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1958
Histologic Types of Lung Carcinoma and Age at Onset
Michaela Kreuzer, Ph.D.1,2
Lothar Kreienbrock, Ph.D.1
Klaus M. Müller, M.D.3
Michael Gerken, M.D.1
Erich Wichmann, M.D., Ph.D.1
1
GSF-National Research Center for Environment
and Health, Institute of Epidemiology, Neuherberg,
Germany.
2
Federal Office of Radiation Protection, Institute of
Radiation Hygiene, Neuherberg, Germany.
3
Berufsgenossenschaftliche Kliniken Bergmannsheil/Ruhr-Universität Bochum, Institute of Pathology, Bochum, Germany.
BACKGROUND. Previous research has demonstrated that adenocarcinoma is the
leading cell type among patients with early age onset lung carcinoma. An increase
in adenocarcinoma at the expense of squamous cell carcinoma in general was
observed in recent years and may be due to the smoking of filtered cigarettes.
METHODS. To rule out whether shifts in smoking patterns or other etiologic factors
are responsible for the high rates of adenocarcinoma in young patients, personal
interviews regarding smoking, occupation, and family history of cancer were
conducted in 251 young patients (age # 45 years) and 2009 older patients (ages
55– 69 years) with histologically confirmed lung carcinoma from selected study
clinics in Germany between 1990 and 1996.
RESULTS. Young male patients were found to have significantly more adenocarcinomas (41%) than older male patients (28%), whereas adenocarcinomas were
dominant in young and older women (43% and 47%, respectively). Because smoking patterns were different between young and older patients, the authors stratified
for comparable levels of smoking exposure. Histology did not differ in never
smokers (dominance of adenocarcinomas in both age groups) and in male heavy
smokers (dominance of squamous cell carcinomas in both age groups), whereas
young male low dose smokers showed significantly more cases of adenocarcinoma
than older low dose smokers. A family history of lung carcinoma was significantly
higher in young patients compared with older patients, but no association with
histologic type was observed.
CONCLUSIONS. The results of the current study show that differences in the histologic type of lung carcinoma based on age at onset can be explained in part by
differences in smoking patterns. However, there still are unknown factors that
appear to favor the development of adenocarcinoma in the young. Cancer 1999;85:
1958 – 65. © 1999 American Cancer Society.
KEYWORDS: lung carcinoma, smoking, histology, family.
C
Supported by the Federal Office of Radiation Protection, Salzgitter, Germany (grant St Sch 1066,
4074, 4074/1, 4006, 4112).
Address for reprints: Dr. Michaela Kreuzer, Federal
Office of Radiation Protection, Institute of Radiation
Hygiene, Ingolstaedter Landstrasse 1, D-85764
Neuherberg, Germany.
Received May 22, 1998; revisions received September 21, 1998 and January 11, 1999; accepted
January 11, 1999.
© 1999 American Cancer Society
arcinoma of the lung occurs most commonly in the sixth and
seventh decades of life and is rarely found in young patients. Most
studies over the past decades reported adenocarcinoma as the most
frequent cell subtype among patients with early onset lung carcinoma
of both genders,1–12 which is in contrast to squamous cell carcinoma
as the most frequent type in older men.13 The predominance of
adenocarcinoma in the young could reflect either a propensity of
young individuals to develop this subtype or an increase in this
subtype in recent years, which initially is reflected in younger cohorts.
Some studies suggest that the reduction of tar yield and the introduction of filtered cigarettes in the 1960s could have favored the development of adenocarcinoma at the expense of squamous cell carcinoma.14,15 Such shifts in the incidences of different histologic types of
lung carcinoma have been found in the United States, where adenocarcinoma had become the most frequent subtype at the beginning of
the 1980s.16 –18 In Europe, squamous cell carcinoma still predomi-
Lung Carcinoma Histology and Age at Onset/Kreuzer et al.
1959
FIGURE 1.
