Characteristics and outcome of synchronous bilateral Wilms tumour in the SIOP WT 2001 Study: Report from the SIOP Renal Tumour Study Group (SIOP-RTSG).

BACKGROUND: Among patients with nephroblastoma, those with bilateral disease are a unique population where maximising tumour control must be balanced with preserving renal parenchyma. METHODS: The SIOP 2001 protocol recommended surgery after neoadjuvant cycle(s) of Dactinomycin and Vincristine (AV) with response-adapted intensification, if needed. Adjuvant treatment was given based on the lesion with the worst histology. RESULTS: Three hundred and twenty seven patients with stage V disease were evaluable: 174 had bilateral Wilms tumour (BWT), 101 unilateral WT and contralateral nephroblastomatosis (NB) and 52 bilateral nephroblastomatosis. In these three groups, the estimated 5y-EFS was 76.1%, 84.6%, and 74.9%, respectively. AV chemotherapy alone was the successful chemotherapy for 58.7% of all the patients and 65.6% of the non-metastatic patients. Among the 174 patients with BWT, 149 (88.2%) had at least one nephron-sparing surgery. Twenty of 61 bilateral stage I patients were treated with four-week AV postoperatively achieving 94.4% 5y-EFS. At last follow-up, 87% of patients had normal renal function. CONCLUSIONS: This study demonstrates that AV without anthracyclines is sufficient to achieve NSS and good survival in the majority of patients. For patients with bilateral stage I WT and intermediate risk histology, only four weeks adjuvant AV seems to be sufficient. CLINICAL TRIAL REGISTRATION: NCT00047138.

Multimodality detection of tumour rupture in children with Wilms tumour.

BACKGROUND AND AIMS: Tumour rupture (TR) signifies stage III disease and requires treatment intensification, which includes radiotherapy. We studied the associations between radiological, surgical and pathology TR in children with Wilms tumour (WT) in a United Kingdom multicentre clinical study. PATIENTS AND METHODS: The IMPORT (Improving Population Outcomes for Renal Tumours of Childhood) study registered 712 patients between 2012 and 2021. Children with TR on central radiology review (CRR) at diagnosis and/or indication of preoperative TR on surgical forms were included. Correlation between radiology/surgery/pathology findings was made. RESULTS: Total 141 patients had TR identified (69 on CRR, 43 on surgical form and 29 on both), and 124/141 had images available for CRR, and 98/124 had features suggestive of TR on diagnostic CRR (63 magnetic resonance imaging/35 computed tomography). TR was limited to the renal fossa in 47/98 (48%) and intraperitoneal in 51/98 (52%). Three of 98(3%) had upfront surgery, and 87/95 (92%) had TR confirmed on post-chemotherapy preoperative scans. Among 80/98 (82%) cases with TR on CRR and available surgical forms, TR was not confirmed on surgery or pathology in 38/80, giving a false-positive rate of 48%. Preoperative TR was indicated on 72 surgical forms, with images available for CRR in 55. Twenty-six of 55 (47%) were false-negative for TR on CRR and of those 10/26 (38%) had TR confirmed on pathology. CONCLUSIONS: Radiology alone should not be used to define TR, as it does not accurately correlate with surgical or pathology findings, and therefore cannot be relied upon for definitive staging and treatment. A multidisciplinary team should take the decision regarding the final abdominal stage and treatment using a multimodality approach considering clinical, radiological, surgical and pathological findings.

Intraoperative ultrasound-guided paediatric urological surgery: a pictorial review.

Intraoperative ultrasound is described widely in multiple pathological scenarios in adult practice and in image-guided interventions in children. We aim to describe the technique and range of potential uses of intraoperative ultrasound in paediatric urological surgery, from outlining the process of case selection, preparation, and logistics to demonstrating the ranging benefits of real-time, high spatial resolution ultrasound during resection. At our centre, we use intraoperative ultrasound to assist in a variety of operations. These include guiding excision margins in nephron-sparing surgery, assessing for vascular infiltration in renal tumours, and identifying salvageable testicular tissue in orchidectomy. By exhibiting these scenarios, we hope to display the unique value that intraoperative ultrasound can have to the paediatric surgeon and inspire additional uses further afield.

Diagnostic magnetic resonance imaging characteristics of congenital mesoblastic nephroma: a retrospective multi-center International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) radiology panel study.

BACKGROUND: Congenital mesoblastic nephroma is the most common solid renal tumor in neonates. Therefore, patients <3 months of age are advised to undergo upfront nephrectomy, whereas invasive procedures at diagnosis in patients ≥3 months of age are discouraged by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Nevertheless, discriminating congenital mesoblastic nephroma, especially from the more common Wilms tumor, solely based on imaging remains difficult. Recently, magnetic resonance imaging (MRI) has become the preferred modality. Studies focusing on MRI characteristics of congenital mesoblastic nephroma are limited. OBJECTIVE: This study aims to identify diagnostic MRI characteristics of congenital mesoblastic nephroma in the largest series of patients to date. MATERIALS AND METHODS: In this retrospective multicenter study, five SIOP-RTSG national review radiologists identified 52 diagnostic MRIs of histologically proven congenital mesoblastic nephromas. MRI was performed following SIOP-RTSG protocols, while radiologists assessed their national cases using a validated case report form. RESULTS: Patients (24/52 classic, 11/52 cellular, and 15/52 mixed type congenital mesoblastic nephroma, 2/52 unknown) had a median age of 1 month (range 1 day-3 months). Classic type congenital mesoblastic nephroma appeared homogeneous with a lack of hemorrhage, necrosis and/or cysts, showing a concentric ring sign in 14 (58.3%) patients. Cellular and mixed type congenital mesoblastic nephroma appeared more heterogeneous and were larger (311.6 and 174.2 cm3, respectively, versus 41.0 cm3 for the classic type (P<0.001)). All cases were predominantly T2-weighted isointense and T1-weighted hypointense, and mean overall apparent diffusion coefficient values ranged from 1.05-1.10×10-3 mm2/s. CONCLUSION: This retrospective international collaborative study showed classic type congenital mesoblastic nephroma predominantly presented as a homogeneous T2-weighted isointense mass with a typical concentric ring sign, whereas the cellular type appeared more heterogeneous. Future studies may use identified MRI characteristic of congenital mesoblastic nephroma for validation and for exploring the discriminative non-invasive value of MRI, especially from Wilms tumor.

Outcomes of patients with Wilms' tumour stage III due to positive resection margins only: An analysis of patients treated on the SIOP-WT-2001 protocol in the UK-CCLG and GPOH studies.

Stage III Wilms' tumour (WT) represents a heterogeneous group which includes different criteria, but all stage III patients are treated according to the same study regiment. The aim of the study was to retrospectively analyse outcomes in patients with stage III due to positive resection margins (RM) only, sub-grouped in RM with viable (RM-v) and nonviable (RM-nv) tumour. Patients were treated pre- and postoperatively according to the SIOP-WT-2001 protocol in the UK-CCLG and GPOH WT trials and studies (2001-2020). There were 197 patients, including 134 with localised, abdominal stage III and 63 with overall stage IV, but abdominal stage III. Stage III due to RM-v had 126 patients, and due to RM-nv 71 patients. The overall 5-year local-relapse-free survival (RFS), event-free (EFS) and overall survival (OS) estimates for all patients with abdominal stage III RM were 95.7% (±SE1.5%), 85.1 (±SE2.6%) and 90.3% (±SE2.2%), respectively. Patients with stage III RM-nv had significantly better RFS and EFS than patients with RM-v (P = .027 and P = .003, respectively). A multivariate analysis showed that RM-v remained a significant factor for EFS when adjusted for age, presence of metastasis at diagnosis, histological risk group and overall stage in Cox regression analysis (P = .006). Patients with stage III due to RM-nv only exhibited no local recurrence and have a significantly better RFS and EFS than patients with RM-v. The results suggest that exclusion of RM-nv as a stage III criterion in the UMBRELLA staging system and consequent treatment reduction is warranted.

