Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / @xirurgi_2025 / @xirurgi_2025 - 926 - файл
.pdf
4 Lynch Syndrome 91
https://t.me/med1917
a b
c
Fig.4.12 a H&E staining of high-grade adenomatous lesion with suspicious glands surrounded
by stromal desmoplasia b MSH2 positive staining (brown colour) c PMS2 loss of staining (no
brown staining)
assessment for MLH1 promoter hypermethylation testing. BRAF V600E mutation
is present in approximately 65% of patients with dMMR CRC due to somatic
MLH1 promoter methylation, but rarely in those without methylation, and thus
may be used in CRC as a corollary test to exclude MLH1 methylation.
Therefore, either MLH1 methylation or BRAF testing may recognise which
CRC patients may have a somatic cause for their dMMR tumour and don’t require
genetic testing. These tests are done through histopathology or molecular pathology departments within hospitals and should be performed on reflex in dMMR
CRC with loss or MLH1 on IHC or where MSI is detected.
Mainstreaming
‘Mainstreaming’ refers to genetic testing provided by non-traditional clinical
genetics specialists, e.g., surgeons or nurses, which is now possible in the UK.
It is increasingly recognised to be the optimal route to diagnosis. In England the
GMSA National Lynch project has implemented a pathway in which mainstreaming of genetic testing in cancer patients can be provided by local MDTs to allow for
more efficient diagnostic pathways and referrals for patients [45]. These patients
can be managed within local cancer MDTs to receive genetic counselling, germline
testing (via next generation sequencing [NGS]) and receive results of this testing.
After the patient receives their genetic testing results, they can be reviewed by
specialist genetics services.
92 P. Edwards and K. J. Monahan
https://t.me/med1917
Pre-implantation genetic testing (PGT)
LS does not directly affect fertility however it is an autosomal dominant condition meaning carriers have a 50% chance of passing this on to their children
(Fig. 4.13). Due to this risk of transmission to offspring LS patients are eligible
for pre-implantation genetic test (PGT) by the Human Fertilisation and Embryology Authority (HFEA). This allows for embryo selection to avoid children being
affected by LS but, can be a demanding process which may not be suitable for
everyone [46].
Diagnosis of LS in other cancer types and the evolution of testing
LS can affect other organs, Latham et al. reviewed the prevalence of LS across
other solid tumours [43]. 15,045 patients received targeted NGS for MSI status,
germline DNA was also assessed for LS typical mutations. Over 50 cancer types
were included with LS identified in 16.3% of MSI-H, 1.9% of MSI-indeterminate
and 0.3% of MSS tumours (p < 0.001). Of patients diagnosed with LS, 50%
had tumours other than endometrial or CRC including pancreatic, adrenocortical,
urothelial, prostate, small bowel, sarcoma, mesothelioma, germ cell tumours and
gastric. 45% of these patients would not have achieved LS testing criteria based on
family/personal history. In patients with confirmed LS, IHC for dMMR was also
performed with a 98.2% concordance. These findings support genetic testing for
LS in dMMR solid tumours despite patients not fulfilling usual clinical criteria for
personal or family history.
The landscape, availability and technology of testing is rapidly evolving. Soon
there may be accessible and timely paired germline and somatic testing available
for patients. Once the pathway for counselling prior to genetic testing is established
this may negate the need for the current testing pathway [47].
Diagnostic prediction tools
These clinical information models have been created to help evaluate risk of
pathogenic variant and guide counselling regarding genetic testing and may have
sone utility in lower resourced settings:
1. MMRpredict
2. MMRpro
3. PREMM5.
Mercado et al. compared the performance of these prediction models in endometrial cancer cases and this was not found to be an effective prediction method over
IHC and MSI tumour testing [48].
MMRpredict has reported sensitivity and specificity of 94, 91% respectively
for MLH1/MSH2 carriers but is not validated for PMS2 carriers. MMRpredict and
PREMM5 were reviewed in a clinical cohort with a specific focus on PMS2 carriers which found neither of these models could predict PMS2 carriers, however
PREMM5 performed better when adding in location of cancer [49].
