clue to etiology
- rule out carcinoma
What stains are routinely performed on liver biopsies and what is their utility?
Perl prussian blue: iron
PAS: glycogen
PASD: ceroid macrophages, alpha-1-antitrypsin, basemet membranes, fungi
Orcein: elastic fibers to differentiate old fibrosis from collapse, HBsAg, copper binding protein
rhodanine: copper
trichrome: collagen (fibrosis)
reticulin: liver architecture, liver cell plate thickness
CK7/CK19 ducts, ductules, duct derived tumors, prognosis in HCC
List 4 common causes of liver cirrhosis
- Alcohol abuse
- Viral hepatitis
- NASH
- biliary disease
Describe some histologic characteristics in 3 common causes of liver cirrhosis
- Cirrhosis secondary to viral hepatitis: portal-portal bridging, regerative nodules, ongoing portal-based inflammation
- Cirrhosis due to cardiac failure: central-central bridging, lack of significant inflammation, central venous congestion, sinusoidal dilatation
- CIrrhosis due to biliary disease: cholestasis, cholate stasis with periseptal halo, coarse fibrous septa subdiving liver into jig-saw pattern with no obvious regeration
List 3 non-infectious causes of cirrhosis
- Alcohol
- Hemochromatosis
- Heart failure
- Wilson’s disease
- A-1-antitrypsin
List 4 clinical consequences of liver cirrhosis
- Portal HTN: ascites, formation of portosystemic venous shunts leading to upper GI bleeding, splenomegally
- Hepatic dysfunction: coagulation defects, hepatic encephalopathy, hyperestronism
- Renal dysfunction: hepatorenal syndrome
- Hepatopulmonary syndrome
- Incresed incidence of HCC
How can cirrhosis be differentiated from massive necrosis on biopsy?
- Necrosis shows a collapsed reticulin network with no regenerative nodules
- CIrrhosis shows collagen deposition with regenerative nodule formation
Cirrhosis vs nodular regenerative hyperplasia: what feature can differentiate them?
- NRH should not have fibrous septae
Without well-formed nodules, what are clues to cirrhosis on biopsy?
- Fragmentation of biopsy
- Thin layers of connective tissue adherant to rounded edges of a fragment
- Abnormal orientation of reticulin fibers
- Abnormal spacing of portal tracts & central veins, more veins than portal tracts
- Liver cell regeneration (2-cell thick plates) or dysplasia (small cell change)
Differentiate active cirrhosis from inactive cirrhosis
active: presence of ongoing liver damage or inflammation, such as interface hepatitis/steatohepatitis
inactive: absence of necroinflammatory activity and sharp delineation of paucicellular septa and liver cell nodules
What is the function of alpha-1-antitrypsin?
- inhibition of proteases, esp. neutrophil elastase, cathespin G, proteinase 3 normally released by neutrophils at site of inflammation
What is the mechanism/pathogenesis of alpha-1-antitrypsin?
- Autosomal recessive disorder
- Selective defect of migration of alpha-1-antitrypsin from endoplasmic reticulum to golgi apparatus
- Alpha-1-antitrypsin polyemerizes, leading to RER stress and apoptosis
- Normal genotype is PiMM, abnormal allele is Z
- PiZZ polypeptide is abnormally folded and cannot be secreted into blood, leading to low serum alpha-1-antitrypsin levels
- alpha-1-antitrypsin accumulates in hepatocytes causing liver damage
List 3 clinical consequences of alpha-1-antitrypsin
- Liver damage, neonatal hepatitis, liver cirrhosis and increased risk of HCC
- Pulmonary emphysema
- Cutaneous panniculitis
What are features of alpha-1-antitrypsin globules on histology?
- morphology (size, shape)
- periportal distribution
- PASD+
- IHC for alpha-1-antitrypsin
Define hemochromatosis and differentiate from hemosiderosis
Hemochromatosis: autosomal recessive disorder characterized by excess iron absorption
Hemosiderosis: accumulation of iron in tissues as a consequence of parental iron (usually transfusions)
List 2 genetic abnormalities that can cause primary adult hemochromatosis
- Mutations are always in HFE, chromosome 6
- Most common mutation: C282Y, cystine to tyrosine
- Other common mutation: H63D, histidine to aspartate
Describe the pathogenesis of primary hemochromatosis
- Unrestricted intestinal absorption of iron due to mutations in HFE gene
- Iron stimulates production of hydroxyl free radicals
- Free radicals damage tissue and stimulate hepatic stellate cells, promoting fibrosis
- Free radical interactions with DNA=DNA damage, predisposing to HCC
- iron deposits in multiple organs: pancreas, heart, joints, skin
List 3 secondary causes of hemosiderosis
- blood transfusions
- aplastic anemia
- long-term dialysis
- other mutations in transport proteins
List 5 organs involved in hemochromatosis and resulting complications
- Liver: cirrhosis, HCC
- Pancreas: diabetes mellitus
- skin: pigmentation
- myocardium: dilated myocardium, arrythmias
- joints: synnovitis, arthritis
List 3 causes of death from hemochromatosis
- cirrhosis
- cardiac failure
- HCC
List 3 different types of pigments in liver and stains that can differentiate them
- Iron: perls
- Copper: rhodanine
- Bilirubin hall stain (green)
How should a liver bx in a suspected case of hemochromatosis be handled?
