© 2005 WebMD, Inc. All rights reserved.
ACS Surgery: Principles and Practice
5 Gastrointestinal Tract and Abdomen
14 HEREDITARY COLORECTAL CANCER
AND POLYPOSIS SYNDROMES
José G. Guillem, M.D., M.P.H., F.A.C.S., and Harvey G. Moore, M.D.
The majority of cases of inherited colorectal cancer (CRC) are
accounted for by two syndromes: hereditary nonpolyposis colo-
rectal cancer (HNPCC) and familial adenomatous polyposis
(FAP). In both, the predisposition to disease is a germline mutation
transmitted in an autosomal dominant fashion. Although the two
syndromes are similar in some respects, differences in their pheno-
typic expression and in the certainty of disease development man-
date distinctly different surgical approaches, including the timing
and extent of prophylactic procedures in carefully selected patients.
In the management of FAP, the role of prophylactic surgery is
clearly defined, though the optimal procedure for an individual
patient depends on a number of factors. In the management of
HNPCC, the indications for prophylactic procedures are emerg-
ing, particularly for unaffected mutation-positive patients.
Two less common polyposis syndromes, Peutz-Jeghers syn-
drome (PJS) and juvenile polyposis syndrome (JPS), are also
inherited in an autosomal dominant fashion and are associated
with a significant risk of CRC. Carefully selected persons affected
by these syndromes may also benefit from prophylactic surgical
procedures. Current evidence supports a role for prophylactic
colectomy in JPS but not in PJS.
Finally, there are a few other, less common, inherited hamar-
tomatous polyposis syndromes, such as Cowden disease and
Ruvalcaba-Myhre-Smith syndrome. At present, these syndromes
appear to be associated with an exceedingly low risk of CRC;
accordingly, prophylactic surgery is not indicated.1
Familial Adenomatous Polyposis
FAP is caused by mutations in the tumor suppressor gene APC,
located at 5q21. Nearly 80% of FAP patients belong to known
FAP kindreds; 10% to 30% have new mutations.1 More than 300
distinct mutations have been identified within the APC gene locus
in persons manifesting the FAP phenotype. More than half of the
known germline mutations associated with the classic FAP phe-
notype are concentrated in the 5′ region of exon 15.1 Genotype-
phenotype correlative studies have revealed a wide range of phe-
notypic heterogeneity, ranging from the relatively mild presenta-
tion associated with attenuated FAP, which is caused by mutations
in the 3′ and 5′ ends of the APC gene,2 to the severe presentation
associated with mutations downstream from codon 1250, partic-
ularly those in codon 1309. It has been reported that as many as
7.5% of patients with a classic FAP phenotype and no demon-
strable APC mutation may have biallelic germline mutations in the
base excision repair gene MYH.3
CLINICAL EVALUATION
FAP, which accounts for less than 1% of the annual CRC
burden, is characterized by the presence of more than 100 ade-
nomatous polyps of the colorectum, virtually 100% pene-
trance, and a nearly 100% risk of CRC by the age of 40 if pro-
phylactic colectomy is not performed.1,4 Extracolonic manifes-
tations are common and include desmoid tumors, osteomas,
14 Hereditary Colorectal Cancer and Polyposis Syndromes — 1
odontomas, sebaceous and epidermoid cysts, congenital hyper-
trophy of the retinal pigment epithelium, and periampullary
neoplasms.1
INVESTIGATIVE STUDIES
Pathologic Findings
The polyps, which develop by the age of 20 years in 75% of
cases, are typically less than 1 cm in size. In severe FAP, they may
carpet the entire surface of the colorectal epithelium or, alterna-
tively, may spare portions of the epithelial lining (e.g., the rectum).
Adenomas may be either pedunculated or sessile and may have
tubular, villous, or tubulovillous histology. Microscopic evaluation
may reveal innumerable microadenomas within grossly normal-
appearing colorectal mucosa. Foci of carcinoma in situ and inva-
sive carcinoma may be found within larger polyps, and the inci-
dence of invasive cancer is proportional to the extent of polyposis.
Unlike CRC in the setting of HNPCC, CRC in the setting of FAP
is more commonly located on the left side.1
Screening and Surveillance
Screening (genetic testing or annual or biennial flexible sigmoi-
doscopy) for at-risk family members should begin around puber-
ty (i.e., at 10 to 12 years of age) [see Table 1]. In families with a
demonstrated APC mutation, informative genetic testing can be
carried out with the protein truncation test [see Table 2]. This test,
which detects foreshortened proteins resulting from truncating
APC mutations, is approximately 80% sensitive5; however, the test
results are commonly misinterpreted, even by physicians.6 Patients
with normal protein truncation test results and a previously iden-
tified mutation in the family may be discharged from further
screening with a nearly 100% certainty that the mutation is
absent, but they should still undergo CRC screening starting at
the age of 50 years, as is recommended for average-risk persons.
When an APC mutation has not previously been identified in the
family of an affected person, the patient should be tested first to
identify the causative mutation. In families in which the protein
truncation test fails to provide conclusive information on carrier
status, at-risk individuals should continue with the recommended
endoscopic surveillance program. Other options for detecting
APC mutations include linkage analysis, single-stranded confir-
mation polymorphism, and direct sequence analysis.1
Genetic counseling is an essential component of the evaluation
of patients for FAP. Patients who have a positive genotype or who
have adenomatous polyps on sigmoidoscopy should undergo full
colonoscopy to establish the extent of polyposis.
MANAGEMENT
Medical Therapy
A number of nonsteroidal anti-inflammatory drugs, including
sulindac, celecoxib, and the sulindac metabolite exisulind, have
been shown to reduce the number and size of polyps in FAP
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
5 Gastrointestinal Tract and Abdomen 14 Hereditary Colorectal Cancer and Polyposis Syndromes — 2

