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Edward L. Cohen, MDChief Section of Gynecology

Department of SurgeryVA Palo Alto Healthcare System

AndAssociate Clinical Professor OB/Gyn

Stanford UniversitySchool of Medicine

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Annual Meeting

NOVA

Milpitas California

26 January 2008

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Endometrium

Most common gyn cancer in the US

6% of all cancer in women

2-3% lifetime risk

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Endometrium

Age Mean is 61 yrs.

Menopausal 75-80%

Pre-menopausal 20-25%

~5% <40 yrs old.

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Endometrium

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

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Endometrium

Prognosis depends on cell type, grade, and stage.

Overall, endometrioid has a better prognosis than adeno-squamous, papillary serous, or clear cell.

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

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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

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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

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

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Endometrium

Exogenous estrogen

ERT effects can be reversed by

addition of a progestin.

Tamoxifen and SERMs

Receptors differ in breast and

endometrium. Stimulates endom.

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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 CANCEREndometrium—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.

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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.

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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.

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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 negativeDecreased specificity means higher false positive

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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%.

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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)

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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)

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Endometrium—Prevention

Progestin with estrogen

Diet, Exercise and Weight control

If genetic mutation, AND done with reproduction, offer hysterectomy and BSO

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Ovary

5% of all cancers in women.

23% of all gynecologic cancer

1.7-2% lifetime risk

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Ovary

Ovarian cancer affects females of

ALL AGES

Prognosis depends on cell type, grade and stage.

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Ovary

Tissue types

Epithelial—About 85-90% (>50 yrs)

Germ cell—10-15% (<20yrs)

Gonadal stroma—5-10%

Mesenchymal

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Ovary

Epithelial

Serous

Mucinous

Endometrioid

Clear cell

Undifferentiated

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

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Ovary

Gonadal Stroma

Granulosa cell

Theca cell

Sertoli-Leydig

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Ovary

Mesenchymal

Lymphoma

Sarcoma

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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.

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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.

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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)

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Ovary Decreasing Risk=Prevention

Effect of Parity

Term Pregnancies RR

0 1

1 0.6

2 or 3 0.5

4 or more 0.33

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Ovary Decreasing Risk=Prevention

Effect of OCPs

Duration of use RR

Never 1

3mos-4yrs 0.65

5-9 yrs 0.4

10 yrs or more 0.2

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Ovary

Increase Risk Factor

BRCA1 35-45%

BRCA2 15-25%

If reproduction is not an issue, offer BSO.

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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.

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

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Ovary

Higher SENSITIVITY, lower false neg

Higher SPECIFICITY, lower false pos

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Ovary

Screening methods

Pelvic examination

CA-125

Ultrasound

Future use of tumor markers

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Ovary

Screening

Pelvic exam—Neither sensitive or

specific. Estimated 10,000 to find 1

early stage ovarian cancer.

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Ovary Screening CA-125

Less than 50% of stage I will have

elevated levels and OTHER

conditions raise the CA-125

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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.

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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)

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Ovary Screening CA-125

Marker Sensitivity Specificity

CA-125 69.5 62

With HE4 73 95

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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 IIFOR EACH CANCER FOUND there were 16 surgeries and 5,200 ultrasounds.

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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.

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Cervix 12% of gynecologic cancers

Mean age is 47. 20% of cases in women >65yrs 10% of cases in women >75yrs

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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.

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Cervix

Types

Squamous Cell 85-90%

Adenocarcinoma 10-15%

Numerous others <5%

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

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Cervix Smoking Effect

Group RR

HPV neg—non smoker 1

Smoker 2

HPV pos 15

HPV pos smoker 66

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Cervix Screening—Major methods Pap—Either traditional or liquid based About equal in early stage disease. (60-75% senstivity; 86-100% specific for HSIL) HPV testing Primary screen—being studied. Some studies=100% sens, but LOW specificity. Supplemental to ASCUS Pap, currently

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Cervix Screening

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

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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.

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Cervix HPV

Over 120 types

Oncogenic types: 16, 18, 45, et.al.

Non oncogenic: 6, 11, et.al.

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Cervix HPV Oncogenic incorporate into host genome.

Association with SCCaCx 16 60% 18 20% 45 7%

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Cervix HPVNon-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

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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.”

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Cervix Prevention—Immunization

In non-exposed individuals, it is 95-100% effective.

If exposed, 80-90% effective, like other vaccines.

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Cervix Prevention—Immunization

Cross protection

A strong immune response will cross

protect to related types.

Antibodies to cross protect

16 31, 33, 52, 58

18 39, 45, 59

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Cervix Prevention—Immunization

Additional benefits Cancer % HPV related

Anal 70

Vulvar, vag, penile 50

Oropharyngeal 20-40

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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