Cytokeratins and other epithelial markers dth ithlil k in...

Cytokeratins and other epithelail markers

Mogens Vyberg 2013 1

CIQC/CAP-ACP SEMINAR 2013:DIAGNOSTIC IHCAND MOLECULAR PATHOLOGY

Cytokeratins d th ith li l k

Mogens Vyberg

Aalborg University HospitalDenmark

and other epithelial markers in diagnostic IHC

• Highly complex family of intermediate filaments

• > 50 distinct types (excl. trichocytic keratins)

• Types CK1-20 diagnostically most relevant:

Class I (type A - Acidic):

CK9 (64 kD ) CK20 (40 kD )

Cytokeratins – a multigene family

CK9 (64 kDa) - CK20 (40 kDa)

Class II (type B - Basic/neutral):

CK1 (68 kDa) - CK8 (52.5 kDa)

(B) (A)

The Moll Cytokeratin catalogue 1982

CK: renal cell carcinoma

Moll et al. Cell 1982; 31:11

• One CK class I and one CK class II ‘always’ paired

• CK class I in a pair ~ 8 kDa smaller than class II

Pairing of cytokeratins

Modified from: Lane & Alexander Semin Cancer Biol 1990, 1:165

Neutral/Basic (B, class II)Acidic (A, class I)

514 17 19

Squamous epithelia:- suprabasal, keratinizing - - + ++ (+) - - - -- suprabasal, non-keratinizing +++ +++ + ++ (+) - - - -

- basal cells (1tonsil, 2mucosa) - - +++ +++ (+)1 (++)12 (+)1 - (+)1

Transit. epith.: superficial cells - - - - - +++ +++ ++ +++

- intermed. / 3basal cells (+)3 +++ (+++)3 - (++)3 +++ +++ (+) +++Mesothelium ++ ++ + +++ +++ +++

Cytokeratin types and cell types

Mesothelium - - ++ ++ + +++ +++ - +++

Bronchus, breast, prost., cerv.:- basal/myoepithelial cells - - +++ ++ +++ ++ - - -- luminal cells - - + + + +++ +++ - +++

Biliary/pancr. ducts, lung alv.,endometr., renal collect. ducts - - - - - +++ +++ - +++4Stomach (foveola), intestine - - - - - +++ (+)4 +++ +++Hepatocytes, pancr. acini,prox. renal tubules - - - - - - - - +++Endocrine cells (5Merkel, 6thyr.) - - - - - (+++)5 (++)6 (+++)5 +++Smooth muscle (vasc., myom.),myofibrobl., 7sm.ves.endothelia - - - - - + (++)7 - ++

HMW Cytokeratin types - squamous epithelia

514 17 19

- intermed. / 3basal cells (+)3 +++ (+++)3 - (++)3 +++ +++ (+) +++Mesothelium ++ ++ + +++ +++ +++Mesothelium - - ++ ++ + +++ +++ - +++

CK5: esophagus CK4: esophagus

CK17: tonsil CK17: skin

LMW Cytokeratin types - squamous epithelia

514 17 19

- intermed. / 3basal cells (+)3 +++ (+++)3 - (++)3 +++ +++ (+) +++Mesothelial cells ++ ++ + +++ +++ +++Mesothelial cells - - ++ ++ + +++ +++ - +++

LMW Cytokeratin types - squamous epithelia

CK19: tonsil CK19: esophagus

Cytokeratin types - urothelium

514 17 19

Transit. epith.: superficial cells - - - - - +++ +++ ++ +++- intermed. / 3basal cells (+)3 +++ (+++)3 - (++)3 +++ +++ (+) +++

Mesothelium ++ ++ + +++ +++ +++Mesothelium - - ++ ++ + +++ +++ - +++

Cytokeratin types - urothelium

CK5 (+CK13) CK20

Cytokeratin types - mesotheliumNeutral/Basic (B, class II)Acidic (A, class I)