Table 1 Genetic Basis, Clinicopathologic Features, Diagnosis, Surveillance, and Surgical

Management of Hereditary CRC and Polyposis Syndromes
Extracolonic Pathologic CRC Screening Surgical Management
Syndrome Genetic Basis Diagnosis GI Manifestations
Manifestations Features and Surveillance

Desmoids Consider genetic

Adenomatous counseling/testing If polyposis is confirmed,
≥ 100 adenoma- polyps of colon
Osteomas
Carry out early sur- colectomy is indicated
tous polyps of and rectum Odontomas
APC, 5q21 Tubular, villous, or veillance with sig- Options include the
colorectum Sebaceous and
FAP (> 90%); MYH 100% risk of colo- tubulovillous moidoscopy (at following:
or rectal cancer by epidermoid cysts histology
(8%) age 10–12 yr)98,99 TPC with ileostomy
APC mutation age 40 without CHRPE TAC with IRA
For at-risk untested
demonstrated colectomy Periampullary TPC with IPAA
individuals, perform
neoplasms FS every 1–2 yr

Affected patient with identi-

fied mutation or meeting
Consider genetic
Amsterdam criteria:
counseling/testing
Possibly few or no Colon cancer or advanced
Adenocarcinoma, If patient is mutation
colorectal polyps adenoma: perform TAC
MMR mutation frequently muci- positive or is
MMR genes: Right-side tumor with IRA or segmental
demonstrated nous or signet- untested but
MLH1 and MSH2 (60%–70%) Associated tumors colectomy with annual
ring cell histology meets criteria, per-
(90%), MSH6 or of endometrium, colonoscopy
HNPCC MSI-high tumor form colonoscopy
(10%), PMS1, Family meets small bowel, Solid or cribriform Rectal cancer: perform TPC
(80%–90%) at 20–25 yr (or
PMS2, MLH3, Amsterdam I or II ureter, or renal growth pattern with IPAA or LAR and
Synchronous/meta- 10 yr earlier than
MSH3 criteria50,51 pelvis Tumor-infiltrating youngest affected annual colonoscopy
chronous tumors
or peritumoral individual), then Unaffected patient with iden-
80% lifetime risk of lymphocytes every 1–2 yr, then tified mutation or meeting
CRC
annually after age Amsterdam criteria:
4098,99 Consider TAC with IRA or
colonoscopy every 1–3 yr

Perform operative or
laparoscopy-assisted
Hamartomas of GI polypectomy or segmental
tract colectomy for polyps > 1.5
and Hamartomatous Consider genetic cm that are not amenable
Hyperplasia of to endoscopic resection
At least two of the polyps throughout counseling/testing
LKB1/STK11, Mucocutaneous smooth muscle of
following: entire GI tract Perform colonosco- Perform segmental bowel
19p13.3 pigmentation muscularis
PJS (small intestine, py starting be- resection for invasive
(18%–63%) Small bowel (perioral and buc- mucosa
90%; colon, 50%) tween puberty and cancers
disease cal areas, 95%) Arborization
Relative risk of age 25, then every In the setting of laparotomy,
Mucocutaneous Pseudoinvasion
CRC = 84 2–3 yr88 perform intraoperative
melanin
endoscopy (peroral or via
Family history of enterotomy)
PJS
Prophylactic colectomy has
no role88

Consider genetic
counseling/testing
Disease is local, and no sig-
50–200 polyps Perform colonosco- nificant symptoms are
≥ 3 juvenile polyps Cystic, mucus-filled
py in middle to late present:
Multiple hamar- teenage years, with
of colon and spaces with Manage endoscopically, with
tomatous polyps EGD and SBS; if
SMAD4/DPC4, juvenile polyps Tumors of stom- epithelial lining colonoscopic surveillance
throughout gas- results are nega-
JPS 18q21.1 (50%); throughout GI ach, pancreas, every 1–3 yr
troduodenum Attenuated smooth tive, repeat in 3 yr,
BMPR1A, tract duodenum
15% risk of CRC muscle layer then every 3 yr if Disease is diffuse or signifi-
10q22.3 or
by age 35, 68% Focal epithelial results remain neg- cant symptoms are
Any number of risk by age 65 hyperplasia and ative; if results are present:
polyps with family dysplasia positive, perform Perform TAC with IRA, and
history of JPS biopsy of polyps carry out rectal surveillance
and intestinal every 1–3 yr
mucosa

CHRPE—congenital hypertrophy of retinal pigment epithelium CRC—colorectal cancer EGD—esophagogastroduodenoscopy FAP—familial adenomatous polyposis FS—flexible
sigmoidoscopy HNPCC—hereditary nonpolyposis colorectal cancer IPAA—ileal pouch–anal anastomosis IRA—ileorectal anastomosis JPS—juvenile polyposis syndrome
LAR—low anterior resection MMR—mismatch repair MSI—microsatellite instability PJS—Peutz-Jeghers syndrome SBS—small bowel series TAC—total abdominal colectomy
TPC—total proctocolectomy

patients.7-10 However, long-term use of chemopreventive agents
for primary treatment of FAP is not recommended.11 In a ran-
domized, placebo-controlled, double-blind study of genotype-
positive, phenotype-negative patients, the use of sulindac had no
effect on the subsequent development of colorectal polyposis.12
Furthermore, the development of rectal cancer has been reported
in patients whose rectal polyps were effectively controlled with
sulindac.10 Finally, these medications necessitate continued com-
pliance9 and may be associated with significant side effects.
Chemopreventive agents may be useful for reducing polyp load
and facilitating endoscopic management of polyps in patients who
have an ileal pouch or in patients who have an iliorectal anasto-
mosis, are at high risk for polyp development, and refuse proctec-
tomy. In such cases, however, it is still necessary to perform care-
ful surveillance of the residual rectum or the ileoanal pouch every
6 months.11
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
5 Gastrointestinal Tract and Abdomen 14 Hereditary Colorectal Cancer and Polyposis Syndromes — 3

