Ihc Colecchia

Department of Pathology
IRCCS National Cancer Institute Milan
MAURIZIO COLECCHIA
MILAN
2013 International Society of Urologic Pathology
Conference on Best Practices Recommendations in
the Application of Immunohistochemistry in
Diagnostic Urologic Pathology: The Role of
Immunohistochemistry in Testicular Neoplasms
http://www.isuporg.org/meetings.cfm
• Thomas M. Ulbright, MD
• Daniel M. Berney, FRCP
• Satish K. Tickoo, MD
• John R. Srigley, MD
Copyright ISUP.ORG
• IHC is very helpful to resolve between differential diagnostic

considerations and should be applied in a conservative
fashion, ideally utilizing 2 or 3 immunostains with different
patterns of reactivity for the differential diagnoses under
consideration
• Diagnostic algorithms for specific differential diagnostic

considerations should therefore be utilized
• There are currently no clinically utilized prognostic IHC

markers for testicular neoplasms.
Useful Antibodies for Testicular Neoplasms Department of Pathology
OCT 4
Teratoma, OCT 4 negative

• Nuclear protein critical for
pluripotency of embryonic stem
cells
• ~100% sensitive for IGCNU,
seminoma, embryonal
carcinoma (EC)
• Negative in other testis tumors
• Other + tumors: rarely, lung &
kidney ca, large cell lymphoma
• Caveat: Post-chemo ECs may be
negative
• Overview: Very valuable for
seminoma vs mimics (yolk sac
tumor [YST], Sertoli cell tumor EC, OCT 4 positive
[SCT]) and to support Dx of
seminoma and EC in Bxs (mets).
Solid YST with clear cells, potentially mimicking seminoma
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Solid YST – OCT4 Seminoma – OCT4
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Seminoma+SynT Seminoma+SynT – OCT4
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Seminoma with syncitiotrophoblasts IRCCS National Cancer Institute Milan
Seminoma with Syncytiotrophoblasts vs Choriocarcinoma Department of Pathology
Preferred markers in
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bold; alternatives in
parentheses Disclaimer: showing this slide please report the web -site source
Useful Antibodies for Testicular Neoplasms Department of Pathology
SALL4 IRCCS National Cancer Institute Milan
• Zinc finger nuclear

transcription factor with role in
embryonic development
• ~100% sensitive for IGCNU,
seminoma, EC & YST; 69% of
CCs & 52% of teratomas
• Negative in other testis tumors
• Other + tumors: ALCL,
rhabdoid tumor, Wilms tumor,
precursor B-cell ALL, AML & ~
5% of GI tract adenoca
• Caveat: Non-neoplastic germ
cells are +
• Overview: Sensitive general
GCT marker valuable for GCT vs
non-GCT of testis and in DX of
metastatic GCTs; sensitive YST
marker, unlike OCT4 Copyright by ISUP
Useful Antibodies for Testicular Neoplasms
CD117 (cKIT)
• Receptor tyrosine kinase in stem
cells
• Membranous expression occurs in
95-100% of seminomas & IGCNU
• Variably + in YSTs and
spermatocytic seminomas (SS)
• ~ negative in ECs &
choriocarcinomas (CC)
• Other + tumors: Numerous
• Caveat: Spermatogonia may be +;
therefore not helpful for IGCNU
• Overview: Main utility is assisting
with the Dx of seminoma vs EC
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CD30 (Ki-1,Ber-H2)
• Protein in the TNF receptor
family with membranous and
Golgi-zone staining
• 93-100% of ECs are positive
• Negative or, at most, stains rare
cells in other GCTs
• Other + tumors: lymphomas, soft
tissue tumors, melanomas &
infrequent carcinomas
• Caveats: Intensity in EC can be
variable requiring close
examination. Loss occurs in some
post-Rx ECs.
• Overview: Very useful for EC vs
seminoma or solid YST.
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Seminoma
Seminoma &–
& EC EC
CD 30
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Seminoma & EC – CD117
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SOX2 (SRY-box 2)
• Member of the SOX family of
nuclear transcription factors
involved in embryonic
development; needed for
pluripotency of undifferentiated
embryonic stem cells
• Positive in 96% of ECs & <1% of
seminomas
• Negative in YSTs, CCs & IGCNU
• Other nuclear + tumors:
immature elements in teratoma,
melanoma & rhabdoid tumors
• Caveat: Non-neoplastic Sertoli
cells are +
• Overview: Mostly useful for
seminoma vs EC. May become a
preferred marker for seminoma
vs EC but the panelists Copyright by ISUP
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technically difficult Disclaimer : showing this slide please report the web -site source
Glypican 3 (GPC3)
• Membrane anchored heparan sulfate proteoglycan

