Chapter 31: Neoplastic Disease

Each year approximately 150 out of every 1 million children younger than 20 years are diagnosed with cancer. For children between the ages of 1 and 20 years, cancer is the fourth leading cause of death, behind unintentional injuries, homicides, and suicides. However, combined-modality therapy, including surgery, chemotherapy, and radiation therapy, has improved survival dramatically, such that the overall 5-year survival rate of pediatric malignancies is now greater than 75%. It is estimated that currently 1 in 570 adults will be a survivor of childhood cancer.

Because pediatric malignancies are rare, cooperative clinical trials have become the mainstay of treatment planning and therapeutic advances. The Children’s Oncology Group (COG), representing the amalgamation of four prior pediatric cooperative groups (Children’s Cancer Group, Pediatric Oncology Group, Intergroup Rhabdomyosarcoma Study Group, and the National Wilms Tumor Study Group), offers current therapeutic protocols and strives to answer important treatment questions. A child or adolescent newly diagnosed with cancer should be enrolled in a cooperative clinical trial whenever possible. Because many protocols are associated with significant toxicities, morbidity, and potential mortality, treatment of children with cancer should be supervised by a pediatric oncologist familiar with the hazards of treatment, preferably at a multidisciplinary pediatric cancer center.

Advances in molecular genetics, cell biology, and tumor immunology have contributed and are crucial to the continued understanding of pediatric malignancies and their treatment. Continued research into the biology of tumors will lead to the identification of targeted therapy for specific tumor types with, it is hoped, fewer systemic effects.

Research in supportive care areas, such as prevention and management of infection, pain, and emesis, has improved the survival and quality of life for children undergoing cancer treatment. Long-term studies of childhood cancer survivors are yielding information that provides a rationale for modifying future treatment regimens to decrease morbidity. A guide for caring for childhood cancer survivors is now available to medical providers as well as families and details suggested examinations and late effects by type of chemotherapy received.

ACUTE LYMPHOBLASTIC LEUKEMIA

General Considerations

Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood, accounting for about 25% of all cancer diagnoses in patients younger than 15 years. The worldwide incidence of ALL is about 1:25,000 children per year, including 3000 children per year in the United States. The peak age at onset is 4 years; 85% of patients are diagnosed between ages 2 and 10 years. Children with Down syndrome have a 10–20 times increase in the overall rate of leukemia.

ALL results from uncontrolled proliferation of immature lymphocytes. Its cause is unknown, and genetic factors may play a role. Leukemia is defined by the presence of more than 25% malignant hematopoietic cells (blasts) in the bone marrow aspirate. Leukemic blasts from the majority of cases of childhood ALL have an antigen on the cell surface called the common ALL antigen (CALLA). These blasts derive from B-cell precursors early in their development, called B-precursor ALL. Less commonly, lymphoblasts are of T-cell origin or of mature B-cell origin. Over 70% of children receiving aggressive combination chemotherapy and early presymptomatic treatment to the central nervous system (CNS) are now cured of ALL.

Clinical Findings

A. Symptoms and Signs

Presenting complaints of patients with ALL include those related to decreased bone marrow production of red blood cells (RBCs), white blood cells (WBCs), or platelets and to leukemic infiltration of extramedullary (outside bone marrow) sites. Intermittent fevers are common, as a result of either cytokines induced by the leukemia itself or infections secondary to leukopenia. Many patients present due to bruising or pallor. About 25% of patients experience bone pain, especially in the pelvis, vertebral bodies, and legs.

Physical examination at diagnosis ranges from virtually normal to highly abnormal. Signs related to bone marrow infiltration by leukemia include pallor, petechiae, and purpura. Hepatomegaly and/or splenomegaly occur in over 60% of patients. Lymphadenopathy is common, either localized or generalized to cervical, axillary, and inguinal regions. The testes may occasionally be unilaterally or bilaterally enlarged secondary to leukemic infiltration. Superior vena cava syndrome is caused by mediastinal adenopathy compressing the superior vena cava. A prominent venous pattern develops over the upper chest from collateral vein enlargement. The neck may feel full from venous engorgement. The face may appear plethoric, and the periorbital area may be edematous. A mediastinal mass can cause tachypnea, orthopnea, and respiratory distress. Leukemic infiltration of cranial nerves may cause cranial nerve palsies with mild nuchal rigidity. The optic fundi may show exudates of leukemic infiltration and hemorrhage from thrombocytopenia. Anemia can cause a flow murmur, tachycardia, and, rarely, congestive heart failure.

B. Laboratory Findings

A complete blood count (CBC) with differential is the most useful initial test because 95% of patients with ALL have a decrease in at least one cell type (single cytopenia): neutropenia, thrombocytopenia, or anemia with most patients having a decrease in at least two blood cell lines. The WBC count is low or normal (= 10,000/μL) in 50% of patients, but the differential shows neutropenia (absolute neutrophil count < 1000/μL) along with a small percentage of blasts amid normal lymphocytes. In 30% of patients, the WBC count is between 10,000/μL and 50,000/μL; in 20% of patients, it is over 50,000/μL, occasionally higher than 300,000/μL. Blasts are usually readily identifiable on peripheral blood smears from patients with elevated WBC counts. Peripheral blood smears also show abnormalities in RBCs, such as teardrops. Most patients with ALL have decreased platelet counts (< 150,000/μL) and decreased hemoglobin (< 11 g/dL) at diagnosis. In approximately 1% of patients diagnosed with ALL, CBCs and peripheral blood smears are entirely normal, but patients have bone pain that leads to bone marrow examination. Serum chemistries, particularly uric acid and lactate dehydrogenase (LDH), are often elevated at diagnosis as a result of cell breakdown.

The diagnosis of ALL is made by bone marrow examination, which shows a homogeneous infiltration of leukemic blasts replacing normal marrow elements. The morphology of blasts on bone marrow aspirate can usually distinguish ALL from acute myeloid leukemia (AML). Lymphoblasts are typically small, with cell diameters of approximately two erythrocytes. Lymphoblasts have scant cytoplasm, usually without granules. The nucleus typically contains no nucleoli or one small, indistinct nucleolus. Immunophenotyping of ALL blasts by flow cytometry helps distinguish precursor B-cell ALL from T-cell ALL or AML. Histochemical stains specific for myeloblastic and monoblastic leukemias (myeloperoxidase and nonspecific esterase) distinguish ALL from AML. About 5% of patients present with CNS leukemia, which is defined as a cerebrospinal fluid (CSF) WBC count greater than 5/μL with blasts present on cytocentrifuged specimen.

C. Imaging

Chest radiograph may show mediastinal widening or an anterior mediastinal mass and tracheal compression secondary to lymphadenopathy or thymic infiltration, especially in T-cell ALL. Abdominal ultrasound may show kidney enlargement from leukemic infiltration or uric acid nephropathy as well as intra-abdominal adenopathy. Plain radiographs of the long bones and spine may show demineralization, periosteal elevation, growth arrest lines, or compression of vertebral bodies. Although these findings may suggest leukemia, they are not diagnostic.

Differential Diagnosis

The differential diagnosis, based on the history and physical examination, includes chronic infections by Epstein-Barr virus (EBV) and cytomegalovirus (CMV), causing lymphadenopathy, hepatosplenomegaly, fevers, and anemia. Prominent petechiae and purpura suggest a diagnosis of immune thrombocytopenic purpura. Significant pallor could be caused by transient erythroblastopenia of childhood, autoimmune hemolytic anemias, or aplastic anemia. Fevers and joint pains, with or without hepatosplenomegaly and lymphadenopathy, suggest juvenile rheumatoid arthritis (JRA). The diagnosis of leukemia usually becomes straightforward once the CBC reveals multiple cytopenias and leukemic blasts. Serum LDH levels may help distinguish JRA from leukemia, as the LDH is usually normal in JRA. An elevated WBC count with lymphocytosis is typical of pertussis; however, in pertussis lymphocytes are mature and neutropenia is rarely associated.

Treatment

A. Specific Therapy

Intensity of treatment is determined by specific prognostic features present at diagnosis, the patient’s response to therapy, and specific biologic features of the leukemia cells. The majority of patients with ALL are enrolled in clinical trials designed by clinical groups and approved by the National Cancer Institute; the largest group is COG. The first month of therapy consists of induction, at the end of which over 95% of patients exhibit remission on bone marrow aspirates by morphology. The drugs most commonly used in induction include oral prednisone or dexamethasone, intravenous vincristine, daunorubicin, intramuscular or intravenous asparaginase, and intrathecal methotrexate.

Consolidation is the second phase of treatment, during which intrathecal chemotherapy along with continued systemic therapy and sometimes cranial radiation therapy are given to kill lymphoblasts “hiding” in the meninges. Several months of intensive chemotherapy follows consolidation, often referred to as intensification. This intensification has led to improved survival in pediatric ALL.

Maintenance therapy can include daily oral mercaptopurine, weekly oral methotrexate, and, often, monthly pulses of intravenous vincristine and oral prednisone or dexamethasone. Intrathecal chemotherapy, either with methotrexate alone or combined with cytarabine and hydrocortisone, is usually given every 2–3 months.

Chemotherapy has significant potential side effects. Patients need to be monitored closely to prevent drug toxicities and to ensure early treatment of complications. The duration of treatment ranges between 2.2 years for girls and 3.2 years for boys in COG trials. Treatment for ALL is tailored to prognostic, or risk, groups. A child aged 1–9 years with a WBC count below 50,000/μL at diagnosis of pre B ALL and without poor biologic features [t(9;22) or an 11q23 rearrangement)] is considered to be at “standard risk” and receives less intensive therapy than a “high-risk” patient who has a WBC count at diagnosis over 50,000/μL or is 10 years of age or greater. An infant younger than 1 year at diagnosis would be considered very high risk and receive even more intensive chemotherapy. Also important is the patient’s response to treatment determined by minimal residual disease (MRD) monitoring. This risk-adapted treatment approach has significantly increased the cure rate among patients with less favorable prognostic features by allowing for early intensification while minimizing treatment-related toxicities in those with favorable features. Bone marrow relapse is usually heralded by an abnormal CBC, either during treatment or following completion of therapy.

The CNS and testes are sanctuary sites for leukemia, meaning that the chemotherapy has a harder time reaching the leukemic cells in these areas. Currently, about one-third of all ALL relapses are isolated to these sanctuary sites. Systemic chemotherapy does not penetrate these tissues as well as it penetrates other organs. Thus, presymptomatic intrathecal chemotherapy is a critical part of ALL treatment, without which many more relapses would occur in the CNS, with or without bone marrow relapse. The majority of isolated CNS relapses are diagnosed in an asymptomatic child at the time of routine intrathecal injection, when CSF cell count and differential show an elevated WBC with leukemic blasts. Occasionally, symptoms of CNS relapse develop: headache, nausea and vomiting, irritability, nuchal rigidity, photophobia, changes in vision, and cranial nerve palsies. Currently, testicular relapse occurs in less than 5% of boys. The presentation of testicular relapse is usually unilateral painless testicular enlargement, without a distinct mass. Routine follow-up of boys both on and off treatment includes physical examination of the testes.

Bone marrow transplantation, now called hematopoietic stem cell transplantation (HSCT), is rarely used as initial treatment for ALL, because most patients are cured with chemotherapy alone. Patients whose blasts contain certain chromosomal abnormalities and patients with a very slow response to therapy may have a better cure rate with early HSCT from a human leukocyte antigen (HLA)-DR–matched sibling donor, or a matched unrelated donor, than with intensive chemotherapy alone. HSCT and newer cellular therapies such as Car T cells are discussed later in this chapter.

Several years ago, imatinib, a tyrosine kinase inhibitor (TKI), directed against the Philadelphia chromosome (Ph+) protein product, was combined in a backbone of intensive chemotherapy for Ph+ ALL in pediatric patients. The results of this trial showed that the patients had an increased leukemia-free survival of 78% as compared to 50% in the past without imatinib. Ongoing trials for COG in Ph+ ALL are now incorporating new TKIs. Two newer targeted agents are now used in relapsed ALL. Blinatumomab is a bispecific T-cell engager (BiTE) that brings the CD19 on a leukemia cell in direct contact with a T cell. This agent is currently being studied in relapsed childhood ALL and will be moved to upfront trials in 2020. Another targeted agent, Inotuzumab is an antibody-drug conjugate against CD22, also frequently found on the surface of the leukemia cells. This drug is also used in relapsed childhood ALL but is also moving to upfront therapy trials. As more is understood about the biology of ALL, further therapy will likely include more of these targeted agents, in order to reduce late effects potentially but maintain and improved leukemia-free survival.

B. Supportive Care

Tumor lysis syndrome, which consists of hyperkalemia, hyperuricemia, hyperphosphatemia, should be anticipated when treatment is started. Maintaining brisk urine output with intravenous fluids and treating with oral allopurinol are appropriate steps in managing tumor lysis syndrome. Rasburicase is indicated for severe tumor lysis syndrome with initial high uric acid values or high WBC at presentation. Serum levels of potassium, phosphorus, and uric acid should be monitored. If superior vena caval or superior mediastinal syndrome is present, general anesthesia is contraindicated temporarily and until there has been some decrease in the mass. If hyperleukocytosis (WBC count > 100,000/μL) is accompanied by hyperviscosity with symptoms of respiratory distress and/or mental status changes, leukapheresis may be indicated to rapidly reduce the number of circulating blasts and minimize the potential thrombotic or hemorrhagic CNS complications. Throughout the course of treatment, all transfused blood and platelet products should be irradiated to prevent graft-versus-host disease (GVHD) from the transfused lymphocytes. Whenever possible, blood products should be leuko-depleted to minimize CMV transmission, transfusion reactions, and sensitization to platelets.

Due to the immunocompromised state of the patient with ALL, bacterial, fungal, and viral infections are serious and can be life-threatening or fatal. During the course of treatment, fever (temperature = 38.3°C) and neutropenia (absolute neutrophil count < 500/μL) require prompt assessment, blood cultures from each lumen of a central line, and prompt treatment with empiric broad-spectrum antibiotics. Patients receiving ALL treatment must receive prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). Trimethoprim-sulfamethoxazole given twice each day on 2 or 3 consecutive days per week is the drug of choice. Patients nonimmune to varicella are at risk for very serious—even fatal—infection. Such patients should receive varicella-zoster immune globulin (VZIG) within 72 hours after exposure and treatment with intravenous acyclovir for active infection.

Prognosis

Cure rates depend on specific prognostic features present at diagnosis, biologic features of the leukemic blast, and the response to therapy. Two of the most important features are WBC count and age. Children aged 1–9 years whose diagnostic WBC count is less than 50,000/μL, standard risk ALL, have an leukemia-free survival of greater than 90% range, while children 10 years or older have about an 88% chance of being cured the first time through therapy. MRD measurements are used to determine both the rapidity of response as well as the depth of remission attained at the end of induction (first 4–6 weeks of therapy). Patients with very low levels or no MRD at the end of induction will have a superior leukemia-free survival as compared to other patients with similar initial risk factors but a higher MRD level. On the flip side, by identifying patients with an increased risk of relapse at end induction, more intensified therapy can be delivered in order to overcome this negative prognostic feature and increase their ultimate chance at staying leukemia free.

