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Hereditary Colorectal Cancer-Part II

ynch SyndromeThere are 2 broad classes of hereditary forms of colorectal cancer

CRC), based on the predominant anatomic location of the CRC: distalersus proximal. CRCs involving the distal colon are more likely to showneuploid DNA content, harbor mutations in APC, p53, and K-ras genes,nd behave more aggressively303,304; proximal CRCs are more likely tohow diploid DNA, possess microsatellite instability, harbor mutations inhe mismatch repair (MMR) genes, and behave less aggressively, as inereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syn-rome.303,304 Familial adenomatous polyposis (FAP) and most sporadicases may be considered a paradigm for the first, or distal, CRC class,hereas Lynch syndrome more clearly represents the second, or proxi-al, CRC class.303,304

The term Lynch syndrome is used in preference to HNPCC, given theact that the syndrome’s phenotype is not completely without polyps, andn addition to CRC it involves a litany of extracolonic cancer types thatre integral to the syndrome. It is the most commonly occurringereditary syndrome that predisposes to CRC304 (Fig 2; Part I). Itsiagnosis requires a sufficiently detailed family history of colorectalarcinoma as well as cancer of all anatomic sites, particularly those thatre integral to this disorder (e.g., carcinoma of the endometrium [theecond most common cancer], ovary, stomach [particularly in familiesrom Japan and Korea],305 hepatobiliary tract, small bowel, pancreas,pper uroepithelial tract, and brain).303,304,306,307

istory of Lynch SyndromeThe history of what is known as Lynch syndrome dates to anbservation of Aldred Warthin, pathologist at the University of Michiganchool of Medicine.308 He became deeply moved when his seamstress, in895, told him that she would likely die of cancer of the colon, stomach,r her female organs, because of the enormous proclivity to these cancers
n her family (unfortunately, just as she had told Warthin, she died at a
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oung age of metastatic endometrial carcinoma). Warthin listened in-ently, developed her pedigree, and along with other similar cancer proneamilies published this work in 1913.309 Warthin updated the family’sistory in 1925.310 The seamstress’s family has since been known asamily G.Lynch and colleagues311 described the natural history and genetics of 2

arge Midwestern kindreds (Families N and M) in 1966. Dr. A. Jamesrench, Warthin’s successor as chairman of pathology at the University ofichigan, heard about Lynch’s research on Families N and M, and

ecalled that Warthin, his predecessor, had discovered a similar familyFamily G) in 1895. Lynch was then invited by French to take custody ofll the detailed documents and pathology specimens that the meticulous

arthin had investigated, catalogued, and published over a span of morehan 30 years.309,310 The history of Family G was then updated andublished in 1971.312 This material is discussed in a more detailed reviewf the history of HNPCC.313 Through the use of conversion technology,n MSH2 mutation was identified in Family G in the year 2000.314 Tablesummarizes the important points in the history of HNPCC.

linical Features and Diagnostic CriteriaThe cardinal clinical features of the Lynch syndrome are listed in Tableand are discussed in more detail in other review articles.303,304,315

everal international diagnostic criteria for the Lynch syndrome haveeen developed, the foremost being the Amsterdam I,316 AmsterdamI,317 and the Bethesda Guidelines.318 The variety of criteria that haveeen developed for the syndrome testifies to its complexity. The originalmsterdam I criteria were developed for the purpose of consistent

lassification of subjects in research programs and focused on CRCTable 9). The subsequent Amsterdam II criteria added the syndrome’sntegral extracolonic cancers to the focus to be more useful for clinicaliagnosis purposes. The Bethesda Guidelines introduced molecular ge-etic considerations, linking the diagnostic criteria of the Lynch syn-rome to the high percentage of Lynch syndrome tumors that are positiveor microsatellite instability (MSI), to provide guidelines for MSI testing.ther criteria, such as those developed in Korea and Japan, make use of

merging knowledge regarding the syndrome’s phenotypic variability inifferent geographic regions. These criteria are based heavily on theamily history, which we consider to be potentially the most cost-eneficial component of a patient’s medical evaluation; however, we are
lso cognizant of the fact that it remains 1 of the most neglected portions
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ABLE 7. Landmarks of Lynch syndrome history*

FeatureFirst

reportReferences

amily G of Warthin (study began 1895) 1913 309enetic counseling 1965 582, 583irst report of Lynch et al. on Families N and M 1966 311arly age of cancer onset 1966 311utosomal dominant inheritance pattern 1966 311amily information session (FIS) 1966 311, 584, 585creening recommendations 1967 586pdate of Family G 1971 312roximal colon involvement 1977 376eginning of study of Lynch syndrome in Uruguay 1977 587ecommendation of prophylactic TAH-BSO 1978 588uir-Torre syndrome (as variant of Lynch syndrome) 1980 382, 589

ncreased incidence of synchronous and metachronous CRC 1982 377, 378ynch syndrome studies begin with the Navajo 1983 590–592ritiated thymidine distribution studies of rectal mucosa 1983 593NPCC named “Lynch syndrome” 1984 594elenium levels in Lynch syndrome studied 1984 595ormation of ICG-HNPCC 1989 317, 596ectin binding studies in FAP and HNPCC 1990 597–599msterdam I criteria 1991 316ccelerated carcinogenesis and interval CRC 1992 365, 395, 396,

600, 601irst cancer susceptibility locus found on 2p through linkageanalysis

1993 326

econd cancer susceptibility locus found on 3p through linkageanalysis

1993 327

NA mismatch repair genes reported 1993 328, 329, 334,335

ER� (MSI) phenotype described 1993 322ermline mutations in the syndrome 1993 328SH2 mutation identified 1993 329xtracolonic adenocarcinomas 1994 307istinctive pathology features 1994 365SH2; MLH1 mutations 1994 329, 335reighton group’s involvement in Uruguayan study 1995 602istorical perspective through 1995 1995 603ole of DNA MMR genes in CRC tumorigenesis 1995 604, 605ecommendations of prophylactic subtotal colectomy 1996 391, 392urvival advantage 1996 374, 379IH NCI workshop on HNPCC (Bethesda Guidelines) 1996 318SH6 mutation 1997 347, 606IH NCI update on MSI 1997 607mall bowel involvement 1998 608ounder mutation in Finland 1998 356msterdam II criteria 1999 317umor infiltrating lymphocytes and their association with MSI 1999 380
onversion technology 2000 314

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f a cancer patient’s medical evaluation in the average clinical practiceetting.319,320

ABLE 7. Continued

FeatureFirst

reportReferences

complex mutation of MLH1 at codon 222 is associated withadolescent onset of CRC (more early-onset CRC familiesneeded for study)

2001 609

luorouracil-based adjuvant chemotherapy benefits patientswith stage II or stage III CRC with MSS or MSI-L tumors butnot those with MSI-H tumors

2003 610

2O2 effect improves survival in DNA MMR-deficient cell line 2003 611SH2 del1-6 founder mutation in the United States 2004 315

Reproduced from Lynch HT, Shaw TG, Lynch JF. Inherited predisposition to cancer a historicalverview. Am J Med Genet C (Semin Med Genet) 2004;129C:5–22.bbreviations: CRC, colorectal cancer; HNPCC, hereditary nonpolyposis colorectal cancer;AH-BSO, total abdominal hysterectomy and bilateral salpingo-oophorectomy; ICG-NPCC, International Collaborative Group on HNPCC; FAP, familial adenomatous poly-osis; MMR, mismatch repair; NIH, National Institutes of Health; NCI, National Cancer

nstitute; MSI, Microsatellite instability; MSS, Microsatellite stable.

ABLE 8. Cardinal features of Lynch syndrome

● Earlier average age of CRC onset than in the general population; the average age of CRConset 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 initialCRC, 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 andsignet-cell features, show a Crohn’s-like reaction, and contain a significant excess ofinfiltrating lymphocytes within the tumor. Microsatellite instability (MSI) is found in mostCRC 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

bbreviations: HNPCC, hereditary nonpolyposis colorectal cancer; CRC, colorectal cancer;MR, mismatch repair.

Differing stages in the development of a Lynch syndrome pedigree


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herein each component provides a pictorial review of its genesis arehown in Figure 16. For example, note that the proband had multiplerimary cancers at an early age (Panel A), which should provide thelinician with vital clues of the possibility of the Lynch syndrome. Thisuch information does not fulfill any of the criteria in Table 9, yet we

elieve the information is sufficient to test for a mismatch repair geneMMR) germline mutation. However, when the pedigree is furtherxtended, it essentially epitomizes an HNPCC diagnosis (Panels B and

ABLE 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 22. At least 2 successive generations affected3. At least 1 of the relatives with colorectal cancer diagnosed at less than 50 years of

age4. 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, smallbowel, hepatobiliary tract, and skin [sebaceous tumors]):1. One is a first degree relative of the other 22. At least 2 successive generations affected3. At least 1 of the hereditary nonpolyposis colorectal cancer-associated cancers

should be diagnosed at less than 50 years of age4. 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 criteria2. 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 thecancers diagnosed at age less than 45 years and the adenoma diagnosed at ageless than 40 years

4. Individuals with colorectal cancer or endometrial cancer diagnosed at age less than45 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 45years‡

7. Individuals with adenomas diagnosed at age less than 40 years

Endometrial, ovarian, gastric, hepatobiliary, or small-bowel cancer or transitional cellarcinoma of the renal pelvis or ureter.Solid/cribiform defined as poorly differentiated or undifferentiated carcinoma composed of

rregular, solid sheets of large eosinophilic cells and containing small gland-like spaces.Composed of more than 50% signet ring cells.

), and when extended even further, as shown in Panel D, it essentially


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volves into highly detailed information that is used for researchurposes. The extended pedigree is also valuable for identifying otheramily members at risk for developing HNPCC and its related extraco-

IG 16. Four stages of a pedigree. (Reproduced with permission from Lynch HT, de la Chapelle A. Hereditaryolorectal cancer. N Engl J Med 2003;348:919-32.) A) The initial ascertainment of what turned out to be alassical hereditary nonpolyposis colorectal cancer pedigree. The proband (IV-1) showed early-onset colorectalarcinoma and carcinoma of the ureter. These findings by themselves are highly significant. However, hisother (III-1) had uterine cervical carcinoma at age 37, a tumor not associated with the syndrome, but at age5 had colorectal carcinoma. B) Further inquiry indicated that the proband’s mother (III-1) had 2 sisters withndometrial carcinoma at ages 57 (III-2) and 61 (III-3). This pattern, notwithstanding Amsterdam criteria, woulde sufficient for a hereditary nonpolyposis colorectal cancer diagnosis. C) Extending the pedigree further, 1 of

hese maternal aunts (III-2) had 3 cancer-affected sons, 1 with early-onset metachronous colon cancer (IV-3), aecond with colon cancer and carcinoma of the ureter (IV-4), and the other with colon cancer only (IV-5). Thether aunt (III-3) had a daughter (IV-6) with cancer of the bile duct. These findings provide strong evidence for

he diagnosis of hereditary nonpolyposis colorectal cancer. D) The fully extended pedigree, with findingsontinuing to support a diagnosis of hereditary nonpolyposis colorectal cancer.

onic cancers.