• Positive in YSTs (100%), CCs (80%), teratomas (“immature”)
(17%) & rare ECs (5%)
• Negative in IGCNU & seminoma
• Other + tumors: : hepatocellular and gastric cancers
• Caveats: Syncytiotrophoblast cells are often positive (71%)
• Overview: More sensitive but less specific for YST among
testis GCTs than AFP
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Solid YST – glypican 3
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Alpha-fetoprotein (AFP)
• A major plasma protein produced
by the yolk sac & liver during fetal
life
• YSTs are variably and often focally
positive (overall, ~80%)
• AFP is negative in the other GCTs,
except for glands and luminal
secretions of some teratomas
• Other + tumors: hepatocellular
neoplasms, hepatoid carcinomas
& occasional other non-GCTs
• Caveat: Negative AFP does not
exclude YST
• Overview: Wide availability &
relative YST specificity make it
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helpful for Dx of YST but has
limited sensitivity Disclaimer : showing this slide please report the web -site source
Human Chorionic Gonadotropin (hCG)
• A dimeric glycoprotein produced by
placental trophoblast cells, mostly
syncytiotrophoblasts; α subunit is
shared by LH, TSH & FSH but the β is
unique
• Primary CC is positive (100%) for
βhCG as are all non-CCs with
syncytiotrophoblast cells
• Other + tumors: any non-germ cell
tumor with trophoblastic
differentiation
• Caveat: CCs after Rx may lose
syncytiotrophoblasts and show scant
to absent reactivity for βhCG
• Overview: Useful for supporting Dx of
CC but usually not necessary Copyright by ISUP
Placental Alkaline Phosphatase (PLAP)
• An allosteric enzyme in placental trophoblast
• + in IGCNU (83-100%) & <1% of non-neoplastic germ cells
• + in 90-100% of usual seminomas with a membranous
pattern. Most ECs & ~ 50% of YSTs & CCs are +
• SS & SCT are negative
• Other + tumors: many adenocas (ovary, colon,
endometrium, lung)
• Caveat: Not a specific GCT marker
• Overview: Mostly helpful for IGCNU; useful for usual
seminoma vs SS or SCT
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Immunohistochemistry Algorithm #1 for Testicular Neoplasia
Germ Cell Tumor Subtyping
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Preferred markers in bold; alternatives in parentheses
Proposed ISUP Recommendations:
Germ Cell Tumor Subtyping
• A reasonable and efficient initial panel is: OCT4,

CD117, CD30 & GPC3
• This panel may be reduced depending on the light
microscopic differential, for instance omitting OCT4
& GPC3 if the question by morphology is limited to
seminoma versus embryonal carcinoma
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Sex cord/gonadal stromal tumors Department of Pathology
useful immunostains
Type LCT SCT USCS GCT LCCST TTAG

