752

extirpated completely; (6) the involvement of the thvroid gland demonstrable by thyroid scan or histological examination. ,From the apex of the

Internal fistula sinus.

ing from otics

originating

from the apex of the left

pyriform

the apex of the left pyriform sinus (see figure). Antibigiven to reduce the neck swelling and the fistula was

were

extirpated. Typically,

the fistula ran antero-inferiorly just external to the left recurrent laryngeal nerve, and then anteriorly along the thyroid. Histological examination in two cases showed a tubular structure lined by stratified squamous or ciliated epithelium. Inflammatory changes, fibrosis, and round-cell infiltration were observed in biopsy specimens taken from the left lobe of the thyroid. There has been no recurrence of abscess after fistelectomy.

pyriform sinus, the fistula ran the into semiclosed space around the antero-inferiorly thyroid gland (spatium perithyreoideum) which is bordered by the middle layer of cervical fascia covering the posterior surface of the sternothyroid muscle anteriorly, the prevertebral fascia posteriorly, the carotid sheath laterally, and the insertion of the sternothyroid muscle to the thyroid cartilage superiorly. After infection through the fistula, purulent exudate appears to accumulate in this space around the thryoid gland and set up an inflammation of the thyroid gland. This condition is thus primarily a perithyroidal abscess. We suspect that many of the previously reported cases of acute suppurative thyroiditis have been cases of perithyroidal abscess with involvement of the thyroid gland which have resulted from infection through a pyriformsinus fistula. We recommend a careful search of the hypopharynx for the fistula in all patients with acute suppurative thyroiditis of unknown origin, especially in young patients with recurrent abscesses. Complete extirpation of the fistula is required for a permanent cure. REFERENCES

Discussion of acute suppurative thyroiditis the fistula originating from the apex of the left pyriform sinus was considered the route of infection. In most reports of acute suppurative thyroiditis, suppuration in the thyroid gland has been deduced from the location and shape of swelling2-6 and a decrease in R.A.l.U. of the thyroid lobe concerned.4-6 The symptoms, signs, and laboratory data (including thyroid scan) in our patients were indistinguishable from those reported in other cases of acute suppurative thyroiditis.2-6 Moreover, the involvement of the thyroid gland was confirmed histologically in two of our patients. A few cases of acute suppurating thyroiditis result from bacteræmia2 or a persistent thyroglossal duct,3 but the route of infection in most cases has not been obvious.4-6 Recurrence of the condition was noted in 4 of 21 patients4-6 who had thyroiditis on the left side and were 4, 5, 16, and 24 years old at onset. 9 patients with an anterior neck abscess caused by a fistula originating from the pyriform sinus have been described in Japanese.7-13 Tucker and Skolnick14 reported a recurrent abscess of the neck in a patient with a sinus tract originating at the pyriform sinus. They had found no report of such a remnant in English.’’’ The fistula has been described as a remnant of the fourth pharyngeal pouch by several authors7,8,13,14 but they made no referIn these

seven cases

ence to acute

suppurative thyroiditis.

The clinical features of seventeen cases with the pyriform-sinus fistula (including our patients) can be summarised as follows: (1) ratio of female to male 7 to 10; (2)onset between 2 and 12 years of age, except for one patient aged 56;(3 abrupt onset of painful swelling in the thyroid region accompanied by fever pain on swallowing, occasionally with upper respiratory infections before swelling; (4) a fistula at the apex of the left pyriform sinus, demonstrable by barium meal or fistelography; 5’ recurrence common unless the fistula is

and

1. Hazard, J. B. J. clin. Path 1955, 25, 289. 2. Hawbaker, E. L. Am. Surgeon, 1971, 37, 290. 3. Saito, S., Katakai, S. Gumma J. med. Sci. 1964, 13, 61. 4. Szego, P. L., Levy, R. P. Can. med. Ass. J. 1970, 103, 631 5. Olin, R., LeBien, W. E., Leigh, J. E. Minnesota Med. 1973, 56, 586. 6. Leers, W. D., Dussault, J., Mullens, J. E., Volpe, R., Arthurs, K. Can. med

Ass. J. 1969, 101, 714. Jibirtnsho, 1957, 50, 140. S., Ito, S., Takeda, S., Kariya, T. Nippon GekagakkaTzasshi, 1961, 62, 797. 9. Fushida, H. Nippon Jibiinkokagakkai-kaiho, 1961, 64, 1469. 10. Honda, H. Nippon Gekagakkai-zasshi, 1966, 67, 429. 11. Aimi, K. Nippon Jibiinkokagakkai-kaiho, 1966, 69, 1919. 12. Umeda, R., Watanabe, Y, Ohshiro, K., Haoka, N. Jibirinsho, 1971, 64, 7. Hiroto, K , Shigyo, H. 8. Takayanagi, Y , Abo,

1341. 13.

Inagaki, H., Kobori, O., Ishikawa,

K.

Nippon Gekagakkai-zasshi, 1976, 77,

137

14. Tucker, H. M., Skolnick, M. L. Trans Am. Acad. Ophth. Otol. 1973, 77, 368.

Hypothesis DIETARY CHOLESTEROL IS CO-CARCINOGENIC FOR HUMAN COLON CANCER MICHAEL LEWIN PETER CRUSE CHARLES G. CLARK

Surgical Unit, University College Hospital Medical School, London WC1E 6JJ Colorectal carcinoma is becoming the most common form of visceral cancer in Western populations. A fat-related dietary factor is implicated in its pathogenesis, and evidence in man suggests that this factor may be cholesterol. Dietary cholesterol is co-carcinogenic in animals with colon cancer, and there is indirect evidence for a similar role in man. It is proposed that prolonged exposure to dietary cholesterol is co-carcinogenic for human colon cancer in that

Summary

753 it facilitates the disease.

development, growth, and spread of this INTRODUCTION

CO-CARCINOGENS facilitate the development, growth, and spread of cancer, but cannot themselves initiate it. The induction of colon cancer is thought to be a multistage process,’ in which the early stages may be initiated by mutational events, with subsequent stages proceeding2 randomly or at. a rate determined by extrinsic agents.2 Much research is directed to the identification of the initiating agents,3.4 although these are likely to be ubiquitous mutagens which act rapidly and irreversibly.s°6 The post-initiation stages provide a more feasible target for preventive and therapeutic action, since they are thought to occur slowly and to be reversible.5·6 Consequently, the removal of co-carcinogenic extrinsic agents capable of facilitating the post-initiation development of colon cancer may be an effective means of preventing or treating the disease. We summarise the evidence suggesting that dietary cholesterol may be such a co-carcinogen in human colon cancer.

studies there were significant reductions of serum-cholesterol in colon cancer patients,20,21 suggesting a reciprocal relation between the serum and fsecal levels of cholesterol in such patients. Time-trend studies correlate the progressive increase in the U.S. incidence of colon cancer with an increase in dietary fat consumption,22 and dietary status and current faecal metabolic findings correlate better with the presence of colon cancer in patients than do past diet or past faecal biochemistry. 23 This suggests a continuing, concurrent effect of the dietary or faecal factor rather than a precursor effect, and favours a co-carcinogenic role for dietary or faecal cholesterol rather than an initiating role.

CORROBORATING EVIDENCE FROM ANIMAL STUDIES

Dietary cholesterol is co-carcinogenic in animals with chemically induced experimental colon cancer.24 A diet high in both cholesterol and polyunsaturated fats also promoted tumours.25 High-fat diets,25-30 and bile salts,31,32 promote the effects of various large-bowel carcinogens in rodents, and animals on such diets excrete fsecal cholesterol and bile salts than do contro]’LS.30 Comparisons between such studies are invalidated by variation in experimental methods. However, intrastudy comparison reveals that in every experimental colon-cancer study of a cholesterol-containing diet (containing either overt cholesterol or cholesterol in the form of meat or lard), the greatest percentage of tumour-bearing animals,24-29 the highest mean number of colon tumours per animal,24-29, and the greatest incidence of metastases2’,27,28 occurred in the animals on the diets containing the most cholesterol. The corollary is equally true-namely, that these tumour indices were lowest in animals on diets containing the least cholesterol. 24,25,28,29

