Cancer of the rectum has been recognised since the Middle Ages. The Fourteenth Century English surgeon John of Aderne, who in his treatise on the treatment of fistulae-in-ano, recognised the importance of distinguishing cancer of the rectum from benign lesions, as in the former there was “no hope for a cure” (Garrison, 1929). The German surgeon Richard von Volkmann performed the first excision of the rectum for cancer in 1878, and Paul Kraske published his sacral method of excision in 1887.
In England and Wales there were 19,000 cases of colon cancer and 10,000 cases of rectal cancer registered in 1994 (Cancer statistics: Registrations, 2000). Annually there are 10,000 deaths from colon cancer and 5,000 deaths from rectal cancer, which makes this the second leading cause of cancer death, after lung cancer, in this country (Cancer statistics: Registrations, 2000, Mortality statistics: Cause, 2000). This comprises approximately 11% of cancer deaths. Colorectal cancer is the fourth commonest cancer in the world and second commonest in the western world and appears to be increasing in incidence estimated to be 2% per year (Levin, 1992b). There were 500,000 cases worldwide in 1975 rising to 783,000 cases in 1990. The cumulative lifetime risk of developing colorectal cancer is 6%, and the overall 5 year survival is 40% (Rhodes, 2000).
There is marked variation in incidence of colorectal cancer worldwide. It is most common in the Western World in particular Northern Europe, North America and Australasia. It is less common in Eastern Europe and South America and rare in Africa and Asia (Boyle and Langman, 2000, Gore, 1997, Slemmer and Cooper, 1991). See Figure 1.4 and Figure 1.5 for graphs of incidence of colon and rectal cancer. There is evidence that the rate in Africa is increasing as lifestyle changes (Iliyasu et al, 1996). Studies on migrant populations in the USA have shown that within one generation the risk of developing colorectal cancer approaches that of the general population (Levin, 1992a).
Figure 1.4 Worldwide Incidence of Colon Cancer
Figure 1.5 Worldwide Incidence of Rectal Cancer
Colorectal cancer is predominantly a disease of the middle aged and elderly. Only 0.2% of cases occur in people under thirty years of age and 1% in those under 40. The incidence rises sharply with age, with 90% of cases in people over the age of 50, with a peak incidence in the seventh decade of life. Approximately 50% of cases occur in the age range 65 to 75 years (Cancer statistics: Registrations, 2000).
In men, colorectal cancer is the third most common malignancy after lung and prostate cancer, with an incidence of 58.5 cases per 100,000 of the population. In women, colorectal cancer is also the third most common malignancy after lung and breast cancer, with a rate of 53.6 per 100,000 (Cancer statistics registrations, 1998).
There is a difference in the sex distribution between colonic and rectal carcinomas. Colon cancer has a higher incidence and mortality in women than in men with a ratio 3:2. Conversely, rectal cancer is 1.4 times more common in men than women (Lloyd-Jones and Giles, 1995, Wynder et al, 1992). Detailed incidence rates are shown in Table 1.1
Table 1.1 Incidence and Death Rate of Colon and Rectal Cancer
|Incidence ( /100,000 pop)||Death Rate ( /1,000,000 pop)|
Data adapted from Cancer statistics: Registrations, 2000
The anatomical distribution of colorectal cancer closely resembles the distribution of polyps, since most cancers arise from polyps. Historical teaching tells us that two-thirds of tumours are within reach of the flexible sigmoidoscope (Figure 1.6, Maglinte et al, 1983, Slemmer and Cooper, 1991). However, there appears to have been a shift in the distribution of colorectal neoplasia over the last 4 decades, with a higher proportion of proximal tumours (Goldstein, 2001, Goldstein et al, 1996, Hernanz et al, 1994, Jessup et al, 1996, Scott and Grace, 1989, Wong et al, 1999). In genetic syndromes, such as FAP and HNPCC, the lesions are more commonly located on the right side of the colon, but in UCAN the majority are left sided (Hardy et al, 2000). Also, in geographic areas of low incidence of colorectal cancer, many tumours are located in the right colon (Slemmer and Cooper, 1991).
Figure 1.6 Anatomical Distribution of Colorectal Cancer
Colorectal cancer can be described as sporadic, familial or hereditary.
Figure 1.7 Aetiology of Colorectal Cancer
Data from Hardy et al, 2000, Kell et al, 2000, Shanahan et al, 2000.
Sporadic colorectal cancer
Sporadic cases of colorectal cancer occur in patients with no recognisable family history of colorectal cancer and make up 70% of cases of colorectal cancer. Most develop from adenomatous polyps, according to the adenoma-carcinoma sequence, which is described in Section 1.6.2. The incidence of polyps in post-mortem studies is 30-40% in Western populations. Flat adenomas, which account for 10% of all polyps, have a higher rate of malignant transformation, and have a more aggressive clinical course.
