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.

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.

Pediatric thyroid-like follicular renal cell carcinoma-a post-neuroblastoma case with comprehensive genomic profiling data.

Thyroid-like follicular renal cell carcinoma (TLFRCC), an emerging subtype of renal cell carcinoma, presents diagnostic challenges due to its resemblance to normal thyroid tissue. Here, we report a rare case of TLFRCC in a pediatric patient, a demographic rarely affected by this subtype. Histologically resembling a typical TLFRCC, our case exhibited unique features including post-neuroblastoma development, occurrence in a male teenager, and diffuse MelanA expression, which has not been previously reported in TLFRCC. Comprehensive genomic profiling revealed the EWSR1::PATZ1 fusion, confirming its genetic basis. Due to the advanced tumor stage, the patient received combined immunotherapy, and after a 9-month follow-up, remains tumor-free. Our case broadens the diagnostic spectrum of pediatric renal cell carcinomas, highlighting the importance of comprehensive molecular profiling in rare subtypes such as TLFRCC. Further research is needed to better understand TLFRCC's genetic landscape and optimize therapeutic strategies, especially in pediatric populations with evolving treatment protocols.

Anaplasia in Wilms tumor: A critical review.

Anaplasia in Wilms tumor is recognized as the most important prognostically unfavorable histological feature. It is subtyped as focal anaplastic Wilms tumor (FAWT) and diffuse anaplastic Wilms tumor (DAWT). Outcomes of patients with DAWT remain poor in patients with stage III and IV tumors. Important issues relevant to anaplasia in Wilms tumor, including prevalence, treatment, outcomes, biomarkers, anaplasia, and chemotherapy, and the concept of tumor aggressiveness, are reviewed and discussed here. We also consider the differences in clinical approaches to anaplasia in Wilms tumor between the two major renal tumor clinical research groups: the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group and the Children's Oncology Group (COG) Renal Tumor Group. We emphasize the importance and implications of recognizing FAWT and DAWT as separate clinico-pathological entities.

Omission of adjuvant chemotherapy in patients with completely necrotic Wilms tumor stage I and radiotherapy in stage III: The 30-year SIOP-RTSG experience.

BACKGROUND: Completely necrotic Wilms tumor (CN-WT) following preoperative chemotherapy has been regarded as low-risk WT since the International Society of Paediatric Oncology (SIOP) 93-01 study, and patients have been treated with reduced postoperative therapy. The aim of the study was to evaluate whether the omission of adjuvant chemotherapy in patients with localized CN-WT stage I and radiotherapy in stage III was safe. PATIENTS AND METHODS: The retrospective observational study of outcomes of patients diagnosed with localized CN-WT on central pathology review and treated according to the SIOP 93-01 and SIOP-WT-2001 protocols (1993-2022). RESULTS: There were 125 patients with localized CN-WT: 90 with stage I, 10 with stage II, and 25 with stage III. Sixty-two of 125 (49.6%) patients had a discrepant diagnosis and/or staging between the institutional pathologist and central pathology review. In the group of 90 patients with stage I, postoperative chemotherapy was not given to 41 (46%) patients, whereas 49 patients received postoperative chemotherapy-in the latter group, two patients relapsed, and one of them died. One stage I and one stage II patient developed chemotherapy-induced toxicity and died. Nineteen of 25 patients with stage III received no flank radiotherapy. No stage III patient relapsed or died. The overall 5-year event-free survival (EFS) estimate for the entire cohort (stages I-III) was 96.8% [95% confidence interval, CI: 93.6%-99.6%] and the overall survival (OS) was 97.6% [95% CI: 95.0-100%]. The EFS and OS were 97% and 98%, respectively, for stage I, and 100% for stage III. CONCLUSION: Omission of postoperative chemotherapy for patients with CN-WT stage I, and radiotherapy for stage III is safe. Rapid central pathology review is required to assign appropriate treatment and avoid treatment-related side effects.

Teratoma-associated and so-called pure Wilms tumour of the ovary represent two separate tumour types with distinct molecular features.

AIMS: Ovarian Wilms tumour (WT)/nephroblastoma is an extremely rare neoplasm that has been reported to occur in pure form or as a component of a teratomatous neoplasm. We hypothesized that teratoma-associated and pure ovarian WT may represent different tumour types with diverging molecular backgrounds. To test this hypothesis, we comprehensively characterized a series of five tumours originally diagnosed as ovarian WT. METHODS AND RESULTS: The five cases comprised three teratoma-associated (two mature and one immature) and two pure WTs. Two of the teratoma-associated WTs consisted of small nodular arrangements of "glandular"/epithelial structures, while the third consisted of both an epithelial and a diffuse spindle cell/blastemal component. The pure WTs consisted of "glandular" structures, which were positive for sex cord markers (including inhibin and SF1) together with a rhabdomyosarcomatous component. The two pure WTs harboured DICER1 pathogenic variants (PVs), while the three associated with teratomas were DICER1 wildtype. Panel-based DNA sequencing of four of the cases did not identify PVs in the other genes investigated. Analysis of the HA19/IGF2 imprinting region showed retention of imprinting in the pure WTs but loss of heterozygosity with hypomethylation of the ICR1 region in two of three teratoma-associated WTs. Furthermore, copy number variation and clustering-based whole-genome DNA methylation analyses identified divergent molecular profiles for pure and teratoma-associated WTs. CONCLUSION: Based on the morphological features, immunophenotype, and molecular findings (DICER1 PVs, copy number, and DNA methylation profiles), we suggest that the two cases diagnosed as pure primary ovarian WT represent moderately to poorly differentiated Sertoli Leydig cell tumours (SLCTs), while the tumours arising in teratomas represent true WTs. It is possible that at least some prior cases reported as pure primary ovarian WT represent SLCTs.

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.

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.

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.

Evidence-based surgical guidelines for treating children with Wilms tumor in low-resource settings.

BACKGROUND: Survival of Wilms tumor (WT) is > 90% in high-resource settings but < 30% in low-resource settings. Adapting a standardized surgical approach to WT is challenging in low-resource settings, but a local control strategy is crucial to improving outcomes. OBJECTIVE: Provide resource-sensitive recommendations for the surgical management of WT. METHODS: We performed a systematic review of PubMed and EMBASE through July 7, 2020, and used the GRADE approach to assess evidence and recommendations. RECOMMENDATIONS: Initiation of treatment should be expedited, and surgery should be done in a high-volume setting. Cross-sectional imaging should be done to optimize preoperative planning. For patients with typical clinical features of WT, biopsy should not be done before chemotherapy, and neoadjuvant chemotherapy should precede surgical resection. Also, resection should include a large transperitoneal laparotomy, adequate lymph node sampling, and documentation of staging findings. For WT with tumor thrombus in the inferior vena cava, neoadjuvant chemotherapy should be given before en bloc resection of the tumor and thrombus and evaluation for viable tumor thrombus. For those with bilateral WT, neoadjuvant chemotherapy should be given for 6-12 weeks. Neither routine use of complex hilar control techniques during nephron-sparing surgery nor nephron-sparing resection for unilateral WT with a normal contralateral kidney is recommended. When indicated, postoperative radiotherapy should be administered within 14 days of surgery. Post-chemotherapy pulmonary oligometastasis should be resected when feasible, if local protocols allow omission of whole-lung irradiation in patients with nonanaplastic histology stage IV WT with pulmonary metastasis without evidence of extrapulmonary metastasis. CONCLUSION: We provide evidence-based recommendations for the surgical management of WT, considering the benefits/risks associated with limited-resource settings.

International Comparisons of Clinical Demographics and Outcomes in the International Society of Pediatric Oncology Wilms Tumor 2001 Trial and Study.