Distribution of histologic
types by age group (in years) at diagnosis (n 5 4500). SCLC: small cell lung
carcinoma; AC: adenocarcinoma; SqCC:
squamous cell carcinoma.
nates in most countries. Levi and colleagues19 reported a remarkable rise in adenocarcinoma incidence in men and women from Switzerland, with rates
of adenocarcinoma incidence among young adults in
the early 1990s being more than three times higher
than rates of squamous cell carcinoma.
Up to now, it is still inconclusive whether or not
high rates of adenocarcinoma in young subjects are
mainly attributable to shifts in smoking pattern or
whether other still unknown factors are causal. In a
previous analysis of a case– control study of lung carcinoma, we found smoking and a possible genetic
predisposition as risk factors for lung carcinoma in
young subjects (#45 years).20 In addition, a high percentage of adenocarcinomas in this young group compared with older patients (55– 69 years) was observed.
The aim of the present analysis of these data is to
further investigate the association between histologic
type and age of onset of lung carcinoma. This study
provides a large number of young and older lung
carcinoma patients of both genders, a detailed quantification of life-long smoking and occupational exposure, and information on family history of cancer.
PATIENTS AND METHODS
Data of patients were derived from a case– control
study on lung carcinoma conducted between 1990
and 1996 in several regions in East Germany
(Thuringia and Saxony) and West Germany (Eastern
Bavaria, the Saarland, parts of Northrhine-Westfalia,
and Rhineland Palatinate).21–23 Patients with histolog-
ically or cytologically confirmed lung carcinoma with
primary tumors were recruited from 15 study clinics in
this study region. Patients were eligible if 1) they were
,75 years of age, 2) they were resident in the study
region, 3) they had lived in Germany for .25 years, 4)
the interviews were conducted within 3 months of
diagnosis, 5) they were not too ill, and 6) their tumor
type was not “carcinoid.” The response rate among
eligible patients was 76%.
According to World Health Organization (WHO)
classification, we coded the microscopic noticeably
leading histologic type into four groups: small cell
lung carcinoma (SCLC), squamous cell carcinomas
(SqCC), and adenocarcinomas (AC). Due to small
numbers we combined large cell carcinomas, mixed
types, and tumors, for which no classification was
possible, into the category “other.” About 60% of diagnoses were derived from histology, 20% were derived from cytology, and 20% were derived from both.
Diagnostic and cell type procedures were established
by each participating hospital. We used a diagnosis
from cytology only if a diagnosis from histology was
not present. A reference pathologist reviewed about
70% of the pathologic material without any knowledge
of age, gender, or tumor type diagnosed by the clinical
pathologist. To avoid misclassification due to different
pathologists, diagnoses of tumor histology from the
reference pathologist were used where available, with
missing reference histology replaced by a diagnosis
from the clinical pathologist. A total of 4500 lung carcinoma cases were included in the study. Figure 1
1960
CANCER May 1, 1999 / Volume 85 / Number 9
shows the frequencies of cell subtypes according to
age at diagnosis in 5-year categories. A clear association between age and histology was observed. The
highest frequencies of adenocarcinomas were seen in
the younger age groups, whereas squamous cell carcinomas were most frequent in the older age groups.
We classified a young and older age group according to our previous analysis.20 Patients were defined as
young if they were #45 years of age and older if they
were 55– 69 years of age. Subjects between 46 –54 years
of age were excluded to clearly separate the two age
groups, and those .69 years of age were excluded,
because their recollection of past exposures might be
less accurate than that in the younger age groups.
After the patient’s informed consent was obtained, an interview with the patient was conducted
by trained interviewers at the beside or at home if the
patient had already been discharged. A standardized
questionnaire was used to determine basic demographic characteristics in addition to details on active
smoking history, occupational history, and a family
history of cancer. Subjects were defined as smokers if
they had ever smoked regularly (at least 1 cigarette per
day, 4 cigarillos per week, or 3 cigars or 3 pipes per
week) for at least 6 months. A life-long history of
smoking exposure was explored in a concept of smoking periods. In each period, information was available
on the type of tobacco, filter usage, daily consumption, duration in years, times of cessation, and year of
starting.