- Usually 2 cores; measure length/diameter, fragmentation
- one core in formalin–routine
- one core wrapped in lens paper for measurement of dry weight iron
How is the hepatic iron index calculated?
- HI=hepatic iron in umoles/g dry weight divided by age
- HI <1=normal
- HI>2: diagnostic of heochromatosis only in non-cirrhotic liver
What are other causes of primary hemosiderosis
Hepatitis C
Fatty liver
HCC
porphyria cutanea tarda
What is the normal iron pool in adults, and how much is seen in hemochromatosis?
- 2-6 g in normal adults, 0.5g in liver
- 50g total in hemochromatosis, >1/3 is in liver
What is a basic classification of iron overload?
- Hereditary hemochromatosis (primary)
- Mutations in HFE, transferrin receptor 2, hepcidin
- Mutations in HJV-juvenile hemochromatosis - Hemosiderosis (secondary)
A. parental iron overload (transfusions, sickle cell)
B. ineffective erythropoesis (b-thalassemia)
C. Increased oral iron intake
D. Congenital atransferrinemia
E. Chronic liver disease
F. Neonatal hemochromatosis
Briefly describe iron absorption/regulation as it relates to iron overload
- Main regulator of iron absorption is hepcidin (HAMP gene), which LOWERS PLASMA IRON LEVELS
- Hepcidin is produced in hepatocytes; transcription increased by inflammation and high iron and decreased with iron deficiency and hypoxia
- Hepcidin binds to ferroportin, preventing release of rion from intestinal cells and macrophages
- Other proteins involved in iron metabolism regulate hepcidin levels:
- hemojuveiln
- transferrin receptor 2
- HFE-hemochromatosis
What is Wilson disease?
- Autosomal recessive disorder
- Mutation in ATP7B gene, chromosome 13, encodes a transmembrane copper-transporting ATPase on hepatocyte canalicular membrane
- Usually compound heterozygote, ie. different mutations on each gene!
- Due to defective hepatocyte transport of copper into bile for excretion
- Leads to failure to incorporate copper into ceruloplasmin and therefore LOW serum ceruloplasmin
- Unbound copper accumulates in blood and deposits in other tissues
List 4 characteristic histologic features of Wilson’s disease?
- Fatty change
- Glycogenated nuclei
- Mallory bodies
- Copper pigment deposition in periportal hepatocytes
- Massive liver necrosis can occur
List 3 organs primarily affected by Wilson’s and consequences
Liver: steatosis, acute/chronic hepatitis, cirrhosis
Eye: Kayser-Fleischer rings, green to brown deposits of copper in Descemet membrane in limbus of cornea
Brain: basal ganglia (putamen) atrophy and cavitatoin, behavioural change, psychosis, tremor
List 4 conditions that can be associated with increased hepatic copper
- Cholestasis
- Alpha-1-antitrypsin
- wilson disease
- Esposure to sprays containing copper sulfate (vineyard workers)
How can Wilson’s disease be diagnosed from a biopsy?
- Exces copper demonstrated by special stains on biopsy
- Demonstrate hepatic content in excess of 250 ug/g dry weight most helpful
What are 2 patterns of amyloid deposition in the liver?
- Amorphous extracellular deposits in sinusoidal spaces, portal tract connective tissue and vessel walls
- Linear or globular
Name the 2 most common types of amyloid in the liver and their associated conditions
- Amyloid light chain–plasma cell dyscrasia
- Amyloid asociated protein-chronic inflammatory disorders
List 5 histologic features of alcoholic steatohepatitis
- Macrovesicular steatosis, especially perivenular
- Mallory hyaline bodies
- Perivenular sinusoidal fibrosis, sclerosing hyaline necrosis
- Lobular focal necroinflammatory change with neutrophils
- Hepatocyte ballooning and necrosis
List 4 clinical complications of alcoholic steatohepatitis
- Liver: steatosis, steatohepatitis, cirrhosis, HCC
- CNS: wernicke-korsakoff psychosis
- GI: pancreatitis, gastritis
- Malnutrition and vitamin deficiency, iron deficiency anemia, dilated cardiomyopathy due to thiamine deficiency
- Pregancy: FAS
Describe how alcohol causes steatosis in liver
Shunting of normal substances away from catabolism and toward lipid biosynthesis, due to excessive alcohol dehydrogenase and acetaldehyde dehydrogenase
- Impaired assembly and secretion of lipoproteins
- Increased peripheral catabolism of fat
What clinicopathologic clues can help distinguish ASH from NASH
ASH: History of ETOH, ASTALT >2, central venous distribution of steatosis/fibrosis, mallorby bodies
NASH: obesity, diabetes, bypass surgery, hyperlipidemia metabolic disease, AST/ALT <1, more diffuse, more microvesicular steatosis, more frequent portal fibrosis fewer mallory bodies
Hepatitis viruses: List type of virus, viral family , transmission, incubation period, frequency of chronic liver disease, diagnosis on serology for ALL of
HEP A, B, C, D E
HAV: ssRNA, hepatovirus, F-O route, 2-4 weeks inc., NO chronic disease, IgM
HBV: dsDNA, hapadnavirus, parenteral/sexual/vertical, 4-16 weeks, 10% chronic, HBsAg/anti-HBcAg
HCV: ssRNA, falviridae, parenteral, 7-8 weeks, 80% chronic, PCR for HCV RNA
HDV: circular defective ssRA, subviral particle deltaviridae, parenteral, 4-16weeks, co-infection, IgM and IgG antibodies
HEV: ssRNA, calcivirus, F-O, 4-5 weeks, no chronic disease, PCR for HEV RNA
What possible drug-related liver injury patterns are there, and what is an associated drug
- Cholestatic; bland cholestasis w/o inflammation eg. contraceptives
- cholestatic hepatitis eg. antibiotics
- hepatocellular necrosis; spotty to massive necrosis; eg acetomenophen, methyldopa
