Hereditary non-polyposis colorectal cancer: The rise and fall of a confusing term

Abstract

The term Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is a poor descriptor of the syndrome described by Lynch. Over the last decade, the term has been applied to heterogeneous groups of families meeting limited clinical criteria, for example the Amsterdam criteria. It is now apparent that not all Amsterdam criteria-positive families have the Lynch syndrome. The term HNPCC has also been applied to clinical scenarios in which CRCs with DNA microsatellite instability are diagnosed but in which there is no vertical transmission of an altered DNA mismatch repair (MMR) gene. A term that has multiple, mutually incompatible meanings is highly problematic, particularly when it may influence the management of an individual family. The Lynch syndrome is best understood as a hereditary predisposition to malignancy that is explained by a germline mutation in a DNA MMR gene. The diagnosis does not depend in an absolute sense on any particular family pedigree structure or age of onset of malignancy. Families with a strong family history of colorectal cancer that do not have Lynch syndrome have been grouped as ‘Familial Colorectal Cancer Type-X’. The first step in characterizing these cancer families is to distinguish them from Lynch syndrome. The term HNPCC no longer serves any useful purpose and should be phased out.

Key Words: Hereditary Non-Polyposis Colorectal Cancer, Colon, Cancer, Hereditary

INTRODUCTION

A fundamental concept in the successful practice of medicine is the recognition of a disease as a distinct entity defined by a clearly recognizable set of clinico-pathological features. Only by recognizing and diagnosing a specific disease is it possible to develop and apply an effective policy of disease management. The recognition of a distinct clinico-pathological entity does not depend on a full understanding of the underlying etiology providing that the appearance and natural history of a disease are sufficiently characteristic to set it apart from all other diseases. Many forms of cancer would fall into this category. The same arguments apply to complex syndromes, though many of these are in fact explained on the basis of a specific and heritable genetic abnormality.

A good example of a hereditary cancer syndrome due to a single gene defect is the autosomal dominant condition familial adenomatous polyposis (FAP) caused by germline mutation of the tumor suppressor gene APC[1]. For many years Henry Lynch and associates drew attention to a second form of familial colorectal cancer (CRC)[2,3]. Initially, this was believed to encompass two separate syndromes. LynchIsyndrome (or Hereditary Site-Specific Colon Cancer) applied to families with colon cancer only, while Lynch II syndrome (or Cancer Family Syndrome) included families with extra-colonic malignancies in addition to colon cancer. In 1985 Lynch introduced the term ‘hereditary non-polyposis colorectal cancer’ (HNPCC) to encompass Lynch syndromesIand II[4]. In 1991 there was further unification with the inclusion of the Muir-Torre syndrome (CRC with associated sebaceous neoplasms) within HNPCC[5]. Lynch viewed HNPCC as a syndrome characterized by an autosomal dominant pattern of inheritance, early onset of malignancy with a predilection for the proximal colon, multiple CRCs, the absence of premonitory lesions (e.g. adenomas), and the occurrence of cancer in certain extracolonic sites, notably endometrium and ovary.

The concept of a second major form of familial CRC to rival FAP was received with general skepticism, being either ignored, dismissed as an exceedingly rare disease or the chance clustering of a common disease, or interpreted as the result of a shared environmental exposure[6]. A breakthrough came with the publication of a series of clinico-pathological investigations conducted in Finland that fully supported the observations of Lynch[7,8]. It was also shown that CRCs associated with HNPCC had particular histological features[9,10]. These included poor differentiation, abundant mucin secretion and marked lymphocytic infiltration. Additionally, CRCs developed within adenomas and it was inferred that HNPCC adenomas were more likely to undergo malignant transformation and within a shorter timeframe than conventional adenomas[9,11,12].

By the 1990s, cancer family clinics and registries for hereditary malignancy were beginning to collect and describe families with the features identified by Lynch and others. In order to standardize clinical and basic research it was suggested in 1991 by the International Collaborative Group on HNPCC that families should only be described as having HNPCC if they met strict criteria, known as the Amsterdam criteria (Table 1)[13]. Initially it was thought that the Amsterdam criteria would be highly specific for HNPCC. Nevertheless, the term HNPCC and the associated diagnostic criteria soon generated problems and confusion that have continued to this day.

