Search Results (16)

Background/Objectives: Cowden syndrome (or PTEN hamartoma tumor syndrome) (CS/PHTS) belongs to a group of inherited disorders associated with the development of multiple hamartomas. The clinical presentation of patients may include dysmorphic facial features, macrocephaly, developmental delay, and multiple benign and malignant tumors of various localizations. At the same time, only thyroid cancer is thought to have an increased risk in childhood. Skin lesions in CS/PHTS occur in 90–100% of patients and include multiple tricholemmoma, papilloma, acral keratosis, pigmentation changes, as well as rarer forms like vascular malformations, fibromas, neuromas, melanoma, and basal cell carcinoma. Methods: Next-generation sequencing and Sanger sequencing were used to search for PTEN genetic variants. A histological and immunohistochemical examination of tumor biopsies and skin lesions was performed. Results: A total of 13 patients from six families with CS/PHTS, including 10 children, were described. Seven pediatric patients belonged to families with paternal transmission of the PTEN pathogenic variants, while three others were de novo cases. Atypical manifestations in CS/PHTS were diffuse large B-cell lymphoma in one adult, a renal cell carcinoma, three germ cell tumors, and a linear epidermal nevus in pediatric patients. A literature review of the identified pathogenic variants in the PTEN gene was performed, assessing their clinical significance and analyzing the traditional and modified diagnostic criteria as applied to the pediatric population. Conclusions: Taking into account the low incidence of CS/PHTS, the data presented significantly expand our current understanding of this disease and guide physicians to consider a wider range of possible malignant neoplasms in pediatric patients with CS/PHTS. Full article

Background/Objectives: Wilms tumors, the most common pediatric renal tumors, are heterogeneous and consist of varying amounts of three components: blastema, epithelium, and stroma. Postoperative chemotherapy is tailored based on risk group classification and stage. Due to this heterogeneity, pathologists perform extensive tumor sampling to ensure accurate classification. Higher-harmonic-generation microscopy (HHGM) is an innovative imaging technique that enables rapid visualization of fresh tissue without preparation or staining. This makes it particularly valuable for sample selection, as the tissue can be reused for further analysis. This study aims to evaluate the accuracy of pathologists in distinguishing normal renal tissue, abnormal renal tissue, and three types of pediatric renal tumors, Wilms tumor, renal cell carcinoma, and congenital mesoblastic nephroma, in HHGM images. Methods: Twenty-nine samples from eighteen patients with a pediatric renal tumor were imaged using an HHG microscope and subsequently processed for histological analysis. Overview images of the samples were acquired at a rate of 10 s per mm², while high-quality images took 1 min per mm². A multi-observer study involving ten international expert pathologists of the SIOP-RTSG was conducted. Results: Pathologists were able to differentiate between normal and abnormal tissue with 100% (29/29) accuracy and correctly identified tumor versus non-tumor tissue with 97% (28/29) accuracy. Conclusions: These results show that HHGM is a highly promising technique for the rapid assessment of pediatric renal tumor samples, particularly for evaluating sample representativeness. Full article

Advances in treatment have dramatically improved the outcomes of pediatric renal malignancies. We reviewed cases of renal malignant tumors that were managed in our institution. The patients’ background factors, pathological diagnoses, stages, outcomes and late complications were retrospectively reviewed using medical records of 28 patients with renal tumors who were treated at our institution from 1984 to 2022. Wilms’ tumors were recognized in 24 patients (85.7%), all of whom had favorable histology. Wilms’ tumors were Stage I in six patients (6/24; 25.0%), Stage II in nine patients (9/24; 37.5%), Stage III in five patients (5/24; 20.8%), Stage IV in two patients (2/24; 8.3%), and Stage V in two patients (2/24; 8.3%). Two patients (7.1%) with clear cell sarcoma of the kidney both had Stage I disease. One patient had Stage IV rhabdoid sarcoma of the kidney (3.5%), and one had Stage IV renal cell carcinoma (3.5%). The overall 5-year survival rate was 85.2% for all renal malignancies. Late complications included chronic renal failure in four patients (14.2%). The outcomes are comparable to those reported previously. However, the prognosis of MRTK and renal cell carcinoma remained poor in advanced cases; thus, another therapeutic protocol should be established. Full article

