Benign & Malignant Diseases of the Female Genital Tract Jennifer McDonald DO F.A.C.O.G February 22, 2008

When to Suspect Gynecologic Cancer Premenopausal woman with: Irregular menses Women older than 35 or with long history of irregular menses Postmenopausal woman with: Vaginal bleeding Abnormal vaginal discharge

o Breast211,240 o Uterus (womb)40,880 o Ovary22,200 o Cervix10,400 o Vulva 3,870 Source: American Cancer Society. Gynecologic Malignancies 2005

Criteria for Screening Test 1. Simple & quick 2. Inexpensive 3. Acceptable to population 4. Accurate 5. Repeatable 6. Sensitive 7. Specific

Screening Tests that Impact Lives o Mammography o Pap Smears o Diabetes screening o Colonoscopy o Thyroid screening o Prostate specific antigen

The Uterus

Leiomyoma o Also known as fibroids o Local proliferation of smooth muscle cells of the uterus o Benign tumors o 20-25% of reproductive aged women o 3-9x more frequent in African American women o Half to one third of hysterectomies performed

Leiomyoma o Majority are asymptomatic (50-65%) o When symptomatic can cause: Metrorrhagia Menorrhagia Pain Infertility o Cause unknown o Hormonally responsive o Commonly multiple

Classified according to location

Indications for Surgical Intervention o Abnormal uterine bleeding causing anemia o Severe pelvic pain o Urinary frequency or retention o Growth after menopause o Infertility o Rapid increase in size

Endometriosis o Endometrial glands/stroma outside the endometrial cavity o Most common sites: pelvic peritoneum, posterior cul-de-sac, round ligament, uterosacral ligaments o Incidence 10-15% reproductive age women o 20% of women with chronic pelvic pain o 40% of women with infertility

Etiology Theories o Halban: endometrial tissue transported via lymphatic system to ectopic sites in the pelvis o Meyer: multipotential cells in peritoneal cells undergo metaplastic transformation into functional endometrial tissue o Sampson: endometrial tissue transported through the tubes during retrograde menstruation

Clinical Manifestations o Dysmenorrhea o Dyspaurenia o Infertility o Abnormal bleeding o Cyclic pelvic pain o Severity of symptoms does not correlate with amount of endometriosis

The Faces of Endometriosis

Adenomyosis o Extension of endometrial glands/stroma into the uterine musculature o Causes diffuse enlargement of the uterus o Incidence 15% o 15% patients with adenomyosis have endometriosis and 50-60% have fibroids o Most common symptoms: secondary dysmenorrhea (30%), menorrhagia (50%) or both (20%) o 30% are asymptomatic

Endometrial Cancer o Most common gynecologic cancer o Early symptoms and accurate diagnostic modalities make it the 3rd leading cause of gyn cancer deaths o Estrogen dependent neoplasm o Mean age 61 years o 25% premenopausal o 75% postmenopausal o 75% at Stage I at diagnosis o 75% adenocarcinomas

Risk Factors for Endometrial Cancer o Early menarche (<age 12) o Late menopause (>age 52) o Infertility or nulliparous o Obesity (>30# overweight) o Treatment with tamoxifen for breast cancer o Estrogen replacement therapy (ERT) after menopause o Diet high in animal fat o Diabetes o Age greater than 40 o Caucasian women o Family history of endometrial cancer or hereditary nonpolyposis colon cancer (HNPCC) o Personal history of breast or ovarian cancer o Prior radiation therapy for pelvic cancer

Endometrial Cancer o Most common symptom is irregular bleeding (90%) o No effective screening test o Endometrial biopsy standard of care o May require D&C o Surgery is first choice for therapy o Overall 5 year survival rate 65% with 85% recurrences within first 3 years

Ovary

Dermoid Cyst o Ovarian cyst containing hair, teeth, cartilage o Stem cells that “forgot” to migrate

