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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)
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)
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.
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