Table 1 Amsterdam I and II criteria and Bethesda (revised) guidelines.

Term	Criteria	Reference
Amsterdam I1	Three 1st degree relatives with CRC	Vasen et al, 1991[13]
	Two generations affected
	One family member below age 50 yr
	Exclude familial adenomatous polyposis
Amsterdam II1	As for Amsterdam I except that CRC may be substituted by cancer of endometrium, small bowel, or pelviureter	Vasen et al, 1999[14]
Bethesda (revised)2		Umar et al, 2004[44]
1	CRC below age 50 yr
2	Multiple CRC or HNPCC-related cancers3
3	CRC with MSI-related histology4, < 60 yr
4	CRC or HNPCC-related cancer in at least one 1st degree relative, < 50 yr
5	CRC or HNPCC-related cancer in at least two 1st or 2nd degree relatives, any age

¹All criteria must be met;

²Any criterion (1-5) can be met;

³Includes cancer of endometrium, small bowel, pelviureter, biliary tract, stomach, ovary, pancreas, and brain (mainly glioblastoma multiforme);

⁴Tumor infiltrating lymphocytes, Crohn-like reaction, mucin/signet ring cell differentation, medullary growth pattern.

THE TERM HNPCC

The term HNPCC implies a familial aggregation of CRC developing in the absence of polyps. However, patients with HNPCC have adenomas that may sometimes be multiple and frequently present with extra-colonic malignancy. For example, a patient with HNPCC could present with endometrial cancer, multiple adenomas and no family history of cancer. By restricting the Amsterdam criteria to CRC, it rapidly became evident that the criteria lacked sensitivity. The Amsterdam II criteria (Table 1) were developed to allow particular cancers that presented in extra-colonic sites to be substituted for colorectal cancer, notably of endometrium, small intestine and pelviureter[14]. When the genetic mechanism underlying HNPCC was eventually discovered (see below) it became apparent that even the Amsterdam II criteria lacked sensitivity. Clinical definitions were therefore relaxed in a variety of ways in different geographical regions in order to avoid missed diagnoses[15-18]. Indeed, single instances of HNPCC might be found as a consequence of new mutation, non-penetrance within small families, denial of family history, non-paternity, or adoption. These new definitions of HNPCC were not used merely to standardize research but were also employed as diagnostic tools for labeling families as having HNPCC. In summary, the term HNPCC was not only a misleading descriptor but came to encompass multiple clinical definitions while nevertheless being applied to families as a specific diagnostic label.

DNA MISMATCH REPAIR

In 1993, soon after the introduction of the Amsterdam criteria, the underlying mechanism for HNPCC was discovered. Most examples were shown to be caused by germline mutation in one of two DNA mismatch repair (MMR) genes: MSH2 or MLH1[19-22]. MSH6 was implicated less frequently but showed a stronger association with endometrial cancer[23]. The MMR genes were shown to be tumor suppressor genes. Following inactivation of the wild-type allele, MMR proteins would no longer be expressed resulting in a failure to repair DNA mismatches occurring as spontaneous errors during DNA replication[24]. This failure applied most particularly within non-encoding tracts of repetitive DNA called microsatellites but could also disrupt tumor suppressor genes with short repetitive tracts within their encoding regions, for example (and in decreasing order of frequency) ACVR2, PTHLH, TGFbetaRII, MARCKS, MSH3, TCF4, RAD50, CASP5, BAX, RIZ, MBD4, MSH6, BLM, IGF2R, PTEN, AXIN2, WISP3 and CDX2[25]. Deficiency of MMR therefore resulted in the distinct phenotype described as the mutator phenotype or, more specifically, as DNA microsatellite instability (MSI)[26,27].

