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Cancer of the lung in young men
Cancer of the lung in young men A series of 102 young male patients with lung cancer were investigated, ages 12 to 45 years. The patients were subdivided into those younger than 40 years of age and those between 40 and 45 years of age. No essential differences were found to exist between the two groups in such parameters as occupation, smoking history, tumor type or size, lymph node involvement, operability, or resectability. It was concluded that the prognosis for young men with this disease is no worse than that for lung cancer patients in general.
Michael Kyriakos, M.D., * and Bruce Webber, M.B.B.Ch. (Rand.), F.F.Path. (S.A.),** St. Louis, Mo.
Cancer of the lung remains the most common malignancy in men, with the peak incidence occurring between 50 and 70 years of age. That the disease also affects young men is well known to thoracic surgeons, but unfortunately there have been few reports dealing specifically with this problem. Most of the large published series on lung cancer contain only an age distribution for their patients without further analysis, while those reports which have specifically dealt with young people have involved relatively few patients. The prevalent view among thoracic surgeons is that, while the younger individual is a better operative risk and can withstand more radical surgery, his prognosis is worse than that for the older patient. We wished to determine whether this conclusion was valid, and we were also interested as to whether their smoking and occupational histories differed from those reported for all patients with lung cancer. In this study, we have arbitrarily chosen the age 45 years as the limit for inclusion, From the Department of Pathology, Division of Surgical Pathology, Barnes Hospital, Washington University School of Medicine, St. Louis, Mo. 63110. Received for publication Jan. 3, 1974. • Associate Professor, Division of Surgical Pathology. • • Resident Fellow, Division of Surgical Pathology. Present address: Department of Pathology. University of Cape Town Medical School, Observatory 7900, C.P., Republic of South Africa.
634
since, relative to the usual patient with lung cancer, this age is indeed "young." However, when necessary, we have separately reported our data for those patients under 40 years so that our results can be compared with reports which have used only patients in this age category. Materials and methods The files of the Division of Surgical Pathology and Cytology, Barnes Hospital, St. Louis, Missouri, were searched, and all reports and histologic material on pulmonary tumors occurring in men 45 years of age or less were obtained for the years 1950 to 1970. Only patients who had a histologic diagnosis of cancer were included in this study. Sixty-one patients were seen during the years 1950 to 1959 and 41 in the years 1960 to 1970, for a total of 102 patients. Hematoxylin and eosin sections of the tumors were reviewed independently by both of us without reference to the original diagnosis. Special stains for mucin or argentaffin reactivity were used when needed. When we could not agree on the histologic classification, the case was referred to Dr. Lauren Ackerman for final determination. Clinical records were reviewed on all patients to obtain necessary clinical and social information. When required, the patient, surviving relative, or personal physician was contacted by mail or telephone for in-
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Cancer of lung in young men
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18 16 Vl
14
I-
Z w
...>=« u..
0
0<
w
""
12 10 8
:E :::J
Z
6 4 2 12
16
20
24
28
32
36
40
44
AGE (YEARS)
Fig.!. Age distribution of young men with lung cancer at Barnes Hospital (1950 to 1970).
formation missing from the records and for follow-up data. No patient was lost to follow-up in this series. In the statistical analysis of the results, whenever the data were considered measurable on a continuous scale, e.g., duration of smoking, survival time, and so on, a Rank-Sum test was used. When a grouping interval was measured, e.g., resectability, operability, and so on, the chi-square test was used. Results Age and race. The mean age for the entire series, consisting of 68 patients between the ages of 40 and 45 years and 34 patients less than 40 years old, was 39.7 years, with a median of 41 years. The mean for patients between ages 40 and 45 was 42.9 years, while for those below age 40 it was 33.3 years, the youngest being 12 years old (Fig. 1). There were 91 Caucasian and 11 Negro patients. Symptoms. Only 2 patients were totally asymptomatic: A pulmonary lesion was found on a routine chest roentgenogram in 1 patient; in the other, hemoptysis, which began immediately following a fall, necessitated a chest roentgenogram, which demonstrated a pulmonary lesion.
In the remaining patients multiple symptoms were present at the time of diagnosis, with weight loss, cough, chest, shoulder, and back pain, hemoptysis, weakness, fatigue, and dyspnea being commonest (Table I). Weight loss, the commonest symptom, was often striking. Sixty-nine patients had lost weight, with the amount lost known in 67. The mean loss was 22 pounds (range 3 to 60 pounds), with 91 per cent having lost 10 or more pounds and 55 per cent having lost 20 or more pounds. The duration of symptoms ranged from 2 weeks to 156 months, with a mean of 10.8 and a median of 6 months. Twenty-six patients had symptoms for over 1 year; 13 of them had symptoms for 2 years or longer, with several having episodes of recurrent pneumonia or hemoptysis for many years. In 1 case, that of a 13-year-old boy with a carcinoid tumor, there had been episodes of hemoptysis, wheezing, and chronic cough since the age of 1 year. A chest roentgenogram taken a year before admission showed a "spot" on the lung which gradually increased in size until at operation it measured 5 em. Smoking history. Ninety-six patients (94.1 per cent) had a history of smoking, while 6 did not smoke. Cigarettes alone were smoked
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Table I. Symptoms at time of diagnosis in young men with lung cancer Per cent with symptom
Symptom Weight loss Cough Chest/shoulder pain Hemoptysis Weakness/fatigue Dyspnea Fever Headache Clubbing Recurrent pulmonary infections Hoarseness Central nervous system disturbance Miscellaneous* Asymptomatic
67.6 57.8 52.9 39.2 24.5 23.5 19.6 7.8 5.9 5.9 5.9 4.9 22.0 2.0
'Wheezing, neck swelling, joint pain, pruritis, dysphagia, jaw pain, night sweats, epistaxis, leg swelling, hematemesis, and increased sputum production.
Table II. Occupations in young men with lung cancer Occupation
Age group < 40 years* Office worker Factory worker Laborer Engineer Salesman Age group 40 to 45 yearsi' Factory worker Laborer Office worker Construction trades Truck driver Mechanic Salesman Engineer Farmer Bartender
No. of patients 7 4 4 3 2 10 8
5 5 5 4 4
2 2 2
• Single examples each for construction trades, coal miner, butcher, farmer, railroad brakeman, grocer, teacher, truck
driver, laboratory technician, and filling station attendant. Mixed occupations: farmer and factory worker; farmer, factory, and garage work. tSingle examples each for coal miner, railroad worker, teacher, merchandise buyer, garage owner, chemist, mortician, electrical worker, surgeon, baliff, fireman, and tractor driver. Mixed occupations: farmer and truck driver; farmer and postal clerk; farmer, machinist, and construction work; farmer, factory, and welder; railroad brakeman and salesman; and chaffeur and salesman. Two patients were mechanics and painters. The occupation of 1 patient was
unknown.
by 89 patients, cigarettes and pipes were reported by 2, cigarettes and cigars by 4, and only cigars and pipe by 1 patient. Hence 95 of the 96 patients had smoked cigarettes. In 9 1 of these the number of cigarettes consumed in packs per day (ppd) was known, the mean being 1.6 ppd. In 27 patients under the age of 40 years the mean was 1.5 ppd; for those ages 40 to 45 years, the mean was 1.7 ppd. The duration of smoking was known for 82 patients: It was less than 20 years in 15 patients; 20 to 24 years in 25; 25 to 29 years in 26; 30 to 34 years in 13; and over 35 years in 3 patients. The mean duration was 23.1 years, with those under age 40 having a mean of 19.9 years and those between 40 and 45 having a mean of 24.5 years. The average age at which the patients started smoking was 17.7 years; those under age 40 started at a mean age of 16.5 years, while those in the 40 to 45 year age bracket began at a mean age of 18.2 years. Fiftyfour patients began smoking before the age of 20 years, 26 began between the ages 20 and 29, and only 2 began after age 30. There was no statistically significant difference between the two age groups in terms of the number of cigarettes smoked per day or the age at which smoking began. As expected, patients between ages 40 and 45 had smoked for a statistically longer time than those under age 40 (p < 0.001). The ages and tumor types in the 6 patients who did not smoke were as follows: age 12, large cell undifferentiated carcinoma; age 13, carcinoid; age 20, small cell undifferentiated carcinoma; age 23, histiocytic lymphoma; age 29, adenocarcinoma; and age 33, carcinoid. Occupation. Patient occupation is shown in Table II. In 1 patient the occupation was unknown, and 2 children had never been employed. In only 10 patients was there a history of more than one job prior to diagnosis. The occupation was primarily outdoor in nature in 34 patients and indoor in 58. Seven patients gave a mixed history, having had both indoor and outdoor occupations sometime in their lives. In 23 patients the
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occupations involved some contact with fumes or dusts, but this is a minimal figure since extensive information on such exposure was not available in the charts. No major differences between job occupation or exposure to fumes and dusts were present in the two age divisions. Bronchoscopy. The results of bronchoscopic examination were known for 94 patients. Four of the 34 patients under the age of 40 years did not have bronchoscopy, and the result is unknown in 1 patient. Twelve of the 29 remaining patients had a positive biopsy, while in 3, tumor was seen but the biopsy was negative, and in 2, the tumor was not biopsied. Hence 58.6 per cent (17/29) had visual or histologic evidence of tumor. Of the 68 patients between 40 and 45 years old, 1 did not have bronchoscopy and the results are unknown in two. Twenty-nine had a positive biopsy, while in 4, tumor was seen but the biopsy was negative, and in 2, the tumor was not biopsied. In this group, 53.8 per cent (35/65) had visual or histologic evidence of tumor. The differences in the two age divisions were not statistically significant. Cytology. Pulmonary cytology specimens were submitted in 82 patients: The results were positive in 29 (35.4 per cent) and suspicious for carcinoma in 11 (13.4 per cent). Of 24 patients under the age of 40 years, 8 had positive cytologies and 3 had cytologies suspicious for carcinoma. There were 21 patients with positive and 8 with suspicious cytologies among 58 patients ages 40 to 45. However, of the total of 82 patients, only 39 had what is considered an adequate cytologic work-up prior to definitive histologic diagnosis, that is, a minimum of three sputum samples and a single bronchial washing. Of these patients, 29 had positive (74.4 per cent) and 3 had suspicious cytologies (7.7 per cent). Hence 82.1 per cent (32/39) of patients with an adequate cytologic work-up had positive or suspicious diagnoses for carcinoma. Therapy. Seventy-eight patients underwent thoracotomy (76.5 per cent). Sixty of these had resections, 58 of which were con-
sidered curative. These curative resections represent 56.9 per cent of the entire series and 74.4 per cent of the exploratory operations. Of the 34 patients under age 40, 28 underwent exploration and 22 had resections; a pneumonectomy was done in 12 and a lobectomy in 10, one of which was palliative. Fifty of the 68 patients between ages 40 and 45 had an exploratory operation, with 38 having resections; a pneumonectomy was done in 30, a lobectomy in 7, and a palliative wedge resection in 1 patient. No statistically significant differences were found between the two major age divisions in terms of total operability or curative resectability or in terms of the curative resectability rate in those who were operable. In the remaining patients the histologic diagnosis was established by bronchoscopic biopsy or exploratory thoracotomy with biopsy in 39, needle biopsy of the lung or chest wall in 2, and a small open biopsy of the lung in 1 patient. Forty-nine patients at some time in their course received external radiation therapy or chemotherapy. In a group of 16 patients who had had pulmonary resections, 10 received only radiation therapy, 4 radiation therapy combined with chemotherapy, and 2 only chemotherapy. In only 1 of these patients was the radiation therapy given preoperatively. Sixteen additional patients had an exploratory thoracotomy without resection, 10 of whom received only postoperative radiation, 5 combined radiation and chemotherapy, and 1 patient only chemotherapy. In a final group of 17 patients who did not have an operation, 11 received only radiation therapy, 5 had combined radiation and chemotherapy, and 1 had only chemotherapy. Nitrogen mustard was the chemotherapy employed in all but 1 of the above patients, who received a combination of hydrourea, vincristine, and methotrexate. With the exception of those patients for whom it was the only method of treatment, and the single patient who received preoperative radiation, the radiation therapy was used to treat
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Thoracic and Cardiovascular Surgery
Table III. Distribution of tumor type by age group Small cell Age (yr.)