- steatosis (macrovesicular) eg. methotrexate, steroids
- steatohepatitis; microvesicular eg. amiodarone
- fibrosis; periportal eg. methotrexate
- granulomas eg. sulfonamides
- vascular (venoocclusive) eg. chemotherapy, OCP, tamoxifen
- neoplasms (adenomas, HCC, cholangio, angioarcoma) eg. OCP, thorotrast
List the classification of neonatal cholestasis
- Bile duct obstruction (extrahepatic biliary atresia)
- Neonatal infection (CMV, bacterial sepsis)
- Toxic (drugs, parenteral nutrition)
- Metabolic disease (tyrosinemia, Niemann-Pick, Galactosemia, a-1-antitrypsin, cystic fibrosis
- Misc (hypoperfusion, Algilles with paucity of bile ducts)
- idopathic neonatal hepatitis
What is the ddx of lobular neutrophilic infiltrate in the liver
- alcoholic steatohepatitis
- Liver infection/sepsis
- Medication
- Surgical hepatitis
- Virus (CMV, herpes) in immunocompromised
What is the role of liver biopsy in diagnosis of fatty liver disease
- Confirm/exclude diagnosis
- Differentiate steatosis from steatohepatitis
- Assess necroinflammatory activity, fibrosis, architecture alterations
Is there a scoring system for steatohepatitis?
- Do not apply scoring systems for chronic hepatitis
- Can assess the following:
% of steatosis , lobular inflammation, hepatocyte ballooning, degree of fibrosis
WHat is the morphology, molecular composition and 3 pathologic conditions associated with Mallory Hyaline
- Eosinophilic cytoplasmic clumps in hepatocytes
- Tangled cytokeratin intermediate filaments, like 8/18, with ubiquitin
- associated with ASH, PBC, Wilson’s disease
What are differences in Mallory hyaline due to ETOH vs. cholestasis
ETOH: central venous distribution, + neutrophils, no ductular damage or cholestasis, steatosis and giant mitochondria present
cholestasis: periportal, no neutrophils, no giant mitochondria, not usually steatosis but duct damage/proliferation and cholestasis
What is Reye syndrome?
- Rare potentially fatal syndrome of mitochondrial dysfunction in the liver, brain occuring predominantly in children
- Associated with administration of acetylsalicylic acid (ASA) after varicella or influenza
- Characterized by extensive microvesicular steatosis in liver without inflammation
What are characteristic histologic changes in livers on total parenteral nutrition
- Intrahepatic cholestasis, perivenular bilirubinostasis, cholelithiasis
- macrovesicular steatosis, periportal
- portal and periportal fibrosis
List 4 diseases in liver unique to pregnancy and their characteristic histology
- Acute fatty liver of pregnancy: microvesicular steatosis
- Intrahepatic cholestasis: perivenular canalicular and hepatocellular bilirubinostasis
- Pre-eclampsia and eclampsia: macr: hemorrhages over capsule/cut surface
micro: fibrin thrombi in portal vessels, sinusoids, periportal necrosis
HELLP: periportal hemorrhage, fibrin and necrosis, glycogenated nuclei
List the most common entities presenting with granulomas in portal tract
- Sarcoidosis
- Infection (mycobacteria)
- Drug hepatotoxicity
PBC
List entities causing macrovesicular steatosis and those that cause microvesicular steatosis
MACRO: ETOH, obesity, diabetes, drugs, deficient diet (TPN)
MICRO: pregnancy, Reye syndrome, drugs, adult onset diabetes
What are histologic clues to drug-induced liver damage
- Eosinophis
- Centrolobular necrosis
- Non-necrotizing granulomas
- Parenchymal giant cell hepatitis in adults
- Cholestasis without inflammation
What findings are seen in the liver with diabetes
- Steatosis (NAFLD)
- hepatocyte glycogenosis
- hepatosclerosis
List 3 disease processes that can cause nutmeg liver
- COngestive heart failure
- Budd-CHiari (hepatic vein thrombosis)
- COnstrictive pericarditis
List 4 diseases that can affect sinusoidal blood flow
- cirrhosis, sickle cell disease, metastatic disease, chemotherapy
List 3 features of Budd-Chiari
- Marked enlargement of caudate lobe on imaging
- Visible dilation of lumbar veins
- Improvement after mesocaval shunt
List 5 causes of hepatic venous thrombosis
- Primary myeloproliferative disorders (polycythemia vera)
- inherited coagulation disorders (protein C deficiency, mutations of factor V)
- Antiphospholipid syndrome
- Paroxysmal nocturnal hemoglobinuria
- Intra-abdominal cancers (HCC)
What is the most common cause of veno-occlusive disease, and list 3 non-infectious causes of portal vein thrombosis
- Bone marrow transplant most common cause of venoocclusive disease
- portal vein thrombosis: vascular injury (trauma), stasis (cirrhosis, HCC), hypercoagulable state (factor V leiden, protein S/C deficiency)
List 5 autopsy findings in portal hypertension (other than cirrhosis)
- Portal vein thrombosis
- Hepatoportal sclerosis
- Nodular regenerative hyperplasia
- Incomplete septal cirrhosis
- Schistosomiasis
List 4 drugs that can cause angiosarcoma
- Thorotrast
- Vinyl chloride
- Arsenic
- Androgens
What IHC stains for Kaposi sarcoma (to differentiate from angiosarcoma)
- HHV8, BCL2
Liver transplant bx: list 3 types of rejection and their histology
- Hyperacute: ischemic necrosis/neutrophilic infiltrates. Look for necrotizing arteritis, Ig deposits, detection of pre-formed donor antibodies
- Acute cellular rejection: mixed, but mononuclear portal inflammation with activated lymphocytes, neutrophils eosionphils. Subendothelial inflammation of portal/central veins. Bile duct inflammation and damage.
