Pediatric Wilms Tumor Research Articles

Roles of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha, a lipid metabolism enzyme, in Wilms tumor patients.

Wilms tumor is a common pediatric malignant tumor that accounts for approximately 95% of kidney tumors in children. The role of lipid metabolism in tumors has attracted increased attention in recent years. We examined the role of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), a lipid metabolism enzyme, in the pathogenesis of Wilms tumor. In a previous study, we screened Wilms tumors and adjacent normal tissues for differentially expressed proteins by mass spectrometry and verified the results by western blot analysis. The Oncomine database and quantitative reverse transcription-polymerase chain reaction were used to verify the expression of HADHA at the genetic level. Immunohistochemistry and immunofluorescence were also used to validate the differential expression of the HADHA protein. The relationship between histopathological typing, clinical pathology, and HADHA expression was analyzed in 65 paraffin-embedded specimens from pediatric Wilms tumor patients. Kaplan-Meier survival curves were used to analyze the relationship between the expression of HADHA and patient prognosis. HADHA was expressed at low levels in Wilms tumor tissue compared with the corresponding normal tissue. The expression of HADHA was closely associated with histopathological typing (P = 0.030). The prognostic analysis of 65 children with Wilms tumor showed that high expression of HADHA was closely associated with poor prognosis (P = 0.046). HADHA expression is downregulated in Wilms tumor tissues, but high expression in tumor tissues is associated with clinical stage and the prognosis of children with this tumor.

Irinotecan Plus Doxorubicin Hydrochloride Liposomes for Relapsed or Refractory Wilms Tumor.

PurposeThe prognosis of relapsed or refractory pediatric Wilms tumor (WT) is dismal, and new salvage therapies are needed. This study aimed to evaluate the efficacy of the combination of irinotecan and a doxorubicin hydrochloride liposome regimen for relapsed or refractory pediatric WT.Patients and MethodsThe present study enrolled relapsed or refractory pediatric WT patients who were treated with the AI regimen (doxorubicin hydrochloride liposomes 40 mg/m2 per day, day 1, and irinotecan 50 mg/m2 per day with 90-min infusion, days 1–5; this regimen was repeated every 3 weeks) at Sun Yat-sen University Cancer Center from July 2018 to September 2020. The response was defined as the best-observed response after at least two cycles according to the Response Evaluation Criteria of Solid Tumors (RECIST 1.1), and toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE 4.03).ResultsA total of 16 patients (male:female, 8:8) with a median age of 4.2 years (0.5–11 years) with relapsed or refractory disease were enrolled in this study, including 14 patients with relapsed disease and two patients with refractory disease. These patients received 1–8 courses (median, 3 courses) of the AI regimen. Fourteen patients were assessable for response: two with complete response (CR), five with partial response (PR), two with stable disease (SD), and five with progressive disease (PD). The objective response rate was 50% (two CR, five PR), and the disease control rate was 64% (two CR, five PR, and two SD). Seven out of 14 patients (50%) were alive at the last follow-up, ranging from 2.6 to 32.4 months. The median progression-free survival and median overall survival were 3.5 months (range 0.5–12 months) and 8 months (range 1–28 months), respectively. Sixteen patients were assessable for toxicity, with the most common grade 3 or 4 adverse events being alopecia (62%), leukopenia (40%), abdominal pain (38%), diarrhea (23%), and mucositis (16%), etc. No fatal adverse events have been observed, and modest adverse effects can be administered.ConclusionIrinotecan and doxorubicin hydrochloride liposome regimens have positive efficacy on relapsed or refractory pediatric WT with well-tolerated toxicity. A prospective clinical trial is warranted.

