Document ZBL1rMD6Ka1vmo40QRGdmMxKd

REVIEW ARTICLE ) Cancer of the Larynx: Occupational and Environmental Associations SALLY R. COWLES, MD, DrPH, Houston, Tex ABSTRACT: This paper briefly reviews the available evidence for the influence of environmental and occupational factors in the development of cancer of the larynx. Although several occupational exposures have been suggested to play a role in the etiology of this disease, few have been convincingly confirmed. The strong association between smoking and cancer of the larynx, the weaker but still important association between alcohol consumption and cancer of the larynx, and the strong synergism between the two is emphasized. Other accepted or suspected environmental and occupational factors are also discussed. It has been estimated that in 1982 roughly 10,900 new cases of cancer of the larynx will have occurred in the United States and that 3,700 deaths due to cancer of the larynx will have been recorded.1 Although less than 1.5% of all new cancers are laryngeal, cancer of the larynx, in common with other cancers of the head and neck, has been strongly linked etiologically to en vironmental factors.2 This makes it a good potential target for cancer control programs. Many of the iden tified environmental factors are related to life-style and personal habits, with only a few related to occupa tion. This review summarizes what is currently known or suspected about such factors in the development of cancer of the larynx. One person in every 74 in the U S will develop cancer of the larynx. The most common cell type is squamous cell carcinoma (over 90%), with most being moderately or well differentiated. The portion of the larynx most commonly affected is the glottic area (which also has the best prognosis); the least common cancers occur in the subglottic region and have the worst prognosis. The over 20-year survival for individuals with cancer of the larynx is 34%.3 Men are affected more than women, and the current male-female ratio of cases in the United States is roughly 4.5:1.0.4 The incidence for white men is highest in the northeastern United States, - From the Department of Family and Community Medicine, University of Texas Medical School. Houston. Reprint requests to Sally R. Cowles, MD, Department of Family and Com munity Medicine, University of Texas Medical School, PO Box 20708, Hous ton, TX 77025. Texas, South Carolina, and Georgia. Rates for white women are high in Maine, northern New York, and along the Gulf Coast. Worldwide, the highest rates are seen in Sao Paulo, Brazil, and Bombay, India. Cancer of the larynx is currently increasing in the United States and most other countries. Incidence in the United States has more than doubled since 1940.3 SMOKING The evidence for a causal association between smok ing and cancer of the larynx is particularly convincing. Studies from all over the world have found a marked predominance of smokers among patients with cancer of the larynx, and the relative risk for smokers has been calculated to be from three to 39 times greater than for nonsmokers.4'14 The striking correlation between studies, and the linear dose-response rela tionship between risk and amount smoked are well illustrated in a review by Rothman et al.3 The decline in male-female ratios for cancer of the larynx (14.9:1.0 in 1956 compared to 4.6:1.0 in 1974) is consistent with the increase, beginning before World War II, in the number of female smokers.15 In France, where cancer of the larynx is very common, the use of black tobacco cigarettes without filters when smoked without inhal ing has been linked to increased risk.14 Cancer of the larynx is comparable to cancer of the lung in the strength of its association with smoking, and the rela tionship is far greater than for any other cancer.13 As with cancer of the lung, the risk to ex-smokers and smokers of filter cigarettes is less than to current smokers or smokers of unfiltered cigarettes. Ex 894 July 1983 SOUTHERN MEDICAL JOURNAL Vol 76, No. 7 HWBUI0000680 smokers who have not smoked for ten to 15 years have approximately half the risk of a current smoker.4 The risks associated with smoking also appear to be age related. In new cases of laryngeal cancer, patients who smoked were an average of 15 years younger than those w ho did not smoke (age 58 compared to age 73, respectively), and long-term ex-smokers (more than ten years) were