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Bioimpedance: Novel use of a minimally invasive

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Article in The Prostate · May 1999

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 The Prostate 39:213–218 (1999)

Bioimpedance: Novel Use of a Minimally Invasive

Technique for Cancer Localization in the
Intact Prostate
Benjamin R. Lee,1* William W. Roberts,1 Dexter G. Smith,2 Harvey W. Ko,2
Jonathan I. Epstein,3 Kristen Lecksell,3 and Alan W. Partin1
1
James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland
2
Johns Hopkins Applied Physics Laboratory, Columbia, Maryland
3
Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland

BACKGROUND. Prostate cancer is presently diagnosed by transrectal ultrasound (TRUS)-

guided sextant needle biopsy. While echo texture of the tissue can prompt localization of
tumor, it is presently imprecise. From 50–75% of men biopsied, based on an abnormal digital
rectal examination (DRE) or elevated prostate-specific antigen (PSA) level, have negative
biopsy results. Improvements in tumor localization during TRUS-guided prostate biopsy are
greatly needed. Bioimpedance is an electrical property of biologic tissue. Electric current is
limited in living tissue by highly insulating cell membranes; however, different tissue archi-
tecture such as cancer may impede current differently and allow detection of differences
between normal and abnormal or malignant prostate tissue. Our goal was to assess the utility
of bioimpedance measurements in differentiating tumor from normal prostatic tissue in an ex
vivo model.
METHODS. Bioimpedance was measured in six ex vivo prostates, which were removed for
clinically localized prostate cancer. Two bioimpedance needles, 1 mm apart, were inserted 3
mm into the posterior surface of the prostate an average of 16 times per gland. Frequencies
ranging from 100 kHz–4 MHz were used to obtain 594 bioimpedance measurements from the
six glands. These measurements were then correlated with histology to determine the pres-
ence or absence of prostate cancer.
RESULTS. Prostate cancer was found to have a higher impedance, of 932 ± 170 ohms,
compared to areas of no cancer within the same prostate, 751 ± 151 ohms, P < 0.0001, at 2
MHz. This phenomenon was observed across all frequencies tested.
CONCLUSIONS. This study demonstrates for the first time application of bioimpedance to
distinguish areas of prostate cancer from areas of normal prostate. This technology may
improve identification and localization of cancer within the prostate. Moreover, bioimped-
ance can potentially guide needle placement during prostate biopsy and thus improve sam-
pling of tumors. Currently, our ex vivo model is limited by variables such as temperature and
lack of blood flow. Further studies in an in vivo model will be needed to assess their effect.
Prostate 39:213–218, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: bioimpedance; prostate; prostate cancer

INTRODUCTION
Prostate cancer is the most commonly diagnosed
cancer and the second leading cause of cancer death in
American men [1]. In 1997, there were more than
209,900 new cases of prostate cancer diagnosed and
more than 41,800 prostate cancer deaths [2]. Currently,
in men with an abnormal digital rectal examination
Grant sponsor: NCI; Grant number: SPORE CA 58236; Johns Hop-
kins Bayview; Grant number: Physicians Grant 162-98.
None of the authors have any financial arrangements with any com-
pany regarding this device.
*Correspondence to: Benjamin R. Lee, M.D., James Buchanan Brady
Urological Institute, Johns Hopkins Hospital, Marburg 215, Balti-
more, MD 21287. E-mail: blee@welchlink.welch.jhu.edu
Received 3 August 1998; Accepted 18 December 1998

© 1999 Wiley-Liss, Inc.