Stage I epithelial or stromal type Wilms tumors are low risk tumors: An analysis of patients treated on the SIOP-WT-2001 protocol in the UK-CCLG and GPOH studies (2001-2020).

BACKGROUND: Patients treated with preoperative chemotherapy with stage I intermediate-risk Wilms tumor (IR-WT) represent the largest group of patients with Wilms tumor (WT), and they have excellent outcomes. METHODS: The authors performed a retrospective analysis of patients with stage I epithelial (ET-WT) or stromal type WT (ST-WT) treated pre- and postoperatively according to the International Society of Paediatric Oncology-WT-2001 protocol in the UK Children's Cancer and Leukaemia Group and Gesellschaft für Pädiatrische Onkologie und Hämatologie groups' participation in the relevant WT trials and studies (2001-2020). RESULTS: There were 880 patients with stage I IR-WT, including 124 with ET-WT, 156 with ST-WT, and 600 with other IR-WT (oIR-WT). Patients with stage I ET-WT or ST-WT were significantly younger than patients with oIR-WT, represented a large proportion of stage I WTs in their groups, and tumors showed poor histologic response to preoperative chemotherapy. The 5-year event-free survival (EFS) estimates for patients with stage I ET-WT (96.8% ± 1.8 SE) or ST-WT (96.8% ± 1.6 SE) were significantly better than for patients with oIR-WT (90.3% ± 1.3 SE) (p = .014 and p = .009, respectively). A multivariate analysis showed that histologic type (ET-WT or ST-WT) remained a significant factor for EFS when adjusted for age and gender (p = .032 and p = .022, respectively). In both groups, relapses occurred in 3.2% of patients, and the overall survival was 99.2%. CONCLUSIONS: The results suggest that stage I ET-WT or ST-WT could be regarded as low-risk WT, for which omission of postoperative chemotherapy should be considered. PLAIN LANGUAGE SUMMARY: Patients with pretreated intermediate-risk Wilms tumor (WT) represent the largest group of patients with WT. This study reports the outcomes of patients with stage I epithelial type (ET-WT) or stromal type WT (ST-WT). These patients were significantly younger and had a larger proportion of stage I cases than patients with other intermediate-risk WT (oIR-WT). The event-free survival for patients with stage I ET-WT and ST-WT was significantly better than for patients with oIR-WT. Rare relapses were curable resulting in 99.2% overall survival.

National advisory panels for childhood cancer in the United Kingdom: An evaluation of current practice and a best practice statement for the future.

BACKGROUND: National advisory panels (NAPs) have been established for the care of children and young people (CYP) with cancer in the United Kingdom since 2011, with an increase in panel number in recent years. Their practice has not previously been reviewed; therefore, we sought to evaluate the role, practice and impact of six selected NAPs offering expertise in ependymoma, histiocytosis, leukaemia, neuroblastoma, renal tumours and sarcoma. PROCEDURE: This service evaluation used mixed methodology, including review of NAP documentation, semi-structured interviews with the NAP chairs and an analysis of the cases referred for discussion. RESULTS: Total 1110 referrals were analysed. Results demonstrated the significant scope and amount of work undertaken by the NAPs, largely testament to the commitment of the panel members. Specific roles fulfilled have been highlighted, and NAP recommendations have been shown to influence clinical decision-making and be implemented in the majority of cases. Despite widespread good practice, areas to address have been identified; these include clarity regarding NAP membership, consistency in recommendations, the consideration of holistic information to promote personalised management and the exploration of wider multidisciplinary team roles. CONCLUSIONS: In the context of increasing demand and the escalating number of NAPs, it is timely to consider how service improvement can be facilitated. Best practice guidelines have been formulated as a product of this study, to promote a sustainable and effective model for NAPs. Review and benchmarking national panel performance against these guidelines will drive high standards of care going forward and they should be embedded as standard practice.

The varied spectrum of nephroblastomatosis, nephrogenic rests, and Wilms tumors: Review of current definitions and challenges of the field.

