 |
Description  |
|
|
This invention relates to the localization and diagnosis of lesions in
vivo. "Lesion" as used herein is a pathologic change in tissue, such as
for example a tumor. Lesions that are too small to be found by palpation
are conventionally located using imaging techniques and surgically
removed. For example, breast lesions can be detected by mammogram as much
as four years earlier than by physical examination. However, a mammogram
is unable to distinguish a benign from a malignant lesion, and detection
of a lesion by mammography must be followed by biopsy. Because a mammogram
has a positive predictive value of 20-30%, a large proportion of breast
biopsies following mammography prove to be for nonmalignant lesions. A
reduction in the number of breast biopsies performed for benign disease
would be extremely imposer and beneficial.
In conventional mammogram-assisted screening for breast disease, a
mammogram of the breast is made, and the resulting image is inspected for
lesions. If a small lesion appears, a radiopaque needle is inserted into
the breast in a region as near as can be estimated to the lesion. Then the
region is imaged with the needle in place, the resulting image is
inspected, and the needle is relocated as necessary to place it witch the
lesion. Once the needle appears to be positioned within the lesion, the
surgeon follows the needle to the lesion and removes the lesion and
surrounding tissue, and the pathological status of the lesion can be
determined. Because the imaging procedure provides only an estimate of the
proximity of the biopsy needle to the lesion, it may often be necessary,
in the interest of removing all the lesion, to remove a substantial
quantity of normal surrounding tissue as well.
The positioning of a biopsy needle in soft tissue as a marker for lesions
has been found to be unreliable, because the biopsy needle can move during
the preparation of the patient for surgery. Kopans et al. (1980,
Radiology, Vol. 134, p. 781) describe inserting a hookwire into the lesion
via the lumen of the hollow needle used during the imaging procedure to
localize the lesion. After the hookwire is in place the needle is
withdrawn, leaving the hookwire in a position estimated to be closest to
the lesion. This needle-hookwire approach has been used successfully to
provide a more secure marker for breast biopsies (Meyer et al., 1982,
Arch. Surg., Vol. 117, pp. 65-68). However, once the hookwire is implanted
in the tissue, it cannot be removed without tissue damage except by
surgery.
Since the development of needle-hookwire assembly by Kopans et al., other
breast biopsy needles have been developed. For example, biopsy needles
have been designed with retractable barbs to anchor the biopsy needle in
tissue, and to facilitate the removal of the needle in case of incorrect
positioning, or in case it is desirable to remove the localization needle
during surgery without requiring surgical removal of excess tissue (U.S.
Pat. Nos. 4,986,279; 4,799,495). In each of these biopsy needle
localization systems, the proximity of the biopsy needle to a lesion is
estimated by imaging techniques.
The effectiveness of therapies currently used for the treatment of lesions,
as for example solid tumors, is limited by the capacity of the therapeutic
to reach the target in vivo in adequate quantities. In animal studies,
solid tumors have been shown to contain a greater volume of interstitial
fluid--that is, of fluid in the extracellular and extravascular space,
than normal tissues contain, suggesting that tumors should be readily
infiltratable by therapeutic macromolecules. However, additional animal
studies have demonstrated that the interstitial fluid pressure ("IFP") is
higher in tumors than in normal tissues, resulting in poor perfusion of
tumors by therapeutic molecules and a radially outward convection of
interstitial fluid from tumors (reviewed in Jain, 1987, Cancer Res., Vol.
47, pp. 3039-3051).
An examination of the microvascular network of rat mammary adenocarcinoma
tumors was conducted to aid in understanding the distribution of blood
flow and its influence on the exchange and uptake of relevant molecules in
chemotherapy, immunotherapy, or radiation treatment (Less et al., 1991,
Cancer Res., Vol. 51, 265-273). The results of this study indicated that
the bifurcation geometry and network structure in tumor vasculature may be
one mechanism responsible for the increased resistance to blood flow
reported in tumors (Sevick et al., 1989, Cancer Res., Vol. 49, pp.
3506-3512).
The elevated IFP of tumors was first described by Young et al. (1950, Jour.
Pathol. Bacteriol., Vol. 62, pp. 313-333) after taking "tissue pressure"
measurements in rabbits. Each of three methods for measuring local
interstitial pressure, known as the needle method, wick-in-needle method,
and micropiper method, has advantages and limitations. In the needle
method, a needle filled with physiological saline and coupled to a
pressure measuring device is inserted into tissue. In the wick-in-needle
method, fibers of polyester or other multifilamentous material are placed
within the lumen of the needle in order to provide a large surface area
continuum with the interstitium and reduce occlusion. Both of these
methods can cause tissue distortion. In the micropipet method a micropiper
connected to a servo-null pressure-measuring system is used, reducing some
problems presented in the needle and wick-in-needle methods, but the
micropipers are susceptible to breakage.
