CHAPTER 51 Colon and Rectum 1359

BOX 51-3 Colonic Ischemia: Indications TABLE 51-2 Familial Risk and
for Surgery Colon Cancer
Acute Indications APPROXIMATE LIFETIME
Peritoneal signs FAMILIAL SETTING* RISK OF COLON CANCER
Massive bleeding General U.S. population 6%
Universal fulminant colitis, with or without toxic megacolon One first-degree relative with colon 2- to 3-fold increased
cancer
Subacute Indications
Two first-degree relatives with colon 3- to 4-fold increased
Failure of an acute segmental ischemic colitis to respond within 2 to 3 weeks,
cancer
with continued symptoms or a protein-losing colopathy
First-degree relative with colon cancer 3- to 4-fold increased
Apparent healing but with recurrent bouts of sepsis
diagnosed at ≤50 years
Chronic Indications One second- or third-degree relative 1.5-fold increased
Symptomatic colon stricture with colon cancer
Symptomatic segmental ischemic colitis Two second- or third-degree relatives 2- to 3-fold increased
with colon cancer
One first-degree relative with 2-fold increased
adenomatous polyp
the operative findings. Ischemia involving the entire colon is rare,
but such cases require total colectomy with ileostomy. More often, From Burt RW: Colon cancer screening. Gastroenterology 119:837–
the ischemia involves a recognizable segment of colon. In these 853, 2000.
cases, segmental resection is appropriate. If there is concern for *First-degree relatives include parents, siblings, and children.
evolving ischemia, leaving the bowel in discontinuity and the Second-degree relatives include grandparents, aunts, and uncles.
abdomen open in preparation for a planned second-look lapa- Third-degree relatives include great-grandparents and cousins.
rotomy is prudent. If there is little concern for ongoing ischemia,
a one-stage operation is reasonable, but deciding between primary presence of other specific tumors and defects. Familial adenoma-
anastomosis and ostomy can be difficult. In general, if emergent tous polyposis (FAP) and hereditary nonpolyposis colorectal
colon resection is required for colonic ischemia, the safest approach cancer (HNPCC) are the subject of many studies that have pro-
is to fashion an end ostomy with either a mucous fistula, if pos- vided significant insights into the pathogenesis of colorectal
sible, or Hartmann closure of the distal colon or rectum. A cancer.
summary of the indications for surgery is presented in Box 51-3. Sporadic colorectal cancer occurs in the absence of family
history, generally affects an older population (60 to 80 years of
age), and usually is manifested as an isolated colon or rectal lesion.
Genetic mutations associated with the cancer are limited to the
NEOPLASIA tumor itself, unlike in hereditary disease, in which the specific
Adenocarcinoma of the colon and rectum is the third most mutation is present in all cells of the affected individual. Never-
common site of new cancer cases and deaths in men (following theless, the genetics of colorectal cancer initiation and progression
prostate and lung or bronchus cancer) and women (following can, in some circumstances, proceed along similar pathways in the
breast and lung or bronchus cancer) in the United States. It was hereditary and sporadic forms of the disease. Studies of the rela-
estimated that in 2015, there were 106,100 new cases of colon tively rare inherited models of the disease have greatly enhanced
cancer (552,010 men and 54,090 women) and 40,870 new cases the understanding of the genetics of the far more common spo-
of rectal cancer (23,580 men and 17,290 women) diagnosed. In radic form.
2015, 49,920 Americans (25,240 men and 24,680 women) were The concept of familial colorectal cancer is relatively recent.
predicted to die of colorectal cancer. It remains the second leading Lifetime risk for colorectal cancer increases for members in fami-
cause of cancer death in the United States. The lifetime risk for lies in which the index case is young (<50 years) and the relative
development of colorectal cancer in the United States is 5.51% is close (first-degree relative). The risk increases as the number of
(1 in 18) for men and 5.10% (1 in 20) for women. The risk for family members with colorectal cancer rises (Table 51-2). An
development of invasive colorectal cancer increases with age, with individual who is a first-degree relative of a patient diagnosed with
more than 90% of new cases being diagnosed in patients older colorectal cancer before the age of 50 years is twice as likely as an
than 50 years. The incidence of colorectal cancer from 1998 to individual in the general population to develop the cancer. This
2005 decreased at a rate of 2.8%/year for men and 2.2%/year for more subtle form of inheritance has been the subject of much
women. The death rate for men and women decreased 4.3% investigation. Genetic polymorphisms, gene modifiers, and defects
annually during the period from 2002 to 2005. There has been a in tyrosine kinases have all been implicated in various forms of
significant increase in 5-year survival rates during the last 30 years. familial colorectal cancer.
The 5-year survival for colon cancer was 52% from 1975 to 1977,
59% from 1984 to 1986, and 65% from 1996 to 2004. The Colorectal Cancer Genetics
5-year survival for Americans with rectal cancer was 49% from The field of colorectal cancer genetics was revolutionized in 1988
1975 to 1977, 57% from 1984 to 1986, and 67% from 1996 to by the description of the genetic changes involved in the progres-
2004.30 sion of a benign adenomatous polyp to invasive carcinoma. Since
Colorectal cancer occurs in hereditary, sporadic, and familial then, there has been an explosion of additional information about
forms. Hereditary colorectal cancer has been extensively described the molecular and genetic pathways that result in colorectal
and is characterized by family history, young age at onset, and the cancer. Tumor suppressor genes, DNA mismatch repair (MMR)
136 0 SECTION X Abdomen

APC K-RAS DCC p53 Other changes?

Normal Dysplastic
Early Intermediate Late
colonic aberrant Carcinoma Metastasis
adenoma adenoma adenoma
epithelium crypt foci

Normal tissue Tumor initiation Tumor progression Neoplasia

Familial Accelerated Normal Nearly 100% risk for

adenomatous (due to germline colorectal cancer
polyposis APC mutation) (5–10 years)

Hereditary Normal Accelerated 70%–80% lifetime risk

nonpolyposis (due to germline mutation of colorectal cancer
colorectal cancer in mismatch repair gene)

(May be 1–3 years)

FIGURE 51-6 0 Adenoma-carcinoma sequence in sporadic and hereditary colorectal cancer. (From Ivanovich
JL, Read TE, Ciske DJ, et al: A practical approach to familial and hereditary colorectal cancer. Am J Med
107:68–77, 1999.)

genes, proto-oncogenes, and promoter hypermethylation events TABLE 51-3 Gene Mutations That
all contribute to colorectal neoplasia in the sporadic and inherited Promote Colorectal Cancer
forms. The Fearon-Vogelstein adenoma-carcinoma multistep
model of colorectal neoplasia represents one of the best-known MUTATION TYPE OF
models of carcinogenesis (Fig. 51-60). This sequence of tumor TYPE GENES INVOLVED DISEASE CAUSED
progression involves damage to proto-oncogenes and tumor sup- Germline APC Familial adenomatous
pressor genes. The multistep carcinogenesis model can serve as a polyposis
template to illustrate how certain early mutations produce accu- MMR HNPCC (Lynch
mulated defects resulting in neoplasia. The specific contributing syndrome)
mutations in genes such as adenomatous polyposis coli (APC) Somatic Oncogenes: myc, ras, src, erbB Sporadic disease
have been intensely studied. It is important to view this model Tumor suppressor genes:
and others as progressive and in flux while interconnected cell TP53, DCC, APC
cycle control pathways and new functions for well-known genes MMR genes: bMSH2, bMLH1,
are becoming apparent (Table 51-3). bPMS1, bPMS2, bMSH6,
bMSH3
Specific Genes and Mutations Genetic APC Familial colon cancer in
Tumor Suppressor Genes polymorphism Ashkenazi Jews
Tumor suppressor genes produce proteins that inhibit tumor for-
mation by regulating mitotic activity and providing inhibitory cell DCC, Deleted in colorectal carcinoma.
cycle control. Tumor formation occurs when these inhibitory
controls are deregulated by mutation. Point mutations, loss of The Wnt signaling proteins are closely associated with the
heterozygosity, frame-shift mutations, and promoter hypermeth- APC–β-catenin pathway. APC also influences cell cycle prolifera-
ylation are all types of genetic and epigenetic changes that can tion by regulating Wnt expression. Wnt gene products are extra-
cause failure of a tumor suppressor gene. The first genes mutated cellular signaling molecules that help regulate tissue development
in the sequence are often referred to as gatekeeper genes because throughout the organism. The Wnt signaling proteins are closely
they provide cell cycle inhibition and regulatory control at specific associated with the APC–β-catenin pathway. Under normal con-
checkpoints in cell division. The failure of regulation of normal ditions, reduced intracytoplasmic β-catenin levels inhibit Wnt
cellular function by tumor suppressor genes is appropriately expression. When APC is mutated, however, β-catenin levels rise
described by the term loss of function. Both alleles of the gene must and Wnt is activated. Overexpression of Wnt leads to activation
be nonfunctional to initiate tumor formation. of Wnt target genes, such as cyclin D1 and MYC, which drive
The APC gene is a tumor suppressor gene located on chromo- cell proliferation and tumor formation.
some 5q21. Its product is 2843 amino acids in length and forms The earliest mutations in the adenoma-carcinoma sequence
a cytoplasmic complex with GSK-3β (a serine-threonine kinase), occur in the APC gene. The earliest phenotypic change present is
β-catenin, and axin. β-Catenin, a multifunctional protein, is a known as aberrant crypt formation, and the most consistent
structural component of the epithelial cell adherens junctions and genetic aberrations within these cells are abnormally short pro-
the actin cytoskeleton; it also binds in the cytoplasm to Tcf/LEF teins known as APC truncations. Most clinically relevant derange-
and is then transported into the nucleus, where it activates tran- ments in APC are truncation mutations created by inappropriate
scription of genes such as c-myc and others that regulate cellular transcription of premature termination codons.
growth and proliferation. APC therefore participates in cell cycle A germline APC truncation mutation is responsible for the
control by regulating the intracytoplasmic pool of β-catenin. autosomal dominant inherited disease FAP. Thirty percent of cases
 CHAPTER 51 Colon and Rectum 136 1

