Lynch syndrome: clinical, pathological, and genetic insights

REVIEWARTICLE

Lynch syndrome: clinical, pathological, and genetic insights

Ralph Schneider & Claudia Schneider & Matthias Kloor &

Alois Fürst & Gabriela Möslein

Received: 25 January 2012 /Accepted: 27 January 2012 /Published online: 24 February 2012# Springer-Verlag 2012

AbstractIntroduction Lynch syndrome as the most common heredi-tary colorectal cancer syndrome and the most commoncause of hereditary endometrial cancer is characterized byan autosomal dominant inheritance with a penetrance of85–90%. The molecular genetic underlying mechanism isa mutation in one of the mismatch repair genes.Methods In order to identify patients with Lynch syndrome, anuclear family history should be ascertained and matched withthe Amsterdam criteria. A different approach for identificationis the adherence to Bethesda criteria and subsequent testingfor microsatellite instability. In patients with unstable tumorsas an indicator for mismatch repair deficiency, geneticcounseling and mutation analysis are warranted. For familiesfulfilling the Amsterdam criteria, intensified screening is rec-ommended, even if a pathogenic mutation is not identified.

Results Individuals from families with a proven pathogenicmutation that are tested negative are at normal populationrisk for cancers and may be dismissed from intensifiedsurveillance. Prophylactic surgery in high-risk individualswithout neoplasia is not generally recommended. At thetime of a colon primary, however, extended surgery shouldbe discussed in the light of a high rate of metachronouscancers. The worries of impairing functional results havenow been evaluated in the light of quality of life in a largeinternational cohort. Interestingly, extended (prophylactic)surgery does not lead to inferior quality of life with equalperioperative risks.Conclusions Therefore, taking the risk reduction intoaccount, extended surgery at the time of the first colonprimary should at least be discussed, if not recommended.Also, prophylactic hysterectomy and bilateral oophorecto-my at the time of a colorectal primary should be recommen-ded if family planning has been completed.

Keywords Lynch syndrome . Prophylactic surgery .

Mismatch repair genes . Genetic testing .MSI analysis .

Immunohistochemistry

Epidemiology

Colorectal (CRC), the most common malignancy in Europe,results as an interaction of genetic and environmental factorsand can be attributed to three risk categories: sporadic, famil-ial, and hereditary [1]. Sporadic CRC, which accounts forapproximately 70% of all CRC, originates from acquiredsomatic mutations over time and therefore is associated witholder age. Approximately 20–30% of all CRCs are classifiedas familial. Polymorphisms and low penetrance susceptibilityloci associated with an increased risk of CRC have beenidentified by genetic association and population studies inthese patients [2–4]. These genetic risk factors combined with

R. SchneiderDepartment of Visceral, Thoracic and Vascular Surgery,Philipps University,Marburg, Germany

C. Schneider :G. MösleinDepartment of General and Visceral Surgery,HELIOS St. Josefs-Hospital,Bochum-Linden, Germany

M. KloorDepartment of Pathology, University of Heidelberg,Heidelberg, Germany

A. FürstDepartment of Surgery, Caritas Hospital St. Josef,Regensburg, Germany

G. Möslein (*)Department of General and Visceral Surgery, Coloproctology,HELIOS St. Josefs-Hospital,Axstrasse 35,44879 Bochum, Germanye-mail: [email protected]

Langenbecks Arch Surg (2012) 397:513–525DOI 10.1007/s00423-012-0918-8

environmental factors lead to an increased risk of CRCobserved in particular families [5]. Thus, familial CRC canalso be characterized as a susceptibility with a classical mul-tifactorial inheritance. The third category of CRC—hereditaryCRC—accounts for approximately 5% of all CRC and ischaracterized by inherited, highly penetrant mutations [3, 5,6]. Lynch syndrome (LS), which accounts for approximately1–3% of all CRC [7–9] and also for 2% of all endometrialcancers [8], is the most common form of hereditary CRC. Thepopulation risk can only be estimated: approximately 6% ofall persons in Germany (80 million inhabitants) will develop aCRC which corresponds to 4.8 million inhabitants. If 2% ofthese are attributed to hereditary predisposition (a conserva-tive estimate), this would translate to 96,000 affected, insinu-ating that 1.2% of the general population would have apathogenic mutation. Taking into account a penetrance of65% for pathogenic mismatch repair (MMR) mutations(MSH2, MLH1, and MSH6), the frequency of MMR muta-tions would be 1.8% or 1:550.

