Common Pediatric Malignancies

The treatment and approaches for children with cancer and blood disorders have advanced considerably during the last few decades, and most children with cancer now survive long-term. Improved cure rates have largely been the result of collaborative efforts and clinical trials such as those of the Children’s Oncology Group (COG), an international collaboration of more than 200 pediatric oncology centers conducting clinical trials in pediatric cancer patients.

Since Sidney Farber demonstrated temporary remission in children with acute leukemia in 1948, innumerable advances have led to 80% or higher cure rates for many pediatric cancers. With so much progress, the focus in the treatment of many pediatric cancers has shifted to providing more-intensive therapy for those at higher risk of relapse while reducing the intensity of therapy and risks of long-term toxicities in cancer survivors whenever feasible (risk-directed therapy). To do this, oncologists use clinical markers and response to treatment to both predict the risk of relapse and guide treatment decisions. Examples of risk-based therapy include the use of minimal residual disease (MRD) to predict the risk of relapse in acute lymphoblastic leukemia and N-MYC gene amplification to stratify risk for neuroblastoma.

Given the substantial number of malignancies, we provide a summary table of important facts about common pediatric malignancies and treatment modalities, followed by an overview of the most common diagnoses in children (leukemias, lymphomas, and solid tumors). Note that while treatment principles remain stable across diagnoses, the approach to specific cancers may vary depending on the treating institution. Although we provide peak ages of onset, the malignancies detailed below can occur at any age.

Hematologic Malignancies

Leukemias

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common type of childhood leukemia (75% of childhood leukemias). In ALL, the bone marrow makes too many immature lymphocytes. ALL is classified based on lineage: Depending on the cell of origin, ALL can be either B-lineage (B-cell acute lymphoblastic leukemia [B-ALL]) or T-lineage (T-cell acute lymphoblastic leukemia [T-ALL]).

Presentation: Common symptoms of ALL include fever, fatigue, anorexia, easy bruising/prolonged bleeding, and bone pain. On exam, there is often lymphadenopathy, hepatosplenomegaly, and evidence of bruising. Hyperleukocytosis in ALL is associated with aggressive tumor lysis syndrome (TLS), thus hydration and control of uric acid and electrolytes are the mainstays of management.

Evaluation: Initial evaluation should be aimed at establishing diagnosis and assessing for presence of tumor lysis syndrome, mediastinal mass, and/or coagulopathy.

• From an examination perspective, the presence of disease in either the central nervous system or testicles contributes to a higher risk classification in either T-ALL or B-ALL. In cases of B-ALL, patients are initially classified using the National Cancer Institute risk criteria as follows:

  • Standard risk: age <10 years AND initial leukocyte count <50,000/mm³ at diagnosis

  • High risk: ≥10 years OR initial leukocyte count ≥50,000/mm³ at diagnosis

• From a laboratory standpoint, the risk stratification of B-ALL depends on the genetics of the cancer cell (presence or absence of favorable/unfavorable mutations). For both B-ALL and T-ALL, additional evaluation confirms the risk stratification of the patient, especially how the disease responds to chemotherapy.

Management: Treatment mainly involves outpatient administration of chemotherapy. Blood or bone-marrow transplantation (BMT) is reserved for a small proportion of patients with very high-risk or relapsed leukemia. More recently, novel targeted therapies and immunotherapies have been developed and can benefit certain subsets of patients. For example, identification of the Philadelphia chromosome on cytogenetics [t(9;22)] warrants targeted treatment to include a tyrosine kinase inhibitor (TKI). Immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy can provide additional therapy options for patients with relapsed or refractory disease and may allow them to avoid BMT.

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the second most common type of childhood leukemia (accounting for 15%-20% of childhood leukemias). AML is characterized by abnormal proliferation of immature myeloid cells in the bone marrow. In the first 5 years of life, children with Down syndrome have 150-fold increased risk of developing AML (and a 20-fold increased risk of developing ALL).

Presentation: Symptoms may be similar to those of ALL. Risk stratification also depends on the genetics of the cancer cells and response to treatment. Hyperleukocytosis can be associated with leukostasis as well as TLS.

Management: Treatment involves intensive chemotherapy administered in the hospital due to extremely high risk of infection and treatment-related mortality during the neutropenic phase. BMT is used for patients with high-risk genetics such as FLT3-ITD mutations.

