JerusalemL practical immuno for hepatobiliary neoplasia

Practical Immunohistochemistry for Hepatobiliary Neoplasia

Neil Theise, MDDepartments of Pathology and Medicine (Digestive Diseases)Mount Sinai Beth Israel Medical CenterNew York City

Icahn School of Medicine atMount SinaiMount Sinai

Practical Immunohistochemistry for Hepatobiliary Neoplasia

Download at: NeilTheise on SlideShare.net

Neil Theise, MDDepartments of Pathology and Medicine (Digestive Diseases)Mount Sinai Beth Israel Medical CenterNew York City

Icahn School of Medicine atMount SinaiMount Sinai

SOLID MASSSOLID MASS

FibroticFibroticBackgroundBackground No No FibroticFibrotic

BackgroundBackground

++ ++ ++ BenignBenign

Hepatoblastoma, Hepatoblastoma, except Fetal except Fetal

TypeType

Large Large Renerative Renerative

NoduleNodule

Dysplastic Dysplastic NoduleNodule

HCCHCC

FNHFNH

HCAHCA

HCCHCC

Fibrolamellar HCCFibrolamellar HCC

Hepatoblastoma,Hepatoblastoma,

Fetal TypeFetal Type

Bile Duct Bile Duct AdenomaAdenoma

Peribiliary Gland Peribiliary Gland HamartomaHamartoma

Biliary Biliary AdenofibromaAdenofibroma

Any of: Bile, HSA, Any of: Bile, HSA, Arg1, CD10, pCEAArg1, CD10, pCEA

Any of: Bile, HSA, Arg1 Any of: Bile, HSA, Arg1 CD10, pCEACD10, pCEA

Hepatocytes with any of:Hepatocytes with any of:

Bile, HSA, CD10, pCEABile, HSA, CD10, pCEA

ANDAND

Ducts/glands/mucin/K19Ducts/glands/mucin/K19

CholangioCaCholangioCa

MetastasisMetastasis

Combined Combined HCC-HCC-

CholangioCaCholangioCa

MalignantMalignant

Immature Immature appearing cellsappearing cells

Hepatocytes or other large Hepatocytes or other large eosinophilic cellseosinophilic cells

Ducts/glands/mucinDucts/glands/mucin Hepatocytes and Hepatocytes and ducts/glands/mucinducts/glands/mucin

MetastasisMetastasis MetastasisMetastasis

MetastasisMetastasis

von Meyenburg von Meyenburg complexcomplex

Bile duct Bile duct adenomaadenoma

HSA, AFP, HSA, AFP, Arg1Arg1 Any of: Bile, HSA, Any of: Bile, HSA,

Arg1, CD10, pCEAArg1, CD10, pCEAAny of: Bile, HSA, Any of: Bile, HSA, Arg1, CD10, pCEAArg1, CD10, pCEA

Hepatocytes with any of:Hepatocytes with any of:

Bile, Arg1, HSA, CD10, Bile, Arg1, HSA, CD10, pCEApCEA

ANDAND

Ducts/glands/mucin/K19Ducts/glands/mucin/K19

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SOLID MASS

FibroticBackground

No FibroticBackground

+ + + Benign

Hepatoblastoma, except Fetal

Type

Large Renerative

Nodule

Dysplastic Nodule

HCC

FNH

HCA

HCC

von Meyenburg complex

Bile duct adenoma

Biliary Adenofibroma

HSA, AFP, Arg1

Any of: Bile, HSA, Arg1, CD10, pCEA

Any of: Bile, HSA, Arg1, CD10, pCEA

Hepatocytes with any of:

Bile, Arg1, HSA, CD10, pCEA

AND

Ducts/glands/mucin/K19

CholangioCa

Metastasis

Combined HCC-

CholangioCa

Malignant

Immature appearing cells

Hepatocytes or other large eosinophilic cells

Ducts/glands/mucin Hepatocytes and ducts/glands/mucin

Metastasis Metastasis

Metastasis

Immunostains for

HEPATOCYTES vs. METASTATIC MIMICS

Immunostains for

HEPATOCYTES vs. METASTATIC MIMICS

(e.g. RCC, Adrenal, Thyroid)

DIFFERENTIATION PANEL:HepPar1, Arginase 1

Canalicular pCEA, CD10AFP, ?LFABP

HepPar1

Arginase-1

CanalicularCD10

CanalicularpCEA

A CASE

H & E

polyclonal anti-CEA

HepPar 1

H & E

Arginase 1 and CD10 negative.

ANOTHER CASE

HepPar1

Arginase 1

Alpha-fetoprotein

CD10 canalicular staining (

pCEA negative.

Immunostains for

BENIGN VS. MALIGNANT HEPATOCYTES

Immunostains for

BENIGN VS. MALIGNANT HEPATOCYTES

CD34 and reticulin!Oldies, but goodies!