Surgical Therapy
The timing of surgical treatment depends to some degree on
the extent of polyposis, in that the risk of CRC is partially depen-
dent on the number of polyps present.13 Patients with mild poly-
posis (and thus a lower cancer risk) can undergo surgery in their
midteens.11 Practically speaking, the best time is usually the sum-
mer between high school and college. Patients with severe polyp-
osis, dysplasia, adenomas larger than 5 mm, and significant symp-
toms should undergo surgery as soon after diagnosis as is practi-
cal.11
There are three basic surgical options for treating FAP: (1) total
proctocolectomy (TPC) with permanent ileostomy, (2) total
abdominal colectomy with ileorectal anastomosis (IRA), and (3)
proctocolectomy with ileal pouch–anal anastomosis (IPAA) [see
5:33 Procedures for Ulcerative Colitis]. The optimal procedure for a
given patient is determined on the basis of a number of factors,
including disease characteristics, differences in postoperative func-
tional outcome, preoperative anal sphincter status, and patient
preference.
TPC TPC with permanent ileostomy is rarely chosen as a
primary procedure. More commonly, it is considered as an option
for patients in whom a proctectomy is required but an IPAA is
contraindicated (e.g., those with rectal tumors involving the
sphincters or the levator complex or those with poor baseline
sphincter function) or for patients in whom an IPAA is not tech-
nically feasible (e.g., those with desmoid disease and foreshorten-
ing of the small bowel mesentery). Occasionally, however, TPC is
chosen as a primary procedure in patients whose lifestyle would be
compromised by frequent bowel movements.
IPAA versus IRA The choice between IPAA and IRA is
generally more challenging. The main considerations to be taken
into account are the risk of rectal cancer development if the rec-
tum is left in situ and the differences in functional outcome (and
associated quality of life) between procedures.
It has been estimated that the risk of rectal cancer after IRA may
be as high as 4% to 8% at 10 years and 26% to 32% at 25
years.14,15 The true risk, however, may be somewhat lower. Most of
the studies from which these figures were derived were completed
before IPAA became available; thus, patients and physicians might
have been more likely to choose IRA even in the setting of more
extensive rectal disease, given that TPC and permanent ileostomy
was the only other option at the time.The magnitude of risk in an
individual patient is related to the overall extent of colorectal poly-
posis. IRA may be an option for patients with fewer than 1,000
colorectal polyps (including those with attenuated FAP) and fewer
than 20 rectal adenomas, because these patients appear to be at
relatively low risk for rectal cancer.11,13,16 Ideally, patients with
severe rectal (> 20 adenomas) or colonic (> 1,000 adenomas)
polyposis, an adenoma larger than 3 cm, or an adenoma with
severe dysplasia should be treated with IPAA.11,13
The risk of secondary rectal excision as a consequence of
uncontrollable rectal polyposis or rectal cancer may be estimated
on the basis of the specific location of the causative APC muta-
tion.15-17 In a study of 87 FAP patients with an identified APC
mutation who underwent IRA, those with a mutation located
downstream from codon 1250 had an approximately threefold
higher incidence of secondary rectal resection than those with a
mutation located upstream of codon 1250.14 Furthermore,
patients with a mutation located between codons 1250 and 1464
had a 6.2-fold higher risk of rectal cancer than those with a muta-
tion before codon 1250 or after codon 1464.15
The risk of polyp and cancer development after index surgery
is not limited to patients undergoing IRA. In patients undergoing
IPAA, the pouch-anal anastomosis may be either handsewn after

Table 2 Availability of Commercial Genetic Testing for Autosomal Dominant Inherited CRC Syndromes

Test Approximate Time Frame Approximate Cost Clinical Availability (in United States)

$1,100; if mutation Mayo Clinic, Rochester, Minn.; (800) 533-1710

Protein truncation test 4–6 wk
known, $475 Washington University, St. Louis, Mo.; (314) 454-7601

Baylor College of Medicine, Houston, Tex.; (800) 411-GENE

DNA sequencing, Huntington Medical Research Institute, Pasadena, Calif.; (626) 795-4343
germline APC 3 wk $1,475
Myriad Inc., Salt Lake City, Utah; (800) 469-7423
University of Pennsylvania, Philadelphia, Pa.; (215) 573-9161

ARUP Laboratories, Salt Lake City, Utah; (801) 583-2787

Baylor College of Medicine, Houston, Tex.; (800) 411-GENE
MSI analysis 2–4 wk $350–850 Mayo Clinic, Rochester, Minn.; (800) 533-1710
Memorial Sloan-Kettering Cancer Center, New York, N.Y.; (212) 639-5170
Ohio State University, Columbus, Ohio; (614) 293-7774

MSI and IHC 2–3 wk $750 Mayo Clinic, Rochester, Minn.; (800) 533-1710

Baylor College of Medicine, Houston, Tex.; (800) 411-GENE

DNA sequencing, Huntington Medical Research Institute, Pasadena, Calif.; (626) 795-4343
germline MMR muta- 3 wk $1,950; if mutation Myriad Inc., Salt Lake City, Utah; (800) 469-7423
tion (MLH1, MSH2) known, $350
Quest Diagnostics, Inc., San Juan Capistrano, Calif.; (949) 728-4279
University of Pennsylvania, Philadelphia, Pa.; (215) 573-9161

6–12 wk $1,176–1,400; if muta- Ohio State University, Columbus, Ohio; (614) 293-7774
LKB1/STK11 testing
tion known, $200–350 GeneDx Inc., Gaithersburg, Md.; (301) 519-2100

$1,234–1,260; if muta-
SMAD4/BMPR1A testing 3 mo Ohio State University, Columbus, Ohio; (614) 293-7774
tion known, $200

