Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.

Frequency of benign tumors after partial nephrectomy and the association between malignant tumor findings and preoperative clinical parameters.

BACKGROUND: Partial nephrectomy (PN) has become the dominant treatment modality for cT1 renal tumor lesions. Tumors suspected of malignant potential are indicated for surgery, but some are histologically classified as benign lesions after surgery. This study aims to analyze the number of benign findings after PN according to definitive histology and to evaluate whether there is an association between malignant tumor findings and individual factors. METHODS: The retrospective study included 555 patients who underwent open or robotic-assisted PN for a tumor in our clinic from January 2013 to December 2020. The cohort was divided into groups according to definitive tumor histology (malignant tumors vs. benign lesions). The association of factors (age, sex, tumor size, R.E.N.A.L.) with the malignant potential of the tumor was further evaluated. RESULTS: In total, 462 tumors were malignant (83%) and 93 benign (17%). Of the malignant tumors, 66% were clear-cell RCC (renal cell carcinoma), 12% papillary RCC, and 6% chromophobe RCC. The most common benign tumor was oncocytoma in 10% of patients, angiomyolipoma in 2%, and papillary adenoma in 1%. In univariate analysis, there was a higher risk of malignant tumor in males (OR 2.13, 95% CI 1.36-3.36, p = 0.001), a higher risk of malignancy in tumors larger than 20 mm (OR 2.32, 95% CI 1.43-3.74, p < 0.001), and a higher risk of malignancy in tumors evaluated by R.E.N.A.L. as tumors of intermediate or high complexity (OR 2.8, 95% CI 1.76-4.47, p < 0.001). In contrast, there was no association between older age and the risk of malignant renal tumor (p = 0.878). CONCLUSIONS: In this group, 17% of tumors had benign histology. Male sex, tumor size greater than 20 mm, and intermediate or high R.E.N.A.L. complexity were statistically significant predictors of malignant tumor findings.

Comprehensive Genomic Profiling of NF2-Mutated Kidney Tumors Reveals Potential Targets for Therapy.

Genomic alterations (GA) in NF2 tumor-suppressor gene have been associated with aggressive behavior in kidney tumors. We used comprehensive genomic profiling (CGP) to evaluate the frequencies of NF2 GA in histologic subtypes of kidney tumors and co-occurring GA in other genes and biomarkers. Advanced kidney tumors included 1875 clear cell (ccRCC), 405 papillary (pRCC), 108 chromophobe (chRCC), 171 sarcomatoid (sRCC), 61 collecting duct (cdRCC), 49 medullary (mRCC), 134 unclassified (uRCC), 906 urothelial carcinoma of renal pelvis (UC), and 147 Wilms tumors underwent hybrid-capture based CGP to evaluate all classes of GA. 192 (4.9%) of kidney tumors featured NF2 GA which were predominantly structural variant mutations (89%), followed by copy number alterations (9%). Gender and age were similar between NF2-mutant (NF2mut) and NF2-wild type (NF2wt) cohorts with male preponderance. NF2 GA frequency was highest in cdRCC (30%), sRCC (21%), uRCC (15%), and pRCC (12%) while lowest in ccRCC (3%), UC (3%) Wilms tumor (1%), and chRCC (0%). NF2 mutational status was associated with loss of Ch 22 (P < .001). NF2mut RCC harbored co-occurring GA including CDKN2A, CDKN2B, SETD2, and BAP1. VHL, PBRM1, PTEN, and FGFR3 GA were significantly more frequent in NF2wt than in NF2mut tumors. MTOR pathway GAs were uncommon in NF2mut tumors. No NF2 mutated RCC featured MSI-high or high TMB. sRCC was associated with high PD-L1 expression. PD-L1 SP142 tumoral (P = .04) and immune cells (P = .013) were more frequent in NF2mut as compared to NF2wt group. Among histologic subtypes of RCC, cdRCC, sRCC, pRCC, and uRCC are enriched in NF2 GA. Co-occurrent GA in CDKN2A/B, SETD2, and BAP1 may represent potential therapeutic targets. Higher level of PD-L1 expression in NF2mut cohort suggests that these tumors might be sensitive to immune checkpoint inhibitor therapies.

