Major Pediatric Neoplastic Diseases

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Current Diagnosis & Treatment: Pediatrics, 26e
Chapter 31: Neoplastic Disease
MAJOR PEDIATRIC NEOPLASTIC DISEASES
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 Bcell precursors early in their
development, called Bprecursor ALL. Less commonly, lymphoblasts are of Tcell origin or of mature Bcell 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 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 (<
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150,000/μL) and decreased hemoglobin (< 11 g/dL) at diagnosis. In approximately 1% of patients diagnosed with ALL, CBCs and peripheral blood
MAJOR PEDIATRIC NEOPLASTIC DISEASES, Amy K. Keating; Jessica KnightPerry; Kelly Maloney; Jean M. Mulcahy Levy; Brian S. Greffe; Page 1 / 37
smears are entirely normal, but patients have bone pain that leads to bone marrow examination. Serum chemistries, particularly uric acid and lactate
Anna R.K. Franklin; Timothy Prince Garrington
dehydrogenase (LDH), are often elevated at diagnosis as a result of cell breakdown.
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The diagnosis of ALL is made by bone marrow examination, which shows a homogeneous infiltration of leukemic blasts replacing normal marrow
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
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(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
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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. Immunophenotyping and histochemical stains will distinguish ALL, either B or T cell and 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 Tcell ALL. Abdominal ultrasound may show kidney enlargement from leukemic infiltration or uric acid nephropathy as
well as intraabdominal 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 EpsteinBarr 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, can 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 used in induction include oral prednisone or dexamethasone, intravenous vincristine, +/
daunorubicin, 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, 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 and 3 years in COG trials. Treatment for ALL is tailored to prognostic, or risk groups. An
infant younger than 1 year at diagnosis would be considered very high risk and receive even more intensive chemotherapy (Table 31–1). Also important
is the patient’s response to treatment determined by minimal residual disease (MRD) monitoring. This riskadapted treatment approach has
significantly increased the cure rate among patients with less favorable prognostic features by allowing for early intensification while minimizing
treatmentrelated toxicities in those with favorable features. Bone marrow relapse is usually heralded by an abnormal CBC, either during treatment or
following completion of therapy.
Table 31–1.
Risk group for Bcell ALL.
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MAJOR PEDIATRIC NEOPLASTIC DISEASES, Amy K. Keating; Jessica KnightPerry; Kelly Maloney; Jean M. Mulcahy Levy; Brian S. Greffe;
NCI Standard Risk NCI High Risk Infant ALL
is the patient’s response to treatment determined by minimal residual disease (MRD) monitoring. This riskadapted treatment approach has
significantly increased the cure rate among patients with less favorable prognostic features by allowing for early intensification while minimizing
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treatmentrelated toxicities in those with favorable features. Bone marrow relapse is usually heralded by an abnormal CBC, either during treatment or
following completion of therapy.
Table 31–1.
Risk group for Bcell ALL.
NCI Standard Risk NCI High Risk Infant ALL
1–9 y ≥ 10 y or > 1 y due to high WBC Age < 1 y
Initial WBC < 50,000/μL Initial WBC ≥ 50,000/μL, regardless of age Any WBC
No CNS leukemia CNS leukemia Could be negative or positive
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 onethird 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. Most 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 followup of boys both on and off treatment includes physical examination of the testes.
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 positive MRD at the end of the second or third month of 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 leukemiafree
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 Tcell engager (BiTE) that brings the CD19 on a leukemia cell in direct
contact with a T cell. Blinatumomab was found to improve outcome following relapse and was recently published. Another targeted agent, Inotuzumab
is an antibodydrug conjugate against CD22, also frequently found on the surface of the leukemia cells. This drug is also used in relapsed childhood
ALL. Both of these drugs have now been moved to initial therapy in the COG studies for standard risk and high risk B ALL, respectively. 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 while
maintaining and improving leukemiafree survival.
B. Supportive Care
Tumor lysis syndrome, which consists of hyperkalemia, hyperuricemia, and 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 graftversushost disease (GVHD) from the transfused lymphocytes. Whenever possible, blood
products should be leukodepleted 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 lifethreatening 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 broadspectrum antibiotics. Patients receiving ALL treatment must
receive prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). Trimethoprimsulfamethoxazole 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 varicellazoster immune globulin (VZIG) within 72 hours after exposure and treatment with intravenous acyclovir for active infection.
Prognosis
and platelet products should be irradiated to prevent graftversushost disease (GVHD) from the transfused lymphocytes. Whenever possible, blood
products should be leukodepleted to minimize CMV transmission, transfusion reactions, and sensitization to platelets.
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Due to the immunocompromised state of the patient with ALL, bacterial, fungal, and viral infections are serious and can be lifethreatening 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 broadspectrum antibiotics. Patients receiving ALL treatment must
receive prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). Trimethoprimsulfamethoxazole 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 varicellazoster 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 a leukemiafree 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 leukemiafree 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 ETV6AML1 rearrangement have a greater chance of cure, approaching 95%–97% eventfree survival (EFS),
than do children without these characteristics.
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ACUTE MYELOID LEUKEMIA
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 onethird of deaths from leukemia in children and teenagers. Congenital conditions
associated with an increased risk of AML include DiamondBlackfan anemia; neurofibromatosis (NF); Down; WiskottAldrich, Kostmann, and Li
Fraumeni syndromes; and 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 31–2). Cytogenetic clonal abnormalities occur in 80% of patients with AML and are
often predictive of outcome.
Page 4 / 37
WHO classification of acute myeloid leukemia (AML) and related neoplasms.
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
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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 31–2). Cytogenetic clonal abnormalities occur in 80% of patients with AML and are
often predictive of outcome.
WHO classification of acute myeloid leukemia (AML) and related neoplasms.
AML with recurrent genetic abnormalities AML with t(8;21)(q22;q22), RUNX1RUNX1T1
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;p22); CBFBMYH11
Acute promyelocytic leukemia with t(15;17)(q22;q12);PMLRARA
AML with t(9;11)(p22;q23)MLLT3MLL
AML with t(6:9)(p23;q34); DEKNUP214
AML with inv(3)(q21q26.2) or t(3.3)(q21;q26.2); RPN1EVl1
AML (megakaryoblastic) with t(1:22)(p13;q13); RBM15MKL1
AML with mutated NPM1
AML with mutated CEBPA
AML with myelodysplasiarelated changes
Therapyrelated myeloid neoplasms
AML, not otherwise specified AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Myeloid proliferation related to Down syndrome Transient abnormal myelopoiesis
Myeloid leukemia associated with Down syndrome
Data from Vardiman JW, Thiele J, Arber DA et al: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia:
rationale and important changes. Blood 2009 Jul 30;114(5):937–951.
Table 31−2.
FAB subtypes of acute myeloid leukemia.
Distribution in
Childhood (Age)
FAB < 2 y Cytogenetic

Common Name > 2 y (%) Clinical Features
Classification (%) Associations
M0 Acute myeloid leukemia, minimally 1 inv (3q26), t(3;3)
differentiated
M1 Acute myeloblastic leukemia without 17 23
maturation
M2 Acute myeloblastic leukemia with 26 t(8;21), t(6;9); rare Myeloblastomas or chloromas
maturation
Myeloid leukemia associated with Down syndrome
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Data from Vardiman JW, Thiele J, Arber DA et al: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia:
rationale and important changes. Blood 2009 Jul 30;114(5):937–951.
Table 31−2.
FAB subtypes of acute myeloid leukemia.
Distribution in
Childhood (Age)
FAB < 2 y Cytogenetic

