- Email: [email protected]
RELATION BETWEEN METAPLASTIC POLYP AND CARCINOMA OF THE COLORECTUM
28
RCDA 1 K04-NS-00601 (MJC); NS-18409 (MJC) AM 22125 (MJC); RCDA 1-KO4-AM-00153(ADR);CIAI K03-HD-00439(WSE);CA-07535(RMM); AM-26741 (PBL); AM-20917 (PBL); AA-03504(PBL); and HD-13527 (PEL). This research was conducted in part by Clayton Foundation for Research, California Division; W. V. and J. S. are Clayton Foundation investigators. S. B. was supported by the Medical Research Council and the British Diabetic Association.
Correspondence should be addressed to M. 0. T., Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908, U.S.A.
Hypothesis RELATION BETWEEN METAPLASTIC POLYP AND CARCINOMA OF THE COLORECTUM
JEREMY R. JASS Department of Histopathology, Westminster Medical School, London SW1P 2AR
REFERENCES 1. Thorner MO, Perryman RL, Cronin MJ, Rogol AD, Draznin M, Johanson A, Vale W, Horvath E, Kovacs K. Somatotroph hyperplasia: Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormonereleasing factor J Clin Invest 1982; 70: 965-77 2. Rivier J, Spiess J, Thorner M, Vale W. Characterization ofa growth hormone-releasing factor from a human pancreatic islet tumour. Nature 1982; 300: 276-78. 3. Spiess J, Rivier J, Thorner M, Vale W. Primary structure of a growth hormone releasing factor from a human pancreatic islet tumor Biochemistry 1982; 21: 6037-40 4. Merrifield RB. Solid phase peptide synthesis. I. The synthesis ofa tetrapeptide. J Am Chem Soc 1963; 85: 2149-56. 5. Rivier J. Somatostatin. Total solid phase synthesis. J Am Chem Soc 1974; 96: 2986-92. 6. Cronin MJ, Rogol AD, Dabney LG, Thorner MO. Selective growth hormone and cyclic AMP stimulating activity is present in a human pancreatic islet cell tumor. J Clin Endocr Metab 1982; 55: 381-83 7. Cronin MJ, Rogol AD, MacLeod RM, Keefer DA, Login IS, Borges JLC, Thorner MO. Biological activity of a growth hormone releasing factor secreted by a human tumor.
Am J Physiol (in press).
8. Thorner MO, Martin WH, Rogol AD, Morris JL, Perryman RL, Conway BP, Howards SS, et al. Rapid regression of pituitary prolactinomas during bromocriptine treatment. J Clin Endocr Metab 1980; 51: 438-45. 9. Miles IEM, Hales CN. Immunoradiometric assay of human growth hormone. Lancet
1968, ii: 492-93. SR, Long RG Radioimmunoassay of gut regulatory peptides. London: W B. Saunders, 1982 11. Sterling RE, Nagao RR. Evaluation of the glucose analyzer. Clin Chem 1969, 15: 10 Bloom
801-02.
P, Bohlen P, Esch F, Ling N, Wehrenberg W. Growth hormonereleasing factor from a human pancreatic tumour that caused acromegaly. Science 1982; 218: 585-87. 13. Imura H. Ectopic hormone syndromes. Clin Endocr Metab 1980; 9: 235-60 14. Brazeau P, Ling N, Bohlen P, Esch F, Ying S, Guillemin R. Growth hormone releasing factor, somatocrinin, releases pituitary growth hormone in vitro. Proc Soc Natl Acad Sci USA (in press). 15. Reichlin S. Growth hormone and the hypothalamus. Endocrinology 1960; 67: 760-73. 16. Deuben RR, Meites J. Stimulation of pituitary growth hormone release by a hypothalamic extract in vitro. Endocrinology 1964; 74: 408-14 17. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R. Hypothalamic polypeptide that inhibits the secretion of immunoreactive growth hormone. Science 1973; 179; 77-79. 18. Harris GW. Neurocontrol of the pituitary gland. Physiol Rev 1948; 28: 139-79. 19. Bogdanove EM, Lipner HJ. Intestinal absorption of glucose in hypothalamic obesity. Proc Soc Exp Biol Med 1952, 81: 410-12. 20. Frohman LA, Bernadis LL, Kant KJ. Hypothalamic stimulation of growth hormone secretion Science 1968; 162: 580-82. 12. Guillemin R, Brazeau
21. Reichlin S. Growth hormone content of pituitaries from rats with 22.
hypothalamic
lesions. Endocrinology 1961; 69: 225-30. Martin JB. Neural regulation of growth hormone secretion. N Engl J Med 1973; 288:
1384-92. 23 Franz J, Haselbach
CH, Libert O. Studies of the effect of hypothalamic extracts on somatotrophic pituitary function. Acta Endocr 1962; 41: 336-50. 24. Schally AV, Steelman SL, Bowers CY. Effect of hypothalamic extracts on release of growth hormone in vitro. Proc Soc Exp Biol Med 1965; 119: 208-12. 25. Vale WW, Rivier JE. Effects of putative growth hormone releasing factor, phorbolmyristate acetate and somatostatin on the secretion of growth hormone in vitro. 6th International Congress of Endocrinology, Melbourne, Australia, 1980. 26 Villarreal JA, Vale W, Brown M, Butcher M, Brazeau P, Rivier C, Burgus R. Myelin basic protein: A substance that releases immunoreactive growth hormone in vitro. Biochem Biophys Res Commun 1976; 70: 551-58 27. Schally AV, Baba Y, Nair RMG, Bennett CD. The amino acid sequence of a peptide with growth-hormone-releasing activity isolated from porcine hypothalamus. J Biol Chem 1971; 246: 6647-50. 28. Frohman LA, Szabo M, Berelowitz M, Stachura ME. Partial purification and characterisation of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acomegaly. J Clin Invest 1980; 65: 43-54. 29. Leveston SA, McKeel DW, Buckley PJ, Deschryver K, Greider MH, Jaffe BM, Daughaday WH. Acromegaly and Cushing’s syndrome associated with foregut carcinoid tumor. J Clin Endocr Metab 1981; 53: 682-89. 30. Bohlen P, Thorner M, Cronin M, Shively J, Scheithauer B. Isolation from human neoplastic tissue and partial characterization of a growth hormone releasing factor (GRF). 63rd Meeting of the Endocrine Society, San Francisco, 1982. 31. Esch FS, Bohlen P, Ling NC, Brazeau WB, Thorner MO, Cronin MJ, Guillemin R. Characterization of a 40 residue peptide from a human pancreatic tumour with growth hormone releasing activity. Biochem Biophys Res Comm 1982; 109: 152-58. 32. Tatemoto K, Mutt V Isolation and characterization of the intestinal peptide porcine PHI[PHI-27], a new member of the glucagon-secretin family. Proc Natl Acad Sci USA 1981; 78: 6603-07.
