Genetic Implication in Surgical Indication

Before the early 1980s, FAP and UC (Ulcerative Colitis) were treated with total colectomy and ileo-rectal anastomosis (IRA) or total proctocolectomy and permanent ileostomy (TP). As this radical option involved the sacrifice of the anal sphincter, both the surgeon and patient tended towards a less invaliding option even when the indication was not correct. As demonstrated by Church et al. [11], the risk of developing rectal cancer was higher before the early eighties before the introduction of restorative procto-colectomy with ileal pouch-anal anastomosis (IPAA) because the technical choice was not based only on clinical criteria, but was also conditioned by the desire to avoid a permanent ileostomy. However, the same author [12] outlined that, if the indication is correct, IRA is a good solution. In cases where there are few polyps in the colon and rectum, the risk of a subsequent proctectomy (because of the development of rectal cancer or of a high number of adenomas no longer endoscopically treatable) was very low.

IPAA made radical treatment possible, preserving the anal sphincter and reducing the risk of an inappropriate choice; therefore, this technique has become increasingly widespread. The rate of compli cations and the functional results are not particularly different to IRA, as described by various authors [13] and as emerging from our experience. Consequently, IPAA has become the primary choice for FAP treatment in centres specialising in major col-orectal surgery. This attitude, justified also by the possibility of eradicating the colorectal disease and avoiding the risk of rectal cancer, should be re-evaluated as even ileo-anal pouches can present a progressive risk of developing adenomas which require endoscopic surveillance, just like the surveillance required for the rectum after IRA [14].

A total proctocolectomy, sacrificing the sphincter, is mandatory when a cancer is located near the dentate line, but the decision is more complex when the rectum can be spared. Clinical criteria appear to be non-univocal as regards the number (classically above or under 20) and characteristics of the polyps, the length of the rectum to spare (20 cm vs. 15 cm vs. 10 cm) [15] and the characteristics of the ileo-rectal anastomosis (hand-sewn or mechanical, side-to-end or end-to-end) that in the end can condition endo-scopic removal of the polyps, functional results and any subsequent restorative proctectomy with IPAA (conversion of IRA to IPAA) respectively. In addition to the factors mentioned, the patient's desire to avoid an ileostomy (even if temporary) or the acknowledgement of sexual risks in men, or even the result of surgical treatment on relatives, appears to condition the choice of an IRA. If we also consider the possibility of performing the operation in a single laparo-scopic time, avoiding temporary ileostomy with minimal aesthetic and abdominal wall damage in patients normally presenting few symptoms, IRA becomes a particularly appealing option. Thus, it has become important to encourage its renouncement in favour of a technique which is more complex and requires two surgical interventions with precise clinical indications and, if possible, supported by evidence of genetic error corresponding to a severe form of FAP destined to become a higher risk of cancer on the residual rectal stump.

Restorative proctocolectomy with IPAA, described by Parks and Nicholls in 1978 [16,2], has a theoretical increased risk of complications compared to IRA, but this occurs only in a small percentage of cases, as opposed to IBD patients. This is probably due to the fact that hand-sewn ileo-anal anastomosis is performed on a healthy mucosa where there is no sign of inflammation.

The major risk in performing IPAA is the potential impossibility of mobilising the terminal ileum to reach the anal canal (usually due to the presence of intra-abdominal desmoids located in the mesentery, which shorten and retract the mesentery itself) in patients for whom the removal of the rectum is inevitable. In this case the only possible surgical solution is TP.

The criteria on which we base the indication of more radical surgery or less radical surgery have not changed in substance; we are always speaking of a maximum of 20 polyps in the residual rectum considering an average length of 15 cm, which is the maximum number acceptable for an IRA with subsequent endoscopic removal of polyps.

After the introduction of the IPAA, the cases of later reoperation to convert IRA also dropped; however, IPAA remains a possibility for those who undergo the less radical surgical treatment, since a tract of affected rectum remains in site and could escape endoscopic control and removal by developing an excessive number of polyps or presenting severe dysplasia or infiltrating carcinoma.

At present however, with refining genetic analysis techniques, the possibility of identifying the mutation carried by the patient (whether it is related to a severe phenotype or not) has taken on a fundamental role in the indication of the type of surgical treatment in terms of radicality.

In the presence of severe clinical features, the indication of radical surgery is clear regarding the entire removal of the affected part. Instead, in the presence of clinical features which are not particularly severe, before choosing a total colectomy with ileo-rectal anastomosis, it is necessary to consider the type of genetic mutation. In fact, it is now well known that mutations have been identified which involve a more indolent trait of the pathology and others which involve a marked severity of the disease irrespective of the clinical features at the moment of diagnosis. We must not forget those cases in this second group of patients for whom the choice of performing less radical surgery in the first place led to the necessity of reoperating at a later date because of the development of clinically more severe lesions in the tract of the residual rectum. In these cases, the surgeon had to convert IRA into a restorative proctectomy with IPAA, or into a TP with permanent ileostomy; the latter option being determined by technical reasons (short ileum vessels to reach the anal canal) or due to the disease (development of carcinoma in patients who did not go through follow-up).

Thus, the results of the genetic test can contribute to indicating the correct surgical treatment suited to the degree and severity of the disease, mainly to avoid patients undergoing a treatment which is under-estimated in terms of the real potential aggressiveness of the pathology. Endoscopic evaluation of clinical features remains without doubt an unavoidable datum, which, however, is subject to factors such as the subjectivity of the operator's judgment, which limit its adequacy and precision.

