|Year : 2017 | Volume
| Issue : 1 | Page : 172-177
The increasing challenge of never smokers with adenocarcinoma lung: Need to look beyond tobacco exposure
A Das1, A Krishnamurthy1, V Ramshankar2, TG Sagar3, R Swaminathan4
1 Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Preventive Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
3 Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
4 Division of Epidemiology and Biostatistics, Cancer Institute (WIA), Chennai, Tamil Nadu, India
|Date of Web Publication||1-Dec-2017|
Dr. A Krishnamurthy
Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
BACKGROUND: Lung cancer continues to remain as one of the leading causes of morbidity and mortality worldwide, despite the decreasing trends in smoking prevalence worldwide. An earlier study from the authors' institute reported the increasing trends of “Nonsmoking associated lung cancers.” MATERIALS AND METHODS: All consecutive histologically confirmed patients with lung cancer who presented to the outpatient department over a year (November 2014–October 2015) were included in this current prospective study. RESULTS: Seven hundred and thirteen patients presented with clinicoradiologically suspicious findings of lung cancer in the said period. A pathological confirmation of lung cancer could be ascertained in 495 patients, and this cohort was further analyzed. The mean age of presentation was 57.76 years; the male to female ratio was approximately 2.5:1. Interestingly, 55.35% of the patients were nonsmokers. Adenocarcinoma (63%) was the predominant histology. Never smokers, both among men (P = 0.02) and women (P = 0.001), presented more frequently with adenocarcinoma histology. Further, 84.9% (45/53) of rural and 76.1% (19/25) of urban women who were never smokers reported exposure to indoor air pollution (secondhand smoke/fuel used for cooking purposes) which was significantly associated with adenocarcinoma histology. CONCLUSION: Our study confirmed our initial observation of the changing epidemiology of lung cancer in the Indian subcontinent, paralleling the global trends of rise in adenocarcinoma. Lung cancer in never smokers outnumbering that among smokers was another interesting observation. The take-home message for both the clinicians as well as the policymakers is to study factors beyond tobacco exposure to understand the direction of the current lung cancer epidemic.
Keywords: Adenocarcinoma, epidemiology, histology, lung cancer, never smokers, nonsmall cell lung cancer
|How to cite this article:|
Das A, Krishnamurthy A, Ramshankar V, Sagar T G, Swaminathan R. The increasing challenge of never smokers with adenocarcinoma lung: Need to look beyond tobacco exposure. Indian J Cancer 2017;54:172-7
|How to cite this URL:|
Das A, Krishnamurthy A, Ramshankar V, Sagar T G, Swaminathan R. The increasing challenge of never smokers with adenocarcinoma lung: Need to look beyond tobacco exposure. Indian J Cancer [serial online] 2017 [cited 2020 Mar 29];54:172-7. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/172/219577
| » Introduction|| |
Lung cancer has transformed from a rare disease into a global epidemic., It is currently one of the leading causes of morbidity and mortality worldwide, accounting for more deaths than any other type of cancer. Many epidemiological studies from India performed across varied demographic cohorts suggest a significantly rising burden of lung cancer in India as well. Traditionally, lung cancer is most commonly attributed to tobacco smoking and termed as smoker's disease. However, an earlier study from the authors' institute reported the increasing trends of “Nonsmoking associated lung cancers;” a similar trend was also seen in a few other published studies from the Indian subcontinent. A larger prospective study aimed at confirming our initial findings was planned, and this formed the basis of the present study.
| » Materials and Methods|| |
The present study was an analysis of prospectively collected data of all consecutive histologically confirmed patients with lung cancer who presented to the outpatient department at a tertiary care center in Chennai, India, over a period of 1 year, from November 2014 to October 2015. A comprehensive questionnaire administered by two trained and dedicated social workers captured all the demographic details including age, sex, occupation, smoking habits including exposure to secondhand smoke, and type of cooking fuel among others. The clinical details pertaining to histopathology stage at presentation among others were captured by the first author. The data were entered and analyzed using SPSS software (SPSS for Windows, version 22.0, Chicago, IBM SPSS Inc.).
| » Results|| |
A total of 713 patients presented with clinicoradiologically suspicious findings of lung cancer in the said period. A pathological confirmation of lung cancer could be ascertained in 495 patients, and this cohort was further analyzed [Table 1].
