The role played by the surgeon in the therapy of Wilms tumor is paramount because a meticulous and well-performed procedure will accurately determine the stage of the tumor and the patient's future therapy. A poorly performed procedure can lead to inadequate therapy if patients are not appropriately staged, or to unnecessarily intensive therapy if operative spill of the tumor occurs or if incomplete resection of the primary tumor is carried out. The main responsibility of the surgeon is to remove the primary tumor completely, without spillage, and to accurately assess the extent to which the tumor has spread.
Approximately 25% of children with Wilms tumor will present with hypertension. Therefore, a preoperative assessment of blood pressure should be performed in all patients, with hypertension being medically controlled prior to surgery. In many patients, but not all, the hypertension will resolve after radical nephrectomy, although it may take some time. Patients with Wilms tumor rarely present with renal insufficiency and so formal preoperative assessment of renal function is usually not required. Although patients with a Wilms tumor-predisposition syndrome may have intrinsic renal disease, it is usually not of clinical significance until a few years later. Appropriate genetic testing may be done, as indicated. Children with Wilms tumor will occasionally present with pulmonary insufficiency due to extensive metastatic disease in the lungs. The clinical assessment of a patient is generally sufficient to determine whether they can tolerate general anesthesia; formal pulmonary function studies are not required. As Wilms tumor is generally very chemosensitive, the tumor burden in the lungs and the functional pulmonary status should improve fairly promptly once chemotherapy has been initiated.
Preoperative, as well as intraoperative, biopsies are generally contraindicated and should only be performed when a tumor is deemed inoperable, or the patient is unable to tolerate a laparotomy. Therefore, if a solid renal mass is unilateral, it should simply be resected (along with the kidney). Wilms tumor can often grow to a very large size prior to detection. However, even large tumors rarely invade surrounding structures, they simply push them away (and may efface them). Because of this, most Wilms tumors are resectable at presentation. A tumor that is completely resected may be a stage I or II tumor and therefore the patient will not require doxorubicin and flank irradiation, thereby avoiding their associated toxicities. Those patients that receive neoadjuvant therapy are assigned a local stage of III and so will receive doxorubicin in addition to vincristine and dactinomycin, and ionizing irradiation, regardless. Similarly, patients who undergo a preoperative or intraoperative biopsy are assigned a local stage of III. Therefore an attempt at primary resection should usually be made, even if the tumor is large.
Indications for delayed resection of the primary tumor include: bilateral disease, disease in a solitary kidney, unilateral disease in a patient with a Wilms tumor predisposition syndrome (such as WAGR, Beckwith–Weidmann and Denys–Drash), pulmonary insufficiency from a heavy metastatic burden in the lungs, extensive intravascular thrombus above the level of the hepatic veins, clear evidence of preoperative rupture (a circumstance unreliably determined by pre-operative imaging), unresectable, in the surgeon's judgment, without resection of adjacent organs (an assessment generally made at laparotomy).
One of the main controversies in the treatment of children with Wilms tumor is whether or not to administer preoperative chemotherapy, as suggested by the International Society of Pediatric Oncology (SIOP). The surgeon considering the use of preoperative chemotherapy should realize that there can be significant adverse effects on staging and histological evaluation in children who receive preoperative chemotherapy which could lead to either overtreatment or undertreatment. Proponents of preoperative therapy suggest that the tumor is easier to resect with a decreased incidence of tumor spill and a lower mortality and morbidity.
Despite the arguments against the use of preoperative therapy, as previously described, specific patient groups can be identified who would seem to benefit from preoperative chemotherapy. These are patients with bilateral tumors, those patients with IVC and intra-atrial involvement and patients with massive tumors considered by the operating surgeon to be unresectable without undue risk to the patient.
As nearly all children with Wilms tumor will receive adjuvant chemotherapy, a central venous access device is generally placed at the time of nephrectomy, usually just before the start of the operation, to ensure secure intravenous access for the procedure. Patients are placed at a supine position with a bump under the appropriate flank. A radical nephrectomy should be carried out through a generous transverse, transperitoneal incision that allows for adequate exposure and complete exploration of the abdomen (Fig. 88-2). Some surgeons prefer a midline incision. A thoracic extension may be necessary but has been associated with a higher complication rate. Whichever incision is used, however, it should be large enough so that the integrity of the specimen is not compromised upon its removal from the abdominal cavity, as tumor rupture and spill have significant consequences.