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From a practical standpoint, the clinician does not need to go into thisuch depth to diagnose the Lynch syndrome. We believe that theodified nuclear pedigree (Fig 17), wherein attention is given to a

etailed description of the proband, with pathologic documentation ofancer, and is extended to that individual’s primary relatives (parents,iblings, and progeny), and then to secondary relatives (maternal andaternal aunts and uncles, and both sets of grandparents), who will beighly genetically informative because they have passed through theancer risk age, will, in most cases, provide enough information toiagnose the Lynch syndrome, should it be present in the family. The sineua non for this diagnosis will be the presence of a germline mutation inof the mismatch repair genes.

enetics of Lynch SyndromeMicrosatellite Instability. Microsatellite instability (MSI) is a phenom-

non observed in some colorectal tumors, especially in patients withNPCC. It is present in approximately 90% to 95% of cancers in Lynch

yndrome, and in approximately 15% of sporadic CRCs. When DNA ismplified using primers derived from highly repetitive DNA sequences,ew alleles frequently appear in tumor DNA relative to normal DNA (Fig8). These new alleles represent small insertions or deletions as aonsequence of uncorrected errors in DNA replication. In 1 of the firsttudies, Thibodeau and colleagues321 found MSI in 25 of 90 (28%)olorectal cancers, which was more common in proximal versus distal

IG 17. The necessary information on first and second degree relatives, which will aid significantlyn hereditary cancer syndrome diagnosis.

ancers (P � 0.003), and these tumors were associated with a better


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rognosis than those without microsatellite instability (P � 0.02).altonen and colleagues322,323 found 86% (25 of 29) of HNPCC

olorectal tumors to be replication error positive (RER�, synonymousith MSI) but only 16% (8 of 49) of sporadic colorectal cancers wereER�. This group found that 3% (1 of 33) of sporadic adenomas and6% (8 of 49) of sporadic carcinomas were RER�, whereas 57% (8 of4) of adenomas from HNPCC patients were RER�. This suggested thatdenomatous polyps were precursor lesions to colorectal cancer inNPCC.323

MSI in colorectal cancers reminded investigators of abnormalities seenn DNA mismatch repair genes from yeast cells, where increases or

IG 18. Microsatellite instability, as demonstrated in 3 normal (N) and colon tumor (T) tissue pairssing the dinucleotide repeat marker D3S1029. Note an extra group of bands in each tumor,epresenting a new allele (reproduced with permission from Lindblom A, Tannergard P, Werelius B,ordenskjold M. Genetic mapping of a second locus predisposing to hereditary non-polyposis colon

ancer. Nat Genet 1993;5:279-82).

ecreases in the number of repeat units within repetitive DNA sequences


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esult.324 DNA mismatch repair genes in bacteria encode for the enzymesutS (which binds to base mismatches), mutH (which binds to methyl-

ted CpG nucleotides and cuts the opposite strand), mutL (a facilitator ofutS and mutH), UvrD (a helicase that excises mismatched strands),NA polymerase III holoenzyme (which adds new bases), and DNA

igase.325 Since yeast lack methylated DNA, they do not have mutH. Theomologous 2 mutL proteins in yeast are PMS1 and MLH1, and theomologous protein to mutS is MSH2 (Fig 19). When these yeast genesre mutated, there is a corresponding 100- to 700-fold increase in MSI. Its believed that these genetic changes lead to errors in the number of

IG 19. An overview of DNA mismatch repair enzymes (reproduced with permission from Chung DC,ustgi AK. The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implica-ions. Ann Intern Med 2003;138:560-70)576.

epetitive sequences replicated, due to lack of repair and DNA polymer-


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se slippage.324 The observation that tumors in patients with Lynchyndrome had similar changes to those seen in bacterial and yeast cellsith DNA mismatch repair gene mutations led investigators to examine

he human homologs of these genes in HNPCC.Identification of Lynch Syndrome Genes. In 1993, Peltomäki and

olleagues326 from Finland and Lindblom and colleagues327 from Swe-en discovered sites on chromosomes 2p and 3p by linkage analysis,espectively, as being etiologic for cancer susceptibility in the Lynchyndrome. Aaltonen and colleagues322 also demonstrated that tumors inynch syndrome were RER�.hMSH2 Gene Mutations. Fischel and colleagues328 identified the mutSomolog MSH2 in humans (hMSH2) and mapped it to chromosome 2.hey found that 2 of 7 MSI� tumors had point mutations affecting aplice acceptor site in hMSH2 and that this same mutation was present inffected members of 2 Lynch syndrome families. The same gene wasdentified by Leach and colleagues329 by using a positional cloningtrategy, and a gene homologous to mutS was found to map within annterval defined by critical recombinants in Lynch syndrome familiesinked to a 2p locus. The gene was 2802 bp in length, and a missenseutation was found in 11 affected members of 1 kindred, a splice siteutation in another, and a nonsense mutation in another. Both germline

nd somatic mutations were found in 1 of 4 RER� sporadic CRC,uggesting that this gene was a tumor suppressor gene. The important rolef hMSH2 in Lynch syndrome was subsequently confirmed by severalnvestigators. Nystrom-Lahti and colleagues330 found that 4 of 6 Lynchyndrome families linked to chromosome 2p had hMSH2 mutations. Liund colleagues331 reported that 10 of 25 Lynch syndrome kindreds hadermline hMSH2 mutations, with 9 mutations leading to a truncatedrotein. Wijnen and colleagues332 described 7 hMSH2 mutations in 34ynch syndrome kindreds leading to protein truncation, and found novidence of correlation of genotype with phenotype in Lynch syndrome.aliaka and colleagues333 found that 4 of 11 Russian and Moldavian

ynch syndrome kindreds had hMSH2 mutations.hMLH1 Gene Mutations. Papadopoulos and colleagues334 screeneduman gene databases for sequences with similarities to the yeast mutLenes and found 3 genes, called hMLH1, hPMS1, and hPMS2. Theseenes were localized to chromosomes 3, 2, and 7, respectively, byomatic cell hybrids. hMLH1 held immediate interest due to the previousnding of genetic linkage in some Lynch syndrome families to chromo-ome 3p21.327 This gene was 2268 bp in length and expressed in a wide
ariety of tissues. They found that 9 of the 10 Lynch syndrome families

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emonstrating linkage to markers on 3p had germline hMLH1 mutationshereas only 1 of 18 Lynch syndrome kindreds that were too small to be

tudied by linkage had mutations, thereby establishing hMLH1 as anothermportant predisposition gene for Lynch syndrome.334

Bronner and colleagues335 independently identified hMLH1 by search-ng a human cDNA library for genes homologous to mutL. They found aene encoding for a 756-amino acid protein that localized to chromosomep21.3-23. They also found that 4 affected members of a Lynch syndromeamily had a germline substitution in a highly conserved exon ofMLH1.335 Han and colleagues336 reported that 8 of 34 (24%) unrelatedynch syndrome patients had hMLH1 mutations, and Nystrom-Lahti andolleagues330 demonstrated that 3 of 4 Lynch syndrome kindreds linkedo 3p had hMLH1 mutations. Kolodner and colleagues337 defined theenomic structure of hMLH1 and found a frameshift mutation in 9 of 19embers of a Lynch syndrome kindred linked to markers on 3p. Wijnen

nd colleagues332 found 12 of 34 (35%) kindreds with hMLH1 mutations,nd exons 15 and 16 were hot spots for mutation, accounting for 50% ofeported mutations. No genotype-phenotype correlations were observedor hMLH1 either, as suggested by 3 Lynch syndrome families with aommon exon 16 deletion, where 1 had Turcot’s syndrome and the otherdid not have family members with CNS tumors.338

In cell lines, Parsons and colleagues339 demonstrated that mutation of 1llele in a DNA mismatch repair gene alone did not result in the RER�henotype. Hemminki and colleagues340 found that one third of patientsith germline mutation in hMLH1 also had somatic loss of wild-typeMLH1 in RER� tumors, consistent with a tumor-suppressor geneunction.Herman and colleagues341 described methylation of the hMLH1 pro-oter in sporadic CRC demonstrating MSI, with subsequent loss of

MLH1 expression. No methylation of hMSH2 was found. Methylationf the hMLH1 promoter is also common in MSI-positive sporadicndometrial cancers, and Simpkins and colleagues342 reported this in 41f 53 such cases.hPMS1 and hPMS2 Mutations. Papadopoulos and colleagues334 dis-

overed the human mutL homologs hPMS1 and hPMS2 in 1994 andapped them to chromosomes 2 and 7. Nicolaides and colleagues343

apped hPMS1 to chromosome to 2q31-33 by FISH and demonstratedhe gene encoded for a 932-amino acid protein; hPMS2 mapped to 7p22nd encoded for a 862-amino acid protein. They examined 22 hMSH2 andMLH1 mutation-negative Lynch syndrome patients and found 1 with a
PMS1 missense mutation and another with a hPMS2 deletion. A tumor

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rom the latter patient demonstrated deletion of the other hPMS2 allele,upporting a tumor suppressor role.343 A family with Turcot’s syndromeas also been reported with a missense mutation of hPMS2.29

hMSH6 Gene Mutations. Another mutS gene homolog was identifiedn 1995, by virtue of it forming heterodimers with hMSH2, called GTBPG/T binding protein) or hMSH6.344,345 It was found to map in closeroximity to hMSH2 on chromosome 2p16, and mutations were rare inynch syndrome patients. Cells lacking hMSH6 generally have changes

n mononucleotide tracts rather than other simple tandem repeat se-uences more commonly present with other MMR genes.346 Miyaki andolleagues347 found that 1 of 5 HNPCC families lacking hMSH2 orMLH1 mutations had an hMSH6 mutation. Wijnen and colleagues348

eported 10 hMSH6 mutations in 214 hMLH1 and hMSH2 mutationegative families, 71 meeting the Amsterdam criteria (3 mutations) and43 suspected of having Lynch syndrome but not meeting the Amsterdamriteria (7 mutations). The age at which colon cancer developed was latern these patients, and there was a higher incidence of atypical endometrialyperplasia and cancer (73%, versus 29% in hMSH2 and 31% in hMLH1utation carriers).348 Wu and colleagues349 demonstrated that 4 of 18

ndividuals with Lynch syndrome-associated tumors that were MSI-lowad hMSH6 mutations. Berends and colleagues350 found hMSH6 muta-ions in 25 of 316 suspected Lynch syndrome cases, and Huang andolleagues351 detected only 1 of 90 cases with hMSH6 mutations in whichMSH2 or hMLH1 mutations were not found.Endometrial Cancer and MMR Germline Mutations. Berends and

olleagues352 examined the frequency of MMR germline mutations in 58atients with endometrial carcinoma who were diagnosed at less than 50ears of age. The objective was to relate the occurrence of MMRutations to family history, as well as to histopathologic data in the

resence of MSI positivity and immunostaining to develop criteria forenetic testing. The results showed that 5 of 22 patients who had aositive first degree family history for Lynch syndrome-related cancersad pathogenic germline mutations (1 MLH1, 3 MSH2, and 1 MSH6).our of the mutation carriers were members of families that fulfilled theevised Amsterdam criteria, whereas no mutations were identified in the5 patients who lacked such family history (P � 0.006). In turn, MSI wasdentified in 20 of 57 cancers in which 1 or more MMR proteins werebsent. Among all 5 MMR mutation carriers, immunostaining identifiedhe involved MMR gene.352 These findings support the conclusion that an
NPCC-related cancer in a first degree relative is an important selection

