IPSO Practice Guidelines on Wilms Tumor
Hafeez Abdelhafeez, Simone Abib
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Version dated on 7 June 2020
Wilms tumor (WT) is the second commonest childhood solid tumor and accounts for more than 90% of childhood renal tumors.
Most children present with a large asymptomatic abdominal mass, and rarely exhibit symptoms secondary to tumor rupture or extensive pulmonary metastasis. A few cases present with hematuria and hypertension. WT is also diagnosed during routine surveillance for patients with known predispositions, which include diffuse hyperplastic perilobar nephroblastomatosis (DHPN) and predisposition syndromes (WT1 related: WAGR (WT, anirida, genitourinary anomalies, and intellectual disability) [risk of WT 30%], Denys–Drash syndrome [risk of WT 90%]; WT2 related: Beckwith–Wiedemann syndrome [risk of WT 5%], Perlman syndrome, and Li–Fraumeni syndrome).
Lab: Complete blood count, complete metabolic profile, and coagulation profile.
Imaging: Chest radiograph or computed tomography (CT) chest, abdominal ultrasound, and CT/MRI abdomen.
The ability to interpret cross-sectional imaging is essential for surgeons managing patients with WT. Differentiating between WT and neuroblastoma, examining vascular anatomy in relation to the tumor, or determining the proximal level of intravascular extension are some competencies required for image interpretation. Basic information for surgical planning includes the following:
- Evaluation of findings suggestive of WT or other differential diagnoses such as DHPN and neuroblastoma.
- Relation of the renal tumor with surrounding organs and vascular structures.
- Evaluation of preoperative tumor rupture and signs of abdominal dissemination and pulmonary metastasis.
- Assessment of cystic areas that are prone to intraoperative rupture.
- Evaluation of bilateral disease (5%) or coexisting urinary malformations (e.g., single or horseshoe kidney).
- Evaluation of intravascular extension (10–15%). If present, assessment of the level and presence or absence of blood flow around it and response to chemotherapy.
- Evaluation of tumor response and pulmonary metastasis response to chemotherapy.
Indications and principles of biopsy
A patient with suspected WT having a typical age and imaging findings will NOT require a diagnostic biopsy (1, 2). The typical age of diagnosis for WT is more than 6 months and less than 7 years. Typical imaging features of WT include mass with renal origin and claw sign, absence of tissue infiltration, and absence of vascular encasement.
Biopsy in the context of the typical presentation is not expected to change therapy, since it is unreliable for diagnosing anaplasia, unlikely to show alternative diagnosis (1-3), and may delay the initiation of therapy if performed routinely for all patients, especially in healthcare centers having limited pathology services. Tissue diagnosis (nephrectomy, if feasible; or biopsy) is required to plan therapy for patients who present at an atypical age or have atypical imaging features.
Role and timing of multimodality therapy
There are two main protocols to treat patients with WT: Children’s Oncology Group (COG) and International Society of Paediatric Oncology (SIOP). Both protocols report similar survival results. The difference between the two protocols is the use of preoperative chemotherapy (SIOP) or upfront surgery (COG). Both protocols recommend upfront resection for patients less than 6 months of age, because of the relatively higher incidence of congenital mesoblastic nephroma and rhabdoid tumors in this age group.
Neoadjuvant chemotherapy may mitigate bleeding, tumor rupture, and the need for radiation therapy (RT) or doxorubicin (4-9); therefore, this strategy may need to be considered if there is limited access to RT, high tumor spillage rate, or limited surgical capacity (4).
Preoperative multidisciplinary planning should include the assessment of comorbidities, magnitude of the operation, capacity of the anesthesia team, intraoperative monitoring, reliable upper extremity vascular access, urinary catheter, availability of blood, appropriate allocation of postoperative level of care and monitoring, and postoperative pain control. If a neoadjuvant chemotherapy protocol is used, surgery should follow blood count recovery, and the planned timing of surgery should not be delayed (10, 11). Treatment with vincristine should continue only when delay is unavoidable to prevent further delay of surgery due to neutropenia.
Goals of surgery (for all stages, including stage IV) are to perform and document a thorough surgical staging, achieve R0 resection, prevent tumor spillage, and mitigate complications and resection of other organs.
