Objective To evaluate the feasibility of using convolutional neural networks (CNNs) and vision transformers (ViTs) to predict renal tumor pathology intraoperatively based on gross appearance. Material and methods Intraoperative images were retrospectively extracted from surgical recordings of patients undergoing partial nephrectomy between 2008 and 2024. Static frames obtained prior to arterial clamping were curated and linked with final pathology. A ResNet50-based CNN and the General Surgery Vision Transformer (GSViT) were trained to classify 6 tumor types: clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC), hybrid oncocytic tumors, oncocytoma, and angiomyolipoma (AML). Models were trained with transfer learning, evaluated on held-out test data, and assessed using accuracy, AUC-ROC, and confusion matrices. Results A total of 443 images from 118 patients (136 surgeries) were analyzed, including ccRCC (n = 149), pRCC (n = 97), chRCC (n = 42), hybrid tumors (n = 81), oncocytoma (n = 43), and AML (n = 31). In binary classification, the CNN achieved the highest AUCs for ccRCC (0.74), chRCC (0.70), hybrid tumors (0.73), and AML (0.70). Multi-class CNN performance was more variable, with notable AUCs for pRCC (0.70) and oncocytoma (0.71). The GSViT model underperformed across most categories, demonstrating prediction bias toward ccRCC. Attempts to unfreeze pretrained backbones led to rapid overfitting, underscoring dataset limitations. Conclusion CNN-based models demonstrate moderate ability to classify renal tumor pathology intraoperatively from gross appearance, providing proof of concept for AI-assisted surgical decision-making. Larger datasets and external validation are needed before clinical application.

Introduction Partial nephrectomy (PN) for localized renal cancer is associated with favorable survival outcomes due to preservation of renal function. Approaches for predicting new-baseline-GFR (NBGFR) after PN have been proposed, including multivariable algorithms and a formula presuming that 90% of the renal parenchyma is preserved during PN. However, these models were developed from cohorts with sporadic single-tumor renal cancer. We evaluate these predictive models in patients undergoing PN for multifocal disease. Accurate prediction of NBGFR has major implications in these patients, as they may require multiple PN for metachronous kidney cancer. Methods Patients who underwent PN for removal of ≥2 tumors from 2006 to 2024 and had available measurements of preop/postoperative GFR were considered. The final cohort included 453 patients, of whom 184 underwent multiple PN. Four predictive models were evaluated. Model performance was assessed using correlation-coefficient(r) and mean-squared-error (MSE). Results Approximately 30% of patients had sporadic, multifocal renal tumors, and 70% had hereditary renal cancer. The 90% formula had a higher r and lower MSE values compared to the multivariable models, and also showed improved accuracy, bias, and precision. In patients undergoing multiple PN, 85% to 91% of the GFR was preserved in each PN. Conclusions Models for predicting NBGFR after PN showed strong performance in our cohort with multifocal renal tumors. The conceptually simple formula presuming 90% renal parenchymal preservation, and thus 90% GFR preservation, most accurately predicted NBGFR. The %GFR preserved with each PN remained stable across sequential PN. These findings suggest that preservation of renal parenchyma is a relevant determinant of NBGFR after PN for multifocal tumors.

OBJECTIVE:To describe the genetic, phenotypic, and pathologic manifestations of patients presenting with inherited kidney cancer and germline variants of the Tuberous Sclerosis Complex (TSC) genes. MATERIALS AND METHODS:Inherited kidney cancer patients were screened for germline RCC susceptibility gene variants and patient histories and clinical evaluations were performed. Renal tumors were evaluated for somatic genetic alterations by DNA sequencing and mRNA expression analysis by RNAseq and immunohistochemical analyses were performed. RESULTS:Nine distinct germline TSC1/TSC2 variants were identified in 13 patients, including seven known or likely pathogenic alterations. Five patients presented with a clinical diagnosis of TSC, and eleven patients had a genetic diagnosis of TSC. Nine patients had bilateral RCC and nine had multifocal RCC. The average initial age at diagnosis of RCC was 47 years old. The TSC-associated tumors demonstrated a variety of histologies including ccRCC, RCC with clear cell and papillary features, chromophobe RCC, and oncocytoma; with ccRCC being the most prevalent. Loss of heterozygosity or secondary somatic alteration of TSC1/TSC2 was observed in ~ 37% of tumors. RNAseq analysis demonstrated specific expression patterns associated within histologically defined tumor clusters and increased expression of CLEAR genes activated by the TFE3/TFEB transcription factors, including GPNMB and NPC1 which were confirmed with immunohistochemistry. CONCLUSION:This study confirms the importance of screening individuals with a family history of kidney cancer for TSC1/TSC2 germline variants, even in the absence of canonical TSC manifestations, and indicates a critical role of TFE3 and TFEB as drivers of human TSC-deficient renal cell carcinoma.

