Figure 105-1. Percentage distribution of childhood solid tumors by age (SEER data, 1975–1995).
In the United States, the cancer survival rate in children has improved over time. This is largely due to multidisciplinary approaches to pediatric oncology care. There have been steady improvements in survival for childhood renal tumors, retinoblastoma, and lymphomas since the beginning of the SEER program. Although mortality rates have declined steadily for nearly all major childhood cancer categories, survival rates for high-risk tumors such as neuroblastoma and rhabdomyosarcoma have not been met with the same survival successes (Fig. 105-2).2 Targeted immunotherapies and tumor genomic sequencing are new innovative treatment strategies that have recently provided hope for improving outcomes in resistant and refractory cases.
Epidemiology and Genetic Risk
3 The most recent SEER data have reported minimal changes in neuroblastoma incidence in the last five decades. The overall survival rate for neuroblastoma is 65% based upon SEER data from 1985 to 2000, and the disease continues to represent approximately 15% of all pediatric cancer deaths.4,5 There is diverse variability in 5-year survival rates based on age and stage. There are no overall differences in survival by race or gender, and survival is highest among infants and patients with localized and regional disease.In the United States, approximately 700 children are diagnosed with tumors of the sympathetic nervous system each year and of these, 650 are neuroblastoma. Neuroblastoma is the most common cancer in infancy and the most common extracranial tumor in all children. The disease accounts for 7.2% of cancers in children younger than 15 years. The incidence of neuroblastoma is slightly higher among males than among females and is highest among Caucasians from North America, Europe, Australia, and Israel.
Figure 105-2. Survival of most common childhood cancer by type (SEER data, 1975–2005).
No causal factors for neuroblastoma have been identified. Studies examining maternal risks have been conflicting for prior miscarriage, induced abortion, repeat Cesarean birth, and vaginal infection.6 There have been international case series reporting the use of maternal hormones for bleeding and ovulation induction. The largest study to date did not find significant association with infertility hormonal use, although results suggested an elevated risk of neuroblastoma in male offspring after maternal Clomid use.7 These results warrant further evaluation but may serve as the focus of larger clinical studies. Parental occupation and environmental exposures have been studied.8 They suggest that the risk of several industrial occupations, particularly those related to power plant operators, painters, and electronic-related fields, should also serve as lead points for further study. A case-control study investigating parental tobacco smoking and alcohol consumption did not find any evidence for lifestyle exposures and increased risk of neuroblastoma.9 Associations between premature delivery (<33 weeks), very low birth weight (<1,500 g), and neuroblastoma have been observed but results are inconsistent.6 Further investigations of parental and perinatal risk factors are required in order to draw definitive conclusions.10
Most cases of neuroblastoma are sporadic and data for inheritance patterns are conflicting. There are studies that link neuroblastoma occurrence with other neural crest cell anomalies such as Hirschsprung disease, neurofibromatosis, and central hypoventilation syndrome.11 These syndromes are components of the neurocristopathies and are considered alterations in neural crest cell development that may occur with inherited loss of function mutations of PHOX2B, a regulator of autonomic nervous system development.12,13 Despite these findings, there is not a strong pattern of inheritance of neuroblastoma and only 1% to 2% of cases are familial in an autosomal dominant manner.14,15 Recently, genome-wide sequencing studies have located heritable mutations in the anaplastic lymphoma kinase (ALK) gene as the cause of most hereditary neuroblastoma cases, the first example of a pediatric cancer arising due to a mutation in a critical oncogene.16 Given this, genetic testing for ALK and PHOX2B should be considered in children with a family history of neuroblastoma. It is recommended that children in families found to have heritable mutations in ALK or PHOX2B undergo screening surveillance with ultrasound and urinary catecholamine metabolites.
ALK copy number mutations are also somatically acquired and highly associated with an aggressive clinical phenotype in 5% to 15% of neuroblastoma tumors.17,18 Genome-wide association studies in sporadic cases of neuroblastoma have also recently discovered susceptibility genes that include FLJ22536, NBPF23, and BARD1 that may increase the relative risk of malignant transformation of developing neuroblastic tissue.19–22 In general, there is a relative paucity of recurrent somatic mutations in neuroblastoma, and the majority of tumors are likely driven by rare germline variants, copy number alterations, and epigenetic modifications.22
Pathology and Biologic Features
Neuroblastoma originates from embryonic cells of the neural crest that appear along the distribution of sympathetic nervous tissue from the neck to pelvis, most commonly in the adrenal medulla. The precise molecular mechanisms that give rise to embryonic neural crest cells that in turn give rise to neuroblastoma are unknown. The current thinking is that defects in genes that control neural crest differentiation and proliferation underlie neuroblastoma tumorigenesis. Peripheral neuroblastic tumors are categorized on a spectrum from malignant neuroblastoma to ganglioneuroblastoma and benign ganglioneuroma. Neuroblastoma tumors have diverse clinical heterogeneity from complete spontaneous regression in neonates to resistant metastatic disease in school-aged children. The origins of this disparity are unknown but may be explained by a spectrum of genetic and biologic features that are used to stratify patients for treatment.
Figure 105-3. Typical neuroblastoma with small round blue cell feature and Homer–Wright pseudorosettes that palisade around blood vessels.
Neuroblastoma generally occurs in the youngest of children with a median age of presentation of 19 months.23 The age at which a child is diagnosed with neuroblastoma is an indicator of biologic features and clinical course. Neonates and infants younger than 18 months are more likely to have disease that either spontaneously regresses or is cured without cytotoxic therapy. In contrast, older children are more likely to have refractory metastatic disease and are at high risk for death despite multimodal cytotoxic therapies. Age contributes to prognosis in a continuous manner with the optimal age cutoff between 15 and 19 months.23 Much of this discrepancy in outcome of neuroblastoma is thought to be associated with underlying tumor biology because there is an association between age and other biologic factors such as MYCN amplification and histopathology. Given this, molecular analysis of neuroblastoma tumor specimen is an important factor in treatment planning and in risk stratification.
Cellular heterogeneity is a hallmark of neuroblastoma. Neuroblastic small round blue cells with hyperchromatic nuclei characterize neuroblastoma cells with varying degrees of differentiation from immature to mature. Homer–Wright pseudorosettes that palisade around blood vessels and neuritic processes are characteristic (Fig. 105-3). Neuroblastoma cells stain for neuron-specific enolase, synaptophysin, NB84, and tyrosine hydroxylase, a neural protein staining pattern that differentiates neuroblastoma cells from other childhood tumors with similar small round blue cells.
Treatment strategies for children with neuroblastoma are largely based on risk as determined by histopathologic and biologic characteristics of the tumor. The Shimada histopathologic classification system is the most widely accepted mechanism for microscopic evaluation of neuroblastoma tumors and distinguishes favorable and unfavorable clinical groups. The International Neuroblastoma Pathology Classification System was developed on the basis of the original Shimada system.24 Morphologic features of neuroblastic differentiation, Schwannian stromal development, mitosis–karyorrhexis index (MKI), and patient’s age at diagnosis determine the important distinction between favorable and unfavorable histology (Table 105-1).