roughly ten years older than smokers.4 An Irish study showed similar results, with the risk of developing cancer of the larynx in a heavy smoker under age 60 being 18 times that of a nonsmoker, while only 5.5 times greater when the smoker was over age 60.7 In studies reviewed, the highest percentage of nonsmokers in cases of cancer of the larynx was only 4%.9 Smoking is a potent risk factor for cancer of the larynx. Because smoking is such a strong risk factor, it is a powerful confounder in any analysis of other pos sible associations with cancer of the larynx, and must be corrected for. ALCOHOL INGESTION Ethanol ingestion has also been shown to be as sociated with cancer of the larynx, but the relationship is far weaker than that with smoking. After adjustment for smoking habits, the ethanol risk has been estimated to be from 1.5 to 4.4 times that of nondrinkers.5'8,13,16 More important than the independent effect of ethanol, nowever, is the apparent potentiation and synergism seen when smoking and drinking are combined.4,i'" Kelative risks associated with heavy drink ing and heavy smoking combined have been reported to be at least 50% greater than would be expected from additive effects of the two factors.17 Ethanol consump tion and smoking have been found to be important in the development of double primary cancers of the head and neck as well, and the development of cancer of the larynx as a second primary shows an associadon with continued ethanol intake after discovery of the first primary.11 As with smoking, the effects of alcohol appear to be greater at younger ages--heavy drinkers under 60 years of age had a relative risk of 5.8 com pared to one of 2.3 for heavy drinkers over age 60.7 The mechanism of action of alcohol in the production of cancer of the larynx is not clear. Ethanol may be a cancer promoter, especially when combined with smoking.12,13 Benz-a-pyrene when diluted in ethanol will produce cancers in animal studies, whereas when diluted in oil it does not.12 This would imply that the alcohol may serve as a vehicle to increase the car cinogenicity of other carcinogens. Poor nutrition is a frequent accompaniment of heavy drinking and may also contribute to cancer development. Specific nutri tional deficits (vitamin B deficiency and iron defi ciency) have been implicated in the increased numbers of laryngeal cancers seen in Scandinavian women (Plummer-Vinson disease)--cancers that are now rarely seen since efforts to correct the nutritional defi cits have been made.12,18 Low vitamin A and low vita min C intake was associated with a slight increase in risk of laryngeal cancer in one study.6 Ethanol may have an effect on micronutrients or result in the pro duction of proximate carcinogens within the oral cav ity. Ethanol has been shown to increase the hydroxylation of nitrosamines.18 A recent preliminary report described ethyl nitrite (a potent mutagen) in the breath of two people who smoked and drank at the same time, but not after smoking or drinking alone.19 Ethanol ingestion, by whatever mechanism, is weakly as sociated with cancer of the larynx in the absence of smoking, and strongly associated when smoking is also present. OTHER ENVIRONMENTAL FACTORS Other nonoccupational environmental factors that have been linked to cancer of the larynx include such habits as chewing betel nuts, using "PAN" (a combina tion of tabacco, slaked lime, and betel leaf) in India, and chewing miang (fermented wild tea leaves) in northern Thailand.20,21 Phenols in tea have been sus pected of cancer promotion as well, and have pro duced suggestive laboratory evidence.21 No study to date, however, has shown an increased risk oflaryngeal cancer in heavy tea drinkers in the absence of other factors. Despite high levels ofPAHs (polycyclic aromat ic hydrocarbons) in south Los Angeles air, no associa tion with laryngeal cancer has been demonstrated, though an increased incidence in lung cancer has been seen in this area.22 Studies are divided as to whether there is a rural or urban predominance for cancer of the larynx, so if such an effect exists, it is likely to be small compared to that of smoking, drinking, and other personal habits. OCCUPATIONAL FACTORS--ACCEPTED Much recent interest has been focused on possible occupadonal associadon of cancer of the larynx. The extremely strong association of cancer of the larynx with smoking makes it difficult to identify potenual occupadonal exposures that may also be exerting an effect. Very few exposures to date have shown con vincing and constant evidence of an association. The strongest evidence for an occupadonal associa tion with cancer of the larynx is found in studies of Japanese and English mustard gas workers, in whom an excessive incidence of laryngeal cancer was found in follow-up.23,24 Mustard gas is highly irritadng to the respiratory tree, and the larynx receives an early con centrated dose. Acute laryngeal findings had been documented in some cases during mustard gas pro duction as well,24 so the cause-effect sequence is con vincing and so far unchallenged. Numbers of cases were small, however, and no control for smoking or drinking was made in these studies. Cowles CANCER OF THE LARYNX 895 HWBUI0000681 Another fairly well accepted occupational associa expected had worked wvithn aassbestos32,33; but this study tion recognized since the early 1940s is that of iso did not control for smoking (all asbestos workers were propanol production and laryngeal cancer. Two smokers), no clear dose-response was seen (nor was cases of cancer of the larynx were found in operators one seen in the Liverpool study), and all had had less at one plant using a strong acid process (in conjunction than one year of exposure or only light intermittent with several other cancers of the head and neck area).25 exposures to asbestos. Another case-control study of Investigation at the time determined that isopropyl oil 47 cases in Washington state (Puget Sound area) found (an animal carcinogen) was the most likely culprit. A a weak, insignificant correladon between asbestos ex more recent study by Exxon of four cases of cancer of posure and cancer of the larynx, with no dose- the larynx associated with a strong acid process for response effect.8 A strong association between smok ethanol production has determined that diethyl sul ing and cancer of the larynx, with a strong fate is the more likely carcinogen.26The diethyl sulfate dose-response effect, was seen. Only one pauent is a potent mutagen found in high concentrations dur was a nonsmoker. ing the strong add process production of both ethanol and isopropanol. Levels are much reduced in the weak acid process currently used, and no associated laryngeal cancers have been seen in conjunction with it. A study of shipyard workers in Virginia also found no overall excess of cancer of the larynx in workers using asbestos, though an excess of lung cancer was found.34 Numbers were small, but a strong smoking association that increased with ethanol intake was OCCUPATIONAL FACTORS--SUSPECTED also seen. Black workers were found at higher risk Other occupational associations witn cancer of the than white workers in this study. A study of more than larynx are based either on one unconfirmed and not 900 chrysodle asbestos miners in Italy found six with entirely convincing report, or on conflicting reports. cancer of the larynx compared to 1.9 expected cases Better controlled studies are needed to definitively (based on Italian cancer stausdcs), but the numbers assess these possible associations. The association for were too small for statistical significance; all were which data continue to be conflicting, and around smokers, and the area in which the study was done has which the most controversy currently revolves, is that* a higher background rate of cancer of the larynx than oT occupational exposure to asbestos and cancer of the the rest of Italy.35 larynx. If there is an association, it is far less important than the~potential link between occupational exposure to asbestos and cancer of the stomach. Several reports lave sue Sstedari association between asbestos expo sure and cancer of the larynx. Three cases of cancer of the larynx occurred in Philadelphia shipyard workers Two reviews of the asbestos and laryngeal cancer association mention two studies, one of London fac tory workers working with asbestos, and the other of American insulators, which showed potentially a 2:1 excess of deaths from cancer of the larynx in these populations, but again, smoking was not controlled who also had chest x-ray evidence of asbestos-related disease.27 They ranged from 54 to 65 years old, and each was a current or ex-smoker. One cancer of the larynx occurred in a series of 879 cases of asbestosis in Italy, but smoking habits were not assessed and the paper