To evaluate the value of autofluorescence bronchoscopy for diagnosis of lung cancer in patients with high risk factors. Subjects and methods: The study was a prospective, cross-sectional, non-randomized trial at the National Lung Institute in the period from October 2016 to December 2018.
Journal of military pharmaco-medicine no9-2019 THE VALUE OF AUTOFLUORESCENCE BRONCHOSCOPY FOR DIAGNOSIS OF LUNG CANCER IN PATIENTS WITH HIGH RISK FACTORS Hoang Thi Bich Viet1; Dinh Ngoc Sy1; Dinh Cong Pho2; Vu Ngoc Hoan2 SUMMARY Objectives: To evaluate the value of autofluorescence bronchoscopy for diagnosis of lung cancer in patients with high risk factors Subjects and methods: The study was a prospective, cross-sectional, non-randomized trial at the National Lung Institute in the period from October 2016 to December 2018 The examination of the tracheobronchial tree started with white light bronchoscopy followed by autofluorescence bronchoscopy Biopsies confirmed to be positive for premalignant or malignant lesions were taken Results and conclusion: Both white light bronchoscopy and autofluorescence bronchoscopy are valuable for detecting lung cancer with p < 0.05, in which autofluorescence bronchosc was much more sensitive than white light bronchoscopy The specificity of the methods was 100% In detecting types of lung cancer such as adenocarcinoma, squamous cell carcinoma, adenocarcinoma, and small cell lung carcinoma, autofluorescence bronchoscopy was more sensitive and accurate and equally specific to white light bronchoscopy Combining the strategy of autofluorescence bronchoscopy and white light bronchoscopy may contribute preferably rather than their alone use for detecting lung cancer for high-risk patients * Keywords: Lung cancer; Autofluorescence bronchoscopy; White light bronchoscopy; Diagnostic value INTRODUCTION Lung cancer is one of the leading causes of cancer mortality worldwide [1], mainly attributed to its biologically aggressive nature and late stage at the time of diagnosis The most important drawbacks of inefficient treatment of lung cancer are delayed diagnosis and absence of effective screening However, the 5-year survival rate of patients stage IA could be up to 74.6%, indicating patients with longer life expectancy after diagnosis and treatment in early stage A long-term follow-up (12.5 years) surveillance study found 34% lung-cancer detection rate in patients harboring endobronchial pre-invasive lesions after median 16.5 months [2], suggesting these patients at high risk of primary or secondary cancer Therefore, diagnosis of pre-cancerous lesions and early-stage lung cancer is crucial National Lung Hospital 103 Military Hospital Corresponding author: Hoang Thi Bich Viet (Hoang_bichviet@yahoo.com) Date received: 13/10/2019 Date accepted: 27/11/2019 241 Journal of military pharmaco-medicine no9-2019 Detection and study of pre-cancerous lesions of the bronchial mucosa might be one of the turning points in the understanding of neoplastic transformation, and therefore creation of most effective treatment However, the use of white light bronchoscopy (WLB) in detection of pre-cancerous lesions yields low sensitivity and specificity Introduction of autofluorescence bronchoscopy (AFB) into diagnostic evaluation of lung cancer significantly improved sensitivity in detection of pre-cancerous lesions Conventional WLB is the most common tool for the detection of central-airway lung pre-cancerous and cancerous lesions In some cases, these lesions may be too thin or diminutive to be detected under the WLB In order to address this limitation, advanced techniques such as AFB have been developed AFB is the technique that emits fluorescent light containing green (520 nm peak) and red spectrum (> 630 nm peak), normal mucosa reflects this fluorescent light and presents a green-color image, while pre-cancerous and cancerous lesions (even a few millimeters in diameter) absorb the green spectrum, and the reflected light turns magenta Therefore, we conducted this study with the aims: To assess the value of AFB for diagnosis of lung cancer in patients with high risk factors SUBJECTS AND METHODS Subjects * Inclusion criteria: Patients in the age over 18 years with high-risk for lung cancer (smoking over ten