10-14 15-19 20-24 25-29 30-34 35-39 40-45 Totals
Epidermoid Adenocarcinoma carcinoma
0 0 0 0 0 5 20 25
0 0 0 1 2 6 16 25
undiff.
carcinoma
0 1 1 0 1 4 16 23
I
Large cell Bronchoundif], alveolar carcinoma Carcinoid carcinoma
1 0 0 0 0 4 7
12
'Includes histiocytic lymphoma, adenoid cystic carcinoma, let. tIFC, Insufficient tumor for classification of cell type.
recurrent tumor within the chest or sites of distant metastases. Pathology. Sufficient material for tumor classification was available in 96 cases. In the remaining 6 cases, material had been obtained by bronchial biopsy or closed needle biopsy of the lung, and, while sufficient to indicate malignancy, it was not adequate for accurate classification by cell type. In the 96 cases, the distribution by tumor type was as follows: epidermoid carcinoma 26 per cent (25 cases); adenocarcinoma 26 per cent (25 cases); small cell undifferentiated (oat cell) carcinoma 24 per cent (23 cases); large cell undifferentiated carcinoma 12.5 per cent (12 cases); bronchoalveolar carcinoma, 2.1 per cent (2 cases); and carcinoid tumor 4.2 per cent (4 cases). A miscellaneous category of 5 tumors made up 5.2 per cent of cases and contained single examples of adenoid cystic carcinoma, giant cell carcinoma, primary histiocytic lymphoma, an unclassified malignant tumor, and a "tumorlet." The epidermoid and adenocarcinomas were further evaluated as to their differentiation. There were 5 weU-differentiated, 12 moderately differentiated, and 8 poorly differentiated epidermoid carcinomas, as well as 3 well-differentiated, 4 moderately differentiated, and 18 poorly differentiated adenocarcinomas. Hence approximately 64 per
1 0 0 1 1 1 0 4
0 0 0 0 1 0 1 2
Other*
IFCt
Totals
0 0 1 0 0 1 3 5
0 0 0 0 1 0 5 6
2 1 2 2 6 21 68 102
giant cell carcinoma, unclassified malignant tumor, and tumor-
cent (61/96) of the classifiable tumors were either poorly differentiated carcinomas or undifferentiated tumors. Table III shows the age distribution and the associated tumor type. There were 33 classifiable tumors in patients below age 40 years. Epidermoid carcinoma made up 15.2 per cent (5 cases); adenocarcinoma 27.3 per cent (9 cases); small cell undifferentiated (oat cell) carcinoma 21.2 per cent (7 cases); large cell undifferentiated carcinoma 15.2 per cent (5 cases); and carcinoid tumor 12.1 per cent (4 cases). There was one example each of histiocytic lymphoma, tumorlet, and bronchoalveolar carcinoma. Statistical analysis showed no significant differences in the per cent distribution of tumor types in patients below age 40 years versus those between 40 and 45 years of age. In addition, the percentage of epidermoid carcinomas in these age groups was not statistically different. The age of the youngest patient in each tumor category was as follows: epidermoid, 35 years; adenocarcinoma, 29 years; small cell undifferentiated, 18 years; large cell undifferentiated, 12 years; carcinoid, 13 years; bronchoalveolar, 32 years; lymphoma, 23 years; adenoid cystic carcinoma, 43 years; giant cell carcinoma, 41 years; and tumorlet, 38 years. The youngest patient to have one of the 6 unclassified tumors was 34 years.
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Table IV. Cumulative survival in men age 45 years or less with lung cancer
Time from diagnosis (yr.)
Alive at beginning of interval
Died during interval
Lost to follow-up during interval
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-15 15-20 20-22
102 38 24 18 17 17 15 13 12 12 12 9 2
63 14 5 0 0 1 2 1 0 0 2 2 0
0 0 0 0 0 0 0 0 0 0 0 0 0
Tumor involved the right lung in 62, the left lung in 35, and both sides by carinal or hilar extension in 5 cases. The right upper lobe was involved alone or in combination with other lobes in 39 cases, while the left upper lobe was involved in 17. The mainstem bronchi contained tumor in 20 cases. Carina 1 involvement was seen in 4 patients, while in 3 others tumor extended to the trachea. Excluding a microscopic tumorlet, dimensions of the resected tumors were available in 53 patients and ranged from 1.0 to 15.0 em., with a mean of 4.9 em. The distribution of tumor size and the number of patients in each category for those younger than 40 years was as follows: zero to 1.9 em., 2; 2.0 to 2.9 em., 3; 3.0 to 3.9 em., 1; 4.0 to 4.9 em., 4; 5.0 to 5.9 em., 2; 6.0 to 6.9 em., 3; and> 7.0 em., 4. The mean size was 5.1 em. The distribution for those 40 to 45 years of age was as follows: zero to 1.9 em., 3; 2.0 to 2.9 em., 4; 3.0 to 3.9 em., 5; 4.0 to 4.9 em., 4; 5.0 to 5.9 em., 8; 6.0 to 6.9 em., 4; and> 7.0 em., 6. The mean size was 4.8 em. No statistically significant difference in tumor size was found in the two age groups. In 59 cases, lymph nodes were excised during resection or exploratory thoracotomy, the average number of nodes examined per
Withdrawn alive during interval 1 0 1 1 0 1 0 0 0 0 1 5 2
No. exposed to risk of dying 101.5 38.0 23.5 17.5 17.0 16.5 15.0 13.0 12.0 12.0 11.5
6.5 1.0
Propor-
Propor-
tion dying
tion surviving
Cumulative survival
0.621 0.368 0.213 0.000 0.000 0.061 0.133 0.077 0.000 0.000 0.174 0.308 0.000
0.379 0.632 0.787 1.000 1.000 0.939 0.867 0.923 1.000 1.000 0.826 0.692 1.000
0.379 0.240 0.189 0.189 0.189 0.177 0.153 0.141 0.141 0.141 0.116 0.082 0.082
case being 16. Positive nodes were present in 55 per cent (22/40) of patients age 40 to 45 years, and 36.8 per cent (7/19) in those under age 40 years. These differences were not statistically significant. Information as to pleural involvement by tumor was available in 73 patients, with 22 of 46 patients between age 40 and 45 (47.8 per cent) and 13 of 27 less than 40 years (48.1 per cent) having tumor in the pleura. Survival. In the total series, 99 patients were eligible for 5 year analysis, 32 below age 40 years and 67 between ages 40 and 45 years. In the former group there were 6 survivors (18.8 per cent), while in the latter there were 11 survivors (16.4 per cent), for a total 5 year survival of 17.2 per cent (17/99). If the 4 carcinoid tumors, the lymphoma, and the tumorlet, all of which occurred in those under 40 years, are eliminated from consideration, the 5 year survival in this age group was 11.1 per cent (3/27), and the total 5 year survival for all patients was 14.9 per cent (14/94). These 6 cases, which are not usually considered in the statistics from other institutions, will henceforth be referred to as "special" cases. In those eligible, there were no statistically significant differences in the 5 year survival rate between the two age groups with or without consideration of these special cases.
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Table V. Five-year survivors among young men with lung cancer (1950 to 1970) Case No. 1 2 3
Occupation
Smoking history
Tumor
Mechanic-painter Bartender Accountant
2 ppd x 30 yr. 2 ppd x 20 yr. 1.5 ppd x 10 yr.
Large cell undiff. Epidermoid well-diff. Carcinoid
RUL LUL RML
Epidermoid mod.-diff. Epidermoid poorly diff.
RUL LUL
Carcinoid
LLL
Location
4 5
45 45
Pottery maker Toolmaker
6
33
Office worker
2 ppd x 28 yr. 1.5 ppd x 25 yr.; cigars, 4/day None
7
36
Purchasing agent
1.5 ppd x 20 yr.
Epidermoid weJl-diff.
RLL
8 9 10
33 38 41
Accountant Grocer J ustice of peace
3 ppd x 20 yr. 2 ppd x 16 yr. 1.5 ppd x 29 yr.
Adenocarcinoma poorly diff. Tumorlet Epidermoid mod.-diff.
RLL RML, RLL LUL
11 12 13 14
45 43 45 41
Salesman Pipefitter Tar roofing worker Office worker
3 ppd x 30 yr. 1.5 ppd x 35 yr. I ppd x ? 3 ppd x 32 yr.
Epidermoid poorly diff. Adenocarcinoma poorly diff. Large cell undiff. Epidermoid well-diff.
RUL, RLL RUL, RML LUL RUL, RML
15
40
Clerk
I ppd x 25 yr.
Adenocarcinoma poorly diff.
RUL
16
39
Metal sander
1.5 ppd x 27 yr.
Large cell undiff.
LUL
17
41
Clerk
Bronchoalveolar
RUL
1 pkg.zwk. x ?
Legend: LN, Lymph nodes. ppd, Cigarette packs per day. RUL, Right upper lobe. LUL, Left upper lobe. RML, Right middle lobe. heart disease.
According to the life-table method, G. " which has the advantage of using all patients for the calculation of survival, the cumulative 5 year survival rate was 17.7 per cent and the 10 year survival rate was I 1.6 per cent (Table IV). If the special cases are eliminated from consideration, the cumulative survival rate at 5 years was 15.4 per cent and at 10 years 8.8 per cent. At the conclusion of the study, there were 12 patients still living free of tumor from 5 months to 22 years after operation. Nine had survived for over 5 years, and 3 others were alive 5, 28, and 48 months after operation. In addition, 8 other patients had survived for more than 5 years but had eventually died. Two of these deaths were attributable to recurrence of the original tumor, with death occurring 73 and 124 months after operation. The remaining
6 patients died of other causes (Table V). With the exception of 3 cases, all other deaths in this series were due to confirmed recurrent or metastatic tumor from the original primary lesion. The three exceptions include 1 patient, age 40 years, who died in an automobile accident 34 months after operation for epidermoid carcinoma; another patient, age 44 years, died of a pulmonary embolus and acute heart failure following hospitalization for codeine addiction 24 months after operation for adenocarcinoma; a final patient, age 13 years, died of pneumonia 7 months after resection of a carcinoid tumor. In none of these 3 was there any clinical evidence of recurrent tumor, but in none was a postmortem examination done. The mean survival for those who died of their tumor was 10.3 months, with a
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L.N,:
Pos.Ztotal
Pleura involved
Operation
Tumor size
Clinical status
Survival time
Alive and well Alive and well Alive and well
12 yr., 7 mo. 17 yr., 8 mo. 18 yr., 2 mo.
Alive and well Alive and well
22 yr. 21 yr., 5 mo.
bx
Alive and well
16 yr., 4 mo.
bx
Alive and well
19 yr., 3 mo.
bx
Alive and well Alive and well Dead, tumor
6 yr. 16 yr., 6 mo. 6 yr., 1 mo.
Dead, tumor Dead, CHF Dead, ASHD Dead, pulmonary insufficiency Dead, Parkinson's disease Dead, carcinoma of opposite lung Dead, cirrhosis
10 yr., 2 mo. 20 yr. 5 yr., 3 mo. 7 yr., 10 mo.
Bronchoscopy
7/25 0/3
? Yes No
Pneumonectomy Pneumonectomy Lobectomy
8.0 em. 5.0 em. 1.4 em.
Negative Negative Tumor seen, no bx Negative ?
0/19 0/18
No ?
Pneumonectomy Pneumonectomy
1.0 em. 4.5 em.
0/2
No
Lobectomy
3.7 em.
0/22
No
Pneumonectomy
6.0 em.
1/19 0/8 3/15
Yes No No
Pneumonectomy Bilobectomy Pneumonectomy
2.1 em. Microscopic 5.0 em.
0/24 1/16 0/20 2/17
Yes No Yes Yes
Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy
? 2.0 em. 8.0 em. "Large"
0/21
Yes
Pneumonectomy
5.0 em.
Negative
6/17
Yes
Pneumonectomy
6.0 em.
Tumor seen, bx neg.
0/3
No
Lobectomy
3.0 em.
Negative
Tumor seen, pos. Tumor seen, pos. Negative ? Tumor seen, pos. Negative Negative Negative Tumor seen, pos.
bx
14 yr. 15 yr., 3 mo. 6 yr., 9 mo.
