SCREENING AND PREVENTION

The slow development of CRC from a benign polyp to an invasive cancer provides a window of

opportunity for the detection and removal of premalignant adenomatous polyps and early-stage cancers.

Removal of adenomatous polyps reduces the incidence of cancer, and the diagnosis of CRC at earlier

stages reduces mortality.62,63 A number of prospective studies have proven that screening for colorectal

polyps and cancer using a variety of methods reduces CRC mortality, and the reduction in mortality

persists long-term after screening.64–66 There is good evidence that screening has contributed

significantly to the drop in CRC mortality rates from a peak a few decades ago. Screening for CRC is

cost-effective, in terms of the quality-adjusted life-years gained, compared to nonscreening. In the

United States, screening for CRC is recommended for men and women over age 50, but compliance

remains suboptimal because more than one-third of Americans report not having participated in a

screening program.

Figure 68-6. Nomogram to predict 5-year and 10-year recurrence-free survival in colon cancer. Used by drawing a straight line up

to the Points axis to determine how many points toward recurrence the patient should receive. Sum of the points received from

each prognostic variable is then located along the total points axis. Then drawing a line down from the total Points axis to the 5-

year or 10-year freedom from recurrence axes provides the patient’s specific risk. RS, rectosigmoid colon; L, left colon; R, right

colon; Sig, sigmoid colon; TC, transverse colon. (From Weiser et al. 2008, J Clin Oncol 26:380–385.)

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Table 68-6 Tools for Colorectal Cancer Screening

Screening Tests

Numerous screening methods for CRC have been used over the years (Tables 68-6 and 68-7). These fall

into one of two categories: stool tests, which detect the presence of blood or altered DNA in the stool;

and structural tests, which identify polyps and cancers. Efficacy in detecting CRC, cost-effectiveness as a

screening tool, supporting evidence, and patient acceptability vary for each of these tests.67–69

Stool Tests

CRCs and polyps bleed more than the normal mucosa, and detecting occult blood in the stool is the basis

of the most widely used screening tests. Blood is detected by searching the stool for hemoglobin using

chemical or immunologic methods; patients found to have blood in the stool should then undergo

colonoscopy. The original fecal occult blood tests (FOBTs) relied on guaiac-based detection of the

pseudoperoxidase activity of hemoglobin. However, as pseudoperoxidase activity is not specific to

human hemoglobin, foods such as red meat can produce false positives. Medications such as aspirin and

nonsteroidal anti-inflammatory drugs can also cause a false-positive reaction. Other foods, in particular

those rich in vitamin C, can cause false-negative results and should also be avoided before a test. Thus,

for improved accuracy, a special diet and avoidance of these drugs should be followed for 2 to 3 days

before FOBT. As most tumors bleed slowly and intermittently, the sensitivity of this test remains low.

Rehydration of the test cards increases sensitivity, at the cost of reducing specificity. The sensitivity of

the test increases with the number of samples tested; testing two samples per stool on three consecutive

bowel movements is recommended. Several prospective, randomized trials have demonstrated that

screening by FOBT, followed by total colonic evaluation with colonoscopy in individuals with a positive

test, reduces mortality from CRC.70–72

Fecal immunochemical tests (FITs) rely on antibodies that are specific to human hemoglobin, and the

analysis of samples by automated quantification methods. FITs are as sensitive as the guaiac-based tests,

but more specific in detecting human hemoglobin in stool. They therefore avoid the false-negative

results in the presence of vitamin C, and the false positives obtained in guaiac-based testing from red

meats. The test does not require dietary modification beforehand, and the handling of the specimens is

less demanding. As with any fecal test, a positive result with FIT requires a complete colonoscopic

examination. Several studies have demonstrated that FIT has better screening performance, compared to

FOBT.73,74 As an additional consideration, FIT may be more easily implemented as a screening regimen,

compared with sole usage of colonoscopy.75 Based on this evidence, a number of countries have

introduced screening programs utilizing these tools.

Detection of altered DNA from exfoliated tumor cells has been investigated as a screening test for

CRC for years. Similar to the detection of hemoglobin, detection of altered DNA triggers patient referral

for colonoscopy. Large, prospective studies of this test show fair sensitivity in detecting CRC and low

sensitivity in detecting large adenomas, compared with colonoscopy.76,77 A more recent study using new

stabilizing buffers, more discriminating markers, and more sensitive analytical methods, has shown that

stool DNA testing is more sensitive than FIT in detecting CRC and advanced precancerous lesions.

However, the specificity of stool DNA testing was found to be inferior to FIT, with roughly 10% of the

screened individuals having a false-positive result.78 There are concerns that a positive stool DNA test

and negative colonoscopy may lead to additional and unnecessary work-up for malignancy. Therefore,

screening guidelines of the U.S. Preventive Services Task Force do not currently recommend the fecal

DNA test as a screening option.

Structural Tests

Two-thirds of CRCs and polyps are located in the sigmoid colon and rectum, and can be reached with a

60-cm flexible sigmoidoscope. The presence of adenomatous polyps in the rectosigmoid colon increases

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the probability of finding additional polyps or cancers in more proximal segments of the large bowel. If

an adenomatous polyp is found during flexible sigmoidoscopy, the patient should undergo a complete

colonoscopy. Flexible sigmoidoscopy is safe, fast, requires minimal preparation, and can be performed

in an office-based setting, as conscious sedation is not needed. The risk of perforation with flexible

sigmoidoscopy is approximately 1 in 20,000, but the lack of sedation can occasionally be associated

with discomfort, deterring some patients from undergoing future examinations. The effectiveness of

flexible sigmoidoscopy as a screening modality requires examination to at least 40 cm from the anal

verge, and the ability of the endoscopist to biopsy-suspected adenomas. The main limitation of flexible

sigmoidoscopy is that it does not examine the entire colon. However, as distal tubular adenomas are

often indicative of proximal advanced neoplasia, the efficacy of flexible sigmoidoscopy is greatest when

patients with distal adenomas are subsequently referred for colonoscopy. Due to differences in the

distribution of colorectal neoplasia in patients of different age, gender, and racial groups, the efficacy of

flexible sigmoidoscopy may vary. Several case-control studies have demonstrated that screening by

sigmoidoscopy reduces mortality from CRC by two-thirds in the setting of tumors located within reach

of the sigmoidoscope.79,80 More recently, several prospective studies have demonstrated that screening

with flexible sigmoidoscopy reduced CRC incidence and mortality by approximately 25%.81–83 The

reduction in incidence occurs in both the proximal and distal colon, while the reduction in mortality

applies mainly to tumors in the distal colon. The optimal interval between tests is still controversial. In

some studies, flexible sigmoidoscopy was performed every 3 to 5 years. At least two prospective trials

demonstrated a reduction in CRC incidence and mortality with only one flexible sigmoidoscopy

screening between 55 and 64 years of age.83,84

Although the evidence for combining FOBT and flexible sigmoidoscopy is weak, some studies have

shown that the combination of these two screening methods is more effective in detecting colorectal

neoplasia than each method used individually.85 The combined approach has a theoretical advantage of

detecting lesions located throughout the colon, but its impact on mortality from CRC is unknown. In the

United States, annual FOBT combined with flexible sigmoidoscopy every 5 years is a common screening

method for the average-risk population.

Colonoscopy is considered the most accurate test for the early diagnosis and prevention of CRC. It

allows direct visualization of the mucosa of the entire colon and rectum, simultaneously allowing the

biopsy or removal of suspicious lesions. Colonoscopy is also used to evaluate patients who have tested

positive on other screening tests. However, colonoscopy is inconvenient, requires dietary modification

and bowel preparation beforehand, is usually performed under conscious sedation, and carries a risk of

complications of 1–2 per 1,000. Colonoscopy is also more expensive compared to other screening

methods. Overall, patient acceptability of colonoscopy seems to be higher compared to other invasive

screening methods, and it is now the most commonly used screening method in the United States. There

is indirect evidence from microsimulation and case-control studies that colonoscopy reduces mortality.86

However, randomized controlled trials proving that screening with colonoscopy reduces CRC mortality

are lacking. Comparative studies show that colonoscopy is more effective in detecting advanced colonic

neoplasia, in both men and women, than a single FOBT combined with sigmoidoscopy. Colonoscopy is

more likely to detect preneoplastic polyps, but just as likely to detect invasive CRC as FITs. In addition,

colonoscopy provides the protective benefit of screening the proximal colon.87 For average-risk

individuals colonoscopy screening should start at 50 years of age and be repeated every 10 years.

Table 68-7 Screening and Surveillance for Colorectal Cancer According to Risk7

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treatment and defining prognosis in patients with CRC. The tumor–node–metastasis (TNM) classification

developed by the UICC/AJCC is firmly established as the preferred staging system (Table 68-4). It

classifies CRC according to the extent of the primary tumor (T), the involvement of the regional lymph

nodes (N), and the presence or absence of distant metastasis (M). The TNM classification is important

for both clinical and pathologic staging. Most colon cancers, and many rectal cancers, are staged after

surgery and pathologic examination of the surgical specimen (pTNM). Many rectal cancer patients, and

a small but growing number of colon cancer patients, do not receive surgery as the initial therapy,

which makes clinical TNM (cTNM) staging based on medical history, physical examination, endoscopy,

and imaging, increasingly important. As tumors experience a variable degree of regression with

preoperative chemotherapy and/or radiation, it is important that patients receiving neoadjuvant therapy

are assigned an accurate cTNM stage before starting treatment. For patients who have received

neoadjuvant therapy, a modified pathologic staging is generated after surgical resection, annotated by

the prefix y (ypTNM). The 7th edition of the AJCC Cancer Staging Manual incorporates a four-tier

tumor regression grading (TRG) system for patients receiving neoadjuvant therapy. In this grading

system TRG 0 represents Complete Response, no viable tumor cells or complete pathologic response

(pCR); TRG 1, Moderate Response; TRG 2, Minimal Response; and TRG 3, Poor Response. Tumor

regression seems to correlate closely with prognosis and long-term oncologic outcome.41

HISTOLOGIC GRADE

Table 68-3 Histologic Grading

The AJCC staging system is updated periodically in response to newly acquired clinical data and

understanding of the biology of the tumor. The 7th edition of the AJCC Cancer Staging Manual, for all

cancers diagnosed after January 1, 2010, was updated based on observed survival outcomes obtained

from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.42

Relative survival in CRC patients decreases according to the depth of tumor penetration into the bowel

wall and number of lymph nodes involved, but the presence of distant metastasis is the single most

important predictor of survival in these patients (Table 68-4). Other tumor and treatment-related

prognostic factors, in addition to the TNM stage, are listed in Table 68-5.

