The Management of Cervical , Vulvar and Vaginal Cancers Kerry J. Rodabaugh, M.D. Division of Gynecologic Oncology University of Nebraska Medical Center

Incidence: global public health issue 450,000 – 500,000 women diagnosed each year worldwide In developing countries, it is the most common cause of cancer death 340,000 deaths in 1985

United States Incidence 15,000 women diagnosed annually 4,800 annual deaths

Mortality Rates <2/100,000: Finland, France, Greece, Israel, Japan, Korea, Spain, Thailand 2.7/100,000: USA 12-15.9/100,000: Chile, Costa Rica, Mexico

Lifetime risk of developing cervical cancer 5% - South America 0.7% - USA

Cervical CA Risk Factors Early age of intercourse Number of sexual partners Smoking Lower socioeconomic status High-risk male partner Other sexually transmitted diseases Up to 70% of the U.S. population is infected with HPV

Screening Guidelines for the Early Detection of Cervical Cancer, American Cancer Society 2003 Screening should begin approximately three years after a women begins having vaginal intercourse, but no later than 21 years of age. Screening should be done every year with regular Pap tests or every two years using liquid-based tests. At or after age 30, women who have had three normal test results in a row may get screened every 2-3 years. However, doctors may suggest a woman get screened more if she has certain risk factors, such as HIV infection or a weakened immune system. Women 70 and older who have had three or more consecutive Pap tests in the last ten years may choose to stop cervical cancer screening. Screening after a total hysterectomy (with removal of the cervix) is not necessary unless the surgery was done as a treatment for cervical cancer. The American Cancer Society cervical cancer screening guidelines state that women should begin screening approximately three years after she begins having vaginal intercourse, but no later than 21 years of age. Screening should be done every year with regular Pap tests or every two years using liquid-based tests. At or after age 30, women who have had three normal tests in a row may get screened every 2-3 years. Women 70 and older who have had three or more consecutive normal Pap tests in the last 10 years may choose to stop cervical cancer screening. American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005

Pap Smear Single Pap false negative rate is 20%. The latency period from dysplasia to cancer of the cervix is variable. 50% of women with cervical cancer have never had a Pap smear. 25% of cases and 41% of deaths occur in women 65 years of age or older.

Clinical Presentation CIN/CIS/ACIS – asymptomatic Irregular vaginal bleeding Vaginal discharge Pelvic pain Leg edema Bowel/bladder symptoms

Physical Findings Exophytic, cauliflower like mass Cervical ulcer, friable or necrotic Firm “barrel-shaped” cervix Hydronephrosis Anemia Weight loss

Histology Squamous 85-90% Adenocarcinoma 10-15% Lymphoma Neuroendocrine/small cell Melanoma

Route of Spread Cervical cancer spreads by direct invasion or by lymphatic spread Vascular spread is rare

Staging Physical exam Cervical biopsies Chest x-ray IVP (Ct scan) Barium enema, cystoscopy, proctoscopy Surgical staging

Staging Stage I – confined to the cervix IA1 – <3mm depth of invasion IA2 – stromal invasion 3-5mm in depth or <7 mm in width IB1- tumor < 4 cm IB2 - tumor > 4 cm in diameter Stage II – extension beyond cervix IIA – upper 2/3 of vagina IIB – Parametrial involvement

Staging Stage III IIIA – lower 1/3 of vagina IIIB – extension to pelvic sidewall or hydronephrosis Stage IV IVA – bladder or rectal mucosa IVB – distant metastases

5 year survival rates Stage IA 90-100% Stage IB 70-90% Stage II 50-60% Stage III 30-40% Stage IV 5%

Therapy Cervical conization Simple hysterectomy Radical hysterectomy Radiation therapy with chemosensitization

5 year Survival Stage I 70% Stage II 51% Stage III 33% Stage IV 17%

Pros and Cons Surgery Radiation Bladder dysfunction Vesico/uretero fistula Bowel obstruction Ovarian preservation Vaginal preservation Radiation Sigmoiditis Rectovaginal fistula Bowel obstruction Vesico/uretero fistula Ovarian failure

Radiation Therapy External Beam Brachytherapy Whole pelvis or para-aortic window 4000-6000 cGy Over 4-5 weeks Brachytherapy Intracavitary or interstitial 2000-3000 cGy Over 2 implants

Recurrent Cervical Cancer 10-20% of patients treated with radical hysterectomy Recurrence has an 85% mortality 83% are diagnosed within the first two years of post-treatment surveillance