years), clinical 242 symptoms that suspected malignancy such as prolonged cough, weight loss, dyspnea, hemoptysis… and radiological suspicion for lung cancer * Exclusion criteria: Patients who did not want to participate in the study and had any contraindications to bronchoscopy Prior to the enrollment in the study, all patients must have had chest X-ray, computed tomography (CT) scan of the thorax, complete blood count, and blood biochemistry Methods The study was a prospective, crosssectional, non-randomized trial, conducted at the National Lung Institute in the period from October 2016 to December 2018 It was approved by the institutional review and ethics board All the patients who decided to participate in the study were informed about the procedure, its potential benefits, and the risks, and all of them had signed institutional informed consent form * Technique: Bronchoscopy was performed in a dedicated respiratory endoscopy unit by bronchoscopists experienced in the use of AFB All procedures were performed in analgosedation The routine vital parameters were monitored: noninvasive arterial blood pressure, oxygen saturation on pulse oximetry, and ECG for cardiac rhythm Bronchoscopic equipment used in the study were D-light Autofluorescence System (Karl Storz Endoscopy America; Culver City, CA, USA) The examination of the tracheobronchial tree started with Journal of military pharmaco-medicine no9-2019 WLB followed by AFB All the suspected changes in bronchial mucosa were first examined with the WLB, followed by AFB modes Once the pathologic sites were identified, we performed targeted biopsies in order to obtain material for pathological examination A dedicated lung pathologist evaluated the biopsy specimens In all patients, at least one but no more than three biopsies were taken from places identified as pathologic, either by WLB, AFB or their combination Visually pathologic areas under AFB were defined as reddish-brown or magenta-colored area, while the healthy area was green Visual scoring system for the detection of pathologically altered mucosal areas under AFB was given in table Table 1: Visual appearance of normal and pathologically altered mucosa under autofluorescence videobronchoscopy Visual appearance AFB (autofluorescence imaging) appearance Normal mucosa Green autofluorescence with normal endobronchial architectonics Abnormal, not suspicious for malignancy (inflammation) Discrete decrease in fluorescence with vaguely defined margins, dark green or light violet (light purple) Suspicious neoplasia The definitive decrease in fluorescence, clearly defined margins, violet (or brownish) with clear distortion of endobronchial architectonics Tumor for intraepithelial Visible tumor, reddish-brown (magenta) colored Biopsies were identified as positive if squamous metaplasia, dysplasia, or invasive carcinoma were identified in the tissue If needed, for confirmation of the disease, additional transbronchial biopsies were taken, these biopsies were not counted into consideration for the purposes of this study Biopsy-based specificity, sensitivity, accuracy for detection of each individual technique and their combination were calculated Only the biopsies confirmed to be positive for premalignant or malignant lesions were taken into the calculation of sensitivity and specificity * Statistical analysis: All statistical analyses were performed with STATA version 15.0 The test was used to compare the diagnostic sensitivity and specificity, and statistically significant differences between categorical variables, sensitivity, specificity, the accuracy of WLB or AFB for the detection of precancerous lesions were calculated All probability values were calculated by assuming a two-tailed α value of 0.05 with confidence intervals at the 95% level 243 Journal of military pharmaco-medicine no9-2019 RESULTS AND DISCUSSION Table 2: Pre-cancerous lesions detecting by WLB and AFB (n = 245) WLB Endoscopic findings AFB Total Pathology without cancer (n = 109) Pathology with cancer (n = 136) Pathology without cancer (n = 109) Pathology with cancer (n = 136) Total (n = 245) % Hyperplasia 16 (14.7%) 21 (15.4%) 21 (19.4%) (5.2%) 56 22.9 Metaplasia (4.6%) (2.9%) (1.9%) (0.0%) 11 5.5 Mild dysplasia (1.8%) (1.5%) (6.4%) (0.7%) 12 5.5 Moderate dysplasia (0.9%) (2.2%) (5.5%) (2.9%) 14 5.7 Severe dysplasia (0.0%) 16 (11.8%) (4.6%) (6.6%) 30 11.8 87 (79.8%) 52 (38.2%) 67 (61.5%) 18 (13.2%) 155 63.3 Bronchitis Overall, the rate of hyperplasia in 56 cases accounting for 22.9% WLB detected 37 cases accounting for 66.1% while AFB detected only 28 cases accounting for 50% In 11 cases of metaplasia, WLB detected cases (81.8%), while AFB just detected cases (18.2%) A total of 56 cases with dysplasia were detected with 24 cases (42.8%) by WLB and 32 cases (57.2%) by AFB The combination of white light and AFB has been reported to show better sensitivity in detecting dysplasia and cancer of the bronchus than white light alone Ikeda et al used autofluorescence diagnosis system integrated into a video endoscope (SAFE 3000, Pentax, Tokyo) to evaluate the relationship between endoscopic findings and pathology results The sensitivity of the system for CIS + dysplasia was 65% in white light and 90% in SAFE This video endoscopy-based autofluorescence system had significantly higher sensitivity for intraepithelial lesions than white light video endoscopy alone In population with abnormal sputum cytology, the results of study from Lam et al 244 showed that AFB was more sensitive than WLB (91 versus 58%) at detecting dysplasia, but less specific (26 versus 50%) The results of this study suggested that the combination of white-light and AFB can increase the diagnostic yield in this situation Jang et al used the same system with our system (DLight/AFB) in the detection of pre-cancerous lesions The results showed that the relative sensitivity of adjunctive AFB to WLB vs WLB alone was 1.5 in moderate dysplasia or worse lesions, and 3.2 in intraepithelial neoplasia The adjunctive AFB to the standard WLB increased the detection rate of the localized pre-invasive lesions But the high rate of false positive in AFB also recorded In general, the sensitivity and specificity of AFB for diagnosing lung cancer were higher than those of WLB AFB showed high sensitivity for detecting lung cancer in cases in which WLB revealed hyperplasia, infiltration, and stenosis AFB combined with WLB could effectively improve the diagnosis of airway lesions [3] Journal of military pharmaco-medicine no9-2019 Table 3: Diagnostic value of WLB and AFB for lung cancer Endoscopic findings WLB AFB Pathology without cancer (n = 109) Pathology with cancer (n = 136) n % n % Suspected malignancy 39 28.7 0.0 Non-suspected malignancy 97 71.3 109 100 Suspected malignancy 97 71.3 0.0 Non-suspected malignancy 39 28.7 109 100 Sen Spec ACC p 28.7% 100% 60.4 0.000 b 71.3% 100 84.8 0.000 b (b: Fisher’s exact test) Both WLB and AFB were valuable for detecting lung cancer with p < 0.05, in which AFB was much more sensitive than WLB The specificity of the methods was 100% AFB was reported with more advantages for early lung cancer than WLB In detecting lung cancers and pre-cancerous lesions, the sensitivity of AFB was higher than that of WLB, the overall diagnostic performance of AFB was slightly better than that of WLB while the specificity of AFB was lower than that of WLB In detecting lung cancers and pre-cancerous lesions [8] In detecting intraepithelial neoplasia of lung cancer, the specificity of AFB + WLB was lower than WLB alone, AFB + WLB seems to significantly improve the sensitivity [6] Andreev et al concluded that AFB has an advantage over WLB in diagnosing endobronchial malignant lesions Sensitivity for AFB and WLB was 94.83%, but specificity was 52.83% and 55.66% if histology was used [10] In our study, when using AFB to diagnose lung cancer, the sensitivity and specificity were 71.3% and 100% Compared with Li et al, sensitivity in our study was lower (71.3 % vs 94.7%), but specificity was higher (100% vs 57%) [9] Systemic review and meta-analysis from Chen et al provided the pooled sensitivity and specificity of AFB and WLB were 0.90 and 0.56, 0.66 and 0.69 The result indicated that AFB was superior to conventional WLB in detecting lung cancer and pre-neoplastic lesions [7] The reason for the sensitivity of AFB in our study was lower than other studies because we only evaluated the detection of lung cancer while other studies evaluated the detection of