non endometrioid carcinoma , Middle Eurphrates cancer center Iraq , Najaf by Dr.Mustafa Alazam Gp oncology 2018

2. Anatomy
›The uterus is a hollow, muscular organ located in the true pelvis
between the bladder and the rectum. The average adult uterus is about
8 cm long, 5 cm width, and 2.5 cm thick.
›It is divided into the fundus, body (corpus), and cervix. The junction
between the body and cervix is called the isthmus. The fundus is
connected at each cornu by the fallopian tubes. The uterine surface is
partially covered by peritoneum. The uterine cavity is lined by
endometrium, made up of columnar cells forming tubular glands.
›The wall of the uterus is composed of myometrium, consisting of
smooth muscle fibers.
›The major supports of the uterus are the broad, round, uterosacral and
cardinal ligaments.
›The major blood supply to the uterus is the uterine artery, which enters
the uterus at the isthmus after it crosses over the ureter.
›The lymphatic drainage for the body of the uterus is mainly to the
obturator and internal and external iliac lymph nodes,The lymphatics
from the fundus accompany the ovarian artery and drain into the para-
aortic lymph nodes.

4. Endometrial cancer is the most common gynecologic cancer and the fourth
most frequently diagnosed cancer in women in the United States.
Although it is a cancer that affects predominantly postmenopausal women,
5% to 30% of women are <50 years of age at the time of diagnosis.
- Eighth-leading cause of death from cancer in women.
1. Estrogen exposure
that is unopposed by progesterone increases the risk for endometrial carcinoma by
four- to eightfold. Tamoxifen acts as a weak estrogen. Data suggest that the use of
tamoxifen is associated with a twofold increased risk for endometrial cancer.
2. Medical conditions producing increased exposure to unopposed estrogens
Its associated with increased risk of endometrial carcinoma are:
a. Polycystic ovarian disease (anovulatory menstrual cycles with or without
hirsutism and other endocrine abnormalities)
b. Anovulatory menstrual cycles
c. Obesity
d. Granulosa cell tumor of the ovary, or any other estrogen-secreting tumor
e. Advanced liver disease
Epidemiology & Risk factors

5. 3. Other medical conditions:
associated with increased risk for endometrial carcinoma are:
a. Infertility, nulliparity, irregular menses
b. Diabetes mellitus
c. Hypertension
d. History of multiple cancers in the family
e. Patient history of breast or rectal cancer
4. Hereditary factors:
resulting from germ line mutations in DNA mismatch repair (MMR)
genes. Mutations in MMR genes (MSH2, MLH1, or MSH6) can
result in Lynch syndrome II (hereditary nonpolyposis colorectal
cancer). By age 70, up to 40% of these individuals may be
diagnosed with endometrial cancer.

6. Histology: There are Two main pathological conditions in the
Endometrium:
A. Endomertial Hyperplasia: is an increase in the number of proliferating
glands.The rate of underlying concurrent carcinoma in the uterus was 42.6%
in these patients.
B. Endometrial carcinoma: About 95% of uterine cancers arise
from the endometrium, and the histologic subtype are:
1. Endometrioid adenocarcinoma: Endometrioid adenocarcinoma is
the most common endometrial carcinoma, constituting 75% to 80% of
all.
2-Mucinous Carcinoma: This designation requires >50% of the tumor
cells to be mucinous. Mucinous carcinomas are usually well
differentiated and have the same prognosis as ordinary endometrioid
carcinomas.

7. 3 -Serous Carcinoma: Serous carcinomas, known as papillary
serous cancers, resemble ovary cancer in histology and
behavior.
4-Clear-Cell Carcinoma: Clear-cell carcinoma of the endometrium
resembles renal carcinoma, but its origin from Müllerian
structures is now well established. Unlike vaginal and cervical
clear-cell.
5. squamous cell carcinoma: account for the other 10% of
endometrial cancers.This type of cancer is extremely rare, and the
diagnosis made after the exclusion of cervical origin.
6-Undifferentiated Carcinoma : WHO classification describes
endometrial undifferentiated carcinomas as “malignant poorly differentiated
endometrial carcinomas.
7-Mixed Histology: Mixed-cell-type endometrial cancer composed of two or
more pure types is uncommon.

8. Mode of spread:
Tumors are confined to the body of the uterus in
75% of cases. Endometrial cancer most
commonly spreads by direct extension. Deep
myometrial invasion and involvement of the
uterine cervix are associated with a high risk for
pelvic lymph node metastases. Hematogenous
spread is an uncommon late finding in
adenocarcinoma but occurs early in sarcoma.
The lungs are the most frequent site of distant
metastatic involvement.

