Acs0514 Hereditary Colorectal Cancer And Polyposis Syndromes 2005

© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
5 Gastrointestinal Tract and Abdomen 14 Hereditary Colorectal Cancer and Polyposis Syndromes — 1

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


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 pliance9 and may be associated with signiﬁcant side effects.
for primary treatment of FAP is not recommended.11 In a ran- Chemopreventive agents may be useful for reducing polyp load
domized, placebo-controlled, double-blind study of genotype- and facilitating endoscopic management of polyps in patients who
positive, phenotype-negative patients, the use of sulindac had no have an ileal pouch or in patients who have an iliorectal anasto-
effect on the subsequent development of colorectal polyposis.12 mosis, are at high risk for polyp development, and refuse proctec-
Furthermore, the development of rectal cancer has been reported tomy. In such cases, however, it is still necessary to perform care-
in patients whose rectal polyps were effectively controlled with ful surveillance of the residual rectum or the ileoanal pouch every
sulindac.10 Finally, these medications necessitate continued com- 6 months.11


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

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


complete anal mucosectomy or stapled to a 1 to 2 cm anal transi- going a subsequent completion proctectomy after an initial IRA.11
tion zone. Neoplasia may occur at the site of the anastomosis, and This possibility should be considered in making the choice between
the incidence appears to be higher after stapled anastomosis (28% IRA and IPAA as the initial procedure for FAP.
to 31%) than after mucosectomy and handsewn anastomosis
(10% to 14%).18,19 Function, however, may be better after stapled Medical therapy. When desmoid tumors are clinically inert,
anastomosis.19 In the case of anal transition zone neoplasia after they may be treated with sulindac.11 Tamoxifen or other antiestro-
stapled anastomosis, transanal mucosectomy can often be per- gens may be added for slow-growing or mildly symptomatic
formed, followed by advancement of the pouch to the dentate line. tumors.11,31,32 More aggressive desmoid tumors may be treated
Of additional concern is the development of adenomatous polyps with chemotherapy. Vinblastin and methotrexate achieve some
in the ileal pouch itself, which occurs in 35% to 42% of patients degree of response in 40% to 50% of patients.33 For more rapidly
at 7 to 10 years.20-22 growing desmoids, antisarcoma agents, such as doxorubicin and
With respect to postoperative bowel function and associated dacarbazine, may be administered.34,35 Radiation therapy may also
quality of life, IPAA has been associated with a higher frequency be effective, but it can result in substantial small bowel morbidity.
of both daytime and nocturnal bowel movements, a higher inci-
dence of passive incontinence and incidental soiling, and higher Surgical therapy. Surgical treatment of intra-abdominal
postoperative morbidity than IRA.23 Accordingly, some authors desmoid tumors should be reserved for small, well-defined lesions
recommend IRA for patients with mild rectal polyposis. Other with clear margins.11 When intra-abdominal desmoids involve the
authors, however, have found the two approaches to be equivalent small bowel mesentery, they should be treated according to their
in terms of functional results24 and quality of life25 and therefore initial presentation and rate of growth. In patients with desmoid
recommend IPAA for most patients because of the risk of rectal lesions that are refractory to all medical treatment and call for sur-
cancer associated with IRA. gical treatment with extensive small bowel resection, small bowel
Regardless of which procedure is performed, however, lifetime transplantation may be feasible in selected cases.36
surveillance of the rectal remnant (after IRA) or the ileal pouch
(after IPAA) is required.11 Endoscopic surveillance of the bowel at Periampullary neoplasms In approximately 80% to 90%
intervals of 6 months to 1 year after index surgery is recommend- of persons with FAP, duodenal adenomas, periampullary adeno-
ed.5,11 After IRA, small (< 5 mm) adenomas may be safely mas, or both will develop.37 Of these patients, 14% to 50% will
observed, with biopsy performed to rule out severe dysplasia. If eventually exhibit advanced polyposis, and as many as 6% will
