20-cancer and benign tumors nelson 18th

. [ancer Tumors BenlUn Part )()(I and A-PDF Split DEMO : Purchase from www.A-PDF.com to remove the watermark Chapter492l.The most notablegeneticconditionsthat impart childhood cancersusceptibilityare neurofibromatosistypes 1 and Cancer in individuals <I9 yr of age is uncommon, with an ageadjusted annual incidence rate of t6.51L00,000, representingonly about lo/" (1.2,400 cases/yr)of all new cancer casesin the USA. Although relative 5-yr survival rates have improved from 56"/oin 7974 to >8t7" in 2000 (Fig. 49t-11, malignant neoplasmsremain the second most common cause of all deaths (12.8%) among persons l-1.4 yr of age in the USA. Multiinstitutional cooperative clinical trials investigating novel therapies and investigating ways to improve survival rates even further are currently underway. Because increasingly more patients survive their disease, clinical investigation also is focusing on the quality of life among survivors and the late outcomes of therapy experienced by pediatric and adult survivors of childhood cancer. The National Cancer Institute estimates that, in 1997 , there were 269,700 individuals alive (in all age groups) who had survived childhood cancer,corresponding to 1 in 810 of individuals <20yr of age and 1 in 1000 of individuals 20-39 yr of age in the US population. Pediatric cancers differ markedly from adult malignancies in both prognosis and distribution by histology and tumor site. Lymphohematopoietic cancers (i.e., acute lymphoblastic leukemia, lymphomas) account for approximately 407o, nervous system cancers for approximately 30"/", and embryonal and sarcomas for approximately l0% each among the broad categories of childhood cancers (Table 491-1). In contrast, epithelial tumors of organs such as lung, colon, breast, and prostate are most common among adults. Unlike incidence patterns in adults, where cancer rates tend to increase rapidly with increasing age, a relatively wide age range exists in the pediatric age group, with two peaks-the first in early childhood and the second in adolescence (Fig. a91-2). During the first year of life, embryonal tumors such as neuroblastoma, nephroblastoma (\films tumor), retinoblastoma, rhabdomyosarcoma, hepatoblastoma, and medulloblastoma are most common (Fig. a91-3). These tumors are much less common in older children and adults after cell differentiation processeshave slowed considerably.Embryonal tumors, acute leukemias, non-Hodgkin lymphomas, and gliomas peak in incidence from 2-5 yr of age. As children age, bone malignancies, Hodgkin disease,gonadal germ cell malignancies (testicular and ovarian carcinomas), and other carcinomas increasein incidence. Adolescence is a transitional period between the common early childhood malignancies and characteristic carcinomas of adulthood. Childhood neoplasms include a diverse array of malignant tumors, termed "cancers," and nonmalignant tumors arising from disorders of genetic processesinvolved in control of cellular growth and development. Although many genetic conditions are associated with increased risks for childhood cancer, such conditions are believedto account for <5%" of all occurrences(see oTheauthor would like to acknowledge the work of JamesG. Gurneyand of ChildhoodandAdolesMelissaL. Bondyon Chapter483, "Epidemiology centCancer."in the oreviouseditionof this work. additional genetic and epidemiologic risk factors that remain uncharacterized. Compared with adult epithelial tumors, an extremely small fraction of pediatric cancersappear to be explained by known environmentalexposureslTable 491"2).Ionizing radiation expoagentsexplain only a small sure and severalchemotherapeutic Hodgkin lymphoma, but the etiologic importance remains unclear.Becauiethe etiology of cancerin children still is poorly understood,for the most part, epidemiologystudieshaverecognizedthat the likely mechinismis multifactorial,possiblyresulting from potential interactions between genetic susceptibility triits and environmentalexposures.Ongoingstudiesare investiencoding enzymes' gating the role of polymorphisms of genes_ whic[ function in the activationor metabolismof xenobiotics; protectionof cellsagainstoxidativestress;DNA repair; and/or immunemodulation. Curative therapywith chemotherapgradiation, and/or surgery may adverselyaffect a child's developmentand result in serious long-termmedicaland psychosocialeffectsin both childhood and adulthood. Potential adverse late effects include subsequent Itfu). Given the relative rarity of specifictypes of childhood cancer and the sophisticatedtechnologyand expertiserequired-fordiagnosis,treaiment,and monitoringof late effects,all childrenwith cancershould be treated on standardizedclinical protocols in pediatricclinicalresearchsettingswheneverpossible.Promoting iuch treatment, the Children's Oncology Group is a multiinstitutional researchconsortium that facilitates cooperative clinical,biologic,and epidemiologicresearchin more than 200 affiliated instiiutions in the United States,Canada,and other Coordinatedparticip,acountries (http:i/www.curesearch.org/). tion in such researchtrials has been a major factor in the increasedsurvival for many children with cancer.Such ongoing efforts are critical to better understandthe etiology of childhood cancers,improve survival for malignancieswith a Poor prognosis,and maximizethe quality of life for survivors. 20i97 2098r PARTXXI r CancerandBenignTumors o (gaR >6U = a I i s u r c ' 1 . ) l , l F i v e - y e a r e l a t i v es u r v i v a lr a t e s( % ) b y y e a r o f d i a g n o s i so f a l l cancersin children S19 yr of age. Rates based on follow-up of patients into 2003 (From Ries LAG, Harkins D, Krapcho M, et al (editors): SEER Cancer Statistics Reuiea 1975-2003 Bethesda, MD, National Cancer Institute http://seer.cancer.govlcsrl1,975 2003/, basedon November2005 SEERdata submission,posted to the SEERweb site, 2005.) IC a7n. JOJ o LOU 1975- 1985 1987 1989 1991 1993 1995 1997 1979 Yearof diagnosis ro 300 250 200 Figr.rrc.191-2. Age- and ser-specificcancer incidenceratesper million children in the USA. (From R i e sL A G , S m i t h M A , G u r n e yJ G , e t a l ( e d i t o r s ) : Cancer Incidence and Suruiual Among Children and Adolescents:United St,TresSEER Program 1 9 7 5 - 1 9 9 5 B e r h e s d a ,M D , N a r i o n a l C a n c e r Institute, SEERProgram, 1999.) 150 100 50 0 tttl 0123 I I I 45 67 89 I 10 11 12 r I 13 T 14 T --r----r-----r-----l 15 16 17 18 19 Age at Diagnosis(yr) Allmalignanries rombined Leukemias Acute lymphoid Acute myeloid Lympn0mas Hodgkin disease Non-Hodgkin lymphomas (entral nervous system andmiscellaneous intracranial andintraspinal tumors Astro(ytoma Embryonal tumors Ependymomas plexus andchoroid tum06 Neuroblastoma peripheral andother nervouS ceiltum0r5 Retinoblanoma Renal tumors Nephroblastoma ilepatrc tum06 Hepatoblastoma Bone tumon Osteosarcoma Ewing tumor andrelated satcomas 50fttissue sarcomas Rhabdomyosarcoma Germ celltumors [arcinomas andmelanoma <14YR 141 8 478 319 t5 1 51 53 62 1 19 ANNUAT IHCIDENCT MIESPER MITIIOI* ftITDREN,2(!OO-2()O] <19YR <1 YR <4 YR 5-9YR 10^14 YR 1632 230 8 2051 1 191 1242 43) 45) 863 184 283 327 196 794 319 19.7 80 1 85 90 41 72 )34 8.5 84 137 228 114 11 41 101 84 37 63 8.9 289 323 M1 3t9 25.0 156 75 30 99 143 66 16 76 125 113 44 505 191 104 52 192 3,9 t8 /5 25 21 63 39 20 t07 53 55 57 l0 62 57 21 16 85 52 25 121 49 115 162 )38 1 11 1 71 125 118 87 187 185 44 43 14 175 51 20.8 10 107 8.3 39 18 tl l 116 7.5 2) t4 4b 1/ | /) 17 11 l 5 - 1 9Y R )091 )96 1 11 9) 481 295 151 199 104 38 t4 13 09 al 09 50 31 15 79 44 21 11 124 80 16 122 38 74 1)1 151 90 40 t 63 38 291 4/t s.YRSURVIVAI, <19 YROFAGt ATDrA6N05rs, 1e96-2000 {%i tl9 75) 8 14 505 869 946 794 117 826 6/l /35 689 910 871 883 471 59) 651 658 590 692 6 10 897 892 Cancerr 2099 andAdolescent of Childhood 491r Epidemiology Chapter Figurc -i91-3. Generalized incidence of the most common types of cancer in children by age The cumulatrve incidence of all cancers is shown as a dashed line (Courtes-v of Archie Bleyer, MD.) Acutelymphoid leukemia Non-Hodgkin lymphoma Glioma Neuroblastoma Wilmstumor Retinoblastoma Primitive neuroectodermal tumor(PNET) I a Sarcomas Osteosarcoma Ewingsarcoma Softtissuesarcoma Hodgkindisease Testicularcancer Ovariancancer 10 Age(yr) THEINCIDENCE INFLUENCING OFCANCER Pediatricianshave a unique opportunity to educatechildren and adolescents,and their parents, regarding means of preventing cancer.There are onl,v a few recognized environmental causesof childhood cancer that can be avoided. One examole is immunization againsthepatitisB, which doesdecreasethe incidenceol TYPt CANCER A(ute lymphoid teuKemta Aculemyeloid leukemias Bratn cancers disease Hodgkin Non-Hodgkin rympn0ma .S€eTab e4922 RISK TAfiOR (OMMENTS and the more likely it is to be present and sustained during adulthood. (ANCfR TYPE RI5KTACTOR (0Mil1rr,tT5 (ancer exposure andhighradium radiation therapy prena{al pnmarily Although ofhistorical significance, !ntrease t 5K x+ayexposure increases risk diagnostic Iisk rn(rease Alkylating agents Ihemotherapy irradiati0n forcancer treatment also Therapeutrc syndr0me w thL Fraumefi risk!sapparent lncreased facto6* Genetic Increases nsk astoma retinob andhereditary White rhildren have a2{oldhighurate thanblack Race ncidence a9 foldhigher have about White chldren Race sartoma Ewing intheUSA chiidren '10intheIJSA ratethanbackchildfef withanestimated Genetic fa(06* Down syndrome lsassociated riskfactors Noestablished Neuroblastoma intleased fisk t0 20-f0ld other risklaito6 Noestablished fa(t06* Retinobla$oma Geneti( type1,Bloom syndrome, ataxiaNeurofibromalosis andother syndrome, Wiedemann Beckwith anomaliesAnridia, [ongenital Wilms tumor Langerhan( cellhistiocytosis, telangiectasia,and areassociated t0nditi0ns alldgenetii c0ngerita wrthanelevated risk among others, areassoclated rtsk wlthincreard lnoease ChemotherapeuticAlkylating agents andepipodophyllotoxins haLfthe rates have about reportedly Asanchldren Race fls|( agents andblxkchlldren ofwhrte type1are factors* Down syndrome andn€urofibromatos6 Genetic unknown Etlology R e n a l m e d u l l a r yS i c k e c e l l t r a i t Familial monosomy 7 andsevetal strongly asoriated carctn0ma with syndr0mes arealsoassotiated othergenetii type1 andneurofibromatosis Li-Fraumefi syndr0me [0ngefitalan0malies Rhabdomyosarcoma risk inoeased risk wtthinoeased tobeassociated arebeieved andgenetl( radiation therapy, hgher i0nzlng Wlththeexieptl0n 0fcancer Iherapeutir birthdefe(ts withmal0r concordanie There lssorne tondltions 0f riskfromcdiatl0n treatment lsessentlally radiation t0the hemihypertr0phy, syndr0me, Beckwith-Wiedemann faito6* Hepatoblastoma Genetii importance head historjcal hlstoty of andfamily syndrome, Gardner assocrated with Genetic factors* Neurofbromatosis type1isstrongly polypos wlthincreased sareassociated adenomatous a esser extent,with othel optcgliomas,and,to nsK system tumors Tuberous sclerosis central nervous tor withleomyosarcoma virus isassociated on Epstein Barr Lelomyosarcomalmmunosuppress genetir areassociated andseveral other syrdr0mes andacquired 0f(0ngenital allf0rms andIBVinfeoion wrthncreased rlsk blt notlei0myosarcoma rmmunosuppresron risk Monozygotrc twins andsrblrngs areatinoeased Famlly hstory among mmunocomPetentPels()ns rlsk wth ncreased lnfections Epstein Barvirus isasso(lated germ f0rtestl(ular isariskfactor germ cell Cryptorchidism (ryptorchldism lVaignant lmmunodeficrency Acqurredandcongenitalimmunodefcrentydisorders, cellIUm0rs tufn0rs r sk therapy, lncrease andimmunosuppresive \/irus withBurk tt ymphoma Infe(tions Epstein Bafr sassoriated inAtrra lonizing radiation radiation 0steosaKoma lonizing r Canceland 2100r PARTXXI BenignTumols ;.h*#r@*j+jji1r.,{n -.-, - : .' :i. :,: ! - 1 j: -=:::iera Ahlbom IC, Cardis E, Green A, er al: ICNIRP (InternationalCommissionfor Non-lonizing Radiation Protection)StandingCommittee on Epidemiology: Review of the epidemiologicliteratureon EMF and Health. Enuiron Health P e r s p e c2t 0 0 1 ; 1 0 9 ( S u p p6l ) : 9 1 " 1 - 9 3 3 . Anderson RN, Smith BL: Deaths:leadingcausesfor 2001. National Vital Stat i s t r c sR e p o r t2 0 0 3 ; 5 2 9 ( ) :1 - 8 5 . BufflerPA, Kwan ML, ReynoldsP,et al: Environmenraland geneticrisk factors for childhood leukemia: appraising the evidence. Cancer lnuest 2005;1:50-7 5. Childhood CancerSurvivorship:Improving Care and Quality of Life. Institute of Medrcine, August 2003. http://www.iom.edulCMSl28312l4931./ 14782.aspx Draper G, VincentT, Kroll ME, et al: Childhood cancerin relation to distance from high voltage power lines in England and Wales:a case-controlstudy. B M l 2 0 0 5 ; 3 3 0I :2 e 0 - l 2 e z Gurney JG, Bondy ML: Epidemiologic research merhods and childhood cancer.In Pizzo PA, Poplack DG (editors):Principlesand practice of pedidtric Oncology,4th ed. Philadelphia,Lippincott Williams & r07ilkins,2002, pp 13-20 Gurney JG, Smith MA, Olshan AF, et al: Clues to rhe etiology of childhood brain cancer: N-nirroso compounds, polyomavirusesand other factors of interest Cancer Inuest 2001;19:640-650. Hudson MM, Merrens AC, Yasui ! et al: Healrh status of adult long-term survivors of childhood cancer:A report from the Childhood Cancer Surv i v o r S t u d yJA M A 2 0 0 3 ' 2 9 0 : 1 5 8 3 - 1 5 9 2 . KaatschP, Steliarova-Foucher E, Crocerti E. et al: Time trends of cancerincidencein Europeanchildren 17978-1997)tReport from the automatedchildhood cancerinformation systemproject.Eur J Cancer 2006;42:1967-1971. Merks JHM, Caron HN, Hennekam RCM: High incidenceof malformation syndromesin a seriesof 1,073 children with cancer.Am J Med Genetics 2005;134A:132-143 Ness KK, Mertens AC, Hudson MM, et al: Limitations on physical performance and daily activiriesamong long-term survivorsof childhood cancer. Ann Intern Med 2005;143:639-647 Ries LAG, Harkins D, Krapcho M, et al (editors): SEER Cancer Statistics Reuteu, 1975-2003. Bethesda, MD. National Cancer Institute. http://seerca ncer.govI csr/ 1975_2003/, basedon November 2005 SEERdata s u b m i s s i o np, o s t e dr o t h e S E E Rw e b s i t e , 2 0 0 6 . Ries LAG, Smith MA, Gurney JG, et al (editors):Cancer Incidenceand Sururual Among Children and Adolescents: United States SEER program -1975-1995. Bethesda,MD, National Cancer Institute, SEER program, 1.999. Steliarova-FoucherE, Stiller C, Kaarsch P, et al: Geographicalpatterns and rime trendsof cancerincidenceand survival amongchildren and adolescents in Europe since the 1970s (the ACCIS projecr):An epidemiologicalstudy. Lancet 2004 Dec 11;364(9451):2097-2705. Cancer is a complex of diseasesarising from alterations that can occur in a wide variety of genes. Alterations in normal cellular (hromosomal transloration Gene amp|tfrcation Point mutation CHROMOSOME l(9;22) t(1:19) t(14:18) t(15;17) Amplicon Ampliron lp loq GTNEs B(R.ABL 12A-PBXl (MY( APL-RARa NMY( EGfR NRAS Rtr processessuch as signal transduction, cell cycle control, DNA repair, cellular growth and differentiation, translational regulation, senescence and apoptosis (programmed cell death) can result in a malignant phenotype. In addition, cancer stem cells may have a role in certain malignancies such as CML, AML, ALL, gliomas, and breast cancer. These tumor-initiating cells have self renewal and proliferative properties similar to nonmalignant stem cells. GENES INVOLVED IN ONCOGENESIS Two major classesof genes are implicated in the development of cancer: oncogenesand tumor suppressorgenes.Proto-oncogenes are cellular genesthat are important for normal cellular function and code for various proteins, including transcriptional factors, growth factors, and growth factor receptors. These proteins are vital components in the network of signal transduction that regulate cell growth, division, and differentiarion. Proto-oncogenes can be altered to form oncogenesthat, when translated, can result in the malignant transformation of a cell. The three main mechanisms by which proto-oncogenescan be activated include amplification, point mutation, and translocation (Table 492-I). MYC codes for a protein that regulates rranscription and is an example of a proto-oncogene that is activated by amplification (Fig. 492-l). Patients wirh neuroblastoma in which the MYC gene is amplified 10- to 300-fold have a poorer outcome (Fig. 492-2). Point mutations also can activate protooncogenes. The NRAS proto-oncogene codes for a guanine nucleotide-binding protein with guanosine triphosphatase activity that is important in signal transduction and is mutated in 25-30% of acute nonmyelogenous leukemias, resulting in a constitutively active protein. The RET gene encodes a rransmembrane tyrosine kinase receptor that is important in signal transduction. A point mutarion in the RET gene resulrs in the constitutive activation of a tyrosine kinase, as found in multiple neoplasia syndromes and familial thyroid carcinoma. The third mechanism by which proto-oncogenes become activated is chromosomal translocations. In some leukemias and lymphomas, transcription factor controlling sequencesare relocated in front of T-cell receptors or immunoglobulin genes,resulting in unregulated transcription of the genes and leukemogenesis.Chromosomal translocations also can result in fusion genes;transcription of the fusion gene can result in the production of a chimeric protein with new and potentially oncogenic activity. Cancers associatedwith fusion genesinclude the childhood solid tumors, such as Ewing sarcoma [t(1t;22)l and alveolar rhabdomyosarcoma [t(2;13) or t(1;13)]. The translocationsresult in novel proteins that are useful as diagnostic markers. The best described translocation in leukemia is the Philadelphia chromosome t(9;22), which results in the BCR/ABL protein found in chronic myelogenousleukemia. This rranslocation results in a tyrosine kinase protein that is constirurively activared. In addition, the protein is localized to the cytoplasm instead of the nucleus, exposing the kinase to a new spectrum of substrates. Alteration in the regulation of tumor suppressor genes rs another mechanism involved in oncogenesis.Tumor suppressor PROTEIN fUNOION (himerir tyroslne kinase (himeric transciption fa(tor Iranscription factor Ihimeric transcription factor Transcription factor 6rowth factor kinase, tyrosine kinase GlPase Tyrosine kinase TUMOR Acutelymphocytrc leukemia,chronic myelocytk eukemia ymphocytir Pre-B acute leukemia Burkrtt lymphoma promyelocytic Acute leukemta Neuroblastoma Glioblastoma Acute myelo(ytk leukemia Multiple endocrine neoplasia, type2 Biologyof Gancerr 2t01 andCellular 492I Molecular Chapter Growth factor Signal ir*s.ription-..--@ Figrrre-192-1.The major featuresof cellularregulation.Externalgrowth growthfactor)bind andsteroidhormones suchasepidermal /aclors(proteins growthfdctorreceptors on thecellsurface, activating to membrane-spanning pathwaysin whichgenessuchas RASparticipate. Comsignal-transductloz ponentsof thesignal-transduction pathwayin turn interactwith nucledrtranregions scriptionfactors,suchasMYC andFOS,whichcanbindto regulatory MJ, et al feditorsl:Medical in DNA (FromJordeI B, CareyJC, Bamshad Cenetrcs,3rd ed.St.Lours,Mosby,2006,p 231) genes are important regulators of cellular growth and programmed cell death or apoptosis. They have been called recessiue oncogenesbecausethe inactivation of both allelesof a tumor suppressor gene is required for expressionof a malignant phenotype. Knudson's "two-hit" model of cancer development was based on observation of the behavior of the tumor suppressorgene RB. In sporadic casesof retinoblastoma, both allelesof the RB gene must be inactivated (Fig. 492-3). However, in familial cases,children inherit an inactivated allele from one parent' and consequently require the inactivation of the only remaining normal allele. This helps explain why familial casesof retinoblastoma present earlier in childhood than sporadic cases'since only one "hit" is required' Another major tumor suppressor prorein is p53, which is known as the "guardian of the genome" because it detects the presence of chromosomal damage and prevents the cell from dividing until repairs have been made. In the presenceof damage beyondrepair, p53 initiates apoptosis and the cell dies' More than 50% of ail tumors have abnormal p53 proteins. Mutations in the P53 gene are important in many cancers, including breast, colorectal, lung, esophageal,stomach, ovarian' and prostatic carcinomas as well as gliomas, sarcoma, and some leukemias. TOCANCER PBEDISPOSING SYNDROMES Severalsyndromes are associatedwith an increasedrisk of developing malignancies, which can be characterized by different mechanisms (Table 492-2). One mechanism involves the inactivation of tumor suppressor genes, such as RB in familial retinoblastoma. Interestingly, a patient with retinoblastoma in which one of the alleles is inactivated throughout all of his or her cells is at a very high risk for developing osteosarcoma.A familial syndrome, Li-Fraumeni syndrome, in which one mutant PsJ allele is inherited, also has been described in patients who can develop sarcomas, leukemias, and cancers of the breast, bone, lung, Jnd brain. Neurofibromatosis is characterized by,the prolifeiation cells of neural crest origin, leading to neurofibromas. These patients are at a higher risk of developing malignant schwannomasand pheochromocytomas.Neurofibromatosis often is inherited in an autosomal dominant fashion, although 50"/" of the casespresent without a family history and develop because of the high rate of spontaneous mutations of the NFl gene. A second mechanism responsible for an inherited predisposition to develop cancer involves defectsin DNA repair. Syndromes associatedwith an excessivenumber of broken chromosomes due orders display an autosomal recessivepattern. in situ hybridizationwith MYCN probe in advancedneuroblastoma.A, Metaphasespreadof a tetraploid neuroblastomacell showing f;igurc492-2. Fluorescence double minutes.Intensityof fluorescentsignal variesaccordingto the sizeof the double minute and the number of MYCN copiesit contains.White-arrowspoint to fluorescentsignalarising from the normal MYCN l..us onlistal chromosome2p. B, Interphasenuclei of neuroblastomacells showing varying degreesof fluorescenrinrensitlyarising fiom double minute chromosomes.(PhotographcourtesyofJ. Biegel,Children'sHospital of Philadelphia.Previouslypublishedin NussI07BSaunders,2004' p 331.) baum RL, Mclnnes RR, \ilillard HF [eds]: Thompson and Thompson Geneticsin Medicine, 5th ed. Philadelphia, 2102I PARTXXI r CancerandBenignTumors Inheritance of first hit TumorDNA nomozygous for RBl Secondhit during embryonic developmenl Loss and reduplication In QA ? RBl RBl RBl Mutationof normargene RBI Somatic recombination F i g u r c. 1 9 2 - 3 .P e r s o n si n h e r i t i n ga n R B 1 m u r a r i o na r e heterozygousfor the mutation in all cellsof their body. The second"hit" occursduring embryonicdevelopment and may consistof a poinr mutation, a deletion,loss of the normaLchromosomeand duplication of the abnormal one, or somatic recombination.Each processleads to homozygosityfor the mutant RBI allele and thus to tumor developmenr. (From Jorde LB, Carey JC, BamshadMJ, et al [editorsj: Medical Cenetics,3rd ed. St Louis, Mosby, 2006, p 233. Modilied from Cavenee WK, Dryia TP, Phillips RA, er al: Expressionof recessive allelesby chromosomalmechanismsin retinoblastoma Nature 1983;305:779-784.) Constitutional DNA heterozygoustor RBl COMMINI GROM()sOMAISYNDROMES ftromosome 11p-(deletion) withsporadi( aniridiaWilms tumor Chromosomal 13q-(deletion) Retinoblastoma Trisomy 21 (47, Klinefelter syndrome XXY) Trisomy 8 Noonan syndrome Monosomy 5or7 CHROMOSOMAI INSTABITITY pigmentosum Xeroderma Fanconi anemia Bloom syndrome Sarcoma Lymph0cytk 0rnonlymphocytic leukemia, especially megakaryorytic leukemia Transient leukemoid reaction Breast cancer germcelltumors Extragonadal Preleukemia Juvenile myelomonocylc leukemia Myelodysplastk syndrome Baulcellandsquamous cellcarcinomas Melanoma Leukemia Myelodysplatic syndrome liverneoplasias Rare head andneck tumon Gastrointestinal andge0itourinary caRCers Leukemia Lymphoma Solid tumon Assocrated withgenit0unnary anomalies, mental retardation, l4ll gene Associated withmental retardation, (bilateral) skeletal malformations; autosomal dominant or sp0radi( newmutati0ns intheR8igene Risk ofacute lymphocytic leukemia isincreased 20%;risk ofacute myelocytir leukemia isrncreased patients 400Y0; have anrncreased sensitivity t0chemotherapy Autosomal d0minant; mulati0ns inPIP,4// / gene Recurrent infe(tions mayprerede neoplasia Autosomal recessive; failure to repairUV-damaged DNAMutarions in,{Pqeneonchromosome 3p25 Autosomal re(essive; positive chromosome fiagilrty; diepoxybutane testrestlt; mutatrons int/4NCX gene family Autosomal recessive; in(reased slstet chromatid exchange; mutations inBlMgene, amember ofthe gene RecQ helicase family Biologyof Cancer* 2103 andCellular 492ry Molecular Ghapter DI50RDTR Ataxra telangie(tasra Dysplastrc nevus syndrome Rothmund-Thompson syndrome (premature Werner syndrome aging) IMMUNODETI(|EtICY SYiIDROMES Wrskott-Aldrich syndrome lUMORICANGR {0MMEiT in,4IM tum0r drugs, mutati0n ati0n, fadiom metlc sensitive t0x-ifrad recess!ve; Lymphoma Autosomal gene LEUKCM A s|]ppress0r (less netvous tumors commonly) [enttal sy$em andnon-neural solrd gene in[DK|V2,4 asotiated withmutati0n5 cases Aut0soma d0mrnant;some Melanoma qene family n RecQ heJicase reressve;mutati0n Autosomal 0steosarcoma Skin cancers gene family gene-member oftheRec0 helicase inthel4frN recesive;mutati0n Autosomal 50fttissue sarcomas (Duncan X-linked immunodefi cjeniy syndrome) Lymphoproliferative disorder (Bruton X-linked agammaglobulinemia disease) Lymphoma, leukemia 5evere combined immunodefi ciency Leukemia,lymphoma (Xp1 protein in signal transducti0n fun(tions qenemutati0n 1 22-23);WAsp 14,45 X linkedrecessive; fiiament reanangement actin associated withcytoskeletal gene locus inJff2Dl,4 infection maybefatal; mutation vrral X linked; Epnein-Barr inabsence ofmature Bcells resulting in8(Igene X inked;mutation gene in,4D,4 X inked;mutations OTHERS Neurof bromatosis typel gene, Ntl suppresor mutati0n dominant, intumor Autosomal Lymphoma, leukemia Neurofibroma glioma 0ptic Acoustic neuroma Astroiytoma Meningioma Pheochromocytoma Sarcoma Neurofi bfomatosis type2 Bilateral acoustic neuromas Meningiomas Tuberous sclerosis Fibroangiomatous nevi l,,4yocardial rhabdomyoma (nevus Gotlrn syndtome basal cellcarcinoma Goltz l\4ultiple basal cellrarcinomas syn0r0meJ Medulloblastoma Li{raumeni syndrome Bone safroma 50fttissue Brea$ Retinoblastoma 5arcoma + Beckwith Hemihypertrophy syndrorne Wilms tumor Hepatobla$oma (ar0noma Adrenal vonHippel{indau disease Hemangioblastoma ofthecerebeilum andretina Pheochromocytoma Renal cancer pancreaic N4ultiple endo(ine neoplasia syndrome,type 1 Parathyroid, islet, andpitrirtary tum06 (Wermer syndrome) Multiple endocrine neoplasla syndrome, type2A Medullary carcinoma ofthethyf0id (5ipple syndrome) Hyperparathyroidism Pheochromocytoma M"h'ple erdot r neneoplasia neuroma type2B(multrple Mucosal mucosal neuroma syndrome) Pheochromocytoma Medullary thyroid carcinoma habitus Marfan Neuropathy polyposis Famrlial adenomatous [olorectal andthyroid carcinoma carcinomas Duodenal andperiampullar Pediatri( hepatoblastoma juvenile polyposis Familial Colorectal GKrnoma (Lynch Hereditary n0np0lyposis colon cancer oncer Colon NHPTC) syndrome, Turcot syndrome Pediatric brain tumors lncreased riskofcolon rarcinoma andpolyps polyposis Familial coli ofcolon adenomatous Adenocarcinoma syndrome ofcolon Gardner Adenocarcrnoma tumors Skull andsofttrssue (aninoma Peuu-Jeghers syndrome Ga$rointestinal neoplasia Ovarian carcinoma Hemo(hromatosrs Hepaocellular storage I (von rarcinoma Glycogen drsease 6ietke disease) Hepatocellular gala(tosemia Tyrosinemia, BR(A1 andBRCA2 celltrait Sickl€ Hepatoceliular carcinoma andovarian Brea$ canre6 Renal medullary carcinoma gene NF2 intumotsuppressor mutation Autos0mal d0minant; Aut0s0mal d0minant inPI(Hgene mutation Autosomal domrnan! gene, d0minant aut0s0mal Mutation 0fPiJtum0r-suppressor inRBtumor 10-20yrlatetmutatlon riskofsecondary malignancy Inaeased Autosomal recessive; gene suppress0r tumotmostinfi6t 5 yr0flife l{I/ gene25%develop gene, /Hl gene 0ftumor-suppressot mutatron Aulosomal dominant, gene mutation inPf6Mtumorsuppressor dominant; Autosomal activates thispr0t0-0nc0gene oftheBfl gene richregions mutations if Cys Autosomal dominant; (akitonin levels andcalcjum m0nitor foratyrosine kinase; Sflcodes proto-oncogene Rff 883or914)activates incatalyti{ site(codon mutati0n d0minant; Autosomal kinase fora tyrosine codes gene in/4Pf dominant; mutation Autosomal gene in5,i14,4r4 mutation Autosomal domrnant; repaigenes;hMSH2,hMLH1,PMS!,PM52'\MSH6, mutation inmismatch Aftosomal dominant; ht4s63 inthe,4Pfgene Mutation gene Autosomal dominant,,4PC gene dominanl,,4P( Autosomal metab0lism, cell cellcy(le, kinase thatregulates todes foraSer/Thr dominant, l(81 gene Autosomal polartty with[irhoti(liver malignancy associated dominant; Autosomal inglu(ose-6-phosphatase liver. iVutati0n withcirrhotic malignancy a5sociated recesive; Autosomal gene ttanslocase 6-phosphatase orglucose liver ass0ciated with(irrh0tic recessive;tum0r Autosomal reparr DNA defect unknown Etiology 2104r PARTXXI r Gancerand BenignTumors The third category of inherited cancer predisposition is characteized by defects in immune surveillance. This group includes patients with \fiskott-Aldrich syndrome, severe combined immunodeficiency, common variable immunodeficiency, and the X_-linked lymphoproliferarive syndrome. The mosr common rypes of malignancy in these patients are lymphoma and leukemia. Cure rates for immunodeficient children with cancer are much poorer than for nonimmunodeficient children with similar malignancies, suggestinga role for the immune system in cancer treatment as well as in cancer prevention. Beckwith-ufeidemann syndrome, an overgrowth syndrome characterized by macrosomia, macroglossia, hemihypertrophy, omphalocele, and renal anomalies also is associated with an 'Wilms increased risk of tumor, hepatoblastoma, rhabdomyosarcoma, neuroblastoma, and adrenal cortical carcinoma. The increased risk of developing cancer is associated with changes in the methylation pattern of genes on the 1lpl5 chromosome. In vitro fertilization has been associated with imprinting defects and the development of some casesof Beckwith-Weideminn syndrome-associatedWilm tumor and retinoblastoma. OTHER FACTORS ASSOCIATED WITHONCOGET{ESIS TEI0MERASE.Telomeres are a series of tens to thousands of TTAGGG repeats at the ends of chromosomes that are important for stabilizing the chromosomal ends and limiting breakage, translocation, and loss of DNA material. With DNA replication there is a progressive shortening of telomere length, which is a hallmark of cellular aging and may be a senescencesignal. In some instances telomerase, an enzyme that adds telomeres to the ends of chromosomes, becomes active. The addition of telomeres can be found in immortalized cell lines and most tumor types, and as a consequence, these cells may have a survival advantage that allows them to undergo additional cell divisions. Therapy aimed at inhibition of telomeraseacriviry may result in cell death. compromisedpersons. In childrenwith chronichepatitisB infection(HBsAg-positive), the risk of developinghepatocellularcarcinoma ii increased Attiyeh EF, London WB, Mosse YP, et al: Chromosome 1p and 1lq deletions and outcome in neuroblastoma. N Engl J Med 2005;353:2243-2253. Blackburn E: Telomeres and telomerase; their mechanisms of action and the effects of altering their functions. FEBS Letters 2005;579:859-862. Hitchens MP, u7ong JJL, Suthers G, et al: Inheritance of a cancer-associated MLHI germJine epimutation. N Engl J Med 2007;356:697-705. Jordan Cl Guzman ML, Noble M: Cancer stem cells. N Engl J Med 2006:355:7253-1260. Messahel B, Hing S, Nash R, et al: Clinical features of molecular pathology of solid tumours in childhood. Lancet Oncol 2005;6:421430. Mitelman F, Johansson B, Mertens F: Fusion genesand rearranged genesas a linear function of chromosome aberrations in cancer. Nature Genetics 2004:36:337-334. Moll AC, Imhof SM, Cruysberg JRM, et al: Incidence of retinoblastoma in children born after in-vitro fertilization. Lancet 20031351:309-310. Prawitt D, Enklar I Gartner-Rupprecht B, et al: Microdeletion and IGF2 loss of imprinting in a cascade causing Beckwith-Wiedemann syndrome with Wilms' tumor. Nature G enetics 2O05;37 :785-7 86. Quackenbush J: Microarray analysis and tumor classification. N Engl J Med 2006:354:2463-2472. ReinhartB, ChailletJR: Genomicimprinting: cis-actingsequences and regional control. Int Reu Cytol 2005:243;173-213. Schiavi F, Boedeker CC, Bausch B, et al: Predictors and prevalence oI paraganglioma syndrome associatedwith mutations of the SOHC gene.IAMA 2005;294:2057-2062. lfindschwendter M, Fiegl H, Egle D, et al: Epigenetic stem cell signature in cancer.N4t Genet 2007:39:l 57-164. Symptoms and physical findings are important in the recognition of malignant diseasesand life-threatening benign tumors in children and adolescents.In addition to the classic manifestations, any persistent,unexplained symptom or sign should be evaluated as potentially emanating from a cancerous or precancerouscondition. As part of the diagnostic evaluation, thi pediatrician and 493 r Principlesol Diagnosisr 2105 Chapter line the ducts and glands of organs and composethe skin. In children, metastasesare present at diagnosis in approximarcly 80"/" of cases,whereas only about 20% of adults have evidenceof ADU[T5* inbowel orbladder habits [hange In$ool Blood inbreast orelsewhere Lump Hoa6eness ornagging rough Diffirulty inswallowing Sore that willnotheal inwart ormole Change CHIIDREN} mass Abdominal Persistent lymphadenopathy hematopoietk lineage >1abnormal 5pecifrc neurologic defcit presure intracranial lncreased ofpons Diffuse enlargement Proptosis pupillary reflex White painAwelling Unilateral knee orshoulder Vaginal bleeding ormas *Developed (ancer S0ciety inthe'1950s bytheAmerrcan 'Developed (enter. 0flexas lvlDAnderson [ancer bythelJnrvenity diagnosis are particularly problematic during late adolescence, ,r. due to a variety of factors prominent in this age group, "nd pediatric oncologist must convey the diagnosis to the patient and family in a sensitive and informative manner. SIGNSAND SYMPTOMS.In contrast to the classicwarning signs of cancer in adults (Table 493-1), there is no establishedset of symptoms and signs of cancer in children, for a number of reasons.The symptomsand signsof cancerare more variable and nonspecific in pediatnc than adult patients. The types of cancer that occur dr.rringthe first 20 yr of life vary dramatically as a f unction of age-more so than at any other comparableage range (see Chapter 491). Unlike cancersin adults,childhood cancersusually originate from the deeper, visceral structures and from the parenchymaof organs rather than from the epitheliallayers that i n c h i l d r e n( T a b l e4 9 3 - 3 ) . The most common pediatric cancers PHYSICALEXAMINATI0N^ malignancy. Abnormalities of the hematopoietic system manifest as pallor, which indicates anemia; bleeding from orifices, petechiae, 5I6H5 AIiDsYMPIOMS st6l{fleAH(t ixAf{Flt HEMAT()TOGIC Pallor;anemia Petechiae, thrombocytopenia pharyngitrs, neutropenia Fever, manow infltration Bone manow infiltration Bone infiltration Bone manow neuroblastoma Leukemia, neuroblastoma Leukemia, neuroblastoma Leukemia, SYSTEMIC pain, arthralgia Eone hmp, night sweats Fever ofunknown origin, weight loss, Painless lymphadenopathy lesion Cutaneous mass Abdominal Hypertension Diarrhea mas 50fttissue metastasis tobone Primary bone tumor, malignancy Lymphoreticular tum0r s0lid maliqnancy, metastatic Lymphoreticular disease Primary ormetastati( tumor Adrenal+enal tumor system Sympathetrc nervous p0lypeptide intestinal Vas0active tumor Lo(al ormetastatic neur0bla$0ma leukemia, satcoma, Ewing 0steosarcoma, lymphoma non-Hodgktn disease, Hodgkin carcin0ma Burkittlymphoma,thyroid lymphoma, non-Hodgkin disease, l'lodghn Leukemia, melanoma cellhistiocytosis, Langerhans leukemia, Neuroblastoma, tumollymphoma Neuroblastoma,Wlms tum0r pheochr0m0cytoma,Wilms Neuroblastoma, ganglioneuroma Neuroblastoma, rcoma, rhabd0my0sa carcinoma, thyroid neuroblastoma, osteosarcoma, sarcoma, Ewing granuloma eosirophilk cellhistiocytosis prolacttnoma, Langerhanl craniopharyngroma, Adenoma, metastasts tumor; brain Primary gland orpituitary galactonhea, poorgrowth involvement ofhypothalamus Neuroendooine insipidus, Diabetes presure papilledema, Inoeased intratheral disturbances, ataxia, headarhe, Emesis,visual palsies nerve cranral SIGlI5 OPHTHATMOTOGI( Leukokoria Periorbital ecchymosis ptosis, Miosis, hetero(hromia 0psomyodonus, alaxia proptosis Exophthalmos, pupil White Metastasis nelves sympatheti( ofcervical Horner syndrome. compression Autoimmunity? Neurotransmifiefs? 0rbital tumor Retinoblastoma Neuroblastoma Neuroblastoma Neurobla$oma lymphoma Rhabdomyosarcoma, THORACI( MASS mediastinal Anterior Posterior mediastinal (ough,stridor, pneumonia,ttacheal-bronchial c0mpfession dysphagia root c0mpression; Vertebral ornerve disease Hodgkin celllymphoma, Germ celltumor,T cyst neuroenteric Neuroblastoma, p 729 WBSaunde6, ?006, Essentilh o/Pedttr?t 5thedPhiladdph8, RM,Mdrcdanre KJ,Jenson HB,eral{ediros).l,lels}n tromKliegman 2106r PARTXXI I GancerandBenignTumors REIAIED DIRTCTIY T()TUMOR Superjor vena caval syndrome Subcutaneou5 nodulej Leukemoid readion gravis Myasthenia Heterochromia N()T RETATED DIREOTY TOTUI,IOR GROWTH Ihronic dianhea Polymyoclonus-opsodonus Failure tothrive [ushing syndrome Pseudomuscular dystrophy Modifi€d fromViefti TJ,Steub€r [P:0ini(al as5e5sment anddifferential diagnosis 0fth€childwithsuspeded Gn(er. lnPizo PA,Pophck DG(editors): Prin(ipl6 lnd pwtke 0f pediltrk1nolqy, 4rhd phttdelphia, Lippin@n lvilliams& Wlkins, 2002,pp 149-160 purpura, and ecchymosis,which indicate thrombocytopenia or disseminatedinrravascular coagulation; cellulitis or oiher evidence of infection, which indicates leukopenia; skrn nodules, which indicate leukocyrosis; and orher abnormalities of the Abnormalities of the cenrral nervous system that indicate cancerinclude decreasedlevel of consciousness, paresisof cranial nerve VI, seizures,ptosis,decreasedvisual activity, and increased intra.cranialpressure, which may be diagnosed by the presenceof papilledema (Fig. a93-3). Any focal neurologic deficit in the motor or sensory system,especiallya decreasein cranial nerve function, should prompt further investigation for malignancy. Abnormalities of the embryonal systim usually are-appaient on physicalexaminarionas organomegalyor an abdominaf mass. Fignrc'{93 l. Cervicallymphadenopathy. Manifestations on physicalexamination(A) andon ultrasound (B).N, abnormally examination enlarged lymph nodes.(From SinniahD, D'Angio GJ, ChattenJ, et al: Atlas of pediatric Ontology.London,Arnold,1996.) genital or gonadal malignancies, as well as for Hodgkin disease. p.redominate. Hence, for infants and toddlers, special attention should be paid to the possibility of embryonal and intra- Figurc .193l. Anterior upper mediastinal mass from non-Hodgkin lymphoma. (From Sinniah D, D'Angio GJ, Chatten J, et al: Atlas of Pediatric Oncology.London, Arnold, 1996.) 493 r Principlesof Diagnosisr 2107 Chapter . Vhite pupillaryreflexin the left eye.(FromSinniahD, D'Angio J, er aI:Atlas of PediatricOncology.London'Arnold, 1996.) Figure .19.3-3.Papilledemaon funduscopic examination. (From Sinniah D, D'Angio GJ, Chatten J, et al: Atlas of Pediatric Oncology. London, Arnold, 1.996.) EARTY DETECTION Becausemost childhood cancers are curable, early detection is crucial. In addition, for several types of childhood cancer, less aggressivetherapy is indicated for early-stage disease than for advanced disease. In fact, early detection often minimizes the amount and duration of treatment required for cure and, therefore, may not only lead to a higher potential for cure but also spare the patient intensive or prolonged therapy. The prognosis of malignancy in children depends primarily on tumor type, extent of disease at diagnosis, and rapidity of responseto treatment. Early diagnosis helps to ensurethat appropriate therapy is given in a timely fashion and, hence, optimizes the chances of cure. Becausemost physicians in general practice rarely encounter children with undiagnosed cancer, they should remember to investigate the possibility of malignancy, especially when they encounter an atypical course of a common childhood cells are not seen in the blood smear. Malignancy can also occur in neonates and should be considered in children with massesin any arca or with "blueberry muffin" spots on their skin; the latter sign is indicative of neuroblastoma. STAGING Vhen a malignant neoplasm is suspected,the immediate,goal is to determine its type and extent. A tentative diagnosis often can be establishedon the basis of the patient's age, presenting symptoms, and the location of a suspectedmass. A thorough search for metastatic disease usually precedes biopsy of a suspicious lesion (Table 493-4). The surgeon can make a more informed choice between an attempt at complete resection and a more limited procedure when the presence or likelihood of disseminated disease is known. The appropriate preoperative studies depend on the tentative diagnosis. CT and MRI are noninvasive t..hniqrr., that may be useful in evaluating patients for the prese.rce ol metastatic lesions; bone marrow asPiration' biopsy, or both also may be needed. These studies also are used in assessing the diseasestage, information that is critical in determining thi prognosis and developing a treatment plan' In addition to traditional methods, DNA microarray analysis may help identify gene expression patterns of many, tumors' which adds to more iccnrat. staging and tumor classification' HISTOPATHOTOGY Figure493-4. Brain stemtumor apparenton MRI. (From SinniahD, D'Angio GJ, ChattenJ, er al: Atlas of Pediatric Oncology.London, Arnold, 1996.) Central to the diagnosis of any tumor is histologic examination of specimens. The inltlal specimen of, tumor.-tissue should be obtained under conditions that allow for a full range of pathologic studies. In some cases,such as suspectedlymphomas, fresh 2108r PARTXXI r CancerandBenignTumors BONT MARROW CHEST ASPIRAIUBIOPSY X.RAY os(AH Yes Yes Yes Yes Yes Leukemia Non-Hodgkin rympn0ma Hodgkin disease [NStumors Neuroblastoma Ye5 Wilms tumor Rhabdomyosanoma Yes 0steosarcoma Ewing sarcoma Yes 6erm cell tumors Lwer tumors Retrnoblastoma+** :5 YS Yes Ye5 Ye5 Yes res Yes Yes Yes re5 (ofchest) Yes Ya(ofchest) Yes Yes Yes, if MRInotavailable Yes rcs Ye5 re5 Yes sPEflFre MARKTRS OTHER TT5T5 BOI{E 5CAN CSF ANATYSIS MRI yes Ye5 Gallium scan Ies VMA, HVA (forparameningeal Yes tumors only) Ya(forprimarytumors) Yes (fffprimary Yes tumo6) Yes [onsider MRI ofbrain Yes(ofbain) t AFB H(G AFP Yes Retin0bla$oma gene analysis *lndividual (ases mayre0uiE additional ftdi€s **lf manow involvement issuspected F0mKliEman RM,Marcdante U,lenson HB,€t al{editots).Nets}n ksentills ofPedi0tri6, 5thedPhiladelphia,WB Saunders,2006,p 710 tissue may be required for specialstudies.Some of thesestudies _ In many cases,the diagnosiscan be confirmed by means of a fine-needlebiopsy, thus eliminating the need for an incision or MIBG scan ...r, :,ir rr{i.:r:i:::i1r:i4ilr;,,.:j :,:::qrir!,iitlirr llr.ilglfta:..e:.;!itt,;.-:-! rl Guillerman RP, BravermanRM, Parker BR: Imaging studiesin the diagnosis and managementof pediatric malignancies In Ptz.zoPA, Poplack DG (editors): Principlesand Practiceof Pediatric Oncology,5th ed. philadelphia, Lippincott \Williams& Wilkins, 2006; pp 256-289. Malogolowkin M, Quinn JJ, Vierti TJ, SteuberCP: Clinical assessmenr and differential diagnosis of the child with suspectedcancer. In przzo pA, PoplackDG (editors):Principlesand Practiceof PediatricOncology, Sth ed. Philadelphia,Lippincott Villiams & Wilkins, 2006; pp 145-159. QuackenbushJ: Microarray analysisand tumor classificatrcn.N Engl I Med 2006;354:2453-2472. SinniahD, D'Angio GJ, ChattenJ, et al: Atlas of PediatricOncology.London, Arnold, 1995. Triche TJ, SorensonPHB: Molecular parhology of pediatric malignancies.In Pizzo PA, PoplackDG (edrtors):Principlesand Practiceof PediatricOncology, 4rh ed. Philadelphia, Lippincott S7illiams & Vilkins, 2002, pp t61-204. ing subsequenttreatment. DISCUSSING THEDIAGNOSTIC EVATUATION Treatment of children with cancer is one of the most comolex endeavors in pediatrics. It begins with an absolute requiremenr for the correct diagnosis (including subtype), proceed; through accurate and thorough staging of the extent of diseaseand determination of prognostic subgroup, provides appropriate multidisciplinary and usually multimodal therapy, and requires assiduous evaluation of the possibilities of recurrent diseaseand of adverse late effects of the diseaseand rhe therapies rendered. Throughout treatment, every child with cancer should have the benefit of seriously ill children. I Plinciplesof Tleatmentr 21119 Ghapter494 16 14 U.S.SEERCancerlncidence amongChildren<15Years ttz f fro 8a xl ra LO q) A o . a^al4l U,S.CancerMonality Rate ^ ^^^^^^^. --^u4!ru^ amongChildren<15Years 6a (r 2 1960 U 1970 1980 1990 dren. AccordinglS children with a better prognosis are treated with less intensive therapg including lower doses of chemotherapy or radiation therapy, a shorter duration of treatment, or elimination of at least one treatment modality (radiation therapy, chemotherapy, surgery). Accurate staging thus reducesthe risk of excessiveacute adverse effects and long-term complications of therapy in patients whose prognosis indicates that lesstherapy is required for cure. Overtreatment of patients with a more favorable prognosis is a definite risk if the patient is not referred to a cancer treatment center for management of adverse effects of such treatment. Conversely, undertreatment also is a clear risk if the diagnosis and stage are not correct, resulting in a compromise of an otherwise high potential for cure. Diagnostic imaging is a critical phase of evaluation in most children with solid tumors (i.e., cancers other than leukemia)' MRI, CT, ultrasonographS scintigraphy (nuclear medicine scans), 2000 Children's Oncology Group Children's Cancer Group Pediatric Oncology Group Southwest Oncology Group Cancer and Acute Leukemia Group B National Wilms Tumor Study Group Intergroup Rhabdomyosarcoma Figure494-1. Reductionin the national cancermortality rate among children <15 yr of age (triangles)in the USA as a direct consequenceof the National CooperativeGroup Program sponsoredby the National CancerInstitute,and in comparisonto the rising incidenceof cancerbefore age 15 yr (circles).The horizontal bars indicate the duration of the existenceof the national pediatric cancer cooperative groups, beginning with the Children's Cancer Group (CCG) in 1955. Other groupsare the PediatricOncology Group (POG),which was derived from the Pediatrics Divisions of the Southwest Oncology Group and the Cancer and Acute Leukemia Group B, the National \0UilmsTumor Study Group, and the Intergroup RhabdomyosarcomaStudy Group. In 2000, the four pediatric cooperative groups merged into the Children's Oncology Group. (Incidenceand mortality rate data from Ries LAG, Eisner MP, Kosary CL, et al [editors]: SEER Cancer StatisticsReuiew 1975-2002, National based Cancer Institute, Bethesda, MD; http://seer.cancer.gou/csrlL975_2002/, on November 2004 SEERdata submission,postedto the SEERweb site2005. The mortality rate data are national rates, and the incidence data are derived from the SEERprogram, representingabout 157o of the USA.) of cancer is susoected. AII such centers in North America are identified on the Children's Oncology Group website (wwwchildrensoncologygroup.org) and on the National Cancer Institute cancer trials website (www.clinicaltrials.gov). The remarkable increases in cure rates for childhood malignancies over the past 30 yr would not have occurred without the collective participation of patients and their physicians in clinical research programs at these centers. In the USA, the National Cancer Institute's Clinical Trials Cooperative Groups Program has been associatedwith a >80Yo reduction in the incidence of mortality due to cancer among children <15 yr of age despite an overall increasein cancer incidence during this interval (Fig. a94-l). This remarkable achievement represents the effects of an effective multimodal, multi-institutional, multidisciplinary collaboration. ANDSTAGING DIAGNOSIS Accurate diagnosis and staging of the extent of diseaseis imperative, especially for childhood cancers that have high cure rates, because the nature of therapy depends strongly on the type of cancer. In addition, prognostic subgroups based on the stage of diseasehave been establishedfor most cancersthat occur in chil- tion of frozen sections of the surgical margins for tumor cells is essential in many tumor operations. A MUtTIMODAt, MULTIDISCIPLINABYAPPROACH Many pediatric subspecialties are involved in the evaluation, treatment, and management of children with cancer, including provision of primary modalities and multiple supportive care services (Fig. 494-2). More than two of the primary modalities are often used together, with chemotherapy being the most widely used, followed, in order of use, by surgery' radiation therapy' and biologic agent therapy (Fig. 494-31. The leukemias that occur in childhood usually are managed with chemotherapy alone, with a small proportion of patients receiving cranial or craniospinal radiation therapy for prevention or treatment of overt central nervous system leukemia. Most children with non-Hodgkin lymphoma also are treated with systemic multiagent chemotherapy usually is necessarybeca-u-se tumor dissemination generally is present even if undetectable. Chemotherapy alone usually is not adequate to eradicate gross residual tumors. Hence, it is not unusual for children with malignant tumors to require treatment with all three modalities (see Fig. 494-3). Unfortunately, most treatments that are effective in children with cancer have a narrow therapeutic index (a low ratio of efficacy to toxicity). The acute and chronic adverse effects of these treatments can be minimized but not entirely avoided. r Cancerand 2110I PARTXXI BenignTumors Psychosocial care Vascular Childlife care Antibiotics Surgery Nursing Antiemetics Chemotherapy Fine-needle bropsy Radiotherapy -:_-_::-]_, 1!'\\! child '/ Pathotogy{withjenarmacyiGrowrh Diagnostic Nutrition ...'l'n'nn Parenteral alimentation ',J:::,. ''\ 'i Cancer __,. il!9t.-i1i, Cytokines g factors Figure 494-2. Multidisciplinary care of children with cancer. The inner circle designatesprimary modalities,and the outer ring identifiessupportive care elementsto which all children with cancerhave access. transPlantati-f-f sedatives, biologY anesthetics Analgesrcs Dentalcare Supportivecare Over rhe past 10 yr, biologic agent therapy has become an important modality in a feu' childhood cancers(seeFig. 