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GYNECOLOGIC CARCINOMAS CHRISTOPHER P. DESIMONE, M. D. ASSOCIATE PROFESSOR DIVISION OF GYNECOLOGIC ONCOLOGY GYNECOLOGIC CARCINOMAS CHRISTOPHER P. DESIMONE, M. D. ASSOCIATE PROFESSOR DIVISION OF GYNECOLOGIC ONCOLOGY

OUTLINE • • Endometrial Carcinoma Ovarian Carcinoma Cervical Carcinoma Vulvar Carcinoma • Epidemiology • OUTLINE • • Endometrial Carcinoma Ovarian Carcinoma Cervical Carcinoma Vulvar Carcinoma • Epidemiology • Clinical symptoms • Risk factors • Diagnosis • Staging • Treatment

ENDOMETRIAL CARCINOMA • Most common gynecologic malignancy • 4 th most common malignancy among ENDOMETRIAL CARCINOMA • Most common gynecologic malignancy • 4 th most common malignancy among women • Estimated 52, 630 new cases per year in the United States • 1 in 38 women will develop this cancer • 7 th most common cause of malignancy related deaths among women • 8, 590 deaths annual from endometrial cancer Seigel et al. CA J Clin. 2014

CLINICAL TYPES OF ENDOMETRIAL CANCER • Type one occurs in obese women with hyper-estrogenism. CLINICAL TYPES OF ENDOMETRIAL CANCER • Type one occurs in obese women with hyper-estrogenism. Tend to have diabetes, hypertension and hyperlipidemia as co-morbid medical conditions • Pathology tends to be well to moderately differentiated, superficially invasive and has a good prognosis (85% five year survival) Bokhman, Gynecol Oncol. 1983

CLINICAL TYPES OF ENDOMETRIAL CANCER • Type two occurs in elderly thin women who CLINICAL TYPES OF ENDOMETRIAL CANCER • Type two occurs in elderly thin women who have no signs of hyper-estrogenism. • No clear pathway causing carcinoma other than genetic and cellular mutations • Pathology tends to be poorly differentiated with deep invasion, lymph node metastasis and poor prognosis (58% five year survival) Bokhman, Gynecol Oncol, 1983

SYMPTOMS • Postmenopausal bleeding (90%) • Back pain • Vaginal discharge • Unusual but SYMPTOMS • Postmenopausal bleeding (90%) • Back pain • Vaginal discharge • Unusual but can happen… • • SOB (multiple pulmonary metastases) CNS symptoms (isolated cranial metastasis)

RISK FACTORS • Nulliparous • Late menopause • Diabetes • HTN • Obesity >30 RISK FACTORS • Nulliparous • Late menopause • Diabetes • HTN • Obesity >30 lbs • Obesity >50 lbs • Unopposed estrogen Mac. Mahon, Gynecol Oncol 1974 2 x 2. 4 x 2. 8 x 1. 5 x 3 x 10 x 9. 5 x

ESTROGEN STIMULATION • Adipose converts androstenedione into estrone, a weak estrogen • Increased adipose ESTROGEN STIMULATION • Adipose converts androstenedione into estrone, a weak estrogen • Increased adipose correlates into increased estrone levels • estrone causes proliferation of endometrial cells • Prolonged estrone exposure causes endometrial carcinoma

DIAGNOSIS • Endometrial biopsy • Dilatation and curettage (D&C) • 90% accuracy in detecting DIAGNOSIS • Endometrial biopsy • Dilatation and curettage (D&C) • 90% accuracy in detecting endometrial cancer • Vaginal ultrasound • Endometrial thickness (ET) evaluated in 205 postmenopausal women • • No cancers detected with an ET < 5 mm PPV 87%, Sensitivity 100%, Specificity 96% Granberg et al. Am J Obstet Gynecol. 1991.

