1 Endometriosis & Cancer AssociationPaul Yong, MD, PhD, FRCSC Gynaecologist, VGH/UBC Hospital and BC Women’s Hospital Assistant Professor, UBC Dept of Obstetrics & Gynaecology Research Director, Centre for Pelvic Pain and Endometriosis Member, Ovarian Cancer Research team (OVCARE)
2 Disclosures None
3 Learning objectives Identify the epidemiology and classification of endometriosis State the impact of atypical endometriosis on malignant gynecologic tumours Discuss potential ways to prevent future ovarian cancer in women with endometriosis
4 Learning objectives Identify the epidemiology and classification of endometriosis State the impact of atypical endometriosis on malignant gynecologic tumours Discuss potential ways to prevent future ovarian cancer in women with endometriosis
5 Endometriosis 1 in 10 reproductive-aged women (~1 million in Canada)~$2 billion and ~$50 billion in annual costs in Canada and the United States
6 Endometriosis Definition: EtiologyUterine endometrial tissue, present ectopically elsewhere in the pelvis (or elsewhere) Etiology Retrograde menstruation/Immune Metaplasia Blood/lymphatic dissemination
7 Endometriosis Pathophysiology Lesions Uterus ComorbiditiesEstrogen-dependent (systemic and local) Inflammation (prostaglandins) Genetics (inherited and somatic) Uterus Similar changes as in ectopic lesions Comorbidities Myofascial, Urologic, Gastrointestinal Central sensitization
8 Symptoms Pelvic pain Infertility Asymptomatic Menstrual crampsPainful intercourse (deep) Painful bowel movements Cyclical or chronic pelvic pain Infertility Asymptomatic
9 Classification Anatomic subtype: Stage Superficial Ovarian DeepI/II: minimal-mild III/IV: moderate-severe
10 Superficial endometriosisSuperficially attached to peritoneum Classically pigmented Can have other appearances Red White Increased vascularity
11 Ovarian endometriomasChocolate cysts Virtually pathognomonic at ultrasound and surgery
12 Deep endometriosis Invasive > 5mm Forms “nodules”Can “obliterate” the pouch of Douglas
13 American Society of Reproductive Medicine: Surgical staging of endometriosis<1 cm 1-3 cm >3 cm Peritoneum Superficial 1 2 4 Deep 6 Ovary Right Superficial 16 20 Left superficial POSTERIOR CUL-DE-SAC OBLITERATION Partial Complete 40 ADHESIONS <1/3 Enclosure 1/3 - 2/3 Enclosure >2/3 Enclosure R Filmy Dense 8 L filmy Tube 41 81 L Filmy Key message: The American Society for Reproductive Medicine (ASRM) has developed a classification to allow staging of endometriosis at laparoscopy. Further discussion notes: This type of classification may have limited utility for clinical management since disease stage may not correlate with the patient’s symptoms. It is important to appreciate that the diagnosis and description of disease are highly subjective and will vary among practitioners. Video and image capturing systems allow for objective documentation of disease at laparoscopy. 1 If the fimbriated end of the fallopian tube is completely enclosed, change the point assignment to 16. Staging: Stage I (minimal): 1-5; stage II (mild): 6-15; stage III (moderate): 16-40; stage IV (severe): >40. Revised ASRM Classification. Fertil Steril 1997; 67: 819.
14 American Society of Reproductive Medicine: Surgical staging of endometriosisScoring system for Stages: Poorly correlated to symptoms (and malignancy?) Stage Description Scoring Range Stage I minimal 1-5 Stage II mild 6-15 Stage III moderate 16-40 Stage IV severe >40 Key message: Most communications to health care providers will include a classification of disease as minimal, mild, moderate, or severe, which is described in the ASRM classification system depicted on this slide. Revised ASRM Classification. Fertil Steril 1997; 67: 819.
