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Ann Thorac Surg 1999;67:1451-1455
© 1999 The Society of Thoracic Surgeons

Original Articles

Young lung cancer patients in Japan: different characteristics between the sexes

Ikuo Sekine, MDa, Yutaka Nishiwaki, MDa, Tomoyuki Yokose, MDb, Kanji Nagai, MDa, Kenji Suzuki, MDa, Tetsuro Kodama, MDa

a Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
b Pathology Division, National Cancer Center Research Institute East, Kashiwa, Japan

Accepted for publication November 20, 1998.

Address reprint requests to Dr Sekine, Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
e-mail: isekine{at}gan2.ncc.go.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Lung cancer in younger people is uncommon and has characteristics that distinguish it from cancer in older patients. The percentage of smokers among younger patients ranges from 40% to 50% in Asia to 90% in Western countries. The prognosis for young patients with this disease is controversial.

Methods. Medical records of 91 young (40 years of age or younger) and 3,221 older (more than 40 years of age) Japanese patients with lung cancer were reviewed to compare smoking habits, distribution of histopathologic types, clinical stage, and survival.

Results. Among female patients, only 39% were smokers in both age groups, whereas smokers were less common among the young male patients (84%) than the older male patients (95%) (p < 0.0001). Adenocarcinomas were diagnosed in 92% of the young and 73% of the older female patients (p = 0.021) versus only 71% and 42% of the corresponding male patients (p < 0.0001). There was no difference in tumor extent or survival between the two groups of female patients. In the male groups, advanced disease (stages IIIB and IV) was more common in the young patients (75%) than in the older patients (54%) (p = 0.0031), but there was no survival difference between the two groups.

Conclusions. Young male and female lung cancer patients in Japan have different characteristics from each other and from older patients of the same sex. Their survival did not differ from that of older patients.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Because several genetic changes are required for a normal progenitor cell to acquire a neoplastic nature, most human cancers tend to occur after the fourth decade of life [1]. Therefore, lung cancer in patients aged 40 years or less is uncommon and has characteristics that distinguish it from cancer in older patients, including a higher incidence of adenocarcinoma and a lower male-to-female ratio in young patients [2–4]. Early onset of the disease has been attributed to heavy smoking, as documented in more than 90% of young patients with lung cancer in Western countries [2, 4–7]. However, only 40% to 50% of young lung cancer patients in Turkey, Mexico, and eastern Asia have reportedly smoked habitually during their lifetime [8–10]. Thus, another factor in addition to active smoking may be involved in the development of lung cancer in young adults with different cultural and genetic backgrounds.

The influence of external factors including smoking on the development of lung cancer should be studied in male and female patients separately because the exposure to these factors and the hormonal environment are different between the sexes [11]. However, no reports involving young lung cancer patients have done this.

The prognosis for young patients with lung cancer is controversial. Some investigators [6, 12, 13] have suggested that lung cancer in this population is more aggressive and more rapidly fatal than in older patients, whereas others [2, 4, 14] have asserted that the prognosis is no worse than that associated with tumors in older patients. McCambridge and Eliasson [13] pointed out that these inconsistent results may be attributable, in part, to selection bias in the study population, and the authors emphasized the importance of including patients with both operable and inoperable disease in the analysis because advanced-stage presentation is very common in young patients.

This retrospective study was designed to characterize young lung cancer patients in regard to smoking habits, distribution of histopathologic types, clinical stage, and survival in comparison to older patients. We analyzed these factors in male and female patients separately because in Japan, smoking habits differ markedly between the sexes.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Of 2,474 lung cancer patients registered at the National Matsudo Hospital from 1977 to 1991 and 899 registered at the National Cancer Center Hospital East from 1992 to 1996, 3,312 were selected for this study. Sixty-one patients were excluded because smoking history data were not available. There were 1,198 surgically treated patients and 2,114 medically treated patients. The median observation period for the study population was 11 months (range, 0 to 207 months) and for the censored patients, 46 months (range, 0 to 206 months).

We categorized the patients into two groups by age: the young group consisted of patients 40 years of age or less and the older group, patients more than 40 years of age. Smoking status (never, former, or current) and the number of cigarettes smoked per day were recorded at the time of admission. Former smokers were defined as patients who had stopped smoking at least 1 year before admission. Histologic types were determined according to the World Health Organization classification of lung tumors [15]. Histologic type was confirmed by histologic examination in 1,508 (71%) of the 2,114 medically treated patients and by cytologic examination alone in 606 (29%).

