1. Endometrial carcinoma
Dr. B. Zuckerman
SZMC
2014

2. Endometrial Carcinoma in US (2011)
The most common gynecological malignancy
46,470 new cases
8,120 deaths
Median age of diagnosis: 61 (most – )
90% - over the age 50
20% - before menopause
5% - before age 40
Siegel R, Ward E, Brawley O, Jemal A. CA Cancer J Clin. 2011;61:212-36

3. Endometrial Carcinoma
90% experiencing abnormal uterine bleeding
75% - early stage disease
Stage 1 – 72%
Stage 2 – 12%
Stage 3 – 13%
Stage 4 – 3%

4. Endometrial Carcinoma
Early onset of symptoms
Well-established diagnostic guidelines
Overall – good prognosis
High-risk or advanced disease – poor prognosis and death

5. Malignancies of uterine body: Classification
Epithelial – 90%
Endometrioid, serous, clear cell, mucinous
Mesenchymal – 5%
Endometrial stromal sarcoma, leiomyosarcoma, other sarcomas
Mixed – 3%
Carcinosarcoma, adenosarcoma
Secondary – 2%

6. Carcinoma of endometrium

7. Types of endometrial carcinoma

8. Epidemiological risk factors
Chronic estrogenic stimulation
Associated medical illness
Demographic characteristics

9. Chronic estrogenic stimulation
Relative risk
Factors
2-12
Estrogen replacement (no progestin)
Early menarche / Late menopause
2-3
Nulliparity ND
Anovulation
Estrogen-producing tumors

10. Associated medical illness
Relative risk
Factors 3
Diabetes mellitus
2-4
Obesity
1.5
Hypertension
3.7
Gallbladder disease 8
Prior pelvic radiotherapy

11. Demographic characteristics
Relative risk
Factors
4-8
Increasing age 2
White race
1.3
High socioeconomic status
2-3
European/North American country
Family history of endometrial cancer

12. Precursors of endometrial carcinoma
Simple hyperplasia
Increased number of glands but regular glandular architecture

13. Precursors of endometrial carcinoma
Complex hyperplasia without atypia
Crowded irregular glands. Cytological atypia is absent

14. Precursors of endometrial carcinoma
Simple atypical hyperplasia
Simple hyperplasia with presence of cytological atypia (prominent nucleoli and nuclear pleomorphism)

15. Precursors of endometrial carcinoma
Complex atypical hyperplasia
The endometrial glands are irregular in size and shape with branching and outpouchings (complex hyperplasia) with cytological atypia

16. Precursors of endometrial carcinoma
Foci of well-differentiated endometrioid adenocarcinoma
Areas of complex atypical hyperplasia

17. Precursors of endometrial carcinoma
Malpica, Deavers, and Euscher. Biopsy interpretation of the uterine cervix and corpus. Lippincott, William & Wilkins, p , 2010

18. Hereditary Syndromes
Endometrial cancer is not typically a hereditary disorder
Genetic predisposition is seen in up to 10% of patients (5% women with Lynch syndrome)

19. Lynch syndrome Hereditary non-polyposis colorectal cancer (HNPCC)
Autosomal dominant inherited cancer susceptibility syndrome

20. Lynch syndrome
Germ line mutation in one of the DNA mismatch repair genes (MSH2, MLH1, MSH6, PMS2)
Early age at cancer diagnosis and the development of multiple cancer types, particularly colon and endometrial cancers
40% to 60% risk of endometrial cancer

21. Cellular classification
Endometrioid type 80%
Non-endometrioid type (G3) 20%
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated
Other
Papillary serous <10%
Clear cell 4%
Mucinous 1%
Squamous cell <1%
Mixed 10%
Undifferentiated

