16 ferrell liver - ucsf cme · reported cases are hcc from the outset but we don’t know the...

5/28/2016

1

I have nothing to disclose.DISCLOSURES

CHANGES IN FOCUS IN LIVER PATHOLOGY: ONE HEPATOPHILE’S VIEW ON TWO TOPICS

Linda Ferrell, MDUniversity of California San FranciscoDistinguished Professor of PathologyVice Chair, Director of Surgical Pathology

Early 80’s, >30 years ago….

“When I was young….”

Ronald Reagan was in his first termas President

Fatty liver was due to AlcoholHepatocellular Adenoma was REALLY RARE and called Hepatic AdenomaTransplant liver pathology didn’t really exist yetHCV was not identified and so was known as nonA-nonB hepatitisA diagnosis of cirrhosis was “the end” HIV/AIDS was the evolving epidemic and all consuming medical issue

When I was young….

5/28/2016

2

Fatty liver was due to AlcoholHepatocellular Adenoma was REALLY RARE and called Hepatic AdenomaTransplant liver pathology didn’t really exist yetHCV was not identified and so was known as nonA-nonB hepatitisA diagnosis of cirrhosis was “the end” HIV/AIDS was the evolving epidemic and all consuming medical issue

When I was young…. Fatty liver was due to AlcoholHepatocellular Adenoma was REALLY RARE and called Hepatic Adenoma

A new epidemic emerged: Obesity/metabolic syndrome changed the face of fatty liver disease


Obesity Trends* Among U.S. Adults 1996(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. Adults 2008(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

5/28/2016

3

Obesity Trends* Among U.S. Adults 2013

Data now goes >35% with shift of color scheme

Non-Alcoholic Fatty Liver Disease (NAFLD): Lesions and Terminology

NAFLD NASH Cirrhosis

Steatosis Steatosis Fibrosis (>5%) Ballooning + Inflammation

Inflammation + Steatosis+ Fibrosis

NAFLD: Natural HistorySteatosis

SteatohepatitisCirrhosis

Prior to NASH Clinical Research Network (NASH-CRN) in 2002, very few longitudinal studies doneGeneral concept for pathogenesis of NASH: Consequence of over-supply of fatty acids in combination with defects in their metabolism (such as insulin resistance)

?20-30%?

5/28/2016

4

NASH: USUAL Associated Risks

�Metabolic Diseases�Obesity �Diabetes type 2�Hyperlipidemia

NASH or NASH-like lesions: Other risks

� Drugs� Amiodarone� Perhexilene maleate� Tamoxifen� Irinotecan (CASH)

� Gray areas- Questionable?� Risperidone (antipsychotic)� Steroids� Estrogens� HAART, ART for HIV therapy� Calcium channel blockers (ex:

nifedipine)� Methotrexate

� Other (genetic/surgical)� HISPANIC ethnicity� Genetic metabolic disorders, ex:

Wilson disease, tyrosinemia, abetalipoproteinemia� FABP1 genetic defects related to

hyperlipidemia� Lipodystrophy� Sudden decrease in liver size/volume� Jejunoileal bypass or similar variants

NASH: Typical Histology� Large and small droplet fat (use of macrovesicularand microvesicular no longer recommended as per NASH CRN group)� Centrizonal predominance for fat and scarring

�Key to activity: Ballooned hepatocytes

NASH: Fat, typically noted in zone 3 (central zone)

5/28/2016

5

Centrizonal Fibrosis: Trichrome stain Key to activity: Ballooned Hepatocytes

Swollen cells

Focally condensed cytoplasmic contents

May or may not have Mallory hyaline

And no entity is complete unless it has variants….

Pediatric NASH

� Incidence increasing� Similar risk factors as adults � BUT histology may show variant type:� No zone 3 pattern of fat or fibrosis� Fibrosis may be periportal� Lack of ballooned hepatocytes� “Type 2 NASH”Minority of patients have typical NASH (“Type 1”)Schwimmer, Behling, et al. Hepatol 2005;42:641-9

5/28/2016

6

Pediatric NASH “Type 2 NASH”Occurs more commonly in: � Younger patients� Boys� Hispanic, Asian, Native American ethnicityAssociated with more advanced fibrosis(Can also occur in adults at low rate)

Schwimmer, Behling, et al. Hepatol 2005;42:641-9

Newer Findings in NASH Histology(NASH Clinical Research Network)

Apoptosis as marker for activityNASH CRN ancillary study: Acidophil bodies correlate

with active steatohepatitis similar to ballooned hepatocytes

Yeh M…Brunt E…Ferrell L. Hepatol 48 (Suppl 1) 2008, poster at AASLD, manuscript in preparation.