Common Name > 2 y (%) Clinical Features
Classification (%) Associations
M0 Acute myeloid leukemia, minimally 1 inv (3q26), t(3;3)
differentiated
M1 Acute myeloblastic leukemia without 17 23
maturation
M2 Acute myeloblastic leukemia with 26 t(8;21), t(6;9); rare Myeloblastomas or chloromas

maturation
M3 Acute promyelocytic leukemia 4 t(15;17); rarely, Disseminated intravascular coagulation

t(11;17) or (5;17)
M4 Acute myelomonoblastic leukemia 30 24 11q23, inv 3, t(3;3), Hyperleukocytosis, CNS involvement,

t(6;9) skin and gum infiltration
M4Eo Acute myelomonoblastic leukemia with inv16, t(16;16)

abnormal eosinophils
M5 Acute monoblastic leukemia 46 15 11q23, t(9;11), Hyperleukocytosis, CNS involvement,

t(8;16) skin and gum infiltration
M6 Erythroleukemia 2
M7 Acute megakaryoblastic leukemia 7 5 t(1;22) Down syndrome frequent (< age 2 y)
CNS, central nervous system; FAB, FrenchAmericanBritish classification.
Aggressive induction therapy currently results in a 75%–85% complete remission rate. However, longterm 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 lifethreatening 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
Hyperleukocytosis may be associated with lifethreatening 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
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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 may undergo allogeneic bone marrow transplant while those without an appropriate related donor are treated with additional
cycles of aggressive chemotherapy for a total of five cycles. Inv16 and t(8;21) herald a more chemotherapyresponsive 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, chromosomal
rearrangements at 11q23, FLT3 internal tandem duplications (ITDs), and newer molecular subtypes. 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. Acute promyelocytic leukemia, associated with t(15;17)
demonstrated either cytogenetically or molecularly, is currently treated with all transretinoic acid, a differentiating therapy, and arsenic trioxide in
addition to chemotherapy with highdose cytarabine and daunorubicin when needed. All transretinoic acid leads to differentiation of promyelocytic
leukemia cells and can induce remission, but cure requires conventional chemotherapy as well. This subtype has an increased EFS over other AML
subtypes.
Another biologically distinct subtype of AML occurs in children with Down syndrome, almost exclusively acute megakaryoblastic leukemia. 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 group of agents called FLT3
inhibitors appear to be active against AML with Flt3 ITDs. Combining these agents with AML therapy has been useful in relapsed disease and is now
being studied in upfront trials for pediatric patients. In addition, gemtuzumab ozogamicin, an antibodydrug conjugate directed against CD33 on AML
cells, is used to treat AML, both upfront and in relapse.
B. Supportive Care
Tumor lysis syndrome occurs less often during induction treatment of AML (treatment outlined in ALL section). Hyperleukocytosis (WBC > 100,000/μL)
is a medical emergency and, in a symptomatic patient, requires rapid intervention 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 APML and monocytic AML subtypes prior to beginning induction
chemotherapy. Other supportive care measures are similar to ALL.
There is an increased risk for fever and neutropenia in patients being treated with AML as compared to AML and a higher risk of mortality associated
with infection. These patients received prophylactic antibiotics with conversion to prompt initiation of broadspectrum antibiotics with fever. Because
of the high incidence of invasive fungal infections, patients should receive prophylactic antifungals with a low threshold to change to treatment doses.
It must be stressed that the supportive care for this group of patients is as important as the leukemiadirected 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 5year 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 70%–75% longterm 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.
Cooper TM, Ries RE, Alonzo TA et al: Revised risk stratification criteria for children with newly diagnosed acute myeloid leukemia: a report from the
Prognosis Universidad del Rosario
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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 5year 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 70%–75% longterm 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.
Cooper TM, Ries RE, Alonzo TA et al: Revised risk stratification criteria for children with newly diagnosed acute myeloid leukemia: a report from the
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Getz KD, Alonzo TA, Sung L et al: Four versus five chemotherapy courses in patients with low risk acute myeloid leukemia: a Children’s Oncology
Group report. J Clin Oncol 2017;35:10515–10515.
Klein K, de Haas V, Kapers GJL: Clinical challenges in de novo pediatric acute myeloid leukemia. Expert Rev Anticancer Ther 2018 Mar;18(3):277–293
[PubMed: 29338495] .
Rubnitz JE: Current management of childhood acute myeloid leukemia. Paediatr Drugs 2017 Feb;19(1):1–10
[PubMed: 27785777] .
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 31–3).
Table 31−3.
Comparison of JMML, CML, and TMD.
CML TMD JMML
Age at onset > 3 y < 3 mo < 2 y
Clinical Nonspecific constitutional complaints, DS features, often no or Abrupt onset; eczematoid skin rash, marked

presentation massive splenomegaly, variable few symptoms; or lymphadenopathy, bleeding tendency, moderate
hepatomegaly hepatosplenomegaly, hepatosplenomegaly, fever
respiratory symptoms
Chromosomal t(9;22) Constitutional trisomy Monosomy or del (7q) in 20% of patients

alterations 21, but usually no other
abnormality
Laboratory Marked leukocytosis (> 100,000/μL), normal to Variable leukocytosis, Moderate leukocytosis (> 10,000/μL), thrombocytopenia,

