Dr. Francisco Javier Gallego Rojo
Hospital de Poniente. El Ejido (Almería)
For more than 50 years it has been assumed that the risk of developing colorectal cancer (CRC) in patients with ulcerative colitis (UC) is higher than that in the general population. However, the exact magnitude is not well known due to the great variation and heterogeneity of the various studies (geography of the studied population, duration of the work and methodology used).
In the meta-analysis done by Eaden et al.1 on 116 studies that included 54,478 cases of UC, CRC has a prevalence of 3.7%, which increased to 5.4% in patients who had pancolitis. Söderlund et al.2 find an annual incidence 2.3 times higher than that of the general population. However, in other studies, the risks are a lot lower, with an annual crude incidence rate of 0.06% and only an accumulated risk of 2.1% at 30 years, without finding any differences with the general population3.
In the same regard, the risk of CRC varied from 1.4% at 18 years from the onset of the disease to 34% after 30 years. In the meta-analysis done by Eaden et al.1, the risk ranges from 2% at 10 years after being diagnosed with the disease, 8% at 20 and 18% at 30.
One significant observation to take into consideration is the fact that the incidence and risk of CRC in colitis-associated inflammatory bowel disease (IBD) is decreasing over time. Rutter et al.4 find a drop in CRC incidence over a 30-year observation period, especially for proximally localised cancers (not for rectal or advanced cancers) (Dukes C or D). Söderlund et al.2 observe similar data for the relative risk (RR) of developing CRC in a population study of patients with inflammatory bowel disease (IBD) diagnosed between 1954 and 1989 with follow-up until 2004 (RR was 1.7 within the period between 1960–1969, 1.3 between 1970–1979, 1.2 between 1980–1989, 1.1 between 1990–1999 and 1.0 between 2000–2004). The reasons for this decrease are not well known, although it is attributed to better surveillance of patients with colonoscopy and to the generalised use of salicylates with preventive properties for the development of CRC in these patients.
Despite all of this, CRC mortality in IBD is between 10–15% of the cause in these patients5, with the average age of occurrence at 43.2 years old (10–15 less than patients without IBD). Survival at 5 years is similar to that for CRC in the general population (50%)6.
Identifying higher risk patients and establishing proper surveillance is essential in these patients.
RISK FACTORS FOR DEVELOPING DYSPLASIA AND COLORECTAL CANCER
Duration of colitis
For left or extensive UC, the risk of CRC significantly increases between the 8th–10th year after diagnosis, at which time the guidelines recommend starting the endoscopic surveillance. For Crohn’s Disease (CD) affecting more than a third of the extension of the colon, most lesions (clinical case) start at the 10th or 12th year (similar to UC)7.
In various studies analysed, CRC diagnosis after the onset of the disease ranges between 16.3 and 23.5 years8.
Currently, the duration of the disease is considered one of the main risk factors for the development of CRC in IBD.
There is disagreement regarding whether the early age of the IBD diagnosis is an independent risk factor for developing CRC. Some studies have found an association between both events, with an accumulated risk of 40% when the colitis diagnosis is made under 15 years old, with respect to 25% of the risk for the age bracket between 15 and 39 years old9. However, it seems that the most significant factor, in actuality, pertains to the longer duration of the disease when the diagnosis is established at earlier ages (Fig. 1).
Extension of the disease
This is a clearly established factor, along with the duration of the disease. Thus, patients with proctitis and proctosigmoiditis have a low CRC risk, similar to the general population, which is why additional surveillance is not necessary. For left colitis (extension to the splenic flexure), the risk is intermediate with respect to high risk patients with extensive colitis or pancolitis7,8 (Fig. 2).
When determining the extension it is important to apply endoscopic and histologic criteria.
In various studies, the risk of developing CRC in patients with pancolitis ranges between 14.8%–19.2%; 2.8% for the left colitis and only 1.7% for proctitis and proctosigmoiditis9. However, in left colitis and pancolitis, the risk levels off after the fourth decade from the onset of disease.
Severity of inflammation and other related factors
Although the results on this potential risk factor are contradictory according to the studies assessed, we can conclude that it is also a recognised risk factor.
In a case-control study on 68 patients with UC, we found a higher relative risk (RR) for patients with higher endoscopic activity (odds ratio [OR]: 2.5, p <0.001) and especially histologic (OR: 5.1; p <0.001)10 (Fig. 3). This association was maintained in the logistic regression multivariate analyses. However, other studies show that the disease in a quiescent state has the same risk of developing CRC as those with inflammatory activity6.
