Age of onset of inflammatory bowel disease is the strongest risk factor for the development of malignancy

Nicole Sciberrasa, Lara Miruzzia, Luke Bugejaa, Adrienne Gattb, Suzanne Cauchia, Zane Attardb, Pierre Ellula, Stefania Chetcuti Zammita

Mater Dei Hospital, Msida, Malta

aDepartment of Gastroenterology, Mater Dei Hospital, Msida, Malta (Nicole Sciberras, Lara Miruzzi, Luke Bugeja, Suzanne Cauchi, Pierre Ellul, Stefania Chetcuti Zammit); bDepartment of Medicine, Mater Dei Hospital, Msida, Malta (Adrienne Gatt, Zane Attard)

Correspondence to: Dr Nicole Sciberras MD MRCP(Edin), Medical Ward 2, Mater Dei Hospital, Msida, Malta, e-mail: nikk_scib@hotmail.com
Received 21 October 2024; accepted 10 February 2025; published online 28 February 2025
DOI: https://doi.org/10.20524/aog.2025.0952
© 2025 Hellenic Society of Gastroenterology

Abstract

Background Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a multifactorial inflammatory disorder of the gastrointestinal system that impairs the patient’s quality of life. Its presentation includes a spectrum of symptoms that may also be secondary to IBD complications, such as malignancy. On the other hand, immunosuppressive treatment to maintain remission also carries a risk of malignancy, which can cause patients distress due to the risk/benefit balance of IBD control and malignancy.

Methods In this nationwide retrospective study, we aimed to elucidate which patient and treatment factors have the greatest impact on the development of malignancy in IBD patients. Statistical analysis was performed on patient factors, including treatment types, and nominal regression analysis was carried out to assess the effects of multiple risk factors on the incidence of malignancy in patients with IBD.

Results Age at diagnosis of IBD correlated significantly with malignancy development, as did the diagnosis of ulcerative colitis. IBD patients diagnosed with malignancy had an older age of onset of IBD than those who did not develop malignancy. Sex, treatment type, treatment duration, and extent or location of disease did not correlate significantly with malignancy development.

Conclusion We conclude that age of onset of IBD plays the greatest role in malignancy development, whilst immunosuppressive treatment is not a significant risk factor.

Keywords Keywords Malignancy, inflammatory bowel disease, risk factors

Ann Gastroenterol 2025; 38 (2): 182-186

Introduction

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a multifactorial inflammatory disorder of the gastrointestinal system that impairs the patient’s quality of life. Chronic gastrointestinal inflammation may present with a multitude of symptoms, as well as extraintestinal manifestations or complications such as intestinal obstruction or perforation. Other sequelae of prolonged or untreated inflammation include the development of malignancy.

The malignancy risk associated with IBD has been a topic of interest for several decades, with research initially focusing on colonic malignancy risk in IBD patients [1,2]. Over the years, interest shifted to extracolonic malignancies associated with IBD, whose spectrum includes dermatological, hepatobiliary, hematological and respiratory types [3]. Eventually, research was directed at identifying risk factors for malignancy in IBD patients, and several conclusions emerged. In CD, a penetrating (Montreal B3) subtype confers greater malignancy risk than Montreal B1 (non-stricturing, non-penetrating) and B2 (stricturing) subtypes, whereas in UC, extent of disease (pancolitis) and abdominal surgery for UC present a greater malignancy risk [4]. Furthermore, skin and urinary tract malignancy risk increase with IBD duration [4]. Another documented risk factor for malignancy in IBD patients is treatment-associated. Whilst thiopurine therapy is linked to lymphoproliferative disorders and non-melanoma skin malignancy [5,6], biological agents such as anti-tumor necrosis factor (TNF) therapy are associated with melanoma skin malignancy [7]. Other potential risk factors for malignancy in IBD patients include sex [8] and duration of therapy [9]. The aim of this nationwide retrospective multivariate analysis was to elicit statistically significant variables conferring a risk for malignancy development in IBD patients locally.