LLL, Left lower lobe. RLL, Right lower lobe. bx, Biopsy. pos., Positive. CHF, Congestive heart failure. ASHD, Arteriosclerotic
mean of 14.8 months for patients who had resection versus 6.1 months for those not resected. Fifty-five patients who had curative resections were eligible for 5 year analysis. Six of 19 (31.6 per cent) patients under age 40 survived, while 11 of 36 (30.6 per cent) ages 40 to 45 years survived, for an over-all survival rate of 30.9 per cent (17/55). Excluding the special cases, the 5 year survival in those under age 40 years was 20 per cent (3/15), and the over-all 5 year survival rate was 27.5 per cent (14/51). The differences in 5 year survival between the two age groups having curative resections, with or without consideration of the special cases, were not statistically significant. Thirteen of 40 pneumonectomy patients eligible for 5 year analysis survived (32.5
per cent), while 4 of 15 lobectomy patients survived (26.7 per cent). The single wedge resection patient did not survive. The mean length of survival by cell type from the time of diagnosis in those patients dead of tumor, or its consequences, was as follows for the larger tumor categories: epidermoid carcinoma, 18.7 months (median 7 months); small cell undifferentiated carcinoma, 7.8 months (median 4 months); adenocarcinoma, 12.2 months (median 10 months); and large cell undifferentiated carcinoma, 7.3 months (median 3 months). Seven of the 25 patients with epidermoid carcinoma survived 5 years or longer, and another is alive and well 28 months postoperatively. Two of these survivors, however, later died of recurrence of their tumor at 73 and 122 months. Three of 25 patients with adenocarcinoma survived longer than
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5 years, and another is alive and well 4 years after operation. Three of 12 patients with large cell undifferentiated tumor survived over 5 years. Of the 4 patients with carcinoid tumors, 2 survived longer than 5 years and 1 is alive and well 5 months after operation. One 5 year survivor had bronchoalveolar carcinoma and another had a tumorlet. None of the 23 patients with small cell undifferentiated carcinoma survived 5 years. In the 59 patients in whom the status of the lymph nodes was known, 56 were eligible for 5 year analysis. In those younger than 40 years of age, 3 of 10 (30 per cent) with negative nodes and 2 of 7 (28.6 per cent) with positive nodes survived. In those ages 40 to 45 years, 7 of 17 (41.2 per cent) with negative nodes and 4 of 22 (18.2 per cent) with positive nodes survived. The 3 patients alive less than 5 years all had negative nodes. Of the 73 patients in whom information regarding pleural involvement was known, 70 were eligible for 5 year analysis and 50 per cent had pleural involvement. In patients under 40 years of age, 2 of 13 with and 4 of 12 without pleural involvement survived. In the 40 to 45 year age group, 5 of 22 patients with and 4 of 23 without involvement survived. None of the patients alive less than 5 years had pleural involvement. No relationship between survival and tumor size was found, with some survivors having had lesions as large as 8 em. While 5 of 6 patients with lesions smaller than 2 em. were either long-term survivors or are presently living, 2 of these had carcinoid tumors, and 1 had a microscopic tumorlet. The nonsurvivor in the group, who died in 2 months, had a 1.5 em, small cell undifferentiated carcinoma. The average size of lesions in the long-term survivors was 4.3 em. Only 2 of 49 patients who received radiation or chemotherapy survived 5 years. One is alive and well 12 years, 7 months postoperatively, and he had received a single dose of 11.7 mg. of nitrogen mustard at the time of operation. The other patient sur-
Thoracic and Cardiovascular Surgery
vived 5 years, 3 months before dying of arteriosclerotic heart disease. He had received postoperative radiation therapy of 4,324 rads to the mediastinum because of invasion found at the time of pneumonectomy. Discussion
The peak age for cancer of the lung usually occurs between the sixth and seventh decades of Iife.": 12, 27, 29, 34 In a previous report on 1,008 lung cancer patients from our institution, 81 per cent were between 50 and 89 years of age.' In a British study of 629 cases, 75 per cent were between 50 and 70 years of age." The per cent of patients who fall within what has been considered a "young" group, i.e., less than 40 years of age, has varied from 1.7 to 6.1 per cent." B, 24. 3:J In a report by Belcher and Anderson" of 1,134 male and female patients, 1.8 per cent were less than 40 years old and 8.1 per cent were less than 45 years of age. In our institution, 2 per cent of the patients were less than 40 years old." There have been few reported cases of lung cancer in patients less than 20 years of age. At the Mayo Clinic from 1943 to 1954, the youngest patient was 24 years," while in the period 1955 to 1970, at the Sheffield Royal Infirmary, England, the youngest was 21 years." Anderson 1 reviewed the literature in 1954 and found 16 cases of pulmonary cancer in children which were histologically confirmed, with the youngest boy being 5 years old. Hanbury," in 1958, added 2 cases in children and found 60 in the literature, 34 of which were not adequately described. Large and Morgan" reported on 2 patients, ages 18 and 19 years. Iverson and Straehley'" described a pulmonary blastoma in an l1-year-old boy and, in a review, found a case with metastasis and death in a 15-month-old girl. Relative to the usual patients with lung cancer, our patients are "young" with an average age of 39.7 years. To our knowledge there have been only six publications, other than isolated case reports, dealing
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April, 1974
with this problem in patients younger than 40 years of age, and only two of the reports have dealt solely with male patients.': i s. 20, N, 20, 30 Of the 184 male subjects reported upon in these six papers, the youngest was 20 years old (Table V). Throughout these reports a common finding has been the low incidence of epidermoid carcinoma and the relatively high occurrence of small cell undifferentiated carcinoma or anaplastic tumors. The per cent distribution for the major histologic subtypes of tumors in a review of several large reported series of lung cancers in patients of all ages was as follows: epidermoid carcinoma, 34 to 61 per cent; adenocarcinoma, 9 to 22 per cent; and small cell undifferentiated carcinoma, 2 to 38 per cent. In addition, an undefined category of "undifferentiated" has accounted for 9 to 34 per cent of the tumors.>v 12, D, 24, 20, 28, 3:1 At Barnes Hospital, 60 per cent of lung tumors in men have been classified as epidermoid, 9 per cent as adenocarcinoma, 13 per cent as small cell undifferentiated carcinoma, 2 per cent as bronchiolar carcinoma, 9 per cent as undifferentiated, and 7 per cent as unclassified.' Some of the reports on young patients have failed to separate small cell undifferentiated carcinoma from other anaplastic and undifferentiated tumors, which makes accurate comparisons between series difficult. Our results do show a lower incidence of epidermoid carcinoma and a higher incidence of small cell undifferentiated carcinoma and adenocarcinoma than found in older patients. Even if one excludes from the per cent calculations the 4 cases of carcinoid tumor, and the single examples of lymphoma and tumorlet, all of which occurred in patients under the age of 40 years, the per cent distribution figures do not change significantly for the remaining patients in this age bracket; that is, there are no significant differences between the distribution of cell types for those under age 40 years and those 40 to 45 years old. This distribution of cell types in younger individuals could indicate one of two possibilities: (l) The necessary inciting stimu-
Ius for the transformation of the respiratory mucosa to epidermoid carcinoma must act over a longer time span to be effective; (2) the cells which produce adenocarcinomas and the undifferentiated tumors are more susceptible and hence these develop earlier than the epidermoid tumors. On the other hand, there may certainly be more than one factor involved in the production of cancer in the younger patient. Environmental exposure to other agents may, in concert with such factors as smoking, predispose to an earlier development of cancer. In addition, there may be genetic factors which of themselves might be responsible in part or whole for these tumors. We feel that every young patient with lung cancer should have a full and careful epidemiologic investigation into his family and medical histories, exposure to drugs, occupational history, and so on. The recent findings relating to vaginal carcinoma in women whose mothers had taken stilbestrol during pregnancy should serve as a model as to what might be found if such investigations were carried out. Regardless of age, lung cancer is still discovered as a symptomatic disease, as emphasized by the fact that only 2 per cent of patients in our series were asymptomatic. This is not very different from data reported for older patients with lung cancer, as Eastridge," in a series of 1,284 patients, reported that 5 per cent were asymptomatic, and Ochsner" found only 0.3 per cent who were asymptomatic among 948 lung cancer patients. In young patients, the per cent of asymptomatic cases has varied from zero to 23 per cent.': 18, N. 26. 30 The dominant presenting symptoms in these latter series has varied and differs somewhat from ours, with chest and shoulder pain being the major symptoms in some studies": 2fl and hemoptysis being an uncommon symptom in other reports.': :10 Only 8 per cent of the patients reported by Hood and colleagues" had symptomatic weight loss. In our series, two thirds of the patients had weight loss and almost 40 per cent had hemoptysis. We do not believe that the symptomatology in young patients differs significantly from that
644
The Journol of Thoracic and Cardiovascular Surgery
Kyriakos and Webber
Table VI. Summary of reported series on young patients with lung cancer Per cent of patients with Sex Author
M
I
F
Age limit (youngest)
Anderson et al. (1954)
30
0
<
Neuman et al. (1956)
39
12
<
Rivkin and Salyer (1958)
26
0
<
Kwong and Slade (1964)
37
Hood et al. (1965)
23
10
<
Kennedy 1972
29
11
<
Present series (1973)
34
0
<
68 102
~
I
Epidermoid
40
18.5 (5/27 )
40 (24)
10.3 (4/39)
(?)
40 (20)
<
40
(?)
40 (21 )
I
Small cell undiff.
A denocarcinoma
40.7 (11/27) 23.0 (9/39)
35.9 (14/39) 26.9 (7/26)
34.6 (9/26) 25.0 (11/44 )
I
54.5 (24/44)
9.1 (4/44) 46.0
18.0
(?)
(?)
20.7 (6/29)
65.5 (19/29)
3.4 ( 1/29)
40 (12)
15.2 (5/33 )
21.2 (7/33 )
27.3 (9/33)
0
40-45
31.7 (20/63)
25.4 (16/63 )
25.4 (16/63 )
0
45 (12)
26.0 (25/96)
24.0 (23/96)
26.0 (25/96)
seen in older patients. With this in mind, there should not be any less an aggressive clinical work-up in young patients with pulmonary symptoms simply because of their age. The fact that 26 of our patients had symptoms for over 1 year indicates the need for a higher level of suspicion in these younger symptomatic patients. The establishment of an early diagnosis or suspicion of cancer is of prime importance. The value of pulmonary cytology in establishing such a diagnosis cannot be overemphasized, but unfortunately, of the reports on young patients, only two even mention the cytologic results. Anderson! reported that only 14 of 30 patients had had a cytologic evaluation, the results of which were suggestive of cancer in only 2 patients. In the 51 patients reported by Neuman and colleagues," positive cytology was found in only 9; however, it was not stated whether all the patients had a cytologic examination. In addition, in neither of these papers is it indicated whether a sufficient number of cytologic specimens were ob-
40 (21)
tained on the patients who did have the examination. In our series, almost half of the patients who had a cytologic examination had a positive or suspicious result, while just over 80 per cent of those who had what we consider to be a minimum cytologic work-up had a positive or suspicious result. Any patient, regardless of age, who has suspicious pulmonary symptoms should be investigated by pulmonary cytology. Approximately 60 per cent of lung cancer patients have exploratory operations, while 30 to 40 per cent have resections- s, "'; in some notable exceptions the resection rates were as high as 95 per cent." It is apparent from inspection of Table VI that our per cent of operable and resectable patients is considerably higher than in previously reported series in young patients. This is in direct contrast to the opinion expressed by Kwong and Slade:" that young patients are more frequently inoperable and unresectable than older patients with lung cancer. These high surgical rates reflect the prevailing view in our geographic area about lung
Volume 67
645
Cancer at lung in young men
Number 4 April, 1974
tumor classification Large cell undif].
UndifJ./ anaplastic
Unclassified
Other types
40.7 (11/27) 28.2 (11/39)
2.6 (1/39 ) 30.8 (8/26 )
7.7 (2/26)
11.4 (5/44) 30.0
(?)
4.0
(?)
10.3 (3/29 )
Per cent operable (No.)
Per cent resectable (No.)
46.7 (14/30 )
16.7 (5/30)
4.8 (1/21 )
37.3 (19/51)
17.7 (9/51 )
0
38.5 (10/26)
15.4 (4/26)
3.8 ( 1/26)
36.4 (16/44)
25.0 (11/44 )
11.4 (5/44)
60.0
?
