Endometrial Cancer Is the Gynaecology and obstetrics

SAMUEL BEZABIH(MD)- MMeskrem 2005
ENDOMETRIAL
CANCER
16

Endometrial Ca
 Uterine corpus malignancies - 3 types
A. Carcinoma-----epithelial
B. Sarcoma--------stromal/connective tissue
C. Carcinosarcoma
• mixed tumors demonstrating both epithelial
and stromal components and are also known
as malignant mixed müllerian tumors
(MMMTs)
 The latter two categories (B and C)
– rare
– tend to behave more aggressively and contribute
to a disproportionate number of uterine cancer
deaths
SAMUEL BEZABIH(MD)- MMeskrem 2005 17

Endometrial Hyperplasias
 Correlation between endometrial thickness and incidence of E. cancer
% carcinomas
Endometrial thickness in mm (postmenopausal women only)

Endometrial Ca -Epidemiology
 Age distribution of endometrial cancer (n = 1,797, FIGO Annual
Report).
 Median age 66 years, highest incidence 55 - 65 years,
 20 % before menopause, 5 % < 40 years.

Endometrial Ca Epidemiology
• 75% postmenopausal
• 25% - premenopausal-
– 20% > 40 , 5%< 40
• Risk factors
– most obese
– chronically anovulatory

Endometrial Ca- Epidemiology
• During their lifetime, 1 in 38 American women
(3 %) will develop endometrial cancer.
• In the US, 46,470 new cases are estimated to
develop in 2011, but only 8120 deaths are
expected.
• Most patients are diagnosed early and are
subsequently cured.
• As a result, among women, endometrial cancer is
– the 4th leading cause of cancer,
– but only the 8th leading cause of cancer
deaths(Siegel, 2011).
• The average age at diagnosis is in the early 60s
(Creasman, 1998; Farley, 2000; Madison, 2004).

Endometrial Ca
• Fortunately, patients typically seek medical
attention early due to vaginal bleeding, and
endometrial biopsy leads quickly to diagnosis.
• The primary treatment for most women is
hysterectomy with BSO and staging
lymphadenectomy.
• ¾ of patients will have stage I disease that is
curable by surgery alone.
• Patients with more advanced disease typically
require postoperative combination
chemotherapy, radiotherapy, or both.

Risk Factors for Endometrial ca
• Conditions triggering increased estrogenic environment
– Obesity
– Unopposed E therapy
– Granulosa cell tumors ( more associated with EHP than Eca
– Menstrual factors=> Anovulatory cycles, uninterrupted menstrual
cycle
– PCOS
– Nulli/low parity
– Early menarchae; Late menopause
• Older age (peak at 70)
• Family hx (HNPCC (lynch syndrome)-
– 40-60% life time risk in mutation carriers)-mostly premenopausal
<5% of all Em Ca are 20 to HNPCC
• Tamoxifen rx of breast ca-creates modest “ unopposed” E state,
– 2-3x↑ risk ,almost exclusively in postmenopausal women
• DM, HTN, GB disease
– (frequent seqeie of obesity/ chronic excess E environment)

Em Ca- Protective factors
 OCP
– 01yr use confers 30-50% risk reduction
– Risk reduction extends to 10-20 yrs
– Chemoprevention via progestin component
 LNG IUD is protective too-longterm
 Smoking
– Smokers have reduced risk of developing Em ca
– Multifactorial biologic mechanism which in part
involves
• reduced levels of circulating E through weight reduction,
• an earlier age at menopause, and
• altered hormonal metabolism.
– Both current and past smoking has a long-lasting
influence (Viswanathan, 2005).

Risk Factors for Endometrial Cancer
 most risk factors are associated with direct or indirect creation of an
excessive estrogen environment.

