ACUTE LYMPHOBLASTIC LEUKEMIA
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 14-fold increase in the overall rate of leukemia.
ALL results from uncontrolled proliferation of immature lymphocytes. Its cause is unknown, and genetic factors may play a role. Leukemia is defined by the presence of more than 25% malignant hematopoietic cells (blasts) in the bone marrow aspirate. Leukemic blasts from the majority of cases of childhood ALL have an antigen on the cell surface called the common ALL antigen (CALLA). These blasts derive from B-cell precursors early in their development, called B-precursor ALL. Less commonly, lymphoblasts are of T-cell origin or of mature B-cell origin. Over 70% of children receiving aggressive combination chemotherapy and early presymptomatic treatment to the central nervous system (CNS) are now cured of ALL.
Presenting complaints of patients with ALL include those related to decreased bone marrow production of red blood cells (RBCs), white blood cells (WBCs), or platelets and to leukemic infiltration of extramedullary (outside bone marrow) sites. Intermittent fevers are common, as a result of either cytokines induced by the leukemia itself or infections secondary to leukopenia. Many patients present due to bruising or pallor. About 25% of patients experience bone pain, especially in the pelvis, vertebral bodies, and legs.
Physical examination at diagnosis ranges from virtually normal to highly abnormal. Signs related to bone marrow infiltration by leukemia include pallor, petechiae, and purpura. Hepatomegaly and/or splenomegaly occur in over 60% of patients. Lymphadenopathy is common, either localized or generalized to cervical, axillary, and inguinal regions. The testes may occasionally be unilaterally or bilaterally enlarged secondary to leukemic infiltration. Superior vena cava syndrome is caused by mediastinal adenopathy compressing the superior vena cava. A prominent venous pattern develops over the upper chest from collateral vein enlargement. The neck may feel full from venous engorgement. The face may appear plethoric, and the periorbital area may be edematous. A mediastinal mass can cause tachypnea, orthopnea, and respiratory distress. Leukemic infiltration of cranial nerves may cause cranial nerve palsies with mild nuchal rigidity. The optic fundi may show exudates of leukemic infiltration and hemorrhage from thrombocytopenia. Anemia can cause a flow murmur, tachycardia, and, rarely, congestive heart failure.
A complete blood count (CBC) with differential is the most useful initial test because 95% of patients with ALL have a decrease in at least one cell type (single cytopenia): neutropenia, thrombocytopenia, or anemia with most patients having a decrease in at least two blood cell lines. The WBC count is low or normal (= 10,000/μL) in 50% of patients, but the differential shows neutropenia (absolute neutrophil count < 1000/μL) along with a small percentage of blasts amid normal lymphocytes. In 30% of patients the WBC count is between 10,000/μL and 50,000/μL; in 20% of patients it is over 50,000/μL, occasionally higher than 300,000/μL. Blasts are usually readily identifiable on peripheral blood smears from patients with elevated WBC counts. Peripheral blood smears also show abnormalities in RBCs, such as teardrops. Most patients with ALL have decreased platelet counts (< 150,000/μL) and decreased hemoglobin (< 11 g/dL) at diagnosis. In approximately 1% of patients diagnosed with ALL, CBCs and peripheral blood smears are entirely normal, but patients have bone pain that leads to bone marrow examination. Serum chemistries, particularly uric acid and lactate dehydrogenase (LDH), are often elevated at diagnosis as a result of cell breakdown.
The diagnosis of ALL is made by bone marrow examination, which shows a homogeneous infiltration of leukemic blasts replacing normal marrow elements. The morphology of blasts on bone marrow aspirate can usually distinguish ALL from acute myeloid leukemia (AML). Lymphoblasts are typically small, with cell diameters of approximately two erythrocytes. Lymphoblasts have scant cytoplasm, usually without granules. The nucleus typically contains no nucleoli or one small, indistinct nucleolus. Immunophenotyping of ALL blasts by flow cytometry helps distinguish precursor B-cell ALL from T-cell ALL or AML. Histochemical stains specific for myeloblastic and monoblastic leukemias (myeloperoxidase and nonspecific esterase) distinguish ALL from AML. About 5% of patients present with CNS leukemia, which is defined as a cerebrospinal fluid (CSF) WBC count greater than 5/μL with blasts present on cytocentrifuged specimen.
Chest radiograph may show mediastinal widening or an anterior mediastinal mass and tracheal compression secondary to lymphadenopathy or thymic infiltration, especially in T-cell ALL. Abdominal ultrasound may show kidney enlargement from leukemic infiltration or uric acid nephropathy as well as intra-abdominal adenopathy. Plain radiographs of the long bones and spine may show demineralization, periosteal elevation, growth arrest lines, or compression of vertebral bodies. Although these findings may suggest leukemia, they are not diagnostic.
The differential diagnosis, based on the history and physical examination, includes chronic infections by Epstein-Barr virus (EBV) and cytomegalovirus (CMV), causing lymphadenopathy, hepatosplenomegaly, fevers, and anemia. Prominent petechiae and purpura suggest a diagnosis of immune thrombocytopenic purpura. Significant pallor could be caused by transient erythroblastopenia of childhood, autoimmune hemolytic anemias, or aplastic anemia. Fevers and joint pains, with or without hepatosplenomegaly and lymphadenopathy, suggest juvenile rheumatoid arthritis (JRA). The diagnosis of leukemia usually becomes straightforward once the CBC reveals multiple cytopenias and leukemic blasts. Serum LDH levels may help distinguish JRA from leukemia, as the LDH is usually normal in JRA. An elevated WBC count with lymphocytosis is typical of pertussis; however, in pertussis the lymphocytes are mature, and neutropenia is rarely associated.
Intensity of treatment is determined by specific prognostic features present at diagnosis, the patient’s response to therapy, and specific biologic features of the leukemia cells. The majority of patients with ALL are enrolled in clinical trials designed by clinical groups and approved by the National Cancer Institute; the largest group is COG. The first month of therapy consists of induction, at the end of which over 95% of patients exhibit remission on bone marrow aspirates by morphology. The drugs most commonly used in induction include oral prednisone or dexamethasone, intravenous vincristine, daunorubicin, intramuscular or intravenous asparaginase, and intrathecal methotrexate.
Consolidation is the second phase of treatment, during which intrathecal chemotherapy along with continued systemic therapy and sometimes cranial radiation therapy are given to kill lymphoblasts “hiding” in the meninges. Several months of intensive chemotherapy follows consolidation, often referred to as intensification. This intensification has led to improved survival in pediatric ALL.
Maintenance therapy can include daily oral mercaptopurine, weekly oral methotrexate, and, often, monthly pulses of intravenous vincristine and oral prednisone or dexamethasone. Intrathecal chemotherapy, either with methotrexate alone or combined with cytarabine and hydrocortisone, is usually given every 2–3 months.
Chemotherapy has significant potential side effects. Patients need to be monitored closely to prevent drug toxicities and to ensure early treatment of complications. The duration of treatment ranges between 2.2 years for girls and 3.2 years for boys in COG trials. Treatment for ALL is tailored to prognostic, or risk, groups. A child aged 1–9 years with a WBC count below 50,000/μL at diagnosis of pre B ALL and without poor biologic features [t(9;22) or an 11q23 rearrangement)] is considered to be at “standard risk” and receives less intensive therapy than a “high-risk” patient who has a WBC count at diagnosis over 50,000/μL or is 10 years of age or greater. An infant less than 1 year at diagnosis would be considered very high risk and receive even more intensive chemotherapy. Also important is the patient’s response to treatment determined by minimal residual disease (MRD) monitoring. This risk-adapted treatment approach has significantly increased the cure rate among patients with less favorable prognostic features by allowing for early intensification while minimizing treatment-related toxicities in those with favorable features. Bone marrow relapse is usually heralded by an abnormal CBC, either during treatment or following completion of therapy.
The CNS and testes are sanctuary sites of extramedullary leukemia. Currently, about one-third of all ALL relapses are isolated to these sanctuary sites. Systemic chemotherapy does not penetrate these tissues as well as it penetrates other organs. Thus, presymptomatic intrathecal chemotherapy is a critical part of ALL treatment, without which many more relapses would occur in the CNS, with or without bone marrow relapse. The majority of isolated CNS relapses are diagnosed in an asymptomatic child at the time of routine intrathecal injection, when CSF cell count and differential show an elevated WBC with leukemic blasts. Occasionally, symptoms of CNS relapse develop: headache, nausea and vomiting, irritability, nuchal rigidity, photophobia, changes in vision, and cranial nerve palsies. Currently, testicular relapse occurs in less than 5% of boys. The presentation of testicular relapse is usually unilateral painless testicular enlargement, without a distinct mass. Routine follow-up of boys both on and off treatment includes physical examination of the testes.
Bone marrow transplantation, now called hematopoietic stem cell transplantation (HSCT), is rarely used as initial treatment for ALL, because most patients are cured with chemotherapy alone. Patients whose blasts contain certain chromosomal abnormalities, hypodiploidy (< 44 chromosomes), and patients with a very slow response to therapy may have a better cure rate with early HSCT from a human leukocyte antigen (HLA)-DR–matched sibling donor, or perhaps a matched unrelated donor, than with intensive chemotherapy alone. HSCT cures about 50% of patients who relapse, provided that a second remission is achieved with chemotherapy before transplant. Children who relapse more than 1 year after completion of chemotherapy (late relapse) may be cured with intensive chemotherapy without HSCT.
Several new biologic agents, including tyrosine kinase inhibitors and immunotoxins, are currently in various stages of research, development, and in chemotherapeutic trials. Some of these therapies may prove relevant for future treatment of poor risk or relapsed ALL.
Several years ago, Imatinib, a tyrosine kinase inhibitor (TKI), directed against the Philadelphia chromosome (Ph+) protein product, was combined in a backbone of intensive ALL therapy for Ph+ ALL in pediatric patients. The preliminary results of this trial showed a 3-year event-free survival (EFS) of 78% compared to about 50% in historical controls. An ongoing trial for COG in Ph+ ALL is incorporating a newer, more targeted TKI, Dasatinib, into a very similar intensive chemotherapy background with the goal of improving EFS further for this select group of patients. As more is understood about the biology of ALL, further therapy will likely include more of these targeted agents.
Tumor lysis syndrome, which consists of hyperkalemia, hyperuricemia, hyperphosphatemia, should be anticipated when treatment is started. Maintaining brisk urine output with intravenous fluids plus/minus alkalinization of urine with intravenous sodium bicarbonate 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, leukophoresis may be indicated to rapidly reduce the number of circulating blasts and minimize the potential thrombotic or hemorrhagic CNS complications. Throughout the course of treatment, all transfused blood and platelet products should be irradiated to prevent graft-versus-host disease (GVHD) from the transfused lymphocytes. Whenever possible, blood products should be leuko-depleted to minimize CMV transmission, transfusion reactions, and sensitization to platelets.
Due to the immunocompromised state of the patient with ALL, bacterial, fungal, and viral infections are serious and can be life-threatening or fatal. During the course of treatment, fever (temperature = 38.3°C) and neutropenia (absolute neutrophil count < 500/μL) require prompt assessment, blood cultures from each lumen of a central line, and prompt treatment with empiric broad-spectrum antibiotics. Patients receiving ALL treatment must receive prophylaxis against Pneumocystis jiroveci (formerly Pneumocystis carinii). Trimethoprim-sulfamethoxazole given twice each day on 2 or 3 consecutive days per week is the drug of choice. Patients nonimmune to varicella are at risk for very serious—even fatal—infection. Such patients should receive varicella-zoster immune globulin (VZIG) within 72 hours after exposure and treatment with intravenous acyclovir for active infection.