TREATMENT • Surgery • • Hysterectomy, bilateral salpingo-oophorectomy, pelvic and para aortic lymphadenectomy and TREATMENT • Surgery • • Hysterectomy, bilateral salpingo-oophorectomy, pelvic and para aortic lymphadenectomy and pelvic washings ± adjuvant treatment • Radiation • Reserved for women who have an absolute contraindication to surgery • Hormonal • • Progestin therapy Best for women who want to preserve fertility

ENDOMETRIAL CANCER ENDOMETRIAL CANCER

SURGICAL STAGING • • IA IB tumor invasion < ½ myometrium tumor invasion > SURGICAL STAGING • • IA IB tumor invasion < ½ myometrium tumor invasion > ½ myometrium • II cervical involvement • • IIIA IIIB IIIC 1 IIIC 2 + pelvic cytology, adnexa or uterine serosa parametrial or vaginal involvement pelvic lymph node involvement para-aortic lymph node involvement • • IVA IVB rectal or bladder mucosa involvement inguinal node involvement, intra abdominal disease or distant metastasis

PROGNOSIS BY STAGE • • IA IB 88% 75% • II 69% • • PROGNOSIS BY STAGE • • IA IB 88% 75% • II 69% • • • IIIA IIIB IIIC 58% 50% 47% • • IVA IVB 17% 15% ACS Webpage 2013

LYMPH NODES • Two schools of thought among GYN/Oncologists regarding pelvic lymphadenectomy for endometrial LYMPH NODES • Two schools of thought among GYN/Oncologists regarding pelvic lymphadenectomy for endometrial adenocarcinoma: • Everyone receives a pelvic lymphadenectomy and para aortic lymph node sampling or… • Selective lymphadenectomy for high-risk patients

LYMPH NODES • University of Kentucky is conducting a trial regarding lymphadenectomy for endometrial LYMPH NODES • University of Kentucky is conducting a trial regarding lymphadenectomy for endometrial cancer • • Our division favors selective lymphadenectomy • Both studies did show an increase in Stage III disease (~10%) which did change post-operative treatment • One of the studies showed significantly more early and late post operative morbidity in patients undergoing lymphadenectomy (late morbidity – lymph edema) Two European randomized trial revealed no significant difference in OS with pelvic lymphadenectomy

UNIVERSITY OF GYNECOLOGIC ONCOLOGY POSITION ON PELVIC LYMPHADENECTOMY • No lymphadenectomy • • • UNIVERSITY OF GYNECOLOGIC ONCOLOGY POSITION ON PELVIC LYMPHADENECTOMY • No lymphadenectomy • • • Small tumors < 2 cm and… Grade 1 or 2 adenocarcinomas and… Less than ½ myometrial invasion on frozen section < 5% risk of positive lymph nodes Pelvic Lymphadenectomy and para aortic lymph node sampling • • Large tumors > 2 cm and/or… • Caveat: multiple studies evaluating preoperative imaging have failed to reliably predict myometrial invasion Grade 3 adenocarcinoma and/or… Greater than ½ myometrial invasion 10 -35% risk of positive lymph nodes

ILIAC LYMPH NODES ILIAC LYMPH NODES

OBTURATOR LYMPH NODES OBTURATOR LYMPH NODES

ADJUVANT TREATMENTS • Pelvic radiation (brachytherapy and external beam) is used for adjuvant therapy ADJUVANT TREATMENTS • Pelvic radiation (brachytherapy and external beam) is used for adjuvant therapy • Use of adjuvant radiation is stratified according to the stage of the patient. • High risk groups (Stages: III, IV) are at an increased risk for local and distal recurrences. Adjuvant pelvic radiation and chemotherapy is universally recommended • Intermediate risk groups (Stage IB, II) are treated with pelvic radiation according to risk factors • Age, grade, lymph vascular space invasion, depth of myometrial invasion

RADIATION • Stages IB, II frequently receive adjuvant radiation • XRT decreases significantly decreases RADIATION • Stages IB, II frequently receive adjuvant radiation • XRT decreases significantly decreases pelvic recurrence • XRT does not change disease specific survival (it has little impact on distal disease) • Side effects include • • • Diarrhea Pain Vaginal stenosis

ADJUVANT CHEMOTHERAPY • Used with Stage III, IV endometrial cancer. • Carboplatin, Taxol ± ADJUVANT CHEMOTHERAPY • Used with Stage III, IV endometrial cancer. • Carboplatin, Taxol ± Adriamycin are used • Current trend is to incorporate pelvic radiation with the chemotherapy • Common side effects include • Fatigue • Neuropathy • Myelosuppresion • Alopecia

