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POSTMENOPAUSAL BLEEDING IS DUE TO MALIGNANCY UNTIL PROVEN OTHERWISE

Endometrial cancer is a common oestrogen-dependent gynaecological cancer which tends to affect older women. Unlike cervical cancer, it is currently not a screened-for cancer in the UK, and it is therefore important that doctors maintain a high index of suspicion in order to pick it up as early as possible.

Endometrial cancer typically presents with post-menopausal bleeding, so I’ve included a differential diagnosis for this. I’ve also outlined potential future screening programmes for endometrial cancer.

 


Introduction

Uterine anatomy

Normal Uterine Anatomy 1

ANATOMY OF THE UTERUS

  • the uterus (or “womb”) is a small, hollow muscular organ situated in the female pelvis between the bladder and the rectum. It forms part of the female reproductive system and acts as the site for fertilisation of an ovum by sperm, and its subsequent implantation and growth into a fetus. It also contracts to expel the fetus during labour.
  • it has two hollow uterine tubes, which lie in the upper border of the broad ligament and act as a conduit connecting the ovary and peritoneal cavity with the cavity of the uterus. These guide the passage of the ovum from the ovary to the uterus and are usually the site where fertilisation occurs.
  • the main part of the uterus is divided into three sections: a fundus lying above the entrance of the uterine tubes, a body lying below the entrance of the tubes, and a lower cervix which communicates with the upper part of the vagina through a narrow canal.
  • the wall of the uterus has four distinct layers: the endometrium, myometrium, parametrium and perimetrium (peritoneum)
  • the endometrium is the thin inner mucous membrane which lines the cavity of the uterus and is shed during the monthly menstrual period. Its high cell turnover makes it the most common site for cancers of the uterus to develop.
  • the myometrium is the thick layer of smooth muscle and connective tissue lying beneath the endometrium. It contracts during a period to reduce blood loss (causing cramps) and during labour to expel the fetus. It often gives rise to benign growths called fibroids (leiomyomas) but rarely undergoes malignant change.
  • the parametrium is a fibrous fascial layer which lines the outer surface of the upper part of the cervix and separates it from the bladder. It contains the uterine artery and the ovarian ligament. The parametrium is important, as cervical cancers often spread out to invade it as they grow.
  • the perimetrium is the membranous layer of visceral peritoneum which lines the outer surface of the whole uterus, apart from a small area anteriorly where it deflects forwards to cover the bladder.
  • the visceral peritoneum also forms a large sheet-like fold called the broad ligament which spreads out laterally to connect the uterus to the walls and floor of the pelvis. This contains the ovarian and uterine arteries and the round ligament.
  • the uterus is well supported by ligaments which allow it to hold the weight of a pregnancy; these include the levator ani (pelvic floor) and the pubocervical, transverse cervical (or cardinal), and uterosacral ligaments. If these become lax, the uterus is liable to prolapse.

PHYSIOLOGY

  • the uterus is extremely responsive to the actions of sex hormones which regulate the changes associated with puberty, the menstrual cycle, pregnancy and menopause
  • these hormones (especially oestrogens) are implicated in the development of endometrial cancer
  • oestrogen causes proliferation of the endometrium, with increased vascularity and secretory glands, as well as growth of the uterus during pregnancy
  • progesterone causes the endometrium to become receptive to implantation of a fertilised ovum. If fertilisation does not take place, a fall in progesterone levels triggers menstruation and shedding of the thickened endometrial layer.
  • for more detail on the menstrual cycle, see here for the Geeky Medics guide

 

TERMINOLOGY

  • endometrial cancer refers to an oestrogen-dependent malignant neoplasm arising from the endometrium of the uterus
  • uterine cancer refers to any malignant neoplasm arising from the tissues of the body of the uterus, including the endometrium, myometrium and connective tissues
  • generally in practice you will notice that the term “endometrial cancer” is used to refer to cancers of the uterus, as it is by far the most common type
  • postmenopausal bleeding (PMB) is vaginal bleeding occurring after 12 months of amenorrhoea in a woman of menopausal age or who has experienced the menopause – this affects 4-11% of postmenopausal women and accounts for 5% of all gynaecology outpatient referrals

