Fecal Hemoglobin and Severity of Colorectal Neoplasia
Fecal Hemoglobin and Severity of Colorectal Neoplasia
Wide distribution of the f-Hb of FIT-positive participants existed, with considerable overlap between different clinical outcomes. Thus, a single f-Hb measurement on a sample from an individual might not be a reliable indicator of stage of neoplasia. However, there was statistical evidence of a relationship between increasing f-Hb concentration and stage of colorectal neoplasia. In addition to a significantly higher median f-Hb concentration in participants with any neoplasia detected compared with those with no or non-neoplastic pathology, increasing f-Hb concentration is related to the severity of the lesion among those with neoplasia detected.
Median f-Hb concentration was statistically significantly higher in HRA compared with LRA. Furthermore, median f-Hb in LRA was perhaps surprisingly low in comparison with those with no neoplasia detected, lower than in those with HPP (although not statistically significant). Indeed, relatively low concentrations of f-Hb in non-advanced adenomas have been documented with most having f-Hb under 75 ng Hb/ml. The higher median f-Hb seen with a large adenoma compared with a small adenoma, but not seen when comparing those who had ≥3 adenomas with only one or two adenomas detected, demonstrates that the difference between the HRA and LRA group can be attributed to lesion size. Indeed, the median maximum dimension of HRA was over double that of LRA and significantly greater (p<0.0001).
Further, the group with an adenoma displaying HGD had a significantly higher median f-Hb than with LGD. This may indicate that the severity of the dysplastic change can reflect propensity of the lesion to bleed. However, multivariate analysis showed no significant difference between HGD and LGD adenomas when size was taken into account. Thus, the grade of dysplasia and f-Hb was primarily related to adenoma size. Adenomas displaying HGD were significantly larger than those with LGD, and with 27.2% of participants with larger adenomas also displaying HGD compared with 7.5% in those with smaller lesions, increasing f-Hb is associated with larger lesions which, in turn, are more likely to display more severe dysplasia.
FIT are possibly less effective at detecting lesions located in the proximal colon than distally. Here, 77.8% of adenomas and 69.2% of cancers were located in the distal colon. Levi et al have also shown that f-Hb was similar between participants with advanced adenomas in the proximal and distal colon. Despite distal adenomas being significantly larger than proximal and median f-Hb appearing to be higher in those with distal adenomas, our findings confirm that this difference is not statistically significant (p=0.08). Moreover, our results confirm the findings of Ciatto et al that a relationship exists among increased f-Hb and increasing size, severe dysplasia, villousness and location in the left colon.
Although the median f-Hb in those with cancer was not statistically significantly different to those with HRA, they had a higher proportion with f-Hb above the cut-off f-Hb, with 74.4% with cancer having an f-Hb concentration greater than 1000 ng Hb/ml, compared with 58.4% with HRA, providing further evidence of a potential continuum of risk with increasing f-Hb. In addition, 90% of cancers with f-Hb within the analytical range (<1000 ng Hb/ml) were early stage and 40% of these were polyp cancers as compared with 53.8% of early stage cancers above the upper analytical limit.
Non-neoplastic pathology, particularly diverticular disease, was not associated with f-Hb significantly different from those where no pathology was detected. This is an important observation since it indicates that false positive results arising from benign disease are likely to be no more common than false positive results when no abnormality is found on colonoscopy.
This study has limitations. First, the distributions of f-Hb could not be fully assessed since the upper analytical limit was 1000 ng Hb/ml. Of the 813 examined here, 393 had an f-Hb>1000 ng/ml: quantitative f-Hb was not recorded for 48.3% of participants. Perhaps those who had large cancers had f-Hb far higher than 1000 ng Hb/ml. This might explain the lack of a statistically significant difference in f-Hb between cancer and HRA, despite the malignant lesions being significantly larger. Second, only participants with a positive result were referred for colonoscopy. Analysis of the relationship between f-Hb and disease could only be carried out on those with an f-Hb concentration above the cut-off. False negative f-Hb has not been taken into account. However, we plan to investigate this by identifying interval cancers.
A major strength of this study is that we have detailed the relationship between f-Hb and severity of disease in an average-risk, population. These findings, from ostensibly healthy, asymptomatic individuals, have potential implications for future selection of optimum cut-off f-Hb in bowel cancer screening, particularly where colonoscopy capacity is limited. With the aim of screening being to detect cancer and its precursors, our results reinforce the argument for the use of quantitative FIT with an adjustable cut-off concentration through confirming that cancer and HRA arise in lesions that are larger and more prone to bleed, the very lesions screening aims to detect.
