AUTHOR INFORMATION

Section 1 of 9

Authored by Gary M Kupfer, MD, Assistant Professor, Departments of Microbiology and Pediatrics, University of Virginia

Gary M Kupfer, MD, is a member of the following medical societies: American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Edited by Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	Gary M Kupfer, MD
Editor's Email:	Samuel Gross, MD

eMedicine Journal, December 15 2006, VOLUME 7, Number 12

INTRODUCTION

Section 2 of 9

Approximately 1.2 million new cases of invasive cancer were diagnosed in the United States. Of these cases, more than 12,000 affected children. The heterogeneity of pediatric cancer is substantial, and even the most common pediatric cancer, namely, acute lymphoblastic leukemia (ALL), comprises considerable diversity. As a result of this diversity and the low incidence of childhood cancers, the ability of epidemiologists to ascribe causes to specific childhood cancers is extremely limited.

Epidemiology has enabled researchers to evaluate sparse data to demonstrate the effects of cancer genetics, define family pedigrees and penetrance, and identify subsets of certain cancers and their implications for treatment and prognosis. In addition, study of obscure genetic diseases that increase the risk of malignancy in childhood has led to an understanding of important cancer genes that has wide applicability to oncology in both children and adults. These factors represent both a challenge and an opportunity in the discipline of pediatric oncology.

TOOLS OF STUDY

Section 3 of 9

Measures

The understanding of the epidemiology of any medical problem demands the use of basic terminology from the language of statistics. Important terms are defined below.

• Ratio - Relationship between 2 quantities, ie, x/y

• Proportion - Ratio in which the denominator also includes the numerator, ie, x/(y + x)

• Rate - Proportion occurring per time period, ie, x/(x + y)/time

• Incidence - Proportion of new cases within a population over time, ie, x/(y + x)/time

• Prevalence - Number of existing cases in a population at a set time

• Crude rate - Measure of actual events in a population

• Standardized rate - Crude rate adjusted for a factor in the population (eg, age, sex, economic status)

• Standardized mortality-incidence ratios - Observed rates adjusted by comparison with the expected rate derived from a large population

• Relative risk - Incidence in a population with a specific characteristic compared to that in a population without the characteristic

Study designs

Study designs useful to epidemiology include the following:

• Descriptive design - Used to define the characteristics of a particular disease entity

• Ecological design - Used to compare large populations (eg, populations of nations)

• Prospective design - Used to identify 2 similar populations to be treated in different ways in the future for subsequent analysis

• Retrospective design - Used to identify and analyze 2 similar populations that were treated in different ways in the past

• Clinical trials - Administered chiefly under the auspices of national groups with supervision by and interaction with the National Cancer Institute (NCI) of the National Institutes of Health (NIH) and the US Food and Drug Administration (FDA)

Clinical drug trials

New cancer drugs were historically adapted for pediatric use after they were first used in adult patients. New drug development has recently incorporated pediatric trials performed concurrently with adult trials, which follow research and development in private industry and academia. The Cancer Therapy Evaluation Program (CTEP) of the NIH monitors drug development.

A typical clinical trial protocol includes the following information: objectives of the trial, background, patient eligibility criteria, study design, treatment plan, drug information, treatment evaluation criteria, data collection methods, plan for statistical analysis, consent form to be signed by the patient (or parent or guardian) and the investigator, and supporting references. Relevant appendices are also attached.

Phase 1 trials

Phase I trials are specifically designed to assess toxicity. Pediatric patients are treated in cohorts of 3 starting at a dose that is either 75% the adult dose or 10% the lethal dose in mouse studies. The dose is increased in predetermined steps for each new cohort of patients. Toxicity is assessed in several body systems, and a level of dose-limiting toxicity (DLT) is defined. If DLT occurs in at least 1 of the 3 patients, the protocol drops back to the previous dose level unless the DLT involves only hematologic toxicity in a patient with a hematologic malignancy.