IHC—immunohistochemistry MMR—mismatch repair MSI—microsatellite instability

© 2005 WebMD, Inc. All rights reserved.
5 Gastrointestinal Tract and Abdomen 14 Hereditary Colorectal Cancer and Polyposis Syndromes — 4
complete anal mucosectomy or stapled to a 1 to 2 cm anal transi-
tion zone. Neoplasia may occur at the site of the anastomosis, and
the incidence appears to be higher after stapled anastomosis (28%
to 31%) than after mucosectomy and handsewn anastomosis
(10% to 14%).18,19 Function, however, may be better after stapled
anastomosis.19 In the case of anal transition zone neoplasia after
stapled anastomosis, transanal mucosectomy can often be per-
formed, followed by advancement of the pouch to the dentate line.
Of additional concern is the development of adenomatous polyps
in the ileal pouch itself, which occurs in 35% to 42% of patients
at 7 to 10 years.20-22
With respect to postoperative bowel function and associated
quality of life, IPAA has been associated with a higher frequency
of both daytime and nocturnal bowel movements, a higher inci-
dence of passive incontinence and incidental soiling, and higher
postoperative morbidity than IRA.23 Accordingly, some authors
recommend IRA for patients with mild rectal polyposis. Other
authors, however, have found the two approaches to be equivalent
in terms of functional results24 and quality of life25 and therefore
recommend IPAA for most patients because of the risk of rectal
cancer associated with IRA.
Regardless of which procedure is performed, however, lifetime
surveillance of the rectal remnant (after IRA) or the ileal pouch
(after IPAA) is required.11 Endoscopic surveillance of the bowel at
intervals of 6 months to 1 year after index surgery is recommend-
ed.5,11 After IRA, small (< 5 mm) adenomas may be safely
observed, with biopsy performed to rule out severe dysplasia. If
adenomas increase in number, the frequency of surveillance
should be increased, and polyps larger than 5 mm should be
removed. When fulguration and polypectomy are repeated over a
period of many years, subsequent polypectomy may become diffi-
cult, rectal compliance may be reduced, and flat cancers may be
hard to identify against a background of scar tissue. The develop-
ment of severe dysplasia or a villous adenoma larger than 1 cm is
an indication for proctectomy.11
Extracolonic Disease
After total abdominal colectomy with IRA and regular surveil-
lance, the risk of death appears to be three times higher for FAP
patients than for an age- and sex-matched control population.26
The main causes of death after IRA are desmoid disease and
upper gastrointestinal malignancy.
Desmoid disease Desmoids are histologically benign
tumors that arise from fibroaponeurotic tissue and occur in 12%
to 17% of FAP patients.11,27,28 Unlike those in the general popula-
tion, desmoids in FAP patients tend to be intra-abdominal (up to
80% of cases) and mainly occur after abdominal surgical proce-
dures.27,28 Patients with APC mutations located between codons
1310 and 2011 are at increased risk for these tumors.29 Desmoids
often involve the small bowel mesentery (> 50% of cases),28 mak-
ing complete resection difficult or impossible, and they may also
involve the ureters.27 Not uncommonly, patients present with
small bowel obstruction.27,28 Morbidity after attempted resection,
which often involves removal of a significant length of small bowel,
is substantial.The recurrence rate after attempted resection is also
high, and the recurrent disease is often more aggressive than the
initial desmoid.27,28
Intra-abdominal desmoid formation may be more common
after IRA than after IPAA, and the disease may be more severe
after IRA as well.28,30 When desmoid tumors involve the small
bowel mesentery, the mesentery may become foreshortened and
thereby render IPAA impracticable, especially in patients under-
ACS Surgery: Principles and Practice
going a subsequent completion proctectomy after an initial IRA.11
This possibility should be considered in making the choice between
IRA and IPAA as the initial procedure for FAP.
Medical therapy. When desmoid tumors are clinically inert,
they may be treated with sulindac.11 Tamoxifen or other antiestro-
gens may be added for slow-growing or mildly symptomatic
tumors.11,31,32 More aggressive desmoid tumors may be treated
with chemotherapy. Vinblastin and methotrexate achieve some
degree of response in 40% to 50% of patients.33 For more rapidly
growing desmoids, antisarcoma agents, such as doxorubicin and
dacarbazine, may be administered.34,35 Radiation therapy may also
be effective, but it can result in substantial small bowel morbidity.
Surgical therapy. Surgical treatment of intra-abdominal
desmoid tumors should be reserved for small, well-defined lesions
with clear margins.11 When intra-abdominal desmoids involve the
small bowel mesentery, they should be treated according to their
initial presentation and rate of growth. In patients with desmoid
lesions that are refractory to all medical treatment and call for sur-
gical treatment with extensive small bowel resection, small bowel
transplantation may be feasible in selected cases.36
Periampullary neoplasms In approximately 80% to 90%
of persons with FAP, duodenal adenomas, periampullary adeno-
mas, or both will develop.37 Of these patients, 14% to 50% will
eventually exhibit advanced polyposis, and as many as 6% will
eventually have invasive cancer.1,38-42 Although the risk of peri-
ampullary or duodenal cancer in FAP patients is relatively low, it
is still several hundred times higher than that in the general popu-
lation. Among FAP patients, those with APC mutations between
codons 976 and 1067 appear to have the highest incidence of duo-
denal adenoma.
Surveillance should begin with side-viewing esophagogastro-
duodenoscopy (EGD) and biopsy of suspicious polyps either at
the age of 20 years or at the time of prophylactic colectomy,
whichever is earlier.11 The purpose of screening is not to remove
all disease but to watch for the development of high-grade dyspla-
sia. Small, tubular adenomas without high-grade dysplasia may be
biopsied and observed; adenomas that are larger than 1 cm or that
exhibit high-grade dysplasia, villous changes, or ulceration should
be removed. Surgical options include endoscopic removal and
transduodenal excision, but both approaches have drawbacks:
endoscopic ablation generally requires multiple settings,38 and
recurrence is high after either procedure.38,43 Endoscopic ablation
is a reasonable initial approach for most patients without invasive
cancer and is an attractive alternative for patients who are unfit for
duodenal resection. For patients with persistent or recurrent high-
grade dysplasia in the papilla or duodenal adenomas and for
patients with Spigelman stage IV disease, pancreas-preserving
duodenectomy or pancreaticoduodenectomy is recommended.11
The results reported for duodenal resection in patients with pre-
malignant lesions are encouraging, with good local control and
low morbidity.38,44,45 Duodenectomy also greatly reduces the need
for upper GI surveillance.
Hereditary Nonpolyposis Colorectal Cancer