Terminology

The first description of a family with a hereditary cancerpattern dates back to Aldred Scott Warthin in 1913 whodescribed the family of his seamstress. Henry T. Lynch laterfollowed up on this first family “G” and added observations offurther families, triggered by the consultation of a youngpatient with CRC in the absence of overt polyposis denomi-nating this observation “cancer family syndromes” [10–14].In 1985, the term “hereditary non-polyposis colorectal cancer(HNPCC)” was introduced emphasizing the heritable nature,the predisposition to CRC, and the absence of a widespreadpolyposis [15, 16]. In the following decades, HNPCC and“Lynch syndrome” have been used synonymously [17, 18].Today, there is an agreement on the terminology to classifyfamilies with an identified mutation in one of the mismatchrepair genes as LS, whereas other families fulfilling theBethesda or Amsterdam criteria (Tables 1 and 2) withoutmutation detection are denominated HNPCC [19, 20].

This overlap is a problem since as many as 40% of thepatients meeting the Amsterdam I criteria lack evidence of

hereditary deficiency in mismatch repair genes [21]. Onehundred sixty-one pedigrees fulfilling the Amsterdam I cri-teria were grouped according to the microsatellite instability(MSI) status. Patients with an MSI-high status which wasinterpreted as a surrogate for a germline mismatch repairgene mutation had a standardized incidence ratio for CRC inthe first-degree and second-degree relatives of the patientsof 6.1 and a statistically significant increased risk for thepresentation of LS-associated extracolonic tumors [21]. Incontrast, patients with an MSI-low status or a microsatellitestable tumor had a lower standardized incidence ratio of 2.3and had no increased risk for extracolonic tumors [21].

We strongly encourage the use of Lynch syndrome sincethe term HNPCC is misleading for several reasons [21, 22].HNPCC implies the absence of polyps, although studieshave shown that LS patients harbor similar numbers ofpolyps as the general population [23]. Moreover, the termfails to acknowledge the wide spectrum of frequent extrac-olonic cancers such as cancers of the endometrium, stom-ach, small bowel, ovary, pelviureter, and skin [24].

Clinical insights

Clinical features

LS is characterized by an increased cancer risk at a youngerage than in the sporadic counterpart (Table 3). In theGerman HNPCC Consortium, a total of 1,309 families withan identified mutation have been reported. MLH1 mutationcarriers have a lifetime risk (until age 75) for a CRC of80.1%, followed by a risk of 65.1% for MSH2 carriers. Therisk of CRC in MSH6 carriers in accordance to literaturewas significantly lower being 37.3%. Males have a higherlifelong CRC risk of 73% compared to females with a risk of59%. After 30 years, 54.3% of all CRC patients had devel-oped a metachronous CRC.

Younger age at diagnosis is typical for LS-associatedCRC with a reported mean age of CRC diagnosis rangingfrom 42 to 61 years [25, 26] as compared to 71 years in thegeneral population [27]. The mean age of endometrial

Table 1 Amsterdam I criteria [121]

1. CRC has been diagnosed in at least three relatives.

2. One of them should be a first-degree relative of the other two.

3. At least two successive generations are affected.

4. At least one CRC was diagnosed before the age of 50 years.

5. Familial adenomatous polyposis (FAP) has been excluded.

6. CRC are verified by histopathological examination.

Families must fulfill all criteria

Table 2 Amsterdam II criteria [17]

1. Lynch syndrome-associated cancer has been diagnosed in at leastthree relatives.a

2. One of them should be a first-degree relative of the other two.

3. At least two successive generations are affected.

4. At least one cancer was diagnosed before the age of 50 years.

5. Familial adenomatous polyposis (FAP) has been excluded.

6. Tumors are verified by histopathological examination.

Families must fulfill all criteriaa CRC, cancer of the endometrium, small bowel, ureter, or renal pelvis

514 Langenbecks Arch Surg (2012) 397:513–525

cancer diagnosis is reported to be 47–55 years in somestudies, which is younger than in general population [25,28, 29]. In contrast, others studies found a mean age ofendometrial cancer diagnosis of 62 years, which is the sameas in the general population [27, 30].

