Endometrial Cancer

1. Endometrial Cancer Speaker : Shinenoam Chen Department of OBS/GYN. VGHKS

3. Introduction • Endometrial carcinoma is the most common gynecologic malignancy in the United States. • Most cases are diagnosed at an early stage when surgery alone may be adequate for cure.

4. Introduction • Type I endometrial carcinoma is estrogen-related: 1. tends to be associated with endometrial hyperplasia. 2. low grade endometrioid tumor 3. risk factors such as obesity, nulliparity, endogenous or exogenous estrogen excess, diabetes mellitus, and hypertension.

5. Introduction • Type II endometrial carcinoma appears unrelated to estrogen : 1. older , multiparous. 2. poor prognostic cell types, such as papillary serous or clear cell tumors.

8. ERT • Estrogen Tx alone increases the risk for endometrial hyperplasia and carcinoma. • Endometrial hyperplasia: 20-50% of women receiving unopposed estrogen in one year. • RR: 3.1-15 (related to dose and duration)

9. ERT • Risk can be reduced by the concomitant administration of progestins.

11. Endogenous estrogen • Functional ovarian tumors • Endogenous conversion of adrenal precursors into estrogen by adipose cells (estrone hypothesis) • Higher circulating estrogen and androgen levels, and lower SHBG levels.

12. Tamoxifen • Competitive inhibitor of estrogen binding to estrogen receptors. • adjuvant therapy in women with early stage breast cancer, as treatment for recurrent disease, and for reduction of breast cancer incidence in high-risk women. • partial agonist activity, stimulating the endometrial lining.

13. Tamoxifen • 2-3fold increased risk of endometrial cancer. • ACOG:the benefits outweigh the risks. Recommendations : 1.Annually Gyn exam. 2.Report vagina bleeding 3.Tx limited to 5 years 4. Hysterectomy if atypical hyperplasia.

15. Obesity • high levels of endogenous estrogen. • Conversion of androstenedione to estrone and the aromatization of androgens to estradiol, both of which occur in peripheral adipose tissue. • lower circulating levels of sex hormone binding globulin.

16. Obesity • Increased risk of death from endometrial cancer. • BMI ( 40 kg/m2) was 6.25-fold higher than that of normal weight women.

17. Diabetes and hypertension • Increased risk for endometrial cancer, associated with obesity. • The effects of hyperinsulinemia, insulin resistance, and insulin-like growth factors on endometrial proliferation are under investigation.

18. Chronic anovulation(ex.PCOS) • Adequate estrogen since androgens can be converted peripherally to estrogens. • Lack the progesterone normally present in the luteal phase. • constant estrogenic stimulation leading to endometrial hyperplasia and endometrial cancer.

19. Age • 12 % of all patients with endometrial adenocarcinoma were under 50 years of age. • Common features of these cases were obesity (56 percent had a BMI 30 kg/m(2)) and nulliparity (44 percent).

20. Parity • Nulliparity • High frequency of anovulatory cycles in infertile (and thereby nulliparous) women.

21. Menarche and menopause • Early menarche or late menopause was a risk factor for endometrial cancer. • Prolonged estrogen stimulation without the protection of progesterone is the presumed mechanism.

22. Protective factors • Oral contraceptives-progestin component suppresses endometrial proliferation. The protective effect persisted for at least 15 years after cessation of use. • Physical activity-changes in endogenous sexual and metabolic hormone levels and growth factors, decreased obesity and central adiposity, and changes in immune function • Smoking-smoking stimulates hepatic metabolism of estrogens.

25. HISTOPATHOLOGY • The most common type of endometrial cancer is endometrioid adenocarcinoma (75-80%). • Clear cell type(1-5%) and papillary serous carcinomas(5-10%): much poorer prognosis • Well differentiated (gade I) : proliferation of back-to-back endometrial glands without intervening stroma. There is no more than 5% solid growth.

26. HISTOPATHOLOGY • Moderate differentiated (grade 2) tumors have 6-50% of the tumor composed of solid tumor without glands, as well as greater nuclear atypia. • Poorly differentiated (grade 3) tumors contain more than a 50% solid component.