All occupations during a patient’s lifetime were
evaluated in a concept of job periods. Subjects were
classified as having been exposed occupationally to
known or suspected lung carcinogens if they had
worked for at least 6 months in a job entailing exposure to recognized (A-list) or suspected (B-list) carcinogens, mostly based on the International Agency for
Research on Cancer monographs program.24 Information on history of cancer among first-degree relatives
was gathered, including age at diagnosis and cancer
site. Subjects were defined as having cancer in the
family if at least one parent or sibling with cancer was
reported. This factor was defined for lung carcinoma,
carcinoma at age #45 years, and lung carcinoma at
age #45 years. One-year measurements of radon concentrations in the bedroom and living room of the
patient’s last dwelling were obtained by a-track detectors.25 To date, these measurements have been completed for '70% of all patients. For this subsample,
the time-weighted average of radon concentrations
measured in the bedroom and living room was calculated.
Variables of interest were analyzed by means of
cross tabulations on contingency tables. Chi-square
statistics with associated significance levels were calculated. Tests for differences in histology by age were
performed after stratification by gender and, separately, for different exposure levels of smoking.
RESULTS
Table 1 shows characteristics of the study population.
A total of 251 young and 2009 older lung carcinoma
cases were included in the analysis. The ratio between
men and women was appreciably lower in the young
group (2.7:1.0) than in the older group (5.6:1.0). The
relative frequency of adenocarcinoma was substantially higher in young men (41%) than in older men
(28%), whereas squamous cell carcinoma was more
common among older men (42%) than among young
men (26%). Both age groups of women showed adenocarcinoma as the leading tumor type (43% in the
young women, 47% in the older women). Significantly
more young female patients were smokers (91%) compared with older female patients (68%), whereas there
was no statistically significant difference in the smoking status between young and older men (97% and
99%, respectively). On average, regardless of gender,
older patients smoked about 15 years longer than
young patients and smoked about four cigarettes
fewer per day. Life-long consumption of filtered cigarettes was considerably higher in young patients (62%
of men and 92% of women) than in older patients
(13% of men and 47% of women).
A family history of lung carcinoma in first-degree
relatives revealed a significantly increased proportion
in young men compared with older men (P 5 0.0045).
Young patients reported significantly more cancer
with age at diagnosis , 46 years in first-degree relatives than older patients (P 5 0.000 among men; P 5
0.004 among women). The most notable difference
was a higher proportion of familial aggregation of
early onset lung carcinoma among young lung carcinoma patients compared with older patients (2.2%
among young male cases vs. 0.1% among older male
cases; 2.9% vs. 1.0% among women, respectively).
No significant differences in exposure to known or
suspected occupational carcinogenic substances were
observed between age groups in both genders. Also, in
the indoor air radon concentrations did not differ
between young and older patients. The median radon
concentration was between 40 Bq/m3 and 42 Bq/m3
among young and older men and among older
women. It was somewhat smaller among young
women, but the sample size was very small in this
group. Because of this lack of a statistically significant
difference between age groups, occupational exposure
and radon exposure were not controlled for in the
analysis.
Lung Carcinoma Histology and Age at Onset/Kreuzer et al.
1961
TABLE 1
Characteristics of Lung Carcinoma Patients by Gender and Age Group
Men
Women
Characteristic
<45 yrs
55–69 yrs
<45 yrs
55–69 yrs
Total
Mean age (yrs)
Histology (%)
Small cell carcinoma
Squamous cell carcinoma
Adenocarcinoma
Other
Smoking status (%)
Never smokersa
Ever smoked cigarettes
Other smokers (pipes, cigars)
Characteristics of cigarette smokers
Duration of smoking (yrs)b
Average daily consumption (cigarettes/day)
Life-long filtered cigarettes only (%)
Occupation (%)
Ever A-listc
Ever A or B-listd
Family history of cancer (at least one parent or sibling) (%)
Lung cancer
Cancer at age #45 yrs
Lung cancer at age #45 yrs
Radon concentration at home
Number of subjects with valid 1-year measurements
Median (Bq/m3)
183
41
1709
63
68
42
300
62
24.0
26.2
41.0
8.7
22.5
42.1
28.0
7.5
30.9
19.1
42.7
7.4
20.3
22.7
47.0
10.0
3.3
96.7
0.0
1.3
97.2
1.5
8.8
91.2
0.0
31.7
67.3
1.0
22.9 6 4.3
22.8 6 9.3
62
37.3 6 10.7
19.5 6 9.2
13
20.9 6 6.5
19.2 6 12.0
92
35.5 6 10.9
15.2 6 8.5
47
15.8
38.8
16.4
43.2
2.9
16.2
4.0
17.0
10.3
8.6
2.2
6.3
3.2
0.1
9.0
11.9
2.9
10.9
3.4
1.0
93
41.1
1207
41.5
36
35.4
182
39.7
a
Never smoked more than one cigarette per day regularly for longer than 6 months.
