Journal of Kidney Cancer and VHL (JKCVHL)
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Novel Case of Bilateral Adrenal Tumors Confirms Pathogenicity of Previously Described c.463+4C>G Variant in the von-Hippel Lindau Gene
Full text linkWe report a case of a pathogenic variant c.463+4C>G in the von Hippel-Lindau (VHL) gene identified in a patient presenting with bilateral adrenal tumors, including a histologically confirmed pheochromocytoma with no significant family history of VHL-associated tumors. This same variant was first reported as having pathogenic significance in an unrelated proband with a hemangioblastoma and a family history of pheochromocytoma. In our patient, next-generation sequencing and subsequent RNA (ribonucleic acid) analysis confirmed this mutation to be a pathogenic (class 4) variant in intron 2. The lack of family history of VHL-associated tumors correlated with the proband further suggests that this mutation may have reduced penetrance. This case confirms the pathogenicity of the same previously described variant in the VHL gene and underscores the utility of genetic testing in patients with atypical presentations of adrenal tumors, even in the absence of a relevant family history
Expression of Follicle-Stimulating Hormone Receptor in Von Hippel-Lindau Associated Tumors and Cysts: An Immunohistochemical Study
Full text linkVon Hippel-Lindau (VHL) disease is a hereditary condition caused by mutations in the VHL-tumor suppressor gene leading to constitutive overproduction of HIF-1alpha and HIF-2alpha, two proangiogenic factors, involved in the development of highly vascular tumors. Published evidence has shown that FSH-receptor is expressed in endothelial cells of blood vessels (BV) in several types of tumors. Given that VHL-associated tumors are highly vascular, it is plausible that FSH-receptor could be expressed in their vasculature as well. This immunohistochemical study involved 71 patients diagnosed with VHL-associated tumors, who required surgical intervention. Tissue specimens from these patients included CNS-hemangioblastoma, pancreatic neuroendocrine tumors (panNET), and clear cell renal cell carcinoma (ccRCC). Immunohistochemical staining was performed using a highly specific monoclonal antibody against the human FSH-receptor to assess its expression in the endothelial cells and tumor cells. The distribution of FSH-receptor staining was analyzed using digital imaging techniques. FSHR-protein expression was detected in the BV endothelial cells in 100% of VHL-associated CNS-hemangioblastoma, panNET, and ccRCC cases. In CNS-hemangioblastoma, 96% of cases showed FSH-receptor positivity in tumor stromal cells. In panNET, 88% of the cases displayed FSH-receptor expression in tumor cells. No tumor cells showed FSH-receptor expression in ccRCC. This is the first study to demonstrate FSH-receptor expression by cells of VHL-associated tumors, with distinct expression patterns in different tumor types
Narrative Review of Von Hippel-Lindau Syndrome: From Discovery to Modern Medical and Surgical Therapies
Full text linkThe von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant disorder caused by mutations in the VHL tumor suppressor gene, leading to the development of benign and malignant tumors in multiple organs, including the kidneys, brain, spine, retina, and pancreas. Since its initial description in the early 20th century, significant progress has been made in understanding its pathogenesis, genetic basis, and clinical management. This narrative review provides a comprehensive overview of VHL syndrome, from its discovery to the latest medical and surgical therapies. A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, incorporating the Egger test to assess publication bias. The review highlights the evolution of diagnostic criteria, the role of genetic testing, and the development of targeted therapies such as hypoxia-inducible factor 2-alpha (HIF-2α) inhibitors. Surgical interventions, including nephron-sparing surgery and minimally invasive techniques, are also discussed. This review emphasizes the importance of a multidisciplinary approach to managing VHL syndrome and explores emerging therapies that hold promise for improving patient outcomes
Precision Medicine: Seeing the Tree in the Forest!
Full text linkGenetic diagnosis has changed the way we diagnose and treat multiple cancers. Germline testing has expanded horizons and is now considered a standard of care for many diseases
Meet-URO Score Validation in Real-world Patients with Metastatic Renal Cell Carcinoma Receiving First-line Pembrolizumab Plus axitinib: A Subanalysis of the Prospective ProPAXI Study
Full text linkThe Meet-URO score provided a more accurate prognostication than the international metastatic RCC database consortium (IMDC) risk group classification for patients with metastatic renal cell carcinoma (mRCC) by incorporating the pretreatment neutrophil-to-lymphocyte ratio (NLR) and the presence of bone metastases in different settings of the disease. To additionally validate the Meet-URO score on overall survival (OS) in a cohort of mRCC patients treated with first-line pembrolizumab plus axitinib, a post hoc analysis of the observational prospective ProPAXI study was conducted. Progression-free survival (PFS) was also considered. Harrell’s C-index was used to compare the discriminative ability on OS and PFS. Overall, the ProPAXI study included 170 patients. Both the five- and the three-risk group Meet-URO score were evaluated to account for the small sample size. The five Meet-URO risk group score showed a mOS of 27.1 months (p = 0.064) and 10.3 (p = 0.014) months for group 4 and group 5, respectively, while it was not reached for the other groups (p < 0.01). Although a worsening of PFS was observed with increasing the risk group, these differences were not statistically significant (p =0.19). Similar results were observed fot the three-risk group Meet-URO score. Both five and the three Meet-URO risk groups showed a better C-index for OS (0.69 and 0.66, respectively) compared to IMDC (0.62) and for PFS (0.60 and 0.59, respectively) compared to IMDC (0.56). These findings suggest that the Meet-URO score may provide more accurate prognostic stratification than IMDC alone in mRCC patients treated with first-line pembrolizumab and axitinib
