METHODOLOGIC VARIABLES

Subject Selection— Tobacco-use Histories—
1. Males and/or females 1. By type of smoking (separately and
2. Occupational groups combined)
3. Hospitalized cases 2. By amount and type
4. Autopsy series 3. By amount, type, and duration
5. Total lung cancer deaths in an area 4. By inhalation practices
6. Samplings of nationwide lung cancer

Other Variables Concurrently Studied—
1. Geographic distribution
a) Regional
1. Age matching vs. age groups b) Urban-rural

deaths

Control Selection—

2. Healthy individuals 2. Occupation

3. Patients hospitalized for other cancers 3. Marital status

4. Patients hospitalized for causes other 4. Coffee and alcohol consumption

than cancer 5 Other nutritional factors

5. Deaths from cancers of other sites 6. Parity

6. Deaths from other causes than cancer 7. War gas exposures

7. Samplings of the general population 8. Other pathologic conditions
Method of Interviewing— 9. Hereditary factors

. . 10. Air pollution
1. Mailed questionnaires 11. Previous respiratory conditions

2. Personal interviewing of subjects (or
telatives) and controls
a) By professional personnel
b) By non-professional personnel

This listing of methodologic variations is by no means complete, nor
does it imply that the individual retrospective studies should be criticized for
their choice of study methods and factors for observation. The individual
points of criticism have usually applied to one or two studies but not to all.

It is indeed striking that every one of the retrospective studies of male
lung cancer cases showed an association between smoking and lung
cancer, All have shown that proportionately more heavy smokers are
found among the lung cancer patients than in the control populations and
proportionately fewer non-smokers among the cases than among the con-
trols. Furthermore, the disparities in proportions of heavy smokers between
“test” groups and controls are statistically significant in all the studies.
The differences in proportions of non-smokers among the two groups are
also statistically significant in all studies but one (236) ; in the latter study,
although there were fewer non-smokers among lung cancer patients, the
difference was very small.

In the studies which dealt with female cases of lung cancer, similar find-
ings are noted in all of them with one exception (238). In this latter study,
although significantly more heavy smokers were found among the lung
Cancer cases than among the controls, the proportion of non-smokers among
the cases was distinctly higher than among the controls. This is the only
inconsistent finding among all the retrospective studies. Its meaning is not
clear but the authors have indicated that non-response among their female
Cases was 50 percent.

The weight to be attached to the consistency of the findings in the retro-
spective studies is enhanced when one considers that these studies exhibit
considerable diversity in methodologic approach.

151
oSI

TABLE 2.—Qutline of methods used in retrospective studies of

smoking in relation to lung cancer

 

 

 

Number of persons and method of selection

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Investigator, year, and Country Sex of Collection of data
reference cases
Cases Controls
Miiller 1939 (250) Germany M 86 Lung cancer decedents, Biirger | 86 Healthy men of the same age Cases: Questionnaire sent to relatives of
Hospital, Cologne. deceased. Controls: Not stated,
Schairer and Schoeniger | Germany M 93 Cancer decedents autopsied at Jena | 270 Men of the city of Jena aged 53 and | Cases: Questionnaire sent to next of kin
1943 (309). Pathological Institute, 1930-1941. 54 (average age of lung cancer victims= (195 for lung cancer). Controls: Ques-
53.9). tionnaire sent to 700.
Potter and Tully 1945 (280) | U.S.A. M 43 Male patients aged over 40 in Mas- 1,847 Patients of same group with | Cases and controls interviewed in clinics
sachusetts cancer clinies with cancer diagnoses other than cancer.
of respiratory tract.
Wassink 1948 (363) Netherlands 134 Male clinic patients with lung can- | 100 Normal men of same age groups as | Cases: Interviewed in clinic. Controls:
cer. cases. Not stated.
Schrek et al., 1950 (311) U.S.A. 82 Male lung cancer cases among 5,003 | 522 Miscellaneous tumors other than Smoking habits recorded during routine
Patients recorded, 1941-48. lung, larynx and pharynx, hospital interview,
Mills and Porter 1950 (237) | U.S.A. 444 Respiratory cancer decedents in | 430 Sample of residents matched by age | Cases: Relatives queried by mail ques-
Cincinnati, 1940-45 and in Detroit, in Columbus, Obio, from census tracts tionnaire or personal visit. Controls:
1942-46. Stratified by degree of air pollution, House-to-house interviews.
Levin et al., 1950 (207) U.S.A, 236 Cancer hospital patients diagnosed | 481 Patients in same hospital with non- | Cases and controls: Routine clinical
lung cancer. cancer diagnoses. history taken before diagnosis,
Wynder & Graham 1950 | U.S.A. M-F | 605 Hospital and private lung cancer | 780 Patients of several hospitals with | Nearly all data by personal interview; a
(381). Patients in many cities. diagnoses other than lung cancer. few cases by questionnaire: a few from
intimate acquaintances, Some inter-
views with knowledge or presumption
of diagnosis, some with none.
McConnell et al., 1952 (236) | England M-F | 100 Lung cancer patients, unselected, | 200 Inpatients of same _ bospitals, | Personal interviews by the authors of
in 3 hospitals in Liverpool area, matched by age and sex, without can- both cases and controls, with few ex-
194649. cer, 1948-50. ceptions. .
Doll and Hill 1952 (82) Great M-F | 1,465 Patients with lung cancer in hos- 1,465 Patients in same hospitals, | Personal interviews of cases and controls
Britain. Pitals of several cities. matched by sex and age group; some by almoners,
with cancer of other sites, some with-
out cancer.
Sadowsky et al., 1953 (301) | U.S.A. M 477 Patients with lung cancer in hos- | 615 Patients in same hospitals with ill-

 

 

Ditals in 4 states.

nesses other than cancer.

Personal questioning by trained inter-
viewers.
esl

 

 

 

 

 

 

 

 

 

 

 

Wynder and Cornfield , U.S.A. M 63 Physicians reported in A.M.A. | 133 Physicians of same group dying of ; Mall questionnaire to estates of decedents
1983 (3798). journal as dying of cancer of the cancer of certain other sites.
ung.
Koulumies 1953 (192) Finland M-F | 812 Lung cancer patients diagnosed at | 300 Outpatients of same hospital aged | Cases and controls questioned about
one hospital in 16 years. over 40, living in similar circum- smoking habits when taking case
stances, and without cancer, February histories.
and March 1052.
Lickint 1953 (211) Germany M-F | 246 Lung cancer patients in a number | 2.002 Sample of persons without cancer | Personal interviews by staff members of
: of hospitals and clinics. living in the same area and of same sex cooperating hospitals and _ clinics,
and age range as cases. corresponding in time to interviews of
cases.
Breslow et al., 1954 (38) U.S.A. M-F | 518 Lung cancer patients in 11 Califor- | 518 Patients admitted to same hospitals | Cases and controls questioned by trained
nia hospitals, 1949-52 about the same time, for conditions interviewers, each matched pair by the
other than cancer or chest disease, same person.
matched for race, sex, and age group.
Watson and Conte 1954 | U.S.A. M-F | 301 All patients of Thoracic Clinic at | 468 All patients of same clinic during | The 789 consecutive Patients of case and
(365). Memorial Hospita! who were diag- same period with diagnoses other than control groups were questioned by the
nosed lung cancer, 1950-52, lung cancer. same trained interviewer,
Gsell 1954 (138) Switzerland | M 135 Men with diagnosis of bronchial | 135 Similar hospital patients with diag- | Personal interviews, all by the same
carcinoma. noses other than jung cancer, and of Person.
the same age.
Randig 1954 (283) Germany M-F | 448 Lung cancer patients in a number | 512 Patients with other diagnoses, | Controls were interviewed at about the
of West Berlin hospitals, 1952-1954. matched for age. same time as the cases, each case-
control] pair by the same physician.
eon and Campbell 1955 | (Preliminary: see 1957 report below.)
337).
Wynder et al., 1956 (375) U.S.A. F 105 Patients with lung cancer in sev- | 1,304 Patients at Memorial Center with | Cases: Personal interview or question-
eral New York City hospitals, 1953- tumors of sites other than respiratory naire mailed to close relatives or friends
55. or upper alimentary, 1953-1955. Controls: Personal interview.
Segi et al., 1957 (316) Japan M-F | 207 Patients with lung cancer in 33 | 5,636 Patients free of cancer in 420 local | Cases and controls by personal interview
hospitals in all parts of the country, health centers, selected to approxi- using long questionnaire on occupa-
1953-55. mate the sex and age distributions of tional and medical history and living
cases. habits.
Mills and Porter 1957 (238) | U.S.A. M-F | 578 Residents of defined areas dying of | 3,310 Population sample approximately | Cases: From death certificates, hospital
respiratory cancer, 1947-55, proportional to cases as regards areas records, and close relatives or friends.
of residence, and 10 years or more in | Controls: Personal home visits or tele-
the area. phone calls, usually interviewing
housewife.
Stocks 1957 (335) England M-F | 2,356 Patients suffering from or dying | 9,362 Unselected patients of the same | Cases: Histories taken at the hospital or

 

 

 

with lung cancer within certain
areas.

