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Relative sensitivity of the fecal occult blood test and flexible sigmoidoscopy in detecting polyps
PREVENTIVE
MEDICINE
14, 55-62 (1985)
Relative Sensitivity of the Fecal Occult Blood Test and Flexible Sigmoidoscopy in Detecting Polyps RAYMOND Y. DEMERS, M.D.,M.PH., *,I LAWRENCE E. STAWICK, M.D.,? PAUL DEMERS, B.S.* Departments
of ‘Family Medicine and fInternal 4201 St. Antoine, Detroit,
Medicine, Wayne Michigan 48201
State
AND
University,
A group of 1,002 male pattern and model makers, an occupational group at high risk for colorectal cancers, was screened for the presence of polyps and malignancies of the lower gastrointestinal tract. Flexible sigmoidoscopy and serial fecal occult blood testing were both performed on 988 of the participants, and 165 were found to have at least one colorectal polyp. Only 3% of all men with visualized polyps showed Hemoccult-positive stools. Only 2 (4%) of the 51 men with histologically proven adenomatous polyps were Hemoccult positive. Adenomatous polyps of 1 cm or greater in diameter are malignant 8% of the time. This study concludes that the fecal occult blood test sensitivity in detecting colorectal polyps is unacceptably low. It should be supplemented by more rigorous procedures, especially in populations at high risk for colorectal cancer. 0 1985 Academic Press, Inc.
INTRODUCTION
Concentrated attention has been given to the screening for colon and rectal neoplasia since the landmark study by Greegor in 1967 (2). The preponderance of studies has focused on malignancies, not adenomas, and show the Hemoccult test to be highly sensitive in the detection of cancer (3, 10). However, considerably less is known of its sensitivity in discovering polyps of the colon and rectum. The present study assesses the sensitivity of the Hemoccult slide test in detecting polyps, particularly adenomatous polyps, of the descending colon and rectum. Most, if not all, adenocarcinomas of the colon and rectum begin as or with polyps (8). Specific attention has focused on polyps that are histologically adenomatous. Adenomas exhibit characteristics of true neoplasia and should be considered significant in the evaluation of carcinoma (6). The other major type of polyp, those that are histologically hyperplastic, are of little clinical significance. Visual differentiation between the two types through the sigmoidoscope is of questionable reliability -although hyperplastic polyps rarely achieve a size of greater than 5 mm in diameter, and only 10% of very small polyps (<4 mm) are adenomatous (7). The clinical significance of adenomatous polyps was further reinforced by Gilbertsen, who showed that their removal significantly lowered the incidence of colorectal cancer (1). Winawer et al., comparing findings on rigid sigmoidoscopic exam and stool Hemoccult tests, cited a false-negative rate for adenomas of 76% (24% sensitivity) (14). Herzog et al. studied 44 consecutive patients, all of whom had adenomatous ’ To whom reprint requests should be addressed at the Department of Family Medicine, State University, 4201 St. Antoine, 4-J, Detroit, Mich. 48201.
Wayne
55 0091-7435185 $3.00 Copyright 0 1985 by Academic Press. Inc. All rights of reproduction in any form reserved.
56
DEMERS,
STAWICK,
AND
DEMERS
polyps of at least 1.5 cm in diameter and had been referred for polypectomy (4). Hemoccult sensitivity was found to be 86% in patients with polyps of the descending colon and rectum and 26% in those with lesions of the ascending and transverse colon. Lipshutz et al. found a 16.7% Hemoccult sensitivity in 39 patients with polyps discovered during flexible sigmoidoscopic examination conducted on United States veterans (9). The wide range of sensitivities determined from the latter three studies makes it difficult to draw a meaningful conclusion on this topic. Furthermore, each study has important drawbacks. The study by Herzog contains a major selection bias since subjects were limited to those having prediagnosed large polyps, with 25 of the 44 participants originally diagnosed by their family doctors through a positive Hemoccult test. The studies by Lipshutz and Winawer lack details on histology and size of the polyps, making it difficult to evaluate the significance of the data. Neither of these studies focused primarily on Hemoccult sensitivity, although each contained enough data to calculate the sensitivity of stool Hemoccult testing for polyps. Red cell labeling with 51Cr provides an estimate of the amount of gastrointestinal bleeding required to yield a positive Hemoccult test (10, 13). Sensitivity increases progressively with greater amounts of daily blood loss, achieving 93% with losses of greater than 30 ml. The test seems to be insensitive to less than 2 ml of fecal blood per day. Test sensitivity also seems to increase with polyp size, the critical polyp diameter being approximately 2 cm (10). High sensitivity or low false-negative test rates are important in a screening program. However, clarity is needed in tying sensitivity to a specific phase of disease. The focus of this study is to evaluate the sensitivity of the Hemoccult test in detecting adenomatous polyps. Polyps are visually identified through a 60cm flexible sigmoidoscope. Their presence serves as the reference against which Hemoccult sensitivity is measured. Winawer stated in a recent editorial on the sensitivity of fecal occult blood testing that a “reasonable sensitivity of the fecal occult blood test for the detection of adenomas would make the test a more attractive screening and case-finding technique for colorectal neoplasia” (16). This statement is bolstered by the fact that between 10 and 50% of the adenomatous polyps greater than 1 cm in diameter are malignant. An analysis of sensitivity of the Hemoccult test in detecting adenomas of the distal 60 cm of the colon is possible by performing both Hemoccult testing and flexible sigmoidoscopy on a healthy population. METHODS
Participants were chosen from among the active and retired membership of three local chapters of the Pattern and Model Makers League of North America and active workers from two nonunion pattern making shops. All participation was voluntary and fully endorsed by both the union and shop owners. An orientation session to explain the protocol to participants preceded the examination screening date by approximately 2 weeks. The sessions explained the Hemoccult diet and stressed the importance of complying with it. This diet consisted of avoiding red meats and selected peroxidase-containing fruits and