Cure rates depend on specific prognostic features present at diagnosis, biologic features of the leukemic blast, and the response to therapy. Two of the most important features are WBC count and age. Children aged 1–9 years whose diagnostic WBC count is less than 50,000/μL, standard risk ALL, have an EFS greater than 90% range, while children 10 years or older have an EFS of approximately 88%. MRD measurements are now frequently 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 of MRD at the end of induction will likely have a superior EFS as compared to other patients with similar initial risk factors but a higher MRD level. On the flip side, by identifying patients with higher MRD at end induction, more intensified therapy can be delivered in order to reduce the MRD and thus, improve the EFS.
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, now have improved outcome with the incorporation of a directed TKI. Likewise, infants younger than 6 months with 11q23 rearrangements have a poor chance of cure with conventional chemotherapy. In contrast, patients whose blasts are hyperdiploid (containing > 50 chromosomes instead of the normal 46) with trisomies of chromosomes 4, and 10, and patients whose blasts have a t(12;21) and ETV6-AML1 rearrangement have a greater chance of cure, approaching 95%–97% EFS, than do children without these characteristics.
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Approximately 500 new cases of AML occur per year in children and adolescents in the United States. Although AML accounts for only 25% of all leukemias in this age group, it is responsible for at least one-third of deaths from leukemia in children and teenagers. Congenital conditions associated with an increased risk of AML include Diamond-Blackfan anemia; neurofibromatosis; Down syndrome; Wiskott-Aldrich, Kostmann, and Li-Fraumeni syndromes; as well as chromosomal instability syndromes such as Fanconi anemia. Acquired risk factors include exposure to ionizing radiation, cytotoxic chemotherapeutic agents, and benzenes. However, the vast majority of patients have no identifiable risk factors. Historically, the diagnosis of AML was based almost exclusively on morphology and immunohistochemical staining of the leukemic cells. AML has eight subtypes (M0–M7) according to the French-American-British (FAB) classification (Table 31–1). 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. Cytogenetic clonal abnormalities occur in 80% of patients with AML and are often predictive of outcome.
Table 31–1.FAB subtypes of acute myeloid leukemia. ||Download (.pdf) Table 31–1. FAB subtypes of acute myeloid leukemia.
|FAB Classification ||Common Name ||Distribution in Childhood (Age) ||Cytogenetic Associations ||Clinical Features |
|< 2 y (%) ||> 2 y (%) |
|M0 ||Acute myeloid leukemia, minimally differentiated ||1 || ||inv (3q26), t(3;3) || |
|M1 ||Acute myeloblastic leukemia without maturation ||17 ||23 || || |
|M2 ||Acute myeloblastic leukemia with maturation ||26 || ||t(8;21), t(6;9); rare ||Myeloblastomas or chloromas |
|M3 ||Acute promyelocytic leukemia ||4 || ||t(15;17); rarely, t(11;17) or (5;17) ||Disseminated intravascular coagulation |
|M4 ||Acute myelomonoblastic leukemia ||30 ||24 ||11q23, inv 3, t(3;3), t(6;9) ||Hyperleukocytosis, CNS involvement, skin and gum infiltration |
|M4Eo ||Acute myelomonoblastic leukemia with abnormal eosinophils || || ||inv16, t(16;16) || |
|M5 ||Acute monoblastic leukemia ||46 ||15 ||11q23, t(9;11), t(8;16) ||Hyperleukocytosis, CNS involvement, skin and gum infiltration |
|M6 ||Erythroleukemia ||2 || || || |
|M7 ||Acute megakaryoblastic leukemia ||7 ||5 ||t(1;22) ||Down syndrome frequent (< age 2 y) |
WHO Classification of AML and Related Neoplasms
|Acute myeloid leukemia with recurrent genetic abnormalities || |
AML with t(8;21)(q22;q22), RUNX1-RUNX1T1
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;p22); CBFB-MYH11
Acute promyelocytic leukaemia with t(15;17)(q22;q12);PML-RARA
AML with t(9;11)(p22;q23)MLLT3-MLL
AML with t(6:9)(p23;q34); DEK-NUP214
AML with inv(3)(q21q26.2) or t(3.3)(q21;q26.2); RPN1-EVl1
AML (megakaryoblastic) with t(1:22)(p13;q13); RBM15-MKL1
AML with mutated NPM1
AML with mutated CEBPA
|Acute myeloid leukemia with myelodysplasia-related changes |
|Therapy-related myeloid neoplasms |
|Acute myeloid leukemia, 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
Aggressive induction therapy currently results in a 75%–85% complete remission rate. However, long-term survival has improved only modestly to approximately 50%, despite the availability of several effective agents, improvements in supportive care, and increasingly intensive therapies.
The clinical manifestations of AML commonly include anemia (44%), thrombocytopenia (33%), and neutropenia (69%). Symptoms may be few and innocuous or may be life threatening. The median hemoglobin value at diagnosis is 7 g/dL, and platelets usually number fewer than 50,000/μL. Frequently the absolute neutrophil count is under 1000/μL, although the total WBC count is over 100,000/μL in 25% of patients at diagnosis.
Hyperleukocytosis may be associated with life-threatening complications. Venous stasis and sludging of blasts in small vessels cause hypoxia, hemorrhage, and infarction, most notably in the lung and CNS. This clinical picture is a medical emergency requiring rapid intervention, such as leukophoresis, 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.
AML is less responsive to treatment than ALL and requires more intensive chemotherapy. Toxicities from therapy are common and likely to be life threatening; therefore, treatment should be undertaken only at a tertiary pediatric oncology center.
Current AML protocols rely on intensive administration of anthracyclines, cytarabine, and etoposide for induction of remission. After remission is obtained, patients who have a matched sibling donor undergo allogeneic HSCT, while those without an appropriate related donor are treated with additional cycles of aggressive chemotherapy for a total of four to five cycles. Inv16 and t(8;21) herald a more responsive subtype of AML. In patients with a rapid response to induction chemotherapy, intensive chemotherapy alone may be curative in patients whose blasts harbor these cytogenetic abnormalities. Additional recognized genetic risk factors that carry a poor outcome for children with AML include monosomy 7 and FLT3 internal tandem duplications (ITDs). HSCT is recommended for all these patients, using either a related or unrelated donor. Trials with risk grouping are ongoing as more is understood about the varying biologic factors.
The biologic heterogeneity of AML is becoming increasingly important therapeutically. The M3 subtype, associated with t(15;17) demonstrated either cytogenetically or molecularly, is currently treated with all trans-retinoic acid in addition to chemotherapy with high-dose cytarabine and daunorubicin. All trans-retinoic acid leads to differentiation of promyelocytic leukemia cells and can induce remission, but cure requires conventional chemotherapy as well. The use of arsenic trioxide has also been investigated in the treatment of this subtype of AML with favorable results. This subtype has an increased EFS over other AML subtypes.
Another biologically distinct subtype of AML occurs in children with Down syndrome, almost exclusively megakaryocytic AML. Using less intensive treatment, remission induction rate and overall survival of these children are dramatically superior to non–Down syndrome children with AML. It is important that children with Down syndrome receive appropriate treatment specifically designed to be less intensive due to their increased rate of toxicity with chemotherapeutic agents.
As with ALL, newer biologic agents with more specific targeting are available and undergoing clinical trials. One such agent, sorafenib, appears to be active against AML with Flt3 ITDs. Combining sorafenib with AML therapy has been useful in relapsed disease and is now being studied in to upfront trials.
Clofarabine, a nucleoside analogue, also has activity in AML and is currently undergoing trials in relapsed and refractory patients with promising results.
Tumor lysis syndrome rarely occurs during induction treatment of AML. Nevertheless, when the diagnostic WBC cell count is greater than 100,000/μL or significant adenopathy or organomegaly is present, one should maintain brisk urine output, and follow potassium, uric acid, and phosphorous laboratory values closely. Hyperleukocytosis (WBC > 100,000/μL) is a medical emergency and, in a symptomatic patient, requires rapid intervention such as leukophoresis to rapidly decrease the number of circulating blasts and thereby decrease hyperviscosity. Delaying transfusion of packed RBCs until the WBC can be decreased to below 100,000/μL avoids exacerbating hyperviscosity. It is also important to correct the coagulopathy commonly associated with M3, M4, or M5 subtypes prior to beginning induction chemotherapy. As with the treatment of ALL, all blood products should be irradiated and leukodepleted; Pneumocystis prophylaxis must be administered during treatment and for several weeks afterward; and patients not immune to varicella must receive VZIG within 72 hours of exposure and prompt treatment with intravenous acyclovir for active infection.
Onset of fever (temperature ≥ 38.3°C) or chills associated with neutropenia requires prompt assessment, blood cultures from each lumen of a central venous line, other cultures such as throat or urine as appropriate and prompt initiation of broad-spectrum intravenous antibiotics. Infections in this population of patients can rapidly become life-threatening. Because of the high incidence of invasive fungal infections, there should be a low threshold for initiating antifungal therapy. Filgrastim (granulocyte colony-stimulating factor) may be used to stimulate granulocyte recovery during the treatment of AML and results in shorter periods of neutropenia and hospitalization. It must be stressed that the supportive care for this group of patients is as important as the leukemia-directed therapy and that this treatment should be carried out only at a tertiary pediatric cancer center.
Published results from various centers show a 50%–60% survival rate at 5 years following first remission for patients who do not have matched sibling hematopoietic stem cell donors. Patients with matched sibling donors fare slightly better, with 5-year survival rates of 60%–70% after allogeneic HSCT.
As treatment becomes more sophisticated, outcome is increasingly related to the subtype of AML. Currently, AML in patients with t(8;21), t(15;17), inv 16, or Down syndrome has the most favorable prognosis, with 65%–75% long-term survival using modern treatments, including chemotherapy alone. The least favorable outcome occurs in AML patients with monosomy 7 or 5, 7q, 5q–, 11q23 cytogenetic abnormalities, or FLT 3 mutations with internal tandem duplications (ITD).
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Myeloproliferative diseases in children are relatively rare. They are characterized by ineffective hematopoiesis that results in excessive peripheral blood counts. The three most important types are chronic myelogenous leukemia (CML), which accounts for less than 5% of the childhood leukemias, transient myeloproliferative disorder in children with Down syndrome, and juvenile myelomonocytic leukemia (Table 31–2).
Table 31–2.Comparison of JMML, CML, and TMD. ||Download (.pdf) Table 31–2. Comparison of JMML, CML, and TMD.
| ||CML ||TMD ||JMML |
|Age at onset ||> 3 y ||< 3 mo ||< 2 y |
|Clinical presentation ||Nonspecific constitutional complaints, massive splenomegaly, variable hepatomegaly ||DS features, often no or few symptoms; or hepatosplenomegaly, respiratory symptoms ||Abrupt onset; eczematoid skin rash, marked lymphadenopathy, bleeding tendency, moderate hepatosplenomegaly, fever |
|Chromosomal alterations ||t(9;22) ||Constitutional trisomy 21, but usually no other abnormality ||Monosomy or del (7q) in 20% of patients |
|Laboratory features ||Marked leukocytosis (> 100,000/μ L), normal to elevated platelet count, decreased to absent leukocyte alkaline phosphatase, usually normal muramidase ||Variable leukocytosis, normal to high platelet count, large platelets, myeloblasts ||Moderate leukocytosis (> 10,000/μ L), thrombocytopenia, monocytosis (> 1000/μ L), elevated fetal hemoglobin, normal to diminished leukocyte alkaline phosphatase, elevated muramidase |
1. Chronic Myelogenous Leukemia
CML with translocation of chromosomes 9 and 22 (the Philadelphia chromosome, Ph+) is identical to adult Ph+CML. Translocation 9;22 results in the fusion of the BCR gene on chromosome 22 and the ABL gene on chromosome 9. The resulting fusion protein is a constitutively active tyrosine kinase that interacts with a variety of effector proteins and allows for deregulated cellular proliferation, decreased adherence of cells to the bone marrow extracellular matrix, and resistance to apoptosis. The disease usually progresses within 3 years to an accelerated phase and then to a blast crisis. It is generally accepted that Ph+ cells have an increased susceptibility to the acquisition of additional molecular changes that lead to the accelerated and blast phases of disease.
