EDITORIALS
Therefore, from all available evidence postmenopausal bone loss is related to estrogen withdrawal and can be prevented by estrogen treatment. But it is not certain what this means for the vertebral crush fracture syndrome, or whether experience with prevention of peripheral bone loss can be extrapolated to treatment of spine and hip fractures. Gordan is quite right in focusing on fracture rate as the important criterion in evaluating efficacy of estrogen treatment, and he cites, in results reported elsewhere,4 a remarkable reduction in fracture rate following start of therapy. Other clinicians working with estrogen in such women have not had such good experience.5 And indeed it would be surprising if they had, for compression fractures must be the result of prior bone loss. The prevention of further loss may reasonably be expected from estrogen treatment, but a dramatic cessation of fracturing seems too much to expect. Many observers find that patients tend to stabilize spontaneously after a few compression fractures, with or without treatment. Hence future studies will certainly require better untreated controls than have been available in any of the results reported to date. Finally, what of safety? I quite agree with Gordan that estrogens do not harm the osteoporotic skeleton. How much they help is perhaps less certain, but they certainly do not harm bone. Endometrial cancer is quite another matter. The morbidity of spine and hip fractures seems sufficiently great to justify the small risk of increased endometrial cancer associated with estrogen, if it could be securely established that estrogens were an effective preventive measure. Hence, at a phenomenological level, long-term, well-controlled studies still need to be done, both in treatment of crush fracture patients and in defining the relationship, if any, between estrogen effects on agerelated bone loss and the prevention of crush fractures. ROBERT P. HEANEY, MD Vice President for Health Sciences Creighton University Omaha REFERENCES 1. Heaney RP: Editorial: A unified concept of osteoporosis. Am J Med 39:877-880, 1965 2. Reeve J, Hesp R, William D, et al: Anabolic effect of low doses of a fragment of human parathyroid hormone on the skeleton and post-menopausal osteoporosis. Lancet 1:1035-1038, 1976 3. Heaney RP, Recker RR: Estrogen effects on bone remodelling at menopause. Clin Res 23:535, Oct 1975 4. Gordan GS, Picchi J, Roof BS: Antifracture efficacy of longterm estrogens for osteoporosis. Trans Assoc Am Physicians 86:
326-332, 1973 5. Saville PD: In Barzel US (Ed): Osteoporosis. New York, Grune and Stratton, Inc., 1970
150
AUGUST 1976 * 125 * 2
Colonic Polyps and Carcinoma THE ROLE OF epithelial polyps in the pathogenesis of carcinoma of the colon continues to be controversial. Basil Morson has been instrumental in defining the natural history and histopathology of -colonic epithelial polyps and in resolving some of the controversy regarding the polyp-cancer sequence hypothesis. Much of the previous confusion relates to disagreement regarding histopathologic appearances of epithelial polyps and their potential for malignant transformation. In the article by Morson appearing in this issue of the WESTERN JOURNAL, these points are reviewed and clarified. Some authors may still contend that most colon carcinomas arise de novo from colonic mucosa and not from benign epithelial polyps. It is now clear that there are four distinct histologic types of epithelial polyps of the colon: (1) hyperplastic (metaplastic), (2) adenomatous (tubular, glandular), (3) mixed type (papillary, villoglandular, tubulovillous) and (4) villous adenoma. Hyperplastic polyps are very common and appear as tiny, smooth "mammilations" at time of proctosigmoidoscopic or colonoscopic examinations. These lesions have only a minor imbalance in the cycle of cell renewal and release,'-3 with minimal excess cellular production (hyperplasia). A slight expansion in the zone of cell division occurs but complete differentiation into goblet and absorptive cells is maintained. These polyps are not neoplastic and have no apparent malignant potential.1-3 On the other hand, in adenomatous, mixed or villous polyps the zone of cellular proliferation, which is normally restricted to the lower portion of the colonic crypts, is expanded and deoxyribonucleic acid (DNA) synthesis is not repressed.4 This leads to a prolonged DNA synthetic phase (prolonged S-phase). As these proliferative lesions progress, the cells develop properties that enable them to be retained in the mucosa in increasing numbers leading to the formation of polypoid structures.4 The malignant potential of these lesions is associated with the predominant histologic appearance of the
EDITORIALS
