Uterine Cancer


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Uterin Cancer epidemiology, risk factors, staging and treatment

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Uterine Cancer

  1. 1. Uterine Cancer Pedro T. Ramirez, M.D. Associate Professor Director of Minimally Invasive Research & Education Department of Gynecologic Oncology
  2. 2. Uterine Cancer <ul><li>Fourth most common cancer in women in the U.S. behind breast, lung, and colon cancer </li></ul><ul><li>Most common gynecologic malignancy </li></ul><ul><li>Eighth leading cause of female mortality from cancer </li></ul><ul><li>97% arise from the endometrium (endometrial carcinoma) </li></ul><ul><li>3% arise from the mesenchymal components (sarcoma) </li></ul>
  3. 3. Epidemiology <ul><li>Median age of diagnosis: 60 years </li></ul><ul><ul><li>Most common in women > age 50 years </li></ul></ul><ul><li>Incidence is highly dependent on age </li></ul><ul><li>75% of uterine cancers occur in post-menopausal women </li></ul><ul><li>There are two major pathogenic types of endometrial cancer </li></ul><ul><ul><li>Type I </li></ul></ul><ul><ul><li>Type II </li></ul></ul>
  4. 4. Type I Endometrial Carcinoma <ul><li>Younger/peri-menopausal women </li></ul><ul><li>Obese </li></ul><ul><li>Associated with estrogen excess </li></ul><ul><li>Well differentiated endometrioid </li></ul><ul><li>Superficial myometrial invasion </li></ul><ul><li>Infrequent lymph node metastases </li></ul><ul><li>Associated with hyperplasia </li></ul><ul><li>Genetic mutations in K-ras, PTEN, MLH1 </li></ul><ul><li>Better prognosis </li></ul>
  5. 5. Type II Endometrial Carcinoma <ul><li>Older/post-menopausal women </li></ul><ul><li>Thin </li></ul><ul><li>Poorly differentiated carcinoma </li></ul><ul><ul><li>Papillary Serous </li></ul></ul><ul><ul><li>Clear Cell </li></ul></ul><ul><li>Deep myometrial invasion </li></ul><ul><li>Frequent lymph node metastases </li></ul><ul><li>Associated with atrophy </li></ul><ul><li>Genetic mutations in p53, Erb-B2 </li></ul><ul><li>Not associated with typical risk factors </li></ul>
  6. 6. RISK FACTORS <ul><li>Exposure to estrogen is a key risk factor </li></ul><ul><ul><ul><li>Risk is increased with dose and time exposed </li></ul></ul></ul><ul><ul><ul><li>Endogenous estrogen </li></ul></ul></ul><ul><ul><ul><ul><li>Morbid obesity </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Polycystic ovary syndrome </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Oligomenorrhea </li></ul></ul></ul></ul><ul><ul><ul><li>Exogenous estrogen </li></ul></ul></ul><ul><ul><ul><ul><li>Hormone replacement without progestin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Tamoxifen (estrogen agonist in the endometrium) </li></ul></ul></ul></ul>
  7. 7. Risk Factors <ul><li>OBESITY </li></ul><ul><ul><li>21-50lb overweight – 3x incidence </li></ul></ul><ul><ul><li>>50lb weight - 10x incidence </li></ul></ul><ul><li>Nulliparity – incidence increased 2x </li></ul><ul><li>Late Menopause - incidence increased 2.5x </li></ul><ul><li>Diabetes, hypertension, hypothyroidism are associated with endometrial cancer </li></ul>
