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Hereditary Colorectal Cancer-Part II
Lynch Syndrome
There are 2 broad classes of hereditary forms of colorectal cancer
(CRC), based on the predominant anatomic location of the CRC: distal
versus proximal. CRCs involving the distal colon are more likely to show
aneuploid DNA content, harbor mutations in APC, p53, and K-ras genes,
and behave more aggressively303,304; proximal CRCs are more likely to
show diploid DNA, possess microsatellite instability, harbor mutations in
the mismatch repair (MMR) genes, and behave less aggressively, as in
hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome.303,304 Familial adenomatous polyposis (FAP) and most sporadic
cases may be considered a paradigm for the first, or distal, CRC class,
whereas Lynch syndrome more clearly represents the second, or proximal, CRC class.303,304
The term Lynch syndrome is used in preference to HNPCC, given the
fact that the syndrome’s phenotype is not completely without polyps, and
in addition to CRC it involves a litany of extracolonic cancer types that
are integral to the syndrome. It is the most commonly occurring
hereditary syndrome that predisposes to CRC304 (Fig 2; Part I). Its
diagnosis requires a sufficiently detailed family history of colorectal
carcinoma as well as cancer of all anatomic sites, particularly those that
are integral to this disorder (e.g., carcinoma of the endometrium [the
second most common cancer], ovary, stomach [particularly in families
from Japan and Korea],305 hepatobiliary tract, small bowel, pancreas,
upper uroepithelial tract, and brain).303,304,306,307
History of Lynch Syndrome
The history of what is known as Lynch syndrome dates to an
observation of Aldred Warthin, pathologist at the University of Michigan
School of Medicine.308 He became deeply moved when his seamstress, in
1895, told him that she would likely die of cancer of the colon, stomach,
or her female organs, because of the enormous proclivity to these cancers
in her family (unfortunately, just as she had told Warthin, she died at a
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young age of metastatic endometrial carcinoma). Warthin listened intently, developed her pedigree, and along with other similar cancer prone
families published this work in 1913.309 Warthin updated the family’s
history in 1925.310 The seamstress’s family has since been known as
Family G.
Lynch and colleagues311 described the natural history and genetics of 2
large Midwestern kindreds (Families N and M) in 1966. Dr. A. James
French, Warthin’s successor as chairman of pathology at the University of
Michigan, heard about Lynch’s research on Families N and M, and
recalled that Warthin, his predecessor, had discovered a similar family
(Family G) in 1895. Lynch was then invited by French to take custody of
all the detailed documents and pathology specimens that the meticulous
Warthin had investigated, catalogued, and published over a span of more
than 30 years.309,310 The history of Family G was then updated and
published in 1971.312 This material is discussed in a more detailed review
of the history of HNPCC.313 Through the use of conversion technology,
an MSH2 mutation was identified in Family G in the year 2000.314 Table
7 summarizes the important points in the history of HNPCC.
Clinical Features and Diagnostic Criteria
The cardinal clinical features of the Lynch syndrome are listed in Table
8 and are discussed in more detail in other review articles.303,304,315
Several international diagnostic criteria for the Lynch syndrome have
been developed, the foremost being the Amsterdam I,316 Amsterdam
II,317 and the Bethesda Guidelines.318 The variety of criteria that have
been developed for the syndrome testifies to its complexity. The original
Amsterdam I criteria were developed for the purpose of consistent
classification of subjects in research programs and focused on CRC
(Table 9). The subsequent Amsterdam II criteria added the syndrome’s
integral extracolonic cancers to the focus to be more useful for clinical
diagnosis purposes. The Bethesda Guidelines introduced molecular genetic considerations, linking the diagnostic criteria of the Lynch syndrome to the high percentage of Lynch syndrome tumors that are positive
for microsatellite instability (MSI), to provide guidelines for MSI testing.
Other criteria, such as those developed in Korea and Japan, make use of
emerging knowledge regarding the syndrome’s phenotypic variability in
different geographic regions. These criteria are based heavily on the
family history, which we consider to be potentially the most costbeneficial component of a patient’s medical evaluation; however, we are
also cognizant of the fact that it remains 1 of the most neglected portions
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TABLE 7. Landmarks of Lynch syndrome history*
Feature
First
report
References
Family G of Warthin (study began 1895)
Genetic counseling
First report of Lynch et al. on Families N and M
Early age of cancer onset
Autosomal dominant inheritance pattern
Family information session (FIS)
Screening recommendations
Update of Family G
Proximal colon involvement
Beginning of study of Lynch syndrome in Uruguay
Recommendation of prophylactic TAH-BSO
Muir-Torre syndrome (as variant of Lynch syndrome)
Increased incidence of synchronous and metachronous CRC
Lynch syndrome studies begin with the Navajo
Tritiated thymidine distribution studies of rectal mucosa
HNPCC named “Lynch syndrome”
Selenium levels in Lynch syndrome studied
Formation of ICG-HNPCC
Lectin binding studies in FAP and HNPCC
Amsterdam I criteria
Accelerated carcinogenesis and interval CRC
1913
1965
1966
1966
1966
1966
1967
1971
1977
1977
1978
1980
1982
1983
1983
1984
1984
1989
1990
1991
1992
First cancer susceptibility locus found on 2p through linkage
analysis
Second cancer susceptibility locus found on 3p through linkage
analysis
DNA mismatch repair genes reported
1993
309
582, 583
311
311
311
311, 584, 585
586
312
376
587
588
382, 589
377, 378
590–592
593
594
595
317, 596
597–599
316
365, 395, 396,
600, 601
326
1993
327
1993
RER⫹ (MSI) phenotype described
Germline mutations in the syndrome
MSH2 mutation identified
Extracolonic adenocarcinomas
Distinctive pathology features
MSH2; MLH1 mutations
Creighton group’s involvement in Uruguayan study
Historical perspective through 1995
Role of DNA MMR genes in CRC tumorigenesis
Recommendations of prophylactic subtotal colectomy
Survival advantage
NIH NCI workshop on HNPCC (Bethesda Guidelines)
MSH6 mutation
NIH NCI update on MSI
Small bowel involvement
Founder mutation in Finland
Amsterdam II criteria
Tumor infiltrating lymphocytes and their association with MSI
Conversion technology
1993
1993
1993
1994
1994
1994
1995
1995
1995
1996
1996
1996
1997
1997
1998
1998
1999
1999
2000
328, 329, 334,
335
322
328
329
307
365
329, 335
602
603
604, 605
391, 392
374, 379
318
347, 606
607
608
356
317
380
314
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TABLE 7. Continued
Feature
A complex mutation of MLH1 at codon 222 is associated with
adolescent onset of CRC (more early-onset CRC families
needed for study)
Fluorouracil-based adjuvant chemotherapy benefits patients
with stage II or stage III CRC with MSS or MSI-L tumors but
not those with MSI-H tumors
H2O2 effect improves survival in DNA MMR-deficient cell line
MSH2 del1-6 founder mutation in the United States
First
report
References
2001
609
2003
610
2003
2004
611
315
*Reproduced from Lynch HT, Shaw TG, Lynch JF. Inherited predisposition to cancer a historical
overview. Am J Med Genet C (Semin Med Genet) 2004;129C:5–22.
Abbreviations: CRC, colorectal cancer; HNPCC, hereditary nonpolyposis colorectal cancer;
TAH-BSO, total abdominal hysterectomy and bilateral salpingo-oophorectomy; ICGHNPCC, International Collaborative Group on HNPCC; FAP, familial adenomatous polyposis; MMR, mismatch repair; NIH, National Institutes of Health; NCI, National Cancer
Institute; MSI, Microsatellite instability; MSS, Microsatellite stable.
TABLE 8. Cardinal features of Lynch syndrome
● Earlier average age of CRC onset than in the general population; the average age of CRC
onset in HNPCC is ⬃45 years, whereas the average age of onset in sporadic CRC is
⬃63 years
● Proximal colon involvement (70% of CRCs arise proximal to the splenic flexure)
● A significant excess of synchronous and metachronous CRCs (⬃25% to 30% among
patients having a second primary CRC within 10 years of surgical resection for initial
CRC, if the operation was anything less than a subtotal colectomy)
● Autosomal dominant inheritance pattern
● Increased risk for malignancy at certain extracolonic sites, foremost of which is
endometrial carcinoma, followed by carcinoma of the ovary, stomach, small bowel,
hepatobiliary tract, pancreas, upper uroepithelial tract, and brain
● CRC tumors in HNPCC are more often poorly differentiated, with an excess of mucoid and
signet-cell features, show a Crohn’s-like reaction, and contain a significant excess of
infiltrating lymphocytes within the tumor. Microsatellite instability (MSI) is found in most
CRC tumors in the Lynch syndrome
● Increased survival from CRC
● Accelerated carcinogenesis and interval CRC; a tiny adenoma may emerge into a
carcinoma within 2–3 years, as opposed to 8–10 years in the general population
● Sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas in the
Muir-Torre syndrome (MTS) variant of Lynch syndrome
● The sine qua non, the identification of a germline MMR mutation segregating with
syndrome-affected individuals in the family
Abbreviations: HNPCC, hereditary nonpolyposis colorectal cancer; CRC, colorectal cancer;
MMR, mismatch repair.
of a cancer patient’s medical evaluation in the average clinical practice
setting.319,320
Differing stages in the development of a Lynch syndrome pedigree
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TABLE 9. Amsterdam I and Amsterdam II criteria and Bethesda Guidelines
Amsterdam I criteria316
At least 3 relatives with histologically verified colorectal cancer:
1. One is a first degree relative of the other 2
2. At least 2 successive generations affected
3. At least 1 of the relatives with colorectal cancer diagnosed at less than 50 years of
age
4. Familial adenomatous polyposis has been excluded
Amsterdam II criteria317
At least 3 relatives with an hereditary nonpolyposis colorectal cancer-associated cancer
(colorectal cancer, endometrial, stomach, ovary, ureter/renal pelvis, brain, small
bowel, hepatobiliary tract, and skin [sebaceous tumors]):
1. One is a first degree relative of the other 2
2. At least 2 successive generations affected
3. At least 1 of the hereditary nonpolyposis colorectal cancer-associated cancers
should be diagnosed at less than 50 years of age
4. Familial adenomatous polyposis should be excluded in any colorectal cancer cases
Tumors should be verified whenever possible.
Bethesda Guidelines for testing of colorectal tumors for microsatellite instability318
1. Individuals with cancer in families that meet the Amsterdam criteria
2. Individuals with 2 HNPCC-related cancers, including synchronous and metachronous
colorectal cancers or associated extracolonic cancers*
3. Individuals with colorectal cancer and a first degree relative with colorectal cancer
and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; 1 of the
cancers diagnosed at age less than 45 years and the adenoma diagnosed at age
less than 40 years
4. Individuals with colorectal cancer or endometrial cancer diagnosed at age less than
45 years
5. Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/
cribiform) on histopathology diagnosed at age less than 45 years†
6. Individuals with signet-ring-cell-type colorectal cancer diagnosed at age less than 45
years‡
7. Individuals with adenomas diagnosed at age less than 40 years
*Endometrial, ovarian, gastric, hepatobiliary, or small-bowel cancer or transitional cell
carcinoma of the renal pelvis or ureter.
†Solid/cribiform defined as poorly differentiated or undifferentiated carcinoma composed of
irregular, solid sheets of large eosinophilic cells and containing small gland-like spaces.
