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Surgical Oncology (2007) 16, S17–S23

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REVIEW

Inherited multitumoral syndromes includingcolorectal carcinoma

F. Cetta�, A. Dhamo

Department of Surgery, University of Siena, Nuovo Policlinico, Viale Bracci 1, 53100 Siena, Italy

KEYWORDSMultitumoralsyndromes;Familial adenomatouspolyposis;Papillary thyroidcarcinoma;Brain tumors;Primary liver tumor

nt matter & 2007.2007.10.013

thor. Tel.: +39 577

etta@unisi.it (F. C

SummaryInherited multitumoral syndromes including colorectal carcinoma are the followings:familial adenomatous polyposis (FAP), hereditary non-polyposis colon cancer (HNPCC) andPeutz–Jeghers syndrome (PJS).The studies of genotype–phenotype correlation have shown that various types of colonicpolyposis are related with germline mutation of adenomatous polyposis coli (APC) gene,that is also responsible for a wide number of extracolonic manifestations. Concerningseverity of polyposis, it has been suggested to perform ileorectal anastomosis in patientswith intermediate FAP, whereas it has been suggested to remove the rectum from thebeginning and to perform ileopouch anastomosis in patients with severe FAP (germline APCmutations between codons 1250 and 1464, i.e. mutation cluster region—MCR). Concerningextracolonic manifestations, original studies from our laboratory have shown that threepeculiar, even if unusual extracolonic manifestations of FAP, were in the 50 portion of thegene, but almost always outside of MCR. In particular, in some patients or in some kindredsall these manifestations may be present together. It is suggested, from one hand, becauseof the wide variety of genotype–phenotype correlation word of caution before selectingsurgical treatment simply on the basis of the germline mutations, on the other hand co-segregation of some extracolonic manifestations could facilitate intensive screening, earlydiagnosis and optimal time for treatment.& 2007 Elsevier Ltd. All rights reserved.

Contents

FAP and MYH gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S22Conflict of Interest Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S22References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S22

Elsevier Ltd. All rights reserved.

585122, +39 3204325432 (cell); fax: +39 577 233426.

etta).

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F. Cetta, A. DhamoS18

Inherited multitumoral syndromes represent one of the moststimulating challenges of the last decades. They require acombined approach by surgeons, oncologists and molecularbiologists. Early diagnosis permits surgical treatment in thepreinvasive stage, before full development of the malignantphenotype occurs, with obvious advantages in terms of bothradical treatment and better prognosis [1–3].

In particular, some inherited multitumoral syndromesshow colorectal carcinoma, as a manifestation integral tothe syndrome. They include: familial adenomatous polyposis(FAP), hereditary non-polyposis colon cancer (HNPCC) andPeutz–Jeghers Syndrome (PJS). Still open questions are thefollowing: timing of the various therapeutic options,selection of tumors, i.e. which must be treated earlier,ideal timing for surgery, extension of surgery. Genotype–

phenotype correlation may guide both the ideal timing ofoperation and the extension of surgery [1–3].

HNPCC (Lynch syndrome) is a syndrome related togermline mutations of mismatch repair genes (MSH, MLH).It includes colorectal carcinoma, breast cancer, carcinomaof the endometrium, carcinoma of the ovary.

PJS is an autosomic dominant syndrome characterized bymelanotic mucocutaneous pigmentation, associated withmultiple polyps of the gastrointestinal tract. It is deter-mined by germline mutations of the gene STK11/LKB1, aserine–threonine kinase. Mutations of this gene are de-tected in 30–80% of cases at chromosome 19p13.3. Theoverall risk that an affected patient will develop cancer atan age of 70 is 85%. The most frequent neoplasms includethe following: esophagus, stomach, small bowel, colonrectum, pancreas. Less frequent neoplasms: breast, ovary,endometrium, cervix, lung. Patients with evident clinicalPJS, but without detection of the germline mutation on thegene STK11 at 19p13.3, showed a very high incidence ofcholangiocarcinomas (40%).

FAP is an autosomal dominant hereditary syndrome,characterized by the presence of hundreds to thousands ofcolorectal adenomatous polyps which, if not surgicallytreated, develop into colorectal cancer (CRC) in 100% ofcases. The prevalence of FAP is 1:5000–10,000, affectingboth genders equally, with a uniform worldwide distribution.In FAP, colorectal adenomatous polyps begin to appear at amean age of 16 years (range 7–36), invariably evolving intocarcinomas between 30 and 50 years of age.

Table 1 Classification of FAP.