  8. 8. Familial Syndromes <ul><li>Lynch Syndrome/HNPCC (Hereditary Nonpolyposis Colorectal Cancer) </li></ul><ul><ul><li>Caused by inherited germline mutation in DNA-mismatch repair genes (MLH1, MSH2, MSH6, PMS2) </li></ul></ul><ul><li>Cowden Syndrome </li></ul><ul><ul><li>PTEN mutation </li></ul></ul>
  9. 9. Endometrial Cancer Screening <ul><li>ACS (2001) </li></ul><ul><ul><li>No routine screening </li></ul></ul><ul><ul><li>Inform patients at average/increased risk about the signs and symptoms </li></ul></ul><ul><ul><li>Screen based on presence of symptoms </li></ul></ul><ul><ul><li>Lynch Syndrome – screen annually with endometrial biopsy at age 35yrs </li></ul></ul>
  10. 10. Signs and Symptoms <ul><li>Bleeding </li></ul><ul><ul><li>Present in 90% of all cases </li></ul></ul><ul><ul><li>15% of patients with postmenopausal bleeding will have endometrial cancer </li></ul></ul><ul><li>Other Signs/Symptoms </li></ul><ul><ul><li>Vaginal Discharge(80-90%) </li></ul></ul><ul><ul><li>Pelvic Pain, Pressure </li></ul></ul><ul><ul><li>Referred Leg Pain </li></ul></ul><ul><ul><li>Change in Bowel Habits </li></ul></ul><ul><ul><li>Pyometria/Hematometria </li></ul></ul>
  11. 11. Diagnosis <ul><li>Pap Smear </li></ul><ul><ul><li>Only 30-50% patients with cancer will have an abnormal result </li></ul></ul><ul><ul><li>AGUS predictive of carcinoma </li></ul></ul><ul><li>Endometrial Biopsy </li></ul><ul><ul><li>False negative rate of 5-10% </li></ul></ul><ul><li>Transvaginal Ultrasound </li></ul><ul><ul><li>Not for routine screening or diagnosis </li></ul></ul><ul><ul><li>Suspicious findings include endometrial stripe >5mm, polypoid mass, or fluid collection in uterus </li></ul></ul>
  12. 12. Diagnosis: Gold Standard <ul><li>Fractional Dilation and Curettage </li></ul><ul><ul><li>Use in cases of cervical stenosis, patient intolerance to exam, recurrent bleeding after negative biopsy, or bleeding unexplained by endometrial biopsy result </li></ul></ul><ul><ul><li>Sample endocervix and endometrium </li></ul></ul><ul><ul><li>False neg – 2-6% </li></ul></ul><ul><li>May add hysteroscopy to identify non-malignant causes of bleeding </li></ul>
  13. 13. Endometrial Hyperplasia <ul><li>Simple </li></ul><ul><li>Complex </li></ul>
  14. 14. Hyperplasia: Progression to Cancer <ul><li>NO ATYPIA </li></ul><ul><li>Simple – 1.3% </li></ul><ul><li>Complex – 3% </li></ul><ul><li>ATYPIA </li></ul><ul><li>Simple – 8% </li></ul><ul><li>Complex – 29% </li></ul>Significant percentage (43%) of complex hyperplasia with atypia will have coexisting adenocarcinoma
  15. 15. Management: Hyperplasia NO ATYPIA <ul><ul><li>No Treatment (only for simple) </li></ul></ul><ul><ul><li>Continuous Progestins </li></ul></ul><ul><ul><li>Re-examination if bleeding </li></ul></ul><ul><li>PROGESTIN OPTIONS </li></ul><ul><ul><li>Medroxyprogesterone 10mg/d (10-30mg/d) </li></ul></ul><ul><ul><li>Norethindrone 2.5mg/d (2.5-10mg/d) </li></ul></ul><ul><ul><li>Megestrol 160mg/d* </li></ul></ul><ul><ul><li>Oral contraceptive pills </li></ul></ul><ul><ul><li>Levonorgestrel-eluting Intrauterine Device </li></ul></ul>
  16. 16. Management: Hyperplasia ATYPIA <ul><li>Hysterectomy </li></ul><ul><li>If poor surgical candidate/ desires fertility sparing </li></ul><ul><ul><li>Continuous high dose progestin </li></ul></ul><ul><ul><ul><li>Megestrol acetate 160mg/day divided doses </li></ul></ul></ul><ul><ul><li>Levonorgestrel intrauterine device </li></ul></ul><ul><ul><li>Re-exam every 3 months </li></ul></ul><ul><ul><li>Response to hormones 50-75% </li></ul></ul>
