Introduction

Cancer is, in general, associated with aging. In theUnited States, cancer incidence rates per 100,000 per-sons per year rise almost 100-fold, from 23.4 in the firstyear of life to 2177.2 in the 85th year and beyond.1

Among adults, the four most common cancers are solidtumors of the prostate, breast, colon, and lung.Hematologic malignancies, leukemias and lymphomas,are much less common. However, among children,leukemias and lymphomas account for a much largershare of all malignancies (Fig. 1.1). At ages 2–14 years,the hematologic malignancies account for more than40% of new cancer diagnoses. At ages 15–19 years, theyaccount for 40.1% of malignant diseases among malesbut only 33.3% among females. At ages 20–39 years,hematologic malignancy incidence rates are slightlylower among females than males, but all-site incidencerates are much higher among females, primarily due tobreast, cervical, and thyroid cancer.2 As a result, by thelate 1930s, hematologic malignancies account for18.6% of newly diagnosed cancers per year amongmales but only 6.7% among females (Table 1.1).

Leukemia is a set of diseases of the blood or bonemarrow (in which blood cells originate), involving anabnormal proliferation of (white) blood cells. The acuteleukemias involve the rapid proliferation of immature

blood cells, crowding the bone marrow and spreadingthrough the bloodstream into other organs. Thechronic leukemias involve a more gradual increase inmore mature blood cells. The acute leukemias are themost common hematologic malignancies in children;incidence rates peak among 2–3-year-olds.

Lymphoma is a term used for cancers that originatein lymphocytes, usually within lymph nodes, but,unlike lymphoid leukemias, which involve only circu-lating blood and bone marrow, lymphomas typicallypresent as solid tumors of the lymph nodes. More than40 types of lymphoma have been identified,3 but mostcan be classified as involving T-cells, B-cells, or NK cells.Lymphomas are very rare among young children; inci-dence rates are lower than 1/100,000 per year amongchildren younger than 8 years, but are as high asleukemia rates by the early teens and rise considerablyhigher by the early 1920s (Figs. 1.2A–B).

The Leukemias

Among children aged 0–14 in the United States,leukemias are responsible for 33% of cancers and 30%of cancer deaths.2 Incidence rates of leukemia are 5.0per 100,000 per year in that age range, age-specific ratesrise from birth to age 2 and then fall; the association

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Mark B. Geyer and Judith S. Jacobson

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Fig. 1.1. Incidence rates of hematologic malignancies per 100,000,by age.

Fig. 1.3. Leukemia in children and adolescents age 0–19: 5-yearsurvival by year of diagnosis (data from Horner, 2009).

Table 1.1. Incidence rates (per 100,000) of all sites and hemato-logic malignancies in children, adolescents, and young adults.

Hematologic as All sites Leukemias Lymphomas % of all sites

Males

< 1 25.1 5.3 0.0 21.11–4 22.3 10.1 0.7 48.45–9 12.2 4.3 1.8 50.0

10–14 13.6 3.5 2.9 47.115–19 22.2 3.7 5.2 40.120–24 33.4 3.0 7.2 30.525–29 46.7 3 8 23.630–34 61.3 3.3 9.5 20.935–39 86.5 4.2 11.9 18.6

Females

< 1 21.6 4.3 0.0 19.91–4 19.0 8 0.4 44.25–9 10.5 3.6 0.8 41.9

10–14 12.8 2.7 1.9 35.915–19 20.1 2.4 4.3 33.320–24 37.0 2.2 6.4 23.225–29 63.2 2.1 7.4 15.030–34 105.3 2.8 7.7 10.035–39 166.9 3.0 8.1 6.7

Fig. 1.2. (A) Incidence rates of hematologic malignancies per100,000 males, by age group. (B) Incidence rates of hematologicmalignancies per 100,000 females, by age group.

(A)

(B)

with age is driven by acute lymphoblastic leukemia(ALL), the most commonly diagnosed leukemia ofchildren (Fig. 1.1). Untreated acute leukemias areuniformly fatal. However, leukemia was the first cancerin which chemotherapy was successful, and in thepast 35 years, combination chemotherapy has achieveddramatic results (Fig. 1.3). Overall 5-year survivalamong children and adolescents with leukemia hasrisen from 50% to nearly 80%. Several etiologic factors

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in leukemia in children and young adults are summa-rized in Table 1.2.

