CLINICAL INVESTIGATIONS
Histologic Type of Lung Cancer in Relation to Smoking Habits, Year of Diagnosis and Sites of Metastases* Oscar Auerbach, M.D., F.C.C.P.,oo Lawrence Gar{inkel,t and VeTta R. Parkst
A study was made of histologic type of lung cancer in relation to smoking habit, year of diagnosis, age and sites of metastasis. It comprised 662 autopsies of men during the period from 1955 to 1972. As classified by the WHO system, 35.2 percent were epidermoid carcinoma, 24.6 percent were small cell carcinoma, 25.2 percent were adenocarcinoma and 14.2 percent were large cell undifferentiated carcinoma. The six non-smokers of the series were all found to be in class 3, adenocarcinoma. No clearcut and consistent relationships were observed. Although there was a steady decrease in the incidence of small cell
carcinoma during this time period, this observation did not prove to be statistically significant. Small cell carcinomas increased with amount of smoking but not for aU age groups. Adenocarcinomas decreased with advancing age but not in aD smoking groups. Metastases were found in 96.3 percent of the cases and the sites most frequently involved were regional lymph nodes, liver, brain, distant lymph nodes, adrena~ and bone. Small cell carcinomas showed the greatest percentage of involvement for those major sites and for the same sites, epidennoid carcinoma showed the lowest percentage.
There has been considerable interest in studying histologic types of lung cancer and their distribution in relation to clinical diagnosis, course of disease, and survival. As the proportion of lung cancers seen at autopsy increased over the last 30 years, the need for a system of classification of the histologic types became greater and various designs have been proposed. Pathologists have been particularly interested in determining if there is an association between histologic type and etiologic factors such as smoking, and if there is an association between histologic type and metastatic pattern. In 1962 Kreyberg! divided lung tumors between two major groups and published his findings using that system. In 1965 the WHO classification was published2 and has since been generally used. This is an elaboration
of Kreyberg's system and uses five major divisions with subgroupings in each. This study was undertaken for the following reasons: (1) the amount of tar and nicotine in cigarette smoke has changed considerably in the last 15 to 20 years, and it would be of interest to know whether there has been a concomitant change in the proportion of histologic types of lung cancer seen at autopsy during this period of time; (2) it would be of considerable interest to compare the distribution of smoking habits in relation to histologic type; and (3) it would be of interest to see if there is a relationship between the histologic type of lung cancer and the observed sites of metastases.
°From the Veterans Administration Hospital, East Orange, New Jersey and the Department of Epidemiology and Statistics, American Cancer Society, Inc., New York. o ° Senior Medical Investigator, VA Hospital, East Orange, New Jersey and Professor of Pathology, College of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark. tAssistant Vice President, Department of Epidemiology and Statistics, American Cancer Society, Inc., New York. tResearch .Biologist, Senior Medical Investigator Laboratory, VA HospItal, East Orange, New Jersey. Manuscript received June 27; accepted September 3. Reprint requests: Dr. Auerbach, VA Hospital, East Orange, New Jersey 07019
During the period from 1955 to 1972 at the Veterans Administration Hospital, East Orange, New Jersey, we collected autopsy specimens and smoking and residence histories for a series of studies relating smoking habits to histologic changes. The smoking histories were obtained by trained interviewers from the relatives of the deceased. Of the autopsies performed during this period of time, primary lung cancer was found to be the underlying cause of death in 1,093 cases. For this study, there were 662 cases with usable smoking and residence histories. All were of men. For each case, the detaned autopsy protocol and all of the microscopic lung slides were initially reviewed to select a
382 AUERBACH, GARFINKEL, PARKS
MATERIALS AND METHODS
CHEST, 67: 4, APRil, 1975
shows the number and percentage of discrepancies between the two readings which fall within the same major classification and the number and percentage of discrepancies between two readings which involved two separate classifications within the five major classifications. Of the eleven subclassifications shown in Table 1, completely consistent readings were made in 91.2 percent of the 662 pairs of readings (Table 2). As for the 58 pairs (8.8 percent) which were discrepant, in 47 the difference occurred within subgroupings of the same class-that is, for example, a reading of class 12 (moderately well differentiated epidermoid carcinoma) at the first reading, and class 13 (poorly differentiated epidermoid carcinoma) on the second reading. In the eleven discrepant pairs with differences that were between two of the five major classes, seven of them were 13:33 or 13:42 combinations, a discrepancy resulting from a dilemma common among pathologists in classifying these poorly differentiated tumor types.
