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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 4 1351-1356
Copyright © 2006 by The Endocrine Society

Identification of Acromegalic Patients at Risk of Developing Colonic Adenomas

Fausto Bogazzi, Chiara Cosci, Chiara Sardella, Aurelio Costa, Luca Manetti, Maurizio Gasperi, Giuseppe Rossi, Luigi Bartalena and Enio Martino

Departments of Endocrinology and Metabolism (F.B., C.C., C.S., L.M., M.G., E.M.) and Oncology (A.C.), University of Pisa, 56124 Pisa, Italy; Unit of Epidemiology and Biostatistics (G.R.), Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; and Department of Clinical Medicine (L.B.), University of Insubria, 21100 Varese, Italy

Address all correspondence and requests for reprints to: Fausto Bogazzi, M.D., Dipartimento di Endocrinologia e Metabolismo, Università di Pisa, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy. E-mail: f.bogazzi{at}endoc.med.unipi.it; or fbogazzi{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Acromegaly seems to be associated with an increased prevalence of colonic adenomas, although factors affecting their development and recurrence of the latter are not fully known.

Subjects and Methods: Seventy-nine patients with active acromegaly were prospectively followed up for 5 yr. Two hundred eighty healthy subjects served as controls. Colonoscopy and assessment of acromegaly activity were performed at 1-yr intervals. Acromegaly was defined as controlled if serum IGF-I levels were within the normal age-adjusted range.

Results: Colonic adenomas were found in 26 of 79 acromegalic patients (32.9%) and 60 of 280 controls (21.4%) at baseline (P = 0.035, adjusted for age and sex, odds ratio 1.82, 95% confidence interval, 1.02–3.25). Seven patients had hyperplastic polyps; the remaining 46 acromegalic patients had no detectable lesions at baseline and did not develop adenomas during the study period. Of the 26 patients with colonic adenomas at baseline, 16 (61.5%) had at least one recurrence of colonic adenomas (P < 0.0001 vs. patients without colonic lesions at baseline), and multiple recurrences were more frequent in patients with uncontrolled acromegaly (66.7% vs. 17.6% in patients with controlled acromegaly, P = 0.028).

Conclusions: The first colonoscopy helps to identify acromegalic patients at high risk of developing colonic adenomas. If colonic adenomas are not present initially, it is unlikely that they develop thereafter, independently of metabolic control of acromegaly. Conversely, new lesions are frequent (and often multiple) in patients who already have colonic adenomas at baseline, particularly if acromegalic disease is poorly controlled by treatment.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ACROMEGALY SEEMS TO be associated with an increased risk of developing colonic tumors, although the prevalence of either colonic polyps or cancers widely varies in different series (1, 2, 3, 4, 5, 6, 7, 8, 9). Due to these conflicting results and absence of prospective studies specifically addressing this issue, acromegaly has been considered as either a low-risk or a high-risk condition for the development of colonic neoplasms (10, 11, 12). IGF-I may be involved in this process, and the rise in serum IGF-I concentrations observed in acromegaly was related to the increased prevalence of colonic polyps (3, 4) or adenomas (5) and proliferation of colonic epithelial cells (3). Genetic susceptibility might also play a role in this process. Mutations in the adenomatous polyposis gene (APC) and the mismatch repair genes are responsible for genetic colorectal cancers (13), and the loss of the APC predisposes to an increased risk of colonic tumors. APC is part of a protein complex regulating degradation of ß-catenin (14), which plays a central role in the interaction between oncogenic targets in the progression to intestinal malignancy (15). Whether these molecular mechanisms are involved in colonic tumorigenesis in acromegaly is unknown. Likewise, it is unclear whether acromegaly activity (i.e. high serum GH and/or IGF-I levels) is relevant to development or progression of colonic tumors. Development of new colonic adenomas has been associated with the increase in serum IGF-I concentrations and the presence of adenomas at previous colonoscopy (16). Recently a large multicenter retrospective study suggested that high serum IGF-I levels might be an independent risk factor for subsequent occurrence of colonic polyps (17).