of FAP are de novo germline mutations, presenting without a

family history of the disease. FAP is rare, with an estimated inci-
dence of 1 in 10,000 live births in the United States, occurring
without gender predilection. It is typically characterized by more
than 100 adenomatous polyps present in the colon and rectum.
These polyps often number in the thousands and are almost
always manifested by the late second or early third decade of life
(Fig. 51-61). Because some of these polyps proceed through the
adenoma-carcinoma sequence, most patients with FAP die of
colon cancer by their fifth decade of life in the absence of surgical
intervention. FAP is of great interest to those studying sporadic
colorectal cancer because APC truncation mutations similar to
those found in APC patients occur in 85% of sporadic colorectal
cancers.
Most APC truncation mutations occur in the mutational
cluster region of the gene, an area responsible for β-catenin
binding. However, genotype-phenotype correlations exist with A
mutations in other regions of the gene. For example, mutations
close to the 5′ end of the gene produce a short truncated protein
that causes the syndrome known as attenuated FAP or (AFAP).
These patients usually have far less than the hundreds of polyps
usually associated with FAP, and the disease has a tendency to
spare the rectum.
Classic FAP is characterized by truncation mutations occurring
in the gene from codon 1250 to codon 1464. Mutations occurring
farther along the gene toward the 3′ end are rare and most likely
result in a much attenuated phenotype or no detectable abnormal-
ity (Fig. 51-62).
The variability of the FAP phenotype is also demonstrated by
the presence or absence of extraintestinal manifestations of disease.
In the past, the term Gardner syndrome was used to describe the
coexpression of profuse colonic adenomatous polyps along with
osteomas of the mandible and skull, desmoid tumors of the mes-
entery, and periampullary neoplasms.
B
Many other associated disorders have been subsequently
described, including thyroid papillary tumors, medulloblastomas,
hypertrophic gastric fundic polyps, and congenital hypertrophy
of the retinal pigmented epithelium of the iris (CHRPE). The
expression of extraintestinal manifestations of FAP is dependent
on mutation location, with most of these signs seen only when
the truncation occurs in a very small area of the mutational cluster
region.
Another APC mutation implicated in approximately 25% of
colorectal cancers afflicting Ashkenazi Jews is the I1307 point
mutation caused by the substitution of a lysine for isoleucine at
codon 1307. This was initially believed to be a genetic polymor-
phism, a substitution that does not affect the protein structure.
However, it is now recognized as probably the most important
cause of familial colorectal cancer in this population.

MYH Mutations and MYH-Associated Polyposis

A number of families have been characterized with a phenotype C
resembling that of FAP or AFAP but without a discoverable APC
gene defect. In 2002, a report of a Welsh family (family N) with FIGURE 51-6 1 Familial adenomatous polyposis, macroscopic appear-
ance. The colonic mucosa exhibits numerous small polyps, both
apparent recessive inheritance of multiple colorectal polyps and a
pedunculated and sessile. The entire colon contained hundreds of
cancer was published. On analysis of tumor APC, frequent somatic polyps. (Courtesy Dr. Jeffrey P. Baliff, Thomas Jefferson University,
mutations were found characterized by G : C to T : A substitutions Philadelphia.)
typically caused by oxidative DNA damage. The authors found
that those family members affected had two distinct mutations in
the MYH gene, a gene responsible for base excision-repair and
used to repair oxidative DNA damage, thereby indicating that
unlike FAP, its inheritance pattern is recessive in nature. From
136 2 SECTION X Abdomen

500 1000 1500 2000 2500 2843

Amino acids

Oligomerization
Catenin binding I
Catenin binding II/GSK sites
Functional Microtubule binding
domains EB1 binding
DLG binding
Apoptosis

Attenuated polyposis
Diseases Classic polyposis
CHRPE
Gardner
Sequence
features

Heptad repeats Catenin 20 AA Basic TXV-COOH

binding repeats region
ARM repeats
repeats

FIGURE 51-6 2 Functional and pathogenic properties of APC. The product of APC is a protein heterodimer
2843 amino acids in length. The figure depicts the functional domains of APC schematically as blue bars
where regional mutations result in loss of protein binding, as described in the column on the right side of
the figure. Mutations in these regions result in truncations that may affect cellular structure and cell signal-
ing, such as the inability to bind catenins and interference with microtubule binding. Cellular processes such
as apoptosis are affected by mutations occurring at many sites along the gene. Some mutational effects are
unknown, such as those preventing EB1 and DLG binding (proteins with unclear functions). Diseases are
similarly represented by tan bars. Mutations within the regions depicted result in the disease phenotypes
described in the right column, including attenuated polyposis, classic polyposis, CHRPE, and Gardner syn-
drome (extraintestinal manifestations of FAP). (From Kinzler KW, Vogelstein B: Lessons from hereditary
colorectal cancer. Cell 87:159–170, 1996.)

several subsequent surveys of kindreds with familial colorectal The most frequently mutated tumor suppressor gene in human
cancer or polyp inheritance patterns, it has become clear that a neoplasia is p53 (TP53), located on chromosome 17p. Mutations
number of MYH mutations exist and may coexist in the same in p53 are present in 75% of colorectal cancers and occur rather
patient. The mutation has been characterized in northern Euro- late in the adenoma-carcinoma sequence. Under normal condi-
pean, Indian, and Pakistani populations; it appears to affect the tions, p53 acts by inducing apoptosis in response to cellular
production of polyps and tumors by promoting APC defects and damage or by causing G1 cell cycle arrest, allowing DNA repair
is called MYH-associated polyposis (MAP). Although the propor- mechanisms to occur. One of the features of mutated p53 is that
tion of colorectal cancers attributable to germline MYH mutations it is unable to activate the BAX gene to induce apoptosis. For its
is unknown, all patients with biallelic MYH mutations are at role in regulating apoptosis, p53 is known as the guardian of the
increased risk for colorectal cancer. Greater numbers of polyps genome. The minority of colon cancer patients who have intact
(100 to 1000) and even extracolonic manifestations, such as duo- p53 in their tumors may possess a survival advantage. Studies have
denal adenomas, are associated with the presence of more than indicated that prognostic significance may be related to tumor
one germline MYH mutation in a single patient.31 p53 status.
It is evident that the MAP phenotype is highly variable and A number of genes on chromosome 18q are implicated in
that clinical management, for now, should follow guidelines previ- colorectal cancer, including SMAD2, SMAD4, and DCC. SMAD
ously established for FAP and AFAP. Surgery in carriers who have proteins are involved in the transforming growth factor-β signal
polyps is IPAA or ileorectal anastomosis, depending on the status transduction pathway. SMAD2 and SMAD4 are mutated in 5%
of the rectum. Colonoscopic and duodenal surveillance every 1 to 10% of sporadic colorectal cancers. DCC is a large gene
or 2 years for those with biallelic mutations is warranted, given involved in cell-cell or cell-matrix interactions. It is not clear how
the uncertainty of the natural history of the disease. DCC is directly involved in colorectal neoplasia. DPC4 is a gene
It remains unclear whether heterozygotes are at increased risk adjacent to DCC and may be the tumor suppressor gene deleted
for colorectal cancer; all offspring of those with the disease can in 18q mutations.
be reasonably assured that they are heterozygotes unless they too
have multiple polyps, an extremely unlikely event. However, it is Mismatch Repair Genes
certain that patients with MAP need to be distinguished from MMR genes are called caretaker genes because of their important
those with FAP or AFAP because it implies increased risk in sib- role in policing the integrity of the genome and correcting DNA
lings rather than in offspring. For those with biallelic mutations, replication errors. MMR genes that undergo a loss of function
spouses can also be tested in the unlikely event that both spouses contribute to carcinogenesis by accelerating tumor progression.
possess a recessive MYH allele at the same locus. Mutations in MMR genes (including hMLH1, hMSH2, hMSH3,
 CHAPTER 51 Colon and Rectum 136 3

