Elsevier

Radiotherapy and Oncology

Volume 97, Issue 2, November 2010, Pages 217-224
Radiotherapy and Oncology

Magnetic resonance imaging
Dynamic contrast-enhanced magnetic resonance imaging of human cervical carcinoma xenografts: Pharmacokinetic analysis and correlation to tumor histomorphology

https://doi.org/10.1016/j.radonc.2010.06.011Get rights and content

Abstract

Background and purpose

Biomarkers that can predict the outcome of treatment accurately are needed for treatment individualization in advanced carcinoma of the uterine cervix. The potential of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was investigated in the present preclinical study.

Materials and methods

CK-160 and TS-415 human cervical carcinoma xenografts were subjected to DCE-MRI at 1.5 T using a spatial resolution of 0.23 × 0.47 × 2.0 mm3. Parametric images of Ktrans (the volume transfer constant of Gd-DTPA) and ve (the extravascular extracellular volume fraction) were produced by pharmacokinetic analysis of the DCE-MRI data and compared with the histomorphology of the imaged tissue.

Results

Analysis of small homogeneous tumor regions showed that Ktrans, but not ve, differed significantly between parenchymal tissue, connective tissue, and necrotic tissue, consistent with the vascularity of these compartments. However, strong correlations between Ktrans and the fractional volume of the compartments could not be detected for larger tumor regions, primarily because the majority of the voxels represented a chaotic mixture of parenchymal, connective, and necrotic tissue.

Conclusion

The potential of DCE-MRI in providing detailed information on the histomorphology of cervical carcinoma is limited, mainly because the tumor tissue shows significant morphological heterogeneity at the subvoxel level.

Section snippets

Tumor models

CK-160 and TS-415 cervical carcinoma xenografts, initiated by inoculating ∼5 × 105 cells into the gastrocnemius muscle of adult female BALB/c nu/nu mice, were used as tumor models [15]. DCE-MRI was carried out with anesthetized mice (0.63 mg/kg of fentanyl citrate, 20 mg/kg of fluanisone, and 10 mg/kg of midazolam) when the tumors had grown to a volume of 200–600 mm3. Animal care and experimental procedures were approved by the Institutional Committee on Research Animal Care and were performed in

Results

The histological appearance of representative CK-160 and TS-415 tumors is illustrated in Fig. 1, which shows HE-stained sections (Fig. 1a), sections stained for collagen (Fig. 1b), and sections stained for CD31 (Fig. 1c). Scattered necrotic regions differing in size and shape were seen in all tumors. In the CK-160 tumors, the boundary between viable and necrotic tissue was diffuse due to the presence of keratin, whereas this boundary was sharp in the TS-415 tumors (Fig. 1a). The tumors of both

Discussion

In clinical studies of advanced cervical carcinoma, significant but weak correlations have been found between DCE-MRI-derived parameters and some biological characteristics of the tumors, including microvascular density, expression of vascular endothelial growth factor-A, and oxygen tension [7], [8], [9], [10], [11], [12]. Furthermore, significant associations between DCE-MRI-derived parameters and tumor regression, primary tumor control, and disease-free survival after radiotherapy have been

Acknowledgments

Financial support was received from the Norwegian Cancer Society and the South-Eastern Norway Regional Health Authority.

References (28)

  • Y. Yamashita et al.

    Carcinoma of the cervix: dynamic MR imaging

    Radiology

    (1992)
  • H. Hawighorst et al.

    Angiogenesis of uterine cervical carcinoma: characterization by pharmacokinetic magnetic resonance parameters and histological microvessel density with correlation to lymphatic involvement

    Cancer Res

    (1997)
  • H. Hawighorst et al.

    Angiogenic activity of cervical carcinoma: assessment by functional magnetic resonance imaging-based parameters and a histomorphological approach in correlation with disease outcome

    Clin Cancer Res

    (1998)
  • Y. Yamashita et al.

    Dynamic contrast-enhanced MR imaging of uterine cervical cancer: pharmacokinetic analysis with histopathologic correlation and its importance in predicting the outcome of radiation therapy

    Radiology

    (2000)
  • Cited by (15)

    • DCE-MRI of the hypoxic fraction, radioresponsiveness, and metastatic propensity of cervical carcinoma xenografts

      2014, Radiotherapy and Oncology
      Citation Excerpt :

      Values of ve below 0.1 or above 0.8 were used as exclusion criteria, and because we have seen that voxels with ve values slightly above 0.1 and voxels with ve values slightly below 0.8 can have high values of Ktrans, these criteria were probably the optimal ones for CK-160 and TS-415 tumors. All voxels with low Ktrans values were not excluded by using these criteria, and this is in agreement with the observation that regions of CK-160 and TS-415 tumors consisting exclusively of viable tissue can have a significant fraction of voxels with very low Ktrans values [24]. Moreover, this observation suggests that an exclusion criterion based on the value of Ktrans would not be useful for excluding necrotic tissue from analysis in CK-160 and TS-415 tumors.

    • On the relationship between the apparent diffusion coefficient and extravascular extracellular volume fraction in human breast cancer

      2011, Magnetic Resonance Imaging
      Citation Excerpt :

      Though such a relationship did not exist in our study (data not shown), it is possible that the elimination of necrotic regions can improve the relationship between ve and ADC; but this would be very difficult to assess without ex vivo (postmortem) alignment of histological data to imaging data—data that is difficult to acquire in clinical studies. However, another preclinical study did not find a strong correlation between ve (or Ktrans) and histomorphological parameters [25]. The authors concluded this was mostly likely due to the heterogeneity of tumor tissue found at the subvoxel level.

    View all citing articles on Scopus
    View full text