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P O I N T O F V I E W
Virtual BiopsyBy J . U . KANG
Biopsy is a medical procedure involving the surgical removal of
tissue for close examination. As a rule, a biopsy is performed on
suspected cancerous tissue in order to determine the appearance
of cancer cells and the cancer stage [1]. Obtaining accurate
evaluation of the suspected tissue requires high-resolution optical imaging that
allows a clear view of the cell structure. This requires chemical treatment insome cases, freezing, dying, thinly slicing, and examining the tissue under a
high-magnification microscope. The downside of the biopsy is that it is an
invasive surgical procedure, there could be serious surgical complications such
as bleeding and/or infection, and it can take several days to weeks before the
final pathological report is ready to be presented to the patient [2].
These limitations have motivated researchers to develop ways to achieve a
high-resolution internal cellular imaging of the cancerous tissue noninvasively
and in real time. From the advent of noninvasive three-dimensional (3-D)imaging techniques such as ultrasound and magnetic resonance imaging (MRI)
for more than 50 and 30 years, respectively, there have been extensive efforts
by many researchers to attain Bvirtual biopsy.[ Some techniques have been
shown and proven to be highly effective diagnostic tools for different cancer
types. However, none is being effectively developed as a screening tool that can
replace traditional biopsy. Consequently, many people in the field are asking
and wondering if virtual biopsy is a realistic screening tool for the future.
The benefits of the virtual biopsy would be unmistakable. The noninvasivenature of the method eliminates the need to disturb the possible cancerous tissue,
reducing the chance of infection and bleeding. This procedure would also be
cheaper and faster. Most important, it would eliminate the long wait-time before the
patient receives information about his/her condition from his/her doctor. Waiting
for the test results can be highly stressful and terrifying for the patient and family.
A proper screening of the cancerous
tissue requires highly magnified imagesof an internal cellular structure. In
order to perform subsurface imaging,
3-D imaging modalities such as comput-
ed tomography (CT) scan, MRI, ultra-
sound, optical coherence tomography
(OCT) [3], and confocal microscope [4]
could be used and could be candidates
for Bvirtual biopsy.[There have been proposals for
spectroscopic technique based Bvirtual
biopsies[ that use absorption, fluores-
cence, or Raman spectrum to Blook[noninvasively for spectroscopic fea-
tures of cancer tissues [5]. However, I
will only focus on the imaging Bvirtual
biopsy[ technique in this paper.Three-dimensional imaging mo-
dalities such as CT-scan, MRI, and
ultrasound are well-established diag-
nostic tools that are capable of imaging
deep tissues and can differentiate tissue
density. Thus, they have been widely
used to locate the presence of abnormal
tissues and tumors. However, becausecell sizes are typically on the order
of tens of micrometers, they do not
have sufficient transverse resolution to
image cells. Therefore, at the present
stage, it would be accurate to state that
these techniques are inadequate to pro-
vide biopsy-comparable images of can-
cer tissue noninvasively.Since traditional biopsy is per-
formed using an optical microscope,
recent research efforts have been
focused on using optical 3-D imaging
modalities to achieve virtual biopsy.
Both confocal microscope and OCT
can achieve 3-D imaging by scanning a
laser beam over the tissue object,collecting scattered and/or reflected
laser beam to reconstruct depth re-
solved images. In the case of confocal
microscopes, the depth discrimination
is achieved by focal plane gating, which
has also been proven to provide su-
perior image quality than traditionalDigital Object Identifier: 10.1109/JPROC.2010.2041830
Vol. 98, No. 4, April 2010 | Proceedings of the IEEE 5030018-9219/$26.00 �2010 IEEE
wide-field microscopes since it sig-nificantly reduces background light
from the out-of-focus plane. OCT uses
an ultrabroadband laser source and low
coherence interferometry to acquire
many ultrathin Bsliced tissue[ images
on the order of a few micrometers
simultaneously.
There are several other technicalconsiderations that have to be discussed
before determining whether or not
these two optical techniques can be
used to obtain virtual biopsy. One is the
speed of the image acquisition. This
is important because, unlike a frozen
tissue sample imaging, involuntary
patient motion due to physiologicalprocesses such as breathing and
cardiac pulsation significantly deterio-
rates the image quality. Thus, the
imaging system should either have
motion-compensation capability or be
extremely fast, on the order of tens of
millisecond per sliced image. Confocal
microscopes are inherently slower thanOCT because it takes one image slice at
a time. OCT can take a large number of
slices at high resolution simultaneously.
In both cases, the physical scanning of
the laser beam limits the image acqui-
sition time, and the motion compensa-
tion may be a key component in both
cases. Another important issue is thedepth of imaging. Unfortunately, most
cancerous tissues are optically dense
and highly scattering. Therefore, the
incident laser beam does not penetrate
deeper than a few millimeters, which
limits the maximum imaging depth
to around 1 mm. Nevertheless, fortu-
nately, most cancers (> 85%) arecarcinomas. That is, they are cancers
of the epithelial cells and occur on the
surface of the organs. Deeper tissue
cancers such as gliomas and sarcomas
can also be imaged if they occur very
close to the surface of the organs.