The IFP of subcutaneous tumors was measured in rats using micropipets
(Boucher et al., 1990, Cancer Res., Vol. 50, 4478-4484). This study
describes a steep IFP gradient that begins at the surface of the tumor, or
the skin/tumor interface, and quickly reaches a plateau value in the tumor
mass within 0.2-1.1 mm of the tumor surface. These results confirmed an
earlier mathematical model of interstitial fluid transport in tumors (Jain
et al., 1988, Cancer Res., Vol 48, pp. 7022-7032) which proposed that very
little filtration of macromolecules into tumors occurs even from blood
vessels which pass through the tumor, and that the convective outward flow
of the interstitial fluid pushes solutes toward the periphery. These
conclusions are also supported by work from Dvorak et al. (1988, Am. Jour.
Pathol., Vol. 133, pp. 95-105) who demonstrated that small molecules can
readily penetrate tumors, and large macromolecules are limited to the
tissue-tumor interface. The inability of therapeutic drugs to reach the
center of tumors has grave implications for cancer therapies, and based
upon these results Boucher et al. (1990) proposes methods by which drug
delivery to tumors could be enhanced.
The wick-in-needle technique was developed by Fadnes et al. (1977,
Microvasc. Res., Vol 14, pp. 27-36). Fadnes et al. describes a thin
hypodermic needle open at the end and having a side-hole, its lumen filled
with multifilamentous nylon thread and connected by polyethylene tubing to
a pressure transducer. Fadnes et al. describes using this pressure-sensing
needle to compare the subcutaneous IFP in anesthetized rats under normal
and dehydrated conditions.
The interstitial fluid pressure of human melanomas and uterine cervix
carcinomas was measured using the wick-in-needle technique in studies that
demonstrated for the first time in humans that IFP is higher in tumors
than in normal tissue. Boucher et al. (1991), Cancer Res., Vol. 51, pp.
6691-6694, demonstrated that the IFPs of large human melanomas far exceed
the values expected from measurements of rodent tumors or human
xenografts. Roh et al. (1991), Cancer Res., Vol. 51, pp. 6695-6698,
demonstrated that a lowering of the IFP in some cervical tumors during
fractionated radiation therapy correlates well with therapeutic outcome.
Both Boucher et al. and Roh et al. conclude that the IFP of tumors will be
valuable for designing future cancer therapies and predicting treatment
outcome.
K. P. Wang, U.S. Pat. No. 4,799,494, describes a needle assembly for
collection of lung tissue. The needle assembly includes a blunt hollow
outer needle having a side-hole for tissue collection, and a non-removable
inner hollow needle attached to a solid wire, slidably engaged within and
snugly fitting the lumen of the outer needle, used for piercing the
tissue. The lumen of the outer needle is connected to a crude balloon
pressure sensor. The '494 patent states that the localization of the
needle tip in the lung lesion to be sampled results in a pressure decrease
detectable at the balloon.
SUMMARY OF THE INVENTION
We have discovered that a lesion can be accurately located within a tissue
mass by measuring, at several points in a path through the tissue mass, a
selected parameter that is known to measure differently in lesions (or at
least in some types of lesions) and in normal tissues; and we have
developed apparatus for carrying out such measurements, particularly of
interstitial fluid pressure.
Using the method, the location and, at least to some extent the size and
the boundary of a lesion can be determined accurately and without a
requirement for repeated reimaging of the tissue mass. Moreover, some
selected parameters can, depending upon the extent of deviation of their
measure from normal, provide information regarding the pathological
condition of the lesion; for example, some parameters deviate more from
normal in malignant tumors than in benign lesions.
In one aspect, the invention features a method for locating a lesion within
a tissue mass, including measuring a parameter at a plurality of points in
at least one path through the tissue mass, the measure of the parameter in
lesions being different from the measure in normal tissue.
In preferred embodiments, the parameter is interstitial fluid pressure, and
more than one parameter may be measured at one or more of the points; the
method may further include a step of inserting a tissue marker, such as a
hookwire, into the lesion along a portion of the path, to mark the lesion
for subsequent removal.
Typically, the method of the invention may be used to mark the location of,
and if desired to gain additional information as to the condition of, a
lesion located by imaging or by palpation.
In another general aspect, the invention features apparatus for measuring a
tissue parameter at a number of points along at least one path through the
tissue mass, including an insertion tube, sharpened at a distal end and
made sufficiently rigid so that it can be inserted distal end foremost
into the tissue mass along the path, and, insertable with the insertion
tube, a sensor capable of providing a measure of the tissue parameter at a
point in the tissue mass along the path.
