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“Carol Davila” University of Medicine & Pharmacy

Bucharest

Endometrial cancer
Manuela Russu
Habilitated Professor
Head of “Dr. I. Cantacuzino” Discipline of
Obstetrics & Gynecology

MCR, 2018
Definition: Endometrial carcinoma is the proliferative
endometrial lesion which invades stroma
Incidence & Prevalence
 Endometrial cancer: more common in developed countries in
which dietary fat is high
• In US: is the 4th most common cancer in women, affecting 1 in
50, and the 1st in the genitalia
• approximately 37,000 cases are diagnosed & about 6000 women
die from the disease each year
 affects mainly postmenopausal women- 75%, particularly aged 50
to 65, also recognized in younger women, ~ 27 yrs being the
youngest age of discovery
 In US: more common in Caucasian women & uterine sarcoma is
more common in African American women
Classification & terminology
2 categories of endometrial carcinomas:
 Low grade, estrogen-dependent: younger women (~ 59yrs)
minimal myometrial invasion, good prognosis: ≥80% survive
after 5 yrs
- Typical Endometrioid Adenocarcinoma- well or moderate
differentiated, with or without squamous differentiation: 80-
85% of all endometrial carcinoma
 High grade, non estrogendependent: 10-15% of
endometrial carcinoma, including different subtypes: papillary
serous, clear cell, squamous, mucinous carcinoma, or other
types with high nuclear grade (mixed, undifferentiated)
• In late menopause: deep myometrial, lymph & vascular channel
invasion; extrauterine spread with peritoneal surface dissemination
proved during hysterectomy; early metastasis, without deep
myometrial invasion
Endometrial adenocarcinoma
 It appears on a
background of endometrial
hyperplasia
 Tumor cells are atypical
& form irregular glands,
with multiple lumens,
pluristratification
The stroma is reduced,
producing the "back to back"
aspect. With evolution of the
disease, the myometrium is
infiltrated
Endometrial Adenocarcinomas Classification- WHO, 1995
Endometrioid Carcinomas, NOS*
Variants: with cilliar cells
secretory
Adenocarcinoma, NOS, with squamous differentiation
Mucinous adenocarcinoma
Serous adenocarcinoma
Adenocarcinoma with clear cells
Squamous carcinoma
Undifferentiated carcinoma
Mixt* carcinoma
Metastatic carcinoma
NOS*- not otherwise specified
*Tumor with more than a second type of cells
Corpus uteri malignant tumors
Types of uterine sarcoma include:
 carcinosarcoma: most common type
 leiomyosarcoma: develops in the muscular tissue of
the myometrium
 endometrial stromal sarcoma: develops in
supporting connective tissue
This malignancy represents biologically &
morphologically different groups of tumours,
with different pathogenesis
Etiology & Pathology
Ferenczy A, Gelfand MM, Tzipris F, 1983
 Major risk factors: obesity, diabetes, hypertension
 Other risk factors: unopposed estrogen, tamoxifen
(Nolvadex®) use for > 5 yr, previous pelvic radiation therapy, & a
personal or family history of breast or ovarian cancer
 Nulliparity
 Early menarche: before 12 yrs of age
 Late menopause: after 52 yrs of age
 Unopposed estrogen (high circulating levels of E with no
or low levels of progesterone) may be associated with
obesity, polycystic ovarian syndrome, estrogen-producing
tumors (granulosa & thecal cell tumors), anovulation
(ovulatory dysfunction), & estrogen therapy without
progesterone/progestins
Etiology & Pathology
Risk factors for endometrial carcinoma
 Heredity contributes to endometrial cancer in ~ 6% of
cases, usually in families with hereditary nonpolyposis
colorectal cancer (HNPCC) syndrome
Protecting factors for endometrial
carcinoma
 Smoking
 Use of oral contraceptives
Dual model of endometrial carcinoma
Lax S F, Kurman R J, 1997-Department of Pathology in Johns Hopkins
Medical Institutions - Baltimore
 Endometrioid carcinoma: a slow development from hyperplasia on
a continuous unopposed estrogen stimulation like hereditary
nonpolyposis colorectal cancer, but pappilary serous & clear cell
carcinoma develop from an atrophic endometrium, starting from
a precursor lession “endometrial intraepithelial carcinoma” -EIC,
like serous ovarian carcinoma
 Genetic molecular analysis differ in these types of carcinoma:
• High grade: strong expression for p53 & its mutations, high level of Ki-67
• Low grade: genetic instability: 25-30% mutants of K-ras, only 10%
mutants of p53
• P53 mutants appear early in serous carcinomas’ carcinogenesis, fact
explaining their agresivity
• Hyperplasia: associated to endometrioid carcinoma, never appears in serous
carcinoma and rarely in clear cell carcinoma with serous characters (Lax SF,
Pizer E S, Ronett B M, Kurman R J, 1998)
Pathogenesis (1)

