The initial clinical criteria suggested by the International Collaborative Group on HNPCC (ICG-HNPCC) are outlined in Table 1.2 and are referred to as the classic criteria (or Amsterdam Criteria I) (Vasen et al., 1991). Subsequently this has been revised (Amsterdam Criteria II) because of families with the mismatch repair mutation genotype but who do not have colorectal cancer (Table 1.3) (Vasen et al., 1999).

 

Table 1.2 Amsterdam Criteria I (1990) (Vasen et al., 1991)

 

Classic ICG-HNPCC Criteria Amsterdam Criteria I

At least three relatives with CRC with the following criteria One should be a first degree relative of the other two ≥ 2 successive generations should be affected ≥ 1 patient with CRC should have been diagnosed before age 50 FAP must be excluded All tumours should be histologically confirmed

 

Table 1.3 Amsterdam Criteria II (1999) (Vasen et al., 1999)

 

Revised ICG-HNPCC Criteria Amsterdam Criteria II

At least three relatives with an HNPCC-associated cancer (CRC, endometrium, small bowel, ureter or renal pelvis) with the following criteria One should be a first degree relative of the other two ≥ 2 Successive generations should be affected ≥ 1 Patient with cancer diagnosed before age 50 FAP must be excluded in cases of CRC All tumours must be histologically confirmed

 

HNPCC is due to mutations of DNA mismatch repair (MMR) genes and are characterised by the phenomenon called microsatellite instability. Microsatellite instability (MSI) is defined as ‘a change of any length due to either insertion or deletion of repeating units in a microsatellite within tumour DNA when compared to DNA from normal tissue’ (Boland et al., 1998). MSI is produced by the inability of mutated MMR genes to repair errors of mismatched nucleotides which occur during normal DNA replication.
MMR genes are also referred to as caretaker genes because they repair errors that take place throughout the genome during DNA replication. This results in an accumulation of genetic defects that may ultimately result in the development of cancer.

In comparison, the tumour suppressor gene APC is believed to act as a gatekeeper gene (Kinzler and Vogelstein, 1996). Mutations in this gene lead to Familial Adenomatous Polyposis (FAP), in which individuals develop thousands of benign adenomas. The accumulation of further mutations within these adenomas eventually leads to malignant transformation. This is discussed later.

MSI has been shown in most HNPCC tumours and in about 15% of sporadic colorectal tumours. Tumours with MSI can be subdivided into 3 groups depending on the number of markers showing microsatellite instability.
Tumours are classified into MSI-high (MSI-H), if two or more markers show instability; MSI-low (MSI-L), if only one marker shows instability and MSI-stable (MSS), if none of the markers show instability (Boland et al., 1998).
The majority of patients with HNPCC have microsatellite instability (MSI) and tumours tend to be MSI-H (see below).

The revised Bethesda guidelines (Table 1.4) provide criteria that determine which patients in the general population should be screened for microsatellite instability in order to identify individuals at risk for HNPCC (Umar et al., 2004). These revised guidelines were published following a HNPCC workshop held in 2002, at the National Cancer Institute in Bethesda, Maryland. The new guidelines supersede previously published criteria in the original Bethesda guidelines (Rodriguez-Bigas et al., 1997).

It was also suggested at the 2002 workshop that a pentaplex panel of 5 quasi-monomorphic mononucleotide markers should be included in the evaluation of MSI because the previously recommended panel of 5 microsatellite markers (2 mononucleotide and 3 dinucleotide repeats) would tend to underestimate the frequency of microsatellite instability.

Table 1.4 Revised Bethesda guidelines

Revised Bethesda guidelines

Colorectal cancer diagnosed in a patient younger than age 50 The patient has synchronous or metachronous colorectal or HNPCC-associated tumours regardless of age of presentation A patient younger than age 60 with colorectal cancer that has histological characteristics associated with MSI-high tumours A patient who has one or more first-degree relatives that had an HNPCC-related tumor at age 50 or younger A patient who has two or more first- or second-degree relatives that had HNPCC-related tumors at any age

 

FAP (Familial Adenomatous Polyposis)

This is an AD (autosomal dominant) disease characterised by the development of multiple adenomatous colorectal polyps commonly by the second decade of life. The number of polyps varies from 100s to 1000s and the incidence is about 1 in 10,000 individuals.

The lifetime risk of malignant transformation in at least one of the polyps is nearly 100% and usually occurs at a mean age of 40 years. This is referred to as classic FAP and is due to mutations within the APC (Adenomatous Polyposis Coli) gene; located on chromosome 5q 21-22 (Bodmer et al., 1987; Leppert et al., 1987).
Different mutations of the APC gene lead to varying clinical entities and other syndromes such as attenuated FAP (Spirio et al., 1993) and Gardner’s syndrome (vide infra).

Other clinical features of FAP include:

• Duodenal adenomatous polyps

50 to 90% of patients develop duodenal polyps but less than 5% develop duodenal cancer. They tend to occur in the second and third part of the duodenum and periampullary polyps appear to have a higher malignant potential (Kadmon et al., 2001). After panproctocolectomy, patients with FAP still have an increased relative risk of dying and this is due mainly to death from upper gastrointestinal malignancy (Wallace and Phillips, 1998).