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riterion for mutation analysis. Immunostaining of MMR proteins willhen aid in targeting the gene(s) that should be analyzed.Overview of Genetic Changes. Lynch syndrome is an autosomalominant condition, caused by germline changes in DNA mismatch repairenes, which behave as tumor suppressor genes. Individuals born withhese germline alterations have 1 normal copy (wild-type) of the gene inach cell and 1 mutant copy. When the wild-type (functional) copy is losts a somatic event (in a nongerm cell), that cell develops the characteristicf microsatellite instability. The inevitable mistakes that occur duringNA replication are not efficiently repaired, and these changes may lead

o unrestrained growth that leads to adenoma, then carcinoma. Theumbers of the mutations of various MMR genes in 49 Lynch syndromeamilies fulfilling the Amsterdam criteria were 21 hMLH1 (43%; 19 pointutations, 2 deletions), 22 hMSH2 (45%; 10 point mutations, 12

eletions), 2 hMSH6 (4%), and 4 (8%) were negative for point mutationsr genomic rearrangements.353 The frequency of hMSH2 mutations mayave been overestimated in this study, however, because 7 families hadhe same 20 kb deletion encompassing exons 1-6 and appeared potentiallyo share a common ancestor. A compilation of published and unpublishedutations have been established by the International Collaborative Group

n HNPCC (http://www.nfdht.nl), in which the numbers of hMLH1utations reported were 323 (63% of total), hMSH2 156 (25%), hMSH6

0 (6%), hPMS2 2 (0.4%), and hPMS1 1 (0.2%). The mutations found inhe hMLH1 and hMSH2 genes are distributed throughout the exons, ando clear correlations between genotype and phenotype are known, withhe exception of the higher incidence of MSI-low and endometrial cancersn those patients with hMSH6 mutations.One might appropriately probe more deeply into the question about whynly approximately one half of Lynch syndrome families will have anMR mutation identified, or why some classical FAP families may not

ave an APC germline mutation identified. This vexing problem has beenddressed by Renkonen and colleagues354 in both HNPCC and FAPamilies that lack any sequence changes for their respective knownusceptibility genes. These authors suggest that these genes either havelterations that have escaped detection by conventional techniques, orlternatively, other, as yet unknown, susceptibility genes are involved.urthermore, they suggest that significant proportions of families that areresumed to be mutation negative (11 of 26 families in their study, or2% 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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onclusion that such changes may be detected by expression-basedethods.354,355

Founder Mutations in Lynch Syndrome. De la Chapelle and Wright356

valuated 2 founder mutations in the hMLH1 gene in Finland, whichccounted for approximately one half of all Lynch syndrome germlineutations in that country.357,358 They identified haplotype sharing “. . .

ver a genomic region as large as 18 cM indicated a relatively recentounding of the more prevalent mutation. . . wherein the ‘age’ of thisutation in most of the 19 kindreds studied could be estimated at 16-43

enerations in keeping with historical records and compatible with aounding in a regional subisolate in new Finland in the early500s.”357,359 This research, once the mutations became more fullynderstood and characterized, indicated that their presence in a patient oramily could identify individuals who could benefit significantly fromighly targeted cancer control programs.360

A founder mutation consisting of a 4-bp deletion beginning at the firstucleotide of codon 727 in hMLH1 has been identified in Navajo familiesrom Arizona. A deletion encompassing exons 1-6 of the MSH2 gene haseen identified in an extended American kindred of German origin.315

Foulkes and colleagues361 described a founder mutation ofMSH2(1906G¡C) in the Ashkenazi Jewish population. This mutationesults in a substitution of proline for alanine at codon 636 in the MSH2rotein and was identified in 15 unrelated Ashkenazi Jewish families withynch syndrome who met the Amsterdam criteria. These families shared

he same alleles with 18 polymorphic loci within and flanking the MSH2egion, which was consistent with a single origin for this mutation.hrough immunohistochemical analysis, all CRCs that were tested were

ound to harbor MSI and absence of the MSH2 protein. These authorshen provided an analysis of a population-based incidence series of 686shkenazi Jews from Israel who manifested CRC. Their results showed

hat 3 (0.44%) were mutation carriers. Furthermore, those patients with aamily history of CRC or endometrial cancer were more likely to harborhe mutations than those without such a family history (P � 0.042).ndividuals with CRC who were mutation carriers were, on average,ounger than CRC-affected individuals who were noncarriers (P �.033). Five hundred sixty-six unaffected Ashkenazi Jews from Israel and022 controls from New York were all found to be noncarriers. Inospital-based series, the 1906 allele was identified in 5 of 463 Ashkenaziews with CRC, 2 of 197 with endometrial cancer, and 0 of 83 withvarian cancer.
Guillem and colleagues362 identified this rare founder mutation, hMSH2

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906C¡G, in Ashkenazi Jews in 8 of 1345 individuals (0.6%) with CRC.hey then investigated the proportion of individuals of Ashkenazieritage who manifested early-onset CRC (age � 40 years) that could bexplained by hMSH2 1906C¡G. They detected this mutation in 3 of the1 samples (7.14%) among Ashkenazi patients with CRC diagnosedefore age 40, an incidence found to be significantly greater than the 8 in345 (0.6%) that was observed in CRC among Ashkenazi Jews who wereot selected for age (P � 0.004). They concluded that their results meritesting for the hMSH2 1906C¡G mutation among Ashkenazi Jewsanifesting early-onset CRC.362

Strategy for Genetic Testing. As in other autosomal dominantonditions, the affected proband should be studied thoroughly forutations to allow for directed testing later in other members at risk.his should be performed in patients meeting the Amsterdam criteria,r in those who are suspected of having Lynch syndrome but do noteet the criteria (as in the Bethesda guidelines). The Lynch syndrome

atient’s tumor should first be tested for MSI, and testing for MSH2 orLH1 expression by immunohistochemistry can also be quite helpful

n determining which gene is most likely affected in the family. If MSIs not found, then sequencing of MMR genes is not warranted. If theumor is MSI-positive or loss of protein expression is found, thenequencing of hMLH1 and/or hMSH2 is indicated. The frequency ofMS gene mutations is so low that their sequencing is not generallyerformed; hMSH6 sequencing may be indicated in cases with aamily history suggestive of Lynch syndrome where tumors are

SI-low or there is a high incidence of endometrial cancer. In rareases, there may be mutations in PMS2, MLH3, and EXO1.363

Lynch Syndrome Versus Early Onset Sporadic Colon Cancer. Even inhose cases in which the Amsterdam criteria have not been met, Jass hasuggested that the profile of early-onset MSI-high (MSI-H) CRCsesembles that of Lynch syndrome cancer, with emphasis on the histo-ogic features and site of tumors. Furthermore, Jass provides 5 cogent andnterrelated reasons for questioning the presumption that early-onsetsporadic” MSI-H CRCs are truly sporadic. Specifically, he notes that. . . first is the fact that the incidence of HNPCC peaks at around 45ears. Second is the finding of germline mutations in DNA mismatchepair genes in subjects presenting with early-onset “sporadic” MSI-Holorectal cancer. Third is the evidence that methylation of hMLH1 inporadic MSI-H cancer is strongly age-related. Fourth is the fact thatethylation of hMLH1 may occur selectively in HNPCC cancers in

ubjects who carry a germline mutation in hMLH1. Fifth is the finding of


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NPCC-type molecular features among early-onset “sporadic” MSI-Holorectal cancers.”364

Pathologic Features in Lynch Syndrome. The pathologic features ofynch syndrome CRCs include a solid growth pattern, which appears toe responsible for the high frequency of poorly differentiated carcino-as.365,366 Surprisingly, however, is the finding that CRCs in the Lynch

yndrome are not as aggressive as their failure to form tubules mightuggest. Lynch and colleagues have called attention to the “undifferen-iated carcinoma” described by Gibbs367 and the “medullary carcinoma”escribed by Jessurun and Manivel,368 which were published in smallase series and shown to have a more favorable prognosis when comparedith typical CRC.369 It is also noteworthy that similar histologic features

haracterize the 15% of sporadic CRCs that harbor microsatellite insta-ility (MSI�), which have been found to constitute a molecular aberra-ion in CRCs that lack MMR activity.370 This special histologic featureas been referred to as “solid cribiform growth” wherein there is aositive predictive value of 53% for MSI� status.371

Smyrk and colleagues372 described a postlymphoid response referred tos “Crohn’s-like reaction” to be more common in Lynch syndromes aspposed to sporadic cancers, a finding that has been shown to beonsistent in all series,365 but which is similar to the tendency to formymphoid aggregates around the tumor, and which is a frequent feature ofporadic MSI� CRCs.370 Importantly, the Crohn’s-like reaction is oftenssociated with improved prognosis373 in the general population, suggest-ng that this phenomenon may account for the more favorable prognosisf CRC that occurs in HNPCC.374 De Jong and colleagues375 studied theole of MMR defects and the manner in which they promote developmentf adenomas in Lynch syndrome families compared with controls fromhe Dutch HNPCC Registry. They identified 249 MMR mutation carriersnd 247 controls. They found that the proportion of patients lacking andenoma at the age of 60 years was 29.7% for carriers and 70.8% forontrols (P � 0.05). They verified previous studies showing that thedenomas in carriers were larger and showed a higher proportion ofillous components and/or high-grade dysplasia (P � 0.05, all analyses).urthermore, they found the adenomas and carcinomas of the carriers toe located predominantly in the proximal colon, and most of thedenomas showed absent staining of the MMR proteins. They concludedhat their study “. . . indicates that the MMR defect is involved in the earlytages of development of adenomas.” They recommended immunohisto-
hemical staining of large adenomas showing high-grade dysplasia in

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atients younger than 50 years old, in the interest of identifying patientsith suspected Lynch syndrome.375

Pattern Recognition. An alternative to the Amsterdam I, Amsterdam II,ethesda, and other criteria is what we have described as “pattern

ecognition.” This involves careful scrutiny of the phenotypic cancereatures expressed in the family in accord with their mode of distributionnd transmission throughout the family. This is particularly importanthen evaluating small families, or for problems of reduced penetrance of

he deleterious MMR mutation, should this be present in the family. It isaluable then to follow what have been considered to be the cardinaleatures of hereditary forms of cancer, including the Lynch syndrome,hen present even in a single patient. These phenotypic features haveften been sufficient to raise the confidence level of a possible Lynchyndrome diagnosis and include the following: 1) autosomal dominantnheritance pattern311; 2) gene penetrance for CRC of �85% to 90%304;) gene carriers develop CRC at an early age (�45 years)311; 4) most�70%) of the CRCs are proximal to the splenic flexure376; 5) multipleRCs, both synchronous and metachronous, are common377,378; 6) therognosis is better than that for sporadic CRC374,379; 7) the pathologiceatures365 of CRC are often distinguishable (but not pathognomic) andnclude poor differentiation, mucoid excess with increased signet cells,

edullary features, peritumoral lymphocytic infiltration, Crohn’s-likeeaction, and tumor infiltrating lymphocytes (TILs) admixed with tumorells380; and 8) there is an increased risk for malignancy at severalxtracolonic sites, particularly the endometrium, ovary, stomach, smallowel, hepatobiliary tract, pancreas, ureter, renal pelvis, and brain.306 Inddition, breast cancer excess may be present in some HNPCC fami-ies.381 Although gastric cancer has declined in Lynch syndrome familiesince 1900, paralleling its decline in the general population,312 it is still anmportant feature of the syndrome in geographic areas in which gastricancer is endemic, most notably Japan and Korea.305