Patients with CML may present with nonspecific complaints similar to those of acute leukemia, including bone pain, fever, night sweats, and fatigue. However, patients can also be asymptomatic. Patients with a total WBC count of more than 100,000/μL may have symptoms of leukostasis, such as dyspnea, priapism, or neurologic abnormalities. Physical findings may include fever, pallor, ecchymoses, and hepatosplenomegaly. Anemia, thrombocytosis, and leukocytosis are frequent laboratory findings. The peripheral smear is usually diagnostic, with a characteristic predominance of myeloid cells in all stages of maturation, increased basophils and relatively few blasts.
Historically, hydroxyurea or busulfan has been used to reduce or eliminate Ph+ cells and HSCT was the only consistently curative intervention. Reported survival rates for patients younger than 20 years transplanted in the chronic phase from matched-related donors are 70%–80%. Unrelated stem cell transplants result in survival rates of 50%–65%.
The understanding of the molecular mechanisms involved in the pathogenesis of CML has led to the rational design of molecularly targeted therapy. Imatinib mesylate (Gleevec) is a tyrosine kinase inhibitor that has had dramatic success in the treatment of CML, with most adults and children achieving cytogenetic remission. There are now newer, more targeted TKIs including dasatinib, erlotinib, nilotinib, and ponatinib. These medications in adults have an increased incidence of molecular remissions and may be all that is required for long-term survival in adults. The durability of the remission for children with TKIs therapy alone is unclear but is now the accepted upfront therapy.
2. Transient Myeloproliferative Disorder
Transient myeloproliferative disorder is unique to patients with trisomy 21 or mosaicism for trisomy 21. It is characterized by uncontrolled proliferation of blasts, usually of megakaryocytic origin, during early infancy and spontaneous resolution. The pathogenesis of this process is not well understood, although mutations in the GATA1 gene have recently been implicated as initial events.
Although the true incidence is unknown, it is estimated to occur in up to 10% of patients with Down syndrome. Despite the fact that the process usually resolves by 3 months of age, organ infiltration may cause significant morbidity and mortality.
Patients can present with hydrops fetalis, pericardial or pleural effusions, or hepatic fibrosis. More frequently, they are asymptomatic or only minimally ill. Therefore, treatment is primarily supportive. Patients without symptoms are not treated, and those with organ dysfunction receive low doses of chemotherapy or leukophoresis (or both) to reduce peripheral blood blast counts. Although patients with transient myeloproliferative disorder have apparent resolution of the process, approximately 30% go on to develop acute megakaryoblastic leukemia within 3 years.
3. Juvenile Myelomonocytic Leukemia
Juvenile myelomonocytic leukemia (JMML) accounts for approximately one-third of the myelodysplastic and myeloproliferative disorders in childhood. Patients with neurofibromatosis type 1 (NF-1) are at higher risk of JMML than the general population. It typically occurs in infants and very young children and is occasionally associated with monosomy 7 or a deletion of the long arm of chromosome 7.
Patients with JMML present similarly to those with other hematopoietic malignancies, with lymphadenopathy, hepatosplenomegaly, skin rash, or respiratory symptoms. Patients may have stigmata of NF-1 with neurofibromas or café au lait spots. Laboratory findings include anemia, thrombocytopenia, leukocytosis with monocytosis, and elevated fetal hemoglobin.
The results of chemotherapy for children with JMML have been disappointing, with estimated survival rates of less than 30%. Approximately 40%–45% of patients are projected to survive long term using HSCT, although optimizing conditioning regimens and donor selection may improve these results.
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The classic triad of morning headache, vomiting, and papilledema is present in fewer than 30% of children at presentation. School failure and personality changes are more common in older children while irritability, failure to thrive, and delayed development are common in very young children with brain tumors. Recent-onset head tilt can result from a posterior fossa tumor.
Brain tumors are the most common solid tumors of childhood, accounting for 1500–2000 new malignancies in children each year in the United States and for 25%–30% of all childhood cancers. In general, children with brain tumors have a better prognosis than do adults. Favorable outcome occurs most commonly with low-grade and fully resectable tumors as well as with chemoradiation responsive tumors such as medulloblastoma. Unfortunately, cranial irradiation in young children can have significant neuropsychological, intellectual, and endocrinologic sequelae.
Brain tumors in childhood are biologically and histologically heterogeneous, ranging from low-grade localized lesions to high-grade tumors with neuraxis dissemination. High-dose systemic chemotherapy is used frequently, especially in young children with high-grade tumors, in an effort to delay, decrease, or completely avoid cranial irradiation. Such intensive treatment may be accompanied by autologous HSCT or peripheral stem cell reconstitution.
The causes of most pediatric brain tumors are unknown. The risk of developing astrocytomas is increased in children with neurofibromatosis or tuberous sclerosis. Several studies show that some childhood brain tumors occur in families with increased genetic susceptibility to childhood cancers in general, brain tumors, or leukemia and lymphoma. A higher incidence of seizures has been observed in relatives of children with astrocytoma. The risk of developing a brain tumor is increased in children who received cranial irradiation for treatment of meningeal leukemia. All children with gliomas and meningiomas should be screened for neurofibromatosis (NF) type 1. In children with meningiomas, without the skin findings of NF-1, NF type 2 and von Hippel-Lindau syndrome should be considered. Inherited germline mutations are possible in atypical teratoid/rhabdoid tumors (AT/RTs) and in choroid plexus carcinomas. The syndrome of constitutional mismatch repair deficiency (CMMRD) should be considered carefully in the child presenting with a glioma who has been previously diagnosed with leukemia/lymphoma. There are treatment implications in recognizing CMMRD as these patients require additional life-long screening and may have an improved response to immunotherapy. Careful family histories should be taken in these tumors and genetic counseling considered if this is indicative of CMMRD, familial polyposis or Li Fraumeni.
Because pediatric brain tumors are rare, they are often misdiagnosed or diagnosed late; most pediatricians see no more than two children with brain tumors during their careers.
Clinical findings at presentation vary depending on the child’s age and the tumor’s location. Children younger than 2 years more commonly have infratentorial tumors. Children with such tumors usually present with nonspecific symptoms such as vomiting, unsteadiness, lethargy, and irritability. Signs may be surprisingly few or may include macrocephaly, ataxia, hyperreflexia, and cranial nerve palsies. Because the head can expand in young children, papilledema is often absent. Measuring head circumference and observing gait are essential in evaluating a child for possible brain tumor. Eye findings and apparent visual disturbances such as difficulty tracking can occur in association with optic pathway tumors such as optic glioma. Optic glioma occurring in a young child is often associated with neurofibromatosis.
Older children more commonly have supratentorial tumors, which are associated with headache, visual symptoms, seizures, and focal neurologic deficits. Initial presenting features are often nonspecific. School failure and personality changes are common. Vaguely described visual disturbance is often present, but the child must be directly asked. Headaches are common, but they often will not be predominantly in the morning. The headaches may be confused with migraine.
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.
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.
Magnetic resonance imaging (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 computed tomography (CT) scan. In contrast, a CT scan can be done in less than 10 minutes—as opposed to the 30 minutes or more required for an MRI scan—and is still useful if an urgent diagnostic study is necessary or to detect calcification of a tumor. Both scans are generally done with and without contrast enhancement. Contrast enhances regions where the blood-brain barrier is disrupted. Postoperative scans to document the extent of tumor resection should be obtained within 48 hours after surgery to avoid postsurgical enhancement.
Imaging of the entire neuraxis and CSF cytologic examination should be part of the diagnostic evaluation for patients with tumors such as medulloblastoma, ependymoma, and pineal region tumors. Diagnosis of neuraxis drop metastases (tumor spread along the neuraxis) can be accomplished by gadolinium-enhanced MRI incorporating sagittal and axial views. MRI of the spine should be obtained preoperatively in all children with midline tumors of the fourth ventricle or cerebellum. A CSF sample should be obtained during the diagnostic surgery or, if that is not possible, 7–10 days after the surgery. Lumbar CSF is preferred over ventricular CSF for cytologic examination. Levels of biomarkers in the blood and CSF, such as human chorionic gonadotropin and α-fetoprotein, may be helpful in diagnosis and follow-up. Both human chorionic gonadotropin and α-fetoprotein should be obtained from the blood preoperatively for all pineal and suprasellar tumors and if positive, the need for an operation should be discussed with a neuro-oncologist.
Except in emergencies, it is recommended that the neurosurgeon discuss staging and sample collection with an oncologist before surgery in a child newly presenting with a scan suggestive of brain tumor.
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 atypical teratoid/teratoid tumors. Some tumors contain both glial and neural elements (eg, ganglioglioma). A group of less common CNS tumors does not fit into either category (ie, craniopharyngiomas, germ cell tumors, choroid plexus tumors, and meningiomas). Low- and high-grade tumors are found in most categories. Table 31–3 lists the locations and frequencies of the common pediatric brain tumors.
Table 31–3.Location and frequency of common pediatric brain tumors. ||Download (.pdf) Table 31–3. Location and frequency of common pediatric brain tumors.
|Location ||Frequency of Occurrence (%) |
|Hemispheric ||37 |
| Low-grade astrocytoma ||23 |
| High-grade 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. Low-grade astrocytomas are in many cases, especially in the cerebellum curable by complete surgical excision alone. Upfront chemotherapy may be effective alone in about 40%–50% of low-grade astrocytomas but many will need to be treated multiple times. The recent advent of targeted therapy for mutations common in these tumors offers the potential for better outcomes.
Medulloblastoma are the most common high-grade brain tumors in children. These tumors usually occur in the first decade of life, with a peak incidence between ages 5 and 10 years and a female-male ratio of 2.1:1.3. The tumors typically arise in the midline cerebellar vermis, with variable extension into the fourth ventricle. Neuraxis dissemination at diagnosis affects from 10% to 46% of patients. Prognostic factors are outlined in Table 31–4. Determination of risk to date has largely used histology, age and stage but molecular classifications will be increasingly used to determine therapy.
Table 31–4.Prognostic factors in children with medulloblastoma. ||Download (.pdf) Table 31–4. 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 long-term survival rate of less than 5%. There has been considerable biologic discovery, largely from autopsy samples, in diffuse pontine gliomas in the very recent past. The discovery that most pontine gliomas have the histone mutation H3 K27M and that these diffuse gliomas can occur anywhere in the midline has led to a change in their classification. Diffuse pontine intrinsic gliomas are now largely subsumed, depending on mutational status in the new classification of diffuse midline glioma H3 K27M. It is hoped that the understanding of the mutational drivers in this tumor will result in improved therapy. Brainstem tumors that occur above or below the pons grow in an eccentric or cystic manner and do not have the K27M mutation have a somewhat better outcome. Exophytic tumors in this location may be amenable to surgery. Generally, brainstem tumors are treated without a tissue diagnosis although improved safety in the biopsy of brainstem tumors is increasing diagnostic sampling of these patients.
