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Gynecologic Carcinomas

Gynecologic Carcinomas . Christopher P. DeSimone, M.D. Associate Professor Division of Gynecologic Oncology. Outline. Endometrial Carcinoma Ovarian Carcinoma Cervical Carcinoma Vulvar Carcinoma Epidemiology Clinical symptoms Risk factors Diagnosis Staging Treatment.

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Gynecologic Carcinomas

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  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 • 4th most common malignancy among women • Estimated 52,630 new cases per year in the United States • 1 in 38 women will develop this cancer • 7thmost common cause of malignancy related deaths among women • 8,590 deaths annual from endometrial cancer Seigelet 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 • Nulliparous 2x • Late menopause 2.4x • Diabetes 2.8x • HTN 1.5x • Obesity >30lbs 3x • Obesity >50lbs 10x • Unopposed estrogen 9.5x 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 • IA tumor invasion <½ myometrium • IB tumor invasion > ½ myometrium • II cervical involvement • IIIA + pelvic cytology, adnexa or uterine serosa • IIIB parametrial or vaginal involvement • IIIC1 pelvic lymph node involvement • IIIC2 para-aortic lymph node involvement • IVA rectal or bladder mucosa involvement • IVB inguinal node involvement, intra abdominal disease or distant metastasis

  13. Prognosis by Stage • IA 88% • IB 75% • II69% • IIIA 58% • IIIB 50% • IIIC 47% • IVA 17% • IVB 15% 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 • 5th most common cause of cancer related mortality among women • Peak incidence at age 65-85 • Slowly decreasing in incidence since the mid 1980’s Seigelet 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

  30. Ovarian Cancer

  31. Ovarian Cancer

  32. Ovarian Cancer

  33. 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 • IA 94% • IB 90% • IC 81% • IIA 76% • IIB 67% • IIC 57% • IIIA 45% • IIIB 39% • IIIC 35% • IV 18% 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 debulkingsurgery 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 • 3rd most common cancer among women world wide • Estimated 475,000 new cases • 250,000 deaths annually worldwide • 12th 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

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