In addition, therefore, to its distinctive clinico-pathological features, the diagnosis of HNPCC could now also be suggested through the demonstration of DNA MSI and/or through the loss of expression of DNA MMR proteins, once monoclonal antibodies to these proteins became commercially available[28,29]. The corollary that MMR deficiency was a specific biomarker for the syndrome was not however correct[30]. This is because one of the DNA MMR genes, namely MLH1, may be inactivated through hypermethylation of its promoter region[31]. Through this acquired epigenetic mechanism most CRCs with MSI present sporadically and not as a result of a germline mutation. Nevertheless, in families with the clinico-pathological features of HNPCC, the demonstration of MMR deficiency in one or more tumors is a very strong indicator of a germline mutation in a MMR gene (though not 100% specific, see below). In summary, it was now possible to precisely demarcate and therefore diagnose HNPCC on the basis of the distinctive combination of clinical, pathological and molecular phenotype.

LACK OF SPECIFICITY OF CLINICAL CRITERIA FOR HNPCC

It was initially assumed that the Amsterdam criteria would be highly specific but not necessarily sensitive for HNPCC. However, the advent of testing for MSI showed that this assumption was not correct. In families meeting the Amsterdam criteria but in which CRCs did not show evidence of MSI, the classical clinical and pathological features of HNPCC were lacking[32]. Compared with Amsterdam criteria families in which CRCs showed MSI, the non-MSI-positive families comprised fewer affected subjects and CRCs were less likely to be proximally located, show mucinous or poor differentiation, be associated with positive lymph nodes, or have diploid DNA content[32]. CRCs were also less likely to be multiple or to present at a young age[32]. Additionally, when subjects from non-MSI-positive families were colonoscoped, they were more likely to have adenomas but the adenomas were less likely to be advanced than in MSI-positive families[33]. Despite these different clinicopathological findings, families continued to be diagnosed as having HNPCC merely on the basis of meeting the Amsterdam or similar clinical criteria[34-36].

At this point the question arises whether the term ‘HNPCC’ is the most appropriate label for a specific hereditary cancer syndrome caused by a germline mutation in a DNA MMR gene. Henceforth, for the purposes of this discussion and in accordance with a recent suggestion[6], the term ‘Lynch syndrome’ will be applied to the specific form of hereditary malignancy caused by germline mutation of a DNA mismatch repair gene. The term ‘HNPCC’ will be used merely to indicate that certain clinical criteria suggestive of a hereditary basis for CRC (excluding FAP) have been met. Families meeting one of the several clinical definitions of HNPCC may or may not have Lynch syndrome. There are three reasons why families may meet the Amsterdam criteria and yet not have the Lynch syndrome. In the first place, CRC is a common disease. Within a large sibship the finding of two affected siblings and one parent with CRC could occur by chance, even when one subject was diagnosed with CRC at the age of 49 years. Indeed, one would be appropriately skeptical of the diagnosis of Lynch syndrome if the other two affected subjects were diagnosed in their seventies or eighties. The labeling of a family with the diagnosis of Lynch syndrome on the basis of the preceding findings would be unwise, even though no ‘rule’ is being broken. A second reason is the possible clustering of low- or intermediate-risk genes within a family. The third reason is the possibility of family clusters occurring through known (e.g. attenuated FAP[37] or MYH polyposis[38]) or unknown high-risk genes. Although the lack of specificity of the Amsterdam criteria was first mooted in 1995[32], recognition that families meeting the criteria are clinically heterogeneous has come about only comparatively recently. For example, four recent studies have highlighted the lack of features of Lynch syndrome in Amsterdam criteria positive families that lack evidence of DNA MMR deficiency[39-42]. Features of particular note are the older age of onset of CRC, the reduced penetrance among relatives, the lack of predilection for the proximal colon, the lack of lymphocytic infiltration, the lack of extra-colonic malignancies, and the higher frequency of colorectal adenoma[39-42].