Lymphomas

Childhood lymphomas can be categorized as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).

Hodgkin Lymphoma

Hodgkin lymphoma arises from abnormal leukocytes in the lymphatic system.

Presentation: Common symptoms include lymphadenopathy, mediastinal mass, fatigue, and anorexia.

Diagnosis: Diagnosis requires biopsy of an enlarged lymph node as well as imaging to evaluate the extent of the disease. Based on the Ann Arbor staging method, patients with Hodgkin lymphoma are categorized according to the location and size of lymphadenopathy (assigned as a number I-IV) and the absence (A) or presence (B) of specific symptoms (unexplained fever, >10% weight loss, and/or drenching night sweats). Reed-Sternberg cell is pathognomonic of Hodgkin lymphoma. B symptoms and bulky disease (masses that occupy more than one-third of the chest), tumors >6 cm elsewhere, or disease in the spleen can modify disease stage.

Management: Treatment involves chemotherapy, radiotherapy, or both for patients with high-risk disease or poor response to chemotherapy (assessed by imaging modalities such as CT or fluorodeoxyglucose-positron-emission tomography [FDG-PET] scan).

Hodgkin lymphoma is associated with high cure rates; however, patients can experience significant late effects (e.g., secondary malignancies associated with radiation). A current focus is on reducing late effects among survivors. New therapies such as brentuximab vedotin (Bv), an anti-CD30 monoclonal antibody, have recently been integrated into front-line therapy as standard of care for high-risk patients, as a substitute for bleomycin. Although the late effects of these targeted therapies are not yet known, the hope is that substituting treatments with significant toxicities (bleomycin confers a risk of significant pulmonary toxicity) can reduce the late effects of chemotherapy (and potentially the need for radiation) in certain patient groups.

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) only comprises 7% of cancers among patients younger than 20 years. The most common types of NHL in children include:

• Burkitt lymphoma is a mature B-cell NHL with the fastest rate of cell division of any cancer in humans. It follows that it is aggressive and fast-growing, and associated with brisk tumor lysis. Burkitt lymphoma is characterized by a hallmark t(8;14) translocation involving the N-MYC gene.

  • Sporadic Burkitt lymphoma is most common in the United States and Western Europe and more often involves the abdomen and other areas of the body, but not the jaw.

  • Endemic Burkitt lymphoma is a tumor of the jaw associated with Epstein-Barr virus and primarily occurs in Africa, South America, and Oceania.

• Lymphoblastic lymphoma represents >25% of pediatric NHLs and is more common in boys. Most (80%) arise from T cells and the remainder arise from B cells. In children, lymphoblastic lymphomas and lymphoblastic leukemias often involve the same aberrant lymphoblast and are differentiated only by the absence (lymphoma) or presence (leukemia) of disease in the bone marrow (defined as involvement of 25% or more of bone marrow).

• Diffuse large-B-cell lymphoma (DLBCL) is also an aggressive mature B-cell NHL. DLBCL accounts for 10% of pediatric NHL cases but is the most common NHL in adults. Outcomes are far superior among children with DLBCL due to the higher proportion of children having the subtype with a favorable prognosis (expression of CD10 and BLC6).

• Other NHL entities in children include primary mediastinal large-B-cell lymphoma (PMLBCL), follicular lymphoma, and anaplastic large-cell lymphoma (ALCL). ALCL is characterized by large CD30+ cells; ALCL in children often has a t(2;5) encoding an NPM-ALK fusion protein and conferring a more favorable prognosis.

Presentation: In children, the symptoms of NHL are often similar to that of HL. However, patients with Burkitt lymphoma can present with robust tumor lysis syndrome (high LDH, hyperuricemia, hyperkalemia), recurrent intussusception outside of the common age of intussusception, or both. Rapidly growing lymph node clusters or masses can lead to mass effect and compression, including superior vena cava syndrome. Patients with ALCL can present with extranodal disease of the skin, liver, or lungs.

Diagnosis: Diagnosis requires biopsy of lymph nodes and imaging to evaluate the extent of disease and the size and location of lymph nodes for staging.

