Gynaecological Cancers in Lynch Syndrome


Written by Dr Pauline Skarrott Updated 23.03.2015

The information here is to advise you and isn’t meant to take the place of your doctors, counsellors and family. However complicated Lynch syndrome seems, there is always a simpler way of explaining it.



This section deals with cancers of the uterus and ovary in Lynch syndrome (LS) and some medical research relating to them. Lynch syndrome gynaecological cancers behave slightly differently to ordinary or “sporadic” cancers and this affects how they should be monitored and treated. Lynch syndrome was previously called HNPCC or hereditary non-polyposis colorectal cancer.

This section is in two parts. The first deals with endometrial cancer (uterus) and the second is about ovarian cancer.


“For women with Lynch syndrome, risk of gynaecological cancers is substantial, often equaling or exceeding their risk of colon cancer. In a study of women with Lynch syndrome who developed both a colon and a gynaecological cancer, at least 50% of cases presented with a gynaecological cancer as their sentinel (or first) cancer”. 1


                               Genetics of Lynch syndrome gynaecological cancers


Lynch syndrome is inherited in an autosomal dominant pattern; offspring have a 50% chance of having the mutated gene, which they carry from birth. The population incidence of Lynch syndrome in the UK is approximately 1 per 1000 but may be as many as 1 per 330.4

Lynch syndrome carriers have abnormalities in one of four mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. A further gene called EPCAM, not a mismatch repair gene, which lies close to the MSH2 gene also causes Lynch syndrome.2

The majority of Lynch syndrome patients who have gynaecological cancer will carry either the MLH1 or MSH2 mutated genes.

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


1  It has “incomplete penetrance” meaning not everyone who carries a Lynch syndrome gene gets cancer – approximately 40% in endometrial cancer by the age of 70 yrs.


2  Each of the LS genes has a different risk of gynaecological cancers. For example, it is 40% for endometrial cancer in MLH1 but approx. 25% in PMS2.


3  Environmental factors do play a part such as medication and body weight.



At the moment women are advised to have genetic counselling if they have 2 or more relatives below the age of 50 years with colorectal, endometrial cancer or another of the Lynch spectrum of cancer. (See our genetics section) If their family fits the criteria of The Amsterdam and Bethesda algorithms, it can point to an MMR mutation. Unfortunately those formulae have false positive as well as false negative results and they will miss approximately a quarter of cases.


                                                                                                Anatomy of female pelvis:
















                                                           Diagram reference Dr Beverly Kenny ,



                                             Part 1 Endometrial cancer in Lynch syndrome

Number of cases of all types of endometrial (uterine) cancer per year in UK


The incidence of endometrial cancer in the normal population by the age of 70 years is 2.35%.3


In 2011, 8475 women in the UK were diagnosed with all types of cancer of the uterus.3

There were 2025 deaths from all types of cancer of the uterus in the UK in 2012.


78% of adult cancer of the uterus patients in 2010 -2011 in England and Wales are predicted to survive more than 10 years.

Number of cases of endometrial cancer due to Lynch syndrome each year


Of all the endometrial cancers in the UK each year (8500), 3% are due to Lynch syndrome (approx. 255 cases per year)

The lifetime incidence of endometrial cancer up to the age of 70 years in each of the gene mutations is;-


MLH1 40% )


MSH2 40% ) spread 17% - 60% 1 6 7 8 9


MSH6 40% )


PMS2 25% 10


EPCAM 12% 5


(Dr Ian Frayling, Consultant in genetics at Cardiff is currently researching the latest figures on these).



                          Age of onset of Lynch syndrome endometrial cancers

The usual age of onset of sporadic (ordinary) endometrial cancer is 60 yrs and the women affected are post-menopausal.11 This means that the symptoms of bleeding are so long after the woman’s periods have stopped that she usually seeks medical advice.

However, the average age of onset of Lynch syndrome endometrial cancers is 48 years – not a time when women necessarily worry about irregular bleeding.


Results of studies in 2009 and 2011 on Lynch syndrome endometrial cancer show that on average, the age of onset is 49 years (range 26 – 87 years)8 9. MSH6 has a later onset.


                                Risk factors in endometrial cancer in Lynch syndrome

Risk factors that increase sporadic endometrial cancers11 include the following:-


  • Obesity

  • Long term treatment with unopposed oestrogen HRT (without progesterone) during and after menopause


                              Pathology of endometrial cancers (cancer of the uterus)

Most of the women who get sporadic (ordinary) endometrial cancer but who do not have Lynch syndrome have one of two types.

