Carcinoma of the Endometrium

It is a malignant cancer of endometrial lining (epithelial lining)

In developing countries it ranks third after cervix and ovaries

In developed countries, where deaths from cervical cancer have been reduced by up to 50% because of screening, endometrial cancer ranks alongside ovarian cancer as the leading types of gynecological cancer.

Incidence

Reported global cancer statistics show the incidence to be highest in North America, then Europe and temperate South America.

The incidence of endometrial carcinoma is low in southern and eastern Asia, as well as in most of Africa.

Ilorin: 10.7%

Benin: 6.47% Okobia et al 2005

Maiduguri: 8.5% Kyari et al 2004

Port Harcourt: 8.3% Briggs et al 1990

Zimbabwe: 6% 1989

Cause not known but there are known predisposing /risk factors

NOTE that both major and minor risk factors have one common thread –unopposed estrogen stimulation of the endometrium.

Obesity:

• Major risk factor.
• Circulating androgens in the fatty tissue can be converted to estrone.
• Increase in free, unbound estrogen because SHBG which inactivates E2 is decreased.
• Upper body fat localization is a significant risk factor & have poorer prognosis.
• Associated with the other major risk factors like DM & hypertension.

Syndromes of increased endogenous estrogen stimulation:

• Early menarche (4 fold increase especially in premenopausal women) & late menopause (menstruation span >39yrs have 4.2X increase than <25yrs).
• Infertility and low parity:
• PCOS, probably due to long anovulatory cycles.
• One-third of patients are nulliparous.
• Risk decreases with increased parity.

Estrogen producing ovarian tumors:

• Granulosa cell tumors.
• Theca cell tumors.

Familial and hereditary factors:

• Familial adenocarcinoma syndrome (Lynch type II).
• Hereditary non poliposis colorectal cancer.

Life style factors:

• Diet: animal fat & proteins increases risk.
• Sedentary life styles increases the risk.

Other factors:

• Age is an important risk factor. It is a cancer of post & perimenopausal women.
• Race: White race have twice lifetime risk than black race.
• High social class.
The last 2 factors may be related to the availability of exogenous estrogen.

Exogenous estrogens: well established

Prolonged use of unopposed estrogen is associated with high risk of endometrial cancer.

Stimulation of the endometrium occurs despite the route of administration.

Increasing duration of use also increases the risk. The risk persists for many years after use.

Risk also increases with increasing dose of conjugated estrogen.

An increased incidence has also been found in association with tamoxifen treatment of breast cancer, perhaps related to the estrogenic effect of tamoxifen on the endometrium.

The cancers associated with exogenous estrogen may behave biologically differently from their non-estrogen associated counterparts.

Most estrogen induced tumors are of low virulence, well differentiated, with minimal myometrial invasion.

The use of concomitant or cyclic progestins will greatly reduce the risk.

• It inhibits the synthesis of both estrogen & progesterone receptors.
• Within the cell, it stimulates the 17-β-dehydrogenase enzyme that converts estradiol to the less potent estrone.
• In some women, moderately to poorly differentiated adenocarcinoma may develop despite the use of progestins.

Prior use of COCP reduces the risk.

• Protection may be due to the net progestational effect that results in virtually inactive endometrium with long term use.
• The protection may last 20 or more years after discontinuation in long term users (10 or more years) but may be reversed by unopposed postmenopausal estrogen.

Life style factors

• Smoking may have a protective effect probably due to the reduced circulating estrogen it induces.
• Active life style may be protective.
• Consumption of vegetables, fresh fruits & high fiber reduces the risk.
• Alcohol in moderate quantities may be protective.

The most common symptom is post-menopausal bleeding (75%) women usually in their 60s

Bleeding may be slight, irregular or continuous

In postmenopausal women any vaginal bleeding is considered to be from cancer until proven not to be.

5-10% occur in women < 40yrs

Some may have offensive vaginal discharge if there is infection.

Pain may be colicky

Few are asymptomatic

Screening/Diagnosis

Screening

• Routine screening of women is not of any proven benefit.
• Occasionally, however, the Pap smear may fortuitously identify endometrial abnormalities.

Diagnosis

• Detailed history and physical examination
• Help identify risk factors and associated medical conditions.

Pattern of spread

Lymphatic spread via:

• Lymphatics from the infundibulopelvic ligament
• Paracervical & parametrial lymphatics
• Round ligament lymphatics to external iliac, obturator, hypogastric, common iliac and para-aortic.

Direct spread into the peritoneal cavity

Hematogenous to liver, lung, bone.

Definitive diagnosis

• Dilatation and (fractional) curettage
• Traditional 4 quadrant biopsy

Other investigations

Other means of obtaining sample— lavage, brush or use of suction devices

Hematological profile, E/U/Cr, LFTs, FBS

USS abdo/pelvic.