Newer findings (NASH CRN) Arterialization of Centrizonal ScarsGill R…Ferrell L: AJSP, 35, 1400-04, 2011. � Increased microvessels� Increased CD34 staining of sinusoidal endothelial cells as effect of loss of fenestrations (“capillarization”)� Finding most prevalent in late stage disease� Diagnostic Problem:� Diagnosis of central-based versus portal-based disease

5/28/2016

7

NASH, Trichrome: Centrizonal Fibrosis (1b)NASH, Trichrome: Centrizonal Fibrosis (1b)NASH, Trichrome: Centrizonal Fibrosis (1b)NASH, Trichrome: Centrizonal Fibrosis (1b)

Newer Findings in Later Stages of Fibrosis, Stage 3 and 4 (NASH CRN)Ballooned HepatocytesParaseptal location in late stages (such as periphery of nodule in cirrhosis)

Can be scant in numberPortal lnflammationDegree of portal lymphocytic inflammation often more prominent

Amount of FATOften little to no fatCan be difficult to recognize features of steatohepatitisetiology in “cryptogenic cirrhosis”

Cryptogenic Cirrhosis (and Risk Factors for NASH)

Caldwell 1999

Some things don’t change:Alcoholic steatohepatitis still exists


5/28/2016

8

NASH or Alcohol (ASH)? Features that favor ASHCholestasis in the absence of end-stage cirrhosisAbundant, well-formed Mallory hyalineMany PMNs

NASH or Alcohol (ASH)?

Features that favor ASH-Prominent cholestasis-Abundant Mallory bodies-Many neutrophils

ASH may also demonstrate:-More central vein sclerosis/obliteration-More extensive pericellular and sinusoidal fibrosis-Micronodular pattern of cirrhosis

NASH and the Future-Liver disease complications have been relatively under-recognized by public-There is much we don’t know about pathogenesis-Not much we can do for a cure other than remove risk factors-Pediatric NASH increasing-Hepatocellular adenomas and hepatocellular carcinomas are an unexpected manifestation of this epidemic…

Hepatocellular Adenoma was REALLY RARE and called Hepatic Adenoma

When I was young….Part 2

5/28/2016

9

Adenoma (HCA): Historical Features

“THE OLD VERSION of HCA”� A RARE lesion in women in child-bearing age

with history of OCP�Unusual to see 1-2/yr in big centers

� Risk of HCC thought to be extremely rare � Common risk of hemorrhagic complications� Histology: bland cytology, intact reticulin

framework, no mitoses, no ductules

Adenoma (HCA): Historical Histologic Features

Reticulin framework intact, plate architecture and cytology mimics normal patterns

Hepatocellular Adenomas Today

• HCAs are not rare anymore

• Each subtype has specific clinical associations and treatment issues

Adenoma (HCA) Variants of Today

� Variant 1. HNF1α-inactivated HCA� Hallmark: Fatty change� Variant 2. β-catenin mutated HCA� Hallmark: Increased risk for HCC� Variant 3. Inflammatory adenoma� Hallmark: Obesity/metabolic syndrome association� Others (Variant 4 + ?)� Hallmark: No specific trait

5/28/2016

10

Variant 1 HCA (HHCA): HNF1α-inactivated (HHCA

Fatty change, large and small droplet Reticulin: small acinar changes

Variant 1 HCA (HHCA): HNF1α-inactivated

Adenomatosis association: small foci of fatty change (“focal fatty change”) with increased CD34 (not shown)


IHC feature:Negative for Liver Fatty Acid Binding Protein (LFABP)


Summary of clinical features� 10% with germline mutations, so can be familial, rarely in men� Association with maturity-onset diabetes of the young type 3 (MODY3)� Adenomatosis (defined as >10 lesions)� Low risk for HCC� (Can’t use as marker for HCC, though, as there are LFABP neg HCCs)

5/28/2016

11

Variant 2 HCA (BHCA): β-catenin-mutated

� Rare, solitary adenomas with HIGH risk of HCC transformation

� Association with male hormone use and male gender� Linked to mutation in Exon 3 of CTNNB1 (β-catenin)

gene

Bioulac-Sage et al. HCA subtype classification using molecular markers and IHC: Hepatol 2007;46:740-8.

Variant 2 HCA: β-catenin-mutated

Glutamine synthetase:Intense, diffuse stainingStrong β-catenin nuclear

staining

Variant 2 HCA: β -catenin-mutated High risk for HCC

HCC features illustrated here: Loss of reticulinOther features: cytologic atypia, pseudoglandular change

Variant 2 HCA (BHCA): β-catenin-mutated High risk for HCCQUESTION: Are these really very well-differentiated, adenoma-like HCCs?� Chromosomal studies suggest at least some reported cases are HCC from the outset

But we don’t know the entire story yet…..� S Kakar, J P Grenert, V Paradis, N Pote, S Jakate MD, and L Ferrell. HCCs Arising in Adenomas: Similar Immunohistochemical and Cytogenetic Features in Adenoma and HCC Portions of the Tumor. MODERN PATHOL 27:1499-509, 2014.