RECURRENCES • Vaginal recurrence is the most common, next pulmonary • 70% of patients RECURRENCES • Vaginal recurrence is the most common, next pulmonary • 70% of patients with isolated vaginal recurrences can be salvaged with XRT • Isolated distal recurrences (pulmonary) can be surgically managed • Otherwise distal disease is uniformly fatal • Combination chemotherapy can improve disease free interval

OVARIAN CANCER • Epithelial ovarian cancer statistics • 21, 980 new cases a year OVARIAN CANCER • Epithelial ovarian cancer statistics • 21, 980 new cases a year in the United States • 14, 270 women will die each year • 5 th most common cause of cancer related mortality among women • Peak incidence at age 65 -85 • Slowly decreasing in incidence since the mid 1980’s Seigel et al. Ca J Clin. 2014

SYMPTOMS • Nebulous, Vague and Insidious • • Abdominal swelling or fullness • By SYMPTOMS • Nebulous, Vague and Insidious • • Abdominal swelling or fullness • By the time these symptoms elicit an exam or radiologic evidence of disease, 80% of women will be diagnosed with stage IIIC disease Early satiety Dyspepsia Urinary frequency

RISK FACTORS • Northern European descent/ Ashkenazi Jews • Nulliparous • Late menopause • RISK FACTORS • Northern European descent/ Ashkenazi Jews • Nulliparous • Late menopause • Infertility • Talc • Hereditary (10% of all epithelial ovarian cancer) • • BRCA 1 & 2 HNPCC • Birth control pills decrease the risk of ovarian carcinoma by 50%

DIAGNOSIS • Excision and pathologic evaluation (gold standard) • Vaginal ultrasound • • • DIAGNOSIS • Excision and pathologic evaluation (gold standard) • Vaginal ultrasound • • • UK ovarian ultrasound experience (asymptomatic women) 89 cancers among 35, 000 screenings Sensitivity 86%, Specificity 70%, PPV 10% • CA 125 • • • Laughable 50% of stage I cancers do not have elevated CA 125’s Endometriosis, PID, hepatitis, CHF all cause false positive results

TYPES OF OVARIAN CANCER • Epithelial • • • 80 -90% of all ovarian TYPES OF OVARIAN CANCER • Epithelial • • • 80 -90% of all ovarian cancers Affects women 65 -85 Papillary serous histology most common • • • 10 -15% of all ovarian cancers Affects women 10 -30 Highly curable • • • Rare Produce estrogen or testosterone Usually cured with surgery • Germ Cell • Sex-cord Stromal

TREATMENT • Surgery followed by adjuvant chemotherapy • Neoadjuvant therapy followed by interval debulking TREATMENT • Surgery followed by adjuvant chemotherapy • Neoadjuvant therapy followed by interval debulking • Surgery- Hyst/BSO, omentectomy, ± colon or bowel resection, pelvic lymph nodes • Aim to optimally debulk the patient leaving all remaining tumor less than 1 cm

OVARIAN CANCER OVARIAN CANCER

OVARIAN CANCER OVARIAN CANCER

OVARIAN CANCER OVARIAN CANCER

OVARIAN CANCER OVARIAN CANCER

OVARIAN CANCER OVARIAN CANCER

STAGING • I - limited to the ovary • II - pelvic extension • STAGING • I - limited to the ovary • II - pelvic extension • III – abdominal extension • IV – distant metastasis • IVA- malignant pleural effusion • IVB- Hepatic or splenic parenchyma, distal spread outside the abdomen • • • IA one ovary (capsule intact, no tumor on surface, negative cytology) IB both ovaries IC 1 surgical spillage IC 2 spontaneous rupture, tumor on surface of ovary IC 3 positive cytology IIA extension to uterus/tubes IIB other pelvic intraperitoneal tissues (bladder/colon serosa) IIIA 1 - positive retroperitoneal lymph nodes IIIA 2 - microscopic seeding of abdominal peritoneal surfaces IIIB - abdominal implants < 2 cm IIIC - abdominal implants > 2 cm

