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

[1] J. C. E. Underwood, Ed., General andSystematic Pathology. Philadelphia, PA:Saunders, Jan. 1996.

[2] J. Perrault, D. B. McGill, B. J. Ott, andW. F. Taylor, BLiver biopsy: Complicationsin 1000 inpatients and outpatients,’’Gastroenterology, vol. 74, no. 1, pp. 103–106,1978.

[3] J. G. Fujimoto, M. E. Brezinski, G. J. Tearney,S. A. Boppart, B. Bouma, M. R. Hee,J. F. Southern, and E. A. Swanson, BOpticalbiopsy and imaging using optical coherence

tomography,’’ Nature Med., vol. 1,pp. 970–972, 1995.

[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

physiological origins,’’ Appl. Opt., vol. 43,no. 13, pp. 2643–2650, 2004.

[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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