both neoplasia and lung cancer The diagnostic value of AFB in detecting pre-cancerous lesions may depend greatly on many factors such as the use of the bronchoscopy system, the lesions, and the experience of doctor * Pathology results in group of lung cancer (according to WHO) (n = 136) Squamous cell carcinoma: 16 patients (11.8%); adenocarcinoma: 96 patients (70.6%); small cell lung carcinoma: 20 patients (14.7%); adenosquamous carcinoma: patients (2.9%); other types: patient 245 Journal of military pharmaco-medicine no9-2019 In a pathohistological-based study over patients were aged between 51 and 60 a 20-year period showed squamous cell years (36.6%) with squamous cell carcinoma carcinoma predominated in both genders; and adenocarcinoma predominance Three in 44.7% females and 68.0% males patients with small cell lung carcinoma Adenocarcinoma frequently were operated in 61 - 70 age-group diagnosed (21.8%) than squamous cell Other studies confirmed squamous cell carcinoma (64.0%) in both genders and all carcinoma had the highest incidence This age groups The most frequently operated results in line with our study was less Table 4: Diagnostic value of WLB and AFB for squamous cell carcinoma Endoscopic findings Pathology of squamous cell carcinoma (n = 16) Pathology of other lesions (n = 120) n % n % Squamous cell carcinoma 37.5 0.0 Non-squamous cell carcinoma 10 62.5 120 100.0 Squamous cell carcinoma 15 93.8 0.0 Non-squamous cell carcinoma 6.2 120 100.0 Sen Spec ACC p-value 37.5% 100% 92.7 0.03 93.8% 100% 99.3 0.000 b WLB b AFB (b: Fisher’s exact test) In the detection of squamous cell carcinoma, both WLB and AFB had statistically significant with p < 0.05 The sensitivity and accuracy of WLB were 93.8% and 99.3%, respectively, higher than that of WLB (37.5% and 92.7%) The specificity of the two methods was equal Peng et al showed the same conclusion, but some indexes were lower Diagnostic sensitivity of AFB group was 85.7%, specificity 73.3%, positive predictive value 95.1%, false predictive value 45.8% Diagnostic sensitivity of WLB group was 72.5%, specificity 60.0%, positive predictive value 91.7%, false predictive value 26.5% [11] 246 Journal of military pharmaco-medicine no9-2019 Table 5: Diagnostic value of WLB and AFB for adenocarcinoma Endoscopic findings WLB AFB Pathology of adenocarcinom a (n = 96) Pathology of other lesions (n = 40) n % n % Adenocarcinoma 20 20.8 0.0 Non-adenocarcinoma 76 79.2 40 100.0 Adenocarcinoma 59 61.5 0.0 Non- adenocarcinoma 37 38.5 40 100.0 Sen Spec 20.8% 61.5% ACC p-value 100% 44.1 % 0.000 b 72.8 % 0.000 b 100 % (b: Fisher’s exact test) In the detection of adenocarcinoma, both WLB and AFB were statistically significant with p < 0.05 The sensitivity and accuracy of AFB were 61.5% and 72.8%, respectively, were significantly higher than that of WLB at 20.8% and 44.1% The specificity of the two methods was equal Masako Chiyo et al used lightinduced fluorescence endoscopy (LIFE) and AFB to detect dysplasia with the sensitivities were 96.7% and 80%, respectively The specificity of AFB (83.3%) was significantly higher than that of LIFE (36.6%) (p = 0.0005) These results indicated that AFB appears to represent a significant advance in distinguishing preinvasive and malignant lesions from bronchitis or hyperplasia under circumstances where LIFE would identify these all as abnormal lesions Kurie et al used the same system with population of current and former smokers with resulted abnormalities detected by LIFE bronchoscopy did not improve the detection of squamous metaplasia or dys plasia These results supported that AFB is valuable in diagnosing precancerous lesions such as dysplasia and metaplasia in high-risk patients for lung cancer Table 6: Diagnostic value of WLB and AFB for small cell lung carcinoma Endoscopic findings WLB AFB Pathology of small cell lung carcinoma (n = 20) Pathology of other lesions (n = 116) n % n % Small cell lung carcinoma 13 65.0 0.0 Non-small cell lung carcinoma 35.0 116 100.0 Small cell lung carcinoma 20 100.0 0.0 Non-small cell lung carcinoma 0.0 116 100.0 Sen Spec ACC p-value 65% 100 % 94.9% 0.001 b 100% 100% 100% 0.000 b (b: Fisher’s exact test) 247 Journal of military pharmaco-medicine no9-2019 In the detection of small cell lung