Diagnosis of dysplasia using laser induced fluoroescence

• US 5,421,339 A
• Filed: 05/12/1993
• Issued: 06/06/1995
• Est. Priority Date: 05/12/1993
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Ramanujam, Nirmala, Richards-Kortum, Rebecca R., Mahadevan, Anita, Mitchell, Michele F., Thomsen, Sharon
• Primary Examiner(s): Smith, Ruth S.
• Application Number:
  US08/060,432
• Time in Patent Office: 755 Days
• Field of Search: 128/664-665, 128/633, 128/634, 607/88-93, 606/3, 606/14-16
• US Class Current: 600/477
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• CPC Class Codes: A61B 5/0075 by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy A61B5/0071 takes precedence
• CPC Class Codes: A61B 5/0084 for introduction into the body, e.g. by catheters A61B5/1459 takes precedence
• CPC Class Codes: A61B 5/4331 of the cervix A61B5/435 takes precedence
• CPC Class Codes: G01N 2021/6417 Spectrofluorimetric devices
• CPC Class Codes: G01N 21/6402 Atomic fluorescence; Laser induced fluorescence

Abstract

Apparatus and in vivo methods to distinguish normal and abnormal cervical tissue and to detect cervical intraepithelial neoplasia (CIN) in a diagnostic cervical tissue sample. Induced fluorescence intensity spectra from known normal cervical tissue and a diagnostic tissue sample are obtained from the same patient. Peak fluorescence intensity values for normal tissue samples are averaged, as are slope measurements from predetermined portions of spectra induced in both known normal cervical tissue and the diagnostic tissue sample. Peak fluorescence intensities of diagnostic tissue spectra are divided by average peak fluorescence intensity values for normal tissue in the same patient to yield relative peak fluorescence intensity values. Normal and abnormal cervical tissues are distinguished using a predetermined empirical discriminant function of slope measurements derived from normal tissue spectra and relative peak fluorescence intensity measurements in the same patient. CIN is distinguished from tissue with human papilloma virus injection or inflammation using a predetermined empirical discriminant function of average slope measurements on spectra from known normal tissue and slope measurements on a diagnostic tissue spectrum.

Claims

1. An in vivo method of detecting tissue abnormality in a diagnostic cervical tissue sample in a patient, comprising:

illuminating the diagnostic cervical tissue sample and a presumptively histologically normal cervical tissue sample with electromagnetic radiation;

detecting a first fluorescence intensity spectrum from the diagnostic tissue sample;

detecting a second fluorescence intensity spectrum from the presumptively histologically normal cervical tissue sample;

calculating from a predetermined portion of said first fluorescence intensity spectrum, a first slope parameter which is indicative of tissue abnormality;

calculating from a predetermined portion of said second fluorescence intensity spectrum, a second slope parameter which is indicative of presumptively histologically normal cervical tissue; and

detecting tissue abnormality in the diagnostic cervical tissue sample as a function of said first and second slope parameters.

2. The method of claim 1, said illuminating step comprising, illuminating said diagnostic cervical tissue sample and said presumptively histologically normal cervical tissue sample with electromagnetic radiation having a wavelength of about 337 nm.

3. The method of claim 1, said step of calculating said first slope parameter comprising, calculating said first slope parameter from a portion of said first fluorescence intensity spectrum corresponding to wavelengths between about 440 nm and about 460 nm.

4. The method of claim 1, said step of calculating said second slope parameter comprising, calculating said second slope parameter from a portion of said second fluorescence intensity spectrum corresponding to wavelengths between about 410 nm and about 430 nm.

5. The method of claim 1, said step of calculating said first slope parameter comprising, calculating said first slope parameter after normalization of said first fluorescence intensity spectrum with a peak fluorescence intensity value of said first fluorescence intensity spectrum.

6. The method of claim 5, wherein said first slope parameter is a function of an average slope in said predetermined portion of said normalized first fluorescence intensity spectrum.

7. The method of claim 1, said step of calculating said second slope parameter comprising, calculating said second slope parameter after normalization of said second fluorescence intensity spectrum with a peak fluorescence intensity value of said second fluorescence intensity spectrum.

8. The method of claim 7, wherein said second slope parameter is a function of an average slope in said predetermined portion of said normalized second fluorescence intensity spectrum.

9. The method of claim 1, said step of detecting tissue abnormality comprising, detecting tissue abnormality as a predetermined empirical discriminant function of said first and second slope parameters.

10. The method of claim 9, said step of detecting tissue abnormality comprising, detecting tissue abnormality as a predetermined linear empirical discriminant function of said first and second slope parameters.

11. An in vivo method of detecting tissue abnormality in a diagnostic cervical tissue sample in a patient, comprising:

identifying a presumptively histologically normal cervical tissue sample from the patient;

illuminating the diagnostic tissue sample and said presumptively histologically normal tissue sample with electromagnetic radiation;

detecting a first fluorescence intensity spectrum from the diagnostic tissue sample;

detecting a second fluorescence intensity spectrum from said presumptively histologically normal tissue sample;

calculating a slope parameter indicative of tissue abnormality from said first fluorescence intensity spectrum;

calculating an intensity parameter characteristic of normal tissue from said second fluorescence intensity spectrum;

calculating a discriminant parameter as a function of said slope and intensity parameters;

detecting tissue abnormality in the diagnostic cervical tissue sample by substituting said discriminant parameter in a predetermined discriminant function.

12. An in vivo method of detecting CIN in a diagnostic cervical tissue sample in a patient having presumptively known normal cervical tissue, comprising:

illuminating the diagnostic tissue sample and presumptively known normal cervical tissue with electromagnetic radiation;

detecting a first fluorescence intensity spectrum from the diagnostic tissue sample;

detecting a second fluorescence intensity spectrum from the presumptively known normal cervical tissue;

calculating from a predetermined portion of said first fluorescence intensity spectrum a first slope parameter which is indicative of CIN in the diagnostic cervical tissue sample;

calculating from a predetermined portion of said second fluorescence intensity spectrum a second slope parameter which characterizes presumptively normal cervical tissue in the patient; and

detecting CIN in the diagnostic cervical tissue sample as a function of said first and second slope parameters.

13. The method of claim 12, said illuminating step comprising, illuminating said diagnostic tissue sample with electromagnetic radiation having a wavelength of about 337 nm.

14. The method of claim 12, said step of calculating said first slope parameter comprising, calculating said first slope parameter from a portion of said fluorescence intensity spectrum corresponding to wavelengths between about 440 nm and about 460 nm.

15. The method of claim 12, said step of calculating said second slope parameter comprising, calculating said second slope parameter from a portion of said second fluorescence intensity spectrum corresponding to wavelengths between about 410 nm and about 430 nm.

16. The method of claim 12, wherein said first and second slope parameters are calculated after normalization of said first and second fluorescence intensity spectra to peak fluorescence intensity values of 1.

17. The method of claim 14, wherein said first and second slope parameters are functions of average slopes in said normalized first and second fluorescence intensity spectra respectively, said slopes being measured in predetermined regions of said normalized first and second fluorescence intensity spectra respectively, said regions lying substantially between wavelengths corresponding to said predetermined portions of said first and second fluorescence intensity spectra respectively.

18. The method of claim 12, said step of detecting CIN comprising, detecting CIN as a predetermined empirical discriminant function of said first and second slope parameters.

19. The method of claim 18, said step of detecting CIN comprising, detecting CIN as a predetermined linear empirical discriminant function of said first and second slope parameters.

20. An apparatus for in vivo detection of tissue abnormality in a diagnostic cervical tissue sample in a patient having presumptively known normal cervical tissue, comprising:

means for applying electromagnetic radiation to a diagnostic cervical tissue sample and to presumptively known normal cervical tissue;

radiation detection means for detecting a fluorescence intensity spectrum induced in the diagnostic cervical tissue sample, and for detecting a plurality of normal fluorescence intensity spectra induced in the presumptively known normal cervical tissue by said means for applying;

a computer, connected to said means for applying and to said means for detecting, including,

means for measuring a peak normal fluorescence intensity value in each normal fluorescence intensity spectrum,

means for calculating an average peak normal fluorescence intensity from said peak normal fluorescence intensity values,

means for measuring a peak fluorescence intensity value from said fluorescence intensity spectrum induced in the diagnostic cervical tissue sample,

means for calculating from a predetermined portion of said fluorescence intensity spectrum a slope parameter, which is indicative of tissue abnormality,

means for calculating relative peak fluorescence intensity as a function of said peak fluorescence intensity value and said average peak normal fluorescence intensity, and

means for detecting tissue abnormality as a function of said slope parameter and said relative peak fluorescence intensity.