Abstract 102: Breakpoints in Protocol Compliance and Their Influence on Outcomes for Children with Wilms Tumor in Northern Tanzania

Abstract Purpose: Standardized treatment protocols for Wilms tumor have been developed for use in low- and middle-income countries (LMICs), but equivalent outcomes as high-income countries are not achieved outside of clinical trials. To identify critical breakpoints in protocol adherence contributing to reduced outcomes, we evaluated treatment compliance and impact of the completion of each stage of therapy on outcomes for Wilms tumor patients at a regional cancer referral hospital in northern Tanzania. Methods: This is a retrospective single-center cohort study for children diagnosed with Wilms tumor from 2016-2019 in Tanzania, treated per the International Society of Pediatric Oncology (SIOP) Africa adapted (2016-17) or standard (2018-19) therapy protocols. Treatment compliance was evaluated for both timing of chemotherapy initiation, and completion of risk-adapted therapy duration per protocol. Results: A total of 72 patients were evaluated. The two-year overall survival and event-free survival rates were 44% and 27%, respectively. Only 22% of patients completed recommended chemotherapy per protocol. There were delays at each stage of treatment, especially time to surgery (74 days), pathology report (32 days), and initiation of postoperative chemotherapy (39 days). A total of 38% of patients abandoned care, with 44% of abandonment occurring prior to surgery, 30% immediately after surgery, and 26% during post-operative chemotherapy. Compliance with surgical resection (p=0.05) and postoperative chemotherapy (p=0.04) were predictive of two-year overall survival. Conclusion: Standardized Wilms tumor treatment protocol compliance outside of clinical trials is low in many LMICs. In the current study, noncompliance with recommended chemotherapy correlated to reduced overall survival rates, with several identified key health system delays contributing to poor compliance. Future interventions targeting health system delays are critical to improve protocol compliance, increasing overall survival for pediatric Wilms tumor patients in LMICs. Citation Format: Austin Wesevich, Mocha George, Frank Kiwara, Colin Chao, Idd Shabani, John Igenge, Kristin Schroeder. Breakpoints in Protocol Compliance and Their Influence on Outcomes for Children with Wilms Tumor in Northern Tanzania [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 102.

Spatio-Phenotypic Tumor Profiling via Single-Cell 3-D Image Analysis.

Single-cell 3-D imaging was used to spatially and phenotypically profile a pediatric Wilms tumor.

Revealing the spatio-phenotypic patterning of cells in healthy and tumor tissues with mLSR-3D and STAPL-3D.

Despite advances in three-dimensional (3D) imaging, it remains challenging to profile all the cells within a large 3D tissue, including the morphology and organization of the many cell types present. Here, we introduce eight-color, multispectral, large-scale single-cell resolution 3D (mLSR-3D) imaging and image analysis software for the parallelized, deep learning-based segmentation of large numbers of single cells in tissues, called segmentation analysis by parallelization of 3D datasets (STAPL-3D). Applying the method to pediatric Wilms tumor, we extract molecular, spatial and morphological features of millions of cells and reconstruct the tumor’s spatio-phenotypic patterning. In situ population profiling and pseudotime ordering reveals a highly disorganized spatial pattern in Wilms tumor compared to healthy fetal kidney, yet cellular profiles closely resembling human fetal kidney cells could be observed. In addition, we identify previously unreported tumor-specific populations, uniquely characterized by their spatial embedding or morphological attributes. Our results demonstrate the use of combining mLSR-3D and STAPL-3D to generate a comprehensive cellular map of human tumors.

EV PD-L1 Contributes to Immunosuppressive CD8+ T Cells in Peripheral Blood of Pediatric Wilms Tumor.

Wilms tumor (WT) is the most common renal cancer and the most prevalent abdominal cancer in children. Children with recurrent or progressive forms of WT could benefit from novel immune-targeted approaches. While the immune status of these patients, especially the immunosuppression of peripheral T cells, was rarely reported. The present study enrolled a consecutive series of 14 Chinese WT children and 14 age- and gender-matched healthy controls. We demonstrated that plasma extracellular vesicular (EV) PD-L1 levels significantly increased in WT patients than in healthy controls. EV PD-L1 significantly inhibited the activation of human CD8+ T cells by down-regulating the cell surface CD69 expression and the intracellular IFNγ and TNFα production in vitro. In peripheral CD8+ T cells of WT patients, the intracellular IFNγ and TNFα production significantly decreased than healthy controls. The level of plasma EV PD-L1 significantly correlated with the intracellular TNFα production in peripheral CD8+ T cells of WT patients. In conclusion, the significantly increased plasma EV PD-L1 in WT patients contributed to the immunosuppression of peripheral CD8+ T cells. Monitoring the level of plasma EV PD-L1 will be helpful for the selection of immune-targeted therapies for WT patients.