hPMS1, hPMS2, and hMSH6) result in the HNPCC syndrome. • Benign polyps have been observed to develop into cancers.
Approximately 3% of colorectal cancers in the United States are There have been reports of the direct observation of benign
caused by HNPCC. Mutations in MMR genes produce micro- polyps that were not removed progressing over time into malig-
satellite instability. Microsatellites are repetitive sequences of nant neoplasms.
DNA that appear to be randomly distributed throughout the • Colonic adenomas occur more frequently in patients who have
genome. Stability of these sequences is a good measure of the colorectal cancer. Almost one third of all patients with colorec-
general integrity of the genome. MMR gene mutations result in tal cancer will also have a benign colorectal polyp.
errors in S phase when DNA is newly synthesized and copied. • Patients who develop adenomas have an increased lifetime risk
Microsatellite instability exists in 10% to 15% of sporadic tumors for development of colorectal cancer.
and in 95% of tumors in patients with HNPCC. • Removal of polyps decreases the incidence of cancer. Patients
with small adenomas have a 2.3 times increased risk for cancer
Oncogenes after the polyp is removed, compared with an eightfold
Proto-oncogenes are genes that produce proteins that promote increased incidence of colorectal cancer in patients with polyps
cellular growth and proliferation. Mutations in proto-oncogenes who do not undergo polypectomy.
typically produce a gain of function and can be caused by muta- • Populations with a high risk for colorectal cancer also have a
tion in only one of the two alleles. After mutation, the gene is high prevalence of colorectal polyps.
called an oncogene. Overexpression of these growth-oriented • Patients with FAP will develop colorectal cancer in almost
genes contributes to the uncontrolled proliferation of cells associ- 100% of cases in the absence of surgical intervention. The
ated with cancer. The products of oncogenes can be divided into adenomas that characterize this syndrome are histologically the
categories. For example, growth factors (e.g., transforming growth same as sporadic adenomas.
factor-β, epidermal growth factor, insulin-like growth factor), • The peak incidence for the discovery of benign colorectal
growth factor receptors (e.g., erbB2), signal transducers (e.g., src, polyps is 50 years of age. The peak incidence for the develop-
abl, ras), and nuclear proto-oncogenes and transcription factors ment of colorectal cancer is 60 years of age. This suggests a
(myc) are all oncogene products that appear to have a role in the 10-year time span for the progression of an adenomatous polyp
development of colorectal neoplasia. The ras proto-oncogene is to a cancer. It has been estimated that a polyp larger than 1 cm
located on chromosome 12, and mutations are believed to occur in diameter has a cancer risk of 2.5% in 5 years, 8% in 10
early in the adenoma-carcinoma sequence. Mutated ras has been years, and 24% in 20 years.
found to be present in aberrant crypt foci and adenomatous These observations and studies by molecular biologists have
polyps. Activated ras leads to constitutive activity of the protein, documented that colonic mucosa progresses through stages to the
which stimulates cellular growth. eventual development of an invasive cancer. Colonic epithelial
cells lose the normal progression to maturity and cell death and
Adenoma-Carcinoma Sequence begin proliferating in an increasingly uncontrolled manner. With
The adenoma-carcinoma sequence is recognized as the process this uncontrolled proliferation, the cells accumulate on the surface
through which most colorectal carcinomas develop. Clinical and of the bowel lumen as a polyp. With more proliferation and
epidemiologic observations have long been cited to support the increasing cellular disorganization, the cells extend through the
hypothesis that colorectal carcinomas evolve through a progres- muscularis mucosae to become invasive carcinoma. Even at this
sion of benign polyps to invasive carcinoma, and the elucidation advanced stage, the process of colorectal carcinogenesis generally
of the genetic pathways to cancer described earlier has confirmed follows an orderly sequence of invasion of the muscularis mucosae,
the validity of this hypothesis. However, before the molecular pericolic tissue, and lymph nodes and, finally, distant metastasis
genesis of colorectal cancer was appreciated, there was consider- (Figs. 51-63 and 51-64).
able controversy about whether colorectal cancer arises de novo
or evolves from a polyp that was initially a benign precursor. Colorectal Polyps
Although there have been a few documented cases of small colon A colorectal polyp is any mass projecting into the lumen of the
cancers arising de novo from normal mucosa, these are rare, and bowel above the surface of the intestinal epithelium. Polyps arising
the validity of the adenoma-carcinoma sequence is now accepted from the intestinal mucosa are generally classified by their gross
by almost all authorities. The historical observations that led to appearance as pedunculated (with a stalk; Fig. 51-65) or sessile
the hypothesis are of interest because of the therapeutic implica- (flat, without a stalk; Fig. 51-66). They are further classified by
tions implicit in an understanding of the adenoma-carcinoma their histologic appearance as tubular adenoma (with branched
sequence. Observations that provided support for the hypothesis tubular glands), villous adenoma (with long finger-like projec-
include the following: tions of the surface epithelium; Fig. 51-67), or tubulovillous
• Larger adenomas are found to harbor cancers more often than adenoma (with elements of both cellular patterns). The most
smaller ones, and the larger the polyp, the higher the risk for common benign polyp is the tubular adenoma, constituting
cancer. Although the cellular characteristics of the polyp are approximately 65% to 80% of all polyps removed. Approximately
important, with villous adenomas carrying a higher risk than 10% to 25% of polyps are tubulovillous, and 5% to 10% are
tubular adenomas, the size of the polyp is also important. The villous adenomas. Tubular adenomas are most often peduncu-
risk for cancer in a tubular adenoma smaller than 1 cm in lated; villous adenomas are more commonly sessile. The degree of
diameter is less than 5%, whereas the risk for cancer in a cellular atypia is variable across the span of polyps, but there is
tubular adenoma larger than 2 cm is 35%. A villous adenoma generally less atypia in tubular adenomas, and severe atypia or
larger than 2 cm carries a 50% chance of containing a cancer. dysplasia (precancerous cellular change) is found more often in
• Residual benign adenomatous tissue is found in most invasive villous adenomas. The incidence of invasive carcinoma being
colorectal cancers, suggesting progression of the cancer from found in a polyp is dependent on the size and histologic type of
the remaining benign cells to the predominant malignant ones. the polyp. As noted, there is less than a 5% incidence of carcinoma
136 4 SECTION X Abdomen

Normal epithelium
Initiation 5q loss APC

Hyperproliferative epithelium (dysplasia)

Alterations in DNA methylation (early adenoma)

Promotion 12p activation K-ras
A

Intermediate adenoma
18q loss DCC

Late adenoma
Malignant conversion 17p loss p53

B
Carcinoma

Metastasis
FIGURE 51-6 3 Model of colorectal carcinogenesis. (Adapted from
Corman ML, editor: Colon and rectal surgery, ed 4, Philadelphia,1998,
Lippincott-Raven, p 593.)

in an adenomatous polyp smaller than 1 cm in diameter, whereas

there is a 50% chance that a villous adenoma larger than 2 cm in
diameter will contain a cancer.
The treatment of an adenomatous or villous polyp is removal, C
usually by colonoscopy. The presence of any polypoid lesion is an
indication for a complete colonoscopy and polypectomy, if fea- FIGURE 51-6 4 Colon adenocarcinoma arising in an adenoma, micro-
scopic appearance. A, Tubulovillous adenoma with finger-like projec-
sible. Polyps on a stalk are often removed by a snare passed
tions (right) reveals a deeper area of infiltrating glands (left). B, Glands
through the colonoscope, whereas sessile (flat) polyps present have penetrated the muscularis mucosae. C, On high power, neoplastic
technical problems with this method because of the danger of angulated glands with central dirty necrosis present within a desmo-
perforation associated with the snare technique. Although it is plastic stroma. (Courtesy Dr. Jeffrey P. Baliff, Thomas Jefferson Uni-
often feasible to elevate the sessile polyp from the underlying versity, Philadelphia.)
muscularis with saline injection, permitting subsequent endo-
scopic excision, sessile lesions that are large or have a central
depression or cannot be “lifted” with saline may be perforation
 CHAPTER 51 Colon and Rectum 136 5

FIGURE 51-6 5 Pedunculated adenomatous polyp, microscopic FIGURE 51-6 7 Villous adenoma. This photomicrograph reveals the
appearance. The head of the polyp is lined with dysplastic epithelium, finger-like projections that give the appearance of villi. (Courtesy Dr.
whereas the stalk is lined with nondysplastic epithelium. (Courtesy Dr. Jeffrey P. Baliff, Thomas Jefferson University, Philadelphia.)
Jeffrey P. Baliff, Thomas Jefferson University, Philadelphia.)

FIGURE 51-6 6 Sessile adenomatous polyp, microscopic appearance.

This tubular adenoma is called sessile because of its broad base, the
preservation of the muscularis mucosae underneath, and the absence
of a stalk. (Courtesy Dr. Jeffrey P. Baliff, Thomas Jefferson University,
Philadelphia.)

FIGURE 51-6 8 Colonoscopic view of sessile polyp. This polyp proved

risks and should be surgically excised by segmental colectomy for to be a carcinoma after it was removed by segmental resection.
complete removal and lymph node examination (Fig. 51-68).
Adenomatous polyps should be considered precursors of required. Haggitt and colleagues have proposed a classification for
cancer, and when cancer arises in a polyp, careful consideration polyps containing cancer according to the depth of invasion, as
needs to be given to ensure the adequacy of treatment. Invasive follows (Fig. 51-69):
carcinoma describes the situation in which malignant cells have Level 0: Carcinoma does not invade the muscularis mucosae
extended through the muscularis mucosae of the polyp, whether (carcinoma in situ or intramucosal carcinoma)
it is on a stalk or a sessile lesion. Cellular changes confined to the Level 1: Carcinoma invades through the muscularis mucosae
muscularis mucosae above the lamina propria do not metastasize, into the submucosa but is limited to the head of the polyp
and the cellular abnormalities should be described as atypia or Level 2: Carcinoma invades the level of the neck of the polyp
dysplasia. Complete endoscopic excision of this type of polyp is (junction between the head and stalk)
adequate treatment. Level 3: Carcinoma invades any part of the stalk
If invasive carcinoma penetrates the muscularis mucosae, the Level 4: Carcinoma invades into the submucosa of the bowel
risk for lymph node metastasis and local recurrence must be con- wall below the stalk of the polyp but above the muscularis
sidered to determine whether a more extensive resection is propria
136 6 SECTION X Abdomen

Adenocarcinoma

Level 0

Level 1 Adenomatous
epithelium
Adenocarcinoma
Level 2
Normal colonic
Level 3 mucosa

Level 4 Submucosa Muscularis Submucosa

mucosae
Muscularis Muscularis
propria propria

Subserosal connective tissue Subserosal connective tissue

Pedunculated adenoma Sessile adenoma

FIGURE 51-6 9 Anatomic landmarks of pedunculated and sessile adenomas. (From Haggitt RC, Glotzbach
RE, Soffer EE, et al: Prognostic factors in colorectal carcinoma arising in adenomas: Implications for lesions
removed by endoscopic polypectomy. Gastroenterology 89:328–336, 1985.)