- Chronic rejection: early bile duct atrophy, later bile duct loss. NEcroinflammatory zone 3 lesions, later perivenular fibrosis and bridging with obliteration of central vein. Foam cell obliterative arteriopathy.
Describe the BANFF scoring system for acute cellular rejection
First grade descriptively: Indeterminate, mild, moderate, severe
Criteria given in rejection activity index (RAI) to subjectively score from 0-3 each of portal inflammation, bile duct damage, venous endothelial inflammation
What is the ddx of portal eosinophils in a transplant liver bx?
- Drugs
- Parasite
- Acute rejection
- Recurrence of initial problem including autoimmune hepatitis, PBC, PSC
- extramedullary hematopoesis
Classify benign liver nodules
- Tumor like conditions: hydatid cyst, macroregenerative nodules, dysplastic nodule, NRH, focal nodular hyperplasia
- benign liver cell tumor: adenoma
- benign bile duct tumors: bile duct hamartoma, bile duct adenoma
- benign vascular tumors: hemangioma
What is importance of bx in hepatocellular adenoma?
- differentiate from HCC
- determine phenotype: B-catenin mutation related have risk of HCC, also those in glycogen storage disease
- identify subcapsular adenomas, tendency to rupture
What is the pathogenesis of FNH and NRH. What do they have in common?
- Both have focal/diffuse alterations in hepatic blood supply, arising from obliteration of portal vein radicles and compensatory augmentation of arterial blood supply
- FNH is usually solitary, with a central scar and fibrous septae with aberrant arterioles
What are 3 gross features of FNH
- Well-demarcated, poorly encapsulated nodule in NON-CIRRHOTIC liver
- Central grey-white stellate scar
- No bile staining (vs. fibrolamellar HCC)
List 3 histologic features of FNH
- Central scar containing large arteries with fibromuscular hyperplasia and eccentric/concentric narrowing of lumen
- Radiating septae with lymphocytic infiltrates, exuberant bile duct proliferation along septal margins
- Parenchyma between septae lacks normal portal tracts or normal sinusoidal plate architecture, contains normal hepatocytes forming thick plates
How can you differentiate hepatocellular adenoma from HCC on histology?
Adenoma: non-cirrhotic background liver, 2 or fewer cell plates, no cytologic atypia, no invasioin into surrounding liver or LVI
HCC: usually cirrhotic, >2 cell plates, cytologic atypia, invasion into liver/LVI
How do you classify hepatocellular adenomas?
HNF-1 alpha inactivated; 46%, steatosis no atypia, no inflammation, 7% HCC
B-catenin activated; 13%, activating CTNNB1 mutation, cytologic atypia and speudoglandular formation, 46% HCC
INflammatory; no mutations, 40-50%, looks like FNH, cytologic atypia, ductular reaction, dystrophic vessels, no HCC risk
Unclassified: no mutations, nothing specific, 10%
Frozen section for subcapsular liver nodules. List 5 ddx:
- Metastatic carcinoma
- BIle duct hamartoma (von myenburg)
- Bile duct adenoma
- Fibrous scar
- Hemangioma
DIfferentiate FNH and hepatocellular adenoma based on clinical, gross and histology
FNH:
- females, all ages, no OCP relation
- asymptomatic, no risk of bleed/HCC
- no capsule, nodular stellate scar
- no hemorrhage, necrosis, bile ductules present, no bile stasis
Hepatocellular adenoma:
- females, 20-40, OCP
- mass lesion, risk of hemorrhage, HCC
- partially encapsulated, homogenous w/ hemorrhage, necrosis
- bile ductules absent, bile stasis present
HCC: list 3 non-infectous etiologies for development
- Aflatoxin exposure
- Steatohepatitis secondary to ASH/NASH
- metabolic disease including hemochromatosis, alpha-1-antitrypsin
- Drugs: thorotrast, steroids
- hepatic adenoma (b-catenin mutation, HNF-1 alpha)
List some specific etiologies highly associated with HCC (>15%)
- HBV, HCV
- Hereditary hemochromatosis
- Hereditary tyrosinemia
- Porphyria cutana tarda
- Hypercitrullinemia
- Membranous obstruction of IVC
What are the carcinogenetic mechanisms of HBV?
