{
  "abstract": "Conventional diagnostic strategies for imaging patients with renal cell carcinoma (RCC) have predominantly relied on ultrasonography, CT and MRI. However, a paradigm shift is underway with the emergence of several new radiotracers for molecular imaging. Carbonic anhydrase IX (CA-IX) imaging and sestamibi imaging can assist with identifying malignant renal tumours, whereas fluorodeoxyglucose, prostate-specific membrane antigen and CA-IX tracers can give guidance for diagnosis and staging of RCC. These tracers can assist in enabling better decision-making by minimising overtreatment of renal masses with biopsy, better selecting patients for curative-intented management and optimising treatment for patients with oligo-metastatic disease, among other emerging indications. However, none of them is yet recommended as a standard clinical diagnostic procedure. In this review, we investigate the latest developments in molecular imaging for detecting and staging RCC, aiming to advance precision diagnosis and improve patient outcomes.",
  "authors": [
    {
      "affiliations": [
        "Prostate Cancer Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia"
      ],
      "name": "Jasmin Weindler"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia",
        "Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia"
      ],
      "name": "Muhammad Ali"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, GenesisCare, Melbourne, Victoria, Australia"
      ],
      "name": "Cristian Udovicich"
    },
    {
      "affiliations": [
        "Prostate Cancer Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia",
        "Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia"
      ],
      "name": "Michael S Hofman"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia",
        "Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia"
      ],
      "name": "Shankar Siva"
    }
  ],
  "full_text": "Introduction Renal cell carcinomas (RCC) account for 3% of all cancers worldwide, 1 2 with a 5-year survival rate decreasing from 93% for localised to 12% for advanced RCC.1 3–5 RCC classification includes clear cell RCC (ccRCC, 80%) and non-clear cell RCC (non-ccRCC), which includes papillary RCC (pRCC, 10%–15%), chromophobe RCC (4%–5%) as well as other subtypes often identified through molecular analysis, such as succinate dehydrogenase-deficient RCC.6 Histological features like sarcomatoid differentiation or rhabdoid features are associated with high grade and aggressive tumour behaviours with poor prognosis.6There are no specific blood markers for RCC, and it is often diagnosed incidentally via imaging studies conducted for other reasons. Most incidentally diagnosed renal tumours have a size <4 cm and are consistent with stage T1 RCC (with size ≤7 cm; 80%–90%)3 7 8 but also include benign tumours (10%–20%), for example, oncocytomas or hybrid oncocytic chromophobe tumours (HOCT).7 8 Depending on CT/MRI results, the next step can include a renal biopsy or a partial nephrectomy.8 9 Biopsies are invasive, with an 80%–90% diagnostic accuracy, but 10%–20% yield in indeterminate findings. Although uncommon, biopsies can be complicated by retroperitoneal bleeding,8 10 whereas proceeding directly to partial nephrectomy may result in overtreatment, especially in small kidney masses with a higher likelihood for benign cases (up to 20%).11 12 12–14Given the risk of adverse effects or overtreatment from decisions based on imaging alone, there is a pressing need for improved diagnostic modalities. Currently, positron emission tomography (PET)/CT is not part of the standard procedure according to the European Society of Medical Oncology 2024 update and the guidelines of the European Association of Urology.15–17 Therefore, this review aims to provide an overview of various molecular imaging tracers, their use and their advantages and disadvantages.Methods We conducted a narrative review of the literature to synthesise current evidence on molecular imaging of RCC. The search focused on English-language articles and conference abstracts published within the last 10 years, pertaining to molecular imaging and nuclear medicine in RCC. Relevant articles were identified based on the keywords renal cell carcinoma/RCC, renal mass, specific tumour stages (localised RCC, metastatic RCC), molecular imaging, including Sestamibi/MIBI, prostate-specific membrane antigen (PSMA), fluorodeoxyglucose (FDG), carbonic anhydrase IX (CA-IX), girentuximab, vascular endothelial growth factor (VEGF) and cluster of differentiation 70 (CD70). Given the narrative nature of this review, no formal inclusion/exclusion criteria or quality appraisal tools were applied.Diagnostic of renal masses Limitations of conventional imaging The Bosniak classification is widely used to predict malignancy risk for cystic masses and guide decision-making. 