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4 Lynch Syndrome 101
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yearly intervals and Finland with 2–3 yearly intervals albeit the adenoma detection
rate in this study was low at 14% and the quality of colonoscopy was not assessed
[87]. There was no significant association of interval with CRC risk but, there was
some individualisation of screening based on age, sex, mutation and evidence of
previous cancer or adenoma.
Data from the PLSD suggests that increasing the frequency of colonoscopies
does not improve survival, albeit study numbers were small [83]. From Møller
et al.’s review, 25% of post colonoscopy CRC develops between 12 and 23 months
post initial colonoscopy [83]. For PMS2 carriers the benefit of surveillance
endoscopy is unclear given the lower penetrance and risk with suggestion that
frequency could be decreased to 5 yearly. There is also the suggestion that some
precursors that are difficult to recognise endoscopically, for example MMR-DCF
and flat lesions, may only be present in MLH1 and MSH2 pathogenic variant
carriers as these represent the bulk of evidence [57].
These factors suggest colonoscopy intervals could be personalised and risk
stratified but, it is difficult to predict likelihood of cancer in a screening population. In the UK, “FIT for Lynch”, is trialling in a single-arm prospective,
non-randomised study, enrolling 400 LS patients to receive baseline faecal
immunochemical testing (FIT) (already utilised in sporadic cancer population) and
then annually including years 1 and 3 (when they would not routinely receive a
colonoscopy). If the result shows ≥ 6ug of haemoglobin per gram of faeces in years
1 or 3 they would be referred for an urgent interval colonoscopy. This method may
have clinical utility alongside routine surveillance endoscopy but, should not be
performed instead of colonoscopy [96]. Similarly, there is no data which supports
the use of colon capsule or CT colonography in the LS population and it is currently not recommended. Excessive use of radiation may have adverse effects in
the context of LS and should be avoided [97].
4.6.5 Barriers to Colonoscopy Adherence
It is important to support patients to attend regular colonoscopies as they can
have a psychological impact on patients. This may lead to poor adherence and
missed lesions [83]. A retrospective study of 1098 colonoscopies in patients
showed rates of moderate/severe discomfort as follows: men 5.8%, women without
hysterectomy 10.4% and post hysterectomy 17.8% [98] (Fig. 4.16a, b).
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Fig.4.16 a Polyp at ileocolic anastomosis in a patient with a pathogenic variant of the MLH1
gene and previous resection for CRC, histology from pre-polypectomy biopsy demonstrated a
tubulovillous adenoma and low-grade dysplasia b Histopathology of the polypectomy confirmed
tubulovillous adenoma but with a focus of submucosal adenocarcinoma. At subsequent colectomy
separate microscopic submucosal CRCs were identified
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4.7 Colorectal Surgical Management of Lynch Syndrome
4.7.1 Extensive or Segmental Resection?
For LS patients who are diagnosed with CRC (with confirmed MLH1 or MSH2
pathogenic variant), there is evidence to support extended resection. A laparoscopic approach can reduce adhesional burden in case of required further colectomy. This must be factored on a patient-by-patient basis taking into consideration
functional consequence of surgery, risk of metachronous cancer, patient age and
patient wishes [88]. Based on the evidence, without large prospective clinical trials,
the best practice is total abdominal colectomy with ileorectal anastomosis, however
this may not be suitable for all patients. For patients with MSH6 or PMS2 the evidence is insufficient to support this recommendation but, this may be appropriate
in some cases [88].
For rectal cancers a standard low anterior resection is a reasonable choice
over abdominoperineal excision despite the risk of metachronous neoplasm in
the remaining colon. A retrospective study with 296 patients showed when comparing extended surgery with segmental colectomy, a cancer risk reduction of
25% vs 8% [99]. A large cohort analysis of the Colon Cancer Family registry
reviewed 382 patients, in patients who underwent segmental resection 22% developed metachronous CRC, and 0% in total colectomy group [100]. In Finland
reported risk of subsequent CRC was 20% and 47% within 10- and 25- years
respectively, in standard resection and 4% and 9% in extended surgery [101].
Reviewing the subgroups here, the increased risk is in carriers of MLH1 or MSH2
rather than MSH6 or PMS2 [102].