In view of the uncertainty on the real prevalence and incidence of colonic tumors and the lack of reliable genetic markers, some (5, 10) but not all authors (11, 12) have proposed that colonoscopy should frequently be repeated in acromegaly.

This prospective study was undertaken with the aim to identify acromegalic patients at risk of developing colonic adenomas and assess the role of disease activity in this process.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study group initially included 82 consecutive patients with active acromegaly referred to our institution during the period January 1994 to July 2000 (34 men; 48 women; mean age 56 ± 11.6 yr). Three patients were affected with a colonic adenocarcinoma (T1N0M0) underwent colectomy and were excluded from the study: there were two women and a man (age range 72–77 yr); all had a GH-secreting pituitary macroadenoma and the mean estimated duration of disease of 5–16 yr. One patient was submitted to partial excision of the pituitary tumor, one refused pituitary neurosurgery, and the third patient had contraindications to surgery (severe cardiomyopathy); all patients received somatostatin analog (SMSa) treatment, which controlled disease activity fully in one patient and partially in the remaining two.

The remaining 79 patients were 33 men and 46 women, mean age 55 ± 11.1 yr. Three patients had positive family history for colorectal neoplasm. Diagnosis of acromegaly was based on clinical and laboratory features, including: 1) increased serum GH (>2.5 µg/liter, mean of five samples); 2) serum IGF-I levels above the normal range for the age; and 3) lack of suppression of serum GH levels less than 1 µg/liter after a 75-g oral glucose tolerance test (18) (Table 1Go). As assessed by magnetic resonance imaging, acromegaly was due to a pituitary GH-secreting microadenoma (26 cases, 32.9%) or macroadenoma (53 cases, 67.1%). Treatment of acromegaly was based on clinical grounds and was independent of colonoscopic findings. Acromegaly was defined in remission after pituitary surgery when serum IGF-I levels were within the normal age-adjusted range and serum GH was suppressed less than 1 µg/liter after the oral glucose tolerance test (19). Acromegalic disease under SMSa treatment was defined as controlled when serum IGF-I levels were within the normal age-adjusted range and serum GH concentrations were less than 1 µg/liter. Metabolic control of disease was assessed yearly, consisting of the outcome of serum IGF-I measurements every 4 months. In addition, metabolic control of disease was evaluated at the end of the follow-up for those patients who did not develop new adenomas or when, in the other patients, this occurred. SMSa dose was adjusted every 4 months, as required. Estimated duration of acromegaly (years) was the time interval between the onset of symptoms and diagnosis of acromegaly. All patients completed the 5-yr follow-up period. Colonoscopy was performed yearly for 5 yr in all acromegalic patients to evaluate the recurrence rate of colonic adenomas.


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  		TABLE 1. Clinical and biochemical features of patients with acromegaly and subjects of the control group

 
The control group consisted of 280 nonacromegalic subjects (166 men, 114 women, mean age 50.9 ± 10.8 yr). They were consecutive donors for kidney or liver transplantation referred to the Department of Oncology; none of them had symptoms of abnormal intestinal function, and colonoscopy was performed as a part of the transplantation work-up. Serum GH and IGF-I levels were normal in all control subjects (Table 1Go). Thirteen subjects of the control group had a positive family history for colonic tumors.

All patients and controls gave their informed consent to this study, which was approved by the institutional ethical committee.

Pancolonoscopy

Colonoscopy was performed using a CFQ14SL apparatus (Olympus, Milan, Italy) by the same operator (A.C.). Standardized and very accurate preparation with polyethylene glycol-based electrolyte solution was given to all patients. Ileocaecal valve was reached in all patients. Polyps were recovered during colonoscopy and were formalin fixed, paraffin embedded, and analyzed by conventional microscopy. No complications occurred during colonoscopy.