Epidemiology

  • endometrial cancer accounts for 5% of cancers in UK women (around 8000 cases per year)
  • it is the fourth most common cancer and causes 2.5% of cancer deaths (about 2000 per year)
  •  there is a lifetime risk of 2.35%, or 1 in 43, for women in the UK
  • it usually affects women in their 50s, 60s and 70s, and is rare in those aged under 40
  • incidence is increasing, probably due to increasing population age, obesity and use of HRT
  • it is the most commonly diagnosed gynaecological cancer in developed countries – incidence is significantly lower in developing countries, where cervical cancer is far more common

 


Aetiology and risk factors

  • endometrial cancer is believed to result from the stimulation of excess endometrial proliferation by prolonged exposure to unopposed oestrogens which are, for whatever reason, not being modified and controlled by the effects of progesterone
  • endogenous oestrogen exposure – contributing factors include early menarche, late menopause, delayed childbearing, nulliparity (2-3x risk), obesity (2-3x risk), PCOS, diabetes mellitus (1.5x risk), metabolic syndrome, anovulatory menstrual cycles (means patient lacks luteal phase progesterone), and oestrogen-secreting tumours e.g. granulosa-thecal cell ovarian tumours (10x risk)
  • exogenous oestrogen exposure can result from use of oestrogen-only HRT (1.5x risk), tamoxifen (3x risk) or tibolone (1.8x risk)
  • sedentary lifestyle has been shown to increase risk
  • family history is important as inherited genetic traits, such as hereditary non-polyposis colon cancer (HNPCC – lifetime risk 40-60%) and PTEN, can confer significantly increased risk
  • protective factors include parityOCP use, exercise, smokingaspirin and drinking coffee

 


Histopathological types

TYPE I – ENDOMETRIOID HISTOLOGY (75-80%)

  • this typically occurs in pre- and perimenopausal women
  • it may be preceded by premalignant atypical endometrial hyperplasia (EH)
  • it is associated with oestrogen exposure, a low grade and a favourable prognosis
  • 75% endometrioid adenocarcinoma, which has squamous (aka adenosquamous), villoglandular, secretory and ciliated cell variants
  • 5% mucinous adenocarcinoma

 

TYPE II – NON-ENDOMETRIOID HISTOLOGY (~20%)

  • this occurs more frequently in postmenopausal women
  • it may be preceded by premalignant endometrial intraepithelial carcinoma (EIC)
  • it has little association with oestrogen exposure and tends to be high grade and more aggressive
  • 5-10% serous carcinoma
  • 1-5% clear cell carcinoma
  • ~10% mixed adenocarcinoma
  • <1% very rare types: squamous cell carcinoma, neuroendocrine tumours (large cell and small cell), transitional cell carcinoma, undifferentiated carcinoma, metastases from other sites

 

UTERINE SARCOMAS (<5%)

  • these are tumours arising from the myometrium and connective tissues of the uterus
  • this is a rare diagnosis with an aggressive clinical course and a poor prognosis
  • 2% leiomyosarcoma
  • 1% carcinosarcoma (aka mixed mesodermal Mullerian tumour)
  • <1% endometrial stromal carcinoma
  • <1% very rare types: fibrosarcoma, adenosarcoma, undifferentiated sarcoma, metastases

 


Symptoms

  • postmenopausal bleeding is the classical presenting symptom – 8-10% will have endometrial cancer, ~30% will have endometrial hyperplasia (of which ~5% will be atypical), ~10% will have endometrial polyps and the remaining 50% will have endometrial atrophy due to menopause
  • likelihood of cancer is increased if bleeding is profuse or persistent over time, particularly if it occurs in an older woman
  • in pre- or perimenopausal women (20-25% of cases), symptoms can include intermenstrual bleeding or menorrhagia
  • increased vaginal discharge
  • pyometra (a collection of pus in the uterine cavity) is a less common but important symptom – 50% of postmenopausal women with pyometra will have an underlying malignancy
  • rarely (1% of cases), it may be an incidental finding on a cervical smear
  • symptoms of advanced disease include pelvic pain, pelvic mass, leg swelling, haematuria, PR bleeding, weight loss and fatigue
  • symptoms of metastatic disease may include cough, shortness of breath or haemoptysis (lungs), abdominal pain and jaundice (liver) bone pain, hypercalcaemia and pathological fractures (bones)