Some childhood leukemias have been linked to cer-tain genetic disorders, including Down syndrome (tri-somy 21). Children with Down syndrome (DS) have a10- to 20-fold increased risk of developing acuteleukemia, compared to children without DS.4 A largecase control study from the Children’s Cancer Groupfound significantly increased risk of ALL (odds ratio4.85) and dramatically increased risk of acute myeloge-nous leukemia (AML) (odds ratio 76.80) among chil-dren with DS.5 However, children with DS account foronly 2% of cases of pediatric ALL, and 15% of cases ofpediatric AML).6 Among children with acute leukemia,children with DS differ substantially from those with-out DS in leukemia-related cytogenetics and acquiredgene mutations. Children with DS also have more thana 400-fold increased risk for acute megakaryoblasticleukemia (AMkL), the most common subtype of DS-associated AML.7 AMkL is frequently preceded by a pre-leukemic myelodysplastic syndrome (MDS) in childrenwith DS.8 Kleinfelter syndrome (XXY) has been incon-sistently associated with ALL.9

Several inherited marrow failure syndromes, includ-ing Fanconi anemia (FA), Schwachman–DiamondSyndrome (SDS), and to a lesser extent Diamond

Blackfan anemia (DBA) are associated with increasedrisk of MDS and AML. FA is a rare, genetic disorder,usually with an autosomal recessive pattern of inheri-tance, affecting some 1–5 per million. The incidence ofFA is considerably higher among Spanish Gypsies,white Afrikaners in South Africa, and Ashkenazi Jews10

than among other groups, probably due to foundermutations in small, isolated populations. FA is associ-ated with progressive marrow failure, numerous con-genital abnormalities, and high incidence of cancer.Among patients with FA, approximately 8% developAML by age 20, and 22% by age 36.11 SDS is a rare, auto-somal recessive disorder (approximately 1.33 per100,000 live births) characterized by marrow failure,pancreatic insufficiency, and skeletal abnormalities;some 30% of SDS patients develop MDS or AML.12

DBA is a rare disorder characterized by macrocytic ane-mia and erythroblastopenia, associated with severalmutations in genes encoding for ribosomal proteins.Familial DBA seems to be autosomal dominant withincomplete penetrance and an incidence rate ofapproximately 1 in 100,000. DBA is associated withincreased risk of hematologic malignancies, particularlyMDS and AML, as well as solid tumors. However, theincidence of AML and MDS in children with DBA isconsiderably lower than in children with FA or SDS.

Children and adolescents who have receivedchemotherapy or radiation therapy for a prior malig-nancy are at increased risk for acute leukemia (usuallyAML) and other myeloproliferative disorders, com-pared to individuals of similar age who have not beentreated for cancer. It is not clear whether genetic factorsplay a role in this association. Patients treated withmechlorethamine or cyclophosphamide for Hodgkinlymphoma (HL), have a more than 300-fold or 100-fold, respectively, increased risk of acute leukemia com-pared to that in the general population. Patientsreceiving mechlorethamine-containing combinationchemotherapy (the MOPP regimen) for HL have acumulative 3.4–9.5% risk of leukemia in the 15 yearsfollowing treatment.13 Such cases of AML are often pre-ceded by MDS and tend to occur 5–7 years after the pri-mary diagnosis.14 Other chemotherapeutic agents usedin the treatment of childhood hematologic or solid can-cers, such as the epipodophyllotoxins (e.g. etoposide,teniposide) and the anthracyclines (e.g. doxorubicin,daunorubicin), also increase the risk of secondary AMLsignificantly; these cases of AML tend to occur moreacutely, without antecedent MDS, at a mean of 2–3years following the primary diagnosis. The dose of

Epidemiology of Hematological Malignancies of Children, Adolescents, and Young Adults 3

Table 1.2. Etiologic factors in leukemia.

Subtype Factor

ALL Male gender2

White race (in USA)2

Down Syndrome4–7

Kleinfelter Syndrome?9

Born with TEL-AML1 translocation62

Born with 11q23 rearrangement22

Prior chemoradiotherapy13

Ionizing radiation16

Unidentified infection?24,25

Lack of early daycare attendance62

AML Male gender2

White race (in USA)2

Down Syndrome4–7

Prior chemoradiotherapy13–15,17,18

Ionizing radiation16

Inherited marrow failure syndromes10–12

MDS Inherited marrow failure syndromes10–12

Prior chemoradiotherapy13–15,17,18

CML Male gender2

Ionizing radiation16

JMML Neurofibromatosis type 131

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epipodophyllotoxins and the frequency of dosing arepositively associated with increased risk of secondaryAML.15

