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Purpose: Hepatocyte growth factor (HGF) and its receptor Met are known to play diverse roles in both organogenesis and cancer. Wilms' tumor (WT) is a prototype for the link between abrogated development and neoplasia, with dysregulation of growth factor/receptor pathways playing key roles. Despite this, an understanding of the HGF/Met axis in the process is lacking.Experimental Design: Observing copy number alterations at the loci for these genes in WTs and their precursor lesions nephrogenic rests, we examined protein expression by immunohistochemistry and investigated the effects of HGF on an in vitro model of kidney development.Results: HGF was preferentially expressed in the blastemal cells of nephrogenic rests but not WTs. Met expression was infrequent and restricted to well-differentiated epithelial cells and stroma in both lesions. In an independent cohort of favorable histology WTs on a tissue microarray, HGF was expressed in 15 of 193 (8%) cases and correlated with a predominance of epithelial cells, whereas Met expression was observed in 25 of 179 (14%) cases and was associated with stromal subtypes. In a mouse mesonephric cell line model, we observed Met expression in culture conditions reflecting both mesenchymal and epithelial differentiation, whereas HGF was up-regulated in association with acquisition of a more epithelial-like phenotype. This could be mimicked by exogenous exposure of mesenchymal-like cells to recombinant HGF.Conclusions: These data show that the relatively infrequent expression of HGF and Met in WT tumorigenesis reflects their roles in nephrogenesis, particularly the mesenchymal-to-epithelial transition, rather than a dependence on oncogenic signaling pathways.

Supplementary Data from Expression of Hepatocyte Growth Factor and Its Receptor Met in Wilms' Tumors and Nephrogenic Rests Reflects Their Roles in Kidney Development

To review surgical management, tumour stage and clinical outcomes in children with intravascular extension of Wilms tumour (WT) registered in a national clinical study (2012-19).WTs with presence/suspicion of tumour thrombus in the renal vein (RV) or beyond on radiology, surgery or pathology case report forms were identified. Only cases where thrombus was confirmed by surgeon and/or reference pathologist were included. Surgical management, disease stage, overall (OS) and event free survival (EFS) were investigated.69/583 (11.8%) patients met the inclusion criteria. Forty-six (67%) had abdominal stage III due to thrombus-related reasons: 11 had macroscopically incomplete resection, including 8 cases where cavotomy was not performed; 20 had piecemeal complete resection of thrombus; 15 had microscopically positive resection margins at the RV. 66% of tumour thrombi contained viable tumour. There were eight relapses and five deaths. EFS, but not OS, was significantly associated with completeness of surgical resection (P0.05). OS and EFS were also significantly associated with histological risk group (P0.05) but not with viability of tumour thrombus (P=0.19; P=0.59).WTs with intravascular extension have a high risk of local stage III due to thrombus-related reasons. Controlled complete removal of the thrombus should be the aim of surgery.Level II.

Society of International Pediatric Oncology - Renal Tumor Study Group (SIOP-RTSG) treatment recommendations for relapsed Wilms tumour (WT) are stratified by the intensity of first-line treatment. To explore the evidence for the treatment of patients relapsing after vincristine and actinomycin-D (VA) treatment for primary WT, we retrospectively evaluated rescue treatment and survival of this patient group. We included 109 patients with relapse after VA therapy (no radiotherapy) for stage I-II primary low- or intermediate-risk WT from the SIOP 93-01 and SIOP 2001 studies. Univariate Cox regression analysis was performed to study the effect of relapse treatment intensity on event-free survival (EFS) and overall survival (OS). Relapse treatment intensity was classified into vincristine, actinomycin-D, and either doxorubicin or epirubicin (VAD), and more intensive therapies (ifosfamide/carboplatin/etoposide [ICE]/≥ 4 drugs/high-dose chemotherapy with haematopoietic stem cell transplantation [HD HSCT]). Relapse treatment regimens included either VAD, or cyclophosphamide/carboplatin/etoposide/doxorubicin (CyCED), or ICE backbones. Radiotherapy was administered in 62 patients and HD HSCT in 15 patients. Overall, 5-year EFS and OS after relapse were 72.3% (95% confidence interval [CI]: 64.0-81.6%) and 79.3% (95% CI: 71.5-88.0%), respectively. Patients treated with VAD did not fare worse when compared with patients treated with more intensive therapies (hazard ratio EFS: 0.611 [95% CI: 0.228-1.638] [p-value = 0.327] and hazard ratio OS: 0.438 [95% CI: 0.126-1.700] [p-value = 0.193]). Patients with relapsed WT after initial VA-only treatment showed no inferior EFS and OS when treated with VAD regimens compared with more intensive rescue regimens. A subset of patients relapsing after VA may benefit from less intensive rescue treatment than ICE/CyCED-based regimens and deserve to be pinpointed by identifying additional (molecular) prognostic factors in future studies.

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93-01, 2001 and UK-IMPORT databases, were included. Event-free survival (EFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT-RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE-cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5-year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%-80.6%) and 84.5% (95% CI = 77.5%-92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE-testing.

Background WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence. Methods Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) registries and the SIOP‐RTSG network (1989‐2019). Events were defined as relapse, metachronous tumors, or death. Results Forty‐three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6‐44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5‐year event‐free survival rate was 84.3% (95% confidence interval, 72.4%‐98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%‐100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1). Conclusions Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised. Lay Summary WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor.In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) and the SIOP‐RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur.Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised., Patients with WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) and Wilms tumor/nephroblastomatosis, identified through the International Society of Pediatric Oncology Renal Tumor Study Group registries and network, have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing Wilms tumor protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised.

BACKGROUND Wilms tumor (WT) demonstrates epidemiological differences by world region and ethnicity. To enhance understanding of these differences, we retrospectively analyzed clinical trial data sets from the UK and Japan over a 20-year period. PROCEDURE We used data from three consecutive clinical trials in the UK and a single study in Japan that enrolled patients diagnosed during 1996-2015, to compare clinical characteristics and outcomes between countries. RESULTS During 1996-2015, 1395 patients in the UK and 537 in Japan were included. Japanese patients have a significantly younger median age at diagnosis than those in the UK (28 months vs 39 months). The proportion of patients with stage IV, large tumors, and anaplastic histology appears to be higher in the UK than in Japan (18% vs 11%, 62% vs 49%, 8% vs 3%, respectively). During 2005-2015, 77 hospitals treated WT in Japan compared with only 20 hospitals in the UK. Five-year overall survival of patients with WT was over 90% in both countries, but five-year event-free survival of patients with stage IV was significantly lower in Japan than in the UK (50.0% vs 76.2%, P = 0.001). CONCLUSIONS Differences in age of onset, tumor size at diagnosis, and histology may reflect differences in the genetic background of patients with WT between countries, but population-based phenotype-genotype data are lacking. The difference in survival probability for stage IV patients may be due to different diagnostic criteria or different treatment strategies. Prospective, international clinical studies including genomic analyses are needed to confirm these findings and improve clinical practice.