Clinical Forms
TYPE I (Estrogen Dependent)
– The most common(~75%) and most indolent
– Usually in younger and perimenopausal women
– Lower grade nuclei (well differentiated, high
estrogen receptor content)
– derived from atypical endometrial hyperplasia.
– Endometroid histologic cell type
– Phosphatase and tensin homologue mutation
– Good prognosis

Clinical Forms
TYPE II
–More lethal variety, 10% of all cases
– In older post menopausal women
– Aggressive high grade nuclei (less/poorly
differentiated) or serous/papillary, clear cell
Histology
– no precursor lesion
– P53 tumor supressor mutation
– Underlying (back ground) endometrium is
Atrophic/ associated with polyps
– No clear epidimologic profile

TYPE I Vs Type II( Germ. PPT)
•
FEATURES TYPE I TYPE II
ESTROGEN DEPENDENCE E-Dependent E-independent
ASSOCIATION WITH
MENOPAUSE
Pre/Postmenopausal Post Menopausal
DIFFRENTIATION Grade I/II Grade III
MYOMETRIAL INVASION Minimal Deep
HYPERPLASIA Yes No
Sub types Endometroid
adenocarcinoma,
secretory
Adenosquamous,
clear cell, serous
prognosis good Poor

pathology
WHO Histologic Classification of Endometrial Carcinoma 29

Endometrial Ca Diagnosis
Symptoms
• Prolonged, heavy, irregular menstruation
• Postmenopausal V bleeding ( 5-10% likelihood)
• Abnormal vaginal discharge may be another
symptom in older women.
• In more advanced disease, pelvic pressure and
pain may reflect uterine enlargement or extra-
uterine tumor spread.
• Patients with serous or clear cell tumors often
present with signs and symptoms suggestive of
advanced epithelial ovarian cancer

Endometrial Biopsy
• Office pipelle biopsy,
– if inadequate D and C
• Outpatient hysteroscopy is more sensitive for
focal endometrial lesions and thus has proved
less helpful in diagnosing hyperplasia (Ben Yehuda,
1998).
• Hysteroscopy is shown to have a risk of
Intraperitoneal contamination with malignant
cells.

Pap smear
• Not sensitive, ~ 50% False Negative
• LBC- better detection of abnormal cells
• inadequate for shift of practice
.

Lab and Imaging
 Ca 125
 CXR
 CT

Histologic Grade
• Grading is determined microscopically by the
architectural growth pattern
– Arch is judged by the percentage of differentiated
(glandular) versus nondifferentiated (solid) elements
within the tumor specimen.
• If nuclear atypia is advanced (NG 3) relative to the
architectural grade, then grades 1 or 2 will be
raised by one level
this modification was shown to have prognostic value
in the GOG study(protocol #33) (Zaino, 1995).
– The nuclear grade depends on the appearance of the
nucleus, e.g., size of nucleus, chromatin pattern, and is
more subjective
• Acc. to FIGO Nuclear Grading is used for all serous
and clear cell adeno cas

Histologic Grading
• The most widely used grading system for Em
Ca is the three-tiered FIGO system.
• Grade 1:
– lesions typically are indolent with little
propensity to spread outside the uterus or
recur.
• Grade 2:
– tumors have an intermediate prognosis.
• Grade 3:
– cancers are associated with an increased potential
for myometrial invasion and nodal metastasis.

Histopathologic Criteria for Assessing Grade
GRADE DEFFINITIONS(growth pattern)
1 < 5% of a non-squamous or non-morular
solid growth pattern
2 6–50% of a non-squamous or nonmorular
solid growth pattern
3 > 50% of a non-squamous or nonmorular
solid growth
 Areas of squamous differentiation are not considered to be
solid tumor growth.
36

Patterns of Spread
• Endometrial cancers have several different potential
ways to spread beyond the uterus (Morrow, 1991).
• Type I endometrioid tumors and their variants most
commonly spread, in order of frequency, by:
1. Direct extension,
2. Lymphatic metastasis,
3. Hematogenous dissemination, and
4. Intraperitoneal exfoliation.
• Type II serous and clear cell carcinomas have a
particular propensity for extra-uterine disease, in a
pattern that closely resembles epithelial ovarian
cancer.
• In general, the various patterns of spread are
interrelated and often develop simultaneously.