Quantitative parameters of lymph node evaluation – number of positive lymph nodes, total number of

lymph nodes examined, and lymph node ratio – have prognostic implications in CRC. The number of

nodes involved by tumor is included in the N category of the TNM system. The current staging system

recommends examining a minimum of 12 lymph nodes for adequate staging.42 The total number of

lymph nodes retrieved is lower in rectal cancer patients treated with preoperative chemotherapy and

radiation, but the minimal number of nodes required for adequate staging in these patients is unknown.

The total number of nodes examined has an important impact on outcome in patients with colon and

rectal cancer; in patients with all T and N combinations, the probability of survival increases linearly

with the number of lymph nodes examined. The lymph node ratio, defined as the number of positive

lymph nodes divided by the total number of retrieved nodes, has also been considered an independent

predictor of survival.43,44 However, the results have not been extensively validated and the lymph node

ratio is not currently included in staging. Irregular tumor deposits in the mesocolon or mesorectum

without surrounding lymph node tissue, are considered peritumoral tumor deposits; they are not

counted as lymph nodes but are classified as N1c, and contribute to stage III.42 These are considered to

represent large vessel or perineural invasion. The significance of micrometastasis detected by

immunohistochemistry (usually with anticytokeratin antibodies) in H&E negative nodes of patients with

stage II disease is controversial. Although some studies have reported an association between

micrometastasis, increased recurrence and reduced survival, the detection of micrometastasis has not

been incorporated into clinical practice, and at the present time should be considered

investigational.45,46

The location of the tumor also provides prognostic information. In general, tumors located in the

right colon have better prognosis compared with tumors located in the left or transverse colon. This

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may be attributed, in part, to the higher proportion of MSI tumors in the right side of the colon. In

patients with rectal cancer, tumors located in the distal rectum have worse prognosis compared to

tumors located in the upper rectum.

The quality of the surgery and the completeness of tumor resection also provide important prognostic

information. The distance of tumor to the circumferential resection margin (CRM) – defined as the

surgically dissected nonperitonealized surface of the specimen – provides important prognostic

information in both colon and rectal cancers. The presence of tumor at the CRM, because of advanced

stage or inadequate resection, is associated with a high rate of recurrence and decreased probability of

survival. In rectal cancer patients, the CRM is defined as positive if the tumor, either by direct tumor

extension or positive lymph node, is equal to or less than 1 mm from the resection margin.

The AJCC has established codes for completeness of the resection, which should be reported for each

procedure.42 A resection is defined as R0 when the entire tumor is resected and the margins are

histologically negative; R1 when the margins are grossly uninvolved but histologically positive; and R2

when the tumor is not completely resected, and there is gross residual tumor at the primary site,

regional lymph nodes, or metastatic sites.

Other factors associated with worse outcomes include elevated CEA levels before surgery, high

histologic grade, signet ring cell and small cell histopathologic type, lymphatic and blood vessel

invasion, and perineural invasion.47–52 Vascular invasion is considered a sign of aggressive behavior in

CRC, and has been associated with a higher risk of disease progression and poor prognosis. Capillary

invasion is often associated with lymphatic invasion, and these are commonly designated as

lymphovascular invasion. Large vessel invasion, detectable on magnetic resonance imaging (MRI), is

now reported separately.

While the TNM staging system provides important prognostic information, it is inadequate for

individual prognostication. Outcomes for individual patients within each tumor stage are variable.

Recently, nomograms using a number of clinical and pathologic characteristics have been designed to

improve prediction and survival beyond TNM staging in patients with colon or rectal cancer,

particularly in the setting of stage II tumors (Fig. 68-6).53 In addition to providing prognostic

information, nomograms may potentially guide clinical decisions, such as the use of adjuvant

chemotherapy or the regularity of surveillance. However, nomograms have not become part of the

treatment strategy.

A number of molecular markers such as MSI, 18q loss of heterozygosity, TP53, p21, among others,

have been associated with prognosis in CRC patients. But none of these are routinely incorporated into

clinical practice. Somatic RAS mutations have been associated with lack of response to anti–EGFR

targeted therapies, and clinical guidelines worldwide now recommend testing for both KRAS and NRAS

mutations if anti-EGFR therapy is contemplated in patients with stage IV disease.54 In addition, when a

KRAS or NRAS mutation is not found, some recommend V600E BRAF testing because the data suggest

that those tumors are also unresponsive to anti-EGFR therapy. However, these mutations have not been

incorporated into the staging system.

Based on recent advances in the molecular characterization of CRC, a number of multigene molecular

signatures have been designed as prognosticators of recurrence and outcomes. The Oncotype DX Colon

Cancer Assay, developed by Genomic Health, Inc. (Redwood City, CA, USA) is an assay based on the

expression of 12 genes that play roles in cell-cycle and stromal responses.55,56 The assay was designed

and validated using formalin-fixed, paraffin-embedded tissue samples from patients enrolled in the

Cancer and Leukemia Group B (CALGB) 9581 cohort.57,58 The predictive model provides a score

predicting 3-year recurrence risk in stage II colon cancers, and appears most effective in MMR-proficient

T3 tumors. Another commercially available tool is ColoPrint, developed by Agendia (Amsterdam, The

Netherlands). With a similar premise, this tool is an 18-gene signature found to be predictive of distant

metastasis in stage II colon cancers.59,60 ColDx, developed by Almac (Craigavon, UK) is a microarraybased tool that uses 634 probes to identify patients with stage II colon cancer at high risk of

recurrence.61 While these molecular signatures seem to determine risk of recurrence independent of

other well-established risk factors, they have not been fully incorporated into clinical practice.

Table 68-4 Clinical and Pathologic Staging4

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Table 68-5 Colorectal Cancer Prognostic Factors

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The hypermutated tumors, representing 16% of all CRCs, are deficient in the mismatch-repair (MMR)

mechanisms controlling the correction of errors that occur during DNA replication. The end result of

MMR deficiency is a form of genetic instability characterized by the accumulation of mutations

throughout the genome, primarily in repetitive sequences known as microsatellites; this is known as

microsatellite instability (MSI).29 The mutational burden ultimately provides these MSI tumors with

their malignant potential. Unlike CIN tumors, MSI tumors generally remain diploid or near-diploid.

They are less likely to have KRAS, TP53, SMAD4 mutations, and more likely to have BRAF and TGFBR2

mutations (Fig. 68-4). MSI can arise from either the germline inactivating mutations or the epigenetic

silencing of one of several MMR genes (MLH1, MLH3, MSH2, MSH3, and MSH6). Research into the

mechanisms of epigenetic silencing of MSI tumors has helped elucidate the CpG Island Methylator

Phenotype (CIMP), whereby the methylation of CpG sequences in the promoter region of MMR genes

(most commonly MLH1) leads to their transcriptional silencing.

The classification of CRC according to the type of genomic instability is clinically relevant. MSI

tumors tend to be preferentially right sided, have a solid or cribriform histologic pattern, contain large

number of tumor-infiltrating lymphocytes, are less responsive to fluoropyrimidine, and in general carry

a better prognosis, compared to CIN tumors.

The genomic instability that characterizes CRC is associated with alterations in a number of key

pathways; among others, the WNT, MAPK, PI3K, TGF-β and p53 pathways (Fig. 68-5). The WNT

signaling pathway contributes to the tightly regulated homeostasis of intestinal epithelial crypts, and its

alteration is considered an initiating event in colorectal carcinogenesis. The WNT signaling pathway is

altered in greater than 90% of both hypermutated and nonhypermutated CRCs. The most prevalent

alteration leading to dysregulation of the WNT pathway occurs through biallelic inactivation of the

tumor suppressor adenomatous polyposis coli (APC) gene.30 Patients with familial adenomatous

polyposis (FAP) have a germline mutation in one allele of the APC gene, and their risk of developing

CRC is virtually 100%. The WNT pathway is also commonly altered as a result of stabilizing mutations

of the CTNNB1 gene coding for β-catenin, a protein normally targeted for degradation by APC. The

accumulation of β-catenin as a result of APC loss or stabilizing CTNNB1 mutations leads to its

translocation to the nucleus, where it interacts with transcription factors of the TCF/LCF family, turning

them into transcriptional activators. The end result is an increase in the transcription of genes that are

normally important for stem cell renewal and differentiation but, when inappropriately expressed at

high levels, can cause cancer.

Figure 68-4. Most significantly mutated genes in hypermutated and nonhypermutated tumors. Blue bars represent genes identified

using the MutSig algorithm, and black bars represent genes identified by manual examination of sequence data. (From

Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. The Cancer Genome Atlas Network. Nature

2012;487(7407):330–337.)

Mutational inactivation of the TGF-β pathway, important in regulating cell growth arrest and

apoptosis, is a common event in CRC.31 In the majority of hypermutated tumors, the TGF-β gene is

inactivated by a frameshift mutation in a polyadenine repeat within the coding sequence. It can also be

inactivated by point mutation in the kinase domain. Downstream effectors of this pathway such as the

transcription factor SMAD4, and associated proteins SMAD2 and SMAD3, are also inactivated by

mutation or homozygous deletion of chromosomal segment 18q. Another member of this pathway,

deleted in CRC (DCC), is also commonly inactivated by deletion of chromosome 18q.

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Figure 68-5. Frequency of genetic changes leading to deregulation of recognized signaling pathways in CRC. Alterations are

defined as somatic mutations, homozygous deletions, high-level focal amplifications, and in some cases, significant up- or

downregulation of gene expression. Red/blue denote activation/inactivation, respectively. Bottom panel shows alterations across

samples in five main pathways (WNT, TGF-B, RTK/KRAS, PI3K, TP53, if at least one gene in the pathway is altered). nHM,

nonhypermutated; HM, hypermutated. (From Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. The

Cancer Genome Atlas Network. Nature 2012;487(7407):330–337.)

A common theme of the WNT and TGF-β signaling pathways is the increased activity of c-Myc, a

regulator gene that codes for a multifunctional transcription factor which plays a role in cell cycle

progression, apoptosis, and cellular transformation. c-Myc seems to play a central role in colorectal

carcinogenesis.32

The TP53 gene is a member of a pathway of regulators of cell cycle arrest and cell death in response

to a variety of genotoxic stresses. Mutations in the TP53 tumor suppressor gene occur in more than half

of nonhypermutated CRCs. In most tumors, both alleles of the gene are inactivated by a combination of

a mutation in one allele, and loss of the second allele by deletion of the chromosomal segment 17p. Loss

of the TP53 tumor suppressor gene is generally considered an early event that plays a role in the

transition from adenoma to invasive carcinoma.33 In hypermutated tumors, the TP53 pathway may be

attenuated by mutations in other genes, such as the proapoptotic BAX.

