Tumor is a descriptive term for a growth or mass of cells that are independent of the physiologic function or demand of their surrounding structures. The 2 characteristic biologic growth patterns of tumors include the ability to (1) disrespect tissue boundaries and invade other structures (invasiveness) and (2) gain access to blood and lymph vessels or other structures to spread tumor cells to distant locations and allow these specially equipped cells to survive and grow new remote tumors (metastases). If a tumor does not have either property, it is benign; if a tumor can invade locally but even at a large size does not have a tendency to metastasize, it is called semimalignant; and if a tumor has the ability to metastasize once a sufficient size is reached, it is a malignant tumor.

Colorectal lesions may be classified as benign, potentially malignant, or malignant based on their pathologic features (Table 49-1); the semimalignant variant with invasion only but no affinity to later form of metastases is not common in the colon. The overwhelming majority of colorectal tumors are of epithelial origin and arise from the mucosal surface, where they become visible descriptively as a polyp. Benign polyps include nonneoplastic polyps (eg, hyperplastic, hamartomatous, or inflammatory polyps); the potentially malignant group consists of adenomatous polyps. Once dysplastic cells in a polyp cross the boundaries of the mucosa (basement membrane and muscularis mucosae) and start to invade the submucosa and the muscularis mucosae, a true cancer (carcinoma) with the potential to metastasize is established. Tumors of nonepithelial or mesenchymal origin are comparably rare and include, among others, lipoma, lymphoma, carcinoid, and sarcoma.^1-3

Colonic tumors are important for 2 reasons. First, they are frequent and account for both a significant mortality rate as well as high cumulative health care costs. Second, the sequence of events leading from a normal mucosa to a manifest cancer occurs through largely preventable precursor stages over the course of several years. Thus, this chapter predominantly focuses on the detection, management, and prevention of these conditions.

Colorectal cancer is the most common malignancy in the gastrointestinal tract. In the United States, colorectal cancer is the third leading cause of cancer death in both men and women and the second leading cause of cancer death when men and women are combined.⁴ With an estimated 134,490 newly diagnosed cases, this disease will be responsible for an estimated 49,290 deaths in the year 2016. The lifetime risk of approximately 6% in our Western civilization means that 1 in 18 individuals of the general population will be affected by colorectal cancer and many more by polyps, making it an important public health issue.⁵ Worldwide, colorectal cancer shows large geographical differences, with a crude incidence of 6.5 and 7.7 cases per 100,000 females and males, respectively, in less developed areas as opposed to 50.9 and 60.8 cases, respectively, in more developed regions.⁶ Regardless of ethnicity, there is an age-dependent increase in incidence with each decade starting at age of 40 years, and the mean age at presentation is around 70 to 75 years.

In the period between 1975 and 2006, the Surveillance, Epidemiology, and End Results (SEER) Registry of the National Cancer Institute (NCI) showed a gradual decline in all cases of colorectal cancer in the United States from 69.7 to 50.6 cases per 100,000.⁷ However, although these numbers reflect the trend in whites, the incidence of colorectal cancer in the United States for African Americans has remained at the same level of 59.3 to 61.5 cases per 100,000 individuals. African American males therefore now represent the ethnic subgroup with the highest risk.^8,9

The specific cause of colorectal cancer is not known. However, a number of genetic and environmental risk factors have been associated with the disease.¹⁰ From a practical and screening standpoint, it has been helpful to group individuals into 3 risk categories (ie, average risk, increased risk, and high risk) based on their presumptive genetic profile as reflected in their individual and family history.^11,12 The high-risk and increased-risk groups consist of patients with known hereditary syndromes or bowel diseases or patients with a personal or family history of polyps or cancer, all of which are discussed in a later section of the chapter (Table 49-2).

The majority of cases, however, are sporadic colon cancers that typically arise within a polyp. Geographic and migrational studies have suggested that the Western lifestyle increases the risk for colon cancer, hence suggesting that nutritional and environmental factors may play a key role.¹³ A large number of epidemiologic studies have been undertaken to identify these individual, nutritional, lifestyle, genetic, and environmental factors that would either predispose to or prevent the development of colorectal polyps and cancer (Table 49-3).^14-19

Extrinsic Risk Factors

DIETARY FIBER, MEAT, AND FAT

One of the characteristics of a Western diet generally has been the lack of fiber as opposed to the increased amount of meat, total fat, and animal fats.^20,21 In view of the known geographic differences, with the highest colorectal cancer incidence in industrialized nations,⁶ a high-fat and low-fiber diet generally has been considered a risk factor for the development of colorectal cancer.²² This concept gained support from epidemiologic studies²³ and resulted in common recommendations of high-fiber supplements to increase the stool bulk, dilute toxins, and reduce the colonic transit time and thus the exposure time to fecal carcinogens.^24-27 More recent prospective trials, however, have questioned the benefit of dietary fiber supplementation in that they were at best inconclusive and did not reduce the incidence of colorectal cancer.^28,29 However, selected fats such as n-3 fatty acids found in fish oils may have a protective effect,³⁰ even though a direct effect to the mucosa could not be observed.³¹ Therefore, it could be concluded that the total amount of fats or fibers is of lesser importance than their quality and origin.^19,20,32 The protective effect of vegetables and fruits^33,34 may come not only from their fiber content but also from the content of antioxidative and antiproliferative agents, such as isothiocyanates in cruciferous vegetables (eg, broccoli), which may enhance the expression of carcinogen-metabolizing enzymes and induce apoptosis in neoplastic cells.^16,35

CALCIUM, VITAMINS, AND MICRONUTRIENTS

Several prospective studies suggested that increased oral calcium and selenium intake may protect from colorectal polyps and cancers,^36-41 whereas other studies could not verify a significant benefit.⁴² The mechanism by which calcium supplements are thought to reduce the risk of colon cancer is 2-fold. First, calcium can bind bile and fatty acids in the stool to insoluble complexes that are less likely to attack the colonic mucosa, and second, it can interfere directly with the mucosal cells and decrease their proliferative potential on a cellular level.²³