Although patients with LS have an earlier age of CRCdiagnosis, they have improved survival compared to spo-radic CRC. This could be demonstrated in a study fromFinland with a one third lower mortality of LS-associatedCRC [31]. In concordance, the 5-year survival rate of LS-associated CRC is reported to be 53% as compared to 35%for sporadic CRC [32]. This effect may be attributed to theobservation that LS-associated cancers have a much lowerdisposition to metastasize.

Further typical features of LS-associated CRC are the slightpredominance of cancers proximal to the left colonic flexureof 56–62% [33, 34] as well as the frequent presentation ofsynchronous and/or metachronous CRC. The frequency ofsynchronous CRC for LS is 18% and of metachronous CRCis 30% at 10 years and 50% at 15 years [35, 36]. In compar-ison, the risk for synchronous and metachronous CRC inpatients with sporadic CRC is 2–4% and 2–3%, respectively[32, 37]. An analysis of 1,381 tumors in LS families revealedCRC as the most frequent malignancy with 78% in MLH1mutation carriers and 65% in MSH2 mutation carriers. Asalready described above, there was a high number of right-sided CRC of 60%. Interestingly, the number of rectal cancerswas 21% in MLH1 mutation carriers and 20% in MSH2mutation carriers [38].

As the presentation of keratoacanthomas or sebaceousskin tumors such as sebaceous adenomas, sebaceous carci-nomas, or sebaceous epitheliomas is fairly common inpatients with LS, all patients with LS have to be consideredat risk for these skin tumors [39–41]. For patients with LS

and the presence of skin tumors, the term “Muir–Torresyndrome” is widely used [40–42].

Identification of patients at risk for Lynch syndrome

Unfortunately, an increased familial risk for cancers per se isnot frequently questioned or acknowledged in clinical (sur-gical) practice. In the event of a colorectal cancer or a cancerin one of the associated target organs, alertness for thecondition is pivotal. Since not all index LS patients areyoung, nuclear family history in all cancer patients mustbe obtained and documented, as a basis for selecting thosepatients. Genetic counseling and perhaps molecular testingshould be recommended. In a clinical setting, the nuclearpedigree suffices. Due to the structure of small families andsocial separation, reliable family information is restricted toclose relatives. If the nuclear pedigree detects a pattern ofhereditary susceptibility, an extended pedigree is essential(Fig. 1). To date, it is recommended to test for mismatchrepair deficiency [MSI or immunohistochemistry (IHC)] inneoplastic lesions from affected persons whenever possible.The Bethesda criteria have clearly been set up as a guidelineto decide when to perform this testing in order to thenrecommend mutation analysis for microsatellite instable ormismatch repair-deficient tumors in index persons. For sin-gle patients, that appear to have an underlying geneticpredisposition. The Bethesda Guidelines including patho-logical and morphological characteristics were published in1997 to detect patients whose tumors should be analyzed formicrosatellite instability [43]. In 2004, the revised BethesdaGuidelines were published (Table 4) [18] which have asensitivity of approximately 90% [7–9, 26, 44–48].

MSI testing can either be performed via PCR or muchmore economical in the immunohistochemical assessmentof loss of protein expression in one of the mismatch repairgenes (IHC) as a standardized procedure in pathologicalinstitutes. The additional benefit of IHC lies in the fact thatloss of expression in one of the genes pinpoints towards theunderlying gene disabled, enabling more directed sequenceanalysis. Due to economic constraints, it does not seenreasonable to test all patients with CRC as a non-directedgermline mutation detection exercise with costs involvingapproximately US $1,000 per gene with four genes requir-ing testing [24, 49]. However, since sequencing costs arerapidly decreasing and logistics rapidly evolving, it isenvisaged that broader testing will be available in the nearfuture at an affordable cost. Nevertheless, until today, theAmsterdam II criteria especially, taking associated extraco-lonic cancers into regards, have proven to be clinically mostvaluable in identifying LS families.