lesions as they enlarge. When the histologic appearance of the polyp is that of a villous adenoma, the likelihood of the polyp containing foci of invasive adenocarcinoma is high. Detection of foci of invasive carcinoma within the villous adenomas depends on the number of sections examined by the pathologist after resection of these lesions. The nature of the growth of villous structures may also influence the frequency of appearance of metastatic or invasive carcinoma. These lesions tend to remain sessile enabling the foci of invasive carcinoma to reach the submucosa and muscularis mucosa early in the natural history of this neoplasm.2'3 The malignant cells will then have ready access to lymphatics in the muscularis mucosa, the normal route for metastatic spread of large bowel cancer. Adenomatous (glandular tubular) polypoid lesions may give rise to malignant leisons of the bowel but at a reduced frequency when compared with villous adenomas. To a large extent this notably reduced potential, as well as a tendency in the past to include hyperplastic polyps in the same category as adenomatous polyps, is the source of much of the controversy. As Morson indicates, the common adenomatous polyp is usually small and rarely contains invasive cancer. Investigations5'6 on adenomatous polyps have defined a histologic spectrum of adenomatous polyps which ranges from well differentiated to poorly differentiated lesions containing foci of severe dysplasia (carcinoma in situ). The findings in these studies suggest that well differentiated adenomatous polyps are stable whereas those containing dysplasia are more likely to become invasive malignancies. Kalus7 showed in organ tissue cultures that more than two thirds of the adenomatous polyps cultured underwent morphologic transition from cytologically benign adenomatous polyps to focal carcinoma in situ. Moreover, a few polyps developed invasive features similar to those observed in organ-tissue cultures of colonic adenocarcinoma. Another feature of adenomaotus polyps which may contribute to the reduced incidence of invasive malignancies relates to the tendency of these polyps to become pedunculated. As the glandular head of the polyp is drawn away from the mucosa, the lymphatics are left behind in the muscularis mucosa, reducing the chance for malignant cells to reach the lymphatic channels.3 Polyps containing both glandular and villous structures have an intermediate malignant poten-
tial as compared with pure glandular or villous tumors. This is related to the presence of villous pattern and the increased size of these lesions. Previous controversy regarding malignant potential of adenomatous polyps probably relates in part to this category of lesions which in the past may have been confused with either pure glandular or pure villous adenomas. Results of several studies5'6 have shown that larger polyps are more likely to have areas of severe dysplasia, villous structures or invasive carcinoma. However, even small villous adenomas have a high risk of containing foci of invasive carcinoma. The aforementioned evidence does not refute observations that some polypoid structures, regardless of size, are polypoid carcinomas that do not originate from benign epithelial polyps. Many polypoid carcinomas are small, contain no remnants of benign tissue and, therefore, support the concept that carcinoma can arise de novo from colonic epithelium without the intermediary adenomatous polyp phase. Patients with adenocarcinoma of the colon, however, are likely to have epithelial polyps elsewhere in the colon. In patients with polyps, additional polyps are more likely to develop and there is a higher risk of colonic adenocarcinoma developing than in persons without polyps. This suggests that the intra-luminal or host factors-or both-which induce neoplasia in the colon affect the entire colonic epithelium leading to either benign neoplastic polyps or adenocarcinoma. Although the controversy regarding the malignant potential of adenomatous and villous polyps of the colon will probably continue, it should not alter the clinical approach to these lesions, particularly since introduction of fiberoptic colonoscopy. This instrument has improved the accuracy of diagnosis of colonic lesions and simplified removal of polyps. Before the introduction of fiberoptic colonoscopy, the decision to remove a polyp that was beyond range of the proctoscope meant a major surgical procedure. In skilled hands the fiberoptic colonoscope has reduced the morbidity and mortality of polypectomy to a very acceptable level even in elderly persons with other medical diseases. Wolff and Shinya8 reported their experience of endoscopic removal of more than 2,000 polyps. There were no deaths and only one complication requiring operative intervention. They state that laparotomy is now reserved for polyps not suitable for endoscopic resection or where a question of THE WESTERN JOURNAL OF MEDICINE
151
EDITORIALS
residual cancer exists. They emphasize the need for proper orientation of the excised polyp before sectioning in order to distinguish superficial areas of atypia from foci of invasive carcinoma extending into the submucosa. They recommend abdominal exploration for "polypoid carcinomas" and broad, flat lesions showing invasive cancer. If a polyp has foci of invasive carcinomas but has a long stalk with no evidence of lymphatic permeation into the stalk, leaving a zone of clearance between the level of maximal tumor penetration and the plane of cautery resection, they recommend follow-up examinations of the patient with periodic colonoscopy. The basis for conservative management relates to 12 of their patients in this category in whom abdominal exploration was carried out, and no residual cancer was detected. As a result, they now reexamine the area of previous polypectomy by colonoscopy at appropriate intervals rather than proceeding with a laparotomy and segmental resection in this group of patients. A larger series of patients managed in this fashion is required to establish this as the appropriate approach. Developments in radiologic techniques using double contrast techniques have improved the radiologic detection of colonic polyps. This approach in combination with colonoscopy provides a more reliable approach for early detection of polypoid lesions of the colon. As these techniques become more widely used and neoplastic lesions removed from the colon at an earlier time, perhaps we will see a reduction in the mortality from carcinoma of the colon. JOHN Q. STAUFFER, MD Assistant Professor of Medicine State University of New York Upstate Medical Center
College of Medicine Syracuse
REFERENCES 1. Lane N, Kaplan H, Pascal RR: Minute adenomatous and hyperplastic polyps of the colon: Divergent patterns of epithelial growth with specific associated mesenchymal changes. Gastro-
enterology 60:536-551, Apr 1971 2. Fenoglio CM, Kaye GI, Lane N: Distribution of human colonic lymphatics in normal hyperplastic, and adenomatous tissue. Gastroenterology 64:51-66, Jan 1973 3. Fenoglio DM, Lane N: The anatomical precursor of colorectal carcinoma. Cancer 34 Suppl: 819-823, Sep 1974 4. Lipkin M: Phase 1 and phase 2 proliferative lesions of colonic epithelial cells in diseases leading to colonic cancer. Cancer 34 Suppl: 878-888, Sep 1974 5. Ekelund G, Lindstrom C: Histopathological analysis of benign polyps in patients with carcinoma of the colon and rectum. Gut 15:654-663, Aug 1974 6. Potet F, Soullard J: Polyps of the rectum and colon. Gut 12:468-482, Jun 1971 7. Kalus M: Carcinoma and adenomatous polyps of the colon and rectum in biopsy and organ tissue culture. Cancer 30:972982, Oct 1972 8. Wolff WI, Shinya H: Endoscopic polypectomy: Therapeutic and clinicopathologic aspects. Cancer 36:683-690, 1975
152
AUGUST 1976 * 125 * 2
An Awesome Force in Government IT IS SUGGESTED that governmental bureaucracy, particularly the federal bureaucracy, is becoming an awesome force in government which is beginning to affect and in some instances to control the lives of Americans. In a way this is a natural result of the growing interdependence of modern society and the growing complexity of government. But most notably at the federal level the bureaucracy is beginning to develop an authority of its own capable of influencing both the executive and legislative branches of government in important ways, and even making them significantly dependent upon it for information and advice, and thus to a significant extent these elected officials become responsive to it. This can be and is rapidly becoming a source of awesome power. It makes it possible to influence the laws that are passed, and then by writing regulations which have the full effect of law, to control the manner and extent to which the laws are implemented. All too often the elected officials find themselves at an extraordinary disadvantage and curiously impotent when it comes to bringing about any change which is not desired or approved by the bureaucracy. As seems to be the case so often these days, medicine and health care find themselves at the interface where the need for some regulation of a complex and interdependent social, economic and political system confronts the rights of citizens to individual freedom and personal fulfillment. These rights, under our system, the government is supposed to protect. Government therefore is actually found to be in a kind of conflict of interest, and at the moment the regulators seem to have the upper hand in the health care field at least. In theory our system of representative government and the judiciary should strike a balance and to the extent possible achieve both goals. It is possible that this may yet be accomplished. But the awesome growth and strength of the governmental bureaucracy was not anticipated and so
Therefore, from all available evidence postmenopausal bone loss is related to estrogen withdrawal and can be prevented by estrogen treatment. But it is not certain what this means for the vertebral crush fracture syndrome, or whether experience with prevention of peripheral bone loss can be extrapolated to treatment of spine and hip fractures. Gordan is quite right in focusing on fracture rate as the important criterion in evaluating efficacy of estrogen treatment, and he cites, in results reported elsewhere,4 a remarkable reduction in fracture rate following start of therapy. Other clinicians working with estrogen in such women have not had such good experience.5 And indeed it would be surprising if they had, for compression fractures must be the result of prior bone loss. The prevention of further loss may reasonably be expected from estrogen treatment, but a dramatic cessation of fracturing seems too much to expect. Many observers find that patients tend to stabilize spontaneously after a few compression fractures, with or without treatment. Hence future studies will certainly require better untreated controls than have been available in any of the results reported to date. Finally, what of safety? I quite agree with Gordan that estrogens do not harm the osteoporotic skeleton. How much they help is perhaps less certain, but they certainly do not harm bone. Endometrial cancer is quite another matter. The morbidity of spine and hip fractures seems sufficiently great to justify the small risk of increased endometrial cancer associated with estrogen, if it could be securely established that estrogens were an effective preventive measure. Hence, at a phenomenological level, long-term, well-controlled studies still need to be done, both in treatment of crush fracture patients and in defining the relationship, if any, between estrogen effects on agerelated bone loss and the prevention of crush fractures. ROBERT P. HEANEY, MD Vice President for Health Sciences Creighton University Omaha REFERENCES 1. Heaney RP: Editorial: A unified concept of osteoporosis. Am J Med 39:877-880, 1965 2. Reeve J, Hesp R, William D, et al: Anabolic effect of low doses of a fragment of human parathyroid hormone on the skeleton and post-menopausal osteoporosis. Lancet 1:1035-1038, 1976 3. Heaney RP, Recker RR: Estrogen effects on bone remodelling at menopause. Clin Res 23:535, Oct 1975 4. Gordan GS, Picchi J, Roof BS: Antifracture efficacy of longterm estrogens for osteoporosis. Trans Assoc Am Physicians 86:
326-332, 1973 5. Saville PD: In Barzel US (Ed): Osteoporosis. New York, Grune and Stratton, Inc., 1970
150
AUGUST 1976 * 125 * 2
Colonic Polyps and Carcinoma THE ROLE OF epithelial polyps in the pathogenesis of carcinoma of the colon continues to be controversial. Basil Morson has been instrumental in defining the natural history and histopathology of -colonic epithelial polyps and in resolving some of the controversy regarding the polyp-cancer sequence hypothesis. Much of the previous confusion relates to disagreement regarding histopathologic appearances of epithelial polyps and their potential for malignant transformation. In the article by Morson appearing in this issue of the WESTERN JOURNAL, these points are reviewed and clarified. Some authors may still contend that most colon carcinomas arise de novo from colonic mucosa and not from benign epithelial polyps. It is now clear that there are four distinct histologic types of epithelial polyps of the colon: (1) hyperplastic (metaplastic), (2) adenomatous (tubular, glandular), (3) mixed type (papillary, villoglandular, tubulovillous) and (4) villous adenoma. Hyperplastic polyps are very common and appear as tiny, smooth "mammilations" at time of proctosigmoidoscopic or colonoscopic examinations. These lesions have only a minor imbalance in the cycle of cell renewal and release,'-3 with minimal excess cellular production (hyperplasia). A slight expansion in the zone of cell division occurs but complete differentiation into goblet and absorptive cells is maintained. These polyps are not neoplastic and have no apparent malignant potential.1-3 On the other hand, in adenomatous, mixed or villous polyps the zone of cellular proliferation, which is normally restricted to the lower portion of the colonic crypts, is expanded and deoxyribonucleic acid (DNA) synthesis is not repressed.4 This leads to a prolonged DNA synthetic phase (prolonged S-phase). As these proliferative lesions progress, the cells develop properties that enable them to be retained in the mucosa in increasing numbers leading to the formation of polypoid structures.4 The malignant potential of these lesions is associated with the predominant histologic appearance of the
EDITORIALS
lesions as they enlarge. When the histologic appearance of the polyp is that of a villous adenoma, the likelihood of the polyp containing foci of invasive adenocarcinoma is high. Detection of foci of invasive carcinoma within the villous adenomas depends on the number of sections examined by the pathologist after resection of these lesions. The nature of the growth of villous structures may also influence the frequency of appearance of metastatic or invasive carcinoma. These lesions tend to remain sessile enabling the foci of invasive carcinoma to reach the submucosa and muscularis mucosa early in the natural history of this neoplasm.2'3 The malignant cells will then have ready access to lymphatics in the muscularis mucosa, the normal route for metastatic spread of large bowel cancer. Adenomatous (glandular tubular) polypoid lesions may give rise to malignant leisons of the bowel but at a reduced frequency when compared with villous adenomas. To a large extent this notably reduced potential, as well as a tendency in the past to include hyperplastic polyps in the same category as adenomatous polyps, is the source of much of the controversy. As Morson indicates, the common adenomatous polyp is usually small and rarely contains invasive cancer. Investigations5'6 on adenomatous polyps have defined a histologic spectrum of adenomatous polyps which ranges from well differentiated to poorly differentiated lesions containing foci of severe dysplasia (carcinoma in situ). The findings in these studies suggest that well differentiated adenomatous polyps are stable whereas those containing dysplasia are more likely to become invasive malignancies. Kalus7 showed in organ tissue cultures that more than two thirds of the adenomatous polyps cultured underwent morphologic transition from cytologically benign adenomatous polyps to focal carcinoma in situ. Moreover, a few polyps developed invasive features similar to those observed in organ-tissue cultures of colonic adenocarcinoma. Another feature of adenomaotus polyps which may contribute to the reduced incidence of invasive malignancies relates to the tendency of these polyps to become pedunculated. As the glandular head of the polyp is drawn away from the mucosa, the lymphatics are left behind in the muscularis mucosa, reducing the chance for malignant cells to reach the lymphatic channels.3 Polyps containing both glandular and villous structures have an intermediate malignant poten-
tial as compared with pure glandular or villous tumors. This is related to the presence of villous pattern and the increased size of these lesions. Previous controversy regarding malignant potential of adenomatous polyps probably relates in part to this category of lesions which in the past may have been confused with either pure glandular or pure villous adenomas. Results of several studies5'6 have shown that larger polyps are more likely to have areas of severe dysplasia, villous structures or invasive carcinoma. However, even small villous adenomas have a high risk of containing foci of invasive carcinoma. The aforementioned evidence does not refute observations that some polypoid structures, regardless of size, are polypoid carcinomas that do not originate from benign epithelial polyps. Many polypoid carcinomas are small, contain no remnants of benign tissue and, therefore, support the concept that carcinoma can arise de novo from colonic epithelium without the intermediary adenomatous polyp phase. Patients with adenocarcinoma of the colon, however, are likely to have epithelial polyps elsewhere in the colon. In patients with polyps, additional polyps are more likely to develop and there is a higher risk of colonic adenocarcinoma developing than in persons without polyps. This suggests that the intra-luminal or host factors-or both-which induce neoplasia in the colon affect the entire colonic epithelium leading to either benign neoplastic polyps or adenocarcinoma. Although the controversy regarding the malignant potential of adenomatous and villous polyps of the colon will probably continue, it should not alter the clinical approach to these lesions, particularly since introduction of fiberoptic colonoscopy. This instrument has improved the accuracy of diagnosis of colonic lesions and simplified removal of polyps. Before the introduction of fiberoptic colonoscopy, the decision to remove a polyp that was beyond range of the proctoscope meant a major surgical procedure. In skilled hands the fiberoptic colonoscope has reduced the morbidity and mortality of polypectomy to a very acceptable level even in elderly persons with other medical diseases. Wolff and Shinya8 reported their experience of endoscopic removal of more than 2,000 polyps. There were no deaths and only one complication requiring operative intervention. They state that laparotomy is now reserved for polyps not suitable for endoscopic resection or where a question of THE WESTERN JOURNAL OF MEDICINE
151
EDITORIALS