SURVIVAL BY STAGE – OLD CLASSIFICATION • • • IA IB IC 94% 90% SURVIVAL BY STAGE – OLD CLASSIFICATION • • • IA IB IC 94% 90% 81% • • • IIA IIB IIC 76% 67% 57% • • • IIIA IIIB IIIC 45% 39% 35% • IV 18% ACS website 2013

FACTOIDS • 80% of all epithelial ovarian cancers are diagnosed as • • stage FACTOIDS • 80% of all epithelial ovarian cancers are diagnosed as • • stage IIIC Occult stage I ovarian cancer is upstaged 30% of the time to stage IIIC when lymph node sampling is performed Patients with microscopic residual disease do better than patients with ≤ 2 cm residual disease than patients with > 2 cm of residual disease (4 year survival rates 60%, 35%, <20%)

CHEMOTHERAPY • • • Gold standard following debulking surgery is Taxol and Carboplatin • CHEMOTHERAPY • • • Gold standard following debulking surgery is Taxol and Carboplatin • • Despite this therapy, 70% of patients with Stage III disease will recur Response rate of 80% Tumors resistant to this combination are refractory to most other types of chemotherapy 100% of patients who have recurrent ovarian cancer will die from their disease

BETTER BULLET • New combinations of chemotherapy (Carboplatin/Taxol • • and Avastin) Intraperitoneal chemotherapy BETTER BULLET • New combinations of chemotherapy (Carboplatin/Taxol • • and Avastin) Intraperitoneal chemotherapy offers a survival advantage for optimally debulked ovarian cancer Dose Dense Chemotherapy (weekly Taxol) also has a survival advantage over traditional therapy Both IP and dose dense chemotherapy have higher morbidity than standard therapy New agents

RECURRENT DISEASE • Chronic disease • Salvage chemotherapy (Doxil, Gemzar, Taxotere, etc) • • RECURRENT DISEASE • Chronic disease • Salvage chemotherapy (Doxil, Gemzar, Taxotere, etc) • • most utilized Most produce clinical responses, thereby, keep patients alive longer Women living on average 4 to 5 years with ovarian cancer Some live 8 to 9 years with the disease Inevitably, the cancer becomes resistant to chemotherapy and the patient dies of bowel obstruction and malnutrition

CERVICAL CANCER • 3 rd most common cancer among women world wide • Estimated CERVICAL CANCER • 3 rd most common cancer among women world wide • Estimated 475, 000 new cases • 250, 000 deaths annually worldwide • 12 th most common cancer among women in the United States • Estimated 12, 360 new cases each year • 4, 020 deaths annually from cervical cancer Seigel et al. Ca J Clin, 2014.

WHO DEVELOPS CERVICAL CANCER? • 50% of women diagnosed with cervical cancer have not WHO DEVELOPS CERVICAL CANCER? • 50% of women diagnosed with cervical cancer have not had a Pap test in 5 years • 25% of all cervical cancers are diagnosed in women older than 65 • In women older than 65, it is estimated that over 50% have not had a Pap test in the past 10 years • Bottom Line – the majority of women with cervical cancer fail to get annual Pap tests

SYMPTOMS • Early stages • • • Vaginal bleeding Post coital spotting Foul smelling, SYMPTOMS • Early stages • • • Vaginal bleeding Post coital spotting Foul smelling, yellowish discharge • Late stages • • Back pain Lethargy Nausea/vomiting Most symptoms attributable to renal failure from ureteral obstruction

CLASSIC RISK FACTORS FOR CERVICAL CANCER • Early first age of sexual contact • CLASSIC RISK FACTORS FOR CERVICAL CANCER • Early first age of sexual contact • Multiple sexual partners • Smoking • Multiple sexually transmitted diseases • Immunocompromised • Lower socio-economic class • Family history is not a risk factor

MAIN RISK FACTORS FOR CERVICAL CANCER • Human papillomavirus (HPV) is the cause of MAIN RISK FACTORS FOR CERVICAL CANCER • Human papillomavirus (HPV) is the cause of cervical cancer • Estimated that 80% of men and women will have been exposed to the virus by the age of 50 • Smoking is an important cofactor for malignant transformation