According to the invention, apparatus for locating a lesion in a tissue
mass includes such apparatus for measuring a selected tissue parameter at
a number of points along one or more paths through the tissue mass; at any
point in the tissue mass a measure by the sensor of the selected parameter
that is distinguishably different from that in normal tissue indicates
that the point is within a lesion.
In preferred embodiments the tissue parameter is interstitial fluid
pressure and the sensor includes a pressure sensor. The wall of the
insertion tube includes a port near its distal end, and the sensor
includes a sensor tube, containing filaments, slidably engageable within
the lumen of the insertion tube; the sensor tube is distally closed and
has a port near its distal end, and the ports are positioned so that when
the sensor tube is engaged within the insertion tube lumen the ports can
be substantially aligned to provide fluid communication between the lumen
of the sensor tube and the tissue adjacent the ports; and the sensor tube
lumen is operationally connected to a pressure measurement device such
that it is responsive to fluid pressure within the sensor tube lumen.
The apparatus of the invention makes use of a thin-walled fine-gauge
distally sharpened needle for the insertion tube, so that by use of the
apparatus the method of the invention can be carried out without
anesthesia. The pressure-sensing apparatus according to the invention can
be used to accurately determine the interstitial pressure within a lesion
in approximately 10 minutes' time. The invention provides for reliable
measurements of interstitial fluid pressure in any variety of types of
lesions in any of a variety of tissues with a minimum of discomfort to the
patient.
The invention can provide for estimating the location, size and biological
potential of a lesion by measuring the interstitial fluid pressure, by
passing the insertion tube, with the associated sensing device, into
tissue that has been shown by palpation or imaging techniques to contain a
lesion (such as a tumor), in a path that is estimated to pass through the
lesion, and measuring the pressure at multiple points along the path.
"Biological potential" as used herein encompasses all pathological types
of lesions, including benign lesions.
The higher IFP of a lesion allows the operator, making several measurements
along the path, to determine when the insertion needle has both entered
and exited the lesion. The IFP of a lesion can additionally be indicative
of its biological potential. In malignant lesions the IFP is elevated
above the IFP of normal tissue and the IFP increases with lesion size. In
benign lesions, on the other hand, the IFP may be comparable to that of
normal tissue.
Insertion of the sensor through the lesion along more than one path allows
the IFP and the entry and exit points to be determined along more than one
transect of the lesion. The size and extent of the lesion and its
biological potential can then be estimated. Preferably, the IFP of the
lesion is measured in two different locations, and the IFP is recorded
first of normal tissue then repeatedly at close intervals or continuously
as the needle is advanced into the lesion and exits the lesion into normal
tissue again. The pressure reading for the excursion of the insertion
needle along each path takes approximately 10 minutes, and the entire
procedure takes approximately 20 minutes to complete.
For example, where palpation or mammography has shown that a lesion is
present in the breast, the interstitial fluid pressure of the lesion can
be determined as described above, and if the interstitial fluid pressure
indicates a benign lesion then the patient will not need to undergo
surgery. If, on the other hand, the pressure measurement indicates a
malignant lesion, a hookwire can be very accurately placed within the
lesion as a marker for the subsequent surgical removal.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Drawings
FIG. 1A is a longitudinal section of part of a pressure-sensing needle
assembly, according to the invention, showing the positions of the
components.
FIG. 1B is a cross-sectional view thru 1--1' of the pressure-sensing needle
assembly of FIG. 1A.
FIG. 1C is a cross-sectional view thru 2--2' of the pressure-sensing needle
assembly of FIG. 1A.
FIG. 1D is a longitudinal section of a needle assembly, according to the
invention, showing a hookwire within the lumen of the insertion needle.
GENERAL DESCRIPTION
In the method according to the invention, the location of a lesion within a
tissue mass is accurately determined by measuring a parameter, known to
measure higher or lower within such lesions than in normal tissues, at a
plurality of points in one or more paths through the tissue mass. Any one
or more of a variety of parameters can be measured according to the
invention; in particular, elevated interstitial fluid pressure within a
lesion can be a reliable indicator not only of the location and size of
the lesion, but also of its biological potential; for example, malignant
tumors can have interstitial fluid pressures elevated to a greater degree
than benign tumors. Moreover, apparatus for introducing the sensor into
the tissue mass can be provided with two or more sensors, capable of
detecting more than one parameter. Some such parameters can be selected to
aid in locating the lesion or in diagnosing its pathological condition,
and others can provide information that may be useful to medical personnel
who subsequently treat the lesion.