Values represent mean 6 standard deviation.
c
Ever exposed to a known lung carcinogen (A-list).
d
Ever exposed to a known or suspected lung carcinogen (A- or B-list).
b
Smoking and Histology
Table 2 provides the distribution of histologic type by
smoking exposure among men. Never smokers, as expected, exhibited the highest frequency of adenocarcinoma in both male age groups (67% in young men
and 57% in older men). Among young male cigarette
smokers, statistically significantly more adenocarcinomas and fewer squamous cell carcinomas were observed than among older men. After stratification of
tobacco consumption into three categories, a strong
decrease in the frequency of adenocarcinoma and
small cell lung carcinoma accompanied by an increase
in squamous cell carcinomas with increasing average
daily consumption was observed in the young group.
This tendency was not found or was found only in a
very weak form in the older group. Among heavy
smokers (.30 cigarettes per day), the histologic type
between older and young cases did not differ statistically, but it is notable that differences in histology by
age group were seen in low and medium dose smokers. The group of weak smokers (,14 cigarettes per
day) showed significantly more adenocarcinomas
(46%) and fewer squamous cell carcinomas (13%) in
the young group compared with the older group (27%
and 41%, respectively). Because the underlying duration of smoking between both age groups was completely different, we divided consumption of tobacco
into a group of subjects who smoked for ,30 years
and those who smoked .30 years. Again, in weak
smokers (,30 years, ,20 cigarettes/day), we found
significantly more adenocarcinomas (48%) and fewer
squamous cell carcinomas (25%) in young men than
in older men (31%, 40%, respectively) and found no
differences in histologic type between young and
older “heavy” cigarette smokers.
An appreciably higher proportion of squamous
cell carcinomas (37%) among young smokers of nonfiltered cigarettes was seen compared with pure filtered cigarette smokers (20%) (Table 2). This effect
was not so pronounced in older patients. Again “heavy
smokers” (life-long nonfiltered or mixed filtered cigarettes) exhibited no statistical difference in tumor type
1962
CANCER May 1, 1999 / Volume 85 / Number 9
TABLE 2
Distribution of Histologic Type by Age Group and Various Smoking Variables among Men Only Never Smokers and Cigarette Smokers (Pure
Smokers of Pipes, Cigars, or Cigarillos Excluded)
<45 yrs: cell type (%)
55–69 yrs: cell type (%)
Smoking variable
SCLC
SqCC
AC
Other
Total
SCLC
SqCC
AC
Other
Total
P valuea
Never smokers
Ever smokers
Daily consumption
1–14 cig/day
15–29 cig/day
301 cig/day
Duration/consumption
,30 yrs, ,20 cig
,30 yrs, 201 cig
301 yrs, ,20 cig
301 yrs, 201 cig
Filter usage
Filtered cig only
Nonfiltered and mixed filtered cig
—
25.4
33.3
26.6
66.7
41.2
—
6.8
6
177
13.0
22.1
13.0
41.8
56.5
27.6
17.4
8.5
23
1653
—
0.000
37.5
24.8
18.8
12.5
27.7
34.4
45.8
41.3
37.5
4.2
6.6
9.4
24
121
32
23.7
22.2
17.2
40.5
41.8
44.6
27.3
27.3
30.9
8.6
8.7
7.3
477
972
204
0.02
0.003
0.74
22.5
27.8
0
25.0
25.4
25.8
100.0
37.5
47.9
38.1
0
25.0
4.2
8.3
0
12.5
71
97
1
8
20.0
19.8
25.5
18.2
39.5
38.5
41.0
44.2
31.2
31.3
25.1
29.5
9.3
10.4
8.3
8.2
215
96
792
550
0.03
0.20
—
—
29.4
19.1
20.2
36.8
44.0
36.8
6.4
7.4
109
68
22.2
22.0
39.2
42.1
30.2
27.4
8.5
8.5
212
1439
0.003
0.42
SCLC: small cell lung carcinoma; SqCC: squamous cell carcinoma; AC: adenocarcinoma; cig: cigarettes.
