Very Low Risk and Low Risk

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 lowrisk, 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.

Intermediate Risk

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,

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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

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

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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 highrisk 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.

Future Directions

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 patientspecific 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 colony3081

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 (http://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.

WILMS TUMOR

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

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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

5 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.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.

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.

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