Management: Treatment involves chemotherapy, radiotherapy, or both. Some types of low-grade NHL can be managed with surgical resection alone. Thus, treatment is often the same for lymphoblastic lymphoma and leukemia. Adding targeted agents to a disease-specific standard chemotherapy backbone can increase survival, prevent relapses, and avoid radiation.

• For mature B-cell lymphomas (e.g., diffuse large-B-cell lymphoma or Burkitt lymphoma), rituximab, an anti-CD20 monoclonal antibody, has been shown to markedly prolong survival when added to a traditional chemotherapy backbone.

• For T-cell acute lymphoblastic lymphomas, the addition of bortezomib (proteasome inhibitor) has been found to improve outcomes.

• In children with anaplastic lymphoma kinase positive (ALK+) ALCL, the addition of brentuximab vedotin has been shown to improve outcomes.

Solid Tumors

Brain tumors are the most common solid tumors in children. Neuroblastoma is the most common extracranial solid tumor in children, the third most common pediatric cancer, and the most common cancer in infants. Adult-type cancers such as carcinomas are extremely rare in children.

Brain Tumors

Brain tumors in children include:

• medulloblastoma: most common malignant brain tumor in children

• astrocytoma: most common type of glioma diagnosed in children; may be benign, cystic, and slow-growing

• brain-stem gliomas: rare and associated with low survival rates

Presentation: Children with brain tumors can present with gradual or sudden-onset headache or neurologic symptoms, including signs of increased intracranial pressure (nausea, vomiting, weakness, blurry vision) or other neurologic changes (depending on the tumor location) from mass effect of the tumor. In addition, brain tumors can cause endocrinopathies due to mass effect on the hypothalamic-pituitary axis.

Diagnosis: Diagnosis relies on imaging (MRI), often including both the brain and spine to evaluate for drop metastases. If available, MR spectroscopy can be used to distinguish different diagnostic entities. Some brain tumors (e.g., medulloblastoma) require evaluation of spinal fluid for central nervous system (CNS) contamination.

Management: Treatment traditionally involves a combination of chemotherapy, radiation, and/or surgical resection. Unfortunately, aggressive therapies often lead to significant morbidity in survivors. Immunotherapy has had a positive impact on many adult tumors, and various approaches are being studied in pediatric populations in the hope of avoiding long-term treatment-related morbidity.

Extracranial Solid Tumors in Childhood

Extracranial solid tumors in childhood that arise from immature embryonic cells include neuroblastoma, Wilms tumor (nephroblastoma), and hepatoblastoma. These tumors typically present in younger children, often as palpable abdominal masses with associated gastrointestinal symptoms. Staging for each of these entities involves imaging to identify metastatic disease, including bone-marrow evaluation in applicable diseases (e.g., neuroblastoma).

Neuroblastoma

Neuroblastoma results from neural crest precursors that lead to aberrant differentiation and transformation; tumors with high levels of differentiation and higher proportion of Schwann cells have lower malignant potential. Neuroblastoma most commonly arises from the adrenal gland but may arise anywhere along the sympathetic nervous system. It may present as a paraspinal mass, diffuse abdominal lymphadenopathy, or with opsoclonus-myoclonus syndrome.

Diagnosis: Additional evaluation when considering neuroblastoma includes assessment of urine catecholamine metabolites (homovanillic acid [HVA] and vanillylmandelic acid [VMA]). Imaging in neuroblastoma includes the use of metaiodobenzylguanidine (MIBG), a compound that is preferentially picked up by neural crest cells and is therefore used to identify metastatic disease in patients with neuroblastoma.

Prognosis: Neuroblastoma is generally associated with overall favorable outcomes, but patients with high-risk neuroblastoma may have poor outcomes. Prognostic features include stage (metastases), age (children younger than 18 months have better outcomes), cytogenetics, and pathology. The original Shimada pathologic classification was integrated into the International Neuroblastoma Pathology Classification system, both of which integrate the histologic features of the tumor (proportion of neural-type cells and Schwann cells as well as the spectrum of differentiation of cells), the mitosis-karyorrhexis index (MKI), and age at diagnosis. Additional characteristics factored into the risk assessment of neuroblastoma and stratification for treatment include amplification of the N-MYC oncogene, ploidy (hyperdiploid is favorable), and chromosomal aberrations such as loss of heterozygosity. A special category is reserved for infants younger than 12 months with metastatic disease limited to the skin, liver, and bone marrow; such tumors may spontaneously regress and not require aggressive therapy.

