Repeated colonoscopic screening of patients with acromegaly: 15-year experience identifies those at risk of new colonic neoplasia and allows for effective screening guidelines

Introduction

Acromegaly is associated with increased morbidity and mortality. Several previous studies have suggested that these patients are also at an increased risk of neoplasia, especially colorectal cancer and pre-malignant adenomatous polyps, although the degree of risk remains under debate (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). In our original series, we observed 5% to have a carcinoma and 25% to have one or more adenomas (11). Similar findings have been reported by other groups (12). In the non-acromegalic population, the vast majority of colorectal cancers derive from adenomatous polyps through the progressive accumulation of mutations in oncogenes and tumour suppressor genes, a process that takes ∼10–20 years (13, 14). More recently, hyperplastic polyps, which were previously considered to have no malignant potential, have also been shown to either undergo malignant transformation or be associated with an increased risk of future neoplasia (15, 16). Taken together, this implies that with adequate surveillance colon cancer may, at least in part, be a preventable disease, since several studies have demonstrated that the colonoscopic screening and removal of colonic polyps reduce the incidence of colorectal cancer (17). Many endocrinologists and gastroenterologists therefore recommend this procedure to patients with acromegaly, a view endorsed by a recent consensus document (18). However, the frequency with which colonoscopic screening should be offered remains unclear. We have previously suggested 3–5 yearly intervals, starting over the age of 40 years, based on serum insulin-like growth factor 1 (IGF1) levels and the presence of previous neoplasia (19). However, the length of follow-up of these patients was relatively short. As we now have a much longer duration of experience of our colonoscopic screening programme, the aims of the current study were i) to review the optimum frequency for repeated colonoscopic surveillance of acromegalic patients, ii) to determine the influence of serum IGF1 levels and iii) to establish the role of previous neoplasia on the development of new neoplasia.

Patients and methods

Results

At the first colonoscopy, 10 patients were found to have a cancer, and an additional 89 (35%) patients were found to have a polyp – 39 patients (15%) with a hyperplastic and 50 patients (20%) with an adenoma. At the second, third and fourth colonoscopies, the number (%) of patients with hyperplastic or adenomatous polyps respectively was as follows: second colonoscopy – 31 (20%) and 24 (15%) of patients respectively; third colonoscopy – 14 (23%) and 8 (14%) patients; fourth colonoscopy – 3 (20%) and 4 (27%) patients (Table 2). One cancer was detected at the second surveillance, but no other cancers were found. There was no association between colonoscopic findings and patient age or gender at any of the screening procedures.

Discussion

Most authorities now accept that patients with acromegaly have an increased risk of colorectal neoplasia, even if the exact degree of risk remains uncertain (18, 21, 22, 23, 24, 25, 26, 27). In the non-acromegalic population, the majority of colonic cancers develop from pre-malignant colonic adenomas, and several studies have demonstrated that colonoscopic screening and removal of adenomas reduce the incidence of colorectal cancer. There is also some evidence that hyperplastic polyps may be pre-malignant or be associated with an increased risk of future malignancy (15, 16, 28, 29). With this in mind, colonoscopic screening has been increasingly offered to patients with acromegaly. However, the frequency with which this should be performed remains unclear. A recent consensus document recommended that the frequency of follow-up surveillance should be the same as the general population (18). Based on our findings from a previous study, we suggested that the frequency should be 3–5 yearly: 3 yearly for patients who had an adenoma or who had elevated serum IGF1 levels and 5 yearly in other patients (19). The present study details our cumulative experience of a large cohort in a single centre over a 15-year period. Our results extend our earlier findings and allow for revision and optimisation of the guidelines.

The frequency of new polyps at the second and third colonoscopies was very similar. After a mean interval of ∼4 years between each colonoscopy, the overall incidence of new polyps at the second and third surveillance was 36 and 37% respectively, compared with 38% at the initial screening. The higher incidence of 47% at the fourth colonoscopy may reflect a higher risk group, as well as the smaller number of patients. The fact that at each colonoscopy more than one-third of patients had a polyp supports the need for a regular surveillance programme.

