GYNECOLOGIC CANCER Edward L. Cohen, MD Chief Section of Gynecology Department of Surgery VA Palo Alto Healthcare System And Associate Clinical Professor OB/Gyn Stanford University School of Medicine

GYNECOLOGIC CANCER Annual Meeting NOVA Milpitas California 26 January 2008

GYNECOLOGIC CANCER Endometrium Most common gyn cancer in the US 6% of all cancer in women 2-3% lifetime risk

GYNECOLOGIC CANCER Endometrium Age Mean is 61 yrs. Menopausal 75-80% Pre-menopausal 20-25% ~5% <40 yrs old.

GYNECOLOGIC CANCER Endometrium Types Endometrioid 89% Adeno-squamous 4% Papillary Serous 3% Clear cell

GYNECOLOGIC CANCER Endometrium Prognosis depends on cell type, grade, and stage. Overall, endometrioid has a better prognosis than adeno-squamous, papillary serous, or clear cell.

GYNECOLOGIC CANCER Endometrium Increased risk factors Age Estrogen Obesity Diabetes (Type II) PCOS Late menopause (>55yr) (Define menopause) Nulliparity Tamoxifen Hereditary nonpolyposis colorectal cancer (HNPCC)

GYNECOLOGIC CANCER Endometrium Risk factors and RR Estrogen 10 (3-15) Obesity 3-4 Diabetes 2.8 PCOS 3 Late menopause 2 Nulliparity 2 Tamoxifen Increase of 6/1000 (Decrease breast 121/1000) HNPCC 40-60% lifetime risk

GYNECOLOGIC CANCER Endometrium Decreased risk factors: --Add progestin to ERT (RR=1) --Use of OCPs for at least 12 mos (RR=0.5). Effect lasts at least 15 years. --Exercise—decreases obesity and favorable changes in immune function and sexual and metabolic hormone levels and growth factors --Diet of fresh fruit, vegetables, whole grain foods

GYNECOLOGIC CANCER Endometrium—Risk Factors Estrogen (unopposed) Exogenous ERT Tamoxifen Endogenous Chronic anovulation PCOS and obesity

GYNECOLOGIC CANCER Endometrium Exogenous estrogen ERT effects can be reversed by addition of a progestin. Tamoxifen and SERMs Receptors differ in breast and endometrium. Stimulates endom.

GYNECOLOGIC CANCER Endometrium Endogenous Chronic anovulation (PCOS and obesity) means no progesterone in premenopausal women. Obesity:--Adrenal precursors to E1 and E2 --Decreased SHBG --Increased insulin-like GF

GYNECOLOGIC CANCER Endometrium—Risk Factors HNPCC (Lynch Syndrome II) is a mutation of “DNA mismatch repair” genes MLH1, MSH2 & 6, and PMS2 most often. High risk for tumors of endometrium, ovary, stomach, small bowel, hepato- biliary system, urologic system. In half of the women, endometrial and ovarian cancer PRECEDE colon cancer.

GYNECOLOGIC CANCER Endometrium HNPCC should be considered if hx of three relatives with colorectal, endometrial, small bowel, urologic system One first degree relative Two successive generations At least one under age 50.

GYNECOLOGIC CANCER Endometrium Presentation—Abnormal Bleeding EVEN ONE DROP OF BLOOD IN A MENOPAUSAL WOMAN NOT ON HORMONES DEMANDS WORKUP 10-20% will have endometrial cancer, and probability increases with age.

GYNECOLOGIC CANCER Endometrium Screening should be sensitive early in the disease so clinical course can be altered. It should be specific to reduce women needing diagnostic tests. Decreased sensitivity means higher false negative Decreased specificity means higher false positive

GYNECOLOGIC CANCER Endometrium Screening Methods: As no reliable, inexpensive, non invasive method exists, screening in asymptomatic women is not warranted. 90% have abnormal bleeding, and about 70-75% of women are stage I if we test only after symptoms arise. 5 year survival is 90-95%.