Certain chromosomal abnormalities present in the leukemic blasts at diagnosis influence prognosis. Patients with t(9;22), the Philadelphia chromosome, had a poor chance of cure in the past, but as discussed earlier in this chapter, they now have improved outcome with the incorporation of a directed TKI. Likewise, infants younger than 6 months with 11q23 rearrangements have a poor chance of cure with conventional chemotherapy. In contrast, patients whose blasts are hyperdiploid (containing > 50 chromosomes instead of the normal 46) with trisomies of chromosomes 4, and 10, and patients whose blasts have a t(12;21) and ETV6-AML1 rearrangement have a greater chance of cure, approaching 95%–97% event-free survival (EFS), than do children without these characteristics.

ACUTE MYELOID LEUKEMIA

General Considerations

Approximately 500 new cases of AML occur per year in children and adolescents in the United States. Although AML accounts for only 25% of all leukemias in this age group, it is responsible for at least one-third of deaths from leukemia in children and teenagers. Congenital conditions associated with an increased risk of AML include Diamond-Blackfan anemia; neurofibromatosis (NF); Down; Wiskott-Aldrich, Kostmann, and Li-Fraumeni syndromes; as well as chromosomal instability syndromes such as Fanconi anemia. Acquired risk factors include exposure to ionizing radiation, cytotoxic chemotherapeutic agents, and benzenes. However, the vast majority of patients have no identifiable risk factors. Historically, the diagnosis of AML was based almost exclusively on morphology and immunohistochemical staining of the leukemic cells. Immunophenotypic, cytogenetic, and molecular analyses are increasingly important in confirming the diagnosis of AML and subclassifying it into biologically distinct subtypes that have therapeutic and prognostic implications. Recently the World Health Organization (WHO) classification was published to describe AML as AML with recurrent genetic abnormalities with a list of genetic abnormalities sufficient to diagnose AML and then AML not otherwise specified with morphologic descriptions of AML including similar to the FAB classification (Table 31–1). Cytogenetic clonal abnormalities occur in 80% of patients with AML and are often predictive of outcome.

Aggressive induction therapy currently results in a 75%–85% complete remission rate. However, long-term survival has improved only modestly to approximately 50%, despite the availability of several effective agents, improvements in supportive care, and increasingly intensive therapies.

Clinical Findings

The clinical manifestations of AML commonly include anemia (44%), thrombocytopenia (33%), and neutropenia (69%). Symptoms may be few and innocuous or may be life threatening. The median hemoglobin value at diagnosis is 7 g/dL, and platelets usually number fewer than 50,000/μL. Frequently the absolute neutrophil count is under 1000/μL, although the total WBC count is over 100,000/μL in 25% of patients at diagnosis.

Hyperleukocytosis may be associated with life-threatening complications. Venous stasis and sludging of blasts in small vessels cause hypoxia, hemorrhage, and infarction, most notably in the lung and CNS. This clinical picture is a medical emergency requiring rapid intervention, such as leukapheresis, to decrease the leukocyte count. CNS leukemia is present in 5%–15% of patients at diagnosis, a higher rate of initial involvement than in ALL. Certain subtypes, such as myelomonocytic and monocytic/monoblastic leukemia, have a higher likelihood of meningeal infiltration than do other subtypes. Additionally, clinically significant coagulopathy may be present at diagnosis in patients with these two subtypes as well as acute promyelocytic leukemia. This problem manifests as bleeding or an abnormal disseminated intravascular coagulation screen and should be at least partially corrected prior to initiation of treatment, which may transiently exacerbate the coagulopathy.

Treatment

A. Specific Therapy

AML is less responsive to treatment than ALL and requires more intensive chemotherapy. Toxicities from therapy are common and likely to be life threatening; therefore, treatment should be undertaken only at a tertiary pediatric oncology center.

Current AML protocols rely on intensive administration of anthracyclines, cytarabine, and etoposide for induction of remission. After remission is obtained, patients who have a matched sibling donor undergo allogeneic bone marrow transplant while those without an appropriate related donor are treated with additional cycles of aggressive chemotherapy for a total of four to five cycles. Inv16 and t(8;21) herald a more responsive subtype of AML. In patients with a rapid response to induction chemotherapy, intensive chemotherapy alone may be curative in patients whose blasts harbor these cytogenetic abnormalities. Additional recognized genetic risk factors that carry a poor outcome for children with AML include monosomy 7 and FLT3 internal tandem duplications (ITDs). HSCT is recommended for all these patients, using either a related or unrelated donor. Trials with risk grouping are ongoing as more is understood about the varying biologic factors.

The biologic heterogeneity of AML is becoming increasingly important therapeutically. The M3 subtype, associated with t(15;17) demonstrated either cytogenetically or molecularly, is currently treated with all trans-retinoic acid in addition to chemotherapy with high-dose cytarabine and daunorubicin. All trans-retinoic acid leads to differentiation of promyelocytic leukemia cells and can induce remission, but cure requires conventional chemotherapy as well. The use of arsenic trioxide has also been investigated in the treatment of this subtype of AML with favorable results. This subtype has an increased EFS over other AML subtypes.

Another biologically distinct subtype of AML occurs in children with Down syndrome, almost exclusively megakaryocytic AML. Using less intensive treatment, remission induction rate and overall survival of these children are dramatically superior to non–Down syndrome children with AML. It is important that children with Down syndrome receive appropriate treatment specifically designed to be less intensive due to their increased rate of toxicity with chemotherapeutic agents.

As with ALL, newer biologic agents with more specific targeting are available and undergoing clinical trials. One such agent, sorafenib, appears to be active against AML with Flt3 ITDs. Combining sorafenib with AML therapy has been useful in relapsed disease and is now being studied in to upfront trials.

B. Supportive Care

Tumor lysis syndrome rarely occurs during induction treatment of AML. Nevertheless, when the diagnostic WBC cell count is greater than 100,000/μL or significant adenopathy or organomegaly is present, one should maintain brisk urine output, and follow potassium, uric acid, and phosphorous laboratory values closely. Hyperleukocytosis (WBC > 100,000/μL) is a medical emergency and, in a symptomatic patient, requires rapid intervention such as leukapheresis to rapidly decrease the number of circulating blasts and thereby decrease hyperviscosity. Delaying transfusion of packed RBCs until the WBC can be decreased to below 100,000/μL avoids exacerbating hyperviscosity. It is also important to correct the coagulopathy commonly associated with M3, M4, or M5 subtypes prior to beginning induction chemotherapy. As with the treatment of ALL, all blood products should be irradiated and leukodepleted; Pneumocystis prophylaxis must be administered during treatment and for several weeks afterward; patients not immune to varicella must receive VZIG within 72 hours of exposure and prompt treatment with intravenous acyclovir for active infection.

Onset of fever (temperature ≥ 38.3°C) or chills associated with neutropenia requires prompt assessment, blood cultures from each lumen of a central venous line, other cultures such as throat or urine as appropriate and prompt initiation of broad-spectrum intravenous antibiotics. Infections in this population of patients can rapidly become life-threatening. Because of the high incidence of invasive fungal infections, there should be a low threshold for initiating antifungal therapy. Filgrastim (granulocyte colony-stimulating factor) may be used to stimulate granulocyte recovery during the treatment of AML and results in shorter periods of neutropenia and hospitalization. It must be stressed that the supportive care for this group of patients is as important as the leukemia-directed therapy and that this treatment should be carried out only at a tertiary pediatric cancer center.

Prognosis

Published results from various centers show a 50%–60% survival rate at 5 years following first remission for patients who do not have matched sibling hematopoietic stem cell donors. Patients with matched sibling donors fare slightly better, with 5-year survival rates of 60%–70% after allogeneic HSCT.

As treatment becomes more sophisticated, outcome is increasingly related to the subtype of AML. Currently, AML in patients with t(8;21), t(15;17), inv 16, or Down syndrome has the most favorable prognosis, with 65%–75% long-term survival using modern treatments, including chemotherapy alone. The least favorable outcome occurs in AML patients with monosomy 7 or 5, 7q, 5q–, 11q23 cytogenetic abnormalities, or FLT 3 mutations with ITD.

MYELOPROLIFERATIVE DISEASES

Myeloproliferative diseases in children are relatively rare. They are characterized by ineffective hematopoiesis that results in excessive peripheral blood counts. The three most important types are chronic myelogenous leukemia (CML), which accounts for less than 5% of the childhood leukemias, transient myeloproliferative disorder in children with Down syndrome, and juvenile myelomonocytic leukemia (Table 31–2).

1. Chronic Myelogenous Leukemia

General Considerations

Chronic myelogenous leukemia (CML) with translocation of chromosomes 9 and 22 (the Philadelphia chromosome, Ph+) is identical to adult Ph+CML. Translocation 9;22 results in the fusion of the BCR gene on chromosome 22 and the ABL gene on chromosome 9. The resulting fusion protein is a constitutively active tyrosine kinase that interacts with a variety of effector proteins and allows for deregulated cellular proliferation, decreased adherence of cells to the bone marrow extracellular matrix, and resistance to apoptosis. The disease usually progresses within 3 years to an accelerated phase and then to a blast crisis. It is generally accepted that Ph+ cells have an increased susceptibility to the acquisition of additional molecular changes that lead to the accelerated and blast phases of disease.

Clinical Findings

Patients with CML may present with nonspecific complaints similar to those of acute leukemia, including bone pain, fever, night sweats, and fatigue. However, patients can also be asymptomatic. Patients with a total WBC count of more than 100,000/μL may have symptoms of leukostasis, such as dyspnea, priapism, or neurologic abnormalities. Physical findings may include fever, pallor, ecchymoses, and hepatosplenomegaly. Anemia, thrombocytosis, and leukocytosis are frequent laboratory findings. The peripheral smear is usually diagnostic, with a characteristic predominance of myeloid cells in all stages of maturation, increased basophils and relatively few blasts but needs to be confirmed at a pediatric center with hematology/oncology expertise.

Treatment & Prognosis

Historically, hydroxyurea or busulfan has been used to reduce or eliminate Ph+ cells, and HSCT was the only consistently curative intervention. Reported survival rates for patients younger than 20 years transplanted in the chronic phase from matched-related donors are 70%–80%. Unrelated stem cell transplants result in survival rates of 50%–65%.

The understanding of the molecular mechanisms involved in the pathogenesis of CML has led to the rational design of molecularly targeted therapy. Imatinib mesylate (Gleevec) is a TKI that has had dramatic success in the treatment of CML, with most adults and children achieving cytogenetic remission. There are now newer, more targeted TKIs including dasatinib, erlotinib, nilotinib, and ponatinib. These medications in adults have an increased incidence of molecular remissions and may be all that is required for long-term survival in adults. The durability of the remission for children with TKIs therapy alone is unclear but is now the accepted upfront therapy.

2. Transient Myeloproliferative Disorder

Transient myeloproliferative disorder is unique to patients with trisomy 21 or mosaicism for trisomy 21. It is characterized by uncontrolled proliferation of blasts, usually of megakaryocytic origin, during early infancy and spontaneous resolution. The pathogenesis of this process is not well understood, although mutations in the GATA1 gene have recently been implicated as initial events.

Although the true incidence is unknown, it is estimated to occur in up to 10% of patients with Down syndrome. Despite the fact that the process usually resolves by 3 months of age, organ infiltration may cause significant morbidity and mortality.

Patients can present with hydrops fetalis, pericardial or pleural effusions, or hepatic fibrosis. More frequently, they are asymptomatic or only minimally ill. Therefore, treatment is primarily supportive. Patients without symptoms are not treated, and those with organ dysfunction receive low doses of chemotherapy or leukapheresis (or both) to reduce peripheral blood blast counts. Although patients with transient myeloproliferative disorder have apparent resolution of the process, approximately 30% go on to develop acute megakaryoblastic leukemia within 3 years.

3. Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) accounts for approximately one-third of the myelodysplastic and myeloproliferative disorders in childhood. Patients with neurofibromatosis type 1 (NF-1) are at higher risk of JMML than the general population. It typically occurs in infants and very young children and is occasionally associated with monosomy 7 or a deletion of the long arm of chromosome 7.

Patients with JMML present similarly to those with other hematopoietic malignancies, with lymphadenopathy, hepatosplenomegaly, skin rash, or respiratory symptoms. Patients may have stigmata of NF-1 with neurofibromas or café au lait spots. Laboratory findings include anemia, thrombocytopenia, leukocytosis with monocytosis, and elevated fetal hemoglobin.

The results of chemotherapy for children with JMML have been disappointing, with estimated survival rates of less than 30%. Approximately 40%–45% of patients are projected to survive long term using HSCT, although optimizing conditioning regimens and donor selection may improve these results.

BRAIN TUMORS

General Considerations

The classic triad of morning headache, vomiting, and papilledema is present in fewer than 30% of children at presentation. School failure and personality changes are more common in older children while irritability, failure to thrive, and delayed development are common in very young children with brain tumors. Recent-onset head tilt can result from a posterior fossa tumor.

Brain tumors are the most common solid tumors of childhood, accounting for 1500–2000 new malignancies in children each year in the United States and for 25%–30% of all childhood cancers. In general, children with brain tumors have a better prognosis than do adults. Favorable outcome occurs most commonly with low-grade and fully resectable tumors as well as with chemoradiation responsive tumors such as medulloblastoma. Unfortunately, cranial irradiation in young children can have significant neuropsychological, intellectual, and endocrinologic sequelae.

Brain tumors in childhood are biologically and histologically heterogeneous, ranging from low-grade localized lesions to high-grade tumors with neuraxis dissemination. High-dose systemic chemotherapy is used frequently, especially in young children with high-grade tumors, in an effort to delay, decrease, or completely avoid cranial irradiation. Such intensive treatment may be accompanied by autologous HSCT or peripheral stem cell reconstitution.

The causes of most pediatric brain tumors are unknown. The risk of developing astrocytomas is increased in children with NF or tuberous sclerosis. Several studies show that some childhood brain tumors occur in families with increased genetic susceptibility to childhood cancers in general, brain tumors, or leukemia and lymphoma. A higher incidence of seizures has been observed in relatives of children with astrocytoma. The risk of developing a brain tumor is increased in children who received cranial irradiation for treatment of meningeal leukemia. All children with gliomas and meningiomas should be screened for NF-1. In children with meningiomas, without the skin findings of NF-1, NF-2, and von Hippel-Lindau syndrome should be considered. Inherited germline mutations are possible in atypical teratoid/rhabdoid tumors (AT/RTs) and in choroid plexus carcinomas. The syndrome of constitutional mismatch repair deficiency (CMMRD) should be considered carefully in the child presenting with a glioma who has been previously diagnosed with leukemia/lymphoma. There are treatment implications in recognizing CMMRD as these patients require additional life-long screening and may have an improved response to immunotherapy. Careful family histories should be taken in these tumors and genetic counseling considered if this is indicative of CMMRD, familial polyposis, or Li-Fraumeni syndrome (LFS).

Because pediatric brain tumors are rare, they are often misdiagnosed or diagnosed late; most pediatricians see no more than two children with brain tumors during their careers.

