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Pharmacokinetic Analysis of Malignant Pleural Mesothelioma—Initial Results of Tumor Microcirculation and its Correlation to Microvessel Density (CD-34)

Posted Apr 30, 2008 Updated Apr 7, 2023
By Frederik L. Giesel MD MBA , Peter L. Choyke MD , Amit Mehndiratta MBBS , Christian M. Zechmann MD , Henrik von Tengg-Kobligk MD , Klaus Kayser MD , Helge Bischoff MD , Christian Hintze MD , Stefan Delorme MD , M.A. Weber MD MSc , Marco Essig MD , Hans-Ulrich Kauczor MD , Michael V. Knopp MD PhD
9 min read

Rationale and Objectives

Malignant mesothelioma (MM) of the pleura is an aggressive and often fatal neoplasm. Because MM frequently demonstrates marked angiogenesis, it may be responsive to antiangiogenic therapy, but effective methods for selecting and monitoring of patients are further needed. We employed dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and quantitative immunohistochemistry (IHC) to characterize the microvascularity of MM using both a physiologic and ultrastructural method.

Materials and Methods

Nineteen patients diagnosed with MM were enrolled and DCE-MRI was performed before antiangiogenic treatment. For each patient, tumor regions were characterized by their DCE-MRI–derived pharmacokinetic parameters (Amp, k ep , k el ), which were also compared to those of normal tissue (aorta, liver, spleen, and muscle). In addition, quantitative IHC of representative samples was performed with CD-34 staining to compare the calculated microvessel density (MVD) results with DCE-MRI results.

Results

MM demonstrated markedly abnormal pharmacokinetic properties compared with normal tissues. Among the parameters tested, Amp was significantly different in MM ( P ≤ .001) compared to normal organs. Despite the observation that the MVD of mesotheliomas in this series was high compared to other tumors, DCE-MRI pharmacokinetic parameters had a moderately positive correlation with MVD ( r = 0.5).

Conclusions

DCE-MRI and IHC can be used in patients with MM to visualize tumor microvascularity and to characterize tumor heterogeneity. DCE-MRI and IHC results positively correlated, though moderately, but these two methods present as essential tumor biomarkers. This multimodal characterization may be useful in selecting possible tumor subtypes that would benefit from antiangiogenic therapy.

Malignant epithelioid mesothelioma (MM) is one of the three main types of mesotheliomas. It is an aggressive tumor of the pleura and often fatal. Most, if not all, MMs are associated with prior exposure to asbestos ( ). Although this epithelioid type has the best prognosis, standard treatment regimens, including surgery, chemotherapy, and radiation are often unsuccessful (median survival 9 months). Nevertheless, long-term survivors have been reported, and new chemotherapy and multimodal regimens show promising results ( ).

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a new biomarker imaging technique and a method of characterizing tumor’s neovascularity in situ ( ) as well as assessing the effects of therapy on tumor angiogenesis ( ). DCE-MRI is a noninvasive procedure in which sequential images with high spatial and temporal resolution are obtained to observe the kinetics of contrast media arrival and clearance through the tumor microcirculation and adjacent tissues. The contrast agent enhancement pattern enables visualization, characterization, and quantification of lesion microcirculation ( ). DCE-MRI parameters allowed the prediction of response to therapy in some cases ( ); however, not all tumors have shown strong correlations between their DCE-MRI patterns and their angiogenic expression.

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Material and methods

Patients and Diagnostic Evaluation

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MRI and Pharmacokinetic Analysis

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Microvessel Density: CD-34 Staining of MM

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Quantitative Staining Assessment

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Statistical Analysis

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Technical Implementation and Pharmacokinetic Analysis

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Figure 1, (a) Subtraction image (color-wash) presenting regions of high- and low-contrast delivery. Detailed characteristics of different microcirculation are not visible (tumor highlighted with red boundary). (b,c) Pharmacokinetic threshold analysis in malignant mesothelioma. By choosing different fix thresholds, the tumors are presented homogeneously or heterogeneously. These threshold adaptations are essential for each tumor entity; otherwise, region of interest (ROI) analysis might get misled. (b) A low amplitude (Amp) = 1.0 (a.u.) and k ep = 3.0 min −1 threshold, which is due to overestimation of tumor hot spots. By lowering the threshold for the redistribution rate constant (Amp = 1.3 and k ep = 1.0), the tumor heterogeneity is better represented (c) . Differentiation of other physiologic perfused regions (ie, heart and aorta) is still inappropriately visualized. With additional threshold adaptation of Amp = 2.0 and k ep = 2.3, the MM and its adjunct tissue are best visualized and microcirculatory tumor regions are visible (d) .

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Figure 2, (a)–(c) The parametric maps presenting different axial cuts from a patient with malignant mesothelioma (MM) (Butchart Stage IV). (d) Signal intensity time curves of physiologic (spleen, liver, and muscle) and tumor regions. The T tot -ROI_1 displays the signal intensity curve of the two-dimensional total tumor area, whereas T hot -ROI_2 and T hot _3 are from hot spot regions of the MM. The hot spot tumor ROI describes contrast enhancement with mainly accumulation characteristics followed by slight elimination phase (tumor high lighted with yellow boundary). ROI: region of interest.

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Results

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Figure 3, Pharmacokinetic region of interest (ROI) analysis of the amplitude (inter alia) in different tissue regions (total tumor, hot spot, muscle, spleen, and liver [ n = 19]) are presented. Comparing these different tissue regions can be clearly differentiated from the tumor tissue ( P ≤ .001), apart from the spleen. No statistical differences could be found between tumor hot spot and spleen parenchyma. TT_ROI: total tumor ROI; THot_ROI: tumor hot spot ROI; Tpix_ROI: tumor hotspot one pixel ROI.

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Microvascular Density by CD-34 Staining

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Figure 4, (a,b) CD-34 staining of malignant mesothelioma (MM) tissue (anti CD34, PAP, 10×). Several densely packed microvessels can be noted (a) (arrow) as well as areas with enlarged vascular bundles (b) .

Figure 5, CD-34 immunohistochemical presentation and automated computerized detection of vessels in a localized fibrous tumors. (Anteroposterior, ×40, segmentation of vascular endothelial cells by Electronic Automated Morphometry User System [EAMUS]). Note the quite large distances between the vessels.

Table 1

Vascular Features of Malignant Epithelial Mesothelioma Obtained by Image Analysis at Light Microscopy Magnification

Counts ( n ) Area (μm 2 ) Circumference (μm) Diffusion Length (μm) Median 53.00 241.0 50.00 31.00 Minimum 18 130 38 13 Maximum 71 737 82 57

Table 2

Comparison of Vascular Features in Malignant Mesotheliomas, LFTs of Pleura, and Primary Lung Carcinomas ( )

Cell Type Number of Cases Diffusion Length (μm) Mean Area (μm 2 ) Mean Circumference (μm) Mesothelioma 19 31 241 50 LFT ⁎ 36 220 105 34 Adeno † 94 27 1765 109 Squamous † 113 29 1803 108 Large cell † 30 22 1901 114 Small cell † 9 22 2091 119

LFT: localized fibrous tumors.

LFTs of the pleura: clinical data, asbestos burden, and syntactic structure analysis applied to newly defined angiogenic/growth regulatory effectors.

In respect to their vascularization, the analyzed tumors form three different, statistically highly significant ( P < .001) cohorts as indicated by (*):

Cohort 1: diffuse epithelial mesotheliomas (small diffusion length, small vascular size).

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Correlation of the Pharmacokinetic Parameters and CD-34 Microvascular Staining

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Discussion

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Academic Radiology, Volume 15, Issue 5
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