Typical transabdominal incision.
Upon entering the peritoneal cavity, the presence of preoperative rupture should be documented, with bloody peritoneal fluid being considered a sign of rupture, whether or not gross or microscopic tumor is identified in the fluid. Isolation of the hilar vessels prior to mobilization of the primary tumor is no longer recommended since major vascular injury to the mesenteric arteries, celiac vessels, and aorta has been reported.
Dissection generally begins at the lateral margin after the colon and its mesentery have been mobilized medially to more completely expose the kidney and tumor. The posterior surface of the tumor/kidney is also usually an avascular, safe plane of dissection. Exposure of the superior extent of right-sided tumors may benefit from mobilization of the right hepatic lobe while exposure of the superior extent of left-sided tumors may benefit from medial mobilization of the pancreas and spleen. Generally, the normal adrenal gland can be separated from the tumor and preserved; however, the ability to remove the tumor mass without rupture should not be compromised in an attempt to preserve the adrenal gland. The inferior tumor dissection should include removal of the ureter in continuity with the kidney. The ureter should be followed from the renal hilum to as low as conveniently possible, where it should be ligated and divided after palpating for the possible presence of intraureteral tumor. Once the kidney and tumor have been mobilized laterally, posteriorly, superiorly and inferiorly, the only remaining attachments are medial; these attachments contain the renal artery(s) and vein(s) (Fig. 88-3). Palpation of the renal vein prior to dividing it is recommended to exclude the possibility of a tumor thrombus, as occurs in about 10% of cases. Once the artery and vein have been tied and divided, the kidney and tumor should be free and can be passed off the field. Biopsy of the primary tumor should not be carried out prior to removal and a meticulous dissection to avoid rupture of the tumor capsule with spillage of tumor cells is imperative, as tumor spill is strongly associated with recurrence. Spillage refers to transgression of the tumor capsule during operative removal, whether accidental, unavoidable or by design. Spill can be “local,” confined to the renal fossa, or “diffuse,” occurring beyond those limits. The degree of spill will change the field of adjuvant radiation therapy, and so should be reported in the operative note.
A–C. Identification of the hilar vessels.
Intraoperative inspection of the liver and the contralateral kidney is no longer required, unless lesions had been identified on preoperative imaging studies, because of the high accuracy of current imaging modalities. However, lymph node sampling is critically important, despite the absence of abnormal nodes on preoperative imaging, or upon gross inspection during operative exploration, since a review of lymph node sampling by the NWTS demonstrated a false negative rate of 31% and a false positive rate of 18% based on preoperative and intraoperative assessment. Unfortunately, there is currently a fairly high incidence of inadequate intraoperative staging, primarily due to failure to sample lymph nodes. Lymph nodes in the pericaval (right-sided tumors) and periaortic region (left-sided tumors) should be removed and submitted for histologic evaluation; visual assessment alone of the lymph nodes poorly predicts their pathologic involvement.
Wilms tumors rarely invade surrounding structures but frequently adhere to adjacent organs. If the tumor cannot be cleanly separated from adjacent structures then excision of the tumor with surrounding structures can be carried out in continuity if the operating surgeon feels that all tumor tissue can be completely removed. Since patients with small residual disease respond well to present chemotherapy and ionizing radiation, and since an increased incidence of complications has been associated with tumor resections that include adjacent structures, radical resection is only indicated if all tumor can be removed. In the case of hepatic invasion a resection of part of the liver along with the primary tumor can usually be carried out. However, a formal hepatectomy is rarely indicated. The use of titanium clips is strongly recommended to identify gross residual tumor and the margins of the resected primary tumor.
