GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR.
GARCIA)
NEOPLASTIC DISEASES OF THE UTERUS
VICTORINO C. GARCIA, JR., MD, FPOGS, FPSCPC, FSGOP
Overview
 Most common gynecologic malignancy- US
 54,870 new cases diagnosed each year, in ACS
2015 figures
 Resulting in 10000 deaths annually
 Normally occurs in perimenopausal and
postmenopausal women
 Average age at diagnosis 50-65 years old
 < 5% under age 40, 10-15% under age 50
Risk Factors
 Unopposed estrogen stimulation
 Unopposed menopausal estrogen (4-8x)
replacement
o Women using higher doses and prolonged
use estrogen replacement alone increases
risk
o Can be markedly reduced with the use of
progestin
o Combination OCP decreases risk (relative
risk reduction by 0.5
 Menopause after 52 years (2.4x)
 Obesity (2-5x)
o BMI >30 (2-3x risk)
o Increased circulating estrogen, conversion
of androstenendione to estrone in the
adipose tissue, decreased sex hormone-
binding globulin and insulin resistance
 Diabetes (2.8x)
 Insulin resistance
 Estrogen secreting ovarian tumors
 Polycystic ovarian syndrome (Stein-Leventhal
syndrome)
 Tamoxifen therapy for breast cancer
 Nulliparity (2x)
 Hypertension: Often related to obesity
 Race: White women 2x the rate than black
women
LYNCH SYNDROME
 Hereditary nonpolyposis colorectal cancer
syndrome
 An autosomal dominant hereditary cancer
susceptibility syndrome caused by germline
defect in a DNA mismatch repair gene (MLH1,
MSH2 or MSH6)
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 40% to 60% lifetime risk of endometrial cancer
 40% to 60% lifetime risk of developing colon
cancer
 12% lifetime of developing ovarian cancer
 General population risk: 3% for endometrial
cancer, %% for colon cancer and 1.7% risk for
ovarian cancer
 Screening recommendation: annual endometrial
biopsy and TV ultrasound
 Women with endometrial cancer and family
history of colon cancer: refer for geentic
evaluation and colonoscopy
MOLECULAR ABERRATIONS IN ENDOMETRIAL CANCER
 PTEN mutations are frequently seen
 Microsatellite instability occurs in 25-30% of all
endometrial cancer and is the result of the
germline mutation DNA mismatch
 In uterine papillary serous carcinoma, a high
frequency of p53 mutations
 HER-2/neu amplification is seen in 10 to 20% of
UPSC and is likely associated with advanced stage
and poor prognosis
DECREASED RISK
 Ovulation
 Progestin therapy
 Combination oral contraceptives
 Menopause before 49 years
 Normal weight
 Multiparity
ENDOMETRIAL HYPERPLASIA
- Is believed to result from excess of estrogen
relative to progestin, such as with anovulation
SIMPLE HYPERPLASIA
o Endometrium with dilated glands that may
contain some outpouching and abundant
endometrial stroma
o The term cystic hyperplasia has been used to
describe dilation of the endometrial glands,
which often occurs in a hyperplastic
endometrium in menopausal or
postmenopausal women (cystic atrophy)
o It is considered to be weakly premalignant
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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA) 2017
- Complex atypical hyperplasia had a 29% rate of
progression to cancer
- A recent GOG study showed that 40% of women
with complex atypical hyperplasia had endometrial
cancer in their hysterectomy specimen

DIAGNOSIS AND ENDOMETRIAL SAMPLING

- Abnormal uterine bleeding: most frequent
symptom
 Younger patients: anovulatory cycles-
SIMPLE HYPERPLASIA oligomenorrhea or amenorrhea
 Premenopausal: irregular vaginal bleeding
COMPLEX HYPERPLASIA  Postenopausal: any vaginal bleeding
- Office endometrial sampling: thin plastic pipelle
o Glands are crowded - D&C
with very little - Transvaginal ultrasound:
endometrial stroma  96% of women with carcinoma had an
and a very complex  abnormal ultrasound scan (endometrial
gland pattern and thickness >5mm)
outpouching  In post menopausal women with any vaginal
formations bleeding. A finding of endometrial thickness
o A variant of adenomatous hyperplasia with less than 4 mm is a reasonable predictor of
moderate to severe degrees of architectural atypia lack endometrial pathology
but with no cytologic atypia  However persistent bleeding should lead to
o These hyperplasia have a low premalignant endometrial sampling regardless of
potential ultrasound findings