• The presence of stenosis in UC (not in CD) is a significant risk factor (Fig. 4). In a retrospective study prepared by Lashner et al. of a registry of patients with UC, 15 (3.2%) had stenoses identified over a time period of 13.3 years. Of the patients with stenosis, 13 (86%) had dysplasia (11 cases) or CRC (2 cases) at the time of diagnosis. All abnormalities were located in the stenoses. RR was 5.7 times higher11.
• A colon with a tubular and shortened appearance increases the RR 28.4 times.
• The presence of pseudopolyps increases the RR of CRC between 2.1 and 2.5 times, not due to the fact that they are considered pre-malignant lesions, but because they are manifestations of a more severe chronic inflammation. In addition, it is more difficult to identify dysplastic lesions within the context of a colon with pseudopolyps4.
Primary sclerosing cholangitis
It is also considered an independent risk factor. The accumulated risk can become 31–33% at 20 years and 40–50% at 25–30 years from the onset of the disease. The RR for dysplasia or cancer is 3–4 times higher with respects to UC patients with primary sclerosing cholangitis (PSC)12. It is believed that PSC patients have more prolonged forms over time, with quiescent forms of the disease (Fig. 5).
Family history of colorectal cancer
The various existing studies suggest that genetic (family history of CRC) and acquired (chronic inflammation) factors play a role in the development of CRC in patients with IBD. Overall, the existence of a family history of CRC carries an RR that is 2–3 times greater, and 9 times greater if the affected family member is first degree and less than 50 years old when diagnosed with CRC13.
In recent years, the recognized identification of all these risk factors has changed the recommendations on CRC surveillance in patients with IBD in order to make it more rational and cost-effective. Most of the guidelines from the various gastroenterology and gastrointestinal endoscopy associations include them. In Figure 6, the general recommendations state that the frequency at which colonoscopies are performed during patient follow-up is based on their stratification in risk groups (low, intermediate, high and very high).
DYSPLASIA IN INFLAMMATORY BOWEL DISEASE. MICROSCOPIC AND MACROSCOPIC LESIONS
Both in UC and in CD, CRC usually appears after a complex sequence of: inflammation – low-grade dysplasia (LGD) – high-grade dysplasia (HGD) – carcinoma. In fact, dysplasia
is the best malignancy risk marker in IBD patients and is present in more than 90% of cases14. However, it can develop in patients with no microscopic evidence of dysplasia or with LGD only15.
From a macroscopic (endoscopic) perspective, dysplasia can occur as “endoscopically visible” lesions and “non-endoscopically visible” lesions (Video 1).
Currently, from a microscopic perspective, dysplasia is stratified based on the Vienna Classification16 or the Riddell Classification (more simplified) (Table I).
The Vienna Classification establishes five categories (according to severity):
• Negative for neoplasia/dysplasia.
• Undefined for dysplasia/neoplasia.
• Non-invasive, low-grade neoplasia.
• Non-invasive, high-grade neoplasia..
• Invasive neoplasia.
The Riddell Classificationhas four categories:
• Negative for dysplasia.
• Undefined for dysplasia.
The latter does not include invasive carcinoma. There are significant clinical differences between both classifications.
One of the controversial areas in studying dysplasia is the differentiation between LGD and reparative-inflammatory lesions, as well as between HGD and micro-invasive carcinoma (interobserver variability). For these undetermined cases, a second assessment by an expert pathologist in gastrointestinal pathology is crucial before making any decision in treating the patient. In order to differentiate these cases, studies have been done to identify molecular and non-molecular markers. The most promising of them all is the alpha-methylacyl-CoA racemase (AMACR). Some studies reach a sensitivity (S) for LGD of 96% and 80% for HGD, with a specificity close to 100% for LGD17. However, its applicability in the clinic is still not established.
The natural history of dysplasia is not clearly defined and has several limitations. For example, CRC can develop in 10–25% of cases in patients without a history of dysplasia. Furthermore, there are cases of CRC that developed from a LGD in the absence of HGD15. There are several factors that influence these findings:
• The presence of undetermined dysplasia reveals problems that may exist in establishing its true existence. When it appears, the progression to HGD and CRC ranges from 13%–28%18. In this regard, the aforementioned aspects influence the difficulty in differentiating dysplasia from inflammatory reparative-regenerative changes. The finding of dysplasia during the follow-up of patients (incidental dysplasia) carries a much lower risk than when it is diagnosed in the initial colonoscopy (prevalent dysplasia). The risk of HGD and CRC in the latter is rather high (29% vs 16%).