The MAPK pathway consists of a cascade of tightly coordinate kinases that work together to regulate

cell division and proliferation. KRAS, a protooncogene that becomes constitutively activated by

mutation, resulting in uncontrolled cell proliferation, is mutated in 37% of CRC. Interestingly, a number

of studies from model organisms reveal that KRAS mutation by itself is not sufficient to initiate

tumorigenesis; in order to have oncogenic potential it requires a previous APC mutation. The MAPK

pathway is the molecular pathway that has successfully been therapeutically targeted in CRC. Inhibition

of this pathway using antibodies against the epidermal growth factor receptor (EGFR) reduces

progression in wild-type KRAS/NRAS metastatic CRC.34 Activating mutations of BRAF, also an effector

member of the MAPK pathway downstream of KRAS, are seen in 13% of CRC. The BRAF mutation,

found almost exclusively in hypermutated tumors, has been associated with poor prognosis.

The PI3K/AKT/mTOR signaling pathway, with important roles in cell proliferation and apoptosis, is

abnormally activated in nearly half of all CRCs. Moreover, in the TCGA cohort, PI3K and RAS pathways

are simultaneously affected by mutations in one-third of all CRCs, suggesting that simultaneous

inhibition of both pathways may be required to achieve a therapeutic effect.35

The characterization of genome-level alterations in CRC has led to the identification of new subclassifications that share marked similarities across genomic structure, gene and protein expression, and

even the activity of the tumor microenvironment.36–39 While these sub-classifications continue to be

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resolved and studied, they have shown potential to prognosticate tumor behavior and oncologic

outcomes.40

The advances in genomic characterizations have revealed CRC to be a heterogeneous and complex

disease. While the patterns of genomic instability and alterations of signaling pathways are aligned with

specific phenotypic tumor characteristics, many tumors do not fit cleanly into any single category.

Rather, they may host elements of genomic instability and dysregulated signaling pathways that may

not be well characterized yet.

HISTOPATHOLOGY AND PROGRESSION

CRC is an adenocarcinoma arising from the epithelial lining of the large bowel. Some CRCs may

develop de novo, but most result from malignant transformation of adenomatous polyps. In the past,

only tubular and villous adenomas were considered to develop into invasive adenocarcinomas.

However, recent evidence suggests that serrated polyps can also develop into CRCs. Polyps arise from

normal mucosa, and gradually increase in size. Some polyp characteristics – size larger than 1 cm,

tubulovillous or villous histology, multiple occurrences – are associated with a high risk of malignant

transformation. Most screening programs are designed to recognize the presence of polyps, or early

malignant change in polyps or the surrounding mucosa.

HISTOPATHOLOGIC TYPES OF COLORECTAL CANCER

Table 68-2 Colorectal Cancer: Histopathologic Types

The majority of CRCs are typically adenocarcinomas that form glandular structures resembling the

normal colonic epithelium. However, there are several histologic types of adenocarcinoma (Table 68-2).

Colorectal adenocarcinomas are assigned to one of four histologic grades according to their histologic

resemblance to the normal colonic epithelium (Table 68-3). The histologic grade is associated with

oncologic outcome independent of other risk factors, including tumor staging.

CRC is locally invasive, potentially spreading through the full thickness of the bowel wall into

adjacent tissues. From the primary site, CRC often extends to the regional lymph nodes and to other

organs. CRC can metastasize to almost any organ, but the most common sites are the liver and lungs.

Approximately 20% to 34% of patients have metastases at the time of diagnosis, and another 30% of

those initially treated with curative intent will subsequently develop distant metastases. Other sites of

distant metastasis are the brain and bones, but these are unusual in the absence of liver metastases.

Patients may also develop peritoneal spread, with the formation of malignant ascites. The risk of nodal

metastasis increases with the depth of tumor invasion into the bowel wall, and the risk of distant

metastasis is higher for patients with nodal metastasis.

STAGING AND PROGNOSIS

The anatomical extent or stage of the tumor at the time of diagnosis is a key factor in deciding upon

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proximal tumors in women.

There are great disparities in CRC incidence and mortality between ethnic and racial groups. Both are

highest for African Americans and lowest for Asians/Pacific Islanders, but the differences in mortality

are proportionally larger compared to the differences in incidence. The decline in mortality for CRC that

began in the 1980s did not start affecting African Americans until the 1990s. These differences are

attributed to disparities in access to screening and care. The decline in CRC-related mortality among

African Americans has also accelerated in recent years.2

CRC is the third most common cancer in men and the second most common cancer in women

worldwide, with an estimated 1.4 million new cases diagnosed in 2012 (Fig. 68-2). It is responsible for

8% of cancer deaths worldwide. The age-standardized incidence of CRC varies significantly in different

countries. It is highest in North America, New Zealand, Australia and Western Europe and lowest in

India and many African countries. While the incidence is decreasing in some developed countries

(United States) and stabilizing in others (France, Australia), it is increasing in Asia (Japan) and the

Middle East (Kuwait), Eastern European countries (Czech Republic, Slovakia, Slovenia), and some

Southern European countries (Spain). The increase in incidence has been attributed to changes in risk

factors, such as the Westernization of diets, obesity, and smoking. However, despite the increase in

incidence, mortality for CRC is decreasing in many countries, most likely because of improvements in

both screening and treatment.2

RISK FACTORS

There are numerous factors associated with the risk of CRC (Table 68-1).3 Some are behavioral, and

potentially modifiable. Others are genetic or hereditary, and therefore nonmodifiable. Information

about individual risk factors can be used to reduce incidence and mortality through behavior

modification and screening programs.4 Except for the relatively uncommon hereditary syndromes with

known patterns of inheritance, the relative contribution of inherited and environmental factors to the

development of CRC is controversial. Analysis of cohorts of twins from Scandinavian countries suggests

a significant but relatively minor contribution of hereditary factors to the development of sporadic CRC;

the environment seems to play a larger role in the development of sporadic cancers.5

Figure 68-1. Trends in Colorectal Cancer Incidence and Death Rates by Sex, USA, 1930–2010. (From The American Cancer Society,

Colorectal Cancer Facts and Figures 2014–2016.)

The list of behavioral or modifiable factors includes obesity, physical inactivity, smoking, diet, and

alcohol intake.6 Obesity is associated with increased risk of developing CRC in both men and women.7,8

Abdominal obesity, measured as waist size, seems to be more important than excess weight, particularly

in men. Being overweight increases the risk of CRC, independent of the level of physical activity. The

most physically active people have a 25% lower risk of developing CRC, compared to the least active

people. Both recreational and occupational physical activity reduces CRC risk, and sedentary people

who become physically active later in life do reduce their CRC risk.9 The geographical differences in the

incidence of CRC, and the change in incidence in migrant populations, suggest that diet is probably an

important risk factor.10 The risk of CRC has been associated with a high consumption of red or

processed meats.11,12 On the other hand, the risk of CRC is inversely correlated with the intake of fiber

and whole grains, fruits and vegetable, dairy products and calcium, vitamin D, and folates.6 Alcohol

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consumption is causally associated with the development of CRC, and the effect seems to be dosedependent. The risk seems to be higher for men than for women. There is no difference in the effect

with regard to the type of alcohol.13 Smoking increases the incidence and mortality from CRC, and in

particular, rectal cancer.14,15

Table 68-1 Factors Associated with Risk of Developing Colorectal Cancer

Three-quarters of CRCs occur in people who do not have any particular predisposing factors, and who

are therefore considered to be at average risk. The remaining 25% of patients have hereditary risk

factors that predispose them to the development of CRC: either a well-defined hereditary CRC

syndrome (5%) or a close relative who has been diagnosed with the disease (20%). People with a firstdegree relative with CRC have between a 1.9 and 4.4 relative risk of developing CRC, compared to the

average population. The risk is higher when the affected relative was diagnosed at an early age, or

when several relatives have been affected.16,17 CRC survivors have four times the lifetime risk of

developing a new (metachronous) CRC, compared with people at average risk. The estimated mean

annual incidence of metachronous CRC is 0.3%, with a cumulative incidence of 3.1% at 10 years.18 A

personal history of adenomatous colorectal polyps also increases the risk of CRC, in particular for

patients with larger or multiple polyps and an early age at diagnosis.19

Patients with chronic inflammatory bowel disease, both ulcerative colitis and Crohn disease, are at

increased risk of developing CRC.20,21 The risk increases with the duration of the disease. It is estimated

that, after 10 years of disease, the risk of developing CRC increases by around 1% each year. Thus, it is

estimated that patients with 30 years of inflammatory bowel disease have an 18% risk of developing

CRC. The risk is higher for patients diagnosed with inflammatory bowel disease at an early age, and

with disease extending proximal to the splenic flexure. However, the incidence of CRC in patients with

ulcerative colitis seems to be decreasing. A recent meta-analysis of population-based cohort studies

reported a 1.7 increased risk of CRC among inflammatory bowel disease patients, compared to the

general population, after adjusting for age, gender, and duration of disease.22 These changes are

probably due to more effective treatments and the efficacy of surveillance programs.23

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Figure 68-2. Estimated New Cancer Cases and Deaths Worldwide for Leading Cancer Sites by Sex and Level of Economic

Development, 2012 (excluding nonmelanoma skin cancers). (From Torre LA, Bray F, Siegel RL, et al. Global Cancer Statistics,

2012. CA Cancer J Clin 2015;65:87–108.)

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Figure 68-3. Mutation frequency across 224 human colorectal cancer samples from The Cancer Genome Atlas. Note the clear

separation of hypermutated (median of 728 nonsilent mutations per tumor) and nonhypermutated (median of 58 nonsilent

mutations). Red, MSI high, CIMP high, or MLH1 silenced; light blue, MSI low, or CIMP low; black, rectum; white, colon; gray, no

data. (From Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. The Cancer Genome Atlas Network.

Nature 2012;487(7407):330–337.)

Patients with type II diabetes have a higher risk of developing CRC compared to the nondiabetic

individual, even when adjusting for factors such as obesity and sedentary lifestyle.24 In addition, CRC

survival rates are lower for diabetic patients compared to nondiabetic patients.25 The relationship

between diabetes and CRC seems to be stronger for men than for women.

MOLECULAR CHARACTERISTICS

2 The traditional model of CRC tumor development is often represented as a linear and sequential

progression from normal epithelium to small adenoma, to large adenoma, to invasive carcinoma, and

finally to metastatic disease.26 This so-called adenoma–carcinoma sequence has been deemed the result

of the progressive accumulation of alterations in the genome. This model has shaped our understanding

of key genetic alterations that result in colorectal tumorigenesis, and has had an enormous clinical

impact by highlighting the importance of screening and surveillance. Whole genome analysis with highthroughput technologies has added new information that is broadening our understanding of colorectal

carcinogenesis. Every CRC has a multitude of distinct genetic alterations that perturb a number of

molecular pathways. This genetic heterogeneity ultimately has a bearing on the speed of growth, local

invasiveness, metastatic potential, and response to therapy. As our understanding of these molecular

changes improves, we anticipate that we will be able to provide better screening and prognostic tools,

and discover new tumor-specific therapies.