Clinical Findings

A. Symptoms and Signs

Clinical findings at presentation vary depending on the child’s age and the tumor’s location. Children younger than 2 years more commonly have infratentorial tumors. Children with such tumors usually present with nonspecific symptoms such as vomiting, unsteadiness, lethargy, and irritability. Signs may be surprisingly few or may include macrocephaly, ataxia, hyperreflexia, and cranial nerve palsies. Because the head can expand in young children, papilledema is often absent. Measuring head circumference and observing gait are essential in evaluating a child for possible brain tumor. Eye findings and apparent visual disturbances such as difficulty tracking can occur in association with optic pathway tumors such as optic glioma. Optic glioma occurring in a young child is often associated with NF. These eye and visual changes have some potential for improvement with therapy, although permanent loss of vision may occur with these tumors. These patients should be closely followed by ophthalmology for potential eye patching, eye muscle surgery, or specialty glasses with prisms to manage double vision and vision loss.

Older children more commonly have supratentorial tumors, which are associated with headache, visual symptoms, seizures, and focal neurologic deficits. Initial presenting features are often nonspecific. School failure and personality changes are common. Vaguely described visual disturbance is often present, but the child must be directly asked. Headaches are common, but they often will not be predominantly in the morning. The headaches may be confused with migraine. If neurologic symptoms are severe, persistent, or worsening with time, a magnetic resonance imaging (MRI) of the brain would be recommended. Focal neurologic deficits or the presence of any indications of increased intracranial pressure (ie, papilledema) should be investigated by an MRI or a computed tomography (CT) if MRI is not readily available.

Older children with infratentorial tumors characteristically present with symptoms and signs of hydrocephalus, which include progressively worsening morning headache and vomiting, gait unsteadiness, double vision, and papilledema. Cerebellar astrocytomas enlarge slowly, and symptoms may worsen over several months. Morning vomiting may be the only symptom of posterior fossa ependymomas, which originate in the floor of the fourth ventricle near the vomiting center. Children with brainstem tumors may present with facial and extraocular muscle palsies, ataxia, and hemiparesis; hydrocephalus occurs in approximately 25% of these patients at diagnosis.

B. Imaging and Staging

In addition to the tumor biopsy, neuraxis imaging studies are obtained to determine whether dissemination has occurred. It is unusual for brain tumors in children and adolescents to disseminate outside the CNS.

MRI has become the preferred diagnostic study for pediatric brain tumors. MRI provides better definition of the tumor and delineates indolent gliomas that may not be seen on CT scan. In contrast, a CT scan can be done in less than 10 minutes—as opposed to the 30 minutes or more required for an MRI scan—and is still useful if an urgent diagnostic study is necessary or to detect calcification of a tumor. Both scans are generally done with and without contrast enhancement. Contrast enhances regions where the blood-brain barrier is disrupted. Postoperative scans to document the extent of tumor resection should be obtained within 48 hours after surgery to avoid postsurgical enhancement.

Imaging of the entire neuraxis and CSF cytologic examination should be part of the diagnostic evaluation for patients with tumors such as medulloblastoma, ependymoma, and pineal region tumors. Diagnosis of neuraxis drop metastases (tumor spread along the neuraxis) can be accomplished by gadolinium-enhanced MRI incorporating sagittal and axial views. MRI of the spine should be obtained preoperatively in all children with midline tumors of the fourth ventricle or cerebellum. A CSF sample should be obtained during the diagnostic surgery or, if that is not possible, 7–10 days after the surgery. Lumbar CSF is preferred over ventricular CSF for cytologic examination. Levels of biomarkers in the blood and CSF, such as human chorionic gonadotropin and α-fetoprotein, may be helpful in diagnosis and follow-up. Both human chorionic gonadotropin and α-fetoprotein should be obtained from the blood preoperatively for all pineal and suprasellar tumors, and if positive, the need for an operation should be discussed with a neuro-oncologist.

Except in emergencies, it is recommended that the neurosurgeon discuss staging and sample collection with an oncologist before surgery in a child newly presenting with a scan suggestive of brain tumor.

C. Classification

About 50% of the common pediatric brain tumors occur above the tentorium and 50% in the posterior fossa. In the very young child, posterior fossa tumors are more common. Most childhood brain tumors can be divided into two categories according to the cell of origin: (1) glial tumors, such as astrocytomas and ependymomas, or (2) embryonal tumors, such as medulloblastoma and AT/teratoid tumors. Some tumors contain both glial and neural elements (eg, ganglioglioma). A group of less common CNS tumors does not fit into either category (ie, craniopharyngiomas, germ cell tumors, choroid plexus tumors, and meningiomas). Low- and high-grade tumors are found in most categories. Table 31–3 lists the locations and frequencies of the common pediatric brain tumors.

Astrocytoma is the most common brain tumor of childhood. Most are juvenile pilocytic astrocytoma (WHO grade I) found in the posterior fossa with a bland cellular morphology and few or no mitotic figures. Low-grade astrocytomas occur in many cases, especially in the cerebellum curable by complete surgical excision alone. Upfront chemotherapy may be effective alone in about 40%–50% of low-grade astrocytomas but many will need to be treated multiple times. The recent advent of targeted therapy for mutations common in these tumors offers the potential for better outcomes.

Medulloblastoma are the most common high-grade brain tumors in children. These tumors usually occur in the first decade of life, with a peak incidence between ages 5 and 10 years and a female-male ratio of 2.1:1.3. The tumors typically arise in the midline cerebellar vermis, with variable extension into the fourth ventricle. Neuraxis dissemination at diagnosis affects from 10% to 46% of patients. Prognostic factors are outlined in Table 31–4. Determination of risk to date has largely used histology, age, and stage, but molecular classifications will be increasingly used to determine therapy.

Brainstem tumors are third in frequency of occurrence in children. They are frequently of astrocytic origin and often are high grade. Children with tumors that diffusely infiltrate the brainstem and involve primarily the pons (diffuse intrinsic pontine gliomas) have a long-term survival rate of less than 5%. There has been considerable biologic discovery, largely from autopsy samples, in diffuse pontine gliomas in the very recent past. The discovery that most pontine gliomas have the histone mutation H3 K27M and that these diffuse gliomas can occur anywhere in the midline has led to a change in their classification. Diffuse pontine intrinsic gliomas are now largely subsumed, depending on mutational status in the new classification of diffuse midline glioma H3 K27M. It is hoped that the understanding of the mutational drivers in this tumor will result in improved therapy. Brainstem tumors that occur above or below the pons grow in an eccentric or cystic manner and do not have the K27M mutation have a somewhat better outcome. Exophytic tumors in this location may be amenable to surgery. Generally, brainstem tumors are treated without a tissue diagnosis although improved safety in the biopsy of brainstem tumors is increasing diagnostic sampling of these patients.

Other brain tumors such as ependymomas, germ cell tumors, choroid plexus tumors, and craniopharyngiomas are less common, and each is associated with unique diagnostic and therapeutic challenges.

Treatment

A. Supportive Care

Dexamethasone should be started prior to initial surgery to help relieve symptoms. There is little proof that very high doses of dexamethasone have any advantage and we have now adopted dosages of 4 mg every 6 hours in those children greater than 4 years and 2 mg every 6 hours in those less than 4. Anticonvulsants should be started if the child has had a seizure or if the surgical approach is likely to induce seizures. Levetiracetam (Keppra) is now the preferred anticonvulsant in this population as it does not induce liver enzymes. Because postoperative treatment of young children with high-grade brain tumors incorporates increasingly more intensive systemic chemotherapy, consideration should also be given to the use of prophylaxis for Pneumocystis infection. Dexamethasone potentially reduces the effectiveness of chemotherapy and should be discontinued as soon after surgery as possible.

Optimum care for the pediatric patient with a brain tumor requires a multidisciplinary team including subspecialists in pediatric neurosurgery, neuro-oncology, neurology, endocrinology, neuropsychology, radiation therapy, and rehabilitation medicine, as well as highly specialized nurses, social workers, and staff in physical therapy, occupational therapy, and speech and language science.

B. Specific Therapy

The goal of treatment is to eradicate the tumor with the least short- and long-term morbidity. Long-term neuropsychological morbidity becomes an especially important issue related to deficits caused by the tumor itself and the sequelae of treatment. Meticulous surgical removal of as much tumor as possible is generally the preferred initial approach. Technologic advances in the operating microscope, the ultrasonic tissue aspirator, and the CO₂ laser (which is less commonly used in pediatric brain tumor surgery); the accuracy of computerized stereotactic resection; and the availability of intraoperative monitoring techniques such as evoked potentials and electrocorticography have increased the feasibility and safety of surgical resection of many pediatric brain tumors. Second-look surgery after chemotherapy is increasingly being used when tumors are incompletely resected at initial surgery.

Radiation therapy for pediatric brain tumors is in a state of evolution. For tumors with a high probability of neuraxis dissemination (eg, medulloblastoma), craniospinal irradiation is still standard therapy in children older than 3 years. Attempts at elimination of craniospinal radiation for certain types of intracranial germ-cell tumors and further reduction of craniospinal radiation dosing in medulloblastoma have not been successful. In others (eg, ependymoma), craniospinal irradiation has been abandoned because neuraxis dissemination at first relapse is rare. Conformal radiation and the use of three-dimensional treatment planning are now in routine. Proton beam radiation has become routine in some centers although safety studies in comparison to photon radiation are lacking in childhood.

Chemotherapy is effective in treating low-grade and malignant astrocytomas and medulloblastomas. Intensive chemotherapy is effective in a minority of children AT/RTs. The utility of chemotherapy in ependymoma is being reexplored in national trials. A series of brain tumor protocols for children younger than 3 years involved administering intensive chemotherapy after tumor resection and delaying or omitting radiation therapy. The results of these trials have generally continued to be disappointing but have taught valuable lessons regarding the varying responses to chemotherapy of different tumor types. Superior results seem to have been obtained in the very young with high-dose chemotherapy strategies with stem cell rescue often followed by conformal radiotherapy. Conformal techniques allow the delivery of radiation to strictly defined fields and may limit side effects.

Perhaps the most exciting development in pediatric neuro-oncology is the development of biologically and clinically relevant subclassifications in both medulloblastoma and ependymoma. This development will drive a new generation of targeted therapy aimed at these biologically defined groups. The consensus definition of four biologically defined entities in medulloblastoma, including the Wnt and SHH groups, is the best example of this. New studies based on this new-defined biology are ongoing.

In older children with malignant glioma, the current approach is surgical resection of the tumor and combined-modality treatment with irradiation and intensive chemotherapy. It has recently been realized there is considerable heterogeneity in pediatric high-grade gliomas. Some, such as the congenital tumors, may do well with relatively modest therapy. Others, such as epithelioid glioblastomas, may harbor BRAF mutations and may be targetable with specific agents. Generally, however, the prognosis is poor for children with high-grade gliomas, and there has been little progress in finding better chemotherapeutic agents and strategies for most children with these devastating tumors.

The treatment of low-grade astrocytomas with chemotherapy has likewise shown only disappointing progress. However, there are potentially exciting targeted agents in ongoing, and completed but unreported, low-grade astrocytoma trials that have the potential to greatly improve outcomes for these patients.

Prognosis

Despite improvements in surgery and radiation therapy, the outlook for cure remains poor for children with high-grade glial tumors. For children with high-grade gliomas, an early CCG study showed a 45% progression-free survival rate for children who received radiation therapy and chemotherapy, but this may have been due to the inclusion of low-grade patients. More recent studies would suggest survival rate of less than 10%. The major exception to this is congenital glioblastomas that appear to have a much more favorable prognosis. Biologic factors that may affect survival are being increasingly recognized. The prognosis for diffuse pontine gliomas remains very poor, with the standard therapy of radiation alone, being only palliative.

The 5- and even 10-year survival rate for low-grade astrocytomas of childhood is 60%–90%. However, prognosis depends on both site and grade and, as it is increasingly realized, on biology. A child with a pilocytic astrocytoma of the cerebellum has a considerably better prognosis than a child with a fibrillary astrocytoma of the cerebral cortex. For recurrent or progressive low-grade astrocytoma of childhood, relatively moderate chemotherapy may improve the likelihood of survival.

Conventional craniospinal irradiation for children with low-stage medulloblastoma results in survival rates of 60%–90%. Ten-year survival rates are lower (40%–60%). Chemotherapy allows a reduction in the craniospinal radiation dose while improving survival rates for average-risk patients (86% survival at 5 years on the most recent COG average-risk protocol). However, even reduced-dose craniospinal irradiation has an adverse effect on intellect, especially in children younger than 7 years. Five-year survival rates for high-risk medulloblastoma have been 25%–40%, but this may be improved with the introduction of more chemotherapy during radiation although this still awaits the reporting of formal trials.

The previously poor prognosis for children with AT/RTs seems improved by intensive multimodality therapy in a national study.

Major challenges remain in treating brain tumors in children younger than 3 years and in treating diffuse midline glioma K27M and malignant gliomas. Given the inadequate results for treatment of childhood brain tumors, reduction of therapy trials should be fully evaluated and considered in the context of recent treatment failures using reduced therapy regimens. The increasing emphasis is on the quality of life of survivors, not just the survival rate.

LYMPHOMAS & LYMPHOPROLIFERATIVE DISORDERS

The term lymphoma refers to a malignant proliferation of lymphoid cells, usually in association with and arising from lymphoid tissues (ie, lymph nodes, thymus, spleen). In contrast, the term leukemia refers to a malignancy arising from the bone marrow, which may include lymphoid cells. Because lymphomas can involve the bone marrow, the distinction between the two can be confusing. The diagnosis of lymphoma is a common one among childhood cancers, accounting for 10%–15% of all malignancies. The most common form is Hodgkin disease, which represents nearly one-half of all cases. The remaining subtypes, referred to collectively as non-Hodgkin lymphoma (NHL), are divided into four main groups: lymphoblastic lymphoma (LL), small noncleaved cell lymphoma, large B-cell lymphoma (LBCL), and anaplastic large cell lymphoma (ALCL).

In contrast to lymphomas, lymphoproliferative disorders (LPDs) are quite rare in the general population. Most are polyclonal, nonmalignant (though often life-threatening) accumulations of lymphocytes that occur when the immune system fails to control virally transformed lymphocytes. However, a malignant monoclonal proliferation can also arise. The posttransplant LPDs arise in patients who are immunosuppressed to prevent solid organ or bone marrow transplant rejection, particularly liver and heart transplant patients. Spontaneous LPDs occur in immunodeficient individuals and, less commonly, in immunocompetent persons.

1. Hodgkin Lymphoma

General Considerations

Children with Hodgkin lymphoma have a better response to treatment than do adults, with greater than 90% 5- to 10-year overall survival rate when all stages are evaluated. Although adult therapies are applicable, the management of Hodgkin lymphoma in children younger than 18 years frequently differs. Because excellent disease control can result from several different therapeutic approaches, selection of staging procedures (radiographic, surgical, or other procedures to determine additional locations of disease) and treatment are often based on the potential long-term toxicity associated with the intervention.

Although Hodgkin lymphoma represents 50% of the lymphomas of childhood, only 15% of all cases occur in children aged 16 years or younger. Children younger than 5 years account for 3% of childhood cases. There is a 4:1 male predominance in the first decade. Notably, in underdeveloped countries the age distribution is quite different, with a peak incidence in younger children.

Hodgkin disease is subdivided into four histologic groups, and the distribution in children parallels that in adults: lymphocyte-predominant (10%–20%); nodular sclerosing (40%–60%) (increases with age); mixed cellularity (20%–40%); and lymphocyte-depleted (5%–10%). Prognosis is independent of subclassification, with appropriate therapy based on stage (see section Staging).

Clinical Findings

A. Symptoms and Signs

Children with Hodgkin lymphoma usually present with painless cervical adenopathy. The lymph nodes often feel firmer than inflammatory nodes and have a rubbery texture. They may be discrete or matted together and are not fixed to surrounding tissue. The growth rate is variable, and involved nodes may wax and wane in size over weeks to months.

As Hodgkin lymphoma nearly always arises in lymph nodes and spreads to contiguous nodal groups, a detailed examination of all nodal sites is mandatory. Lymphadenopathy is common in children, so the decision to perform biopsy is often difficult or delayed for a prolonged period. Indications for consideration of early lymph node biopsy include lack of identifiable infection in the region drained by the enlarged node, a node greater than 2 cm in size, supraclavicular adenopathy or abnormal chest radiograph, and lymphadenopathy increasing in size after 2 weeks or failing to resolve within 4–8 weeks.

Constitutional symptoms occur in about one-third of children at presentation. Symptoms of fever greater than 38.0°C, weight loss of 10% in the previous 6 months, and drenching night sweats are defined by the Ann Arbor staging criteria as B symptoms. The A designation refers to the absence of these symptoms. B symptoms are of prognostic value, and more aggressive therapy is usually required for cure. Generalized pruritus and pain with alcohol ingestion may also occur.

One-half of patients have asymptomatic mediastinal disease (adenopathy or anterior mediastinal mass), although symptoms due to compression of vital structures in the thorax may occur. A chest radiograph should be obtained when lymphoma is being considered. The mediastinum must be evaluated thoroughly before any surgical procedure is undertaken to avoid airway obstruction or cardiovascular collapse during anesthesia and possible death. Splenomegaly or hepatomegaly is generally associated with advanced disease.

B. Laboratory Findings

The CBC is usually normal, although anemia, neutrophilia, eosinophilia, and thrombocytosis may be present. The erythrocyte sedimentation rate (ESR) and other acute-phase reactants are often elevated and can serve as markers of disease activity. Immunologic abnormalities occur, particularly in cell-mediated immunity, and anergy is common in patients with advanced-stage disease at diagnosis. Autoantibody phenomena such as hemolytic anemia and an idiopathic thrombocytopenic purpura–like picture have been reported.

C. Staging

Staging of Hodgkin lymphoma determines treatment and prognosis. The most common staging system is the Ann Arbor classification that describes extent of disease by I–IV and symptoms by an A or a B suffix (eg, stage IIIB). A systematic search for disease includes chest radiography; CT scan of the chest, abdomen, and pelvis; and bilateral bone marrow aspirates and biopsies. In recent years, positron emission tomography (PET) is increasingly used in the staging and follow-up of patients with Hodgkin disease.

D. Pathologic Findings

The diagnosis of Hodgkin lymphoma requires the histologic presence of the Reed-Sternberg cell or its variants in tissue. Reed-Sternberg cells are germinal-center B cells that have undergone malignant transformation. Nearly 20% of these tumors in developed countries are positive for EBV. EBV has been linked to Hodgkin disease, and the large portion of Hodgkin patients with increased EBV titers suggests that EBV activation may contribute to the onset of Hodgkin lymphoma.

Treatment & Prognosis

Treatment decisions are based on presence of B symptoms, stage, tumor bulk, and number of involved nodal regions. To achieve long-term disease-free survival while minimizing treatment toxicity, Hodgkin disease is increasingly treated by chemotherapy alone—and less often by radiation therapy.

Several combinations of chemotherapeutic agents are effective, and treatment times are relatively short compared with pediatric oncology protocols for leukemia. Clinical trials have shown that only 9 weeks of therapy with AV-PC (Adriamycin [doxorubicin], vincristine, prednisone, and cyclophosphamide) is sufficient to induce a complete response in patients with low-risk Hodgkin lymphoma. Two additional drugs, bleomycin and etoposide, are currently added in the treatment of intermediate-risk patients for a total of 4–6 months of therapy for patients with intermediate-risk disease. The removal of involved field irradiation in patients with intermediate-risk Hodgkin lymphoma who respond early to chemotherapy has been shown to maintain excellent outcomes. Combined-modality therapy with chemotherapy and irradiation is used in advanced disease.

Current treatment gives an overall 5-year survival of 90–95% to children with stages I and II Hodgkin lymphoma. Two-thirds of all relapses occur within 2 years after diagnosis, and relapse rarely occurs beyond 4 years. Although patients with advanced disease (stages III and IV) have slightly lower overall survival, more patients are becoming long-term survivors of Hodgkin disease. As a result, the risk of secondary malignancies, both leukemias and solid tumors, is becoming more apparent and is higher in patients receiving radiation therapy. Therefore, elucidating the optimal treatment strategy that minimizes such risk should be the goal of future studies.

Relapsed Hodgkin lymphoma remains responsive to treatment with chemotherapy and radiation therapy. Autologous HSCT after remission is achieved is used as consolidative therapy to minimize the risk of subsequent relapse. Allogeneic HSCT is reserved for second or greater relapse as it carries increased risks of complications and may not offer added survival benefit.

Targeted therapies are being tested for children with high-risk Hodgkin lymphoma, including antibody conjugates targeting CD30, a transmembrane receptor highly expressed in Hodgkin lymphoma. A current COG trial is investigating if an anti-CD30 murine/human chimeric monoclonal antibody linked to monomethyl auristatin E is able to target the Reed-Stenberg cell in newly diagnosed high-risk Hodgkin lymphoma. Checkpoint inhibitors pembrolizumab and nivolumab that block PD-1 have recently been approved for recurrent Hodgkin lymphoma, as the tumor cells consistently express their target PDL-1 and PDL-2.

2. Non-Hodgkin Lymphoma

General Considerations

Non-Hodgkin lymphomas (NHLs) are a diverse group of cancers accounting for 5%–10% of malignancies in children younger than 15 years. About 500 new cases arise per year in the United States. The incidence of NHLs increases with age. Children aged 15 years or younger account for only 3% of all cases of NHLs, and the disease is uncommon before age 5 years. There is a male predominance of approximately 3:1. In equatorial Africa, NHLs cause almost 50% of pediatric malignancies due to EBV and the associated Burkitt lymphoma (BL).

Most children who develop NHL are immunologically normal. However, children with congenital or acquired immune deficiencies (eg, Wiskott-Aldrich syndrome, severe combined immunodeficiency syndrome, X-linked lymphoproliferative syndrome, human immunodeficiency virus [HIV] infection, immunosuppressive therapy following solid-organ or marrow transplantation) have an increased risk of developing NHLs. It has been estimated that their risk is 100–10,000 times that of age-matched control subjects.

Animal models suggest a viral contribution to the pathogenesis of NHL, and there is evidence of viral involvement in human NHL as well. In equatorial Africa, 95% of BLs contain DNA from the EBV. But in North America, less than 20% of Burkitt tumors contain the EBV genome. The role of other viruses (eg, human herpes viruses 6 and 8), disturbances in host immunologic defenses, chronic immunostimulation, and specific chromosomal rearrangements as potential triggers in the development of NHL are under investigation.

Unlike adult NHL, virtually all childhood NHLs are rapidly proliferating, high-grade, diffuse malignancies. These tumors exhibit aggressive behavior but are usually very responsive to treatment. Nearly all pediatric NHLs are histologically classified into four main groups: LL, small noncleaved cell lymphoma (BL and Burkitt-like lymphoma [BLL]), LBCL, and ALCL. Immunophenotyping and cytogenetic features, in addition to clinical presentation, are increasingly important in the classification, pathogenesis, and treatment of NHLs. Comparisons of pediatric NHLs are summarized in Table 31–5.

Clinical Findings

A. Symptoms and Signs

Childhood NHLs can arise in any site of lymphoid tissue, including the lymph nodes, thymus, liver, and spleen. Common extralymphatic sites include bone, bone marrow, CNS, skin, and testes. Signs and symptoms at presentation are determined by the location of lesions and the degree of dissemination. Because NHL usually progresses very rapidly, the duration of symptoms is quite brief, from days to a few weeks. Nevertheless, children present with a limited number of syndromes, most of which correlate with cell type.

Children with LL often present with symptoms of airway compression (cough, dyspnea, orthopnea) or superior vena cava obstruction (facial edema, chemosis, plethora, venous engorgement), which are a result of mediastinal disease. These symptoms are a true emergency necessitating rapid diagnosis and treatment. Pleural or pericardial effusions may further compromise the patient’s respiratory and cardiovascular status. CNS and bone marrow involvement are not common at diagnosis. When bone marrow contains more than 25% lymphoblasts, patients are diagnosed with ALL.

Most patients with BL and BLL present with abdominal disease. Abdominal pain, distention, a right lower quadrant mass, or intussusception in a child older than 5 years suggests the diagnosis of BL. Bone marrow involvement is common (∼ 65% of patients). BL is the most rapidly proliferating tumor known and has a high rate of spontaneous cell death as it outgrows its blood supply. Consequently, children presenting with massive abdominal disease frequently have tumor lysis syndrome (hyperuricemia, hyperphosphatemia, and hyperkalemia). These abnormalities can be aggravated by tumor infiltration of the kidney or urinary obstruction by tumor. Although similar histologically, numerous differences exist between cases of BL occurring in endemic areas of equatorial Africa and the sporadic cases of North America (Table 31–6).

Large cell lymphomas are similar clinically to the small noncleaved cell lymphomas, although unusual sites of involvement are quite common, particularly with ALCL. Skin lesions, focal neurologic deficits, and pleural or peritoneal effusions without an obvious associated mass are frequently seen. With improved diagnostic techniques, new categories of LBCLs including primary mediastinal B-cell lymphoma and gray zone lymphomas have been identified. The distinction is an important one as the approach to therapy differs significantly.

B. Diagnostic Evaluation

Diagnosis is made by biopsy of involved tissue with histology, immunophenotyping, and cytogenetic studies. If mediastinal disease is present, general anesthesia must be avoided if the airway or vena cava is compromised by tumor. In these cases samples of pleural or ascitic fluid, bone marrow, or peripheral nodes obtained under local anesthesia (in the presence of an anesthesiologist) may confirm the diagnosis. Major abdominal surgery and intestinal resection should be avoided in patients with an abdominal mass that is likely to be BL, as the tumor will regress rapidly with the initiation of chemotherapy. The rapid growth of these tumors and the associated life-threatening complications demand that further studies be done expeditiously so that specific therapy is not delayed.

After a thorough physical examination, a CBC, liver function tests, and a biochemical profile (electrolytes, calcium, phosphorus, uric acid, renal function) should be obtained. An elevated LDH reflects tumor burden and can serve as a marker of disease activity. Imaging studies should include a chest radiograph and CT scans of the neck, chest, abdomen and pelvis, and a PET scan. Bone marrow and CSF examinations are also essential.

Treatment

A. Supportive Care

The management of life-threatening problems at presentation is critical. The most common complications are superior mediastinal syndrome and acute tumor lysis syndrome. Patients with airway compromise require prompt initiation of specific therapy. Because of the risk of general anesthesia in these patients, it is occasionally necessary to initiate corticosteroids or low-dose emergency radiation therapy until the mass is small enough for a biopsy to be undertaken safely. Response to steroids and radiation therapy is usually prompt (12–24 hours).

Tumor lysis syndrome should be anticipated in all patients who have NHL with a large tumor burden. Maintaining a brisk urine output (> 5 mL/kg/h) with intravenous fluids and diuretics is the key to management. Allopurinol will reduce serum uric acid. Rasburicase is an effective intravenous alternative to allopurinol and is increasingly used for patients with high risk of tumor lysis based on tumor burden or in patients who do not have an optimal response to allopurinol. Renal dialysis is occasionally necessary to control metabolic abnormalities. Every attempt should be made to correct or minimize metabolic abnormalities before initiating chemotherapy; however, this period of stabilization should not exceed 24–48 hours.

B. Specific Therapy

Systemic chemotherapy is the mainstay of therapy for NHLs. Nearly all patients with NHL require intensive intrathecal chemotherapy for CNS prophylaxis. Surgical resection is not indicated unless the entire tumor can be resected safely, which is rare. Partial resection or debulking surgery has no role. Radiation therapy does not improve outcome, so its use is confined to exceptional circumstances.

Therapy for LL is generally based on treatment protocols designed for ALL and involves dose-intensive, multiagent chemotherapy. Current trials are testing whether the addition of bortezomib to the current multiagent chemotherapy regimen will decrease the risk of relapse for patients with T-cell LL. The duration of therapy is 2 years. Treatment of BL and BLL consists of alkylating agents and intermediate- to high-dose methotrexate administered intensively, but for a relatively short time it produces the highest cure rates. LBCLs are treated similarly, whereas ALCL has been treated with both BL and LL protocols. Dose-adjusted EPOCH-R has demonstrated improved outcomes in adults with primary mediastinal B-cell lymphoma and gray zone lymphomas. Clinical trials utilizing this regimen are ongoing in children with these rare NHLs.

Monoclonal antibodies such as rituximab (anti-CD20) allow for more targeted therapy of lymphomas and have been successful in improving outcomes in adults. Recent studies in children with high-risk mature B-cell lymphomas demonstrated improved outcomes with the addition of rituximab to conventional chemotherapy regimens. Additionally, oral small molecule inhibitors against the ALK oncogene are being explored as novel therapy for specific subsets of patients with ALCL. The ALK oncogene is activated by a 2;5 translocation leading to juxtaposition of NPM N-terminal region to the intracellular part of ALK and is the defining genetic lesions in ALK-positive ALCL. ALCL often express CD30 and studies are ongoing combining brentuximab vedotin and ALK inhibitors.

Prognosis

A major predictor of outcome in NHL is the extent of disease at diagnosis. Ninety percent of patients with localized disease can expect long-term, disease-free survival. Patients with extensive disease on both sides of the diaphragm, CNS involvement, or bone marrow involvement in addition to a primary site have a 70%–80% failure-free survival (FFS) rate. Relapses occur early in NHL; patients with LL rarely have recurrences after 30 months from diagnosis, whereas patients with BL and BLL very rarely have recurrences beyond 1 year. The cure rate for patients with relapsed T-cell lymphoblastic leukemia/lymphoma is particularly poor (3-year EFS rates < 20%). Patients who experience relapse may have a chance for cure by autologous or allogeneic HSCT.

3. Lymphoproliferative Disorders

Lymphoproliferative disorders (LPDs) can be thought of as a part of a continuum with lymphomas. Whereas LPDs represent inappropriate, often polyclonal proliferations of nonmalignant lymphocytes, lymphomas represent the development of malignant clones, sometimes arising from recognized LPDs.

A. Posttransplantation Lymphoproliferative Disorders

Posttransplantation lymphoproliferative disorders (PTLDs) arise in patients who have received substantial immunosuppressive medications for solid organ or bone marrow transplantation. In these patients, reactivation of latent EBV infection in B cells drives a polyclonal proliferation of these cells that is fatal if not halted. Occasionally a true lymphoma develops, often bearing a chromosomal translocation.

LPDs are an increasingly common and significant complication of transplantation. The incidence of PTLD ranges from approximately 2% to 15% of transplant recipients, depending on the organ transplanted and the immunosuppressive regimen.

Treatment of these disorders is a challenge for transplant physicians and oncologists. The initial treatment is reduction in immunosuppression, which allows the patient’s own immune cells to destroy the virally transformed lymphocytes. However, this is only effective in approximately half of the patients. For those patients who do not respond to reduced immune suppression, chemotherapy of various regimens may succeed. The use of anti–B-cell antibodies, such as rituximab (anti-CD20), for the treatment of PTLDs has been promising in clinical trials. More recently, T-cell–based immune therapies, such as donor lymphocyte infusions and adoptive transfer of EBV-specific cytotoxic T lymphocytes, have also been explored as novel approaches.

B. Spontaneous Lymphoproliferative Disease

Immunodeficiencies in which LPDs occur include Bloom syndrome, Chédiak-Higashi syndrome, ataxia-telangiectasia, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, congenital T-cell immunodeficiencies, and HIV infection. Treatment depends on the circumstances, but unlike PTLD, few therapeutic options are often available. Castleman disease is an LPD occurring in pediatric patients without any apparent immunodeficiency. The autoimmune lymphoproliferative syndrome (ALPS) is characterized by widespread lymphadenopathy with hepatosplenomegaly, and autoimmune phenomena. ALPS results from mutations in the Fas ligand pathway that is critical in regulation of apoptosis.

NEUROBLASTOMA

General Considerations

Neuroblastoma arises from neural crest tissue of the sympathetic ganglia or adrenal medulla. It is composed of small, uniform cells with scant cytoplasm and hyperchromatic nuclei that may form a rosette pattern. It must be differentiated from other “small, round, blue cell” malignancies of childhood, such as Ewing sarcoma, rhabdomyosarcoma (RMS), peripheral neuroectodermal tumor (PNET), and NHL.

Neuroblastoma accounts for 7%–10% of pediatric malignancies and is the most common solid neoplasm outside the CNS. Fifty percent of neuroblastomas are diagnosed before age 2 years and 90% before age 5 years. It is a biologically diverse disease with clinical behavior that can range from spontaneous regression to relentless progression despite aggressive therapy. Historically, cure rates for patients with high-risk neuroblastoma were very poor. With promising recent advances, however, cure rates have been steadily improving, albeit at the price of significant toxicity from treatment.

Clinical Findings

A. Symptoms and Signs

Clinical manifestations vary based on tumor location and neuroendocrine function of the tumor. Many children present with constitutional symptoms such as fever, weight loss, and irritability. Bone pain suggests metastatic disease, which is present in 60% of children older than 1 year at diagnosis. Physical examination may reveal a firm, fixed, irregularly shaped midline abdominal mass. Although most children have an abdominal primary tumor (40% adrenal gland, 25% paraspinal ganglion), neuroblastoma can arise wherever there is sympathetic nervous tissue. In the posterior mediastinum, the tumor is usually asymptomatic and discovered incidentally on a chest radiograph. Patients with cervical neuroblastoma present with a neck mass, sometimes misdiagnosed as infection. Horner syndrome (unilateral ptosis, myosis, and anhidrosis) or heterochromia iridis (differently colored irises) may accompany cervical neuroblastoma. Paraspinous tumors can extend through the spinal foramen, causing cord compression and leading to paresis, paralysis, or bowel/bladder dysfunction.

The most common sites of metastases are bone, bone marrow, lymph nodes, liver, and subcutaneous tissue. Neuroblastoma has a predilection for metastasis to the skull, particularly the sphenoid bone and retrobulbar tissue, causing periorbital ecchymosis (“raccoon eyes”) and proptosis. Liver metastasis, particularly in the newborn, can lead to massive hepatomegaly. Skin metastases can appear as bluish or purplish subcutaneous nodules (“blueberry muffin baby”) and can be associated with an erythematous flush followed by blanching when compressed, probably due to catecholamine release.

Neuroblastoma can have paraneoplastic manifestations, the most striking example being opsoclonus-myoclonus-ataxia (OMA) syndrome (“dancing eyes/dancing feet”). This phenomenon is characterized by rapid and chaotic eye movements, myoclonic jerking of the limbs and trunk, ataxia, and behavioral disturbances. This process, which often persists after treatment of the neuroblastoma is complete, is due to cross-reacting anti-neuronal autoantibodies. Treatment is with immunosuppression. Intractable, watery diarrhea can occur due to secretion of vasoactive intestinal peptide (VIP) by the tumor. Interestingly, both of these paraneoplastic syndromes, despite their morbidity are associated with more favorable curative potential for the tumor itself.

B. Laboratory Findings

Anemia is present in 60% of children with neuroblastoma and can be due to chronic disease or marrow infiltration. Occasionally, thrombocytopenia is present, but thrombocytosis is a more common finding, even with metastatic disease in the marrow. Urinary catecholamines (vanillylmandelic acid [VMA] and homovanillic acid [HVA]) are elevated in at least 90% of patients at diagnosis and should be measured prior to surgery.

C. Imaging

Radiographs of the primary tumor may show stippled calcifications. Metastases to bone can appear irregular and lytic. Periosteal reaction and pathologic fractures may also be seen. CT scanning shows extent of the primary tumor, effects on surrounding structures, and the presence of metastatic disease. Classically, in tumors originating from the adrenal gland, the kidney is displaced inferolaterally, which helps to differentiate neuroblastoma from Wilms tumor. MRI is useful in determining the presence of spinal cord involvement in tumors that invade neural foramina.

I-123-Metaiodobenzylguanidine (MIBG), a radiolabeled compound that localizes to adrenal tissue, is used to detect and quantify the degree of metastatic disease at diagnosis and to track response to treatment. PET-CT can be utilized in patients whose tumors are MIBG non-avid (8.7% of cases). MIBG and PET-CT scanning have supplanted technetium-99m bone scanning for evaluation of bone metastases in neuroblastoma.

D. Staging

Staging of neuroblastoma is usually performed according to the International Neuroblastoma Staging System (INSS) (Table 31–7), though a newer, International Neuroblastoma Risk Group (INRG) staging system that incorporates image-defined risk factors as part of the staging process is being used more commonly. Biopsy of the tumor is essential to confirm the diagnosis and determine the biologic characteristics of the tumor. In addition, bilateral bone marrow aspirates and biopsies must be performed to evaluate for bone marrow involvement.

Tumors are classified as favorable or unfavorable based on histologic characteristics and the age of the patient at diagnosis, with younger age (<18 months) being associated with a more favorable prognosis. Amplification of the MYCN protooncogene is a reliable marker of aggressive clinical behavior. Tumor cell DNA content is also predictive of outcome. Hyperdiploidy is a favorable finding, whereas diploid DNA content is associated with a worse outcome. Loss of heterozygosity at chromosome bands 1p36 and 11q23 also confers a worse prognosis.

Treatment & Prognosis

Patients are treated according to a risk stratification system that takes into account INSS or INRG stage, patient age, MYCN status, histology, cytogenetic findings, and DNA index. Based on these factors, patients are classified as having low-, intermediate-, or high-risk disease.

For low-risk disease (INSS stages 1 and 2, with favorable biologic features), surgical resection of more than 50% of the tumor is usually sufficient for cure. Aggressive surgery to remove the entire tumor at the expense of surrounding normal structures is not necessary and can lead to unnecessary morbidity. Infants younger than 6 months with small adrenal masses consistent radiographically with neuroblastoma can be treated with close observation alone, even in the absence of a biopsy. Survival rates for patients with low-risk neuroblastoma are more than 98%. Infants younger than 1 year with INSS stage 4S disease may need little if any therapy, with the disease regressing spontaneously, although chemotherapy may be initiated because of bulky disease (generally massive hepatomegaly) causing mechanical complications. Survival rates with 4S disease are more than 90%.

With intermediate-risk neuroblastoma (subsets of patients with INSS stages 3 and 4 disease), the primary treatment approach is surgery combined with chemotherapy. The size or location of the tumor often makes primary resection impossible. Under these circumstances, a biopsy alone is performed to make a definitive diagnosis and evaluate biologic characteristics. Shrinkage of the tumor with chemotherapy often allows a second surgery with more complete tumor resection. Chemotherapeutic agents typically used include carboplatin, etoposide, cyclophosphamide, vincristine, and doxorubicin. The number of cycles used (usually 2–8) depends on the multiple factors, including the age of the patient, the INSS stage, biologic features of the tumor, and response to treatment. Radiation therapy is rarely necessary. Survival rates for intermediate risk neuroblastoma are 90–95%.

High-risk patients (the majority with INSS stages 3 and 4 disease, generally with older age and unfavorable tumor biology) require intensive, multimodal therapy including chemotherapy, surgery, autologous HSCT, irradiation, biologic therapy, and immunotherapy. Several cycles of intensive chemotherapy are followed by resection of as much of the tumor as possible. Following this induction phase, tandem (two sequential) autologous HSCTs are performed as consolidative therapy. Following the HSCTs, the site of the primary tumor and any areas with evidence of active disease prior to transplant are irradiated. At this point, patients have reached a state of MRD. To reduce the risk of recurrence, a maintenance phase follows. Patients receive immunotherapy with an antibody directed against the GD2 antigen expressed on the surface of the neuroblastoma cells together with or GM-CSF to enhance immune-mediated cell killing. These treatments are alternated with treatments with 13-cis-retinoic acid, an agent that induces terminal differentiation of neuroblastoma cells. Results of recent studies incorporating all of these treatment modalities are encouraging, with 5-year EFS rates of 56% and overall survival rates of 73%. An upcoming COG treatment study will be looking at the incorporation of therapeutic radioactive I-121-MIBG into the upfront treatment regimen. Also, use of targeted therapies, such as ALK inhibition in patients whose tumors express ALK mutations, are being investigated. Despite advancements, high risk neuroblastoma remains a challenging disease, and much work remains to improve cure rates while minimizing the toxicity of treatment.

WILMS TUMOR (NEPHROBLASTOMA)

General Considerations

Approximately 460 new cases of Wilms tumor occur annually in the United States, representing 5%–6% of cancers in children younger than 15 years. After neuroblastoma, this is the second most common abdominal tumor in children. The majority of Wilms tumors are of sporadic occurrence. However, in a few children, Wilms tumor occurs in the setting of associated malformations or syndromes, including aniridia, hemihypertrophy, genitourinary (GU) malformations (eg, cryptorchidism, hypospadias, gonadal dysgenesis, pseudohermaphroditism, and horseshoe kidney), Beckwith-Wiedemann syndrome, Denys-Drash syndrome, and WAGR syndrome (Wilms tumor, aniridia, ambiguous genitalia, mental retardation).

The median age at diagnosis is related both to gender and laterality, with bilateral tumors presenting at a younger age than unilateral tumors, and males being diagnosed earlier than females. Wilms tumor occurs most commonly between ages 2 and 5 years; it is unusual after age 6 years. The mean age at diagnosis is 4 years.

Clinical Findings

A. Symptoms and Signs

Most children with Wilms tumor present with increasing size of the abdomen or an asymptomatic abdominal mass incidentally discovered by a parent and/or health care provider. The mass is usually smooth and firm, well demarcated, and rarely crosses the midline, though it can extend inferiorly into the pelvis. About 25% of patients are hypertensive at presentation. Gross hematuria is an uncommon presentation, although microscopic hematuria occurs in approximately 25% of patients.

B. Laboratory Findings

The CBC is usually normal, but some patients have anemia secondary to hemorrhage into the tumor. Blood urea nitrogen and serum creatinine are usually normal. Urinalysis may show some blood or leukocytes.

C. Imaging and Staging

Ultrasonography or CT of the abdomen should establish the presence of an intrarenal mass. It is also essential to evaluate the contralateral kidney for presence and function as well as synchronous Wilms tumor. The inferior vena cava needs to be evaluated by ultrasonography with Doppler flow for the presence and extent of tumor propagation. The liver should be imaged for the presence of metastatic disease. Chest CT scan should be obtained to determine whether pulmonary metastases are present. Approximately 10% of patients will have metastatic disease at diagnosis. Of these, 80% will have pulmonary disease and 15% liver metastases. Bone and brain metastases are extremely uncommon and usually associated with the rarer, more aggressive renal tumor types, such as clear cell sarcoma or rhabdoid tumor; hence, bone scans and brain imaging are not routinely performed. The clinical stage is ultimately decided at surgery and confirmed by the pathologist.

Treatment & Prognosis

In the United States, treatment of Wilms tumor begins with surgical exploration of the abdomen via an anterior surgical approach to allow for inspection and palpation of the contralateral kidney. The liver and lymph nodes are inspected and suspicious areas biopsied or excised. En bloc resection of the tumor is performed. Every attempt is made to avoid tumor spillage at surgery as this may increase the staging and treatment. Because therapy is tailored to tumor stage, it is imperative that a surgeon familiar with the staging requirements perform the operation.

In addition to the staging, the histologic type has implications for therapy and prognosis. Favorable histology (FH; see later discussion) refers to the classic triphasic Wilms tumor and its variants. Unfavorable histology (UH) refers to the presence of diffuse anaplasia (extreme nuclear atypia) and is present in 5% of Wilms tumors. Only a few small foci of anaplasia in a Wilms tumor give a worse prognosis to patients with stage II, III, or IV tumors. Loss of heterozygosity of chromosomes 1p and 16q are adverse prognostic factors in those with favorable histology. Following excision and pathologic examination, the patient is assigned a stage that defines further therapy.

Improvement in the treatment of Wilms tumor has resulted in an overall cure rate of approximately 90%. The National Wilms’ Tumor Study Group’s fourth study (NWTS-4) demonstrated that survival rates were improved by intensifying therapy during the initial treatment phase while shortening overall treatment duration (24 vs 60 weeks of treatment).

Table 31–8 provides an overview of the current treatment recommendations in NWTS-5. Patients with stage III or IV Wilms tumor require radiation therapy to the tumor bed and to sites of metastatic disease. Chemotherapy is optimally begun within 5 days after surgery, whereas radiation therapy should be started within 10 days. Stage V (bilateral Wilms tumor) disease dictates a different approach, consisting of possible bilateral renal biopsies followed by chemotherapy and second-look renal-sparing surgery. Radiation therapy may also be necessary.

Using these approaches, 4-year overall survival rates through NWTS-4 are as follows: stage I FH, 96%; stages II–IV FH, 82%–92%; stages I–III UH (diffuse anaplasia), 56%–70%; and stage IV UH, 17%. Patients with recurrent Wilms tumor have a salvage rate of approximately 50% with surgery, radiation therapy, and chemotherapy (singly or in combination). HSCT is also being explored as a way to improve the chances of survival after relapse.

Future Considerations

Although progress in the treatment of Wilms tumor has been extraordinary, important questions remain to be answered. Questions have been raised regarding the role of prenephrectomy chemotherapy in the treatment of Wilms tumor. Presurgical chemotherapy seems to decrease tumor rupture at resection but may unfavorably affect outcome by changing staging. Future studies will be directed at minimizing acute and long-term toxicities for those with low-risk disease and improving outcomes for those with high-risk and recurrent disease.

BONE TUMORS

Primary malignant bone tumors are uncommon in childhood with only 650–700 new cases per year. Osteosarcoma accounts for 60% of cases and occurs mostly in adolescents and young adults. Ewing sarcoma is the second most common malignant tumor of bony origin and occurs in toddlers to young adults. Both tumors have a male predominance.

The cardinal signs of bone tumor are pain at the site of involvement, often following slight trauma, mass formation, and fracture through an area of cortical bone destruction.

1. Osteosarcoma

General Considerations

Although osteosarcoma is the sixth most common malignancy in childhood, it ranks third among adolescents and young adults. This peak occurrence during the adolescent growth spurt suggests a causal relationship between rapid bone growth and malignant transformation. Further evidence for this relationship is found in epidemiologic data showing patients with osteosarcoma to be taller than their peers, osteosarcoma occurring most frequently at sites where the greatest increase in length and size of bone occurs, and osteosarcoma occurring at an earlier age in girls than boys, corresponding to their earlier growth spurt. The metaphyses of long tubular bones are primarily affected. The distal femur accounts for more than 40% of cases, with the proximal tibia, proximal humerus, and mid and proximal femur following in frequency.

Clinical Findings

A. Symptoms and Signs

Pain over the involved area is the usual presenting symptom with or without an associated soft tissue mass. Patients generally have symptoms for several months prior to diagnosis. Systemic symptoms (fever, weight loss) are rare. Laboratory evaluation may reveal elevated serum alkaline phosphatase or LDH levels.

B. Imaging and Staging

Radiographic findings show permeative (“moth-eaten” appearance) destruction of the normal bony trabecular pattern with indistinct margins. In addition, periosteal new bone formation and lifting of the bony cortex may create a Codman triangle. A soft tissue mass plus calcifications in a radial or sunburst pattern are frequently noted. MRI is more sensitive in defining the extent of the primary tumor and has mostly replaced CT scanning. The most common sites of metastases are the lung (≤ 20% of newly diagnosed cases) and the additional boney sites (10%). CT scan of the chest and bone scan are essential for detecting metastatic disease. PET-CT may be a consideration in monitoring response to therapy. Bone marrow aspirates and biopsies are not indicated.

Despite the rather characteristic radiographic appearance, a tissue sample is needed to confirm the diagnosis. Placement of the incision for biopsy is of critical importance. A misplaced incision could preclude a limb salvage procedure and necessitate amputation. The surgeon who will carry out the definitive surgical procedure should perform the biopsy. A staging system for osteosarcoma based on local tumor extent and presence or absence of distant metastasis has been proposed, but it has not been validated.

Treatment & Prognosis

Historical studies showed that over 50% of patients receiving surgery alone developed pulmonary metastases within 6 months after surgery. This suggests the presence of micrometastatic disease at diagnosis. Adjuvant chemotherapy trials showed improved disease-free survival rates of 55%–85% in patients followed for 3–10 years.

Osteosarcomas are highly radioresistant lesions; for this reason, radiation therapy has no role in its primary management. Chemotherapy is often administered prior to definitive surgery (neoadjuvant chemotherapy). This permits an early attack on micrometastatic disease and may also shrink the tumor, facilitating a limb salvage procedure. Preoperative chemotherapy also makes detailed histologic evaluation of tumor response to the chemotherapy agents possible. If the histologic response is poor (> 10% viable tumor tissue), postoperative chemotherapy can be changed accordingly, but a recently completed COG Group study showed increased toxicity with no additional benefit. Chemotherapy may be administered intra-arterially or intravenously, although the benefits of intra-arterial chemotherapy (IAC) are disputed. Agents having efficacy in the treatment of osteosarcoma include doxorubicin, cisplatin, high-dose methotrexate, ifosfamide, and etoposide.

Definitive cure requires en bloc surgical resection of the tumor with a margin of uninvolved tissue. Amputation, limb salvage, and rotationplasty (Van Ness rotation) are equally effective in achieving local control of osteosarcoma. Contraindications to limb-sparing surgery include major involvement of the neurovascular bundle by tumor; immature skeletal age, particularly for lower extremity tumors; infection in the region of the tumor; inappropriate biopsy site; and extensive muscle involvement that would result in a poor functional outcome.

Postsurgical chemotherapy is generally continued until the patient has received 1 year of treatment. Relapses are unusual beyond 3 years, but late relapses do occur. Histologic response to neoadjuvant chemotherapy is an excellent predictor of outcome. Patients with localized disease having 90% or greater tumor necrosis have a 70%–75% long-term, disease-free survival rate. Other favorable prognostic factors include distal skeletal lesions, longer duration of symptoms, age older than 20 years, female gender, and near-diploid tumor DNA index. Patients with metastatic disease at diagnosis or multifocal bone lesions do not fair well, despite advances in chemotherapy and surgical techniques.

2. Ewing Sarcoma

General Considerations

Ewing sarcoma accounts for only 30% of primary malignant bone tumors; fewer than 200 new cases occur each year in the United States. It is a disease primarily of white males, almost never affects blacks, and occurs mostly in the second decade of life. Ewing sarcoma is considered a “small, round, blue cell” malignancy. The differential diagnosis includes RMS, lymphoma, and neuroblastoma. Although most commonly a tumor of bone, it may also occur in soft tissue (extraosseous Ewing sarcoma or PNET).

Clinical Findings

A. Symptoms and Signs

Pain at the site of the primary tumor is the most common presenting sign, with or without swelling and erythema. No specific laboratory findings are characteristic of Ewing sarcoma, but an elevated LDH may be present and is of prognostic significance. Associated symptoms include fevers and weight loss.

B. Imaging and Staging

The radiographic appearance of Ewing sarcoma overlaps with osteosarcoma, although Ewing sarcoma usually involves the diaphyses of long bones. The central axial skeleton gives rise to 40% of Ewing tumors. Evaluation of a patient diagnosed as having Ewing sarcoma should include an MRI of the primary lesion to define the extent of local disease as precisely as possible. This is imperative for planning future surgical procedures or radiation therapy. Metastatic disease is present in 25% of patients at diagnosis. The lung (38%), bone (particularly the spine) (31%), and the bone marrow (11%) are the most common sites for metastasis. CT scan of the chest, bone scan, and bilateral bone marrow aspirates and biopsies are all essential to the staging workup. PET-CT may be considered to help monitor therapy response.

A biopsy is essential to establishing the diagnosis. Histologically, Ewing sarcoma consists of sheets of undifferentiated cells with hyperchromatic nuclei, well-defined cell borders, and scanty cytoplasm. Necrosis is common. Electron microscopy, immunocytochemistry, and cytogenetics may be necessary to confirm the diagnosis. A generous tissue biopsy specimen is often necessary for diagnosis but should not delay starting chemotherapy.

A consistent cytogenetic abnormality, t(11;22), has been identified in Ewing sarcoma and PNET and is present in 85%–90% of tumors. These tumors also express the protooncogene c-myc, which may be helpful in differentiating Ewing sarcoma from neuroblastoma, in which c-myc is not expressed.

Treatment & Prognosis

Therapy usually commences with the administration of chemotherapy after biopsy and is followed by local control measures. Depending on many factors, including the primary site of the tumor and the response to chemotherapy, local control can be achieved by surgery, radiation therapy, or a combination of these methods. Following local control, chemotherapy continues for approximately 6 months. Effective treatment for Ewing sarcoma uses combinations of dactinomycin, vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide. Recent data showed that giving chemotherapy every 2 weeks, rather than every 3 weeks, improved the EFS for localized Ewing sarcoma. The current COG nonmetastatic Ewing sarcoma study is looking at whether the addition of topotecan to the present five-drug regimen will improve survival.

Patients with small localized primary tumors have a 70%–75% long-term, disease-free survival rate. For patients with metastatic disease, survival is poor. Autologous HSCT may be considered as part of the treatment of these high-risk patients. Patients with pelvic tumors have an intermediate prognosis of around 50% long-term, disease-free survival.

RHABDOMYOSARCOMA

General Considerations

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and accounts for 10% of childhood solid tumors. The peak incidence is at age 2–5 years. A second, smaller peak is seen in adolescents with extremity tumors. Males are affected more commonly than females. Seventy percent of children with RMS are diagnosed before age 10 years.

RMS can occur anywhere in the body. When it imitates striated muscle and cross-striations are seen by light microscopy, the diagnosis is straightforward. Immunohistochemistry looking for expression of myogenic regulatory factors such as myoD and myogenin can support the diagnosis. Electron microscopy and chromosomal analysis are also helpful diagnostic tools. RMS is classified into subtypes based on pathologic features: embryonal RMS (ERMS), including the botryoid variant (so named because of its gross appearance similar to a bunch of grapes), makes up approximately 70% of childhood RMS. It tends to occur in the GU tract and the head and neck, particularly the orbit, and is typically seen in young children. Alveolar RMS (ARMS) makes up most of the remaining cases. It tends to occur in the trunk or extremities in older children and adolescents and has a worse prognosis than ERMS. Two characteristic chromosomal translocations, t(2;13) and t(1;13), are seen in 80% of cases of ARMS, leading to fusion of the FOXO1 transcription factor gene on chromosome 13 to the PAX3 or PAX7 gene on chromosome 2 or 1, respectively. Some studies suggest that patients with t(2;13) have a poorer outcome than patients with t(1;13), particularly when there is metastatic disease at diagnosis. Sclerosing/spindle cell RMS (SRMS) is a less common subtype that tends to occur in the paratesticular and head and neck regions and behaves similarly to ERMS. Pleomorphic RMS (PRMS) is rare and occurs mostly in adults.

In young children with RMS, the possibility that they may harbor an underlying cancer predisposition syndrome should be considered. LFS is an inherited mutation of the p53 tumor suppressor gene that results in a high risk of bone and soft tissue sarcomas, including RMS, in childhood as well as breast cancer and other malignant neoplasms in adulthood. RMS in children with LFS typically exhibits anaplasia. In a patient with RMS with anaplasia, LFS should be strongly considered as a predisposing cause. Patients with NF-1 are also predisposed to develop RMS, typically ERMS involving the GU tract.

Clinical Findings

A. Symptoms and Signs

The presenting symptoms and signs of RMS result from disturbances of normal body function due to tumor growth (Table 31–9). For example, patients with orbital RMS present with proptosis, whereas patients with RMS of the bladder can present with hematuria, urinary obstruction, or a pelvic mass.

B. Staging

A CT and/or MRI scan should be obtained to determine the extent of the primary tumor and to assess regional lymph nodes. A CT scan of the chest is used to assess for pulmonary metastasis, the most common site of metastatic disease at diagnosis. A bone scan screens for bony metastases. PET-CT is another useful imaging modality when evaluating for metastatic disease, though its role in the management of RMS continues to be studied. Bilateral bone marrow biopsies and aspirates are obtained to look for bone marrow involvement. Additional studies may occasionally be warranted. For example, for parameningeal primary tumors, a lumbar puncture is performed to evaluate for CNS involvement. Also, sentinel node biopsy for extremity ARMS or biopsy of any suspicious lymph nodes is important for staging and treatment planning.

Treatment

Optimal treatment of RMS is complex and requires combined modality therapy delivered by a multidisciplinary team, including oncologists, surgeons, and radiation oncologists. When feasible, the tumor should be completely excised with clear margins at diagnosis, but this is frequently not possible because of the site of origin and size of the tumor. When only partial tumor resection is feasible, the operative procedure is usually limited to biopsy and sampling of lymph nodes. Chemotherapy can often convert an inoperable tumor to a resectable one. Radiation therapy is effective for local tumor control with both microscopic and gross residual disease. Most patients end up receiving radiation, the exception being those with a localized tumor that has been completely resected. All patients with RMS receive chemotherapy, even when the tumor is fully resected at diagnosis. The exact regimen and duration of chemotherapy are determined by the histologic subtype, age at diagnosis, the primary site, the TNM (tumor-lymph node-metastasis) staging classification, and the grouping classification (disease extent after initial surgery). Based on these factors, patients are categorized into low risk, with an FFS of approximately 90%, intermediate risk, with an FFS of 60%–70%, and high risk, with an FFS of less than 20%.

The combination of vincristine, dactinomycin, and cyclophosphamide (VAC) has shown the greatest efficacy in the treatment of RMS. For low-risk patients, recent COG studies have focused on reducing the amount of cyclophosphamide to minimize late effects such as infertility and secondary cancers while maintaining high cure rates. For intermediate-risk patients, current studies are looking at incorporating irinotecan into treatment and adding a maintenance phase that includes cyclophosphamide and vinorelbine. High-risk (metastatic) RMS remains a major therapeutic challenge. For high-risk patients, several treatment strategies have been attempted. The most recent COG high-risk RMS study added several agents (irinotecan, ifosfamide, etoposide, doxorubicin) to standard VAC therapy. It also compressed the timing of some of the cycles from every 3 weeks to every 2 weeks. Early results showed improvement in survival, but with longer follow-up most patients eventually relapsed, and survival rates were no better than what was seen historically. Clearly, new strategies are needed. A recent study treating patients with relapsed or refractory RMS with a combination of temsirolimus, vinorelbine, and cyclophosphamide showed promising results, prompting consideration of this drug combination for upfront treatment regimens. Agents targeting the insulin-like growth factor (IGF) pathway are also being investigated.

RETINOBLASTOMA

General Considerations

Retinoblastoma is a neuroectodermal malignancy arising from embryonic retinal cells. It is rare, accounting for 3% of cases of childhood cancer. It is the most common intraocular tumor in children and causes 5% of cases of childhood blindness. In the United States, 200–300 new cases are diagnosed yearly. This is a malignancy of early childhood, with 90% of the tumors diagnosed before age 5 years. Retinoblastoma is the prototypic heritable cancer.

In almost all cases, retinoblastoma is caused by loss of function of RB1, a tumor suppressor gene located on the long arm of chromosome 13 (13q14). This gene encodes a protein that regulates progression through the cell cycle. When the gene is lost or inactivated, uncontrolled cell growth leads to tumor formation. Each cell carries two copies of RB1, one from each parent, and both copies must be lost or inactivated for tumor formation to occur.

Retinoblastoma exists in both a heritable and nonheritable form. The heritable form (30%–40% of cases) tends to have multiple tumors, is usually bilateral, and tends to occur at a younger age (median 14 months) while the nonheritable form is unilateral and tends to occur at an older median age (23 months). Based on these observations, Alfred Knudson proposed a “two-hit” hypothesis for retinoblastoma tumor development. He postulated that for a cell to become tumorigenic, it had to lose function of both copies of a tumor suppressor gene (later identified as RB1). In heritable cases, the first mutation is either inherited from a parent (10% of cases) or occurs very early in development (90% of cases), with the progeny of that cell all carrying the same mutation. In someone with germline loss of one allele, loss of function of the second RB1 allele in a retinal cell is a likely event, occurring in 90% of persons who carry the germline mutation. Most will have multiple tumors and most will have bilateral disease. In nonheritable cases, both mutations must arise spontaneously in the same somatic cell, a much less likely event. Therefore, nonheritable cases are unilateral, single tumors. Because of the implications for both the patient and the patient’s family, genetic counseling and RB1 mutational analysis are essential for all patients diagnosed with retinoblastoma.

Clinical Findings

A. Symptoms and Signs

Children with retinoblastoma in the United States generally come to medical attention while the tumor is still confined to the globe. Although sometimes present at birth, retinoblastoma is not usually detected until it has grown to a considerable size. Leukocoria (white pupillary reflex) is the most common sign (found in 60% of patients). Parents may note an unusual appearance of the eye or asymmetry of the eyes in a photograph. The differential diagnosis of leukocoria includes Toxocara canis granuloma, astrocytic hamartoma, retinopathy of prematurity, Coats disease, and persistent hyperplastic primary vitreous. Strabismus (in 20% of patients) is seen when the tumor involves the macula and central vision is lost. Rarely (in 7% of patients), a painful red eye with glaucoma, hyphema, or proptosis is the initial manifestation. A single focus or multiple foci of tumor may be seen in one or both eyes at diagnosis.