Management and outcome of pediatric Wilms tumor with malignant inferior Vena cava thrombus: largest cohort of single-center experience.

Wilms tumor (WT) with an inferior Vena cava (IVC) malignant thrombus comprises 4-10% of all WT cases. This retrospective analysis included 51 pediatric patients presenting at Children Cancer Hospital Egypt-57357 from July 2007 to December 2016 with the diagnosis of WT with malignant IVC thrombus. Median age at presentation = 4.4years and 28 cases (55%) were females. Twenty-five patients (49%) were metastatic and 4 patients (7.8%) had bilateral disease. Forty-seven cases (92.2%) had favorable histology with no evidence of anaplasia. Level of thrombus extension at presentation was classified as infra-hepatic, retro-hepatic, supra-hepatic and intra-cardiac in 33, 9, 6 and 3 patients, respectively. Fifty patients started neoadjuvant chemotherapy (CTH) with 16 patients showing complete resolution of thrombus after 6weeks of CTH. None of the patients developed thrombus progression after neoadjuvant CTH; one patient had stationary intra-cardiac thrombus, while remaining patients showed partial regression of their thrombus and had nephrectomy with en-bloc thrombectomy. The mean cranio-caudal dimension of IVC thrombi at initial presentation was 6.5cm, and 3.6cm post 6th week of CTH. The 5-year OS and EFS were 75.9% and 71.1%, respectively. There was no significant correlation of initial levels of thrombus extension with survival. Neoadjuvant chemotherapy followed by radical nephrectomy with en-bloc thrombectomy and radiotherapy seems a successful approach for management of patients with WT and IVC tumor thrombus. Measurement of the cranio-caudal dimension of thrombus and its response to treatment should be considered in the surgical planning.

Identification of a five-mRNA signature as a novel potential prognostic biomarker in pediatric Wilms tumor.

BackgroundThe aim of this study was to generate a prognostic model to predict survival outcome in pediatric Wilms tumor (WT).MethodsThe data including mRNA expression and clinical information of pediatric WT patients were downloaded from the Therapeutically Available Research to Generate Effective Treatments (TARGET) database. The differentially expressed genes were identified and a prognostic signature of pediatric WT was generated according to the results of univariate and multivariate Cox analysis. Receiver operating characteristic (ROC) curve was used to evaluate the five‐mRNA signature in pediatric Wilms tumor patients. Bootstrap test with 500 times was used to perform the internal validation.ResultsWe identified 6,964 differentially expressed mRNAs associated with pediatric WT, including 3,190 downregulated mRNAs and 3,774 up‐regulated mRNAs. Univariate and multivariate Cox analysis identified five mRNAs (SPRY1, SPIN4, MAP7D3, C10orf71, and SPAG11A) to establish a predictive model. The risk score formula is as follows: Risk score = 0.3036*SPIN4 + 0.8576*MAP7D3 −0.1548*C10orf71 −0.7335*SPRY1 −0.2654*SPAG11A. The pediatric WT patients were divided into low‐risk group and high‐risk group based on the median risk score (value = 1.1503). The receiver operating characteristic (ROC) curve analysis revealed good performance of the 5‐mRNA prognostic model (the area under the curve [AUC] was 0.821). Bootstrap test (Bootstrap resampling times = 500) was used to perform the internal validation and revealed that the AUC was 0.822. REACTOME, KEGG, and BIOCARTA pathway analyses demonstrated that these survival‐related genes were mainly enriched in ErbB2 and ErbB3 signaling pathways, and calcium signaling pathway.ConclusionThe five‐mRNA signature can predict the prognosis of patients with pediatric WT. It has significant implication in the understanding of therapeutic targets for pediatric WT patients. However, further study is needed to validate this five‐mRNA signature and uncover more novel diagnostic or prognostic mRNAs candidates in pediatric WT patients.

