Clinico-pathological Profile of Lung Cancer Patients in a Tertiary Care Hospital, India: A Prospective, Cross-sectional Study

ABBREVIATIONS USED IN THIS ARTICLE

ADC = Adenocarcinoma; ALK = Anaplastic lymphoma kinase; CECT = Contrast enhanced computed tomography; COPD = Chronic obstructive pulmonary disease; CT = Computed tomography; EBUS = Endobronchial ultrasound; ECOG = Eastern Cooperative Oncology Group; EGFR = Epidermal growth factor receptor; FISH = Fluorescence in situ hybridization; FNAC = Fine needle aspiration cytology; FOB = Fibreoptic bronchoscopy; IASLC = International Association of Study of Lung Cancer; LCNEC = ; NE = ; NOS = ; NSCLC = Nonsmall cell lung cancers; PET = Positron emission tomography; SCC = Squamous cell carcinoma; SCLC = Small cell lung carcinoma; SVC = Superior vena cava; TB = Tuberculosis; TBNA = Transbronchial needle aspiration; USG = Ultrasound sonography

INTRODUCTION

Lung cancer is the leading cause of death in both males and females worldwide. In 2017, there were an estimated 558,250 people living with lung and bronchus cancers in the United States. In 2020, an estimated 228,820 new cases and 135,720 deaths due to lung cancer were reported. Only one-fifth of all patients with lung cancer were alive 5 years or more after diagnosis.^1,2 In India, lung cancer is the commonest and the most lethal cancer among males accounting for 5.9% of all cancer cases and accounts for 8.1% of cancer-related deaths.³

The incidence of lung cancer is rising at an alarming rate in the developing countries. In India, there have been a lot of shifts in the incidence trends among males and females, histology, and molecular profile of lung cancer.⁴ Many risk factors of lung cancer have been identified, but smoking which included cigarettes, bidis, chillum, and hukkah, etc., remains the most common. Chest pain, cough, hemoptysis, hoarseness of voice, fatigue, weakness, loss of appetite, weight loss, fever, etc., form a cluster of symptoms in lung cancer and very few studies have compared the clinical features in various histological and molecular groups. These symptoms are similar to tuberculosis (TB), and differentiating the two conditions is imperative, as it is not uncommon to find a lung cancer being treated as TB initially.⁵

Radiologically, most patients of lung cancer present with a mass lesion. Most of the previous studies addressing radiological findings were based on chest radiographs. Histopathologically, approximately 75–80% of newly diagnosed lung cancers cases are nonsmall cell lung cancers (NSCLC) and the remaining 20–25% are small cell lung cancers (SCLC). Among NSCLC, ADC is the more common histopathological pattern as reported in recent studies,⁵ while most of the older studies observed squamous cell carcinoma of lung to be the most common histological subtype.

Recent molecular advances, like detection of EGFR/ALK mutations and programmed death ligand-1(PDL-1) testing, have changed the treatment outlook of NSCLC patients.⁶ The EGFR mutations are more likely to occur in nonsmoking Asian females who have ADC; however, there are only a few studies assessing the clinico-demographic profile of patients with EGFR and ALK mutations in the Indian population.⁷

Although many researchers have studied the clinico-pathological profile of lung cancer, most of these studies were performed retrospectively and followed the World Health Organization (WHO) 2004 classification of lung cancer. In the present prospective study, the International Association of Study of Lung Cancer (IASLC) 2011 classification of lung cancer was used and comparison was made with respect to various demographic, clinical, and radiological characteristics pertaining to different histopathological and molecular subgroups.

MATERIALS AND METHODS

A prospective, cross-sectional, comparative study was conducted in a tertiary care hospital in North India. All consecutive patients of lung cancer diagnosed from December 2014 to January 2017 were included in the study. Patients who were not willing and patients with metastatic lung secondary were excluded from the study. The study was approved by the Institutional Ethics Committee.

The clinico-pathological, radiological, and molecular profile data were entered in a predesigned proforma, which comprises demographic features, detailed history with their duration of symptoms, clinical examination, and radiological findings. Relevant radiological investigations were performed to evaluate local extent of the disease and metastases, including positron emission tomography–computed tomography (PET-CT) scan, contrast enhanced computed tomography (CECT) chest, CT abdomen and magnetic resonance imaging (MRI) brain and bone scan, as and when required.

Specimens for histopathological examination of the suspected lung cancer patients were obtained by CT/ultrasound-guided lung biopsy or fine needle aspiration cytology (FNAC), endobronchial biopsy, transbronchial needle aspiration [conventional or EBUS (endobronchial ultrasound)], and pleuroscopic biopsy, whichever was deemed necessary. Histopathological interpretation of the biopsy/cytology specimen was done according to 2011IASLC classification for lung tumors and was recorded.