36P 72M 13P 5M T 6 P 3M 4 2
8
SF-1 92 75 57 50 50 100
FOXL2 21 83 67 100 - -
ß-catenin 50 83 60 100 50 100
Inhibin 97 67 38 67 75 100
Melan A 94 67 75 50 50 100
Calretinin 97 56 75 44 75 100
WT-1 0 82 57 50 75 50
CD99 74 56 25 86 0 0
Synaptophyin 65 24 29 0 0 50
CK 22 78 17 43 67 -
S100 28 28 43 38 75 0
LCT = Leydig CT ; SCT = Sertoli CT; USCST = Unclassified CST; Useful immunohistochemistry
GCT = Granulosa CT; LCCST = Large cell calcifying SCT ; TTAG
Divatia et. al. USCAP 2015 Abstract 860 (pp.216A)
= Testicular tumor of adrenogenital syndrome
Mukul Divatia, Steven Smith, Maurizio Colecchia, Manju Aron, Mitual Amin, Steven
Shen, Donna Hansel, Pheroze Tamboli, Gladell Paner, Mariza de Peralta- Department of Pathology
Venturina, Loren Herrera Hernandez, Allen Gown, Mahul Amin. USCAP 2015
Abstract 860
(pp.216A)
Conclusions: SF-1 is the
most sensitive marker
amongst the common
types of TSCSTs.
Among traditional
markers, inhibin,
calretinin and Melan A
offer overall similar
sensitivity, although
calretinin lacks specificity
considering the tumors in
the differential diagnosis
at this site.
A combination of SF-1,
inhibin and Melan A or
calretinin as a first line
IHC panel provides
maximum sensitivity
identifying > 80% of
TSCSTs.
Immunohistochemistry Algorithm #2b* for Testicular Neoplasia:
* Alternative algorithm if Copyright by ISUP

SALL4 not available http://www.isuporg.org/meetings.
Proposed ISUP
Recommendations:
Germ Cell Tumor versus Sex
Cord-Stromal Tumor
• A reasonable and efficient initial panel is: SALL4, Inhibin &
Calretinin
• An alternative panel is OCT4, GPC3, Inhibin & Calretinin
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Epithelial Membrane Antigen (EMA)
• Glycoprotein in human milk fat globule membranes

• Positive in most carcinomas and some sarcomas & lymphomas
(ALCL)
• Rarely positive in seminomas (2%), YSTs (2%) & ECs (2-12%)
• Caveat: Negative GCT marker; not entirely specific in DX of GCT
vs non-GCT
• Overview: Useful in the differential of GCT versus somatic
carcinoma.
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Immunohistochemistry Algorithm #4a for Testicular Neoplasia:
Germ Cell Tumor vs Metastatic High Grade Carcinoma
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*Embryonal carcinoma and Seminoma only
Cytokeratin 7 (CK7)
• Type II keratin of simple nonkeratinizing epithelium

• Positive in many carcinomas
• Negative in YST
• May be positive in non-YST GCTs
• Caveat: A negative YST marker & some carcinomas are negative
(prostate, colon, etc.)
• Overview: Mostly useful in the differential of YST vs somatic
carcinoma
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Immunohistochemistry Algorithm #4b* for Testicular Neoplasia:
Germ Cell Tumor vs Metastatic High Grade Carcinoma
* Alternative algorithm if SALL4 not available Copyrightby ISUP

† Hepatocellular carcinomas, hepatoid carcinomas of other organs and squamous cell carcinomas
may be glypican 3 positive.
Proposed ISUP Recommendations:
Germ Cell Tumor versus Metastatic High
Grade Carcinoma
• A reasonable and efficient initial panel is:

SALL4, OCT4 & EMA
• An alternative panel is OCT4, GPC3, EMA &
CK7
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Department of Pathology

IRCCS National Cancer Institute Milan

• IHC is very helpful to resolve between differential diagnostic

• Diagnostic algorithms for specific differential diagnostic

• There are currently no clinically utilized prognostic IHC

Teratoma, OCT 4 negative

SALL4 IRCCS National Cancer Institute Milan

• Zinc finger nuclear

Copyright by ISUP http://www.isuporg.org/meetings.

• Membrane anchored heparan sulfate proteoglycan

• A reasonable and efficient initial panel is: OCT4,

Type LCT SCT USCS GCT LCCST TTAG

* Alternative algorithm if Copyright by ISUP

• An alternative panel is OCT4, GPC3, Inhibin & Calretinin

• Glycoprotein in human milk fat globule membranes

• Type II keratin of simple nonkeratinizing epithelium

* Alternative algorithm if SALL4 not available Copyrightby ISUP

• A reasonable and efficient initial panel is:

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