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology‐Renal Tumor Study Group (SIOP‐RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93‐01, 2001 and UK‐IMPORT databases, were included. Event‐free survival (EFS) and overall survival (OS) were analyzed using the Kaplan‐Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT‐RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE‐cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5‐year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%‐80.6%) and 84.5% (95% CI = 77.5%‐92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE‐testing., What's new? Pediatric renal cell carcinoma (RCC) is a rare malignancy, knowledge of which is based largely on adult RCC. Here, pediatric RCC was retrospectively studied using data from the International Society of Pediatric Oncology – Renal Tumor Study Group (SIOP‐RTSG). Pediatric RCC patients had a 5‐year overall survival rate of 84.5 percent, with notably lower survival for patients with metastatic disease. In pediatric RCC patients tested for transcription factor E3 and EB, 56.3 percent presented with translocation type. The findings highlight the importance of full registration of pediatric RCCs, with information on germline genetics and transcription factor testing.

Chapter 3 discusses cancer diagnosis, risk stratification, and therapeutic choices in children and young people. Radiological investigations support the diagnosis and provide staging information for accurate risk stratification. Interventional radiology is useful for obtaining tissue for pathological examination. Histopathology and molecular studies define the precise tumour type and subtype and are used to confirm or rule out the presence of metastatic disease. Post-operative histopathology defines the extent of spread and is important for the staging of some tumours. Together, these findings inform multidisciplinary team discussion and help to identify the best treatment schedule. A significant proportion of cancers have a genetic basis, and it is important to identify these from the family history, predisposing syndromes, or tumour type. Modern molecular genomic techniques have made definitive diagnosis easier. Some genetic conditions lead to increased radiosensitivity and may predispose the patient to excessive radiation-related morbidity and a high risk of second primary tumours.

International audience; Renal tumors comprise approximately 7% of all malignant pediatric tumors. This is a highly heterogeneous group of tumors, each with its own therapeutic management, outcome, and association with germline predispositions. Histopathology is the key in establishing the correct diagnosis, and therefore pathologists with expertise in pediatric oncology are needed for dealing with these rare tumors. While each tumor shows different histologic features, they do have considerable overlap in cell type and histologic pattern, making the diagnosis difficult to establish, if based on routine histology alone. To this end, ancillary techniques, such as immunohistochemistry and molecular analysis, can be of great importance for the correct diagnosis, resulting in appropriate treatment. To use ancillary techniques cost-effectively, we propose a pattern-based approach and provide recommendations to aid in deciding which panel of antibodies, supplemented by molecular characterization of a subset of genes, are required.

DICER1 syndrome1 predisposes to a variety of cancers, including pleuropulmonary blastoma (PPB),2 ovarian Sertoli-Leydig cell tumor (SLCT),3 embryonal rhabdomyosarcoma,4 and kidney tumors.5–8 In DICER1 syndrome, most patients bear a germline null mutation in DICER1, and the tumors uniformly bear a second-hit missense substitution at one of five hotspot positions (1705E, 1709D, 1809G, 1810D, and 1813E). A wide range of clinical phenotypes can be seen in DICER1 syndrome5,9; some patients are asymptomatic, whereas others develop multiple tumors. In the classic cases, patients with a germ-line null mutation develop different somatic hotspot mutations in each tumor.7,10–16 However, in some patients, multiple tumors arise from germline mosaicism of the hotspot mutation, with subsequent somatic loss of the wild-type allele.17–19 Here we report a patient with DICER1 syndrome who developed four tumor types at six anatomic sites over the course of 12 years. These tumors harbor four distinct hotspot mutations, which is one of the highest numbers of distinct somatic DICER1 mutations reported in a single patient. By identifying these mutations, we show that the patient’s bilateral renal tumors and bilateral ovarian SLCTs each constituted a new primary tumor. Because we found no other mutations to explain her particularly severe clinical course, we speculate that her subsequent tumors were a product of the intense chemotherapy and radiation regimens she received.

On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP–RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP–RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP–RTSG pathology panel., In this Consensus Statement, the pathology panel of the International Society of Paediatric Oncology–Renal Tumour Study Group (SIOP–RSTG) present the pathology and molecular biology protocol for Wilms tumours in the UMBRELLA SIOP-RTSG 2016 protocol.

The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) has developed a new protocol for the diagnosis, treatment, and follow-up monitoring of childhood renal tumours - the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). This protocol has been designed to continue international collaboration in the treatment of childhood renal tumours and will be implemented in over 50 different countries. Clear cell sarcoma of the kidney, which is a rare paediatric renal tumour that most commonly occurs in children between 2 and 4 years of age, is specifically addressed in the UMBRELLA protocol.

Solid tumors in childhood are extremely rare entities, which are usually treated in specialized centers. Diagnosis and therapy are carried out according to a joint European protocol, whereby the pathological evaluation and therapy are carried out according to international guidelines. For the correct diagnosis and/or therapy of most tumors, analysis of specific genetic changes is mandatory; therefore, tumors have to be adequately sampled for parallel genetic analysis during the pathological work-up. A second opinion reference of the histopathological assessment is part of the international guidelines. Neuroblastomas, congenital mesoblastic nephromas and rhabdoid tumors are examples of solid tumors in childhood that are not restricted to one organ and occur exclusively during childhood.