COMPLEX ATYPICAL HYPERPLASIA

o Hyperplasias that contain
glands with cytologic
atypia and are
considered premalignant

o There is an increase in
the nuclear/cytoplasmic
ratio with irregularity in
the size and shape of
nuclei

o Cytologic atypia occurs

primarily with complex hyperplasia, and simple
hyperplasia with atypia is rarely seen

o Complex atypical hyperplasia has the greatest

malignant potential

 Endometrial ablation is sometimes used to

NATURAL HISTORY control severe uterine bleeding
- Simple hyperplasia had a 1% rate of progression to  Thorough evaluation of the endometrium
cancer should be performed before ablation in order to
- Complex hyperplasia without atypia had a 3% rate rule out an underlying endometrial hyperplasia
of progression to cancer or cancer

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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA) 2017
MANAGEMENT  Older patients: moderate or severe atypia:
HYSTERECTOMY
 If Hysterectomy is not advisable: MEGESTROL
ACETATE 40 to 160 mg/day
 Periodic sampling of the endometrium

ENDOMETRIAL CARCINOMA

Symptoms, Signs and Diagnosis

 Postmenopausal bleeding and abnormal
premenopausal and perimenopausal are the
primary symptoms of endometrial cancer

 The diagnosis of is established by histopathologic

examination of the endometrium

 Initial diagnosis by endometrial biopsy, if carcinoma

found: endocervical curettage is performed to rule
out invasion of the endocervix

 Pap smear detect endometrial carcinoma in only

approximately 50% of cases

 If outpatient evaluation cannot be obtained:

fractional
 D&C, usually with hysteroscopy should be
performed
 For women with simple hyperplasia or complex
hyperplasia without atypia, a diagnostic D&C can
also be therapeutic, and progestins or combination
OCP will likely be effective

 For complex atypical hyperplasia:

o Women who desire to preserve childbearing
function are treated with high-dose progestin,
usually megestrol acetate 40 mg tid to qid, and
should have long term follow up and periodic
sampling, the first at 3 months and at least
every six months

o Once complex hyperplasia is cleared,

consideration should be given to periodic
progestin treatment or oral contraception until
the patient chooses to attempt pregnancy

 Younger patients: once the complex hyperplasia

with atypia is cleared: periodic progestin treatment
or oral contraception until the patient chooses to
attempt pregnancy
NORMAL ENDOMETRIUM

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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA) 2017
Histologic Types

Typical Endometrioid Adenocarcinoma

o Tumor grading
 Grade 1
- Well differentiated
- Has less than 6% solid component
 Grade 2
- Moderately differentiated with 6% to 50%
solid component
 Grade 3
ENDOMETRIAL POLYP
- Poorly differentiated with solid sheets of
tumor, more than 50% solid component