SENSITIVITY
OF
FECAL
OCCULT
BLOOD
TESTING
57
vegetables, along with a maintenance of high roughage intake, beginning 2 days prior to the first stool collection and continuing until the third stool collection. Participants were asked to begin stool specimen collection 4 days prior to the scheduled exam. They were further advised to avoid all vitamins and aspirin during this time and to keep the stool Hemoccult slides at room temperature until their screening exam. Stool specimens were collected consecutively and samples from two different parts of the stool were applied to the two windows supplied for each collection. The SKD Hemoccult II slide collection kit produced by Smith Kline Diagnostic of Sunnyvale, California, was used. Completed slides were tested when participants entered for screening. The developing solution was added, and after 30 set each slide was examined independently by two observers, a male attendant and a physician, with 99% interobserver agreement. The slides were not hydrated prior to testing. The Hemoccult slide interpretations were blinded from the sigmoidoscopic examination results. Tests showing trace positive or equivocal results were repeated. All nine such repeated tests were negative and these nine participants were normal on sigmoidoscopic examination. Preparation for the sigmoidoscopic examination included two Ducolax tablets the night before the examination, light meals (breakfast and lunch), avoidance of caffeine products during the day of examination, and one, or possibly two, Fleets enemas administered just prior to the sigmoidoscopic procedure. One enema provided adequate bowel cleansing in over 95% of the participants. The average exam lasted slightly over 8 min. Experienced endoscopists performed the flexible sigmoidoscopy exams using an Olympus 60-cm flexible sigmoidoscope. Insertion of the scope to 50 cm or greater was achieved in 78% of the cases and beyond 40 cm in 95%. The size of each polypoid mass was visually assessed by the endoscopists who had performed numerous polypectomies in private practice, and whose visual assessment of polyp size seen through the flexible sigmoidoscope was consistently within 1 mm of error. The endoscopists recorded their visual impressions of polyp type. Photographs of positive or suspicious sigmoidoscopic findings were taken. Comprehensive attempts were made to assure medical follow-up of patients with polyps greater than 5 mm. Participants were advised to follow-up with their personal physicians or to receive direct care from one of the five Board-certified gastroenterologists who received referrals from the program. Attempts were made to facilitate visits directly to gastroenterologists or surgeons who were skilled in colonoscopy and polypectomy. Numerous phone contacts were made to arrange medical follow-up of those with polyps and subsequently to retrieve their medical and histological reports from various hospitals and doctors’ offices. Appropriate consent forms for transfer and release of information were signed. The majority of the histologic/pathologic information was obtained after referral, although some of the small (<5 mm) hyperplastic-appearing polyps were biopsied at the screening site. Diagnoses of malignancy, carcinoma in situ, or adenoma were usually made at hospitals other than the screening hospital. All reported histological interpretations were given by Board-certified, hospital-based M.D. pathologists. Reliability and accuracy of histological material were not as-
58
DEMERS,
STAWICK,
AND DEMERS
certained by other pathologists due to the time and monetary limitations of the screening program. Analysis was performed for all visualized polyps and for those specifically defined by histology since adenomatous polyps were of primary interest to the study. Stool Hemoccult results, medical history, illnesses, medications, and sigmoidoscopic results were recorded. Information on the sigmoidoscopic findings included the distance of the polyp(s) from the anal verge, and other colonic tindings (such as colitis, diverticulae, cancer). Additional recorded information included the patient’s report of compliance with Hemoccult preparatory diet and polyp histology from the follow-up reports. RESULTS
A total of 988 of the 1,002 participants in the screening program completed both the Hemoccult testing and the flexible sigmoidoscopic exam. The participants were all men averaging 42 years of age (standard deviation = 12.23, range = 18 to 70 years of age). At least one colorectal polyp was found in 165 participants, with 38 having multiple polyps. Fifty-one had at least one histologically confirmed adenomatous polyp. Forty-four percent of the polyps were found beyond 20 cm from entry, 18% beyond 30 cm. Twenty-one (2%) of the total study population had at least one positive stool Hemoccult. Only 4 of 36 (11%) participants with polyps greater than or equal to 1 cm in diameter showed Hemoccultpositive tests. Three of the four positive Hemoccult tests occurred with polyps greater than 2 cm in diameter. The prevalence of polyps varied predictably by age from a 5% prevalence in men under 30 years to 29% in men 51 years or older. No perforations or other major complications occurred in any of the participants. Table 1 categorizes the presence or absence of all polyps, regardless of histology, by the Hemoccult test results. As shown, the overall sensitivity of fecal Hemoccult tests in predicting the presence of any colorectal polyps is approximately 3%. This table includes all patients with polyps discovered (visualized) through the flexible sigmoidoscope. Table 2 presents Hemoccult test results for those patients whose pathology TABLE RESULTS
OF FECAL HEMOCCULT POLYPS VISUALIZED
TEST IN PATIENTS DURING FLEXIBLE
1 BY PRESENCE OR ABSENCE OF COLORECTAL SICMOIDOSCOPIC EXAMINATION
Diagnosis of polyps with flexible sigmoidoscope
Hemoccult test results
Polyps present
Polyps absent
Positive” Negative
5 160
14b 807
Total
165
821
Sensitivity = 0.03 Specificity = 0.98 0 At least one of the three hemoccult tests was positive. b Two frank malignancies (cases 10 and 12, Table 3) were not classified in this table.