more

EVIDENCE FROM HUMAN STUDIES

Colorectal cancer is common in the urbanised West, and is rare in Africa, Asia, and Japan.’ Epidemiological evidence3.7.8 implicates excessive consumption of animal fats and meat in the pathogenesis of the disease. The precise fat subcomponent responsible is unknown, but a significant proportion of animal fat in a mixed Western diet is derived from red meat, milk products, and eggs, which are also the major source of dietary cholesterol,9 and there is a significant correlation between high consumption of cholesterol-containing food items and the world-wide distribution of colon cancer.3.1O Furtherbetween populations at risk more, the overlap for colon cancer and those at risk for arteriosclerotic heart-disease,3.7 suggests shared xtiological factors, and excessive cholesterol intake is a risk factor for the lat-

observed

POSSIBLE MECHANISMS OF CHOLESTEROL

CO-CARCINOGENESIS

ter.1l.12 Patients with colon cancer have significantly higher levels of faecal cholesterol and cholesterol metabolites than do patients with other gastrointestinal disease and their healthy compatriots." Similarly, patients with all the diseases known to predispose them to colonic cancer-i.e., familial polyposis,14 ulcerative colitis,15 adenomatous polyps," and Gardner’s syndromel6-are distinguished from appropriate controls by a single common finding, that of raised levels of faecal cholesterol or cholesterol metabolites. Healthy Americans (at high risk of colon cancer) on a mixed Western diet excrete higher levels of these components than do rural South African Blacks (at low risk), and these findings are attributable to differences in dietary cholesterol and fat intake." Raised faecal levels of cholesterol or its metabolites are therefore consistently associated with all gradations of increased risk of the development of colon cancer.

Serum-cholesterol concentrations have

correlated with the incidence of colon cancer in different populations,7 but such concentrations are known to alter little over a wide range of dietary intakes18.19 and are a poor reflection of total body cholesterol.19 However, in two not

Cholesterol may operate as a co-carcinogen in the development of colon cancer along any of the theoretical lines suggested by Berenblum’s5 approach to co-carcinogenesis (or by other, hitherto undiscovered,

mechanisms). 1. Cholesterol may

epithelium, rendering

exert a

it

more

preparative action on the colonic susceptible to subsequent cancer-

initiating factors. 2. Cholesterol may be a permissive agent, affecting the solubility, metabolism, or excretion of a cancer-initiating factor. 3. Cholesterol may promote the action of an already initiated, incomplete, carcinogenic process. 4. Cholesterol may exert a systemic, conditional influence, acting indirectly via hormonal or immunological mechanisms.

There is little evidence from experimental studies in other tumour systems33 to support mechanisms 1 or 2. Mechanism 4 is a possibility, since cholesterol is the precursor of all the steroid hormones, and inter-relations between cholesterol and immune function have been

suggested. 34,35 Mechanism 3,

namely

that cholesterol acts as a since dietary fats pro-

tumour promoter, is more likely, mote the action of several

Since there is

experimental carcinogens.33

no

evidence that cholesterol per

se can

in-

754

itiate

a carcinoma in either man or animals,3 this mechanism presupposes the action of an initiating agent. Possible initiating agents in man include intrinsic genetic factors (e.g., adenoma-proneness) and several extrinsic agents, namely agricultural chemicals,36 asbestos,3’ and chemicals involved in synthetic-yarn manufacture.38 In theory, any carcinogenic environmental mutagen could initiate a colonic cancer, provided it had access to the colonic epithelial cells. Whilst mutations can occur spontaneously, mutagens have already been isolated from human food39 and faeces,40 and the widespread use of synthetic chemicals in industrialised countries provides additional sources of such carcinogenic mutagens.6 Colon cancers almost certainly arise from pre-existing adenomas,41 and Hill et a1. postulated a mechanism for this adenoma-carcinoma sequence. They implicated bile salts as "agent B"-the factor causing adenomas to grow-but cholesterol fits the profile of agent B equally well. The bile-salt theory of colon carcinogenesis was postulated by Aries et al. 42 and Hill et a1.,3,8,43 but some of their findings have not been confirmed.44,45 Since cholesterol is the obligatory precursor of bile salts and the metabolic pathways of these substances are inextricably interrelated,46 their relative contributions are difficult to determine. In our view, cholesterol is a more likely candidate as a colon tumour promoter than its bile-salt derivatives. Firstly, cholesterol is present in both diet and fxces, thereby accounting for both the fat-related epidemiological associations and the faecal metabolic finding in colon-cancer patients. Secondly, several cholesterol-related mechanisms for facilitating carcinogenesis may be envisaged. Cholesterol, which is essential for the structure and function of all biological membranes, is involved in membrane-bound enzyme activity and is the precursor of all steroid hormones.46 Furthermore, a cholesterol ester, "carcinolipin", 47 is a potent stimulator of several stages of protein synthesis, and cholesterol is of importance in the stabilisation of the D.N.A. helix.46 By contrast, the major function of bile salts is to facilitate the passage of lipids (especially cholesterol) into and out of the body.48 Bile salts are recycled in the enterohepatic circulation, so that less than 5% reaches the colon.48 Bile salts inhibit the intermediate metabolism of intestinal epithelial cells and are toxic and disruptive to cellular membranes.49 Moreover, bile salts are not present in the diet and increased faecal concentrations are produced by the cholereic enteropathies, 50 conditions usually associated with diarrhoea rather than predisposition to colon cancer. We therefore ascribe an indirect role to bile salts in colon carcinogenesisnamely, that of fulfilling their normal physiological function of solubilising cholesterol and facilitating its

absorption. DISCUSSION

Cholesterol is not an essential nutrient, since the daily metabolic requirement is met by endogenous synthesis.46 Western man consumes cholesterol in excess of requirements,46 and, since there are homoeostatic limitssl to the amount of cholesterol the body can absorb, where does the excess go? The only important route of excretion of cholesterol (be it dietary, biliary, or derived from intestinal secretions) from the body is via the colon-i.e., in

the faeces.52 The colonic epithelial cells of Western man are therefore constantly exposed to faecal cholesterol. Should a carcinoma or precancerous lesion arise from these cells, it would have an adequate local supply of cholesterol with which to generate new cell membranes or to drive cholesterol-dependent cellular metabolism. The dietary supply of cholesterol could thus be a factor determining the rate of development, growth, or spread of such a tumour. The most salient xtiological link so far identified in the postulated chain of causal factors leading to the development of colon cancer in general populations is the fat-related dietary association. We postulate that cholesterol is the dietary fat responsible for this observed association, and that it acts as a co-carcinogenic tumour promoter. Does this hypothesis account for the observed differences in the geographical distribution of colon cancer? The incidence of colon carcinoma is low in rural Africans,’ Japanese,’ and Eskimos.53 Rural Africans are exposed to few mutagenic initiators and not to the dietary promoter (cholesterol); the Japanese are industrialised and hence exposed to initiators but eat little cholesterol ; Eskimos, who are not industrialised but have a very high cholesterol intake53 are exposed to the pro-

only. In contrast, high-risk populations (e.g., U.S.A., U.K.) are exposed to both initiators and promoter and in these populations colonic cancer is common. Furthermore, the hypothesis accounts for apparently anomalous subgroups-e.g., Japanese migrants to moter

the U.S.A. whose increased colon cancer incidence has already been attributed to their adoption of American dietary habits,54 and American vegetarians55 in whom colon cancer incidence is lower than that in their meat-

eating compatriots. Our hypothesis differs in several respects from earlier theories linking dietary fat and human colon cancer.1,3,4,8,42,43 Firstly, it ascribes specific responsibility to cholesterol for the fat-linked epidemiological associations. Secondly, it emphasises the primary importance of ingested cholesterol, implying that the disease is one of lifestyle or habit. Thirdly, it suggests a direct mechanism-i.e., that cholesterol itself is a co-carcinogen. Finally, the hypothesis accounts for both the clinical and epidemiological observations and for the anomalies. Do concepts derived from this hypothesis provide any practical contributions to the problems of human colon cancer? As has already been demonstrated in animals,2. the removal of the co-carcinogen by a low or cholesterolfree diet may retard the overall process, thereby decreasing the risk of colon cancer developing. If dietary cholesterol can facilitate the development, growth, and spread of colon cancer, then patients who have already had a colon carcinoma resected may benefit from a low-cholesterol diet, since removal of the co-carcinogen might inhibit the growth of residual tumour cells or retard the spread of metastases. These preventive and therapeutic suggestions are feasible, inexpensive, and without risk. It is conceivable that the different stages in the genesis of colon cancer could proceed in the complete absence of dietary cholesterol as the result of another cause. However, evidence in man and animals is consistent with the interpretation that exposure to dietary cholesterol