B. Diagnostic Evaluation

Suspected retinoblastoma requires a detailed ophthalmologic examination under general anesthesia. An ophthalmologist makes the diagnosis based on the appearance of the tumor within the eye, without pathologic confirmation. A white to creamy pink mass protruding into the vitreous matter suggests the diagnosis. Intraocular calcifications and vitreous seeding are virtually pathognomonic findings. A CT scan of the orbits and MRI of the orbits and brain detect intraocular calcification, evaluate the optic nerve for tumor infiltration, and detect extraocular extension of tumor or involvement of the pineal gland (trilateral retinoblastoma). Metastatic disease to the marrow or meninges can be detected with bilateral bone marrow aspirates and biopsies and CSF cytology, respectively.

Treatment

The first goal of treatment is prevention of metastatic disease. While cure rates for retinoblastoma confined to the orbit are excellent, survival rates decrease precipitously once the disease has spread beyond the orbit. An important secondary goal is preservation of the eye and of useful vision, and a third goal is prevention of late effects of therapy. Each eye is treated according to its potential for useful vision, and every attempt is made to preserve vision. The choice of therapy depends on the size, location, and number of intraocular lesions as well as if the disease is unilateral or bilateral.

Children with retinoblastoma confined to the retina (whether unilateral or bilateral) have an excellent prognosis, with 5-year survival rates greater than 95% in the United States. Small lesions may be amenable to local therapies such as cryotherapy or laser therapy, or, depending on the location, placement of a radioactive plaque outside of the globe to provide localized radiation therapy. Larger tumors may require use of systemic chemotherapy to shrink the tumors and allow local therapies to be used in conjunction. The most commonly used agents are vincristine, etoposide, and carboplatin (VEC). For large intraocular tumors, a therapy that has been gaining in popularity is intra-arterial chemotherapy, where a catheter is threaded into the ophthalmic artery so that chemotherapy can be injected directly into the blood supply to the tumor. IAC is generally done in conjunction with other local therapies. Intravitreal injection of chemotherapy, usually melphalan, can be a particularly useful adjunctive therapy for treatment of vitreal tumor seeds. With use of these treatment modalities, many more eyes have been able to be saved and useful vision preserved.

Sometimes, enucleation of the eye is the best option. Absolute indications for enucleation include no salvageable vision, neovascular glaucoma, inability to examine the treated eye, suspicion of extraocular extension of tumor, and inability to control tumor growth with conservative treatment. Once the eye is removed, it is examined histopathologically to see if there are any high-risk features such as tumor invasion posterior to the lamina cribrosa of the optic nerve or extensive choroidal invasion by the tumor. In those situations, systemic chemotherapy is given to decrease risk of metastatic recurrence. Extraocular spread along the optic nerve or within the orbit requires treatment with systemic chemotherapy and external beam radiation. With proper treatment, cure rates remain good. With metastatic spread of disease outside of the orbit, however, cure rates are much poorer, with few patients cured of their disease. Treatment usually involves intensive chemotherapy followed by autologous HSCT. External beam irradiation was formerly a mainstay of therapy but now is used only in very select cases or with extraocular spread. Radiation leads to risk for significant late effects, including hypoplasia of the orbit and a greatly increased risk for secondary malignancies within the radiation field, particularly in patients with germline RB mutation.

Patients with the germline RB1 mutation (heritable form) have a significant risk of developing second primary tumors. Osteosarcomas account for 40% of such tumors. The 30-year cumulative incidence for a second neoplasm is 35% in patients who received radiation therapy and 6% in those who did not receive radiation therapy. The risk continues to increase over time. Although radiation contributes to the risk, it is the presence of the retinoblastoma gene itself that is responsible for the development of nonocular tumors in these patients.

HEPATIC TUMORS

Two-thirds of liver masses found in childhood are malignant (see also Chapter 22). Ninety percent of hepatic malignancies are either hepatoblastoma or hepatocellular carcinoma. Hepatoblastoma accounts for the vast majority of liver tumors in children younger than 5 years, hepatocellular carcinoma for the majority in children aged 15–19 years. The features of these hepatic malignancies are compared in Table 31–10. Of the benign tumors, 60% are hamartomas or vascular tumors such as hemangiomas. There is mounting evidence for a strong association between prematurity and the risk of hepatoblastoma.

Children with hepatic tumors usually come to medical attention because of an enlarging abdomen. Approximately 10% of hepatoblastomas are first discovered on routine examination. Anorexia, weight loss, vomiting, and abdominal pain are associated more commonly with hepatocellular carcinoma. Serum α-fetoprotein is often elevated and is an excellent marker for response to treatment.

Imaging studies should include abdominal ultrasound, CT scan, or MRI. Malignant tumors have a diffuse hyperechoic pattern on ultrasonography, whereas benign tumors are usually poorly echoic. Vascular lesions contain areas with varying degrees of echogenicity. Ultrasound is also useful for imaging the hepatic veins, portal veins, and inferior vena cava. CT scanning and, in particular, MRI are important for defining the extent of tumor within the liver. CT scanning of the chest should be obtained to evaluate for metastatic spread. Because bone marrow involvement is extremely rare, bone marrow aspirates and biopsies are not indicated.

The prognosis for children with hepatic malignancies depends on the tumor type and the resectability of the tumor. Complete resectability is essential for survival. Chemotherapy can decrease the size of most hepatoblastomas. Following biopsy of the lesion, neoadjuvant chemotherapy is administered prior to attempting complete surgical resection. Monitoring the rate of decline of the α-fetoprotein levels can help indicate favorable versus poor responders to chemotherapy. Chemotherapy can often convert an inoperable tumor to a completely resectable one and can also eradicate metastatic disease. Approximately 50%–60% of hepatoblastomas are fully resectable, following preoperative chemotherapy, whereas only one-third of hepatocellular carcinomas can be completely removed. Even with complete resection, only one-third of patients with hepatocellular carcinoma are long-term survivors. A recent CCG/Pediatric Oncology Group trial has shown cisplatin, fluorouracil, and vincristine to be as effective as but less toxic than cisplatin and doxorubicin in treating hepatoblastoma. The current open COG trial is using cisplatin, fluorouracil, vincristine, and doxorubicin along with the cardioprotectant dexrazoxane in intermediate-risk patients with the addition of temsirolimus in high-risk patients. Other drug combinations that have demonstrated benefit include carboplatin plus etoposide and doxorubicin plus ifosfamide. Liver transplantation has been shown to be a successful surgical option in patients whose tumors are considered to be unresectable.

LANGERHANS CELL HISTIOCYTOSIS

General Considerations

Langerhans cell histiocytosis (LCH) used to be called histiocytosis X, a name that highlighted its mysterious nature. It was long debated whether LCH was a dysregulation of the immune system or a neoplastic disorder. Our understanding of the biology of LCH has dramatically improved in recent years as we have learned more about the origin and genetics of the LCH cell. The discovery that most cases of LCH involve a V600E mutation of the BRAF gene or mutation of other genes in the RAS-RAF-MEK-ERK pathway has led us to view LCH as a neoplastic disorder, albeit one that does not typically behave in a malignant fashion. Studies on the origin of the LCH cell show that it is derived from a myeloid cell precursor rather than a mature Langerhans cell, placing it in the category of a myeloproliferative neoplasm. These discoveries have helped us to better understand the biology of LCH so that targeted treatments can be developed.

The distinctive pathologic feature of LCH is proliferation of abnormal histiocytes in an inflammatory background of eosinophils, neutrophils, macrophages, and lymphocytes. On light microscopy, the nuclei are deeply indented and elongated (“coffee bean–shaped”), and the cytoplasm is pale and abundant. Additional diagnostic characteristics include expression of CD1a, S-100, and CD207 (langerin), as detected by immunostaining, and the presence of Birbeck granules, recognizable by their tennis racquet appearance with electron microscopy.

Clinical Findings

LCH can present as a wide spectrum of disease, ranging from an isolated bone lesion or chronic skin rash to a multisystem, life-threatening illness. Historically, LCH was classified into different descriptive categories, including eosinophilic granuloma (single or multiple lytic bone lesions, usually seen in older children and adolescents), Hand-Schüller-Christian disease (lytic bone lesions, exophthalmos, and diabetes insipidus [DI], typically in younger children), Letterer-Siwe disease (a severe, multisystem disorder involving the liver, spleen, lung, skin, and bone marrow, typically in infants aged < 2 years) and Hashimoto-Pritzker disease (also known as congenital self-healing reticulohistiocytosis, a cutaneous form of LCH in neonates that self-resolves during the first months of life). More recently, this terminology has been set aside in favor of a classification scheme based on site of disease, number of sites/organs involved, and the involvement of risk organs (bone marrow, liver, spleen), indicative of more aggressive disease, or CNS-risk lesions, indicative of an increased risk of development of neurodegenerative complications and DI.

The most common sites of disease are bone (80%), skin (33%), and the pituitary (25%). Bone lesions can be single or multiple and can occur anywhere in the skeleton, most commonly the skull. The lesions are usually painful. On plain film, a well-demarcated lytic bone lesion is seen. Vertebral lesions can present as vertebra plana. Lesions of the jaw can lead to loose or missing teeth. The skin rash can resemble seborrheic dermatitis, manifesting as a chronic rash resistant to treatment, or as a scattered papular rash. Involvement of the ear canal can lead to chronic ear drainage. Involvement of the pituitary most often manifests as DI. An MRI scan will show a thickened pituitary stalk and disappearance of the posterior pituitary bright spot on T1-weighted imaging, indicative of loss of vasopressin-containing granules. Other hormones produced by the anterior pituitary, such as growth hormone, can also be affected, leading to other endocrinopathies. Neurodegenerative LCH, manifested as neuromuscular, cognitive, and behavioral changes, is a rare but devastating complication of LCH. Liver, spleen, and bone marrow involvement are less common, though they indicate higher-risk disease. Lung involvement can be seen in young children with multisystem disease or in adults, usually associated with cigarette smoking. CT imaging of the lungs shows a reticulonodular pattern and bullae formation, with risk for spontaneous pneumothorax.

Diagnosis is confirmed by biopsy. Additional workup includes a CBC with differential, ESR, coagulation studies (PT/INR, PTT, fibrinogen), and liver and kidney function studies to screen for multisystem involvement. Measurement of urine osmolality from a first-morning void is a useful screen for DI. Chest x-ray (CXR) screens for pulmonary involvement, skeletal survey evaluates for multifocal bone involvement, and abdominal ultrasound assesses hepatosplenomegaly. PET-CT or technetium-99m bone scan can be used to evaluate extent of disease. PET-CT is particularly helpful in identifying active LCH lesions and monitoring response to therapy. Brain MRI should be obtained with suspicion of pituitary or CNS involvement.

Treatment & Prognosis

Because LCH is a rare disorder with a wide clinical spectrum, it has been difficult to develop standardized diagnostic criteria and treatment regimens. The Histiocyte Society was founded in 1985 to advance knowledge of the disease and develop effective treatments through international collaboration. The society is currently supporting its fourth prospective trial, LCH-IV. The North American Consortium for Histiocytosis (NACHO) has also recently been formed to advance treatment for LCH refractory to standard treatments.

Treatment is based on the location and extent of disease. Isolated lytic bone lesions are generally treated with biopsy and curettage, which leads to healing and resolution of the lesion. Low-dose radiation is effective, though it is avoided in children due to concern for late effects. A study is underway to see if isolated skull lesions can be managed without biopsy and with observation alone if the lesion has a classic appearance by imaging. Isolated skin rashes can be observed and can resolve spontaneously or can be treated with topical steroids or nitrogen mustard. Young patients with isolated skin LCH need to be followed closely, since a significant percentage of them can progress to multisystem disease. Isolated lung LCH in adult smokers will often resolve with smoking cessation.

Multifocal bone disease, multisystem disease, disease involving CNS-risk sites (bones of the skull base and face, which have increased risk for development of DI or neurodegenerative LCH), disease involving risk organs, and disease that involves “special sites” (lesions that risk organ function and are not amenable to surgical treatment, such as vertebral lesions with soft tissue intraspinal extension) are all indications for systemic treatment. First-line treatment is usually with vinblastine and prednisone. The LCH-III study showed that treatment for 1 year led to reduced risk for disease recurrence compared with treatment for 6 months, so 1 year of treatment is currently the standard. LCH-IV is comparing 2 years of treatment with 1 year. Patients with multisystem disease with risk organ involvement also receive 6-mercaptopurine. For adolescent and young adult patients who may not tolerate the side effects of this regimen, single-agent treatment with cytarabine is effective and can be considered.

Multiple other options exist for disease that is recurrent or resistant to first-line treatments. A combination of vincristine and cytarabine is being studied as a second-line treatment in the LCH-IV study. Clofarabine or cladribine (2-Cda) used as single agents can be effective. Other effective agents include methotrexate and indomethacin. A combination of high-dose cytarabine and cladribine is being studied in patients with high-risk disease that fails first-line therapy, a patient population that has a particularly poor prognosis. Allogeneic bone marrow transplant may also be indicated in high-risk patients who fail other therapies.

The discovery of the role of BRAF mutations and the ERK pathway in the pathogenesis of LCH has led to the investigation of the use of kinase inhibitors such as vemurafenib (a BRAF kinase inhibitor) and trametinib (a MEK kinase inhibitor) in treatment of refractory disease. Early results are promising, and studies are ongoing.

In most cases, prognosis for LCH is excellent, though late effects can be problematic. If DI develops, it is usually permanent, requiring lifelong treatment. Late neurodegenerative changes can lead to severe disability or death. A major focus of current research is development of strategies to prevent these complications.

GENERAL CONSIDERATIONS

Blood and marrow transplant (BMT) is considered standard therapy for a variety of pediatric disorders including malignancies, hematologic disorders (bone marrow failure syndromes, aplastic anemia, hemoglobinopathies), inborn errors of metabolism, and severe immunodeficiencies. Autologous transplantation, often referred to as “stem cell rescue,” is infusion of the patient’s own hematopoietic stem cells. This is restricted to the treatment of certain pediatric malignancies, including neuroblastoma, lymphoma, selected brain tumors, germ cell tumors, and Ewing sarcoma. In contrast, allogeneic transplantation rescues hematopoiesis with stem cells from either a related family member or an unrelated individual from a volunteer bank. The selection of a suitable donor who matches the recipient most closely at key HLA loci, HLA-A, B, C, and DR, is critical, as disparities mediate graft rejection and graft-versus-host disease (GVHD). Every child expresses one set of paternal and one set of maternal HLA antigens. Thus, the probability of one child fully matching another full sibling is one in four. When selecting a donor, a fully matched sibling is preferred, assuming they do not have the same underlying disease as the recipient. If a matched sibling is unavailable, alternative donor sources include a matched unrelated donor, umbilical cord blood, or a haploidentical (half-matched) family member, each with their own unique risk/benefit profile. Large worldwide registries of unrelated bone marrow and umbilical cord blood donors have been developed. Unfortunately, identification of a closely matched unrelated donor can be challenging, especially for underrepresented minorities, making haploidentical transplant an important option.

