Previous pulmonary infection in lung cancer: A review

J. chron. Dis. 1967,

Vol. 20, pp. 65-78. Pergamon Press Ltd. Printed in Great Britain

PREVIOUS PULMONARY

INFECTION IN LUNG CANCER: A REVIEW

JEAN P. MCCLUNG Department of Anthropology, Harvard University, Cambridge,Massachusetts (Received 23 June

1966)

LINKS between previous non-malignant respiratory disease and lung cancer, hypothesized at the beginning of this century, have assumed increased importance with the epidemic rise in lung cancer incidence. The hypothesized causal linkage is supported by theoretical deductions and detailed histological evidence. However, the welldocumented connexion between cigarette smoking and lung cancer has overshadowed this less potent factor, and statistical studies on the relation between lung cancer and previous pulmonary infection have produced conflicting results. Further studies in this area are needed and may be useful in understanding host factors and mechanisms in lung cancer.

THE LUNG CANCER PROBLEM Since 1930 lung cancer mortality has shown a steady rise amounting to a more than eight-fold increase in rates for U.S. males. Lung cancer accounts for all the increase in cancer death rates in the U.S. and England in this period [I]. Figures from New York state for 1947-1960 indicate an overall yearly rate increase of 7 per cent for men and about 3 per cent for women. United States statistics show an increased lung cancer death rate at all ages for each successive cohort since 1890 [2]. Despite improvements in diagnostic and therapeutic techniques, the 5-yr survival rate for lung cancer remains less than 10 per cent. Epidemiology, in establishing the association between cigarette smoking and lung cancer, has provided one of the most useful approaches to understanding and perhaps eventually preventing or controlling this disease. Epidemiologic methods are especially suited to the study of the multiple causes and host factors involved in lung cancer. THE PREVIOUS INFECTION HYPOTHESIS: ORIGIN AND ASSUMPTIONS When tissue is traumatized, as in an infection, cells multiply in the course of repairing tissue damage. This rapid increase in cell number, called hyperplasia, was recognized by nineteenth century pathologists as similar to the rapid proliferation and lack .of differentiation observed in cancerous tissue [3]. 65

66

JEANP. MCCLUNG

Such hyperplastic changes were reported by WINTERNITZ et al. [4] in the lungs of victims of the 1917-1920 influenza epidemic. During the same period German pathologists noted hyperplasia in lungs of victims of mustard gas poisoning, and predicted that these populations would experience increased lung cancer incidence. Stages in the progression from hyperplasia to neoplasia were described in mice as early as 1914. COWDRY completed this description through studies in the 1920’s of the stepwise development of pulmonary adenomas in sheep with the pneumonia-like disease ‘jaagsiekte’ [5]. As summarized by ROSENBLATT [3], the hypothesized carcinogenic process includes (1) hyperplasia-after infection or other injury cells multiply rapidly; (2) metaplasia -cells fail for some reason to resume their normal forms; (3) carcinoma-in-situabnormal cells congregate to form a non-metastasizing lesion; (4) neoplasia-the tumor becomes capable of metastasis. The progression as a whole is represented as continuous, each stage including a wide range of cell abnormality. All stages are frequently found in the same lung [6]. Early human evidence supporting this model came largely from individual autopsies in which cancers were found in lung scars and surrounding ingested foreign bodies [7]. This connexion between previous injury and lung cancer parallels cancer-initiating sequences at other sites. Previous injury is a well-known etiologic factor in skin cancer; statistical data summarized by ARONS et al. [8] indicate that at least one-third of all skin carcinomas arise in sites of previous lesions-burns, traumatic wounds, fistulas or ulcers. Papanicolaou in the 1930’s demonstrated the four hypothesized stages in the development of cervical cancer. Pre-cancerous lesions have also been identified in the esophagus, stomach and breast [9]. The four-stage sequence seems to be a characteristic response of epithelial tissue to injury of any kind. Statistical evidence has been used to corroborate these deductions. The peak of lung cancer in the 40-69 age group is similar to the peaks for other epithelial cancers [9]. This risk-increase with age is consistent with a model of cancer as primarily a degenerative disease, the product of a cumulative series of injuries [lo]. Recent studies relating lung cancer to previous pulmonary damage still emphasize the four-stage progression or some modification of it. Many questions remain unanswered: metaplasia is more frequent in the trachea than the bronchi [ll]; why are tracheal cancers relatively infrequent? ANDRIAL [ 121 has asked why the 13 earlier influenza epidemics in the nineteenth century caused no lung cancer rise and why Iceland, the hardest hit country in the 1917 epidemic, has maintained uniformly low lung cancer rates. Future studies must rest on an increasingly complex view of lung cancer as a disease entity and of the many levels-gross anatomic, cellular and subcellular-at which injury can occur. Many recent studies consider separately the main histological types of carcinoma: squamous or epidermoid carcinomas, adenocarcinomas, and oat cell or atypical carcinomas. Investigators who advance the four-stage hypothesis tend also to separate peripheral cancers, usually adenomas, from the cancers, predominantly squamous in type, which arise in the larger bronchi. The lumen of the larger bronchial air passages is lined with tall columnar ciliated cells. PAPANICOLAOU, LISA, ROSENBLATTand others [13, 141 regard the carcinogenic process leading to squamous neoplasia as a metaplastic reversion of this columnar epithelium to an embryonic, stratified squamous type. In the peripheral region of the respiratory