 

area admitted for conditions other
than cancer.

 

from relatives by health visitors.
Controls: Personal interview in hospital.

 
PT

TaBLE 2.—Outline of methods used in retrospective studies of smoking in relation to lung cancer—Continued

 

Number of persons and method of selection

 

 

 

 

 

 

 

 

Investigator, year, and Country Sex of Collection of data
reference cases
Cases Controls
Schwartz and Denoix 1957 | France M 602 Patients with bronchopulmonary | 1,204; 3 groups: patients in same hospi- | Persona] interviews in the hospital; cases
(313). cancer in hospitals in Paris and a tals with other cancer, with non- and controls at about the same time by
few other cities. cancer illness, and accident cases, the same interviewer.
matched by age group.
Haenszel et al., 1958 (150) U.S.A. F 158 Lung cancer patients available for | 339 Patients in same hospital and service | Personal interviews by resident, medical
interview in 2@ hospitals, 1955-57. at same time, next older and next social worker, or clinic secretary.
younger than each case.
Lombard and Snegireff | U.S.A. M 500 Men dying of lung cancer, micro- | 4,238 Controls in 7 groups including | Personal interviews by trained workers.
1959 (222). scopically confirmed, 1952-53. volunteers, hospital and clinic pa-
tients, random population sample,
and house-to-house survey samples.
Pernu 1960 (277) Finland M-F | 1,606 Respiratory cancer patients in 4 | 1,773 Cancer-free persons recruited by | Cases: From case histories or mailed
hospitals and from cancer registry Parish Sisters of 2 institutes in all questionnaires.
between 1944 and 1958. parts of the country. Controls: Questionnaires distributed by
Parish Sisters.
Haensze) et al., 1962 (147) U.LB.A. M 2,191 Sample of 10 percent of white | 31,516 Random sample from Current | Cases: By mail from certifying physi-
male lung cancer deaths in the U.S. Population Survey used to estimate clans and family informants.
in 1958. population base. Population: Personal interview by
ensus enumerators.
Lancaster 1962 (199) Australia M 238 Hospital patients with lung cancer | 476 Two groups, one with other cancer, | Personal interviews of both cases and
one with some other disease, matched controls in hospitals.
by sex and age.
Haenszel and Taeuber ; U.S.A. F 749 Sample of 10 percent of white | 34,339 Random sample from Current | Cases: By mail from certifying physi-
1963 1 (152). female lung cancer deaths in the opulation Survey used to estimate cians and family informants.

 

 

 

U.S. in 1958 and 1959.

 

population base.

 

Population: Personal interview by
ensus enumerators.

 

1 To be published.
Germane to this concordance is a recent study (386) of Seventh Day
Adventists, a religious group in which smoking and alcohol consumption
are uncommon. On the basis of expectancy of male lung cancer incidence
derived from the control population, only 10 percent of the cases expected
were actually found among Seventh Day Adventists.

FORM OF TOBACCO USE

In considering the details of the individual retrospective studies listed in
Tables 2 and 3, 13 of the studies, combining all forms of tobacco consump-
tion, found a significant association between smoking of any type and lung
cancer (138, 199, 211, 250, 277, 280, 283, 309, 316, 363, 365, 379, 381) ; 16
studies yielded an even stronger association with cigarettes alone as com-
pared to pipe and/or cigar smoking (38, 82, 147, 192, 207, 222, 236, 237.
238, 277, 283, 301, 311, 314, 335, 379) when these forms of smoking were
considered separately and in combinations for males. The females, in the
studies investigating the relationship of smoking and lung cancer among
them, were almost invariably cigarette smokers so that comparisons with
other forms of tobacco use were not indicated.

AMOUNT SMOKED

Twenty-six of the studies quantitated the amount of smoking per day
either by combining weights of tobacco consumed in any form, or, more
often, by quantities of the specific forms of tobacco. In each of the studies
investigating male lung cancer, the degree of association increased as the
amount of smoking increased (38, 82, 138, 147, 150, 192, 199, 211, 222,
236, 250, 277, 280, 283, 301, 309, 311, 314, 316, 335, 363, 365, 379, 381).
One retrospective study (82) by Doll and Hill found a sharper difference in
amount smoked between cases and controls among recent smokers (10 years
Preceding onset of the disease) than in a comparison of the maximum
‘mount ever smoked. The authors cautioned against accepting this finding
as being against their hypothesis of a gradient of risk (which would more
Properly be tested by the whole life history of “exposure to risk”) by citing
the inaccuracies resulting from “requiring the patient to remember habits
of many years past.”

Of the 11 retrospective studies with data on females and tobacco use by
amount smoked daily, six (211, 236, 277, 283, 365, 381) showed trends of
increasing association with amount smoked daily, but had too few cases for
teliability of the trend. However, five studies (82, 150, 152, 335, 375) did

ave large numbers of female lung cancer cases for analysis by smoking
class; three of these (150, 152, 375) were directed towards female cases
only. In each of these latter five studies, the degree of association increased
with the amount of cigarettes smoked daily.

Four of the retrospective studies dealt with ex-smokers as well (147, 152,
21, 314) ; in one of these (314), where relative risks were derived indirectly
by the Comfield method (61), and in another by conventional use of stand-
ardized mortality ratios (147), male ex-smokers showed a lower risk than

155
9ST

TABLE 3.—Group characteristics in retrospective studies on lung cancer and tobacco use

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Males Females
Refer- Cases Controls Cases Controls
Authors ence | Year Remarks
Num-| Percent | Percent |Num-| Percent | Percent |Num-| Percent | Percent [Num-| Percent! Percent
ber non- heavy ber non- heavy ber non- heavy ber non- heavy
smokers | smokers ! smokers | smokers ! smokers | smokers ! smokers | smokers !
Miiller_-__...2.---2 222. (250)| 19389 | 86 3.5 65.1 86 16.3 36.0) (*) (*) (*) (*) (*) (9
Schairer & Schoeniger...| (309)| 1943 93 3.2. 31.2] 270 15.9. 9.3 is} *) (*) se (*) (*) 16 female cases not analyzed.
Potter & Tully. - 43 7.0 30. 2 /1, 847 26.0 23.0 *) *) (*) » (sy (")
Wassink_.._.-2.-2--.... 134 4.8 54.8 | 100 19.2 19.2] (*) *) “ @) *) (*) Percentages estimated from
chart.
Schrek et al_...-2-2.. 22. 82 14.6 18. 522 23.9 92] (*) (*) (*) (*) (*) (*)
Mills & Porter. 444 7.2 °*) 430 30.5 (s*) (*) (*) (*) (*) (*) (*)
Levin et al__--..--- 2222. 236 16.3 (**) 481 21.7 cw) (*) “ (*) “ *) “% Quantity smoked not con-
a sidered.
Wynder & Graham. ___. (381)} 1950 | 605 13 61.2 | 780 14.6 19.1 40 57.5 25.0 | 552 79.6 12
McConnell et al._....__. (236)| 1962 93 5.4 38.5 | 186 6.5 23,2 7 87.1 (**) 14 78.6 c*)
Doll & Hill... 22___ ee (82){ 1952 |1, 357 0.5 25.1 |1. 387 4.5 13.4] 108 37.0 11.1] 108 54.6 0.9 Percentage “heavy” smokers
understated.
Sadowsky et al.__.._.__. (301)| 19538 | 477 38 (**) 615 13.2 (**) 60] a“) (*) *) ) *) beets ad with amount
smoked.
Wynder & Cornfield..-.| (379)} 1953 | 63 4.1 67.6 | 1338 20.6 29.3) (*) (*) (*) $3 (3) (*)
Koulumies.....-.__--._.-} (192)| 1953 | 812 0.6 38.9 | 300 18.0 25.0; (*) | (e*) co") *) (*) (*)
Lickint._--..2.--22222.. (211)| 1953 224 1.8 35.8 {1. 000 16.0 4.8 22 64. 4.5 11, 002 90. 4 0.1
Breslow et al.._-__.____- (38)| 1954] 518 3.7 74.1] 518 10.8 4277 CO) |) ce) (**) (**) (**) Data pelude 493 males, 25
females.
Watson & Conte..._.._. (365)| 1954 | 265 1.9 71.7 | 287 9.7 51.6 36 58.3 2.8 181 82.0 11
Gesell. --- eee ee (138)) 1954 | 135 0.7 68.1 | 135 16.0 14.0] (*) (*) (*) (*) (*) *)
Randig....---_.--..-.... 283)| 1954 | 415 L2 34, 381 6.8 17.9 33 51.5 3.07; 131 70.3 0
Stocks & Campbell 337)| 1955 | (See reference (335) below)
Wynder et al -| (75)| 1956 | (*) (*) (*) ) (*) (*) 105 56. 2 16. 2 /1, 304 66.0 3.4
Begi et al... 8. le (316); 1957 | 166] (**) (*) j2,124]  *) (**) ms) f(t) (**) yy cr) (**) Quantities smoked stated as
averages only. Differences
are statistically significant.
Mills & Porter.......__. (238); 1987 | 484 8.4 26. 0 1, 588 27.6 5.3 04 83.0 4.3 |1, 722 73.3 0.5 Percent “heavy’’ smokers
understated. Only 50%
survey response among
fernale cases.
Stocks_....._---..-..... 1957 |2, 101 1.9 28. 2 |5, 960 8.7 22.3} 255 57.6 17.2 |8, 402 68. 6 10.7
Schwartz & Denoix. 1987 1 58.2 |1, 204 05 36.2 | (°) “ * (*) (@) *
Haenszel et al_.....-.._. 1958 | (*) (*) (*) (*) (*) (*) 158 51.9 14.6! 339 69. 6 8.2

 

 

 

 

 

 
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157
current smokers but greater than non-smokers. In a third study (152) of
lung cancer in women, the ex-smoker risk was lower than the current-smoker
risk but approximately equal to that for the non-smoker.

DURATION OF SMOKING

Duration of smoking was considered in 12 of the retrospective studies
(82, 150, 207, 222, 236, 283, 301, 311, 316, 335, 375, 381). In only six of
them, however, were the data treated in such a way as to permit evaluation
of the relationship between duration of smoking and lung cancer—two
studies in males (207, 301); two in males and females (82, 236); and two
in females only (150, 375). Among the studies of male lung cancer, Levin
(207), correcting his data for age, found a relationship between the number
of years of cigarette smoking and lung cancer. McConnell (236) found a
significant difference in duration of smoking between cases and controls,
but was reluctant to draw any definite conclusions. On the other hand,
Doll and Hill (82), in their age- and sex-matched study, showed a distinct
and statistically significant association between the duration of smoking
among males. In a well-conceived analytic study, Sadowsky et al. (301),
recognizing that duration of smoking is a function of age, controlled the
age variable, and found an increasing prevalence rate of lung cancer with
an increase in duration of smoking among all age groups (age at diagnosis) .

Among the studies including data on female lung cancer, McConnell had
too few female cases to resolve the question of duration of smoking (236)
and Doll and Hill, though finding differences between cases and controls,
could not establish statistical significance (82). In the two investigations
in which only female lung cancer cases were studied (150, 375), neither
showed an independent association between duration of smoking and lung
cancer. Haenszel states, however, that “among women, the association of
starting age and duration of tobacco use with current rate is so strong that
it may be unrealistic to expect to find a separate duration effect in retro-
spective studies of limited size” (150).

AGE STARTED SMOKING

Closely related to duration of smoking and thus pertinent to the length
of time that subjects have been exposed to tobacco smoke is the variable
of age when smoking was started. Relatively few of the retrospective studies
have dealt with this variable. Koulumies (192) found that males with lung
cancer had started smoking significantly earlier in life. In fact, 143 of his
845 cases or 17 percent began to smoke below 10 years of age as compared
to 6.5 percent among his matched controls. The study of male cases and
controls by Breslow et al. (38) found a definite trend in the same direction.
Pernu (277) found a statistically significant difference in age at start of
smoking, with a higher proportion of the male lung cancer group starting
at under 15 years of age. Lancaster (199) indicated that the male lung
cancer patients began to smoke at a significantly younger age. One other
study (283) showed no difference.

Of the three investigations of female lung cancer which explored this
variable, there were too few smokers in one study for a test of significance
(277), and in the remaining two (150, 283), no differences were found.

158
INHALATION

If the association between smoking, particularly cigarette smoking, and
lung cancer is a causal relationship, then inhalation should provide more
exposure than non-inhalation and should thus contribute significantly to the
lung cancer load. Four retrospective investigations were addressed to this
question. In the earlier Doll and Hill study (82), no difference in the
proportion of smokers inhaling was found among male and female cases and
controls. However, four subsequent studies of men (38, 211, 222, 313)
found inhalation of cigarettes significantly associated with lung cancer.
Although in Breslow’s study (38) of age-, sex- and race-matched case and
control patients, the variable “quantity-smoked” was not held constant in
the comparison when type of smoking though not quantity was controlled,
an association was found between inhalation and lung cancer. In the study
by Schwartz and Denoix (313) who held constant both type of smoking and
amount of cigarettes smoked, the relationship of inhalation was significant
for those smoking cigarettes alone but not for the smokers of both cigarettes
and pipes. Furthermore, although inhalers among lung cancer patients
averaged a significantly higher number of cigarettes per day than did the
controls, the relative risk differences between inhalers and non-inhalers,
calculated by the Cornfield method (61), become smaller and almost equal
each other at the highest cigarette consumption levels. Lombard and
Snegireff (222) demonstrated similar relative risk ratios.

HISTOLOGIC TYPE

The earliest retrospective study which considered histologic type of lung
cancer was by Wynder and Graham (381) in 1950. These authors presented
data on smoking habits of male and female adenocarcinomatous patients and
for female patients with epidermoid cancers which were but 25 in number.
With this partial analysis only a hint of a higher proportion of smokers
among female epidermoid cases could be derived. Of the 1,465 lung cancers
in the Doll and Hill retrospective study (82), 995 were histologically con-
firmed (916 males and 79 females). Of the confirmed cases, 85 percent of the
males and 71 percent of the females were of the epidermoid or anaplastic types.
Although no statistically significant difference in smoking habits was elicited
for the several types, a relatively higher proportion of non-smokers and light
smokers were found among patients of both sexes with adenocarcinoma.

Following the presentation by Kreyberg of a Typing Classification of the
epidermoid and oat cell or anaplastic types as Group I and the adenocar-
cinoma and bronchiolar or alveolar cell types as Group II, and the suggestion
of a relationship between Group I and smoking (196), several ensuing
Tetrospective studies dealt with this question.

Breslow’s study revealed a higher percentage of non-smokers among the
patients with adenocarcinoma than among those with epidermoid types (38).
In rapid succession six additional retrospective studies analyzed the rela-
tionship between histologic type of lung cancer and smoking. The 1956
study of female lung cancers by Wynder et al. (375) indicated that adeno-
carcinomata apparently had little or no relationship to smoking but that a
relationship did exist between smoking and the epidermoid and anaplastic
types. Schwartz et al. (313), similarly, in 1957, found a highly significant

714-422 O-64—12 159
association between smoking of cigarettes, amount of smoking as well as
inhaling, and the epidermoid and anaplastic types of tumors. No such
association with “type cylindrique” was noted. In that same year Doll and
Hill furnished Kreyberg with lung cancer slides from 933 British patients,
Kreyberg, without knowledge of the patients’ smoking history or clinical
data, separated these into two groups. A strong correlation was found
between smoking history and histologic type; smoking and amount were
highly associated with the epidermoid and anaplastic types, and non-smokers
were predominantly among the adenocarcinomatous types (86).

In this study of lung cancer in women, Haenszel, et al. (150) found statis.
tically significant relative risk gradients for amount of cigarette smoking
among Group I cancer patients. No increased risk was established for
Group II cancers. In his later study of a current mortality sample of white
males for 1958, Haenszel found relative risk gradients for the several smok-
ing classes for both adenocarcinomas and epidermoid cancers (147). A
parallel study of white females for the current mortality sample of 1958 and
1959 showed essentially the same findings, except possibly for a lower effect
on adenocarcinomas among smokers of less than one pack daily (152).