The first called “endometriod cancers” is the commonest type (80%) and has a good prognosis or outcome. The second is more aggressive and has a less good outcome.11


Lynch syndrome cancers of the uterus also have these two types and fortunately, the most common is the “endometriod” with a good prognosis.6


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 than the ordinary sporadic cancers, which tend to be higher up in the uterus. It has not been explained why this is so but cancers in the lower segment are more likely to bleed, bringing attention to it and it is easier to collect cells from an examination in outpatients from this area.




Symptoms 11


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


About 20% of women with postmenopausal bleeding are found to have a cancer – so 80% do not. Of those who do have a cancer, most are endometrial but some are from the cervix.


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


                                  How is the diagnosis of endometrial cancer made?

It is important to see a GP as soon as possible after the onset of symptoms. Don’t delay if worried.

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.


Investigations 11


A transvaginal ultrasound scan (TVUS) can assess depth of endometrium but cannot definitely diagnose early endometrial cancer. It involves a small probe put into the vagina. It helps in the preoperative assessment of possible cancers and is used to screen for cancer of the ovary.


Endometrial biopsy 11


This is done in out-patients using a pipelle (like a suction pipette) or by hysteroscopy and dilatation and curettage under general anaesthesia. Both 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) 11


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.




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.


                                                  Staging of endometrial cancer11

5 year survival


Stage 1 cancer confined to body of uterus 85%


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

extend beyond uterus


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


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


Staging of endometrial cancer (of uterus) from website of Cancer Research UK3j

Stage 1 endometrial cancer


Stage 1 cancers are the easiest to treat. The cancer is within the uterus. There are 2 categories of stage 1 cancer of the uterus:-

  • 1A means that the cancer may have grown into the muscle wall (myometrium) of the uterus, but no more than halfway

  • 1B means the cancer has grown halfway or more into the muscle wall of the uterus.


Stage 2 Cancer of the uterus

This means that the cancer has grown into the cervix


Stage 3 uterine cancer

This stage means the cancer has spread outside the uterus but is still within the pelvis. There are 3 categories of stage 3 uterine cancer

  • 3A means the cancer has grown into the outer covering of the uterus (the serosa) or to the ovaries or fallopian tubes

  • 3B means the cancer has grown into the vagina or tissues surrounding the uterus (parametrium)

  • 3C means the cancer has spread to nearby lymph nodes(glands)



Stage 4 cancer of uterus


Stage 4 means the cancer has spread to another area of the body. There are 2 categories of stage 4 cancer of uterus

  • 4A means the cancer has grown into the bowel or bladder

  • 4B means the cancer has spread to lymph nodes further away or to other parts of the body, such as the lungs, liver, bones or brain (secondary cancers or metastases)




                                                                   Post-operative care

Women who have a preventative hysterectomy will usually recover and be back to normal function within 3 months. Those who have had extensive surgery for cancer with or without chemotherapy or radiotherapy will usually take longer.

The prescribing of HRT after cancer surgery needs to be decided with a gynaecologist.

Women who have had hysterectomy for cancer that involves the cervix or vagina should have vault smears.


                                                Screening of the uterus in Lynch syndrome

Screening has to save lives and this has not been shown to be the case for endometrial cancer (uterus) in Lynch syndrome. Endometrial cancer has early symptoms (bleeding) and the 80% 5 year survival rate means that improvements in outcome as a result of screening are difficult to demonstrate.12


Nevertheless, there is a 20% mortality which is very significant to women with Lynch syndrome. The Mallorca group guidelines2 do in fact suggest screening annually from the age of 30 – 35 years until definitive preventative surgery is done.


Transvaginal ultrasound (TVUS) is not effective as a screening method alone for showing up early endometrial cancer, simply because it is not sensitive enough to demonstrate early cancers within the uterus.6


Endometrial biopsy has been shown to be a feasible method of screening for Lynch syndrome endometrial cancers (This is taking a sample of the uterine lining through the cervix). Manchanda et al have demonstrated the feasibility and efficacy of this being done with pipelles in outpatients. (Outpatient hysteroscopy and endometrial sampling or OHES)12


Ways of preventing endometrial cancer in Lynch syndrome


1  Keep weight normal.


2  Take aspirin. There is evidence that daily long term aspirin (600mg) reduces not only colorectal cancers in Lynch syndrome but endometrial and ovarian cancers as well by as much as 50% as shown in the CaPP2 trial by Burn et al.14 A trial (CaPP3) is just starting to ascertain which dose of aspirin is best, 100mg, 300mg or 600mg.14


3  Take contraceptive pill or similar hormonal contraceptive. Several studies have shown that taking the oral contraceptive pill (both combined and progesterone only) have reduced the changes leading to endometrial cancer and ovarian cancer in the general population.6 There are encouraging signs that this may also be true for Lynch syndrome gene carriers and that these medications might reduce the risk of each cancer by 50%.