An accurate sensor for carrying out the method of the invention can
conveniently be associated with a fine-gauge, thin-walled tube, made
sufficiently rigid and sharpened so that it can be passed into the tissue
mass without causing intolerable discomfort to the subject; a sharpened
hollow needle such as a fine-gauge biopsy needle may be suitable, for
example. Where initial imaging methods indicate the presence of a lesion
within a tissue mass, the hollow sharpened needle with the associated
sensor is inserted into the tissue mass along a direction estimated to
pass into the lesion, and measurements are made at close intervals. If the
measurements do not indicate that the sensor has passed into a lesion, the
needle and sensor can be withdrawn and reinserted along a different path.
These steps can be repeated until the lesion has been located and
sufficient information has been obtained to provide an indication for
biopsy; repeated reimaging is unnecessary. Once the sensor indicates that
the needle has passed into a lesion, it can be passed further into the
tissue mass and further measurements can be made along the path, until the
measurements indicate that the sensor has passed through and out from the
lesion into normal tissue. A record of the positions along the path where
the measurements were made can provide an estimate of the dimension of the
lesion along the line of the path. Then the needle can be partly
withdrawn, so that its open tip is again within the lesion. Then a marker,
such as for example a hookwire, can be introduced via the needle to a
point within the lesion near the needle tip, and the needle can be
withdrawn, leaving the marker in place.
By way of example, an embodiment of apparatus for lesion localization and
diagnosis according to the invention is described below, including a
pressure sensor insertable into a thin-walled hollow insertion needle. The
pressure sensor itself includes a hollow tube containing filaments,
dimensioned and configured so that it slides within the lumen of the
hollow insertion needle in sealed relation to the needle wall. The
filament-containing sensor tube is closed at its distal end; and the walls
of the sensor tube and of the insertion needle are each provided with a
port near the distal end, and the ports are alignable to provide
communication between the interstitial fluid surrounding the insertion
needle and fluid within the lumen of the sensor tube. A pressure measuring
device is operatively connected to the sensor tube so that it is
responsive to the hydrostatic pressure within the sensor tube lumen,
providing a measure of the interstitial fluid pressure in the tissue mass
near the insertion needle adjacent the ports.
APPARATUS
The distal portion of an embodiment of apparatus for lesion localization
and diagnosis according to the invention, including a pressure sensor
insertable into a thin-walled hollow insertion needle, is shown by way of
example in a diagram in FIG. 1A and in sectional views in FIGS. 1B and 1C.
With reference now to FIG. 1A, the pressure-sensing apparatus, a distal
portion of which is shown, includes a fine-gauge, thin-walled hollow
insertion needle 1 and, shown in operative relation within insertion
needle 1, a removable hollow inner sensor tube 2. Within the lumen 7
throughout the length of sensor tube 2 are filaments 6. Sensor tube 2 is
operatively connected to a pressure measurement device (not shown in the
Figs.) in such a manner that the pressure measurement device is responsive
to hydrostatic fluid pressure within the lumen 7 of sensor tube 2. The
distal tip 5 of sensor tube 2 is plugged, while the insertion needle 1 is
left open. A port 3 in the wall of the insertion needle 1 and a port 8 in
the wall of sensor tube 2 are substantially aligned when the insertion
needle and sensor tube are in operational relation, as shown in the Figs.
In one embodiment, the insertion needle 1 is a 20 gauge stainless steel
needle, and port 3 is a 2-3 mm hole, located 2 cm from the open sharp
distal insertion needle tip 4. Sensor tube 2 is a stainless steel hollow
needle, 23 gauge so that it fits snugly within insertion needle 1, and
port 8 is a 2-3 mm hole, located about 2 cm from the distal sensor tube
tip 5, which is sealed with solder. The sensor tube 2 contains within its
lumen 7 and throughout its length 4-5 monofilamentous surgical suture
fibers 6, preferably 6-0 ethilon or other monofilamentous nylon of the
same size, which occupy the length of the inner needle 2.
Insertion needle 1 and sensor tube 2 are each provided at the proximal end
(not shown in the Figs.) with a plastic hub for ease in manipulation by
the user, as is well-known in the needle biopsy art. Alignment marks on
the plastic hubs (not shown) are provided to aid the user infolding the
ports 3, 8 in alignment during use, as shown in FIGS. 1A, 1C. When the
ports 3, 8 are aligned substantially as shown in the Figs., they provide
for direct communication between fluid in the sensor tube lumen 7 and the
interstitial fluid in tissues outside the insertion needle 1 near the
ports.
