Endometrial Cancer and Endometrial Hyperplasia

Question 1

Describe the anatomy of the endometrium (location, cell type)

Answer 1

• The endometrium is the mucosal layer of the uterus, which undergoes monthly cyclic changes
• Made up of a single layer of simple columnar epithelium, which has ciliated and secretory cells, that sit on top of connective tissue (stroma)
• Within the stroma, there are uterine glands which secrete a glycogen rich fluid essential for the developing embryo during pregnancy

Question 2

Definition of endometrial hyperplasia

Answer 2

Irregular proliferations of the endometrial glands with an increase in the gland to stroma ratio when compared to proliferative endometrium. The incidence of endometrial hyperplasia is estimated to be three times higher than endometrial cancer and if left untreated can progress to cancer.

Question 3

Presentation of endometrial hyperplasia

Answer 3

• Most common presentation is abnormal uterine bleeding. This includes heavy menstrual bleeding, intermenstrual bleeding, irregular bleeding, unscheduled bleeding on hormone replacement therapy (HRT) and postmenopausal bleeding

Question 4

What are some risk factors for endometrial hyperplasia

Answer 4

• Develops when oestrogen, unopposed by progesterone, stimulates endothelial cell growth
• Risk factors: Increased BMI (get excessive peripheral conversion of androgens in adipose tissue), PCOS, oestrogen-secreting ovarian tumours, systemic oestrogen replacement, long-term tamoxifen

Question 5

How can endometrial hyperplasia be categorised

Answer 5

Endometrial hyperplasia can be categorised into two groups based on the presence or absence of cytological atypia:
* i- hyperplasia without atypia
* ii- atypical hyperplasia (complexity of architecture is no longer part of the classification)

Question 6

Investigations for endometrial hyperplasia

Answer 6

• Diagnosis of endometrial hyperplasia requires histological examination of endometrial tissue. Samples can be obtained either by:
  o Using miniature outpatient suction devices designed to blindly abrade and/or aspirate endometrial tissue from the uterine cavity
  o Inpatient endometrial sampling, such as dilation and curettage performed under GA
• TVUSS- may detect an irregularity in endometrial profile or an abnormal endometrial thickness measurement (gives further indication for biopsy)
• Hysteroscopy with additional endometrial assessment may be necessary if abnormal bleeding persists or if intrauterine structural abnormalities such as polyps are suspected on TVUSS or endometrial biopsy

Question 7

Management of hyperplasia without atypia

Answer 7

• Women should be informed that the risk of hyperplasia without atypia progressing to endometrial cancer is less than 5% over 20 years (majority will regress spontaneously)
• Reversible risk factors such as obesity and prolonged use of HRT should be addressed if possible
• Observation alone with follow-up endometrial biopsies should be considered

Progestogen treatment is indicated in women who fail to regress following observation alone and in symptomatic women with abnormal uterine bleeding
* Both continuous oral and LNG-IUS are effective treatment options (LNG-IUS first line due to higher regression rate)
* Treatment should be given for a minimum of 6 months, should be encouraged to retain LNG-IUS to reduce risk of relapse
* Endothelial surveillance should be arranged at a minimum of 6-monthly intervals
* Hysterectomy should not be considered as a first-line treatment for hyperplasia without atypia because progestogen therapy induces histological and symptomatic remission
* Hysterectomy is indicated if women do not wish to preserve their fertility or there is progression to atypical hyperplasia
* For premenopausal women, the decision to remove the ovaries should be individualised; however, bilateral salpingectomy should be considered as this may reduce the risk of a future ovarian malignancy

Question 8

Management of atypical hyperplasia of the endometrium

Answer 8

• Should undergo a total hysterectomy due to the risk of underlying malignancy or progression to cancer
• A laparoscopic approach to total hysterectomy is preferable to an abdominal
• Bilateral salphingo-oophorectomy should be considered in pre-menopausal women (recommended in post-menopausal women)
• Women wishing to retain their fertility should be counselled about the risks of underlying malignancy and subsequent progression to endometrial cancer
• Should be offered LNG-IUS and reviewed every 3 months

Question 9

Incidence of endometrial cancer. Peak age of prevalence

Answer 9

• The most common type of uterine cancer
• Incidence: Endometrial carcinoma is the most common gynaecological malignancy in the Western world (6th most common cancer in females worldwide). In the UK, 8,000 new cases are registered a year.
• Highest prevalence is at 60 years

Question 10

Classification of endometrial cancer

Answer 10

Type 1- Endometrial adenocarcinoma
* Most common and oestrogen-driven. Arises from a background of endometrial hyperplasia

Type 2- High grade serous and clear-cell carcinoma
* Arises from an atrophic endometrium- not linked with oestrogen. Tends to affect women who have endometrial atrophy and lower body weight (presents later in life)
* Serous carcinoma involves p53 mutations and aneuploidy

Question 11

Pathophysiology of type 1 endometrial cancer (type 2 less well understood)

