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Previous pulmonary disease and lung cancer: A case-control study
J. chron. Dis. 1967, Vol. 20, pp. 59-64. Pergamon Press Ltd. Printed in Great Britain
PREVIOUS PULMONARY DISEASE AND LUNG A CASE-CONTROL STUDY*
CANCER:
ALBERT DAMONand JEAN P. MCCLUNG Department
of Anthropology,
Harvard University,
Cambridge,
Massachusetts
(Received 23 June 1966) INTRODUCTION
ALTHOUGHcigarette smoking is now recognized as a major cause of lung cancer, it does not completely explain the epidemiology of the disease. Some non-smokers develop lung cancer-about 5 cases of cancer per 100,000 persons in the United States, or oneseventh of all cases of lung cancer, occur among non-smokers. On the other hand, only a tiny fraction of the heaviest smokers develop lung cancer. In one study by BOUCOT[l], for example, among Philadelphia men only 4.4 per cent of 580 heavy cigarette smokers (more than a pack a day for more than 40 years) developed lung cancer. Other factors, particularly host resistance or susceptibility, must play a large part. In HAENSZEL’Swords [2], “Pulmonary carcinoma is a response dependent on a variety of environmental and host factors, and no single agent or attribute must always be present and precede the development of this disease , . . . No one should regard the epidemiology of lung cancer in its present state of development as a closed subject.” Previous pulmonary infection was first suggested as a causative factor in lung cancer by pathologists studying influenza and mustard gas poisoning during the First World War. WINTERNITZ[3] described the histological similarities between the rapid, nondifferentiated growth observed in influenza-infected lungs and that found in cancer tissues. He predicted that the cohort which survived the 1917-18 influenza epidemic would experience increased incidence of lung cancer. It was suggested that carcinogenesis in the lung proceeds through four stages: hyperplasia, metaplasia, carcinoma-in-situ, and neoplasia. The sequence is analogous to that described for the development of pulmonary adenomas in sheep with the viral pneumonia-like disease, ‘jaagsiekte,’ and parallels sequences demonstrated in man for skin and cervical cancers. Recent investigations provide histological support for this hypothesis. RAEBURN and SPENCER[4], describing a series of alveolar lung cancers arising in scars and lung cavities, estimated that one-quarter of all lung cancers arise in scars. MEYER and LIEBOW [5] proposed an etiological connexion between alveolar carcinoma and the ‘honeycombing’ scars which accompany interstitial pneumonia. ROSENBLATT [6] has summarized the histological evidence on cancers arising in tuberculosis scars. He suggested that part of the current rise in lung cancer may be due to the survival to *This work was done during the tenure of an Established Investigatorship of the American Heart Association (A.D.) and was supported by research grants from the same source and from the Council for Tobacco Research-U.S.A. 59
60
ALBERT DAMON and JEANP. MCCLIJNG
cancer-susceptible age of many persons with a diathesis toward pulmonary disease in general who in previous eras would have died of tuberculosis. KITAGAWA [7] broadened the concept of scar cancer to include many kinds of infection. Metaplastic changes in the bronchial epithelium detectable by cytological examination of sputum have been described by PAPANICOLAOU et al. [S] as ‘ciliocytophthoria’ (‘ccp’). ROSENBLATT et al. [9] found the percentage of ‘ccp-positive’ individuals in a series of pulmonary-disease patients highest among lung cancer patients and patients with acute viral infections such as bronchitis and pneumonia. AUERBACHet al. [lo], in an autopsy study of the bronchial epithelium of 22 women who died of pneumonia (agent unspecified), reported pronounced hyperplasia and cell loss, but few cells with the atypical nuclei found in heavy smokers. In a series of 35 children who had died of pneumonia, however, Auerbach found no appreciable abnormalities in the bronchial epithelium. In a review [ 1l] of histological and epidemiological evidence on the relation between lung cancer and previous pulmonary disease, conflicting results were noted in both retrospective and prospective epidemiological studies. Two retrospective studies with controls [12, 131 reported an association between chronic bronchitis and lung cancer, but differed as to the role of tuberculosis and other infections. A prospective study of British First World War