Carcinomas and metaplastic polyps of the colorectum share a variety of phenotypes which are not evidenced by either tubular adenomas or normal colorectal mucosa. This supports the view that adenomas and metaplastic polyps are separate entities with differing aetiologies. To explain the functional overlap between metaplastic polyps and carcinoma, it is suggested that the two separate sets of factors which lead to the development of adenomas and metaplastic polyps are both required to bring about malignant transformation within the colorectum. Identification of the factors causing metaplastic polyp formation could therefore have important implications in the prevention of colorectal cancer.
Summary
INTRODUCTION
THE commonest polyps of the colorectum are the adenoma and the metaplastic polyp. The majority of colorectal cancers arise in pre-existing adenomas.l,2 On the other hand, the metaplastic polyp is regarded as an innocuous lesion, unrelated to colorectal cancer.2,3 Metaplastic polyps have been assumed not to differ qualitatively from normal colorectal mucosa, but several exceptions to this rule have been documented. Thus metaplastic polyps show:
1. Increased
expression of carcinoembryonic antigen
(CEA).4,5
2. Reduced secretion ofO-acylated sialomucin.s 3. Reduced activity of various cytoplasmic enzymes.6,7 4. Absence of IgA secretory activity (Jass JR, unpublished
observation). In these respects, metaplastic polyps not only reveal differences from normal colorectal mucosa but also show a functional overlap with colorectal carcinoma. On the other hand, these functional changes are not necessarily revealed in adenomas. Increased expression of CEA is demonstrated only in areas of severe adenomatous dysplasia.8,9 Reduced secretion of 0-acylated sialomucin is observed in villous adenomas and areas of severe adenomatous dysplasia but not in tubular adenomas.10 A similar profile of reduced enzyme activities occurs in villous adenomas and foci of severe adenomatous dysplasia but not in tubular adenomas. 6,7 In the last, certain enzyme activities are increased, notably succinic dehydrogenase, glycerophosphate dehydrogenase, and monoamine oxidase. Reduced IgA secretory activity parallels the grade of dysplasia in adenomas. Absence of cytoplasmic IgA is revealed only in severe dysplasia and carcinoma. ’ These observations invite a reappraisal of the metaplastic polyp and its role in colorectal carcinogenesis.
qualitative
HYPOTHESIS
There between
are three explanations for the functional overlap metaplastic polyps and colorectal carcinoma:
29
1. The overlap is entirely fortuitous. 2. Metaplastic polyps and colorectal carcinoma have
overlapping aetiologies. 3. Metaplastic polyps are precancerous. If the association were entirely fortuitous, it would still be necessary to explain why metaplastic polyps differ in various ways from normal colorectal mucosa. The columnar cells of normal colorectal epithelium have a secretory function, elaborating various glycoproteins including secretory component13 and CEA. 14 The ratio of these columnar cells to goblet cells is greatly increased in metaplastic polyps. Furthermore, the migration of cells from crypt base to surface is slower in metaplastic polyps than in normal mucosa.15 Metaplastic cells therefore have a lengthened lifespan, and reveal a resultant electron-microscopic studies 16 of various "hypermaturation" cytoplasmic organelles. This includes a prominence of secretory vesicles within the columnar cell population, indicating an accentuation of their normal secretory function. These factors might explain, at least in part, the various histochemical changes, including the increased expression of CEA. However, IgA secretory activity is not exaggerated, being notably absent in
metaplastic polyps (Jass JR, unpublished observation). Colorectal carcinoma is characterised by a low mitotic index, a low percentage of cells in DNA synthesis and in the proliferative cycle, and long cell-cycle times.17 Thus, as in the metaplastic polyp, normal rapid cell turnover is blocked, and the lifespan of individual cells is increased. It is therefore possible that the functional overlap of metaplastic polyps and colorectal carcinoma is indeed fortuitous and due to a shared hypokinesis. However, this explanation becomes less acceptable in the light of the following observations: 1. Metaplastic polyps show a greater tendency than adenomas to congregate in the rectum and sigmoid colon, the principal sites for the development of colorectal cancer. 18,19 2. The incidence of metaplastic polyps is raised in populations at a high risk of developing colorectal cancer. 19 3. The incidence of metaplastic polyps rises in patients migrating from low-risk to high-risk areas. 18 4. The incidence of metaplastic polyps is not necessarily
age-dependent. 20 It therefore seems reasonable to challenge the widely held view that the metaplastic polyp is a degenerative lesion associated with ageing and unrelated to colorectal cancer. 2,3 However, a satisfactory explanation for the above findings should not contradict clinical experience regarding the natural history of this lesion. The metaplastic polyp cannot be regarded as a precancerous lesion. The Columbia University group describe their experience as follows:2 of 1000 randomly chosen surgically excised polyps, 900 will be metaplastic, 90 will be small adenomas, and 10 will be large adenomas in which one has invasive carcinoma. However, detailed necropsy studies of the entire colorectum indicate the ratio of adenoma to metaplastic polyp to be closer to unity.18,20 Furthermore, dysplastic and even malignant change has been described within metaplastic polyps. 21-23 This is a rare event, however, and appears to occur in patients with large, multiple
metaplastic polyps (metaplastic polyposis). Several workers regard the metaplastic polyp and adenoma 24-26 as manifestations of the same basic dyskinetic disorder. It is certainly possible to observe hybrid lesions in which features of metaplastic, adenomatous, and even juvenile polyps are combined. It is also possible that epithelium undergoing regenerative change is rendered more susceptible
factors causing metaplastic polyp formation. However, a compilation of structural, functional, and clinical data indicates that adenomatous and metaplastic changes are quite distinct, with separate aetiologies.’6 The majority of tubular adenomas will never develop into malignant lesions. The tubular adenoma reveals a degree of cytological and architectural atypia, but not the changes in phenotype characterising malignant epithelium. On the other hand, metaplastic polyps show the appropriate functional changes without the prerequisite architectural and cytological atypia. It is suggested, therefore, that the factors which produce metaplastic polyps and tubular adenomas are both required for the development of a malignant neoplasm. Clearly the generation of a clone of malignant cells cannot lead to an invasive growth if the cells are allowed to migrate normally and slough from the epithelial surface. In metaplastic polyps migration and shedding are retarded. It is possible that the same retarding factor prevents the rapid loss of adenomatous cells, increases their exposure time to carcinogens, and provides transformed cells with time to to
invade the host. As noted above, the alterations of phenotype characterising metaplastic changes are combined with epithelial dysplasia in two circumstances. Thus, both villous adenomas and areas of severe dysplasia (within any type of adenoma) reveal the appropriate changes in mucin 10 and enzyme6,7 histochemistry. In addition, increased expression of CEA and an absence of IgA secretory activity are observed in severe dysplasia.8,9 It is significant that severe dysplasia and a villous growth pattern are selective markers of increased malignant
risk.’1 CONCLUSION
It is suggested that separate sets of factors lead to the formation of metaplastic polyps and adenomas within the colorectum but that both sets are required for the development of a malignant neoplasm. This hypothesis explains why the metaplastic polyp and carcinoma share a constellation of functional changes and similar sites within the colorectum. It also obviates the need to regard the metaplastic polyp as a precancerous lesion, for which there is no clinical evidence. The metaplastic polyp may therefore be regarded as a marker of high-risk populations but as of no significance to the individual. However, the identification of the factors causing metaplastic polyp formation could have important implications in the prevention of colorectal cancer. REFERENCES 1. Morson BC. Evolution of cancer of the colon and rectum. Cancer 1974; 34: 845-49. 2. Fenoglio CH, Lane N. The anatomical precursor of colorectal carcinoma Cancer 1974; 34: 918-23 3. Arthur JF. Structure and significance of metaplastic nodules in the rectal mucosa. J Clin Pathol 1968; 21: 735. 4. Skinner JM, Whitehead R. Tumour-associated antigens in polyps and carcinoma of the human large bowel. Cancer 1981; 47: 1241-45. 5. Jass JR, Filipe MI, Abbas S, Falcon CAJ, Wilson Y, Lovell D. A morphological and histochemical study of metaplastic polyps of the colorectum. Cancer (in press). 6. Czernobilsky B, Tsou KC Adenocarcinoma, adenomas and polyps of the colon Cancer 1968; 21: 165-77. 7 Wattenberg LW. A histochemical study of five oxidative enzymes in carcinoma of the large intestine in man. Am J Pathol 1959, 35: 113-26 8. O’Brien MJ, Zamcheck N, Burke B, Kirkham S, Saravis CA, Gottolieb LS. Immunocytochemical localisation of carcinoembryonic antigen in benign and malignant colorectal tissues. Am JClin Pathol 1981; 75: 283-90. 9. Isaacson P, Le Vann HP. The demonstration of carcinoembryonic antigen in colorectal carcinoma and colonic polyps using an immunoperoxidase technique. Cancer 1976; 38: 1348-56. 10. Culling CFA, Reid PE, Clay MG, Dunn WL. A new histochemical technique of use in the interpretation and diagnosis of adenocarcinoma and villous lesions in the large intestine. J Clin Pathol 1977; 30: 1056-62
30
Infection and the
Reviews of Books Understanding and Treating Tardive Dyskinesia Dilip V. Jeste and Richard J. Wyatt, National Institute of Mental Health, Bethesda, Maryland. New York: Guildford Press. 1982. Pp. 363.$29.50. THE introduction of neuroleptics has revolutionised the treatof psychotic disorders. It has greatly elucidated the basic biochemical mechanisms involved in the psychoses, but its longterm use has caused no less puzzling a phenomenon than tardive dyskinesia, a syndrome of complex and often bizarre choreic and dystonic movements which often persists and is even exacerbated by the withdrawal of the causative drug. It poses many tantalising questions: Why is it apparently more common in the elderly? Is it more likely to occur in patients with pre-existing cerebral pathology? Why, if it is caused by antipsychotic drugs, are these very drugs one of the few beneficial forms of therapy? This book is a comprehensive review of this subject by two authors, and the unity of style and purpose sets it apart from many other multiauthor books on the same topic. It has major sections dealing with the epidemiology and prevalence of the disorder, and with those characteristics which define patients at high risk of tardive dyskinesia. The wide variety of biochemical theories which have been advanced to explain the phenomenon are reviewed and dismissed as being inadequate. Relevant neurophysiological and neuropathological studies are considered and tardive dyskinesia is compared with other drug-induced dyskinesias. There is a very useful section on animal models of tardive dyskinesia, and the book ends with a general discussion of possible methods of treatment and ment
prevention. The book represents an excellent and up-to-date review of the subject which will be invaluable to both psychiatrists and neurologists. The authors adopt a critical attitude to the large volume of work they review, and their suggestions for a clinical definition of the syndrome and future clinical studies of treatment are long overdue. However, the overall conclusions are diappointing. We remain ignorant of the mechanisms by which this troublesome movement disorder is mediated, have no effective treatment, and, more worryingly, are unable to define a means of preventing its
onset.
Department of Neurology, Walton Hospital, LIverpool
D. W. CHADWICK
Weisz-Carrington P, Poger ME, Lamm ME. Secretory immunoglobulins in colonic neoplasms. Am J Pathol 1976; 85: 303-14. 12. Isaacson P. Immunoperoxidase study of the secretory immunoglobulin System in colonic neoplasia. J Clin Pathol 1982; 35: 14-25. 13. Poger ME, Hirsch BR, Lamm ME. Synthesis of secretory component by colonic neoplasms. Am J Pathol 1976; 82: 327-38. 14. Ahnen DJ, Nakane PK, Brown WR. Ultrastructural localisation of carcinoembryonic 11.
antigen 15.
16.
17.
in
normal intestine and colon
cancer.
Cancer 1982; 49: 2077-90.
Hayashi T, Yatani R, Apostol J, Stemmerman GN. Pathogenesis of hyperplastic polyps of the colon. A hypothesis based on ultrastructure and in-vitro kinetics. Gastroenterology 1974; 66: 347-56. Kaye GI, Fenoglio CM, Pascal RR, Lane N. Comparative electron microscopic features of normal, hyperplastic and adenomatous human colonic epithelium. Gastroenterology 1973; 64: 926-45. Lipkin M, Deschner EF. Gastrointestinal cells: proliferation and differentiation. In: Sircus W, Smith AN, eds. Scientific foundations of gastroenterology. Heinemann
Medical Books Ltd. London, 1980. 25-30. 18. Stemmerman GN, Yatani R. Diverticulosis and polyps of the large intestine. A necropsy study of Hawaii Japanese. Cancer 1972; 31: 1260-70. 19. Correa P. Epidemiology of polyps and cancer. In: Morson BC, ed. The pathogenesis of colorectal cancer. Major problems in pathology vol. 10. Philadelphia, London, Toronto: WB Saunders, 1978: 126-52. 20. Vatn MH, Stalsberg H. The prevalence of polyps of the large intestine in Oslo. An autopsy study. Cancer 1982; 49: 819-25. 21. Cooper HS, Patchefsky AS, Marks G. Adenomatous and carcinomatous changes within hyperplastic colonic epithelium. Dis Colon Rectum 1979; 22: 152-56. 22. Sumner HW, Wasserman NF, McClain CJ. Giant hyperplastic polyposis of the colon. Dig Dis Sci 1981; 26: 85-89. 23. Estrada RG, Spjut HJ Hyperplastic polyps of the large bowel. Am J Surg Pathol 1980; 4: 127-33. 24. Potet F, Soullard J Polyps of the rectum and colon. Gut 1971; 12: 468-82. 25. Goodman ZD, Yardley JH, Milligan FD. Pathogenesis of colonic polyps in multiple juvenile polyposis. Cancer 1979; 43: 1906-13. 26. Grigioni WF, Alampi G, Martinelli G, Piccaluga A. Atypical juvenile polyposis. Histopathology 1981; 5: 361-76.
Surgical Patient
Clinical Surgery International, vol. IV. Edited by Hiram C. Polk, Jr, University of Louisville School of Medicine. Edinburgh: Churchill Livingstone. 1982. Pp. 219.;CI5.
last, a short readable text on surgical microbiology which is bedevilled by turgid accounts of minimum inhibitory concentrations and differential colony counts. This excellent monograph will give "the medical student beginning his clinical clerkship" a comprehensive account of the host, the pathogen, and the environment as determinants of infection. For the "seasoned and skilled practitioner" it provides authoritative views on the prevention and treatment of common surgical infections, with a strong emphasis on practical details. Though there are only three European contributors and fifteen from North America, I believe that most of the therapeutic advice will be acceptable on both sides of the Atlantic. Perhaps metronidazole is somewhat undervalued as an anti-anaerobic agent, but this must be due to the initial prescribing difficulties in the U.S.A. No doubt when the fourth and fifth generation cephalosporins are developed some of the details on "antibiotic choice" may have to be updated. In his epilogue, the editor is too modest by far when he aims for "the average patient in the care of the median surgeon"-his book is at least two standard deviations better than that. AT
not
Department of Surgery, City Hospital, Nottingham
T. W. BALFOUR
Essentials of Endocrinology Edited by J. L. H. O’Riordan, P. G. Malan, and R. P. Gould, Middlesex Hospital Medical School, London. Oxford: Blackwell. 1982. Pp. 230.
7.50. THE authors of this book, which is based on the teaching given during the second year of the basic medical sciences course at the Middlesex Hospital, hope that it will appeal to medical students and to those taking a science degree. It certainly will, but it should also become compulsory (and probably compulsive) reading for anyone,
medical or basic scientist, with a continuing postgraduate interest in endocrinology and metabolism. Several mammoth tomes on endocrinology have appeared recently, which are daunting and certainly not easy to read from cover to cover; it is therefore heartening to be presented with a succinct, stylish, and inexpensive volume which contains the nitty-gritty of current endocrinology and is short enough to be read and re-read. It is always refreshing to hear the slant which others in one’s own field put on problems that are so familiar that one has almost stopped thinking about them. Repeatedly in this book I found myself interested and enlightened either by a new fact or a new angle on old facts. There is an introductory chapter on the endocrine system and the molecular basis for hormone action, and chapters on the hypothalamus and pituitary, the adrenal gland, reproductive endocrinology, the thyroid gland, calcium-regulating hormones, and pancreatic and gastrointestinal hormones. Each chapter begins with an interesting historical introduction. The morphology, physiology and biochemistry, and development of the particular part of the endocrine system are then considered, followed by a brief description of the salient features of clinical disorders and an outline of their treatment. Overall the authors and editors have achieved a remarkable uniformity of style and great clarity. The editors and publishers are also to be congratulated on a remarkably low incidence of errors and misprints. Most of the figures are simple line-drawings with a few histological pictures; I would have welcomed more of both, for example, illustrating the histology of the testis, the morphology of normal bone cells, and histology of bone disorders such as osteomalacia. I detected remarkably few errors-although I know of no human being (as distinct from desert rat) who can concentrate his urine up to 1400 mosmol/kg (page 55). This is principally a book about human endocrinology, although there are welcome meanders into comparative and evolutionary aspects (for example, the origin of the C cells). The book deserves to be very successful, and I am sure that at its price it will be. Department of Medicine, Hope Hospital, Salford
D. C. ANDERSON
RCDA 1 K04-NS-00601 (MJC); NS-18409 (MJC) AM 22125 (MJC); RCDA 1-KO4-AM-00153(ADR);CIAI K03-HD-00439(WSE);CA-07535(RMM); AM-26741 (PBL); AM-20917 (PBL); AA-03504(PBL); and HD-13527 (PEL). This research was conducted in part by Clayton Foundation for Research, California Division; W. V. and J. S. are Clayton Foundation investigators. S. B. was supported by the Medical Research Council and the British Diabetic Association.
Correspondence should be addressed to M. 0. T., Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908, U.S.A.
Hypothesis RELATION BETWEEN METAPLASTIC POLYP AND CARCINOMA OF THE COLORECTUM
JEREMY R. JASS Department of Histopathology, Westminster Medical School, London SW1P 2AR
REFERENCES 1. Thorner MO, Perryman RL, Cronin MJ, Rogol AD, Draznin M, Johanson A, Vale W, Horvath E, Kovacs K. Somatotroph hyperplasia: Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormonereleasing factor J Clin Invest 1982; 70: 965-77 2. Rivier J, Spiess J, Thorner M, Vale W. Characterization ofa growth hormone-releasing factor from a human pancreatic islet tumour. Nature 1982; 300: 276-78. 3. Spiess J, Rivier J, Thorner M, Vale W. Primary structure of a growth hormone releasing factor from a human pancreatic islet tumor Biochemistry 1982; 21: 6037-40 4. Merrifield RB. Solid phase peptide synthesis. I. The synthesis ofa tetrapeptide. J Am Chem Soc 1963; 85: 2149-56. 5. Rivier J. Somatostatin. Total solid phase synthesis. J Am Chem Soc 1974; 96: 2986-92. 6. Cronin MJ, Rogol AD, Dabney LG, Thorner MO. Selective growth hormone and cyclic AMP stimulating activity is present in a human pancreatic islet cell tumor. J Clin Endocr Metab 1982; 55: 381-83 7. Cronin MJ, Rogol AD, MacLeod RM, Keefer DA, Login IS, Borges JLC, Thorner MO. Biological activity of a growth hormone releasing factor secreted by a human tumor.
Am J Physiol (in press).
8. Thorner MO, Martin WH, Rogol AD, Morris JL, Perryman RL, Conway BP, Howards SS, et al. Rapid regression of pituitary prolactinomas during bromocriptine treatment. J Clin Endocr Metab 1980; 51: 438-45. 9. Miles IEM, Hales CN. Immunoradiometric assay of human growth hormone. Lancet
1968, ii: 492-93. SR, Long RG Radioimmunoassay of gut regulatory peptides. London: W B. Saunders, 1982 11. Sterling RE, Nagao RR. Evaluation of the glucose analyzer. Clin Chem 1969, 15: 10 Bloom
801-02.
P, Bohlen P, Esch F, Ling N, Wehrenberg W. Growth hormonereleasing factor from a human pancreatic tumour that caused acromegaly. Science 1982; 218: 585-87. 13. Imura H. Ectopic hormone syndromes. Clin Endocr Metab 1980; 9: 235-60 14. Brazeau P, Ling N, Bohlen P, Esch F, Ying S, Guillemin R. Growth hormone releasing factor, somatocrinin, releases pituitary growth hormone in vitro. Proc Soc Natl Acad Sci USA (in press). 15. Reichlin S. Growth hormone and the hypothalamus. Endocrinology 1960; 67: 760-73. 16. Deuben RR, Meites J. Stimulation of pituitary growth hormone release by a hypothalamic extract in vitro. Endocrinology 1964; 74: 408-14 17. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R. Hypothalamic polypeptide that inhibits the secretion of immunoreactive growth hormone. Science 1973; 179; 77-79. 18. Harris GW. Neurocontrol of the pituitary gland. Physiol Rev 1948; 28: 139-79. 19. Bogdanove EM, Lipner HJ. Intestinal absorption of glucose in hypothalamic obesity. Proc Soc Exp Biol Med 1952, 81: 410-12. 20. Frohman LA, Bernadis LL, Kant KJ. Hypothalamic stimulation of growth hormone secretion Science 1968; 162: 580-82. 12. Guillemin R, Brazeau
21. Reichlin S. Growth hormone content of pituitaries from rats with 22.
hypothalamic
lesions. Endocrinology 1961; 69: 225-30. Martin JB. Neural regulation of growth hormone secretion. N Engl J Med 1973; 288:
1384-92. 23 Franz J, Haselbach
CH, Libert O. Studies of the effect of hypothalamic extracts on somatotrophic pituitary function. Acta Endocr 1962; 41: 336-50. 24. Schally AV, Steelman SL, Bowers CY. Effect of hypothalamic extracts on release of growth hormone in vitro. Proc Soc Exp Biol Med 1965; 119: 208-12. 25. Vale WW, Rivier JE. Effects of putative growth hormone releasing factor, phorbolmyristate acetate and somatostatin on the secretion of growth hormone in vitro. 6th International Congress of Endocrinology, Melbourne, Australia, 1980. 26 Villarreal JA, Vale W, Brown M, Butcher M, Brazeau P, Rivier C, Burgus R. Myelin basic protein: A substance that releases immunoreactive growth hormone in vitro. Biochem Biophys Res Commun 1976; 70: 551-58 27. Schally AV, Baba Y, Nair RMG, Bennett CD. The amino acid sequence of a peptide with growth-hormone-releasing activity isolated from porcine hypothalamus. J Biol Chem 1971; 246: 6647-50. 28. Frohman LA, Szabo M, Berelowitz M, Stachura ME. Partial purification and characterisation of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acomegaly. J Clin Invest 1980; 65: 43-54. 29. Leveston SA, McKeel DW, Buckley PJ, Deschryver K, Greider MH, Jaffe BM, Daughaday WH. Acromegaly and Cushing’s syndrome associated with foregut carcinoid tumor. J Clin Endocr Metab 1981; 53: 682-89. 30. Bohlen P, Thorner M, Cronin M, Shively J, Scheithauer B. Isolation from human neoplastic tissue and partial characterization of a growth hormone releasing factor (GRF). 63rd Meeting of the Endocrine Society, San Francisco, 1982. 31. Esch FS, Bohlen P, Ling NC, Brazeau WB, Thorner MO, Cronin MJ, Guillemin R. Characterization of a 40 residue peptide from a human pancreatic tumour with growth hormone releasing activity. Biochem Biophys Res Comm 1982; 109: 152-58. 32. Tatemoto K, Mutt V Isolation and characterization of the intestinal peptide porcine PHI[PHI-27], a new member of the glucagon-secretin family. Proc Natl Acad Sci USA 1981; 78: 6603-07.