The diagnosis of multiple or diffuse renal lesions in a child is challenging by imaging and/or pathology. Optimal management requires distinguishing benign lesions such as nephrogenic rests from cancerous lesions such as Wilms tumor, but this is often difficult or impossible. This difficulty is compounded by the overlapping nature of our current radiologic and pathologic definitions of lesions along the spectrum of nephrogenic rests/nephroblastomatosis. We provide a review of these issues, as a collaborative effort between the Children's Oncology Group Renal Tumor Committee and International Society of Pediatric Oncology Renal Tumor Study Group. Our aim is to discuss current challenges in diagnosis and management of these renal lesions, encouraging future work toward consensus definitions for research and patient care.

White paper: Oncofertility in pediatric patients with Wilms tumor.

The survival of childhood Wilms tumor is currently around 90%, with many survivors reaching reproductive age. Chemotherapy and radiotherapy are established risk factors for gonadal damage and are used in both COG and SIOP Wilms tumor treatment protocols. The risk of infertility in Wilms tumor patients is low but increases with intensification of treatment including the use of alkylating agents, whole abdominal radiation or radiotherapy to the pelvis. Both COG and SIOP protocols aim to limit the use of gonadotoxic treatment, but unfortunately this cannot be avoided in all patients. Infertility is considered one of the most important late effects of childhood cancer treatment by patients and their families. Thus, timely discussion of gonadal damage risk and fertility preservation options is important. Additionally, irrespective of the choice for preservation, consultation with a fertility preservation (FP) team is associated with decreased patient and family regret and better quality of life. Current guidelines recommend early discussion of the impact of therapy on potential fertility. Since most patients with Wilms tumors are prepubertal, potential FP methods for this group are still considered experimental. There are no proven methods for FP for prepubertal males (testicular biopsy for cryopreservation is experimental), and there is just a single option for prepubertal females (ovarian tissue cryopreservation), posing both technical and ethical challenges. Identification of genetic markers of susceptibility to gonadotoxic therapy may help to stratify patient risk of gonadal damage and identify patients most likely to benefit from FP methods.

Characteristics and outcomes of preoperatively treated patients with anaplastic Wilms tumors registered in the UK SIOP-WT-2001 and IMPORT study cohorts (2002-2020).

BACKGROUND: Since the International Society of Paediatric Oncology Wilms' Tumour 2001 (SIOP-WT-2001) study, focal anaplastic Wilms tumors (FAWTs) have been treated as intermediate-risk Wilms tumors (WTs), and diffuse anaplastic Wilms tumors (DAWTs) have been treated as high-risk tumors. METHODS: The authors performed a retrospective analysis of preoperatively treated patients with FAWT or DAWT recruited in 2 consecutive UK Children's Cancer and Leukaemia Group WT studies. RESULTS: One hundred twenty-one of 1237 patients (10%) had an anaplastic WT confirmed by central pathology review (CPR): 93 (77%) had DAWT, and 28 (23%) had FAWT. The 4-year event-free survival (EFS) was 51% (95% confidence interval [CI], 41%-63%) for DAWT, 88% (95% CI, 76%-100%) for FAWT, and 84% (95% CI, 82%-87%) for intermediate-risk nonanaplastic Wilms tumor (IR-non-AWT). Overall survival (OS) was 58% (95% CI, 48%-70%) for DAWT, 95% (95% CI, 86%-100%) for FAWT, and 95% (95% CI, 93%-96%) for IR-non-AWT. In a multivariate analysis, the presence of DAWT was a significant prognostic factor for both EFS and OS in stages II, III, and IV. In a multivariate analysis of unilateral DAWT, stages III and IV remained the only significant prognostic factors for both EFS and OS. In 28% of the cases, there were discrepancies affecting the recognition of anaplasia, classification (DAWT vs FAWT), or the local pathologic stage. CONCLUSIONS: Preoperatively treated patients with FAWT had excellent outcomes in comparison with those with identically treated IR-non-AWT, whereas patients with DAWT showed significantly worse outcomes. All patients with stage I disease had comparable good outcomes, regardless of the presence/absence of anaplasia. In contrast, the presence of DAWT was associated with significantly worse outcomes for patients with stage II to V disease. Finally, significant diagnostic discrepancies emphasize the value of CPR. LAY SUMMARY: Anaplasia is an unfavorable feature in Wilms tumor (WT), and it is classified as focal (focal anaplastic Wilms tumor [FAWT]) or diffuse (diffuse anaplastic Wilms tumor [DAWT]). This study reports the outcomes of patients with FAWT and DAWT who were, for the first time, treated differently. Patients with FAWT received less intensive treatment, and their outcomes were comparable to the outcomes of patients with identically treated nonanaplastic WT. Patients with stage I DAWT also had good outcomes when they were treated without radiotherapy, whereas patients with stage II to V DAWT had poor outcomes despite more intensive treatment.