Children exposed to ionizing radiation also face anincreased risk for hematological and other malignan-cies, including the leukemias. Among more than 86,000survivors of the 1945 atomic bomb blasts in Hiroshimaand Nagasaki, long-term follow-up has suggested that103 leukemia deaths were attributable to radiationexposure; about 28 of these deaths occurred in children,adolescents and young adults under age 30. A dose-response relationship between radiation dose andexcess leukemia risk was observed; individuals whoreceived radiation doses > 2 Gy, 10.4, 14.5, and 59.1times the risk of ALL, AML, and chronic myelogenousleukemia (CML), respectively, compared to thosereceiving only background levels of radiation expo-sure.16 The therapeutic use of ionizing radiation alsopredisposes patients to ALL, AML, and CML, with riskgreatest 5–9 years following exposure. For example,among 10,000 patients receiving 25 Gy of radiotherapyfor testicular cancer, an excess of nine leukemias is pre-dicted over 15 years.17 Patients treated with combina-tion chemotherapy and total body irradiation (mean:12.6 Gy) for non-Hodgkin lymphoma (NHL) had a17% risk of AML in 15 years of follow-up.18

Acute lymphoblastic leukemia

Acute lymphoblastic leukemia is an aggressive, malig-nant neoplasm of B- or T-lymphocyte precursor cells(lymphoblasts) (see Chapters 11 and 12). Unlike otherleukemias, ALL is primarily a disease of childhood, witha median age at diagnosis of 13 years. In the UnitedStates, ALL is the most common malignancy of childrenaged 0–14, representing 26% of all cancers and 79% ofall leukemias.2 Among children aged 0–14, the inci-dence of ALL is 4.0 per 100,000 per year, peaking at 9.4per 100,000 per year at age 3. In 2002–2006, an esti-mated 5,760 individuals per year, approximately 3,500of them under the age of 20, were diagnosed with ALL.

Acute lymphoblastic leukemia incidence rates arehigher among males than among females at all ages.Among children aged 0–14, incidence rates are 4.4 per100,000 in boys and 3.5 per 100,000 in girls. ALL ismore common in whites (1.7 per 100,000) than in blacks(0.9 per 100,000) across all age groups. Acute lympho-blastic leukemia incidence is highest among childrenaged 1–4 in both groups, but is substantially higher inwhites (8.5 per 100,000) than blacks (3.3 per 100,000).

From 1975 to 2006, the incidence of childhood ALLincreased by nearly 50% in children aged 0–14; theaverage annual increase was 0.8%.

Aneuploidy is the most commonly observedacquired abnormality in ALL, occurring in some formin 92% of cases of childhood ALL.19 Specific geneticabnormalities have been observed in childhood ALL,including the TEL-AML1 gene fusion generated by atranslocation involving chromosomes 12 and 21 (seeChapters 5 and 6). This fusion gene is present inapproximately 25% of cases of ALL; studies by theChildren’s Oncology Group and others suggest theTEL-AML1 gene carries positive prognostic signifi-cance.20 However, although approximately 1% of chil-dren are born with the TEL-AML1 translocation, onlyapproximately 1 in 8000 of those with the translocationwill develop childhood ALL.21 Translocations involvingchromosome 11q23, with resulting arrangement of theMLL gene, may occur in utero and are found in someinfants with ALL; such translocations are also fre-quently observed in secondary AML following therapywith topoisomerase II inhibitors, including etoposideand doxorubicin.22 The Philadelphia chromosome, gen-erated by translocation involving chromosomes 9 and22, is observed in 3–5% of children with ALL and isassociated with poor prognosis; in one large retrospec-tive study, only 28% of patients achieved 5-year event-free survival. Matched sibling donor allogeneic stem celltransplantation and good response to initial glucocorti-coid therapy were associated with superior outcomes inthese patients.23

Several investigators have hypothesized an infectiousetiology for childhood ALL. Greaves has postulated thattwo genetic events — one occurring in utero and a sec-ond following antigenic stimulation — may underliechildhood ALL. He suggests that among infants whoseexposure to pathogens is delayed, proliferation mayoccur in the preleukemic clone.24 Kinlen believes thatexposure to a yet-unidentified viral infection leads toALL as a rare outcome, particularly when infectious andsusceptible populations come into contact. He has iden-tified several studies demonstrating a significantlyincreased incidence of leukemia in situations where dif-ferent populations mix, such as urban and rural popu-lations or groups with very different socioeconomicbackgrounds.25 These hypotheses are not wholly incon-sistent; abnormal immune responses to infection couldbe leukemogenic. Although numerous small clusters ofchildhood ALL have been observed in the United States,no specific environmental etiology has been identified.26

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However, a recent meta-analysis has demonstrated anassociation of daycare attendance before age 2 withreduced risk of pediatric ALL21; investigators have sug-gested that the hygiene hypothesis, originally proposedas a risk factor for asthma,27 may also apply to ALL;early daycare attendance is hypothesized to be a markerof early exposure to pathogens, which may protectagainst ALL.

