Brigitte M. Ronnett, M.D. Department of Pathology The Johns Hopkins University School of Medicine Baltimore, MD. Disclosures

Transcription

1 Uterine Adenocarcinomas: Ancillary Techniques in the Distinction of Endometrial and Endocervical Adenocarcinomas and Subtyping of Endometrial Adenocarcinomas Brigitte M. Ronnett, M.D. Department of Pathology The Johns Hopkins University School of Medicine Baltimore, MD Disclosures A reagent (antibody) discussed in this presentation is manufactured by mtm laboratories Inc. Dr. Ronnett is a paid lecturer for mtm laboratories. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Ronnett retains full control and authority over professional material she presents and does not allow the presentation to be subject to prior approval by any commercial interest. "All opinions expressed and implied in this presentation are solely those of Dr. Ronnett. The content of the presentation does not represent or reflect the views of the Johns Hopkins University or the Johns Hopkins Hospital and Health System.

2 Cultural Linguistic Care The Latina population, similar to all women with exposure to HPV and all women who have not had their uterus removed, is at risk for both HPV-related cervical adenocarcinomas and uterine endometrial adenocarcinomas. Accordingly, providers of gynecologic care (clinicians and pathologists) need to be aware of modern diagnostic techniques that can improve the distinction of these different types of adenocarcinomas. Differential Diagnosis of Uterine Adenocarcinomas Determination of site of origin: Endocervical versus endometrial»shared cellular differentiation Endometrioid Mucinous»Shared architecture (glandular, villoglandular) Subtyping of endometrial adenocarcinomas: Endometrioid versus serous»subsets with shared architectural patterns Glandular variants of serous Papillary variants of endometrioid

3 Problematic Aspects of Determining Site of Origin of a Uterine Adenocarcinoma (Endometrium versus Endocervix) Tumors cannot always be distinguished in biopsy and curettage specimens precursors lesions (CAH, AIS) can be lacking both fractions can be positive for carcinoma Tumors involving both lower uterine segment and endocervix in hysterectomy specimens cannot always be assigned a primary site precursor lesions can be lacking (overgrown by CA) growth of carcinoma into adjacent mucosa Distinction of Uterine Adenocarcinomas: Endometrial versus Endocervical Traditional immunohistochemical approach using CEA and vimentin proclaims: VIM+/CEA- endometrial CA VIM-/CEA+ endocervical CA This approach has serious limitations Expression of markers can be focal Staining can be difficult to interpret» CEA: apical/glycocalyceal versus cytoplasmic» Vimentin: in glands versus closely apposed stroma Expression can be opposite of expected results CD10 has no role in determining location/origin of t

4 Diagnosis of Uterine Adenocarcinomas: Determining Site of Origin and Subtype Markers targeting distinctive biologic features of the tumors are more useful Endocervical carcinomas (~90%) are high-risk HPV-related neoplasms [p16] Endometrial endometrioid carcinomas are related to unopposed estrogenic stimulation with complex atypical hyperplasia as a precursor [ER/PR] Serous carcinomas are unrelated to estrogenic stimulation and have a high frequency of p53 mutations [p53] Topics/Objectives Distinction of endocervical and endometrial adenocarcinomas Understand the utility of a biologically relevant immunohistochemical marker panel (ER/PR, p16, HPV ISH) Distinction of endometrial endometrioid and serous carcinomas Understand the utility of a biologically relevant immunohistochemical marker panel