The Amsterdam II criteria (Table 2) were published in1999 [17]. However, many families with LS do not meetthese criteria due to small family size, late onset of the

Table 3 Cumulative lifetime risks for patients with Lynch syndrome[26–30, 39, 40, 122–127]

Cancer Lynchsyndrome (%)

Generalpopulation (%)

CRC—male 54–74 5CRC—female 30–52

Endometrium 28–60 2

Ovarian 6–7 1

Stomach 6–9 <1

Small bowel 3–4 <1

Pancreatic <1–4 1

Hepatobiliary 1 Rare

Urinary tract 3–8 Rare

Brain 2–3 <1

Sebaceous skin tumor/keratoacanthoma

1–9 Rare

Langenbecks Arch Surg (2012) 397:513–525 515

disease, young age of death due to other causes, or adoption[50]. Others reasons for reduced sensitivity may be non-

paternity, new mutations as well as reduced penetrance [18].Moreover, recording an accurate family history is often verydifficult in clinical practice since patients often have limitedknowledge of their family history [51–54].

Pathological insights

Histology

The first systematic histological evaluation of LS-associatedCRC revealed an increased incidence of mucinous cancersin 39% of tumors compared to 20% in sporadic controlswith more poorly differentiated tumors (24% versus 12%)[23]. Based on this observation, several tumor types andhistological features have been described to be common inLS-associated CRC.

Characteristic tumor types include mucinous cancer cellscomposed of more than 50%mucin and signet ring cell cancercontaining more than 50% signet ring cells [24]. The thirdmost common tumor types were medullary carcinomas [24].

Fig. 1 Pedigree of a Lynch syndrome family

Table 4 Revised Bethesda Guidelines [18]

1. CRC has been diagnosed before the age of 50 years.

2. Presence of synchronous, metachronous CRC or other Lynchsyndrome associated tumorsa, regardless of age.

3. CRC with MSI-H histologyb diagnosed in a patients who is less than60 years of age.

4. CRC diagnosed in a patient with one or more first-degree relativeswith Lynch syndrome associated tumor, with one of the cancersbeing diagnosed before the age of 50 years.

5. CRC diagnosed in a patient with two or more first- or second-degreerelatives with Lynch syndrome associated tumors, regardless of age.

Fulfillment of only one criterion necessary to warrant MSI testinga Endometrial, stomach, ovarian, pancreas, biliary tract, small intestine,brain tumors (usually glioblastoma in Turcot syndrome), sebaceous glandadenomas and keratoacanthomas in Muir–Torre syndrome, hepatobiliary,transitional cell carcinoma of renal pelvis or ureterb Presence of tumor-infiltrating lymphocytes, Crohn’s-like lymphocyticreaction, mucinous/signet ring differentiation, or medullary growth pattern


In all of these, neoplasia tumor-infiltrating lymphocytes,which largely consist of CD3/CD8 coexpressing cytotoxic Tcells and peritumoral lymphocytes have been a very commonfeature. These “Crohn’s-like” lesions are prominent nodularlymphoid aggregates at the infiltrating edge of the tumor [24,55–58]. A poor differentiation and tumor heterogeneity areadditional characteristic features of LS-associated CRC [23,33, 55–57, 59–64].

Immunohistochemistry

If a patient fulfills the Amsterdam or Bethesda criteria,testing for microsatellite instability via PCR or IHC stainingof the tumor is recommended [18]. A negative IHC in one ormore of the mismatch repair genes is caused by a geneticevent in the particular gene and is indicative for the defec-tive gene. As further described below, a large number of lossof expression is due to promoter methylation and not mis-match repair deficiency. Particularly for the other mismatchrepair genes, molecular genetic testing can be focused on thegene with the loss of protein expression [27].

However, 10% of patients with LS do not demonstrateloss of protein expression of the mismatch repair genes[65–67]. The reasons may be a lack of standardization infixatives of material, a varying ability in performing andinterpreting IHC staining results, and also differences in thestaining protocol (lack of expertise or standardization,insufficient protocol, historical blocks, and type of fixation)[68].

Genetic insights

Mismatch repair genes

The MMR system corrects errors in DNA replication. It is acombination of proteins, specifically MLH1, MSH2, MSH6,and PMS2, whereby MLH1 and PMS2 as well as MSH2and MSH6 work as partners at the binding site. A deficiencyin the MMR system leads to increased mutability in onco-genes and tumor suppressor genes, leading to the clinicalexpression (phenotype) of LS. The estimated 2–5% of allCRCs [26] are attributed to LS, although this may still be anunderestimate. MLH1 and MSH2 are the predominantlyinvolved genes notably leading to nonsense or frameshiftmutations.