0
?
40.0 (16/40)
5.7 (2/35)
(?)
Per cent 5 year survival (No.)
15.2 (5/33 )
21.2 (7/33)
82.4 (28/34)
61.8 (21/34 )
18.8 (6/32)
ILl (7163 )
6.3 (4/63)
73.5 (50/68)
54.4 (37/68)
16.4 (11/67)
12.5 (12/96)
11.5 (11/96)
76.5 (78/102)
56.9 (58/102)
17.2 (17 /99)
cancer in young patients. In a poll of seventeen board certified thoracic surgeons, thirteen believed that these patients had a worse prognosis than the usual patient with lung cancer, and ten said they would be more aggressive in their surgical approach to such a patient. Four of the five thoracic surgeons at our institution held this view. Positive bronchoscopic biopsy in young people has varied from a low of 17 per cent to a high of 66 per cent. 1, 18, 26, 30 Over half of our patients who had bronchoscopy had visual evidence of tumor, with about 46 per cent of the biopsies proving to be positive. A history of smoking is prominent in any series of patients with lung cancer. Ninetyfour per cent of our patients had a positive smoking history. In three series in young patients where this information is given, the range has been 87 to 93 per cent.'- 20, 30 In 1,357 lung cancer patients reported by Doll and Hill," only 7 (0.5 per cent) were nonsmokers, with 80 per cent having started smoking before age 20 years and only 3.4
per cent having smoked for less than 20 years. Passey" found that only 4 of 499 men (0.8 per cent) with lung cancer were nonsmokers, with a mean starting age of 17 and an average duration of smoking of 40 years. Wynder and Graham" found that 1.3 per cent of men with lung tumors other than adenocarcinomas did not smoke, while 10.3 per cent with adenocarcinoma were nonsmokers. One half of their patients had smoked for 40 or more years, while only 2.5 per cent had smoked for less than 20 years. Kreyberg" found an almost identical percentage of nonsmokers in his Group I and Group II tumors as did Wynder and Graham, with most having started smoking between the ages of 15 to 19 years and having an average exposure of 40 years. Only 2 of 293 Group I patients had smoked for less than 20 years. In the Philadelphia Pulmonary Neoplasm Research Project, which comprised over 6,000 men, no cancer was found in men who had smoked for less than 20 years.' In our patients, 18 per cent had smoked for less than 20 years, and
646
Kyriakos and Webber
almost half had smoked for less than 25 years. The per cent of our patients who began smoking before age 20 years is similar to that reported by Oschner and colleagues," who found that 67 per cent of teen-agers between 16 and 19 years of age had already begun to smoke. Cigarette smoking has been identified by the United States Public Health Service as the major cause of lung cancer in the United States, with the risk directly related to the number of cigarettes smoked per day, the number of years of smoking, the total number of cigarettes smoked in a lifetime, and the age of initiation." The significance of smoking in the younger patients, however, has been debated. Wynder and Graham" found that the younger patients who developed cancer smoked more than older patients. They concluded that the greater the degree of intake, the sooner cancer would develop in the susceptible individual. Passey," however, found that the age of onset of cancer was not related to the amount smoked nor to the age at which smoking began. Kreyberg" also found that the mean age of appearance of lung cancer did not differ if a patient started smoking at age 14 or waited until after age 20 years. He concluded that young men develop lung cancer because they are the most susceptible of those exposed to low-levels of carcinogens. In British studies, Hems";' 17 noted that the lung cancer mortality rate for men ages 20 to 24 years was not correlated with the per capita number of cigarettes smoked but rather with the use of solid fuel; he felt that in this age group lung cancer could be attributed to causes other than cigarette smoking. Kreyberg," however, concluded that the increasing incidence of lung cancer in Norway could not be attributed to air pollution, and Doll and Hill!' were not able to find any gross correlation with occupation nor any more frequent incidence of cancer in those exposed to motor fumes or road dusts. Kreyberg" found that those who work in "dusty" occupations, as well as clerical and professional occupations, are more liable to develop lung cancer than those in
The Journol of Thorocic ond Cordiovasculor Surgery
"open air" or "housework" occupations. Smoke and fumes from industry did not seem to influence lung tumor development, whereas urban living did. In our series, the majority of patients had occupations which kept them indoors. No occupation appeared to predominate, nor did exposure to fumes or dust appear in the background of most of the patients. The prevailing view among our thoracic surgeons is that young patients have a worse prognosis than their older counterparts with lung cancer. In the literature, the 5 year survival rate for all patients with lung cancer is approximately 8 to 9 per cent with occasional figures being somewhat higher." 8, 10, 28, 33 At Barnes Hospital the over-all 5 year survival rate was 8.7 per cent for all patients and 22 per cent for those having curative resections. H Patients below the age of 50 years have been reported to have a better prognosis than older patients. H. 2" Belcher and Anderson," however, found almost identical 5 year survival rates for those patients above and below 45 years of age. They concluded that young patients, including those below age 40 years, have as good a prognosis as the usual patient with lung cancer. In reports specifically dealing with young patients, the prognosis, with few exceptions, has been dismal. Anderson and co-workers! reported only one 5 year survivor in 21 patients who could be traced, and this patient subsequently died of metastatic disease. The average interval till death was 14 months. In addition, they reviewed the literature on the results in children and found only one 5 year survivor among 16 patients. Neuman and associates" reported no 5 year survivors among their young patients who had resections, as compared to a 37 per cent survival rate for resected patients of all ages at the Mayo Clinic. They concluded that the chances of cure or even long-term survival were small for patients under the age of 40 years, and they considered these possibilities practically nonexistent if lymph node metastases were present. Rivkin and Salyer," while having only one 5 year survivor in 26 patients under the age of 40 years, claimed
Volume 67 Number 4 April, 1974
that the disease was no more malignant in this age group than in older patients. However, this was based on a very small number of older patients in the total series. In a series of 33 young patients, Hood and associates> had no 5 year survivors, and only 2 patients were alive after 3 and 4 years, respectively. Kennedy-" who was able to follow only 34 of 40 patients, reported that 2 survived for 5 years. Large and Morgan" reported on five patients, ages 18 to 23, with no survivors and a fairly rapid course from diagnosis to death. The only exception to these dismal results is the report by Kwong and Slade,> who had an 11.4 per cent 5 year survival rate (5/44) with 4 of the 5 survivors being male subjects. The results in our series are in sharp contrast to most of the above reports. We had a total 5 year survival rate of 17.2 per cent for those eligible and a rate of 18.8 per cent for those under the age of 40 years. In an attempt to view our total experience with pulmonary malignancy, we have included cases of carcinoid tumors, lymphoma, and a tumorlet. All of these are lesions with the capability of causing death or metastases, as exemplified by the mention by Kreyberg-" of a metastasizing carcinoid in a 12-year-old boy and by our 13year-old boy who died of "pneumonia" 7 months after surgery for a carcinoid tumor. Since most previous reports have confined themselves to "carcinomas" and have eliminated these tumor types from consideration, we have also reported our survival figures with these lesions eliminated. When this is done, it is seen that the survival figures for the entire group and for those under 40 years of age remain comparable to the survival rates for lung carcinoma patients in general. In fact, the survival figures for the entire group are somewhat better than the previously reported 5 year survival figures at Barnes Hospital. We believe that these results stem from the aggressive attitude of our thoracic surgeons as can be seen in the high operability and resection rates. The incidence of lymph node involvement in operative cases in our series (46.8 per cent) is somewhat lower than the approxi-
Cancer of lung in young men
647
mate figure of 60 per cent reported for older patients generally. 28, 31 While lymph node involvement did lower survival, it is obvious from our results that the mere presence of positive node involvement does not preclude survival, since 6 of our long-term survivors had positive nodes. We could discern no effect on survival of tumor size or pleural involvement. Tumor differentiation also had no effect, as 8 of the survivors had either undifferentiated or poorly differentiated tumors. As in older patients, survival rates were best in epidermoid carcinoma; 32 per cent of patients either survived 5 years or are presently alive without tumor. Similarly, small cell undifferentiated carcinoma had the same dismal prognosis as in older patients, with no patient surviving for more than 3 years. In conclusion, we feel that while differences exist in the cell type of lung cancer in young patients, the prognosis, with the exception of those rare cases occurring in children, is certainly no worse than that found in older patients. While our age limit of 45 years was an arbitrary one, we feel that such a limit is valid when speaking of "young" men with lung cancer. Furthermore, it permits a more realistic appraisal of results due to the larger number of patients which can be analyzed. In support of this, we found no statistically significant differences between patients below or above age 40 years in terms of distribution of tumor cell types, symptomatology, operability, resectability, lymph node or pleural involvement, or survival. Occupation and smoking histories were also similar in both groups. It must be remembered, however, that failure to reject the null hypothesis does not prove that no differences exist, but only that no evidence was demonstrated against the null hypothesis. Interestingly, we found no evidence of an increasing incidence of lung cancer in young patients at our hospital. In fact, more patients were found distributed in the decade 1950 to 1959 than in the years 1960 to 1970. We wish to acknowledge the assistance of Dr. R. Wette and Mrs. Barbara Hixon of the
648
Division of Biostatistics, Washington University School of Medicine, for their statistical analysis of our data. We also thank Dr. Lauren Ackerman for his histologic evaluation of some of our cases. REFERENCES
2
3 4 5 6 7 8
9
10 11 12
13
14 15 16 17
The Journal of Thoracic and Cardiovascular Surgery
Kyriakos and Webber
Anderson, A. E., Buechner, H. A., Yager, I., and Ziskind, M. M.: Bronchogenic Carcinoma in Young Men, Am. 1. Med. 16: 404, 1954. Barrett, R. I., Day, I. c., O'Rourke, P. Y., Chapman, P. T., Sadeghi, H., Perry, R. W., and Tuttle, W. M.: Primary Carcinoma of the Lung: Experience With 1,312 Patients, I. THORAC. CARDIOVASC. SURG. 46: 292, 1963. Belcher, I. R., and Anderson, R.: Surgical Treatment of Carcinoma of the Bronchus, Br. Med. I. 1: 948, 1965. Bennett, D. E., Sasser, W. F., and Ferguson, T. B.: Adenocarcinoma of the Lung in Men, Cancer 23: 431, 1969. Berkson, I., and Gage, R. P.: Calculation of Survival Rates for Cancer, Proc. Mayo Clin. 25: 270, 1950. Bignall, I. R., Martin, M., and Smithers, D. W.: Survival in 6,086 Cases of Bronchial Carcinoma, Lancet 1: 1067, 1967. Boucot, K. R., Cooper, D. A., Weiss, W., and Carnahan, W. I.: Cigarettes, Cough, and Cancer of the Lung, I. A. M. A. 196: 985, 1966. Burford, T. H., Center, S., Ferguson, T. 8., and Spjut, H. I.: Results in the Treatment of Bronchogenic Carcinoma, I. THORAc. SURG. 36: 316, 1958. Cutler, S. I., and Ederer, F.: Maximum Utilization of the Life Table Method in Analyzing Survival, I. Chronic Dis. 8: 699, 1958. Dillon, M. L., and Postlethwait, R. W.: Carcinoma of the Lung, Ann. Thorac. Surg. 11: 193, 1971. Doll, R., and Hill, A. B.: A Study of the Aetiology of Carcinoma of the Lung, Br. Med. I. 2: 1271, 1952. Eastridge, C. E., Hughes, F. A., Jr., and Greenberg, B. E.: Primary Carcinoma of the Lung: Treatment of 1,284 Cases, Am. Surg. 33: 700, 1967. Galofre, M., Payne, W. S., Woolner, L. B., Clagett, O. T., and Gage, R. P.: Pathologic Classification and Surgical Treatment of Bronchogenic Carcinoma, Surg. Gynecol, Obstet. 119: 51, 1964. Green, N., Kurohara, S. S., and George, F. W., III: Cancer of the Lung, Cancer 28: 1229, 1971. Hanbury, W. I.: Bronchogenic Carcinoma in Young Persons, Br. I. Cancer 12: 202, 1958. Hems, G.: Factors Associated With Lung Cancer, Br. I. Cancer 22: 466, 1968. Hems, G.: Lung Cancer: Smoking and Other
18 19 20 21
22 23 24 25 26
27 28 29 30 31 32
33
34
35
Associated Factors, Br. I. Cancer 23: 661, 1969. Hood, R. H., Ir., Campbell, D. c., r-., Dooley, B. N., and Dooling, I. A.: Bronchogenic Carcinoma in Young People, Chest 48: 469, 1965. Iverson, R. E., and Straehley, C. I.: Pulmonary Blastoma; Longterrn Survival of I uvenile Patient, Chest 63: 436, 1973. Kennedy, A.: Lung Cancer in Young Adults, Br. I. Dis. Chest 66: 147, 1972. Kreyberg, L.: Occupational Influences in a Norwegian Material of 235 Cases of Primary Epithelial Lung Tumours, Br. I. Cancer 8: 605, 1954. Kreyberg, L.: Lung Tumours: Histology, Aetiology and Geographic Pathology, Acta Un. Int. Cancer 15: 78, 1959. Kreyberg, L.: Aetiology of Lung Cancer, Universitetsforlaget, Oslo, 1969. Kwong, K. H., and Slade, P. R.: Carcinoma of the Bronchus in Young Adults, Br. I. Dis. Chest 58: 124, 1964. Large, S. E., and Morgan, W. K. C.: Bronchial Carcinoma in Young Adults, Br. I. Tuberc. 52: 185, 1958. Neuman, H. W., Ellis, F. H., and McDonald, I. R.: Bronchogenic Carcinoma in Persons Under Forty Years of Age, N. Eng!. I. Med. 254: 502, 1956. Ochsner, A., DeCamp, P. T., De Bakey, M. E., and Ray, C. I.: Bronchogenic Carcinoma, I. A. M. A. 148: 691, 1952. Ochsner, A., Ochsner, A., Jr., H'Doubler, C., and Blalock, I.: Bronchogenic Carcinoma, Chest 37: 1, 1960. Passey, R. D.: Some Problems of Lung Cancer, Lancet 2: 107, 1962. Rivkin, L. M., and Salyer, I. M.: Bronchogenic Carcinoma in Men Under 40 Years of Age, Chest 34: 521, 1958. Spjut, H. I., Roper, C. L., and Butcher, H. R.: Pulmonary Cancer and Its Prognosis, Cancer 14: 1251, 1961. The Health Consequences of Smoking, U. S. Department of Health, Education, and Welfare; Public Health Service. DHEW Publication No. (HSM) 73-8704, January, 1973. Weiss, W., Cooper, D. A., and Boucot, K. R.: Operative Mortality and 5-Year Survival Rates in Men With Bronchogenic Carcinoma, Ann. Intern. Med. 71: 59, 1969. Whitwell, F.: The Histopathology of Lung Cancer in Liverpool: The Specificity of the Histological Cell Types of Lung Cancer, Br. J. Cancer 15: 440, 1961. Wynder, E. L., and Graham, E. A.: Tobacco Smoking as a Possible Etiologic Factor in Bronchogenic Carcinoma, I. A. M. A. 143: 329, 1950.
