- Email: [email protected]
New Studies of the Colonic Polyp and Cancer
New Studies of the Colonic Polyp and Cancer CLYDE E. CULP, M.D.
In recent years considerable doubt has been cast upon the role of the adenomatous polyp in the development of colonic or rectal carcinoma. 7 Confusion has been created in the minds of many practitioners - perhaps to the point of disservice to the patient, since the annual proctosigmoidoscopic examination may be treated as unimportant or even waived by his medical adviser. Ideal proof-or disproof-of the adenoma-carcinoma sequence would require that an adenomatous polyp be removed from the bowel, sectioned for intimate study, reassembled, returned to its original site, and allowed to progress to its ultimate fate. Meanwhile, the presence of one or more adenomatous polyps in the rectum or colon implies an altered response of the epithelial lining to biological factors as yet undetermined. If cancers arose de nova,! one should discover their presence as tiny polyps. Accordingly, the investigations reviewed here were formulated on the basis of polyp diameter. Since the majority of carcinomas and polyps are located in the terminal 25 em of the bowel, polyps occupying this segment were utilized in these studies. A total of 1,510 polyps were examined and placed in four categories: diminutive, medium-sized, large, and satellite.
CATEGORIES OF POLYPS Diminutive Polyps Pagtalunan and associates, drawing upon 1,000 cases, conducted a" histopathologic analysis of 1,000 polyps whose diameter varied up to 5 mm. Of these, 861 proved to be adenomatous and the remainder were miscellaneous (Table 1). In the study of this material it was noted that the majority of adenomas of the bowel were not static entitites. Definite micro architectural alterations represented progressive degrees of hyperplasia and atypia. (Here the latter term implies varying degrees of loss of the ability to produce mucus and the loss of cellular polarity.) Depending upon the Surgical Clinics of North America- Vol. 47, No.4, August, 1967
955
956
CLYDE
E.
CULP
Table 1. 254 Non-adenomatous Polyps SATELLITE DIMINUTIVE
LARGE
(5 mm or less) (5-10 mm) (> 10 mm)
TYPE
Hypertrophic mucosal tag ("bump") Pseudopolyp Lymphoid nodule Hamartoma Leiomyoma Carcinoid Lipoma Lymphangioma
88
19
24 18 3 4 1 1
1
(2 mm to 7x4x 1 cm) 87
1 1
1 1 2
22 (of 202)
TOTAL
194 26 18 5 6 3 1 1
1 139 (of 1,000)
TOTAL
Table 2.
MEDIUM
5 (of 133)
88 (of 175)
254 (of 1,510)
Histopathologic Classification of 1,255 Adenomatous Polyps HYPERPLASIA
Without Atypia
With Atypia
CARCINOMA
STUDY GROUP
Minimal
Mild
Moderate
Severe
In Situ
Diminutive (0-5 mm)
309 36%
260 30%
234 27%
52 6%
6 1%
861 (of 1,000)
Medium (5-10 mm
60 33%
60 33%
47 26%
13 8%
180 (of 202)
Large (>10 mm)
17 13%
46 36%
30 24%
24 19%
10 8%
127 (of 133)
Satellite
17 19%
20 23%
15 17%
31 36%
4 5%
87 (of 175)
354 28%
360 29%
144 11%
74 6%
14 1%
1,255 (of 1,510)
TOTAL
309 25%
Invasive
TOTAL
degree of these microscopic variations, it was possible to distribute the adenomatous polyps among several categories (Table 2). Of the 861 microadenomas, 309 showed minimal glandular hyperplasia without evidence of cellular atypia. Among the 260 classed as having mild hyperplasia with atypia, up to 25% of the cells showed changes. Moderate hyperplasia and atypia were noted in 234 adenomas, 25 to 50% of the cells displaying an enlarged hyperchromatic nucleus which no longer was in its usual basal position. Severe hyperplasia and atypia, found in 52 additional adenomatous polyps, featured a distinct reversal in the ratio of goblet cells to cells not secreting mucus. In this category, among 50 to 75 % of the polyp cells studied, pseudostratification, nuclear hyperchromatism, and pleomorphism were accentuated
NEW STUDIES OF THE COLONIC POLYP AND CANCER
957
and mitotic figures were frequent. Six of the 861 displayed the overall cellular and nuclear disorganization of carcinoma in situ.