 It was originally hypothesized: endometrial hyperplasia


is a morphologic continuum from benign cystic
hyperplasia to atypical complex hyperplasia, which is
the immediate precursor of endometrial carcinoma
 Several studies have suggested that endometrial
hyperplasia & endometrial cancer are 2 different
entities, & the distinguishing feature: presence/
absence of cytologic atypia
 Atypia indicates risk for progression to cancer.
Studies of endometrial hyperplasia: > than 80 % of
those without atypia responded to progestin
therapy, compared with only 50 % of those with
atypia
Pathogenesis (2)

Atypical hyperplasia called endometrial intraepithelial


neoplasia-EIN is considered as a precancer, because it was proved to
be monoclonal by studies of chromosome X inactivation
 It is identified: morphological by significant atypias of glandular
cells & morphometrical by a reduction of ≥ 50% of stroma vs glands
Mutter G, Richart RM, Ferenczy A, et al, 2000
 By contrast, endometrial hyperplasia (EH) without atypia is
polyclonal and it is not a precursor of carcinoma
 EH may induce abnormal uterine bleeding and develop clone of
cells which by genetic mutations of k-RAS and later by p-53 genes
may have « growth advantages » over the surounding cells. These cells
may progress to carcinoma by subclonal expansion
 EIN & EH: estrogendependent, but malignant endometrial
evolution does not need sustained estrogen stimulation
 EH is progestins sensitive, EIN is progestins nonrespondent
Pathogenesis (3)

 Carcinoma developed in 25 % of patients with atypia


as opposed to < than 2 % of those without atypia
Kurman RJ, Kaminski PF, Norris HJ,1985: The
behavior of endometrial hyperplasia: a long-term study of
"untreated" hyperplasia in 170 patients; Ferenczy RJ,
Gelfand M, 1989
Median duration of evolution from hyperplasia without
atypia to carcinoma:~ 10 yrs, 4 yrs being necessary for
atypical hyperplasia to progress to evident clinical
endometrial carcinoma
17 to 25% cases diagnosed by endometrial biopsy as
atypical hyperplasia, show a well differentiated
carcinoma 1 month later, at hysterectomy
Symptoms. Signs. Tests
• Prolonged periods or bleeding between periods
• More frequent vaginal bleeding or spotting during the years leading up
to menopause (perimenopause)
• Any bleeding in menopause
• A pink, watery or white discharge
• Pus discharge from vagina
• Pelvic pain, especially late in the disease
• Pain during intercourse
• Weight loss
Mayo Clinic Guide to Women's Cancers, 2006
 A pelvic examination is frequently normal, especially in the early
stages of disease
 Changes in the size, shape, or consistency of the uterus or its
surrounding, supporting structures may be seen when the disease is
more advanced
Complications of Endometrial Carcinoma

 Anemia may result, caused by chronic loss of blood


(This may occur if the woman has ignored symptoms of
prolonged or frequent abnormal menstrual bleeding)