Table I--ClaslJifieation 01 Hi.tologie Cell Type 01 Lung Caneer
Class 1. Epidermoid carcinomas 11 : Highly differentiated epidermoid 12 : Moderately differentiated epidermoid 13 : Poorly differentiated epidermoid Class 2. Small cell carcinomas 21 : Oval cell structure (Uoat cell" carcinoma) 22 : Polygonal cell structure Class 3. Adenocarcinomas 31 : Acinar carcinoma 32 : Papillary and/or bronchiolar carcinoma 33 : Poorly differentiated adenocarcinoma Class 4. Large cell undifferentiated carcinomas 41 : With giant cells 42 : Without giant cells Class 5. All mixed combined carcinomas (any variety of mixed epithelial carcinomas) representative slide for the final study. Slides from all of the 662 cases were placed in random order, read by one of us ( OA) and assigned a detailed (two digit) WHO classification. Classification was based on the most differentiated part of the tumor regardless of the percentage of the tumor showing that degree of differentiation. The slides were then put into a diHerent random order and read a second time. When there was a discrepancy in the two readings, the slides were read once again for a final reading which was used for the study. In addition to a review of the protocols of each case, all the histologic slides (averaging about 40 per case) were reexamined for metastatic sites. The classification system used is shown in Table 1. It is the modification of the WHO system as used by Yesner and colleagues,3 with two subdivisions added in the class 4 category.
Year of Diagnosis
Table 3 shows the final major histologic classification for the entire study, especially by years of diagnosis. In this series epidermoid carcinoma comprised 35.2 percent of the cases, small cell carcinoma 24.6 percent, adenocarcinoma 25.2 percent, and large cell undifferentiated carcinoma 14.2 percent. Only five cases (0.8 percent) were of the mixed epidermoid and adenocarcinoma type. As for years of diagnosis, the cases were arbitrarily divided into four groups: 1955-1959, 1960-1964, 19651967, and 1968-1972. According to this sequence, the pattern appears to indicate a decrease in the proportion of small cell carcinoma (class 2); an increase in large cell undifferentiated (class 4) particularly in class 41, with giant cells. Not much consistency of
RESULTS
Consistency of Readings
Table 2 shows the final classification by detailed histologic type of each of the 662 cases crosstabulated by the classification at the other reading. It also Table
in T",o Reatliftlf. 01 CllU.i/ication of
2-Di~repaneie.
Final Classification Classification of Cell Type· Epidermoid Small Cell
11 12 13 21
Hi.tolo~e
Total Number
Classification at Other Reading 11 74
22
Adenocarcinoma 31 32 33 Large Cell 41 Undifferentiated 42 Mixed Types 5
12 3 53
13 4 91
21
22
137 3
1 4 19
31
32
33
41
42
5
6 115 13 1
2 34 31 1
16 46
3
Total
Type of Lung Cancer
Discrepancies No. %
Discrepant Outside of Major Class No. %
77 57 99 141 22 118 47 2 47 47 5
3 4 8 4 3 3 13 1 16 1 2
3.9 7.0 8.1 2.8 13.6 2.5 27.7 50.0 34.4 2.1 40.0
0 0 8 0 0 1 0 0 0 0 2
40.0
662
58
8.8
11
1.7
8.1 0.8
·When there was a discrepancy, a third reading was made for the final classification.
CHEST,
~7:
4, APRIL, 1975
TYPE OF LUNG CANCER IN RELATION TO SMOKING HABITS 383
Table 3-Di.tribution of Lun« Caneer Ca.eII by Hi.tolopc Type and Year of Diqno.i.
