Screening for squamous intraepithelial lesions with fluorescence spectroscopy

doi:10.1016/S0029-7844(99)00408-1

Obstetrics & Gynecology

Volume 94, Issue 5, Part 2, November 1999, Pages 889-896

https://doi.org/10.1016/S0029-7844(99)00408-1 Get rights and content

Abstract

Objective: To evaluate the accuracy of fluorescence spectroscopy in screening for squamous intraepithelial lesions (SILs) and to compare its performance with that of Papanicolaou smear screening, colposcopy, cervicoscopy, cervicography, and human papillomavirus (HPV) testing.

Data Sources: Receiver operating characteristic (ROC) curve analysis was used to analyze performance by fluorescence spectroscopy (primary data) and other methods (secondary data).

Methods of Study Selection: In our search, 275 articles were identified in MEDLINE (1966–1996). Articles were included if the investigators had studied a population in whom low disease prevalence was expected; used either Papanicolaou smear screening and colposcopy or colposcopically directed biopsy as a standard against which the screening technique was measured, and included enough data for recalculation of reported sensitivities and specificities.

Tabulation, Integration, and Results: Receiver operating characteristic curves for fluorescence spectroscopy were calculated using a Bayesian algorithm, and ROC curves for the other screening methods were constructed using meta-analytic techniques. Areas under the ROC curves and Q points were calculated. Screening colposcopy had the highest area under the curve (0.95), followed by screening cervicography (0.90), HPV testing (0.88), cervicoscopy (0.85), fluorescence spectroscopy (0.76), and Papanicolaou smear screening (0.70).

Conclusion: In terms of screening for SILs, fluorescence spectroscopy performed better than the standard technique, Papanicolaou smear screening, and less well than screening colposcopy, cervicography, HPV testing, and cervicoscopy. The promise of this research technique warrants further investigation.

Section snippets

Data sources

Two methods of data collection were required for this study. For fluorescence spectroscopy, we used primary data collected from women in the screening setting.5 Subjects in the clinical study were recruited using an advertisement offering a free screening Papanicolaou smear, cancer-screening gynecologic examination, colposcopic examination, and fluorescence spectroscopic measurement of the cervix. Women were scheduled for screening if they had no histories of abnormal Papanicolaou smears, had

Tabulation and integration

Bayesian statistical methods were used to classify primary data collected with fluorescence spectroscopy. Details of the algorithm have been reported elsewhere.3, 4 The results of the algorithm were used to determine an ROC curve and calculate the area under the curve using the Excel software program (Microsoft Corp., Redmond, WA) following the method of Metz7 and Moses et al.10

For the other screening techniques, data from the published studies were used to reproduce the reported calculations

Results

The ROC curve calculated for fluorescence spectroscopy using Bayesian statistical methods is presented in Figure 1. The area under the curve was 0.76. The ROC curves for Papanicolaou smear screening, colposcopy, cervicoscopy, cervicography, and HPV testing are shown individually in Figure 2. The curves for all screening techniques are superimposed in Figure 3. The areas under the curves were 0.70 for Papanicolaou smear screening, 0.95 for colposcopy, 0.85 for cervicoscopy, 0.90 for

Discussion

Cervical cancer is a disease for which screening is suitable because it is a serious disease for which early treatment is beneficial. Good screening tests should be easy to administer, be inexpensive, and cause minimal discomfort. Papanicolaou smear screening meets those requirements, although as assessed by Fahey et al,11 it has a sensitivity of 58% and specificity of 68%. Given these low levels, strategies that increase sensitivity and specificity may be called for. Adding a second screening

References (49)

M.F Mitchell et al.
Fluorescence spectroscopy for the diagnosis of squamous intraepithelial lesions of the cervix
Obstet Gynecol
(1999)
C.E Metz
Basic principles of ROC analysis
Semin Nucl Med
(1978)
M.A Bigrigg et al.
Colposcopic diagnosis and treatment of cervical dysplasia at a single clinic visit. Experience of low-voltage diathermy loop in 1000 patients
Lancet
(1990)
O.A Olatunbosun et al.
Screening for cervical neoplasia in an African populationSimultaneous use of cytology and colposcopy
Int J Gynaecol Obstet
(1991)
E Megevand et al.
Acetic acid visualization of the cervixAn alternative to cytologic screening
Obstet Gynecol
(1996)
J.J Baldauf et al.
Cervical cancer screening with cervicography and cytology
Eur J Obstet Gynecol Reprod Biol
(1995)
A Schneider et al.
Screening for cervical intraepithelial neoplasia grade 2/3Validity of cytologic study, cervicography, and human papillomavirus detection
Am J Obstet Gynecol
(1996)
J Cuzick et al.
Human papillomavirus testing in primary cervical screening
Lancet
(1995)
S.B Cantor et al.
Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions
Obstet Gynecol
(1998)
R Richards-Kortum et al.
In vivo fluorescence spectroscopyPotential for non-invasive, automated diagnosis of cervical intraepithelial neoplasia and use as a surrogate endpoint biomarker
J Cell Biochem Suppl
(1994)

N Ramanujam et al.

In vivo diagnosis of cervical intraepithelial neoplasia (CIN) using 337-nm-excited laser-induced fluorescence

Proc Natl Acad Sci U S A

(1994)

N Ramanujam et al.

Cervical pre-cancer detection using a multivariate statistical algorithm based on laser induced fluorescence spectra at multiple excitation wavelengths

Photochem Photobiol

(1996)

K Tumer et al.

Ensembles of radial basis function networks for spectroscopic detection of cervical pre-cancer

IEEE Trans Biomed Eng

(1998)

C.K Brookner et al.

Cervical fluorescence of normal women

Lasers Surg Med

(1999)

B Littenberg et al.

Estimating diagnostic accuracy from multiple conflicting reportsA new meta-analytic method

Med Decis Making

(1993)

J.A Swets

Measuring the accuracy of diagnostic systems

Science

(1988)

L.E Moses et al.

Combining independent studies of a diagnostic test into a summary ROC curveData-analytic approaches and some additional considerations

Stat Med

(1993)

M.T Fahey et al.

Meta-analysis of Pap test accuracy

Am J Epidemiol

(1995)

D.J Anderson et al.

Mild and moderate dyskaryosisCan women be selected on the basis of social criteria?

BMJ

(1992)

B.S Bolger et al.

A prospective study of colposcopy in women with dyskaryosis or koilocytosis

Br J Obstet Gynaecol

(1988)

J Chomet

Screening for cervical cancerA new scope for general practitioners? Results of the first year of colposcopy in general practice

BMJ

(1987)

A.D Engineer et al.

The role of routine outpatient cytologic screening for early detection of carcinoma of the cervix in India

Diagn Cytopathol

(1987)

L.E Frisch et al.

Improving the sensitivity of cervical cytologic screening

Acta Cytol

(1990)

J.A Giles et al.

Colposcopic assessment of cervical cytology screening

BMJ

(1988)

Cited by (39)