15 Diagnosis Can be suspected based on history and examSymptoms and/or infertility Tenderness on pelvic exam Diagnosis made by surgery and pathology; or Nodularity on pelvic examination Routine or specialized ultrasound MRI CA-125 can be elevated; but not a diagnostic or screening tool
16 Treatment Hormonal Surgical (laparoscopic) NSAIDEstrogen-progestin contraceptive Progestin (dienogest, norethindrone) Progestin IUD (treatment efficacy can be < 5 yrs) GnRH agonists Surgical (laparoscopic) Conservative: ablation or excision Definitive: hysterectomy +/- BSO
17 Learning objectives Identify the epidemiology and classification of endometriosis State the impact of atypical endometriosis on malignant gynecologic tumours Discuss potential ways to prevent future ovarian cancer in women with endometriosis
18 Other clinical implicationsExtra-pelvic endometriosis (e.g. thoracic) Pregnancy complications (e.g. placenta related) Autoimmune disease (e.g. MS) Coronary heart disease Cancer Ovarian: higher Endometrial and breast: equivocal Cervical: lower
19 What’s the risk of ovarian CA?Risk estimates for endometriosis and ovarian CA
20 Ovarian CA subtypes Endometriosis is a risk factor for clear cell and endometrioid (and low-grade serous?)
21 Atypical endometriosisObservation of histologically atypical endometriosis contiguous with ovarian CA Crowding of cells Increase of nuclear/cytoplasmic ratio NOTE: Other meanings of “atypical” endometriosis “Atypical” ovarian endometriomas on ultrasound “Atypical” appearance at laparoscopy Anglesio and Yong, Clin Obstet Gynecol, in press
22 Atypical endometriosisGenomic evidence that atypical endometriosis is the precursor to endometrioid/clear cell ovarian CA: Shared regions of loss-of-heterozygosity Shared ARID1A mutations (Weigand et al., NEJM) Shared up to 98% of somatic mutations (Anglesio et al., J Path) Suggests that endometriosis can accumulate somatic mutations and become atypical, and eventually transform to ovarian CA Anglesio and Yong, Clin Obstet Gynecol, in press
23 However… Deep endometriosis can also harbour somatic mutations (Anglesio et al., NEJM) But extremely rare for deep endometriosis to become atypical and undergo malignant transformation Thus, there must be role of ovarian micro-environment Anglesio and Yong, Clin Obstet Gynecol, in press
24 Learning objectives Identify the epidemiology and classification of endometriosis State the impact of atypical endometriosis on malignant gynecologic tumours Discuss potential ways to prevent future ovarian cancer in women with endometriosis
25 What’s the risk of ovarian CA?Endometriosis: approx 2 fold increase in risk May be higher with tissue confirmed ovarian endometriosis compared to self-reported history However, this is average risk and likely to be heterogeneous – e.g. estrogen exposure Goal: Identifying the endometriosis patient who is at higher risk for ovarian CA.
26 Crux of the problem Endometriosis Common Time?Atypical endometriosis Uncommon Clear cell or endometrioid ovarian CA
27 Gyne oncologist What the gyne oncologist is likely to seeConcurrent endometriosis found in 30-40% of clear cell ovarian cancer Atypical endometriosis can be seen in this context Sometimes a continuum is seen consisting of endometriosis, atypical endometriosis, and frank carcinoma
28 General gynecologist or family physicianWhat we’re more likely to see Patient with benign ovarian endometrioma 1) What’s the risk of ovarian CA? 2) How can we prevent and who’s at higher risk? Atypical endometriosis found on pathology, in what looked like a benign endometrioma 1) How frequent is this finding? 2) How to manage?
29 General gynecologist or family physicianWhat we’re trying to avoid Published case report Age 24: MIS left ovarian cystectomy endometrioma Age 29: MIS right ovarian cystectomy endometrioma with atypical endometriosis Age 33: MIS bilateral ovarian cystectomies right endometrioid ovarian CA
30 General gynecologist or family physicianWhat we’re more likely to see Patient with benign ovarian endometrioma 1) What’s the risk of ovarian CA? 2) How can we prevent and who’s at higher risk? Atypical endometriosis found on pathology, in what looked like a benign endometrioma 1) How frequent is this finding? 2) How to manage?