SENSITIVITY
OF
FECAL
OCCULT TABLE
BLOOD
2
FECAL HEMOCCULT TEST RESULTS FOK PATIENTS WITH PATHOLOGY ADENOMATOUS POLYPS" Hemoccult Size of largest polyph (cm) so.4 0.5-0.9 1.0-1.4 1.5-1.9 32.0 Total
59
TESTING
REPORTS SHOWING
results
All three negative
One or more positive
9 18 10 8 4
0 0 I 0 I
49
2
a Does not include patients with cancer or cancer in situ. b In patients with multiple polyps, only the largest adenomatous polyp patients with one or more histologically proven adenomatous polyps.
is included.
Numbers
reflect
reports were obtained and which showed histologically proven adenomatous colorectal polyps. Patients who did not complete follow-up, including polyp biopsies, or who had proven hyperplastic polyps were omitted from Table 2. Patients whose pathology reports indicated polyps with cancer or cancer in situ rather than adenomatous polyps were also excluded. Twenty-four of the 36 individuals with polyps of 1 cm or greater received polypectomies verifying the polyps as adenomatous. Only two of these large adenomas (8%) were Hemoccult positive. The Hemoccult sensitivity in detecting histologically proven adenomatous polyps of all sizes, based on data shown in Table 2, is 4% (2/51). No individual with a histologically proven adenomatous polyp less than 1 cm in diameter had a Hemoccult-positive stool. Table 3 displays descriptions of patients with positive Hemoccult tests. Fourteen of the 21 individuals with positive results presented explanations that may have resulted in Hemoccult-positive testing. The seven without discernable reasons for Hemoccult positivity were advised to follow-up with their personal physicians. Two of the seven did follow up, but no site of bleeding was discovered. The remaining five refused follow-up. Only one of these 21 admitted to nonconformity with the Hemoccult testing diet. Seven cases of carcinoma or carcinoma in situ of the distal colon were discovered, along with two carcinoid tumors. Five of the malignancies, excluding cases 10 and 12 in Table 3, were classified as polyps in Table 1 since they were initially visually described as polyps at the screening site. Only one of these five, the carcinoma in situ noted in Table 3, was Hemoccult positive. DISCUSSION
Criteria for a good screening test include low cost, simplicity, acceptability to the patient, importance of the disease and the existence of an effective mode of treatment for it, and test accuracy (12). There should be a presymptomatic or early phase when disease detection would be advantageous, before it becomes
DEMERS,
60
STAWICK, TABLE
CHARACTERISTICS
OF PATIENTS
(N
Age
Positive testsa
1 2
21 36
3 1
3 4’ 5
55 28 55
1 1 1
6 7
58 60
2
8
56
1
9 10
66 49
2 3
11 12
47 69
2 3
13 14
29 39 42 24 58 33 29 25 27
1 1 3 1 1 1 2 3 1
20d 21d
3
= 21) WITH ONE OR MORE
Client
15d 16d 17d lgd 19d
AND DEMERS
1
POSITIVE
Endoscopic diagnosis Normal Hyperplastic POlYP Normal Normal Diverticulosis A l-cm polyp A 2- to 2.5-cm Polyp A 2-cm polyp cancer in siiu A 3-cm polyp Adenocarcinoma caecum Normal Adenocarcinoma of descending colon Normal Normal Normal Normal Normal Normal Normal Normal Normal
STOOL HEMOCCULT
TESTS
“Other” diagnoses or medicines” Gastritis Internal hemorrhoids Ileitis, Prednisone None Hemorrhoids diverticulosis None None None None None Peptic ulcer None Peptic ulcer Duodenal ulcer Vitamin C None None None None None None
a Number of positive Hemoccult tests of three slides prepared. b Only diagnoses that might explain positive tests are included. c Did not adhere to Hemoccult diet. d No known cause for positive Hemoccult test found.