Previous Pulmonary

Infection in Lung Cancer:

A Review

67

tree, air-filled alveoli are surrounded by a thin single-cell layer of squamous epithelium which is freely permeable to gaseous interchange with capillaries in the surrounding connective tissue. Many cancers arising in this region are adenocarcinomas composed of columnar cells with some secretory function. LISA et al. explain the carcinogenic process in this peripheral area of the lung as cell reversion under traumatic stress to the embryonic morphology of the alveoli [14]. J. BALO [15] cites an experiment by von Hayek in which alveolar cells in tissue culture became rounded under anoxic stress. BEAVERand SHAPIRO,on the other hand, have described the process as an invasion of the alveolar spaces by regenerating bronchiolar epithelium [16]. Apart from speculation about mechanisms, the correlation between cell type and site of origin is still only a hypothesis based on statistical distributions like that found by Lisa et al. (Table 1). There are alternative explanations for this distribution, some of which will be discussed in relation to smoking and cancer. TABLE I. RELATION OF CELL TYPE TO SITEOFORIGIN (from LISA et al.

Bronchial

squamous Adenocarcinoma Oat cell*

Peripheral

No.

%

75 0 4

*Oat cell types are underrepresented

[23]) Total

No.

%

NO.

%

95

6

20

81

74

0 5

21 4

67 13

21 8

19 7

in this sample from surgically resected lungs.

Differences in histological technique make controversy possible even at the level of interpretation of raw data. The Kreyberg tripartite classification described here is only the simplest of many commonly used alternatives; the World Health Organization classification, for instance, lists twelve different histological types [2]. A single neoplasm may contain more than one cell type, squamous or columnar colonies grading into the more malignant, undifferentiated oat cell types. It is often difficult to ascertain the exact site of origin of a lung carcinoma; even when the site is identified, further subjective terminological judgements may be required to distinguish, for example, a small bronchiole from an alveolar sac [17]. Although unproven, the hypothesized correlation between cell type and site is, with the hyperplasia-neoplasia progression, an important corollary to theories linking previous infections with lung cancer. It reflects concern with the anatomy and physiology of the host rather than with the action of exogenous factors. HISTOPATHOLOGICAL

EVIDENCE

Detailed mechanisms have been proposed linking specific infections to lung carcinoma of the alveolar type. The relationship of previous infection to carcinoma of the upper bronchi is less well-defined, but metaplastic changes of the columnar epithelial cells have been found in association with many non-malignant respiratory conditions. BEAVERand SHAPIRO[16] in 1956 published seven case histories of alveolar cell carcinomas in patients with a history of pneumonia. They cited the concurrent increase of both this type of carcinoma and of the ‘organizing’ types of pneumonia which lead to fibrosis. Fibrous proliferation in infections, they theorized, places