514 17 19

Squamous epithelia:- suprabasal, keratinizing - - + ++ (+) - - - -- suprabasal, non-keratiniz.ep. +++ +++ + ++ (+) - - - -

Cytokeratin types - mesothelium

CK5: mesothelium(adenocarcinoma neg.)CK19: mesothelium

Cytokeratin types - complex epithelia

514 17 19

- basal cells (1tonsil, 2mucosa) - - - +++ (+)1 (++)12 (+)1 - (+)1

Cytokeratin types - complex epithelia

CK5 (14,17): breast CK18 (8,7): breast

Cytokeratin types - simple epithelia

514 17 19

Squamous epithelia:- suprabasal, keratinizing - - + ++ -(+) - - - -- suprabasal, non-keratinizing +++ +++ + ++ (+) - - - -

- basal cells (1tonsil, 2mucosa) - - - +++ -(+)1 (++)12 -(+)1 - -(+)1

Cytokeratin types - simple epithelia (liver, kidney)

CK7(19): bile ducts CK7(19): renal col.

514 17 19

CK20: gastric foveolae CK20: colon

514 17 19

CK8: liver CK8: kidney

514 17 19

CK20: Merkel cells CK8: Pancreas

Islet of Langerhans

Cytokeratin types - mesenchymal cells

514 17 19

Cytokeratin types - mesenchymal cells

CK7: endotheliumCK8: lymph node fibroblastic reticulum cells

514 17 19

Squamous cell carcinoma + + ++ ++ (+) (+) (+) - (+)Transitional cell tumour + + + + + ++ ++ ++ ++

Malignant mesothelioma - - ++ ++ + ++ + - ++

Adenocarcinoma: complexepithelia (bronch., breast, prost.) - - (+) (+) (+) ++ ++ - ++Adenocarc.: biliary tract,

Cytokeratins in epithelial neoplasias

pancr., endom., ovary - - (+) (+) (+) ++ ++ (+) ++Adenocarc.: stomach - - - - - ++ + + ++Adenocarc.: intestine - - - - - ++ + ++ ++Hepatocellular carcinomaRenal cell carcinoma - - - - - - + - ++Endocrine tumours: carcinoids - - - - - + + - ++- Merkel cell carcinoma - - - - - + - ++ ++- Thyroid carcinoma - - - - - + ++ - ++

514 17 19

Squamous cell carcinoma + + ++ ++ + + + - +Transitional cell tumour + + + + + ++ ++ ++ ++

Cytokeratins in squamous cell carcinoma

esophagus

CK4CK5

CK13 CK4 (loss)

CK7 (gain) CK8 (gain)

514 17 19

Squamous cell carcinoma + + ++ ++ + + + - +Transitional cell tumour + + ++ + ! + ! ++ ++ ++ ++Malignant mesothelioma - - ++ ++ + ++ + - ++

Cytokeratins in urothelial carcinoma

CK20 CK5

514 17 19

Malignant mesothelioma - - ++ ++ + ++ + - ++Adenocarcinoma: complexepithelia (bronch., breast, prost.) - - (+) (+) (+) ++ ++ - ++Adenocarc.: biliary tract,

Cytokeratins in malignant mesothelioma

CK5CK5

CK8 (loss)

514 17 19

Adenocarcinoma: complexepith. (bronch., breast, prost.) - - (+) (+) (+) ++ ++ - ++Adenocarc.: biliary tract,

Cytokeratins in adenocarcinomas

CK5: Breast lob. carcinoma CK5: Breast duct. carc.