HNPCC, which accounts for 5% to 7% of CRCs, results from
a mutation in one of the DNA mismatch repair (MMR) genes
(MLH1, MSH2, MSH6, PMS1, PMS2, MLH3, and MSH3).46,47
Two genes (MLH1, MSH2) may be responsible for as many as
90% of causative germline MMR mutations. However, only 50%
© 2005 WebMD, Inc. All rights reserved.
5 Gastrointestinal Tract and Abdomen
to 70% of patients meeting clinical criteria for HNPCC have an
identifiable germline MMR mutation, which suggests that one or
more unidentified genes may be involved. A significant percentage
of cases may be attributable to large germline deletions that are
difficult to detect by means of direct sequencing. It appears that
genomic deletions may account for as many as 7% of HNPCC
cases defined on the basis of clinical criteria.48
CLINICAL EVALUATION
HNPCC is characterized by early-onset CRC, a predominance
of lesions proximal to the splenic flexure (60% to 70% of cases),
benign and malignant extracolonic tumors, and a predilection for
synchronous and metachronous colorectal tumors.4 Microsatellite
instability (MSI), reflecting a deficiency in DNA repair secondary
to a mutation in the MMR genes, is noted in approximately 80%
to 90% of HNPCC-related tumors.4 The lifetime risk of CRC in
HNPCC patients is approximately 80%.11,49
Establishing a clinical diagnosis of HNPCC is much more chal-
lenging than establishing a clinical diagnosis of FAP, in that it
requires a careful and detailed family history. The Amsterdam II
criteria [see Table 3] require that there be three relatives (of which
one must be a first-degree relative of the other two) with an
HNPCC-related cancer (of the colorectum, the endometrium, the
small bowel, the ureter, or the renal pelvis), that two or more suc-
cessive generations be involved, and that at least one relative have
a CRC diagnosed before the age of 50.50,51 Finally, FAP should be
excluded. CRC occurs in 78% to 80% of MMR mutation–posi-
tive patients at a mean age of 46 years.1,49,52 Endometrial cancer
occurs in 43%, gastric cancer in 19%, urinary tract cancer in 18%,
and ovarian cancer in 9%.53
INVESTIGATIVE STUDIES
Pathologic Findings
Adenomas in HNPCC patients show high-grade dysplasia and
villous changes more frequently than adenomas in sporadic CRC
patients.1 Adenomas may also appear at an earlier age and are
often larger than those found in the general population. Other
pathologic features reported to be more common in HNPCC-
related cancers include a mucinous or poorly differentiated histol-
ogy, a solid or cribriform growth pattern, signet-ring cell tumors,
and the presence of tumor-infiltrating and peritumoral lympho-
cytes. HNPCC-related CRCs have also been shown to have a
lower rate of lymph node involvement.54
Screening and Surveillance
CRC patients who belong to known HNPCC kindreds, who
have a pedigree suggestive of HNPCC, or who meet the Bethesda
criteria [see Table 4]55 should be offered screening by MSI testing.
MSI evaluation will yield positive results (i.e., an MSI-high tumor)
in 80% to 90% of patients belonging to families that meet the
Amsterdam criteria. Patients with MSI-high tumors should
undergo testing for germline MMR mutations (tests for MSH2
and MLH1 are available commercially [see Table 2]). If tumor tis-
sue is not available, initial germline testing may be considered. As
in FAP, a mutation in an affected individual must first be estab-
lished for testing in at-risk individuals to be informative.5
Recommended surveillance for HNPCC includes colonoscopy,
initially every 1 to 2 years beginning at the age of 20 to 25, then
annually after the age of 40.56 Given the increasing evidence of an
accelerated adenoma-carcinoma sequence in HNPCC, annual
colonoscopy should be strongly considered.4 Female patients
should undergo annual transvaginal ultrasonography and mea-
ACS Surgery: Principles and Practice
14 Hereditary Colorectal Cancer and Polyposis Syndromes — 5
Table 3 Clinical Criteria for Diagnosis of HNPCC
Three or more relatives with CRC
One first-degree relative of the other two
Amsterdam criteria I
50
One CRC diagnosed at age < 50 yr
Two or more successive generations
FAP excluded
Three or more relatives with an HNPCC-associated
cancer (in colorectum, endometrium, small bowel,
ureter, or renal pelvis)
51
Amsterdam criteria II One first-degree relative of the other two
Two or more successive generations
One CRC diagnosed at age < 50 yr
FAP excluded
surement of CA125 levels starting at 25 to 35 years of age, as well
as annual endometrial aspiration.56 Annual EGD is recommend-
ed for patients belonging to kindreds with a history of gastric can-
cer. Finally, ultrasonography and urine cytology every 1 to 2 years
may be considered to screen for urinary tract malignancy.
MANAGEMENT
Surgical Therapy
Although the development of CRC in persons with HNPCC is
not a certainty, the 80% lifetime risk,1 the 45% rate of metachro-
nous tumors, and the possibility of an accelerated adenoma-carci-
noma sequence4 mandate consideration of prophylactic surgical
options. Patients who have HNPCC as defined by their genotype
or the Amsterdam criteria [see Table 3] and who have a colon can-
cer or more than one advanced adenoma should be offered either
(1) prophylactic total abdominal colectomy with IRA or (2) seg-
mental colectomy with yearly colonoscopy [see 5:34 Laparoscopic
Colectomy].11,57,58 (The first option, however, is open only to
patients with normal rectal and anal sphincter function.) Although
the risk of metachronous colon cancers may be higher after partial
colectomy than after total colectomy with IRA, intensive colono-
scopic surveillance and polypectomy may minimize the number of
metachronous cancers in the remaining colon.52,59 Careful surveil-
lance is also necessary after total colectomy and IRA, given that
the risk of metachronous rectal cancer after total colectomy is
approximately 12% at 10 to 12 years.60
HNPCC patients with an index rectal cancer that is amenable
to a sphincter-preserving resection should be offered either (1)
total proctocolectomy with IPAA [see 5:33 Procedures for Ulcerative
Colitis] or (2) low anterior resection (LAR) with primary recon-
struction [see 5:35 Procedures for Rectal Cancer].11,58 The rationale
Table 4 Revised Bethesda Guidelines for
Testing CRC Patients for MSI55
CRC diagnosed at age < 50 yr
Presence of synchronous or metachronous CRC or other HNPCC
tumors (regardless of age)
CRC with HNPCC-like histology at age < 60 yr
CRC in one or more FDR with an HNPCC-related tumor (one diagnosed
at age < 50 yr)
CRC in two or more first- or second-degree relatives with HNPCC-
related tumors (regardless of age)
FDR—first-degree relative
© 2005 WebMD, Inc. All rights reserved.
5 Gastrointestinal Tract and Abdomen 14 Hereditary Colorectal Cancer and Polyposis Syndromes — 6
for total proctocolectomy is based on the 17% to 45% rate of
metachronous cancer in the remaining colon associated with an
index rectal cancer in HNPCC patients.61 The decision between
the two procedures depends in part on the patient’s willingness to
undergo intensive surveillance of the retained proximal colon, as