There are reports of surgeons performing unilateral partial nephrectomy and laparoscopic nephrectomy (radical or partial) for Wilms tumor, particularly in Europe where children routinely receive preoperative chemotherapy. However, the appropriateness and adequacy of these approaches has not been confirmed and they are not currently endorsed by COG.
A complication rate of approximately 20% is seen following primary nephrectomy for Wilms tumor. The most frequent complication is small-bowel obstruction followed by major intraoperative hemorrhage, wound infection, vascular injury, and injury to other organs. In the majority of cases, the etiology of the small-bowel obstruction is adhesions, followed by intussusception and internal hernia. Most of the cases occur within the first 3 months following nephrectomy; nearly all cases of intussusception occur within the first 3 weeks after surgery. The incidence of small-bowel obstruction does not appear to be increased in children who receive postoperative radiation therapy.
Vascular extension into the renal vein, cava and atrium presents special surgical challenges. Intravascular tumor extension can occur in Wilms tumor cases; renal vein involvement has been noted in 11% of cases (most often detected at operation) and caval and atrial involvement in about 6% of Wilms tumor cases. It should be sought by preoperative imaging and its presence or absence confirmed intraoperatively. Tumor extension into the renal vein and proximal inferior vena cava can in most cases be removed en-bloc with the kidney. Thrombus that extends into the vena cava can often be withdrawn from the IVC by opening the IVC (after gaining proximal and distal control). If the thrombus is not adherent to the wall of the IVC and is removed intact, the tumor may still be stage II if none of the other criteria for assigning a higher stage are met. Proximal and distal control of the IVC can generally be achieved if the superior extent of the thrombus is below the level of the hepatic veins. However, primary resection of tumors with extension into the inferior vena cava above the level of the hepatic vein or into the atrium is associated with higher operative morbidity. Thrombus that extends above the hepatic veins may require cardiopulmonary bypass to safely remove the full extent of disease. Alternatively, neoadjuvant chemotherapy may be given in an attempt to shrink the thrombus to a level below the hepatic veins. This may result in tumor adherence to the wall of the IVC, however, thereby precluding its complete removal. In this circumstance, ionizing radiation to the IVC and residual tumor thrombus may be indicated.
Historically, the most important prognostic variables for patients with Wilms tumor have been the histopathologic tumor classification and surgical stage. Survival statistics based on these factors, which have largely guided treatment, are shown in Table 88-3. However, more recently, it has been recognized that a Wilms tumor risk stratification system based on histology and stage alone does not accurately identify all patients at risk for recurrence. New clinical and genetic risk factors for recurrence have been validated and have now been incorporated into the assigning of therapy in the current COG clinical trials for patients with Wilms tumor. These factors include patient age at the time of diagnosis, tumor weight, histologic response to therapy, and the allelic status of chromosomes 1p and 16q in resected tumors. Since 2006, several new clinical trials have opened within COG for the treatment of patients with Wilms tumor. Together these protocols cover the entire spectrum of Wilms tumor. Central to the approach to therapy for these patients is a risk classification scheme, which is defined in Table 88-4. To facilitate accurate and timely risk assessment, enrollment in an overarching tumor collection and biology classification protocol, “AREN03B2: Renal Tumors Classification, Biology, and Banking Study,” is a prerequisite. Patients are then enrolled on one of the therapeutic protocols.