Familial colorectal cancer
Clusters of colorectal cancers that occur in the same family but do not fit into the recognised criteria of the hereditary colorectal cancer syndromes are termed familial. They represent up to 25% of cases of colorectal cancer and may occur as a result of common environmental exposure, the effects of multiple low penetrance genes or a combination of both. The risk of colorectal cancer does increase markedly with the number of affected relatives (Table 1.2).
Table 1.2 Lifetime Risk of Death from CRC
|Population Risk||1 in 50|
|1 FDR (any age)||1 in 17|
|1 FDR and 1 SDR||1 in 12|
|1 FDR <45 years||1 in 10|
|2 FDR||1 in 6|
|Juvenile Polyposis or Peutz-Jegher’s||1 in 3|
|FAP||1 in 2.5|
|HNPCC or >2 FDR||1 in 2|
FDR: First Degree Relative,
SDR: Second Degree Relative
Hereditary Colorectal Cancer Syndromes
Recognised hereditary syndromes, such as FAP and HNPCC, account for up to 5% of cases of colorectal cancer. They are usually associated with a germ line mutation of a gene, which predisposes the patient to a high risk of colorectal cancer, and are discussed in detail in Section 1.6.3. Patients with these syndromes have a family history of colorectal cancer, presenting at an early age.
Risk Factors for Colorectal Cancer
Combinations of genetic and environmental factors predispose an individual to the risk of developing colorectal cancer. Environmental factors appear to have most influence, accounting for up to 90% of cases and genetic predisposition accounts for a further 10% (Cole and Sleightholme, 2000, Rhodes, 2000).
Diet is one of the most important risk factors in determining risk of colorectal cancer, probably accounting for 80% of cases of colorectal cancer. There are considerable difficulties when trying to evaluate dietary influences on carcinogenesis (Wynder et al, 1992). Methodological differences between study types can make comparison difficult. Differences in definition of dietary constituents, in particular fibre and fat, add to the problems. Controlling for a single dietary component is extremely difficult. For example, a diet that is high in meat content is usually high in fat and in calorific intake, whereas, diets high in fruit and vegetables are also high in fibre and in micronutrients. Also, the long timescale over which dietary factors exert their effects make it necessary to perform studies over a prolonged time period.
Meat, Fat and Calorie Intake
Countries that have a Westernised diet, which is high in meat content, animal fat and low in fibre, have a higher incidence of colorectal cancer (Burnstein, 1993, Levin, 1992b). The constituents that seem to have most influence are the intake of beef, saturated fat and calorie intake. All three have a positive correlation with the incidence of colorectal cancer. Regression analysis has predicted that in the USA, if there was a 50% decrease in beef intake, the rate of colorectal cancer would halve (Gore, 1997). When fat intake is studied, it appears that saturated animal fats are associated with high incidence of colorectal cancer, but that unsaturated and vegetable fats and oils make no difference (Boyle and Langman, 2000). In addition, diets with a high calorie intake, particularly if a large proportion (>40%) of calories come from animal fat, are associated with a higher incidence of colorectal cancer (Levin, 1992b). In countries such as Japan where the traditional low–fat diet has been replaced my a more Westernized diet, the incidence of colorectal cancer has increased by 2.5 times (Cohen, 2000).
The role of dietary fibre as being protective against colorectal cancer was first put forward by Burkitt et al, 1974. A number of mechanisms have been suggested to explain the protective effect of fibre; Dietary fibre reduces colonic transit time, thereby limiting the exposure to environmental carcinogens; Fibre bulk dilutes faecal constituents including carcinogens; Fibre affects the concentration of bile acids in stool, firstly by binding bile acids and secondly by reducing pH, which inhibits the conversion to secondary bile acids which are potentially more carcinogenic. Dietary fibre is divided into two types; soluble and insoluble. Soluble types of fibre such as pectins, gums and mucilages are mainly found in fruits and vegetables whereas insoluble fibre such as cellulose, hemicellulose and lignins are mainly found in cereals. A large number of studies have been conducted to look at the influence of dietary fibre on colorectal cancer. The definitions of fibre and differing methodologies used make comparisons difficult. However, the consensus being reached is that the soluble fibre in fruit and vegetables is more protective than the insoluble fibre found in cereals (Levin, 1992b).
Vitamins and Trace Elements
Vitamins A, C, and E, and the trace element Selenium all have an antioxidant action. Diets which are rich in these factors have been shown to be associated with a lower risk of colorectal cancer (Milsom, 1993). Calcium intake is also inversely correlated with incidence of colorectal cancer. There is a 75% decrease in colorectal cancer in populations with calcium intake greater than 1200mg/day (Burnstein, 1993). Saponification of bile acids and decreased proliferation of colonocytes are proposed mechanisms of action (Levin, 1992b). Vitamin D is also protective from colorectal cancer. Increasing latitude is associated with decreased sunlight exposure and also with higher incidence of colorectal cancer, which is very rare within 10° of the equator. The rate of colorectal cancer is halved in patients ingesting more than 3.75?g/day of vitamin D (Burnstein, 1993).
