Endometrial cancer JNMCH AMU ALIGARH

ENDOMETRIAL CARCINOMA

1. endometrial CANCER Dr. Neha Jain Dept. Obs & Gyn Jawaharlal Nehru Medical College & Hospital A.M.U., Aligarh

2. Learning objectives The learner will be able to understand: The nature of endometrial cancer The various preventable & non preventable risk factors of endometrial ca. The pitfalls in screening of this carcinoma The evaluation & management of a case of endometrial carcinoma.

3. INTRODUCTION In U.S. it is the most common malignancy of the female genital tract. 4 th most common cancer after breast, lung & colorectal cancer. 8 th most common cause of death from malignancy. Incidence of endometrial cancer is very low in India. Highest in Delhi – 4.3/ lac Bangalore – 4.2/ lac Mumbai – 2.8/ lac (GLOBOCAN - 2008)

4. types TYPE- I :- Estrogen Dependent (Unopposed estrogen) (75-85%) Perimenopausal age Hyperplastic endometrium  Carcinoma Better differentiated Favourable prognosis Type- II :- Estrogen Independent (15-25%) African American & Asian women Post menopausal women Atrophic endometrium  Carcinoma Less differentiated Poorer diagnosis

5. RISK FACTORS

6. Estrogen Estrogen Estrogen Estrogen Estrogen Estrogen ESTROGEN

7. NULLIPARITY (2-3 TIMES)

8. EARLY MENARCHE LATE MENOPAUSE (2.4 TIMES)

9. OBESITY 21-50 lb over wt.- 3 times >50 lb over wt.- 10 times Most common cause of endogenous production of estrogen (Williams gyne ) Coexisting medical condition / sequele - HTN, DM & Gall bladder disease increases risk (Williams gyne )

10. DIABETES MELLITUS (2.8 TIMES)

11. Diabetes Hypertension obesity Corpus cancer Corpus cancer syndrome

12. Hormone Replacement Therapy (4-8 times)

13. TAMOXIFEN (2-3 times) Risk also increases with : > Duration of therapy > Cumulative dose

14. Simple hyperplasia Complex hyperplasia Without atypia (3%) Without atypia (1%) With atypia (29%) With atypia (8%)

15. ?

16. ?

17. -II <5% of endometrial cancer Hereditary non polyposis colorectal cancer syndrome (HNPCC). Autosomal Dominant disorder Germline mutation in mismatch repair gene, MLH1, MSH2 & MSH6. Colorectal, endometrial, ovarian, gastric, ureter & skin cancer. 40-60% life time risk of endometrial and colorectal cancer. Cancer tends to occur in premenopausal age. Life time risk of ovarian cancer-10-12%. ( Novaks ), (Williams gyne )

18. Preventing factors Oral contraceptive pills- 1 yr. of use confers 30-50% reduced risk Risk reduction is upto 10-20 yrs. Progestin component has chemo protective role Progesterone IUCDs confers long term protection. Earlier age of menopause Smoking Factors decreasing estrogen.

19. screening

20. Screening tests Pap smear Progesterone challenge test TVS Endometrial biopsy VABRA or Pipelle

21. should screening be performed in whole Population= ???... no

22. Screening=???... Disease is not so prevalent Screening test should be: Acceptable Reproducible Valid (sensitivity) Cost effective Pap test: Inadequate Insensitive Progesterone challenge test: Inconclusive Trans vaginal sonography : Too expensive Invasive Endometrial biopsy: Too expensive Invasive

23. should screening be performed in high risk population???... no

24. The current tests can only detect half of all cases of Ca. endometrium

25. Now what to do ?

26. EARLY DIAGNOSIS & TREATMENT If a lady comes with: Premenopausal AUB Post menopausal BPV Abnormal perimenopausal BPV 25% of the endometrial cancer occurs premenopausally . 5% under the age of 40 yrs. Early diagnosis & prompt treatment has high cure rate.

27. Hereditary endometrial cancer 10% (HNPCC or predisposition for endometrial cancer alone) Autosomal dominant What to do in these patients ??? There are 2 alternatives- Annual pelvic examination, TVS & EB from the age of 30-35yrs. OR Prophylactic TAH & BSO after completion of child bearing (Preferred Alternative)

28. Classification of endometrial cancer (Histological) Endometroid adenocarcinoma With squamous differentiation Villoglandular / papillary Secretory Mucinous carcinoma Papillary serous carcinoma Clear cell carcinoma Squamous carcinoma Undifferentiated carcinoma Mixed carcinoma

29. Differentiation is expressed in grades (which in determined by architectural growth pattern & nuclear features): G1- < 5% of the tumor shows solid growth pattern G2- 6-50% shows solid growth pattern G3- >50% shows solid growth pattern If nuclear atypia is present c is inappropriate for the architectural grade – raises grade by 1 grade. In endometroid ca. with squamous differentiation, serous, clear cell and squamous ca. nuclear grading takes precedence.

