⁶⁸Ga-NY104 PET/CT in the Differential Diagnosis of FDG-Negative Renal Masses: A Two-Case Illustration of Clear Cell Carcinoma Versus Renal Hemangioma

Abstract

FDG PET/CT often underperforms in characterizing hyper-enhancing, FDG-non-avid renal masses. We present two cases illustrating the potential of ⁶⁸Ga-NY104, a novel small-molecule tracer targeting carbonic anhydrase IX (CAIX), for this differential diagnosis. Both patients presented with a hyper-enhancing right renal mass suspicious for clear cell renal carcinoma (ccRCC) and subsequently underwent both ¹⁸F-FDG and ⁶⁸Ga-NY104 PET/CT, with histopathology and CAIX immunohistochemistry (IHC) as the reference standard. On ¹⁸F-FDG, both lesions were non-avid (SUVmax 2.6 and 2.2, Tumor-to-Liver Ratio [TLR] 0.87 and 0.69, respectively). However, on ⁶⁸Ga-NY104 PET/CT, Patient 1 (a 65-year-old man) showed intense, homogeneous uptake (SUVmax 26.0, TLR 4.64), while Patient 2 (a 67-year-old woman) showed negligible uptake (SUVmax 2.5, TLR 0.68). It was consistent with histopathology and IHC results that Patient 1 was CAIX-positive ccRCC, while Patient 2 was CAIX-negative hemangioma. Our preliminary cases suggest the potential utility of CAIX-targeted PET/CT imaging with ⁶⁸Ga-NY104 in differentiating ccRCC from benign mimickers like renal hemangioma, which warrants further prospective evaluation.

Figure 1. Two patients with right renal mass found during routine examination were presented. For Patient 1 (a 65-year-old man, (a–f)), contrast-enhanced CT (CECT) revealed a 4.1 cm heterogeneously hyper-enhancing lesion ((c), arrow) peaking in the corticomedullary phase (mean attenuation 86.3 HU). For Patient 2 (a 67-year-old woman, (g–l)), CECT revealed a 2.2 cm lesion that also demonstrated heterogeneous, avid enhancement ((i), arrow) peaking in the nephrographic phase (mean attenuation 106 HU). Both lesions raised suspicion of clear cell renal cell carcinoma (ccRCC). For image analysis, scans were performed on a time-of-flight PET/CT scanner (Polestar m680, Sino Union Healthcare Inc., Beijing, China) at 60 min post-injection of approximately 370 MBq ¹⁸F-FDG or 200 MBq ⁶⁸Ga-NY104. Images were reconstructed using an ordered subsets expectation maximization algorithm (2 iterations, 10 subsets, 192 × 192 matrix) and corrected for CT-based attenuation, dead time, random events, and scatter. Tumor-to-Liver Ratios (TLR) were calculated based on SUVmax. We defined “FDG non-avid” a priori as a TLR < 1.2. PET/CT with ¹⁸F-FDG (Patient 1, MIP, (a), fusion, (d), arrow; Patient 2, MIP, (g), fusion, (j), arrow) was performed. Both lesions were FDG non-avid (SUVmax, Patient 1, 2.6, Patient 2, 2.2; TLR, 0.87 and 0.69, respectively). To further characterize the lesions, PET/CT with ⁶⁸Ga-NY104, a small molecule PET tracer targeting carbonic anhydrase IX (CAIX), was also performed. While Patient 1 showed heterogeneous avid uptake of ⁶⁸Ga-NY104 (MIP, (b), fusion, (e), arrow, SUVmax 26.0, TLR 4.64), indicating CAIX overexpression, Patient 2 demonstrated minimal, background-level uptake (MIP, (h), fusion, (k), arrow, SUVmax 2.5, TLR 0.68). Both patients underwent surgery within a month after the PET/CT scans. Patient 1 was confirmed to be ccRCC (WHO Grade 1), while Patient 2 was hemangioma. The CAIX expression was also confirmed using immunohistochemical staining, with diffuse expression in Patient 1 (f) and no expression in Patient 2 (l). Clear cell RCC (ccRCC) is the most common histological subtype of renal cancer [1,2]. While multiparametric MRI (mpMRI) remains the non-invasive reference, it has known pitfalls in differentiating ccRCC from benign mimickers like oncocytoma and hemangioma [3]. FDG PET/CT, which is often used for staging in other types of cancer [4], has limited sensitivity in detecting RCC due to the relatively low glucose metabolism of RCC cells [5]. CAIX is overexpressed in over 90% of ccRCC due to von Hippel–Lindau (VHL) mutation, making it an ideal target for molecular imaging [6,7,8]. Our cases demonstrated that CAIX-targeted PET/CT imaging using ⁶⁸Ga-NY104 may aid in diagnosing ccRCC and in the differential diagnosis of hyper-enhancing lesions mimicking ccRCC. This tracer contributes to the broader PET landscape for RCC (which includes PSMA [9] and SSTR [10] targets) and may have future theranostic potential in selecting patients for CAIX-directed therapies. However, potential false negatives (in CAIX-negative ccRCC) and false positives (from other hypoxic lesions) should be taken into consideration. Meanwhile, the limitations of this two-case report are clear, including selection bias. Further investigations on other ccRCC mimickers such as oncocytoma, chromophobe, and papillary RCC are warranted. As a novel tracer, ⁶⁸Ga-NY104 is currently for research only and not yet commercially available.

Figure 1. Two patients with right renal mass found during routine examination were presented. For Patient 1 (a 65-year-old man, (a–f)), contrast-enhanced CT (CECT) revealed a 4.1 cm heterogeneously hyper-enhancing lesion ((c), arrow) peaking in the corticomedullary phase (mean attenuation 86.3 HU). For Patient 2 (a 67-year-old woman, (g–l)), CECT revealed a 2.2 cm lesion that also demonstrated heterogeneous, avid enhancement ((i), arrow) peaking in the nephrographic phase (mean attenuation 106 HU). Both lesions raised suspicion of clear cell renal cell carcinoma (ccRCC). For image analysis, scans were performed on a time-of-flight PET/CT scanner (Polestar m680, Sino Union Healthcare Inc., Beijing, China) at 60 min post-injection of approximately 370 MBq ¹⁸F-FDG or 200 MBq ⁶⁸Ga-NY104. Images were reconstructed using an ordered subsets expectation maximization algorithm (2 iterations, 10 subsets, 192 × 192 matrix) and corrected for CT-based attenuation, dead time, random events, and scatter. Tumor-to-Liver Ratios (TLR) were calculated based on SUVmax. We defined “FDG non-avid” a priori as a TLR < 1.2. PET/CT with ¹⁸F-FDG (Patient 1, MIP, (a), fusion, (d), arrow; Patient 2, MIP, (g), fusion, (j), arrow) was performed. Both lesions were FDG non-avid (SUVmax, Patient 1, 2.6, Patient 2, 2.2; TLR, 0.87 and 0.69, respectively). To further characterize the lesions, PET/CT with ⁶⁸Ga-NY104, a small molecule PET tracer targeting carbonic anhydrase IX (CAIX), was also performed. While Patient 1 showed heterogeneous avid uptake of ⁶⁸Ga-NY104 (MIP, (b), fusion, (e), arrow, SUVmax 26.0, TLR 4.64), indicating CAIX overexpression, Patient 2 demonstrated minimal, background-level uptake (MIP, (h), fusion, (k), arrow, SUVmax 2.5, TLR 0.68). Both patients underwent surgery within a month after the PET/CT scans. Patient 1 was confirmed to be ccRCC (WHO Grade 1), while Patient 2 was hemangioma. The CAIX expression was also confirmed using immunohistochemical staining, with diffuse expression in Patient 1 (f) and no expression in Patient 2 (l). Clear cell RCC (ccRCC) is the most common histological subtype of renal cancer [1,2]. While multiparametric MRI (mpMRI) remains the non-invasive reference, it has known pitfalls in differentiating ccRCC from benign mimickers like oncocytoma and hemangioma [3]. FDG PET/CT, which is often used for staging in other types of cancer [4], has limited sensitivity in detecting RCC due to the relatively low glucose metabolism of RCC cells [5]. CAIX is overexpressed in over 90% of ccRCC due to von Hippel–Lindau (VHL) mutation, making it an ideal target for molecular imaging [6,7,8]. Our cases demonstrated that CAIX-targeted PET/CT imaging using ⁶⁸Ga-NY104 may aid in diagnosing ccRCC and in the differential diagnosis of hyper-enhancing lesions mimicking ccRCC. This tracer contributes to the broader PET landscape for RCC (which includes PSMA [9] and SSTR [10] targets) and may have future theranostic potential in selecting patients for CAIX-directed therapies. However, potential false negatives (in CAIX-negative ccRCC) and false positives (from other hypoxic lesions) should be taken into consideration. Meanwhile, the limitations of this two-case report are clear, including selection bias. Further investigations on other ccRCC mimickers such as oncocytoma, chromophobe, and papillary RCC are warranted. As a novel tracer, ⁶⁸Ga-NY104 is currently for research only and not yet commercially available.