clinically apparent. This latter criteria is satisfied if one accepts the majority view that most cancers of the colon and rectum originate in adenomatous colonic polyps. At least a portion of colonic polyps are premalignant, as demonstrated in the study by Gilbertsen which shows that removal of colonic polyps reduces the number of subsequent colonic malignancies (1). The stool Hemoccult test fulfills all screening criteria except for that of sensitivity, if one considers adenomatous colorectal polyps as the screening focus. This study concludes that the number of false-negative tests, for all polyp sizes, is excessively high. The sensitivity ranges depend on the size or the histologic classification of polyps, which in this study varied from 3% for all polyps and 4% for histologically proven adenomatous polyps, to 11% for polyps measuring 1.O cm or greater in diameter. Hydrating the Hemoccult slides prior to addition of the developer would in-
SENSITIVITY
OF FECAL
OCCULT
BLOOD TESTING
61
crease sensitivity but would also increase the number of false positives (11). Falsepositive tests can lead to work time and income loss, excessive medical costs, inconvenience, and unnecessary discomfort to the patient. The credibility of the entire screening program falls into jeopardy if too many false positives are referred for follow-up. The manufacturer also advised against hydration of slides. The programmatic decision was therefore made not to hydrate the Hemoccult slides. Compliance with both the preparatory diet and Hemoccult slide preparations is important. Only 2.7% of the 988 people studied stated they did not adhere to the dietary instructions. However, false-positive, not false-negative results would have increased had overall compliance been lower (11). Vitamin C, which can increase false negatives, was taken by only one person during the stool collection period, and he was Hemoccult positive (case 1.5, Table 3). All Hemoccult slides were collected within 4 days of testing. Although small amounts of blood fail detection with extended delay in testing, 4 days is insufficient to produce false negatives (15). Populations at high risk for colon and rectal cancer, such as pattern and model makers, have the most to gain from screening programs. Such programs need to focus on detection and removal of not only those lesions that are frankly malignant, but also those that are potentially cancerous or premalignant, such as adenomatous polyps. The American Cancer Society recommends annual Hemoccult testing for colorectal cancer in those over 50 years of age (5). However, 92% (22) of adenomatous colorectal polyps measuring 1 cm or greater in diameter would have been missed by using Hemoccult testing alone in the present study. Four of these polyps contained malignant foci. This number of missed diagnoses presents a serious disadvantage to using the stool Hemoccult test to detect colorectal
POlYPS. The stool Hemoccult test, because of its low sensitivity, must be supplemented by other measures if detection and removal of colorectal polyps is a priority in screening populations. REFERENCES 1. Gilbertsen, V. A., McHugh, R., &human, L., and Williams, S. E. The earlier detection of colorectal cancers: A preliminary report of the results of the Occult Blood Study. Cancer 45, 2899-2901 (1980). 2. Greegor, D. H. Diagnosis of lower bowel cancer in the asymptomatic patient. JAMA 201, 943945 (1967). 3. Griffith, C. D. M., Turner, D. J., and Saunders, J. H. False-negative results of Hemoccult test in colorectal cancer. Brit. Med. J. 283. 472 (1981). 4. Herzog, P., Holtermuller, K. H., Preiss, J., Fischer, J., Ewe, K., Schreiber, H. J., and Berres, M. Fecal blood loss in patients with colonic polyps: A comparison of measurements with 51Chromium-labelled erythrocytes and with the Haemoccult test. Gastroenferology 83, 957962 (1982). 5. Holleb, A. I. ACS report on the cancer-related health check-up. Ca-A &zncer J. C/in. 30, 231 (1980). 6. Kaye, G. I., Fenoglio, C. M., Pascal, R. R., and Lane, N. Comparative electron microscopic features of normal, hyperplastic, and adenomatous human colonic epithelium. Gastroenterology 64, 926-945 (1973). 7. Lane, N., Kaplan, H., and Paschal, R. Minute adenomatous and hyperplastic polyps of the colon: Divergent patterns of epithelial growth with specific associated mesenchymal changes. Gastroenterology 60, 537-551 (1971).
62
DEMERS,
STAWICK,
AND DEMERS
8. Leffall, L. S. D. Colorectal cancer-Prevention and detection. Cancer 47, 1170-1172 (1981). 9. Lipshutz, G. R., Katon, R. M., McCool, M. F., Mayer, B., Smith, F. W., Duffy, T., and Melnyk, C. S. Flexible sigmoidoscopy as a screening procedure for neoplasia of the colon. Surg. Gynecol. Obsret. 148, 19-22 (1979). 10. Macrae, F. A., and St. John, D. J. B. Relationship between patterns of bleeding and Hemoccult sensitivity in patients with colorectal cancers or adenomas. Gastroenterology 82, 891-898 (1982). 11. Macrae, F. A., St. John, D. J. B., Caligiore, P., Taylor, L. S., and Legge, J. W. Optimal dietary conditions for Hemoccult testing. Gasrroenrerology 82, 899-903 (1982). 12. Spitzer, W. 0. The periodic health exam. JAMA 121, 1103-1254 (1979). 13. Stroehlein, J. R., Fairbanks, V. F., McGill, D. B., and Go, V. L. W. Hemoccult detection of fecal occult blood quantitated by radioassay. Dig. Dis. 21, 841-844 (1976). 14. Winawer, S. J., Andrews, M., Flehinger, B., Sherlock, P., Schottenfeld, D., and Miller, D. G. Progress report on controlled trial of fecal occult blood testing for the detection of colorectal neoplasia. Cancer 45, 2959-2964 (1980). 15. Winawer, S. J., and Fleisher, M. Sensitivity and specificity of the fecal occult blood test for colorectal neoplasia. Gastroenterology 82, 986-991 (1982). 16. Winawer, S. J., Fleisher, M., and Sherlock, P. Sensitivity of fecal occult blood testing for adenomas. Gastroenferology 83, 1136-1138 (1982).