Patterns of Care and Survival Comparison of Adult and Pediatric Wilms Tumor in the United States: A Study of the National Cancer Database

ObjectiveTo describe and compare the management of WT and oncologic outcomes by patient age using a large national database. MethodsThe National Cancer Database was queried for patients with WT diagnosis from 2004 to 2013. Patients were grouped by age and compared: pediatric (<16 years), young adults (16-35 years) and adult (>35 years). Overall survival (OS) was the primary endpoint. Factors associated with OS were determined using multivariate analysis. ResultsThe majority of patients were pediatric (n = 2686), followed by young adult (n = 91), and adult (n = 35). Five-year OS was significantly better for children vs young adults or adults (93.1% vs 79.1% vs 78.9%, respectively; P <.001), as was 10-year OS (91.5% vs 52.4% vs 70%; P <.001). On multivariate analysis, OS was significantly better for children vs young adult (HR 3.62; 95% CI 2.25-5.8; P <.001), and adult (HR 3.38; 95% CI, 1.49-7.7; P <.004). Other variables associated with worse OS included bilateral disease (HR 2.06; P = .003), stage II disease (HR 2.92; P = .036), stage IV disease (HR 4.1; P = .004), and positive lymph nodes (HR 1.97-4.90; P = .018). Patients >15 years were less likely to undergo lymph node sampling (OR 0.19; P <.001), radiation therapy (OR 0.62; P = .03), or chemotherapy (OR 0.38; P <.001). ConclusionAdults with WT experience worse 5- and 10-year OS when compared to children with WT. Survival decrements in adults are likely multifactorial including modifiable factors such as inadequate staging due to low rates of lymph node sampling, and underutilization of adjuvant therapies.

Neurocognitive outcomes in long-term survivors of Wilms tumor: a report from the St. Jude Lifetime Cohort

To examine prevalence and predictors of neurocognitive outcomes, social attainment, emotional distress, and health-related quality of life (HRQOL) in long-term survivors of pediatric Wilms tumor (WT). One hundred fifty-eight WT survivors (59% female; mean [SD] age 33 [9.1] years; time since diagnosis 29 [9.1] years) and 354 community controls (55.6% female; 35 [10.2] years) completed comprehensive neuropsychological testing and physical examination, including echocardiography/electrocardiography, pulmonary function tests, and endocrine evaluation. Self-report of emotional distress, HRQOL, and social attainment were collected. Impairment was defined in relation to both controls and normative data. Generalized linear models were developed to examine impact of treatment and chronic health conditions on outcomes. WT survivors performed poorer than norms and controls in 6 of 16 cognitive variables and 1 of 8 HRQOL variables, with scores ranging from - 0.64 (mathematics) to - 0.21 (verbal fluency) standard deviations below expectations. Compared to controls, WT survivors were less likely to graduate college (odds ratio 2.23, 95% confidence interval 1.46-3.41) and had more moderate to severe neurologic conditions (18.4% vs 8.2%, p < 0.001), which were associated with poor memory (β = - 0.90, p < 0.001), attention (β = - 1.02, p < 0.001), and HRQOL general health (β = - 0.80, p = 0.0015). Treatment variables and cardiopulmonary morbidity (higher in survivors) were not associated with outcomes. Survivors of WT demonstrate impairment in neurocognitive function and have lower social attainment during adulthood, with poorer neurocognitive function associated with neurologic morbidity. Survivors of WT should be offered neurocognitive evaluations and rehabilitation. Neurologic conditions should be routinely assessed, and appropriate support offered to reduce risk for functional limitations.

MiR-144-3p inhibits the proliferation and metastasis of pediatric Wilms' tumor cells by regulating Girdin.

