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Gynecologic Cancers: Prevention and Early Detection

Gynecologic Cancers: Prevention and Early Detection. Jan Shepherd, MD, FACOG. Objectives. Discuss current theories on the etiologies of common gynecologic cancers Discuss recent evidence regarding risk factors for, early detection of, and prevention of gynecologic cancers

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Gynecologic Cancers: Prevention and Early Detection

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  1. Gynecologic Cancers: Prevention and Early Detection Jan Shepherd, MD, FACOG

  2. Objectives • Discuss current theories on the etiologies of common gynecologic cancers • Discuss recent evidence regarding risk factors for, early detection of, and prevention of gynecologic cancers • Appreciate the pivotal role of all practitioners of women’s health care in improving gynecologic cancer outcomes

  3. What we know about: • Ovarian • Endometrial • Vulvar • Cervical • Epidemiology • Etiology • Risk Factors • Clinical Presentation • Prognosis • Early diagnosis • Prevention

  4. Estimated Cancer Incidence inWomen(US, 2010) • Breast - 28% • Lung – 14% • Colon & rectum – 10% • Endometrium – 6% • Thyroid – 5% • Non-Hodgkin lymphoma – 4% • Melanoma – 4% • Ovary – 3% • #13 Cervix – 1.6%

  5. Estimated Cancer Deaths inWomen(US, 2010) • Lung – 26% • Breast – 15% • Colon & rectum – 9% • Pancreas – 7% • Ovary – 5% • #8 Endometrium – 3%

  6. Ovarian Cancer: Epidemiology • 1/70 to 1/55 women (1.4% lifetime risk) • Leading cause of death from gyn cancer • 70-75% detected at advanced stage • Mean age 61 years

  7. Ovulation and the Ovary

  8. Ovarian CancerRisk Factors • Aging • Nulliparity (frequent ovulation) • Incidence  with parity, breastfeeding, anovulation, OCs • May  with prolonged use of fertility drugs • Environmental factors • Increased in industrialized countries (e.g. asbestos) • Vulvar carcinogens (e.g. talc) • Incidence  1/3 after tubal sterilization • Incidence  with anti-inflammatories (RR.60)1, low-fat diet (RR.60)2, caffeine (RR.80)3 1. Prev Med 2001;33:682-7. 2. J Natl Cancer Inst 2007;99:1534-43. 3. Cancer 2008;112:1169-77.

  9. Ovarian CancerGenetic Risk Factors • Familial tendency • One 1st degree relative – 5% risk (3x normal) • Two 1st degree relatives - 7% risk • Family history of breast or colon cancer • Hereditary cancer syndromes • BRCA1 and BRCA2 • Up to 85% risk of breast and/or ovarian cancer • Autosomal dominant mutations • Lynch Syndrome (HNPCC) • 80% risk of colorectal ca, 71% risk of endometrial, 12% risk of ovarian, also  kidney, stomach, pancreas, brain

  10. Hereditary Cancer Syndromes • Hallmarks • Multiple affected family members • Early onset • Multiple or bilateral cancers in one family member • 20-25% chance of BRCA mutation • Both breast and ovarian ca < age 50 • Ashkenazi Jewish ancestry • 20-25% chance of HNPCC mutation • Both endometrial and colorectal ca < age 50

  11. Guidelines for BRCA Testing Women with > 20–25% chance of having an inherited predisposition to breast and ovarian cancer : • Personal history of both breast and ovarian cancer • Ovarian cancer and a close relative † with breast cancer at ≤ 50 years or ovarian cancer at any age • Ovarian cancer at any age and Ashkenazi Jewish ancestry • Breast cancer at ≤ 50 years and a close relative † with ovarian or male breast cancer at any age. • Breast cancer at ≤ 40 years and Ashkenazi Jewish ancestry • Close relative † with a known BRCA1 or BRCA2 mutation † Close relative is defined as a first, second or third degree relative (i.e. mother, sister, daughter, aunt, niece, grandmother, granddaughter, first cousin, great grandmother, great aunt). Gynecol Oncol 2007;107:159-62.

  12. Guidelines for Genetic Testing • Refer to genetic counselor if possible • Informed consent • Assess risk of unaffected family members • Not recommended for patients < age 21 • If possible, test a cancer patient first to find the known familial mutation  Tailored care now proven to reduce mortality1 1. GynecolOncol 2005;96:222-6.

  13. CasesWho should consider genetic testing? • A 30 year-old g2p2 whose mother had ovarian cancer at age 60. Maternal grandmother had breast cancer at age 75. • A 30 year-old g0 has 2 paternal aunts who had breast cancer in their 40s. Paternal grandmother died of ovarian cancer at 50. • A 20 year-old g0 whose mother age 40 is currently being treated for ovarian cancer.

  14. Ovarian CancerClinical Presentation • Symptoms • Epithelial tumors - thought to be asymptomatic until late • New finding - 95% have symptoms prior to diagnosis1 • Triad – ↑ abdominal girth, abdominal bloating, urinary symptoms: severe and of recent onset • Symptom diary at www.ovariancancer.org 1. Goff BA. JAMA 2004;291:2705-12.