features elevated platelet count, decreased to absent normal to high platelet monocytosis (> 1000/μL), elevated fetal hemoglobin,
leukocyte alkaline phosphatase, usually count, large platelets, normal to diminished leukocyte alkaline phosphatase,
normal muramidase myeloblasts elevated muramidase
CML, chronic myelogenous leukemia; DS, Down syndrome; JMML, juvenile myelomonocytic leukemia; TMD, transient myeloproliferative disorder.
1. Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) with translocation of chromosomes 9 and 22 (the Philadelphia chromosome, Ph+) is identical to adult Ph+CML.
normal muramidase myeloblasts elevated muramidase
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CML, chronic myelogenous leukemia; DS, Down syndrome; JMML, juvenile myelomonocytic leukemia; TMD, transient myeloproliferative disorder.
1. Chronic Myelogenous Leukemia
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. Without treatment, CML usually progresses within 3 years to
an accelerated phase and then to a blast crisis. 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. 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. Tumor lysis syndrome and leukostasis secondary to hyperleukocytosis are rare in CML, in contrast to acute
leukemias.
Treatment & Prognosis
TKIs are standard upfront therapy for CML, which were rationally designed based on the molecular mechanism of the pathogenesis of CML.
Hydroxyurea can be added in the beginning for cytoreduction. There are a variety of TKIs to choose from for CML, all with different side effect profiles.
Typically, imatinib and dasatinib are common choices for initial therapy. Bosutinib is a newer TKI for CML that may be important for young children
with CML as it does not target PDGFR and other tyrosine kinases that affect growth.
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 onethird of the myelodysplastic and myeloproliferative disorders in
childhood. Patients with neurofibromatosis type 1 (NF1) 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 NF1 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 longterm using HSCT, although optimizing conditioning regimens and donor selection may improve these results.
Hasle H: Myelodysplastic and myeloproliferative disorders of childhood. Hematology Am Soc Hematol Educ Program 2016 Dec 2;2016(1):598–604
[PubMed: 27913534] .
Patients with JMML present similarly to those with other hematopoietic malignancies, with lymphadenopathy, hepatosplenomegaly, skin rash, or
respiratory symptoms. Patients may have stigmata of NF1 with neurofibromas or café au lait spots. Laboratory findings include anemia,
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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 longterm using HSCT, although optimizing conditioning regimens and donor selection may improve these results.
Hasle H: Myelodysplastic and myeloproliferative disorders of childhood. Hematology Am Soc Hematol Educ Program 2016 Dec 2;2016(1):598–604
[PubMed: 27913534] .
Hijiya N, Millot F, Suttorp M: Chronic myeloid leukemia in children: clinical findings, management, and unanswered questions. Pediatr Clin North Am
2014 Feb;62(1):107–119
[PubMed: 25435115] .
Hijiya N, Suttorp M: How I treat chronic myeloid leukemia in children and adolescents. Blood 2019 May 30;133(22):2374–2384
[PubMed: 30917954] .
Niemeyer CM: JMML genomics and decisions. Hematology Am Soc Hematol Educ Program 2018 Nov 30;2018(1):307–312
[PubMed: 30504325] .
Tunstall O et al: Guidelines for the investigation and management of transient leukaemia of Down syndrome. Br J Haematol 2018;182:200–211
[PubMed: 29916557] .
BRAIN TUMORS
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. 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. In general, children with brain tumors have a better prognosis than adults.
Brain tumors in childhood are biologically and histologically heterogeneous, ranging from lowgrade localized lesions to highgrade tumors with
neuraxis dissemination. Highdose systemic chemotherapy is used frequently, especially in young children with highgrade 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, although some are associated with genetic predisposition syndromes such as astrocytomas
in children with NF or tuberous sclerosis. All children with gliomas and meningiomas should be screened for NF1. In children with meningiomas,
without the skin findings of NF1, NF2, and von HippelLindau 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 lifelong screening and may have an improved response to immunotherapy.
The risk of developing a brain tumor is also increased in children who received cranial irradiation for treatment of meningeal leukemia. Careful family
histories should be taken in these tumors and genetic counseling considered if this is indicative of CMMRD, familial polyposis, or LiFraumeni
syndrome (LFS).
Clinical Findings
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. Eye findings and apparent visual disturbances
such as difficulty tracking can occur in association with optic pathway tumors. These eye and visual changes have some potential for improvement with
therapy, although permanent loss of vision may occur. 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. Headaches are common, but they often will not be predominantly in the morning and may be confused with migraine. If neurologic
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
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children, papilledema is often absent. Measuring head circumference and observing gait are essential. Eye findings and apparent visual disturbances
such as difficulty tracking can occur in association with optic pathway tumors. These eye and visual changes have some potential for improvement with
therapy, although permanent loss of vision may occur. 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. Headaches are common, but they often will not be predominantly in the morning and 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 bloodbrain 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 gadoliniumenhanced 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 for cytologic examination 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. Levels of biomarkers in the blood and CSF, such as
human chorionic gonadotropin and αfetoprotein, may be helpful in diagnosis and followup. Both human chorionic gonadotropin and αfetoprotein
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 neurooncologist.
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/RT 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 highgrade tumors are found in most categories. Table 31–4 lists the locations and frequencies of the
common pediatric brain tumors.
Table 31−4.
Location and frequency of common pediatric brain tumors.
Location Frequency of Occurrence (%)
Hemispheric 37 Page 11 / 37
Lowgrade astrocytoma 23
astrocytomas and ependymomas, or (2) embryonal tumors, such as medulloblastoma and AT/RT 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
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plexus tumors, and meningiomas). Low and highgrade tumors are found in most categories. Table 31–4 lists the locations and frequencies of the
common pediatric brain tumors.
Table 31−4.
Location and frequency of common pediatric brain tumors.
Location Frequency of Occurrence (%)
Hemispheric 37
Lowgrade astrocytoma 23
Highgrade astrocytoma 11
Other 3
Posterior fossa 49
Medulloblastoma 15
Cerebellar astrocytoma 15
Brainstem glioma 15
Ependymoma 4
Midline 14
Craniopharyngioma 8
Chiasmal glioma 4
Pineal region tumor 2
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. Lowgrade astrocytomas, especially those in the cerebellum may be curable by complete
surgical excision alone. Upfront chemotherapy is effective alone in about 40%–50% of lowgrade astrocytomas but many will need multiple treatment
courses. The recent advent of targeted therapy for mutations common in these tumors offers the potential for better outcomes.
Medulloblastoma are the most common highgrade brain tumors in children and are now molecularly classified into four subgroups: WNT, SHH, Group
3, and Group 4. These tumors usually occur in the first decade of life, with a peak incidence between ages 5 and 10 years and a femalemale ratio of
2.1:1.3. The tumors typically arise in the midline cerebellar vermis, with variable extension into the fourth ventricle. Neuroaxis dissemination at
diagnosis affects from 10% to 46% of patients. Prognostic factors are outlined in Table 31–5. Determination of risk to date has largely used histology,
age, and stage, but molecular classifications is increasingly used to determine therapy.
Table 31−5.
Prognostic factors in children with medulloblastoma.
Factor Favorable Unfavorable
Extent of disease Nondisseminated Disseminated
Histologic features Undifferentiated, desmoplastic Large cell, anaplastic