Phase 2 trials

Phase 2 trials are typically designed to directly assess the efficacy of a drug in particular tumor types. A dose presumed to be safe from the results of phase 1 trials is used. An objective measure of response, such as percentage decrease in tumor size on scans, is used to evaluate efficacy. Phase 2 trials typically involve a 2-stage process to establish a firm likelihood and then to measure small differences.

Phase 3 trials

Phase 3 studies are intended to test the efficacy of novel ways of using accepted drugs (eg, combination chemotherapy, neoadjuvant therapy, timing variations, dose intensification) compared with standard therapy or the natural history of the disease. The design must permit investigators to measure and account for potential false-positive and false-negative data. The potential for error can be calculated and used to decide on the number of patients who need to be enrolled to ensure a certain level of confidence in the results. A type I error occurs when the P value suggests that a proposed treatment is better than standard when it is not. (The P value is the probability of obtaining the observed data (or data that are more extreme) if the null hypotheses were exactly true.)

Phase 3 trial design can be sequential to allow data to be evaluated continuously to find effective treatments as quickly as possible. However, type I errors can be magnified in this type of trial. This phenomenon can be blunted by requiring increased significance for the study. Factorial designs are used to examine several factors with a randomization method. Equivalence trials can be designed to determine if a treatment strategy of reduced duration and dosage is as effective as standard therapy.

A key element in phase 3 trials is the inclusion of at least 1 question or criterion that is randomized among 2 or more possibilities. This question or criterion ensures that patients are allocated to respective arms without bias. A method of allocating patients based on random numbers removes predictability from the assignment. Stratification is also desirable to group patients with identifiable prognostic characteristics. In the ideal situation, such assignments are conducted at the onset of therapy.

Careful analysis of the protocol and a clear understanding of its goal are essential if the introduction of bias is to be minimized. In general, all patients who are started on the study protocol should be included in the data analysis. Several analyses of a sample can introduce bias by summing type I errors in the subgroups, and an additional study may be needed to confirm the results. The results of subgroup analysis are usually given in the context of a large study. Data are typically presented in the form of Kaplan-Meier curves, which represent probabilities of survival over time. Responses to treatment may also be presented in terms of objective measurement of a tumoral response, such as shrinkage.

Phase 4 trials

In phase 4 trials, investigators apply positive findings from research centers to generic use in the community. Phase 4 studies can include large-scale population analysis for marketing and promotion by a company or for surveillance as mandated by the FDA. Phase 4 trials also can be conducted for safety and efficacy analysis of old drugs. These trials can include the use of controlled randomized studies.

CANCER INCIDENCE

Section 4 of 9

Incidence and mortality rates of childhood cancers differ worldwide. The differences depend on how extensively data are reported. Incidences vary from as high as 155 per million persons in Nigeria to 40 per million persons in the Indian population of Fiji. Rates for the United States are likely to be more accurate than these because 94% of all patients with cancer reportedly are seen at 1 of the institutions of the Children’s Oncology Group (COG).

In the United States, the incidence of childhood cancer overall is approximately 125 per million persons, with slightly increased rates in boys and Caucasian children. Leukemias account for approximately 25% of all childhood cancers, followed by tumors of the CNS (17%), neuroblastoma (7%), non-Hodgkin lymphoma (NHL) (6%), Wilms tumor (6%), Hodgkin disease (5%), rhabdomyosarcoma (3%), retinoblastoma (3%), osteosarcoma (3%), and Ewing sarcoma (2%). Numerous rare tumor types account for the remainder.

The decreased mortality rate of pediatric cancers has been one of the major success stories of medicine in the last 30 years. Improvements in the survival rates of leukemias, Hodgkin disease, and sarcomas have been notable successes. Most of these improvements can be traced to the use of aggressive multimodal therapy and to blood banking, use of cytokines, and improved supportive care to prevent and treat infections.

