Authors: Richard D. Glick (1 -Division of Pediatric Surgery, Cohen Children’s Medical Center, Zucker School of Medicine at Northwell/Hofstra, New Hyde Park, NY), Rodrigo LP Romao (2 -Divisions of Pediatric General Surgery and Pediatric Urology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada), Max Pachl (3 -Department of Paediatric Surgery and Urology, Birmingham Children’s Hospital, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK), Meera Kotagal (4 -Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center; Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH), Amanda F. Buchanan (5 -University of Kentucky, Departments of Urology and Pediatrics, Lexington, KY), Andrew J. Murphy (6 -Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN), Elisabeth T. Tracy (7 -Division of Pediatric Surgery, Duke Children’s Hospital and Health Center, Durham, North Carolina), Luca Pio (8 -Paediatric Surgery Unit, Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France.), Nicholas G. Cost (9 -Division of Urology, Department of Surgery, University of Colorado School of Medicine and the Surgical Oncology Program at Children’s Hospital Colorado, Aurora, CO), Jan Godzinski (10 -Department of Pediatric Surgery, Marciniak Hospital, Wroclaw, Poland; Department of Pediatric Traumatology and Emergency Medicine, Medical University, Wroclaw, Poland.), Peter F. Ehrlich (11 -University of Michigan Department of Surgery, Section of Pediatric Surgery, Ann Arbor Michigan 48104, USA)
Categories: Article, Pediatric, Renal tumor, Kidney tumor, Wilms tumor, Renal cell carcinoma
Source: Pediatric blood & cancer
Doi: 10.1002/pbc.31118
Authors: Richard D. Glick, Rodrigo LP Romao, Max Pachl, Meera Kotagal, Amanda F. Buchanan, Andrew J. Murphy, Elisabeth T. Tracy, Luca Pio, Nicholas G. Cost, Jan Godzinski, Peter F. Ehrlich
Pediatric renal tumors are among the most common pediatric solid malignancies. Surgical resection is a key component in the multi-disciplinary therapy for children with kidney tumors. Therefore, it is imperative that surgeons caring for children with renal tumors fully understand the current standards of care in order to provide appropriate surgical expertise within this multi-modal framework. Fortunately, the last 60 years of international, multidisciplinary pediatric cancer cooperative group studies have enabled high rates of cure for these patients. This review will highlight the international surgical approaches to pediatric patients with kidney cancer to help surgeons understand the key differences and similarities between the European (International Society of Pediatric Oncology) and North American (Children’s Oncology Group) recommendations.
Pediatric renal tumors account for approximately 6% to 7% of all childhood cancers. Wilms tumor (WT) is the most common renal tumor of childhood.^1^ The average annual age-adjusted incidence rate of WT is 7.5 person-years per million globally for patients between the ages of 0 and 14 years-old.^2,3^
Median age at diagnosis for WT is 3.5 years, with more than 80% of cases diagnosed before 5 years of age.^1^ Age at diagnosis is lower in children with bilateral WT and those with a syndromic predisposition to WT.^4,5^
WT is slightly more frequent in females than in males globally, with slight variations in the female ratio based on the region of the world studied.^3^ With regard to ethnicity, the incidence of WT is lower in East Asian populations and higher in Black populations compared with the incidence reported for North American and European whites.^2^ Black children often have a more advanced stage of disease at presentation, but it is not clear if this is related to tumor biology or reflects delays in diagnosis resulting from negative social determinants of health.
Non-Wilms histology makes up about 20% of renal tumors in children. Renal cell carcinoma (RCC) and clear cell sarcoma of the kidney (CCSK) are the two entities most commonly reported.^6^ Median age at diagnosis for RCC is 13 years old with a slight male preponderance; at this age, RCC becomes more common than WT as the primary renal tumor most frequently observed.^3,7^ In contrast to what is seen in adults, the most common subtype observed in children and adolescents is translocation RCC involving Xp11.2 (TFE3 gene locus).^7^
CCSK is also seen in young children with most patients diagnosed around age 2 years.^8^ Congenital mesoblastic nephroma (CMN) and rhabdoid tumor of the kidney (RTK) are other examples of non-Wilms renal tumors that are commonly observed, particularly in the younger age strata.^9^
Most children with renal tumors are asymptomatic at presentation and predominantly have a distended abdomen with a palpable mass. Frequently, the child’s parents notice such a mass during bathing or dressing. Alternatively, the general practitioner or the pediatrician identifies an asymptomatic abdominal mass during a regular clinical assessment of a well child or a child with non-specific symptoms. Renal tumors usually form a non-tender, large flank mass, which does not move with respiration, in contrast to splenomegaly.