5 Immunohistochemistry for Evaluation of Uterine Adenocarcinomas: p16 Over-expression associated with high-risk HPV: HPV E7 inactivates prb p16 over-expression Diffuse/strong expression expected in high-risk HPV-related endocervical adenocarcinomas Focal/patchy, multifocal, or absent expression expected in most non-hpv uterine adenocarcinomas Endometrial endometrioid carcinomas Minimal deviation type endocervical adenocarcinoma Adenocarcinomas of other types and sites can have diffuse/strong expression unrelated to HPV S i f d t i d Immunohistochemistry for Evaluation of Uterine Adenocarcinomas: p53 Tumor suppressor gene involved in cell cycle regulation Diffuse/strong expression has been associated with p53 mutation in uterine adenocarcinomas Most serous carcinomas» Lack of expression in a subset with p53 mutation (truncated protein not immunoreactive) Subset of high-grade endometrioid carcinomas Varying degrees of weaker/limited expression have been associated with lack of p53 mutation ( wild-type p53 ) Most endometrioid carcinomas All HPV related endocervical carcinomas

6 Immunoprofile of Uterine Adenocarcinomas Marker Endocervical adenocarcinoma (usual HPV+ type) Endometrial endometrioid carcinoma Serous carcinoma (and EIC) ER Negative^ Positive Negative^ PR Negative^ Positive Negative^ p53 Negative (scattered weak) Often negative* (variable) Positive** (diffuse/strong) p16 Positive (diffuse/strong) Positive (patchy) Positive (diffuse/strong) HPV Positive Negative Negative ^minority retain expression [ER>PR]; *high-grade can be positive; **small subset is negative Endocervical adenocarcinoma, usual type (mucinous)

7 Endocervical adenocarcinoma, usual type (endometrioid) Endocervical adenocarcinoma, usual type (hybrid)

8 ER/PR p16

9 HPV ISH AIS

10 p16 HPV ISH

11 Endometrial endometrioid carcinoma (FIGO grade 1)

12 p16 ER/PR

13 Endometrial endometrioid carcinoma (FIGO grade 2)

14 p16 p53

15 Endometrial endometrioid carcinoma (FIGO grade 1)

16 p16 Endometrial endometrioid carcinoma (FIGO grade 1, metaplastic-type)

17 p16

18 p53 Endometrial endometrioid carcinoma (FIGO grade 3)

19 p16 Endometrial endometrioid carcinoma (FIGO grade 3)

20 p16 p53

21 Endometrial endometrioid carcinoma (FIGO grade 3) Endometrial endometrioid carcinoma (FIGO grade 3)

22 p16 p53

23 ER Endometrial serous carcinoma

24 Endometrial serous carcinoma Endometrial serous carcinoma

25 p53 p16

26 Endometrial serous carcinoma Endometrial serous carcinoma

27 p16 p53

28 Endometrial biopsy with adenocarcinoma,?origin/type

29 p16 p53 DX: Endometrial endometrioid carcinoma

30 75 y.o., Endometrial biopsy with adenocarcinoma,?origin/type

31 p16 p53 DX: Serous carcinoma

32 Endocervical biopsy with adenocarcinoma,?origin/type Papillary adenocarcinoma, marked atypia,? serous

33 p53 p16

34 HPV ISH DX: Endocervical adenocarcinoma (usual type) 57 y.o., Endometrial and endocervical curettages with adenocarcinoma (EMC>ECC);?origin/type

35

36

37 ER

38 PR p16

39 HPV ISH DX: Endocervical adenocarcinoma (usual type) Hysterectomy with adenoca, endometrial tumor component

40 Hysterectomy with adenoca, endocervical tumor component

41 ER

42 PR p16

43 p16 HPV ISH DX: Endocervical adenocarcinoma (usual type)

44 Immunoprofile of Uterine Adenocarcinomas Marker Endocervical adenocarcinoma (usual HPV+ type) Endometrial endometrioid carcinoma Serous carcinoma (and EIC) ER Negative^ Positive Negative^ PR Negative^ Positive Negative^ p53 Negative (scattered weak) Often negative* (variable) Positive** (diffuse/strong) p16 Positive (diffuse/strong) Positive (patchy) Positive (diffuse/strong) HPV Positive Negative Negative ^minority retain expression [ER>PR]; *high-grade can be positive; **small subset is negative