a
P values were determined by chi-square test for differences in histologic types between age groups (each row indicates one test).
TABLE 3
Distribution of Histologic Type by Age Group and Various Smoking Variables among Women Only Never Smokers and Cigarette Smokers (Pure
Smokers of Pipes, Cigars, or Cigarillos Excluded)
<45 yrs: cell type (%)
55–69 yrs: cell type (%)
Smoking variables
SCLC
SqCC
AC
Other
Total
SCLC
SqCC
AC
Other
Total
P valuea
Never smokers
Ever smokers
Daily consumption
1–14 cig/day
15–29 cig/day
301 cig/day
Duration/consumption
,30 yrs, ,20 cig
,30 yrs, 201 cig
301 yrs, ,20 cig
301 yrs, 201 cig
Filter usage
Filtered cig only
Nonfiltered and mixed filtered
16.7
32.3
33.3
17.7
16.7
45.2
33.3
4.8
6
62
10.5
24.4
11.6
26.8
66.3
38.5
11.6
10.2
95
202
—
0.18
40.0
32.1
11.1
12.0
21.4
22.2
40.0
46.4
55.6
8.0
0
11.1
25
28
9
24.0
25.3
27.3
29.0
25.3
27.3
37.0
38.5
45.5
10.0
11.0
0
100
91
11
0.09
0.10
0.49
41.9
11.8
0
0
11.6
35.3
0
0
41.9
52.9
0
50.0
4.6
0
0
50.0
43
17
0
2
26.2
66.7
21.9
29.0
19.1
33.3
29.4
29.0
47.6
0
37.8
31.6
7.1
0
10.9
10.5
42
3
119
38
0.44
—
—
—
29.8
60.0
17.5
20.0
47.4
20.0
5.3
0
57
5
26.0
23.8
26.0
28.6
36.5
39.1
11.5
8.6
96
105
0.28
—
SCLC: small cell lung carcinoma; SqCC: squamous cell carcinoma; AC: adenocarcinoma; cig: cigarettes.
a
P values were determined by chi-square test for differences in histologic types between age groups (each row indicates one test).
between young and older patients, whereas life-long
smokers of filtered cigarettes differed according to
histologic type.
In the large group of never smoking older women
(n 5 95), adenocarcinomas were dominant (66%).
Only 6 young female lung carcinoma patients had
never smoked in their life, among whom 1 case of
adenocarcinoma occurred. The proportion of adenocarcinomas in female cigarette smokers (Table 3) was
reduced compared with never smokers but remained
the dominant subtype in both age groups (45% in the
young group and 39% in the older group), followed by
small cell lung carcinoma. No statistically significant
differences in histologic type by age group were observed, even after stratification for comparable levels
of exposure. The detailed analyses of subgroups of
smoking women are difficult to evaluate due to the
very small numbers.
Lung Carcinoma Histology and Age at Onset/Kreuzer et al.
1963
TABLE 4
Distribution of Histologic Type by Age Group and Family History of Cancer (at Least One Parent or Sibling)
<45 yrs: cell type (%)
Family history
Lung carcinoma
Yes
No
Cancer at age #45 yrs
Yes
No
55–69 yrs: cell type (%)
SCLC
SqCC
AC
Other
Total
SCLC
SqCC
AC
Other
Total
33.3
24.7
29.2
23.4
29.2
42.7
8.3
9.2
24
218
20.1
22.4
38.9
39.1
33.1
30.6
7.9
7.9
139
1845
43.5
23.6
26.1
25.0
26.0
42.7
4.4
8.6
23
220
12.3
22.5
41.5
38.9
29.2
30.7
16.9
7.9
65
1923
SCLC: small cell lung carcinoma; SqCC: squamous cell carcinoma; AC: adenocarcinoma.