Several vitamins were found to have a cancer-protective effect. Vitamins A, C, and E have been shown to have antioxidant activity. Results from interventional studies, however, have remained somewhat disappointing or controversial.^43,44

In a study on postmenopausal women, another correlation was found between dietary heme iron and an increased risk of proximal colon cancer, especially in conjunction with alcohol consumption, whereas intake of dietary zinc reduced the risk of both proximal and distal colon cancer.⁴⁵

ASPIRIN AND COX-2 INHIBITORS

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the development of colorectal neoplasms by blocking the cyclooxygenase (COX)-dependent prostaglandin pathway.⁴⁶ The targets are the constitutive COX-1, as well as the cytokine-inducible COX-2, which has been found at increased expression levels in both polyps and cancers.⁴⁷ Therefore, several trials have studied these agents (eg, aspirin and sulindac) for the chemoprevention of colorectal cancer both in sporadic polyps and cancers⁴⁸ and in familial adenomatous polyposis (FAP).^49-51 In both settings, controlled studies have provided contradictory results.⁵² Regular prophylactic medication with low-dose aspirin may reduce the risk of sporadic colorectal cancer.^48,53 Data from chemoprevention trials in FAP suggest that COX inhibition may delay the onset and number of adenomatous polyps, but it is not yet clear whether it is able to prevent the cancers overall or reduce their respective risk.^49-51 COX-2–independent mechanisms may play a role in the beneficial effect of some COX-2 inhibitors.⁴⁶ A major concern, however, has been the documented increased risk of serious cardiovascular events with the use of COX-2 inhibitors.^54,55

Because data on the benefits remain conflicting, physicians must decide how to use these pharmacologic tools in the management of their patients. Based on the presumed small risks in general and the supporting data on a possible benefit, most physicians would be inclined to err on the side of a potential benefit in preventing colon polyp formation. Low doses of aspirin and calcium may be helpful in preventing polyps and cancers. However, concern about cardiovascular side effects and increased mortality has resulted in a withdrawal of more potent COX-2 inhibitors until further redefinition of the indications and risk groups has been accomplished.^54,55

CHOLECYSTECTOMY AND BILE ACIDS

Evidence that bile acids may act as cocarcinogens or tumor promoters comes from both experimental and epidemiologic studies.^56,57 Bile acids can induce hyperproliferation of the intestinal mucosa via a number of intracellular mechanisms. Cholecystectomy, which alters the enterohepatic cycle of bile acids, has been associated with a moderately increased risk of proximal colon cancers.^58,59 It cannot be ruled out, however, that it is less the effect of the cholecystectomy than the impact of other, not yet identified factors in the lithogenic bile of such patients. A number of cofactors have been identified that may enhance or neutralize the carcinogenic effects of bile acids, for example, the amount of dietary fat, fiber,²³ or calcium.⁶⁰ Calcium, in fact, binds bile acids and thus may reduce their negative impact. However, other more intrinsic mucosa-protective mechanisms of calcium supplements probably are more relevant for the demonstrated reduction of recurrent adenomatous colon polyps.

SMOKING AND ALCOHOL CONSUMPTION

The risk of colorectal cancer is increased, though modestly, among long-term smokers compared with nonsmokers.^26,45,61,62 The data suggested a dose-response relationship between pack-years of tobacco use and the development of adenomatous polyps.^63-66 Equally, excessive alcohol consumption has been associated with an increased risk for colon cancer.^26,45,61,62

OTHER FACTORS

An ever-increasing number of other factors are accumulating that have been attributed to an increased risk of colon cancer, such as lack of physical activity, diabetes, serum insulin levels, elevated concentrations of insulin-like growth factor 1, and low concentrations of insulin-like growth factor–binding protein 3 (IGFBP-3).⁶⁷ The complexity of interactions between these factors and the previously mentioned parameters, however, makes it difficult at the present time to draw conclusions that have an impact on clinical practice.

Intrinsic Risk Factors

PERSONAL AND FAMILY HISTORY

There is generally little debate on whether the presence of an adenomatous pathology or chronic inflammatory bowel disease (IBD) in itself represents a risk factor for a subsequent colon cancer. In patients with a colon cancer, synchronous colorectal cancers are found in 5% to 10%, whereas about 10% to 20% of patients with a history of colorectal cancer will develop metachronous primary cancers in the large intestine. A personal history of adenomatous colonic polyps is an indicator for an increased colonic predisposition to develop subsequent adenomatous or cancerous changes.^12,68-72

Compared with the general population, relatives of patients with colon cancer have a 2 to 4 times increased risk of developing the disease themselves (Table 49-4).^26,73,74 A similar, even though proportionally lesser, risk is observed for family members of individuals with colonic adenomatous polyps.

INFLAMMATORY BOWEL DISEASE

IBD is a strong risk factor for colorectal cancer. The risk correlates with the age of onset and extent and duration of active disease.^75,76 In contrast, however, the disease activity historically was not thought to be correlated with the risk, but recent studies have challenged this view.⁷⁷ In patients with ulcerative colitis, the risk of colorectal cancer increases from approximately 3% in the first decade to 10% to 20% in the second decade.^75,76 In patients with Crohn’s disease with colonic involvement, the disease-associated risk for colorectal cancer is also elevated but generally to a lesser extent.^78-80

OTHER FACTORS

Less frequent risk factors for colorectal cancers may include a history of a ureterocolostomy⁸¹ or previous radiation treatment.⁸² The former requires the combination of fecal bacteria and urine because the microbes degrade urinary metabolites into strong carcinogens.^81,83,84 When colonic mucosa is used for bladder augmentation, no increased cancer risk is observed owing to the absence of bacteria. The findings in radiation-induced colorectal cancer are a little less clear, but it has been suggested that it may be associated with a mucinous histology and poor prognosis.⁸²