FAP phenotype No. ofpolyps

Age of onsetof polyps

Mean age ofonsets of CRC (y

Severe (classicalFAP)

45000 I and IIdecades

34

Intermediate(classical FAP)

100–5000 II and IIIdecades

42

Attenuated(AFAP)

o100 IV and Vdecades

Delayed

FAP, familial adenomatous polyposis; CRC, colorectal cancer.a50 end exons 4 and 5.bWithin exon 9.c30 distal end of APC gene.

FAP is determined by germline mutations of the adeno-matous polyposis coli (APC) gene, mapped at chromosome5q21 [4]. APC consists of 15 transcribed exons. The APC geneproduct comprises 2843 amino acids with a molecular massof 311.8 kD. Because of the accumulation of mutationswithin the 50 end of exon 15, between codons 1250 and1513, this region is termed the ‘‘mutation cluster region’’(MCR), which represents approximately 60% of reportedsomatic mutations.

APC gene is basic for the Wnt pathway. It is part of aprotein complex, modulated by the Wnt signaling pathway,which regulates the phosphorylation and degradation of b-catenin. Wnts are a family of secreted glycoproteins, thatbind to the 7-transmembrane receptors, frizzled, and co-receptors. Activation of the Wnt signaling pathway leadsto inhibition of GSK-3b, by dissociating the enzyme froma multiprotein complex that involves axin, APC, andb-catenin.

The APC protein plays a crucial role in the followingprocesses: epithelial cell–cell adhesion through associationwith E-cadherin and microtubule bundles, regulation of cellmigration up the colonic crypt, proliferation and cell cyclecontrol helping to suppress tumorigenesis, differentiation,apoptosis and intracellular signal transduction. In addi-tion, APC stabilizes microtubules, promoting chromosomalstability.

Germline mutations of tumor suppressor genes, such asAPC, are responsible for a wide range of phenotypicalterations, occurring in various ages of life, dependingeither on biallelic inactivation of the APC gene, i.e. loss offunction of the residual allele, or interactions with modifergenes, environmental factors, sex related factors (hor-mones, etc.), affecting in various ways the genetic function.

In particular, studies of genotype–phenotype correlationhave shown that various types of colonic polyposis areprominently related to the site of APC germline mutation[1–3] (Table 1). Severe (classical) FAP, with thousand ofcolorectal polyps, occurring early, sometimes within the firstor second decade of life, and usually determining the onsetof carcinoma before age 35, is usually associated withgermline mutations in the MCR, i.e. between codons 1250and 1464, whereas intermediate FAP is associated with APCmutations between codons 157–311 and 412–1597 (except1250–1464). Finally, attenuated FAP (AFAP), with less than

r)Site ofCRC

Sites of mutation codonno.

Extracolonicmanifestations

Left 1250–1464 (MCR) Extremely

Left 157–311 and 412–1597(except 1250–1464)

Common

Right 1–57a, 311–412b and1596–2644c

Limited

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Table 2 Extracolonic manifestations.

Embryonic cell layer Extracolonic manifestations Benign/malignant expression Frequency (%)

Ectoderm CHRPE Benign 58–92Epidermoid cysts, lipomas Benign 53Dental, bone abnormalities Benign 17CNS tumors Malignant 1

Mesoderm Osteomas Benign 14–93Desmoid tumors Benign/malignant 4–17Adrenocortical tumors Potentially malignant o1Ovarian tumors Malignant o1

Entoderm Duodenal polyps Potentially malignant 33–73Gastric fundic gland polyps Potentially malignant 23–56Thyroid carcinomas Malignant 1–2Liver tumors Malignant 1–2

Table 3 Genotype–phenotype correlations with germ-line APC mutations.

Extracolonicmanifestation

Germline APC mutation codonno.

CHRPE 311–1444Palpable osteomas 767–1513 (41444)a

Desmoid tumors 1310–2011 (1444–1578)a

Gastric fundic glandpolyposis

1456–1578b

Duodenal adenomas 1395–1493b

PTC 140–1220 (1309)c

CNS tumors 140–1220(1284, 1427)c

HB 141–1230

APC, adenomatous polyposis coli; CHRPE, congenital hyper-trophy of the retinal pigment epithelium; CNS, centralnervous system; PTC, papillary thyroid carcinoma; HB,hepatoblastoma.

aHigher incidence.bAlso described in other regions of the APC gene.cTwo patients with FAP/PTC had APC mutations at codon

1309, and two patients with FAP/BTP had APC mutations atcodons 1284 and 1427, respectively.

Inherited multitumoral syndromes including colorectal carcinoma S19

100 polyps, with late onset of both polyps (IV–V decade) andcarcinoma (delayed), is associated with mutations 50 tocodon 157 or 30 to codon 1596 (Table 1).

