Predicting Outcome in Colonoscopic High-Risk Surveillance

Research Article

Austin J Gastroenterol. 2015;2(3): 1041.

Predicting Outcome in Colonoscopic High-Risk Surveillance

Anna M Forsberg1*, Eva Hagel4, Edgar Jaramillo2, Carlos A Rubio3, Erik Bjorck1 and Annika Lindblom1

1Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden

2Department of Medicine, Karolinska Institutet, Sweden

3Department of Oncology Pathology, Karolinska Institutet, Sweden

4Department of Medical Statistics Unit, Learning, Informatics, Management and Ethics, Karolinska Institutet, Sweden

*Corresponding author: Anna M Forsberg, Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden

Received: October 22, 2014; Accepted: March 03, 2015; Published: March 09, 2015


Objective: Surveillance with colonoscopy in risk groups for colorectal cancer needs to be based on adequate selection of individuals to examine and a well-devised timing. To stratify the risk of finding neoplasia at colonoscopy a cohort with increased familial risk of colorectal cancer was studied.

Design: Based on family history, 1203 individuals with an at least twofold increased risk of colorectal cancer were offered regular colonoscopies. The impact of different variables in the family history was assessed by logistic regression for the prevalence of adenomas and advanced adenomas.Findings at the first colonoscopy were assessed regarding the association with risk of future lesions.

Results: The prevalence of advanced lesions, when controlling for age, was associated with the number of first-degree relatives with colorectal cancer, with an age below 50 in the youngest family-member with colorectal cancer, but not with gender. Family history had a low impact on the prevalence of simple adenomas. The risk of future advanced lesions was only associated with the prevalence of advanced lesions at the screening colonoscopy, whereas a finding of subsequent adenomas was associated with advanced lesions, adenomas and hyper plastic polyps.

Conclusion: Adenomas and advanced lesions were not associated with the same risk factors. In this study the most important risk factors for advanced lesions, including cancer, were the number of first-degree relatives and a young family member with colorectal cancer. Findings of simple adenomas and hyper plastic polyps did not seem to be associated with subsequent advanced lesions.

Keywords: Colorectal cancer; Family history; Colonoscopy; Surveillance; Risk stratification


Ad: Adenomas; AAd: Advanced Adenomas; CRC: Colo Rectal Cancer; HP: Hyper Plastic Polyps; FDR: First-Degree Relatives; SDR: Second-Degree Relatives; TDR: Third-Degree Relatives; MMR: Mismatch-Repair; OR: Odds Ratio; CI: Confidence Interval; N: Number


Colorectal Cancer (CRC) is the third most common cancer worldwide and often a lethal disease [1]. Approximately 25% of all CRC cases occur in individuals with a family history of CRC. A monogenic disorder causing the disease is diagnosed in less than 5% of the cases [2]; the most common are Lynch Syndrome (LS), caused by a mutation in one of the Mismatch-Repair Genes (MMR), and Familial Adenomatous Polyposis (FAP), caused by an APC-gene mutation. Besides having an inherited high-risk mutation, the most important risk factors for CRC are number of First-Degree Relatives (FDR) with CRC and increasing age. Depending on the number of FDR, the relative risk is increased two- to eightfold compare with those without family history [3,4]. In the majority of cases, CRCs arise from adenomas in the adenoma-carcinoma-sequence [5]. Progression from normal colonic mucosa to invasive carcinoma was usually suggested to occur over a period of 4–10 years [6], except in LS where the progression is observed to be faster [7]. Colonoscopic prevention of CRC is feasible by removal of premalignant lesions, adenomas, which has been shown to reduce both incidence and mortality in CRC [8]. Thus, colonoscopy surveillance is recommended in moderate risk groups for CRC [9]. On the other hand, colonoscopy is costly and scarce, and therefore it is important to select individuals suitable for prevention and to have a well-selected timing, regarding both surveillance interval and age at initiation of surveillance. In moderate risk groups, based on different factors in the family history, it would be profitable to identify subgroups that have the highest risk and assign priority of the colonoscopy resources to these.

Besides age and sex, parameters that can be assessed for impact on risk of CRC are the number of First-Degree Relatives (FDR), Second- Degree Relatives (SDR) and Third-Degree Relatives (TDR) with CRC [4,10,11], the kind of FDR relationship (sibling or parent) [3,4], and the age of the youngest affected individual in the family [12]. Development of colorectal adenomas is an important precursor to the subsequent development of CRC, and therefore adenomas could serve as a marker for subsequent CRC [10,13]. Thus, the detection of polyps –regarding multiplicity and adenoma advancement - has been suggested to have an impact on detection of additional lesions during surveillance [14].

We have analyzed the outcome of a 20-years colonoscopy surveillance programme to test predictors of future adenomas and advanced lesions. Based on family history of CRC, 1203 individuals with at least twofold increased risk of CRC were included. Factors taken into account were age; sex; number of FDR, SDR and TDR (cousins) with CRC; kind of FDR (sibling or parent/child); and age of the youngest affected individual in the family.



Since 1990, individuals with an at least twofold increased relative risk of CRC were offered a programme with genetic counselling and surveillance at the Department of Clinical Genetics at the Karolinska University Hospital in Stockholm, Sweden [15]. Data for this study were collected until June 2010. Individuals were included if they had two or more FDR, SDR or cousins (TDR) with CRC, or if they had one FDR with CRC below the age of 50. FAP and LS was excluded according to the current clinical protocol, using family history of CRC or polyposis, microsatellite instability, BRAF-mutation, immunohistochemistry on tumours or MMR gene screening [16]. All individuals were offered screening with an ileocolonoscopy every third year. Patients who had cancer before they entered the surveillance programme were not included in the study. All data were anonymized. The study was approved by the Stockholm regional ethical committee (KI 241/02; 2005/566 - 31/1).