Objective: Renal cell carcinoma (RCC) is a rare but severe and aggressive pediatric malignancy. While incidence is uncommon, survival is relatively low with respect to acute lymphocytic leukemia (ALL), AML, lymphoma, ependymoma, glioblastoma, and Wilms Tumor. The pediatric renal cell carcinoma (pRCC) incidence, cumulative incidence (period prevalence), and mortality vary by health disparities’ indicators, namely sex, race, ethnicity, age at tumor diagnosis, and social determinants of health (SDHs) as well as Epigenomic Determinants of Health (EDHs). However, studies are unavailable on some pRCC risk determinants, such as area of residence and socio-economic status (SES). The current study aimed at assessing the temporal trends, cumulative incidence, household median income, urbanity, mortality, and pRCC survival differentials. Materials and Methods: A retrospective cohort design was utilized to examine the event-free survival of children (0–19) with RCC using the Surveillance Epidemiology and End Result Data, 1973–2015. While the time-dependent variable, namely survival months, was utilized, we assessed the predictors of pRCC survival, mainly sex, age at diagnosis, education, insurance status, income, and tumor grade, as prognostic factors. In examining the joint effect of area of residence and race, as an exposure function with time in survival, we utilized the Cox proportional hazard model, while the annual percent change was assessed using a generalized linear model, implying a weighted average. Results: Between 1973 and 2015, there were 174 cases of pRCC, of whom 49 experienced mortality (28.2%). The pRCC cumulative incidence tends to increase with advancing age. A significant survival differential was observed between black/AA children with RCC and their white counterparts. Compared with white children, black/AA children were almost three times as likely to die, hazard ratio (HR) = 2.90, 95% CI = 1.56–5.31, p = 0.001. A survival differential was observed in sex, with males presenting with a 21% increased likelihood of dying, HR = 1.21; 95% CI, 0.69–2.11. In the metropolitan area, the risk of dying was almost three times as likely among black/AA children compared to their white counterparts, HR = 2.78; 95% CI, 1.45–5.43, while in the urban area, the risk of dying was almost four times as likely among black/AA children compared to their white counterparts, HR = 4.18; 95% CI, 0.84–20.80. After controlling for age, sex, education, and insurance, the risk of dying increased amongst black/AA children in metropolitan areas, adjusted HR (aHR) = 3.37, 99% CI = 1.35–8.44. In the urban area, after adjustment for age, sex, and insurance, there was an increased risk of dying for black/AA children, compared with their white counterparts with pRCC, aHR = 8.87, 99% CI = 2.77–28.10. Conclusion: pRCC indicates an increased trend in males and age at diagnosis between 10 and 14, as well as a survival disadvantage among black/AA children, compared with their white counterparts. Additionally, urbanity significantly influences the racial differences in survival. These data are suggestive of the conjoined effect of environment and race in pRCC survival, indicative of further assessment of gene–environment interaction (epigenomics) in incidence, mortality, and survival in pRCC. Full article

The Bosniak classification of renal cysts aims to provide a probabilistic risk assessment indicating the likelihood of malignancy from imaging findings. Originally designed to classify adult renal cysts based on computed tomography findings, the Bosniak classification has been extended to pediatric patients, with some adjustments made with the aim of accommodating magnetic resonance imaging (MRI) and ultrasonography (US). Bosniak IV lesions are rare in adolescents, indicating localized renal cell carcinoma and requiring surgical intervention. In contrast, Bosniak III lesions can be treated conservatively, although there is a lack of specific guidelines on their management. We present a case of a 14-year-old boy with a Bosniak III lesion, which was incidentally detected during the US evaluation of a left varicocele. After a 12-month follow-up, MRI revealed progression to a Bosniak IV cyst. Robot-assisted tumor enucleation was performed with selective artery clamping when the patient was 15. Histopathology showed tubulocystic renal cell carcinoma without adverse features. Immunocytochemistry supported a favorable prognosis of this rare tumor (<1% of renal tumor), thus obviating the need for adjuvant treatment. At the 18-month follow-up, no recurrence or distant metastasis were observed. This case highlights the importance of an aggressive treatment in persistent Bosniak III and Bosniak IV renal cysts in children and adolescents and the necessity to offer a nephron-sparing surgery. Full article