adenomas increase in number, the frequency of surveillance eventually have invasive cancer.1,38-42 Although the risk of peri-
should be increased, and polyps larger than 5 mm should be ampullary or duodenal cancer in FAP patients is relatively low, it
removed. When fulguration and polypectomy are repeated over a is still several hundred times higher than that in the general popu-
period of many years, subsequent polypectomy may become diffi- lation. Among FAP patients, those with APC mutations between
cult, rectal compliance may be reduced, and flat cancers may be codons 976 and 1067 appear to have the highest incidence of duo-
hard to identify against a background of scar tissue. The develop- denal adenoma.
ment of severe dysplasia or a villous adenoma larger than 1 cm is Surveillance should begin with side-viewing esophagogastro-
an indication for proctectomy.11 duodenoscopy (EGD) and biopsy of suspicious polyps either at
the age of 20 years or at the time of prophylactic colectomy,
Extracolonic Disease whichever is earlier.11 The purpose of screening is not to remove
After total abdominal colectomy with IRA and regular surveil- all disease but to watch for the development of high-grade dyspla-
lance, the risk of death appears to be three times higher for FAP sia. Small, tubular adenomas without high-grade dysplasia may be
patients than for an age- and sex-matched control population.26 biopsied and observed; adenomas that are larger than 1 cm or that
The main causes of death after IRA are desmoid disease and exhibit high-grade dysplasia, villous changes, or ulceration should
upper gastrointestinal malignancy. be removed. Surgical options include endoscopic removal and
transduodenal excision, but both approaches have drawbacks:
Desmoid disease Desmoids are histologically benign endoscopic ablation generally requires multiple settings,38 and
tumors that arise from fibroaponeurotic tissue and occur in 12% recurrence is high after either procedure.38,43 Endoscopic ablation
to 17% of FAP patients.11,27,28 Unlike those in the general popula- is a reasonable initial approach for most patients without invasive
tion, desmoids in FAP patients tend to be intra-abdominal (up to cancer and is an attractive alternative for patients who are unfit for
80% of cases) and mainly occur after abdominal surgical proce- duodenal resection. For patients with persistent or recurrent high-
dures.27,28 Patients with APC mutations located between codons grade dysplasia in the papilla or duodenal adenomas and for
1310 and 2011 are at increased risk for these tumors.29 Desmoids patients with Spigelman stage IV disease, pancreas-preserving
often involve the small bowel mesentery (> 50% of cases),28 mak- duodenectomy or pancreaticoduodenectomy is recommended.11
ing complete resection difficult or impossible, and they may also The results reported for duodenal resection in patients with pre-
involve the ureters.27 Not uncommonly, patients present with malignant lesions are encouraging, with good local control and
small bowel obstruction.27,28 Morbidity after attempted resection, low morbidity.38,44,45 Duodenectomy also greatly reduces the need
which often involves removal of a significant length of small bowel, for upper GI surveillance.
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 Hereditary Nonpolyposis Colorectal Cancer
Intra-abdominal desmoid formation may be more common HNPCC, which accounts for 5% to 7% of CRCs, results from
after IRA than after IPAA, and the disease may be more severe a mutation in one of the DNA mismatch repair (MMR) genes
after IRA as well.28,30 When desmoid tumors involve the small (MLH1, MSH2, MSH6, PMS1, PMS2, MLH3, and MSH3).46,47
bowel mesentery, the mesentery may become foreshortened and Two genes (MLH1, MSH2) may be responsible for as many as
thereby render IPAA impracticable, especially in patients under- 90% of causative germline MMR mutations. However, only 50%


to 70% of patients meeting clinical criteria for HNPCC have an Table 3 Clinical Criteria for Diagnosis of HNPCC
identifiable germline MMR mutation, which suggests that one or
more unidentified genes may be involved. A significant percentage
Three or more relatives with CRC
of cases may be attributable to large germline deletions that are
One first-degree relative of the other two
difficult to detect by means of direct sequencing. It appears that Amsterdam criteria I
50
One CRC diagnosed at age < 50 yr
genomic deletions may account for as many as 7% of HNPCC Two or more successive generations
cases defined on the basis of clinical criteria.48 FAP excluded

