Gastrointestinal Malignancy in Iron Deficiency Anemia
IDA is a problem that is commonly encountered in current clinical practice. Our recent experience would suggest an increasing overall incidence that now approaches one case diagnosed per 1000 population per annum. The age-specific incidence of IDA in the elderly is considerably higher than this, and it is noteworthy that the median age of the study population was 75 years. This may of course reflect enhanced ascertainment due to the escalating number of requests for routine blood count estimations, particularly in the elderly.
Several mechanisms underlie the development of IDA, but the major categories are dietary insufficiency, malabsorption, and chronic low-grade haemorrhage from a mucosal surface. IDA in premenopausal women most commonly relates to dietary inadequacy and/or menstrual losses. About 30% of men and postmenopausal women, however, will prove to have significant underlying GI pathology, with malignancy accounting for about a third of these, often in the absence of clear clinical pointers to the diagnosis. Malignancy is undoubtedly the most important cause, and indeed it is the primary justification for the urgent investigation of subjects with IDA.
Bidirectional endoscopy (BDE), combining gastroscopy and colonoscopy in the same session, is generally accepted as the most efficient method of assessing the GI tract in IDA unless there are clear clinical clues as to the cause. BDE is labour-intensive, however, taking up to one hour to complete for each patient. Furthermore, endoscopy carries a small but significant risk of complications, particularly in the elderly and those with major comorbidities.
Given that over 90% of endoscopic examinations in individuals with IDA will fail to reveal a GI malignancy, it is obviously important to consider the risk-benefit ratio for investigation of IDA on an individual case basis. There is, therefore, a need for a simple and reliable pretest predictor of the risk of underlying malignancy that is sufficiently discriminating to be clinically (and not just statistically) significant.
To the authors' knowledge, there are only three published multivariate analyses of variables predictive of the risk of GI malignancy in IDA to date. The findings are summarised in Table 4, along with those of the current study for comparison. There is universal agreement that age is a risk factor, but the findings for the other variables are somewhat discordant. However, two of the studies had a rather small sample size, and it is notable that the two largest studies are fully concordant for all five risk factors assessed. The findings from this current study confirm the results from the Nottingham study, identifying age, sex and Hb as independent variables predictive of underlying GI malignancy in IDA. This conclusion fits well with the findings of a large study using electronic primary care records employing a case-control methodology, which correlated age and degree of anaemia with colorectal cancer risk.
The predictive value of age and sex is not unexpected, given that the incidence of the major GI malignancies rises steeply after the age of 70 years, particularly in males. It may simply be that Hb is predictive of cancer risk because the nature of the pathology means that GI malignancy is disproportionately more likely than the other (non-malignant) causes of IDA to lead to greater degrees of anaemia. Why this is not reflected by the results of iron studies is less clear, though of course ferritin and transferrin saturation are surrogate markers of body iron stores, and may be influenced by other factors—serum ferritin, in particular, is an acute-phase protein, and may therefore be spuriously high in individuals with malignancy.
Given an overall probability of underlying GI malignancy of 10%, it was arbitrarily considered that identifying a low-risk subgroup with a cancer risk of less than 2%, and a high-risk subgroup with a cancer risk of greater than 20%, might be useful in clinical practice. The results suggest that over a quarter of subjects with IDA can be predicted to be of extremely low or high risk on the basis of these simple and objective clinical criteria. This may be of clinical relevance for patient counselling and prioritisation of investigations. It might also inform the decision as to whether to submit patients at extreme low risk to an invasive investigational strategy, though rigorous validation of the study results is essential before such a move can be contemplated.
The findings are unlikely to be the result of referral bias. Younger women with mild anaemia are probably the subgroup least likely to be referred unless there was some other reason for suspecting GI disease, for example, a positive family history of GI cancer. This might have been expected to result in a falsely high prevalence of GI malignancy in this subgroup, yet in the event the figure was 0%.
The study presented was retrospective and exploratory, carrying the inevitable issues associated with multiple significance testing. The limitations of multivariate analysis are also well established. Further work is clearly required to validate prospectively the predictive value of the risk factors identified, and this is underway. The results to date represent a first cut, using simple clinical information available from our IDA register. It is possible that additional clinical or laboratory variables could be added to improve the discriminatory capacity of the model still further—for example, a family history of GI malignancy, the use of aspirin, or faecal occult blood testing—and this avenue is also being explored.
In conclusion, this study has extended previous observations, confirming that sex, age and Hb are strong and independent predictors of the risk of underlying GI malignancy in subjects with IDA. It has also demonstrated that, in combination, these variables can identify over 25% of the study population who are at particularly high or low risk. The incremental nature of the model lends itself to the development of a simple scoring system for malignancy risk stratification that could be of practical value in a clinical setting.