Gene mutation study for EGFR gene was performed by Gene Sequence Analysis and mutations in exons 18–21 of EGFR gene were screened. Fluorescence in situ hybridisation (FISH) technique was used for ALK gene rearrangement assay using Ventana anti-ALK (D5F3) rabbit monoclonal primary antibody along with Ventana detection kit on a Ventana Benchmark XT autostainer.

After histopathological diagnosis, staging was done with the help of PET-CT scan, MRI brai,n and EBUS-TBNA [transbronchial needle aspiration]. Treatment was offered according to the then latest NCCN guidelines.

RESULTS

We analyzed 312 consecutive, pathologically confirmed lung cancer patients. Table 1 shows the general characteristics of all lung cancer patients.

The median (range) and mean (± standard deviation) age (years) of the study population were 58 (27–85) and 57.2 (10.8) years, respectively. On subgroup analysis of the histopathological subgroups, the age differences between ADC and SCC had statistically significant relationship (p = 0.003) (Table 2). Of all the patients, 80.5% were males with a male-to-female ratio of 4.2:1. On subgroup analysis, the sex distribution in various histopathological groups was not statistically significant (Table 2). Majority of the patients (73.4%) were either active or former smokers. Prevalence of smoking was lower in ADC group as compared to SCC and SCLC. The most common lung cancer in nonsmokers was ADC (Table 2). Bidi was the commonest mode of smoking while cigarettes constituted only 7.4% of the patients. Most of the smokers had a smoking index of >300 (77.3%).

Chronic obstructive pulmonary disease was the most common comorbid condition followed by old pulmonary TB. About 17% cases had history of anti-TB treatment at presentation due to misdiagnosis as TB. Wrong diagnosis of TB in lung cancer patients was more significantly made in case of adenocarcinoma as compared to other histopathological subgroups.

The number of patients having cumulative symptom burden 5 or >5 was 63.5%. The most common symptom was cough followed by chest pain, anorexia, expectoration, breathlessness, fever, back pain, hoarseness of voice, hemoptysis, and dysphagia. The most common finding revealed in clinical examination was weight loss followed by clubbing, anemia, and signs of superior vena cava obstruction. Chest pain, hoarseness of voice, dysphagia, and signs of superior vena cava obstruction were significantly higher in SCLC patients as compared to other histopathological subgroups. Hemoptysis was significantly more common in SCC (Table 2).

Large cell carcinoma (n = 3) was not included in subgroup analysis. Lung cancer other than ADC, SCC lung, and SCLC was not included in subgroup analysis.

The most common radiological finding was a mass lesion, which most commonly involved the upper lobes in 43.3% cases followed by hilar region and lower lobes. Most common involved site was right upper lobe followed by left upper lobe, left lower lobe, right hilar, and left hilar location. Predominant hilar involvement was significantly higher in SCLC patients (Table 3).

Other findings like pleural effusion, atelectesis, complete opaque hemithorax, cavitation, lymphangitis carcinomatosis, and pericardial effusion were present in 46.8, 36.2, 8.7, 8.0, and 5.4, and 6.1%, respectively. Local invasion of major vessels was present in almost one-third of the cases. Chest wall involvement due to local invasion was present in 8.7% of cases. Pleural effusion was a more common finding in ADC as compared to small and squamous cell carcinoma. SVC obstruction was significantly higher in patients of SCLC.

Majority of the lung cancer patients presented in stage IV, constituting 77.9% of all cases followed by Stage IIIB, IIIA, IIB, and IIA, suggestive of presentation of patients at advanced stages of the disease.

Of the 243 stage IV cancer patients, only 25% had isolated M1a metastatic involvement. Most common site for distant metastasis was the bone in 32.5% cases followed by the liver, adrenal, brain, and other organs. Bone metastasis was significantly higher in ADC patients as compared to small and squamous cell carcinoma while liver and brain metastases were significantly higher in SCLC patients (Table 3).

Tissue samples were obtained with the help of bronchoscopy (conventional/radial or linear EBUS) in 71.8% of cases while CT/USG guided biopsy and pleuroscopy were done in 17.3% and 9.9% of cases, respectively. Diagnosis was made by other methods in 1.0% cases. Immunohistochemistry (IHC) was done in 79.5% of the cases.