Other brain tumors such as ependymomas, germ cell tumors, choroid plexus tumors, and craniopharyngiomas are less common, and each is associated with unique diagnostic and therapeutic challenges.
Dexamethasone should be started prior to initial surgery to help relieve symptoms. There is little proof that very high doses of dexamethasone have any advantage and we have now adopted dosages of 4 mg every 6 hours in those children greater than 4 years and 2 mg every 6 hours in those less than 4. Anticonvulsants should be started if the child has had a seizure or if the surgical approach is likely to induce seizures. Keppra is now the preferred anticonvulsant in this population as it does not induce liver enzymes. Because postoperative treatment of young children with high-grade brain tumors incorporates increasingly more intensive systemic chemotherapy, consideration should also be given to the use of prophylaxis for Pneumocystis infection. Dexamethasone potentially reduces the effectiveness of chemotherapy and should be discontinued as soon after surgery as possible.
Optimum care for the pediatric patient with a brain tumor requires a multidisciplinary team including subspecialists in pediatric neurosurgery, neuro-oncology, neurology, endocrinology, neuropsychology, radiation therapy, and rehabilitation medicine, as well as highly specialized nurses, social workers, and staff in physical therapy, occupational therapy, and speech and language science.
The goal of treatment is to eradicate the tumor with the least short- and long-term morbidity. Long-term neuropsychological morbidity becomes an especially important issue related to deficits caused by the tumor itself and the sequelae of treatment. Meticulous surgical removal of as much tumor as possible is generally the preferred initial approach. Technologic advances in the operating microscope, the ultrasonic tissue aspirator, and the CO2 laser (which is less commonly used in pediatric brain tumor surgery); the accuracy of computerized stereotactic resection; and the availability of intraoperative monitoring techniques such as evoked potentials and electrocorticography have increased the feasibility and safety of surgical resection of many pediatric brain tumors. Second-look surgery after chemotherapy is increasingly being used when tumors are incompletely resected at initial surgery.
Radiation therapy for pediatric brain tumors is in a state of evolution. For tumors with a high probability of neuraxis dissemination (eg, medulloblastoma), craniospinal irradiation is still standard therapy in children older than 3 years. Attempts at elimination of craniospinal radiation for certain types of intracranial germ-cell tumors and further reduction of craniospinal radiation dosing in medulloblastoma have not been successful. In others (eg, ependymoma), craniospinal irradiation has been abandoned because neuraxis dissemination at first relapse is rare. Conformal radiation and the use of three-dimensional treatment planning are now in routine. Proton beam radiation has become routine in some centers although safety studies in comparison to photon radiation are lacking in childhood.
Chemotherapy is effective in treating low-grade and malignant astrocytomas and medulloblastomas. Intensive chemotherapy is effective in a minority of children with AT/RTs. The utility of chemotherapy in ependymoma is being reexplored in national trials. A series of brain tumor protocols for children younger than 3 years involved administering intensive chemotherapy after tumor resection and delaying or omitting radiation therapy. The results of these trials have generally continued to be disappointing but have taught valuable lessons regarding the varying responses to chemotherapy of different tumor types. Superior results seem to have been obtained in the very young with high-dose chemotherapy strategies with stem cell rescue often followed by conformal radiotherapy. Conformal techniques allow the delivery of radiation to strictly defined fields and may limit side effects.
Perhaps the most exciting development in pediatric neuro-oncology is the development of biologically and clinically relevant subclassifications in both medulloblastoma and ependymoma. This development will drive a new generation of targeted therapy aimed at these biologically defined groups. The consensus definition of four biologically defined entities in medulloblastoma, including the Wnt and SHH groups, is the best example of this. New studies based on this new-defined biology are ongoing.
In older children with malignant glioma, the current approach is surgical resection of the tumor and combined-modality treatment with irradiation and intensive chemotherapy. It has recently been realized there is considerable heterogeneity in pediatric high-grade gliomas. Some, such as the congenital tumors, may do well with relatively modest therapy. Others, such as epithelioid glioblastomas may harbor BRAF mutations and may be targetable with specific agents. Generally, however, the prognosis is poor for children with high-grade gliomas and there has been little progress in finding better chemotherapeutic agents and strategies for most children with these devastating tumors.
The treatment of low-grade astrocytomas with chemotherapy has likewise shown only disappointing progress. However, there are potentially exciting targeted agents in ongoing, and completed but unreported, low-grade astrocytoma trials that have the potential to greatly improve outcomes for these patients.
Despite improvements in surgery and radiation therapy, the outlook for cure remains poor for children with high-grade glial tumors. For children with high-grade gliomas, an early CCG study showed a 45% progression-free survival rate for children who received radiation therapy and chemotherapy, but this may have been due to the inclusion of low-grade patients. More recent studies would suggest survival rate of less than 10%. The major exception to this is congenital glioblastomas which appear to have a much more favorable prognosis. Biologic factors that may affect survival are being increasingly recognized. The prognosis for diffuse pontine gliomas remains very poor, with the standard therapy of radiation alone, being only palliative.
The 5- and even 10-year survival rate for low-grade astrocytomas of childhood is 60%–90%. However, prognosis depends on both site, grade and, it is increasingly realized, on biology. A child with a pilocytic astrocytoma of the cerebellum has a considerably better prognosis than a child with a fibrillary astrocytoma of the cerebral cortex. For recurrent or progressive low-grade astrocytoma of childhood, relatively moderate chemotherapy may improve the likelihood of survival.
Conventional craniospinal irradiation for children with low-stage medulloblastoma results in survival rates of 60%–90%. Ten-year survival rates are lower (40%–60%). Chemotherapy allows a reduction in the craniospinal radiation dose while improving survival rates for average-risk patients (86% survival at 5 years on the most recent COG average-risk protocol). However, even reduced-dose craniospinal irradiation has an adverse effect on intellect, especially in children younger than 7 years. Five-year survival rates for high-risk medulloblastoma have been 25%–40%, but this may be improved with the introduction of more chemotherapy during radiation although this still awaits the reporting of formal trials.
The previously poor prognosis for children with AT/RTs seems improved by intensive multimodality therapy in a national study.
Major challenges remain in treating brain tumors in children younger than 3 years and in treating diffuse midline glioma K27M and malignant gliomas. Given the inadequate results for treatment of childhood brain tumors, reduction of therapy trials should be fully evaluated and considered in the context of recent treatment failures using reduced therapy regimens. The increasing emphasis is on the quality of life of survivors, not just the survival rate.
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et al: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011;29:1408
et al: Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2006;24:4202
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 half of all cases. The remaining subtypes, referred to collectively as non-Hodgkin lymphoma (NHL), are divided into four main groups: lymphoblastic, small noncleaved cell, large B-cell, and anaplastic large-cell lymphomas.
In contrast to lymphomas, lymphoproliferative disorders (LPDs) are quite rare in the general population. Most are polyclonal, nonmalignant (though often life-threatening) accumulations of lymphocytes that occur when the immune system fails to control virally transformed lymphocytes. However, a malignant monoclonal proliferation can also arise. The posttransplant LPDs arise in patients who are immunosuppressed to prevent solid organ or bone marrow transplant rejection, particularly liver and heart transplant patients. Spontaneous LPDs occur in immunodeficient individuals and, less commonly, in immunocompetent persons.
Children with Hodgkin lymphoma have a better response to treatment than do adults, with greater than 90% 5- to 10-year overall survival rate when all stages are evaluated. Although adult therapies are applicable, the management of Hodgkin lymphoma in children younger than 18 years frequently differs. Because excellent disease control can result from several different therapeutic approaches, selection of staging procedures (radiographic, surgical, or other procedures to determine additional locations of disease) and treatment are often based on the potential long-term toxicity associated with the intervention.
Although Hodgkin lymphoma represents 50% of the lymphomas of childhood, only 15% of all cases occur in children aged 16 years or younger. Children younger than 5 years account for 3% of childhood cases. There is a 4:1 male predominance in the first decade. Notably, in under-developed 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 of adults: lymphocyte-predominant (10%–20%); nodular sclerosing (40%–60%) (increases with age); mixed cellularity (20%–40%); and lymphocyte-depleted (5%–10%). Prognosis is independent of subclassification, with appropriate therapy based on stage (see section Staging).
Children with Hodgkin lymphoma usually present with painless cervical adenopathy. The lymph nodes often feel firmer than inflammatory nodes and have a rubbery texture. They may be discrete or matted together and are not fixed to surrounding tissue. The growth rate is variable, and involved nodes may wax and wane in size over weeks to months.
As Hodgkin lymphoma nearly always arises in lymph nodes and spreads to contiguous nodal groups, a detailed examination of all nodal sites is mandatory. Lymphadenopathy is common in children, so the decision to perform biopsy is often difficult or delayed for a prolonged period. Indications for consideration of early lymph node biopsy include lack of identifiable infection in the region drained by the enlarged node, a node greater than 2 cm in size, supraclavicular adenopathy or abnormal chest radiograph, and lymphadenopathy increasing in size after 2 weeks or failing to resolve within 4–8 weeks.
Constitutional symptoms occur in about one-third of children at presentation. Symptoms of fever greater than 38.0°C, weight loss of 10% in the previous 6 months, and drenching night sweats are defined by the Ann Arbor staging criteria as B symptoms. The A designation refers to the absence of these symptoms. B symptoms are of prognostic value, and more aggressive therapy is usually required for cure. Generalized pruritus and pain with alcohol ingestion may also occur.
Half of patients have asymptomatic mediastinal disease (adenopathy or anterior mediastinal mass), although symptoms due to compression of vital structures in the thorax may occur. A chest radiograph should be obtained when lymphoma is being considered. The mediastinum must be evaluated thoroughly before any surgical procedure is undertaken to avoid airway obstruction or cardiovascular collapse during anesthesia and possible death. Splenomegaly or hepatomegaly is generally associated with advanced disease.
The CBC is usually normal, although anemia, neutrophilia, eosinophilia, and thrombocytosis may be present. The erythrocyte sedimentation rate and other acute-phase reactants are often elevated and can serve as markers of disease activity. Immunologic abnormalities occur, particularly in cell-mediated immunity, and anergy is common in patients with advanced-stage disease at diagnosis. Autoantibody phenomena such as hemolytic anemia and an idiopathic thrombocytopenic purpura–like picture have been reported.
Staging of Hodgkin lymphoma determines treatment and prognosis. The most common staging system is the Ann Arbor classification that describes extent of disease by I–IV and symptoms by an A or a B suffix (eg, stage IIIB). A systematic search for disease includes chest radiography; CT scan of the chest, abdomen, and pelvis; and bilateral bone marrow aspirates and biopsies. In recent years, positron emission tomography (PET) is increasingly used in the staging and follow-up of patients with Hodgkin disease.
The diagnosis of Hodgkin lymphoma requires the histologic presence of the Reed-Sternberg cell or its variants in tissue. Reed-Sternberg cells are germinal-center B cells that have undergone malignant transformation. Nearly 20% of these tumors in developed countries are positive for EBV. EBV has been linked to Hodgkin disease and the large portion of Hodgkin patients with increased EBV titers suggests that EBV activation may contribute to the onset of Hodgkin lymphoma.