  15. http://www.ovariancancer.org/

  16. Ovarian CancerClinical Presentation • Physical findings • Mass – solid, irregular, fixed, nontender, bilateral • Palpable postmenopausal ovary

  17. Ovarian CancerPrognosis • 5-year survival • Stage I (confined to ovary) – 89.3% • Stage II (confined to pelvis) – 57.1% • Stage III (confined to abdomen) – 23.8% • Stage IV (distant metastases) – 11.6% • Intermittent small bowel obstruction/ascites • Starvation/wasting

  18. Ovarian CancerEarly diagnosis • Pay attention to subtle symptoms • Pelvic exam (must include recto-vaginal) • Detects only 5% of asymptomatic disease • Screening • Only for high-risk women • Efficacy not established • Most effective in postmenopausal women

  19. Ovarian Cancer Screening • Tumor marker - CA 125 • > 200 abnormal in pre, >35 in postmenopausal woman • High false positive rate in premenopausal women • Negative results often misleading • Positive in only 80% of ovarian cancers • Detects only 16-30% of Stage I disease • Potential future tumor markers • Proteomics, reflection of cDNA (e.g. osteopontin) • Multi-marker panels (e.g. recently approved OVA1 – now only for women with suspicious pelvic mass)

  20. Ovarian Cancer: Screening • Transvaginal Ultrasound (+/- Morphologic scoring, Doppler) • High false positive in premenopausal women • More sensitive (81%) and specific (98.9%) in postmenopausal and high-risk women1 • 9.4 surgeries for every cancer detected • Does not detect ca with normal ovarian volume  No effect on mortality Combining CA 125 and U/S may be most effective Gynecol Oncol 2000;77:350-6.

  21. Ovarian Cancer: Screening • Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO Trial - US) • ~ 70,000 women age 55-74, ½ screened with vaginal u/s and CA125 yearly x 4 • 89 patients in screening arm diagnosed - only 60 screen detected • 20 surgeries for every one cancer found • 72% of cancers Stage III Or IV • Mortality data not yet available ObstetGynecol 2009;113:775-82.

  22. Ovarian Cancer: Screening • Collaborative Trail of Ovarian Cancer Screening (UKCTOCS) • ~200,000 women age 50-74, followed for 4 years • ½ no screening • ¼ transvaginal u/s alone • 35 surgeries for every cancer detected • ¼ “Multi-modal screening” - CA 125 + risk factors  transvaginal u/s if suspicious • 50% detected at Stage I, 3 surgeries for every cancer found2 • 4 additional cases in next year (false negatives) • Mortality data not yet available  • Combined screen recommended only for high-risk women Lancet Oncol 2009;10:327-40.

  23. Ovarian CancerPrevention • Refer high-risk patients for genetic testing, if positive: • Increased screening • OCPs • Prophylactic oophorectomy after childbearing1 • Counseling • Awareness of subtle symptoms • Potential risks of talc, ovulation induction • Others: Anti-inflammatory agents? Low-fat diet? Caffeine? • ORAL CONTRACEPTIVES 1. GynecolOncol 2005:96:222-6.

  24. Oral Contraceptives and Prevention of Ovarian Cancer • 40% – 80% decrease in risk • Protection conferred by OCs • Begins with one year of use • Increases with increasing duration of use • Persists nearly 20 years after OCs are stopped CASH Data. N Engl J Med 1987;316:650-5.

  25. Newer Data(Lancet Jan. 26, 2008) “Reduction in risk persisted for > 30 years after OC use had ceased.” Conclusion: OCs “have already prevented some 200,000 ovarian cancers and 100,000 deaths from the disease, and over the next few decades the number of cancers prevented will rise to at least 30,000 per year.”

  26. Oral Contraceptives and Prevention of Ovarian Cancer • Consider OC use for ovarian cancer prophylaxis, especially in high-risk women • 5 years use by nulliparous women reduces risk to that of parous never-users • 10 years use by women with a family history reduces risk to a level below that of negative family history/never-users NIH Consensus Panel. JAMA 1995;273:491-7.

  27. Endometrial CancerEpidemiology • Most common gynecologic cancer (2-3% lifetime risk) • 6% of all cancers in US women • 4th most common cancer in US women • On the rise • Mean age 61 years

  28. Hormonal Changes and the Endometrium

  29. Endometrial CancerRisk Factors • Excess estrogen • Chronic anovulation (especially PCOS) • Obesity (~3x risk), hypertension, diabetes • Nulliparity, late menopause • Unopposed estrogen replacement therapy • Tamoxifen • Genetic (esp. HNPCC  40-60% risk)

  30. Endometrial CancerClinical Presentation • Abnormal vaginal bleeding (90%) • Any bleeding in postmenopausal woman • Increased flow or intermenstrual bleeding, especially in a high-risk woman • Endometrial cells on Pap test • Any in postmenopausal woman (including on HRT) • Atypical endometrial cells at any age • Consider with AGC if over 35 or high risk

  31. Endometrial CancerPrognosis • 5-year survival • Stage I (confined to uterus) – 85% • Stage II (uterus and cervix) – 60% • Stage III (vagina, pelvis) – 30% • Stage IV (bowel, bladder, distant mets) – 10% • 75% diagnosed at Stage I

  32. Endometrial CancerEarly Diagnosis Abnormal Bleeding in Premenopausal Women • Endometrial biopsy for all suspicious AUB • Especially high-risk women • Endometrial hyperplasia – precursor lesion • Can be treated hormonally, esp. if no atypia

  33. Endometrial CancerEarly Diagnosis • Endometrial biopsy or • Endometrial stripe on transvaginal ultrasound • If < 4 mm, biopsy not necessary (unless bleeding persists) • If > 4mm, biopsy required • If unable to perform, or biopsy insufficient  D&C +/- hysteroscopy Any Bleeding in Postmenopausal Women

  34. Endometrial HyperplasiaProgression to Cancer • Simple <1% • Complex ~3% • Atypical • Simple ~6% • Complex ~30% • BUT up to 50% have concurrent endometrial cancer1 follow Bx with D&C/hysteroscopy 1. Cancer 2006;106:812-9.

  35. Precancerous Conditions: Management • TAH and BSO for complex atypical hyperplasia if no future childbearing • Medical options • Oral progestins cyclically or continuously • Depo medroxyprogesterone acetate • Levonorgestrel IUD • Follow up • Repeat biopsy in 3 months • If not converted, increase dose • If converted repeat, biopsy q 6-12 months Will persist in up to ¼ of patients1 1. Obstet Gynecol 2009;113:655-62.

  36. Endometrial CancerPrevention • Always make sure ERT is adequately balanced with progestin • Correct oligomenorrhea, especially in high-risk women • Cyclic medroxyprogesterone, norethindrone, or progesterone • Depo Provera, Levonorgestrel IUC

  37. Oral Contraceptives and Prevention of Endometrial Cancer • Protection conferred by OCs1 • 50% decrease in risk • Begins with one year of use • Increases with increasing duration of use • Persists > 20 years after OCs are stopped • Consider prophylactically in high-risk pts2 1. CASH Study. JAMA 1987;257:796-800. 2. Obstet Gynecol 2008;112:56-63.

  38. Vulvar Cancer (Squamous Cell)Epidemiology • 3-5% of US gynecologic malignancies • Fewer than 1% of all cancers in US women • Mean age 65 years, but decreasing • Incidence increasing, esp. in young women • Doubled from 1973-2003 • Greatest increase in white women < age 35

  39. Vulvar CancerRisk Factors • HPV • History of condylomata • Smoking • Chronic Irritation • Obesity, hypertension, diabetes • Poor hygiene  We are likely seeing two different diseases

  40. Types of Squamous Vulvar Cancer

  41. Vulvar CancerPresentation • Late diagnosis is common due to both patient and clinician delay1 • Symptoms • Often none • Pruritus is most common • Vulvar lesion, sometimes with bleeding or discharge • Physical findings • Vulvar lesion • Ulcerated, fleshy, leukoplakic, pigmented, wartlike • Present for over one month 1. J Reprod Med 1999;44:766-8.

  42. Vulvar CancerPrognosis • 5-year survival related to lymph node spread • Nodes negative – 90% • Positive 24% (5-6 nodes) – 75% (1-2 nodes) • VIN and VIS curable with simple excision • Advanced disease requires disfiguring, debilitating surgery

  43. Vulvar CancerTreatment

  44. Vulvar CancerEarly Diagnosis • Examine all patients with persistent vulvar complaints • Careful vulvar exam with every pelvic • Biopsy all suspicious lesions, especially in high-risk women • Like CIN, VIN can be recognized and treated in precancerous state

  45. Management of VIN • VIN I, Undifferentiated • Most regresses within 9 months  Observe • VIN III, Undifferentiated/Differentiated1 • 87.5 % progress to cancer within 7 years • Laser excision recommended • High cure rate, anatomy preservation, tissue diagnosis • 2-4% develop invasive disease after treatment • Follow-up q 6 mos. X 2 yrs, then annually • Potential role for imiquimod (Off-label)2 1. ObstetGynecol 2005;106:1319-26. 2. N Engl J Med 2008;358:1465-73.

  46. Vulvar CancerPrevention • Clinician attention to vulvar exam/early biopsy • Vulvar self examination • Young women • Safer sexual practices • Avoid smoking • HPV vaccine • Elderly, obese, and debilitated women • Improve hygiene • Recognize and treat vulvar dystrophies (lichen sclerosis, lichen planus, lichen simplex)

  47. Conclusion • Much is known about gynecologic cancers • We can make a difference! • Education • Early detection • Prevention

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