Carcinomas and metaplastic polyps of the colorectum share a variety of phenotypes which are not evidenced by either tubular adenomas or normal colorectal mucosa. This supports the view that adenomas and metaplastic polyps are separate entities with differing aetiologies. To explain the functional overlap between metaplastic polyps and carcinoma, it is suggested that the two separate sets of factors which lead to the development of adenomas and metaplastic polyps are both required to bring about malignant transformation within the colorectum. Identification of the factors causing metaplastic polyp formation could therefore have important implications in the prevention of colorectal cancer.
Summary
INTRODUCTION
THE commonest polyps of the colorectum are the adenoma and the metaplastic polyp. The majority of colorectal cancers arise in pre-existing adenomas.l,2 On the other hand, the metaplastic polyp is regarded as an innocuous lesion, unrelated to colorectal cancer.2,3 Metaplastic polyps have been assumed not to differ qualitatively from normal colorectal mucosa, but several exceptions to this rule have been documented. Thus metaplastic polyps show:
1. Increased
expression of carcinoembryonic antigen
(CEA).4,5
2. Reduced secretion ofO-acylated sialomucin.s 3. Reduced activity of various cytoplasmic enzymes.6,7 4. Absence of IgA secretory activity (Jass JR, unpublished
observation). In these respects, metaplastic polyps not only reveal differences from normal colorectal mucosa but also show a functional overlap with colorectal carcinoma. On the other hand, these functional changes are not necessarily revealed in adenomas. Increased expression of CEA is demonstrated only in areas of severe adenomatous dysplasia.8,9 Reduced secretion of 0-acylated sialomucin is observed in villous adenomas and areas of severe adenomatous dysplasia but not in tubular adenomas.10 A similar profile of reduced enzyme activities occurs in villous adenomas and foci of severe adenomatous dysplasia but not in tubular adenomas. 6,7 In the last, certain enzyme activities are increased, notably succinic dehydrogenase, glycerophosphate dehydrogenase, and monoamine oxidase. Reduced IgA secretory activity parallels the grade of dysplasia in adenomas. Absence of cytoplasmic IgA is revealed only in severe dysplasia and carcinoma. ’ These observations invite a reappraisal of the metaplastic polyp and its role in colorectal carcinogenesis.
qualitative
HYPOTHESIS
There between
are three explanations for the functional overlap metaplastic polyps and colorectal carcinoma:
29
1. The overlap is entirely fortuitous. 2. Metaplastic polyps and colorectal carcinoma have
overlapping aetiologies. 3. Metaplastic polyps are precancerous. If the association were entirely fortuitous, it would still be necessary to explain why metaplastic polyps differ in various ways from normal colorectal mucosa. The columnar cells of normal colorectal epithelium have a secretory function, elaborating various glycoproteins including secretory component13 and CEA. 14 The ratio of these columnar cells to goblet cells is greatly increased in metaplastic polyps. Furthermore, the migration of cells from crypt base to surface is slower in metaplastic polyps than in normal mucosa.15 Metaplastic cells therefore have a lengthened lifespan, and reveal a resultant electron-microscopic studies 16 of various "hypermaturation" cytoplasmic organelles. This includes a prominence of secretory vesicles within the columnar cell population, indicating an accentuation of their normal secretory function. These factors might explain, at least in part, the various histochemical changes, including the increased expression of CEA. However, IgA secretory activity is not exaggerated, being notably absent in
metaplastic polyps (Jass JR, unpublished observation). Colorectal carcinoma is characterised by a low mitotic index, a low percentage of cells in DNA synthesis and in the proliferative cycle, and long cell-cycle times.17 Thus, as in the metaplastic polyp, normal rapid cell turnover is blocked, and the lifespan of individual cells is increased. It is therefore possible that the functional overlap of metaplastic polyps and colorectal carcinoma is indeed fortuitous and due to a shared hypokinesis. However, this explanation becomes less acceptable in the light of the following observations: 1. Metaplastic polyps show a greater tendency than adenomas to congregate in the rectum and sigmoid colon, the principal sites for the development of colorectal cancer. 18,19 2. The incidence of metaplastic polyps is raised in populations at a high risk of developing colorectal cancer. 19 3. The incidence of metaplastic polyps rises in patients migrating from low-risk to high-risk areas. 18 4. The incidence of metaplastic polyps is not necessarily
age-dependent. 20 It therefore seems reasonable to challenge the widely held view that the metaplastic polyp is a degenerative lesion associated with ageing and unrelated to colorectal cancer. 2,3 However, a satisfactory explanation for the above findings should not contradict clinical experience regarding the natural history of this lesion. The metaplastic polyp cannot be regarded as a precancerous lesion. The Columbia University group describe their experience as follows:2 of 1000 randomly chosen surgically excised polyps, 900 will be metaplastic, 90 will be small adenomas, and 10 will be large adenomas in which one has invasive carcinoma. However, detailed necropsy studies of the entire colorectum indicate the ratio of adenoma to metaplastic polyp to be closer to unity.18,20 Furthermore, dysplastic and even malignant change has been described within metaplastic polyps. 21-23 This is a rare event, however, and appears to occur in patients with large, multiple
metaplastic polyps (metaplastic polyposis). Several workers regard the metaplastic polyp and adenoma 24-26 as manifestations of the same basic dyskinetic disorder. It is certainly possible to observe hybrid lesions in which features of metaplastic, adenomatous, and even juvenile polyps are combined. It is also possible that epithelium undergoing regenerative change is rendered more susceptible