Decoding the Possible Molecular Mechanisms in Pediatric Wilms Tumor and Rhabdoid Tumor of the Kidney through Machine Learning Approaches.

Objective: Wilms tumor (WT) and Rhabdoid tumor (RT) are pediatric renal tumors and their differentiation is based on histopathological and molecular analysis. The present study aimed to introduce the panels of mRNAs and microRNAs involved in the pathogenesis of these cancers using deep learning algorithms. Methods: Filter, graph, and association rule mining algorithms were applied to the mRNAs/microRNAs data. Results: Candidate miRNAs and mRNAs with high accuracy (AUC: 97%/93% and 94%/97%, respectively) could differentiate the WT and RT classes in training and test data. Let-7a-2 and C19orf24 were identified in the WT, while miR-199b and RP1-3E10.2 were detected in the RT by analysis of Association Rule Mining. Conclusion: The application of the machine learning methods could identify mRNA/miRNA patterns to discriminate WT from RT. The identified miRNAs/mRNAs panels could offer novel insights into the underlying molecular mechanisms that are responsible for the initiation and development of these cancers. They may provide further insight into the pathogenesis, prognosis, diagnosis, and molecular-targeted therapy in pediatric renal tumors.

Anaplastic Sarcoma of the Kidney With Heterologous Ganglioneuroblastic Differentiation: Another DICER1-Associated Tumor.

Anaplastic sarcoma of the kidney (ASK) is a rare renal tumor for which less than thirty cases have been described in the literature to date. Diagnosis of ASK is primarily based on histology, which features solid spindle cell neoplastic islands arranged in a fascicular pattern, prominent anaplastic nuclear morphology, brisk mitoses, and multiple multiloculated cysts lined by hobnail epithelium reminiscent of cystic nephroma. Chondroid or rhabdomyocytic differentiation is often present within the sarcoma. It has been recently suggested that this tumor entity belongs to the DICER1 syndrome tumors based on identification of DICER1 mutations. We report on a case of this rare tumor found in a twenty-month-old female. In addition to the typical histologic findings of ASK, this case also displayed heterologous neuroblastic-gangliocytic differentiation, which has not been previously described in the literature. TP53 and BRAF v600E had aberrant immunostaining. Chromosomal microarray and genomic sequencing revealed loss of chromosome 10 p15.3-p11.2 and both somatic and germline DICER1 mutations, consistent with recent research and further supporting the classification of this tumor within the DICER1 syndrome associated tumors.

[Rare kidney tumor - thyroid-like follicular carcinoma]. / Redkaya opukhol' pochki ­ tireoidopodobnaya follikulyarnaya kartsinoma.

The literature review provides an analysis of a rare malignant tumor of the kidney: thyroid-like follicular carcinoma of the kidney (TLFCK). In morphology, this tumor is extremely similar to thyroid follicular carcinoma, but the immunophenotype of tumor cells is different. TLFCK has an indolent clinical course, rarely metastasizes, and even the development of metastases does not mean an unfavorable prognosis for the patient. The literature review presents the features of the clinical course of the disease, macroscopic, microscopic, immunohistochemical characteristics of the tumor and typical cytogenetic breakdowns. Particular attention is paid to the issues of differential diagnosis of the tumor with other pathological processes that may microscopically resemble TLFCK.

[Are multiple trichodiscomas/fibrofolliculomas the Birt-Hogg-Dubé syndrome?] / Mnozhestvennye trikhodiskomy/fibrofollikulomy ­ sindrom Berta­Khogg­D'yuba?

Birt-Hogg-Dubé syndrome is a rare autosomal dominant disease caused by a mutation in the FLCN gene and presents with a triad of multiple fibrofolliculomas, trichodiscomas, and masses that clinically resemble fibroepithelial polyps (acrochordones), accompanied by an increased risk of kidney tumors and lung cysts. The paper provides a literature review supplemented by clinical cases and the morphological pattern of skin lesions. It presents the clinical and morphological features of cutaneous manifestations of the syndrome and gives diagnostic criteria.

