6/5/2010. Outline of Talk. Endometrial Alterations That Mimic Cancer & Vice Versa: Metaplastic / reactive changes. Problems in Biopsies/Curettages

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1 Outline of Talk Endometrial Alterations That Mimic Cancer & Vice Versa: Problems in Biopsies/Curettages Metaplastic / reactive changes Mucinous change Microglandular hyperplasia-like change Squamous metaplasia Papillary metaplasia Arias Stella / clear cell / hobnail change Evaluating hormonally treated atypia/cancer Joseph Rabban MD MPH Associate Professor Atypical changes in endometriosis Grade 1 Endometrioid Adenocarcinoma Minimal Diagnostic Criteria Atypical Hyperplasia (WHO System) Diagnostic Criteria Kurman et al. Cancer 1985; Architecture: Gland Fusion Loss of Endometrial Stroma Expansive Labrynthine Pattern Atypical Cytology: Enlarged nuclei Round, oval nuclei Vacuolated chromatin Nucleoli Loss of polarity 1

2 Outline of Talk Metaplastic / reactive changes Mucinous change Microglandular hyperplasia-like change Squamous metaplasia Papillary metaplasia Arias Stella / clear cell / hobnail change Evaluating hormonally treated atypia/cancer Atypical changes in endometriosis Clinical Correlation Red Flags in EMB with Benign Findings Post-menopausal patient Thickened endometrial stripe on ultrasound Uterine mass on imaging Prior history of atypical hyperplasia or cancer Morphologic Red Flags in EMB with Benign Findings: Foamy histiocytes in endometrial stroma Atypical hyperplasia Endometrioid adenocarcinoma Abundant necrosis Degenerative or neoplastic origin Is sampling representative of target? Outline of Talk Metaplastic / reactive changes Mucinous change Microglandular hyperplasia-like change Squamous metaplasia Arias Stella / hobnail change Evaluating hormonally treated atypia/cancer Atypical changes in endometriosis 2

3 Mucinous Change in Endometrium Mucinous endometrium with gland complexity Intracytoplasmic mucin without gland complexity Within spectrum of normal endometrium In degenerating endometrium (breakdown) Mucinous endometrium with gland complexity Possibly tip of the iceberg of adenocarcinoma Risk of unsampled cancer Risk in EMB: unsampled adenocarcinoma (up to 64% to 100%) Typically low grade Mucinous or endometrioid adenocarcinoma Confined to endometrium Risk is a function of architectural complexity Cribriform pattern, rigid pseudolumens Microglandular pattern Villous / papillary pattern Extensive glandular budding Nucci et al. Mod Pathol 1999; 12:1137 Vang et al. Int J Surg Pathol 2003; 11: 261 Mucinous proliferation in EMB Mucinous proliferation in EMB 3

4 Architectural complexity raises further concern despite lack of cytologic atypia EMB: Mucinous proliferation Hysterectomy: Mucinous adenocarcinoma Architectural complexity raises further concern despite lack of cytologic atypia Architectural complexity raises further concern despite lack of cytologic atypia 4

5 Architectural complexity raises further concern despite lack of cytologic atypia Foamy stromal histiocytes raise further concern Foamy stromal histiocytes raise further concern EMB: Mucinous proliferation with foamy histiocytes Hysterectomy: Mucinous adenocarcinoma 5

6 Recommended Diagnosis: Differential Diagnosis of Mucinous Glands in EMB Complex mucinous glandular proliferation. Comment: Discuss risk of unsampled cancer. Provide references: Nucci et al. Mod Pathol 1999; 12:1137 Vang et al. Int J Surg Pathol 2003; 11: 261 Normal endocervical mucosa Endocervical adenocarcinoma, intestinal type Non-GYN mucinous adenocarcinoma Colorectal/upper GI Pancreas Lung Endocervical adenocarcinoma, intestinal type Signet ring colorectal / gastric cancer in EMB 6

7 Outline of Talk Microglandular hyperplasia-like changes in EMB Metaplastic / reactive changes Mucinous change Microglandular hyperplasia-like change Squamous metaplasia Arias Stella / hobnail change Evaluating hormonally treated atypia/cancer Atypical changes in endometriosis Endocervix with MGH Typical MGH Atypical MGH MGH-like uterine adenocarcinoma Typically mucinous or endometrioid cancer MGH-like change is at surface/periphery Often post-menopausal patients MGH involving endocervical polyp Typical MGH of Endocervix 7