In addition to histopathology, combinations of prognostic features are utilized for risk assignment and treatment stratification in neuroblastoma. The DNA content (DNA index or ploidy) is the amount of DNA within the nucleus of tumor cells compared to normal cells and is an important indicator of treatment success. DNA index is determined by flow cytometry or by cytogenetic analysis. Hyperploidy or near-triploid tumors (DNA index >1) are whole chromosome gains and losses without structural genetic alterations and are associated with a better response to chemotherapy.25 In contrast, diploid tumors are characterized by segmental chromosomal alterations and predict poor response to therapy.
Table 105-1 Shimada Histopathologic Classification of Neuroblastoma
The MYCN oncogene is a transcription factor located on chromosome 2p and also predicts survival and risk in neuroblastoma. The amplification of MYCN is the best characterized genetic abnormality, occurring in approximately one-third of neuroblastoma patients.26,27 Significant amplification of MYCN within tumor cells (more than 10 copies detected by fluorescent in situ hybridization) reliably predicts poor survival and advanced-stage disease.28 Although the molecular mechanism of MYCN amplification is unknown, targeted expression in transgenic mice leads to the development of neuroblastoma tumors.29 Enhanced expression of MYCN increases proliferation and confers growth potential both in vitro and in vivo, adding to the notion that MYCN has a critical role in neuroblastoma tumorigenesis.30 Approximately 30% of neuroblastoma tumors have MYCN amplification, and of these, 90% are high-stage or refractory to multimodal cytotoxic therapies.31
Nerve growth factor (NGF) and its receptor tyrosine kinase (TRK) also correlate with disease outcome in neuroblastoma tumors. The TRK receptors are thought to have a role in regulating growth and differentiation of normal nerve cells and have been implicated in neuroblastoma pathogenesis. The expression of TRK-A, a transmembrane TRK that is required for high-affinity binding of NGF, is strongly predictive of a favorable outcome in neuroblastoma tumors.32,33 TRK-B, the receptor for brain-derived neurotrophic factor, is preferentially expressed in neuroblastoma tumors with MYCN amplification while TRK-C, the primary receptor for neurotrophin-3 (NT-3), mirrors TRK-A and is expressed primarily in lower-stage tumors with favorable outcomes.33 The absence or lack of TRK-A correlates inversely with MYCN amplification and reliably predicts poor overall survival. Differential expression of TRK-A and TRK-B indicates that NGF receptors may function in growth arrest and differentiation in neuroblastoma tumors, critical factors that may have a role in clinical course.34
35 The loss of heterozygosity (LOH) of chromosome 1p is a reliable prognostic factor in neuroblastoma tumors that is independent of age and stage. The loss of 1p identifies patients who are at high risk of poor survival outcomes despite otherwise favorable biologic predictors (Stage 1, 2, and 4S disease).36 LOH at 1p is most clinically valuable in predicting patients at high risk of death in the subgroup of patients without MYCN amplification, specifically those with low-stage disease.36 Gain at 17q most commonly occurs with loss of 1p in an unbalanced translocation. Unbalanced gain of chromosome arm 17q is the most frequent segmental genetic alteration in neuroblastoma cells and is also associated with adverse outcomes.37 The gain of 17q is strongly associated with other negative risk factors including age of more than 1 year, presence of high-stage disease, MYCN amplification, and diploidy. The most likely candidate genes involved at 17q are NM23 and BIRC5 (surviving gene).38 Chromosome 11q loss is found in approximately 40% of patients with neuroblastoma and is associated with high-risk disease features and decreased survival.39 Similar to loss of chromosome 1p, loss of 11q is independently associated with decreased survival in the subgroup of patients with low-stage disease and in patients without MYCN amplification. In all, the genomic alterations that have consistently been shown to predict prognosis are DNA ploidy, MYCN amplification, loss of chromosome 1p, 17q gain, loss of 14q, and loss 11q. A systematic review of prognostic tumor markers and meta-analysis showed that of these, MYCN amplification and DNA ploidy have the strongest prognostic impact.40Several nonrandom genomic imbalances have been identified in neuroblastoma, and the presence of segmental chromosome alterations is the strongest predictor of neuroblastoma relapse.
Presentation, Diagnosis, and Staging
The majority of children with neuroblastoma are diagnosed at less than 4 years of age, with median age between 19 and 22 months. Forty percent of tumors occur in the adrenal medulla, with the remaining occurring in the neck, chest, abdomen, and pelvis along the sympathetic chain. The organ of Zuckerkandl is the second most common site of neuroblastoma of abdominal origin. Compared to older children, infants are more likely to present with thoracic and cervical primary sites. Tumors at the sympathetic chain along the spinal column may expand into the intraforaminal spaces and can cause spinal cord compression (5% to 15% of patients) (Fig. 105-4). More than half of the patients may present with regional or distant spread through lymphatic and hematogenous routes. Metastatic disease most commonly involves regional lymph nodes, bone marrow, and cortical bone. The most common cortical bone sites are metaphyseal, skull, and the orbit. Patients with orbital bone metastases commonly present with periorbital ecchymosis and swelling (raccoon eyes), and cortical bone metastases may result in generalized bone pain and limping. Liver metastases occur most commonly in patients with stage 4S tumors. Neonates with stage 4S neuroblastoma may present with massive hepatomegaly, respiratory compromise, and abdominal compartment syndrome requiring urgent surgical intervention. Incidental findings on prenatal ultrasound may identify fetal neuroblastoma, and there may be associated maternal signs of catecholamine excess with excessive sweating, headaches, flushing, or anxiety.41
Most often patients with localized disease are asymptomatic, with tumors diagnosed on routine physical examinations or testing for other medical conditions. In contrast, children may have a mass or abdominal distention as presenting symptoms. There are several well-documented clinical syndromes that can be present at diagnosis of neuroblastoma. Opsoclonus/myoclonus syndrome and/or ataxia can occur in children with neuroblastoma and present as irregular jerking movements of the muscles. The underlying mechanism of opsoclonus is unknown but an immunologic mechanism-related antineuronal antibody is likely, and patients may have late neurologic sequelae despite tumor removal.42 The condition may be treated with adrenocorticotrophic hormone, with plasmapheresis and intravenous gamma-globulin reserved for refractory cases.43 Most patients with opsoclonus/myoclonus syndrome tend to have localized disease and excellent survival. Up to 50% of patients with opsoclonus/myoclonus syndrome are found to have neuroblastoma tumors while only a small percentage of patients with neuroblastoma present with opsoclonus. Neuroblastoma tumors that occur in the neck or the upper chest may present with Horner syndrome (ptosis, miosis, anhidrosis), symptoms that may not recover and often worsen with surgical excision.