Treatment of childhood ALL consists of severalphases of combination chemotherapy to induce remis-sion, to eradicate leukemia cells in the central nervoussystem, and ultimately to suppress leukemic cellgrowth. Sibling or unrelated donor stem cell transplan-tation may be employed for children with relapsed orrefractory ALL and for those with other poor prognos-tic features, as will be discussed in subsequent chapters(see Chapters 11, 12 and 20). Five-year survival for ALLhas increased substantially in the past 35 years and iscurrently 89.2% for children aged 0–14 and 85.9% forchildren and adolescents aged 0–19.1

Acute myelogenous leukemia

Acute myelogenous leukemia (AML) is an aggressivecancer of myeloid precursor cells that crowd the bonemarrow and interfere with normal hematopoiesis (seeChapter 13). It is estimated that 12,810 individuals,more than 800 of whom were younger than 20 years,were diagnosed with AML in the United States in 2009.AML is primarily a disease of older adults, with amedian age at diagnosis of 67 years. AML incidencerates have a J-shaped age distribution. Among childrenaged 0–14 years, the AML incidence rate is 0.8 per100,000 per year, but among infants (< 1 year old), therate is 2.1 per 100,000 per year. In adolescents (15–19years), the incidence rate is 1.0 per 100,000 per year andcontinues to rise through middle and older age groups,peaking at 22.9 cases per 100,000 among those aged80–84. AML is the second most common leukemia inchildhood, representing 16% of leukemias in childrenaged 0–14 and 18% in adolescents aged 15–19.2

Although age-adjusted AML incidence rates are higheramong males than among females (4.3 per 100,000 inmales and 2.9 per 100,000 in females), age-specific ratesare similar in males and females younger than 30 years.AML is slightly more common in whites (3.6 per 100,000)than blacks (3.0 per 100,000) overall. Like that of child-hood ALL, childhood AML incidence increased signifi-cantly between 1975 and 2006 (63.3% in children aged0–14), with an average annual increase of 1.4%.

Treatment of AML employs combination chemother-apy to induce disease remission. Consolidation therapyfor pediatric AML generally consists of high-dosechemotherapy or stem cell transplantation. Treatmentregimens will be reviewed in subsequent chapters (seeChapters 13 and 20). Like that of patients with ALL, thesurvival of patients with AML has increased substan-tially in the past 35 years; five-year survival is currently60.2% for children aged 0–14 and 55.0% for childrenand adolescents aged 0–19. Although pediatric AMLcarries a less favorable prognosis than ALL, childrenand adolescents with AML have a far better 5-year sur-vival rate than the general population of AML patients,whose 5-year survival is only 23.8%.2

Chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a neoplasmof pluripotent stem cells still capable of terminal differ-entiation (see Chapter 15). It is uniformly associatedwith the presence of the BCR-ABL fusion gene; 95% ofpatients have a translocation involving chromosomes 9and 22. Some 5,050 Americans, of whom approximately120 were aged 0–19 years, were diagnosed with CML in2009; the median age at diagnosis is 66 years. The inci-dence of CML approaches 0.1 per 100,000 in childrenaged 0–14 years and increases to 0.2 per 100,000 amongthose aged 15–19 years. CML accounts for approxi-mately 3% of leukemias in children and adolescentsaged 0–19. Like the acute leukemias, CML has a malepredominance; incidence rates are 1.9 per 100,000among males and 1.1 per 100,000 among females. Inchildren and adolescents, however, CML is similarlyrare in both sexes.

Chronic myelogenous leukemia is associated withslow progression from indolent growth in chronicphase, through an acute phase characterized by treat-ment failure and worsening hematologic derangements,to a blast crisis similar to that in the acute leukemias.Historically, busulfan, hydroxyurea, and interferon-αwere used for cytoreduction in chronic phase CML.However, the development and success of tyrosinekinase inhibitors (such as imatinib) that target the Bcr-abl fusion protein has changed the treatment of CML.Upfront therapy with imatinib has become the stan-dard care for most patients with pediatric CML.Although tyrosine kinase inhibitors are not curativetherapy, they achieve very high rates of cytogeneticresponse and can extend survival substantially. Allogeneicstem cell transplantation offers the potential for cure,

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although it entails substantial risks of morbidity andmortality, particularly for unrelated donor transplants.Children with CML undergoing matched sibling donortransplantation in chronic phase have had 60–75%5-year relapse-free survival, while those undergoingmatched unrelated donor transplantation have had lessfavorable 5-year survival rates, approximately 55% inone recent large study.28 In some pediatric patients,such as those in whom tyrosine kinase inhibitors fail tocontrol disease, or those in accelerated phase or blastcrisis, allogeneic stem cell transplant from related orunrelated donors may clearly be indicated. Subsequentchapters will review the therapeutic approach to child-hood and adolescent CML. Significant unresolvedquestions remain regarding the ideal front-line treat-ment of CML in this population.29