PURPOSE: International comparisons of patient demographics, tumor characteristics, and survival can shed light on areas for health care system improvement. The International Society of Pediatric Oncology Wilms Tumor 2001 trial/study registered patients through national clinical study groups in Western Europe and Brazil. This retrospective post hoc analysis of the International Society of Pediatric Oncology Wilms Tumor 2001 database aims to make visible and suggest reasons for any variations in outcomes. METHODS: All patients with unilateral Wilms tumor (WT), age > 6 months, treated with preoperative chemotherapy as per protocol, and registered between 2001 and 2011 were eligible. Countries were grouped to give comparable case numbers and geographical representation. Cox univariable and multivariable (MVA) statistics were applied, with the German collaborative group (Gesellschaft für Pädiatrische Onkologie und Hämatologie-Austria, Germany, and Switzerland) as reference for hazard ratios for event-free survival (EFS) and overall survival (OS). RESULTS: A total of 3,176 eligible patients were registered from 24 countries assigned into six groups. Age and histologic risk group distribution were similar across all groupings. The distribution of WT stage varied by country grouping, with 14.9% (range, 11.1%-18.2%) metastatic at diagnosis. Median follow-up was 78.9 months. For localized WT, 5-year EFS varied from 80% (Brazilian group) to 91% (French group; P < .0001), retaining significance only for Brazil in MVA (P = .001). Five-year OS varied from 89% (Brazilian group) to 98% (French group; P < .0001). In MVA, only superior OS in France was significant (P = .001). Five-year EFS/OS for stage IV did not vary significantly. High-risk histology and tumor volume at surgery were significantly associated with increased risk of death in MVA for metastatic disease. CONCLUSION: International benchmarking of survival rates from WT within a large trial/study database has demonstrated statistically significant differences. Clinical interpretation should take account of variation in tumor stage but also treatment factors.

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.

Renal cell carcinoma in children and adolescents: a retrospective study of a French-Italian series of 93 cases.

AIMS: Renal cell carcinomas (RCCs) represent 2-5% of kidney malignancies in children and adolescents. Appropriate diagnostic and classification are crucial for the correct management of the patients and in order to avoid inappropriate pre-operative chemotherapy, which is usually recommended if a Wilms' tumour is suspected. METHODS AND RESULTS: A French-Italian series of 93 renal cell carcinomas collected from 1990 to 2019 in patients aged less than 18 years was reclassified according to the 2016 World Health Organization (WHO) classification and the latest literature. TFE3 and TFEB fluorescence in-situ hybridisation (FISH) analyses and a panel of immunohistochemical stains were applied. The median age at diagnosis was 11 years (range = 9 months-17 years). MiT family (MiTF) translocation RCCs accounted for 52% of the tumours, followed by papillary (20%) and unclassified RCCs (13%). Other subtypes, such as SDHB-deficient and fumarate hydratase-deficient RCCs, represented 1-3% of the cases. We also described a case of ALK-rearranged RCC with a metanephric adenoma-like morphology. CONCLUSION: A precise histological diagnosis is mandatory, as targeted therapy could be applied for some RCC subtypes, i.e. MiTF-translocation and ALK-translocation RCC. Moreover, some RCC subtypes may be associated with a predisposition syndrome that will impact patients' and family's management and genetic counselling. A precise RCC subtype is also mandatory for the clinical management of the patients and inclusion in new prospective clinical trials.

Treatment of patients with stage I focal anaplastic and diffuse anaplastic Wilms tumour: A report from the SIOP-WT-2001 GPOH and UK-CCLG studies.

BACKGROUND: Anaplasia is an unfavourable prognostic histological feature in Wilms tumour (WT). Patients with stage I anaplastic WT (AWT) typically achieve good outcomes, albeit with more treatment than for stage I non-AWT. Since the SIOP-WT-2001 study, patients with focal AWT (FAWT) have been classified as intermediate risk and received less intense treatment than patients with diffuse AWT (DAWT). The aim of the study was to analyse outcomes in these patients. PATIENTS AND METHODS: This was a retrospective analysis of clinicopathological features and outcomes of 59 patients with stage I AWT (19 FAWT, 40 DAWT) from the SIOP-WT-2001 GPOH and UK-CCLG groups. The patients with FAWT were treated as intermediate-risk WT, with 8 weeks of vincristine and actinomycin D (4 weeks pre-operatively, and 4 weeks post-operatively). For comparison, we also assessed outcomes in 818 patients with stage I intermediate-risk non-AWT (IR-non-AWT). The patients with DAWT were treated with vincristine, actinomycin D and doxorubicin for 31 weeks. No group received radiotherapy. RESULTS: Median follow-up was 67.6 months; 4-year event-free survival and overall survival were 87% (95% confidence interval [CI] = 72-100) and 100%, respectively, in the FAWT group, 85% (95% CI = 74-98) and 93% (95% CI 85-100), respectively, in the DAWT group and 91% (95% CI = 89-93) and 98% (95% CI = 97-99), respectively, in the IR-non-AWT group. CONCLUSIONS: Outcomes for patients with stage I FAWT were comparable with those of other, identically treated, patients with stage I IR-non-AWT. Patients with stage I DAWT also showed good outcomes, albeit with more intensive chemotherapy than IR-non-AWT, but without radiotherapy.

