Abstract:
An apparatus for image elastic scattering spectroscopy is disclosed that is comprised of a light source for generating polarized light. Means are provided to convey the polarized light to a target. A collector receives light reflected from the target. A detector is responsive to the collector for generating images at both parallel and perpendicular polarizations for each of a plurality of wavelengths. A range finder detects a distance to the target. Control electronics control the image generation and the range finder. The apparatus may be configured to image areas on the surface of the body or configured so as to be inserted into various body cavities. Typically, the apparatus will be used in conjunction with an analyzer for analyzing the images for evidence of abnormal cells. Methods of gathering data and of screening for abnormal cells are also disclosed.

Description:
BACKGROUND OF THE INVENTION 
   1. Field of the Invention 
   The present invention is broadly concerned with providing a non-invasive technique for the early detection of cancer and other abnormal tissue and, more particularly, to the field of imaging elastic scattering spectroscopy (IESS). 
   2. Description of the Background 
   Detecting abnormal tissue early is critical to the successful treatment of disease. Life expectancy of patients with malignancy or cancer, for example, can increase dramatically when abnormal tissue is identified while still in a pre-malignant state. Such tissue regions, dysplasia and carcinoma in situ being typical examples, are ordinarily detected by surgical biopsy. The removed tissue is sent to a pathologist, where it is examined under a microscope for the characteristic morphological changes that indicate abnormal cell growth. Upon receiving the pathology report, the physician can then decide whether further removal of the tissue is indicated. 
   This method of treatment has a number of serious drawbacks. For example, only a limited number of regions can be biopsied, with the choice of region determined only by its gross appearance in the eyes of the physician. It is therefore quite likely that a problem area, particularly one in an early stage of abnormality, may be missed completely. Another serious drawback of this method of treatment is that since the identification of abnormality must await the pathology report, surgical removal of the abnormal tissue often must be performed during a separate procedure (and sometimes even by successive iterations), thereby increasing risk to the patient, and inconvenience and cost for both the patient and the physician. 
   Within the last decade or so, a number of all-optical techniques for identifying abnormal tissue have been developed in an attempt to avoid these problems. These approaches have the potential for allowing problem sites to be detected over a large area sensitively and quickly, without having to rely on the subjective judgment of the physician. In addition, because suspicious areas can be identified during the initial examination, diseased tissue can be removed immediately, and completeness of the excision assessed by prompt reimaging of the area in question. 
   The most developed of these optical techniques makes use of differences in the spectra of fluorescence exhibited by normal and abnormal tissue. This fluorescence is ordinarily excited by laser illumination, and can be either intrinsic or extrinsic. Although numerous groups are working on the development of fluorescence-based systems for cancer diagnosis, to date only one device has reached the commercial market. The LIFE scope, manufactured by Xillix Inc. and marketed by Olympus, Inc., uses ultraviolet laser light to excite tissue autofluorescence through a bronchoscope. It is presently being used by approximately 50 groups worldwide with a cost of upwards of $200,000 per unit. Although this device provides much greater sensitivity than standard white-light bronchoscopy, single procedures can be very time consuming. Even experienced surgeons often require 45 minutes to perform one examination which would take only 3 minutes using standard bronchoscopy equipment. The use of the LIFE scope is not only quite draining for the patient and physician, but also limits greatly the number of patients that can be seen, thereby substantially increasing procedure cost. 
   Other groups have used Raman signals to identify abnormal tissue, however these signals are extremely weak, and it may be difficult to implement as a practical clinical tool. 