Age ≥ 4 y < 4 y Page 12 / 37
Molecular tumor characteristics WNT, young patients with SHH MYC, MYCN
diagnosis affects from 10% to 46% of patients. Prognostic factors are outlined in Table 31–5. Determination of risk to date has largely used histology,
age, and stage, but molecular classifications is increasingly used to determine therapy. Universidad del Rosario
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Table 31−5.
Prognostic factors in children with medulloblastoma.
Factor Favorable Unfavorable
Extent of disease Nondisseminated Disseminated
Histologic features Undifferentiated, desmoplastic Large cell, anaplastic
Age ≥ 4 y < 4 y
Molecular tumor characteristics WNT, young patients with SHH MYC, MYCN
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 longterm 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 to diffuse midline glioma with or without 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 with recommended 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 as it does not induce liver enzymes or interact with
chemotherapy. Because postoperative treatment of young children with highgrade 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 longterm morbidity. Longterm neuropsychological morbidity becomes an
especially important issue related to deficits caused by the tumor itself and the sequelae of treatment. Maximal safe surgical resection 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. Secondlook 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 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 germcell tumors and further reduction of craniospinal radiation dosing in medulloblastoma have not been successful. In others (eg,
ependymoma), craniospinal irradiation has been abandoned because 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. Page 13 / 37
Chemotherapy is effective in treating lowgrade 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
pediatric brain tumors. Secondlook 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 dissemination (eg, medulloblastoma),
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craniospinal irradiation is still standard therapy in children older than 3 years. Attempts at elimination of craniospinal radiation for certain types of
intracranial germcell tumors and further reduction of craniospinal radiation dosing in medulloblastoma have not been successful. In others (eg,
ependymoma), craniospinal irradiation has been abandoned because 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 lowgrade 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 intensive chemotherapy after tumor resection and delaying or omitting radiation therapy. Superior results seem to have
been obtained in the very young with highdose 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 neurooncology 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 newdefined biology are ongoing.
In older children with malignant glioma, the current approach is surgical resection of the tumor and combinedmodality treatment with irradiation and
intensive chemotherapy. It has recently been realized there is considerable heterogeneity in pediatric highgrade 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 highgrade gliomas, and there has been little progress in
finding better chemotherapeutic agents and strategies for most children with these devastating tumors.
The treatment of lowgrade astrocytomas with chemotherapy has likewise shown only disappointing progress. However, there are potentially exciting,
targeted agents in ongoing, and completed but unreported, lowgrade 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 highgrade glial tumors. For children with
highgrade gliomas, an early CCG study showed a 45% progressionfree survival rate for children who received radiation therapy and chemotherapy,
but this may have been due to the inclusion of lowgrade 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 10year survival rate for lowgrade 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 lowgrade astrocytoma of childhood, relatively moderate chemotherapy may
improve the likelihood of survival.
Conventional craniospinal irradiation for children with lowstage medulloblastoma results in survival rates of 60%–90%. Tenyear survival rates are
lower (40%–60%). Chemotherapy allows a reduction in the craniospinal radiation dose while improving survival rates for averagerisk patients (86%
survival at 5 years on the most recent COG averagerisk protocol). However, even reduceddose craniospinal irradiation has an adverse effect on
intellect, especially in children younger than 7 years. Fiveyear survival rates for highrisk 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.
Buczkowicz P et al: Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1
mutations. Nat Genet 2014;46(5):451–456
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context of recent treatment failures using reduced therapy regimens. The increasing emphasis is on the quality of life of survivors, not just the survival
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Buczkowicz P et al: Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1
mutations. Nat Genet 2014;46(5):451–456
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Chi SN et al: Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol 2009;20:385
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insights. Curr Neuropharmacol 2018 Aug;16(7):1045–1058 [PMCID: PMC6120114].
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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 onehalf
of all cases. The remaining subtypes, referred to collectively as nonHodgkin lymphoma (NHL), are divided into four main groups: lymphoblastic
lymphoma (LL), small noncleaved cell lymphoma, large Bcell 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 lifethreatening) 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
Children with Hodgkin lymphoma have a better response to treatment than do adults, with 5 to 10year overall survival rate of greater than 90% 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 longterm 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: nodular lymphocytepredominant
(10%–20%); nodular sclerosing (40%–60%) (increases with age); mixed cellularity (20%–40%); and lymphocytedepleted (5%–10%). Prognosis is
independent of subclassification, with appropriate therapy based on stage (see section Staging). Of note, nodularlymphocyte predominant HL is
treated differently than the other subtypes, which compromise classical HL.
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.
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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: nodular lymphocytepredominant
(10%–20%); nodular sclerosing (40%–60%) (increases with age); mixed cellularity (20%–40%); and lymphocytedepleted (5%–10%). Prognosis is
independent of subclassification, with appropriate therapy based on stage (see section Staging). Of note, nodularlymphocyte predominant HL is
treated differently than the other subtypes, which compromise classical HL.
Clinical Findings
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 onethird 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.
Onehalf 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.
The CBC is usually normal, although anemia, neutrophilia, eosinophilia, and thrombocytosis may be present. The erythrocyte sedimentation rate (ESR)
and other acutephase 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 advancedstage 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 CT scan of the neck, chest,
abdomen, and pelvis, as well as a positron emission tomography (PET) scan. Bone marrow aspirates and biopsies may not be required or performed
but often bone marrow involvement can be determined by PET scan.
D. Pathologic Findings
The diagnosis of Hodgkin lymphoma requires the histologic presence of the ReedSternberg cell or its variants in tissue. ReedSternberg cells are
germinalcenter 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 decisions are based on stage and presence of B symptoms, tumor bulk, and number of involved nodal regions. To achieve longterm
diseasefree survival while minimizing treatment toxicity, Hodgkin disease is increasingly treated by chemotherapy and or immunotherapy alone—and
less often by radiation therapy. Page 16 / 37
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 AVPC (Adriamycin [doxorubicin], vincristine, prednisone, and
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.
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Treatment decisions are based on stage and presence of B symptoms, tumor bulk, and number of involved nodal regions. To achieve longterm
diseasefree survival while minimizing treatment toxicity, Hodgkin disease is increasingly treated by chemotherapy and or immunotherapy 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 AVPC (Adriamycin [doxorubicin], vincristine, prednisone, and
cyclophosphamide) is sufficient to induce a complete response in patients with lowrisk Hodgkin lymphoma. Two additional drugs, bleomycin and
etoposide, are currently added in the treatment of intermediaterisk patients for a total of 4–6 months of therapy for patients with intermediaterisk
disease. The removal of involved field irradiation in patients with intermediaterisk Hodgkin lymphoma who respond early to chemotherapy has been
shown to maintain excellent outcomes. Combinedmodality therapy with chemotherapy and irradiation is used in advanced disease.
Current treatment gives an overall 5year survival of 90%–95% to children with stages I and II Hodgkin lymphoma. Twothirds 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 longterm 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 immunotherapies have been incorporated into clinical trials for children with highrisk Hodgkin lymphoma, including antibody drug
conjugates and checkpoint inhibitors. Brentuximab vedotin is an antiCD30 murine/human chimeric monoclonal antibody linked to monomethyl
auristatin E that targets CD30 which is highly expressed in Hodgkin lymphoma. Checkpoint inhibitors pembrolizumab and nivolumab that block PD1
have recently been approved for recurrent Hodgkin lymphoma, as the tumor cells consistently express their target PDL1 and PDL2.
Friedman DL et al: Doseintensive responsebased chemotherapy and radiation therapy for children and adolescents with newly diagnosed
intermediaterisk Hodgkin lymphoma: a report from the Children’s Oncology Group Study AHOD0031. J Clin Oncol 2014;32:3561
[PubMed: 25311218] .
Kelly K: Hodgkin Lymphoma in children and adolescents: improving the therapeutic index. Blood 2015 Nov 26;126(22):2452–2458
[PubMed: 26582374] .
MauzKörholz C et al: Pediatric Hodgkin lymphoma. J Clin Oncol 2015 Sep 20;33(27):2975–2985. doi: 10.1200/JCO.2014.59.4853. Epub 2015 Aug 24
[PubMed: 26304892] .
Younes A, Ansell SM: Novel agents in the treatment of Hodgkin lymphoma: biological basis and clinical results. Semin Hematol 2016 Jul;53(3):186–189
[PubMed: 27496310] .
2. NonHodgkin Lymphoma
NonHodgkin 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, WiskottAldrich
syndrome, severe combined immunodeficiency syndrome, Xlinked lymphoproliferative syndrome, human immunodeficiency virus [HIV] infection,
immunosuppressive therapy following solidorgan or marrow transplantation) have an increased risk of developing NHLs. Their risk is estimated to be
100–10,000 times that of agematched 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
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).
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Most children who develop NHL are immunologically normal. However, children with congenital or acquired immune deficiencies (eg, WiskottAldrich
syndrome, severe combined immunodeficiency syndrome, Xlinked lymphoproliferative syndrome, human immunodeficiency virus [HIV] infection,
immunosuppressive therapy following solidorgan or marrow transplantation) have an increased risk of developing NHLs. Their risk is estimated to be
100–10,000 times that of agematched 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 are potential triggers in the development of NHL.
Unlike adult NHL, virtually all childhood NHLs are rapidly proliferating, highgrade, 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 Burkittlike 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 31–6.
Table 31−6.
Comparison of pediatric nonHodgkin lymphomas.
Small Noncleaved Cell Large BCell Anaplastic Large Cell