Alternatively, approximately 1 in 5 children present with distinct symptoms but this varies by country and healthcare setting.^10^ Pritchard Jones et al looked at routes to diagnosis for asymptomatic (found incidentally or on screening) and symptomatic children in the United Kingdom (UK) and Germany.^11^ They found that in the UK, 85% of children had tumor-related symptoms (pain, hematuria, fever, hypertension, urinary tract infections, constipation and weight loss) leading to diagnosis and that they were significantly younger and had higher stage tumors than children who were asymptomatic. Comparing this to data from Germany revealed that in the UK, tumors were significantly larger at presentation and there was a poorer event free survival (EFS). This was postulated to be due to differences in national well-child care practices with scheduled physical examinations performed only until 12 weeks of age in the UK and that general practitioners did these. This compares to the practices in Germany where annual physical exams are typically done up to the age of 7 years-old by primary care pediatricians. This difference can result in earlier diagnosis and consequently smaller volume tumors.
Although rare, symptoms related to metastases, such as dyspnea (lung), abdominal pain (liver) or tumor thrombus in the renal vein or vena cava leading to venous collaterals or varicocele, may occur. Ultimately, a few children with severe subcapsular hemorrhage or rupture may present with rapid abdominal enlargement, anemia, and severe pain.
A stepwise approach to investigation for children with a renal tumor ideally starts with an ultrasound followed by cross-sectional radiology in the form of computed tomography (CT) or magnetic resonance imaging (MRI).^12^ On International Society of Pediatric Oncology (SIOP) protocols,^13^ a core needle biopsy is performed in everyone with non-Wilms features on imaging and in those over 7 years of age.^14–16^ In contrast, on Children’s Oncology Group (COG) protocols, biopsy upstages the disease in WT, CCSK, RTK, and CMN and so should be carefully considered, with preference given to upfront resection.
Tumor stage was the first identified prognostic factor for WT with increasing stage portending poorer outcomes.^17^ The current COG staging system was originally developed in the 1970s by the National Wilms Tumor Study Group (NWTSG) and refined in 1995 for the NWTS5 study to what it is now.^18,19^ The staging system used by SIOP is quite similar and shown in Table 2. The main conceptual difference between the 2 systems is that the COG system determines local stage prior to chemotherapy and the SIOP system determines stage after chemotherapy.^20^ The basics of staging Stage I tumors are confined to the kidney and completely excised; Stage II tumors are locally infiltrative beyond the confines of the kidney itself but complete excised; Stage III tumors have some evidence of residual abdominal disease postoperatively; Stage IV tumors have distant metastases; and Stage V tumors are bilateral.
Of note, an interesting difference exists with respect to Stages II and III such that the SIOP system designates a tumor percutaneously core biopsied by retroperitoneal approach prior to chemotherapy or surgery as a Stage II whereas in the COG system, any breach of the tumor prior to therapy would make it a Stage III.^21^
Risk stratification is key to the evaluation and management of children with renal tumors. In this setting, risk stratification focuses on several factors, which may include age, stage, histology, tumor biology and genetic predisposition. Understanding these factors and the risk stratification is important for both treatment approach and estimating prognosis.