MEDICINE
14, 55-62 (1985)
Relative Sensitivity of the Fecal Occult Blood Test and Flexible Sigmoidoscopy in Detecting Polyps RAYMOND Y. DEMERS, M.D.,M.PH., *,I LAWRENCE E. STAWICK, M.D.,? PAUL DEMERS, B.S.* Departments
of ‘Family Medicine and fInternal 4201 St. Antoine, Detroit,
Medicine, Wayne Michigan 48201
State
AND
University,
A group of 1,002 male pattern and model makers, an occupational group at high risk for colorectal cancers, was screened for the presence of polyps and malignancies of the lower gastrointestinal tract. Flexible sigmoidoscopy and serial fecal occult blood testing were both performed on 988 of the participants, and 165 were found to have at least one colorectal polyp. Only 3% of all men with visualized polyps showed Hemoccult-positive stools. Only 2 (4%) of the 51 men with histologically proven adenomatous polyps were Hemoccult positive. Adenomatous polyps of 1 cm or greater in diameter are malignant 8% of the time. This study concludes that the fecal occult blood test sensitivity in detecting colorectal polyps is unacceptably low. It should be supplemented by more rigorous procedures, especially in populations at high risk for colorectal cancer. 0 1985 Academic Press, Inc.
INTRODUCTION
Concentrated attention has been given to the screening for colon and rectal neoplasia since the landmark study by Greegor in 1967 (2). The preponderance of studies has focused on malignancies, not adenomas, and show the Hemoccult test to be highly sensitive in the detection of cancer (3, 10). However, considerably less is known of its sensitivity in discovering polyps of the colon and rectum. The present study assesses the sensitivity of the Hemoccult slide test in detecting polyps, particularly adenomatous polyps, of the descending colon and rectum. Most, if not all, adenocarcinomas of the colon and rectum begin as or with polyps (8). Specific attention has focused on polyps that are histologically adenomatous. Adenomas exhibit characteristics of true neoplasia and should be considered significant in the evaluation of carcinoma (6). The other major type of polyp, those that are histologically hyperplastic, are of little clinical significance. Visual differentiation between the two types through the sigmoidoscope is of questionable reliability -although hyperplastic polyps rarely achieve a size of greater than 5 mm in diameter, and only 10% of very small polyps (<4 mm) are adenomatous (7). The clinical significance of adenomatous polyps was further reinforced by Gilbertsen, who showed that their removal significantly lowered the incidence of colorectal cancer (1). Winawer et al., comparing findings on rigid sigmoidoscopic exam and stool Hemoccult tests, cited a false-negative rate for adenomas of 76% (24% sensitivity) (14). Herzog et al. studied 44 consecutive patients, all of whom had adenomatous ’ To whom reprint requests should be addressed at the Department of Family Medicine, State University, 4201 St. Antoine, 4-J, Detroit, Mich. 48201.
Wayne
55 0091-7435185 $3.00 Copyright 0 1985 by Academic Press. Inc. All rights of reproduction in any form reserved.
56
DEMERS,
STAWICK,
AND
DEMERS
polyps of at least 1.5 cm in diameter and had been referred for polypectomy (4). Hemoccult sensitivity was found to be 86% in patients with polyps of the descending colon and rectum and 26% in those with lesions of the ascending and transverse colon. Lipshutz et al. found a 16.7% Hemoccult sensitivity in 39 patients with polyps discovered during flexible sigmoidoscopic examination conducted on United States veterans (9). The wide range of sensitivities determined from the latter three studies makes it difficult to draw a meaningful conclusion on this topic. Furthermore, each study has important drawbacks. The study by Herzog contains a major selection bias since subjects were limited to those having prediagnosed large polyps, with 25 of the 44 participants originally diagnosed by their family doctors through a positive Hemoccult test. The studies by Lipshutz and Winawer lack details on histology and size of the polyps, making it difficult to evaluate the significance of the data. Neither of these studies focused primarily on Hemoccult sensitivity, although each contained enough data to calculate the sensitivity of stool Hemoccult testing for polyps. Red cell labeling with 51Cr provides an estimate of the amount of gastrointestinal bleeding required to yield a positive Hemoccult test (10, 13). Sensitivity increases progressively with greater amounts of daily blood loss, achieving 93% with losses of greater than 30 ml. The test seems to be insensitive to less than 2 ml of fecal blood per day. Test sensitivity also seems to increase with polyp size, the critical polyp diameter being approximately 2 cm (10). High sensitivity or low false-negative test rates are important in a screening program. However, clarity is needed in tying sensitivity to a specific phase of disease. The focus of this study is to evaluate the sensitivity of the Hemoccult test in detecting adenomatous polyps. Polyps are visually identified through a 60cm flexible sigmoidoscope. Their presence serves as the reference against which Hemoccult sensitivity is measured. Winawer stated in a recent editorial on the sensitivity of fecal occult blood testing that a “reasonable sensitivity of the fecal occult blood test for the detection of adenomas would make the test a more attractive screening and case-finding technique for colorectal neoplasia” (16). This statement is bolstered by the fact that between 10 and 50% of the adenomatous polyps greater than 1 cm in diameter are malignant. An analysis of sensitivity of the Hemoccult test in detecting adenomas of the distal 60 cm of the colon is possible by performing both Hemoccult testing and flexible sigmoidoscopy on a healthy population. METHODS
Participants were chosen from among the active and retired membership of three local chapters of the Pattern and Model Makers League of North America and active workers from two nonunion pattern making shops. All participation was voluntary and fully endorsed by both the union and shop owners. An orientation session to explain the protocol to participants preceded the examination screening date by approximately 2 weeks. The sessions explained the Hemoccult diet and stressed the importance of complying with it. This diet consisted of avoiding red meats and selected peroxidase-containing fruits and
SENSITIVITY
OF
FECAL
OCCULT
BLOOD
TESTING
57
vegetables, along with a maintenance of high roughage intake, beginning 2 days prior to the first stool collection and continuing until the third stool collection. Participants were asked to begin stool specimen collection 4 days prior to the scheduled exam. They were further advised to avoid all vitamins and aspirin during this time and to keep the stool Hemoccult slides at room temperature until their screening exam. Stool specimens were collected consecutively and samples from two different parts of the stool were applied to the two windows supplied for each collection. The SKD Hemoccult II slide collection kit produced by Smith Kline Diagnostic of Sunnyvale, California, was used. Completed slides were tested when participants entered for screening. The developing solution was added, and after 30 set each slide was examined independently by two observers, a male attendant and a physician, with 99% interobserver agreement. The slides were not hydrated prior to testing. The Hemoccult slide interpretations were blinded from the sigmoidoscopic examination results. Tests showing trace positive or equivocal results were repeated. All nine such repeated tests were negative and these nine participants were normal on sigmoidoscopic examination. Preparation for the sigmoidoscopic examination included two Ducolax tablets the night before the examination, light meals (breakfast and lunch), avoidance of caffeine products during the day of examination, and one, or possibly two, Fleets enemas administered just prior to the sigmoidoscopic procedure. One enema provided adequate bowel cleansing in over 95% of the participants. The average exam lasted slightly over 8 min. Experienced endoscopists performed the flexible sigmoidoscopy exams using an Olympus 60-cm flexible sigmoidoscope. Insertion of the scope to 50 cm or greater was achieved in 78% of the cases and beyond 40 cm in 95%. The size of each polypoid mass was visually assessed by the endoscopists who had performed numerous polypectomies in private practice, and whose visual assessment of polyp size seen through the flexible sigmoidoscope was consistently within 1 mm of error. The endoscopists recorded their visual impressions of polyp type. Photographs of positive or suspicious sigmoidoscopic findings were taken. Comprehensive attempts were made to assure medical follow-up of patients with polyps greater than 5 mm. Participants were advised to follow-up with their personal physicians or to receive direct care from one of the five Board-certified gastroenterologists who received referrals from the program. Attempts were made to facilitate visits directly to gastroenterologists or surgeons who were skilled in colonoscopy and polypectomy. Numerous phone contacts were made to arrange medical follow-up of those with polyps and subsequently to retrieve their medical and histological reports from various hospitals and doctors’ offices. Appropriate consent forms for transfer and release of information were signed. The majority of the histologic/pathologic information was obtained after referral, although some of the small (<5 mm) hyperplastic-appearing polyps were biopsied at the screening site. Diagnoses of malignancy, carcinoma in situ, or adenoma were usually made at hospitals other than the screening hospital. All reported histological interpretations were given by Board-certified, hospital-based M.D. pathologists. Reliability and accuracy of histological material were not as-
58
DEMERS,
STAWICK,
AND DEMERS
certained by other pathologists due to the time and monetary limitations of the screening program. Analysis was performed for all visualized polyps and for those specifically defined by histology since adenomatous polyps were of primary interest to the study. Stool Hemoccult results, medical history, illnesses, medications, and sigmoidoscopic results were recorded. Information on the sigmoidoscopic findings included the distance of the polyp(s) from the anal verge, and other colonic tindings (such as colitis, diverticulae, cancer). Additional recorded information included the patient’s report of compliance with Hemoccult preparatory diet and polyp histology from the follow-up reports. RESULTS
A total of 988 of the 1,002 participants in the screening program completed both the Hemoccult testing and the flexible sigmoidoscopic exam. The participants were all men averaging 42 years of age (standard deviation = 12.23, range = 18 to 70 years of age). At least one colorectal polyp was found in 165 participants, with 38 having multiple polyps. Fifty-one had at least one histologically confirmed adenomatous polyp. Forty-four percent of the polyps were found beyond 20 cm from entry, 18% beyond 30 cm. Twenty-one (2%) of the total study population had at least one positive stool Hemoccult. Only 4 of 36 (11%) participants with polyps greater than or equal to 1 cm in diameter showed Hemoccultpositive tests. Three of the four positive Hemoccult tests occurred with polyps greater than 2 cm in diameter. The prevalence of polyps varied predictably by age from a 5% prevalence in men under 30 years to 29% in men 51 years or older. No perforations or other major complications occurred in any of the participants. Table 1 categorizes the presence or absence of all polyps, regardless of histology, by the Hemoccult test results. As shown, the overall sensitivity of fecal Hemoccult tests in predicting the presence of any colorectal polyps is approximately 3%. This table includes all patients with polyps discovered (visualized) through the flexible sigmoidoscope. Table 2 presents Hemoccult test results for those patients whose pathology TABLE RESULTS
OF FECAL HEMOCCULT POLYPS VISUALIZED
TEST IN PATIENTS DURING FLEXIBLE
1 BY PRESENCE OR ABSENCE OF COLORECTAL SICMOIDOSCOPIC EXAMINATION
Diagnosis of polyps with flexible sigmoidoscope
Hemoccult test results
Polyps present
Polyps absent
Positive” Negative
5 160
14b 807
Total
165
821
Sensitivity = 0.03 Specificity = 0.98 0 At least one of the three hemoccult tests was positive. b Two frank malignancies (cases 10 and 12, Table 3) were not classified in this table.