HPV AND CERVICAL CANCER • Bosch et al in 1995, accrued 932 cases of HPV AND CERVICAL CANCER • Bosch et al in 1995, accrued 932 cases of cervical cancer from around the world • Using polymerase chain reactions (PCR), his group amplified HPV DNA from the tumor and recorded their findings • 93% of cervical carcinoma had HPV DNA • Common types included 16, 18, 31, 33, 35, 39, 45, 51 (high risk HPV subtypes) Bosch et al. J Natl Cancer Inst, 1995

HPV AND CERVICAL CANCER • Walboomers et al. repeated Bosch’s experiment using new PCR HPV AND CERVICAL CANCER • Walboomers et al. repeated Bosch’s experiment using new PCR primers • Those cancers that failed to test positive for HPV DNA were retested with these new primers • Results showed that 99. 7% of Bosch’s original cases tested positive for HPV DNA Walboomers et al. J Pathol, 1999

INCIDENCE OF HPV • 608 college aged women studied from 1992 -1994 • Followed INCIDENCE OF HPV • 608 college aged women studied from 1992 -1994 • Followed 3 years at 6 month intervals • Incidence of infection 43% • Median duration of any HPV infection, 8 months • 70% cleared in one year, 90% in two years Ho et al. NEJM 1998

RISK FACTORS FOR HPV • African American and Hispanic races (RR 4. 4 and RISK FACTORS FOR HPV • African American and Hispanic races (RR 4. 4 and 2. 1) • Etoh consumption > 4 times a month (RR 2) • > 2 -3 sexual partners in one year (RR 3) • > 6 sexual partners of main regular partner (RR 10. 1) Ho et al. NEJM 1998

HPV AND CERVICAL DYSPLASIA • Persistent HPV more likely to progress to cervical dysplasia HPV AND CERVICAL DYSPLASIA • Persistent HPV more likely to progress to cervical dysplasia • High risk types take longer to clear (Median of 12 month) • Women infected with high risk types documented at two 6 month visits were 38 times more likely to develop dysplasia Ho et al. NEJM 1998

HPV AND ONCOGENESIS • Viral DNA E 6 and E 7 believed to be HPV AND ONCOGENESIS • Viral DNA E 6 and E 7 believed to be crucial in stimulating cellular proliferation • E 6 acts by inhibiting p 53 which is a crucial cell protein involved in programmed cell death (apoptosis) • E 7 acts by binding the retinoblastoma (Rb) protein • Once bound, Rb releases E 2 F transcription factor which causes cellular proliferation • Combined they inhibit the regulatory mechanism for apoptosis while stimulating the cell to proliferate

HPV AND SMOKING HPV AND SMOKING

SMOKING AND HPV • Prior to understanding the role of HPV in cervical cancer, SMOKING AND HPV • Prior to understanding the role of HPV in cervical cancer, studies which focused on smoking as a risk factor were often contradictory • Once stratified for HPV status, many recent studies have shown that smokers with HPV are more likely to develop cervical cancer and CIN 3

SMOKING AND ONCOGENESIS • Two probable causes for oncogenesis • Accumulation of carcinogens from SMOKING AND ONCOGENESIS • Two probable causes for oncogenesis • Accumulation of carcinogens from tobacco smoke in cervical mucous • Decreased host immune system • Decreased T cells more likely to lead to uncontrolled cell growth

SMOKING AND CERVICAL CANCER • Plummer et al. and the IARC performed a case- SMOKING AND CERVICAL CANCER • Plummer et al. and the IARC performed a case- control study to determine if smoking was a cofactor for progression of HPV to cancer • Included: • • 1463 squamous cell carcinomas 124 adenocarcinomas 211 CIN 3 cases 254 control women • Only women positive for HPV DNA were included Plummer et al. Cancer Causes Control, 2003

