Molecular imaging of the solid renal mass: What does the future look like?

An important challenge in the current management of renal cell carcinoma (RCC) is the inability to differentiate between benign and aggressive tumors with conventional diagnostic imaging. The widespread use of abdominal imaging over the past 2 decades has led to increased diagnosis of incidental small renal masses (SRMs) and often overtreatment, with up to 30% of patients found to have benign tumors after undergoing partial nephrectomy.¹ Renal mass biopsy (RMB) remains an underutilized diagnostic adjunct for select patients with SRMs. Widespread utilization of RMB has been limited due to concerns of high rates of nondiagnostic biopsies and poor negative predictive value, in part due to tumor heterogeneity.^2,3 Additionally, liquid biopsies hold potential to improve diagnostic accuracy for patients with SRMs but remain investigational and not ready for clinical practice.⁴

Contemporary oncologic management seeks precise and personalized care through advanced diagnostic algorithms. In contrast to other cancers, patients with SRMs often undergo surgery without any information on the histology, biology, or aggressiveness of the tumor. To address this limitation, there has been increased focus on molecular imaging, which uses radionuclide-labeled molecular tracers targeting biological processes at the cellular and molecular levels that are highly specific for RCC.

The potential for molecular imaging to influence clinical practice was highlighted by the recently published ZIRCON trial (NCT03849118).⁵ This prospective, open-label, multicenter, phase 3 trial evaluated [⁸⁹Zr]Zr-girentuximab PET/CT imaging for detecting and characterizing clear cell RCC (ccRCC). Girentuximab is a monoclonal antibody that targets carbonic anhydrase IX (CAIX), a tumor-associated antigen highly expressed in ccRCC. In

a cohort of 284 patients undergoing partial or radical nephrectomy for indeterminate renal masses 7 cm or smaller, [⁸⁹Zr]Zr-girentuximab PET/CT accurately detected ccRCC with a mean sensitivity of 85.5% and a mean specificity of 87%. Among patients with renal masses 4 cm or smaller, who may be candidates for active surveillance, [⁸⁹Zr]Zr-girentuximab PET/CT remained accurate with a mean sensitivity of 85% and mean specificity of 89%. After exceeding the predefined sensitivity and specificity end points in the ZIRCON trial with a favorable safety profile, [⁸⁹Zr]Zr-girentuximab has been submitted for regulatory approval in many regions.

Although [⁸⁹Zr]Zr-girentuximab PET/CT is the most recent advanced application of molecular imaging in RCC, it represents one of several radiotracer strategies, each with distinct advantages and limitations related to tumor biology. One of the first agents examined was 18F-fluorodeoxyglucose (FDG) PET/CT, owing to its widespread use in other cancers to detect distant metastasis. Although 18F-FDG PET/CT demonstrates high sensitivity for extrarenal disease (91%) when compared with standard imaging, its utility in the detection of primary renal tumors is limited due to high physiologic uptake and excretion of FDG by the kidney, resulting in significant background interference.⁶

Prostate-specific membrane antigen (PSMA)–targeted PET/CT has shown promise for evaluating RCC, particularly metastatic RCC, owing to the high expression of PSMA in carcinoma-associated neovasculature. According to a recent meta-analysis, PSMA-targeted PET/CT showed a pooled PSMA detection rate of 0.74 in staging or evaluation of primary RCC lesions and 0.87 in restaging of metastatic or recurrent lesions.⁷ The results were notable for high heterogeneity among included studies, likely secondary to the differential expression of PSMA in different histological subtypes of RCC and the variable inclusion of these subtypes among included studies. PSMA expression is highest in ccRCC, significantly lower in chromophobe RCC, and very low or undetectable in papillary RCC.⁸ Therefore, PSMA-targeted PET/CT shows significantly improved sensitivity for detecting ccRCC (94.7%) as opposed to non-ccRCC (75%).⁹

It is important to note that all radiotracers discussed so far have been based on PET/CT, which represents a significant cost to the health care system and is inaccessible to many patients, particularly those in rural and underserved areas. To date, there are no published cost-effectiveness analyses that have evaluated PSMA- or CAIX-targeted PET/CT in RCC.

A more cost-effective and available solution may be the use of single-photon emission computed tomography (SPECT) combined with CT. SPECT/CT is cheaper than PET/CT and available in most hospitals. The most successful SPECT/CT radiotracer in RCC is ⁹⁹Tc-sestamibi, which detects oncocytomas with high sensitivity and specificity.¹⁰ However, there is potential to develop more SPECT/CT tracers to identify ccRCC or other histological subtypes. For example, there are promising phase 1 data for SPECT/CT using ^99mTc-PHC-102, a radiolabeled derivative of acetazolamide with high affinity to CAIX, which showed safety and effectiveness in both primary and metastatic ccRCC in a sample of 5 patients.¹¹

In the future, there may be a shift away from using monoclonal antibodies in molecular imaging, such as [⁸⁹Zr]Zr-girentuximab, which was used in the ZIRCON trial. Monoclonal antibodies have a relatively high molecular weight, which leads to slower uptake and tumor penetration. For example, [⁸⁹Zr]Zr-girentuximab requires intravenous injection 5 days before the PET/CT, increasing the burden on both patients and providers. To solve this issue, there are a handful of small-molecule ligands undergoing early clinical evaluation that target CAIX and can be delivered the same day as the PET/CT, including VM4-037, XYIMSR-06, and ⁴Cu-XYIMSR-06.¹²

Emerging evidence indicates that molecular imaging may enable more accurate detection of primary RCC, improve surveillance for recurrence, and enhance identification of metastatic lesions compared with conventional imaging. Molecular imaging may also be used to monitor response to specific treatments in the metastatic setting. For patients with SRMs, these imaging studies can serve as an adjunctive diagnostic tool to further risk-stratify the decision between primary intervention and active surveillance. In this setting, one important limitation is the lack of prognostic information provided. Although most SRMs behave in an indolent manner, a small subset behave more aggressively and have metastatic potential. Currently, we still lack the tools to accurately predict which SRMs will have aggressive behavior. Additionally, it is important to highlight that both PSMA- and CAIX-targeted PET/CT accurately detect ccRCC but perform poorly or are untested in other histological subtypes.

The future of molecular imaging for RCC is likely to be defined by increasing precision, accessibility, and integration into personalized oncologic care. The success of the ZIRCON trial with [⁸⁹Zr]Zr-girentuximab PET/CT demonstrates that highly specific tracers targeting tumor-associated antigens, such as CAIX, can improve the diagnostic accuracy of RCC and gain regulatory approval. The ultimate clinical utility of molecular imaging in RCC will rest on demonstrating cost-effectiveness, broader histologic applicability, and, perhaps most importantly, the ability to incorporate prognostic information into management algorithms to guide decisions for patients and providers.

REFERENCES

1. Kim JH, Li S, Khandwala Y, Chung KJ, Park HK, Chung BI. Association of prevalence of benign pathologic findings after partial nephrectomy with preoperative imaging patterns in the United States from 2007 to 2014. JAMA Surg. 2019;154(3):225-231. doi:10.1001/jamasurg.2018.4602

2. Patel HD, Johnson MH, Pierorazio PM, et al. Diagnostic accuracy and risks of biopsy in the diagnosis of a renal mass suspicious for localized renal cell carcinoma: systematic review of the literature. J Urol. 2016;195(5):1340-1347. doi:10.1016/j.juro.2015.11.029

3. Ball MW, Bezerra SM, Gorin MA, et al. Grade heterogeneity in small renal masses: potential implications for renal mass biopsy. J Urol. 2015;193(1):36-40. doi:10.1016/j.juro.2014.06.067

4. Zieren RC, Zondervan PJ, Pienta KJ, Bex A, de Reijke TM, Bins AD. Diagnostic liquid biopsy biomarkers in renal cell cancer. Nat Rev Urol. 2024;21(3):133-157. doi:10.1038/s41585-023-00818-y

5. 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):1277-1287. doi:10.1016/S1470-2045(24)00402-9

6. Ma H, Shen G, Liu B, Yang Y, Ren P, Kuang A. Diagnostic performance of 18F-FDG PET or PET/CT in restaging renal cell carcinoma: a systematic review and meta-analysis. Nucl Med Commun. 2017;38(2):156-163. doi:10.1097/MNM.0000000000000618

7. Sadaghiani MS, Baskaran S, Gorin MA, et al. Utility of PSMA PET/CT in staging and restaging of renal cell carcinoma: a systematic review and metaanalysis. J Nucl Med. 2024;65(7):1007-1012. doi:10.2967/jnumed.124.267417

8. Baccala A, Sercia L, Li J, Heston W, Zhou M. Expression of prostate-specific membrane antigen in tumor-associated neovasculature of renal neoplasms. Urology. 2007;70(2):385-390. doi:10.1016/j.urology.2007.03.025

9. Singhal T, Singh P, Parida GK, Agrawal K. Role of PSMA-targeted PET-CT in renal cell carcinoma: a systematic review and meta-analysis. Ann Nucl Med. 2024;38(3):176-187. doi:10.1007/s12149-024-01904-w

10. 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. doi:10.1016/j.eururo.2023.07.013

11. Kulterer OC, Pfaff S, Wadsak W, et al. A microdosing study with ^99mTc-PHC-102 for the SPECT/CT imaging of primary and metastatic lesions in renal cell carcinoma patients. J Nucl Med. 2021;62(3):360-365. doi:10.2967/jnumed.120.245530

12. Su ZT, Singla N, Allaf ME. Advances in molecular imaging for renal tumors. J Urol. 2024;211(6):794-796. doi:10.1097/JU.0000000000003904