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clonal prolif-eration of B lymphocytes arrested in differentiation.Although CLL is the most common leukemia, with15,490 new diagnoses among Americans in 2009, it pri-marily affects older adults; the median age at diagnosisis 72.2 Cases of CLL in children and adolescents are van-ishingly rare. Those described in case reports may beassociated with a translocation involving chromosomes2 and 14.30

Myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are a group ofdisorders characterized by clonal proliferation ofpluripotent hematopoietic stem cells, resulting in disor-dered and ineffective hematopoiesis (see Chapter 15).MDS in the setting of the congenital marrow failuresyndromes, severe aplastic anemia, or prior chemother-apy or radiation therapy is known as secondary MDS.MDS/AML observed in the setting of DS is consideredto be a separate entity, as previously discussed. Othercases of MDS are considered “primary” or “de novo,” butmay still be associated with genetic predisposition.Monosomy 7 or loss of the long arm of chromosome 7occurs in approximately 30% of childhood MDS casesand 50% of therapy-related MDS.31 Abnormalities ofchromosome 5 are frequently observed in adult MDSbut are very rare in childhood MDS.

Childhood MDS is very rare; in the United Kingdom,which has an MDS registry, the incidence rate of non–DS-related MDS among children under 15 is estimated

at 0.81 per million (0.66 per million for de novo MDS).In Denmark and British Columbia, incidence ratesare estimated at 2.1 per million and 1.4 per million,respectively.32

Myelodysplastic syndrome may progress to AML.Different subtypes of MDS demonstrate differing rates ofprogression; patients with the subtype of MDS known asrefractory anemia with excess blasts (i.e. 5–20% marrowblasts) have approximately 50% risk of developing AMLwithin 5 years; patients with less than 5% marrow blastshave a 20% 5-year risk of progression to AML.33

Juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a rarehematopoietic disorder of early childhood character-ized by uncontrolled proliferation of monocytes andgranulocytes, as well as myelodysplastic features of ane-mia and thrombocytopenia (see Chapter 14). Accordingto the UK MDS registry, the JMML incidence rate isestimated at 0.69 per million among children under 15.In Denmark and British Columbia, estimates are 1.3and 1.0 per million, respectively.32 JMML usually pres-ents in children younger than 6 years; the median age atdiagnosis is 2 years. Later presentation of disease is anadverse prognostic indicator.

About 11% of JMML patients have neurofibromatosistype 1, an autosomal dominant disorder found in 1 in4,000 births and characterized by café au lait spots on theskin and predisposition to neurofibromas, and schwan-nomas. A genetic defect in the NF1 gene underlies neu-rofibromatosis type 1; NF1 is a negative regulator of theRas signal transduction pathway.31 For children bornwith one defective copy of Ras, a second somatic muta-tion in NF1 can lead to uncontrolled Ras activation andcell proliferation. Indeed, the pathogenesis of JMML isrelated to abnormalities in the Ras signaling pathway.34

Similar to MDS, JMML is associated with monosomy 7,which is found in approximately 25% of cases. However,many cases are associated with a normal karyotype.31

Standard chemotherapy is generally ineffective intreating JMML and allogeneic stem cell transplantationoffers the only potential for cure. Even with stem celltransplantation, the high risk of leukemic relapse lowers5-year event-free survival to only 50%.35

The Lymphomas

The lymphomas are cancers of the lymphatic system,which consists of lymph (interstitial fluid similar to blood

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plasma, containing white blood cells and other compo-nents) and the lymphatic vessels, lymph nodes, and otherlymphatic organs (tonsils, spleen, thymus, and Peyerpatches on the small intestine) through which the lymphcirculates (SEER training). Lymphomas are categorizedby cell type as T-cell, representing about 10% of lym-phomas, or B-cell, representing the other 90%. Chapter 2of this volume deals with the 2008 World HealthOrganization (WHO) classification of lymphomas.

Lymphoma incidence rates rise with age, althoughpatterns of incidence vary by cell type. All the lym-phomas diagnosed among children are more commonamong adults; some types found among adults are vir-tually unknown among children. These include thechronic/small/prolymphocytic/mantle and B-cellNHLs, which account for more than 15% of adult lym-phomas. Malignant lymphoma is the most commoncancer affecting adolescents.36

Overall, lymphoma incidence has been rising in thepast few decades.1 Although lymphomas have generallybeen more common among whites than non-whites,the recent increase is greater and the age distribution isyounger among blacks than among whites. Lymphomasare overall more common among males than females,although the gender difference is smaller among adultsthan among children.