Discussion
Wide distribution of the f-Hb of FIT-positive participants existed, with considerable overlap between different clinical outcomes. Thus, a single f-Hb measurement on a sample from an individual might not be a reliable indicator of stage of neoplasia. However, there was statistical evidence of a relationship between increasing f-Hb concentration and stage of colorectal neoplasia. In addition to a significantly higher median f-Hb concentration in participants with any neoplasia detected compared with those with no or non-neoplastic pathology, increasing f-Hb concentration is related to the severity of the lesion among those with neoplasia detected.
Median f-Hb concentration was statistically significantly higher in HRA compared with LRA. Furthermore, median f-Hb in LRA was perhaps surprisingly low in comparison with those with no neoplasia detected, lower than in those with HPP (although not statistically significant). Indeed, relatively low concentrations of f-Hb in non-advanced adenomas have been documented with most having f-Hb under 75 ng Hb/ml. The higher median f-Hb seen with a large adenoma compared with a small adenoma, but not seen when comparing those who had ≥3 adenomas with only one or two adenomas detected, demonstrates that the difference between the HRA and LRA group can be attributed to lesion size. Indeed, the median maximum dimension of HRA was over double that of LRA and significantly greater (p<0.0001).
Further, the group with an adenoma displaying HGD had a significantly higher median f-Hb than with LGD. This may indicate that the severity of the dysplastic change can reflect propensity of the lesion to bleed. However, multivariate analysis showed no significant difference between HGD and LGD adenomas when size was taken into account. Thus, the grade of dysplasia and f-Hb was primarily related to adenoma size. Adenomas displaying HGD were significantly larger than those with LGD, and with 27.2% of participants with larger adenomas also displaying HGD compared with 7.5% in those with smaller lesions, increasing f-Hb is associated with larger lesions which, in turn, are more likely to display more severe dysplasia.
FIT are possibly less effective at detecting lesions located in the proximal colon than distally. Here, 77.8% of adenomas and 69.2% of cancers were located in the distal colon. Levi et al have also shown that f-Hb was similar between participants with advanced adenomas in the proximal and distal colon. Despite distal adenomas being significantly larger than proximal and median f-Hb appearing to be higher in those with distal adenomas, our findings confirm that this difference is not statistically significant (p=0.08). Moreover, our results confirm the findings of Ciatto et al that a relationship exists among increased f-Hb and increasing size, severe dysplasia, villousness and location in the left colon.
Although the median f-Hb in those with cancer was not statistically significantly different to those with HRA, they had a higher proportion with f-Hb above the cut-off f-Hb, with 74.4% with cancer having an f-Hb concentration greater than 1000 ng Hb/ml, compared with 58.4% with HRA, providing further evidence of a potential continuum of risk with increasing f-Hb. In addition, 90% of cancers with f-Hb within the analytical range (<1000 ng Hb/ml) were early stage and 40% of these were polyp cancers as compared with 53.8% of early stage cancers above the upper analytical limit.
Non-neoplastic pathology, particularly diverticular disease, was not associated with f-Hb significantly different from those where no pathology was detected. This is an important observation since it indicates that false positive results arising from benign disease are likely to be no more common than false positive results when no abnormality is found on colonoscopy.
This study has limitations. First, the distributions of f-Hb could not be fully assessed since the upper analytical limit was 1000 ng Hb/ml. Of the 813 examined here, 393 had an f-Hb>1000 ng/ml: quantitative f-Hb was not recorded for 48.3% of participants. Perhaps those who had large cancers had f-Hb far higher than 1000 ng Hb/ml. This might explain the lack of a statistically significant difference in f-Hb between cancer and HRA, despite the malignant lesions being significantly larger. Second, only participants with a positive result were referred for colonoscopy. Analysis of the relationship between f-Hb and disease could only be carried out on those with an f-Hb concentration above the cut-off. False negative f-Hb has not been taken into account. However, we plan to investigate this by identifying interval cancers.
A major strength of this study is that we have detailed the relationship between f-Hb and severity of disease in an average-risk, population. These findings, from ostensibly healthy, asymptomatic individuals, have potential implications for future selection of optimum cut-off f-Hb in bowel cancer screening, particularly where colonoscopy capacity is limited. With the aim of screening being to detect cancer and its precursors, our results reinforce the argument for the use of quantitative FIT with an adjustable cut-off concentration through confirming that cancer and HRA arise in lesions that are larger and more prone to bleed, the very lesions screening aims to detect.
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