Table 88-3Ten-Year Outcomes for Patients with Wilms Tumor Treated on NWTS-4 |Favorite Table|Download (.pdf) Table 88-3 Ten-Year Outcomes for Patients with Wilms Tumor Treated on NWTS-4
|Histology ||Stage ||10 yr Relapse Free Survival (RFS)% ||10 yr Overall Survival (OS)% |
|Favorable ||I ||91 ||96 |
| ||II ||85 ||93 |
| ||III ||84 ||89 |
| ||IV ||75 ||81 |
| ||V ||65 ||78 |
|Anaplastic ||I ||69 ||82 |
| ||II–III ||43 ||49 |
| ||IV ||18 ||18 |
Table 88-4Risk Stratification and Treatment Study Assignment for Patients with Favorable Histology Wilms Tumor |Favorite Table|Download (.pdf) Table 88-4 Risk Stratification and Treatment Study Assignment for Patients with Favorable Histology Wilms Tumor
|Patient Age ||Tumor Weight ||Stage ||LOH ||Rapid Response ||Final Risk Group ||COG Treatment Study |
|<2 yrs ||<550 g ||I ||Any ||N/A ||Very Low ||AREN0532 |
|Any ||>550 g ||I ||None ||N/A ||Low ||None |
|>2 yrs ||Any ||I ||None ||N/A ||Low ||None |
|Any ||Any ||II ||None ||N/A ||Low ||None |
|>2 yrs ||Any ||I ||LOH ||N/A ||Standard ||AREN0532 |
|Any ||>550 g ||I ||LOH ||N/A ||Standard ||AREN0532 |
|Any ||Any ||II ||LOH ||N/A ||Standard ||AREN0532 |
|Any ||Any ||III ||None ||N/A ||Standard ||AREN0532 |
|Any ||Any ||III ||LOH ||N/A ||Higher ||AREN0533 |
|Any ||Any ||IV ||LOH ||Any ||Higher ||AREN0533 |
|Any ||Any ||IV ||None ||Yes ||Standard ||AREN0533 |
|Any ||Any ||IV ||None ||No ||Higher ||AREN0533 |
|Any ||Any ||V ||Any ||Any ||Bilateral ||AREN0534 |
Surgery alone is proscribed as definitive treatment for children less than 2 years of age with Stage I, favorable histology disease where the tumor weight is less than 550 g, as these patients are at “very low risk” for recurrence. Children with Stage I (or II) disease who do not qualify for surgery alone are still considered “low risk” for recurrence, but, in addition to surgery, are treated with 22 weeks (7 cycles) of 2-drug chemotherapy (vincristine and dactinomycin) on regimen EE-4A. However, if the tumor from these patients is subsequently found to have LOH of both 1p and 16q, these patients are switched to “standard” risk therapy consisting of 28 weeks (9 cycles) of 3-drug chemotherapy, in which doxorubicin is added to vincristine and dactinomycin, on regimen DD-4A. Stage III patients whose tumors do not have 1p and 16q are also treated with “standard risk” DD-4A, plus radiation therapy. However, if their tumor is subsequently found to have both 1p and 16q LOH, these patients with Stage III disease are considered “higher risk” and are treated as described below.
Patients with favorable histology Wilms tumor that is either Stage III disease with 1p and 16q LOH, or Stage IV (metastatic) disease are at “higher-risk” of recurrence. Those with Stage III disease and 1p and 16q LOH are treated for 33 weeks (11 cycles) with vincristine, dactinomycin, and doxorubicin plus cyclophosphamide and etoposide on regimen M, as well as abdominal irradiation. Patients with Stage IV disease without 1p and 16q whose pulmonary lesions respond “rapidly and completely” (see later discussion) are treated with regimen DD-4A chemotherapy and no pulmonary irradiation. All other patients with metastatic disease (those with 1p and 16q LOH, those with “slow, incomplete” response of their pulmonary disease (see later discussion), or those whose metastases are extra-pulmonary are treated with regimen M and radiation to the site(s) of metastatic disease.
All patients with anaplastic Wilms tumor are at “high risk” for tumor recurrence. For risk assessment and treatment purposes, a distinction is made between focal (anaplasia confined to one or a few discrete foci within the primary tumor, with no anaplasia or marked nuclear atypia elsewhere) and diffuse anaplasia. Patients whose tumors have focal anaplasia, Stages I–III, or diffuse anaplasia, Stage I, are treated with regimen DD-4A. Patients with Stage IV focal anaplasia, Stages II–III, diffuse anaplasia, and Stage IV diffuse anaplasia without measurable disease are treated for 30 weeks with cyclophosphamide/carboplatin/etoposide and vincristine/doxorubicin/cyclophosphamide plus radiation therapy (regimen UH-1). Patients with Stage IV diffuse anaplasia with measurable disease are treated with 1 to 2 cycles of irinotecan/vincristine as window therapy to evaluate tumor response and determine whether this combination should be added to the backbone treatment with UH-1.