Hodgkin lymphoma

Hodgkin lymphoma, first described by the Britishpathologist Thomas Hodgkin in 1832, is usually distin-guished from the many and collectively more commonNHLs. Four cell types of HL have been identified:nodular sclerosing (NS), lymphocyte predominant(LP), lymphocyte depletion (LD), and mixed cellularity(MD) (see Chapter 18). Most, but not all, HL involves Bcells. Although rare among young children, HL is themost common cancer of young adults and the mostcommon hematologic malignancy among males andfemales aged 15–30 years (Figs. 1.2A–B) (see Chapter 3).Incidence rates are less than 1.0 per 100,000 per yearamong children younger than 10 years, 1.0 among thoseaged 10–14 years, and rise to 4.0 per 100,000 amongthose aged 15–30 years (The age distribution of HLincidence is bimodal, peaking for the second timeamong persons aged > 55 years.). Among children < 15years, HL is at least twice as common in males as infemales.37 In older age groups, the gender difference isnot evident (Figs. 1.2A–B). Unlike the incidence rates ofthe NHLs, those of HL had been relatively stable in the

final decades of the 20th century, but they now appearto be rising overall, especially among individuals aged20–29 years.

Family history is a strong risk factor for HL, espe-cially among relatives of young probands. In a studyconducted in the Swedish and Danish cancer registries,linked to other registries, first-degree relatives of casesdiagnosed at age < 40 years had a fourfold increased riskcompared to relatives of controls; the associations werestronger for siblings than for parents or offspring andfor male than for female relatives of probands,38

although the latter association may reflect the generallyhigher risk in males than in females.

For more than a decade, the Epstein–Barr virus(EBV) has been understood to play a causal role in HL,especially among young children.39 EBV has been iden-tified in close to 50% of patients < 15 years and 25% ofthose aged 15–35 years.39 In specimens from thosepatients, the multinucleated Reed–Sternberg cells thatconfirm the diagnosis of HL contain the EBV genome,and EBV gene products are expressed in those cells.Other viruses have also been associated with HL. Anassociation with human immunodeficiency virus(HIV) is well established, but most HL patients withHIV also appear to have EBV (see Chapter 19).40

Measles virus has been associated with HL41 in some,but not all, studies.42

In the 0–14 age group, patients diagnosed with HLhave more siblings and come from families of lowersocioeconomic status (SES) than controls. Incidencerates are higher in developing countries than in indus-trialized countries43–44; they are highest in Western Asiaand North Africa. Among adolescents and young adults15–35 years of age, those associations are generallyreversed. The socioeconomic risk factor pattern amongyoung children is consistent with an etiology involvinginfectious agents (viruses) and underdevelopment ofthe immune system that may be genetic in origin. Thepattern among adolescents and young adults mayreflect a relative lack of exposure to infectious agents inchildhood among individuals of higher SES, and theexpansion of social networks that leads to EBV andinfectious mononucleosis among college-age youth andyoung adults. In a study of EBV and lymphoma among18,642 organ transplant recipients in Europe, NorthAmerica, and Australia, 40% of kidney transplantpatients aged 0–9 years, 70% of those 10–19 years, 85%of those 20–29 years, and ≥ 90% of older patients wereEBV-seropositive prior to transplant.45 EBV prevalenceamong transplant recipients may not be representative

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of EBV prevalence in the general population, but itsassociation with age is unlikely to be very different.

Among young children, the histology of HL, espe-cially EBV-related HL, is most commonly of mixed cel-lularity; among adolescents and young adults, it ispredominantly nodular sclerosis.

Autoimmune disorders, notably rheumatoid arthri-tis and systemic lupus eythematosus, sarcoidosis, andimmune thrombocytopenic purpura have been associ-ated with HL,46 but their relevance to adolescents andyoung adults is difficult to establish because of the verysmall numbers of cases and controls in that age groupwith a history of such disorders.