The most comprehensive molecular analysis of CRC to date has been conducted by The Cancer

Genome Atlas Consortium.27 They have used state of the art technology to elucidate the mutational

spectrum, the chromosomal and sub-chromosomal changes, the epigenetic regulation and transcriptional

alterations in a large number of CRCs. A key finding that has helped frame our molecular understanding

of CRC is the wide variation in the number of somatic mutations present in most tumors. According to

the number of mutations, CRC can be effectively classified as hypermutated, harboring a median of 728

nonsilent mutations per tumor, and nonhypermutated, with a median of 58 nonsilent mutations (Fig. 68-

3). Nonhypermutated tumors comprise 84% of CRCs, and are characterized by chromosomal instability

(CIN). CIN is the result of missegregation of chromatids in tumor cells, resulting in gains and losses of

entire chromosomes or chromosomal segments; manifesting as aneuploidy and copy number alterations

(CNA).28 Common patterns of aneuploidy and CNAs in nonhypermutated CRC include amplifications in

chromosome arms 1q, 7p and q, 8q, 13q, 17q, and 20p/q, and deletions in 8p, 14q, 15q, 17p, and

18p/q. Some of these CNAs could account for the loss of important tumor suppressors such as TP53 (on

17p), DCC, and SMAD4 (on 18q), and the amplification of oncogenes such as ERBB2 (on 17q). In short,

CIN in nonhypermutated tumors can activate critical oncogenes, and inactivate tumor suppressors that

contribute to the acquisition of tumorigenic traits.

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9. Crockett SD, Snover DC, Ahnen DJ, et al. Sessile serrated adenomas:an evidence-based guide to

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11. Snover D, Ahnen D, Burt R, et al. Serrated polyps of the colon and rectum and serrated

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12. Raju GS, Vadyal V, Slack R, et al. Adenoma detection rate in patients undergoing a comprehensive

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13. Winawer SJ, Zauber AG, Gerdes H, et al. Risk of colorectal cancer in the families of patients with

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14. Brenner H, Hoffmeister M, Stegmaier C, et al. Risk of progression of advanced adenomas to

colorectal cancer by age and sex: estimates based on 840,149 screening colonoscopies. Gut

2009;56:1585–1589.

15. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of

colorectal cancer deaths. N Engl J Med 2012; 366:687–696.

16. Yurgulun MB, Goel A, Hornick JL, et al. Microsatellite instability and DNA mismatch repair protein

deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res(Phila) 2012;5:574–582.

17. Edelstein DL, Axilbund J, Baxter M, et al. Rapid development of colorectal neoplasia in patients

with Lynch syndrome. Clin Gastroenterol Hepatol 2011; 9:340–343.

18. Boland CR, Lynch HT. The history of Lynch syndrome. Fam Cancer 2013; 12:145–157.

19. Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot’s syndrome. N Engl J Med

1995;332:839–847.

20. Levin B, Lieberman DA, Mcfarland B, et al. Screening and surveillance for the early detection of

colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer

Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of

Radiology. CA Cancer J Clin 2008;58:130–160.

21. U.S. Preventative Services Task Force. Screening for colorectal cancer: U.S. Preventative Services

Task Force recommendation statement. Ann Int Med 2008;149:627–637.

22. Rex DK, Johnson DA, Anderson HC, et al. American College of Gastroenterology guidelines for

colorectal cancer screening 2008. Am J Gastroenterol 2009;104:739–750.

23. Segnan N, Patrick J, von Karsa L (eds). European guidelines for quality assurance in colorectal

screening and diagnosis. Luxembourg: International Agency for Research on Cancer; 2010;1–386.

24. Swan S, Siddiqui AA, Meyers RE. International colorectal cancer screening programs: population

contact strategies., testing methods and screening rates. Pract Gastroenterol 2012;20–29.

25. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for

fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993;328:1365–1371.

26. Mandel JS. Screening of patients at average risk for colon cancer. Med Clin North Am 2005;89:43–

59.

27. Haug UH, Hundt S, Brenner H. Quantitative immunochemical fecal occult blood testing for

colorectal adenoma detection: evaluation in the target population of screening and comparison with

qualitative tests. Am J Gastroenterol 2010;105:682–690.

28. De Wijkerslooth TR, Stoop EM, Bossuyt PM, et al. Immunochemical fecal occult blood testing is

equally sensitive for proximal and distal advanced neoplasia. Am J Gastroenterol 2012;107:1570–

1578.

29. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal cancer

screening. N Engl J Med 2014;371:187–188.

30. Atkin W, Edwards R, Kralj-Hans I, et al. Once-only sigmoidoscopy screening in the prevention of

colorectal cancer :a multicenter randomized controlled trial. Lancet 2010;375:1624–1633.

31. Schoen RE, Pinsky PF, Weissfeld JL, et al. Colorectal incidence and mortality with screening

flexible sigmoidoscopy. N Engl J Med 2012;366:2345–2357.

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32. Segnan N, Armoroli P, Bonelli L, et al. Once-only sigmoidoscopy in colorectal cancer screening:

follow up findings of the Italian randomized controlled trial–SCORE. J Natl Cancer Inst

2011;103:1310–1322.

33. Lakoff J, Paszat LF, Saskin R, et al. Risk of developing proximal versus distal colorectal cancer after

a negative colonoscopy: a population based study. Clin Gastroenterol Hepatol 2008;6:1117–1121.

34. Baxter NN, Goldwasser MA, Paszat LF, et al. Association of colonoscopy and death from colorectal

cancer. Ann Int Med 2009;150:1–8.

35. Rabeneck L, Paszat LF, Saskin R, et al. Association between colonoscopy rates and colorectal cancer

mortality. Am J Gastroenterol 2010;105:1627–1632.

36. Brenner H, Hoffmeister M, Volker A, et al. Protection from right-and left-sided colorectal

neoplasms after colonoscopy: population-based study. J Natl Cancer Inst 2010;102:89–95.

37. Stock C, Knudsen AB, Lansdorp-Vogelaar L, et al. Colorectal cancer mortality prevented by use and

attributable to colonoscopy. Gastrointestuinal Endosc 2011;73:435–443.

38. Singh H, Nugent Z, Demers AA, et al. The reduction in colorectal cancer mortality after

colonoscopy varies by site of cancer. Gastroenterology 2010;139:1128–1137.

39. Imperiale TF, Wagner DR, Lin CY, et al. Risk of advanced proximal neoplasms in asymptomatic

adults according to the distal colorectal findings. N Engl J Med 2000;343:169–174.

40. Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to screen asymptomatic adults for

colorectal cancer. Veterans Affairs Cooperative Study Group 380. N Engl J Med 2000;343:162–168.

41. Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed)

colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299:1027–1035.

42. Johnson DJ, Chen M-H, Toledano AY, et al. Accuracy of CT colonography for detection of large

adenomas and cancer. N Engl J Med 2008;359:1207–1217.

43. Kim D, Pickhardt PJ, Taylor AJ, et al. CT colonography versus colonoscopy for the detection of

advanced neoplasia. N Engl J Med 2007;357:1403–1412.

44. Patel S, Ahnen DJ. Prevention of interval colorectal cancers: what every clinician needs to know.

Clin Gastroenterol Hepatol 2013;12:7–15.

45. Kaminski MF, Regula J, Krazewska E, et al. Quality indicators for colonoscopy and the risk of

interval cancer. N Engl J Med 2010;362:1995–1803.

46. Baxter NN, Sutradhar R, Forbes SS, et al. Analysis of administrative data finds endoscopist quality

measures associated with postcolonoscopy colorectal cancer. Gastroenterology 2011;140:65–72.

47. Lieberman DA, Weiss DG, Harford WV, et al. Five year colon surveillance after screening

colonoscopy. Gastroenterology 2007;133:1077–1085.

48. Lieberman DA. Colon polyp surveillance: clinical decision tool. Gastroenterology 2014;146:305–306.

49. Laiyemo AO, Murphy G, Albert PS, et al. Postpolypectomy colonoscopy surveillance guidelines:

predictive accuracy for advanced adenomas at 4 years. Ann Int Med 2008;148:419–426.

50. Logan RF, Grainge MJ, Shepherd VC, et al. Aspirin and folic acid for prevention of recurrent

colorectal adenomas. Gastroenterology 2008;134:29–38.

51. Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas.

N Engl J Med 2003;348:891–899.

52. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal

adenomas. N Engl J Med 2006;355:873–884.

53. Meyskins FL, McLaren CE, Pelot D, et al. Difluoromethylornithine plus sulindac for the prevention

of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev

Res 2008;1:9–11.

54. Grau M, Baron JA, Sandler RS, et al. Prolonged effect of calcium supplementation on risk of

colorectal adenomas in a randomized trial. J Natl Cancer Inst 2007;99:129–136.

55. West N, Phillips RK, Hutchinson JM, et al. Eicosapentaenoic acid reduces rectal polyp number and

size in familial adenomatous polyposis. Gut 2010; 59:918–925.

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polyposis in 11 unrelated families with identical APC gene mutation. Gastroenterology

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57. Vasen HF, Moslein G, Alonso A, et al. Guidelines for the clinical management of familial

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adenomatous polyposis. Gut 2008;57:704–713.

58. Skipworth JR, Morkane C, Raptis DA, et al. Pancreaticoduodenectomy for advanced duodenal and

ampullary adenomatosis in familial adenomatous polyposis. HBP (Oxford) 201;13:342–349.

59. Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas, classic adenomatous

polyposis, and germ-line mutations in MYH. N Engl J Med 2003;348:791–799.

60. Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor spectrum in MUTYH-associated

polyposis. Gastroenterology 2009;137:1976–1985.

61. Wang L, Baudhuin LM, Boardman LA, et al. MYH mutations in patients with attenuated and classic

polyposis and with young-onset colorectal cancer without polyps. Gastroenterology 2004;127:9–16.

62. Jones N, Vogt S, Nielsen M, et al. Increased colorectal cancer incidence in obligate carriers of

heterozygous mutations in MUTYH. Gastroenterology 2009;137:489–494.

63. Bresalier RS. Management of high-risk colonoscopy patients. Gastrointest Endos Clin N Am.

2010;20:629–640.

64. Howe JR, Sayed MG, Ahmed AF, et al. The prevalence of MADH4 and BMPR1A mutations in

juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet

2004;41:484–491.

65. Howe JR, Shellnut J, Wagner B, et al. Common deletion of SMAD4 in juvenile polyposis is a

mutational hotspot. Am J Hum Genet 2002;70:1357–1362.

66. Marsh DJ, Coulon V, Lunetta KL, et al. Mutation spectrum and genotype-phenotype analyses in

Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN

mutation. Hum Mol Genet 1998;7:507–515.

67. Chi SG, Kim HJ, Park BJ, et al. Mutational abrogation of the PTEN/MMAC1 gene in

gastrointestinal polyps in patients with Cowden disease. Gastroenterology 1998;115:1084–1089.

68. Marra G, Armelao F, Vecchio FM, et al. Cowden’s disease with extensive gastrointestinal polyposis.

J Clin Gastroenterol 1994;18:42–47.

69. Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN

mutations. Clin Cancer Res 2012;18:400–407.

70. Eng C. PTEN: one gene, many syndromes. Hum Mutat 2003;22:183–198.

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Chapter 68

Colorectal Cancer

Julio Garcia-Aguilar

Key Points

1 Incidence and overall mortality for colorectal cancer (CRC) are decreasing, most likely due to

increased screening. Risk-factor modification and improved therapy also likely contribute to this

trend.

2 Our greater understanding of the molecular biology of CRC may provide a means of identifying

disease biomarkers and developing more targeted therapies.

3 Advances in imaging techniques have improved risk stratification via more accurate baseline tumor

staging and treatment selection.

4 Improved risk stratification and neoadjuvant therapy have enabled physicians to eliminate some

therapeutic components in some patients’ treatment regimens.

5 Use of laparoscopic and robotic surgical techniques in combination with enhanced recovery

programs has accelerated patient recovery, reduced length of hospital stay, and reduced

postoperative complications.

6 While long-term survival for patients with stage IV disease remains low, median survival for these

patients has improved significantly in recent years, probably due to more effective chemotherapy

and more aggressive surgery.

7 Multidisciplinary treatment involving surgical oncologists, medical oncologists, radiation

oncologists, as well as liver surgeons, gastroenterologists, and stoma therapists improves outcomes

and quality of life in patients with CRC.

Colorectal cancer kills tens of thousands of people every year in the United States. If diagnosed at an

early stage, however, it is one of the most curable malignancies. Identification of populations at risk

and screening of asymptomatic patients are therefore crucial imperatives. This chapter provides a

comprehensive overview of the disease, including epidemiology, risk factors, molecular characteristics,

progression, staging, screening, diagnosis, and treatment.

EPIDEMIOLOGY

1 Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of

cancer death in the United States. It is estimated that in 2015, a total of 132,700 people were diagnosed

with CRC in the United States, and 49,700 died from the disease.1 Approximately 1 in 20 Americans will

be diagnosed with CRC in their lifetime. Death from CRC could be reduced significantly by applying

current knowledge about screening, early diagnosis, and treatment standards. The incidence and

mortality rates for CRC have been decreasing for the last three decades, but the decreases have

accelerated since 2001 (Fig. 68-1). Between 2007 and 2011, the incidence of CRC decreased at a rate of

3.6% for both genders, and mortality at a rate of 2.6% in males and 3% in females. The declines in

incidence and mortality have been attributed to the detection and removal of precancerous polyps as a

result of CRC screening programs, changing patterns in CRC risk factors, and improvements in

treatment.

The incidence and mortality rates for CRC increase with age. The median age at colon cancer

diagnosis is 69 years in men and 74 years in women; for rectal cancer, 63 in men and 65 in women.

More than 90% of CRCs are diagnosed in patients 50 years or older. Both the incidence and mortality

for CRC are 30% to 40% higher in men than in women. The reasons for these differences are not

completely understood but probably reflect an interaction between risk factors and hormonal

differences. There are also gender differences in the distribution of CRC, with a higher proportion of

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renumbering of the coding sequence), and these carriers have a slight increase in colon cancer risk. The

Y179C variant has less enzymatic activity than G396D mutation; therefore, homozygotes with Y179C

have the most severe phenotype, followed by those with one Y179D and some other mutation, followed

by other mutations, which explain the phenotypic heterogeneity in this disease.62 Many reference

laboratories test for the three commonest MutYH mutations on DNA sent from patients with a diagnosis

of FAP if there is no detectable germline mutation (or deletion) in APC. This strategy is only rational

when dealing with European-based mutations. For non-European populations in which this diagnosis is

being considered, it is necessary to have the entire MutYH gene sequenced. MAP patients can sometimes

be managed with frequent colonoscopy when the phenotype is mild, but a colectomy or

proctocolectomy may be indicated depending upon the size and distribution of the adenomas, or in

patients who choose not to comply with regular colonoscopic surveillance.

Peutz–Jeghers Syndrome

Peutz–Jeghers syndrome is an autosomal dominant familial syndrome associated with multiple

gastrointestinal polyps and characteristic skin pigmentation. The gene responsible for this disease

encodes a serine/threonine kinase called LKB1 or STK11 (Table 67-5); carriers of the gene are highly

predisposed to a number of early-onset cancers.

Gastrointestinal Features. The gastrointestinal polyps in Peutz–Jeghers syndrome are nonneoplastic

hamartomas consisting of a supportive framework of smooth muscle tissue covered by somewhat

hyperplastic epithelium (Fig. 67-20). These are histologically distinct from juvenile polyps and show no

inflammatory cell infiltrate. Polyps may be found in the stomach, small intestine, or colon, and in each

instance they have a distinctive appearance. Peutz–Jeghers polyps can usually be identified as such by

the pathologist, and the characteristic cutaneous pigmentation makes this syndrome readily

recognizable.

Table 67-5 Genetic Alterations in Colonic Polyposis Syndromes

Skin Lesions. The cutaneous manifestations of Peutz–Jeghers syndrome may be found early in life and

consist of dark, macular lesions on the mouth (both on the skin and in the buccal mucosa), nose, lips,

hands, feet, genitalia, and anus. These lesions tend to become less obvious by the time of puberty.

Unlike ordinary freckles, the cutaneous lesions of Peutz–Jeghers syndrome are present from birth.

Moreover, ordinary freckles typically do not extend beyond the vermilion border of the lips, nor is the

buccal mucosa involved, as it is in Peutz–Jeghers syndrome.

Clinical Complications. The principal complication of Peutz–Jeghers syndrome is intestinal

obstruction, which may develop in infancy or childhood. This complication is most prominent in the

small intestine because of its narrower diameter. Gastrointestinal bleeding may also be seen in this

disease.

Cancer in the small intestine or colon can occur in Peutz–Jeghers syndrome; however, this is an

uncommon complication.63 It is thought that neoplasia may arise from foci of adenomatous epithelium

found in some Peutz–Jeghers polyps. The risk for cancer is such that prophylactic surgery is not

recommended.

Patients with Peutz–Jeghers syndrome are at increased risk for cancers within and outside the

1753

gastrointestinal tract. Cancer developed in about half of the patients in one large study at a median age

of about 50 years. At risk are the stomach, small intestine, colorectum, gonads, breasts, pancreas, and

biliary tree. Ovarian cysts and sex cord tumors are seen in 5% to 12% of female patients, and boys are

at risk for endocrinologically active Sertoli cell testicular tumors that may produce feminizing features

before puberty. No internal organ is individually at sufficiently high risk for cancer that a specific

screening regimen or prophylactic surgery is indicated. The clinician should be aware of these risks,

however, and should be particularly alert to gonadal tumors (which are otherwise rare) and breast

cancer (for which screening should start at an early age and bilateral disease should be suspected).

Management. The management of Peutz–Jeghers syndrome is limited to the removal of polyps;

endoscopic techniques should be used when possible. Surgery may be required for intussusception

caused by small-intestinal polyps. The risk for neoplastic development should be kept in mind, but these

patients are not candidates for prophylactic removal of any section of the gastrointestinal tract. As

mentioned earlier, gonadal neoplasms and breast cancer are potential complications that may require

surgery.

Figure 67-19. Peutz–Jeghers syndrome. A: Perioral hyperpigmentation. B: Hyperpigmented buccal mucosa. C: Gross specimen of a

Peutz–Jeghers polyp illustrating a large multilobular lesion. D: Low-power photomicrograph of a Peutz–Jeghers polyp of the colon

revealing smooth muscle stroma covered by nonneoplastic colonic epithelium. E: Photomicrograph of the Peutz–Jeghers polyp at

higher power indicates that the stroma contains arborizing bands of smooth muscle.

1754

Juvenile Polyposis

Juvenile polyps are pathologically characteristic lesions that can be solitary or part of a polyposis

syndrome. Juvenile polyps are most commonly solitary lesions found in the rectum during childhood.

The lesions may be large and are made up of an edematous, mildly inflamed lamina propria covered by

normal colonic epithelium (Fig. 67-17). If multiple polyps are found, a familial JPS should be suspected.

Three different syndromic presentations have been reported; it is not known, however, whether these

are truly distinctive syndromes. They may consist of JPS limited to the colon, JPS throughout the

gastrointestinal tract, and JPS limited to the stomach. The genetic basis of this syndrome is not

completely understood, but germline mutations in the SMAD4 (also called the MADH4 gene) and

BMPR1A genes each account for about 20% of JPS cases in which the genetic cause can be found.64,65

Both these genes are involved in the TGF-β signaling pathway. Also, there are rare cases of patients who

have both JPS and hereditary hemorrhagic telangiectasia; these patients typically have mutations in the

SMAD4 gene. Although alterations in the PTEN gene were reportedly linked to JPS, germline mutations

in this gene are only found in the rare Bannayan–Riley–Ruvalcaba variant, a childhood disorder

characterized by macrocephaly, intestinal hamartomatous polyps, and unique pigmented macules of the

penis.66 Other characteristics include ocular abnormalities, delayed motor development, lipid storage

myopathy, and Hashimoto disease. This disorder shares features with Cowden syndrome, which is also

caused by PTEN mutations.67

Figure 67-20. Photomicrograph of a juvenile polyp reveals an attenuated surface epithelium overlying an edematous lamina

propria with fluid- and mucus-filled cystic structures.

The manifestations of JPS can vary but are usually limited to bleeding, intussusception, obstruction,

and the passage of autoamputated lesions. In some children, a life-threatening protein-losing

enteropathy may develop that requires surgical resection of the affected segment of intestine. Patients

with familial juvenile polyposis are at increased risk for the development of colorectal cancer and

require careful surveillance.

Other Familial Polyposis Syndromes

A variety of other rare syndromes may give rise to multiple gastrointestinal polyps. Cowden syndrome

consists of multiple gastrointestinal hamartomas and may be complicated by multiple lesions of the face

that arise from follicular epithelium and are pathologically trichilemmomas.68 This disease is most often

linked to germline mutations in the PTEN gene. The diagnosis of Cowden syndrome should be

considered for patients with multiple trichilemmomas. Gastrointestinal polyps, which are usually

asymptomatic, may develop in these patients. The polyps may include hamartomas, HPs, and

ganglioneuromas of the colon. Glycogenic acanthosis of the esophagus may also occur and usually is

found incidentally as multiple, diminutive, flat polyps of the esophagus. These patients have an increase

in the estimated lifetime risks for the development of breast cancer (85%), thyroid cancer (35%),

endometrial cancer (28%), colorectal cancer (9%), kidney cancer (34%), and melanoma (6%).69 Cowden

syndrome patients should be in the care of someone knowledgeable with these risks. Germline

mutations of the PTEN gene can be identified in most families with Cowden syndrome.70

Other diseases, such as neurofibromatosis (von Recklinghausen syndrome) and the basal cell nevus

syndrome, may be associated with multiple gastrointestinal polyps; however, symptomatic

complications of these polyps are uncommon.