68

JEANP. MCCLUNG

alveolar cells under physical tension which could lead to metaplasia. Loss of respiratory function due to thickening of the fibrous walls of the alveolar septa would also favor the survival of malignant cells, which, according to one hypothesis, have increased capacity for anaerobic metabolism [18]. RAEBURNand SPENCER[7] published another series of case histories of alveolar cancers arising in scars and lung cavities. They estimated that about one quarter of all lung cancers are associated with old scars. They cited the association of asbestosis with lung cancer as statistical support for the role of pulmonary fibrosis in peripheral carcinogenesis. Fibrous obstruction of lymph drainage would, they suggested, concentrate carcinogenic pigments and cholesterol within the scar, further increasing the susceptibility of adjacent cells to malignant changes. They stressed the long latent period of these small, highly-differentiated carcinomas. MEYERand LIEBOW[3] published in 1964 the most recent review of the association between alveolar carcinomas and pneumonia. They described the ‘honeycombing’ distortion of alveolar architecture resulting from connective tissue changes which accompany interstitial pneumonia. This type of fibrosing, organizing pneumonia can follow many other types of insult, including chemicals such as nitric acid and surgery as in nerve resection. It may accompany ‘collagen diseases’ such as rheumatoid arthritis and may in some cases be a familial trait. Some degree of fibrosis is considered a normal concomitant of ‘aging’. The authors contend that ‘bronchiolar’ emphysema and ‘bronchiolitis obliterans’ are manifestations of this same ‘honeycombing’ tissue response to irritation. In a series of 153 resected tumours, 34 (22 per cent) were found in association with ‘honeycomb’ scars. Of these 34,28 (83 per cent) were of peripheral origin and 11 (3 1 per cent) were adenocarcinomas. In a control series of 404 autopsies, honeycombing was observed in only 4.7 per cent of the patients. Of these 19 controls with honeycomb scars, four were found to have small carcinomas. The authors found 95 per cent of their lung cancer patients were tuberculin-positive, a significantly higher percentage than that found in a control group. Many case histories have been published of cancers found in tubercular cavities [19, 201. BERKHEISER[6] has reported lung carcinomas arising in sites of previous infarction or embolization. BALO [15] noted in a 1965 paper the parallel increase in both cardiovascular disease and lung cancer. He hypothesized that cancers arising in sites of infarction may account for some of this parallelism. In an excellent recent paper, KITAGAWA[21] has reviewed 16 autopsy studies of lung scar cancer, those by RAEBURNand SPENCER[7], YOKOOand SUCKOW[20], and 14 more not summarized here. In his own series of 129 lung cancers, all those detected at autopsy at the Department of Pathology, University of Tokyo, between 1953 and 1963, were four instances of scar cancer-namely a precedent subpleural scar surrounded by carcinoma, with coexistence of epithelial hyperplasia and carcinoma at the edge of the scar. All four were small, peripheral adenocarcinomas, 3 cm or less in diameter. For 15 additional cases, a causal connexion between scar and carcinoma could not be histologically demonstrated. These may represent more advanced cases of scar cancer or incidental coexistence of scars with cancers. Despite the lack of detailed description of scars and carcinomas in earlier studies, Kitagawa speculated that the real proportion of scar cancers may be higher than that demonstrated for his series. The association of lung infection with metaplasia of the central regions of the bron-

Previous Pulmonary

Infection in Lung Cancer:

A Review

69

chial tree is based principally on sputum cytology rather than on the type of autopsy evidence used in the study of peripheral cancers. Scars in this central region are less easily identified, and the short latent period of the more invasive cancer types makes autopsy findings of pre-cancerous lesions less common [16]. PAPANICOLAOUin 1956 defined metaplasia of ciliated bronchial epithelia as ciliocytophthoria (‘ccp’). He described affected cells as displaying (1) pyknotic or deeply staining nuclei resulting from condensation and clumping of the nuclear chromatin; (2) acid-staining inclusions in the cytoplasm; and (3) fragmentation, with the ciliated tuft of the cell pinched off from the proximal nucleated portion. In a series of 1000 patients he found the percentage of ccp-positive cases highest in patients with acute viral infection or malignant disease (Table 2). Unfortunately the 1956 flu epidemic moved many of Papanicolaou’s controls into the acute viral infection category, so that the ‘normal’ baseline of ‘ccp’-positive individuals in a healthy population is uncertain. ROSENJSLATT [22] repeated the experiment with a hospital population of infectious and non-infectious pulmonary cases. His results confirmed the trend found in the earlier study.

TABLET. CILIOCYTOPHTHORIAMPULMONARYDISEASE(~~~~ ROSENBLA~ [35]) Pulmonary

disease

Congestive heart failure Chronic lung abscess Bronchiectasis Allergic bronchial asthma Chronic bronchitis and emphysema Chronic pulmonary tuberculosis Bronchiectasis Bacterial pneumonia Upper respiratory infection (viral) Viral pneumonia Metastatic lung cancer Bronchogenic lung cancer Acute bronchitis (viral)

No. of cases

ccp-positive (%)

6 4 10 4 28 62 10 26 52 41 8 44 16

0.0 0.0 0.0 0.0 8.0 9.7 10.0 11.5 25.0 26.8 50.0 57.0 75.0 -

SANDERUD [23],using autopsy material to gauge squamous metaplasia, confirmed the association between metaplasia and acute viral infections such as influenza and pneumonia. But equally strong associations with syphilis, uremia and vitamin A insufficiency indicate the need for studies using better controls-especially in regard to smoking habits and general health. ROSENBLATT [171in a recent paper summarized the mechanisms by which tuberculosis can lead to lung cancer. In addition to noting the association mentioned above of fibrosis and cavitation with peripheral cancers, Rosenblatt hypothesized that the calcification of lymph nodes caused by tuberculosis may irritate the principal bronchi. He contends that much of the current lung cancer increase is attributable to the increased numbers of patients with tuberculosis who survive to ages of high cancer risk.