DIAGNOSIS AND MANAGEMENT OF LYNCH SYNDROME

The discussion above has outlined how over the last decade the Amsterdam or similar clinical criteria have often been the mainstay in reaching a purported diagnosis of Lynch syndrome. While larger, multi-case families with the classical spectrum of early onset colorectal and extra-colonic malignancies were probably diagnosed correctly in most cases using this approach, the diagnosis is less likely to have been correct in families meeting only the minimum set of clinical criteria. The effective management of Lynch syndrome includes informing and counseling affected and at-risk subjects, but this can only happen after the correct diagnosis has been reached and not before. Fortunately, a reliable working diagnosis of Lynch syndrome can usually be reached through the analysis of tissue samples prior to the discovery of a pathogenic germline mutation. Apart from confirming the diagnosis of cancer, evaluation of tissue samples provides both morphological and molecular evidence of tumorigenesis driven by defective DNA mismatch repair, the molecular hallmark of Lynch syndrome. The use of immuno-histochemistry to detect loss of expression of DNA MMR proteins can even identify the likely genetic cause and thereby simplify the ultimate diagnostic step of genetic screening[28,29].

As noted above, the Amsterdam criteria were established to provide a standard definition of HNPCC presenting within the setting of high-risk cancer family clinics and registries. The Bethesda guidelines were developed as a guide for testing MMR status in CRCs that presented in the population setting (Table 1)[43,44]. Family history, age at onset of malignancy, and pathology features were utilized as independent markers and in a way that would not only identify new cases of possible Lynch syndrome but would also exclude late-onset CRCs with MSI. The latter would in most instances be sporadic MSI-positive CRCs explicable by age-related methylation of MLH1. On this basis, the utilization of the Bethesda guidelines in order to diagnose Lynch syndrome should be more sensitive than the Amsterdam criteria and, through the inclusion of MMR testing within the algorithm, more specific[45,46].

The Bethesda guidelines highlight the importance of pathology review. This has not always been used in achieving a diagnosis of Lynch syndrome despite the fact that the attempt to arrive at an exclusively clinical definition of Lynch syndrome has been described as a ‘search for the impossible’[47]. There are three reasons for this over-reliance on limited clinical features: (1) The Amsterdam criteria were initially thought to be highly stringent and therefore specific for Lynch syndrome, (2) It is easier and cheaper to reach the diagnosis using clinical features alone, and (3) It has been argued that both MSI testing and immuno-histochemistry are genetic tests that should not be undertaken without the consent of the patient. With respect to the last, MSI testing and immuno-histochemistry are diagnostic tests capable of demonstrating an acquired and tumor-specific alteration that is indicative of but not conclusive with respect to germline status. Mismatch repair deficiency may be acquired exclusively at the somatic level, for example through methylation of a DNA mismatch repair gene (see above). Like all diagnostic tests of tumor phenotype, the results of MSI testing do not stand alone but must be interpreted in the light of all the available clinical and pathological features.

Because the term HNPCC was introduced as an alternative to the eponymous Lynch syndrome before that condition was fully characterized and explained on the basis of a set of genes with closely related function, it came to be applied in an overly broad sense to any form of CRC that appeared to be inherited but was not FAP (or the other rarer precancerous polyposes). However, it is not possible to use a term that has different and mutually exclusive meanings without generating confusion. The following two sections describe additional scenarios in which the term HNPCC (implying Lynch syndrome) has been used inappropriately.

GERMLINE HEMI-ALLELIC METHYLATION OF MLH1

Extrapolating from the Bethesda guidelines (see above), an early-onset CRC that shows MSI is likely to occur in the setting of Lynch syndrome. In 2002, Gazzoli et al identified an early onset CRC in which one MLH1 allele showed methylation[48]. Intriguingly, the same allele was also methylated in the subject’s lymphocytes. By elegantly exploiting the existence of a common polymorphism in the promoter region of MLH1, Gazzoli et al were able to show that the second or wild-type MLH1 allele had been lost in the CRC. They therefore introduced the concept of germline hemi-allelic methylation of MLH1 as a cause of HNPCC[48]. However, they were skeptical of the possibility that a methylated allele could be transmitted vertically from an affected subject to offspring and suggested that the phenomenon was both rare and sporadic. Miyakura et al discovered four additional examples of early onset MSI-positive CRC associated with germline hemi-allelic methylation of MLH1[49]. Although the patients were ascertained through cancer family clinics they did not have family histories suggestive of Lynch syndrome. They were merely young and some were affected with multiple tumors consistent with Lynch syndrome. Again, Miyakura et al did not infer that germline hemi-allelic methylation of MLH1 could be transmitted vertically[49].

