Picture of the female gynaecological organs (www.patient.co.uk/diagrams)

Genetics of Lynch syndrome endometrial cancers

Lynch syndrome is inherited in an autosomal dominant pattern: children have a 50% chance of having the mutated gene, which they carry from birth. The population incidence (prevalence) of Lynch syndrome in the UK is approximately 1 in 350 of the population. It is more common than previously thought.


Lynch syndrome carriers have abnormalities in one of four mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. A further ‘gene regulator’ called EPCAM, not a mismatch repair gene, which lies close to the MSH2 gene also causes Lynch syndrome. Some women with EPCAM only have raised colorectal cancer risk while others have a full range of cancers similar to MSH2.

Should you ask for a genetic test if you or one of your relatives has endometrial cancer? (3)

The Amsterdam 2 guidelines are used by GPs to decide whether a family should be referred for genetic counselling. The following criteria must be met :-


* There should be at least 3 relatives (one a first-degree relative) with an LS-associated cancer (verified by pathology) of the most common LS cancers ie. colorectal, endometrium, kidney/ureter/bladder, ovary, gastric, small bowel.


* At least one person should be diagnosed before the age of 50 years


* At least 2 successive generations should be affected


 This won’t pick up all LS families and so testing of colorectal and uterine specimens is also done.

However complicated Lynch syndrome seems, there is always a simpler way of explaining it. Lynch syndrome was previously called HNPCC or hereditary non-polyposis colorectal cancer.


Only 3% of endometrial cancers are due to Lynch syndrome. The vast majority are not and are non-genetic or “sporadic”.


This section deals with cancer of the uterus in Lynch syndrome (LS). Endometrial cancer is one of the commonest cancers in LS. It may occur before a women gets colorectal cancer and knowledge about it is therefore very important.1 The good news is that it has a very good cure rate. You should also read information about cancer of the ovary in LS.

Not everyone with Lynch syndrome gets gynaecological cancers and this is because:-


(a) It has “incomplete penetrance” meaning not everyone with Lynch syndrome gene gets cancer. Approximately 40% of LS gene mutation carriers get endometrial cancer by the age of 70 yrs which means that 60% don’t.


(b) Each of the LS genes has a different risk of gynaecological cancers. For example, it is 34% by age 70yrs for endometrial cancer in MLH1 but approx. 24% in PMS2.2


(c) Environmental factors do also play a part such as medication and body weight.

Automatic testing of endometrial cancer specimens

Many women under the age of 50 years (without known Lynch syndrome) will now have their specimen examined for signs that indicate Lynch syndrome; microsatellite instability (MSI) and immunohistochemistry (IHC). Approximately 9% of specimens from this group are positive for LS. If this was automatically done throughout the UK it would increase the number of Lynch syndrome diagnoses and find new LS families. For the women involved and their families, a diagnosis of LS is crucial for future management of cancer risk.

Number of cases of endometrial cancer due to Lynch syndrome. About 8500 cases of endometrial cancer are diagnosed in the UK each year and approximately 3% of these are due to Lynch syndrome (255 cases per year). (4)
The cumulative incidence (risk) of endometrial cancer up to the age of 70 years in each of the gene mutations of Lynch syndrome“Risk by age 70 yrs” is how many women out of 100 women with LS will get endometrial cancer by the age of 70yrs.


“Age of onset” is the age at which risk rises up significantly.

Endometrial (uterine) cancer in Lynch Syndrome

Writtenby:  Dr Pauline Skarrott.                   

The information here is to advise you and isn’t meant to take the place of that from your doctors, counsellors and family.

(2) Figures from Moller, P in Cancer incidence and survival in Lynch syndrome Gut 2015

Age of increased risk of Lynch syndrome endometrial cancers

The usual age of onset of endometrial cancer in the general population is around 60 years, at least ten years after the menopause. In this case, the main symptom of postmenopausal bleeding, is obvious to spot and the woman nearly always seeks medical advice. (5)


In the case of endometrial cancer due to Lynch syndrome (LS), the symptoms occur much earlier – from the age of 40 years (50 years in PMS2) and they are not always easy to spot. However the spread of age onset of endometrial cancer in LS is extremely wide – as young as 26 yrs and as late as 87 years so if you are worried, seek advice whatever your age.