4 Lynch Syndrome 93
https://t.me/med1917
Fig.4.13 Autosomal dominant inheritance of pathogenic variant associated with LS. Created with
Biorender.com
Cascade testing
If a patient is diagnosed with LS, cascade testing should be offered to their adult
close relatives and before screening begins. These relatives will receive an ‘at
risk’ letter via the newly diagnosed proband suggesting that they be referred for
genetic counselling from primary care, however uptake of cascade testing is variable. Understanding and overcoming barriers to cascade testing is important to
help achieve this public health impact within this precision health intervention
94 P. Edwards and K. J. Monahan
https://t.me/med1917
[50]. Some methods employed by local services include involving GP of a relative
without identifying the proband, giving patients with letters to disseminate and
providing patients with contact details and resources. Given that a lifetime risk of
CRC can be as high as 70%; risk reduction is assisted by enrolling patients within
screening programmes with associated health economic benefits.
Globally, issues regarding medical insurance may be a barrier for predictive
testing. In the UK, a patient is not required to disclose predictive testing results
to their medical insurance provider. However, a patient may choose to do so if
the test results are in their favour, for example to prove they have not inherited a
familial condition.
4.4 Biology of Lynch Syndrome; Molecular Pathways
As LS is characterised by a monoallelic loss of MMR gene, when the second allele
is lost these cells are then dMMR. These dMMR cells accumulate a high frequency
of somatic mutations to drive tumorigenesis, notably insertion/deletion mutations
(indels) (Fig. 4.14). Indels may preferentially alter repetitive microsatellite (MS)
sequences where replication errors more frequently occur, albeit in the context of
dMMR these errors are not effectively repaired [17, 18, 51]. If these indels are
in coding sequence microsatellites (cMS) this results in errors in DNA replication
and generation of truncated frameshift peptide (FSP) neoproteins. Some of these
FSP neoantigens encompass neoepitopes to which the host immune system is naïve
[52].
Due to this high burden of FSP caused by indel mutations, there are distinct clinical and histopathological features in dMMR CRCs. The immune system
recognises these FSP mutation produced neoantigens as “tumour antigens” and
therefore there are increased tumour infiltrating lymphocytes (TIL), memory T
cells and improved survival compared to patients with low TIL CRC. Due to
the high mutation rates, there is overexpression of immune checkpoint proteins
(e.g., PD-1 and CTLA-4) [53, 54]. Therefore, dMMR tumours are susceptible
to immune checkpoint inhibition which enhances endogenous adaptive immunity
against tumour cells by recognising tumour antigens. The TILs present in MSI
tumours compared to MSS show reactivity specifically against FSPs [55]. There
is evidence that FSP specific T-cell reactivity is present in the blood of healthy LS
patients, representing the immune response to neoantigens that have been produced
and responded to, halting the development of a cancer.
Alongside this, when comparing local tumour advancement and stage, the rate
of metastasis is reduced compared with sporadic CRC, which is related to immune
regulation of dMMR cancers induced by FSPs [56].
4 Lynch Syndrome 95
https://t.me/med1917
Fig.4.14 Mismatch repair machinery, function in health T and G are a mismatch pair as it should
be C and G, this is recognised by the hMutS machinery and DNA strand containing the incorrect
nucleotide is excised and the gap is resynthesised by DNA polymerase using the remaining DNA
strand as a template subsequently replacing the incorrect T with a C. Created with Inkscape
4.5 Pathways to Carcinogenesis; Adenomatous
and Non-adenomatous
Whilst many LS associated tumours may be indistinguishable from sporadic
tumours there are unique pathways to CRC related to the biology of the disease
and molecular mechanism of dMMR cancer [57] (Fig. 4.15). Most (80%) sporadic
CRCs develop due to somatic initiating events in the APC gene however, in LS the
initiating event is dMMR which leads to cascade of distinct molecular and biological events in carcinogenesis including the changes of proliferation and regulation
of colonic crypts [58].