In most instances, high doses of chemotherapy and/or radiation are given to the BMT patient for myeloablation prior to infusion of stem cells that rescue hematopoietic and lymphoid function. In patients with nonmalignant conditions, allogeneic donor stem cells replace the absent or defective hematopoietic or lymphoid elements of the recipient, curing the underlying disease. For children with oncologic disorders, high doses of chemotherapy and/or radiation are used to optimize tumor cell kill by overcoming cancer cell resistance. Additionally, in allogeneic BMT, the donor lymphoid cells may recognize the cancer as foreign and provide an immunologic attack on the malignancy, a concept known as graft-versus-leukemia (GVL).

BMT COMPLICATIONS

Supportive care after BMT includes management of chemotherapy side effects, nutritional support, prevention and treatment of infection, and the use of immunosuppressive medications to reduce the risk of GVHD in allogeneic BMT recipients. For the first several weeks, until the newly transplanted cells engraft, patients are most often pancytopenic and require frequent blood product support. These blood products should be leukocyte reduced to decrease the risk of CMV transmission and irradiated to prevent GVHD from residual lymphocytes that remain even in leukocyte-reduced blood products.

For many months following transplant, patients are profoundly immunocompromised. Infections from bacteria, viruses, fungi, and protozoa account for significant morbidity and mortality, and therefore routine prophylaxis and close surveillance are warranted. During profoundly neutropenic periods, patients often receive empiric coverage with broad-spectrum antibiotics to prevent bacteremia. Acyclovir prophylaxis is used to prevent the reactivation of herpes simplex virus that may occur early in up to 70% of seropositive patients as well as varicella zoster reactivation. Antifungal agents are routinely used to prevent infections from Candida and Aspergillus (Figure 31–1). Trimethoprim-sulfamethoxazole (or equivalent) is used to reduce the risk of P jirovecii pneumonia. While transplant patients will frequently recover neutrophil function within the first few weeks, they remain very lymphopenic for many months, requiring ongoing infectious prophylaxis and prevention often thru the first year or more post-transplant. Despite prophylaxis, overwhelming illness from viral pathogens still occurs. CMV reactivation or de novo infection is relatively common and can result in retinitis, enteritis, and pneumonia. Treatment is usually successful if CMV infection is recognized early therefore routine surveillance is recommended. Common community-acquired viruses can also be life threatening, so prevention is critical. The use of frequent hand washing, contact restriction, and early treatment with available antiviral therapies, such as ribavirin and oseltamivir, can be lifesaving in this population.

GVHD occurs after allogeneic BMT when donor lymphocytes recognize the recipient tissues as foreign and mount an immunologic attack. Despite the use of immunosuppressive agents, anti–T-cell antibodies, and T-cell depletion of the donor graft, 20%–70% of allogeneic BMT patients experience some degree of acute GVHD. Factors influencing GVHD risk include the degree of HLA match, stem cell source, patient age, and donor sex. Acute GVHD generally occurs within the first 100 days after transplant but, on occasion, may occur later. Acute GVHD typically presents with a maculopapular skin rash, secretory diarrhea, and/or cholestatic jaundice. Chronic GVHD generally occurs after day 100 and may involve multiple organ systems; sclerotic skin, malabsorption, weight loss, keratoconjunctivitis sicca, oral mucositis, chronic lung disease, and cholestatic jaundice are common manifestations. Prevention and treatment of GVHD involves use of immunosuppressive agents. Patients on immunosuppressive treatment for GVHD have an increased and protracted risk of all types of infections.

Long-term follow-up of HSCT patients is essential. Patients are at risk for numerous complications, including pulmonary disease, cataracts, endocrine dysfunction affecting growth and fertility, cardiac dysfunction, avascular necrosis of bone, developmental delay, and second malignancies. Although HSCT has many challenges, it represents an important advance in curative treatment for a variety of serious pediatric illnesses.

CELLULAR THERAPEUTICS

Cellular therapy is the transfusion of cells designed to treat or to cure an underlying disease process, such as cancer or a viral infection. To date, the majority of cellular therapy has been administered to patients through clinical research trials. However, in 2017 the FDA approved the first cellular therapy known as CAR T cells for the treatment of pediatric ALL. This therapy involves collection of the patient’s own T cells, which are then genetically engineered to produce chimeric antigen receptors (CARs) expressed on the cell surface. These receptors allow the T cells to recognize an antigen on the tumor cells. In the case of pediatric ALL, this receptor is CD19. After the T cells are engineered to express the CAR, they are expanded in the lab prior to infusion back into the patient. If successful, these T cells expand within the patient and eradicate any cells expressing the antigen the CAR T cells are designed to recognize. Development of CAR T cells against many other tumor antigens is ongoing. Similarly, T cells with activity against specific viruses such as CMV, EBV, and adenovirus can also be selected and expanded ex vivo and then infused into a patient with a known infection. These viral-specific T cells can be obtained from third-party donor banks or, after BMT, can be collected from the stem cell donor. Currently, all administration of viral-specific T cells is done on clinical research trials.

Late effects of treatment by surgery, radiation, and chemotherapy have been identified in survivors of pediatric cancer. Current estimates are that 1 in every 640 adults between the ages of 20 and 39 years is a pediatric cancer survivor. Recently it was reported that the prevalence of poor health status in this group is higher among adult survivors of pediatric cancer than siblings and increases rapidly with age, particularly among female survivors. One recent study found that 60% of survivors of pediatric cancer diagnosed between 1970 and 1986 have at least one chronic condition. Virtually any organ system can demonstrate sequelae related to previous cancer therapy. This has necessitated the creation of specialized oncology clinics whose function is to identify and provide treatment to these patients.

The Childhood Cancer Survivor Study, a pediatric multi-institutional collaborative project, was designed to investigate the various aspects of late effects of pediatric cancer therapy in a cohort of over 13,000 survivors of childhood cancer.

GROWTH COMPLICATIONS

Children who have received cranial irradiation are at highest risk of developing growth complications. Growth complications of cancer therapy in the pediatric survivor are generally secondary to direct damage to the pituitary gland, resulting in growth hormone deficiency. However, new evidence in children treated for ALL suggests that chemotherapy alone may result in an attenuation of linear growth without evidence of catch-up growth once therapy is discontinued. Up to 90% of patients who receive more than 30 Gy of radiation to the CNS will show evidence of growth hormone deficiency within 2 years. Approximately 50% of children receiving 24 Gy will have growth hormone problems. The effects of cranial irradiation appear to be age-related, with children younger than 5 years at the time of therapy being particularly vulnerable. These patients usually benefit from growth hormone therapy. Currently, there is no evidence that such therapy causes a recurrence of cancer.

Spinal irradiation inhibits vertebral body growth. In 30% of treated children, standing heights may be less than the fifth percentile. Asymmetrical exposure of the spine to radiation may result in scoliosis.

Growth should be monitored closely, particularly in young survivors of childhood cancer. Obesity may become an issue for selected survivors who are young at diagnosis and have received whole brain radiation. Follow-up studies should include height, weight, growth velocity, scoliosis examination, and, when indicated, growth hormone testing.

ENDOCRINE COMPLICATIONS

Thyroid dysfunction, manifesting as hypothyroidism, is common in children who received total body irradiation, cranial irradiation, or local radiation therapy to the neck and/or mediastinum. Particularly at risk are children with brain tumors who received more than 3000 cGy and those who received more than 4000 cGy to the neck region. The average time to develop thyroid dysfunction is 12 months after exposure, but the range is wide. Therefore, individuals at risk should be monitored yearly for at least 7 years from the completion of therapy. Although signs and symptoms of hypothyroidism may be present, most patients will have a normal thyroxine level with an elevated thyroid-stimulating hormone level. These individuals should be given thyroid hormone replacement because persistent stimulation of the thyroid from an elevated thyroid-stimulating hormone level may predispose to thyroid nodules and carcinomas. In a recent report from the Childhood Cancer Survivor Study, thyroid cancer occurred at 18 times the expected rate for the general population in pediatric cancer survivors who received radiation to the neck region. Hyperthyroidism, although rare, also occurs in patients who have received neck irradiation.

Precocious puberty, delayed puberty, and infertility are all potential consequences of cancer therapy. Precocious puberty, more common in girls, is usually a result of cranial irradiation causing premature activation of the hypothalamic-pituitary axis. This results in premature closure of the epiphysis and decreased adult height. Luteinizing hormone (LH) analogue and growth hormone are used to halt early puberty and facilitate continued growth.

Gonadal dysfunction in males is usually the result of radiation to the testes. Patients who receive testicular irradiation as part of their therapy for ALL, abdominal irradiation for Hodgkin disease, or total body irradiation for HSCT are at highest risk. Radiation damages both the germinal epithelium (producing azoospermia) and Leydig cells (causing low testosterone levels and delayed puberty). Alkylating agents such as ifosfamide and cyclophosphamide can also interfere with male gonadal function, resulting in oligospermia or azoospermia, low testosterone levels, and abnormal follicle-stimulating hormone (FSH) and LH levels. Determination of testicular size, semen analysis, and measurement of testosterone, FSH, and LH levels will help identify abnormalities in patients at risk. When therapy is expected to result in gonadal dysfunction, pretherapy sperm banking should be offered to adolescent males.

Exposure of the ovaries to abdominal radiation may result in delayed puberty with a resultant increase in FSH and LH and a decrease in estrogen. Girls receiving total body irradiation as preparation for HSCT and those receiving craniospinal irradiation are at particularly high risk for delayed puberty as well as premature menopause. In patients at high risk for development of gonadal complications, a detailed menstrual history should be obtained, and LH, FSH, and estrogen levels should be monitored if indicated.

No studies to date have confirmed an increased risk of spontaneous abortions, stillbirths, premature births, congenital malformations, or genetic diseases in the offspring of childhood cancer survivors. Women who have received abdominal irradiation may develop uterine vascular insufficiency or fibrosis of the abdominal and pelvic musculature or uterus, and their pregnancies should be considered high risk.

CARDIOPULMONARY COMPLICATIONS

Pulmonary dysfunction generally manifests as pulmonary fibrosis. Therapy-related factors known to cause pulmonary toxicities include certain chemotherapeutic agents, such as bleomycin, the nitrosoureas, and busulfan, as well as lung or total body irradiation. Pulmonary toxicity due to chemotherapy is related to the total cumulative dose received. Pulmonary function tests in patients with therapy-induced toxicity show restrictive lung disease, with decreased carbon monoxide diffusion and small lung volumes. Individuals exposed to these risk factors should be counseled to refrain from smoking and to give proper notification of the treatment history if they should require general anesthesia.

Cardiac complications usually result from exposure to anthracyclines (daunorubicin, doxorubicin, and mitoxantrone), which destroy myocytes and lead to inadequate myocardial growth as the child ages, and eventually result in congestive heart failure. The incidence of anthracycline cardiomyopathy increases in a dose-dependent fashion. A recent report indicates that survivors receiving cumulative doses larger than 360 mg/m² were more than 40 times more likely to die of cardiac disease. In a recent study, complications from these agents appeared 6–19 years following administration of the drugs. Pregnant women who have received anthracyclines should be followed closely for signs and symptoms of congestive heart failure, as peripartum cardiomyopathy has been reported.

Radiation therapy to the mediastinal region, which is a common component of therapy for Hodgkin disease, has been linked to an increased risk of coronary artery disease; chronic restrictive pericarditis may also occur in these patients.

Current recommendations include an echocardiogram and electrocardiogram every 1–5 years, depending on the age at therapy, total cumulative dose received, and presence or absence of mediastinal irradiation. Selective monitoring with various modalities is indicated for those who were treated with anthracyclines when they were younger than 4 years or received more than 500 mg/m² of these drugs. Biomarkers such as cardiac troponins and brain natriuretic peptides may be useful in assessing cardiotoxicity of anthracyclines.

RENAL COMPLICATIONS

Long-term renal side effects stem from therapy with cisplatin, alkylating agents (ifosfamide and cyclophosphamide), or pelvic irradiation. Patients who have received cisplatin may develop abnormal creatinine clearance, which may or may not be accompanied by abnormal serum creatinine levels, as well as persistent tubular dysfunction with hypomagnesemia. Alkylating agents can cause hemorrhagic cystitis, which may continue after chemotherapy has been terminated and has been associated with the development of bladder carcinoma. Ifosfamide can also cause Fanconi syndrome, which may result in clinical rickets if adequate phosphate replacement is not provided. Pelvic irradiation may result in abnormal bladder function with dribbling, frequency, and enuresis.

Patients seen in long-term follow-up who have received nephrotoxic agents should be monitored with urinalysis, appropriate electrolyte profiles, and blood pressure. Urine collection for creatinine clearance or renal ultrasound may be indicated in individuals with suspected renal toxicity.

NEUROPSYCHOLOGICAL COMPLICATIONS

Pediatric cancer survivors who have received cranial irradiation for ALL or brain tumors appear to be at greatest risk for neuropsychological sequelae. The severity of cranial irradiation effects varies among individual patients and depends on the dose and dose schedule, the size and location of the radiation field, the amount of time elapsed after treatment, the child’s age at therapy, and the child’s gender. Girls may be more susceptible than boys to CNS toxicity because of more rapid brain growth and development during childhood.

Auditory complications can be seen in childhood cancer survivors exposed to platinum-based chemotherapy and/or temporal or posterior fossa radiation. Difficulty hearing sounds, tinnitus, or hearing loss requiring an aid have been reported.

The main effects of CNS irradiation appear to be related to attention capacities, ability with nonverbal tasks and mathematics, and short-term memory. Recent studies support the association between treatment with high-dose systemic methotrexate, triple intrathecal chemotherapy, and, more recently, dexamethasone and more significant cognitive impairment.

Additionally, pediatric cancer patients have been reported as having more behavior problems and as being less socially competent than a sibling control group. Adolescent survivors of cancer demonstrate an increased sense of physical fragility and vulnerability manifested as hypochondriasis or phobic behaviors.

A recent report from Childhood Cancer Survivor Study noted that when compared to population norms, childhood cancer survivors and siblings report positive psychological health, good health-related quality of life, and life satisfaction. There are, however, subgroups that could be targeted for intervention.

SECOND MALIGNANCIES

Approximately 3%–12% of children receiving cancer treatment will develop a new cancer within 20 years of their first diagnosis. This is a 10-fold increased incidence when compared with age-matched control subjects. Particular risk factors include exposure to alkylating agents, epipodophyllotoxins (etoposide), and radiation therapy, primary diagnosis of retinoblastoma or Hodgkin disease, or the presence of an inherited genetic susceptibility syndrome (LFS or NF). In a recent report, the cumulative estimated incidence of second malignant neoplasms for the cohort of the Childhood Cancer Survivor Study was 3.2% at 20 years from diagnosis.

Second hematopoietic malignancies (acute myelogenous leukemia) occur as a result of therapy with epipodophyllotoxins or alkylating agents. The schedule of drug administration (etoposide) and the total dose may be related to the development of this secondary leukemia.

Children receiving radiation therapy are at risk for developing second malignancies, such as sarcomas, carcinomas, or brain tumors, in the field of radiation. A recent report examining the incidence of second neoplasms in a cohort of pediatric Hodgkin disease patients showed the cumulative risk of a second neoplasm to be as high as 8% at 15 years from diagnosis. The most common solid tumor was breast cancer (the majority located within the radiation field) followed by thyroid cancer. Girls aged 10–16 years when they received radiation therapy were at highest risk and had an actuarial incidence that approached 35% by age 40 years. Secondary gastrointestinal cancer is also increased in pediatric cancer survivors and is related to radiation exposure as well as to certain types of chemotherapeutic agents (procarbazine, platinum).