Haenszel points out that in both these studies a “true differential in risks”
for the two histologic types could well have been diluted seriously by report-
ing and classification errors which were definitely known to exist from re-
inquiry of a sub-sample of deaths (152). (For current evaluation, see
section on Typing of Lung Tumors, )

RELATIVE RISK RATIOS FROM RETROSPECTIVE STUDIES

Retrospective studies are usually designed to establish the probability
of association of an attribute A with disease X; or, given disease X, what is
the probability that A will be found in association (P [A/X])?  Pro-
cedurally, one compares a supposedly representative group of patients with
disease X, with another group as controls, in regard to the percentages of
individuals with and without the attribute A. This procedure may reveal
significant differences leading to judgments of association but it does not
yield an estimate of the magnitude of the relative risk of disease X among
those with attribute A and those without. A method which estimates this
relative risk, developed by Cornfield (61), has been referred to several
times earlier and can be applied to data derived from retrospective studies
if two assumptions, inherent in the first procedure of judging the association,
are made: (a) that patients with disease X interviewed or otherwise studied
are a representative sample of all cases with disease X, and (b) that the
controls without disease X or who have escaped disease X are a representative
sample of all persons without disease X. An estimate of the prevalence of
disease X in the population is a requisite.

Such an approach was utilized by a number of investigators in retro-
spective studies on lung cancer. Doll and Hill (82) made similar calcula-
tions and found a linear gradient of deaths from lung cancer for men and
women increasing with amount of tobacco smoked daily. Sadowsky et al.
(301) found similar increases in risk for amount smoked daily in virtually
all but the oldest age groups and calculated an age-standardized risk ratio
of 4.6:1 for all smokers compared to non-smokers. These authors also

160
utilized the data of Wynder and Graham (381) and Doll and Hill (82) for
calculating similar risk ratios, deriving ratios of 13.6:1 and 13.8:1, respec-
tively. Their calculations of estimated prevalences by quantity smoked daily
for age groupings similar to their own also showed linear increases of risk.

Breslow et al. (38) treated their retrospective data similarly and developed
relative risk ratios of 7.7:1 for males aged 50-59 years and 4.6:1 for those
aged 60-69. In considering heavy smokers (40 or more cigarettes per
day), they showed relative risk ratios of 17:1 and 25.5:1, respectively.
Randig (283) also demonstrated a linear progression of risk with increasing
amounts of daily tobacco consumption and an over-all ratio of 5.1:1 for all
smokers to non-smokers among males and 2.2:1 for females. Schwartz
and Denoix (313) reported similar findings in amount smoked daily and
a risk ratio of smokers to non-smokers of approximately 8:1. Lombard
and Snegireff (222) approached their data in a different way, utilizing “life-
time number of packs of cigarettes consumed” as a measure of exposure.
Their estimated prevalence rates also increase linearly with amount smoked.
The risk ratio which can be calculated from their tabulated data ranges
from 2.4:1 for light smokers to 34.1:1 for heaviest smokers.

Haenszel, in his two studies on male and female lung cancer mortality
as related to residence and smoking histories, calculated relative risk ratios
of 4.1:1 for one pack or less daily and 16.6:1 for more than one pack a day
among males (147), and 2.5:1 and 10.8:1, respectively, among females
(152). Table 4 summarizes the relative risk findings of the nine studies.

TaBLE 4.—Relative risks of lung cancer for smokers from retrospective

 

 

 

 

 

 

 

 

 

 

studies
Author and Reference Year Sex Relative risk—Smokers:
non-smokers
Sadowsky et al. (301) 1953 M 4.6
Doll and Hill (82) 1952 M 83.8
Wynder and Graham (381) 1950! M 13.6
7.7 age 50-59
Breslow et al. (38) 1954 M 4.6 “ 60--f9
ar 8 “ a very heavy smokers
Randig (283) 1054 M-F]} 51M
22 F
Schwartz and Denoix (313) 1957 M 8.0
Lombard and Snegireff (222) 1959 M 2.4 light smokers
34.1 heavy smokers
Haenszel (147) 1962 M 4.1<1 pack/day
: 16.6>1 pack/day
Haenszel (152) Unpublished | F 2.5<1 pack/day
10. 8>1 pack/day

 

 

 

 

‘ Calculated by Sadowsky et al. (301) from other authors’ data.

Prospective Studies

It has been pointed out that in retrospective studies the usual approach is
to determine the frequency of an attribute among cases and controls. This
measure does not provide estimates of the risks of developing the disease

161
among individuals with and without the attribute unless one makes assump-
tions referred to above. The validity of such assumptions may at times be
suspect, for the cases may not be representative of the total population with
the disease nor the controls representative of the population without the
disease. Thus, some retrospective studies may not truly assess the existent
risks with reasonable accuracy. However, when ail the cases of a disease in
an area and a representative sample of the population without the disease are
included in a study, the estimates of risk bear high validity.

Despite the criticisms leveled at the retrospective method in general and
its obvious defects as practiced by some investigators, a number of the retro.
spective studies on lung cancer have indeed overcome most of the criticisms
of major import leveled at the method. These criticisms and their implica.
tions will be treated specifically below in the section on an Evaluation of the
Association Between Smoking and Lung Cancer. Suffice it to ‘say at this
point that certain shortcomings of the retrospective survey approach, some
real and some exaggerated, led several courageous investigators to under.
take the necessarily protracted, expensive, and difficult prospective approach.

The first prospective study encompassing total and cause-specific mortality
in a human population was initiated in October 195] among British physi-
cians by Doll and Hill (83, 84). There then followed in rather rapid suc.
cession, five additional independent studies in the United States and Canada
(25, 87, 88, 96, 97, 157, 162, 163), all but one of which continue to be active,
The earlier study, by Hammond and Horn, among 187,783 white males aged
50-69 years, initiated between January and May 1952, was terminated after
44 months of follow-up (162, 163). This has been succeeded by the current
Hammond study which broadened its age-base (35-89 years) and contains
1,085,000 persons (in 25 states) of whom 447,831 are males (157).

These studies have been described in detail, analyzed, and evaluated in
Chapter 8 of this Report where a discussion of differences in total mortality
between smokers and non-smokers has been presented, and are summarized
in Table 1 of that chapter. All the prospective studies thus far have shown
a remarkable consistency in the significantly elevated mortality ratios of
smokers particularly among the “cigarettes only” smoking class. Of special
interest is the fact that in a number of the studies the magnitude of the as.
sociation between cigarette smoking and total death rates has increased as
the studies have progressed. This has particularly been true for lung can-
cer. The presently calculated total mortality ratios have been presented in
Table 2 of Chapter 8 of this Report.

With reference to the smoking and lung cancer relationship, each of the
seven prospective studies has thus far revealed an impressively high lung
cancer mortality ratio for smokers to non-smokers. Examination of Table
5, which presents in summary form the lung cancer mortality ratios for the
seven studies by smoking type and amount, derived both from the published
reports of these studies and current information from the investigators
wherever available, reveals a range of ratios from 6.0 to 25.2 with a median
value of 10.7 for all smokers irrespective of type or amount. For smokers
currently using cigarettes only at the time of enrollment in the studies, the
ratios range from 4.9 to 20.2 with a mean value of 10.4 as derived from
a summation of observed and expected values of most recent data.

162
Several of the studies have fortunately provided data for a measure of
the “dose of exposure” relationship (84, 88, 96, 157, 163). It can readily
he seen from Table 5 that the mortality ratios increase progressively with
amount of smoking. The pivot level appears to be 20 cigarettes per day.
Cigar and/or pipe smokers (to the exclusion of cigarettes) manifest ratios
lower than any of the cigarette smoking classes, including combinations of
cigarettes with pipes and/or cigars (25, 84, 88, 157, 163). One study pro-
vided data on occasional smokers (163). These have a ratio very close to
that of non-smokers. Ex-smokers of cigarettes (83, 88, 163) fall into levels
of risk ratios below those for current smokers of cigarettes depending upon
the length of the interval since smoking was stopped. In the Doll and Hill
study (83), the ex-smoker ratio was less than the current smoker ratio
even when cessation had occurred less than 10 years before entry into the
study. This, however, was not true for the first Hammond and Horn study
(163). In this latter study, if smoking had ceased more than 10 years
before entry, the lung cancer mortality ratios were lower than for current
smokers at the corresponding daily consumption levels, but if cessation of
smoking had occurred less than 10 years before entry, the ratios were
virtually identical to those for current cigarette smokers at the corresponding
daily consumption levels. The Dorn material (87, 88), currently brought
up to date (89), provides a measure of relative risk by amounts of smoking
prior to stopping. The ratios thus elicited are again below those for cur-
rent cigarette smokers of corresponding daily amounts.