9. Prognostic factors
1.Age:older patients tend to present with aggressive histology and more-
advanced disease and are generally treated less aggressively.
2-Race: White women tend to fare better than African Americans,
3-histologic subtype : According to the FIGO annual report, the 5-
year survival rate was 83.2% for endometrioid adenocarcinoma, compared
to 52.6% for serous cancer and 62.5% for clear-cell cancer.
4-Grade:
Grade directly affects the depth of myometrial penetration and the
frequency of lymph node involvement.
5-Myometrial Invasion.
6-lymphovascular invasions.
This is seen in about 15% of the cases of endometrial cancer.
7-Cervical Involvement.

10. 9-Adnexal/Serosal Involvement:
About 5% of patients with stage I and occult stage II disease have adnexal
involvement.
10-Pelvic and Para-Aortic Lymph Node Involvement:
The pattern of lymphatic spread in endometrial cancer is different than that in
cervical cancer. In endometrial cancer, a simultaneous spread to both pelvic and
para-aortic nodes could occur, whereas in cervical cancer the spread to
paraaortic nodes is almost always secondary to pelvic lymph node involvement.
biggest risk factor for para-aortic node involvement is pelvic nodal
metastases; more than 30% of patients with pelvic nodal involvement have
para-aortic disease
11 -Molecular Prognostic Factors: overexpression of p53 and
Overexpression of HER-2 are associated with more advanced disease
and poor outcome.

11. Work Up
(The preoperative evaluation includes):
A. Signs and Symptoms :
1. Abnormal vaginal bleeding is the most common symptom (97%).
a. Premenopausal women with prolonged menses, excessive menstrual
bleeding, or intermenstrual bleeding must be evaluated for endometrial
cancer, particularly if they have a history of irregular menses, diabetes mellitus,
hypertension, obesity, or infertility.
b. All postmenopausal women with vaginal bleeding >1 year after the last
menstrual period are considered to have endometrial cancer unless proved
otherwise.
2. Patients without symptoms and with atypical endometrial cells on Pap
smears should undergo endometrial sampling.
3. Women with AGC (atypical glandular cells) on Pap smears who are >35
years, as well as younger women with AGC who have unexplained vaginal
bleeding, must undergo an endometrial biopsy in addition to colposcopy.
4. Locally extensive tumors may be palpable on pelvic examination.

12. 1.Chest –X ray.
1.Vaginal ultrasonography:
In the past, the increased use of vaginal ultrasonography to
evaluate the endometrial stripe has been reported. Some
investigators believe that this should be the first diagnostic
procedure because vaginal ultrasonography is less invasive
than endometrial biopsy.
2.Hydroultrasonography
If a thickened endometrium is present, obtain a
hydroultrasonogram to make sure a false-positive result is
not present. This is accomplished by placing a small volume
of saline into the endometrial cavity and then repeating the
vaginal ultrasonogram.

13. 3. (CT) scans can demonstrate the extent of the endometrial
tumor.
4.MRI : Dynamic contrast-enhanced (MRI) is the best tool to
assess the cervical involvement.
5.(PET/ CT There seems to be little benefit in assessing the
primary tumor extension.
main limitation of PET/CT is its inability to detect metastasis in
lymph nodes ≤5 mm in size.

16. 1.Complete blood count:
The complete blood count (CBC) is a test that help to detect the
anemia due to bleeding.
2.CA-125 blood test:
CA-125 is a substance released into the bloodstream by
many, but not all, endometrial and ovarian cancers. If a
woman has endometrial cancer, a very high blood CA-125
level suggests that the cancer has probably spread beyond
the uterus. Some doctors check CA-125 levels before
surgery or other treatment. If they are elevated, they can be
checked again to find out how well the treatment is working
(for example, levels will drop after surgery if all the cancer is
removed).

18. 1.Pap smears:
Conventional Pap smears from endocervical aspiration or brushing have a
much lower yield than fractional curettage or washout. Pap smears alone
should not be used to exclude suspected endometrial cancer. Only half of
patients with endometrial cancer have abnormal cells on Pap smear.
A.Dilatation and curettage was historically the definitive diagnostic
procedure to help rule out endometrial cancer.
B. Hysteroscopically directed biopsy:
Another diagnostic procedure that has been advocated by some as an
even more accurate way of determining the status.
2. Endometrial biopsy:
C.Examination with the patient under anesthesia:
This may be necessary in patients who are bleeding and have
a cervical os that is very stenotic. Anesthesia may be required
to perform adequate dilatation for endometrial sampling.

