When To Operate for Endometrial Hyperplasia

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When To Operate for Endometrial Hyperplasia David

Faulconer Distinguished Chair in Medical Science

Oncology Professor of Obstetrics & Gynecology

1 When To Operate for Endometrial Hyperplasia David Scott Miller, M.D., F.A.C.O.G., F.A.C.S. Amy and Vernon E. Faulconer Distinguished Chair in Medical Science Director and Dallas Foundation Chair in Gynecologic Oncology Professor of Obstetrics & Gynecology University of Texas Southwestern Medical Center at Dallas

2 Learning Objectives Identify patients at risk for endometrial hyperplasia Incorporate into practice contemporary medical and surgical standards of care for endometrial hyperplasia Prevent endometrial cancer

3 Defining Menopause & Perimenopause A woman s lifetime Perimenopause First signs of change Menopause Diagnosed 12 months retrospectively NAMS. Menopause Curriculum Study Guide Utian, WH. Menopause

4 Endometrial Cancer

5 US Mortality, 2006 Rank Cause of Death No. of deaths % of all deaths 1. Heart Diseases 631, Cancer 559, Cerebrovascular diseases 137, Chronic lower respiratory diseases 124, Accidents (unintentional injuries) 121, Diabetes mellitus 72, Alzheimer disease 72, Influenza & pneumonia 56, Nephritis* 45, Septicemia 34, *Includes nephrotic syndrome and nephrosis. Source: US Mortality Data 2006, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009.

7 CA: A Cancer Journal for Clinicians. Volume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: /caac

8 Cancer Incidence Rates* Among Women, US, Rate Per 100, Breast Colon and rectum Lung & bronchus Uterine Corpus Ovary Non-Hodgkin lymphoma *Age-adjusted to the 2000 US standard population and adjusted for delays in reporting. Source: Surveillance, Epidemiology, and End Results Program, Delay-adjusted Incidence database: SEER Incidence Delay-adjusted Rates, 9 Registries, , National Cancer Institute, 2008.

9 Cancer Death Rates* Among Women, US, Rate Per 100, Uterus Breast Lung & bronchus 20 Stomach Colon & rectum Ovary 0 Pancreas *Age-adjusted to the 2000 US standard population. Source: US Mortality Data , US Mortality Volumes , National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.

10 Cancer Sites in Women for Which African American Death Rates* Exceed White Death Rates*, US, Site African American White Ratio of African American/White All sites Stomach Myeloma Uterine cervix Esophagus Uterine corpus Small intestine Larynx Colon and rectum Pancreas Breast Gallbladder Urinary bladder Liver and intrahepatic bile duct *Per 100,000, age-adjusted to the 2000 US standard population. Source: Surveillance, Epidemiology, and End Results Program, , Division of Cancer Control and Population Sciences, National Cancer Institute, 2008.

11 Epidemiology Known cancer causes Occupational exposure Lifestyle factors Biologic agents Iatrogenic factors Genetic mutations Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;

12 Epidemiology Genetic risk factors: mechanisms of cancer predisposition Germline tumor suppressor gene inactivation Germline oncogene activation DNA repair defects Ecogenetic traits Bale AE, Li FP. Cancer: Principles & Practice of Oncology. 5th ed. 1997;

13 Endometrial Cancer: Annual Incidence and Mortality ACS Estimates Year Cases Deaths ,000 2, ,130 8,010 American Cancer Society 2012

14 Endometrial Cancer: Risk Factors Characteristic Obesity >30 LBS >50 LBS Nulliparous Late Menopause Unopposed Estrogen Atypical Hyperplasia Diabetes Hypertension Relative Risk [X]

18 Risk of Endometrial Cancer With ERT and HRT Cyclic and Continuous <5 Years RR (95% CI) >5 Years RR (95% CI) ERT HRT (cyclic) HRT (continuous) 2.0* ( ) 1.5 ( ) 0.8 ( ) 7.5* ( ) 2.9*( ) 0.2*( ) *CI do not include 1.0. Weiderpass E et al. J Natl Cancer Inst. 1999;91:

