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©2015 MFMER | slide-1
Hepatocellular Carcinoma:Pathogenesis,Epidemiology, and
Diagnosis
Michael Torbenson, MDMayo Clinic, Rochester MN, [email protected]
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©2015 MFMER | slide-2
Conflicts of interest
• None
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©2015 MFMER | slide-3
Objectives
• Practical
• Focus: diagnostic approach to well differentiated hepatocellular tumor
HCA vs HCC
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HCC vs HAA
HCA vs HCC: not always so easy
“All too often the diagnosis of an adenoma from a biopsy specimen has been followed sooner or later
by proof at surgical operation or at autopsy that the tumor was in reality a liver cell carcinoma”
Edmondson, AFIP fascicle, 1958
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Illustrative case
• 53 year old woman
• Single 6 cm liver mass in liver
• Serum AFP levels are normal
• No history of chronic liver disease
• Radiology differential: hepatic adenoma versus hepatocellular carcinoma versus less likely FNH
• Undergoes resection
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Not FNH
? HCC or HA
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Approach to Diagnosis
What other tools are available?
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Approach to Diagnosis
Immunohistochemistry
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Fork in the road: choice of two different pathways:
Based on H&E findings, which of the following is true:
A. The tissue is all liver, but I’m not sure if it is cancer.
B. The tissue has definite cancer, but I’m not sure if its HCC or cholangiocarcinoma or metastatic.
Approach to Diagnosis
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Approach to Diagnosis
Benign liverTumor
Versus
Well diffHCC
HCC
Versus
CholangioCA ,metastases
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Approach to Diagnosis
Benign liverTumor
Versus
Well diffHCC
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Helpful stains when the biopsy shows a well differentiated hepatocellular tumor:
• Reticulin stain• Ki-67• Glypican 3• CD34
• Consider others depending on the results of these morphology; egGlutamine synthetase for FNH
Approach
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• Our case– Convincing reticulin loss
– Glypican 3 positive, focal
– Mild but definite increase in Ki-67
• Final Diagnosis:
Hepatocellular carcinoma
Our case
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Most important points
on most important stains
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• Reticulin stain
• Ki-67
• Glypican 3
• CD34
Diagnostic Approach
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Key points for Reticulin
• Reticulin is diminished in HCC
• Particularly helpful in benign vs malignant
• Look for loss of reticulin– “plate thickening in HCC”
– “All cells touching reticulin in benign liver”
– In most cases, reticulin is not entirely lost
– Focal minimal loss doesn’t count
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Key points for Reticulin
• Key dates
– 1977 (PMID: 197780)—Retic loss in HCC
– 1986 (PMID: 2430547)—Retic loss to distinguish HCC from benign liver tumors
– Since then: Confirmed by decades of experience from centers across the world in all liver diseases
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Key points for Reticulin
• World wide experience
– >99% of clinically aggressive HCCs have reticulin loss
– ~100% of clinically benign tumors have normal reticulin
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Key points for Reticulin
But, how do you know retic loss is meaningful in EVERY very well differentiated hepatocellular tumor that has it?
Might some of these
still be benign?
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Key points for Reticulin
Usually in the context of resected specimens– “Well differentiated tumors are cured by surgery,
so you have no way of really knowing if it’s a HCC or HA, even if it has retic loss”
– True that--these are cured by resection, but at this point reticulin loss is a strong guide for classification of well differentiated tumors
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Interpretation of Retic
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Hepaticadenoma
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Near totalloss
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Patchy, mild loss
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Interpretation of Retic
5 pitfalls to avoid
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ReticulinPitfall 1 Make sure stain quality is good
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Focal platethickening
Not HCC
Pitfall 2. Morphology importantfor interpreting retic
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Reticulin: pitfallPitfall 3Non-neoplastic liver can have patchy reticulin loss due to fat
(Am J Surg Pathol. 2012 May;36(5):710-5.)
