Endometrial carcinoma Dr. B. Zuckerman SZMC 2014

Endometrial Carcinoma in US (2011) The most common gynecological malignancy 46,470 new cases 8,120 deaths Median age of diagnosis: 61 (most – 50-60 ) 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

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

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

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%

Carcinoma of endometrium

Types of endometrial carcinoma

Epidemiological risk factors Chronic estrogenic stimulation Associated medical illness Demographic characteristics

Chronic estrogenic stimulation Relative risk Factors 2-12 Estrogen replacement (no progestin) 1.6-4.0 Early menarche / Late menopause 2-3 Nulliparity ND Anovulation Estrogen-producing tumors

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

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

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

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

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

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

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

Precursors of endometrial carcinoma Malpica, Deavers, and Euscher. Biopsy interpretation of the uterine cervix and corpus. Lippincott, William & Wilkins, p. 167-168, 2010

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)

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

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

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

Natural history Primary sign: abnormal bleeding

Natural history Myometrial invasion

Natural history Lymph vascular invasion

Natural history Lymph none metastases

Staging Surgical

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

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

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

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

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

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

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

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

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)

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

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

Surgical staging controversy: RCT Italian trial 514 patients, 31 centers in two countries, 10-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.

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.

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

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.

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

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

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

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

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

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

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;30:695-700

Robotics

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

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

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

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

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

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

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

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

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