Advanced MRI in renal tumours

About 2-3% of newly diagnosed cancer concerns renal cell carcinoma (RCC).
Approximately 85-90% of all diagnosed renal malignancies is accounted for by
RCC. The three major subtypes of RCC are clear cell (80-90%), papillary
(10-15%) and chromophobe (4-5%).

In solid renal masses, presence of enhancement in CT or MR imaging is used for
detecting malignant lesions. However, differentiation between histological
subtypes of renal tumours (malignant versus benign and subtypes of malignant
tumours) on imaging is not yet proven to be unequivocal. Because CT and MRI
cannot reliably distinguish malignant renal tumours from oncocytoma and
(fat-free) angiomyolipoma false positive scans do occur. When reviewing
surgical series regarding partial nephrectomy, up to 20% of all resected
lesions of suspected malignant nature on imaging, are shown to be benign. Even
higher percentages have been reported for radical nephrectomy. Identifying
these benign lesions in an early stage through imaging may avoid invasive
diagnostics such as biopsy, and eventually unnecessary surgery. Also when
patients are unsuitable for surgery but histological confirmation of a renal
mass is needed, for instance with the intended purpose of starting systemic
therapy, additional information regarding subtype obtained by MRI may be of
value.

Diffusion weighted imaging (DWI) is based on the Brownian motion of water
molecules. When the environment is totally unrestricted, the motion of water
molecules is completely random (Brownian motion or free diffusion). Within
tissue however, the movement is not random but restricted by interactions with
tissue compartments, cell membranes and intracellular organelles. The amount of
restriction of the movement of the water molecules within tissue is measured
using DWI sequences. The strength of the sequence used (diffusion sensitizing
gradient) is characterized by the b value. Three different factors affect the b
value: gradient amplitude, duration of the applied gradient and the time
interval between paired gradients. The unit of the b value is seconds per
square millimeter. Using linear regression, an apparent diffusion coefficient
(ADC) can be calculated using the images obtained at different b values. The
images can be reviewed qualitatively by visually assessing DW and ADC images,
but also qualitatively by measuring the ADC value of the lesion. Impeded
diffusion will appear bright on DW images even at higher b values due to
maintained signal. Restricted diffusion can be observed on the ADC map as it
appears as a dark area in relation to the surrounding structures. When
measuring a reduced ADC value, this indicates impeded diffusion which is
associated with increased cellularity.

As malignant tissue is associated with impeded diffusion, DWI using ADC
measurements has been shown to be able to discriminate between benign and
malignant renal tumors. A recent meta analysis concluded that identification of
oncocytoma by ADC value might be the greatest advantage in DWI. However,
differentiating angiomyolipoma*s (AMLs) from malignant tumors was not possible
using ADC values, as AMLs showed comparable results with RCCs.

Diffusion tensor imaging (DTI) is based on the principles of DWI. For ADC
imaging using DWI usually 3 gradient directions are be applied. Meaning that
ADC measurements are performed along three axes and are integrated thereafter,
leading to an image based on mean ADC values along 3 axes. However, the
calculated ADC values are still very dependent on the direction of the
diffusion encoding because diffusion can occur in an infinite amount of
directions. To better assess the true direction of diffusion DTI is developed.
This system measures mean ADC values along different axes that fit to a 3D
ellipsoid. By assessing 6 parameters (the length and orientation of the three
axes) of the ellipsoid, its properties can be assessed. Because of these
measurements, with DTI it is possible to assess the speed of movement of the
water molecules (as in regular DWI) but also the direction in which the
molecules move and thereby fully characterising the diffusion in 3D instead of
only 3 directions.

Unrestricted diffusion in all directions is referred to as isotropic,
anisotropy means that diffusion along certain axes are not equal. Using
anisotropy DTI enables to calculate in which direction the diffusion occurs. A
widely used metric of diffusion anisotropy is fractional anisotropy (FA). The
current soft- and hardware is enabled to provide FA images and values, thus
showing in which direction diffusion is more or less restricted. Higher FA
values indicate more anisotropy within the tissue. Anisotropy data can be used
in for instance brain imaging to assess the orientation of fibers along brain
tissue. For examples also see Appendix C. DTI has previously been studied in
patients with chronic kidney disease (CKD), showing decreasing ADC an FA values
with more severe stages of CKD. Kidney tumours also have previously been
studied using DTI, conclusions regarding ADC and FA values of this study
however are based on a very small group.

To evaluate the diagnostic performance of diffusion weighted MR imaging (MRI)
techniques by using apparent diffusion coefficient (ADC) maps and Diffusion
Tensor Imaging (DTI) on 3 tesla MRI in assessing the nature of renal masses.

Single center, prospective, observational.

The only risks consist of additional risk by MRI (burden of heating and noise,
risks of adverse reactions against gadolinium). Patients with previous allergic
reaction to gadolinium based contrast agent are at higher risk to develop a
subsequent allergic reaction upon administration, therefore they are excluded
in order to minimize the risk of an adverse reaction.[19] The overall frequency
of acute adverse events after an injection gadolinium based contrast agent
ranges from 0.07% to 2.4%. The vast majority of these reactions are mild:
coldness at the injection site, nausea, headache, warmth or pain at the
injection site, paresthesias, dizziness and itching. Allergic reactions are
very unusual and vary in frequency from 0.004% to 0.7%. Rash, hives, or
urticaria are the most frequent, and very rarely there may be bronchospasm.
Life-threatening anaphylactoid or nonallergic anaphylactic reactions are
exceedingly rare (0.001% to 0.01%). [20]

Gadolinium agents are considered to have no nephrotoxicity at approved dosages
for MR imaging. Gadolinium based contrast agent administration to patients with
severe impairment of renal function (eGFR <30 mL/min) can result in a syndrome
of nephrogenic systemic fibrosis (NSF). Therefore no contrast will be
administered to this group of patients. [20]

By screening all patients as in clinical use before undergoing MRI, and by
additionally assessing previous adverse reactions to gadolinium based contrast
agents and renal function, the risk on adverse reactions is minimized.

With minimal burden for the studied group with good applicability towards the
study endpoint, the objective of the study outweighs the individual risk.