One clarification I would like to
make at this point is that thesetechniques cannot be used to image
cancerous tissues completely non-
invasively from outside the body. They
have to be performed endoscopically.
That is, these types of screening have
to be performed using optical fiber
and scanning and imaging optics at the
distal and/or proximal end of the fiber.So the techniques can be considered
noninvasive relative to the cancer tissue
but would be minimally invasive to the
patient. Although fiber-optic endo-
scopic confocal microscopes are highly
promising [6], it is unlikely the confocal
microscope technique will be used
to perform endoscopic virtual biopsy.The ideal application for the confocal
microscope-based cancer screening
would be for a nonendoscopic-type
screening such as that of skin cancers.
OCT is a promising technique for
endoscopic virtual biopsy. As was
alluded to from the beginning, a
virtual biopsy tool needs to be able toobtain ultra-high-resolution internal
cellular imaging. It is known that OCT
can perform internal cellular imaging.
The main question is whether or not
it can obtain ultra-high-resolution
images. The axial resolution of the
OCT is determined by the bandwidth
of the light, and one can achieve a1–2 �m axial resolution. The trans-
verse resolution is determined by the
imaging optics. Because of the spatial
constraints associated with the endo-
scopic tools, the imaging optics have
to be relatively compact, which limits
the smallest beam waist one can
obtain that is directly related to thetransverse resolution. This is the same
problem that limits the endoscopic
confocal microscopes. Nevertheless,
in the case of OCT, trying to obtain the
best transverse resolution by tightly
focusing the beam is not desirable
since the depth of view is inversely
proportional to the beam waist. Thetightly focused optics will prevent
the system from obtaining images
over a sufficient depth range. This can
be circumvented by using an adoptive
focusing system. Scattering of the
tissue, tissue dispersion, vibration,
and a whole array of other problems
associated with clinical settings wouldhamper the system from obtaining
the theoretical resolution. But there is
help: image processing. The point
spread function of the OCT system,
axial, and transverse would be known,
and one can use various deconvolution
methods, coupled with speckle reduc-
tion, contrast enhancement, and anarsenal of other signal-processing
tools to enhance not only the resolution
but also the contrast and signal-to-noise
ratio of the images. My prediction is
that OCT will eventually achieve sub-
micrometer resolution in both axial and
transverse.
Earlier in this paper, I mentionedspectroscopy techniques. Because OCT
uses a broadband laser source to ob-
tain the image, the broadband light
source can also simultaneously be used
to obtain spectroscopic information,
say, around 800 nm center wave-
length, which overlaps with a large
number of protein absorption features.This information could indicate the
chemical/biological composition change
in the cells.
A collective effort by many re-
searchers, in all likelihood, will be
able to develop a technology based on
OCT that could provide a pathologist
with biopsy-like images having submic-rometer resolution and contrast en-
hancement features that will maximize
the optical imaging disparity present
between cancerous cells and normal
cells, in the near future. The technology
would also provide differentiating spec-
troscopic information. However, this
would be only half of the story, with theother half coming from a clinical
counterpart dedicated to the devel-
opment of screening standards and
correlative data that establishes relation-
ships between traditional histopatholog-
ical findings and OCT cellular imaging
data. The process of discovery and
development of this concept is analo-gous to drilling a long tunnel through a
mountain with researchers and pathol-
ogy counterpart starting from opposite
sides of the mountain. A perfect mid-
mountain meeting will require exten-
sive planning, communication, and
coordination of efforts. The realization
of the virtual biopsy in clinical practicecould only be achieved with extensive
planning, communication, and coordi-
nation of efforts between engineers,
clinicians, and biological scientists de-
riving from diverse backgrounds and
with broad perspectives.
Well, I didn’t say it would be easy. h
Point of View
504 Proceedings of the IEEE | Vol. 98, No. 4, April 2010
RE FERENCES
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[4] V. Campo-Ruiz, G. Y. Lauwers, R. R. Anderson,E. Delgado-Baeza, and S. Gonzalez, BIn vivoand ex vivo virtual biopsy of the liver withnear-infrared, reflectance confocal microscopy,’’Mod. Pathol., vol. 18, no. 2, pp. 290–300,Feb. 2005.
[5] A. Garcia-Uribe, N. Kehtarnavaz, G. Marquez,V. Prieto, M. Duvic, and L. V. Wang, BSkin cancerdetection by spectroscopic oblique-incidencereflectometry: Classification and
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[6] D.-H. Kim, I. K. Ilev, and J. U. Kang,BFiber-optic confocal microscopy using a1.55 �m fiber laser for multimodalbiophotonics applications,’’ J. Special TopicsQuant. Electron., vol. 14, no. 1, pp. 82–87,2008.
Point of View
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