Prevention and Screening

Because symptoms are not reliable for early detection of colorectal cancer, risk-adjusted screening programs for asymptomatic individuals are important. Effective screening has to be based on an understanding of the adenoma-carcinoma sequence, which may take up to 5 to 10 years from the first molecular change to a clinically manifest cancer, and should reflect an individual’s genetic and disease- or age-dependent risk for the development of colorectal cancer.^11,12,85-87 Any prevention program has to be sensitive but also practical and cost-effective in order to achieve a broad screening of the population at risk. The term “screening” is applicable only to asymptomatic people; if symptoms are present, it is not screening but diagnostic tests that are initiated. Common tools for screening include fecal occult blood tests (FOBTs), flexible sigmoidoscopies or colonoscopies, and contrast enemas or computed tomography (CT) colonography.⁸⁸

The American Cancer Society, endorsed by the major professional societies, recommends starting colorectal cancer screening in asymptomatic average-risk adults at age 50.^11,12,85-87 A slightly earlier screening start at age of 45 has been recommended recently for African American patients based on their statistically significant increased risk.⁹ A first baseline colonoscopy is to be performed and, if no pathology is found, repeated every 10 years. In addition, an FOBT should be done on an annual basis, and any positive result should precipitate a full colonic evaluation. Every 5 years, a limited endoscopy (flexible sigmoidoscopy) or barium enema is indicated. If precursor lesions are found, they should be removed, and a colonoscopy should be performed after 1 to 3 years to detect missed (20%) or recurrent polyps.^89-91

In individuals at increased risk (eg, personal/family history of polyps or cancer or African American ethnicity) or at high risk (eg, cancer syndromes or IBD), the screening has to start earlier (see Table 49-2) and has to be performed at a higher frequency.⁹ Successful screening programs have been shown to reduce the colorectal cancer incidence by 76% to 90%.⁹²

Carcinogenesis in the colon is a complex multistep process in which a multitude of alterations must coincide in order to transform a normal cell into a malignant cell. Several categories of genes are involved that normally are regulated in a sophisticated network to keep a tight balance between cell growth and turnover, cell death, DNA replication, and mismatch repair. Disruption of the fine balance between oncogenes, which promote cell proliferation, and tumor suppressor genes, which inhibit excessive growth, results in a growth advantage and allows malignant cells to expand.

Colon Cancer: A Genetic Disease

All cells of even such a complex organism as a human being have DNA that is virtually identical to the DNA found in the zygotes. DNA mutations can occur either as a germline mutation or as a somatic mutation. The former may be transmitted from one to the next generation as an inherited defect. More commonly, a spontaneous mutation occurs in a non-germline cell during the growth, development, and maintenance of a tissue or organ (somatic mutation). Even in the cycle of a normally functioning cell, there is a high chance of spontaneous gene mutations, most of which will not result in a growth advantage to the harboring cell. Genesis of a cancer therefore requires several independent accidents to occur in 1 cell. One can assume that a normal cell will be able to detect damage to its own DNA and maintain an effective repair mechanism. However, if the cell is too severely damaged, it might rather initiate the inherent suicide program called apoptosis. When a cell fails to recognize or correct DNA damage and continues to replicate, accumulation of faulty gene products within the cell may eventually lead to a proliferative response. If that replication exceeds the growth potential of the neighboring normal cells, the mutation provides a growth advantage that will increase the state of “genetic instability” and hence lead toward a malignant cell.⁹³ Despite this potential, most mutations are silent or lethal to the cell rather than beneficial in terms of providing the cell a biologic advantage. The triggers and the step-by-step cumulative failures that lead to carcinogenesis still are relatively poorly understood.

Two types of genetic instability may occur: at the chromosome level or at the DNA level. A loss of chromosomal material, that is, a chromosomal instability (CIN), results when the chromosomes are not divided symmetrically during mitosis such that 1 daughter cell receives both copies and the other cell receives none. On an electrophoretic gel, this can be visualized as a loss of 1 or more bands, which is described as loss of heterozygosity (LOH), and has been associated with a worse prognosis in colorectal cancer.² The second form of genetic instability, at the DNA level, occurs when replication errors in repetitive short polymorphisms lead to an additional band or bands.⁹⁴ This phenomenon is described as microsatellite instability (MSI), and it has been a characteristic feature of hereditary nonpolyposis colon cancers (HNPCCs).⁹⁵

During the process of cell division, DNA is duplicated, with the original DNA serving as a template for the replicated copy. DNA polymerase serves as a “proofreader” that recognizes mismatched genes, halts the DNA synthesis, removes the defective sequence, and then resynthesizes the DNA. Failure of the DNA mismatch repair system predisposes to the development of mutations within daughter cells. Enzymes that monitor newly formed DNA and correct replication errors are called DNA mismatch repair (MMR) systems.

Specific gene functions are lost when both copies (alleles) of a gene are inactivated. Thus, when a germline mutation occurs in a suppressor gene, only the mutation of the remaining normal allele is required for the gene’s loss of function. When both copies of the gene are normal, 2 mutational events are required for the gene’s loss of function. This 2-hit hypothesis may explain why inherited diseases usually manifest at an earlier age than sporadic disease.⁵