8 Atypical MGH of Endocervix Solid MGH of Endocervix Solid / sheet like pattern (mimic clear cell carcinoma) Reticular pattern ( mimic yolk sac tumor) Myxoid stroma (creates pseudoinfiltrative appearance) Mitoses (<1 per 10 hpf) Mild atypia Young et al. Am J Surg Pathol 1989: 13:50 Solid MGH of Endocervix MGH-like Endometrial Adenocarcinoma Clinical Post-menopausal age Not linked to exogenous hormone use Morphology Mucinous or endometrioid adenocarcinoma Grade 1, Stage 1A MGH-like changes at tumor surface / periphery Zaloudek et al. Int J Gyn Pathol 1997; 16: 52 Young et al. Am J Surg Pathol 1992;16:

9 Mucinous adenocarcinoma with MGH-like surface MGH-like proliferation Mucinous adenocarcinoma with MGH-like surface MGH-like proliferation 9

10 Mucinous adenocarcinoma with MGH-like surface Mucinous adenocarcinoma with MGH-like surface MGH-like carcinoma is deceptive in EMB MGH-like morphology: benign or malignant? 10

11 MGH-like morphology: depends on sampling MGH-like Findings in EMB Recommended Approach: Use caution before reporting endocervical MGH in EMB especially in post-menopausal women Unless clear cut evidence of endocervical tissue associated with the MGH-like changes: Report as MGH-like proliferation Comment on sampling issue and DDX Outline of Talk Squamous Metaplasia in EMB Metaplastic / reactive changes Mucinous change Microglandular hyperplasia-like change Squamous metaplasia Arias Stella / hobnail change Evaluating hormonally treated atypia/cancer Atypical changes in endometriosis Squamous metaplasia (non-morular) Morular squamous metaplasia Keratin granulomas outside of uterus 11

12 Squamous differentiation in benign EMB Squamous differentiation in malignant EMB Squamous Metaplasia (non-morular) in EMB Isolated, focal, scattered distribution? reactive to irritation, trauma, infection No significance on its own Differential diagnosis: Placental site nodule Extension of cervical dysplasia/carcinoma Endometrial squamous cell carcinoma Ichthyosis uteri Placental Site Nodule Epithelioid cells embedded in hyaline nodule Positive keratin, inhibin, PLAP 12

13 Endometrial Extension of Cervical HSIL Myometrial Invasion by Cervical Squamous Cell Carcinoma Ichthyosis Uteri Rare benign alteration Stratified proliferation of benign squamous cells replacing endometrium Associated with: chronic endometritis heat ablation of endometrium Squamous Squamous Placental Ichthyosis Metaplasia Dysplasia Site Nodule Uteri Distribution Focal Diffuse Atypia None Present None None Mitoses None/rare Present None None Hyaline stroma Present 13

14 Morular metaplasia in EMB Morular metaplasia in EMB Well-defined circumscribed solid round nests Squamous differentiation (cytologically bland) Fill and expand underlying existing glands Central necrosis common Most common: Less common: atypical hyperplasia grade 1 adenocarcinoma hyperplasia atypical polypoid adenomyoma Significance Risk of subsequent carcinoma: 5% of morules in non-atypical hyperplasia 19% of morules in atypical endometrium Interpretation: Lin et al Mod Pathol 2009; 22: 167 Based on the surrounding glands non-atypical hyperplasia or proliferative pattern? atypical hyperplasia? adenocarcinoma? Not based on the morule itself Crowded glands + squamous morules 14

15 Diagnosis Depends on Glandular Epithelium Not Squamous Cells Differential Diagnosis of Morular Metaplasia Atypical Polypoid Adenomyoma Epithelioid Uterine Smooth Muscle Tumor Epithelioid Trophoblastic Tumor Uterine PEComa Cervical Squamous Dysplasia/Cancer Atypical Polypoid Adenomyoma Unique Clinical Entity Typically years old Lower uterine segment Exophytic/polypoid growth Limited recurrent potential Local excision Polypoid glandular proliferation Foci of atypical hyperplasia Myoid / fibromyoid stroma Squamous morules Central necrosis Atypical Polypoid Adenomyoma 15