19 Endometrial Tumorigenesis Cellular milieu Stem Cell Genetic predisposition?? Multiple Genetic Insults (mutations) PTEN, TP53, KRAS2, other events?? Atypical hyperplasia Loss of DNA mismatch repair Adenocarcinoma

20 HNPCC Increases Colorectal and Endometrial Cancer Risks Up to 80% General Population HNPCC Risk of Cancer (%) >25% 20% Up to 71% 0 0.2% CRC by age 50 2% CRC by age % 1.5% EC by age 50 EC by age 70 Gastroenterology 1996;110: Int J Cancer 1999;81:214-8 Gastroenterology 2004;127:17-25

22 In Summary: 1. Screen for Red Flags Multiple colorectal adenomas Colorectal cancer before age 50 Endometrial cancer before age 50 Two or more HNPCC-related cancers in an individual or family 2. Discuss genetic testing options 3. Establish appropriate medical management plan

23 Endometrial Cancer: Types Type I Estrogen Related Younger and heavier patients Low grade Perimenopausal Exogenous estrogen Type II Aggressive Unrelated to estrogen stimulation Occurs in older & thinner women Potential genetic basis

24 Endometrial Cancer: Types

25 Endometrial hyperplasia Simple hyperplasia Risk for Carcinoma without atypia 1% with atypia 8% Complex hyperplasia without atypia 3% with atypia 29% Kurman et al. Cancer 56:403 85

26 Cancer Risk In Endometrial Hyperplasia Nested case control study at Kaiser. N = 194 Median interval of EH to Ca 6.7 yrs CAH (OR=20.6, 95% CI, ) CH (OR=0.8, 95% CI, ) SH (OR=1.7, 95% CI, ) CAH diagnoses were associated with substantially increased endometrial carcinoma risk, which persisted for over 5 years. Risks associated with SH and CH were similar to those for DPEM Lacey et al. AACR 2007, #4294

27 Atypical Endometrial Hyperplasia AEH dx not confirmed in 61% Ca found in 40% (31% > IA GI) 37% in confirmed AEH 67% with no agreement Zaino et al. Cancer 106: Trimble et al. Cancer 106:812 06

28 EIN and WHO94 Baak & Mutter. J Clin Pathol. 58:1 05

29 EIN vs. WHO Baak et al. Cancer 103:

30 Endometrial Cancer: Screening Patient Primary* Cytology Not satisfactory Histology - Secondary Hysteroscopy Not satisfactory Sonography Cost-effective issue *Patient/physician awareness

31 OMINOUS SIGNS Any bleeding from the genital tract of a woman which occurs after a period of amenorrhoea lasting 6 months or longer at the age of the menopause is regarded a postmenopausal bleeding Menstruation in a woman older than 55 yr Abnormal bleeding at ± menopause

32 Postmenopausal bleeding Definition: bleeding that occurs after 12 months of amenorrhea Sources: Uterine corpus: Endometrial atrophy, endometritis, polyp, endometrial hyperplasia, cancer, sarcoma Uterine Cervix: Polyp, cervicitis, cancer Vagina: Atrophy, infection, cancer, trauma, foreign body Vulva Ulcerations, excoriations, trauma, cancer Urinary tract Urethral caruncle, urethral mucosal prolapse, hematuria Gastrointestinal tract Rectal polyp, hemorrhoids, hematochezia, Other: Metastases, oviduct cancer, endometriosis, Systemic illness Coagulation disorder, hepatic cirrhosis Iatrogenic Anticoagulation, estrogen therapy

33 Postmenopausal Uterine Bleeding 10% of women with postmenopausal bleeding will be diagnosed with endometrial cancer and an equal number with hyperplasia. 1 PMB incurs a 64-fold increased risk for developing endometrial CA.² ¹Karlsson, et al. AJOG 172: ²Gull, et al. AJOG 188:401 03

34 Diagnosis of disease: Patient Awareness* More than 95% of patients with Endometrial Cancer report having symptoms Postmenopausal bleeding Menorrhagia Metrorrhagia Bloody Discharge Endometrial biopsy is the main diagnostic tool performed either in the office or via D&C in OR

35 Post menopausal bleeding ETIOLOGY (%) Exogenous estrogen 30 Atrophy (uterus/vag) 30 Endo. Ca. 15 Polyps 10 Hyperplasia 5 Miscellaneous 10