‡Composed of more than 50% signet ring cells.
wherein each component provides a pictorial review of its genesis are
shown in Figure 16. For example, note that the proband had multiple
primary cancers at an early age (Panel A), which should provide the
clinician with vital clues of the possibility of the Lynch syndrome. This
much information does not fulfill any of the criteria in Table 9, yet we
believe the information is sufficient to test for a mismatch repair gene
(MMR) germline mutation. However, when the pedigree is further
extended, it essentially epitomizes an HNPCC diagnosis (Panels B and
C), and when extended even further, as shown in Panel D, it essentially
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FIG 16. Four stages of a pedigree. (Reproduced with permission from Lynch HT, de la Chapelle A. Hereditary
colorectal cancer. N Engl J Med 2003;348:919-32.) A) The initial ascertainment of what turned out to be a
classical hereditary nonpolyposis colorectal cancer pedigree. The proband (IV-1) showed early-onset colorectal
carcinoma and carcinoma of the ureter. These findings by themselves are highly significant. However, his
mother (III-1) had uterine cervical carcinoma at age 37, a tumor not associated with the syndrome, but at age
55 had colorectal carcinoma. B) Further inquiry indicated that the proband’s mother (III-1) had 2 sisters with
endometrial carcinoma at ages 57 (III-2) and 61 (III-3). This pattern, notwithstanding Amsterdam criteria, would
be sufficient for a hereditary nonpolyposis colorectal cancer diagnosis. C) Extending the pedigree further, 1 of
these maternal aunts (III-2) had 3 cancer-affected sons, 1 with early-onset metachronous colon cancer (IV-3), a
second with colon cancer and carcinoma of the ureter (IV-4), and the other with colon cancer only (IV-5). The
other aunt (III-3) had a daughter (IV-6) with cancer of the bile duct. These findings provide strong evidence for
the diagnosis of hereditary nonpolyposis colorectal cancer. D) The fully extended pedigree, with findings
continuing to support a diagnosis of hereditary nonpolyposis colorectal cancer.
evolves into highly detailed information that is used for research
purposes. The extended pedigree is also valuable for identifying other
family members at risk for developing HNPCC and its related extracolonic cancers.
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FIG 17. The necessary information on first and second degree relatives, which will aid significantly
in hereditary cancer syndrome diagnosis.
From a practical standpoint, the clinician does not need to go into this
much depth to diagnose the Lynch syndrome. We believe that the
modified nuclear pedigree (Fig 17), wherein attention is given to a
detailed description of the proband, with pathologic documentation of
cancer, and is extended to that individual’s primary relatives (parents,
siblings, and progeny), and then to secondary relatives (maternal and
paternal aunts and uncles, and both sets of grandparents), who will be
highly genetically informative because they have passed through the
cancer risk age, will, in most cases, provide enough information to
diagnose the Lynch syndrome, should it be present in the family. The sine
qua non for this diagnosis will be the presence of a germline mutation in
1 of the mismatch repair genes.
Genetics of Lynch Syndrome
Microsatellite Instability. Microsatellite instability (MSI) is a phenomenon observed in some colorectal tumors, especially in patients with
HNPCC. It is present in approximately 90% to 95% of cancers in Lynch
syndrome, and in approximately 15% of sporadic CRCs. When DNA is
amplified using primers derived from highly repetitive DNA sequences,
new alleles frequently appear in tumor DNA relative to normal DNA (Fig
18). These new alleles represent small insertions or deletions as a
consequence of uncorrected errors in DNA replication. In 1 of the first
studies, Thibodeau and colleagues321 found MSI in 25 of 90 (28%)
colorectal cancers, which was more common in proximal versus distal
cancers (P ⫽ 0.003), and these tumors were associated with a better
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FIG 18. Microsatellite instability, as demonstrated in 3 normal (N) and colon tumor (T) tissue pairs
using the dinucleotide repeat marker D3S1029. Note an extra group of bands in each tumor,
representing a new allele (reproduced with permission from Lindblom A, Tannergard P, Werelius B,
Nordenskjold M. Genetic mapping of a second locus predisposing to hereditary non-polyposis colon
cancer. Nat Genet 1993;5:279-82).
prognosis than those without microsatellite instability (P ⫽ 0.02).
Aaltonen and colleagues322,323 found 86% (25 of 29) of HNPCC
colorectal tumors to be replication error positive (RER⫹, synonymous
with MSI) but only 16% (8 of 49) of sporadic colorectal cancers were
RER⫹. This group found that 3% (1 of 33) of sporadic adenomas and
16% (8 of 49) of sporadic carcinomas were RER⫹, whereas 57% (8 of
14) of adenomas from HNPCC patients were RER⫹. This suggested that
adenomatous polyps were precursor lesions to colorectal cancer in
HNPCC.323
MSI in colorectal cancers reminded investigators of abnormalities seen
in DNA mismatch repair genes from yeast cells, where increases or
decreases in the number of repeat units within repetitive DNA sequences
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FIG 19. An overview of DNA mismatch repair enzymes (reproduced with permission from Chung DC,
Rustgi AK. The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implications. Ann Intern Med 2003;138:560-70)576.
result.324 DNA mismatch repair genes in bacteria encode for the enzymes
mutS (which binds to base mismatches), mutH (which binds to methylated CpG nucleotides and cuts the opposite strand), mutL (a facilitator of
mutS and mutH), UvrD (a helicase that excises mismatched strands),
DNA polymerase III holoenzyme (which adds new bases), and DNA
ligase.325 Since yeast lack methylated DNA, they do not have mutH. The
homologous 2 mutL proteins in yeast are PMS1 and MLH1, and the
homologous protein to mutS is MSH2 (Fig 19). When these yeast genes
are mutated, there is a corresponding 100- to 700-fold increase in MSI. It
is believed that these genetic changes lead to errors in the number of
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ase slippage.324 The observation that tumors in patients with Lynch
syndrome had similar changes to those seen in bacterial and yeast cells
with DNA mismatch repair gene mutations led investigators to examine
the human homologs of these genes in HNPCC.
Identification of Lynch Syndrome Genes. In 1993, Peltomäki and
colleagues326 from Finland and Lindblom and colleagues327 from Sweden discovered sites on chromosomes 2p and 3p by linkage analysis,
respectively, as being etiologic for cancer susceptibility in the Lynch
syndrome. Aaltonen and colleagues322 also demonstrated that tumors in
Lynch syndrome were RER⫹.
hMSH2 Gene Mutations. Fischel and colleagues328 identified the mutS
homolog MSH2 in humans (hMSH2) and mapped it to chromosome 2.
They found that 2 of 7 MSI⫹ tumors had point mutations affecting a
splice acceptor site in hMSH2 and that this same mutation was present in
affected members of 2 Lynch syndrome families. The same gene was
identified by Leach and colleagues329 by using a positional cloning
strategy, and a gene homologous to mutS was found to map within an
interval defined by critical recombinants in Lynch syndrome families
linked to a 2p locus. The gene was 2802 bp in length, and a missense
mutation was found in 11 affected members of 1 kindred, a splice site
mutation in another, and a nonsense mutation in another. Both germline
and somatic mutations were found in 1 of 4 RER⫹ sporadic CRC,
suggesting that this gene was a tumor suppressor gene. The important role
of hMSH2 in Lynch syndrome was subsequently confirmed by several
investigators. Nystrom-Lahti and colleagues330 found that 4 of 6 Lynch
syndrome families linked to chromosome 2p had hMSH2 mutations. Liu
and colleagues331 reported that 10 of 25 Lynch syndrome kindreds had
germline hMSH2 mutations, with 9 mutations leading to a truncated
protein. Wijnen and colleagues332 described 7 hMSH2 mutations in 34
Lynch syndrome kindreds leading to protein truncation, and found no
evidence of correlation of genotype with phenotype in Lynch syndrome.
Maliaka and colleagues333 found that 4 of 11 Russian and Moldavian
Lynch syndrome kindreds had hMSH2 mutations.
hMLH1 Gene Mutations. Papadopoulos and colleagues334 screened
human gene databases for sequences with similarities to the yeast mutL
genes and found 3 genes, called hMLH1, hPMS1, and hPMS2. These
genes were localized to chromosomes 3, 2, and 7, respectively, by
somatic cell hybrids. hMLH1 held immediate interest due to the previous
finding of genetic linkage in some Lynch syndrome families to chromosome 3p21.327 This gene was 2268 bp in length and expressed in a wide
variety of tissues. They found that 9 of the 10 Lynch syndrome families
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demonstrating linkage to markers on 3p had germline hMLH1 mutations
whereas only 1 of 18 Lynch syndrome kindreds that were too small to be
studied by linkage had mutations, thereby establishing hMLH1 as another
important predisposition gene for Lynch syndrome.334
Bronner and colleagues335 independently identified hMLH1 by searching a human cDNA library for genes homologous to mutL. They found a
gene encoding for a 756-amino acid protein that localized to chromosome
3p21.3-23. They also found that 4 affected members of a Lynch syndrome
family had a germline substitution in a highly conserved exon of
hMLH1.335 Han and colleagues336 reported that 8 of 34 (24%) unrelated
Lynch syndrome patients had hMLH1 mutations, and Nystrom-Lahti and
colleagues330 demonstrated that 3 of 4 Lynch syndrome kindreds linked
to 3p had hMLH1 mutations. Kolodner and colleagues337 defined the
genomic structure of hMLH1 and found a frameshift mutation in 9 of 19
members of a Lynch syndrome kindred linked to markers on 3p. Wijnen
and colleagues332 found 12 of 34 (35%) kindreds with hMLH1 mutations,
and exons 15 and 16 were hot spots for mutation, accounting for 50% of
reported mutations. No genotype-phenotype correlations were observed
for hMLH1 either, as suggested by 3 Lynch syndrome families with a
common exon 16 deletion, where 1 had Turcot’s syndrome and the other
2 did not have family members with CNS tumors.338
In cell lines, Parsons and colleagues339 demonstrated that mutation of 1
allele in a DNA mismatch repair gene alone did not result in the RER⫹
phenotype. Hemminki and colleagues340 found that one third of patients
with germline mutation in hMLH1 also had somatic loss of wild-type
hMLH1 in RER⫹ tumors, consistent with a tumor-suppressor gene
function.
Herman and colleagues341 described methylation of the hMLH1 promoter in sporadic CRC demonstrating MSI, with subsequent loss of
hMLH1 expression. No methylation of hMSH2 was found. Methylation
of the hMLH1 promoter is also common in MSI-positive sporadic
endometrial cancers, and Simpkins and colleagues342 reported this in 41
of 53 such cases.
hPMS1 and hPMS2 Mutations. Papadopoulos and colleagues334 discovered the human mutL homologs hPMS1 and hPMS2 in 1994 and
mapped them to chromosomes 2 and 7. Nicolaides and colleagues343
mapped hPMS1 to chromosome to 2q31-33 by FISH and demonstrated
the gene encoded for a 932-amino acid protein; hPMS2 mapped to 7p22
and encoded for a 862-amino acid protein. They examined 22 hMSH2 and
hMLH1 mutation-negative Lynch syndrome patients and found 1 with a
hPMS1 missense mutation and another with a hPMS2 deletion. A tumor
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from the latter patient demonstrated deletion of the other hPMS2 allele,
supporting a tumor suppressor role.343 A family with Turcot’s syndrome
has also been reported with a missense mutation of hPMS2.29
hMSH6 Gene Mutations. Another mutS gene homolog was identified
in 1995, by virtue of it forming heterodimers with hMSH2, called GTBP
(G/T binding protein) or hMSH6.344,345 It was found to map in close
proximity to hMSH2 on chromosome 2p16, and mutations were rare in
Lynch syndrome patients. Cells lacking hMSH6 generally have changes
in mononucleotide tracts rather than other simple tandem repeat sequences more commonly present with other MMR genes.346 Miyaki and
colleagues347 found that 1 of 5 HNPCC families lacking hMSH2 or
hMLH1 mutations had an hMSH6 mutation. Wijnen and colleagues348
reported 10 hMSH6 mutations in 214 hMLH1 and hMSH2 mutation
negative families, 71 meeting the Amsterdam criteria (3 mutations) and
143 suspected of having Lynch syndrome but not meeting the Amsterdam
criteria (7 mutations). The age at which colon cancer developed was later
in these patients, and there was a higher incidence of atypical endometrial
hyperplasia and cancer (73%, versus 29% in hMSH2 and 31% in hMLH1
mutation carriers).348 Wu and colleagues349 demonstrated that 4 of 18
individuals with Lynch syndrome-associated tumors that were MSI-low
had hMSH6 mutations. Berends and colleagues350 found hMSH6 mutations in 25 of 316 suspected Lynch syndrome cases, and Huang and
colleagues351 detected only 1 of 90 cases with hMSH6 mutations in which
hMSH2 or hMLH1 mutations were not found.