In practice, leaving a short segment of sigmoid colon in patients undergoing
subtotal colectomy improves functional symptoms and does not greatly increase
risk of metachronous cancers in the remaining colon. The residual colorectum
should continue to undergo surveillance at standard intervals. The morbidity associated with total colectomy is comparatively severe with limited or no additional
benefit in LS patients [103].
In addition, for female MLH1, MSH2 and MSH6 gene carriers undergoing
resection for a new CRC diagnosis, synchronous prophylactic bilateral salpingooopherectomy and hysterectomy (TAH-BSO) may be considered.
4.8 Prophylactic Surgery and Screening
in Gynaecological Cancer
4.8.1 Gene-Specific Risk and R isk Reduction Surgery
Endometrial cancer (EC) is the most common extra-colonic cancer in LS, each
pathogenic variant conveys a varying risk as in CRC detailed in (Table 4.2). There
is an associated increased but less prominent risk with ovarian cancer, particularly
for carriers of pathogenic variants in MSH2 and MLH1 genes which convey a
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Tab le 4.2 Incidence of gynaecological cancers according to pathogenic variant
% cumulative incidence at age 40 (95%
CI)
Endometrial gene
MLH1 3.1 (0.4–5.8) 42.7 (33.1–52.5)
MSH2 1.5 (0.0–4.4) 56.7 (41.8–71.6)
MSH6 0 46.2 (27.3–65.0)
PMS2 0 26.3 (0.8–51.9)
Ovarian gene
MLH1 2.6 (0.1–5.2) 10.1 (4.8–15.4)
MSH2 3.8 (0.0–8.0) 16.9 (5.7–28.0)
MSH6 4.2 (0.0–12.3) 13.1 (0.0–31.2)
PMS2a0 0
a
Not evaluable
% cumulative incidence at age 70 (95%
CI)
lifetime risk of 8–38% and 4–20% respectively (Dominguez-Valentin et al., 2020).
The data for patients with PMS2 variants is insufficient to offer risk-reduction
surgery [104].
Women diagnosed with LS, without EC, should have the opportunity to be
reviewed by a gynaecologist around age 25 years regarding highlighting red flag
symptoms of cancer, risk reduction strategies i.e., hysterectomy as well as family
planning include pre-implantation genetic testing. The risk for endometrial cancer
rises sharply after age 40 years:
Prophylactic hysterectomy has the highest evidence base with 0% patients diagnosed with endometrial cancer after 13 years follow up compared with 33% of
patients who did not have a hysterectomy. It is important to coordinate both teams
(gynaecology and colorectal surgery) with timing of any surgical procedures. Clinicians should consider that usually LS related endometrial and ovarian cancers have
a good prognosis therefore the survival benefit is not high [105].
4.8.2 Considerations Post-surgery
If women are pre-menopausal, bilateral oophorectomy causes surgical
menopause – this can initiate vasomotor symptoms, vaginal dryness and atrophy
and resultant reduced sexual function, emotional lability and cognitive decline. It
can also increase the risk of cardiovascular disease, CRC and osteoporosis [106].
In this situation, women should be counselled about use of oestrogen replacement
which does not increase breast cancer risk and has a protective quality against
colon cancer. They may also benefit from review in a menopause clinic.
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4.8.3 Pathological Features of Gynaecologic Cancers
in Lynch Syndrome
There is an increased risk of both endometrial (EC) and ovarian cancer in LS
pathogenic variant carriers. Diagnosis of endometrial cancer is often the first or
‘herald’ cancer diagnosis in women with LS. Around 3% of women diagnosed
with endometrial cancer will have LS and 1–2% of those with ovarian cancer
[107]. The most common histological subtypes of gynaecological cancer in LS are:
endometrioid endometrial tumours [107] NICE recommends universal diagnostic
testing of new cases of EC, since October 2020 Ryan et al. [107]. This has been
assessed for economic viability and found testing women with endometrial cancer
for LS is cost effective however, some of the studies of clinical effectiveness of
endometrial cancer surveillance were excluded. They found that including MLH1
promoter hypermethylation testing with IHC for loss of MMR proteins was the
most cost-effective method [108].