Assays

Serum GH and IGF-I (Nichols Institute Diagnostics, San Juan Capistrano, CA) were determined by commercial kits. Intra- and interassay coefficient of variation has previously been reported (20). Normal values in our laboratory are as follows: GH, 0–5 µg/liter; IGF-I, 182–780 µg/liter, 16–24 yr; 90–492 µg/liter, 25–50 yr; 71–290 µg/liter, older than 50 yr.

The outcome of IGF-I in each patient was represented by the IGF-I index:

Formula
The use of the IGF-I index accounted for variations in the IGF-I levels in the different classes of age.

Statistics

Qualitative data were reported as percentage, and quantitative data were expressed as mean ± SD. Comparison of parameters of patients with acromegaly and control group, patients with single, multiple, or no recurrence, and patients with or without adenoma at baseline was carried out by one-way ANOVA or the Kruskal-Wallis test for quantitative variables and the {chi}2 test or the two-tailed Fisher’s exact test for qualitative variables. Multiple logistic regression was used to compare the occurrence of colonic adenomas between patients with acromegaly and the subjects of the control group. For each test P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical and biochemical features of the study groups at baseline are shown in Table 1Go. Acromegalic patients were slightly older (mean age 55.0 ± 11.1 yr) than controls (mean age 50.9 ± 10.8 yr), and there was a female prevalence (58.2 vs. 40.7%) in the former group. However, acromegalic patients and controls did not significantly differ when distributed in classes of age (Table 1Go).

Colonic adenomas were found in 26 of 79 patients with acromegaly (32.9%) and 60 of 280 controls (21.4%) (P = 0.035. Seven patients (8.9%) had single or multiple hyperplastic polyps and 46 patients (58.2%) had no colonic lesions. Because hyperplastic polyps are not considered a premalignant lesion, they were not further analyzed. Of 26 acromegalic patients with colonic adenomas, 13 had a single adenoma, and 13 had multiple adenomas (Table 1Go). According to the more advanced lesion, 90% adenoma had mild dysplasia and 10% had moderate/severe dysplasia. Most adenomas (86%) were less than 1 cm. As shown in Table 2Go, prevalence of colonic adenomas was higher in acromegalic patients than controls, also after adjusting for age and sex (odds ratio 1.82, 95% confidence intervals 1.02–3.25, P = 0.044).


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  		TABLE 2. Multiple logistic regression: risk of occurrence of colonic adenomas in acromegaly

 
During the 5-yr follow-up period, none of the 46 acromegalic patients without initial colonic lesions developed new adenomas (Table 3Go). Only one the 46 patients with initial negative colonoscopy developed a 2-mm hyperplastic polyp at the second colonoscopy.


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  		TABLE 3. Development of new adenomas in the 72 acromegalic patients

 
Of the 26 acromegalic patients with colonic adenomas at first colonoscopy, 16 (61.5%) developed new adenomas, which were found either in the same colonic portion as the original adenomas or at different locations (Table 4Go).


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  		TABLE 4. Localization of colonic adenomas at the first colonoscopy and at recurrences

 
Among the 16 patients who developed new adenomas, seven patients had a single recurrence, demonstrated during the first (six cases) or the second (one patient) colonoscopy control. No recurrence occurred thereafter. The remaining nine patients had multiple recurrences during the follow-up period: three patients had recurrences at the each colonoscopy; two during four controls; three at the first, third, and fifth colonoscopy; one at the first, third, and fourth colonoscopy; and one patient at the first and third colonoscopy.

Acromegalic patients with (n = 26) or without (n = 46) adenomas at baseline did not significantly differ as to gender, age, estimated duration of disease, baseline serum GH or IGF-I levels, prevalence of pituitary micro- or macroadenomas, and control of disease during the follow-up (Table 5Go). Acromegaly was controlled in 35% of patients with or without adenomas at baseline. In addition, patients with or without initial adenomas did not differ for the prevalence of the common risk factors for colonic tumors [(diet, hereditary syndromes, inflammatory bowel disease, Streptococcus bovis bacteremia, ureterosigmoidoscopy or tobacco use); data not shown].


