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Published: October 2011Print Record of Viewing
Colorectal cancer is the third most common cancer in the United States and accounts for 9% of cancer deaths. Most colorectal cancers originate from adenomatous polyps as a precursor lesion. Early detection is essential to a positive outcome. Drs. Saenger and Ahlquist describe a new immunochemical assay for the testing of fecal occult blood, which can lead to earlier detection of colorectal cancer. They address this and other fecal blood tests in the context of appropriate clinical utilization.
Presenters: David A. Ahlquist, MD
Presenters: Amy K. Saenger, PhD
Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.
Our presenters for this program are David A. Ahlquist, MD, Professor of Medicine and Consultant in Gastroenterology at Mayo Clinic in Rochester, Minnesota and Amy K. Saenger, PhD, Assistant Professor of Laboratory Medicine and Pathology and Director of Cardiovascular Laboratory Medicine in the Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minnesota. Dr. Ahlquist and Dr. Saenger will describe a new approach to the detection of fecal occult blood. They will discuss the appropriate use of a new immunochemical assay and other fecal blood tests for current practice.
After viewing the Hot Topic, we invite you to participate in Beyond Hot Topic. This question and answer session will be posted online approximately 1 month after the Hot Topic presentation is posted. You can submit a question for Dr. Thorland or Karen at the end of the presentation. Alternatively, you can submit a question by selecting the Beyond Hot Topic link on the Hot Topic page. Thank you, Dr. Saenger and Dr. Ahlquist.
Let’s start with some basic concepts. By definition, occult GI bleeding is hidden or unseen. It may be surprising…but we all lose blood through our GI tract daily, as is shown in this plot of the distribution of fecal blood levels quantified by HemoQuant on specimens from 1000 consecutive asymptomatic Mayo Clinic patients. As you can see, occult bleeding is not present or absent….but rather occurs along a continuum from normal physiologic bleeding to abnormal bleeding. This “physiologic” blood loss averages less than 2mL/day. Levels above a 2mL/day threshold occur in 5% and are considered abnormal. If blood loss chronically exceeds 5mL/day, iron deficiency ensues. So, at what level does bleeding become visible or overt?
The answer is that it depends. It depends on both the anatomic source and rate of bleeding. Large amounts of blood can be lost from upper GI sites and remain occult. Based on a number of observational studies with quantitative fecal blood tests, it takes more than 200mL/day for gastric bleeding to be uniformly overt, 150 mL/day from the cecum, 5-30 from the rectosigmoid, and just trace amounts from the anal canal (such as can commonly occur with hemorrhoids). So, bleeding rates can far exceed that required to produce iron deficiency and yet remain occult.
Because occult blood is not visible….a stool blood test is required to detect it. There are essentially 3 types of fecal occult blood tests, and it is important to understand how they differ. Guaiac tests (like Hemoccult) develop a blue color in the presence of heme or other peroxidase-like or oxidizing compounds. It is a nonspecific reaction that can be influenced by a number of foods and medications. The fecal immunochemical test (often referred to as FIT) specifically detects the globin portion of human hemoglobin, and is less affected by diet or medications. However, globin is rapidly digested in the upper GI tract which compromises the use of FIT for global detection of occult bleeding. Porphyrin-based tests (like HemoQuant) target both heme and heme-derived porphyrins, are not affected by anatomic site of bleeding, and are quantitative. In contrast, both other types of tests are insensitive for upper GI bleeding because of analyte digestion. For all 3 types of tests, performance in the laboratory is recommended, and I will elaborate further on this point. While the laboratory costs and test pricing vary, Medicare reimburses each at the same $22 rate. Typically, results from both Guaiac and FIT tests are available either the same or next day; HemoQuant results are usually reported the following day.
So why detect occult GI bleeding? Well, there are 2 clear indications….first, iron deficiency or anemia and, second, colorectal cancer screening. Let’s briefly address each indication.
Iron deficiency can be caused by an iron-poor diet, malabsorption, non-GI blood loss (which is almost always overt and clinically apparent, such as by menstruation), and GI bleeding (usually chronic occult bleeding). Note that at all age ranges, GI bleeding is a common culprit…in men and postmenopausal women, GI bleeding is overwhelmingly the most common mechanism.