Radiologic Differences Benign o Simple cysts < 10 cm o Septations < 1mm thickness o Unilateral o Calcifications esp teeth o Gravity dependent layering of cyst contents Malignant o Solid or cystic & solid o Multiple Septations > 3mm size o Bilateral o Ascites

Ovarian Cancer o Worldwide the incidence of ovarian cancer is 12.7/100,000 at all ages o In USA the incidence is 10.2 /100,000 before 65 years and is 57.1/100,000 at or above 65 years o Only 30% survive for 5 years after diagnosis 75% Patients have disease beyond the ovary at time of diagnosis (Stage III or higher)

o 25,000 new cases/yr o 2 nd most common GYN cancer o Usually NOT due to a predisposing genetic factors o Only 5-10% of ovarian cancers are related to genetic mutations BRCA1 BRCA2 Increased risk in patients with hereditary nonpolyposis colon cancer (HNPCC)  mismatch repair gene mutations Increased risk in patients with Peutz-Jeghers syndrome  STK11 tumor suppressor gene mutation Ovarian Cancer

Early menarche (< age 12) Late menopause (> age 52) Age (> 50) Later age of first pregnancy (> age 30) Infertility Personal history of breast or colon cancer Family history of ovarian, breast or colon cancer Risk Factors for Ovarian Cancer Oral contraceptives have been found to have a protective effect for ovarian cancer

Lower abdominal discomfort Bloated or fullness Loss of appetite Nausea, gas, indigestion Vaginal bleeding Weight loss Constipation or diarrhea Frequent urination (due to pressure from growing tumor on bladder) o Unfortunately symptoms do NOT normally present until the cancer is at an advanced stage Symptoms

Screening o Pelvic ultrasound has not been proven to be an effective screening tool Serum markers CA-125: Secreted by 80% of epithelial ovarian cancers o Sensitive but not specific o Used to monitor progression and regression but no value for screening purposes

Conditions Associated with Elevated CA-125 Malignancies o Epithelial Ovarian Cancer o Fallopian Tube Cancer o Endometrial Cancer o Endocervical Cancer o Pancreatic Cancer o Lung Cancer o Breast Cancer o Colon Cancer Benign Conditions o Normal & ectopic pregnancy o Endometriosis o Fibroids o Pelvic Inflammatory Disease o Pancreatitis o Peritonitis o Cirrhosis o Recent abdominal surgery

Treatment o Surgery is preferred in almost all cases when possible for debulking of tumor load o Surgically staged: Total hysterectomy, oomentectomy, and tumor debulking o Epithelial ovarian cancers are highly chemosensitive to cisplatin based combination chemotherapy agents and Taxol o Radiation plays little role in the treatment of ovarian cancers

Survival Stage I 80-95% Stage II40-70% Stage III30% Stage IV< 10%

Germ Cell Tumors o 15-20% Ovarian tumors o Arise from totipotential germ cells o 95% are benign o Women in their teens and 20s o Rapidly enlarging adnexal mass and pain o Diagnosed earlier and treatment usually limited to removal of affected ovary o Highly curable with surgery and chemotherapy

Cervix

o The incidence of cervical cancer in USA is 7.2/100,000 under the age of 65 and 16.1/100,000 at or above 65 years o Worldwide the incidence at all ages is 7.6/100,000 o The endocervix epithelium contains receptors for sex hormones Cervical Cancer

o 500,000 women worldwide die of cervical cancer annually o million women in the U.S. have a Pap test each year o 3-5 million women in the U.S. have an abnormal result o 10,400 new cervical cancers diagnosed in the U.S. per year o 3,900 deaths from cervical cancer in the U.S. per year Cervical Cancer Statistics

Risk Factors for Cervical Cancer o Cigarette smoking o High number of sexual partners o Early onset of sexual activity o History of sexually transmitted diseases o In patients with HIV invasive cervical cancer is considered an AIDS defining illness

