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

Background: ^99mTc-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 ^99mTc-sestamibi SPECT/CT for renal masses. Fifty renal masses imaged with ^99mTc-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 ^99mTc-sestamibi uptake. Results: 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 ^99mTc-sestamibi uptake in almost all tumors except chromophobe renal cell carcinoma. Conclusions: Our findings confirm that renal tumors with high mitochondrial content and relatively low MDR pump expression activity accumulate ^99mTc-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 ^99mTc-sestamibi SPECT/CT, allowing for high confidence in the diagnosis of renal cell carcinoma.