18 In contrast, solid renal masses are assessed for contrast enhancement or restriction, although differentiating malignant from benign, such as chromophobe RCC, benign oncocytoma or fat-free angiomyolipoma, is challenging owing to shared features.2 19 20 Additionally, collecting duct carcinoma, a rare and aggressive tumour, lacks specific radiological characteristics, making it difficult to assess with conventional imaging.20 Dual-energy CT may help address these difficulties, but further research is needed to evaluate its value.20 [99mTc]Tc-Sestamibi single PET (SPECT)[99mTc]Tc-Sestamibi is a widely used tracer that accumulates in mitochondria-rich tissues.8 21 Several studies have explored its use in differentiating indeterminate renal masses, for example, oncocytomas and HOCT, from RCC.8 21–23 RCCs, being poor in mitochondria, express multidrug-resistance pumps that actively efflux (99mTc)Tc-Sestamibi, whereas oncocytomas and HOCT are known to be mitochondria-rich.8 22 24Basile et al reviewed eight studies with 501 renal masses, showing a good differentiation of oncocytomas/HOCT with a specificity of 89% and sensitivity of 89% by [99mTc]Tc-Sestamibi from RCC.7 A pooled sensitivity and specificity up to 86% and 91%, as well as detection rates ranging between 67% and 89.5%, have been reported for [99mTc]Tc-Sestamibi-SPECT in differentiating benign from malignant renal tumours using lesion-to-kidney ratios without clear cut-offs being reported.7 8 25 Parihar et al. suggested a lesion-to-kidney ratio of 0.64 as a cut-off but also introduced the concept of combining lesion-to-kidney ratio with Hounsfield units on SPECT/CT in a retrospective design.8 For renal tumours <7 cm, a lower sensitivity of 88.6% and specificity of 77% of differentiation between malignant and benign findings have been reported for the use of [99mTc]Tc-Sestamibi-SPECT compared with the review of Basile et al.7 25 Sistani et al. suggested improving diagnostic accuracy by correlating [99mTc]Tc-Sestamibi uptake with morphological changes in the tumour (e.g., cystic proportions, haemorrhagic and necrotic changes) to enhance sensitivity in a prospective study.11 Ali et al cautioned against [99mTc]Tc-Sestamibi in general practice due to the heterogeneity of studies and limited data on other tumour types26 (table 1).Table 1Comparison of tracers and their advantages and disadvantages for RCC and renal massesTracerMechanismSettingAdvantagesDisadvantagesFDG Glucose metabolismLocoregional RCC staging.Metastatic RCC staging.Therapy response.High SUVmax (>8.8) correlates with poor prognosis and aggressive RCCs (accuracy up to 90%).42Beneficial for aggressive tumour histology.42 43Moderate to high sensitivity (up to 86%) and specificity (up to 88%) for detecting distant metastases.15Widely available.Overall low diagnostic accuracy in RCC (slow and fast growing RCC, 59.1%).25 38 39Low TBRs.40[68Ga]Ga-PSMA Tumour-associated neovasculatureLocoregional RCC staging.Metastatic RCC staging.Therapy response assessment.Theranostic agent [177Lu]Lu-PSMA possible.Good detection of ccRCCs.53 55Higher SUVmax than FDG.56Better diagnostic accuracy compared with FDG (86.4% vs 59.1%).57Superior for identification of bone metastases and reactive lymphadenopathy than CT.20 39 53High baseline total tumour volume and total lesions in [68Ga]Ga PSMA-PET associated with models for poor prognosis.72Impact on clinical management up to 48% reported.60Widely available.Low TBR for lesions close to the kidney cortex.40Treatment with [177Lu]Lu-PSMA limited due to possible faster PSMA washout because of neovasculature.74 75CA-IX tracers Antibody against CA-IX:[89Zr]Zr-girentuximabDifferentiation of renal masses.Primary ccRCC staging.High expression of CA-IX in ccRCC.30Sensitivity of 85.5% and specificity of 87% reported.36Good TBR.34–36Low SUVmax towards longer periods of watch and wait.46Superior to CT and FDG in detection of metastatic ccRCCs with good or intermediate prognosis.45 46Not widely available yet.Limited clinical experiences outside of trials yet.36 45 46 Small molecule against CA-IX: [68Ga]Ga-DPI-4452Differentiation of renal masses.Primary ccRCC staging.Theranostic approach.Very good TBR—[68Ga]Ga-DPI-4452 with SUVmax >10048[[68Ga]Ga-DPI-4452 results in on site on demand production, lower activity and rapid tumour uptake.48Theranostic agent [177Lu]Lu-DPI-4452 is promising.48Not widely available yet.Limited clinical experiences outside of trials yet.48Side effects of radiation gastritis when used for theranostics.