Medium-Sized Polyps Polyps considered medium-sized were those measuring from 0.5 to 1.0 cm in diameter. Wychulis and associates collected 202 specimens, of which 22 proved to have origins other than adenomatous (Table 1). All the adenomas had evidence of cellular hyperplasia and atypia (Table 2), and carcinoma in situ was found in 13 of them. Large Polyps Lescher and co-workers studied in detail 133 polyps having a diameter greater than 1.0 cm. Five proved not to have an adenomatous origin (Table 1), and 127 showed adenomatous structure with varying degrees of cellular alteration (Table 2). Carcinoma in situ was noted in 24 of these, and invasive adenocarcinoma was found in 10. Evidence of benignity-varying degrees of hyperplasia and atypia-were present in all of these 127 polyps. The remaining polyp was a polypoid adenocarcinoma. Scrutiny of serial sections failed to reveal benign elements, and it was assumed that this neoplasm had been carcinomatous from its origin. Satellite Polyps Since about 25%4.9.10 of patients with carcinoma of the colon and rectum have associated polyps, a study was undertaken to ascertain the character of these satellite lesions. 2 Review was made of 180 fixed surgical specimens of the terminal 25 cm of bowel resected in 1 calendar year; and 49 of these were found to contain 175 polyps. The size of the polyps varied from 2-mm diameter to 7 by 4 by 1 cm. Those having an adenomatous character were classified histopathologically as had been done in the investigation of the diminutive polyps.6 Of the 87 adenomatous polyps, 31 contained carcinoma in situ (Table 2) and 4 others showed invasive adenocarcinoma. Together, these carcinomatous polyps were 40 % of the total adenomatous group. Hypertrophy of the normal mucosa, or "bumps" constituted an additional 87 polyps; and the remaining lesion was of an inflammatory nature. COMMENT Development of Malignancy An important fact substantiated by these combined investigations is evident in the right-hand columns of Table 2. With an increase in diameter of the adenoma there was a corresponding increase in the frequency of carcinoma in situ, and polyps having a diameter greater than 1 cm might contain invasive carcinoma. SiInilar observations were made among the adenomatous polyps associated with adenocarcinoma of the distal 25 cm of bowel (Table 2).
958
CLYDE
E. CULP
A histopathologic diagnosis of carcinoma in situ is held by some authorities to have doubtful significance or none. No adequate alternative explanation is offered. It is difficult to comprehend why in situ carcinoma in an adenomatous polyp should not be given the same respect as it would if discovered in any other epithelial structure. Dockerty has repeatedly expressed the opinion that every carcinoma passes through an in situ stage. Since many carcinomas of the bowel fail to reveal benign elements, it has been argued that the growth must have arisen directly from the mucosa and been malignant from the start. Our pathologists often note partially ulcerated polyps or "wine-glass lesions" caused by carcinomatous involvement. With the passage of time, and with an appropriate degree (grade) of malignant activity, the benign tissue could readily be replaced by cancer cells. Stearns was right in stating: " ... it appears that essentially the only tiny cancers of the rectum found clinically are in adenomas, and that the de novo, tiny, sessile cancer, while it does occur, is certainly too infrequent to explain the origin of the majority of carcinomas of the rectum and colon." During the past year the Section of Proctology of the Mayo Clinic performed over 26,000 proctosigmoidoscopic examinations. We have not found a single tiny (2-mm to 5-mm) carcinoma, which one would anticipate finding if the majority of adenocarcinomas had their malignant character from the inception of the lesion. Significance of Villosity We are aware of the definite malignant tendency in villous adenomas. Of the 1,255 adenomatous polyps analyzed in our composite investigation, 94 had villous features in part or throughout. This group included 11 micro adenomas and 22 medium-sized polyps. Among the subtotal of 33, there were 2 carcinomas in situ, one being recorded in each group. Another diminutive satellite polyp was the site of an invasive carcinoma. The remaining 61 villous polyps had diameters greater than 1 cm; and in situ carcinoma was found in 11 of these, and invasive cancer in 6 others. If the 88 adenomatous polyps having in situ or invasive carcinoma are considered as a group, only 23% contained villous features. Thus it appears that villosity is not sufficiently common to justify all of the retrospective diagnoses of villosity made when tumors formerly pronounced benign recur and metastasize. Arrested Development Every so often, understanding of colonic polyps is challenged by a strange case: the patient refuses not only therapy but even biopsy of a small to moderate-sized rectal polyp, and yet repeated periodic examinations fail to demonstrate any change in the excrescence. There are several observations from the foregoing studies which may aid in explaining this course. (1) The polyp may not have been adenomatous in its origin; or if it
NEW STUDIES OF THE COLONIC POLYP AND CANCER
959
was, its cellular composition is of a mature nature. The latter condition (minimal hyperplasia without atypia) was found only in polyps of 5 mm or less. (2) The excrescence could have been a hypertrophic mucosal tag or a bump. None of this category was larger than 10 mm, and the majority were less than 5 mm. They made up almost 50% of the satellite polyps. The cause and significance of their presence are unknown at this stage in our knowledge; but as Valdes-Dapena and Beckfield have pointed out, such bumps account for biopsy reports of benign rectal mucosa or hypertrophic rectal mucosa. (3) Still another possibility exists in the likelihood that, as in the cervix, it may take from 10 to 20 years for an in situ carcinoma to ulcerate and thus present as a clinical carcinoma. Indeed, my colleagues and I-and others elsewhere-have seen retained polyps classified as benign on the basis of both clinical impression and biopsy which nevertheless showed invasive carcinoma when re-examined at a later date.
SUMMARY AND CONCLUSION A composite study of 1,510 polyps revealed that 1,255 were adenomatous in origin. As the diameter of the adenoma increased, the frequency of carcinoma in situ became greater; and in some polyps whose diameter exceeded 10 mm, the carcinoma was invasive. One polyp proved to be a polypoid carcinoma of 10-mm diameter, and serial sections of it revealed no benign tissue. This lesion was thought to have been malignant from its beginning (de novo). No tiny lesion carcinomatous from its origin was found in more than 26,000 proctosigmoidoscopic examinations carried out by the Section of Proctology, Mayo Clinic, during the past year. Since investigative methods do not yet enable us to follow intimately the development of a colonic polyp from adenoma to carcinoma, we must use periodic clinical and pathologic findings as best we can. Whether carcinomatous polyps are malignant from the beginning or only become so in the course of time, adenomatous polyps should be destroyed when encountered. REFERENCES 1. Castleman, B., and Krickstein, H. I.: Do adenomatous polyps of the colon become malig-
nant? New Eng J Med 267:469-475 (Sept. 6) 1962. 2. Culp, C. E., Dockerty, M. B., and Jackman, R. J.: Histopathology of satellite polyp. Arch Surg (Chicago) 92:65-70 (Jan.) 1966. 3. Dockerty, M. B.: Personal communication to the author. 4. Ekelund, G.: On cancer and polyps of colon and rectum. Acta Path Microbiol Scand 59: 165-170, 1963. 5. Lescher, T. C., Dockerty, M. B., Jackman, R. J., and Beahrs, O. H.: Histopathology of the larger colonic polyp. Dis Colon Rectum 10:118-124 (March-April) 1967. 6. Pagtalunan, R. J. G., Dockerty, M. B., Jackman, R. J., and Anderson, M. J., Jr.: The histopathology of diminutive polyps of the large intestine. Surg Gynec Obstet 120:12591265 (June) 1965. 7. Spratt, J. S., Jr., Ackerman, L. V., and Moyer, C. A.: Relationship of polyps of the colon to colonic cancer. Ann Surg 148:682-696 (Oct.) 1958. 8. Stearns, M. W., Jr.: Where are the tiny carcinomas of the rectum? (Editorial.) Surg Gynec Obstet 116:625 (May) 1963.
960
CLYDE
E.
CULP
9. Stewart, M. J.: Precancerous lesions of the alimentary tract. Lancet 2:669-675 (Sept. 26) 1931. 10. Swinton, N. W., and Haug, A. D.: The frequency of precancerous lesions in the rectum and colon. Lahey elin Found Bull 5:84-88 (July) 1946. 11. Valdes-Dapena, A., and Beckfield, W. J.: Adenomatous polyps of the large intestine: Pathology and histogenesis. Gastroenterology 32:452-461 (March) 1957. 12. Wychulis, A. R., Dockerty, M. B., Jackman, R. J., and Beahrs, O. H.: Histopathology of small polyps of the large intestine. Surg Gynec Obstet 124:87-92 (Jan.) 1967.
In recent years considerable doubt has been cast upon the role of the adenomatous polyp in the development of colonic or rectal carcinoma. 7 Confusion has been created in the minds of many practitioners - perhaps to the point of disservice to the patient, since the annual proctosigmoidoscopic examination may be treated as unimportant or even waived by his medical adviser. Ideal proof-or disproof-of the adenoma-carcinoma sequence would require that an adenomatous polyp be removed from the bowel, sectioned for intimate study, reassembled, returned to its original site, and allowed to progress to its ultimate fate. Meanwhile, the presence of one or more adenomatous polyps in the rectum or colon implies an altered response of the epithelial lining to biological factors as yet undetermined. If cancers arose de nova,! one should discover their presence as tiny polyps. Accordingly, the investigations reviewed here were formulated on the basis of polyp diameter. Since the majority of carcinomas and polyps are located in the terminal 25 em of the bowel, polyps occupying this segment were utilized in these studies. A total of 1,510 polyps were examined and placed in four categories: diminutive, medium-sized, large, and satellite.
CATEGORIES OF POLYPS Diminutive Polyps Pagtalunan and associates, drawing upon 1,000 cases, conducted a" histopathologic analysis of 1,000 polyps whose diameter varied up to 5 mm. Of these, 861 proved to be adenomatous and the remainder were miscellaneous (Table 1). In the study of this material it was noted that the majority of adenomas of the bowel were not static entitites. Definite micro architectural alterations represented progressive degrees of hyperplasia and atypia. (Here the latter term implies varying degrees of loss of the ability to produce mucus and the loss of cellular polarity.) Depending upon the Surgical Clinics of North America- Vol. 47, No.4, August, 1967
955
956
CLYDE
E.
CULP
Table 1. 254 Non-adenomatous Polyps SATELLITE DIMINUTIVE
LARGE
(5 mm or less) (5-10 mm) (> 10 mm)
TYPE
Hypertrophic mucosal tag ("bump") Pseudopolyp Lymphoid nodule Hamartoma Leiomyoma Carcinoid Lipoma Lymphangioma
88
19
24 18 3 4 1 1
1
(2 mm to 7x4x 1 cm) 87
1 1
1 1 2
22 (of 202)
TOTAL
194 26 18 5 6 3 1 1
1 139 (of 1,000)
TOTAL
Table 2.
MEDIUM
5 (of 133)
88 (of 175)
254 (of 1,510)
Histopathologic Classification of 1,255 Adenomatous Polyps HYPERPLASIA
Without Atypia
With Atypia
CARCINOMA
STUDY GROUP
Minimal
Mild
Moderate
Severe
In Situ
Diminutive (0-5 mm)
309 36%
260 30%
234 27%
52 6%
6 1%
861 (of 1,000)
Medium (5-10 mm
60 33%
60 33%
47 26%
13 8%
180 (of 202)
Large (>10 mm)
17 13%
46 36%
30 24%
24 19%
10 8%
127 (of 133)
Satellite
17 19%
20 23%
15 17%
31 36%
4 5%
87 (of 175)
354 28%
360 29%
144 11%
74 6%
14 1%
1,255 (of 1,510)
TOTAL
309 25%
Invasive
TOTAL
degree of these microscopic variations, it was possible to distribute the adenomatous polyps among several categories (Table 2). Of the 861 microadenomas, 309 showed minimal glandular hyperplasia without evidence of cellular atypia. Among the 260 classed as having mild hyperplasia with atypia, up to 25% of the cells showed changes. Moderate hyperplasia and atypia were noted in 234 adenomas, 25 to 50% of the cells displaying an enlarged hyperchromatic nucleus which no longer was in its usual basal position. Severe hyperplasia and atypia, found in 52 additional adenomatous polyps, featured a distinct reversal in the ratio of goblet cells to cells not secreting mucus. In this category, among 50 to 75 % of the polyp cells studied, pseudostratification, nuclear hyperchromatism, and pleomorphism were accentuated
NEW STUDIES OF THE COLONIC POLYP AND CANCER
957
and mitotic figures were frequent. Six of the 861 displayed the overall cellular and nuclear disorganization of carcinoma in situ.
Medium-Sized Polyps Polyps considered medium-sized were those measuring from 0.5 to 1.0 cm in diameter. Wychulis and associates collected 202 specimens, of which 22 proved to have origins other than adenomatous (Table 1). All the adenomas had evidence of cellular hyperplasia and atypia (Table 2), and carcinoma in situ was found in 13 of them. Large Polyps Lescher and co-workers studied in detail 133 polyps having a diameter greater than 1.0 cm. Five proved not to have an adenomatous origin (Table 1), and 127 showed adenomatous structure with varying degrees of cellular alteration (Table 2). Carcinoma in situ was noted in 24 of these, and invasive adenocarcinoma was found in 10. Evidence of benignity-varying degrees of hyperplasia and atypia-were present in all of these 127 polyps. The remaining polyp was a polypoid adenocarcinoma. Scrutiny of serial sections failed to reveal benign elements, and it was assumed that this neoplasm had been carcinomatous from its origin. Satellite Polyps Since about 25%4.9.10 of patients with carcinoma of the colon and rectum have associated polyps, a study was undertaken to ascertain the character of these satellite lesions. 2 Review was made of 180 fixed surgical specimens of the terminal 25 cm of bowel resected in 1 calendar year; and 49 of these were found to contain 175 polyps. The size of the polyps varied from 2-mm diameter to 7 by 4 by 1 cm. Those having an adenomatous character were classified histopathologically as had been done in the investigation of the diminutive polyps.6 Of the 87 adenomatous polyps, 31 contained carcinoma in situ (Table 2) and 4 others showed invasive adenocarcinoma. Together, these carcinomatous polyps were 40 % of the total adenomatous group. Hypertrophy of the normal mucosa, or "bumps" constituted an additional 87 polyps; and the remaining lesion was of an inflammatory nature. COMMENT Development of Malignancy An important fact substantiated by these combined investigations is evident in the right-hand columns of Table 2. With an increase in diameter of the adenoma there was a corresponding increase in the frequency of carcinoma in situ, and polyps having a diameter greater than 1 cm might contain invasive carcinoma. SiInilar observations were made among the adenomatous polyps associated with adenocarcinoma of the distal 25 cm of bowel (Table 2).
958
CLYDE
E. CULP
A histopathologic diagnosis of carcinoma in situ is held by some authorities to have doubtful significance or none. No adequate alternative explanation is offered. It is difficult to comprehend why in situ carcinoma in an adenomatous polyp should not be given the same respect as it would if discovered in any other epithelial structure. Dockerty has repeatedly expressed the opinion that every carcinoma passes through an in situ stage. Since many carcinomas of the bowel fail to reveal benign elements, it has been argued that the growth must have arisen directly from the mucosa and been malignant from the start. Our pathologists often note partially ulcerated polyps or "wine-glass lesions" caused by carcinomatous involvement. With the passage of time, and with an appropriate degree (grade) of malignant activity, the benign tissue could readily be replaced by cancer cells. Stearns was right in stating: " ... it appears that essentially the only tiny cancers of the rectum found clinically are in adenomas, and that the de novo, tiny, sessile cancer, while it does occur, is certainly too infrequent to explain the origin of the majority of carcinomas of the rectum and colon." During the past year the Section of Proctology of the Mayo Clinic performed over 26,000 proctosigmoidoscopic examinations. We have not found a single tiny (2-mm to 5-mm) carcinoma, which one would anticipate finding if the majority of adenocarcinomas had their malignant character from the inception of the lesion. Significance of Villosity We are aware of the definite malignant tendency in villous adenomas. Of the 1,255 adenomatous polyps analyzed in our composite investigation, 94 had villous features in part or throughout. This group included 11 micro adenomas and 22 medium-sized polyps. Among the subtotal of 33, there were 2 carcinomas in situ, one being recorded in each group. Another diminutive satellite polyp was the site of an invasive carcinoma. The remaining 61 villous polyps had diameters greater than 1 cm; and in situ carcinoma was found in 11 of these, and invasive cancer in 6 others. If the 88 adenomatous polyps having in situ or invasive carcinoma are considered as a group, only 23% contained villous features. Thus it appears that villosity is not sufficiently common to justify all of the retrospective diagnoses of villosity made when tumors formerly pronounced benign recur and metastasize. Arrested Development Every so often, understanding of colonic polyps is challenged by a strange case: the patient refuses not only therapy but even biopsy of a small to moderate-sized rectal polyp, and yet repeated periodic examinations fail to demonstrate any change in the excrescence. There are several observations from the foregoing studies which may aid in explaining this course. (1) The polyp may not have been adenomatous in its origin; or if it
NEW STUDIES OF THE COLONIC POLYP AND CANCER
959
was, its cellular composition is of a mature nature. The latter condition (minimal hyperplasia without atypia) was found only in polyps of 5 mm or less. (2) The excrescence could have been a hypertrophic mucosal tag or a bump. None of this category was larger than 10 mm, and the majority were less than 5 mm. They made up almost 50% of the satellite polyps. The cause and significance of their presence are unknown at this stage in our knowledge; but as Valdes-Dapena and Beckfield have pointed out, such bumps account for biopsy reports of benign rectal mucosa or hypertrophic rectal mucosa. (3) Still another possibility exists in the likelihood that, as in the cervix, it may take from 10 to 20 years for an in situ carcinoma to ulcerate and thus present as a clinical carcinoma. Indeed, my colleagues and I-and others elsewhere-have seen retained polyps classified as benign on the basis of both clinical impression and biopsy which nevertheless showed invasive carcinoma when re-examined at a later date.