Figure 105-4. Primary distribution of neuroblastoma tumors in children.
The improvement of ultrasound and maternal imaging techniques has increased the diagnosis of neuroblastoma within the fetal and neonatal periods. Most perinatal tumors are located within the adrenal gland and are localized tumors. Upon detection, tumor growth is monitored with serial ultrasound prior to birth, and maternal care proceeds to ensure optimal health of the mother. As long as there are no complications, pregnancy is carried to term. Nearly all perinatal cases have favorable biology without adverse prognostic indicators, including non-MYCN amplification. Several lines of evidence suggest that small, localized adrenal tumors detected during the perinatal period may be managed with expectant observation without surgical resection.44–46 Given the considerable evidence of spontaneous regression in this subset of neuroblastoma tumors and the risk of adrenal surgery in infants, the COG conducted a prospective trial (ANBL00P2) of expectant observation of infants diagnosed within the first 6 months of life.47 This study found that observation of small adrenal masses in infants younger than 6 months, without biopsy and without surgical resection, was safe with excellent event-free and overall survival. Adrenal tumors smaller than 3 cm (16 mL) if solid or 5 cm (65 mL) if ≥25% cystic are safely monitored with ultrasound volume measurements, computed tomographic (CT) scan, and urine catecholamine metabolite levels. If there are signs of tumor growth or dedifferentiation, the patient is referred for surgical resection without risk of upstaging of disease.
The diagnosis of neuroblastoma requires an adequate biopsy specimen and a pathologist experienced with pediatric tumors. The diagnosis is established with histologic confirmation from either tissue biopsy or the presence of tumor cells within a bone marrow biopsy and increased urinary catecholamine metabolite levels.48 The majority of patients with neuroblastoma have elevated urinary vanillylmandelic acid and homovanillic acid levels and these should be evaluated during the diagnostic workup. Complete blood count and serum chemistries are evaluated as components of initial diagnostics. Levels of lactate dehydrogenase, ferritin, and neuron-specific enolase are biologic markers that may indicate poor prognosis in patients with neuroblastoma.49,50 Elevated ferritin (>150) and lactate dehydrogenase (>1,000) may indicate increased risk of adverse outcomes. Seventy percent of patients present with metastatic disease at presentation; therefore, initial evaluation should include cross-sectional imaging by either computerized tomography or MRI to define the primary tumor size and to determine regional or distant spread (Fig. 105-5). Calcifications are commonly detected on imaging in patients with neuroblastoma, and the mass tends to displace structures inferiorly and toward the midline. Unless the patient has neurologic symptoms or an abnormal neurologic examination, lumbar puncture or brain imaging is not indicated. Sympathetic nervous tissue concentrates metaiodobenzylguanidine (MIBG), an analog of norepinephrine. Radioactive iodine-labeled MIBG scan is utilized in neuroblastoma staging and is used to determine treatment response.51 MIBG scan is accurate in detecting metastatic spread, particularly cortical bone disease that may have otherwise been missed by traditional imaging techniques. Posterior iliac crest aspirates and core biopsies are required as a component of initial diagnostic testing to exclude bone marrow involvement. PET scanning or bone scanning may be utilized in patients with non-MIBG avid disease.
Figure 105-5. Computed tomographic scan of a child with stage 3 neuroblastoma, crossing the midline displacing the aorta, vena cava, kidney, pancreas, and spleen.
Table 105-2).48 Stage 1 is localized tumor with complete gross excision with or without microscopic residual disease and negative ipsilateral lymph nodes. Partially resected tumors and tumors without or with ipsilateral lymph node involvement are either stage 2A or 2B. A tumor that is unresectable or has contralateral lymph nodes involved is stage 3. Any tumor with distant metastases is stage 4. Stage 4S is localized neuroblastoma tumor with distant disease limited to skin, liver, or bone marrow in infants younger than 1 year. Stage 4S is a poorly understood unique subset of neuroblastoma tumors that often spontaneously regress without surgical resection or cytotoxic therapy. INSS is largely based on the surgeon’s definition of resectability and surgical approach to the primary tumor and lymph nodes. There is international variation in surgical decision making and approach to locoregional disease that may alter the prognostic value of INSS staging. This has made the performance and comparison of international clinical trials difficult. Moreover, biologic prognostic factors have become increasingly important in treatment planning and risk stratification. To address this, the European International Society of Pediatric Oncology neuroblastoma group proposed radiographic characteristics of the primary tumor as useful predictors of resectability and risk for developing postoperative complications (International Neuroblastoma Risk Group Staging System [INRGSS]).52 INRGSS, determines the extent of locoregional disease by the presence or absence of image-defined risk factors (IDRF).53 Stage L1 tumors are localized tumors that are confined within one body compartment and do not involve vital structures or major blood vessels, without any IDRF. L2 tumors are locoregional tumors with one or more IDRF that may involve ipsilateral continuous body compartments and have lower event-free survivals compared to L1 tumors. Stage M is distant metastatic disease and MS is limited to children younger than 18 months with skin, liver, and/or bone marrow metastases. The benefit of INRGSS is that treatment stratification is based on preoperative diagnostic imaging, rather than variable operative approaches. INRGSS now functions as one of the seven prognostic factors in the new International Neuroblastoma Risk Group (INRG) pretreatment classification system.54 The INRG classification system defines pretreatment patient cohorts based on expected 5-year event-free survival at the time of diagnosis before treatment. INRG classification includes INRG stage, age, histologic category, grade of tumor differentiation, MYCN status, 11q alterations status, and DNA ploidy. These criteria are used to define 16 clinically different pretreatment groups that include very low-, low-, intermediate-, and high-risk categories in terms of 5-year event-free survivals of >85%, >75 to ≤85, ≥50% to ≤75, and <50%, respectively. These clinical categories may further assist physicians and cooperative groups in risk-group stratification based on reliable expected event-free survival cutoffs. Importantly, INRG classification will allow comparison of international risk-based clinical trials with potential to enhance international collaborative efforts.The criteria for diagnosis and staging of neuroblastoma have traditionally been based upon the International Neuroblastoma Staging System (INSS). Standard staging criteria allows physicians to tailor treatment plans based on patient risk. INSS is the most widely accepted staging system and was established in efforts to standardize risk-group stratification by cooperative groups (
The treatment of neuroblastoma requires a multidisciplinary approach in order to ensure the most optimal outcomes. Treatment is often multimodal with surgery, chemotherapy, radiation, bone marrow/stem cell transplantation, and immunotherapy. Risk group assignment is essential for surgical and medical treatment decisions, as therapies are tailored to risk. Patients are categorized on the basis of INRG classification as very low-, low-, intermediate-, or high-risk. In general, the overall goal is to minimize surgical risks and to limit exposure to chemotherapy in patients with localized disease and favorable biologic features.
