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High detection rate of adenomas in familial colorectal cancer
  1. A E van der Meulen-de Jong1,
  2. H Morreau2,
  3. M C J M Becx3,
  4. L F S J Crobach3,
  5. M van Haastert3,
  6. W R ten Hove3,
  7. J H Kleibeuker3,
  8. M A C Meijssen3,
  9. F M Nagengast3,
  10. M C M Rijk3,
  11. J M J I Salemans3,
  12. A Stronkhorst3,
  13. H A R E Tuynman3,
  14. J Vecht3,
  15. M L Verhulst3,
  16. W H de Vos tot Nederveen Cappel3,
  17. H Walinga3,
  18. O K Weinhardt3,
  19. B D Westerveld3,
  20. A M C Witte3,
  21. H J Wolters3,
  22. H F A Vasen1,4
  1. 1Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Dept. of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Member of Collaborative group FACTS study
  4. 4The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands
  1. Correspondence to Andrea E van der Meulen-de Jong, Leiden University Medical Center, Department of Gastroenterology, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; a.e.de_jong{at}lumc.nl

Abstract

Background and aims Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) <50 years old or two FDRs with CRC have an increased risk for CRC (RR 4–6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas.

Patients and methods Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC <50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded.

Results A total of 551 subjects (242 male) met the selection criteria. Ninety-five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (>1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09).

Conclusion The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population.

  • Familial colorectal cancer
  • adenomas
  • surveillance
  • adenoma
  • family cancer
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Significance of this study

What is already known about this subject?

  • Familial colorectal cancer (FCC) is generally defined as clustering of colorectal cancer (CRC) without evidence for one of the inherited syndromes.

  • Subjects with FCC have an RR of 4–6 of developing CRC.

  • Prevalence data on adenomas in FCC are known from small series of patients or retrospective series.

What are the new findings?

  • The detection rate of adenomas including adenomas with advanced pathology in FCC is substantially higher than the detection rate reported for the general population.

  • The detection rate of adenomas was higher in relatives with two first-degree relatives with CRC compared with those with one first-degree relative with CRC aged <50 years.

  • Surveillance in FCC is effective.

How might it impact on clinical practice in the foreseeable future?

  • More efforts should be undertaken to improve identification of families with FCC.

Introduction

Familial colorectal cancer (FCC) is generally defined as clustering of colorectal cancer (CRC) without evidence for one of the inherited syndromes (Lynch syndrome, dominant clustering of CRC without Lynch or familial adenomatous polyposis). Probably a combination of environmental and inherited genetic factors plays a role in the development of CRC in these families. Subjects with one first-degree relative (FDR) with CRC diagnosed at age >50 years have an RR of developing CRC of 2–3. Subjects with two (or more) FDRs with CRC diagnosed at any age, or with one FDR with CRC diagnosed before the age of 50 years have an RR of 4–6 for developing CRC.1–4 Adenomas are the precursor lesions of CRC. Surveillance for CRC in families with Lynch syndrome or individuals who have had a polypectomy has shown that removal of the adenomas prevents the development of carcinoma. Colonoscopic surveillance at 3–6 year intervals is currently advised for subjects with a moderately increased risk of developing CRC (RR≥4), starting 5–10 years before the first diagnosis of CRC or at age >45 years. There are several, mostly small or retrospective, studies that evaluated the outcome of surveillance in such families.5–10

The FAmilial ColorecTal cancer Surveillance study (FACTS study) was started in The Netherlands in 2002. The aim of this national randomised clinical trial is to evaluate the outcome of surveillance in FCC and to assess the optimal surveillance interval (3 vs 6 years). This article describes the objectives, methods and organisation of this study and reports the yield of the first lifetime colonoscopy.

Methods

Inclusion criteria

Subjects were included if they were asymptomatic, aged between 45 and 65 years and if they had one FDR with CRC diagnosed before the age of 50 years (group A), or two FDRs with CRC diagnosed at any age (group B). Individuals with additional second-degree relatives with CRC and individuals with a personal history of inflammatory bowel disease or previous colorectal surgery were excluded. Also patients with an FDR with CRC with known microsatellite instability (MSI) were excluded. For the current prevalence study, subjects were also excluded if they had undergone a previous endoscopy (colonoscopy/sigmoidoscopy) or barium enema in their lifetime.