494-3). This type of treatment generally refers to immunotherapn biologic responsemodifiers, or endogenouslyoccurring molecules that have therapeuticeffectsin supraphysiologicdoses.Examples are retinoic acid therapy in acure progranulocytic leukemia, monoclonal antibodv rherapy for certain non-Hodgkin lymphomas, imatinib mesylate for chronic myelog.ious and Philadelphia chromosome-positive leukemias, and radioactive meta-iodobenzylguanidine therapy for neuroblastoma. Chemorherapyis used more widely in children than in adults becausechildren better tolerarerhe acute adverseeffectsand the malignant diseasesthat occur in childhood are more responslve to chemotherapythan are malignant diseasesof adults. Radiation therapv is used sparingly in children becausethey are more vulnerable rhan adults to its late adverseeffects. \Thenever possible,treatment is given on an outpatient basis. Children should remain living at home and in school as much as possible throughour t..rt-ent. Increasingly, pediatric cancer therapiesare being administeredto ambulatory patienrs,with the advent of such innovations as programmable infusion pumps, oral chemotherapeutic regimens, early discharge from hospital with intensive outpatient supportive care, and home health care services.Some patients miss a considerable amount of school in the 1st yr after diagnosis due to the intensity of therapy or its adverseeffects and to the ensuing complications of the diseaseor therapy. Tutoring should be encouraged so that children do not fall behind in their schooling; counseling should be provided as appropriate. In-hospital school services should be provided for those patients who must spend much of their time as inpatients receiving therapy for diseaseor for managing adverse effects. Development of selective,highly effective therapy for cancer in both children and adults had been hindered by a lack of understanding of the molecular mechanisms that underlie malignant transformation. Ongoing discoveries of molecular and cellular mechanisms that explain the cancer process have led to increasingly specific antineoplastic therapies. generally referred to as molecularly targeted therapies. Their most prominent feature is a relative lack of normal tissue toxicity, such that the additional therapeutic benefit occurs with minimum additional toxiciry. Many of the new biologic agent therapies, such as imatinib and rituximab, fall into this category (Table 494-1). Complementary AGENT lmatinib KINAST MAtIGNANft B(R-ABL tMt I<ellALL Hypereosinophilic syndrome Systemrc ma$ocytosis IML Systemic mastocytos s Gastrointestina stromal 0\,1t Phadelphia p0sitive chromosome ALL PDGFRa PDGFRg cKlT Figure49.1-3.The primary modalitiesof therapyusedin the treatmentof children with cancer The relative sizesof the circles designatethe approximate proportion of overall role in the managementof pediatric cancers. Dasatinib BiR.ABt Nilotinib BIRABt Gefirinib EGFR Erlotinib E6FR Irastuzumab [etuxlmab ERBB2iHER 2 EGFR Bevacizumab VEGFR-1,.2 (lVL,(hrof ALl,a(ute lymphoblasl c leukemia; i( mye0genOus e|]kemia ct\/t Philadelphia positive chromosome ALL Non-small celllungrancer Glioblastoma Non-small celllungcancer Glioblastoma Breast can(eT Non-smal cellungcancer 5qramous cellcancer ofhead/neck Non-small celllungcanrer Ereast canier Renal rel carcinoma r 2111 I Principlesof Treatment Ghapter494 ATKYTATING AGENTS [ydophospham de/lfosfam de Dacarbazine Irsplatin [arbopla n ANTIMETABOI.ITE5 l\,4ethotrexate Mercaptopurine tytarablne Fluorouracil 'f DNA repalt, t freeradical scavengen, l aldehyde dehydrogenase katabolism) 1 DN,l repair J uptake,'f DNA repail t freeradical scavenqen J uptake, t Dlerepair, t freeradkai scavenges Becausemost antineoplastic agents are cell cycle-dependent, their adverseeffects usually are related to the proliferation kinetics of individual cell populations. Most susceptible are those tissues or organs with high rates of cell turnover: bone marroq oral and intestinal mucosa, epidermis, liver, and spermatogonia. The most common acute adverse effects are myelosuppression (with neutropenia and thrombocytopenia being the most problematic), immunosuppression, nausea and vomiting, hepatic dysfunction, upper and lower gastrointestinal mucositis, dermatitis, and alopecia. Fortunately, the tissues affected also recover rela- (targo), J transport, t DHFR ty ofDHFR, J polygluomaion J affin J artvation, T catabollsm (ytidine (aaivation), J deoxycyt dinekinase t d0qJ transp0rt,'l (catabolism) deaminase (target), J activaion, t thymidylate synthase 0fthymidylate J affinlty synthase ANTITUMOR ANTIBIOTICS Anthracyclines MDR, J topoisomerase ll aitivity, T freeradi(al scavengers Dadnomycin I\'1DR ening and often disabling. Least susceptible to chemotherapy and radiation therapy are that do not replicate or that replicate slowlS such as cells (target), J affinity oftubulin MDR neurons, muscle cells, connective tissue, and bone' However, chilI DNA repait, tr,'tDR, J topoisomerase ll acuvny dren are not exempt from toxicities of these tissues, probably ]\,4DR becausethey are still undergoing proliferation, albeit at a slower MI5CEtI.ANEOUS pace than other tissues, during growth and growth spurts. (()steroids [l]rt Certain chemotherapeutic agents are particularly toxic to these L Asparaginase but more so in adults than childrenl for instance, children tissues, reductase; resl$an(e t, incaased; J, deseased; DHFR, dihydofolate fiTed€0xyrytidirF triphosphate; M0&muliidllg glymprotein. mediated by1 mernbrane P-170 are spared the neurotoxic effects of vincristine and methotrexate finthan From DG, ftlin 5H, GinsbuE D,lookAT(edt:l&ridr& o,kkttsnz@yafkltArlq 6thd $!dthildttoM, and the cardiotoxic effect of anthracyclines that occur in adults. Saunders, 2003,p 1295 PhiladelFhiaWB Physically, children can endure the acute adverse effects of chemotherapy better than adults can, in many ways. The maximum tolerated dose in children, when expressedon the basis of body surface area or body weight, commonly is greater than and alternative remedies are increasingly being provided by that in adults. A comparison of anticancer drugs tested in phase parents to their children with cancer,with or without knowledge I trials in both adult and pediatric patients showed that the of the medical professionals entrusted with the child's care (see maximum tolerated dose in children was greater than that in Chapter 59). Many of these have not been evaluated by rigorous adults for 707' ol the agents, equal to that in adults for l5% of testing and most are ineffective; some are toxic or interfere with the agents, and less than the adult dose for only 15'/" of the the metabolism of other drugs. De novo or acquired resistanceto agents.For all the drugs that were compared, the mean pediatric chemotherapy and radiation therapy remains an obstacle (Table maximum tolerated dose was greater than the adult mean' 494-21. Dramatic advances in the discipline have reduced the Evolving treatment approaches that have not reached general empiricism of therapy for cancer, but much remains to be clinical application in children are specific tumor-directed theradiscovered. pies such as tumor antigen-specificmonoclonal antibodies, tumor vaccines, antisense DNA and RNA transcripts, and antiangioCHEMOTHERAPY genlc agents. PI.ANT AI.KALOIDS Vinca alkaloids Epipodophyllotoxins Pac itaxel The most widely used modality in pediatric cancer therapy is chemotherapy (see Fig. 494-3). Therapy nearly always involves combinations of drugs, such as VAC (vincristine, doxorubicin [Adriamycin] or dactinomycin [Actinomycin D], and cyclophosphamide) and CHOP (cyclophosphamide, doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone). Historically, sequential single-drug therapy rarely resulted in complete responses, and partial responses usually were infrequent and transient and gr:ew progressively shorter in duration with each drug used. Combination chemotherapy became the standard when combinations of drugs with different mechanismsof action and nonoverlapping toxicities (e.g., POMP [mercaptopurine, vincristine (Oncovin), methotrexate, and prednisone], VAMP [vincristine, doxorubicin (Adriamycin), methotrexate, and prednisone], and MOPP Initrogen mustard, vincristine (Oncovin), prednisone, and procarbazine] were first demonstrated to be effective in childhood leukemia. Most of the cytotoxic drugs for childhood cancer are selectedfrom severalclassesof agents,including alkylating agents, antimetabolites, antibiotics, hormones, plant alkaloids, and topoisomerase inhibitors (Table 494-31. The increased metabolic and cell cycle activity of malignant cells makes them more susceptibleto the cytotoxic effectsof thesetypes of agents (Frg. 494-4\. SURGERY Superb pediatric surgical and anesthesiaservices are indispensable for children with cancer.The pediatric surgeon'srole varies, depending on the type of tumor. For solid tumors' complete-resection with documented evidence of negative margins often is required for cure or long-term control. Considerable prolongation of life nearly always depends on whether the tumor is resectableand on the actual extent of resection. 'With the exception of brainstem tumors and retinoblastoma' all solid tumors in children require a tissue diagnosis; therefore, biopsy of the suspectedneoplasm is paramount. Stagingwith sentinel node biopsies has become the standard of care for several pediatric malignancies. Surgical expertise is essentialfor implaniation of vascular accessdevices and removal and replacement of such devices when infection or thrombosis supervenes (see C h a o t e r1 7 8 ) . Irrcreasingly,minimally invasive endoscopic surgical techniques are being used when indicated and, if the patient's condition permits, for biopsy and resection of tumor, direct ascertainment of residual diseaseand assessmentof response,lysis of adhesions, and splenectomy. r Cancerand 2112r PARTXXI BenignTumors DBUG MEftANISM ff AAIOiI OR(LASSITICATION INDIffIION(S) ADVERsT RTACITONS MONITORY LEVET C(]MMTHIS ORUG M e t h o t r e x a t e F 0 l i C a c i d a n t a g 0 n i 5 t ; i n h i b i t s A L L n o n _ H o d g k i n | y m p h o m a , M y e | o s u p p r e 5 5 i o n , m U ( 0 5 i t i 5 , s t 0 m a t i t i s , dsy$emic e r m a tadministration itis, may dihydrofolate reductase osteosarcoma, Hodgkin hepatitis withhigh-dose therapy and bePglM,orlV;also may be lymphoma, medulloblastomaWithlong-term administratlon;osteopenid dnd whenlowdoses are administered intrathecally bone fractures administered with t0patients Withhigh-dose renal administntion; andcentral renal dysfundion and leucworinrscueapplred -,i:lHffl',til:ilil.on;ara(hn.iditis. leukoencephalopathy, leuk0myelopathy 6-llercaptopurine Purine purineALL analog; inhibits Myelosuppression, hepati( nerrosis, mucositis; lherapeutic drug monitoring not Allopurinol inhibits metabolism (Pudnethol) synthesis allopurinol Inoeases toxicity available orindkated (ytarabine (Ara{) Pyrimidine analog; inhibits ALL, AML, non-Hodgkin lymphoma, Nausea,v0miting, myelosuppression, conjunctivitis, Iherapeuti( drug monitoring not Systemi( adminlstration may polymerase DNA Hodgkin lymphoma mu(0sitis,(entral nervous system dysfundion available orindicated bePo, lM,or lV;may also be intrathecal With administration; arachnoiditis, administered intrathecally leukoenrephal0pathy, leukomyelopathy (ydophosphamideAlkylnes guanine; inhibits ALL, non-Hodgkin lymphoma, Nausea,vomiting, myelosuppresion, hemorrhagic Therapeutk drug monitoring not Requires hepaflc activation and ((ytoxan) DNA synthesis Hodgkin lymphoma,soft pulmonafy tissue cystitis, fibrosis, inappropriate ADH available orindicated thus leseffective inpresence sarcoma,Ewingsarcoma se(retjon,bladdercancer,anaphylaxis ofliver dysfunction lfofimide(lfex) guanine;inhibits Alkylates Non-Hodgkin lymphoma,Wilms Nausea,vomiring myelosuppresion,hemorrhagic Jherapeuti( monitoring drug not DNAsvnthesis avairabre0rindicared liilil,lll',lilll''."""0 ;flk|,1il:ffiiilT:;':i'1,',l,TfiiTo* Doxorubicin (Adriamycin) and daunorubicin (Cerubidine) Dactinomycin Bleomycin (Blenoxane) (0ncovin) Vincdstine (Velban) Vinblastine t-Asparaginase Pegaspargase (Pegaspat) Prednisone and Dexamethasone (Decadrcn) Catmustine (nitrosourea) (arboplatinand cisplatin(Platinol) (VePesid) Etoposide (Tegison) Etletinate (vitaminA analog) andtretinoin (ardiac sy$em dysfu n(ti0n, t0xi(ity, anaphylaxis Binds t0DNA, imercalation ALL, AML,osteosarcoma, Ewing Nausea, vomiting,cardiomyopathy, redurine, tissue Therapeutic drugmonitoring not sarcoma, Hodgkin lymphoma, ne(rosrs 0nextravasation, myelosuppresion, available 0rindieted non-Hodgkin lymphoma, conjunctivitis, radiation dermatititarrhythmia neuroblastoma Binds t0 DNA, inhibits Wilms tumor; rhabdomyosarcoma, Nausea,vomiting tissue necrosis 0nextravasation, Therapeutic drugmonitoring not trans(ripti0n Ewing sarcoma myelosuppresion, radiosensitizer, mucosal available orindicated uttetafl0n Binds t0DNA deaves DNA Hodgkin dlsease, rron-Hodgkin Naused,v0mitinq, pneumonitis,stomaritit RaynaudTherapeutic drugmonitoring not strands germcelltumors tympnoma, phenomenon, pulmonary fibrosis, dermatitis available orindicated |nhibit5microtubule ALL, non-Hodgkin lymphoma, Local peripheral cellulitis, neuropathy, constipation,Therapeutk drugmonitoring not formation Hodgkin disease,Wilms tumor, paln, ileus,jaw inappropriate ADH secretion, available orindicated Ewingsarcoma,neuroblastoma seizures,pt0sis,minimalmyelosuppression fhabdomyosaKoma Inhibits mi(rotubule Hodgkin disease; Langerhanl cell Local celluliris, leukopenia Therapeuti( drugmonitoring not formation histiorltosts available orindicated Depletion ofL-asparagine ALL; AML, whenused in panoeatitis, Allergic reartron hyperglycemia, Therapeutic drugmonitoring not c0mbination withasparaginase platelet dysfunction andcoagulopathy, available orindirated encephalopathy Polyethylene glycol conlugateALt Indicaed forprolonged asparagine depletion Therapeuti( drugmonitoring not ofL-asparagine andforpatients wirhallergy tor-asparaginase available orindicated (elllysis Lymphati( ALL; Hodqkin dhease non-Hodqkin[ushing syndrome, cataraft, diaberes, therapeutic drugmoniroring not tympnoma hypertension, my0pathy,0$e0p0r0sis, infection, availabie orindicated pepric ul(eratign,psychgsis (arbamylation ofDNA; [N5tumors, non-Hodgkin vomiting, Nausea, delayed myelosuppresion Therapeutic drugmonitoring not inhibits DNA (4-6 wk);pulmonary synthess lymphoma, Hodgkin disease fibrosis,carcinogenic ayailable orindirated st0matrtis Inhibits DNA synthesis Gonadal tumors; osteosarcoma, Nausea, vomiting, renal dysfunction, Therapeutir drugmonitoring not neuroblastoma,(N5,tumors,myelosuppression,ototoxicity,tetan, available orindicaed germ(elltumors neurotoxi(ity, hemolytic-uremic syndromg ana0nvtaxts Topoisomerase inhibitor ALL, non-Hodgkin lymphoma, Nausea, vomiting, myelosupprssion,secondary lherapeutic drugmonrronng nor germ(elltumor leukemia available orindkated [nhances normal progranulocytic Acute leukemia; Drymouth, pseudotumor hairloss, rerebri, Therapeutic drugmonitoring not differentiation neuroblastoma premature epiphyseal closure available orindicated lVadministration only; musl notbeallowed toextravasate lVadminhtration only; must not beallowed toextravasate PEG-asparaginase nowprefened t0L-asparagtnase Phenobarbital increases metabolism, decreases a(tivity Aminoglycosides mayinoease nephrotoxicity ADH,antidiUreti(h0mone;ALL,acUte|ymph0b|a$ic|eukemia;AML,arutemye|ogenous|eukemia;(N5,centta|ner0U55y5tem;lM,intIamU5(U|ar;|V,inarn0Us;PqoIal BADIATION THERAPY Radiation therapy is used sparingly rn children, who are more susceptiblethan are adults ro rhe adversedelayedeffectsof innizing radiation. A major advance in pediatric radiation therapy has been the application of conformal irradiation to children with cancer.This technique,most commonly applied as intensitymodulated radiation therapy (IMRT), spares normal tissue by conforming the radiation volurne to the shape of the tumor, thereby enabling delivery of higher doses ro the rumors with lower exposure of normal tissueadlacentto the tumor or in the path of the radration beam. Another example is proton beam therapy, which has just begun to be more widely available for children with cancer. lfith more focused beams and better sedation and immobilization techniques, radiation therapy is becoming more frequently used in children. Acute adverse effects from radiation therapy are lessseverethan those from chemotherapy and depend on which part of the body is irradiated and the means of administration. Dermatitis is the most common general adverse effect. b e c a u s es k i n i s a l w a y s i n r h e r r e a r m e n rf i i l d . N a u s e aa n d d i a r - Ghapter4!14r Principlesof TreatmentI 2113 .-.**.* i Etoposide i Teniposide i Topotecan : lrinotecan \ Topoisomerasemediated StrandBreaks CMP -\ \ / 'v,/ \ dCMP / DNA - FreeRadical Damase Alkylation Replication dUMP De Novo Synthesis Salvage Pathway ./ Protein / Drug inhibitsthis step Tubulin ' Drug incorporatedinto i macromolecule Figurc 494-4. Site of action of the commonly usedanticancerdrugs. CMP, cytidine monophosphate;dCMP, deoxycytidinemonophosphate;dTMP, deoxythymidine monophosphate;dUMP, deoxyuridine monophosphate;FH. dihydrofolate; FHr, teirahydrofolate.(Redrawn from Balis FM' HolcenbergJS, Blaney SM: General principies of chemother^py. In Pirtn PA, ioplack DG [editorsi: Principles and Practice of Pediatic Oncology, 4'h ed. Philadelphia, Lippincott ITilliams & Wilkins, 2002, p 241..) rhea are common subacute adverse effects with abdominal radiation therapy. Mucositis nearly always occurs to some extent whenever oral or intestinal mucosa is in the treatment volume. Somnolenceis common with cranial irradiation. Alopecia occurs where hair is in the radiation port. Most radiation therapy schedulesrequire treatment 5 days/wk for 4-7 wk, depending on the dose needed to control the tumor and on the amount and nature of normal tissue in the field. Most adverse effects are not noted until the second half of the course of irradiation. Late effects may occur months to years after radiation therapy and usually are dose-limiting manifestations. The type of delayed toxicity also depends on the site of irradiation. Examples are impaired growth resulting from cranial or vertebral irradiation, endocrine dysfunction from midbrain irradiation, Dulmonary or cardiac insufficiency from chest irradiation, striciures and'adhesions from abdominal irradiation, and infertility from pelvic irradiation. CARE ANDSUPPORTIVE EFFECTS TOXIC ACUTE Adverse treatment effects that occur early in therapy include metabolic disorders, bone marrow suppression, and immunosuppression (Table 494-5). Patients with a large tumor burden -ry h"". had substantial breakdown of tumor cells, which,-in some cases,causesrenal function impairment, owing to tubular OTINFEOION SITE ETIOTOGY pneumonia, softtissue, bone manow Sepsis, shock, Chemotherapy, Neutropenia proctitis, mucosilis infrltration prednisone Pneum0nia, disseminated rneningitis, lymphopenia, Ihemotherapy, lmmunosuppres5ion, infe(tion viral dysfunft ion lymphoc4e-monoryte FAOOR PREDISPOSING 5plenectomy venous lndwelling central ratheter ofHodgkin disease Suging of Nutrition, administration chemotherapy Sepsis,shock, meningitis exitsite tra(t0fIunnel, Line sepsis, p 733 Saundets,2006, Philadelphia,WB HB,et al(edito6):/Ve/ion fJie,ltldb 0fPedilttks,Slhd Kliegman RM,Marcdante U,Jens0n From r Cancerand 2114r PARTXXI BenignTumors ONDII()H MANIFESTATIOI{S ETIOTOGY MATIGNANCY TNEATMENT METABOTIC Hyperuri(emia Hyperkalemia gout Uric acid nephropathy; Anhythmias, cardiac anest Tumor lysis syndrome Tumor lysis syndrome Lymphoma,leukemia Lymphoma, leukemia Tumor lysis syndrome Lymphoma, leukemia Allopurinol, alkalinize urine; hydration rasburicase anddiuresis, Kayexa glurose, late, sodium bicarbonale, andinsulin; check for pseudohyperkalemia fiomleukemic celllysis rntesttube Hydration, forced diuresis; stop alkalinization; oralaluminum hydroxide tobindphosphate Restrirt freewater forSIADH; replare sodium if depleted HyperphosphatemiaHypocalcemi( (alcifi tetany; metastati( cati0n, photophobia, pruritus Hyponatremia 5eizurg lethargy, asymptomatlc Hypercakemia HEMATOIOGI( Anemia .[hrombocytopenia polyuria, pan(reatitis, Anorexia, nausea, gastnc prolonged ukers; PR,shonened 0Tinterval Pallor, weaknes, heart failure Petechiae, hemorrhage Dhseminatedintravascular Shock,hemonhage coagulation Neutropenia lnfection 5IADH;fluid,sodium loses Leukemra, CNS tumor invomiting Bone resorption; ectopic Metastasis tobone, Hydration andfurosemide drures6; c0rtic0ster0ids; parathormone,vitamin D,or rnaD00my0sarcoma mrthramy(in; ckitonin, diph0sphonates prostaglandins Bone manow suppression or infiltntion; blood los Bone manow suppression or infihration 5epsis, hypotension, faoors tumor Anywithchemotherapy Packed redblood cellrransfusior Anywithchemotherapy Platelet transfusion Promyelocytic plasma; plateiets, leukemra, others Fresh frozen treatlnfection Bone marcw suppresion or Anywithchemotherapy lffebnlg administer broad*pectrum antibiotia, and infiltration ifappropriate G-[5F HyperleukocytosisHemorrhage,thrombosis;pulmonaryinfltrates, Leuko$asis; vascular occlusion Leukemia Leukapheresis; chemotherapy (>50000/mmr) hypoxia;tumor lysis syndrome Graft-versus-hostdhease Dermatitis,diarrhea,hepatitis lmmunosuppression andn0nirradiated Anywithimmunosuppression [orticosterords; rydosp0rine; gl0b|1lin antithym0cyte products; blood bone manow transplantation SPACE.{X(UPYII{G I,ESIOI{S + radicular Splnal cord pain compression Back Metastasis tovertebra and Neuroblastoma; medulloblastoma (ordobovell0: synnetic weaknest inrreased deep extramedullary (0l.ti(oster0ids; spa(e MRI ormyelography fordiagnosis; tendon reflex;sensory present;toes level up radiothenpy; laminectomy; chemothenpy (l 10-12): hnusnedulloris symmetric weaknes, increased knee refiexes; derreased ankle reflues; saddle xnsory los;toes upordown (below hudoequino L2)r asymmetric weakness; losofdeep reflex tendon andsensory defciq totsdown (onfusion,coma,emesis,headache,hypertension, Increasedintracranial (0rticoster0ids; Primary ormetastatir brain tumor Neuroblastoma, astrocytoma;(TorMRI fordiagnosis; pheni.toir; pressure papilledema, bradycardia, seizures, glioma \/entricul0stomy tube; radiotherapy; chemotherapy hydrocephalus;cranial nerve llland Vlpahies Superior venacava syndrome Distended plethora,edema ne(kveins ofhead Superior media$inal mas Lympn0ma propt0sis, andne(k,cyanosis, Homer syndr0me Tnchealcompression Respiratorydlstress Mediastinal mascompressing tra(hea Lympn0ma Chemotherapy; radlotherapy Radiation, corticosteroids FromKliegman RM,Marcdante |(i,Jenson H8,etal (edittots),Nehln Rsenti,ls 0fpedkfus,sthd, [N5,central nervous system;6-[5[granuloryte rolonyitimulating factor;5|ADH,syndmme ofinappropriate antidiuretk hormone se(retion precipitates of uric acid crystals. This effect occurs most often in patientswith leukemia and lymphoma (particularly Burkitt lymphoma) but also can occur in patients with large solid tumors (e.g.,hepatoblastoma,germ cell rumors, neuroblistoma). Before therapy is initiated, the serum levels of uric acid and creatinine Vrtually all chemotherapy regimens can produce myelosuppression, as can tumors that invade and repiace bone marrow. Anemia can be corrected by transfusions of packed erythrocytes, and thrombocvtopenia by platelet infusions. parients receiving immunosuppressivetherapy should receive irradiated blood of blood, urine, or any obvious sites of infection (see Chapter 177\.Treatment is conrinued until fever resolves and the granulocyte count rises. If fever persists for >1 wk while the patient is receiving broad-spectrum antibiorics, the possibility of fungal infection must be considered. Fungal infections caused bv Candida and Aspergillus are comm;n in immunosuppressed patients. Opportunistic organisms such as Pneumocystis carinii can produce fatal pneumonia. Prophylactic treatment with rrimethoprim-sulfamethoxazole is given when severe or prolonged immunosuppression is anticipated. Viruses of low pathogenicity can produce serious diseasein the setting of immunosuppression caused by malignancy or its trearment. Patients should not be given live virus vaccines. Children who are receiving chemotherapy and who are exposed to chickenpox should receive varicella-zosterimmunoglobulin and. if c l i n i c a ld i s e a s ed e v e l o p ss. h o u l db e h o s p i r a l i z e a d n d t r e a t e dw i t h lntravenous acyclovrr. Adequate pain management is critical. The World Health Organization (IfHO) guidelines are particularly useful in the management of pain associatedwith cancer and cancer therapy { s e eL n a D t e r / / } . It is common for patients undergoing cancer therapy to lose >70"/" of body weight. Patients sometimes reduce their food intake because of temporary, treatment-associated nausea, p 2115 a Principles of Treatment Chapter494 sfornatrtis,and vomitrng. Appetrte loss is not a cause for alarm. N'lalnutrition is a particular risk in patients receiving radiation therapv involving the abdomen or the head and neck, intensive chemotherapv, or total body irradiation and high-dose chenrorherapv bcfore marrow transplantation. If oral supplementatiorl proves inadequate,such patients may require enteral tube feedingsor parenteralhyperalimentation. I.fFETTS POTTIiTIAL A6tilTs 5YsTTM vedysfunction Cognit nervous lntrathecal [entral opathy chemotherapyLeukencepha systern (ardiac LATE EFFECTS ADVERSE Injurv tu rissues with low repair potential often results in l o n g - l a s t i n go r p e r m a n e n t d e f i c i t . F o r e x a m p l e , a b r a i n o r t a r e s i so r . l u t ( r s p r n a lt u m o r c a n l e a v et h e c h i l d w i t h a p e r m a n e n p nomic dvsfunctior-r, anthracycline-induced cardiomyopathv refractorycardiacd;-sfunction,and the leukoenusuallv prodr,rccs cephaloparhvcausedbv intrathecal nethotrexate and by central nervous systeln radiation therapy often is onlv partiall,v reversible.The potcntial types of late adverseeffectsdepend on the child's age at the time of treatment, the location(s) of the cancer,and the therapv administered.A good resource for the pediatrician,patient, ancl family who have to anticipatethc posipguidelines.org. sibi lities is available ar www. suruiu<';rsh I-ate adverseeffectsof therapy can cause substantialmorbid itv (Tables494-6 and 494-7). Successfulsurgical resectionmay result in loss of important functional structures.Irradiation can Hearing Pulmonary Uroogir rleparc Rena 6onadal sYsrtM nervous [entral synem GUIDEI"INES PoTtNTtArtFttos MONITORING growth monitorlng, ln(luding hormone Neuroendorrine Precoc ouspuberty, pituitary growth status other and andgonadal deficiency and hypothalamic dysfunctron Neurocognitive andpsychological Cognitive dysfunctron, (risk increases with Highdose in(reased dose) metn0trexate Anthracydines Iardiomyopathy Arrhythmias MONITORING GUIDETINES evaluation Neurorognitrve evaluation Neurologrc E[G, echotardiogram, Holter orcardiac stress dependent ondose, attime oftreatmenl age sympt0rlls,0l ra0rat0n exposure Audrology evaluatlon function tests Pulmonary loss Hearing Platinurns lungdisease Restfictr\/e Bleomycin Nitrosureas tystitis Urinalysis hemorrhagi( [hronic [ydophosphamide rancers bladder 5econd lfosfamlde funition tests Liver dysfunttion Hepatic Methotrexate ultrasound Doppler disease Venooi(lusive Thioguanine busulfan, l\,,lercaptopurine (Dactinomycin, thiogllanine) Da(tinomyrin Busulfan Urinalysis tnsufficiency Renal Platrnums fun(tion tests Renal orfailure Hghdose (learante wasting/ Ifeatinine electrolyte meth0trexate Renal insufficienry lfosfamide LH, F5H failure;early ngagents Ovarian Alkylat ortestosterone Estradrol men0pause Nttrosureas or cou|lselinq Reproductive failure; Leydig Testiculat evaluation endocrinology celldysfunction evaluatron Gynecologtc analysis 5perm Tanner staqing history lvlenstrual count [omplete blood agents: Leukemia Alkylating Second malignancies Mechlorethamine > Olne15 ll Topoisomerase inhibito6 Platintlms Transitionalbladdet Urinalysis fyclophosphamide carcln0ma tening leukenrephalopathy, second IN5 examrnation tum06(worsens within(reased Neurologic 00sel andophthalmic evaluatron myelrtis, blindness, Audrt0ry 5tr0ke, 0totoxici{y, peripheral Neurologi( examination neuropathy 0phthaimic examination 1485 Am2042,49 Eye [ataracts Ped,?tr lin Nafth therapy cancet [ateeffeos ofthildhood AT: DL,lMeadows From kiedman h0rm0ne I|-I,luteinizlng h0rm0ne; lacrimal duo,retina, f0Llicle-stlm!lating Cornea, F5H, eectro(ardi0gram, E[C, conjunctrva, sclera, op|cneuropathy or E[G, echocardrogram, Holter Iardiomyopathy [ardiac ondose, cardia( stress dependent Pencrditis damage, with svmptoms and funcageattimeottreatment,symptomsproduce irreversibie organ [oronary artery dhease iional limitations dependingon the organ involved and the sever0rantntatycltne exp0sure Valvular disease itv of the damage.Many radiation therapy-relatedproblems do fufrtion tests Puimonary Pulmonary fibrosis Pulmonary fLrn(tion te$s Thyroid Thyroid 0vert orcompensated hypothyroldhm not becomeobvious until the patient is fully grown, such as asymorcancer Thyroid nodules metrv betweenirradiated and nonirradiated areasor extremities. |lyperthyroidrsm Irradiation of fields that include endocrine organs can cause tH,F5H Ovar anfailure GonadaL hvpothyroidism, pituitary dysfunction, or infertility' .In sufficient ortestosterone Estradiol 0ligospermia/azospermla doses,cranial irradiation can produce neurologicdysfunctionand Reproductive counseling or Leydig relldysfunction endocrinology evaluation evaluation Gynecologic analysis 5perm Ianner staging history Men$rual physi(a] examinations [omplete Satcomas Secondmalignancies (NStumors annually paid inradiat 0n Attenti0n t00rgans Breast cancer field Melanoma hearing loss from cisplatin. Development of these sequelaemay forfemale Mammography toscreen skin cancer Non-melanoma be dose-relaredand usually is irreversible.Appropriate baseline breast cancer Thyroid cancet and intermittent testing should be performed before these drugs 0ther solid tumors are administeredto ensure that there is no pre-existingdamage functi0n f0r tests 0f0rgan within Anyorgan thefield0fradiatl0n R0utine Any to the organs likely to be affected and to permit moniroring of atrisk organs maydevelop dysfun(ion, ormaybe ofasecond atriskfordevelopment the adverseeffectsof treatment-inducedchanges. iancer Perhaosthe most seriouslate adverseeffect is the occurrence (linN1nhAn )402;49,p1484 effe(ts 0fchildh00d cn{e[the{apy.Pedldtr DL,lvl€adows AI:Late k0mFdedman (NS,central horm0ne;LH, uteinizinq h0rm0ne folide-stimulating sy(em, EIG,electrocardi0gram;F5H, nerv0us of secondcancersin patients successfullycured of a first malignancy. The risk appearsto be cumulative, increasingby about r Cancerand 2116I PARTXXI BenignTumor 0.5% per year, resulting in approximately a 1,2o/" incidence at 25 yr after treatment. Patients who have been treated for childhood cancer should be examined annually, with particular attention rc possible late adverse effects of therapy, including second malignancies. PATLIATIVE CARE At all stagesof caring for children with cancer,principles of palliative care should be applied to relieve pain and suffering and to provide comforr (see Chapter 40). Pain is a serious cause of suf- Bradlyn AS: Health-relatedquality of life in pediatriconcology:current status and future challenges.J Pediatr Oncol Nurs 2004:21.:137-140. Cardous-Ubbink MC, Heinen RC, Langeveld NE, et al: Long-term causespecific mortality among five-year survivors of childhood cancer.pediatr B lood Cancer 2004;42:5 63- 57 3. Dickerman JD: The late effects of childhood cancer theraDy. pediatrics 2007;l l9:554-568. Eshelman D, Landier W, Sweeney T, et al: Facilitating care for childhood cancer survivors: integrating children's oncology group long-term follow-up guidelines and health links in clinical practice. J pediatr Oncol Nurs 2004;27:271,-280. Fallon M, Hanks G, Cherny N: Principles of control of cancer pain. BMJ 2006;332:1022-1024. Harris MB: Palliative care in children with cancer: which child and when? ,f Natl Cancer Inst Monogr 2004i]21t144-149. Hoffer FA: Intervenrional radiology in pediarric oncology. Eur J Radiol 2 0 0 5 ; 5 3 : 3 - 13 . Hudson MM, Merrens AC, Yasui ! et al: Health status of adult long-term survivors of childhood cancer.JAMA 2003;290:1583-1592. Joensuu A: Sunitinib for imatinib-resisrantGIST. Lancet 2006i68:13031304. Juweid ME, Cheson BD: Positron-emissiontomography and assessment of cancer therapy. N Engl J Med 2006;354:496-507. Kelly KM: Complementary and alternative medical therapies for children with cancer.Eur J Cancer 2004i40:2041-2046. Krause DS, Van Etten RA: Tyrosine kinases as targets for cancer rherapy. N Engl J Med 2005;353:772-1.87. Lobo RA: Potential options for preservation of feniliry in women. N Engl J Med 2005353:54-73. Mack jwi Grier HE. The Day One Talk. J CIin Oncot 2004;22:563-566. Mocellin S, MandruzzatoS, Bronte V, et al: part 1: Vaccinesfor solid rumours. Lancet Oncol 200\5:681-689. Mocellin S, SemenzatoG, Mandruzzato S, et al: part II: Vaccinesfor haematological malignancydisorders.Lancet Oncol 2004;5:727-7 37. Nathan PC, Furlong W, Barr RD: Challengesto the measurementof healthrelated quality of life in children receiving cancer therapy. pediatr Blood Cancer 2004 ;43 :21.5-223. Oeffinger KC, Mertens AC, Sklar AC, et al: Chronic health conditions in adult survivors of childhood cancer.N Engl J Med 2006;355:1572-7582. Offit K, Sagi M, Hurley K: Preimplantarion genetic diagnosis for cancer syndromes.,/AMA 2006;296 :2727-27 30. Patenaude AF, Kupst MJ: Psychosocial functioning in pediatric cancer. ,f Pediatr Psychol 2005 ;30 :9-27 . Pollock BH, Knudson AG: Preventing cancer in adulthood: Advice for the pediatrician. ln Pizzo PA, Poplack DG (editors): principles and practice of Pediatric Oncology,5th ed. Philadelphia, Lippincott Williams & Wilkins, 2006;pp 1617-1628. Prasad D, Schiff D: Malignant spinal-cord compression. Lancet Oncol 2005;6:15-24. Pui CH, Relling MV Can the genotoxiciry of chemotherapy be predicted? Lancet 2004;364 :977-9 18. Reaman GH: Pediatric cancer research from past successesthrough collaboration to future transdisciplinary research. J Pediatr Oncol Nurs 2004;2L:1,23-1,27. Ross L, Johansen C, Dalton SO, et al: Psychiatric hospitalization among survivors of cancer in childhood or adolescence. N Engl J Med 2003;349:550-656. ShambergerRC, Jaksic T, Ziegler MM: General principles of surgery.In Pizzo PA, Poplack DG (editors): Principles and Practice of Pediatric Oncology, 5th ed. Philadelphia, Lippincott Williams & Vilkins, 2006; pp 405420. Sharma R, Tobin P, Clarke SJ:Managemenr of chemotherapy-inducednausea, vomiting, oral mucositis, and diarrhoea. Lancet Oncol 205:6:93-102. Spielberger R, Stiff P, Bensinger rV, et al: Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004;351: 2590-2598. Steward AF: Hypercalcemia associated with cancer. N Engl J Med 2005;352:373-378. Tarbefl NJ, Yock Kooy TH: General principles of radiation oncology. lnPizzo PA, Poplack DG (editors): Principles and Practice of Pediatric Oncology, 6th ed. Philadelphia, Lippincott Villiams & Wilkins, 2006; pp 421432. Uren A, Toretsky JA: Pediatric malignancies provide unique cancer rherapy targets. Curr Opin Pediatr 2005;17:14-19. The leukemias are the most common malignant neoplasms in childhood, accounting for about 4I'/" of all malignancies that occur in children <15 yr of age. In 2002, approximately 2,500 children <15 yr of age were diagnosed with leukemia in the USA, an annual incidence of 4.5 casesper 1.00,000children. Acute lymphoblastic leukemia (ALL) accounts for about 77"/o of cases of childhood leukemia, acute myelogenous leukemia (AML) for about 1,7o/o,chronic myelogenous leukemia (CML) for 2-3Yo, and juvenile chronic myelogenous leukemia (JCML) for l-2"/o. The remaining cases consist of a variety of acute and chronic leukemias that do not fit classicdefinitions for ALL, AML, CML, or JCML. The leukemias may be defined as a group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to an unregulated clonal proliferation of cells. The progeny of these cells have a growth advantage over normal cellular elements, because of their increased rate of proliferation, and a decreasedrate of spontaneous apoptosis. The result is a disruption of normal marrow function and, ultimatelS marrow failure. The clinical features, laboratory findings, ano responses ro therapy vary depending on the type of leukemia. PizzoPA and Poplack DG (editors): Principles and Proctice of Pediatric Oncology, 5th ed. Philadelphia, Lippincott l7illiams & Wilkins, 2005. 495.1. Acurr LyilrpHoeusnc LEUKEMTA Childhood ALL was the first disseminated cancer shown to be curable and consequently has representedthe model malignancy 495 r Theleukemiasr 2117 Ghapter for the principles of cancer diagnosis,prognosis,and treatment. It actually is a heterogeneous group of malignancies with a number of distinctive genetic abnormalities that result in varying clinical behaviorsand responsesto therapy. Approximatelv 2,000 children <15 yr of age arc EPfDEMI0L0GY. diagnosedwith ALL in the USA each year.It has a striking peak incidence between 2-6 yr of age and occurs more frequently in boys than in girls, at all ages.This peak age incidencewas apparent decadesago in white populations in advancedsocroeconomrc countries, but has since been confirmed in the black population of the USA as well. The diseaseis more common in children with certain chromosomal abnormalities, such as Down syndrome, Bloom syndrome! ataxia-telangiectasia, and Fanconi syndrome. Among identical rwins, the risk to the secondtwin if one develops leukemia is greaterthan that in the generalpopulation. The risk is >70% if the first twin is diagnosedduring the first year of life and the twins shared the same (monochorionic)placenta.If the first trvin develops Al.L by 5-7 yr of age, the risk to the second twin is at least twice that in the general population, regardlessof zvgositv. In virtually all cases,the etiology of ALL is unknown, ET|0L0GY. although severalgenericand environmentalfactors are associated with childhood leukemia (Table 495-1). Exposure to medical diagnostic radiation both in utero and in childhood has been associatedwith an increasedincidenceof ALL. In addition, published descriptionsand investigationsof geographic clusters of cases have raised concern rhat environmental factors may increasethe incidence of ALL. Thus far, no such factors other than radiation have been identified in the USA. In certain developing countries,therehas beenan associationbetweenB-cellALL and Epstein-Barrviral infections. PATH0GENESIS. The classificationof ALL dependson characterizing the malignant cells in the bone marrow to determine the morphology, phenotypic characteristicsas measured by cell membrane markers, and cytogenetic and molecular genetic features. Morphology alone usually is adequateto establisha diagnosis, but the other studiesare essentialfor diseaseclassification,which may have a major influence on both the prognosis and the choice of appropriate therapy. The most important distinguishing morphologic feature is the French-American-British (FAB) L3 subtvoe.which is evidenceof a mature B-cell leukemia. The L3 GENETIC CONDITIONS syndrome Down Fanroni syndrome Eloom syndrome Blackfan anemia Diamond syndrome 5rhwachman Klinefelter syndrome Turner syndrome type 1 Neurofi bromatosis Ataxia{elangiertasia combined immune defiriency Severe hemoglobrnuria Paroxysmal nocturnal syndrome Li-Fraumeni ENVIRONMENTAT FACTORS radiation lonizing Drugs Alkylating agents Nitrosourea Epipodophyllotoxin exposure Benzene Advanred maternal age PRT.BMATURIBl.CELt EAfiLYPRT-B,CDl01 PRO-B.CD1O124 156 39 635 75 50 85 s3 , Nopatieflts (%male) 19 Sex (years) Age 3l <1(%) 50 t-<10(96) 11 >10(%) < 100x l0'/t count Leuko(yte 38 lVledian 38 <701%) 44 >50(%) 77 < 100x Platelet count 10'q L(%) <8 gidL(70) Hemoglobin (%). Splenomqaly (90). liepatomegaly (70) Mediastlnal mass Lymphadenopathy (N5disease 58 50 56 0 35 10 16ll 82 11 80 14 64 33 62 31 33 75 11 75 42 77 53 69 21557 56 81 81 23 40 34 46 0 36 I 60 46 48 10 41 10 21 28 16 15 57 54 56 ol 72 78 11 nervous system [NS,cenlral *>4cmbelow the(o(almarqin (hildhaod, 6thedPhiladelnnd oflnfanty &lski's Henlt\l1gy GiNburg D,etal(edit06):Nlthln D6,0rkin 5H, From Narhan phia,W8saunde6,2ml,p.l139.DatafmmReite schrappel\il,LudwigWDetal:themotherapyin998uns patients. trialALlBFll 86.8/00d 0fthemulti(enter ultsandconrlusmns leilkemia a(ute lymphoblaslic h00d 1994;84:3122-3123 type, also known as Burkitt leukemia, is one of the most rapidly growing cancers in humans and requires a different therapeutic approach. Phenotypically surface markers show that about 85% ofia..r of ALL are derived from progenitors of B cells, about '15"h are derived from T cells, and about 1'"h are derived from B cells. A small percentage of children diagnosed with leukemia have a diseasecharacterizedby surface markers of both lymphoid and myeloid derivation. Immunophenotypes often correlate to diseasemanifestations (Table 495-2). Chromosomal abnormalities are found in most patients with ALL (Table 495-3,Ftg. 495-l). The abnormalities,which may be related to chromosomal number, translocations, or deletions, the concept that additional genetic modifications also are required for disease expression. Specific chromosomal findings, such as the t(9:22\ translocation, which expresses BCR-ABL fusion protein, suggest a need for additional, molecular genetic ONPROCN05IS ASNORMAtITY INFTUINCE DISEAST SUBTYPT CHROM05OMAT Favorable 4and10 Trisomy Pre-B ALL t(12;21 ) pre-B Unfavorable t(4;1 1) Unfavorable N0ne Favorable llnfavoable Favorable t(8;21 l\41AML ) Favorable inv{16) M4' Favorable t(5;17) M3unfavorable General del(7) Unfavorable t(4;11) Infant *Per (seeTable 495-4) leukemia 0fatule myelogenous datslfication theFrench-Ameritan-Blitish leukemia Al\4L,acute myel0genous leukemia; lymphoblastic ALL, acute Pre-B B<ell General General t\9,D) r(8;14) Hyperdiploidy Hypodiploidy r Cancerand 2118r PARTXXI EenignTumors Children Hypodiploidy <45 chromosomes Others 227" BCR-ABL t(9;22) 3% MLL rearrangements t ( 4 ; 1 ) , t ( 1; 19 ) , t(9;11) 8% HOXl1L2 5q35 25% LYL| 19p13 TALl 15% lp32 HOXll 10q24 E2A-PBXl MLL-ENL t(1;19) T-CellLineage 03% 5% B-CellLineage Hyperdiploidy >50 chromosomes 257" F'igure'19-5-1.Estimatedfrequencyof specificgenorypesof acute lymphoblastic leukemia (ALL) in children. The genetic lesrons that are exclusivelyseenin casesof T-cell-lineageleukemiasare indicated in purple. AII other geneticsubtypesare either exclusively or primarily seenin casesof B-cell-lineage ALL. (From Pui CH, Relling MV, Downing JR: Acute lymphoblasticleukemia.N EnglJ Med 2004;350:1535-1548.) TEL-AML1 t(12;21) 22T" MYC t(8;1a),t(2;8), t(8;22) 2% studies.The polvmerasechain reaction and fluorescencein situ hybridization techniques,for example, offer the ability to pinpoint molecular genetic abnormalities and ro detect small numbers of malignant cells during follow-up; however,the clinical utilit,v of these findings has yet to be firmly established.The developmentof DNA microanalysismakes it possibleto analyze the expressionof thousands of genesin rhe leukemic cell. This techniquepromisesto further enhancethe understandingof the fundamental biolog,v and to provide clues to the theiapeutic approach of ALL. The initial presentation of ALL latively brief. Anorexia, fatigue, and as is an intermittent, low-grade fever. Bone or, lessoften, joint pain, particularlv in the lower extremities, may be presenr.Patientsoften have a history of an upper pallor, fatigue, bruising, or episraxis,as well as fever,which may be causedbv infection. On physical examination, findings of pallor, listlessness,purpuric and petechial skin lesions,or mucous membrane hemor- 10 vr of age. The median leukocyte count at presenrarion is 33,000, although 75% ol patients have counrs <20,000; thrombocytopenia is seenin 75'/' of patienrs, and hepatosplenomegaly is seen in 3040%" of patients. In all types of leukemia, CNS symptoms are seen at presentation in 5o/" of patients (10-20% have blasts in the CSF). Testicular (20%) and ovarian (30"/") involvement occurs but does not require a biopsy. and thrombocytopenia are seen in most patienrs. Leukemic cells often are not observed in the peripheral blood in routine laboratory examinations. Many patients with ALL present with total leukocyte counts of <10,000/pL. In such cases,the leukemic cells often are reported initially to be atypical lymphocytes, and it is only on further evaluation that the cells are found to be part of a malignant clone. When the results of an analysis of peripheral blood suggestthe possibility of leukemia, a bone marrow examination should be done promptly to establish the diagnosis. Bone marrow aspiration alone usually is sufficient, but sometimes a bone marrow biopsy is needed to provide adequate tissue for study or to exclude other possible causesof bone marrow failure. ALL is diagnosed by a bone marrow evaluation that demonstrates >257o of the bone marrow cells as a homogeneous population of lymphoblasts. Staging of ALL is based partly on a cerebrospinal fluid (CSF) examination. If lymphoblasrs are found and the CSF leukocyte count is elevated,overt CNS or meningeal leukemia is present. This finding reflects a worse stage and indicates the need for additional CNS and systemic therapies. The staging lumbar puncture may be performed in conjunction with the first dose of intrathecal chemotherapy if the diagnosis of leukemia has been previously establishedfrom bone marrow evaluailon. DIFFEBENTIAIDIAGN0SIS. Acute lymphoblasticleukemia must be differentiated from acute myelogenous leukemia (AML). Other malignant diseases that invade the bone marrow and cause marrow failure include neuroblastoma, rhabdomyosarcoma, cyte count. Early pre-B-cellALL (CD10- or CALLAT) is the most common immunophenotype (see Table 495-2), with onset between 1- Chapter4{15r TheLeukemiasI 2119 100 (N=274) iSil .*or 15,2ooo-2005 90 S t u d i e s1 3 A , 1 3 8 ,a n d 1 4 , 1 9 9 1 - 1 9 9 9( N : 4 6 5 ) 8ao (! S t u d i e s1 1a n d 1 2 , 1 9 8 4 - 1 9 9 1( N : 5 4 6 ) :f 7 0 a or 60 E 5 ccu o uta Studies5 to 9, 1967-1979(N= 825) =en E"" (! € zo o- Studies1 to 4, 1962- 1966 (N= 90) 10 15 20 25 30 YearsafterDiagnosis 100 (N:274) .tror 15,2ooo-2005 !?il 90 8Bo chromosomal abnormalities such as t(9;221 or t(4;1'L), have an even higher risk of relapsedespite intensive therapy. Clinical trials have demonstrated that the prognosis for patients with a slower response to initial therapy may be improved by therapy that is moie intensive than the therapy considered necessaryfor patients who respond more rapidly. Most ihildren with ALL are treated on clinical trials conducted by national or international cooperative groups. In general, the initial therapy is designedto eradicate the leukemic cells from the bone marrow; this is known as remission induction. During this 13A, 138, and 14, 1991- 1999 (N:465) 8 1 + 2 S t u d i e s1 1a n d 1 2 , 1 9 8 4 - 1 9 9 1( N : 5 4 6 ) CE >70 74+2 z- S t u d y1 0 , 1 9 7 9 - 1 9 8 3( N : 4 2 8 ) f counts to near-normal levels after 4-5 wk of treatment' Intrathecal chemotherapy is usually given at the start of treatment and once more during induction. 260 g >5U 48+2 3oo 6 Studies5 to 9, 1967-1979(N=825) ltu Y a20 10 0 Studies1 to 4, 1962-1966(N:90) 051015202530354045 YearsafterDiagnosis Figure,{9-5-2.Kaplan-Meier survival(A) and overall analyses of event-free ALL. Thepatienrsparticsurvrval(B) in 2628childrenwith newlydiagnosed studiesconducted at St. JudeChildren'sResearch ipatedin 15 consecutive Hospitalfrom 1962-2005. The5-yearevent-free andoverallsurvivalestimates (+SE)areshown,exceptfor Study15,for whichpreliminary resultsat 4 years in clinicaloutcome areprovidedTheresultsdemonstrate steadyimprovement Thedifference in event-free andoverallsurvivalrates overrhepast4 decades. or second that relapses hasnarrowedin the morerecentperiods,suggesting therapyaremorerefractoryto treatcancers that occuraftercontemporary leukemia. ment (FromPui CH, EvanslWE:Treatment of acutelymphoblastic N EngLI Med 2006;354:166-1,78.) bone marrow examination. A high index of suspicion is required to differentiate ALL from infectious mononucleosis in patients with acute onset of fever and lymphadenopathy and from rheumatoid arthritis in patients with fever and ioint swelling. These presentationsalso may require bone marrow examination. TREATMENT. The single most important prognostic factor in ALL is the treatment: without effective therapy, the disease is fatal. The survival rates of children with ALL over the past 40 yr have improved as the results of clinical trials have improved the therapies and outcomes (Fig. 495-2). The choice of treatment of ALL is based on the estimated clinical risk of relapse in the patient, which varies widely among the subtypes of ALL. Three of the most important predictive factors are the age of the patient at the time of diagnosis,the initial leuko- features that predict a high risk of CNS relapse may receive irradiation to the brain and spinal cord' This includes those patients who, at the time of diagnosis, have lymphoblasts in the CSF and either an elevated CSF leukocyte count or physical signs of CNS leukemia, such as cranial nerve palsy. After remission has been induced' many regimens provide lasts for 2-3 yr, depending on the protocol used. Many patients benefit from administration of a delayed intensive phase of treatment (delayed intensification), approximately 5-7 mo after the beginning of therapn and after a relatively nontoxic phase of (interim maintenance) to allow recovery from the t..rt-.tri initial intensive therapy. A small number of patients with particularly poor prognostic features,principally those with the t(9;221 translocation known as the Philadelphia chromosome, may undergo bone marrow transplantation during the first remission' In ALL, this chromosome is similar but not identical to the Philadelphia chromosome of chronic myelogenous leukemia (seeChapter 56). 2120I PARTXXI r CancerandBenignTumors The major impediment to a successfuloutcome is relapse of the disease.Relapse occurs in the bone marrow in t5-26"/" of serum uric acid can be prevented with the use of urate oxidase. Chemotherapy often produces severe myelosuppression, which may require erythrocyte and platelet transfusion and which always requires a high index of suspicion and aggressiveempirical antimicrobial rherapy for sepsis in febrile children with neutropenia. Patients must receive prophylactic treatment for Pneumocystis carinii pneumonia during chemotherapy and for several months after completing treatment. The successof therapy has changed ALL from an acute disease with a high mortality rate to a chronic disease.However, such chronic treatment can incur substantial academic, developmental, and psychosocial cosrs for children with ALL and considerable financial costs and stress for their families. Becauseof the intensity of therapy, long-term and acute toxicity effects may occur. An array of cancer care professionals with training and experience in addressing the myriad of problems that may arise is essentialto minimize the complications and achieve an optimal outcome. tained in leukemic cells. MRD can be quantitative and can provide an estimate of the burden of leukemic cells present in the marrow. Although it is not known how much MRD can be eliminated by the patient's immune host defensemechanisms, an elevated degree of MRD present at the end of induction suggests a poor prognosis and a strong possibility of relapse. Balduzzi A, Valsecchi MG, Uderzo C, et al: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in 6rst complete remission: Comparison by genetic randomization in an international prospective study. Lancet 2005;366:63 5-642. Carroll WL, Bholwani D, Min DJ, et al: Pediatric acute lymphoblastic leukemia. Hematology Am SocHematol Educ Program 2003:102-131. Claudio J, Rocha C, Cheng C, et al: Pharmacogenericsof outcome in children with acute lymphoblasticleukemia.B lood 2005;105 :475247 58. Hijiya N, Hudson MM, Lensing S, et al: Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JA M A 2 0 0 7; 2 9 7: 1 2 0 7- l 2 l 5 . Holleman A, Cheok MH, den Boer ML, et al: Gene-expressionpatterns in drug-resistant acute lymphoblastic leukemia cells and responseto trearment. N Engl J Med2004;351:533-542. Kadan-Lottick NS, Ness KK, Bhatia S, et al: Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA 2003290:2008-2014. Murray MJ, Tang I Ryder C, et al: Childhood leukaemia masquerading as juvenile idiopathic arthritis. BMJ 2004;329:9 59-961. Pui CH, Cheng C, Leung W, et al: Extendedfollow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl I Med 2003i349:540-648. 1078: Pui CH, Evans Treatment of acute lymphoblastic leukemia. N Engl I Med 2005;354:166-178. Pui CH, Relling MV, Downing JR: Acute lymphoblastic leukemia. N Engl J Med 200\350:1535-l548 Ravindranath Y Down syndrome and leukemia: New insights into the epidemiology, pathogenesis, and treatment. Pediatric Blood dy Cancer 2005;44:1-7. SahaV Simplifying treatmenr for children with ALL. Lancet 2007;359:82-83. Stanulla M, SchaeffelerE, Flohr T, et al: Thiopurine methyltransferase(TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblasticleukemia.JAMA 2005;293:7485-1489. Stanulla M, Schiinemann HJ: Thioguanine versus mercaptopurine in childhood ALL. Lancet 2006;368:1304-1306. l7inick NJ, Carroll $7L, Hunger SP: Childhood leukemia-new advancesand challenges.N Engl J Med 2004;351:601-604. 495.2o AcurEMvelocrr'rous LEUKEMIA EPfDEM|OI0GY.AML accounrs for 71Y" of the casesof childhood leukemia in the USA, with approximately 370 children diagnosed with AML annually. One subtype, acute promyelocytic leukemia (APL), is more common in certain other regions of the world, but incidence of the other types is generally uniform. Several chromosomal abnormalities associatedwith AML have been identified, but no predisposing generic or environmental factors can be Fanconi anemia, Bloom syndrome, Kostmann syndrome, Shwachman-Diamond syndrome, Diamond-Blackfan syndrome, Li-Fraumeni syndrome, and neurofibromatosis type 1. or t(4;11)], portend a poorer outcome. More favorable characteristics include a rapid response to therapy, hyperdiploidS trisomy of specific chromosomes, and rearrangemints bf the TEL/AMLI genes. Minimal residual disease(MRD) can be detected with specific molecular probes to translocations and other DNA markeri con- H0GENESIS.The characteristic feature of AML is that >307o of bone marrow cells on bone marrow aspiration or biopsy touch preparations constitute a fairly homogeneouspopulation of blast cells, with features similar to those that characterize early differentiation statesof the myeloid-monocyte-megakaryocyteseriesof Chapter495 I TheLeukemias. 2721 blood cells. The most common classification of the subtypes of AML is the FAB system (Table 495-41. Although this system is based on morphologic criteria alone, current practice also reouires the use of flow cvtometrv for identification of cell surface u.riig.n, and of chromoiomal and molecular genetic techniques for additional diagnostic precision and also to aid the choice of tnerapy. The Droduction of symptoms and CIINICALMANIFESTATI0NS. signsof AML. as in ALL, is due to replacementof-bone marrow by malignant cells and to secondary bone marrow failure. Thus, patients with AML may present with any or all of the findings associatedwith marrow failure in ALL. In addition, patients with AML present with signs and symptoms that are uncommon in ALL, including subcutaneous nodules or "blueberry muffin" lesions, infiltration of the gingiva, signs and laboratory findings of disseminatedintravascular coagulation (especiallyindicative of acute promyelocytic leukemia), and discrete masses,known as chloromas or granulocytic sarcomas.These massesmay occur in the absenceof apparent bone marrow involvement and typically are associatedwith the M2 subcategoryof AML with a t(8;21) translocation. Chloromas also may be seen in the orbit and epidural space. CNS symptoms are more common in AML than ALL. Analysisof bone marrow aspirationand biopsy specDIAGN0SIS. imens of patients with AML typically reveals the features of a hypercellular marrow consisting of a rather monotonous pattern of cells with features that permit FAB subclassificationof disease. Specialstains assistin identification of myeloperoxidase-containing cells, thus confirming both the myelogenous origin of the leukemia and the diagnosis. Some chromosomal abnormalities and molecular genetic markers are characteristic of specific subtypes of disease(seeTable 495-21. Aggressivemultiagent chemotherapy is successfulin TREATMENT. inducing remission in about 80% of patients. Targeting therapy to geneticmarkers may be beneficial(Table 495-5). Up to 10% of patients die of either infection or bleeding before a remission can be achieved. Matched-sibling bone marrow or stem cell transplantation after remission has been shown to achieve longterm disease-free survival in 60-707' of patients. Continued chemotherapy for patients who do not have a matched donor is less effective than marrow transplantation but, nevertheless,is curative in some patients. Matched, unrelated marrow or stem cell transplants may be effective therapy but have the risk of significant graft-versus-host disease as well as the complications associatedwith intensive myeloablative therapy. One factor that favors allogeneic transplantation is that graft-versus-leukemia effect is known to occur in AML, whereas it has been difficult to demonsrrate that this immunologic antileukemic process occurs when patients with ALL undergo allogeneic hematopoietic stem cell transplantation. AENORMATITY CHROMOSOMAT t(8;21 ) inv(16), t(16;16) t(15;1/) t ( 11 ; 1 7 ) 11q23 abnormalities t(3;v) r(jJ) del(7q),-7 del(5q),-5 GENIS AI.TERED AMLI-EtA CBTB-MYHII PML-RARA PLZ|-RARA Mll rearrangements tvtl NPM-MLI Unknown Unknown 5UBTYPE tvtl i\,42 M3 M4 M5 [46 tv17 Acute Acute A(ute leukemia myelomonocytk Acute monocytic leukemia Acute Erythroleukemia leukemia megakaryocytic Acute Acute promyelocytic leukemia, characterized by a gene rearrangement involving the retinoic acid receptor, is very responstve to ritinoic acid combined with anthracyclines.The successof this therapy makes marrow transplantation in first remission unnecessary for patients with this disease. The supportive care needs of patients with AML are basically rhe same as those for patients with ALL. The very intensive therapy required in AML produces prolonged bone marrow supptession with a very high incidence of serious infections. w.Fgr@@.