Early Detection of Lung Cancer Using Bronchoscopy

Although the overall lung cancer survival is poor with only
15% of patients surviving 5 years after diagnosis, 1 patients
with tumors 2 cm have a 5-year survival of 77%. 1 The
survival of those with preinvasive or microinvasive bronchial
cancers is even better at 90%. 2 Over the last 2 decades,
the largest gain in life expectancy in lung cancer patients is
among those with localized disease versus those with regional
or distant metastasis. 3 Clearly, strategies to improve outcome
by detecting and treating the disease in the preinvasive or
localized stages is needed.
There are unique challenges to localize preneoplastic lesions
or early cancers in the lung. In contrast to other epithelial
organs such as the oral cavity, cervix, or colon, the lung
consists of a complex branching system of conducting airways
leading to alveoli with a surface area the size of a tennis court.
In addition, instead of a single cell type, lung cancer consists of
several cell types and they are preferentially located in different
parts of the tracheobronchial tree. Squamous cell carcinoma
and small cell carcinoma, accounting for approximately 45%
to 50% of the lung cancers are preferentially located in the
central airways (trachea, main, lobar, and segmental bronchi).
Adenocarcinoma, accounting for approximately 40% to 50%
of all lung cancers, is preferentially located in the peripheral airways
inaccessible to standard fiberoptic/video bronchoscopes
because of the size of these instruments with an outer diameter
of 4.9 mm. Ultrathin bronchoscopes with an outer diameter
of 2.9 mm are available, but they cannot reach peripheral
airways 2 mm in diameter. Thus, there is no single method
that can scan the entire bronchial epithelium and allow tissue
sampling for pathological diagnosis and molecular profiling.
DETECTION OF EARLY CANCER IN
CENTRAL AIRWAYS
Rapid evaluation of the central airways became possible with
the development of flexible fiberoptic white-light bronchoscopy
by Dr. Shigeto Ikeda in the late 1960s. There has been
continuing technological advancement over the last 40 years.
The development of videobronchoscopy, with better image
resolution and quality, is now replacing the former fiberoptic
systems. However, early central lung cancers remain difficult to
detect with white-light bronchoscopy even with the improved
image capability of videobronchoscopy. 4 Recent incorporation
of optical zoom or magnifying lenses may enhance the
examination of the bronchial mucosa and improve the detection
of early vascular changes that can be associated with early
malignant change. 5 Other developments that can be used in
adjunct with white-light imaging for localization of preneoplastic
lesions and early lung cancer include autofluorescence
bronchoscopy (AFB), narrow-band imaging (NBI), and optical
coherence tomography (OCT). The recent development of
endobronchial ultrasound is an additional tool for the bronchoscopic
assessment of central early lung cancers.
Autofluorescence Reflectance Bronchoscopy Auto
fluorescence reflectance bronchoscopy has been shown in multiple
studies to significantly increase the detection of preneoplastic
lesions and carcinoma in situ when used as an adjunct
to white-light bronchoscopy 6–26 (Table 19.1). In addition, it is
important in the staging of early central lung cancers prior to
curative endobronchial therapy. 27,28 It enables the bronchoscopist
to obtain a more accurate visualization of the margins
and assessment of lesion size. 27,28
This technique utilizes the spectral differences in fluorescence
and absorption properties of normal and dysplastic
bronchial epithelium and has served as the basis for the design
of several autofluorescence imaging devices for localization
of early lung cancer. 6,12,13 More recent versions of these
devices use a combination of reflectance and fluorescence for
imaging. 14,22,23,25,29,30
AFB was first developed in the early 1990s at the British
Columbia Cancer Research Centre in Vancouver, British
Columbia, and became commercially available in 1998. 10 The
LIFE-Lung system ( Xillix Technologies, Vancouver, BC) used a
helium–cadmium laser for illumination (442 nm) and detected
the emitted red and green autofluorescent light with two imageintensified
charge-coupled device (CCD) cameras. Normal areas
appear green, and abnormal areas appear reddish brown because
of reduced green autofluorescence in preneoplastic and neoplastic
lesions.