At this time it is difficult to assess the effect of other variables such as
duration of smoking and starting age on lung cancer mortality since cross-
classification by these variables, and amount smoked as well, leads to cells
with small numbers of deaths. Most prospective studies have thus far con-
fined themselves to analyzing the effect of these additional variables on
deaths from all causes, or in one case (157) from cardiovascular diseases.
The current Hammond study is concerned with inhalation practices, but
here also the total number of lung cancer deaths analyzed to date does not
permit extensive classification by age, type of smoking, amount smoked
daily, present smoking status, and age when smoking was begun. In the
studies of total mortality ratios, duration of smoking, obviously immediately
dependent upon the age of the individual, was in turn dependent upon age
when smoking (cigarettes) was begun. Age when smoking began was also
a determinant, not only of the number of cigarettes smoked daily, but of the
degree of inhalation, with smokers starting at earlier ages very distinctly
lending to smoke more and inhale more deeply than those starting to smoke
at older ages (157). According to Hammond, men who smoke more per
day also tended to inhale more deeply than those who smoke fewer ciga-
rettes per day. When inhalation and quantity smoked were held constant,
the total mortality ratios also increased as age at start of smoking decreased.

The stability of the lung cancer mortality ratios referred to in Table 5 is
to a great extent dependent upon the number of observed lung cancer deaths
among non-smokers from which the expected values for the several smoker
classes are calculated. Referring again to Table 5, in at least two of the
studies (83, 96), calculation of the expected deaths among smoker classes
ad to be based on extremely small numbers of non-smokers. However,

163
POT

TaBLe 5.—Mortality ratios for lung cancer by smoking status, type of smoking, and amount smoked, from seven prospective

 

 

 

 

 

 

 

  
 
  
  
 
  

 

 

studies
Dunn, Dunn, Best,
Study Doli and Hammond Dorn Linden and | Buell and Josie and Hammond
All and Hom Breslow— Breslow— Walker
Occupational Legion
Lung cancer deaths in Study ___..--.---.-_- 2.2222. ee eee eee eee 120 448 635 189 98 221 414
Lung cancer deaths Non-smokers_.__.__--_.---------------------2eeee ee 3 125 156 13 $12 18 $16
(Reference number) (83) (163) (88) (96) (97) (25) (157)
MORTALITY RATIOS:
AH Smokers......-.--.----------2---- +222 eee eee eee 12,8 10.7 6.0 - - *25.2 $8.1
1-14 gm. tobacco _. 6.7 - ~ - - - -
15-24 gm. tobacco. 12.3 - - - - - -
25 gm. tobaceo.__.-------.-.--- 2 e ee eee eee 23.7 - - - - - -
Current: **
Cigarettes only_---.-----.------------------+--- 2-2 --2- ee ee eee eee 20.2 10.0 $12.0 115.9 14.9 f1l.7 $9.6
<10 4.4 {5.8 13 f 5)- 8.3 - 8.4 -
10.8 $7.3 9.4 10)- 9.0 - 13. -
} 43.7 T15.9 $18.1 a eed - 15.1 -
. 421.7 423.3 30)-25 1 7 } #15. -
(40)-28.7
Sl pack f.--.--..---------------- eee eee 81 6.9 8.1 13.6 42 11.8 -
>1 pack t-..--- 43.8 16.9 18.0 1 74 15.1
Pipes only 5.4 2.6 1.3 - ~
Cigars only-..- 14.6 1.07 tL.3 1.5 1.6 - - tll 1.5
Pipes and cigar: ~ - - -
Cigarettes, pipes and cig: 9.7 10.7 6.2 - - 724. 4 ~
Occasional ....-.-.-.- 2.2022 ee nen eee eee ee nee eee - 13 - - - - -
Ex-Smokers:
>10 yrs. since stopped 5.0 - - - - - ~
<20 cigarettes. . - - 2.4 - - - - ~
>20 cigarettes. -- -|o7 17.8 - - ~ - -
<10 yrs. since stopped -| 8&4 - - - - - -
<20 cigarettes. ._ -| o- 10.4 - - - - ~
> 20 cigarettes_._._._.--.----- 2-2 eee 7 - 22. 8 - - - = -
<20 cigarettes (irrespective of when stopped)... -| 7 - 1.3 - - ~ -
>20 cigarettes (irrespective of when stopped)___._..-.....--...--- - ~ 71.6 - - ~ -

 

 

 

 

 

 

 

 

*Current and ex-smokers combined.

tMost recent information.

-Data not available or not available for designated classes,

**T-wo California studies and current Hammond study include all cigarette smokers (cigarettes and other and current and ex-cigarette smokers).
the other studies have now yielded significantly greater numbers of non-
smoker lung cancer deaths and in at least three of them (88, 157, 163) these
are now appreciable.

Experimental Pulmonary Carcinogenesis

ATTEMPTS TO INDUCE LUNG CANCER WITH TOBACCO AND
TOBACCO SMOKE

Few attempts have been made to produce bronchogenic carcinoma in
experimental animals with tobacco extracts, smoke, or smoke condensates.
With one possible exception (289), none has been successful (331).

Mice rarely develop spontaneous bronchogenic. oral, esophageal. gastric,
prostatic, laryngeal, or vesical carcinomas, but certain inbred strains have
a high incidence of spontaneous pulmonary adenomas (6). The adminis-
tration, by any route, of carcinogenic polycyclic hydrocarbons, including
some found in tobacco tar, increases the incidence and decreases the time
of occurrence of pulmonary adenomas. These tumors are usually regarded
as benign, and probably arise from the alveolar epithelium (4, 5, 6, 131, 330)
rather than the bronchial wall. They have no resemblance to most human
bronchogenic carcinomas.

Essenberg (106) and Miihlbock (248) exposed mice to cigarette smoke,
but their reported results are equivocal. Lorenz et al. (224) and Leuchten-
berger et al. (206) did not observe an increase in pulmonary adenomas in
mice that inhaled cigarette smoke.

Leuchtenberger et al. (205a.) described a sequence of microscopic changes
in lungs of mice exposed to cigarette smoke resembling somewhat those
found by Auerbach et al. in the lungs of human smokers. No dose-response
effect was reported. The morphologic findings consisted of bronchitis with
proliferation of the epithelium. Some areas of hyperplasia showed atypical
changes. However, the changes were reversible when exposure to smoke
was stopped. The production of bronchogenic carcinomas has not been
reported by any investigator exposing experimental animals to tobacco
smoke.

Most experiments in which tobacco tars were brought into direct contact
with the lung and tracheobronchial tree of experimental animals have
yielded negative results (273, 274, 275). Blacklock (29) found one car-
cinoma when tar from cigarette filters was placed in olive oil together
with killed tubercle bacilli and injected into the hilum of a small number
of rats. Rockey et al. (289) painted tobacco tar three to five times each
week on the trachea of dogs with a tracheocutaneous fistula. Hyperplastic
changes with squamous metaplasia of the bronchial epithelium were seen
in seven dogs that survived 178 to 320 days. Carcinoma-in-situ was reported
to occur in three, and invasive carcinoma in one out of 137 dogs, but this
work has not yet been confirmed.

Summary.—Bronchogenic carcinoma has not been produced by the
application of tobacco extracts, smoke, or condensates to the lung or the

tracheobronchial tree of experimental animals with the possible exception
of dogs.

165
SUSCEPTIBILITY OF LUNG OF LABORATORY ANIMALS TO
CARCINOGENS

PotycycLtic AROMATIC HypRocaRBoNs.—Epidermoid carcinoma has
been induced in mice by Andervont by the transfixion of the lungs or bronchi
with a thread coated with a carcinogen (5) and by Kotin and Wiseley (191)
by treatment with an aerosol of ozonized gasoline plus mouse-adapted
influenza viruses.

Kuschner et al. (197, 197a) induced epidermoid carcinomas in the lungs
of rats by the local application of polycyclic aromatic hydrocarbons, either
by thread transfixation or pellet implantation. Distant metastases occurred
from some of the carcinomas. The changes in the bronchial tree at different
times prior to the appearance of cancer included hyperplasia, metaplasia
and anaplasia of the surface epithelium as well as of the subjacent glands,
These changes resembled those described by Auerbach in the tracheo-
bronchial tree of human smokers (9).