@fiw Clark JJ, Smith FO, Arceci RJ: Update in childhood acute myeloid leukemia: Recentdevelopmentsin the molecular basisof diseaseand novel therapies' Curr Opin Hematol 2003;10:31-39. Cushing! ClericuzioC, Wilson C, et al: Risk for leukemia in infants without Down syndromewho have transientmyeloproliferativedisorder.I Pediatr 2006;748:687-689. Kantarjian H, Giles F, lVunderle L, et al: Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positiveALI-. N Engl J Med 2006;354:2542-2550 ' Kolb EA, Pan Q, Ladanyi M, et al: Imatinib mesylatein Philadelphiachromosome-positiveleukemia of childhood. Cancet 2003;98:2643-2650' Linabery AM, Olshat AF, Gamis AS, et al: Exposureto medicaltest irradiation and acute leukemia among children with Down Syndrome:A report from the children'soncology grotp. Pediatrics2006i18:e1499-e1508. Pui CH, Relling MV, Downing JR: Acute lymphoblasticleukemia.N Engl J Med 2004;350:1535-1548. Ross ME, Mahfouz R, Onciu M et al: Gene expressionprofiling of pediatric acute myelogenousleukemia.Blood 2004;104:3679-3687' Talpaz M, Shah NP, Kantarjian H, et al: Dasatinib in imatinib-resistant lhiladelphia chromosome-positiveleukemias. N Engl J Med 2006;354: 2531.-2540 'Woods \VG, Barnard DR, Alonzo TA, er al: Prospectivestudy of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome.J Clin Oncol 2002120:434440. r07irodsI7G, Neudorf S, Gold S, et al: A comparison of allogeneicbone marrow transplantation, autologous bone marrow transplantation, and chemotherapyin children with acutemyeloid leukemiain remisaggressive sion. B lood 2001;97:56-62. USUAT MORPHOTOGY PR06N05rS AML-M2 FAB FAB AML-M4Eo FAB AML-I\4] FAB Ai,ilL-M3 Favorable Favorable Favorable Favorable Unfavorable Unfavorable Unfavorable Unfavorable Unfavorable orAl'4L-l\45 FAB AlilL-M4 MDYAML MDYA[.45 I\.4DYFAB Al\41-M0 I\IDYFABAML-M0 1177 5aundert200l,p ondChildhoo4 6thedPhiladelphla,WB Henotalogy aflnfancy 5H,Ginsburg D,etal(edir06) .Nothon and}ski's Fr0m Nathan DG,0rkin iytarabine htgh-dose induding Intensive chemotherapy, cytarabine high-dose including chemotherapy, lntensive andanthra(ydines ATRA intluding chemothetapy, Intensive andanthrarydines induding ATRA chemotherapy, Intensive (ytarabine andMRDHSiT high-dose lntensive chemotherapy,with H5[T with0rwithout chem0therapy Intensive HSCT with0rwithout chemotherapy Intensive HSIT with0rwithout chemotherapy Intensive HS[T withorwithout chemothetapy Intensive 2122I PARTXXI I CancerandBenignTumors o DowNSvruononar 495.3 AND AcurELrurrnan ANDMYETOPBOLIFERATION tivity to methotrexate and other antimetabolites, which can result in substantial toxicity if standard doses are administered. In AML, however, patients with Down syndrome have much better outcomes, with a >80%o long-term survival rate, than do children who do not have Down syndrome. After induction therapy, these patients require less intensive therapy to achieve better results. tion, although characteristicof CML, also is found in a small percentage of patients with ALL or AML. Imatinib mesylate, an agent designed specifically to inhibit the BCR-ABL tyrosine kinase, has been used in adults and has shown an ability to produce major cytogeneticsresponsesin over 70To of patients (seeTable 494-7). Limited experiencein children suggests it can be used safely with results comparable to those seen in adults. ri7hile waiting for a responsewith imatinib, disabling or threatening signs and symptoms of CML can be controlled 495.5o JuvENr[E Cnnorurc Myerocrnous LEUKEMTA leukemia(JCML), also known as Juvenilechronic myelogenous patients may be trisomy 21, suggestinga mosaic state. 495.4o CHRoNtc Mvnocrruous LEUKEMTA CML is a clonal disorder of the hematopoietic tissue that accounts for 2-37" of all cases of childhood leukemia. About numbers of immature granulocytes. The spleen often is greatly enlarged, often resulting in pain in the left upper quadrant"of the abdomen. In addition ro leukocytosis, blood counts may reveal mild anemia and thrombocyrosrs. Typically, the chronic phase terminates 3-4 yr after onset, when the CML moves into the acceleratedor ..blast crisis" phase. At this..point, the blood counts rise dramatically and cannot be controlled with drugs such as hydroxyurea. Additional manifestatrons may occut including hyperuricemia and neurologic symptoms, which are related to increased blood viscosiqy with decreasedCNS perfusion. The presenting symptoms of CML are nonspecific and may . include fever, fatigue, weight loss, and anorexii. Splenomegaly also .may be present. The diagnosis is suggested by increised numbers of myeloid cells with differentiation to mature forms in the peripheral blood and bone marrow and is confirmed by cytogenetic studies that demonstrate the presenceof the characteristic Philadelphia chromosome. Molicular techniques usuallv demonstrate the BCR-ABL gene rearrangement. This transloca- classicCML. 495.6o INFANT LrurrmrR About 27" of cases of leukemia durine childhood occur before the age ollyr.In contrasr to older children, the ratio of ALL to AML is 2 : 1. Some casesmay be due to maternal exposure to naturally occurring DNA topoisomeraseII inhibitors. Severalunique biologic features and a particularly poor prognosis are charicteristic of ALL during infancy. More rhan two thirds of the cases demonstrate rearrangementsof the MLL gene, found at the site of the 11q23 band translocation; rhis subset of patients largely accounts for the very high relapse rate. These patients often present with hyperleukocytosis and extensive tissue infiltration producing organomegaly, including CNS disease.Subcutaneous nodules, known as leukemia cutis, and tachypnea due to diffuse pulmonary infiltration by leukemic cells are observed more often in infants than in older children. The leukemic cell morphology is usually that of large irregular lymphoblasts (FAB L2), with a phenotype negative for the CD10 (cALLa) marker. Very intensive chemotherapy programs including stem cell transplantation are being explored in infants with rearrangemenr of _MLL in band 11q23, but none has yet proved satisfictory. Infants with leukemia who lack the 1,'1,q23 rearranqemenrshave a prognosis similar to rhat of older children with Rt-L. Infants with AML often present with CNS or skin involvement and have Chapter 496 . . Lymphoma 2123 degrees of fibrosis and the presence of collagen bands, necrosis, Bajwa RPS, Skinner R, W~ndebankKP, et al: Demographic study of leukaemia presenting within the first 3 months of life in the Northern Health Region of England. J Clzn Path01 2004;57:186-188. ;hapter498 Lymphma Mitchell S. Carire and M. Biiidd&adley Lymphoma is the third most common cancer among children in the USA, with an annual incidence of 1 5 per million children 214 yr of age. The two broad categories of lymphoma, Hodgkin disease ( H D ) and non-Hodgkin lymphoma (NHL), have different clinical manifestations and treatments. H D is a malignant process of the lymphoreticular system that constitutes 6% of childhood cancers. In the USA, H D accounts for about 5% of cancers in persons 1 1 4 yr of age and for about 1 5 % in persons 15-19 yr of age. It is rare in children < I 0 yr of age. EPIDEMIOLOGY. The incidence of H D is bimodal with regard to age. In industrialized countries, the early peak occurs in the middle to late 20s, with a second peak after 5 0 yr of age. In developing countries, the early peak occurs before adolescence. A male : female predominance is found among young children, with a ratio of 4 : 1 for children 3-7 yr of age, 3 : 1 for children 7-9 yr of age, and 1.3: 1 for children >10 yr of age. Clustering of cases in families or races may suggest a genetic predisposition to the disease or a common exposure to an etiologic agent. The risk is 100-fold for an unaffected monozygotic twin of an affected twin; there is no increased risk for dizygotic twins. Studies of families suggest an increased association of H D with specific HLA antigens. Several studies suggest that infectious agents may be involved, such as human herpesvirus 6, cytomegalovirus, and Epstein-Barr virus (EBV). The role of EBV is supported by prospective serologic studies. The large proportion of patients with H D who have high EBV antibody titers suggests that enhanced activation of EBV may precede the development of HD, a possibility that also is supported by in situ hybridization evidence of the EBV genomes in Reed-Sternberg cells. EBV antigens have been demonstrated in H D tissues, although EBV status is not prognostic of outcome. HD may represent a common result of multiple pathologic processes that include viral infection and exposure of a genetically susceptible host to a sensitizing agent. Pre-existing immunodeficiency, either congenital, such as ataxiatelangiectasia, or acquired, such as HIV infection, increases the risk of HD. ETIOLOGY. The Reed-Sternberg cell (Fig. 496-1E) is a large cell (15-45 Fm in diameter) with multiple or multilobulated nuclei. This cell type is considered the hallmark of HD, although similar cells are seen in infectious mononucleosis, NHL, and other conditions. The Reed-Sternberg cell is clonal in origin and arises from the germinal center B cells. H D is characterized by a variable number of Reed-Sternberg cells surrounded by an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils in different proportions, depending on the H D histologic subtype. Other features that distinguish the histologic subtypes include various or malignant reticular cells. The Rye classification system (Table 496- t ) defines four major histologic subtypes: lymphocyte predominant (LP)(see Fig. 4961A and B), nodular sclerosing (NS) (see Fig. 496-lC),mixed cellularity (MC) (see Fig. 496-ID), and lymphocyte depleted (LD). LP affects 10-15% of patients, is more common among male and younger patients, and usually presents as localized disease. MC is observed in 3 0 % of patients, is more common among children 510 yr of age, and often presents as advanced disease with extranodal extension. LD is rare in children but is common in patients with HIV infection patients. NS is the most common subtype, affecting 4 0 % of younger patients and 70% of adolescents with HD. The Revised European-American Classification of Lymphoid Neoplasms (REAL) classification system (see Table 496-1) includes two modifications of the older Rye system. In addition to classical HD, it defines lymphocyte predominance (LPHD] but also anaplastic large cell lymphoma Hadgkin-like. The lymphocyte predominance subtype closely resembles a low-grade B-cell lyn~phornain clinical behavior and Reed-Sternberg cell phenotype. Most patients with LPI-lD present with early disease and have an excellent prognosis. Anaplastic large cell lympl~oma Hodgkin-like has a poor response to conventional HD chemotherapy and has been reported to respond better to aggressive NHL therapy regimens. HD appears to arise in lylnphoid tissue and spreads to adjacent lymph node areas in a relatively orderly fashion. Hematogenous spread also occurs, leading to involvement of the liver, spleen, bone, bone marrow, or brain, and usually is associated with systemic symptoms. Levels of various cytokines have been shown to be elevated in patient sera or are produced by cultured cell lines or HD tissue. They may be responsihle for the systemic symptoms of fever and night sweats (interleukin-1 or -2) and weight loss (tissue necrosis factor ITNFl), in addition to influencing the proliferation of ReedSternberg cells and inducing immunosuppression (transforming growth fac~or-p).Various degrees of cellular immune impairment can be identified in most newly diagnosed rases of HD. The severity of the immune defect varies with rhe extent of disease and persisrs even after successful curative therapy. Whether it predisposes to the disease or results from it is unknown. CLINICAL MANIFESWONS. Patients commonly present with pa~nless,non-tender, firm, rubbery, cervical or supraclavicular lymphadenopathy. Affected lymph nodes are firmer than inflammatory nodes. Most patients present with some degree of mediastinal involvement. Clinically detectable hepatosplcnomegaly rarely is encountered. Depending on the extent and location of nodal and extranodal disease, patients m a p present with symptoms and signs of airway obstruction (dyspnea, hypoxia, cough), pleural or pericardial effusion, hepatocelluiar dysfunction, or 2124I PARTXXI r Gancerand BenignTumors Figwe 496-1. Histological subtypes of Hodgkin lymphoma. A, Hematoxylin and eosin stains of lymphocyte-predominant Hodgkin lymphoma (NLPHL) demonstrating a nodular proliferation with a motheaten appearance. B, High-power view demonstrating the neoplastic L and H cells found in NLPHL. C, Classic Hodgkin lymphoma, nodular sclerosis subtype. Large mononuclear and binucleate ReedSternberg cells are seen admixed in the inflammatory cell background. D, Classic Hodgkin lymphoma, mixed cellularity subtype, demonstrating increased numbers of ReedSternberg cells in a mixed inflammatory background without sclerotic changes. E, HigFpower view of a classic Reed-Sternbergcell showing binucleate cells with promr nent eosinophilic nucleoli and relatively abundant cltoplasm. S._ Any parient with persistent,unexplained lymathy unassociatedwith an obvious unde;lying inflammatory or infectious processshould have a chest radiograph to identify the presenceof a mediastinal mass before undergoing node biopsy(Fig.496-2).Unlesssignsor symptomsdictateotherwise, additional laboratory studiescan be delayeduntil the biopsy results are available. Patientswith persistentlyenlarged lymph nodes,evenafter serologicallyproven infectiousmono;ucleosis,also should be consideredfor biopsy.Formal excisional biopsy is preferredover needlebiopsy to ensurethat adequate tissueis obtained, both for light microscopyand for appropriate immunocytochemicaland molecularstudies,culture, and cytogenetic analysisif routine studiesfail to provide a firm diagnoJis. HD rarely is diagnosedwith certaintyon frozensecion. Ideally a portion of the biopsy specimenshould be frozen and stored to allow for additionalstudies.Once the diagnosisof HD is established,extent of disease(stage)should be determinedto select appropriate therapy (TabIe 496-2). Evaluation includes history, physicalexamination,and imagingstudies,includingchestradi- I 2125 496 I Lymphoma Chapter fiigure .19(r-2.A, Anterior mediastinal massin a patient with Hodgkin disease before therapy. B, After 2 mo of chemotherapy, rhe mediastinal mass has disappeared ograph; CT scansof the chest, abdomen and pelvis; gallium scan; and positron emission tomography (PET) scan. Laboratory studies include a complete blood cell counr (CBC) to identify abnormalities that might suggest marrow involvement, eryrhrocyte sedimentation rate (ESR), and serum copper and serum ferritin levels, which are of some prognostic significance and, if abnormal at diagnosis, serve as a baselineto evaluate the effects of treatment. Liver function tests, although not particularly sensitive to the presence of liver involvement, can influence treatment and treatment complications. A chest radiograph is particularly important for measuring the size of the mediastinal mass in relation to the maximal diameter of the thorax. Chest CT more clearly definesthe extent of a mediastinal mass if present and identifieshilar nodes and pulmonary parenchymal involvement, which may not be evident on chesr radiographs. Abdominal CT or MRI can identify gross subdiaphragmatic involvement of nodes and enlargement and defects in the liver and spleen. Bone marrow aspiration and biopsy should be performid in patients with advanced disease (stage III or IV) or B symptoms (fever, weight loss, night sweats). Bone scans are performed in patients with bone pain and/or elevated alkaline phosphatase. Lymphangiograms, used in the past to evaluate involvement of the abdominal lymph nodes, rarely are used today. More falsepositives occur in children than in adults, and the studies are technrcally difficult to perform. Gallium-67 scan is parricularly helpful in identifying aieas of increased uprake, whiih can then be re-evaluatedat the end of treatment, especiallyin patienrs with mediastinal massesthat do not resolve completely on chest radiographs or CT. Fluorodeoxyglucose (FDG)-PET has advantages STAGE DEfINITION (1)orofasingle Involvement ofasingle lymph node extralymphatl( organ 0rsite(lJ (ll)or Involvement oftwoormore lymph node regions onthesame side ofthediaphragm localDed involvement ofanextralymphatir organ orsiteandoneormore lymph node (llr) regions onthesame side ofthediaphragm (lll), lll lnvolvement oflymph node regions onbothsides ofthediaphragm which maybe (lils) aaompanied byinvolvement ofthespleen orbylocalized involvement ofan extralymphatic organ 0rsite(llli)orboth(lllse) lV Diffuse ordisseminated involvement ofoneormore extralymphatic organs orthsues wrthor without associated lymph node involvement The absence orpresence offever>38T forI consecutive days,drenching night sweats,or urexplained loss ofbody 0f210% preceding inthe6month5 welght admission aret0beden0ted inallcases bythesuffix letteb A0r8,resFitively. From ListerTA,trowiher 58,etal:Report 0fa(ommiftee r0nvened t0discus theevaluation andstaging ofpatients Dsut(liffe wirhHodgklns disease: [0tswolds meeting / fiir0n@l 1989,7.1630-1636 I ll over gallium-67 scanning becausethe scan is a 1-day procedure with higher resolution, better dosimetry, and less intestinal activity and has a quantitation potential. However, its false-positiveand false-negativerates are still under investigation in childhood HD. When standard-doseradiation therapy was an acceptabletreatment strategy for patients with early-stage HD, exploratory laparotomy with splenectomy was performed to determine the presenceand extent of abdominal involvement. There is no longer lny role for surgical staging laparotomies in the treatment of pediatric HD patients. The staging classification currently used for HD was adopted at the Ann Arbor Conference in 1'971,and was revisedin 1.989(seeTable 496-21. HD can be subclassified into A or B categories:A is used to identify asymptomatic patients and B is for patients who exhibit any B symptoms. Extralymphatic disease resulting from direct extension of an involved lymph node region is designated by category E. A complete response in HD is defined as the complete resolution of disease on clinical examination and imaging studies or at least 70-80% reduction of diseaseand a change from initial positivity to negativity on either gallium or PET scanning becauseresidual fibrosls ln common. Chemotherapy and radiation therapy are effective in TBEATMENT. the treatment of HD. Current treatment of HD in pediatric patients involves the use of combined chemotherapy with or without low-dose involved field radiation therapy. Treatment is determined largely by disease stage, age at diagnosis, presence or absence of B symptoms, and the presence of hilar lymphadenopathy or bulky nodal disease.Radiation therapy alone, ar standard doses of 3,500-4,000 cGy, initially was used and resulted in prolonged remission and cure rates of 40-95% in patients with surgically low-staged HD. This treatment approach, however, resulted in significant long-term morbidity in pediatric patients, including growth retardation, thyroid dysfunction, and cardiac and pulmonary toxicity. The MOPP regimen (mechlorethamine Initrogen mustard], vincristine, procarbazine, and prednisone) introduced in 1964 was the first combination chemotherapy regimen used in the treatment of HD and was a major milestone in the treatment of advanced stage HD. It resulted in a complete responserate of 70-80% and cure rate of 40-50% at I0 yr in patients with advanced stage disease.This regimen also resulted, however, in significant acute and long-term toxicity. The desire to reduce side effects has stimulated attempts ro reduce the intensity of chemotherapy and radiation dose and volume. Chemotherapy agents commonly used to treat children and adolescents with HD include cyclophosphamide, procarbazine, 2126I PARTXXI I CancerandBenignTumors alone or combined modality therapy have the best prognosis and usually respond to additional standard therapS resulting in a long-term survival of 60-70%. A myeloablative autologous stem (ORRESPOIIt)IIIG CHTMOTHERAPY RE6IMENS AGENTS cell transplant in patients with refractory diseaseor relapsewithin (Adrramycin), ABVD D0x0rubicin bleomyrin, vinblastine, dacarbazine L2 mo ol therapy results in a long-term survival rate of 40-50%. (DBVD (Adriamyt ABVE Doxorubicin in),beomycin, vin(ristine, et0p0side Long-term complications are related to radiation or chemother(Adridmycin), VAMP prednisone Vin(ristine, d0x0rubicin methotrexate, apy; these include secondarymalignancy (e.g.,acute myelogenous (females) Vincristine (0nrovin), (Adriamycin), prednisone, procarbazine,doxorubicin 0PPA t t0PP leukemia, breast,lung, thyroid, non-Hodgkin lymphoma), sepsis (0n(0vin), prednis0ne, procarbazine vincristine rydophosphamide, (e.g., splenectomy or splenic irradiation), sterility, short stature, + (0PP (males) (0n(0vin), (Adriamycin), 0EPA prednisong Vincristine etoposide, doxorubicin hypothyroidism, dental caries, subclinical pulmonary dysfunc(0ncovin), prednisone, prorarbazine rydophosphamidg vincristine (0n(0vin), iOPP/ABV prednisone, procarbazine, tion, and ischemic heart disease. [ydophosphamide, vincristine (advanced BEAt0PP stage) COPP THOP (D8VE.P() AEVE-P( (Adriamycin), doxorubicin vinblastine bleomycin, (Adriamycin), Eleomycin, etoposide,doxorubicin cydophosphamide, (0ncovin), prednisone, prorarbazine vinarstine (0n(0vin), prednisone, prorarbazine [ydophosphamide, vincristine (0ncovrn), (Adriamycrn), [ydophosphamide, doxorubuin vrncristrne prednisone (Adriamycin), prednisone, D0x0rubkin bleomycin,vin(ristine, etoposide, cydophosphamide vincristine or vinblastine, prednisone or dexamethasone,doxorubicin, bleomycin, dacarbazine,etoposide,methotrexate,and cytosine arabir-roside. The combination chemotherapy regimens ir.rcnrrent use are basedon COPP (cyclophosphamide, vincristine IOncovinl, procarbazine, and prednisone) or ABVD (doxorubicin lAdriamvcin], bleomycin, vinblastine, and dacarbazine), with BEACOPP (bleomycin,etoposide,doxorubicin, cyclophosphanride,vincrisrine,procarbazine,prednisone)typically usedfor patients with advanced stage disease(Table 495-3). Different combination regimens to reduce potential toxicities have been developed.The COPP/ABV (cyclophosphamide,vincrisrine,procarbazine, prednisone/doxorubicin,bleomycin and vinblastine) regimen is an example. Originally, a minimum of six cycles of chemotherapy was given, with significant cumulative toxicity, including second malignancies,sterilitn and cardiac and pulmonary dvsfunction. "Risk-adapted" prorocols are based on staging criteria as well as rapiditv of response to initial chemotherapv.The aim is to reduce total drug dosesand treatmenr duration and even eliminate radiation therapy. RELAPSE. Most relapsesoccur within the first 3 yr from diagno, sis but relapsesas late as 10 yr have been reported. Relapse cannot be predicted accuratelywith this disease.Poor prognostic featuresinclude tumor bulk, stagear diagnosis,and presence of B svmptoms. Patientswho never achieveremissionor relapse <12 rno after initiarion of therapy are candidatesfor myeloablative chemotherapv and autologous stem cell transplant with or without rhe addition of radiarion theraov.This trearmenrrs mosr successfulrn parientswith chemorerponriu. disease.Myeloablative allogeneicstem cell transplantation reducesthe relapserate in patients rvirh high-risk relapsedor refracrory HD. However, there was no improvemenr in overall survival in the studies reported,due to a high transplant-relatedmortality.Theseresults, however, do suggesta graft-versus-HDeffect. The use of nonmyeloablative nontoxic regirnens to reduce regimen-related morbidity and morraliry associatedwith myeloablativeallogeneic stem cell transplantationbut still achievea graft-versus-HDeffect ls unoer lnvestlgatlon. PBOGN0SIS.Using current therapeutic regimens, patients wirh favorable prognostic factors and early-stagedisease have an event-freesurvival (EFS)of 85-90% and an overall survival (OS) at 5 yr of 957o. Patientswith advancedstagedrseasehave an EFS and OS of 80-85% and 90o/", respectively.Prognosisafter relapse depends on the time from completion of treatment to recurrence, site of relapse(nodal vs. extranodal), and presenceof B symptoms at relapse.Patients who relapse>12 mo after chemotherapy Claviez A, Klingebiel T, BeyerJ, et al: Allogeneicperipheral blood stem cell transplantation following fludarabine-basedconditioning in six children with advancedHodgkin diseaseAnn Hematol 2004;83:237-24L. Hjalgrim HH, Askling J, RostgaardK, et al: Characteristicsof Hodgkin's lymphoma after infectiousmononucleosis.N Engl J Med2003;349:L324-1.332. Hudson MM, Donaldson SS: Hodgkin disease.In Pizzo PA, Poplack DG (editors):Principlesand Practice of Pediatric Oncology,4th ed. Philadelphia, l.ippincott Williams & Wilkins, 2002, pp 637-660 Hueltenschmidt B, Sautter-BihlML, Lang O, et al: Vhole body positron emission tomography in the treatment of Hodgkin disease. Cancer 2 0 0 1 ; 9 1 : 3 0 2 -130 . PeggsKS, Hunter A, Chopra R, et al: Clinical evidenceof a graft-versusHodgkin's-lymphomaeffect after reduced-intensityallogeneictransplantanon Lancet 2005:365:"1934-1940. Pileri SA, Ascani S, Leoncini L, et al: Hodgkin lymphoma: the pathologist's v i e w p o i n t J. C l i n P a t h o l2 0 0 2 ; 5 5 : L 6 2 - 1 7 6 . SchwartzCL: The managementof Hodgkin diseasein the young chrld. Curr Opin Pedidtr 2003;1-5:10-1 5. Thomson AB, Wallace WH: Treatment of paediatric Hodgkin disease.A balanceof risks Eur J Cancer 2002;38:468477 Yung L, Linch D: Hodgkin's lymphoma. Ldncet 2003;361:943-950. (NHL} 496.2O NON'HODGKIN LYMPHOMA NHL accounts for approximately 50"/oof all lymphomas in children and adolescents.It represents8-10% of all malienanciesin c h i l d r e nb e t w e e n5 - 1 9 y r o f a g e .w i t h a n a n n u a l i n c i d e n c ei n t h e USA of 750-800 cases per year in children <19 yr of age. Although >707o of patients present with advanced disease at diagnosis,the prognosis has improved dramatically, with survival rates of 90-95% for localized disease and 60-90o/" with advanced disease. EPlDEMl0t0GY. !7hile most children and adolescentswith NHL present with de novo disease,a small number of patients develop NHL secondary to specific etiologies, including inherited or acquired immune deficiencies(e.g., severecombined immunodeficiency syndrome, Wiskott-Aldrich syndrome), viral etiologies (e.g., HIV, EBV) or as part of genetic syndromes (e.g., ataxia-telangiectasia, Bloom syndrome). Most children who develop NHL, however, have no obvious genetic or environmental etrology. PATH0GENESIS. The four major pathological subtypes of childhood and adolescent NHL are Burkitt lymphoma (BL), constituting 40% of NHL; lymphoblastic lymphoma (LL), accounting for 30%o;diffuse large B-cell lymphoma (DLBCL), constituting 20"h; and anaplastic large cell lymphoma (ALCL), accounting for 10% (Fig. 496-3). Most childhood and adolescent NHLs are high-grade tumors with an aggressiveclinical behavior compared to those of adult NHL, which usually are low- to intermediategrade indolent tumors. Almost all childhood and adolescentNHL is derived from germinal center aberrations. Almost all forms of I 2127 496 I Lymphoma Ghapter Figure 496-3. Distribution of childhood and adolescentnon-Hodgkin lymphoma. Hematoxylin and eosin stains showing morphology o{ Burkitt lymphoma (A, high power), diffuse large B-cell lymphoma (B, high power). precur5or T-lym phoblasrie lymphoma (C. high power), and anaplasticlargecell lymphoma (D, high power). (From Cairo MS, Raetz E, Lim MS, et al: Childhood and adolescentnon-Hodgkin lymphoma: New insights in biology and critical challengesfor the future. Pediatr Blood Cancer 2005;45: 7s3-769.) * BL and DLBCL are of B cell origin; casesof LL are 80% T cell and 20oA B cell; and casesof ALCL are 70% T cell, 20% null cell, and 10% B cell in origin. Some pathological subtypes have specific cytogenetic aberrations. Children with BL commonly have a t(8;14) translocation(90%olor,lesscommonly, a t(2;8) or t(8;221translocarion(10%). Patientswith ALCL commonly have a t(2;5) translocation (>5%\. Patientswith DLBCL and LL have a variety of different cytogenetic abnormalities. CLINICAIMANIFESTATIONS. The clinical manifestations of childhood and adolescent NHL depend primarily on pathological subtype and primary and secondary sites of involvement. NHLs are rapidly growing tumors and can cause symptoms based on size and location. Approximately 70% present with advanced disease of stages III or IV (Table 496-4), including extranodal disease that manifests as gastrointestinal, bone marrow, and central nervous system (CNS) involvement. BL commonly presents with abdominal (sporadic type) or head and neck (endemic type) diseasewith involvement of rhe bone marrow or CNS. LL commonly presents with an intrathoracic or mediastinal supradiaphragmatic mass, and also has a predilection for spreading to the bone marrow and CNS. DLBCL commonly presents with either an abdominal or mediastinal primary and, rarely, dissemination to the bone marrow or CNS. ALCL presents either with a primary cutaneous manifestation (10%) or with systemic disease (fever, weight loss) with dissemination to liver, spleen, lung, mediastinum, or skin; spread to the bone marrow or CNS ls fare. Site-specificmanifestations include painless, rapid lymph node enlargement; cough, superior vena cava (SVC) syndrome, dyspnea with thoracic involvement; abdominal (massive and rapidly enlarging) mass, intestinal obstruction, intussusception-like symptoms, asciteswith abdominal involvement; nasal stuffiness, earache, hear:ing loss, tonsil enlargement with Waldeyer ring involvement; and localized bone pain (primary or metastatic). Three clinical manifestations that require special alternative treatment strategiesinclude SVC syndrome secondary to a large mediastinal mass obstructing various blood flow or respiratory airways; acute paraplegias secondary to spinal cord or central nervous system compression from neighboring localized NHL; and tumor lysis syndrome (TLS) secondary to severe metabolic abnormalities, including hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia from massive tumor cell lysis. FINDINGS.Recommended laboratory and radiologic (extranodal) (nodal), Asingle tumor orsingle anatomic area withtheexdusion ofmedlaslnum LAB0RAT0RY orabdomen testing includes: complete blood count (CBC); electrolytes, uric (extranodal) Asingle tumor wlthreg0nalnode involvement acid, calcium, phosphorus, bilirubin urea nitrogen, creatinine' Two ormore nodal areas 0nthesame side 0fthediaphragm alanine aminotransferase, and aspartate aminotransferase; bilat(extranodal) Iwosinqle tum0rs with0rwith0ut regional node involvement 0nthesame side 0f eral bone marrow aspiration and biopsies; lumbar puncture with thediaphragm CSF cytologn cell count and protein; chest x-ray; and neck, A p r i m a r y g a s t r o i n t e s t i n a l t r a cnt t uhm e i0l e[ u0scuea( al yl a r e a , w i t h o r w i t h 0 | ] t i n v 0 l v e m e n t abdominal, and pelvic CT scans, PET scan and bone scan chest, (>9070) ofassociated mesenteric nodes only, which must begrossly resected (optional), and head CT scan (optional) (Table 496-5). The tumor Two single tumon(exvanodal) onopposite sides ofthedlaphragm tissue (i.e., biopsn bone marrow, CSF, or pleural/paracentesis Two ormore nodal areas above andbelow thediaphragm (medias|nai, fluid) should be tested by flow cytometry for immunophenotypic Anyprimary iftrath0ra0r plzural, tLlm0r orthymiQ Anyextens \/eprimary intraabdominal dlsease origin (! B, or null) and cytogenetics (karyotype). Additional A n y o f t h e a b o v en,iwt iiatnhl \ / 0 l v e m e n t 0 f ( : e n t r a l n e r v o u s s y s t e m o r b o n e m atests n o w amight t t r m e o iinclude fluorescent in situ hybridization (FISH) or daqnosis quantitative RT-PCR for specific genetic translocations, T and B From Murphy 58:(asslfrcdtion,staging andendresults 0fveatment 0frhildh0od non-l-]odqkins lymphomas:Dhsimi arities fromymphomas inadults SeninAn@l 198U1:3r-339 cell gene rearrangement studies, and molecular profiling by oligonucleotide microarray. 2t28 I PARTXXI r CancerandBenignTumors SUPPORTIVE CARE (omplete blood cellcount phmphorus Serum elecrolyles, urkacid, lactate dehydrogenase, creatinine, cakium, (ALI, function Liver tests A5T) Chest radiognph pelvk Neck, chest,abdominal, fi Positive emission tomography ran Bilatenl bone manow aspirate andbiopsy (erebrospinal pmtein fluidcytology, cellcount, ALI alanine aminotnndens€; ASI aspanale aminotmnshras€ DIFFEBENTIAL DIAGN0SIS.Head and neck lymphadenopathy should be differentiatedfrom infectious nodal etiologies;mediastinal masses from HD and germ cell tumors; abdominal involvement from other abdominal malignant massessuch as '!(ilms tumor, neuroblastoma, and rhabdomyosarcoma; and bone marrow involvement from precursor B (Pre-B) acute lymphoblasticleukemiaand T-cell acurelymphoblasticleukemia. CT and PET scans, along with flow cytometry, cytogenetic and molecular Beneticson biopsy and tumor tissue,usually differentiate NHL from other ennnes. TREATMENT. The primary modality of treatment for childhood and adolescentNHL is multiagent systemicchemotherapyand intrathecal chemotherapy. Surgery is used mainly for diagnostic and/or biologic specimensand staging but rarely is used for debulking large masses.Radiation therapy is rarely, if ever,used, except in specialcircumstancessuch as CNS involvement in LL or occasionallyBL, acute SVC, and acureparaplegias.Patientsat diagnosisand ar risk of TLS, especiallyadvanced/bulkyBL or LL, require vigorous hydration and eirher a xanthine oxidase inhibitor (allopurinol, 10 mglkglday PO divided tid) or, more often, recombinanturate oxidase (rasburicase,0.2 mg/kg/dayPO o n c ed a i l v f o r l - 3 d a y s ) . Specifictreatmenrfor localizedand advanceddiseaseis similar for BL and DLBCL. Localized BL and DLBCL reouire 6 wk to 6 mo of multiagent chemotherapy.Common regimens include COPAD (cyclophosphamide,vincristine, prednisone and doxorubicin), as demonstrated by the recenr inrernational B-NHL study (FAB/LMB 96 [French-American-BritishLymphoma, marure B cell]) or COMP (cyclophosphamide,vincristine,merhotrexate, 6-mercaptopurineand prednisone).Advanced diseaseusually is treated by 4-5 mo of multiagent chemotherapy such as FAB/LMB 96 protocol therapy or BFM (Berlin Frankfurt Munich) NHL90 protocol tnerapy. Localized and advanced LL usuallv reouire almost 24 mo of therapy. The besr results in advanced Li have been obtained using the BFM NHL 90 protocol, which uses therapeutic approachessimilar to those for childhood acute leukemia,which includes an induction cycle of chemotherapy, consolidation phase,interim maintenancephase,reinduction phase (advanced disease only), and a year of maintenance therapy with 6mercaptopurine and methotrexate. LocalizedALCL may require only cutaneousexcision or more aggressivetherapy similar to that for advancedALCL. Advanced ALCL commonly is treated with a BFM NHL 90 prorocol or with a COG protocol of APO (doxorubicin, prednisone and vincristine) with additional VP-15, Ara-C, or vinblastine. Intrathecal chemotherapy is administered to moderate to advanced diseasein all subtypesof childhood and adolescentNHL and may include intrarhecal methotrexate, hydrocortisone, or Ara-C. Patientswith NHL who develop progressiveor relapseddisease require reinduction chemotherapy and either allogeneic or aurologous stem cell transplantation. The specificreinduction regimen or transplant depends on the pathologic subtype, previous therapy, site or reoccurrence, and stem cell donor availability. Somepatients require G-CSF prophylaxis to prevent fever and neutropenia following myelosuppressivechemotherapy and prophylactic antibiotics to prevent infections. Indwelling central venous catheters routinely are placed to facilitate frequent blood draws, chemotherapy and transfusion administration, and parenteral nutrition to prevent weight loss and nutritional debilitation. COMPLICATIONS Patients receiving multiagent chemotherapy for advanced disease are at acute risk for serious mucositis, infections, cytopenias requiring red cell and platelet blood product transfusions, electrolyte imbalance, and poor nutrition. Long-term complications may include growth retardation, cardiac toxicity, gonadal toxicity with infertility, and secondary malignancies. PROGNOSIS The prognosis is excellent for most forms of childhood and adolescent NHL. Patients with localized disease have a 90-100% chance of survival, and patients with advanced disease have a 60-95% chance of survival. The variation in survival depends on pathological subtype, tumor burden at diagnosis as reflected in serum LDH level, presenceor absenceof CNS disease,and specific sites of metastatic spread. Specific cytogenetic and molecular genetic subtyping also may be important in predicting outcome and influencing specific therapeutic strategies. Carro MS, BishopM: Tumour lysis syndrome:new therapeuticsrrategiesand classificationBr .l Haematol 2004;127:3-11.. Cairo MS, SpostoR, Hoover-ReganM, et al; Chitdhood and adolescentlargecell lymphoma (LCL): A review of the Children'sCancerGroup experience. Am I Hematol 2003:72:53-63. Cairo MS, SpostoR, PerkinsSL, et al: Burkitt's and Burkitt-like lymphoma in children and adolescents: A review of the Children'sCancer Group experience.Br I Haematol 2003;120:660-670. Dave SS,Wright G, Tan B, et al: Predictionof survival in follicular lymphoma based on molecular featuresof tumor-infiltrating immune cells. N Engl / Med 2004;35 1:2159-2169. Hummel M, Bentink S, Berger H, et al: A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N EngL J Med 2006:354:241.9-2430. Patte C, Auperin A, Michon J, et al: The SocieteFrancaised'Oncologie Pediatrique LMB89 protocol: highly effectivemultiagentchemotherapytailored to the tumor burden and initial responsein 551 unselectedchildren with Bcell lymphomas and L3 leukemia. Blood 2001;97:3370-3379. PeniketAJ, Ruiz de Elvira MC, TaghipourG, et al: An EBMT registrymatched study of allogeneicstem cell transplantsfor lymphoma: allogeneictransplantation is associatedwith a lower relapserate but a higher procedurerelated morrality rate than autologous transplantation. Bone Marrow Transplant 2003;31:557-67 8. Reiter A, SchrappeM, Tiemann M, et al: Improved treatmentresultsin child^ hood B-cell neoplasmswith tailored intensificationof therapy: A reporr of the Berlin-Frankfurt-Munster Grouo Trial NHL-BFM 90. Blood 1999:94:3294-3306. Primary central nervous system (CNS) tumors are a heterogeneous group of diseasesthat are, collectively, the second most Ghapter 497 : BrainTumorsin Childhoodr 2129 SYNDROME CN5MANIfESTATIONS Neurofibromalosis type1{aut0s0mal dominant) Neurofibromatosis type2 (autosomal dominant) (artosomal vonHippel-Lindau dominant) (autosomal Iuberous sclerosis dominant) gliomas, peripherai 0pticpathway neurofbromas astrocytoma, maliqnant nerve sheath tumors, Vestibular schwannomas, hdmartomas meningiomas, spinal cordependymoma, spinalcordastrocytoma, Hemangioblastoma giant Subependymal cellastrocytoma, cortrcal tubers (autosomal LiJraumeni dominant) (autosomal Cowden dominant) (autosomal Iurcot domrnant) primitive Astroryt0ma, neuroectodef maltum0r (Lhermine-Dudos qangliocytoma Dysplaslc ofthecerebellum disease) Medulloblastoma Glioblastoma (autosomal Nevoid basal cellcarcinoma dominant) l\4edulloblastoma CHROMOSOMT 11ql1 22q12 3p25-)6 9q34 16q13 17q13 10q23 5q2l 3p21 7Q) 9q31 6[NE Nfl VHL TS(1 LSC2 LP53 PIIN AP( hMLHI hP'M2 PI(H l\,40difedfr0mK]eihUe5g(auenee,'l'lK:Wor|dHeolth0rg0nE0ti0nC|0ssin&ti0n0f|una6:P0th0l0gy0nd6enetks0f|Una|saftheNe|y0U55ys frequent malignancy in childhood and adolescence. The overall mortality among thrs group approaches4.5%.Thesepatientshave the highest morbidity. primarily neurologic, of all childhood malignancies.Outcomes have improved over time with innovations in neurosurgeryand radiation therapy as well as introduction of chemorherapvas a therapeuticmodaiity. The treatment approach for thesetumors is multimodal. Surgervwith complete resection,if feasible,is the foundation, with radiation therapy an.dchemotherapyused basedon the diagnosis,parienr age, and otner Iactors. ETIOLOGV. The etiology of pediatric brain rumors is not well defined.A male predominanceis noted in the incidenceof medulloblastomaand ependymoma.Familial and hereditarysyndromes associatedwith increasedincidenceof brain tumors account for approximately 57' of cases(Table 497-7). Cranial exposure ro ionizing radiation also is associatedwith an increasedrncidence of brain tumors. There are sporadic reports of brain tumors within families without evidenceof a heritable syndrorne.The moleculareventsassociatedwith rumorigenesisof pediatric brain tumors are not known. EPIDEMI0L0GY Approximately 2,200 primary brain rumors are diagnosedeach year in children and adolescents,with an overall annual incidenceof 28 casesper million children <19 yr of age. The incidenceof CNS tumors is higher in infants and young children <7 yr of age (=36 cases/millionchildren) compared r,vith older children and adolescents(=21 cases/millon children) [Fig. 497-11. CLiNICALMANIFES I0NS. The clinical presentationof patients with brain tumors dependson the tumor location, the tumor type, and the age of the child. Signs and symptoms are related to obstruction of cerebrospinalfluid (CSF) drainage paths by the tumor, leading to increasedintracranial pressure (ICP) or causing focal brain dysfunction.Subtlechangesin personality,mentation, and speechmay precedetheseclassicsigns and symptoms; rhese often occur with supratentorial(cortical) lesions.In young children, rhe diagnosisof a brain tumor may be delayedbecausetheir svmDtomsare similar to those of more common illnessessuch as gast;ointestinaldisorders.Infants with open cranial suturesmay present with signs of increased ICP such as vomiting, lethargy, and irritability, as well as the later finding of macrocephaly. The classictriad of headache,nauseaand vomiting, and papilledema is associatedwith midline or infratentorial tumors. Disorders of 45 + AilCNS - 40 Astrocytomas 35 c E o a:25 Cg PATH0GENESIS. Among the >100 histologic categoriesand subtvpes of primary brain tumors described in the World Health Organization (\7HO) classificationof tumors of the CNS and meninges, 5 categories constitute 80"k of all pediatric brain tumors: juvenile pilocytic astrocytoma; medulloblastoma/primitive neuroectodermaltumor (PNET); diffuse astrocytomas:ependi'moma; and craniopharyngioma(Table 497-2). The Childhood Brain Tumor Consortium reporteda slight predominanceof infratentorialtumor location (43.2%1,followed by the supratentoriallocation (40.9%), spinalcord (4.9yo),and multiple sites (11%). There are age-relateddifferencesin primary location of tumor (Fig. 497 -2). Within the first year of life, supratenrorial tumors predominate and include, most commonln choroid plexus complex tumors and teratomas.From 1-10 yr of age, infrarenrorial tumors predominate,owing to the high incidence of juvenile pilocytic astrocytoma and rnedulloblastoma. After 10 .vrof age,supratentorialtumors again predominate,with diffuseastrocytomasmost common. Tumors of the optic pathway and hypothalamus region, the brainstem, and pineal-midbrain region are more common in children and adolescentsthan in adults. (o f c-- (o 0) 10 s ".f 0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 31 4 1 5 1 6 1 7 1 8 1 9 2 0 Age at diagnosis(yr) a fl i g n a n t b r a i n t u m o r s oc fh i l d so t i r r r r r J { i - - l . A g e s p e c i f i c i n c i d e n c e r a t em ; NliT, primitive h o o d f r o m S E E R 1 9 8 6 - 1 9 9 4 .C N S , c e n t r a ln e r v o u ss y s t e m P neuroectodermaltumor (Redrawn from Gurney JC, Smith MA, Bunin GR: Natictnal Oancer Institute SEF.RProgram. NIH publication No 99-4549. B e t h e s d aM, l ) , N a t i o n a l C a n c e rI n s t i t u t e ,1 , 9 9 9 p, p 5 1 ' - 6 3 . ) 2130r PARTXXI r CancerandBenignTumors metastatic diseasefrom brain tumors or leukemia are similar to those of infratentorial tumors. (%0f I0TAt) DrSTR|BUTr0N HISTOTOGY Medulloblasmma/prrmitive neur0ectodermal tum0r 20 pilocyti( Juvenile astrorytoma 20 Low-grade astrorytoma t5 Hiqh-grade astrorytoma Ependymoma Iraniopharyngioma primary Undassified tumo6 plexus germ Ihoroid tumors, group) celltumors,oliqodendroglioma, l-2 (each histologir pineal parenchymal meningioma, mixed tumors, tumors Adapted from Fulhr GN:[entral nervous rysrcm tum06 InParham DM(ed'tor]: MinrkNeoflono: Ilorptnloqy ond Bidogy. Philadelphia, pp153-204 Lipptncott-Raven, 1996, equilibrium, gait, and coordination occur with infratentorial tumors. Torticollis may result in cerebellar tonsil herniation. Blurred vision, diplopia, and nystagmusalso are associatedwith infratentorial tumors. Tumors of the brainstem region may be associaredwith gaze pals,v,multiple cranial nerve palsies,and upper motor neuron deficits (e.g., hemiparesis,hyperreflexia, clonus). Supratentorial tumors more commonly are associated wirh focal disorderssuch as motor weaknesses, sensorychanges, speechdisorders,seizures,and reflex abnormalities.Infants with supratentorialtumors may presentwith hand preference.Optic pathway tumors presenr with visual disturbances such as decreasedvisual acuity, Marcus Gunn pupil (afferent papillary defect),nystagmus,and/or visual field defects.Suprasellarregion tumors and third ventricular regron tumors may presentinitially with neuroendocrine deficits such as diabetes insipidus, galactorrhea, precociouspubert.y,delayedpuberty, and hypothyroidism. The diencephalic syndrome presenrswith failure to rhrive, emaciation, increasedappetite, and euphoric affect, and occurs in infants and voung children with tumors in these regions.Parinaud syndrome presenrswith pineal region tumors and is manifested by paresisof upward gaze, pupillary dilation reacrive ro accommodation but not to light, nystagmusto convergenceor retraction, and e,velidrerraction. Spinal cord tumors and spinal cord disseminarionof brain tumors may manifest as long nerve tract motor and/or sensorydeficits, bowel and bladder deficits, and back or radicular pain. The signsand sympromsof meningeal 0|AGNOSIS.The evaluation of a patient suspected of having a brain tumor is an emergency.Initial evaluation should include a complete historS physical (including ophthalmic) examination, and neurologic assessmentwith neuroimaging. For primary brain tumors, MRI is the neuroimaging standard. Tumors in the pituitary/suprasellar region, optic path, and infratentorium are better delineated with MRI than with CT. Patients with tumors of the midline and the pituitary/suprasellar/optic chiasmal region should undergo evaluation for neuroendocrine dysfunction. Formal ophthalmoiogic examination is beneficial in patients with optic path region tumors to document the impact of the diseaseon oculomotor function, visual acuity, and fields of vision. The suprasellar region and pineal region are preferential sites for germ cell tumors. Both serum and CSF measurementsof p-human chorionic gonadotropin and cr-fetoprotein can assist in the diagnosis of germ cell tumors. In tumors with a propensity for spreading to the leptomeninges, such as medulloblastoma/PNEI ependymoma, and germ cell tumors, lumbar puncture and cytologic analysis of the CSF is indicated; lumbar puncture is contraindicated in individuals with newly diagnosed hydrocephalus secondary to CSF flow obstruction or in individuals with infratentorial tumors. Lumbar Duncture in these individuals mav lead to brain hernjation, resulting in neurologiccompromiseand death. Therefore, in children with newly diagnosed intracranial tumors and signs of increased ICP, the lumbar puncture usually is delayed until surgery or shunt placement. SPECIFIC TUMORS ASTROCYTOMAS. Astrocytomas are a heterogeneous group of pediatric CNS tumors that account for approximately 40o/" o{ cases.These tumors occur throughout the CNS. Low-grade astrocytomas (LGAs) are the predominant group of astrocytomas in childhood and are characterized by an indolent clinical course. Juvenile pilocytic astrocytoma (JPA) is the most common astrocytoma in children, accounting for 20o/" of all brain tumors (Fig. 497-31. Based on clinicopathologic features using the VHO Classification System,JPA is classifiedas a WHO grade I tumor. Although JPA can occur anywhere in the CNS, the Hemispheric Gliomas:37o2" Low-gradeastrocytomas:237o High-grade astrocytomas: 11% Other:3% Midline: 1 . C h i a s m agl l i o m a s4: % 2. Craniopharyngiomas: 8% 3. Pinealregiontumors:2% l I Posteriorfossa: 1 Brainstemgliomas:15olo 2 Medulloblastomas: 157o 3. Ependymomas: 4% 4. Cerebellar astrocytomas: 157o Figtre 497-2. Childhood brain tumors occur at any location within the central nervous system.The relative frequencyof brain tumor histologic types and the anatomic distribution are shown. (Redrawn from Albright AL: Pediatrjc brain tumors CA CancerJ Clin 1993;43:272-288) 497 r BrainTumorsin Childhoodr 2131 Ghapter Figure 497-3. A, Axial T1-weighted MRI of a patient with cerebellarpilocytic astrocytoma, demonstrating predominantly cystic (hypointense) component (arrows) involving the left cerebellar hemisphere and vermis. B, Gadolinium-enhanced axial T1-weighted MRI in the same child demonstratesenhancementof the solid component (large arrou), enhancement of rhe capsule (small arrows), and layering of contrast material (open arrou) ar the bottom of the cyst. (From Kuhn JP,Slovis TL, Haller JO: Caffey's Pediatric Diagnostic lmaging, 10th ed. Philadelphia, Mosby, 2004, p 576 ) classicsite of presentation is the cerebellum. Other common sites include the hypothalamic/third ventricular region and the optic nerve and chiasmal region. The classic but not exclusive neuroradiologic findings of JPA are the presenceof a contrast mediumenhancing nodule within the wall of a cystic mass (seeFig. 