96 P. Edwards and K. J. Monahan
https://t.me/med1917
Fig.4.15 The three pathways to carcinogenesis in LS [57]. 1. pMMR adenoma to dMMR ade-
noma to carcinoma, 2. dMMR crypt focus to dMMR adenoma to carcinoma, 3. dMMR crypt focus
direct to carcinoma. Created with lucidchart.com
4.5.1 Cancer from pMMR Adenoma
The classical ‘sporadic’ adenoma to carcinoma sequence occurs over an estimated
17 years meaning that infrequent colonoscopy intervals may be adequate to reduce
future CRC risk within the general population [59, 60]. Some studies show a
slightly increased adenoma rate in LS compared to unaffected population [61].
One theory is that MMR gene deficiency does not increase numbers of adenomas
but, accelerates progression of pre-existing pMMR adenomas that have developed
via a sporadic pathway [62]. Supporting this is evidence of polyps in LS that retain
expression of MMR proteins [63]. In meta-analysis 76.3% of adenomas in patients
with LS are dMMR [57]. Conversely sporadic MLH1 promoter methylation is a
late event in carcinogenesis and thus adenomas are invariably pMMR in non-LS
patients.
The fact that LS adenomas may have an accelerated progression to cancer
implies biological difference [64, 65]. Most adenomas show lack of MMR protein expression in the dysplastic cells and even adenomas < 5 mm have high grade
dysplasia [66]. The hypothesis is that dMMR is an early event with other driving
mutations such as APC and KRAS occurring later [67, 68]. The analysis of different pathways comparing sporadic, and LS associated adenocarcinomas shows in
LS, APC mutations are frameshift mutations with small indels or changes at CpG
sites, different to sporadic adenomas. 75% of LS patients with APC mutations
were found to have “MSI features”, compared to 35% of those in MSS cancers.
When comparing these proportions, the rates of “MSI related” APC mutations are
consistent with suggested rates of adenomas in LS [67–69]. Most studies into adenomas can provide some information about the past events and pathways of these
adenomas but, do not in themselves help us understand how tumours progress to
cancer.
4 Lynch Syndrome 97
https://t.me/med1917
4.5.2 Cancer from dMMR Precursor, Adenoma
The presence of dMMR-crypt foci (dMMR-CF) in the colon indicate these as precursors. They have been found adjacent to dMMR adenomas and cancers [57]. In
literature review 491/640 dMMR adenomas appear to have more aggressive features with 50% of dMMR adenomas < 5 mm having high grade dysplasia [67].
MSH2 carriers appear to have the highest proportion of adenomas, and these may
be responsible for development of interval cancers as the cells become genetically
unstable earlier in the pathway, when compared to the adenoma to carcinoma
route [70]. Ahadova et al. evaluated the mutational profiles of interval cancers
when compared with prevalent cancers to identify signature findings showing
higher rates of dMMR related mutational events when compared with surveillance
detected lesions [71].
4.5.3 Cancer from dMMR Precursor, ‘Non-Polypous’ Route
There is evidence to suggest some cancers may arise from dMMR precursors
independent of adenoma or polyp formation. The sub-mucosal lesions which
can also be described as “immediately invasive” are associated with somatic
CTNNB1 mutations (up to 50% versus 20% adenomatous) which activate rather
than inactivate of APC (polypoid feature). The flat lesions are difficult to recognise
endoscopically, and this could explain the higher rates of interval cancers despite
high quality colonoscopy [see section on colonoscopy]. This has been described
as a ‘two-in-one hit’ when MLH1 pathogenic variant and somatic mutations in
CTNNB1 segregate, and this may account for up to 40% of the MLH1 CRCs [72].
Additionally, TP53 mutations were only found in cancers without polypous
growth [73].
MMR-DCF can be found in normal appearing, non-dysplastic mucosa of LS
carriers which is not present in CRCs that display MSI from sporadic cause. These
MMR-DCF contain mutations in microsatellites and display MSI. The crypts are
both macroscopically and microscopically unidentifiable unless staining for MMR
proteins is performed. A study from Italy in 2001 showed “aberrant crypt foci”
with evidence of dysplasia with increasing microsatellite instability in correlation with grade of dysplasia but these were small numbers [74]. There has been
recognition of morphologically normal MMR-DCF directly adjacent to adenomas,
suggestive of this being a true precursor. Given that there are many thousand
MMR-DCF in the large bowel of a patient with LS compared to the rates of
cancer which are relatively lower it is not clear the process or rate by which these
develop into cancer [58].