• Recurrent dysplasia (LGD finding in two consecutive colonoscopies) has a great impact in the indication of colectomy.
• Lastly, finding multifocal dysplasia in a colonoscopy (especially if one of them is HGD) is a clear indication of colectomy for a lot of clinics, although its natural history is not well known.
Macroscopic (endoscopic) lesions
As mentioned before, dysplasia in IBD is initially divided into two categories, the endoscopically invisible (diagnosed with random biopsies) and those that are visible (directed biopsies).
Some information is disputed in regards to the frequency at which such types of lesions occur, and it usually varies based on the endoscopic method used. Thus, in the Toruner et al.19 study, using standard videoendoscopy, 40% of dysplastic lesions were endoscopically invisible, while endoscopies that use chromoendoscopy (dye and electronic) and magnification endoscopy increase the detection of dysplasia 2–3 times20,21. Presently, it is agreed that between 60–90% of lesions are endoscopically detectable, which greatly limits the use of random biopsies.
Likewise, there is also a lack of nomenclature and characterisation (classification) of endoscopically visible dysplastic lesions. Initially, all were named dysplasia-associated mucosal lesion (DALM)22. In recent years, based on morphological characteristics from an endoscopic perspective, a differentiation was established between flat and pedunculated lesions with well-defined edges, similar to adenomas in patients without IBD (adenoma like lesion [ALM]) and other more complex lesions (irregular and extensive, with poorly defined edges, ulcerated or within the context of stenosis) called non-ALM or DALM. ALM lesions generally are endoscopically resectable while DALM or non-ALM are indicated for surgery. However, other works establish the classification of raised lesions in ALM (based on previous criteria) and DALM based on the morphology and/or existence of dysplasia in the mucosa surrounding the lesion21. Other authors also consider the location of ALM lesions based on whether or not they are located in areas with inflammatory activity. Therefore, this classification is very subjective and has an uncertain significance. The current trend is to establish morphological classifications based on potential endoscopic resectability.
In this regard, Hurlstone et al.21 conducted a prospective study on 712 patients who had extensive UC for more than eight years by using chromoendoscopy along with magnification endoscopy x100. They grouped ALM lesions based on the Paris-Japan classification and grouped lesions as DALM if they had dysplasia in the surrounding mucosa. Patients with DALM lesions, with a type V pit pattern (Kudo Classification)23 in magnification chromoendoscopy and asymmetrical elevation of the lesion with submucosal injection, were excluded from endoscopic resection and were treated via colectomy. Of the 204 lesions found in 169 patients, 170 were ALM (83.3%), 18 DALM (8.8%) and 16 CRC (7.8%). Of the ALMs, 61% were flat lesions with a Paris classification morphology of 0-II, 34% had a type I morphology and 5% were lesions with lateral extension (laterally spreading tumours [LST]). All DALM lesions had a Kudo V pattern, 77% with a type 0-II morphology (flat) and 23% with type I (protruding). The study concluded that most dysplastic lesions are endoscopically visible, type ALM (potentially resectable) and have a flat morphology.
The trend in the next few years will most likely be to identify and classify lesions with systems as well as those described in order to try, in most cases, to treat and endoscopically follow-up on the raised colon lesions associated with IBD.
Figure 7 and Figure 8 schematically represent the Paris and Kudo classifications.
TREATMENT AND OPERATING STANDARDS FOR DYSPLASIA
Considering that most dysplastic lesions are endoscopically visible (>85% if magnification chromoendoscopy is used) and the development of advanced resection techniques (mucosectomy and submucosal dissection), currently, most gastroenterologists usually treat and monitor these patients endoscopically. However, it is important to establish a few tailored operating standards for each case.
Patients with endoscopically visible dysplasia (raised lesions)
Most lesions are endoscopically visible with the new techniques described above (magnification chromoendoscopy).
Using the endoscopic classification models for early neoplasms of the colon (Paris-Japan), the pattern of the mucosal surface with magnification (Kudo classification) (Fig. 7 and Fig. 8) and current microscopic dysplasia classifications (Vienna classification), lesions defined as ALM can safely be resected endoscopically virtually in their entirety with a low risk of developing dysplasia or CRC during endoscopic follow-up21,24.