The loss of function of the MMR system is not complete,since the second (wild type) allele further encodes intactMMR proteins. In malignant tumors in LS patients, thesecond gene is somatically mutated [69]. Adenomas in LSpatients demonstrate a complete loss of one of the MMRproteins in 66% of cases, with a higher percentage in prox-imal and larger adenomas [70].

Microsatellite instability

Microsatellites are repetitive DNA sequences throughout thewhole genome. Due to these frequent repetitions, micro-satellites are liable for errors during DNA replication—errors that are corrected by an intact mismatch repair sys-tem. Alterations in the length of the microsatellite sequenceslead to MSI. As microsatellites are also present in genesinvolved in the regulation of cell growth, their dysfunctionmay cause tumorigenesis. MSI-unstable tumors account forapproximately 15–20% of unselected CRC cases [59] andare the underlying pathogenic mechanism for the vastmajority of CRC in LS patients [71].

Testing for MSI (via PCR) requires a comparisonbetween healthy and tumor tissue due to individual variabil-ity of microsatellite size and can be performed in fresh aswell as in a formalin-fixed specimens. Criteria and panels todefine microsatellite instability-high (MSI-H), microsatelliteinstability-low (MSI-L), and microsatellite stable (MSS)were defined on two NCI workshops [18, 72]. However,to date, the clinical significance of MSI-L remains unclear.While MSI colon tumors generally have an overall betterprognosis [73], it is still unclear, whether they have a worseresponse to 5-fluorouracil [74, 75].

The domain of MSI testing is to prescreen for LSpatients. However, in the past years, IHC loss of proteinexpression in one of the known mismatch repair genesidentifies reliably the vast majority of unstable tumors at amuch lower cost. Additionally, this approach reduces theeffort of sequencing, since the gene that showed loss ofexpression can be prioritized for sequence analysis. Never-theless, it is necessary to distinguish clearly between LSpatients and patients with BRAF-V600 mutation.

Promoter hypermethylation/BRAF analysis

CRC evolves via three different pathways. Approximately85% of unselected CRC show chromosomal instability andconsecutive loss of genes like APC or p53 and are predomi-nantly microsatellite stable MSS. Only a minority of the MSItumors are due to inactive MMR genes caused by germlinemutation in LS [76, 77], called MSI pathway. Most sporadicMSI tumors follow the serrated pathway (approximately 12%of all CRC and 75% ofMSI tumors), characterized by biallelicloss of the MMR system, due to hypermethylation of thepromoter region of the MLH1 gene [78, 79]. Sessile serratedadenomas are regarded as precursor lesions for these sporadicMSI cancers [80, 81]. The serrated pathway accounts for up to30% of all CRC [82].

A characteristic feature of serrated pathway is methylationof cytosine–guanosine dinucleotides, so-called CpG islands.If located in the promoter region of genes, methylation causesdownregulation of the affected genes, leading to the so-called


CpG island methylator phenotype (CIMP) [83, 84]. Thehypermethylation affects tumor suppressor genes, characteris-tically MLH1, leading to inactivation and consecutively loss ofexpression in IHC. BRAF mutations are significantly associ-ated with CIMP or the serrated pathway [84]. The BRAF gene,encoding serine/threonine-protein kinase B-Raf, is involved incell growth signaling. BRAF mutations are known to be asso-ciated with different cancers, such as malignant melanoma(40–60%) [85], papillary thyroid cancer (45%) [86], recentlyalso in hairy cell leukemia (100%) [87] and in (MSI) CRC;almost in all cases caused by BRAF-V600E mutation [valine(V) in codon 600 was substituted by glutamate (E)].

The frequency of BRAFmutations in CRC ranges from 5%inMSS to 45% inMSI tumors [88]. BRAF mutations seem tobe associated with a deteriorated outcome in CRC, especiallyin combination with MSS tumors [74, 89, 90]. WhetherBRAF mutation status has an influence on the response tocetuximab remains unclear [91–93]. BRAF-V600E mutationsare common in sporadic MSI colorectal cancer (40–50%), butextremely rare in LS. Therefore, prior testing for BRAF-V600E mutations before sequence analysis is recommendedfor patients with a loss of MLH1 in IHC [94].