Renal tumors comprise ~7% of all malignant pediatric tumors. Approximately 90% of pediatric kidney tumors comprise Wilms tumors, and the remaining 10% include clear cell sarcoma of the kidney, malignant rhabdoid tumor of the kidney, renal cell carcinoma and other rare renal tumors. Over the last 30 years, the role of cytokines and their receptors has been considerably investigated in both cancer progression and anti-cancer therapy. However, more effective immunotherapies require the cytokine profiling of each tumor type and comprehensive understanding of tumor biology. In this study, we aimed to investigate the activation of signaling pathways in response to cytokines in three pediatric kidney tumor cell lines, in WT-CLS1 and WT-3ab cells (both are Wilms tumors), and in G-401 cells (a rhabdoid kidney tumor, formerly classified as Wilms tumor). We observed that interferon-alpha (IFN-α) and interferon-gamma (IFN-γ) very strongly induced the activation of the STAT1 protein, whereas IL-6 and IFN-α activated STAT3 and IL-4 activated STAT6 in all examined tumor cell lines. STAT protein activation was examined by flow cytometry and Western blot using phospho-specific anti-STAT antibodies which recognize only activated (phosphorylated) STAT proteins. Nuclear translocation of phospho-STAT proteins upon activation with specific cytokines was furthermore confirmed by immunofluorescence. Our results also showed that both IFN-α and IFN-γ caused upregulation of major histocompatibility complex (MHC) class I proteins, however, these cytokines did not have any effect on the expression of MHC class II proteins. We also observed that pediatric kidney tumor cell lines exhibit the functional expression of an additional cytokine signaling pathway, the tumor necrosis factor (TNF)-α-mediated activation of nuclear factor kappa B (NF-κB). In summary, our data show that human pediatric renal tumor cell lines are responsive to stimulation with various human cytokines and could be used as in vitro models for profiling cytokine signaling pathways. Full article

Pediatric renal cell carcinoma (RCC) is a rare malignancy. Magnetic resonance imaging (MRI) is the preferred imaging modality for assessment of these tumors. The previous literature has suggested that cross-sectional-imaging findings differ between RCC and other pediatric renal tumors and between RCC subtypes. However, studies focusing on MRI characteristics are limited. Therefore, this study aims to identify MRI characteristics of pediatric and young-adult RCC, through a single-center case series and literature review. Six identified diagnostic MRI scans were retrospectively assessed, and an extensive literature review was conducted. The included patients had a median age of 12 years (63–193 months). Among other subtypes, 2/6 (33%) were translocation-type RCC (MiT-RCC) and 2/6 (33%) were clear-cell RCC. Median tumor volume was 393 cm³ (29–2191 cm³). Five tumors had a hypo-intense appearance on T2-weighted imaging, whereas 4/6 were iso-intense on T1-weighted imaging. Four/six tumors showed well-defined margins. The median apparent diffusion coefficient (ADC) values ranged from 0.70 to 1.20 × 10⁻³ mm²/s. In thirteen identified articles focusing on MRI characteristics of MiT-RCC, the majority of the patients also showed T2-weighted hypo-intensity. T1-weighted hyper-intensity, irregular growth pattern and limited diffusion–restriction were also often described. Discrimination of RCC subtypes and differentiation from other pediatric renal tumors based on MRI remains difficult. Nevertheless, T2-weighted hypo-intensity of the tumor seems a potential distinctive characteristic. Full article