31 How can we prevent ovarian CA?Factors that may reduce risk: Hormonal therapy Combined oral contraceptives (dose response) Progestin Progestin IUD Parity (vs. nulliparity or infertility) Tubal ligation (salpingectomy); Hysterectomy Oophorectomy and complete surgical removal of endometriosis
32 Who’s at higher risk of ovarian CA?Examples of women with endometriosis who may be at higher risk for ovarian CA: Problem: we don’t know which of our patients are at genetic risk quintile 4-5 *
33 Case 1 50 year old perimenopausal G0 with symptomatic left sided 5 cm endometrioma Hypertension, Smoker BMI 40 Previous laparotomy, left ovarian cystectomy No previous tubal ligation CA-125: 100 Exam: evidence of Stage IV endometriosis
34 Case 1 Management: Surveillance until menopause?Try hormonal therapy, and surveillance? Surgery (oophorectomy)?
35 Case 1 Surveillance until menopause? Advantages DisadvantagesAvoid surgical risk Disadvantages Will endometrioma resolve, and if so, how long will it take? If endometrioma no longer apparent on ultrasound, is it truly resolved or is there still endometriosis in the ovary that could become atypical?
36 Case 1 Hormonal therapy, with surveillance? Advantages DisadvantagesImprovement in symptoms and reduce size of cyst Chemoprevention Disadvantages Clot risk (if combined estrogen-progestin) If endometrioma no longer apparent on ultrasound, is it truly resolved or is there still endometriosis in the ovary that could become atypical?
37 Case 1 Surgery? (oophorectomy, removal of endometriosis, +/- hysterectomy and bilateral salpingectomy) Advantages Tissue diagnosis Prevention of future ovarian CA? Disadvantages Surgical risk (Stage IV endometriosis)
38 Case 1 Patient opts for surgery: hysterectomy, BSO, complete removal of endometriosis 6 week post-op visit: Patient presents with significant hot flushes. What type of HRT? Estrogen and Progesterone Hum Reprod Update 23(4):
39 General gynecologist or family physicianWhat we’re more likely to see Patient with benign ovarian endometrioma 1) What’s the risk of ovarian CA? 2) How can we prevent and who’s at higher risk? Atypical endometriosis found on pathology, in what looked like a benign endometrioma 1) How frequent is this finding? 2) How to manage?
40 Atypical endometriosis in (benign) endometriomaHow frequent? Risk of atypical endometriosis in ovarian endometriosis approx 1-2% (4/255) How to manage? No guidelines Possibilities: Surveillance? Hormonal therapy? Repeat surgery? Histopathology 1997;30:249-55
41 Case 2 30 year old, G0, with infertilityHistory/physical suspicious for endometriosis AMH = 2.0 ng/mL Workup shows 5cm right endometrioma Patient opts for laparoscopy, cystectomy done Pathology: right endometrioma with evidence of atypical endometriosis, no malignancy Post-operative U/S: 1cm “follicle” in right ovary
42 Case 2 Management? Expectant and try for pregnancy, re-evaluate postpartum? Hormonal therapy and proceed to ART, then re-evaluate postpartum? Oophorectomy, then try for pregnancy?
43 Case 2 Expectant and try for pregnancy, re-evaluate postpartum?Advantages Preserve fertility, spontaneous conception Disadvantages Residual atypical endometriosis present?
44 Case 2 Hormonal therapy and proceed to ART, then reevaluate post-partum? Advantages Chemoprevention Preserve fertility Disadvantages Residual atypical endometriosis present? ART required (e.g. cost)
45 Case 2 Oophorectomy, then try for pregnancy? Advantages DisadvantagesPrevention of ovarian CA? Disadvantages Loss of ovary – but AMH reasonable and could conceive from other ovary
46 Case 2 Patient opts for oophorectomy, conceives spontaneously from remaining ovary 6 week post-partum visit: Patient asks about spacing next pregnancy. What type of family planning? Hormonal (estrogen-progestin or progestin)
47 Take home points Identify the epidemiology and classification of endometriosis Endometriosis is common, and the ovarian subtype appears to be at risk for malignant transformation
48 Take home points State the impact of atypical endometriosis on malignant gynecologic tumours Genomic evidence that endometriosis can become atypical, which is a precursor to ovarian CA (clear cell or endometrioid)
49 Take home points Discuss potential ways to prevent future ovarian cancer in women with endometriosis Possibilities: Hormonal therapy, Parity, Tubal ligation (Salpingectomy), Hysterectomy, Oophorectomy, Complete surgical removal of endometriosis
50 Questions? Email: [email protected] or [email protected]BC Women’s Centre for Pelvic Pain and Endometriosis: