Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 4  |  Page : 771-779

A clinico-epidemiological, pathological, and molecular study of lung cancer in Northwestern India


1 Department of Medical Oncology, Artemis Hospital, Gurugram, Haryana, India
2 Department of Medical Oncology, Army Hospital Research and Referral, New Delhi, India

Date of Submission03-Jun-2017
Date of Decision20-Aug-2017
Date of Acceptance26-Feb-2018
Date of Web Publication30-Oct-2018

Correspondence Address:
Sundaram Viswanath
Department of Medical Oncology, Army Hospital Research and Referral, New Delhi
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_473_17

Rights and Permissions
 > Abstract 


Introduction: Lung cancer is the most common malignant disease and is the topmost cause of cancer deaths in the world across all age groups and in both sexes. It is the most common cause of cancer deaths in developed countries and is also rising at an alarming rate in the developing countries.
Objective: The present study was undertaken to explore the clinicopathological and molecular profile of bronchogenic carcinoma in northwestern population of India.
Materials and Methods: A total of 136 consecutive patients with histologically proven bronchogenic carcinoma, registered between May 2014 and April 2016 at a tertiary care hospital in New Delhi, India, were analyzed.
Results: Out of a total of 136 diagnosed cases, 6% were in the third to fourth decade of life, 49% in the fifth to sixth decade, and 45% in the seventh decade and above. Seventy-one percent of patients were male. Smoking was the major risk factor in 65.40% of patients. About 33% of female patients were smokers with a significant overlap in the use of smoking objects. Twenty-one percent of patients had been initially empirically treated with antitubercular therapy. Most common symptoms at presentation were cough, dyspnea, weight loss, and chest pain. Pleural effusion, paraneoplastic phenomenon, clubbing, peripheral lymphadenopathy, and Pancoast syndrome were the major signs at presentation. Twenty-one percent of nonsmokers and 40% of smoker patients presented with ECOG Performance Status 3 or 4. Ninety-three percent of patients presented in stage III or IV. Metastases to skeleton, brain, liver, pleura, adrenals, lung, and distant lymph nodes were present in 30.8%, 16.9%, 15.4%, 15.4%, 14.7%, 13.2%, and 11.8%, respectively. Fiberoptic bronchoscopy was found to be the most efficient diagnostic procedure as compared to transthoracic and thoracoscopic methods. Histologically, squamous cell carcinoma, adenocarcinoma, and small cell carcinoma and its variants were seen in 35.30%, 44.9%, and 15.40% cases, respectively. Nearly 4.4% of patients were diagnosed as poorly differentiated carcinoma. Driver mutations (epidermal growth factor receptor or anaplastic lymphoma kinase) were detected in 48% (25 of 52 tested) of adenocarcinomas and 55.55% (5 of 9 tested) of young, nonsmoker, female squamous cell carcinoma patients.
Conclusion: This study highlights that the adenocarcinoma incidence is surpassing squamous cell carcinoma in Indian lung cancer patients also, as observed in Western population. Mean age at diagnosis is about one decade earlier than in the Western population. Driver mutations are more common in India than in the West as also reported in other Asian studies.

Keywords: Adenocarcinoma, bronchogenic carcinoma, driver mutations, squamous cell carcinoma


How to cite this article:
Darling H S, Viswanath S, Singh R, Ranjan S, Pathi N, Rathore A, Pathak A, Sud R. A clinico-epidemiological, pathological, and molecular study of lung cancer in Northwestern India. J Can Res Ther 2020;16:771-9

How to cite this URL:
Darling H S, Viswanath S, Singh R, Ranjan S, Pathi N, Rathore A, Pathak A, Sud R. A clinico-epidemiological, pathological, and molecular study of lung cancer in Northwestern India. J Can Res Ther [serial online] 2020 [cited 2020 Sep 23];16:771-9. Available from: http://www.cancerjournal.net/text.asp?2020/16/4/771/244463




 > Introduction Top


As per the Centers for Disease Control and Prevention global cancer statistics (2012), lung cancer accounted for 13% of all cancers diagnosed worldwide (i.e., 1.8 million) and it caused 19% of all cancer deaths killing 1.6 million people. Smoking is responsible for about 85% of lung cancers in the world. There are other exogenous carcinogens undoubtedly proven to cause lung cancer. Of late, studies have shown changing smoking patterns and histology trends, variable geographic clinico-epidemiological profile, molecular characteristics, and treatment responses. This emphasizes the importance of meticulous data collection, sharing of data, and experiences in different geographic and socioeconomic strata. In this context, we present this study about clinico-epidemiological, histological, and molecular profile of lung cancer in Northwestern India.[1]


 > Materials and Methods Top


Study area and study population

All patients visiting our center, with suspected or proven diagnosis of lung cancer, between May 2014 and April 2016 based on the inclusion criteria were included. Majority of our clientele were from Northwestern India.

Inclusion criteria

  1. Histologically proven diagnosis
  2. Any performance status (PS)
  3. Any age/sex
  4. Irrespective of smoking history
  5. Treatment naïve.


Exclusion criteria

  1. Unavailability of histopathological diagnosis
  2. Alternative medication
  3. Previously treated.


Study duration

The study was conducted between May 2014 and April 2016.

Study design

This was a prospective analytical study.

Data collection methods

Each patient included in the study was allotted a unique identity number for the ease of data collection. At each visit of the patient to the hospital, the data were updated in the records.

Methodology

Patients were initially questioned about the demographic status, assessed through detailed history of present illness, history, personal habits, comorbidities, and examination for clinical signs and PS. Selected patients were subjected to appropriate procedure to obtain tissue diagnosis from a primary site, e.g., transbronchial/transthoracic lung biopsy/fine needle aspiration, or a metastatic site, e.g., pleural fluid aspiration or peripheral lymph node sampling. Biopsy was preferred for better yield, tissue characterization, and molecular typing. Obtained tissue was sent for histopathology examination and immunohistochemistry (IHC) as per the latest World Health Organization (WHO) guidelines. Molecular analysis was done for epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK) mutation on all adenocarcinoma patients where sufficient tissue was available and on some of the young, nonsmoker squamous cell carcinoma patients. EGFR mutation was tested by “polymerase chain reaction and gene sequence analysis” for exons 18–21 of EGFR gene. These samples were also tested for ALK mutation by IHC using “Ventana anti-ALK (D5F3) rabbit monoclonal primary antibody along with Ventana detection kit using Ventana Benchmark XT autostainer.” Staging evaluation was done by imaging (contrast-enhanced computed tomography [CT], whole-body positron emission tomography/CT, brain magnetic resonance imaging, bone scan as required).

Data analysis

The data were entered in the excel sheet and then analyzed through the SPSS-23 software (IBM, New York, USA) through univariate and multivariate analysis. Appropriate statistical tests, such as Pearson's Chi-square test, were applied to establish the significance of correlation between different variables.


 > Results and Observations Top


Among the 136 patients, 97 were male and 39 were female, with a male to female ratio of 2.48. Eight (5.9%) patients were between 21 and 40 years of age, 67 (49%) were between 41 and 60 years of age, and remaining 61 (45%) patients were above 60 years [Table 1]. Median age was 60 years, and mean age was 57.6 years. The youngest patient was a 26-year-old male and the eldest patient was a 78-year-old male. One hundred and twelve patients were from rural background with poor educational and socioeconomic status. Fifty-seven of them were farmers. Seventy-eight percent (76 out of 97) of males and 33% (13 out of 39) of females were smokers. This correlation was statistically significant (P = 0.001). Majority (70%) of them were heavy smokers. Among the heavy smokers, about 50% had a smoking index (SI) of more than 1000. Most of them smoked beedis and also consumed smokeless tobacco in various forms. Some of the smokers (5%) were mixed smokers, who smoked beedis, cigarettes, chilm, as well as hucca in various proportions.
Table 1: General description of the study population (n=136)

Click here to view


Among all patients, 2.2%, 5.1%, 58.8%, 31.6%, and 2.2% presented with a Karnofsky PS of 0, 1, 2, 3, and 4, respectively. Out of 80 patients presenting with PS 2, 37 were of adenocarcinomas, 27 were of squamous histology, and seven were of small cell lung cancer (SCLC) histology. Among the 43 patients presenting with a PS of 3, 13 were of adenocarcinoma, 17 were of squamous histology, and 11 were of small cell histology. Fifty-nine percent (53 out of 90) of patients presenting with PS 0–2 were smokers, whereas 78% (36 out of 46) of patients with PS 3–4 were smokers. Most common symptom [Table 2] at presentation was cough (53.7%). Most of them had dry cough. Dyspnea was the second most common symptom (45%); however, severe symptomatic dyspnea (modified Medical Research Council [MMRC] Grade III–IV) was only 16.2%. Other symptoms in the decreasing order of frequency were weight loss (25.7%), chest pain (22.1%), hemoptysis (21.3%), anorexia (14.7%), and hoarseness (9.6%). Apart from that, many patients had symptoms attributable to local effects of tumor, metastases, comorbidities, secondary infections, and paraneoplastic phenomenon. About 20% of patients had minimal or mild pleural effusion. Twenty-one percent had one or other manifestations of paraneoplastic phenomenon which included anemia (17%), leukocytosis (9.5%), thrombocytosis (21%), deep venous thrombosis (4%), and syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) (5%) (2 SCLC and 2 adenocarcinoma and hypercalcemia). Clubbing was seen only in 11.8% of patients and peripheral lymphadenopathy was found in 11%. Eight percent of patients manifested with Pancoast syndrome and 2.2% had Horner's syndrome also. Superior vena cava obstruction syndrome was the presentation in 3.7% of patients, majority of whom were small cell lung carcinomas [Table 3]. Five percent of patients had no symptoms related to lung cancer at presentation, and they were incidentally detected at an earlier stage. Patients presenting at stage I, II, III, and IV were 6 (5 nonsmokers and 1 smoker), 3 (all smokers), 35 (9 nonsmokers and 26 smokers), and 92 (33 nonsmokers and 59 smokers), respectively. Most common metastatic site [Table 4] was skeletal (30.8%). Other common sites were brain (16.9%), liver (15.4%), pleura (15.4%), adrenal (14.7%), contralateral lung (13.2%), and distant lymph nodes (11.8%). Two patients also had choroidal metastases. There was no statistically significant correlation of sex with the stage at presentation. Smoking status did not have a statistically significant correlation with stage (P = 0.2) and PS (P = 0.122).
Table 2: Presenting symptoms

Click here to view
Table 3: Presenting signs and laboratory findings (number of patients=136)

Click here to view
Table 4: Sites of metastases (total number of patients=136)

Click here to view


Fiberoptic bronchoscopy (FoB) was maximally and successfully utilized as compared to transthoracic and thoracoscopic methods, which were associated with more complications. Bronchoscopy showed positive findings, e.g., mucosal rugosities, hyperemia, nodularity, chinking of airways, and endobronchial growths in 47% of patients, and it yielded adequate tissue in most of them (42.6%). Histopathology and IHC were performed in all cases depending on tissue availability. Most common histology in this study was adenocarcinoma (44.9%). Among adenocarcinoma group, majority were poorly differentiated (33.1%). Second common histology was squamous cell carcinoma. Third common histology was neuroendocrine tumors (15.4%) which included SCLC, neuroendocrine carcinoma, large cell neuroendocrine carcinoma, and typical and atypical carcinoids. Rest of them were poorly differentiated carcinomas (4.4%). Adenocarcinoma histology [Table 5] was more common in females (27 of 39), squamous cell carcinoma was more common in males (42 of 97), and small cell carcinoma was equally common in both genders (15 of 97 in males and 6 of 39 in females, P = 0.001). Relationship of disease histology was highly significant with the smoking status [Table 6], adenocarcinoma being more common in nonsmokers and squamous and small cell carcinoma in smokers (P = 0.001).
Table 5: Correlation of sex with other variables

Click here to view
Table 6: Correlation of smoking status with other variables

Click here to view


Out of 61 adenocarcinomas, 52 were tested for mutations. Twenty-seven were negative, 16 were positive for exon 19 mutation (30.7%), one positive for exon 20 (1.9%), five positive for exon 21 (9.6%), and three positive for ALK mutation (5.7%). Likewise, among 48 squamous cell carcinomas, nine were tested for mutations, three were positive for exon 19, one each for exon 21 and ALK, and none was positive for exon 20. Mutations were more common in females (18 out of 28 tested) and less common in males (14 out of 38 tested). Thirteen females had exon 19 mutation, one had exon 20 mutation, and two had exon 21 mutation. Similarly, seven males had exon 19 and four males had exon 21 mutation. No male had exon 20 mutation. ALK mutation was detected in two females and three males. The incidence of driver mutations was more in nonsmokers (24 out of 37 tested) than smokers (8 out of 29 tested), and this correlation was highly statistically significant (P = 0.001).

Certain peculiar observations

  • Two patients were simultaneously detected to have microbiologically proven tuberculosis (1 pleuropulmonary and 1 spinal)
  • Twenty-nine patients of 136 were empirically started on antitubercular therapy at various peripheral medical facilities before being finally diagnosed as lung cancer
  • Dual malignancy was found in four patients. One young male was emergently operated for carcinoma ileum and incidentally detected to have squamous cell carcinoma lung. Two patients had received treatment for carcinoma hypopharynx many years back and were in complete remission for the same. One female had received treatment for early-stage carcinoma cervix 4 years back and was in complete remission for carcinoma cervix
  • Most of the women from rural background in this study were definitely exposed to secondhand smoke and chulha smoke, which could not be quantified.



 > Discussion Top


According to the WHO, lung cancer is the most common cancer worldwide. It accounted for 1.8 million (12.9%) new cancer cases in 2012 and is the cause of nearly one in five cancer-related deaths. In fact, it claims more lives yearly than breast, colon, and prostate cancers combined.[1] In India, lung cancer incidence and cancer-related mortality are 6.9% and 9.3%, respectively. Despite all the advances in diagnosis and treatment modalities, the overall 5-year survival rate of lung cancer is dismal with approximately 15% in developed countries and 5% in developing countries.[2] In high-risk population, low-dose CT screening has demonstrated a relative risk reduction of 20% but with a false positivity of 96%. In tuberculosis rampant India, the applicability of this tool is dubious. We need more specific noninvasive techniques/biomarkers for screening.[3]

Epidemiology as per the American Cancer Society data, the average age at the time of diagnosis of lung cancer is about 70 years. In India, the median age is 56 years.[4],[5] As per the GLOBOCAN 2008, worldwide, male to female lung cancer ratio was 2.13, and in India, it was 4.27. In 2012, these figures were 2.13 and 3.17, respectively. Although clear data about the urban versus rural incidence of lung cancer are not available, various studies quote different figures, for example, studies from 1958 to 1985 quote a ratio of 19.6:81.6 and those from 1986 to 2001 quote 18.4:80.4.[6]

Smoking is the most important risk factor for the development of lung cancer. Tobacco smoke contains about 4000 toxic compounds including oxidative gases, cyanide, heavy metals, and a minimum of 50 carcinogens.[7] Furthermore, secondhand smoke is an important cause of lung cancer. Gender-based smoking habits reflect the epidemiologic changes in the lung cancer incidence. With the increasing trend of smoking in females, there was an increase in lung cancer incidence. On the contrary, with the gradual decrease in smoking in men, lung cancer incidence has reached a plateau and then dropped slightly.[8] There is 10–30-fold relative risk of lung cancer in the smokers versus nonsmokers depending upon the SI.[9] Age at smoking onset, severity and depth of inhalation, nicotine and tar content of cigarettes, and unfiltered tobacco use, e.g., beedis, are also important factors.[10] Occupational exposure and environmental air pollution by waste burning, cooking, automobile, chimneys, and factories are also important contributory factors.

Clinical features

Most patients with lung cancer have advanced disease at presentation. This may reflect the aggressive disease biology and the paucity of symptoms until the advanced disease is present. In developed countries, many high-risk asymptomatic patients are diagnosed due to an effective screening test. Symptoms may result from local tumor effects, from regional or distant spread or from paraneoplastic syndromes. A study of 2293 consecutive patients with non-SCLC (NSCLC) concluded that the mean age was 64 years and the most common symptoms at presentation were cough (55%), dyspnea (45%), pain (38%), and weight loss (36%).[11] In an Indian study by Noronha et al., symptoms at presentation were cough (70%), weight loss (84.7%), anorexia (68.8%), chest pain (50%), dyspnea (33%), and hoarseness of voice (15%).

Extrathoracic metastases

Lung cancer can metastasize to any part of the body and may result in the symptoms at the onset or later in the course of disease. The most frequent sites of nonregional metastasis are the liver, adrenals, bones, and brain. Among patients with otherwise resectable NSCLC in the chest, imaging evidence of liver metastasis has been reported in about 3%. Autopsies have shown hepatic metastases in 50% of lung cancer patients.[12] Approximately 20% of patients with NSCLC and 30%–40% of SCLC have bone metastases on presentation.[13] Only a fraction of imaging detected adrenal masses represent metastasis. In a series of 330 patients with operable NSCLC, in which 32 (10%) had an isolated adrenal mass, only 8 (25%) were malignant.[14] Neurologic manifestations include metastases and paraneoplastic syndromes. In NSCLC, brain metastases are most frequent with adenocarcinoma and least with squamous cell carcinoma. In SCLC, brain metastases are present in 20%–30% at presentation.[15] In a study from Eastern India, metastases to nodes, liver, adrenals, and bones were present in 55%, 13.33%, 8.33%, and 16.67%, respectively.[16]

Paraneoplastic phenomena

In one study of 1149 consecutive lung cancers, 6% had hypercalcemia. Among those, squamous cell carcinoma, adenocarcinoma, and SCLC were responsible in 51%, 22%, and 15% of cases, respectively.[17] Approximately 10% of SCLC patients exhibit SIADH. SCLC causes 75% of all malignancy-related SIADH.[18] Neurologic paraneoplastic manifestations include, but are not limited to, Lambert-Eaton myasthenic syndrome (LEMS), cerebellar ataxia, sensory neuropathy, autonomic neuropathy, retinopathy, limbic encephalitis, encephalomyelitis, and opsomyoclonus. The most common of these is LEMS, seen in 3% of SCLC.[19] Anemia is common in lung cancer and may aggravate dyspnea and fatigue. In one series, 40% of untreated patients and 80% of those on chemotherapy had a hemoglobin ≤12 g/dL.[20] Unexplained leukocytosis was found in 15% of patients with lung cancer in another series.[21] Thrombocytosis is may be present in 14% lung cancer patients at presentation.[22] Hypertrophic osteoarthropathy, dermatomyositis, polymyositis, and Cushing's syndrome are rare.

Histology

Before the mid-1980's literature, squamous cell carcinoma was the predominant histology. In the West and in many of the Asian countries, adenocarcinoma has surpassed squamous cell histology.[23],[24] In India, multiple studies have shown the squamous histology to be more common than adenocarcinoma; however, some recent studies show a changing pattern in India. This shift might be owing to the smoking habits, particularly filtered cigarettes. Nonetheless, there is also increasing incidence of lung carcinoma in females and nonsmokers.

Driver mutations

Mutations in the EGFR tyrosine kinase are observed in approximately 15% of NSCLC adenocarcinoma in the United States and occur more frequently in females and nonsmokers. In Asian populations, the incidence of EGFR mutations is substantially higher, up to 62%.[25] The overall incidence of ALK gene rearrangements in multiple series has been about 4%. Except in rare cases, the presence of ALK gene rearrangements in NSCLC tumors tends to occur independent of EGFR or KRAS mutations. Similar frequencies of ALK gene rearrangements have been reported in Asian and Western populations. In NSCLC patients with clinical characteristics associated with EGFR mutation but with negative EGFR testing, as many as one in three may harbor the ALK fusion oncogene.[26],[27],[28],[29],[30]

Despite enormous research in the field of lung cancer, and ironically, even after having developed highly efficient targeted therapies, it constitutes the major proportion of cancer-related morbidity and mortality worldwide. In contrast to the 5-year survival of 52% in all cancers, the lung cancer survival rates continue to be poor. On the contrary, despite the mass level awareness campaigns and smoking cessation strategies, the rural population of India is smoking tobacco at a rampant level. The SI is a very crude method of estimating smoking exposure, especially in beedi smokers. Although there are no worldwide standard criteria, a SI of more than 200 or 300 is considered heavy smoking by some Asian studies.[31] Astonishingly, it was found during this study that 80% of the smokers were heavy smokers, reaching up to a SI of 3000. Apart from that, most of these rural Indians also smoke hucca and chew tobacco in various other forms. Although a plenty of worldwide data are available on lung cancer, this disease has many peculiarities in Indian population, such as relation with beedi smoking and hucca smoking (in areas such as Rajasthan), occurrence of disease at a younger age, high prevalence of mutations positivity, and changing histological trends, which makes the dedicated study on Indian population essential and amazing. Hence, this comprehensive study of lung cancer has produced many interesting and intriguing results.

Lung cancer generally occurs in the elderly population. As per the American Cancer Society data, the average age at the time of diagnosis of lung cancer is about 70. In India, the median age is 56 years. In our study also, median age was 60 years and average age was 57.6 years, reconfirming the fact that Indians have disease onset one decade before the west. Nonsmokers presented at a younger age (41–60 years) as compared to smokers (51–70 years), similar to that seen in studies from other Asian countries, including Singapore, Japan, and Hong Kong. This is in contrast to the studies from the United States and Europe. Likewise, females presented at a younger age (41–60 years) as compared to males (51–70 years).

Males have always predominated in lung cancer incidence. In the previous Indian studies of 1958–1985, male to female lung cancer ratio was 6.67:1, and in 1986–2001 studies, it was 5.76:1. This ratio is further gradually decreasing. As per the GLOBOCAN 2008, worldwide male to female ratio was 2.13, and in India, it was 4.27. In 2012, these figures were 2.13 and 3.17, respectively. In a study from Mumbai, out of 489 patients, there were 380 males and 109 females, i.e., a male:female ratio of approximately 3.5:1. In the current study, out of a total of 136 patients, 97 were male and 39 were female, with a ratio of 2.48, which is nearly equal to worldwide data. This goes in line with the changing scenario of lung cancer in the world, where its incidence in males is plateauing, but in females, it is increasing, partly due to increasing trend of smoking in females. Another possible explanation for the lowest male to female ratio in our study as compared to other Indian studies may be relatively increased awareness and expenditure-free treatment available at our institute. Higher proportion of nonsmokers in female patients shows that even without smoking, females are more prone to have lung cancer. It needs to be kept in mind that the incidence of lung cancer in a subset of smokers reflects the effect of last many decades of smoking. Likewise, a smoking cessation program or a decreasing trend of smoking is going to show its effect on incidence of lung cancer after many decades only.

Although clear data about the urban versus rural incidence of lung cancer are not available, various studies quote different figures, for example, studies from 1958 to 1985 and 1986 to 2001 show an approximate 1:4 ratio. In the present study, the urban to rural patient population ratio was 17.6:82.4. In the previous Indian studies, major portion of the disease burden has been born by farmers (approximately 48%). Similarly, in the present study also, 36.3% of patients were farmers. This may predominantly be due to rampant beedi smoking among farmers although exposure to dust, hay, and pesticides may be other contributing factors. Among 57 farmers in the present study, 49 were heavy smokers (40 heavy beedi smokers and 9 hucca smokers). Seventeen of them had adenocarcinoma, 28 had squamous histology, and 10 had SCLC, and only five of them had EGFR mutation positive and none had ALK mutation positive.

In the present study, 65.4% of patients were smokers and 34.6% were nonsmokers. This is in accordance with the changing worldwide trend of rising lung cancer in nonsmokers. This may be due to secondhand smoke, increasing air pollution including chullah smoke, and increasing longevity. It was found in our study that sex was significantly related with smoking status, histology, and mutations. As per the ICMR Cancer Registry 2002, the smoker to nonsmoker ratio was high up to 20:1. In a study by Viswanath et al. from Kolkata, 28.33% of patients were nonsmokers. Among females, 73.33%, and among males, 13.33% were nonsmokers. Smoker to nonsmoker ratio was 6.5:1 in male and 0.36:1 in female. In the study by Noronha et al. from Mumbai, of the 489 patients, 52.1% were nonsmokers and 47.9% were smokers. A larger proportion of females (88.1%) as compared to only 41.8% of males were nonsmokers, whereas in the current study, 66.66% of females and 21.65% of males were nonsmokers. Out of 80 patients presenting with PS 2, 37 were of adenocarcinoma, 27 were of squamous histology, and seven were of SCLC, whereas among the 43 patients presenting with a PS 3, 13 were of adenocarcinoma, 17 were of squamous histology, and 11 were of SCLC. Fifty-nine percent (53 of 90) of patients presenting with PS 0–2 and 78% (36 of 46) of patients with PS 3–4 were smokers.

A significant proportion of lung cancer patients present at an advanced stage with poor PS. Majority of them are elderly smokers, especially those with squamous cell and SCLC. They also have poor reserve of various body organs owing to heavy smoking and age, which further compromises treatment tolerability as well as response and predisposes them to suffer more treatment-related complications. Squamous and small cell histologies present with a relatively poorer PS. In our study, smokers presented with a higher stage of cancer than nonsmokers. This may be due to them being treated initially at peripheral centers as chronic obstructive pulmonary disease and general casual attitude toward health. Fifty-nine percent (53 of 90) of patients presenting with PS 0–2 were smokers, whereas 78% (36 of 46) of patients with PS 3–4 were smokers, concluding that smokers presented at a higher stage with poorer PS. Poor PS and weight loss have been associated with shortened survival. Reduced appetite, a precursor of weight loss, also has negative prognostic implications.[32]

Cough was the most common symptom at presentation (53.7%) in the present study followed by dyspnea, weight loss, chest pain, hemoptysis, and hoarseness. Forty percent of patients presented with dyspnea of MMRC Grade II–IV. In a study of 2293 consecutive patients with NSCLC noted that the common symptoms at presentation were cough (55%), dyspnea (45%), pain (38%), and weight loss (36%).[11] In the study by Noronha et al., symptoms at presentation were cough (70%), weight loss (84.7%), anorexia (68.8%), chest pain (50%), dyspnea (33%), and hoarseness of voice (15%).

In our study, 23% of patients had pleural effusions, majority having a minimal ipsilateral effusion. About 20% of minimal-to-mild pleural effusions were found to be malignant and almost all moderate-to-massive effusions or pleural plaques were malignant. Twenty-one percent of patients had one or the other manifestations of paraneoplastic phenomenon which included anemia (17%), leukocytosis (9.5%), thrombocytosis (21%), deep venous thrombosis (4%), SIADH (2 SCLC and 2 adenocarcinomas, 3%), and hypercalcemia (5%). In one study of 1149 consecutive lung cancers, 6% had hypercalcemia. Among those with hypercalcemia, squamous cell carcinoma, adenocarcinoma, and SCLC were responsible in 51%, 22%, and 15% of cases, respectively. Approximately 10% of patients who have SCLC exhibit SIADH. In another study, 40% of untreated patients had a hemoglobin ≤12 g/dL. A series reported tumor-associated leukocytosis in 15% of patients. Nearly all had NSCLC, and leukocytosis was thought to be due to overproduction of granulocyte-colony stimulating factor. Thrombocytosis is common and may be present in as many as 14% of patients at presentation.

In the present study, skeleton (30%), brain (16%), and liver (15%) were the most common metastatic sites. In the study by Nonoha et al., lung (11.5%) was the most common site followed by bone (4.7%), brain (2%), liver (2%), and adrenals (1.6%). In the study by Viswanath et al., metastases to nodes, liver, adrenals, and bones were present in 55%, 13.33%, 8.33%, and 16.67%, respectively. Approximately 20% of patients with NSCLC and 30%–40% of SCLC have bone metastases on presentation.[33],[34]

Twenty-nine (21.3%) patients in the present study were treated with antitubercular therapy at various peripheral centers before being diagnosed as lung cancer. In another Indian study, about 30% of patients received antitubercular treatment during the current episode before a diagnosis of lung cancer was made.[35] Similarly, 69 patients (14.1%) were incorrectly diagnosed and treated with antituberculosis treatment in another study. However, there being high prevalence of tuberculosis in India, it is self-explanatory.

FoB is the procedure of choice to obtain diagnosis, especially for large central lesions. In the present study, FoB-guided biopsy was attempted in 47% of cases, and out of them, positive yield was obtained in 90%. As per the ACCP guidelines, for primary lesions that are large, central, or obstructive, the diagnostic yield of conventional bronchoscopy with endobronchial or transbronchial biopsy is 65%–88%.[36]

In our study, percentage of NSCLC was 84.6% and of SCLC and its variants was 15.4%. Among NSCLC, 44.9% were of adenocarcinomas, 35.3% squamous cell carcinomas, and 4.4% poorly differentiated carcinomas. Adenocarcinoma histology was more common in females, squamous cell carcinoma was more common in males, and small cell carcinoma was equally common in both genders (P = 0.001). Similarly, in the study by Nonoha et al., adenocarcinomas were 40%, squamous cell carcinomas 30%, others 20%, and SCLC 10%. The relative incidence of adenocarcinoma has risen dramatically, and there has been a corresponding decrease in the incidence of other types of NSCLC and SCLC. The increased incidence of adenocarcinoma is thought to be due to the introduction of low-tar filter cigarettes in the 1960s although this relationship is unproven. Most of the Indian studies have described squamous cell carcinoma as the most common histology; however, the study by Krishnamurthy et al. has shown adenocarcinoma: squamous cell carcinoma ratio as 42.6:15.8.[37] It has been reported that adenocarcinoma has become the most common subtype, provided a careful pathology review is done. Our study confirms this and follows the same trend, and we found the largest proportion of adenocarcinomas (44.9%) being reported till date in India. First noticed in 1961, and confirmed consistently during the last two decades, a shift of lung cancer has occurred to more peripheral locations. This is likely an outcome of the changes made in cigarettes. Tar, being considered to be the main carcinogen in cigarette smoke, was hoped that production of low-tar, low-nicotine, filtered cigarettes might decrease cancer risk. However, the smokers proved it wrong by altering the smoking pattern. To fulfill the nicotine craving, they inhale more deeply into the lung and retain it longer. Filters remove polycyclic aromatic hydrocarbons (PAHs), hence leaving tobacco-specific nitrosamines and volatile carcinogens as preponderant carcinogens, in the gas phase. Animal experiments lend plausibility to this; PAHs cause squamous cell carcinomas, whereas nitrosamines more likely cause adenocarcinomas.[38] In Indian population, especially Rajasthan, hooka smoking is prevalent where the inbuilt mechanism causes filtering of smoke through water, probably letting finer particles to traverse to more distal parts of the lung. Proximal tumors are easier to sample through traditional FoB; however, newer techniques such as navigational bronchoscopy have enabled more distal and adequate sampling, increasing yield of adenocarcinomas more than squamous carcinomas. Better histological methods and IHC support lead to more tissue characterization, leading to more specific diagnosis. Slowly, as the awareness about smoking risks is increasing and with smoking cessation strategies, number of nonsmoker lung cancer patients is increasing, in whom adenocarcinoma is itself more common than other etiologies.

As on date, this is probably the second prospective study being reported from India, where majority of metastatic lung adenocarcinoma and nonsmoker metastatic squamous cell carcinoma patients have been tested for EGFR mutations and/or ALK gene rearrangements, except for those where adequate tissue was not available. Mutations were more common in female and less common in male. The ALK gene rearrangements are present in 2%–3% of western patients with NSCLC.[27] PIONEER is the first prospective study to confirm high EGFR mutation frequency (51.4% overall) in tumors from Asian patients with adenocarcinoma.[25] The observed high mutation rate in Asians compared with Whites suggested mutation testing for all stage IIIB/IV adenocarcinoma patients, even males and regular smokers. EGFR mutation frequency was significantly higher in female (61.1% [384 of 628]) than male (44.0% [362 of 822]). In a similar manner, smoking was significantly associated with histology and mutations. EGFR mutation frequency was significantly higher among patients with adenocarcinoma. [Table 6] shows a comparison of various clinico-epidemiological and pathological studies from different parts of India. It is evident that temporally male to female ratio, as well as smoking rates, is gradually decreasing whereas adenocarcinoma: squamous cell carcinoma ratio is showing increasing trend. Apparently, the present study is a prospective Indian study where EGFR/ALK mutation profile is being reported. Mutational analysis studies are shown in [Table 7]. As compared to the Indian study done by Doval et al., our study showed an EMK4-ALK mutation of 5.7%.[44]
Table 7: Table depicting the various mutation analysis studies in lung cancer in India

Click here to view



 > Conclusion Top


The following conclusions could be drawn from the present study:

  • Lung cancer still remains more common in male than female in India although male to female ratio is gradually decreasing
  • Average age of onset is one decade younger than Western populations
  • Adenocarcinoma histology has surpassed squamous cell carcinoma in frequency of occurrence
  • Smokers are more prone to have squamous cell carcinoma than nonsmokers, in whom adenocarcinoma is more common
  • More than one-third of adenocarcinoma patients are positive for driver mutation, EGFR or ALK
  • With the support of IHC, most of the unclassifiable cancers are now classified into adenocarcinoma, squamous cell carcinoma, and small cell carcinoma
  • An adequate tissue biopsy is must to obtain complete histological and IHC diagnosis and complete molecular characterization
  • Smokeless tobacco, secondhand smoke, and other unquantifiable pollutants are probably responsible for significantly more occurrence of lung cancer in nonsmoker rural population as compared to urban population.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Available from: http://www.globocan.iarc.fr/. [Last accessed on 2018 Apr 23].  Back to cited text no. 1
    
2.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.  Back to cited text no. 2
    
3.
Malik PS, Raina V. Lung cancer: Prevalent trends & emerging concepts. Indian J Med Res 2015;141:5-7.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Noronha V, Dikshit R, Raut N, Joshi A, Pramesh CS, George K, et al. Epidemiology of lung cancer in India: Focus on the differences between non-smokers and smokers: A single-centre experience. Indian J Cancer 2012;49:74-81.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare N, Joshi A, et al. EGFR mutations in Indian lung cancer patients: Clinical correlation and outcome to EGFR targeted therapy. PLoS One 2013;8:e61561.  Back to cited text no. 5
    
6.
Behera D. Epidemiology of lung cancer – Global and Indian perspective. JIACM 2012;13:131-7.  Back to cited text no. 6
    
7.
Florescu A, Ferrence R, Einarson T, Selby P, Soldin O, Koren G, et al. Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: Focus on developmental toxicology. Ther Drug Monit 2009;31:14-30.  Back to cited text no. 7
    
8.
Thun MJ, Carter BD, Feskanich D, Freedman ND, Prentice R, Lopez AD, et al. 50-year trends in smoking-related mortality in the United States. N Engl J Med 2013;368:351-64.  Back to cited text no. 8
    
9.
Samet JM. Health benefits of smoking cessation. Clin Chest Med 1991;12:669-79.  Back to cited text no. 9
    
10.
Harris JE, Thun MJ, Mondul AM, Calle EE. Cigarette tar yields in relation to mortality from lung cancer in the cancer prevention study II prospective cohort, 1982-8. BMJ 2004;328:72.  Back to cited text no. 10
    
11.
Kocher F, Hilbe W, Seeber A, Pircher A, Schmid T, Greil R, et al. Longitudinal analysis of 2293 NSCLC patients: A comprehensive study from the TYROL registry. Lung Cancer 2015;87:193-200.  Back to cited text no. 11
    
12.
Hillers TK, Sauve MD, Guyatt GH. Analysis of published studies on the detection of extrathoracic metastases in patients presumed to have operable non-small cell lung cancer. Thorax 1994;49:14-9.  Back to cited text no. 12
    
13.
Cheran SK, Herndon JE 2nd, Patz EF Jr. Comparison of whole-body FDG-PET to bone scan for detection of bone metastases in patients with a new diagnosis of lung cancer. Lung Cancer 2004;44:317-25.  Back to cited text no. 13
    
14.
Oliver TW Jr., Bernardino ME, Miller JI, Mansour K, Greene D, Davis WA, et al. Isolated adrenal masses in nonsmall-cell bronchogenic carcinoma. Radiology 1984;153:217-8.  Back to cited text no. 14
    
15.
Mujoomdar A, Austin JH, Malhotra R, Powell CA, Pearson GD, Shiau MC, et al. Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: Primary tumor size, cell type, and lymph node metastases. Radiology 2007;242:882-8.  Back to cited text no. 15
    
16.
Sundaram V, Sanyal N. Clinicopathological profile of bronchogenic carcinoma in a tertiary care hospital in eastern part of India. Clin Cancer Investig J 2014;3:220-4.  Back to cited text no. 16
  [Full text]  
17.
Hiraki A, Ueoka H, Takata I, Gemba K, Bessho A, Segawa Y, et al. Hypercalcemia-leukocytosis syndrome associated with lung cancer. Lung Cancer 2004;43:301-7.  Back to cited text no. 17
    
18.
List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA, Johnson DH, et al. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J Clin Oncol 1986;4:1191-8.  Back to cited text no. 18
    
19.
Honnorat J, Antoine JC. Paraneoplastic neurological syndromes. Orphanet J Rare Dis 2007;2:22.  Back to cited text no. 19
    
20.
Kosmidis P, Krzakowski M, ECAS Investigators. Anemia profiles in patients with lung cancer: What have we learned from the European cancer anaemia survey (ECAS)? Lung Cancer 2005;50:401-12.  Back to cited text no. 20
    
21.
Kasuga I, Makino S, Kiyokawa H, Katoh H, Ebihara Y, Ohyashiki K, et al. Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer 2001;92:2399-405.  Back to cited text no. 21
    
22.
Hamilton W, Peters TJ, Round A, Sharp D. What are the clinical features of lung cancer before the diagnosis is made? A population based case-control study. Thorax 2005;60:1059-65.  Back to cited text no. 22
    
23.
Valaitis J, Warren S, Gamble D. Increasing incidence of adenocarcinoma of the lung. Cancer 1981;47:1042-6.  Back to cited text no. 23
    
24.
Janssen-Heijnen ML, Coebergh JW. The changing epidemiology of lung cancer in Europe. Lung Cancer 2003;41:245-58.  Back to cited text no. 24
    
25.
Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. Aprospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-62.  Back to cited text no. 25
    
26.
Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247-53.  Back to cited text no. 26
    
27.
Perner S, Wagner PL, Demichelis F, Mehra R, Lafargue CJ, Moss BJ, et al. EML4-ALK fusion lung cancer: A rare acquired event. Neoplasia 2008;10:298-302.  Back to cited text no. 27
    
28.
Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 2009;115:1723-33.  Back to cited text no. 28
    
29.
Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol 2008;3:13-7.  Back to cited text no. 29
    
30.
Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: A new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol 2009;4:1450-4.  Back to cited text no. 30
    
31.
Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Quantified smoking status and non-small cell lung cancer stage at presentation: Analysis of a North Indian cohort and a systematic review of literature. J Thorac Dis 2012;4:474-84.  Back to cited text no. 31
    
32.
Hoang T, Xu R, Schiller JH, Bonomi P, Johnson DH. Clinical model to predict survival in chemonaive patients with advanced non-small-cell lung cancer treated with third-generation chemotherapy regimens based on eastern cooperative oncology group data. J Clin Oncol 2005;23:175-83.  Back to cited text no. 32
    
33.
Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancer: A review of the current evidence. Chest 2003;123:137S-46S.  Back to cited text no. 33
    
34.
Schumacher T, Brink I, Mix M, Reinhardt M, Herget G, Digel W, et al. FDG-PET imaging for the staging and follow-up of small cell lung cancer. Eur J Nucl Med 2001;28:483-8.  Back to cited text no. 34
    
35.
Mohan A, Latifi AN, Guleria R. Increasing incidence of adenocarcinoma lung in India: Following the global trend? Indian J Cancer 2016;53:92-5.  Back to cited text no. 35
[PUBMED]  [Full text]  
36.
Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2013;143:e142S-e165S.  Back to cited text no. 36
    
37.
Krishnamurthy A, Vijayalakshmi R, Gadigi V, Ranganathan R, Sagar TG. The relevance of “Nonsmoking-associated lung cancer” in India: A single-centre experience. Indian J Cancer 2012;49:82-8.  Back to cited text no. 37
[PUBMED]  [Full text]  
38.
Witschi H. A short history of lung cancer. Toxicol Sci 2001;64:4-6.  Back to cited text no. 38
    
39.
Koul PA, Kaul SK, Sheikh MM, Tasleem RA, Shah A. Lung cancer in the Kashmir valley. Lung India 2010;27:131-7.  Back to cited text no. 39
[PUBMED]  [Full text]  
40.
Mohan A, Latifi AN, Guleria R. Increasing incidence of adenocarcinoma lung in India: Following the global trend?. Indian J Cancer 2016;53:92-5.  Back to cited text no. 40
[PUBMED]  [Full text]  
41.
Gupta RC, Purohit SD, Sharma MP, Bhardwaj S. Primary bronchogenic carcinoma: Clinical profile of 279 cases from mid-west Rajasthan. Indian J Chest Dis Allied Sci 1998;40:109-16.  Back to cited text no. 41
    
42.
Prasad R, James P, Kesarwani V, Gupta R, Pant MC, Chaturvedi A, et al. Clinicopathological study of bronchogenic carcinoma. Respirology 2004;9:557-60.  Back to cited text no. 42
    
43.
Dey A, Biswas D, Saha S K, Kundu S, Kundu S, Sengupta A. Comparison study of clinicoradiological profile of primary lung cancer cases: An Eastern India experience. Indian J Cancer 2012;49:89-95.  Back to cited text no. 43
[PUBMED]  [Full text]  
44.
Doval D, Prabhash K, Patil S, Chaturvedi H, Goswami C, Vaid A, et al. Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. Onco Targets Ther 2015;8:117-23.  Back to cited text no. 44
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

Top
 
 
  Search
 
Similar in PUBMED
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>IntroductionMaterials and Me...Results and Obse...>Discussion>Conclusion>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed1450    
    Printed254    
    Emailed0    
    PDF Downloaded251    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]