Feasibility of adopting retroperitoneal robotic partial nephrectomy after extensive transperitoneal experience.

PURPOSE: Adoption of robotic retroperitoneal surgery has lagged behind robotic surgery adoption in general due to unique challenges of access and anatomy. We evaluated our initial results with robotic retroperitoneal robotic partial nephrectomy (RRPN) after transitioning from exclusively transperitoneal robotic partial nephrectomy (TRPN) to evaluate safety and any identifiable learning curve. METHODS: We evaluated our single-surgeon (RA) prospective partial nephrectomy database since adopting RRPN routinely for posterior tumors in 2017. The surgeon had previously performed 410 partial nephrectomies by this time. Outcomes were compared after the initial 30 RRPN. RESULTS: Of 137 patients since adopting RRPN, two attempted RRPN were converted to TRPN without complications due to morbid obesity affecting access, and 30 RRPN were completed (107 TRPN). There were no statistically significant differences in demographics, mean tumor size, or RENAL score between groups. Mean blood loss was lower in RRPN (53 mL vs 99 mL, P < 0.05), but there were no transfusions in either group. There was no difference in mean operative (127.8 min vs 141.2 min, P = 0.06) or ischemia time (11.1 min vs 10.8 min, P = 0.98). There were no positive margins in either group. Mean length of stay was lower in RRPN due to more same-day discharges (0.7 vs 0.9 days). There were no 90-day Clavien III-V complications. One RRPN patient was readmitted POD#8 overnight for hypoxia, and one visited the emergency room POD#7 for persistent pain. All three TRPN complications were managed as outpatients. CONCLUSIONS: Successful adoption of RRPN can be achieved readily after experience with TRPN. Outcomes were immediately comparable without any identifiable learning curve.

Circulating tumor DNA analysis enables molecular characterization of pediatric renal tumors at diagnosis.

Circulating tumor DNA (ctDNA) is a powerful tool for the molecular characterization of cancer. The most frequent pediatric kidney tumors (KT) are Wilms' tumors (WT), but other diagnoses may occur. According to the SIOP strategy, in most countries pediatric KT have a presumptive diagnosis of WT if they are clinically and radiologically compatible. The histologic confirmation is established after post-chemotherapy nephrectomy. Thus, there is a risk for a small fraction of patients to receive neoadjuvant chemotherapy that is not adapted to the disease. The aim of this work is to perform molecular diagnosis of pediatric KT by tumor genetic characterization based on the analysis of ctDNA. We analyzed ctDNA extracted from plasma samples of 18 pediatric patients with KT by whole-exome sequencing and compared the results to their matched tumor and germline DNA. Copy number alterations (CNAs) and single nucleotide variations (SNVs) were analyzed. We were able to detect tumor cell specific genetic alterations-CNAs, SNVs or both-in ctDNA in all patients except in one (for whom the plasma sample was obtained long after nephrectomy). These results open the door to new applications for the study of ctDNA with regards to the molecular diagnosis of KT, with a possibility of its usefulness for adapting the treatment early after diagnosis, but also for disease monitoring and follow up.

Pediatric Anastomosing Hemangioma: Case Report and Review of Renal Vascular Tumors in Children.

The case involves a 10-year-old child who underwent a left radical nephrectomy for what was believed to be a Wilms' tumor. Histopath examination indicated a benign vascular lesion, subsequently determined to be an anastomosing hemangioma of the kidney. A comparison with the previously cited pediatric patients with renal vascular tumors is provided, and the inconsistent diagnostic terminologies for these conditions are highlighted. The therapeutic implications of these predominantly benign renal tumors, in the context of the much more frequently encountered malignant neoplasms in children, are additionally discussed.

[Laparoscopic ultrasound guided partial nephrectomy].