Michael Kyriakos, M.D., * and Bruce Webber, M.B.B.Ch. (Rand.), F.F.Path. (S.A.),** St. Louis, Mo.
Cancer of the lung remains the most common malignancy in men, with the peak incidence occurring between 50 and 70 years of age. That the disease also affects young men is well known to thoracic surgeons, but unfortunately there have been few reports dealing specifically with this problem. Most of the large published series on lung cancer contain only an age distribution for their patients without further analysis, while those reports which have specifically dealt with young people have involved relatively few patients. The prevalent view among thoracic surgeons is that, while the younger individual is a better operative risk and can withstand more radical surgery, his prognosis is worse than that for the older patient. We wished to determine whether this conclusion was valid, and we were also interested as to whether their smoking and occupational histories differed from those reported for all patients with lung cancer. In this study, we have arbitrarily chosen the age 45 years as the limit for inclusion, From the Department of Pathology, Division of Surgical Pathology, Barnes Hospital, Washington University School of Medicine, St. Louis, Mo. 63110. Received for publication Jan. 3, 1974. • Associate Professor, Division of Surgical Pathology. • • Resident Fellow, Division of Surgical Pathology. Present address: Department of Pathology. University of Cape Town Medical School, Observatory 7900, C.P., Republic of South Africa.
634
since, relative to the usual patient with lung cancer, this age is indeed "young." However, when necessary, we have separately reported our data for those patients under 40 years so that our results can be compared with reports which have used only patients in this age category. Materials and methods The files of the Division of Surgical Pathology and Cytology, Barnes Hospital, St. Louis, Missouri, were searched, and all reports and histologic material on pulmonary tumors occurring in men 45 years of age or less were obtained for the years 1950 to 1970. Only patients who had a histologic diagnosis of cancer were included in this study. Sixty-one patients were seen during the years 1950 to 1959 and 41 in the years 1960 to 1970, for a total of 102 patients. Hematoxylin and eosin sections of the tumors were reviewed independently by both of us without reference to the original diagnosis. Special stains for mucin or argentaffin reactivity were used when needed. When we could not agree on the histologic classification, the case was referred to Dr. Lauren Ackerman for final determination. Clinical records were reviewed on all patients to obtain necessary clinical and social information. When required, the patient, surviving relative, or personal physician was contacted by mail or telephone for in-
Volume 67
Cancer of lung in young men
Number 4
635
April, 1974
18 16 Vl
14
I-
Z w
...>=« u..
0
0<
w
""
12 10 8
:E :::J
Z
6 4 2 12
16
20
24
28
32
36
40
44
AGE (YEARS)
Fig.!. Age distribution of young men with lung cancer at Barnes Hospital (1950 to 1970).
formation missing from the records and for follow-up data. No patient was lost to follow-up in this series. In the statistical analysis of the results, whenever the data were considered measurable on a continuous scale, e.g., duration of smoking, survival time, and so on, a Rank-Sum test was used. When a grouping interval was measured, e.g., resectability, operability, and so on, the chi-square test was used. Results Age and race. The mean age for the entire series, consisting of 68 patients between the ages of 40 and 45 years and 34 patients less than 40 years old, was 39.7 years, with a median of 41 years. The mean for patients between ages 40 and 45 was 42.9 years, while for those below age 40 it was 33.3 years, the youngest being 12 years old (Fig. 1). There were 91 Caucasian and 11 Negro patients. Symptoms. Only 2 patients were totally asymptomatic: A pulmonary lesion was found on a routine chest roentgenogram in 1 patient; in the other, hemoptysis, which began immediately following a fall, necessitated a chest roentgenogram, which demonstrated a pulmonary lesion.
In the remaining patients multiple symptoms were present at the time of diagnosis, with weight loss, cough, chest, shoulder, and back pain, hemoptysis, weakness, fatigue, and dyspnea being commonest (Table I). Weight loss, the commonest symptom, was often striking. Sixty-nine patients had lost weight, with the amount lost known in 67. The mean loss was 22 pounds (range 3 to 60 pounds), with 91 per cent having lost 10 or more pounds and 55 per cent having lost 20 or more pounds. The duration of symptoms ranged from 2 weeks to 156 months, with a mean of 10.8 and a median of 6 months. Twenty-six patients had symptoms for over 1 year; 13 of them had symptoms for 2 years or longer, with several having episodes of recurrent pneumonia or hemoptysis for many years. In 1 case, that of a 13-year-old boy with a carcinoid tumor, there had been episodes of hemoptysis, wheezing, and chronic cough since the age of 1 year. A chest roentgenogram taken a year before admission showed a "spot" on the lung which gradually increased in size until at operation it measured 5 em. Smoking history. Ninety-six patients (94.1 per cent) had a history of smoking, while 6 did not smoke. Cigarettes alone were smoked
636
The Journal 0/ Thoracic and Cardiovascular Surgery
Kyriakos and Webber
Table I. Symptoms at time of diagnosis in young men with lung cancer Per cent with symptom
Symptom Weight loss Cough Chest/shoulder pain Hemoptysis Weakness/fatigue Dyspnea Fever Headache Clubbing Recurrent pulmonary infections Hoarseness Central nervous system disturbance Miscellaneous* Asymptomatic
67.6 57.8 52.9 39.2 24.5 23.5 19.6 7.8 5.9 5.9 5.9 4.9 22.0 2.0
'Wheezing, neck swelling, joint pain, pruritis, dysphagia, jaw pain, night sweats, epistaxis, leg swelling, hematemesis, and increased sputum production.
Table II. Occupations in young men with lung cancer Occupation
Age group < 40 years* Office worker Factory worker Laborer Engineer Salesman Age group 40 to 45 yearsi' Factory worker Laborer Office worker Construction trades Truck driver Mechanic Salesman Engineer Farmer Bartender
No. of patients 7 4 4 3 2 10 8
5 5 5 4 4
2 2 2
• Single examples each for construction trades, coal miner, butcher, farmer, railroad brakeman, grocer, teacher, truck
driver, laboratory technician, and filling station attendant. Mixed occupations: farmer and factory worker; farmer, factory, and garage work. tSingle examples each for coal miner, railroad worker, teacher, merchandise buyer, garage owner, chemist, mortician, electrical worker, surgeon, baliff, fireman, and tractor driver. Mixed occupations: farmer and truck driver; farmer and postal clerk; farmer, machinist, and construction work; farmer, factory, and welder; railroad brakeman and salesman; and chaffeur and salesman. Two patients were mechanics and painters. The occupation of 1 patient was
unknown.
by 89 patients, cigarettes and pipes were reported by 2, cigarettes and cigars by 4, and only cigars and pipe by 1 patient. Hence 95 of the 96 patients had smoked cigarettes. In 9 1 of these the number of cigarettes consumed in packs per day (ppd) was known, the mean being 1.6 ppd. In 27 patients under the age of 40 years the mean was 1.5 ppd; for those ages 40 to 45 years, the mean was 1.7 ppd. The duration of smoking was known for 82 patients: It was less than 20 years in 15 patients; 20 to 24 years in 25; 25 to 29 years in 26; 30 to 34 years in 13; and over 35 years in 3 patients. The mean duration was 23.1 years, with those under age 40 having a mean of 19.9 years and those between 40 and 45 having a mean of 24.5 years. The average age at which the patients started smoking was 17.7 years; those under age 40 started at a mean age of 16.5 years, while those in the 40 to 45 year age bracket began at a mean age of 18.2 years. Fiftyfour patients began smoking before the age of 20 years, 26 began between the ages 20 and 29, and only 2 began after age 30. There was no statistically significant difference between the two age groups in terms of the number of cigarettes smoked per day or the age at which smoking began. As expected, patients between ages 40 and 45 had smoked for a statistically longer time than those under age 40 (p < 0.001). The ages and tumor types in the 6 patients who did not smoke were as follows: age 12, large cell undifferentiated carcinoma; age 13, carcinoid; age 20, small cell undifferentiated carcinoma; age 23, histiocytic lymphoma; age 29, adenocarcinoma; and age 33, carcinoid. Occupation. Patient occupation is shown in Table II. In 1 patient the occupation was unknown, and 2 children had never been employed. In only 10 patients was there a history of more than one job prior to diagnosis. The occupation was primarily outdoor in nature in 34 patients and indoor in 58. Seven patients gave a mixed history, having had both indoor and outdoor occupations sometime in their lives. In 23 patients the
Volume 67 Number 4
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April, 1974
occupations involved some contact with fumes or dusts, but this is a minimal figure since extensive information on such exposure was not available in the charts. No major differences between job occupation or exposure to fumes and dusts were present in the two age divisions. Bronchoscopy. The results of bronchoscopic examination were known for 94 patients. Four of the 34 patients under the age of 40 years did not have bronchoscopy, and the result is unknown in 1 patient. Twelve of the 29 remaining patients had a positive biopsy, while in 3, tumor was seen but the biopsy was negative, and in 2, the tumor was not biopsied. Hence 58.6 per cent (17/29) had visual or histologic evidence of tumor. Of the 68 patients between 40 and 45 years old, 1 did not have bronchoscopy and the results are unknown in two. Twenty-nine had a positive biopsy, while in 4, tumor was seen but the biopsy was negative, and in 2, the tumor was not biopsied. In this group, 53.8 per cent (35/65) had visual or histologic evidence of tumor. The differences in the two age divisions were not statistically significant. Cytology. Pulmonary cytology specimens were submitted in 82 patients: The results were positive in 29 (35.4 per cent) and suspicious for carcinoma in 11 (13.4 per cent). Of 24 patients under the age of 40 years, 8 had positive cytologies and 3 had cytologies suspicious for carcinoma. There were 21 patients with positive and 8 with suspicious cytologies among 58 patients ages 40 to 45. However, of the total of 82 patients, only 39 had what is considered an adequate cytologic work-up prior to definitive histologic diagnosis, that is, a minimum of three sputum samples and a single bronchial washing. Of these patients, 29 had positive (74.4 per cent) and 3 had suspicious cytologies (7.7 per cent). Hence 82.1 per cent (32/39) of patients with an adequate cytologic work-up had positive or suspicious diagnoses for carcinoma. Therapy. Seventy-eight patients underwent thoracotomy (76.5 per cent). Sixty of these had resections, 58 of which were con-
sidered curative. These curative resections represent 56.9 per cent of the entire series and 74.4 per cent of the exploratory operations. Of the 34 patients under age 40, 28 underwent exploration and 22 had resections; a pneumonectomy was done in 12 and a lobectomy in 10, one of which was palliative. Fifty of the 68 patients between ages 40 and 45 had an exploratory operation, with 38 having resections; a pneumonectomy was done in 30, a lobectomy in 7, and a palliative wedge resection in 1 patient. No statistically significant differences were found between the two major age divisions in terms of total operability or curative resectability or in terms of the curative resectability rate in those who were operable. In the remaining patients the histologic diagnosis was established by bronchoscopic biopsy or exploratory thoracotomy with biopsy in 39, needle biopsy of the lung or chest wall in 2, and a small open biopsy of the lung in 1 patient. Forty-nine patients at some time in their course received external radiation therapy or chemotherapy. In a group of 16 patients who had had pulmonary resections, 10 received only radiation therapy, 4 radiation therapy combined with chemotherapy, and 2 only chemotherapy. In only 1 of these patients was the radiation therapy given preoperatively. Sixteen additional patients had an exploratory thoracotomy without resection, 10 of whom received only postoperative radiation, 5 combined radiation and chemotherapy, and 1 patient only chemotherapy. In a final group of 17 patients who did not have an operation, 11 received only radiation therapy, 5 had combined radiation and chemotherapy, and 1 had only chemotherapy. Nitrogen mustard was the chemotherapy employed in all but 1 of the above patients, who received a combination of hydrourea, vincristine, and methotrexate. With the exception of those patients for whom it was the only method of treatment, and the single patient who received preoperative radiation, the radiation therapy was used to treat
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Thoracic and Cardiovascular Surgery
Table III. Distribution of tumor type by age group Small cell Age (yr.)