214 Lee et al.
Fig. 1. Bioimpedance needle probe. The probe was constructed
from two stainless steel needles, each 1 mm in diameter and
tapered to a point. Frequencies ranging from 100 kHz–4 MHz
were passed between the points, and bioimpedance was mea-
sured.
(DRE) and/or elevated prostate-specific antigen (PSA)
level, who are candidates for therapy, a transrectal
ultrasound (TRUS) with prostatic biopsy (Bx) is rec-
ommended. According to the U.S. Bureau of the Cen-
sus in 1998, there are an estimated 30 million men
currently in the United States over the age of 50 [3]. A
subset of this population represents those men who
should undergo screening according to recommenda-
tions by the American Urological Association [4]. In a
study by Arcangeli et. al. [5], 8–15% of men who were
screened were estimated to have an abnormal PSA test
(i.e., serum PSA at least 4.1 ng/ml by monoclonal as-
say). Of men who have abnormal DREs, half will have
no identifiable pathology on biopsy [6]. As well, with
abnormally elevated PSA levels, about 66% of men
will have a negative biopsy [5]. Only 19–32% of men
who agreed to undergo biopsy were found to have
prostate cancer [6]. A more sensitive and specific im-
aging modality to better direct prostate biopsy is
needed to aid the clinician in localizing cancer.
Bioimpedance is an electrical property of cells that
has been applied to many biomedical applications,
such as quantification of brain edema in neurosurgery
[7] and in differentiating a pulmonary mass such as
cancer from pneumonia [8]. In 1997, a bioimpedance
needle probe was developed in collaboration by sci-
entists and engineers at the Johns Hopkins Hospital
and Johns Hopkins Applied Physics Laboratory (Fig.
1). The goal of this project was to determine whether
application of this new technology to prostate cancer
detection could distinguish an area of prostate cancer
from normal prostate, using needle electrode probes
and passage of electrical current through the paren-
chyma.
To our knowledge, this is the first study investigat-
ing use of bioimpedance for identification of prostate
cancer. A wide spectrum of frequencies from 100
kHz–2 MHz was tested as well, to ascertain the best
frequency to use. The investigative model for this
study was ex vivo prostates, tested immediately after
surgical removal for localized clinical prostate cancer.
Probe development, factors which can distort bio-
impedance measurements, and future implications for
use of this technology are discussed.
MATERIALS AND METHODS
Bioimpedance Equipment
The bioimpedance measurement apparatus consists
of a probe, a Hewlett Packard 4275A LCR (inductance,
capacitance, and resistance) meter, and a thermistor.
The probe was fabricated from two stainless steel
needles, each 1 mm in diameter, 30 mm long, and
tapered to a point. The needles were coated with a
nonconducting epoxy, leaving the distal 1.0 mm ex-
posed. The needles were then secured in an insulated
fiberglass cylinder in parallel alignment, with 1 mm
spacing between them. During the evolution of the
technique, three different probes were fabricated. Al-
though all three probes were constructed in similar
fashion, the variance in measurements improved as
the technique for probe construction was refined.
However, each probe recorded higher resistance val-
ues in prostate cancer tissue compared to areas of nor-
mal prostate. We report our findings using the third
probe, which produced reliable, reproducible results.
The same apparatus was utilized for all measurements
discussed in this study.
Data from the Hewlett Packard LCR meter includes
both R (resistance) and Z (impedance − magnitude
and phase). Initial results concentrated on R measure-
ments. This measurement was then temperature-
corrected (assuming a linear temperature profile from
the start to the end of a measurement series). One may
calculate conductivity by dividing conductance (1/R)
by the spacing between the needles; however, in this
series of experiments the probes were calibrated using
test solutions of known conductivities. Using coaxial
cables, the probe was connected to the LCR meter
upon which the resistance values were measured be-
tween the two needles of the probe. A thermistor,
placed intraurethrally, was used to record the tem-
perature of the ex vivo prostate. The probe was cali-
brated before and after each set of bioimpedance mea-
surements, using known calibration solutions of so-
dium chloride in order to ensure that the probe
measurements were consistent during the course of an
experiment and from day to day. Moreover, tempera-
 Bioimpedance for Prostate Cancer Localization
Fig. 2. Needle insertion points. Area of parenchyma surround-
ing needle insertion site is minimally distorted histologically. Mea-
surement of bioimpedance does not significantly alter pathologic
diagnosis.
ture measurements were made before and after the set
of measurements, in order to calculate the change in
temperature of the prostate during the course of the
experiment. The calibration solutions used for the
probes were standards of known conductivity, allow-
ing accurate conversion of measured values to stan-
dard conductivity units.
Prostate Specimens
Prostates were obtained fresh from patients imme-
diately following radical retropubic prostatectomy for
clinically localized prostate cancer. A grid of 10–15
points was marked on the posterior aspect of the pros-
tate by applying orange pathology chalk with a 2-mm
wooden probe. At each marked point, the impedance
probe was inserted to a depth of 3 mm, and imped-
ance measurements were recorded from the LCR me-
ter (Fig. 2). Following probe measurements, one drop
(∼0.25 cc) of blue printer’s ink was injected into each of
the probed points for later histologic localization. The
prostate was then step-sectioned and prepared in stan-
dard fashion. Areas with blue ink were identified on
