Impact of Tumour 1q Gain in French Pediatric and Young Adult Patients With Renal Tumours

French patients with nephroblastoma (Wilms tumour, WT) have been treated for > 40 years according to International Society of Paediatric Oncology (SIOP) protocols with currently 267 centres across 28 countries collaborating internationally within the SIOP Renal Tumour Study Group (RTSG).

Over the last decades more than 10,000 children have been prospectively enrolled in SIOP WT studies and trials. This has resulted in more standardised diagnostic procedures, improved risk stratification, and adjusted treatment recommendations for most renal tumours. The treatment of patients with renal tumours according to SIOP protocols include preoperative chemotherapy, surgery (tumour-nephrectomy + node-picking ± metastasectomy) followed by risk- and stage-based postoperative chemotherapy ± radiotherapy. Central pathology review is nowadays routinely performed in order to prevent misclassification of stage and histology risk group.

The current SIOP 2001 protocol has come to an end with as major achievement the scientific proof of omitting doxorubicin in stage II and III patients with as a consequence less risk of sequelae. Moreover, in the SIOP 2001 protocol, several tumour biological aspects have been assessed that seem to interfere with outcome (chromosomal gain of 1q, or loss of 1p and 16q, blastemal residual volume). Chromosomal 1q gain is considered to be present in 25-35% of patients with nephroblastoma with a negative impact on event-free survival (EFS) in retrospective analyses. These biological aspects will be studied prospectively as a primary objective in the new SIOP RTSG 2016 UMBRELLA protocol that integrates diagnostics, treatment and follow-up guidelines as well as several research projects.

The main mission of the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group (RTSG) is to increase survival and to reduce acute treatment toxicity and late effects in all children diagnosed with any renal tumour. In this context, SIOP RTSG is aiming to offer all these patients the same standardized high quality diagnostics and treatment, independent of the tumour type. The new SIOP RTSG 2016 integrated diagnostic and research UMBRELLA protocol serves as an entry for including all children with a renal tumour in the SIOP-RTSG centers, including prospective biomarker analyses. Subsequently, treatment is recommended according to the SIOP RTSG 2016 UMBRELLA treatment guidelines, which provides treatment strategies for all patients with Wilms tumour (WT) and other renal tumours. Central radiology review (CRR) has been proposed as a novel tool within the diagnostic UMBRELLA protocol in order to optimize the diagnostics and hence the treatment.

The definition of metastatic disease in WT remains difficult since pulmonary nodules may not always be of malignant origin. The differential diagnosis of a pulmonary lesion seen in a child with WT is broad. In addition to malignancy, it includes atelectasis, fibrosis, pneumonitis, subpleural lymph nodes, and other infectious or inflammatory lesions. In addition, the issue of "CT-only" nodules in WT and adequate treatment needs to be solved. In previous protocols, the treatment strategy was based on the diagnosis of pulmonary metastases (92% of all metastases) by conventional pulmonary X-ray. Patients with CT-only nodules (= nodules not visible on conventional X-ray) were supposed to be treated as having localized WT. However, retrospective analyses of SIOP series (Smets et al), showed that patients with CT-only nodules had a less favourable prognosis as compared to patients with truly localized disease with a 12% difference in three-year event-free survival.

The diagnostics of bilateral renal tumours (stage V) often is complicated since it may be difficult to distinguish true WT from nephroblastomatosis/ nephrogenic rests, a pre malignant renal (multifocal) anomaly, which may respond to preoperative chemotherapy. An optimal multi-disciplinary sequential diagnostic procedure is required in order to propose the best adapted therapeutic approach to preserve sufficient renal tissue.