SUMMARY AND CONCLUSION A composite study of 1,510 polyps revealed that 1,255 were adenomatous in origin. As the diameter of the adenoma increased, the frequency of carcinoma in situ became greater; and in some polyps whose diameter exceeded 10 mm, the carcinoma was invasive. One polyp proved to be a polypoid carcinoma of 10-mm diameter, and serial sections of it revealed no benign tissue. This lesion was thought to have been malignant from its beginning (de novo). No tiny lesion carcinomatous from its origin was found in more than 26,000 proctosigmoidoscopic examinations carried out by the Section of Proctology, Mayo Clinic, during the past year. Since investigative methods do not yet enable us to follow intimately the development of a colonic polyp from adenoma to carcinoma, we must use periodic clinical and pathologic findings as best we can. Whether carcinomatous polyps are malignant from the beginning or only become so in the course of time, adenomatous polyps should be destroyed when encountered. REFERENCES 1. Castleman, B., and Krickstein, H. I.: Do adenomatous polyps of the colon become malig-
nant? New Eng J Med 267:469-475 (Sept. 6) 1962. 2. Culp, C. E., Dockerty, M. B., and Jackman, R. J.: Histopathology of satellite polyp. Arch Surg (Chicago) 92:65-70 (Jan.) 1966. 3. Dockerty, M. B.: Personal communication to the author. 4. Ekelund, G.: On cancer and polyps of colon and rectum. Acta Path Microbiol Scand 59: 165-170, 1963. 5. Lescher, T. C., Dockerty, M. B., Jackman, R. J., and Beahrs, O. H.: Histopathology of the larger colonic polyp. Dis Colon Rectum 10:118-124 (March-April) 1967. 6. Pagtalunan, R. J. G., Dockerty, M. B., Jackman, R. J., and Anderson, M. J., Jr.: The histopathology of diminutive polyps of the large intestine. Surg Gynec Obstet 120:12591265 (June) 1965. 7. Spratt, J. S., Jr., Ackerman, L. V., and Moyer, C. A.: Relationship of polyps of the colon to colonic cancer. Ann Surg 148:682-696 (Oct.) 1958. 8. Stearns, M. W., Jr.: Where are the tiny carcinomas of the rectum? (Editorial.) Surg Gynec Obstet 116:625 (May) 1963.
960
CLYDE
E.
CULP
9. Stewart, M. J.: Precancerous lesions of the alimentary tract. Lancet 2:669-675 (Sept. 26) 1931. 10. Swinton, N. W., and Haug, A. D.: The frequency of precancerous lesions in the rectum and colon. Lahey elin Found Bull 5:84-88 (July) 1946. 11. Valdes-Dapena, A., and Beckfield, W. J.: Adenomatous polyps of the large intestine: Pathology and histogenesis. Gastroenterology 32:452-461 (March) 1957. 12. Wychulis, A. R., Dockerty, M. B., Jackman, R. J., and Beahrs, O. H.: Histopathology of small polyps of the large intestine. Surg Gynec Obstet 124:87-92 (Jan.) 1967.