16 Atypical endometrium in APA Morules in APA Morules in APA Myoid stroma in APA 16

17 Differential Diagnosis of Morular Metaplasia Epithelioid Leiomyoma Atypical Polypoid Adenomyoma Epithelioid Uterine Smooth Muscle Tumor Epithelioid Trophoblastic Tumor Uterine PEComa Rare! Cervical Squamous Dysplasia/Cancer Epithelioid Leiomyoma Epithelioid Trophoblastic Tumor 17

18 Epithelioid Trophoblastic Tumor Uterine PEComa HMB45 Uterine PEComa Desmin Peritoneal Keratin Granulomas Granulomatous peritonitis admixed with Keratin Anucleate squamous cells No adenocarcinoma Patients with endometrioid adenocarcinoma Uterus (or uterine APA) Ovary Tube Significance: None (in the absence of adenocarcinoma in granuloma) Do not upstage AJCC/FIGO based on this alone 18

19 Peritoneal Keratin Granulomas Peritoneal Keratin Granulomas Peritoneal Keratin Granulomas Other Origins of Peritoneal Keratin Granulomas GYN endometrioid adenocarcinoma Ruptured ovarian teratoma squamous epithelium spilled into peritoneum Spilled amniotic fluid (vernix caseosa peritonitis) traumatic C-section Peritoneal squamous metaplasia without granulomas Intraperitoneal renal-dialysis 19

20 Vernix Caseosa Peritonitis ( reaction to spilled amniotic fluid) Squamous Metaplasia of Peritoneum Peritoneal dialysis Peritonitis Hosfield et al. Int J Gyn Pathol 2008; 27: 465 Outline of Talk Metaplastic / reactive changes Mucinous change Microglandular hyperplasia-like change Squamous metaplasia Arias Stella / hobnail change Evaluating hormonally treated atypia/cancer Atypical changes in endometriosis Atypical Hyperplasia / Grade 1 Endometrioid Adenocarcinoma Surgery Management Options Non-surgical: High Dose Progestin Pre-menopausal desiring fertility Poor surgical candidate 20

21 High dose Progestin Therapy High dose Progestin Therapy Oral progestin or progesterone-releasing IUD Down-regulates ER Success in 60-70% patients May take up to 9-12 months to achieve success Interval 3 month surveillance samplings Progestin Start Atypia EMB EMB EMB 3 months 6 months 9 months No atypia Successful No Surgery Progestin Start Atypia Atypia High dose Progestin Therapy EMB EMB EMB 3 months 6 months 9 months Atypia Cancer Pathology of Interval Samples on Progestin What do we need to report? Presence or absence of atypical findings Comparison to original EMB and prior surveillance EMB Quantity of atypia: More / same / less Quality of atypia: Worse / same / less Hysterectomy 21

22 Pathology of Interval Samples on Progestin Pathology of Interval Samples on Progestin Progestin effects on atypia / cancer Reduction in architectural complexity Reduction in cytologic atypia Reduction in quantity of abnormalities Successful end point: No residual atypical findings Decidualized stroma Sparse, atrophic benign glands Atypical Architecture Crowding Papillary / branching Fusion Cribriform Atypical Cytology Nucleoli Coarse chromatin Any 1 feature: Residual Disease Wheeler et al. Am J Surg Pathol 2007; 31: 988 Residual Disease on High dose Progestin Therapy Residual Disease on High dose Progestin Therapy Progestin Start EMB EMB EMB Progestin Start EMB EMB EMB 3 months 6 months 9 months 3 months 6 months 9 months continue Progestin 40% will be successful unlikely successful 40% will be successful unlikely successful Hysterectomy Wheeler et al. Am J Surg Pathol 2007; 31:

23 Successful Progestin 6 months Complex atypical hyperplasia No residual gland crowding Successful Progestin 6 months No gland crowding, irregular shapes or cytologic atypia Residual Disease in Interval Samples on Progestin Pre Treatment Progestin, 3 months Progestin, 10 months Any 1 Feature Atypical Architecture Crowding Papillary / branching Fusion Cribriform Atypical Cytology Nucleoli Coarse chromatin may not be present Wheeler et al. Am J Surg Pathol 2007; 31:

24 Residual Disease in Interval Samples on Progestin Complex Atypical Hyperplasia 36 y woman desires fertility preservation May not fullfill WHO criteria for atypia May look like benign polyp or crowding May look cytologically bland BUT..patient needs continued therapy Residual Progestin-treated atypical 4 months Residual Progestin-treated complex atypical 4 months atypical nuclei non-atypical nuclei 24