All-trans retinoic acid is a morphogen during embryogenesis and a teratogen. Cancer is an error of development, and the retinoic acid receptors (RAR) for all-trans retinoic acid play a role in cancer. Expression of the cytosolic aldehyde dehydrogenases, which mediate the last step to the synthesis of all-trans retinoic acid, is deregulated in various human cancers. Inhibiting these enzymes using a variety of agents reduced the proliferation of lung cancer cells, reduced the proliferation and induced apoptosis of ovarian, prostate, squamous, and uterine cancer cells, and sensitised breast, colorectal and ovarian cancer cells to chemotherapeutic agents. RARγ is an oncogene within some cases of AML, cholangiocarcinoma, colorectal cancer, clear cell renal cell carcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, prostate cancer, and ovarian cancer. Pan-RAR and RARγ antagonist inhibition of the action of RARγ led to necroptosis of human prostate and pediatric brain tumour cancer stem cells. Treatment of hepatocellular carcinoma cells with the flavenoid acacetin, which interferes with the action of RARγ, decreased cell growth and induced apoptosis. Targeting the retinoic acid pathway is promising regarding the development of new drugs to eradicate cancer stem cells. Full article

MiTF/TFE translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of RCC representing the most prevalent RCC in the pediatric population (up to 40%) and making up 4% of all RCCs in adults. It is characterized by translocations involving either TFE3 (TFE3-tRCC), TFEB (TFEB-tRCC) or MITF, all members of the MIT family (microphthalmia-associated transcriptional factor). TFE3-tRCC was first recognized in the World Health Organization (WHO) classification of kidney cancers in 2004. In contrast to TFEB-tRCC, TFE3-tRCC is associated with many partners that can be detected by RNA or exome sequencing. Both diagnoses of TFE3 and TFEB-tRCC are performed on morphological and immunohistochemical features, but, to date, TFE break-apart fluorescent in situ hybridization (FISH) remains the gold standard for diagnosis. The clinical behavior of tRCC is heterogeneous and more aggressive in adults. Management of metastatic tRCC is challenging, especially in the younger population, and data are scarce. Efficacy of the standard of care-targeted therapies and immune checkpoint inhibitors remains low. Recent integrative exome and RNA sequencing analyses have provided a better understanding of the biological heterogeneity, which can contribute to a better therapeutic approach. We describe the clinico-pathological entities, the response to systemic therapy and the molecular features and techniques used to diagnose tRCC. Full article

Renal medullary carcinoma (RMC) is a rare renal malignancy that has been associated with sickle hemoglobinopathies. RMC is aggressive, difficult to treat, and occurs primarily in adolescents and young adults of African ancestry. This cancer is driven by the loss of SMARCB1, a tumor suppressor seen in a number of primarily rare childhood cancers (e.g., rhabdoid tumor of the kidney and atypical teratoid rhabdoid tumor). Treatment options remain limited due in part to the limited knowledge of RMC biology. However, significant advances have been made in unraveling the biology of RMC, from genomics to therapeutic targets, over the past 5 years. In this review, we will present these advances and discuss what new questions exist in the field. Full article

Sunitinib is a broad-spectrum multitargeted tyrosine kinase inhibitor mainly used as second-line therapy for non-resectable gastrointestinal stromal or first-line treatment option of metastatic renal cell carcinoma (mRCC), and as an “off-label” option in pediatric oncology. It has been previously reported that sunitinib elevates the mean corpuscular volume of erythrocytes (MCV) in treated subjects. The aim of this study was to assess time-dependent changes of this effect and evaluate its possible clinical relevance. In this study, 179 adult and 21 pediatric patients with solid tumors treated with sunitinib were retrospectively analyzed. The laboratory and treatment-related data were collected for each treatment period. The regression model with a broken-line relationship was used to fit time dependence of the MCV. In the adult group, the MCV was increasing during the first 21.6 weeks (median) of treatment in a median level of 99.8 fL, where it stabilized. MCV increase was faster in the patients who suffered from treatment-related adverse events (21.3 vs. 24.6 weeks, p = 0.010). In the pediatric cohort, the MCV dynamics were similar to adults. In conclusion, MCV changes during sunitinib treatment in pediatric and adult patients may be of clinical utility in monitoring sunitinib treatment course. Full article