Seventy to ninety percent of colorectal cancers develop in pre-existing polyps, usually adenomas, which may be tubular, tubulovillous or villous (Table 1.3, Kent and Mitros, 1991). Risk of malignant progression in polyps is determined by four factors: size, stalk, architecture and dysplasia. Polyps less than 6mm in size have less than 1% chance of malignant change. This rises to 5% in polyps 1-2cm in size, to greater than 10% in polyps over 2cm. Pedunculated polyps have less chance of malignant change compared to sessile ones, where up to 75% develop invasive carcinoma. Villous adenomas are more likely than tubular to become invasive and the more severe the degree of dysplasia the greater the chance of malignancy (Gore, 1997).
Table 1.3 Types of Benign Colorectal Polyps
|% of Total No Polyps||75||15||10|
|% Showing Invasive Ca||5||22||42|
Tubular adenomas are the most common and often multiple. They range in size from 0.1 to 3cm in size. Most are pedunculated, but up to 30% may be sessile. The distribution throughout the colon is: caecum 11%, transverse colon 12%, descending colon 24%, sigmoid 48%, rectum 5%. These polyps are usually found to be less than 1cm in size, with a malignant transformation rate of 1%. Five percent are larger than 2cm, with 35% risk of carcinoma.
Villous adenomas are rarer and usually occur singly. They can be up to 20cm in size, and even benign ones may be circumferential. They have a friable surface that may ulcerate or bleed (65%). They produce copious amounts of mucus, which can lead to troublesome diarrhoea (43%). More than 75% are found in the rectum and 30% will show evidence of invasive carcinoma at presentation.
Tubulovillous adenomas have glandular elements of both types of polyp. Many of their characteristics are intermediate between tubular and villous polyps. They tend to progress more like villous adenomas and have a high rate of malignant transformation.
Previous Colorectal Cancer
Five percent of patients with colorectal cancer will have a second synchronous tumour in the large bowel. A further 5 – 8% will develop metachronous tumours, of which over one third will have a second synchronous tumour. The greatest risk of recurrence is in the first 5 to 7 years following diagnosis of the primary.
Local irradiation of the pelvis also predisposes to the development of carcinoma of the rectum and sigmoid colon (Lloyd-Jones and Giles, 1995). This trend is most noticeable in cancer of the cervix, but has been described in cancer of the bladder, prostate, and in Wilm’s tumour. The risk becomes apparent after 10 years, in patients who have received more than 3000rad (Gore, 1997).
Inflammatory Bowel Disease
Crohn’s disease is associated with an increased risk of both small and large bowel malignancy. The risk of colorectal cancer being 4 to 20 times that of the general population. There are a high proportion of tumours arising in inflamed sections, strictures and fistulae. Defunctioned or bypassed segments of small and large bowel are also particularly at risk (Levin, 1992b).
Ulcerative Colitis Associated Neoplasia
Important differences exist between the adenoma-carcinoma sequence (ACS) and the mechanism involved in ulcerative colitis associated neoplasia (UCAN). In UCAN the cancer probably evolves from microscopic areas of dysplasia, without evidence of a mass lesion. The progression from dysplasia to carcinoma in UCAN is more rapid than the progression from adenoma to carcinoma. Lag-time in UCAN is estimated at less than 8 years, compared with 10-20 for ACS. Also, patients with both a family history of colorectal cancer and ulcerative colitis are at higher risk of colorectal cancer, suggesting that additive factors may be present (Eaden et al, 2001).
Patients with idiopathic inflammatory bowel disease are at a higher risk of developing colorectal cancer than the general population. They tend to develop cancers between 10 and 20 years earlier than the general population (average age at presentation of colorectal cancer in patients with UC is 40 – 45). The difficulty in distinguishing symptoms from carcinoma from their usual symptoms means that many tumours present at an advanced stage.
Patients with long-standing ulcerative colitis (UC) have a 10 to 25 times increased risk of developing colorectal cancer. The risk starts after 10 years of having the disease, with an annual risk of 1% per year (Nicholls, 2001). The effect is only noticeable in patients with pan-colitis, but the degree of inflammation and quiescent phases do not seem to be predictive of risk. Patients with an isolated ulcerative proctitis have a risk of colorectal cancer only marginally higher than the national average. The increased incidence is more noticeable in younger patients with the risk of developing colorectal cancer up to 40% in patients diagnosed with UC before age 15 (Levin, 1992a).