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  		TABLE 5. Clinical and biochemical features of patients with or without adenoma at baseline

 
Among the 26 patients with initial colonic adenomas, those who developed new adenomas did not significantly differ from those who had no recurrence as to gender, age, initial serum GH or IGF-I levels, estimated duration of disease, or prevalence of pituitary micro- or macroadenomas. In addition, the presence of single or multiple adenomas at baseline did not affect the recurrence rate of adenomas.

A single recurrence of colonic adenoma occurred in 14.9% of the whole group of patients whose acromegalic disease was in good metabolic control (cured after pituitary surgery or under SMSa treatment) and in no patient whose acromegalic disease was uncontrolled (high serum IGF-I levels). Conversely, multiple recurrences occurred in 24% of patients with uncontrolled acromegaly and 6.4% of those with controlled acromegaly (Table 3Go, P = 0.020).

When patients were stratified on the basis of presence or absence of colonic adenomas at baseline (Table 6Go), acromegalic disease under control had no effect on the development of adenomas in patients without colonic lesions at baseline. At variance, 67% of acromegalic patients who had colonic adenomas at baseline and whose disease was not controlled had multiple recurrences (P = 0.016).


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  		TABLE 6. Relationship between control of acromegaly and formation of new adenomas

 
All patients whose disease was controlled showed normalization of serum IGF-I levels at the time of the first control (i.e. during the first year of follow-up) with no subsequent variations. The remaining nine patients with uncontrolled disease had constantly elevated serum IGF-I concentrations until the end of follow-up, despite the use of increasing doses of SMSa (Fig. 1Go).


Figure 1
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  		FIG. 1. Control of acromegaly in patients with colonic adenomas at baseline. Control or absent control of acromegaly was based on serum IGF-I concentrations and determined each year during all the follow-up period. The IGF-I index was obtained by the following formula:


Formula

Number refers to individual patients. The shaded area indicates the IGF-I values below the upper limit of the normal range. Patients with several recurrences (A) had more frequently poor controlled disease than those with a single recurrence (B) (P = 0.028).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Patients with acromegaly have been reported to be at either high or low risk of developing colonic tumors, the prevalence of which ranges 9–38% in different series (3, 4, 9, 12, 17). Studies have related the increased mortality rate of acromegalic patients to either the increased serum GH and IGF-I levels (10) or GH but not IGF-I concentrations (21). Vascular accidents are the leading cause of death in acromegaly, but mortality rate due to colon cancer was found increased in relation to high GH levels in one large study (2). The reported variations in the prevalence of colonic tumors might reflect differences in selection of patients (age, sex, visualization of the entire colon, autoptic vs. colonoscopy series). In addition, acromegalic patients with a previous history of colonic adenomas and high serum IGF-I levels have higher risk to develop new colonic neoplasm (17). In addition to the observation that IGF-I has proliferative and antiapoptotic effects in cell lines (17, 22, 23, 24), direct evidence of the involvement of the GH-IGF-I system in proliferation of intestinal epithelial cells was recently provided by studies showing the antiapoptotic effect of GH and IGF-I in human colonic cell lines and the reduced degree of apoptosis in the colonic mucosa of acromegalic patients (25, 26).

Despite the above evidence on the proliferative and antiapoptotic effects of GH and IGF-I in vitro and in vivo, the role of these growth factors in human colonic tumor pathogenesis still is a matter of argument and accounts for different opinions on the clinical relevance of colonic polyps in acromegalic patients (3, 5, 11, 12, 15, 16, 17, 27). As a consequence, it is unsettled how often colonoscopy should be performed or, in other words, how acromegalic patients should be managed regarding the risk of colonic lesions (10, 11, 15, 17, 27). The prevalence of colonic adenomas in our series of active untreated acromegalic patients was significantly higher than in the control group. Control subjects belonging to the control group were slightly younger than acromegalic patients. However, the prevalence of colonic adenomas, when adjusted for age and sex, remained significantly higher in acromegalic patients, even after adjustment for age and sex. More importantly, our study shows that two different populations of acromegalic patients can be identified: those who are prone to develop adenomas and those who are not. A single colonoscopy at the time of the diagnosis effectively identifies these two populations of patients and is helpful as a guidance for the subsequent follow-up: the risk of developing new adenomas is negligible in patients without adenomas at baseline, much higher in patients with single or multiple polyps at the first evaluation.