• Gastric polyps

There are two main types of gastric polyps that occur in FAP. Fundic-gland hamartomatous polyps occur in about 50% of patients and are located in the fundus and body of the stomach; they have very little, if any, malignant potential. The other type is the adenomatous polyps which occur in only about 10% of patients and are located mainly in the antrum; these have some malignant potential (Offerhaus et al., 1999).

• Osteomas

These are benign tumours of bone which commonly occur on the skull and may present in childhood even before gastrointestinal polyposis is evident. They do not have malignant potential but may need to be removed for cosmetic reasons.

• Dental abnormalities

A variety of disorders of dentition occur including absent or extra teeth, odontomas and dentigerous cysts.

• Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)

These are asymptomatic discrete, round, pigmented lesions of the retina. They are usually multiple and bilateral in association with FAP but may occur as single lesions sporadically. They are present in up to 80% of FAP patients and are present from birth, so may be used as a clinical indicator of inheritance of APC mutation, even before colonic polyps occur. These lesions are usually associated with mutations between codons 463 and 1387 of the APC gene (Olschwang et al., 1993).

• Soft tissue tumours

Epidermoid cysts, fibromas and lipomas are common in FAP. They may require excision for cosmetic reasons.

• Desmoid tumours

These are benign fibrous tumours which are locally invasive but without metastatic potential. They occur commonly within the abdomen and the abdominal wall, usually at the site of abdominal scars and after intra-abdominal operations. They are more frequent in females and regression can sometimes occur with anti-oestrogen therapy, cyclo-oxygenase inhibitors or chemotherapy.

Attenuated FAP

This is characterised by fewer colonic polyps than in classic FAP; usually less than a hundred. The mean age of diagnosis of colorectal cancer is 50 to 55 years and the polyps tend to be located more proximally in the bowel. Other features of classic FAP may also occur but CHRPE lesions and desmoid tumours are rare.

Gardner syndrome

This syndrome is phenotypically related to FAP and is characterised by gastrointestinal polyps associated with mesenchymal tumours such as osteomas and epidermoid cysts (Gardner and Richards, 1953). It was believed to be a completely separate clinical entity but is now known to be due to mutations in the APC gene which also causes classic FAP.

Turcot’s syndrome

Turcot’s syndrome is characterised by the association of various central nervous system tumours, especially medulloblastoma, with colorectal adenomatous polyps. The first documented cases of Turcot’s syndrome were described in 1959 by Jacques Turcot in a teenage brother and sister (Turcot et al., 1959). It appears that this clinical syndrome can arise from two distinct types of germ line aberrations which include mutation of the APC gene or mutation of a mismatch repair gene (Hamilton et al., 1995).

Other syndromes predisposing to colorectal polyps:-

Cowden Disease (CD)

This is an AD condition predisposing to a variety of proliferative lesions including gastrointestinal polyps, breast and thyroid cancer. It was first described in 1963 and named after the family name of the proband who was a 20 year old lady presenting with various developmental abnormalities, multiple hamartomas as well as breast and thyroid cancer (Lloyd and Dennis, 1963). Cowden disease has been found to be due to germline mutations in PTEN (a tumour suppressor gene located on chromosome 10q, see below).
Bannayan-Riley-Ruvalcaba (BRR) syndrome: this disease shares phenotypic similarities with Cowden’s disease and is due to deletions in the same tumour suppressor gene; PTEN (Marsh et al., 1997).

Juvenile Polyposis Syndrome (JPS)

This is also an AD condition with variable penetrance and causing hamartomatous gastrointestinal polyps with a predisposition to malignant transformation.
JPS has been found to be due to germline mutations in DPC4/SMAD4 (Deleted in Pancreatic Carcinoma locus 4/Small Mothers Against Decapentaplegic locus 4, which is located on chromosome 18q21.1. This gene has a sequence similar to the Drosophila gene, MAD, and is involved in transforming factor-beta signalling pathways) (Howe et al., 1998). In addition, BMPR1A (Bone Morphogenetic Protein Receptor 1A), which is located on chromosome 10q22.3 may be involved in a subset of cases (Howe et al., 2001).

Peutz-Jeghers syndrome (PJS)

This disorder was first described in 1896 by Sir Jonathan Hutchinson, an English pathologist and surgeon. However, a Dutch physician, Johannes L. A. Peutz, in 1921 and an American physician, Harold J. Jeghers, in 1944 were responsible for characterising the various features of the syndrome (www.whonamedit.com). The term ‘Peutz-Jeghers syndrome’ was first introduced into medical literature in 1954.

Peutz-Jeghers syndrome is an autosomal dominant condition, characterised by the association of hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. Polyps are most frequent in the small intestine, particularly the jejunum, but can occur elsewhere in the gastrointestinal tract including the colon.

Mucocutaneous hyperpigmented dark blue/brown macules present usually in young children and may fade by adulthood. Macules occur around the mouth, buccal mucosa, eyes, nose, perianal area and fingers.

Patients are at a relatively high risk of developing tumours at various sites including the colon (Giardiello et al., 2000).

The gene responsible for PJS has been found to reside at 19p13.3 by linkage analysis in most families with PJS (Olschwang et al., 1998), this gene has been denoted as LKB1 (Hemminki et al., 1998) and STK11 (serine/threonine protein kinase 11) (Jenne et al., 1998).