  17. 17. Endometrial Carcinoma <ul><li>HISTOLOGY </li></ul><ul><ul><li>Endometrioid – 80% </li></ul></ul><ul><ul><li>Papillary Serous 5-7% </li></ul></ul><ul><ul><li>Mucinous – 5% </li></ul></ul><ul><ul><li>Clear cell – 3% </li></ul></ul><ul><ul><li>Villoglandular – 2% </li></ul></ul><ul><ul><li>Secretory – 1% </li></ul></ul><ul><ul><li>Pure Squamous – Rare </li></ul></ul>
  18. 18. Important Histology Points <ul><li>Papillary serous carcinomas are aggressive </li></ul><ul><ul><li>Even when mixed with other types, if there is > 25% serous they will retain aggressive behavior </li></ul></ul><ul><li>Clear cell carcinomas act similar to high grade endometrioid type carcinoma </li></ul><ul><li>Mucinous carcinomas act similar to well differentiated endometrioid type carcinoma </li></ul><ul><li>Squamous carcinomas have a poor prognosis </li></ul>
  19. 19. Endometrial Cancer Grade <ul><li>The grade is based on the percentage of the solid component. </li></ul><ul><ul><li>Well Differentiated (Grade 1): <5% </li></ul></ul><ul><ul><li>Moderately Differentiated (Grade 2): 5-50% </li></ul></ul><ul><ul><li>Poorly Differentiated (Grade 3): > 50% </li></ul></ul>
  20. 20. Synchronous Endometrial and Ovarian Cancer <ul><li>Incidence of 1.4 - 3.8% </li></ul><ul><li>Both tumors are typically well differentiated cancers </li></ul><ul><li>Good prognosis because ovarian tumor found at earlier stage </li></ul><ul><li>30% of patients with endometrioid ovarian cancer will have associated endometrial cancer </li></ul><ul><li>15-20% of patients with granulosa cell tumors will have associated endometrial cancer </li></ul>
  21. 21. Pretreatment Evaluation <ul><li>History & Physical </li></ul><ul><li>Laboratory </li></ul><ul><ul><li>CBC, Chem, Liver </li></ul></ul><ul><ul><li>Ca-125 – useful in advanced disease </li></ul></ul><ul><li>Radiology </li></ul><ul><ul><li>Chest X-Ray </li></ul></ul><ul><ul><li>MRI/ Ultrasound – do not reliably assess depth of invasion </li></ul></ul><ul><ul><li>All other studies are ordered as needed based on symptoms </li></ul></ul>
  22. 22. Endometrial Cancer Treatment <ul><li>Surgery is the mainstay of treatment followed by adjuvant radiation and/or chemotherapy based on stage of disease. </li></ul><ul><li>Primary radiotherapy or hormonal therapy may be employed in patients who have contraindications to surgery. </li></ul>
  23. 23. Primary Radiation Therapy <ul><li>3-5% of patients who cannot tolerate surgery </li></ul><ul><ul><li>Elderly, obese, multiple medical co-morbidities </li></ul></ul><ul><li>Excellent survival and local control rates </li></ul><ul><li>5 year disease-specific survival is 87% </li></ul>
  24. 24. Hormone Therapy <ul><li>Appropriate in patients that desire fertility preservation </li></ul><ul><ul><li>Young patient </li></ul></ul><ul><ul><li>Well differentiated cancer </li></ul></ul><ul><li>Approximately 75% response rate </li></ul><ul><ul><li>25% recurrence at a median of 19 months </li></ul></ul><ul><li>High dose progestins </li></ul><ul><li>ONLY-G1 tumors!! </li></ul>