The success of the treatment of pediatric cancer engenders the new challenge of caring for the growing numbers of cancer survivors. The risk of a second cancer appearing 20 years after an initial diagnosis of cancer is approximately 8%, indicating the emergence of a challenging patient population. The existence of this group also suggests that risk factors (eg, treatment, heredity, other environmental factors) might be identifiable. For instance, the risk of acute myelogenous leukemia (AML) with the 9;11 translocation is approximately 10% within 5 years of therapy that includes high-dose etoposide. A similar risk has been noted after treatment with alkylating agents.

TUMORS

Section 5 of 9

Leukemias

Leukemias are the most common type of childhood cancer, accounting for 34% of new diagnoses. The greatest advances in treatment and outcomes have occurred in leukemias, in no small part because of the ability to treat relatively large numbers of patients with uniform treatment protocols.

Acute lymphoblastic leukemia

Nearly 80% of childhood leukemias are ALL. Multicomponent chemotherapy regimens have resulted in long-term survival rates approaching 90% in patients with favorable prognostic factors, which include presenting peripheral WBC count <20 X 10⁹/L (<20,000 X 10³/mL); age > 1 and <10 years; early pre–B-cell phenotype; presence of the TEL-AML1 translocation; lack of mature T-cell, B-cell, and myeloid-cell markers; lack of 9;22 translocation; early remission; lack of CNS disease; female sex; lack of mediastinal mass or organomegaly; initial hemoglobin >10 g/dL; platelet count >100 X 10⁹/L; good nutritional status; and normal immunoglobulin G (IgG) levels.

The advent of modern molecular techniques has resulted in the further dissection of ALL into several subtypes with therapeutic implications. For example, the recently described TEL-AML1 translocation is present in approximately 20% of pediatric cases of ALL. The TEL-AML1 translocation is now considered to be a favorable prognostic indicator for the outcome of ALL, whereas the presence of Philadelphia chromosome, a 9;22 translocation involving the bcr and abl oncogenes, is a poor prognostic indicator.

Acute myelogenous leukemia

Approximately 18% of childhood leukemias are AMLs. This ratio of ALL to AML holds true throughout childhood except for a predilection for AML in the neonatal period. AML comprises a heterogeneous array of subtypes M0-M7. Molecular diagnostic methods have advanced the ability to subtype myeloid leukemias; the analysis of translocations is helping to define and confirm the histologic designations.

For example, the t(8;21) translocation associated with the M2 subtype is found in 15% of patients with AML. Of interest, this translocation is a favorable predictor of long-term survival. The M3 subtype, which is associated with a 15;17 translocation, is similarly correlated with a favorable outcome by virtue of its response to therapy with all–trans-retinoic acid. In contrast, the chromosome 9;11 translocation associated with the M4 and M5 subtypes indicates a poor prognosis. Abnormalities of chromosome 11 at the malignant lymphoma, lymphoblastic (MLL) locus are often observed in individuals with secondary AML after treatment with etoposide.

Chronic leukemias

Chronic leukemias account for <5% of all pediatric leukemias. Chronic myelogenous leukemia (CML) is the most common type and corresponds to the adult type of CML marked by the Philadelphia chromosome. This adult type of CML appears in children > 4 years and is linked to radiation exposure in many individuals with CML. Juvenile myelomonocytic leukemia (JMML), a chronic leukemia that lacks the bcr-abl fusion, is a disease of younger children, with most diagnosed in children younger than 2 years. Other rare forms of chronic childhood leukemia include chronic myelomonocytic, monocytic, and lymphocytic leukemias.

Brain tumors

Tumors of the CNS constitute the other major type of childhood cancer. A full 17% of childhood cancers involve brain tumors. Patients with CNS tumors remain an underreported segment of the pediatric population with cancer because only one half are referred to specialty centers. Morbidity is clearly the greatest problem in patients with brain tumors because many of these tumors are in locations that are difficult to treat. Unlike adult brain tumors, most true childhood brain tumors occur in the posterior fossa.

Brain tumors are heterogeneous, which makes their categorization difficult. The most common single-entity brain tumor in children is medulloblastoma, which accounts for 10-20% of childhood brain tumors and 40% of tumors in the posterior fossa. Most brain tumors, chiefly medulloblastomas and glial tumors, involve the posterior fossa. Most CNS tumors are glial tumors, which are classified by their location as supratentorial, cerebellar, or brainstem. Unique variants in each of these groups have strong prognostic significance. For example, patients with exophytic gliomas do extremely well, whereas individuals with diffuse infiltrative tumors do poorly.

Hodgkin disease

Rates of Hodgkin disease, which accounts for 5% of childhood cancers, peak in children younger than 14 years, in young adults, and in adults older than 55 years. Most statistical reports comment on childhood cancers up to age 14 years. Therefore, the overall impact of Hodgkin disease in the adolescent population tends to be understated. Like NHL, Hodgkin disease is reported to be associated with immunodeficiency and infection with the Epstein-Barr virus (EBV), as well as cytomegalovirus and human herpesvirus 6.

Classification of Hodgkin disease includes specific subtypes, including nodular sclerosing, lymphocyte predominant, mixed cellularity, and lymphocyte depleted. Nodular sclerosing appears to be the most common subtype, and lymphocyte depleted seems to be associated with severe disease and worsened outcomes. Patients who survive Hodgkin disease remain at high risk for secondary tumors, a phenomenon that may indicate an underlying immunodeficient state. Breast cancer in young patients with a history of Hodgkin disease is mostly associated with irradiation as a treatment modality.

Burkitt lymphoma

Burkitt lymphoma, a type of NHL, is associated with EBV infection and endemic on the African continent. Burkitt lymphoma accounts for roughly one half of all incidents of NHL, a number which translates to an incidence of approximately 2-3% among childhood cancers. In its endemic form, the incidence of Burkitt lymphoma can increase up to 50-fold. Endemic Burkitt lymphoma is associated with EBV, and it appears to occur in equatorial Africa. Additional environmental factors appear to be at work in the pathogenesis of Burkitt lymphoma because the endemic form differs from even the sporadic form, which also can be found along with EBV in North America as the breakpoints of the 8:14 translocation differ.

Small, round, blue-cell tumors

The predominant solid tumors in children are the small, round, blue-cell tumors, which together comprise approximately 30% of childhood malignancies. Within this group, subtype classification has been both obvious and muddled. For instance, the primitive neuroectodermal tumors remain a classification of great controversy, resulting in differences in reporting and treatment. Most small, round, blue-cell tumors have characteristics that lend themselves to pathologic analysis. All of the tumor types described below are considered small, round, blue-cell tumors.

Neuroblastoma

Neuroblastoma is the most common non-CNS solid tumor. Its round, blue-cell appearance is marked by neuropils on specimens stained with hematoxylin and eosin. Both long-term survival and short-term treatment remain challenges in the care of patients with neuroblastoma. Of interest, the patient's age at presentation has prognostic implications. The form that emerges in infancy greatly improves the likelihood of long-term survival and is marked by a lack of N-myc amplification; by hyperdiploidy; by low-stage, limited distant sites in stage I or II disease (marrow, liver, or skin involvement in <10% of patients); by the absence of 1p chromosomal abnormalities; by a lack of changes on chromosome 17; and by evidence of neuronal differentiation. However, the form that emerges in children aged 1-10 years has a much worsened prognosis.

Non-Hodgkin lymphoma

Lymphomas make up a large, if heterogeneous, category of childhood cancers. Chief among these cancers are the NHLs, which are responsible for 6% of all pediatric cancers. NHL is a disease of young children and has an overall predilection for boys, probably because of a subset of T-cell lymphoma. A major factor in NHL is its association with immunodeficiency secondary to underlying genetic diseases, viral infection, or drugs.