Wilms tumor (WT) may show a diverse range of heterologous elements (HEs). Cases with predominant/prominent HEs have been reported as "teratoid" WT, albeit on the basis of poorly defined criteria. It has been suggested that "teratoid" WTs are rare, and associated with a poor response to chemotherapy, but a good outcome. However, these claims have not been tested previously in any large cohort of cases. Here, we performed a systematic study to determine the incidence, diversity, and clinicopathologic association of HEs in 691 WTs, all of which were treated according to the same protocol, which included preoperative chemotherapy, and all with central pathology review. We found that 4% (28/691) of WTs showed ≥3 HEs ("teratoid" WT in our study), which was comparable to the numbers of completely necrotic, epithelial, focal anaplastic, and blastemal WTs. "Teratoid" WTs were strongly associated with younger age at presentation (21 vs. 39 mo, P=0.0001), bilateral disease (28.6% vs. 7.2%, P=0.001), stromal-type WT (57.1% vs. 11.0%, P0.00001), and intralobar nephrogenic rests (35.7% vs. 11.9%, P=0.0001), when compared with non-"teratoid" WT. We also found that stromal-type WT, regardless of HE differentiation, was itself associated with younger age, bilateral disease, and intralobar nephrogenic rest. Furthermore,80% of cases with ≥3 HEs, and also of cases with 2 HEs and 1 HE, showed ≥50% stroma in their viable components. We conclude that a tendency toward stromal differentiation is a strong and unifying factor in HE formation. "Teratoid" WT represents the more extreme end of HE differentiation, rather than a separate entity, and therefore the term should not be used in the final diagnosis. The prognosis of WTs depends only on their overall histologic type and stage, and it is not additionally influenced by the presence of "teratoid" features.

Introduction High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome. Methods Here, we report the results of HR (diffuse anaplastic [DA] or blastemal type [BT]) stage IV WT treated patients according to the HR arm in the SIOP2001 prospective study. Results From January 2002 to August 2014, 3559 patients with WT were included in the SIOP2001 trial. Among the 525 patients (15%) with metastatic WT, 74 (14%) had stage IV HR-WT. The median age at diagnosis was 5.5 years (range: 1.4–18.3). Thirty-four patients (47%) had BT-WT and 40 (53%) had DA-WT. Five-year event-free survival rates were 44 ± 17% and 28 ± 15% for BT-WT and DA-WT, respectively (p = 0.09). Five-year overall survival rates were 53 ± 17% and 29 ± 16% for BT-WT and DA-WT, respectively (p = 0.03). Metastatic complete response after preoperative treatment was significantly associated with outcome in univariate and multivariate analyses (hazards ratio = 0.3; p = 0.01). Postoperative radiotherapy of metastatic sites might also be beneficial. Forty-three of 74 patients experienced a relapse or progression predominantly in the lungs (80%). The median time to relapse/progression after diagnosis was 7.3 months (range: 1.6–33.3) and 4.9 months (range: 0.7–28.4) for BT-WT and DA-WT, respectively (p = 0.67). This is the first prospective evidence of inferior survival of stage IV BT-WT as compared with historical intermediate-risk WT. Survival of patients with stage IV DA-WT has not improved compared to the previous SIOP93-01 study. Conclusion These results call for new treatment approaches for patients with HR stage IV WT.

We read with interest the article by de la Monneraye et al on the experience of the Institut Curie of renal tumor biopsy in children treated according to SIOP protocols over a 22‐year period. By presenting the relative proportion of children with non‐Wilms tumors who had clinical, radiological, and biochemical features that are considered “atypical” of Wilms tumors (WT), they support a change to an evidence‐based approach to biopsy in the SIOP community. However, some of their recommendations are not adequately supported by a single institutional series, and we would like to add some reflections from our work based on the national‐ and population‐level data.

Background: To enhance risk stratification for Wilms' tumour (WT) in a pre-operative chemotherapy setting, we explored the prognostic significance and optimal age cutoffs in patients treated according to International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG) protocols. Methods: Patients (6 months-18 years) with unilateral WT, treated with pre-operative chemotherapy, were selected from prospective SIOP 93-01 and 2001 studies (1993-2016). Martingale residual analysis was used to explore optimal age cutoffs. Outcome according to age was analyzed by uni- and multivariable analysis, adjusted for sex, biopsy (yes/no), stage, histological classification and tumour volume at surgery. Findings: 5631 SIOP-registered WT patients were included with a median age of 3·4 years (interquartile range, IQR: 2-5·1). Median follow-up was 6·3 years (IQR: 3·0-8·7). Estimated 5-year event-free survival (EFS) and overall survival (OS) were 85% (95%CI 83·5-85·5) and 93% (95%CI 92·0- 93·4), respectively. Martingale residual plots detected no optimal age cutoffs. Multivariable analysis showed lower EFS with increasing age (linear trend p

Pathogenic germline variants in DICER1, a gene encoding an RNase key in microRNA-mediated silencing, cause DICER1 syndrome. This genetic disorder predisposes to the development of a wide array of mainly childhood-onset conditions including genitourinary tumors such as cystic nephroma (CN), anaplastic sarcoma of the kidney, Wilms’ tumor (WT), Sertoli-Leydig cell tumor (SLCT), and cervical embryonal rhabdomyosarcoma (ERMS). As the spectrum of clinical manifestations is not yet fully defined, we sought to explore the involvement of DICER1 mutations in pediatric genitourinary lesions not previously well studied. A series of 31 formalin-fixed, paraffin-embedded tumor samples including 15 paratesticular ERMS (ptERMS), one unclassifiable ovarian sex cord-stromal tumor, one fallopian tube ERMS (ftERMS), six cystic partially differentiated nephroblastomas (CPDN), two cystic WT, two CN, and four rare renal lesions were collected. Median age at diagnosis was 4 years. Tumor DNA was screened for DICER1 variants using Sanger sequencing or a Fluidigm array. Sanger sequencing on tumor DNA was used to validate the variants, and on normal DNA, to determine the germline status. Seven samples harbored biallelic DICER1 mutations and in 6/7 cases, the loss-of-function variant was confirmed to be of germline origin. The paratesticular tumors were initially diagnosed as ERMS, but pathology review reclassified one as an ectomesenchymoma and another as an undifferentiated low-grade myxoid sarcoma. No DICER1 mutation was identified in any of the ptERMS, but the myxoid sarcoma had DICER1 mutations. Interestingly, the patient with the paratesticular myxoid sarcoma also developed a CN. We identified DICER1 mutations in a tumor originally classified as an ovarian WT. Subsequent pathologic evaluation of the lesion led to its reclassification as a retiform SLCT with rhabdomyosarcomatous elements. A typical hotspot and a potential splicing mutation were detected in the ftERMS. Also, two atypical cystic kidney lesions harbored DICER1 mutations: one composed of blastema-type cells expressing nuclear WT1 diagnosed as a CPDN and another unusual multicystic renal lesion considered to be a CN that had moved into a proliferative phase but lacked blastema and anaplastic foci. The patient with the latter renal lesion had previously developed a unilateral CN with a distinct hotspot mutation. As expected, the two classical CN had DICER1 mutations. Based on these results, patients diagnosed with rare genitourinary tumors (except for ptERMS), may have DICER1 syndrome, especially if these individuals have a personal or family history of DICER1-associated lesions. In these cases, surveillance for DICER1-related conditions is advised given that the risk of tumor development is highest in early childhood. In summary, specialist pathology review and DICER1 testing in this setting will lead to improved diagnosis with potential implications for clinical care. Citation Format: Maria V. Apellaniz-Ruiz, Catherine Goudie, Noelle Cullinan, Elvis T. Valera, Krisztina Z. Hanley, Luiz G. Tone, Paula Marrano, Ronald Grant, W. Glenn McCluggage, Gordan M. Vujanic, Paul S. Thorner, William D. Foulkes. Novel childhood genitourinary manifestations of DICER1 syndrome [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A01.

