ORIGINAL ARTICLE

An unusual case of familial adenomatous polyposis with very earlysymptom occurrence

Maurizio Ponz de Leon • Maria Anastasia Bianchini • Luca Reggiani-Bonetti •

Monica Pedroni • Carmela Di Gregorio • Alberto Merighi • Giuseppina Rossi •

Giulia Magnani • Federica Domati • Alfredo Cacciari

� Springer Science+Business Media Dordrecht 2014

Abstract We report the clinical case of a patient who

showed an ‘‘accelerated’’ form of polyposis, with develop-

ment of major lesions within the first decade of life. The

patient belongs to a familial adenomatous polyposis family—

already described in 2001—featured by profuse polyposis at

an early age of onset and desmoid tumors in the majority of

affected individuals (of both sexes). The family was charac-

terized by an uncommon mutation of the APC gene (c.4391_

4700del310insCACCTACTGCTGAAA, previously defined

as c.4394ins15del310) consisting in a large deletion of

310 bp at codon 1,464 with duplication of the breakpoint

leading to a stop codon at position 1,575. The proband was

affected by desmoids tumors at the age of 3 years. In the same

year (2004) numerous polyps in the large bowel and a

hepatoblastoma developed. After several months new

desmoids appeared in the surgical scar. In 2010, at age 9, the

patient was operated of total colectomy and endorectal pull-

through of the small intestine owing to profuse colorectal

adenomatosis. New desmoids developed in 2011 and 2012,

and required chemotherapy. Further analysis of the APC gene

in the proband revealed several polymorphisms. One of these

(c.398A[G) had not been previously reported, nor was

present in two other affected members of the family. The

clinical case, and the practical implications for therapy, are

discussed according to the most recent theories of colorectal

cancer development. Long-term treatment with Cox-2

inhibitors might represent a good option for this patient.

Keywords FAP � APC � Mutation � Gene � Cancer �Adenoma

Introduction

Patients with familial adenomatous polyposis (FAP) are at

increased risk for neoplasms (both benign and malignant)

of the entire gastrointestinal tract, from cardias to the lower

rectum [1, 2]. Moreover, malignancies of other organs—

liver (hepatoblastoma), adrenal glands, thyroid, pancreas

and biliary tract—are observed with increased frequency as

compared to the general population. For instance, the

incidence of hepatoblastoma (a very rare embryonal liver

tumor) among children with FAP is on the order of 1 in

235, versus 1 in 100,000 in common individuals [3].

According to most FAP series [4–6], colorectal adeno-

mas tend to appear in the second or in the third decade of

life, whereas colorectal cancer, in untreated patients, usu-

ally develops in the third or fourth decade, some

10–15 years after polyp detection. Multiple adenomas or

even full-blown polyposis may also develop in the first

decade of life, but the event is decisely rare [7, 8].

In 2001, we described a large kindred with FAP featured by

profuse polyposis at a relatively early age of onset (mean

24 years; range 17–38) and desmoid tumors in the majority of

affected individuals (11 of 15, 73.3 %) [9]. The family

showed an uncommon mutation of the APC gene (c.4391_

M. Ponz de Leon (&) � L. Reggiani-Bonetti � M. Pedroni �C. Di Gregorio � G. Rossi � G. Magnani � F. Domati

Dipartimento di Medicina Diagnostica, Clinica e Sanita

Pubblica, Universita di Modena e Reggio Emilia, Policlinico,

Via del Pozzo 71, 41100 Modena, Italy

e-mail: deleon@unimore.it

M. A. Bianchini � A. Cacciari

Cattedra ed Unita Complessa di Chirurgia Pediatrica, Policlinico

di Modena, Modena, Italy

A. Merighi

Divisione di Gastroenterologia, Policlinico di Modena, Modena,

Italy

123

Familial Cancer

DOI 10.1007/s10689-014-9718-3

Explanation of Symbols:

Man Woman Deceased

Cancer by family history

Adenomatous Polyposis Coli

Cancer developed over a background of FAP

Proband (fist member of the family who came to our observation)