Wilms tumor

Wilms tumor is the most common renal tumor, constituting approximately 5-6% of childhood cancers. As in neuroblastoma, the patient's age affects the prognosis in that patients who present in infancy have the best outcomes. Wilms tumor is strongly associated with a host of genetic syndromes, including Beckwith-Wiedemann syndrome; Denys-Drash syndrome; and Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome. Studies of chromosome 11 have led to the description of the products of the WT1 and WT2 genes, which are associated with WAGR syndrome and Beckwith-Wiedemann syndrome, respectively. Prognostic factors associated with long-term survival include low-stage disease, favorable histology, and young age.

Retinoblastoma

Retinoblastoma is the classic tumor that led to the development of the 2-hit hypothesis of carcinogenesis. Study of family trees and analysis of known mutations have demonstrated a breakdown in incidence as unilateral plus sporadic (60%), unilateral plus inherited (15%), and bilateral plus inherited (25%). Hereditary cancer occurs early and is most likely to be bilateral, implying that a second hit has occurred in more than 1 location, with the first hit having been inherited in the germline.

Incidents of sporadic cancer are simply most likely to be unilateral by virtue of the lowered likelihood of 2 hits occurring in a normal somatic cell. Inherited incidents of retinoblastoma illustrate the importance of the Rb protein in suppressing tumorigenesis in that patients with inherited retinoblastoma remain at risk for other tumors, chiefly osteosarcoma.

Rhabdomyosarcoma

Rhabdomyosarcoma is another solid tumor with an incidence that peaks in children younger than 6 years and again in early adolescence. This incidence is roughly correlated with the type of tumor. Head and neck tumors are generally diagnosed in young patients, and the histology is usually embryonal. Older patients are most likely to have tumors in the extremities with alveolar histology. In general, patients with embryonal tumors and individuals with hyperdiploidy have improved outcomes; however, these data remain somewhat controversial.

Osteosarcoma

Osteosarcoma is a bone tumor associated with the rapid bone growth characteristic of the adolescent growth spurt. Osteosarcoma is most common in patients who are taller than their peers, and osteosarcoma is diagnosed at an early age in more girls than boys. Tumors are localized to the growth plates of long bones. Radiation and alkylating agents have been implicated in the etiology of osteosarcoma, along with retinoblastoma and Li-Fraumeni syndrome. The subtype of osteosarcoma is probably the most important prognostic factor. Well-differentiated variants (eg, parosteal and intraosseous tumors, diploid tumors) are associated with improved outcomes.

Ewing sarcoma

Ewing sarcoma is a collection of tumors that includes peripheral primitive neuroectodermal tumors and primary bony tumors. The diagnostic standard involves detecting either chromosome 11;22 or the 21;22 translocation, at least one of which is found in as many as 95% of individuals with Ewing sarcoma. An interesting feature of Ewing sarcoma is its extreme rarity among African Americans. Although the greatest incidence is observed in the second decade of life, Ewing sarcoma occurs more throughout the age spectrum than does osteosarcoma. Ewing sarcoma is not associated with rapid bone growth and may be found anywhere along the bone or adjacent soft tissue, or it may even occur as an isolated soft-tissue mass.

FACTORS OF CANCER PREDISPOSITION

Section 6 of 9

Relatively few causative factors have been identified for childhood cancer. The increased numbers of adults with cancer have enabled the ascertainment of causative factors, such as alcohol and smoking, whereas the small numbers of children with cancer have made environmental factors difficult to evaluate. However, analysis for inherited factors is increasingly fruitful and expanding in scope, given the explosion in availability of molecular biologic technology and resources engendered by the Human Genome Project.

Inherited predisposition

At its most basic level, cancer is a genetic disease. Production of genetic instability that confers some kind of mutator phenotype is most likely the chief characteristic of any inherited predisposition for cancer. These instabilities take one of several forms: (1) mutations in key genes that are directly involved in tumoral development (eg, WT1, WT2), (2) mutations in genes that generate mutations and gross chromosomal deletions at key loci (eg, in Fanconi anemia and mismatch repair), (3) mutations in genes directly involved in DNA repair of specific lesions (eg, xeroderma pigmentosum), and (4) complex chromosomal syndromes that increase the person's susceptibility to develop cancer.