Hereditary kidney cancer syndromes predispose patients to multifocal, bilateral and/or recurrent renal tumors, requiring repeated interventions over a lifetime. Despite nephron-sparing surgery being the preferred management strategy, some patients ultimately require completion nephrectomy-radical nephrectomy following prior ipsilateral partial nephrectomy-when tumor burden, declining renal function, surgical complications, or pre-transplant indications necessitate definitive kidney removal. Data on outcomes in this population remain limited. We evaluated a prospectively maintained cohort of 58 patients who underwent completion nephrectomy at the National Institutes of Health between 2000 and 2024, following at least one prior ipsilateral partial nephrectomy. Perioperative complication rates and renal functional change were the primary outcomes of interest. Von Hippel-Lindau disease was the most common hereditary diagnosis (62.1%). Open surgery was performed in 56.9% of cases. Overall complications occurred in 43.1% of patients, with 24.1% experiencing a Clavien-Dindo grade ≥ 3 event; perioperative mortality was 6.9%. The median preoperative estimated glomerular filtration rate was 72 mL/min/1.73 m2, declining to 50 mL/min/1.73 m2 at the first postoperative clinic visit. Completion nephrectomy in hereditary kidney cancer syndrome patients is associated with substantial perioperative morbidity, mortality, and expected renal functional decline. These findings inform patient counseling and surgical decision-making in this high-risk population.

BACKGROUND:Randomized controlled trials are the gold standard for demonstrating treatment efficacy. When infeasible, external control arm (ECA) analysis is an effective way to interpret treatment arm results. We developed an ECA for a single-arm trial (LS-004) for a HIF-2α inhibitor (belzutifan) in 61 patients with VHL renal cell carcinoma (RCC) to help interpret results. With a median follow-up of 37.8 months in LS-004, the ORR was 64% (95% CI = 50.6 to 75.8); median time to surgery was not reached. METHODS:The ECA was developed using natural history study data for VHL RCC patients undergoing active surveillance with ≤5 years of follow-up. Key LS-004 eligibility criteria were applied. Propensity score (PS) weighting was used to balance prognostic factors, with balance evaluated using standardized mean difference (SMD). PS adjusted point estimates and 95% CI for ORR and time to surgery (TTS) are presented. For the ECA, ORR was evaluated among patients with ≥3 scans to allow opportunity for a confirmed response. RESULTS:The ECA included 244 patients (167 for ORR analysis). Prognostic factors were balanced with SMD < 0.1 for all covariates. PS adjusted ORR for LS-004 and ECA was 63.9% (95% CI = 51.9 to 76.0) and 1.5% (95% CI = 0.0 to 3.3), respectively. Median TTS was 51.3 (95% CI = 43.8 to not yet reached) months in ECA; not yet reached in LS-004. CONCLUSIONS:The belzutifan treatment effect is large compared with the ECA, supporting belzutifan efficacy in VHL RCC. Although residual confounding is possible, the large effect is unlikely due to chance.