The success of our surveillance programme may be judged from the fact that no cancers were discovered during the third or fourth colonoscopies. The single cancer at the second colonoscopy was discovered in a patient who underwent the initial screening colonoscopy at a different institution; at that time, the hepatic flexure was reported to be normal, but the second examination 18 months later revealed a carcinoma in the transverse colon and four adenomas. Although these lesions have been classified here as being new, it is more probable that they were missed at the original screening. This emphasises the need for visualisation to the caecum by an experienced operator. The advantage of the present study is that it reflects the experience of a single large cohort of patients from a single institution, and all the colonoscopies, except two, were performed by the same skilled operator, who visualised the entire colon in 99% of procedures. For less experienced operators, the success rate is only 70% (11).

This study has further clarified the influence of GH and IGF1 in the development of colonic polyps. At the first colonoscopy, patients with hyperplastic polyps had significantly higher GH and IGF1 levels than those with normal colons. This was also the case at the third colonoscopy when patients with both hyperplastic polyps and adenomas had higher IGF1 ratios. The absence of any significant association at the second colonoscopy is initially puzzling as our previous analysis of 66 patients undergoing a second colonoscopy revealed the eight patients with a new adenoma to have significantly higher IGF1 levels (19). However, the current size of the cohort undergoing a second colonoscopy is almost threefold larger, and although IGF1 levels were higher in those with a new adenoma, statistical significance was not achieved. One reason for the apparent discrepancy might be the introduction of new medical treatments, such as somatostatin analogues and more recently GH antagonists, which has enabled more effective control of disease activity reflected in the progressive lowering of mean IGF1 levels amongst the entire cohort at each successive colonoscopy. Certainly, at the second surveillance, the majority of patients had IGF1 levels within the normal range. Thus, the number of patients with poorly controlled acromegaly is very low. However, supporting a role for IGF1 in the development of new adenomas is that at the second screening, patients with elevated IGF1 levels had a 2.8-fold increased prevalence of neoplasia compared to patients with controlled disease, although 10% of the latter still had an adenoma. An even more striking effect was noted in those patients with a normal initial colonoscopy in whom an elevated IGF1 level was associated with a 7.5-fold increased risk of a subsequent adenoma.

Our findings on the influence of IGF1 are largely in agreement with previous studies by other groups in smaller series over shorter follow-up periods (12). Bogazzi et al. recently reported on yearly colonoscopic screening over a 5-year period and observed IGF1 levels to be higher in individuals who developed multiple new adenomas (30). This influence of IGF1 in the development of colonic neoplasia is in keeping with its known proliferative and anti-apoptotic effects, and increased proliferation of the colonic epithelium in proportion to IGF1 levels has been recorded in acromegalic individuals (31). Furthermore, in the non-acromegalic population, individuals with higher IGF1 levels have an increased risk of developing colonic cancer (32, 33). In addition to the endocrine actions of IGF1, a paracrine or autocrine role within the colonic epithelium cannot be excluded, perhaps in response to circulating GH. Certainly, the latter has been reported to exert direct anti-apoptotic effects in human colon cancer cells (34). It is possible that other factors might also be responsible for adenoma recurrence, such as hyperinsulinaemia, diabetes mellitus or altered bowel transit times. A further possibility might relate to the use of somatostatin analogue therapy. While this was not directly investigated in this study, we found no association between somatostatin analogue use and prevalence of colorectal neoplasia in our original study (11).

This study had several limitations. First, was the absence of a control group for the study, although this is the case in the majority of retrospective studies of the prevalence of colorectal neoplasia in acromegaly. In addition, not all patients attended the second and third colonoscopies. Reasons for this included the patient's unwillingness to undertake the procedure, being lost to follow-up, moving away from the hospital catchment area, or other morbidity. However, this does not detract from the main findings of the present study, namely those factors which are associated with polyp recurrence.

Our findings demonstrated a high incidence of hyperplastic polyps, with ∼20% of patients at each colonoscopy having a new hyperplastic polyp. These also appear to be related to high IGF1 levels, perhaps as a result of its pro-proliferative actions. In the non-acromegalic population, the influence of hyperplastic polyps in the malignant process is controversial; while they have traditionally been regarded as benign, several recent studies suggest that they may also have a potential to become malignant or act as markers for the subsequent development of colorectal cancer (15, 16, 28, 29). Therefore, with regard to developing screening guidelines for patients with acromegaly, it may be prudent to take into account the influence of all polyps rather than adenomas alone.