Down syndrome

Children with Down syndrome have a 1% risk of developing leukemia before they are aged 10 years. The ratio of types is different in these children than in children overall in that 60% of children with Down syndrome develop ALL, and 40% develop AML. In general, the prognosis seems to be worse in children with Down syndrome and ALL than in children without Down syndrome and without ALL. In contrast, outcomes tend to be better in children with Down syndrome and AML than in children without DS and without AML. Patients with Down syndrome may have associated transient myeloproliferative disease of infancy, which not only resembles congenital leukemia but also confers a 30% risk of subsequent AML.

Turner syndrome mosaicism or androgen insensitivity syndrome

Retention of the Y chromosome in female individuals with Turner-syndrome mosaicism or androgen-insensitivity syndrome increases their lifetime risk of gonadoblastoma. This risk is as high as 25% by adulthood.

Wilms tumor

Association of gross deletions at the 11p13 locus with Wilms tumor led to isolation of the WT1 gene. Clinical abnormalities associated with WT1 mutations include aniridia, genital abnormalities, and mental retardation. As many as 40% of individuals with Wilms tumor have some familial component.

Syndromes associated with increased growth have also been associated with Wilms tumor. Examples include the Beckwith-Wiedemann syndrome and hemihypertrophy. Beckwith-Wiedemann syndrome is linked to chromosomal band 11p15, where a putative WT2 gene resides. Insulin growth factor 2 and p57kip2 are the leading candidates for the WT2 tumor suppressor gene.

Mendelian inheritance of genetic cancer predisposition

Autosomal dominant disorders

In his study of retinoblastoma, Knudson (1971) first described the 2-hit hypothesis of carcinogenesis. This hypothesis describes the process whereby, given the genetic transmission of these disorders through the germline, the loss of a second allele of the same gene in a predisposed patient leads to the onset of cancer at an early age. Germline defects in 1 allele may predispose the person to or may promote the loss of the other corresponding allele. These disorders are more likely than other cancers to be associated with bilateral and multiple tumors. Concomitant with this risk is the person's risk of developing several tumors at various times during his or her lifetime, depending on the tissue at risk.

With regard to retinoblastoma, the deleted Rb gene not only increases the risk of the patient born with the mutation but also entails unknown risk for 2 other groups: patients with newly diagnosed sporadic cases and familial carriers who do not develop retinoblastoma as children. Mutation in the Rb gene also confers a lifetime risk of osteosarcoma and melanoma.

Gene p53 represents the gene most commonly mutated in human cancers, and it is the dysfunctional gene responsible for the rare familial Li-Fraumeni cancer syndrome. Numerous cancers cluster in Li-Fraumeni cancer syndrome, including sarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. The study of Li-Fraumeni cancer syndrome has improved our understanding of cancer in general, as p53 appears to be a convergence point for many cancers in the long, multistep process of carcinogenesis.

The development of several colonic polyps is associated with the early development of familial colon cancer and hepatoblastoma. The APC gene was found by means of positional cloning. This gene affects signaling by means of the beta-catenin pathway.

Hereditary nonpolyposis colon cancer (HNPCC) was first defined as a genomic instability disorder in which the underlying genetic defect promotes the loss of the other allele, giving rise to the tumor. The HNPCC group involves at least the mismatch repair proteins that are implicated in an array of adult cancers. The mismatch repair genes are analyzed at the protein level and as an in vitro test to determine a person's carrier status for HNPCC.

The gene complex for multiple endocrine neoplasia (MEN) is marked by an association of cancers of the thyroid, parathyroid, pancreas, pituitary, and adrenal medulla. MEN type 2 syndrome appears to be due to activating mutations of the ret oncogene rather than to a 2-hit mechanism.