BACKGROUND AND OBJECTIVE:Bilateral or multifocal (BMF) papillary renal cell carcinoma (pRCC) arising without a confirmed pathogenic germline variant represents a clinically distinct entity with a poorly defined natural history. We aimed to establish clinical benchmarks for tumor growth kinetics, oncologic outcomes, and renal functional impact in this entity. PATIENTS AND METHODS:We identified 89 patients with histopathologically confirmed clinically sporadic BMF pRCC from a prospectively maintained, institutional review board-approved database at the National Cancer Institute (1999-2025). Tumor growth rate was calculated with a linear mixed-effects model. Active surveillance was assessed in 105 tumors from 44 patients with ≥6 mo of serial cross-sectional imaging. KEY FINDINGS AND LIMITATIONS:Over a median follow-up of 50 months, metastatic disease developed in six patients (6.7%), exclusively among patients whose largest tumor exceeded 3 cm at the time of assessment. A total of 156 renal procedures were performed, with partial nephrectomy predominating (81%). Variant pathology was identified in 18 of the 649 tumors (2.8%; 95% confidence interval 1.8%-4.3%). Among the 105 radiographically surveilled tumors, 64% demonstrated interval growth. The median tumor growth rate was 1.55 mm/yr (interquartile range 1.24-1.81). Repeat ipsilateral partial nephrectomy was associated with a significant decline in renal function (median estimated glomerular filtration rate 80.9-63.5 ml/min/1.73 m2; p = 0.002). CONCLUSIONS AND CLINICAL IMPLICATIONS:Sporadic BMF pRCC demonstrates predominantly indolent growth and low metastatic potential, with no metastatic events observed in patients presenting with a largest tumor <3 cm. These findings provide growth-rate benchmarks consistent with active surveillance for small renal masses and nephron-sparing surgery when intervention is warranted.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a hereditary cancer syndrome associated with germline pathogenic variants of the fumarate hydratase (FH) are at risk for the development of benign renal cysts as well as an aggressive form of renal cell carcinoma which can occur inside the cysts. This study was conducted in order to assess the role of MR imaging characteristics of HLRCC-associated cystic lesions for distinguishing benign from malignant complex renal cysts in this patient population. This IRB-approved retrospective study included 42 HLRCC patients (mean age, 46 ± 14 years; men: women, 22:20) with a pathogenic FH germline variant with renal cysts on abdominal MRI. Between June 2002 and May 2022 these patients underwent partial or radical nephrectomy for surgical removal of 76 renal lesions suspicious for renal carcinomas. Two abdominal radiologists independently reviewed the MRI images of all lesions while blinded to the surgical pathology. The lesion characteristics, including location, 3D dimensions, internal composition, characteristics of the cyst wall, nodules, septations, enhancement patterns in different series and restricted diffusion on ADC, and b-2000 series were recorded. Out of the 76 histologically characterized renal lesions, 44 (58 https://BioRender.com/w45f229

PURPOSE:Hereditary pheochromocytomas and paragangliomas can be associated with mutations in the mitochondrial enzyme succinate dehydrogenase. Due to their heterogenous clinical presentation, no clear universal screening guidelines are currently available. We sought to examine the utility of metabolic testing and imaging in diagnosing hereditary pheochromocytomas and paragangliomas. MATERIALS AND METHODS:Our retrospective study included patients with confirmed familial succinate dehydrogenase mutations and histologically proven pheochromocytomas/paragangliomas or with suggestive metabolic and imaging features. We extracted information on age, race, sex, tumor size, tumor location, presence of metastatic disease and other succinate dehydrogenase-associated manifestations, urine and plasma metabolic testing, and diagnostic imaging. Patients who lacked any diagnostic information were excluded. RESULTS:Our cohort consisted of 9 patients with 13 tumor occurrences from 2003 to 2023. The average age at diagnosis was 31.7 years with a 2.9 cm average tumor size. Three patients developed metastatic disease. Five tumors (38.5%) were biochemically silent, with all tumors detected on imaging. Most of the remaining tumors had a noradrenergic profile, with positive norepinephrine and normetanephrine in plasma and urine. I-123 MIBG was the least sensitive (50%) imaging modality, and Ga-68 DOTATATE PET/CT was the most sensitive (100%). 10 (76.9%) tumors were treated with surgical resection; all metabolic results were subsequently negative, except in patients with metastatic disease. CONCLUSIONS:Our investigation adds to the current literature on diagnosing hereditary pheochromocytomas and paragangliomas. We highlight the importance of multimodal screening that consists of both imaging and metabolic screening, especially given the prevalence of biochemically silent tumors.