Age (younger than 24 months) generally confers the best prognosis for children with WT. More so than other pediatric renal tumors, genetic predisposition plays a key role in the risk factors and classification of children with WT. WT1 disorders (including the phenotypes of Denys-Drash syndrome and Frasier syndrome), Wilms tumor-Aniridia-GU Anomalies-Retardation (WAGR) Syndrome, Beckwith-Wiedemann Syndrome, and Perlman syndrome, amongst others, all confer higher risk of developing WT (between 5 and 20% increased risk).^22,23^ In addition to genetic predisposition, tumor-specific molecular markers such as loss of heterozygosity (at chromosomes 11p, 16q, and 1p) as well as chromosome 1q gain are associated with more aggressive disease behavior and higher risk of relapse depending on disease stage and management.^24,25^ Histology also plays the most impactful role in the prognosis, the subsequent selection of treatment, and ultimately, the likelihood of cure. WT can be classified as favorable histology (FH) or unfavorable histology (UH, also known as anaplastic WT).^26^ Triphasic tumors are the most characteristic FH tumors and contain histological blastemal, stromal, and epithelial elements, while UH tumors have either focal or diffuse anaplasia. Anaplasia is histologically defined by enlarged hyperchromatic nuclei with abnormal multipolar mitoses and is strongly associated with pathogenic variants in TP53 and/or chromosomal copy number loss at 17p13.3 (TP53 locus). Tumor stage and histology are the most important risk factors for survival.
Unlike WT, RCC is rarely associated with genetic predisposition, although cases can occasionally be associated with von Hippel Lindau Syndrome, germline Succinate Dehydrogenase mutations, Hereditary Leiomyoma and RCC Syndrome, and tuberous sclerosis.^27^ However, RCC, especially in children and adolescents, is commonly associated with translocation morphology (TFE RCC).^28^ This is particularly important in thinking about surgical approach as even smaller (<7cm) TFE RCC tumors have an increased likelihood of lymph node involvement.^29^ In addition to consideration of genetic rearrangements and associated histology, age and advanced stage are also associated with increased risk of recurrence.
In other pediatric renal tumors, including CCSK and RTK, the key factors are both age and advanced stage. In RTK, younger age (0–5 months) is associated with worse outcomes.^30^ Germline deletions in the SMARCB1 gene are the primary genetic predisposition for RTK.^31^ There are no clear genetic predispositions associated with CCSK. Older children, adolescents and young adults may present with a rare, but aggressive renal tumor, Renal Medullary Carcinoma, and this is associated with Sickle Cell Trait.
The goal of surgical resection is complete removal of the tumor, sampling of regional lymph nodes and any suspicious masses in the abdomen, without spillage of tumor and without resection of any other major abdominal organs. Table 4 describes the approaches used by COG and SIOP.
Both SIOP and COG agree that if neoadjuvant chemotherapy is chosen, surgery must be performed at or before 12 weeks as further reduction in tumor volume after 12 weeks is unlikely while the exposure to potential toxicity increases.
One major concern around percutaneous biopsy is the risk of tract seeding. Fortunately this is rare, occurring in about 0.5% of cases,^33^ and when controlling for other factors known to influence local recurrence (histology, age), there is no statistically significant association with local recurrence.^34^
When the UK adopted SIOP protocols in the early 2000s, it maintained the routine use of diagnostic biopsy. The idea was to identify patients with non-WT pathology and permit early change in therapy. They found an early change in stage distribution with neoadjuvant chemotherapy (lower stages) but no difference in local recurrence rates, suggesting this practice is likely safe.^34,35^
Percutaneous renal mass biopsy has a 91.7% concordance with final pathology and a 6.5% non-diagnostic rate. With respect to the detection of non-WT, sensitivity and accuracy were very high (97.5%).^16^ However, there is emerging consensus that biopsy is only helpful when there is sufficient uncertainty about the type of tumor in question in a way that would change subsequent management. A recent series clarified that age was very important in making the decision about biopsy. Overall, in patients age <10y, biopsy results changed management in <5% of cases. However, in patients aged ≥10y, it changed management in about 25% of cases.^16^
In a report from the NWTS-4 evaluating whether different initial biopsy techniques had the ability to identify anaplasia in patients with bilateral WT, both core needle biopsy and open wedge biopsy had poor concordance with final histopathology due to pathologic sampling error or discordant pathology between each of the bilateral tumors. Therefore, tumor biopsy may be inadequate for reliably identifying anaplasia at diagnosis in WT.^36^
Taken together, this suggests that renal mass biopsy is likely safe, the risk of tract seeding is very low, it is accurate but most importantly, it rarely changes management in patients age <10y. The rate of management change based on biopsy results is less than the complication rate associated with the biopsy, so this practice has been abandoned by the UK.^16^
For those utilizing COG studies, oncologists will likely enroll and treat per the current or most recent trial. In this scenario, despite its safety, any biopsy mandates a Stage III designation that would include therapy intensification with both radiation and doxorubicin. Note that for patients with bilateral renal masses who undergo biopsy (not recommended), these patients receive Stage III chemotherapy intensification but do not need flank radiation. If patients are otherwise Stage I or II after nephrectomy, there are no COG data omitting a preoperative biopsy for staging so prognostic discussions with family are difficult and the treating oncologist has a clinical conundrum of how to blend different treatment regimens and outcomes from SIOP and COG. An upfront renal mass biopsy may have the unintentional consequence of therapy intensification for a patient who may have no other clinical criteria for such.
