Primary and metastatic ovarian cancer: Characterization by 3.0T diffusion-weighted MRI

Abstract

Objectives: We aimed to investigate whether apparent diffusion coefficients (ADCs) measured by 3.0T diffusion-weighted magnetic resonance imaging (DWI) associate with histological aggressiveness of ovarian cancer (OC) or predict the clinical outcome. This prospective study enrolled 40 patients with primary OC, treated 2011-2014.

Methods: DWI was performed prior to surgery. Two observers used whole lesion single plane region of interest (WLsp-ROI) and five small ROIs (S-ROI) to analyze ADCs. Samples from tumours and metastases were collected during surgery. Immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to measure the expression of vascular endothelial growth factor (VEGF) and its receptors.

Results: The interobserver reliability of ADC measurements was excellent for primary tumours ICC 0.912 (WLsp-ROI). Low ADCs significantly associated with poorly differentiated OC (WLsp-ROI P = 0.035). In primary tumours, lower ADCs significantly associated with high Ki-67 (P = 0.001) and low VEGF (P = 0.001) expression. In metastases, lower ADCs (WLsp-ROI) significantly correlated with low VEGF receptors mRNA levels. ADCs had predictive value; 3-year overall survival was poorer in patients with lower ADCs (WLsp-ROI P = 0.023, S-ROI P = 0.038).

Conclusion: Reduced ADCs are associated with histological severity and worse outcome in OC. ADCs measured with WLsp-ROI may serve as a prognostic biomarker of OC.

Key points: • Reduced ADCs correlate with prognostic markers: poor differentiation and high Ki-67 expression • ADCs also significantly correlated with VEGF protein expression in primary tumours • Lower ADC values are associated with poorer survival in ovarian cancer • Whole lesion single plane-ROI ADCs may be used as a prognostic biomarker in OC.

Keywords: Cell proliferation; Diffusion magnetic resonance imaging; Neoplasm metastasis; Neovascularization pathologic; Ovarian neoplasms.

Fig. 1

Images in a 67-year-old woman with high grade serous ovarian adenocarcinoma. A large primary tumour was imaged with (a) T2-weighted, (b) T2 spectral attenuated inversion recovery (SPAIR) fat-saturated, and (c) diffusion-weighted imaging with background body signal suppression (DWIBS) (b 800) MRI. * Bright ascites in (a) and (b). The tumour appears dark in the apparent diffusion coefficient (ADC) map (d), which illustrates the region of interest placement for ADC measurements. The whole lesion single plane region of interest (WLsp-ROI) was placed to cover the whole tumour in the slice in which the tumour appeared largest. ADC value is 0.695 × 10^-3mm²/s. The five small ROIs (S-ROI) were placed on subregions appearing to have the lowest signal on the ADC map. Lowest ADC value 0.543 × 10^-3mm²/s, is used in statistical analyses

Fig. 2

Bland Altman plots show ADC measurements in a whole lesion single plane region of interest (WLsp-ROI) and a small subregion region of interest (S-ROI) positioning as performed by the two readers. The difference in ADC values between two readers (y-axis) is plotted against the mean ADC of both readers (x-axis). The red line represent the mean absolute difference (bias) in ADC between the two readers; the blue lines represent the 95% confidence intervals (1.96 times the standard deviation) of the mean difference (limits of agreement). The mean absolute difference in ADC measurements between two readers is higher when using S-ROI

Fig. 3

Relationship between apparent diffusion coefficients (ADCs) and the histopathological grade of ovarian cancer. Lower grade cancer was associated with significantly higher ADCs in the whole lesion covering region of interest (WLsp-ROI) (A) and in the small subregion regions of interest (S-ROI) (B) of the primary tumour. Whiskers represent standard deviation. ADCs measured from the WLsp-ROI were higher than those measured from the S-ROI (P < 0.001)

Fig. 4

Differences in vascular endothelial growth factor C (VEGF-C) and VEGF receptors (VEGFR) mRNA levels in metastases and primary tumours (n = 35). VEGF-C (P = 0.038) and VEGFR-1 (P = 0.021), VEGFR-2 (P = 0.008), and VEGFR-3 (P = 0.011) relative expressions were higher in metastases (M) than in related primary lesions (P) according to quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses. Box-plots represent mean and whiskers standard deviation. The expression levels were normalized to peptidylprolyl isomerase A (PPIA)

Fig. 5

Histological samples of ovarian cancer tumours at 20x magnification and connection to apparent diffusion coefficients (ADCs). a Staining of vascular endothelial growth factor (VEGF) in epithelial cells with high and low expression. Scatter-dot graph illustrates the correlation between ADC when the ADC was measured using the whole lesion single plane region of interest (WLsp-ROI) and VEGF expression. b Ki-67 staining of the nucleus in high grade serous adenocarcinoma with high and low expression. Scatter-dot graph illustrates the correlation between ADC when the ADC was measured using the WLsp-ROI and Ki-67 expression

Fig. 6

Univariate analysis of cumulative overall survival in relation to dichotomized apparent diffusion coefficients (ADCs). The 3-year overall survival was significantly prolonged in patients with high ADCs measured using the whole lesion single plane covered region of interest (WLsp-ROI)