10-14 15-19 20-24 25-29 30-34 35-39 40-45 Totals
Epidermoid Adenocarcinoma carcinoma
0 0 0 0 0 5 20 25
0 0 0 1 2 6 16 25
undiff.
carcinoma
0 1 1 0 1 4 16 23
I
Large cell Bronchoundif], alveolar carcinoma Carcinoid carcinoma
1 0 0 0 0 4 7
12
'Includes histiocytic lymphoma, adenoid cystic carcinoma, let. tIFC, Insufficient tumor for classification of cell type.
recurrent tumor within the chest or sites of distant metastases. Pathology. Sufficient material for tumor classification was available in 96 cases. In the remaining 6 cases, material had been obtained by bronchial biopsy or closed needle biopsy of the lung, and, while sufficient to indicate malignancy, it was not adequate for accurate classification by cell type. In the 96 cases, the distribution by tumor type was as follows: epidermoid carcinoma 26 per cent (25 cases); adenocarcinoma 26 per cent (25 cases); small cell undifferentiated (oat cell) carcinoma 24 per cent (23 cases); large cell undifferentiated carcinoma 12.5 per cent (12 cases); bronchoalveolar carcinoma, 2.1 per cent (2 cases); and carcinoid tumor 4.2 per cent (4 cases). A miscellaneous category of 5 tumors made up 5.2 per cent of cases and contained single examples of adenoid cystic carcinoma, giant cell carcinoma, primary histiocytic lymphoma, an unclassified malignant tumor, and a "tumorlet." The epidermoid and adenocarcinomas were further evaluated as to their differentiation. There were 5 weU-differentiated, 12 moderately differentiated, and 8 poorly differentiated epidermoid carcinomas, as well as 3 well-differentiated, 4 moderately differentiated, and 18 poorly differentiated adenocarcinomas. Hence approximately 64 per
1 0 0 1 1 1 0 4
0 0 0 0 1 0 1 2
Other*
IFCt
Totals
0 0 1 0 0 1 3 5
0 0 0 0 1 0 5 6
2 1 2 2 6 21 68 102
giant cell carcinoma, unclassified malignant tumor, and tumor-
cent (61/96) of the classifiable tumors were either poorly differentiated carcinomas or undifferentiated tumors. Table III shows the age distribution and the associated tumor type. There were 33 classifiable tumors in patients below age 40 years. Epidermoid carcinoma made up 15.2 per cent (5 cases); adenocarcinoma 27.3 per cent (9 cases); small cell undifferentiated (oat cell) carcinoma 21.2 per cent (7 cases); large cell undifferentiated carcinoma 15.2 per cent (5 cases); and carcinoid tumor 12.1 per cent (4 cases). There was one example each of histiocytic lymphoma, tumorlet, and bronchoalveolar carcinoma. Statistical analysis showed no significant differences in the per cent distribution of tumor types in patients below age 40 years versus those between 40 and 45 years of age. In addition, the percentage of epidermoid carcinomas in these age groups was not statistically different. The age of the youngest patient in each tumor category was as follows: epidermoid, 35 years; adenocarcinoma, 29 years; small cell undifferentiated, 18 years; large cell undifferentiated, 12 years; carcinoid, 13 years; bronchoalveolar, 32 years; lymphoma, 23 years; adenoid cystic carcinoma, 43 years; giant cell carcinoma, 41 years; and tumorlet, 38 years. The youngest patient to have one of the 6 unclassified tumors was 34 years.
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April, 1974
Table IV. Cumulative survival in men age 45 years or less with lung cancer
Time from diagnosis (yr.)
Alive at beginning of interval
Died during interval
Lost to follow-up during interval
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-15 15-20 20-22
102 38 24 18 17 17 15 13 12 12 12 9 2
63 14 5 0 0 1 2 1 0 0 2 2 0
0 0 0 0 0 0 0 0 0 0 0 0 0
Tumor involved the right lung in 62, the left lung in 35, and both sides by carinal or hilar extension in 5 cases. The right upper lobe was involved alone or in combination with other lobes in 39 cases, while the left upper lobe was involved in 17. The mainstem bronchi contained tumor in 20 cases. Carina 1 involvement was seen in 4 patients, while in 3 others tumor extended to the trachea. Excluding a microscopic tumorlet, dimensions of the resected tumors were available in 53 patients and ranged from 1.0 to 15.0 em., with a mean of 4.9 em. The distribution of tumor size and the number of patients in each category for those younger than 40 years was as follows: zero to 1.9 em., 2; 2.0 to 2.9 em., 3; 3.0 to 3.9 em., 1; 4.0 to 4.9 em., 4; 5.0 to 5.9 em., 2; 6.0 to 6.9 em., 3; and> 7.0 em., 4. The mean size was 5.1 em. The distribution for those 40 to 45 years of age was as follows: zero to 1.9 em., 3; 2.0 to 2.9 em., 4; 3.0 to 3.9 em., 5; 4.0 to 4.9 em., 4; 5.0 to 5.9 em., 8; 6.0 to 6.9 em., 4; and> 7.0 em., 6. The mean size was 4.8 em. No statistically significant difference in tumor size was found in the two age groups. In 59 cases, lymph nodes were excised during resection or exploratory thoracotomy, the average number of nodes examined per
Withdrawn alive during interval 1 0 1 1 0 1 0 0 0 0 1 5 2
No. exposed to risk of dying 101.5 38.0 23.5 17.5 17.0 16.5 15.0 13.0 12.0 12.0 11.5
6.5 1.0
Propor-
Propor-
tion dying
tion surviving
Cumulative survival
0.621 0.368 0.213 0.000 0.000 0.061 0.133 0.077 0.000 0.000 0.174 0.308 0.000
0.379 0.632 0.787 1.000 1.000 0.939 0.867 0.923 1.000 1.000 0.826 0.692 1.000
0.379 0.240 0.189 0.189 0.189 0.177 0.153 0.141 0.141 0.141 0.116 0.082 0.082
case being 16. Positive nodes were present in 55 per cent (22/40) of patients age 40 to 45 years, and 36.8 per cent (7/19) in those under age 40 years. These differences were not statistically significant. Information as to pleural involvement by tumor was available in 73 patients, with 22 of 46 patients between age 40 and 45 (47.8 per cent) and 13 of 27 less than 40 years (48.1 per cent) having tumor in the pleura. Survival. In the total series, 99 patients were eligible for 5 year analysis, 32 below age 40 years and 67 between ages 40 and 45 years. In the former group there were 6 survivors (18.8 per cent), while in the latter there were 11 survivors (16.4 per cent), for a total 5 year survival of 17.2 per cent (17/99). If the 4 carcinoid tumors, the lymphoma, and the tumorlet, all of which occurred in those under 40 years, are eliminated from consideration, the 5 year survival in this age group was 11.1 per cent (3/27), and the total 5 year survival for all patients was 14.9 per cent (14/94). These 6 cases, which are not usually considered in the statistics from other institutions, will henceforth be referred to as "special" cases. In those eligible, there were no statistically significant differences in the 5 year survival rate between the two age groups with or without consideration of these special cases.
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Kyriakos and Webber
Table V. Five-year survivors among young men with lung cancer (1950 to 1970) Case No. 1 2 3
Occupation
Smoking history
Tumor
Mechanic-painter Bartender Accountant
2 ppd x 30 yr. 2 ppd x 20 yr. 1.5 ppd x 10 yr.
Large cell undiff. Epidermoid well-diff. Carcinoid
RUL LUL RML
Epidermoid mod.-diff. Epidermoid poorly diff.
RUL LUL
Carcinoid
LLL
Location
4 5
45 45
Pottery maker Toolmaker
6
33
Office worker
2 ppd x 28 yr. 1.5 ppd x 25 yr.; cigars, 4/day None
7
36
Purchasing agent
1.5 ppd x 20 yr.
Epidermoid weJl-diff.
RLL
8 9 10
33 38 41
Accountant Grocer J ustice of peace
3 ppd x 20 yr. 2 ppd x 16 yr. 1.5 ppd x 29 yr.
Adenocarcinoma poorly diff. Tumorlet Epidermoid mod.-diff.
RLL RML, RLL LUL
11 12 13 14
45 43 45 41
Salesman Pipefitter Tar roofing worker Office worker
3 ppd x 30 yr. 1.5 ppd x 35 yr. I ppd x ? 3 ppd x 32 yr.
Epidermoid poorly diff. Adenocarcinoma poorly diff. Large cell undiff. Epidermoid well-diff.
RUL, RLL RUL, RML LUL RUL, RML
15
40
Clerk
I ppd x 25 yr.
Adenocarcinoma poorly diff.
RUL
16
39
Metal sander
1.5 ppd x 27 yr.
Large cell undiff.
LUL
17
41
Clerk
Bronchoalveolar
RUL
1 pkg.zwk. x ?
Legend: LN, Lymph nodes. ppd, Cigarette packs per day. RUL, Right upper lobe. LUL, Left upper lobe. RML, Right middle lobe. heart disease.