Organisation and patient accrual

The study was coordinated by the Netherlands Foundation for the Detection of Hereditary Tumours in Leiden. The study protocol was approved by the medical ethical committee at the Leiden University Medical Center. If patients underwent colonoscopy in other hospitals, local medical ethical committees were also consulted and permission was received in all cases.

All gastroenterologists in The Netherlands were informed about the study by email, regular mail and also by personal contact. All general practitioners (GPs) (n=8400) in The Netherlands received an information package about the FACTS study by regular mail, including a poster for the waiting room. Moreover, the study was announced in several newspapers and magazines.

Eligible subjects were informed about the study by their gastroenterologist, GP or by phone by the study coordinator. If they were interested in participating, they received an information package, including an information leaflet, an informed consent and a questionnaire about their own medical history and their family history. The informed consent had to be signed by the participant as well as by their gastroenterologist. After receiving the informed consent and the completed questionnaire, the family history was verified by collecting medical and pathology reports. Tumours from patients with recently diagnosed CRC <50 years old underwent investigation such as MSI analysis, and referral of patients to a clinical genetic centre was initiated. Then, the randomisation was performed by the study coordinator (AvdM), as outlined in figure 1. The participants, gastroenterologist and GP were informed about the outcome of the randomisation (colonoscopy after 3 and 6 years or after 6 years) and follow-up colonoscopies were scheduled. The inclusion period was 2002–2007.

Figure 1

Flow scheme of the study protocol.

Colonoscopic surveillance

For the present study the yield of the first (lifetime) colonoscopy was evaluated. All endoscopy and pathology reports were evaluated, and histology of all removed adenomas was revised by one pathologist (HM) for the degree of dysplasia and the presence of a villous architecture. Advanced adenomas (adenomas with advance pathology; AAPs) were defined as adenomas with high grade dysplasia and/or with (tubulo-)villous characteristics and/or adenomas with a size ≥1 cm in diameter. Risk factors for the development of adenomas that have been studied were sex, type of family history (group A vs B) and age at diagnosis of CRC in group B. Also we corrected for the age of the subjects at time of the endoscopy.

Statistical analyses

Basic descriptive analyses of the study population are presented. Analysis of variance (ANOVA) test and the χ2 test were used (SPSS version 16.0). All reported p values are two sided, and p<0.05 was considered statistically significant.

Results

A total of 551 subjects, all of European descent, were included in the FACTS study from 119 different hospitals (1–58 subjects/hospital). Ninety-five subjects with a previous endoscopy (colonoscopy/sigmoidoscopy) or barium enema were excluded from the current prevalence study. The 456 remaining subjects (204 male) belong to 317 families. The number of participants per family varied from one to six. A total of 224 subjects had one FDR with CRC at <50 years (group A), and 232 subjects had two FDRs with CRC at any age (group B). In all subjects the family history was confirmed by medical record, and the family history for CRC was confirmed by pathology report in 73.2% of the participants. The participants had a mean of 4.8 siblings (0–14) and the mean age of the participants at the time of their first lifetime colonoscopy was 53.9 years (range: 45–65 years). Average age was 52.2 years in group A and 55.4 years in group B (non-significant (NS)). Average age of the 204 males was 54.2 years and of the 252 females it was 53.6 years (NS). All colonoscopies were performed in the period 2002–2007. The caecum was reached in 93.3%. Additional barium enema in participants in which the caecum was not visualised did not reveal any abnormalities.

Yield of the first colonoscopy

Two colorectal tumours, one CRC and one carcinoid (size 7 mm, located in the rectum), (0.4%) were diagnosed in the total study group. In 85 (18.6%) of 456 participants, 126 adenomas were detected including eight serrated adenomas. In 37 participants (8.1%), 45 adenomas with advanced pathology were detected. Thirty participants (6.6%) had multiple (>1) adenomas. In 23 subjects two adenomas were detected, three subjects had three adenomas and four subjects four adenomas.

Of all adenomas, 64.8% were left sided (at and distal from the splenic flexure), and of the AAPs, 72.7% were detected in the left colon. A total of 102 hyperplastic polyps were reported in 79 (17.3%) participants. Of the hyperplastic polyps, 79.0% were located distal from the flexura lienalis.