Sensor tube 2 is operatively connected to a pressure measurement device
(not shown in the Figs.), such as the model P23XL pressure transducer
available from Spectramed Inc., Oxnard, Calif., by way of noncompliant
sterilized plastic tubing filled with sterile heparinized saline,
preferably 70 Units/ml, connected between the pressure transducer and the
proximal end of the sensor tube. The pressure transducer is connected to
signal processing means, such as, for example a preamplifier, and a
recorder or other data storage device. In one embodiment the signal from
the transducer is sent through a preamplifier, such as the model
11-4113-01 available from Gould Inc., Cleveland, Ohio, and the amplified
signal is sent to a dual-channel chart recorder, such as the model
30-V7202-11 available from Gould Inc.; or the amplified signal is
digitized and stored.
The lengths of the sensor tube 2 and insertion needle 1 are selected to be
sufficiently long to reach to the expected path length within the tissue
mass to the deepest measurement point. The lesion is located and the tip
of the insertion needle is relocated within the lesion as described above,
General Description, and the sensor tube is withdrawn from the insertion
needle. Then, as shown in FIG. 1D, a flexible hookwire 15 such as, for
example, a 0.03 cm diameter hookwire having 22,600 kg/cm.sup.2 tensile
strength, 11.4 kg breakload or, for example, a 0.02 cm diameter hookwire
having 20,000 kg/cm.sup.2 tensile strength, 6.5 kg breakload, is inserted
into the tissue by way of the lumen 9 of the properly emplaced insertion
needle. Then insertion needle 1 is withdrawn from the site, leaving the
hookwire 15 implanted in the lesion as an accurate marker of the position
of the lesion. The portion of the hookwire that emerges from the wound
(not shown) is taped to the subject's skin until surgery. If desired, the
outer needle 1 can be reintroduced over the hookwire during surgery to
provide a firm guide for the surgeon's knife.
The embodiment described above with respect to the Figs. is particularly
adapted for use in localizing breast lesions. As will be appreciated the
dimensions of the insertion tube can differ from those described, and for
some given applications, e.g. investigations of lesions in other tissue
masses or in children, the diameter may preferably be larger or smaller.
Needles as large as 16 or 18 gauge may be used depending upon the tissue
to be pierced, and smaller gauge needles may be used so long as they are
sufficiently rigid to permit insertion into the tissue mass. The diameter
of the sensor tube will be chosen accordingly to provide a snug fit within
the insertion tube. The material of the insertion tube need not be
stainless steel yet must be chosen to provide sufficient rigidity for
insertion into the tissue containing a lesion. The material of the sensor
tube need not be stainless steel. The sensor tube also does not need to be
as rigid as the insertion tube, as it is carried within and supported by
the insertion tube. The filaments contained within the sensor tube can be
any type of nonabsorbent monofilament, and the size of each filament and
the number of filaments placed within the sensor tube can be easily
determined without undue experimentation. The filaments function to aid
the fluid communication between the sensor and the tissue without
occluding the lumen of the sensor, and for example the placement of 6 or 7
filaments, of the type described above, within the lumen of a 23 gauge
sensor may too completely fill the lumen of the sensor and cause too much
resistance. The port of the insertion tube and the sensor tube can be
located at varying distances from the distal end, as is convenient.
Positioning the ports as little as 4-5 mm from the distal end of the
insertion needle can yield less satisfactory results; and, if the ports
are located much further than 2 cm behind the tip then the tip may be
situated inconveniently far beyond the lesion when the port is located
within it. The distal end of the sensor tube is preferably closed in order
to restrict the measurement of the parameter to a single region of the
lesion or tissue, and to prevent incursion of tissue into the end as the
insertion tube is passed into the tissue mass.
USE
The pressure measuring apparatus according to the invention can be used for
measuring the interstitial fluid pressure in tissues, and for locating
lesions in the tissues, at any of various sites within the subject's body.
Preferably the apparatus is calibrated just prior to use. Such calibration
can conveniently be performed using a water column, and a zero reference
point is preferably obtained by placing the sensor tube tip and insertion
needle tip at skin level. The user then introduces the insertion needle,
containing the sensor tube in proper alignment as indicated by the
alignment marks on the hubs, into the tissue mass at a point where the
ports can be expected to be situated in normal tissue. Then proper
communication between the saline in the lumen of the sensor tube and the
interstitial fluid in the tissues can be checked as follows. First the
plastic tubing connecting the pressure transducer with the sensor tube is
compressed with a screw clamp. This displaces a small amount of fluid
within the tubing and the lumen of the sensor tube, which should cause a
transient rise in the pressure measured by the transducer; the fluid | | |