By definition, all sessile polyps with invasive carcinoma are level

4 by Haggitt’s criteria.
If a polyp contains a histologically poorly differentiated inva-
sive carcinoma or if there are cancer cells observed in the lym-
phovascular spaces, there is a more than 10% chance of
metastases, and these lesions should be treated aggressively. A
pedunculated polyp with invasion to levels 1, 2, and 3 has a low
risk for lymph node metastasis or local recurrence, and complete
excision of the polyp is adequate if the poor prognostic factors
mentioned earlier are absent and margins are negative. A sessile
polyp containing invasive cancer has at least a 10% chance of
metastasis to regional lymph nodes, but if the lesion is well or
moderately differentiated, there is no lymphovascular invasion
noted, and the lesion can be completely excised, the depth of
invasion by the cancer may provide useful prognostic informa-
tion. There is a high risk for lymph node and distant metastases
associated with sessile cancers in the rectum, and these lesions
should be treated aggressively.
Hyperplastic polyps are the most common colonic polyps but
are usually small and composed of cells showing dysmaturation
and hyperplasia. The small diminutive polyps have been regarded
as benign in nature, with no neoplastic potential. The histologic
appearance of these polyps is serrated (saw-toothed; Figs. 51-70
and 51-71). Of these polyps, 90% are smaller than 3 mm in FIGURE 51-7 0 Hyperplastic polyp. Elongated crypts reveal a serrated
(saw-toothed) or star-shaped appearance. There is no epithelial dyspla-
diameter, and these diminutive lesions are generally considered to
sia. (Courtesy Dr. Jeffrey P. Baliff, Thomas Jefferson University,
have no malignant potential. However, adenomatous changes can Philadelphia.)
be found in hyperplastic polyps, and therefore the polyps should
be excised for histologic examination. These serrated adenomas
have been observed to be associated with the development of Hereditary Cancer Syndromes (Table 51-4 )
cancers that predominate in the right side of the colon, more Familial Adenomatous Polyposis
frequently in older women and smokers. They appear to be associ- FAP is the prototypical hereditary polyposis syndrome. The dis-
ated with the microsatellite instability characteristic of defects in covery of the gene responsible for the transmission of the disease,
DNA repair mechanisms. the APC gene, located on chromosome 5q21, lagged behind the
 CHAPTER 51 Colon and Rectum 136 7

related to FAP is 39 years. Eponymous polyposis syndromes now

recognized to belong to the general disorder of FAP include
Gardner syndrome (colonic polyps, epidermal inclusion cysts,
osteomas) and Turcot syndrome (colonic polyps, brain tumors).
Osteomas usually present as visible and palpable prominences
in the skull, mandible, and tibia of individuals with FAP. They are
almost always benign. Radiographs of the maxilla and mandible
may reveal bone cysts, supernumerary and impacted molars, or
congenitally absent teeth. Desmoid tumors can present in the
retroperitoneum and abdominal wall of affected patients, usually
after surgery. These tumors seldom metastasize but are often
locally invasive; direct invasion of the mesenteric vessels, ureters,
or walls of the small intestine can result in death.
Surgical treatment of patients with FAP is directed at removal
of all affected colonic and rectal mucosa. Restorative proctocolec-
tomy with IPAA has become the most commonly recommended
operation. The procedure is usually accompanied by a distal rectal
mucosectomy to ensure that all premalignant colonic mucosa is
FIGURE 51-7 1 Sessile serrated adenoma. This view shows basilar
removed, and the IPAA is fashioned between the ileal pouch and
crypt dilation, epithelium proliferating in a serrated (saw-toothed)
manner, and so-called crypt architectural dysplasia in the form of mal-
dentate line of the anal canal. Patients who undergo this proce-
oriented crypts, with one crypt extending horizontally. There is no dure for FAP have a better functional result than patients similarly
cytologic dysplasia of the epithelium. (Courtesy Dr. Jeffrey P. Baliff, treated for ulcerative colitis. The incidence of inflammation in the
Thomas Jefferson University, Philadelphia.) ileal pouch (pouchitis) is much lower in patients with FAP than
in patients with ulcerative colitis.
An alternative approach, total abdominal colectomy with ileo-
first descriptions of cases of FAP by an entire century. In 1863, rectal anastomosis, was used extensively before the development
Virchow reported a 15-year-old boy with multiple colonic polyps. of the technique of IPAA and has certain advantages. If an FAP
In 1882, Cripps described the occurrence of numerous colonic patient has relatively few polyps in the rectum, consideration may
polyps in multiple family members. In 1927, Cockayne demon- be given to this option. The abdominal colon is resected and an
strated that FAP was genetically transmitted in an autosomal anastomosis fashioned between the ileum and rectum. It is techni-
dominant fashion. Dukes was the first to establish some form of cally a simpler operation to perform, and the pelvic dissection is
a familial tumor registry, which he reported with Lockhart- avoided. This eliminates the potential complication of injury to
Mummery in 1930. Throughout the 20th century, many reports the autonomic nerves that could result in impotence. In addition,
described various extraintestinal manifestations associated with there is theoretically less risk for anastomotic leak from the rela-
FAP. In 1986, Lemuel Herrera demonstrated that the underlying tively simple ileorectal anastomosis fashioned in the peritoneal
genetic abnormality was a mutation in the APC gene. cavity compared with the long suture (or staple) lines required to
The common expression of the syndrome is the invariable form the ileal pouch and then to fashion the anastomosis between
presence of multiple colonic polyps; frequent occurrence of the ileal pouch and anus.
gastric, duodenal, and periampullary polyps; and occasional asso- An additional argument in favor of abdominal colectomy and
ciation of extraintestinal manifestations, including epidermoid ileorectal anastomosis is the observation that sulindac and cele-
cysts, desmoid tumors in the abdomen, osteomas, and brain coxib have caused the regression of adenomatous polyps in some
tumors. Gastric and duodenal polyps occur in approximately 50% patients with FAP. The disadvantages are that the rectum remains
of affected individuals. Most of the gastric polyps represent fundic at high risk for the formation of new precancerous polyps, a
gland hyperplasia, rather than adenomatous polyps, and have proctoscopic examination is required every 6 to 12 months to
limited malignant potential. However, duodenal polyps are ade- detect and to destroy any new polyps, and there is a definite
nomatous in nature and should be considered premalignant. increased risk for cancer arising in the rectum with the passage of
Patients with FAP have an increased risk for ampullary cancer. time.
Adenomatous polyps and cancer have also been found in the It has been suggested that genetic testing may help make the
jejunum and ileum of patients with FAP. Rare extraintestinal decision between restorative proctocolectomy with IPAA and
malignant neoplasms in FAP patients include cancers of the extra- abdominal colectomy with ileorectal anastomosis. It has been
hepatic bile ducts, gallbladder, pancreas, adrenals, thyroid, and observed that the risk for rectal cancer is almost three times higher
liver. An interesting marker for FAP is CHRPE, which can be in FAP patients with a mutation after codon 1250 than in patients
detected by indirect ophthalmoscopy in approximately 75% of with mutations before this codon. This may influence the decision
affected individuals. to offer abdominal colectomy with ileorectal anastomosis to those
The gene is expressed in 100% of patients with the mutation. whose mutation occurs proximal to codon 1250 if proctoscopic
Autosomal dominance results in expression in 50% of offspring. examination reveals no or few polyps in the rectum.
There is a negative family history in 10% to 20% of affected Patients who choose to be treated by abdominal colectomy
individuals, who apparently acquire the syndrome as the result of with ileorectal anastomosis should realize that the risk for develop-
a spontaneous germline mutation. All patients with the defective ment of rectal cancer is real and has been shown to be 4%, 5.6%,
gene will develop cancer of the colon if left untreated. The average 7.9%, and 25% at 5, 10, 15, and 20 years after the operation,
age at discovery of a new patient with FAP is 29 years. The average respectively. Even though sulindac and celecoxib can produce
age of a patient who is newly discovered to have colorectal cancer partial regression of polyps, semiannual surveillance of the rectal
 136 8

TABLE 51-4 Hereditary Cancer Syndromes

HEREDITARY ADENOMATOUS POLYPOSIS HEREDITARY HAMARTOMATOUS
SYNDROMES POLYPOSIS SYNDROMES RUVALCABA-MYHRE-
HEREDITARY FAMILIAL ADENOMATOUS FAMILIAL SMITH SYNDROME
SECTION X Abdomen

NONPOLYPOSIS POLYPOSIS (FAP)/ TURCOT COWDEN JUVENILE PEUTZ-JEGHERS (BANNAYAN-ZONANA

COLON CANCER GARDNER SYNDROME SYNDROME DISEASE POLYPOSIS SYNDROME SYNDROME)
GI Features
Small number of colorectal Hundreds to thousands of Colorectal polyps, which Polyps most Juvenile polyps mostly Small number of polyps Hamartomatous GI polyps,
polyps colorectal polyps; duodenal may be few or commonly of colon in colon but throughout GI tract but usually lipomas,
adenomas and gastric polyps, resemble classic FAP and stomach throughout GI tract; most common in small hemangiomas, or
usually fundic gland defined by ≥ 10 intestine lymphangiomas
juvenile polyps

Other Clinical Features

Muir-Torre variant: sebaceous Osteomas, desmoid tumors, Brain tumors, including Mucocutaneous Congenital Pigmented lesions of skin; Dysmorphic facial features,
adenomas, epidermoid cysts, and congenital cerebellar lesions, thyroid abnormalities in at benign and malignant macrocephaly, seizures,
keratoacanthomas, hypertrophy of retinal epithelium medulloblastoma and adenomas and least 20%, including genital tumors intellectual impairment,
sebaceous epitheliomas, glioblastomas goiter, malrotation, pigmented macules of shaft
and basal cell epitheliomas fibroadenomas and hydrocephalus, and glans of penis
fibrocystic disease cardiac lesions,
of the breast, Meckel’s
uterine leiomyomas, diverticulum,
macrocephaly mesenteric
lymphangioma