 


Signs

  • general examination findings are usually normal except in advanced disease
  • abdominal examination may reveal a pelvic mass in advanced cases
  • Cusco speculum examination is usually normal; very rarely cancer may be visible in the cervix
  • bimanual palpation is usually normal, but the uterus may be enlarged or immobile in locally advanced disease

 


Differential diagnosis – postmenopausal bleeding

  • trauma
  • ovarian pathology – oestrogen-secreting ovarian tumours e.g. granulosa-thecal cell
  • uterine pathology – endometrial atrophy, endometritis/PID, endometrial polyps, endometrial hyperplasia, endometrial cancer
  • cervical pathology – cervicitis, cervical polyps, cervical cancer
  • vaginal pathology – vaginitis (e.g. severe thrush, atrophic), vaginal cancer
  • vulval pathology – vulval dermatitis, vulval dystrophy, vulval cancer
  • systemic problem – bleeding disorders, metastatic cancer e.g. ovarian, colorectal
  • iatrogenic – trauma, oestrogens e.g. HRT
  • exclude bleeding from somewhere else e.g. urethra, bladder, rectum, anus or perineum – 0.7% of patients with postmenopausal “vaginal” bleeding will actually have bladder cancer

 


Investigations

Diagnostic tests for women with suspected cancer include:

  • history and clinical examination including Cusco speculum examination and bimanual palpation
  • it is always worth performing a cervical smear “while you’re down there” if the patient is due one, but if there is any suspicion of cervical cancer she should be referred for urgent colposcopy
  • transvaginal ultrasound (TVUSS) to measure endometrial thickness>5mm is worrying (7.3% risk of cancer), but remember in younger women the endometrium may be up to 12mm thick if they are about to have their period
  • endometrial sampling should be performed in all women over 40 and those with worrying features; this can either be done as a Pipelle biopsy or a formal hysteroscopy
  • outpatient Pipelle biopsy is easily performed in clinic, but it only samples about 4% of the endometrial surface and is performed blindly, so the abnormal area could easily be missed
  • hysteroscopy and curettage biopsy is performed as an inpatient under general anaesthetic – this allows visualisation of the endometrium and sampling of most of its surface, but carries an anaesthetic risk and is more lengthy and expensive to perform

Most gynaecology units now have a one-stop clinic for “2 week wait” endometrial cancer referrals – this usually comprises TVUSS on arrival, followed by assessment by a doctor and further investigations (Pipelle biopsy or hysteroscopy) as required.

(Tumour markers are not really used in the diagnosis of endometrial cancer – CA-125 may be raised, but is much more strongly associated with ovarian cancer and is also associated with other cancers)

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Endometrial cancer

Endometrial cancer 2

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Staging investigations for women with biopsy-confirmed malignancy include:

  • blood tests FBC (for anaemia), U+E (for renal function), LFTs (for metastases)
  • pre-operative assessmentG&S, ECG, CXR
  • surgical staging is the gold standard for staging of endometrial cancer – it allows removal of the tumour at the same time as gathering required samples for histopathological assessment
  • imaging is rarely required if surgical staging is carried out, but in certain cases of advanced disease or where the diagnosis is uncertain, imaging could involve MRI pelvis to assess local invasion and pelvic lymph nodes +/- CT abdomen and pelvis or PET scan for metastases
  • invasive tests such as cystoscopy, proctosigmoidoscopy and barium enema are generally not required but could be used to assess the extent of invasion in locally advanced disease

 


Grading – how aggressive is it?

Endometrial cancer is graded using the FIGO grading system:

  • G1 5% or less of a non-squamous or non-morular solid growth pattern (good)
  • G2 6-50% of a non-squamous or non-morular solid growth pattern (OK)
  • G3 >50% of a non-squamous or non-morular solid growth pattern (bad)

Grading is used alongside staging to provide an estimate of the patient’s prognosis. Survival is roughly halved with a grade 3 (high grade) malignancy.

