Uterine Cancer

1. Uterine Cancer

2. Amita Maheshwari Assoc. Professor of Gynecologic Oncology Tata Memorial Hospital maheshwariamita@yahoo.com

3. Introduction • The most common gynecologic cancer in developed countries. • In India, it ranks third amongst gynecologic cancer. • 70% cases are diagnosed in stage-I. • 5-year survival rate ~80%.

4. Risk factors Factors increasing risk • Increased exposure to unopposed estrogen • estrogen-replacement therapy, obesity, anovulatory cycles, estrogen-secreting tumors • Nulliparity • Years of menstruation • HNPCC family syndrome • Tamoxifen • Increasing age Factors decreasing risk • Grand multiparity • Oral contraceptives • Smoking • Physical activity

5. Role of Screening Routine screening NOT recommended. • Postmenopausal women on exogenous estrogens without progestins • Women from families with hereditary nonpolyposis colorectal cancer syndrome. • Premenopausal women with anovulatory cycles, such as those with polycystic ovarian disease

6. Patients in Whom a Diagnosis of Endometrial Cancer Should Be Excluded • All patients with postmenopausal bleeding • Postmenopausal women with a pyometra • Asymptomatic postmenopausal women with endometrial cells on a Pap smear, particularly if they are atypical • Perimenopausal patients with inter-menstrual bleeding or increasingly heavy periods • Premenopausal patients with abnormal uterine bleeding, particularly if there is a history of anovulation

7. Causes of Postmenopausal Bleeding • Atrophic endometritis/vaginitis • Endometrial or cervical polyps • Exogenous estrogens • Endometrial hyperplasia • Endometrial cancer • Miscellaneous (e.g., cervical cancer, uterine sarcoma, urethral caruncle, trauma)

8. Management of endometrial hyperplasia

9. Diagnosis & Pre-op investigations • Office endometrial biopsy: 10% false negative rate. • Fractional curettage under anesthesia: The gold standard. • Hysteroscopy : may identify polyps Fluid hysteroscopy may facilitate the abdominal dissemination of malignant cells, but there is no evidence that it has any impact on the disease-free survival. • X-ray chest, USG, CT scan, MRI, PET-CT, • Serum CA-125 • CBC, Renal function tests, Liver function tests, Blood sugar

10. WHO histological classification

11. Clinico-pathologic Types • Type-1 (low grade): ~90% Eo related- Arise on a background of hyperplasia. Long duration of unopposed estrogenic stimulation. Well-moderately differentiated. Favorable prognosis. • Type-2 (high grade): ~10% Eo non-related- Arise in atrophic endometrium. Non-estrogen dependent. Poorly differentiated or non-endometroid types. High risk of relapse and metastasis. Prognosis poor.

12. Ca-Endometrium & Ca-Ovary • ~8% Ca-endometrium associated with simultaneous presence of endometroid type Ca-ovary. • Synchronous: Independent primary • Both tumors are well differentiated and endometrial tumor is superficially invasive. • Metastatic: small, bilateral, or multi-nodular with surface implants and angiolymphatic invasion in the ovarian cortex. • D/Dx: by IHC and molecular genetic.

13. Spread Patterns • Direct extension to adjacent structures • Transtubal passage of exfoliated cells • Lymphatic dissemination • Hematogenous dissemination

14. Management of Endometrial Ca • 1900s Primary surgery • Mid 1930s Pre-operative RT • 1970s Primary surgery- clinical staging • 1988 FIGO Surgico-pathological staging • 2008 Revised FIGO staging

15. FIGO Surgico-pathologic staging (1988 vs 2008) St.-I Tumor confined to the corpus uteri IA No myometrial invasion IB Myometrial invasion < half IC Myometrial invasion ≥ half IA No or < half myometrial invasion IB Myometrial invasion ≥ half St.-II Cervical involvement IIA Cervical glandular involvement IIB Cervical stromal involvement II Tumor invades cervical stroma Revised FIGO staging. IJGO, 2009

16. FIGO Surgico-pathologic staging (1988 vs 2008) St.-III Local and/or regional spread IIIA Tumor invades the serosa of the uterus and/or adnexa and/or positive cytology IIIB Vaginal involvement parametrial involvement IIIC Pelvic and or para-aotic LN involvement IIIC1 Positive pelvic nodes IIIC2 Positive para-aortic nodes ± pelvic LNs St.-IV Tumor invades bladder and/or bowel mucosa or distant metastases IVA Invasion of bladder and/or bowel mucosa IVB Distant metastases

17. FIGO-Grade • Applies to Endometroid type; serous and clear cell carcinomas are considered to be high grade. • Grade 1: well formed glands with  5% solid, non-squamous areas. • Grade 2: 6%-50% solid non-squamous areas. • Grade 3:>50% solid non-squamous areas.