Treatment decisions are based on presence of B symptoms, stage, tumor bulk, and number of involved nodal regions. To achieve long-term disease-free survival while minimizing treatment toxicity, Hodgkin disease is increasingly treated by chemotherapy alone—and less often by radiation therapy.
Several combinations of chemotherapeutic agents are effective, and treatment times are relatively short compared with pediatric oncology protocols for leukemia. Clinical trials have shown that only 9 weeks of therapy with AV-PC (Adriamycin [doxorubicin], vincristine, prednisone, and cyclophosphamide) is sufficient to induce a complete response in patients with low-risk Hodgkin lymphoma. Two additional drugs, bleomycin and etoposide, are currently added in the treatment of intermediate-risk patients for a total of 4–6 months of therapy for patients with intermediate-risk disease. The removal of involved field irradiation in patients with intermediate-risk Hodgkin lymphoma who respond early to chemotherapy has been shown to maintain excellent outcomes. Combined-modality therapy with chemotherapy and irradiation is used in advanced disease.
Current treatment gives an overall 5 year survival of 90%–95% to children with stages I and II Hodgkin lymphoma. Two-thirds of all relapses occur within 2 years after diagnosis, and relapse rarely occurs beyond 4 years. Although patients with advanced disease (stages III and IV) have slightly lower overall survival, more patients are becoming long-term survivors of Hodgkin disease. As a result, the risk of secondary malignancies, both leukemias and solid tumors, is becoming more apparent and is higher in patients receiving radiation therapy. Therefore, elucidating the optimal treatment strategy that minimizes such risk should be the goal of future studies.
Patients with relapsed Hodgkin lymphoma are often salvageable using chemotherapy and radiation therapy. An increasingly popular alternative is autologous HSCT, which may improve survival rates. Allogeneic HSCT is also used, but carries increased risks of complications and may not offer added survival benefit.
Targeted therapies are being tested for children with high-risk Hodgkin lymphoma, including antibody conjugates targeting CD30, a transmembrane receptor highly expressed in Hodgkin lymphoma. A current COG trial is investigating if an anti-CD30 murine/human chimeric monoclonal antibody linked to monomethyl auristatin E is able to target the Reed-Stenberg cell in newly diagnosed high-risk Hodgkin Lymphoma. Checkpoint inhibitors pembroluzimab and nivolumab that block PD-1 have recently been approved for recurrent Hodgkin Lymphoma, as the tumor cells consistently express their target PDL-1 and PDL-2.
et al: Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk Hodgkin lymphoma: a report from the Children’s Oncology Group Study AHOD0031. J Clin Oncol 2014;32:3561
et al: The challenging aspects of managing adolescents and young adults with Hodgkin’s lymphoma. JAMA Acta Haematol 2014;132:274
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
SM: Novel agents in the treatment of Hodgkin lymphoma: biological basis and clinical results. Semin Hematol 2016 Jul;53(3):186–189
Non-Hodgkin lymphomas (NHLs) are a diverse group of cancers accounting for 5%–10% of malignancies in children younger than 15 years. About 500 new cases arise per year in the United States. The incidence of NHLs increases with age. Children aged 15 years or younger account for only 3% of all cases of NHLs, and the disease is uncommon before age 5 years. There is a male predominance of approximately 3:1. In equatorial Africa, NHLs cause almost 50% of pediatric malignancies.
Most children who develop NHL are immunologically normal. However, children with congenital or acquired immune deficiencies (eg, Wiskott-Aldrich syndrome, severe combined immunodeficiency syndrome, X-linked lymphoproliferative syndrome, human immunodeficiency virus (HIV) infection, immunosuppressive therapy following solid-organ or marrow transplantation) have an increased risk of developing NHLs. It has been estimated that their risk is 100–10,000 times that of age-matched control subjects.
Animal models suggest a viral contribution to the pathogenesis of NHL, and there is evidence of viral involvement in human NHL as well. In equatorial Africa, 95% of Burkitt lymphomas (BLs) contain DNA from the EBV. But in North America, less than 20% of Burkitt tumors contain the EBV genome. The role of other viruses (eg, human herpes-viruses 6 and 8), disturbances in host immunologic defenses, chronic immunostimulation, and specific chromosomal rearrangements as potential triggers in the development of NHL is under investigation.
Unlike adult NHL, virtually all childhood NHLs are rapidly proliferating, high-grade, diffuse malignancies. These tumors exhibit aggressive behavior but are usually very responsive to treatment. Nearly all pediatric NHLs are histologically classified into four main groups: lymphoblastic lymphoma (LL), small noncleaved cell lymphoma (BL and Burkitt-like lymphoma [BLL]), large B-cell lymphoma (LBCL), and anaplastic large cell lymphoma (ALCL). Immunophenotyping and cytogenetic features, in addition to clinical presentation, are increasingly important in the classification, pathogenesis, and treatment of NHLs. Comparisons of pediatric NHLs are summarized in Table 31–5.
Table 31–5.Comparison of pediatric non-Hodgkin lymphomas. ||Download (.pdf) Table 31–5. Comparison of pediatric non-Hodgkin lymphomas.
| ||Lymphoblastic Lymphoma ||Small Noncleaved Cell Lymphoma (BL and BLL) ||Large B-Cell Lymphoma ||Anaplastic Large Cell Lymphoma |
|Incidence (%) ||30–40 ||35–50 ||10–15 ||10–15 |
|Histopathologic features ||Indistinguishable from ALL lymphoblasts ||Large nucleus with prominent nucleoli surrounded by very basophilic cytoplasm that contains lipid vacuoles ||Large cells with cleaved or noncleaved nuclei ||Large pleomorphic cells |
|Immunopheno-type ||Immature T cell ||B cell ||B cell ||T cell or null cell |
|Cytogenetic markers ||Translocations involving chromosome 14q11 and chromosome 7; interstitial deletions of chromosome 1 ||t(8;14), t(8;22), t(2;8) ||Many ||t(2;5) |
|Clinical presentation ||Intrathoracic tumor, mediastinal mass (50%–70%), lymphadenopathy above diaphragm (50%–80%) ||Intra-abdominal tumor (90%), jaw involvement (10%–20% sporadic BL, 70% endemic BL), bone marrow involvement ||Abdominal tumor most common; unusual sites: lung, face, brain, bone, testes, muscle ||Lymphadenopathy, fever, weight loss, night sweats, extranodal sites including viscera and skin |
|Treatment ||Similar to ALL therapy; 24 mo duration ||Intensive administration of alkylating agents and methotrexate; CNS prophylaxis; 3–9 mo duration ||Similar to therapy for BL/BLL ||Similar to therapy for lymphoblastic lymphoma or BL/BLL |
Childhood NHLs can arise in any site of lymphoid tissue, including the lymph nodes, thymus, liver, and spleen. Common extralymphatic sites include bone, bone marrow, CNS, skin, and testes. Signs and symptoms at presentation are determined by the location of lesions and the degree of dissemination. Because NHL usually progresses very rapidly, the duration of symptoms is quite brief, from days to a few weeks. Nevertheless, children present with a limited number of syndromes, most of which correlate with cell type.
Children with LL often present with symptoms of airway compression (cough, dyspnea, orthopnea) or superior vena cava obstruction (facial edema, chemosis, plethora, venous engorgement), which are a result of mediastinal disease. These symptoms are a true emergency necessitating rapid diagnosis and treatment. Pleural or pericardial effusions may further compromise the patient’s respiratory and cardiovascular status. CNS and bone marrow involvement are not common at diagnosis. When bone marrow contains more than 25% lymphoblasts, patients are diagnosed with ALL.
Most patients with BL and BLL present with abdominal disease. Abdominal pain, distention, a right lower quadrant mass, or intussusception in a child older than 5 years suggests the diagnosis of BL. Bone marrow involvement is common (~ 65% of patients). BL is the most rapidly proliferating tumor known and has a high rate of spontaneous cell death as it outgrows its blood supply. Consequently, children presenting with massive abdominal disease frequently have tumor lysis syndrome (hyperuricemia, hyperphosphatemia, and hyperkalemia). These abnormalities can be aggravated by tumor infiltration of the kidney or urinary obstruction by tumor. Although similar histologically, numerous differences exist between cases of BL occurring in endemic areas of equatorial Africa and the sporadic cases of North America (Table 31–6).
Table 31–6.Comparison of endemic and sporadic Burkitt lymphoma. ||Download (.pdf) Table 31–6. 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 c-myc locus ||Chromosome 8 breakpoint within c-myc locus |
|EBV association ||≥ 95% ||≤ 20% |
|Disease sites at presentation ||Jaw (58%), abdomen (58%), CNS (19%), orbit (11%), marrow (7%) ||Jaw (7%), abdomen (91%), CNS (14%), orbit (1%), marrow (20%) |
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 LBCL including primary mediastinal B cell lymphoma and grey zone lymphomas have been identified. The distinction is an important one as the approach to therapy differs significantly.
Diagnosis is made by biopsy of involved tissue with histology, immunophenotyping, and cytogenetic studies. If mediastinal disease is present, general anesthesia must be avoided if the airway or vena cava is compromised by tumor. In these cases samples of pleural or ascitic fluid, bone marrow, or peripheral nodes obtained under local anesthesia (in the presence of an anesthesiologist) may confirm the diagnosis. Major abdominal surgery and intestinal resection should be avoided in patients with an abdominal mass that is likely to be BL, as the tumor will regress rapidly with the initiation of chemotherapy. The rapid growth of these tumors and the associated life-threatening complications demand that further studies be done expeditiously so that specific therapy is not delayed.
After a thorough physical examination, a CBC, liver function tests, and a biochemical profile (electrolytes, calcium, phosphorus, uric acid, renal function) should be obtained. An elevated LDH reflects tumor burden and can serve as a marker of disease activity. Imaging studies should include a chest radiograph and CT scans of the neck, chest, abdomen and pelvis, and a PET scan. Bone marrow and CSF examinations are also essential.
The management of life-threatening problems at presentation is critical. The most common complications are superior mediastinal syndrome and acute tumor lysis syndrome. Patients with airway compromise require prompt initiation of specific therapy. Because of the risk of general anesthesia in these patients, it is occasionally necessary to initiate corticosteroids or low-dose emergency radiation therapy until the mass is small enough for a biopsy to be undertaken safely. Response to steroids and radiation therapy is usually prompt (12–24 hours).
Tumor lysis syndrome should be anticipated in all patients who have NHL with a large tumor burden. Maintaining a brisk urine output (> 5 mL/kg/h) with intravenous fluids and diuretics is the key to management. Allopurinol will reduce serum uric acid. Rasburicase is an effective intravenous alternative to allopurinol and is increasingly used for patients with high risk of tumor lysis based on tumor burden or in patients who do not have an optimal response to allopurinol. Renal dialysis is occasionally necessary to control metabolic abnormalities. Every attempt should be made to correct or minimize metabolic abnormalities before initiating chemotherapy; however, this period of stabilization should not exceed 24–48 hours.
Systemic chemotherapy is the mainstay of therapy for NHLs. Nearly all patients with NHL require intensive intrathecal chemotherapy for CNS prophylaxis. Surgical resection is not indicated unless the entire tumor can be resected safely, which is rare. Partial resection or debulking surgery has no role. Radiation therapy does not improve outcome, so its use is confined to exceptional circumstances.