Malignancy Risk
70%-80% lifetime risk for Colorectal cancer risk approaches Colorectal carcinoma and 10% risk for thyroid 9% to 25% risk for ↑ Risk for GI malignant Malignant GI tumors
colorectal cancer; 30%-60% 100%; ↑ risk for periampullary brain tumors cancer and up to colorectal cancer; ↑ disease and pancreatic identified but lifetime risk
lifetime risk for endometrial malignant disease, thyroid 50% risk for risk for gastric, cancer and adenoma for malignant disease
cancer; ↑ risk for ovarian carcinoma, central nervous adenocarcinoma of duodenal, and malignum of cervix; unknown
cancer, gastric carcinoma, system tumors, hepatoblastoma breast in affected pancreatic cancer unknown risk for breast
transitional cell carcinoma women cancer
of the ureters and renal
pelvis, small bowel cancer,
and sebaceous carcinomas
 Screening Recommendations
Colonoscopy at age 20-25 Flexible proctosigmoidoscopy at Same as for FAP; also Annual physical Screening by age 12 Upper GI endoscopy, small No known published
years; repeat every 1-3 age 10-12 years; repeat every 1-2 consider imaging of the examination with years if symptoms bowel radiography, recommendations
years; transvaginal years until age of 35 years; after brain special attention to have not yet arisen; colonoscopy every 2 years;
ultrasound or endometrial the age of 35 years, repeat every thyroid; colonoscopy with pancreatic ultrasound and
aspiration at age 20-25 3 years; upper GI endoscopy mammography at multiple random hemoglobin levels
years; repeat annually every 1-3 years starting when age 30 years or 5 biopsy specimens annually; gynecologic
(expert opinion only) polyps first identified years before every several years examination, cervical
earliest breast (expert opinion only) smear, pelvic ultrasound
cancer case in the annually; clinical breast
family; routine examination and
colon cancer mammography at age 25
surveillance (expert years; clinical testicular
opinion only) examination and testicular
ultrasound in males with
feminizing features (expert
opinion only)
Genetic Basis
AD AD AD AD AD inheritance in AD AD
some families
MLH1 (chromosome 3p) APC (chromosome 5q) APC mutations identified PTEN (chromosome Subset of families STK11 (chromosome 19p) PTEN (chromosome 10q) in
MSH2 (chromosome 2p) predominantly in 10q) with mutation in some
MSH6/GTMP (chromosome families with cerebellar SMAD4 (DRC4)
2p) medulloblastoma (chromosome 10q)
PMS1 (chromosome 2q) MLH1, PMS2 mutations
PMS2 (chromosome 7q) identified in families
with predominance of
glioblastomas

Genetic Testing
Clinical testing of MLH1 and Clinical testing of APC gene Clinical testing of APC Research testing of Families being Research testing of STK11 Research testing of PTEN
MSH2 genes available available and MLH1 genes PTEN gene collected for gene available gene available
available available research studies
only
AD, Autosomal dominant; GI, gastrointestinal; ↑, increased.
CHAPTER 51 Colon and Rectum
136 9
137 0 SECTION X Abdomen

mucosa is required, and approximately one third of patients hereditary syndromes were initially described. Lynch I syndrome
treated by abdominal colectomy and ileorectal anastomosis is characterized by cancer of the proximal colon occurring at a
develop florid polyposis of the rectum that will require proctec- relatively young age; Lynch II syndrome is characterized by fami-
tomy (and ileostomy or IPAA) within 20 years. lies at risk for both colorectal and extracolonic cancers, including
Polyps of the stomach and duodenum are not uncommon in cancers of endometrial, ovarian, gastric, small intestinal, pancre-
patients with FAP. The gastric polyps are usually hyperplastic and atic, and ureteral and renal pelvic origin. Currently, the term
do not require surgical removal. However, the duodenal and Lynch syndrome refers to both patterns, and it is understood that
ampullary polyps are generally neoplastic and require attention. there is overlap between the two described variants.
A reasonable surveillance program is for upper GI surveillance Before the genetic mechanisms underlying the Lynch syn-
every 2 years after the age of 30 years and endoscopic polypec- drome were understood, is was defined by the Amsterdam criteria,
tomy, if possible, to remove all large adenomas from the duode- which required three criteria for the diagnosis:
num. If numerous polyps are identified, the endoscopy obviously 1. Colorectal cancer in three family members (first-degree
should be repeated with greater frequency. If an ampullary cancer relatives)
is discovered at an early stage, pancreatoduodenectomy (Whipple 2. Involvement of at least two generations
procedure) is indicated. 3. At least one affected individual being younger than 50 years at
The abdominal desmoid tumor can be an especially vexing and the time of diagnosis
difficult extraintestinal manifestation of FAP. After surgical pro- These requirements were recognized as being too restrictive,
cedures, dense fibrous tissue forms in the mesentery of the small and the modified Amsterdam criteria expanded the cancers to be
intestine or within the abdominal wall in some patients with FAP. included to not only colorectal but also endometrial, ovarian,
If the mesentery is involved, the intestine can be tethered or gastric, pancreatic, small intestinal, ureteral, and renal pelvic
invaded directly by the tumor. The locally invasive tumor can also cancers. Further liberalization for identifying patients with
encroach on the vascular supply to the intestine. Small desmoid HNPCC occurred with the introduction of the Bethesda criteria
tumors confined to the abdominal wall are appropriately treated (Box 51-4).
by resection, but the surgical treatment of mesenteric desmoids is Molecular biologists have demonstrated that the increased
dangerous and generally futile. There have been sporadic reports cancer risk in these syndromes is caused by malfunction of the
of regression of desmoid tumors after treatment with sulindac, DNA repair mechanism. Specific genes that have been shown to
tamoxifen, low-dose methotrexate, radiation, and various types of be responsible for the syndrome include hMSH2 (located on
chemotherapy. The initial treatment is usually with sulindac or chromosome 2p21), hMLH1 (3p21), hMSH6 (2p16-21), and
tamoxifen. hPMS2 (7p21). A mutation in hMSH2 has been shown to be
The ability to identify the genetic mutation in most patients responsible for the cancer prevalence in cancer family G. Muta-
with FAP—although the mutation may not be identified in as tions in hMSH2 or hMLH1 account for more than 90% of
many as 20% of patients with a well-documented, transmissible identifiable mutations in patients with Lynch syndrome. The
FAP syndrome—permits a method of screening family members
at risk for inheriting the mutation. It is imperative that the APC
mutation be clearly identified in the DNA of a family member BOX 51-4 Clinical Criteria for Hereditary
known to have the disease. The DNA of other family members Nonpolyposis Colorectal Cancer
can then be analyzed directly, requiring only a venipuncture. If
the analysis demonstrates noninheritance of a mutated APC gene, Amsterdam Criteria
the individual can avoid annual endoscopic screening and should At least three relatives with colon cancer and all of the following:
require only an occasional colonoscopy. • One affected person is a first-degree relative of the other two affected
persons
Lynch Syndrome • Two successive generations affected
Lynch syndrome (also called hereditary nonpolyposis colon cancer • At least one case of colon cancer diagnosed before the age of 50 years
or HNPCC) is the most frequently occurring hereditary colorectal • FAP excluded
cancer syndrome in the United States and western Europe. It
Modified Amsterdam Criteria
accounts for approximately 3% of all cases of colorectal cancer
Same as the Amsterdam criteria, except that cancer must be associated with
and for approximately 15% of these cancers in patients with a
HNPCC (colon, endometrium, small bowel, ureter, renal pelvis) instead of
family history of colorectal cancer. Alder S. Warthin, Chairman
specifically colon cancer
of Pathology at the University of Michigan, initially recognized
this hereditary syndrome in 1885. Dr. Warthin’s seamstress proph- Bethesda Criteria
esied that she would die of cancer because of her strong family The Amsterdam criteria or one of the following:
history of endometrial, gastric, and colon cancer. Dr. Warthin’s • Two cases of HNPCC-associated cancer in one patient, including syn-
investigations of her family’s medical records revealed a pattern of chronous or metachronous cancer
autosomal dominant transmission of the cancer risk. This family • Colon cancer and a first-degree relative with HNPCC-associated cancer
(family G) has been further studied and characterized by Henry and/or colonic adenoma (one case of cancer diagnosed before age 45
Lynch, who described the prominent features of the syndrome, years and adenoma diagnosed before age 40 years)
including onset of cancer at a relatively young age (mean, 44 • Colon or endometrial cancer diagnosed before age 45 years
years), proximal distribution (70% of cancers located in the right • Right-sided colon cancer that has an undifferentiated pattern (solid,
colon), predominance of mucinous or poorly differentiated (signet cribriform) or signet cell histopathologic characteristics diagnosed
cell) adenocarcinoma, increased number of synchronous and before age 45 years
metachronous cancers, and, despite all these poor prognostic indi- • Adenomas diagnosed before age 40 years
cators, a relatively good outcome after surgery. Originally, two
 CHAPTER 51 Colon and Rectum 137 1

initially reported difference in the types of cancers in Lynch I and in the urine should also be carried out because of the risk for
II syndromes cannot be accounted for by mutations in specific ureteral and renal pelvic cancer.
MMR genes. The cancer family syndrome involving hMSH6 It has been shown that annual colonoscopy and removal of
is characterized by an increased incidence of endometrial polyps, when found, will decrease the incidence of colon cancer
carcinoma. in patients with HNPCC. However, there have been well-
The mainstay of the diagnosis of Lynch syndrome is a detailed documented cases of invasive colon cancers occurring 1 year after
family history. Still, as many as 20% of newly discovered cases of a negative colonoscopy. It is obvious that the slow evolution from
HNPCC are caused by spontaneous germline mutations, so a benign polyp to invasive cancer is not a feature of the pathogenesis
family history may not accurately reflect the genetic nature of the in HNPCC patients, and this phenomenon of accelerated carci-
syndrome. Colorectal cancer, or a Lynch syndrome–related cancer, nogenesis mandates frequent (annual) colonoscopic examinations.
arising in a person younger than 50 years should raise suspicion Even with annual colonoscopic examinations, there is a docu-
for this syndrome. Genetic counseling and testing should be mented risk for colon cancer, but when a cancer arises while the
offered. If the individual proves to have Lynch syndrome by iden- patient is under a vigorous surveillance program, the cancer stage
tification of a mutation in one of the known MMR genes, other is usually favorable (Fig. 51-72).
family members can be tested after obtaining genetic counseling. When colon cancer is detected in a patient with Lynch syn-
However, failure to identify a causative MMR gene mutation in drome, an abdominal colectomy–ileorectal anastomosis is the
a patient with a suggestive history does not exclude the diagnosis procedure of choice. If the patient is a woman with no further
of Lynch syndrome. In as many as 50% of patients with a family plans for childbearing, a prophylactic total abdominal hysterec-
history that clearly demonstrates Lynch syndrome–type transmis- tomy and bilateral salpingo-oophorectomy are recommended.
sion of cancer susceptibility, DNA testing will fail to identify the The rectum remains at risk for the development of cancer, and
causative gene. annual proctoscopic examinations are mandatory after abdominal
The management of patients with Lynch syndrome is some- colectomy. Other forms of cancer associated with Lynch syn-
what controversial, but the need for close surveillance in patients drome are treated according to the same criteria as for nonheredi-
known to carry the mutation is obvious. It is usually recom- tary cases. The role of prophylactic colectomy for patients with
mended that a program of surveillance colonoscopy begin at the Lynch syndrome has been considered in some cases, but this has
age of 20 years. Colonoscopy is repeated every 2 years until the not received universal acceptance. It is an interesting but well-
age of 35 years and then annually thereafter. In women, periodic documented fact that the prognosis is better for cancer patients
vacuum curettage is begun at age 25 years, as are pelvic ultrasound with Lynch syndrome than for non–Lynch syndrome patients
and determination of CA-125 levels. Annual tests for occult blood with cancer of the same stage.