Lifestyle and Occupation
Smoking may be a factor in the development of colorectal cancer. Smokers have a three times increased risk of developing adenomas, compared with non-smokers. High intake of alcohol is also associated with higher levels of colorectal cancer. Whether this is due to the poor diet of people with excessive alcohol intake is unclear. There is however, a strong correlation with beer intake and rectal cancer which is not seen with other types of alcoholic beverage (Burnstein, 1993). Exercise has also been implicated as being protective from colorectal cancer. Individuals who have strenuous occupations have half the risk of developing left-sided colonic lesions, than people with sedentary occupations. A number of chemical carcinogens have been identified which contribute to the development of colorectal cancer. Industrial exposure to asbestos, oil, organic paints, solvent and dyes, metal fumes, acrylonitrile and ethylacryloate have all been implicated (Gerhardsson de Verdier et al, 1992).
Patients who have had a cholecystectomy have been noted to have a 1.5 times increased risk of developing right-sided colonic neoplasia, but not rectal cancer. This is thought to be due to the continued deposition of lithogenic bile acids into the bowel lumen. (Shao and Yang, 2005), and the risk may decrease with distance from the common bile duct (Lagergren et al, 2001).
Patients who have had urinary diversion procedures into the sigmoid colon are at risk of developing cancer at the anastomosis of the bowel and ureter. The majority are adenocarcinomas, but transitional cell and squamous tumours have been described more rarely (Woodhouse, 2002).
Gastrin has a trophic effect on colonic mucosa causing proliferation. Patients with pernicious anaemia have hypergastrinaemia, which leads to a higher incidence of colorectal cancer (Milsom, 1993). A similar increase is noted in patients with acromegaly, who have increased circulating levels of growth hormone, and in patients with parathyroid adenomas, who have high levels of circulating parathormone. The role of sex steroids in the development of colorectal cancer is unclear at present, but up to two-thirds of tumours in women and a third in men will express oestrogen receptors (Jassam et al, 2005).
The Genetics of Colorectal Cancer
Cancer occurs as a result of the accumulation of genetic damage in the nucleus of a cell and results in a change to a neoplastic phenotype. In hereditary syndromes there is a germ line mutation that is inherited from a parent which confers a risk of developing colorectal cancer. In sporadic colorectal cancer there are somatic mutations in an individual cell which give rise to the transformation. Evidence exists that colorectal cancer results from a step-wise accumulation of multiple genetic defects that gradually give rise to increasing cellular atypia.
Mechanisms of Malignant Transformation
There are three main categories of changes in the genetic make-up of the cell which give rise to neoplastic behaviour. They are oncogenes, tumour suppressor genes and DNA damage repair genes. Proto-oncogenes are genes in which the mutation of one allele results in a gene with inappropriate expression or function. This usually takes the form of a gain of function and is deleterious to the regulation of cell growth. Oncogene mutations thus behave in a dominant fashion. Tumour suppressor genes normally act within the cell to regulate cell growth or division, usually to act as a negative influence, particularly in the process of apoptosis. Mutation of these genes results in a loss of this regulatory function. Mutation, inactivation or loss must occur in both alleles (recessive pattern) for a complete loss of function and uncontrolled cell growth and proliferation. The third category is the DNA mismatch repair (MMR) genes, in which loss or mutation of these genes is associated with a gradual accumulation of DNA damage through transcriptional errors.
Chromosomal instability, which may be in the form of aneuploidy or chromosomal alterations, may result in deletion or inactivation of tumour suppressor genes or may lead to inappropriate transcription of oncogenes if the gene is relocated adjacent to a promoter region of DNA. The other mechanism of DNA damage is microsatellite instability. This occurs when there is defective DNA repair, particularly loss of DNA MMR genes and occurs particularly in HNPCC. Microsatellites are areas within the genome which have short tandem repeat sequences of base pairs. These repeat sequences are particularly at risk from DNA replication errors, due to DNA slippage, where one strand of DNA slides up along the other strand (analogous to a zip fastener becoming snagged due to improper linkage). Where the length of a microsatellite changes somatically within a tumour, it is termed a replication error (RER, or microsatellite alteration). If multiple microsatellites are changed, with multiple sizes at each microsatellite locus, this is termed microsatellite instability (MSI). MSI occurs more frequently when there is defective DNA MMR and leads to generalised genetic instability, with risk of multiple mutations. Five such MMR genes have been identified; MSH2, MLH1, PMS1, PMS2 and GTBP. These genes act together in complexes to identify and excise mismatched or unmatched base pairs. MSH2 and MLH1 are vital to the normal functioning of the cell, with the remaining three genes being largely redundant. As a result the majority of mutations seen in HNPCC occur in MSH2 and MLH1. MSI occurs in over 95% of carcinomas in HNPCC, but also occurs in up to 15% of sporadic tumours.
As a result of both chromosomal instability and microsatellite instability other specific genetic alterations occur with increased frequency.