   A third approach, elastic scattering spectroscopy (ESS), illuminates the sample, and looks at the spectral content of the light scattered from tissue right beneath the surface by using a point probe in contact with the tissue surface. This method has the capability of detecting disorganized epithelial orientation and architecture, morphological changes in epithelial surface texture and thickness, cell crowding, enlargement and hyperchromicity of cell nuclei, increased concentration of metabolic organelles, and the presence of abnormal protein packages. ESS has been used to study the skin, the eyes, the bladder, the prostate and many different regions of the gastrointestinal tract. In one study, ESS was used to differentiate neoplastic from non-neoplastic tissue and adenomatous polyps from hyperplasic polyps in the colon with a predictive accuracy of ˜85%. In another study ESS was used to detect bladder cancer with a sensitivity of 100% and a specificity of 97%. Preliminary tests of this technique in the lower GI tract demonstrated the ability of differentiating between dysplasia, adenoma/adenocarcinoma, and normal mucosa with a sensitivity of 100% and a specificity of 98%. Studies in the skin have demonstrated a sensitivity of 90.3% and a specificity of 77.4% for distinguishing primary melanomas from benign nevi. Over a decade of clinical trials with this instrument in a variety of organ systems has shown that these spectra can provide a sensitivity means of detecting even early abnormal tissue. At present, however, this method is capable of providing single point measurements only, thereby making it inappropriate for routine clinical use. 
   Therefore, there is a need in the art for a system for detecting ESS signals in a full imaging mode which can be equally applicable to imaging endoscopically and imaging externally for routine clinical use. 
   SUMMARY OF THE PRESENT INVENTION 
   One aspect of the present invention is a method of generating data which comprises illuminating a target with polarized light and serially imaging the target at both parallel and perpendicular polarizations for each of a plurality of different wavelengths. The serially imaging may include: illuminating the target with a wavelength-tunable light source; illuminating the target with a broadband light source in series with a wavelength-tunable filter; illuminating the target with a broadband light source and detecting reflected light with a wavelength-tunable detector, including, for example, a detector whose wavelength acceptance can be chosen by interposing chromatic filters in the light path; or illuminating the target with a broadband light source and detecting reflected light with a wavelength-tunable filter in series with a detector. 
   Another aspect of the present invention is a method of generating data which comprises illuminating a target with polarized light, serially imaging the target at both parallel and perpendicular polarizations for each of a plurality of different wavelengths and determining range information indicative of a distance to the target. Again, the serially imaging may include: illuminating the target with a wavelength-tunable light source; illuminating the target with a broadband light source in series with a wavelength-tunable filter; illuminating the target with a broadband light source and detecting reflected light with a wavelength-tunable detector, including, for example, a detector whose wavelength acceptance can be chosen by interposing chromatic filters in the light path or illuminating the target with a broadband light source and detecting reflected light with a wavelength-tunable filter in series with a detector. Additionally, determining range information may be accomplished optically, sonically and/or mechanically. Further, determining range information may be accomplished by illuminating a spot of the target with a collimated beam of known diameter and degree of collimation, recording the size of the illuminated spot reflected from the target, and calculating the distance to the target using the size of the illuminated spot and the known diameter and degree of collimation of the beam. 
   Another aspect of the present invention is screening for abnormal cells and is comprised of illuminating a target with polarized light, serially producing a series of images of the target at both parallel and perpendicular polarizations for each of a plurality of different wavelengths, determining a distance to the target, and analyzing the series of images based on the distance to identify abnormal cells. The analysis may include an analysis based on Mie theory mathematics. 
   The present invention is also directed to an apparatus comprising a light source for generating polarized light. Means are provided to convey the polarized light to a target. A collector receives light reflected from the target. A detector is responsive to the collector for generating images at both parallel and perpendicular polarizations for each of a plurality of wavelengths. A range finder detects a distance to the target. The apparatus is under the control of control electronics and may be configured to image areas on the surface of the body, or configured so as to be inserted into various body cavities. Typically, the apparatus would be used in conjunction with an analyzer for analyzing the images for evidence of abnormal cells. 
   To enable the generation of images at a plurality of wavelengths, either the source of light or the detector is wavelength tunable. The polarizers may include any of a variety of known polarizing devices including, but not limited to a polarizing sheet, a polarizing beamsplitter, or a polarizing-preserving fiber. The range finder may be an optical, acoustical and/or mechanical device. 
