The role of immunohistochemistry in surgical pathology of the uterine corpus and cervix Prof. Ben Davidson, MD PhD Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
Cervix Low-grade squamous intraepithelial lesion High-grade squamous intraepithelial lesion Squamous cell carcinoma Adenocarcinoma (endocervical, usual type; mucinous; villoglandular; endometrioid; clear cell; mesonephric) Benign glandular lesions Neuroendocrine carcinoma Soft tissue tumors Melanoma Hematological malignancies Metastases
SIL vs. reactive Ki-67 p16: clone E6H4 Ki-67: clone MIB1 p16
AIS vs. hyperplasia and reactive changes Ki-67 p16: clone E6H4 Ki-67: clone MIB1 p53: clone DO-1 p16
Cervix adenoca. vs. SqCC vs. ASq ca. CK8: clone C51 Not useful Ber-EP4: clone Ber-EP4 CEA CK5/6: clone D5/16B4 p16 p63: clone 4A4 CK7 p40: rabbit polyclonal
SqCC p40 p63 CK5/6 CK8 Ber-EP4
Carcinoma, NOS CK8 Ber-EP4 CK5/6 p40 p63
Neuroendocrine carcinoma Chromogranin A Synaptophysin Synaptophysin: clone 27G12 Chromogranin A: clone MAB5268
Avoid CD56 CD56 CD56 HGSC
Clear cell carcinoma - cervix p53 mcea HNF1β Napsin p16 p16: clone E6H4 p53: clone DO-1 HNF1β: polyclonal rabbit Napsin A: clone TMU-Ad02
Mesonephric carcinoma EMA: clone E29 Vimentin: clone 3B4 Calretinin: clone Calret1 CD10: clone 56C6 (PAX8, TTF1, p16: +/-) (mcea, ER, PR: negative)
Mesonephric carcinoma EMA p16 PAX8 EMA: clone E29 Vimentin: clone 3B4 CA 125: clone M11 p16: clone E6H4 PAX8: rabbit polyclonal CA 125 Vimentin
Corpus uteri Adenocarcinoma (endometrioid; mucinous; clear cell, serous; neuroendocrine; mixed; undifferentiated; dedifferentiated) Carcinosarcoma Leiomyoma Sarcoma (ESS, LMS, Undifferentiated HGUS, RMS) Other soft tissue tumors (PECOMA, UTROSCAT) Trophoblastic tumors Invasion of gynecologic tumors of other origin Metastases
Endometrioid Serous Clear cell
Endometrial carcinoma Matias-Guiu and Davidson, Virchows Arch 2014;464:315-331
Differentiating uterine AC of various histology ER: clone 6F11; positive in the majority of EC and in some SC, negative in CCC PR: clone 16; positive in the majority of EC and in some SC, negative in CCC p16: clone E6H4; patchy in EC, diffusely positive in SC, variable in CCC p53: clone DO-1; aberrant in SC + in some EC and CCC HNF1β: polyclonal rabbit; positive in CCC and some EC, usually negative in SC PTEN: clone 6H2.1; negative in majority of EC, positive in SC and CCC ARID1A: polyclonal rabbit; negative in 50% of EC and CCC, positive in SC Napsin A: clone TMU-Ad02; positive in CCC, negative in other histotypes Other: Vimentin: clone 3B4; positive in EC, variable in SC, often negative in CCC Ki-67: clone MIB1; high score in SC and CCC + in some EC mcea: clone II-7; focally positive in EC, negative in SC and CCC
Serous carcinoma p16 p53 p16: clone E6H4 p53: clone DO-1
Serous carcinoma ER p16 p53 ER: clone 6F11 p16: clone E6H4 p53: clone DO-1
Clear cell carcinoma HNF1β p53 p16 mcea Vimentin ER PR ER: clone 6F11 PR: clone 16 p16: clone E6H4 p53: clone DO-1 mcea: clone II-7 HNF1β: polyclonal rabbit Vimentin: clone 3B4
Endometrioid and clear cell carcinoma HNF1b ER PR p53 ER: clone 6F11 PR: clone 16 p53: clone DO-1 HNF1β: polyclonal rabbit
Endometrioid/serous carcinoma ER PR p53 p16 ER: clone 6F11 PR: clone 16 p16: clone E6H4 p53: clone DO-1
Serous ARID1A Endometrioid Clear cell Clear cell ARID1A: rabbit polyclonal
Serous PTEN Serous Endometrioid Endometrioid PTEN: clone 6H2.1
IMP2 & IMP3 IMP2 IMP2 IMP3 IMP3 IMP3 IMP3 IMP3 IMP2: rabbit polyclonal IMP3: clone N-19
Spindle cell tumor panel Actin: clone HHF35 Desmin: clone D33 SMA: 14D S100: polyclonal rabbit EMA: clone E29 Pan-cytokeratin: clone AE1/AE3 CD31: clone JC/70A CD34: QBEND-10 CD68: clone KP-1 CD99: clone EPR3097Y (rabbit)
Actin: clone HHF35 Desmin: clone D33 SMA: 14D h-caldesmon: clone h-cd CD10: clone 56C6 ESS vs. LMS Sub-optimal!
