Endometrial hyperplasia
• They are lesions that progress with proliferation in the glandular epithelium and stroma of the endometrium lining the uterine cavity and may undergo malignant degeneration. The pathological process can cover the entire endometrial cavity diffusely, or it can be seen focally in one or more areas.
• Severe hyperplasia often develops on the background of the proliferative endometrium, which occurs as a result of prolonged estrogen stimulation in the absence of progestin effect.
Risk factors
1. Anovulatory cycles in teenage girls and perimenopausal women (most common cause)
2. Endogenous estrogen-producing tumors (granulosa cell tumor, thecoma)
3. Early menarche (menarche before 12 years old)
4. Use of exogenous estrogen without progesterone
5. Liver failure (decreased estrogen breakdown and increased serum estrogen level)
6. Tamoxifen use
7. Obesity
Clinic
• The most common symptom is abnormal uterine bleeding. However, they can also be asymptomatic.
Diagnosis
• In order to predict endometrial hyperplasia in individuals with abnormal uterine bleeding, first of all, endometrial thickness should be measured by ultrasonography. Endometrial biopsy is required for definitive diagnosis.
Classification
• Hyperplasia without Atypia
► Simple (cystic) hyperplasia
► Complex (adenomatous) hyperplasia
• Hyperplasia with Atypia
► Simple (cystic) hyperplasia
► Complex (adenomatous) hyperplasia
|
Prognosis of
endometrial hyperplasia |
||
|
Type of Hyperplasia |
Regression |
Progression to cancer |
|
Simple atypia (cystic) hyperplasia |
80% |
1% |
|
Complex atypia (adenomatous) hyperplasia |
% 70 - 75 |
3% |
|
Simple atypia (cystic) hyperplasia |
% 70 - 75 |
8% |
|
Hyperplasia with complex atypia (adenomatous) |
50% |
29% |
• The vast majority (74%) of hyperplasia regresses or remains constant (18%). The risk of hyperplasia progressing to cancer depends on the presence and severity of cytological atypia.
• When hysterectomy was performed in 25-43% of cases diagnosed with atypical hyperplasia as a result of endometrial biopsy, it was found to be associated with well-differentiated endometrial cancer.
Treatment
• Progesterone (oral, intramuscular or intrauterine LNG-IUD) is used in treatment
. Periodic endometrial biopsy or transvaginal ultrasonography should be performed, especially in patients treated for hyperplasia with atypia, since 25-43% have an undiagnosed endometrial cancer and a high recurrence rate (25%) after treatment.
• In premenopausal cases with complex hyperplasia with atypia, hysterectomy is recommended if there is no expectation of fertility. Hysterectomy should be performed in postmenopausal hyperplasia with atypia.
Oral progesterones are ineffective in the prevention and treatment of endometrial hyperplasia that may develop as a result of tamoxifen use.
ENDOMETRIUM CANCER
• It is the most common gynecological cancer in developed countries.
• It is a disease of especially old, postmenopausal women. The average age at diagnosis is 60 years. It is the cancer with the best prognosis among gynecological cancers. 80% of endometrial cancer patients are diagnosed in stage I.
pathogenetic classification
• There are 2 different types pathogenetically.
Types of endometrial cancer
Type 1 endometrial cancer; Estrogen-related, endometrioid
• More often (80-90%)
• Young age, perimenopausal period, obese, Caucasian patients
• Estrogen dependent (unopposed estrogen exposure; chronic anovulation, PCOS or estrogen replacement)
• Estrogen and progesterone receptors are generally positive.
• It develops on the background of endometrial hyperplasia
• Good histological type (endometrioid adenocarcinoma)
• Well and moderately differentiated (low grade)
• Minimal myometrial invasion
• Good prognosis and stable tumor
• Diploid
• PTEN gene mutation (most common mutation in Type 1 tumor), CTNNB1 (Beta-catenin), PIK3CA, K-ras and gene mutation and microsatellite instability
Type 2 endometrial cancer; estrogen unrelated, non-endometrioid
• Less (10-20%)
• Elderly, postmenopausal, thin, non-white, multiparous and smoking women
• Estrogen independent (sporadic)
• Estrogen and progesterone receptors are generally negative.