22. Natural history
Primary sign: abnormal bleeding

23. Natural history
Myometrial invasion

24. Natural history
Lymph vascular invasion

25. Natural history
Lymph none metastases

26. Staging
Surgical

27. Stage 1 IA: No or < ½ myometrial invasion
IB: Invasion >= ½ of the myometrium

28. Stage 2
II: Invasion of cervical stroma, but does not extend beyond the uterus.

29. Stage 3
IIIC: Cancer has spread to lymph nodes in the pelvis - IIIC1 and/or around the aorta - IIIC2
IIIA: Cancer has spread to the outer layer of the uterus and/or to the fallopian tubes, ovaries, or ligaments of the uterus
IIIB: Cancer has spread to the vagina and/or to the parametrium

30. Stage 4 IVA: Cancer has spread into the bladder and/or bowel
IVB: Cancer has spread beyond the pelvis to other parts of the body

31. Diagnosis: endometrial biopsy
Abnormal uterine bleeding (older than 40)
Atypical glandular cells in PAP (older than 35)

32. Ultrasound
96% of bleeding postmenopausal women with cancer have endometrial thickness greater than 5 mm

33. US triage patients with PMB
Postmenopausal bleeding
We will find
carcinoma
in 15% of
cases
US triage: Endometrial thickness
<5 mm
>5 mm
Next step
Follow up / Office hysteroscopy
Endometrial biopsy

34. Hysteroscopy
Indication: symptoms of AUB continue and cannot by explained by the office biopsy

35. Preoperative evaluation
Type I tumors
Type II tumors
Physical examination
Chest radiograph
Electrocardiogram
CT or MRI
(CT scan imaging changed treatment in 11%)
Serum CA 125
(may be a predictor of extrauterine disease)

36. Comprehensive surgical staging
Hysterectomy
Bilateral salpingo-oophorectomy
Pelvic and para-aortic lymphadenectomy

37. Surgical staging controversy
Proponents
Opponents
No staging in clinical early stage disease:
low likelihood of lymph node metastases and the risks of a lymphadenectomy outweigh the potential benefits of having the information gained from staging
Full staging should be performed on all patients regardless of tumor grade or depth of invasion
A third group: surgical staging is indicated in a select group of women at highest risk for extrauterine disease; however, the precise definition of a high-risk patient remains elusive

38. Surgical staging controversy: RCT
Italian trial
514 patients, 31 centers in two countries, year period
Both early and late postoperative complications occurred more frequently in patients who had undergone a pelvic lymphadenectomy
The 5-year disease-free and overall survival rates were similar between the two groups (81% and 86%)
Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial Panici PB, Stefano S, Maneschi F, et al J Natl Cancer Inst 2008;100:1707.

39. ASTEC (A Study in the Treatment of Endometrial Cancer)
Surgical staging controversy: RCT
ASTEC (A Study in the Treatment of Endometrial Cancer)
Objective: to determine if lymphadenectomy increases survival independent of adjuvant irradiation
1,408 women, 85 centres, 4 countries, over 7 years
Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomized study The writing committee on behalf of the ASTEC study group Lancet 2009;373:125.

40. ASTEC (A Study in the Treatment of Endometrial Cancer)
1st randomization: standard surgery vs. standard surgery plus lymphadenectomy
2nd randomization in intermediate and high-risk group (IA or IB with high-grade pathology, or IIA): radiation vs. no further therapy
no evidence of a benefit in terms of overall survival or recurrence-free survival for pelvic lymphadenectomy in women with early endometrial cancer

41. Surgical staging controversy
Retrospective data
The outcomes of 27,063 women with unstaged endometrioid uterine cancer.
From Surveillance, Epidemiology and End Results (SEER) database
39,396 patients
Surgical staging procedures that included a lymphadenectomy vs. no lymphadenectomy
Chan JK, Wu H, Cheung MK, et al. Gynecol Oncol 2007;106:282.