SMOKING AND CERVICAL CANCER • Results: • • ever smoking and HPV had an SMOKING AND CERVICAL CANCER • Results: • • ever smoking and HPV had an OR 2. 17 (95% CI 1. 46 -3. 22) Stronger risk for squamous cell carcinomas OR 2. 3 (95% CI 1. 31 -4. 04) Ex-smokers also had an increased risk for developing squamous cell carcinoma, OR 1. 8 (95% CI 0. 95 -3. 44) No increased risk for smoking and adenocarcinoma

STAGING OF CERVICAL CANCER • • Clinically staged (at least partially) Stage I is STAGING OF CERVICAL CANCER • • Clinically staged (at least partially) Stage I is confined to the cervix • IA 1 (microinvasive disease) • • IA 2 IB 1 IB 2 Stromal invasion ≤ 3 mm and lateral spread ≤ 7 mm • Stromal invasion 3 -5 mm and lateral spread < 7 mm lateral spread • Clinically visible lesion ≤ 4 cm • Clinically visible lesion > 4 cm in greatest dimension

STAGING OF CERVICAL CANCER • Stage IIA- Upper 2/3 of vagina • Stage IIB STAGING OF CERVICAL CANCER • Stage IIA- Upper 2/3 of vagina • Stage IIB • Stage IIIA • Stage IIIB • Stage IVA • Stage IVB • • IIA 1 - visible lesion ≤ 4 cm IIA 2 - visible lesion > 4 cm Parametrial involvement Lower 1/3 of vagina Pelvic sidewall or hydronephrosis Rectal or bladder mucosa Distant disease

CERVICAL ANATOMY CERVICAL ANATOMY

CELL TYPES • Squamous (90%) • • Large cell keratinizing Large cell non-keratinizing • CELL TYPES • Squamous (90%) • • Large cell keratinizing Large cell non-keratinizing • Adenocarcinoma (10%) • Incidence is increasing ~30% • Adenosquamous • Small cell • Neuroendocrine tumor

SURVIVAL RATES • IA • IB • IIA • IIB • IIIA • IIIB SURVIVAL RATES • IA • IB • IIA • IIB • IIIA • IIIB • IVA • IVB ACS website, 2013 93% 80% 63% 58% 35% 32% 16% 15%

STAGE IB 1 CERVICAL CANCER STAGE IB 1 CERVICAL CANCER

TREATMENT • Surgery is reserved for early staged cervical cancer • Stage IA 1 TREATMENT • Surgery is reserved for early staged cervical cancer • Stage IA 1 • • Cervical cone Hysterectomy • Stage IA 2, IB 1 and IB 2 • Radical hysterectomy

RADICAL HYSTERECTOMY • Objective is to remove tissue adjacent to the uterus • • RADICAL HYSTERECTOMY • Objective is to remove tissue adjacent to the uterus • • Parametrial tissue • • Upper 2 cm of the vagina Complete pelvic lymphadenectomy (internal, external, common iliac nodes and obturator nodes) Higher morbidity than a simple hysterectomy

RADICAL HYSTERECTOMY ANATOMY RADICAL HYSTERECTOMY ANATOMY

RADICAL HYSTERECTOMY ANATOMY RADICAL HYSTERECTOMY ANATOMY

RADICAL HYSTERECTOMY ANATOMY RADICAL HYSTERECTOMY ANATOMY

TREATMENT • Stages II-IVB receive radiation (XRT) and chemotherapy • XRT given in two TREATMENT • Stages II-IVB receive radiation (XRT) and chemotherapy • XRT given in two phases • 1 st 5 -6 weeks of external beam radiation • • • Total dose 45 to 50 Gy Or 180 to 200 c. Gy each day Cisplatin 40 mg/m 2 Q week • 2 nd Brachytherapy • • HDR or LDR Positions a radioactive implant adjacent to the carcinoma