FAP HNPCC

APC Tumor
Accelerated Normal
initiation

RAS

• Tumor
• Normal Accelerated
progression
•

p53

FIGURE 51-7 2 Comparison of the development of cancer in FAP and HNPCC patients. (From Kinzler KW,
Vogelstein B: Lessons from hereditary colorectal cancer. Cell 87:159–170, 1996.)
137 2 SECTION X Abdomen

Peutz-Jeghers Syndrome images and increases its sensitivity. In addition, the proximity of
Peutz-Jeghers syndrome is an autosomal dominant syndrome the rectum to the anus permits easy access of ultrasound probes
characterized by the combination of hamartomatous polyps of the for more accurate assessment of the extent of penetration of the
intestinal tract and hyperpigmentation of the buccal mucosa, lips, bowel wall and the involvement of adjacent lymph nodes. The
and digits. Germline defects in the tumor suppressor serine- limited accessibility of the rectum, proximity to the anal sphincter,
threonine kinase 11 (STK11) gene are implicated in this rare and close association with the autonomic nerves supplying the
autosomal dominant inherited disease. Although the syndrome bladder and genitalia require special and unique consideration in
was first described by Hutchinson in 1896, later separate descrip- planning of treatment for cancer of the rectum. Therefore, colon
tions by Peutz and then Jeghers in the 1940s brought recognition and rectal adenocarcinomas are discussed separately.
to the condition. The syndrome is associated with an increased The signs and symptoms of colon cancer are varied, nonspe-
(2% to 10%) risk for cancer of the intestinal tract, with cancers cific, and somewhat dependent on the location of the tumor in
reported throughout the intestinal tract, from the stomach to the the colon as well as the extent of constriction of the lumen caused
rectum. There is also an increased risk for extraintestinal malig- by the cancer. In the past 4 decades, the incidence of cancer in
nant neoplasms, including cancer of the breast, ovary, cervix, the right colon has increased in comparison to cancer arising
fallopian tubes, thyroid, lung, gallbladder, bile ducts, pancreas, in the left colon and rectum. This is an important consideration
and testicles. in that about 40% of all colon cancers are located proximal to the
The polyps may cause bleeding or intestinal obstruction (from area that can be visualized by the flexible sigmoidoscope. Colorec-
intussusception). If surgery is required for these symptoms, an tal cancers can bleed, causing red blood to appear in the stool
attempt should be made to remove as many polyps as possible (hematochezia). Bleeding from right-sided colon tumors can
with the aid of intraoperative endoscopy and polypectomy. Any produce dark tarry stools (melena). Often, the bleeding is asymp-
polyp that is larger than 1.5 cm should be removed if possible. It tomatic and detected only by anemia discovered by a routine
is reasonable to survey the colon endoscopically every 2 years, and hemoglobin determination. Iron deficiency anemia in any man or
patients should be screened periodically for malignant neoplasms nonmenstruating woman should lead to a search for a source of
of the breast, cervix, ovary, testicle, stomach, and pancreas. bleeding from the GI tract. Bleeding is often associated with colon
cancer, but in approximately one third of patients with a proven
Juvenile Polyposis Syndrome colon cancer, the hemoglobin level is normal and the stool test
Juvenile polyposis is an autosomal dominant syndrome with high results are negative for occult blood.
penetrance that carries an increased risk for both GI and extrain- Cancers located in the left colon are often constrictive in
testinal cancer. The syndrome is usually discovered because of GI nature. Patients with left-sided colon cancers may notice a change
bleeding, intussusception, or hypoalbuminemia associated with in bowel habit, most often reported as increasing constipation.
protein loss through the intestine. The juvenile polyps in this Sigmoid cancers can mimic diverticulitis, presenting with pain,
syndrome are predominantly hamartomas, but the hamartomas fever, and obstructive symptoms. At least 20% of patients with
may contain adenomatous elements, and adenomatous polyps sigmoid cancer also have diverticular disease, making the correct
also are common. There is an increased cancer risk in afflicted diagnosis difficult at times. Sigmoid cancers can also cause colo-
individuals, with a malignant potential of at least 10% in patients vesical or colovaginal fistulas. Such fistulas are more commonly
with multiple juvenile polyps. Mutations in the tumor suppressor caused by diverticulitis, but it is imperative that the correct diag-
gene SMAD4 are believed to cause up to 50% of reported cases. nosis be established because the treatment of colon cancer is
In patients with relatively few juvenile polyps, endoscopic pol- substantially different from treatment of diverticulitis.
ypectomy should be carried out. However, patients with numer- Cancers in the right colon more often are manifested with
ous polyps should be treated with abdominal colectomy, ileorectal melena, fatigue associated with anemia, or, if the tumor is
anastomosis, and frequent endoscopic surveillance of the rectum. advanced, abdominal pain. Although obstructive symptoms are
If the diffuse form of polyposis involves the rectal mucosa, con- usually associated with cancers of the left colon, any advanced
sideration should be given to restorative proctocolectomy with colorectal cancer can cause a change in bowel habits and intestinal
IPAA. Sporadic juvenile polyps can occur as well and can be a obstruction (Figs. 51-73 and 51-74).
lead point for intussusception. Juvenile polyps are benign polyps Colonoscopy is the “gold standard” for establishing the diag-
composed of cystic dilations of glandular structures within the nosis of colon cancer. It permits biopsy of the tumor to verify the
fibroblastic stroma of the lamina propria. They are relatively diagnosis while allowing inspection of the entire colon to exclude
uncommon yet may cause bleeding or intussusception. Therefore, metachronous polyps or cancers; the incidence of a synchronous
the polyps should be treated by endoscopic removal. cancer is approximately 3%. Colonoscopy is generally performed
even after a cancer is detected by barium enema to obtain a biopsy
Sporadic Colon Cancer specimen and to detect (and remove) small polyps that may be
It is important to recognize the increased risk for cancer in patients missed by the contrast study (Fig. 51-75).
with hereditary cancer syndromes, but the most common form of
colorectal cancer is sporadic in nature, without an associated Staging
strong family history. Although the cause and pathogenesis of Staging may be defined as the process whereby objective data are
adenocarcinoma are similar throughout the large bowel, signifi- assembled to define the state of progression of disease. Data are
cant differences in the use of diagnostic and therapeutic modalities summated to provide a designated stage for an individual’s disease,
separate colonic from rectal cancers. This distinction is largely from which inferences may be drawn about the likelihood of
because of the confinement of the rectum by the bony pelvis and residual disease and hence the chance of cure with or without
possible biologic differences that may mandate more aggressive further treatment.
treatment and surveillance, stage per stage, for rectal cancer. The At present, the stage of the tumor is assessed by indicating the
limited mobility of the rectum allows MRI to generate better depth of penetration of the tumor into the bowel wall (T stage),
 CHAPTER 51 Colon and Rectum 137 3

FIGURE 51-7 5 Resected right colon containing large benign sessile

polyp adjacent to an ulcerated carcinoma.

hospitals in the United States and was developed by the AJCC

and approved by the International Union Against Cancer. This
classification, known as the TNM (tumor, node, metastasis)
system, combines clinical information obtained preoperatively
FIGURE 51-7 3 Radiograph of barium enema demonstrating apple core with data obtained during surgery and after histologic examina-
or napkin ring lesion caused by a constricting carcinoma.
tion of the specimen. There have been numerous and significant
modifications in the system since its introduction in 1987; the
seventh edition of the AJCC Cancer Staging Manual has taken into
account survival and relapse data that refine the prognostic value
of accurate staging of colorectal cancer (Table 51-5).22