Lymphoblastic Lymphoma
Lymphoma (BL and BLL) Lymphoma Lymphoma
Incidence (%) 30−40 35−50 10−15 10−15
Histopathologic Indistinguishable from ALL Large nucleus with prominent Large cells with cleaved or Large pleomorphic cells

features lymphoblasts nucleoli surrounded by very noncleaved nuclei
basophilic cytoplasm that contains
lipid vacuoles
Immunopheno Immature T cell B cell B cell T cell or null cell

type
Cytogenetic Translocations involving t(8;14), t(8;22), t(2;8) Many t(2;5)

markers chromosome 14q11 and
chromosome 7; interstitial
deletions of chromosome 1
Clinical Intrathoracic tumor, mediastinal Intraabdominal tumor (90%), jaw Abdominal tumor most Lymphadenopathy, fever,

presentation mass (50%−70%), involvement (10%−20% sporadic BL, common; unusual sites: weight loss, night sweats,
lymphadenopathy above 70% endemic BL), bone marrow lung, face, brain, bone, extranodal sites including
diaphragm (50%−80%) involvement testes, muscle viscera and skin
Treatment Similar to ALL therapy; 24 mo Intensive administration of Similar to therapy for Similar to therapy for

duration alkylating agents and methotrexate; BL/BLL lymphoblastic lymphoma or
CNS prophylaxis; 3−9 mo duration BL/BLL
ALL, acute lymphoblastic leukemia; BL, Burkitt lymphoma; BLL, Burkittlike lymphoma; CNS, central nervous system.
Clinical Findings
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 similar to ALL. For Tcell LL, symptoms of airway compression (cough, dyspnea, orthopnea) or superior
Clinical Findings Universidad del Rosario
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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 similar to ALL. For Tcell LL, symptoms of airway compression (cough, dyspnea, orthopnea) or superior
vena cava obstruction (facial edema, chemosis, plethora, venous engorgement) 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 31–7).
Table 31−7.
Comparison of endemic and sporadic Burkitt lymphoma.
Endemic Sporadic
Incidence 10 per 100,000 0.9 per 100,000
Cytogenetics Chromosome 8 breakpoint upstream of cmyc locus Chromosome 8 breakpoint within cmyc locus
EBV association ≥ 95% ≤ 20%
Disease sites at Jaw (58%), abdomen (58%), CNS (19%), orbit (11%), marrow Jaw (7%), abdomen (91%), CNS (14%), orbit (1%), marrow