   The present invention provides a non-invasive technique for the early detection of cancer and other abnormal tissue. The present invention allows for detecting ESS signals in a full imaging mode which can be equally applicable to imaging endoscopically and imaging externally for routine clinical use. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
     To enable the present invention to be easily understood and readily practiced, the present invention will now be described for purposes of illustration and not limitation, in connection with the following figures wherein: 
       FIG. 1  illustrates an apparatus constructed according to the present invention used in a process for screening for abnormal cells; 
       FIG. 2  is a block diagram of one embodiment of the apparatus shown in  FIG. 1 ; 
       FIG. 3  is a diagram illustrating the steps of a method of screening according to the present invention; 
       FIG. 4  is a diagram of another embodiment of the present invention useful for screening for abnormal cells in a body cavity; 
       FIG. 5A  is a detailed diagram illustrating a port element which may be a component of the present invention; 
       FIGS. 5B and 5C  are detailed diagrams illustrating a range finding mechanism useful for determining the distance between the tissue and probe which may be a component of the present invention; and 
       FIGS. 6A and 6B  are detailed diagrams illustrating alternative embodiments for the collection components of the present invention. 
   

   DETAILED DESCRIPTION OF THE INVENTION 
   One embodiment of an apparatus  10  constructed according to the teachings of the present invention and useful for screening for abnormal cells is illustrated in  FIG. 1 . In  FIG. 1 , a patient  12  is positioned on an examining table  14 . A target  16  is examined by apparatus  10  as will be described in detail below. Those of ordinary skill in the art will recognize that target  16  is meant to be exemplary and not limiting. 
   Most internal and external surfaces of the body are covered with a layer of cells known as the epithelium. One of the more common types of epithelial tissue is known as the “columnar epithelium”, in which a single layer of epithelial cells lies on top of the thicker sub-mucosal layer. In such a case, the epithelial nuclei can be considered as scattering spheres embedded in a surrounding uniform medium of different optical composition. 
   The way that light scatters in such a situation depends upon a number of factors: scattering angle, sphere size, wavelength and polarization of the light being scattered, as well as the optical properties of the spheres and surrounding medium. The mathematics used to describe this scattering is known as the Mie theory. Hence, if the wavelengths and polarization of the illumination light, the detection angle, and the optical properties of the tissue are know, the Mie theory can be used to calculate the size of the nuclear spheres responsible for the observed scatter. If a camera is used to produce images of the light reflected from the target  16 , then an analysis of the images will result in a map of nuclear size at each point in the tissue imaged. This is the basis of imaging elastic scattering spectroscopy (IESS). 
   The apparatus  10  shown if  FIG. 1  is illustrated in greater detail in  FIG. 2 . In  FIG. 2 , a light source  20  is used to generate polarized light. The light source  20  may be comprised of a filament  22  or other source of light. Filament  22  may be a tunable light source or a broadband light source. Should filament  22  be a tunable light source, it is preferably capable of rapidly switching between wavelengths. Should filament  22  be a broadband light source, a tunable filter  24  may optionally be used in series with filament  22  to provide light at discrete wavelengths. Tunable filter  24  should be a device that is capable of rapidly switching between wavelengths, such as an acousto-optic tunable filter (AOTF) or monochromator. The light  29  from light source  20  exists device  10  through an illumination port  30  for illuminating the target  16 . The light source  20  is directly in line with illumination port  30 , or fiber optics may be used to convey light to the illumination port  30 . Additionally, a polarizer  26  may be included in light source  20  within the light path to polarize the light. Polarizer  26  could be any device that polarizes light, for example, a polarizing sheet, a polarizing beamsplitter, a polarizing-preserving fiber, among others. Those of ordinary skill in the art will recognize that polarizer  26  may be any polarizing element known in the art. The light source is under the control of control electronics  28 . 
   Target  16  may be any tissue, including external tissue, such as the skin, or internal tissue such as those accessible endoscopically or otherwise, as will be described below. The light  29  is polarized at this point and may be serially tuned through a plurality of wavelengths by the filter  24 . Alternatively, and as will become apparent, the light could remain broadband, with the tuning occurring on the detection side of apparatus  10 . 