36 Postmenopausal bleeding Histology Office procedure (Accurette, Pipelle, etc) Formal dilation and curettage Hysteroscopy

37 Numerous sampling devices available Easy to perform Sensitivity 90-95% EMB

38 Endometrial Biopsy

glandular cells on Pap Perimenopausal intermenstrual

39 Who Needs an Endometrial Biopsy? Postmenopausal bleeding Postmenopausal women with atypical glandular cells on Pap Perimenopausal intermenstrual bleeding Abnormal bleeding with history of anovulation Thickened endometrial stripe via sonography

40 Leitao et al. Gyn Onc 113: Comparison of D&C vs EMB

41 Endometrial Cancer: Transvaginal Ultrasound N=250 Diagnosis <5m m Endometrial Stripe Thickness 6-10mm 11-15m m >15m m Atrophy 93% 7% Hyperplasia 58% 42% Polyp 53% 47% Cancer 18% 41% 41% Grigoriou: Maturitus 23:9-14,1996

42 ACOG. Ob Gyn 114:409 09

43 Thin Edometrium

44 Saline-Infusion Sonography Endometrial Sampling Moschos et al. Ob Gyn 113:881 09

45 TVS & EMB for PMB Hanegem et al. Maturitas 68:155 11

46 3D Techniques For Endometrial Hyperplasia & Cancer best predictor of endometrial carcinoma was an endometrial volume of 3.56 cc or more (sensitivity 93.1%, specificity 36.2%) Odeh et al. Gyn Onc 106:348 07

47 Hysteroscopy

48 Accuracy of Hysteroscopy Systematic Quantitative Review of Endometrial Cancer & Hyperplasia Sixty-five primary studies were analyzed, including 26,346 women Positive hysteroscopy result (pooled LR, 60.9; 95% CI, ) increased the probability of cancer to 71.8% (95% CI, 67.0%-76.6%), whereas a Negative hysteroscopy result (pooled LR, 0.15; 95% CI, ) reduced the probability of cancer to 0.6% (95% CI, 0.5%- 0.8%) diagnostic accuracy of hysteroscopy is high for endometrial cancer Clark et al. JAMA 288:

49 PMB: Cost-Effectiveness USS using a 5-mm cutoff was the least expensive Conclusion: PMB should undergo initial evaluation with USS or EB Clark et al. BJOG 113:502 06

50 PMB Recommendations PMB requires assessment to exclude cancer by US or EMB Insufficient EMB requires further evaluation <4mm endometrial stripe does not require EMB >4mm requires further evaluation Unsatisfactory US requires further evaluation Recurrent/persistant PMB requires further evaluation Asymptomatic >4mm requires no further evaluation ACOG. Ob Gyn 114:409 09

51 Comparison of Relative Risks with Tamoxifen Therapy vs. Placebo: NSABP P-1 Fisher et al. JNCI (2005) 97;1652.

52 Tamoxifen and endometrial pathology: to screen or not to screen with TVU? Mean age Duration of Tamoxifen Mean EEC Benign Endometrium 51.8 yrs (+ 10.1) 33.1 mos ( mos) 7.6 mm (+ 3.9) Endometrial Hyperplasia/Ca 50 yrs (+ 7.5) 23 mos ( mos) 8.8 mm (+ 5.0) Median EEC 7 mm 7 mm P value Premenopausal EEC Post menopausal EEC 8.1 mm (+ 3.4) 7.6 mm (+ 4.7) 9.5 mm 0.5 (+ 5.4) 6.0 mm 0.7

53 Tamoxifen and Endometrial Pathology ACOG recommendations Any abnormal uterine bleeding should be investigated in women taking tamoxifen Screening procedures in women with breast cancer undertaking tamoxifen therapy should be performed at the discretion of the gynecologist ACOG. Ob Gyn 107:

54 TVS Doubilet, et al. Menopause 18:421 11

55 EMB Doubilet, et al. Menopause 18:421 11

56 Endometrial Hyperplasia Hyperplasia: without atypia continuous progesterone treatment (e.g. medroxyprogesterone acetate 5 mg daily for three months) followed by repeat histology if normal then, consider hormone replacement therapy