The impact of biopsying Wilms tumour (WT) at diagnosis on assigning the tumour stage and recommended treatment remains controversial. To address this important question, we analysed the potential association of all types of biopsy with local recurrence in patients treated in the SIOP WT 2001 trial, where needle biopsy was permitted without 'upstaging' the tumour to stage III. Only open biopsy required treatment as stage III.Among 2971 patients with unilateral WT (stages I-IV), 420 relapsed (139 local). Risk factors for recurrence were analysed by Cox proportional hazard methods.Biopsy was performed in 969 of 2971 (33%) patients (64% cutting needle, 30% fine needle aspiration [FNA] and 6% open biopsy). Biopsied patients were older, with larger tumours and a greater proportion with high-risk histology. In multivariate analysis that included all factors associated with local recurrence in univariate analysis, only high-risk histology (hazard ratio [HR] = 2.32; 95% confidence interval [CI]: 1.58-3.42, p=0.0001), age≥2 years (HR = 2.24; 95% CI: 1.22-4.09, p = 0.01) and preoperative tumour volume (HR = 1.07 per 100 ml; 95% CI: 1.02-1.12, p = 0.01) were significant. The HR for the association of local recurrence and event-free and overall survival with biopsy was not significant (HR = 1.4; 95% CI: 0.9-2.17, p = 0.13; HR = 1.1; 95% CI: 0.85-1.42, p = 0.46 and HR = 1.13; 95% CI: 0.79-1.62, p = 0.51, respectively). These results were not materially different whether FNA or open biopsy were included in the biopsy group or not.This post hoc analysis provides some reassurance that needle biopsy is not an independent adverse factor for either local recurrence or survival after adjustment for all relevant risk factors. Needle biopsy should not be an automatic criterion to 'upstage' WT.

Wilms tumors growing in a botryoid fashion into the renal pelvis have been reported since the 1960s as a rare tumor type usually associated with stromal histology and a good prognosis. However, the true frequency, association with Wilms tumor subtypes, and stage have never been comprehensively studied. We analyzed all Wilms tumors enrolled into the International Society of Paediatric Oncology (SIOP) United Kingdom 2001 Trial (2001-2011), which showed botryoid growth. In addition, we reviewed published series reporting papers on botryoid Wilms tumors. 77/739 patients (10.4%) showed at least one Wilms tumor with a botryoid pattern, and they were sub-classified according to the SIOP criteria as follows: 28 stromal, 21 mixed, 7 regressive, 3 completely necrotic, 4 blastemal, 2 epithelial, 3 diffuse anaplasia, 1 focal anaplasia, and 10 non-anaplastic type (treated with primary surgery). Stage was as follows: 25 stage I, 21 stage II, 12 stage III, 11 stage IV, and 8 stage V. In six cases, local pathologists incorrectly upstaged the tumor from stage I to stage II based on botryoid growth. The event-free and overall survivals were 90 and 96%, respectively. We concluded that botryoid growth pattern is a common finding in Wilms tumor and that all histological types and stages can share this feature. The botryoid growth itself is not a criterion for stage II. Botryoid Wilms tumor is not an entity but merely represents a pattern of tumor growth; such tumors should be sub-classified according to their overall histological features, which will determine treatment and prognosis.

The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) has developed a new protocol for the diagnosis, treatment, and follow-up monitoring of childhood renal tumours - the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). This protocol has been designed to continue international collaboration in the treatment of childhood renal tumours and will be implemented in over 50 different countries. Clear cell sarcoma of the kidney, which is a rare paediatric renal tumour that most commonly occurs in children between 2 and 4 years of age, is specifically addressed in the UMBRELLA protocol.

Background and purpose To describe the outcome of patients with stage III Wilms tumours (WT) treated in the UKW3 trial. Material and methods Patients with a pathologically confirmed stage III non-anaplastic WT at nephrectomy (Group A) or with an ‘inoperable’ tumour at diagnosis managed by biopsy and pre-operative chemotherapy (Actinomycin D-Vincristine-Doxorubicin) but stage I or II at subsequent nephrectomy (Group B) were included. Results The 4-year overall (OS)/event free survival (EFS) for Group A (n = 117) patients was 90%(95%CI:83–94)/81%(CI:73–87) and for Group B (n = 32) 94%(CI:77–98)/88%(CI:70–95). The 4-year OS/EFS of patients with pathological stage III WT according to whether they received flank/abdominal radiotherapy (95 patients) or not (37 patients, 22 from UKW3 pooled with 17 patients from UKW2) were 91%(CI:83–95)/82%(CI:73–89), and 84%(CI:67–92)/78%(CI:61–89), respectively. The 4-year OS/EFS for patients having one reason to be stage III versus two or three was 92%(CI:84–96)/83%(CI:73–90) and 85%(CI:70–93)/78%(CI:61–88), respectively. Conclusion Our findings question the inclusion of biopsy or pre-operative chemotherapy as sole criterion for assigning a tumour stage III. Selected patients with pathological stage III WT can survive without radiotherapy. Whilst cautious interpretation is needed due to the post hoc nature of these analyses, further biological studies may better characterise those who could benefit from reduced therapy.