carcinoma, both AFB and WLB were statistically significant with p < 0.05 Especially, the sensitivity, specificity, and accuracy of AFB were 100% It is valuable index to detect lung cancer as well The clinical value of AFB for the diagnosis of lung cancer was reconfirmed in patients exhibiting abnormal sputum cytology In detecting types of lung cancer such as adenocarcinoma, squamous cell carcinoma, adenocarcinoma, and small cell lung carcinoma, AFB is more sensitive and accurate and equally specific to WLB The difference in the detection of lung cancer types may be due to the ability of AFB to identify lesions through visible changes in the bronchial mucosa Therefore, AFB can identify malignant lesions from the mucosa This is very significant in raising the diagnostic value of lung cancer and pre-cancerous lesions on endoscopy It is recommended to recommend a combination of fluorescence bronchoscopy and white light endoscopy in improving diagnosis and treatment orientation for patients AFB should find its place in routine bronchoscopic examination and may improve the diagnostic outcomes the strategy of AFB and WLB may contribute preferably rather than their alone use for detecting lung cancer for high-risk patients REFERENCES Torre L.A et al Global cancer statistics CA Cancer J Clin 2015, 65 (2), pp.87-108 van Boerdonk R.A et al Close surveillance with long-term follow-up of subjects with preinvasive endobronchial lesions Am J Respir Crit Care Med 2015, 192 (12), pp.1483-1489 Liu Z et al Clinical relevance of using autofluorescence bronchoscopy and white light bronchoscopy in different types of airway lesions J Cancer Res Ther 2016, 12 (1), pp.69-72 Stojsic J et al Histological types and age distribution of lung cancer operated patients over a 20-year period: A pathohistological based study Srp Arh Celok Lek 2011, 139 (9-10), pp.619-624 Stojsic J et al Gender and age trends of histological types of lung cancer in a 20-year period: Pathological perspective J Buon 2010, 15 (1), pp.136-140 CONCLUSION Sun J et al The value of autofluorescence bronchoscopy combined with white light bronchoscopy compared with white light alone in the diagnosis of intraepithelial neoplasia and invasive lung cancer: A meta-analysis J Thorac Oncol 2011, (8), pp.1336-1344 In conclusion, with remarkable sensitivity, we believe potential lesions of precancerous and cancerous lesions could be covered by AFB, especially precancerous lesions, almost invisible and easily missed by WLB Combining Chen W et al A comparison of autofluorescence bronchoscopy and white light bronchoscopy in detection of lung cancer and preneoplastic lesions: A meta-analysis Lung Cancer 2011, 73 (2), pp 183-188 Wang Y et al Comparison of autofluorescence imaging bronchoscopy and 248 Journal of military pharmaco-medicine no9-2019 white light bronchoscopy for detection of lung cancers and precancerous lesions Patient Prefer Adherence 2013, 7, pp.621-631 Li Y et al Comparison of the autofluorescence bronchoscope and the white light bronchoscope in airway examination Chin J Cancer 2010, 29 (12), pp.1018-1022 10 Andreev V.Y et al Autofluorescence and white light bronchoscopy in the diagnosis of endobronchial malignant lesions Folia Med (Plovdiv) 2018, 60 (3), pp.439-446 11 Peng A et al The value of autofluorescence bronchoscopy in assessment of tumor extent and guide of therapeutic strategy in central lung cancer Zhonghua Nei Ke Za Zhi 2015, 54 (1), pp.40-43 12 Zheng X et al Application of quantitative autofluorescence bronchoscopy image analysis method in identifying bronchopulmonary cancer Technology in Cancer Research & Treatment 2017, 16 (4), pp.482-487 249 ... assess the value of AFB for diagnosis of lung cancer in patients with high risk factors SUBJECTS AND METHODS Subjects * Inclusion criteria: Patients in the age over 18 years with high- risk for lung. .. as well The clinical value of AFB for the diagnosis of lung cancer was reconfirmed in patients exhibiting abnormal sputum cytology In detecting types of lung cancer such as adenocarcinoma, squamous... the specificity of AFB was lower than that of WLB In detecting lung cancers and pre-cancerous lesions [8] In detecting intraepithelial neoplasia of lung cancer, the specificity of AFB + WLB was