The most common histological presentation was ADC (48.1% cases), followed by SCC (32.1%), SCLC (14.4%), NSCLC favoring ADC, and NSCLC favoring SCC. Only 1.6% cases comprise NSCLC with neuroendocrine morphology with positive NE markers (possible LCNEC). Of all lung cancer patients, 25 were diagnosed as undifferentiated NSCLC which were further classified as NSCLC favoring ADC (n = 10) and NSCLC favoring SCC (n = 11) with the help of IHC. Diagnosis of NSCLC not otherwise specified (NSCC, NOS), carcinoid tumor, adenosquamous carcinoma of lung, carcinosarcoma of lung, and adenocystic carcinoma of trachea was observed in 1.3, 1.3, 0.6, 0.3, and 0.3% of patients, respectively.

Epidermal growth factor receptor and ALK mutation study were done in 83 patients of ADC, of which 26.5% patients were found to be positive for EGFR mutation. The most common EGFR mutation was exon 19 deletion (15/83, 18.1%) followed by exon 21 L858R point mutation (n = 5, 6%). Exon 20 mutation was seen only in two patients, and none of the patients had mutations in exon 18. Among all EGFR positive patients, 40.9% were less than 55 years of age. Most of the EGFR positive patients were nonsmokers (72.7%) and females (68.2%). ALK rearrangement was detected in 7.2% of cases. EGFR and ALK mutations were found mutually exclusive to each other (Table 4).

DISCUSSION

The present study was undertaken to study the demographic, clinico-pathological, and molecular profile of lung cancer patients. Among demographic features, median age of presentation, sex distribution, and pattern of smoking in our patients were significantly different from the western population. Median age of patients in the present study was similar to most of the previous Indian studies while a decade younger as compared to the western studies.^2,3,8–12 This may be in part due to the lower life expectancy in India as compared to the West, resulting in decreased number of elderly patients reporting to hospital.

In the present study, male-to-female ratio was 4.2:1 which was similar to other Indian studies.^9,11–14 This ratio is higher than that reported in western literature probably due to higher prevalence of female smokers in western countries. In this study, 74.7% study patients were smokers with bidi being the most common form of tobacco smoking, a presentation similar to previous Indian series.^10,13,15 In contrast, studies from the western countries^5,13,16 report cigarette smoking as the commonest form of tobacco smoking. This reflects the difference in the pattern of smoking in India where bidi smoking is more prevalent than cigarette smoking. Another possible factor for the high incidence of bidi smoking in our study could be that being a general hospital offering free medical services the clientele of this hospital is mainly from the lower socio-economic strata in whom bidi smoking is more prevalent.¹⁰ Regardless of significant difference in demographic profile as compared to west, commonest histopathology in our study group was adenocarcinoma similar to the western population.

Majority of the patients in the present study had a performance status ≤2, though they presented with metastatic disease. This indicates suitability of most of the patients with stage IV lung cancer to receive palliative chemotherapy and potential for improvement in quality-of-life measurements, which is in contrast to other studies from our country.¹¹

One important observation made in this study was a substantial delay in presentation of many lung cancer patients to our center. Majority of these cases, especially ADC and SCC patients, were misdiagnosed as TB. This suggests a higher threshold for suspicion of lung cancer among clinicians, thus causing delay in diagnosis with majority being diagnosed in advanced incurable stage. It may be due to high prevalence of TB, which presents with similar symptoms hence considerably diluting the clinical suspicion of malignancy. Misdiagnosis as TB was more frequently seen in ADC and SCC patients, which may present radiologically as collapse-consolidation and cavitatory lung lesions. In our study, the delay in seeking treatment was observed to vary from 2 to 6 months, which is similar to other studies.^14,17 This emphasizes the importance of keeping lung cancer as a close differential in patients suspected to have TB, more so in elderly, male smokers.

In our study, cough was the commonest symptom as reported in other Indian studies.^5,13,18 This may be due to the fact that even early mucosal changes induced by the tumor can result in cough. The most common sign in patients with lung cancer in the present study was clubbing, as reported by other authors.^13,19

The commonest radiological presentation in the present study was mass lesion which is consistent with previous studies.^14,19 This was followed by pleural effusion (51%). A higher incidence of pleural effusion as compared to previous studies^6,14 may be due to a higher proportion of patients presented in advanced stage with higher prevalence of ADC lung, which is more frequently associated with pleural effusion as compared to SCC and SCLC.

The incidence of atelectasis and pericardial effusion was similar to that found in previous Indian studies.^18,19 We found that upper lobes were involved more frequently than lower lobes which may be attributable to a higher exposure of upper lobes to tobacco smoke and air pollutants. SVC obstruction was significantly higher in patients of SCLC.

