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]
The systems differ slightly in their approaches to staging and treatment, and in many centres, 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 histological subclassification of the tumour, combined with additional prognostic factors, such as tumour 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]
Stage I: tumour is limited to the kidney, not ruptured, completely resected, and renal capsule is intact. No biopsy done prior to resection. Margins are clear of tumour
Stage II: tumour 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 tumour involvement
Stage III: microscopic or gross residual or unresectable non-haematogenous tumour is present and confined to the abdomen. This may represent tumour-positive lymph nodes within the abdomen or pelvis, peritoneal implants or penetration through the peritoneal surface. Tumour is removed in more than one piece (i.e., removed separately from the nephrectomy specimen) from other locations such as adrenal gland or intravascular tumour thrombus. The tumour is a stage III if an excisional biopsy was performed or if there is spillage of tumour before or during surgery
Stage IV: haematogenous 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 (favourable 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 (unfavourable 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 tumour
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:
Favourable histology Wilms' tumours are subdivided by COG into the following recurrence risk categories based on staging, histology, molecular markers, and biological factors:[73][74]
Very-low risk: <2 years of age, <550 g tumour weight, stage I, any loss of heterozygosity (LOH) status
Low risk: any age or tumour weight, stage I or II, but no LOH at 1p and 16q
Standard risk: stage I tumours ≥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 localised (stages I-III), metastatic (stage IV), or bilateral (stage V) disease in order to decide on duration of preoperative chemotherapy.[41][75]
Stage I: tumour limited to the kidney, complete excision, renal sinus not involved (intrarenal vessels maybe involved)
Stage II: tumour extending outside the kidney, complete excision. The tumour is completely resected and there is no evidence of tumour at or beyond the margins of resection. The tumour extends beyond the kidney, as:
regional extension of the tumour (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: tumour invasion beyond capsule, incompletely excised tumours. This includes:
viable tumour is present at a resection margin (non-viable tumour or chemotherapy-induced change present at resection margins is not regarded as stage III)
abdominal lymph node involvement is present by either viable or non-viable tumour
preoperative/perioperative rupture
viable or non-viable tumour 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 tumour implants (viable or non-viable)
tumour has penetrated peritoneal surface
Stage IV: haematogenous metastases (i.e., lung, liver, bone, brain) or lymph node metastases outside the abdominopelvic region are present
Stage V: bilateral renal tumours.
Histology:[55]
Based on histological features of residual tumour after preoperative chemotherapy.
Low-risk tumour: completely necrotic, cystic, partially differentiated (equivalent to COG favourable histology).
Intermediate-risk tumour: ≥33% of tumour is viable. Epithelial or stromal types have ≥67% of the viable component as epithelial or stromal elements and the rest of the viable tumour has <10% of blastemal cells. Mixed type has epithelial, stromal, and blastema elements (can be >10%), but no component is ≥67% (equivalent to COG favourable histology). Tumours with focal anaplasia are considered to be intermediate risk as per SIOP protocol.
High-risk tumour: blastemal, diffuse anaplastic (equivalent to COG unfavourable 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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