Treatment o Stage IA1/IA2 cone biopsy may be sufficient o Surgery helpful in only Stage IIA or less o 40% will be diagnosed at IB (85% cure rate) o Combination chemotherapy/radiation just as good as surgery in IB disease o More advanced lesions treated with radiation and platinum chemotherapy

Screening Tools - Pap Smear o Premalignant phase of many years o Inexpensive o Readily accepted o Easy to perform o 50% of women who receive cervical cancer diagnosis never had a pap smear o 10% had not been screened in 5 years

Timing of Screening o Three years after initiation of sexual intercourse but no later than 21 years of age o Annual cytology screening for women younger than 30 o Women 30 years and older who have had three negative cytology tests in a row may be screened every 2-3 years o Women with HIV, immunosuppression, or DES exposure may require more frequent screening

Discontinuation of Screening o ACS recommends discontinuation at age 70 in low risk women o Women with previous hysterectomy and no history of high grade CIN may discontinue screening

Cytologic Abnormalities o Dysplasia thought to be precursor to cervical cancer o On average takes 7 years for a CIN1 lesion to progress to a cancer and 4 years for a CIN2 lesion o 75-90% of CIN1 lesions will resolve spontaneously o 50% of CIN2 spontaneously resolve o 30% of CIN3

ASCUS Atypical Squamous Cells of Undetermined Significance o May be anything from inflammatory process to a neoplastic process o Reflex HPV testing performed o If positive for high risk types should proceed with further testing o If negative for high risk types may continue yearly screening

Colposcopy o Done in follow-up to abnormal smear o Magnified view of cervix o Surfaced stained with acetic acid o Biopsies taken to rule out advanced disease

Low Grade/CIN1 o Usually caused by transient HPV infection o 75-90% regress o Confirmed by coloposcopic biopsy o Repeat pap smears every 6 months until 3 normal smears in a row then may return to yearly screening

HGSIL/CIN2-3 o Less chance of regression than progression o Usually destructive procedures or excision performed o Cryotherapy o Laser therapy o LEEP (loop electrosurgical excision procedure)

Human Papillomavirus (HPV) o 200 different subtypes o More than 30 transmitted sexually o Primary causative agent of cervical cancer in over 95% of cases o Predominantly types 16 and 18 (70%) o More than 75% sexually active women tested have been exposed to HPV by age o Most people who have been exposed will display no symptoms and will clear the infection on their own

Gardasil o Quadrivalent HPV vaccine o Targets type 16,18 (cervical cancer) as well as types 6 and 11 (genital warts) o Released June 2006 o Approved for all women aged 9 to 26 o 3 doses ($120/dose)

Vaccine Efficacy

Vaginal & Vulvar Cancer

o The incidence of cancer of vagina and vulva is low i.e 0.5 and 2/100,000 women respectively o These cancers are common at an advanced age. o No relevant information is known about any connection between HRT and these cancers Vaginal & Vulvar Cancer

o Lesion(s) on surface of vulva or labia; malignancy most often on labia majora or minora o 3,870 new cases and 870 deaths in the US in 2005 o Rare disease  0.5% of all cancers in women o 90% of vulvar cancers are squamous cell carcinomas o Melanoma 2 nd most common  found in labia minora or clitoris o Other types of vulvar cancer: Adenocarcinoma Paget's disease Sarcomas Verrucous carcinoma Basal cell carcinoma Vulvar

Age: 3/4 patients >50; 2/3 >70 Chronic vulvar inflammation/irritation Infection with the human papillomavirus (HPV) Human immunodeficiency virus (HIV) infection Lichen sclerosis Melanoma or atypical moles on non-vulvar skin  Family history of melanoma and dysplastic nevi anywhere on the body may increase risk of vulvar cancer Vulvar intraepithelial neoplasia (VIN)—some increased risk for vulvar cancer in women with VIN Other genital cancers Smoking Diabetes Risk Factors