INTRODUCTION: The choice of method of surgical treatment for endophytic kidney tumors depends on the precise definition of the location and size, the extent of invasion into adjacent tissues and the type of vascularization. Intraoperative ultrasound (IOUS) in combination with 3D-CT allow to receive this information. The aim of this study was to compare the laparoscopic-assisted extracorporeal partial nephrectomy and laparoscopic partial nephrectomy with IOUS and visualization in Full HD, 3D Full HD and 4K modes. MATERIALS AND METHODS: A total of 77 patients aged 43-75 years with endophytic renal tumors were included in the study. They were undergone either extracorporeal partial nephrectomy or laparoscopic partial nephrectomy with IOUS. We compared the rate of positive surgical margins, early postoperative bleeding, de novo renal failure or aggravation of preexisting renal failure and stricture of vesico-ureteric anastomosis. RESULTS: The rate of early postoperative bleeding, chronic kidney failure and pathologically-proven positive surgical margin in patients who underwent extracorporeal partial nephrectomy followed by kidney autotransplantation was 23.1%, 13.4% and 13.4%, respectively. After laparoscopic partial nephrectomy these values were 12%, 16.7% and 8.3%, respectively. The best outcomes were achieved in patients who underwent laparoscopic partial nephrectomy with IOUS and with a use of visualization in Full HD, 3D Full HD and 4K modes.

The Effect on Survival and Mortality of the Highest SUVmax Value on Metastatic Foci in Postoperative Kidney Tumors.

OBJECTIVE: One-third of patients newly diagnosed with a kidney tumor have metachoronous disease, 25-50% have synchronous metastasis, and approximately 30-40% of patients have metastasis at the time of diagnosis. Metastasis mostly occurs in the lungs, regional lymph nodes, bones, and liver. The present study was aimed to determine the effect on mortality the values of standard uptake value (SUV)max measured with positron emission tomography (PET) in metastases of kidney tumors. MATERIAL AND METHODS: A retrospective review was conducted of the files of 77 patients newly diagnosed with kidney tumor and disease staging determined with PET in the Nuclear medicine Department of Saglik Bilimleri University Diyarbakir Gazi Yasargil Training and Research Hospital between August 2007 and April 2012. The gender, age, histological types, metastases, SUVmax values, and dates of death of the patients were recorded in the SPSS software. RESULTS: It was observed that higher SUVmax values indicated a shorter survival time (r = .303) (P = 0.022). Patients with metastasis lived for a shorter period (P < 0.001), particularly those with liver metastasis (r = .515) (P = 0.049). Metastases were most frequently seen in lymph nodes (42.1%); the SUVmax values of lung metastases were higher (P = 0.025) and papillary carcinomas showed higher SUVmax uptake (P = 0.015). CONCLUSIONS: In the present study, it was concluded that the higher the SUVmax value the shorter the survival time. The survival time of patients with metastasis was shorter, and this could be estimated through the measured SUVmax values.

Personalized 3D printed model of kidney and tumor anatomy: a useful tool for patient education.

PURPOSE: To assess the impact of 3D printed models of renal tumor on patient's understanding of their conditions. Patient understanding of their medical condition and treatment satisfaction has gained increasing attention in medicine. Novel technologies such as additive manufacturing [also termed three-dimensional (3D) printing] may play a role in patient education. METHODS: A prospective pilot study was conducted, and seven patients with a primary diagnosis of kidney tumor who were being considered for partial nephrectomy were included after informed consent. All patients underwent four-phase multi-detector computerized tomography (MDCT) scanning from which renal volume data were extracted to create life-size patient-specific 3D printed models. Patient knowledge and understanding were evaluated before and after 3D model presentation. Patients' satisfaction with their specific 3D printed model was also assessed through a visual scale. RESULTS: After viewing their personal 3D kidney model, patients demonstrated an improvement in understanding of basic kidney physiology by 16.7 % (p = 0.018), kidney anatomy by 50 % (p = 0.026), tumor characteristics by 39.3 % (p = 0.068) and the planned surgical procedure by 44.6 % (p = 0.026). CONCLUSION: Presented herein is the initial clinical experience with 3D printing to facilitate patient's pre-surgical understanding of their kidney tumor and surgery.

[The potential of endovideosurgical technologies for simultaneous ipsilateral presentation of a kidney tumor and kidney stone].