• There is no endometrial hyperplasia (it develops even on the background of atrophy), some of it may develop from the background of serous in situ cancer (endometrial intraepithelial carcinoma).
• Poor histological type (clear cell carcinoma, papillary serous carcinoma)
• Poorly differentiated (high grade)
• Deep myometrial invasion
• Poor prognosis and aggressive tumor
• Aneuploid
• P53 tm suppressor gene mutation, high Ki-67 index, chromosomal instability, loss of HER/2neu, p16, e-caderin and heterozygosity
Risk factors
• The most common risk factor is prolonged unopposed estrogen stimulation and most cases are due to unopposed estrogen.
|
Endometrial cancer risk factors |
relative risk |
|
|
1. Complex endometrial hyperplasia with atypia |
29 |
|
|
2. Hereditary nonpolyposis colorectal cancer Syndrome
(Lynch syndrome) |
20 |
|
|
3. Simple endometrial hyperplasia with atypia |
8 |
|
|
4. Obesity(It increases 3 times in those who are
10-23 kg overweight, 1O times in those who are >23 kg overweight) |
3--20 |
2--3 |
|
5. Unopposed estrogen therapy; The risk increases
with duration and dose. |
4--8 |
10--20 |
|
6. Tamoxifen treatment |
2--3 |
|
|
7. Nulliparity |
2--3 |
3 |
|
8. Diabetes mellitus and insulin resistance |
2,8 |
1,3-3 |
|
9. Late menopause (> 52 years) |
2,4 |
2--3 |
|
10. Early menarche |
|
1,5-2 |
|
11. History of menstrual irregularity, |
|
1,5 |
|
12. Anovulatory cycles and polycystic ovary syndrome |
|
>5 |
|
13. Infertility |
|
2--3 |
|
14. Estrogen-secreting ovarian tumors (granulosa
cell ovarian tumor, thecoma) |
|
>5 |
|
15. Hypertension (concurrent pathology) |
|
1,3-3 |
|
16. Hypothyroidism (concurrent pathology) |
|
1,3-3 |
|
17. Gallbladder diseases |
|
1,3-3 |
|
18. Advanced age |
|
2--3 |
|
19. Residing in North America or Northern Europe |
|
3--18 |
|
20. High socioeconomic or cultural level |
|
1,5-2 |
|
21. White race |
|
2 |
|
22. History of Pelvic Radiotherapy |
|
|
Multiparity, combined oral contraceptives, progesterone therapy (eg, progesterone-containing intrauterine devices), smoking, and menopause before age 49 reduce the risk of endometrial cancer.
Histopathological Classification
Endometrioid adenocarcinoma (80%)
► It is the most common endometrial adenocarcinoma.
► Variants of endometrioid adenocarcinoma:
- Endometrial carcinoma with squamous differentiation: In the past, benign ones were called adenoacanthoma, and malignant ones were called adenosquamous carcinomas.
- Villoglandular (papillary) carcinoma
- Secretory carcinoma: These are the tumors with the best prognosis and are usually in the early stage and do not metastasize
Mucinous carcinoma 45%
► More than half of the tumor cells contain intracytoplasmic mucin. The prognosis of these tumors is good. Cervical, ovarian and intestinal tumor metastases should be investigated.
Tumors that are estrogen receptor positive, progesterone receptor positive, vimentin positive and p16 negative are almost always of endometrial origin.
Serous carcinoma (3-4%)
► It is the most aggressive histological type among endometrial cancers. These tumors are considered high-grade lesions and show deep myometrial invasion, mostly with lymphovascular space involvement. It tends to mimic epithelial ovarian carcinoma and spread into the abdomen.
► Serous carcinomas usually occur in elderly, hypoestrogenic women with advanced disease. Psammoma bodies are present in most cases. Severe p53 immune reactivity is observed in serous cancers.