27. CLINICAL PRESENTATION • The classic symptom of endometrial carcinoma is abnormal uterine bleeding. • 20%of women with postmenopausal bleeding will have endometrial cancer. • Pre- and perimenopausal women with menometrorrhagia also should be evaluated.

28. Endometrial cells on Pap smear • The presence of endometrial cells on a Pap smear of a woman 40 years of age can signify endometrial disease. • Endometrial disease was identified in 36%, including endometrial hyperplasia in 13% and adenocarcinoma in 11%. • Endometrial biopsy is recommended.

29. DIAGNOSIS • Diagnosis of endometrial cancer is most easily made by office endometrial biopsy. • Hysteroscopy with dilation and curettage (D&C) remains the gold standard. • A higher grade based on the hysterectomy specimen may be assigned in as many as 30% of cases.

30. DIAGNOSIS Transvaginal ultrasonography • measuring the endometrial wall thickness • In postmenopausal women, an endometrial thickness of less than 4 to 5 mm is associated with a low risk. • The mean endometrial thickness in 759 women with endometrial cancer is 20 mm.

32. DIAGNOSIS Sonohysterography • Differentiate Polyp or cancer. • Biopsy or resection via the hysteroscope.

35. Pre-operative survey • ECC • MRI- assess cervical involvement and depth of myometrial invasion. • Tumor marker: CEA, Ca125, Ca199- predicting extrauterine spread of endometrial cancer, and for following patients after initial treatment

36. Deep invasion (>50% of the myometrial thickness) of endometrial carcinoma (arrow).

37. TREATMENT • Surgery • Chemotherapy • Radiation therapy • Hormone therapy

38. Surgery • ATH+BSO+BPLND+ Paraaortic LN sampling. • Washing cytology. • MRH if cervix involved. (proved by ECC) • Laparoscopic lymphadenectomy combined with vaginal hysterectomy, provide an acceptable alternative to traditional laparotomy in patients with early stage disease.

39. Endometrial cancer with <1/2 myometrial invasion

40. Surgical staging *Grade 1.2 *No or minimal myometrial invasion Ib or G3 IbG3 or Ic.II.III *Adnexal spread *Intraperitoneal dz completely resected Positive peritoneal cytology Observe Vagina radiaion Pelvic RT&vagina Boost(extended filed if positive Para-aortic LN) Whole abdominal radiation or C/T Observe or progestins Management of stage I and II endometrial cancer

41. Treatment by stage • Stage Ib or G3 : vagina R/T • IbG3 or Ic: pelvic R/T. • Stage II: +C/T

43. Radiotherapy • Intermediate risk- Ic, II adjuvant RT : vaginal cuff brachytherapy +/- external beam RT is controversial. *Reduction in the rate of vaginal or pelvic recurrence, but not the survival. • High risk- vaginal cuff brachytherapy, pelvic external beam RT, and whole abdominal irradiation (WAI). *Reduce the likelihood of local recurrence, and possibly prolong survival.

44. Chemoherapy • Regimens: PEI – Cisplatin + Epirubicin + Holoxan ( q3w X6 courses). • GOG122- Chemotherapy versus RT -Stage III or IV -WAI vs (doxorubicin 60 mg/m2 plus cisplatin 50 mg/m2 q3w for 7 courses, followed by an additional course of cisplatin) -Chemotherapy was superior to WAI in terms of two-year overall survival. • Taxol+carboplatin • CCRT

45. Hormone therapy • PR: PR(-) correlated to LN metastasis and poor survival rate. • ER: less predictive than PR. Absence of ER was predictive of recurrence for stage I tumors • Progestin (synthetic progesterone) may be used to help stop the cancer from spreading. • response rate :30%

46. Decision tree concerning the treatment of recurrent endometrial carcinoma.Legend: ENCA = endometrial carcinoma; QoL = Quality of Life; RT = radiotherapy; HT = endocrine treatment; CHT = chemotherapy

47. Prognosis • 5 year survival:

48. Prognosis • LN metastasis rate: • Stage I: 10% ( stageII: 15%) • G1:3% G2: 9% G3:18% • <1/2M: 5% >1/2M: 20% • Prognostic factor: Stage, grade, cell type, LN.