Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For acute myeloid leukemia, the 5-year survival rate increased over the same time from less than 20% to 68% for children younger than 15 years and from less than 20% to 57% for adolescents aged 15 to 19 years. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Myeloid Leukemias in Children
Approximately 20% of childhood leukemias are of myeloid origin and they represent a spectrum of hematopoietic malignancies. The majority of myeloid leukemias are acute, and the remainder include chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia (CML) and juvenile myelomonocytic leukemia (JMML). Myelodysplastic syndromes occur much less frequently in children than in adults and almost invariably represent clonal, preleukemic conditions.
Acute myeloid leukemia (AML) is defined as a clonal disorder caused by malignant transformation of a bone marrow–derived, self-renewing stem cell or progenitor, which demonstrates a decreased rate of self-destruction as well as aberrant, and usually limited, differentiation capacity. These events lead to increased accumulation in the bone marrow and other organs by these malignant myeloid cells. To be called acute, the bone marrow usually must include greater than 20% leukemic blasts, with some exceptions as noted in subsequent sections.
CML represents the most common of the chronic myeloproliferative disorders in childhood, although it accounts for only 10% to 15% of childhood myeloid leukemia. Although CML has been diagnosed in very young children, most patients are aged 6 years and older. CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the white blood cell (WBC) count can be extremely elevated, the bone marrow does not show increased numbers of leukemic blasts during the chronic phase of this disease. CML is nearly always characterized by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22 (i.e., t(9;22)) resulting in fusion of the BCR and ABL genes. Other chronic myeloproliferative syndromes, such as polycythemia vera and essential thrombocytosis, are extremely rare in children.
JMML represents the most common myeloproliferative syndrome observed in young children. JMML occurs at a median age of 1.8 years and characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated WBC count and increased circulating monocytes. In addition, patients often have an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte-macrophage colony-stimulating factor (GM-CSF), monosomy 7, and leukemia cell mutations in a gene involved in RAS pathway signaling (e.g., NF1, KRAS/NRAS, PTPN11, or CBL).[4,5]
The transient myeloproliferative disorder (TMD) (also termed transient leukemia) observed in infants with Down syndrome represents a clonal expansion of myeloblasts that can be difficult to distinguish from AML. Most importantly, TMD spontaneously regresses in most cases within the first 3 months of life. TMD blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the GATA1 gene.[6,7] TMD may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TMD is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk for developing subsequent AML. Approximately 20% of infants with Down syndrome and TMD eventually develop AML, with most cases diagnosed within the first 3 years of life.[7,8] Early death from TMD-related complications occurs in 10% to 20% of affected children.[8,9] Infants with progressive organomegaly, visceral effusions, and laboratory evidence of progressive liver dysfunction are at a particularly high risk for early mortality.
The myelodysplastic syndromes in children represent a heterogeneous group of disorders characterized by ineffective hematopoiesis, impaired maturation of myeloid progenitors with dysplastic morphologic features, and cytopenias. Although the majority of patients have hypercellular bone marrows without increased numbers of leukemic blasts, some patients may present with very hypocellular bone marrow, making the distinction between severe aplastic anemia and low-blast count AML difficult.
There are genetic risks associated with the development of AML. There is a high concordance rate of AML in identical twins; however, this is not believed to be related to genetic risk, but rather to shared circulation and the inability of one twin to reject leukemic cells from the other twin during fetal development.[10-12] There is an estimated twofold to fourfold risk of fraternal twins both developing leukemia up to about age 6 years, after which the risk is not significantly greater than that of the general population.[13,14] The development of AML has also been associated with a variety of predisposition syndromes that result from chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, as well as altered protein synthesis.
Inherited and Acquired Genetic Syndromes Associated with Myeloid Malignancies
- Inherited syndromes
- Chromosomal imbalances:
- Down syndrome.
- Familial monosomy 7.
- Chromosomal instability syndromes:
- Fanconi anemia.
- Dyskeratosis congenita.
- Bloom syndrome.
- Syndromes of growth and cell survival signaling pathway defects:
- Neurofibromatosis type 1 (particularly JMML development).
- Noonan syndrome (particularly JMML development).
- Severe congenital neutropenia (Kostmann syndrome).
- Shwachman-Diamond syndrome.
- Diamond-Blackfan anemia.
- Congenital amegakaryocytic thrombocytopenia.
- CBL germline syndrome (particularly in JMML).
- Chromosomal imbalances:
- Acquired syndromes
- Severe aplastic anemia.
- Paroxysmal nocturnal hemoglobinuria.
- Amegakaryocytic thrombocytopenia.
- Acquired monosomy 7.
- Familial myelodysplastic syndrome (MDS) and AML syndromes
- Familial platelet disorder with a propensity to develop AML (associated with germline RUNX1 mutations).
- Familial MDS and AML syndromes with germline GATA2 mutations.
- Familial MDS and AML syndromes with germline CEBPA mutations.
- Telomere biology disorders due to a mutation in TERC or TERT (i.e., occult dyskeratosis congenita).
Nonsyndromic genetic susceptibility to AML is also being studied. For example, homozygosity for a specific IKZF1 polymorphism has been associated with an increased risk of infant AML.
- Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
- Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997. [PUBMED Abstract]
- Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 17-34. Also available online. Last accessed October 26, 2014.
- Niemeyer CM, Arico M, Basso G, et al.: Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Blood 89 (10): 3534-43, 1997. [PUBMED Abstract]
- Loh ML: Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152 (6): 677-87, 2011. [PUBMED Abstract]
- Hitzler JK, Cheung J, Li Y, et al.: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101 (11): 4301-4, 2003. [PUBMED Abstract]
- Mundschau G, Gurbuxani S, Gamis AS, et al.: Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101 (11): 4298-300, 2003. [PUBMED Abstract]
- Massey GV, Zipursky A, Chang MN, et al.: A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 107 (12): 4606-13, 2006. [PUBMED Abstract]
- Homans AC, Verissimo AM, Vlacha V: Transient abnormal myelopoiesis of infancy associated with trisomy 21. Am J Pediatr Hematol Oncol 15 (4): 392-9, 1993. [PUBMED Abstract]
- Zuelzer WW, Cox DE: Genetic aspects of leukemia. Semin Hematol 6 (3): 228-49, 1969. [PUBMED Abstract]
- Miller RW: Persons with exceptionally high risk of leukemia. Cancer Res 27 (12): 2420-3, 1967. [PUBMED Abstract]
- Inskip PD, Harvey EB, Boice JD Jr, et al.: Incidence of childhood cancer in twins. Cancer Causes Control 2 (5): 315-24, 1991. [PUBMED Abstract]
- Kurita S, Kamei Y, Ota K: Genetic studies on familial leukemia. Cancer 34 (4): 1098-101, 1974. [PUBMED Abstract]
- Greaves M: Pre-natal origins of childhood leukemia. Rev Clin Exp Hematol 7 (3): 233-45, 2003. [PUBMED Abstract]
- Puumala SE, Ross JA, Aplenc R, et al.: Epidemiology of childhood acute myeloid leukemia. Pediatr Blood Cancer 60 (5): 728-33, 2013. [PUBMED Abstract]
- West AH, Godley LA, Churpek JE: Familial myelodysplastic syndrome/acute leukemia syndromes: a review and utility for translational investigations. Ann N Y Acad Sci 1310: 111-8, 2014. [PUBMED Abstract]
- Ross JA, Linabery AM, Blommer CN, et al.: Genetic variants modify susceptibility to leukemia in infants: a Children's Oncology Group report. Pediatr Blood Cancer 60 (1): 31-4, 2013. [PUBMED Abstract]