GYNECOLOGIC CANCER Endometrium Screening Methods Pap is very insensitive Ultrasound is insensitive in asymptomatic women. Endometrial biopsy is sensitive, but invasive, painful, and often QNS for diagnosis. (Recommended by ACS after age 35 for HNPCC, but no data)

GYNECOLOGIC CANCER Endometrium Variation of screening considerations: Of women with endometrial cancer under age 50, and one first degree relative with HNPCC related cancer, 23% will have a gene mutation and should be screened for that. (Beware other cancers)

GYNECOLOGIC CANCER Endometrium—Prevention Progestin with estrogen Diet, Exercise and Weight control If genetic mutation, AND done with reproduction, offer hysterectomy and BSO

GYNECOLOGIC CANCER Ovary 5% of all cancers in women. 23% of all gynecologic cancer 1.7-2% lifetime risk

GYNECOLOGIC CANCER Ovary Ovarian cancer affects females of ALL AGES Prognosis depends on cell type, grade and stage.

GYNECOLOGIC CANCER Ovary Tissue types Epithelial—About 85-90% (>50 yrs) Germ cell—10-15% (<20yrs) Gonadal stroma—5-10% Mesenchymal

GYNECOLOGIC CANCER Ovary Epithelial Serous Mucinous Endometrioid Clear cell Undifferentiated

GYNECOLOGIC CANCER Ovary Germ Cell Dysgerminoma Endodermal Sinus Embryonal Choriocarcinoma Polyembryoma Immature Teratoma Gonadoblastoma

GYNECOLOGIC CANCER Ovary Gonadal Stroma Granulosa cell Theca cell Sertoli-Leydig

GYNECOLOGIC CANCER Ovary Mesenchymal Lymphoma Sarcoma

GYNECOLOGIC CANCER Ovary Symptoms are all non specific Abdominal swelling/bloating Abdominal/Pelvic pressure or pain GI upset/dyspepsia Urinary frequency EXAMINE THE PATIENT. Routine CAT scan may take weeks to perform.

GYNECOLOGIC CANCER Ovary Cancer should be suspected in any woman between 40 and 80 with persistent gi symptoms cannot be diagnosed. Diagnosis is difficult. 70% of diagnoses are stage III or IV.

GYNECOLOGIC CANCER Ovary Decreased Risk Factors (Prevention) Parity OCPs ??Low fat diet Increased Risk Factors Age Genetic Mutation-- Only 10% of cancers. (BRCA1 and 2, and HNPCC)

GYNECOLOGIC CANCER Ovary Decreasing Risk=Prevention Effect of Parity Term Pregnancies RR or or more 0.33

GYNECOLOGIC CANCER Ovary Decreasing Risk=Prevention Effect of OCPs Duration of use RR Never 1 3mos-4yrs yrs yrs or more 0.2

GYNECOLOGIC CANCER Ovary Increase Risk Factor BRCA % BRCA % If reproduction is not an issue, offer BSO.

GYNECOLOGIC CANCER Ovary Screening There are no reliable data that ANY mode of screening is effective in improving the length and quality of life in women with ovarian cancer.

GYNECOLOGIC CANCER Ovary Screening -Asymptomatic -Find at early stage -Reasonable return for effort -Reliable tests—sensitivity and specificity

GYNECOLOGIC CANCER Ovary Higher SENSITIVITY, lower false neg Higher SPECIFICITY, lower false pos

GYNECOLOGIC CANCER Ovary Screening methods Pelvic examination CA-125 Ultrasound Future use of tumor markers

GYNECOLOGIC CANCER Ovary Screening Pelvic exam—Neither sensitive or specific. Estimated 10,000 to find 1 early stage ovarian cancer.

GYNECOLOGIC CANCER Ovary Screening CA-125 Less than 50% of stage I will have elevated levels and OTHER conditions raise the CA-125

GYNECOLOGIC CANCER Ovary Screening CA-125 is elevated Gyn—Endometriosis, adenomyosis, fibroids, functional ovarian cysts, menstruation, benign neoplasms, PID Non-Gyn—Liver disease (acute and chronic infectious and alcoholic), pancreatitis, CHF, colitis, diverticulitis, pneumonia, pericarditis, renal disease, SLE and PAN.

