Aetiology and Risk Factors

The aetiology of DTs is unknown and their true nature is controversial. DTs are considered dysplas-tic lesions of connective tissue and classified as fibromatoses, which cover diseases such as Dupuytren's contracture, Peyronie's disease, plantar fibromatosis, idiopathic retroperitoneal fibrosis, etc. The absence of metastatic spread, the generally benign behaviour with slow growth or even regression, the histological features consisting of mature fibroblast without atyp-ia or mitoses, and the absence of telomerase are consistent with a reactive or dysplastic lesion. However, their potentially rapid and aggressive growth and their tendency to recur after surgical removal have suggested a neoplastic origin. Favouring this view is also the fact that DTs will arise after inactivation of the APC tumour suppressor gene, occurring by point mutation or allelic deletion. Furthermore, it has been observed that the majority of the cells are represented by a clonal population [28]. It has also been shown that the proliferation of desmoid cell cultures is inhibited by the cellular transfection of wild-type APC [29]. The hypothesis has been proposed that the DPLs undergo a multi-step process analogous to the cascade suggested for the adenoma-carcinoma sequence developing firstly mesenteric fibromatosis and finally mesenteric DTs [6, 28]. The surgical trauma could favour somatic mutations of mesenteric fibroblasts, inducing their clonal expansion to produce a DT. This interpretation suggests the need of preventive measures in order to avoid the transformation of DPLs in true DTs, as well as for a rational oncological approach to aggressive DTs.

Gender and Pregnancy

The influence of the female gender regarding the development of DTs in FAP patients is controversial.

In the past, several authors found no significant sex differences [2,30] or a slight prevalence in the female sex, with a female/male ratio of 1.4 [31, 18]. More recently a clear preponderance of DTs among females clearly has been noted in studies concerning large series of FAP patients, and females have twice the odds of developing DTs compared with males [12, 32].

The effect of pregnancy on the behaviour of intraabdominal DTs has been investigated in retrospective studies. Some authors have shown a tendency for DTs to develop soon after pregnancy [30, 33, 34], but others find that DTs present later, are smaller and significantly less aggressive in females who have been pregnant than in females who have not [35]. These authors suggest that hormones of pregnancy such as progesterone or prolactin, could have a beneficial effect and suggest that this type of hormonal treatment should be attempted. In their opinion, further prospective studies are needed to determine the consequences of pregnancy on DTs and the risk for a pregnant female of developing a DT, in order to advise women with a family history of DT against pregnancy [35].

Surgery

A surgical trauma is generally indicated as a precipitating factor for DT development (Table 3). In particular, in 68-83% of FAP patients, an abdominal operation precedes formation of DTs by a few months up to a few years. The mean time to DT development varies, but it is usually around 2 years [4,11,15, 30]. It appears that there is no correlation between the entity of the surgery and the occurrence of DTs. Desmoid tumours affect patients operated by subtotal colectomy and ileo-rectal anastomosis or by restorative proctocolectomy and IPAA in a similar percentage [13,19, 31, 32], but even a minor abdominal surgical procedure such as appendectomy can induce DTs. Iterative surgery can increase the risk as Penna et al. [13] have shown, considering that 41% of DTs are discovered after at least two surgical interventions.

Early age at time of colectomy represents a risk factor. In the experience of Jarvinen [11], patients with postoperative DTs had undergo colectomy at a mean age of 26.1 years, significantly earlier than those not developing DTs (37.8 years, p<0.01).

Family History and Genetic Predisposition

The hereditary nature of DTs has become clearer when DTs and mesenteric fibromatosis were recog

Table 3. Characteristics of desmoid lesions: personal experience in familial adenomatous polyposis

Type ofD

Sex (M-F)

Age at diagnosis, mean (range)

Size: cm (range)

Time from colectomy, mean (range) years

Type of surgery IRA/IPAA

Abdominal wall D

9-10

29.3(11-61)

8.5(3-12)

4.9 (1-30)"

7/ 11b

Mesenteric D

1-7

35(25-61)

10 (3-17)

15.5(1-17)

6/2

Mesenteric FB

6-6

45(24-58)

4.8(4-9)

15(4-34)

11/1

DPL

4-3

35.8(14-57)

3.6(1-5)

3.4 (1-8)

2/2c

Retroperitoneal fibrosis

3-3

28.8 (11-36)

NAd

12 (1-17)

1/5

Extra-abdominal D

1

22

4

1

0/1

D, Desmoid; FB, Fibromatosis; DPL, Desmoid precursor lesion; IRA, Ileo-Rectal-Anastomosis; IPAA, Ileo pouch-anal anastomosis "Diagnosis before colectomy: one case; at colectomy: one case; bOne proctocolectomy and definitive ileostomy; cDiagnosis at colectomy in three patients; dNot applicable

D, Desmoid; FB, Fibromatosis; DPL, Desmoid precursor lesion; IRA, Ileo-Rectal-Anastomosis; IPAA, Ileo pouch-anal anastomosis "Diagnosis before colectomy: one case; at colectomy: one case; bOne proctocolectomy and definitive ileostomy; cDiagnosis at colectomy in three patients; dNot applicable nized as stigmata of FAP and a more accurate diagnosis of these complications was achieved. Desmoid tumours have been reported to be frequently associated with Gardner's syndrome [5]: a 32% incidence of desmoid reaction is found among affected members of the original Gardner's syndrome kindred 109. First-degree relatives of FAP patients with DTs have a greater risk of developing DTs than more distant relatives (25% for first degree vs. 11% for second degree and 8% for third degree) [2]. Bertario et al. [25] estimated the risk of developing DTs in 897 FAP patients scheduled on the Italian hereditary colorec-tal tumour registry and found that family history of DTs, osteomas and epidermoid cysts was significantly associated with the presence of the disease. Similarly, Sturt et al. [32] found that family history (especially if more than 50% of the members were affected with DTs) increased the odds ratio over sevenfold.

The APC gene responsible for the development of FAP has been investigated for specific mutations which may be related to DT development. Desmoid tumours will develop when both alleles of the APC gene are faulty, but one of the mutations encompasses the region 3' of codon 1444 [32, 36, 37]. Genotype-phenotype correlation within the location of APC mutation, the occurrence of DTs and the number of colonic polyps has been observed: APC mutations between codons 1444 to 1578 is associated with DTs and a severe form of polyposis, while mutations at the 3' region of APC are linked with DTs and an attenuated form of FAP [38, 39]. An aggressive growth pattern of DTs has been attributed to the presence of a germline APC mutation in codon 14451578 [38]. Mutations beyond codon 1309 or 1444

confer, respectively, a 17- and a 12-fold higher risk of DT development, compared with mutations located at or before codon 452 [12]. Therefore, families with a high incidence of DTs usually have the inherited germline mutation at 3' of codon 1444 and may have the environmentally induced somatic mutation in any point of the APC gene, whereas families with sporadic occurrence of DT have the germline mutation at 5' of codon 1444 and must have the somatic mutation at 3' of codon 1444. This fact explains the difference in the percentage of DTs among APC kindreds.

An uncommon mutation of the APC gene due to frameshift of codon 1924 is accompanied by a high incidence of DTs, a few or no colonic polyps and the rare occurrence of colorectal cancer. This syndrome is called hereditary desmoid disease [40].

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