Endometrial Cancer and MMR Germline Mutations. Berends and
colleagues352 examined the frequency of MMR germline mutations in 58
patients with endometrial carcinoma who were diagnosed at less than 50
years of age. The objective was to relate the occurrence of MMR
mutations to family history, as well as to histopathologic data in the
presence of MSI positivity and immunostaining to develop criteria for
genetic testing. The results showed that 5 of 22 patients who had a
positive first degree family history for Lynch syndrome-related cancers
had pathogenic germline mutations (1 MLH1, 3 MSH2, and 1 MSH6).
Four of the mutation carriers were members of families that fulfilled the
revised Amsterdam criteria, whereas no mutations were identified in the
35 patients who lacked such family history (P ⫽ 0.006). In turn, MSI was
identified in 20 of 57 cancers in which 1 or more MMR proteins were
absent. Among all 5 MMR mutation carriers, immunostaining identified
the involved MMR gene.352 These findings support the conclusion that an
HNPCC-related cancer in a first degree relative is an important selection
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criterion for mutation analysis. Immunostaining of MMR proteins will
then aid in targeting the gene(s) that should be analyzed.
Overview of Genetic Changes. Lynch syndrome is an autosomal
dominant condition, caused by germline changes in DNA mismatch repair
genes, which behave as tumor suppressor genes. Individuals born with
these germline alterations have 1 normal copy (wild-type) of the gene in
each cell and 1 mutant copy. When the wild-type (functional) copy is lost
as a somatic event (in a nongerm cell), that cell develops the characteristic
of microsatellite instability. The inevitable mistakes that occur during
DNA replication are not efficiently repaired, and these changes may lead
to unrestrained growth that leads to adenoma, then carcinoma. The
numbers of the mutations of various MMR genes in 49 Lynch syndrome
families fulfilling the Amsterdam criteria were 21 hMLH1 (43%; 19 point
mutations, 2 deletions), 22 hMSH2 (45%; 10 point mutations, 12
deletions), 2 hMSH6 (4%), and 4 (8%) were negative for point mutations
or genomic rearrangements.353 The frequency of hMSH2 mutations may
have been overestimated in this study, however, because 7 families had
the same 20 kb deletion encompassing exons 1-6 and appeared potentially
to share a common ancestor. A compilation of published and unpublished
mutations have been established by the International Collaborative Group
on HNPCC (http://www.nfdht.nl), in which the numbers of hMLH1
mutations reported were 323 (63% of total), hMSH2 156 (25%), hMSH6
30 (6%), hPMS2 2 (0.4%), and hPMS1 1 (0.2%). The mutations found in
the hMLH1 and hMSH2 genes are distributed throughout the exons, and
no clear correlations between genotype and phenotype are known, with
the exception of the higher incidence of MSI-low and endometrial cancers
in those patients with hMSH6 mutations.
One might appropriately probe more deeply into the question about why
only approximately one half of Lynch syndrome families will have an
MMR mutation identified, or why some classical FAP families may not
have an APC germline mutation identified. This vexing problem has been
addressed by Renkonen and colleagues354 in both HNPCC and FAP
families that lack any sequence changes for their respective known
susceptibility genes. These authors suggest that these genes either have
alterations that have escaped detection by conventional techniques, or
alternatively, other, as yet unknown, susceptibility genes are involved.
Furthermore, they suggest that significant proportions of families that are
presumed to be mutation negative (11 of 26 families in their study, or
42% for Lynch syndrome; 4 of 16 families, or 25% for FAP) harbor
“hidden” alterations in known predisposition genes, leading to their
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conclusion that such changes may be detected by expression-based
methods.354,355
Founder Mutations in Lynch Syndrome. De la Chapelle and Wright356
evaluated 2 founder mutations in the hMLH1 gene in Finland, which
accounted for approximately one half of all Lynch syndrome germline
mutations in that country.357,358 They identified haplotype sharing “. . .
over a genomic region as large as 18 cM indicated a relatively recent
founding of the more prevalent mutation. . . wherein the ‘age’ of this
mutation in most of the 19 kindreds studied could be estimated at 16-43
generations in keeping with historical records and compatible with a
founding in a regional subisolate in new Finland in the early
1500s.”357,359 This research, once the mutations became more fully
understood and characterized, indicated that their presence in a patient or
family could identify individuals who could benefit significantly from
highly targeted cancer control programs.360
A founder mutation consisting of a 4-bp deletion beginning at the first
nucleotide of codon 727 in hMLH1 has been identified in Navajo families
from Arizona. A deletion encompassing exons 1-6 of the MSH2 gene has
been identified in an extended American kindred of German origin.315
Foulkes and colleagues361 described a founder mutation of
hMSH2(1906G¡C) in the Ashkenazi Jewish population. This mutation
results in a substitution of proline for alanine at codon 636 in the MSH2
protein and was identified in 15 unrelated Ashkenazi Jewish families with
Lynch syndrome who met the Amsterdam criteria. These families shared
the same alleles with 18 polymorphic loci within and flanking the MSH2
region, which was consistent with a single origin for this mutation.
Through immunohistochemical analysis, all CRCs that were tested were
found to harbor MSI and absence of the MSH2 protein. These authors
then provided an analysis of a population-based incidence series of 686
Ashkenazi Jews from Israel who manifested CRC. Their results showed
that 3 (0.44%) were mutation carriers. Furthermore, those patients with a
family history of CRC or endometrial cancer were more likely to harbor
the mutations than those without such a family history (P ⫽ 0.042).
Individuals with CRC who were mutation carriers were, on average,
younger than CRC-affected individuals who were noncarriers (P ⫽
0.033). Five hundred sixty-six unaffected Ashkenazi Jews from Israel and
1022 controls from New York were all found to be noncarriers. In
hospital-based series, the 1906 allele was identified in 5 of 463 Ashkenazi
Jews with CRC, 2 of 197 with endometrial cancer, and 0 of 83 with
ovarian cancer.
Guillem and colleagues362 identified this rare founder mutation, hMSH2
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1906C¡G, in Ashkenazi Jews in 8 of 1345 individuals (0.6%) with CRC.
They then investigated the proportion of individuals of Ashkenazi
heritage who manifested early-onset CRC (age ⱕ 40 years) that could be
explained by hMSH2 1906C¡G. They detected this mutation in 3 of the
41 samples (7.14%) among Ashkenazi patients with CRC diagnosed
before age 40, an incidence found to be significantly greater than the 8 in
1345 (0.6%) that was observed in CRC among Ashkenazi Jews who were
not selected for age (P ⫽ 0.004). They concluded that their results merit
testing for the hMSH2 1906C¡G mutation among Ashkenazi Jews
manifesting early-onset CRC.362
Strategy for Genetic Testing. As in other autosomal dominant
conditions, the affected proband should be studied thoroughly for
mutations to allow for directed testing later in other members at risk.
This should be performed in patients meeting the Amsterdam criteria,
or in those who are suspected of having Lynch syndrome but do not
meet the criteria (as in the Bethesda guidelines). The Lynch syndrome
patient’s tumor should first be tested for MSI, and testing for MSH2 or
MLH1 expression by immunohistochemistry can also be quite helpful
in determining which gene is most likely affected in the family. If MSI
is not found, then sequencing of MMR genes is not warranted. If the
tumor is MSI-positive or loss of protein expression is found, then
sequencing of hMLH1 and/or hMSH2 is indicated. The frequency of
PMS gene mutations is so low that their sequencing is not generally
performed; hMSH6 sequencing may be indicated in cases with a
family history suggestive of Lynch syndrome where tumors are
MSI-low or there is a high incidence of endometrial cancer. In rare
cases, there may be mutations in PMS2, MLH3, and EXO1.363
Lynch Syndrome Versus Early Onset Sporadic Colon Cancer. Even in
those cases in which the Amsterdam criteria have not been met, Jass has
suggested that the profile of early-onset MSI-high (MSI-H) CRCs
resembles that of Lynch syndrome cancer, with emphasis on the histologic features and site of tumors. Furthermore, Jass provides 5 cogent and
interrelated reasons for questioning the presumption that early-onset
“sporadic” MSI-H CRCs are truly sporadic. Specifically, he notes that
“. . . first is the fact that the incidence of HNPCC peaks at around 45
years. Second is the finding of germline mutations in DNA mismatch
repair genes in subjects presenting with early-onset “sporadic” MSI-H
colorectal cancer. Third is the evidence that methylation of hMLH1 in
sporadic MSI-H cancer is strongly age-related. Fourth is the fact that
methylation of hMLH1 may occur selectively in HNPCC cancers in
subjects who carry a germline mutation in hMLH1. Fifth is the finding of
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281
HNPCC-type molecular features among early-onset “sporadic” MSI-H
colorectal cancers.”364
Pathologic Features in Lynch Syndrome. The pathologic features of
Lynch syndrome CRCs include a solid growth pattern, which appears to
be responsible for the high frequency of poorly differentiated carcinomas.365,366 Surprisingly, however, is the finding that CRCs in the Lynch
syndrome are not as aggressive as their failure to form tubules might
suggest. Lynch and colleagues have called attention to the “undifferentiated carcinoma” described by Gibbs367 and the “medullary carcinoma”
described by Jessurun and Manivel,368 which were published in small
case series and shown to have a more favorable prognosis when compared
with typical CRC.369 It is also noteworthy that similar histologic features
characterize the 15% of sporadic CRCs that harbor microsatellite instability (MSI⫹), which have been found to constitute a molecular aberration in CRCs that lack MMR activity.370 This special histologic feature
has been referred to as “solid cribiform growth” wherein there is a
positive predictive value of 53% for MSI⫹ status.371
Smyrk and colleagues372 described a postlymphoid response referred to
as “Crohn’s-like reaction” to be more common in Lynch syndromes as
opposed to sporadic cancers, a finding that has been shown to be
consistent in all series,365 but which is similar to the tendency to form
lymphoid aggregates around the tumor, and which is a frequent feature of
sporadic MSI⫹ CRCs.370 Importantly, the Crohn’s-like reaction is often
associated with improved prognosis373 in the general population, suggesting that this phenomenon may account for the more favorable prognosis
of CRC that occurs in HNPCC.374 De Jong and colleagues375 studied the
role of MMR defects and the manner in which they promote development
of adenomas in Lynch syndrome families compared with controls from
the Dutch HNPCC Registry. They identified 249 MMR mutation carriers
and 247 controls. They found that the proportion of patients lacking an
adenoma at the age of 60 years was 29.7% for carriers and 70.8% for
controls (P ⬍ 0.05). They verified previous studies showing that the
adenomas in carriers were larger and showed a higher proportion of
villous components and/or high-grade dysplasia (P ⬍ 0.05, all analyses).