Serous Adenocarcinoma in situ; It is called endometrial intraepithelial carcinoma because of its intraepithelial spread pattern and is considered as a precursor of serous carcinoma.
Clear cell carcinoma ( < 5%)
It is frequently seen in elderly women and has a very poor prognosis.
squamous carcinoma
It is very rare. Cervical stenosis, chronic inflammation often occurs at the time of diagnosis.
and together with the pyometra. It is one of the tumors with a poor prognosis.
Endometrial and ovarian cancers are the most frequently associated tumors among genital malignancies.
Serous and clear cell tumors can always be considered high grade and may not be graded.
Screening and Diagnosis
• There is no suitable method to screen populations for endometrial cancer. Since only 50% of the cases can be detected with scans, screening should be done in certain cases. These:
► Those with Lynch Syndrome (familial hereditary non-polyposis colorectal cancer) syndrome
► Those who use hormone replacement therapy without progesterone, especially in the postmenopausal period
► Premenopausal women with a history of anovulatory cycles such as Polycystic Ovary Syndrome
Contrary to these situations, routine screening with transvaginal ultrasonography or endometrial biopsy is not beneficial in patients using tamoxifen for breast cancer.
• Pap smear: In endometrial cancer, the probability of seeing malignant cells in smear is 30-50%, and therefore it is not a reliable screening method.
• Transvaginal ultrasonography; Ultrasonographic findings requiring further evaluation in postmenopausal women; endometrial double wall thickness >= 5 mm, presence of polypoid endometrial mass and presence of fluid in the uterus.
• Endometrial biopsy: Pipelle endometrial aspiration biopsy is the most appropriate method and is the first-line method in research.
Patients whose diagnosis of endometrial cancer should be excluded
1. All patients with postmenopausal bleeding
2. Postmenopausal women with pyometra
3. Perimenopausal women with intermenstrual bleeding or increased heavy menstrual bleeding
4. Premenopausal women with abnormal uterine bleeding (especially those with a history of anovulation)
5. Asymptomatic postmenopausal women with benign endometrial cells in PAP smear
6. Women aged 35 years and older with atypical glandular cells (AGC) in the PAP smear; Patients under 35 years of age with risk factors for endometrial disease (history suggestive of abnormal uterine bleeding or chronic anovulation).
• Abdomino-pelvic tomography; It is useful in cases where metastasis is suspected such as elevated LFT, hepatomegaly, ascites in the abdomen, abdominal mass, and extrauterine disease. Cystoscopy should be performed for suspected bladder involvement, rectosigmoidoscopy for suspected rectal involvement, colonoscopy if stool occult blood (+) should be performed. Magnetic resonance imaging gives information about myometrial invasion.
Spread
Direct spread to neighboring organs (most common form of spread)
► It is the most common form of spread. Cervix, tuba, and finally the vagina and parametrium can be invaded.
Transtubal spread of exfoliated cells into the peritoneal cavity
► Responsible for peritoneal relapses.
lymphatic spread
► Lymphatic spread is more common especially in those with lymph node involvement or cervical stromal invasion.
Hematogenous spread
► It is the least common form of spread (most commonly lung, liver, brain and bone). The strongest predictor of hematogenous recurrences is the presence of deep myometrial invasion.
Clinic
• There is vaginal bleeding in 90% of cases. Sometimes bleeding may not be observed due to cervical stenosis in very elderly patients, in such cases hematometra or pyometra may also be added to the picture, and this is usually associated with a poor prognosis.
