Accurate prostate tumour detection with multiparametric magnetic resonance imaging: dependence on histological properties.

BACKGROUND: To benefit most of focal treatment of prostate tumours, detection with high precision of all tumour voxels is needed. Although diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have good diagnostic performance, perfect tumour detection is challenging. In this study, we investigated the variation in prostate tissue characteristics Gleason score (GS), cell density (CD) and microvessel density (MVD) to explain the limitations in tumour voxel detection with a MRI-based logistic regression model. MATERIAL AND METHODS: Twelve radical prostatectomy patients underwent a pre-operative 3.0T DWI and DCE-MRI exam. The MRI scans were used to calculate voxel-wise tumour probability with a logistic regression model for the peripheral zone (PZ) of the prostate. Tumour probability maps were correlated and validated with whole-mount histology. Additionally, from the whole-mount histological sections CD, MVD and GS were retrieved for every single voxel. GS, CD and MVD of true- and false-positive voxels and of true- and false-negative voxels were compared using Mann-Whitney U-tests. RESULTS: False-negative tumour voxels had significantly lower CD and MVD (p < 0.0001) and were similar to non-tumour PZ. True-positive detected tumour voxels had high CDs and MVDs (p < 0.0001). In addition, tumour voxels with higher GS showed a trend towards more frequent detection (p = 0.06). Tumour voxels with GS ≥ 3 + 4 showed higher CD and MVD compared to tumour voxels with GS 3 + 3 (p < 0.0001). CONCLUSION: Tumour voxels with low CD and MVD resemble healthy tissue and are limiting tumour voxel detection using DWI and DCE-MRI. Nevertheless, the most aggressive tumour voxels, containing high CD, MVD and GS, are more likely to be detected and can therefore be treated with high dose using focal therapy or focal boosting.

Why prostate tumour delineation based on apparent diffusion coefficient is challenging: an exploration of the tissue microanatomy.

BACKGROUND: Focal boosting of prostate tumours to improve outcome, requires accurate tumour delineation. For this, the apparent diffusion coefficient (ADC) derived from diffusion-weighted MR imaging (DWI) seems a useful tool. On voxel level, the relationship between ADC and histological presence of tumour is, however, ambiguous. Therefore, in this study the relationship between ADC and histological variables was investigated on voxel level to understand the strengths and limitations of DWI for prostate tumour delineation. MATERIAL AND METHODS: Twelve radical prostatectomy patients underwent a pre-operative 3.0T DWI exam and the ADC was calculated. From whole-mount histological sections cell density and glandular area were retrieved for every voxel. The distribution of all variables was described for tumour, peripheral zone (PZ) and central gland (CG) on regional and voxel level. Correlations between variables and differences between regions were calculated. RESULTS: Large heterogeneity of ADC on voxel level was observed within tumours, between tumours and between patients. This heterogeneity was reflected by the distribution of cell density and glandular area. On regional level, tumour was different from PZ having higher cell density (p = 0.007), less glandular area (p = 0.017) and lower ADCs (p = 0.017). ADC was correlated with glandular area (r = 0.402) and tumour volume (r = -0.608), but not with Gleason score. ADC tended to decrease with increasing cell density (r = -0.327, p = 0.073). On voxel level, correlations between ADC and histological variables varied among patients, for cell density ranging from r = -0.439 to r = 0.261 and for glandular area from r = 0.593 to r = 0.207. CONCLUSIONS: The variation in ADC can to a certain extent be explained by the variation in cell density and glandular area. The ADC is highly heterogeneous, which reflects the heterogeneity of malignant and benign prostate tissue. This heterogeneity might however obscure small tumours or parts of tumours. Therefore, DWI has to be used in the context of multiparametric MRI.

Expression of hypoxia-inducible factor-1α and -2α in whole-mount prostate histology: relation with dynamic contrast-enhanced MRI and Gleason score.

The aim of this study was to investigate the association between the immunohistochemical expression of hypoxia-inducible factor (HIF)-1α and HIF-2α and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters Ktrans and kep in prostate cancer. Therefore, 15 patients with biopsy-confirmed prostate cancer underwent a pre-operative 3T DCE-MRI scan. Immunohistochemical analysis of HIF-1α and HIF-2α, and of CD31 for microvessel density (MVD) was performed. Tumor areas were delineated on whole-mount histopathological sections. Nuclear HIF expression was correlated with the quantitative DCE-MRI parameters Ktrans and kep, MVD and Gleason score. HIF expression was highly heterogeneous within tumors and between patients. Pronounced expression of HIF-2α was present, while HIF-1α expression was more limited. Larger tumors showed higher HIF-2α expression (p=0.041). A correlation between HIF-2α and Ktrans p5th was found (r=0.30, p=0.02), but no differences in Ktrans, kep and MVD were observed for different levels of HIF expression. HIF expression was not associated with Gleason score. In conclusion, in this whole-mount prostate cancer study, larger prostate tumors showed frequently high HIF-2α expression, suggesting that larger tumors are clinically most relevant. However, HIF-1α and HIF-2α were not correlated with DCE-MRI parameters. Given the pronounced expression of HIF-2α and independence of Gleason score, HIF expression may function as a biomarker to guide boost dose prescription.

Pathologic validation of a model based on diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging for tumor delineation in the prostate peripheral zone.

PURPOSE: For focal boost strategies in the prostate, the robustness of magnetic resonance imaging-based tumor delineations needs to be improved. To this end we developed a statistical model that predicts tumor presence on a voxel level (2.5×2.5×2.5 mm3) inside the peripheral zone. Furthermore, we show how this model can be used to derive a valuable input for radiotherapy treatment planning. METHODS AND MATERIALS: The model was created on 87 radiotherapy patients. For the validation of the voxelwise performance of the model, an independent group of 12 prostatectomy patients was used. After model validation, the model was stratified to create three different risk levels for tumor presence: gross tumor volume (GTV), high-risk clinical target volume (CTV), and low-risk CTV. RESULTS: The model gave an area under the receiver operating characteristic curve of 0.70 for the prediction of tumor presence in the prostatectomy group. When the registration error between magnetic resonance images and pathologic delineation was taken into account, the area under the curve further improved to 0.89. We propose that model outcome values with a high positive predictive value can be used to define the GTV. Model outcome values with a high negative predictive value can be used to define low-risk CTV regions. The intermediate outcome values can be used to define a high-risk CTV. CONCLUSIONS: We developed a logistic regression with a high diagnostic performance for voxelwise prediction of tumor presence. The model output can be used to define different risk levels for tumor presence, which in turn could serve as an input for dose planning. In this way the robustness of tumor delineations for focal boost therapy can be greatly improved.

Radiofrequency ablation of colorectal liver metastases induces an inflammatory response in distant hepatic metastases but not in local accelerated outgrowth.

BACKGROUND: Recently, we have shown in a murine model that radiofrequency ablation (RFA) induces accelerated outgrowth of colorectal micrometastases in the transition zone (TZ) surrounding the ablated lesion. Conversely, RFA also induces an anti-tumor T-cell response that may limit tumor growth at distant sites. Here we have evaluated whether an altered density of inflammatory cells could be observed in the perinecrotic (TZ) metastases compared to hepatic metastases in the distant reference zone (RZ). METHODS: RFA-treated tumor-bearing mice (n = 10) were sacrificed. The inflammatory cell density (neutrophils, macrophages, CD4(+) T-cells, and CD8(+) T-cells) of tumors in the TZ (TZ tumors) was compared to that in tumors in the RZ (RZ tumors). Sham-operated, tumor-bearing mice (n = 10) were analyzed simultaneously as controls (sham-treated tumors). RESULTS: In RFA-treated, tumor-bearing mice RZ tumors contained a significantly higher density of neutrophils and CD4(+) T-cells, but not macrophages and CD8(+) T-cells compared to sham-treated tumors. Notably, TZ tumors had a significantly lower density of neutrophils, CD4(+) T-cells, and CD8(+) T-cells, but not macrophages, when compared to RZ tumors. CONCLUSIONS: The accelerated perinecrotic tumor outgrowth following RFA is associated with a reduced density of neutrophils and T-cells compared to distant hepatic metastases. This may have implications for local tumor recurrence following RFA.

Ageing and hepatic steatosis exacerbate ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases.

BACKGROUND: Ischemia/reperfusion (I/R) injury is frequently encountered during hepatic surgery. We recently showed that I/R accelerates the outgrowth of pre-established colorectal micrometastases. The aim of this study was to assess the influence of ischemia time, gender, age, and liver steatosis on the accelerated outgrowth of colorectal metastases following I/R. METHODS: Five days after tumor cell inoculation, mice were subjected to 20, 30 or 45 min of left lobar I/R. To assess the influence of age, gender, and liver steatosis on I/R-accelerated tumor growth, we compared old with young mice, male with female mice, and mice with healthy livers with mice with steatotic livers. Endpoints were extent of tissue necrosis and tumor growth. RESULTS: With increasing ischemia times, tissue necrosis and I/R-accelerated tumor growth increased, with a significant stimulatory effect at 30 and 45 min of ischemia. I/R-stimulated outgrowth of micrometastases was further increased by 33% in aged mice and by 42% in steatotic livers and was associated with increased tissue necrosis. In female mice tissue necrosis had decreased by 47% and tumor growth was reduced in both control and clamped liver lobes. The stimulatory effect of I/R on metastasis outgrowth was similar in male and female mice. CONCLUSIONS: I/R-accelerated outgrowth of colorectal micrometastases largely depends on the duration of the ischemic period, with a safe upper limit of 20 min in mice. The stimulatory effects of I/R on tumor growth are exacerbated in aged mice and in steatotic livers.