Cell Type
Classification
Epidermoid
11 12 13
Total-Class 1 Small Cell
21
22
Total-Class 2 Adenocarcinoma
31 32 33
Total-Class 3 Large Cell UndifJerentiated
41 42
Total-Class 4 Mixed Types-Class 5 Grand Total
1955-1957 No. %
YEAR OF DEATH 1960-1964 1965-1967 No. No. % %
19 11 14
12.0 6.9 8.8
21 12 28
12.4 7.1 16.5
24
25 29
12.3 12.8 14.9
13 9 28
9.4 6.5 20.3
77 57 99
11.6 8.6 15.0
44
27.7
61
35.9
78
40.0
50
36.2
233
35.2
43 5
27.0 3.1
36 8
21.2 4.7
38 5
19.5 2.6
24 4
17.4 2.9
141 22
21.3 3.3
48
30.2
44
25.9
43
22.1
28
20.3
163
24.6
32 15 1
20.1 9.4 0.6
28 11
16.5 6.5
30 15 1
15.4 7.7 0.5
28 6
20.3 4.4
118 47 2
17.8 7.1 0.3
48
30.2
39
22.9
46
23.6
34
24.6
167
25.2
11
6
3.8 6.9
10 14
5.9 8.2
12 15
6.2 7.7
19 7
13.8 5.1
47 47
7.1 7.1
17
10.7
24
14.1
27
13.8
26
18.8
94
14.2
2 159
1.2 100.0
2 170
1.2 100.0
1 195
0.5 100.0
138
100.0
5 662
0.8 100.0
pattern appears for epidennoid carcinomas or for adenocarcinomas. All the diHerences in year of diagnosis by major classification are rather small and are not statistically significant by the chi-square test. Age and Smoking Habits
Table 4 shows the percentage distribution for major histologic type by age groups at death: less than 55, 55 to 69, and 70 years and older. The proportion of cases with a diagnosis of epidermoid carcinoma increased with age and the adenocarcinomas tended to decrease with advancing age. Small cell carcinoma and large cell undifferentiated carcinoma showed no age trend. Table 5 shows the percentage distribution by cigarette smoking habits within the three age groups. There were only six subjects in the study who had never smoked and died of lung cancer; all of these had adenocarcinoma (class 3). Nineteen of the subjects were pipe and cigar smokers; and 26 Table 4--Percentage Di.tribution 0/ Major Hi.tolopc Type of Lung Cancer by A«e
Classification of Cell Type
Histologic Type of Lung Cancer in Relation to Smoking Habits, Year of Diagnosis and Sites of Metastases* Oscar Auerbach, M.D., F.C.C.P.,oo Lawrence Gar{inkel,t and VeTta R. Parkst
A study was made of histologic type of lung cancer in relation to smoking habit, year of diagnosis, age and sites of metastasis. It comprised 662 autopsies of men during the period from 1955 to 1972. As classified by the WHO system, 35.2 percent were epidermoid carcinoma, 24.6 percent were small cell carcinoma, 25.2 percent were adenocarcinoma and 14.2 percent were large cell undifferentiated carcinoma. The six non-smokers of the series were all found to be in class 3, adenocarcinoma. No clearcut and consistent relationships were observed. Although there was a steady decrease in the incidence of small cell
carcinoma during this time period, this observation did not prove to be statistically significant. Small cell carcinomas increased with amount of smoking but not for aU age groups. Adenocarcinomas decreased with advancing age but not in aD smoking groups. Metastases were found in 96.3 percent of the cases and the sites most frequently involved were regional lymph nodes, liver, brain, distant lymph nodes, adrena~ and bone. Small cell carcinomas showed the greatest percentage of involvement for those major sites and for the same sites, epidennoid carcinoma showed the lowest percentage.
There has been considerable interest in studying histologic types of lung cancer and their distribution in relation to clinical diagnosis, course of disease, and survival. As the proportion of lung cancers seen at autopsy increased over the last 30 years, the need for a system of classification of the histologic types became greater and various designs have been proposed. Pathologists have been particularly interested in determining if there is an association between histologic type and etiologic factors such as smoking, and if there is an association between histologic type and metastatic pattern. In 1962 Kreyberg! divided lung tumors between two major groups and published his findings using that system. In 1965 the WHO classification was published2 and has since been generally used. This is an elaboration
of Kreyberg's system and uses five major divisions with subgroupings in each. This study was undertaken for the following reasons: (1) the amount of tar and nicotine in cigarette smoke has changed considerably in the last 15 to 20 years, and it would be of interest to know whether there has been a concomitant change in the proportion of histologic types of lung cancer seen at autopsy during this period of time; (2) it would be of considerable interest to compare the distribution of smoking habits in relation to histologic type; and (3) it would be of interest to see if there is a relationship between the histologic type of lung cancer and the observed sites of metastases.