On the basis of these correlations, it has been suggestedthat, while planning surgical treatment, colectomyshould be the intervention of choice, with primary ileorec-tal anastomosis (IRA) for patients with APC germlinemutations before codon 1250, whereas primary proctoco-lectomy with ileopouch anastomosis (IPAA) should bethe treatment of choice for patients with APC germlinemutations between codons 1250 and 1464 [1,3].This approach seems justified on the basis of the resultsof Wu et al. [2] who, observed 34 patients with formerIRA, who were followed up for decades. Of eight, whorequired reoperation, seven had APC mutations beyondcodon 1250.

However, disruption of the Wnt pathways, due to germ-line APC mutations, which are present since birth in all cells,does not determine only the occurrence of colonic polypsand subsequent malignant transformation, but the inheritedgenetic abnormality is responsible for a wide number ofextracolonic manifestations. They include the occurrence ofbenign and malignant tumors in other sites, such as gastricand duodenal polyps and cancers [5], liver tumors [6–9],tumors of the pancreatobiliary district [10], thyroid carci-noma [11–19], and tumors of the central nervous system(CNS) [20–23], desmoid tumors [24], or tumors of ovary orthe adenocortical gland, as well as non-malignant manifes-tations such as congenital hypertrophy of the retinalpigment epithelium (CHRPE) [25], or epidermoid cysts,lipomas, dental or bone abnormalities.

This association between benign and malignant abnorm-alities of various districts is typical of all inherited multi-tumoral syndromes. Therefore, a perfect knowledge isrequired of which is which, i.e. the sites of the variousextracolonic manifestations (Table 2), the age of onset, andgenotype–phenotype correlations (Table 3), in order toobtain early diagnosis, and proper and timed treatment.

In the present paper, three peculiar, even if unusual,extracolonic manifestations of FAP have been extensivelyanalyzed: (1) hepatoblastoma (HB) and primary liver tumors

[6–9]; (2) thyroid carcinoma [11–19]; (3) brain tumors[20–23].

Genotype–phenotype correlations in patients with FAP-associated HB are shown in Table 4. HB is a rare embryonictumor that occurs in children with an average age of 2–3years. A pronounced increased relative risk of HB has beenfound in FAP patients and their first degree relatives(relative risk RR ¼ 847,95: confidence limits 230 and 2168)[6]. Despite this increased risk, FAP-associated HB is veryrare. Only 33 cases (24 men, 9 women) have been reportedby Giardiello et al. [6]. Table 4 shows genotype–phenotypecorrelations in the 15 patients who had detection of theirAPC germline mutations: seven of these patients wererecruited during our international cooperative study [7,8].

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Table 4 Genotype–phenotype correlations in patients with FAP-associated HB.

No. Sex Age (yr) CHRPE APC germline mutations

Exon Codon Wild-type sequence Mutant sequence

1 M 3.8 � 3 141 GTCATTGC GTCTGC2 F 2.3 � 4 Intron 3 G T3 M 4.0 � 5 213 CGA TGA4 F 0.1 � 5 215 CAG TAG5 M 3.2 � 8 279 GGTTAA GGTAA6 M 0.7 � 8 302 CGA TGA7 M 4.6 � 13 541 CAG TAG8 M 3.1 + 13 554 CGA TGA9a F 3.5 + 15 1061 AAACAAAGT AAGT

10a,b F 2 + 15 1061 AAACAAAGT AAGT11a M 3.3 + 15 1061 AAACAAAGT AAGT12 M 3.4 + 15 1061 AAACAAAGT AAGT13 M 2.4 + 15 1105 CGGGGA CGGGA14 M 9.9 + 15 1189 GATATTCCT –

15c M 2.5 + 15 1230 CAG TAG16c F 1.4 + 15 1230 CAG TAG

aThyroid carcinoma associated in one member of the kindred.bThyroid carcinoma associated in three members of the kindred.cSiblings belonging to the same kindred.

F. Cetta, A. DhamoS20

Interestingly, all of these germline mutations were located50 to codon 1230. Most of them were at codon 1061.However, some mutations were at codons 141, 213, 215,275, 302, respectively, i.e. in the very 50 portion of thegene.

Interestingly, one patient who had right liver resection atage 2 after neoadjuvant treatment for HB, underwentsubsequent resection for hepatocellular carcinoma (HCC) atage 14. Therefore, in the same liver, HB occurred at age 2and HCC, i.e. a completely different tumor, at age 14 [7,8].