Muir-Torre Syndrome (MTS). In 1981, Lynch and colleagues382

eported the first observation of MTS in the Lynch syndrome. MTS isharacterized by multiple cutaneous sebaceous adenomas, sebaceousarcinomas, multiple keratoacanthomas, and multiple visceral cancers, inynch syndrome families. Several publications have elucidated thelinical and molecular genetic features of MTS in the Lynch syn-rome.383-386 Kruse and colleagues387 examined 13 patients with CRCnd sebaceous lesions of the skin and found that 8 had hMSH2 mutationsnd 1 had an hMLH1 mutation. Data suggest that the identification of
hese MTS cutaneous features in a patient merit a detailed family history

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n the search for evidence of the Lynch syndrome. Indeed, patients withhese stigmata merit MMR germline testing, particularly for evidence ofMSH2 germline mutation. The pedigree of an extended Lynch syndromeamily with MTS that is known to carry an hMSH2 mutation is shown inig 20.Surgical Management. In Lynch syndrome patients diagnosed with

olorectal cancer, the preferred treatment is subtotal colectomy. Fitzgib-ons and colleagues388 studied 116 patients with Lynch syndrome andemonstrated several significant differences in this patient populationelative to patients with sporadic CRC. They found that 69% of Lynchyndrome CRC were proximal to the splenic flexure, whereas 23% weren the rectosigmoid. Eighteen percent had synchronous cancers, and 40%eveloped metachronous lesions over 10 years of follow-up.388 Becausef the predominance of proximal lesions and the high risk of developingew cancers in the future, subtotal colectomy with IRA and lifetimeurveillance of the rectosigmoid is recommended. For women beyondhildbearing age, serious consideration should also be given to perform-ng prophylactic hysterectomy and bilateral salpingo-oophorectomy.388

In reviewing this subject, Church389 suggests that interval CRCsevelop from normal epithelium within 3 years and/or from adenomashat were missed. It is also important to realize that colonoscopy “miss”ates are as high as 29% for polyps less than 5 mm in diameter.390

herefore, patients should be advised that colonoscopy, although not aerfect screening procedure, is nevertheless highly effective.360 Theption of prophylactic colectomy should be discussed, weighing it againstifetime colonoscopy.391-394 The problem in effective cancer controlhrough the use of prophylactic colectomy is a decision based heavily onhe attitudes, feelings, and concerns of the patient and the manner inhich these could impact on his/her compliance with annual colonos-

opy. For example, the presence of fear and anxiety about what might beound at colonoscopy, in our experience, has deterred patients in showingompliance with this screening procedure for CRC. Criteria for prophy-actic surgery are the following: 1) lack of compliance with surveillance;) morbid fear and desire to have these high risk organs surgicallyxcised; 3) presence of colonic adenomas, particularly at a young agend/or with features of moderate to severe dysplasia and carcinoma in situn polyps.Women at risk for the Lynch syndrome should have annual screening

or endometrial and ovarian cancer beginning at age 30 to 35 years.ndometrial aspiration coupled with transvaginal ultrasound is advised.
A-125 testing, in addition to transvaginal ultrasound and Doppler color

FIG 20. Pedigree shows the Muir-Torre syndrome.

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lood flow imagery, should be performed semiannually for ovarianancer. Prophylactic hysterectomy and oophorectomy can be consideredhen childbearing is completed.Screening in Lynch Syndrome. Jass395 has elucidated the pathologicature of precursor lesions in HNPCC. He has postulated the “aggres-ive adenoma” theory (i.e., adenomas form earlier but about as oftenn HNPCC patients as in the general population).395 However, onceormed, these colonic adenomas progress to carcinoma more quicklynd/or more often than their sporadic counterparts. A tiny colonicdenoma in the Lynch syndrome may evolve into a carcinoma in ashort a time frame as 2 to 3 years, compared with approximately 8 to0 years in the general population.303,365,396 Strong clinical evidencen support of a more rapid evolution of adenoma to carcinoma comesrom a Finnish study showing a marked decrease in colon cancerncidence for HNPCC patients given regular colonoscopic surveillanceith removal of adenomas.397 Because of accelerated carcinogenesis,roximal colonic predilection, and early age of CRC onset in theynch syndrome, we strongly recommend that annual full colonos-opy be initiated at age 25 (Fig 21). A good clean-out is necessary andxcellent visualization of the cecum is mandatory, because approxi-ately one third of CRCs occur at that particular site.Järvinen and colleagues360 demonstrated the benefit of colonoscopic

creening in HNPCC through a controlled clinical trial extending over5 years. The incidence of CRC was compared in 2 cohorts of at-riskembers of 22 HNPCC families. CRC developed in 8 screened

ubjects (6%), compared with 19 controls (16%; P � 0.014). The CRCate was reduced by 62% in those who were screened. All CRCs in thecreened group were local, causing no deaths, compared with 9 deathsaused by CRC in the controls. It was concluded that CRC screeningt 3-year intervals more than cuts in half the risk of CRC, preventsRC deaths, and decreases the overall mortality rate by approximately5% in HNPCC families.360 The relatively high incidence of CRCven in the screened subjects (albeit without deaths) in our opinionrgues for shorter screening intervals (i.e., 1 year). For example,asen and colleagues398 discovered 5 interval cancers in HNPCCatients within 3.5 years following a normal colonoscopy. Prophylac-ic colectomy, as discussed, is an alternative to intensive colonoscopicurveillance in highly selected members of Lynch syndrome families.n algorithm showing the appropriate sequence for diagnosis and
anagement of Lynch syndrome is shown in Figure 21.

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uvenile PolyposisThe colorectal polyps most commonly found in children are different

rom those found in adults and are called juvenile polyps. Polyps in adultsre generally adenomatous, whereas polyps in children tend to beamartomatous (juvenile polyps being a type of hamartomatous polyp). Inost children, the juvenile polyps are few in number or solitary, will

lough off and not require treatment, and are not associated with aeritable predisposition. Juvenile polyposis (JP; OMIM 174900) is aeritable syndrome in which there are multiple juvenile polyps (Fig 22).atients with juvenile polyposis, Cowden syndrome (CS; OMIM58350), and Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM53480) may all develop juvenile polyps of the GI tract, which arendistinguishable microscopically. Patients with Peutz-Jeghers syndromePJS; OMIM 175200) also have hamartomatous polyps, but these can be

IG 21. Algorithm depicting the appropriate sequence for A) diagnosis and management and B)creening and management of the Lynch syndrome. CRC, colorectal cancer; MSI, microsatellitenstability; MMR, mismatch repair.

ifferentiated histologically from juvenile polyps.


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History. The first description of a juvenile polyp was by Diamond399 in939, who originally called this a rectal adenoma. Diamond399 describedt grossly as a 2.5 by 2.0 cm pedunculated tumor that was injected andriable. One small area on the polyp surface was covered with a fibrinousxudate. Histologically, the polyp was lined with high columnar epithelialells with an occasional bare area. The glands were distended and filledith a fibrinous cellular material. The stroma was diffusely infiltratedith lymphocytes, plasma cells, eosinophils, and neutrophils.399 In 1957,auro and Prior400 clearly distinguished between juvenile polyps and

denomatous polyps. Contrasting the 2, they found juvenile polyps to belobular in shape, gray to slightly red, with a granular external surface.illous processes were not present. It was common to have areas ofenudation of the columnar epithelium replaced by granulation tissue.here was cystic gland dilation, containing mucous and nuclear debris.he abundant stroma contained an inflammatory cell infiltrate with aredominance of eosinophils.400 Later in the same year, Horrilleno andolleagues401 coined the term juvenile polyp for these histologically

IG 22. Juvenile polyposis of the colon.

imilar polyps described previously by Diamond and by Mauro and Prior.


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n 1962, Morson402 supported the view that juvenile polyps were differentrom adenomatous polyps and suggested they were hamartomatousolyps. Hamartomas are an overgrowth of mature cells and tissues thatormally occur in the affected part, but often with 1 element predomi-ating. Juvenile polyps satisfy this definition with their excessive prolif-ration of the lamina propia and attenuation of the muscularis mucosaFig 23).Definition and Manifestations. The term juvenile polyposis (JP) wasefined by McColl and colleagues403 in 1964. This distinguished juvenileolyps from JP, a heritable syndrome in which there are multiple juvenileolyps involving the GI tract. In 1974, following the definition of JP bycColl, Sachatello and colleagues404 proposed a working definition, laterodified by Jass and colleagues,405 with the following diagnostic criteria:

) more than 5 juvenile polyps involving the colon and rectum, 2) juvenileolyps throughout the GI tract, and 3) any number of juvenile polypsnvolving the GI tract with a family history of JP. JP has been furtherivided based on the clinical presentation and disease course into the

IG 23. Photomicrograph of a juvenile polyp. Note the normal epithelium, with a markedly expandedamina propria, infiltrated by inflammatory cells and dense stroma. Cystically dilated glands are alsorominent in this layer.

ollowing three classifications404,405: 1) juvenile polyposis of infancy, 2)


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uvenile polyposis coli, and 3) generalized juvenile polyposis. Sachatellond colleagues defined juvenile polyposis of infancy in a case report andeviewed 6 similar cases in the literature.404,406-410 In all 7 cases, thenfants died before 1 year of age. Characteristic symptoms includediarrhea (usually bloody), protein losing enteropathy, hypoproteinemia,nemia, anasarca, and eventually failure to thrive. It was common to findectal polyp prolapse and intussusception. Congenital anomalies ranged inhese series from none to clubbing, motor retardation, macrocephaly,lopecia, double renal pelvis, and bifid uterus/vagina.404

Juvenile polyposis coli and generalized juvenile polyposis are definedy the sites of GI involvement with juvenile polyps. As the name implies,uvenile polyposis coli occurs when juvenile polyps are limited to theolon and rectum, whereas in generalized juvenile polyposis, the polypsre present in both the upper and lower GI tract (Fig 24). Both subtypesill usually manifest in the first and second decades with rectal bleeding,

IG 24. Juvenile polyposis affecting the stomach, resulting in a dense carpet of polyps.