Staging
• Surgical staging should be performed in all eligible patients.
|
FIGO
Staging (Surgical) |
|
|
1 |
The tumor is confined to the corpus |
|
1A |
No myometrial invasion or myometrial invasion <
1/2 |
|
1B |
Myometrial invasion >=1/2 |
|
2 |
There is cervical stromal invasion but no extension
beyond the uterus |
|
3 |
Tumor outside the uterus, with pelvic extension |
|
3A |
Invasion of serosa and/or adnexa |
|
3B |
Vaginal metastases and/or parametrial involvement
are present |
|
3C |
Pelvic and/or paraaortic lymph node metastasis |
|
3C1 |
Pelvic lymph node metastasis |
|
3C2 |
Paraaortic lymph node metastasis (with or without
pelvic lymph node) |
|
4 |
Bladder mucosal invasion and/or bowel mucosal
invasion and/or distant metastases |
|
4A |
Invasion of the bladder and/or intestinal mucosa |
|
4B |
Metastases, including intra-abdominal metastases
and/or inguinal lymph node metastases |
It is a gynecological malignancy in which inguinal lymph node involvement is distant metastasis (Stage 4B). Endocervical glandular involvement is in Stage I. Positive abdominal cytology, size of the uterus and grade of the tumor do not change the stage.
Prognosis
Prognosis Factors
1. Stage of the disease (the most important prognostic factor)
2. Lymph node metastasis (clinically the most important prognostic factor in early stage cancers)
3. Age; Advanced age is a poor prognostic criterion
4. Histological type (recurrence and distant metastasis increased in nonendometrioid types)
5. Histological grade
6. Nuclear grade
7. Myometrial invasion (involvement of the outer 1/2 leads to passage into the lymphatic system and is a strong predictor of hematogenous recurrences)
8. Lymphovascular space invasion
9. Isthmus-cervix extension
10. Adnexal involvement
11.Intraperitoneal tumor
12. Tumor size (> 2 cm, the prognosis worsens)
13. Peritoneal cytology
14. Hormone receptor status (P and E receptor (+) cases have a better prognosis)
15. DNA ploidy (prognosis worsens as aneuploidy increases)
16. Type of treatment (surgery versus radiotherapy)
17. Genetic/molecular tumor markers:
K-ras mutation
Decreased expression of E-cadherin
Increased expression of the HER-2/neu oncogene
c-erb-B2 expression
Mutation in the p53 suppression gene (present in 90% of serous tumors and accompanying advanced stage)
PTEN gene mutations (accompanies endometrioid tumor and good differentiation)
MIB-1 (Ki 67) expression: It is a poor prognostic criterion
Microsatellite instability: It is a good prognostic criterion.
MLHL inactivation: It is a common evidence of type I cancer.
p16 inactivation
Treatment
• The standard approach is hysterectomy + bilateral salpingooopherectomy + peritoneal cytology and surgical staging. During surgical staging, lymphadenectomy should also be performed if the following conditions are accompanied;
► Grade III tumors
► Patients with Grade II and >2 cm tumors
► Patients with clear cell or serous carcinoma
► Myometrial invasion >50%
► Patients with cervical involvement;
► Extrauterine disease (abdominal metastasis)
• Adjuvant radiotherapy is used to prevent recurrence in cases such as grade 3 tumors, tumors with deep myometrial invasion, and tumors with lymph node metastases. Adjuvant radiotherapy is not required in stage IA, grade 1 or 2 tumors without lymphovascular invasion.
• Fertility-preserving treatment is generally preferred only in grade I (type 1 tumor) adenocarcinomas without myometrial invasion in imaging methods, and high-dose progesterone is used.
recurrence
• More than 10% of recurrences occur within the first 2 years, and nearly half of asymptomatic recurrences are detected by chest radiographs. CA-125 level is usually high in relapses.
• Local recurrences are most common (most common in the vaginal cuff). The places where extrapelvic metastases are seen are; most commonly lung, followed by abdomen, lymph nodes (paraaortic, supraclavicular, inguinal), liver, brain and bone.
uterine sarcomas
0 They are malignancies arising from tissues of embryonic mesodermal origin. They constitute 3-7% of malignant tumors of the uterus. Their biological behavior is aggressive and their prognosis is poor.
• Risk factors include chronic excessive estrogen exposure (eg, use of combined hormone replacement therapy for 5 years or more), tamoxifen use, race (African-American), and history of pelvic radiotherapy.