1755

NONFAMILIAL GASTROINTESTINAL POLYPOSIS SYNDROMES

Multiple gastrointestinal polyps are occasionally seen in nonfamilial syndromes. The Cronkhite–Canada

syndrome is an acquired, nonfamilial syndrome characterized by cutaneous lesions (Fig. 67-21), chronic

diarrhea, protein-losing enteropathy, and gastrointestinal polyps. The enteropathy may produce

progressive inanition and dehydration that can result in death. The diarrhea is attributable to diffuse

mucosal injury of the small intestine but may be complicated by bacterial overgrowth. Gastrointestinal

polyps are present in most patients and occur in the stomach, small intestine, colon, and rectum. These

polyps are pathologically similar to juvenile retention-type polyps. The lamina propria is edematous and

contains an inflammatory infiltrate. As has been reported in juvenile polyps, the lesions in this

syndrome may contain adenomatous epithelium, and occasionally carcinomas have complicated this

disease, but this is not a usual feature of the disease. A variety of medical and surgical measures have

been used as treatment, and primary attention should be drawn to the treatment of the diarrhea and

maintenance of the nutritional status. The cutaneous lesions consist of onycholysis, alopecia, and

hyperpigmentation. Multiple therapeutic approaches have been tried, including broad-spectrum

antibiotics, steroids, antihistamines, and extended bowel rest with parenteral nutritional support. Each

approach has had occasional success, but none is uniformly effective. The disease is more common in

Asia than in North America or Europe. Curiously, the cutaneous features may resolve despite persistence

of the gastrointestinal polyps.

Figure 67-21. Cronkhite–Canada syndrome. Onycholysis and hyperpigmentation are characteristic cutaneous manifestations of

Cronkhite–Canada syndrome, a nonfamilial, poorly understood, and acquired condition in which multiple juvenile, inflammatorytype gastrointestinal polyps and characteristic cutaneous features are found.

Other acquired lesions that may present with multiple gastrointestinal polyps include inflammatory

pseudopolyps in the setting of inflammatory bowel disease, lymphoma, pneumatosis cystoides

intestinalis, and multiple lipomas or HPs. None of these syndromes requires specific surgical treatment.

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Figure 67-18. Extraintestinal manifestations of familial adenomatous polyposis (FAP). A: Skull film demonstrating osteomas of the

calvarium (arrows). B: Photograph of the mandible demonstrating protuberant mandibular osteomas. C: Mandibular radiograph

demonstrating a large osteoma of the mandible. D: Chest radiograph demonstrating multiple fibromas (arrows) in a patient with

FAP.

Malignant tumors in the colon are considered to be nearly inevitable in FAP patients, and they may

occur occasionally in the duodenum or (less commonly) elsewhere in the gastrointestinal tract. Patients

with FAP are also at increased risk for brain tumors, thyroid tumors, adrenal tumors, and malignant

tumors of the hepatobiliary tree. Medulloblastomas are a rare complication of FAP, but the risk for this

tumor is increased 99-fold in FAP families.

Desmoid Tumors

Desmoid tumors are currently the major cause of mortality and morbidity in FAP (after colorectal

cancer) and develop in 10% to 15% of such patients, often as a complication of laparotomy, but

sometimes spontaneously. These are benign but aggressive tumors of mesenteric fibroblasts that can

encase and obstruct the gastrointestinal tract, arteries, veins, or ureters. They frequently occur in the

abdominal wall. In some instances, desmoid tumors can virtually fill the abdominal cavity, and can be

lethal. Desmoids are readily visualized on CT of the abdomen, and surgical management of these should

be avoided unless they are superficially located. These are more common in women and in those with a

positive family history of desmoid tumors.

Genetic Basis of FAP

FAP occurs when a germline mutation in the APC gene inactivates the function of the APC protein. In

most instances, the genetic lesion creates a premature stop codon in the APC gene, which in turn leads,

to nonsense-mediated decay of the mRNA or the translation of a truncated, nonfunctional APC protein.

Germline deletions of APC also cause FAP. The APC gene encodes a large protein (311 kd) that binds to

other intracellular proteins – most importantly, the catenins. The APC gene encodes 2,843 codons (one

for each amino acid) and is broken into 15 translated exons. The structure of the APC gene is unique in

that the 15th exon makes up about 75% of the coding sequence of the gene. Because it is unusually

large, this long, open reading frame is a large target for mutations. This genetic vulnerability probably

accounts for the fact that about 25% of mutations in the APC occur de novo, in which neither parent

carries the mutation, and there is no prior family history of FAP.

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The location of the germline mutation is of some clinical significance (Fig. 67-19). For example,

mutations that occur at the 5′ end of the gene, particularly in the first three exons, result in a clinically

mild or “attenuated” form of FAP, in which the number of polyps is smaller and the onset of disease

occurs about 10 years later, with cancer developing in the sixth or seventh decade. This occurs because

the APC gene has an internal ribosomal reentry site downstream of the mutation, which permits the cell

to bypass and ignore the premature stop codon. To complicate the situation, family members with the

same mutation may have variable manifestations of the disease. Indeed, some members who inherit this

mutation have few polyps and no cancer, yet can pass an increased risk for cancer to their progeny.

In contrast, mutations that occur in the “mutation cluster region” of the 15th exon, in a segment

between codons 1,250 and 1,464, are associated with a particularly virulent form of the disease, in

which the number of polyps is greater than 5,000 and the average age for the development of colorectal

cancer is significantly earlier (median age, 34 years). Also, mutations at the extreme 3′ end of the gene

may be associated with a milder phenotype, with fewer polyps and later onset of cancer. In families

who have FAP with CHRPE lesions, the mutations are usually in exons 9 through 15 and only rarely in

families whose mutations are in the first 8 exons. Thus, knowledge of the location of the germline

mutation can be useful in predicting the clinical manifestations and guide therapy.

Diagnosis

The clinical diagnosis of FAP is usually obvious clinically, but the availability of a genetic diagnosis has

changed the approach to this disease. Currently, optimal practice is to obtain a germline diagnosis in an

individual who is definitely affected, in order to characterize and counsel the family. A mutation in APC

can be found in most (90%) of these individuals using commercially available diagnostic laboratories.

This will assist in the early and definitive identification of family members who carry the diseasecausing mutation and will alleviate anxiety for those who do not. The risk to inherit the mutated gene

from an affected parent is 50%, and there is no gender preference. A genetic diagnosis is particularly

useful in the attenuated forms of FAP, where the diagnosis is not obvious, and this can help select those

family members who need additional surveillance and reassure those who do not. Family members who

have the APC mutation should begin endoscopic surveillance from their early teens at yearly intervals.57

About 25% of patients have FAP that is not present in either parent. This can represent the autosomal

recessive form of the disease (MutYH-associated polyposis; see later), misattribution of paternity, or

phenotypic variation in which a parent actually has a milder form of the disease.

Genetic testing is an essential part of the clinical management of the hereditary cancer, but it can be a

challenge. The genetic results are sometimes ambiguous and difficult for the physician to interpret.

Additionally, some patients mistake the germline test as a test for cancer. Issues of guilt and denial are

prominent in genetic disorders. It is strongly recommended that physicians enlist the involvement of

genetic counselors when performing genetic testing and counseling in such patients. The federal

“Genetic Information and Non-Discrimination Act” (GINA) protects asymptomatic patients carrying a

germline mutation for a serious disease from discrimination in the workplace or with health insurance.

Management

Surgery is the only reasonable management option in FAP, and the clinical decision involves the

selection and timing of the operation. The diagnosis of FAP is often made in adolescence, but the

development of cancer may not be anticipated for 20 to 30 years after the first polyp appears,

depending on the location of the mutation in the APC gene. When a child is found to have a germline

mutation in APC, sigmoidoscopy should begin in the early teenage years, particularly if the mutation is

in the “mutation cluster region” or the family’s phenotype is known to be associated with thousands of

polyps. Ideally, one would like a patient to reach adulthood prior to the colectomy, as the pelvis is

larger and the individual is better able to cope with the disease psychologically.

The safest surgical approach is a total proctocolectomy with an ileoanal J-pouch anastomosis. No

rectal mucosa should be left behind, since it is at risk for the development of neoplasia. Even with

careful endoscopic surveillance of the rectal segment, invasive carcinomas may develop.

The fact that small adenomatous polyps of the rectum can spontaneously regress visibly after a

subtotal colectomy and ileorectal anastomosis underscores the reversible nature of the benign adenoma.

Additionally, it has been found that adenomas can regress in FAP in response to treatment with

sulindac. Several reports have confirmed that even large numbers of polyps regress in patients on 150 to

200 mg of sulindac twice per day. Unfortunately, the polyps reappear when the drug is stopped, and

cancer may develop despite treatment with sulindac. Medical treatment is therefore not a safe or

reliable first-line treatment for FAP. Furthermore, such treatment may create the illusion of false

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assurance of preventing cancer. Sulindac is not effective in the management of upper gastrointestinal

tract neoplasia.

Management of Extracolonic Disease. In addition to the risks for colorectal neoplasia, patients with

FAP are at risk for the development of osteomas, lipomas, fibromas, and a variety of other lesions.

Although these mesenchymal tumors can degenerate into sarcomas, this is a sufficiently rare event that

prophylactic surveillance and surgery are not indicated. Likewise, CHRPE lesions do not require

treatment. Gastric carcinoma is distinctly uncommon in North American populations where the lifetime

risk for gastric cancer in FAP is 0.5%. The bigger problem is that the gastric polyps may look ominous

endoscopically and dysplastic pathologically, and one should be reluctant to perform a gastrectomy on a

person who has already had a colectomy. Caution is advised when following large gastric polyps in FAP.

The two major management issues after removal of the colon and rectum are periampullary neoplasia

and desmoid tumors. One or more adenomas are found in the duodenum in 90% of patients with FAP,

usually close to the ampulla of Vater. These lesions should be excised for biopsy and destroyed by

electrocautery, laser, or other ablative approaches. Subsequent examination of the upper

gastrointestinal tract is guided by the Spigelman criteria (Table 67-4). Complex neoplasms, including

adenomas with varying degrees of dysplasia, may require individualized management, including the use

of biliary stents while extensive ablative therapy of the periampullary region is performed. Surgical

approaches may be required for advanced neoplasms (i.e., carcinoma in situ or invasive carcinoma), but

therapeutic endoscopy remains the first option. Duodenotomy with local surgical excision is an option

for some of these lesions; occasionally, a Whipple procedure is required for invasive lesions in this

region, with low mortality, but considerable morbidity.58

Desmoid tumors are aggressive benign tumors of fibroblasts that can cause multiple clinical

complications; they are a significant cause of morbidity and mortality in FAP. They typically grow

slowly and can surround or compress vascular structures, nerves, or the abdominal viscera. They are

more common in women and may be hormonally responsive, so estrogen administration (oral

contraceptives or hormone replacement therapy) should be avoided in these patients. Surgical

management is generally avoided unless simple local excision of an abdominal wall lesion is possible,

and postoperative recurrences are common. Radiotherapy has been used to control the growth of some

of these but is generally reserved for superficial lesions. No medical approach to this disease has been

uniformly successful. A combination of sulindac plus tamoxifen may be tried for intra-abdominal tumors

and has been successful in some patients. Cytotoxic chemotherapy with doxorubicin was successful in a

patient whose tumor was refractory to other treatment. Anecdotally, some of these lesions may have ckit mutations and are responsive to imatinib (Gleevec).