The Adenoma-Carcinoma Model

After identifying several genetic alterations in colorectal specimens at various stages of their neoplastic transformation and progression, Vogelstein and colleagues in 1988 pioneered a genetic model for colorectal tumorigenesis that since has been known as the adenoma-carcinoma sequence (Fig. 49-1).³ This multistep model described the carcinogenesis as an accumulation of genetic events, uninhibited cell growth, and proliferation and clonal development. Gene mutations and chromosomal/gene losses that were observed in sporadic colon cancer include the APC gene (adenoma–polyposis coli), MMC gene (mutated in colon cancer), K–ras, DCC (deleted in colon cancer), and p53.^2,96,97 Mutations of the APC gene, which is involved in the control of cell-to-cell adhesions and intercellular communication, are found in 60% of even small adenomatous polyps, as well as in carcinomas,⁹⁸ and therefore are believed to occur as a very early event in carcinogenesis. Mutations of K–ras, which under normal function plays a role in intracellular signal transduction and stimulated cell division, occur in larger adenomas and carcinomas and are thought to stimulate cell growth. Deletion of the tumor suppressor gene DCC may be important in the progression from a benign polyp to a malignant condition.⁹⁹ Mutations of the p53 gene, which are among the most frequent gene mutations in human cancers, are also common in invasive colon cancers but rare in adenomas, suggesting that p53 mutations occur as a late event in the development of the invasive phenotype.¹⁰⁰ The wide range of gene mutations, inactivations, and deletions in the progression to carcinoma seems to hold the secret code for the various tumor behaviors observed in the clinical setting. It is important to note, however, that an increasing number of other genetic events have been observed and reported and that no single event seems to be equally present in all colon cancers. One therefore should caution that the described sequence is only one possible model and that the scenario may not reflect all aspects of colonic carcinogenesis.

The Cancer Stem Cell Model

Tumors arise from the expansion of a mutated cell and contain a heterogenous cellular population. There is increasing evidence that not all cells within a tumor have the same capacity for proliferation and tumorigenesis. Instead, tumor growth is driven by a subset of the population, termed cancer stem cells, that have the ability to self-renew and differentiate to form all the lineages found within the tumor. This has implications for future therapeutic treatment as current radiotherapy and chemotherapy target all rapidly dividing cells nonspecifically. If all cancer stem cells within the tumor are not destroyed, this could lead to disease relapse and metastasis.^101,102

Cancer stem cells are thought to arise from normal stem cells that have lost their regulation of self-renewal or from progenitor cells with a defined lineage fate that have obtained the ability to self-renew. Normal stem cells are likely targets for transformation because the machinery for self-renewal is already active, and they can persist in normal tissue for a long time and accumulate transforming DNA damage. The intestinal stem cell niche provides a unique environment to regulate self-renewal and differentiation of these stem cells. Multiple signaling pathways are used to regulate stemness within the niche, including the Wnt, BMP, and Hedgehog pathways, and aberrations in these signals can disrupt the normal crypt-villus axis.¹⁰³ Myofibroblasts are thought to play an important role in regulating the microenvironment found within the stem cell niche, in normal tissue, primary tumors, and metastatic lymph node disease.¹⁰⁴ The centers of tumors often have a lack of blood supply and oxygen, and there is evidence that hypoxia maintains the niche for colorectal cancer stem cells by maintaining stemness and inhibiting lineage differentiation via BMI1 and Notch1.¹⁰⁵ Various cell surface markers have been identified to enrich for colorectal cancer stem cells, including CD133,^106,107 CD44,¹⁰² and CD24.¹⁰² It is hoped that treatments that specifically target the cancer stem cell population within a tumor will allow more complete treatment of the disease and prevent relapse.

Nonhereditary Colon Cancer

SPORADIC COLON CANCER

Sporadic colon cancer, that is, colon cancer arising in individuals without a family history or an inherited predisposition, accounts for approximately 60% of all colorectal cancers and affects patients commonly older than 50 years. The risk factors associated with sporadic development of colon cancer have been discussed previously in the epidemiology section of this chapter (see Table 49-3).

FAMILIAL COLON CANCER

Familial colon cancer is the second most common (25%-30%)⁵ and, at the same time, least understood pattern of genetic colon cancer development. In affected families, colon cancer develops too frequently to be considered a sporadic colon cancer, but the pattern is not consistent with the known inherited syndromes.¹⁰⁸ An association of familial colon cancer has been found with polymorphisms, which reflect subtle genetic changes in the form of variations in the nucleotide base sequences but which do not affect protein structure.⁵ Familial colon cancer in the Ashkenazi Jewish population probably is the result of an APC germline mutation on codon 1307 (I1307K). This mutation, which predisposes to sporadic mutations at distant sites of the gene and later results in structural protein abnormalities, is found in 6% of all Ashkenazi Jews and in 28% of those with both a personal and a family history of colon cancer.¹⁰⁹

Hereditary Colon Cancer

FAMILIAL ADENOMATOUS POLYPOSIS

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome with near-complete penetrance. The offspring of affected individuals thus have a 50% risk of inheriting FAP. However, up to 20% of patients with FAP have new mutations without a family history. This condition is attributed to a truncating mutation in the germline adenomatous polyposis coli (APC) gene on chromosome 5q21.¹¹⁰ Variants of the polyposis syndrome are classified as Gardener syndrome (ie, osteomas, desmoid tumors, thyroid neoplasms, and congenital hypertrophy of the retinal pigment epithelium) and Turcot syndrome (ie, brain tumors).

The inherited syndrome of FAP and its variants accounts for less than 1% of all colon cancers. It is characterized by greater than 100 and often several thousand adenomatous intestinal polyps that start to develop in the late teens and early twenties and turn into cancer by age 40 to 45. An attenuated variant of the disease is relatively rare and is characterized by a lower number and a later onset of both the polyps and the resulting cancer (see the following text). Nearly all FAP patients develop duodenal adenomas that are severe in 10% and account for the group’s second highest cancer risk, with adenocarcinoma developing in the periampullary region in 3% to 10% of patients.^111,112 Carcinoma arising in the antrum and duodenum after colectomy is the main cause of cancer-related deaths in FAP patients.^111,113,114 Nonadenomatous fundic gastric polyps develop in approximately 10% to 30% of patients with FAP¹¹⁴ but usually do not have a malignant potential. Ten percent of FAP patients develop desmoid tumors either intra-abdominally or on the abdominal wall, extremities, and trunk.¹¹⁵ Histologically, desmoids are fibromatous lesions consisting of large proliferation of myofibroblasts. Even though they do not necessarily carry features of a malignant lesion, the recent literature suggests a low-grade sarcoma-like behavior. Desmoids are lethal in 10% and are the third most frequent cause for mortality of FAP patients, mainly due to the intra-abdominal variants, which cause small bowel and ureteral obstructions.^115,116

Approximately 25% of FAP patients remain without an identified APC mutation (APC negative),^116,117 and using a detailed analysis, they seem to differ in terms of lower polyp number, later age at diagnosis, and lower occurrence of extracolonic manifestations as compared with classic FAP patients.^114,118 This variant of FAP is known as attenuated familial adenomatous polyposis (AFAP).