In the United States, the current treatment of children with neuroblastoma is guided by protocols established by the COG, and it is recommended that every child diagnosed be enrolled on a clinical trial. ANBL00B1 is the most recently opened COG study that will determine risk stratification and treatment plans based on histology, MYCN amplification, ploidy, and serum analysis (clinicaltrials.gov/ct2/show/NCT00904241). This study will also further investigate other tumor biologic properties including the prevalence of segmental chromosomal alterations 1p, 11q, 14q, and 17q and analyze for independent clinical significance compared to standard prognostic indicators such as MYCN, INSS, and age.
Table 105-2 International Staging Criteria for Neuroblastoma
For tumors that are classified as very low risk and low risk with favorable biologic characteristics (INSS stage 1, 2A/2B non-MYCN, no 11q alteration), survival rates are >95% with surgery alone without the need for postoperative chemotherapy.55 Children with low-risk neuroblastoma are treated on the basis of results of the Children’s Oncology Group Study P9641 that demonstrated excellent survival rates in asymptomatic low-risk patients with stages 1, 2a, and 2b neuroblastoma after surgery alone.56 The study demonstrated 3-year overall survival of 95% or greater with surgery alone in patients with low-risk, favorable histology disease. The goal of surgery in low-risk patients is complete surgical resection without compromising surrounding organs or blood vessels.
Surgical standards for low-risk neuroblastoma are to establish diagnosis and to resect as much tumor as safely possible without damage to contiguous structures or major blood vessels. Sampling of nonadherent regional lymph nodes and obtaining adequate tissue for biologic studies is critical. Chemotherapy in this group is reserved for patients who relapse or have treatment failure. Chemotherapy is also for patients with less than partial primary tumor resection (<50%), disease that compromises organ function or is life threatening, and patients at risk of developing spinal cord compression. If utilized, low-dose chemotherapy is carboplatin, cyclophosphamide, doxorubicin, and etoposide. Chemotherapy is 6 to 24 weeks depending upon patient’s age, weight, and extent of disease. Radiation is seldom given in this group and is reserved for patients with life-threatening symptoms.
Stage MS neuroblastoma tumors without MYCN amplification are very low-risk classification and most often spontaneously regress. Children with MS disease require biopsy of either primary or metastatic tumor for biology studies. This subset may be spared for both surgery and chemotherapy. Exceptions are patients with massive hepatomegaly causing abdominal compartment syndrome when low-dose chemotherapy and radiotherapy is given to reduce organ dysfunction. Patients with MS tumors may require decompressive laparotomy and ventilator support. In this case, attempts should be made to biopsy extra-abdominal sites, and diagnosis may also be made by bone marrow biopsy. In rare and extreme life-threatening cases, treatment may be initiated on the basis of diagnostic imaging characteristics alone.
The intermediate-risk group encompasses a broad spectrum of neuroblastoma tumors. The survival rate for patients in this group is between 75% and 90%. All patients in this subgroup receive surgery and chemotherapy. The goals of surgical resection are similar to low-risk cases to establish the diagnosis with enough tissue for histologic and genetic testing with the most complete tumor resection, preserving organ function. If the primary tumor is resectable without damage to surrounding organs and major blood vessels, then full resection is performed with lymph node sampling for staging upfront. Many patients in the intermediate-risk group will have locoregional disease that encroaches upon surrounding organs and major blood vessels (aorta, vena cava, mesenteric vessels, kidney, spleen). The surgeon should defer to the INRG IDRF during assessment for resectability. For L2 tumors with INRG IDRF and those judged to be unresectable at diagnosis, biopsy is performed with plan for neoadjuvant chemotherapy. Delayed surgical resection after four to six cycles of induction chemotherapy minimizes surgical complications and may improve resection of the primary tumor and overall survival.57 Moderate-dose chemotherapy for intermediate-risk tumors consists of 12 to 24 weeks of cisplatin, cyclophosphamide, doxorubicin, and etoposide. The prognosis in this subgroup depends upon patient’s age, tumor histology, and biologic properties. Treatment protocols for children with intermediate-risk neuroblastoma are currently based on results of the COG trial A3961. This study demonstrated a high rate of survival with biologically based treatment assignment utilizing substantially reduced duration and doses of chemotherapy agents compared with previously used intensive regimens.58 The promising results have reduced cytotoxic therapy for patients with regional disease and favorable biologic characteristics and provided framework for ANBL0531, a COG trial further examining reduction in cytotoxic therapy as more refined risk factors emerge.38,59
High-risk neuroblastoma remains one of the most challenging problems in pediatric oncology. Survival in this group remains poor despite multimodal therapy that includes aggressive surgery, intensive cytotoxic chemotherapy, and radiation. The long-term survival is between 10% and 30%. High-risk tumors are characterized by undifferentiated neuroblasts with unfavorable histology and poor prognostic indicators (MYCN amplification, 11q alterations, and diploidy). The initial surgical management of high-risk tumors begins with an adequate operative biopsy and vascular access placement. Initial biopsy can be approached by open or minimally invasive techniques including thoracoscopy, laparoscopy, and percutaneous core biopsy. Obtaining an adequate sample size to allow for histologic and cytogenetic studies is of utmost importance and is the primary focus when determining biopsy technique. An initial biopsy should obtain tissue greater than 1 cm3 of viable tumor tissue with avoidance of placement of the specimen in formalin in order to optimize cytogenetic studies. The adequacy of the biopsy specimen should be confirmed with the pediatric pathologist before leaving the operating room. Standard treatment then begins with induction chemotherapy, followed by surgical local control, myeloablative consolidation therapy, and biologic agents.
Induction chemotherapy is administered to improve tumor resectability and to decrease tumor growth. Most neuroblastoma primary tumors and bone marrow are initially sensitive to chemotherapy and will have high response rates. Standard induction therapy consists of combinations of cisplatin, cyclophosphamide, vincristine, doxorubicin, and etoposide. The response rate of induction chemotherapy correlates with survival.60 Postinduction persistent bone lesions and bone marrow involvement predict poor overall survival.61
Local control is achieved with the combination of aggressive surgical resection and external-beam radiotherapy to the primary tumor site. Delayed resection with postinduction chemotherapy excision of as much of tumor as safely possible offers the highest treatment success. After induction chemotherapy consisting of four to five cycles, surgical exploration with the goal of gaining local control of the primary tumor is undertaken. Although the role of primary tumor resection in high-risk patients with neuroblastoma has been controversial, recent studies have shown that aggressive removal of all primary tumors in high-risk patients with neuroblastoma improves survival to 50% and decreases local recurrence to 10%.62 Gross total resection of the primary tumor is defined as the removal of all visible and palpable neuroblastomas from the primary tumor site and regional lymph node tissue. The microscopic margin is nearly always positive; therefore, the goal is safe gross total resection with external beam radiation therapy to the surgical bed (2,000 to 2,100 cGy).