Therapy for LL is generally based on treatment protocols designed for ALL and involves dose-intensive, multiagent chemotherapy. Current trials are testing whether the addition of bortezomib to the current multiagent chemotherapy regimen will decrease the risk of relapse for patients with T-cell LL. The duration of therapy is 2 years. Treatment of BL and BLL using alkylating agents and intermediate- to high-dose methotrexate administered intensively but for a relatively short time produce the highest cure rates. LBCL are treated similarly, whereas ALCL has been treated with both BL and LL protocols. Dose-Adjusted EPOCH-R has demonstrated improved outcomes in adults with PMBL and grey zone lymphomas. Clinical trials utilizing this regimen are ongoing in children with these rare NHLs.
Monoclonal antibodies such as rituximab (anti-CD20) allow for more targeted therapy of lymphomas and have been successful in improving outcomes in adults. Recent studies in children with high-risk mature B-cell lymphomas demonstrated improved outcomes with the addition of Rituximab to conventional chemotherapy regimens. Additionally, oral small molecule inhibitors against the ALK oncogene are being explored as novel therapy for specific subsets of patients with ALCL. The ALK oncogene is activated by a 2;5 translocation leading to juxtaposition of NPM N-terminal region to the intracellular part of ALK and is the defining genetic lesions in ALK-positive ALCL. ALCL often express CD30 and studies are ongoing combining brentuximab vedotin and ALK inhibitors.
A major predictor of outcome in NHL is the extent of disease at diagnosis. Ninety percent of patients with localized disease can expect long-term, disease-free survival. Patients with extensive disease on both sides of the diaphragm, CNS involvement, or bone marrow involvement in addition to a primary site have a 70%–80% failure-free survival rate. Relapses occur early in NHL; patients with LL rarely have recurrences after 30 months from diagnosis, whereas patients with BL and BLL very rarely have recurrences beyond 1 year. The cure rate for patients with relapsed T-cell lymphoblastic leukemia/lymphoma is particularly poor (3-year EFS rates < 20%). Patients who experience relapse may have a chance for cure by autologous or allogeneic HSCT.
et al: Rituximab
and FAB/LMB 96 chemotherapy in children with stage III/IV B-cell non-Hodgkin lymphoma: a Children’s Oncology Group report. Leukemia 2013;27:1174
et al: Treatment of adolescents with aggressive B-cell malignancies: the pediatric experience. Curr Hematol Malig Rep 2013;8:226
et al: Adolescents and young adults with non-Hodgkin’s lymphoma: slipping between the cracks. Acta Haematol 2014;132:279
et al: Mature B-cell lymphoma and leukemia in children and adolescents—review of standard chemotherapy regimen and perspectives. Pediatr Hematol Oncol 2013;30(6):465
3. Lymphoproliferative Disorders
Lymphoproliferative disorders (LPDs) can be thought of as a part of a continuum with lymphomas. Whereas LPDs represent inappropriate, often polyclonal proliferations of nonmalignant lymphocytes, lymphomas represent the development of malignant clones, sometimes arising from recognized LPDs.
A. Posttransplantation Lymphoproliferative Disorders
Posttransplantation lymphoproliferative disorders (PTLDs) arise in patients who have received substantial immunosuppressive medications for solid organ or bone marrow transplantation. In these patients, reactivation of latent EBV infection in B cells drives a polyclonal proliferation of these cells that is fatal if not halted. Occasionally a true lymphoma develops, often bearing a chromosomal translocation.
LPDs are an increasingly common and significant complication of transplantation. The incidence of PTLD ranges from approximately 2% to 15% of transplant recipients, depending on the organ transplanted and the immunosuppressive regimen.
Treatment of these disorders is a challenge for transplant physicians and oncologists. The initial treatment is reduction in immunosuppression, which allows the patient’s own immune cells to destroy the virally transformed lymphocytes. However, this is only effective in approximately half of the patients. For those patients who do not respond to reduced immune suppression, chemotherapy of various regimens may succeed. The use of anti–B-cell antibodies, such as rituximab (anti-CD20), for the treatment of PTLDs has been promising in clinical trials. More recently, T-cell–based immune therapies, such as donor lymphocyte infusions and adoptive transfer of EBV-specific cytotoxic T lymphocytes, have also been explored as novel approaches.
B. Spontaneous Lymphoproliferative Disease
Immunodeficiencies in which LPDs occur include Bloom syndrome, Chédiak-Higashi syndrome, ataxia-telangiectasia, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, congenital T-cell immunodeficiencies, and HIV infection. Treatment depends on the circumstances, but unlike PTLD, few therapeutic options are often available. Castleman disease is an LPD occurring in pediatric patients without any apparent immunodeficiency. The autoimmune lymphoproliferative syndrome (ALPS) is characterized by widespread lymphadenopathy with hepatosplenomegaly, and autoimmune phenomena. ALPS results from mutations in the Fas ligand pathway that is critical in regulation of apoptosis.
et al: Identifying predictive factors for posttransplant lymphoproliferative disease in pediatric solid organ transplant recipients with Epstein-Barr virus viremia. J Pediatr Hematol Oncol 2014;36:e481
et al: Lymphoproliferative disorders in immunocompromised individuals and therapeutic antibodies for treatment. Immunotherapy 2013;5:415
Neuroblastoma arises from neural crest tissue of the sympathetic ganglia or adrenal medulla. It is composed of small, fairly uniform cells with little cytoplasm and hyperchromatic nuclei that may form rosette patterns. Pathologic diagnosis is not always easy, and neuroblastoma must be differentiated from the other “small, round, blue cell” malignancies of childhood (Ewing sarcoma, rhabdomyosarcoma, peripheral neuroectodermal tumor, and lymphoma).
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.
Neuroblastoma is a biologically diverse disease with varied clinical behavior ranging from spontaneous regression to progression through very aggressive therapy. Unfortunately, despite significant advances in our understanding of this tumor at the cellular and molecular level, the overall survival rate in advanced disease has changed little in 20 years, with 3-year EFS being less than 15%.
Clinical manifestations vary with the primary site of malignant disease and the 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 mass that extends beyond the midline. The margins are often poorly defined. Although most children have an abdominal primary tumor (40% adrenal gland, 25% paraspinal ganglion), neuroblastoma can arise wherever there is sympathetic tissue. In the posterior mediastinum, the tumor is usually asymptomatic and discovered on a chest radiograph obtained for other reasons. Patients with cervical neuroblastoma present with a neck mass, which is often 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 foramina, causing cord compression. Patients may present with paresis, paralysis, and bowel or bladder dysfunction.
The most common sites of metastases are bone, bone marrow, lymph nodes (regional as well as disseminated), liver, and subcutaneous tissue. Neuroblastoma has a predilection for metastasis to the skull, in particular the sphenoid bone and retrobulbar tissue. This causes periorbital ecchymosis and proptosis. Liver metastasis, particularly in the newborn, can be massive. Subcutaneous nodules are bluish in color and associated with an erythematous flush followed by blanching when compressed, probably secondary to catecholamine release.
Neuroblastoma may also be associated with unusual paraneoplastic manifestations. Perhaps the most striking example is opsoclonus-myoclonus, also called dancing eyes/dancing feet syndrome. This phenomenon is characterized by the acute onset of rapid and chaotic eye movements, myoclonic jerking of the limbs and trunk, ataxia, and behavioral disturbances. This process, which often persists after therapy is complete, is thought to be secondary to cross-reacting antineural antibodies. Intractable, chronic watery diarrhea is associated with tumor secretion of vasoactive intestinal peptides. Both of these paraneoplastic syndromes are associated with favorable outcomes.
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 and homovanillic acid) are elevated in at least 90% of patients at diagnosis and should be measured prior to surgery.
Plain radiographs of the primary tumor may show stippled calcifications. Metastases to bone appear irregular and lytic. Periosteal reaction and pathologic fractures may also be seen. CT scanning provides more information, including the extent of the primary tumor, its effects on surrounding structures, and the presence of liver and lymph node metastases. 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 appear to invade neural foramina.
Technetium bone scanning is obtained for the evaluation of bone metastases, because the tumor usually takes up technetium. Metaiodobenzylguanidine (MIBG) scanning is also performed to detect metastatic disease.
Staging of neuroblastoma is performed according to the International Neuroblastoma Staging System (INSS) (Table 31–7). A biopsy of the tumor is performed to determine the biologic characteristics of the tumor. In addition, bilateral bone marrow aspirates and biopsies must be performed to evaluate marrow involvement.
Table 31–7.International neuroblastoma staging system. ||Download (.pdf) Table 31–7. 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 age < 1 y. Marrow involvement should be < 10% of nucleated cells. |
Tumors are classified as favorable or unfavorable based on histologic characteristics. Amplification of the MYCN protooncogene is a reliable marker of aggressive clinical behavior with rapid disease progression. Tumor cell DNA content is also predictive of outcome. Hyperdiploidy is a favorable finding, whereas diploid DNA content is associated with a worse outcome.
Patients are treated based on a risk stratification system adopted by the COG based on INSS stage, age, MYCN status, histology, cytogenetic findings, and DNA index. The mainstay of therapy is surgical resection coupled with chemotherapy. The usually massive size of the tumor often makes primary resection impossible. Under these circumstances, only a biopsy is performed. Following chemotherapy, a second surgical procedure may allow for resection of the primary tumor. Radiation therapy is sometimes also necessary. Effective chemotherapeutic agents in the treatment of neuroblastoma include cyclophosphamide, doxorubicin, etoposide, cisplatin, vincristine, and topotecan. About 80% of patients achieve complete or partial remission, although in advanced disease, remission is seldom durable.
For low-risk disease (stages 1 and 2, with good biologic features), surgical resection alone may be sufficient to affect a cure. Infants younger than 1 year with stage 4S disease may need little if any therapy, although chemotherapy may be initiated because of bulky disease causing mechanical complications. In intermediate-risk neuroblastoma (subsets of patients with stages 3 and 4 disease), the primary treatment approach is surgical combined with chemotherapy. High-risk patients (the majority with stages 3 and 4 disease) require multimodal therapy, including surgery, irradiation, chemotherapy, and autologous HSCT. The administration of cis-retinoic acid, a differentiating agent, was shown to prolong disease-free survival in advanced-stage neuroblastoma when administered in the setting of MRD after HSCT.
A recent cooperative clinical trial concluded that administration of ch14.18 (a monoclonal antibody specific for the predominant antigen on neuroblastoma cells) and cytokines improves outcome in the high-risk population following HSCT. All patients with high-risk disease are offered this therapy, with the 2-year EFS being around 75%. The current COG trial for high-risk patients is investigating whether addition of radiolabeled MIBG to the induction regimen will improve outcome.
For children with stage 1, 2, or 4S disease, the 5-year survival rate is 80%–100%. Infants younger than 547 days have a greater than 80% likelihood of long-term survival.
et al: Hyperdiploidy plus nonamplified MYCN
confers a favorable prognosis in children 12–18 months old with disseminated neuroblastoma: a Pediatric Oncology Group Study. J Clin Oncol 2005;23:64–66
et al: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children’s Oncology Group. J Clin Oncol 2005;23:6459
JM: Recent advances in neuroblastoma. N Engl J Med 2010;362:2202–2211
et al: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis
-retinoic acid: a Children’s Oncology Group Study. J Clin Oncol 2009;27:1007
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
et al: Favorable prognosis for patients 12–18 months of age with stage 4 nonamplified MYCN
neuroblastoma: a Children’s Cancer Group Study. J Clin Oncol 2005;23:6474
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 malformations (eg, cryptorchidism, hypospadias, gonadal dysgenesis, pseudohermaphroditism, and horseshoe kidney), Beckwith-Wiedemann syndrome, Denys-Drash syndrome, and WAGR syndrome (Wilms tumor, aniridia, ambiguous genitalia, mental retardation).
The median age at diagnosis is related both to gender and laterality, with bilateral tumors presenting at a younger age than unilateral tumors, and males being diagnosed earlier than females. Wilms tumor occurs most commonly between ages 2 and 5 years; it is unusual after age 6 years. The mean age at diagnosis is 4 years.
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.
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 (NWTS-4) demonstrated that survival rates were improved by intensifying therapy during the initial treatment phase while shortening overall treatment duration (24 vs 60 weeks of treatment).
Table 31–8 provides an overview of the current treatment recommendations in NWTS-5. Patients with stage III or IV Wilms tumor require radiation therapy to the tumor bed and to sites of metastatic disease. Chemotherapy is optimally begun within 5 days after surgery, whereas radiation therapy should be started within 10 days. Stage V (bilateral Wilms tumor) disease dictates a different approach, consisting of possible bilateral renal biopsies followed by chemotherapy and second-look renal-sparing surgery. Radiation therapy may also be necessary.
Table 31–8.Treatment of Wilms tumor.
Using these approaches, 4-year overall survival rates through NWTS-4 are as follows: stage I FH, 96%; stages II–IV FH, 82%–92%; stages I–III UH (diffuse anaplasia), 56%–70%; and stage IV UH, 17%. Patients with recurrent Wilms tumor have a salvage rate of approximately 50% with surgery, radiation therapy, and chemotherapy (singly or in combination). HSCT is also being explored as a way to improve the chances of survival after relapse.
Although progress in the treatment of Wilms tumor has been extraordinary, important questions remain to be answered. Questions have been raised regarding the role of prenephrectomy chemotherapy in the treatment of Wilms tumor. Presurgical chemotherapy seems to decrease tumor rupture at resection but may unfavorably affect outcome by changing staging. Future studies will be directed at minimizing acute and long-term toxicities for those with low-risk disease and improving outcomes for those with high-risk and recurrent disease.
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et al: The feasibility and outcome of nephron-sparing surgery for children with bilateral Wilms tumor. The St Jude Children’s Research Hospital experience: 1999–2006. Cancer 2008;112(9):2060
JS: Current and emerging chemotherapy treatment strategies for Wilms tumor in North America. Paediatr Drugs 2008;10(2):115
et al: Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2005;23:7312
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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.
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.
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 destruction of the normal bony trabecular pattern with indistinct margins. In addition, periosteal new bone formation and lifting of the bony cortex may create a Codman triangle. A soft tissue mass plus calcifications in a radial or sunburst pattern are frequently noted. MRI is more sensitive in defining the extent of the primary tumor and has mostly replaced CT scanning. The most common sites of metastases are the lung (≤ 20% of newly diagnosed cases) and the additional boney sites (10%). CT scan of the chest and bone scan are essential for detecting metastatic disease. PET-CT may be a consideration in monitoring response to therapy. Bone marrow aspirates and biopsies are not indicated.
Despite the rather characteristic radiographic appearance, a tissue sample is needed to confirm the diagnosis. Placement of the incision for biopsy is of critical importance. A misplaced incision could preclude a limb salvage procedure and necessitate amputation. The surgeon who will carry out the definitive surgical procedure should perform the biopsy. A staging system for osteosarcoma based on local tumor extent and presence or absence of distant metastasis has been proposed, but it has not been validated.
Historical studies showed that over 50% of patients receiving surgery alone developed pulmonary metastases within 6 months after surgery. This suggests the presence of micrometastatic disease at diagnosis. Adjuvant chemotherapy trials showed improved disease-free survival rates of 55%–85% in patients followed for 3–10 years.
Osteosarcomas are highly radioresistant lesions; for this reason, radiation therapy has no role in its primary management. Chemotherapy is often administered prior to definitive surgery (neoadjuvant chemotherapy). This permits an early attack on micrometastatic disease and may also shrink the tumor, facilitating a limb salvage procedure. Preoperative chemotherapy also makes detailed histologic evaluation of tumor response to the chemotherapy agents possible. If the histologic response is poor (> 10% viable tumor tissue), postoperative chemotherapy can be changed accordingly but a recently completed COG Group study showed increased toxicity with no additional benefit. Chemotherapy may be administered intra-arterially or intravenously, although the benefits of intra-arterial chemotherapy are disputed. Agents having efficacy in the treatment of osteosarcoma include doxorubicin, cisplatin, high-dose methotrexate, ifosfamide, and etoposide.
Definitive cure requires en bloc surgical resection of the tumor with a margin of uninvolved tissue. Amputation, limb salvage, and rotationplasty (Van Ness rotation) are equally effective in achieving local control of osteosarcoma. Contraindications to limb-sparing surgery include major involvement of the neurovascular bundle by tumor; immature skeletal age, particularly for lower extremity tumors; infection in the region of the tumor; inappropriate biopsy site; and extensive muscle involvement that would result in a poor functional outcome.
Postsurgical chemotherapy is generally continued until the patient has received 1 year of treatment. Relapses are unusual beyond 3 years, but late relapses do occur. Histologic response to neoadjuvant chemotherapy is an excellent predictor of outcome. Patients with localized disease having 90% or greater tumor necrosis have a 70%–75% long-term, disease-free survival rate. Other favorable prognostic factors include distal skeletal lesions, longer duration of symptoms, age older than 20 years, female gender, and near-diploid tumor DNA index. Patients with metastatic disease at diagnosis or multifocal bone lesions do not fair well, despite advances in chemotherapy and surgical techniques.
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 rhabdomyosarcoma, lymphoma, and neuroblastoma. Although most commonly a tumor of bone, it may also occur in soft tissue (extraosseous Ewing sarcoma or peripheral neuroectodermal tumor [PNET]).
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. PET-CT may be a consideration in helping to monitor therapy response.
A biopsy is essential in establishing the diagnosis. Histologically, Ewing sarcoma consists of sheets of undifferentiated cells with hyperchromatic nuclei, well-defined cell borders, and scanty cytoplasm. Necrosis is common. Electron microscopy, immunocytochemistry, and cytogenetics may be necessary to confirm the diagnosis. A generous tissue biopsy specimen is often necessary for diagnosis but should not delay starting chemotherapy.
A consistent cytogenetic abnormality, t(11;22), has been identified in Ewing sarcoma and PNET and is present in 85%–90% of tumors. These tumors also express the protooncogene c-myc, which may be helpful in differentiating Ewing sarcoma from neuroblastoma, in which c-myc is not expressed.
Therapy usually commences with the administration of chemotherapy after biopsy and is followed by local control measures. Depending on many factors, including the primary site of the tumor and the response to chemotherapy, local control can be achieved by surgery, radiation therapy, or a combination of these methods. Following local control, chemotherapy continues for approximately 6 months. Effective treatment for Ewing sarcoma uses combinations of dactinomycin, vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide. Recent data showed that giving chemotherapy every 2 weeks, rather than every 3 weeks, improved the EFS for localized Ewing sarcoma. The current COG nonmetastatic Ewing sarcoma study is looking at whether the addition of topotecan to the present five-drug regimen will improve survival.
Patients with small localized primary tumors have a 70%–75% long-term, disease-free survival rate. For patients with metastatic disease survival is poor. Autologous HSCT may be considered as part of the treatment of these high-risk patients. Patients with pelvic tumors have an intermediate prognosis of around 50% long-term, disease-free survival.
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et al: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 2012;30(33):41–48
Rhabdomyosarcoma is the most common soft tissue sarcoma occurring in childhood and accounts for 10% of solid tumors in childhood. The peak incidence occurs at ages 2–5 years; 70% of children are diagnosed before age 10 years. A second smaller peak is seen in adolescents with extremity tumors. Males are affected more commonly than females.
Rhabdomyosarcoma can occur anywhere in the body. When rhabdomyosarcoma imitates striated muscle and cross-striations are seen by light microscopy, the diagnosis is straightforward. Immunohistochemistry, electron microscopy, or chromosomal analysis is sometimes necessary to make the diagnosis. Rhabdomyosarcoma is further classified into subtypes based on pathologic features: embryonal (60%–80%), of which botryoid is a variant; alveolar (~15%–20%); undifferentiated sarcoma (8%); pleomorphic, which is seen in adults (1%); and other (11%). These subtypes occur in characteristic locations and have different metastatic potentials and outcomes.
Although the pathogenesis of rhabdomyosarcoma is unknown, in rare cases a genetic predisposition has been determined. Li-Fraumeni syndrome is an inherited mutation of the p53 tumor suppressor gene that results in a high risk of bone and soft tissue sarcomas in childhood plus breast cancer and other malignant neoplasms before age 45 years. Two characteristic chromosomal translocations [t(2;13) and t(1;13)] have been described in alveolar rhabdomyosarcoma. The t(1;13) translocation appears to be a favorable prognostic feature in patients with metastatic alveolar rhabdomyosarcoma, whereas t(2;13) is associated with poor outcomes.
The presenting symptoms and signs of rhabdomyosarcoma result from disturbances of normal body function due to tumor growth (Table 31–9). For example, patients with orbital rhabdomyosarcoma present with proptosis, whereas patients with rhabdomyosarcoma of the bladder can present with hematuria, urinary obstruction, or a pelvic mass.
Table 31–9.Characteristics of rhabdomyosarcoma. ||Download (.pdf) Table 31–9. Characteristics of rhabdomyosarcoma.
|Primary Site ||Frequency (%) ||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 prostate ||13 ||Hematuria, urinary obstruction || |
|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 |
A plain radiograph and a CT and/or MRI scan should be obtained to determine the extent of the primary tumor and to assess regional lymph nodes. A chest CT scan is obtained to rule out pulmonary metastasis, the most common site of metastatic disease at diagnosis. A skeletal survey and a bone scan are obtained to determine whether bony metastases are present. Bilateral bone marrow biopsies and aspirates are obtained to rule out bone marrow infiltration. Additional studies may be warranted in certain sites. For example, in parameningeal primary tumors, a lumbar puncture is performed to evaluate CSF for tumor cells.
Optimal management and treatment of rhabdomyosarcoma is complex and requires combined modality therapy. When feasible, the tumor should be excised, but this is not always possible because of the site of origin and size of tumor. When only partial tumor resection is feasible, the operative procedure is usually limited to biopsy and sampling of lymph nodes. Debulking of unresectable tumor may improve outcomes by decreasing the assigned stage/group. Chemotherapy can often convert an inoperable tumor to a resectable one. A second-look procedure to remove residual disease and confirm the clinical response to chemotherapy and radiation therapy is generally performed at about week 20 of therapy.
Radiation therapy is an effective method of local tumor control for both microscopic and gross residual disease. It is generally administered to all patients, the only exception being those with a localized tumor that has been completely resected. All patients with rhabdomyosarcoma receive chemotherapy, even when the tumor is fully resected at diagnosis. The exact regimen and duration of chemotherapy are determined by primary site, group, and tumor node metastasis classification. Vincristine, dactinomycin, and cyclophosphamide have shown the greatest efficacy in the treatment of rhabdomyosarcoma. Irinotecan is now being studied in upfront treatment of metastatic rhabdomyosarcoma based on good responses in relapsed disease. Newer treatment strategies for high-risk patients include different drug combinations, including the use of temozolomide and cixutumumab (monoclonal antibody against IGF-IR) in a current COG randomized trial.
The age of the patient, the extent of tumor at diagnosis, the primary site, the pathologic subtype, and the response to treatment all influence the long-term, disease-free survival rate from the time of diagnosis. Children with localized disease at diagnosis have a 70%–75% 3-year disease-free survival rate, whereas children with metastatic disease at presentation have a worse outcome (39% 3-year disease-free survival).