18. Steps of Surgical Staging • Peritoneal washings for cytology • Exploration of the abdomen & pelvis • Biopsy of any suspicious lesion • Total hysterectomy + BSO* • Pelvic & para-aortic lymphadenectomy * Ovarian preservation

19. Value of Surgical Staging Prognostic: • Accurately defines the extent of disease spread – Upstaging in up-to 23% clinical stage I • Determines the prognosis Adjuvant Rx: • Determines the need for and extent of adjuvant treatment Therapeutic:

20. Prognostic Value of Lymph Node Metastases -Morrow et al. Gynecol Oncol,1991

21. Morbidity of Lymphadenectomy Intra-operative: • Blood loss • Visceral injuries • Neuro-vascular injuries Post-operative: • Thrombo-embolism • Lymphocele • Lower limb/abdominal wall edema • GI complications

22. Controversies in the surgical staging • Complete surgical staging including pelvic and para-aortic lymphadenectomy for all patients. • Complete surgical staging NOT needed for any patient. Uterine risk factors are sufficient to identify high risk cases. • An identifiable group of intermediate/high risk patients will benefit from complete staging while those at low risk will not.

23. Predictors of LN Metastases • Depth of myometrial invasion • Tumor grade • Tumor size >2cm • Extra-uterine disease • Lymph vascular space invasion • Histologic sub-types – type II

24. Risk Stratification • Low risk:grade 1 or 2 histology with inner half of myometrial invasion,<2cm size, endometroid sub-type, without evidence of intra-peritoneal disease LN mets. 3-5% • High risk: grade 3 histology, any grade with deep myometrial invasion, non-endometroid sub-type or extra-uterine disease LN mets 10% - 20%

25. Extent of Lymphadenectomy Para-aortic LN Common iliac LN External iliac LN

26. Extent of Lymphadenectomy • Fifty percent of patients with pelvic node metastases will have additional para-aortic nodal metastases. • In 25% patients, para-aortic lymph node metastases can occur with negative pelvic nodes • Para-aortic LN involvement can occur above the IMA to the renal vessels directly

27. Role of Adjuvant Therapy Adjuvant therapy decisions -- Based on prognostic factors

28. Prognostic factors • Age • Histologic type • Histologic grade • Myometrial invasion • Vascular space invasion • Tumor size • Hormone receptor status • DNA ploidy and other biological markers

29. Risk stratification & Adjuvant Rx

30. Mx of Advanced/recurrent disease • Multimodality Rx – Sx, RT, CT, HT. • Surgical cytoreduction in appropriately selected cases: Pts. with optimal cytoreduction have better survival than those with sub-optimal cytoreduction

31. Follow up protocol Every 3 mthly for 2 years Every 6 mthly for 3 years Annually life long History Clinical examination Vaginal cytology Radiological tests

32. Role of Minimally Invasive Surgery

33. Laparoscopy seems to be an appropriate alternative to open surgery Laparoscopic pelvic lymphadenectomy

34. Robotic Surgery Robotic surgery for Endometrial-Ca can be accomplished in heavier patients and results in shorter operating times and hospital stay, a lower transfusion rate, and less frequent conversion to laparotomy compared to laparoscopy. - Seamon et al. Gynecol Oncol,2009

35. Robotic Surgery For Endometrial Cancer

36. Vaginal Surgery for Endometrial Ca • Vaginal hysterectomy with BSO: • Extreme obesity • Significant medical co-morbidity • Well differentiated tumors • Disadvantages • Upper abdominal exploration is not possible • Lymph nodes cannot be addressed

37. Endometrial Ca in Young Women Fertility preservation • Early stage, grade 1 and PR positive. • MRI to exclude significant myometrial invasion and adequate imaging of the ovaries • High dose progestins: megestrol acetate orally 160 to 320 mg/day or medroxyprogesterone acetate 200 to 500 mg/day • 40% of these patients will carry a successful pregnancy. • Hysterectomy is recommended once childbearing has been completed

38. Mx of Incompletely Staged Patient Review HPR- Grade, Invasion, adnexa + CT/MRI/ PET-scan No gross disease Gross disease IA,IB G1,2 IC, any grade IIA,IIB Surgical removal Observe Restaging Pelvic RT RT +/-CT

39. Conclusions • Disease of postmenopausal women. • Symptoms occur early in the course: most women have early stage disease at presentation. • Overall 5-year survival ~80%. • Type-1 (low grade, hormone sensitive): excellent prognosis • Type-2 (high grade, hormone independent): poor outcome.

40. Conclusions • Surgery is the primary modality; surgical staging offers the opportunity for the most accurate assessment of occult extra-uterine disease including nodal metastases. • Nodal metastasis is the most important risk factor. • The likelihood of nodal metastasis increases with the extent of disease and tumor grade. • Adjuvant Rx is needed in high risk cases.

41. Uterine Sarcomas Pathological subtypes Incidence • Leiomyosarcoma25-30% • Endometrial stromal tumors 10-15% Endometrial stromal nodule Endometrial stromal sarcoma-low grade Undifferentiated sarcoma • Mixed epithelial-mesenchymal tumors Adenosarcoma 5% Carcinosarcoma (Mixed Mullerian Tumor) 45-50% Homologous Heterologous • Undifferentiated 5%

42. Management of uterine sarcomas • Surgery is the cornerstone of the treatment. • Total abdominal hysterectomy + B/L SO is the gold standard. • Debulking surgery in advanced cases. • ESS is hormone dependent so SO is indicated . • High recurrence rates even in early stage disease. • Adjuvant treatment has shown to significantly improvement in survival.