prolapsed rectal polyp, abdominal cramps or pain, diarrhea, or ane-


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ia.411,412 In addition, generalized GI juvenile polyposis may includerotein-losing enteropathy, intussusception, and severe malnutrition.owever, these children, unlike those with juvenile polyposis of infancy,

ventually recover. Coburn and colleagues413 reviewed the Englishiterature and identified 218 patients meeting the criteria for JP. Theseatients with JP were stratified into 2 groups: juvenile polyposis coli andeneralized juvenile polyposis. Patients with juvenile polyposis colisually presented during childhood between the ages of 5 and 15 years,hereas patients diagnosed with generalized juvenile polyposis present at

n earlier age. Otherwise, there did not appear to be any difference in theamily history of juvenile polyposis in either subtype.413 It should beentioned that the distinction between juvenile polyposis of infancy,

uvenile polyposis coli, and generalized juvenile polyposis may beomewhat arbitrary. Stemper and colleagues414 reported a kindred withome members having generalized GI juvenile polyposis whereas othersad juvenile polyposis coli, suggesting the phenotype of juvenile poly-osis is of variable penetrance. Similarly, Grotsky and colleagues415

escribed an extended family with both juvenile polyposis coli anduvenile polyposis of infancy.Associated Anomalies. In their 1964 series, McColl and colleagues403

escribed 4 of 11 patients with associated congenital anomalies. Coburnnd colleagues413 reported nearly a 15% prevalence of congenitalalformations with JP. Interestingly, Desai and colleagues,416 who

outinely obtained radiographs and an echocardiogram if clinicallyndicated, reported 18 of 23 (78%) patients with JP having extracolonicanifestations. This number is clearly skewed since after the extensive

e-evaluation 5 patients had alternative syndromes diagnosed, and annspecified number were described as having similarities to knownyndromes. Removing these cases leaves 8 of 13 (62%) patients withresumed JP associated with extracolonic manifestations. Throughouthe JP literature, some of the recurrent anomalies include the follow-ng: macrocephaly, mental retardation, atrial and ventricular septalefects, pulmonary arteriovenous malformations, pulmonary stenosis,eckel’s diverticulum, malrotation, cryptorchidism, hypertelorism,

nd telangectasias.403,413,416

Malignant Potential. An extensive portion of the literature on JP haseen dedicated to the discussion of its malignant potential. It was initiallyhought that JP did not predispose to GI malignancy, since juvenile polypsre hamartomatous. As it became apparent that adenomatous polyps hadalignant potential, an increased prevalence of colorectal cancer was

ecognized with JP patients. During this time adenomatous changes in


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uvenile polyps were recognized414,415,417-434 and hypothesized occasion-lly to undergo dysplastic change and eventually progress to adenocar-inoma. In 1979, Goodman and colleagues422 reported a 23-year-oldoman undergoing a colectomy with numerous juvenile polyps mainly

ocalized to the cecum, ascending colon, and rectum. Several of theuvenile polyps showed adenomatous changes, and an adenocarcinomaad also developed in the rectum.After adenomatous changes, the next step in the progression toalignancy would be dysplasia/carcinoma in situ changes in the juvenile

olyps of patients with JP. Jass and colleagues405 reviewed the pathologiceatures of 1038 polyps collected from 80 patients in the St. Mark’solyposis Registry with JP. They divided the polyps into 2 groups: 1)ultilobulated or having a villous configuration, and 2) typical juvenile

olyps. Seventy-nine of 169 (47%) atypical juvenile polyps had epithelialysplasia, whereas 76 of the 840 (9%) typical juvenile polyps had similarysplastic changes.405 Several other investigators have reported thending of dysplastic changes in juvenile polyps in JP patients.428,435,436

here have been many cases of documented colorectal adenocarcinomaeported in patients with JP.414,422,427,428,430-432,437,438 These cancers areften closely associated with juvenile polyps and juvenile polyps withdenomatous changes, supporting a juvenile polyp-adenomatous changes-ysplasia-carcinoma sequence of events.The establishment of JP registries has allowed estimates of the cumu-

ative risk for developing GI malignancies to be made. Howe andolleagues439 examined a 117-member Iowa JP family and found that 11f the 59 (38%) affected kindred members developed colon cancer,hereas 6 of 59 (21%) developed upper GI cancers. The cumulative risk

or upper and lower GI cancers was 55%. The cumulative risk forolorectal cancer in JP patients has ranged from 17% to 68% in othereports.413,440

The distinction between JP and patients with juvenile polyps ismportant when estimating the risk of GI malignancy. Many authoritiesave suggested that there is no inherent increased risk of GI malignancyor patients with solitary juvenile polyps not meeting the definition of JP.iardello and colleagues432 found that only 1 of 26 patients with only 1r 2 juvenile polyps and a negative family history had adenomatoushanges in a polyp, whereas 9 of 31 (29%) patients with 3 or moreuvenile polyps or a positive family history of JP had colonic adenomasr adenocarcinoma. There is only 1 reported case of an adenocarcinomarising from a presumed solitary juvenile polyp in a 16-year-old boy.441

ugent and colleagues442 reported that the relative risk of dying of


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olorectal malignancy in a patient with a solitary juvenile polyp was 0.66,nd therefore these patients are not at an increased risk of death fromolorectal carcinoma.Genetics. The autosomal dominant nature of JP was first suggested bymilow and colleagues437 and Veale and colleagues443 in 1966. Furtherescriptions of kindreds with juvenile polyposis confirmed an autosomalominant inheritance.414,444 More recent investigation has shifted fromhe clinical to the molecular basis of JP. Jacoby and colleagues described

patient in 1997 with JP having a deletion at chromosome 10q22.445

oon thereafter, Olschwang and colleagues446 reported 3 cases of JP withermline PTEN mutations, which maps to 10q22. However, on closervaluation by Eng and Ji,447 these patients either had a phenotypeuggestive of CS or, due to their young age, CS could not be ruled out.owe and colleagues448 examined a family of 43 individuals of which 13ad the clinical diagnosis of JP and found no linkage to chromosome 10qarkers. Marsh and colleagues449 were unable to identify germlineutations in PTEN in 14 familial and 11 sporadic JP cases. Riggins and

olleagues450 also found no PTEN mutations in 11 JP patients. In 1998,owe and colleagues448 demonstrated genetic linkage to markers on

hromosome 18q21, and subsequently reported germline mutations ofADH4 in 5 of 9 JP cases.451 This was independently confirmed inultiple small series.452-455 Woodford-Richens and colleagues456 foundof 44 (16%) cases of JP with MADH4 mutations, and Howe and

olleagues457 reported mutations in 14 of 77 JP cases (18.2%). In theatter report, 8 mutations were deletions and 6 were substitutions (1onsense, 5 missense). Reviewing all published mutations, Howe andolleagues457 described a total prevalence of 23% (32 of 141 cases withADH4 mutations). One mutation had been described in 6 cases, a 4-bp

eletion in exon 9.458 Of 32 total mutations, 1 mapped to the MH1omain, 5 to the linker region and the remainder to the MH2 domain (Fig5).457

The MADH4 protein is the common mediator involved in the trans-orming growth factor-� (TGF-�) superfamily, which includes TGF-�,ctivin, and bone morphogenetic protein (BMP) signal transductionathways. Functionally, MADH4 acts as a tumor suppressor gene, asemonstrated by Hahn and colleagues,459 who found loss of heteorozy-osity (LOH) of MADH4 in 25 of 84 (30%) pancreatic xenografts.embers of the TGF-� superfamily initiate a wide spectrum of effects onvariety of cell types, including control of differentiation, proliferation,

nd apoptosis. TGF-� binds to plasma membrane serine/threonine ki-
ases, specifically the type II TGF-� receptor. TGF-� and the type II

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GF-� receptor complex then binds with the type I receptor, causinghosphorylation in a glycine-serine-rich domain of the receptor (Fig 26).n the TGF-� pathway, these activated type I receptors then phosphory-ate cytoplasmic MADH2 or MADH3. Phosphorylation allows theseroteins to oligomerize and then to associate with MADH4. The complexhen migrates to the nucleus, where it recruits a DNA binding protein, andhe complex binds to specific DNA sequences, regulating the transcriptionf various genes, many of which remain to be identified. The MH2omain of MADH4, which is frequently altered in JP patients andporadic pancreatic cancers, is important in nuclear localization, MADH4

IG 25. MADH4 mutations reported in juvenile polyposis (JP). The upper rectangle represents theADH4 gene, with the exons shown within the rectangle and nucleotides above and below. Lines

esignate mutations identified in JP cases, with those shown above each exon corresponding to thosedentified by Howe and colleagues,457 whereas those below are derived from the reports of Roth andolleagues,454 Kim and colleagues,455 Woodford-Richens and colleagues,456 and Friedl andolleagues.464 (Reproduced with permission from Howe JR, Sayed MG, Ahmed AF, Ringold J,arsen-Haidle J, Merg A, et al. The prevalence of MADH4 and BMPR1A mutations in juvenileolyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 2004;41:484-91.)

inding, and activation of transcription. There are 8 known MADHs in


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ertebrates, with MADH2 and MADH3 functioning as the cytoplasmicffectors in the TGF-� and activin pathways; MADH1, MADH5, andADH8 are those involved in the BMP pathway. MADH4 is the

ommon mediator for these pathways, whereas MADH6 and MADH7unction as inhibitors of all these pathways by binding to the type Ieceptors and by interfering with phosphorylation.460 To date, no otherADH genes have been implicated in the development of JP. Roth and

olleagues454 found no mutations in MADH2, MADH3, or MADH7 in 4nrelated patients without MADH4 mutations, and Bevan and col-eagues461 found no mutations in MADH1, MADH2, MADH3, or MADH5n 30 JP patients without MADH4 mutations.Since MADH4 mutations only accounted for one fifth of JP cases, Howe

IG 26. Overview of the TGF-� signaling pathway (reproduced with permission from Merg A, HoweR. Genetic conditions associated with intestinal juvenile polyps. Am J Med Genet 2004;129C:44-5).577

nd colleagues462 searched for another JP gene through a linkage-based


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enome screen in 4 additional JP families. They found linkage to markersn chromosome 10q22-23, and subsequently each family was found toave a truncating mutation in the BMPR1A gene.462 Since the initialeport of BMPR1A mutations in JP patients, there have been 2 confirma-ory studies published.463,464 In a total of 77 JP cases studied by Howend colleagues, there have been 16 (21%) with BMPR1A mutations,onsisting of 6 deletions and 10 substitutions (4 nonsense, 6 missense).457

ooling all 3 reports, 31 unique mutations have been described, distrib-ted in 8 of 11 exons with nearly one half affecting the intracellularrotein kinase region in exons 7 and 8. One quarter of mutations affect thextracellular cysteine-rich domain (Fig 27).457 BMPR1A is anotherember of the TGF-� superfamily involved in a pathway that also

epends on MADH4 as the intracellular mediator of signal transductionFig 26). Like TGF-�, the various BMPs bind to specific type II receptorsr to the type II and type I receptors together, then the type II receptorhosphorylates a type I receptor, such as BMPR1A or BMPR1B.465 Theype I/type II receptor complex then phosphorylates MADH1, MADH5,nd/or MADH8, which then form oligomers with MADH4, and theseroteins migrate to the nucleus to regulate transcription of specificenes.460 BMPs exert many effects on a variety of tissues, includingontrol of osteogenesis, chondrogenesis, mesoderm development, synthe-is of extracellular matrix, and epithelial/mesenchymal cell relationshipsontributing to morphogenesis.466