Bivariate meta-analysis of predictive values of diagnostic tests can be an alternative to bivariate meta-analysis of sensitivity and specificity
2012, Journal of Clinical Epidemiology
Citation Excerpt :
Twenty-three meta-analyses fulfilled our criteria. They contained 346 original studies in total, varying in sample size from 10 to 20,381 patients (Table 1) [13–36]. The variability in sensitivity, specificity, PPV, and NPV is shown in Fig. 2.
Meta-analysis of predictive values is usually discouraged because these values are directly affected by disease prevalence, but sensitivity and specificity sometimes show substantial heterogeneity as well. We propose a bivariate random-effects logitnormal model for the meta-analysis of the positive predictive value (PPV) and negative predictive value (NPV) of diagnostic tests.
Twenty-three meta-analyses of diagnostic accuracy were reanalyzed. With separate models, we calculated summary estimates of the PPV and NPV and summary estimates of sensitivity and specificity. We compared these summary estimates, the goodness of fit of the two models, and the amount of heterogeneity of both approaches.
There were no substantial differences in the goodness of fit or amount of heterogeneity between both models. The median absolute difference between the projected PPV and NPV from the summary estimates of sensitivity and specificity and the summary estimates of PPV and NPV was 1% point (interquartile range, 0–2% points).
A model for the meta-analysis of predictive values fitted the data from a range of systematic reviews equally well as meta-analysis of sensitivity and specificity. The choice for either model could be guided by considerations of the design used in the primary studies and sources of heterogeneity.
Optical technologies and molecular imaging for cervical neoplasia: A program project update
2012, Gender Medicine
There is an urgent global need for effective and affordable approaches to cervical cancer screening and diagnosis. In developing nations, cervical malignancies remain the leading cause of cancer-related deaths in women. This reality may be difficult to accept given that these deaths are largely preventable; where cervical screening programs have been implemented, cervical cancer–related deaths have decreased dramatically. In developed countries, the challenges of cervical disease stem from high costs and overtreatment. The National Cancer Institute–funded Program Project is evaluating the applicability of optical technologies in cervical cancer. The mandate of the project is to create tools for disease detection and diagnosis that are inexpensive, require minimal expertise, are more accurate than existing modalities, and can be feasibly implemented in a variety of clinical settings. This article presents the status and long-term goals of the project.
Serum amino acid levels as a biomarker for renal cell carcinoma
2011, Journal of Urology
Citation Excerpt :
We identified a logistic regression model in which a combination of 8 amino acids could be used to distinguish cases from controls. ROC analysis of this model indicates that the AUC is 0.81, a range similar to that used in other cancer screening tests such as Pap smears (0.70) and prostate specific antigen tests (0.68).13,14 An important feature of the test is that it was possible to identify early stage tumors with only slightly less efficiency as late stage tumors (AUC 0.76).
Prognosis in renal cell carcinoma is dependent on tumor stage at presentation, with significant differences in survival between early and late stage disease. Currently to our knowledge no screening tests or biomarkers have been identified for the early detection of kidney cancer. Therefore, we investigated whether serum amino acid profiles are a potentially useful biomarker in patients with renal cell carcinoma.
The concentrations of 26 amino acids were determined in serum taken preoperatively from 189 patients with renal cell carcinoma, and from 104 age and sex matched controls.
Statistically significant changes were observed in patient levels of 15 amino acids, with 13 being decreased and 2 being increased. A logistic regression model using 8 amino acids including cysteine, ornithine, histidine, leucine, tyrosine, proline, valine and lysine was created to distinguish cases from controls. A receiver operator curve based on this model had an area under the curve of 0.81. This same model also had predictive value in terms of overall survival and tumor recurrence in patients with renal cell carcinoma.
Our findings suggest that serum amino acid levels may be useful as a screening tool for the identification of individuals with renal cell carcinoma and the prediction of outcomes.
The performance of fluorescence and reflectance spectroscopy for the in vivo diagnosis of cervical neoplasia; point probe versus multispectral approaches
2007, Gynecologic Oncology
This review evaluates the diagnostic efficacy of fluorescence spectroscopy, reflectance spectroscopy, and their combination that use both point probe and multispectral imaging approaches in diagnosing cervical neoplasia in vivo.
Articles were selected for this review from a literature search which report the performance of fluorescence and reflectance spectroscopy devices in diagnosing cervical neoplasia in vivo. This analysis focused on the comparison of point probe versus multispectral approaches; the use of fluorescence, reflectance, and their combination; and finally the types of populations that have been studied for in vivo diagnosis of squamous intraepithelial lesions (SIL).
Twenty-six studies were included and their heterogeneity precluded formal meta-analysis. Though point probes were expected to have greater specificity and multispectral approaches greater sensitivity, there was considerable overlap in the performance of point probe and multispectral devices. There were few studies that studied fluorescence spectroscopy alone and reflectance spectroscopy alone. Combined fluorescence and reflectance approaches showed considerable overlap among point probe and multispectral devices. The overlap of performance suggests that fluorescence and reflectance may have similar performance. Currently the paucity of data precludes definitive conclusions regarding the additive effect of both approaches. Only two of twenty-six trials have recruited patients with no history of an abnormal Papanicolaou smear (screening populations) and twenty-four trials include patients with a range of cervical abnormalities from atypia to cancer (diagnostic populations).
Optical spectroscopy using a point probe and multispectral approaches appears to overlap in performance. Fluorescence and reflectance spectroscopies examine different aspects of epithelial–stromal biology and appear to yield similar diagnostic performance. While intuitively appealing, their combination may or may not be additive. There have been few studies of these technologies in screening populations. Better definitions of device trial design and reporting requirements would facilitate combining analyses to formally examine performance.
The clinical effectiveness of optical spectroscopy for the in vivo diagnosis of cervical intraepithelial neoplasia: Where are we?
2007, Gynecologic Oncology
In this review, we evaluate the diagnostic efficacy of optical spectroscopy technologies (fluorescence and reflectance spectroscopy) for the in vivo diagnosis of cervical neoplasia using both point probe and multispectral imaging approaches.
We searched electronic databases using the following terms: cervical cancer, cervical intraepithelial neoplasia, squamous intraepithelial lesion, and spectroscopy, fluorescence spectroscopy, or reflectance spectroscopy. We included studies that evaluated fluorescence and reflectance spectroscopy devices for in vivo diagnosis, compared those results with biopsy results, and reported on the sensitivity and specificity of the devices tested.
Twenty-six studies, including seven phase II trials and one randomized clinical trial, met our acceptability criteria. We found several important differences across the studies including device approach (multispectral versus point probe), study population, disease classification system, and disease threshold. This heterogeneity prevented formal combination of sensitivity and specificity results.
Optical spectroscopy has similar performance to colposcopy and may help localize lesions and therefore be an effective adjunct to colposcopy. Reports on the diagnostic accuracy of these devices should use common thresholds for the construction of receiver operating characteristic curves to enable comparisons with standard technologies and facilitate their adoption. Optical spectroscopy has also been identified for possible use as ASCUS triage and primary screening, yet neither has been sufficiently evaluated to warrant a conclusion as to their suitability in this role.
The clinical effectiveness of fluorescence and reflectance spectroscopy for the in vivo diagnosis of cervical neoplasia: An analysis by phase of trial design
2007, Gynecologic Oncology
In this review, we focus on the pilot, Phase I, II, and III clinical trials of fluorescence spectroscopy, reflectance spectroscopy, and their combination for the in vivo diagnosis of cervical neoplasia using both point probe and multi-spectral imaging approaches. Research groups that have progressed from pilot through Phase II/III clinical trials were analyzed.
A formal search was conducted to identify articles which report the performance of fluorescence and reflectance spectroscopy trials which diagnose cervical neoplasia in vivo. This report focuses on the funding source, prevalence of disease in the trials, type of population (screening versus diagnostic), gold standard criterion for diagnosis (histopathology versus colposcopy alone and histopathology), histopathologic classification (World Health Organization (WHO) 8 categories, Bethesda 5 categories, or both (13 categories)), number of clinical trial sites, number of medical investigators, number of histopathology reviews by histopathologists for a consensus diagnosis, use of acetic acid, explicit sample size calculation in the published report, actual sample size in the trial, ages of patients included in the trial, and the phase of the trial design, as they affect performance and plotted as sensitivity and 1 − specificity.
Twenty-six studies were included and their heterogeneity precluded formal meta-analytic combination. While most factors inherent in the review were not significant sources of variability; there were three variables that affected performance, i.e., sample size, age of patients, and phase of trial design.
As with pharmaceutical trials, as the sample size increased, as the heterogeneity of the population increased, as the age of the patients included patients over 50 years old, and as the phase of clinical trial design progressed from pilot through Phase III randomized trial, the performance of all devices decreased.