497-3). The microscopy findings exhibit a biphasic appearanceof bundles of compact fibrillary tissue interspersed with loose microcystic, spongy areas. The presenceof Rosenthal fibers, which are condensed massesof glial filaments occurring in the compact areas, helps establish the diagnosis. JPA has a low metastatic potential and rarely is invasive. A small proportion of these tumors can progress and develop leptomeningeal spread, particularly tumors occurring in the optic path region. JPA very rarely undergoes malignant transformation to a more aggressivetumor. JPA of the optic nerve and chiasmal region is a relatively common finding in patients with neurofibromatosis fype 1 (15% incidence). Unlike diffuse fibrillary astrocytomas, there are no characteristic cytogenetic abnormalities in JPA nor are there any known molecular abnormalities. Other tumors occurring in the pediatric age group with clinicopathologic characteristics similar to those of JPA include pleomorphic xanthoastrocytoma, desmoplastic cerebral astrocytoma of infancS and subependymal giant cell astrocytoma. The second most common astrocytoma is fibrillary infiltrating astrocytoma, a group of tumors characterized by a pattern of diffuse infiltration of tumor cells among normal neural tissue and potential for anaplastic progression. Based on their clinicopathologic characteristics,they are grouped as low-grade astrocytomas (\fHO grade II), malignant astrocytomas (anaplastic astrocytoma, IilfHO grade III), and glioblastoma multiforme (GBM, !7HO grade IV). Of this group, the fibrillary LGA is the second most common astrocytoma in children, accounting for 15% of brain tumors. Histologically, these low-grade tumors demonstrate increased cellularitv comoared with normal brain parenchyma, with few mitotic hgur.r, nuclear pleomorphism, and microcysts. The characteristic MRI finding is the lack of enhancement after contrast agent infusion. Molecular genetic abnormalities found among low-grade diffuse infiltrating astrocytomas include mutations of P53 and overexpressionof plateletderived growth factor c,-chain and platelet-derived growth factor receptor-cx,. These tumors have the potential to evolve into malignant astrocytomas, a development that is associatedwith cumulative acquisition of multiple molecular abnormalities. The clinical management of LGAs focuses on a multimodal approach incorporating surgery as the primary treatment as well as radiation therapy and chemotherapy. The outcome of JPA is better than with fibrillary LGAs. With complete surgical resection the overall survival approaches 80-100%. In patients with Dartial resection (<80% resection). overall survival varies from SO-95%, depending on the anatomic location of the tumor. In patients with partial resection and stable neurologic status, the current approach is to follow the patient closely by examination and imaging. With evidence of progression, surgical re-resection should be considered. In patients in whom second surgery was less than complete or is not feasible, radiation therapy is beneficial. Radiation therapy is delivered to the tumor bed at a total cumulative dose ranging from 50-55 Gy given on a daily schedule over 6 wk. Historically, patients with deep midline tumors were treated empirically without surgery or biopsy using radiation therapy, with variable survival rates from 33-75%. However, modern surgical techniques and innovative radiation therapy methodology may have a positive impact on the survival and clinical outcome of these patients. The role of chemotherapy in the management of LGAs is evolving. Because of concerns regarding morbidity from radiation therapy in young children, severalchemotherapy approacheshave been evaluated, especially in children <5 yr of age. Complete response to chemotherapy is low; however, these approaches have yielded prolonged disease control in 70-100% of patients. Patients with midline tumors in the hypothalamic/optic chiasmatic region have tended to do lesswell. Taken together,the chemotherapy approacheshave permitted delay and, potentiallS avoidance of radiation therapy. In a national trial currently underway, investigators are comparing the effectivenessand tolerance of a carboplatin-based chemotherapv schedule with a lomustine (CCNU)-based schedule in childien <10 yr of age with a progressive LGA. Clinical trials investigating either temozolomide or vinblastine also are underway. Observation is the primary approach in clinical management of selectivepatients with LGAs that are biologically indolent. One group includes patients with neurofibromatosis type 1, who may develop an LGA of the optic chiasm/optic pathway or brainstem that is found incidentally. Another group includes patients with midbrain astrocytomas who have resolution of clinical symptoms after ventricular shunting and do not require further intervention. Malignant astrocytomas are much less common in children and adolescentsthan in adults, accounting for 7-10% of all child- 2132I PABTXXI r CancerandBenignTumors astrocytomas of children is an adverseprognostic factor. The frequency of mutations in P53 in childhood malignant astrocytomas is similar to that noted in adults, although the frequency of such mutations in malignant astrocytomas of children <3 yr of age is lower. This suggestsdiffering mechanismsof oncogenesisbetween younger and older children. Optimal therapeutic approaches for malignant astrocytomas have yet to be defined. Standard therapy continues to be surgical resection followed by involved-field radiation therapn usually followed by a nitrosourea-containing chemotherapy regimen. A pediatric trial showed improved survival with lomustine and vincristine after radiation comDared ro radiation alone. A study of adult glioblastoma showed significantly improved survival with temozolomide during and after radiation, compared to radiation alone. This combined temozolomide and radiation currently is under investigation for pediatric high-grade gliomas. Oligodendrogliomas are uncommon tumors of childhood. These infiltrating tumors occur predominantly in the cerebral cortex and originate in the white matter. Histologically, oligodendrogliomas consist of rounded cells with little cytoplasm and microcalcifications. Observation of a calcified cortical mass on CT in a patient presenting with a seizure is suggestiveof oligodendroglioma. Treatment approaches are similar to those for infiltrating astrocytomas. MIXED GLI0MAS. Mixed gliomas are composed of two or more distinct glial cell types-astrocytoma, oligodendroglioma, and ependymoma-and are rare in pediatric patients. EPINDYMAI TUM0RS, Ependymal tumors are derived from the ependymal lining of the ventricular system. Ependymoma (\7HO grade II) is the most common of these neoplasms, occurring predominantly in childhood and accounting for t07" of childhood tumors. Approximately 70% of ependymomas in childhood occur in the posterior fossa.The mean age of patients is 5 yr, with approximately 30% of casesoccurring in children <3 yr of age. The incidence of leptomeningeal spread approaches 10"/" overall. Clinical presentation depends on the anatomic location of the tumor. MRI demonstrates a well-circumscribed tumor with variable and complex patterns of gadolinium enhancement, with or without cystic structures (Fig. 497-5|t. These tumors usually are noninvasive, extending into the ventricular lumen and/or displacing normal structures. Histologic characteristics include perivascular pseudorosettes,ependymal rosettes, monomorphic nuclear morphology, and occasional nonpalisading foci of necrosis. Surgery is the primary treatment modality, with extent of surgical resection a maior prognostic factor. Two other major prognostic factors are age, with younger children having poorer outcomes, and tumor location, with localization in the posterior Figure.197-.{. A, Gadolinium-enhanced axialT1-weighted MRI of gradeIII fossa, which often is seen in young children, associated with astrocytomaof the right thalamusdemonstrating diffuse enhancement poorer outcomes. Surgery alone rarely is curative. Multimodal (arrotu). B, Gadolinium-enhanced sagittal T1-weightedMRI showing therapy incorporating radiation with surgery has resulted in longenhancement of gradeIII astrocytoma of thethalamus with extension into the term survival in approximately 40"/" of patients after gross total midbrain(blackarrow) and hypothalamus (whitearrotu).\From Kuhn JP, SlovisTL, HallerJO: Caffey's Pediatric Diagnosttc Imdging,lOthed.Philadel- resection. Recurrence is predominantly local. Radiation therapy phia,Mosby,2004,p. 595.) of the involved field is recommended for most children with ependymoma and anaplastic ependymoma. Ependymoma is sensitive to a spectrum of chemotherapeutic agents;however, the role hood tumors. Among this group, anaplastic astrocytoma (WHO of chemotherapy in multimodal therapy of ependymoma is still grade III) fFig. a97-a] is more common than glioblastoma unclear. Severallimited trials have shown no benefit of high-dose multiforme (WHO grade IV). The histopathology of anaplasric chemotherapy with peripheral blood stem cell rescue in ependyastrocytomas demonstrares increased cellularity compared with moma. Current investigations are directed toward identification low-grade diffuse astrocytomas, cellular and nuclear arypia, presof optimal radiation dose, surgical questions addressing the use ence of mitoses, and, variabln microvascular proliferation. Charof second-look procedures after chemotherapy, and further evalacteristic histopathology findings in glioblastoma multiforme uation of classicas well as novel chemotherapeutic agents.There include dense cellularitn high mitoric index, microvascular proare no characteristic cytogenetic or molecular genetic alterations liferation, and foci of tumor necrosis. Limited information is in ependymoma. However, preliminary studies suggestthat there available regarding the molecular abnormalities in malignant are genetically distinct subtypes, exemplified by an association astrocytomas of children. Overexpression of P53 in malignant between alterations in the NF2 gene and spinal ependymoma. Ghapter497 r BrainTumorsin ChildhoodI 21i|i| Figurc 497-5. A, Sagittal T1-weighted MRI of a patient with ependymoma, demonstrating a hypointense mass (arrows) within the fourth ventricle. B, Axial T2-weighted image of an ependymoma showing a hyperintense mass(open arrows) and.a hypointense central area of calcification (closedarrotu) within the fourth ventricle. C, Gadolinium-enhanced sagittal T1-weighted image demonstrating an ependymoma (arrows). (From Kuhn JP,Slovis TL, Haller JO: Caffey's PediatricDiagnostic lmaging, 10th ed. Philadelphia,MosbX 2004, p 579.) Anaplastic ependymoma (!(HO grade III) is much less common in childhood, and these tumors are characterized by a high mitotic index and histologic features of microvascular proliferation and pseudopalisadingnecrosis.Myxopapillary ependymoma (WHO grade I) is a slow-growing tumor arising from the filum terminale and conus medullaris. CHOR0|DPLEXUSTUMORS.Choroid plexus rumors account for 24Y" of childhood CNS tumors. They are the most common CNS tumor in children <1 yr of age and account for l0-20"h of CNS tumors occurring in infancy. These tumors are intraventricular epithelial neoplasms arising from choroid plexus. Children present with signs and symptoms of increased ICP. Infants may present with macrocephaly and focal neurologic deficits. In children, these tumors occur predominantly supratentorially in the lateral ventricles. Choroid plexus papilloma (WHO grade I), the most common of this group, is a well-circumscribed lesion by neuroimaging and closely resembles normal choroid plexus histologically. Choroid plexus carcinoma (rJfHO grade III) is a malignant tumor with metastatic potential to seed into the CSF pathways. This malignancy has histologic characteristics of nuclear pleomorphism, high mitotic index, and increased cell density. Immunopositivity for transthyretin (prealbumin) is useful in confirming the diagnosis of these tumors. These tumors are associated with the Li-Fraumeni syndrome. Simian virus 40 (SV40) may play an etiologic role in choroid plexus tumors. After complete surgical resection, outcome for choroid plexus papilloma approaches 100%, whereas outcome for choroid plexus carcinoma approaches 2040%. Reports suggest that radiation therapy and/or chemotherapy may lead to better diseasecontrol for choroid plexus carcinoma. EMBRYONALTUMORS,Embryonal tumors or primitive neuroectodermal tumors (PNET) are the most common group of malignant CNS tumors of childhood, accounting for 20-25"/' of pediatric CNS tumors. These tumors have the potential to metastasize to the neuraxis. This group includes medulloblastoma, supratentorial PNET, ependymoblastoma, medulloepithelioblas- 2134r PARTXXI I GancerandBenignTumors toma, and atypical teratoid/rhabdoid tumor (ATRT), all of which are histologically classifiedas WHO grade IV tumors. Medulloblastoma, accounting for 90% of embryonal tumors, is a cerebellar tumor occurring predominantly in males and at a median age of 5-7 yr. Most of these tumors occur in the midline cerebellar vermis; however, older patients may present with tumors in the cerebellar hemisohere. CT and MRI demonstrate a solid, homogeneous, contrrri medium-enhancingmass in the posterior fossa causing 4th ventricular obstruction and hydrocephalus.Up to 30% of patients presentwith neuroimagingevidence of leptomeningealspread. Among a variety of diverse histologic patterns of this tumor, rhe most common rs a monomorphic sheet of undifferentiatedcells classicallynoted as small, blue, round cells. Neuronal differentiation is more common among thesetumors and is characterizedhistologically by the presenceof Homer Wright rosetresand by immunopositivity for svnaptophysin.An anaplasticvariant may be associated with worse prognosis. Patients present with signs and symptoms of increasedICP (i.e., headache,nausea,vomiting, mental status changes, and hypertension) and cerebellar dysfunction (i.e., ataxia, poor balance,dysmetria).Standard clinical staging evaluation includesMRI of the brain and spine, both preoperatively and postoperatrvely, as well as lumbar puncture after the increased ICP has resolved (Fig. a97-5). The Chang staging system,originallv basedon surgical information, has been modified to incorporate information from neuroimaging to identify risk categories.Clinical featuresthat have consistenrlydemonstrated prognosricsignificanceinclude age at diagnosis,extent of disease, and extent of surgical resection. Patients <4 yr o{ age have a poor outcome, partly as the result of a higher incidence of disseminateddiseaseon presentation and past therapeutic approachesrhat have used less intense therapies.Patientswith disseminareddiseaseat diagnosis(M>0), including positive CSF cytology alone (Ml), have a markedly worse outcome than those patients with no dissemination (M0). Similarly, patients with gross residual diseaseafter surgery have worse outcomes compared with those who had gross total resection of their disease. Cytogeneticand moleculir genericstudieshave demonstrated multiple abnormalities in medulloblastoma.The most common abnormality involveschromosome 17p deletions,which occur in 30-40% of all cases.These deletions are not associatedwith P53 mutations. Two new risk stratification systemsfor medulloblastoma combining molecular markers with clinical factors have been proposed. One system is based on retrospective analysis of information about histological variants (classic, nodular desmoplastic, anaplastic large cell); TRKC, MYCC, ERBB2, and MYCC expression; and clinical characteristics in children with medulloblastoma. One study found that the combination of clinical characteristicsand ERBB2 expression provided a highly accurate means of discriminating disease risk. Another study found that gene expression profiling predicted medulloblastoma outcome independent of clinical variables. Both approaches still 'Sfith the evolumust be validated in larger prospective studies. tion of gene array technologn preliminary studies have identified clusters of genes/geneexpression that appear to be associated with metastatic medulloblastoma and outcome. A multimodal treatment approach is pursued in medulloblastoma, with surgery the starting point of treatment. Medulloblastoma is sensitive to both chemotherapy and radiation therapy. Historically, surgery alone was ineffective. In the 1940s radiation therapy was found to be effective, improving overall outcome to 'With a 307o survival rate. technologic advancesin neurosurgery, neuroradiology, and radiation therapy, as well as identification of chemotherapy as an effective modality, overall outcome among all patients approaches60-70%. Standard radiation trea[ment in medulloblastoma incorporates craniospinal radiation at a total cumulative dose of 30-36 Gy, with a cumulative dose of 5055 Gy to the tumor bed. Craniospinal radiation at this dose in children <3 yr of age results in severe late neurologic sequelae, including microcephaly, learning disabilities, mental retardation, neuroendocrine dys{unction (growth failure, hypothyroidism, hypogonadism, and absent/delayedpuberty), and/or second malignancies. Similarly, in older children, late sequelae, such as learning disabilities, neuroendocrine dysfunction, and/or second malignancies,can occur. These observations have resulted in stratification of treatment approaches into three strata: (1) patients <3 yr of age; (21 standard risk patients >3 yr of age with surgical total resectionand no diseasedissemination(M0); and (3) highrisk patients >3 yr of age with disease dissemination (M>0) andlor bulky residual diseaseafter surgery. rlfith the risk-based Figtre 197-6. MRI scan of medulloblastoma.A, Sagittal T1-weighted image shows hypointense mass involving the vermis (arrows). B, Axial T2-weighted image shows hyperintense mass (arrotus) with a r e a s o f h y p o i n t e n s i t yr e p r e s e n f i n g acute hemorrhagic infarction within the medulloblastoma involving the vermis. (From Kuhn JP, Slovis TL, Haller JO: Caffey\ Pediatric Diagnostic Imaging, 1Oth ed. Philadelphia, Mosby, 2004, p 57a.) 497 I BrainTumorsin GhildhoodI 2135 Chapter approach to treatment, children with high-risk medulloblastoma receive full-dose cranial-spinal radiation with chemotheraov during and after radiarion iherapy. In children with nonmetastaiic medulloblastoma and sross total tumor resection, chemotherapy alone (methotrexate, ryclophosphamide, vincristine, carboplatin, etoposide) results in an overall survival of 90%". The presenceof residual tumor (56% survival) or metastases(38%) confers a poor prognosis. Supratentorial primitive neuroectodermal tumors (SPNET) account for 2-3"/" of childhood brain rumors, primarilv in children within the first decade of life. These tumors are similar histologically to medulloblastoma and are composed of undifferentiated or poorly differenriated neuroepithelal cells. Historically, patients with SPNET have had poo.ir ourcomes than those with medulloblastoma after combined modality therapy. In current clinical trials, children with these tumors are considered among the high-risk group and receive dose-intensechemotherapy with craniospinal radiation therapy. Atypical teratoid/rhabdoid tumor (ATRT) is a very aggressrve embryonal malignancy that occurs predominantly in children <5 yr of age and can occur at any location in the neuraxis. The histology demonstrates a heterogeneouspattern of cells, including rhabdoid cells that express epithelial membrane anrigen and neurofilament antigen. The characteristic cytogeneric parrern is partial or complete deletion of chromosome 22q that has been associatedwith mutation in the lNll gene.The relation between this mutation and tumorigenesis is unclear. Outcome after combined modality therapy with inrensivechemotherapyis very poor, but long-term survival has been reported in some children. Ependymoblastoma and medullomyoblastoma are rare, highly malignant embryonal tumors of early childhood and infancy. PINEAI PARENCHYMAT TUM0RS.The pineal parenchymal rumors are the second most common malignancies, after germ cell tumors, that occur in the pineal region. These include pineoblastoma, occurring predominantly in childhood, pineocytoma, and the mixed pineal parenchymal tumors. The therapeutic approach in this group of diseasesis multimodal. In the past, there was significant concern regarding the location of these massesand the potential complications of surgical intervention. With recent developmentsin neurosurgical technique and surgical technology, the morbidity and mortality associared with these approaches have markedly decreased. Stereotactic biopsy of these tumors may be adequate to establish diagnosis; however, consideration should be pursued for total resection of the lesion before institution of additional therapy. Pineoblastoma is the more malignant variant and is considered a subgroup of childhood PNET. Chemotherapy regimensincorporate cisplatin, cyclophosphamide (Cytoxan), etoposide (VP-16), and vincristine and/or lomustine. Data have shown that survival outcome of pineal region PNET with combined modality therapy of chemotherapy and radiation approaches 707o at 5 yr, similar to that noted for medulloblastoma. Pineocytoma usually is approached with surgical resection. NEUE0NAVMIXEDNEUR0NAL-GI|ALTUM0RS. Neuronal and mixed neuronal-glial tumors are a heterogeneous group of tumors that are slow-growing and of low malignant progression. They are associatedwith favorable outcome after surgical resection. They are categortzed as !7HO grade I or WHO grade II tumors. Diseasesin this category include ganglioglioma, dysembryoplastic neuroepithelial tumor, desmoplastic infantile astrocytoma, and desmoplastic infantile ganglioglioma. CRANI0PHARYNGI0MA. Craniopharyngioma (\fHO grade I) is a common tumor of childhood, accounting for 7-107" of all childhood tumors. The adamantinomatous variant of craniooharvngioma predominates in childhood. These rumors ,.. ,o[id *irh cystic components and occur within the suprasellar region. They are minimally invasive, adhere to adjacent brain parenchyma, and engulf normal brain structures. MRI demonstrates the solid tumor with cystic structures containing fluid of intermediate density. CT may show calcifications associatedwith the solid and cystic wall components. Surgery is the primary treatment modality, with gross total resection curative in small lesions. Controversy exists regarding the relative roles of surgery and radiation therapy in large, complex tumors. There is significant morbidity (panhypopituitarism, growth failure, visual loss) associatedwith these tumors and their therapy owing to the anatomic location. There is no role for chemotherapy in craniopharyngioma. MENINGEAI TUMORS.Meningiomas are uncommon tumors of childhood. These tumors arise from the arachnoid layer of the meninges and usually are very slow-growing. Among children, a large proportion of these tumors can be associatedwith either a genetic disposition such as neurofibromatosis type 2 or basal cell nevus syndrome or prior radiation exposure (secondary malignancy). GERMCEtt TUMORS.Germ cell tumors of the CNS are a heterogeneousgroup of tumors that are primarily tumors of childhood arising predominantly in midline structures of the pineal and suprasellar regions. They account fior l-2"/" of pediatric brain tumors. The peak incidence of these tumors is 10-12 yr of age. Overall, there is a male preponderance,although there is a female preponderance for suprasellar tumors. These tumors occur multifocally in 5-1.0Y" of cases.This group of tumors is much more prevalent in Asian populations than European populations. As in peripheral germ cell tumors, the analysis of protein markers, ctfetoprotein, and p-human chorionic gonadotropin may be useful in establishing the diagnosis and monitoring treatment response. Surgical biopsy is recommended to establish the diagnosis; however, nongerminomatous germ cell tumors may be diagnosed based on protein marker elevations. Therapeutic approaches to germinomas and mixed germ cell tumors are different. The survival proportion among patients with pure germinoma exceeds 90"h. The postsurgical treatment of pure germinomas is somewhat controversial in defining the relative roles of chemotherapy and radiation therapy. Excellent outcomes are reported in Datients who have received local field doses of radiation of >40 Gy and craniospinal radiation therapy. Similarly, groups have reported excellent outcomes when chemotherapy has been incorporated in regimens that utilize reduced doses of radiation therapy (24 Gy to the local field alone). More recently clinical trials have investigated the use of chemotherapy and reduceddose radiation after surgery in pure germinomas. The therapeutic approach in nongerminomatous germ cell tumors is more aggressive,combining more intense chemotherapy regimens with craniospinal radiation therapy. Survival rates among thesetumors are markedly less than noted in germinoma, ranging from 40-70% at 5 yr. Trials have shown benefit using high doses of chemotherapy with blood stem cell rescue.If confirmed in larger studies, future approaches may test the use of high doses of chemotherapy with dose-reducedradiation therapy. TUM0RS 0F THE BRAINSTEM.Tumors of the brainstem are a heterogeneousgroup of tumors that account for l0-15'/" of childhood primary CNS tumors. Outcome dependson tumor location, imaging characteristics,and the patient's clinical status. Patients with these tumors may present with motor weakness, cranial nerve deficits, cerebellar deficits, andlor signs of increased ICP. Based on MR evaluation and clinical findings, tumors of the brainstem can be classified into four types: focal (5-L0% ol patients); dorsally exophytic (5-L0%l; cervicomedullary (5l0'/"1; and diffuse intrinsic tumors (70-85%) fFigs. 497-7 and 497-81. Surgical resection is the primary treatment approach for focal and dorsally exophytic tumors and leads to a favorable 2136r PABTXXI I CancerandBenignTumors common in adults. The standard approach for treatment in diffuse infiltrating pontine gliomas has been radiation therapy, and median survival with this treatment is 12 mo, at best. Use of chemotherapy, including high-dose chemotherapy with blood stem cell rescue,has not yet been of survival benefit in this group of patients. Current approaches include evaluation of investigational agents alone or in combination with radiation therapy, similar to approaches being pursued in patients with malignant gllomas. Figure497-7.T1-weighred post-gadolinium sequence MRI (saginalimage)of a pontinediffuseinfilrratingglioma in a 10-yr-oldgirl presentingwith headache, cranialnervepalsies, and left-sided weakness. METASTATICTUMORS. Metastatic spread of other childhood malignancies to the brain is uncommon. Childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma can spread to the leptomeninges, causing symptoms of communicating hydrocephalus. Chloromas, which are collections of myeloid leukemia cells, can occur throughout the neuraxis. Rarely, brain parenchymal metastases occur from lymphoma, neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, and clear cell sarcoma of the kidney. Therapeutic approaches are based on the specific histologic diagnosis and may incorporate radiation therapg intrathecal administration of chemotherapy and/or systemic administration of chemotherapy. Medulloblastoma is the childhood brain tumor that most commonly metastaslzesextraneuronally. Less commonlS extraneuronal metastases from malignant glioma, PNEI and ependymoma can occur. Ventriculooeritoneal shunts have been known to allow extraneural metastaies, primarily within the peritoneal cavity but also systemically. MANAGEMENT ANDLONG-TERM COMPLICATIONS outcome. Histologically, these two groups usually are low-grade gliomas. Cervicomedullary tumors, owing to their location, may not be amenable to surgical resection but are sensitive to radiation therapy. Diffuse intrinsic tumors, characterizedby the diffuse infiltrating pontine glioma, are associated with very poor outcome independent of histologic diagnosis. These tumors are not amenable to surgical resection. Biopsy in children with MR findings of a diffuse intrinsic tumor is controversial and is not recommended unlessthere is suspicion of another diagnosis,such as infection, demyelination, vascular malformation, multiple sclerosis,or metastatic tumors. These diagnoses are much more Data from the National Cancer Institute SEER Program indicate that >707" of patients with childhood brain tumors will be longterm survivors. At least t/, of these survivors will experience chronic oroblems as a direct result of their tumor and treatment. These pioblems include chronic neurologic deficits such as focal motor and sensory abnormalities, seizure disorders, neurocognitive deficits (e.g., developmental delays, learning disabilities), and neuroendocrine deficiencies (e.g., hypothyroidism, growth failure, delayed or absent puberty). These patients also are at significant risk of secondary malignancies. Supportive multidisciplinary interventions for children with brain tumors both during Figure 497-8. A, SagittalT1-weighted MRI demonstratingbrainstem astrocytomawirh enlargementof the pons by a slightly hypointensemass(arrows). B, Gadolinium-enhancedsagittalT1-weightedimage demonsrratingbrainstemastrocytoma,without enhancemenr,and slightly hypointensemass (arrows) enlarging the pons (From Kuhn JP,SlovisTL, Haller lO: Caffey'sPediatric Diagnosticlmaging, 1Othed. Philadelphia,Mosby,2004,p 577.) r 2137 498 r Neuroblastoma Ghapter and after therapy may help improve their ultimate outcome. Optimal seizure management, physical therapy, endocrine management with timely growrh hormone and thyroid replacement therapn tailored educational programs, and vocational interventions may enhance the childhood brain tumor survivor's quality of life. r&jfinP.ffir,'-.r j,-*:??ji:,.