Based on aggregate data from recent reports, the majority of pathologic occult GI bleeding arises from the upper GI tract….nearly twice as often as from the lower GI tract. Any lesion that involves vascular disruption can bleed, and the potential specific causes of occult bleeding are legion. By general category, these can be inflammatory (the most common cause of iron deficiency anemia in adults is peptic ulcer or erosive disease), traumatic (which may account for up to 10% of iron deficiency in older adults, primarily from large hiatal hernias). The picture here shows linear erosions caused by respiratory or diaphragmatic trauma within a hiatal hernia, vascular (there are many types of vascular malformations, and they are often multiple), and finally, neoplastic (cancers invade mucosal vessels and cause bleeding, such as might occur with this colorectal cancer shown in the image).
As mentioned earlier, detection of upper GI bleeding differs dramatically by type of fecal blood test used. Based on recovery of ingested blood (simulating upper GI bleeding), only the HemoQuant test proves to be reliable. With simulated bleeding rates of over 15 mL/day (3 times the amount required to produce iron deficiency or anemia), FIT remains negative. In contrast, HemoQuant detected 100% of that level of bleeding. Based on correlation with HemoQuant tests in patients, >150 mL blood/day is required for upper GI bleeding to be reliably detected by the FIT test. As upper GI bleeding is the most common cause of iron deficiency, it is especially important that the tool used is capable of sensitive detection of upper GI bleeding.
So, for iron deficiency or anemia, which test is the logical choice? Because of its performance characteristics (particularly its ability to detect bleeding throughout the GI tract), the answer is the HemoQuant test. Use of other tests for this clinical indication can yield misleading data, especially through false-negative results.
Let’s move to the indication of colorectal cancer screening, and first consider the target lesions. These ideally include curable stage cancer as shown here, advanced adenomas (this is usually referring to precursor lesions larger than or equal to 1cm and most likely to progress), and….as is increasingly apparent….serrated polyps. Serrated polyps are precursors to roughly 30% of colorectal cancers, typically right-sided, aggressive in their behavior (with perhaps a more rapid growth and progression rate than adenomas), and inconspicuous on colonoscopy. This is a picture of a serrated polyp. One can hardly see this flat, flesh-colored lesion. That is it. To treat these lesions safely, it often requires a submucosal injection of saline before they are removed by incision. Importantly, these lesions have often been ignored in screening trials, and while there are no data reported on their bleeding rates, given their morphology, it is unlikely that they will be detected by fecal blood testing.
Colorectal cancers do bleed…but bleeding is often intermittent and, at times, absent. In a study we conducted on 10 patients with colorectal cancer in whom fecal blood levels were quantified by HemoQuant and also tested by Hemoccult over a 2 week intensive collection period, this point is illustrated. Fecal blood levels commonly fell within the normal range of <2mL/day as shown in the blue shaded area, and Hemoccult was positive in only 3 patients. The positive patients were the green circles, the negative were the blue circles. In patients with hemorrhagic cancers, high fecal blood levels may be expected as shown here….but, in those with normal levels, small nonhemorrhagic tumors are more likely. An important take home point is that occult blood, however well measured, is an imperfect and inconsistent marker for colorectal neoplasia.
In the screening setting when fecal blood tests are compared against colonoscopy as the gold standard, both FIT and sensitive guaiac tests (such as HemoccultSENSA) do moderately well in detecting colorectal cancers. Detection rates can exceed 60%. However, the standard Hemoccult test detects cancer at much lower rates. It is important to emphasize that the FIT test achieved this sensitivity with just a single test per screen whereas the guaiac test did so with 3 tests per screen. All tests perform poorly in detecting advanced adenomas, which typically do not bleed, with sensitivities of 20% or less. Early stage cancer detection can reduce cancer mortality, but it requires detection of precancers in order to prevent cancer or reduce cancer incidence.
To underscore this point, a meta-analysis of the 4 randomized controlled trials with Hemoccult screening showed only a modest reduction in cancer mortality (about 14% overall over 12 to 18 years) but no effect on cancer incidence. This collective finding would be consistent with a test that detects some early stage cancers but few precancers. Health care providers and their patients who choose to use fecal blood testing as an approach to colorectal cancer screening should be mindful of these reported outcomes.