Index case of the present report

FAP Familial Adenomatous Polyposis

Age of appearance of polyps

29

Age of appearance of cancer

39

++ Presence of the c.4391_4700del310insCACCTACTGCTGAAA mutation

Fig. 1 Genealogical tree of the FAP family MO-20 [9]

M. Ponz de Leon et al.

123

4700del310insCACCTACTGCTGAAA, previously defined

as c.4394ins15del310) consisting in a large deletion of 310

base pairs at codon 1,464 with duplication of the breakpoint

leading to a stop codon at position 1,575 [10]. We now report

the clinical case of a young patient in this family who showed

hepatoblastoma, full-blown adenomatosis (leading to colec-

tomy) and multiple desmoid tumors in the first decade of life,

between age 3 and 9 years. The possible explanations and

interpretations of this anomalous and ‘‘accelerated’’ clinical

behaviour are discussed in relation to the most recent theories

on cancer origin and development [11].

Case report

Figure 1 shows the genealogical tree of the FAP family

MO-20 which came to our observation for the first time in

1985 (the proband was IV-9, indicated by the black arrow).

The mother of the index case (V-5, white arrow), was

diagnosed with adenomatosis coli at age 18; she died at age

25 for complications of aggressive desmoids. The grand-

father of the proband died of colorectal cancer (over a

background of polyps) at the age of 43 years.

The index case, P.R.L., born in 2001, as early as April

2004, when he had not completed the third year of life, was

operated for a desmoid tumor of the back; a first colon-

oscopy showed the presence of 4 adenomatous polyps with

low-degree dysplasia. Two months later, in June 2004,

liver blood tests, ultrasound, CAT scan and liver biopsy led

to the diagnosis of hepatoblastoma. Within few weeks the

patient was operated of partial liver resection. Grossly, the

surgical specimen consisted of a well demarcated and

lobulated mass measuring 4.5 9 3.5 cm (main diameters)

surrounded by apparently normal liver tissue. At histology,

the mass was composed by small regular cuboidal cells

with eosinophilic cytoplasm and vesicolar nuclei with

dispersed chromatin, resembling fetal hepatocytes. The

cells were arranged in trabeculae separated by narrow

sinusoids. Foci of hematopoiesis could be observed

(Fig. 2). The tumor was immunoreactive for antihuman

hepatocyte (Hep Par 1) and anticytokeratin antibodies. The

final diagnosis was ‘‘Epithelial Hepatoblastoma of fetal

type’’.

The patient underwent genetic testing which showed the

presence of the heterozygote mutation of APC

(c.4391_4700del310insCACCTACTGCTGAAA) already

reported in all affected members of the family [10]. Table 1

summarizes the genetic polymorphisms of APC detected in

the DNA of the index case in addition to the main mutation

present in this family. One of these alterations (c.398A[G,

p.Tyr133Cys, Exon 3) was not reported in the main database

available on the web [12, 13], nor was detected in two other

affected members of the family (patients IV-17 and V-28 of

Fig. 2 Hepatoblastoma of Fetal type. Epithelioid cells with acido-

philic cytoplasm, vesicular nuclei and dispersed chromatin. Myelo-

poiesis can be observed in the sinusoids (a ematoxylin and eosin,

930). b the same tumor shows intense positivity with cytokeratin

antibodies (MN F116)

Table 1 Main genetic changes of APC (constitutional DNA) detec-

ted in the proband

Main mutation

detected in all

affected family

members

c.4391_4700del310insCACCTACTGCTGAAA,

previously defined as c.4394ins15del310 (Ref.

