Molecular Imaging for the Indeterminate Renal Mass
Two tracers that read in opposite directions: ⁸⁹Zr-girentuximab for clear cell, ⁹⁹ᵐTc-sestamibi for oncocytoma.
Small renal masses turn up in their thousands on scans ordered for something else. Most are settled by CT. A minority sit in a grey zone between benign oncocytoma and clear-cell carcinoma, and a kidney is removed to settle the argument. The 2025 SNMMI/EANM/ACNM procedure standard addresses exactly that mass.
What makes a mass indeterminate
- Definition. A solid, enhancing, fat-free renal mass that imaging cannot name: in practice, oncocytoma against clear-cell RCC.
- Fat. Macroscopic fat means angiomyolipoma. Benign, and the workup stops there.
- Enhancement. A rise of 20 HU or more after contrast means vascular tissue.
- CT grey zone. Above 140 HU in the corticomedullary phase, 92% were clear cell; papillary tumours enhance weakly and late. But oncocytoma peaks as high as clear cell, so the two overlap.
- MRI grey zone. A clear cell likelihood score (ccLS) of 1 to 2 argues against clear cell (NPV 88%); 4 to 5 favours it (PPV 76%). ccLS 3 is clear cell in only 32%.
- Biopsy may not settle it. About 8% are non-diagnostic, and an oncocytic result does not exclude malignancy.
- FDG does not help. Renal excretion can bury the lesion.
Two targets, two tracers
- Carbonic anhydrase IX. VHL loss stabilises HIF-1α, which drives constitutive CAIX expression in clear-cell tumours; benign tissue expresses little. ⁸⁹Zr-girentuximab is the antibody against it.
- Mitochondria. Oncocytomas and chromophobe tumours are packed with them; clear-cell and papillary tumours downregulate them. ⁹⁹ᵐTc-sestamibi, a lipophilic cation, is drawn to the negative mitochondrial membrane potential.
| Tracer | Hot | Cold |
|---|---|---|
| ⁸⁹Zr-girentuximab PET | Clear-cell RCC (uptake above adjacent kidney) | Not clear cell: papillary, chromophobe, oncocytoma |
| ⁹⁹ᵐTc-sestamibi SPECT | Oncocytic tumours, chromophobe: benign or indolent | Clear-cell and papillary RCC: more aggressive |
Pearl
Girentuximab is hot only above the adjacent kidney; on sestamibi, any uptake localised to the tumour is hot, even below renal background. Sestamibi-cold and girentuximab-hot is almost certainly RCC; cold on both, consider biopsy.
The evidence
| Study | Design | Result |
|---|---|---|
| ZIRCON | Phase 3, 284 evaluable, masses ≤7 cm | Sensitivity 85.5%, specificity 87.0%; PPV 93%, NPV 75% |
| REDECT | ¹²⁴I-girentuximab against contrast-enhanced CT, 195 patients | Sensitivity 86.2% vs 75.5%; specificity 85.9% vs 46.8% |
| Sestamibi | Meta-analysis, 8 studies, 489 patients | Oncocytic tumours: sensitivity and specificity 89%; specificity 98% against clear-cell and papillary |
- Remember REDECT specificity: 86% against 47%.
- ⁸⁹Zr-girentuximab was not FDA-approved at the time of writing (a 2025 complete response letter cited manufacturing). Sestamibi costs under $50 and needs only SPECT/CT.
Doing the study
| ⁸⁹Zr-girentuximab | ⁹⁹ᵐTc-sestamibi | |
|---|---|---|
| Activity | 37 MBq (1 mCi) | 925 MBq (25 mCi) |
| Uptake time | 3 to 5 days | About 75 minutes |
| Half-life | 78 hours | 6 hours |
| Acquisition | PET/CT, single bed covering both kidneys | SPECT/CT, step-and-shoot 360° |
- Order matters. Sestamibi first: inject, wait 75 minutes, SPECT/CT, then inject girentuximab; PET/CT 3 to 5 days later. The reverse order needs a third visit about two weeks on, five ⁸⁹Zr half-lives.
- Report tracer, activity and uptake time; size, side and site of the mass; and a visual call: positive, negative or equivocal.
- Safety. In pregnancy, use ultrasound or MRI. Breastfeeding: pause 24 hours after ⁹⁹ᵐTc, longer after ⁸⁹Zr.
Take home
- Indeterminate means solid, enhancing and fat-free, where oncocytoma and clear-cell RCC cannot be told apart.
- Hot girentuximab means clear cell; hot sestamibi means benign or indolent. The two tracers read in opposite directions.
- Sestamibi first, or the ⁸⁹Zr half-life costs the patient a fortnight.
Sources
- Rowe SP, Shuch BM, Ball MW, et al. SNMMI/EANM/ACNM procedure standard/procedure guideline on the use of molecular imaging for renal mass characterization. J Nucl Med. 2025;66(12):1863-70.
- Shuch B, Pantuck AJ, Bernhard JC, et al. [89Zr]Zr-girentuximab for PET-CT imaging of clear-cell renal cell carcinoma: a prospective, open-label, multicentre, phase 3 trial. Lancet Oncol. 2024;25(10):1277-87.
- Divgi CR, Uzzo RG, Gatsonis C, et al. Positron emission tomography/computed tomography identification of clear cell renal cell carcinoma: results from the REDECT trial. J Clin Oncol. 2013;31(2):187-94.
- Basile G, Fallara G, Verri P, et al. The role of 99mTc-sestamibi single-photon emission computed tomography/computed tomography in the diagnostic pathway for renal masses: a systematic review and meta-analysis. Eur Urol. 2024;85(1):63-71.
- Pierorazio PM, Hyams ES, Tsai S, et al. Multiphasic enhancement patterns of small renal masses (≤4 cm) on preoperative computed tomography: utility for distinguishing subtypes of renal cell carcinoma, angiomyolipoma, and oncocytoma. Urology. 2013;81(6):1265-71.
- Schieda N, Davenport MS, Silverman SG, et al. Multicenter evaluation of multiparametric MRI clear cell likelihood scores in solid indeterminate small renal masses. Radiology. 2022;303(3):590-9.
- Silverman SG, Pedrosa I, Ellis JH, et al. Bosniak classification of cystic renal masses, version 2019: an update proposal and needs assessment. Radiology. 2019;292(2):475-88.
- Marconi L, Dabestani S, Lam TB, et al. Systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. Eur Urol. 2016;69(4):660-73.
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