Patients and methods

Population studied

Following ethical approval from the local regulatory body, data were collected from the local IBD registry in an anonymized manner. All Maltese patients with IBD under active treatment between 2008 and 2022 were included. Our study excluded foreign patients residing in Malta to eliminate genetic bias and environmental differences. Data were collected from patient records, and included sex, IBD phenotype histologically, extent of disease at diagnosis, disease behaviour at diagnosis, age at diagnosis, current age, treatment at diagnosis, current treatment, duration of treatment/s, age at malignancy diagnosis (if any) and histology of malignancy.

Statistical analysis

The statistical analysis was carried out using SPSS Statistics v29 (IBM Corp. Released 2015. IBM SPSS Statistics for Mac, Version 29.0. Armonk, NY: IBM Corp.). We evaluated descriptive statistics, including sex, mean and median age at diagnosis, the percentages of patients on different treatment types and the percentages of IBD patients diagnosed with malignancy. The Mann-Whitney test was used to assess statistical significance across individual continuous variables. Fisher’s exact test was used to assess statistical significance across individual non-continuous variables. Results were considered statistically significant if the P-value was <0.05. Nominal regression analysis was carried out to assess the effects of multiple risk factors on the incidence of malignancy in patients with IBD.

Results

Demographic data

One thousand five hundred sixty-six patients were included in the study, of whom 713 (45.5%) were female. The predominant type of IBD was UC (65.2%), followed by CD (33.4%), and 1.3% had unclassified IBD (IBD-U). Mean age at diagnosis was 42.4±18.47 years (range 4-88 years), and the median age was 41 years.

One hundred thirty-five patients (8.6%) had a malignancy diagnosis during their lifetime; 2.7% (n=42) of patients had a malignancy diagnosis preceding the diagnosis of IBD, whereas 5.9% (n=93) developed malignancy following the IBD diagnosis. In the latter group, the mean time between IBD diagnosis and malignancy diagnosis was 6.4±5.1 years. Ten patients developed 2 or more malignancies following IBD diagnosis, with an average time to diagnosis of first malignancy of 10.6±6.83 years. The commonest malignancy types were dermatological (n=39, 2.49%), prostate (n=17, 1.09%) and breast (n=14, 0.89% of the whole population). These findings are summarized in Supplementary Table 1.

Correlation of variables with incidence of malignancy

Sex was not a significant risk factor for malignancy in our population: 8.2% (59 of 713) of females and 8.9% (76 of 853) male IBD patients were diagnosed with malignancy during their lifetime (P=0.718). Malignancy prevailed in a statistically significant manner in patients with UC, as 10.5% (n=107) of UC patients were diagnosed with malignancy, compared with 5.3% (n=28) of CD patients (P=0.001). None of the IBD-U patients developed malignancy.

There was no statistical association between occurrence of malignancy and extent of disease in UC patients (P=0.571), and location of disease according to the Montreal classification in the Crohn’s population (P=0.209). Among the latter group, ileal location (L1) carried the highest risk of malignancy (10/155 patients), followed closely by colonic (L2) (9/146 patients).

Age at diagnosis was also a significant risk factor for malignancy in our population (range 4-88 years, mean 42.4±18.5 years; P<0.001). In patients who never developed malignancy, median age at IBD diagnosis was 39±17.9 years, whereas in those who developed malignancy it was 60±15.6 years.

With respect to treatment, age at start of treatment correlated with age at diagnosis (median age 41 years). A statistically significant difference for age at treatment initiation was noted: patients without malignancy had a lower median age at start of treatment (41±19.7 years) compared to those who developed malignancy (52±18.6). Duration of treatment was not a risk factor for malignancy in this population, as the median duration of treatment was 5±2.7 years in both those with and without malignancy (P=0.959).