- integration of viral DNA into host genome, leading to chromosomal instability
- Insertional mutations at specific sites leading to activation of genes involved in proliferation
- Expression of HVX viral protein to modulate cellular proliferation and inactivate p53
List IHC stains to differentiate HCC from metastatic carcinoma, and from adenoma
Confirm hepatocellular origin: HepPar 1, cytoplasmic TTF-1, AFP, CK8/18, FISH for albumen
Confirm malignancy: CD34, reticulin, polyclonal CEA, CD10
Confirm mets: monoclonal CEA, MOC31, mucin
List 5 conditions with elevated AFP levels
- HCC
- Hepatoblastoma
- Pregnancy
- Yolk sac tumor
- Massive liver necrosis with regeneration
What is size cutoff for early HCC, and for defining a dysplastic nodule?
- 2 cm for early HCC
- 1mm for dysplastic nodule (but usually between 1-2 cm)
- dysplastic focus <1mm
List 4 architectural patterns and 3 cytologic variants of HCC in addition to fibrolamellar
architecture: trabecular, compact, pseudoglandular, scirrhous
cytology: pleomorphic, clear cells, sarcomatoid
List 3 clinical features in fibrolamellar HCC
- Young (20-40), male or female
- No underlying chronic liver disease
- Better prognosis that conventional HCC
What are 3 gross features of fibrolamellar HCC
- Single, large, hard scirrhous tumor with fibrous bands running through it
- background liver without cirrhosis
List 2 microscopic features of fibrolamellar HCC
- well-differntiated polygonal cells with abudant eosinophilic cytoplasm and prominent nucleoli
- Nests/cords of tumor cells separated by parallel lamellae of dense collagen bundles
Compare and contrast HCC and fibrolamellar HCC
Fibrolamellar: peak 3rd decade, M=F, 1-5% of HCC, normal liver enzymes, calcification/scar on imaging. Macro: solitary, left lobe, w/o necrosis/hemorrhage, fibrous septae, no associated cirrhosis. Micro: large cells with granular cytoplasm, hyaline globules, lamellar stromal bands, EM mitochondria frequent, 5 year survival 30%, 60% resectable
Conventional HCC: peak 6-7 decade, M>>>F, 95-99% of cases, liver enzymes abnormal. Macro: both lobes, multifocal, associated cirrhosis. Micro: fewer large cells, fewer fibrous bands, fewer mitochondria on EM. 5 year survival 7%, 25% resectable.
Describe the criteria for selecting HCC patients for transplant
Milan criteria: single lesion <5cm, if multiple lesions, none larger than 3cm or more than 3 lesions
-other criteria for ETOH use, etc.
Describe the histologic patterns in hepatoblastoma:
- Epithelial type: fetal, embryonal, macrotrabecular, small cell
Mixed epithelial-mesenchymal: teratoid, non-teratoid
List clinical, gross and microscopic features of hepatoblastoma
Clinical: age <5yrs, M:F 2:1, associated with B-catenin mutation in 70-90%, FAP, Beckwith-Wiedemann, Li-fraumeni
Gross: pseudocapsule, usually single lesion, no cirrhosis
Micro: light and dark pattern, 2-3 cell thick trabeculae, small cells, no pleomorphism, no giant cells, no intranuclear inclusions or hyaline, extramedullary hematopoeisis often present
Also B-catenin nuclear stain +
List 5 diseases causing development of cholangiocarcinoma
- PSC
- congenital fibropolycystic diseases of biliary system (caroli, choledochal cysts)
- HCV
- Exposure to thorotrast
- CHronic infection of biliary tract by liver fluke Opisthorchis sinensis
How can you differentiate cholangio from HCC on histology?
- Gland formation, no trabeculae, no bile, mucin production, stromal desmoplasia, no cirrhosis, CK7+/CK19+, claudin 4+
List 3 IHC stains that “may” be helpful to differentiate cholangiocarcinoma from metastatic colon
- CK7, CK19, CK20
cholangio: 7 & 19, colon 20
What is a Klatskin tumor?
- Extrahepatic form of cholangiocarcinoma located at junction of left and right hepatic ducts
How can you differentiate bile duct hamartoma from bile duct adenoma?
Bile duct hamartoma: <0.5cm, multiple nodules, associated with portal tract, ducts with ectatic lumen, contain bile, no mucin or lymphocytes
BIle duct adenoma: solitary, portal tracts trapped in nodule, no bile, usually small ducts with absent lumen, mucin, and lymphocytes
What features are reported on a liver wedge resection?
- Specimen type
- Tumor type, size, grade
- Extent of invasion: liver capsule, LVI, PNI
- Tumor necrosis
- Resection margin
- Non-lesional liver pathology
Classify jaundice and causes of jaundice
Predominantly unconjugated hyperbilirubinemia:
- Excessive extrahepatic production of bilirubin (hemolytic anemia)
- Reducted hepatocyte uptake (drugs)
- Impaired conjugation (viral hepatitis)
Predominantly conjugated hyperbiirubinemia:
- Decreased hepatocellular excretion (deficiency of membrane transporters)
- Impaired bile flow (PSC, PBC, choledocholithiasis)
Compare and contrast mechanical duct obstruction, PBC and PSC
Duct obstruction: associated with biliary atresia, gallstones, stricture. No sex predilection. ? cancer risk. Mainly conjugated hyperbilirubinemia. Usually proximal duct dilatation on cholangiogram. Histology: acute cholangitis, cholestasis, bile lakes, ductular proliferation with neutrophils
PBC: 30% with autoimmune arthropathy, F>M, middle age, HCC risk, elevated IgM, antimitochondrial antibody (AMA), normal cholangiogram. Histology: intrahepatic small ducts with florid duct lesions.