30. Endometroid adenocarcinoma ~80% of endometroid carcinoma Composed of glands that resemble normal endometrial gland D/d- Atypical hyperplasia- Differentiated by presence of invasion .

31. Endometroid adenocarcinoma poorly differentiated Mod. differentiated Well differentiated

32. Variants of endometroid ca. Squamous differentiation (15-25%) Villoglandular / papillary (2%) Secretory (1%)

33. Mucinous carcinoma 5% of endometrial carcinoma On half of the tumor is composed is composed of cells with intracytoplasmic mucin . Prognosis is good D/d- Endocervical adenocarcinoma

34. Serous carcinoma 3-4% of the endometrial carcinoma Elderly Hypoestrogenic women Aggressive Often associated with Lympho -vascular & deep myometrial invasion Prognosis- poor Accounts for 50% of the deaths from endometrial cancer

35. Clear cell carcinoma <5% of the endometrial carcinoma Elderly Mixed histological pattern Cells have Hobnail configuration Prognosis- very poor Survival rate- 33-64%

36. Squamous carcinoma Rare Often associated with cervical stenosis , chronic inflammation & pyometra . Prognosis- poor Survival rate- 36% in stage-I

37. Simultaneous tumors of endometrium & ovary Most frequent simultaneously occurring genital malignancies Incidence- 1.4-3.8% Both are well differentiated Prognosis - Excellent Mostly postmenopausal C/f : AUB (ovarian ca diagnosed incidentally) 29% of endometroid adeno ca. of ovary have associated endometrial cancer.

38. Clinical features Average age of presentation- 60 yrs. Mostly 6 th & 7 th decades of life. 5% presents premenopausally ( Novaks 15 th ed.) Presenting symptoms: Vaginal bleeding Vaginal discharge (may be purulent) Pelvic discomfort/ pain (due to uterine enlargement due to mass or hematometra or pyometra or extrauterine d/s spread) < 5% - Asymptomatic 90%

39. Causes of post menopausal BPV ???

40. Points never to be forgotten Post menopausal BPV is seen in 3% of the post menopausal patients. Amount & type of bleeding is not important 20% of the cases with post menopausal BPV have significant pathology The primary aim is to exclude Atypical Hyperplasia & Endometrial Carcinoma. It is easier to diagnose than to exclude

41. History &Physical examination History: Obesity, Diabetes, Hypertension, bladder & bowel symptoms Gen. Examination: Weight LN enlargement (Inguinal, abdominal) Breast examination P/A exam: + ve in advanced disease Ascites Hepatic or omental metastasis Pelvic exam: Vaginal introitus , sub urethral area, vagina, cervix P / V exam., P / R exam. (uterus, adenexa , parametrium , cul-de-sac)

42. investigations Routine investigations Transvaginal sonography * Office based endometrial biopsy (VABRA or Pipelle ) * Endocervical curettage (in suspected cervical pathology) Hysteroscopy Dilatation & Curettage Only used if there is: Cervical stenosis Recurrence of bleeding after – ve OBEB Inadequate sampling in specimen

43. Endometrial Carcinoma have been diagnosed

44. Pre treatment evaluation Examination: Routine investigations: ECG Chest X-ray CA-125- ↑ sed in advanced metastatic Ca. USG & MRI- Degree of invasion Cystoscopy, Colonoscopy, IVP, Barium enema- acc. to symptoms

45. Surgical Staging Hysterectomy B/L Salpingo-oopherectomy Biopsy of all metastatic deposits Peritoneal fluid cytology Cytology in clockwise fashion Pelvic & Para-aortic LN dissection only in high risk- Tumor size >2cm. Grade-III tumor Non endometroid tumor

46. Figo 2009 staging Stage I - Tumor confined to corpus uteri IA- No or <50% of myometrial invasion IB- > 50% of myometrial invasion Stage II - Tumor invades cervical stroma , but does not extend beyond the uterus Stage III - Local &/or regional spread of tumor IIIA- Serosa of uterus &/or adenexa IIIB- Vaginal &/or parametrial involvement IIIC- Pelvic (IIIC1) &/ or Para-aortic LN (IIIC2) Stage IV - Bladder &/or Bowel mucosa &/or distant mets . IVA- Bladder &/or Bowel mucosa IVB- Distant metastasis