Survival among young people with HL is one of thegreat success stories of hematology and oncology in thelatter part of the 20th century and HL treatment hasplayed a key role in the development of the field. In the1940s, the effects of nitrogen mustard and radiationtherapy on the lymphatic system were discovered; theimplications of the discoveries for HL were quicklyexplored in clinical trials. Subsequently, chemotherapywas introduced and steadily improved. Five-year sur-vival among children, adolescents, and young adults isnow > 90%. However, the increasing numbers of HLsurvivors have found themselves at risk for secondcancers and other late effects of treatment (seeChapter 24).47 Many patients who received radiationtherapy prior to puberty before standard doses werelowered, have experienced bone or soft tissue hypopla-sia. Doxorubicin has been found to have greatercardiotoxicity among children than among adults.Treatment can also have adverse effects on fertility.48

Second malignant neoplasms associated with prior HLand its treatment include leukemias, sarcomas, andbreast, thyroid, gastrointestinal, and lung carcinomas;49

overall, HL survivors have more than a 10-fold higherrisk of those malignancies than the general population.These increased risks may be due in part to the HL or tothe exposures that caused it, but they are also clearlyrelated to treatment. Both overall and HL-specificmortality risk have been associated with low SES andnon-white race.50 Improvements in long-term survivaland quality of life for patients with HL depend on mod-ifying existing treatments, facilitating access to care, anddeveloping new treatments with fewer side effects.

Non-Hodgkin lymphoma

The past few decades have seen a dramatic rise in theincidence of NHL, except in the youngest age groups.51

In the United States, from the 1970s to the 1990s, ratesincreased by 3–4% each year, and NHL became the fifthmost commonly diagnosed malignancy.52 However,among children, adolescents, and young adults < 30 yearsof age, NHL is still less common than HL (Figs. 1.2A–B).

Like HL, NHL is associated with the male gender,family history, infectious agents, autoimmune disor-ders, immunosuppression,53 birth order (at least forsome cell types)54 and perhaps some chemical expo-sures, mainly in the setting of occupational exposures55

(Table 1.3). An association with white race has also beenobserved.56–57 The most common NHLs are diffuse largeB-cell lymphoma, lymphoblastic lymphoma, anaplasticlarge cell lymphoma, and Burkitt lymphoma (seeChapters 16 and 17).

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Table 1.3. Etiologic factors in lymphoma.

Subtype Factor

HL Male gender37

White race (in USA)57

Epstein-Barr virus62

Family history38

Measles?41

Residing in Western Asia or North Africa43,44,59

Socioeconomic status37

Low for ages 0–14 yearsHigh for ages 15–30 years

Transplant recipient status45

Autoimmune disorders?46

Birth order37

Late/last for ages 0–14 yearsEarly/first for ages 15–30 years

NHL Male gender2

White race (in USA)57

Epstein–Barr virus62

Family history38

Birth order54

Socioeconomic status51

Immunosuppression53

DLBCL Primary congenital immunodeficiency51

Ataxia telangiectasiaWiskott–Aldrich syndrome

Epstein–Barr virus62

Birth order (late/last)54,72

BL Male gender60

Epstein–Barr virus62

HIV62

LL Male gender64

HIV65

ALCL Adolescent predominance66,67

PMBCL No male predominance68

Older age distribution68

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Diffuse large B-cell lymphoma (DLBCL)

Diffuse large B-cell lymphoma (DLBCL) is the mostcommon NHL among adolescents and young adults inindustrialized countries, and the second most common,after Burkitt lymphoma, among children.36 Nearly 40%of new lymphoma cases in adolescents and about 20%in children under 14 years are DLBCL. However, inci-dence rates are lower than 1 per 100,000 per year forthose aged 0–20 years and rises above 1 per 100,000only for those older than 25 years. Pediatric patientshave better outcomes than older patients, possiblybecause treatment strategies or tumor biology vary byage group.58 Birth order (having many older siblings)has been associated with DLBCL.71 Congenital immun-odeficiency syndromes, including ataxia telangiectasiaand Wiskott–Aldrich syndrome are associated with a10–15% risk of DLBCL.51

Burkitt lymphoma (BL)

Burkitt lymphoma (BL) is the most common childhoodcancer in much of tropical Africa59; it is much less com-mon in industrialized countries, including the UnitedStates; incidence rates hover around 0.6 per 100,000 peryear among males and 0.2 per 100,000 among femalesaged 0–30 years. Among children, it is 3–4 times ascommon among males as among females. Overall, BLhas been found to have a trimodal age-specific incidencepattern, with peaks near ages 10, 40, and 75 years amongmales; the peak near age 40 years is much less pro-nounced among females than males.60 From 1982–1985to 2002–2005, incidence rates in the US population aged0–20 years increased from 0.41 to 0.55 per 100,000 or34%, but the increase in older age groups was muchgreater. Data from Surveillance Epidemiology and EndResults (SEER) for those aged 0–29 years illustrate theincrease and the peak around age 10 years.61 In Africa,BL also has almost the same geographical distribution asPlasmodium falciparum malaria; mosquito eradicationprograms and sickle cell trait are associated withreduced risk of BL.62 Most adult-onset BL also appearsto be AIDS-related. Both DLBCL and BL are also associ-ated with EBV.63