Safe tumor dissection typically requires exposure of the great vessels and spine (Fig. 105-6). The incision type depends on the location of the primary tumor with thoracoabdominal or transverse abdominal for large adrenal masses and midline incision for pelvic neuroblastoma. Thoracic neuroblastoma typically has favorable biology and better survival outcomes than abdominal tumors and surgical resection is often curative. Primary thoracoscopic gross total resection is safe in neuroblastoma tumors smaller than 6 cm and may yield surgical and survival outcomes similar to open thoracotomy.63,64 Cervical chain tumors may be approached by radical neck incisions and if located at the lower cervical region or apex of hemithorax, a trap-door incision often utilized in the setting of vascular trauma may be applied.65 Every effort should be made to preserve the vagus and phrenic nerves. In general, for all neuroblastoma resections, organs and structures should be preserved, particularly the kidney. The operative complications to avoid are excessive blood loss, kidney and renal vessel injury, damage to surrounding major blood vessels or nerves, and postoperative infection and abscess. The tumor is removed by meticulous dissection in the peritumoral capsular plane. Early control of the aorta and the vena cava is essential as the major blood vessels are traced. The major blood vessels often include the celiac axis, superior mesenteric artery, renal vessels, and inferior mesenteric artery. Tightly adherent tumor to blood vessels or major nerves should be left rather than risk injury though neuroblastoma typically does not invade beyond the adventitia. At times, it is beneficial to divide the tumor over major blood vessels for safe exposure when en bloc resection is not possible at encased blood vessels. Pelvic neuroblastoma typically arises from the organ of Zuckerkandl or elsewhere along the sympathetic chain and is associated with excellent long-term survival, despite residual or microscopic disease. Injuries to the lumbosacral plexus or damage to innervation to the bowel or bladder should be avoided. Selective MRI for pelvic lesions may help define neural involvement and enhance surgical planning. Nerve stimulation may be useful when approaching the pelvic sidewall. The presence of residual tumor correlates with risk of recurrence. Patients with incomplete resection may benefit from higher-dose radiation.66
Figure 105-6. Intraoperative depiction of critical exposure during neuroblastoma resection exposing the aorta and the vena cava from bifurcation distal to proximal.
Myeloablative consolidation therapy was investigated in the CCG-3891 study that demonstrated myeloablative therapy with purged bone marrow transplant improved outcome for patients with high-risk neuroblastoma.60 The data from this trial have been confirmed with several international studies.67 High-dose myeloablative megatherapy (cisplatin, etoposide, cyclophosphamide) with autologous stem cell transplantation improves outcome and progression-free survival compared to maintenance chemotherapy or observation. Over the last several decades, intensification of consolidation therapy with myeloablative doses of chemotherapy, followed by autologous stem-cell rescue has allowed for steady reduction in relapse rates in first remission and has now become standard of care for patients with high-risk disease.68 The ability to harvest peripheral blood stem cells along with advances in transplant methodology has enhanced the safety and feasibility of bone marrow transplantation.
Maintenance and biologic therapies have also improved high-risk neuroblastoma treatment. Isotretinoin (cis-RA) is a synthetic retinoid that is now standard of care after induction, local control, and cytotoxic chemotherapy. Currently all patients with high-risk neuroblastoma receive 6 months of high-dose cis-RA therapy after myeloablative therapy and bone marrow transplantation. The COG (ANBL0032) found that the addition of monoclonal antibodies (MAB ch14,18) targeting disialoganglioside GD2 improved survival rates in patients with high-risk disease.69,70 GD2 is a sialic acid-containing glycosphingolipid expressed uniformly on the surface of neuroblastoma cells. The Food and Drug Administration recently approved Unituxin (dinutuximab, formerly MAB ch14,18) specifically for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multimodality treatment.
Despite advances in cytotoxic and biologic multimodality therapies, up to 60% of patients with high-risk neuroblastoma relapse and there are currently no curative salvage treatment regimens. Advances in understanding neuroblastoma tumor biology are essential for the development of novel therapies for high-risk tumors. The use of high-throughput genomic sequencing technologies will aid in patient-specific prognostic data and allow for a personalized approach to treatment. The success of anti-GD2 monoclonal antibody has launched great interest and research into improving antibody-based approaches and synergistic immunotherapies. A recent study showed promise in humanized anti-GD2 engineered to target the delivery of interleukin-2 to tumor microenvironment in patients with small tumor burden.71 The addition of MAB ch14,18 and cytokines granulocyte/macrophage colony-stimulating factor and interleukin-2 to cis-RA may prevent late relapse. Radiolabeled MIBG is also being investigated as a therapeutic agent in neuroblastoma and has a high response rate in patients with relapse and refractory disease.51,72,73 Targeted radionucleotide has little nonhematologic toxicity though most patients experience some level of myelosuppression requiring autologous hematopoietic cell transfusion.
The challenges also remain the ability to identify patients with low-risk and intermediate-risk tumors who benefit from reduction in therapy versus those who are at risk for relapse and refractory disease. There are several large collaborative research efforts focusing on the discovery of new therapeutic targets with respect to understanding the relationship between risk and the molecular basis of neuroblastoma. One such effort is the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (target.cancer.gov). TARGET in conjunction with the Cancer Genome Atlas project conducts genomic profiling and tumor sequencing for neuroblastoma along with other pediatric solid tumors with the goal of discovering novel mechanisms that drive tumorigenesis and identifying new molecular targets for drug development.