Furthermore, they found the adenomas and carcinomas of the carriers to
be located predominantly in the proximal colon, and most of the
adenomas showed absent staining of the MMR proteins. They concluded
that their study “. . . indicates that the MMR defect is involved in the early
stages of development of adenomas.” They recommended immunohistochemical staining of large adenomas showing high-grade dysplasia in
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patients younger than 50 years old, in the interest of identifying patients
with suspected Lynch syndrome.375
Pattern Recognition. An alternative to the Amsterdam I, Amsterdam II,
Bethesda, and other criteria is what we have described as “pattern
recognition.” This involves careful scrutiny of the phenotypic cancer
features expressed in the family in accord with their mode of distribution
and transmission throughout the family. This is particularly important
when evaluating small families, or for problems of reduced penetrance of
the deleterious MMR mutation, should this be present in the family. It is
valuable then to follow what have been considered to be the cardinal
features of hereditary forms of cancer, including the Lynch syndrome,
when present even in a single patient. These phenotypic features have
often been sufficient to raise the confidence level of a possible Lynch
syndrome diagnosis and include the following: 1) autosomal dominant
inheritance pattern311; 2) gene penetrance for CRC of ⬃85% to 90%304;
3) gene carriers develop CRC at an early age (⬃45 years)311; 4) most
(⬃70%) of the CRCs are proximal to the splenic flexure376; 5) multiple
CRCs, both synchronous and metachronous, are common377,378; 6) the
prognosis is better than that for sporadic CRC374,379; 7) the pathologic
features365 of CRC are often distinguishable (but not pathognomic) and
include poor differentiation, mucoid excess with increased signet cells,
medullary features, peritumoral lymphocytic infiltration, Crohn’s-like
reaction, and tumor infiltrating lymphocytes (TILs) admixed with tumor
cells380; and 8) there is an increased risk for malignancy at several
extracolonic sites, particularly the endometrium, ovary, stomach, small
bowel, hepatobiliary tract, pancreas, ureter, renal pelvis, and brain.306 In
addition, breast cancer excess may be present in some HNPCC families.381 Although gastric cancer has declined in Lynch syndrome families
since 1900, paralleling its decline in the general population,312 it is still an
important feature of the syndrome in geographic areas in which gastric
cancer is endemic, most notably Japan and Korea.305
Muir-Torre Syndrome (MTS). In 1981, Lynch and colleagues382
reported the first observation of MTS in the Lynch syndrome. MTS is
characterized by multiple cutaneous sebaceous adenomas, sebaceous
carcinomas, multiple keratoacanthomas, and multiple visceral cancers, in
Lynch syndrome families. Several publications have elucidated the
clinical and molecular genetic features of MTS in the Lynch syndrome.383-386 Kruse and colleagues387 examined 13 patients with CRC
and sebaceous lesions of the skin and found that 8 had hMSH2 mutations
and 1 had an hMLH1 mutation. Data suggest that the identification of
these MTS cutaneous features in a patient merit a detailed family history
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283
in the search for evidence of the Lynch syndrome. Indeed, patients with
these stigmata merit MMR germline testing, particularly for evidence of
hMSH2 germline mutation. The pedigree of an extended Lynch syndrome
family with MTS that is known to carry an hMSH2 mutation is shown in
Fig 20.
Surgical Management. In Lynch syndrome patients diagnosed with
colorectal cancer, the preferred treatment is subtotal colectomy. Fitzgibbons and colleagues388 studied 116 patients with Lynch syndrome and
demonstrated several significant differences in this patient population
relative to patients with sporadic CRC. They found that 69% of Lynch
syndrome CRC were proximal to the splenic flexure, whereas 23% were
in the rectosigmoid. Eighteen percent had synchronous cancers, and 40%
developed metachronous lesions over 10 years of follow-up.388 Because
of the predominance of proximal lesions and the high risk of developing
new cancers in the future, subtotal colectomy with IRA and lifetime
surveillance of the rectosigmoid is recommended. For women beyond
childbearing age, serious consideration should also be given to performing prophylactic hysterectomy and bilateral salpingo-oophorectomy.388
In reviewing this subject, Church389 suggests that interval CRCs
develop from normal epithelium within 3 years and/or from adenomas
that were missed. It is also important to realize that colonoscopy “miss”
rates are as high as 29% for polyps less than 5 mm in diameter.390
Therefore, patients should be advised that colonoscopy, although not a
perfect screening procedure, is nevertheless highly effective.360 The
option of prophylactic colectomy should be discussed, weighing it against
lifetime colonoscopy.391-394 The problem in effective cancer control
through the use of prophylactic colectomy is a decision based heavily on
the attitudes, feelings, and concerns of the patient and the manner in
which these could impact on his/her compliance with annual colonoscopy. For example, the presence of fear and anxiety about what might be
found at colonoscopy, in our experience, has deterred patients in showing
compliance with this screening procedure for CRC. Criteria for prophylactic surgery are the following: 1) lack of compliance with surveillance;
2) morbid fear and desire to have these high risk organs surgically
excised; 3) presence of colonic adenomas, particularly at a young age
and/or with features of moderate to severe dysplasia and carcinoma in situ
in polyps.
Women at risk for the Lynch syndrome should have annual screening
for endometrial and ovarian cancer beginning at age 30 to 35 years.
Endometrial aspiration coupled with transvaginal ultrasound is advised.
CA-125 testing, in addition to transvaginal ultrasound and Doppler color
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Curr Probl Surg, May 2005
FIG 20. Pedigree shows the Muir-Torre syndrome.
285
blood flow imagery, should be performed semiannually for ovarian
cancer. Prophylactic hysterectomy and oophorectomy can be considered
when childbearing is completed.
Screening in Lynch Syndrome. Jass395 has elucidated the pathologic
nature of precursor lesions in HNPCC. He has postulated the “aggressive adenoma” theory (i.e., adenomas form earlier but about as often
in HNPCC patients as in the general population).395 However, once
formed, these colonic adenomas progress to carcinoma more quickly
and/or more often than their sporadic counterparts. A tiny colonic
adenoma in the Lynch syndrome may evolve into a carcinoma in as
short a time frame as 2 to 3 years, compared with approximately 8 to
10 years in the general population.303,365,396 Strong clinical evidence
in support of a more rapid evolution of adenoma to carcinoma comes
from a Finnish study showing a marked decrease in colon cancer
incidence for HNPCC patients given regular colonoscopic surveillance
with removal of adenomas.397 Because of accelerated carcinogenesis,
proximal colonic predilection, and early age of CRC onset in the
Lynch syndrome, we strongly recommend that annual full colonoscopy be initiated at age 25 (Fig 21). A good clean-out is necessary and
excellent visualization of the cecum is mandatory, because approximately one third of CRCs occur at that particular site.
Järvinen and colleagues360 demonstrated the benefit of colonoscopic
screening in HNPCC through a controlled clinical trial extending over
15 years. The incidence of CRC was compared in 2 cohorts of at-risk
members of 22 HNPCC families. CRC developed in 8 screened
subjects (6%), compared with 19 controls (16%; P ⫽ 0.014). The CRC
rate was reduced by 62% in those who were screened. All CRCs in the
screened group were local, causing no deaths, compared with 9 deaths
caused by CRC in the controls. It was concluded that CRC screening
at 3-year intervals more than cuts in half the risk of CRC, prevents
CRC deaths, and decreases the overall mortality rate by approximately
65% in HNPCC families.360 The relatively high incidence of CRC
even in the screened subjects (albeit without deaths) in our opinion
argues for shorter screening intervals (i.e., 1 year). For example,
Vasen and colleagues398 discovered 5 interval cancers in HNPCC
patients within 3.5 years following a normal colonoscopy. Prophylactic colectomy, as discussed, is an alternative to intensive colonoscopic
surveillance in highly selected members of Lynch syndrome families.
An algorithm showing the appropriate sequence for diagnosis and
management of Lynch syndrome is shown in Figure 21.
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FIG 21. Algorithm depicting the appropriate sequence for A) diagnosis and management and B)
screening and management of the Lynch syndrome. CRC, colorectal cancer; MSI, microsatellite
instability; MMR, mismatch repair.
Juvenile Polyposis
The colorectal polyps most commonly found in children are different
from those found in adults and are called juvenile polyps. Polyps in adults
are generally adenomatous, whereas polyps in children tend to be
hamartomatous (juvenile polyps being a type of hamartomatous polyp). In
most children, the juvenile polyps are few in number or solitary, will
slough off and not require treatment, and are not associated with a
heritable predisposition. Juvenile polyposis (JP; OMIM 174900) is a
heritable syndrome in which there are multiple juvenile polyps (Fig 22).
Patients with juvenile polyposis, Cowden syndrome (CS; OMIM
158350), and Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM
153480) may all develop juvenile polyps of the GI tract, which are
indistinguishable microscopically. Patients with Peutz-Jeghers syndrome
(PJS; OMIM 175200) also have hamartomatous polyps, but these can be
differentiated histologically from juvenile polyps.
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287
FIG 21. Continued
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FIG 22. Juvenile polyposis of the colon.
History. The first description of a juvenile polyp was by Diamond399 in
1939, who originally called this a rectal adenoma. Diamond399 described
it grossly as a 2.5 by 2.0 cm pedunculated tumor that was injected and
friable. One small area on the polyp surface was covered with a fibrinous
exudate. Histologically, the polyp was lined with high columnar epithelial
cells with an occasional bare area. The glands were distended and filled
with a fibrinous cellular material. The stroma was diffusely infiltrated
with lymphocytes, plasma cells, eosinophils, and neutrophils.399 In 1957,
Mauro and Prior400 clearly distinguished between juvenile polyps and
adenomatous polyps. Contrasting the 2, they found juvenile polyps to be
globular in shape, gray to slightly red, with a granular external surface.
Villous processes were not present. It was common to have areas of
denudation of the columnar epithelium replaced by granulation tissue.
There was cystic gland dilation, containing mucous and nuclear debris.
The abundant stroma contained an inflammatory cell infiltrate with a
predominance of eosinophils.400 Later in the same year, Horrilleno and
colleagues401 coined the term juvenile polyp for these histologically
similar polyps described previously by Diamond and by Mauro and Prior.
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289
FIG 23. Photomicrograph of a juvenile polyp. Note the normal epithelium, with a markedly expanded
lamina propria, infiltrated by inflammatory cells and dense stroma. Cystically dilated glands are also
prominent in this layer.
In 1962, Morson402 supported the view that juvenile polyps were different
from adenomatous polyps and suggested they were hamartomatous
polyps. Hamartomas are an overgrowth of mature cells and tissues that
normally occur in the affected part, but often with 1 element predominating. Juvenile polyps satisfy this definition with their excessive proliferation of the lamina propia and attenuation of the muscularis mucosa
(Fig 23).
Definition and Manifestations. The term juvenile polyposis (JP) was
defined by McColl and colleagues403 in 1964. This distinguished juvenile
polyps from JP, a heritable syndrome in which there are multiple juvenile
polyps involving the GI tract. In 1974, following the definition of JP by
McColl, Sachatello and colleagues404 proposed a working definition, later
modified by Jass and colleagues,405 with the following diagnostic criteria:
1) more than 5 juvenile polyps involving the colon and rectum, 2) juvenile
polyps throughout the GI tract, and 3) any number of juvenile polyps
involving the GI tract with a family history of JP. JP has been further
divided based on the clinical presentation and disease course into the
following three classifications404,405: 1) juvenile polyposis of infancy, 2)
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FIG 24. Juvenile polyposis affecting the stomach, resulting in a dense carpet of polyps.
juvenile polyposis coli, and 3) generalized juvenile polyposis. Sachatello
and colleagues defined juvenile polyposis of infancy in a case report and
reviewed 6 similar cases in the literature.404,406-410 In all 7 cases, the
infants died before 1 year of age. Characteristic symptoms included
diarrhea (usually bloody), protein losing enteropathy, hypoproteinemia,
anemia, anasarca, and eventually failure to thrive. It was common to find
rectal polyp prolapse and intussusception. Congenital anomalies ranged in
these series from none to clubbing, motor retardation, macrocephaly,
alopecia, double renal pelvis, and bifid uterus/vagina.404
Juvenile polyposis coli and generalized juvenile polyposis are defined
by the sites of GI involvement with juvenile polyps. As the name implies,
juvenile polyposis coli occurs when juvenile polyps are limited to the
colon and rectum, whereas in generalized juvenile polyposis, the polyps
are present in both the upper and lower GI tract (Fig 24). Both subtypes
will usually manifest in the first and second decades with rectal bleeding,
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291
mia.411,412 In addition, generalized GI juvenile polyposis may include
protein-losing enteropathy, intussusception, and severe malnutrition.