Limitations of molecular analysis

MSI testing has its merits as a prescreening for identificationof LS patients, with a reported sensitivity of close to 100%[76], but there are limitations. MSI is still not broadlyavailable and remains costly. In contrast, IHC is availablein all pathologic institutes and is a routine procedure alreadyfor several indicators of prognosis such as response toadjuvant treatment. Also, MSI does not indicate the specificMMR gene involved and further does not distinguish be-tween LS and sporadic MSI cancer arising from BRAF-V600E mutation. The main limitation of IHC testing is thehigh frequency of MLH1 loss in sporadic cancers due topromoter methylation, mostly in old patients.

The gold standard for demonstrating MMR deficiencyremains germline analysis with the identification of a clearlypathogenic mutation in one of the MMR genes. Homozy-gous mutations have been demonstrated and lead to delete-rious outcome at young age. As a standard, full genesequencing has been established for mutation detection innewly identified index patients, that either fulfill Bethesdacriteria and have shown MSI or loss of expression in one ofthe MMR proteins in neoplasia (Fig. 2) or were identifieddue to fulfillment of clinical criteria (Amsterdam criteria). Ifa pathogenic mutation was not identified after sequenceanalysis of four MMR genes (MSH2, MLH1, MSH6, andPMS2), LS cannot be ruled out. However, the opportunity ofpredictive testing for at-risk relatives cannot be offered, imply-ing that 50% of relatives are subjected to intensified screeningprocedures without having an elevated cancer risk.

Genetic counseling considerations for Germany

A new Genetic Diagnostics Act was introduced in Germanyin February 2010. As from February 2012, a new regulationentered into force, determining that special training forgenetic counseling is required—a regulation that affectssurgeons in their practice with hereditary conditions. Aformalized special training will become necessary in orderto perform genetic counseling in case of diagnostic or pre-dictive genetic examinations, for all physicians that are not aspecialist in human genetics (Facharzt für Humangenetik)(§10 Abs. 1 and 2 as well as §7 Abs. 1 and 3 GenDG).

In the absence of such special training courses, a transi-tional period of 5 years has been determined. Within thisperiod, any physician who counsels patients with geneticconditions is required to accomplish an online formalizedinterrogation. A voluntary preparatory class is being estab-lished, but to date, it is not in place.

We recommend formalizing the expertise for surgeonsthat are interested in hereditary conditions, especially sinceour knowledge regarding the recommendations towardsprophylactic surgery on one hand and identification ofunderlying genetic causes on the other is rapidly increasing.In the interest of good clinical practice and patients’ right toreceive adequate counseling prior to surgeries, this aspect isenvisaged to become important for daily surgical routine.After 2016, physicians will be required to absolve a72-h obligatory class prior to a knowledge test in order tolegally counsel patients with genetic conditions, accordingto §10 GenDG.

Screening recommendations

As illustrated in Table 5, LS patients require an intensifiedsurveillance not only for the substantial risk of CRC, butalso for a variety of extracolonic cancers, especially endo-metrial, gastric, and small bowel cancer among others.Recently, unpublished observations report a higher thanestimated rate of cancers of the bladder and breast. Severalguidelines regarding surveillance for LS mutation carriersrecommend slightly different surveillance programs. TheGerman S3 Guideline [95] in comparison with the recom-mendations of the Mallorca Group [96] (European branch ofInSiGHT; www.mallorca-group.eu), the EGAPP [97], andthe NCCN [98] recommendations are shown in Table 5.

Yearly versus two- or three-yearly colonoscopies has notshown any additional benefit to date. Interval cancers –referring to those metachronous cancers arising betweentwo scheduled screening colonoscopies – are the expressionof the biology of LS with a vastly accelerated adenomacarcinoma sequence. The benefit of yearly gastroscopies thathas been established due to a high frequency of gastric


http://dx.doi.org/10.1002/cncr.26500

cancer regardless of familial clustering for this condition hasnot yet been proven to be beneficial but continues to berecommended. Screening for endometrial cancer has beenupgraded towards the truly invasive recommendation ofyearly endometrial biopsies. Since then, more women haverequested prophylactic hysterectomy, which has been rec-ommended as the procedure of choice for women aftercompletion of family planning elsewhere.