Epidemiology and Genetic Risk
Various tumors arise in the kidneys in children that range from benign to malignant. Wilms tumor (nephroblastoma) is the most common renal tumor in children and is the second most common solid tumor outside of the brain in infants behind neuroblastoma. Wilms tumors occur almost exclusively in the kidney. Extremely rare extrarenal sites include the retroperitoneum, pelvis, and inguinal canal.74 The overall incidence of Wilms tumor is eight per million children younger than 15 years, with approximately 500 new cases per year in the United States.4 Children most commonly present within the first 2 years of life, with nearly all diagnosed before the age of 5 years. The incidence of Wilms tumor varies by ethnicity with highest incidence in Africa and African-American children and lowest in East Asian populations.75 The National Wilms Tumor Study (NWTS) reported that the median age for Wilms tumor in boys is 36 months and 43 months for girls with unilateral tumors.76 Bilateral Wilms tumors occur in slightly younger children with median ages of 23 months for boys and 30 months for girls. The survival of children with Wilms tumor has improved significantly over the past several decades from 30% to more than 90% 5-year survival currently.77
Table 105-3 Syndromes Associated with Increased Susceptibility to Wilms Tumor
Most Wilms tumors are sporadic with only 1% to 2% of cases being familial. Several genetic syndromes are uniquely associated with Wilms tumor. Sporadic aniridia, hemihypertrophy, genitourinary tract abnormalities, and Beckwith–Wiedemann syndrome are known to be associated with an increased risk of Wilms tumor in children.78 The study of patients with sporadic aniridia and Beckwith–Wiedemann syndrome led to the discovery of WT1, a tumor suppressor gene located on chromosome 11p necessary for normal renal development.79,80 Inactivating mutations lead to the development of most Wilms tumors, and germline mutations account for most of the syndromic anomalies that are associated with chromosome 11 including WAGR (Wilms tumor, aniridia, genitourinary abnormalities, intellectual disability), Denys–Drash syndrome (pseudohermaphroditism, glomerulopathy, renal failure, Wilms tumor), and Beckwith–Wiedemann syndrome.81 Inactivating point mutations in the WT1 gene, located on chromosome 11p13, are associated with Denys–Drash syndrome, and LOH at the 11p15 locus (WT2) is found in Beckwith–Wiedemann syndrome, with 5% to 10% of patients having Wilms tumors.82 Patients with WAGR syndrome have associated somatic germline mutations of 11p13. FWT1 (17q) and FWT2 (19q) have been identified in familial Wilms tumor disposition (Table 105-3).83 Table 105-3 lists known genetic syndromes associated with increased susceptibility to Wilms tumor.
Pathology and Biologic Features
84 Importantly, anaplastic cells characterize 7% of Wilms tumors and are defined by the presence of enlarged nuclei and hyperchromasia with multipolar polypoid mitotic figures (Fig. 105-7).85 Compared to tumors without anaplasia, anaplastic Wilms tumors are generally found in older children and are more likely to have lymph node metastases. Differences in race are also observed with African or Latin-American children having the highest proportion of tumors with anaplasia. Tumors with diffuse anaplasia (present in more than one area of the tumor or extrarenal sites) are defined “unfavorable histology” and have higher resistance to chemotherapy than tumors without anaplasia.86 The single most important prognostic indicator in Wilms tumors is the presence of anaplasia.Wilms tumors arise from pluripotent developmental renal precursor cells. In most cases, only one kidney is affected but may present as bilateral disease in up to 6% of children. Multicentric disease is found in 7% of patients. Wilms tumors arise within the renal medulla and cortex and may invade renal calyces, renal vein, and inferior vena cava. The tumor is most commonly a well-circumscribed mass with a fibrous capsule. The most common sites of metastatic spread are lungs, lymph nodes, and liver. Wilms tumors are composed of a classic triphasic combination of blastemal, stromal, and epithelial cells. Characterization of histologic subtype is critical for risk stratification and for treatment planning. Blastemal predominance may indicate a high-risk category of patients with increased risk of recurrence.
Clear cell sarcoma and rhabdoid tumor of the kidney are also unfavorable histologic subtypes and are now considered distinct entities from Wilms tumors.77,87 Nephrogenic rests represent the persistence of developmental renal tissue in the kidney after the 36th week of gestation and 1% undergo malignant transformation to Wilms tumor. Two major categories of nephrogenic rests have been characterized, perilobar and intralobar, distinguished by their position within the renal lobe.80 Nephrogenic rests are considered precursor lesions of Wilms tumor and are found in nearly half of cases.88 Intralobar characterizes early developmental disturbances and occurs in aniridia and Denys-Drash syndrome, while perilobar develops later in nephrogenesis and occurs in patients with Beckwith–Wiedemann syndrome and hemihypertrophy. Nephroblastomatosis is the term used to describe the presence of diffuse nephrogenic rests and typically involves both kidneys. The presence of nephrogenic rests demonstrates the vast degree of heterogeneity in Wilms tumor biology as they either involute or progress to hyperplastic overgrowth or neoplastic induction.77 Patients with nephrogenic rests are at risk for bilateral kidney involvement that decreases with age.
Figure 105-7. Microscopic examination of Wilms tumor showing highly cellular areas composed of undifferentiated blastemal cells with loose surrounding stroma with undifferentiated mesenchymal cells and immature tubules. (From Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999, permission granted with previous edition.)
Several biologic factors have been identified in Wilms tumors that associate with risk. Tumor-specific LOH at chromosomes 1p and 16q are independent prognostic indicators and are associated with greater risk of relapse and mortality. The fifth National Wilms Tumor Study Group trial (NWTS-5) found that tumors with LOH at 16q had an adverse effect on prognosis with relapse rates three times higher and mortality rate 12 times higher than those without LOH at chromosome 16q.89 Patients with LOH for chromosome 1p also had relapse and mortality rates higher than those without LOH at 1p.90 LOH for both chromosomes 1p and 16q are found in up to 5% of Wilms tumors.
Presentation, Diagnosis, and Staging
Children may present with a palpable asymptomatic abdominal mass identified by parents or pediatrician during well-visit examination. If present, symptoms may include intermittent abdominal pain, gross or microscopic hematuria (25% of patients), and hypertension (25% of patients). Hypertension occasionally results from either an increase in renin secretion by the tumor or by compression of the renal artery by tumor mass effect. Intraparenchymal bleeding and preoperative rupture may occur causing systemic symptoms of fever and anemia. The mass is typically nontender and nonmobile on physical examination. The child should be examined for aniridia, macroglossia, hemihypertrophy, and genitourinary abnormalities. Signs of intravascular spread may present as ascites, hepatosplenomegaly, and cardiac murmur. Standard complete blood count and serum chemistries should be assessed though renal function is usually unaffected. Red blood cells may be present on urinalysis.
The diagnostic imaging workup is initiated with abdominal ultrasound and CT scan with oral and intravenous contrast. CT scan is the standard imaging modality that will provide information about mass location, size, extent of tumor invasion, and involvement of the contralateral kidney (Fig. 105-8). Critical examination of renal vasculature and intracaval extension is evaluated by Doppler ultrasonography. A good posteroanterior and lateral chest radiograph is obtained to determine the presence of lung metastases. It is critical to determine whether a patient with Wilms tumor has lung metastases because these patients are assigned to higher disease stage and receive radiation to the lungs and more intensive chemotherapy. There is considerable controversy regarding the utilization of chest CT scan versus plain chest radiograph to detect lung metastases in patients with Wilms tumor because of interobserver variability in interpretation.91 If utilized for staging workup, chest CT should be performed with standardized techniques and interpretation through a central review process considered. Pulmonary metastases identified on chest CT but not on plain chest radiograph may identify a subgroup of patients at increased risk of pulmonary relapse.92 It may be beneficial to obtain histopathologic confirmation of pulmonary metastases by surgical biopsy given the potential for upstaging and radiotherapy.93
In the United States, nephrectomy follows the initial diagnostic workup, allowing the combination of surgical and histologic parameters to be included in staging at diagnosis. During the procedure, the surgeon must determine tumor extent, tumor rupture, and the status of regional, paraaortic, and paracaval lymph nodes. Distant metastatic disease should also be determined by inspecting the peritoneal surfaces, diaphragm, and liver. The COG no longer recommends direct visualization and manual palpation of the contralateral kidney as long as the contralateral kidney is clear of tumor on cross-sectional imaging.