Wilms tumor is a malignant renal tumor comprising 85%–90% of all renal tumors in children under 15 years of age. It is bilateral in 5%–8% of cases and familial in 1%–2% of cases. In a significant number of cases (9%–17%) it is associated with congenital anomalies, syndromes or conditions which predispose to Wilms tumor. Genes identified in Wilms tumor include WT1 gene (on chromosome 11p13, mutated in ~ 15% of cases), CTNNB1 gene (mutated in ~ 15% of cases), and WTX gene (mutated or deleted in ~ 18% of cases). Histologically, Wilms tumor consists of three components: blastemal, epithelial, and stromal. These may be present in any proportion, resulting in a large number of histological patterns. Prognosis depends on histology, stage, and some biological markers, but is in general excellent, with over 90% overall survival.

Background and Purpose: Wilms tumor (WT) is the commonest pediatric renal malignancy. A significant minority of cases have mutations in known genes or recurrent copy number aberrations, but few of these have prognostic value. We have previously observed MYCN copy number gain in WT, an aberration associated with poor outcome in several other childhood cancers. We therefore set out to assess the prognostic significance of MYCN gain in a large WT series, and to explore other mechanisms by which the function of this gene may be dysregulated. Methods: MYCN copy number was measured in 293 tumours by Multiplex ligation-dependent probe amplification. Whole exome sequencing (Agilent SureSelect V4+UTR/Illumina HiSeq) was carried out on 51 WT tumour/germline pairs. Sanger sequencing was used to confirm variants of interest and to assess an independent panel of 168 WTs. 65 WTs were profiled on Affymetrix SNP arrays (250K Nsp or SNP 6.0), Illumina HumanMethylation450 arrays, and Illumina HumanHT-12 expression arrays, and additional selected tumors on Illumina HumanCytoSNP-12 arrays. Results: MYCN gain is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. A somatic p.P44L (c.131C>t) mutation was detected in 3/45 exomes that gave informative data at this position, and in 5/168 additional tumors screened for this variant, an overall frequency of 3.8%. MYCN overexpression in high risk tumors was associated with hypomethylation at specific loci. We observed parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumors of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolved over time. In a second bilateral case, we detected MYCN gain as a germline aberration. Conclusions: MYCN gain is associated with poor outcome and anaplastic histology in WT. MYCN also appears to be disrupted by other mechanisms in WT, including DNA hypomethylation and a recurrent potential gain of function mutation, P44L. The discovery of a germline aberration suggests that MYCN dysregulation may contribute to tumor predisposition. Citation Format: Richard D. Williams, Tasnim Chagtai, Marisa Alcaide-German, John Apps, Jenny Wegert, Sergey Popov, Gordan Vujanic, Harm van Tinteren, Marry M. van den Heuvel-Eibrink, Marcel Kool, David Gisselsson, Norbert Graf, Manfred Gessler, Kathy Pritchard-Jones. Multiple mechanisms of MYCN dysregulation in Wilms tumor. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-59.

Background and Purpose: Treatment of Wilms tumor (WT) patients under International Society of Paediatric Oncology (SIOP) protocols is currently stratified by staging and histopathology at nephrectomy after neoadjuvant chemotherapy. However, most relapses occur in cases without specific histopathological risk factors, and there is a clinical need for better prognostic biomarkers. Combined loss of heterozygosity (LOH) of 1p and 16q has recently been introduced in the US as an adverse prognostic indicator, while previous work in our and other laboratories suggests that 1q gain may have a similar association with poor outcome. To examine the clinical significance of 1q gain and assess its potential as a WT biomarker, we developed a simple, effective assay that measures its genomic copy number together with that of several other loci of interest, and applied it to a large tumor series. Methods: 686 frozen tumor samples from the SIOP WT 2001 trial (from a total of 7 countries) were assayed using a rapid multiplex ligation-dependent probe amplification (MLPA) assay that was developed and optimized in association with MRC-Holland b.v. to assess the copy number status of 1p, 1q, 16q, WT1, WTX, TP53, MYCN and FBXW7. Analyses were conducted in 3 laboratories, with exchange of a blinded quality assurance sample set. Results: 1q gain was present in 28% (190/686) of the cases. The 5- year Event Free Survival (EFS) rate was 72.6% (95% Confidence Interval (CI), 66.3%-85%) for those with 1q gain and 86.4% (95% CI, 83.4%-89.6%) for those who lacked 1q gain (p= Conclusion: Gain of 1q is a potential adverse biomarker for WT. Its association with high risk histological features after pre-operative chemotherapy and independent impact on survival require assessment in a larger number of patients before consideration for clinical use. Citation Format: Tasnim Chagtai, Christina Zill, Linda Dainese, Jenny Wegert, Mariana Maschietto, Gordan Vujanic, Neil Sebire, Ivo Leuschner, Peter Ambros, Maureen O'Sullivan, Christophe Bergeron, David Gisselsson, Marcel Kool, Marry van den Heuvel-Eibrink, Norbert Graf, Harm van Tinteren, Aurore Coulomb, Manfred Gessler, Richard Williams, Kathy Pritchard-Jones. Prognostic significance of copy number aberrations in Wilms tumor. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-67.

Clear cell sarcoma of the kidney (CCSK) although uncommon, is the second most frequent renal malignancy of childhood. Until now, the sole recurrent genetic aberration identified in CCSKs is t(10;17)(q22;p13), which gives rise to a fusion transcript of YWHAE and NUTM2B/E. So far, the clinical relevance of this fusion transcript is unknown. The aim of this descriptive study was to determine the clinical phenotype of t(10;17)(q22;p13) positive CCSKs. Snap-frozen tissues, formalin-fixed paraffin-embedded tissues or RNA previously extracted from CCSK samples throughout European, North-American and Japanese study groups were screened by RT-PCR for the YWHAE-NUTM2B/E transcript. Clinical characteristics, tumor characteristics, and outcome of patients with and without the fusion transcript were studied. The cohort comprised 51 previously published cases to which were added 139 internationally collected CCSK samples. RNA from 57 of these additionally collected cases was of sufficient quality to be successfully screened for the YWHAE-NUTM2B/E transcript. In total, seven of the 108 cases harbored the fusion transcript. Patients with tumors containing the fusion transcript were relatively young (median age 10 months), had associated low median tumor volumes and stage I disease was not observed in these patients. Two of seven patients relapsed and one of seven patients died of disease. Ranges of values were not overtly different between patients with and without the fusion transcript; however, the number of fusion transcript positive cases turned out to be too small to permit reliable statistical analysis. The current study did not identify an explicit clinical phenotype of CCSK cases harboring the YWHAE-NUTM2B/E fusion transcript.