veterans by CASEand LEA [14] indicated a 2:l excess of lung cancer deaths over the expected number (p< 0.01) among men exposed to mustard gas and also among those with pulmonary infection (chronic bronchitis), whereas a similar study of BEEBE[ 151 among American veterans showed a 3 : 2 excess (p < 0.05) among gas victims but none among men with lung infection (influenza1 pneumonia). The divergent results within both sets of studies, retrospective and prospective, were ascribed in the review cited [l l] to differences in the study populations and design, in the environments, and in diagnostic criteria of disease, but the real explanation is by no means clear. It was concluded that further retrospective or case-control studies are needed to determine whether any association exists strong enough to warrant a definitive prospective investigation. We report here such a case-control study, with negative findings. SUBJECTS AND METHODS Between 1880 and 1920, over 17,000 Harvard men were measured in considerable anthropometric detail by the late Dudley A. Sargent and two assistants. These subjects were homogeneous ethnically and ultimately became so socio-economically. About 85 per cent were Old Americans (all four grandparents born in the United States), largely of British descent, and another 10 per cent were of immediate British or other Northern European ancestry. At the time of measurement, each man was asked about family diseases, the cause of parental death, if any, and his own previous illnesses, the check list for which included four pulmonary diseases: asthma, bronchitis, pleurisy, and pneumonia. In a consecutive sample of 611 men, 81 per cent reported no previous pulmonary disease, 17 per cent reported one, and 2 per cent reported two or more. Influenza was not listed. Tuberculosis, not included on the check list, was noted, when it occurred, under ‘general health.’ Death certificates returned by 1 January 1966 showed that 130 men had died of lung cancer. Each such subject was matched with the next man measured at Harvard who was of the same age. The median age at measurement for the 130 pairs was 19.6 yr,
Previous Pulmonary Disease and Lung Cancer : A Case-Control Study
61
the mean age 19.9 5 s.e. 0.2 years. Death certificates provided age at death for all the lung cancer cases and age at death and cause of death for those controls who had died by 1 January 1966. RESULTS Tables 1 and 2 show that subsequent lung cancer was not associated in this series with either total number of pulmonary diseases or with any specific pulmonary disease. Moreover, there was no significant difference between lung cancer cases and controls TABLE 1. NUMBER
OF PREVIOUSP~LMONARYDBEASES REPORTED* BY LUNG CANCER CASES AND AGEMATCHED CONTROLS
No. of previous pulmonary diseases
Lung cancer cases
Controls
0
102 21 5 2 0 130
100 26 3 1 0 130
1 2 3 4 No. of subjects
*During medical and anthropometric examination at Harvard University, at a mean age of 19.9 yr.
as to the number of all diseases reported, non-pulmonary as well as pulmonary. No subject in either group reported previous tuberculosis. The two series did not differ significantly either in the number of individuals who had a dead parent at the time of examination (lung cancer-26; controls-25) or in the number whose parent had died of pulmonary disease such as pneumonia or tuberculosis (lung cancer-7; controls--+. TABLET.
TWE OF PREVIOUS PULMONARY
DISEASE RFPORTED* BY 130 LUNG CANCER CASES AND 130 CONTROLS
Pulmonary disease Asthma Bronchitis Pneumonia Pleurisy Total
Lung cancer cases 4 18 12 3 37
Controls 4 13 13 5 35
*See footnote, Table 1.
The two groups did not differ significantly in height, weight, or lung capacity at the time of measurement (Table 3). Age at death was further analyzed to check the comparability of the two groups. Conceivably some of the matches who could have died of lung cancer might have died of some other cause before reaching the susceptible age. This was not the case, however. Table 4 shows no difference in mean age at death of cases and controls. The surviving control subjects were of course older than the men who had died of lung cancer, so that the controls had indeed lived long enough to have developed the disease. Incidentally, Table 4 also shows that among the control subjects, significantly more of those without preceding pulmonary disease were alive than of those with such
ALBERTDAMONand JEAN P. MCCLUNG
62 TABLE3.
HEIGHT, WEIGHT,AND
LUNG
CAPACITYOF LUNG CANCERCASES HARVARD
Number
Mean&se.
AND
CONTROLS
WHILE
AT
S.D.
Significance of difference
Height (cm) Lung cancer cases Controls
129 130
176.0 175.2
0.6 0.6
6.6 6.9
n.s.
Weight (kg) Lung cancer cases Controls
129 130
66.6 66.5
0.3 0.9
2.9 10.0
n.s.
Lung capacity (cc) Lung cancer cases Controls
124 120
4,279.0 4,167.0
57.0 65.0
633.0 711 .o
n.s.
disease (39/100, or 39 per cent, vs. 4/30, or 13.3 per cent; p-cO.001). Among control subjects still alive, however, those with and without previous pulmonary disease were of similar age. TABLET. AGE
ATDEATH(ORON
1 JANUARY 1966) OFLUNGCANCERCASESAND WITHOUT PREVIOUS PULMONARY DISEASE
CONTROLS
Lung cancer cases Previous pulmonary disease (dead) (1) Number Mean age (yr) at death or on 1 January 1966 S.D. SE. of mean Significance of differences:
No previous pulmonary disease (dead) (2)
28
102
65.3 10.7 2.0 Cols. Cols. Cols. Cols. Cols.
1 vs. 1, 3, 1+2 2 vs. 4 vs.
68.9 9.6 1.0 2: 5: vs. 5: 6:
~HAND
Controls Previous pulmonary disease alive dead (3) (4)
No previous pulmonary disease dead alive (5) (6)
26
61
39
63.5 17.4 2.2
16.4 6.7 1.1
65.4 11.9 3.5
4 75.0 -
n.s. n.s. 3+4+5+6: n.s. 0.03>p>O.O2 n.s.
DISCUSSION
The negative results among Harvard men agree with BEEBE’S findings [15] in a prospective study among American veterans of the First World War. The veterans had been hospitalized with influenza1 pneumonia at ages 25 to 30. The Harvard men’s pulmonary disease, occurring before age 20, was also likely to have been acute rather than chronic, judging from the type of disease (Table 2) and the fact that men entered the series when they wished to rent lockers for.exercise in college. Other epidemiological studies, both retrospective [12, 13, 16, 171 and prospective [14, 151, have emphasized chronic pulmonary disease and have not specified age of onset. Possibly, therefore, the association found in these studies may reflect a real carcinogenic effect of pulmonary disease which is chronic or occurs in middle or late adult life.
Previous Pulmonary
Disease and Lung Cancer:
A Case-Control
Study
63
Other possibilities that could explain positive findings in other studies are (1) the increased frequency of other lung diseases among smokers, who constitute the vast preponderance of lung cancer cases; (2) over-reporting of previous pulmonary diseases by lung cancer patients who are ‘lung conscious’; and (3) reporting of pre-cancerous symptoms as other lung diseases. As for smoking, DENOIX [12], in a retrospective study that controlled this variable, found the association of previous pulmonary disease with lung cancer to hold within smoking classes. In BEEBE’S prospective study [15], however, smoking habits did not differ between men with pneumonia and controls, but still no difference was found in lung cancer deaths. Failure to control for smoking habits in the present study, unavoidable in the absence of such information, could possibly mask a real association, but Beebe’s finding makes this unlikely. The problems of over-reporting and mis-reporting were avoided here by obtaining information on pulmonary infection early in life, decades before lung cancer developed. The most impressive histological evidence for a connexion between lung cancer and previous disease comes from studies of alveolar cell carcinoma. Death certificates used in the present study did not provide information about cell type in the lung cancer cases. Alveolar cell carcinoma is rare, and a specific association between previous disease and this type of neoplasm is unlikely to appear in a small series. The lack of association between early pulmonary disease and lung cancer among Harvard men by no means disproves the hypothesis, but we suspect that other host characteristics will prove more rewarding to explore. The highly significant association between early pulmonary disease and death from all other causes warrants further research. SUMMARY
Among more than 17,000 men examined medically and anthropometrically at Harvard University between 1880 and 1920, 130 had died of lung cancer by 1 January 1966. Each lung cancer decedent was matched with the next man of the same age to be ,examined. Mean age at examination was 19.9 yr. Of the controls, 87 had died and 43 were still alive on 1 January 1966. The lung cancer decedents and the controls did not differ in the number or nature of prior pulmonary diseases reported during their medical examination at Harvard. Among the controls, significantly more of those without early pulmonary disease were still alive than of those with early pulmonary disease.
REFERENCES 1. BOUCOT,K. R., COOPER,D. A. and WEISS,W. : The Philadelphia Project: an interim report, Ann. intern. Med. 54, 363, 1961.
2.
Pulmonary Neoplasm Research
6.
HAENSZEL,W.: Quantitative evaluation of the etiologic factors in lung cancer, in Tobacco and Health (Ed. by JAMESand ROSENTHAL).Thomas, Springfield, 1962. WINTERNITZ,M., WASON, I. and MCNAMARA,F.: The Pathology of Znfkenza, pp. 4G-49. Yale University Press, New Haven, 1920. RAEBURN,C. and SPENCER,H.: Lung scar cancers, Br. J. Tuberc. Dis. Chest 51,237, 1957. MEYER, C. and LIEBOW,A. : Relationship of interstitial pneumonia honeycombing and atypical epithelial proliferation to cancer of the lung, Cancer 17, 322, 1964. ROSENBLATT,M. : Association of bronchogenic carcinoma and pulmonary tuberculosis,
7.
KITAGAWA,
3. 4. 5.
Geriatrics
20, 99, 1965.
M. : Autopsy study of lung cancer with special reference to scar cancer, Acta path.
Jap. 15, 199, 1965.
64
ALBERT DAMON and JEAN P. M&LUNG
8. PAPANICOLAOU, G., BRIDGES, E. and RAILEY, C.:
bronchial epithelium (ciliocytophthoria) 83, 641, 1961.
Degeneration of the ciliated cells of the in its relation to pulmonary disease, Am. Rev. resp. Dis.
9. ROSENBLATT,M., TRINIDAD, S., LISA, J. and TCHERTKOFF,V.: Specific epithelial degeneration (ciliocytophthoria) in intlammatory and malignant respiratory disease, Dis. Chest. 44,605, 1963. 10. AUERBACH,O., STOUT, A. P., HAMMOND,E. C. and GARFINKEL,L.: Changes in bronchial epithelium in relation to sex, age, residence, smoking and pneumonia, New Engl. J. Med. 267, 111, 1962. 11. MCCLUNG, 3. P.: Previous pulmonary disease in lung cancer: a review. J. chron. Dis. 20, 65, 1967. 12. DENOM, P., L’enqu&te francaise sur l’etiologie du cancer bronchopulmonaire, Bull. Ass. fr. Z&de Cancer 45,1, 1958. 13. FINKE, W. : Chronic pulmonary disease in patients with lung cancer, N. Y. med. J. 58,3183,1958, 14. CASE, R. and LEA, A. : Mustard gas poisoning, chronic bronchitis, and lung cancer, Br. J. prev. sot. Med. 9,62, 1955. 15. BEEBE,G.: Lung cancer in World War I veterans-possible relation to mustard-gas injury and 1918 influenza epidemic, J. natn. Cancer Inst. 25,1231,1960. 16. ROSENBLAIT,M. and Y~DJZ, M. : Bronchogenic carcinoma-relation to antecedent pulmonary infection, Dis. Chest. 44,598, 1963. 17. GYURECH-VAoo, E. and SCHERRER,M. : t’lber die Beziehungen zwischen chronischer Bronchitis und Bronchuskarzinom, Schweiz. med. Wschr. 88, 1132, 1958.