CK5: Breast lob. carcinoma CK5: prostate adenocarc.CK5: Prostate hyperplasia

514 17 19

pancr., endom., ovary - - (+) ! (+) ! (+) ! ++ ++ (+) ! ++Adenocarc.: stomach - - - - - ++ + + ++Adenocarc.: intestine - - - - - ++ + ++ ++Hepatocellular carcinomaRenal cell carcinoma - - - - - - + - ++Endocrine tumours: carcinoids - - - - - + + - ++- Merkel cell carcinoma - - - - - + - ++ ++- Thyroid carcinoma - - - - - + ++ - ++

CK17: Pancreas adenocarcinoma

CK5: Biliary tract adenocarcinoma

CK17CK5: Serous ovarian carcinoma

CK20: Gall bladder adenocarcinoma

514 17 19

pancr., endom., ovary - - (+) (+) (+) ++ ++ (+) ++Adenocarc.: stomach - - - - - ++ + + ++Adenocarc.: intestine - - - - - ++ + ! ++ ++Hepatocellular carcinomaRenal cell carcinoma - - - - - - + - ++Endocrine tumours: carcinoids - - - - - + + - ++- Merkel cell carcinoma - - - - - + - ++ ++- Thyroid carcinoma - - - - - + ++ - ++

CK7CK7Colon: Typical Colon: Deviant

514 17 19

CK7CK7

CK7HCC: typical HCC: deviant

Mallory body

CK7: RCC CK7: RCC

514 17 19

Cytokeratins in endocrine tumours

pancr., endom., ovary - - (+) (+) (+) ++ ++ (+) ++Adenocarc.: stomach - - - - - ++ + + ++Adenocarc.: intestine - - - - - ++ + ++ ++Hepatocellular carcinomaRenal cell carcinoma - - - - - - + - ++Endocr. tumours: carcinoids - - - - - + + - ++- Merkel cell carcinoma - - - - - + - ++ ++- Thyroid carcinoma - - - - - + ++ - ++

Cytokeratins in endocrine tumours

CK20: Merkel cell carc. CK19: Thyr. papill. carc.

CK20+ CK20 amb CK20-

Lung MBAC1

EsophagusBiliary tractPancreasOvary muc.

Lung 1

Breast d./l.Thyroid p./f.

Endom. c.Cervix ad.Ovar. nonmuc

Coordinate cytokeratin 7/20 expression

Urothelium

CK7 ambAppendixSmall intest.Rectum

StomachNeuroend.2

Germ cell t.5

Chr.phobe rc.6

ColonMerkel cell 2

Carcinoid 2

Liver cell c.Renal cell. c.6

Adrenal cort.c.Prostate

Lung MBAC1

Lung 1

Urothelium

StomachNeuroend.2

Germ cell t.5

Chr.phobe rc.6

ColonMerkel cell 2

Carcinoid 2

CK7CK7♀ 48, biopsy from vaginal ”polyp”

CK7CK7

CK7CK7CK7

CK7 CK20

Lung MBAC1

Lung 1

Urothelium

StomachNeuroend.2

Germ cell t.5

Chr.phobe rc.6

ColonMerkel cell 2

Carcinoid 2

Lung MBAC1

Lung 1

Urothelium

StomachNeuroend.2

Germ cell t.5

Chr.phobe rc.6

ColonMerkel cell 2

Carcinoid 2

CK7CK7

CK7CK7CK20

Lung MBAC1

Lung 1

Urothelium

StomachNeuroend.2

Germ cell t.5

Chr.phobe rc.6

ColonMerkel cell 2

Carcinoid 2

Urothelial carcinoma

Lung MBAC1

Lung 1

Urothelium

StomachNeuroend.2

Germ cell t.5

Chr.phobe rc.6

ColonMerkel cell 2

Carcinoid 2

Lung MBAC1

Lung 1

Urothelium

StomachNeuroend.2

Germ cell t.5

Chr.phobe rc.6

ColonMerkel cell 2

Carcinoid 2

Optimal: 11%Good: 13%Insuff.: 76%

Cytokeratins: Selection of antibodies

optimal too diluted HIER Prot.

CK5: XM-26CK5/6: clone D5/16 B4

34BE12:CK5/14/1/10/19?