Background Topotecan has been variably incorporated in the treatment of patients with relapsed Wilms tumour (WT) who failed initial treatment with three or more effective drugs. Our objective was to describe outcome and to retrospectively investigate the potential role of topotecan in relapsed WT patients. Methods Children who were treated with topotecan as part of their chemotherapeutic regimens for relapsed WT were identified and included in our retrospective study. Patient charts were reviewed for general patient characteristics, histology and stage at initial diagnosis, number and type of relapse, salvage treatment schedules, toxicity, response to treatment and outcome. Results From 2000 to 2012, 30 children (median age at relapse 5.5 years, range 1.6–14.5 years) were identified to have received topotecan as part of their salvage regimens (primary progressive disease n = 3, first, second and third relapse n = 13, 9 and 2 respectively, partial response n = 3). Topotecan was administered as a single agent (12 patients) or in combination with other drugs (18 patients). Sixteen patients had high-risk histology according to the SIOP classification, 15 died within 12 months because of progressive disease. Fourteen patients had SIOP intermediate-risk histology of which four patients displayed objective responses to topotecan. Overall, 6 out of 14 intermediate-risk patients survived (median follow up of 6 years), however, three of whom (stage V) had bilateral nephrectomy after topotecan treatment. Conclusions Topotecan does not seem to show effectiveness in the treatment of relapsed WT patients with initial high-risk histology. In patients with intermediate-risk histology, the role of topotecan might deserve further attention, to prove its efficacy.

Germ-line interstitial deletions involving the 14q32 chromosomal region, resulting in 14q32 deletion syndrome, are rare. DICER1 is a recently described cancer-predisposition gene located at 14q32.13. We report the case of a male child with a ∼5.8 Mbp 14q32.13q32.2 germ-line deletion, which included the full DICER1 locus. We reviewed available clinical and pathological material, and conducted genetic analyses. In addition to having congenital dysmorphic features, the child developed multiple DICER1 syndrome-related tumors before age 5 y: a pediatric cystic nephroma (pCN), a ciliary body medulloepithelioma (CBME), and a small lung cyst (consistent with occult pleuropulmonary blastoma Type I/Ir cysts seen in DICER1 mutation carriers). He also developed a cerebral spindle-cell sarcoma with myogenous differentiation. Our investigations revealed that the deletion encompassed 31 protein-coding genes. In addition to the germ-line DICER1 deletion, somatic DICER1 RNase IIIb mutations were found in the CBME (c.5437G > A, p.E1813K), pCN (c.5425G > A, p.G1809R), and sarcoma (c.5125G > A, p.D1709N). The sarcoma also harbored a somatic TP53 mutation: c.844C > T, p.R282W. Additional copy number alterations were identified in the CBME and sarcoma using an OncoScan array. Among the 8 cases with molecularly-defined 14q32 deletions involving DICER1 and for whom phenotypic information is available, our patient and one other developed DICER1-related tumors. Biallelic DICER1 mutations have not previously been reported to cause cerebral sarcoma, which now may be considered a rare manifestation of the DICER1 syndrome. Our study shows that DICER1-related tumors can occur in children with 14q32 deletions and suggests surveillance for such tumors may be warranted.

Anaplastic sarcoma of the kidney is a rare tumor (≤25 reported cases) characterized by the presence of cysts, and solid areas composed of bundles of undifferentiated spindle cells, showing marked cellular anaplasia (usually accompanied by TP53 overexpression). These tumors often feature prominent areas of cartilage or chondroid material. Germline mutations in DICER1, encoding the microRNA (miRNA) processor DICER1, cause an eponymous syndrome. Recent reports suggest that anaplastic sarcoma of the kidney should be included in DICER1 syndrome as germline DICER1 mutations are associated with the occurrence of such tumors. Therefore, we sought to determine the following: (1) what proportion of anaplastic sarcoma of the kidney have DICER1 mutations; (2) whether the identified mutations affect both alleles of DICER1 (ie, are biallelic); (3) whether somatic missense mutations in the DICER1 RNase IIIb domain impact miRNA generation; and (4) whether TP53 alteration always occurs in these tumors. DICER1 mutations were evaluated by Sanger sequencing and next-generation sequencing in nine tumor/normal pairs. Impact of DICER1 mutations on miRNA generation was evaluated via an in vitro DICER1 cleavage assay. TP53 status was assessed by immunohistochemistry and next-generation sequencing. Eight of the nine cases had at least one RNase IIIb DICER1 mutation that impacted the generation of miRNAs. There were six tumors with truncating DICER1 mutations and in four of them, the mutation found in the tumor was also detected in adjacent normal tissue, and therefore was likely to be either mosaic or germline in origin. Analysis of mutation phase revealed that two of three tumors had biallelic DICER1 mutations. Six of nine anaplastic sarcomas of the kidney had aberrant TP53 immunohistochemisty with damaging TP53 mutations identified in three cases. Taken together, these data suggest that the great majority of anaplastic sarcomas of the kidney have DICER1 mutations and confirm that these tumors are part of the DICER1 syndrome.

BACKGROUND: Nephrogenic rests (NRs) are abnormally persistent foci of embryonal cells, thought to be the precursor lesion of Wilms tumors (WTs). To date, their presence has not been systematically examined in WTs treated with preoperative chemotherapy. METHODS: A systematic analysis of the data on NRs in WTs treated with preoperative chemotherapy obtained from the UK cohort of the International Society of Pediatric Oncology (SIOP) WT 2001 Trial. The study was based on central pathology review of full sets of slides from pathological specimens, with a median of 28 slides reviewed per case. RESULTS: NRs were identified in 40% of unilateral WTs, including 25% perilobar nephrogenic rest (PLNR), 9% intralobar nephrogenic rest (ILNR), 5% both PLNR and ILNR, and 1% nephroblastomatosis, and in 93% of cases with bilateral lesions. ILNRs were associated with stromal histology and a younger age at diagnosis and found frequently in patients with congenital anomalies associated with WT1 mutation. PLNRs were found frequently in patients with overgrowth syndromes. CONCLUSIONS: The prevalence of NRs in WTs after preoperative chemotherapy observed in SIOP UK WT 2001 Trial is similar to the previously published data on NRs not treated with preoperative chemotherapy. Their epidemiology supports at least two pathways to Wilms tumorigenesis.