Recurrent Cervical Cancer Radiation Pelvic exenteration Palliative chemotherapy

Vulvar Cancer 3870 new cases 2005 870 deaths Approximately 5% of Gynecologic Cancers American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005

Vulvar Cancer 85% Squamous Cell Carcinoma 5% Melanoma 2% Sarcoma 8% Others

Vulvar Cancer Biphasic Distribution Average Age 70 years 20% in patients UNDER 40 and appears to be increasing

Vulvar Cancer Etiology Chronic inflammatory conditions and vulvar dystrophies are implicated in older patients Syphilis and lymphogranuloma venereum and granuloma inguinal HPV in younger patients Tobacco

Vulvar Cancer Paget’s Disease of Vulva 10% will be invasive 4-8% association with underlying Adenocarcinoma of the vulva

Symptoms Most patients are treated for “other” conditions 12 month or greater time from symptoms to diagnosis

Symptoms Pruritus Mass Pain Bleeding Ulceration Dysuria Discharge Groin Mass

Symptoms May look like: Raised Erythematous Ulcerated Condylomatous Nodular

Vulvar Cancer IF IT LOOKS ABNORMAL ON THE VULVA BIOPSY!

Tumor Spread Very Specific nodal spread pattern Direct Spread Hematogenous

Staging Based on TNM Surgical Staging Tumor size Node Status Metastatic Disease

Staging Stage I T1 N0 M0 Tumor ≤ 2cm IA ≤1 mm depth of Invasion IB 1 mm or more depth of invasion

Staging Stage II T2 N0 M0 Tumor >2 cm Confined to Vulva or Perineum

Staging Stage III T3 N0 M0 T3 N1 M0 T1 N1 M0 T2 N1 M0 Tumor any size involving lower urethra, vagina, anus OR unilateral positive nodes

Staging Stage IVA T1 N2 M0 T2 N2 M0 T3 N2 M0 T4 N any M0 Tumor invading upper urethra, bladder, rectum, pelvic bone or bilateral nodes

Staging Stage IVB Any T Any N M1 Any distal mets including pelvic nodes

Treatment Primarily Surgical Wide Local Excision Radical Excision Radical Vulvectomy with Inguinal Node Dissection Unilateral Bilateral Possible Node Mapping, still investigational

Treatment Local advanced may be treated with Radiation plus Chemosensitizer Positive Nodal Status 1 or 2 microscopic nodes < 5mm can be observed 3 or more or >5mm post op radiation

Treatment Special Tumor Verrucous Carcinoma Indolent tumor with local disease, rare mets UNLESS given radiation, becomes Highly malignant and aggressive Excision or Vulvectomy ONLY

Vulva 5 year survival Stage I 90 Stage II 77 Stage III 51 Stage IV 18 Hacker and Berek, Practical Gynecologic Oncology 4th Edition, 2005

Recurrence Local Recurrence in Vulva Reexcision or radiation and good prognosis if not in original site of tumor Poor prognosis if in original site

Recurrence Distal or Metastatic Very poor prognosis, active agents include Cisplatin, mitomycin C, bleomycin, methotrexate and cyclophosphamide

Melanoma 5% of Vulvar Cancers Not UV related Commonly periclitoral or labia minora

Melanoma Microstaged by one of 3 criteria Clark’s Level Chung’s Level Breslow

Melanoma Treatment Wide local or Wide Radical excision with bilateral groin dissection Interferon Alpha 2-b

Vaginal Carcinoma 2140 new cases projected 2005 810 deaths projected 2005 Represents 2-3% of Pelvic Cancers American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005

Vaginal Cancer 84% of cancers in vaginal area are secondary Cervical Uterine Colorectal Ovary Vagina Fu YS, Pathology of the Uterine Cervix, Vagina and Vulva, 2nd ed. 2002

Vaginal Carcinoma Squamous Cell 80-85% Clear Cell 10% Sarcoma 3-4% Melanoma 2-3%

Clear Cell Carcinoma Associated with DES Exposure In Utero DES used as anti abortifcant from 1949-1971 500+ cases confirmed by DES Registry Usually occurred late teens

Vaginal Cancer Etiology Mimics Cervical Carcinoma HPV 16 and 18

Staging Stage I Confined to Vaginal Wall Stage II Subvaginal tissue but not to pelvic sidewall Stage III Extended to pelvic sidewall Stage IVA Bowel or Bladder Stage IVB Distant mets

Treatment Surgery with Radical Hysterectomy and pelvic lymph dissection in selected stage I tumors high in Vagina All others treated with radiation with chemosensitization