The Adenoma-Carcinoma Sequence
It has long been believed that colorectal cancer evolves from a precursor lesion known as the adenomatous polyp. This concept was based on the studies published by Lockhart-Mummery and Dukes, 1928 and culminating in the concept of the polyp-cancer sequence published in by Muto et al, 1975.
The change from normal colonic or rectal mucosa to malignant tumour requires a number of discrete steps, or transformations, which have been termed the adenoma-carcinoma sequence (Figure 1.8.). At least 4 or 5 such mutations are required for the development of the malignant phenotype. This mechanism is thought to account for most cases of sporadic colorectal cancer, but similar mechanisms are involved in the hereditary colorectal cancer syndromes.
Figure 1.8 Genetic Events in the Adenoma-Carcinoma Sequence
Mutation of the adenomatous polyposis coli (APC) gene occurs early in the sequence and leads to a hyperproliferative epithelium. Later events include k-ras oncogene mutations, and loss of the deleted in colon cancer (DCC) gene which result in adenoma formation. p53 gene mutations lead to malignant transformation, but the exact order of these mutations can vary. There are many genes involved in the development of colorectal cancer, the main ones of which are summarised in Table 1.4.
Table 1.4 Gene Mutations in Colorectal Cancer
|Gene||Location||Type||Frequency in CRC|
|TGF? receptor||Tumour Suppressor||25-30%|
|Smad2||Tumour suppressor||< 5%|
Somatic mutation of the adenomatous polyposis coli (APC) gene occurs early and leads to a hyperproliferative epithelium. APC gene mutations are prevalent in early adenomas, as well as colorectal cancers, suggesting that APC mutation may be an initiating event in carcinogenesis (Zauber et al, 2004). One or more of these hyperproliferative cells may undergo clonal expansion and form a benign tubular adenoma. Progression of the adenoma results in increased size, cellular atypia and a villous architecture. Mutations of k-ras, especially codons 12 and 13, are present in 50% of adenomas greater than 1cm in size and in 50% of carcinomas, but in less than 10% of adenomas <1 cm (Conzelmann et al, 2004). The same mutation is seen in both the adenomatous and carcinomatous portions of the same lesion, suggesting that k-ras mutation precedes malignant transformation. K-ras mutations are detected with increasing frequency in adenomas with dysplasia. This association with dysplasia and carcinoma has suggested a role of k-ras in the progression from adenoma to carcinoma. Loss of wild type (normal) p53 is infrequent in adenomas, but occurs in over 75% of carcinomas. Loss of function of p53 can usually be detected in both alleles in tumours showing p53 damage. The normal role of p53 is in control of the cell cycle, and induction of apoptosis in the presence of irreparable DNA damage. Loss of p53 appears to be a late event in the progression to invasive carcinoma (Steele et al, 1998). The DCC gene encodes for a cell adhesion molecule similar to the neural cell adhesion molecule (NCAM) family. Loss of DCC also appears to be a late event, occurring in 50% of late adenomas and 70% of carcinomas. Virtually all tumours that have metastasised to the liver show inactivation of DCC, indicating a role of DCC in tumour progression and the development of metastatic potential (Zauber et al, 2004).
Hereditary Colorectal Cancer Syndromes
Recognised hereditary syndromes account for up to 5% of cases of colorectal cancer. They are usually associated with a germ line mutation of a gene which predisposes the patient to a high risk of colorectal cancer. Features of these syndromes are summarised in Table 1.5.
Table 1.5 Features of Hereditary CRC Syndromes
|Mean Age of Diagnosis of CRC||32-39||45-55||42-49|
|Distribution of Cancer||Random||Mainly Right Colon||Mainly Right Colon|
|Sex Ratio (M:F)||1:1||1:1||1.5:1|
|No. of Polyps||>100||1-100||1|
|Polyp Morphology||Pedunculated||Mainly Flat||Pedunculated 45%
|Gene Mutations||APC||APC||MSH2, MLH1, PMS1, PMS2|
|Associated Cancers||Duodenal Adenomas
|Duodenal Adenomas||Endometrial Ca
Urinary Tract Ca
Familial Adenomatous Polyposis
Familial adenomatous polyposis (FAP) is an autosomal dominant condition affecting 1 in 5,000 to 1 in 10,000 of the population and accounts for 1% of colorectal cancers. The gene responsible is the APC gene located on chromosome 5q21. This codes for a 310kD protein which is believed to be involved in cytoskeletal organisation. Mutation of the gene results in the synthesis of a truncated protein which disrupts this process. It is characterised by hundreds of adenomatous polyps throughout the large bowel. The average age at onset of polyps is 25 years, and all patients have polyps by mid-forties. Symptoms include abdominal pain and gastrointestinal bleeding (average age of onset 33 years). Malignant transformation is inevitable, and average age of diagnosis of cancer is 42 years. Cancers are frequently left-sided. One fifth of index patients have no family history of FAP, suggesting a new mutation of the gene (Spigelman, 2001).