42. Retrospective data
In stage I grade 3 patients, those who underwent lymphadenectomy had a better 5-year disease-specific survival than those without lymphadenectomy
no benefit for lymphadenectomy was seen for patients with stage I grade 1 and grade 2

43. Surgical staging controversy
Additional studies are needed to determine the role of lymphadenectomy, the extent of lymphadenectomy, and the indications for surgical staging in patients with endometrial cancer

44. Lymphatic mapping and sentinel lymph node biopsy
Alternative to complete pelvic and para-aortic lymphadenectomies
Endometrial cancer tumors: difficult to visualize and to inject

45. Lymphatic mapping and sentinel lymph node biopsy
In a prospective multicentre study (SENTI-ENDO) of sentinel lymph node biopsy via cervical injection, pelvic sentinel lymph nodes (SLNs) were detected in 89% of patients; and the sensitivity and negative predictive value of SLN biopsy were 84% and 97%, respectively.
Ballester M, Dubernard G, Lécuru F, et al Lancet Oncol 2011;12:469-76

46. Surgical Approaches
Surgery represents the cornerstone for treatment of endometrial cancer
Standard approach: exploratory laparotomy, hysterectomy and bilateral salpingo-oophorectomy
Comorbidity: severe obesity, diabetes mellitus, cardiovascular diseases

47. Surgical Approaches
Minimizing surgical morbidity: minimally invasive surgery (Laparoscopic surgery, robotic-assisted surgery )
Less blood loss, decreased transfusion rates, shorter length of hospitalization, and a faster return to daily activities

48. GOG trial: laparotomy vs. laparoscopy
Laparoscopic surgical staging for uterine cancer is feasible and safe in terms of short-term outcomes (2010)
Fewer complications and shorter hospital stays
Potential for a small increased risk of cancer recurrence with laparoscopy versus laparotomy
5-year overall survival being almost identical in both arms at 89.8% (2012)
Walker JL, Piedmonte MR, Spirtos NM, et al.
J Clin Oncol 2012;30:

49. Robotics

50. Robotics
In 2005 the U.S. FDA approved the daVinci robotic system for gynecologic procedures
The advantages of the robotic system over standard laparoscopy: high-definition three-dimensional vision, more surgical precision and dexterity, improved ergonomics for the surgeon, improved teaching capabilities for trainees
The disadvantage: very high cost

51. Robotics
To date, there are no prospective trials comparing laparotomy vs. laparoscopy vs. robotic surgery in the management of patients with endometrial cancer

52. Major prognostic factors
Uterine risk factors
Major prognostic factors
Grade or cell type
Depth of myometrial invasion
Tumor extension to the cervix
Less important
Extent of uterine cavity involvement
Lymph–vascular space invasion
Tumor vascularity

53. Extrauterine risk factors
Adnexal metastases
Pelvic or para-aortic lymph node spread
Peritoneal implant metastases
Distant organ metastases
Positive peritoneal cytology

54. Radiation Therapy
Today it is delivered almost exclusively following surgery in women with adverse pathologic features
External beam approach is whole pelvic radiotherapy
Brachytherapy

55. Adjuvant Radiation Therapy
Reduces the risk of pelvic recurrence in early stage patients with adverse pathologic features
Does not improve survival
Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomized trials): pooled trial results, systematic review and meta-analysis ASTEC/EN.5 Study Group, Blake P, Swart AM, et al Lancet 2009;373:137

56. Adjuvant brachytherapy alone
Brachytherapy vs. pelvic radiotherapy: no differences in overall or disease-free survival
Less toxicity
Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority randomised trial Nout RA, Smit VT, Putter H, et al. Lancet 2010;375:816
Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial Nout RA, Putter H, Jurgenliemk-Schulz IM, et al. J Clin Oncol 2009;27:3547

57. Adjuvant chemotherapy in early stage disease
Pelvic radiotherapy versus chemotherapy (cyclophosphamide, doxorubicin, and cisplatin [CAP])
No differences in progression-free or overall survivals were seen at 5 years
Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study Susumu N, Sagae S, Udagawa Y, et al. Gynecol Oncol 2008;108:226

58. Hormone (Progesterone) Therapy
Complex atypical hyperplasia and low-grade endometrial cancers diagnosed in young women who are still considering child-bearing
Very high risk surgery group