View all citing articles on Scopus

^☆: This study was supported by the National Science Foundation and the Whitaker Foundation. The contributions of E. Neely Atkinson, PhD, and Judy Sandella, CNP, MS, are gratefully acknowledged.

View full text

ReviewsScreening for squamous intraepithelial lesions with fluorescence spectroscopy☆

Abstract

Section snippets

Data sources

Tabulation and integration

Results

Discussion

Obstet Gynecol

Semin Nucl Med

Lancet

Int J Gynaecol Obstet

Obstet Gynecol

Eur J Obstet Gynecol Reprod Biol

Am J Obstet Gynecol

Lancet

Obstet Gynecol

In vivo fluorescence spectroscopyPotential for non-invasive, automated diagnosis of cervical intraepithelial neoplasia and use as a surrogate endpoint biomarker

J Cell Biochem Suppl

In vivo diagnosis of cervical intraepithelial neoplasia (CIN) using 337-nm-excited laser-induced fluorescence

Proc Natl Acad Sci U S A

Cervical pre-cancer detection using a multivariate statistical algorithm based on laser induced fluorescence spectra at multiple excitation wavelengths

Photochem Photobiol

Ensembles of radial basis function networks for spectroscopic detection of cervical pre-cancer

IEEE Trans Biomed Eng

Cervical fluorescence of normal women

Lasers Surg Med

Estimating diagnostic accuracy from multiple conflicting reportsA new meta-analytic method

Med Decis Making

Measuring the accuracy of diagnostic systems

Science

Combining independent studies of a diagnostic test into a summary ROC curveData-analytic approaches and some additional considerations

Stat Med

Meta-analysis of Pap test accuracy

Am J Epidemiol

Mild and moderate dyskaryosisCan women be selected on the basis of social criteria?

BMJ

A prospective study of colposcopy in women with dyskaryosis or koilocytosis

Br J Obstet Gynaecol

Screening for cervical cancerA new scope for general practitioners? Results of the first year of colposcopy in general practice

BMJ

The role of routine outpatient cytologic screening for early detection of carcinoma of the cervix in India

Diagn Cytopathol

Improving the sensitivity of cervical cytologic screening

Acta Cytol

Colposcopic assessment of cervical cytology screening

BMJ

Reviews
Screening for squamous intraepithelial lesions with fluorescence spectroscopy☆