Gardner’s Syndrome occurs when extra-colonic features are present, such as mandibular osteomas which may be multiple. Upper GI polyps are common. Proximal gastric polyps are hyperplastic with no cancer risk, but distal gastric and duodenal and periampullary polyps may be adenomatous. These occur in 40-90% of patients and confer an increased risk of duodenal and periampullary cancer. Congenital hypertrophy of retinal pigment also occurs, being manifest as multiple, ovoid, pigmented lesions seen on fundoscopy. Rarer manifestations include epidermoid cysts, lipomata, fibromata and neoplasia of adrenals, thyroid, biliary tree and liver (Galiatsatos and Foulkes, 2006).
Hereditary Flat Adenoma Syndrome/
Attenuated Familial Adenomatous Polyposis
HFAS and AFAP are considered to be genetic variants of FAP with incomplete penetrance and hence differing spectra of clinical manifestations (Jo and Chung, 2005). The age of diagnosis of cancer is much later (45-55 years) and the distribution of cancers is mainly right sided, with rectal sparing. Approximately 0.5% of colorectal cancer cases are due to HFAS and AFAP.
This is a rare autosomal recessive syndrome. It is characterised by the association of colonic adenomas and malignant brain tumours, often high-grade glioblastomas. The gene responsible has not been conclusively identified, but some reports show a link with APC germ-line mutations which may make it a further variant of FAP and Gardner’s Syndrome (Galiatsatos and Foulkes, 2006).
This autosomal dominant condition comprises pigmentation of mucocutaneous junctions and gastro-intestinal polyposis. The gene responsible in some patients is the STK11 gene on chromosome 19. Polyps may occur in stomach, small intestine or colon and are hamartomata. They are associated with cancers of the duodenum, jejunum, ileum and colon, within an adenomatous area of a hamartoma. Other benign polyps may occur in nose, bronchi, bladder and gallbladder. Malignant tumours of ovary (sex-cord tumours), testis (Sertoli cell tumours), breast (often bilateral) and pancreas, gallbladder and bile duct are all more common (Spigelman et al, 1995).
Three types have been described producing colonic, gastric or generalised gastro-intestinal polyps. The condition is an autosomal dominant one in which multiple hamartomatous polyps occur. The risk of gastrointestinal cancer is over 50%. Some patients with this syndrome have germ-line mutations in the SMAD4 gene (Friedl et al, 1999).
Hereditary non-polyposis colorectal cancer is an autosomal dominant condition, which accounts for 5-15% of colorectal cancers. Originally described by Lynch in two American families in 1984, it also known as Lynch Syndrome (Thorson et al, 1999). Polyposis is not a consistent feature of the disease and some patients have only a single polyp which becomes neoplastic. However, despite the name, some patients may develop up to 100 adenomatous polyps. They are usually smaller and less numerous than in FAP, are often flat adenomas and have a predominantly right-sided distribution (Hurlstone et al, 2004). Due to lack of demonstrable clinical features, diagnosis is often on the basis of family history alone, with clearly defined criteria for inclusion (Table 1.6). HNPCC has an early age of onset of colorectal cancer, mean 44 years. The tumours in HNPCC are often multiple, mucinous or poorly differentiated. There are two variants of the condition, named Type I and Type II. Type I disease is confined solely to the colon, but Type II has extra-colonic manifestations. These include cancers of endometrium, ovary, ureter, renal pelvis, stomach, pancreas, biliary tree, bone marrow, skin and larynx. Of these endometrial cancer is the most common.
Table 1.6 The Amsterdam Criteria for HNPCC
|Three or more cases of colorectal cancer, in at least two generations|
|One affected individual must be a first degree relative of the other two (or more) cases. One case must be diagnosed before age 50|
|Colorectal cancer can be replaced by endometrial or small bowel adenocarcinoma|
|FAP must be excluded|
From Vasen et al, 1999
The HNPCC Syndromes are caused by mutations in the genes, which are responsible for DNA damage repair, the so-called mismatch repair (MMR) genes. The protein products of these genes are responsible for repair of minor damage to DNA caused by replication errors. If these genes are mutated, then there is the progressive accumulation of DNA damage within the cell. This eventually leads to the damage of other genes, such as oncogenes and tumour-suppressor genes, which are responsible for cell cycle regulation. This leads to a progressively aggressive phenotype as discussed above. To date 5 such DNA MMR genes have been identified (MSH2, MLH1, PMS1, PMS2, and GTBP) which are located on chromosomes 2, 3 and 7 (Table 1.4).
This is thought to be a member of the HNPCC group of conditions. Patients develop colorectal cancer in adenomatous polyps, usually located in the proximal colon. They also develop skin lesions, including basal-cell, sebaceous and squamous-cell cancers (Coldron and Reid, 2001).