However, these children, unlike those with juvenile polyposis of infancy,
eventually recover. Coburn and colleagues413 reviewed the English
literature and identified 218 patients meeting the criteria for JP. These
patients with JP were stratified into 2 groups: juvenile polyposis coli and
generalized juvenile polyposis. Patients with juvenile polyposis coli
usually presented during childhood between the ages of 5 and 15 years,
whereas patients diagnosed with generalized juvenile polyposis present at
an earlier age. Otherwise, there did not appear to be any difference in the
family history of juvenile polyposis in either subtype.413 It should be
mentioned that the distinction between juvenile polyposis of infancy,
juvenile polyposis coli, and generalized juvenile polyposis may be
somewhat arbitrary. Stemper and colleagues414 reported a kindred with
some members having generalized GI juvenile polyposis whereas others
had juvenile polyposis coli, suggesting the phenotype of juvenile polyposis is of variable penetrance. Similarly, Grotsky and colleagues415
described an extended family with both juvenile polyposis coli and
juvenile polyposis of infancy.
Associated Anomalies. In their 1964 series, McColl and colleagues403
described 4 of 11 patients with associated congenital anomalies. Coburn
and colleagues413 reported nearly a 15% prevalence of congenital
malformations with JP. Interestingly, Desai and colleagues,416 who
routinely obtained radiographs and an echocardiogram if clinically
indicated, reported 18 of 23 (78%) patients with JP having extracolonic
manifestations. This number is clearly skewed since after the extensive
re-evaluation 5 patients had alternative syndromes diagnosed, and an
unspecified number were described as having similarities to known
syndromes. Removing these cases leaves 8 of 13 (62%) patients with
presumed JP associated with extracolonic manifestations. Throughout
the JP literature, some of the recurrent anomalies include the following: macrocephaly, mental retardation, atrial and ventricular septal
defects, pulmonary arteriovenous malformations, pulmonary stenosis,
Meckel’s diverticulum, malrotation, cryptorchidism, hypertelorism,
and telangectasias.403,413,416
Malignant Potential. An extensive portion of the literature on JP has
been dedicated to the discussion of its malignant potential. It was initially
thought that JP did not predispose to GI malignancy, since juvenile polyps
are hamartomatous. As it became apparent that adenomatous polyps had
malignant potential, an increased prevalence of colorectal cancer was
recognized with JP patients. During this time adenomatous changes in
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juvenile polyps were recognized414,415,417-434 and hypothesized occasionally to undergo dysplastic change and eventually progress to adenocarcinoma. In 1979, Goodman and colleagues422 reported a 23-year-old
woman undergoing a colectomy with numerous juvenile polyps mainly
localized to the cecum, ascending colon, and rectum. Several of the
juvenile polyps showed adenomatous changes, and an adenocarcinoma
had also developed in the rectum.
After adenomatous changes, the next step in the progression to
malignancy would be dysplasia/carcinoma in situ changes in the juvenile
polyps of patients with JP. Jass and colleagues405 reviewed the pathologic
features of 1038 polyps collected from 80 patients in the St. Mark’s
Polyposis Registry with JP. They divided the polyps into 2 groups: 1)
multilobulated or having a villous configuration, and 2) typical juvenile
polyps. Seventy-nine of 169 (47%) atypical juvenile polyps had epithelial
dysplasia, whereas 76 of the 840 (9%) typical juvenile polyps had similar
dysplastic changes.405 Several other investigators have reported the
finding of dysplastic changes in juvenile polyps in JP patients.428,435,436
There have been many cases of documented colorectal adenocarcinoma
reported in patients with JP.414,422,427,428,430-432,437,438 These cancers are
often closely associated with juvenile polyps and juvenile polyps with
adenomatous changes, supporting a juvenile polyp-adenomatous changesdysplasia-carcinoma sequence of events.
The establishment of JP registries has allowed estimates of the cumulative risk for developing GI malignancies to be made. Howe and
colleagues439 examined a 117-member Iowa JP family and found that 11
of the 59 (38%) affected kindred members developed colon cancer,
whereas 6 of 59 (21%) developed upper GI cancers. The cumulative risk
for upper and lower GI cancers was 55%. The cumulative risk for
colorectal cancer in JP patients has ranged from 17% to 68% in other
reports.413,440
The distinction between JP and patients with juvenile polyps is
important when estimating the risk of GI malignancy. Many authorities
have suggested that there is no inherent increased risk of GI malignancy
for patients with solitary juvenile polyps not meeting the definition of JP.
Giardello and colleagues432 found that only 1 of 26 patients with only 1
or 2 juvenile polyps and a negative family history had adenomatous
changes in a polyp, whereas 9 of 31 (29%) patients with 3 or more
juvenile polyps or a positive family history of JP had colonic adenomas
or adenocarcinoma. There is only 1 reported case of an adenocarcinoma
arising from a presumed solitary juvenile polyp in a 16-year-old boy.441
Nugent and colleagues442 reported that the relative risk of dying of
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293
colorectal malignancy in a patient with a solitary juvenile polyp was 0.66,
and therefore these patients are not at an increased risk of death from
colorectal carcinoma.
Genetics. The autosomal dominant nature of JP was first suggested by
Smilow and colleagues437 and Veale and colleagues443 in 1966. Further
descriptions of kindreds with juvenile polyposis confirmed an autosomal
dominant inheritance.414,444 More recent investigation has shifted from
the clinical to the molecular basis of JP. Jacoby and colleagues described
a patient in 1997 with JP having a deletion at chromosome 10q22.445
Soon thereafter, Olschwang and colleagues446 reported 3 cases of JP with
germline PTEN mutations, which maps to 10q22. However, on closer
evaluation by Eng and Ji,447 these patients either had a phenotype
suggestive of CS or, due to their young age, CS could not be ruled out.
Howe and colleagues448 examined a family of 43 individuals of which 13
had the clinical diagnosis of JP and found no linkage to chromosome 10q
markers. Marsh and colleagues449 were unable to identify germline
mutations in PTEN in 14 familial and 11 sporadic JP cases. Riggins and
colleagues450 also found no PTEN mutations in 11 JP patients. In 1998,
Howe and colleagues448 demonstrated genetic linkage to markers on
chromosome 18q21, and subsequently reported germline mutations of
MADH4 in 5 of 9 JP cases.451 This was independently confirmed in
multiple small series.452-455 Woodford-Richens and colleagues456 found
7 of 44 (16%) cases of JP with MADH4 mutations, and Howe and
colleagues457 reported mutations in 14 of 77 JP cases (18.2%). In the
latter report, 8 mutations were deletions and 6 were substitutions (1
nonsense, 5 missense). Reviewing all published mutations, Howe and
colleagues457 described a total prevalence of 23% (32 of 141 cases with
MADH4 mutations). One mutation had been described in 6 cases, a 4-bp
deletion in exon 9.458 Of 32 total mutations, 1 mapped to the MH1
domain, 5 to the linker region and the remainder to the MH2 domain (Fig
25).457
The MADH4 protein is the common mediator involved in the transforming growth factor-␤ (TGF-␤) superfamily, which includes TGF-␤,
activin, and bone morphogenetic protein (BMP) signal transduction
pathways. Functionally, MADH4 acts as a tumor suppressor gene, as
demonstrated by Hahn and colleagues,459 who found loss of heteorozygosity (LOH) of MADH4 in 25 of 84 (30%) pancreatic xenografts.
Members of the TGF-␤ superfamily initiate a wide spectrum of effects on
a variety of cell types, including control of differentiation, proliferation,
and apoptosis. TGF-␤ binds to plasma membrane serine/threonine kinases, specifically the type II TGF-␤ receptor. TGF-␤ and the type II
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FIG 25. MADH4 mutations reported in juvenile polyposis (JP). The upper rectangle represents the
MADH4 gene, with the exons shown within the rectangle and nucleotides above and below. Lines
designate mutations identified in JP cases, with those shown above each exon corresponding to those
identified by Howe and colleagues,457 whereas those below are derived from the reports of Roth and
colleagues,454 Kim and colleagues,455 Woodford-Richens and colleagues,456 and Friedl and
colleagues.464 (Reproduced with permission from Howe JR, Sayed MG, Ahmed AF, Ringold J,
Larsen-Haidle J, Merg A, et al. The prevalence of MADH4 and BMPR1A mutations in juvenile
polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 2004;41:484-91.)
TGF-␤ receptor complex then binds with the type I receptor, causing
phosphorylation in a glycine-serine-rich domain of the receptor (Fig 26).
In the TGF-␤ pathway, these activated type I receptors then phosphorylate cytoplasmic MADH2 or MADH3. Phosphorylation allows these
proteins to oligomerize and then to associate with MADH4. The complex
then migrates to the nucleus, where it recruits a DNA binding protein, and
the complex binds to specific DNA sequences, regulating the transcription
of various genes, many of which remain to be identified. The MH2
domain of MADH4, which is frequently altered in JP patients and
sporadic pancreatic cancers, is important in nuclear localization, MADH4
binding, and activation of transcription. There are 8 known MADHs in
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295
FIG 26. Overview of the TGF-␤ signaling pathway (reproduced with permission from Merg A, Howe
JR. Genetic conditions associated with intestinal juvenile polyps. Am J Med Genet 2004;129C:4455).577
vertebrates, with MADH2 and MADH3 functioning as the cytoplasmic
effectors in the TGF-␤ and activin pathways; MADH1, MADH5, and
MADH8 are those involved in the BMP pathway. MADH4 is the
common mediator for these pathways, whereas MADH6 and MADH7
function as inhibitors of all these pathways by binding to the type I
receptors and by interfering with phosphorylation.460 To date, no other
MADH genes have been implicated in the development of JP. Roth and
colleagues454 found no mutations in MADH2, MADH3, or MADH7 in 4
unrelated patients without MADH4 mutations, and Bevan and colleagues461 found no mutations in MADH1, MADH2, MADH3, or MADH5
in 30 JP patients without MADH4 mutations.