HEREDITARY NONPOLYPOSIS COLON CANCERS

Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch I and II syndromes, is an inherited autosomal dominant disease that accounts for 3% to 5% of all colorectal cancers.¹¹⁹ It is characterized by an early onset of colorectal cancers predominantly but not exclusively on the right side of the colon with synchronous and metachronous cancers. Despite its name, these cancers typically arise from colonic polyps, but a diffuse polyposis is not present. The penetrance of the HNPCC predisposition is high and results in an 80% to 85% lifetime risk of colorectal cancer and a 40% to 50% risk of endometrial cancer.^15,120,121 Furthermore, HNPCC patients are at increased risk of developing extracolonic malignancies, such as cancer of the small bowel, stomach, hepatobiliary tract, urinary tract, ovary, and brain. The Lynch variants describe patients with predominantly colorectal cancer at a young age (Lynch I) and those with both colorectal and extracolonic cancers (Lynch II).¹¹⁹

An initial observation of expansions and contractions of microsatellite DNA in the genome of colorectal tumor specimens from HNPCC patients established a link between HNPCC and the DNA MMR system.^122-124 In contrast to the gatekeeper concept applicable to the APC gene in FAP, the DNA MMR genes belong to the so-called caretakers, which, when inactivated, do not promote tumorigenesis directly but rather lead to a genetic instability that then promotes tumor growth indirectly.¹²⁵

To facilitate the clinical diagnosis of HNPCC, the International Collaborative Group on HNPCC (ICG-HNPCC) proposed the Amsterdam Criteria in 1990.¹¹⁹ Linkage studies in HNPCC families fulfilling Amsterdam Criteria I (Table 49-5) led to the discovery of the first 2 human MMR genes—hMSH2 and hMLH1. These genes accounted for 45% to 86% of all classic HNPCC families.¹²⁶ There also was a higher risk for hMSH2 mutation carriers to develop extracolonic cancers, in particular endometrial cancer, as compared with hMLH1 mutation carriers.^121,127 Several other MMR genes have been identified in conjunction with HNPCC and include hPMS1, hPMS2, and hMSH6. A recent study reported that endometrial cancer represents the most common clinical manifestation of HNPCC among female hMSH6 mutation carriers and that colorectal cancer cannot be considered an obligate requisite to define HNPCC.¹²⁸ The ICG-HNPCC therefore revised the criteria (Amsterdam Criteria II), which now better weigh extracolonic manifestations (eg, endometrial, breast, small bowel, and upper renal tract cancers) as part of the family history (see Table 49-5). In addition, the less restrictive revised Bethesda Criteria (Table 49-6) were adopted to better serve patients who carry hMSH2 or hMLH1 gene mutations but otherwise do not fulfill the Amsterdam Criteria. Testing for MSI has become a valuable diagnostic tool to identify individuals with suspected HNPCC because 85% to 90% of HNPCC tumors have MSI as opposed to only 15% to 20% of sporadic colon cancers.⁹⁵

HAMARTOMATOUS POLYPOSIS SYNDROMES

Approximately 4% of colonic cancers are seen in the context of rare syndromes. Among these are inherited hamartomatous polyposis syndromes that are characterized by the presence of gastrointestinal hamartomatous polyps and an increased risk of gastrointestinal malignancy. Hamartomas result from a disordered differentiation during embryonic development and are characterized morphologically by disrupted representations of normal tissue components.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome is the second most common hamartomatous syndrome, occurring as an autosomal dominant condition with variable penetrance. Genetic alterations in the LKB1/STK (19p13) gene are responsible for approximately 50% of the cases of Peutz-Jeghers syndrome.¹²⁹ The syndrome is associated with hamartomatous polyps of the gastrointestinal tract and cutaneous melanin deposition. The most common location of Peutz-Jeghers polyps is in the upper gastrointestinal tract, specifically the upper jejunum. One of the most characteristic features is the melanin depositions, which are seen most frequently in the perioral region or buccal mucosa but also can occur in the genital region and on the hands and the feet. While a majority of these patients remain relatively asymptomatic, some may present with abdominal pain secondary to obstruction or impending obstruction due to an intussuscepted polyp and others with gastrointestinal bleeding. Patients with Peutz-Jeghers syndrome have a moderately increased risk in the range of 2% to 3% to develop gastrointestinal malignancies and extraintestinal malignancies.

Juvenile Polyposis Syndrome

Juvenile polyposis syndrome is the most common hamartomatous syndrome and is inherited as an autosomal dominant trait. The average age of onset is approximately 18 years, and there is an association with congenital birth defects in 15% of patients.¹³⁰ Although the diagnostic criteria for juvenile polyposis syndrome are somewhat controversial, the most commonly used criteria include 3 or more juvenile polyps of the colon, polyposis involving the entire gastrointestinal tract, or any number of polyps in a member of a family with a known history of juvenile polyps.¹³¹

In infancy, patients may present with acute or chronic gastrointestinal bleeding, intussusception, rectal prolapse, or a protein-losing enteropathy. In adulthood, patients commonly present with either acute or chronic gastrointestinal blood loss. Most of these patients will be found to have polyps, which are located most frequently in the rectosigmoid region.

A germline mutation in the SMAD-4 gene (18q21) accounts for approximately 50% of the reported cases of the syndrome.¹³² A significant risk of colorectal cancer is associated with juvenile polyposis syndrome, and this syndrome should not be confused with isolated juvenile polyps because the latter have virtually no malignant potential.