POLYP AND ATYPICAL HYPERPLASIA

FOCAL SIMPLE HYPERPLASIA

GRADE 3 ENDOMETRIAL CANCER

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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA)
GRADE 3 ENDOMETROID CANCER
Histologic Types
o Squamous epithelium commonly coexists with the
glandular elements of the endometrial carcinoma
o Previously known:
 ADENOACANTHOMA -- a well differentiated
tumor
 ADENOSQUAMOUS CARCINOMA -- a poorly
differentiated tumor with squamous elements
o Recently:
 ADENOCARCINOMA WITH SQUAMOUS
DIFFERENTIATION -- prognosis related to the
grade of the glandular component and the
degree of the myometrial invasion
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Histologic Types
o Uterine Papillary Serous Carcinoma (UPSC)
o Highly virulent and uncommon subtype of
endometrial carcinoma (5-10%)
o Resemble papillary serous carcinoma of the ovary
and found to have a high rate of extrauterine
disease even in cases without myometrial invasion
Histologic Types
o Clear cell carcinoma of the endometrium are
less common (<5%)
o Resemble clear cell carcinoma of the ovary,
cervix and vagina
o Tend to develop in postmenopausal women
and carry a prognosis much worse than typical
endometrial adenocarcinoma
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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA) 2017
Histologic Types o Spread of tumor outside the uterus to the
retroperitoneal nodes, peritoneal cavity or uterine
o Secretory Carcinomas adnexae
 Rare
 Diagnosed in the presence of
progestational stimulation and corpus
luteum
 Prognosis is good
o Mucinous Carcinoma
 Rare
o Primary Squamous Cell Carcinoma of the
Endometrium PATTERNS OF SPREAD
o A small lymphatic branch along the round
ligaments that runs to the inguinal femoral nodes
o Branches from the tubal and Ovarian pedicles
(infundibulopelvic ligaments), which are large
lymphatics that drain into the paraaortic nodes
o The broad ligament lymphatics that drain directly
to the pelvic nodes