Surgical recommendations

Despite regular surveillance, the relative risk ratio of devel-oping cancer (CRC, endometrial and ovarian cancer) is 5.8compared with a mutation negative cohort in a setting withcolonoscopy, transvaginal ultrasound, and endometrial bi-opsy every 2 or 3 years [99]. The rate of interval CRC in thisstudy was 12.4% in 11.5 years, whereas in a Dutch cohort ofLS families with colonoscopy every 1–2 years, the rate ofinterval CRC was 6% in a 10-year follow-up. In a Germanstudy, 19 of 43 interval cancers occurred after a normalsurveillance colonoscopy within the recommended intervalof 12 months. Therefore, the option of extended resection asa subtotal colectomy with an ileosigmoidal anastomosismust be addressed [100].

Despite the high rate of metachronous colon cancers, inguidelines to date, at the most, there is the view of equipoise

regarding the recommended extent of colonic resection (onco-logic segmental versus prophylactically extended subtotal re-section) at the time of first colon cancer. The high risk ofmetachronous cancer after segmental resection must beweighed against a facilitated surveillance (sigmoidoscopy ver-sus colonoscopy) and a supposed worse functional outcomeafter subtotal colectomy [100–102].

Results from a large international study demonstrate anequal postoperative quality of life after subtotal colectomycompared to segmental resection (Schneider et al. “Qualityof life (QOL) in LS patients with colon cancer”, in prepara-tion) showed no impairment after extended (prophylactic)colonic resection. The authors carefully recommend subtotalcolectomy in LS patients at the time of their first coloncancer.

In biopsies of colorectal cancer, MSI can be identified with100% sensitivity and specificity [103]. In colorectal adeno-mas, a combination of MSI and immunohistochemical assaydetects pathological findings in 73% of LS patients [104]. Itmay be concluded that preoperative assessment of colon can-cer patients with suspected LS is easy to perform and hasmajor implications for patients’ right for knowledge andextensive information prior to surgery (Fig. 2). Not taking anunderlying genetic predisposition into regard that may influ-ence therapeutic decisions could be regarded as an offenseagainst patients right “Patientenrechtegesetz” (BürgerlichesGesetzbuch, §630a, Absatz 2). Also, the guidelines of the

Fig. 2 Strategy for CRC patients with a suspected MMR gene defect


Mallorca Group [96] and others have clearly claimed the needof discussing the option of prophylactic hysterectomy andsalpingo-oophorectomy at the time of abdominal surgery,especially after completion of family planning or olderage.

Effects of aspirin on colorectal neoplasia

Aspirin is known to act as a preventive agent in the devel-opment of sporadic CRC, merely the weighing of this ben-efit versus side effects of the medication impedes the generalrecommendation towards aspirin intake. In a recent meta-analysis of long-term data from five randomized trials ofcardiovascular prevention, aspirin reduced the 20-year riskof colorectal cancer-associated mortality by 35% [105].Overall, only two aspirin studies published failed to dem-onstrate a cancer preventive effect, one of these being theWomen’s Health Study [106]. The interval of aspirin admin-istration has been argued to be more influential on this effectthan the actual doses (daily versus every second day). Insummary, aspirin studies appear to correlate the overallintake of aspirin with a long-term benefit in cancer preven-tion. However, to date, prospective randomized trials withcancer prevention as an endpoint have not been pursued.

The Colorectal Adenoma/Carcinoma Prevention Programme2 (CAPP2) study of aspirin in LS was designed as such a trial.In CAPP2, 937 carriers of LS were randomly assigned to fourgroups in a two-by-two factorial design: high-dose aspirin(600 mg daily) plus resistant starch placebo, resistant starch(30 g) plus aspirin placebo, aspirin plus resistant starch, oraspirin placebo plus starch placebo. The initially reportedanalysis (after a mean 29 months on treatment) suggested thataspirin or resistant starch, or both, did not reduce the risk ofcolorectal neoplasia (adenomas plus colorectal cancer). Burnet al. now most recently reported the long-term (mean56 months) follow-up analysis in 861 individuals. Contrastingstrikingly with the short-term findings, colorectal cancer (notcombined with adenoma) developed in fewer patients withaspirin (4%) than in those on aspirin (7%, hazard ratio 0.63,95% CI 0.35–1.13, p00.12) in an intention to treat analysis;for participants completing 2 years of intervention, the hazardratio in a per protocol analysis was 0.41 (95% CI 0.19–0.86,p00.02). This effect is as preventive for CRC as the yearlycolonoscopies recommended as a screening measure! Also,aspirin reduces approximately 50% of all extracolonic cancersassociated with LS [107]. This study arguably supports moregeneral recommendations to consider aspirin for prevention ofcolorectal cancer in the context of individualized risk–benefitassessments.

