The value of autofluorescence bronchoscopy for diagnosis of lung cancer in patients with high risk factors

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 VALUE OF AUTOFLUORESCENCE BRONCHOSCOPY FOR DIAGNOSIS OF LUNG CANCER IN PATIENTS

WITH HIGH RISK FACTORS

Hoang Thi Bich Viet 1 ; Dinh Ngoc Sy 1 ; Dinh Cong Pho 2 ; Vu Ngoc Hoan 2

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 2 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

1 National Lung Hospital

2 103 Military Hospital

Corresponding author: Hoang Thi Bich Viet (Hoang_bichviet@yahoo.com)

Date received: 13/10/2019

Date accepted: 27/11/2019

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

1 Subjects

* Inclusion criteria: Patients in the age

over 18 years with high-risk for lung

cancer (smoking over ten years), clinical

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

2 Methods

The study was a prospective, cross-sectional, 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

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 1

autofluorescence videobronchoscopy

Abnormal, not suspicious for

malignancy (inflammation)

Discrete decrease in fluorescence with vaguely defined margins, dark green or light violet (light purple)

neoplasia

The definitive decrease in fluorescence, clearly defined margins, violet (or brownish) with clear distortion of endobronchial architectonics

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 pre-cancerous 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

RESULTS AND DISCUSSION

Table 2: Pre-cancerous lesions detecting by WLB and AFB (n = 245)

Endoscopic

findings without cancer Pathology

(n = 109)

Pathology with cancer (n = 136)

Pathology without cancer (n = 109)

Pathology with cancer (n = 136)

Total

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 9 cases (81.8%), while AFB just

detected 2 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

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]

Table 3: Diagnostic value of WLB and AFB for lung cancer

Pathology without cancer (n = 109)

Pathology with cancer (n = 136)

Endoscopic findings

WLB

b

AFB

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 2 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: 4 patients (2.9%); other types:

0 patient

In a pathohistological-based study over

a 20-year period showed squamous cell

carcinoma predominated in both genders;

in 44.7% females and 68.0% males

Adenocarcinoma was less frequently

diagnosed (21.8%) than squamous cell

carcinoma (64.0%) in both genders and all

age groups The most frequently operated

patients were aged between 51 and 60 years (36.6%) with squamous cell carcinoma and adenocarcinoma predominance Three patients with small cell lung carcinoma were operated in 61 - 70 age-group Other studies confirmed squamous cell carcinoma had the highest incidence This results in line with our study

Table 4: Diagnostic value of WLB and AFB for squamous cell carcinoma

Pathology of squamous cell carcinoma (n = 16)

Pathology of other lesions (n = 120)

Endoscopic findings

Squamous cell

WLB

Non-squamous

Squamous cell

AFB

Non-squamous

(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]

Table 5: Diagnostic value of WLB and AFB for adenocarcinoma

Pathology of adenocarcinom

a (n = 96)

Pathology of other lesions (n = 40)

Endoscopic findings

WLB

AFB

%

(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

light-induced 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

Pathology of small cell lung carcinoma (n = 20)

Pathology of other lesions (n = 116)

Endoscopic findings

Small cell lung

WLB

Non-small cell lung

Small cell lung

AFB

Non-small cell lung

(b: Fisher’s exact test)

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

CONCLUSION

In conclusion, with remarkable sensitivity,

we believe potential lesions of

pre-cancerous and pre-cancerous lesions could

be covered by AFB, especially

pre-cancerous lesions, almost invisible and

easily missed by WLB Combining

the strategy of AFB and WLB may contribute preferably rather than their alone use for detecting lung cancer for high-risk patients

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