Pathologic diagnosis in medically treated patients was based on examination of biopsy specimens, postmortem specimens, cytology specimens, or a combination of these. Transbronchoscopic lung biopsy, percutaneous needle biopsy, exploratory thoracotomy, biopsy of metastatic sites, and cytologic examinations were positive in 1,192, 171, 29, 135, and 1,879 patients, respectively, and postmortem examination was performed in 115 instances. Clinical staging was used to estimate tumor extent in both surgically and medically treated patients according to the TNM staging system of the Union Internationale Contre Cancer issued in 1986 [16].

Smoking status, number of cigarettes smoked per day, tumor histology, clinical stage, and survival time were compared between the two age groups for both male and female patients. The {chi}2 test was used to evaluate the significance of observed differences in the proportions of patients in the various outcome categories. The {chi}2 test with Yates’ correction was applied if the observed count in a category was 5 or less. Survival curves were plotted using the Kaplan-Meier method. Survivals for the two age groups were compared with the log-rank test.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Of the 3,312 patients with lung cancer, 91 (2.7%) were 40 years of age or younger. There were 55 male and 36 female patients, for a male to female ratio of 1.5. Of the 3,221 patients in the older group, 2,314 were male and 907, female, for a male to female ratio of 2.6. The patients in the young group were initially treated between March 1977 and February 1996 (median time, January 1988); those in the older group were treated between January 1977 and April 1996 (median time, April 1988).

Among female patients, 39% in both age groups were smokers (former or current), but heavy smokers (40 cigarettes per day or more) were found only in the older group (Table 1). Among male patients, in contrast, there were fewer smokers (former or current) in the young group (84%) than in the older group (95%) (p < 0.0001). In addition, heavy smokers were more numerous in the older male group (18%) than in the young group (7%) (p = 0.056).


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  		Table 1. Clinicopathologic Characteristics of the Two Age Groupsa

 
Distribution of tumor histology differed between young and older groups for both sexes (see Table 1). Adenocarcinomas accounted for 92% of tumors in the young female group versus 73% in the older female group (p = 0.021). Among male patients, 71% of the young group and 42% of the older group had adenocarcinoma (p < 0.0001). There were no differences in tumor extent, treatment, and survival between the two groups of female patients (Fig 1). In male patients, advanced disease (stages IIIB and IV) was more common in the young patients (41/55, 75%) than in the older ones (1,260/2,314, 54%) (p = 0.0031), but there were no differences in treatment and survival between the two groups (Fig 2).



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  		Fig 1. Survival curves by age group for female patients with lung cancer. (Thick line = young group [n = 36]; thin line = older group [n = 907].)

 


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  		Fig 2. Survival curves by age group for male patients with lung cancer. (Thick line = young group [n = 55]; thin line = older group [n = 2,314].)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
We identified 91 young patients (2.7%) among 3,312 lung cancer patients. The male to female ratio of 1:5 in this study for the young group is consistent with other reported ratios in the international literature except those from Italy and France (Table 2). Smokers accounted for only 66% of the young patients with lung cancer. This finding concurs with findings in reports from Turkey, Mexico, and eastern Asia but not with those from Western countries, where more than 85%–90% of young lung cancer patients are heavy smokers (see Table 2).


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  		Table 2. Characteristics of Young Lung Cancer Patients in International Literature

 
The frequency of nonsmokers among female patients was relatively high (61%) and did not differ between the two age groups. However, the percentage of female patients with adenocarcinoma was higher in the young group (92%) than in the older group (73%). Therefore, we should seek causal factors for adenocarcinoma other than active smoking in this population. Exposure to environmental tobacco smoke in childhood and adulthood may be among the factors predisposing to lung cancer in Japanese women [18].

Despite the weak association between smoking and adenocarcinoma in traditional epidemiologic studies, N-nitrosamines in tobacco smoke, which are known to induce lung adenocarcinoma in rodents when injected systematically, have been regarded as one of the major contributors to the development of lung adenocarcinoma [19]. This carcinogen is 20-fold higher in sidestream smoke than in mainstream smoke and is detected in smoking areas at substantial levels. Further, a recent experimental study [20] showed that lung adenocarcinomas developed in mice exposed to environmental tobacco smoke for 5 months. Heavy exposure to N-nitrosamines in environmental tobacco smoke may be one of the causes of lung adenocarcinoma in female patients.

Other types of indoor air pollution are also possible. The odds ratio for lung cancer was increased (1.78; 95% confidence interval, 1.02 to 3.10) in women who had used firewood and straw as fuels for cooking [21]. However, this factor cannot explain the recent increase in the incidence of lung cancer in Japanese women, as few Japanese have used these fuels for daily cooking over the past two decades.