Suter et al arrived at a different conclusion with respect to germline hemi-allelic methylation of MLH1 (which they termed ‘epimutation’)[50]. They documented two additional subjects carrying an MLH1 epimutation who also met clinical criteria indicative of a diagnosis of HNPCC. Additionally, the epimutation was present in spermatozoa of one of the affected subjects. The latter finding was not only consistent with a germline defect but also provided evidence for transmission of the defect to offspring. The authors therefore advanced the concept of MLH1 epimutation as a new cause of HNPCC (implying Lynch syndrome) in which there was vertical transmission of a methylated MLH1 allele[50]. Nevertheless, it may be questioned if epimutations can in fact be inherited. While germline hemi-allelic methylation was indeed demonstrated in single members of two families that met certain clinical criteria for HNPCC, this is hardly surprising since the search for the epimutation was conducted exclusively in members of families registered in cancer family clinics. This ascertainment bias aside, it is now abundantly clear (see discussion above) that when a family happens to meet a particular clinical definition of HNPCC this does not automatically prove the existence of a heritable cause of cancer that is due to an altered DNA MMR gene[32,39-42]. It is true that one of the affected subjects showed methylation of MLH1 within spermatozoa, but this was in less than 1% of spermatozoa[50]. Even if such a sperm succeeded in fertilizing an ovum, subsequent clearance of methylation during early embryogenesis would negate the effects of vertical transmission of the affected allele.

The same authors who advanced the concept of the heritability of MLH1 epimutation subsequently demonstrated the de novo origin of germline hemi-allelic methylation of MLH1 in a male subject who was shown to have inherited the methylated allele from his mother in whom the same allele was not methylated[51]. These authors nevertheless continued to claim that MLH1 epimutation was ‘weakly’ heritable[51]. The fact that genetic alterations may be passed from parent to child and result in syndromes of familial cancer associated with early onset of disease and multiple neoplasia is a dismal truth for affected families and presents multiple problems with respect to the provision of medical solutions that are ethical, compassionate and effective. Therefore, the labeling of a form of cancer as heritable should be backed up by good evidence. The existing evidence does not support the heritability of germline hemi-allelic methylation of MLH1.

SERRATED POLYPS, DNA METHYLATION AND HNPCC

In 1997 a family was described as having HNPCC but did not meet the Amsterdam I or II criteria[52]. There were four siblings in a sibship of six with a total of eight CRCs between them. The initial CRCs presented at the ages of 44, 27, 44 and 55 years (eldest to youngest sibling respectively) and an offspring of the second eldest developed a gastric cancer at the age of 29 years. Gastric cancer is linked to Lynch syndrome but is not included in the Amsterdam II criteria. MSI testing using four markers was initially performed on the CRCs from the eldest and third eldest siblings and all four markers were unstable in both CRCs[32]. Overall, therefore, the features were consistent with a diagnosis of Lynch syndrome. Only one of the colectomy specimens, a right hemicolectomy performed on the youngest sibling for two metachronous CRCs, was available for detailed study at the time of surgery. The pathology was atypical for Lynch syndrome insofar as there were five tubular adenomas, seven hyperplastic polyps and seven mixed polyps. The hyperplastic polyps and mixed polyps were noted to be larger than the adenomas[52]. In retrospect, the correct diagnosis would now be hyperplastic polyposis[53]. The smaller CRC showed conspicuous lymphocytic infiltration, instability at three of three microsatellite markers, and was arising from a mixed polyp. The large CRC was mucinous and showed instability at two of three microsatellite markers. One of the offspring of this subject had developed a tubulovillous adenoma and two hyperplastic polyps at around the age of 40 years and a second was found to have multiple hyperplastic polyps after the report was published. Overall, it was inferred that this family had Lynch syndrome but that there was a modifying genetic factor in the youngest sibling giving an unusual phenotype[52]. Nevertheless, no germline mutation in a DNA mismatch repair gene has been found in this family.