Rules for Classification

Clinical staging. A clinical assessment of the stage of disease
(cTNM) is based on evidence obtained by medical history, physi-
cal examination, and endoscopy. Examinations designed to detect
metastatic disease include chest radiographs, CT (including pelvis,
abdomen, and chest), MRI, and positron emission tomography
(PET) or fused PET/CT scans. Clinical staging in patients with
rectal cancer often determines whether preoperative adjuvant
treatment is indicated. Modalities to assess the preoperative stage
of rectal cancer include endorectal ultrasound, pelvic CT, and
pelvic MRI, with or without an endorectal coil.
Pathologic staging. The pathologic examination of the resected
specimen (pTNM) provides a basis for prognosis and consider-
ation of the need for further (adjuvant) treatment. Patients who
were given a clinical stage (cTNM) before the initiation of pre-
operative adjuvant treatment, usually combined radiation therapy
and chemotherapy, will have a modified pathologic stage assessed
after examination of the surgically resected specimen; that stage
is indicated by the y prescript (ypTNM).
FIGURE 51-7 4 Radiograph of barium enema demonstrating a polypoid Cancer cells confined within the glandular basement mem-
carcinoma arising in the cecum of a 35-year-old woman (arrows). (Cour-
brane (intraepithelial) or lamina propria (intramucosal) with no
tesy Dr. Dina F. Caroline, Temple University Hospital, Philadelphia.)
extension through the muscularis mucosae are not associated with
a risk of metastasis and are defined as in situ carcinoma, pTis.
the extent of lymph node involvement (N stage), and the presence Accumulated survival data reviewed by the AJCC have allowed
or absence of distant metastases (M stage). The standard staging the provision of more accurate prognostic data with further strati-
system was based on a system developed in 1932 by Cuthbert fication based on accuracy of staging. For example, it is now
Dukes, a pathologist at St. Mark’s Hospital in London, that was recognized that outcomes are different for tumors within the pT4
later modified. The classification was developed for rectal cancer, category based on extent of disease. T4 cancers that penetrate to
but it was generally also used to describe the stage of colon cancer. the surface of the visceral peritoneum (pT4a) have a better prog-
The Dukes classification is simple to remember but has rapidly nosis than tumors that directly invade or adhere to other organs
been replaced by the American Joint Committee on Cancer (pT4b), and the staging classification has been refined to reflect
(AJCC) staging system. This classification is in use by most this. In addition, it is recognized that increasing numbers of
137 4 SECTION X Abdomen

TABLE 51-5 American Joint Committee on Cancer TNM Staging System for Colorectal Cancer
STAGE FEATURES
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ—intraepithelial or invasion of lamina propria*
T1 Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor invades through the muscularis propria into pericolorectal tissues
T4a Tumor penetrates to the surface of the visceral peritoneum†
T4b Tumor directly invades or is adherent to other organs or structures†,‡

Regional Lymph Nodes (N)

NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in one to three regional lymph nodes
N1a Metastasis in one regional lymph node
N1b Metastasis in two or three regional lymph nodes
N1c Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis
N2 Metastasis in four or more regional lymph nodes
N2a Metastasis in four to six regional lymph nodes
N2b Metastasis in seven or more regional lymph nodes

Distant Metastasis (M)

M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to one organ or site (e.g., liver, lung, ovary, nonregional node)
M1b Metastases in more than one organ/site or the peritoneum

STAGE GROUPING
STAGE T N M DUKES§ MAC§
0 Tis N0 M0 — —
I T1 N0 M0 A A
T2 N0 M0 A B1
IIA T3 N0 M0 B B2
IIB T4a N0 M0 B B2
IIC T4b N0 M0 B B3
IIIA T1-T2 N1/N1c M0 C C1
T1 N2a M0 C C1
IIIB T3-T4a N1/N1c M0 C C2
T2-T3 N2a M0 C C1/C2
T1-T2 N2b M0 C C1
IIIC T4a N2a M0 C C2
T3-T4a N2b M0 C C2
T4b N1-N2 M0 C C3
IVA Any T Any N M1a — —
IVB Any T Any N M1b — —

Histologic Grade (G)

GX Grade cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated
G4 Undifferentiated
 CHAPTER 51 Colon and Rectum 137 5

TABLE 51-5 American Joint Committee on Cancer TNM Staging System for
Colorectal Cancer—cont’d
STAGE FEATURES
Residual Tumor (R)
R0 Complete resection, margins histologically negative, no residual tumor left after resection (e.g., primary tumor, regional nodes)
R1 Incomplete resection, margins histologically involved, microscopic tumor remains after resection of gross disease (primary tumor,
regional nodes)
R2 Incomplete resection, margins macroscopically involved or gross disease remains after resection (e.g., primary tumor, regional nodes, or
liver metastasis)
From Edge S, Byrd D, Compton C, et al, editors: AJCC cancer staging manual, ed 7, New York, 2010, Springer.
*This includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal), with no
extension through the muscularis mucosae into the submucosa.
†
Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct examination (e.g., invasion of
the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or
structures by extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left
kidney or lateral abdominal wall, or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).
‡
Tumor that is adherent to other organs or structures, grossly, is classified as cT4b. However, if no tumor is present in the adhesion,
microscopically, the classification should be pT1-4a, depending on the anatomic depth of wall invasion. The V and L classifications should be
used to identify the presence or absence of vascular or lymphatic invasion, whereas the PN site-specific factor should be used for perineural
invasion.
§
Dukes B is a composite of better (T3 N0 M0) and worse (T4 N0 M0) prognostic groups, as is Dukes C (any T N1 M0 and any T N2 M0). MAC
is the modified Astler-Coller classification.

involved lymph nodes are associated with a worsening prognosis, and construction of a colostomy (Hartmann operation). Intestinal
and the most recent classification system takes this into account. continuity could be reestablished later by taking down the colos-
The recent AJCC manual also recognizes prognostic factors in tomy and fashioning a colorectal anastomosis.
addition to serum carcinoembryonic antigen (CEA) levels that Alternatives to this approach have been to resect the segment
should be ascertained. These include the following: tumor depos- of left colon containing the cancer and then to cleanse the remain-
its, the number of satellite tumor deposits discontinuous from the ing colon with saline lavage by inserting a catheter through the
edge of the cancer that are not associated with a residual lymph appendix or ileum into the cecum and irrigating the contents from
node; a tumor regression grade that permits the pathologic the colon. A primary anastomosis between the prepared colon and
response to neoadjuvant therapy to be graded; the circumferential rectum can then be fashioned without the need for a temporary
resection margin, the distance from the edge of tumor to the colostomy. This can be done only in patients who are hemody-
nearest dissected margin of the surgical resection; microsatellite namically stable and have pliable, nonedematous, well-vascularized
instability; perineural invasion, histologic cancerous invasion of bowel. More recently, endoscopic techniques have been developed
the regional nerves; and KRAS mutation status. The KRAS muta- that permit the placement of a stent introduced with the aid of a
tion has been shown to be associated with lack of response to colonoscope that traverses the obstructed tumor and expands,
treatment with monoclonal antibodies directed against the epi- re-creating a lumen, relieving the obstruction, and permitting a
dermal growth factor receptor (EGFR) in patients with metastatic bowel preparation and elective operation with primary colorectal
colorectal cancer. anastomosis. This can be of temporary benefit, allowing the edema
Tumor regression grade. Although the data are not definitive, to resolve and the patient’s bowel to be prepared. Stents can,
it appears that a significant pathologic response to preoperative however, be complicated by perforation and erosion and are used
adjuvant treatment is associated with a better prognosis. Patients either in the palliative setting or as a short bridge to surgery.
with minimal or no residual disease after therapy may have a Complete obstruction of the right colon or cecum by cancer occurs
better prognosis than patients with extensive residual cancer. A less frequently because the stool is more liquid. These patients
four-point regression grade has been developed to assess the present with signs and symptoms of a small bowel obstruction. If
response to neoadjuvant therapy (Table 51-5). an obstruction of the proximal colon is suspected, a water-soluble
contrast study is useful to verify the diagnosis and to evaluate the
Obstructing Colon Cancers distal colon for the presence of a synchronous lesion. Obstructing
In patients with tumors causing complete obstruction, the diag- cancer of the proximal colon is treated by right colectomy, with
nosis is best established by resection of the tumor without the primary anastomosis between the ileum and transverse colon, as
benefit of preoperative colonoscopy and often without benefit of long as the terminal ileum is viable, the patient is stable, and the
good staging. A water-soluble contrast enema is often useful in bowel is minimally edematous. Otherwise, end ileostomy with
such circumstances to establish the anatomic level of the obstruc- long Hartmann or mucous fistula is required.
tion. Primary anastomosis between the proximal colon and the Patients with nonobstructing tumors should undergo a thor-
colon distal to the tumor has been avoided in the past in the ough evaluation for metastatic disease. This includes a thorough
presence of obstruction because of a high risk for anastomotic leak physical examination, chest radiograph, and measurement of
associated with this approach. Thus, such patients were usually the CEA level. CT or MRI to inspect the intra-abdominal cavity
treated by resection of the segment of colon containing the for metastases and to search for other intra-abdominal disease
obstructing cancer, suture closure of the distal sigmoid or rectum, is an important aspect of preoperative staging. If possible, a
137 6 SECTION X Abdomen