factors causing metaplastic polyp formation. However, a compilation of structural, functional, and clinical data indicates that adenomatous and metaplastic changes are quite distinct, with separate aetiologies.’6 The majority of tubular adenomas will never develop into malignant lesions. The tubular adenoma reveals a degree of cytological and architectural atypia, but not the changes in phenotype characterising malignant epithelium. On the other hand, metaplastic polyps show the appropriate functional changes without the prerequisite architectural and cytological atypia. It is suggested, therefore, that the factors which produce metaplastic polyps and tubular adenomas are both required for the development of a malignant neoplasm. Clearly the generation of a clone of malignant cells cannot lead to an invasive growth if the cells are allowed to migrate normally and slough from the epithelial surface. In metaplastic polyps migration and shedding are retarded. It is possible that the same retarding factor prevents the rapid loss of adenomatous cells, increases their exposure time to carcinogens, and provides transformed cells with time to to
invade the host. As noted above, the alterations of phenotype characterising metaplastic changes are combined with epithelial dysplasia in two circumstances. Thus, both villous adenomas and areas of severe dysplasia (within any type of adenoma) reveal the appropriate changes in mucin 10 and enzyme6,7 histochemistry. In addition, increased expression of CEA and an absence of IgA secretory activity are observed in severe dysplasia.8,9 It is significant that severe dysplasia and a villous growth pattern are selective markers of increased malignant
risk.’1 CONCLUSION
It is suggested that separate sets of factors lead to the formation of metaplastic polyps and adenomas within the colorectum but that both sets are required for the development of a malignant neoplasm. This hypothesis explains why the metaplastic polyp and carcinoma share a constellation of functional changes and similar sites within the colorectum. It also obviates the need to regard the metaplastic polyp as a precancerous lesion, for which there is no clinical evidence. The metaplastic polyp may therefore be regarded as a marker of high-risk populations but as of no significance to the individual. However, the identification of the factors causing metaplastic polyp formation could have important implications in the prevention of colorectal cancer. REFERENCES 1. Morson BC. Evolution of cancer of the colon and rectum. Cancer 1974; 34: 845-49. 2. Fenoglio CH, Lane N. The anatomical precursor of colorectal carcinoma Cancer 1974; 34: 918-23 3. Arthur JF. Structure and significance of metaplastic nodules in the rectal mucosa. J Clin Pathol 1968; 21: 735. 4. Skinner JM, Whitehead R. Tumour-associated antigens in polyps and carcinoma of the human large bowel. Cancer 1981; 47: 1241-45. 5. Jass JR, Filipe MI, Abbas S, Falcon CAJ, Wilson Y, Lovell D. A morphological and histochemical study of metaplastic polyps of the colorectum. Cancer (in press). 6. Czernobilsky B, Tsou KC Adenocarcinoma, adenomas and polyps of the colon Cancer 1968; 21: 165-77. 7 Wattenberg LW. A histochemical study of five oxidative enzymes in carcinoma of the large intestine in man. Am J Pathol 1959, 35: 113-26 8. O’Brien MJ, Zamcheck N, Burke B, Kirkham S, Saravis CA, Gottolieb LS. Immunocytochemical localisation of carcinoembryonic antigen in benign and malignant colorectal tissues. Am JClin Pathol 1981; 75: 283-90. 9. Isaacson P, Le Vann HP. The demonstration of carcinoembryonic antigen in colorectal carcinoma and colonic polyps using an immunoperoxidase technique. Cancer 1976; 38: 1348-56. 10. Culling CFA, Reid PE, Clay MG, Dunn WL. A new histochemical technique of use in the interpretation and diagnosis of adenocarcinoma and villous lesions in the large intestine. J Clin Pathol 1977; 30: 1056-62
30
Infection and the
Reviews of Books Understanding and Treating Tardive Dyskinesia Dilip V. Jeste and Richard J. Wyatt, National Institute of Mental Health, Bethesda, Maryland. New York: Guildford Press. 1982. Pp. 363.$29.50. THE introduction of neuroleptics has revolutionised the treatof psychotic disorders. It has greatly elucidated the basic biochemical mechanisms involved in the psychoses, but its longterm use has caused no less puzzling a phenomenon than tardive dyskinesia, a syndrome of complex and often bizarre choreic and dystonic movements which often persists and is even exacerbated by the withdrawal of the causative drug. It poses many tantalising questions: Why is it apparently more common in the elderly? Is it more likely to occur in patients with pre-existing cerebral pathology? Why, if it is caused by antipsychotic drugs, are these very drugs one of the few beneficial forms of therapy? This book is a comprehensive review of this subject by two authors, and the unity of style and purpose sets it apart from many other multiauthor books on the same topic. It has major sections dealing with the epidemiology and prevalence of the disorder, and with those characteristics which define patients at high risk of tardive dyskinesia. The wide variety of biochemical theories which have been advanced to explain the phenomenon are reviewed and dismissed as being inadequate. Relevant neurophysiological and neuropathological studies are considered and tardive dyskinesia is compared with other drug-induced dyskinesias. There is a very useful section on animal models of tardive dyskinesia, and the book ends with a general discussion of possible methods of treatment and ment
prevention. The book represents an excellent and up-to-date review of the subject which will be invaluable to both psychiatrists and neurologists. The authors adopt a critical attitude to the large volume of work they review, and their suggestions for a clinical definition of the syndrome and future clinical studies of treatment are long overdue. However, the overall conclusions are diappointing. We remain ignorant of the mechanisms by which this troublesome movement disorder is mediated, have no effective treatment, and, more worryingly, are unable to define a means of preventing its
onset.