[68Ga]Ga-FAPI FAP expression of cancer-associated fibroblastPrimarily metastatic RCC staging.Favourable TBR.77Case reports of high [68Ga]Ga-FAPI uptake in aggressive metastatic RCCs available.42 76High interindividual and intraindividual differences in [68Ga]Ga-FAPI-uptake.77Only few studies available (up to a case series of 20 patients).77Sestamibi Mitochondria-rich tissueDifferentiation of renal masses (especially identification of oncocytomas and hybrid oncocytic chromophobe tumours).High specificity and sensitivity (up to 89%) to differentiate benign and malignant kidney tumours.7 8Difficulty to differentiate benign lesions from chromophobe and oncocytic RCCs.11 27No clear lesion-to-kidney-ratio cut-offs available.7 8 25Wide range of reported sensitivity and specificity.7 8 26CA-IX, carbonic anhydrase IX; ccRCC, clear cell RCC; FAP, fibroblast activation protein; FAPI, FAP inhibitor; FDG, fluorodeoxyglucose; PET, positron emission tomography; PSMA, prostate-specific membrane antigen; RCC, renal cell carcinoma; SUVmax, maximum standardised uptake value; TBR, tumour-to-background ratio.Despite the benefits, [99mTc]Tc-Sestamibi-SPECT has limitations. Chromophobe and oncocytic RCC also accumulate [99mTc]Tc-Sestamibi, limiting its use in these tumours,11 27 which are typically indolent with low metastatic potential.28 Additionally, some oncocytoma subtypes may not express mitochondria, leading to misdiagnosis as RCC.8 SPECT and SPECT/CT also have more limited spatial resolution and slower imaging than PET/CT.29[89Zr]Zr-girentuximab-(CA-IX antibody) PET/CTCarbonic anhydrase IX (CA-IX) is highly and homogenously expressed in >95% of ccRCC cases due to the frequent loss of the Von-Hippel-Lindau gene, resulting in activation of hypoxia-inducible factor 1α (HIF-1α), making it a promising target.30 In general, CA-IX is upregulated by hypoxia and HIF-1α is a known marker for hypoxia, but in ccRCC, high CA-IX expression is due to activation of HIF-1α in the absence of a hypoxic environment and can be used to differentiate between ccRCC and non-ccRCC.30–33 Promising results with [124I]I-girentuximab PET/CT, a radiolabelled antibody with hepatobiliary excretion, in a prospective trial34 led to the development of [89Zr]Zr-girentuximab due to higher rates of tumour clearance and renal excretion of 124I.35 89Zr has a half-life of 3.2 days, enabling imaging at an optimal period of 5 days postinjection, necessitating a separate visit for imaging after administration of the tracer, which can be challenging for patients.36 At the moment, [89Zr]Zr-girentuximab is available only in certain access programmes around the world (especially the USA, Europe and Australia), which may improve after the recent approval of the US Food and Drug Administration.The Zircon phase III trial with 332 patients showed 85.5% sensitivity and 87% specificity for [89Zr]Zr-girentuximab in detecting localised ccRCC, supporting its potential for assessing renal masses.36 In this trial, patients with indeterminate renal tumours ≤7 cm were enrolled and underwent [89Zr]Zr-girentuximab PET/CT before surgery. Only abdominal PET/CT was performed as standard with the option of whole-body imaging in case of evidence of unsuspected metastatic disease, resulting in limited data for oligometastatic ccRCC (see figure 1). Interestingly, sensitivity and specificity were highest in indeterminate renal mass ≤2 cm (90%–100% and 90%–100%, respectively) in a total of 20 patients (7% of all patients). No clear cut-off for maximum standardised uptake value (SUVmax) for differentiation between ccRCC and non-ccRCC could be found, but SUVmax values ranged between 24.1 and 25.2 within the three readers reporting the scan. All PET-positive lesions were malignant36 (table 1).Figure 1Initial staging with [89Zr]Zr-girentuximab in a patient with ccRCC. Male patient with a ccRCC WHO/ISUP grade 1. On CT contrast, a suspicious lesion of the left kidney was seen with contrast enhancement and septal changes (C). Performance of [89Zr]Zr-girentuximab PET/CT revealed a highly avid renal lesion (SUVmax 43) suspicious for ccRCC (A and B). ccRCC, clear cell renal cell carcinoma; PET, positron emission tomography; SUV, standardised uptake value; ISUP, International Society of Urological Pathology.However, chromophobe