Conflict of interest. Gynecologic Pathology. Gynecologic Pathology

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1 The role of immunohistochemistry in surgical pathology of the uterine corpus and cervix, vagina and vulva Conflict of interest None (but the ovary is my favorite organ) Ålborg, June 10, 2015 Prof. Ben Davidson, MD PhD Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway Gynecologic Pathology Vulva Vagina Cervix Corpus uteri Ovary/fallopian tube/peritoneum Vulva Vagina Cervix Corpus uteri Gynecologic Pathology Morphology is the basis for correct diagnosis

2 Vulva Low-grade squamous intraepithelial lesion High-grade squamous intraepithelial lesion (Usual VIN) Differentiated VIN Squamous cell carcinoma Basal cell carcinoma Paget disease and invasive adenocarcinomas Melanoma Soft tissue tumors Other Vagina Low-grade squamous intraepithelial lesion High-grade squamous intraepithelial lesion Squamous cell carcinoma Adenocarcinoma (clear cell; mesonephric; other) Melanoma Soft tissue tumors Metastases 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 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

3 Usual VIN vs. reactive p16 Primary epithelial tumors of the vulva, vagina and cervix p16: clone E6H4 SIL vs. reactive Ki-67 AIS vs. hyperplasia and reactive changes Ki-67 p16: clone E6H4 Ki-67: clone MIB1 p16 p16: clone E6H4 Ki-67: clone MIB1 p16 p53: clone DO-1

4 Paget disease CK7 Paget disease CK8 Melan A: clone A103 HMB45: clone HMB45 CK7: clone OV-TL-12/30 CK8: clone C51 CEA: clone II-7 GCDFP-15 (AP-15): clone 23A3 Her-2: clone 4B5 Melan A HMB-45 Adenocarcinoma (Bartholin gland) Adenocarcinoma (Bartholin gland) CK7 CK7 mcea mcea CK18 CK18 mcea: clone II-7 CK7: clone OV-TL 12/30; CK18: clone DC-10

5 Basal cell carcinoma Ber-EP4 EMA Ber-EP4: clone Ber-EP4; CK14: clone LL02; CK17: clone E3 Ber-EP4: clone Ber-EP4; EMA: clone E29 Other: p16: equivocal; HPV analysis: useful DD with trichoepithelioma: more overlap Cervix adenoca. vs. SqCC vs. ASq ca. SqCC p40 p63 CK5/6 CK8 Ber-EP4 CK8: clone C51 Ber-EP4: clone Ber-EP4 CK5/6: clone D5/16B4 p63: clone 4A4 p40: rabbit polyclonal Not useful CEA p16 CK7

6 Carcinoma, NOS Neuroendocrine carcinoma CK8 Ber-EP4 CK5/6 Chromogranin A Synaptophysin p40 p63 Synaptophysin: clone 27G12 Chromogranin A: clone MAB5268 Avoid CD56 Mesonephric carcinoma CD56 CD56 HGSC EMA: clone E29 Vimentin: clone 3B4 Calretinin: clone Calret1 CD10: clone 56C6 (PAX8, TTF1, p16: +/-) (mcea, ER, PR: negative)

7 Mesonephric carcinoma EMA p16 PAX8 Primary epithelial tumors of the uterine corpus EMA: clone E29 Vimentin: clone 3B4 CA 125: clone M11 p16: clone E6H4 PAX8: rabbit polyclonal CA 125 Vimentin Endometrioid Serous Endometrial carcinoma Clear cell Matias-Guiu and Davidson, Virchows Arch 2014;464:

8 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 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 HNF1β: polyclonal rabbit; positive in CCC and some EC, usually negative in SC Vimentin: clone 3B4; positive in EC, negative in SC and CCC 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 (IMP2, IMP3: positive in SC) Serous carcinoma Serous carcinoma p16 p53 ER p16 p53 p16: clone E6H4 p53: clone DO-1 ER: clone 6F11 p16: clone E6H4 p53: clone DO-1

