Endometrial carcinoma
Dr. B. Zuckerman
SZMC
2014
Endometrial Carcinoma in US (2011)
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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%
Stage
St 1
St 2
St 3
St 4
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%
Uterine malignancies
Carcinoma of endometrium
Types of endometrial carcinoma
Epidemiological risk factors
• Chronic estrogenic stimulation
• Associated medical illness
• Demographic characteristics
Chronic estrogenic stimulation
Factors
Relative risk
Estrogen replacement (no progestin)
2-12
Early menarche / Late menopause
1.6-4.0
Nulliparity
2-3
Anovulation
ND
Estrogen-producing tumors
ND
Associated medical illness
Factors
Relative risk
Diabetes mellitus
3
Obesity
2-4
Hypertension
1.5
Gallbladder disease
3.7
Prior pelvic radiotherapy
8
Demographic characteristics
Factors
Relative risk
Increasing age
4-8
White race
2
High socioeconomic status
1.3
European/North American country
2-3
Family history of endometrial cancer
2
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%
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G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated
Other
Non-endometrioid type (G3) 20%
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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
Hysteroscopy
Indication:
symptoms of AUB
continue and cannot by
explained by the office
biopsy
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)
Comprehensive surgical staging
• Hysterectomy
• Bilateral salpingo-oophorectomy
• Pelvic and para-aortic lymphadenectomy
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
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.
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 salpingooophorectomy
• 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
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
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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