A full complement of labs, including complete blood count and electrolytes, should be obtained prior to surgery. Children with these tumors can be anemic at presentation as they can bleed internally. As well, resection of WT can be difficult with possibility of blood loss and thus starting hemoglobin is important. As well, it is important to be aware of baseline blood urea nitrogen, creatinine, and other blood chemistry values and verify them to be within normal limits in preparation for this major surgery with fluid shifts and nephron loss. Type and crossmatch should be sent to blood bank and packed red blood cell availability must be confirmed for the surgery. Of note, coagulation studies are also important due to the rare incidence of acquired von Willebrand Syndrome (avWS), which has been reported in patients with WT and other malignancies.^37,38^ This issue has obvious and important implications for the surgeon.^39^ In most reported cases, this entity has been found to be clinically mild; but, there are reports of profuse intraoperative bleeding that only stopped after ligation of the renal vessels.^40^ The mechanism of avWS in WT is secondary to adsorption of the protein to nephroblastoma cells. Recommend obtaining a complete von Willebrand function panel, and DDAVP testing for response when possible/relevant prior to intervention to evaluate adequacy of response.^41^ Although correction of factor levels prior to surgery appears to help in most cases, it does not guarantee that significant intraoperative bleeding will not occur.^40^ Preoperative embolization should be considered as a management strategy in select very large tumors with abnormal preoperative coagulation studies.
Essential surgical principles for all WT (1) safe resection of the tumor; (2) accurate staging of the tumor; (3) avoidance of complications that may increase the intensity of subsequent treatment by “upstaging” the tumor; and (4) accurate and consistent documentation of operative findings.^42,43^
The surgical approach to resection of renal tumors should prioritize adequate visualization and ability to manipulate the tumor without intraoperative spill. This is best accomplished through an abdominal incision (including transverse, subcostal, or hemichevron) or thoracoabdominal incision. A flank or retroperitoneal incision limits assessment of tumor spread and extent of disease and should not be used. Struggling through an inadequate incision may result in tumor spillage, increasing the stage and risk for intra-abdominal recurrence. Tumor spillage most frequent occurs during the mobilization of the posterior portion of the tumor due to adhesions to the diaphragm, and can be prevented by adequate exposure and resection the adherent portion of diaphragm.^44,45^
Upon entry to the abdomen, the amount and quality of the peritoneal fluid is noted (e.g., bloody ascites may suggest preoperative rupture) and a general assessment for preoperative rupture should be carried out and documented. Next, the extent of disease should be assessed by inspection of the peritoneal surfaces, diaphragm, and omentum. If accessible, the inferior vena cava and renal vein should be palpated to assess for intravascular extension of the tumor. These findings, even when negative, should be documented in the operative note.^43^
The colon is then mobilized off the anterior aspect of the renal mass. Although early descriptions of the operative technique recommended initial control of the renal hilum, this is often not feasible with extremely large tumors. For these tumors, mobilization of the mass may be necessary to allow safe exposure of the hilum. Premature attempts at vascular control may result in vascular injury, including inadvertent ligation of the superior mesenteric artery, particularly for left-sided tumors.^46^
As the tumor is being mobilized, the ureter is palpated for tumor and resected close to the bladder. Cystoscopy should be considered when gross hematuria is present to identify urinary collecting system involvement to prevent inadvertent transection of a ureteral tumor thrombus^47^. If the tumor involves the upper pole of the kidney, resection of the adrenal gland may be necessary for negative margins.^44,48^
Biopsy of an adequate number of lymph nodes in the ipsilateral renal hilum and along the inferior vena cava and aorta is critical for adequate staging. Nodal sampling for right sided tumors should target hilar, para-caval and inter-aortocaval nodes while sampling for left sided tumors should target hilar, para-aortic and inter-aortocaval nodes. Current evidence supports at least 5 lymph nodes be biopsied.^43,44,49,50^ However, formal retroperitoneal lymph node dissection has not been demonstrated to improve local control. At least one lymph node must be sampled to be eligible for the upcoming COG clinical trial AREN2231.
Approximately 10% of children with WT present with bilateral WT (BWT). This condition can include bilateral tumors or unilateral WT with nephrogenic rests or nephroblastomatosis in the contralateral kidney.^51^ Such cases are often found in the context of previously mentioned predisposition syndromes.
Initial management involves chemotherapy with a goal of enabling nephron-sparing surgery (NSS). Initial biopsy is not indicated either on SIOP or COG protocols. On both protocols, patients receive 2 cycles of neoadjuvant chemotherapy (Vincristine, Actinomycin D and Doxorubicin on COG; and Vincristine, Actinomycin on SIOP). A further 2 cycles can be given if the tumors are not suitable for NSS with an option to add Carboplatin and Etoposide on the SIOP regime. The goal is then surgical resection of all tumor with preservation of as much normal renal tissue as possible. This can involve a combination of either unilateral nephrectomy and contralateral nephron sparing surgery (NSS); bilateral NSS; or the worst-case scenario of bilateral nephrectomies. Adopting a standard approach to BWT has resulted in an increase in nephron sparing.^4^ One study from a center very experienced in NSS showed that up to 90% of BWT may undergo successful bilateral NSS.^52^
Concerning features for NSS are large tumor size as well as abutment on the vasculature or collecting system. The use of preoperative 3-dimensional reconstruction can help predict the anatomy but the amenability to NSS can only truly be ascertained intraoperatively.^53,54^ The technique involves complete mobilization of the kidney and vascular isolation. Some authors describe clamping the vasculature and cooling while others do not. Parenchymal transection is commonly done with electrocautery, and in some cases intraoperative ultrasound can be useful in planning the plane of dissection. Raw surfaces can be controlled with cautery as well as focused suture ligation and topical hemostatics. Partial resection of the collecting system can be undertaken if needed with reconstruction using an absorbable suture with or without a JJ stent. Lymph node sampling should be performed on each side. Perinephric drains may be left if extensive collecting system reconstruction has been done. The goal is negative margins to avoid the need for radiation therapy with its associated morbidities.
A special note is regarding the adolescent with bilateral renal masses, this is highly likely to be related to a predisposition syndrome such as VHL. Genetic testing to establish a diagnosis is indicated. These cases are generally managed with nephron sparing surgery once the dominant lesion in the affected kidney is >3cm in size. Each kidney is typically addressed independently as separate operations. There is a prioritization for preserving renal function in these patients as their oncologic outcomes should be good. There is a novel therapeutic option (Belzutifan) approved for patients with VHL and RCC where surgical resection may be especially morbid or require radical nephrectomy. However, the use of this agent in a pre-surgical setting has not been studied specifically.
COG protocols call for primary tumor resection. However, there are certain preoperative and intraoperative findings that should be managed by tumor biopsy only, without upfront resection, followed by neoadjuvant chemotherapy. These findings (1) A tumor with extension of tumor thrombus into the IVC that extends to the level of the hepatic veins or above;^55^ (2) A tumor involving contiguous structures that would necessitate removal the adjacent organs (e.g., spleen, pancreas, colon, but excluding the adrenal gland and diaphragm);^44^ (3) Bilateral tumors;^4^ (4) Tumor in a solitary kidney;^4,42^ (5) Pulmonary compromise due to extensive pulmonary disease burden.
There is a consensus that the surgical steps of MIS pediatric tumor nephrectomy should be identical to the open procedure, but it remains controversial, especially in those patients who have not received pre-operative chemotherapy. A deeper discussion of this topic will be covered in a separate article of this Supplemental issue.