PREVIOUS PULMONARY DISEASE AND LUNG A CASE-CONTROL STUDY*
CANCER:
ALBERT DAMONand JEAN P. MCCLUNG Department
of Anthropology,
Harvard University,
Cambridge,
Massachusetts
(Received 23 June 1966) INTRODUCTION
ALTHOUGHcigarette smoking is now recognized as a major cause of lung cancer, it does not completely explain the epidemiology of the disease. Some non-smokers develop lung cancer-about 5 cases of cancer per 100,000 persons in the United States, or oneseventh of all cases of lung cancer, occur among non-smokers. On the other hand, only a tiny fraction of the heaviest smokers develop lung cancer. In one study by BOUCOT[l], for example, among Philadelphia men only 4.4 per cent of 580 heavy cigarette smokers (more than a pack a day for more than 40 years) developed lung cancer. Other factors, particularly host resistance or susceptibility, must play a large part. In HAENSZEL’Swords [2], “Pulmonary carcinoma is a response dependent on a variety of environmental and host factors, and no single agent or attribute must always be present and precede the development of this disease , . . . No one should regard the epidemiology of lung cancer in its present state of development as a closed subject.” Previous pulmonary infection was first suggested as a causative factor in lung cancer by pathologists studying influenza and mustard gas poisoning during the First World War. WINTERNITZ[3] described the histological similarities between the rapid, nondifferentiated growth observed in influenza-infected lungs and that found in cancer tissues. He predicted that the cohort which survived the 1917-18 influenza epidemic would experience increased incidence of lung cancer. It was suggested that carcinogenesis in the lung proceeds through four stages: hyperplasia, metaplasia, carcinoma-in-situ, and neoplasia. The sequence is analogous to that described for the development of pulmonary adenomas in sheep with the viral pneumonia-like disease, ‘jaagsiekte,’ and parallels sequences demonstrated in man for skin and cervical cancers. Recent investigations provide histological support for this hypothesis. RAEBURN and SPENCER[4], describing a series of alveolar lung cancers arising in scars and lung cavities, estimated that one-quarter of all lung cancers arise in scars. MEYER and LIEBOW [5] proposed an etiological connexion between alveolar carcinoma and the ‘honeycombing’ scars which accompany interstitial pneumonia. ROSENBLATT [6] has summarized the histological evidence on cancers arising in tuberculosis scars. He suggested that part of the current rise in lung cancer may be due to the survival to *This work was done during the tenure of an Established Investigatorship of the American Heart Association (A.D.) and was supported by research grants from the same source and from the Council for Tobacco Research-U.S.A. 59
60
ALBERT DAMON and JEANP. MCCLIJNG
cancer-susceptible age of many persons with a diathesis toward pulmonary disease in general who in previous eras would have died of tuberculosis. KITAGAWA [7] broadened the concept of scar cancer to include many kinds of infection. Metaplastic changes in the bronchial epithelium detectable by cytological examination of sputum have been described by PAPANICOLAOU et al. [S] as ‘ciliocytophthoria’ (‘ccp’). ROSENBLATT et al. [9] found the percentage of ‘ccp-positive’ individuals in a series of pulmonary-disease patients highest among lung cancer patients and patients with acute viral infections such as bronchitis and pneumonia. AUERBACHet al. [lo], in an autopsy study of the bronchial epithelium of 22 women who died of pneumonia (agent unspecified), reported pronounced hyperplasia and cell loss, but few cells with the atypical nuclei found in heavy smokers. In a series of 35 children who had died of pneumonia, however, Auerbach found no appreciable abnormalities in the bronchial epithelium. In a review [ 1l] of histological and epidemiological evidence on the relation between lung cancer and previous pulmonary disease, conflicting results were noted in both retrospective and prospective epidemiological studies. Two retrospective studies with controls [12, 131 reported an association between chronic bronchitis and lung cancer, but differed as to the role of tuberculosis and other infections. A prospective study of British First World War veterans by CASEand LEA [14] indicated a 2:l excess of lung cancer deaths over the expected number (p< 0.01) among men exposed to mustard gas and also among those with pulmonary infection (chronic bronchitis), whereas a similar study of BEEBE[ 151 among American veterans showed a 3 : 2 excess (p < 0.05) among gas victims but none among men with lung infection (influenza1 pneumonia). The divergent results within both sets of studies, retrospective and prospective, were ascribed in the review cited [l l] to differences in the study populations and design, in the environments, and in diagnostic criteria of disease, but the real explanation is by no means clear. It was concluded that further retrospective or case-control studies are needed to determine whether any association exists strong enough to warrant a definitive prospective investigation. We report here such a case-control study, with negative findings. SUBJECTS AND METHODS Between 1880 and 1920, over 17,000 Harvard men were measured in considerable anthropometric detail by the late Dudley A. Sargent and two assistants. These subjects were homogeneous ethnically and ultimately became so socio-economically. About 85 per cent were Old Americans (all four grandparents born in the United States), largely of British descent, and another 10 per cent were of immediate British or other Northern European ancestry. At the time of measurement, each man was asked about family diseases, the cause of parental death, if any, and his own previous illnesses, the check list for which included four pulmonary diseases: asthma, bronchitis, pleurisy, and pneumonia. In a consecutive sample of 611 men, 81 per cent reported no previous pulmonary disease, 17 per cent reported one, and 2 per cent reported two or more. Influenza was not listed. Tuberculosis, not included on the check list, was noted, when it occurred, under ‘general health.’ Death certificates returned by 1 January 1966 showed that 130 men had died of lung cancer. Each such subject was matched with the next man measured at Harvard who was of the same age. The median age at measurement for the 130 pairs was 19.6 yr,
Previous Pulmonary Disease and Lung Cancer : A Case-Control Study
61
the mean age 19.9 5 s.e. 0.2 years. Death certificates provided age at death for all the lung cancer cases and age at death and cause of death for those controls who had died by 1 January 1966. RESULTS Tables 1 and 2 show that subsequent lung cancer was not associated in this series with either total number of pulmonary diseases or with any specific pulmonary disease. Moreover, there was no significant difference between lung cancer cases and controls TABLE 1. NUMBER
OF PREVIOUSP~LMONARYDBEASES REPORTED* BY LUNG CANCER CASES AND AGEMATCHED CONTROLS
No. of previous pulmonary diseases
Lung cancer cases
Controls
0
102 21 5 2 0 130
100 26 3 1 0 130
1 2 3 4 No. of subjects
*During medical and anthropometric examination at Harvard University, at a mean age of 19.9 yr.
as to the number of all diseases reported, non-pulmonary as well as pulmonary. No subject in either group reported previous tuberculosis. The two series did not differ significantly either in the number of individuals who had a dead parent at the time of examination (lung cancer-26; controls-25) or in the number whose parent had died of pulmonary disease such as pneumonia or tuberculosis (lung cancer-7; controls--+. TABLET.
TWE OF PREVIOUS PULMONARY
DISEASE RFPORTED* BY 130 LUNG CANCER CASES AND 130 CONTROLS
Pulmonary disease Asthma Bronchitis Pneumonia Pleurisy Total
Lung cancer cases 4 18 12 3 37
Controls 4 13 13 5 35
*See footnote, Table 1.
The two groups did not differ significantly in height, weight, or lung capacity at the time of measurement (Table 3). Age at death was further analyzed to check the comparability of the two groups. Conceivably some of the matches who could have died of lung cancer might have died of some other cause before reaching the susceptible age. This was not the case, however. Table 4 shows no difference in mean age at death of cases and controls. The surviving control subjects were of course older than the men who had died of lung cancer, so that the controls had indeed lived long enough to have developed the disease. Incidentally, Table 4 also shows that among the control subjects, significantly more of those without preceding pulmonary disease were alive than of those with such
ALBERTDAMONand JEAN P. MCCLUNG
62 TABLE3.
HEIGHT, WEIGHT,AND
LUNG
CAPACITYOF LUNG CANCERCASES HARVARD
Number
Mean&se.
