Characterization of indeterminate renal masses with molecular imaging: how do we turn potential into reality?

The MIDOR (Molecular Imaging for Differential Diagnosis of Oncocytoma from Renal Cell Carcinoma) Trial, from which the manuscript by Tzortzakakis et al. [11] reports initial results, is the first report in the literature on the implementation of ^99mTc-sestamibi SPECT/CT outside of Johns Hopkins Hospital in Baltimore, MD, USA. Additional prospectively collected data are critical for validating the robustness of this imaging test across centers, scanners, and interpreting imaging experts. Ultimately, we can expect that the pearls and pitfalls of using ^99mTc-sestambib SPECT/CT for renal mass characterization will become most apparent with increased patient numbers. Additionally, larger datasets are required to ensure that all renal tumor histologies (some of which are quite rare) are studied in sufficient numbers to establish the various patterns of ^99mTc-sestamibi uptake.

SPECT imaging has long been considered a qualitative modality; however, new methods for attenuation correction, scatter correction, compensation for distance-dependent blurring/collimator-detector response, and partial volume correction have allowed for true quantitative SPECT to be performed [16]. While both Rowe et al. [9] and Gorin et al. [10] utilized a semi-quantitative method to describe the uptake of ^99mTc-sestamibi by renal masses, the method used in these reports (ratio of the highest count voxel in the mass to the highest count voxel in the ipsilateral renal parenchyma) is subject to potential error. Moreover, the images that were used for this analysis were from standard clinical non-quantitative acquisitions.

As Tzortzakakis et al. [11] astutely point out in the “Discussion” section of their manuscript that quantitative methods may be of importance for optimal characterization of renal masses with ^99mTc-sestamibi SPECT/CT. Although a visual analysis of renal masses imaged with ^99mTc-sestamibi SPECT/CT will always be an important part of interpreting these studies, a numerical threshold (as has been proposed by Gorin et al. [10]) may be a useful interpretational adjunct. However, determination of true SPECT standardized uptake values is likely to be a more reliable means of characterizing these tumors. Thus, further investigation of quantitative SPECT methodologies is needed.

The promise of ^99mTc-sestamibi SPECT/CT must be tempered by the fact that an imaging test that uses a single radiotracer can provide only limited information for characterizing indeterminate renal masses. Indeed, while ^99mTc-sestamibi uptake appears to allow for the reliable identification of benign/indolent oncocytomas and HOCTs [9‐11], not all masses that fail to accumulate ^99mTc-sestamibi will behave in an aggressive manner (e.g., chromophobe RCC and low-grade papillary RCCs). As such, the use of other radiotracers in addition to ^99mTc-sestamibi may allow for more complete risk stratification. Already, the radiolabeled monoclonal antibody ¹²⁴I-girentuximab has been used in a phase III clinical trial to identify clear cell RCCs using positron emission tomography (PET) imaging through binding to carbonic anhydrase IX (CAIX), a cell surface enzyme that is not expressed in normal renal tissue or by other renal tumor histologies [17]. New small molecule SPECT and PET radiotracers that target carbonic anhydrase IX are in preclinical development (for example [18] and [19]). The SPECT agent described in Yang et al. [18] is of particular interest given its labeling with ¹¹¹In which would allow for dual radiotracer SPECT in combination with ^99mTc-sestamibi.

Although lacking dual radiotracer capability, PET does have advantages over SPECT including established methods of quantitation and superior spatial resolution. As such, the development of PET radiotracers for renal mass characterization should be of significant interest to the field. As noted above, a CAIX PET radiotracer (¹²⁴I-girentuximab) has already been extensively studied and may prove clinically useful in the future [17]. Furthermore, mitochondrial PET imaging agents have been described for cardiac and non-cardiac applications [20, 21] and deserve to be explored for their potential utility in identifying mitochondrial-rich renal masses such as oncocytomas and HOCTs.