Spread Pattern
• Lymphatic channel invasion and metastasis to
the pelvic and paraaortic nodal chains can
follow tumor penetration of the myometrium.
– The lymphatic network draining the uterus is
complex, and patients can have metastases to any
single nodal group as well as combinations of
groups (Burke, 1996).
– This haphazard pattern is in contrast to cervical
cancer, in which lymphatic spread usually follows
a stepwise progression from pelvic to paraaortic
to scalene nodal groups.

Spread Pattern
• Hematogenesis dissemination
– most commonly results in metastases to the
lung and less commonly, to the liver, brain,
bone, and other sites.
– Deep myometrial invasion is the strongest
predictor of this pattern of spread (Mariani,
2001a).
• Retrograde transtubal transport of exfoliated
endometrial cancer cells is one mechanism
by which malignant cells reach the peritoneal
cavity.

Spread Pattern
• Serosal perforation of the tumor is another possible
pathway.
• Most types of endometrial cancer cells found in the
peritoneal cavity disappear within a short time and
have low malignant potential (Hirai, 2001).
• Alternatively, in the presence of other high-risk
features, such as adnexal metastases or serous
histology, widespread intraabdominal disease may
result.
• Port-site metastasis is a rare but potential method of
cancer spread.
– Martínez and coworkers (2010)evaluated nearly 300
laparoscopic staging procedures for endometrial cancer.
Port-site metastases complicated 0.33 percent of cases.

Surgical Staging
• Peritoneal washing/asciteis sampling
• Pelvic and abdominal exploration and resection
of visible lesion
• TAH + BSO
• Pelvic and paraaortic lymphadenectomy
• Patients with low grade T seem at low risk for LN
met ( G1 and 2 Endometroid T, <50%MM, < 2cm T Diam-
Preop biopsy + intraop FS) may not need LN
dissection (ACOG 2015)
• UPSC (uterine papillary serous ca) histology
should have extended surgical staging with an
infracolic omentectomy and bilateral peritoneal
biopsies of the pelvis, percolic gutter, and
diaphragm and resection of any met as in Ov Ca.

I. Tumor confined to corpus uteri
Ia:-No or < ½ MM invasion
Ib:-> ½ Myometrial (MM)
II.Cx stromal invasion, but no
extension beyond UX (Ecx
glandular involvement alone- S1)
III.Local regional spread of T
IIIa.Serosa of corpus and/or
adnexa.
IIIb.Vagina and /or parametrium
IIIc. Met to pelvic or Paortic LN
IIIc1- Positive Pelvic LN
IIIc2-Paortic LN + Pelvic LN
IV.T invades bladder/bowel
mucosa (distant
metastasis)
– Iva.Bladder and /or bowel
mucosa invasion
– Ivb.Distant Metastasis
•Any stage can be Grade 1, 2 or 3
•Endocervical G involvement alone- no
more S2
•Positve cytology doesn’t change stage,
reported separately
FIGO Staging of Endometrial Ca- ACOG 2015

Poor Prognostic Variables in Endometrial Cancer
• Advanced surgical stage
• Older age
• Histologic type:
– UPSC or clear cell adenocarcinoma
• Advanced tumor grade
• Presence of myometrial invasion
• Presence of lymphovascular space invasion
• Peritoneal cytology positive for cancer cells
• Increased tumor size
• High tumor expression levels of ER and PR

Treatment
• Primary RX
– Primary Surgical rx (staging)
• Hysterectomy + Bilateral Salpingoophorectomy
– Primary radiation therapy
– Primary hormonal therapy
• Adjuvant
– Chemotherapy
– Radiation
– Hormonal