23. Surgical management
Surgery is the main treatment for endometrial cancer. It consists of
simple hysterectomy, bilateral salpingo-oophorectomy (BSO), and
inspection of the pelvic and abdominal cavities, with biopsy of any
suspicious extrauterine lesions, accompanied in most cases by peritoneal
washings.
1. Hysterectomy: in the main it consists of removal of
the entire uterine corpus and cervix without contiguous parametrial
tissue.
2.Total abdominal hysterectomy/BSO:is the
most prevalent form of simple hysterectomy in endometrial cancer..
3. Laparoscopic vaginal hysterectomy/BSO ): the
uterus is removed vaginally rather than abdominally., The benefit of
using the laparoscope is to enable the surgeon to have a thorough intra-
abdominal exploration and to perform BSO, which is difficult to
accomplish with just a vaginal hysterectomy.

24. 4. robotic-assisted hysterectomy/BSO: has emerged as an
alternative minimally invasive surgery in endometrial cancer.
5.Radical hysterectomy: is not routinely performed in endometrial
cancer due to low incidence of parametrial involvement. There is no
evidence to show that the cure rates are any better with such radical
operations. The possible exception to this might be in patients with
gross cervical involvement.
6.Lymphadenectomy:
The uncertainty about lymphadenectomy relates to whether the
benefit from it is prognostic rather than therapeutic.
Lymphadenectomy in endometrial cancer includes removal of the fat
pads surrounding the major vessels in the abdomen and pelvis
For the sampling to be adequate, five lymphatic stations need to be
removed—para-aortic, common iliac, internal iliac, external iliac, and
obturator—or total of 10 nodes.
The conclusion was that pelvic lymphadenectomy significantly improved
surgical staging, that is, it is a good prognosticator, but it did not improve
disease-free or overall survival.

25. It is often used as an adjuvant treatment after surgery or as
definitive treatment for patients who are medically inoperable
or with local recurrence.
Role of RT in stages I and II:
oTreatment options for patients with early-stage endometrial cancer after
hysterectomy include:
I. observation.
II. intravaginal RT.
III. pelvic RT.
oAt MSKCC, intravaginal RT is the preferred approach for
most patients because it provides the best therapeutic ratio.
oobservation may have the best morbidity profile, but it does
not provide the best therapeutic ratio because of the
increased risk of local recurrence.
oPelvic RT very effective in reducing recurrence, has a
higher morbidity profile than intravaginal RT.

26. Role of RT in stage III:
Mariani et al. reported on 122 patients with
node-positive disease; at 5 years the risk of
pelvic recurrence was 57% after inadequate
lymph node dissection and/or no RT compared
to 10% with adequate lymph node dissection
(>10 pelvic nodes and ≥5 para-aortic nodes) and
RT.
› This difference was statistically significant and
multivariate analysis indicating the need for
postoperative radiation even after adequate
surgical staging.

27. 1.Preoperative RT.
2.Postoperative RT.

28. Preoperative RT

30. Postoperative RT

34. Risk factors classification for patients with
endometrial carcinoma

35. Recommendations :

38. Advanced risk factors :
›Multiple factors have been identified for
relative high risk of recurrence:
›1.Histological subtype.
›2.Grade 3 histology.
›3. Myometrial invasion ≥50%.
›4. Lymphovascular space invasion (LVSI).
›5. Lymph node metastases.
›6.Tumor diameter >2 cm.

42. Stage I IA G1–G2 Observation
IA G3 Observation or vaginal brachytherapy
If negative prognostic factors pelvic
radiotherapy and/or adjunctive
chemotherapy could be considered
IB G1 G2 Observation or vaginal brachytherapy
If negative prognostic factors pelvic
radiotherapy and/or adjunctive
chemotherapy could be considered
IB G3 Pelvic radiotherapy
If negative prognostic factors combination of
radiation and chemotherapy could be
considered
Stage II
Pelvic radiotherapy and- vaginal
brachytherapy
If grade 1–2 tumor, myometrial invasion
<50%, negative LVSI and complete surgical
staging: brachytherapy alone
If negative prognostic factors: chemotherapy
± radiation
Stage III–IV Chemotherapy
If positive nodes: sequential radiotherapy
If metastatic disease: chemotherapy–
radiotherapy for palliative treatment

43. Treatment Of recurrence disease

44. Most recurrences will occur within the first 3
years after treatment. Patients should
undergo follow-up every 3–4 months with
physical and gynecological examination for
the first 2 years, and then with a 6 month
interval until 5 years. Further investigations
can be performed if clinically indicated.