Background Wilms tumour postoperative chemotherapy is ideally stratified according to the pathologist's assessment of tumour stage and risk classification (tumour type). In sub-Saharan Africa results are often not available in time to influence therapy and in Malawi surgical staging has been used to stratify postoperative chemotherapy. Here we compare the results from surgical and both local pathology and central pathology review. Procedure Children diagnosed with a Wilms tumour in Blantyre, Malawi between 2007 and 2011 were included if they had a nephrectomy and the pathology slides were available. All tumour specimens were assessed in three different ways: the local surgeon documented the surgical stage of the tumour, and the risk classification and pathology stage were assessed both by the local pathologist and by a SIOP central review pathologist in Europe. Results Fifty patients had complete data available and were included in the analyses. Tumour risk classification differed between the local and central pathology review in only two patients (4%). Using central pathology review as the gold standard 60% of patients received the correct postoperative chemotherapy treatment based on surgical staging and 84% based on the local pathology stage and risk classification. Conclusion Local pathology capacity building is needed to enable timely assessment and reporting. Pediatr Blood Cancer 2014;61:2180–2184. © 2014 Wiley Periodicals, Inc.

Background: Clear cell sarcoma of the kidney (CCSK) is an uncommon paediatric renal tumour. Relapses occur in about 15% of the patients. Since detailed clinical information on relapsed CCSK is scarce, the current study aims to describe outcome of patients with relapsed CCSK treated according to recent European protocols. Patients and methods: We analysed prospectively collected data of all CCSK patients who developed a relapse after complete remission at the end of primary treatment, entered onto SIOP and AIEOP trials between 1992 and 2012. Results: Thirty-seven of 237 CCSK patients (16%) treated according to SIOP and AIEOP protocols developed a relapse. Median time from initial diagnosis to relapse was 17 months (range, 5.5 months - 6.6 years). Thirt-five out of thirty-seven relapses (95%) were metastatic; the most common sites of relapse were the brain (n=13), lungs (n=7) and bone (n=5). Relapse treatment consisted of chemotherapy (n=30), surgery (n=19) and/or radiotherapy (n=18), followed by high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in 14 patients. Twenty-two out of thirty-seven patients (59%) achieved a second complete remission (CR); 15 of whom (68%) developed a second relapse. Five-year event-free survival (EFS) after relapse was 18% (95% CI: 4%–32%), and 5-year overall survival (OS) was 26% (95% CI: 10%–42%). Conclusions: In this largest series of relapsed CCSK patients ever described, overall outcome is poor. Most relapses are metastatic and brain relapses are more common than previously recognised. Intensive treatment aiming for local control, followed by high dose chemotherapy and ABMT, seems to be of benefit to enhance survival. Novel development of targeted therapy is urgently required.

The >90% rates of overall survival for children with Wilms tumour are remarkable and have been achieved at the same time as reducing treatment for most patients. However, beneath this headline figure, 20% of patients still relapse after first-line therapy and up to 25% of survivors report severe late effects. The aim of the SIOP-RTSG is to improve outcomes and to reduce acute and late treatment toxic effects in all children

In the version of this article initially published online it was not open access, this has now been corrected.

Wilms' tumor (WT) trials aim to better tailor treatment intensity to the risk of relapse and death. Currently, stage, histology, age ( 24 months), and combined loss of heterozygosity at 1p and 16q in chemotherapy-naive WTs are the only risk factors used for treatment stratification. However, they predict only less than one-third of all relapsing patients, implying that other factors are involved in treatment failure. Previous studies have associated 1q gain with adverse outcome. Therefore, in this study, the role of 1q gain and other common cytogenetic aberrations (CAs) in WTs was investigated and related to follow-up data from patients with WT treated in the United Kingdom; 19% (64/331) had 1q gain. Gain of 1q was significantly associated with 16q loss (P

Wilms tumour is a relatively common and curable paediatric tumour. Known challenges to cure in low income countries are late presentation with advanced disease, malnutrition, failure to complete treatment and limited facilities. In this article, management recommendations are given for a low income setting where only the minimal requirements for treatment with curative intent are available (setting 1). These include general management, supportive care, social support and registration of patients. Recommendations specific for Wilms tumour care include diagnostic procedures with emphasis on the role of ultrasonography, preoperative chemotherapy with a reduced dosage for malnourished children and postoperative chemotherapy based on surgical staging.

Clear cell sarcoma of the kidney (CCSK) is a rare renal tumour that is observed most often in children under 3 years of age. Only a few large series of CCSK have been reported and patients with CCSK are often included among patients with other types of childhood renal tumours. The purpose of this paper is to review the published series and case reports of CCSK and to create an up-to-date overview of clinical and histological features, genetics, treatment, and outcome.

A coexistence of different renal tumors has rarely been reported. The most commonly described association is of Wilms tumor and renal cell carcinoma. Metanephric adenofibroma has also been associated with Wilms tumor or papillary renal cell carcinoma. Another reported association is metanephric adenoma and papillary renal cell carcinoma with sarcomatoid dedifferentiation. Herein we describe a complex renal tumor containing areas of metanephric adenofibroma, Wilms tumor, and undifferentiated renal cell carcinoma in a previously healthy 18-year-old boy. The tumor showed histologic and immunohistochemical features of these 3 different tumors, offering additional support to the view that these 3 tumors are related.

Wilms tumor is the most common renal tumor of childhood. However, other epithelial, mesenchymal, and neuroectodermal neoplasms may also arise in the kidney during childhood, several of which show specific age distributions; in the 1st year of life, mesoblastic nephroma and rhabdoid tumor are more common, whereas renal cell carcinoma, primitive neuroectodermal tumor, and anaplastic Wilms tumors are relatively more frequent in older children and adolescents. The aim of this study is to describe the spectrum of renal tumors in children aged 10–16 years using data from 1492 patients registered in the UK Wilms Tumour 3 Trial (1991–2001) and International Society of Paediatric Oncology Wilms Tumour Trial 2001 (2002–2008) clinical trials of renal tumors in childhood. There were 67 (4.6%) tumors in children aged 10–16 years: 50 Wilms tumors (74.6%), 10 (14.9%) renal cell carcinomas, 3 (4.5%) renal medullary carcinomas, 2 (3%) primitive neuroectodermal tumors, 1 clear cell sarcoma of kidney, and 1 desmoplastic small round cell tumor. Fourteen percent of the Wilms tumors in this age group had diffuse anaplasia. Among the 10 renal cell carcinomas, 4 were associated with t(Xp-11.2), 3 were of papillary type II, 1 was papillary type I, 1 was clear cell type, and 1 was unclassified. Five-year overall survival for Wilms tumor was 63% (43% for anaplastic tumors), significantly lower than reported overall survival for all pediatric Wilms tumors. Only 40% of patients with renal cell carcinoma survived, and all patients with other tumors died.