The mean age of patients in the study was 57.76 years (standard deviation [SD] =10.44, range between 31 and 85 years [SD = 10.44]). The mean age among the smokers (57.14 years) was not statistically significant when compared with the never smokers (58.53 years). The mean age among men was 58.14 years, while among women, it was 56.81 years. More than half of the patients (54.7%) were in the age group 41–60 years, 5.1% were in the <40 years group, and 40.2% were >60 years.
The male to female ratio was approximately 2.5:1, comprising 354 (71.5%) males and 141 (28.5%) females. A large proportion of females (97.8%) were never smokers as compared to only 38.4% males being never smokers (P = 0.001).
Smoking and tobacco use
Of the 495 patients, 274 patients (55.4%) had no history of smoking as compared to 221 patients (44.6%) who were current smokers. A great majority of the smokers (98.6%) were males, and only three females had a history of smoking. Of the 274 never smokers, 22 (8.1%) patients consumed smokeless tobacco, while among smokers, 13 patient (5.9%) additionally also consumed smokeless tobacco.
Nonsmall cell lung cancer (NSCLC) was the predominant histology in 271 patients (95.2%) while small cell lung carcinoma was diagnosed in 24 patients (4.8%). Within NSCLC, the most common histology was adenocarcinoma (62.9%), followed by squamous cell carcinoma (23.6%), large cell carcinoma (0.9%), and others (0.6%). In 35 patients (7.1%), only cytology-based diagnosis was done, and subclassification was hence not possible.
Histology, smoking habit, and gender correlations
Adenocarcinoma was the most common histology both among never smokers (73.3%) and smokers (48.9%), but it was significantly more common among never smokers (204/312; 65.4%) (P = 0.005) [Table 2]. Squamous cell carcinoma was more commonly seen among smokers (76/117; 65%) than in the never smokers (35%). Small cell lung cancer was marginally higher among smokers (13 vs. 11 cases among the never smokers). In addition, we found that among male smokers, squamous cell carcinoma (75/218; 34.4%) is a statistically significantly higher than in never smokers (27/138; 19.5%) (P = 0.05). Among females, adenocarcinoma was the most common histology both in never smokers (110/138; 79.7%) and smokers (2/3; 66.7%) (P = 0.60).
The urban to rural ratio was approximately 1:1.25. The distribution of smokers was not significantly different among the two populations (rural - 45.8% vs. urban - 43.2%, P - 0.31) Smoking among females was only seen among urban population (4.5%) (P = 0.001).
Exposure to indoor air population
Data regarding fuel used for cooking and household use were also captured in this study. Among the urban population, 78 patients of 125 never smokers (62.4%) are not exposed to indoor air pollution causing fuel, but in rural population, 95 out of 149 patients (63.8%) are exposed to indoor air pollution (P = 0.012). Among the never-smoking females, 23 of 63 urban and 53 of 75 rural women were exposed to indoor air pollution. Interestingly, 84.9% (45/53) of rural and 78.3% (18/23) of urban women who were never smoker reported exposure to indoor air pollution which was significantly associated with adenocarcinoma histology (P = 0.001) [Table 3].
|Table 3: Correlation of histology of never smoking females based on indoor air pollution exposure|
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Smoking is more prevalent among patients engaged in agriculture, daily wage laborer, and drivers. The prevalence of smoking was less among teachers and the service class and was virtually nonexistent among the housewives.
The most common symptom at presentation was cough (78.8%) followed by dyspnea (57.8%). Other symptoms at presentation included anorexia (39.2%), loss of weight (38.8%), chest pain (35.8%), hemoptysis (20.2%), hoarseness (8.7%), and fever (6.5). Hemoptysis and hoarseness incidentally were observed to be more common among smokers than the never smokers. Sixteen patients were diagnosed incidentally (asymptomatic at presentation) and out of which 12 were never smokers. Further, in our study, >75% patients presented with a delayed diagnosis (>6 months of symptom presentation) either due to self-medication without consulting any physician (43.2%) casual symptomatic treatment for respiratory tract infection by the treating physician (25.9%) or starting empirical antitubercular treatment (8.5%) [Table 4].