The follow-up period (5 yr) in our series was sufficiently long, but we cannot completely rule out the occurrence of new adenomas after this period, although this appears unlikely. Because the estimated duration of the disease did not differ in patients with or without colonic adenomas at baseline, it is conceivable that yet unidentified genetic factors predisposing to colonic adenomas might be differently present in acromegalic patients. In addition, acromegalic patients with or without adenomas at baseline did not differ for the common risk factors for colonic tumors. In this regard, GH-IGF-I excess, as seen in untreated acromegalic patients, might act as a promoting agent, favoring or accelerating the development of colonic adenomas in susceptible individuals. SMSa lengthens colonic transit and increase bowel bile acids; this might enhance activity of the enzymatic pathway converting cholic acid to deoxycholic acid (28), thus making a link with colorectal tumorigenesis (29). However, in our series, the proportion of acromegalic patients who received SMSa treatment was similar in the two subgroups with or without new adenomas. Thus, it seems unlikely that SMSa treatment may play relevant role in the colonic tumorigenesis of acromegalic patients, at variance with GH-IGF-I excess.

Our long-term prospective study suggests that recurrences occurred only in acromegalic patients who had colonic adenomas at baseline. Within this subgroup of patients, the control of disease activity plays a crucial role in development of new adenomas. As a matter of fact, patients with poorly controlled acromegalic disease had a higher prevalence of multiple recurrences during the 5-yr follow-up period than those with controlled acromegaly. Our data extend previous observations (16, 17), that patients with recurrent colonic adenomas had significantly higher serum IGF-I levels than those without new adenomas. Our findings clearly indicate that the detrimental effect of GH-IGF1 excess on colonic adenoma (re-) formation occurs only in a subset of (predisposed) acromegalic subjects.

It is worth noting that all seven patients with a single recurrence had controlled acromegaly and that the new adenoma was found mostly during the first colonoscopy control. This might imply that new adenomas may represent, in this group, rather than recurrence, the unraveling of adenomas that were already present at baseline but could not be identified because of their very small size.

In conclusion, we suggest that: 1) baseline colonoscopy should be performed in all acromegalic patients, owing to the small but definite increased risk of colonic tumors; 2) patients with colonic adenomas at baseline should be strictly followed up and any effort should be taken for a prompt and close control of disease activity; considering that 5–10 yr are usually required for the adenoma-carcinoma progression, colonic surveillance at 3-yr intervals seems reasonable for this subgroup patients, particularly if acromegalic disease is not controlled; and 3) patients without colonic lesions at first examination should be considered as bearing the same risk as general population and be followed up using the screening programs.


   Acknowledgments
 
We thank Professor Aldo Pinchera (Department of Endocrinology, University of Pisa) for his continuous support and advice.


   Footnotes
 
This work was partially supported by grants from the University of Pisa (Fondi d’Ateneo) and Ministero dell’Istruzione, dell’Università, e della Recerca, Rome (to E.M.), the University of Insubria at Varese (Fondi di Ateneo per la Ricerca), and Ministero dell’Istruzione, dell’Università, e della Recerca, Rome (to L.B.).

F.B., C.C., C.S., A.C., L.M., M.G., G.R., L.B., and E.M. have nothing to declare.

First Published Online January 31, 2006

Abbreviations: APC, Adenomatous polyposis gene; SMSa, somatostatin analog.

Received November 16, 2005.

Accepted January 19, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals