D. R. Sandison1, R. Richards-Kortum2
1Sandia National Laboratories, P.O. Box 5800/MS0986, Albuquerque, NM, 87185, email: email@example.com
2Department of Electrical and Computer Engineering, University of Texas at Austin, Austin, TX, 78712, firstname.lastname@example.org
Cervical cancer is a leading killer of women worldwide, but Pap smear screening holds the disease to less than 5000 deaths per year in the United States. In this screening procedure, cervical cells are smeared on a microscope slide for evaluation. If an initial smear yields abnormal results, the patient is scheduled for a second test. Two abnormal smears lead to a colposcopic examination. A colposcopist views the cervix directly through a magnifying lens and biopsies abnormal tissue. A pathologist examines the biopsies and makes a diagnosis.
The time from an initial abnormal Pap smear to reevaluation and/or treatment can take weeks. In addition, Pap smear sensitivity can fall below 60% (which means more than 40% false negatives) and specificity can fall below 70% (which means more than 30% false positives).
Tissue spectroscopy has the potential to improve the accuracy of cervical tissue evaluation and to make a noninvasive analysis in seconds. Researchers at the University of Texas at Austin examined cervical lesions in 200 women using a fiber optic probe that samples a 1 mm2 area . A pulsed nitrogen laser delivered 337 nm excitation light to the cervix via a single fiber, and fluorescence emission returned to a spectrometer via multiple collection fibers. The optically interrogated tissue was biopsied and analyzed by a pathologist.
Tissue spectral shapes were correlated with the pathological findings to reveal significant differences between the fluorescence spectra of normal and abnormal tissue as shown in Figure 1. Spectral differences arise from both compositional and structural tissue differences. UT went on to develop algorithms that differentiate tissue based on these spectral differences.
Figure 1. Fluorescence spectra from normal cervical tissue and from high and low grade squamous intraepithelial lesions (SIL). All measurements were made in situ.
Multiple-fiber probes were then developed to speed cervical examinations by simultaneously evaluating many 2 mm diameter spots using a pair of fibers one for excitation and one fluorescence collection . Figure 2 shows a cervix on the left, and on the right a probe with 31 fiber pairs is placed four times to cover the cervix. The 31 fiber pairs collect fluorescence data from a 1 cm diameter area in a few seconds. The data from each spot is analyzed, and gray scale for each spot represents the probability that the tissue within that spot is abnormal.
Figure 2. (Left) A photograph of the cervix taken at colposcopy. The entrance to the endocervical canal lies at the center of the image, which is roughly 4 cm across. (Right) The probability of the tissue being abnormal (black is normal and white is abnormal) is calculated for each fiber of a 31-fiber probe. Each fiber collects a fluorescence spectrum from a 2 mm diameter area, and the probe is placed at four nonoverlapping locations to sample the entire cervix.
In 1994, UT and LifeSpex, Inc. teamed with Sandia National Laboratories to reduce the size and cost of the device. UT's instrument specifications and spectral data were used to calculate a tissue optical transfer function. This transfer function was used to quickly simulate the performance of many possible device configurations and allowed design tradeoffs to be made early in the development cycle.
Figure 3 shows a schematic of our final configuration. The 334 nm line of a continuous mercury arc lamp replaces the nitrogen laser. The advantage of high intensity pulses is lost, but higher average power allows more fibers to be simultaneously illuminated at lower cost. The spectrometer is replaced by a filter wheel and CCD detector that can accommodate simultaneous collection from many tens of fibers. However, increasing the number of collection fibers comes at the expense of spectral resolution, and a limited number of discrete filters at key wavelengths are chosen from spectral data as shown in Figure 1. The result is a portable cost effective device that can potentially map multiple spots in tens of seconds.
Figure 3. Schematic diagram of the Sandia/UTA device for exciting and collecting fluorescence from cervical tissue.
Clinical tests at the MD Anderson Cancer Center in Houston, Texas, verified the instrument's performance and validated our simulation and design techniques. These techniques are now being applied to next generation devices through sponsored research agreements between UT and LifeSpex and through a Cooperative Research and Development Agreement between Sandia Labs and LifeSpex, Inc..
This work was performed at the University of Texas at Austin and at Sandia National Laboratories, which is supported by the U.S. Department of Energy under contract DE-AC04-94AL85000.
For more information contact Dr. Dave Sandison at fax: 505-844-3271 or Dr. Rebecca Richards-Kortum at fax: 512-471-0616.
 M. T. Fahey, L. Irwig, P. Macaskill, Meta-analysis of Pap Test Accuracy, American Journal of Epidemiology, Vol. 141, No. 7, pp. 680-689, 1995.
 N. Ramanujam, M. F. Mitchell, E. Silva, S. Thomsen, R. Richards-Kortum, A Study of the Fluorescence Properties of Normal and Neoplastic Human Cervical Tissue, Lasers in Surgery and Medicine, No. 13, pp. 647-655, 1994.
 C. D. Pitris, Fluorescence Imaging Instrumentation and Clinical Study for the Diagnosis of Cervical Pre-Cancer and Cancer, Masters Thesis with Dr. Rebecca Richards-Kortum, University of Texas at Austin, 1995.
(c) Copyright 1996, The Institute of Electrical and Electronics Engineers, Inc.
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