10)

Polymorphisms

(already

reported)

c.423-4delA (Intron 3)

c.1458C[T (Exon 11)

c.1635A[G (Exon 13)

c.5034A[G (Exon 15)

c.5465A[T (Exon 15)

c.5880A[G (Exon 15)

c.5267G[T (Exon 15)

Alterations not

previously

reported

c.398A[G, p.Tyr133Cys (Exon 3)

An unusual case of FAP

123

Fig. 1), thus suggesting that this variant is on the other allele of

the APC gene. Moreover, search of the main MUTYH muta-

tions (Y179C and G396D) in constitutional DNA of the pro-

band was negative [14]. Finally, DNA mismatch repair

(microsatellite instability and immunohistochemical expres-

sion of MSH2, MSH6, MLH1 and PMS2), evaluated in the

resected hepatoblastoma, resulted normal [15].

Rather surprisingly, the patient recovered promptly and

continued to develop normally. In 2007 (age 6) a control

colonoscopy showed several polyps (adenomas with low-

grade dysplasia), especially in the descending colon. At

gastroduodenoscopy polyps were also seen in the stomach

and duodenum. In 2008 there was an increase of polyps in

the large bowel, which maintained smaller than 5 mm and

with low-grade dysplasia. In addition, two round masses of

8 cm in diameter were palpable at the margins of the sur-

gical scar, and interpreted as desmoid tumors. The neo-

plasms were removed, but one year later a new 5-cm mass

developed near the surgical scar. Two additional 10-cm

desmoids developed in 2010 between the abdominal wall,

the liver and the stomach. The patient was operated again,

with the (apparent) removal of all desmoid neoplasms. In

June 2010, at colonoscopy the entire large bowel was

carpeted by small polyps (1–5 mm, adenomas with low-

grade dysplasia), and the decision was taken to proceed

with the removal of the colon within that year. In Sep-

tember 2010 (age 9) the patient was operated of total

colectomy with endorectal pull-through [16] of the ileum

with primary anastomosis [17]. Moreover, a small desmoid

was removed from the superior margin of the surgical

incision. An intestinal tract of 66 cm was analyzed con-

taining [100 polyps between 0.1 and 0.5 cm in diameter;

all observed lesions were tubular adenomas with low-

medium degree dysplasia and no evidence of malignancy.

In successive controls (2011, 2012) small adenomas

(again with low-grade dysplasia) were removed from the

ileorectal anastomosis and the duodenum. New desmoid

tumors developed contiguous to the surgical scars; in 2011

chemotherapy was initiated with Vinoreblin and Metot-

rexate (and, after few months, with other drugs), but with a

very scarce effect on desmoid size.

At the last control of May 2013 the situation was stable.

The 12-year-old boy attended regularly his school and

physical examination was unremarkable. Two 2–3 mm

small polyps (adenomatous lesions, with low-grade dys-

plasia) were removed from the rectal stump. A total of 5

small (2–4 mm) adenomatous polyps were removed from

the duodenum, while numerous polyps were seen in the

stomach, some of which were removed (glandular type at

histology). The dimension of desmoids was virtually

unchanged. The patient stopped chemotherapy at the end of

2012. Blood tests, ECG and other routine examinations

were normal.

Discussion

This report describes the unusual clinical finding of a very

young patient with FAP in whom the disease had an ‘‘accel-

eration’’ and very aggressive course. The patient developed a

fetal type hepatoblastoma when he was\3 years old; subse-

quently, between age 3 and 9, he was operated several times of

large, recurring desmoid tumors of surgical scars; polyps were

already present at age 3, they increased over time in number,

ad at age 9 the patient underwent total colectomy. New

desmoids developed in the follow-up. This young individual is

a member of an already described family [9, 10] carrying a

rather uncommon APC mutation, and characterized by pro-

fuse polyposis since the adolescence (in many members),

early colorectal carcinoma and large, recurring, complex and

highly invalidating desmoid tumors of the surgical scars and

retroperitoneum. However, the patient was an exception even

within this family, since no other member of this large kindred

cumulated major clinical symptoms of FAP within the first

decade of life.

The reasons whereby the disease had an anomalous clinical

course (as compared to the other members of the family and to

most FAP patients) remain unclear and purely speculative.