Subsequent improvements in technology made it possible
to use nonimage intensified CCDs for detection. Two secondgeneration
devices approved by Food and Drug Administration
(FDA) made use of a combination of fluorescence and reflectance
to enhance contrast between normal and abnormal tissues
(Table 19.2). The Onco-LIFE system (Novadq Technologies,
Richmond, Canada) utilizes a combination of reflectance and
fluorescence imaging. Blue light (395 to 445 nm) and small
amount of red light (675 to 720 nm) from a filtered mercury
arc lamp is used for illumination (Fig. 19.1). A red reflectance
image is captured in combination with the green autofluorescence
image to enhance the contrast between premalignant,
malignant, and normal tissues as well as to correct for differences
in light intensities from changes in angle and distance
of the bronchoscope from the bronchial surface. 14 Using reflected
near infrared red light as a reference has the theoretical
advantage over reflected blue light in that it is less absorbed by
hemoglobin and hence less influenced by changes in vascularity
associated with inflammation. The D-Light system (Karl Storz
Endoscopy of America, Culver City, California) consists of a
red/green/blue (RGB) CCD camera and a filtered Xe lamp
(380 to 460 nm). It combines an autofluorescence image from
wavelengths 480 nm with a blue reflectance image. 25 Frame
averaging is used to amplify the weak autofluorescence signal.
These earlier autofluorescence systems were developed
to be used with fiberoptic bronchoscopes. With the advanced
CCD sensor technology and more widespread use of videobronchoscopy,
autofluorescence systems that can be used
with videobronchoscopes have been developed (Table 19.2).
The Pentax SAFE-3000 system (Pentax Corporation, Tokyo,
Japan) uses a semiconductor laser diode that emits 408 nm
wavelength light for illumination and detects autofluorescence
using a single high-sensitivity color CCD sensor in the fluorescence
spectrum 430 to 700 nm (Fig. 19.2). Reflected blue
light is used to generate a fluorescence-reflectance image. The
white-light and fluorescence images can also be made displayed
simultaneously. 29 The Olympus autofluorescence imaging
bronchovideoscope system (Olympus Corporation, Tokyo,
Japan) uses blue light (395 to 445 nm) for illumination. An
autofluorescence image (490 to 700 nm) as well as two reflectance
images, one green (550 nm) and one red (610 nm)
are captured sequentially and integrated by a videoprocessor to
produce a composite image. 30
A reduction in specificity has been associated with the increased
sensitivity for detection of early lesions. However, there is
some data that shows that areas with abnormal autofluorescence
contain increased chromosomal aberrations despite a benign histopathology,
and that the presence of multiple areas of abnormal
autofluorescence is an indicator of overall increased lung cancer
risk. 31,32 Recently, the use of a quantitative score during autofluorescence
examination has been shown to improve specificity. 33
Optical Coherence Tomography Currently, there are
two imaging modalities with sufficient spatial resolution and
tissue depth penetration to address the relatively high falsepositive
AFB results and to determine whether the tumor has
already invaded through the basement membrane (Fig. 19.3).
Confocal microendoscopy offers spatial resolution down to
the submicron range, but epithelial cells do not autofluoresence
strong enough to allow detection without application of
a contrast agent. 34,35 In addition, because contact with the
bronchial surface is required, fragile epithelium can be scraped
off during imaging. Motion artifacts caused by cardiac pulsation
and respiratory movements can also lead to suboptimal
confocal imaging of cellular details. OCT is a promising micron-
scale–resolution method that may be more suitable for
rapid endoscopic imaging. OCT is a noncontact method that
delivers near infrared light to the tissue and allows imaging of
cellular and extracellular structures from analysis of the backscattered
light with a spatial resolution of 3 to 15 m and a
depth penetration of approximately 2 mm to provide near-histological
images in the bronchial wall. 36–39 Preliminary studies
showed that invasive cancer can be distinguished from carcinoma
in situ (CIS), and that dysplasia can be distinguished
from metaplasia, hyperplasia, or normal. 39–41 A progressive
increase in the epithelial thickness was found to parallel the
severity of the histopathology grade. The nuclei of the cells
also became darker and less light scattering in lesions that
were moderately dysplastic or worse. The basement membrane
became disrupted or disappeared with invasive carcinoma. 41
However, CIS could not be distinguished from high-grade dysplasia.
