Journal of Kidney Cancer and VHL最新文献

Cutaneous 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.

Central nervous system hemangioblastoma (CNS-HB) is the most common manifestation of von Hippel-Lindau disease (VHL). The main axis of the CNS-HB pathway is the VHL-HIF signaling pathway. Recently, we proposed an alternative VHL-JAK-STAT pathway in CNS-HB. In contrast, the VHL substrate transcription factor zinc fingers and homeoboxes 2 (ZHX2) have been identified as the oncogenic drivers in VHL-deficient clear cell renal cell carcinoma (RCC). However, ZHX2 expression in CNS-HB has not been previously reported. Furthermore, the VHL-ZXH2-NF-κB signaling pathway in CNS-HB remains unresolved. In this study, we aimed to investigate ZHX2 expression and VHL gene alteration in CNS-HB and propose the role of ZHX2 in CNS-HB. Using the MACS method, Scl+ hemangioblastoma-like cells were isolated from multipotent nestin-expressing stem cells. The ubiquitination of ZHX2 in these cells and the immunoprecipitation between ZHX2 and VHL were investigated. In addition, the VHL genes of patients with hemangioblastoma were analyzed. ZHX2 expression in CNS-HB tissues was examined by immunohistochemistry and western blotting. In addition, VHL gene mutations in CNS-HB were analyzed by sequencing. The association between ZHX2 expression and VHL gene mutation was analyzed. ZHX2 was ubiquitinated in Scl+hemangioblastoma-like cells after the transfer of the VHL expression vector into these cells. ZHX2 expression in these cells was well detected before transfer but disappeared after the transfer. ZHX2 expression was detected in 18 of the 21 CNS-HB tissues by immunoblotting and/or immunohistochemistry. Sporadic CNS-HB showed weak expression, whereas VHL-related CNS-HB showed moderate or strong expression. In particular, CNS-HB with severe VHL gene mutations, including large deletions, showed strong or moderate ZHX2 expression. The association between VHL gene mutation and ZHX2 expression revealed a significant correlation between VHL gene alteration severity and the level of immunoblotting (P < 0.05). In conclusion, the severity of VHL gene alteration correlates with the level of ZHX2 expression. ZHX2 is predominantly expressed in CNS-HB, especially in VHL-related cases with severe VHL gene alterations, suggesting a potential role in tumorigenesis and proliferation of CNS-HB.

Von Hippel-Lindau (vHL) is a hereditary disease characterized by the development of benign and malignant tumors across multiple organ systems. It is seen in approximately 1 in 36,000 live births. Given that vHL is a rare disease, studies that seek to characterize vHL are often hampered by small sample sizes. The TriNetX database, which contains data from over 100 million patients, may offer the ability to define and describe a large number of vHL patients. The primary objectives of this study were to describe the prevalence of vHL-associated conditions and investigate clinical outcomes using TriNetX. The secondary objective was to compare the results of this analysis to what has been reported in the published vHL literature. TriNetX was queried to establish a cohort of patients with a diagnosis of vHL. This cohort was then used to define the prevalence of the following conditions: reproductive organ (epididymal and broad ligament) cystadenomas, renal cell carcinoma (RCC), pheochromocytomas, endolymphatic sac tumors (ESLTs), central nervous system (CNS) and retinal hemangioblastomas, and pancreatic neuroendocrine tumor (pNETs). A total of 1232 patients in TriNetX had a recorded diagnosis of vHL. Of this, 34 (6.0% of males) patients had epididymal cystadenoma, 21 (3.4% of females) had broad ligament cystadenoma, 352 (28.6%) had RCC, 251 (20.4%) had pheochromocytoma, <10 had ELST, 171 (13.9%) had CNS hemangioblastoma, 34 (2.8%) had pNETs, and 66 (5.4%) had retinal hemangioma. Compared to the existing literature, vHL and associated conditions are underdiagnosed in TriNetX, suggesting its limited use in studying this disease.