PSC: 70% with UC, 70% male, 70% less than 45, cholangiocarcinoma risk, serum IgM, p-ANCA, beading on cholangiogram. Histology: extra and intrahepatic periductal fibrosis and segmental stenosis
List 4 conditions associated with polycystic kidney disease
- Polycystic liver disease
- Congenital hepatic fibrosis
- Caroli disease
- VOn Meyenberg complexes
-
What is overlap syndrome
Overlap betwen autoimmune hepatitis and PBC or PSC
List entities with ductular proliferation at portal-lobular interface
- Extrahepatic biliary obstruction
- Massive hepatocyte necrosis
- PSC
- PBC
What are histologic features of cholestasis
Parenchymal changes: bilirubin stasis, cholestatic liver cell rosettes, canalicular cholestasis, feathery degeneration, xanthomatous cells, bile infarcts, copper accumulation
periportal: portal edema, cholate stasis, ductular reaction, periductular fibrosis, biliary fibrosis/cirrhosis in jigsaw pattern
What is the role of extrahepatic bile duct bx in PSC
to rule out malignancy
What is the ddx of portal neutrophilic infiltrate
- ascending cholangitis
- ductular proliferation
- TPN
- drugs
- extrahepatic obstruction
- treated autoimmune hepatitis
What is the ddx of granulomatous biiiary inflammation
- Sarcoid
- Drugs
- Infection
- PBC
- Foregin material
- lipogranuloma
- chronic granulomatous disease of childhood
- neonatal age
5 entities causing absence of bile ducts in portal tract
- Pediatric: extrahepatic bile duct atresia, alagille
- PBC, PSC
- chronic liver allograft rejection
- Drugs, idopathic
- Overlap syndromes
Liver tumor
fibrolamellar HCC
liver lesion
cholangiocarcinoma (note tubular structures in dense sclerotic stroma)
Liver lesion, 40f
hepatic adenoma. Note non-cirrhotic liver, hemorrhage, no central scar
Liver lesion, 40f
focal nodular hyperplasia (note non-cirrhotic liver, central scar)
35 f, pregnant
-eclapmsia with subcapsular hemorrhage
70 m, myelodysplasia
budd-chiari
Liver
Liver infarct. A thrombus is lodged in a peripheral branch of the hepatic artery and compresses the adjacent portal vein; the distal hepatic tissue is pale, with a hemorrhagic margin.
Vascular flow liver disorders
liver
polycystic liver disease
liver
biliary cirrhosis
liver cyst
ecchinococcus
liver. Dx?
Massive necrosis. A, Cut section of liver. The liver is small (700 gm), bile-stained, and soft. The capsule is wrinkled
Diagnosis, favoured etiology
Cirrhosis resulting from chronic viral hepatitis. Note the broad scar and coarse nodular surface
Synoptic report HCC: what are features to report?
- Specimen
- procedure (major hepatectomy >3 segments)
- tumor size
- tumor focality
- histologic type
- histologic grade
- tumor extension
- margins
- Vascular invasion: large or small vessel
- TNM staging
- fibrosis score **
HCC: What are histologic subtypes?
Hepatocellular carcinoma
–Variant: Fibrolamellar hepatocellular carcinoma
Undifferentiated carcinoma
Multiple histologic architectural patterns: trabecular, solid, and pseudoglandular patterns
Tumors with both fibrolamellar and HCC should be called conventional HCC
How are HCCs graded?
Easy way–grade 1 need to prove invasion, grade 2 you know it’s HCC and invasive, grade 3 higher grade than 2, grade 4 need IHC to prove it’s liver
Grade I- difference between the tumor cells
and hyperplastic liver cells is so minor that a diagnosis of carcinoma rests upon the
demonstration of more aggressive growths in other parts of the neoplasm (so it’s hard to use b/c highest grade is assigned!)
Grade II marked resemblance to normal hepatic cells. Nuclei are larger and more hyperchromatic than in normal cells. Cytoplasm is abundant and acidophilic. Cell borders are sharp and clear cut. Acini are frequent and variable in size. Lumina are often
filled with bile or protein precipitate.
Grade III Nuclei are larger and more hyperchromatic than in grade II cells. The nuclei occupy a
relatively greater proportion of the cell (high nuclear to cytoplasmic [N:C] ratio). Cytoplasm is granular and acidophilic, but less so than grade II tumors. Acini are less frequent and not as often filled with bile or protein precipitate. More single-cell growth in
vascular channels is seen than in grade II.
Grade IV Nuclei are intensely hyperchromatic. Nuclei occupy a high percentage of the cell.
Cytoplasm is variable in amount, often scanty. Cytoplasm contains fewer granules. The
growth pattern is medullary in character, trabeculae difficult to find, and cell masses seem to lie loosely without cohesion in vascular channels. Only rare acini are seen. Spindle cell areas have been seen in some tumors. Short plump cell forms, resembling
“small cell” carcinoma of the lung, are seen in some grade IV tumors.
What are margins in hepatectomy specimens and how should they be evaluated?
- Evaluation of margins depends on specimen, extent of resection. Consult surgeon for important margins.
- The transection margin of a partial hepatectomy may be large, so can’t be sampled entirely. Grossly positive margins should be microscopically confirmed and documented.
