Postmenopausal bleeding and endometrial cancer

Abstract

Postmenopausal bleeding is a common presentation in primary care. There is great emphasis placed on rapid referral for investigation to exclude endometrial malignancy, and it is the most common symptom for which women are referred to gynaecological rapid access clinics. However, it is widely accepted that only approximately 10% of patients at a postmenopausal bleed clinic will have cancer. Endometrial cancer is now often easily treatable with laparoscopic surgery, and certain pre-malignant changes can be managed with an intrauterine system, so it is important to deal with this common presentation effectively, while also knowing about the frequent causes.

The GP curriculum and postmenopausal bleeding and endometrial cancer

Clinical module 3.06: Women’s health states that:

Women-specific health matters including contraception, pregnancy, menopause and disorders of reproductive organs will account for over 25% of your time as a GP

You should demonstrate an understanding of the importance of risk factors in the diagnosis and management of women’s problems

You should intervene urgently with suspected malignancy

You should recognise common signs and symptoms of, and know how to manage, gynaecological disease

You should be familiar with and implement the key national guidelines that influence healthcare provision for women’s problems

Postmenopausal bleeding (PMB) is defined as unexplained vaginal bleeding more than 12 months after menstruation has stopped due to the menopause (National Institute for Health and Care Excellence (NICE), 2015a).

Epidemiology

PMB is a common presentation, occurring in approximately 4–11% of postmenopausal women (Goodman, 2016): the lifetime risk of developing endometrial cancer is 1:41. Fifty-eight percent of cases are diagnosed in women over the age of 65 years, with a peak incidence between 60 and 79 years of age: there were 9000 new cases diagnosed in 2013 (Cancer Research UK, 2013). With the shift in demographics over the past few decades towards an increasingly ageing and obese population, the incidence has risen by 65% (Otify, Fuller, Ross, Shaikh, & Johns, 2015). The 5-year survival rate is 78.1% (Office for National Statistics, 2015), therefore it is an important cancer to detect, given it can be relatively easy to treat and potentially cure in the early stages.

It is important to note that approximately 25% of women diagnosed with endometrial cancer are premenopausal (Shafi, Earl, & Tan, 2009), and therefore PMB will not be the presenting symptom. Practitioners should be alert to this fact, and vigilant towards other red flag symptoms, for example, a change in bleeding pattern such as new onset menorrhagia or intermenstrual bleeding.

Causes of PMB

Endometrial cancer is the most serious cause of PMB; however, most patients will have benign diagnoses. The most common cause is urogenital atrophy, as a result of the menopausal status. Table 1 summarises the causes of PMB.
Table 1.
Causes of PMB.

Benign causes Malignant causes

Urogenital atrophy (most common cause) Endometrial cancer

Hormone replacement therapy Cervical cancer

Tamoxifen Vaginal cancer

Endometrial polyps Ovarian cancer

Endometrial hyperplasia Vulval cancer

Fibroids Fallopian tube cancer (rare)

Sexually transmitted infections

Dermatoses such as lichen sclerosus

Urogenital atrophy

Urogenital atrophy is the most common cause of PMB seen in clinical practice. Symptoms other than bleeding can include recurrent urinary tract infections, lower urinary tract symptoms, dyspareunia, vaginal itching, and vaginal dryness.

Hormone replacement therapy

Currently, women take combined oestrogen and progesterone either in a continuous or sequential fashion, as it is well-recognised that oestrogen alone increases the risk of hyperplasia and carcinoma. New national guidance has been published recently with further information about this problem (NICE, 2015b). It has been shown that women on continuous hormone replacement therapy (HRT) have a lower overall risk of endometrial cancer than women who have never used HRT. Women using sequential HRT have a higher risk of endometrial cancer if the progestogens are used for less than 12 days per cycle. Irregular bleeding is common in the first 3 months of use; however, women with any unscheduled bleeding after this should be referred on a cancer referral pathway.

Tamoxifen use

Tamoxifen is a selective oestrogen receptor modulator that inhibits proliferation of breast cancer by competitive antagonism at oestrogen receptors; however, it acts as a partial agonist on the tissues of the female genital tract. The British National Formulary (British National Formulary, 2016) states that tamoxifen causes ‘increased endometrial changes, including hyperplasia, polyps, cancer, and uterine sarcoma’ and advises that ‘prompt investigation is required’ for women taking tamoxifen or who have received tamoxifen previously who experience abnormal vaginal bleeding (including menstrual irregularities), vaginal discharge, and/or pelvic pain or pressure. Therefore, patients prescribed tamoxifen should be informed of the risk of endometrial cancer and told to report relevant symptoms promptly.

Endometrial polyps

Endometrial polyps are benign overgrowths of the endometrium, but do have a malignant potential, which can occur in up to 2.4% of asymptomatic polyps (Goldstein, 2009). They are more common in postmenopausal women, and it is estimated that the risk of cancer is highest in this group. Risk factors for polyp development include tamoxifen use, obesity and hypertension (Otify et al., 2015).

Endometrial hyperplasia

Fifteen percent of women presenting with PMB will have hyperplasia, which is defined as a proliferation of glands of irregular size and shape with an increase in the gland-to-stroma ratio within the endometrial tissue. It is a pre-malignant state and if untreated can progress to cancer. Endometrial hyperplasia is divided into hyperplasia with or without atypia. This will be reported on endometrial biopsy. Patients with hyperplasia with atypia are much more likely to develop cancer (23% compared with 2% without atypia) (Otify et al., 2015) and cancer can often be present in these patients at diagnosis. The risk factors for endometrial hyperplasia are the same as for endometrial cancer.

Endometrial cancer

Risk factors for endometrial cancer

Two types of endometrial cancer have been recognised. Their characteristics and respective risk factors are summarised in Table 2.
Table 2.
Characteristics of endometrial cancers.

Type-1 cancer Type-2 cancer

Histology Mainly endometrioid Clear cell, serous, carcinosarcoma

Proportion of diagnoses (%) 75–80 20

Recognised precancerous lesion Yes No

Risk factors • Increasing age • Obesity • Anovulation, e.g. polycystic ovarian syndrome • Unopposed oestrogen • Diabetes mellitus • Hypertension • Lynch syndrome • Tamoxifen • Possibly increasing age • Possibly obesity

Obesity (body mass index (BMI) greater than 30 kg/m²) is an independent risk factor for endometrial cancer and it is predicted that 50% of adult women will be obese by 2050 (Otify et al., 2015). There is an association between Lynch syndrome type II (hereditary nonpolyposis colorectal cancer) and endometrial cancer, about which practitioners should be aware. Patients with the syndrome have a 30–60% lifetime risk of developing endometrial cancer, and it accounts for 5% of all endometrial cancer diagnoses (Colombo et al., 2013). Protective factors against endometrial cancer include the use of the combined contraceptive pill, childbearing and physical activity.

Types of endometrial cancer

Type-1 endometrial cancers are related to unopposed oestrogen stimulation of the endometrium and account for 75–80% of cases. They are mainly of endometrioid histology. Atypical endometrial hyperplasia is a precancerous lesion, and in up to 27.5% of the cases this can progress to endometrial cancer if untreated (American College of Obstetricians and Gynaecologists (ACOG), 2015).

Type-2 tumours represent approximately 20% of the cases of endometrial cancer. Histological types include serous carcinomas, clear cell tumours and carcinosarcomas. These are high-grade tumours that often present in the advanced stage, and patients are more likely to have extra-uterine disease at diagnosis (ACOG, 2015). They also have no recognisable pre-cancerous lesion or definitive risk factors.

Primary care assessment

Menopausal status should be checked, with specific focus on the age at which the last period occurred, especially in recently menopausal patients. Relevant history should include gathering information about the bleeding, including whether it was a single or recurrent episode (and if recurrent, when was the last episode and was it investigated), the quantity of blood, any trigger factors (e.g. intercourse), and a discussion about whether there are any symptoms suggestive of vaginal atrophy, e.g. recurrent urinary tract infections and vaginal dryness. Risk factors for endometrial cancer should be identified. Cervical screening history should be checked, and sexually transmitted infections and their symptoms should be discussed if relevant - this is an ideal opportunity for health promotion if time allows.

Although examination is unlikely to affect the decision to refer, it is important to perform an abdominal, speculum and bimanual examination. These can be focused to consider the potential cause of PMB, and exclude a pelvic mass or cervical lesion, which would be dealt with via a different referral pathway. It can also help to visually inspect for signs of urogenital atrophy, including vaginal dryness, poor skin condition, fusing of the labia, and skin tears or trauma. If urogenital atrophy is found, this could explain the PMB, but as endometrial pathology cannot be excluded from examination alone, a referral is still indicated.

Primary care referral pathway

All women with PMB should be referred for investigation to exclude malignancy. Despite this, evidence suggests that only 61.4% of women with PMB are actually referred (McBride, Hardoon, Walters, Gilmour, & Raine, 2010). The latest NICE (2015a) cancer referral guidelines are clear in their recommendations that primary care should:
Refer on a suspected cancer pathway (2-week wait) if a woman is 55 years or older with postmenopausal bleeding

Consider a suspected cancer pathway if women are less than 55 years in age with postmenopausal bleeding

In practice, all women who present with PMB are likely to be referred on such pathways regardless of age. The new guideline also places emphasis on considering investigation in women over the age of 55 years who have unexplained vaginal discharge with either thrombocytosis or haematuria, and women with visible haematuria along with low haemoglobin levels, thrombocytosis or elevated blood glucose. No values are specified for the blood measurements. These recommendations are likely to stem from the risk factor of diabetes in endometrial cancer, the possibility of reported haematuria actually arising from an intrauterine source, and the recognition throughout the cancer referral guideline that thrombocytosis can be a marker of malignancy.

Investigations in secondary care

The aim of the investigations for women presenting with PMB is to exclude malignancy, especially endometrial cancer. Evidence suggests that either transvaginal ultrasound scanning (TVUSS) or office-based endometrial biopsy can be used as the initial investigation tool. Once referred on suspicion of endometrial cancer, each referral centre will offer some form of PMB assessment clinic. In some hospitals this will be a ‘one stop’ approach, aiming to complete both the clinical assessment and investigations in one visit.

TVUSS is used to assess the endometrium, in particular with regards to its appearance and thickness, which is the key measurement. An endometrial thickness (ET) threshold of 4 mm is commonly used in PMB patients, as with an ET of less than 4 mm, the risk of endometrial cancer is 1 in 917 (Goldstein, 2009). This is considered an acceptable threshold to discharge patients without the need for endometrial sampling if it is their first presentation. If the ET is 4 mm or greater, then further investigation with an endometrial biopsy must be performed.

Endometrial biopsy can be used as an initial investigation or in combination with TVUSS. If the ET measurement is 4 mm or greater on TVUSS then a biopsy must be performed. There are a number of office-based devices that can be used to obtain a biopsy. The Pipelle device is one commonly used, and is well-tolerated. The sensitivity of endometrial sampling for detecting cancer is 90% or higher (Goodman, 2016). Patients can expect to have some abdominal cramping after a biopsy, and can be advised to take simple anti-inflammatories to treat this problem.

Hysteroscopy is the gold standard investigation for women presenting with PMB. However, it is invasive and requires both specialist skills and equipment. Hysteroscopy is now being performed regularly as an outpatient procedure, often without analgesia. Patients tolerate the procedure well in the majority of cases, and a general anaesthetic procedure is available if needed. The benefit of hysteroscopy is it allows complete visualisation of the endometrium and can allow direct endometrial sampling. In addition, if other causes of PMB are found, for example, endometrial polyps, these can potentially be removed at the same time. Hysteroscopy should always be combined with biopsy, as hysteroscopy alone can miss cancer in up to 34% of cases (Feldman, 2016).

Management of the causes of PMB

Urogenital atrophy

Atrophy can be treated with topical oestrogen. Topical vaginal oestrogen in the form of pessaries or cream can both be used safely in many women. Those with a previous history of female cancer are also able to use these options, but it is recommended that this should be managed by the secondary care team. Alternative non-hormonal preparations such as moisturisers and lubricants could be considered in these patients. Topical treatments can be used in conjunction with systemic HRT if necessary, starting with the lowest dose and with regular review of treatment (NICE, 2015b). The use of local oestrogen does not require endometrial monitoring, as the systemic absorption is negligible.

Endometrial polyps

Diagnosis of polyps is often made by pelvic ultrasound scan with polyps being an incidental finding. The gold standard for diagnosis and confirmation of histology is a hysteroscopy and biopsy. Polyps associated with bleeding are commonly removed to reduce the risk of malignant change, and although the management of asymptomatic polyps is less clear, they are also commonly removed.

Endometrial hyperplasia

Hyperplasia management will be guided by the gynaecology oncology team and is treated in the same way as endometrial cancer, or sometimes with a levonorgestrel-secreting intrauterine system (LNG-IUS).

Endometrial cancer

Treatment of women diagnosed with endometrial cancer depends on the histology results and stage of the tumour, the age of the patient, their performance status and their preferences. Treatment is often surgical and, after initial diagnosis, the cancer needs to be staged in order to guide this process. Preoperative investigations may include chest X-ray, computerised tomography (CT), magnetic resonance imaging (MRI) and blood tests. High-grade tumours (any type-2 cancer or a grade-3 endometrioid tumour) on biopsy histology, or any patients who are not fit for surgery, should be considered for CT/MRI evaluation (ACOG, 2015).

In women with suspected early-stage disease, the aim of treatment is to remove the uterine tumour, exclude metastatic disease, and assess the risk of recurrence. This will then guide postoperative treatment should it be required. Surgery is the mainstay of treatment, which involves a total hysterectomy and bilateral salpingo-oopherectomy, potentially with lymphadenectomy. Laparoscopic or robotic-assisted laparoscopic approaches are replacing traditional open surgery in endometrial cancer.

Total laparoscopic hysterectomy (TLH) is becoming an increasingly common procedure as surgical skills advance, and most major gynaecological cancer centres will now offer this as first line treatment for early-stage disease. Operative rates of TLH for endometrial cancer vary between centres, but are increasing. The procedure can be undertaken as an overnight-stay case, and is suitable even for patients with morbid obesity. The main relative contraindication is previous abdominal surgery, especially recurrent caesarean sections. The uterus, fallopian tubes and ovaries are removed via the vagina, after dissecting this open from inside the abdomen. The vaginal vault is then sutured laparoscopically. Patients tolerate the operation well, recover quickly, and often go home the next day. Follow-up will be performed by the cancer centre or secondary care unit and follow-up protocols vary from centre to centre, but patients require regular visualisation of the vaginal vault to check for recurrence.

GPs should be aware of the risk of recurrence at the vaginal vault, which may be asymptomatic. They should also be mindful of the potential complications of the surgery, which include intra-abdominal bleeding, infection, vault dehiscence, and intra-abdominal damage to structures including the urinary tract.

For patients with metastatic endometrial cancer, cytoreductive surgery, followed by chemotherapy and/or radiotherapy may improve survival outcomes. Patients with advanced disease or those who are poor surgical candidates (e.g. advanced age, co-morbidities, obese) can be counselled about the use of LNG-IUS or oral progestogens as management options. Also, these treatment options should be considered in women diagnosed with endometrial cancer or hyperplasia who wish to preserve their fertility. If medical management is decided, the endometrium should be monitored to confirm regression of changes.

Advanced disease can be managed in conjunction with the oncologists and palliative care team, and can include blood transfusions if required. Patients will often have access to a gynaecological oncology specialist nurse who is an invaluable source of advice and support throughout their diagnosis and treatment.

Other important clinical scenarios

Recurrent PMB

Recurrent PMB always needs investigating to rule out malignancy as a cause, and an urgent suspected cancer referral should be made. Discrete episodes separated by large spaces of time are easy to diagnose as recurrent, although there is no formal definition of what constitutes recurrent bleeding. An endometrial biopsy must always be taken in cases of recurrent PMB, regardless of the ET on ultrasound scanning. Some cancers can arise in a patient with an ET less than the 4 mm accepted cut-off, and therefore a biopsy is always indicated in these patients (ACOG, 2015).