Since MADH4 mutations only accounted for one fifth of JP cases, Howe
and colleagues462 searched for another JP gene through a linkage-based
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genome screen in 4 additional JP families. They found linkage to markers
on chromosome 10q22-23, and subsequently each family was found to
have a truncating mutation in the BMPR1A gene.462 Since the initial
report of BMPR1A mutations in JP patients, there have been 2 confirmatory studies published.463,464 In a total of 77 JP cases studied by Howe
and colleagues, there have been 16 (21%) with BMPR1A mutations,
consisting of 6 deletions and 10 substitutions (4 nonsense, 6 missense).457
Pooling all 3 reports, 31 unique mutations have been described, distributed in 8 of 11 exons with nearly one half affecting the intracellular
protein kinase region in exons 7 and 8. One quarter of mutations affect the
extracellular cysteine-rich domain (Fig 27).457 BMPR1A is another
member of the TGF-␤ superfamily involved in a pathway that also
depends on MADH4 as the intracellular mediator of signal transduction
(Fig 26). Like TGF-␤, the various BMPs bind to specific type II receptors
or to the type II and type I receptors together, then the type II receptor
phosphorylates a type I receptor, such as BMPR1A or BMPR1B.465 The
type I/type II receptor complex then phosphorylates MADH1, MADH5,
and/or MADH8, which then form oligomers with MADH4, and these
proteins migrate to the nucleus to regulate transcription of specific
genes.460 BMPs exert many effects on a variety of tissues, including
control of osteogenesis, chondrogenesis, mesoderm development, synthesis of extracellular matrix, and epithelial/mesenchymal cell relationships
contributing to morphogenesis.466
A recent study examining MADH4 and BMPR1A mutation-positive
(MUT⫹) and negative (MUT⫺) cases found that that 17 of 19 (89%)
MUT⫹ patients and 13 of 25 (52%) MUT⫺ patients cases had a family
history of GI cancer (P ⫽ 0.01), and that 89% of MUT⫹ and 63% of
MUT– cases were familial (P ⫽ 0.09).467 The familial prevalence of
upper GI juvenile polyps was 86% in MADH4 mutation-positive JP
families, 10% in BMPR1A families, and 23% in MUT– cases. Friedl and
colleagues464 reported gastric polyposis in 4 of 7 MADH4 mutationpositive cases, in 1 of 5 cases with BMPR1A mutations, and 2 of 17
mutation-negative cases. It therefore appears that MADH4 mutations
predispose to generalized juvenile polyposis, whereas MADH4 mutationnegative cases more commonly cause juvenile polyposis coli. Since
MADH4 and BMPR1A mutations only account for 40% of JP cases, there
are likely other genes responsible for JP that await discovery.
Treatment. Because of the malignant potential of juvenile polyps in JP,
endoscopic screening and polypectomy, and prophylactic surgery in some
cases, are very important means of cancer control. Screening should begin at
age 15, and include esophagogastroduodenoscopy, colonoscopy, and a
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297
FIG 27. BMPR1A mutations reported in juvenile polyposis (JP). The upper rectangle represents the
BMPR1A gene, with the exons shown within the rectangle and nucleotides above and below. Lines
designate mutations identified in JP cases, with those shown above each exon corresponding to those
identified by,457 while those below are derived from the reports of.463,464 The lower rectangle
represents the different known domains of the BMPR1A gene (reproduced with permission from Howe
JR, Sayed MG, Ahmed AF, Ringold J, Larsen-Haidle J, Merg A, et al. The prevalence of MADH4 and
BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.
J Med Genet 2004;41:484-91).
hemogram in those at risk for JP.468 If a mutation of MADH4 or BMPR1A is
found in a family, then the process is simplified by testing individuals at risk
for the same mutation. If no mutation is found, then that individual can be
followed by using the guidelines for screening the general population for
sporadic colorectal cancer. If either a mutation is found in an at-risk patient,
or a mutation has not been found in the family, then colonoscopy and upper
endoscopy should be performed every 3 years. When juvenile polyps are
found in the colon, they should be removed endoscopically, which may
require multiple sessions if the number is greater than 20 to 50 polyps.
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TABLE 10. International Cowden Consortium diagnostic criteria*
Pathognomonic criteria
Facial trichilemmomas
Acral keratoses
Papillomatous papules
Mucosal lesions
Major criteria
Breast carcinoma
Thyroid carcinoma, nonmedullary
Macrocephaly
Lhermitte-Duclos disease (LDD)
Endometrial carcinoma
Minor criteria
Thyroid lesions, adenoma or multinodular goiter
Mental retardation
Gastrointestinal hamartomas
Fibrocystic disease of the breast
Lipomas
Fibromas
Genito-urinary tumors (renal cell carcinoma or uterine fibroids) or malformations
Operational diagnosis in an individual
1) Mucocutaneous lesions alone if there are
i) Six or more facial papules, of which 3 or more must be trichilemmomas
ii) Cutaneous facial papules and oral mucosal papillomatosis
iii) Oral mucosal papillomatosis and acral keratoses
iv) Six or more palmar or plantar keratoses
2) Two major criteria, 1 of which must be macrocephaly or LDD
3) One major and 3 minor criteria
4) Four minor criteria
Operational diagnosis in a family in which 1 individual has had a diagnosis of Cowden
syndrome
1) One or more of pathognomonic criteria
2) Any 1 major criterion with or without minor criteria
3) Two minor criteria
*Reproduced with permission from Waite KA, Eng C. Protean PTEN: form and function. Am J
Hum Genet 2002;70:829 – 44.612
Subsequently, annual endoscopy should be performed until the all polyps are
removed, and then every 3 years after this if no dysplastic polyps are found.
If the colon cannot be rendered polyp free using the endoscope, then surgical
management may be needed. The range of surgical options include segmental
colectomy, subtotal colectomy, and total proctocolectomy with ileoanal
pull-through.468 Since the malignant potential of juvenile polyps in JP is low
relative to more aggressive polyposis syndromes, one must consider carefully
the impact of the chosen procedure on quality of life versus the need for
future endoscopic surveillance. Subtotal colectomy is preferred over segmental colectomy since it limits the amount of colon at risk, and patients can be
screened easily by flexible sigmoidoscopy. Total proctocolectomy should be
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299
FIG 28. A and B) Trichilemmomas of the face in patients with Cowden syndrome (reproduced with
permission from Brownstein MH, Wolf M, Bikowski JB. Cowden’s disease: a cutaneous marker of
breast cancer. Cancer 1978;41:2393-8).578
reserved for those with significant involvement of both the colon and the
rectum, or those with dysplastic rectal polyps. Polyps of the stomach are
usually diffuse and cannot be effectively removed endoscopically. Significant
anemia is often present, and these patients may require subtotal or total
gastrectomy.468 Patients with JP or at risk for JP should receive genetic
counseling. Here, recommendations for endoscopic screening, the risk of
upper and lower GI symptoms and cancer, and the ramifications of genetic
testing should be discussed.
Cowden Syndrome
Cowden Syndrome (CS) was first described by Lloyd and Dennis469 in
the propositus Rachel Cowden, and Weary and colleagues470 later
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FIG 28. Continued
designated CS as a multiple hamartoma syndrome after observing its
autosomal dominant inheritance in her family. CS involves hamartomatous changes in all 3 germ layers, including predominantly the skin,
mucous membranes, breast, thyroid, GI tract, and CNS. The International
Cowden Consortium has established a group of features that establish the
diagnosis of CS (Table 10). Lhermitte and Duclos disease (LDD) is
included in these criteria, which causes a variety of CNS symptoms.471,472 In the 1990s, it was realized that LDD and CS were variants
of the same genetic condition, which manifest as neurologic and cutaneous hamartomas, respectively.473-477
Phenotype. Lesions of the skin and mucous membranes are pathognomonic for CS, and are present with nearly 100% prevalence.478,479
Trichilemmoma, 1 of the characteristic lesions in CS, is a hamartoma of
the hair follicle’s root sheath. Typically trichilemmomas are found around
the eyes, nose, and mouth (Fig 28). Oral fibromas with a papillomatosis
morphology can cause a cobblestoning appearance of the gingiva and/or
tongue, also referred to as a scrotal tongue (Fig 29). Acral keratosis is also
prominent in CS (Fig 30).478,480,481 Three quarters of patients with CS
have thyroid abnormalities, most commonly goiters or adenomas. NonCurr Probl Surg, May 2005
301
FIG 29. A) Papillomatous lesions of the tongue seen in a patient with Cowden syndrome (CS)
(reproduced with permission from Botma M, Russell DI, Kell RA. Cowden’s disease: a rare cause of
oral papillomatosis. J Laryngol Otol 2002;116:221-3).579 B) Gingival papules in a CS patient
(reproduced with permission from Sogol PB, Sugawara M, Gordon HE, Shellow WV, Hernandez F,
Hershman JM. Cowden’s disease: familial goiter and skin hamartomas. A report of three cases. West
J Med 1983;139:324-8).580
medullary thyroid malignancies are more common than in the general
population and range in prevalence from 3% to 7%.478,479,482-486
Two large series of CS patients have demonstrated breast involvement
in approximately 70%. Fifty percent to 60% have benign lesions, and
breast cancer is found in approximately 20% to 30% of cases.478,479
Owing to the lack of prospective, long-term follow-up studies, the
lifetime risk of breast cancer in CS patients may be underestimated.
302
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FIG 30. Keratodermas of the palm in a patient with Cowden syndrome (reproduced with permission
from Hover AR, Cawthern T, McDanial W. Cowden disease. A hereditary polyposis syndrome
diagnosable by mucocutaneous inspection. J Clin Gastroenterol 1986;8:576-9).
Approximately 30% of patients with breast cancer have bilateral involvement, and the mean age at presentation is younger than for the general
population, ranging from 38 to 46 years.478,487 Breast cancer is not
limited to women with CS; 2 cases of breast cancer have been reported in
men with CS.488
The GI tract manifestations in CS are adenomas, hamartomas, ganglioneuromas, leiomyomas, lipomas, lymphoid, neuromas, as well as hyperplastic, inflammatory, and occasionally juvenile polyps.470,485,489-495 The
incidence of GI involvement may range from 35% to 85%, depending
on whether patients have contrast studies and endoscopy performed.478,495,496 In contrast to JP, there are only 4 reported cases of
colon carcinoma.478,482,497,498
Menstrual irregularities and ovarian cysts are found in approximately
20% of patients with CS, and leiomyomas of the uterus may also be
present.478,491,496 Other cancers associated with CS are uterine adenocarcinoma (6%), transitional cell carcinoma (5%), and cervical carcinoma
(3%).478 Eng499 recently suggested a possible association between CS
and both renal cell carcinoma as well as melanoma, based on anecdotal
evidence.
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303
Lhermitte-Duclos Disease. Lhermitte and Duclos500 first described this
syndrome in the French literature in 1920. This was later referred to as
dysplastic gangliocytoma of the cerebellum, due to the histologic features
of this peculiar hamartoma. This cerebellar hamartoma usually manifests
with symptoms of increased pressure or cerebellar ataxia, which include
headaches (75%), papilledema (70%), cerebellar syndrome (50%), megalencephaly (40%), cranial nerve deficit (30%), ataxia (20%), and pyramidal syndrome (20%). Associated anomalies found in patients with
Lhermitte-Duclos disease (LDD) have also included macrocephaly,
megalencephaly, hydrocephalus, heterotopia, and hydromyelia.471,472
Ambler and colleagues501 found LDD to be autosomal dominant in
nature. By the 1980s, the diagnosis could be established by MRI findings,
manifesting as a nonenhancing gyriform pattern with enlargement of the
cerebellar folia.502 In 1921, Padberg and colleagues473 reported 2 patients
with biopsy-proven LDD and CS. This was followed by similar reports,
leading to the realization that these were the same hamartomatous
syndrome involving cutaneous and neurologic ectoderm.474-477,503-506
This was supported in 1996, when Nelen and colleagues507 reported the
localization of the predisposing gene for CS to chromosome 10q22-23.
Among the12 families studied for linkage, 4 families had clear evidence
of LDD that showed the same linkage to 10q22-33.507 Hence, LDD was
incorporated into the diagnostic criteria for CS (Table 10).
Genetics. CS was demonstrated to have an autosomal dominant
inheritance by Gentry and colleagues494 in 1974 and Nuss and colleagues508 in 1978. Although within families there were generally equal
numbers of affected men and women, between families, interfamilial
series may show a female predisposition ranging from 1:1 to 1.6:
1.478,496,509 This could also reflect a bias for presentation in females due
to the breast disease predisposition in CS.