The staging of Wilms tumor is based on the anatomy of the tumor and lymph nodes as detailed by the NWTSG staging system. The staging system incorporates clinical, surgical, and pathologic information and allows stage-based approach to treatment to minimize exposure to cytotoxic agents (Table 105-4). Stage 1 tumors are limited to the kidney and completely resected with an intact renal capsule without involvement of the renal sinus vessels. Stage 2 tumors extend beyond the kidney by either penetration of the renal capsule or invasion of sinus vessels. Biopsy before removal or local tumor spillage is classified as stage 3. Tumors that are unresectable or incompletely resected with positive margins are also stage 3 tumors. Tumors with regional lymph node metastases are stage 3 criteria as well. Stage 4 tumors have distant spread (liver, lung, bone, brain) or lymph node spread outside of the abdomen. Bilateral Wilms tumors are classified as stage 5 though precise staging for patients with bilateral Wilms tumor is based on local stage for each kidney. Advanced tumor stage at diagnosis predicts an increased risk of recurrence and tumor rupture at surgery predisposes to relapse.94 Older age is also an adverse prognostic factor and predicts disease recurrence.95 Tumor stage and histology are the most significant prognostic factors for children with Wilms tumor.
Most children diagnosed with Wilms tumor are cured by multimodal therapy. Much of the success in therapy is the result of collaboration and research trials conducted by three cooperative groups, the NWTSG, now a part of the COG, the United Kingdom Children’s Cancer Study Group (UKCCSG), and the SIOP. In the United States and Canada, nearly all children are treated according to protocols established by the NWTSG. The primary goals of therapy are to treat on the basis of well-defined risk groups and to achieve the highest cure rates with minimal toxicity.
Figure 105-8. A: Abdominal CT scan with left Wilms tumor displacing midline organs and vessels, rim of kidney enhancing at lateral border. B: Intraoperative view of right Wilms tumor arising from retroperitoneum, displacing colon and midline structures, approached via a generous right supraumbilical transverse abdominal incision.
96 In contrast to this treatment approach, SIOP therapy begins with chemotherapy administration for several weeks prior to nephrectomy in all patients presenting with Wilms tumors.97 The standard chemotherapeutic drugs with activity against Wilms tumors are vincristine and actinomycin-D. Doxorubicin is added to patients with stage 3 tumors and to those with unfavorable histology or adverse biologic prognostics markers such as LOH at chromosome 1p or 16q. Combinations of cyclophosphamide, ifosfamide, carboplatin, and etoposide are utilized for select stage 3 and 4 cases with unfavorable biology and for resistant or relapsed cases. In the United States, the optimal combination, duration, and mode of administration of chemotherapy are optimized through clinical trials and studies of the NWTSG and COG.Surgery is a critical component of local primary tumor control and treatment outcomes. In the United States, the standard of care starts with radical nephrectomy at the time of diagnosis of resectable primary tumors, followed by chemotherapy and radiation to sites of residual and metastatic disease. Preoperative chemotherapy is given to patients with inoperable tumors, bilateral disease, solitary kidney, and for tumors with intravascular extension above the hepatic veins. A significant number of patients are downstaged after preoperative chemotherapy without altering recognizable anaplasia.
The first two NWTS, NWTS-I and NWTS-II, found that routine postoperative radiation was unnecessary in patients with tumors confined to the kidney and completely resected. Combination therapy of vincristine and actinomycin-D was more effective than single-agent therapy, and the addition of doxorubicin improved survival in higher-stage patients. In addition, the duration of combination chemotherapy was successfully reduced in low-stage patients from 15 months to 6 months without compromising survival outcomes.98,99 These studies established criteria that identify unfavorable (anaplasia) and favorable histologic features that stratify patients into high-risk and low-risk treatment groups. High-risk patients are at a higher risk of recurrence and also include those with unresectable tumors, lymph node metastases, and diffuse tumor spill. This patient group benefits from intensified chemotherapy and abdominal radiation. These findings paved the way for NWTS-III that demonstrated successful treatment of stage 1 favorable histology Wilms tumors with lower dosing and further reduced duration of vincristine and actinomycin D. The 4-year relapse-free and survival rates with this regimen were 89% and 95%.100 This study found that stage 2 patients with favorable histology were treated successfully with vincristine and actinomycin D without postoperative radiotherapy or doxorubicin, and stage 3 patients had no differences in abdominal recurrence with reduction of abdominal radiotherapy compared to patients with high-dose radiotherapy when doxorubicin was administered (10.8 Gy compared to 20 Gy). The NWTS-III also found that patients with stage 4 favorable histology tumors were successfully treated with vincristine, actinomycin D, doxorubicin and local radiotherapy based on local tumor stage. The addition of cyclophosphamide was without benefit. This group received lung radiation to both lungs (12 Gy), with 4-year relapse-free and overall survival of 79% and 80.9%. The NWTS-IV trial was largely based on improving treatment results through modifying drug administration utilizing shorter and “pulse-intensive” chemotherapy regimens compared to standard divided dose regimens.101 The results of this study revealed that shorter pulse-intensive regimens were equivalent to standard treatment regimens in terms of overall survival with total chemotherapy duration of 6 months. Since the NWTS-IV trial, survival rates for children with Wilms tumor have steadily improved with shorter chemotherapy schedules and lower treatment costs.102 Based on results of NWTS-IV, the current overall survival rate for children with favorable histology Wilms tumor approaches 90%. Current 10-year relapse and overall survival for stage 1 favorable histology Wilms tumors are 91% and 96%, and for stage 2 tumors, 85% and 93%, respectively.103 NWTS-V completed enrollment in 2003 and was designed as a nonrandomized single arm therapeutic trial to treat patients with stage- and histology-specific treatment plans. In this study, patients were not randomized to therapy, rather biologic properties of tumors were assessed. The aims included determining whether tumor LOH for chromosomes 1p and 16q was associated with poorer prognosis in patients with favorable histology Wilms tumors and to determine whether increased DNA content in tumor cells was associated with adverse outcomes.104 LOH for 1p and 16q identified a subgroup of favorable histology patients who have a significantly increased risk of relapse and death.90 LOH for these chromosomes is now used as an independent prognostic factor as patients with LOH for chromosome 1p and 16q have 75% relapse-free survival.