4.8.4 Gynaecological Surveillance
Surveillance for gynaecological cancers in LS is controversial and many modalities have been explored, however most studies have been observational and there is
uncertainty regarding impact on survival [109]. Transvaginal ultrasound is unhelpful in pre-menopausal women due to cyclical change in endometrial thickness.
Endometrial biopsy via hysteroscopy carries morbidity (predominantly pain) and
these strategies have not conclusively reduced morbidity or mortality, often the evidence contradicts each other [104, 109]. Some countries, outside the UK, continue
to recommend endometrial biopsy.
Common symptoms of endometrial cancer include per vaginal bleeding leading
to diagnosis at an early stage. Of women who have had “surveillance” detected
endometrial cancer, many report to be symptomatic at the time [110].
Within familial ovarian cancer (including but, not exclusively LS) CA125 and
TVUSS screening improved outcomes in women with lifetime risk of > 10%
however, few LS cases were involved within this study [111].
There are emerging data evaluating cervical screening samples or urinary
metabolites [112, 113] however these have not yet been validated.
4.9 Role of Screening in Other Cancers
4.9.1 Upper Gastrointestinal (GI) Cancer Screening
The natural history of gastric cancer in LS is poorly understood and therefore
the role of precursors in this context is controversial. LS associated gastric cancer
has a preponderance towards intestinal type 60–80% cases, compared to poorly
differentiated or diffuse type 20–40% cases [114, 115]. Upper GI endoscopy is the
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Tab le 4.3 Variant specific
rates of gastric cancer
MLH1 21.8 (16–29.9) 11 (7.4–16.9)
MSH2 and EPCAM 19.5 (14–27.6) 12.8 (8.8–19.3)
MSH6 19.5 (14–27.6) 4.2 (1.2–26)
PMS2 3.6 (1–33.5)
Males Females %
clear choice for surveillance for UGI cancer which can allow recognition of earlier
stage disease [116], but is limited by the fact that, unlike colorectal, there rarely
are polyps or macroscopic evidence of cancer precursors that can be removed to
reduce incidence of cancer.
The original “Family G” found to have the MSH6 pathogenic variant noted
gastric cancer as the third most common cancer, after endometrial and colorectal,
noting incidence decreasing over the decades (Table 4.3). This is true for gastric
cancer within the general population which has shown decrease [117, 118], there
are also global variations in gastric cancer which may contribute to the varying
reported incidence within LS [119].
Lifetime risk of gastric cancer:
The German Consortium for Familial Intestinal Cancer evaluated use of upper
GI endoscopy in surveillance (1–3 yearly) for LS [120]. They reviewed endoscopies of 1128 LS patients. Early stage was recognised in 83% surveillance
patient’s vs 25% of those with symptoms and 28% of patients were diagnosed
aged less than 45. 68% of patients with gastric cancer did not have a family
history. Overall, they found gastric cancer in 2.3% of all patients and 0.93% of
endoscopies (all MLH1 or MSH2 variant carriers). This is relatively low rate of
diagnosis however, advanced gastric cancer has a poor prognosis and if combined
with a colonoscopic procedure under sedation, may be more acceptable to patients.
There is some opinion that surveillance may benefit certain groups however no
consensus on what classifies as high-risk, the frequency of surveillance or age of
initiation. NCCN and ESMO guidelines recommend a one-off gastroscopy at age
30–35 and subsequently every 2–3 years based on individual risk factors however,
the Mallorca group does not recommend ongoing surveillance [121, 122]. UGI
endoscopic surveillance is not yet recommended by the BSG or ESGE.
H. pylori
Diagnosing and treating H pylori infection reduces risk of gastric cancer in the general population [123, 124] and is recommended in the UK in the context of LS,
given that it is related to lifetime gastric cancer risk [125]. Rates of H. pylori in
LS do not differ from the general population and are not increased in patients with
family history of gastric cancer [126]. A South Korean study recruited patients
with a family history of gastric cancer (in first degree relatives) and infected
with H. pylori—1676 patients were randomised to receive eradication therapy or
placebo with primary outcome development of gastric cancer. Median follow up
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was 9.2 years, the hazard ratio for development of gastric cancer following eradication was 0.45 95% CI 0.21-0.94 p = 0.03, therefore demonstrating a marked
risk reduction [127].