 


Staging – how far has it spread?

Endometrial cancer is staged by the International Federation of Gynaecology and Obstetrics (FIGO) system. The TNM system can also be used, but generally, gynae-oncologists prefer to use FIGO.

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endometrial cancer staging

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Uterine sarcomas each have their own different FIGO staging systems and carry a much poorer overall prognosis. With both endometrial and uterine cancers, prognosis depends on grade as well as stage.

 


Management

Surgical management is the mainstay of treatment, and allows formal surgical staging as well as removal of the tumour:

  • stage I total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO)
  • stage IIexploratory laparotomy and surgical staging with radical hysterectomy, bilateral pelvic lymph node dissection (BPND) +/- para-aortic lymph node clearance, pelvic and peritoneal washings for cytology and omental sampling if indicated
  • stage III/IVexploratory laparotomy with maximal tumour debulking and full surgical staging as above
  • laparoscopic hysterectomy is becoming more popular, and studies have shown equivalent survival rates and better post-operative recovery in early stage disease

 

Medical therapies are used alongside surgery in more advanced disease:

  • radiotherapy – external beam irradiation and/or intracavity brachytherapy are given post-operatively to women with stage Ib grade 3 disease, and stage II-IV disease of any grade – the PORTEC trial showed that adjuvant radiotherapy reduces the risk of local pelvic recurrence, but confers no survival advantages to women with disease severity less than stage Ib grade 3. Radical radiotherapy can also be used effectively to treat local recurrences (50% response rate), and as a primary treatment in frail patients unsuitable for major surgery.
  • chemotherapy – can be used in stage III/IV disease, but response rates in endometrial cancer tend to be poor. Commonly used drugs include doxorubicin, paclitaxel and carboplatin/cisplatin.
  • hormonal therapies such as tamoxifen and progestogens can be used in advanced or recurrent disease, with a reasonable response rate (15-30%). They can also be used for palliation of symptoms such as excessive bleeding.
  • advanced metastatic cancer (stage IVb) requires individualised palliative treatment with tumour debulking, chemoradiotherapy and symptom control.

 


Follow-up and prognosis

  • the overall prognosis is good (77.3% 5-year survival) but varies significantly depending on the stage, grade and type of cancer (see above)
  • women who undergo surgery for endometrial cancer are generally followed up and monitored by a specialist gynae-oncology centre

 


Prevention strategies – potential for screening

There are several potential future options for screening for endometrial cancer:

  • genetic screening can be offered to high-risk women with a significant family history of cancer (e.g. endometrial, ovarian, breast, GI, urothelial) – this generally involves testing for HNPCC and PTEN. Patients who test positive for a mutation can be monitored using TVUSS and endometrial sampling, or may choose to undergo prophylactic interventions such as hysterectomy.
  • cervical screening contributes slightly to screening for endometrial cancer – 1% of cases are incidental findings on smear tests.
  • transvaginal ultrasound (TVUSS) can be used to assess endometrial thickness – if >5mm there is a 7.3% likelihood of cancer, if <5mm there is a 2% likelihood of cancer.
  • endometrial sampling using Pipelle biopsy is an easy way to screen for premalignant and malignant changes – endometrial hyperplasia represents a high risk of malignancy and is easily treatable once diagnosed.

However, none of these methods have been shown by studies to reduce mortality from endometrial cancer. It is also arguable that as both endometrial hyperplasia and endometrial cancer tend to present early with postmenopausal bleeding, and have an excellent prognosis when diagnosed at an early stage, the need for a population screening programme is less compelling when compared to something like ovarian cancer, which has few symptoms and tends to present late with a poor prognosis.

Currently, screening is only recommended in women with a proven genetic predisposition to endometrial cancer.

 


References

Images:

1. By BruceBlaus [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)], from Wikimedia Commons

2. By Blausen Medical Communications, Inc. (Donated via OTRS, see ticket for details) [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

 

Other further reading sources:

 


 

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