47. ROUTES OF METASTASIS Pattern of spread Predictors Contiguous extension: Hematogenous : Lymphatic: Peritoneal: Grade 3 & LVSI Deep myometrial invasion Cervical stromal invasion & positive lymph nodes Stage-IV d/s Stage-II or III d/s with > 2 risk factors: Cervical invasion Peritoneal cytology + ve + ve LN Non- endometroid histology

48. Prognostic variables Age Histologic type Histologic grade Tumor size Myometrial invasion Lympho -vascular space invasion Isthmus-cervix extension Peritoneal cytology Adnexal involvement Lymph node metastasis Intra peritoneal tumor Hormone receptor status DNA ploidy / proliferative index Genetic/ molecular tumor marker AGE Independent prognostic variables Younger age- better prognosis Older pts- More rate of recurrence For every 1 yr. inc. in age – 7% inc. in rate of recurrence HISTOLOGICAL TYPE Non Endometroid subtype (10%)- Inc. risk of : Recurrence Distant spread HISTOLOGICAL GRADE Strongly asso . with prognosis Inc. tumor grade is asso . with: Deep myometrial invasion Cervical extension Lymph node metastasis Local recurrence Distant metastasis TUMOR SIZE Determines the risk of lymph node metastasis >2cm.~ 18% chances of nodal metastasis MYOMETRIAL INVASION Tumor <5 mm from the serosal surface- worse prognosis Non/sup. Invasion- 80-90% 5 yr survival rate Deep invasion- 60% survival LYMPH-VASCULAR SPACE INVASION Independent risk factor 15% in early stage Strong predictor of : Lymphatic dissemination Lymphatic recurrence ISTHMUS & CERVIX EXTENSION Strong predictor of : Lymphatic dissemination Lymphatic recurrence Cx involvement is asso . with: High grade Larger tumor size Deep invasion Inc. risk of recurrence PERITONEAL CYTOLOGY Dependent prognostic variable If asso . with other poor prognostic variables there is inc. chance of: Distant spread Disease recurrence Poor survival ADNEXAL INVOVEMENT High risk of recurrence LYMPH NODE METASTASIS Most imp. Prognostic factor in early stage ca. 6 times inc. risk of developing recurrent ca. 5 yr. d/s free survival rate: + ve - 54% - ve - 90% INTRAPERITONEAL METASTASIS Correlated with lymph node metastasis Significantly asso . with tumor recurrence HORMONE RECEPTOR STATUS Independent prognostic variable ER or PR + ve tumor- better prognosis PR stronger predictor Higher the absolute level of receptors better the prognosis DNA PLOIDY & PROLIFERATIVE INDEX Proportion of Non-diploid tumor increases with: Stage Lack of differentiation Depth of myometrial invasion GENETIC / MOLECULAR TUMOR MARKERS Type I- Mutation in PTEN & ß – catenin genes Type II- Mutation in p53, p16, e- cadherin genes

49. treatment

50. Principles of treatment Uterus should be removed in all the patients Pelvic LN metastasis is ~36% in Stage-II, so protocol should include removal of them Chances of d/s spread outside the pelvis (Para-aortic nodes, Adnexal structures & upper abd .) is high, there should be evaluation & treatment of extrapelvic disease.

51. treatment

52. GRADE-1,2 No/minimal myometrial invasion OBSERVE OBSERVE 100% 5 yr disease free survival rate GRADE-2,Superficial myometrial invasion GRADE-3,No myometrial invasion VAGINAL IRRADIATION STAGE-IA Tumor confined to corpus uterus, IA- No or <50% of myometrial invasion

53. STAGE-IB Tumor confined to corpus uteri, IB- > 50% of myometrial invasion GRADE-3, Any myometrial invasion Deep myometrial invasion PELVIC RADIOTHERAPY & VAGINAL BOOST Stage-I survival rate 5yr 87%

54. Should radical hysterectomy Be performed in clinical stage I tumor no

55. STAGE-II Tumor invades cervical stroma , but does not extend beyond the uterus Cervix spread PELVIC RADIOTHERAPY & VAGINAL BOOST Survival rate 5yr 76% Radiotherapy 4500-5040 cGy . 5-6 wks Vaginal boost 6000-7000 cGy