5/28/2016

12

Variant 3 HCA (IHCA): Inflammatory type

� Formerly known as Telangiectatic FNH� Pathologic features include:� Ill-defined borders, difficult to identify grossly�Dilated sinusoids� Focal inflammatory change around arteries�Arteries can be in clusters�Mild ductular reaction common in periarterialzones


Gross: Slightly redder than background liverPoorly-defined borders, irregular edges

Can be difficult to identify radiographicallyand on gross


Dilated sinusoids, focal inflammation around arteries

Artery, inflammation, and ductules


Ductulespresent with smallarteries; hepatocyte cytology usually unremarkable

5/28/2016

13


Serum amyloid A (SAA): diffuse staining

C-reactive protein (CRP): more sensitive than SAA but not as specific


� Clinical features include:�Close association with obesity�Also seen in men�Age includes 40-50+ year olds�Risk for hemorrhage increases with size,

with significant diameter at 5 cm�Adenomatosis may be common!!


Other histologic features:� Background liver with fat and/or SAA, CRP+� May also have increase risk for HCC�10% with β-catenin mutation�Could be both two lesions, adenoma and HCC occurrence related to metabolic syndrome and background fatty liver

NOTE: There is increased incidence of HCCin patients with fatty liver without cirrhosis!

HCA: 4th Category

� Remaining adenomas remain “unclassified”� This category is a catch-all for others that don’t

fit into first 3 variants �Account for <10%�Other types may still be defined

5/28/2016

14

HCA: Overview of ProblemsWe don’t know how big the problem of fatty liver-associated adenomas will be and….

We don’t know exact pathophysiology of these NEW lesions….May be difficult to get the experience to: � Type variants: can be important (risk of HCC, multifocality, etc)� Differentiate from FNH � Differentiate from HCC� Identify variants of variants… and other variants……

Variants of Variants of HCA Described morphology of variants can varyFor example….� IHCA (Inflammatory variant)� Variation in amounts of scarring, ductular reaction, fat, cytologic changes

� BHCA (β-catenin variant)� Variants of Glutamine synthetase staining

Problem cases brought before panel of self-identified HCA “experts” in NYC 2014

Variants of Variants of HCA

Problem Case 1: Variant of VariantLesion sent in consultation because:� 57 year old man� Atypical large cell change In background of: � Intact reticulin framework as a pattern of adenoma� No acinar change, no wide plates, no reticulin loss to suggest HCC

5/28/2016

15

Problem Case 1: Variant of Variant

Cytologic atypia SAA: moderate to strong diffuse

Problem Case 1: Variants of Variants

� SAA moderate to strong � GS focal and + near septa, minimal to mild in other zones� Beta-catenin negativePanel: Cytology possibly “senescent” change

Glutamine synthetase stain

Panel conclusion:Inflammatory adenoma (IHCA)


31 year old womanLesion sent because:� Extensive ductularreaction� Increased fibrosisQuestion posed: Is this FNH?


GS: ductular area at top CRP with background of ductular reaction

5/28/2016

16


� CRP strongly positive throughout� SAA weak or absent in about 80% of lesion� GS was patchy around veins and positive in ductules, so no map-like pattern for FNH� Beta-catenin negative

Panel conclusion:Inflammatory adenoma (IHCA)


30 yr old womanAdenoma with patchy staining for glutamine synthetaseFollowup: Molecular studies + Beta-catenin mutation

Bordeaux case: Glutamine synthetase

Panel conclusion:β-catenin + HCA (BHCA)

HCAs: What to do? (advice from the one who’s been there, done that) Get the most out of your sample !� How to process small biopsy samples: � Look for history of obesity, diabetes, mass, fatty liver�Don’t do standard panel of Tri, iron, PAS, etc.� Get unstained X 8-10 at first cut� Learn how to use “adenoma” stains: Glutamine synthetase, CRP, LFABP, SAA, β-catenin� Do a good RETICULIN stain

HCAs: What to do? (advice from the one who’s been there, done that) My Experience:� >5 years of FNH and HCA biopsies and resections (>300) stained with full panels to see spectrum of overlapping and diagnostic features� Interpretation issues, especially on small biopsies:

�Many overlapping features with FNH and HCC; � artifacts or variations with staining patterns

Problem diagnosis: Well-differentiated hepatocellular lesion� Followup important/resection may be necessary� Molecular testing may prove helpful

5/28/2016

17

Fatty liver is more common than everHepatocellular adenomas aren’t rare anymoreTake home lesson:Unexpected complications of evolving health problems can change pathologyKeep you eyes open for the unexpected!

Conclusions

Thank you for the invitation!

16 ferrell liver - ucsf cme · reported cases are hcc from the outset but we don’t know the...

Documents