How we approach paediatric renal tumour core needle biopsy in the setting of preoperative chemotherapy: A Review from the SIOP Renal Tumour Study Group.

The International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG) advocate treating children with Wilms tumour (WT) with preoperative chemotherapy, whereas the Renal Tumor Committee of the Children's Oncology Group (COG) advocates primary nephrectomy (without biopsy) when feasible. Successive SIOP-RTSG trial protocols recommended pretreatment biopsy of children with unilateral tumours only where there were features to suggest an increased probability of a non-WT requiring a change in management. The UK experience in the SIOP WT 2001 trial showed that an alternate approach of performing biopsies on all children with renal tumour masses to determine histology at diagnosis rarely changes management, and can result in misdiagnosis (particularly patients in the age range typical for WT). Although a more selective approach to biopsy has been routine practice in all other countries participating in SIOP-RTSG trials, there was variation between national groups. To address this variation and provide evidence-based recommendations for the indications and recommended approach to renal tumour biopsy within the SIOP paradigm, an international, multidisciplinary working group of SIOP-RTSG members was convened. We describe the resulting recommendations of this group, which are to be incorporated in the ongoing SIOP-RTSG UMBRELLA study.

Long-term kidney function in children with Wilms tumour and constitutional WT1 pathogenic variant.

BACKGROUND: Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children. METHODS: Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome. RESULTS: We identified 25 patients (60% male, median age at diagnosis 14 months, range 4-74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3-16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years. CONCLUSIONS: Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation.

Prognostic significance of histopathological response to preoperative chemotherapy in unilateral Wilms' tumor: An analysis of 899 patients treated on the SIOP WT 2001 protocol in the UK-CCLG and GPOH studies.

In the SIOP Wilms' tumor (WT) studies, preoperative chemotherapy is used as primary treatment, and tumors are classified thereafter by pathologists. Completely necrotic WTs (CN-WTs) are classified as low-risk tumors. The aim of the study was to evaluate whether a subset of regressive type WTs (RT-WTs) (67%-99% chemotherapy-induced changes [CIC]) showing an exceptionally good response to preoperative chemotherapy had comparably excellent survivals as CN-WTs, and to establish a cut-off point of CIC that could define this subset. The study included 2117 patients with unilateral, nonanaplastic WTs from the UK-CCLG and GPOH-WT studies (2001-2020) treated according to the SIOP-WT-2001 protocol. There were 126 patients with CN-WTs and 773 with RT-WTs, stages I-IV. RT-WTs were subdivided into subtotally necrotic WTs (>95% CIC) (STN-WT96-99) (124 patients) and the remaining of RT-WT (RR-WT67-95) (649 patients). The 5-year event-free survival (EFS) and overall survival (OS) for CN-WTs were 95.3% (±2.1% SE) and 97.3% (±1.5% SE), and for RT-WTs 85.7% (±1.14% SE, P < .01) and 95.2% (±0.01% SE, P = .59), respectively. CN-WT and STN-WT96-99 groups showed significantly better EFS than RR-WT67-95 (P = .003 and P = .02, respectively), which remained significantly superior when adjusted for age, local stage and metastasis at diagnosis, in multivariate analysis, whereas OS were superimposable (97.3 ± 1.5% SE for CN-WT; 97.8 ± 1.5% SE for STN-WT96-99; 94.7 ± 1.0% SE for RR-WT67-95). Patients with STN-WT96-99 share the same excellent EFS and OS as patients with CN-WTs, and although this was achieved by more treatment for patients with STN-WT96-99 than for patients with CN-WT, reduction in postoperative treatment of these patients may be justified.

Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience.

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.

The diagnostic accuracy and clinical utility of pediatric renal tumor biopsy: Report of the UK experience in the SIOP UK WT 2001 trial.

INTRODUCTION: The International Society of Paediatric Oncology (SIOP) protocols recommend preoperative chemotherapy appropriate for Wilms tumors (WTs) in children with renal tumors aged ≥6 months, reserving biopsy for "atypical" cases. The Children's Cancer and Leukaemia Group (CCLG) joined the SIOP-WT-2001 study but continued the national practice of biopsy at presentation. METHOD: Retrospective study of concordance between locally reported renal tumor biopsies and central pathology review nephrectomy diagnoses of children enrolled by CCLG centers in the SIOP-WT-2001 study. RESULTS: Biopsy reports were available for 552/787 children with unilateral tumors. 36 of 552 (6.5%) were nondiagnostic: 2 normal tissue, 12 necrotic, 9 insufficient sample, and 13 indeterminate results (disproportionately non-WTs). The sensitivity and specificity of biopsy to identify tumors that did not require SIOP empirical preoperative chemotherapy were 86.0% and 99.6%, respectively. 13 of 548 (2.4%) biopsy results were discordant with nephrectomy; non-WTs other than renal cell carcinoma and clear cell sarcoma of the kidney (CCSK) were poorly recognized. In children aged 6-119 months, 480 of 518 (91.6%) had WT or nephroblastomatosis. 5 of 518 (1%) had benign tumors, and only one diagnosed on biopsy. Biopsy results correctly changed clinical management in 25 of 518 (4.8%), including identifying 19 of 20 CCSKs, but would have led to overtreatment in 5 of 518 (1%) or undertreatment in 4 of 518 (0.8%). In children aged ≥10 years, biopsy correctly changed management in 5 of 19 (26%) cases with no discordance. CONCLUSION: Biopsy is less effective at identifying non-WTs than WTs and rarely changes management in younger children. Biopsy should be reserved in SIOP protocols for children ≥10 years and in younger children with clinical or radiological features inconsistent with WT.

High-Risk Histopathology Features in Primary and Secondary Enucleated International Intraocular Retinoblastoma Classification Group D Eyes.

PURPOSE: To evaluate the rate and identify the risk factors for high-risk histopathologic features in group D retinoblastoma eyes enucleated as primary or secondary treatment. DESIGN: Retrospective analysis. PARTICIPANTS: A total of 64 enucleated group D eyes (62 patients), of which 40 (40 patients) were primary and 24 (22 patients) were secondary to other treatments. METHODS: Clinicopathologic correlation of consecutive group D eyes enucleated from 2002 to 2014. High-risk histopathologic features were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body/muscle infiltration, massive (≥3 mm) choroidal invasion, retrolaminar optic nerve invasion, or combined non-massive choroidal and prelaminar/laminar optic nerve invasion. MAIN OUTCOME MEASURES: High-risk histopathologic features, metastasis, and death. RESULTS: Of the 64 group D eyes, 37 (58%) were classified as cT2bN0M0H0, 24 (38%) were classified as cT2bN0M0H1, and 3 (5%) were classified as cT2aN0M0H1, according to the 8th edition cTNMH Retinoblastoma Staging. High-risk histopathologic features were detected in 10 eyes (16%) in the entire cohort, 5 eyes (13%) of the primary enucleated group (pT3aNxM0, n = 2 and pT3bNxM0, n = 3, 8th edition pTNM), and 5 eyes (21%) of the secondary enucleated group (pT2bNxM0, n = 2, pT3aNxM0, n = 2 and pT3cNxM0, n = 1). Absence of vitreous seeds at presentation was the only predictive factor found for high-risk histopathologic features in the primary enucleation group (P = 0.042), whereas none were found in the secondary group (P ≥ 0.179). Invasion of the anterior structures (anterior chamber, iris, ciliary body/muscle) was detected significantly more after secondary enucleation (P = 0.048). All patients with high-risk histopathologic features were treated with adjuvant chemotherapy, and no metastases were recorded in a median follow-up time of 73.2 months (mean, 71.5; range, 13.7-153.0). CONCLUSIONS: The choice of primary treatment for group D retinoblastoma should be carefully weighed, because according to this study, 13% of eyes harbor high-risk histopathologic features at presentation, with the absence of vitreous seeds being a potential risk factor. It is of special importance in group D eyes being considered for nonsystemic treatment, such as primary intraophthalmic artery chemotherapy. Secondary enucleated group D eyes with high-risk histopathologic features more commonly involved anterior structures, warranting meticulous clinical and histologic examinations for this subset of patients.

