Correlation of 99mTc-sestamibi uptake in renal masses with mitochondrial content and multi-drug resistance pump expression

Steven P. Rowe, Michael A. Gorin, Lilja B. Solnes, Mark W. Ball, Ajuni Choudhary, Phillip M. Pierorazio, Jonathan I. Epstein, Mehrbod S. Javadi, Mohamad E. Allaf, Alex S. Baras

(99m)Tc-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) has recently been explored for the characterization of indeterminate renal masses. As judged by increased intra-tumoral radiotracer uptake, we have previously reported the excellent diagnostic performance characteristics of this test for identifying benign/indolent oncocytomas and hybrid oncocytic/chromophobe tumors (HOCTs). In this study, we investigated potential molecular mechanisms underlying the discriminatory ability of (99m)Tc-sestamibi SPECT/CT for renal masses. Fifty renal masses imaged with (99m)Tc-sestamibi SPECT/CT prior to surgical resection were evaluated by immunohistochemistry for mitochondrial content and expression of the multi-drug resistance pump 1 (MDR1/P-gp). Immunohistochemical staining was scored semi-quantitatively, and results were compared across renal tumor histologies and correlated with (99m)Tc-sestamibi uptake. In total, 6/6 (100%) and 2/2 (100%) HOCTs demonstrated strong mitochondrial content staining combined with low MDR1 staining. Clear cell renal cell carcinoma showed an opposite pattern with the majority having low mitochondrial (14/26, 54%) and high MDR1 staining (18/26, 69%). Other tumor types were more variable in staining pattern, although the staining pattern reliably predicted (99m)Tc-sestamibi uptake in almost all tumors except chromophobe renal cell carcinoma. Our findings confirm that renal tumors with high mitochondrial content and relatively low MDR pump expression activity accumulate (99m)Tc-sestamibi and allow for the accurate diagnosis of the benign/indolent tumor class that includes oncocytomas and HOCTs. For masses in which MDR activity outweighs the presence of mitochondria, the tumors appear cold on (99m)Tc-sestamibi SPECT/CT, allowing for high confidence in the diagnosis of renal cell carcinoma.