Uterine Cancer

Dr Khalid Akkour MD FRCSC

Assistant professor & consultant
Gynecologic Onclogy
college of medicine
King Saud University
Endometrial Cancer

 The most common gyne malignancy in the

U.S.

 6% of all cancers in women

 Generally high rate of survival due to early

diagnosis (90% stage 1)
Risk factors…

Epidemiologic diffences:
Risk related to hormonal stimulation
or unrelated to estrogen at all.

Estrogen-related endometrial cancer (Type I) tends to

be a lower grade histologically.

Endometrial cancers unrelated to hormones (Type II)

tend to be a higher grade and stage eg. Papillary serous
or clear cell tumors.
How endometrial hyperplasia is associated with
endometrial cancer
Endometrial hyperplasia is a continuum…

Simple hyperplasiacomplex hyperplasia

without atypiacomplex hyperplasia w/
atypia endometrial cancer (well
differentiated adenocarcinoma)
How endometrial hyperplasia is associated with
endometrial cancer
Simple hyperplasia without atypia– 1% progress
to endometrial cancer
Simple hyperplasia with atypia 9%
Complex hyperplasia without atypia– 3%
Complex hyperplasia with atypia—28%
(30-40% of endometrial cancers are found in a
background of atypical hyperplasia). Overall,
these tend to be lower grade tumors.
 Risk factors for endometrial cancer
These risk factors are only helpful in identifying
women at risk for type I disease.
For type I disease, what would be some common
exogenous estrogen sources?

Unopposed estrogen in HRT

Tamoxifen
What would be endogenous sources of estrogen
as a risk factor for endometrial cancer?
Obesity.

Anovulatory cycles.

Estrogen secreting tumors

Endometrial cancer NOT assoc. w/ estrogen
(Type II)
Papillary serous

Clear cell tumors

Usually these affect multiparous, but generally

healthy, older patients.
For type I disease, what would be some common
exogenous estrogen sources?

Unopposed estrogen in HRT

Tamoxifen
 The Benefits and Risks of Estrogen in
HRT
Benefits: helps relieve hot flashes, vaginal dryness, and
preventing osteoporosis.

Unopposed estrogen increases the risk of endometrial hyperplasia

and endometrial cancer.

With unopposed estrogen 20-50% of women will develop

endometrial hyperplasia after 1 year.
Risk of endometrial cancer is related BOTH to dose and duration
of treatment, the incidence of endometrial cancer goes from
1/1000 to 42/1000.
 Tamoxifen

Tamoxifen– a competitive inhibitor of estrogen

binding to estrogen receptors that also has
partial agonist activity (tamoxifen is a weak
estrogen)

- used in pts. w/ early stage breast ca

- as treatment of recurrent disease
- risk reduction in high risk women
 Tamoxifen

Unfortunately while it suppresses breast tissue

growth, it stimulates endometrial lining.

Probably a 2 to 3 fold risk of endometrial cancer

w/tamoxifen.
Especially in women older than 50
 Tamoxifen

What did ACOG say about tamoxifen?...

Even though tamoxifen is associated with endometrial cancer,

the benefits in treating women with breast ca. outweigh the
risks…but…
-women need a yearly gyne exam
-women should monitor themselves for abnormal vaginal
sx., e.g . Bleeding, discharge, etc
-screening such as pelvic U.S. is NOT recommended (too
many false positives)
-Limit tamoxifen use to 5 years
-if there is atypical endometrial hyperplasia, treat and reassess
tamoxifen (ie. Consider hysterectomy)
Other risk factors for endometrial cancer

Obesity
obese women have high levels of endogenous
estrogen probably from the conversion of androstenedione to
estrone and the aromatization of androgens to estrogen both of
which occur in the adipose tissue
Other risk factors for endometrial cancer

Diabetes and HTN

a risk factor because these conditions are
often associated with obesity, and also because
of the effects of hyperinsulinemia and insulin-
like growth factors.
Other risk factors for endometrial cancer

Chronic anovulation

women with chronic anovulation have unopposed or mildly

opposed estrogen.
PCOS as an example
Other risk factors for endometrial cancer

Familial predisposition

Lynch syndrome
(up to 43% of women of affected families will develop
ovarian cancer)
Other risk factors for endometrial cancer

Parity

Nulliparity itself is not a risk factor as much as

the anovulatory cycles that are associated with
infertility.
Other risk factors for endometrial cancer

Diet– especially high fat

Menarche/Menopause: early menarche and late

menopause
Prolonged estrogen exposure
Protective Factors

Oral contraceptives:
decreases both the risk of ovarian and
endometrial cancer (RR = 0.6 if used for one
year…effect lasts for 15 years!)

Protective effect probably due to

progesterone.
Protective Factors

Physical activity

Smoking
Histopathology

Most common types of endometrial cancer:

Endometriod adenocarcinoma (70-80%)

Clear cell and serous tumors are more aggressive and

probably present at a more advanced age. (together
5-10%)

Mucinous and squamous about 2%

Clinical presentation

The “classic symptom” is abnormal uterine

bleeding

20-30% of women with post-menopausal

bleeding will have uterine cancer.