well as on the level of bowel function.
Mutation-positive patients with a normal colorectum may also
be offered prophylactic colectomy in selected cases.56,62 This
approach is supported by the similarity of lifetime cancer risk
between patients with germline APC mutations and those with
MMR mutations, as well as by the observation that total abdomi-
nal colectomy with IRA yields less functional disturbance than the
prophylactic procedure recommended for FAP (total proctocolec-
tomy with IPAA).56,62 An alternative strategy in these patients is to
carry out colonoscopic surveillance at 1- to 3-year intervals. This
strategy has proved to be cost-effective63 and to reduce both the
rate of CRC development and overall mortality.52,64,65 There is a
risk that CRC may develop in the intervals between colonos-
copies64,66; however, when the surveillance interval is shorter than
2 years, tumors tend to be found in their early stages and to be cur-
able when found.52,64
A study using a decision-analysis model suggested that prophy-
lactic total abdominal colectomy at the age of 25 might offer a sur-
vival benefit of 1.8 years when compared with colonoscopic sur-
veillance. The benefit of prophylactic colectomy decreased when
surgery was delayed until later in life and became negligible when
it was performed at the time of cancer development.65 However,
surveillance provided a greater benefit with respect to quality of
life (measured in quality-adjusted life years).65 On the basis of this
evidence, some surgeons recommend that prophylactic colectomy
be performed only in highly selected situations (e.g., when colono-
scopic surveillance is not technically possible or when a patient
refuses to undergo regular surveillance). Thus, the decision
between prophylactic surgery and surveillance for gene-positive
unaffected patients is based on many factors, including the pene-
trance of disease in a family, the age of cancer onset in family
members, functional and quality-of-life considerations, and the
likelihood of patient compliance with surveillance.
Extracolonic Disease
Management of extracolonic cancers in HNPCC patients is not
yet well defined. Female patients with a family history of uterine
cancer should be offered prophylactic total abdominal hysterecto-
my (TAH) if their childbearing is complete or if they are under-
going abdominal surgery for other conditions.11 This recommen-
dation is based on the high (43%) rate of endometrial cancer in
mutation-positive persons,53 particularly those with hMSH2
mutations, and on the inefficacy of screening in some studies.67
Oophorectomy should be added to TAH because of the high (9%)
incidence of ovarian cancer in HNPCC patients53 and the fre-
quent coexistence of endometrial cancer with ovarian cancer.68
The optimal timing for prophylactic TAH is unclear; however,
endometrial cancer has been reported in HNPCC patients before
the age of 35. At present, it seems reasonable to begin surveillance
at the age of 25 and delay prophylactic surgery until childbearing
is complete.11
Peutz-Jeghers Syndrome
Like FAP and HNPCC, PJS follows an autosomal dominant
pattern of inheritance with variable penetrance. It is caused in part
by mutations in the gene LKB1/STK11, which maps to the telo-
meric region of chromosome 19p13.3.This gene, which codes for
ACS Surgery: Principles and Practice
a multifunctional serine-threonine kinase, is thought to function
as a tumor suppressor gene.69-72 Germline mutations in
LKB1/STK11 can be demonstrated in 18% to 63% of PJS
patients, which suggests the existence of additional PJS loci.72-75
Genetic testing for PJS can be accomplished through direct
sequencing of the LKB1/STK11 gene [see Table 2]; however, such
testing is not widely available. In families with an established
mutation, genetic testing of at-risk individuals is informative, with
a reported accuracy of 95%.76
CLINICAL EVALUATION
PJS is a hereditary polyposis syndrome characterized by hamar-
tomas of the GI tract, as well as by mucocutaneous melanin pig-
mentation. Hamartomatous polyps may occur throughout the GI
tract but are most frequently found in the small intestine (90%).
Other common sites of hamartomas in PJS are the large intestine
(50%) and the stomach; less common sites are the renal pelvis,
the bile ducts, the urinary bladder, the lungs, and the nasophar-
ynx.1,77,78 Mucocutaneous pigmentation generally appears during
infancy.The perioral and buccal areas are involved in 95% of cases;
the periorbital and facial areas, the genital region, and the acral
areas (including the hands and feet) may be involved as well.1 The
average age of diagnosis of PJS is 22 years in men and 26 years in
women.
In as many as 86% of cases, the initial presentation of PJS is
small bowel obstruction secondary to intussusception of hamar-
tomas. Other presentations include acute or chronic GI bleeding,
biliary and gastric outlet obstruction, and anal protrusion of
polyps. The diagnosis of PJS is established by the presence of his-
tologically confirmed hamartomas of the GI tract plus two of the
following three criteria: (1) small bowel polyposis, (2) mucocuta-
neous melanotic pigmentation, and (3) a family history of PJS [see
Table 1].79
Patients with PJS are at significantly increased risk for both
intestinal and extraintestinal malignancies. A meta-analysis found
that in comparison with the general population, PJS patients were
at a relative risk of 15.2 for the development of any malignancy.80
The relative risks for the development of specific cancers were as
follows: small bowel, 520; gastric, 213; pancreatic, 132; colorectal,
84; esophageal, 57; ovarian, 27; lung, 17; endometrial, 16; and
breast, 15.The cumulative risk for the development of any cancer
between the ages of 15 and 64 was 93%.80 Other cancers associ-
ated with PJS are cholangiocarcinomas, testicular neoplasms, and
duodenal tumors.1
Although the relative risk for the development of CRC was high
in this study,80 the reported magnitude of risk in the individual
studies included in the meta-analysis varied considerably. Previous
studies also reported a wide range of CRC incidences in these
patients.1 Thus, the true incidence of CRC in PJS patients remains
unclear.
INVESTIGATIVE STUDIES
Pathologic Findings
The polyps seen in PJS are hamartomas characterized by hyper-
trophy or hyperplasia of the smooth muscle of the muscularis
mucosa. Smooth muscle extends into the superficial epithelial
layer of the bowel wall in a treelike fashion (a process referred to
as arborization). Epithelial cells may become entrapped within the
muscle layer, and this “pseudoinvasion” can be mistaken for
malignant transformation.Therefore, to diagnose a malignancy in
a PJS polyp, cellular atypia or an elevated mitotic rate must be
documented.81 Sporadic PJS polyps do occur, generally secondary
© 2005 WebMD, Inc. All rights reserved.
5 Gastrointestinal Tract and Abdomen 14 Hereditary Colorectal Cancer and Polyposis Syndromes — 7
to somatic LKB1/STK11 mutations in one or both alleles, and are
histologically identical to their hereditary counterparts.These spo-