Now, in retrospect, it is possible to suggest a simpler and more plausible mechanism underlying this Lynch syndrome-like family. In 2005, a paper described a series of eleven Lynch syndrome-like families in which some CRCs were MSI-high but others had low-level MSI or were microsatellite stable (MSS)[54]. A more consistent finding across the CRCs and polyps in these ‘MSI-variable’ families was mutation of the oncogene BRAF and methylation of MINT31[54]. In addition, many subjects had advanced serrated polyps and two had hyperplastic polyposis. Based on these observations it was suggested that an inherited predisposition to acquired DNA methylation within somatic tissues could give rise to a ‘serrated pathway syndrome’[54]. Should MLH1 be implicated then one might observe the development of CRCs that were MSI-high. This would only apply to a subset of CRCs, but could by chance, as in the case of the family described in 1997[52], affect all CRCs tested within a single family.

What is the evidence for an inherited predisposition to CRCs with DNA methylation In a family cancer clinic-based study that excluded families with the Lynch syndrome, subjects with CRCs showing the CpG island methylator phenotype (CIMP) had a 13-fold increased risk of having a first degree relative with cancer (not necessarily CRC) as compared with subjects without CIMP-positive CRC[55]. A hospital-based study could not confirm this finding but removed families meeting a clinical definition for HNPCC[56]. The latter exclusion clearly introduced a major bias since not all families meeting a clinical definition for HNPCC in fact carry a germline defect in a DNA MMR gene (see above). This is another example of how a loose definition of HNPCC can be confounding.

An inherent difficulty in establishing whether genetic factors may explain CIMP is the lack of an agreed definition of CIMP. It is clear, however, that mutation of BRAF co-segregates with extensive CIMP and may therefore be used as a surrogate for high-level CIMP. In a large population-based study, CRCs were stratified on the basis of BRAF mutation and DNA MSI status[57]. In the larger subset of MSS CRCs, the odds ratio for having a positive family for subjects with BRAF mutation-positive CRCs was 4.23 (95% CI = 1.65-10.84) (as compared with subjects with BRAF mutation-negative CRCs). The same finding was not observed in patients with MSI-high CRCs[57]. However, this is not surprising since the subjects with MSI-high CRCs that lacked BRAF mutation were relatively young and many would be expected to have Lynch syndrome.

In summary, it is likely that genetic mechanisms will be found to at least partially explain the evolution of CIMP-positive CRCs and to account for a subset of families that may mimic Lynch syndrome but in whom both colorectal polyps and cancers show extensive DNA methylation and frequent mutation of BRAF.

LYNCH SYNDROME VARIANTS

The more clearly one defines Lynch syndrome, the simpler it becomes to distinguish the syndrome from clinical scenarios that provide close mimicry. In the preceding two sections we encountered different clinical situations in which there was diagnosis of CRCs with DNA MSI and an inappropriate label of HNPCC. The essential feature of Lynch syndrome is that it is a hereditary disorder that is explained by a germline mutation in a DNA MMR gene. DNA MSI is a useful diagnostic hallmark but is not requisite for the diagnosis. Some mutations in DNA MMR repair genes may be tumorigenic but may not result in the mutator phenotype[58]. DNA MMR repair genes are multifunctional and certain mutations may be deleterious because they disrupt cell-cycle checkpoint control and/or apoptosis[59]. These variants may be associated with lower penetrance and a milder clinical phenotype but should probably be regarded as variants of Lynch syndrome. Mutations in the DNA MMR gene PMS2 may result in a syndrome that is inherited as an autosomal recessive trait[60]. The combination of very early onset malignancy involving brain, colon and other sites has been described as Turcot syndrome and linked with bi-allelic mutation of PMS2 in a small number of families[60,61]. Drawing a distinction between Turcot syndrome and Lynch syndrome becomes difficult given the fact that PMS2 mutation has also been linked with autosomal dominant patterns of inheritance[62,63] while certain MLH1, MSH2 and MSH6 mutations may give rise to an autosomal recessive trait[61,64]. Individuals with homozygous MMR gene mutations may show features of neurofibromatosis with café-au-lait spots. This has been associated with somatic mutation of the neurofibromatosis type-1 gene[65]. The preceding examples could be considered as variants of Lynch syndrome. However, clinical scenarios in which CRCs with MMR deficiency occur in the absence of a vertically transmissable genetic alteration in a MMR gene should not be termed Lynch syndrome.