the histologic sections as regions which had been
probed, and histology was correlated with the associ-
ated points on the surface of the prostate. The 3-mm
region on the microscope slide around each identified
probe location was marked for histologic evaluation
by a pathologist who determined if cancer was present
at each marked region (Fig. 3).
RESULTS
During the evolution of the technique, three differ-
ent probes were fabricated. Although all three probes
were constructed in similar fashion, the variance in
215
measurements improved as the technique for probe
construction was refined. The first and second probes
suffered from a change in the epoxy coating on the
needles. The third used a quicker-drying, harder-
setting epoxy that has held up over a number of ex-
periments. Due to a learning curve in construction of
the probes, there was a great variance in the measure-
ments using the first two probes due to movement of
the needle electrodes. However, each probe recorded
higher resistance values in prostate cancer tissue com-
pared to areas of normal prostate. We report our find-
ings using the third probe, which produced reliable,
reproducible results. The same apparatus was utilized
for all measurements discussed in this study. Calibra-
tion solutions were used to calibrate probe vs. tem-
perature and frequency. Solutions with known con-
ductivities of 0.1–2.1 S/m (Siemens/meter) were used
along with standard 0.9% saline. Two or more calibra-
tion solutions were used both before and after each
series of tissue measurements. The calibration solu-
tions spanned the conductivity range of interest.
In all, 594 bioimpedance measurements were made
on six human ex vivo prostates removed for localized
prostate cancer. Using the same probe for each pros-
tate, measurements at frequencies of 100 kHz, 1 MHz,
2 MHz, and 4 MHz were performed. These frequen-
cies match previously reported clinically significant
wavelengths. Table I shows the number of measure-
ments made at each frequency. Using a Wilcoxon
rank-sum (Mann-Whitney) test of unpaired, nonpara-
metric data, it was determined that P < 0.00001. At
frequencies of 1 MHz and 100 kHz, similar determi-
nations were calculated with P = 0.01 and P < 0.0001,
respectively. At 4 MHz, there was not found to be a
statistical difference, in part due to the few measure-
ments made at this frequency. At 2 MHz, 200 mea-
surements were performed. With histologic correla-
Fig. 3. Prostate. Outline demonstrates area of prostate cancer
adjacent to an area of benign prostatic hyperplasia, a situation in
which bioimpedance may help improve biopsy sampling.
216 Lee et al.
TABLE I. Comparison of Bioimpedance Measurements at Biologically Significant Frequencies
Bioimpedance
Frequency Histology N (ohms)
100 kHz No cancer 137 1,123
Cancer 61 1,312
1 Mhz No cancer 137 872
Cancer 43 950
2 Mhz No cancer 126 751
Cancer 74 932
4 Mhz No cancer 11 753
Cancer 5 688
tion, areas of benign prostate (n = 126) had a mean
bioimpedance of 751 ± 151 ohms (range, 538–1,359
ohms). Areas containing prostate cancer (n = 74) had a
mean bioimpedance of 932 ± 170 ohms (range, 560–
1,305 ohms).
One explanation as to why bioimpedance increases
in cancer tissue is because of the distorted architecture
of the glands, which prevents flow of current through
the tubes. Histologically, the prostate can be thought
of as being composed of multiple layers of hollow
glands (tubes). Solid or gross tumor is also composed
of a histological array of tubes (Fig. 3). The lumens of
normal prostate are open and have relatively large
diameters, providing little resistance to flow. Con-
versely, as resistance increases, the current flow will
decrease. Accordingly, in cancerous prostate, the nor-
mal architecture of tubes and lumens becomes dis-
torted. The lumens of the tubes become much smaller,
the walls of the glands become crowded, and the flow
of current is impeded. Overall resistance can be
viewed as a combination in series of a number of
shorter segments. The sum total of these smaller com-
ponents makes up the total resistance.
DISCUSSION
Bioimpedance is an electrical property of cells that
has been applied for the first time to distinguish and
identify areas of cancer from areas of normal prostate
tissue. One potential use for this technology is to help
guide the clinician during a prostate biopsy. To put
this in perspective, with 30 million men over the age of
50 in the United States who are potential candidates to
be screened, one would expect 8–15% of these men to
have an abnormally elevated PSA level (>4.1 mg/dl)
[5]. Thus, 2.4 million–4.5 million men would poten-
tially receive a recommendation to undergo biopsy [6].
Of these men who are biopsied, generally 66% will
have a negative biopsy, meaning about 1.6 million
men would have a negative biopsy [5]. Potential
causes of an abnormally elevated PSA level besides
SD Minimum Maximum
(ohms) (ohms) (ohms)
245 727 2,001
265 804 2,048
158 616 1,437
179 661 1,388
151 538 1,359
170 560 1,305
122 583 962
71 611 769
carcinoma include significant benign prostatic hyper-
plasia (BPH), prostatitis, and previous prostate needle
biopsy, cystoscopy, transurethral resection, or trans-
rectal ultrasound [5]. During these biopsies, only ul-
trasound is used to help direct needle placement.
There has not been good correlation between ultra-
sound findings of hypoechoic areas and cancer [9].
With a negative biopsy, there is always the potential
that cancer has been missed; a more sensitive and spe-
cific imaging modality to better direct prostate biopsy
is needed to aid the clinician in localizing cancer.
Any modality which could help direct the clinician
to which area to biopsy would improve sampling rates
and decrease the number of false-positive biopsies. An
advantage to this technique of bioimpedance is that a