- If the margins are grossly clear, sample cut surface nearest tumor
- If t neoplasm is found near the surgical margin, the distance from the margin should be reported. For
multiple tumors, the distance from the nearest tumor should be reported. - In total hepatectomy, hilar margin (ie. portal vein, hepatic artery, bile duct) and venous margin (may be IVC or hepatic vein)
Vascular invasion in HCC: how to report and what is the significance?
- Vascular invasion includes gross AND microscopic invasion of vessels
- If macro, micro probably present, less common than micro alone (15 vs. 43%)
- Both are associated with lower survival post-resection.
- Larger tumors (greater than 5 cm) or multiple tumors are more likely to exhibit vascular invasion than single small lesions.
Staging in HCC: what tumors are excluded, and what are the parameters for staging?
- Applies only to HCC (mets, sarcomas and cholangiocarcinomas not included)
- T classification depends on the number of tumor
nodules, the size of the largest nodule, and the presence or absence of blood vessel invasion. - No difference between multiple independent primary tumors or intrahepatic metastasis from a single primary hepatic carcinoma
Give the T staging for HCC
T1 Solitary tumor without vascular invasion
T2 Solitary tumor with vascular invasion; or multiple tumors, none more than 5 cm in greatest
dimension
T3 Multiple tumors more than 5 cm in greatest dimension or tumor involving a major branch of theportal or hepatic veins(s)
T3a Multiple tumors **more than 5 cm** T3b Tumor(s) any size involving a major branch of the **portal or hepatic vein(s**)
T4 Tumor(s) with d**irect invasion of adjacen**t organs o**ther than the gallbladder** or with perforation of visceral peritoneum
What is the N and M staging in HCC?
N0=no nodes, N1=regional nodes
- regional lymphadenectomy specimen usually involves examination of 3 ormore lymph nodes.
- The regional lymph nodes of the hepatic region include the hilar, hepatoduodenal ligament, inferior phrenic, and caval lymph nodes.
- Nodal involvement of lymph nodes distal to the hilar,
hepatoduodenal ligament, and caval lymph nodes are considered as indicative of distant metastasis
(pM1)
Describe a method of scoring fibrosis in liver, and when should you report it in a synoptic for HCC?
- Cirrhosis or severe fibrosis (Ishak score 5 or 6) should be specifically reported because it has an adverse effect on outcome.
- 0: none
- 1: fibrous expansio some portal areas
- 2: fibrous expansion most portal areas with small incomplete septa
- 3: fibrous expansion most portal areas, occasional portal-portal bridging
- 4: fibrous expansion of portal areas, marked bridging, portal central bridging
- 5: marked bridging with occasional nodules (incomplete cirrhosis)
- 6: cirrhosis
What are risk factors for HCC and most common worldwide?
-Hepatocellular carcinoma (HCC) is highly linked to chronic liver disease, in particular chronic hepatitis B
(HBV) and C (HCV) infection and alcoholic liver disease.
- Overall, 50% to 55% of cases of HCC worldwide
are attributed to HBV and 25% to 30% to HCV
-The annual risk of HCC developing in a cirrhotic
liver is estimated at 1% to 6%
- Highest risk chronic viral and hereditary hemochromatosis
What are dysplastic nodules in the liver, and how are they classified?
- Nodular lesions displaying some degree of cytologic or architectural atypia but lacking definitive histologic features of malignancy.
- Subdivided into low- and high-grade
Intrahepatic bile duct carcinoma: synoptic checklist features to report
- Specimen
- Procedure
- Tumor size
- Tumor focality
- histologic type
- Histologic grade
- Tumor growth pattern
- Microscopic extension
- Margins
- vascular invasion
TNM staging
- other findings including cirrhosis
What are the divisions and proper designations for bile ducts based on location?
Intrahepatic: from periphery of liver to second-order bile-ducts
Perihilar: from hepatic duct bifurcation to extrahepatic biliary tree proximal to origin of cystic duct
Distal extrahepatic bile duct: junction of cystic duct/CBD to ampulla of vater
What is the significance of multiple intrahepatic cholangiocarcinomas, and how should they be sampled?
Sections should be prepared from each major tumor nodule, with representative sampling of smaller
nodules if macroscopically different in appearance.
For purposes of staging, satellite nodules,
multifocal primary cholangiocarcinomas, and intrahepatic metastases are not distinguished and are
considered multiple tumors.
In intrahepatic cholangiocarcinoma, multiple tumor deposits have been associated with poorer survival.
What is the histologic classification of intrahepatic biliary carcinomas?
Cholangiocarcinoma
Combined hepatocellular and cholangiocarcinoma
Bile duct cystadenocarcinoma
High-grade neuroendocrine carcinoma
-Large cell neuroendocrine carcinoma
- Small cell neuroendocrine carcinoma
Combined or mixed hepatocellular-cholangiocarcinoma: rare, should shos definite hepatocellular and cholangio differentiation (eg. mucin), poor prognosis.
How would you grade intrahepatic cc?
Grade 1 Well differentiated (more than 95% of tumor composed of glands)
Grade 2 Moderately differentiated (50% to 95% of tumor composed of glands)
Grade 3 Poorly differentiated (5% to 49% of tumor composed of glands)
Grade 4 Undifferentiated (less than 5% of tumor composed of glands)
What are 3 patterns of growth in intrahepatic CC?