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Retinoblastoma is a neuroectodermal malignancy arising from embryonic retinal cells that accounts for 3% of malignant disease in children younger than 15 years. It is the most common intraocular tumor in pediatric patients and causes 5% of cases of childhood blindness. In the United States, 200–300 new cases occur per year. This is a malignancy of early childhood, with 90% of the tumors diagnosed before age 5 years. Bilateral involvement occurs in 20%–30% of children and typically is diagnosed at a younger age (median age 14 months) than unilateral disease (median age 23 months).
Retinoblastoma is the prototype of hereditary cancers due to a mutation in the retinoblastoma gene (RB1), which is located on the long arm of chromosome 13 (13q14). This gene is a tumor-suppressor gene that normally controls cellular growth. When the gene is inactivated, as in retinoblastoma, cellular growth is uncontrolled. Uncontrolled cell growth leads to tumor formation. Inactivation of both RB1 alleles within the same cell is required for tumor formation.
Retinoblastoma is known to arise in heritable and nonheritable forms. Based on the different clinical characteristics of the two forms, Knudson proposed a “two-hit” hypothesis for retinoblastoma tumor development. He postulated that two independent events were necessary for a cell to acquire tumor potential. Mutations at the RB1 locus can be inherited or arise spontaneously. In heritable cases, the first mutation arises during gametogenesis, either spontaneously (90%) or through transmission from a parent (10%). This mutation is present in every retinal cell and in all other somatic and germ cells. Ninety percent of persons who carry this germline mutation will develop retinoblastoma. For tumor formation, the loss of the second RB1 allele within a cell must occur; loss of only one allele is insufficient for tumor formation. The second mutation occurs in a somatic (retinal) cell. In nonheritable cases (60%), both mutations arise in a somatic cell after gametogenesis has taken place.
Children with retinoblastoma generally come to medical attention while the tumor is still confined to the globe. Although 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, a hyphema, or proptosis is the initial manifestation. A single focus or multiple foci of tumor may be seen in one or both eyes at diagnosis. Bilateral involvement occurs in 20%–30% of children.
Suspected retinoblastoma requires a detailed ophthalmologic examination under general anesthesia. An ophthalmologist makes the diagnosis of retinoblastoma by 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 of retinoblastoma. A CT scan of the orbits and MRI of the orbits/brain detects intraocular calcification, evaluates the optic nerve for tumor infiltration, and detects extraocular extension of tumor. A single focus or multiple foci of tumor may be seen in one or both eyes at diagnosis. Metastatic disease of the marrow and meninges can be ruled out with bilateral bone marrow aspirates and biopsies plus CSF cytology.
Each eye is treated according to the 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. Absolute indications for enucleation include no vision, neovascular glaucoma, inability to examine the treated eye, and inability to control tumor growth with conservative treatment. External beam irradiation has been the mainstay of therapy. A total dose of 35–45 Gy is administered. However, many centers are investigating the role of systemic chemotherapy for the treatment of retinoblastoma confined to the globe and the elimination of external beam radiotherapy is now accepted. Cryotherapy, photocoagulation, and radioactive plaques can be used for local tumor control. Patients with metastatic disease receive chemotherapy.
Children with retinoblastoma confined to the retina (whether unilateral or bilateral) have an excellent prognosis, with 5-year survival rates greater than 90%. Mortality is correlated directly with extent of optic nerve involvement, orbital extension of tumor, and massive choroid invasion. Patients who have disease in the optic nerve beyond the lamina cribrosa have a 5-year survival rate of only 40%. Patients with meningeal or metastatic spread rarely survive, although intensive chemotherapy and autologous HSCT have produced long-term survivors.
Patients with the germline mutation (heritable form) have a significant risk of developing second primary tumors. Osteosarcomas account for 40% of such tumors. Second malignant neoplasms occur in both patients who have and those who have not received radiation therapy. The 30-year cumulative incidence for a second neoplasm is 35% in patients who received radiation therapy and 6% in those who did not receive radiation therapy. The risk continues to increase over time. Although radiation contributes to the risk, it is the presence of the retinoblastoma gene itself that is responsible for the development of nonocular tumors in these patients.
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Two-thirds of liver masses found in childhood are malignant (see also Chapter 22). Ninety percent of hepatic malignancies are either hepatoblastoma or hepatocellular carcinoma. Hepatoblastoma accounts for the vast majority of liver tumors in children younger than 5 years, hepatocellular carcinoma for the majority in children aged 15–19 years. The features of these hepatic malignancies are compared in Table 31–10. Of the benign tumors, 60% are hamartomas or vascular tumors such as hemangiomas. There is mounting evidence for a strong association between prematurity and the risk of hepatoblastoma.
Table 31–10.Comparison of hepatoblastoma and hepatocellular carcinoma in childhood. ||Download (.pdf) Table 31–10. Comparison of hepatoblastoma and hepatocellular carcinoma in childhood.
| ||Hepatoblastoma ||Hepatocellular Carcinoma |
|Median age at presentation ||1 y (0–3 y) ||12 y (5–18 y) |
|Male-female ratio ||1.7:1 ||1.4:1 |
|Associated conditions ||Hemihypertrophy, Beckwith-Wiedemann syndrome, prematurity, Gardner syndrome ||Hepatitis B virus infection, hereditary tyrosinemia, biliary cirrhosis, α1-antitrypsin deficiency |
|Pathologic features ||Fetal or embryonal cells; mesenchymal component (30%) ||Large pleomorphic tumor cells and tumor giant cells |
|Solitary hepatic lesion ||80% ||20%–50% |
|Unique features at diagnosis ||Osteopenia (20%–30%), isosexual precocity (3%) ||Hemoperitoneum, polycythemia |
|Laboratory features || || |
|Hyperbilirubinemia ||5% ||25% |
|Elevated AFP ||> 90% ||50% |
|Abnormal liver function tests ||15%–30% ||> 30%–50% |
Children with hepatic tumors usually come to medical attention because of an enlarging abdomen. Approximately 10% of hepatoblastomas are first discovered on routine examination. Anorexia, weight loss, vomiting, and abdominal pain are associated more commonly with hepatocellular carcinoma. Serum α-fetoprotein is often elevated and is an excellent marker for response to treatment.
Imaging studies should include abdominal ultrasound, CT scan, or MRI. Malignant tumors have a diffuse hyperechoic pattern on ultrasonography, whereas benign tumors are usually poorly echoic. Vascular lesions contain areas with varying degrees of echogenicity. Ultrasound is also useful for imaging the hepatic veins, portal veins, and inferior vena cava. CT scanning and, in particular, MRI are important for defining the extent of tumor within the liver. CT scanning of the chest should be obtained to evaluate for metastatic spread. Because bone marrow involvement is extremely rare, bone marrow aspirates and biopsies are not indicated.
The prognosis for children with hepatic malignancies depends on the tumor type and the resectability of the tumor. Complete resectability is essential for survival. Chemotherapy can decrease the size of most hepatoblastomas. Following biopsy of the lesion, neoadjuvant chemotherapy is administered prior to attempting complete surgical resection. Monitoring the rate of decline of the α-fetoprotein levels can help indicate favorable versus poor responders to chemotherapy. Chemotherapy can often convert an inoperable tumor to a completely resectable one and can also eradicate metastatic disease. Approximately 50%–60% of hepatoblastomas are fully resectable, following preoperative chemotherapy, whereas only one-third of hepatocellular carcinomas can be completely removed. Even with complete resection, only one-third of patients with hepatocellular carcinoma are long-term survivors. A recent CCG/Pediatric Oncology Group trial has shown cisplatin, fluorouracil, and vincristine to be as effective as but less toxic than cisplatin and doxorubicin in treating hepatoblastoma. The current open COG trial is using cisplatin, fluorouracil, vincristine, and doxorubicin along with the cardioprotectant dexrazoxane in intermediate-risk patients with the addition of temsirolimus in high-risk patients. Other drug combinations that have demonstrated benefit include carboplatin plus etoposide and doxorubicin plus ifosfamide. Liver transplantation has been shown to be a successful surgical option in patients whose tumors are considered to be unresectable.
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LANGERHANS CELL HISTIOCYTOSIS
Langerhans cell histiocytosis (LCH; formerly called histiocytosis X) is a rare and poorly understood spectrum of disorders. It can occur as an isolated lesion or as widespread systemic disease involving virtually any body site. Eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease are all syndromes encompassed by this disorder. LCH is not a true malignancy, but instead is a clonal, reactive proliferation of normal histiocytic cells, perhaps resulting from an immunoregulatory defect.
The distinctive pathologic feature is proliferation of histiocytic cells beyond what would be seen in a normal inflammatory process. Langerhans histiocytes have typical features: on light microscopy, the nuclei are deeply indented (coffee bean–shaped) and elongated, and the cytoplasm is pale, distinct, and abundant. Additional diagnostic characteristics include Birbeck granules on electron microscopy, expression of CD1 on the cell surface, and positive immunostaining for S-100 protein.
Because LCH encompasses a broad spectrum of diseases; its presentation can be variable, from a single asymptomatic lesion to widely disseminated disease. Skin and bone lesions are the most frequent sites of disease.
Patients with localized disease present primarily with lesions limited to bone. Occasionally found incidentally on radiographs obtained for other reasons, these lesions are well-demarcated and frequently found in the skull, clavicles, ribs, and vertebrae. These lesions can be painful. Patients can also present with localized disease of the skin, often as a diaper rash that does not resolve.
Bony lesions, fever, weight loss, otitis media, exophthalmos, and diabetes insipidus (in 10%–15% of patients) occur in a fewer number of children with the disease. Children with this multifocal disease, formerly called Hand-Schüller-Christian disease, commonly present with generalized symptoms and organ dysfunction, mainly of the liver and lungs.
Children with disseminated LCH (formerly called Letterer-Siwe disease) typically present before age 2 years with a seborrheic skin rash, fever, weight loss, lymphadenopathy, hepatosplenomegaly, and hematologic abnormalities.
Diagnosis is made with biopsy of the involved organ. The workup should include a CBC, liver and kidney function tests, a skeletal survey or technetium bone scan, and a urinalysis with specific gravity to rule out diabetes insipidus.
The outcome in LCH is extremely variable and may spontaneously resolve. Isolated lesions may need no therapy at all. Intralesional corticosteroids, curettage, and low-dose radiation therapy are useful local treatment measures for symptomatic focal lesions. Patients with localized disease have an excellent prognosis, nearing 100%.
Multifocal disease is often treated with systemic chemotherapy. Prednisone and vinblastine are used for multifocal disease or disease involving other organs such as liver, spleen, hematopoietic system. The agents are given repeatedly or continuously until lesions heal; the drugs can then be reduced and finally stopped. A common therapeutic protocol for LCH is LCH III. Other active chemotherapeutic agents include 6-mercaptopurine, methotrexate, and etoposide. HSCT can also be used with some success in refractory cases. “High-risk” LCH has approximately 85% 5-year overall survival.
Multifocal disease is less predictable, but most cases resolve without sequelae. Age, degree of organ involvement, and response to therapy are the most important prognostic factors. Infants with disseminated disease tend to do poorly, with mortality rates approaching 50%. New treatment approaches for patients who do not respond to conventional chemotherapy have been evaluated in small studies. With some success, 2-Chlorodeoxyadenosine (2-CDA) has been used. Therapeutic strategies targeting the dysregulated immune response using interferon-α or etanercept (anti–tumor necrosis factor-α) have also been reported.
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