Cowden Disease

Cowden disease, first described in 1963, is known as multiple hamartoma-neoplasia syndrome. It is an autosomal dominant condition with nearly complete penetrance by age 20 that is caused by germline mutations in the PTEN tumor suppressor gene located at 10q22.^133,134 Cowden disease is unique among the hamartomatous syndromes because polyps arise more commonly from ectodermal rather than endodermal elements. Eighty percent of patients present with trichilemmoma, a benign tumor of the hair shaft. The central nervous system is the second most involved system, with approximately 40% of affected individuals suffering from macrocephaly. Only 35% of patients who meet the diagnostic criteria for Cowden disease have gastrointestinal polyposis, but no increased risk of invasive gastrointestinal malignancy has been reported to date. The majority of patients with Cowden disease suffer from benign thyroid or breast disease, in addition to a projected lifetime risk of 10% for thyroid cancer and of 30% to 50% for breast cancer.

Bannayan-Riley-Ruvalcaba Syndrome

Formerly known as its subentity, the Ruvalcaba-Myhre-Smith syndrome, this rare autosomal dominant condition includes 2 other syndromes, both of which, like Cowden disease, are associated with genetic alterations in the PTEN gene on chromosome 10q23 and may be considered a variant of juvenile polyposis coli.^135-137 It is characterized by hamartomatous polyps of the gastrointestinal tract, macrocephaly, mental retardation, delayed psychomotor development, lipid storage myopathy, Hashimoto thyroiditis, and hyperpigmentation of the skin of the penis. No increased risk of colorectal carcinoma, other gastrointestinal malignancies, or extraintestinal malignancy has been documented in these patients.

Cronkite-Canada Syndrome

Cronkite-Canada syndrome is characterized by diffuse polyposis and ectodermal abnormalities such as alopecia, onychodystrophy, and skin hyperpigmentation. The syndrome can be distinguished by the diffuse distribution of polyps throughout the entire gastrointestinal tract with exception of the esophagus, which is spared.¹³⁸ Symptoms include diarrhea, weight loss, nausea, vomiting, and anorexia, as well as paresthesias, seizures, and tetany related to electrolyte abnormalities. Cancer occurs in the stomach, colon, and rectum, but it remains controversial whether polyps in Cronkite-Canada syndrome possess malignant potential. As many as 15% of patients with Cronkite-Canada syndrome have a malignant tumor at the time of diagnosis.

Polyps

Polyp is a descriptive clinical term for any mucosal elevation. Polyps are further categorized along several dimensions, including

1. 
   

   Size

   
   
2. 
   

   Character of their attachment to the bowel wall (eg, sessile or pedunculated)

   
   
3. 
   

   Cellular architecture (eg, adenomas, hyperplastic, hamartomas, inflammatory) and histologic appearance (eg, tubulous, tubulovillous, villous)

   
   
4. 
   

   Progression from benign to malignant behavior (eg, benign, dysplastic, cancer)

Most polyps are neoplastic but not necessarily malignancies. Neoplastic polyps consist of cells with the potential to acquire over time the ability to invade and to spread, that is, metastasize. Dysplasia is a term used to describe the intervening state between normal tissue and invasive malignancy.

POLYP SIZE

The most immediate way in which a polyp can be described is by its size. Intuitively, polyps with a larger mass have a greater volume of neoplastic cells, and hence a higher likelihood of harboring cancer. The relationship between adenomatous polyp size and the presence of invasive malignancy was analyzed elegantly by Nusko et al¹³⁹ (Table 49-7).

POLYP ATTACHMENT TO BOWEL WALL

Polyps of any size or architecture may be pedunculated, sessile, or some combination of both. The main clinical relevance of this distinction lies in the ease of endoscopic removal, with pedunculated polyps being clearly more amenable to removal without surgical intervention.^140,141

It is important to note that the way in which a polyp is attached to the wall of the colorectum does not accurately predict the presence versus absence of an invasive malignancy. Malignant polyps of the colon can be either pedunculated or sessile. The type of treatment that should be offered to a patient depends much more on the other characteristics of the polyp.

POLYP ARCHITECTURE

Based on their histologic structure, polyps can be categorized into adenomatous and nonadenomatous polyps, the latter of which consists of hyperplastic, hamartomatous, and inflammatory polyps.

Adenomatous Polyps (Adenomas)

The most common type of polyp in the colon is the adenomatous polyp. Adenomatous polyps are categorized as tubular, tubulovillous, or villous based on the extent to which the dysplastic epithelium is organized with the normal-appearing tubular architecture.¹⁴² Tubular adenomas are defined by the presence of tubules within 80% or more of the lesion; adenomas with less than 20% showing a tubular configuration are villous lesions; and the remainder is considered tubulovillous. The majority of polyps are tubular (87%), with a minority being either tubulovillous (8%) or villous (5%).¹⁴³

With few exceptions, the treatment for an adenomatous polyp is endoscopic polypectomy. Colorectal cancer screening programs that include colonoscopy with polypectomy have demonstrated a reduction in the incidence of colorectal cancer and colorectal cancer mortality.¹⁴⁴ It is difficult, however, to estimate the likelihood that a small adenoma will progress to a dysplastic adenoma and eventually into cancer. A number of biologic and molecular markers have been analyzed as predictors of a malignant potential, but these are not widely used.¹⁴⁵ Longitudinal and comparative data suggest that polyps not only progress but also may regress.¹⁴⁶ Despite these vagaries, any adenomatous polyp should be considered a premalignant lesion and be treated as such.