Distant metastatic spread of molecularly proven infantile fibrosarcoma of the chest in a 2-month-old girl: case report and review of literature.

Infantile fibrosarcoma (IFS) is a malignant neoplasm, arising in children younger than 2 years of age and with a hallmark chromosomal translocation t(12;15)(p13;q26) encoding an ETV6-NTRK3 fusion oncoprotein. A review of the world literature found no reported cases of molecularly proven IFS with distant metastatic spread at presentation. We report the case of a 2-month-old infant girl presenting with a chest wall primary IFS bearing and expressing the ETV6-NTRK3 fusion, who had several pulmonary metastatic deposits at diagnosis. She achieved complete remission with chemotherapy and surgery. To our knowledge, this is the first reported case of molecularly proven IFS with distant metastatic spread.

Outcome after treatment with axitinib in children, young adults, and adults with renal cell carcinoma: a narrative review.

Renal cell carcinoma (RCC) is a very rare type of renal cancer in children and young adults. When metastasized or recurrent, no standards of care are available, and outcome is still poor. The tyrosine kinase inhibitor axitinib is approved for treatment of RCC in adults, but its effects in children and young adults with RCC remains unclear. Due to the histological and biological differences between children and adults, it is difficult to extrapolate knowledge on treatments from the adult to the pediatric and young adult setting. This paper summarizes the clinical characteristics and outcomes of patients with RCC who were treated with axitinib, with the aim to gain insight in the clinical efficacy of this compound in this young patient group.

Targeted therapies in children with renal cell carcinoma (RCC): An International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG)-related retrospective descriptive study.

INTRODUCTION: Introduction: Renal cell carcinoma (RCC) is a very rare pediatric renal tumor. Robust evidence to guide treatment is lacking and knowledge on targeted therapies and immunotherapy is mainly based on adult studies. Currently, the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) 2016 UMBRELLA protocol recommends sunitinib for metastatic or unresectable RCC. METHODS: This retrospective study describes the effects of tyrosine kinase inhibitors (TKI), anti-programmed cell death 1 (PD-(L)1) monoclonal antibodies, and immunotherapeutic regimens in advanced-stage and relapsed pediatric RCC. RESULTS: Of the 31 identified patients (0-18 years) with histologically proven RCC, 3/31 presented with TNM stage I/II, 8/31 with TNM stage III, and 20/31 with TNM stage IV at diagnosis. The majority were diagnosed with translocation type RCC (MiT-RCC) (21/31) and the remaining patients mainly presented with papillary or clear-cell RCC. Treatment in a neoadjuvant or adjuvant setting, or upon relapse or progression, included mono- or combination therapy with a large variety of drugs, illustrating center specific choices in most patients. Sunitinib was often administered as first choice and predominantly resulted in stable disease (53%). Other frequently used drugs included axitinib, cabozantinib, sorafenib, and nivolumab; however, no treatment seemed more promising than sunitinib. Overall, 15/31 patients died of disease, 12/31 are alive with active disease, and only four patients had a complete response. The sample size and heterogeneity of this cohort only allowed descriptive statistical analysis. CONCLUSION: This study provides an overview of a unique series of clinical and treatment characteristics of pediatric patients with RCC treated with targeted therapies.