Lymphoblastic lymphoma

Lymphoblastic lymphoma is a T-cell lymphoma thatoverlaps in many respects with T-cell lymphoblasticleukemia.64 It is the second most common NHL among

patients younger than 15 years, but is less common inolder adolescents and young adults.36 Incidence ratesare 0.4 per 100,000 among children younger than 5 yearsbut close to 0.1 per 100,000 in older age groups. It issimilar to pediatric T-cell acute lymphoblastic leukemiain gender and age, but generally does not present withbone marrow involvement. In Africa, LL has beenassociated with HIV.65

Anaplastic large cell lymphoma (ALCL)

Anaplastic large cell lymphoma (ALCL) is a relativelyrare NHL, with incidence rates of about 0.2 per 100,000per year overall. About 13% of NHL among children,and somewhat more among adolescents, but much lessamong adults is ALCL.66,67

Primary mediastinal B-cell lymphoma (PMBCL)

Primary mediastinal B-cell lymphoma (PMBCL) isanother rare NHL that has been classified by WHO as asubtype of DLBCL but appears to be a distinct entitythat also has some features of classical HL.36,68

Although the varying descriptive features of thevarious cell types suggest differences in etiology, theirrarity makes it difficult to study them, and their com-monalities also appear to be informative.

For example, an important clue to the etiology ofthe NHLs among children is the occurrence of post-transplant lymphoproliferative (usually B-cell) disease,69

a relatively common complication of organ transplan-tation, probably due to the immunosuppression thattransplantation requires. Risk is greatest among chil-dren who are EBV- or CMV-negative prior to receivinga transplant from an EBV- or CMV-positive donor. Asimilar risk factor is atopic dermatitis treated with top-ical steroids. Immunosuppression favors infectiousagents, perhaps in the presence of a genetic factor orfactors that also facilitate malignant transformation.

Other environmental factors that may play a role inpediatric lymphomas as well as other cancers are agri-cultural chemicals and occupational exposures of par-ents. Future studies with larger samples may make itpossible to home in on these exposures and to developeffective interventions to improve outcomes for chil-dren, adolescents, and young adults at risk.

As Figs. 1.4A–B shows, survival continues to improvefor most lymphoma subtypes, but is better for childrenand adolescents than for young adults.70 Tai et al.suggest that lack of health insurance leading to late

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diagnosis contributes to the inferior survival of youngadult patients.

Conclusions

If childhood cancers were as common as adult cancers,their etiology would be much better understood. Theexample of lung cancer and smoking illustrates the con-trast. The rise in smoking prevalence preceded the identi-fication of the causal role of smoking in lung cancer byabout 20 years; without that increase, lung cancer wouldstill be rare and the association might still be controver-sial. Childhood cancers, by definition, take less than 20years from initial exposure to diagnosis, but because can-cers in the young are, fortunately, rare it has generallybeen difficult to identify and recruit enough cases forwell-designed epidemiologic studies. Even to the extentthat etiologic agents are known, the rarity of childhoodcancer is a deterrent to effective prevention. For example,EBV is now implicated in HL as well as several NHL, butEBV infection is almost ubiquitous. The pathway bywhich it increases the risk of lymphoma, the co-factors inthat pathway, and their relationship to specific lymphomasubtypes need to be much better understood. Other infec-tious agents, genetic factors, and other environmental fac-tors, such as nutrition, are likely to affect individual riskand specific disease outcome. Age at exposure may alsoplay a role, as it does in the hygiene hypothesis invoked toexplain the rise of asthma.71 However, childhood ALLrates have not risen in parallel with asthma rates. Thecrossover association between socioeconomic status andHL is also suggestive of a similar pattern.

The acquired immune deficiency (AIDS) epidemicand the related rising rates of lymphoma among chil-dren and young adults, especially in the third world, aretragic. However, they give us the opportunity to observewhether AIDS treatment increases risk by prolonginglife or reduces risk by addressing the immunocompro-mised state; and the role of concomitant tuberculosisand other co-infections and their treatment may also beinstructive. Studying these patterns may help us toimprove outcomes for all children and young adultswith hematologic malignancies. The dramatic successesin treating patients with these diseases have notdepended on knowledge of etiology, but they have comeat a cost in long-term morbidity and risk of secondmalignancies. Epidemiologic studies now in progressare identifying etiologic factors, teasing out interactionsbetween infectious agents, and other associations thatmay provide a basis for more targeted treatments. Suchtreatments may lead to further improvement in out-comes for young patients and those at risk for hemato-logic malignancies.

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