A recent study examining MADH4 and BMPR1A mutation-positiveMUT�) and negative (MUT�) cases found that that 17 of 19 (89%)

UT� patients and 13 of 25 (52%) MUT� patients cases had a familyistory of GI cancer (P � 0.01), and that 89% of MUT� and 63% ofUT–cases were familial (P � 0.09).467 The familial prevalence of

pper GI juvenile polyps was 86% in MADH4 mutation-positive JPamilies, 10% in BMPR1A families, and 23% in MUT– cases. Friedl andolleagues464 reported gastric polyposis in 4 of 7 MADH4 mutation-ositive cases, in 1 of 5 cases with BMPR1A mutations, and 2 of 17utation-negative cases. It therefore appears that MADH4 mutations

redispose to generalized juvenile polyposis, whereas MADH4 mutation-egative cases more commonly cause juvenile polyposis coli. SinceADH4 and BMPR1A mutations only account for 40% of JP cases, there

re likely other genes responsible for JP that await discovery.Treatment. Because of the malignant potential of juvenile polyps in JP,

ndoscopic screening and polypectomy, and prophylactic surgery in someases, are very important means of cancer control. Screening should begin at
ge 15, and include esophagogastroduodenoscopy, colonoscopy, and a

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emogram in those at risk for JP.468 If a mutation of MADH4 or BMPR1A isound in a family, then the process is simplified by testing individuals at riskor the same mutation. If no mutation is found, then that individual can beollowed by using the guidelines for screening the general population forporadic colorectal cancer. If either a mutation is found in an at-risk patient,r a mutation has not been found in the family, then colonoscopy and upperndoscopy should be performed every 3 years. When juvenile polyps areound in the colon, they should be removed endoscopically, which may

IG 27. BMPR1A mutations reported in juvenile polyposis (JP). The upper rectangle represents theMPR1A gene, with the exons shown within the rectangle and nucleotides above and below. Linesesignate mutations identified in JP cases, with those shown above each exon corresponding to those

dentified by,457 while those below are derived from the reports of.463,464 The lower rectangleepresents the different known domains of the BMPR1A gene (reproduced with permission from HoweR, Sayed MG, Ahmed AF, Ringold J, Larsen-Haidle J, Merg A, et al. The prevalence of MADH4 andMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.Med Genet 2004;41:484-91).

equire multiple sessions if the number is greater than 20 to 50 polyps.


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ubsequently, annual endoscopy should be performed until the all polyps areemoved, and then every 3 years after this if no dysplastic polyps are found.f the colon cannot be rendered polyp free using the endoscope, then surgicalanagement may be needed. The range of surgical options include segmental

olectomy, subtotal colectomy, and total proctocolectomy with ileoanalull-through.468 Since the malignant potential of juvenile polyps in JP is lowelative to more aggressive polyposis syndromes, one must consider carefullyhe impact of the chosen procedure on quality of life versus the need foruture endoscopic surveillance. Subtotal colectomy is preferred over segmen-al colectomy since it limits the amount of colon at risk, and patients can be

ABLE 10. International Cowden Consortium diagnostic criteria*

Pathognomonic criteriaFacial trichilemmomasAcral keratosesPapillomatous papulesMucosal lesions

Major criteriaBreast carcinomaThyroid carcinoma, nonmedullaryMacrocephalyLhermitte-Duclos disease (LDD)Endometrial carcinoma

Minor criteriaThyroid lesions, adenoma or multinodular goiterMental retardationGastrointestinal hamartomasFibrocystic disease of the breastLipomasFibromasGenito-urinary tumors (renal cell carcinoma or uterine fibroids) or malformations

Operational diagnosis in an individual1) Mucocutaneous lesions alone if there are

i) Six or more facial papules, of which 3 or more must be trichilemmomasii) Cutaneous facial papules and oral mucosal papillomatosisiii) Oral mucosal papillomatosis and acral keratosesiv) Six or more palmar or plantar keratoses

2) Two major criteria, 1 of which must be macrocephaly or LDD3) One major and 3 minor criteria4) Four minor criteria

Operational diagnosis in a family in which 1 individual has had a diagnosis of Cowdensyndrome

1) One or more of pathognomonic criteria2) Any 1 major criterion with or without minor criteria3) Two minor criteria

Reproduced with permission from Waite KA, Eng C. Protean PTEN: form and function. Am Jum Genet 2002;70:829–44.612

creened easily by flexible sigmoidoscopy. Total proctocolectomy should be


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eserved for those with significant involvement of both the colon and theectum, or those with dysplastic rectal polyps. Polyps of the stomach aresually diffuse and cannot be effectively removed endoscopically. Significantnemia is often present, and these patients may require subtotal or totalastrectomy.468 Patients with JP or at risk for JP should receive geneticounseling. Here, recommendations for endoscopic screening, the risk ofpper and lower GI symptoms and cancer, and the ramifications of geneticesting should be discussed.

owden SyndromeCowden Syndrome (CS) was first described by Lloyd and Dennis469 in

IG 28. A and B) Trichilemmomas of the face in patients with Cowden syndrome (reproduced withermission from Brownstein MH, Wolf M, Bikowski JB. Cowden’s disease: a cutaneous marker ofreast cancer. Cancer 1978;41:2393-8).578

he propositus Rachel Cowden, and Weary and colleagues470 later


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esignated CS as a multiple hamartoma syndrome after observing itsutosomal dominant inheritance in her family. CS involves hamartoma-ous changes in all 3 germ layers, including predominantly the skin,ucous membranes, breast, thyroid, GI tract, and CNS. The Internationalowden Consortium has established a group of features that establish theiagnosis of CS (Table 10). Lhermitte and Duclos disease (LDD) isncluded in these criteria, which causes a variety of CNS symp-oms.471,472 In the 1990s, it was realized that LDD and CS were variantsf the same genetic condition, which manifest as neurologic and cutane-us hamartomas, respectively.473-477

Phenotype. Lesions of the skin and mucous membranes are pathogno-onic for CS, and are present with nearly 100% prevalence.478,479

richilemmoma, 1 of the characteristic lesions in CS, is a hamartoma ofhe hair follicle’s root sheath. Typically trichilemmomas are found aroundhe eyes, nose, and mouth (Fig 28). Oral fibromas with a papillomatosis

orphology can cause a cobblestoning appearance of the gingiva and/orongue, also referred to as a scrotal tongue (Fig 29). Acral keratosis is alsorominent in CS (Fig 30).478,480,481 Three quarters of patients with CS

IG 28. Continued

ave thyroid abnormalities, most commonly goiters or adenomas. Non-


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edullary thyroid malignancies are more common than in the generalopulation and range in prevalence from 3% to 7%.478,479,482-486

Two large series of CS patients have demonstrated breast involvementn approximately 70%. Fifty percent to 60% have benign lesions, andreast cancer is found in approximately 20% to 30% of cases.478,479

wing to the lack of prospective, long-term follow-up studies, the

IG 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 ofral papillomatosis. J Laryngol Otol 2002;116:221-3).579 B) Gingival papules in a CS patientreproduced with permission from Sogol PB, Sugawara M, Gordon HE, Shellow WV, Hernandez F,ershman JM. Cowden’s disease: familial goiter and skin hamartomas. A report of three cases. WestMed 1983;139:324-8).580

ifetime risk of breast cancer in CS patients may be underestimated.


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pproximately 30% of patients with breast cancer have bilateral involve-ent, and the mean age at presentation is younger than for the general

opulation, ranging from 38 to 46 years.478,487 Breast cancer is notimited to women with CS; 2 cases of breast cancer have been reported inen with CS.488

The GI tract manifestations in CS are adenomas, hamartomas, gangli-neuromas, leiomyomas, lipomas, lymphoid, neuromas, as well as hyper-lastic, inflammatory, and occasionally juvenile polyps.470,485,489-495 Thencidence of GI involvement may range from 35% to 85%, dependingn whether patients have contrast studies and endoscopy per-ormed.478,495,496 In contrast to JP, there are only 4 reported cases ofolon carcinoma.478,482,497,498

Menstrual irregularities and ovarian cysts are found in approximately0% of patients with CS, and leiomyomas of the uterus may also beresent.478,491,496 Other cancers associated with CS are uterine adenocar-inoma (6%), transitional cell carcinoma (5%), and cervical carcinoma3%).478 Eng499 recently suggested a possible association between CSnd both renal cell carcinoma as well as melanoma, based on anecdotal

IG 30. Keratodermas of the palm in a patient with Cowden syndrome (reproduced with permissionrom Hover AR, Cawthern T, McDanial W. Cowden disease. A hereditary polyposis syndromeiagnosable by mucocutaneous inspection. J Clin Gastroenterol 1986;8:576-9).

vidence.


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Lhermitte-Duclos Disease. Lhermitte and Duclos500 first described thisyndrome in the French literature in 1920. This was later referred to asysplastic gangliocytoma of the cerebellum, due to the histologic featuresf this peculiar hamartoma. This cerebellar hamartoma usually manifestsith symptoms of increased pressure or cerebellar ataxia, which includeeadaches (75%), papilledema (70%), cerebellar syndrome (50%), mega-encephaly (40%), cranial nerve deficit (30%), ataxia (20%), and pyra-idal syndrome (20%). Associated anomalies found in patients withhermitte-Duclos disease (LDD) have also included macrocephaly,egalencephaly, hydrocephalus, heterotopia, and hydromyelia.471,472

mbler and colleagues501 found LDD to be autosomal dominant inature. By the 1980s, the diagnosis could be established by MRI findings,anifesting as a nonenhancing gyriform pattern with enlargement of the

erebellar folia.502 In 1921, Padberg and colleagues473 reported 2 patientsith biopsy-proven LDD and CS. This was followed by similar reports,

eading to the realization that these were the same hamartomatousyndrome involving cutaneous and neurologic ectoderm.474-477,503-506

his was supported in 1996, when Nelen and colleagues507 reported theocalization of the predisposing gene for CS to chromosome 10q22-23.mong the12 families studied for linkage, 4 families had clear evidencef LDD that showed the same linkage to 10q22-33.507 Hence, LDD wasncorporated into the diagnostic criteria for CS (Table 10).Genetics. CS was demonstrated to have an autosomal dominant

nheritance by Gentry and colleagues494 in 1974 and Nuss and col-eagues508 in 1978. Although within families there were generally equalumbers of affected men and women, between families, interfamilialeries may show a female predisposition ranging from 1:1 to 1.6:.478,496,509 This could also reflect a bias for presentation in females dueo the breast disease predisposition in CS.Excellent progress has been made in understanding the genetic basis ofS in the last decade. In 1996, Nelen and colleagues507 found linkage forS to markers on chromosome 10q22-23, with a lod score of 8.92 (theta

0.02) in 12 families. This was closely followed by independentdentification of the PTEN gene on chromosome 10 by 3 groups: Li andun,510 Li and colleagues,511 and Steck and colleagues.512 Li andolleagues511 found PTEN to have a sequence consistent with a proteinyrosine phosphatase domain, and homology to the chicken protein tensinnd bovine protein auxilin. In the name PTEN, the phosphatase functions represented by P; TEN refers to the homology to tensin and its locationn chromosome 10. They also found mutations of the PTEN gene in
reast cancer, glioblastoma, and prostate cancer cell lines.511 Liaw and