JEANP. MCCLUNG

70

RELATION TO THE While proponents of the prior-infection

SMOKING hypothesis

evidence on lung cancer,

other investigators

different viewpoint. The relation between

cigarette

smoking

HYPOTHESIS were compiling

approached

the problem

and lung cancer

and interpreting from an entirely

was deduced

from early

epidemiological and statistical evidence rather than from the detailed histological research which has implicated infections and injuries as etiological agents. AUERBACH’S [24] autopsy investigations of the effect of smoking on human lung tissue came only after more than 25 epidemiologic

studies had shown that lung cancer

with number of cigarettes smoked. On the other hand, statistical tion hypothesis still lags far behind histological evidence. The

smoking

hypothesis

emphasizes

a chemical

risk increases

support for the infec-

or pharmacological

theory

of

carcinogenesis. Until recently, the focus of attention has been the presumptive mutagenic, initiating action of the carcinogens in tobacco rather than metabolic processes

taking place in the host.

Although this difference is primarily a question heredity ‘vs.’ environment, conclusions reached

of perspective, as in discussions of from the viewpoint of one or the

other hypothesis may differ radically-even when based on the same body of data. For instance there is controversy as to the meaning of the age distribution of lung cancer.

Although

it resembles

in general

sites, serial ratios show pronounced acceleration

increase

at older age levels [25].

the distribution in the 30-49

for epitheliomas

of other

age group, with a decreased

This is the sort of abrupt rise not expected

in a

population exposed that the distribution

to continuing external stimuli. PASSEY [lo], however, contends indicates that cancer results from cumulative, non-specific tissue

damage.

499 lung cancer

Analyzing

cases, he found no association

between

amount

smoked and age at onset or between duration of smoking and average age at onset. PIKE and DOLL [26] criticized Passey’s use of average age at onset in a non-cohort population. By hypothesizing massive doses of cigarette smoke they produced an age curve which, they contend, does approximate the cancer distribution in experimental animals

exposed

to carcinogens.

However,

the controversy

since uncertainty as to many of the mechanisms difficult to disprove hypotheses. Interpretation

of the distribution

will probably

continue,

and stages of carcinogenesis

of histological

makes it

types has also led to radically

divergent conclusions. the specific carcinomas,

Sex and age distribution have been interpreted as indicating that effect of cigarette smoking is to increase the incidence of squamous while incidence of other histological types of cancer is unaffected. Data

from DOLL and HILL [27] and OCHSNER [28] (Tables TABLE3.

3 and 4) are supported

by evidence

SEX RATIOIN HISTOLOGIC TYPESOF LUNGCANCER(from DOLL and HILL [41]) Epidermoid Adenocarcinoma Oat cell

M:F 26: 1 8: 1 3.3: 1

that adenocarcinomas have shown little increase in rate over the past twenty years as opposed to the spectacular increase in squamous cancers [2]. Rather than emphasizing -as do Lisa et al. and Passey-the unity of the degenerative process in the lung, those who favor the smoking hypothesis contend that the two cell types represent distinct

Previous Pulmonary

Infection in Lung Cancer:

A Review

71

disease entities with entirely different etiologic mechanisms [28]. Despite the controversy, some support for the previous-infection come from studies concerned primarily with the effects of smoking.

hypothesis has

TABLE 4. CELLTYPE ANDAGEATONSET

OF LUNG

CANCER

(from

OCX-ISNER [28])

Total lung cancers per age group (%)

Epidermoid Adenocarcinoma

o-49

50-59

70+

44.1 20.5

52 20

75 11.5

AUERBACHet al. [24] in an autopsy study which showed an increase in cell abnormality with increase in number of cigarettes smoked, also studied cell abnormalities in patients who had died of pneumonia. In a series of 22 female pneumonia victims he found pronounced hyperplasia and loss of cilia, but few cells with the atypical nuclei were found in heavy smokers.The bronchial epithelium of 35 children who had died of pneumonia did not differ appreciably from that of controls. Although Auerbach concluded that infection is a relatively insignificant factor in lung damage, his data open several areas for further investigation. His study emphasizes the necessity of considering the effect of age in tissue response to lung damage. Such a factor has been documented in skin cancer, where the latent period*between injury and cancer was found to be inversely proportional to age at injury [8]. Auerbach’s work also suggests the possibility of a synergistic relation between the initiating effect of cigarette smoke on cell nuclei and the promoting effect of infection in inducing cell hyperplasia. DOLL and HILL [27] in their classic prospective study of lung cancer in British doctors queried their subjects about previous lung complaints as well as about smoking habits. They judged their results inconclusive because of a problem which recurs in studies of this association: both heavy smokers and pre-cancerous subjects tend to experience bronchitis-like symptoms and consequently are more likely than others to recall previous pulmonary disorders [I]. Incidence rates for bronchitis in smokers are from two to eight times higher than rates for non-smokers [2]. This difficulty in separating cause and effect has not yet been resolved in lung cancer studies. The magnitude of the lung cancer increase directly attributable to cigarettes-loto 20-fold depending on amount smoked-has tended to overshadow the other risk factors implicated in these collateral studies. But the establishment of the smoking-lung cancer association is only the first step in understanding the disease. More data are needed to explain why some non-smokers develop lung cancer and why the vast preponderance (over 90 per cent) of heavy smokers do not. Much of the lung cancer incidence in non-smokers may represent adenocarcinomas [28, 291. If this histological type proves to be separable from squamous carcinoma, studies of previous infection in relation to peripheral lung cancers have already supplemented this gap in the smoking hypothesis. TOKUHATA’S [30, 311 research on the genetic factor in lung cancer indicates that heavy smokers who escape carcinoma may have low genetic susceptibility. Tokuhata estimates that the genetic factor may increase risk by as much as 1Cfold. More data are needed to support such a projection. However, other evidence indicates that the genetic suscepti-

72

JEAN

P. MCCLUNG

bility of different tissues to cancer varies independently [9]. The lung susceptibility factor in cancer may correlate with genetic susceptibility of other lung diseases such as that demonstrated in twin studies of tuberculosis and asthma [32]. There are other tissues in which both infectious and neoplastic diseases are increased in certain hosts; thyroid and gallbladder susceptibility in women are well-known examples. Further study of lung infection and injury might help distinguish the physical and chemical components of the carcinogenic effect of cigarette smoking. Both infection and smoking reduce or destroy ciliary activity and increase mucus secretion in the bronchial mucosa [26]. If the principal effect of tobacco smoke is histological damage affecting cytoplasmic metabolic regulators or membrane permeability, as PASSEY[ 10) and STEVENS[33] suggest, there should be a threshold (perhaps genetically determined in each individual) at which that damage becomes carcinogenic. However, if the effect is on the germ-cell material, any dose is potentially cancer-causing. As BERKSON[34] has pointed out, the non-specific effect of smoking in increasing disease susceptibility at the organ level puts severe strain on classical theories of chemical carcinogenesis. AUFXBACH’S[24] demonstration of regression of ‘pre-cancerous’ pathology in exsmokers also implies a more complex carcinogenic mechanism than simple ‘target theory’ [35] provides. The smoking controversy involves not only the differentiation between physical and chemical extracellular agencies but also a basic dichotomy between extracellular and intracellular agents. Theories of the smoking-susceptible type and of whole-organ susceptibility emphasize the intracellular, hereditary, enzymatic factor in lung cancer [34], rather than the extracellular carcinogen. EPIDEMIOLOGICAL STUDIES RELATING LUNG CANCER TO PREVIOUS DISEASE Tables 5 and 6 summarize the major published epidemiologic studies of this problem. Miscellaneous additional data exist. BEAVERand SHAPIRO[16], reviewing a previous study by Storey on alveolar carcinomas, found a history of previous lung disease in 62 per cent of 121 cases. In 84 per cent of the patients they found microscopic evidence of chronic inflammation, but they presented no control evidence for non-cancerous patients. The 1952 Doll and Hill study, already discussed, found that both bronchitis and lung cancer correlated with smoking. In DORN’S[37] prospective study, mortality from bronchitis and emphysema was 3.3 times as great in current regular cigarettesmokers as in non-smokers. Deaths from chronic nonspecific respiratory disease and from lung cancer have shown a significant rank correlation in national statistics from Britain, the United States and the Scandinavian countries [2]. Smoking is probably the link between these diseases. In his pioneer retrospective study, FINKE [38] specified that previous disease should have occurred at least 10 yr prior to diagnosis of carcinoma. He found chronic disease of more than 10 yr duration in 65 per cent of his lung cancer patients. Information on acute illnesses obtained for 78 of his cases showed that 40 per cent of them had experienced a near-fatal respiratory illness in childhood. Of 59 patients for whom information was obtained on pneumonia and influenza, 77 per cent had histories of at least one of these infections; 43 per cent had had multiple attacks. He did not report control data for these partial-sample studies. Finke also studied the roentgenological histories of 63 of these patients. In 17 he found evidence of pre-cancerous lesions l-5 yr before diagnosis.

Previous Pulmonary Infection in Lung Cancer : A Review TABLE%

PREVIOUSPULMONARYINFECTIONANDLUNGCANCER:

Subjects*

Study

Controls

73

RETROSPECTIVESTUDIES

Percentage with previous disease subjects

Finke, 1958 Rochester, New York

86

Gyurech-Vago & Scherrer, 1958 Bern, Switzerland

I26

Denoix et al. 1958 6 Paris hospitals, France

602

Rosenblatt & Yildiz, 1963 New York City

176

yest

none

YeSS

none

bronchitis asthma tuberculosis

(suspected)

infections (repeated TB, pleurisy, pneumonia) bronchitis asthma

controls

65 30 30

30 7 13

25 38 11

tuberculosis viral infections other infections chronic bronchitis

I1.S.

n.s. n.s. 0.01 11.7 9.8 5.9

influenza bronchitis pleurisy pneumonia tuberculosis

50.9

21.7

*Hospital-diagnosed patients with lung cancer. t86 sex- and age-matched hospital patients with non-malignant disease. $602 age-matched hospital patients with non-malignant disease. 602 age-matched hospital patients-accident victims.

Conclusions in the GYURECH-VAGO and SCHERRER [39] study stressed the difficulty of separating previous respiratory infections from those resulting from the malignancy. They also measured vital capacity in their patients and found, predictably, average values much lower than those of a control group. DENOIX [40] obtained detailed smoking data for his study group. Patients with lung cancer gave a history of bronchitis more often, even when patients and controls were smoking the same number of cigarettes per day. At the smoking levels 10-19 and 20-plus cigarettes per day, the differences were highly significant (P > 0.01). TABLE 6.

PREVIOUS PULMONARY

INJURYORINFECTION AND LUNG CANCER: VETERANS,FIRSTWORLD WAR

Gas poisoning Case & Lea Total 1267 29 Lung cancer deaths 14 Expected lung cancer 0.01 Significance Lung cancer as percentage of total* 2.3 Lung cancer as percentage of total deathst 5.3 *Not calculated by Case and Lea. tNot calculated in either report.

Infections

PROSPE~TIVESTIJDIESOF

Wounds

Beebe

Case & Lea

Beebe

Case & Lea

2718 39 26.6 0.05

1421 29 14.4 0.01

1855 15 18.6 n.s.

1114 15 15.5 n.s.

2578 30 26.2 n.s.

Beebe

1.3

2.0

0.8

1.2

1.0

4.1

3.1

2.3

3.4

0.54

74

JEANP. MCCLUNG

At lower smoking levels, however, the increased risk associated with bronchitis was not significant. The data do not completely separate the causative effect of smoking in bronchitis from the hypothetical independent action of bronchitis in causing lung cancer. The results may be interpreted as indicating that individuals susceptible to the bronchitic effects of cigarette smoke are also susceptible to its carcinogenic effects. ROSENBLATTand YILDIZ [5] also studied the histological type and site of origin of lung cancer among 176 patients. Except for alveolar carcinoma, they found no significant difference in cell type between the group with previous infection and the group without infection; of seven patients with the alveolar type of carcinoma, five had had previous histories of pneumonia. However, Rosenblatt and Yildiz did not find the excess of peripheral tumors in the previously-infected group which histological research would have predicted. Of the 102 cases with previous infection, 84 per cent were Of tumors of the major, secondary or tertiary bronchi, and 16 per cent were peripheral. the 121 cases without previous infection 80 per cent were central and 20 per cent peripheral-a virtually identical distribution. Considering the range of factors which can affect the incidence of lung cancer and of pulmonary disease, it is not surprising that these four studies produced divergent results. For one thing, Gyurech-Vago and Scherrer’s and Denoix’ subjects were all men, whereas 12 per cent of Finke’s patients and 19 per cent of Rosenblatt’s were women. Given the sex ratios for the different histological types of lung cancer, it is difficult to draw general conclusions from these results. Also, study hospitals were located in Bern, Paris, Rochester and New York City. Differences in socio-economic, atmospheric, ethnic and climatic environments plus different diagnostic conventions undoubtedly influenced distributions found among patients from these different hospitals [41]. Such differences are better controlled in the two prospective studies of previous infection, but Table 6 shows that these results, too, are conflicting. Despite apparent similarities of these investigations they represent important differences of technique. CASE and LEA’S [42] study group included all British veterans receiving pensions in 1930 for three disability categories: (1) chronic bronchitis resulting from mustard gas poisoning, (2) chronic bronchitis without previous exposure to mustard gas, and (3) amputations resulting from wounds. The three groups of men were not agematched but were ‘matched’ statistically by the method of comparative composite cohort analysis. Case and Lea used national statistics from the Registrar-General’s office to construct a profile for the age-specific death rates for each birth cohort. Birth and death dates of individuals in the study population were then fitted into this standard model to determine ‘expected’ numbers of deaths. BEEBE’S[43] subjects were members of the American Expeditionary Forces hospitalized in 1918 for (1) mustard gas poisoning, (2) pneumonia and (3) wounds. All were white males born in the years 1888-1893. Beebe initially planned to use percentage of total sample to compare lung cancer mortality in his gassed and infected groups with that of the wounded controls. After reading Case and Lea’s paper he applied their method to his study group. However, his group, as indicated by control figures, may not have been as representative of the ‘open’ population from which vital statistics were drawn as was the British study group. Beebe’s failure to duplicate a two-fold lung cancer increase in mustard gas and respiratory victims, as demonstrated by the British investigators, can be explained by

Previous Pulmonary Infection in Lung Cancer : A Review

75

other differences in the two studies. Pensioned British veterans probably experienced a more severe and prolonged exposure to mustard gas than did hospitalized Americans. Similarly, soldiers who had survived amputation might be expected to be constitutionally distinctive. Uncontrolled differences in the two studies involve geographical factors as well. All groups in the British series showed higher general mortality rates and higher lung cancer rates than did the American series. A total of 49 per cent of Case and Lea’s subjects had died as compared to 29 per cent of those in Beebe’s study. Further studies will have to determine whether differences in these results relate to a real differential between the etiological role of acute diseases like pneumonia and that of chronic conditions like bronchitis. If, as has been theorized, the principal effect of pneumonia is in the etiology of alveolar carcinoma, large groups will be needed to detect a difference in this relatively rare type of cancer. POSSIBILITIES FOR FUTURE STUDIES At the present stage of research on the previous-infection factor in lung cancer, the immediate need is for replication of the earlier studies. With better controls and larger numbers of cases, it may be possible to demonstrate a consistent relationship (or the lack of one) between previous infection and subsequent lung carcinoma. The most useful type of retrospective study would combine features of the four such studies outlined above : matched controls, rigorous protocol for defining ‘previous disease’, information on smoking histories, and detailed diagnosis of histological type and site of origin of the neoplasm. The role of childhood disease, discussed by FINKE [38], should be re-examined. Identification of lung infection before smoking age and before possible pre-cancerous symptoms offers perhaps the best escape from the circle of cause and effect described by Doll and Hill. The ultimate goal of epidemiological research in lung cancer is prevention, reached via definition of risk factors and, eventually, recognition of individuals susceptible to these factors [9]. If studies like those of BEAVERand SHAPIRO [16] and of MEYER and LIEBOW [3] on alveolar cell carcinomas are statistically confirmed, patients with organizing pneumonias could be recognized as high-risk individuals who should be regularly examined for early stages of lung cancer. Causative factors in the more common lung carcinomas seem more complex, and present knowledge suggests that a profile of the susceptible individual will include such factors as smoking, urban residence, and possibly personality and heredity. Investigations of previous pulmonary involvement are valuable in this general problem of identifying the susceptible man because they provide additional information as to host constitution. The definitive investigation would be a prospective study like DOLL and HILL’s [27] investigation of lung cancer in British doctors. Not only would genetic, smoking and disease histories be obtained for each member of the cohort, but subjects would receive periodic clinical tests to evaluate factors which might be diagnostically useful. Family histories should include data on lung cancer deaths, as collected by TOKUHATA and LILIENFELD [31], plus information on the incidence and severity of other pulmonary disease. Ideally, disease histories would specify age at occurrence, etiology, site, duration and frequency of respiratory illness. Somatotype and blood group secretion factors [44], which may correlate with pulmonary susceptibility, could be recorded for