Study protocol

The majority of the colonoscopies were performed in a single centre at Karolinska University Hospital, and the remaining endoscopies were performed elsewhere but reported to the study centre. A standard routine video endoscope was used. The quality of the colonoscopy procedure concerning complete colonoscopies, bowel cleansing and pain control and adenoma detection rate was consistent with European guidelines for quality control of CRC screening [17]. For all polyps’ localization, size and appearance was recorded and all polyps were removed and sent for histological diagnosis. In the vast majority of cases, polyps were removed endoscopically: snared, taken by cold biopsy or coagulated. The size of the polyp was estimated with the use of open-biopsy forceps. Lesions in or proximal to the splenic flexure were assigned as right-sided and those distal to the flexure as left-sided. The adenomas were classified according to the WHOclassification as tubular, tubulo-villous, villous, or serrated adenomas. The dysplasia was graded as High-Grade (HGD) or Low-Grade (LGD). An advanced lesion was defined as either a cancer, or an adenoma with an estimated diameter >10mm, a villous component larger than 20% or high-grade dysplasia. The surveillance period was defined as the time from the first colonoscopy to the last colonoscopy.

A thorough pedigree of each family was constructed, where all FDR, SDR and cousins (TDR) with CRC, as well as the youngest affected individual, were recorded. For FDRs with CRC, it was recorded whether they were siblings or children/parents. By utilizing the curves, constructed by Butterworth et al. [3] of the cumulative absolute risk of developing CRC over 20 years the absolute risk was estimated, taken into account the age of the individual and the number of FDR with CRC. Low age (<50 years) of the index-person was not considered for the absolute risk assessment in this study.

Statistical Methods

Analyses were undertaken using the statistical software programme Statistical (version 10.0), Stat Soft Inc. ©, Tulsa, Oklahoma, USA. A p-value of <0.05 was considered to be statistically significant. Logistic regression with the modelled probability of having an advanced lesion or an adenoma during screening or surveillance was used to determine the impact of different risk factors. Age of the individual, age of the youngest in the pedigree, age of the youngest FDR, sex, number of FDR, SDR and TDR, and the kind of FDR relationship (sibling or parent), were considered. When assessing inheritance only individuals with either parents or siblings, not both, with CRC were analysed. Age at the first lesion (adenoma or advanced lesion) or, when no lesion was detected, the age at the last colonoscopy was employed in the logistic regression analyses.

Multicolinearity and interaction were considered when fitting the models, and this was the reason why a Cox-regression model was not employed. The number of FDR and the sum of the numbers of SDR and TDR were not independent covariates, and therefore two separate models were employed. In validating the multivariate fitted model, the HosmereLemeshow “goodness-of-fit” statistic (HL) was employed. A large p-value (>0.05) indicated that the null hypothesis (lack of fit) could not be rejected, meaning we do not have reason to believe that the model fitted the data on a non-acceptable level. The Student’s t test employed for comparing ages in different subgroups. Incidence of adenomas and advanced lesions at surveillance were analysed by χ2-test, and for the multivariate analysis, a logistic regression model was employed considering age, sex, time in study and prevalence of Hyper plastic Polyps (HP), adenomas and advanced lesions at screening. The estimated number of screening cancers in the cohort was calculated by adding the expected number for each age group extracted from the age and gender specific incidence in the Swedish population [18].


Descriptive data

The study covered 20 years of colonoscopy examinations (January 1990 to June 2010). There were 1203 individuals, 470 (39%) men, from 521 families included in the study. There were 676 (56%) individuals with one FDR, 299 (25%) with two or more FDR and 228 (19%) with only SDR and TDR with CRC. Five hundred seventy one (47%) individuals had a FDR with CRC below age 50. In the total population, the mean age at the first colonoscopy was 51.9 (range 17- 86; SD 11.8) years, and for men it was 51.1 (range 21-86; SD 12.1) years, and for women 52.3 (range 17-84; SD 11.3). In total, 2293 colonoscopies were performed, and 594 (49.4%) individuals had two or more examinations performed. A relatively large cohort was recruited by the end of the study, and therefore 50.6% had only one colonoscopy examination performed. The mean follow-up time for those who participated in surveillance was 55 (SD 32) months.

Colonoscopy findings

There were five individuals (0.4%) with six cancers; four were detected at the screening colonoscopy and two during surveillance. The expected number of screening-cancers in the Swedish population matched for age and gender (18)was calculated to be 0.8 compared to four that were found (p<0.001).

At least one simple adenoma was found in 228 (19%) of the individuals and 94 (8%) had at least one advanced adenoma or cancer as the most advanced lesion. HP was encountered as the most advanced lesion in 208 (17%) persons. In 672 (56%) of the individuals no polyps were recorded.

Risk factors in family history

Table 1 shows data for univariate and bivariate (controlling for age) analyses, and Table 2 shows the multivariate logistic regression analysis for the outcome of having adenomas and advanced lesions during screening or surveillance. Increased age was the strongest risk factor for both adenomas and advanced lesions. A difference was that the risk of adenomas was weakly associated with the sum of SDR and of TDR, while the risk of advanced lesions was associated with the number of FDR. There was also an association with early age at onset in the family (<50 years) with having advanced lesions but not with having adenomas. There was no difference between men and women regarding the risk of adenomas or advanced lesions. Likewise, there was no difference in the risk related to the kind of FDR relationship, except in the univariate analysis for advanced lesions where a strong association for siblings was seen, although this association could not be observed when controlling for age in the bivariate analysis.