9 Clear cell carcinoma Endometrioid and clear cell carcinoma HNF1β p53 p16 HNF1b mcea Vimentin ER PR ER PR p53 ER: clone 6F11 PR: clone 16 p16: clone E6H4 p53: clone DO-1 mcea: clone II-7 HNF1β: polyclonal rabbit Vimentin: clone 3B4 ER: clone 6F11 PR: clone 16 p53: clone DO-1 HNF1β: polyclonal rabbit ER Endometrioid/serous carcinoma PR Serous ARID1A Endometrioid p53 p16 Clear cell Clear cell ER: clone 6F11 PR: clone 16 p16: clone E6H4 p53: clone DO-1 ARID1A: rabbit polyclonal

10 Serous PTEN Serous IMP2 & IMP3 (experimental) IMP2 IMP2 IMP3 IMP3 Endometrioid Endometrioid IMP3 IMP3 IMP3 PTEN: clone 6H2.1 IMP2: rabbit polyclonal IMP3: clone N-19 Clear cell carcinoma - cervix p53 mcea Soft tissue tumors HNF1β Napsin p16 p16: clone E6H4 p53: clone DO-1 HNF1β: polyclonal rabbit Napsin A: clone TMU-Ad02

11 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 Sub-optimal! ESS vs. LMS ESS vs. LMS ESS with sex cord pattern SMA - ESS Desmin - LMS AE1/AE3 Vimentin Inhibin ER CD10 H-Caldesmon - ESS Pan-cytokeratin: clone AE1/AE3 Vimentin: clone 3B4 Inhibin: clone R1 ER: clone 6F11 (also clones SP1 and EP1) CD10: clone 56C6

12 CD10 Potential markers? ESS LMS Small cell sarcoma Small cell sarcoma Davidson et al., Gynecol Oncol 2013;128: 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 sarcoma with RMS areas Myf-4 HG Cyclin D1 HG Actin Desmin Myogenin Cyclin D1 LG Cyclin D1: clone SP4 Myf-4: clone LO26 Myogenin: clone F5D

13 PECOMA LMS vulva Ki-67 HMB-45 HMB-45 h-caldesmon Desmin Actin SMA Ki-67: clone MIB1 HMB-45: clone HMB45 h-caldesmon: clone h-cd Desmin: clone D33 Actin: clone HHF35 SMA: 14D Complete mole p57 Trophoblastic tumors p57: clone 25B2

14 Partial mole Epithelioid Trophoblastic Tumor (ETT) p57 PLAP p63 hpl p57: clone 25B2 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

15 HCG-producing SqCC EMA Other CK5/6 CK8 HCG EMA: clone E29 CK5/6: clone D5/16B4 CK8: clone C51 HCG: rabbit polyclonal Melanoma HMB45 Melanoma Melan A Melan A: clone A103 HMB-45: clone HMB45 S100: polyclonal rabbit Vimentin: clone 3B4 Pan-cytokeratin: clone AE1/AE3 AE1/AE3 Vimentin

16 Diffuse large B-cell lymphoma CD20 Myelosarcoma CD15 CD79a MUM1 PAX5 MPO Ki-67 CD68 CD20: clone L-26 CD79a: clone JCB-117 MUM1: clone MUM1p PAX5: clone 24/PAX5 CD15: clone Carb-3 MPO: rabbit monoclonal Ki-67: clone MIB1 CD68: clone KP-1 Vaginal recurrence of endometrial carcinoma ER PR Local extension and metastasis 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

17 Lobular breast ca. Appendiceal NET in cervix 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 Urothelial carcinoma in vagina mcea mcea CK20 Synaptophysin CDX2 Chromogranin A URO III CK20 Synaptophysin: clone 27G12 Chromogranin A: clone MAB5268 mcea: clone II-7 CDX2: clone DAK-CDX2 CK20: clone Ks20.8 CK20: clone Ks20.8 GATA3: clone L URO III: clone AU1

18 Granulosa cell tumor in vagina Inhibin HGSC met. to cervix WT1 Calretinin SF-1 (ovary) SF-1 (ovary) ER p53 mcea Inhibin: clone R1 Calretinin: clone Calret1 SF-1: clone 1665 (FOXL2) WT1: clone 6F-H2 ER: clone 6F11 (also clones SP1 and EP1) p53: clone DO-1 mcea: clone II-7 HGSC met. to cervix Take-home message Ber-EP4 WT1 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 WT1: clone 6F-H2 Ber-EP4: clone Ber-Ep4

19 Acknowledgements Thank you for your attention IHC lab, Oslo University Hospital Dr. Elin Borgen, MD PhD Inger Johanne Ryen, MSc

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