presentation (7%) (20%)
CNS, central nervous system; EBV, EpsteinBarr virus.
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 Bcell 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 may need to be avoided if the airway or vena cava is significantly 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 lifethreatening 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
Page 19 / 37
A. Supportive Care
The management of lifethreatening problems at presentation is critical. The most common complications are acute tumor lysis syndrome, superior
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
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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 lifethreatening problems at presentation is critical. The most common complications are acute tumor lysis syndrome, superior
vena cava syndrome, airway compromise, and cardiac tamponade. 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 lowdose 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 doseintensive, multiagent chemotherapy. The duration of
therapy is 2 years. Treatment of BL, BLL, and LCBL consists of alkylating agents and intermediate to highdose methotrexate administered intensively,
but for a relatively short time as it produces the highest cure rates. Addition of rituximab (antiCD20 monoclonal antibody) to the chemotherapy
backbone has improved EFS and OS. Doseadjusted EPOCHR has demonstrated improved outcomes in adults with primary mediastinal Bcell
lymphoma and gray zone lymphomas. Clinical trials utilizing this regimen are ongoing in children with these rare NHLs.
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 Nterminal region to the intracellular part of ALK and is the
defining genetic lesions in ALKpositive ALCL. ALCL often express CD30 and studies are ongoing combining chemotherapy with brentuximab vedotin or
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 longterm,
diseasefree 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% failurefree 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 Tcell lymphoblastic
leukemia/lymphoma is particularly poor (3year EFS rates < 20%). Patients who experience relapse may have a chance for cure by autologous or
allogeneic HSCT.
Minard Collin et al: Rituximab for high risk, mature Bcell NonHodgkin lymphoma in children. N Engl J Med 2020;382:2207–2219. [PubMed: 32492302]
Sandlund et al: NonHodgkin lymphoma across the pediatric and adolescent and young adult age spectrum. Hematology Am Soc Hematol Educ
Program 2016 Dec 2;2016(1):589–597
[PubMed: 27913533] .
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.
Page 20 / 37
A. Posttransplantation Lymphoproliferative Disorders
[PubMed: 27913533] .
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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 (antiCD20), for the treatment of PTLDs has been promising in clinical trials. More recently, Tcell–based immune
therapies, such as donor lymphocyte infusions and adoptive transfer of EBVspecific cytotoxic T lymphocytes, have also been explored as novel
approaches.
B. Spontaneous Lymphoproliferative Disease
Immunodeficiencies in which LPDs occur include Bloom syndrome, ChédiakHigashi syndrome, ataxiatelangiectasia, WiskottAldrich syndrome, X
linked lymphoproliferative syndrome, congenital Tcell 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.
Weintraub L et al: Identifying predictive factors for posttransplant lymphoproliferative disease in pediatric solid organ transplant recipients with
EpsteinBarr virus viremia. J Pediatr Hematol Oncol 2014;36:e481
[PubMed: 24878618] .
Yang X et al: Lymphoproliferative disorders in immunocompromised individuals and therapeutic antibodies for treatment. Immunotherapy
2013;5:415
[PubMed: 23557424] .
NEUROBLASTOMA
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 highrisk 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
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.
from spontaneous regression to relentless progression despite aggressive therapy. Historically, cure rates for patients with highrisk neuroblastoma
were very poor. With promising recent advances, however, cure rates have been steadily improving, albeit at the price of significant toxicity from
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treatment.
Clinical Findings
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 opsoclonusmyoclonusataxia (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 crossreacting antineuronal
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.
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.
I123Metaiodobenzylguanidine (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. PETCT can be utilized in patients whose tumors are MIBG nonavid (8.7% of cases).
MIBG and PETCT scanning have supplanted technetium99m 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 31–8), though a newer,
International Neuroblastoma Risk Group (INRG) staging system that incorporates imagedefined 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.
Table 31−8.
International Neuroblastoma Staging System.
Stage Description
1 Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for
tumor microscopically.
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. Universidad del Rosario
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Table 31−8.
International Neuroblastoma Staging System.
Stage Description
1 Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for
tumor microscopically.
2A Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
2B Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged lymph nodes
must be negative microscopically.
3 Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor
with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node
involvement. The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or
beyond the opposite side of the vertebral column.
4 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, or other organs, except as defined for stage 4S.
4S Localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, or bone marrow, and limited to infants aged <
1 y. Marrow involvement should be < 10% of nucleated cells.
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.
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 highrisk disease.
For lowrisk 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 lowrisk 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 intermediaterisk 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%.
Highrisk 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 GMCSF to enhance immunemediated cell killing. These treatments are alternated with treatments with 13cisretinoic acid, an agent that induces
terminal differentiation of neuroblastoma cells. Results of recent studies incorporating all of these treatment modalities are encouraging, with 5year
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
Highrisk 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
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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 GMCSF to enhance immunemediated cell killing. These treatments are alternated with treatments with 13cisretinoic acid, an agent that induces
terminal differentiation of neuroblastoma cells. Results of recent studies incorporating all of these treatment modalities are encouraging, with 5year
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
121MIBG into the upfront treatment regimen. Also, use of targeted therapies, such as ALK inhibition in patients whose tumors express ALK mutations,
is being investigated. Despite advancements, highrisk neuroblastoma remains a challenging disease, and much work remains to improve cure rates
while minimizing the toxicity of treatment.
Maris JM: Recent advances in neuroblastoma. N Engl J Med 2010;362:2202–2211
[PubMed: 20558371] .
National Cancer Institute: http://www.cancer.gov/cancertopics/types/neuroblastoma.
Nuchtern JG et al: A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children’s Oncology Group
study. Ann Surg 2012;256:573–580
[PubMed: 22964741] .
Park J et al: Effect of tandem autologous stem cell transplant vs single transplant on eventfree survival in patients with highrisk neuroblastoma: a
randomized clinical trial. JAMA 2019 Aug 27;322(8):746–755 [PMCID: PMC6714031].
Tolbert VP, Matthay KK: Neuroblastoma: clinical and biological approach to risk stratification and treatment. Cell Tissue Res 2018 May;372(2):195–209
[PMCID: PMC5918153].
WILMS TUMOR (NEPHROBLASTOMA)
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, DenysDrash 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
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.
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 Page 24 / 37
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
occurs in approximately 25% of patients.
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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.
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 (NWTS4) 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 31–9 provides an overview of the current treatment recommendations in NWTS5. 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 secondlook renalsparing surgery. Radiation therapy may also be necessary.
Table 31−9.
Treatment of Wilms tumor.
Stage/Histologic Subtype Treatment
III FH and I UH 18 wk (dactinomycin and vincristine)
IIIIV FH and IIIV focal anaplasia 24 wk (dactinomycin, vincristine, and doxorubicin) with radiation
IIIV UH (diffuse anaplasia) 24 wk (vincristine, doxorubicin, etoposide, and cyclophosphamide) with radiation
FH, favorable histology; UH, unfavorable histology.
Using these approaches, 4year overall survival rates through NWTS4 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 longterm toxicities for
FH, favorable histology; UH, unfavorable histology.
Using these approaches, 4year overall survival rates through NWTS4 are as follows: stage I FH, 96%; stages II–IV FH, 82%–92%; stages I–III UH (diffuse
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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 longterm toxicities for
those with lowrisk disease and improving outcomes for those with highrisk and recurrent disease.
Aldrink JH et al: Update on Wilms tumor. J Pediatr Surg 2019 Mar;54(3):390–397
[PubMed: 30270120] .
Buckley KS: Pediatric genitourinary tumors. Curr Opin Oncol 2010;23(3):297
[PubMed: 21460723] .
Caldwell BT, Wilcox DT, Cost NG: Current management of pediatric urologic oncology. Adv Pediatr 2017 Aug;64(1):191–223
[PubMed: 28688589] .
Lopes RF, Lorenza A: Recent advanced in the management of Wilms’ tumor. F1000Res 2017 May 12;6:670. doi: 10.12688/f1000research.10760.1.
eCollection 2017
[PubMed: 28620463] .
Oostveen RM, PritchardJones K: Pharmacotherapeutic management of Wilms tumor: an update. Paediatr Drugs 2019 Feb;21(1):1–13
[PubMed: 30604241] .
Sadak KT, Ritchey ML, Dome JS: Paediatric genitourinary cancers and late effects of treatment. Nat Rev Urol 2013 Jan;10(1):15–25
[PubMed: 19657990] .
Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®): Health Professional Version. PDQ Pediatric Treatment Editorial Board. PDQ
Cancer Information Summaries [Internet]. Bethesda, MD: National Cancer Institute (US); 2002–2019 Jun 13
[PubMed: 26389282] .
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
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 Page 26 / 37
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
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
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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
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.
Radiographic findings show permeative (“motheaten” 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. PETCT 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.
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 diseasefree 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
intraarterially or intravenously, although the benefits of intraarterial chemotherapy (IAC) are disputed. Agents having efficacy in the treatment of
osteosarcoma include doxorubicin, cisplatin, highdose methotrexate, ifosfamide, and etoposide.
Definitive cure requires en bloc surgical resection of the tumor with a margin of uninvolved tissue. Amputation, limb salvage, and rotation plasty (Van
Ness rotation) are equally effective in achieving local control of osteosarcoma. Contraindications to limbsparing 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% longterm, diseasefree survival rate. Other favorable prognostic factors include distal skeletal lesions,
longer duration of symptoms, age older than 20 years, female gender, and neardiploid 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
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). Page 27 / 37
Clinical Findings
2. Ewing Sarcoma
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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
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.
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. PETCT 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, welldefined 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 cmyc, which may be helpful in differentiating Ewing sarcoma from neuroblastoma, in which cmyc is not expressed.
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 fivedrug regimen will improve survival.
Patients with small localized primary tumors have a 70%–75% longterm, diseasefree survival rate. For patients with metastatic disease, survival is
poor. Autologous HSCT may be considered as part of the treatment of these highrisk patients. Patients with pelvic tumors have an intermediate
prognosis of around 50% longterm, diseasefree survival.
Geller DS, Gorlick R: Osteosarcoma: a review of diagnosis, management and treatment strategies. Clin Adv Hematol Oncol 2010;8(10):705
[PubMed: 2137869] .
Harrison DJ, Geller DS, Gill JD, Lewis VO, Gorlick R: Current and future therapeutic approaches for osteosarcoma. Expert Rev Anticancer Ther 2018
Jan;18(1):39–50
[PubMed: 29210294] .
Jackson TM, Bittman M, Granowetter L: Pediatric malignant bone tumors: a review and update on current challenges, and emerging drug targets.
Curr Probl Pediatr Adolesc Health Care 2016 Jul;46(7):213–228
[PubMed: 27265835] .
Moore DD et al: Ewing sarcoma of bone. Cancer Treat Res 2014;162:93
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Womer R et al: Randomized controlled trial of intervalcompressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the
Children’s Oncology Group. J Clin Oncol 2012;30(33):41–48
Jackson TM, Bittman M, Granowetter L: Pediatric malignant bone tumors: a review and update on current challenges, and emerging drug targets.
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Curr Probl Pediatr Adolesc Health Care 2016 Jul;46(7):213–228
[PubMed: 27265835] .
Moore DD et al: Ewing sarcoma of bone. Cancer Treat Res 2014;162:93
[PubMed: 25070232] .
Womer R et al: Randomized controlled trial of intervalcompressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the
Children’s Oncology Group. J Clin Oncol 2012;30(33):41–48
[PubMed: 23091096] .
RHABDOMYOSARCOMA
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 crossstriations 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 NF1 are also predisposed to develop RMS, typically ERMS
involving the GU tract.
Clinical Findings
The presenting symptoms and signs of RMS result from disturbances of normal body function due to tumor growth (Table 31–10). 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.
Table 31−10.
Characteristics of rhabdomyosarcoma.
Frequency
Primary Site Symptoms and Signs Predominant Pathologic Subtype
(%)
Head and neck 35 Embryonal
Orbit 9 Proptosis
Parameningeal 16 Cranial nerve palsies; aural or sinus obstruction with or without
Page 29 / 37
drainage
Other 10 Painless, progressively enlarging mass
patients with orbital RMS present with proptosis, whereas patients with RMS of the bladder can present with hematuria, urinary obstruction, or a pelvic
mass. Universidad del Rosario
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Table 31−10.
Characteristics of rhabdomyosarcoma.
Frequency
Primary Site Symptoms and Signs Predominant Pathologic Subtype
(%)
Head and neck 35 Embryonal
Orbit 9 Proptosis
Parameningeal 16 Cranial nerve palsies; aural or sinus obstruction with or without
drainage
Other 10 Painless, progressively enlarging mass
Genitourinary 22 Embryonal (botryoid variant in bladder and
vagina)
Bladder and 13 Hematuria, urinary obstruction
prostate
Vagina and uterus 2 Pelvic mass, vaginal discharge
Paratesticular 7 Painless mass
Extremities 18 Adolescents, swelling of affected body part Alveolar (50%), undifferentiated
Other 25 Mass Alveolar, undifferentiated
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. PETCT 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 (tumorlymph nodemetastasis)
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 lowrisk
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 intermediaterisk patients, current studies are looking at incorporating irinotecan into treatment and
adding a maintenance phase that includes cyclophosphamide and vinorelbine. Highrisk (metastatic) RMS remains a major therapeutic challenge. For
highrisk patients, several treatment strategies have been attempted. The most recent COG highrisk 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.
and duration of chemotherapy are determined by the histologic subtype, age at diagnosis, the primary site, the TNM (tumorlymph nodemetastasis)
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%.Access Provided by:
The combination of vincristine, dactinomycin, and cyclophosphamide (VAC) has shown the greatest efficacy in the treatment of RMS. For lowrisk
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 intermediaterisk patients, current studies are looking at incorporating irinotecan into treatment and
adding a maintenance phase that includes cyclophosphamide and vinorelbine. Highrisk (metastatic) RMS remains a major therapeutic challenge. For
highrisk patients, several treatment strategies have been attempted. The most recent COG highrisk 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 followup 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 insulinlike growth factor (IGF) pathway are also being investigated.
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rationale for current COG studies. Pediatr Blood Cancer 2012;59(1):5–10
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Martins AS et al: Targeting the insulinlike growth factor pathway in rhabdomyosarcomas: rationale and future perspectives. Sarcoma
2011;2011:209736
[PubMed: 21437217] .
National Cancer Institute: http://www.cancer.gov/cancertopics/types/childrhabdomyosarcoma.
Rudzinski ER et al: The World Health Organization classification of skeletal muscle tumors in pediatric rhabdomyosarcoma: a report from the
Children’s Oncology Group. Arch Pathol Lab Med 2015;139(10):1281–1287
[PubMed: 25989287] .
RETINOBLASTOMA
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 “twohit” 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
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.
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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 “twohit” 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
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, hyphemia, 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 5year 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 intraarterial 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 highrisk 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.
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 highrisk features such as tumor invasion posterior to the lamina
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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 30year 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.
Dimaras H et al: Retinoblastoma. Nat Rev Dis Primers 2015;1:1–22
[PubMed: 27189421] .
Dimaras H, Corson TW: Retinoblastoma, the visible CNS tumor: a review. J Neurosci Res 2019 Jan;97(1):29–44 [PMCID: PMC6034991].
Lin P, O’Brien JM: Frontiers in the management of retinoblastoma. Am J Ophthalmol 2009;148(2):192
[PubMed: 19477707] .
Sastre X et al: Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for
the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med 2009;133(8):1199
[PubMed: 19653709] .
Shields C et al: Targeted retinoblastoma management: when to use intravenous, intraarterial, periocular, and intravitreal chemotherapy. Curr Opin
Ophthalmol 2014;25(5):374–385
[PubMed: 25014750] .
Shinohara ET et al: Subsequent malignancies and their effect on survival in patients with retinoblastoma. Pediatr Blood Cancer 2014;61:116–119
[PubMed: 23918737] .
HEPATIC TUMORS
Twothirds 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 31–11. 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.
Table 31−11.
Comparison of hepatoblastoma and hepatocellular carcinoma in childhood.
Hepatoblastoma Hepatocellular Carcinoma
Median age at 1 y (0−3 y) 12 y (5−18 y)