In the Hurlstone et al.21 study, a total of 132 ALM lesions (over 135; 98%) that were endoscopically visible with chromoendoscopy and magnification (Paris, Kudo and Vienna classification) were endoscopically resected (polypectomy, mucosectomy and submucosal dissection) in the initial endoscopy. Of these, 46 (34.9%) belonged to type I (pedunculated, semi-pedunculated or sessile lesions), 79 (59.8%) were type 0-II (flat and raised lesions) and 7 (5.3%) were type LST of the Paris classification; 18 of the resected lesions had HGD (more prevalent in lesions 0-II; 18%). In this patient group, none developed CRC or non-endoscopically visible dysplasia (random biopsies) during the study’s follow-up period. Only in four patients did the mucosal resection have to be extended due to a recurrence of the first lesion. Furthermore, when taking random biopsies while following up on patients with LGD, no dysplastic lesions were identified in 31/59, and the patients continued in the surveillance program. Only one patient (0.14%) had CRC (8-mm lesion in the caecum) that was not identified in the initial colonoscopy.
Conversely, complex non-ALM DALM lesions (due to morphological criteria or those with dysplastic areas in the surrounding mucosa) and non-endoscopically resectable ALM lesions (asymmetrical elevation with submucosal injection or technical difficulty) must be indicated for colectomy. Complex DALM lesions usually have a higher prevalence of HGD areas and synchronous or metachronous CRC (Video 2).
Patients who have undergone resection of ALM lesions, especially in areas with colitis or who presented LGD in random biopsies, are considered very high risk and must undergo close endoscopic surveillance every 3–6 months until two consecutive colonoscopies are performed without dysplastic findings25.
Taking all factors involved into consideration, we propose an algorithm (Fig. 9) for the actions to be taken if a raised (endoscopically visible) dysplasia is found.
Non-endoscopically visible dysplasia (random biopsies)
Although the current trend is to perform directed biopsies and endoscopic resection of the endoscopically visible lesions with chromoscopy and magnification techniques, many sites do not have the technology available and/or enough experience. In these cases, directed biopsies for suspected lesions combined with random biopsies of the caecum, taking 4 samples (one per quadrant of colon lumen) for every 10 cm of mucosa visualised, are the most appropriate alternative. The minimum numerical reference for biopsies is 33. Some authors recommend taking 4 biopsies every 5 cm in the rectum and sigmoid colon due to the higher prevalence of CRC in this area (in this manner an average of 64 biopsies could be achieved). However, with this method, only 1% of the mucosal surface is analysed, and only 90% of dysplastic lesions are detected. In addition, it is very time-consuming (endoscopist and pathologist) and few gastroenterologists take the recommended number (<50%).
When HGD is found with this strategy, whether or not it is associated with DALM, a colectomy is a formal indication since the presence of CRC can be present in these patients in 42–67% of cases26. In fact, when patients do not undergo surgery (the least amount), between 25–32% develop CRC during follow-up.
That attitude is a lot more disputed for the finding of an LGD, since its natural history is unknown. The studies show very mixed results in regards to the finding of HGD, CRC and progression to CRC during follow-up. In some works this ranges between 22–36%. The progression to CRC ranged from 0–3% at 10 years up to 35–54% at 5 years.
Thus, the decision to perform a colectomy vs endoscopic surveillance must be tailored and closely discussed between the gastroenterologist, the gastrointestinal surgeon and the patient. If endoscopic surveillance is chosen, it must be very close together (every 3–6 months until 2 consecutive colonoscopies are performed without any abnormalities). However, if dysplasia is multifocal or appears consecutively in two colonoscopies, colectomy is strongly recommended.
A management algorithm that is highly used in the follow-up of dysplasia is the one proposed by Itzkowitz27 (Fig. 10).
Chemoprevention for dysplasia in inflammatory bowel disease
Endoscopic surveillance has limitations when detecting dysplasia since some patients can develop CRC despite it being performed. Intervening before the development of dysplasia could also prevent the development of CRC, avoiding colectomy in these patients.