  25. 25. Surgical Treatment <ul><li>Exploration </li></ul><ul><li>Simple hysterectomy </li></ul><ul><ul><li>Radical if suspected cervical involvement </li></ul></ul><ul><li>Bilateral salpingo-oophorectomy </li></ul><ul><li>Pelvic washings </li></ul><ul><li>Lymphadenectomy </li></ul><ul><ul><li>Pelvic </li></ul></ul><ul><ul><li>Para-aortic </li></ul></ul><ul><li>+/- Omentectomy </li></ul>
  26. 27. Risk of Lymph Node Metastasis <ul><li>Grade </li></ul><ul><ul><li>Grade 1 = 3% </li></ul></ul><ul><ul><li>Grade 2 = 9% </li></ul></ul><ul><ul><li>Grade 3 = 18% </li></ul></ul><ul><li>Myometrial Invasion </li></ul><ul><ul><li>None/Superficial = <5% </li></ul></ul><ul><ul><li>> ½ myometrium = 20% </li></ul></ul><ul><li>Cervical Involvement </li></ul><ul><ul><li>15% </li></ul></ul>
  27. 28. Routine Lymphadenectomy <ul><li>No clear evidence of impact of routine lymphadenectomy on survival </li></ul><ul><ul><li>Retrospective studies have shown a survival benefit from lymphadenectomy, however, recent randomized control trials fail to show this benefit. </li></ul></ul><ul><li>Benefit may be directly related to appropriate surgical staging and treatment planning </li></ul>
  28. 29. Laparoscopic Staging <ul><li>GOG LAP–2 </li></ul><ul><ul><li>Randomized trial of laparoscopy versus laparatomy for endometrial cancer staging </li></ul></ul><ul><ul><li>2,616 Stage I/IIa patients enrolled </li></ul></ul><ul><ul><li>Data suggest that laparoscopic surgical staging is feasible for most patients </li></ul></ul><ul><ul><ul><li>23% conversion to laparotomy </li></ul></ul></ul><ul><ul><ul><li>Equivalent complications </li></ul></ul></ul><ul><ul><ul><li>Shorter length of stay and longer operative times in laparoscopic group </li></ul></ul></ul><ul><ul><li>Long-term results of progression-free and overall survival are not yet available </li></ul></ul>
  29. 30. Laparotomy vs. Laparoscopy?
  30. 31. Laparotomy vs. Laparoscopy?
  31. 32. Survival by Surgical Stage <ul><li>3-Year 5-Year </li></ul><ul><li>Stage I 93% 90% </li></ul><ul><li>Stage II 84% 78% </li></ul><ul><li>Stage III 70% 62% </li></ul><ul><li>Stage IV 30% 21% </li></ul>
  32. 33. Prognostic Factors <ul><li>Stage is the most significant predictor of survival </li></ul><ul><li>Lymph node metastasis is the most important prognostic factor in clinically early endometrial cancer </li></ul><ul><li>(6-fold higher recurrence rate) </li></ul><ul><li>Prognostic Factor Reduction in 5-yr survival </li></ul><ul><li>Lymph node metastasis 40% </li></ul><ul><li>Histology Type </li></ul><ul><ul><li>Papillary serous/Clear cell 40-60% </li></ul></ul><ul><ul><li>High grade endometrioid 25% </li></ul></ul><ul><li>Deep myometrial invasion 30% </li></ul><ul><li>Tumor Size </li></ul><ul><ul><li>Entire uterine cavity 30% </li></ul></ul><ul><ul><li>>2cm 10% </li></ul></ul><ul><li>Lymphovascular space invasion 20% </li></ul><ul><li>Adnexal involvement alone 5% </li></ul>
  33. 34. Adjuvant Therapy <ul><li>Observation </li></ul><ul><li>Vaginal vault radiation </li></ul><ul><li>External pelvic radiation </li></ul><ul><li>Extended-field (pelvic/para-aortic) radiation </li></ul><ul><li>Hormonal therapy </li></ul><ul><li>Chemotherapy </li></ul>
  34. 35. Low Risk Endometrial Cancer <ul><li>Stage IA (grade 1 or 2) </li></ul><ul><li>Excellent prognosis </li></ul><ul><li>No further treatment </li></ul>