Invasive carcinoma is present in 5% of all adenomas, but the incidence correlates with the size and type of the adenoma (Table 49-8).^139,147

The Haggitt classification, which defines 4 levels within the polyp, has evolved as a useful tool to describe the degree of cancer invasion into a pedunculated or sessile adenomatous polyp.¹⁴⁸ This classification forms the basis of the management of malignant polyps (Fig. 49-2). In Haggitt levels 1, 2, and 3, the risk of lymph node metastasis in a surgical specimen is less than 1%, whereas a level 4 invasion of the stalk behaves like a sessile T1 lesion and carries a higher risk of 12% to 25% of having lymph node metastases. A similar, but less well-known, classification was developed in 1993 by Kudo and associates, who for prognostic purposes suggested to divide the submucosal invasion of sessile malignant lesions into 3 levels (Sm1, Sm2, and Sm3) (Fig. 49-3).¹⁴⁹

Flat and/or depressed adenomas are a subtype of colonic adenoma with a propensity for high-grade dysplasia in 10% to 41% of affected patients regardless of the small size of these lesions.¹⁵⁰ The entity was first described in Japan, where they seem to occur at a regular frequency. These lesions, which are flat or slightly raised to less than 2 mm and commonly less than 1 cm in size, may be overlooked easily on colonoscopy and turn into a cancer before having reached a size comparable with classic cancers.^150-153 Recent screening studies, which took advantage of chromoendoscopy techniques, have confirmed that flat adenomas represent up to 25% to 36% of all polyps found in a random cohort and are present in 8% to 11% of the population.^153,154

Hamartomatous Polyps

A hamartomatous polyp is composed of a spectrum of different cellular elements and is considered a nonneoplastic entity with no significant premalignant potential.^155,156 Several clinical syndromes manifest with a polyposis of hamartomatous polyps (eg, juvenile polyposis, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Cronkite-Canada syndrome), and these have been discussed earlier in this chapter. These syndromes carry varying risks of intestinal and extraintestinal disease, and several also impose an increased likelihood of developing intestinal cancer due to immature glandular elements in the hamartomatous polyp. Stable estimates of this risk are difficult to calculate because of the relative rarity of these diseases.

Hyperplastic Polyps

Hyperplastic polyps are small, sessile mucosal outgrowths that display an exaggerated crypt architecture. They are usually small, with only very few (1%-4%) larger than 1 cm; however, these larger polyps actually may be serrated adenomas rather than hyperplastic polyps (see the following text).¹⁵⁷ Within the colorectum, hyperplastic polyps commonly have a distal distribution pattern, predominantly in the rectum and sigmoid colon, and they have been reported in up to 75% of patients older than 60 years at autopsy.¹⁵⁸ It is not unusual to find several of these polyps in a single individual.

Histologically, hyperplastic polyps display well-formed glands and crypts that are lined by nonneoplastic epithelial cells. Because of their small size, hyperplastic polyps are generally clinically silent, but large or multiple hyperplastic polyps occasionally can be responsible for gastrointestinal symptoms.

Historically, hyperplastic polyps have been considered benign and not premalignant.¹⁵⁷ This paradigm has been increasingly questioned, beginning in 1990 with work by Longacre and Fenoglio-Preiser.¹⁵⁹ The ability of hyperplastic polyps to develop defective mismatch repair genes and foci of microsatellite unstable cancers has been documented, strengthening this concept.¹⁶⁰ Additional research has illuminated an epigenetic pathway, whereby a promoter region in the DNA of hyperplastic polyps is methylated, resulting in progression along a sequence of steps that leads to a serrated adenoma and eventually carcinoma.¹⁶¹ The clinical significance of hyperplastic polyps and serrated adenomas is a topic of emerging importance in the field of colorectal cancer prevention.

As with adenomatous polyps, individuals who have a predisposition to developing hyperplastic polyps may be at increased risk for developing colorectal cancer. The endoscopic and radiologic appearance of the mucosal abnormalities in hyperplastic polyposis closely resembles FAP, but the syndrome is not believed to be heritable and does not have any extraintestinal manifestations. The World Health Organization (WHO) has defined criteria for this entity as follows: (1) at least 5 histologically diagnosed hyperplastic polyps of which 2 are greater than 20 mm or (2) any number of hyperplastic polyps occurring proximal to the sigmoid colon in someone who has a first-degree relative with hyperplastic polyposis, or (3) more than 30 hyperplastic polyps of any size that are distributed throughout the colon and rectum.¹⁶² The risk of colorectal cancer being present or developing subsequently in a patient meeting these criteria is high in case series, but population-based studies have not yet been performed.¹⁶³ While prophylactic colectomy has been proposed for patients with hyperplastic polyposis, there are no consensus opinions at this time regarding the appropriateness of this approach.¹⁶⁴ At a minimum, a program of intensive colonic surveillance is indicated.

Inflammatory Polyps

Inflammatory polyps are the result of reactive regenerative processes occurring in or next to a damaged epithelium. Because of the extent and chronicity of IBD, inflammatory polyps are most commonly seen in that context. The prominence of inflammatory pseudopolyps often is the result of the presence of adjacent ulcerations. Histologically, a combination of distorted crypt architecture in conjunction with granulation tissue and inflammatory infiltrates is characteristic. Even though the underlying chronic IBD represents a high risk for colorectal cancer, the inflammatory polyps as such do not carry a malignant potential. Biopsies in IBD should therefore also include the more flat-appearing areas rather than the polyps only.

POLYP TRANSFORMATION

By definition, the neoplastic nature of an adenomatous polyp represents dysplasia. In an effort to quantify the clinical severity/importance of dysplasia, however, the degree of dysplasia is categorized and reported in 3 grades. This categorization is based on the histopathologic differentiation and architecture of the epithelial cells within the polyp.

Common terms for polyps include low-grade dysplasia, intermediate-grade dysplasia, and high-grade dysplasia (by some also referred to as in situ [Tis] adenocarcinoma). Once there are clear microscopic features of tumor invasion through the muscularis mucosa of the colorectum, an invasive cancer (T1 or greater) is present. This important demarcation is based on the finding that lymphatic vessels are almost never found superficial to the muscularis mucosa. The descriptive terms for invasive cancer include well-differentiated (grade I), moderately differentiated (grade II), or poorly differentiated (grade III) adenocarcinoma.