reporung this case was more concerned with the significant excess of lung cancer and pleural mesothelioma in this population.28 for. Similar results have not been seen in Canadian chrysodle miners or millers, or in a prospective casecontrol study in an ENT hospital in London.36,37 At this point the associauon between asbestos exposure and cancer ot tne larynx is unpiuvcil, but evidence suggests there may bea mild synergism between smolcThg and asbestos exposure similar to that seen between ^Tnokhm and L'lllaHul intake laid tough possttriVuT a A retrospective case-control study in Liverpool, En "lesser degree). In cancer registry studies, both in the gland, showed that mo~e patients than controls had United States and the United Kingdom, occupauons had occupational exposure to asbestos (including ten dockworkers who had unloaded raw asbestos), but with high asbestos exposures do not consistently show greater risks for cancer of the larynx.38'43 smoking was not adequately controlled for. Questions Other occupations that have been linked in at least also remain regarding possible selection bias in this one report to cancer of the larynx, but for which con study (three reports of the study each give different firming evidence is not currently available, include numbers of exposed patients), and only one patient farmers and laborers in Croaua10; farmers, fishermen, showed chest x-ray changes related to asbestos and laborers in Japan9; barbers, chemical industry exposure.29'31 In addiuon, in the last report of this operatives, leather industry operatives, and paper study31 a caveat was added pointing out that the report workers in the US42,43; leather workers, pulp and was based on a small number of male patients "who paper workers, sawyers, and woodworkers in may have been influenced by the prospect of compen Washington state41; persons exposed to wood dust in sation." A similar case-control study in Toronto of 54 the US4; stevedores and dock laborers; recreation cases of cancer of the larynx found that more than workers, laborers, machine tool operators, deck and 896 July 1983 SOUTHERN MEDICAL JOURNAL Vol 76, No. 7 HWBUI0000682 ni^lfto TABLE. Summary of Factors of Potential ImpSHfice in the Development of Cancer of the Larynx (in Relative Order of Importance) Factors Importance 1. Smoking Increased risk 4-40x ) 2. Alcohol consumption Increased risk up to Sx J ^yner8'sm between S. Mustard gas Occupational relationship well accepted 4. Isopropanol production Occupational relationship well accepted (probably due to diethyl sulfate) 5. Chewing betel, PAN, miang Consistent results--probably relationship between these habits and increased risks seen in India, Southeast Asia 6. Dietary deficiencies Suspected from several studies and by (iron, vitamin B, vitamin virtual elimination of Plummer-Vinson A, vitamin C) disease from Sweden through nutrition supplements 7. Asbestos Conflicting reports; may be mild asbestos/smoking synergism 8. Nickel Occupational relationship reported from one country--unconfirmed by other studies 9. Vocal abuse Suggested from several studies 10. Soots, tars, mineral oil Anecdotal reports--no confirming evidence 11. Pesticides Anecdotal reports--no confirming evidence 12. Dental x-ray studies Relationship in heavy smokers in one study 13. Naphthalene workers Reported in one study--so far unconfirmed 14. Leather workers Suggested from case registry data; unconfirmed by study of English leather workers 15. Wood dust Suggested from case registry data but unconfirmed; not seen m English furniture workers 16. Bearing plant workers Cluster reported--no follow-up 17. Air pollution No evidence engine room personnel, and barkeepers in England38; farmers, gardeners, and forest workers in North Bohemia44; gardeners in England45; nickel workers in Norway46; bearing plant workers47 and thorium dioxide workers in the US48; naphthalene cleaners in Germany49; and brewery workers in Denmark.16 Cancer of the larynx w'as not found to be increased in a study of English furniture workers.50 Vocal abuse has been proposed as a possible factor in the development of cancer of the larynx as well, and many of the occupations statistically linked to this cancer do have increased potential for vocal abuse.9,38,51,53 Agents potentially related to the in creased risks seen in some of these occupations include mineral oil, pesticides, coal tar, and dental x-rays.8,45,53,54 