Host factors should also be taken into account, especially in a discussion of the difference between female and male patients. Taioli and Wynder [22] revealed a decreased risk of lung adenocarcinoma in patients with early menopause and an increased risk in those who received estrogen replacement therapy. Thus, endogenous and exogenous estrogen may be associated with adenocarcinoma development in women. Finally, the surprisingly high percentage of adenocarcinoma (92%) in young female patients in this study could be explained by an inherent predisposition to lung adenocarcinoma in these patients. We [23] previously reported that genetic instability was more frequently observed in tumor tissues from young patients than in such tissues from older patients. However, the affected genes remain unknown.

In male patients, lifetime nonsmokers were more common in the young group than in the older group, although this estimate was based on observation of a limited number of patients. The number of cigarettes smoked per day was also fewer in young male patients than in the older group. The percentage of patients with adenocarcinoma was higher in the young group (71%) than in the older group (42%). This figure was greater for both male and female patients than data reported from other countries (see Table 2). One possible explanation for the higher percentage of adenocarcinoma in young men is the relatively low incidence of squamous cell carcinoma in this population; an analysis [24] of the relationship between the duration of cigarette use and the risk of lung cancer exhibited a steeper gradient for the risk of squamous cell carcinoma than for adenocarcinoma. Moreover, a factor other than smoking for the development of lung cancer may play a role in disease development in nonsmoking young men, although smoking is still the major factor in the remaining 84% of young male patients.

Young patients with lung cancer often have advanced disease at the time of diagnosis [6, 12]. This study confirmed the percentage with advanced disease to be higher in the young group than in the older group among male patients. Pemberton and associates [12] pointed out that because lung cancer is rare in younger people, respiratory symptoms are often minimized and initially considered benign conditions and consequently are overlooked until the disease has reached an advanced stage. In female patients, however, we found no difference in the percentage with advanced disease between young and older patients. Differences in the level of concern regarding health and disease shown by men and women in Japan may be reflected in these results.

It has been suggested that lung cancer in young patients is aggressive and highly malignant in nature [13]. The low degree of tumor differentiation and the high frequency of vascular invasion noted in these tumors tend to support this idea [23]. However, the survival of young patients did not differ from that of the older patients in this study analyzing both surgically and medically treated patients. None of the reports [6, 12, 13] indicating a poor prognosis for young lung cancer patients presented survival curves for both young and older patients. Thus, we are convinced that there is no difference in survival between young and older lung cancer patients.

The major limitation of this study was the accuracy of the smoking history data. Misclassification of smoking habits can lead to incorrect estimation of smoking in patients with lung cancer. Lee [25] pointed out that the rate of misclassification was high in Japan, especially among nonsmoking women. However, any such inaccuracy presumably would have been distributed randomly between the young and older groups in this study.

In conclusion, young male and female lung cancer patients in Japan have different characteristics from each other and from older patients of the same sex. Survival of young patients with lung cancer did not differ from that of older patients, although the percentage of men with advanced disease was higher in the young group than in older group.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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  7. Nugent W.C., Edney M.T., Hammerness P.G., Dain B.J., Maurer L.H., Rigas J.R. Non–small cell lung cancer at the extremes of age: impact on diagnosis and treatment. Ann Thorac Surg 1997;63:193-197.[Abstract/Free Full Text]
  8. Tsai C.M., Perng R.P., Huang W.L. Lung cancer in young Chinese. Cancer Detect Prev 1988;11:235-238.[Medline]
  9. Misirligil Z., Gurbuz L., Sin B., Doganay K., Tuccar E. Lung cancer in young patients in Turkey. J Pakistani Med Assoc 1988;38:38-40.
  10. Green L.S., Fortoul T.I., Ponciano G., Robles C., Rivero O. Bronchogenic cancer in patients under 40 years old. The experience of a Latin American country. Chest 1993;104:1477-1481.[Abstract/Free Full Text]
  11. Ernster V.L. Female lung cancer. Annu Rev Public Health 1996;17:97-114.[Medline]
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  13. McCambridge M.M., Eliasson A.H. Lung cancer in the young [Letter]. Ann Thorac Surg 1993;55:809-810.
  14. Roviaro G.C., Varoli F., Zannini P., Fascianella A., Pezzuoli G. Lung cancer in the young. Chest 1985;87:456-459.[Abstract/Free Full Text]
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  17. Icard P., Regnard J.-F., de Napoli S., Rojas-Miranda A., Dartevelle P., Levasseur P. Primary lung cancer in young patients: a study of 82 surgically treated patients. Ann Thorac Surg 1992;54:99-103.[Abstract]
  18. Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan. Br Med J 1981;282:183-185.
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