  35. 36. Adjuvant Radiation Therapy <ul><li>Reduces risk of recurrence </li></ul><ul><li>NO impact on overall survival </li></ul><ul><li>Vaginal brachytherapy </li></ul><ul><li>-Intermediate risk tumors </li></ul><ul><li> (Stage IA, grade 2/3 or Stage IB, grade 1/2) </li></ul><ul><li>External beam radiation therapy </li></ul><ul><li>-High risk tumors </li></ul><ul><li> (Positive lymph nodes, cervical involvement) </li></ul>
  36. 37. Follow Up <ul><li>First 2 year – Q3- 4months </li></ul><ul><li>Every 6 months until 5 years NED </li></ul><ul><li>Each visit </li></ul><ul><ul><li>Pelvic Exam </li></ul></ul><ul><ul><li>PAP annually </li></ul></ul><ul><ul><li>CXR annually </li></ul></ul>
  37. 38. Recurrence <ul><li>50% recurrences occur within 2 years of treatment </li></ul><ul><li>Most common site of recurrence is vaginal or pelvic </li></ul><ul><li>Most common sites of extra-pelvic metastasis: lung </li></ul><ul><li>Isolated vaginal recurrence has the best prognosis </li></ul><ul><li>Estrogen/progesterone receptor: hormonal therapy </li></ul><ul><li>Chemotherapy options metastatic disease </li></ul>
  38. 39. Uterine Sarcoma <ul><li>3% of all uterine cancers </li></ul><ul><li>15% of all deaths from uterine cancer </li></ul><ul><li>Types </li></ul><ul><ul><li>Carcinosarcoma </li></ul></ul><ul><ul><li>Leiomyosarcoma </li></ul></ul><ul><ul><li>Endometrial Stromal Tumors </li></ul></ul>
  39. 40. Carcinosarcoma <ul><li>Post-menopausal- median age of 62 years </li></ul><ul><li>Associated with diabetes, hypertension, and obesity </li></ul><ul><li>Increased in African-American women </li></ul><ul><li>7-37% of patients have prior pelvic irradiation </li></ul>
  40. 41. Carcinosarcoma Survival <ul><li>Poor prognosis: </li></ul><ul><li>2-year survival </li></ul><ul><li>Stage I disease-50% </li></ul><ul><li>Stage II disease-10% </li></ul><ul><li>Extrauterine 40-60% at diagnosis </li></ul>
  41. 42. Leiomyosarcoma <ul><li>Leiomyosarcoma: </li></ul><ul><ul><li>Mitotic count: > 10 mitosis per HPF </li></ul></ul><ul><ul><li>Cellular atypia </li></ul></ul><ul><ul><li>Coagulative necrosis </li></ul></ul><ul><li>Median age 52 years </li></ul><ul><li>Premenopausal have a better prognosis </li></ul><ul><li>Leiomyomata: sarcomatous rate of 0.13% </li></ul><ul><li>Survival rates range from 20 – 63% </li></ul>
  42. 43. Sarcoma Treatment: Surgery <ul><li>Stage I/II sarcomas should be treated with hysterectomy </li></ul><ul><li>Lymphadenectomy is indicated in all sarcomas except leiomyosarcoma </li></ul><ul><li>Bilateral salpingo-ophorectomy </li></ul><ul><li>NOT necessary in premenopausal women </li></ul>
  43. 44. Sarcoma Treatment: Radiation <ul><li>Radiation therapy results in lower pelvic recurrence rates but NO change in overall survival rate </li></ul><ul><li>The use of radiation in leiomyosarcoma does not impact recurrence, progression-free, or overall survival </li></ul>
  44. 45. Sarcoma Treatment: Recurrence <ul><li>Isolated lesions </li></ul><ul><li>-surgical excision </li></ul><ul><li>Recurrent carcinosarcoma </li></ul><ul><li>-paclitaxel, platinum or ifosfamide </li></ul><ul><li>Recurrent leiomyosarcoma </li></ul><ul><li>-doxorubicin, ifosfamide, docetaxel and gemcitabine </li></ul>
  45. 46. MD Anderson Cancer Center