4  Risk reducing surgery (see below)


                                        Risk reducing surgery for gynaecological cancers

“Given the increased risks of both endometrial and ovarian cancer in women with Lynch syndrome, and the limitations of screening for these cancers, risk reducing hysterectomy and bilateral salpingo-oophorectomy (HBSO) is a consideration for women with Lynch syndrome.”6

In Manchanda’s study, up to 33% of women who had not had hysterectomy developed endometrial cancer.12


HBSO as a means of reducing risk of endometrial cancer has been recommended by the following studies, Schmeller 200613, Manchanda 200912 and NCCN (National Cancer Network of America6


Timing of HBSO is crucial because the incidence of gynaecological cancer in women with Lynch syndrome is very low (2%) until the age of 40 years when it starts to rise significantly. Similarly with ovarian cancer the incidence is only 1% until the age of 40 years and then rises steeply leading to the advice that gynaecological screening and surgery in Lynch syndrome should concentrate on women who are 40 and over.8 6


Prior to preventative HBSO, endometrial biopsy should be done to pick up any undiagnosed endometrial cancer.6

If a woman is known to have Lynch syndrome and also needs colon surgery, HBSO could be performed at the same time.6


                       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 can cause an increase in blood clotting (thrombosis), heart attacks, strokes, cancers of the breast, ovary and endometrium (uterus). These tend to be worse the longer the HRT is taken and with larger doses. Each person’s case is different and therefore it is essential that this is discussed with GPs and gynaecologists.




1  If HRT is contemplated at the time of the menopause for a woman who has not had her uterus of ovaries removed (HBSO), and is being given for menopausal symptoms, unopposed oestrogen without progesterone should never be given because of the increased risk of endometrial cancer. Combined preparations are best, preferably transdermal and as small a dose as possible for the shortest length of time. 1 year is better than 10 years but there is no right dose or time. GPs should oversee.


2  HRT after preventative hysterectomy and oophorectomy. HRT can be combined or unopposed oestrogen. Surgery causes sudden fall in oestrogen and therefore replacement therapy is indicated and should continue until 50 years to prevent osteoporosis. The only cancer to worry about is breast cancer.


3  HRT after cancer of uterus or ovary


This must be discussed with a gynaecologist, especially if the cancer was oestrogen dependent.


                                    Reflex testing of endometrial cancer specimens

It is possible to screen the specimens of all women with endometrial cancer for the signs that indicate Lynch syndrome; microsatellite instability (MSI) and immunohistochemistry (IHC). It would increase the number of Lynch syndrome diagnoses and find new LS families. This has a cost in terms of manpower, equipment and finances and could not be done yet on all women with endometrial cancer.


9% of specimens of endometrial cancer from women under the age of 50 yrs are known to be positive for MSI/IHC type tests so this would be worthwhile if it is economically viable.12

For the women involved and that of their families, a diagnosis of Lynch syndrome would be crucial for future management of cancer risk.



REDUCING RISK – Lynch syndrome endometrial cancer















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. But don’t delay if things don’t seem right

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 person has

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



REFERENCES The majority of these are free articles


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

  2. 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

  3. Cancer research UK website searched Feb 2015

  1. Frayling I, 2015 private communication

  2. Klempers MJ et al in “Risk of colorectal and Endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study” in The Lancet Oncology 2011;12:49-55

  3. Lu, K and Daniels, M in “Endometrial and ovarian Cancer in Women with Lynch syndrome: Update in Screening and Prevention” in Fam Cancer, Jun 2013 12(2) 10.1007

  4. Baglietto L et al in “Risks of Lynch syndrome cancers for MSH6 mutation carriers” in

Journal of the National Cancer Institute 2010; 102:193-201

  1. Bonadona, V et al in “Cancer risks associated with germline mutations in MLH1, MSH2

And MSH6 in Lynch syndrome” in JAMA: the Journal of the American Medical Association 2011; 305:2304-2310

  1. Stoffel E et all, in “Calculation of Risk of Colorectal and Endometrial Cancer Among

Patients with Lynch Syndrome” in Gastroenterology 2009; 137:1621-27

  1. Senter et al in “The Clinical Phenotype of Lynch syndrome due to germ-line PMS2

mutations” in Gastroenterology 2008; 135:419-28

11. Saso S, et al in “Endometrial cancer” in BMJ 2011;343:d3954

12. Manchanda R et al in “Hereditary non-polyposis colorectal cancer or Lynch syndrome:

the gynaecological perspective” in Current Opinion in Obstetrics and Gynaecology


13. Schmeler KM et al in “Prophylactic surgery to reduce the risk of gynaecologic cancers in

the Lynch syndrome” in N Engl J Med 2006;354:261-269

14. 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

17 378:2081-2087




FINISH – The next section is about ovarian cancer


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