Fecal blood tests, whether by FIT or guaiac, are also less sensitive for detection of right-sided colorectal neoplasms with sensitivities only about half that seen for left-sided neoplasms. This reflects the degradation of the analytes (both globin and heme) that occurs with bacterial digestion during colon transit.
An issue that has come up historically regards use of digital rectal exam for clinical diagnosis or screening. Based on results from multiple studies, this practice is now discouraged by professional societies and in national screening guidelines. In one such study, Hemoccult testing from a single digital rectal exam was compared to 3 stools tested in the laboratory. As shown, digital rectal exam detected only 5%, which was about the same rate as over all false-positivity rate versus nearly 30% by laboratory testing. Furthermore, quality is difficult to control in the office setting due to monitoring of outdated kits, wide variation in interpretation of results, and inconsistent documentation that fecal blood test was checked. So, one could argue that digital rectal examination as an approach to fecal blood testing has little value.
We recently completed a simple comparison of a quantitative and a qualitative FIT test. The former is semi-automated and is objectively reported as a number and the later reported subjectively by presence of a colored band on the immuno-strip.
Among the more than 750 asymptomatic adults aged 50-85 with normal colonoscopy in this study, specificity proved to be higher with the quantitative FIT test which was endorsed for clinical use at Mayo Clinic. Note the false-positive rate was twice as high with the qualitative FIT test.
So, let’s compare fecal blood test features for the application of colorectal cancer screening. Both sensitive guaiac and FIT tests achieve moderate sensitivity for cancer of >60% but FIT does so, as I mentioned previously, with a single test per patient screen. No test detected advanced adenomas well. FIT generally yields not only the highest sensitivity, but the highest specificities, and uniquely requires no diet or medication restriction. Finally, because of its numerical reporting, the result comes out objectively. Because HemoQuant detects upper GI bleeding so well, it yields lower specificity for colorectal cancer screening and is not recommended for this application.
Current colorectal cancer screening guidelines discourages use of standard guaiac testing. For those choosing to use fecal blood tests, they recommend either sensitive guaiac or FIT and at an annual frequency. Fecal blood tests are approved for early detection of colorectal cancer and not for prevention (as precursor lesions are not adequately detected).
So, which test for colorectal cancer screening? Based on the performance data and user-friendly features, the FIT test seems to be most suitable.
There are other potential or “soft” indications for use of fecal blood testing, but these are not supported by evidence and have not been addressed in formal guidelines. For example, what about the value of fecal blood testing in patients with dark stools? The most important action in such circumstances is to assess the hematologic and hemodynamic status and let these parameters direct management decisions. Guaiac testing can be misleading, as causes other than bleeding (such as iron ingestion) can lead to both black stools and positive guaiac reactions. Furthermore, reducing agents (like vitamin C) can cause false negatives in face of elevated blood levels. Fecal blood testing may be reasonable if the patient is stable and a lab-based test, such as HemoQuant, would be best choice. In those with GI symptoms, some have advocated that use of fecal blood testing will help identify those with organic etiologies. However, studies addressing this application have shown that the positive predictive value is minimally affected and this practice has generally not been advised.
In summary, clear indications for fecal blood testing include iron deficiency or anemia and colorectal cancer screening. For the indication of iron deficiency anemia, the HemoQuant test would be the procedure of choice. For colorectal cancer screening, it is our impression at the Mayo Clinic that the FIT test would be most suitable. It should be remembered that there are limitations of fecal blood testing with colorectal cancer screening and these should be understood, especially the poor detection of precursor lesions. Office use of fecal blood tests via digital rectal examination is of questionable value and should be discouraged. And now, my colleague, Dr. Saenger will discuss fecal blood tests and their availability through Mayo Medical Laboratories.
The tests available for fecal occult blood testing through Mayo Medical Laboratories include test #60693 which is the Immunochemical Fecal Occult Blood test or FIT. A random stool sample which can be collected with the fecal occult blood test kit listed here, supply number T682. It is important that specimens are shipped refrigerate. This test is performed quantitatively but will be reported with a qualitative result. Another fecal occult blood test available is test #9220, the HemoQuant assay, which is useful for detection of occult blood in situations of suspected iron deficiency or anemia. In this case, we ask that patients refrain from meat and aspirin 3 days prior to the collection of the specimen. This is a random feces collection. It should be collected with the kit listed here, supply number T134. It is important that specimens are shipped frozen.