MANAGEMENT OF COLORECTAL POLYPS

The overarching goal of physicians treating patients with colorectal polyps is to minimize the risks associated with invasive malignancy, while simultaneously avoiding complications of diagnosis and treatment. Colorectal cancer prevention programs are widely believed to reduce the risk of colorectal cancer mortality through endoscopic removal of premalignant lesions and the detection of invasive lesions at a point in their progression where they are asymptomatic. The efficacy of colorectal cancer prevention programs has been proven in multiple randomized and nonrandomized studies.^144,165-169

The majority of colonic polyps can be removed via colonoscopy, but this may not be the case for 1 of 2 reasons. First, a polyp may not be resectable due to size, attachment to bowel wall, or other reasons related to the anatomy of the patient or polyp. In these situations, a careful assessment of the risks of surgical resection versus observational management is warranted, as 12% to 18% of these polyps harbor an invasive malignancy.^170-172 Second, polypectomy may not be reasonable in the presence of innumerable polyps.

When invasive cancer is found in a polyp, the management is based mainly on the level of invasion and the completeness of the polypectomy. Based on Haggitt’s observations (see Fig. 49-2), it has been suggested that colonic cancers invasive to Haggitt levels 1, 2, and 3 can be adequately treated with polypectomy (2-mm margin), whereas polyps with invasion into Haggitt level 4 should be treated like a sessile lesion.^148,173

Management of sessile lesions is more controversial. If a sessile lesion cannot be snared in 1 intact piece with a microscopically clear margin of at least 2 mm or if it demonstrates lymphovascular invasion or deep invasion into level Sm3 (lower third of submucosa) (see Fig. 49-3), the patient should undergo a formal oncologic resection of the colon. The approach for an adequately removed lesion with a lesser extent of invasion into the submucosa—Sm1 (invasion only into upper third of submucosa) or Sm2 (invasion only into upper two-thirds of submucosa)—should be individualized based on the risk of a surgery versus the risk of lymph node metastases.^173,174 It is advisable in any case to tattoo the area of a suspect polyp endoscopically with India ink for later identification of the site.

Malignant Tumors of the Colon

The vast majority of malignant colon neoplasms are cancers (carcinoma), that is, malignant neoplasms of epithelial origin. Based on the endodermal glandular tissue origin, adenocarcinoma and its histologic variants are by far the predominant histopathology and account for 90% to 95% of all colorectal malignancies. The majority of this section is therefore devoted to these types of tumors, but it also briefly discusses nonepithelial tumors of the colon.

ADENOCARCINOMA

Colorectal cancer (adenocarcinoma) is the most frequent malignancy of the gastrointestinal tract, the fourth most frequently diagnosed malignancy, and the fourth most common cause of cancer-related mortality in the world.¹⁷⁵ Squamous and adenosquamous carcinomas are exceptionally rare and are located characteristically in the rectoanal junction. The histopathologic classification of colorectal cancer as defined by the WHO is illustrated in Table 49-9.

Macroscopically, most colorectal cancers have either a polypoid or an ulcerative-infiltrating appearance, but combinations are frequent. Very rarely, colorectal cancer may have a dissolute growth pattern and resemble linitis plastica of the stomach, in which case a metastatic lesion from another primary site (eg, lobular breast cancer, stomach cancer) or a nonepithelial neoplasia (eg, lymphoma, carcinoid) would need to be ruled out.

Adenocarcinoma, the exceedingly predominant histopathology of colon cancer, has a less frequent variant of mucinous adenocarcinoma that includes signet ring cell carcinoma and accounts for approximately 10% of all colorectal cancers. Compared to nonmucinous colon cancers, mucinous carcinomas usually present at a more advanced stage and thus have an overall poorer prognosis.^176-178

A rare variant of colorectal cancer is small cell cancer, which accounts for less than 1% of all cases and, similar to small cell cancer of the lung, appears to be related to some degree to a neuroendocrine origin. These tumors have a high tendency to develop widespread metastasis early in the course and have an extremely poor prognosis.

The distribution of colorectal cancers among the various segments has seen a continued shift toward right-sided colon cancer.^179-180 An estimated 45% to 55% of colorectal cancers are located in the rectum (10%-15%) or sigmoid colon (40%), and 25% to 35% are located in the cecum or ascending colon, whereas the remaining are equally distributed through the rest of the colon. The local growth pattern for colorectal cancer involves circumferential and transmural invasion of the tumor through the intestinal wall into the peritoneal cavity or surrounding organ structures. Tumor dissemination primarily occurs through access to the lymphatic vessels into the locoregional lymph nodes or through access to the bloodstream as hematogenous metastasis to distant organs. The most common site of bloodborne spread is via the portal venous system to the liver; other secondary locations include the lung or, less frequently, kidneys, bone, and other sites. In addition, tumor dissemination can occur by transperitoneal seeding and result in peritoneal carcinomatosis.¹⁸¹ Following gravity, peritoneal seeds may accumulate in the pelvic cul-de-sac or paracolic gutters where they can grow to a considerable size (Blumer’s shelf). Growth by perineural infiltration may be seen on microscopic examination and has a negative prognostic impact. About 20% of the patients have evidence of distant metastases (stage IV disease) at the time of presentation.

STAGING OF COLON CANCER

Modern staging of colorectal cancer defines 4 clinical stages (I-IV) based on the TNM (tumor-node-metastasis) system, which has just recently been updated by the American Joint Committee on Cancer (AJCC) (Tables 49-10 and 49-11).^176,182,183 Independent parameters are (1) the depth of tumor invasion (T) into or through the layers of the intestinal wall with or without invasion of adjacent organs, (2) the number of regional lymph nodes involved (N), and (3) the presence or absence of distant metastases (M). Additional modifiers are used to reflect the method of stage determination (p for pathology, c for clinical, u for ultrasound); y indicates the status after neoadjuvant treatment.