CD34 in HCC – always complete and diffuse

CD34 in HCC – always complete and diffuse

CD34 in HCA – usually incomplete or “patchy”

A CASE:44 y.o. obese man with 5 cm liver tumor

(“incidental” on imaging for other reason); MRI showed typical diagnostic HCC features in a

central part of the tumor. Underwent chemoembolization with NO response.

Decision to resect.

CD34

CD34

HCC

HCA

Non-tumor

C-reactive protein

Tumor diagnosis:HCC arising in Inflammatory HCA

(we will return to this shortly…)

TRIPLE MALIGNANCY PANEL:Glypican-3

Heat Shock Protein-70Glutamine Synthetase

Case ACase A Case BCase B

Glypican-3: In hepatocellular lesions, positive stainstrongly supportive of HCC

PLEASE NOTE!!!!

Glypican-3: In hepatocellular lesions, positive stainstrongly supportive of HCC.

IF AND ONLY IF THE TUMOR CELLSARE HEPATOCYTIC do we order this stain!

If NOT hepatocytic, this is NOT an hepatocytic marker!

PLEASE NOTE!!!!

SOLID MASS

FibroticBackground

No FibroticBackground

+ + + Benign

Hepatoblastoma, except Fetal

Type

Large Renerative

Nodule

Dysplastic Nodule

HCC

FNH

HCA

HCC

von Meyenburg complex

Bile duct adenoma

Biliary Adenofibroma

HSA, AFP, Arg1

Any of: Bile, HSA, Arg1, CD10, pCEA

Any of: Bile, HSA, Arg1, CD10, pCEA

Hepatocytes with any of:

Bile, Arg1, HSA, CD10, pCEA

AND

Ducts/glands/mucin/K19

CholangioCa

Metastasis

Combined HCC-

CholangioCa

Malignant

Immature appearing cells

Hepatocytes or other large eosinophilic cells

Ducts/glands/mucin Hepatocytes and ducts/glands/mucin

Metastasis

Metastasis

HCAFNH

DIAGNOSIS

OR?OR?

Dx: Benign hepatocellular nodule, ? FNH vs LCADx: Benign hepatocellular nodule, ? FNH vs LCA

Dx: Benign hepatocellular nodule, ? FNH vs LCADx: Benign hepatocellular nodule, ? FNH vs LCA

2121stst century: century: Check immunostaining for: Check immunostaining for:Glutamine Synthase, LFABP, beta-CateninGlutamine Synthase, LFABP, beta-Catenin

Serum Amyloid A and/or C-reactive ProteinSerum Amyloid A and/or C-reactive Protein >> LCA >> LCAsee: papers of Bioulac-Sage/Zucman-Rossisee: papers of Bioulac-Sage/Zucman-Rossi

FNHFNH WH

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Glutamine Synthetase (GS):Glutamine Synthetase (GS):

Adenoma Variants: search “Bioulac-Sage P”

FromFrom “WHO Tumours of the Digestive Tract”, 4 “WHO Tumours of the Digestive Tract”, 4thth Ed. Ed.

LFABP

Adenoma Variants: search “Bioulac-Sage P”

FromFrom “WHO Tumours of the Digestive Tract”, 4 “WHO Tumours of the Digestive Tract”, 4thth Ed. Ed.

Beta-catenin in normal liver

Beta-catenin

Beta Catenin Activation

Glutamine synthetase expression

Glutamine synthetase

Beta Catenin Activation

Glutamine synthetase expression

Beta-catenin

10%

GlutamineSynthetase

90%

CAVEAT!!!

Adenoma Variants: search “Bioulac-Sage P”

FromFrom “WHO Tumours of the Digestive Tract”, 4 “WHO Tumours of the Digestive Tract”, 4thth Ed. Ed.

Inflammatory HCA

Keratin 7

Case 3

C-reactive proteinC-reactive protein

A CASE

C-reactive protein

DX: Inflammatory HCA

ANOTHER (PROBLEM!) CASE

Features:Fibrous stroma

Ductular reactionsInflammation

Could be FNH orInflammatory HCA

Features:Sinusoidal dilatation and

congestion.

Suggests Inflammatory HCA?

Glutamine SynthetaseAppears relatively normal distribution in original biopsy

C-reactive protein

C-reactive proteinAppears widespread in the lesional pieces of tissue

C-reactive protein

Inflammatory HCA

vs.

Focal Nodular Hyperplasia

?

Relatively normal GS + Diffuse, strong CRP = ?

Inflammatory HCA

vs.

Focal Nodular Hyperplasia

?

Relatively normal GS + Diffuse, strong CRP = iHCA

Inflammatory HCA

vs.

Focal Nodular Hyperplasia

?

Relatively normal GS + Diffuse, strong CRP = iHCA

SO THE TUMOR IS RESECTED, BECAUSE I TOLD THEM TO!