presentation
Malefemale ratio 1.7:1 1.4:1
Associated Hemihypertrophy, BeckwithWiedemann syndrome, Hepatitis B virus infection, hereditary tyrosinemia, biliary cirrhosis,

conditions prematurity, Gardner syndrome α1antitrypsin deficiency
Pathologic features Fetal or embryonal cells; mesenchymal component (30%) Large pleomorphic tumor cells and tumor giant cells
Solitary hepatic 80% 20%–50%
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. Universidad del Rosario
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Table 31−11.
Comparison of hepatoblastoma and hepatocellular carcinoma in childhood.
Hepatoblastoma Hepatocellular Carcinoma
Median age at 1 y (0−3 y) 12 y (5−18 y)

presentation
Malefemale ratio 1.7:1 1.4:1
Associated Hemihypertrophy, BeckwithWiedemann syndrome, Hepatitis B virus infection, hereditary tyrosinemia, biliary cirrhosis,

conditions prematurity, Gardner syndrome α1antitrypsin deficiency
Pathologic features Fetal or embryonal cells; mesenchymal component (30%) Large pleomorphic tumor cells and tumor giant cells
Solitary hepatic 80% 20%–50%

lesion
Unique features at Osteopenia (20%−30%), isosexual precocity (3%) Hemoperitoneum, polycythemia

diagnosis
Laboratory features
Hyperbilirubinemia 5% 25%
Elevated AFP > 90% 50%
Abnormal liver 15%−30% > 30%−50%