Family History of Cancer and Histology
There was no evidence of differences in histology between patients with or without a family history of lung
carcinoma in either in the young group or in the older
age group (Table 4). The same was seen for a family
history of early onset carcinoma. It is notable that
there was no tendency for adenocarcinoma to be associated with a reported family history of lung carcinoma. Only one young patient who had reported a
family history of lung carcinoma was a nonsmoker. A
stratification of groups into weak smokers and heavy
smokers did not change the distribution of cell subtypes by reported family cancer history.
DISCUSSION
Two findings have emerged from our analysis of histologic type and age of onset of lung carcinoma. The
first was that there are many similarities between the
findings in our study population and others reported
in literature. In all of the reports that include both men
and women, there are more women in the younger
group than in the general population of patients with
lung carcinoma.7,10,12,26,27 We found a male-to-female
ratio of 2.7:1 in the young group and 5.6:1 in the older
group. The relative increase in the number of women
among the younger patients may reflect the more
recent increase in smoking among women. Previous
analysis of population controls matched by age, gender, and region to our patients with lung carcinoma
exhibited 52% current or exsmokers among young
female controls and 36% among older female controls.20 Several studies conducted over the past three
decades reported a preponderance of adenocarcinoma in young patients.1–12,28 This is consistent with
our results of about 41% adenocarcinoma in young
male patients (43% in young female patients) compared with 28% adenocarcinoma in older male patients (47% in older female patients). Only a few of
these studies included data on smoking history,1,10
and none reported histologic type analyses stratified
by smoking exposure.
The most important new finding in our study,
however, was that differences in histology by age
could be explained in part by differences in smoking
pattern and gender. It is evident that the proportion of
smokers in young women is higher than in older
women, that young patients smoke more filtered cigarettes and more cigarettes per day and are less likely
to be long term smokers than older patients, regardless of gender. Among the group of women, no statistically significant differences in age-related histology
were observed, but the statistical power to detect such
differences was small. It should be noted that there is
a markedly greater number of small cell carcinomas
among young women compared with older women.
This either could be random (due to the small numbers) or may reflect the trend of a reduction in adenocarcinomas and an increase in small cell carcinomas in female smokers, which was found in the
United States.29
Histology of men differed significantly by age.
However, after stratification for comparable smoking
exposure levels, some of the differences disappeared.
For example, adenocarcinoma was the most frequent
histologic type in life-long never smokers in both age
groups. Among “heavy male smokers,” like those who
smoked more than 30 cigarettes per day on average,
those who were life-long smokers of nonfiltered or
mixed filtered cigarettes, and those who smoked more
than 20 cigarettes longer than 30 years, squamous cell
carcinoma was the most predominant cell subtype in
young and older male patients, and no statistically
significant differences were observed between the age
groups. Differences in histology by age remain only in
low and medium dose male smokers, with a higher
frequency of adenocarcinomas in young patients than
in older patients.
Most recent studies suggest that the increasing
1964
CANCER May 1, 1999 / Volume 85 / Number 9
predominance of adenocarcinoma over squamous cell
carcinoma may be due in part to the reduced risk of
squamous cell carcinoma associated with life-long filtered cigarette smoking.14,30 Filters remove larger particles in cigarette smoke, thus reducing the deposition
of those particles into central airways, where the squamous cell carcinoma develops preferentially.31,32 This
could lead to a reduction in the incidence of squamous cell carcinoma but not of adenocarcinoma,
which occurs primarily in peripheral lung areas.15,33 In
fact, in the group of young men, we observed more
frequent squamous cell carcinomas among nonfiltered and mixed filtered cigarette smokers (37%) than
among life-long smokers of filtered cigarettes (20%
squamous cell carcinoma). Among older men, this
effect was not so clear (42% vs. 39%).