PROGNOSTIC FACTORS

CLINICAL FACTORS
o Age at time of diagnosis: Older patients have
tumors of higher stage and grade than younger
patients MANAGEMENT
o Race:
STAGE 1
 White patients have higher survival rate than
Surgery:
black patients
- Extrafascial hysterectomy with BSO, PFC, pelvic
 Black women are more likely to develop UPSC
and paraaortic lymph node
o Clinical tumor Stage
- Laparoscopy assisted vaginal hysterectomy
(LAVH) or total laparoscopic hysterectomy with
PATHOLOGIC FACTORS
a laparoscopic lymphadenectomy
o Histologic grade: well to poor differentiated
- Adjuvant radiotherapy: for G3 tumor, tumor
o Histologic type:
diameter >2cm, unfavorable histologic type,
 Best prognosis: typical adenocarcinomas,
>50% myometrial invasion
better differentiated tumors with or without
squamous elements, secretory carcinomas
STAGE II (TUMOR EXTENSION TO THE CERVIX)
 Poor prognosis: UPSC, clear cell, poorly
- Primary operation (radical hysterectomy and
differentiated tumor with or without
pelvic node dissection)
squamous elements
- Primary radiation (intrauterine and vaginal
o Degree of myometrial invasion
implant and external irradiation) followed by an
o Tumor size
operation (extrafascial hysterectomy)
o Microscopic involvement of vascular spaces in the
- Simple hysterectomy followed by external
uterus by tumor
beam irradiation
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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA)
STAGE III (TUMOR EXTENSION OUTSIDE THE UTERUS,
WITHIN THE PELVIS)
- Surgery: EHBSO, PFC, LN dissection, debulking
- Adjuvant treatment: chemotherapy followed by
radiotherapy
STAGE IV (TUMOR INVADES BLADDER AND/OR
BOWEL, +/-DISTANT METASTASIS)
- Surgery: EHBSO, debulking
- Adjuvant treatment: chemotherapy followed by
radiotherapy (EFRT + Vaginal brachy)
- Individualized treatment
STAGE I or II UPSC
o Best treatment is still unknown
o Comprehensive surgical staging may provide benefit
o Combined chemotherapy and radiotherapy may
play a role in management of early disease
o Chemotherapy: Carboplatin-Paclitaxel
o 5-year survival with Stage I disease: 94%
CHEMOTHERAPY FOR ADVANCED AND RECURRENT
ENDOMETRIOID ADENOCARCINOMA
 Single agent doxorubicin- response rate 25%
 Single agent Cipslatin – 20-42% response rate
 Cisplatin-Doxorubicin: 45-60%
 Single agent Paclitaxel: 36%
 Cisplatin-Paclitaxel: 65%
 TAP (Doxorubicin, Cisplatin, Paclitaxel) with
granulocyte colony stimulating factor
 Carboplatin Paclitaxel
CHEMOTHERAPY FOR ADVANCED & RECURRENT UPSC
o Cyclophosphamide, doxorubicin and cisplatin-toxic
o Carboplatin-Paclitaxel
PROGESTINS FOR ADVANCED OR RECURRENT DISEASE
o Initial clinical date response rates 30-50%
o Larger studies: 11-24%
o Oral medroxyprogesterone acetate (Provera),
intramuscular medroxyprogesterone acetate
(Depo-Provera), megestrol acetate (Megace)
o GOG study: Response to hormone therapy: 8%
response rate for PR-, 37% for PR+; 7% response
rate for ER-, 26% for ER+
o Patients with poorly differentiated tumors or
hormone- receptor negative tumors have lower
response rate to progestin therapy
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SELECTIVE ESTROGEN RECEPTOR MODULATORS AND
AROMATASE INHIBITORS
o First generation SERM: Tamoxifem have mixed
estrogenic agonist and antagonistic activity
o Early response rates for tamoxifen in advance
recurrent endometrial cancer 20 - 36%, but phase
II study 20mg daily: 10% objective response
o Phase II trials: Tamoxifen plus alternating cycles of
progestins: 27-33% response rates
o ECOG: no significant difference: progestin vs
progestin plus tamoxifen
o Anastrazole: oral nonsteroidal aromatase
inhibitor, for postmenopausal women with
progressive breast cancer following tamoxifen
therapy
o Phase II GOG study, found minimal activity (9%
response rate) in an unselected population of
patients with advanced or recurrent endometrial
cancer
o In the subset of women with FIGO grade 1 and 2
tumor with endometrioid histology, the response
rate was 30%
TARGETED THERAPY
o Abnormalities in the PTEN/AKT pathway
o Several studies have shown efficacy of Mtor
inhibitors including temsirolimus, everolimus, and
ridaforolimus in endometrial cancer recurrence
o Response rates 9 -24% with clinical benefit rates
up to 90%
o Everolimus plus Letrozole have a reported
response rate of 31%
SARCOMA
o Comprise less than 5 % of uterine malignancies
Homologous Sarcoma
Resemblance of the sarcomatous elements to
mesenchymal tissues of the uterus
 Leiomyosarcomas
 Endometrial stromal sarcomas
 Angiosarcomas
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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA) 2017
Heterologous Sarcomas
Tissues foreign to the uterus o Despite low incidence of high stage disease,
 Rhabdomyosarcoma approximately 50% of patients will have a
 Chondrosarcoma recurrence within 2 years
 Osteosarcoma
 Liposarcoma o Latest GOG trial on adjuvant radiation therapy in
Stage I and II showed no significant difference in
Malignant Mixed Mullerian Tumor (MMMT) PFS, absolute 2 year survival or the first site of
 Carcinosarcoma recurrence
 Sarcoma admixed with epithelial
adenocarcinoma o Adjuvant chemotherapy with Adriamycin compared
 Homologous or heterologous with observation arm showed no statistical
significance
Other classification
 Mullerian adenosarcoma o Vincristine, Actinomycin D and Cyclophosphamide,
 Lymphoma noted 13% complete response rate and 16% partial
*Please see photo at the last page response in 74 patients with advanced metastatic
uterine sarcoma

o Best responses with patients with lung metastasis

with doxorubicin and dacarbazine (DTIC)

o Cisplatin, Adriamycin, Paclitaxel (Taxol), Ifosfamide,

and etoposide (VP-16) all appear to have some
effectiveness

o Gemcitabine and docetaxel showed 54% overall

response rate in a phase II study

o A phase III GOG study failed to show additional

benefit to the addition of bevacizumab to
LEIOMYOSARCOMA gemcitabine and docetaxel
o Represent 1 to 2% of uterine malignancies
o Approximately one third of uterine sarcomas
o Development of leiomyosarcoma from leiomyoma
is rare
 Risk: 0.4% for those in their 30’s
 1.4% for those in their 50’s
o A finding of 5 mitoses or more per 10 hpf leads to
the diagnosis of leiomyosarcoma
o 4 or fewer mitoses usually have a more benign
course