Introduction Active surveillance is a consideration for small renal tumors, particularly in patients with certain types of genetically-defined hereditary renal-cell-carcinoma (RCC) syndromes. Triggers for intervention may include factors such as tumor size >3cm, fast tumor growth-rate (GR), and tumor progression. Across genetically-defined hereditary RCC syndromes, tumor GR vary based on underlying genetic alterations and histology, and faster GR have been noted in younger cohorts. These differences, along with earlier RCC onset, pose challenges in managing patients with hereditary RCC syndromes.Women with RCC before or during pregnancy present a special challenge. Women experience variations in sex hormones and glucocorticoids during this time, and estrogenic and androgenic pathways have been implicated in carcinogenesis. However, there is a paucity of data regarding renal tumor growth/invasiveness during pregnancy in hereditary or sporadic RCC. We evaluate renal tumor GR in pregnant patients with VHL, as these patients offer special insights into peripartum tumor growth. Methods Renal tumor growth kinetics and pathologic correlates were evaluated in patients with VHL who had renal tumors during pregnancy and were prospectively followed on an Institutional Review Board-approved protocol at the National Institutes of Health between 2009 and 2022. Inclusion required availability of at least two renal imaging scans prior to last menstrual period, one scan either during pregnancy or shortly after delivery, and at least one scan within one year of the previous pregnancy/post-delivery scan to allow for calculation of renal tumor GR. Tumor sizes were measured before, during, and after pregnancy from cross-sectional abdominal imaging using the RECIST v1.1 criteria (Figure 1A-C). Tumor GR (cm/year) were calculated in the pre-pregnancy, during pregnancy, and post-pregnancy time periods. Results A total of nine renal tumors in three patients with VHL were analyzed (Table 1, Figure 1D). The median pre-pregnancy tumor size was 1.8 cm and the median post-pregnancy size was 2.9 cm, corresponding to a median GR of 0.72 cm/year. The pre-/during/post-pregnancy GR for VHL-associated renal tumors were 0.28/0.72/0.36 cm/year. Of the renal tumors, 6/9 (67%) had a > 50% increase in GR during vs. before pregnancy, and 5/9 (56%) had a > 50% decrease in GR after vs. during pregnancy. The median change in tumor size when comparing the first post-pregnancy size to the final size during pregnancy was 0.0 cm. Among the tumors that had pathologic analysis available (6/9), all were of clear cell histology and Fuhrman grade 2. Conclusions Growth kinetics of nine renal tumors from three pregnant VHL patients were analyzed. While the small sample size limits the generalizability of the data, this is, to date, the largest cohort of patients with VHL RCC undergoing active surveillance during pregnancy. Pre- and post-pregnancy GR were comparable to GR reported in the literature (∼0.3cm/year); however, the GR increased considerably during pregnancy (0.72cm/year) and exceeded the GR threshold for potential intervention described in guidelines for sporadic RCC (0.50cm/year). A general plateau in tumor size was observed in the immediate postpartum period, following the increased growth during pregnancy. These findings suggest potential roles for reproductive hormonal, physiologic, and/or vascular changes in promoting RCC growth and/or progression in VHL patients during pregnancy. These preliminary findings may help inform patient counseling regarding timing of intervention for women of childbearing age with VHL-associated RCC who are planning for pregnancy.

Background/Objectives: Thousands of nephrectomies are performed annually in the United States, but the short-term metabolic effects of surgically induced renal ischemia remain unclear. The conventional metabolic markers used to characterize post-surgical renal function, such as creatinine and GFR, are measured in the serum but do not provide metabolic information about the renal parenchyma itself. We aimed to characterize the immediate metabolic effects of surgical ischemia on renal parenchyma within a temporal framework. Methods: Timed renal parenchyma biopsies were collected from eight patients undergoing nephrectomy for renal cell carcinoma both prior to and after ligation of the renal hilum. These samples were ground, extracted, and analyzed using nuclear magnetic resonance (NMR) spectroscopy to measure changes in lactate, succinate, glucose, alanine, and glycine levels. Results: Due to experimental limitations, we were only able to draw limited conclusions from three patients. Of the five remaining patients, all had significant increases in lactate and succinate levels as a function of time, though the degree to which these increases occurred varied between each patient. Glucose levels generally decreased in the renal parenchyma but did not necessarily correlate with lactate production, assuming all glucose underwent fermentation to lactate in a hypoxic environment. Alanine and glycine levels did not change in a predictable pattern across patients. Conclusions: There are significant changes in lactate, glucose and succinate levels within minutes of the onset of renal ischemia in human patients. The degree of change in the metabolites analyzed varied significantly between patients. The length of surgical ischemia must be considered during surgical procurement of tumor specimens for metabolomic analysis.

OBJECTIVE:To evaluate the proportion of von Hippel-Lindau (VHL) patients with high-grade disease and analyze the association of clinical, pathologic, and genetic factors with high-grade disease. METHODS:Clear cell renal cell carcinoma (ccRCC) specimens resected from VHL patients between 2006 and 2021 at the National Cancer Institute were evaluated. Pathologic, demographic, and genetic data were obtained from clinical records. Multivariate logistic regression models analyzed the association between pathologic grade and demographic information, tumor size, history of previous ipsilateral partial nephrectomy (PN), and germline VHL gene variant. RESULTS:From 229 patients with VHL, we identified 2555 ccRCC tumor specimens, of which 203 (7.94%) tumors were high-grade. Over the whole study period, 99 (43.2%) patients developed a high-grade tumor. Older age (odds ratio (OR) 1.02, P<.0001) and increasing tumor size (OR 1.58, P<.0001) were associated with high-grade pathology. Prior ipsilateral PN (OR 2.10, P=.002) and germline frameshift VHL variants (OR 2.38, P=.01) were also associated with high-grade pathology. CONCLUSION:These results demonstrate a strong association between tumor size, age at surgery, re-operative surgery status, and VHL frameshift genetic variant and high-grade pathology in VHL-associated RCC. These factors can be used clinically to assist in surgical intervention decision-making.

PURPOSE:To present our experience with re-operative retroperitoneal partial nephrectomy (Re-RetroPN), evaluate its feasibility and safety, and compare perioperative outcomes, including renal function metrics, pathology, and complication rates, between patients that underwent Re-RetroPN and those that underwent re-operative transperitoneal robotic partial nephrectomy (Re-TransPN). METHODS:A retrospective cohort study was conducted identifying patients who underwent re-operative robotic partial nephrectomy (PN) at our institution from January 2008 to December 2024. Demographic, clinical, perioperative, and pathological data were recorded and analyzed. RESULTS:A total of 186 patients who underwent robotic re-operative PN were analyzed (173 Re-TransPN vs. 13 Re-RetroPN), and 1 patient was converted from Re-RetroPN to Re-TransPN. Overall, 17 (9.1%) had a solitary kidney, 138 (74.2%) underwent their second ipsilateral partial nephrectomy, and 48 (25.8%) had their third. A total of 894 tumors were removed (825 with Re-TransPN, 69 with Re-RetroPN), with a median of 3 (2-6) tumors per procedure. Perioperative metrics, including estimated blood loss, operative time, and percentage of cases performed without hilar clamping were similar between groups. Positive surgical margins were observed in 7 (4.0%) patients in the Re-TransPN group, with no positive margins reported in the Re-RetroPN group. Renal function parameters at 3 months and complication rates were comparable between groups, with 1 (7.7%) patient in the Re-RetroPN group experiencing a Clavien-Dindo grade ≥3 complications. CONCLUSION:Re-RetroPN is a feasible and safe option for carefully selected patients, with comparable outcomes to Re-TransPN. It provides advantages in certain scenarios, such as improved access to posteriorly located tumors and avoidance of the peritoneal cavity.

Anatomic imaging of renal masses provides limited information on the histology or likely aggressiveness of the tumor, leading to the use of invasive procedures such as renal mass biopsy or empiric partial or radical nephrectomy. Molecular imaging can assist in risk stratification of indeterminate renal masses, potentially contributing to optimal patient decision-making. Two primary approaches have been explored for renal mass molecular imaging. The first is the use of agents that target carbonic anhydrase IX (CAIX), a cell-surface protein that is over-expressed on clear cell renal cell carcinoma (ccRCC) and generally not expressed on other renal tumors. A recent phase III trial (ZIRCON) is widely believed to have laid the groundwork for United States Food and Drug Administration approval of the CAIX monoclonal antibody 89Zr-girentuximab. The second approach is the use of mitochondrial imaging agents, most notably 99mTc-sestamibi, which are lipophilic cations that accumulate in tumors with an abundance of mitochondria with negative charge potential (e.g., oncocytomas and other benign/indolent lesion) and do not accumulate in tumors with multidrug resistance pumps (e.g., ccRCC). The complementary information from 89Zr-girentuximab and 99mTc-sestamibi can provide improved risk stratification. Further, emerging new targeted radiotracers and techniques such as imaging biomarker discovery with artificial intelligence will bolster those concepts. In this manual, we synthesize key data into a recommended approach.

469 Background: Randomized controlled trials are the gold standard for demonstrating treatment efficacy but are not feasible in certain disease settings. In such cases, external control arm (ECA) analysis can be an effective way to interpret experimental treatment results. Our aim, based on a natural history study (NHS), was to develop an ECA for a Phase 2 single-arm trial (LITESPARK [LS]-004) for belzutifan in 61 patients with VHL disease-associated RCC. With a median follow-up of 37.8 months in LS-004, the objective response rate (ORR) for VHL RCC patients was 64% (95%CI: 50.6, 75.8) and the median time to surgery (TTS) was not reached. Methods: The ECA was developed using NHS data for VHL RCC patients undergoing active surveillance at the US National Cancer Institute with up to 5 years of follow-up. Key LS-004 eligibility criteria (e.g., no prior systemic therapy or metastasis) were applied. Propensity score (PS) weighting was used to balance baseline characteristics (age, sex, number and size of RCC, prior surgery and time from prior surgery, VHL mutation status) between LS-004 and ECA, with balance evaluated using standardized mean difference (SMD). PS adjusted point estimates and 95% CI for ORR, assessed by independent blinded committee review using RECIST 1.1, and TTS were estimated. For the ECA, the ORR was evaluated among patients with ≥3 serial scans to allow the opportunity for a confirmed response. Results: The ECA included 244 patients with 178 patients in the ORR analysis. Prognostic factors were well balanced between the ECA and LS-004 with a SMD<0.1 for all covariates. The PS adjusted ORR (95% CI) for LS-004 and the ECA was 63.9% (51.9, 76.0) and 1.5% (0.0, 3.3), respectively. Median (95% CI) TTS was 44.4 (35.7, 51.1) months in the ECA, and not yet reached in LS-004. Conclusions: The magnitude of the treatment effect with belzutifan is large compared with the ECA. Although residual confounding is still possible, including effects of unmeasured confounders, observing such a large effect is unlikely due to chance. The results support the demonstrated antitumor activity and efficacy of belzutifan in the treatment of VHL RCC.

BACKGROUND AND OBJECTIVE:Metastatic hereditary leiomyomatosis renal cell cancer (HLRCC)-associated and succinate dehydrogenase-deficient (SDH-deficient) renal cell carcinoma (RCC) have aggressive oncological behavior. Thus, in this study we aimed to describe our experience with patients diagnosed with metastatic HLRCC-associated and SDH-deficient RCC who underwent surgical metastasectomy (SM). MATERIALS AND METHODS:A retrospective study was conducted selecting patients with either germline variant confirmed HLRCC-associated or SDH-deficient RCC who underwent SM at our institution between 2002 and 2024. Clinical and oncological variables were analyzed. Kaplan-Meier analysis was used to estimate the median (95% confidence interval; CI) systemic therapy-free survival, time to subsequent SM, and overall survival (OS) following the initial SM. RESULTS:A total of 23 patients were identified; 17 (73.9%) had HLRCC-associated, and 6 (26.1%) had SDH-deficient RCC. The age at index renal surgery was 35 [24-47] years, and 38.6 years [27-52.4] at first SM. The median systemic therapy-free survival following initial SM was 2.58 years (95% CI: 0.31-4.86), and OS following initial SM was 8.17 years (95% CI: 2.94-13.39). At 1, 3, and 5 years after SM, 55%, 32%, and 32% of the patients, respectively, had not received systemic therapy. The OS at 3, 5, and 10 years after initial SM was 72%, 53%, and 40%, respectively. CONCLUSIONS:SM in well-selected patients with metastatic HLRCC-associated and SDH-deficient RCC offers favorable oncologic outcomes and over 2 years of systemic therapy-free survival. This surgical approach should be carefully considered within a multidisciplinary setting, emphasizing thorough patient selection.

Molecular testing in renal cell carcinoma (RCC) has allowed for a better understanding of the biology of both sporadic and hereditary diseases, where genetic testing is currently recommended in the guidelines for a select population with risk factors. Historically, screening, surveillance, and management decisions were based solely on clinicopathologic data; however, we now know that molecular profiling can enhance decision making, altering the treatment plan, approach, or selection of systemic therapy and enhancing the delivery of precision oncologic care. Advances and the increasing availability of next-generation sequencing technologies have improved the identification of germline and somatic variants in key RCC-associated genes. Given the molecular heterogeneity of RCC, these modern methods can identify unique genetic events that occur in a single individual, allowing for distinction between a metachronous tumor from metastases. Separate four-tier systems have been proposed to categorize germline and somatic variants according to their clinical significance, which should be highlighted. Additionally, emerging technologies, such as liquid biopsy, show potential for enhancing precision oncology in RCC. With this said, challenges, such as variant interpretation, ethical considerations, and accessibility, persist. This review examines the molecularly defined RCC, genetic testing methodologies currently available, their current clinical applications, limitations, and future directions.