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olleagues513 found that 4 of 5 CS families had PTEN germline mutationsn 1997 and Nelen and colleagues514 found that 9 of 19 CS cases hadTEN mutations.PTEN is a dual specificity phosphatase that causes dephosphorylation of

erine/threonine and tyrosine residues and of protein and lipid sub-trates.515 PTEN is involved in embryonic development, the cell cycle,poptosis, and tumor formation. It plays an important role in thehosphatidylinositol 3-kinase (PI3K) protein kinase B (PKB)/antiapop-otic serine threonine kinase (AKT) pathway. Upregulation of PI3K-PKB/KT promotes cell growth and survival, which is regulated by PTEN-ediated dephosphorylation of the phosphatidylinositol3-5 triphosphate

PIP3) substrate. Reduced PIP3 levels leads to lower PKB/AKT in the cellembrane, causing cell cycle arrest in G1 and apoptosis.516 Other

athways regulated by PTEN may include the mitogen-activated kinaseMAPK) pathway, which is involved in cell proliferation and differenti-tion and the insulin signaling pathway.517 Li and Sun,510 Li andolleagues,511 and Steck and colleagues512 all recognized that theutation of PTEN leads to inactivation of its phosphatase activity and

nactivation of its role in growth inhibition, implying a tumor suppressorole.Marsh and colleagues518 examined a series of 37 families with CS and

dentified 30 families with germline PTEN mutations, for an incidence of1%. Zhou and colleagues519 re-examined 97 patients with CS that wereegative for PTEN mutations. They found mutations in the promoteregion of PTEN in 9 (9.3%) patients. Combining both mutations in theTEN promoter and coding sequence therefore accounts for approxi-ately 90% of germline mutations seen in patients with CS.Treatment. The first step in appropriate screening for CS is recognitionf its predisposition to malignancy. Once CS is diagnosed, patients shoulde considered for genetic counseling. This provides an opportunity forupport and education, including its social, familial, and personal rami-cations. In a family in which a PTEN mutation has been detected, if the

ndividuals at risk are negative for the same mutation, they may thenndergo routine health and cancer screening. At-risk CS patients oratients in families without identified PTEN mutations should undergo aeneral comprehensive physical examination starting at 18 years of age or

years before the earliest cancer was diagnosed in another familyember.The most common cancers encountered in CS patients are of the breast

nd thyroid gland. Starink and colleagues478 reported 3 patients younger
han the age of 30 years in whom breast cancer developed. Therefore,

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t-risk patients should perform monthly breast self-examinations startingt age 18, with annual physical examinations beginning at age 25, or 5o 10 years earlier than the youngest case of breast cancer in theamily.499,520 Mammography should be performed beginning at age 30o 35 years, or at least 5 years before the youngest age of onset ofreast cancer in the family.499,521

Thyroid cancer in CS patients may develop by 10 to 30 years ofge.470,485,486,522 Screening should begin with a thyroid ultrasound at age8, with annual physical examinations thereafter and repeat ultrasoundss determined by the level of clinical suspicion.To screen for endometrial cancer, annual endometrial suction biopsies

hould be performed beginning at the age of 35 to 40 years, or 5 yearsounger than the earliest premenopausal case of endometrial cancer in theamily. Postmenopausal women should have an annual endometrialltrasound. Families with a history of renal cancer should have annualrine cytology, and renal ultrasound as indicated. Dermatologic exami-ation is also suggested annually to screen for melanoma.499

annayan-Riley-Ruvalcaba SyndromeThe name Bannayan-Riley-Ruvalcaba syndrome (BRRS) was proposed

n 1990 to encompass 3 phenotypically similar syndromes (Ruvalcaba-yhre-Smith syndrome, Bannayan-Zonana syndrome, and the Riley-

mith syndrome). The syndromes are defined by macrocephaly, andariable penetrance of developmental delay, hemangiomas, lipomas,enital pigmentation, intestinal polyps, and lipid myopathy.523-536 Theredominant features of BRRS as reported by Gorlin and colleagues areisted in Table 11.The GI polyps associated with BRRS were initially described asamartomatous.523,527,529,537 Further review by Haggitt and Reid538 ofhe histologic features of polyps reported by Ruvalcaba found that theyere juvenile polyps, except for 1 ganglioneuroma. Recent reports have

onfirmed that most polyps are juvenile polyps, which occasionally willisplay adenomatous changes.539-541

Genetics. It may be difficult to distinguish between BRRS and CS.argnoli and colleagues542 described a patient with findings consistentith both BRRS and meeting the diagnostic criteria for CS. This patientad macrocephaly, 2 lipoma resections, a thyroid follicular adenoma (thatad been removed), scoliosis, colonic polyps, and hyperpigmentedacules on the glans penis (Fig 31).542 Both BRRS and CS have an

utosomal dominant inheritance.527,531,532,536,543 Marsh and col-
eagues518 found a PTEN germline mutation in 4 of 7 unrelated BRRS

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amilies in 1998. One of the these PTEN mutations had previously beenound in 2 CS families,513 suggesting that the 2 syndromes were allelic.he largest series to date has been that of Marsh and colleagues,544 whovaluated 43 individuals with BRRS. Of these 43 patients with BRRS, 16ere sporadic and 27 were familial.544 Eleven of the 27 familial casesere mixed, having individuals of both CS and BRRS phenotypes. PTENutations were found in 26 of 43 individuals, for a prevalence of 60%.544

dditional reports of PTEN mutations associated with patients havingRRS have been published.545,546

In families with BRRS, the recommendations for follow-up are lesslear, because the risk for cancers has not been established. The findingsrom genetic studies that BRRS and CS are allelic syndromes suggestshat the clinician maintain an elevated level of suspicion and examine theatient annually for the same tumors seen in patients with CS.

eutz-Jeghers SyndromePeutz-Jeghers syndrome (PJS) is characterized by hamartomatousolyps of the upper and lower GI tract, and lentigines (pigmented lesions)f the buccal mucosa, perioral region, palms, feet, or anus (Fig 32). Thessociation of melanosis and polyposis was first recognized by Peutz547 in921, and Jeghers and colleagues548 described an autosomal dominantnheritance in 1949. The prevalence of PJS has been estimated to beetween 1 in 8300 and 1 in 29,000.549 The mean age of diagnosis of PJS

ABLE 11. Bannayan-Riley-Ruvalcaba syndrome, common signs*

CraniofacialMacrocephalyProminent corneal nerves/Schwalbe lines

NeurologicDevelopmental delays (motor, mental, speech)

MuscularLipid myopathy

CutaneousLipomasGenitalia pigmentationAngiolipomas

GastrointestinalIntestinal polyps (hamartomatous, juvenile)

SkeletalAccelerated 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. Bannayan-iley-Ruvalcaba syndrome. Am J Med Genet 1992;44:307–14.

anges between 22 and 26 years.174,550


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The intestinal polyps are most commonly found in the jejunum, andarge series have found the incidence of polyps in the small intestine to be8%, colon 42%, stomach 38%, and rectum 28%.174,550,551 These polypsesemble the hamartomatous polyps in patients with juvenile polyposisnd Cowden syndrome, but differ in the fact that there is prominentmooth muscle tissue found within the lamina propria (Fig 33). Adeno-atous and hyperplastic polyps may also be encountered. Gastric polyps

end to be more sessile, whereas small and large intestinal polyps areenerally pedunculated. The most common problems arising from theseI polyps are intussusception and GI bleeding, as highlighted by the

eport of 1 family with 12 affected members that had 32 abdominalperations and more than 70 endoscopic procedures performed foremoval of polyps.552

The skin lesions in PJS patients are pigmented macules, caused byncreased numbers of melanocytes. These lesions are not premalignant.hey are most commonly seen around the lips, mouth, hands, feet, buccalucosa, eyes, nose, and perianal areas.174,548 The degree of pigmentation

n cutaneous regions may decrease with age, but it may persist in the

IG 31. Macules of the glans penis seen in a patient with Bannayan-Riley-Ruvalcaba syndromereproduced with permission from Gorlin RJ, Cohen MM Jr, Condon LM, Burke BA. Bannayan-Riley-uvalcaba syndrome. Am J Med Genet 1992;44:307-14).

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In a study of 72 PJS patients, Spigelman and colleagues553 found that6 (22%) had developed cancer, with 10 GI cancers (4 small bowel, 3tomach, 2 colon, 1 pancreas) and 7 non-GI cancers (2 unknown primary,ovary, 1 lung, 1 thyroid, 1 fallopian tube, 1 basal cell carcinoma). The

elative risk of GI cancer death was 13, and 48% of those with cancer hadied by age 57.553 Giardiello and colleagues554 found that 15 of 31 (48%)JS patients developed cancers over a 12-year follow-up interval. Fourad GI cancers (2 stomach, 2 colon), 4 had pancreatic cancers, and 7 hadther cancers (2 breast, 2 lung, 1 ovary, 1 uterus, 1 myeloma). Theelative risk of cancer was calculated to be 18 times higher than theormal population, and the average age at diagnosis was 25 yearsranging from 1 to 64 years) after the diagnosis of PJS (at mean age of 17ears).554 Lim and colleagues555 found that 8 of 70 affected PJS patientseveloped cancers (2 stomach, 2 breast, 2 colorectal, 1 pancreas, 1ervical). They calculated the risk of developing cancer by age 65 inutation carriers to be 47%, with a standardized mortality ratio of 13.2

or all cancers, 32.0 for GI cancer, and 13.9 for breast cancer. Boardman

IG 32. Pigmented lesions of the oral mucosa in a patient with Peutz-Jeghers syndrome (reproducedith permission from Aaltonen LA, Järvinen H, Gruber SB. Peutz-Jeghers syndrome. In: Hamilton SR,altonen LA, editors. WHO Classification: Tumours of the Digestive System. Lyon: Internationalgency for Research on Cancer; 2000:74-6).581

nd colleagues556 found that 18 of 34 PJS patients developed cancer, in


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hich there were 10 GI (7 colon, 1 duodenum, 1 esophagus, 1 stomach)nd 16 extraintestinal cancers (6 breast, 3 lung, 2 cervix, 1 ovary, 1 uterus,

thyroid, 1 prostate, 1 unknown primary). Six patients had multipleancers. Women were at an 18.5-fold increased risk for cancer, 20.3 timesigher for breast and gynecologic malignancies. Men were at a 6.2-foldncreased risk for cancer, and the mean age of cancer diagnosis was 39.4ears in all patients.556 In a review of PJS, Hemminki557 found 39 casesf small bowel, 31 colorectal, 17 gastric, 8 pancreatic, and 1 esophagealancer. There were 22 cases of breast cancer, 13 cervical, 9 lung, 8varian, 3 hepatobiliary, 2 thyroid, 2 myelomas, 2 leiomyosarcomas, 2ndometrial, 1 testicular, 1 fallopian tube cancer, and 1 osteosarcoma.enign tumors of the breast, ovary, thyroid, and of sex cord origin havelso been reported.557 Giardiello and colleagues558 performed a meta-nalysis and showed that the relative risk of small bowel cancer in PJSas 520, stomach 213, pancreas 132, colon 84, esophagus 57, ovary 27,

ung 17, breast 15, and uterus 16. The risk of cervical and testicular canceras not increased.558 The mechanism of GI cancer development is likely

hrough hamartoma to adenoma to carcinoma, although this has not beenompletely elucidated. Spigelman and colleagues553 did find that 4 to 5 ofheir 10 GI cancers appeared to have developed within a hamartomatousolyp.