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JEAN P. MCCLUNG

this cohort. Physical tests which have been suggested as valuable in early lung cancer diagnosis-roentgenology, ciliocytophthoria, vital capacity, possibly the tuberculin test-could be made at regular intervals. They might be useful in arriving at a factoranalytic or discriminant-function delineation of the individual most likely to develop lung cancer. Cancers which actually appear in the cohort would be carefully defined histologically and anatomically. Statistical analysis of such material could, theoretically, provide information about carcinogenic mechanisms in addition to indicating possible preventive measures. If previous pulmonary disease is important in lung cancer etiology, it could act through many mechanisms. Several theoretical ones have been proposed. WYNDER [45] has suggested that both smoking and non-malignant lung disease may lead indirectly to lung cancer through cilia-destroying bronchial cough. Although bronchitis is correlated with smoking, pneumonia and influenza are not. Wynder suggests that a connexion found between these infectious diseases and lung cancer could be explained as the result of coughing injury to the bronchial mucosa. He attributes part of the high lung cancer rate in England to lack of central heating, the custom of keeping windows open at night, and the climate-all factors that favor high incidence of chronic cough. Of 44 non-smokers examined in Wynder’s New York study of chronic cough, only 6 had persistent cough. Three of these had histories of respiratory illness, and the other three were exposed to occupational irritants. No control information was reported from non-smokers without chronic cough. The geographic distribution of lung cancer does not unequivocally support this hypothesis, and it has not yet been proven that the coughing smoker is the cancer-susceptible smoker. A cohort study stressing the role of pulmonary disease could test this theory and also PASSEY’S [lo] hypothesis that cancer results from a mechanical degeneration or aging of lung cells. Age curves of cancer deaths, smoking and disease histories, and tests of lung function and cell degeneration could also be used to investigate the proposed ‘latent period’ between carcinogenic trauma and appearance of the carcinoma. Time associations might also detect co-carcinogenic action of infections with cigarette smoke. Recent cancer research indicates that epigenetic agents like viruses may be as important in human as they are in animal cancers. Influenza virus has been implicated in animal studies of viral carcinogenesis. SIRTORI [46] in experiments with C57 black mice found hydrocarbons were carcinogenic only when administered jointly with Myxovirus influenza B. Electronmicroscopic studies showed that virus-infected alveolar cells contained fewer lamellar structures of a type which secretes carcinogenemulsifying phospholipids. When the lung is deprived of this defense mechanism, cancer-causing hydrocarbons can accumulate. In a later study SIRTORI [47] found reduction of the number and efficiency of these lamellar structures in senile mice. The carcinogenic process in man is certainly more complex than Sirtori’s model for mouse cancers. A cohort study might detect any differences in the effectiveness of viral and bacterial infections as cancer-precursors. A cohort study of the previous-infection problem alone is still impractical. The classic prospective smoking studies of Doll and Hill, of Hammond and of Dorn came only after many case-history investigations had repeatedly found strong correlations of smoking with lung cancer. Before comparable prospective evidence can be obtained for the previous-disease hypothesis, small-scale studies will have to focus on high-risk

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diseases, on specified age groups, and on clinically measurable co-factors. If such studies demonstrate a consistent association of significant magnitude, the ‘ideal’ prospective study will justify the effort. In the meantime, insurance records and the massive American Cancer Society investigation currently under way may provide useful information on the effect of previous pulmonary disease on lung cancer. SUMMARY Recent autopsy investigations of lung cancers arising in tuberculosis scars, infarcts and in pneumonia-infected alveoli seem to confirm the connexion, predicted on the basis of histological evidence, between lung cancer and previous injury. The hypothesized correlation emphasizes host factors in lung cancer and physical rather than chemical carcinogenic mechanisms. Statistical evidence is, however, contradictory. Four retrospective studies of previous lung infections in lung cancer patients fail to demonstrate a consistently significant excess of previous disease in lung cancer patients or, when an excess has been found, to distinguish the portion attributable to smoking or to pre cancer-diagnosis symptoms from that which may play a direct causal role in lung cancer. A prospective study of British veterans of the First World War reported a two-fold lung cancer increase in veterans with chronic bronchitis over a matched sample, whereas a similar study of American veterans failed to show a significant increase among soldiers hospitalized with pneumonia during the 1917 influenza epidemic. The immediate need is for replication of the statistical studies with better controls and larger numbers.

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