Stanton and Blackwell (324) induced epidermoid carcinoma in the lungs
of rats that had received 3-methylcholanthrene intravenously. The car-
cinogen was deposited in areas of pulmonary infarction.

Saffiotti et al. (302) produced squamous cell bronchogenic carcinomas in
hamsters by weekly intubation and insufflation of benzo(a)pyrene (4 per-
cent) ground with iron oxide (96 percent) resulting in a dust with particles
smaller than 1.0 micron. A proliferative response followed by metaplasia pre-
ceded the appearance of the carcinomas, but was not an invariable antecedent.

VirusEs.—Bronchogenic carcinoma has been induced in animals inocu-
lated with polyoma virus by Rabson et al. (282). Carcinogens enhance the
effect of viruses known to cause cancer in animals (99) and localize the
neoplastic lesions at the site of inoculation of the virus (98). However,
no evidence has been forthcoming to date implicating a virus in the etiology
of cancer in man.

PossipLe INDUSTRIAL CaRCINOGENS.—Vorwald reported that exposure of
rats to beryllium sulfate aerosol resulted in carcinomas of the lung; 12 per-
cent were epidermoid but most were adenocarcinomas. The tumors usually
arose from the alveolar or bronchiolar epithelium. He also produced broncho-
genic carcinomas in two out of ten rhesus monkeys injected with beryllium
oxide and in three out of ten exposed to beryllium oxide by inhalation (357).

Lisco and Finkel in 1949 (217) reported the production of epidermoid
cancer of the lung in rats with radioactive cerium. Subsequently many
other investigators have succeeded in producing carcinomas of the lung,
predominantly of the epidermoid type, in a high percentage of rats and
mice with other radioactive substances. The various modes of exposure
included inhalation, intratracheal injection, or insufflation and implantation
of wire or cylinder. These experiments were reviewed by Gates and Warren
in 1961 (125).

Hueper exposed rats and guinea pigs to nickel dust and found metaplastic
and anaplastic changes in the bronchi (180). Following up earlier work
in which squamous metaplasia of the bronchial epithelium was found in rats
exposed to nickel carbonyl (341), Sunderman and Sunderman (342) in-
duced bronchogenic carcinoma in rats by exposure to this compound. This

166
-group also found 1.59 to 3.07 yg. of nickel per cigarette in the ash and in

the smoke in several different brands. About three-fourths was contained
in the ash. Although Hueper and Payne (182, 183) and Payne (270) have
demonstrated that pure chromium compounds will produce both sarcomas
and carcinomas in several tissues in rats and mice, bronchogenic carcinomas
have not been produced by inhalation of chromium compounds in experi-
mental animals. Experiments designed to test the carcinogenicity of ar-
senical compounds have been either negative or inconclusive.

Asbestosis can be produced without difficulty in experimental animals by
inhalation of asbestos fibers (359), but efforts to produce bronchogenic
carcinoma have been unsuccessful (129, 181, 227, 358).

SUMMARY.—The lungs of mice, rats, hamsters, and primates have been
found to be susceptible to the induction of bronchogenic carcinoma by the
administration of polycyclic aromatic hydrocarbons, certain metals, radio-
active substances, and oncogenic viruses. The histopathologic characteristics
of the tumors produced are similar to those observed in man and are fre-
quently of the squamous variety.

ROLE OF GENETIC FACTORS IN PULMONARY ADENOMAS IN MICE

Genetic factors exert a determining influence on the spontaneous develop-
ment and induction of lung tumors in mice. Early studies of Murphy and
Sturm (251) and of Lynch (225, 226) demonstrated the development of
pulmonary tumors in mice after the skin was painted with coal tar, and
Lynch (225) indicated the existence of genetic factors in the developnrent
of these tumors. Later investigations of Heston (169, 170) on the effect
of intravenous injection of dibenzanthracene and thé studies of several other
investigators (3, 4, 27, 47, 320) utilizing different techniques gave addi-
tional evidence of the operation of genetic factors in induced tumors. Link-
age between multiple genes for susceptibility to spontaneous and induced
tumors in mice and specific chromosomes has also been established (47,
168) and transplantation experiments (171, 173) indicate that the genetic
susceptibility resides within the pulmonary parenchyma. A number of in-
vestigators (36, 47, 124, 131) demonstrated conclusively that these tumors
usually arise distal to the bronchus and are probably alveogenic. Metastases
tarely occur. The relative importance of genes for susceptibility to these
tumors of the lung is indicated by an incidence ranging from a few tumors
to over 90 percent, depending on the inbred strain examined.

Spontaneous tumors of the lungs are rare in species of laboratory animals
other than mice, and the genetics of these neoplasms in other species has
been investigated only superficially.

SuMMary.—Genetic susceptibility plays a significant role in the develop-
ment of pulmonary adenomas in mice.

Pathology—Mor phology

RELATIONSHIP OF SMOKING TO HISTOPATHOLOGICAL CHANGES
IN THE TRACHEOBRONCHIAL TREE .

In an extensive and controlled blind study of the tracheobronchial tree
of 402 male patients, Auerbach et al. (11, 13, 15) observed that several

167
kinds of changes of the epithelium were much more common in the trachea
and bronchi of cigarette smokers and subjects with lung cancer than of
non-smokers and of patients without lung cancer (Table 6). The epithelial
changes observed were (a) loss of cilia, (b) basal cell hyperplasia (more
than two layers of basal cells), and (c) presence of atypical cells. The
atypical cells had hyperchromatic nuclei which varied in size and shape.
The arrangement of such cells was frequently disorderly (see illustrations
below). Hyperplastic changes were also seen in the bronchial glands.

TaBLE 6.—Percent of slides with selected lesions, by smoking status and
presence of lung cancer

 

Percent of slides with cilia absent and

averaging 4 or more cell rows in depth

Group Number | Number
cases slides

 

No cells |Somecells} All cells | Totai
atypical | atypical | atypical 2

 

Cases without lung cancer

  
   
 
 

Never smoked regularly__--__.-.----- 65 0.03 |..-.22 2. Ll
Ex-cigarette smokers. _.._ - 72 0.4 0.2 4.1
Cigarettes—1¢ pk. a day-- - 36 4.2 0.3 4.7
Cigarettes—16-1 pk. a day. - 59 7.1 0.8 7.9
Cigarettes—1-2 pks. a day. - a 143 12.6 4.3 16.9
Cigarettes—2+ pks. a day a 36 26. 2 11.4 37.5
Lung cancer cases ?__..-__. 2222-2 63 12.5 14.3 8

 

 

 

 

 

 

! In some sections, two or more lesions were found. In such instances, all of the lesions were counted and
are included in both individual columns and in the total column of the table. Lesions found at the edge of
an ulcer were excluded.

2 These lesions may be called carcinoma-in-situ.

3 Of the 63 who died of lung cancer, 55 regularly smoked cigarettes up to the time of diagnosis, 5 regularly
smoked cigarettes but stopped before diagnosis, 1 smoked cigars, 1 smoked pipe and cigars, 1 was an occa-
sional cigar smoker.

Each of the three kinds of epithelial changes was found to increase with
the number of cigarettes smoked (Table 6). In smokers who had no cancers,
frequency and intensity of these changes correlated with the number of

EXAMPLES OF NORMAL AND ABNORMAL BRONCHIAL EPITHELIUM

 

1. Normal

168
 

2. Basal-cell hyperplasia—replacement of ciliary epithelium with a thick layer of cells
resembling stratified squamous epithelium.

 

3. Extensive basal-cell hyperplasia with numerous atypical cells.

Source: Auerbach, Oscar. Special communication to the Surgeon General’s Advisory
Committee on Smoking and Health.

cigarettes smoked. Among non-smokers, lesions composed entirely of atypi-
cal cells with loss of cilia were uniformly absent, although a few could be
seen with more than two rows of basal cells containing some atypical cells.
In contrast, atypical cells were found in all lesions seen in the tracheobron-
chial tree of patients who smoked two or more packs of cigarettes a day,
irrespective of the presence of hyperplasia and/or cilia loss or whether the
Patients died of lung cancer. The most severe lesion, aside from invasive
carcinoma, consisted of loss of cilia, and hyperplasia up to five or more cell
Tows composed entirely of atypical cells. This lesion was never found
among men who did not smoke regularly and was found only rarely among
light smokers. However, it was found in 4.3 percent of sections from men

169
who smoked one to two packs a day, in 11.4 percent of sections from those
who smoked two or more packs a day, and in 14.3 percent of sections from
smokers who died of lung cancer (15).

While epithelial changes were found in all portions of the tracheobronchial
tree, quantitative differences were found between the changes in the trachea
and those in the bronchi; hyperplastic lesions consisting entirely of atypical
cells without cilia were found in all regions of the bronchial mucosa but only
rarely in the trachea. It is notable that cancer rarely occurs in the trachea,

In 35 children less than 15 years of age, Auerbach et al. (16) found the
same percent of epithelial changes in the tracheobronchial tree as in the same
number of adults who had never smoked regularly (16.6 percent of children
and 16.8 percent of adults). No hyperplasia with atypical cells was seen
in any section.

Later, Auerbach et al. (15a.) studied the morphology of the tracheobron-
chial tree from 302 women and 456 men with respect to additional variables—
sex, age, pneumonia, and amount smoked. One or more epithelial lesions
were found in 68.2 percent of sections from men smokers and 68.6 percent
from women smokers when matched groups were examined. However, on
further study, hyperplastic lesions composed entirely of atypical cells were
found in 6.9 percent of the sections from the male group and in 2.5 percent
of those from females.

Matched groups of male cigarette smokers of two age groups (averages
of 37 and 67 years) were compared. Many more lesions, characterized by
a large number of cells with atypical nuclei, were observed in the older than
in the younger group. In a parallel study of women who did not smoke
(average ages of 46 and 76 years), no difference in the number or type of
lesions was noted. Few changes in the bronchial epithelium were found in
sections from 27 women non-smokers over 85 years of age.

Occasional atypical changes were found in women non-smokers (a) who
died of pneumonia, (b) who died of various other causes but had pneumonia
at the time of death, and (c) who died with no evidence of pneumonia.
However, basal cell hyperplasia, loss of cilia, and ulceration were found more
frequently in sections from women who died with pneumonia than from
women who had no evidence of pneumonia. These observations are in
agreement with those of other investigators who found metaplasia of the
bronchial epithelium to be more frequent in patients with various non-
neoplastic pulmonary diseases than in controls without such disease (256,
305, 352, 366).

Far fewer epithelial lesions were found in non-smokers than in pipe, cigar,
or cigarette smokers (15a.), the difference being particularly evident in the
occurrence of atypical cells. However, sections from pipe and cigar smokers
showed fewer epithelial lesions than did sections from cigarette smokers.
Cells with atypical nuclei were found far more frequently in cigarette smokers
than in cigar or pipe smokers (Table 7).

In 72 male ex-cigarette smokers who had smoked for at least ten years
and had not smoked for at least five years prior to the time of death, there
were less hyperplasia, less loss of cilia, and fewer atypical cells than in
sections from current cigarette smokers (14). An interesting by-product
of this study was the finding of “cells with disintegrating nuclei” in the

170
TL1

TasLe 7.—Changes in bronchial epithelium in matched triads 0 f male non-smokers and smokers of different types of tobacco!

 

 

 

 

 

 

 
 
   

   
 
 

 

Number; Total | Sections with 1 | 3+-cell rows with Atypical cells | Entirely atypical
Group of sub- | sections | or more epithelial cilia present Cilia absent Atypical cells | present with cilia | cells with’ cilia
jects | with epi- lesions present absent absent 2
thelium
Number) Percent |Number| Percent |Number| Percent |[Number| Percent Number! Percent Number] Percent
7th set (none vs. pipe vs. cigarette)?
Non-smokers 20 985 214 21.7 110 12 101 10.3 26 2.6 3 0.3
Pipe smokers 20 924 605 65. 5 352 38.1 117 12.7 342 37.0 20 3.1
Cigarette smoker__s. 20 914 885 96. 8 810 88.6 116 12.7 870 95. 2 lit 12.1
8th set (none vs. pipe vs. cigarette)
Non-smokers 25 1, H6 285 22.9 167 13.4 132 10.6 9 0.7 1 0.1 0 |--__eee. -
Pipe smokers___.__ 7 25 1, 164 800 68.7 451 38.7 172 14.8 445 38, 2 38 3.3 ee
Cigarette smokers. ___ 25 1, 126 1, 084 96.3 999 88.7 B38 21.1 1, 008 89.5 205 18.2 70 6.2
9th set (none vs. cigar vs. cigarette)
Non-smokers 35 1, 706 467 27.4 216 12,7 281 16.5 14 0.8 3 0.2 0 foe e eee.
Pipe smokers... ._.._- 35 1, 733 1, 573 90. 8 694 40.0 247 14.3 1, 275 73.6 173 10.0 5 0.3
Cigarette smokers 35 1, 526 1, 511 99.0 1,414 92.7 428 28.0 1, 493 97.8 417 27.3 196 12.8

 

 

 

 

 

 

 

 

 

! Modified table from Auerbach et al. (15a).
2 Carcinoma in situ.
| Triads were matched for age, occupation, residency and (for smokers) by amount of tobacco used.
bronchial epithelium of 43 out of 72 ex-smokers. These cells were not
found in the bronchial epithelium of current cigarette smokers or non.
smokers. They were considered by Auerbach et al. to be pathognomonic
of the ex-smoker.

Many of the histopathologic findings observed by Auerbach et al. in the
bronchial epithelium of smokers have been confirmed by other investigators
(64, 155, 189, 304).

The significance of the hyperplastic changes in the bronchial epithelium
for the pathogenesis of lung cancer in smokers is not fully understood. The
establishment of a link between the hyperplastic changes and the subsequent
development of lung cancer would relate smoking causally to lung cancer,
However, the non-specificity of hyperplasia of the bronchial epithelium js
universally recognized. Furthermore, similar changes are known to be
reversible.

On the other hand, evidence from both human and experimental observa.
Hons points strongly to the conclusion that some hyperplastic changes of
the bronchial epithelium, especially those with many atypical alterations,
are probably premalignant.

It is well documented that the bronchial trees of patients with lung cancer
have areas, sometimes very widespread, of epithelial hyperplasia containing
many atypical and bizarre cells. This was reported by Lindberg in 1935
(216) and by many other investigators (10, 12, 28, 52, 134, 265, 285, 349,
370). Black and Ackerman (28) have carried out an extensive study
of the relationship between metaplasia and anaplasia and lung cancer in
human lungs and have presented strong circumstantial evidence for the opin-
ion that the basal cell hyperplasia with advanced atypical changes and
loss of cilia (the so-called carcinoma in-situ) represent a stage in the devel-
opment of lung cancer. They also emphasized, as has Auerbach et al. (12),
the frequent occurrence of atypical basal cell hyperplasia at multiple sites
in the bronchial tree considerably removed from the site of the lung cancer.
They have pointed out the similarities between the atypical hyperplasias in
the tracheobronchial tree and carcinoma in-situ in other sites, such as the
cervix, skin, and larynx.

Lung cancer was induced in animals by radioactive substances (198, 217),
chemical carcinogens (198, 340), and air pollutants plus influenza virus
(191). These studies have demonstrated the occurrence of extensive atyp-
ical hyperplastic changes in the bronchial epithelium of experimental animals
preceding the appearance of lung cancer. The changes described are, on
the whole, similar to those seen by Auerbach et al. in the bronchial epithelium
of heavy cigarette smokers and by others in patients with lung cancer. The
hyperplastic lesions in animals do not invariably develop into cancer. This
appears to be the case also in man (14).

In view of these observations, it seems probable that some of the lesions
found in the tracheobronchial tree in cigarette smokers are capable of de-
veloping into lung cancer. Thus, these lesions may be a link in the patho-
genesis of lung cancer in smokers.

SUMMARY.—Several types of epithelial changes are much more common
in the trachea and bronchi of cigarette smokers, with or without lung cancer,
than of non-smokers and of patients without lung cancer. These epithelial

172
changes are (a) loss of cilia, (b) basal cell hyperplasia, and (c) appearance.
of atypical cells with irregular hyperchromatic nuclei. The degree of each
of the epithelial changes in general increases with the number of cigarettes
smoked. Extensive atypical changes have been seen most frequently in men
who smoked two or more packs of cigarettes a day. Hyperplasia without
atypical changes was seen in the bronchial tree of children under 15 years
of age and in women non-smokers at all ages who died with pneumonia.
Women cigarette smokers, in general, have the same epithelial changes as
do men smokers. However, at given levels of cigarette use, women appear
to show fewer atypical cells than do men. Older men smokers have many
more atypical cells than do younger men smokers. Men who smoke pipes
or cigars have more epithelial changes than do non-smokers, but have fewer
changes than do cigarette smokers consuming approximately the same amount
of tobacco. Male ex-cigarette smokers have less hyperplasia and fewer
atypical cells than do current cigarette smokers.