Most of the tumours studied were higher penetrant MLH1 or MSH2 mutation
carriers—further research needs to explore whether these pathways also exist in
MSH6 and PMS2 carriers (although data in small numbers of patients suggested
no CTNNB1 mutations [75]), and the relative contribution of each carcinogenesis
pathway in LS. The proportion of each carcinogenesis pathway varies between
98 P. Edwards and K. J. Monahan
https://t.me/med1917
populations and geographically with multiple modifiers, polygenic risk, dietary
factors and surveillance strategies. Exploring and leveraging these findings gives
weight to the focus of targets via FSP generated vaccines [section on vaccines]
and with chemoprevention [section on chemoprevention].
4.6 Role of Surveillance Colonoscopy
UK guidelines recommend 2-yearly colonoscopy for people with LS. This
should commence at age 25 for MLH1, MSH2 and EPCAM variant carriers,
and age 35 years for MSH6 and PMS2 variant carriers, with completion at
75 years. This may amount to 25 colonoscopies over the lifetime of people
with LS, and therefore patient experience, including management of comfort
is imperative. Non-compliance is associated with significantly inferior out-
comes. Colonoscopy may benefit people with LS either to prevent cancer by
detecting and removing early lesions, such as polyps and/or to detect cancer
at an earlier stage to improve outcomes and reduce morbidity and mortality.
There are LS-specific factors relating to disease biology and colonoscopic
quality which we review.
Within the general population polypectomy during colonoscopy reduces CRC risk
and improves patient survival by either early detection or prevention of CRC [76–
79]. It is reasonable to assume that within familial cancer syndromes such as
LS, there is benefit in performing colonoscopy despite differing mechanisms for
carcinogenesis.
In 2000, a Finnish controlled trial reported, spanning 15 years of surveillance,
with two groups of at-risk HNPCC patients. The screened group, n = 133, received
3 yearly colonoscopy and the unscreened group n = 119, received nothing. The
CRC rate and mortality was reduced by 62% with colonoscopy screening [80].
This is supported by several observational studies showing reduction in CRC incidence (OR 0.23, 95% CI 0.13-0.41) and relative clinical efficacy [81]. Data from
PLSD published in March 2023 studying 8500 patients over 10 years, showed
mortality rates were higher in non-colonic cancers, this may be, in part, related to
the effectiveness of screening colonoscopy [3].
4.6.1 Q uality Factors in Colonoscopy
Quality factors impact on colonoscopy surveillance in LS in specific ways, some
which may be extrapolated from non-LS data, and others more specific to LS
population. Colonoscopic quality can be measured through both operator- and
procedure-related indicators; these include adenoma/polyp detection rate, caecal
intubation rate, comfort/experience (in the LS cohort this is especially significant relevant due to high numbers of procedures required across a lifetime of
4 Lynch Syndrome 99
https://t.me/med1917
surveillance) and crucially, surveillance episode interval or post-colonoscopy CRC
(PCCRC).
Adenoma detection and removal is a surrogate for risk reduction of CRC
although this is predominantly derived from models utilising the classical adenoma
to carcinoma model of carcinogenesis [59, 60]. To standardise colonoscopy the use
of “adenoma detection rate” (ADR) has been used to review quality between centres [82]. ADR in all-comers is associated with reduction in PCCRC, advanced
stage cancer and cancer-associated mortality.
Nevertheless, there are specific issues regarding surveillance and the impact of
early detection and cancer prevention in LS. For example, there are higher proportions of flat (non-polypoid) adenomas in the proximal colon which may be difficult
to detect and benefit from careful inspection of the mucosa during colonoscopy,
and resection of such lesions may be more challenging [76, 83, 84]. As outlined earlier, there may be distinct molecular pathways in LS that account for
the development of submucosal CRC which may not be endoscopically detectable
[57].
Early data from Haanstra of 31 interval CRCs in 29 patients identified biological
and quality factors that contributed to interval CRC risk including 6/9 patients who
had previously had an adenoma detected, cancer found in same segment of colon
and 3 patients had a previous incomplete colonoscopy at the site cancer found [85].