As regards treatment, 45.8% (n=717) of the population were solely on mesalazine treatment since diagnosis, that is, there was no exposure to immunosuppressive treatment during their lifetime; 27.7% (n=434) of patients were on immunomodulatory treatment alone, 2.8% (n=44) were on biological agents alone and 23.6% (n=371) were on combined therapy. Patients who were on combined therapy and downgraded to monotherapy were included in the combined therapy group for exposure purposes. Treatment type did not affect malignancy development in our patients (P=0.943).

Comparing the different types of immunomodulatory treatment, namely azathioprine (n=724, 46.2%), 6-mercaptopurine (n=51, 3.3%) and methotrexate (n=30, 1.9%), no significant risk for malignancy was identified, including in patients exposed to more than 1 immunomodulatory agent (P=0.203). The biological agents used locally are infliximab, adalimumab, vedolizumab and ustekinumab. Comparison of the biological agents showed that infliximab (n=328, 20.9%) carried the highest risk of malignancy, although patients on infliximab were mostly on concomitant immunomodulatory therapy (P=0.012). Fifty-seven patients (3.6%) required switching of biological agents, and this did not significantly increase malignancy risk (n=5, 0.3% vs. n=52, 3.3%; P=0.967).

Nominal regression analysis to determine risk of malignancy

In addition to the above results, we performed likelihood ratio tests to further elicit the significance of risks. Age at diagnosis was a persistently significant risk (P<0.001), whilst type of IBD was not (P=0.060). Combined treatment retained a similar risk profile to that calculated using Fisher’s exact test (P=0.011; Table 1).

Table 1 Variables analyzed for malignancy risk in IBD patients

thumblarge

Discussion

Our study assessed the risks for malignancy development in IBD patients whilst taking into consideration several risk factors. Keeping in mind the available data on risk factors for malignancy in IBD patients, we aimed to establish a correlation between sex, type and extent of IBD, age at diagnosis, treatment exposure and its duration.

Whilst the type of IBD and age at diagnosis emerged as statistically significant risk factors for malignancy development in IBD patients in this study, age at diagnosis was the predominant risk factor locally. Recently, interest in elderly-onset IBD has peaked, with studies aiming to determine disease course, treatment strategies and surgical requirements. However, data on malignancy risk remain scarce, and the few available studies have shown conflicting results concerning the impact of age of IBD onset and malignancy development [3,10,11].

Literature on malignancy risk in IBD tends to focus on intestinal malignancies, whereas our study took into account any type of malignancy. Our study agrees with international data that UC is associated with a higher risk of colorectal malignancy [12]. However, our study fails to correlate with international data suggesting that pancolitis confers the greatest risk of malignancy in patients with UC [12]. This study recorded the extent of disease at diagnosis; thus, there may have been cases of progression of extent over time. CD also increases the risk of small and large bowel malignancy, yet there is no precise quantification of this risk—possibly because the Crohn’s phenotype is extremely variable and hence it is difficult to assess the effect of disease extent on risk of malignancy [13]. On the other hand, a recent Dutch study counters the emphasis placed on increased risk of colorectal malignancy amongst IBD patients, claiming this risk is lower in Dutch patients than previously mentioned [14].

Our study did not reveal any significant increase in risk of malignancy related to treatment. The inclusion of a cohort of patients receiving only mesalazine therapy (oral and/or topical) reduced the possibility of bias in our results. Initiation of treatment at an older age was associated with a higher incidence of malignancy in our study. This indicated that the likely risk factor for malignancy was age at diagnosis and not duration of exposure to treatment. Contrary to common concerns, patients on combined therapy had lower malignancy rates in our study than patients on immunomodulator monotherapy or biological monotherapy. Immunomodulator therapy has been linked to hematological and dermatological malignancies, as described in the CESAME study [5,15]. Hepatosplenic T-cell lymphoma remains a rare entity associated with thiopurine use, and none of the lymphoma patients in our cohort were diagnosed with this subtype [16]. Whilst a single study stated thiopurines may have a protective role in IBD with respect to colorectal neoplasia [17], other studies counter this claim, stating that it is in fact mesalazine that has a protective effect [18]. Our study did not identify any statistically significant difference in the risk of malignancy amongst different immunomodulators, including in patients who switched between immunomodulators.