Aminosalicylates are used as a maintenance treatment in UC in order to reduce the recurrence of the disease. Their possible preventive effect in the development of dysplasia makes it a very attractive agent in this patient group due to its safety and low cost. Among the mechanisms via which they could act, inhibiting the activation of the kappa-B nuclear factor is one of those proposed (NFκB). This molecule is associated with the maintenance of chronic bowel inflammation28. They can also induce apoptosis and inhibit proliferation of epithelial cells in the colon in patients with sporadic adenomas29. Various studies have observed a significant prevention of aminosalicylates. Eaden et al.30 find a 75–90% reduction in the incidence of CRC with the use of mesalazine at a dose of >1.2 g/day, which is more effective than sulfasalazine. In the meta-analysis done by Velayos et al.31, from a total of 1,932 patients with UC, which included 334 CRC and 140 cases of dysplasia, a protective association was observed in the appearance of dysplasia and CRC with the use of mesalazine (OR: 0.51; 95% IC, 0.38–0.69). The benefits occurred with the use of a dose of >1.2 g/day. However, other works have not found such an association. However, most authors generally recommend the use of aminosalicylates as protective agents against dysplasia in colitis-associated IBD.
Ursodeoxycholic acid (UDOA) is another drug with a potential preventive effect. Studies have been conducted primarily in patients with PSC. Alteration in the balance of bile acids in the colon suffered by these patients, predominantly deoxycholic acid, seems to have a carcinogenic effect. The use of UDOA counteracts this alteration. Tung et al.32 find a strong association with a decrease in the prevalence of dysplasia, which was maintained even after the adjustment for sex, age, onset and duration of colitis, PSC duration, severity of the liver disease and the use of salazopyrin. Few studies have been conducted on patients without PSC, although some have showed a preventive effect in patients with LGD and/or aneuploidy of the epithelial cellular DNA. Sjoqvist et al.33 conducted a prospective study of 19 patients (13 UC, 6 CD) with long-standing disease (average: 21 years) and with findings of dysplasia or aneuploidy that were randomised into two groups (placebo vs 500 mg of UDOA twice a day). They found that no patient from the UDOA group developed dysplasia, while two from the placebo group experienced HGD during follow-up. The use of UDOA in patients with PSC is strongly recommended.
For the remaining drugs used in IBD treatment (corticoids, azathioprine, biological therapy) as well as others (folic acid, statins, calcium, vitamins) there is no evidence for their use as preventive agents.
FOLLOW-UP GUIDELINES. ENDOSCOPIC SURVEILLANCE
Table II lists the guidelines for screening and the endoscopic follow-up of ECCO 2008 and 201334,35, BSG 201036 and AGA 20107.
With all the available information based on these guidelines, we can create a series of general recommendations to follow during screening and endoscopic surveillance in patients with IBD:
• These patients should be managed by gastroenterologists or endoscopists with special interest and experience in diagnosing and treating IBD patients.
• Colonoscopy must be done with a thorough cleansing to avoid dysplastic lesion from going unnoticed.
• Begin screening with colonoscopy 6–8 years after the onset of the disease for patients with ulcerative pancolitis or extensive Crohn’s colitis >1/3 of the colon and begin after 10–15 years for left colitis.
• Patients with proctitis or proctosigmoiditis do not require special surveillance (similar to the general population).
• In sites without experience or available chromoendoscopy with/without magnification, the protocol of taking random biopsies every 10 cm in the 4 quadrants, with a minimum of 33 biopsies, along with directed biopsies of DALM (endoscopically visible) lesions, is an effective alternative.
• Colonoscopy with chromoendoscopy (vital dyes or electronic narrow band imaging [NBI] or Fujinon Intelligent Chromoendoscopy [FICE] systems) with magnification and directed biopsies of DALM lesions, along with random biopsies of “not clearly visible” areas is a more effective alternative for screening and follow-up in sites that have sufficient technology and experience available.
• All DALM-ALM lesions have to be resected endoscopically, if possible, and surrounding mucosa has to be biopsied, especially if they are in areas with colitis.
• Biopsies and resected lesions have to be analysed by a pathologist with sufficient experience in IBD, with a second opinion if dysplasia is found.
• Endoscopic monitoring must be done by stratifying patients by risk factors based on four subgroups:
– Very high risk patients (endoscopic resection of ALM lesions with high/low grade dysplasia, or LGD findings in random biopsies): colonoscopy every 3–6 months until two consecutive colonoscopies are performed without dysplastic findings.
– High-risk patients (long-standing colitis, extensive colitis, previous history of significant inflammatory activity, presence of stenosis in UC, tubular colon in UC, PSC or family history of grade 1 CRC <50 years old): annual colonoscopy.
– Intermediate-risk patients (extensive colitis with a previous history of moderate inflammatory activity, presence of pseudopolyps and family history of CRC): colonoscopy every 3 years.
– Low-risk patients (mild inflammatory activity, left colitis or extensive CD <50% of the colon): colonoscopy every 5 years.
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