Excellent progress has been made in understanding the genetic basis of
CS in the last decade. In 1996, Nelen and colleagues507 found linkage for
CS to markers on chromosome 10q22-23, with a lod score of 8.92 (theta
⫽ 0.02) in 12 families. This was closely followed by independent
identification of the PTEN gene on chromosome 10 by 3 groups: Li and
Sun,510 Li and colleagues,511 and Steck and colleagues.512 Li and
colleagues511 found PTEN to have a sequence consistent with a protein
tyrosine phosphatase domain, and homology to the chicken protein tensin
and bovine protein auxilin. In the name PTEN, the phosphatase function
is represented by P; TEN refers to the homology to tensin and its location
on chromosome 10. They also found mutations of the PTEN gene in
breast cancer, glioblastoma, and prostate cancer cell lines.511 Liaw and
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colleagues513 found that 4 of 5 CS families had PTEN germline mutations
in 1997 and Nelen and colleagues514 found that 9 of 19 CS cases had
PTEN mutations.
PTEN is a dual specificity phosphatase that causes dephosphorylation of
serine/threonine and tyrosine residues and of protein and lipid substrates.515 PTEN is involved in embryonic development, the cell cycle,
apoptosis, and tumor formation. It plays an important role in the
phosphatidylinositol 3-kinase (PI3K) protein kinase B (PKB)/antiapoptotic serine threonine kinase (AKT) pathway. Upregulation of PI3K-PKB/
AKT promotes cell growth and survival, which is regulated by PTENmediated dephosphorylation of the phosphatidylinositol3-5 triphosphate
(PIP3) substrate. Reduced PIP3 levels leads to lower PKB/AKT in the cell
membrane, causing cell cycle arrest in G1 and apoptosis.516 Other
pathways regulated by PTEN may include the mitogen-activated kinase
(MAPK) pathway, which is involved in cell proliferation and differentiation and the insulin signaling pathway.517 Li and Sun,510 Li and
colleagues,511 and Steck and colleagues512 all recognized that the
mutation of PTEN leads to inactivation of its phosphatase activity and
inactivation of its role in growth inhibition, implying a tumor suppressor
role.
Marsh and colleagues518 examined a series of 37 families with CS and
identified 30 families with germline PTEN mutations, for an incidence of
81%. Zhou and colleagues519 re-examined 97 patients with CS that were
negative for PTEN mutations. They found mutations in the promoter
region of PTEN in 9 (9.3%) patients. Combining both mutations in the
PTEN promoter and coding sequence therefore accounts for approximately 90% of germline mutations seen in patients with CS.
Treatment. The first step in appropriate screening for CS is recognition
of its predisposition to malignancy. Once CS is diagnosed, patients should
be considered for genetic counseling. This provides an opportunity for
support and education, including its social, familial, and personal ramifications. In a family in which a PTEN mutation has been detected, if the
individuals at risk are negative for the same mutation, they may then
undergo routine health and cancer screening. At-risk CS patients or
patients in families without identified PTEN mutations should undergo a
general comprehensive physical examination starting at 18 years of age or
5 years before the earliest cancer was diagnosed in another family
member.
The most common cancers encountered in CS patients are of the breast
and thyroid gland. Starink and colleagues478 reported 3 patients younger
than the age of 30 years in whom breast cancer developed. Therefore,
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305
at-risk patients should perform monthly breast self-examinations starting
at age 18, with annual physical examinations beginning at age 25, or 5
to 10 years earlier than the youngest case of breast cancer in the
family.499,520 Mammography should be performed beginning at age 30
to 35 years, or at least 5 years before the youngest age of onset of
breast cancer in the family.499,521
Thyroid cancer in CS patients may develop by 10 to 30 years of
age.470,485,486,522 Screening should begin with a thyroid ultrasound at age
18, with annual physical examinations thereafter and repeat ultrasounds
as determined by the level of clinical suspicion.
To screen for endometrial cancer, annual endometrial suction biopsies
should be performed beginning at the age of 35 to 40 years, or 5 years
younger than the earliest premenopausal case of endometrial cancer in the
family. Postmenopausal women should have an annual endometrial
ultrasound. Families with a history of renal cancer should have annual
urine cytology, and renal ultrasound as indicated. Dermatologic examination is also suggested annually to screen for melanoma.499
Bannayan-Riley-Ruvalcaba Syndrome
The name Bannayan-Riley-Ruvalcaba syndrome (BRRS) was proposed
in 1990 to encompass 3 phenotypically similar syndromes (RuvalcabaMyhre-Smith syndrome, Bannayan-Zonana syndrome, and the RileySmith syndrome). The syndromes are defined by macrocephaly, and
variable penetrance of developmental delay, hemangiomas, lipomas,
genital pigmentation, intestinal polyps, and lipid myopathy.523-536 The
predominant features of BRRS as reported by Gorlin and colleagues are
listed in Table 11.
The GI polyps associated with BRRS were initially described as
hamartomatous.523,527,529,537 Further review by Haggitt and Reid538 of
the histologic features of polyps reported by Ruvalcaba found that they
were juvenile polyps, except for 1 ganglioneuroma. Recent reports have
confirmed that most polyps are juvenile polyps, which occasionally will
display adenomatous changes.539-541
Genetics. It may be difficult to distinguish between BRRS and CS.
Fargnoli and colleagues542 described a patient with findings consistent
with both BRRS and meeting the diagnostic criteria for CS. This patient
had macrocephaly, 2 lipoma resections, a thyroid follicular adenoma (that
had been removed), scoliosis, colonic polyps, and hyperpigmented
macules on the glans penis (Fig 31).542 Both BRRS and CS have an
autosomal dominant inheritance.527,531,532,536,543 Marsh and colleagues518 found a PTEN germline mutation in 4 of 7 unrelated BRRS
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TABLE 11. Bannayan-Riley-Ruvalcaba syndrome, common signs*
Craniofacial
Macrocephaly
Prominent corneal nerves/Schwalbe lines
Neurologic
Developmental delays (motor, mental, speech)
Muscular
Lipid myopathy
Cutaneous
Lipomas
Genitalia pigmentation
Angiolipomas
Gastrointestinal
Intestinal polyps (hamartomatous, juvenile)
Skeletal
Accelerated growth of 1st metacarpal, and 1st proximal and 2nd middle phalanges
Joint hyperflexibility, pectus excavatum, and scoliosis
*Reproduced with permission from Gorlin RJ, Cohen MM Jr, Codon LM, Burke BA. BannayanRiley-Ruvalcaba syndrome. Am J Med Genet 1992;44:307–14.
families in 1998. One of the these PTEN mutations had previously been
found in 2 CS families,513 suggesting that the 2 syndromes were allelic.
The largest series to date has been that of Marsh and colleagues,544 who
evaluated 43 individuals with BRRS. Of these 43 patients with BRRS, 16
were sporadic and 27 were familial.544 Eleven of the 27 familial cases
were mixed, having individuals of both CS and BRRS phenotypes. PTEN
mutations were found in 26 of 43 individuals, for a prevalence of 60%.544
Additional reports of PTEN mutations associated with patients having
BRRS have been published.545,546
In families with BRRS, the recommendations for follow-up are less
clear, because the risk for cancers has not been established. The findings
from genetic studies that BRRS and CS are allelic syndromes suggests
that the clinician maintain an elevated level of suspicion and examine the
patient annually for the same tumors seen in patients with CS.
Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome (PJS) is characterized by hamartomatous
polyps of the upper and lower GI tract, and lentigines (pigmented lesions)
of the buccal mucosa, perioral region, palms, feet, or anus (Fig 32). The
association of melanosis and polyposis was first recognized by Peutz547 in
1921, and Jeghers and colleagues548 described an autosomal dominant
inheritance in 1949. The prevalence of PJS has been estimated to be
between 1 in 8300 and 1 in 29,000.549 The mean age of diagnosis of PJS
ranges between 22 and 26 years.174,550
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307
FIG 31. Macules of the glans penis seen in a patient with Bannayan-Riley-Ruvalcaba syndrome
(reproduced with permission from Gorlin RJ, Cohen MM Jr, Condon LM, Burke BA. Bannayan-RileyRuvalcaba syndrome. Am J Med Genet 1992;44:307-14).
The intestinal polyps are most commonly found in the jejunum, and
large series have found the incidence of polyps in the small intestine to be
78%, colon 42%, stomach 38%, and rectum 28%.174,550,551 These polyps
resemble the hamartomatous polyps in patients with juvenile polyposis
and Cowden syndrome, but differ in the fact that there is prominent
smooth muscle tissue found within the lamina propria (Fig 33). Adenomatous and hyperplastic polyps may also be encountered. Gastric polyps
tend to be more sessile, whereas small and large intestinal polyps are
generally pedunculated. The most common problems arising from these
GI polyps are intussusception and GI bleeding, as highlighted by the
report of 1 family with 12 affected members that had 32 abdominal
operations and more than 70 endoscopic procedures performed for
removal of polyps.552
The skin lesions in PJS patients are pigmented macules, caused by
increased numbers of melanocytes. These lesions are not premalignant.
They are most commonly seen around the lips, mouth, hands, feet, buccal
mucosa, eyes, nose, and perianal areas.174,548 The degree of pigmentation
in cutaneous regions may decrease with age, but it may persist in the
buccal mucosa.
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FIG 32. Pigmented lesions of the oral mucosa in a patient with Peutz-Jeghers syndrome (reproduced
with permission from Aaltonen LA, Järvinen H, Gruber SB. Peutz-Jeghers syndrome. In: Hamilton SR,
Aaltonen LA, editors. WHO Classification: Tumours of the Digestive System. Lyon: International
Agency for Research on Cancer; 2000:74-6).581
In a study of 72 PJS patients, Spigelman and colleagues553 found that
16 (22%) had developed cancer, with 10 GI cancers (4 small bowel, 3
stomach, 2 colon, 1 pancreas) and 7 non-GI cancers (2 unknown primary,
1 ovary, 1 lung, 1 thyroid, 1 fallopian tube, 1 basal cell carcinoma). The
relative risk of GI cancer death was 13, and 48% of those with cancer had
died by age 57.553 Giardiello and colleagues554 found that 15 of 31 (48%)
PJS patients developed cancers over a 12-year follow-up interval. Four
had GI cancers (2 stomach, 2 colon), 4 had pancreatic cancers, and 7 had
other cancers (2 breast, 2 lung, 1 ovary, 1 uterus, 1 myeloma). The
relative risk of cancer was calculated to be 18 times higher than the
normal population, and the average age at diagnosis was 25 years
(ranging from 1 to 64 years) after the diagnosis of PJS (at mean age of 17
years).554 Lim and colleagues555 found that 8 of 70 affected PJS patients
developed cancers (2 stomach, 2 breast, 2 colorectal, 1 pancreas, 1
cervical). They calculated the risk of developing cancer by age 65 in
mutation carriers to be 47%, with a standardized mortality ratio of 13.2
for all cancers, 32.0 for GI cancer, and 13.9 for breast cancer. Boardman
and colleagues556 found that 18 of 34 PJS patients developed cancer, in
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309
which there were 10 GI (7 colon, 1 duodenum, 1 esophagus, 1 stomach)
and 16 extraintestinal cancers (6 breast, 3 lung, 2 cervix, 1 ovary, 1 uterus,
1 thyroid, 1 prostate, 1 unknown primary). Six patients had multiple
cancers. Women were at an 18.5-fold increased risk for cancer, 20.3 times
higher for breast and gynecologic malignancies. Men were at a 6.2-fold
increased risk for cancer, and the mean age of cancer diagnosis was 39.4
years in all patients.556 In a review of PJS, Hemminki557 found 39 cases
of small bowel, 31 colorectal, 17 gastric, 8 pancreatic, and 1 esophageal
cancer. There were 22 cases of breast cancer, 13 cervical, 9 lung, 8
ovarian, 3 hepatobiliary, 2 thyroid, 2 myelomas, 2 leiomyosarcomas, 2
endometrial, 1 testicular, 1 fallopian tube cancer, and 1 osteosarcoma.
