Endometrial Carcinoma: Investigation and Management

Introduction 

Endometrial Carcinoma is the most common gynecological malignancy in developed countries and the 4th most common cancer in women. 20% of women develop endometrial carcinoma in lifetime

Peak incidence of endometrial cancer is seen at 60 years but in 25% cases it can occur before menopause or in young females.
The rise in the incidence of EC due to the prolonged life span of women in general, more liberal use of hormone therapy in the management of menopause.

Risk Factors 

Endometrial cancer occurs as a result of unopposed estrogen exposure in body.

1) Family history: Approximately 5% of endometrial cancer is hereditary, with majority of these presenting as a part of the Lynch II or Hereditary Non Polyposis Colorectal Cancer (HNPCC) syndrome. 

• Women with HNPCC syndrome have 39% risk of developing endometrial cancer by the age of 70 years.
• Besides endometrial cancer, individuals in this family are at increased risk of colorectal cancer, ovarian, urinary, biliary, gastric and small intestinal cancer.

2) Hypertension 
3) Obesity: BMI > 30 kg/m2 will triple the risk of endometrial cancer
4) Early menarche & Late menopause age > 55 years
5) Diabetes
6) Atypical endometrial hyperplasia
7) PCOS (chronic anovulation results long periods of E2 unopposed by PRG)

• Estrogen replacement without concomitant progesterone carries a relative risk of 4.5 to 8 & persists for 10 years after treatment is stopped.

8) Nulliparity
9) Tamoxifen Therapy and Radiation Therapy: A woman taking Tamoxifen has an annual risk of 2 in 1000 of developing endometrial cancer and 40% of women will develop cancer more than 12 months after stopping therapy.
10) History of infertility/menstrual irregularity 
11) Senile endometritis/Pyometra

Protective Factors

1. Oral contraceptive pills (combined pills with addition of progesterone to HRT). OCP’s decrease endometrial cancer risk by 40%, even uptil 15 years after discontinuation and the protection increases with the length of use.
2. Smoking (as it decreases levels of estrogen, decreases weight and is associated with earlier age of menopause).
3. Multiparity 
4. Phytoestrogens 
5. Green tea 
6. Coffee 
7. Physical exercise

Histologically Classification

1) Adenocarcinoma/endometrioid: the commonest pathologic type of EC (80%), and carries best prognosis
2) Adenosquamous carcinoma (15%) or adenocarcinoma with squamous differentiation: lt  carries same prognosis as adenocarcinoma.
3) Papillary serous adenocarcinoma 

• Seen in 5-10% of endometrial cancers. 
• Associated with BRCA 1 & BRCA 2 gene. 
• It metastasizes early by spreading through peritoneum therefore in its staging omentectomy and peritoneal biopsy should be done.

4) Mucinous adenocarcinoma 

• Mucinous variety of endometrial CA needs to be differentiated from Adero CA of endo­cervix. It is done by using vimentin stain.

5) Clear cell carcinoma

• It accounts for < 5% of all endometrial carcinomas. 
• Most characteristic histological finding is presence of “hobnail cells”. 
• It characteristically occurs in older women and is very aggressive type of endometrial cancer.
• Prognosis is similar to or worse than papillary serous carcinoma. 
• In staging: Omentectomy and peritoneal biopsy done

Most malignant variety is clear cell carcinoma and papillary serous tumor.

Clinical Features 

1. Irregular vaginal bleeding: M/C complaint 
2. Postmenopausal bleeding: Most specific complaint 
3. Discharge per vagina (1%): Brown, watery offensive discharge Or Watery discharge free from blood (hydrorrhea).
4. Pelvic pressure/discomfort. 
5. Referred pain in hypogastrium or both iliac fossae (Simpson’s pain). 
6. Pain is not severe and tends to occur at the same time each day, lasting only 1-2 hrs.
7. In some older patients, bleeding may not occur due to cervical stenosis, causing hematometra/pyometra.

Spread

1. Direct Spread: Most common mode of spread is direct extension.
2. Lymphatic Spread: Lymphatic spread occurs to pelvic and para-aortic nodes
3. Hematogenous spread (usually to lungs) is rare.

Investigations 

Abnormal bleeding at any age should be evaluated by tissue biopsy in women of HNPCC families.
Routine survillance may consist of yearly USG and endometrial biopsy commencing at the age of 30–35.

Remember:

1. For postmenopausal bleeding: 1st investigation is TVS in endometrial cancer 
2. IOC is Endometrial Aspiration Biopsy.
3. Gold standard for diagnosing endometrial cancer - Fractional curettage.