radic polyps appear not to be associated with an increased risk of
GI cancer.82
Histologically, areas of cutaneous pigmentation reveal an
increased number of melanocytes at the dermal-epidermal junc-
tion, with elevated melanin levels in the basal cells. These lesions
do not appear to have any malignant potential.
Screening and Surveillance
Clinical screening of asymptomatic persons is facilitated by the
appearance of perioral hyperpigmentation during early childhood.
Once the diagnosis of PJS is made, patients generally enter a sur-
veillance program. Recommended surveillance for GI disease
includes annual serum hemoglobin measurement and EGD every
2 to 3 years, beginning between the ages of 10 and 25.79,83-85
Contrast radiography is employed to examine the remainder of the
small bowel, beginning at the age of 10 and repeated every 2 to 3
years.79,85 The frequency of surveillance examinations may be
modified in individual circumstances. Colonoscopic surveillance is
also important, commencing between puberty and the age of 25
and repeated every 2 to 3 years.83,85 Sigmoidoscopy should not be
employed for surveillance, because the rectum may be spared in
some patients with more proximal disease. Organ-specific surveil-
lance for other associated malignancies should also be initiated in
accordance with current high-risk recommendations.
MANAGEMENT
Medical Therapy
Cyclooxygenase-2 (COX-2) is known to be overexpressed in the
hamartomatous tissue of PJS patients, and there is a correlation
between expression of the COX-2 protein and expression of the
LKB1/STK11 protein in PJS polyps and cancers.86,87 These find-
ings suggest that COX-2 may be a potential target for chemopre-
vention of PJS.
Surgical Therapy
Indications for surgical management of PJS include the pres-
ence of polyps larger than 1.5 cm that cannot be removed endo-
scopically, incomplete removal of polyps with adenomatous
changes, the development of polyp-associated complications (e.g.,
obstruction, intussusception, and bleeding), and the management
of malignant disease.88
Endoscopic polypectomy is generally employed as initial thera-
py when it is technically feasible. For some polyps, however, oper-
ative polypectomy performed through an enterotomy is required.
Segmental resection should be avoided. In the context of a laparo-
tomy, intraoperative endoscopy (either peroral or via an enteroto-
my) allows direct visualization of the remainder of the small bowel
and endoscopic clearance of any synchronous polyps. This proce-
dure significantly reduces the need for subsequent laparotomy.
The St. Mark’s Hospital group in London found that none of 25
patients who underwent enteroscopy during laparotomy required
subsequent laparotomy within a 4-year period, whereas 17% of
historical control patients who did not undergo intraoperative
enteroscopy required repeat laparotomy within a 1-year period.89
Laparoscopy-assisted polypectomy and laparoscopic manage-
ment of small bowel intussusception are additional surgical
options.
Given the risk of CRC development in PJS patients, careful
colonoscopic surveillance is clearly warranted. However, the role of
prophylactic colectomy in patients who are at risk or are mutation
ACS Surgery: Principles and Practice
positive is unclear. Because the true risk of CRC in these patients
is unknown and genetic testing for PJS is not widely available, no
recommendations can be made at present regarding the role of
prophylactic colectomy in the PJS population.88
Juvenile Polyposis Syndrome
Initial evidence suggested that mutations in the PTEN gene
were responsible for JPS90; however, subsequent evidence impli-
cated SMAD4/DPC4 at 18q21.1 as a more common cause,
accounting for as many as 50% of familial cases.91-93 Mutations in
BMPR1A at 10q22–q23 have also been reported to cause JPS but
display variable penetrance [see Table 2].94,95 Clonal genetic alter-
ations are detected in stromal rather than epithelial cells, which
suggests that the genetic changes in juvenile polyps originate in the
nonepithelial component of the polyps.
CLINICAL EVALUATION
Like PJS, JPS is characterized by the development of multiple
hamartomas throughout the GI tract. Isolated juvenile polyps are
common in children and are found in approximately 1% of per-
sons younger than 21 years. Juvenile polyposis, however, is much
less common. A family history of juvenile polyposis is present in
20% to 50% of patients.1 Although JPS is an autosomal dominant
disorder, its variable penetrance results in a less obvious pattern of
inheritance than is seen with FAP or HNPCC.
JPS affects the two sexes equally and generally manifests itself
during the first or second decade of life (mean age at diagnosis,
18.5 years).1 Common presenting symptoms include chronic ane-
mia, acute GI bleeding, prolapse of rectal polyps, protein-losing
enteropathy, and intussusception with or without obstruction.1
Extracolonic manifestations of JPS include gastroduodenal and
small bowel polyps, malrotation of the midgut, and mesenteric
lymphangiomas. Extraintestinal manifestations include clubbing,
hypertrophic pulmonary osteoarthropathy, hydrocephalus and
macrocephaly, alopecia, cleft lip and palate abnormalities, super-
numerary teeth, porphyria, congenital cardiac and arteriovenous
malformations, psoriasis, vitellointestinal duct abnormalities, renal
structural abnormalities, and bifid uterus and vagina. JPS is also
part of the phenotype for Ruvalcaba-Myhre-Smith syndrome and
Gorlin syndrome. Cowden disease, which is characterized by
hamartomatous polyposis and is associated with breast and thyroid
cancer, may be a phenotypic variant of JPS.1,95
The diagnostic criteria for JPS are as follows: (1) the presence of
three or more juvenile polyps of the colon; (2) the presence of juve-
nile polyps throughout the entire GI tract; or (3) the presence of
any number of polyps in a patient with known family history of JPS
[see Table 1].85 The clinical presentation of JPS can be divided into
three main clinical variants: (1) JPS of infancy, which is a non–sex-
linked recessive condition characterized by failure to thrive, sus-
ceptibility to infections, protein-losing enteropathy, bleeding, diar-
rhea, rectal prolapse, intussusception, and death by the age of 2
years in severe cases; (2) generalized JPS, which occurs in the first
decade of life and is characterized by juvenile polyps throughout
the GI tract; and (3) JPS of the colon, the most common presen-
tation, which is characterized by colonic polyposis only.1
Patients with JPS appear to be at increased risk for GI malig-
nancies, especially CRC. One study estimated the risk of CRC to
be 15% by age 35 and 68% by age 65.96 In another study, GI
malignancies (mostly CRC) were diagnosed in 36 (17%) of 218
JPS patients at a mean age of 33 years.97 Associated gastric, pan-
creatic, and duodenal cancers have also been reported. CRCs are
thought to arise from malignant transformation of dysplastic
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
5 Gastrointestinal Tract and Abdomen 14 Hereditary Colorectal Cancer and Polyposis Syndromes — 8