( the risk is higher the farther they are away

from menopause)
Clinical presentation

Abnormal pap smear

not a reliable way of picking up endometrial ca.

The presence of endometrial cells on a pap smear in

women > 40 is an indication for bx.

Hyperplasia in 36%
Adenoca in 11%
Diagnosis

Easy to do with office EMB

Hysteroscopy w/ D & C (gold standard)

Detection rates of endometrial ca. by pipelle was

between 91 and 99%
Detection of hyperplasia was 81%

Recommendation: EMB as initial test;

Hysteroscopy/D&C if EMB inconclusive or high
suspicion
Transvaginal ultrasound

In postmenopausal women, an endometrial thickness of 4-5 mm

or less is reassuring.
(only 1-2% will have endometrial ca. if nl endometrial
thickness) ?? If nl TVS do you need an EMB w/abnl bleeding.

A thicker endometrium requires EMB, hysteroscopy/D&C

overall TVS is not recommended as a screening tool.
Transvaginal ultrasound

It is recommended to do an EMB rather than rely

on TVS results in evaluating abnormal uterine
bleeding
Cancer Staging

Staging is always done surgically

Requires a total hysterectomy, BSO, PLND,
+/- PaoLND & omentectomy.
Cancer Staging

Patterns of metastatic spread:

Pelvic and paraaortic lymph nodes, lung,

inguinal and supraclavicular nodes, liver,
peritoneal cavity, bone, brain, and vagina
Cancer Staging

Pre-op imaging

CXR
CT (not necessary unless you think there’s
extra pelvic disease– it doesn’t alter tx and
doesn’t really let you know of depth of
invasion etc.– MRI would be better in
assessing invasion)
Cancer Staging

Labs
CA-125 ?
HNPCC and Screening

 Since 40-60% of patients with this develop

endometrial ca., do an EMB at age 35
-women with HNPCC-associated
mutations
-women with a family member with this
mutation

-Doing an ultra sound is not enough!

 Summary of Recommendations
Ql: Which patients with endometrioid endometrial cancer require no additional
therapy after hysterectomy?

•Following total abdominal hysterectomy with or without node dissection, no radiation therapy
is a reasonable option for patients without residual disease in the hysterectomy specimen despite
positive biopsy (despite a positive pre-hysterectomy biopsy of any grade)
•Following total abdominal hysterectomy with or without node dissection, no radiation therapy
is a reasonable option for patients with grade 1 or 2 cancers with either no invasion or <50%
myometrial invasion.
•Vaginal cuff brachytherapy may be considered in patients with negative node dissection with
grade 3 tumor without myometrial invasion. 
•Vaginal cuff brachytherapy may be considered in patients with negative node dissection with
grade 1 or 2 tumors with <50% myometrial invasion and higher-risk features, such as age >60
and/or LVSI.
 Summary of Recommendations

Q2: Which patients with endometrioid endometrial cancer should receive

vaginal cuff radiation?

•Vaginal cuff brachytherapy is as effective as pelvic radiation therapy at preventing

vaginal recurrence for patients with: (1) grade 1 or 2 tumors with ~50% myometrial
invasion or (2) grade 3 tumors with <50% myometrial invasion.

•Vaginal cuff brachytherapy is preferred to pelvic radiation in patients with the above risk
factors particularly in patients who have had comprehensive nodal assessment.
 Summary of Recommendations
Q3: Which women should receive postoperative external beam radiation?

•To date, there is no documented improvement in overall survival for women with endometrial cancer treated
with EBRl; and long-term complications including bowel and bladder dysfunction or secondary cancers have
been reported.

•Patientswith grade 3 cancer with ~50% myometrial invasion or cervical stroma invasion may benefit from pelvic
radiation to reduce the risk of pelvic recurrence.

•Patientswith grade 1 or 2 tumors with ~50% myometrial invasion may also benefit from pelvic radiation to
reduce pelvic recurrence if other risk factors are present, such as age >60 years and/or LVSI.Vaginal
brachytherapy may be a better option for patients with these features, especially if surgical staging was
adequate and nodes were negative.
 Summary of Recommendations
Q3: Which women should receive postoperative external beam radiation?

• The best available evidence at this time suggests that reasonable options for adjuvant treatment of
patients with positive nodes, or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum
includes external beam radiation therapy, as well as adjuvant chemotherapy. The best evidence for this
population supports the use of chemotherapy, but consideration of external beam radiation is reasonable.

• Chemotherapy without external beam radiation may be considered for some patients with positive nodes, or
involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors
for pelvic recurrence.

• Radiation therapy without chemotherapy may be considered for some patients with positive nodes, or
involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors
for pelvic recurrence. Patients receiving chemotherapy appear to have improved survival compared with
radiation alone, unless the patient is not a candidate for chemotherapy.
 Summary of Recommendations
Q4: When should brachytherapy be used in addition to external beam radiation?