Neurofibromatosis type 1 (NF-1) is one of the most common genetic syndromes and is marked by a propensity to cause brain tumors and peripheral nerve sheath tumors. Defects in ras guanosine triphosphatase (GTPase), termed neurofibromin, are sporadic in at least one half of the cases of NF detectable in the general population. The frequency is 1 case per 3000 persons. Patients with NF-1 are prone to develop optic gliomas, most commonly in early childhood, along with gliomas in other locations. A link to the development of myeloid leukemias is also described; this link is consistent with the connection between ras mutations and myeloid disease. Associations with many other diseases are reported but not proven.

Tuberous sclerosis is a syndrome of seizures, mental retardation, and angiofibromas. Tuberous sclerosis is associated with a range of benign growths. Cardiac rhabdomyomas are a problem of infancy, whereas retinal hamartomas and giant cell astrocytomas develop later in childhood.

von Hippel-Lindau syndrome involves an association of renal cell carcinoma, retinal and cerebellar angiomata, and pheochromocytoma. The VHL gene product is an elongin that is responsible for normal transcription completion.

Autosomal recessive disorders

Xeroderma pigmentosum results from several genetic complementation groups that are part of the nucleotide excision repair system and transcriptional apparatus. Patients with xeroderma pigmentosum are at increased risk for basal cell carcinoma, squamous cell carcinoma, and melanoma. Neurologic and other skin findings are also part of the related disorders trichothiodystrophy and Cockayne syndrome.

Ataxia telangiectasia is a radiation hypersensitivity syndrome that comprises a constellation of ataxia, oculocutaneous telangiectasia, and increased incidence of lymphoid malignancies. The gene product responsible for this disease is ATM (which stands for ataxia-telangiectasia mutated) phosphoinositide (PI) 3-kinase. The protein participates in the Rad50-BRCA1 epistasis group; it is also probably involved in double-strand break repair by means of homologous recombination.

Fanconi anemia, a disorder of hypersensitivity to bifunctional alkylating agents, is marked by congenital defects, bone marrow failure, and susceptibility to several cancers (most commonly AML). At least 12 genes are defective among the known complementation groups for Fanconi anemia. Although many genes have been cloned, the molecular basis for Fanconi anemia remains elusive.

Immunodeficiency states

Although evidence is not plentiful, immune surveillance clearly plays a major role in tumor prevention. The most dramatic example is CML, in which a measurable graft-versus-leukemia effect occurs, whereby immunosuppression to avoid graft versus host disease decreases leukemia-free survival. In addition, theoretical analysis of tumor killing rates after chemotherapy and measurement of residual disease demonstrate that the tumor is still present after therapy. Reliance on the host immune system is assumed to eradicate CML. By extension, immunodeficient states can be postulated to engender cancer susceptibility.

Severe combined immunodeficiency

Patients with severe combined immunodeficiency are difficult to examine because of the severity of their underlying defect. However, their inherent propensity toward lymphoid malignancy is clear. Patients with prolonged survival may have some residual immune function and thus a prolonged period before cancer develops.

Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome is an immunodeficiency disorder characterized by thrombocytopenia, eczema, and T-cell dysfunction. It increases the risk of NHL.

Lymphoproliferative syndromes

Lymphoproliferative syndromes, which may be both genetic and therapeutic, increase the risk of lymphoid proliferation triggered by EBV infection. In the X-linked form of the disease, EBV infection accounts for 70% of deaths. After prolonged immunosuppression (eg, chronic graft versus host disease after bone marrow transplantation), the patient's susceptibility to lymphoproliferative disease increases.

HIV infection

HIV has not left the pediatric population unaffected, despite promising regimens for preventing vertical transmission and promotion of safe-sex practices. The progression to AIDS is generally more rapid in children than in adults. The spectrum of cancers associated with HIV includes Kaposi sarcoma, NHL (especially in the CNS), and leiomyosarcoma.