ConcLusion.—It may be concluded on the basis of human and experimental
evidence that some of the advanced epithelial hyperplastic lesions with many
atypical cells, seen in the bronchi of some cigarette smokers, are probably
premalignant.

TYPING OF LUNG TUMORS

Historical aspects of the typing of lung tumors in relation to possible
etiological agents are reviewed in the section on Retrospective Studies, His-
tologic Types.

Kreyberg (195, 196) noted that the increase of lung cancer in recent dec-
ades seemed to occur for only certain types of lung cancers (his Group I),
and that other types did not increase (his Group II). Kreyberg’s classifica-
tion is compared with the World Health Organization classification in
Table 8. His Group I includes epidermoid carcinomas and small-cell ana-
plastic carcinomas. His Group II includes adenocarcinomas and a few rare
types. He postulated that a determination of the ratio between Groups I
and II is a good index of the occurrence and magnitude of an increase in
lung cancer in a given locality and his epidemiologic studies linked the
increase almost entirely to the use of cigarettes. His thesis has been ac-
cepted by many while disputed by others.

The results of the study of lung cancer at Los Angeles County General
Hospital (LACGH) by Herman and Crittenden (167) did not confirm Krey-
Derg’s conclusions. These investigators, analyzing the autopsy data on lung
cancer from 1927 to 1957 at LACGH, observed a marked increase in the
number of lung cancer cases as had been noted by many other investigators.
However, the ratio of Kreyberg’s Group I to Group II had not changed per-
ceptibly over this period and was notably lower than in other series studied.

The Committee on Smoking and Health sponsored a workshop in which
slides from coded cases of lung cancer from four different institutions in
three areas of the United States were typed “blind” by Dr. Kreyberg and
Pathologists from the cooperating institutions." There was good agreement
48 to typing. The low ratio of Group I to Group II cancers at LACGH was
confirmed. When typing of the reviewed cases was compared with smoking
_—__

“Workshop on typing of lung tumors held in Washington, D.C., April 11, 1963.

173
TaBLE 8.—Relation between WHO and Kreyberg classifications of lung tumors

 

Kreybe

WHO classification ! classifier
tion 2

ee

 

A. Epithelial Tumors
1. Epidermoid carcinomas____..__.....-.------.- 22222-22202 oon Group I

a. highly differentiated
b. moderately differentiated

c. slightly differentiated

2. Small-cell anaplastic carcinomas. .._._____._......-..2-2------ eee Group I
a. with oval-cell structure (“oat-cell” carcinoma)
3, Adenocarcinomas..__._.....---_-----222--22----- 22222 eee eee Group II

a. acinar (with or without formation of mucus)

b. papillary (with or without formation of mucus)

e. tumors with a predominance of “large cells” some of which show forma-
tion of glands and/or production of mucus.

 

4. Large-cell undifferentiated carcinomas. __._........-.-..-.-.--..-.-------------- Other ?
5. Combined eqidermoid and adenocarcinomas . Other

6. Bronchiolo-alveolar cell carcinomas. .__......---._.______ Group II
7. Carcinoid tumors (solid, trabecular, alveolar) Group IT
8. Tumors of mucous glands.........-.--.--..---------2.--- Group IT

a. cylindroma

b, muco-epidermoid tumors
9. Papillomas of the surface epithelium __.___...___.._...2--_-_-. 2-2-2 Other

a. epidermoid

b. epidermoid with goblet cells

 

TR. Sarcomas..__..._..-..---2-2--2 22-22 eee Other
C. Combined Tumors of Epithelial and Mese: Other
TD. Mesotheliomas of the Pleura_..___.........-2-----2------ 20.222 eee Other
1. Localized
2. Diffuse

E. Tumors Unelassifled

 

 

1 Committee on Cancer of the Lung, World Health Organization.

? Kreyberg, L. Histological Lung Cancer Types. A Morphological and Biological Correlation. Nor-
wegian Universities Press, 1962.

‘Types marked ‘other’ are not included in either of Kreyberg groups.

histories, moreover, it became evident that both Group I and Group II were
increased among heavy smokers.

Several factors were recognized to influence Group I/Group II ratios:
(a) source of material (for example, significant differences in the ratio
were found between autopsy and surgical materials, and between surgical
materials obtained by biopsy and by resection during operation for lung
cancer); (b) failure to autopsy certain cases which were judged to be
inoperable (the patient being sent home as incurable); (c) the fact that
Group I (squamous and oval-cell) carcinomas are more likely to be among
the operable cases and among those accessible to bronchoscopy, and (d)
variations in selection of patients in different institutions.

An independent review of the histopathology of 1,146 lung cancer cases
from the U.S. veterans study (policyholders) by Dorn, Herrold and Haens-
zel (Table 9) (89) showed high mortality ratios for both Group I and
Group II cancers in current heavy smokers (over 20 cigarettes/day), al-
though Group I had a higher mortality ratio (31.2) than Group II (7.2).

Another study of Haenszel on white females (152), as well as studies of
female patients at Massachusetts General Hospital (54), Roswell Park
Memorial Institute (133), Presbyterian Hospital (323), and Washington
University (260), indicated that adenocarcinoma is also contributing to the
increment of lung cancer in women.

ConcLusions—{a} The histological typing of lung cancer is reliable.
However, the use of the ratio of Group I and Group II is an index to the mag-
nitude of increase in lung cancer is of limited value.

174
TABLE 9.—Mortality ratios for cancer of the lung by smoking class and
by type of tumor, U.S. veterans study

 

 

 

  

 

 

All Deaths} Group I | Group II
Nonsmokers ! 1.0 10 1.0
Pipe and/or cigar smokers ._._ 1.5 22 0.6
Cigarette smokers, total] 2____ 8.2 15.4 5.1
Current
Total 10.0 18.9 5.R
20 cigarettes/day~ 7.1 12.9 | 5. 1
>20 civarettes/day_ 16.0 31.2 | 7.2
Discontinued (By Maximum Amt. Ever Smoked) 5
Total 4.7 8.4 | 3.7
$0 cigarettes/day - 3.5 6.6 | 2.7
>> 20 cigarettes/day 74 12.1 5.6

 

‘Includes occasional smokers.
? Includes men who were using pipe and/or cigars in addition to cigarettes.

Source: Dorn, H. F., Haenszel, W. and Herrold, K. {89) (see Chapter 8 also).

(b) Squamous and oval-cell carcinomas (Group I) comprise the pre-
dominant types associated with the increase .of lung cancer in both males
and females. In several studies, adenocarcinomas (Group TH) have also
increased in both sexes although to a lesser degree.

Evaluation of the Association between Smoking and Lung Cancer

It is not practical to attempt an experiment in man to test whether a
causal relationship exists between smoking of tobacco and lung cancer. Such
an experiment would imply the random selection of very young subjects
living under environmental conditions as nearly identical as possible, and
random selection of those who were to be smokers and those who were to
be the non-smoker controls. Their smoking and other habits would need
to be held constant for many years. Because of the relatively low incidence
of lung cancer in the human population, both the test and the control groups
would have to be very large.

As such an experiment in man is not feasible, the judgment of causality
must be made on other grounds. The epidemiologic method, when coupled
with clinical or laboratory observations, can provide the basis from which
judgments of causality may be derived.

INDIRECT MEASURE OF THE ASSOCIATION

The crudest indicators of an association between lung cancer and smoking
are certain indirect. measures: (a) a correlative increase in lung cancer
mortality rates and in per capita tobacco consumption in a number of
countries (76, 138, 211, 239, 255), and (b) disparities between male and
female lung cancer mortality rates correlated with corresponding differences
'n smoking habits of men and women, both by amounts smoked and duration
of smoking (65, 151, 344).

; Figure 9 shows a correlation of crude male death rates from lung cancer
’n 1] countries in 1950 with the per capita consumption of cigarettes in these
countries in 1930 as presented by Doll (76). Assuming a 20-year induction
Period for the appearance of lung cancer, Doll found a significant correlation
(0.73+0.30) between the death rates and cigarette consumption. Since
Virtually all the tobacco consumption in 1930 was among men in the countries

714-422 O-64—13 175