polyps.1 Adenocarcinomas occur, on average, 15 years after diag-
nosis of JPS and generally are poorly differentiated or mucinous
tumors with a poor prognosis.1
INVESTIGATIVE STUDIES
Pathologic Findings
The number of polyps seen in JPS patients varies but typically
ranges from 50 to 200.The polyps are usually smaller than 1.5 cm
but can be as large as 3 cm. Grossly, they appear as red-brown,
smooth, pedunculated lesions with lobulated or spherical heads
and superficial ulceration; the cut surface demonstrates cystic
spaces corresponding to mucus-filled glands. Histologically, polyps
are characterized by an inflammatory infiltration of the lamina
propria, an attenuated smooth muscle layer, and cystically dilated
mucus-filled glands lined by columnar epithelium. Focal epithelial
hyperplasia and dysplasia may be present.
Screening and Surveillance
Initial evaluation of the proband and the first-degree relatives,
which ideally would be done in the middle to late teenage years,
should include colonoscopy, EGD, and a small bowel series. If the
initial evaluation yields negative results, a repeat evaluation should
be performed in 3 years, then every 3 years thereafter as long as the
results remain negative. If disease is encountered, random biopsies
of polyps and intervening mucosa should be performed to detect
adenomatous and dysplastic changes. Management depends on
the presence of symptoms and on the extent and severity of polyp-
osis.When polyposis is mild, endoscopic management may be fea-
sible. Continued annual surveillance after endoscopic manage-
ment is required; the surveillance interval may be lengthened to 3
years if subsequent evaluations reveal no disease.1,85
MANAGEMENT
Surgical Therapy
When polyposis is severe or significant symptoms are apparent,
prophylactic colectomy with IRA may be considered for suitable
surgical candidates. Although rectal polyposis can generally be
managed with rigid or flexible proctoscopy, IPAA may be consid-
ered if the polyposis is extensive. Continued annual surveillance
of the rectal remnant (after IRA) or the ileal pouch (after IPAA)
is required initially. Surveillance intervals may be increased to 3
years if subsequent evaluations find no evidence of disease.1,85

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