colonoscopy should be done to evaluate the remainder of the between the terminal ileum and transverse colon. An extended
colon and rectum, and additional disease should be ruled out. CT right hemicolectomy is the procedure of choice for most trans-
colonography (virtual colonoscopy) or contrast enema can be verse colon lesions; this involves division of the right and middle
helpful if there are technical difficulties that precluded colonos- colic arteries at their origin, with removal of the right and trans-
copy. Liver function tests are no longer required as they are neither verse colon supplied by these vessels. The anastomosis is fashioned
sensitive nor specific for liver metastases. Complete blood count between the terminal ileum and proximal left colon. A left hemi-
and electrolyte panels with blood urea nitrogen and creatinine colectomy (resection from the splenic flexure to the rectosigmoid
measurement are required as well. junction) is the procedure of choice for tumors of the descending
The objective of surgery for colon adenocarcinoma is the colon, whereas a sigmoidectomy is appropriate for tumors of the
removal of the primary cancer with adequate margins, regional sigmoid colon. Most surgeons prefer to avoid incorporating the
lymphadenectomy, and restoration of the continuity of the GI proximal sigmoid colon into an anastomosis because of the often
tract by anastomosis. The extent of resection is determined by the tenuous blood supply from the IMA and frequent involvement
location of the cancer, its blood supply and draining lymphatic of the sigmoid colon with diverticular disease.
system, and the presence or absence of direct extension into adja- Abdominal colectomy (sometimes called subtotal colectomy or
cent organs. It is important to resect the lymphatics, which paral- total colectomy) entails removal of the entire colon from the ileum
lel the arterial supply, to the greatest extent possible in an attempt to the rectum, with continuity restored by an ileorectal anasto-
to render the abdomen free of lymphatic metastases. If hepatic mosis. Because of loss of the absorptive and storage capacity of
metastases are subsequently detected, they may still be resected the colon, this procedure causes an increase in stool frequency.
for cure in some cases if the abdominal disease has been com- Patients younger than 60 years generally tolerate this well, with
pletely eradicated. gradual adaptation of the small bowel mucosa, increased water
To restore the continuity of the GI tract, an anastomosis is absorption, and an acceptable stool frequency of one to three
fashioned with sutures or staples, joining the ends of the intestine movements daily. In older individuals, however, abdominal colec-
(small or large). It is important that both segments of the intestine tomy may result in significant chronic diarrhea. Abdominal col-
used for the anastomosis have an excellent blood supply and that ectomy is indicated for patients with multiple primary tumors,
there is no tension on the anastomosis. For lesions involving the for individuals with HNPCC, and occasionally for those with
cecum, ascending colon, and hepatic flexure, a right hemicolec- completely obstructing sigmoid cancers.
tomy is the procedure of choice. This involves removal of the
bowel from 4 to 6 cm proximal to the ileocecal valve to the Treatment and Follow-up
portion of the transverse colon supplied by the right branch of Although the prognosis can be refined by careful and accurate
the middle colic artery (Fig. 51-76). An anastomosis is fashioned pathologic staging, patients treated with appropriate resection for
stage I colon cancer generally have a 5-year survival rate of approx-
imately 90%. The 5-year survival rate for patients with stage II
A colon cancer treated surgically is approximately 75%. The survival
of patients with stage III disease, with lymph node metastasis, is
approximately 50%; and patients with stage IV disease (distant
metastases) have a poor prognosis, with a 5-year survival of less
than 5%.
Further treatment and follow-up of patients treated by seg-
mental colectomy for colon cancer is directed by the stage of the
disease. Approximately 85% of recurrences are detected within 2
B years of the time of resection, so the follow-up strategy should be
especially intensive during that period.
A reasonable strategy to observe patients with stage I colon
cancer is a colonoscopic examination 1 year after the operation
to inspect the anastomosis but also to detect any new or missed
polyps. The colonoscopy should be repeated annually if any
polyps are detected and removed, until an examination reveals
B the absence of polyps. Then, a colonoscopy should be offered
A every 5 years unless a strong family history or other genetic risk
factor is present, in which case more frequent endoscopic exami-
C C nations are obviously indicated. A CEA level should be deter-
mined every 3 months during the first 2 years, even if the
preoperative CEA level was normal. A rising CEA level requires
further tests to search for metastatic disease, including a CT scan
FIGURE 51-7 6 Operative procedures for right-sided colon cancer, (or MRI) of the abdomen and chest and possibly a PET scan.
sigmoid diverticulitis, and low-lying rectal cancer. Right hemicolectomy The goal of close follow-up testing is to detect early recurrence
involves resection of a few centimeters of terminal ileum and colon up
that is amenable to treatment. Isolated hepatic or pulmonary
to the division of the middle colic vessels into right and left segments
(A). Sigmoidectomy consists of removal of the colon between the
metastases are amenable to resection, with a 5-year survival rate
partially retroperitoneal descending colon and the rectum (B). Abdomi- of 20%. Multiple or unresectable metastases may respond to
noperineal resection of the rectum is performed in a combined approach current chemotherapeutic agents.
through the abdomen and through the perineum for the resection of Postoperative treatment of patients with stage II colon cancer
the entire rectum and anus (C). is somewhat controversial. To date, no large randomized trial has
 CHAPTER 51 Colon and Rectum 137 7

shown a benefit from adjuvant chemotherapy for this heteroge- combination with irinotecan and FOLFOX. Bevacizumab, a
neous group of patients. An attempt to stratify patients may vascular endothelial growth factor inhibitor, has also improved
identify a subset that would benefit from chemotherapy. The survival when added to regimens that include irinotecan, 5-FU–
5-year survival rate of patients with stage IIA disease is 85%, leucovorin, or oxaliplatin.
compared with 72% for stage IIB disease, which is actually worse
than for patients with node-positive stage IIIA disease. The Ameri- Rectal Cancer
can Society of Clinical Oncology suggests a course of 5-fluorouracil Cancers arising in the distal 15 cm of the large bowel share many
(5-FU)–based adjuvant chemotherapy for stage II patients with of the genetic, biologic, and morphologic characteristics of colon
at least one poor prognostic indicator, including insufficient cancers. However, the unique anatomy of the rectum, with its
lymph node sampling (<12 nodes resected with the specimen), retroperitoneal location in the narrow pelvis and proximity to the
T4 lesions, poorly differentiated histology, or bowel perforation. urogenital organs, autonomic nerves, and anal sphincters, makes
Whether oxaliplatin-based regimens should be used in stage II surgical access relatively difficult. In addition, precise dissection
disease in addition to 5-FU–leucovorin is controversial, but in appropriate anatomic planes is essential because dissection
current practice in most areas appears to favor the addition of medial to the endopelvic fascia investing the mesorectum may
oxaliplatin in early-stage disease. Further follow-up of stage II doom the patient to local recurrence of the disease, and dissection
patients includes a CEA level every 3 months for 2 years, then laterally to the avascular anatomic space risks injury to the mixed
every 6 months for a total of 5 years, and annual CT scans of the autonomic nerves, causing impotence in men and bladder dys-
abdomen and chest for at least the first 3 years. function in men and women.
Patients with stage III disease clearly benefit from adjuvant Furthermore, the biologic properties of the rectum, combined
chemotherapy. The addition of oxaliplatin to the 5-FU–leucovo- with its anatomic distance from the small intestine afforded by its
rin regimen (FOLFOX) has resulted in an improvement of retroperitoneal pelvic location, provide an opportunity for treat-
disease-free survival rates at 3 years to 78% (compared with 73% ment by radiation therapy that is not feasible for colon tumors.
with 5-FU–leucovorin alone). Irinotecan (Camptosar) has been The large bowel can tolerate properly delivered radiation doses up
investigated as an addition to 5-FU–based therapy in the adjuvant to 6000 cGy, whereas such levels of radiation targeted at colon
setting on the basis of its benefit against metastatic disease. Unfor- tumors would include small bowel in the treatment field. The
tunately, irinotecan has not demonstrated efficacy in the adjuvant small bowel cannot withstand radiation doses of this level without
setting and is not currently used for the treatment of patients with complications of radiation enteritis, including stricture, hemor-
stage III disease. rhage, and perforation.
The method of delivery of chemotherapeutic agents is evolving. The treatment of rectal cancer has changed significantly during
Continuous infusion of 5-FU is now generally considered to be the past 25 years; there is considerable controversy concerning the
superior to bolus infusions, with less toxicity. An oral fluoropy- precise role of surgery, radiation therapy, and chemotherapy and
rimidine, capecitabine (Xeloda), has been shown to be at least the ideal timing of each modality with relation to the others.
equivalent to 5-FU. Although information from clinical trials has provided data sup-
The treatment of patients with stage IV disease depends on the porting the multimodality treatment of rectal cancer, the criteria
location and extent of the metastases. In general, for asymptom- for selection of patients remains controversial. However, some
atic patients with stage IV disease, a chemotherapy first approach generalities can be made:
is often used. It allows the patient to benefit immediately from • Radiation therapy offers significant benefit to many patients
systemic therapy without a waiting period for healing after surgery. with rectal cancer, and preoperative radiation is superior to
Most patients with asymptomatic stage IV disease do not benefit postoperative radiation. Preoperative radiation (combined with
from removal of the primary lesion. Removal is not associated chemotherapy) is used for locally advanced distal rectal cancers
with long-term benefits. However, there are many situations in (within 10 to 15 cm of the anal verge, stage II or higher).
which metastasectomy is associated with reasonable long-term • Chemotherapy that has shown efficacy in the adjuvant setting
survival, with approximately 15% to 24% of patients surviving at in the treatment of colon cancer is also beneficial in the adju-
5 years. Hepatic or pulmonary lesions may be amenable to resec- vant setting for patients with rectal cancer. The combination
tion, typically after three to six cycles of chemotherapy and then of neoadjuvant (preoperative) radiation (usually 4500 to
reimaging to determine response. Good responders with resect- 5040 cGy) with infusional 5-FU–leucovorin, 5-FU alone, or
able disease may have survival rates approaching 25% at 5 years. capecitabine often results in dramatic reduction in tumor size
Agents complementing the 5-FU regimens that remain the key- (downstaging) and may result in apparently complete eradica-
stone of therapy are effective for metastatic disease and are being tion of the tumor in up to 20% of cases.33,34 Although interest
studied in the adjuvant setting. These are the monoclonal antibod- has grown in use of chemoradiation as the sole treatment for
ies bevacizumab (Avastin), cetuximab (Erbitux), and panitu- patients who have demonstrated a complete clinical response
mumab (Vectibix). Cetuximab is a chimeric (mouse-human) to chemoradiation, the ability to predict which patients actu-
monoclonal antibody; panitumumab, a fully human monoclonal ally have a complete response has been shown to be difficult.
antibody, binds to and inhibits the EGFR, which is overexpressed At least one series has shown that a complete clinical response
in 60% to 80% of colorectal cancers and is associated with a occurs in only 10% of patients treated with neoadjuvant
shorter survival time. Cetuximab and panitumumab are effective chemoradiation. There is considerable interest in elucidating
only on tumors that do not have a mutation of the KRAS gene.32 factors associated with complete eradication of rectal cancer
Accordingly, genetic testing is now recommended to confirm the by nonoperative treatment, and strategies and methods for
absence of KRAS mutations (indicating the presence of the KRAS predicting a complete clinical response have been attracting
wild-type gene) before the use of these EGFR inhibitors is recom- international interest.33,35,36
mended. These agents have shown clinical efficacy in patients • The best course of neoadjuvant treatment is not clear, but there
with metastatic colorectal cancer, both as monotherapy and in are regional preferences that may offer equivalent oncologic