It is striking that histology in nonfiltered and
mixed filtered cigarette smokers did not differ between young and older men, whereas significant differences exist in life-long filtered cigarette smokers.
Several factors, however, are likely to have contributed
to a higher percentage of adenocarcinoma in the
young filtered cigarette smokers compared with the
older filtered cigarette smokers. First, the cumulative
consumption of filtered cigarettes over a whole life
time is much greater in older men than in young men,
because they have smoked about 15 years longer on
the average. It is possible that the necessary inciting
stimulus for the transformation of the respiratory mucosa to squamous cell carcinoma must act over a
longer time span to be effective.1 In addition, tar and
nicotine contents have been reduced strongly in Germany since the 1960s. Because we have no information on cumulative tar and nicotine exposure among
young and older men, a possible interaction with age
and its effects on histology could not be determined.
On the whole, young mild smokers are likely to have
less cumulative tobacco exposure than older mild
smokers and are therefore closer to the nonsmokers,
who are known for a predominance of adenocarcinomas for reasons other than smoking.
Environmental exposure to other agents or genetic factors also may play a role in differences in
histology by age. It is widely assumed that cancers
diagnosed at an earlier age may indicate a larger role
of genetic predisposition. Our previous analysis20
showed a threefold increased lung carcinoma risk in
the young group (#45 years) if at least one lung carcinoma case was reported in a first-degree relative and
a twofold increased lung carcinoma risk if cancer at a
young age in a first-degree relative was reported. No
such influence was seen in the older group (55– 69
years). A possible genetic predisposition also is supported strongly by the segregation analysis of Sell-
ers,34,35 who suggested that Mendelian inheritance of
a rare major autosomal gene may produce lung carcinoma at an earlier age of onset. Because adenocarcinoma is seen more often at an earlier age than other
cell types, it is surprising that the excess of reported
family history of cancer is not observed among patients with adenocarcinoma. This phenomenon is
supported by data presented by Ambrosone et al.36
They observed that, of all histologic types of lung
carcinoma, squamous cell carcinoma is the type most
associated with familial clustering of malignancy, and
adenocarcinoma is the least. Sellers et al.37 found little
direct evidence of increased genetic predisposition
among patients with particular types of lung carcinoma.
A strength of this study is that all patients were
interviewed in person; no data were obtained from
next of kin or other surrogates. Use of closely supervised, trained interviewers and standardized questionnaires also served to increase confidence in the results. Refusal rates have consistently been under 23%
in the young patients and under 27% in the older
patients. No statistical differences in histologic type
were observed between study participants and refusals, so that little selection bias is believed to exist.
Review of a subsample ('70%) of all pathologic material exhibited a strong association between histologic diagnosis of the clinical pathologist and the reference pathologist. Eighty-six percent of young
patients with lung carcinoma diagnosed as small cell
carcinoma by the clinical pathologist had their cell
subtype confirmed by the reference pathologist (82%
in older patients), 94% of young patients with adenocarcinoma had their cell subtype confirmed by the
reference pathologist (80% in older patients), and 62%
of young patients with squamous cell carcinoma had
their cell subtype confirmed by the reference pathologist (68% in older patients). A possible classification
bias due to different clinical pathologists was minimized by using the diagnoses of the reference pathologist, where available.
CONCLUSIONS
Adenocarcinoma is the leading cell subtype in young
male and female patients with lung carcinoma,
whereas, among older male patients, squamous cell
carcinoma predominates. Differences in histologic
type between patients with onset of lung carcinoma at
an early age and older patients can be explained in
part by differences in smoking patterns. After stratification for comparable levels of smoking exposure, the
groups of heavy smokers and never smokers exhibited
no statistically significant differences in cell subtype
compared with low dose smokers, like life-long smok-
Lung Carcinoma Histology and Age at Onset/Kreuzer et al.
ers of filtered cigarettes. Results indicate a genetic
predisposition in young patients that shows no influence on histology. There still remain unknown factors
that appear to favor the development of adenocarcinoma in young patients with lung carcinoma.
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