CONCLUSION The Table summarizes the current status of various occupational and environmental factors of potential importance in the development of cancer of the larynx. Obviously, there is much still to be learned about cancer of the larynx. Smoking and the combina tion of smoking and drinking are the two major risk factors for this disease. Mustard gas workers and workers using the strong acid process for ethanol and isopropanol production are the two occupational groups with a well accented increased risk. The evi dence regarding asbestos is suggestive, but as Set utv proven. Other occupational exposures ttav increase risk as well, but the relationships are even less clear than those for asbestos. Certainly more research in this area is needed. As with other cancers strongly associated with smok ing, smoking cessation and control are likelv to produce the greatest dividends in the efforts to decrease the incidence of cancer of the larynx. Should such efforts be successful, other important environmental and occupational factors may become more readily recognized. References 1. Silverberg E: Cancer statistics 1982. Co 32:15-31, 1982 2. 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Skegg DCG, Stell PM, et al: Cancer of the larynx and other occupational hazards of mustard gas workers. Clin Otolaryngol 6:165-170, 1981 25. Weil CS, Smyth HF, Nale TW: Quest for a suspected industrial carcino gen. Arch Ind Hyg Occup Med 5:535-547, 1952 26. Lynch J, Harris NM, Bird MG, et al: An association of upper respiratory cancer with exposure to diethyl sulfate. J Occup Med 21:333-341, 1979 27. Libshitz HI, Wershba MS, Atkinson GW, et al: Asbestosis and carcinoma of the larynx: a possible association. JAMA 228:1571-1572, 1974 28. Vieliani EC, Mottura G. Maranzana P: Association of pulmonary tumors with asbestosis in Piedmont and Lombardv.AnnNYAcodSri 132:558-574, 1965 29. Stell PM, McGill T: Asbestos and cancer of head and neck (Letter). Lancet 804(1):678, 1973 30. Stell PM, McGill T: Asbestos and laryngeal carcinoma. Lancet 805:416417,1973 Cowles CANCER OF THE LARYNX 897 HWBUI0000683 i 31.' Sicll PM, McGill T: Exposure to asbestos and^^Bgeal carcinoma./ Laryngoi Otol 89:513*517, 1975 32. Shettigara PT. Morgan RW: Asbestos, smoking, and laryngeal carcinoma. Arch Environ Health 30:517-519, 1975 33. Morgan RW, Shetdgara PT: Occupational asbestos exposure, smoking, and Taryngej carcinoma. Ann NY Acad Sci 271:308-310, 1976 34. Blot Wj, Morris LE. Stroube R, et al: Lung and laryngeal cancers in relation to shipvard employment in coastal Virginia. J Natl Cancer Inst 65:571-575, 19$0 35. Rubino GF, Piolatto G, Newhouse ML, et al: Mortality of chrysodle asbestos workers at the Balangero Mine, Northern Italy. Br J Ind Med 36:187-194, 1979 36. Newhouse ML, Gregory MM, Shannon H: Etiology of carcinoma of the larynx. Biological effects of mineral fibers. IARC Sci Publ 30:687-695, 1980 37. Newhouse M: Epidemiology of asbestos related tumors. Semin Oncol 8250-257, 1981 38. Chovil A: Laryngeal cancer: an explanation for the apparent occupa tional association. 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Pedersen E, Hogetveit AC, Anderson A: Cancer of respiratory organs among workers at a nickel refinery in Norway. IntJ Cancer 12:32-41,1973 47. Kopelman J, Thind I, Lorina D: Investigating industriallv-related dis eases (Letter). AmJ Public Health 70:436, 1980 48. Assessment ofTechnologiesfor Determining Cancer Risksfrom the Environment. Office of Technology Assessment, Congress of the US, 1981 49. WolfO: Carcinoma of the larynx among naphthalene cleaners. ZGesamte Hyg 24:737-739, 1978 50. Rang EH, Acheson ED: Cancer in furniture workers. Int f Epidemiol 10:253-261, 1981 51. Atkinson L: Some features ofthe epidemiology of cancer of the larvnx in Australia and Papua, New Guinea. Laryngoscope 85:1173-1184, 1975 52. Wynder EL, Bross IJ, Day E: A study of the environmental factors in cancer of the larynx. Cancer 9:86-110, 1957 53. Hueper WC: Occupational and environmental cancers of the respiratory system. Recent Results in Cancer Research. New York, Springer-Venag, Vol 3, 1966 54. Kipling MD. Waldron HA: Polycyclic aromatic hydrocarbons in mineral oil, tar, and pitch, excluding petroleum pitch.Prn;Med 5:262-278,1976 Southern Medical Association's Research Project Fund has distributed over $250,000 since it began in 1970 89B July 1983 SOUTHERN MEDICAL JOURNAL Vol 76, No. 7 Si