°From the Veterans Administration Hospital, East Orange, New Jersey and the Department of Epidemiology and Statistics, American Cancer Society, Inc., New York. o ° Senior Medical Investigator, VA Hospital, East Orange, New Jersey and Professor of Pathology, College of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark. tAssistant Vice President, Department of Epidemiology and Statistics, American Cancer Society, Inc., New York. tResearch .Biologist, Senior Medical Investigator Laboratory, VA HospItal, East Orange, New Jersey. Manuscript received June 27; accepted September 3. Reprint requests: Dr. Auerbach, VA Hospital, East Orange, New Jersey 07019
During the period from 1955 to 1972 at the Veterans Administration Hospital, East Orange, New Jersey, we collected autopsy specimens and smoking and residence histories for a series of studies relating smoking habits to histologic changes. The smoking histories were obtained by trained interviewers from the relatives of the deceased. Of the autopsies performed during this period of time, primary lung cancer was found to be the underlying cause of death in 1,093 cases. For this study, there were 662 cases with usable smoking and residence histories. All were of men. For each case, the detaned autopsy protocol and all of the microscopic lung slides were initially reviewed to select a
382 AUERBACH, GARFINKEL, PARKS
MATERIALS AND METHODS
CHEST, 67: 4, APRil, 1975
shows the number and percentage of discrepancies between the two readings which fall within the same major classification and the number and percentage of discrepancies between two readings which involved two separate classifications within the five major classifications. Of the eleven subclassifications shown in Table 1, completely consistent readings were made in 91.2 percent of the 662 pairs of readings (Table 2). As for the 58 pairs (8.8 percent) which were discrepant, in 47 the difference occurred within subgroupings of the same class-that is, for example, a reading of class 12 (moderately well differentiated epidermoid carcinoma) at the first reading, and class 13 (poorly differentiated epidermoid carcinoma) on the second reading. In the eleven discrepant pairs with differences that were between two of the five major classes, seven of them were 13:33 or 13:42 combinations, a discrepancy resulting from a dilemma common among pathologists in classifying these poorly differentiated tumor types.
Table I--ClaslJifieation 01 Hi.tologie Cell Type 01 Lung Caneer
Class 1. Epidermoid carcinomas 11 : Highly differentiated epidermoid 12 : Moderately differentiated epidermoid 13 : Poorly differentiated epidermoid Class 2. Small cell carcinomas 21 : Oval cell structure (Uoat cell" carcinoma) 22 : Polygonal cell structure Class 3. Adenocarcinomas 31 : Acinar carcinoma 32 : Papillary and/or bronchiolar carcinoma 33 : Poorly differentiated adenocarcinoma Class 4. Large cell undifferentiated carcinomas 41 : With giant cells 42 : Without giant cells Class 5. All mixed combined carcinomas (any variety of mixed epithelial carcinomas) representative slide for the final study. Slides from all of the 662 cases were placed in random order, read by one of us ( OA) and assigned a detailed (two digit) WHO classification. Classification was based on the most differentiated part of the tumor regardless of the percentage of the tumor showing that degree of differentiation. The slides were then put into a diHerent random order and read a second time. When there was a discrepancy in the two readings, the slides were read once again for a final reading which was used for the study. In addition to a review of the protocols of each case, all the histologic slides (averaging about 40 per case) were reexamined for metastatic sites. The classification system used is shown in Table 1. It is the modification of the WHO system as used by Yesner and colleagues,3 with two subdivisions added in the class 4 category.