   Light  32  reflected from target  16  is received by an imaging port  34 . A collector, or series of collection components,  36  is responsive to the light  32  collected at the imaging port  34 . Collection components  36  may include polarization filters  38  and imaging optics  40 . An imaging detector  42  is responsive to the collector  36  for generating images at both parallel and perpendicular polarizations for each of a plurality of wavelengths. If filament  22  is a broadband light source, and light source  20  does not include tunable filter  24 , collection components  36  may contain a tunable filter  24  to provide for spectral discrimination. Tunable filter  24  should be a device that is capable of rapidly switching between wavelengths, such as an acousto-optic tunable filter (AOTF) or monocromator. The imaging detector  42  is under the control of control electronics  28  and, when collector  36  contains a tunable filter, the collector  36  will also be under the control of control electronics  28 . 
   Apparatus  10  includes a range finder  44  for detecting the distance between a range finding port  45  and target  16 . Ranger finder  44  may be implemented using any known form of optical, acoustical (sonic) or mechanical range finding device. Range finder  44  is under the control of control electronics  28  and will produce range information for each target  16 . 
   An analyzer  46 , which may be integral with apparatus  10  or remote from apparatus  10 , is responsive to the images and the range information. Based on the range information, the images are analyzed to identify abnormal cells using the aforementioned Mie theory. 
   A method of operating the apparatus  10  of the present invention is illustrated in  FIG. 3 . In  FIG. 3 , at step  50 , polarized light  29  is used to illuminate target  16 . At step  52 , light reflected from the target is collected. At step  54  the collected light is used to serially create images at both parallel and perpendicular polarizations at a plurality of wavelengths. The resulting set of images provides elastic scattering spectra at each imaged point. 
   Step  50  may include illuminating the target with a tunable light source or a broadband light source in series with a tunable filter. Alternatively, step  50  may include illuminating the target with a broadband light source and step  54  may include detecting reflected light with a tunable detector or with a tunable filter in series with a detector. 
   At step  56  range information indicative of the distance to the target, e.g. the distance between the target and the range finding port  45 , is generated. The range information may be generated optically, sonically, or mechanically. Although  FIG. 3  illustrates the range finding step after steps  50 ,  52  and  54 , the range finding operation can be performed either before or in parallel with steps  50 ,  52  and/or  54 . 
   Steps  50 ,  52  and  54  may be referred to as a method of generating data as those steps result in the production of the images needed to screen for abnormal cells. The method of generating data may also include the range finding operation represented by step  56 . 
   At step  58  the generated images are analyzed based on the distance information. This analysis may include an analysis based on the Mie theory. The analysis may determine the nuclear size distribution point-by-point throughout the imaged region. Because size information is a parameter often used by a pathologist when diagnosing biopsied tissue, the analysis results may optionally be pictorially displayed before the physician (with, for example, different sizes depicted in false color), thereby providing a near real-time assessment of the nature of the tissue being examined. Those of ordinary skill in the art will recognize that the screening for abnormal cells can be done offline. That is, steps  50 ,  52 ,  54  and  56  may be performed and the data transmitted to a remote location for analysis or stored for later analysis. 
     FIG. 4  illustrates another embodiment of the present invention in which the apparatus  10 ′ is configured for screening for abnormal cells in a body cavity. A portion of the apparatus  10 ′ may be designed as an imaging probe to be inserted into and removed from an instrument channel of a conventional endoscope  64 , or incorporated as a permanent additional port in a modified endoscope. 
   As shown  FIG. 4 , light source  20  may be a spectral light source. Light source  20  may be a monochromator (Polychrome IV, Till Photonics, Eugene, Oreg.) or AOTF-based source (ChromoDynamics, Inc., Lakewood, N.J.), fed through a first optical fiber  66  which leads to the distal end of an endoscope probe. First optical fiber  66  provides a means for conveying the polarized light. In an endoscopic embodiment, fiber optics are the most practical way of conveying the light from the light source. In other embodiments, mirrors, beam splitters, prisms, reflective devices, fiber optics, direct paths and the like may be used as means for conveying. Polarization of the illumination light may be provided by sheet polarizers (not shown) at the two illumination ports  30  (see  FIG. 5A ) instead of using polarizer  26  as shown in  FIG. 2 , or by other means. The single imaging port  34  (see  FIG. 5A ) has a second optical path (which may be provided by a pair of optical fibers or a lens system as shown in  FIGS. 6A and 6B ) responsive thereto to direct the collected light to the collector  36  discussed in detail with  FIGS. 6A and 6B . The optical fiber  66  has an outer diameter and length compatible with insertion down the instrument channel of conventional endoscopes (for many scopes, this necessitates an outer diameter less than 2.0 mm). 