CT Scans, MRIs

CXR

Cystoscopy/sigmoidoscopy- if necessary

Simple hyperplasia (cystic hyperplasia). Risk of malignant potential/transformation is very low.

Complex hyperplasia also called adenomyohyperplasia without atypia. Risk about 2% of either harboring or developing a malignancy within one year following that diagnosis. The risk is extremely low.

Atypical hyperplasia also called adenomyohyperplasia with atypia carries a 15-25% risk.

1. Adenocarcinoma (well differentiated columnar cell with glandular pattern (90%)
2. Adenocanthoma (adenocarcinoma with squamous metaplasia 5%)
3. Adenosquamous carcinoma (mixed adenocarcinoma and squamous cell carcinoma)
4. Anaplastic carcinoma- undifferentiated

The clinical staging adopted by FIGO in 1971 based on a standard uterine cavity length and extension of the disease beyond the uterus and pelvis.

The FIGO Committee on Gynecologic Oncology, in 1988, recommended that endometrial cancer be surgically staged.

• Updated FIGO surgical staging 2009

Surgical Staging

Procedure

The procedure include:

• Peritoneal washings.
• TAH (simple) + BSO.
• If there is occult invasion outside the lower segment, the parametria is involved or the uterosacral ligaments are involved, a more radical operation may done.
• Lymph node sampling of all major node bearing areas, the “10 lymphatic zones”.
• Laparoscopic staging may be done.

Histopathology – degree of differentiation.

Cases of carcinoma of the corpus should be grouped with regard to the degree of differentiation of the adenocarcinoma as follows:

• G1: < 5% of a nonsquamous or nonmorular solid growth pattern.
• G2: 6-50% of a nonsquamous or nonmorular solid growth pattern.
• G3: > 50% of a nonsquamous or nonmorular solid growth pattern.

Surgical staging

• I— Tumor confined to the corpus uteri
• IA: No invasion/Tumor invades < 1/2 myometrium
• IB: Tumor invades > 1/2 of myometrium
• II— Tumor invades cervix
• III— Local and/or regional spread
• IIIA: involves serosa and/or adnexa and/or +ve peritoneal washings.
• IIIB: Vaginal involvement.
• IIIC: pelvic / para-aortic lymph nodes (C1&2)
• IV— Distance spread
• IVA: Tumor invades bladder mucosa and/or bower mucosa
• IVB: Distant metastasis including metastasis to intra-abdominal lymph nodes (other than para-aortic

• Surgical
• Radiotherapy
• Medical (chemo, hormonal)
• Palliative

Clinical stage I

TAH, BSO. Routine node sampling not done, but any suspicious node is removed for histological evaluation. If there is deep myometrial involvement, sampling may be done.

Consider post-operative radiation therapy, if deep myometrium involvement or G2, G3

Clinical stage II

Radical TAH, pelvic & para aortic node dissection, followed by irradiation.

Primary irradiation (intracavitary & external beam) followed by surgery. May be done where there are technical problems e.g. extreme balooning of the cx

Radiation alone in patients not medically fit for surgery

Clinical stage III

Complete surgical resection where possible followed by extended field RT and/or systemic therapy with cytotoxic or hormones

Preoperative pelvic irradiation followed by exploratory laparotomy. If good intracavitary radiation was delivered, a subtotal hysterectomy may be done to avoid bladder or bowel fistula.

Clinical stage IV

Optimal cytoreduction followed by systemic chemotherapy.

High doses of progestins may be used especially in distant metastasis and include hydroxy-progesterone (Delalutin), medroxy-progesterone (Provera), and megestrol (Megace).

Pelvic RT may be given to achieve local control & prevent bleeding. Local RT in the brain or bone may be useful.

Primary radiotherapy is in indicated in:

• Unfit for surgery
• Inoperable disease
• Palliation in advanced disease
• High risk for recurrence

Chemotherapy used in advanced and recurrent dis.

Progestogens: well differentiated disease with estrogen and progesterone receptors. Medroxyprogesterone, megestrol acetate in high doses

Cytotoxics: adriamycin,cyclophosphomide, cisplatin paclitaxel singly or in combination

Prognostic factors

Histological grade (Tumor grade 3):

• Decrease survival
• Increased risk of lymph node involvement
• Increased risk of recurrence

Deep myometrial invasion: Most reliable indicator of tumor volume

Lymph vascular channel involvement

Positive peritoneal cytology

Histologic type

• Serous papillary & Clear cell tumours

Cervical involvement (stage II)

Adnexal spread

Intraperitoneal disease

Increasing age

Steroid receptors:

• Most endometroid ca have ER & PR.
• The presence & quantity of the receptors correlate with the histologic differentiation, FIGO staging & survival.
• High levels found in well differentiated tumors & ass with better survival rates.
• Receptor status influence tumor response to progestin therapy.

Prognosis

Overall 5year survival rate:

• Stage I: 80% up to 95% reported.
• Stage II: 60%
• Stage III: 30%
• Stage IV: 5%