Year of Diagnosis
Table 3 shows the final major histologic classification for the entire study, especially by years of diagnosis. In this series epidermoid carcinoma comprised 35.2 percent of the cases, small cell carcinoma 24.6 percent, adenocarcinoma 25.2 percent, and large cell undifferentiated carcinoma 14.2 percent. Only five cases (0.8 percent) were of the mixed epidermoid and adenocarcinoma type. As for years of diagnosis, the cases were arbitrarily divided into four groups: 1955-1959, 1960-1964, 19651967, and 1968-1972. According to this sequence, the pattern appears to indicate a decrease in the proportion of small cell carcinoma (class 2); an increase in large cell undifferentiated (class 4) particularly in class 41, with giant cells. Not much consistency of
RESULTS
Consistency of Readings
Table 2 shows the final classification by detailed histologic type of each of the 662 cases crosstabulated by the classification at the other reading. It also Table
in T",o Reatliftlf. 01 CllU.i/ication of
2-Di~repaneie.
Final Classification Classification of Cell Type· Epidermoid Small Cell
11 12 13 21
Hi.tolo~e
Total Number
Classification at Other Reading 11 74
22
Adenocarcinoma 31 32 33 Large Cell 41 Undifferentiated 42 Mixed Types 5
12 3 53
13 4 91
21
22
137 3
1 4 19
31
32
33
41
42
5
6 115 13 1
2 34 31 1
16 46
3
Total
Type of Lung Cancer
Discrepancies No. %
Discrepant Outside of Major Class No. %
77 57 99 141 22 118 47 2 47 47 5
3 4 8 4 3 3 13 1 16 1 2
3.9 7.0 8.1 2.8 13.6 2.5 27.7 50.0 34.4 2.1 40.0
0 0 8 0 0 1 0 0 0 0 2
40.0
662
58
8.8
11
1.7
8.1 0.8
·When there was a discrepancy, a third reading was made for the final classification.
CHEST,
~7:
4, APRIL, 1975
TYPE OF LUNG CANCER IN RELATION TO SMOKING HABITS 383
Table 3-Di.tribution of Lun« Caneer Ca.eII by Hi.tolopc Type and Year of Diqno.i.
Cell Type
Classification
Epidermoid
11 12 13
Total-Class 1 Small Cell
21
22
Total-Class 2 Adenocarcinoma
31 32 33
Total-Class 3 Large Cell UndifJerentiated
41 42
Total-Class 4 Mixed Types-Class 5 Grand Total
1955-1957 No. %
YEAR OF DEATH 1960-1964 1965-1967 No. No. % %
19 11 14
12.0 6.9 8.8
21 12 28
12.4 7.1 16.5
24
25 29
12.3 12.8 14.9
13 9 28
9.4 6.5 20.3
77 57 99
11.6 8.6 15.0
44
27.7
61
35.9
78
40.0
50
36.2
233
35.2
43 5
27.0 3.1
36 8
21.2 4.7
38 5
19.5 2.6
24 4
17.4 2.9
141 22
21.3 3.3
48
30.2
44
25.9
43
22.1
28
20.3
163
24.6
32 15 1
20.1 9.4 0.6
28 11
16.5 6.5
30 15 1
15.4 7.7 0.5
28 6
20.3 4.4
118 47 2
17.8 7.1 0.3
48
30.2
39
22.9
46
23.6
34
24.6
167
25.2
11
6
3.8 6.9
10 14
5.9 8.2
12 15
6.2 7.7
19 7
13.8 5.1
47 47
7.1 7.1
17
10.7
24
14.1
27
13.8
26
18.8
94
14.2
2 159
1.2 100.0
2 170
1.2 100.0
1 195
0.5 100.0
138
100.0
5 662
0.8 100.0
pattern appears for epidennoid carcinomas or for adenocarcinomas. All the diHerences in year of diagnosis by major classification are rather small and are not statistically significant by the chi-square test. Age and Smoking Habits
Table 4 shows the percentage distribution for major histologic type by age groups at death: less than 55, 55 to 69, and 70 years and older. The proportion of cases with a diagnosis of epidermoid carcinoma increased with age and the adenocarcinomas tended to decrease with advancing age. Small cell carcinoma and large cell undifferentiated carcinoma showed no age trend. Table 5 shows the percentage distribution by cigarette smoking habits within the three age groups. There were only six subjects in the study who had never smoked and died of lung cancer; all of these had adenocarcinoma (class 3). Nineteen of the subjects were pipe and cigar smokers; and 26 Table 4--Percentage Di.tribution 0/ Major Hi.tolopc Type of Lung Cancer by A«e
Classification of Cell Type