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Pitfall 4Rare HCC with no Retic loss
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Pitfall 5Other abnormalPatterns
Not HCC
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Key points for Glypican 3
Glypican 3• Cytoplasmic staining
• Staining diffuse or patchy
• 50% of well diff HCC negative
• Cross check with H&E– Lipofuscin also can stain
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Lipofuschin
Glypican 3
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Key points for Ki-67
KI-67:
• Compare to background liver!– Clearly increased above background suggests HCC
• No absolute cut off– Almost all adenomas are less than 3%
– HCCs can range from less than 2% to greater than 20%
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Ki-67
Check morphology
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Key points for CD34
• HCC: strong and diffuse staining
• Adenoma or FNH: patchy and irregular staining (but 30% of adenomas can be diffuse!)
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Other stains / tests for
HCA vs HCC
5 important points
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ImmunostainsPoint 1. Stains for subtyping hepatic adenomas
–Do not distinguish adenoma from HCC
–Only use these stains after you have made the diagnosis of hepatic adenoma
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Immunostains• Stains for subtyping hepatic adenomas
– LFABP: 25% of HCC show LFABP loss
– CRP: 50% of HCC are CRP positive
– SAA: 17% of HCC are SAA positive
– beta catenin nuclear staining: 30% of
– glutamine synthetase staining: 50% of HCC show diffuse glutamine synthetase staining
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Immunostains• Stains for subtyping hepatic adenomas
– LFABP: 25% of HCC
– CRP: 50% of HCC
– SAA: 17% of HCC
– beta catenin nuclear staining: 30% of HCC
– glutamine synthetase staining: 50% of HCC
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ImmunostainsPoint 2. Stromal invasion
• Helpful in resection specimens
• On biopsy—not so much– Only rarely seen on biopsies with definite HCC
• Many definite HCCs do not have it
– Never seen a case where it helped in distinction of adenoma vs HCC
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Immunostains
Stromal invasion
Supplement With CK7
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Cirrhotic vs non-cirrhotic liver
Point 3: Differential depends on the background liver • Cirrhotic • Non-cirrhotic
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Differential Diagnosis
Noncirrhotic liverMissed the tumor?
MRN (after massive necrosis)FNH
hepatic adenomaHCC
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Differential Diagnosis
Cirrhotic liverMissed the tumor?
Macroregenerative noduleDysplastic nodule
HCC
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Cirrhotic vs non-cirrhotic liver
Cirrhotic liver
Hepatic adenomaMacroregenerativenodule
Point 3a: Cirrhosis: • Natural history of “adenoma-like nodules” unknown
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ImmunostainsPoint 4. Glutamine synthetase, heat shock protein 70, glypican 3
• Used in cirrhotic livers for HCC versus a high grade dysplastic nodule
–GS and GP3 staining are most helpful• My experience with HSP70—high
background, hard to interpret
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ImmunostainsPoint 5. Potential molecular tests
–TERT promoter mutations• Might be specific, unlikely to be sensitive
• Not validated for clinical care
–Chromosomal gains• Promising, not yet been fully explored
• Not validated for clinical care
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Approach to Diagnosis
Benign liverTumor
Versus
Well diffHCC
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Basik Approach to Diagnosis
HCC
Versus
CholangioCA ,metastases
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Immunohistochemical stains
for hepatocellular carcinoma
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HepPar1 vs Glypican 3 vs Arginase 1
Big 3 stains
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Stains for hepatocellular differentiation
Stain 1 Stain 2
Who is the champion?
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Stains for hepatocellular differentiation
Stain 1 Stain 2
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Basik Approach
Well Diff
HepPar1Arginase
Glypican 3
Mod Diff
HepPar1ArginaseGlypican 3
Poor Diff
ArginaseGlypican 3HepPar
UnDiff
ArginaseGlypican 3HepPar
-----Reticulin---
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Rarely these stains are also needed for well differentiated tumors
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HCC mimics
Neuroendocrine tumor
Renal oncocytic tumor
Paraganglioma
Not pictured: Epithelioid AML
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Arginase negative HCC
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Summary
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Summary
1. Comprehensive review of methods for distinguishing benign from malignant hepatocellular proliferations
2. Use H&E to determine what stains are needed– Panel A: Benign, but unsure of adenoma vs FNH
– Panel B: Malignant, but unsure if HCC or metastatic disease
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Diagnostic Summary
3. Use the stains in conjunction with the morphology; never in isolation
– Retic
– Glypican 3
– Ki-67
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The End