Risk factors in endometrial cancer in Lynch syndrome (5)

Risk factors that increase sporadic endometrial cancers include the following (11:-)


* Obesity


* Long term treatment with unopposed oestrogen HRT during and after menopause


* Early puberty


Late menopause


*Never had children

Pathology of endometrial cancers (cancer of the uterus) (5)

There are two kinds of endometrial cancers and fortunately the one which is most common in Lynch syndrome is the least aggressive and has a good prognosis.


The Lynch syndrome endometrial cancers do have a rather unusual feature and that is that they are more commonly found in the lower segment of the uterus compared with the ordinary sporadic cancers, which tend to be higher up in the uterus. This is a good thing because a cancer in the lower segment is more likely to bleed, bringing attention to it and it is easier to collect cells from an examination in outpatients from this area.

Symptoms (5)

Patients with endometrial cancer classically present with post-menopausal bleeding – bleeding at least a year after the last menstrual period.


Women who present around or before the menopause will have symptoms of inter-menstrual bleeding (between periods) and/or irregular, heavy or light menses.


Of those who do have a cancer, most are endometrial but some are from the cervix.

Remember that unusual bleeding does not always mean you have a cancer – the majority of cases are not. But always check with your doctor. If you have LS, and have unusual menstrual bleeding – get it checked out, whatever your age.

(2) Figures from Moller, P in Cancer incidence and survival in Lynch syndrome Gut 2015

Transvaginal ultrasound scan (TVUS)


The operation of choice for cancer of the uterus in the UK is hysterectomy and bilateral salpingo-oophorectomy (H&BSO). The operation may be through an abdominal incision, or laparoscopic. Lymph nodes may or may not be removed.


The long term survival of the patient with endometrial cancer depends on which stage has been found during and after the operation. This is described as “5 year survival” in a percentage. (5)

How is the diagnosis of endometrial cancer made? (5)

All women with a suspected cancer of the uterus will be referred to a gynaecology out-patients. After the consultation with a gynaecological consultant the following investigations may be arranged.

Transvaginal ultrasound scan (TVUS)

TVUS can assess depth of endometrium and can pick up cancers. It involves a small probe put into the vagina. It helps in the preoperative assessment of possible cancers and is also used to screen for cancer of the ovary.

Endometrial biopsy

This is done in out-patients using a pipelle (like a suction pipette) or by hysteroscopy which is a scope examination of the uterus with sedation. Sometimes this is done under general anaesthetic (GA). All of these take a small sample of the lining of the uterus. A definite diagnosis of cancer can only be made by examining a specimen under the microscope (histology) by a pathologist.


If the diagnosis of cancer is confirmed, the patient may be referred for specialized tests such as magnetic resonance imaging (MRI) and/or computed tomography (CT)


Decisions will be made with the patient and her clinicians as to whether she needs any extra treatment such as chemotherapy and/or radiotherapy before her operation.

Stage 1 85% cancer confined to body of uterus (Recent research in LS puts this figure at 95%)


Stage 2 75% cancer grows into the cervix but does not extend beyond uterus


Stage 3 45% local and/or regional spread of the cancer


Stage 4 25% cancer invades bladder and/or bowel mucosa

Screening for cancer of the uterus in Lynch syndrome

At present, there is no easy, effective and safe way of screening the uterus for cancer in the UK. Trials are still on-going and a conclusion has not yet been reached (Feb2016). The screening tools that are available to gynaecologists (see below) are neither universally used nor considered sufficiently reliable. Therefore women in the UK who have Lynch syndrome find that when they are referred to a gynaecologist, they may hear different advice depending on where they live.


The Vasen “European” guidelines 6, published in 2013 and used by many genetic and gynaecology departments state that women with LS should be seen by a gynaecologist and offered the following after being given full advice about pros and cons :-


“Monitoring of the endometrium by gynaecological examination, transvaginal ultrasound and aspiration biopsy starting from the age of 35-40 years because this may lead to the detection of premalignant disease and early cancers. This should be done every 1-2 years.”


In addition, the Vasen guidelines state that a women with LS should be given advice about risk reducing surgery (RRS) (hysterectomy to remove the uterus and oophorectomy to remove the ovaries) because:-


”Hysterectomy and bilateral oophorectomy largely prevents the development of endometrial and ovarian cancer and is an option to be discussed with mutation carriers who have completed their families especially after the age of 40 years. Also if colorectal surgery is scheduled, the option of prophylactic surgery at the same time should be discussed. All pros and cons of surgery should be discussed.”