4.9.2 Urological Cancer Screening; Urothelial and Prostate
Urothelial cancer screening
Urothelial cancer (UC) including urinary tract and bladder, is the third most common cancer in LS associated tumours (5%) [10]. The highest risk of urological
cancer is in MSH2 carriers (up to 73% of confirmed cases) [128] predominantly
with tumours of the lower urinary tract and bladder. Cancers of the upper urinary
tract are a small proportion (5%) of total cases of UC, however, often are invasive
and aggressive, of that proportion 20% are attributable to hereditary causes [129,
130]. In a study, patients without a known predisposition to cancer, 21% were
found to have underlying LS after diagnoses of upper urinary tract cancer [131].
The evidence around bladder cancer association with LS is less clear but is
more common in MSH2 carriers than the general population. Overall cumulative
risks for both upper urinary tract and bladder cancer in MSH2 pathogenic variant
carriers in men was 18.2% and in women 8.4% [132]. Outcomes are good with
5- and 10-year survival 93% and 81%, respectively, for LS-associated bladder
cancers.
Approaches for urological surveillance include urinalysis, CT scan (if patients
are on follow up for CRC) and cystoscopy (with retrograde pyelography). Other
recommendations include ultrasound, urine cytology and sediment in MSH2 mutation carriers beginning aged 40 and repeated every 1–2 years. However, there is
no proven effective approach. Several groups use urinalysis as it is cheap and
minimally invasive however, haematuria has high false positivity rates, leading
to invasive investigations and there is yet no evidence that this improves early
diagnosis or morbidity or mortality.
In the IMPACT study 828 men were recruited—644 with LS (MLH1, MSH2
and MSH6) the remainder were non-carrier controls—and MSH2 and MSH6 carriers had a higher incidence of prostate cancer when compared with age-matched
controls. The authors supported of targeted PSA testing [133], however there is no
data on improved outcomes.
4.9.3 Pancreatic Screening
Pancreatic cancer is linked to LS and is often diagnosed late with advanced stage,
limited treatment options and incurable disease status. There is no current recommended screening however, there is a study enrolling LS patients who have a
family history of pancreatic cancer in Europe called the EUROPAC study in which
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patients receive additional investigations if they fulfil certain criteria [134]. This
study includes multiple surveillance locations in the UK.
4.9.4 Diagnostic Testing Strategies Pan-Cancer Approach
Latham et al. evaluated 15,045 patients with more than 50 cancer types and found
that in patients where LS was found 50% of patients had tumours other than colorectal and endometrial [43]. This shows MSI-H or dMMR is predictive of LS in
atypical cancers and may support genetic testing for a wider range of patients with
an MSI-H/dMMR cancer (Table 4.4).
4.10 Lifestyle and Chemoprevention
4.10.1 Environmental/Lifestyle Modifiers in Lynch Syndrome
There is evidence of environmental and lifestyle cancer risk modifiers in
the LS population however healthy lifestyle advice should be provided to
people with LS. The mechanism of cancer development may be different
compared to sporadic CRC environmental and lifestyle factors. Identification
of these environmental modifiers may help us understand their contribution
to disparities between family members.
Most evidence for lifestyle-related cancer risk modification is in non-LS populations, however there is some direct evidence in this population which demonstrates
consistency with non-LS populations. Therefore, there is likely to be environmental modification or risk, and a healthy lifestyle may benefit people with LS.
Potential factors for which there is some direct evidence in LS include raised BMI
specifically in MLH1 carriers [135], high alcohol consumption and smoking. Diabetes and cholesterol were associated with an increased cancer risk in the general
population, and it appears this is also increased in LS [136]
In a study of 2042 pathogenic variant carriers across Australia, New Zealand,
Canada and the US [137] the levels of self-reported physical activity were collected
via validated questionnaire with results showing that comparing the lowest level
of physical activity with the highest level (equivalent to 10 h of brisk walking
per week) there was a 29% lower risk of developing CRC (HR 0.71; 95% CI
0.53-0.96).
Diet quality has also been assessed in LS patients using the Dutch Healthy Diet
index 2015 which showed no association between diet and development of cancer
[138]. Within this study 490 patients were included and during median follow up
of 53.4 months, 210 patients developed colorectal tumours (42.9%).