AIM: To determine the treatment strategy in patients with kidney tumors co-occurring with ipsilateral kidney stones. MATERIALS AND METHODS: During the period from 2006 to 2015, a combination of kidney tumor and urolithiasis was detected in 159 (11.5%) patients. Of these, 61 patients had indications for surgical treatment for both diseases at the time of hospitalization. The article analyzes the surgical treatment results of 14 patients with ipsilateral combination of kidney stone and kidney tumors and shows the potential of endovideosurgical technologies in managing this category of patients. RESULTS: The surgical treatment for stones was initially conducted in 3 (21.4%) patients, 4 (28.6%) patients underwent the kidney tumor surgery at the first stage, and the remaining 7 (50.0%) patients underwent one-stage surgery for both diseases. Despite the co-occurrence of two pathologies in one kidney, only 2 patients (14.3%) underwent an organ-removing operation. DISCUSSION: Combined minimally invasive organ-sparing surgery for unilateral combination of the kidney stone and kidney tumor is the most preferable treatment option, allowing the patient to get rid of both the tumor and the kidney stone within one anesthesia session. One-stage laparoscopic kidney resection with pyelolithotomy or calycolithoextraction allows preventing possible complications associated with the postoperative stone migration and eliminates the need for repeat surgery.

PD-L1 expression in nonclear-cell renal cell carcinoma.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression in nonclear-cell RCC (non-ccRCC) and its association with clinical outcomes are unknown. METHODS: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 101 patients with non-ccRCC. PD-L1 expression was evaluated by immunohistochemistry in both tumor cell membrane and tumor-infiltrating mononuclear cells (TIMC). PD-L1 tumor positivity was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrate and percentage of positive cells was used. Baseline clinico-pathological characteristics and outcome data [time to recurrence (TTR) and overall survival (OS)] were correlated with PD-L1 staining. RESULTS: Among 101 patients, 11 (10.9%) were considered PD-L1+ in tumor cells: 2/36 (5.6%) of chromophobe RCC, 5/50 (10%) of papillary RCC, 3/10 (30%) of Xp11.2 translocation RCC and 1/5 (20%) of collecting duct carcinoma. PD-L1 positivity (PD-L1+) in tumor cells was significantly associated with higher stage (P = 0.01) and grade (P = 0.03), as well as shorter OS (P < 0.001). On the other hand, PD-L1 positivity by TIMC was observed in 57 (56.4%) patients: 13/36 (36.1%) of chromophobe RCC, 30/50 (60%) of papillary RCC, 9/10 (90%) of Xp11.2 translocation RCC and 5/5 (100%) of collecting duct carcinoma. A trend toward shorter OS was observed in patients with PD-L1+ in TIMC (P = 0.08). PD-L1+ in both tumor cell membrane and TIMC cells were associated with shorter TTR (P = 0.02 and P = 0.03, respectively). CONCLUSION: In non-ccRCC, patients with PD-L1+ tumors appear to have worse clinical outcomes, although only PD-L1 positivity in tumor cells is associated with higher tumor stage and grade.

Comparison of aggressiveness in central versus peripheral T1a clear-cell renal cell carcinoma.

PURPOSE: This study aimed to estimate the difference between peripheral and central small renal lesions in terms of their oncologic potential. METHODS: Cross-sectional retrospective analysis of patients with small renal masses (T1a) who underwent surgical treatment between January 2008 and July 2019 at the affiliated hospital. Only patients with ccRCC pathology were included. Cases were divided into 2 groups depending on tumor location (central or peripheral) based on the R.E.N.A.L and local nephrometry scoring. Presence of nodal involvement, distant metastases, ISUP grade and endophytic growth were defined as aggressiveness predictors. Statistical analyses was performed using a standard statistical software (IBM SPPS Statistics Ver. 22), with P < 0.05 considered statistically significant. Associations between tumor location and Fuhrman grade, exo-/endophytic growth, TNM classification, and type of operation were tested using the Pearson χ² test and 1-way ANOVA test. RESULTS: Patients with centrally located tumors had a higher incidence of clinical and pathological lymph node involvement (P = 0.02, χ2 = 5.1). Patients in both groups had an equal number of distant metastases at the time of diagnosis (P = 0.3, χ2 = 0.8). The operation time was significantly longer in patients with central lesions, which obviously showed higher tumor complexity in this group (P < 0.005). Pathological evaluation revealed differences between ISUP grades in both groups (P < 0.005, χ2 = 29.9). Central masses were characterized by higher aggressiveness, indicating a worse prognosis. Furthermore, the cases in the first group were more often endophytic (P = 0.03, χ2 = 0.9). Nevertheless, this did not affect the surgical strategy in most cases with a tendency toward partial nephrectomy. Eventually, organ-sparing treatment was preferable in both groups (P = 0.13, χ2 = 2.29). CONCLUSION: Centrally located kidney cancer has showed in present study a higher incidence of high ISUP grade, regional nodal involvement and endophytic growth type. Endophytic growth type was associated with worse ISUP grading. Distribution of ISUP grade was not age depended, thus showing no difference by this criterion, when comparing different age groups. Higher ISUP grade was strongly associated with presence of distant metastases in T1a kidney tumors. Further analysis is needed to investigate aggressiveness of centrally located T1a RCC, as it may influence current conservative management options.

