Early detection of high-grade squamous intraepithelial lesions in the cervix with quantitative spectroscopic imaging

Abstract

Quantitative spectroscopy has recently been extended from a contact-probe to wide-area spectroscopic imaging to enable mapping of optical properties across a wide area of tissue. We train quantitative spectroscopic imaging (QSI) to identify cervical high-grade squamous intraepithelial lesions (HSILs) in 34 subjects undergoing the loop electrosurgical excision procedure (LEEP subjects). QSI's performance is then prospectively evaluated on the clinically suspicious biopsy sites from 47 subjects undergoing colposcopic-directed biopsy. The results show the per-subject normalized reduced scattering coefficient at 700 nm (An) and the total hemoglobin concentration are significantly different (p<0.05) between HSIL and non-HSIL sites in LEEP subjects. An alone retrospectively distinguishes HSIL from non-HSIL with 89% sensitivity and 83% specificity. It alone applied prospectively on the biopsy sites distinguishes HSIL from non-HSIL with 81% sensitivity and 78% specificity. The findings of this study agree with those of an earlier contact-probe study, validating the robustness of QSI, and specifically An, for identifying HSIL. The performance of An suggests an easy to use and an inexpensive to manufacture monochromatic instrument is capable of early cervical cancer detection, which could be used as a screening and diagnostic tool for detecting cervical cancer in low resource countries.

Fig. 1

High-grade squamous intraepithelial lesion (HSIL) and non-HSIL (low-grade SIL and benign) regions overlaid on a white-light photograph of the cervix. The disease state and locations were determined by loop electrosurgical excision procedure (LEEP) pathology, where the excised tissue is cut into 12 slices corresponding to the hour positions on a clock, and examined histopathologically. Solid white lines indicate regions of the cervix confirmed to have HSIL by pathology. HSIL may be present in other parts of the cervix, but these sites could not be confirmed due to denuded mucosal surfaces or finite pathology sampling. Dashed white lines indicate non-HSIL regions confirmed by pathology. Green lines indicate the squamo-columnar junction (SCJ), the boundary between endocervix and transformation zone (Tzone). No diagnosis was available at the LEEP specimen positions 10 and 11 o’clock due to denuded mucosa and part of an intrauterine device is visible.

Fig. 2

Spectroscopy parameter maps acquired by quantitative spectroscopic imaging (QSI) overlaid on a white-light photograph of a cervix. (a) $A$, reduced scattering coefficient at 700 nm (${\mathrm{mm}}^{-1}$). (b) $B$, wavelength dependence of reduced scattering coefficient. (c) [Hb], total hemoglobin concentration ($\mathrm{mg}/\mathrm{mL}$). (d) $\alpha$, oxygen saturation (%). (e) Coll, collagen concentration (a.u.). (f) NADH, concentration of reduced form of nicotinamide adenine dinucleotide (a.u.). Pixels with no spectroscopy data due to the presence of specular reflection, motion, acute tissue angle relative to QSI system, or noncervical substances are uncolored in the parameter maps. Note that specular reflection observed in the white-light photographs is not necessarily sites of specular reflection for spectroscopy measurements. A portion of the speculum (bottom of photograph) is visible.

Fig. 3

Box plots of normalized spectroscopy parameters measured from HSIL and non-HSIL pixels in the excised region of the LEEP subjects. Normalization was performed by dividing spectroscopy parameters by their respective average values across ectocervix pixels of the same subject. (a) $A_n$, normalized $A$. (b) $B_n$, normalized $B$. (c) ${[\mathrm{Hb}]}_n$, normalized [Hb]. (d) ${\alpha }_n$, normalized $\alpha$. (e) ${\mathrm{Coll}}_n$, normalized Coll. (f) ${\mathrm{NADH}}_n$, normalized NADH. The horizontal center line is the median and the lower and upper edges of the rectangular box indicate the 25th and 75th percentiles, respectively. The horizontal lines at the ends of the dashed vertical line indicate the extent of the data, and the crosses indicate outliers.

Fig. 4

Receiver operator characteristic (ROC) curve (solid line) for distinguishing HSIL from non-HSIL pixels in the LEEP subjects. Only $A_n$ was used in the analysis. The dashed line indicates the line of chance.

Fig. 5

Mean reflectance (a) and fluorescence (b) spectra acquired from the clinically suspicious biopsy sites of colposcopy subjects. Solid lines indicate non-HSIL sites, and dashed lines indicate HSIL sites. Note that these spectra are not “normalized” like the spectroscopy parameter maps.