Surgical Rx
• Hysterectomy, BSO with surgical staging
• Few CIs to surgery:
• Fertility desire,
• Massive obesity,
• High operative risk,
• unresectable tumor
– Often Extrafacial (simple) Hysterectomy is
sufficient
– Class III Hysterectomy may be preferable if there
is clinically obvious extension of Em Ca to Cx.
– VH + BSO- an option for those who can’t tolerate
systematic S staging due to comorbidities

Distribution of Endometrial Cancer by FIGO Stage
(n =5281 patients)
47

Endometrial Cancer 5-Year Survival Rates for Each Surgical
Stage (n = 5562 Patients)

Post Op Surveillance
• Follow up visit Q 3-6 mths for 2yrs, then Q6mths for 01
year , annually there after.
• At each visit;
– Hx on symptoms of recurrence V bleeding, pelvic pain,
wt loss, lethargy
– Thorough speculum, pelvic and RV exam
• Not recommended are:-
– Vaginal cytology and annual CXr -recurrences are detected
by clinical exam, Cxr low utility in detecting recurrence.
– Routine radiologic exm (CT,PET) unless in suspicion of
recurrence (ACOG 2015)
• Advanced disease that requires chemo/Radiorx warrant
more aggressive monitoring.
– Ca125 for UPSC
– Intermittent CT? MRI

Adjuvant Chemorx
• For advanced or recurrent disease
• Only three cytotoxic drugs with definite
activity have been identified to date:
– doxorubicin, cisplatin, and paclitaxel (Barrena Medel, 2009).
• Other agents, 5-fluorouracil, vincristine,
ifosfamide, and ixabepilone, have possible
activity based on collected data (Miller, 2009a).
• TAP Paclitaxel (Taxol),doxorubicin
(Adriamycin), and cisplatin chemotherapy is
the adjuvant treatment of choice for
advanced endometrial cancer following
surgery. SAMUEL BEZABIH(MD)- MMeskrem 2005 50

Treatment of UPSC
• Comprehensive surgical staging
–Peritoneal washing
–TAH + BSO
–Infracolic omentectomy
–pelvic/and Para aortic LN dissection
–Peritoneal biopsy
–Aggressive debulking

Treatment of UPSC ……
Postop. Follow up
• Stage IA
– simple observation
• Stages Ib and Ic
– chemoradio ( taxol + Carboplatin 3-6 cycles and
vaginal brachytherapy)
• stageII
– benefit from chemo +/- radio
• Stage III
– prone to have recurrence ,Chemoradiatio Taxol
cisplatin+ tumor directed radio
• Stage IV
– debulking- prognostic, atleast 6cycles of Taxol and
Cplatin SAMUEL BEZABIH(MD)- MMeskrem 2005 52

Prevention of Endometrial Ca
Screening
• No role for those with average or increased
risk
• Only for high risk group>35, potential
HNPCC mutation carriers ( family Hx---)
• Genetic counselling to identify those who may
benefit from specific germ line testing
• EmCa- common ‘sentinel Ca’ for Lynch S (Em,
Colonic,Small B, ureter, Renal Pelvis, Ovarian Ca) Gynecologists
play a pivotal role in identification of those
with the syndrome

Prevention of Endometrial Ca
Prophylactic Surgery
• Since women with HNPCC have such a high
lifetime risk of developing endometrial cancer
(40 to 60 %) prophylactic hysterectomy is
another option.
• In a cohort of 315 HNPCC-mutation carriers,
Schmeler (2006) confirmed the benefit of this
approach by reporting a 100-percent risk
reduction.
• In general, BSO should also be performed due
to the 10--12% lifetime risk of ovarian cancer.

Prevention of Endometrial Cancer
Can phyto-estrogens prevent EC ?
(Xu WH et al. BMJ 328, 2004:1285-1288)
• Case control study 832 patients
• RR for EC 0.67 in group with highest soya intake
Explanation:
• Soya contains “isoflavones“ (Genistein, Daidzein)
• Isoflavones block the estrogen receptor and are
• therefore not phytoestrogens, but phyto-SERM‘s
(selective estrogen receptor blockers)
• Therefore women with high BMI profit the most in
the study!

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