Familial Adenomatous Polyposis Variants

5 A number of names, especially Gardner syndrome, have been attached to variations of FAP to

emphasize the presence of particular extracolonic findings. As mentioned, Gardner syndrome is the same

entity as FAP. A few families with prominent sebaceous cysts were historically said to have Oldfield

syndrome, and families with brain tumors were said to have Turcot syndrome. All these syndromes

represent the variable expression of germline mutations in the APC gene and are largely of historical

interest. The current mode of classifying FAP families is based on the APC gene mutation.

MutYH-Associated Polyposis or MAP

An autosomal recessive form of polyposis has been linked to inheritance of germline mutations in the

base excision repair gene MutYH, a DNA glycolase.59–61 MAP should be considered when multiple

adenomatous polyps occur in siblings or in a person who has no vertical family history of polyposis and

there is no detectable germline mutation in the APC gene. These patients have a relatively mild

(attenuated) form of adenomatous polyposis, typically develop 20 to 500 adenomas, and the polyposis

is frequently detected in patients 35 to 65 years old. These patients are at very high risk for colorectal

cancer, and the disease may present with cancer. The extraintestinal manifestations of FAP, such as

duodenal adenomas or CHRPE lesions, occasionally occur but are less common in MAP than FAP. The

pathogenesis of this disease is that the germline mutations in MutYH permit an excess number of

acquired mutations in the APC gene (and other genes) to occur in the colon; these mutations are

typically G:C → T:A transversions, which is a consequence of losing the DNA base excision repair

system. More than 1.3% of the Caucasian population carries a single copy of the MutYH alleles Y179C,

G396D, and E480X (previously designated Y165C, G382D, and E466X, respectively, but changed due to

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Figure 67-14. Submucosal lipomas. A: Lipoma seen at colonoscopy. Submucosal fatty tissue causes the mucosa to protrude into the

lumen; such protrusion appears as a polyp. Overlying mucosa is smooth. B: Lipomatous infiltration of ileocecal valve seen at

colonoscopy. C: Colectomy specimen showing a large submucosal lipoma cut in cross section.

Figure 67-15. Lymphomatous polyposis of the colon. A: Colonoscopic view of B-cell lymphoma presenting as multiple colonic

polyps. B: Histology of lymphoma is one of the polyps.

Colitis cystica profunda is a rare condition in which the intestinal wall is thickened by submucosal

mucus-filled cysts of various sizes and an accumulation of fibroblasts in the lamina propria. It can

present as an ulcerating or mass lesion in the rectosigmoid in association with the solitary rectal ulcer

syndrome. Although the pathogenesis of this condition is unknown, it may result from the downward

displacement of colonic glands during trauma or chronic inflammation followed by healing. The

appearance of aberrant submucosal glandular epithelium and acellular mucous lakes must be

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distinguished from a colloid or mucinous carcinoma, because this lesion has no malignant potential.

Carcinoid tumors of the rectum appear as isolated, small, yellow-gray submucosal nodules. These are

often incidental findings during sigmoidoscopy. Most are smaller than 1 cm, have little malignant

potential, and are amenable to local excision. Lesions larger than 2 cm are more likely to be malignant

but seldom give rise to metastases. These lesions should be treated aggressively with complete excision.

Rectal carcinoid tumors are usually asymptomatic but may present with hematochezia. They are not

associated with the carcinoid syndrome. Carcinoid tumors in the proximal colon may be locally invasive

or metastasize to the liver, liberating vasoactive peptides into the systemic circulation and producing

the carcinoid syndrome.

Other lesions that can present as submucosal polyps include metastatic tumors, such as malignant

melanoma, and benign lesions, such as leiomyomas, fibromas, lymphangiomas, hemangiomas, and

endometriosis.

GASTROINTESTINAL POLYPOSIS SYNDROMES

Gastrointestinal polyposis indicates the presence of a systemic process that promotes the development

of multiple polyps throughout the gastrointestinal tract. In some instances, the polyps are located

predominantly in the colon; however, in others, polyps may be found in the stomach, small intestine,

colon, and rectum. The classification of the polyposis syndromes has traditionally been based on the

histologic characteristics of the polyps, but gradually an awareness of the genetic basis for the most

important of these syndromes has permitted more precise diagnosis and rational approaches to

treatment.

Familial Adenomatous Polyposis

4 FAP is an autosomal dominant, genetic disease characterized by the development of multiple

adenomatous polyps throughout the colon and rectum (Fig. 67-16). The polyps first appear in

adolescence, with the median age of onset being about 16 years. The number of polyps in each patient

is variable, and they increase in number and size with advancing age. The genetic basis for this disease

is an inactivating germline mutation in the APC gene. In part, the age of onset, number of polyps, and

age at which cancer develops are determined by the location of the mutation in the APC gene (Fig. 67-

17). Some mutations (located in the middle of the gene) predispose to a very large number of adenomas

(>5,000), and other mutations in the first three exons to a smaller number (<100). Additional factors

not related to the mutation on the APC gene, some genetic and some environmental, also modify the

clinical characteristics of the disease.56

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Figure 67-16. Familial adenomatous polyposis (FAP). A: Gross specimen of a resected colon from a patient with FAP. B: Sessile

and pedunculated adenomatous polyps in the colon of a patient with FAP. C: Close-up view of a profuse type of FAP, in which the

mucosa is carpeted with innumerable polyps. D: Photomicrograph demonstrating profuse FAP with both sessile and pedunculated

adenomatous polyps.

Figure 67-17. This scheme of the APC (adenomatous polyposis coli) gene illustrates the genotype–phenotype correlations. Most

mutations of APC result in premature stop codons; therefore, the site of the mutation usually indicates the relative length of the

mutant protein product. Mutations at the 5′ end of the gene produce “attenuated” FAP, a milder form of the disease. The retinal

lesions (congenital hypertrophy of retinal pigmented epithelium [CHRPE]) occur when the mutations are between exons 9 and 15.

The portion of the APC gene that binds to other cytoskeletal elements in the cell is represented at the 3′ end of the 15th exon.

Mutations in a hot spot immediately downstream from the β-catenin–binding site (between codons 1250 and 1464) result in a

more virulent, profuse form of familial adenomatous polyposis. This site is also the location of most of the acquired mutations in

sporadic colorectal neoplasms.

Gastrointestinal Features

Polyps in the stomach and small intestine develop in about 90% of patients with FAP. The gastric polyps

consist of fundic gland polyps, which are not premalignant lesions. These may appear to be dysplastic,

but in the Western world (North America and Europe), gastric cancer is rare. Gastric cancer is a

considerable diagnostic problem in FAP in Japan and Korea, however.

Small-intestinal neoplasia is not rare in FAP and principally occurs in the periampullary region of the

duodenum. Duodenal adenomatous polyps, which typically appear later than the colonic lesions, may be

multiple but tend not to carpet the proximal small intestine. The ampulla of Vater is a particular target

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for neoplastic development. With time, carcinoma develops in 5% to 10% of these patients, so that

duodenal surveillance is required. Spigelman has developed a classification system that can be used to

determine optimal surveillance for duodenal neoplasia, which is based on the number, size, and

histologic features of the duodenal polyps (Table 67-4). Adenomas and carcinomas occur in the jejunum

and ileum, but these are rare, and routine screening of the small intestine is not recommended. Polyps

in the terminal ileum may represent lymphoid aggregates rather than adenomas and should be biopsied

for diagnostic purposes.

Classically, it has been stated that the natural history of FAP is for cancer to develop at a median age

in the mid-40s. As mentioned, the development of cancer is variable and is based in part on the location

of the germline mutation in the APC gene. Colon cancer is rather unusual before 30 years of age, and

cancer may not develop in patients with the attenuated form of FAP until they are in their 50s or 60s.

Cancer occurring in the teenage years has been reported as a result of a patient who had both FAP and

Lynch syndrome. Thus, the treatment of these patients relies increasingly on a genetic characterization

of the disease.

Extraintestinal Features

Traditionally, patients with manifestations of FAP together with extraintestinal manifestations were

considered to have Gardner syndrome. It is now appreciated that families with FAP all have

extraintestinal manifestations and that no distinction can be made between families with Gardner

syndrome and those with FAP. FAP is characterized by osteomas of the mandible, skull, and long bones

and a variety of other benign soft tissue tumors, such as fibromas, lipomas (Fig. 67-18), and sebaceous

cysts, which should not be confused with the sebaceous adenomas and carcinomas seen in the Muir–

Torre syndrome variant of Lynch syndrome. Osteomas are commonly found in the skull and may be

multiple. Some of these lesions have been reported to regress and later reappear. Osteomas may also be

found in the mandible, and radiographs of the mouth may reveal impacted or supernumerary teeth.

Congenital hypertrophy of the retinal pigmented epithelium (CHRPE) is present in some families with

FAP, depending on the location of the mutation in the APC gene. CHRPE lesions may be seen in 5% of

the general population but are small and usually single. Multiple, bilateral, and large CHRPE lesions

strongly suggest FAP. It will require a slit-lamp examination and knowledgeable ophthalmologist to

make this diagnosis with confidence, as these are not readily seen in an office ophthalmoscopic

examination.

Table 67-4 Spigelman Classification for Management of Duodenal Adenomas in

Individuals with FAP

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Figure 67-10. Diagram representation of cancer-containing polyps. Pedunculated adenoma is described on the left and a sessile

adenoma on the right. In carcinoma in situ, malignant cells are confined to the mucosa. These lesions are adequately treated by

endoscopic polypectomy. Polypectomy is adequate treatment for invasive carcinoma only if the margin is sufficient (2 mm), the

carcinoma is not poorly differentiated, and no evidence of venous or lymphatic invasion is found. (After Haggitt RC, Glotzbach RE,

Soffen EE, et al. Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic

polypectomy. Gastroenterology 1985;89:328.)