 Perforation (hole) of the uterus may occur during a


D&C or an endometrial biopsy
Diagnosis
 Endometrial cancer is suspected in:
• women with postmenopausal bleeding
• premenopausal women with abnormal bleeding
• postmenopausal women with a routine Pap test showing endometrial
cells and
• any women with a routine Pap test showing atypical endometrial
cells
 If cancer is suspected:
• outpatient endometrial biopsy is done; it is > 90% accurate.
• If results are inconclusive or suggest cancer, inpatient fractional
D & C with hysteroscopy
• An alternative is transvaginal ultrasonography, which may help
in diagnosis
Screening
• Currently, no screening regimens are recommended for
asymptomatic women, including those who take tamoxifen
• The early detection, presenting symptoms, and higher
survival rate make it unlikely that screening can have a
successful impact on earlier detection & increased survival
rates
 Endometrial sampling: the most accurate & widely used
screening technique
 When endometrial specimens show atypia: ~ a 25 % likelihood of
progressing to carcinoma, vs with less than 2 % in patients
without atypia
 Ultrasonographic measurement of endometrial
thickness [double layer stripe]
 Hysteroscopy
Endometrial Sampling
 The gold standard for histologic evaluation of the
endometrium: dilatation & curettage (D&C)
 In-office endometrial sampling devices, however, have proved
to be effective in screening the endometrium for disease without
the inconvenience, cost or risk of an operating-room procedure
 Numerous studies have found the results of office sampling to
approach those of D&C, with an accuracy of 90 to 95 %.
 Several devices have been developed for in-office sampling of
the endometrial lining. These include the Novak or Kevorkian
curette, the Pipelle endometrial-suction curette and the
Vabra aspirator
 Formal curettage is typically reserved for patients with negative
or inadequate findings on endometrial biopsies & either continued
symptomatic genital bleeding or high-risk factors for endometrial
cancer
Options for Endometrium’s Evaluation
Options Advantages Disadvantages Sensitivity Specificity
(%) (%)

Pipelle Cost effective, Not reusable; small Disease: 45 98


suction disposable; risk of perforation Cancer: 100 99
curette no anesthesia
needed
Vabra Disposable; may Possible perforation; 83 Not
aspirator require anesthesia equipment needed; available
noisy; not portable;
expensive
Curette Reusable; may Rigid; possible 94 Not
require anesthesia perforation; available
equipment needed;
patient discomfort
TVS Noninvasive; NPV Expensive; not for Asymptomatic 48
99%; detects screening; positive patients: 90
additional disease; predictive value 9%
little patient Patients with
discomfort; safe 80
bleeding: 82
Endometrial biopsy
Endometrial sampling
 Devices: in-office endometrial sampling: Novak or Kevorkian
curette, Pipelle endometrial-suction curette & Vabra aspirator
 Anesthesia: nothing/paracervical block
Once material is seen in the top of the cannula, the instrument can be
removed
 The specimen is then placed in formalin and sent to the laboratory
for histologic diagnosis
 If no tissue is obtained, a second cannula can be used, or a small
Novak curette can be placed in the uterine cavity and a gentle curettage
can be performed
 Some patients have atrophic endometrium, and little or no tissue
will be obtained
 In these patients, close observation can be maintained, or a D&C
can be performed with general or spinal anesthesia
Paracervical Block
Endometrial carcinoma diagnosis
Four Major Types of Pathologic Findings on
Endometrial Biopsy: Jones MW, Kurman RJ, 1990
 Proliferative, secretory, benign or atrophic
endometrium
 Simple or complex (adenomatous) hyperplasia without
atypia
 Simple or complex (adenomatous) hyperplasia with
atypia
 Endometrial adenocarcinoma
Differentiation degree
G1 well G2 - moderate G3
differentiated differentiated undifferentiate
d
≤ 5% solid 6 to 50% solid  50% solid
nonsquamous nonsquamos or nonsquamos or
or nonmorular nonmorular nonmorular pattern
pattern (tumour is pattern
95% of glandular
tissue)
Nuclear grading (FIGO, 1988)
Grading 1 Grading 2 Grading 3
Oval nuclei, fine Nuclei with Large, pleomorfiq
chromatin, small, characteristics nuclei, with gross
relative uniform between 1 and 3 chromatin, with
nucleoli, and grading proeminent
reduced mitotic macronucleoli
activity multiple, abnormal,
mitosis

Other histological parameters which influence the grading in FIGO System:


1. Nuclear grading is precedent in serous pappilary, clear cells tumors
& squamous carcinomas
2. Adenocarcinomas with squamous differentiation are graded after
nuclear grading of glandular component
Imaging Studies (1)
 Transvaginal ultrasonography (TVS)
• Determination of endometrial stripe thickness in women after
menopause is useful in the workup of PMP bleeding, excluding other
pelvic pathology that might contribute to PMP bleeding
• When using a value of less than 4 mm for a cutoff, essentially no
cancers have been detected histologically
• Considerable variation: among endometrial stripe measurements in
patients with endometrial cancer
• an endometrial stripe of up to 8 mm may be within the reference range
for a woman on estrogen replacement therapy after menopause
• Endometrial stripe thickness helps in determining which women
with negative findings on office endometrial biopsies should have a
formal curettage
 Because performance of an endometrial biopsy in the office is
relatively easy & cost-effective, most physicians choose to perform
this test in lieu of ultrasonography
Imaging Studies (2)
Inpatient or outpatient hysteroscopy
 With the D&C, hysteroscopy is a helpful tool in providing a
diagnosis for abnormal bleeding & guiding directed biopsies of
suspicious areas
 Useful in evaluation of the endocervical canal
 direct inspection of the endometrium, which provides the
opportunity to obtain a biopsy specimen and remove lesions,
especially polyps and leiomyomas
• Its disadvantages include surgical risks - similar to those
of D&C, and the additional concerns of cost and the possible
transtubal spread of malignant cells into the peritoneal cavity.
• Concern: regarding intraperitoneal expulsion of cancer cells
Imaging Studies (3)
Sonohysterography
 Rarely used in the diagnosis of endometrial cancer for the
same reasons as hysteroscopy: concern about transtubal
intraperitoneal expulsion of cancer cells
 Informations: tumor size, site of origin, cervical involvement
 Although this correlates to intraoperative findings, it
contributes little to the preoperative management plan. It is more
useful when the suspicion of endometrial cancer is low
Imaging Studies (3)

Chest radiographs: useful in the workup to


exclude distant metastases
 CT scan and/or MRI:
• are typically not necessary in the workup of
endometrial cancer or uterine sarcomas because the
first-line therapy for the vast majority of these patients
includes exploratory surgery
• Local extension & metastatic disease, requiring
comprehensive staging, can be predicted using clinical
evidence, including obvious cervical disease & high
tumor grade on the endometrial biopsy specimen
Stages of endometrial cancer
Endometrial carcinoma is surgically staged using the FIGO
cancer staging system
Stage IA: tumor is limited to the endometrium
Stage IB: invasion of less than half the myometrium
Stage IC: invasion of more than half the myometrium
Stage IIA: endocervical glandular involvement only
Stage IIB: cervical stromal invasion
Stage IIIA: tumor invades serosa or adnexa, or malignant peritoneal
cytology
Stage IIIB: vaginal metastasis
Stage IIIC: metastasis to pelvic or para-aortic lymph nodes
Stage IVA: invasion of the bladder or bowel
Stage IVB: distant metastasis, including intraabdominal or inguinal
lymph nodes
Linestrenol 10mg/d
Micr progesterone:
200mg/d

Algorithm
for the
management
of hyperplasia
without atypia
Management of hyperplasia
 Hyperplasia without atypia: should be treated with progestins and
have an endometrial biopsy every 3 to 6 months- Jones MW, Kurman
RJ, 1990
 Hysterectomy is an option for those who are unwilling to take
progestins or who have persistent hyperplasia despite progestin
treatment Berek JS, Hacker NF, 1994
 The ideal type and amount of progestin necessary to protect the
endometrium is still unknown, and no data define the optimal duration
of treatment. McGonigle KF, 1997
 If risk factors remain unchanged, the clinician should consider
continuing progestin treatment for an additional 12 months
after a normal biopsy, with annual endometrial biopsies
performed as follow-up
 Many clinicians still recommend that women older than 50 years
consider hysterectomy as a definitive treatment
Treatment (1)

Time waiting from biopsy to surgery does not affect


survival in endometrioid carcinoma
 Treatment options involve surgery, radiation therapy & chemotherapy
 The primary treatment is surgical
 Surgical treatment should consist of: cytologic sampling of the peritoneal fluid,
abdominal exploration, palpation & sampling/biopsy of suspicious lymph nodes
 Abdominal hysterectomy, & removal of both ovaries (bilateral salpingo-
oophorectomy)
 Abdominal hysterectomy was recommended over vaginal hysterectomy because
it affords the opportunity to examine and obtain washings of the abdominal cavity to
detect any further evidence of cancer
 Vaginal surgery is accepted now
 Laparoscopic or robotic hysterectomy
 Lymphadenectomy, or removal of pelvic and para-aortic lymph nodes, is
sometimes performed for tumors that have high risk features, such as pathologic
grade 3 serous or clear-cell tumors, invasion of more than 1/2 the
myometrium, or extension to the cervix or adnexa
 Sometimes, removal of the omentum is also performed
Treatment (2)

