11.3 From Notes - Childhood and Adolescent Cancers

• Cancer is the leading cause of death from disease in children and adolescents.
• More than 15,500 children and adolescents are diagnosed with cancer each year in the United States.
• Fewer than 2,000 deaths occur annually in this age group in the US.
• The 5-year survival rates have significantly improved from 59% in the 1970s to nearly 85% today.
• This improvement is due to combination chemotherapy, targeted therapies, and participation in clinical trials.

Types of Cancer

• Common adult cancers include prostate, breast, lung, and colon cancers.
• In children up to 14 years of age, the most common cancers are leukemias and brain tumors, accounting for 61% of cases.
• Lymphomas are the most common type of cancer among adolescents (15 to 19 years of age).
• Leukemia, thyroid carcinoma, brain tumors, and germ cell tumors are also common adolescent cancers.
• Most childhood and adolescent cancers originate from the mesodermal germ layer.
• Common childhood cancers include leukemias, sarcomas, and embryonal tumors.
• Embryonal tumors originate during intrauterine life and are diagnosed early, usually before age 5.
• Leukemia is the most common malignancy in children, particularly between 2 and 5 years of age.
• Acute lymphoblastic leukemia (ALL) is the most common type, representing approximately 75% of all childhood and 67% of all adolescent leukemia cases.
• Central nervous system (CNS) tumors are the most common solid tumors in children, accounting for 21% of all childhood cancers and 10% of adolescent cancers.
• Pediatric solid tumors usually develop in children and adolescents but can rarely occur in adults such as neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, and Ewing sarcoma.
• Conversely, some adult cancers like hepatocellular carcinoma can occur in children and adolescents.
• Childhood and adolescent cancers are often associated with specific peak times of physical growth and may result from altered cellular regulatory mechanisms.
• Childhood and adolescent cancers are extremely fast-growing, with 80% having distant spread (metastases) at diagnosis.
• Cancer is 10% to 25% more common in white than in black children.
• Boys are more likely to develop cancer than girls.

Etiology

• The causes of cancer in children are largely unknown.
• The development of childhood cancer likely involves multiple factors, involving predisposing characteristics and environmental interactions.

Genetic Factors:

• Oncogenes and tumor-suppressor genes are associated with childhood cancer.
• Mutated proto-oncogenes that regulate cell growth are called oncogenes.
• Examples of oncogenes in pediatric cancer include MYCN (neuroblastoma, glioblastoma), BCR-ABL (acute lymphoblastic leukemia), and TP53.
• When both copies of a tumor-suppressor gene mutate, normal cell function is lost, and cancer can develop.
• Chromosomal aberrations, including aneuploidy, amplifications, deletions, and translocations are implicated.
• Certain chromosomal disorders and congenital malformations are associated with increased risk.
• Down syndrome (Trisomy 21) is the most common genetic defect linked to acute leukemia.
• Wilms tumor can occur with congenital anomalies in WAGR syndrome, caused by a mutation on chromosome 11 involving the WT1 gene.
• Wilms tumor is also associated with neurofibromatosis and Beckwith-Wiedemann syndrome.
• Retinoblastoma results from deletions in chromosome 13 at the RB1 gene locus.
• The Philadelphia chromosome leads to the BCR-Abl fusion protein and is found in chronic myelogenous leukemia and some ALL cases, and involves translocation between chromosomes 9 and 22.
• Several single-gene disorders like Fanconi anemia and Bloom syndrome increase cancer risk, including leukemias and lymphomas. These are autosomal recessive conditions with altered DNA repair and chromosomal fragility.
• Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder with mutations in the TP53 gene that significantly increases the risk of various childhood and adult cancers.
• An increased familial risk is observed for some pediatric cancers, even if not single-gene disorders; a child with a sibling with leukemia has a 2 to 4 times higher risk.
• A recent study found that 8.5% of children and adolescents with cancer had a germline mutation associated with cancer development, compared to 1.1% in those without cancer with the TP53 gene was most frequently affected.
• Mutations in genes, like those encoding histone proteins, can cause epigenetic modifications, leading to altered gene expression and increased cancer vulnerability.

Environmental Factors:

• Few childhood tumors have a strong association with environmental agents, unlike many adult cancers.
• Established risk factors include exposure to high-dose and high-dose rate ionizing radiation for childhood leukemia.
• Prenatal exposure to diethylstilbestrol (DES) has been linked to adenocarcinomas of the vagina and cervix in offspring.
• Prenatal or postnatal environmental tobacco smoke exposure may have a causal relationship with childhood leukemia, lymphoma, and brain tumors.
• Parental exposure to pesticides (before or during pregnancy for mothers, occupationally or household for fathers) is associated with increased risk of childhood leukemia, lymphoma, and brain tumors.
• Maternal exposure to hair dyes and occupational chemicals has been suggested as a risk factor for neuroblastoma.
• Childhood exposure to ionizing radiation, certain drugs, and viruses has been associated with cancer risk.
• There is an increased risk of brain cancer and leukemia following multiple CT scans in childhood; scans should only be done at the lowest possible radiation dose when necessary.
• Exposures to unspecified residential pesticides and insecticides in childhood have been linked to childhood leukemia.
• The relationship between childhood cancer and exposure to radon and electromagnetic fields is inconclusive; some studies suggest a possible association between magnetic field exposure and childhood leukemia.
• Viral exposure, particularly Epstein-Barr virus (EBV), is strongly linked to Burkitt lymphoma, nasopharyngeal carcinoma, and Hodgkin disease.
• Children with acquired immunodeficiency syndrome (AIDS) have an increased risk of non-Hodgkin lymphoma and Kaposi sarcoma (although this has declined with HAART use).
• Certain drugs used in treatment or other conditions may increase childhood cancer risk, such as anabolic androgenic steroids, cytotoxic chemotherapy, and immunosuppressive agents.

Prognosis

• Nearly 85% of children and adolescents diagnosed with cancer are cured.
• Mortality rates have significantly declined due to advances in treatment and increased participation in clinical trials.
• Factors contributing to improved cure rates include combination chemotherapy, multimodal treatment for solid tumors, development of research centers, cooperation among institutions, and cooperative study groups.
• Clinical trials focus on more effective, targeted therapies with fewer side effects.
• Management of treatment side effects has improved due to advancements in nursing and supportive care, recognition of psychological effects, and long-term follow-up care.
• Young children are particularly prone to long-term sequelae of cancer therapy, making the development of more targeted therapies with fewer side effects crucial.
• Supportive care and long-term follow-up guidelines are available for survivors.