ESS vs. LMS SMA - ESS Desmin - LMS H-Caldesmon - ESS
ESS with sex cord pattern AE1/AE3 Vimentin Inhibin ER CD10 Pan-cytokeratin: clone AE1/AE3 Vimentin: clone 3B4 Inhibin: clone R1 ER: clone 6F11 (also clones SP1 and EP1) CD10: clone 56C6
CD10 ESS LMS Small cell sarcoma Small cell sarcoma
Potential markers? Davidson et al., Gynecol Oncol 2013;128:349-55 LMS: fatty acid binding protein-3 (FABP3), transgelin (TAGLN), neuron navigator 2 (NAV2); ESS: Cyclin D2 (CCND2), integral membrane protein 2A (ITM2A)
High-grade vs. low-grade ESS Cyclin D1 HG Cyclin D1 HG Cyclin D1 LG Cyclin D1: clone SP4
HG sarcoma with RMS areas Myf-4 Actin Desmin Myogenin Myf-4: clone LO26 Myogenin: clone F5D
PECOMA HMB-45 HMB-45 HMB-45: clone HMB45
Complete mole p57 p57: clone 25B2
Partial mole p57 p57: clone 25B2
Epithelioid Trophoblastic Tumor (ETT) PLAP p63 hpl p63: clone 4A4 PLAP: clone 8A9 hpl: rabbit monoclonal
Choriocarcinoma presenting as SqCC
Choriocarcinoma presenting as SqCC Pan-CK Vimentin Pan-CK: clone AE1/AE3 Vimentin: clone 3B4 HCG: rabbit polyclonal HCG
HCG-producing SqCC EMA CK5/6 CK8 HCG EMA: clone E29 CK5/6: clone D5/16B4 CK8: clone C51 HCG: rabbit polyclonal
Other
Melanoma Melan A: clone A103 HMB-45: clone HMB45 S100: polyclonal rabbit Vimentin: clone 3B4 Pan-cytokeratin: clone AE1/AE3
Melanoma HMB45 Melan A AE1/AE3 Vimentin
Diffuse large B-cell lymphoma CD20 CD79a MUM1 PAX5 CD20: clone L-26 CD79a: clone JCB-117 MUM1: clone MUM1p PAX5: clone 24/PAX5
Myelosarcoma CD15 MPO Ki-67 CD68 CD15: clone Carb-3 MPO: rabbit monoclonal Ki-67: clone MIB1 CD68: clone KP-1
Local extension and metastasis
Vaginal recurrence of endometrial carcinoma ER PR DD from primary AC in cervix ER: clone 6F11 (also clones SP1 and EP1) PR: clone 16 Vimentin: clone 3B4 mcea: clone II-7 p16: clone E6H4 HPV analysis
Lobular breast ca. CK8 ER PR GCDFP-15 CK8: clone C51 ER: clone 6F11 (also clones SP1 and EP1) PR: clone 16 GCDFP-15: clone 23A3
Appendiceal NET in cervix
Appendiceal NET in cervix mcea mcea CK20 Synaptophysin CDX2 Chromogranin A Synaptophysin: clone 27G12 Chromogranin A: clone MAB5268 mcea: clone II-7 CDX2: clone DAK-CDX2 CK20: clone Ks20.8
Urothelial carcinoma in vagina URO III CK20 CK20: clone Ks20.8 GATA3: clone L50-823 URO III: clone AU1
Granulosa cell tumor in vagina Inhibin Calretinin SF-1 (ovary) SF-1 (ovary) Inhibin: clone R1 Calretinin: clone Calret1 SF-1: clone 1665 (FOXL2)
HGSC met. to cervix WT1 ER p53 mcea WT1: clone 6F-H2 ER: clone 6F11 (also clones SP1 and EP1) p53: clone DO-1 mcea: clone II-7
HGSC met. to cervix Ber-EP4 WT1 WT1: clone 6F-H2 Ber-EP4: clone Ber-Ep4
Take-home message Morphology is the basis for diagnosis There is overlap in the immunophenotype of epithelial lesions in the cervix and corpus Metastases and rare entities should be in the differential diagnosis Molecular methods are likely to play a role in future diagnostics
Acknowledgements IHC lab, Oslo University Hospital Dr. Elin Borgen, MD PhD Inger Johanne Ryen, MSc
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