Multivariate analysis of the parameters affecting the choice of surgical treatment for patients with localized renal cell carcinoma (RCC).

OBJECTIVE: to determine the key factors affecting the surgical treatment selection for patients with localized Renal-Cell Carcinoma (RCC) based on clinical and nephrometry data. MATERIALS AND METHODS: A retrospective cohort study to determine the key factors affecting the surgical treatment on a subset of patients with localized RCC (T1-T2) that underwent surgical treatment at primary investigational center from 2010 to 2017. Primary results were validated on the retrospective dataset of patients treated at high-volume referent center. Validation aimed to test applicability of the predictive model designed during primary analysis. To determine the relationship between the risks of radical or partial nephrectomy, the multivariate predictive modeling method was used. RESULTS: Based on the analysis, for polary and laterally located tumors, the risk of RN was conditioned only by remaining functioning parenchyma volume (RFPV). The average critical value of RFPV for polar lesions was = 58%; for lateral tumors = 67%. For medial location, the risk of RN only depended on the tumor size. Average critical value of the tumor size in the medial location was = 38mm. Based on the ROC curve comparison, there were no statistically significant differences between the predictive models containing 12 and 3 factors (AUCLin_12 and AUCMLP_3; P = 0.12); thus, the reduced amount of the factor indicators from 12 to 3 did not worsen the model predictive qualities. Designed during primary analysis hypothesis was successfully validated in a referent center on the cohort of 300 patients. Predictive model is characterized by high sensitivity (95.2%) and specificity (95.4%) in selecting patients for partial nephrectomy. CONCLUSIONS: For the polar and lateral tumor locations, the functioning parenchymal volumes of over 58 and 67% respectively serve as PN indications. However, for the medial lesions, the primary PN indication is a tumor size less than 38 mm.

A Subacute Presentation of Wunderlich Syndrome in a Young Woman: A Case Report.

Wunderlich syndrome (WS) is a rare, potentially life-threatening medical condition characterized by spontaneous renal or perinephric hemorrhage occurring in the absence of known trauma. WS usually presents as Lenk's triad: acute flank pain, flank mass sensation, and hypovolemic shock; however, the presentation of this condition can vary in terms of symptom type and duration. We present the case of a 23-year-old previously healthy woman who consulted our emergency department with an unusual subacute form of presentation of WS (eight days of pain) due to an angiomyolipoma. Considering that the patient was clinically stable, a conservative approach with strict follow-up with serial computed tomography scans was taken.

Report and follow-up on two new patients with congenital mesoblastic nephroma.