Answer 11

• Aetiology of type 1 endometrial cancer is based on oestrogen exposure- oestrogen acts as a mitogen driving proliferation of oestrogen cells. Progesterone can inhibit this effect. Hyperoestrogenic states increase the risk whereas cyclical/continuous progestin-containing hormone treatments reduce risk
• Type 1 endometrial cancer also involves various mutations in endometrial cells (e.g mutations of PTEN, PIK3CA, ARID1A) these increase signalling in the PI3K/AKT pathway- promotes growth and replication of endometrial cells (linked to expression of oestrogen receptors)

Question 12

Risk factors for endometrial cancer

Answer 12

Obesity, exogenous oestrogens, PCOS, Nulliparity, Late menopause, ovarian tumours, Tamoxifen, Lynch type II syndrome (familial non-polyposis colonic, ovarian and endometrial cancer- 40% lifetime risk), HTN and T2DM

Question 13

Protective factors for endometrial cancer

Answer 13

Hysterectomy, COCP, Progesterone-based contraceptives, IUDs, pregnancy, smoking

Question 14

How are women with Lynch syndrome managed

Answer 14

Prophylactic hysterectomy following completion of childbirth

Question 15

Presentation of endometrial cancer

Answer 15

• Most common symptom is abnormal vaginal bleeding, particularly postmenopausal. May be irregular or intermenstrual bleeding in premenopausal patients. May have haematuria
• Probability of endometrial cancer with postmenopausal bleeding is 5-10%
• Postmenopausal women may also have abnormal vaginal discharge
• Recent onset menorrhagia
• May be detected incidentally on cervical smear (abnormal glandular cytology)
• Other possible symptoms include bowel and urinary dysfunction, abdominal pain
• OE: Normal pelvis may coexist with atrophic vaginitis

Question 16

Investigations for endometrial cancer

Answer 16

• Abdominal, speculum and bimanual examination: May see bleeding from cervical os on speculum and bulky uterus on bimanual
• TVUSS with double thickness measurement of endometrium should be the initial investigation for women with PMB
• An endometrial thickness of < 4 mm and in the absence of any irregularity of the endometrial profile does not require further investigation (if >4mm requires evaluation by hysteroscopy +/- biopsy)
• Should be >10mm if premenopausal or on HRT
• Hysteroscopy is recommended, if outpatient endometrial biopsy by other means is not feasible, for women who have ultrasound irregularities, or for those at high risk of endometrial cancer (should be considered in anyone with endometrial thickness >4mm)
• Endometrial biopsy
• MRI if spread is suspected- high risk histology seen or symptomatic of widespread disease
• FBC, renal function, glucose testing and ECG

Question 17

Grading of endometrial cancer

Answer 17

Graded according to the FIGO classification system:

Stage 1- Confined to the uterus
* 1A: No or less than half myometrial invasion
* 1B: Invasion equal to or more than half of the myometrium

Stage 2- Tumour invades cervical stroma, but does not extend beyond the uterus

Stage 3- Local and/or regional spread of the tumour
* 3A: Serosal involvement
* 3B: Vaginal and parametrial involvement
* 3C: Metastases to pelvis then pelvic nodes etc.

Stage 4- Tumour invades the bladder and/or bowel mucosa, and/or has distant metastasis

Question 18

Management of endometrial cancer

Answer 18

• Standard surgery is a total hysterectomy with bilateral salphingo-oophorectomy without vaginal cuff or parametrectomy
• Hysterectomy/salpingectomy with ovarian conservation can be considered in pre-menopausal patients with grade 1 endometrial cancer
• Can be abdominal or laparoscopic (associated with lower peri-operative morbidity)
• Can consider vaginal hysterectomy in women who cannot undergo abdominal or laparoscopic hysterectomy
• In patients with overt stage II endometrial cancer, radical hysterectomy should be considered only to obtain tumour-free margins
• Lymphadenectomy of non-bulky nodes is a diagnostic procedure and has not been shown to reduce the risk of recurrence or improve survival
• Combined external beam radiation therapy (EBRT) and intra-cavitary brachytherapy may be considered for women with high grade tumours, deep myometrial invasion and/or stage II disease
• Progestin therapy may be considered in women with low grade tumours to postpone standard surgical management for 3-6 months or in those who surgical management is inappropriate (high dose LNG-IUS is preferred)

Question 19

What adjuvant therapy options exist for endometrial cancer

Answer 19

• Postoperative radiotherapy reduces local recurrence rate but does not improve survival
• Local radiotherapy or brachytherapy are options
• Chemotherapy is used for advances or metastatic disease (little evidence to support its use)

Question 20

WHat fertility sparing options exist for endometrial cancer

Answer 20

Alternatives to hysterectomy for pre-menopausal women are only possible for pre-cancer or early-stage low-grade endometrial cancers
* Hormone therapy (oral progestogens or LNG-IUS) is associated with moderate response and high relapse rates
* Women faced with losing their fertility should be referred to a specialist to discuss ovarian conservation and/or stimulation for egg retrieval and surrogacy

Question 21

Summary of endometrial cancer management

Answer 21

Question 22

What is a uterine sarcoma

Answer 22

A rare tumour arising from the myometrium that accounts for 5% of all uterine cancers