Case 5

Case 5

Case 5

Case 5

Case 5

Case 5: Glutamine synthetase

Case 5: Glutamine synthetase

Inflammatory HCA

vs.

Focal Nodular Hyperplasia

?

BUT!!!!Resected lesion the GS appears to be

“Map-like” as seen in FNH and the C-reactive protein not evenly

distributed, so not I-HCA

Dx: Benign hepatocellular nodule, ? FNH vs LCADx: Benign hepatocellular nodule, ? FNH vs LCA

Dx: Benign hepatocellular nodule, ? FNH vs LCADx: Benign hepatocellular nodule, ? FNH vs LCA

What about HCC…?What about HCC…?As discussed, check for: As discussed, check for:

thickness of plates, loss of reticulin, CD34thickness of plates, loss of reticulin, CD34Pleomorphism, and GPC-3/HSP70/GS panelPleomorphism, and GPC-3/HSP70/GS panel

SOLID MASS

FibroticBackground

No FibroticBackground

+ + + Benign

Hepatoblastoma, except Fetal

Type

Large Renerative

Nodule

Dysplastic Nodule

HCC

FNH

HCA

HCC

Fibrolamellar HCC

Hepatoblastoma,

Fetal Type

Bile Duct Adenoma

Peribiliary Gland Hamartoma

Biliary Adenofibroma

Any of: Bile, HSA, Arg1, CD10, pCEA

Any of: Bile, HSA, Arg1 CD10, pCEA

Hepatocytes with any of:

Bile, HSA, CD10, pCEA

AND

Ducts/glands/mucin/K19

CholangioCa

Metastasis

Combined HCC-

CholangioCa

Malignant

Immature appearing cells

Hepatocytes or other large eosinophilic cells

Ducts/glands/mucin Hepatocytes and ducts/glands/mucin

Metastasis Metastasis

Metastasis

von Meyenburg complex

Bile duct adenoma

HSA, AFP, Arg1 Any of: Bile, HSA,

Arg1, CD10, pCEAAny of: Bile, HSA, Arg1, CD10, pCEA

Hepatocytes with any of:

Bile, Arg1, HSA, CD10, pCEA

AND

Ducts/glands/mucin/K19

SOLID MASS

FibroticBackground

No FibroticBackground

+ + + Benign

Hepatoblastoma, except Fetal

Type

Large Renerative

Nodule

Dysplastic Nodule

HCC

FNH

HCA

HCC

Fibrolamellar HCC

Hepatoblastoma,

Fetal Type

Bile Duct Adenoma

Peribiliary Gland Hamartoma

Biliary Adenofibroma

Any of: Bile, HSA, Arg1, CD10, pCEA

Any of: Bile, HSA, Arg1 CD10, pCEA

Hepatocytes with any of:

Bile, HSA, CD10, pCEA

AND

Ducts/glands/mucin/K19

CholangioCa

Metastasis

Combined HCC-

CholangioCa

Malignant

Immature appearing cells

Hepatocytes or other large eosinophilic cells

Ducts/glands/mucin Hepatocytes and ducts/glands/mucin

Metastasis Metastasis

Metastasis

von Meyenburg complex

Bile duct adenoma

HSA, AFP, Arg1 Any of: Bile, HSA,

Arg1, CD10, pCEAAny of: Bile, HSA, Arg1, CD10, pCEA

Hepatocytes with any of:

Bile, Arg1, HSA, CD10, pCEA

AND

Ducts/glands/mucin/K19

Keratins 7 and 20and other differentiationmarkers

SOLID MASS

FibroticBackground

No FibroticBackground

+ + + Benign

Hepatoblastoma, except Fetal

Type

Large Renerative

Nodule

Dysplastic Nodule

HCC

FNH

HCA

HCC

Fibrolamellar HCC

Hepatoblastoma,

Fetal Type

Bile Duct Adenoma

Peribiliary Gland Hamartoma

Biliary Adenofibroma

Any of: Bile, HSA, Arg1, CD10, pCEA

Any of: Bile, HSA, Arg1 CD10, pCEA

Hepatocytes with any of:

Bile, HSA, CD10, pCEA

AND

Ducts/glands/mucin/K19

CholangioCa

Metastasis

Combined HCC-

CholangioCa

Malignant

Immature appearing cells

Hepatocytes or other large eosinophilic cells

Ducts/glands/mucin Hepatocytes and ducts/glands/mucin

Metastasis Metastasis

Metastasis

von Meyenburg complex

Bile duct adenoma

HSA, AFP, Arg1 Any of: Bile, HSA,

Arg1, CD10, pCEAAny of: Bile, HSA, Arg1, CD10, pCEA

Hepatocytes with any of:

Bile, Arg1, HSA, CD10, pCEA

AND

Ducts/glands/mucin/K19

Keratins 7 and 20and other differentiationmarkersAND Keratin 19