BACKGROUND: Tumors are rare in neonatal age. Congenital mesoblastic nephroma (CMN) is a usually benign renal tumor observed at birth, or in the first months of life. It may also be identified prenatally and associated with polyhydramnios leading to preterm delivery. Effective treatment is surgical in most cases, consisting in total nephrectomy. In literature, very few studies report on the neonatal management of such a rare disease, and even less are those describing its uncommon complications. CASES PRESENTATION: We report on two single-center newborns affected with CMN. The first patient is a preterm female baby, born at 30+ 1 weeks of gestation (WG) due to premature labor, with prenatal (25 WG) identification of an intra-abdominal fetal mass associated with polyhydramnios. Once obtained the clinical stability, weight gain, instrumental (computed tomography, CT, showing a 4.8 × 3.3 cm left renal neoformation) and histological/molecular characterization of the lesion (renal needle biopsy picture of classic CMN with ETV6-NTRK3 translocation), a left nephrectomy was performed at 5 weeks of chronological age. The following clinical course was complicated by intestinal obstruction due to bowel adherences formation, then by an enterocutaneous fistula, requiring multiple surgical approaches including transitory ileo- and colostomy, before the conclusive anastomoses intervention. The second patient is a 17-day-old male term baby, coming to our observation due to postnatal evidence of palpable left abdominal mass (soon defined through CT, showing a 7.5 × 6.5 cm neoformation in the left renal lodge), feeding difficulties and poor weight gain. An intravenous diuretic treatment was needed due to the developed hypertension and hypercalcemia, which regressed after the nephrectomy (histological diagnosis of cellular CMN with ETV6-NTRK3 fusion) performed at day 26. In neither case was chemotherapy added. Both patients have been included in multidisciplinary follow-up, they presently show regular growth and neuromotor development, normal renal function and no local/systemic recurrences or other gastrointestinal/urinary disorders. CONCLUSIONS: The finding of a fetal abdominal mass should prompt suspicion of CMN, especially if it is associated with polyhydramnios; it should also alert obstetricians and neonatologists to the risk of preterm delivery. Although being a usually benign condition, CMN may be associated with neonatal systemic-metabolic or postoperative complications. High-level surgical expertise, careful neonatological intensive care and histopathological/cytogenetic-molecular definition are the cornerstones for the optimal management of patients. This should also include an individualized follow-up, oriented to the early detection of any possible recurrences or associated anomalies and to a better quality of life of children and their families.

Evaluation of an institutional series of low-grade oncocytic tumor (LOT) of the kidney and review of the mutational landscape of LOT.

The 2022 WHO classification of urinary and male genital tumors introduced several novel kidney entities exhibiting eosinophilic/oncocytic features with specific mutational backgrounds. Thus, molecular techniques, such as next-generation sequencing (NGS), became more commonly used for their evaluation. We studied 12 low-grade oncocytic tumors (LOT) of the kidney (from 11 patients), identified in a cohort of 210 eosinophilic/oncocytic renal tumors, diagnosed in our institution between October 2019 and May 2023, which represented 5.7% (12/210) of all eosinophilic/oncocytic renal tumors during this period. We reviewed their clinicopathologic, histologic, and immunohistochemical features, as well as their mutational profiles. We also reviewed the literature on NGS-derived data of LOT, by selecting papers in which LOT diagnosis was rendered according to the criteria proposed initially. Median age was 65 years (mean: 63.5; range 43-79) and median tumor size was 2.0 cm (mean: 2.2; range: 0.9-3.1). All tumors were positive for PAX8, CK7, and GATA3, and negative or focally positive for CD117/KIT. We found the following gene mutations: MTOR ((6/11), 54.5%)), TSC1 ((2/11), 18.2%)), and 1 had both NOTCH1 and NOTCH4 ((1/11), 9.1%)). Wild-type status was found in 2/11 (18.2%) patients and one tumor was not analyzable. A review of 8 previous studies that included 79 LOTs revealed frequent mutations in the genes that regulate the mammalian target of rapamycin (mTOR) pathway: MTOR (32/79 (40.5%)), TSC1 (21/79 (26.6%)), and TSC2 (9/79 (11.4%)). Other mutated genes included PIK3CA, NF2, and PTEN, not typically known to affect the mTOR pathway, but potentially acting as upstream and downstream effectors. Our study shows that LOT is increasingly diagnosed in routine practice when applying the appropriate diagnostic criteria. We also confirm that the mTOR pathway is strongly implicated in the pathogenesis of this tumor mainly through MTOR, TCS1, and TSC2 mutations, but other genes could also be involved in the pathway activation, especially in LOTs without "canonical" mutations.