Carcinomas of the large bowel can be described as polypoid, infiltrative or ulcerative. Polypoid lesions are more common in the capacious right colon, where they can become quite large. They often outgrow their blood supply and may become necrotic or ulcerated. Infiltrative tumours are more common on the left colon. They infiltrate into the lymphatics of the bowel wall, which due to the circular distribution of the lymphatics, leads to annular carcinomas, which causes stenosis or obstruction. Ulcerative tumours which have a greater intramural component, and hence are usually of a higher stage, are most commonly found in the transverse and descending colon. Ulcerative and infiltrative tumours tend to have a worse prognosis than polypoid ones. Scirrhous tumours, which show a higher degree of intra-mural spread than the other tumour types, are predominant in cancers associated with inflammatory bowel disease. They are most common in the left colon. Although bowel tumours can become very large, the risk of lymph node metastasis and overall prognosis are independent of tumour size (Slemmer and Cooper, 1991).
The vast majority of tumours are adenocarcinomas (85%), with most of the rest being mucinous carcinomas (15%). Other rare types of tumour include squamous, adenosquamous, carcinoid and small cell. Adenocarcinomas are graded into 3 groups determined by the degree of differentiation; well, moderate or poor (Slemmer and Cooper, 1991). Degree of differentiation has important influences on outcome (See Table 1.7).
Table 1.7 Tumour Characteristics by Degree of Tumour Differentiation
|Degree of Differentiation|
|% of Cases of CRC||20||60||20|
|5 Year Survival Rectal Cancer (%)||77||61||29|
|5 Year Survival CRC (%)||62-83||43-63||11-42|
|% Developing LN Metastases||30||47||81|
Mucinous carcinomas secrete copious amounts of mucin. The poorly differentiated sub-type is known as “signet ring carcinomas.” Mucinous tumours behave more aggressively than adenocarcinomas and have a much worse prognosis (Table 1.8). They are more common in younger age groups. They represent 40-80% of tumours in patients under the age of 40, unlike in the general population in which 15% are poorly differentiated, and 20% are mucinous (Slemmer and Cooper, 1991).
Table 1.8 Survival by Tumour Type
|5 Year Survival (%)|
Natural History of Colorectal Cancer
The natural history of colorectal cancer is shown in Figure 1.9. At presentation 70% of patients will have operable disease, but as many as 25% will already have metastases to the liver (Stower and Hardcastle, 1985). Over half of patients will develop liver metastases at some point during the course of their disease,
Figure 1.9 Natural History of Colorectal Cancer
Recurrence of colorectal cancer
There are a number of mechanisms by which colorectal cancer can become disseminated. Infiltration of adjacent organs can occur by direct invasion through the bowel wall. Haematogenous spread to distant organs such as liver and lung can occur via the portal venous or systemic blood stream (particularly in rectal cancer). Local recurrence, skin metastases or anastomotic recurrence can occur by tumour cell spillage and implantation at the time of surgery, and lymphatic spread can occur to the regional lymph nodes. Finally trans-ceolomic spread can occur to other abdominal organs, in particular ovary.
As previously stated, a quarter of patients will have synchronous liver metastases at presentation and half of those undergoing curative resection will later develop metachronous liver metastases. Autopsy data shows that as many as one third of patients dying of colorectal cancer will have isolated liver metastases at death (Miller et al, 1983), but that over 75% of patients dying of colorectal cancer have liver involvement (Gray, 1980). The only available treatment associated with long-term survival in patients with colorectal cancer metastases is liver resection. While recent studies have shown that liver resection achieves a 5-year overall survival from 37% to 58%, only 10% to 20% of patients with colorectal liver metastases are eligible for resection (Scheele et al, 1990, Vibert et al, 2005).
A further important site of recurrence in colorectal cancer is the lung, with10 to 20% of patients developing pulmonary metastases. Isolated lung metastases, however, only occur in 2% of patients, with concurrent hepatic metastases being common (McCormack and Ginsberg, 1998). There is a role for lung resection in these patients, with 5 year survival rates of up to 40% achievable (McCormack et al, 1992).
A further five percent of patients will develop intra-luminal recurrence, and 6% will develop metachronous tumours. Locoregional recurrence occurs in 20% of patients with colorectal cancer, with the majority of patients in this group having rectal cancer (Galandiuk et al, 1992).
As many as eight percent of women with colorectal cancer will develop metastases to the ovary (Perdomo et al, 1994), many of which will have widespread peritoneal disease (Rayson et al, 2000).
Peritoneal metastases occur synchronously in 10 to 15% of patients, and metachronously in 10 to 35%. In patients with widespread peritoneal disease, cytoreductive surgery and intra-peritoneal chemotherapy may be indicated. Patients in whom cytoreductive surgery was complete had a median survival of 32.4 months, compared with 8.4 months for patients in whom complete cytoreductive surgery was not possible (Glehen et al, 2004).