Transvaginal Sonography (TVS)

• It is the 1st step taken in women who present with post menopausal bleeding to decide whether endometrial sampling is needed or not.
• lncreased endometriol thickness in postmenopausal women above the cut-off value of 5.0 mm is strongly suspicious of EH.
• Thicker endometrium > 10 mm correlates with EC.
• If endometrial thickeness is less than 4 mm, further testing may be deferred. But if their is recurrence of bleeding, a tissue diagnosis is essential.

Endometrial Aspiration Biopsy:

It is the IOC for endometrial cancer. 

• Diagnostic accuracy: 92–98% Endometrial aspiration biopsy can be performed in outpatient setting as it does not require any anesthesia and has the advantage of being simple, quick, safe, inexpensive, convenient. 
• It is combined with endocervical curettage to rule out cancer cervix. It is done using a vibra aspirator, Sharman curette, or Pipelle endometrial sampler.

Fractional Curettage

Fractional currettage is the Gold standard investigation used for ruling out endometrial cancer 
Here the endocervical canal is curreted first followed by dilation and endometrial curettage. 

Indications: 
– Cervical stenosis; 
– If clinical suspicion of malignancy is high; 
– If bleeding recurs after a negative report on endometrial aspiration.

Staging of Endometrium Ca & Management

Revised Staging of Ca Endometrium (2009)

In 2009 FIGO revised the staging for cancer endometrium. In this new staging system, positive cytology no longer changes the stage, but is still reported.

1. Stage IA = Cancer confined to uterus and anything < 50% of myometrium. 
2. Stage IB = Cancer confined to uterus but 50% or more of myometrium involved.
3. Stage II = Endocervical stroma involved. Note endocervical glandular involvement is non-considered stage I.
4. Stage IIIA = Tumor invades serosa or adnexa. Positive cytology has to be reported separately without changing the stage.
5. Stage IIIB = Vaginal and/or parametrial involvement 
6. Stage IIIC1 = Metastasis to pelvic lymph node 
7. Stage IIIC2 = Metastasis to Para-aortic lymph node. 
8. Stage IV = No change

Principle of Management 

1) Stage I:

• Surgery: An exploratory laparotomy with total abdominal hysterectomy and bilateral salpingooophorectomy (TAH-BSO) is the gold standard treatment, performed in all patients, unless there are absolute medical contraindications.
• Pelvic lymphadenectomy is performed on high risk cases including those with serous, clear cell, or grade 3 histology tumors, and in cases with stage lB (either outer half myometrial involvement or cervical glandular extension).

2) Stage II: Modified radical hysterectomy with LN dissection (pelvic and paraaortic) followed by radiotherapy
3) Stage III and stage IV: Debulking surgery followed by chemotherapy and radiotherapy

In stage III and IV:- Chemotherapy is given along with Radiotherapy. Only Patients with stage IA grade 1 and 2 do not require postoperative radiotherapy.

Prognosis

Endometrial Carcinoma is the most curable gynecologic cancer because are diagnosed at an early stage. 5 year survival for stage I disease is more than 90%. Overall 5 year survival for all stages is 60-70%.

• Estrogen induced endometrial hyperplasia (EH), unopposed by progesterone forms the most important background in development of EC.
• Non estrogen dependent EC is a much less common type of the disease, but is more aggressive and carries poorer prognosis than estrogen dependent type

Prognostic factors in endometrial cancer 

1. Most important prognostic factor is lymph node metastasis.
2. Age at diagnosis (older the patient poorer the prognosis).
3. Stage of the disease. 
4. Histologic type (endometriod adenocarcinoma have good prognosis, clear cell carcinoma have poor prognosis).
5. Histologic grade.
6. Myometrial penetration (Increasing depth of invasion is associated with increasing likelihood of extrauterine spread and recurrence).
7. Extension to cervix– Involve­ment of cervix, isthmus or both is associated with increased risk of extrauterine disease and lymph node metastasis.
8. Role of peritoneal cytology is contoversial.
9. Tumor size (> 2 cm– means more lymph node metastasis).
10. Hormone receptor status (receptor positive–better prognosis).
11. Ploidy status: Aneuploid have got better prognosis compared to diploid tumors.
12. Oncogene expression: HER: 2/neu, k-ras poor prognosis.

Recurrent Endometrial Cancer

Most common time of recurrence is within first two years

Management 

• For patients with recurrent endometeriod tumors with hormone receptors positive, initial treatment is progestin.
• If patient has contraindication to progesterone then Tamoxifen can be used. 
• In Recurrent Cancers: which are hormone negative initial management is local management
• If patient is operable-surgery is done 
• If patient is inoperable-RT is given 
• If local T/t cannot be given-Palliative chemotherapy is given.