Conc. Abs: CK types N Optimal Good Bord. Poor Suff.1 Suff. OPS2

mAb clone 34BE12

1/5/10/14 (19?)

89 1 6 75 7 8 % 40 %

mAb clone D5/16B4 5/6 17 6 7 3 1 76 % 82 %

mAb clone XM26 5 6 4 1 1 0 83 % 83 %

CK-HMW run 32, 2011

CK 5 or CK5/6 34BE12

Cytokeratins – which clones

5D3 35βH11C51

CAM5.2DC10

Cytokeratins: Selection of antibodies

optimalEsophagus

CK19 l A53 B/A2 26 CK19 l RCK108CK19: clone A53-B/A2.26 CK19: clone RCK108After proteolysis as recommended by the vendor

Papillary thyroid carcinoma

Cancer Most relevant markers

Lung carcinoma TTF-1, Napsin

Breast carcinoma ER, Mammaglobin, GCDFP-15, GATA3

Colorectal carcinoma CK20, CDX2, CEA, Cadherin17

Prostate carcinoma PSA, Prostein

Malignant melanoma MSA MLA SOX10

Secondary panels for carcinoma identification/subclassification

Malignant melanoma MSA, MLA, SOX10

Non-muc. ovarian carcinoma CA125, WT1, PAX8

Urothelial carcinoma CK20, GATA3

Pancreatic carcinoma SMAD4

Hepatocellular carcinoma Glypican 3, Arginase, canCD66a, canCD10

Neuroendocrine carcinoma Synaptophysin, Chromogranin

Thyroid transcription factor-1

Lung adenocarcinoma 80 70

- large cell carcinoma 50 40

- small cell carcinoma 90 90

- carcinoid 60 20

SPT24 8G7G3/1% pos.:

- squamous cell carcinoma 15 0

Non-lung small cell carcinoma 20-40 ?

Thyroid carc. (non-anaplastic) 100 100

Non-lung carcinomas 0 - 5 0 - 5

Non-lung carcinoids ~ 0 ~ 0

Matoso et al, AIMM 2010,18:142-149

SPT24 8G7G3/1

Thyroid

SPT24 8G7G3/1

Lung adenocarcinoma

8G7G3/1

Lung carcinoid

CDX-2 protein in adenocarcinoma

Colorectum +(–)Mucinous ovar. +(–)Esoph./Stom. +/–Mucinous lung +/–Pancr./biliary –/+

Colon adenocarcinoma

yProstate –(+)Urothelial –(+)Endometrioid –(+)

Yolk sac tumour +

CDX2Normalcolon

EPR-CON EPR-RTUEPR = rmAb EPR2764Y

DAK-CDX2 AMT-28 CDX2-88

CDX2Normalpancreas

EPR-CON EPR-RTU

CDX2Colonadenocarc

EPR-CON EPR-RTU

Carcinoembryonic antigen (CD66e)

Adhesion molecule espc. associated with intestine

Carcinoembryonic antigen (CD66e) in adenocarcinomas

Colorectal +Medull. thyroid +Pancreas/biliary tract +/–Stomach +/–Lung +/–Ovary, mucinous +/–Ovary non-muc –/+Ovary, non-muc. –/+Prostate –Kidney –Liver (!) –

metast. colon adenoc

Carcinoembryonic antigen – which antibody?

Normal liver

II-7 pAb / TF3H8-1

Mal. mesothelioma

mAb II-7 pAb / TF3H8-1

Paired box transcription factors: PAX8

RCC Endometrioid carc.

SMAD4: Loss in pancreaticbiliary carcinomas

Ep-CAM

CIQC/CAP-ACP SEMINAR 2013:DIAGNOSTIC IHCAND MOLECULAR PATHOLOGY

Cytokeratins and other epithelial markers

Mogens Vyberg

Aalborg University HospitalDenmark

in diagnostic IHC

Thank you for your attention

Cytokeratins and other epithelial markers dth ithlil k in...

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