function tests
AFP, αfetoprotein.
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 αfetoprotein 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 αfetoprotein 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 onethird of
hepatocellular carcinomas can be completely removed. Even with complete resection, only onethird of patients with hepatocellular carcinoma are
longterm 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 intermediaterisk patients with the addition of temsirolimus in highrisk 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.
AllenRhoades W, Whittle SB, Rainusso N: Pediatric solid tumors of infancy: an overview. Pediatr Rev 2018 Feb;39(2):57–67
[PubMed: 29437125] .
hepatocellular carcinomas can be completely removed. Even with complete resection, only onethird of patients with hepatocellular carcinoma are
longterm 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
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along with the cardioprotectant dexrazoxane in intermediaterisk patients with the addition of temsirolimus in highrisk 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.
AllenRhoades W, Whittle SB, Rainusso N: Pediatric solid tumors of infancy: an overview. Pediatr Rev 2018 Feb;39(2):57–67
[PubMed: 29437125] .
Czauderna P, LopezTerrada D, Hiyama E, Häberle B, Malogolowkin MH, Meyers RL: Hepatoblastoma state of the art: pathology, genetics, risk
stratification and chemotherapy. Curr Opin Pediatr 2014 Feb;26(1):19–28
[PubMed: 24322718] .
Khaden S et al: Role of liver transplantation in the management of hepatoblastoma in the pediatric population. World J Transplant 2014;4(4):294
[PubMed: 25540737] .
Khan AS et al: Liver transplantation for malignant primary hepatic tumors. J Am Coll Surg 2017 Jul;225(1):103–113
[PubMed: 28232059] .
TrobaughLotrario AD, Katzenstein HM: Chemotherapeutic approaches for newly diagnosed hepatoblastoma: past, present, and future strategies.
Pediatr Blood Cancer 2012 Nov;59(5):809–812
[PubMed: 22648979] .
LANGERHANS CELL HISTIOCYTOSIS
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 RASRAFMEKERK 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, S100, 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, lifethreatening 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), HandSchüllerChristian disease (lytic bone lesions, exophthalmos, and diabetes insipidus [DI], typically in
younger children), LettererSiwe disease (a severe, multisystem disorder involving the liver, spleen, lung, skin, and bone marrow, typically in infants
aged < 2 years), and HashimotoPritzker disease (also known as congenital selfhealing reticulohistiocytosis, a cutaneous form of LCH in neonates that
selfresolves 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
CNSrisk 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 welldemarcated 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 vasopressincontaining 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 higherrisk disease.
CNSrisk 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
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in the skeleton, most commonly the skull. The lesions are usually painful. On plain film, a welldemarcated 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 vasopressincontaining 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 higherrisk 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 firstmorning void is a useful screen for DI.
Chest xray (CXR) screens for pulmonary involvement, skeletal survey evaluates for multifocal bone involvement, and abdominal ultrasound assesses
hepatosplenomegaly. PETCT or technetium99m bone scan can be used to evaluate extent of disease. PETCT 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.
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, LCHIV. 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. Lowdose 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 CNSrisk 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.
Firstline treatment is usually with vinblastine and prednisone. The LCHIII 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. LCHIV is comparing 2 years of treatment with 1
year. Patients with multisystem disease with risk organ involvement also receive 6mercaptopurine. For adolescent and young adult patients who may
not tolerate the side effects of this regimen, singleagent treatment with cytarabine is effective and can be considered.
Multiple other options exist for disease that is recurrent or resistant to firstline treatments. A combination of vincristine and cytarabine is being
studied as a secondline treatment in the LCHIV study. Clofarabine or cladribine (2Cda) used as single agents can be effective. Other effective agents
include methotrexate and indomethacin. A combination of highdose cytarabine and cladribine is being studied in patients with highrisk disease that
fails firstline 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.
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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. Access Provided by:
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Emil JF et al: Revised classification of histiocytoses and neoplasms of the macrophagedendritic cell lineages. Blood 2016;127(22):2672–2681
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Haroche J et al: Dramatic efficacy of vemurafenib in both multisystemic and refractory ErdheimChester disease and Langerhans cell histiocytosis
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Simko SJ et al: Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile
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Page 37 / 37

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Major Pediatric Neoplastic Diseases

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Universidad

NCI Standard Risk NCI High Risk Infant ALL

1–9 y ≥ 10 y or > 1 y due to high WBC Age < 1 y

Initial WBC < 50,000/μL Initial WBC ≥ 50,000/μL, regardless of age Any WBC

No CNS leukemia CNS leukemia Could be negative or positive

FAB < 2 y Cytogenetic

FAB < 2 y Cytogenetic

M2 Acute myeloblastic leukemia with 26 t(8;21), t(6;9); rare Myeloblastomas or chloromas

M3 Acute promyelocytic leukemia 4 t(15;17); rarely, Disseminated intravascular coagulation

M4 Acute myelomonoblastic leukemia 30 24 11q23, inv 3, t(3;3), Hyperleukocytosis, CNS involvement,

M4Eo Acute myelomonoblastic leukemia with inv16, t(16;16)

M5 Acute monoblastic leukemia 46 15 11q23, t(9;11), Hyperleukocytosis, CNS involvement,

M7 Acute megakaryoblastic leukemia 7 5 t(1;22) Down syndrome frequent (< age 2 y)

CML TMD JMML

Age at onset > 3 y < 3 mo < 2 y

Clinical Nonspecific constitutional complaints, DS features, often no or Abrupt onset; eczematoid skin rash, marked

Chromosomal t(9;22) Constitutional trisomy Monosomy or del (7q) in 20% of patients

Laboratory Marked leukocytosis (> 100,000/μL), normal to Variable leukocytosis, Moderate leukocytosis (> 10,000/μL), thrombocytopenia,

Factor Favorable Unfavorable

Extent of disease Nondisseminated Disseminated

Histologic features Undifferentiated, desmoplastic Large cell, anaplastic

Factor Favorable Unfavorable

Extent of disease Nondisseminated Disseminated

Histologic features Undifferentiated, desmoplastic Large cell, anaplastic

Age ≥ 4 y < 4 y

Molecular tumor characteristics WNT, young patients with SHH MYC, MYCN

Small Noncleaved Cell Large B­Cell Anaplastic Large Cell

Incidence (%) 30−40 35−50 10−15 10−15

Histopathologic Indistinguishable from ALL Large nucleus with prominent Large cells with cleaved or Large pleomorphic cells

Immunopheno­ Immature T cell B cell B cell T cell or null cell

Cytogenetic Translocations involving t(8;14), t(8;22), t(2;8) Many t(2;5)

Clinical Intrathoracic tumor, mediastinal Intra­abdominal tumor (90%), jaw Abdominal tumor most Lymphadenopathy, fever,

Treatment Similar to ALL therapy; 24 mo Intensive administration of Similar to therapy for Similar to therapy for

Incidence 10 per 100,000 0.9 per 100,000

Cytogenetics Chromosome 8 breakpoint upstream of c­myc locus Chromosome 8 breakpoint within c­myc locus

EBV association ≥ 95% ≤ 20%

Disease sites at Jaw (58%), abdomen (58%), CNS (19%), orbit (11%), marrow Jaw (7%), abdomen (91%), CNS (14%), orbit (1%), marrow

Extremities 18 Adolescents, swelling of affected body part Alveolar (50%), undifferentiated

Other 25 Mass Alveolar, undifferentiated

Median age at 1 y (0−3 y) 12 y (5−18 y)

Male­female ratio 1.7:1 1.4:1

Associated Hemihypertrophy, Beckwith­Wiedemann syndrome, Hepatitis B virus infection, hereditary tyrosinemia, biliary cirrhosis,

Median age at 1 y (0−3 y) 12 y (5−18 y)

Male­female ratio 1.7:1 1.4:1

Associated Hemihypertrophy, Beckwith­Wiedemann syndrome, Hepatitis B virus infection, hereditary tyrosinemia, biliary cirrhosis,

Pathologic features Fetal or embryonal cells; mesenchymal component (30%) Large pleomorphic tumor cells and tumor giant cells

Solitary hepatic 80% 20%–50%

Unique features at Osteopenia (20%−30%), isosexual precocity (3%) Hemoperitoneum, polycythemia

Elevated AFP > 90% 50%

Abnormal liver 15%−30% > 30%−50%

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Small Noncleaved Cell Large BCell Anaplastic Large Cell

Immunopheno Immature T cell B cell B cell T cell or null cell

Clinical Intrathoracic tumor, mediastinal Intraabdominal tumor (90%), jaw Abdominal tumor most Lymphadenopathy, fever,

Cytogenetics Chromosome 8 breakpoint upstream of cmyc locus Chromosome 8 breakpoint within cmyc locus

Malefemale ratio 1.7:1 1.4:1

Associated Hemihypertrophy, BeckwithWiedemann syndrome, Hepatitis B virus infection, hereditary tyrosinemia, biliary cirrhosis,

Malefemale ratio 1.7:1 1.4:1

Associated Hemihypertrophy, BeckwithWiedemann syndrome, Hepatitis B virus infection, hereditary tyrosinemia, biliary cirrhosis,