CHEMORADIATION Study Stage N Treatment GOG #85 Whitney et al IIb-IVb -PALN 177 EB+BT+ CHEMORADIATION Study Stage N Treatment GOG #85 Whitney et al IIb-IVb -PALN 177 EB+BT+ Cisplatin 50 mg/m 2 5 - FU 1000 mg/m 2 199 EB+BT+ Hydroxyurea 80 mg/kg 2× week 176 EB+BT+ Cisplatin 40 mg/m 2 week 173 EB+BT+ Cisplatin 50 mg/m 2 5 -FU 1000 mg/m 2 Hydroxyurea 2 gm/m 2 177 EB+BT+ Hydroxyurea 3 gm/m 2 195 EB+BT+ Cisplatin 75 mg/m 2 (D 1) Q 3 weeks × 2 5 -FU 1000 mg/m 2 (D 2 -5) 193 EB+BT 183 EB+BT+ Cisplatin 40 mg/m 2 week + hysterectomy 186 EB+BT+ hysterectomy 127 EB+ Cisplatin 70 mg/m 2 (D 1) 5 -FU 1000 mg/m 2 (D 2 -5) 116 EB GOG #120 Rose et al RTOG #9001 Morris et al GOG #123 Keys et al GOG #109 Peters et al IIb-IVb -PALN Ib-IVa Ib-IIa Ia 2 -IIa s/p RAH Follow up (D 1, 29) (D 2 -5 & D 30 -33) Median 3 year Survival (%) Significance 8. 7 years 67 OS p=0. 018, RR 0. 74 57 35 months 2× week OS p=0. 004, RR 0. 61 65 (D 1, 22) (D 2 -5 & D 23 -26) 2× week 65 OS p=0. 002, RR 0. 58 47 43 months 75 OS p=0. 004, RR 0. 59 63 36 months 83 OS p=0. 008, RR 0. 54 74 Q 3 weeks × 2 42 months 87 77 OS p=0. 01, RR 0. 49

ADVANCED/ RECURRENT DISEASE • Main stay is chemotherapy • Advanced (IVA & IVB) palliative ADVANCED/ RECURRENT DISEASE • Main stay is chemotherapy • Advanced (IVA & IVB) palliative XRT and chemo • Recurrent- chemotherapy • Cisplatin/Taxol/Avastin

ACOG RECOMMENDATIONS FOR HPV VACCINATION (CERVARIX OR GARDASIL) • Target age 11 -12 (Males ACOG RECOMMENDATIONS FOR HPV VACCINATION (CERVARIX OR GARDASIL) • Target age 11 -12 (Males and Females)- Cervarix is only approved for women • Females as young as 9 may receive HPV vaccination • Vacination is nearly 100% effective in preventing CIN 2, CIN 3, and VIN • Prevelance of vaccine-type HPV has decreased 56% among females aged 14 -19 years since 2006 • Vaccination is recommended to females age 13 -26 to catch up missed vaccine or to complete the series • Vaccination is not currently recommended for women over the age of 26 or pregnant women (Category B) • Vaccination is acceptable for lactating women • Sexually active women or women with cervical dysplasia/genital condyloma can receive vaccination • Screening for cervical cancer should continue in both vaccinated and unvaccinated women ACOG CO #588, 2014.

VULVAR CANCER • 4850 new cases each year in the United States • 1030 VULVAR CANCER • 4850 new cases each year in the United States • 1030 deaths each year in the United States • Commonly presents at age 70 -80 • Most common cell types: • • • Squamous (90%) Melanoma (6%) Basal Cell (3%) Seigel et al. CA J Clin. 2014

SYMPTOMS • Pruritis • Mass • Pain • Bleeding • Ulceration 45% 23% 14% SYMPTOMS • Pruritis • Mass • Pain • Bleeding • Ulceration 45% 23% 14% • Patients delay medical care by 8 to 12 months • Physicians delay biopsy by 6 to 10 months

RISK FACTORS • Multiple sexual partners • Prior abnormal Pap tests • Genital condyloma RISK FACTORS • Multiple sexual partners • Prior abnormal Pap tests • Genital condyloma • Poor socioeconomic class • Smoking • Human papillomavirus • Associated with 60 -70% of squamous vulvar carcinoma Hording et al. Gynecol Oncol, 1994