A multi-centre study investigated the factors which reduced CRC detection rates
and evaluated the impact on colonoscopy quality indicators. This study evaluated
LS patients who had not previously had a diagnosis of CRC and included 893
patients [86] focusing on adenoma detection and PCCRC. Factors associated with
significant improvement in adenoma detection included adequate bowel preparation, complete colonoscopies and pan-chromoendoscopy use, this is concordant
with other studies [76, 83, 84].
There are higher rates of LS associated PCCRCs (appearing after a recent normal colonoscopy) [84]; cumulative incidence 45% MLH1 carriers, 35% MSH2,
20% MSH6 despite surveillance—compared with 9.3% (general population) [83].
Engel et al. [87] examined the interval between colonoscopy and subsequent cancer diagnosis and whether this was associated with pathological stage and found
they were not correlated. The reasons for this are unknown but, suggest that some
LS-related neoplasia may be recognised by immune surveillance and regress.
4.6.2 Advanced Imaging Techniques
Advanced imaging techniques including chromoendoscopy may improve recognition of flat lesions typical in LS [59]. Chromocolonoscopy is not recommended
in BSG guidelines [88], albeit is weakly recommended in the ESGE guidelines
[89, 90]. Randomised controlled trials did not find it offers advantage over highdefinition white light endoscopy, specifically when optimising adenoma detection
e.g., during a second pass using chromoendoscopy versus white light second pass.
A large Spanish RCT, ENDOLYNCH (n = 256) did not show significant increase
100 P. Edwards and K. J. Monahan
https://t.me/med1917
in adenoma detection rate with chromoendoscopy in LS patients OR 1.34 95% CI
0.79–2.28 [91]. This was supported by a Dutch study with similar adenoma detection rates using chromoendoscopy versus white light endoscopy [92]. However,
in some high-risk cohorts there is some evidence for benefit, e.g., multiple polyp
phenotype [88]. The risk of post colonoscopy CRC was significantly reduced if
performed < 3 yearly [82, 86, 93]. This may be confounded by population and
personal characteristics including time since last colonoscopy, pathogenic variant
distribution and extent of previous surgical procedures.
Given that most prospective studies on surveillance colonoscopy have been conducted in specialist centres, it is unlikely that technical limitations or interobserver
differences alone are responsible for the rates of incident cancer in this surveilled
population of LS patients. Early data has explored the use of artificial intelligence
(AI) to support and improve diagnostic accuracy in LS [94]. As the technology
develops there may be utility for optimisation with AI albeit it has not yet been
demonstrated.
4.6.3 Variables in Sidedness Affecting Ri sk Reduction
A population-based study (not selected by LS diagnosis) from Germany with 1688
CRC cases and 1932 controls reviewed how colonoscopy and polypectomy affects
survival. Overall having a colonoscopy in the previous 10 years was associated
with 77% risk reduction [76]. This was most effective in left sided lesions. The
only subgroup in which this was ineffective was 50–59 years on right side this may
be related to a more limited efficacy of colonoscopy to reduce cancers associated
with LS which tend to have a preponderance to being right sided and develop at a
younger age.
4.6.4 Frequency of Colonoscopy
People with LS are recommended to undergo 2-yearly colonoscopy, from age 25
for MLH1 or MSH2 carriers, and for MSH6 and PMS2 carriers this should be
started age 35 [88]. MLH1 and MSH2 carriers carry a higher lifetime risk of CRC
with median age of onset 45 and 44 respectively, whereas MSH6 and PMS2 carriers have a higher median age of onset 52 and 54 years respectively and a later
age of onset [95]. If there is a family member with exceptionally young onset of
CRC, then earlier commencement of surveillance can be individualised in specific
cases.
When deciding the optimal screening interval, the evidence indicates that intervals over 3 years are associated with increased CRC incidence however, the benefit
of shorter intervals of surveillance is not clear. The ‘3 Nations’ study, including
16,327 colonoscopies in 2747 patients was unable to find any significant reduction in CRC incidence or stage of detection with annual colonoscopic surveillance
between countries i.e., Germany annual surveillance, Netherlands which has 1–2
Соседние файлы в папке @xirurgi_2025