Criteria
There are two main classification systems for histology and staging: those produced by the Children's Oncology Group (COG), previously known as the National Wilms Tumor Study Group (NWTSG), and those produced by the International Society of Paediatric Oncology (SIOP).[3][41][55][72]
Both systems differ slightly in their approaches to staging and treatment, and in many centers, both approaches may be followed, depending on individual case/patient circumstances.[55] The SIOP offers preoperative chemotherapy; whereas COG is based on upfront nephrectomy. Both treatments use a risk-adapted approach that includes histologic subclassification of the tumor, combined with additional prognostic factors, such as tumor volume, response to preoperative chemotherapy, and molecular markers.[41][73] Despite this difference, both approaches to treatment are considered to have excellent and comparable outcomes.
Children's Oncology Group (COG)
The COG approach to risk stratification of upfront nephrectomy allows for immediate histologic diagnosis, molecular analysis, and accurate local staging assessment.[73][74]
Staging:[55]
Stage I: tumor is limited to the kidney, not ruptured, completely resected, and renal capsule is intact. No biopsy done prior to resection. Margins are clear of tumor
Stage II: tumor extends beyond the kidney such as penetration of renal capsule or extensive invasion of the renal sinus, but is completely resected and margins are free of tumor involvement
Stage III: microscopic or gross residual or unresectable non-hematogenous tumor is present and confined to the abdomen. This may represent tumor positive lymph nodes within the abdomen or pelvis, peritoneal implants, or penetration through the peritoneal surface. Tumor is removed in more than one piece (i.e., removed separately from the nephrectomy specimen) from other locations such as adrenal gland or intravascular tumor thrombus. The tumor is a stage III if an excisional biopsy was performed or if there is spillage of tumor before or during surgery
Stage IV: hematogenous metastases (i.e., lung, liver, bone, brain) or lymph node metastases outside the abdomino-pelvic region are present
Stage V: bilateral renal involvement; stage each kidney individually.
Absence of anaplasia (favorable histology):
Typically triphasic in appearance and includes blastemal, stromal, and epithelial elements
Presence of abortive tubules and glomeruli surrounded by a spindled cell stroma.
Presence of anaplasia (unfavorable histology):
Gigantic (>3 times the diameter of adjacent cells) hyperchromatic nuclei
Identification of polypoid mitotic figures
Focal anaplasia: anaplastic nuclear changes confined to restricted foci within the primary tumor
Diffuse anaplasia: involvement of any extrarenal site, renal sinus, extracapsular involvement, sinus, nodal, and distant metastases, or extreme nuclear pleomorphism in one area or involvement of multiple areas within one slide.
Recurrence-risk categories:
Favorable histology Wilms tumors are subdivided by COG into the following recurrence risk categories based on staging, histology, molecular markers, and biologic factors:[73][74]
Very-low risk: <2 years of age, <550 g tumor weight, stage I, any loss of heterozygosity (LOH) status
Low risk: any age or tumor weight, stage I or II, but no LOH at 1p and 16q
Standard risk: stage I tumors ≥550 g with LOH at 1p and 16q, or stage II with LOH, or stage III/IV with no LOH
High risk: stage III or IV with LOH at 1p and 16q.
International Society of Paediatric Oncology (SIOP)
Patients are staged at diagnosis by imaging studies into localized (stages I-III), metastatic (stage IV), or bilateral (stage V) disease in order to decide on duration of preoperative chemotherapy.[41][75]
Stage I: tumor limited to the kidney, complete excision, renal sinus not involved (intrarenal vessels maybe involved)
Stage II: tumor extending outside the kidney, complete excision. The tumor is completely resected and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney, as:
regional extension of the tumor (i.e., penetration of the renal capsule or invasion of the soft tissue of the renal sinus)
infiltration of blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus
infiltration of renal pelvis wall or the ureter
infiltration of vena cava or adjacent organs (except for the adrenal gland)
Stage III: tumor invasion beyond capsule, incompletely excised tumors. This includes:
viable tumor is present at a resection margin (nonviable tumor or chemotherapy-induced change present at resection margins is not regarded as stage III)
abdominal lymph node involvement is present by either viable or nonviable tumor
preoperative/perioperative rupture
viable or nonviable tumor thrombus is present at resection margins of the ureter or extrarenal vessels (renal vein or inferior vena cava)
preoperative biopsy is performed prior to preoperative chemotherapy or surgery
presence of intra-abdominal tumor implants (viable or nonviable)
tumor has penetrated peritoneal surface
Stage IV: hematogenous metastases (i.e., lung, liver, bone, brain) or lymph node metastases outside the abdominopelvic region are present
Stage V: bilateral renal tumors.
Histology:[55]
Based on histologic features of residual tumor after preoperative chemotherapy.
Low-risk tumor: completely necrotic, cystic, partially differentiated (equivalent to COG favorable histology).
Intermediate-risk tumor: ≥33% of tumor is viable. Epithelial or stromal types have ≥67% of the viable component as epithelial or stromal elements and the rest of the viable tumor has <10% of blastemal cells. Mixed type has epithelial, stromal, and blastema elements (can be >10%), but no component is ≥67% (equivalent to COG favorable histology). Tumors with focal anaplasia are considered to be intermediate risk as per SIOP protocol.
High-risk tumor: blastemal, diffuse anaplastic (equivalent to COG unfavorable histology).
The aims of the UMBRELLA protocol are to validate the prognostic value of incorporating biomarkers such as the volume of the blastemal component that survives preoperative chemotherapy and molecular markers, including 1q gain and other copy number alterations (1p/16q, MYCN, and TP53), to shape future therapeutic approaches.[41][75]
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