755

apparently facilitates

the processes

leading

to

colon

23. Gori, J. B. Cancer Res. 1975, 35, 3432. 24. Cruse, J. P., Lewin, M. R., Ferulano, G. P., Clark, C. G. Nature, 1978, 276,

cancer.

822.

P. C. is a Rhodes Scholar and of the Rhodes Trust, Oxford.

gratefully acknowledges

the support

Requests for reprints should be addressed to P. C. REFERENCES 1 Hill, M. J., Morson, B. C., Bussey, H. J. R. Lancet, 1978, i, 245. 2 Peto, R. in Origins of Human Cancer (edited by H. Hiatt); Book C, p. 1403.

25. 26. 27. 28. 29.

30. 31. 32. 33. 34. 35. 36. 37. 38. 39.

Broitman, S. A. et al. Cancer, 1977, 40, 2455. Reddy, B. S., et al. Proc. Soc. exp. Biol. Med. 1976, 151, 237. Nigro, N. D. et al. J. natn. Cancer Inst. 1975, 54, 439. Bansal, B. R., Rhoads, J. E., Bansal, S. C. Cancer Res. 1978, 38, 3293. Reddy, B. S., Nansawa, T., Weisburger, J. H. J. natn. Cancer Inst. 1976,

57, 567. Reddy, B. S., Weisburger, J. H., Wynder, E. L. ibid. 1974, 52, 507. Nigro, N. D. et al. Dis. Colon Rectum, 1973, 16, 438. Narisawa, T., et al. J. natn. Cancer Inst. 1974, 53, 1093. Carroll, K. K., Khor, H. T. Progr. biochem. Pharmac. 1975, 10, 308.

McCance and Widdowson’s The Composition of Foods (edited by A. A. Paul and D. A. T. Southgate). H. M. Stationery Office, 1978. 10 Drasar, B. S., Irving, D. Br. J. Cancer, 1973, 27, 167. 11. Royal College of Physicians Report. J. R. Coll. Physns. 1976, 10, 1. 12. Bronte-Stewart, B., Keys, A., Brock, J. F. Lancet, 1955, ii, 1103. 13. Reddy, B. S., Wynder, E. L. Cancer, 1977, 39, 2533.

Mathews, J. D., Feery, B. J. Lancet, 1978, ii, 1212. Inbar, M., Shinitsky, M. Proc. natn. Acad. Sci. U.S.A., 1974, 71, 4229 Pratt, C. B., et al. Cancer, 1977, 40, 2464. Selikoff, J. J., Churg, J., Hammond, E. C. J. Am. med. Ass. 1964, 188, 22. Vobecky, J., et al. Gastroenterology, 1978, 75, 221. Sugimura, T., et al. in Origins of Human Cancer (edited by H. Hiatt); p. 1561. New York, 1977. 40. Bruce, W. R., et al. ibid. p. 1641. 41. Morson, B. C. Cancer, 1974, 34, 845. 42. Aries, V. C. et al. Gut, 1969, 10, 334. 43. Hill, M. J., Crowther, J. S., Drasar, B. S., Hawksworth, G., Aries, V., Wilhams, R. E. O. Lancet, 1971, i, 95. 44. Murray, W. R., et al. Br. J. Surg. (in the press). 45. Mastromarino, A. J., Reddy, B. S., Wynder, E. L. Cancer Res. 1978, 38,