57 Endometrial Hyperplasia Hyperplasia: with atypia Total abdominal hysterectomy and bilateral salpingo-oophorectomy advised

58 Conservative Treatment For Young Women With Atypical Endometrial Hyperplasia Or Adenocarcinoma Jadoul et al. Fert Ster 80:

59 Thermal balloon

61 Endometrial Ablation Methods

62 ACOG. Endometrial ablation Practice Bulletin #81 Obstet Gynecol 109: Endometrial Ablation

64 Mirena And Endometrial Hyperplasia a 3-month study with Mirena vs historical group treated with systemic MPA Treatment of hyperplasia assessed by light microscopy and nuclear morphometric analysis Regression of hyperplasia was observed in 100% of Mirena cases vs 45% treated with MPA Reduction in nuclear size observed with both treatments More obvious in Mirena group in hyperplasia patients with the highest malignant potential (D score = 0 1) a Mirena is not currently licensed for this indication Vereide et al. Gynecol Oncol 2003;92:526 33

65 Endometrial Cancer: Surgical Staging Conceptual rationale Defines extent of disease Minimizes over/under treatment Minimally increases perioperative morbidity/mortality Decreases overall Rx risks and costs Allows comparison of therapeutic results

66 Endometrial Cancer: Nodal Involvement Situation % Positive Nodes G1, no myometrial invasion, no extrauterine disease. <1% G2 or G3, inner 1/3 invasion, no extrauterine disease 5-9% Pelvic 4% Aortic G3, outer muscle, and/or extrauterine disease 20-60% Pelvic 10-30% Aortic

67 Endometrial Cancer: Surgical Approach TAH-BSO/washings only Grades 1, 2* < 50% myometrial invasion* Endometrioid* < 2 cm tumor diameter* *Verified via frozen section

68 Endometrial Cancer: Surgical Approach Complete Surgical Staging* Grade 3 > 50% myometrial invasion >2 cm tumor diameter Serous/clear cell subtypes Advanced stages *TAH-BSO, washings, lymphadenectomy, omental/peritoneal biopsy

69 Laparoscopic Surgical Staging: GOG LAP-II Trial N = 1500 (Goal: 2550) Open: 4/96 Adenocarcinoma or sarcoma Phase III & Quality of Life Stage I/IIA Grade I-III Any Quetelet Index Laparotomy TAH/BSO Surgical Staging Cytology Laparoscopy LAVH/BSO Surgical Staging Cytology

70 Endometrial Cancer: FIGO Surgical Stage

71 Endometrial Cancer: FIGO Surgical Stage

73 GOG #99 Conclusion: strong evidence for RT in high intermediate risk. not recommended for lower risk Take home: RT will cut recurrence from 27% to 13%, death from 26% to 12% in HIR But, increase toxicity 6% to 14% Thus, 100 patients will be treated to benefit 14 Keys et al. Gyn Onc 92:744 04

74 GOG #153: Phase II Alternating Megestrol Tamoxifen for Recurrent or Persistent Endometrial Cancer MEG 80 mg po bid X 3 wks TMX 20 mg po bid X 3 wks 7/94-11/95, n = 56 G 3/4 vascular toxicity = 7% CR 21% + PR 5% = 27% (90% CI: 17-38%), 53% >20 mo. Grade 1-3 ORR: 38, 24, 22% PFS = 2.7, OS = 14, DOR = 28 MO. active... may offer a prolonged complete response Fiorica et al. Gyn Onc 92:10 04

75 Endometrial Cancer: Single Agent Chemotherapy Response Rates Agent Response Agent Response Paclitaxel 37% HMM 17% Carboplatin 28% Vincristine 16% Doxorubicin 26% Etoposide 14% Cisplatin 25% Ifosfamide 14% 5-FU 21% Cytoxan 11% GOG Symposium July 1999 Goff

77 Endometrial Cancer: Survival by Surgical Stage

Management of Endometrial Hyperplasia

Management of Endometrial Hyperplasia I have nothing to disclose. Stefanie M. Ueda, M.D. Assistant Clinical Professor UCSF Division of Gynecologic Oncology Female Malignancies in the United States New