While the role of surgery for metastatic disease is also covered in a separate article of this Supplemental issue, the surgical management of pulmonary nodules in patients with WT merits specific mention here. Overall, there are the following three time periods at which a surgeon may be needed for the management of pulmonary nodules in patients with WT: (1) At diagnosis, to determine if there is metastatic disease if the treating team is unsure about indeterminate pulmonary nodules. (2) For FHWT, after 2 cycles of chemotherapy to assess if any remaining pulmonary nodules represent active residual disease as the patient may be able to avoid lung radiation if no viable tumor remains in any residual pulmonary nodules. (3) During therapy, or during follow up, if there is a clinically significant increase in the size or number of pulmonary nodules. Surgery or biopsy at this time would be to pathologically evaluate for progression or relapse.
Analysis of consecutive NWTS studies revealed an overall occurrence of surgical complications at 19.8% and 12.7% in NWTS-3 and NWTS-4, respectively. Intestinal obstruction was the predominant complication in both NWTS-3 and NWTS-4, affecting less than 10% of patients, followed by extensive intraoperative hemorrhage. Injuries to other visceral organs (including the intestine, liver, and spleen) and vascular structures occurred in approximately 2% of cases, while wound infections were rarely reported. Intraoperative mortality was reported in less than 1% of cases. Factors contributing to complications included advanced local tumor stage, tumor size (>10 cm), intravascular tumor extension, and resection of other visceral organs during nephrectomy.^56^ Intravascular extension into the inferior vena cava or atrium was associated with increased complication risks, with an overall rate of 30%, including acute kidney injury, extensive intraoperative hemorrhage, and tumor rupture.^57^ Nephron-sparing surgery in bilateral WT presents another surgical scenario, with an overall complication rate of 36.4%, mostly related to urine leaks.^58^
Regarding tumor spillage, COG recommends primary nephroureterectomy with lymph node sampling as the initial management for a renal mass suspected to be WT. The clinical significance of tumor spillage varies depending on histology. For example, intraoperative spillage of tumors has significant implications in WT cases, as it leads to patient upstaging to Stage III and requires subsequent radiation (flank or whole abdomen) and intensified chemotherapy. A study conducted by COG reported the overall incidence of intraoperative spillage to be 11.9%.^45^ Subsequently, Ehrlich et al. found 564 total surgical protocol violations in 3,536 patients enrolled on COG AREN03B2. Among these surgical protocol violations, avoidable intraoperative spill constituted 10.8% and lack of lymph node sampling 64.7%.^44^ Lymph node sampling is crucial for accurate staging, even in the absence of gross or radiographic abnormalities, as it affects trial eligibility and may impact outcome due to under staging.
Preoperative chemotherapy, advocated by SIOP, has shown reduced intraoperative spill rates, though it may compromise the identification of locoregional lymph node involvement and early histology identification.^59^ Furthermore, a randomized controlled trial from the UK Children’s Cancer Study Group confirmed the reduced rate of spillage and surgical complications in patients receiving preoperative chemotherapy.^60^
Vascular injury during nephrectomy is a rare but life-threatening complication, with iatrogenic injuries to the aorta or its major branches. Ligation of the superior mesenteric artery (SMA) can occur during left nephrectomy, with the risk of small bowel infarction and mortality. SMA injury is usually detected intraoperatively, and primary re-anastomosis or artery graft interposition can prevent postoperative morbidity. SMA thrombosis should be investigated in case of intraoperative aortic injury. Surgeons should be cautious of distorted vascular anatomy due to tumor size or post-chemotherapy shrinkage and ensure complete tumor mobilization to facilitate clear identification of renal vessels before ligation.^46^
Postoperative small bowel to small bowel intussusception is infrequent but noteworthy, particularly following laparotomy for retroperitoneal tumor resection such as WT because it will require operative reduction.