14. 15 16 17 18. 19

Reddy, B. S. Cancer, 1976, 38, 1094. Reddy, B. S., Martin, C. W., Wynder, E. L. Cancer Res. 1977, 37, 1697. Core, S. K , Watne, A. L. Fedn. Proc. 1974, 33, 260. Salyers, A. A., et al. S. Afr. Med. J. 1977, 51, 823. Slater, G. G., Alfin-Slater, R. B. Fedn Proc. 1978, 37, 630. McGandy, R. B., Hegsted, D. M. in The Role of Fats in Human Nutrition (edited by A. J. Vergroesen); p. 211. New York, 1975. 20. Rose, G., Blackburn, H., Keys, A., Taylor, H. L., Kannel, W. B., Paul, O., Reid, D. D., Stamler, J. Lancet, 1974, i, 181. 21. Bjelke, E ibid. 1974, i, 1116. 22. Cutler, C. J., Devesa, S. A. Host Environment Interactions in the Etiology of Cancer in Man. p. 14. I.A.R.C., Lyon, 1974.

4458. 46. Sabme, J. R. Cholesterol. New York, 1977. 47. Hradec, J. Prog. Biochem. Pharmac. 1975, 10, 197. 48. Nair, P., Kritchevsky, D. (editors.) The Bile Acids; vol. 1 and 2. New 1973. 49. Dietschy, J. M. Fedn. Proc. 1967, 26, 1589. 50. Hofmann, A. F. Gastroenterology, 1967, 52, 752. 51. Dietschy, J. M., Wilson, J. D. New Engl. J. Med. 1970, 282, 1179. 52. Dietschy, J. M., Wilson, J. D. ibid. 1970, 282, 1241. 53. Sinclair, H. M. Personal communication. 54. Buell, P., Dunn, J. E. Cancer, 1965, 18, 656. 55. Philips, R. L. Science, 1974, 183, 471.

RELATION BETWEEN AFLATOXIN, HEPATITIS-B VIRUS, AND HEPATOCELLULAR CARCINOMA

all been

New York, 1977. 3 Hill, M. J. Crit. Rev. Toxicol. 1975, 4, 31. 4. Wynder, E. L., Reddy, B. S. in Nutrition and Cancer

(edited by M. Winik);

55. New York, 1977. 5 Berenblum, I. J. natn. Cancer Inst. 1978, 60, 723. 6 Miller, E. C Cancer Res. 1978, 38, 1479. 7 Wynder, E. L , Shigematsu, T. Cancer, 1967, 20, 1520. 8. Hill, M. J. Digestion, 1974, 11, 289. p

9

York,

implicated as xtiological agents.6 The two most important factors seem to be hepatitis-B virus (H.B.v.) and the mycotoxin, aflatoxin.

LARRY I. LUTWICK HEPATITIS-B VIRUS AND HEPATOMA

Division

of Infectious Diseases, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, U.S.A.

A new role is postulated for aflatoxin in the production of hepatocellular carcinoma. Rather than acting as a primary carcinogen, as it seems to do in animals, it is suggested that aflatoxin suppresses cell-mediated immunity. This effect on the immune system would allow the hepatitis-B virus, highly endemic in certain populations, to maintain itself more easily in the liver, to produce more chronic infection and cirrhosis, and in the long term to lead to a high incidence of hepatocellular carcinoma.

Summary

H.B.v.-associated antigens and antibodies are significantly more common in patients with hepatoma than in the general population2,5,7-9 or in age and sex matched controls with and without other cancers. to Studies in various parts of the world have shown that H.B.v. is closely associated with a predisposition to hepatic malignancy (table I), but the exact role of the virus is not clear. TABLE I-ASSOCIATION OF H.B.V. WITH HEPATOMA

INTRODUCTION

PRIMARY

pecially

hepatocellular carcinoma (hepatoma) is esin several major population groups. In

common

parts of Africa it is so common that right-sided abdominal pain and massive hepatomegaly are regarded as diagnostic.’ Because of its high incidence in these large population groups it is thought to be the most common cancer in man.2 Although hepatoma has not been a common malignancy in the U.S.A. and Western Europe, its incidence seems to be increasing. 3-5 Genetic factors, alcoholism, malnutrition, iron overload, parasites, and ’. anous natural and synthetic drugs and chemicals have some

*HB, Ag=hepamis-B surface antigen ; anti-HBantibody to tis-B surface; anti-HB=antibody to hepatitis-B core antigen. tControl group age and sex matched with other cancer or no

hepaticancer.