Since tumors usually develop owing to a close interaction

between genetic background and environment, one might

speculate that specific agents or factors related to the way of

living (alimentation, work activity, unusual leisure habits)

may interfere with the lack of function (due to a constitutional

mutation) of APC. However, there was nothing abnormal or

even suspicious in a young boy living in a large and modern

city of Southern Italy and attending regularly his schools. As a

further possibility, the proband might carry a second mutation

in the APC gene, which in some indefinite way cooperates

with the first—already described—mutation in inducing the

early appearance of intestinal, hepatic and fibrous lesions.

Again, since APC mutations inactivate gene function [18] it

seems to us rather hard that a second mutation may further

inactivate the gene. Moreover, several investigations showed

the potential role of specific DNA polymorphisms (such as

SNP at 9p24, 8q23 and 11q23) in modulating the effect of

major genes, thus contributing to early onset or aggressive

behaviour of cancer [19–21]. In our patient several APC

polymorphisms were detected and one of these had not pre-

viously been reported, nor was detected in other affected

members (c.398A[G). The significance of this finding

remains unclear, however, a preliminary bioinformatic eval-

uation of the c.398A[C variant (SIFT, GVGD, PHANTER

and POLY-Phen-2 predictive tests) suggested a possible

inactivating effect of the protein function.

A third, and more appealing, possibility is that the patient

might harbour a (second) mutation in a gene involved in a

different pathway leading to tumor. In a recent review, Vo-

gelstein and collaborators [11] suggested that a total of 52

M. Ponz de Leon et al.

123

main (driver) genes could be classified into one of 12 path-

ways that confer to cells a selective growth advantage. These

carcinogenetic pathways could be further simplified into

three ‘‘core’’ cellular processes, which can be defined ‘‘Cell

Fate’’, ‘‘Cell Survival’’ and ‘‘Genome Maintenance’’. APC,

together with HH, NOTCH and transcriptional regulation

genes, belong to the first group, all genes governing the

balance between cell differentiation and division, and whose

lack of function favors cells to replicate giving origin to

neoplasms. ‘‘Cell Survival’’ genes include RAS, STAT, MET

and several growth factor genes; when cancer cells acquire a

mutation in a gene of this group we can expect the cell to be

able to proliferate under limited nutrient concentrations, thus

obtaining a selective advantage over normal elements. The

third group includes genes involved in the control of DNA

damage—such as genes implicated in the pathogenesis of

Lynch syndrome, (hMSH2, hMLH1, hPMS2, hMSH6) [22],

PT53 and ATM [23]—since tumor cells that can survive

DNA damage should have a selective growth advantage

when compared to normal cells. We can therefore speculate

that in the index case, in addition to the well defined (and

unusual) APC mutation, a second constitutional mutation in

a gene belonging to one of the two other categories (‘‘Cell

Survival’’ or ‘‘Genoma Maintenance’’) may potentiate the

oncogenic effects due to the lack of function of APC, thus

leading to a particularly aggressive phenotype, with the

occurrence of tumors which are usually spread over a

20–30 years in the initial 8–9 years of life. Further molecular

studies are needed to support this pathogenetic interpreta-

tion. In our patient we could obtain evidence (working on the

hepatoblastoma tissue) of a normal DNA mismatch repair

system: stable microsatellite and normal expression of

MSH2, MSH6, MLH1 and PMS2 proteins.

Besides desmoids, the patient remains at risk of cancer

in the anastomosis and of malignancies in the upper gas-

trointestinal tract, primarily in the periampullary region

[24, 25]. Both risks should be assumed to be higher than

those of the common patient with FAP, owing to the

accelerated course of the disease. There is evidence that

Celecoxib—a selective cycloxygenase-2 inhibitor—is safe,

well tolerated and highly effective in reducing the number

of colorectal polyps in young patient with FAP, at the dose

of 16 mg/kg/day [26]. Similarly, the drug might be of help

in lowering the rate of appearing (and presumably of pro-

gression) of duodenal adenomas [27]. Long-term treatment

with Cox-2 inhibitors, therefore, may represent a good

option in this patient.

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