The authors recommend intake of low-dose aspirin forLS patients, taking into account the risk–benefit of aspirinversus expected side effects. It is to be expected that theseT

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compelling results will eventually find integration in guide-lines for LS patients.

The use of vaccines in the prevention of colorectal cancer

A typical feature of LS-associated CRC is pronouncedinfiltration with immune cells [108, 109]. This suggestedearly that the host’s antitumoral immune response plays animportant role for the comparatively favorable prognosis ofLS-associated CRC patients [110, 111]. Studies on the anti-gen specificity of the observed immune responses identifiedMSI-associated antigens [112, 113]. These frameshift pep-tide (FSP) antigens directly result from mismatch repairdeficiency-induced frameshift mutations affecting codingmicrosatellite-bearing genes, like TGFBR2, TAF1B, AIM2,and others, and readily elicit antigen-specific cellular andhumoral immune responses of the host [114, 115]. Recentstudies suggested that FSP antigens are promising targets fornovel therapeutic approaches in MSI-H colorectal cancerpatients. Moreover, prophylactic vaccination with FSP anti-gens may be applicable for cancer prevention in LS mutationcarriers in the future. A clinical trial evaluating vaccinationwith FSP antigens has recently been initiated.

Initiation of a surgical Lynch syndrome database

LS is one of the most frequent monogenetic heritable con-ditions, leading to a high rate of colorectal cancer. Unfortu-nately, even to date, most index persons that lead topredisposed families are identified at the time of a colorectalcancer. However, patients are largely underidentified due toa lack of knowledge and understanding of the significanceof the predisposition.

In order to improve awareness and identify and counselmore patients with the hereditary conditions, a surgicalnetwork has been initiated. Patients at the time of theircancer should be counseled clinically and be embedded ingenetic counseling and testing. More information may befound at www.indexfam.de.

Clinical overlap with other predisposing syndromes(FAP + MYH-associated polyposis)

Biallelic germline mutations in the mutY human homologue(MYH) gene lead to the autosomal recessive MYH poly-posis. MYH plays a key role in base excision repair ofdamages caused by reactive oxygen species [116]. MYHdeficiency leads to somatic C:G –>T:A transversions result-ing in deficient APC and K-ras genes [117]. The clinicalfeature shows a polyp burden of less than 20 to more than100 polyps predominantly located in the proximal colon.The age at diagnosis varies widely with a mean of about

45–55 years. The colorectal cancer risk is estimated of about80% by the age of 70 [118]. Clinically polyposis syndromeswith a low polyp burden and LS are difficult to differentiate.Increased awareness of an underlying hereditary condition iswarranted and genetic counseling is recommended forpatients with multiple polyps. For identification, it is impor-tant to acknowledge that two to three or five synchronouspolyps should be added to the number of polyps at subse-quent colonoscopies.

Due to the recessive nature of MYH polyposis, about1–2% of the general population harbors a deleterious muta-tion of the MYH gene [119] with obviously only a slightlyincreased risk of developing colorectal cancer [120]. Therisk to develop MAP for children of a patient affected withMAP is, assumed a healthy patient’s partner, negligible, butall children are obligate carriers.

Conclusions

The molecular clinical, pathological, and genetic back-ground of LS is well known. Due to this fact, predictivegenetic testing is possible and prophylactic surgery is arecommendable option at the time of colon cancer. Toidentify patients with LS, a high clinical awareness is war-ranted. Therefore, the knowledge of a detailed family histo-ry and the correlation with the Amsterdam I and II criteria aswell as with the Bethesda guidelines is essential.

Conflicts of interest GM has received a fee as speaker at a Bayerworkshop in 2010.

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Lynch syndrome: clinical, pathological, and genetic insights

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