Background. Mesoblastic nephroma (MN) is a rare tumour which occurs mainly in early infancy and for which primary nephrectomy is the treatment of choice. This study aimed to assess surgical complications and outcomes in this patient group and to re-evaluate the age threshold of 6 months for recommending primary nephrectomy. Procedure. A retrospective file review of all cases of MN registered in UK Children's Cancer and Leukaemia Group renal tumour trials between October 1991 and March 2008. Data from the trials were compared with data held by the National Registry of Childhood Tumours, Oxford. Results. Forty-seven (3.5%) confirmed cases of MN were found among 1346 registered renal tumours. Median age at diagnosis was 30 days (range birth-3.8 years). MN was significantly more common in the first 3 months of life compared to between 3 and 6 months (33 vs. 2 cases). Seven cases occurred between 6 months and 1 year and only five cases occurred beyond 1 year of age. There was a significant difference in the age of diagnosis by histological subtype. There were 11 complications in the series; no registered patient developed a recurrent tumour; and all were alive at last follow-up. Conclusions. Outcome for children with MN is excellent at all ages, with little indication for adjuvant chemotherapy. Children presenting at 3 months, alternative diagnoses should be considered, especially in the presence of surgical risk factors. Pediatr Blood Cancer. Pediatr Blood Cancer 2011;56:744-748. (c) 2011 Wiley-Liss, Inc.

Background Survival data of malignant rhabdoid tumour of the kidney (MRTK) registered in SIOP trials, advocating preoperative chemotherapy, are not available. Aim To evaluate characteristics, response and survival of MRTK patients registered in recent SIOP protocols. Methods An evaluation of all MRTK patients treated from 1993 to 2005 (SIOP trials 93-01 and 2001) was performed. Data were obtained from study specific case record forms and entered centrally in a database. Results Hundred and seven patients were identified (57 male), with a median age at diagnosis of 13 months(interquartile range 6-27 months), and a median follow-up time of 60 months. Left and right kidneys were equally affected. Tumour stage distribution was stage I (6%), stage II (22%), stage III (43%), stage IV (22%) and stage V (3%). Stage IV patients included 17 with pulmonary metastasis (8 lung-only) and 12 with multiple organ metastases (bone, brain and liver). Primary surgery was the upfront treatment approach in 22/107 patients (21%), by which 19 patients reached a complete remission (CR). Median difference in tumour volume before and after preoperative chemotherapy was 69 ml (interquartile range: 4.5-158.0, P < 0.0001), indicating marked chemosensitivity. The 5-year event-free survival (EFS) of the total group was 22% (95% CI: 15-33) and overall survival 26% (95% CI: 18-37). Most events (86%) occurred within the first 2 years after diagnosis. Younger age at diagnosis was an important adverse prognostic factors for survival. In contrast, tumour volume at diagnosis, nor volume reduction was associated with outcome. Conclusion MRTK has a poor outcome especially in young and advanced-stage disease patients. Neither tumour volume at diagnosis, nor pre-operative chemosensitivity are prognostic factors for survival. Pediatr Blood Cancer 2011;56:733-737. (c) 2010 Wiley-Liss, Inc.

Background Two principal approaches to Wilms tumor (WT) treatment are immediate surgery (IS) and preoperative chemotherapy (PCT), and both treatments use the risk-adapted approach that includes histological subclassification of the tumor, combined with additional prognostic factors. In the UKW3 trial, these two approaches were compared. The aim of the present study was to compare histological features between the two groups, to assess the impact of PCT on distribution of histological subtyping and staging and to evaluate whether PCT resulted in more staging discrepancies between local and central pathology review (CPR). Materials and methods The cases were identified from the UKW3 trial database. The criteria for inclusion in the study were unilateral, nonmetastatic, nonanaplastic WTs, and submitted for CPR with an adequate number of slides. They were subclassified according to the NWTS and later the SIOP 9301 criteria. Results There were 244 WTs in the IS and 182 in the PCT group subclassified as follows: blastemal 86 (35%) vs 9 (5%), epithelial 34 (14%) vs 12 (7%), stromal 12 (5%) vs 25 (14%), mixed 112 (46%) vs 45 (25%), respectively, plus 40% regressive and 10% completely necrotic WTs in the PCT group. The differences between the two groups for blastemal and mixed types were statistically significant. In the PCT group, there was a significant decrease in stage III tumors. The discrepancies in staging between local and CPR were not significant. Conclusion PCT significantly altered histological features and typing of WTs. It resulted in fewer stage III tumors, and staging discrepancies were equally represented in both groups.

Background. Wilms tumour (WT) has various subtypes that are correlated with prognosis and require distinct therapy. Stromal predominant (SpWT) and epithelial WT (EpWT) have previously been associated with a good outcome. The current analysis describes the outcome and (tumour) characteristics of all patients with SpWT, EpWT, including highly differentiated epithelial type (HDET), treated according to the International Society of Pediatric Oncology (SIOP) 93-01 study. Procedure. All children older than 6 months and below 18 years of age with localized or metastatic WT and intermediate risk (IR) histology or HDET treated with pre-operative chemotherapy were included in the present analysis. Results. A total of 1,389 eligible patients had IR or HDET histology: 1% HDET, 4% EpWT, 10% SpWT, and 85% other IR. For EpWT/HDET, 93% had stage I/IIN-, 5-year EFS was 90.2% and overall survival of (OS) 98.4%, as compared to 84.0% and 92.5% in other IR histology (NS). Stage I EpWT/HDET had a significant better outcome than stage I of other IR. In SpWT 82% of cases had stage I/IIN-; 5-year EFS was 94.3% and OS 99.2%, significantly better compared to other IR histology. All patients with stage I are alive (2/149 relapses); 3/52 stage IIN-, 2/21 stage IIN+/III, and 6/12 stage IV patients relapsed (1 deceased per stage group). Conclusions. The good outcome for EpWT and SpWT generally is very good which may be related to low age and low stage in most cases. A reduction of treatment intensity and/or duration may be justified especially for low stage SpWT that has an EFS close to 100%. Pediatr Blood Cancer 2010;55:233-238. (C) 2010 Wiley-Liss, Inc.