residual cancer exists. They emphasize the need for proper orientation of the excised polyp before sectioning in order to distinguish superficial areas of atypia from foci of invasive carcinoma extending into the submucosa. They recommend abdominal exploration for "polypoid carcinomas" and broad, flat lesions showing invasive cancer. If a polyp has foci of invasive carcinomas but has a long stalk with no evidence of lymphatic permeation into the stalk, leaving a zone of clearance between the level of maximal tumor penetration and the plane of cautery resection, they recommend follow-up examinations of the patient with periodic colonoscopy. The basis for conservative management relates to 12 of their patients in this category in whom abdominal exploration was carried out, and no residual cancer was detected. As a result, they now reexamine the area of previous polypectomy by colonoscopy at appropriate intervals rather than proceeding with a laparotomy and segmental resection in this group of patients. A larger series of patients managed in this fashion is required to establish this as the appropriate approach. Developments in radiologic techniques using double contrast techniques have improved the radiologic detection of colonic polyps. This approach in combination with colonoscopy provides a more reliable approach for early detection of polypoid lesions of the colon. As these techniques become more widely used and neoplastic lesions removed from the colon at an earlier time, perhaps we will see a reduction in the mortality from carcinoma of the colon. JOHN Q. STAUFFER, MD Assistant Professor of Medicine State University of New York Upstate Medical Center
College of Medicine Syracuse
REFERENCES 1. Lane N, Kaplan H, Pascal RR: Minute adenomatous and hyperplastic polyps of the colon: Divergent patterns of epithelial growth with specific associated mesenchymal changes. Gastro-
enterology 60:536-551, Apr 1971 2. Fenoglio CM, Kaye GI, Lane N: Distribution of human colonic lymphatics in normal hyperplastic, and adenomatous tissue. Gastroenterology 64:51-66, Jan 1973 3. Fenoglio DM, Lane N: The anatomical precursor of colorectal carcinoma. Cancer 34 Suppl: 819-823, Sep 1974 4. Lipkin M: Phase 1 and phase 2 proliferative lesions of colonic epithelial cells in diseases leading to colonic cancer. Cancer 34 Suppl: 878-888, Sep 1974 5. Ekelund G, Lindstrom C: Histopathological analysis of benign polyps in patients with carcinoma of the colon and rectum. Gut 15:654-663, Aug 1974 6. Potet F, Soullard J: Polyps of the rectum and colon. Gut 12:468-482, Jun 1971 7. Kalus M: Carcinoma and adenomatous polyps of the colon and rectum in biopsy and organ tissue culture. Cancer 30:972982, Oct 1972 8. Wolff WI, Shinya H: Endoscopic polypectomy: Therapeutic and clinicopathologic aspects. Cancer 36:683-690, 1975
152
AUGUST 1976 * 125 * 2
An Awesome Force in Government IT IS SUGGESTED that governmental bureaucracy, particularly the federal bureaucracy, is becoming an awesome force in government which is beginning to affect and in some instances to control the lives of Americans. In a way this is a natural result of the growing interdependence of modern society and the growing complexity of government. But most notably at the federal level the bureaucracy is beginning to develop an authority of its own capable of influencing both the executive and legislative branches of government in important ways, and even making them significantly dependent upon it for information and advice, and thus to a significant extent these elected officials become responsive to it. This can be and is rapidly becoming a source of awesome power. It makes it possible to influence the laws that are passed, and then by writing regulations which have the full effect of law, to control the manner and extent to which the laws are implemented. All too often the elected officials find themselves at an extraordinary disadvantage and curiously impotent when it comes to bringing about any change which is not desired or approved by the bureaucracy. As seems to be the case so often these days, medicine and health care find themselves at the interface where the need for some regulation of a complex and interdependent social, economic and political system confronts the rights of citizens to individual freedom and personal fulfillment. These rights, under our system, the government is supposed to protect. Government therefore is actually found to be in a kind of conflict of interest, and at the moment the regulators seem to have the upper hand in the health care field at least. In theory our system of representative government and the judiciary should strike a balance and to the extent possible achieve both goals. It is possible that this may yet be accomplished. But the awesome growth and strength of the governmental bureaucracy was not anticipated and so