variety of configurations are possible. The above dual-
needle approach can be extended to a biopsy needle,
i.e., by mounting the electrodes on the tip of a prostate
biopsy needle. A single probe with two electrodes on
it inline is also possible. Another advantage is that
future generations of the bioimpedance probe would
allow a noninvasive probe to be manufactured. Thus,
information concerning the composition of tissue
could be gained without invading the parenchyma.
Bioelectrical impedance is composed of resistance
and reactance and the trigonometrical ratio between
the two variables known as the phase angle [10]. All
substances produce a certain resistance to the passage
of electrical current. An ohm is the electrical unit of
measurement which measures the resistance of an
electrical current in which an electromotive force of 1
volt maintains a current of 1 ampere. Reactance is a
nonconservative force which opposes the passage of
an alternating electrical current because of capacity or
inductance. Human experiments have shown that re-
actance is a parameter of little significance. Impedance
is one parameter which clearly defines how the hu-
man body behaves when a current passes through it,
and the results can be repeated under the most diverse
physiological and pathological conditions.
In 1996, Blad and Baldetorp described ex vivo mea-
 Bioimpedance for Prostate Cancer Localization
surements of impedance from thigh muscle removed
from a mouse [11]. One problem with this study was
that muscle will conduct electrical impulses, and
therefore artifacts may have been introduced with
these measurements. The authors compared cancer-
ous tissue to normal tissue and found that tumor had
a higher resistance. Similar to our findings, the resis-
tance was 1,600 ohms in cancer tissue compared to
1,100 ohms in normal tissue. The measurements were
repeated at 19 hr and 23 hr, and at each time, extra-
cellular resistance was greater in the cancerous tissue
compared to normal tissue. Trillaud and Jossinet in
1990 noticed a phase shift as a function of frequency
between malignant tumors and normal tissues in
breast for frequencies between 100 kHz–1 MHz, the
same frequencies at which this study was performed.
Their findings correlate with our data as well, with
cancer having a greater impedance compared to nor-
mal tissue.
Bioimpedance has been used in the clinical spec-
trum in order to characterize a pulmonary mass.
Kimura et al. [8] applied a needle probe to 53 pulmo-
nary masses and found that the intraoperative imped-
ance values of malignant tumors were significantly
greater than in organizing pneumonias. A value of 604
ohms measured in organizing pneumonia compared
to 2,623 ohms in metastatic lung tumor was found. In
these measurements, one case of organizing pneumo-
nia was found among the cases assessed as pulmonary
cancer; thus, the sensitivity was 100% while the speci-
ficity was 66%. Certainly, any measurement that was
characterized as cancer would have to be validated
further with needle biopsy.
With the ability to distinguish prostate cancer based
on its electrical properties, bioimpedance may poten-
tially aid the clinician in directing prostate biopsies.
The next generation of a bioimpedance probe is under
construction which will allow noninvasive measure-
ments of prostate impedance values. This probe con-
sists of an inductive coil capable of inducing eddy
currents within the tissue and then measuring the im-
pedance values produced. With noninvasive small
coils, this technology could be mounted on a rectal
probe, or on the finger of a physician performing a
DRE.
Other biologic variables which could affect current
flow include differences in body size, body shape,
electrolytes, fluid distribution, or other elements of
body composition. As well, variations in electrode po-
sition and machine settings, hydration status, and am-
bient air and skin temperature play a role. Recent
physical activity can increase vascular perfusion and
warming of muscle tissue, increasing cutaneous blood
flow and vasodilatation. Even the conductance of the
examination table could interfere with these very sen-
217
sitive measurements. To try to separate the compo-
nents of this complex biologic system, we performed
all measurements using the same probe. All animals
were measured at the same room temperature, on sty-
rofoam padding that insulated the animal from pos-
sible distortion.
In 1994, the National Institutes of Health Office of
Medical Applications of Research convened a technol-
ogy assessment conference to evaluate the validity
and interpretation of data derived by the application
of bioimpedance [12]. The NIH addressed the issue of
how safe this technology was. Scientists found that
bioimpedance was safe because of several factors.
Currents of low frequency are reported to be unlikely
to stimulate electrically excitable tissues, such as
nerves or cardiac muscle. In our testing as well, we did
not see stimulation of any muscle fibers. In application
with thousands of individuals undergoing measure-
ment, no untoward events have been reported to be
induced by bioimpedance measurements. Another
factor is the relatively small current magnitudes in-
volved, which are less than the threshold of percep-
tion. The panel did not identify any reason why bio-
impedance measurements were not safe, although
they advised caution with implanted defibrillators.
CONCLUSIONS
In conclusion, this study serves as an starting point
in the development of this technology. This is the ini-
tial use of the electrical property of bioimpedance to
evaluate prostate cancer. Bioimpedance has the poten-
tial to improve identification of prostate cancer to bet-
ter direct clinicians during prostate biopsy and there-
fore improve the ability to manage patients with this
disease.
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