Discussion
IDA is a problem that is commonly encountered in current clinical practice. Our recent experience would suggest an increasing overall incidence that now approaches one case diagnosed per 1000 population per annum. The age-specific incidence of IDA in the elderly is considerably higher than this, and it is noteworthy that the median age of the study population was 75 years. This may of course reflect enhanced ascertainment due to the escalating number of requests for routine blood count estimations, particularly in the elderly.
Several mechanisms underlie the development of IDA, but the major categories are dietary insufficiency, malabsorption, and chronic low-grade haemorrhage from a mucosal surface. IDA in premenopausal women most commonly relates to dietary inadequacy and/or menstrual losses. About 30% of men and postmenopausal women, however, will prove to have significant underlying GI pathology, with malignancy accounting for about a third of these, often in the absence of clear clinical pointers to the diagnosis. Malignancy is undoubtedly the most important cause, and indeed it is the primary justification for the urgent investigation of subjects with IDA.
Bidirectional endoscopy (BDE), combining gastroscopy and colonoscopy in the same session, is generally accepted as the most efficient method of assessing the GI tract in IDA unless there are clear clinical clues as to the cause. BDE is labour-intensive, however, taking up to one hour to complete for each patient. Furthermore, endoscopy carries a small but significant risk of complications, particularly in the elderly and those with major comorbidities.
Given that over 90% of endoscopic examinations in individuals with IDA will fail to reveal a GI malignancy, it is obviously important to consider the risk-benefit ratio for investigation of IDA on an individual case basis. There is, therefore, a need for a simple and reliable pretest predictor of the risk of underlying malignancy that is sufficiently discriminating to be clinically (and not just statistically) significant.
To the authors' knowledge, there are only three published multivariate analyses of variables predictive of the risk of GI malignancy in IDA to date. The findings are summarised in Table 4, along with those of the current study for comparison. There is universal agreement that age is a risk factor, but the findings for the other variables are somewhat discordant. However, two of the studies had a rather small sample size, and it is notable that the two largest studies are fully concordant for all five risk factors assessed. The findings from this current study confirm the results from the Nottingham study, identifying age, sex and Hb as independent variables predictive of underlying GI malignancy in IDA. This conclusion fits well with the findings of a large study using electronic primary care records employing a case-control methodology, which correlated age and degree of anaemia with colorectal cancer risk.
The predictive value of age and sex is not unexpected, given that the incidence of the major GI malignancies rises steeply after the age of 70 years, particularly in males. It may simply be that Hb is predictive of cancer risk because the nature of the pathology means that GI malignancy is disproportionately more likely than the other (non-malignant) causes of IDA to lead to greater degrees of anaemia. Why this is not reflected by the results of iron studies is less clear, though of course ferritin and transferrin saturation are surrogate markers of body iron stores, and may be influenced by other factors—serum ferritin, in particular, is an acute-phase protein, and may therefore be spuriously high in individuals with malignancy.
Given an overall probability of underlying GI malignancy of 10%, it was arbitrarily considered that identifying a low-risk subgroup with a cancer risk of less than 2%, and a high-risk subgroup with a cancer risk of greater than 20%, might be useful in clinical practice. The results suggest that over a quarter of subjects with IDA can be predicted to be of extremely low or high risk on the basis of these simple and objective clinical criteria. This may be of clinical relevance for patient counselling and prioritisation of investigations. It might also inform the decision as to whether to submit patients at extreme low risk to an invasive investigational strategy, though rigorous validation of the study results is essential before such a move can be contemplated.
The findings are unlikely to be the result of referral bias. Younger women with mild anaemia are probably the subgroup least likely to be referred unless there was some other reason for suspecting GI disease, for example, a positive family history of GI cancer. This might have been expected to result in a falsely high prevalence of GI malignancy in this subgroup, yet in the event the figure was 0%.
The study presented was retrospective and exploratory, carrying the inevitable issues associated with multiple significance testing. The limitations of multivariate analysis are also well established. Further work is clearly required to validate prospectively the predictive value of the risk factors identified, and this is underway. The results to date represent a first cut, using simple clinical information available from our IDA register. It is possible that additional clinical or laboratory variables could be added to improve the discriminatory capacity of the model still further—for example, a family history of GI malignancy, the use of aspirin, or faecal occult blood testing—and this avenue is also being explored.
In conclusion, this study has extended previous observations, confirming that sex, age and Hb are strong and independent predictors of the risk of underlying GI malignancy in subjects with IDA. It has also demonstrated that, in combination, these variables can identify over 25% of the study population who are at particularly high or low risk. The incremental nature of the model lends itself to the development of a simple scoring system for malignancy risk stratification that could be of practical value in a clinical setting.
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