Exposure to anti-TNF treatment over a short term (median duration used in quoted study 3.5 years) does not appear to increase malignancy risk [19]. A retrospective study revealed a risk of melanoma skin malignancy with biological agents [20]. Lymphoma risk was found to be greater under either anti-TNF or immunomodulator monotherapy, and even more in combination therapy [21]. As previously mentioned, the results obtained from our study are not concordant with these studies. Malignancy risk with other biological agents and small molecules is still being investigated [22].

To aid physicians in balancing the risks and benefits of IBD treatment, Beaugerie et al advise that in uncontrolled inflammation prompt treatment is advisable, as the risks of severe inflammation outweigh the risks of adverse effects, whereas in patients with sustained deep remission, consideration of long-term treatment side-effects should be taken into account [23].

When treating patients who have a history of malignancy or have ongoing malignancy, one may refer to the European Crohn’s and Colitis Organisation (ECCO) guidelines. Developed in 2015 and recently updated, these guidelines consolidate the knowledge that patients with IBD are at increased risk of specific malignancies. Those with a history of malignancy have a 2-fold greater risk of new or recurrent malignancy, regardless of immunosuppressive treatment. In those diagnosed with malignancy, ECCO advises temporary cessation of thiopurines, calcineurin inhibitors and anti-TNF therapy, at least until cancer therapy is completed [24]. There should always be a discussion with the caring oncologist, and at a multidisciplinary team level, about the treatment of IBD during and following cancer treatment.

Our study had certain limitations that could not be avoided. Firstly, it did not take into account patients diagnosed and treated privately for IBD, who never made contact with the public hospital service, as our population consisted of patients with entitlement to treatment under the national health system. Furthermore, patients may have sought private care in certain instances, such as treatment of dermatological malignancies, which may have led to lower documented malignancy rates. As previously mentioned, we recorded the extent of disease at diagnosis; thus, there may have been cases of progression of extent over time. Our study also assumed that patients were compliant with the treatment prescribed, as duration of treatment exposure relies heavily on compliance.

Despite these limitations, our study had several strengths, namely the strict utilization of the local population with a formal histological IBD diagnosis, a significant number of patients, and a control group of IBD patients who were never exposed to immunosuppressive treatment. Several risk factors for malignancy were recorded and statistically analyzed over a long follow-up period. A comparison of malignancy incidence per 100,000 individuals to the local population is delineated in Table 2, to give an overview of the malignancy incidence in the IBD population and in the general population.

Table 2 Malignancy in inflammatory bowel disease (IBD) vs. general population per year

thumblarge

Our study concludes that previously described risk factors for malignancy in IBD patients may not be as significant as previously thought, especially with regard to treatment, and this may help alleviate physician and patient anxiety when considering these therapies. This is particularly significant with the rising incidence of IBD in the elderly population. Whilst the topic of elderly-onset IBD is gaining momentum, formal guidance is required on the follow up, treatment and malignancy surveillance of this IBD population subtype.

Summary Box

What is already known:

  • Patients with inflammatory bowel disease (IBD) are at risk of malignancy from the inflammatory processes in the gastrointestinal tract, as well as from the treatment required to control this inflammatory process

  • The type of IBD, as well as its extent and phenotype, play a role in malignancy development in IBD patients

  • The side-effects and malignancy risk of different types of immunosuppression, such as immunomodulators and biological agents, have been well documented

What the new findings are:

  • Age of onset of IBD was the greatest risk factor for malignancy in IBD patients, with patients being diagnosed at an older age running a higher risk of malignancy than those diagnosed younger

  • Exposure to immunosuppression plays less of a role than previously predicted, as older age at diagnosis correlated inversely with duration of exposure to immunosuppressive treatment

  • The type of immunosuppressive medication, including whether given as monotherapy or combination therapy, showed no statistically significant correlation with the development of malignancy in IBD patients

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Notes

Conflict of Interest: None