Ways of preventing endometrial cancer in Lynch syndrome

 Ways of preventing endometrial cancer in Lynch syndrome


* Keep weight normal.


* Take aspirin. (The CaPP2 trial showed that 600mg aspirin taken daily long-term cuts LS cancers by 50%. Women are advised to take 100mg coated  aspirin or take part in CaPP3 trial.7


* Take the contraceptive pill or similar hormonal contraceptive. Progesterone only pills or coil and combined pills will reduce the incidence of endometrial cancer in Lynch syndrome.


   Risk-reducing surgery (see above).

Summary – how to reduce your risk of LS endometrial (uterine) cancer

Eat a healthy diet and keep your weight normal.


Take long-term aspirin (dose at least 100mg).


Take hormonal contraceptives.


Have endometrial screening from age 35-40 years if offered to you.


Go promptly to the GP if you have unusual menstrual bleeding.

Consider prophylactic hysterectomy, from age 40 years onwa

Hormone replacement therapy in Lynch syndrome carriers

Hormone replacement therapy (HRT) is extremely good at treating debilitating menopausal symptoms as well as reducing the risk of osteoporosis (thinning of bones) and fractures. However it does have side effects on the vascular system and an increase in some cancers, such as endometrium, ovary and breast.


Unless a woman with LS has had a gynaecological or breast cancer that is hormone dependent, it is safe for her to take hormone replacement therapy (HRT) from any age until the age of her natural menopause would be, around 50yrs.


If a woman with LS has a hysterectomy but keeps her ovaries, specialist advice about HRT must be sought from a gynaecologist because HRT causes a small increase in ovarian cancers.


One LS mutation group, MLH1 already has an increased breast cancer risk (18% by age 70 yrs compared with approx 8% in the general population) and HRT also increases the risk of breast cancer. MLH1 carriers are advised to start mammography at 40 years and especially if they take HRT.



Amsterdam and Bethesda algorithms – formulae to work out how likely your family is to have Lynch syndrome using the number of people with LS cancers and their ages


Autosomal – means inherited in a non sex-linked way


Bilateral oophorectomy – removing both ovaries


Dominantly inherited means it passes direct from one generation to another, 50% risk


Cervix – bottom part of the uterus, pointing into the vagina


Colon – large intestines


DNA – deoxyribonucleic acid, the replicating system inside cell nuclei


Endometrial – strictly this is the “lining” layer of the uterus but now means anywhere in the uterus.


Environmental factors – things from the outside or what you take in – medication, smoking, food, alcohol

Fallopian tube – tube between ovary and uterus, along which eggs pass


Gene – small segment of DNA which contains inherited characteristics


Gynaecological – anything connected with female reproductive organs


Hysterectomy – removal of the uterus. Can be done without ovaries being removed.


IHC – immunohistochemistry – a pointer towards LS in pathology specimens


Incidence – number of people in a population with gene or cancer (eg 1 per 1000) over time


Incomplete penetrance – means not everyone with a mutated gene gets cancer


Mallorca group - a group of European experts who wrote guidelines for LS in 2013


MMR – mismatch repair genes help cells to repair mistakes. Mutations of these can lead to cancer.


MSI – microsatellite instability, one of the pathological pointers to LS


Post menopausal bleeding – regarded as any bleeding after an absence of periods for 1 year.


Prevalence – the percentage of a population affected by a cancer at a given time eg 5%


Reflex testing – specimens from all operations are tested for signs of LS


Sentinel – the first cancer a family has


Sporadic – means cancers that occur by chance and aren’t inherited





(1) Lu K et al in “Gynaecological malignancy as a Sentinel Cancer for women with HNPCC (LS), Gynaecol Oncol, 2004;92:421


(2) Moller P et al in ”Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the Lynch syndrome database” in Gut 2015:0:1-9.doi:10.1136/gutjnl-2015-309675


(3) Manchanda R, in Hereditary non-polyposis colorectal cancer or Lynch syndrome: the gynaecological perspective in Curr Opin Obstet Gynaecol 21:31-38


(4) Cancer research UK website searched Feb 2015



(5) Saso S, et al in “Endometrial cancer” in BMJ 2011;343:d3954


(6) Vasen HFA et al in Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts 2013 Gut Online doi:10.1136/gutjnl-2012-304356


(7) Burn J et al in “Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial” Lancet 2011

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