There is a need for agents that eliminate cancer stem cells, which sustain cancer and are also largely responsible for disease relapse and metastasis. Conventional chemotherapeutics and radiotherapy are often highly effective against the bulk of cancer cells, which are proliferating, but spare cancer stem cells. Therapeutics that target cancer stem cells may also provide a bona fide cure for cancer. There are two rationales for targeting the retinoic acid receptor (RAR)γ. First, RARγ is expressed selectively within primitive cells. Second, RARγ is a putative oncogene for a number of human cancers, including cases of acute myeloid leukemia, cholangiocarcinoma, and colorectal, renal and hepatocellular carcinomas. Prostate cancer cells depend on active RARγ for their survival. Antagonizing all RARs caused necroptosis of prostate and breast cancer stem cell-like cells, and the cancer stem cells that gave rise to neurospheres from pediatric patients’ primitive neuroectodermal tumors and an astrocytoma. As tested for prostate cancer, antagonizing RARγ was sufficient to drive necroptosis. Achieving cancer-selectively is a longstanding paradigm for developing new treatments. The normal prostate epithelium was less sensitive to the RARγ antagonist and pan-RAR antagonist than prostate cancer cells, and fibroblasts and blood mononuclear cells were insensitive. The RARγ antagonist and pan-RAR antagonist are promising new cancer therapeutics. Full article

Recent advances in artificial intelligence (AI) have certainly had a significant impact on the healthcare industry. In urology, AI has been widely adopted to deal with numerous disorders, irrespective of their severity, extending from conditions such as benign prostate hyperplasia to critical illnesses such as urothelial and prostate cancer. In this article, we aim to discuss how algorithms and techniques of artificial intelligence are equipped in the field of urology to detect, treat, and estimate the outcomes of urological diseases. Furthermore, we explain the advantages that come from using AI over any existing traditional methods. Full article

Pediatric renal cancer is rare, and robust evidence for treatment recommendations is lacking. In the perspective of personalized medicine, clinicians need new biomarkers to improve risk stratification and patients’ follow-up. Herein, we analyzed some liquid biopsy tools, which have been never tested in pediatric renal cancer: namely, circulating tumor cells (CTCs); the expression of M30, an apoptosis marker, to test CTC metastatic potential; and c-MET expression in CTCs, because of its role in renal cancer progression and drug-resistance. Furthermore, we evaluated the Circulating Endothelial Cells (CECs), whose utility we previously demonstrated in adult metastatic renal cancer treated with anti-angiogenic therapy. We compared two renal cell carcinomas of clear-cell type, stage I and IV, which underwent surgery and surgery plus Sunitinib, respectively. Baseline CTC level and its changes during follow-up were consistent with patients’ outcome. In case 2, stage IV, the analysis of CECs performed during Sunitinib revealed a late response to treatment consistent with poor outcome, as the finding of M30-negative, viable cells. Noteworthily, few CTCs were MET-positive in both cases. Our study highlights the feasibility for a change in the prognostic approach and follow-up of childhood renal cancer, with a view to guide a better treatment design. Full article

Pediatric renal cell carcinoma (RCC) is a rare type of kidney cancer, most commonly occurring in teenagers and young adolescents. Few relatively large series of pediatric RCC have been reported. Knowledge of clinical characteristics, outcome and treatment strategies are often based on the more frequently occurring adult types of RCC. However, published pediatric data suggest that clinical, molecular and histological characteristics of pediatric RCC differ from adult RCC. This paper summarizes reported series consisting of ≥10 RCC pediatric patients in order to create an up-to-date overview of the clinical and histopathological characteristics, treatment and outcome of pediatric RCC patients. Full article