Predicting factors

An adenoma was detected more often in men than in women (49/204 (24.0%) vs 36/252 (14.3%) (p=0.01)). Thirty-five (15.6%) of the 224 subjects of group A (relatives with one FDR with CRC at <50 years) were found to have at least one adenoma, including 12 AAPs (5.4%). Fifty-one (22%) subjects of the 232 subjects of group B (relatives with two FDRs with CRC) were diagnosed with one or more adenomas including 24 AAPs and 1 CRC (10.8% AAPs). The difference in number of adenomas between group A and B was not significant (p=0.09), but the number of AAPs was significantly higher in group B (p=0.04). When corrected for sex and age of the subjects at the time of colonoscopy this difference was not significant (table 1). There was no evidence for clustering of adenomas in families. In total there were 83 families with two or more participating subjects. In seven of these families there were two subjects with a detected adenoma (three families in group A and four in group B). In group A, there was no significant difference in adenoma detection rate between individuals with either a parent or a sibling affected with CRC.

Table 1

Detection rate of adenomas and adenomas with advanced pathology (AAPs)

In group B, the age at diagnosis of CRC in the affected FDR was associated with the detection rate of adenomas. The higher the age of the FDR with CRC, the more adenomas were detected in the asymptomatic relatives (table 1).

Discussion

The current study demonstrates that the detection rate of adenomas including AAPs in FCC is substantially higher than the detection rate reported for the general population. Most adenomas were located in the distal part of the colon. The adenoma detection rate was significantly higher in men compared with women. The detection rate was also higher in participants with two FDRs with CRC compared with those with one FDR with CRC at <50 years, although the difference was not significant.

Various studies have reported the prevalence of adenomas in subjects at risk for FCC (table 2).5–10 However, most studies comprised only small series of patients or were retrospective. The reported detection rates of adenomas varied from 13.5% to 32.8% of patients and the detection rate of AAPs varied from 4.0% to 10.8%, which is similar to that observed in our study. In all studies including the present study, the adenoma detection rate was higher in individuals with two FDRs with CRC compared with individuals with one FDR with CRC at age <50 years.

Table 2

Prevalence of adenomas and adenomas with advanced pathology (AAPs) in familial colorectal cancer

The strengths of the current study are the prospective design, the well-defined study group, the clearly circumscribed age limits and the relatively large cohort. A possible weakness of the study is that the colonoscopies were performed in >100 hospitals spread throughout The Netherlands. However, all colonoscopies were performed by experienced specialists. In all patients (6%) with an incomplete colonoscopy (caecum not visualised), a barium enema was performed. Another possible weakness is the fact that the MSI status of the early onset (<50 years) CRCs diagnosed in the FDRs was not evaluated in most cases. As a consequence, a few participants might have Lynch syndrome which might have influenced the prevalence of adenomas in this subgroup of families. However, since the detection rate of a pathogenic mutation in patients with CRC when aged <50 years is only 6%11 and because the adenoma detection rate in Lynch syndrome patients is ∼13%,12 we do not believe that our findings would be significantly affected by inclusion of a few Lynch syndrome patients.

An important question is whether the adenoma detection rate in FCC is higher compared with the detection rate in the general population. In table 3 the studies that evaluated the prevalence of adenomas in the general population are summarised.7 13–18 Although, the study groups varied with respect to age, sex distribution or selection criteria, the overall detection rate of adenomas and AAPs in the general population was approximately half the detection rate in subjects at risk for FCC.

Table 3

Prevalence of adenomas in the general population

Evaluation of possible risk factors showed that the adenoma detection rate was higher in men compared with women. This gender difference has also been reported in the general population as well as in Lynch syndrome.15 19 In group A, we found no difference in the yield of colonoscopies with respect to whether a sibling or parent was affected.

In group B we found that the adenoma detection rate was higher in those relatives with one or two FDRs diagnosed with CRC aged ≥70 years compared with those with two FDRs with CRC both diagnosed at <70 years. This emphasises the need for surveillance in subjects with two FDRs with CRC, also when the tumours are diagnosed at an advanced age.

The outcome of the present study confirms the effectiveness of surveillance in FCC. For that reason, it is extremely important to identify these families in the population. In a previous Dutch study among 4000 individuals aged between 45 and 65 years, 2% had a strong family history compatible with an RR of CRC of 4–6. Based on this observation, we calculated that we have 100 000 people in The Netherlands that fulfil the criteria for being at risk for FCC.20 Our experience that it was rather difficult to recruit participants for the present study suggests that many of them are still undetected. More efforts should therefore be made to improve identification of families with FCC.21

References

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Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Leiden University Medical Center and all local hospitals involved.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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