Early identification of patients at risk with von Hippel-Lindau (VHL) syndrome-related pheochromocytoma and paraganglioma (PPGL) is crucial to prevent morbidity. We investigated the current surveillance recommendations in VHL-related PPGL in children and adolescents. German Pediatric Oncology and Hematology-Malignant Endocrine Tumor registry (GPOH-MET) and Freiburg-VHL registry (1996-2022). In all, 75 patients (aged 0-18 years) with VHL syndrome were analyzed and 52 were in the Freiburg screening/surveillance program (median follow-up: 11.5 ± 0.94 years), including annual hormone level measurements, eye examination (starting at the age 6 years), and MRI of the abdomen and central nervous system (CNS) (starting at the age of 12 years). Retrospective analysis of clinical outcomes and descriptive statistics was performed. Of the 75 patients, 60 had a previous clinical diagnosis of PPGL with subsequent genetic testing, and 63% had a positive family history. In spite of having positive family history, large variations of timings between genetic and clinical diagnosis (range: -9 to +40 years) were observed. The mean age of first PPGL was 12.4 ± 0.41 years (range: 4-18 years). Recurrence of PPGL was common (46%; range: 2-7 per patient), and that of other tumors occurred: hemangioblastomas (73%), retinal angiomas (58%), renal cell carcinomas (21%), and pancreatic neuroendocrine tumors (12%). VHL-related PPGL appeared by the age of 12 and recurrences were observed frequently. Hemangioblastomas and retinal angiomas were common. In spite of a positive family history, VHL diagnoses were delayed. Because of high tumor proportions of affected families with children, it needs an optimization of the surveillance framework to enhance compliance and minimize anxiety and worse disease outcomes.

Enhancing renal masses are conventionally treated as malignant unless proven otherwise due to the difficulty distinguishing between malignant and benign tumors based on imaging. Data from the Western registries suggests overtreatment of renal tumors with a Benign Kidney Tumor Resection Rate (BKTRR) ranging from 10 to 33%, with an increasing trend. Since robust, population-based data from India was unavailable, we sought to determine BKTRR in an apex cancer institute, which would provide insight into the rates in the community. The institutional kidney tumor database was queried for all patients aged ≥18 years with renal neoplasms between January 2000 and December 2022. Patients who underwent surgery, either radical or partial nephrectomy, with intent to cure were analyzed and the BKTRR during the study period was evaluated. A total of 330 patients underwent surgery for renal tumors presumed to be malignant. A final pathologic diagnosis of the benign tumor was made in 16 (4.8%) patients, comprising 7.2, 7.2, and 3.7% of resections with LTD ≤4, 4-7, and >7 cm, respectively. Asymptomatic benign tumors ≤7 cm comprised 3.0% of all resections, and these were potentially unnecessary surgeries. A multivariable analysis suggested that no patient or imaging characteristic could predict a final benign extirpative pathology. Our study suggests a lower rate of BKTRR compared to the published international literature but is likely to be the lower limit of that in the community. Population-based studies are required to determine the true BKTRR and the quantum of potentially unnecessary surgeries for benign kidney tumors.

Germ cell tumor (GCT) is a neoplasm typically found in childhood, commonly originating from the testis or ovary. While there have been reported cases of GCT occurring in various extragonadal sites, primary intrarenal GCT is exceptionally rare. We present a case of 37-year-old male who presented with right upper abdomen pain. Imaging revealed a sizable mass within the right kidney. The patient underwent surgical resection of the renal mass during which there was perirenal infiltration into the duodenum and dense desmoplastic reaction all around. Subsequent histopathology confirmed the diagnosis of primary intrarenal nonseminomatous germ cell tumor (NSGCT). The patient underwent four cycles of adjuvant bleomycin, etoposide, and cisplatin (BEP) chemotherapy; at 6 months of follow-up, he is fine. The objective of this case report is to underscore the importance of considering NSGCT as a potential rare differential diagnosis in cases of renal neoplasms and further plan for the management.

Chromophobe renal cell carcinomas (ChRCCs) have a good prognosis and comprise approximately 5-7% of renal cell carcinomas (RCCs). The sarcomatoid differentiation in RCC is found in around 5-10% of cases; however, in ChRCC, it is much less than in other RCCs and poorly responds to chemotherapeutic agents. A study by de Peralta-Venturina et al. found 9% sarcomatoid differentiation in chromophobe RCC. We present the case of a 58-year-old female with a left abdominal mass diagnosed as ChRCC with the existence of sarcomatous differentiation including osteosarcomatous and chondrosarcomatous, which are of adverse prognosis. Osteosarcoma-like divergent differentiation in RCC is extremely rare, with limited documented cases. It should be carefully considered in evaluating and managing renal masses due to its potential impact on clinical outcomes.