STAGING • Stage I – – Tumor confined to the vulva Stage IA- lesions STAGING • Stage I – – Tumor confined to the vulva Stage IA- lesions ≤ 2 cm in size with stromal invasion ≤ 1 mm Stage IB- lesions > 2 cm or with stromal invasion > 1 mm • Stage III Tumor of any size with or without extension to adjacent structures (⅓ lower urethra, vagina, anus) and with positive inguino-femoral lymph nodes Tumor of any size with extension to adjacent structures (⅓ lower urethra, vagina, anus) – – – • Stage IIIA- 1 lymph node (≥ 5 mm) or 1 -2 lymph nodes (< 5 mm) Stage IIIB- 2 lymph nodes (≥ 5 mm) or 3 lymph nodes (< 5 mm) Stage IIIC- with positive nodes with extracapsular spread Stage IV Tumor invades other regional (⅔ upper urethra and vagina) or distant structures – Stage IVA- tumor invades any of the following: • • – (i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa or fixed to pelvic bone (ii) fixed or ulcerated inguino-femoral lymph nodes Stage IVB- any distant metastasis including pelvic lymph nodes 2010 FIGO Staging system

TREATMENT • Surgical excision mainstay of therapy 95% • Lateral lesions are removed (radical TREATMENT • Surgical excision mainstay of therapy 95% • Lateral lesions are removed (radical hemivulvectomy) • • along with the ipsilateral inguinal lymph nodes Central lesions are removed (radical vulvectomy) with bilateral superficial inguinal lymph nodes Patients with positive inguinal lymph nodes receive EB radiation to the groin (45 Gy)

RADICAL HEMIVULVECTOMY RADICAL HEMIVULVECTOMY

VULVAR EXCISION FROM START TO FINISH VULVAR EXCISION FROM START TO FINISH

VULVAR EXCISION FROM START TO FINISH VULVAR EXCISION FROM START TO FINISH

VULVAR EXCISION FROM START TO FINISH VULVAR EXCISION FROM START TO FINISH

VULVAR EXCISION FROM START TO FINISH VULVAR EXCISION FROM START TO FINISH

VULVAR EXCISION FROM START TO FINISH VULVAR EXCISION FROM START TO FINISH

VULVAR EXCISION FROM START TO FINISH VULVAR EXCISION FROM START TO FINISH

VULVAR EXCISION FROM START TO FINISH VULVAR EXCISION FROM START TO FINISH

LARGE VULVAR EXCISIONS • Flap placement is often required to close large defects • LARGE VULVAR EXCISIONS • Flap placement is often required to close large defects • • • V to Y flaps Gracilis muscle flaps Rhomboid flaps

COMPLETE VULVECTOMY COMPLETE VULVECTOMY

COMPLETE VULVECTOMY COMPLETE VULVECTOMY

LARGE VULVAR EXCISIONS LARGE VULVAR EXCISIONS

LARGE VULVAR EXCISIONS LARGE VULVAR EXCISIONS

ADVANCED STAGES • Exenteration • Lengthy • Increased blood loss • Permanent colostomy • ADVANCED STAGES • Exenteration • Lengthy • Increased blood loss • Permanent colostomy • Plastic reconstruction • Chemoradiation • Studied by the GOG • Can spare morbid surgery and achieve reasonable survival

RECURRENT DISEASE • Local recurrence can be salvaged with local excision • 50% 5 RECURRENT DISEASE • Local recurrence can be salvaged with local excision • 50% 5 -year survival • Distant disease is lethal • Chemotherapy • • • Cisplatin 40% RR Bleomycin 30% RR Adriamycin 30% RR

SUMMARY • Endometrial Cancer • Postmenopausal bleeding must be evaluated with an ultrasound or SUMMARY • Endometrial Cancer • Postmenopausal bleeding must be evaluated with an ultrasound or diagnostic biopsy • 80% of patients are cured with surgery alone • Ovarian Cancer • • • Difficult to detect Obtain annual vaginal ultrasounds for your patients Poor prognosis if detected at an advanced stage

SUMMARY • Cervical Cancer • • • Obtain a Pap test Ask the patient SUMMARY • Cervical Cancer • • • Obtain a Pap test Ask the patient when her last Pap test was performed With today's screening, few cancers should be diagnosed past Stage II • Vulvar Cancer • • “Biopsy first, medicine later” Excellent prognosis with surgery