According to the life-table method, G. " which has the advantage of using all patients for the calculation of survival, the cumulative 5 year survival rate was 17.7 per cent and the 10 year survival rate was I 1.6 per cent (Table IV). If the special cases are eliminated from consideration, the cumulative survival rate at 5 years was 15.4 per cent and at 10 years 8.8 per cent. At the conclusion of the study, there were 12 patients still living free of tumor from 5 months to 22 years after operation. Nine had survived for over 5 years, and 3 others were alive 5, 28, and 48 months after operation. In addition, 8 other patients had survived for more than 5 years but had eventually died. Two of these deaths were attributable to recurrence of the original tumor, with death occurring 73 and 124 months after operation. The remaining
6 patients died of other causes (Table V). With the exception of 3 cases, all other deaths in this series were due to confirmed recurrent or metastatic tumor from the original primary lesion. The three exceptions include 1 patient, age 40 years, who died in an automobile accident 34 months after operation for epidermoid carcinoma; another patient, age 44 years, died of a pulmonary embolus and acute heart failure following hospitalization for codeine addiction 24 months after operation for adenocarcinoma; a final patient, age 13 years, died of pneumonia 7 months after resection of a carcinoid tumor. In none of these 3 was there any clinical evidence of recurrent tumor, but in none was a postmortem examination done. The mean survival for those who died of their tumor was 10.3 months, with a
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L.N,:
Pos.Ztotal
Pleura involved
Operation
Tumor size
Clinical status
Survival time
Alive and well Alive and well Alive and well
12 yr., 7 mo. 17 yr., 8 mo. 18 yr., 2 mo.
Alive and well Alive and well
22 yr. 21 yr., 5 mo.
bx
Alive and well
16 yr., 4 mo.
bx
Alive and well
19 yr., 3 mo.
bx
Alive and well Alive and well Dead, tumor
6 yr. 16 yr., 6 mo. 6 yr., 1 mo.
Dead, tumor Dead, CHF Dead, ASHD Dead, pulmonary insufficiency Dead, Parkinson's disease Dead, carcinoma of opposite lung Dead, cirrhosis
10 yr., 2 mo. 20 yr. 5 yr., 3 mo. 7 yr., 10 mo.
Bronchoscopy
7/25 0/3
? Yes No
Pneumonectomy Pneumonectomy Lobectomy
8.0 em. 5.0 em. 1.4 em.
Negative Negative Tumor seen, no bx Negative ?
0/19 0/18
No ?
Pneumonectomy Pneumonectomy
1.0 em. 4.5 em.
0/2
No
Lobectomy
3.7 em.
0/22
No
Pneumonectomy
6.0 em.
1/19 0/8 3/15
Yes No No
Pneumonectomy Bilobectomy Pneumonectomy
2.1 em. Microscopic 5.0 em.
0/24 1/16 0/20 2/17
Yes No Yes Yes
Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy
? 2.0 em. 8.0 em. "Large"
0/21
Yes
Pneumonectomy
5.0 em.
Negative
6/17
Yes
Pneumonectomy
6.0 em.
Tumor seen, bx neg.
0/3
No
Lobectomy
3.0 em.
Negative
Tumor seen, pos. Tumor seen, pos. Negative ? Tumor seen, pos. Negative Negative Negative Tumor seen, pos.
bx
14 yr. 15 yr., 3 mo. 6 yr., 9 mo.
LLL, Left lower lobe. RLL, Right lower lobe. bx, Biopsy. pos., Positive. CHF, Congestive heart failure. ASHD, Arteriosclerotic
mean of 14.8 months for patients who had resection versus 6.1 months for those not resected. Fifty-five patients who had curative resections were eligible for 5 year analysis. Six of 19 (31.6 per cent) patients under age 40 survived, while 11 of 36 (30.6 per cent) ages 40 to 45 years survived, for an over-all survival rate of 30.9 per cent (17/55). Excluding the special cases, the 5 year survival in those under age 40 years was 20 per cent (3/15), and the over-all 5 year survival rate was 27.5 per cent (14/51). The differences in 5 year survival between the two age groups having curative resections, with or without consideration of the special cases, were not statistically significant. Thirteen of 40 pneumonectomy patients eligible for 5 year analysis survived (32.5
per cent), while 4 of 15 lobectomy patients survived (26.7 per cent). The single wedge resection patient did not survive. The mean length of survival by cell type from the time of diagnosis in those patients dead of tumor, or its consequences, was as follows for the larger tumor categories: epidermoid carcinoma, 18.7 months (median 7 months); small cell undifferentiated carcinoma, 7.8 months (median 4 months); adenocarcinoma, 12.2 months (median 10 months); and large cell undifferentiated carcinoma, 7.3 months (median 3 months). Seven of the 25 patients with epidermoid carcinoma survived 5 years or longer, and another is alive and well 28 months postoperatively. Two of these survivors, however, later died of recurrence of their tumor at 73 and 122 months. Three of 25 patients with adenocarcinoma survived longer than
The Journal of
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Kyriakos and Webber
5 years, and another is alive and well 4 years after operation. Three of 12 patients with large cell undifferentiated tumor survived over 5 years. Of the 4 patients with carcinoid tumors, 2 survived longer than 5 years and 1 is alive and well 5 months after operation. One 5 year survivor had bronchoalveolar carcinoma and another had a tumorlet. None of the 23 patients with small cell undifferentiated carcinoma survived 5 years. In the 59 patients in whom the status of the lymph nodes was known, 56 were eligible for 5 year analysis. In those younger than 40 years of age, 3 of 10 (30 per cent) with negative nodes and 2 of 7 (28.6 per cent) with positive nodes survived. In those ages 40 to 45 years, 7 of 17 (41.2 per cent) with negative nodes and 4 of 22 (18.2 per cent) with positive nodes survived. The 3 patients alive less than 5 years all had negative nodes. Of the 73 patients in whom information regarding pleural involvement was known, 70 were eligible for 5 year analysis and 50 per cent had pleural involvement. In patients under 40 years of age, 2 of 13 with and 4 of 12 without pleural involvement survived. In the 40 to 45 year age group, 5 of 22 patients with and 4 of 23 without involvement survived. None of the patients alive less than 5 years had pleural involvement. No relationship between survival and tumor size was found, with some survivors having had lesions as large as 8 em. While 5 of 6 patients with lesions smaller than 2 em. were either long-term survivors or are presently living, 2 of these had carcinoid tumors, and 1 had a microscopic tumorlet. The nonsurvivor in the group, who died in 2 months, had a 1.5 em, small cell undifferentiated carcinoma. The average size of lesions in the long-term survivors was 4.3 em. Only 2 of 49 patients who received radiation or chemotherapy survived 5 years. One is alive and well 12 years, 7 months postoperatively, and he had received a single dose of 11.7 mg. of nitrogen mustard at the time of operation. The other patient sur-
Thoracic and Cardiovascular Surgery
vived 5 years, 3 months before dying of arteriosclerotic heart disease. He had received postoperative radiation therapy of 4,324 rads to the mediastinum because of invasion found at the time of pneumonectomy. Discussion
The peak age for cancer of the lung usually occurs between the sixth and seventh decades of Iife.": 12, 27, 29, 34 In a previous report on 1,008 lung cancer patients from our institution, 81 per cent were between 50 and 89 years of age.' In a British study of 629 cases, 75 per cent were between 50 and 70 years of age." The per cent of patients who fall within what has been considered a "young" group, i.e., less than 40 years of age, has varied from 1.7 to 6.1 per cent." B, 24. 3:J In a report by Belcher and Anderson" of 1,134 male and female patients, 1.8 per cent were less than 40 years old and 8.1 per cent were less than 45 years of age. In our institution, 2 per cent of the patients were less than 40 years old." There have been few reported cases of lung cancer in patients less than 20 years of age. At the Mayo Clinic from 1943 to 1954, the youngest patient was 24 years," while in the period 1955 to 1970, at the Sheffield Royal Infirmary, England, the youngest was 21 years." Anderson 1 reviewed the literature in 1954 and found 16 cases of pulmonary cancer in children which were histologically confirmed, with the youngest boy being 5 years old. Hanbury," in 1958, added 2 cases in children and found 60 in the literature, 34 of which were not adequately described. Large and Morgan" reported on 2 patients, ages 18 and 19 years. Iverson and Straehley'" described a pulmonary blastoma in an l1-year-old boy and, in a review, found a case with metastasis and death in a 15-month-old girl. Relative to the usual patients with lung cancer, our patients are "young" with an average age of 39.7 years. To our knowledge there have been only six publications, other than isolated case reports, dealing
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Cancer of lung in young men
643
April, 1974
with this problem in patients younger than 40 years of age, and only two of the reports have dealt solely with male patients.': i s. 20, N, 20, 30 Of the 184 male subjects reported upon in these six papers, the youngest was 20 years old (Table V). Throughout these reports a common finding has been the low incidence of epidermoid carcinoma and the relatively high occurrence of small cell undifferentiated carcinoma or anaplastic tumors. The per cent distribution for the major histologic subtypes of tumors in a review of several large reported series of lung cancers in patients of all ages was as follows: epidermoid carcinoma, 34 to 61 per cent; adenocarcinoma, 9 to 22 per cent; and small cell undifferentiated carcinoma, 2 to 38 per cent. In addition, an undefined category of "undifferentiated" has accounted for 9 to 34 per cent of the tumors.>v 12, D, 24, 20, 28, 3:1 At Barnes Hospital, 60 per cent of lung tumors in men have been classified as epidermoid, 9 per cent as adenocarcinoma, 13 per cent as small cell undifferentiated carcinoma, 2 per cent as bronchiolar carcinoma, 9 per cent as undifferentiated, and 7 per cent as unclassified.' Some of the reports on young patients have failed to separate small cell undifferentiated carcinoma from other anaplastic and undifferentiated tumors, which makes accurate comparisons between series difficult. Our results do show a lower incidence of epidermoid carcinoma and a higher incidence of small cell undifferentiated carcinoma and adenocarcinoma than found in older patients. Even if one excludes from the per cent calculations the 4 cases of carcinoid tumor, and the single examples of lymphoma and tumorlet, all of which occurred in patients under the age of 40 years, the per cent distribution figures do not change significantly for the remaining patients in this age bracket; that is, there are no significant differences between the distribution of cell types for those under age 40 years and those 40 to 45 years old. This distribution of cell types in younger individuals could indicate one of two possibilities: (l) The necessary inciting stimu-
Ius for the transformation of the respiratory mucosa to epidermoid carcinoma must act over a longer time span to be effective; (2) the cells which produce adenocarcinomas and the undifferentiated tumors are more susceptible and hence these develop earlier than the epidermoid tumors. On the other hand, there may certainly be more than one factor involved in the production of cancer in the younger patient. Environmental exposure to other agents may, in concert with such factors as smoking, predispose to an earlier development of cancer. In addition, there may be genetic factors which of themselves might be responsible in part or whole for these tumors. We feel that every young patient with lung cancer should have a full and careful epidemiologic investigation into his family and medical histories, exposure to drugs, occupational history, and so on. The recent findings relating to vaginal carcinoma in women whose mothers had taken stilbestrol during pregnancy should serve as a model as to what might be found if such investigations were carried out. Regardless of age, lung cancer is still discovered as a symptomatic disease, as emphasized by the fact that only 2 per cent of patients in our series were asymptomatic. This is not very different from data reported for older patients with lung cancer, as Eastridge," in a series of 1,284 patients, reported that 5 per cent were asymptomatic, and Ochsner" found only 0.3 per cent who were asymptomatic among 948 lung cancer patients. In young patients, the per cent of asymptomatic cases has varied from zero to 23 per cent.': 18, N. 26. 30 The dominant presenting symptoms in these latter series has varied and differs somewhat from ours, with chest and shoulder pain being the major symptoms in some studies": 2fl and hemoptysis being an uncommon symptom in other reports.': :10 Only 8 per cent of the patients reported by Hood and colleagues" had symptomatic weight loss. In our series, two thirds of the patients had weight loss and almost 40 per cent had hemoptysis. We do not believe that the symptomatology in young patients differs significantly from that
644
The Journol of Thoracic and Cardiovascular Surgery
Kyriakos and Webber
Table VI. Summary of reported series on young patients with lung cancer Per cent of patients with Sex Author
M
I
F
Age limit (youngest)
Anderson et al. (1954)
30
0
<
Neuman et al. (1956)
39
12
<
Rivkin and Salyer (1958)
26
0
<
Kwong and Slade (1964)
37
Hood et al. (1965)
23
10
<
Kennedy 1972
29
11
<
Present series (1973)
34
0
<
68 102
~
I
Epidermoid
40
18.5 (5/27 )
40 (24)
10.3 (4/39)
(?)
40 (20)
<
40
(?)
40 (21 )
I
Small cell undiff.