All patients were staged based on the 7th edition of American Joint Committee on Cancer tumor-node-metastasis (TNM) staging. Majority of patients presented at advanced stage of disease with 343 patients (69.3%) in Stage IV and 108 patients (21.8%) in Stage III. Presentation at an advanced stage of disease was not significantly different between smokers and the never smokers.
Our study showed that never smokers presented in a better performance status than the smokers. A total of 118 patients (62.4%) who were never smokers presented in Eastern Cooperative Oncology Group performance status of 1 as compared to smokers, only 71 patients presented in performance status 1 (37.6%). Patients presenting in performance status 3 or 4 were mostly smokers (53.1%) (P = 0.007).
Fifty-three percent of the patients were deemed suitable only for best supportive care. Only 97 patients (19.6%) were offered potentially curative treatment, and radical surgery accounted for <3% of the overall management. Irrespective of the smoking status, only a minority of patients were suitable to receive treatment with the intent to cure, and majority landed up with palliative therapy.
| » Discussion|| |
Lung cancer is the most common cause of death from cancer worldwide, accounting for more deaths than any other type of cancer. Because of its high fatality (the overall ratio of mortality to incidence is 0.87) and the relative lack of variability in survival across the world, the patterns in mortality closely follow those in incidence.
According to the GLOBOCAN 2012, the estimated incidence of lung cancer in India was 70,275 cases, which included 53,728 new lung cancer cases among the males and 16,547 new lung cancer cases among the females. Lung cancer incidence in India is very diverse among various regions with its inherent cultural differences as well. According to the National Cancer Registry Program, the rising trends in lung cancer are seen in the major metropolitan cities of New Delhi, Chennai, Mumbai, Bengaluru, and Kolkata. The highest incidence is reported from Manipur state (17.5%). Lung cancer is the most common malignancy among females reported in Mizoram (15.6%). The estimated lung cancer mortality in India in 2012 was 63,759, making it the third most common cause of cancer-related mortality in India after breast and cervical cancer. Among Indian males, lung cancer was the most common cause of cancer mortality at 48,697; the estimated lung cancer mortality among Indian females was 15,062, ranking seventh in terms of cancer-related mortality.
The present demographic trends of lung cancer in India seem to be similar to that seen in the West approximately four decades prior. There appears to be an increase in the mean age of diagnosis of lung cancers in India over the past several decades, from 52.16 years during 1958–1985 to 54.6 years during 1985–2001. The mean age of patients in the present study was 57.76 years. Never smokers tended to present at an earlier mean age than smokers, but this association was not found to be significant.
Lung cancers have traditionally been perceived as a disease of males with a male to female ratio ranging from 5.76:1 to 6.67:1 in the previously published data from Indian studies; however, over the decades, the gap seems to be narrowing down. According to the GLOBOCON 2008 and 2012, the male to female ratio in Indian population was 4.2:1 and 3.25:1, respectively. Published data from the author's institute of consecutive hospital inpatients with lung cancer in 2012 reported a ratio of 3.5:1, the male to female ratio was seen to be further narrowed in the present study (2.5:1).
Traditionally, lung cancer was most commonly attributed to tobacco smoking and was hence termed as smoker's disease. Sir Richard Doll landmark article in the 1950s described the increasing evidence that lung cancer was associated with cigarette smoking. The 1962 report by the Royal College of Physicians and the 1964 warning by the Surgeon General of the United States further established the correlation between cigarette smoking and lung cancer., The published data on lung cancer epidemiology in India over the decades reflect the impact of industrialization and smoking trends. Prior studies from India have shown that the risk of lung cancer varies according to the type of tobacco consumption. Bidi smoking is another popular form of tobacco use across India conferring a high risk of lung cancer. Several studies have reported a higher odds ratio of bidi smoking in comparison with cigarette smoking, with a relative risk of developing lung cancer is 2.64 for bidi smokers and 2.23 for cigarette smokers.
Currently, despite the decreasing trends in smoking prevalence worldwide, the incidence of lung cancer continues to rise. The World Health Organization report on worldwide smoking prevalence of 2015 states that in India, the smoking prevalence among males has decreased from being 29.5% in 2005 to 20.4% in 2015, and among females, it has decreased from 4.6% in 2005 to 1.9% in 2015. The smoker to never smoker ratio has been lower in most of the Indian studies compared to those in the West. In our study, a more than half of our patients (55.4%) were never smokers; interestingly, 38.4% of the males were never smokers.