AND
CONTROLS
WHILE
AT
S.D.
Significance of difference
Height (cm) Lung cancer cases Controls
129 130
176.0 175.2
0.6 0.6
6.6 6.9
n.s.
Weight (kg) Lung cancer cases Controls
129 130
66.6 66.5
0.3 0.9
2.9 10.0
n.s.
Lung capacity (cc) Lung cancer cases Controls
124 120
4,279.0 4,167.0
57.0 65.0
633.0 711 .o
n.s.
disease (39/100, or 39 per cent, vs. 4/30, or 13.3 per cent; p-cO.001). Among control subjects still alive, however, those with and without previous pulmonary disease were of similar age. TABLET. AGE
ATDEATH(ORON
1 JANUARY 1966) OFLUNGCANCERCASESAND WITHOUT PREVIOUS PULMONARY DISEASE
CONTROLS
Lung cancer cases Previous pulmonary disease (dead) (1) Number Mean age (yr) at death or on 1 January 1966 S.D. SE. of mean Significance of differences:
No previous pulmonary disease (dead) (2)
28
102
65.3 10.7 2.0 Cols. Cols. Cols. Cols. Cols.
1 vs. 1, 3, 1+2 2 vs. 4 vs.
68.9 9.6 1.0 2: 5: vs. 5: 6:
~HAND
Controls Previous pulmonary disease alive dead (3) (4)
No previous pulmonary disease dead alive (5) (6)
26
61
39
63.5 17.4 2.2
16.4 6.7 1.1
65.4 11.9 3.5
4 75.0 -
n.s. n.s. 3+4+5+6: n.s. 0.03>p>O.O2 n.s.
DISCUSSION
The negative results among Harvard men agree with BEEBE’S findings [15] in a prospective study among American veterans of the First World War. The veterans had been hospitalized with influenza1 pneumonia at ages 25 to 30. The Harvard men’s pulmonary disease, occurring before age 20, was also likely to have been acute rather than chronic, judging from the type of disease (Table 2) and the fact that men entered the series when they wished to rent lockers for.exercise in college. Other epidemiological studies, both retrospective [12, 13, 16, 171 and prospective [14, 151, have emphasized chronic pulmonary disease and have not specified age of onset. Possibly, therefore, the association found in these studies may reflect a real carcinogenic effect of pulmonary disease which is chronic or occurs in middle or late adult life.
Previous Pulmonary
Disease and Lung Cancer:
A Case-Control
Study
63
Other possibilities that could explain positive findings in other studies are (1) the increased frequency of other lung diseases among smokers, who constitute the vast preponderance of lung cancer cases; (2) over-reporting of previous pulmonary diseases by lung cancer patients who are ‘lung conscious’; and (3) reporting of pre-cancerous symptoms as other lung diseases. As for smoking, DENOIX [12], in a retrospective study that controlled this variable, found the association of previous pulmonary disease with lung cancer to hold within smoking classes. In BEEBE’S prospective study [15], however, smoking habits did not differ between men with pneumonia and controls, but still no difference was found in lung cancer deaths. Failure to control for smoking habits in the present study, unavoidable in the absence of such information, could possibly mask a real association, but Beebe’s finding makes this unlikely. The problems of over-reporting and mis-reporting were avoided here by obtaining information on pulmonary infection early in life, decades before lung cancer developed. The most impressive histological evidence for a connexion between lung cancer and previous disease comes from studies of alveolar cell carcinoma. Death certificates used in the present study did not provide information about cell type in the lung cancer cases. Alveolar cell carcinoma is rare, and a specific association between previous disease and this type of neoplasm is unlikely to appear in a small series. The lack of association between early pulmonary disease and lung cancer among Harvard men by no means disproves the hypothesis, but we suspect that other host characteristics will prove more rewarding to explore. The highly significant association between early pulmonary disease and death from all other causes warrants further research. SUMMARY
Among more than 17,000 men examined medically and anthropometrically at Harvard University between 1880 and 1920, 130 had died of lung cancer by 1 January 1966. Each lung cancer decedent was matched with the next man of the same age to be ,examined. Mean age at examination was 19.9 yr. Of the controls, 87 had died and 43 were still alive on 1 January 1966. The lung cancer decedents and the controls did not differ in the number or nature of prior pulmonary diseases reported during their medical examination at Harvard. Among the controls, significantly more of those without early pulmonary disease were still alive than of those with early pulmonary disease.