CONCLUSION

The term HNPCC is a poor descriptor of the syndrome described by Lynch. Over the last decade, the term has been applied as a specific diagnostic label to families meeting a multiplicity of clinical criteria. A subset of these families will not carry a germline mutation in DNA MMR gene and will not show the clinical and pathological phenotype associated with the Lynch syndrome. Such families may meet or even exceed the Amsterdam criteria despite lacking evidence for a germline defect in a DNA mismatch repair gene. It has been suggested that these families be grouped as ‘Familial Colorectal Cancer Type-X’[40]. The term HNPCC has also been applied to clinical scenarios in which CRCs with DNA MSI are diagnosed but in which there is no vertical transmission of an altered DNA MMR gene. A diagnostic term that has multiple mutually incompatible meanings is problematic. This becomes particularly evident when extrapolating from a diagnostic label to the management of an individual family.

The Lynch syndrome is best understood as a hereditary predisposition to malignancy that is explained by a germline mutation in a DNA MMR gene. The diagnosis does not depend in an absolute sense on any particular family pedigree structure or age of onset of malignancy. If present, these are merely useful clinical pointers that have been accorded undue importance when considered in isolation of other facts. No simple set of clinical criteria can serve as a diagnostic label for Lynch syndrome. At the same time, the careful appraisal of clinical, pathological and molecular features can achieve an accurate working diagnosis prior to the demonstration of a pathogenic germline mutation in a DNA mismatch repair gene. To paraphrase a recent recommendation with respect to the term HNPCC: ‘Clarification of the genetic basis and full phenotypic expression of this disease mandates a more clinically useful name that gives consideration to non-colonic cancers and unifies the diagnosis around germline mutation in a DNA MMR gene. The term Lynch syndrome is proposed for the autosomal dominant disease caused by a germline mutation in a DNA MMR gene’[6]. However, in adopting the term Lynch syndrome in place of HNPCC one must also distinguish Lynch syndrome from the numerous clinical scenarios that give rise to close mimicry. By separating and naming these clinical entities (Table 2) one can begin to undo the considerable confusion that has been generated by the arbitrary use of the imprecise term HNPCC.

Table 2 Conditions and clinical scenarios that may mimic Lynch syndrome.

Attenuated Familial Adenomatous Polyposis[37] (polyps may not be numerous)

MYH polyposis[38] (polyps may not be numerous)

Juvenile polyposis[66] (polyps may not be numerous and may be adenomatous)

Germline mutation of TGFbetaRII[67] and AXIN2[68] (is not associated with DNA MSI)

Hereditary mixed polyposis syndrome[69] (polyps may not be numerous and may be adenomatous)

Hyperplastic polyposis[53] (polyps may not be numerous and may be adenomatous)

Serrated Pathway Syndrome[54] (polyps may not be numerous and may be adenomatous and CRCs may show DNA MSI)

Germline hemi-allelic methylation of MLH1[48-51] (multiple, early onset cancers with Lynch syndrome spectrum and having DNA MSI)

Lynch syndrome variants[61,65] (autosomal recessive Turcot syndrome due to PMS2 mutation)

Familial Colorectal Cancer-Type X[40] (Amsterdam criteria met but Lynch syndrome and conditions listed above have been excluded)