In the Western world and most of Asian countries, adenocarcinoma has surpassed squamous cell carcinoma as the most common histology in lung cancer. The shift is mainly due to change in smoking habits and mainly due to increasing incidence among the never smokers and females. Devesa et al. had initially suggested the trend of a shift in histology from squamous cell carcinoma to adenocarcinoma which was subsequently confirmed in many other studies. Two possible hypotheses to explain the trend were cited, the first pertains to the changing patterns in smoking – with the switch from unfiltered to filtered cigarettes, wherein the depth of inhalation may possibly have been altered. The second hypothesis pertains to the nature of carcinogens in tobacco – reduction in the yield of carcinogenic polycyclic aromatic hydrocarbons with an increase in the yields of carcinogenic tobacco-specific N-nitrosamines, the former being inducers of squamous cell carcinoma and the latter being inducers of adenocarcinomas.,
The majority of the Indian studies published before the last decade and a few recent studies have showed squamous cell carcinoma to be the most common histological subtype followed by adenocarcinoma and small cell carcinoma.,, However, single-center studies from the premier regional cancer center's points toward adenocarcinoma being the most common NSCLC subtype.,,
In a study of 489 patients from the Tata Memorial Hospital, Mumbai, 52% of the lung cancer patients were found to be never smokers, with adenocarcinoma being the most common histology at 43.8% followed by squamous cell carcinoma at 26.2%. The change in epidemiology and histology of lung cancer was also reflected upon by our earlier publication in a cohort of 258 consecutive hospital inpatients with lung cancer over 5 years. Adenocarcinoma was that the most common histology (42.6%), followed by squamous cell carcinoma (15.6%), large cell carcinoma (2.3%), and others (7%). Our present study in a way confirmed the findings of our earlier publication, with adenocarcinoma being the most common histology at 62% followed by squamous cell carcinoma (23.6%), small cell carcinoma (4.8%), and large cell carcinoma (0.9%) Further, on correlation with gender and histology, our study showed that adenocarcinoma was the most common histology both among never smokers and smokers, but it was significantly more common among never smokers. However, squamous cell carcinoma was the most common histology among the smokers.
In another study of 434 pathologically confirmed lung cancer cases registered at the All India Institute of Medical Sciences, New Delhi, over 3 years, squamous cell carcinoma was the most common histological subtype (33.33%) as per the initial independent review; however after an expert pathological review, adenocarcinoma was found to be the most common histology (37.3%), thus emphasizing the critical role of molecular pathology in the diagnosis of lung cancer.
There are inherent challenges with regard to obtaining a histological diagnosis of lung cancers as were seen in our study as well. A formal diagnosis of lung cancer could be made in only about 70% of the cases which were clinicoradiologically suspicious of lung cancer; the reasons for the same primarily being that many patients with poor performance status wished to follow-up with their primary physician once they were deemed to be candidates for best supportive care. Despite the clinical challenges of more invasive procedures and increased technical difficulties with the resultant delay in initiation of treatment while waiting for the results of diagnostic testing, there is a need for every institution to develop a multidisciplinary tissue management protocol to obtain adequate specimens and process them, not only for the initial diagnosis but also for subsequent molecular testing. Historically, the pathologist had only to distinguish between small cell lung cancer and NSCLC to enable appropriate treatment decisions as there were little therapeutic implications, so little attention was given to the subtyping of nonsmall cell lung carcinomas. This situation has changed dramatically over the years with the management of advanced NSCLCs becoming increasingly complex and treatment algorithms personalized based mutation profiling in addition to the histology-based classification, aiming at better therapeutic outcomes.,,,,,,,,
Lung cancer in the never smokers possibly involves complex interplay of genetic and environmental mechanisms.,,,,,,,,,,,, Over the past decade, it has become evident that subsets of NSCLC can be further defined at the molecular level by the presence of “driver” mutations that occur in multiple oncogenes. Never smokers with adenocarcinoma tend to have a higher incidence of epidermal growth factor receptor, anaplastic lymphoma kinase, human epidermal growth factor receptor 2, RET, and ROS1 mutations. The heterogeneity of the lung cancers has compelled the belief that mutation profiling of the lung tumor samples of all patients might have implications in lung cancer management as well. Many small molecule inhibitors are currently available or being developed for specifically targeting the molecularly defined subtypes of NSCLC patients.,,,,
The environmental factors implicated in lung cancer in never smokers include exposure to secondhand smoke, environmental tobacco smoke, and other indoor air pollutants. Secondhand smoking and environmental tobacco smoke are well-known lung carcinogens, and exposure to this has been known to predispose to lung cancer incidence and mortality. A meta-analysis of 41 studies showed that environmental tobacco exposure carried a relative risk of developing lung cancer of 1.48 in males and 1.2 in females, the risk increasing with an increasing level in exposure. Occupational exposure further resulted in a relative risk of 1.16. There is an increasing risk with an increase in the number of smokers in the house and in the duration of exposure.