Management: Treatment depends on risk stratification. Patients with low-risk disease may be managed with observation alone while patients with high-risk disease are treated with surgical resection, chemotherapy, autologous stem cell transplantation, radiation, and immunotherapy.

Wilms Tumor

Wilms tumor arises from the kidney, and lungs are the most common metastatic site.

Diagnosis: Wilms tumor has a characteristic appearance (claw sign) on imaging (CT or MRI); this distinguishes an intrinsic renal mass from a pararenal mass with a secondary mass effect on the renal parenchyma. Urine catecholamines may help differentiate Wilms tumor from neuroblastoma if imaging is equivocal.

Management: Resection as the first step (when possible) is considered standard of care, except in specific situations when resection is not feasible or would complicate surgical outcomes. Resection at diagnosis provides the opportunity for detailed staging (histology) of the entire tumor and molecular testing (loss of heterozygosity), which are prognostic and may guide therapy, along with an avoidance of tumor spillage, which would upstage the disease.

Wilms tumor is treated with chemotherapy and surgical resection (prior to chemotherapy unless contraindicated), with the addition of radiotherapy dependent on stage. Staging relies on both disease extent and tumor rupture or spillage during surgery. Overall, Wilms tumor is associated with excellent cure rates.

Hepatoblastoma

Hepatoblastoma usually occurs in younger children; the overwhelming majority of cases occur in children younger than 2 years and rarely in children older than 5 years. Although most cases are sporadic, hepatoblastoma is associated with genetic syndromes such as Beckwith-Wiedemann syndrome (BWS), trisomy 18, and familial adenomatous polyposis (FAP).

Management: Tumor histology, staging, presence or absence of metastasis, and alpha-fetoprotein (AFP) levels are important prognostic markers. Treatment involves chemotherapy, surgical resection, and/or radiotherapy depending on risk stratification. Some patients with unresectable hepatoblastoma confined to the liver require liver transplantation following chemotherapy.

Bone and Soft-Tissue Sarcomas

Other extracranial solid tumors of childhood fall into the category of bone and soft-tissue tumors or sarcomas (cancers arising from connective tissue) such as:

• Ewing sarcoma

• osteosarcoma

• rhabdomyosarcoma

• non-rhabdomyosarcoma soft-tissue sarcoma

Presentation: Signs and symptoms of bone and soft-tissue sarcomas such as Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma are related to the location of the tumor. For example, osteosarcoma may present with a pathologic fracture, while Ewing sarcoma may present with swelling and pain, often confounded by an injury. Rhabdomyosarcomas commonly occur in either the head or neck or the genitourinary regions (although they may occur anywhere), and therefore present with either proptosis (if retro-orbital), facial swelling (if arising from a sinus), or paratesticular swelling (if arising in the genitourinary region).

Diagnosis: Diagnosis requires imaging to detect the extent of the primary tumor and evaluation for metastatic disease for risk stratification. Biopsies of bone or soft tissue should be performed by surgeons experienced with malignancies in order to prevent contamination of joint spaces or compromise of long-term functional outcomes in terms of limb-sparing procedures. Bone marrow should be evaluated in Ewing sarcoma and rhabdomyosarcoma. Lymph node sampling is indicated for suspicious lymph nodes in rhabdomyosarcoma.

Management: Treatment involves chemotherapy (usually followed by surgical debulking) or radiation, depending on both the surgical accessibility of the tumor and the disease (e.g., Ewing sarcoma and rhabdomyosarcoma are radiosensitive). For osteosarcoma in particular, response to therapy at the time of surgical resection is predictive of outcome. The aim of surgical resection is for limb-sparing procedures if feasible; amputation is considered only when necessary. Resection of metastatic disease is also considered in certain sarcomas, including osteosarcoma. Although the majority of childhood solid tumors are spontaneous, cancer predisposition syndromes also must be considered; for example, congenital bilateral retinoblastoma is associated with an increased predisposition to osteosarcoma (e.g., TP53 mutations, Li-Fraumeni syndrome).