o The prognosis worsens for tumors with more than

10 mitoses per 10 hpf
o Increased mitoses in leiomyoma during pregnancy
and OCP
o Usually presents as enlarged pelvic mass,pain, or
vaginal bleeding in the perimenopausal or
postmenopausal group

o Treatment: THBSO + staging

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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA)
ENDOMETRIAL STROMAL SARCOMA
 Comprise about 10% of uterine sarcoma
 Their behavior correlates with mitotic rate
 Once divided into low and high grade
 More recently all ESS are considered low grade, if
high grade element are present, these tumors
would be classified as undifferentiated high-grade
sarcoma
 Peak incidence 5th decade of life
 No association with previous radiation or risks of
endometrial cancer
 Prognosis depends on the extent of disease and
ability to remove all tumor at the time of surgery
 In general, ESS’s are indolent, slowly progressing
tumors
 Recurrent disease may be diagnosed as many as 30
years after diagnosis
 Tend to recur locally in the pelvis or peritoneal
cavity and frequently spreads to the lungs
 Tumor contain estrogen and progesterone
receptors and are sensitive to hormone therapy
 Complete resolution has been reported with
Megestrol acetate (Megace), medroxyprogesterone
acetate (Provera), letrozole (Femara), tamoxifen,
 17αhydroxyprogesterone caproate (Delalutin)
 Radiation used to treat recurrences, but extensive
experience not availbale
 Systemic chemotherapy not generally effective,
although good responses to doxorubicin
(Adriamycin) have been reported
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UNDIFFERENTIATED SARCOMA
 Behave aggressively and have a poor prognosis
 Microscopically, more than 10 mitoses per 10 hpf
are present and frequently 20 or more mitoses per
10 hpf are present
 Recurrences are common in the pelvis, lung and
abdomen
 Usually pelvic irradiation is prescribed and
multiagent chemotherapy is used
CARCINOSARCOMA (MMMT)
 About 40% of uterine sarcoma
 Consists of carcinomatous and sarcomatous
elements native to the uterus (homologous) or of
sarcomatous elements foreign to the uterus
(heterologous)
 Markedly worse prognosis than patients with
high-grade endometrial carcinoma
 Tend to be older than patients with ESS or
leiomyosarcoma, usually beyond 62
 Common symptom: postmenopausal bleeding
and large uterus
 Diagnosis: D&C, the tumor may appear to be
polypoid excrescence from the cervix, vaginal
ultrasound
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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA) 2017
 Treatment: operative removal of the uterus, The Carcinosarcoma (MMMT): Heterologous
extent of the tumor and the depth of myometrial
invasion are important prognostic factors

 5 year survival: 58% for disease confined to the

uterus

 GOG study: advance and recurrent: ifosfamide

vs,ifosfamide + cisplatin, combination superior
but with significant toxicity: response rate was
superior with the combination regimen but more
toxic (54 vs 36%)
MULLERIAN ADENOSARCOMA
 Phase III: Ifosfamide vs Ifosfamide plus paclitaxel,
response rate higher in the combination were  Rare low grade malignancy
superior (45% vs 29%), with significant difference
 Both sarcomatous stroma (homologous) and a
in the overall survival (13th months vs months)
proliferation of benign globularelements that
 Phase II study, paclitaxel and carboplatin in are intimately associated
women with advanced or recurrent  Women older than 60
carcinosarcoma with an overall response rate of  Treatment: THBSO
54%  Mitotic index and sarcomatous overgrowth
related to prognosis
 Paclitaxel and carboplatin are the current
standard treatments for women with
carcinosarcoma

LYMPHOMA

 Uterus can be the original site of lymphoma on

rare occasion
 About 40 cases reported
 Treatment: irradiation after hysterectomy

--END--

Alunes.Bahni.Lapastora.Manongsong.Robeniol

Carcinosarcoma (MMMT): Homologous

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GYNECOLOGY: NEOPLASTIC DISEASES OF THE UTERUS (DR. GARCIA) 2017

STAGING

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