56. Positive peritoneal cytology OBSERVE OR PROGESTINS

57. STAGE-III Local &/or regional spread of tumor IIIA- Serosa of uterus &/or adenexa IIIB- Vaginal &/or parametrial involvement IIIC- Pelvic (IIIC1) &/ or Para-aortic LN (IIIC2) Eradication of all macroscopic disease PELVIC RADIOTHERAPY & VAGINAL BOOST Paraaortic lymph node + ve - extended field/whole abdomen radiation Survival rate 5yr 59%

58. GRADE-3, Any myometrial invasion Deep myometrial invasion Cervix, serosal , vaginal spread Positive pelvic lymph nodes PELVIC RADIOTHERAPY & VAGINAL BOOST - VE Para-Aortic LN +VE Para-Aortic LN EXTENDED FIELD RADIOTHERAPY 4000-5000 cGy

59. STAGE-IV Bladder &/or Bowel mucosa &/or distant metastasis IVA- Bladder &/or Bowel mucosa IVB- Distant metastasis Eradication of all macroscopic disease Partial Colectomy Partial cystectomy CHEMOTHERAPY (Treatment of choice) + WHOLE ABDOMEN RADIATION Post op Survival rate 5yr 18% 3000 cGy with kidney shielding + 1500 cGy to para aortic LN + 2000cGy to pelvis

60. Algorithm for management Patient with diagnosed endometrial cancer Pre op evaluation & clinical staging Primary radiation Surgical staging Evaluation of prognostic factors Close follow up Post op radiation Selected therapy (progesterone / chemotherapy)

61. Follow up History & Physical examination (Most effective method): 1 st 2 yrs.- Every 3-4 mths Then- Every 6 mths Chest X-Ray: Every year CA- 125 : For patients : Who have elevated CA-125 @ the time of diagnosis Have extrauterine disease

62. Recurrent disease

63. Recurrent disease ~25% of the treated early endometrial cancer recurs. >50% recurs in 1 st 2 years ~75% recurs in 1 st 3 years

64. Points to remember Recurrence is less when the surgery is combined with post op radiation therapy Patient treated with surgery + radiation generally do not have local or pelvic recurrence but have extrapelvic mets . M/C site for mets .- Lung, Abdomen, Lymph nodes (Aortic, Supraclavicular , Inguinal), Liver, Brain & Bone

65. Rates of recurrence Myometrial invasion <50% >50% Lymph nodes - ve + ve Cervical stromal invasion Stage IV disease II/III disease & > 2 risk factors I/II/III disease & < risk factors 4% 28% 2% 31% 31% 63% 21% 1% Rates of recurrence

66. Factors affecting prognosis Isolated vaginal recurrence Initially well differentiated tumor Recurrence after 3 years Younger age of recurrence Good prognosis

67. Clinical features

68. Treatment Isolated vaginal recurrence External radiation + Brachytherapy Pelvic recurrence radiotherapy + Radical surgical resection + Intra op radiotherapy Metastatic carcinoma Combination chemotherapy Progestin therapy in case of Progesterone receptor + ve tumor

69. Incidental diagnosis 3 OPTIONS : Factors which would guide : Risk of nodal/ extrauterine d/s Tumor grade Depth of invasion Evidence of lymphadenopathy on CT abd . or pelvis Patient willingness observe Reoperate for surgical staging Pelvic radiotherapy

70. Lets see the mind power

71. Question 1 Factors which decreases the risk of endometrial cancer? Estrogen replacement therapy Tamoxifen Smoking Poly cystic ovarian syndrome Diabetes

72. Question 2 A lady is diagnosed of endometrial cancer which is extending to the cervical stroma and her pelvic lymph node biopsy came to be + ve . In which stage you would like to keep her? Stage IA Stage II Stage IIIA Stage IIIC

73. Question 3 A 50 yr old lady has been diagnosed of having papillary serous carcinoma endometrium and another lady is diagnosed of having mucinous carcinoma. Both are in stage II. Which lady is going to survive more after therapy?

74. Question 4 In your OPD- 8 if a post menopausal lady since 11yrs. gave history of spotting last night. After history & examination you came to know that there are no risk factors of endometrial cancer & the cervix is also healthy but atrophic. Now what you will do? Ask her to get a TVS done Ask her to come back if BPV recurs Reassure her and give her estrogen cream for LA

75. Question 5 If a lady is diagnosed to have ca endometrium which has spread to the endocervical glands. Under which stage you would like to keep her? Stage IA Stage IB Stage II Stage IIIA

76. Thank you