Most of the patients in our study presented in advanced stage (stage IIIB or IV) as reported in previous studies.^11,20–23 This could be attributed, first, to patient delay with a long duration between onset of the first symptom and seeking medical care, due to lack of awareness about the disease, poor socio-economic status, and lack of access to tertiary healthcare, especially in remote rural areas, and secondly, there may be delay in diagnosis due to high prevalence of the diseases similar in presentation, like TB.

In our study, most of the specimens for histopathological examination were collected with the help of bronchoscopy followed by thoracoscopic and CT/USG guided biopsy. Diagnosis by FNAC and pleural fluid cytology was made in <5% of cases. This enabled the pathologist to report the diagnosis more accurately and also to provide adequate tissue for review, immunohistochemistry, and further mutation studies. Therefore, in the majority of cases, bronchoscopy would remain as the initial modality for evaluation and for obtaining tissue for histopathology. However, the final decision of the initial investigation to be used in an individual case would depend on their clinicoradiological presentation.

In the present study, ADC was found to be the commonest histological subtype, accounting for 48.1% of all lung cancer cases. Over the last few years there has been a shift in histological profile toward ADC worldwide and also in India.^11,24,25 However, most of the earlier Indian series reported SCC to be the commonest subtype.^5,9,10,17 This shift in histopathological cell type could be due to increasing urbanization, which exposes individuals to different carcinogens other than cigarette or bidi smoke. This is further supported by the fact that almost 70% patients of our study group belonged to Delhi or Delhi-NCR, suggesting a possibility of influence of air pollution in the genesis of lung cancer in these patients. However, strong epidemiological studies are warranted to establish this hypothesis.

The prevalence of EGFR mutation and ALK gene rearrangements in our study was 26.5 and 7.8%, respectively, which is similar to that reported earlier from the northern India (16–40%)^26,27 and lower than that seen in studies from the southern India (65–70%).^26,28 The possible reasons for the lower prevalence of EGFR mutation in our group than southern India could be related to differences in ethnicity, higher male-to-female ratio, and the method used to detect mutations. We used the direct gene sequencing method as compared to the more sensitive Scorpion ARMS method used in other studies.^26,28,29 The ratio of exon 19 deletions to exon 21 mutations in EGFR positive patients is highly variable across populations and earlier studies from our subcontinent have shown this ratio to vary from 1.3:1 to 4.6:1. This ratio in our cohort was 4:1 which falls within the range reported in earlier studies.²⁹ The EGFR mutation in nonsmoker ADC patients was significantly higher than that of the smokers as reported in many previous studies while no significant difference was seen in other demographic features, like age, sex, and performance status.

The overall incidence of ALK gene rearrangements in NSCLC is estimated to be 3%, with an incidence of up to 13% in East-Asian populations.^30–32 To date, there are few published reports from India on EML4 ALK mutations with studies demonstrating a positivity of up to 5%.^13,29,32 Our study showed that EML4-ALKgene fusions are present in 7.2% of ADC patients. It is well known that EGFR and ALK mutations are mutually exclusive.^26,31 We reconfirmed this finding suggesting ALK mutations as a potential therapeutic target in EGFR wild-type lung cancer.

This was a prospective study of consecutive patients diagnosed with lung cancer, thus eliminating selection bias and ensuring meticulous collection of data during follow-up. We extensively used IHC testing in majority of histopathological specimens, thus limiting the undifferentiated carcinoma group to a minimum.

There are a few limitations of this study. The current cohort of patients for EGFR and ALK mutation testing is not a consecutive patient analysis. Hence, it can be argued that the estimated prevalence of EGFR and ALK might not represent the true population prevalence. Gene sequencing was used to detect EGFR mutations, which is a less sensitive method than Scorpion ARMS. Subanalysis of EGFR/ALK positive patients could not be done due to small sample size.

CONCLUSIONS

This study strongly supports the fact that ADC may now be replacing SCC as the commonest type of lung cancer even in northern India. Though majority of clinico-radiographic features revealed no significant differences among various histopathological subgroups, clinical features like smoking status, hoarseness of voice, dysphagia, neck veins engorgement, and hemoptysis may still be predictive of a particular histopathology. Radiologically peripheral location of the tumor, pleural effusion, and bone metastases were significantly higher in ADC patients while peri-hilar lesion, liver, and brain metastases were more common in SCC. The overall incidence of EGFR mutations in ADC patients was 26.5%, which was significantly higher in nonsmoking patients with exon 19 deletion being the most common mutation.

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