Department of Neurology, Walton Hospital, LIverpool
D. W. CHADWICK
Weisz-Carrington P, Poger ME, Lamm ME. Secretory immunoglobulins in colonic neoplasms. Am J Pathol 1976; 85: 303-14. 12. Isaacson P. Immunoperoxidase study of the secretory immunoglobulin System in colonic neoplasia. J Clin Pathol 1982; 35: 14-25. 13. Poger ME, Hirsch BR, Lamm ME. Synthesis of secretory component by colonic neoplasms. Am J Pathol 1976; 82: 327-38. 14. Ahnen DJ, Nakane PK, Brown WR. Ultrastructural localisation of carcinoembryonic 11.
antigen 15.
16.
17.
in
normal intestine and colon
cancer.
Cancer 1982; 49: 2077-90.
Hayashi T, Yatani R, Apostol J, Stemmerman GN. Pathogenesis of hyperplastic polyps of the colon. A hypothesis based on ultrastructure and in-vitro kinetics. Gastroenterology 1974; 66: 347-56. Kaye GI, Fenoglio CM, Pascal RR, Lane N. Comparative electron microscopic features of normal, hyperplastic and adenomatous human colonic epithelium. Gastroenterology 1973; 64: 926-45. Lipkin M, Deschner EF. Gastrointestinal cells: proliferation and differentiation. In: Sircus W, Smith AN, eds. Scientific foundations of gastroenterology. Heinemann
Medical Books Ltd. London, 1980. 25-30. 18. Stemmerman GN, Yatani R. Diverticulosis and polyps of the large intestine. A necropsy study of Hawaii Japanese. Cancer 1972; 31: 1260-70. 19. Correa P. Epidemiology of polyps and cancer. In: Morson BC, ed. The pathogenesis of colorectal cancer. Major problems in pathology vol. 10. Philadelphia, London, Toronto: WB Saunders, 1978: 126-52. 20. Vatn MH, Stalsberg H. The prevalence of polyps of the large intestine in Oslo. An autopsy study. Cancer 1982; 49: 819-25. 21. Cooper HS, Patchefsky AS, Marks G. Adenomatous and carcinomatous changes within hyperplastic colonic epithelium. Dis Colon Rectum 1979; 22: 152-56. 22. Sumner HW, Wasserman NF, McClain CJ. Giant hyperplastic polyposis of the colon. Dig Dis Sci 1981; 26: 85-89. 23. Estrada RG, Spjut HJ Hyperplastic polyps of the large bowel. Am J Surg Pathol 1980; 4: 127-33. 24. Potet F, Soullard J Polyps of the rectum and colon. Gut 1971; 12: 468-82. 25. Goodman ZD, Yardley JH, Milligan FD. Pathogenesis of colonic polyps in multiple juvenile polyposis. Cancer 1979; 43: 1906-13. 26. Grigioni WF, Alampi G, Martinelli G, Piccaluga A. Atypical juvenile polyposis. Histopathology 1981; 5: 361-76.
Surgical Patient
Clinical Surgery International, vol. IV. Edited by Hiram C. Polk, Jr, University of Louisville School of Medicine. Edinburgh: Churchill Livingstone. 1982. Pp. 219.;CI5.
last, a short readable text on surgical microbiology which is bedevilled by turgid accounts of minimum inhibitory concentrations and differential colony counts. This excellent monograph will give "the medical student beginning his clinical clerkship" a comprehensive account of the host, the pathogen, and the environment as determinants of infection. For the "seasoned and skilled practitioner" it provides authoritative views on the prevention and treatment of common surgical infections, with a strong emphasis on practical details. Though there are only three European contributors and fifteen from North America, I believe that most of the therapeutic advice will be acceptable on both sides of the Atlantic. Perhaps metronidazole is somewhat undervalued as an anti-anaerobic agent, but this must be due to the initial prescribing difficulties in the U.S.A. No doubt when the fourth and fifth generation cephalosporins are developed some of the details on "antibiotic choice" may have to be updated. In his epilogue, the editor is too modest by far when he aims for "the average patient in the care of the median surgeon"-his book is at least two standard deviations better than that. AT
not
Department of Surgery, City Hospital, Nottingham
T. W. BALFOUR
Essentials of Endocrinology Edited by J. L. H. O’Riordan, P. G. Malan, and R. P. Gould, Middlesex Hospital Medical School, London. Oxford: Blackwell. 1982. Pp. 230.
7.50. THE authors of this book, which is based on the teaching given during the second year of the basic medical sciences course at the Middlesex Hospital, hope that it will appeal to medical students and to those taking a science degree. It certainly will, but it should also become compulsory (and probably compulsive) reading for anyone,
medical or basic scientist, with a continuing postgraduate interest in endocrinology and metabolism. Several mammoth tomes on endocrinology have appeared recently, which are daunting and certainly not easy to read from cover to cover; it is therefore heartening to be presented with a succinct, stylish, and inexpensive volume which contains the nitty-gritty of current endocrinology and is short enough to be read and re-read. It is always refreshing to hear the slant which others in one’s own field put on problems that are so familiar that one has almost stopped thinking about them. Repeatedly in this book I found myself interested and enlightened either by a new fact or a new angle on old facts. There is an introductory chapter on the endocrine system and the molecular basis for hormone action, and chapters on the hypothalamus and pituitary, the adrenal gland, reproductive endocrinology, the thyroid gland, calcium-regulating hormones, and pancreatic and gastrointestinal hormones. Each chapter begins with an interesting historical introduction. The morphology, physiology and biochemistry, and development of the particular part of the endocrine system are then considered, followed by a brief description of the salient features of clinical disorders and an outline of their treatment. Overall the authors and editors have achieved a remarkable uniformity of style and great clarity. The editors and publishers are also to be congratulated on a remarkably low incidence of errors and misprints. Most of the figures are simple line-drawings with a few histological pictures; I would have welcomed more of both, for example, illustrating the histology of the testis, the morphology of normal bone cells, and histology of bone disorders such as osteomalacia. I detected remarkably few errors-although I know of no human being (as distinct from desert rat) who can concentrate his urine up to 1400 mosmol/kg (page 55). This is principally a book about human endocrinology, although there are welcome meanders into comparative and evolutionary aspects (for example, the origin of the C cells). The book deserves to be very successful, and I am sure that at its price it will be. Department of Medicine, Hope Hospital, Salford
D. C. ANDERSON