Primary Prevention of Adenoma Recurrence

Primary prevention relates to the ability of identifying genetic, environmental, and biologic factors that

cause cancer, and to mitigate their outcomes. Laboratory, clinical, and epidemiologic evidence suggests

that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, is associated

with a substantially decreased risk for the development of colorectal cancer. Four published trials have

demonstrated a reduction in adenoma recurrence in chemoprevention trials involving aspirin.50,51 Given

the biologic plausibility, preclinical in vitro and animal data, and data on adenoma regression in

patients with FAP, three large randomized trials, which studied over 6,000 patients in total, were

undertaken to examine the effect of cyclooxygenase-2 (COX-2)–selective inhibitors on new adenoma

formation in individuals with a history of sporadic adenomas. All of these trials demonstrated a highly

significant reduction in new adenoma formation in those taking a COX-2–selective inhibitor (celecoxib

or rofecoxib) compared to placebo over 3 years. In the Adenoma Prevention with Celecoxib (APC)

trial,52 the use of celecoxib was associated with a dose-dependent 33% to 45% reduction in the

development of new adenomas by 3 years, with a 57% to 66% reduction in the number of patients

developing advanced adenomas. Unfortunately, adverse thrombotic cardiovascular events were

associated with COX-2 inhibition in two of these trials. Recent data suggest that increased

cardiovascular risk may be associated with most NSAIDs, and not just COX-2 inhibitors.

Other agents currently undergoing study for chemoprevention of colorectal neoplasia include the

ornithine decarboxylase inhibitor difluoromethylornithine (DFMO), the bile acid ursodiol, the 3-

hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors such as pravastatin and

lovastatin, epidermal growth factor receptor (EGFR) inhibitors, and matrix metalloproteinase (MMP)

inhibitors. The combination of DFMO and the NSAID sulindac were studied in a randomized placebocontrolled trial to assess their efficacy in preventing sporadic adenoma recurrence in 375 subjects. The

use of this regimen was associated with a 70% reduction in new adenomas at 3 years compared to

placebo.53 Larger studies are underway to confirm this result and to fully assess toxicity of this

combination. A population-based case-control study of individuals with colorectal cancer and matched

controls demonstrated a 47% relative reduction of colorectal cancer associated with statin use, but

further investigation is needed to assess the overall benefits of this group of agents.

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Figure 67-11. Invasive carcinoma in the stalk of an adenomatous polyp. A: Low-power view. Malignant glands can be seen

invading fibrovascular stalk. B: High-power magnification of malignant glands in stalk. Nuclei are large, hyperpigmented, and

crowded.

Supplemental calcium reduces proliferative activity in the mucosa of experimental animals and

patients at high risk for the development of colorectal cancer. A large body of observational and

laboratory studies suggests a role for dietary calcium supplementation in chemoprevention. A

prospective, double-blind, placebo-controlled trial showed that supplemental calcium (3,000 mg of

calcium carbonate per day, equivalent to 1,200 mg of elemental calcium) reduced the incidence and

number of recurrent adenomas in subjects with a recent history of such lesions. The protective effect of

calcium supplementation on the risk of colorectal adenoma recurrence extended up to 5 years after

cessation of active treatment, even in the absence of continued supplementation.54 Analysis of serum

vitamin D status in subjects suggested that calcium supplementation and vitamin D status appear to act

together to reduce the risk of adenoma recurrence. A prospective trial designed to assess the individual

effects of calcium and vitamin D and the combination on adenoma recurrence, however, failed to

demonstrate an effect of any of these agents.

“Essential” fatty acids are required for biologic processes, but cannot be synthesized by humans and

must therefore be obtained from dietary sources. The main polyunsaturated fatty acids (PUFAs)

docosahexaenoic acid (DHA, 22:6∆4,7,10,13,16,19) and eicosapentaenoic acid (EPA, 20:5∆5,8,11,14,17) are

considered “essential” and are obtained predominantly from cold water oily fish such as mackerel and

salmon. A randomized trial in subjects with FAP demonstrated that an enteric-coated formulation of

EPA has chemopreventive efficacy in reducing rectal polyp burden to a degree similar to that previously

observed with selective COX-2 inhibitors.55 The role for N-3 PUFAs in “sporadic” colorectal adenoma

prevention is currently being evaluated.

Trials of supplemental dietary fiber, as well as antioxidant vitamins such as β-carotene and vitamins C

and E, have not convincingly demonstrated any effect on adenoma recurrence.

OTHER MUCOSAL SUBMUCOSAL POLYPS

Hyperplastic Polyps

HPs are small, usually sessile lesions most frequently encountered in the distal colon and rectum (Fig.

67-12A). Although grossly indistinguishable from small adenomas, they carry no significant potential for

malignant degeneration particularly when located in the distal colon or rectum. However, HPs must be

distinguished from SSAs, which carry significant malignant potential. Macroscopically, HPs are almost

always less than 1 cm in size, and most are in the distal colon. In fact, when HPs are found proximal to

the rectosigmoid region, one must consider the possibility that this is actually an SSA. Microscopically,

HPs are characterized by a saw-toothed epithelial pattern representing micropapillary luminal infoldings

of columnar absorptive cells and mature, frequently hyperdistended goblet cells (Fig. 67-12B).

Elongation and subsequent infolding of the epithelium may be caused by an expanded, but otherwise

normally located, replication zone in the crypt. The cytologic atypia characteristic of adenomatous

polyps is not seen in these lesions.

HPs are common age-related lesions found in about one-third of the population older than 50 years.

Although they often coexist with adenomas in polyp-bearing patients, no convincing evidence has been

found that HPs per se are harbingers of adenoma development. Because HPs are asymptomatic and carry

1743

no malignant potential, no specific treatment is required for these lesions. If an HP is the only lesion

detected on index-flexible sigmoidoscopy or colonoscopy, no further evaluation is indicated.

Sessile Serrated Adenomas

SSAs or SSPs – the terms are essentially interchangeable – are distinct from conventional adenomas with

respect to histology and molecular biology, and are typically nondysplastic in appearance (Fig. 67-5),

but may contain areas of dysplasia or intramucosal carcinoma. They are characterized by the serrated

appearance of the surface epithelium (common to all serrated lesions), distorted crypt bases and crypt

dilation, and by migration of the proliferative zone to the side of the crypt. SSAs represent 3% to 22%

of serrated lesions and 75% to 90% of SSAs are right-sided.9 They are often flat (>90%), and may be

covered by a so-called “mucous cap.” These features often make endoscopic detection difficult,

emphasizing the importance of high-quality endoscopy including an excellent bowel preparation and

adequate withdrawal times to yield high polyp detection rates. These polyps are thought to be the

precursors of sporadic (non-Lynch syndrome) colorectal cancers with MSI, which are overwhelmingly

found in the proximal colon.

Figure 67-12. Hyperplastic polyps. A: Several diminutive hyperplastic polyps seen in the rectum during flexible sigmoidoscopy. B:

Photomicrograph of a hyperplastic polyp, characterized by elongated glands with papillary infoldings that have a typical serrated

epithelial pattern.

Figure 67-13. Inflammatory polyps. A: Severe mucosal inflammation with infiltrates and granulation tissue shown here

microscopically can appear clinically with a polypoid configuration. B: Resolution of inflammation can leave exuberant polyps

covered by normal epithelium, which are called pseudopolyps, a misnomer. These are truly polyps, but are not neoplastic.

Juvenile Polyps

Juvenile polyps can occur sporadically or as part of a juvenile polyposis syndrome (JPS). These mucosal

1744

polyps consist of dilated cystic mucus-filled glands and abundant lamina propria with an inflammatory

infiltrate. Seventy-five percent of these occur in children younger than 10 years of age, often appearing

as single pedunculated cherry-red polyps with a smooth surface and contour. The exact prevalence of

such lesions has not been determined, but they are thought to be acquired lesions detectable in about

2% of children. Juvenile polyps often present with hematochezia because they are highly vascularized

lesions. Rectal prolapse and auto-amputation may occur with distal lesions, whereas intussusception

may be precipitated by proximal juvenile polyps, particularly in the context of familial syndromes.

Individually, these polyps have no malignant potential, but symptomatic polyps should be removed to

prevent further complications. Juvenile polyposis, on the other hand, is associated with an increased

risk for the early development of cancer.

Inflammatory Polyps

Inflammatory mucosal polyps are common in the setting of idiopathic inflammatory bowel disease.

Marked inflammation and ulceration coexist with granulation tissue in a distorted mucosal architecture

that appears polypoid because of confluent areas of ulceration, leaving behind islands of intact

epithelium (Fig. 67-13A). Subsequent healing leads to the appearance of polypoid, nonneoplastic

excrescences covered by normal colonic epithelium, and are called “pseudopolyps,” in spite of the fact

that they are truly polypoid excrescences (Fig. 67-13B). They need not be removed and are important

largely because they make it difficult to recognize subtle, early neoplastic lesions in these high-risk

patients. Severe chronic inflammation of any kind, including a variety of infectious diseases

(tuberculosis, amebiasis, schistosomiasis, and amebic colitis), may result in inflammatory polyps that

resemble those found in idiopathic inflammatory bowel disease.

Submucosal Polyps

Submucosal masses can expand to push the colonic mucosa into the bowel lumen and thus appear as

polypoid lesions. Many submucosal lesions (e.g., lipomas, leiomyomas) are clinically asymptomatic and

must be differentiated from neoplastic lesions. Others are malignant lesions that require early detection,

such as lymphomas and metastatic tumors. Many submucosal lesions are not detected on endoscopic

mucosal biopsy because standard biopsy forceps do not reach beyond the mucosa. If a submucosal lesion

is suspected, multiple biopsy specimens of the same site sometimes provide tissue for diagnosis.

Lipomas are benign fatty tumors that occur throughout the gastrointestinal tract but are most

commonly found in the cecum near the ileocecal valve (Fig. 67-14). They appear endoscopically as soft,

smooth polyps that are pliable and deformable. The overlying mucosa is intact but may be light yellow

in appearance. These are benign lesions that have little clinical significance and are more commonly

seen in obese patients.

Isolated lymphoid nodules consisting of benign lymphoid tissue may appear as sessile smooth polyps of

various sizes, with a predilection for the distal colon and rectum. These are usually asymptomatic.

Diffuse nodular lymphoid hyperplasia also occurs in children as an incidental finding. The nodules must

be distinguished from primary or secondary lymphoma of the large intestine, which may present as

mucosal nodularity resembling the pseudopolyposis of inflammatory bowel disease or even a familial

polyposis syndrome (Fig. 67-15). Flow cytometry of the lymphocytes in the lesion will be helpful;

benign polyposis is polyclonal, whereas lymphomas are monoclonal and may overexpress cyclin D.

Pneumatosis cystoides intestinalis consists of multiple air-filled cysts within the submucosa. This may be

an incidental finding in patients with chronic obstructive pulmonary disease, scleroderma, or an

asymptomatic pneumoperitoneum secondary to recent surgery or instrumentation, in which air or

colonic gas diffuses into the cysts. These sometimes resolve with administration of oxygen. A far more

virulent form of pneumatosis is associated with fulminant mucosal inflammation, ischemia, or

necrotizing enterocolitis in children. These cysts are thought to result from mucosal invasion by gasproducing bacteria.

1745