ENVIRONMENTAL FACTORS

Section 7 of 9

Ionizing radiation

Although increased cancer rates in children have been associated with radiation exposure, no threshold effect has been noted. Data derived from the atomic-bomb exposures at Hiroshima and Nagasaki are probably the most complete and most convincing evidence. A link also has been established between third-trimester radiologic examinations and leukemia. Data from Japan link atomic-bomb exposures, exposures to nuclear fallout from testing, and therapeutic radiation for tonsillitis and tinea with increased risks of leukemia and thyroid cancer. Preconception radiation exposure remains a source of controversy. One study showed an effect from paternal exposure; however, these data have not been reproduced.

Electromagnetic fields

Research has produced great controversy but little solid evidence of a relationship between cancer and electromagnetic fields. Published reports have suggested that electromagnetic fields have some potential effect on the promotion of leukemia. However, when the available data are combined, the relative risk is probably no more than 1.5.

Chemicals

Most data about chemical exposure and its relationship to adult cancers imply that a lifetime of exposure is required to cause cancer. This implication is evidenced by smoking. However, exceptions have been reported. Dioxin has been associated with thyroid cancer, AML, and Hodgkin disease. Trichloroethane has been implicated in the Woburn, Massachusetts, case that suggested a link between exposure and leukemia. A strong relationship has been suggested between parental exposure and subsequent childhood cancer. Agents and their associated cancers include pesticides (CNS tumors), solvents (eg, CNS tumors, leukemia, neuroblastoma, hepatoblastoma), metals (hepatoblastoma), petroleum products (eg, Wilms tumor, leukemia, hepatoblastoma), lead (Wilms tumor), boron (Wilms tumor), furnaces (lymphoma), and chemotherapy (leukemia).

TEST QUESTIONS

Section 8 of 9

CME Question 1: A 4-year-old child with anemia and leg pain has 90% L1 blasts on the peripheral blood differential. Which additional factor, if present, would increase this patient's risk category?

A: Low peripheral WBC count
B: TEL-AML1 translocation
C: Female sex
D: T-cell immunophenotype
E: None of the above

The correct answer is D: T-cell leukemia is associated with worsened outcomes and predominantly affects boys.

CME Question 2: A new medicinal agent from the Brazilian rain forest has been tested in mice and adults, and recent data revealed a safe dose in children. What type of study should be used to assess the efficacy of this agent in treating relapsed solid tumors?

A: Phase 1 trial
B: Phase 2 trial
C: Phase 3 trial
D: Prospective trial
E: Retrospective trial

The correct answer is B: By definition, phase 2 trials are efficacy trials for new medicinal agents. Phase 2 trials are typically designed to directly assess the efficacy of a drug in particular tumor types. A dose presumed to be safe from the results of phase 1 trials is used. An objective measure of response, such as percentage decrease in tumor size on scans, is used to evaluate efficacy. Phase 2 trials typically involve a 2-stage process to establish a firm likelihood and then to measure small differences.

Pearl Question 1 (T/F): The most common form of leukemia in children is acute myelogenous leukemia (AML).

The correct answer is False: The most common leukemia in children is acute lymphoblastic leukemia (ALL). However, in the neonatal period, the predominant leukemia is AML.

Pearl Question 2 (T/F): Most pediatric CNS tumors are located in the posterior fossa.

The correct answer is True: Unlike most adult CNS tumors, most CNS tumors in children are in the posterior fossa. Morbidity is clearly the greatest problem in brain tumors because many of these tumors are in locations that are difficult to treat.

Pearl Question 3 (T/F): The most common non-CNS solid tumor in children is neuroblastoma.

The correct answer is True: Neuroblastoma accounts for 10% of pediatric cancer diagnoses. The small, round, blue-cell tumors, of which neuroblastoma is one type, constitute 30% of pediatric cancers.

Pearl Question 4 (T/F): Bilateral cases of retinoblastoma are inherited.

The correct answer is True: The inheritance of bilateral cases of retinoblastoma is consistent with the 2-hit hypothesis and with the fact that familial retinoblastoma is inherited through the germline. Therefore, 1 faulty copy (ie, hit) of the Rb gene already exists in the retina at birth, increasing the chance of additional hits occurring at 2 locations.

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Section 9 of 9

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