Adenoid cystic carcinoma (ACC) is a rare tumor, accounting for 1% of all head and neck cancers, with an aggressive nature characterized by local recurrence, delayed metastasis, and survival of less than 50% at 10 years. This is a case of biopsy-proven ACC to the kidney, 1 of 29 known occurrences, managed by metastasectomy by robotic-assisted nephrectomy, with plans for resection of lung metastasis. Thirteen years after diagnosis of sinonasal ACC treated with resection, the patient presented with shortness of breath. This prompted a CT scan of the chest, which led to the incidental finding of left renal mass and pulmonary lesion. Literature suggests improved disease-specific survival in locoregional recurrence treated with surgery versus radiation; in patients with metastasis to the lung, metastasectomy offers greater survival benefit than supportive therapy. But, this is not significantly better than chemotherapy or radiation alone. While the optimal therapeutic approach remains to be identified in distant metastatic ACC, metastasectomy remains a viable option for patients who have potentially completely resectable metastatic tumors, appropriate performance status, and adequate affected-organ function. Preoperative counseling should include discussion on partial nephrectomy with prioritization of nephron-sparing but potential for increased perioperative risk versus radical nephrectomy to ensure negative margins and expedite timeline to systemic therapy.

Clinical trials for immunotherapy-based regimens in metastatic renal cell carcinoma (mRCC) have extensive inclusion and exclusion criteria. We investigated the clinical outcomes in a real-world cohort of patients who would not have met the criteria for inclusion in front-line mRCC trials. Patients treated with ipilimumab/nivolumab and axitinib/pembrolizumab for front-line mRCC were identified and divided into clinical trial eligible (CTE) and clinical trial ineligible (CTI) cohorts based on key inclusion or exclusion criteria from their respective Phase-3 registration trials. Clinical outcomes were compared in CTE and CTI cohorts. A total of 62 patients treated with axitinib/pembrolizumab and 103 treated with ipilimumab/nivolumab were identified. The International Metastatic RCC Database Consortium (IMDC) criteria were similar across CTE and CTI patients in axitinib/pembrolizumab and ipilimumab/nivolumab cohorts. In the axitinib/pembrolizumab cohort (n = 62), 24 (39%) patients were CTI. The major reasons for the ineligibility were lab abnormalities (n = 11), histology (n = 9), and brain metastases (n = 3). There was no significant difference in response rates (P = 0.08). The median progression-free survival (PFS) was numerically longer in CTE patients (28 vs 12 months; P = 0.09). The overall survival (OS) was higher in the CTE patients (P = 0.02). In the ipilimumab/nivolumab cohort (n = 103), 59 (57%) were CTI. The most common reasons for ineligibility were brain metastases (n = 18), lab abnormalities (n = 16), and histology (n = 16). There was no significant difference in response rates (P = 0.22). However, PFS (P = 0.003) and OS (P < 0.0001) were higher in the CTE patients. In conclusion, many real-world patients are ineligible for RCC clinical trials and had worse outcomes when compared to trial-eligible patients. Additional treatment options are needed for these patients, as well as strategies to include them in prospective trials.

This report recounts the diagnostic workup of a pediatric female who presented with hematuria secondary to a large renal mass visualized on abdominal imaging. Histologic assessment and subsequent immunohistochemistry studies were performed. Intense, unequivocal immunohistochemical expression of TFE3 and alpha-methylacyl-CoA-racemase with corresponding negativity for carbonic anhydrase IX, along with highly distinctive clinical, radiologic, gross, and microscopic findings confirmed the diagnosis of a renal cell carcinoma with TFE3 gene rearrangement - the first ever reported case in the Philippines. This case highlights the vital role and significant diagnostic impact of reliable, affordable and accessible immunohistochemistry studies in low-resource settings where molecular modalities for evaluating rare diseases are largely unavailable. Recognition of distinctive morphologic, immunohistochemical, and cytogenetic features in childhood and adolescent renal malignancies allows for the timely institution of therapeutic interventions for this aggressive entity.