Cabozantinib-Exposed Renal Cell Carcinoma Organoids Suggest Transcriptomic Associations with Treatment Resistance in Clear Cell and Nonclear Cell Tumors
Full text linkWhile vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a mainstay of treatment for advanced renal cell carcinoma (RCC), mechanisms of resistance to VEGF-TKIs remain under ongoing investigation. To assess transcriptomic changes in clear-cell RCC (ccRCC) and non-ccRCC exposed to a VEGF-TKI, we analyzed differential single-cell gene expression in RCC tumor-organoids exposed to cabozantinib versus control solvent. In ccRCC organoid cells, LRRC75A was notably highly associated with cabozantinib exposure (log2 fold-change 2.18, detected proportion 0.52 vs. 0.23, false-detection rate adjusted p<0.001). Importantly, our findings were independently validated in a recent study of advanced ccRCC patients treated with cabozantinib, which demonstrated that higher LRRC75A expression was significantly associated with decreased tumor response and less robust reduction of VEGF expression. LRRC75A has been shown to mediate VEGF secretion in a separate study and may potentiate compensatory angiogenesis after cabozantinib exposure. Gene expression scores were then developed based on transcriptomic changes associated with cabozantinib exposure and applied to stage IV patients in several independent cohorts. Higher scores were significant predictors of worse overall survival in TCGA non-RCC patients and worse progression-free survival in JAVELIN Renal 101 ccRCC patients. Overall, this experiment represents an incremental step in a larger effort to elucidate resistance mechanisms to VEGF-TKIs
Identifying Hereditary Leiomyomatosis and Renal Cell Cancer through Unobtrusive Cutaneous Nodules: A Clinical Report
Full text linkCutaneous leiomyomas (CLMs) are associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome (Mendelian Inheritance in Man [MIM]: 150800)—a rare genodermatosis caused by a heterozygous pathogenic variant in the fumarate hydratase (FH) gene. It is characterized by a predisposition to develop cutaneous and/or uterine leiomyomas and an aggressive type of renal cell carcinoma (RCC). We describe a 27-year-old male who presented with a painful nodule on the left upper arm persisting for 5 years and the subsequent emergence of painless nodules in various parts of the body over the past two years. A family history of RCC prompted suspicion of the HLRCC syndrome. Cutaneous examination revealed erythematous subcutaneous nodules, with histological analysis confirming CLM. Genetic testing identified a pathogenic variant in the FH gene, confirming the diagnosis of HLRCC. Management involved surgical excision of the symptomatic nodules and genetic counselling/testing for the proband and his family members. The long-term follow-up plan includes dermatological and nephrological surveillance with annual renal magnetic resonance imaging (MRI) scans. This report aims to enhance the awareness of this disease and highlight the role of cutaneous lesions in facilitating early detection
Systematic Review of Robotic Nephrectomy for Kidney Cancer
Full text linkRobotic nephrectomy has become an increasingly preferred surgical technique for managing renal cell carcinoma (RCC). This review aims to sys-tematically evaluate existing literature on the safety, efficacy, clinical outcomes, and associated costs of robotic nephrectomy, especially in relation to tumor dimensions and other pertinent patient factors. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed an extensive literature search across major databases (PubMed, Scopus, and Cochrane Library) from incep-tion to October 2023. The inclusion criteria encompassed randomized controlled trials (RCTs), cohort studies, and case-control studies that compared robotic nephrectomy with open or laparoscopic nephrectomy. Outcomes analyzed included operative time, intraoperative blood loss, complication rates, length of hospital stay, oncological outcomes, and cost-effectiveness. The Egger test was used to assess publication bias. The review incorporated 30 studies involving 5,432 patients who underwent robotic nephrectomy. Key findings indicated that robotic nephrectomy resulted in significantly reduced intraoperative blood loss (mean difference of −85 mL; p < 0.001) and shorter hospital stays (mean difference of −1.3 days). Tumor size had a notable impact on surgical outcomes, with larger tumors (≥7 cm) being associated with prolonged operative times and slightly higher complication rates. Robotic nephrectomy was also associated with higher costs compared to conventional surgical techniques; however, reduced readmission rates offset some of these costs. Oncological outcomes for robotic nephrectomy were comparable to those of open nephrectomy. Robotic nephrectomy is a safe and effective approach for kidney cancer that demonstrates advantages in perioperative recovery and surgical precision, particularly for smaller tumors. While costs may be higher, the clinical benefits and potential long-term savings from decreased postoperative complications recommend its use. Further high-quality RCTs are essential to validate these findings
Mucinous Tubular and Spindle Cell Carcinoma: Case Report and Literature Review
Full text linkMucinous tubular and spindle cell carcinoma (MTSCC) is a rare type of renal cell carcinoma (RCC) recognized as an independent entity in the latest WHO (World Health Organization) classification. We here report a case of a 51-year-old female patient with MTSCC, who presented with abdominal pain and left lower pole kidney lesion on the computed tomography scan. A robotic-assisted laparoscopic partial nephrectomy was performed. The diagnosis was confirmed on histopathological examination. MTSCC is rare and generally indolent. Either partial or radical nephrectomy is usually curative. The prognosis is usually favorable. However, occasionally, MTSCC could demonstrate aggressive features requiring systemic therapy. There are also several mimickers of MTSCC, which carry different prognostic and treatment profiles. Histological, immunohistochemical, and molecular genetic profile are useful in diagnosing the disease