The aim of this study was to investigate the role of miR-144-3p in the proliferation and metastasis capacity of pediatric Wilms' tumor (WT) cells and to explore the underlying mechanism. The quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) was performed to measure the expression level of miR-144-3p in pediatric WT tissues and cell lines (G401). A bioinformatics software was utilized to predict the interaction between miR-144-3p and Girdin. Subsequently, the interaction was further verified by dual luciferase reporter (DLR) gene assay and Western blot. The proliferation and colony formation ability of G401 cells were examined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and colony formation assay, respectively. Finally, the effect of miR-144-3p on cell invasion and migration was analyzed by transwell assay. In the current study, we found that the expression level of miR-144-3p was significantly reduced in pediatric WT tissues and cells, whereas Girdin expression was upregulated. On-line target gene prediction software was applied to screen Girdin, which was considered as a downstream target gene of miR-144-3p. The interaction between miR-144-3p and Girdin was further verified by dual Luciferase reporter gene assay and Western blot. Subsequent experiments demonstrated that the proliferation and metastasis ability of cells was remarkably suppressed after up-regulating the expression of miR-144-3p. However, an addition of Girdin could reverse the effect of miR-144-3p. MiR-144-3p, which was up-regulated in pediatric WT, might inhibit the proliferation and metastasis of the cells by directly targeting Girdin. This further indicated that miR-144-3p could be a potential therapeutic target for the treatment of pediatric WT.

Timing of Radiation Therapy in Pediatric Wilms Tumor: A Report From the National Cancer Database

Todetermine, using the National Cancer Database (NCDB), the impact of the surgery to radiation therapy interval (SRI) on survival in contemporary patients with Wilms tumor (WT). The NCDB was queried for patients aged ≤25years diagnosed from 2004 to 2013 with unilateral WT who underwent definitive surgery and radiation therapy. The SRI was calculated for each patient. A stratified analysis was performed based on presence of metastasis using logistic regression to calculate risk factors for prolonged SRI, with a focus on the recommended SRI according to recent Children's Oncology Group trials (by day 14) and National Wilms Tumor Study-5 (by day 9). Cox regression was performed to assess the association of SRI with overall survival. A total of 1488 patients were included; 32.1% had metastasis at diagnosis. Among both metastatic and nonmetastatic groups, older patients were more likely to have prolonged SRI. For those without metastasis, SRI > 14days was associated with increased risk of mortality (hazard ratio 2.13, P = .013). Analyzing SRI as a continuous variable also demonstrated an increased risk of death with longer SRI (hazard ratio 1.04 per day, P=.006) in this group. In contrast, among patients with metastasis, no significant association between SRI and mortality was found. Early initiation of radiation therapy remains a critical component of multimodal treatment for patients with nonmetastatic WT. For nonmetastatic patients, SRI ≤ 14days correlates with improved overall survival. However, no such association was noted for patients with metastases. These results may inform the development of future WT trials.

Immunohistochemical Expression of Ki67 and p53 in Wilms Tumor and Its Relationship with Tumor Histology and Stage at Presentation.

Aim. Evaluate tumor proliferation marker (Ki67) and p53 tumor suppressor marker in Wilms tumor and correlate with histology, anaplasia, and staging. Design. Prospective, hospital based study conducted at a tertiary pediatric referral centre in south India. Setting. Wilms tumor is the most common childhood renal malignancy worldwide. Anaplasia on histology is associated with treatment resistance but not with aggressiveness clinical presentation. Chemotherapy for Wilms tumor is based on histology and staging. Most patients respond to current chemotherapy protocol. However, a small fraction relapses or metastasizes. Affordable prognostic markers are needed for histopathological evaluation of this tumor. Subjects. Cases of histologically confirmed Wilms tumor over five years. Cases after chemotherapy were excluded as the immunostaining was inconsistent in necrotic areas. Methods. The clinical and radiological findings of 31 cases of Wilms tumor were documented at a tertiary pediatric referral hospital over five years. In addition to Hematoxylin and Eosin staining, Ki67 proliferation index and p53 expression were correlated with tumor histology and staging. Results. Age incidence was 3–8 years with female preponderance. Significant correlation was noted between Ki67 proliferation index and tumor staging. p53 expression was not useful in stratification of Wilms tumor. Conclusion. Ki67 was cost-effective immunohistochemical marker for prognostication of pediatric Wilms tumor.

Mutations in the SIX1/2 Pathway and the DROSHA/DGCR8 miRNA Microprocessor Complex Underlie High-Risk Blastemal Type Wilms Tumors

Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.

Initial Surgery in Tailoring Treatment for Children With Stage II and III Wilms' Tumor: An Experience From Resource Challenged Settings.

BackgroundAlthough Wilms’ tumor (WT) is ranked first among primary childhood’s renal neoplasm, controversy still exists regarding the best approach for its management. The study aimed at evaluating the role of initial surgery in treatment of stage II and III pediatric WT as a part of the short administration schedule as in National Wilms’ Tumor Study (NWTS)-4 and evaluating its effectiveness compared to the long administration schedule.MethodsThe study included 30 children who were primarily diagnosed as stage II and III WT. They were divided into two equal groups. Group I (n = 15) included those children who had undergone neoadjuvant chemotherapy followed by surgery and postoperative chemotherapy, while group II (n = 15) included those children who had undergone primary surgery as an initial management followed by chemotherapy. After a mean postoperative follow-up period of 14 ± 5 months, clinical and radiological evaluation was performed to all patients.ResultsIn group I, 10 patients were preoperatively diagnosed as stage II and five patients as stage III while in group II, 11 patients were proved to be stage II and four patients were stage III. After a follow-up period, clinical and radiological evaluation using CT was performed to all patients. In patients with stage II, evidence of recurrence was noted in three patients of group I whereas no patient showed any evidence of recurrence in group II. In patients with stage III, rebound increase in size was seen in two patients in group I and only one patient in group II.ConclusionsInitial surgical intervention with appropriate adjuvant therapy has better outcomes than the neoadjuvant chemotherapy and delayed surgery for children primarily diagnosed as stage II and III WT. Moreover, it may act as a short administration schedule for the treatment as it is not less effective than the long administration schedule and can be administered at a substantially lower total treatment cost.

Expression of Ki-67, P53, and VEGF in pediatric Wilms tumor

In this study, we investigated the expression of Ki-67, p53, and VEGF in Wilms tumor and the relationship with clinical and histopathologic findings. The expression of the markers was evaluated with immunohistochemistry methods on samples obtained from surgical resection in 30 patients diagnosed with Wilms tumor. Pathologic examination of resected specimens showed: triphasic mixed-type nephroblastoma (53.3%), monophasic blastemal (30.0%), monophasic epithelial (13.3%), and focal anaplastic (3.3%). The mean proliferation index according to different stages of the tumor was: stage I (1.41%±2.06), stage II (10.91% ± 18.96), stage III (15.00% ±21.21), stage IV (45.00% ± 25.98), stage V (0) ( p = 0.003). P53, and VEGF expression were not associated with tumor stage ( p = 0.59, and 0.85, respectively), and unfavorable histology. Ki-67 expression in Wilms tumor is strongly associated with higher tumor stages. Further investigation of the role of Ki-67 along with other prognostic factors, to build a multivariate model to determine the prognosis, is recommended.

Adult wilms' tumor metastatic to the lung: Endobronchial ultrasound‐guided fine needle aspiration biopsy

Adult Wilms' tumor (WT) is a rare entity with less than 300 cases reported to date in the medical literature. Histologic and cytologic features of adult WT of the kidney are similar to findings in pediatric WT. While the lungs are noted to be the most frequent site of metastatic disease in the pediatric population, the incidence of lung metastases remains unknown for adult WT. A search revealed 38 cases of adult WT with lung metastases published to date in the English literature. Amongst these cases only two have utilized cytology of the lung lesions as a means to arrive at a final diagnosis. We report a case of adult WT metastatic to the lung that was initially diagnosed using endobronchial ultrasound-guided fine needle aspiration biopsy. The aim is to compare the current cytologic and immunohistochemical findings with those cases previously published, to outline the cytologic features of adult WT metastatic to the lung, and to emphasize the significance of cytologic diagnosis in the work-up of adult WT.