Therefore, systems with higher resolution and Doppler
capability and polarization sensitivity that can measure tissue
microstructures in greater detail and quantify microvascular
blood flow are needed. 42 Doppler OCT (DOCT) systems already
exist that can detect extremely slow blood flow ( 20
m/sec in blood vessels as small as 15 m diameter). 43,44
DOCT’s unprecedented micron-scale spatial resolution and
ability to monitor functional blood flow parameters at the microvascular
level should prove valuable for (a) structural and
functional lesion assessment, 45 (b) differential diagnosis/staging
(invasion through the basement membrane and hence may
no longer be curable by endoscopic therapy such as electrocautery
treatment), 39,41 and (c) therapeutic feedback monitoring
during endobronchial therapy such as photodynamic
therapy. 44,46
High-Magnification Videobronchoscopy Increased
vessel density in the bronchial submucosa is often present
in squamous dysplasia and may play an early role in cancer
pathogenesis. 47 Angiogenic squamous dysplasia is a specific
lesion characterized by a collection of blood vessels juxtaposed
to and projecting into an area of epithelial dysplasia.
47 High-magnification bronchoscopy (Olympus Optical
Corporation, Tokyo, Japan) combines both fibreoptic and
videobronchoscope technologies to produce 100 to 110
magnification of the bronchial wall compared with standard
videobronchoscopes. 5,48 This enables the visualization of microvascular
networks in the bronchial mucosa. An increase in
microvessels can be seen by high-magnification imaging in
most areas of abnormal autofluorescence and dysplasia, and
discrimination from bronchial inflammation is possible. 5
Narrow-Band Imaging NBI (Olympus Optical Corpora
tion, Tokyo, Japan) is a novel system that also utilizes the
changes seen in the microvascular network of bronchial dysplasia.
This technique uses a narrow-band filter rather than
the conventional broad RGB filter used in standard videobronchoscopes.
The conventional RGB filter uses 400 to
500 nm (blue), 500 to 600 nm (green), and 600 to 700 nm
(red). NBI uses three narrow bands 400 to 430 nm (blue covers
hemoglobin absorption at 410 nm), 420 to 470 nm (blue),
and 560 to 590 nm (green) to create the images. Blue light
has a short wavelength, reaches into the bronchial submucosa,
and is absorbed by hemoglobin. On evaluation of airway lesions
that were abnormal under autofluorescence imaging,
this technique provides more accurate images of microvessels
compared with high-magnification videobronchoscopy using
broadband RGB technology. 48 Further evaluation of NBI in a
small series has been performed in comparison with standard
white-light videobronchoscopy. It was found to improve the
detection of dysplasia/malignancy when used as an adjunct
to white light compared with white-light imaging alone. The
relative sensitivity was 1.63. 49 A direct comparison between
NBI and AFB to determine their relative merits have not been
conducted.
Endobronchial Ultrasound for Central Lesions
Endobronchial ultrasound is a new technology that is likely to
have a significant contribution to the correct staging of early
central lung cancer. The layers of the bronchial wall can be visualized,
and detection of unsuspected invasion is improved. 50–52
The use of endobronchial ultrasound may also be used as an
adjunct to AFB, where it may be used to further assess lesions
with significantly abnormal autofluorescence and improve prediction
of malignancy. 53
Evaluation of the curability of early central lung cancers
with endobronchial therapies such as photodynamic therapy,
electrocautery, and cryotherapy has previously relied on endobronchial
characteristics. These include size, visual margins,
and nodularity particularly under autofluorescence imaging.
These have been correlated with risk of bronchial wall invasion
and lymph node metastasis. 54–56 However, it is important
to evaluate the depth of invasion and involvement of the cartilaginous
layer to make the most appropriate choice of curative
therapy. Thoracic computed tomography (CT) scan is
not useful for small central lung cancers either for detection
of the lesion or the assessment of intrabronchial wall invasion.
27,51,57 Endobronchial ultrasound using a radial probe inserted
through the working channel of a flexible bronchoscope
can be used to assess depth of invasion of a central cancer into
or through the bronchial wall with a sensitivity of 86% and
specificity of 67% (Fig. 19.4). 51,53 This will assist the physician
in choosing either endobronchial therapy or immediate
referral for surgery if unsuspected invasion is detected.