Treatments are modulated according to clinical and anatomopathological variables, as well as according to national protocols specific to each national health system. Generally, the initial treatment of unilateral Wilms tumor is primary surgical resection (with an approach that can be either anticipated or delayed based precisely on each patient’s histologic and clinical outcomes) followed by adjuvant chemotherapy. A select group of younger patients with small tumors can be cured with surgery alone. The type of chemotherapy drug and the duration of therapy depend on the tumor histology and stage. Chemotherapy regimens depend on the risk group but usually consist of actinomycin D (dactinomycin) and vincristine, with or without doxorubicin, or adriamycin. For more aggressive tumors, intensive multi-agent chemotherapy regimens are used. Children with very large unresectable tumors or bilateral tumors are candidates for chemotherapy followed by re-evaluation and resection at a later time. Radiotherapy is given to children who have the disease at a higher stage (stage III and in the presence of distant metastases, usually of the lungs, which do not regress readily with chemotherapy). In most cases, radical nephrectomy is practiced, i.e., the surgical removal of the affected kidney, associated with the resection of the regional and para-aortic lymph nodes ipsilateral to the neoplasm; in bilateral tumors or patients with specific syndromes predisposed to the onset of nephroblastoma, partial nephrectomy is to be preferred whenever feasible [39,40,41,42,43,44]; when possible, especially in the case of bilaterality, preference should be given to even partial preservation of the renal structure, unless clinical conditions permit and the balance with the renal function to be preserved is compatible with possible tumor recurrence [45]. An improvement in the clinical picture and renal parenchyma over historical outcomes emerges in children with the bilateral form (but not in diffuse anaplasia and inhomogeneous tumors) if the treatment approach includes standardized three-drug preoperative chemotherapy, surgical resection within 12 weeks of diagnosis and response and postoperative therapy based on the histologic picture [46,47,48,49,50,51]; still, in the experimental phase, one study showed that concomitant administration of WT1-immunotherapy and standard neoadjuvant therapy (used in breast cancer) was well tolerated and induced WT1-specific antibodies in patients receiving aromatase inhibitors in the neoadjuvant phase (precisely for patients with Wilms tumor); however, in patients receiving neoadjuvant chemotherapy or the trastuzumab-chemotherapy combination, the humoral response was impaired or attenuated, probably due to the co-administration of corticosteroids and/or the chemotherapeutics themselves [52]. One study finally showed that radiofrequency with cryoablation was also effective for this tumor type [53]. To this day, however, immunotherapy and cryotherapy are not yet generally approved therapies in scientific communities such as the Children’s Oncology Group and the Renal Tumor Study Group of the International Society of Pediatric Oncology (SIOP-RTSG), due to the few studies still in the literature, but it is hoped that in the future they may be considered as alternative and/or concomitant therapies to improve the quality of Wilms tumor treatments. [54] Another study has shown that the International Society of Pediatric Oncology (SIOP) protocol for Wilms tumor (WT), in the part that calls for preoperative chemotherapy as an initial approach, does not take into account the risk of histologic misdiagnosis and thus ineffective or even harmful treatment; therefore, it has been shown that fine-needle aspiration cytology (FNAC) can be a useful and feasible technique in children and can confirm the diagnostic suspicion of unilateral WT, avoiding inadequate preoperative chemotherapy in non-Wilms renal cancer. [55] Surgery, chemotherapy and radiotherapy essentially constitute the current treatment modality for Wilms tumor. The guidelines of the National Wilms Tumor Study Group (NWTSG/COG) and the International Society of Pediatric Oncology (SIOP) provide two different strategies for initial treatment, with some differences: in particular, in North America, the NWTSG/guidelines are adopted by the COG, while in Europe, it is usual to use the SIOP guidelines. Despite differences, determined from the individual case, the overall survival rate for patients treated using the two guidelines is similar, i.e., above 90% (in uncomplicated cases or with metastasis) [5]. Differences in approach between the different European and American currents, however, are resolved through the integration of practical experience, keeping in mind the specific characteristics of the patient’s clinical history and the relevant guidelines. In the table, see the different treatments (Table 2):

The current research group, which replaces the National Wilms Tumor Study Group (NWRSG), is the Children’s Oncology Group Renal Tumor Committee (COGRTC), adhering to the principles enucleated in the previous description [60].

The criteria for subclassifying pretreated WTs are as follows: The completely necrotic type shows no viable tumor elements. If more than 66% (two-thirds) of the tumor is non-viable (i.e., shows chemotherapy-induced changes), it is regarded as a regressive type, irrespective of the presence of remaining viable tumor components. If a viable tumor comprises more than one-third of the tumor mass, subtyping depends on the percentage of viable components: in mixed type, none of the components comprise more than 66% of the tumor; in epithelial (or stromal) type, in addition to having more than 66% of the tumor being composed of epithelial (or stromal) elements, the finding of only up to 10% of blastema is allowed (if the finding is more, then the tumor is subclassified as mixed type). Finally, preoperative chemotherapy is recommended for children with Wilms tumor with intravascular extension, as prolonged chemotherapy may improve resectability but increases tumor adhesion to the vascular endothelium, precluding complete resection. To evaluate the optimal duration of preoperative treatment, a study focused on overall survival (OS) and event-free survival (EFS), tumor regression, complete resection and cavectomy demonstrated that there is no evidence that cycle-prolonged periods of neoadjuvant chemotherapy confer additional benefits in treatment and are therefore not recommended [61].

The classic triphasic Wilms tumor does not present diagnostic difficulties for pathologists, but when only one component is present (especially if small), the differential diagnosis may include renal cell carcinoma, metanephric adenoma and hyperplastic nephrogenic remnant, sarcoma of the kidney, mesoblastic nephroma and synovial sarcoma. Even pure Wilms tumor of the blastemal type may be difficult to distinguish from other embryonic “small round blue cell tumors”, including neuroblastoma, primitive neuroectodermal tumor/Ewing’s sarcoma, desmoplastic small round cell tumor and lymphoma. There are several reasons why making the correct diagnosis of Wilms tumor can be difficult: (1) the rarity of pediatric renal tumors results in a lack of experience with these entities for most pathologists; (2) the presence of different Wilms subtypes (morphological heterogeneity); (3) the morphological aspects can vary considerably from case to case; (4) the histological patterns of some Wilms subtypes may initially appear similar to those of other rare pediatric renal tumors; (5) the lack of clear-cut differential criteria distinguishing Wilms from nephrogenic remnants (NR), especially in limited biopsy material; (6) tumor evaluation and local pathological stage determination are multistep and time-consuming processes [62].