Table 5 shows patients with FAP-associated papillarythyroid carcinoma (PTC) in our personal series (n ¼ 18)[11–19]. A total of 150 patients with FAP-associated PTC hasbeen reported in the literature [11]. There is a strikingfemale prevalence (F:M ratio417:1 vs. a female/male ratioof 2.5:1 in sporadic tumors). The mean age at diagnosis was24.8 years in our series and 28 years in patients from theworld literature [11]. About one third had concomitantdiagnosis, one third first diagnosis of FAP, and one third firstdiagnosis of PTC. The histologic type of PTC was almostalways ‘‘conventional’’ papillary in at least two third ofpatients. However, an unusual pattern, the so-called cribri-form morular pattern, that is very infrequent in sporadictumors (less than 0.16%), was found in one third of thesepatients [14–18]. Interestingly, comparing patients with PTCwith those without PTC, most of cases, i.e. 22 out of 24, hadAPC germline mutations before codon 1220 (p ¼ 0.005) [11].

Noteworthy, there was no LOH for APC in the thyroidtumoral tissue [13], suggesting a dominant negative me-chanism or the concomitance of environmental factors(ionizing radiation?) [19]. Most of patients had RET/PTCactivation [14].

Table 6 shows FAP-associated brain tumors and PTC in thesame patient or kindred. Brain tumors (BTP) were recog-nized as a part of the inherited polyposis colorectalsyndrome by Turcot [20]. However, Turcot’s syndromeincluded both BTP associated with FAP (mostly medullo-blastoma) and with HNPCC (mostly glioblastoma) [21,22].

Attard et al. [23] showed that most of these FAP-associated brain tumors co-segregated with HB. In thepresent series, we show that FAP-associated brain tumors,not only co-segregate in the same genomic area as HB, butalso that there are single patients, or patients belonging tothe same kindred, who concomitantly have colonic polyps,PTC and BTP. Most of these patients also have CHRPE.Interestingly, in addition to medulloblastomas, other tumorssuch as pinealoblastomas or astrocytomas can be found.However, even benign tumors, such as brain fibromatoses orpinealoma or pineal cysts or cystic tumors of the CNS can beobserved. Therefore, even if FAP-associated BTP usually donot include glioblastomas or other aggressive histotypes,prognosis of FAP patients with BTP is often dismal, becausethese patients, as well as those with HB or primary livertumors, have their tumors before the occurrence of colonicpolyps, and tumor recurrence is frequent.

PTC in FAP can also recur, but recurrence is infrequent(o10% of cases) and usually occurs many years later.

One of the main findings of the present study is that BTPco-segregate with PTC in patients with FAP.

In particular, intensive screening for HB before age 2, forBTP after age 2, and for thyroid nodules after age 15,respectively, is recommended, when a single patient or anentire kindred have CHRPE or mutations in exon 15. HB, PTCand BTP, like any other extracolonic manifestation, may

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Table 5 FAP-associated PTC (personal series).

No. Sex Age Histologic variant No.codon

No.exon

CHRPE LOH for APCgene

Ret/PTCactivation

BTP

1 F 30 Papillary 140 3 – n.p. n.p. �

2 F 19 Encapsulated follicularvariant

593 14 + n.p. n.p. �

3 F 22 Solid 778 15 + � + +4 F 31 Cribriform 937 15 + � + �

5 F 18 Papillary 976 15 + n.p. n.p. �

6 F 27 Cribriform 993 15 + n.p. n.p. �

7 F 39 Papillary 1105 15 + n.p. n.p. �

8 F 34 Mixed 1105 15 + n.p. n.p. �

9 F 25 Cribriform 1068 15 + � + �

10 F 26 Cribriform 1061 15 + � + �

11a F 22 Papillary with cribriformareas

1061 15 + � + �

12a F 20 Cribriform with solid areas 1061 15 + � + �

13a F 36 Papillary 1061 15 + � � +14 F 24 Mixed 1061 15 + � � �

15 F 20 Encapsulated follicularvariant

1309 15 + � + �

16 F 27 Papillary 1309 15 n.a. n.p. n.p. �

17 F 22 Cribriform follicular n.a. 15 n.a n.p. n.p. �

18 F 20 Solid n.a n.a. n.a. n.p. n.p. �

FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli; PTC, papillary thyroid carcinoma; CHRPE, congenitalhypertrophy of the retinal pigment epithelium; BTP, brain tumors polyposis.n.p., not performed.n.a., not available.

aHepatoblastoma and hepatocellular carcinoma in a member of this kindred.

Table 6 Brain tumors associated with PTC in the same patient or FAP kindred.