Studies from China have shown that coal burning at home is a significant risk factor for the development of lung cancer in nonsmoking females., In a study of the risk factors of lung cancer, the cumulative exposure to indoor air pollution of >45 years in women from the use of coal or wood for cooking or heating showed an odds ratio of 1.43 (confidence interval = 0.33–6.30). A study from a tertiary center at Nepal reported household air pollution to be a lung cancer risk factor among Nepalese population with a reported odd ratio of 1.77.
There is little information in the Indian literature with regard to the above-mentioned environmental factors, and this was additionally studied in our patient cohort. Our study revealed that among the never-smoking females, 23 of 63 urban and 53 of 75 rural women were exposed to indoor air pollution. Interestingly, 84.9% (45/53) of rural and 78.3% (18/23) of urban women who were nonsmoker reported exposure to indoor air pollution which was significantly associated with adenocarcinoma histology.
We had smokers and the never smokers, both being diagnosed at an advanced stage of the disease, with 343 patients (69.3%) in Stage IV and 108 patients (21.8%) in Stage III (7th edition of TNM staging). The intent of treatment was only palliative in approximately 80.5% patients. Surgery accounted for only 2.2% of the cases.
The advance stage at presentation of lung cancer in a majority of the reported studies in India, including the present study, can be possibly partly explained due to patient's ignorance in reporting the symptoms on time to physician and misinterpretation of the chest radiological findings on the part of physician to be tuberculosis/respiratory tract infection., The symptoms such as cough, hemoptysis, breathlessness, chest pain, and weight loss are common to both tuberculosis and lung cancer. A country where in tuberculosis is still rampant and can mimic the radiological picture of lung cancer; a physician needs to be wary of starting antituberculosis therapy for suspicious opacities on the chest skiagrams without a proper evaluation.
The quality of the data acquired from the hospital-based registries of the various regional cancer centers may be confounded by incomplete penetrance of disease registration, resulting in a possible underestimation of the overall burden. However, many studies from the Indian subcontinent including ours confirm the global trend of a rise in adenocarcinoma; there is a further need to better understand the alarming rise in the incidence of lung cancer among the never smokers, both from the clinical as well as the molecular perspective. The discovery of epithelial growth factor receptor mutations in NSCLCs and the success of tyrosine-kinase inhibitors in treating these patients have led to increased molecular screening and the identification of additional oncogenic driver mutations in >55% of patients of NSCLC. There has been a renewed buzz about immunotherapy in the management of advanced lung cancer with the immune checkpoint inhibitors against the programmed death-1/programmed death-ligand 1 axis showing increased overall survival in randomized clinical trials, which has subsequently led to the approval of nivolumab, pembrolizumab, and atezolizumab. Despite this progress, a majority of patients harboring the novel mutation or translocation have no approved targeted therapies, despite many being currently evaluated in clinical trials.
| » Conclusion|| |
Our study confirmed our initial observation of the changing epidemiology of lung cancer in the Indian subcontinent, paralleling the global trends of rise in adenocarcinoma. Lung cancer in never smokers outnumbering that among smokers was yet another interesting observation. A large study of all the environmental factors, preferably population-based, can possibly better explain the above trends. Further, systematic prospective genotyping of all the lung cancer tumors can help in unraveling the molecular mechanisms involved, and this can further aid in realizing the promise of personalized cancer care. The take-home message for both the clinicians as well as the policymakers is to study factors beyond tobacco exposure to understand the direction of the current lung cancer epidemic.
We wish to acknowledge the contribution of Ms. Sahaya Delma and Ms. Gayathri, Social Workers from our center, for their contribution toward the data capture.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]
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