     FIG. 5A  illustrates range finding port  45 .  FIGS. 5B and 5C  illustrate a simple, inexpensive range finding mechanism useful for determining the distance between the tissue and probe. Range finding may be implemented using a low-power, infrared laser diode fed fiber-optically into an optical range-finding port at the distal end of the endoscope. The output optic on this port will collimate this beam as much as possible to insure that the exiting beam has a very low divergence angle. For a given starting beam diameter and degree of collimation, the size of the spot illuminated on the tissue as a proportion of the entire illuminated field-of-view will vary depending upon the tissue-probe separation, as shown schematically in  FIGS. 5B and 5C . At larger separations (as shown in  FIG. 5B ) the near-collimated range finding laser spot takes up a smaller area of illuminated field of view than at smaller separations (as shown in  FIG. 5C ). The laser can then be pulsed on once, or several times, per image set, the size of the reflected spot in the tissue measure, and from this, the tissue-probe distance calculated. Although this technique will provide a reasonable determination of distance only in the center of the images field, this should be sufficient for the purposes of the IESS analysis, particularly in regions of fairly regular topology (such as, for example, the esophagus) where tissue-probe distances throughout the imaged area can be readily extrapolated from the value measured at the center of the field. In addition, topology of the illuminated region may also be adduced by looking at the size and shape of the illuminated region. 
   A camera  68  is affixed to the proximal end of the endoscope  64 . The images may be captured with a high-speed black-and-white charged coupled device (CCD) camera (SensiCam VGA, Cooke Corporation, Auburn Hills, Mich.) and sent to a PC computer  70  that performs the function of the analyzer in  FIG. 2 . PC  70  may contain software and/or hardware for image analysis, classification and display. Camera  68  may be an independent unit proximately mounted to apparatus  64 , or an integrated part of apparatus  64 , such as an embedded camera chip. Camera  68  is preferably capable of high-speed operation and broad sensitive spectral response for image acquisition. 
     FIGS. 6A and 6B  show examples of other configurations of collection components  36  which may be used. As shown in  FIGS. 6A and 6B  either polarizing sheets  76  or polarization beam splitting optics  84  can be used to split the parallel and perpendicular polarizations. Collector  36  can include imaging optics  40 . Collector  36  may include a portion of optical fibers  79  and  80  or a lens assembly which provide a second optic path  78 . The collector  36  may also include collection optics as shown in  FIG. 6B . Collector  36  may include a tunable filter  24  such as an AOTF-tunable imaging filter (ChromoDynamics, Inc.). 
   The fiber optic path provided by the collector  36  may provide a coherent imaging bundle or bundles of optical fibers to deliver images to external camera  68 , or to focus the images onto a camera chip (not shown) within endoscope  64 . This may also be done by an appropriately designed lens assembly instead of optical fibers. If collection components  36  includes a tunable filter  24  (not shown), tunable filter  24  may be located at any suitable location in the light path. 
     FIGS. 6A and 6B  are intended to illustrate that numerous alternative embodiments of the present invention may be devised by those of ordinary skill in the art. The exact sequence of tuning, polarizing and focusing the light, and whether the tuning is performed on the input side (i.e. prior to the target) or the output side (i.e. after the target) is of no consequence to the present invention. Many components other than those disclosed may be used to perform the desired function, and the selection of one type of component over another may dictate other components that need to be in the light path. Thus, while the present invention has been described in conjunction with presently preferred embodiments, those of ordinary skill in the art will recognize that many modifications and variations are possible. The present invention is intended to be limited only by the scope of the following claims and not by the scope of the disclosed exemplary embodiments.