• Prospective data is lacking to validate the use of vaginal brachytherapy after pelvic radiation and most
retrospective studies show no evidence of a benefit, albeit with small patient numbers. Use of vaginal
brachytherapy in patients also undergoing pelvic external beam radiation is not generally warranted, unless
risk factors for vaginal recurrence are present.
 Summary of Recommendations
Q5: How should radiation therapy and chemotherapy be integrated in the management of
stage I-III endometrioid endometrial cancer?

• The best available evidence suggests that concurrent chemoradiation followed by adjuvant
chemotherapy is indicated for patients with positive nodes or involved uterine serosa, ovaries/fallopian
tubes, vagina, bladder, or rectum. Evidence regarding concurrent chemoradiation is limited at this time,
and this recommendation is based on expert opinion; we anticipate level 1 evidence from upcoming
prospective randomized clinical trials (GOG 0258 and PORTEC-3).Chemotherapy may also be
considered in certain high-risk early stage endometrial cancer patients, and clinical trials of this question
are underway.

• Alternative sequencing strategies with external beam radiation and chemotherapy are also acceptable.
Small, prospective trials have examined sequential radiation followed by chemotherapy.
"SandwichN-type therapy currently has only limited, non-randomized evidence.
LEIOMYOSARCOMA
 Introduction
 ULMS incidence is 0.7-1.0/100,000

 Most ULMS are high grade sarcomas with high risk of recurrence &
progression.
 Overall survival is dependant on the stage , 5y survival for
- stage 1 = 76% , stage 2 = 60%, stage 3 = 45% stage 4 = 29%.

 Metastatic disease usually in the 5th decade or before in a women with a

good performance status.

 Response rate for chemotherapy in the metastatic setting is reported to bé

15-54%.
 Diagnosis
 Some small studies showed that MRI can
distinguish benign from malignant lesions

 Intrauterine tumors increasing in size after

menopause should rise the suspecion for
malignancy.

 In most patients, the diagnosis of LMS is made at

the time of myomectomy or hysterectomy for
persumed benign disease.
Staging - FIGO 2009
 Initial Treatment
 Surgery :
 for patients whose disease is limited to the uterus, hysterectomy is
recommended.
 if malignancy is suspected preoperatively , no mocellation US-FDA
issued a safety alert 2014 against power morcellators .

 routine LN dissection is not recommended , only large or suspecious

nodes have to bé removed.
 BSO is reasonable in perimenopausal & postmenopausal women .
No survival benefits.
 40-70% of ULMS are ER &/or PR positive
 PATIENTS < 50 Y with disease limited to uterus , no difference
whether BSO is done or not.
 Initial Treatment
 If the disease is locally advanced but potentially completely
resectable, an attempt to resect it is reasonable, optimal
cytoreduction increased both PFS & OS.

 For multisite metastasis or unresectable disease >> no role

for hysterectomy ( only palliative e.g severe uterine bleeding )

 Laparoscopic re-evaluation after morecellation hysterectomy

should bé considered to evaluate for & resect any residual
disease.

 Resection of the cervix & doing BSO if not yet done is

reasonable for those had only supracervical hysterectomy.
 Post-resection management of uterus-
limited disease
 Although the risk of recurrent disease is >50%, no adjuvant
intervention has been shown to improve PFS or OS.

 The standard management is observation.

 30% of patients found to have ULMS at the time of surgery will

have metastatic disease.

 CT , PET/CT or MRI is recommended postoperatively to r/o distant

mets.

 Adjuvant radiation did not show any survival benefit (local

recurrence was the same for the radiation & the control group).
 Post-resection management of uterus-
limited disease
 Adjuvant chemotherapy with doxyrubicin did
not show a survival benefit.
 Adjuvant docetaxel + Gemcitabine followed
by doxyrubicin improved 2y PFS to 78% but
failed to improve OS.
 An International randomized phase III trial of
observation versus Gemcitabine/docetaxel for
4 cycles followed by doxyrubicine 4 cycles is
ongoing - GOG 277)
 Post-resection management of locally
advanced disease
 No consensus
 Observation, Chemo , radiation or hormone
blockade therapy are acceptable options.
 Metastatic disease
 If complete resection of the metastatic disease
is possible >> survival benefit.

 No consensus for the adjuvant treatment

 Systemic treatment options for
unresectable or metastatic disease
 No established superior 1st line chemotherapy.
 Reasonable regimens to consider :
- doxyrubicin , 19% RR
- doxyrubicin/ifosfamide 30% RR
- gemcitabine 20% RR
- gemcitabine/docetaxel 27% RR
- ifosfamide 17% RR

 Other chmotherapeutic agents used as 2nd line are : pazopanib 6%

RR, trabectudine 10-16% , decarbazine or temzolomide.

 Hormonal therapy such as aromatase inhibitors should bé considered

when hormone receptors are positive >>10% survival benefit in a
small burden/indolent disease.