Equally worrying is the woman who has a persistent episode of PMB. In clinical practice, a woman should be considered to have persistent PMB if her vaginal bleeding continues for longer than 6 months following initial negative investigations. For example, a woman who attends a PMB clinic and has an ultrasound scan and negative endometrial biopsy but continues to bleed intermittently for the next 6 months would be a concern. In such cases, a further suspected cancer referral should be made, in the same way it would have been for a first episode.

Perimenopausal bleeding

Approximately 25% of endometrial cancer is diagnosed in premenopausal women (Shafi et al., 2009). Any cause of anovulation with the resulting unopposed oestrogenic endometrium can predispose to endometrial cancer. As a result of this, the climacteric is a time when clinicians must be vigilant for symptoms of abnormal bleeding.

Investigation of perimenopausal bleeding

Any significant bleeding change over the age of 40 years should be considered a potential red flag for endometrial pathology, and a referral should be considered, although there are no set referral guidelines on this subject. It is important to consider the patient’s risk factors for endometrial cancer when evaluating perimenopausal bleeding.

Most gynaecologists would recommend an endometrial biopsy for any woman over the age of 40 years who has a change in the menstrual cycle. Local referral pathways should be followed, but it is unlikely these women will be accepted for a PMB clinic assessment. Women under 40 years of age will often have their endometrium sampled if they have other risk factors, such as obesity or polycystic ovarian syndrome. Another indication for biopsy includes those with abnormal bleeding and fibroids, as the endometrial thickness cannot always be reliably seen on an ultrasound scan.

Management of perimenopausal bleeding

For women with perimenopausal bleeding and normal histology at biopsy, the first line of treatment will be a LNG-IUS, as per national guidelines for heavy menstrual bleeding. Through the LNG-IUS effect of maintaining the endometrium with progestogens and reducing proliferation, menorrhagia should be improved and the risk of endometrial cancer and hyperplasia developing is reduced. The LNG-IUS is also strongly advised for any premenopausal women with significant risk factors who are not actively trying to conceive.

Prevention of endometrial hyperplasia and cancer

A large proportion of endometrial cancers are related to lifestyle factors that can be modified, and GPs can be involved in this process. Examples include optimising weight towards a normal BMI, optimising diabetes management and hypertension, and ensuring that patients who are anovulatory have a withdrawal bleed at least every 3 to 4 months. This can be done by using cyclical progestogens, which are used for at least 12 days to cause a withdrawal bleed, or the oral contraceptive pill. An alternative would be to use a LNG-IUS to protect the endometrium in these patients (Royal College of Obstetricians and Gynaecologists, 2014).

Key points

Refer all women with new and/or recurrent postmenopausal bleeding

The majority of cases will be due to benign causes, mostly urogenital atrophy

GPs can help with the management of benign causes

Endometrial hyperplasia and cancer risk can be reduced with good health promotion

Endometrial cancer can be treated successfully and laparoscopically in the majority of early stages, and so early diagnosis is beneficial

Benign causes	Malignant causes
Urogenital atrophy (most common cause)	Endometrial cancer
Hormone replacement therapy	Cervical cancer
Tamoxifen	Vaginal cancer
Endometrial polyps	Ovarian cancer
Endometrial hyperplasia	Vulval cancer
Fibroids	Fallopian tube cancer (rare)
Sexually transmitted infections
Dermatoses such as lichen sclerosus

	Type-1 cancer	Type-2 cancer
Histology	Mainly endometrioid	Clear cell, serous, carcinosarcoma
Proportion of diagnoses (%)	75–80	20
Recognised precancerous lesion	Yes	No
Risk factors	• Increasing age • Obesity • Anovulation, e.g. polycystic ovarian syndrome • Unopposed oestrogen • Diabetes mellitus • Hypertension • Lynch syndrome • Tamoxifen	• Possibly increasing age • Possibly obesity

Footnotes

Acknowledgement

We would like to thank Dr Alice Shiner for her help with the writing of this article under the InnovAiT ‘buddy’ scheme. We are also very grateful to Mr Nikolaos Burbos (Consultant Gynaecological Oncologist) for his expertise and guidance with the specialist content.

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