Benign tumors of the breast, ovary, thyroid, and of sex cord origin have
also been reported.557 Giardiello and colleagues558 performed a metaanalysis and showed that the relative risk of small bowel cancer in PJS
was 520, stomach 213, pancreas 132, colon 84, esophagus 57, ovary 27,
lung 17, breast 15, and uterus 16. The risk of cervical and testicular cancer
was not increased.558 The mechanism of GI cancer development is likely
through hamartoma to adenoma to carcinoma, although this has not been
completely elucidated. Spigelman and colleagues553 did find that 4 to 5 of
their 10 GI cancers appeared to have developed within a hamartomatous
polyp.
Genetics of PJS. In 1997, evidence for a PJS locus on chromosome 19p
was discovered by Hemminki and colleagues,559 who performed comparative genomic hybridization and detected a region that appeared to be
lost in PJS tumors relative to normal tissues. Loss of heterozygosity
studies found consistent losses of markers from 19p in tumors. Then by
genetic linkage, they found a multipoint lod score of 7.00 at theta ⫽ 0
with the marker D19S886 in 12 PJS families.559 Amos and colleagues560
performed genetic linkage studies in 5 PJS families and confirmed linkage
to the same marker (multipoint lod score of 7.52 at theta ⫽ 0), placing the
PJS susceptibility gene within the telomeric 3 megabases of chromosome
19p. Mehenni and colleagues561 also found linkage to D19S886 with a
2-point lod score of 4.74 at theta ⫽ 0.045. Interestingly, they found
FIG 33. A) Gross picture of a small intestinal polyp in a patient with Peutz-Jeghers syndrome (PJS). B)
Photomicrograph of a colonic PJS polyp, similar to the hamartomatous juvenile polyposis polyp shown
in Fig 23, but the lamina propria has large amounts of smooth muscle present (reproduced with
permission from Aaltonen LA, Järvinen H, Gruber SB. Peutz-Jeghers syndrome. In: Hamilton SR,
Aaltonen LA, editors. WHO Classification: Tumours of the Digestive System. Lyon: International
Agency for Research on Cancer; 2000:74-6).581
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Curr Probl Surg, May 2005
311
linkage to the marker D19S891 from the long arm of chromosome 19
(19q) in 1 Indian PJS family (lod of 3.52 at theta ⫽ 0), suggesting a
possible second PJS locus.
Hemminki and colleagues562 mapped cDNA clones to a cosmid contig
created from the human chromosome 19 mapping project, spanning an
800-kb region near D19S886 known to contain the PJS gene by critical
recombinants in PJS families. Twenty-seven genes were mapped to this
region, and mutations were found in 1 called LKB1, a previously
unmapped serine threonine protein kinase gene. Of 12 unrelated PJS
patients sequenced, 11 were found to have LKB1 mutations (5 deletions,
1 insertion, 5 substitutions; Fig 34). This gene was expressed in all tissues
examined, and the mutations found were predicted to diminish the kinase
activity of the protein, in contrast to the activation of kinases seen in other
heritable cancer syndromes (such as RET in MEN2, and CDKN2 in
familial melanoma).562 A similar effort from Jenne and colleagues563
mapped 21 genes from overlapping cosmid clones spanning 400 kb in the
region of D18S886, and 1 of these genes was found to have a rearrangement in a PJS patient. This was a serine threonine protein kinase gene
consisting of 9 exons over 23 kb of genomic DNA, which they called
STK11 (although it had previously been given the name LKB1). The PJS
proband had a deletion of exons 4 and 5, and inversion of exons 6 and 7,
and all 3 affected members of her family also had this rearrangement.
Analysis of 4 other unrelated PJS patients revealed 3 nonsense and 1
splice site mutation of the gene.563
Gruber and colleagues564 found an LKB1 mutation in the original
family reported by Jeghers,548 as well as 5 others (2 deletions, 2
insertions, 2 nonsense mutations). They confirmed that LKB1 was a tumor
suppressor gene by demonstrating that 11 of 12 hamartomas or adenocarcinomas from 4 PJS patients had loss of the wild-type allele with
retention of the mutated allele. The losses seen in hamartomas implied
that this gene is involved at an early stage of tumor progression.564 Jiang
and colleagues565 found only 1 mutation of LKB1 in 10 unrelated PJS
patients, and suggested that there may be other genes responsible for JPS.
Nakagawa and colleagues566 analyzed 15 unrelated PJS patients for
mutations, and found them in 10. Four were deletions causing frameshifts,
3 were insertions, 2 were splice site mutations, and 1 was a nonsense
mutation.
Miyaki and colleagues567 found LKB1 mutations in 6 of 9 PJS families
studied, which consisted of 3 deletions, 2 insertions, and 1 splice site
mutation, all predicted to cause protein truncation. They also found
somatic LKB1 mutations in 5 of 27 (19%) polyps, 4 of which shared a
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4-bp deletion in exon 6. Fourteen other polyps had LOH of 19p markers,
for a total of 70% of polyps showing potential somatic inactivation of
LKB1. Six larger polyps also had ␤-catenin mutations, suggesting these
changes may be important in polyp progression. One carcinomatous
polyp examined had 19p LOH, ␤-catenin mutation, and p53 mutation,
suggesting a hamartoma-adenoma-carcinoma sequence in PJS polyps.567
Gruber and colleagues564 found that 11 of 12 hamartomas and adenocarcinomas had 19p LOH, 1 of 18 had 18q LOH, and 0 of 18 had K-ras
mutations.
Wang and colleagues568 found LKB1 germline mutations in 7 of 12
(58%) PJS patients, which included 4 deletions, 2 nonsense mutations,
and 1 missense mutation. Four families without mutations had findings
compatible with LKB1 linkage, suggesting that alterations might be
present but were not detected by their sequencing or single strand
conformational polymorphism (SSCP) analysis.568 Westerman and colleagues569 found LKB1 mutations in 12 of 19 PJS families (63%), which
consisted of 3 deletions, 3 insertions, 3 missense mutations, 2 splice site
mutations, and 1 nonsense mutation.
Boardman and colleagues570 screened 10 familial and 23 sporadic cases
of PJS for LKB1 changes by conformation-sensitive gel electrophoresis
(CSGE), and only found mutations in 2 and 4 cases, respectively. The low
mutation rate found in this study may have been due to the lower
sensitivity rate of CSGE for identifying base-pair changes (which is
approximately 90%), other mechanisms of LKB1 alteration, or the
possibility that other genetic loci for JPS may exist (genetic heterogeneity).570 Lim and colleagues555 also used CSGE to screen 33 JPS families
for LKB1 mutations, and found mutations in 17 (52%; 5 deletions, 3
splice site mutations, 2 insertions, 3 nonsense, and 4 missense mutations).
Boudeau and colleagues571 studied the functional consequences of 6
germline LKB1 mutations (4 deletions and 2 missense mutations) in PJS
patients by cloning the cDNA into a CMV expression vector. They found
that each of these LKB1 isoforms was unable to autophosphorylate at
Thr336, and to suppress the growth of a melanoma cell line, in contrast
to wild-type LKB1. They concluded that these were loss-of-function
mutations, and that loss of kinase activity was responsible for PJS.571
Esteller and colleagues572 studied 51 cancer cell lines (15 colon, 11
lung, 7 ovary, 5 breast, 3 thyroid, 3 brain, 3 prostate, 3 leukemia, 1 cervix)
for methylation of a CpG island just upstream from LKB1, and found this
in 3 colorectal and 1 cervical cancer cell lines with coincident loss of
LKB1 expression. They also found methylation in 4 of 22 (18%)
Curr Probl Surg, May 2005
313
314
Curr Probl Surg, May 2005
hamartomatous polyps in PJS patients, suggesting that this mechanism of
gene inactivation may be involved in a subset of PJS cases.572
Entius and colleagues573 examined 39 polyps and 5 carcinomas from 17
PJS patients for LOH for markers at the LKB1 locus on 19p13, 5q21
(APC), 17p13 (p53), and 18q21 to 22 (MADH2, MADH4). Fifteen of 39
(38%) polyps had 19p13 LOH, as did 5 of 5 carcinomas. Six of 7 polyps
from the 5 patients with carcinoma demonstrated 19p LOH. No LOH was
seen at 5q21, but 1 cancer had an APC mutation. LOH was not found at
17p13 in any of these samples, but was found in 1 cancer at 18q; however,
all polyps and cancers had p53 and MADH4 expression by immunohistochemistry. The authors concluded that LKB1 loss was important in
tumorigenesis in PJS patients, and the genetic mechanisms responsible
differed from those in sporadic colorectal carcinogenesis.573
Surveillance and Follow-Up. Recommendations for surveillance of
patients with PJS or at risk for PJS are not clear, but must address the
significantly elevated risk of a variety of cancers, such as the aforementioned increased relative risk of small bowel cancer (520-fold increased
risk), stomach,213 pancreas,132 colon,84 esophagus,57 ovary,27 lung,17
uterus,16 and breast.15,558 Dunlop574 recommended that colonoscopy or
barium enema be performed every 3 years beginning at age 18, and that
upper endoscopy be performed every 3 years beginning at age 25.
Hemminki557 recommends biannual upper and lower endoscopy beginning in the mid teen years, and others suggest these be performed every
2 to 5 years.575 How to follow the small bowel in PJS patients remains a
challenge. These polyps can lead to intussusception or anemia and
develop into cancers. Small bowel follow-through and enteroclysis will
show larger polyps, but the relatively new technique of capsule endoscopy may be the best available method for visualization of small bowel
polyps. It would seem prudent to perform capsule endoscopy at least
every 3 years in asymptomatic PJS gene carriers, which might preclude
the need for screening colonoscopy and upper endoscopy, which could be
reserved for therapeutic interventions. If multiple polyps are found, then
screening should be performed at least annually until the polyps are
removed.
Gastric and colonic polyps may be removed endoscopically, with
FIG 34. A) Location of LKB1 on chromosome 19p. B) Genomic and protein structure and mutations
described in LKB1 (reproduced with permission from Hemminki A, Markie D, Tomlinson I, Avizienyte
E, Roth S, Loukola A, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.
Nature 1998;391:184-7).
Curr Probl Surg, May 2005
315
surgery being reserved for lesions with dysplasia or cancer. Less invasive
therapeutic interventions for small bowel polyps are more limited, since
most enteroscopes will only reach the proximal jejunum. Surgery is
therefore the required treatment for symptomatic polyps (causing intussusception, anemia, or pain) or those suspicious for cancer. At operation,
intraoperative endoscopy through an enterotomy can be performed to
examine the entire small bowel, and polyps may be removed through the
endoscope by using a snare cautery. Larger or suspicious polyps will
require enterotomy or small bowel resection for their removal.
Surveillance recommendations for extraintestinal cancers in PJS patients are not well established. Screening for breast cancers should include
annual breast examination and mammography (or ultrasound in patients
younger than age 35), with the latter beginning between the ages of 25
and 35. Gynecologic malignancy should be ruled out by annual transvaginal ultrasound, pap smear, and pelvic examination. Annual testicular
examination and ultrasound should be initiated in males by age 10.
Screening for pancreatic cancer by abdominal ultrasound, endoscopic
ultrasound, or computed tomography should be performed every 1 to 2
years starting at age 30.552,557,575
The diagnosis of PJS gene carriers may be evident from within the first
year of life based on the characteristic mucocutaneous pigmentation.
These patients will clearly need surveillance. Gene testing for PJS
involves direct sequencing of the entire gene for probands and directed
mutation screening of other at-risk individuals once a mutation is found
in the family. Genetic testing of at-risk individuals from families with
known LKB1 mutations will benefit those found not to harbor the
disease-causing mutation because they may be excused from the screening regimens. Those found to be gene carriers will need to be educated
regarding their risk for developing cancer and be given these surveillance
recommendations.
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