- Mass-forming-60%, well demarcated nodule in radial pattern invading parenchyyma
- Periductal infiltrating-20%, spreads diffusely longitudinally along bile duct, worse prognosis
- Mixed mass/periductal infiltrating-20% mix of both
Describe margins and sampling in intrahepatic CC
- Depends on procedure, but parenchymal margin if partial hepatectomy. Sample closest approach.
- The histologic examination of the bile ducts at the cut margin is recommended to evaluate the lining
epithelium for in situ carcinoma or dysplasia. - If the neoplasm is found near the surgical margin, the
distance from the margin should be reported. For multiple tumors, the distance from the nearest tumor
should be reported.
What is the TNM staging for intrahepatic cc?
Tis Carcinoma in situ (intraductal tumor)
T1 Solitary tumor without vascular invasion
T2a Solitary tumor with vascular invasion
T2b Multiple tumors, with or without vascular invasion
T3 Tumor perforates the visceral peritoneum or involves local extrahepatic structures by direct
invasion
T4 Tumor with periductal invasion
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Regional lymph nodes in intrahepatic CC: what are regional and what are distant (ie. M1)
- Varies with tumor location in the liver
- Right lobe (segments 5-8): hilar (common bile duct, hepatic artery, portal vein, and cystic duct),
periduodenal, and peripancreatic lymph nodes. - Left lobe (segments 1-4) hilar and gastrohepatic lymph nodes.
- Distant mets: Nodal involvement of the celiac, periaortic, or caval lymph nodes
What is the target in graft-vs-host disease in the liver
- interlobular bile ducts
List 6 mesenchymal tumors of the liver
- mesenchymal hamartoma
- cavernous hemangioma
- infantile hemangioma
- epithelioid hemangioendothelioma
- angiosarcoma
- kaposi sarcoma
List the clinico pathologic features of mesenchymal hamartoma of liver
- Pediatric tumor, uncommon
- right lobe
- gelatinous mass of bile ducts in ductal plate patter with vesels and loose emematous stroma
- extramedullary hemotpoesis
- rarely transforms into embryonal sarcoma
What are the clinical and histologic features of cavernous hemangioma in the liver?
- most common benign tumor of liver
- clinically important if >4cm
- may increase in size/rupture in pregnancy
- gross; spongy and well-circumscribed
- no risk of malignancy
Infantile hemangioma of the liver: give clinical and pathologic characteristics
- Most common benign mesenchymal tumor in infants/children
- F>M
- Sx CHF or hemangiomas in other organs
- micro: small vascular channels lined by plump endothelial cells in scant stroma, entrapped ducts
Epithelioid hemangioendothelioma of the liver: give clinical and pathologic characteristics
- Also seen in children
- Low-intermediate grade malignancy
- Epithelioid cells with abundant eosinophilic cytoplasm, arranged as single cells or cluster in dense myxoid stroma, occasionally spindled.
- May show intracytoplasmic vacuole
- sinusoidal growth, may grow into veins
- CD34, CD31, Factor VIII on IHC
Malignant vascular lesions of liver: compare Angiosarcoma and Kaposi sarcoma
Angiosarcoma: highly aggressive, most common mesenchymal malignancy in liver, characteristic SINUSOIDAL growth pattern of hyperchromatic, plump, malignant endothelial cells with little stromal response. May show solid pattern. IHC: CD31, CD34…
Kaposi: Seen in HIV patients. Pure spindle-cell prolifeation with slit-like spaces containing extravasated red cells. IHC CD31, CD34, HHV8, BCL2
Liver cytology:
utility, complications, potential findings?
- FNA (ultrasound guided)
- very safe; hemorhage most common complication
- Confounders include all tissues that needle must pass through
- Benign masses: hydatic cysts, abcess, granuloma bile duct adenoma, FNH ( look for neturophils necrotic debris, hooklits, scolices, laminated cyst walls). Do stains.
- Vascular lesions, FNA, HCA, HCC, cholangiocarcinoma, mets
What would be the expected cytologic findings in epithelioid hemangioendothelioma and in angiosarcoma?
- Epithelioid hemangioendothelioma: paucicellular, bland epithelioid and spindle cells intermixed with malignant large tumor cells. CHaracteristic intracytoplasmic lumina or intranuclear cytoplasmic inclusions.
- Angiosarcoma: abundant bloood, isolated cells and loose clusters. Malignant cells spindle to epithelioid, with hyperchromatic nuclei and ill-defined cytoplasm. necrosis prsent. May see vasoformative structures like intracytoplasmic lumina, microacina lumen, vascular channels
What to do you expect ot see on FNA of FNH or HCA?
FNH: abundnat benign hepatocytes & biliary cells
HCA: abundant benign hepatocytes WITHOUT biliary cells
HCC On FNA: what are characteristic features?
HCC: - thickened hepatocyte trabeculae lined by spindle-shaped endothelial cells, hepatocyte tissue fragments with traversing capillaries, increased NC ratio, atypical naked nuclei.
Features favouring hepatocellular origin: polygonal cells, central nuclei, abundant granular cytoplasm bile pigment
Fibrolamellar: large monotonous cells with abundant granular cytoplasm, low NC ratio, prominent nucleoli, intracytoplasmic hyaline globules
What are the cytologic features of cholangiocarcinoma on FNA?
- crowded sheets, 3D clusters, acinar structures, single dispersed cells. Malignant cells with high NC ratio, irregular nuclear membranes, prominent nucleoli, +/- mucin. Need to rule out mets.