SENSITIVITY
OF
FECAL
OCCULT TABLE
BLOOD
2
FECAL HEMOCCULT TEST RESULTS FOK PATIENTS WITH PATHOLOGY ADENOMATOUS POLYPS" Hemoccult Size of largest polyph (cm) so.4 0.5-0.9 1.0-1.4 1.5-1.9 32.0 Total
59
TESTING
REPORTS SHOWING
results
All three negative
One or more positive
9 18 10 8 4
0 0 I 0 I
49
2
a Does not include patients with cancer or cancer in situ. b In patients with multiple polyps, only the largest adenomatous polyp patients with one or more histologically proven adenomatous polyps.
is included.
Numbers
reflect
reports were obtained and which showed histologically proven adenomatous colorectal polyps. Patients who did not complete follow-up, including polyp biopsies, or who had proven hyperplastic polyps were omitted from Table 2. Patients whose pathology reports indicated polyps with cancer or cancer in situ rather than adenomatous polyps were also excluded. Twenty-four of the 36 individuals with polyps of 1 cm or greater received polypectomies verifying the polyps as adenomatous. Only two of these large adenomas (8%) were Hemoccult positive. The Hemoccult sensitivity in detecting histologically proven adenomatous polyps of all sizes, based on data shown in Table 2, is 4% (2/51). No individual with a histologically proven adenomatous polyp less than 1 cm in diameter had a Hemoccult-positive stool. Table 3 displays descriptions of patients with positive Hemoccult tests. Fourteen of the 21 individuals with positive results presented explanations that may have resulted in Hemoccult-positive testing. The seven without discernable reasons for Hemoccult positivity were advised to follow-up with their personal physicians. Two of the seven did follow up, but no site of bleeding was discovered. The remaining five refused follow-up. Only one of these 21 admitted to nonconformity with the Hemoccult testing diet. Seven cases of carcinoma or carcinoma in situ of the distal colon were discovered, along with two carcinoid tumors. Five of the malignancies, excluding cases 10 and 12 in Table 3, were classified as polyps in Table 1 since they were initially visually described as polyps at the screening site. Only one of these five, the carcinoma in situ noted in Table 3, was Hemoccult positive. DISCUSSION
Criteria for a good screening test include low cost, simplicity, acceptability to the patient, importance of the disease and the existence of an effective mode of treatment for it, and test accuracy (12). There should be a presymptomatic or early phase when disease detection would be advantageous, before it becomes
DEMERS,
60
STAWICK, TABLE
CHARACTERISTICS
OF PATIENTS
(N
Age
Positive testsa
1 2
21 36
3 1
3 4’ 5
55 28 55
1 1 1
6 7
58 60
2
8
56
1
9 10
66 49
2 3
11 12
47 69
2 3
13 14
29 39 42 24 58 33 29 25 27
1 1 3 1 1 1 2 3 1
20d 21d
3
= 21) WITH ONE OR MORE
Client
15d 16d 17d lgd 19d
AND DEMERS
1
POSITIVE
Endoscopic diagnosis Normal Hyperplastic POlYP Normal Normal Diverticulosis A l-cm polyp A 2- to 2.5-cm Polyp A 2-cm polyp cancer in siiu A 3-cm polyp Adenocarcinoma caecum Normal Adenocarcinoma of descending colon Normal Normal Normal Normal Normal Normal Normal Normal Normal
STOOL HEMOCCULT
TESTS
“Other” diagnoses or medicines” Gastritis Internal hemorrhoids Ileitis, Prednisone None Hemorrhoids diverticulosis None None None None None Peptic ulcer None Peptic ulcer Duodenal ulcer Vitamin C None None None None None None
a Number of positive Hemoccult tests of three slides prepared. b Only diagnoses that might explain positive tests are included. c Did not adhere to Hemoccult diet. d No known cause for positive Hemoccult test found.
