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

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

3. 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

4. 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

5. 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

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

7. RISK FACTORS Nulliparous2x Late menopause2.4x Diabetes2.8x HTN1.5x Obesity >30lbs3x Obesity >50lbs10x Unopposed estrogen9.5x MacMahon, Gynecol Oncol 1974

8. 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

9. 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.

10. 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

11. ENDOMETRIAL CANCER

12. SURGICAL STAGING IAtumor invasion < ½ myometrium IBtumor invasion > ½ myometrium IIcervical involvement IIIA+ pelvic cytology, adnexa or uterine serosa IIIBparametrial or vaginal involvement IIIC 1 pelvic lymph node involvement IIIC 2 para-aortic lymph node involvement IVArectal or bladder mucosa involvement IVBinguinal node involvement, intra abdominal disease or distant metastasis

13. PROGNOSIS BY STAGE IA 88% IB75% II69% IIIA58% IIIB50% IIIC47% IVA17% IVB15% ACS Webpage 2013

14. 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

15. LYMPH NODES University of Kentucky is conducting a trial regarding lymphadenectomy for endometrial cancer Our division favors selective lymphadenectomy Two European randomized trial revealed no significant difference in OS with pelvic 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)

16. 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 > 2cm and/or… Grade 3 adenocarcinoma and/or… Greater than ½ myometrial invasion 10-35% risk of positive lymph nodes Caveat: multiple studies evaluating preoperative imaging have failed to reliably predict myometrial invasion

17. ILIAC LYMPH NODES

18. OBTURATOR LYMPH NODES

19. 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

20. 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

21. 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

22. 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

23. 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

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

25. 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%

26. 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

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

28. 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

29. OVARIAN CANCER

34. STAGING I - limited to the ovary IA one ovary (capsule intact, no tumor on surface, negative cytology) IB both ovaries IC1 surgical spillage IC2 spontaneous rupture, tumor on surface of ovary IC3 positive cytology II - pelvic extension IIA extension to uterus/tubes IIB other pelvic intraperitoneal tissues (bladder/colon serosa) III – abdominal extension IIIA1- positive retroperitoneal lymph nodes IIIA2 - microscopic seeding of abdominal peritoneal surfaces IIIB - abdominal implants < 2 cm IIIC - abdominal implants > 2 cm IV – distant metastasis IVA- malignant pleural effusion IVB- Hepatic or splenic parenchyma, distal spread outside the abdomen

35. SURVIVAL BY STAGE – OLD CLASSIFICATION IA94% IB90% IC81% IIA76% IIB67% IIC57% IIIA45% IIIB39% IIIC35% IV18% ACS website 2013

36. 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%)

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

38. 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

39. 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

40. 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.

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

50. HPV AND ONCOGENESIS Viral DNA E6 and E7 believed to be crucial in stimulating cellular proliferation E6 acts by inhibiting p53 which is a crucial cell protein involved in programmed cell death (apoptosis) E7 acts by binding the retinoblastoma (Rb) protein Once bound, Rb releases E2F transcription factor which causes cellular proliferation Combined they inhibit the regulatory mechanism for apoptosis while stimulating the cell to proliferate

51. HPV AND SMOKING

52. 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

53. 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

54. 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

55. 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

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

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

58. CERVICAL ANATOMY

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

60. SURVIVAL RATES IA93% IB80% IIA63% IIB58% IIIA35% IIIB32% IVA16% IVB15% ACS website, 2013

61. STAGE IB 1 CERVICAL CANCER

62. 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

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

64. RADICAL HYSTERECTOMY ANATOMY

67. 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 cGy each day Cisplatin 40 mg/m 2 Q week 2 nd Brachytherapy HDR or LDR Positions a radioactive implant adjacent to the carcinoma

68. CHEMORADIATION StudyStageNTreatmentFollow upMedian 3 year Survival (%) Significance GOG #85 Whitney et al IIb-IVb -PALN 177 199 EB+BT+ Cisplatin 50 mg/m 2 (D1, 29) 5- FU 1000mg/m 2 (D2-5 & D30-33) EB+BT+ Hydroxyurea 80mg/kg 2× week 8.7 years67 57 OS p=0.018, RR 0.74 GOG #120 Rose et al IIb-IVb -PALN 176 173 177 EB+BT+ Cisplatin 40mg/m 2 week EB+BT+ Cisplatin 50 mg/m 2 (D1, 22) 5-FU 1000mg/m 2 (D2-5 & D23-26) Hydroxyurea 2gm/m 2 2× week EB+BT+ Hydroxyurea 3gm/m 2 2× week 35 months65 47 OS p=0.004, RR 0.61 OS p=0.002, RR 0.58 RTOG #9001 Morris et al Ib-IVa195 193 EB+BT+ Cisplatin 75 mg/m 2 (D1) Q 3 weeks ×2 5-FU 1000 mg/m 2 (D2-5) EB+BT 43 months75 63 OS p=0.004, RR 0.59 GOG #123 Keys et al Ib-IIa183 186 EB+BT+ Cisplatin 40 mg/m 2 week + hysterectomy EB+BT+ hysterectomy 36 months83 74 OS p=0.008, RR 0.54 GOG #109 Peters et al Ia2-IIa s/p RAH 127 116 EB+ Cisplatin 70 mg/m 2 (D1) Q 3 weeks ×2 5-FU 1000 mg/m 2 (D2-5) EB 42 months87 77 OS p=0.01, RR 0.49

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

70. 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 CIN2, CIN3, 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.

71. 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

72. SYMPTOMS Pruritis45% Mass45% Pain23% Bleeding14% Ulceration14% Patients delay medical care by 8 to 12 months Physicians delay biopsy by 6 to 10 months

73. 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

74. STAGING Stage ITumor confined to the vulva – Stage IA- lesions ≤ 2 cm in size with stromal invasion ≤ 1 mm – Stage IB- lesions > 2cm or with stromal invasion > 1 mm Stage IITumor of any size with extension to adjacent structures ( ⅓ lower urethra, vagina, anus) 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 – Stage IIIA- 1 lymph node (≥ 5mm) or 1-2 lymph nodes (< 5mm) – Stage IIIB- 2 lymph nodes (≥ 5mm) or 3 lymph nodes (< 5mm) – 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

75. 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)

76. RADICAL HEMIVULVECTOMY

77. VULVAR EXCISION FROM START TO FINISH

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

85. COMPLETE VULVECTOMY

87. LARGE VULVAR EXCISIONS

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

90. RECURRENT DISEASE Local recurrence can be salvaged with local excision 50% 5-year survival Distant disease is lethal Chemotherapy Cisplatin 40% RR Bleomycin30% RR Adriamycin30% RR

91. 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

92. 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