CLINICAL EVALUATION Three or more relatives with an HNPCC-associated
cancer (in colorectum, endometrium, small bowel,
HNPCC is characterized by early-onset CRC, a predominance ureter, or renal pelvis)
51
of lesions proximal to the splenic flexure (60% to 70% of cases), Amsterdam criteria II One first-degree relative of the other two
benign and malignant extracolonic tumors, and a predilection for Two or more successive generations
synchronous and metachronous colorectal tumors.4 Microsatellite One CRC diagnosed at age < 50 yr
instability (MSI), reflecting a deficiency in DNA repair secondary FAP excluded
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 surement of CA125 levels starting at 25 to 35 years of age, as well
Establishing a clinical diagnosis of HNPCC is much more chal- as annual endometrial aspiration.56 Annual EGD is recommend-
lenging than establishing a clinical diagnosis of FAP, in that it ed for patients belonging to kindreds with a history of gastric can-
requires a careful and detailed family history. The Amsterdam II cer. Finally, ultrasonography and urine cytology every 1 to 2 years
criteria [see Table 3] require that there be three relatives (of which may be considered to screen for urinary tract malignancy.
one must be a first-degree relative of the other two) with an
MANAGEMENT
HNPCC-related cancer (of the colorectum, the endometrium, the
small bowel, the ureter, or the renal pelvis), that two or more suc-
Surgical Therapy
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 Although the development of CRC in persons with HNPCC is
excluded. CRC occurs in 78% to 80% of MMR mutation–posi- not a certainty, the 80% lifetime risk,1 the 45% rate of metachro-
tive patients at a mean age of 46 years.1,49,52 Endometrial cancer nous tumors, and the possibility of an accelerated adenoma-carci-
occurs in 43%, gastric cancer in 19%, urinary tract cancer in 18%, noma sequence4 mandate consideration of prophylactic surgical
and ovarian cancer in 9%.53 options. Patients who have HNPCC as defined by their genotype
or the Amsterdam criteria [see Table 3] and who have a colon can-
INVESTIGATIVE STUDIES cer or more than one advanced adenoma should be offered either
(1) prophylactic total abdominal colectomy with IRA or (2) seg-
Pathologic Findings mental colectomy with yearly colonoscopy [see 5:34 Segmental Colon
Adenomas in HNPCC patients show high-grade dysplasia and Resection].11,57,58 (The first option, however, is open only to
villous changes more frequently than adenomas in sporadic CRC patients with normal rectal and anal sphincter function.) Although
patients.1 Adenomas may also appear at an earlier age and are the risk of metachronous colon cancers may be higher after partial
often larger than those found in the general population. Other colectomy than after total colectomy with IRA, intensive colono-
pathologic features reported to be more common in HNPCC- scopic surveillance and polypectomy may minimize the number of
related cancers include a mucinous or poorly differentiated histol- metachronous cancers in the remaining colon.52,59 Careful surveil-
ogy, a solid or cribriform growth pattern, signet-ring cell tumors, lance is also necessary after total colectomy and IRA, given that
and the presence of tumor-infiltrating and peritumoral lympho- the risk of metachronous rectal cancer after total colectomy is
cytes. HNPCC-related CRCs have also been shown to have a approximately 12% at 10 to 12 years.60
lower rate of lymph node involvement.54 HNPCC patients with an index rectal cancer that is amenable
to a sphincter-preserving resection should be offered either (1)
Screening and Surveillance total proctocolectomy with IPAA [see 5:33 Procedures for Ulcerative
CRC patients who belong to known HNPCC kindreds, who Colitis] or (2) low anterior resection (LAR) with primary recon-
have a pedigree suggestive of HNPCC, or who meet the Bethesda struction [see 5:35 Procedures for Rectal Cancer].11,58 The rationale
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 Table 4 Revised Bethesda Guidelines for
undergo testing for germline MMR mutations (tests for MSH2 Testing CRC Patients for MSI55
and MLH1 are available commercially [see Table 2]). If tumor tis-
CRC diagnosed at age < 50 yr
sue is not available, initial germline testing may be considered. As Presence of synchronous or metachronous CRC or other HNPCC
in FAP, a mutation in an affected individual must first be estab- tumors (regardless of age)
lished for testing in at-risk individuals to be informative.5 CRC with HNPCC-like histology at age < 60 yr
Recommended surveillance for HNPCC includes colonoscopy, CRC in one or more FDR with an HNPCC-related tumor (one diagnosed
at age < 50 yr)
initially every 1 to 2 years beginning at the age of 20 to 25, then
CRC in two or more first- or second-degree relatives with HNPCC-
annually after the age of 40.56 Given the increasing evidence of an related tumors (regardless of age)
accelerated adenoma-carcinoma sequence in HNPCC, annual
colonoscopy should be strongly considered.4 Female patients FDR—first-degree relative
should undergo annual transvaginal ultrasonography and mea-