Clinical cooperative cancer study groups have greatly advanced the care for children with renal tumors. The two largest are the COG and SIOP. Studies performed by these cooperative groups have led to excellent outcomes for most children.^61,62^ While there are some philosophical differences, there is general agreement in key areas such as the completeness of surgery, need for lymph node sampling, avoidance of tumor spillage, IVC surgery, and approach to bilateral renal tumors.^63,64^ The two major differences between the COG and SIOP approach relate to the timing of the primary nephrectomy in unilateral disease and the use of partial nephrectomy in non-syndromic unilateral disease.^64^
Although in general, COG recommends a primary nephrectomy and SIOP a delayed nephrectomy, a study from van den Heuvel-Eibrink et al examined 750 children diagnosed with a renal tumor in the first 7 months of life.^65^ Because survival rates for infants with WT in this group were exceptionally high, and there was also a high incidence of congenital mesoblastic nephroma, both SIOP and COG now advocate for up-front resection in infants with unilateral renal tumors <6 months. A second area of consensus is the approach to bilateral tumors and unilateral high risk syndromic tumors where initial biopsy is avoided.^4,66^ Preoperative chemotherapy is used, nephron sparing surgery is encouraged, and SIOP post chemotherapy histopathology is utilized to risk stratify rather than just favorable versus unfavorable histology. Other areas where consensus has been reached is the recommendation of a delayed approach to tumors that extend into the IVC at or above the hepatic veins and mandatory lymph node sampling. Additionally, there is agreement that tumors where significant extra renal surgical resection (liver, bowel, pancreas) would be required, pre-resection chemotherapy should be given. Both groups also feel further work is required to clarify definitions and subsequent treatment adjustments for preoperative rupture and intraoperative spill.
Primary nephrectomy (when possible) has the following potential advantages. First, the primary tumor burden is removed prior to the administration of systemic therapy. The morbidity and mortality in the modern age associated with renal surgery is low. Second, COG studies have well characterized treatment based on prechemotherapy biology and pathology and have identified a group that have outstanding outcomes with surgery alone.^67,68^ This approach avoids misdiagnosis and unnecessary exposure to chemotherapy.^69,70^ Conversely, preoperative chemotherapy proved its importance in decreasing the tumor rupture rate and achieving a low rate of surgical complications.^35^ Misdiagnosis of a benign lesion is now rare. Heroic resections with accompanied intraoperative tumor spill are more frequently avoided using this approach.^69^ Tumors are staged after the initial therapy and the rate of radiation therapy is significantly lower in SIOP protocols than in COG/NWTS. This is an important consideration due to the late effects of radiotherapy. Pre-operative chemotherapy also pre-selects patients responding well to chemotherapy. That influences the histological classification which enables identification of a favorable group of patients with 100% necrotic tumors and also an unfavorable cohort of patients with blastema predominant histology persisting after pre-treatment.^71^
A second difference is the use of NSS for unilateral WT. SIOP piloted this concept in SIOP2001 and developed criteria for NSS.^72^ The initial 5-year EFS survival was excellent although there were substantial number of children who were stage III (approximately 30%) due to positive margins. The current umbrella protocol has expanded criteria for NSS in unilateral WT. COG published a report on NSS for non-syndromic unilateral WT with similar excellent 5-year event-free survival but also approximately 30% were Stage III due to positive margins.^73^ Both of these were early series where experience was limited and may not represent the current rate of positive margins. These excellent short term outcomes and the appeal of more residual functioning renal parenchyma after therapy to reduce the risk of long-term renal insufficiency need to be counterbalanced with the increased incidence of stage III disease resulting in radiation and doxorubicin therapy – the two main factors associated with late events such as renal failure and second cancers.^74–76^ Another concern from the COG perspective is that these children often have small tumors and could possibly be part of the very-low risk WT population that is able to avoid adjuvant therapy. Long-term follow-up of these children and possibly a decision tree analysis will help define a group of unilateral WT best suited for NSS.
Fortunately, outcomes of children with renal tumors are quite good thanks to the hard work and dedication of international cooperative groups such as SIOP and COG. Surgery remains a critical component of the multi-modal therapy required to achieve cure. It is important that surgeons understand the role of surgery in the treatment of children with renal tumors, and specifically appreciate nuances around the timing and approach to surgery that may vary by stage, age, and histology. We urge continued dedication to this field, as surgeons will remain vital to the future research done to further improve both short- and long-term outcomes for these children.