General lifestyle recommendations include healthy diet, with high fibre and
low-fat diet with inclusion of fruit and vegetables as well as increased resistant
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Tab le 4.4 Summary of recommendations for each cancer type
Cancer type Estimated lifetime risk
Colorectal 10–57 Regular colonoscopic surveillance;
Endometrial 12–49 Risk reducing hysterectomy > 40
Ovarian 3–17 Risk reducing BSO can be
Gastric 3–22 Surveillance: No proven benefit
Urinary tract 2–18 Surveillance: No proven benefit
Small bowel 3–22 Surveillance: No proven benefit
Pancreas 3–22 Screening in EUROPAC trial, no
Biliary tract 3–22 Surveillance: No proven benefit
Brain < 1–8 Surveillance: No proven benefit
Female breast 12–15 Surveillance: No proven benefit
Prostate 5–24 Surveillance: No proven benefit
Sebaceous adenomas/
carcinomas (skin)
Note lifestyle advice is reviewed separately
(gene-specific) [2](%)
1–9 Dermatologic surveillance is
Prevention strategies
beginning from age 25 (MLH1 and
MSH2) and 35 (MSH6 and PMS2)
Aspirin ≥ 2 years
Extended surgical resection may be
considered for high-risk genotypes
(with consideration of simultaneous
prophylactic hysterectomy + BSO)
(MLH1, MSH2 and MSH6)
No benefit: endometrial
surveillance
Progesterone?
considered
No benefit: ovarian surveillance
with UGI endoscopy, consideration
in individual cases
H. pylori testing and eradication
may reduce risk
Urine screening studies in process
but, so far yield many false
positives
with capsule endoscopy or other
modalities
routine surveillance
compared to general population
recommendations
compared to general population
recommendations
recommended but efficacy unclear
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starch such as plantain and green bananas. CAPP2 clinical trial resistant starch
had no impact on CRC risk but, there was evidence of benefit in non-CRC LS
cancers e.g., UGI tract there were 5 diagnosis on resistant starch compared with
21 in the placebo group [139].
There is little direct evidence on gynaecological cancer risk in the context of
LS but, maintaining a healthy diet, avoiding smoking, moderate alcohol intake and
regular exercise seem reasonable suggestions.
4.10.2 Pharmacologic Agents
Non-steroidal anti-inflammatory drugs, specifically aspirin have been studied in
the context of prevention of GI cancers (Fig. 4.17). They work by reducing
prostaglandin E2 levels which usually drives intestinal tumorigenesis, reduces
immune surveillance and interception of neoantigens from tumour cells [140].
Aspirin and CAPP clinical trials
Originally, a meta-analysis by Rothwell et al. reviewed the effect of long-term risk
reduction of daily aspirin cancer related risk of death [141, 142]. It is theorised
that as aspirin reduces inflammation by inhibition of the cyclooxygenase (COX)
pathways it inhibits both COX, COX-2 and COX-3, COX-2 is only expressed
in inflammatory states such as wound healing and inflammation. The COXs are
enzymes involved in synthesis of prostaglandins and TXA2 (major metabolite
promoting platelet aggregation).
Clinical trials from the Cancer Prevention Program (CAPP) review use of
aspirin as a preventative measure in patients with LS. Firstly, CAPP1 ran from
1999 to 2005 finding daily intake of aspirin 600 mg for two years, significantly
reduced rates of colorectal adenomas [139].
The CAPP2 trial between 1999 to 2010 assessed the long-term effect of aspirin
on cancer prevention in LS. Patients were randomised between aspirin or placebo.
Taking aspirin for 29 months reduced the rates of CRC by 44% after a follow
up of 55 months, the longer use of aspirin, the more protective the effect [143].
Extended follow up showed significant risk reduction with median treatment time
of 2 years. Aspirin may not provide additional benefit if taken for longer than
5 years and therefore patients may be advised to discontinue aspirin after this
period.
CAPP3 completed recruitment in 2019 and is a dose inferiority trial to offset
risks of treatment vs cancer prevention (Fig. 4.18). This initial trial data will report
in 2024, however given the lag period for the efficacy of aspirin the optimal dose
may not be clear for several years [144].
Largely based on evidence from CAPP2 NICE recommended that LS patients
take aspirin for at least 2 years to reduce long-term CRC risk.
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