The Role of Hispanic Ethnicity in Pediatric Wilms’ Tumor Survival

Wilms’ tumors (WT) constitute approximately 6–14% of all childhood cancers and about 95% of all pediatric renal malignancies. While prognostic factors for this malignancy are relatively well-defined, few studies have specifically examined the role of Hispanic ethnicity in pediatric WT survival. The purpose of this study was to compare WT survival among non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic cases using data from the Surveillance, Epidemiology, and End Results (SEER) program. WT cases (ICD-O-3 histological code 8960) under age 20 were isolated from a recent subset of the SEER dataset (1990–2009). Demographics and tumor characteristics were compared by race/ethnicity, and 5- and 10-year survival probabilities were calculated. Multivariable Cox proportional hazards regression was used to assess the effects of race/ethnicity on WT survival, adjusting for relevant covariates. Hispanic ethnicity was significantly associated with WT-specific mortality hazard, controlling for age, sex, diagnosis/treatment era, laterality, SEER stage, cancer-directed surgery, and radiation therapy (HR: 1.52, 95% CI: 1.02–2.25). The results of this study suggest that Hispanic pediatric WT cases may have a higher risk of WT-related death, compared to NHW cases. Additional research on racial/ethnic disparities in WT survival is warranted.

High-resolution genomic profiling of an adult Wilms’ tumor: evidence for a pathogenesis distinct from corresponding pediatric tumors

Wilms' tumor (WT), the most common kidney tumor among children, is characterized by a triphasic morphology consisting of blastemal, epithelial, and stromal components. Adult WT is a rare malignancy displaying similar histological features. We here present the first published high-resolution genomic analysis of a mixed-type adult WT. This revealed a more pronounced genetic complexity than usually observed in children with mixed-type WT. The majority of chromosomes displayed uniparental disomies, and microdeletions were present in genes with known importance for tumor formation (LRP1B, FHIT, and WWOX) or organogenesis (NEGR1 and ZFPM2), abnormalities not previously reported for pediatric WT. Our results indicate that adult WT is a biological entity distinct from the corresponding pediatric tumor type.

PAX2 Expression in Wilms Tumors and Other Childhood Neoplasms

PAX2 plays an important role in kidney development; although small studies have demonstrated PAX2 expression in Wilms tumors (WT), comprehensive studies on formalin-fixed tissue are lacking. Thus, we systematically evaluated PAX2 immunohistochemical staining in a retrospective study of pediatric WT, as compared with other pediatric tumors. We stained formalin-fixed, paraffin-embedded sections from 39 WT, 6 nephrogenic rests, 8 non-Wilms renal tumors, and 43 nonrenal pediatric small round cell tumors with 2 different PAX2 polyclonal antibodies. PAX2 demonstrated strong, diffuse staining of epithelial and blastema components of WT (97% of cases). PAX2 stained WT stroma in fewer cases (23%), but 80% of anaplastic foci were positive. Nephrogenic rests, 1 case of metanephric adenoma, and 1 pediatric renal cell carcinoma were also PAX2 positive; other pediatric renal tumors were negative. Neuroblastoma, primitive neuroectodermal tumor/Ewings, and T-cell acute lymphoblastic lymphoma (ALL) were PAX2 negative. However, PAX2 weakly stained some cases of B-cell ALL rhabdomyosarcoma (RMS) was also stained, especially alveolar RMS (83%), with less staining of embryonal RMS (13%). One of the antibodies also stained maturing myoid cytoplasm of WT and RMS. This study shows that PAX2 is a sensitive marker of WT (sensitivity 97%), but PAX2 shows weak-to-moderate-intensity nuclear staining of RMS and B-cell ALL, somewhat limiting its utility. However, PAX2 may be a helpful marker in certain diagnostic situations. We speculate that RMS and B-cell ALL staining could be due to antibody cross-reactivity with PAX family members with known expression in RMS and B-cell ALL.