and papillary RCC express CA-IX considerably lower than ccRCC, meaning CA-IX imaging may miss these subtypes.30 The Zircon trial focuses on sensitivity and specificity but did not fully articulate how this new imaging modality will be integrated into clinical care to change patient management and improve outcomes.Staging of RCC Staging of locoregional RCC FDG-PET/CT RCC is a heterogeneous tumour and can vary in phenotype from slowly to rapidly progressive variants, with both having the potential to metastasise despite their differing proliferation rates. FDG-PET/CT has proved highly accurate for aggressive tumours on the basis that tumours primarily use glycolytic metabolism for proliferation. Due to their slow proliferation rate, slowly growing tumours are typically not visualised on FDG-PET/CT. FDG uptake can be low in RCC, 37 which has led to reports of low sensitivity, for example, 53.5% for RCCs ≤7 cm,25 38 even lower than CT.39 Moreover, since FDG is eliminated by the kidneys, the tumour-to-background ratio (TBR) for the evaluation of primary tumours is not optimal. Attempts to enhance the sensitivity of FDG uptake in the kidneys using diuretics have been unsuccessful.40However, these reports focused on sensitivity and specificity for lesion identification and do not consider the potential of FDG-PET/CT to characterise disease aggressiveness, which has generally been considered within histopathology. Intraindividual tumour heterogeneity may, however, explain the difficulties encountered in the validation of oncological biomarkers owing to sampling bias when using a single site and may explain unpredictable therapeutic responses when using conventional treatment paradigms. A retrospective study shows increased metabolic activity on FDG-PET/CT in high-risk ccRCC compared with benign lesions and low-grade tumours.41 A high SUVmax with a cut-off >8.8 correlates with poor prognosis and significantly reduced survival compared with patients with an SUVmax <8.8,42 while in pRCC, an SUVmax >3.8 is linked to shorter progression-free survival and worse outcomes.43 In those studies, FDG-PET/CT has altered clinical management by detecting occult metastases missed by conventional imaging in 30% of RCC and 16.7% of patients with pRCC.42–44 While not recommended as a standard diagnostic tool for RCC, FDG-PET/CT can help identify aggressive subtypes with potential influence on treatment decisions (table 1).CA-IX antibody and peptide PET/CT Like detecting localised ccRCC, [ 89Zr]Zr-girentuximab PET has shown encouraging results in staging ccRCC.36 45 In a prospective trial of 42 patients with newly diagnosed good- or intermediate-risk metastatic ccRCCs, [89Zr]Zr-girentuximab PET/CT detected more lesions than either CT or FDG-PET/CT alone (total of 449 lesions; 70% vs 56% vs 59%, respectively). Moreover, the detection rate was higher than FDG-PET/CT and CT combined, with the highest improvement of bone lesions (91% vs 84%, respectively). Despite better delineation of disease, the SUVmax of [89Zr]Zr-girentuximab PET did not show any predictive utility over clinical criteria for the watchful waiting approach.45 46 Indeed, risk stratification systems, such as the International Metastatic RCC Database Consortium (IMDC), are available to identify patients benefiting from watchful waiting. Verhoeff et al could confirm that ≤2 IMDC criteria and involvement of ≤2 organ sites are associated with prolonged periods of watchful waiting.46Due to rapid clearance and smaller molecular weight, radiolabelled peptides targeting CA-IX may offer an advantage over the high molecular weight radiolabelled antibody CA-IX PET/CT.30 Hofman et al. demonstrated striking TBR contrast with DPI-4452, a 68Ga-cyclic peptide that binds to CA-IX, in a prospective case series of three patients with metastatic ccRCC. With SUVmax of over 100 within tumours, [68Ga]Ga-DPI-4452 PET/CT identified 17 lesions out of a total of 36 that would otherwise have been missed by conventional imaging (see figure 2). Compared with antibody PET/CT imaging, 68Ga peptides have the advantage of on-site on-demand production, with rapid tumour uptake and plasma clearance, resulting in optimal imaging of around 60 min.47 These properties enable the completion of imaging in a single clinic visit with a lower radiation burden and rapid PET/CT imaging compared with a return visit and slower imaging with 89Zr owing to low count rates at that time. DPI-4452 can also be labelled to beta emitters like 177Lu, making it a potential theranostic agent48 (table 1). The use of DPI-4452 and other CA-IX molecules as a theranostic agent needs consideration of physiological CA-IX expression, which is highest in the stomach, small intestine and the gallbladder.31 48 Here, the risk of causing radiation-induced side effects, such as radiation gastritis, is possible.48 Further research on the occurrence of such side effects and possible treatment options, such as carboanhydrase inhibitors (e.g., acetazolamide), is needed.Figure 2Initial staging with [68Ga]Ga-DPI-4452-PET/CT in a patient with ccRCC. Male patient with known metastatic ccRCC. PET/CT using a [68Ga]-labelled peptide binding to carbonic anhydrase IX (DPI-4452) demonstrated metastatic disease in bones and lung and the primary in the right kidney. Sites of metastases of 7–8 mm in size could easily be identified owing to high tumour uptake. Physiological uptake is within the gastric wall and small bowel. ccRCC, clear cell renal cell carcinoma; PET, positron emission tomographyPSMA PET/CT Imaging with [ 68Ga]Ga-PSMA or [18F]-PSMA-PET/CT has been successfully introduced for improved lesion detection in prostate cancer. In addition to prostate cancer,49 50 PSMA is overexpressed in the neovasculature of several solid tumours, including RCC, making [68Ga]Ga-PSMA-PET/CT a potentially useful functional imaging modality in vascular tumours.51Physiological expression of PSMA includes proximal tubes of the kidneys, making the detection of tumours close to the renal cortex difficult due to low TBRs.52 Aggarwal et al highlighted the superior effectiveness of PSMA-PET/CT compared with CT in identifying primary or locally recurrent RCCs in a prospective study.53 Another prospective case series by Golan et al showed that dynamic [68Ga]Ga-PSMA-PET/CT could distinguish between malignant and benign lesions using SUVmax values (9.4 and 3.8, respectively) and PSMA washout coefficients.54Gaudreault et al used PSMA-PET/CT to assess the feasibility of biology-guided radiotherapy targeted to metastatic RCC. Interestingly, another PSMA tracer [18F]F-DFCPyL showed statistically lower SUVmax values than [68Ga]Ga-PSMA in RCC.55Compared with [18F]F-FDG-PET/CT, [68Ga]Ga-PSMA-PET/CT showed significantly better results for primary tumour diagnosis (86.4% vs 59.1%) with higher SUVmax values (15.7±9 vs 5.1±3.4)56 and higher diagnostic accuracy.57 However, both modalities may have complementary roles, and the role of dual radiotracer PET/CT to characterise tumour biology rather than merely identify sites of disease warrants further research, as has been shown in endocrine malignancies58 59 (figure 3 and table 1).Figure 3[18F]F-FDG-PET/CT and [68Ga]Ga-PSMA-PET/CT in a patient with localised ccRCC of 4.9×4.2 cm in contrast CT (B). Male patient with a diagnosis of ccRCC WHO/ISUP grade 2 of the left kidney. The FDG-PET/CT shows low non-specific uptake in the renal lesion (SUVmax 3.3) (E and D), whereas the lesion showed intense and suspicious PSMA expression (SUVmax 17.2) (A and C), fitting to a ccRCC. ccRCC, clear cell renal cell carcinoma; FDG, fluorodeoxyglucose; PET, positron emission tomography; PSMA, prostate-specific membrane antigen; SUVmax, maximum standardised uptake value; ISUP, International Society of Urological Pathology.Staging of metastatic RCC FDG-PET/CT At the time of initial staging, 10%–15% of RCC cases present as metastatic disease, and 20% of the remaining cases eventually develop metastases. 60 61 Here, metastases can be found, for example, in lymph nodes, bone, lung, adrenal, liver, pancreas and muscle.60 62Despite its limited role in characterising primary RCC, FDG-PET/CT has shown promising results in detecting early metastatic disease compared with CT. In one study, Bertagna et al reported additional histologically confirmed metastases that were missed on CT using FDG-PET/CT.63 In a systematic review and meta-analysis, Ma et al found pooled sensitivity and specificity of 86% and 88% for FDG-PET/CT, respectively, for detecting distant metastases.15 Similarly, FDG-PET/CT has higher accuracy and negative predictive value for detecting recurrence or metastatic disease in patients with high-risk RCC.64 Additionally, FDG-PET/CT outperforms conventional imaging for identifying musculoskeletal metastases and is widely available and commonly experienced in reporting.65FDG-PET/CT can also stratify prognosis, as Toguchi et al achieved 90% accuracy for the assessment of disease-free survival using SUVmax cut-offs (8.7 for ccRCC and 8.9 for all RCC up to T2b stage) in a preoperative setting.66 Additionally, a high SUVmax (>8.8 for ccRCC) correlates with poor prognosis, which can be helpful for clinical decisions of tumours suspicious for aggressive behaviours due to histopathological features.42 In contrast, an SUVmax <3 indicates a better prognosis in metastatic ccRCC with a low- to intermediate-risk constellation.46 Furthermore, adding FDG SUVmax to the clinical criteria for watch and wait improved the prediction of watchful waiting in patients with low- to intermediate-risk disease46 (table 1).PSMA-PET/CT In metastatic RCC, [ 68Ga]Ga-PSMA-PET/CT detected 55% more bone metastases than conventional imaging, though CT identified more liver metastases in a prospective study of 37 patients.20 53 Raveenthiran et al found that regional nodes of six patients suspicious on CT showed no pathological PSMA uptake, suggesting reactive lymphadenopathy. However, three new synchronous primaries were identified by PSMA-PET/CT, resulting in management changes for 43.8% of patients.67 Gasparro et al further demonstrated that [68Ga]Ga-PSMA-PET/CT identified significantly more metastases than conventional imaging.68Udovicich could show in a retrospective study that [68Ga]Ga-PSMA-PET/CT could detect 25% more lesions than CT but also 26% fewer lesions identified with CT, resulting in a detection rate of 84% for [68Ga]Ga-PSMA-PET/CT and 94% for CT. Here, 7 of 10 [68Ga]Ga-PSMA-negative patients had CT-proven metastases, whereas one of four CT-negative patients had [68Ga]Ga-PSMA-avid metastases. In this study, 40 patients also underwent FDG-PET/CT in order to assess the presence of PSMA-negative FDG-positive lesions. FDG-PET/CT led to a detection rate of 75% (30/40 patients), whereas PSMA-PET/CT had a detection rate of 88% (35/40 patients). Most patients had PSMA-positive FDG-positive metastases (70%, 28/40) with lower probabilities for PSMA-negative FDG-negative (7.5%, 3/40), PSMA-positive FDG-negative (17.5%, 7/40) or PSMA-negative FDG-positive metastases (5%, 2/40). Overall, SUVmax was higher in PSMA than in FDG-PET/CT (see figures 2 and 3)The addition of FDG and PSMA-PET/CT led to changes in clinical management towards systemic therapy/surveillance instead of metastasis direct therapy (MDT) (23%), MDT instead of surveillance (10%) and MDT for additional sites (7%). PSMA-PET/CT had a major impact on clinical management in 48%.60 A case series of eight patients with oligometastatic RCC revealed that PSMA-PET/CT showed higher tumour avidity than FDG-PET/CT; however, treatment-induced changes postradiation were detected earlier with FDG-PET/CT (3–4 months) compared with PSMA-PET/CT (6–12 months).69In addition, a case report of metastatic RCC with sarcomatoid differentiation demonstrated the utility of dual-tracer molecular imaging: [68Ga]Ga-PSMA-PET/CT identified slow-growing ccRCC disease sites (eg, recurrence in nephrectomy bed). At the same time, FDG uptake highlighted fast-growing biopsy-confirmed sarcomatoid lung metastases, reflecting tumour heterogeneity.70 Dual-tracer imaging can assess metastatic aggressiveness, guide biopsy site selection and improve patient outcomes70 71 (see figure 4 and table 1).Figure 4[18F]F-FDG-PET/CT and [68Ga]Ga-PSMA-PET/CT in a patient with metastatic castration-resistant prostate cancer. The patient underwent [18F]F-FDG-PET/CT (A and C) and [68Ga]Ga-PSMA-PET/CT (D and E) for discussion of Lu-PSMA therapy and the [18F]F-FDG-PET/CT revealed new osseous, adrenal and muscle metastases, which led to the diagnosis of metastatic RCC with sarcomatoid differentiation. ccRCC, clear cell renal cell carcinoma; FDG, fluorodeoxyglucose; PET, positron emission tomography; PSMA, prostate-specific membrane antigen.Also, several risk stratification models like IMDC are used for RCC to identify patients with poor prognostic factors. Here, one prognostic trial showed that high baseline total tumour volume and a high number of total lesions in [68Ga]Ga-PSMA are prognostic correlates with therapy response for cabozantinib, a VEGF inhibitor, for ccRCC.72 In RCC, ccRCC shows the highest PSMA expression, whereas PSMA expression is lowest in pRCC.60While PSMA-PET/CT also offers the possibility of a theranostic approach with [177Lu]Lu-PSMA in prostate cancer,73 this approach may not translate to ccRCC. This is likely due to PSMA expression in tumour neovasculature in ccRCC rather than cell surface expression as occurs in prostate cancer. This results in washout of 177Lu rather than retention of the radioligand. 177Lu, with a 7-day half-life, requires radioligand retention to be effective.74 Nevertheless, trials are underway to further evaluate this.60 75Fibroblast activation protein inhibitor (FAPI)-PET/CT [ 68Ga]Ga-FAPI-PET/CT has recently gained attention in cancer imaging for providing insights into the tumour microenvironment. Fibroblast activation protein (FAP) is expressed on cancer-associated fibroblasts, which are often linked to poor prognosis. While several tumours, for example, gastro-oesophageal and head and neck cancers, show high FAPI expression, its role in renal cancer has been less explored yet.76 In the largest study of 20 patients with new or recurrent RCC, Civan et al observed moderate to high FAPI expression in lesions suspected of RCC. [68Ga]Ga-FAPI-PET/CT demonstrated a favourable TBR due to low renal expression and elimination, aiding RCC detection.77 [68Ga]Ga-FAPI SUVmax of RCC lesions differs quite widely intrapatient and interpatient due to the heterogeneity of RCCs.77 Interestingly, FAPI uptake was higher in patients with recurrent RCC compared with FDG uptake.77High [68Ga]Ga-FAPI uptake has also been reported in sarcomatoid RCC metastases. Imaging FDG or [68Ga]Ga-FAPI may enhance lesion detection in aggressive RCCs, as FDG uptake is associated with poor prognosis for ccRCC, and [68Ga]Ga-FAPI expression has been linked to poor prognosis in several tumours.42 76 The role of FAPI compared with PSMA or CA-IX PET/CT imaging approaches is uncertain, and further prospective studies are needed to further define their roles77–79 (table 1).However, diagnosing RCC with [68Ga]Ga-FAPI presents some challenges. For example, lipid-poor angiomyolipoma, a benign kidney tumour, is often mistaken for RCC on conventional imaging and on [68Ga]Ga-FAPI expression due to its high expression.80 81 Similarly, xanthogranulomatous pyelonephritis, a rare granulomatous and chronic inflammatory kidney condition, can mimic malignancy with high [68Ga]Ga-FAPI and FDG uptake.77 82Other novel radiopharmaceuticals CD70 is overexpressed in several malignancies, such as RCC. 83 Physiologically, it is needed for an effective immune response and in malignancies, it can lead to immune suppression.84–86 This is due to the interaction between CD70 and its receptor CD27, which has a cytotoxic effect on B and T lymphocytes by inducing apoptosis.84 86 87 High expression of CD70 was seen in ccRCC, pRCC and sarcomatoid RCC, making it an interesting target for molecular imaging.84 Further advantages of CD70 tracers for RCC include high specificity for RCC and generally low background activity, with unfortunately high uptake in the kidneys. The first use of 18F-labelled CD70 antibodies within preclinical and human clinical trials has shown promising results in metastatic RCC, but identification of the most promising tracer, as well as further research, is needed.88 89Due to the use of several new tracers for RCC in recent years, the development of further new approaches for tracers is of interest. In general, a highly specific molecular target as well as low background uptake is important for successful molecular imaging. Here, some of the existing tracers, such as FDG and PSMA, show high background activity due to renal elimination, and research on possibilities to reduce renal background can improve their use. However, CA-IX imaging, especially with small peptides, offers a highly specific molecular target as well as low renal activity, making it a promising tracer for RCC diagnostics and theranostics. Further research on CA-IX imaging and its clinical value is therefore of great interest.90Due to the tumour heterogeneity of RCC, the use of multiple tracers can be of interest to improve exact diagnosis.70 91 This can lead to the standard use of several tracers in metastatic RCC, resulting in a more challenging diagnosis instead of one main tracer, such as PSMA for prostate cancer.49 92 Furthermore, there remains an unmet need to provide prognostic information. For instance, while CA-IX imaging can detect a greater number of metastases compared with conventional imaging, data on its survival benefit and therapeutic impact are still limited.45 46 48 Further research is needed to clarify how the information obtained from molecular imaging can be used to improve clinical outcomes and to distinguish indolent tumours from aggressive ones.Pretherapeutic assessment of the kidney function Prior to renal surgery, a comprehensive assessment of the size, morphology, perfusion and function of both kidneys is essential, given that one kidney may be partially or entirely resected. 93 94 A reduced renal function is associated with an increased cardiovascular risk and a mortality rate of 20%–50% in severe injury.95–97 In the short term (up to 6 months) following renal mass surgery, renal function tends to remain stable or may even slightly improve due to compensatory mechanisms.98 However, over a longer period of 10 years, a progressive decline in renal function has been observed in 22.4% of the patients.99 Key parameters for renal function include the split renal function and the glomerular filtration rate (GFR).The most common method for estimating GFR involves calculating creatinine clearance or, less often, cystatin C in blood serum. However, this approach has several limitations, such as differences in muscle mass and the delay in detection of kidney damage.100 101 For a more precise measurement, dynamic scintigraphy with [51Cr]Cr-ethylenediaminetetraacetic acid (EDTA) and [99mTc]Tc-diethylenetriamine pentaacetic acid (DTPA), which are exclusively secreted via glomerular filtration, can be employed. This technique enables the calculation of total renal function and plasma flow. [51Cr]-EDTA is superior to [99mTc]TC-DTPA due to its similarity to the gold standard inulin, since DTPA can show varying pharmacokinetics.102–107 In case of compromised renal function, [99mTc]Tc-mercaptoacetyltriglycine is often preferred for patients with compromised renal function, as it undergoes both glomerular filtration (10%) and tubular secretion via the organic anion transport 1 (90%).108 109 Dynamic renal scintigraphy with those tracers is used to evaluate renal perfusion, total renal function and potential outflow tract obstruction. Moreover, they can be used for the assessment of split renal function, but this is limited due to the difficult assessment within the first 3–4 min before tracer uptake in the urine collecting system can be seen.107If an assessment of split renal function or intrarenal function distribution is required, static imaging with [99mTc]Tc-dimercaptosuccinic acid (DMSA) is recommended. DMSA is used for static imaging because it undergoes glomerular filtration and tubular secretion, with only a minor proportion (10%–15%) being excreted, followed by uptake by proximal convoluted tubular cells. Optimal imaging is performed 2–3 hours postinjection, at which point approximately 40%–50% of the agent is bound within the renal cortex.107 110Interestingly, several studies have indicated that renal function is frequently underestimated by nuclear medicine imaging, potentially due to increased vascularisation of renal masses, which may introduce imaging artefacts. Here, the use of SPECT/CT or PET/CT might help improve the estimated kidney function.94 98 107Conclusions Due to the risk of overtreatment and misdiagnosis, there is an unmet need to improve imaging-based diagnostics for renal tumours. Currently, molecular imaging is not routinely used to stage, restage or characterise renal tumours. Due to the given heterogeneity of RCCs, different activated mechanisms can be used for molecular imaging. This review highlights several promising tracers that can address these challenges, such as CA-IX PET/CT tracers like [ 89Zr]Zr-girentuximab and [99mTc]Tc-Sestamibi for the assessment of renal tumours, as well as PSMA, CA-IX and FDG-PET/CT for staging RCC. While [99mTc]Tc-Sestamibi SPECT can help identify indeterminate renal masses of benign origin, [89Zr]Zr-girentuximab PET/CT shows high sensitivity and specificity in detecting ccRCC and further staging of RCC. In addition, PSMA-PET/CT and FDG-PET/CT help improve the staging of RCC, especially by detecting oligometastatic RCCs. However, data on FAPI and CA-IX PET/CT for staging and detection of metastases in RCC are still limited, but the data available show promising results. Use of CA-IX imaging also offers potential future applications as a non-invasive alternative to biopsy and facilitates definitive treatment. Here, improved metastasis detection may also improve guidance for therapeutic decisions. Moreover, potential therapeutic use of molecular imaging tracers within a theranostic approach is under investigation. Besides that, further novel radiotracers targeting CD70 show early promising results for their use in RCC in preclinical and clinical trials. However, further research and standardisation of molecular imaging practices in clinical settings are essential to determine the optimal application of these tracers for the diverse subtypes of renal tumours.",
  "title": "Novel radiopharmaceuticals for molecular imaging of renal cell carcinoma",
  "uid": "a8f2409d-3e1e-525a-a914-ab3c1aafb8bf"
}