Pathology of Wilms' tumour in International Society of Paediatric Oncology (SIOP) and Children's oncology group (COG) renal tumour studies: Similarities and differences.

Excellent outcomes for patients with Wilms' tumour (WT), >90% for all stages together, have been achieved through researching WT in multicentre and multinational trials and studies in the last 50 years, led by two major groups-the International Society of Paediatric Oncology (SIOP) and the Children's Oncology Group (COG) (previously the National Wilms' Tumour Study Group). Despite the two groups having different approaches, the survival outcomes are remarkably similar. In general, in the SIOP approach, which is followed in Europe and most other countries around the world, patients are first treated with preoperative chemotherapy; this is followed by surgery and, if necessary, postoperative chemotherapy and radiotherapy. In the COG approach, which is mainly followed in North America, patients are treated with upfront surgery, followed, if necessary, by postoperative chemotherapy and radiotherapy. In both groups, postoperative treatment primarily depends on tumour histological classification and stage, although, in recent studies, other prognostic factors have also been included (tumour volume, response to preoperative chemotherapy, and molecular markers). Owing to separate initial treatments, there are differences in histological assessment and subtyping of WT, and, more importantly, in staging criteria. In this review, we discuss the similarities and differences between the two groups in order to help pathologists who are dealing with WT to understand and follow the pathological protocol that is appropriate for a particular case, because, in many centres, both approaches may be followed, depending on individual case/patient circumstances.

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.

Outcome of SIOP patients with low- or intermediate-risk Wilms tumour relapsing after initial vincristine and actinomycin-D therapy only - the SIOP 93-01 and 2001 protocols.

PURPOSE: 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. PATIENTS AND METHODS: 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]). RESULTS: 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]). CONCLUSION: 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.

Surgical management, staging, and outcomes of Wilms tumours with intravascular extension: Results of the IMPORT study.

PURPOSE: 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). METHODS: 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. RESULTS: 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 (P<0.05). OS and EFS were also significantly associated with histological risk group (P<0.05) but not with viability of tumour thrombus (P=0.19; P=0.59). CONCLUSIONS: 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 OF EVIDENCE: Level II.

Wilms tumour.

Wilms tumour (WT) is a childhood embryonal tumour that is paradigmatic of the intersection between disrupted organogenesis and tumorigenesis. Many WT genes play a critical (non-redundant) role in early nephrogenesis. Improving patient outcomes requires advances in understanding and targeting of the multiple genes and cellular control pathways now identified as active in WT development. Decades of clinical and basic research have helped to gradually optimize clinical care. Curative therapy is achievable in 90% of affected children, even those with disseminated disease, yet survival disparities within and between countries exist and deserve commitment to change. Updated epidemiological studies have also provided novel insights into global incidence variations. Introduction of biology-driven approaches to risk stratification and new drug development has been slower in WT than in other childhood tumours. Current prognostic classification for children with WT is grounded in clinical and pathological findings and in dedicated protocols on molecular alterations. Treatment includes conventional cytotoxic chemotherapy and surgery, and radiation therapy in some cases. Advanced imaging to capture tumour composition, optimizing irradiation techniques to reduce target volumes, and evaluation of newer surgical procedures are key areas for future research.