The molecular pathways of colorectal carcinoma are very well known.

Sporadic adenocarcinoma follows one of two molecular pathways:

(1) Most cases present a well defined sequence of genetic alterations accumulated during neoplastic progression that involve the APC, Ki-Ras, p53, MCC and DCC genes as well as partial deletions of chromosomes 5,17 and 18. Neoplastic progression has its morphological manifestation in the adenoma-carcinoma sequence. Inactivation of the suppressor gene APC is, in most tumours, the earliest event that influences the subsequent ones [5-9].

(2) Around 10-15% of carcinomas present an early primary event, namely inactivation of mismatch repair genes (e.g., mutator genes: hMSH2, hMSH1, hPMS1, hPMS2). Morphologically this alternative pathway is manifested in epithelial hyperpla-sia and a serrated pattern. These carcinomas, once defined as RER-positive (Replication ERror), are characterised by widespread mutations in the genome, easily identified by the analysis of repeated sequences of 1-4 bases (microsatellite) that are particularly subject to insertions or deletions [10-13]. They are currently referred to as carcinomas with microsatellite instability and are characterised by extensive nucleotide insertions or deletions in numerous, intrinsically unstable repeated sequences in tumour DNA, termed microsatellite. A change in the length of these sequences, located within or near genes involved in cellular proliferation, can alter the quality or quantity of different gene products. Mutation in a target gene such as a proto-oncogene or a tumour suppressor gene will have a defined role in tumour progression. Microsatellite instability is caused by alteration of the DNA mismatch repair genes. MSI cancers are subdivided into high-frequency microsatellite instability (MSI-H) and low frequency microsatellite instability (MSI-L) [14].

In cancers from other gastrointestinal sites, MSI tumours show a low frequency of p53 mutations, less lymph node involvement and a better prognosis [8, 12]; they also show a higher risk of multiple neoplasia [15]. From a morphologic point of view, MSI-H carcinomas show distinctive features: they are generally located in the proximal colon, show high grades and are more frequently mucinous, medullary or undifferentiated carcinomas with a marked "Crohn like" inflammatory infiltrate, and a high number of intraepithelial lymphocytes. Except for the medullary type, they do not show distinctive histological features and their phenotype must be determined by genetic studies (microsatellite analysis by PCR) or immunohistochemical techniques (MLH1 and MSH2 staining).

MSI-H tumours are characteristic of HNPCC, originating from a germline mutation in a DNA mismatch repair gene followed by somatic inactivation of the second allele. In the majority of sporadic ade-nocarcinomas microsatellite instability originates from inactivation of hMLH1 gene by promoter hypermethylation [12,16].

FAP and HNPCC are autosomal dominant disorders [7]. The former is caused by a mutation of the APC gene on the long arm of chromosome 5, while the latter originates from a germline mutation in a DNA mismatch repair gene.

The outcome of rectal cancer is related to stage of disease at time of diagnosis and to the presence of local recurrences with disease progression no longer responsive to therapy [17].

Local recurrences are the primary cause of death and are related to lymph node metastasis, depth of invasion through the wall and involvement of the circumferential (radial) margin. Treatment of colorectal carcinoma has changed dramatically over the last 30 years due to improved information, better surgical techniques and new therapeutic strategies. Surgical resection remains the treatment of choice for stage I disease, but locally advanced neoplasia may also involve new therapeutic options like radiotherapy, chemotherapy and hyperthermia. These therapies are now used as neoadjuvant therapies in advanced colorectal cancer in order to reduce the tumour stage. This will increase the resectability of the tumours, provide a possibility to preserve the anal sphincter and achieve a reduction in local recurrences [18, 19]. These new therapies also change the pathologic evaluation.

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