With the identification of mutations on the APC gene responsible for the disease , the introduction of genetic analysis methods [10] for the affected patients and, above all, the screening of their relatives, it is possible to determine the individuals at risk of developing the disease and the gravity with which it would present itself if it weren't treated. As concerns our case histories, we are not short of examples: we have treated two cousins with IPAA for a severe disease and the sister of one of them had also been operated on (in another surgical unit) for what the surgeon had defined as an IPAA, but which had preserved some centimetres of rectum. This woman came under our observation after annual endoscopic surveillance of the short residual rectum; the impossibility of continuing with endoscopic management led to surgery but at the time of the operation a carcinoma was already present, invading the transitional zone and making a Miles' operation necessary (Fig. 1).

Thus, it could be a matter of discussion whether to treat a patient with IRA who carries a mutation related to a potentially severe genotype that has a high tendency for developing rectal cancer, even if at the moment of surgery the rectum presented a not-so-high number of polyps still controllable via endo-scopic removals. One could force the patient to undergo endoscopic management at ever-closer time intervals, with an increased risk of complications, thereby exposing him to the risk of being forced to undergo more radical surgery later.

Considering the fact that the two surgical solutions are very similar in terms of the quality of life as well as functional results [2] (except that restorative

Fig. 1. Transitional zone invaded by carcinoma proctocolectomy is technically more complex to perform), the choice of the correct operation for FAP treatment seems less bound to the subjective judgment of surgeon; on the contrary it becomes more precise when supported by a prediction on genetic grounds. In order to compare claims made in literature against our case history findings, we highlighted a particular item of data concerning the ratio between the severity of the mutation, the type of operation performed and the need for a further operation (Figs. 2,3).

When a slight mutation was present, IPAA was performed in seven cases and IRA in seven cases. None of the IRA operations performed so far, for a slight mutation, have required conversion to IPAA. Only endoscopic removal of rectal polyps has been necessary, but one patient who escaped follow-up died because of a hepatic metastasis probably due to rectal cancer. In patients with severe mutation, in one case we directly performed a Miles operation, sigmoid resection in one for palliative purposes, IPAA in ten cases and IRA in seven cases. Of the seven cases of IRA, five asked for conversion. In three of the five cases, a Miles operation was performed as cancer was detected in polyps that were so close to the anal canal that conversion to IPAA was not possible, while in two cases conversion was successfully performed to treat widespread polyps which could not be managed by endoscopic removal. However, the histological tests of one of these two patients indicated a stage B1 carcinoma that had not been detected in the preoperative stage. In three of these five cases, IRA had been performed at another hospital and decisions were not dictated by the clinical criteria in use at the time, but by the experience of the surgeon and the patient's wish to avoid a permanent ileostomy. In the two patients we previously operated on by performing IRA, one underwent a Miles operation as a carcinoma was detected on a polyp close to the dentate line which had not been noted during surveillance and endo-scopic removal. IRA had been chosen for this patient due to the presence of a mesenteric desmoid, while in the other patient, genetic testing was not carried out in the preoperative stage, so the decision was dictated by a number of polyps bordering the rectum (around 20) and by the concurrent presence of jaundice, caused by duodenal adenomatous polyp. In this last case, despite the degenerated rectal polyp, conversion to IPAA was possible. To sum up, only two of the seven patients with severe mutation undergoing an IRA are still being treated for the routine removal of rectal polyps and at present have not requested conversion.

From an assessment of the literature and on the basis of our experience, it is clear that today the deci-

Fig. 1. Transitional zone invaded by carcinoma

Fig. 2. IRA-genetic factors-IPAA. Retrospective aspects in our series of FAP patients. Known mutation = 33; unknown = 7; total patients treated = 40

Total proctocolectomy S of which 3 conversion due to cancer

Ileo-pouch-anal anastomosis 22 (4 conversion from IRA)

Ileorectal anastomosis (IRA) l9 (3 conversion to Miles)

Segmentary resection: l

Desmoid tumors: l

Colorectal cancer: l2 (l0 patients)

Duodenotomy to remove an ampullary adenoma: 2

Palliative derivation for advanced ampullary cancer: l

Total gastrectomy for gastric cancer

SS% FAP patient with duodenal and gastric polyps

Dead (l hepatic metastasis, l ampullary c., l C.C., l desmoid t)

Mean follow-up time 9.8 years - lost to follow-up: l

Fig. 3. Case histories of 40 patients: surgical options and mutations. Severe mutations l9; mild mutations = l4; unknown mutations = l sion to leave the rectum must be prompted by the presence of sporadic rectal polyps and a slight genetic mutation, the absence of severe dysplasia or colon of the cancer and more rarely by the presence of intra-abdominal or mesenteric desmoids which advise against IPAA. As stated by several authors, it is difficult to perform endoscopic surveillance when there are many adjoining polyps; this increases the risk of progression to malignant transformation, even in patients who undergo regular follow-ups [17].

Thus, the risk of cancer of the rectum can easily be correlated to the above factors, as noted by Bertario's study [18] on patients in the Italian FAP registry, and particularly when cancer of the colon is present when IRA is performed in conjunction with a genetic error between codon 1250 and codon 1464.

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