Certainly, in addition to IGF1, the presence of a polyp (adenoma or hyperplastic) at the initial screening is the other major determining factor for the development of new polyps. Patients with an initial adenoma had a 4.4- to 8.8-fold increased risk of developing an adenoma at the second and third colonoscopies, and this association was even stronger for the presence of any polyp at the initial surveillance. Conversely, a negative initial screen was highly predictive of subsequent negative colonoscopies, even up to 15 years after the initial screen. This association between the presence of neoplasia influencing future risk also held for the second screen, and is in keeping with other recent studies and also in the non-acromegalic population in whom there was a 2- and 3.5-fold increased risk of adenoma or hyperplastic polyp recurrence in patients with adenomas or hyperplastic polyps respectively at the initial colonoscopy (24, 35). The association in the current study was even stronger when IGF1 levels were also taken into account, and in particular, the combination of a normal initial colonoscopy and normal IGF1 levels was associated with an 81% chance of a negative follow-up colonoscopy.

Taken together, it seems that identification of those at risk of future colonic neoplasia can largely be determined by the findings at the initial colonoscopic evaluation together with the activity of the underlying acromegaly. Whether this persistent predisposition for neoplasia is a reflection of a generalised hyperproliferative epithelium or a genetic predisposition for malignant transformation of adenomas remains uncertain. The majority of the adenomas recorded in the follow-up colonoscopies were small, with a maximum size of 10 mm. In the non-acromegalic population, the risk of malignant transformation is generally considered significant for polyps >10 mm diameter and is thought to take 10–20 years. Whether this is also true for the acromegalic bowel is uncertain. The precise local environmental conditions which predispose to the increased risk of malignancy in acromegaly remain uncertain, but it may be appropriate to assume an accelerated process given that the analysis of all colonoscopic screening studies in acromegalic patients indicates a 2.4-fold increased risk of adenomas but a sixfold risk of an actual cancer (22). It is possible that some of this discrepancy might be accounted for by a malignant transformation of the hyperplastic polyps. While recent guidelines for colorectal cancer screening in the non-acromegalic population suggest that 10-yearly colonoscopic screening beginning at the age of 50 years is adequate, this may not be safe for patients with acromegaly, and more regular colonoscopic screening may be required for some patients (33). Although the numbers of patients with new adenomas or hyperplastic polyps in the current study are too few for formal statistical risk calculation, based on our current long-term data, it would seem appropriate to modify our recommendations to 5-yearly surveillance in patients with either a polyp at the initial screen or an elevated serum IGF1 level, and to reduce surveillance to every 10 years for the remaining low-risk patients. Amongst the latter patients, the presence of a polyp at a subsequent surveillance should warrant their reclassification to a higher risk with subsequent 5-yearly surveillance. The age as to when screening should begin is uncertain. While a recent consensus document has suggested that a screening colonoscopy should be performed on all acromegalic patients at diagnosis irrespective of their age, we suggest that surveillance should begin at the age of 40 years, as in our original study, the earliest age of patients with an adenoma was 39 years and the cancers occurred in older patients (11). This would avoid performing the invasive procedure on younger patients in whom the chances of an adenoma/cancer being present are very low. Given the high prevalence of polyps at follow-up screening in patients with acromegaly, it may be appropriate to perform fibre optic colonoscopy rather than computerised tomography (CT) colonography.

Conclusions

Repeated colonoscopic screening of patients with acromegaly over a 15-year period has demonstrated a high prevalence of new adenomatous and hyperplastic colonic polyps. It suggests that patients with acromegaly at high risk of developing new colonic neoplasia are those with a polyp at the initial screen and/or who have uncontrolled disease with high IGF1 levels. As such, it would seem appropriate to modify our recommendations to 5-yearly surveillance in these patients, while for the remaining low-risk patients it is probably safe to reduce surveillance to every 10 years.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.