A denocarcinoma
40.7 (11/27) 23.0 (9/39)
35.9 (14/39) 26.9 (7/26)
34.6 (9/26) 25.0 (11/44 )
I
54.5 (24/44)
9.1 (4/44) 46.0
18.0
(?)
(?)
20.7 (6/29)
65.5 (19/29)
3.4 ( 1/29)
40 (12)
15.2 (5/33 )
21.2 (7/33 )
27.3 (9/33)
0
40-45
31.7 (20/63)
25.4 (16/63 )
25.4 (16/63 )
0
45 (12)
26.0 (25/96)
24.0 (23/96)
26.0 (25/96)
seen in older patients. With this in mind, there should not be any less an aggressive clinical work-up in young patients with pulmonary symptoms simply because of their age. The fact that 26 of our patients had symptoms for over 1 year indicates the need for a higher level of suspicion in these younger symptomatic patients. The establishment of an early diagnosis or suspicion of cancer is of prime importance. The value of pulmonary cytology in establishing such a diagnosis cannot be overemphasized, but unfortunately, of the reports on young patients, only two even mention the cytologic results. Anderson! reported that only 14 of 30 patients had had a cytologic evaluation, the results of which were suggestive of cancer in only 2 patients. In the 51 patients reported by Neuman and colleagues," positive cytology was found in only 9; however, it was not stated whether all the patients had a cytologic examination. In addition, in neither of these papers is it indicated whether a sufficient number of cytologic specimens were ob-
40 (21)
tained on the patients who did have the examination. In our series, almost half of the patients who had a cytologic examination had a positive or suspicious result, while just over 80 per cent of those who had what we consider to be a minimum cytologic work-up had a positive or suspicious result. Any patient, regardless of age, who has suspicious pulmonary symptoms should be investigated by pulmonary cytology. Approximately 60 per cent of lung cancer patients have exploratory operations, while 30 to 40 per cent have resections- s, "'; in some notable exceptions the resection rates were as high as 95 per cent." It is apparent from inspection of Table VI that our per cent of operable and resectable patients is considerably higher than in previously reported series in young patients. This is in direct contrast to the opinion expressed by Kwong and Slade:" that young patients are more frequently inoperable and unresectable than older patients with lung cancer. These high surgical rates reflect the prevailing view in our geographic area about lung
Volume 67
645
Cancer at lung in young men
Number 4 April, 1974
tumor classification Large cell undif].
UndifJ./ anaplastic
Unclassified
Other types
40.7 (11/27) 28.2 (11/39)
2.6 (1/39 ) 30.8 (8/26 )
7.7 (2/26)
11.4 (5/44) 30.0
(?)
4.0
(?)
10.3 (3/29 )
Per cent operable (No.)
Per cent resectable (No.)
46.7 (14/30 )
16.7 (5/30)
4.8 (1/21 )
37.3 (19/51)
17.7 (9/51 )
0
38.5 (10/26)
15.4 (4/26)
3.8 ( 1/26)
36.4 (16/44)
25.0 (11/44 )
11.4 (5/44)
60.0
?
0
?
40.0 (16/40)
5.7 (2/35)
(?)
Per cent 5 year survival (No.)
15.2 (5/33 )
21.2 (7/33)
82.4 (28/34)
61.8 (21/34 )
18.8 (6/32)
ILl (7163 )
6.3 (4/63)
73.5 (50/68)
54.4 (37/68)
16.4 (11/67)
12.5 (12/96)
11.5 (11/96)
76.5 (78/102)
56.9 (58/102)
17.2 (17 /99)
cancer in young patients. In a poll of seventeen board certified thoracic surgeons, thirteen believed that these patients had a worse prognosis than the usual patient with lung cancer, and ten said they would be more aggressive in their surgical approach to such a patient. Four of the five thoracic surgeons at our institution held this view. Positive bronchoscopic biopsy in young people has varied from a low of 17 per cent to a high of 66 per cent. 1, 18, 26, 30 Over half of our patients who had bronchoscopy had visual evidence of tumor, with about 46 per cent of the biopsies proving to be positive. A history of smoking is prominent in any series of patients with lung cancer. Ninetyfour per cent of our patients had a positive smoking history. In three series in young patients where this information is given, the range has been 87 to 93 per cent.'- 20, 30 In 1,357 lung cancer patients reported by Doll and Hill," only 7 (0.5 per cent) were nonsmokers, with 80 per cent having started smoking before age 20 years and only 3.4
per cent having smoked for less than 20 years. Passey" found that only 4 of 499 men (0.8 per cent) with lung cancer were nonsmokers, with a mean starting age of 17 and an average duration of smoking of 40 years. Wynder and Graham" found that 1.3 per cent of men with lung tumors other than adenocarcinomas did not smoke, while 10.3 per cent with adenocarcinoma were nonsmokers. One half of their patients had smoked for 40 or more years, while only 2.5 per cent had smoked for less than 20 years. Kreyberg" found an almost identical percentage of nonsmokers in his Group I and Group II tumors as did Wynder and Graham, with most having started smoking between the ages of 15 to 19 years and having an average exposure of 40 years. Only 2 of 293 Group I patients had smoked for less than 20 years. In the Philadelphia Pulmonary Neoplasm Research Project, which comprised over 6,000 men, no cancer was found in men who had smoked for less than 20 years.' In our patients, 18 per cent had smoked for less than 20 years, and
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Kyriakos and Webber
almost half had smoked for less than 25 years. The per cent of our patients who began smoking before age 20 years is similar to that reported by Oschner and colleagues," who found that 67 per cent of teen-agers between 16 and 19 years of age had already begun to smoke. Cigarette smoking has been identified by the United States Public Health Service as the major cause of lung cancer in the United States, with the risk directly related to the number of cigarettes smoked per day, the number of years of smoking, the total number of cigarettes smoked in a lifetime, and the age of initiation." The significance of smoking in the younger patients, however, has been debated. Wynder and Graham" found that the younger patients who developed cancer smoked more than older patients. They concluded that the greater the degree of intake, the sooner cancer would develop in the susceptible individual. Passey," however, found that the age of onset of cancer was not related to the amount smoked nor to the age at which smoking began. Kreyberg" also found that the mean age of appearance of lung cancer did not differ if a patient started smoking at age 14 or waited until after age 20 years. He concluded that young men develop lung cancer because they are the most susceptible of those exposed to low-levels of carcinogens. In British studies, Hems";' 17 noted that the lung cancer mortality rate for men ages 20 to 24 years was not correlated with the per capita number of cigarettes smoked but rather with the use of solid fuel; he felt that in this age group lung cancer could be attributed to causes other than cigarette smoking. Kreyberg," however, concluded that the increasing incidence of lung cancer in Norway could not be attributed to air pollution, and Doll and Hill!' were not able to find any gross correlation with occupation nor any more frequent incidence of cancer in those exposed to motor fumes or road dusts. Kreyberg" found that those who work in "dusty" occupations, as well as clerical and professional occupations, are more liable to develop lung cancer than those in
The Journol of Thorocic ond Cordiovasculor Surgery
"open air" or "housework" occupations. Smoke and fumes from industry did not seem to influence lung tumor development, whereas urban living did. In our series, the majority of patients had occupations which kept them indoors. No occupation appeared to predominate, nor did exposure to fumes or dust appear in the background of most of the patients. The prevailing view among our thoracic surgeons is that young patients have a worse prognosis than their older counterparts with lung cancer. In the literature, the 5 year survival rate for all patients with lung cancer is approximately 8 to 9 per cent with occasional figures being somewhat higher." 8, 10, 28, 33 At Barnes Hospital the over-all 5 year survival rate was 8.7 per cent for all patients and 22 per cent for those having curative resections. H Patients below the age of 50 years have been reported to have a better prognosis than older patients. H. 2" Belcher and Anderson," however, found almost identical 5 year survival rates for those patients above and below 45 years of age. They concluded that young patients, including those below age 40 years, have as good a prognosis as the usual patient with lung cancer. In reports specifically dealing with young patients, the prognosis, with few exceptions, has been dismal. Anderson and co-workers! reported only one 5 year survivor in 21 patients who could be traced, and this patient subsequently died of metastatic disease. The average interval till death was 14 months. In addition, they reviewed the literature on the results in children and found only one 5 year survivor among 16 patients. Neuman and associates" reported no 5 year survivors among their young patients who had resections, as compared to a 37 per cent survival rate for resected patients of all ages at the Mayo Clinic. They concluded that the chances of cure or even long-term survival were small for patients under the age of 40 years, and they considered these possibilities practically nonexistent if lymph node metastases were present. Rivkin and Salyer," while having only one 5 year survivor in 26 patients under the age of 40 years, claimed
Volume 67 Number 4 April, 1974
that the disease was no more malignant in this age group than in older patients. However, this was based on a very small number of older patients in the total series. In a series of 33 young patients, Hood and associates> had no 5 year survivors, and only 2 patients were alive after 3 and 4 years, respectively. Kennedy-" who was able to follow only 34 of 40 patients, reported that 2 survived for 5 years. Large and Morgan" reported on five patients, ages 18 to 23, with no survivors and a fairly rapid course from diagnosis to death. The only exception to these dismal results is the report by Kwong and Slade,> who had an 11.4 per cent 5 year survival rate (5/44) with 4 of the 5 survivors being male subjects. The results in our series are in sharp contrast to most of the above reports. We had a total 5 year survival rate of 17.2 per cent for those eligible and a rate of 18.8 per cent for those under the age of 40 years. In an attempt to view our total experience with pulmonary malignancy, we have included cases of carcinoid tumors, lymphoma, and a tumorlet. All of these are lesions with the capability of causing death or metastases, as exemplified by the mention by Kreyberg-" of a metastasizing carcinoid in a 12-year-old boy and by our 13year-old boy who died of "pneumonia" 7 months after surgery for a carcinoid tumor. Since most previous reports have confined themselves to "carcinomas" and have eliminated these tumor types from consideration, we have also reported our survival figures with these lesions eliminated. When this is done, it is seen that the survival figures for the entire group and for those under 40 years of age remain comparable to the survival rates for lung carcinoma patients in general. In fact, the survival figures for the entire group are somewhat better than the previously reported 5 year survival figures at Barnes Hospital. We believe that these results stem from the aggressive attitude of our thoracic surgeons as can be seen in the high operability and resection rates. The incidence of lymph node involvement in operative cases in our series (46.8 per cent) is somewhat lower than the approxi-
Cancer of lung in young men
647
mate figure of 60 per cent reported for older patients generally. 28, 31 While lymph node involvement did lower survival, it is obvious from our results that the mere presence of positive node involvement does not preclude survival, since 6 of our long-term survivors had positive nodes. We could discern no effect on survival of tumor size or pleural involvement. Tumor differentiation also had no effect, as 8 of the survivors had either undifferentiated or poorly differentiated tumors. As in older patients, survival rates were best in epidermoid carcinoma; 32 per cent of patients either survived 5 years or are presently alive without tumor. Similarly, small cell undifferentiated carcinoma had the same dismal prognosis as in older patients, with no patient surviving for more than 3 years. In conclusion, we feel that while differences exist in the cell type of lung cancer in young patients, the prognosis, with the exception of those rare cases occurring in children, is certainly no worse than that found in older patients. While our age limit of 45 years was an arbitrary one, we feel that such a limit is valid when speaking of "young" men with lung cancer. Furthermore, it permits a more realistic appraisal of results due to the larger number of patients which can be analyzed. In support of this, we found no statistically significant differences between patients below or above age 40 years in terms of distribution of tumor cell types, symptomatology, operability, resectability, lymph node or pleural involvement, or survival. Occupation and smoking histories were also similar in both groups. It must be remembered, however, that failure to reject the null hypothesis does not prove that no differences exist, but only that no evidence was demonstrated against the null hypothesis. Interestingly, we found no evidence of an increasing incidence of lung cancer in young patients at our hospital. In fact, more patients were found distributed in the decade 1950 to 1959 than in the years 1960 to 1970. We wish to acknowledge the assistance of Dr. R. Wette and Mrs. Barbara Hixon of the
648
Division of Biostatistics, Washington University School of Medicine, for their statistical analysis of our data. We also thank Dr. Lauren Ackerman for his histologic evaluation of some of our cases. REFERENCES
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