for total proctocolectomy is based on the 17% to 45% rate of a multifunctional serine-threonine kinase, is thought to function
metachronous cancer in the remaining colon associated with an as a tumor suppressor gene.69-72 Germline mutations in
index rectal cancer in HNPCC patients.61 The decision between LKB1/STK11 can be demonstrated in 18% to 63% of PJS
the two procedures depends in part on the patient’s willingness to patients, which suggests the existence of additional PJS loci.72-75
undergo intensive surveillance of the retained proximal colon, as Genetic testing for PJS can be accomplished through direct
well as on the level of bowel function. sequencing of the LKB1/STK11 gene [see Table 2]; however, such
Mutation-positive patients with a normal colorectum may also testing is not widely available. In families with an established
be offered prophylactic colectomy in selected cases.56,62 This mutation, genetic testing of at-risk individuals is informative, with
approach is supported by the similarity of lifetime cancer risk a reported accuracy of 95%.76
between patients with germline APC mutations and those with
CLINICAL EVALUATION
MMR mutations, as well as by the observation that total abdomi-
nal colectomy with IRA yields less functional disturbance than the PJS is a hereditary polyposis syndrome characterized by hamar-
prophylactic procedure recommended for FAP (total proctocolec- tomas of the GI tract, as well as by mucocutaneous melanin pig-
tomy with IPAA).56,62 An alternative strategy in these patients is to mentation. Hamartomatous polyps may occur throughout the GI
carry out colonoscopic surveillance at 1- to 3-year intervals. This tract but are most frequently found in the small intestine (90%).
strategy has proved to be cost-effective63 and to reduce both the Other common sites of hamartomas in PJS are the large intestine
rate of CRC development and overall mortality.52,64,65 There is a (50%) and the stomach; less common sites are the renal pelvis,
risk that CRC may develop in the intervals between colonos- the bile ducts, the urinary bladder, the lungs, and the nasophar-
copies64,66; however, when the surveillance interval is shorter than ynx.1,77,78 Mucocutaneous pigmentation generally appears during
2 years, tumors tend to be found in their early stages and to be cur- infancy.The perioral and buccal areas are involved in 95% of cases;
able when found.52,64 the periorbital and facial areas, the genital region, and the acral
A study using a decision-analysis model suggested that prophy- areas (including the hands and feet) may be involved as well.1 The
lactic total abdominal colectomy at the age of 25 might offer a sur- average age of diagnosis of PJS is 22 years in men and 26 years in
vival benefit of 1.8 years when compared with colonoscopic sur- women.
veillance. The benefit of prophylactic colectomy decreased when In as many as 86% of cases, the initial presentation of PJS is
surgery was delayed until later in life and became negligible when small bowel obstruction secondary to intussusception of hamar-
it was performed at the time of cancer development.65 However, tomas. Other presentations include acute or chronic GI bleeding,
surveillance provided a greater benefit with respect to quality of biliary and gastric outlet obstruction, and anal protrusion of
life (measured in quality-adjusted life years).65 On the basis of this polyps. The diagnosis of PJS is established by the presence of his-
evidence, some surgeons recommend that prophylactic colectomy tologically confirmed hamartomas of the GI tract plus two of the
be performed only in highly selected situations (e.g., when colono- following three criteria: (1) small bowel polyposis, (2) mucocuta-
scopic surveillance is not technically possible or when a patient neous melanotic pigmentation, and (3) a family history of PJS [see
refuses to undergo regular surveillance). Thus, the decision Table 1].79
between prophylactic surgery and surveillance for gene-positive Patients with PJS are at significantly increased risk for both
unaffected patients is based on many factors, including the pene- intestinal and extraintestinal malignancies. A meta-analysis found
trance of disease in a family, the age of cancer onset in family that in comparison with the general population, PJS patients were
members, functional and quality-of-life considerations, and the at a relative risk of 15.2 for the development of any malignancy.80
likelihood of patient compliance with surveillance. The relative risks for the development of specific cancers were as
follows: small bowel, 520; gastric, 213; pancreatic, 132; colorectal,
Extracolonic Disease 84; esophageal, 57; ovarian, 27; lung, 17; endometrial, 16; and
Management of extracolonic cancers in HNPCC patients is not breast, 15.The cumulative risk for the development of any cancer
yet well defined. Female patients with a family history of uterine between the ages of 15 and 64 was 93%.80 Other cancers associ-
cancer should be offered prophylactic total abdominal hysterecto- ated with PJS are cholangiocarcinomas, testicular neoplasms, and
my (TAH) if their childbearing is complete or if they are under- duodenal tumors.1
going abdominal surgery for other conditions.11 This recommen- Although the relative risk for the development of CRC was high
dation is based on the high (43%) rate of endometrial cancer in in this study,80 the reported magnitude of risk in the individual
mutation-positive persons,53 particularly those with hMSH2 studies included in the meta-analysis varied considerably. Previous
mutations, and on the inefficacy of screening in some studies.67 studies also reported a wide range of CRC incidences in these
Oophorectomy should be added to TAH because of the high (9%) patients.1 Thus, the true incidence of CRC in PJS patients remains
incidence of ovarian cancer in HNPCC patients53 and the fre- unclear.
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 Pathologic Findings
at the age of 25 and delay prophylactic surgery until childbearing The polyps seen in PJS are hamartomas characterized by hyper-
is complete.11 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
Peutz-Jeghers Syndrome as arborization). Epithelial cells may become entrapped within the
Like FAP and HNPCC, PJS follows an autosomal dominant muscle layer, and this “pseudoinvasion” can be mistaken for
pattern of inheritance with variable penetrance. It is caused in part malignant transformation.Therefore, to diagnose a malignancy in
by mutations in the gene LKB1/STK11, which maps to the telo- a PJS polyp, cellular atypia or an elevated mitotic rate must be
meric region of chromosome 19p13.3.This gene, which codes for documented.81 Sporadic PJS polyps do occur, generally secondary