Table 105-4 Wilms Tumor Staging System
The NWTS-V also attempted to verify that surgery alone may have acceptable overall survival rates in a subgroup of children younger than 2 years at diagnosis with very low-risk favorable histology of Wilms tumors that weigh less than 550 g.105 The incidence of relapse was higher in this subgroup of patients receiving surgery only, but the salvage rate was surprisingly high with long-term survival being the same as patients receiving conventional postoperative chemotherapy. Given this, cooperative group trials will further study optimal management of surgery alone in this subgroup to determine whether very low-risk patients may be spared adjuvant therapy.
Since 2006, the COG has opened four clinical trials for the treatment of children with Wilms tumors. For these therapeutic studies, patients are stratified into very low-risk, low-risk, standard-risk, and high-risk groups on the basis of tumor histology, stage, biologic assessment, tumor weight, and age. To facilitate accurate risk assessment, it is currently recommended that all patients diagnosed with Wilms tumor be enrolled and follow protocol recommendations of AREN03B2, a biology classification-based trial. The current treatment recommendations are summarized in Table 105-5 and are based on the most recent COG trials developed to build upon and refine results of previous NWTS (Table 105-5).106 The protocol guidelines recommend that stage 1 and 2 favorable histology patients undergo initial nephrectomy and lymph node sampling, followed by vincristine and actinomycin-D chemotherapy (regimen EE-4A). Doxorubicin (regimen DD-4A) is added to the treatment plan in patients with stage 1 and 2 tumors with favorable histology and LOH at chromosome 1p and 16, as this subgroup has been shown to have an increased risk of relapse and death. Stage 1 tumors with unfavorable histology (focal or diffuse anaplasia) have lower 10-year relapse-free and overall survival of 69% and 82% and are treated with vincristine, actinomycin-D, doxorubicin (regimen DD-4A), and abdominal radiotherapy. Stage 3 patients with favorable histology are treated with nephrectomy, lymph node sampling, vincristine, actinomycin-D, and doxorubicin (regimen DD-4A) and abdominal radiotherapy, with 10-year relapse-free and overall survival of 84% and 89%. Cyclophosphamide and etoposide (regimen M) are added to the treatment regimen for stage 3 tumors with favorable histology and LOH at chromosomes 1 and 16q. The presence of diffuse anaplasia also intensifies therapy in stage 2 and 3 tumors with the addition of cyclophosphamide, carboplatin, and etoposide for 30 weeks (regimen UH-1) and abdominal radiotherapy, with 10-year and overall survival rates of 43% and 49%. Stage 4 patients with favorable histology and pulmonary metastases are treated with nephrectomy, lymph node sampling, and vincristine, actinomycin-D, and doxorubicin for 24 weeks. In patients with stage 4 disease, the primary tumor is staged separately to determine the requirement for abdominal radiation. Lung radiotherapy is currently utilized if metastases remain detectable after 6 weeks of chemotherapy. For these reasons, it remains advantageous to resect the primary tumor prior to the initiation of chemotherapy even in patients with stage 4 disease. Based on results of NWTS-4, the 10-year relapse-free and overall survival for patients with stage 4 favorable histology Wilms tumor is 75% and 81%. Stage 4 favorable histology tumors with LOH at chromosomes 1p and 16q are treated with the addition of cyclophosphamide and etoposide (regimen M) and abdominal radiation. Stage 4 tumors with focal or diffuse anaplasia (without measurable disease) are treated with the addition of cyclophosphamide, carboplatin, and etoposide for 30 weeks (regimen UH-1) and radiotherapy. This subgroup of patients has the worst 10-year relapse-free and overall survival of 18%. Stage 5 Wilms tumors (bilateral tumors) with favorable histology have 10-year relapse-free survival and overall survival of 65% and 78%. Patients with bilateral Wilms tumors are treated with preoperative chemotherapy (vincristine, actinomycin-D, doxorubicin) and renal-sparing surgery.
Table 105-5 Recommended Therapy According to COG Protocols
Preoperative biopsies are contraindicated unless a tumor is judged unresectable. For most patients, unilateral radical ureteronephrectomy with abdominal exploration is accomplished through a wide transverse abdominal incision that will allow safe resection and regional lymph node sampling without rupture. A thoracoabdominal incision may be utilized as necessary for tumors reaching the diaphragm. Complete abdominal and pelvic exploration is performed. The contralateral kidney does not require exploration if preoperative imaging does not suggest involvement. The lateral peritoneal reflection is incised and the colon is reflected medially. Although a formal retroperitoneal lymph node dissection is not recommended, lack of adequate lymph node sampling along with the primary tumor resection automatically upstages treatment to stage 3 disease because of the risk of local relapse.106 Gentle handling of the tumor is critical to avoid tumor rupture and spillage as there is a sixfold increase in local relapse and also automatic tumor upstaging to stage 3.107 Both local and diffuse tumor rupture will increase relapse risk. It is often unsafe to attempt to ligate the renal vein prior to tumor manipulation given the size of most Wilms tumors as traditionally recommended by most authors. Later ligation of the renal vein after tumor mobilization has not been shown to adversely affect survival outcomes, and early ligation should not be attempted if technically difficult. The dissection is carried out along the tumor capsule and outside of Gerota fascia identifying the renal hilum and isolating the renal artery, vein, and the ureter (Fig. 105-9). The renal vein and inferior vena cava are palpated for intravascular tumor extension. The ureter is divided as distal as possible to the renal hilum though it is not necessary to remove the entire ureter. The tumor and the kidney are then removed en bloc. The adrenal gland may be left in place if it does not abut the tumor or if the tumor arises from the lower pole of the kidney.108 Titanium clips should be utilized to identify any gross residual tumor. The tumor and the nephrectomy specimen should not be placed into fixative but delivered fresh and sterile to the pathologist to optimize histologic and cytogenetic analysis based on pediatric tumor protocols.
There have been reports of laparoscopic resection of Wilms tumor.109 These are more likely feasible after preoperative chemotherapy with lower risk of tumor rupture, though safety has not been confirmed. Success of laparoscopy for Wilms tumor is hindered by tumor spill and by inaccurate staging.
Patient selection for preoperative chemotherapy is a critical step in surgical and treatment planning. The overall incidence of surgical complications in patients undergoing nephrectomy for Wilms tumor is 12.7%.110 The most common surgical complications are small bowel obstruction (5.1%) and excessive hemorrhage (1.9%), followed by wound infection (1.9%) and vascular injury (1.5%) as reported by the NWTS-IV trial. Higher-stage tumors, intravascular extension, and resection of contiguous organs are risk factors associated with surgical complications. The risk of renal insufficiency after unilateral nephrectomy for Wilms tumor is low (0.25%), and patients with Denys-Drash syndrome are most at risk for progressive tumor in the remaining kidney.111 For these reasons, nephron-sparing procedures are currently reserved for children with bilateral Wilms tumor and for those at risk for developing renal failure and not indicated for patients with standard unilateral tumors with a normal contralateral kidney.
Figure 105-9. Anatomy and operative approach to resection of a Wilms tumor.