REFERENCES 1. BOUCOT,K. R., COOPER,D. A. and WEISS,W. : The Philadelphia Project: an interim report, Ann. intern. Med. 54, 363, 1961.
2.
Pulmonary Neoplasm Research
6.
HAENSZEL,W.: Quantitative evaluation of the etiologic factors in lung cancer, in Tobacco and Health (Ed. by JAMESand ROSENTHAL).Thomas, Springfield, 1962. WINTERNITZ,M., WASON, I. and MCNAMARA,F.: The Pathology of Znfkenza, pp. 4G-49. Yale University Press, New Haven, 1920. RAEBURN,C. and SPENCER,H.: Lung scar cancers, Br. J. Tuberc. Dis. Chest 51,237, 1957. MEYER, C. and LIEBOW,A. : Relationship of interstitial pneumonia honeycombing and atypical epithelial proliferation to cancer of the lung, Cancer 17, 322, 1964. ROSENBLATT,M. : Association of bronchogenic carcinoma and pulmonary tuberculosis,
7.
KITAGAWA,
3. 4. 5.
Geriatrics
20, 99, 1965.
M. : Autopsy study of lung cancer with special reference to scar cancer, Acta path.
Jap. 15, 199, 1965.
64
ALBERT DAMON and JEAN P. M&LUNG
8. PAPANICOLAOU, G., BRIDGES, E. and RAILEY, C.:
bronchial epithelium (ciliocytophthoria) 83, 641, 1961.
Degeneration of the ciliated cells of the in its relation to pulmonary disease, Am. Rev. resp. Dis.
9. ROSENBLATT,M., TRINIDAD, S., LISA, J. and TCHERTKOFF,V.: Specific epithelial degeneration (ciliocytophthoria) in intlammatory and malignant respiratory disease, Dis. Chest. 44,605, 1963. 10. AUERBACH,O., STOUT, A. P., HAMMOND,E. C. and GARFINKEL,L.: Changes in bronchial epithelium in relation to sex, age, residence, smoking and pneumonia, New Engl. J. Med. 267, 111, 1962. 11. MCCLUNG, 3. P.: Previous pulmonary disease in lung cancer: a review. J. chron. Dis. 20, 65, 1967. 12. DENOM, P., L’enqu&te francaise sur l’etiologie du cancer bronchopulmonaire, Bull. Ass. fr. Z&de Cancer 45,1, 1958. 13. FINKE, W. : Chronic pulmonary disease in patients with lung cancer, N. Y. med. J. 58,3183,1958, 14. CASE, R. and LEA, A. : Mustard gas poisoning, chronic bronchitis, and lung cancer, Br. J. prev. sot. Med. 9,62, 1955. 15. BEEBE,G.: Lung cancer in World War I veterans-possible relation to mustard-gas injury and 1918 influenza epidemic, J. natn. Cancer Inst. 25,1231,1960. 16. ROSENBLAIT,M. and Y~DJZ, M. : Bronchogenic carcinoma-relation to antecedent pulmonary infection, Dis. Chest. 44,598, 1963. 17. GYURECH-VAoo, E. and SCHERRER,M. : t’lber die Beziehungen zwischen chronischer Bronchitis und Bronchuskarzinom, Schweiz. med. Wschr. 88, 1132, 1958.