Genetics of PJS. In 1997, evidence for a PJS locus on chromosome 19pas discovered by Hemminki and colleagues,559 who performed com-arative genomic hybridization and detected a region that appeared to beost in PJS tumors relative to normal tissues. Loss of heterozygositytudies found consistent losses of markers from 19p in tumors. Then byenetic linkage, they found a multipoint lod score of 7.00 at theta � 0ith the marker D19S886 in 12 PJS families.559 Amos and colleagues560

erformed genetic linkage studies in 5 PJS families and confirmed linkageo the same marker (multipoint lod score of 7.52 at theta � 0), placing theJS susceptibility gene within the telomeric 3 megabases of chromosome9p. Mehenni and colleagues561 also found linkage to D19S886 with a-point lod score of 4.74 at theta � 0.045. Interestingly, they found

IG 33. A) Gross picture of a small intestinal polyp in a patient with Peutz-Jeghers syndrome (PJS). B)hotomicrograph of a colonic PJS polyp, similar to the hamartomatous juvenile polyposis polyp shownn Fig 23, but the lamina propria has large amounts of smooth muscle present (reproduced withermission from Aaltonen LA, Järvinen H, Gruber SB. Peutz-Jeghers syndrome. In: Hamilton SR,altonen LA, editors. WHO Classification: Tumours of the Digestive System. Lyon: International
gency for Research on Cancer; 2000:74-6).581

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inkage to the marker D19S891 from the long arm of chromosome 1919q) in 1 Indian PJS family (lod of 3.52 at theta � 0), suggesting aossible second PJS locus.Hemminki and colleagues562 mapped cDNA clones to a cosmid contig

reated from the human chromosome 19 mapping project, spanning an00-kb region near D19S886 known to contain the PJS gene by criticalecombinants in PJS families. Twenty-seven genes were mapped to thisegion, and mutations were found in 1 called LKB1, a previouslynmapped serine threonine protein kinase gene. Of 12 unrelated PJSatients sequenced, 11 were found to have LKB1 mutations (5 deletions,insertion, 5 substitutions; Fig 34). This gene was expressed in all tissues

xamined, and the mutations found were predicted to diminish the kinasectivity of the protein, in contrast to the activation of kinases seen in othereritable cancer syndromes (such as RET in MEN2, and CDKN2 inamilial melanoma).562 A similar effort from Jenne and colleagues563

apped 21 genes from overlapping cosmid clones spanning 400 kb in theegion of D18S886, and 1 of these genes was found to have a rearrange-ent in a PJS patient. This was a serine threonine protein kinase gene

onsisting of 9 exons over 23 kb of genomic DNA, which they calledTK11 (although it had previously been given the name LKB1). The PJSroband had a deletion of exons 4 and 5, and inversion of exons 6 and 7,nd all 3 affected members of her family also had this rearrangement.nalysis of 4 other unrelated PJS patients revealed 3 nonsense and 1

plice site mutation of the gene.563

Gruber and colleagues564 found an LKB1 mutation in the originalamily reported by Jeghers,548 as well as 5 others (2 deletions, 2nsertions, 2 nonsense mutations). They confirmed that LKB1 was a tumoruppressor gene by demonstrating that 11 of 12 hamartomas or adeno-arcinomas from 4 PJS patients had loss of the wild-type allele withetention of the mutated allele. The losses seen in hamartomas impliedhat this gene is involved at an early stage of tumor progression.564 Jiangnd colleagues565 found only 1 mutation of LKB1 in 10 unrelated PJSatients, and suggested that there may be other genes responsible for JPS.akagawa and colleagues566 analyzed 15 unrelated PJS patients forutations, and found them in 10. Four were deletions causing frameshifts,were insertions, 2 were splice site mutations, and 1 was a nonsenseutation.Miyaki and colleagues567 found LKB1 mutations in 6 of 9 PJS families

tudied, which consisted of 3 deletions, 2 insertions, and 1 splice siteutation, all predicted to cause protein truncation. They also found

omatic LKB1 mutations in 5 of 27 (19%) polyps, 4 of which shared a


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-bp deletion in exon 6. Fourteen other polyps had LOH of 19p markers,or a total of 70% of polyps showing potential somatic inactivation ofKB1. Six larger polyps also had �-catenin mutations, suggesting thesehanges may be important in polyp progression. One carcinomatousolyp examined had 19p LOH, �-catenin mutation, and p53 mutation,uggesting a hamartoma-adenoma-carcinoma sequence in PJS polyps.567

ruber and colleagues564 found that 11 of 12 hamartomas and adenocar-inomas had 19p LOH, 1 of 18 had 18q LOH, and 0 of 18 had K-rasutations.Wang and colleagues568 found LKB1 germline mutations in 7 of 12

58%) PJS patients, which included 4 deletions, 2 nonsense mutations,nd 1 missense mutation. Four families without mutations had findingsompatible with LKB1 linkage, suggesting that alterations might beresent but were not detected by their sequencing or single strandonformational polymorphism (SSCP) analysis.568 Westerman and col-eagues569 found LKB1 mutations in 12 of 19 PJS families (63%), whichonsisted of 3 deletions, 3 insertions, 3 missense mutations, 2 splice siteutations, and 1 nonsense mutation.Boardman and colleagues570 screened 10 familial and 23 sporadic casesf PJS for LKB1 changes by conformation-sensitive gel electrophoresisCSGE), and only found mutations in 2 and 4 cases, respectively. The lowutation rate found in this study may have been due to the lower

ensitivity rate of CSGE for identifying base-pair changes (which ispproximately 90%), other mechanisms of LKB1 alteration, or theossibility that other genetic loci for JPS may exist (genetic heterogene-ty).570 Lim and colleagues555 also used CSGE to screen 33 JPS familiesor LKB1 mutations, and found mutations in 17 (52%; 5 deletions, 3plice site mutations, 2 insertions, 3 nonsense, and 4 missense mutations).Boudeau and colleagues571 studied the functional consequences of 6ermline LKB1 mutations (4 deletions and 2 missense mutations) in PJSatients by cloning the cDNA into a CMV expression vector. They foundhat each of these LKB1 isoforms was unable to autophosphorylate athr336, and to suppress the growth of a melanoma cell line, in contrast

o wild-type LKB1. They concluded that these were loss-of-functionutations, and that loss of kinase activity was responsible for PJS.571

Esteller and colleagues572 studied 51 cancer cell lines (15 colon, 11ung, 7 ovary, 5 breast, 3 thyroid, 3 brain, 3 prostate, 3 leukemia, 1 cervix)or methylation of a CpG island just upstream from LKB1, and found thisn 3 colorectal and 1 cervical cancer cell lines with coincident loss of
KB1 expression. They also found methylation in 4 of 22 (18%)

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amartomatous polyps in PJS patients, suggesting that this mechanism ofene inactivation may be involved in a subset of PJS cases.572

Entius and colleagues573 examined 39 polyps and 5 carcinomas from 17JS patients for LOH for markers at the LKB1 locus on 19p13, 5q21APC), 17p13 (p53), and 18q21 to 22 (MADH2, MADH4). Fifteen of 3938%) polyps had 19p13 LOH, as did 5 of 5 carcinomas. Six of 7 polypsrom the 5 patients with carcinoma demonstrated 19p LOH. No LOH waseen at 5q21, but 1 cancer had an APC mutation. LOH was not found at7p13 in any of these samples, but was found in 1 cancer at 18q; however,ll polyps and cancers had p53 and MADH4 expression by immunohis-ochemistry. The authors concluded that LKB1 loss was important inumorigenesis in PJS patients, and the genetic mechanisms responsibleiffered from those in sporadic colorectal carcinogenesis.573

Surveillance and Follow-Up. Recommendations for surveillance ofatients with PJS or at risk for PJS are not clear, but must address theignificantly elevated risk of a variety of cancers, such as the aforemen-ioned increased relative risk of small bowel cancer (520-fold increasedisk), stomach,213 pancreas,132 colon,84 esophagus,57 ovary,27 lung,17

terus,16 and breast.15,558 Dunlop574 recommended that colonoscopy orarium enema be performed every 3 years beginning at age 18, and thatpper endoscopy be performed every 3 years beginning at age 25.emminki557 recommends biannual upper and lower endoscopy begin-ing in the mid teen years, and others suggest these be performed everyto 5 years.575 How to follow the small bowel in PJS patients remains a

hallenge. These polyps can lead to intussusception or anemia andevelop into cancers. Small bowel follow-through and enteroclysis willhow larger polyps, but the relatively new technique of capsule endos-opy may be the best available method for visualization of small bowelolyps. It would seem prudent to perform capsule endoscopy at leastvery 3 years in asymptomatic PJS gene carriers, which might precludehe need for screening colonoscopy and upper endoscopy, which could beeserved for therapeutic interventions. If multiple polyps are found, thencreening should be performed at least annually until the polyps areemoved.Gastric and colonic polyps may be removed endoscopically, with

IG 34. A) Location of LKB1 on chromosome 19p. B) Genomic and protein structure and mutationsescribed in LKB1 (reproduced with permission from Hemminki A, Markie D, Tomlinson I, Avizienyte, Roth S, Loukola A, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.
ature 1998;391:184-7).

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urgery being reserved for lesions with dysplasia or cancer. Less invasiveherapeutic interventions for small bowel polyps are more limited, sinceost enteroscopes will only reach the proximal jejunum. Surgery is

herefore the required treatment for symptomatic polyps (causing intus-usception, anemia, or pain) or those suspicious for cancer. At operation,ntraoperative endoscopy through an enterotomy can be performed toxamine the entire small bowel, and polyps may be removed through thendoscope by using a snare cautery. Larger or suspicious polyps willequire enterotomy or small bowel resection for their removal.Surveillance recommendations for extraintestinal cancers in PJS pa-

ients are not well established. Screening for breast cancers should includennual breast examination and mammography (or ultrasound in patientsounger than age 35), with the latter beginning between the ages of 25nd 35. Gynecologic malignancy should be ruled out by annual transvag-nal ultrasound, pap smear, and pelvic examination. Annual testicularxamination and ultrasound should be initiated in males by age 10.creening for pancreatic cancer by abdominal ultrasound, endoscopicltrasound, or computed tomography should be performed every 1 to 2ears starting at age 30.552,557,575

The diagnosis of PJS gene carriers may be evident from within the firstear of life based on the characteristic mucocutaneous pigmentation.hese patients will clearly need surveillance. Gene testing for PJS

nvolves direct sequencing of the entire gene for probands and directedutation screening of other at-risk individuals once a mutation is found

n the family. Genetic testing of at-risk individuals from families withnown LKB1 mutations will benefit those found not to harbor theisease-causing mutation because they may be excused from the screen-ng regimens. Those found to be gene carriers will need to be educatedegarding their risk for developing cancer and be given these surveillanceecommendations.

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