endometrial carcinoma dr. b. zuckerman szmc 2014
TRANSCRIPT
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Endometrial carcinoma
Dr. B. ZuckermanSZMC2014
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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
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Endometrial Carcinoma
• 90% experiencing abnormal uterine bleeding
• 75% - early stage disease
• Stage 1 – 72% Stage 2 – 12% Stage 3 – 13% Stage 4 – 3%
Stage
St 1St 2St 3St 4
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Endometrial Carcinoma
• Early onset of symptoms• Well-established diagnostic guidelines• Overall – good prognosis
• High-risk or advanced disease – poor prognosis and death
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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%
Uterine malignancies
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Carcinoma of endometrium
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Types of endometrial carcinoma
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Epidemiological risk factors
• Chronic estrogenic stimulation• Associated medical illness• Demographic characteristics
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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
ND Estrogen-producing tumors
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Associated medical illness
Relative risk Factors
3 Diabetes mellitus
2-4 Obesity
1.5 Hypertension
3.7 Gallbladder disease
8 Prior pelvic radiotherapy
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Demographic characteristics
Relative risk Factors
4-8 Increasing age
2 White race
1.3 High socioeconomic status
2-3 European/North American country
2 Family history of endometrial cancer
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Precursors of endometrial carcinoma
Simple hyperplasia
Increased number of glands but regular glandular architecture
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Precursors of endometrial carcinoma
Complex hyperplasia without atypia
Crowded irregular glands. Cytological atypia is absent
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Precursors of endometrial carcinoma
Simple atypical hyperplasia
Simple hyperplasia with presence of cytological atypia (prominent nucleoli and nuclear pleomorphism)
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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
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Precursors of endometrial carcinomaFoci of well-differentiated endometrioid adenocarcinoma
Areas of complex atypical hyperplasia
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Precursors of endometrial carcinoma
Malpica, Deavers, and Euscher. Biopsy interpretation of the uterine cervix and corpus. Lippincott, William & Wilkins, p. 167-168, 2010
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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)
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Lynch syndrome
• Hereditary non-polyposis colorectal cancer (HNPCC)• Autosomal dominant inherited cancer susceptibility
syndrome
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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
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Cellular classification
Endometrioid type 80%• G1 Well differentiated• G2 Moderately differentiated• G3 Poorly differentiated• Other
Non-endometrioid type (G3) 20%
• Papillary serous <10%• Clear cell 4%• Mucinous 1%• Squamous cell <1%• Mixed 10%• Undifferentiated
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Natural history
Primary sign: abnormal bleeding
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Natural history
Myometrial invasion
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Natural history
Lymph vascular invasion
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Natural history Lymph none metastases
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Staging
Surgical
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Stage 1
IB: Invasion >= ½ of the myometrium
IA: No or < ½ myometrial invasion
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Stage 2
II: Invasion of cervical stroma, but does not extend beyond the uterus.
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Stage 3
IIIC: Cancer has spread to lymph nodes in the pelvis - IIIC1 and/or around the aorta - IIIC2
IIIB: Cancer has spread to the vagina and/or to the parametrium
IIIA: Cancer has spread to the outer layer of the uterus and/or to the fallopian tubes, ovaries, or ligaments of the uterus
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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
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Diagnosis: endometrial biopsy
• Abnormal uterine bleeding (older than 40)• Atypical glandular cells in PAP (older than 35)
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Ultrasound
96% of bleeding postmenopausal women with cancer have endometrial thickness greater than 5 mm
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US triage patients with PMB
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Hysteroscopy
Indication: symptoms of AUB continue and cannot by explained by the office biopsy
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Preoperative evaluation
Type I tumors• Physical examination• Chest radiograph• Electrocardiogram
Type II tumors• CT or MRI (CT scan imaging changed
treatment in 11%)
• Serum CA 125 (may be a predictor of
extrauterine disease)
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Comprehensive surgical staging • Hysterectomy• Bilateral salpingo-oophorectomy• Pelvic and para-aortic lymphadenectomy
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Surgical staging controversy Proponents
• Full staging should be performed on all patients regardless of tumor grade or depth of invasion
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
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
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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.
Surgical staging controversy: RCT
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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.
Surgical staging controversy: RCT
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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
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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.
Surgical staging controversy
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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
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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
Surgical staging controversy
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Lymphatic mapping and sentinel lymph node biopsy
• Alternative to complete pelvic and para-aortic lymphadenectomies
• Endometrial cancer tumors: difficult to visualize and to inject
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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
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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
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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
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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
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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
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Robotics
To date, there are no prospective trials comparing laparotomy vs. laparoscopy vs. robotic surgery in the management of patients with endometrial cancer
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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
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Extrauterine risk factors
• Adnexal metastases• Pelvic or para-aortic lymph node spread• Peritoneal implant metastases• Distant organ metastases• Positive peritoneal cytology
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Radiation Therapy
• Today it is delivered almost exclusively following surgery in women with adverse pathologic features
• External beam approach is whole pelvic radiotherapy• Brachytherapy
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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
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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
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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
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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