Histopathological Classification
Pure Sarcomas
► Homologous Sarcomas
0 Endometrial stromal sarcoma
- low grade
- High grade or undifferentiated stromal sarcoma
0 Smooth muscle tumors
- Leimyosarcoma
- Leiomyoblastoma
- Metastatic tumors with benign histological appearance
• Intravenous leiomyomatosis
• Metastatic uterine leiomyoma
• Leiomyomatosis peritonealis disseminata
► Heterologous Sarcomas
rhabdomyosarcoma
chondrosarcoma
osteosarcoma
liposarcoma
mixed epithelial-nonepithelial tumors
► Malignant mixed mullerian tumor
0 Homologous (carcinosarcoma) Carcinoma + homologous sarcoma
0 Heterologous (mixed mesodermal sarcoma); Carcinoma + heterologous sarcoma
► Adenosarcoma Benign epithelial component + sarcomatous stroma
The most common uterine sarcomas are leiomyosarcoma (60%) and endometrial stromal sarcoma (20%), respectively.
Carcinosarcomas were classified by FIGO in 2009 as a metaplastic form of high-grade endometrial carcinoma, but the term carcinosarcoma still remains in the 2014 WHO classification.
Clinic
• The most common symptom is abnormal vaginal bleeding. Pelvic or abdominal pain is also common. 1/3 of the cases complain of rapid abdominal enlargement, prolapse of the sarcomatous polyp from the cervix, or bleeding with clots.
Endometrial Stromal Tumors
• Most of the patients are in the perimenopausal 45-50 age group. It has nothing to do with radiotherapy and parity. The most common symptom is abnormal uterine bleeding. Diagnosis can be made by endometrial biopsy, but usually the preliminary diagnosis is leiomyoma.
► Endometrial stromal sarcoma
► Low grade endometrial stromal sarcoma
► High grade endometrial stromal sarcoma (Undifferentiated Sarcoma)
leiomyosarcoma
• Malignant tumors arising from smooth muscle cells in the myometrium or smooth muscle in the uterine blood vessels. It may be associated with a history of pelvic radiotherapy, but not with parity. The mean age at diagnosis is 54 years, and it is seen at a younger age compared to other uterine sarcomas, and survival is higher in the premenopausal group. Especially in a postmenopausal case, if the uterus is growing rapidly, it should be considered.
• Symptoms include abnormal uterine bleeding, a feeling of pressure or pain in the pelvis, and a pelvic mass. It is less likely to be diagnosed with endometrial biopsy. Dynamic MRI together with LDH-3 measurement can diagnose preoperative leiomyosarcoma with high accuracy.
• The histological diagnostic criteria of leiomyosarcomas include the mitotic index, the degree of nuclear atypia, and the presence of coagulation necrosis.
• Total abbominal hysterectomy + bilateral salpingooopherectomy + debulking surgery of tumors outside the uterus + removal of enlarged lymph nodes is applied in the treatment. Adjuvant chemotherapy is given. RT has no relapse-reducing effect in leiomyosarcomas.
Malignant Mixed Müllerian Tumor (MMMT)
• Homologous (Carcinosarcoma): Microscopically, they are in the form of a mixture of malignant epithelial and malignant mesenchymal components (homologous sarcoma). It may be associated with a history of pelvic radiotherapy. Almost all are seen in the postmenopausal age (62 years). The tumor protrudes out of the cervical canal like a polyp in almost half of the patients. The diagnosis is usually made by endometrial biopsy taken from the polypoid mass filling the cavity or from its protruding part. Total hysterectomy, bilateral salpingooopherectomy, pelvic-paraaortic lymph node dissection in treatment
+ adjuvant KT is applied.
• Heterologous: Microscopically, they are a mixture of malignant epithelial and malignant mesenchymal components (heterologous sarcoma).
adenosarcoma
• They are low-grade tumors, typically characterized by a benign epithelial component and a malignant mesenchymal component. It is mostly seen in postmenopausal women. It is typically in the form of a polypoid lesion that protrudes out of the cervical canal. The basis of treatment is hysterectomy and bilateral salpingooopherectomy and adjuvant RT.