Author Year Sex Agea (yr) APC mutation S/C Brain tumor PTC CHRPE

Histotype Age (yr)

Crail 1949 M 24 1061 Medulloblastoma 24 +b n.r.Lynch 2001 F 19 1068 McdLilloblastoma 30 +c n.r.Fcnton 2001 F 29 1061 Medulloblastoma 6 +b +Plawski 2004 n.r. 35 608 Cerebral flax tumor n.a. +c n.r.

n.r. 10 608 Brain fibromatoses 10 +c n.r.Gadish 2006 F 21 1061 Pinealoblastoma 18 +c n.r.Our series – F 22 778 Craniopharyngioma 16 +b +

F 36 1061 Medulloblastoma 32 +c +F 20 1061 – +c +F 22 1061 – +c +

FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli; PTC, papillary thyroid carcinoma; CHRPE, congenitalhypertrophy of the retinal pigment epithelium.n.r., not reported.n.a., not available.

aAge (years) of first diagnosis of colonic polyps.bIn the same patient.cIn another member of the same kindred.

Inherited multitumoral syndromes including colorectal carcinoma S21

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F. Cetta, A. DhamoS22

precede clinical diagnosis of FAP. These data, i.e. thatpatients with HB, PTC and BTP, which usually have APCmutations in the same genomic areas, need furtherconfirmation. However, this observation could facilitateearly diagnosis, better treatment and a deeper insight intogenotype–phenotype correlations in patients with FAP.

In particular, concerning treatment, in addition to theselection of the proper surgical procedure, other choicescan be made, according to germline mutations, includingage at which to begin endoscopic surveillance, intensity ofrectal surveillance, or after colectomy and ileo–rectalanastomosis [26,27].

In FAP patients the severity of the disease cannot bedefined simply on the basis of the number or the early onsetof colonic polyps. In fact, FAP is not merely a preneoplasticdisease of the colon but a genetically determined multi-tumoral syndrome. The diversity and the relative impor-tance of the various tumors is wide, even in terms of lifeexpectancy.

FAP and MYH gene

In a relevant subset of APC patients, 7–23% of APC mutationnegative cases with a phenotype overlapping with AFAP isassociated with biallelic germline variants of the MYH gene.MYH is a DNA glycosilase involved in the repair of oxidativeguanine damage. The recognition of this autosomal reces-sive form of adenomatous polyposis suggests that adenoma-tous polyposis shows genetic heterogeneity. Screening forboth APC and MYH mutations should be considered in casesthat do not have a thyroid family history. Extracolonicmanifestations such as osteomas and desmoid tumors areless frequently associated with MYC mutations [28].

There is legitimate hope that genetic analysis in thefuture will guide not only intensive screening, but alsosurgical practice in patients with inherited multitumoralsyndromes. Particularly in FAP patients, the planning ofsurgical treatment, in terms of extent of colon resection andselection of the reconstructive procedure, as well as theoverall therapeutic strategy for patients who sometimescould have five or more extracolonic manifestations, cannotbe made without an accurate preoperative genetic analysis.

Surgical inferences from genetic analysis seem to bejustified. However, when specific oncogenetic alterationshave already involved a given tissue (such as ret–PTCactivation in patients with FAP-associated thyroid carcino-ma), caution is required while trying to speculate on the riskof occurrence of one type of tumor instead of another, or toestablish the severity of the multitumoral syndrome, simplyon the basis of the germline mutation.

A wide phenotypic variability has been observed, not onlywithin different kindreds carrying the same APC mutation,but also within the same kindred. Modifier genes andenvironmental factors, namely for some peculiar tumorssuch as thyroid carcinoma, play a major role in theoccurrence of the malignant phenotype. In these cases,the germline APC mutation could only give a generic greaterpropensity to tumor development [11,19].

In conclusion, even if tyrosine–kinase inhibitors such asimanitib mesylate have been used in chronic myeloidleukemia and in the treatment of gastrointestinal stromal

tumors as genetically targeted drugs, genetic treatment ofcancerous diseases in not around the corner. In fact,clinically evident tumors usually occur following a multistepcarcinogenetic mechanism, which lasts for years. During thistime lag multiple genes are altered and different pathwaysare going to be disrupted. Therefore, genetic replacementof multiple abnormalities does not seem feasible, at least inthe near future. However, a better knowledge of carcino-genetic mechanisms is in progress. But, even if an intensivescreening is legitimate for specific tumors showingan increased incidence in patients with a givengermline mutation, we suggest a word of caution beforeextrapolating surgical guidelines from mutational analysisand planning surgical treatment simply on the basis ofgermline mutations.

Conflict of Interest Statement

The Authors do not have any potential or actual personal,political, or financial interest in the material, information,or techniques described in the paper.

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