Rarer sites of metastasis include the adrenal, brain, bone and skin. Brain metastases occur in 10%, and bone metastases in 3% of patients (Sundermeyer et al, 2005). Recurrence in the skin occurs in up to 10% of patients, with 1% of patients developing wound recurrence (Watson et al, 2000).
The largest cause of mortality from colorectal cancer is due to metastasis or recurrence, with three-quarters of patients dying of this cause, whilst up to ten percent will die of post-operative complications. A small percentage (0.3%) will die of metachronous colorectal cancer and 2.8% of other cancers. Ten percent of patients will die of unrelated causes (Kune et al, 1990).
Distant spread is the most important factor in determining overall survival in patients with colorectal cancer. Eighty percent of patients dying of colorectal cancer will have liver metastases present at the time of death. The presence of liver metastases at time of primary surgery is associated with a 3% 5 year survival. Prognosis is worse in the presence of hepatic and extra-hepatic disease (Kune et al, 1990).
The next most important factor is the presence of lymph node metastases, with a reduction in 5 year survival from 65% to 38% when they are present. Adjuvant chemotherapy has been shown to give a significant increase in 5 year survival, of 22% in patients with colon cancer and node positive disease (Moertel et al, 1990). The benefits of adjuvant chemotherapy have yet to be determined in patients with rectal cancer and node negative disease.
The presence of local disease following surgery also has an important impact on survival. Patients undergoing complete histological resection of their tumour (R0 resection) have a 55-60% 5 year survival, compared to only 5% in patients with microscopic (R1 resection) or macroscopic (R2 resection) residual disease.
Staging of Colorectal Cancer
Like other solid tumours, colorectal cancer is staged pathologically on the basis of the extent of primary organ involvement and the metastatic spread to lymph nodes or to distant organs. Accurate staging of colorectal cancer is important in order to give prognostic information regarding the expected patient survival following resection.
Pre-operative staging is attempted in all patients in order to determine the best treatment modality for the patient. A variety of methods are used including clinical examination, radiological examination (using ultrasound scan (USS), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and PET-CT, a combined approach using both modalities). This will determine the suitability of neo-adjuvant treatment such as chemotherapy and radiotherapy, whether resection is possible and the order in which treatment modalities are to be applied.
Intra-operative staging is performed by the operating surgeon, who will assess the extent of primary tumour spread, nodal and distant metastases. In addition the surgeon will record the residual tumour (R) status of the patient: R0, no residual tumour; R1, microscopic residual tumour; R2, macroscopic residual tumour. The R classification is a strong predictor of prognosis. An acceptable long-term prognosis can be expected only in R0 patients. Although there exist clear correlations between stage and R classification the differences in prognosis of R0 versus R1, 2 cannot be explained by differences in stage alone (Hermanek and Wittekind, 1994). Therefore, the R classification influences further treatment planning.
Post-operative staging is performed by histopathological examination of the resected specimen, using standard haematoxylin and eosin staining and light microscopy, and is considered the gold standard.
Recent work has focussed on the use of PET and PET-CT in the staging of colorectal cancer, and the search for recurrence. These newer modalities have a higher sensitivity and specificity than traditional radiological techniques (Arulampalam et al, 2004, Bipat et al, 2005, O’Dwyer et al, 2001). They have the advantage of showing tumour activity, due to uptake of the radio-isotope 18F-fluorodeoxyglucose.
There are several staging methods currently in clinical practice. The staging system described by Dukes in 1932 (Table 2.1, Dukes, 1930, Dukes, 1932) was originally applied to rectal cancer, but later adopted for colonic cancer. Dukes’ system is perhaps the best known, and is favoured for its simplicity. There have been several refinements of this system, in order to try to improve its prognostic accuracy (Astler and Coller, 1954, Jass et al, 1987), but none of these match the flexibility of the TNM method.
Table 2.1 Dukes’ Staging System
|Dukes’ Stage||Description||Frequency (%)||5 Yr Survival (%)|
|A||Confined to bowel wall||11||83|
|B||Extension through bowel wall||35||64|
|C||Lymph node metastases||26||38|
Data adapted from Stower and Hardcastle, 1985
The Tumour Node Metastasis system (TNM) described by the Union International Contre Cancer (UICC) is shown in Table 2.2 (Hermanek et al, 1999). With this classification system, patients with stage I and II disease have a 90% to 70% 5-year survival rate. Patients with stage I or II disease are node negative and lack evidence of extracolonic spread. Surgical resection of the primary is potentially curative. However, up to 30% of these patients develop metastatic disease and eventually die from colon cancer, suggesting that there is extracolonic spread of disease at the time of surgery in these patients that is undetectable with standard techniques.
Table 2.2 TNM Staging System
|Stage||T||N||M||5 Yr Survival
|4||T any||N Any||M1||3|