 Women with stage 1 disease who are at increased risk for recurrence and those
with stage 2 disease are often offered surgery in combination with radiation
therapy
 Stage II or III cancer requires pelvic radiation therapy with/ or
without chemotherapy
 Treatment of stage III cancer: must be individualized, but surgery
is an option; generally patients who undergo combined surgery &
radiation therapy have a better prognosis
 Except in patients with bulky parametrial disease, a total abdominal
hysterectomy & bilateral salpingo-oophorectomy must be performed
Treatment of stage IV is variable and patient dependent: typically
involves a combination of surgery, radiation therapy, & chemotherapy.
Occasionally, hormonal therapy may be considered: a progestin causes
regression for up to 3 yr in 35 to 40% cases. Pulmonary, vaginal, &
mediastinal metastases may regress. Treatment continues as long as the
response is favorable
Treatment (3) Radiation therapy (RT)
 RT uses high-energy rays to pinpoint and destroy cancer cells.
Although radiation treatment is similar to having an X-ray, the dose of radiation is
higher and given over a longer period of time.
Radiation therapy may be used to treat endometrial cancer after a hysterectomy/ as
the primary therapy, especially when surgery is not an option.
 Depending on the stage and grade of the cancer, radiation therapy may also be
used at different points of treatment. A radiation therapist delivers the prescribed
treatment and will assist the patient.
 There are two types of radiation therapy and in some cases, both types are given.

!) Brachitherapy (internal radiation therapy)- radioactive materials (radio-isotopes) are inserted


through the vagina and placed in the uterus or other areas where cancer cells are found and remain there
for two to three days. It can be done during a hospital stay or on an outpatient basis. Placing the
radioisotopes takes about 30 to 45 minutes under local or general anesthesia. Depending on cancer type,
several treatments may be needed. Because brachytherapy delivers radiation to a local area with tiny
pellets, there is little effect on nearby structures- as the bladder or rectum. Once treatment is completed,
removal of the radioisotopes is a straightforward procedure, which can be painful.

2) External radiation similar to an X-ray, but takes longer. This treatment is usually done on
an outpatient basis for 4 to 6x wks, 5 dys per week for about 30 to 45 minutes each time.
Treatment (4) Chemotherapy
Several cytotoxic drugs are effective
particularly:
 doxorubicin ADRIAMYCIN®
 cisplatin PLATINOL ®
 paclitaxel TAXOL ®
• With monthly regimens:
doxorubicin (Adriamycin) 60 mg/m2
+
cisplatin (Platinol) 60 mg/m2 IV
• overall response rate may be ≥ 50%
Prognosis
ER/PR presence has an important prognosis
significance regarding global survival and time to
reccurence specially in endometrioid carcinoma
Fukuda K, Mori M, Uchiyama M, Kiwai I, 1998:
• PR : better correlated to FIGO stages of endometrial
carcinoma (I, II versus III, IV, P = .0025), with FIGO
grade (G1 versus G2, G3, P = .007), depth of myometrial
invasion (< or = 1/2 versus > 1/2, P = .006), survival without
reccurence (survival versus death, P =.032)
• ER: better correlated to depth of myometrial invasion
(P =.026), survival without disease (P =.032)
Prognosis in Endometrial carcinoma
PTEN is a cellular ubicuitoir phosphoinositid- 3
phosphatase with tumor suppressor role, that inhibits cell
proliferation, survival, and development (Tamura M, Gu
J, et al, 1998) by inactivation of kinase 3-
phosphoinositid- dependent and can suppress cell mobility
(Gu J, Tamura M, et al, 1999) by mechanisms that are
partial independent of phosphatase activity.
PTEN is inactivates in some endometrial carcinomas
(frequency >15%); or
PTEN is lost in endometrial carcinomas (Zhou XP,
Loukola A, et al, 2002)
Prognosis in Endometrial carcinoma
Expectations Survival rates
The 5-year survival rate for endometrial cancer
Because endometrial following appropriate treatment is:
cancer is usually diagnosed in American Cancer American Cancer
the early stages Society, 2007 Society, 2017
(70 - 75 % cases are in stage 1  75- 95% for stage 1 90- 95% for stage 1
at diagnosis; 10 - 15 % cases  50% for stage 2  75% for stage 2
are in stage 2; 10 - 15 %  30% for stage 3  60% for stage 3
cases are in stage 3 or 4),  < 5% for stage 4  15-26 % for stage 4
National Cancer Data Base, 2017 for endometrial
There is a better probable cancers during 2000-2002
outcome associated with it 75- 88% for stage 1
than with other types of  69-75 % for stage 2
gynecological cancers, such as  47-58 % for stage 3
cervical or ovarian  15- 17 % for stage 4

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