to somatic LKB1/STK11 mutations in one or both alleles, and are positive is unclear. Because the true risk of CRC in these patients
histologically identical to their hereditary counterparts.These spo- is unknown and genetic testing for PJS is not widely available, no
radic polyps appear not to be associated with an increased risk of recommendations can be made at present regarding the role of
GI cancer.82 prophylactic colectomy in the PJS population.88
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 Juvenile Polyposis Syndrome
do not appear to have any malignant potential. Initial evidence suggested that mutations in the PTEN gene
were responsible for JPS90; however, subsequent evidence impli-
Screening and Surveillance cated SMAD4/DPC4 at 18q21.1 as a more common cause,
Clinical screening of asymptomatic persons is facilitated by the accounting for as many as 50% of familial cases.91-93 Mutations in
appearance of perioral hyperpigmentation during early childhood. BMPR1A at 10q22–q23 have also been reported to cause JPS but
Once the diagnosis of PJS is made, patients generally enter a sur- display variable penetrance [see Table 2].94,95 Clonal genetic alter-
veillance program. Recommended surveillance for GI disease ations are detected in stromal rather than epithelial cells, which
includes annual serum hemoglobin measurement and EGD every suggests that the genetic changes in juvenile polyps originate in the
2 to 3 years, beginning between the ages of 10 and 25.79,83-85 nonepithelial component of the polyps.
Contrast radiography is employed to examine the remainder of the
CLINICAL EVALUATION
small bowel, beginning at the age of 10 and repeated every 2 to 3
years.79,85 The frequency of surveillance examinations may be Like PJS, JPS is characterized by the development of multiple
modified in individual circumstances. Colonoscopic surveillance is hamartomas throughout the GI tract. Isolated juvenile polyps are
also important, commencing between puberty and the age of 25 common in children and are found in approximately 1% of per-
and repeated every 2 to 3 years.83,85 Sigmoidoscopy should not be sons younger than 21 years. Juvenile polyposis, however, is much
employed for surveillance, because the rectum may be spared in less common. A family history of juvenile polyposis is present in
some patients with more proximal disease. Organ-specific surveil- 20% to 50% of patients.1 Although JPS is an autosomal dominant
lance for other associated malignancies should also be initiated in disorder, its variable penetrance results in a less obvious pattern of
accordance with current high-risk recommendations. inheritance than is seen with FAP or HNPCC.
JPS affects the two sexes equally and generally manifests itself
MANAGEMENT
during the first or second decade of life (mean age at diagnosis,
18.5 years).1 Common presenting symptoms include chronic ane-
Medical Therapy mia, acute GI bleeding, prolapse of rectal polyps, protein-losing
Cyclooxygenase-2 (COX-2) is known to be overexpressed in the enteropathy, and intussusception with or without obstruction.1
hamartomatous tissue of PJS patients, and there is a correlation Extracolonic manifestations of JPS include gastroduodenal and
between expression of the COX-2 protein and expression of the small bowel polyps, malrotation of the midgut, and mesenteric
LKB1/STK11 protein in PJS polyps and cancers.86,87 These find- lymphangiomas. Extraintestinal manifestations include clubbing,