clinically apparent. This latter criteria is satisfied if one accepts the majority view that most cancers of the colon and rectum originate in adenomatous colonic polyps. At least a portion of colonic polyps are premalignant, as demonstrated in the study by Gilbertsen which shows that removal of colonic polyps reduces the number of subsequent colonic malignancies (1). The stool Hemoccult test fulfills all screening criteria except for that of sensitivity, if one considers adenomatous colorectal polyps as the screening focus. This study concludes that the number of false-negative tests, for all polyp sizes, is excessively high. The sensitivity ranges depend on the size or the histologic classification of polyps, which in this study varied from 3% for all polyps and 4% for histologically proven adenomatous polyps, to 11% for polyps measuring 1.O cm or greater in diameter. Hydrating the Hemoccult slides prior to addition of the developer would in-
SENSITIVITY
OF FECAL
OCCULT
BLOOD TESTING
61
crease sensitivity but would also increase the number of false positives (11). Falsepositive tests can lead to work time and income loss, excessive medical costs, inconvenience, and unnecessary discomfort to the patient. The credibility of the entire screening program falls into jeopardy if too many false positives are referred for follow-up. The manufacturer also advised against hydration of slides. The programmatic decision was therefore made not to hydrate the Hemoccult slides. Compliance with both the preparatory diet and Hemoccult slide preparations is important. Only 2.7% of the 988 people studied stated they did not adhere to the dietary instructions. However, false-positive, not false-negative results would have increased had overall compliance been lower (11). Vitamin C, which can increase false negatives, was taken by only one person during the stool collection period, and he was Hemoccult positive (case 1.5, Table 3). All Hemoccult slides were collected within 4 days of testing. Although small amounts of blood fail detection with extended delay in testing, 4 days is insufficient to produce false negatives (15). Populations at high risk for colon and rectal cancer, such as pattern and model makers, have the most to gain from screening programs. Such programs need to focus on detection and removal of not only those lesions that are frankly malignant, but also those that are potentially cancerous or premalignant, such as adenomatous polyps. The American Cancer Society recommends annual Hemoccult testing for colorectal cancer in those over 50 years of age (5). However, 92% (22) of adenomatous colorectal polyps measuring 1 cm or greater in diameter would have been missed by using Hemoccult testing alone in the present study. Four of these polyps contained malignant foci. This number of missed diagnoses presents a serious disadvantage to using the stool Hemoccult test to detect colorectal
POlYPS. The stool Hemoccult test, because of its low sensitivity, must be supplemented by other measures if detection and removal of colorectal polyps is a priority in screening populations. REFERENCES 1. Gilbertsen, V. A., McHugh, R., &human, L., and Williams, S. E. The earlier detection of colorectal cancers: A preliminary report of the results of the Occult Blood Study. Cancer 45, 2899-2901 (1980). 2. Greegor, D. H. Diagnosis of lower bowel cancer in the asymptomatic patient. JAMA 201, 943945 (1967). 3. Griffith, C. D. M., Turner, D. J., and Saunders, J. H. False-negative results of Hemoccult test in colorectal cancer. Brit. Med. J. 283. 472 (1981). 4. Herzog, P., Holtermuller, K. H., Preiss, J., Fischer, J., Ewe, K., Schreiber, H. J., and Berres, M. Fecal blood loss in patients with colonic polyps: A comparison of measurements with 51Chromium-labelled erythrocytes and with the Haemoccult test. Gastroenferology 83, 957962 (1982). 5. Holleb, A. I. ACS report on the cancer-related health check-up. Ca-A &zncer J. C/in. 30, 231 (1980). 6. Kaye, G. I., Fenoglio, C. M., Pascal, R. R., and Lane, N. Comparative electron microscopic features of normal, hyperplastic, and adenomatous human colonic epithelium. Gastroenterology 64, 926-945 (1973). 7. Lane, N., Kaplan, H., and Paschal, R. Minute adenomatous and hyperplastic polyps of the colon: Divergent patterns of epithelial growth with specific associated mesenchymal changes. Gastroenterology 60, 537-551 (1971).
62
DEMERS,
STAWICK,
AND DEMERS
8. Leffall, L. S. D. Colorectal cancer-Prevention and detection. Cancer 47, 1170-1172 (1981). 9. Lipshutz, G. R., Katon, R. M., McCool, M. F., Mayer, B., Smith, F. W., Duffy, T., and Melnyk, C. S. Flexible sigmoidoscopy as a screening procedure for neoplasia of the colon. Surg. Gynecol. Obsret. 148, 19-22 (1979). 10. Macrae, F. A., and St. John, D. J. B. Relationship between patterns of bleeding and Hemoccult sensitivity in patients with colorectal cancers or adenomas. Gastroenterology 82, 891-898 (1982). 11. Macrae, F. A., St. John, D. J. B., Caligiore, P., Taylor, L. S., and Legge, J. W. Optimal dietary conditions for Hemoccult testing. Gasrroenrerology 82, 899-903 (1982). 12. Spitzer, W. 0. The periodic health exam. JAMA 121, 1103-1254 (1979). 13. Stroehlein, J. R., Fairbanks, V. F., McGill, D. B., and Go, V. L. W. Hemoccult detection of fecal occult blood quantitated by radioassay. Dig. Dis. 21, 841-844 (1976). 14. Winawer, S. J., Andrews, M., Flehinger, B., Sherlock, P., Schottenfeld, D., and Miller, D. G. Progress report on controlled trial of fecal occult blood testing for the detection of colorectal neoplasia. Cancer 45, 2959-2964 (1980). 15. Winawer, S. J., and Fleisher, M. Sensitivity and specificity of the fecal occult blood test for colorectal neoplasia. Gastroenterology 82, 986-991 (1982). 16. Winawer, S. J., Fleisher, M., and Sherlock, P. Sensitivity of fecal occult blood testing for adenomas. Gastroenferology 83, 1136-1138 (1982).