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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
WH
O T
um
ours
of t
he
Dig
est
ive
Tra
ct,
4W
HO
Tu
mou
rs o
f th
e D
ige
stiv
e T
ract
, 4thth
Ed.
Ed.
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
O T
um
ours
of t
he
Dig
est
ive
Tra
ct,
4W
HO
Tu
mou
rs o
f th
e D
ige
stiv
e T
ract
, 4thth
Ed.
Ed.
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