GYNECOLOGIC CANCER Ovary Screening CA-125 with other tumor markers, particularly HE4, look promising. As cancers are abnormal cells, they make abnormal proteins. If patterns can be found that are both sensitive and specific we might have good screening tests. (Proteomics)

GYNECOLOGIC CANCER Ovary Screening CA-125 Marker Sensitivity Specificity CA With HE

GYNECOLOGIC CANCER Ovary Screening Ultrasound University of Kentucky **14,500 asymptomatic women **10 yrs **57,200 scans **180 surgical explorations **11 invasive epithelial cancers found. 8 were stage I or II FOR EACH CANCER FOUND there were 16 surgeries and 5,200 ultrasounds.

GYNECOLOGIC CANCER Ovary Screening Ultrasound Largest study to date using COMBINATION. If CA-125 high, had ultrasound. **41 surgeries **11 ovarian cancer (4 early stage) ***8 women with negative screens developed cancer.

GYNECOLOGIC CANCER Cervix 12% of gynecologic cancers Mean age is % of cases in women >65yrs 10% of cases in women >75yrs

GYNECOLOGIC CANCER Cervix * Prior to Pap smears, this was the most common gynecologic cancer worldwide. *In developed nations, there has been a 75% DECREASE in the past 50 yrs, mainly due to detection and treatment of pre-invasive disease.

GYNECOLOGIC CANCER Cervix Types Squamous Cell 85-90% Adenocarcinoma 10-15% Numerous others <5%

GYNECOLOGIC CANCER Cervix Etiology is oncogenic HPV Risk Factors Early onset coitus Multiple partners, or high risk partner Smoking is co-carcinogen Immunosuppression

GYNECOLOGIC CANCER Cervix Smoking Effect Group RR HPV neg—non smoker 1 Smoker 2 HPV pos 15 HPV pos smoker 66

GYNECOLOGIC CANCER Cervix Screening—Major methods Pap—Either traditional or liquid based About equal in early stage disease. (60-75% senstivity; % specific for HSIL) HPV testing Primary screen—being studied. Some studies=100% sens, but LOW specificity. Supplemental to ASCUS Pap, currently

GYNECOLOGIC CANCER Cervix Screening Frequency of screening is undergoing continual re-evaluation. There are guidelines, but these must be modified for the individual patient.

GYNECOLOGIC CANCER Cervix HPV *80% of sexually active women will acquire HPV. *Most will be cleared in 12-18mos *80-90% will resolve in 2-5yrs. ***Persistence and subtype=cancer.

GYNECOLOGIC CANCER Cervix HPV Over 120 types Oncogenic types: 16, 18, 45, et.al. Non oncogenic: 6, 11, et.al.

GYNECOLOGIC CANCER Cervix HPV Oncogenic incorporate into host genome. Association with SCCaCx 16 60% 18 20% 45 7%

GYNECOLOGIC CANCER Cervix HPV Non-oncogenic types are associated with formation of condylomata, an emotional and quality of life issue. Oncogenic virus doesn’t cause condylomata, and non-oncogenic types don’t lead to cancer

GYNECOLOGIC CANCER Cervix Prevention—Immunization HPV quadrivalent vaccine contains virons, virus-like particles (NOT live virus) of 6 & 11 (warts), and 16 & 18 (cervical, vaginal and vulvar cancer). “An ounce of prevention is worth a pound of cure.”

GYNECOLOGIC CANCER Cervix Prevention—Immunization In non-exposed individuals, it is % effective. If exposed, 80-90% effective, like other vaccines.

GYNECOLOGIC CANCER Cervix Prevention—Immunization Cross protection A strong immune response will cross protect to related types. Antibodies to cross protect 16 31, 33, 52, , 45, 59

GYNECOLOGIC CANCER Cervix Prevention—Immunization Additional benefits Cancer % HPV related Anal 70 Vulvar, vag, penile 50 Oropharyngeal 20-40

GYNECOLOGIC CANCER Cervix Prevention—Immunization Schedule: Initial, 2mos, 6mos. Population: Females 9-26 yrs. *Ongoing studies show effective to give to age 45. *Effective in males also, but not yet approved. *Pregnancy Category B