ings suggest that COX-2 may be a potential target for chemopre- hypertrophic pulmonary osteoarthropathy, hydrocephalus and
vention of PJS. macrocephaly, alopecia, cleft lip and palate abnormalities, super-
numerary teeth, porphyria, congenital cardiac and arteriovenous
Surgical Therapy malformations, psoriasis, vitellointestinal duct abnormalities, renal
Indications for surgical management of PJS include the pres- structural abnormalities, and bifid uterus and vagina. JPS is also
ence of polyps larger than 1.5 cm that cannot be removed endo- part of the phenotype for Ruvalcaba-Myhre-Smith syndrome and
scopically, incomplete removal of polyps with adenomatous Gorlin syndrome. Cowden disease, which is characterized by
changes, the development of polyp-associated complications (e.g., hamartomatous polyposis and is associated with breast and thyroid
obstruction, intussusception, and bleeding), and the management cancer, may be a phenotypic variant of JPS.1,95
of malignant disease.88 The diagnostic criteria for JPS are as follows: (1) the presence of
Endoscopic polypectomy is generally employed as initial thera- three or more juvenile polyps of the colon; (2) the presence of juve-
py when it is technically feasible. For some polyps, however, oper- nile polyps throughout the entire GI tract; or (3) the presence of
ative polypectomy performed through an enterotomy is required. any number of polyps in a patient with known family history of JPS
Segmental resection should be avoided. In the context of a laparo- [see Table 1].85 The clinical presentation of JPS can be divided into
tomy, intraoperative endoscopy (either peroral or via an enteroto- three main clinical variants: (1) JPS of infancy, which is a non–sex-
my) allows direct visualization of the remainder of the small bowel linked recessive condition characterized by failure to thrive, sus-
and endoscopic clearance of any synchronous polyps. This proce- ceptibility to infections, protein-losing enteropathy, bleeding, diar-
dure significantly reduces the need for subsequent laparotomy. rhea, rectal prolapse, intussusception, and death by the age of 2
The St. Mark’s Hospital group in London found that none of 25 years in severe cases; (2) generalized JPS, which occurs in the first
patients who underwent enteroscopy during laparotomy required decade of life and is characterized by juvenile polyps throughout
subsequent laparotomy within a 4-year period, whereas 17% of the GI tract; and (3) JPS of the colon, the most common presen-
historical control patients who did not undergo intraoperative tation, which is characterized by colonic polyposis only.1
enteroscopy required repeat laparotomy within a 1-year period.89 Patients with JPS appear to be at increased risk for GI malig-
Laparoscopy-assisted polypectomy and laparoscopic manage- nancies, especially CRC. One study estimated the risk of CRC to
ment of small bowel intussusception are additional surgical be 15% by age 35 and 68% by age 65.96 In another study, GI
options. malignancies (mostly CRC) were diagnosed in 36 (17%) of 218
Given the risk of CRC development in PJS patients, careful JPS patients at a mean age of 33 years.97 Associated gastric, pan-
colonoscopic surveillance is clearly warranted. However, the role of creatic, and duodenal cancers have also been reported. CRCs are
prophylactic colectomy in patients who are at risk or are mutation thought to arise from malignant transformation of dysplastic


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

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