Advanced stages and relapsed disease:
The outcome of chemo-responsive metastatic disease is favorable; therefore, there is no clear therapeutic need for upfront resection of metastatic sites. Examination of viable tumor in persistent pulmonary metastasis after chemotherapy may help guide therapy and prevent RT. Outcomes of patients with recurrent disease remain poor, and the role of surgery in recurrent disease is not defined.
Lower tumor rupture rate and fewer complications are reported when the surgeon performs a higher volume of resections for patients with WT (9). Both transverse abdominal and thoracoabdominal incisions provide adequate access. The latter is associated with more complications (12), but may be considered for huge upper pole tumors that grow behind the liver. Midline incision provides limited access, resulting in a higher rate of tumor rupture and complications (9, 12, 13).
Surgery includes a staging component and local control components. Therapy depends on accurate documentation of surgical findings, including peritoneal seeding, tissue infiltration, lymph node sampling, capsular integrity, and tumor spillage. Failure to sample lymph nodes is associated with local recurrence. Regional lymph nodes in the hilum, periaortic, or peri-cava zones (Figure 1) should be sampled even if they appear morphologically normal (14, 15). A radical lymphadenectomy is not necessary, but proper lymph node sampling is crucial.
It is recommended that approximately seven lymph nodes be sampled (16). This can be achieved by actively collaborating with pathologists to examine the lymph node found in the hilar area of the tumor specimen and the lymph node harvested from perivascular dissection (IPSO33 SIOP19-0533).
The initial step of tumor exposure involves mobilization of the colon medially; en-bloc resection of the involved part of the colon is rarely needed. The adrenal gland and diaphragm can be resected en-bloc if they appear to be invaded by the tumor. Colon mobilization is followed by lateral, superior, and inferior mobilization of the mass. The inferior-medial mobilization exposes the ureter, aorta, or vena cava. The ureter should be ligated and divided as close as possible to the bladder. The renal vein and vena cava should be palpated for intravascular tumor extension. Access to hilar vessels is facilitated by adequate circumferential tumor mobilization. There is no reliable evidence supporting the theoretical advantage of early control of vessels before tumor mobilization; on the contrary, this approach may obscure vascular anatomy due to limited exposure and increase the risk of major technical errors (12, 17-21). Inadvertent injuries to major vessels are reported and intraoperative catastrophe can occur due to limited mobilization and identification of critical vascular anatomy (12, 17-21). Huge tumors distort anatomy, and it is paramount to delineate the anatomical landmarks of major branches of the aorta to prevent ligation of the contralateral renal vein or the superior mesenteric artery.
The renal vein and artery are ligated sequentially. The order of the vessel to be ligated first is likely not consequential, especially when the two vessels are controlled within a few minutes of each other. It may be easier and also a sound oncologic step to control the anteriorly positioned renal vein first, followed expeditiously by controlling the renal artery (22).
Intravascular tumor thrombus extension occurs in 15% of cases and involves only the renal vein in at least two thirds of cases. Tumor thrombus may extend to the vena cava and rarely to the atrium. Both protocols mandate neoadjuvant chemotherapy for tumor thrombus extending up to the hepatic vein or above. Neoadjuvant chemotherapy for 6 weeks induces thrombus reduction and may avoid the need for cardiopulmonary bypass in up to two thirds of patients with supradiaphragmatic extension of tumor thrombus; further extension of chemotherapy cycles beyond 6 weeks offers no added advantages (23-28). Surgery for WT with intravascular extension should be performed at referral centers and in collaboration with the cardiothoracic team for patients with supradiaphragmatic extension of the thrombus. Although patients with supradiaphragmatic thrombus extension require cardiopulmonary bypass, for patients with transitional diaphragmatic level thrombus (up to the level of hepatic veins), cardiopulmonary bypass may be avoided by achieving supradiaphragmatic vena cava, hepatic veins control, and complete liver isolation; however, bypass backup should be readily available if safe control above the thrombus was not achieved (23-28). Cavotomy and thrombus resection is indicated when there is blood flow around the thrombus. On the other hand, a robust venous collateral drainage is already established whenever there is complete cava occlusion without flow. Cavectomy is the procedure of choice in this situation, as cava replacement is not physiologically needed and unlikely to remain patent because of shunting of venous return mostly through collaterals and the low flow through the cava route (29). RT is required when the thrombus is resected piece meal or when residual viable tumor is suspected. In facilities lacking the surgical capacity to resect the intravascular extension of the WT, RT may be the only option for local control of the intravascular component of the tumor.
Nephron-sparing resection is indicated for patients with a predisposition, such as bilateral WT, solitary kidney, or horseshoe kidney. Neoadjuvant chemotherapy should be used for 6 or 12 weeks, depending on tumor response, but should not be extended for more than 12 weeks, as the poor response may be secondary to anaplastic histology (30).
The vascular and ureteric anatomy of horseshoe kidney is remarkably variable. Special precautions to delineate the collecting system anatomy need to be taken to prevent injuring the ureter of the contralateral kidney. Tactile feedback is instrumental in identifying tumor margin for nephron-sparing resection; therefore, an open approach is more widely accepted. Nephron-sparing resection is associated with risks such as urine leak, significant blood loss, positive resection margin, and recurrence. A double J stent or perinephric drains are not routinely used but should be considered when resection involves complex collecting system reconstruction. Parenchyma pressure or intermittent hilar compression can be used to control blood loss and minimize ischemia time; surface cooling can be used if the length of warm ischemia is anticipated to be more than 30 min. Bench surgery and auto-transplantation are rarely needed.
Documentation for nephron-sparing resection should include assessment of the pseudo capsule breach, the type of resection (partial nephrectomy or enucleation), and the percentage of residual kidney.
Bilateral tumors should be treated in referral centers, bilateral resection can be done in one operation or staged. Partial nephrectomy is more ontologically sound and is the procedure of choice when feasible, however enucleation is acceptable provided that anaplasia is ruled out. At least one adrenal gland should be preserved to maintain function.
Nephron-sparing surgery for unilateral WT and a minimal invasive approach are not yet evidence-based practice and should only be performed in centers with a high volume of cases and under established collaborative protocols.
Tips, Pitfalls, and Complications
Tumor spillage can result in significant therapy escalation and have prognostic implications. The key steps to prevent spillage are ensuring adequate access and gentle handling of the tumor. Attempts to minimize access should not be made at the expense of sound oncologic principles. Recovery after large laparotomy is excellent, but the recurrence of WT might be unsalvageable. Adherence to adequate lymph node sampling and complete documentation of surgical staging improves local control strategy and outcome.
Adequate planning and special skills set are required for WT with intravascular extension. Therefore, preoperative diagnosis of intravascular thrombus extension may prevent intraoperative catastrophes.
The incidence of end-stage renal failure in unilateral and bilateral WT is 0.2% and 12% respectively, and this risk is higher in patients with predisposition syndromes, especially the Denys–Drash syndrome.
The postoperative period is usually uneventful, and the child is usually discharged on the second or third postoperative day. The incidence of intussusception and adhesions is low and should be considered if the patient develops signs of obstruction.
Postresection locoregional RT is indicated for patients with stage III disease (when microscopic residual disease is suspected, as in positive lymph node, tumor spillage, or piecemeal resection of the intravascular thrombus) and for stage II patients with anaplasia. RT, when indicated, should not be delayed beyond postoperative day 10.
Patients having complete remission of pulmonary metastasis post-chemotherapy do not need lung radiation (31-34). When surgical resection of residual pulmonary metastasis is feasible, pathological confirmation of no viable tumor may help avoid lung radiation in patients with favorable histology and good partial remission of pulmonary disease (33).
Prognosis, Prognostics, and Follow up
Overall survival of patients can be as high as 90%, and outcomes for those with metastatic-stage tumors with favorable histology are equally excellent. The most powerful prognostic factor is histology; other prognostic factors include stage, age, and molecular factors, the strongest of which is 1q gain.
Surgery has an important role in performing adequate lymph node sampling and preventing tumor rupture. Lymph node involvement and tumor spillage increase the risk of recurrence; survival rate for those with recurrent disease is 40%. Biannual imaging follow-up for the first 2 years is essential, as most recurrences occur within that time period.
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