Elsevier

The Lancet

Volume 348, Issue 9025, 17 August 1996, Pages 433-435
The Lancet

Articles
Molecular genetic tests as a guide to surgical management of familial adenomatous polyposis

https://doi.org/10.1016/S0140-6736(96)01340-2Get rights and content

Summary

Background

In familial adenomatous polyposis the only curative treatment is colectomy, and the choice of operation lies between restorative proctocolectomy (RPC) and colectomy with ileorectal anastomosis (IRA). The RPC procedure carries a higher morbidity but, unlike IRA, removes the risk of subsequent rectal cancer. Since the course of familial adenomatous polyposis is influenced by the site of mutation in the polyposis gene, DNA analysis might be helpful in treatment decisions.

Methods

We evaluated the incidence of rectal cancer in polyposis patients who had undergone IRA, and examined whether the requirement for subsequent rectal excision because of cancer or uncontrollable polyps was related to the site of mutation.

Findings

Between 1956 and mid-1995, 225 patients registered at the Netherlands Polyposis Registry had undergone IRA. In 87 of them, a pathogenetic mutation was detected. 72 patients had a mutation located before codon 1250 and 15 patients after this codon. The cumulative risk of rectal cancer 20 years after surgery was 12%, and at that time 42% had undergone rectal excision. The risk of secondary surgery was higher in patients with mutations in the region after codon 1250 than in patients with mutations before this codon (relative risk 2·7, p<0·05).

Interpretation

On this evidence, IRA should be the primary treatment for polyposis in patients with mutations before codon 1250, and RPC in those with mutations after this codon.

Introduction

Familial adenomatous polyposis (FAP) or Bussey-Gardner polyposis1 is an autosomal dominant disease characterised by hundreds of adenomas in the colon and by various extracolonic features.2 The disease is due to a mutation in the adenomatous polyposis coli (APC) gene which is located on chromosome 5.3, 4 The APC gene consists of 15 coding exons and probably influences interactions between cells. Most patients develop adenomatous polyps in their colon in the second and third decade of life2 and if untreated they get colorectal cancer in their thirties. We now know that individuals with identical mutations can show differences in phenotypic expression of the disease;5, 6 nevertheless, several investigators report correlations between mutations occurring within specific regions of APC and the phenotypic expression. Mutations within exons 3 and 4 are associated with a less severe form of FAP characterised by a low number of colorectal adenomas and a late age of onset of colorectal cancer.7 Nagase8 reports that patients with mutations located in a region between codons 1250 and 1464 at exon 15 tend to have more than 5000 adenomatous polyps and to develop colorectal cancer at an average age of 34. Whereas those with mutations outside this region have fewer than 2000 polyps and develop colorectal cancer at 41·8 years. A severe form of FAP has been associated with a deletion in codon 13099 and with mutations after codon 1250.10, 11

Might information on the location of the mutation be useful in determining the most appropriate surgical treatment? There has been a long debate about the extent of colonic surgery. If the rectum is carpeted with polyps or if the patient is unlikely to attend regularly for follow-up, there is a good case for restorative proctocolectomy (RPC). If the rectum is relatively free of adenomas, colectomy with ileorectal anastomosis (IRA) is the most attractive surgical procedure because of its satisfactory functional results. A drawback of IRA, however, is the substantial risk of cancer in the residual rectum;12, 13 moreover, a high proportion of the patients need rectal excision because of uncontrollable polyps. In the present study, we evaluated the cumulative risk of rectal cancer in a large series of patients in the Netherlands. We also assessed the rate of rectal excision after IRA and whether the probability of secondary surgery is associated with the location of the mutation.

Section snippets

Methods

In 1985 a registry of families with familial adenomatous polyposis was set up in the Netherlands,14 and by July 1, 1995, genealogical studies had been performed in 200 families with FAP referred from all parts of the country. Medical and pathological data were collected to verify the family history. Data collection was complete in 150 of the 200 families and these families were selected for the present study.

Between 1956 and mid-1995, 230 patients had IRA performed as a primary procedure for

Results

Of the 230 patients who had an IRA, 5 had follow-up of less than one year after surgery and were excluded. The remaining 225 had a mean follow-up of 11 yr (range 1–38). Mean age at surgery was 28·3 yr (range 11–70). 16 of these patients developed a rectal cancer (mean age 45 yr; range 29–61). Of these 16 patients, information on screening was available in 12: 11 had undergone surveillance within the previous 12 months. The interval since the last endoscopic examination ranged from 3 to 14

Mutation analysis

DNA analysis was conducted in 105 of the 150 polyposis families and the pathogenic mutation was detected in 56 families. 32 of these families had at least one member who underwent an IRA. 21 families including 72 patients with an IRA (group A) had a mutation before codon 1250 and the remaining 11 families including 15 individuals with an IRA (group B) had a mutation after this codon. 14 of the patients from group A and eight of the patients from group B required rectal excision because of

Discussion

Although non-steroidal anti-inflammatory drugs may have some beneficial effect on colonic adenomas,17 prophylactic surgery of the colon is still the only curative treatment for polyposis. Restorative proctocolectomy might seem the ideal operation. By removal of all or nearly all the large-bowel mucosa the risk of cancer can be almost completely avoided. There are disadvantages, however, and the most important are the greater morbidity and duration of convalescence than with IRA and the possible

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