Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
  • A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
  • A61B5/0084—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
  • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission

Definitions

• the present invention relates to apparatus and methods for investigating epithelial lined viscus, and more particularly to apparatus and methods for characterizing normal and dysplastic tissue of the endocervical canal.
• CIN cervical intraepithelial neoplasia
• the traditional definition calls it a spectrum of intraepithelial changes that begins as a generally well differentiated intraepithelial neoplasm, which has traditionally been classified as a very mild dysplasia, and ends with invasive carcinoma.
• Neoplastic changes are confined to the squamous epithelium and include nuclear pleomorphism, loss of polarity, and presence of abnormal mitoses.
• CIN is graded 1 to 3, based on the amount of undifferentiated cells present from the basement membrane to the surface epithelium.
• the grade When one third of that distance is involved, the grade is 1 ; when more than one third and up to two thirds is involved, the grade is 2; when more than two thirds is involved, the grade is 3.
• Full-thickness involvement from the surface epithelium to the basement membrane is referred to as carcinoma in situ (CIS).
• CIS carcinoma in situ
• the median transit time from CIN to CIS depends on the grade of CIN: for grade 1 CIN, the time is approximately 6 years; for grade 2 CIN, approximately 2 years; and for grade 3, approximately 1 year.
• SILs squamous intraepithelial lesions
• CIN II, CIN III, CIS high grade SIL
• CIN I, HPV low grade SIL
• Cervical intraepithelial neoplasia is usually detected by screening Pap smears from asymptomatic women. Patients with abnormal Pap smears are referred for colposcopy and possibly biopsy. Acetic acid is applied to the cervix, and areas with abnormal DNA content, such as those with CIN, turn white.
• the colposcope a mounted magnifying lens, is used to direct biopsies of the abnormal white areas.
• An appropriate evaluation of the abnormal Pap smear involves review of the referral and repeat Pap smears, endocervical curettage, and multiple biopsies of the aceto white areas; the results of such analysis will indicate whether the patient has CIN.
• This system provides more effective patient management, as 1 ) fluorescence measurements, and hence diagnostic information, can be obtained in real time and 2) the technique is non-invasive.
• the system includes a fiber optic probe, illumination source and optical multi channel analyzer.
• the probe is inserted through the vaginal canal until its tip is flush with the surface of the cervix.
• the probe delivers light at specific excitation wavelengths and collects fluorescence from the entire emission wavelength range from a predetermined area of the cervix.
• spectra are collected from each colposcopically abnormal area of the cervix prior to biopsy and from 1 to 4 colposcopically normal areas.
• laser induced fluorescence acquired from human cervical tissues in vivo at 337, 380 and 460 nm excitation is analyzed to identify cervical intraepithelial neoplasia (CIN).
• This transformation zone (also known as the squamocolumnar junction) is often located well within the endocervical canal and is not easily subjected to colposcopy or fluorescence spectroscopy using existing systems which are intended primarily to assess the ectocervix.
• cervical lesions that exist on the ectocervix often extend into the endocervical canal, and characterization of the lesion within the endocervical canal is often an important matter. It would therefore be desirable to provide a means to subject the endocervical canal, including the transformation zone, to fluorescence spectroscopy.
• endocervical canal tissue is characterized in vivo, by illuminating endocervical canal tissue in vivo with electromagnetic radiation wavelengths to produce a plurality of fluorescence intensity spectra, detecting a plurality of emission wavelengths from the fluorescence intensity spectra, and characterizing the endocervical canal tissue as a function of the emission wavelengths.
• the characterizing step may distinguish squamous epithelium and columnar epithelium tissue, normal squamous and abnormal tissue, normal columnar epithelium and abnormal tissue, inflamed and abnormal tissue, low grade SIL and high grade SIL tissue, or normal and high grade SIL tissue.
• the illuminating and detecting steps may comprise, illuminating a substantially cylindrical area of the endocervical canal tissue, and detecting the plurality of emission wavelengths from selected portions of the cylindrical area.
• the illuminating and detecting steps may further comprise illuminating an area of the endocervical canal in a vicinity of a single pixel, and detecting the plurality of emission wavelengths from the single pixel, and repeating the illuminating and detecting steps to substantially cover the cylindrical surface.
• the illuminating and detecting steps may further comprise illuminating a substantially ring-shaped area of the endocervical canal, detecting the plurality of emission wavelengths from the substantially ring-shaped area, and repeating the illuminating and detecting steps to substantially cover the cylindrical surface.
• the illuminating and detecting steps may further comprise, illuminating a substantially line-shaped area of the endocervical canal, detecting the plurality of emission wavelengths from the substantially line-shaped area, and repeating the illuminating and detecting steps to substantially cover the cylindrical surface.
• the electromagnetic radiation wavelengths used to practice the method of the present invention may be in the ranges of 317-357 nm, 360-400 nm and 440-480 nm.
• an apparatus embodying the present invention for characterizing endocervical tissue comprises, a light source for emitting a plurality of electromagnetic radiation wavelengths; a probe connected to the light source, the probe adapted to apply the plurality of electromagnetic radiation wavelengths to an interior surface of endocervical canal tissue under test and to gather fluorescence emitted from the tissue under test; a detector, connected to the probe, for detecting at least one fluorescence spectrum emitted from the tissue under test, and a programmed computer connected to the detector means, for processing the at least one fluorescence spectrum according to a predetermined algorithm to characterize the tissue under test.
• the light source may be a laser light source or a filtered white light source and the plurality of electromagnetic radiation wavelengths may be about 337 nm, about 380 nm and about 460 nm.
• the probe may include excitation optical fibers for applying the plurality of electromagnetic wavelengths to an interior surface of the endocervical tissue under test, and collection optical fibers for gathering the fluorescence emitted from the endocervical tissue under test.
• FIG. 1 is an exemplary apparatus in accordance with the present invention usable to perform the method of the present invention.
• FIG. 2 is another exemplary apparatus in accordance with the present invention usable to perform the method of the present invention.
• FIGS. 3A-3F illustrate various states of the endocervical canal.
• FIGS. 4A and 4B are an exemplary single pixel probe usable in the present invention.
• FIG. 5 is another exemplary embodiment of a single pixel probe usable with the present invention.
• FIGS. 6-11 are various exemplary embodiments of a ring probe useable in the present invention.
• FIGS 12A and 12B are an exemplary embodiment of a line probe useable in the present invention.
• FIG. 13 is a graphical representation of a study of endocervical canal size.
• FIGS. 14 and 15 are graphs showing the optical transmission and excitation emission of cervical mucus.
• FIGS. 16 and 17 are graphs showing the optical transmission and excitation emission of fluorinated ethylcne-propylene (FEP). - 1 -
• FIGS. 18, 19 and 20 are exmplary fluoresence spectra obtained from endocervical canal tissue.
• Figures 1 and 2 present exemplary embodiments of the apparatus of the present invention which are useable to practice the method of the present invention.
• an apparatus is disclosed using a single pixel optical probe. Exemplary embodiments of the single pixel probe are presented in more detail below with reference to Figures 4 and 5.
• the apparatus includes endocervical probe 1 1 which, as described below in more detail, incorporates a number of optical fibers including excitation fibers 12, 13 and 14 and collection fiber 16.
• the excitation fibers are connected to an illumination source which may be, for example, two nitrogen lasers 17,18 (LN300C,
• Laser Photonics with a dye module.
• Other illumination sources for example a Xenon lamp and filter wheel (disclosed in more detail with reference to Figure 2), may also be used.
• Other illumination sources may also be acceptable, including, for example, various types of lasers (for example, HeCd or Ag lasers) used with or without dye modules, and various types of so-called white light sources (for example, Xe, Hg, or XeHg lamps) used with filter wheels.
• This illumination source produces light at frequencies that have been selected for their ability to produce fluorescence in tissue that permits characterization of the tissue, For example light at approximately 337, 380 and 460 nanometers has proven useful. This light is coupled into excitation fibers 12, 13, 14.
• Standard Microbench components Spindler Hoyer
• planoconvex lenses 19 were used for coupling.
• the light coming out of the two dye modules is bandpass filtered by bandpass filters 21 to minimize fluorescence from the dye being coupled into the excitation fibers 12, 13 and 14.
• Collection fiber 16 collects the fluorescence which is projected through a coupling optics 22 (for example, Microbench, magnification 50/30) into a detector 24, for example an F/3.8 spectrograph (Monospec 18, Thermo Jarrel Ash, Scientific Measurement Systems,
• longpass filter 23 for example, color glass filters. Schott
• the spectrograph disperses the light onto an intensified diode array 26.
• Exemplary diode array 26, electronics and controller 27 are manufactured by Princeton Instruments.
• the system also includes gate pulser 28 which is used to control the operation of lasers 17 and 18. Lasers 17 and 18 may be controlled, for example at a 30 Hz repetition rate with a 5 nanosecond pulse duration, but other repetition rates and pulse durations may also be acceptable.
• the apparatus also includes programmed computer 29 which operates to energize lasers 17 and 18 and to analyze the fluorescence spectra collected by collection fiber 16 in order to characterize the tissue sample under study. Details of this control and analysis may be found in copending Application Serial No. 08/666,021 , filed July 19, 1996, the disclosure of which is incorporated herein by reference.
• the apparatus includes a multiple pixel optical probe 21 which incorporates excitation optical fibers 22 and collection optical fibers 23.
• Excitation optical fibers 22 are connected to receive light from illumination source 24 which may be, for example, a Xenon lamp 26 in combination with a filter wheel 27.
• illumination source 24 may be, for example, a Xenon lamp 26 in combination with a filter wheel 27.
• illumination source 24 produces light at frequencies that have been selected for their ability to produce fluorescence in tissue that permits characterization of the tissue.
• Collection fibers 23 from probe 21 are connected to detector 28 which includes, for example, an imaging spectrograph 29 (for example, a Chromex 250 IS), and a CCD array 31 (for example, a thermoelectric cooled CCD Princeton Instruments EV 578x384).
• the output of detector 28 is applied to computer 32 which is programmed to control illumination source 24 and to analyze the fluorescence spectra collected by collection fibers 23 and detected by detector 28 using, for example, the analysis methods disclosed in the aforementioned copending application.
• FIGS 3A-F shown are simplified representations of the cross section of the os of the endocervical canal and surrounding tissue illustrating the locations of the squamous epithelium (SE), columnar epithelium (CE) and transformation zone (TZ) of the uterus at various stages of maturity and for various medical conditions.
• Figure 3A shows the neonate uterus
• Figure 3B shows the premenarchal uterus
• Figure 3C shows the menarchal uterus
• Figure 3D shows the menstruating uterus
• Figure 3E shows the menopausal uterus
• Figure 3F shows the postmenopausal uterus.
• the transformation zone TZ can appear on the ectocervix (for example, menstruating. Figure 3D), or well within the edocervical canal (for example, postmenopausal, Figure 3F), or anywhere in between. Since the most common location for CIN and metaplasia is at or near the transformation zone, it is critical that the transformation zone be imaged when conducting fluorescence spectroscopy. This is of particular importance in menopause and postmenopause because most cervical carcinomas occur at this age, and this is when the transformation zone is most deeply within the endocervical canal.
• the endocervical canal After the external os, which follows a funnel type opening, the endocervical canal enlarges and gets smaller again at the inner os.
• the uterus opens to its full size after the internal os by a small angle.
• the canal can be filled inside with non-neoplastic additional tissue like polyps and synechia. Polyps may fill the canal. Atrophy may be present, which results in an abnormal form of the wall (missing folds).
• stenosis may occur after LEEP treatments.
• the folds of the columnar epithelium may typically be several centimeters deep with varying shapes.
• the folds were a maximum of 7.83 mm with a mean depth of 3.38 mm.
• the folds were observed to have two main directions: axial and with an angle of approximately 30 degrees to the axis of the canal. The top of this pine tree-like form points outwards the canal.
• the folds are filled with mucus that sticks strongly to the tissue. Flushing with saline solution will not remove the mucus.
• a study of the fluorescence characteristics of cervical mucus are presented below with reference to Figures 14 and 15.
• Figures 4A and 4B are a single pixel probe 1 1 that may be used in the apparatus of Figure 1 in accordance with the present invention.
• optical probe 1 1 includes a bundle of optical fibers 41 which are packed in a fluorinated ethylene- propylene (FEP) tubing 42 that is substantially transparent to visible light and that also transmits in the ultraviolet.
• FEP tubing 42 containing the fibers 41 is flexibly mounted within a second tubing 43 which may also be made of FEP.
• the outer diameter of tubing 43 is preferably less than 2 mm, however other dimensions may be used.
• the outer diameter of tube 43 is determined primarily by anatomical constraints of the endocervical canal, and is discussed in more detail below with reference to Figure 13.
• This dimension allows the passage of the probe through an endocervical canal with a stenosis at the outer os.
• the fiber 41 within tubing 42 may be rotated and axially displaced within tubing 43 in order to permit the testing of several tissue sites without moving tubing 43.
• FEP has proven useful for use as the material for the tubings used in the optical probes of the present invention
• other materials including, for example, other plastics such as polytetrafluorethylen (PTFE), glass and quartz.
• PTFE polytetrafluorethylen
• a short piece of a large diameter fiber 45 is used, as a reflector and the end surface 47 of fiber 45 is polished with an oblique angle (for example, 40°) relative to the axis of probe 1 1.
• Reflection of light emitted by fibers 41 toward the tissue sample under study (downward in Figure 4A) and reflection of light emitted by the tissue sample back toward fibers 41 occurs because of total internal reflection.
• An alternative reflector may be made using an angled mirrored surface of polished metal, glass, sapphire, or the like.
• Figure 4B is a cross section through section 4B-4B of Figure 4A, and shows the configuration of fibers 41.
• illumination fibers 48 and 51 are used for 337 nm
• fibers 49 and 52 are used for 380 nm
• fibers 50 and 53 are used for 460 nm
• collection fiber 54 provides a single pixel collection for fluorescence spectroscopy. It should be noted that any combination of illumination and collection fibers may be used without departing from the scope of the invention. For example, three illumination fibers and one collection fiber may be used, three illumination fibers and three collection fibers may be used., one illumination fiber and one collection fiber may be used, one fiber used for the combined purpose of illumination and collection may be used, and so forth.
• Fibers 48-54 may be, for example, type SFS320/385T optical fibers, and fiber 46 may be a type SFS1500/1650N optical fiber, both available from Fiberguide Industries, however other types may also be used.
• the single pixel embodiment results in a single substantially elliptical measurement and illumination spot, or pixel.
• the part of probe 11 that extends outside the vagina preferably has a rigid tube with markings which may be used as an aid in positioning the probe both axially and rotationally. Saline solution may be flushed though the openings 61 in tip 62 of probe 1 1 before or during a testing procedure.
• Figure 5 is an alternative embodiment of the single-pixel probe of the present invention.
• probe 11 includes fiber bundle 41 like that of the embodiment of Figure 4A.
• light emitted from the end of fibers 41 is focused by lens 66 and reflected by reflecting surface 67 toward a tissue sample 68 under study.
• light emitted by a tissue sample 68 is focused by lens 66, and reflected by reflective surface 67 back toward fibers 41.
• Other structural details remain substantially as in Figure 4A.
• a ring optical probe 21 is disclosed that may be used in the apparatus of Figure 2
• Probe 21 includes a number of optical fibers 72 coaxially arranged in a ring shape. In one embodiment every other one of fibers 72 are used for illumination, with the remaining fibers being used for collection. Alternatively, each fiber 72 may be used for both illumination and collection.
• every other one of fibers 72 are used for illumination, with the remaining fibers being used for collection.
• each fiber 72 may be used for both illumination and collection.
• Figures 10 and 11 reflection of both illuminating light and collected light is done by a metal plug 73 with a polished reflecting surface 74
• a sapphire tip 81 may be used as shown in Figure 8.
• the ends of fibers 72 may be cleaved and polished as shown in Figure 9.
• every other fiber may be used as an illumination fiber with all remaining fibers being collection fibers.
• each of fibers 72 may have the combined function of illumination and collection. It should be noted that for the sake of clarity, the surrounding tube is not shown in the embodiment of Figure 9.
• the ring probe 21 In all embodiments of the ring probe 21 , light is reflected from fibers 72 toward a tissue sample located adjacent the exterior wall of probe 21 and light emitted by the tissue sample is reflected back toward fibers 72. This results in a plurality of substantially elliptical measurement and illumination spots, or pixels distributed in a ring shape.
• channel 76 may be included to permit the flushing of the tissue under test with saline either before or during a test.
• the diameter of probe 21 may be, for example, approximately 2.8 mm, however other diameters may also work.
• optical probe 21 usable in the apparatus of Figure 2.
• the optical probe 21 of Figures 12A and 12B is a line probe.
• the probe 21 includes of an illuminator that serves to illuminate a tissue sample under study, and a collector that serves to collect light emitted by the tissue sample under study.
• the collector in the exemplary embodiment is made of 19 100 micrometer optical fibers 122 (type SFS100/1 10T available from Fiberguide Industries), however, any number of optical fibers may be used.
• the collection of the fluorescence occurs every 1.5 mm with one of the collection fibers 122.
• the collection fibers 122 are polished at an oblique angle relative to the longitudinal axis of the fiber 122 (for example, 40°).
• the ends 123 of the collection fibers 122 are positioned at different axial locations along the probe as shown in Figure 12 A. In the exemplary embodiment this results in a simultaneous collection every 1.5 mm along a line approximately 2.5 cm. long.
• the diameter of the line probe 21 of Figure 12A is approximately 3 mm, however other diameters would also be acceptable.
• the illuminator of probe 21 in Figure 12A includes a diffuser 124.
• Diffuser 124 is mounted on the top of a bundle of fibers 127.
• Fibers 127 may be for example type SFS200 200 micrometer optical fibers available from Fiberguide Industries, however other types of fibers may be acceptable.
• a reflective coating 128 over 270 degrees of diffuser 124 allows a directed illumination over approximately 90 degrees of the circumference, of probe 21.
• the diffuser 124 is available, for example, from Rare Earth Medical.
• the diffuser 124 is packed in a FEP tubing 131 that is substantially transparent in the visible and also in the ultraviolet. Included within tubing 131 is the collection bundle 122, the diffuser 124 and flushing channels 132 used to carry saline to ports 133 in probe 21 thus permitting flushing of the tissue either before or during testing.
• the outer diameter of tubing 131 is preferably less than 3 mm, however, other diameters may also be acceptable. This allows the passage of the probe through most endocervical canals.
• the probe is manually placed into the endocervical canal. Because of its stiffness the whole probe can be pressed against the walls of the endocervical canal while still keeping a minimal bendability.
• each measured spot or pixel in the exemplary embodiment of Figure 12 A will be smaller than approximately 0.5 mm.
• the diameter depends on the distance of the collection fiber 122 to the tissue. This distance may not be constant for all fibers and typically varies from approximately 0.3 to 1 mm.
• the illumination light passes perpendicular through the collection fibers 122. Therefore the jacket of these fibers 122 should be removed. Collection fibers 122 will then act as cylindrical lenses.
• FIG 13 presented in graphical form are the results of a study of cervical size. Because the design of the probe used in the present invention depends on the canal properties the geometrical aspects of the endocervical canal were studied.
• a database of 362 patients at the MD Anderson Cancer Center contained measurements of the diameter of the external os. The obtained diameter is based on the size of a dilator used at MD Anderson to measure the endocervical canal prior a LEEP or LEEP cone treatment. In a following checkup visit the canal is checked again to assure no stenosis occurred. This parameter was measured in another series of 22 patients with similar results.
• the endocervical canal has a mean diameter at the outer os of 5 mm. In most patients the outer os is larger than 3 mm and smaller than 7 mm.
• the length of the canal was estimated from a uterus removed by hysterectomy.
• the endocervical canal was measured to be approximately 4 cm long.
• FEP tubing (the presently preferred material for use as the housing for the probes of the present invention) was measured, and the results are presented in Figures 16 and 17.
• the fluorescence of the FEP tubing is low.
• the auto fluorescence of the FEP tubing is about 1/10 of the tissue fluorescence at 337 nm excitation.
• the present invention has as its purpose the characterization of epithelial viscus tissue, such as , for example, tissue of the endocervical canal.
• epithelial viscus tissue such as , for example, tissue of the endocervical canal.
• the present invention when applied to the characterization of endocervical tissue, has as its purposes to: a) identify lesions extending from the ectocervix into the endocervical canal; b) detect the position of the transformation zone if present inside the endocervical canal; and c) identify squamous lesions with columnar involvement inside the endocervical canal.
• these purposes are accomplished by measuring fluorescence spectra at spatially resolved locations inside the endocervical canal over a substantially cylindrical area of the interior surface of the tissue of the canal, and using mathematical models to characterize that tissue as a function of the measured spectra.
• the measuring apparatus Before beginning a clinical procedure, the measuring apparatus should be calibrated.
• the background signals arc obtained without any excitation which reflects the dark current of the device. This background is stored and is automatically subtracted from any fluorescence measurement.
• the autofiuorescence of the probe is determined, for example, by placing the probe in a brown bottle containing sterile H2O and measuring fluorescence spectra with the excitation light on. This signal is not subtracted from the tissue fluorescence, however it may be subtracted if desired.
• Rhodamine has been shown to have approximately twice the intensity of squamous cervical tissue fluorescence.
• the spectra may be accumulated 100 and 200 times, respectively at 380 and 460 nm At 337 nm 50 accumulations have proven sufficient. However, other methods to improve the signal to noise ratio may also be used. For all three wavelengths a different background subtraction file may be used with the corresponding accumulations.
• the measuring ring of pixels is advance axially in order to image a sufficient number of pixels over the substantially cylindrical tissue surface.
• the measuring line of pixels is incremented angularly in order to image a sufficient number of pixels over the substantially cylindrical tissue surface
• four individual measurement may be taken, one each at 12, 3, 6, and 9 o'clock (i.e., every 90°). This procedure takes approximately 3 minutes to complete.
• saline solution may be flushed over the tissue in order possibly to improve measurement accuracy by removing mucus or blood or loose tissue form the measurement site.
• the margin of the first specimen at the endocervical side is free of dysplasia or cancer and the second specimen shows no changes it may be assumed that the canal is in a normal condition. If this margin is involved with changes it may be assumed that the first 5 mm of the canal are in an abnormal state. If the margin of the endocervical specimen contains no changes it may be assumed that the margins extend no deeper than 2 cm. If this specimen shows abnormal cells it may be assumed that the measurements in the canal were abnormal even after 5 mm. If the second specimen is marked as metaplasia it may be assumed that the transformation zone is inside the endocervical canal. If the first specimen shows metaplasia the transformation zone is located around the os or on the ectocervix.
• Figures 18, 19 and 20 present groups of normalized fluorescence intensity spectra obtained in vivo from endocervical canals of several different patients using the method and apparatus of the present invention
• Figure 18 is a group of normalized fluorescence intensity spectra obtained with 337 nm excitation
• Figure 19 is a group of fluorescence intensity spectra obtained using 380 nm excitation
• Figure 20 is a group of normalized fluorescence intensity spectra obtained using 460 nm excitation.

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• 1997
  • 1997-07-31 WO PCT/US1997/013300 patent/WO1998005253A1/en not_active Application Discontinuation
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