25 Residual Progestin-treated complex atypical months Residual crowding without cytologic atypia is still abnormal and requires continued therapy Squamous metaplasia in residual disease on Progestin Squamous metaplasia in residual disease on Progestin 25

26 Squamous metaplasia in residual disease on Progestin Squamous metaplasia in residual disease on Progestin Morules do not express hormone receptors Reporting Surveillance EMB on Progestin Residual Progestintreated hyperplasia ER PR Avoid a premature message of success WHO criteria may not be met by abnormalities that still require treatment. 26

27 Reporting Surveillance EMB on Progestin Decidualized Stroma: A Red Flag in Otherwise Benign Non-secretory EMB If no residual disease: be descriptive If residual disease persists If it meets WHO criteria for atypia/cancer Residual treated adenocarcinoma Residual treated atypical hyperplasia Compare to prior EMB If it does not meet WHO criteria Residual treated atypical glandular proliferation Comment and compare to prior EMB Common reasons to have decidualized stroma: Contraception (oral or IUD) Hormone replacement therapy Treatment of atypia / cancer Outline of Talk Alterations in Endometriosis Metaplastic / reactive changes Mucinous change Microglandular hyperplasia-like change Squamous metaplasia Arias Stella / hobnail change Evaluating hormonally treated atypia/cancer Atypical changes in endometriosis Proliferative / architectural alteration: Hyperplasia with or without atypia Polypoid endometriosis Borderline mucinous tumor Adenocarcinoma (Endometrioid / Clear Cell) Adenosarcoma / Endometrial stromal tumor Non-proliferative / cytologic alteration: Nuclear atypia without hyperplasia 27

28 Endometriosis May Give Rise to Adenocarcinoma Atypia May be Seen in Transition to Cancer Atypical Hyperplasia May Arise in Endometriosis Clinical Significance of Atypia in Endometriosis When There is No Cancer and No Hyperplasia? Non-proliferative endometriosis with: Variable Nuclear Enlargement Variable Nuclear Shapes Nucleoli Hobnail Pattern Clear Cytoplasm 28

29 Atypia without hyperplasia in endometriosis Atypical Endometriosis (without hyperplasia) Atypical cytology: Nuclear enlargement Nucleocytomegaly Hyperchromasia Tiny nucleoli Significance: Smudged / degenerative chromatin None Follow up advised Seidman et al. Int J Gynecol Pathol 1996;15:1 Czernobilsky et al. Obstet Gynecol 1979; 53:318 Atypical Endometriosis: Nucleoli Atypical Endometriosis: Smudged chromatin 29

30 Atypical Endometriosis Clear cytoplasm Hobnail Pattern Mucinous change in Endometriosis Tubal (Ciliated) Metaplasia in Endometriosis Not Atypical 30

31 Squamous Metaplasia in Endometriosis Squamous Metaplasia in Endometriosis: Consider Extra Sampling to Exclude Cancer Atypical endometriosis and inflammation: Reactive etiology? Atypical endometriosis and inflammation: Reactive etiology? 31

32 Atypical endometriosis and inflammation: Reactive etiology? Atypia without hyperplasia in endometriosis Differential Diagnosis Reactive atypia Serous carcinoma in endometriosis Clear cell carcinoma in endometriosis Severe atypia + brisk mitoses in endometriosis Serous Carcinoma Severe atypia + brisk mitoses in endometriosis Serous Carcinoma p53 32

33 Clear cytoplasm + papillary buds + nuclear atypia in endometriosis Need to exclude Clear Cell Carcinoma Clear cell carcinoma arising in endometriosis Atypia without hyperplasia in endometriosis Endometriosis Adenocarcinoma Check how much of tissue is sampled Peritoneal biopsy or Oophorectomy? Consider additional sampling to exclude cancer 33

34 Recommended Diagnosis: Outline of Talk Atypical endometriosis. Comment: No hyperplasia or cancer Advise follow-up References: Seidman et al. Int J Gynecol Pathol 1996;15:1 Czernobilsky et al. Obstet Gynecol 1979; 53:318 Metaplastic / reactive changes Mucinous change Microglandular hyperplasia-like change Squamous metaplasia Arias Stella / hobnail change Evaluating hormonally treated atypia/cancer Atypical changes in endometriosis 34