-!-:.-yrt+!\.i:::jrr ilitli ri:.r::.,rr,rr;.r i -r:j..jl Fernandez-Teijeiro A, BetenskvRA, Sturla LM, et al: Combinrnggeneexpression profiles and clinical paramerersfor risk stratificationin medulloblastomas../ Clin Oncol 200\ 22:994-998. FreemanCR, PerilongoG: Chemorherapyfor brain stemgliomas.Childs Neru S y s /1 9 9 9 ; 1 5 : 5 4 5 - 5 5 3 . Gajjar A, Hernan R, Kocak M, et al: Clinical, hisropathologic,and molecular markers of prognosis:Toward a new diseaserisk stratificationsystemfor medulloblastomaI Clin Oncol 2004;22:984-993. Grill J, Sainte-RoseC, Jouvet A, et al: Treatment of medulloblasromawith postoperativechemotherapyalone:An SFOPprospectivetrial in young children. Lancet Oncol 2005:6: 573-580. Gurney JC, Smith MA, Bunin GR: In Reis LAG, Smith MA, Gurney JC, et al (editors):CancerSuruual and lncidenceAmong Children and Adolescents: United StatesSEF.RProgram 1975-1995. Bethesda,MD, Narional Cancer Institute SEER Program NIH publicarion No. 99-4649, 1999, pp 51-6j. Kleihues P, Cavenee WK: World Heahh Organization Classification of Tumours:Pathologyand Geneticsof Tumours of the NeruousSystem.Lryon, I A R C P r e s s2, 0 0 0 . Mellinghoff IK, Wang M\ Vivanco I, er al: Molecular determinationsof rhe response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353:2012-2024 Merchant TE, Mulhern RK, Krasin MJ, et al: Preliminaryresultsfrom a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effectsfor pediatricpatienrswirh localizedependymoma./ Clin Ontol 2004115:3156-3162. Packer RJ, Cohen BH, Coney K: Inrracranial germ cell tumors. Oncologls/ 2 0 0 0 : 5 : 31 2 - 3 2 0 Pollack Il FinkelsteinSD, Woods J, et al: Expressionof p53 and prognosisin children with malignant gliomas N Engl I Med 2002i346:420426. Rutkowskr S, Bode U, Deinlein F, er al: Trearmentof early childhood medulloblastoma by postoperarive chemotherapy alone. N Engl J Med 2 0 0 - 5 ; 3 5 2 : 9 7 88 - 96 . Shaw EG, \Tisoff JH: Prospectiveclinical trials of inrracranial low-grade g l i o m a i n a d u l t sa n d c h i l d r e n .N e u r o o n c o l2 0 0 3 ; . 5 : 1 5 3 - 1 6 0 . StrotherDR, PollacIF, FisherPG, et al: Tumors of the centralnervoussystem ln Przzo PA, Poplack DG (editors): Principles and Practice of Pedntric ()ncology,5th ed. Philadelphia,Lippincott Williams & Wilkins, 2005. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapyplus concomitant and adjuvant temozolomide for glioblastoma N Engl I Med 2005l'352:987-996 Zebrack BJ, Gurney JG, Oeffinger K, et al: Psychologicaloutcomesin longterm survivors of childhood brain cancer: A report from rhe Childhood Cancer SurvivorsStudy./ Clin Oncol 2004)2:999-1006. {;:aj:=:::qi:-;-.:s{"ir:ti!ll!Mr**i.n+:: :i 28-39% of neonatal malignancies. The median age at diagnosis is 2 yr, and 90% ol casesare diagnosed by 5 yr of age. The incidence is slightly higher in boys and in whites. FATH0LOGYNB includes a sDectrum of tumors with variable degrees of neural differentiati,on. ranging from undifferentiated small round cells (neuroblastoma)to tumors containing mature ganglion cells (ganglioneuroblastoma or ganglioneuroma). The tumors may resembleother small round cell tumors, such as rhabdomyosarcoma, Ewing sarcoma, and non-Hodgkin lymphoma. The prognosis varies with the histologic definition of tissue pattern (Shimada classification). Prognostic factors include the amount of stroma, degree of tumor cell differentiation, presence and prominent nucleoli, and the mitosis-karyorrhexis :j#:r*.0 PATH0GENESIS. The genetic event that initially triggers formation of NB is not known. The pathogenesisis likely to be related to a successionof mutational events,prenatally and perinatally, that may be caused by environmental and genetic factors. Increased incidence of NB is associatedwith some maternal and paternal occupational chemical exposures, work in farming, and work related to electronics. Familial NB is found rn 1,-2%' of cases. Neuroblastoma and consenital cardiovascular malformations also may be associated. Genetic characteristics of NB tumor tissue that are of prognostic importance and currently are used along with clinical factors to determine treatment include amplification of the MYCN (N-myc) proto-oncogene and hyperdiploidy of tumor cell DNA content (Table 498-1). Amplification of MYCN has prognostic importance independent of stage and age and is strongly associatedwith advanced tumor stage and poor outcome. Hyperdiploidy confers better prognosis if the child is <1 yr of age at diagnosis. Genetic abnormalities, including loss of heterozygosity (LOH) of 1p, 11q, and 14q, and gain of 1,7q,commonly are found in NB tumor tissue.In addition, other biologic factors that correlate with prognosis include the level of nerve growth factor receptor (Trk-A) expression, multidrug-resistance-associated protein. and telomerase activity. These factors are under investigation in clinical trials to determine whether they can be used to further refine risk-based therapy. Thus, therapy can be reduced for children predicted to fare well with minimal therapy and intensified in those predicted to be at high risk of relapse. NB can mimic many other disorders CtINICALMANfFESTATI0f{S. and may be difficult to diagnose. NB may develop at any site of sympathetic nervous system tissue. The signs and symptoms of NB reflect the tumor site and extent of disease.Most casesof NB arise in the abdomen, either in the adrenal gland or in retroperitoneal sympathetic ganglia. Usually a firm, nodular mass that is palpable in the flank or midline is causing abdominal discomfort. RISI( 6ROUP IN555TA6T A6E Neuroblastoma (NB) is an embryonal cancer of the peripheral sympathetic nervous system with heterogeneousclinical presenfation and course. The clinical spectrum of NB varies, ranging from spontaneousregressionin some types to very aggressive tumors unresponsiveto multimodality therapy in others. It is now recognized that more than one type of NB exists. Low Averaqe H,gh EPIDEMI0LOGY. NB is the third most common pediatric cancer, accountingfor about 8% of childhood malignancies.About 500 new cases are diagnosed each year in rhe USA. NB is the most commonly diagnosed neoplasm in infants, accounting for 1 ) ) 45 { Jand4 45 2 3 4 4 All < 1y r > 1y r < 1Y r >l yr <1yr <l Y' > 1y r All <lyr > 1Y l 5faging synem N€ur0bla5t0ma 1N55, Intemati0nai MYCI.i sTATU5 SHIMADA HI5TOLO6Y SURVIVAL Any Any Any < 1 0( o p i e s <10copies <10copies <10copies Any >10copies >10copies Any Any Any Favorable Favorable Favorable Any Unfavorable Unfavorable Any Any Any 90-10070 15-98V0 20-6070 2138I PARTXXI r CancerandBenignTumors eral lymph node involvement. Stage 3 tumors extend beyond the midline, with or without bilateral lymph node involvement. Stage 4 tumors are disseminated to distant sites (e.g., bone, bone marrow, liver, distant lymph nodes, other organs). Stage45 refers to children <1 yr of age with dissemination to liver, skin, or bone marrow without bone involvement and with a Drimary tumor that would otherwise be stase 1, or 2. TREATMENT. The most important clinical and biologic prognostic factors currently used to determine treatment are the age of the patient at diagnosis, stage of disease, MYCN status, and Shimada histology (seeTable 498-1,).The prognosis has improved with current treatment reeimens. The usual treatment for lowrisk NB is surgery for stages 1 and 2 and observation for stage F i g u r c . 1 9 8 - 1 .P e r r o r b i t a metastases l of neuroblastomawith proptosis and ecchymoses. On plain radiographv or CT the massoften containscalcification and hemorrhage. Wilms tumor, another common flank mass in a young child, usually does not calcify. NB originatesfrom cervical, thoracic, or pelvicgangliain 30% of cases.Metastaticdisease can be associatedwith myriad signs and symptoms, including fever,irritability, failure ro thrive, bone pain, bluish subcutaneous nodules, orbital proptosis, and periorbital ecchymoses(seeFig. 498-1). The most common sitesof metastasisare the long bones and skull, bone marrow, liver, lymph nodes, and skin. Lung metastasesare rare, occurring in <3o/" of cases.Prenataldiagnosis of NB sometimesis possibleon maternal ultrasound scans. Lesscommonl,v,children present firsr with neurologic signs and symptoms. Location in the superior cervical ganglion can result in Horner syndrome, Paraspinal NB can invade the neural foramina, producing symptoms of spinal cord and nerve root compression.NB can present as a paraneoplasticsyndrome of autoimmune origin manifesting as ataxia or opsomyoclonus ("dancing eyes and dancing feet"). In such cases,the primary tumor is in the chest or abdomen, and the brain is negative for tumor. Some tumors produce catecholaminesthat can cause increasedsweating and hypertension,and some releasevasoactive intestinal peptide, causing a secretory diarrhea. Children <1 yr of age also can presentwith a unique stage,45, which often includessubcutaneoustumor nodules,massiveliver involvement, and a small primary tumor without bone involvement. DIAGNOSIS. NB usually is discoveredas a massor multiple masses on plain radiographs,Cl or MRI (Fig.498-2). Tumor markers, including homovanillic acid (HVA) and vanillylmandelic acid (VMA) in urine, are elevatedrn 95'/" of casesand help to confirm the diagnosis.A pathologic diagnosisis establishedfrom tumor tissueobtained by biopsy.NB can be diagnosedin a typical presentationwithout a primary tumor biopsy if the patient has neuroblastsobservedin bone marrow (Fig.a98-3) and elevatedVMA or HVA in the urine. Evaluationsfor metastaticdiseaseshould include bone scan to detect cortical bone involvement and bone marrow asoiratesand biopsies to detect marrow disease.On experimental protocols, positron emission tomography and iodine 131 or iodine 123 meta-iodobenzylguanidine (I-123 MIBG) studies also may be used to better define the extent of disease.The clinical extent of diseaseand the patient's age, together with cytogenetic and molecular marker testingperformed on the tumor tissue,are used to estimate rhe prognosis and to guide the choice of which riskdirected therapy. Although severalstaging systemshave been used in the past, the International Neuroblastoma Staging System (INSS) now is universallyused (Table 498-2\.In the INSS, stage 1 includes tumors confined to the organ or structure of origin. Stage 2 tumors extend beyond the structure of origin but not across the midline, with (stage28) or without (stage2A) ipsilat- t, i .:' \ Figure 498-2. Top, CT scan of a thoracic neuroblastomawith intraspinal extension at diagnosis.Middle, CT scan of adrenal primary with extensive lymph node involvement.Bottom, Bone scintigraphywith technetiumdiphosphonate demonstratingdiffuse skeletalinvolvement. . 2139 498 ! Neuroblastoma Chapter Iiqurc-19$-),. Neuroblastoma cellsaspirated fromthebonl -"r.o*. Clu-p, of cellsoftencontain23 cellswith or withoutevidence of rosetteformation Rosettes of cellssurrounding an innermassof fibrillarymaterial arecharacteristic of neuroblastoma 45. Even in stage 2 wrth small amounts of residual tumor, the cure rate is >90% without further theraov. Treatment with chemotherapvor radiation for the rare child wlth local recurrence still can be curative. Children with spinal cord compressionar diagnosisalso may require urgent treatment with chemorherapn surgery,or radiation to avoid neurologtcdamage.Stage45 has a verv favorable prognosis,with nearly 1007o survivai with supportive care onlv, becausethe tumor regressesspontaneously. Chemotherapv or resection of the primary tumor does not improve survival. Infanrs <2 mo of age wirh stage45 are more at risk if they have massive liver involvement and respiratorv compromise. In such infants, low-dose cyclophosphamideor verv-low-dosehepatic radiation mav be recommendedto alleviate svmptoms.For children with stage45 NB who require trearment for symptoms,the survival rate is 817". Treatment of intermediate-risk NB includes surgery, chemotherapv. and, in some cases, radiation therapy. The chemotherapvusuallvincludesmoderatedosesof cisplarinor carboplatin, c,vclophosphamide, etoposide,and doxorubicin given for severalmonths. Radiation therapy is used for tumors with incomplete response to chemotherapv. Children with stage 3 drseaseand infants with stase4 diseaseand favorable characteristics have an excellent prognosis ol >90'/" survival with this moderate treatment. In this intermediate-risk group, obtaining adequate diagnostic material for determination of the Shimada pathologic classification and for MYCN amplficatron is critical, can receivemore so that children wrth unfavorablecharacteristics aggressivetreatment and those with favorable features can be spared excessivetoxic therapy. The usual treatment for high-risk NB (see Table 498-1) is induction chemotherapy to achieve complete response or very good partial response. lfith partial response, resection of the primary tumor followed by focal radiation to residual tumor is recommended. Induction is then followed by high-dose chemotherapyand autologousstem cell transplantation(SC'I). A national randomized study showed significantly improved survival with SCT compared with chemotherapy without SCT. The addition of cls-retinoic acid after SCT for 1 yr further improved the 5-yr event-free survival to 50%, compared with 20''/" for rhose treated with chemotherapy without SCT or cis-retinoic acid. Better therapy is needed for most patients with high-risk NB. New therapies currently under investigation include new chemotherapeutic agents, high-dose chemotherapv with multiple srem cell rescues,monoclonal antibodrescombined wrth growth facrors, and antitumor vaccines.It also is hoped that biologic studies of NB eventually will lead ro new genetic targets for therapy. PREVENTI0N. Currently there is no recognizedway to prevent neuroblastoma. A worldwide attempt to improve survival by early detection through infant catecholamine screening has proven to be ineffective. 1p and 11qdeletions AniyehEF,l.ondonWts,MosseYP,., ul Ch.ornorome N L.nglJ Med 2005;353:2243-2253andoutcomein neuroblastoma. autoantibodies to cereBlaesF,Fuhlhuber V, KorferM, et al: Surface-binding in opsoclonus syndrome. Ann Neurol2005;58:313-317 bellarneurons Biologicalinsightsinto a clinicalenigma BrodeurGM: Neuroblastoma: 6. Nature ReuCancer2003;3:203-21. exposures K, et al: Parental occupational to De RoosAJ, OlshanAF,Teschke chemicalsand incidenceof neuroblastomain offspring Am I Eltdemiol 2 0 0 1 ; 1 - 5 4 : 1 0 51-41 (ieorge RE, Lipshultz SE, Lipsitz SR, et al: Associationbetweencongenital cardicrvascularmalformations and neuroblastoma J Pediatr 2004;144: 144-448. (iolclsby RE, Matthay KK: Neuroblastoma:Evolving therapiesfor a disease of manv faces Pdedntr Drugs 2004;6:1,07-1,22 STAGT DEIINITION I Localized gross tum0r withcomplete ex(isi0n, wrth0rw thout negative mraoscopir residual lpsilateral lymph nodes disease; representative (nodes fortumor microscopically attached toandremoved withtheprimary tum0r maybeposltive) Lotalized gross tum0r withincomplete excision; representative ipsilateral nonadherent lymph negative fortumor microscopkally nodes Localized tumor gross with0twithout complete posit excrsion, withipsilateral convalateral nonadherent lymph nodes vefortumor. [nlarged lymph nodes y must benegative mirroscopicl Unresectable ilnilateral tum0r infiltrat!ng aCross themldline,r with0rwithout unilateral tumor reqional lymph node involvement; orlocalized (resenable) withc0ntralateral regional lymph invo vement; node ormidltne tum0r orbylymph withbilaterai enensl0n bylnfltrati0n node involvement Anyprimary (except tumor withdssemination forstage t0distaft lymph nodes; bong bone marrow, organs asdefined live[ skin, andother 2A )B J 4 sURVIYAI AT5 YR' 5 2900/o t! I 70-8AVo 70-8090 )t 40-740,6 c! 85-900/0 ifageatdagnosis is<]8 m0 js>,18mo 30-4070 ifagea daqnosis >8AVa 4t 45 (asdefined primary (limited Loialized tumor forstage 1,2A, or28),withdissemination limlted toskin, liver; andbone manowt toinfants < 1y r o f a g e ) 5 *5urvrval srnfluenced byother chara(teristl(s such asMyt{ampliicatton Per(entaqes areapprcxlmate .]hemid|ineisdefnedastheVefebral(0|UmnJUm0r50riginatng0|0ne5ideand(|o55ingthemid|inen]Ustinn]Uatet00Ibey0ndthe0pp0site5ide0ftheVerteb|(0]U benegative n themanow t0lreatment / [r, ,rr0l 1993,11 1466-1411 N/18G, metaiodobenzylguanidin€ 2140 I PARTXXI I Cancer and Benign Tumors Inagaki J, Yasui M, SakaraN, et al: Successfultreatment of chemoresistant stage3 neuroblastomausing irinotecanas a single agent.J Pediatr HematoL Oncol 2005:27:604-606 Matthay KK, Villablanca JG, Seeger RC, et al: Trearment of high-risk neuroblastoma with inrensive chemotherapy, radiotherapy, autologous bone marrou' transplantarion, and 13-cis-retinoicacid. N Engl J Med 1 . 9 9 9 : 3 4:1 , 1 .56- 1 1 73 N i c k e r s o nH J , M a n h a v K K , S e e g eR r C , e t a l : F a v o r a b l eb i o l o g ya n d o u t c o m e of stage IV S neuroblasromawith supportive care or minimal therapy: A Children'sCanccr Ciroup studv. i C/rz Oncol 2000;18:477486. P e r e zC A , M a t r h a vK K , A t k i n s o nJ B ,e t a l : B i o l o g i c avl a r i a b l e si n r h eo u t c o m e of stagesI and Il neuroblasromatrearedwirh surgery as primary therapy: A Children's(.ancer Group Srudy / C/ln ()ncol 2000;18:78-26. R u d n i c kE , K h a k o o Y , A n t u n e sN l . , e t a l : O p s o c l o n u s - m y o c l o n u s - a t asxyrna d r o m e i n n e u r o b l a s t o m aC; l i n i c a l o u t c o r n ea n d a n t i n e u r o n a a l ntibodies: A reporc fronr the Children\ C.ancer(iroup Study Med Pediatr Oncol 200I:36:61.2-622 S c h m i d tM l , I - u k e n sJ N , S e e g eR r C , e t a l ; B i o l o g i cf a c t o r sd e t e r m i n ep r o g nosis in infanrs u,ith stage IV neuroblastoma:A prospectiveChildren's Cancer Group Studr. / C/rr Oncol 2000;1,8:1260-1268 Van Noesel N{M, VersteegR: Pediarricneuroblastomas:Genetic and epigen e t i c ' D a n s eM a c a b r e . 'C e n e 2 0 0 4 , . 1 2 . 5 : 1 - 1 . 5 Woods \JfG: Screenrngfor neuroblasroma:The final chapters ] Pedntr Hentatol Oncol 200325 :3-4. oWrrrus 499.1 Turuon ET|OL0GY. Wilms tumor, also known as nephroblastoma, is a complex mixed embryonal neoplasmof the kidney composedof three elements:blasrema,epithelia, and stroma. Most casesof Wilms tumor are sporadic, aithough 1-2%" of patients have a 'Wilms family hisrorv. Familial predispositionto tumor is inherited in an autosomal dominant manner. Familial casesare associated with a lower age at diagnosisand an increasedfrequency of bilateral disease,although these featuresare not observedin all families. Congenital anomalies are absent in most families. Nephrogenic rests often are associatedwith tWilms tumor. One Wilms tumor gene,\WT1 located at 11pl3, has been isolated among the geneticalterationsobservedwith Wilms tumor (Table 499-1). WT1 encodesa zinc finger transcription factor, which is critical for normal kidney development.Roughly 20% of all \films tumors carry WT1 mutations, and most of these mutations are tumor-specific. Parients with Wilms tumor who have associatedcongenital anomaliesoften carry germline WT1 mutations. Familial predispositionto Wilms rumor usually is nor 6EI,|E wrl (HARACITRISTIC WItMS TUMOR IREQUEI'IflTYPE OTALTERATION -20% Unselected Deletions, trunratinq mutations, F(atenin Unselected ,(? Tumors withWT'lmutations (-20%ofrotal) Anapla$ic histology (-570oftotal) -15% -50% -80% SYNDR()ME WAGR CHROMOSOME OROTHEB (HAftACIERISTI(SABIIORMALITIES CTIHI$I" (l{Il andP,#{6 Del11p13 loci) Aniridia,genitouriMryabnormalities, ' mental'retordation Early.onset reialfailure withrenal l4ll mutations mesangial s(lerosis, male pseudohermaphrodism, tumor inrreased risk ofWlms (liver,kidney,adrenal, paternal Uniparental disomy,duplication 0rganomegaly Beckwith-Wedemann pancreas), 11p15 5,losofimpdnthq mutation ma(mglossia hemihypertrophyofp57KlP57 have been destribed. omphalocel€, (l{I2locus) Del11p15.5 Htggenes May involve /6F2 also and/or Denys-Drash associated with WT1 alterations; familial predisposition genes have been localizedto 19q13 and L7q. Severalsyndromes and congenital abnormalities commonly are reported in patients with Wilms tumor (Table 499-2ir. WAGR syndrome is a contiguous gene deletion syndrome that consists of Wilms tumor, aniridia, genitourinary abnormalities (cryptorchidism, streak ovaries, bicornate uterus, ambiguous genitalia), and mental retardation. Patients with this syndrome have a constitutional deletion of chromosome 11p13 where the Wilms 'WT1, and the aniridia gene, PAX6, are located. tumor gene, Denys-Drash syndrome is characterized by male pseudohermaphrodism, early-onset renal failure characterizedby mesangial with this sclerosis,and an increasedrisk of Wilms tumor. Patients .WT1 gene. syndrome typically carry a missensemutation in the Beckwith-Wiedemann syndrome is characterized by hemihypertrophy, macroglossia, and visceromegaly, with a 3-5"/" risk of developing Wilms tumor. A variety of 11p15.5 abnormalities have been reported in patients with this syndrome, and it is postulated that a second Wilms tumor gene, WT2, is located in this region. Loss of imprinting of the insulin-like growth factor 2 gene, an epigenetic process,also is associatedwith'Wilms tumor. Other syndromes or conditions with an increased risk of Vilms tumor include hemihypertrophy, sporadic aniridia, genitourinary anomalies, Pearlman syndrome, Sotos syndrome, neurofibromatosis (von Recklinghausen disease), and von Willebrand disease.The genirourinary anomalies most commonly associated with Wilms tumor are hypoplasia, fusion and ectopia of the kidney, duplications of the collecting systems,hypospadias, and cryptorchidism. EPIDEMI0L0GY. The incidence of \7ilms tumor is approximately 8 casesper million children <15 yr of age. It usually occurs in children between 2-5 yr of age, although it has also been encountered in neonates,adolescents,and adults. It accounts for approximately 6o/oof pediatric cancers and is the second most common malignant abdominal tumor in childhood. It may arise in one or both kidneys; the incidence of bilateral Wilms tumor is 7"/".It may be associatedwith hemihypertrophy, aniridia, and other congenital anomalies,usually of the genitourinary tract. It also has been described in association with a varietv of svndromes. PATH0GENESIS. Two broad categoriesof Wilms tumor have been recognized:favorable and unfavorable. The favorable form is the missense mutations rnzinc finger more common form and usually carries a good prognosis. It is encoding exons characterized by blastema, epithelia, and stroma devoid of mutations Mrsense ordeletions proteln phosph0rylation ectopia or anaplasia. Small amounts of sarcomatous elements in affecting the stroma in an otherwise favorable type apparently do not sites adversely influence the prognosis. The unfavorable form is characterizedby marked enlargement of the nuclei, hyperchromatism Missense andtruncating mutations of the enlarged nuclei, and multipolar mitotic figures. Areas of anaplasia may be focal or diffuse and predict probable high rates r Neoplasmsof theKidneyr 2141 Chapter499 of tumor relapseand death. It tends to occur in older, non-white patients.Clear cell sarcomais a subtypeof the unfavorableform, and usually metastasizesto bone. Rhabdoid tumor, which may metastasizeto the brain, is no longer classifiedas a subtype of 'Wilms tumor. Nodal or other potential metastaticsites usually are the best areasfor identifying anaplasia,which is extremelyuncommon rn children <2yr of age. A high index of suspicionand more rhorough samplingtechniquesare appropriateif anaplasiais detected, particularly in older children. The phenomenon usually is not found once chemotherapy has been administered. Anaplasia related to skeletalmuscle cells does not appear to be associated with an increasedincidenceof relaose. MANIFESTATI0NS. CLINICAL Wilms tumor usually presenrsas an abdominal mass. It generallyis discoveredfortuitously, and ir is not uncommon for the parent to notice it while bathing the infant. It also may be identifiedduring a well child examination. Theserenal massesvary in size,usually are smooth and firm, and occasionallymay cross the midline. Some patients may present with abdominal pain and vomiting, and hematuria is seen in 12-25% of patients. Hypertension also has been describedand probably is due to renal ischemia.Occasionally,rapid abdominal enlargement and anemia may occur due to bleeding into the renal parenchyma or pelvis. Tumor growth into the renal veins or vena cava may embolizeto the heart or lungs,with grave consequences. DIAGNOSIS" Any abdominal mass in a child must be considered malignant until diagnosticimaging and laboratory findingsdefine its true nature. If there is any doubt, biopsy or excision and histological verification is the final arbiter. Wrlms tumor must be differentiated from a variety of malignant abdominal and pelvic tumors (Table 499-3). Once an abdominal mass is discovered,a completephysicalexamination should be performed,followed by a complete blood count, liver and kidney function studies,and a search for specific tumor markers secreted by the suspected tumor. Imaging studiesinclude a flat plate of the abdomen,ultrasonography,and CT and/or MRI. CT scanningprovides confirmation of the intrarenal origin of the mass (Fig.499-1). It also may provideinformation on the extent of tumor, growth into the inferior vena cava, and integrity TUMOR AGE Wilms Preschool Unilateralflankmass,anindia, llematuria; bone scintiqraphy (clear hemihypertrophy cellsarcoma) CTINICAL SIGNS I,ABORAIORY f It,IDINGS Neurobla$omaPreschoolGI/GUobstruction,raccooneyes, Increased VMA; increased my0cr0nus-0ps0cr0nus, HVA; increased diarrhea, skin nodules ferritin; stippled (infants) calcifcation inmass positive Bone marrcw Non-Hodgkin >1 yr lntussusception in>2-yr-old Increased urate; bone marrow lympn0ma p0srtlve Rhabdomyosarcoma All Gl/GU obstruction,sarcoma botryoides, vaginal bleeding, ^.,"+^.ri.,,!., -,.. p0r0tf)uLul0t iltd)) pain, Germcell/teratoma Preschool, 6irls: vaginal abdominal teens bleeding Increased AFP h(6;lncreased Eoys:testicular mass, new-onsel "hydrocele" 5acrococcygeal mas/dimple yr [arggflrm Hepatoblastoma Birth-3 liver ncreased AFP Hepatoma School age, Large,firm Increased liver;hepaitis B, AFP teens cifrhosis gonadotropin; AFedjetoprotein; G1,gastrointestinal, GlJ,genitourinary; h[G,humanchoron]c HVA, homovanill( a0d; VMA.vanillvlmarde icacid I:igure 4!)c)-l A, CT scan of the abdomen demonstrating a massive left \films tumor B. Morbid anatomic view of the resected tumor seen in A of the contralateral kidney. Tumors enhance slightly after injection of contrast medium, which is useful for determining the function of the uninvolved kidney in the event that nephrectomy is required. MRI also helps to define the extent of tumor. Ultrasonography also may contribute to identification of the tumor and provide rnformation regardrng the integrity of the inferior vena cava as well as the presenceof tumor in the renal vein or vena cava. Occasionally, angiography may be requested to plan rhe surgical procedure. Bone scans are obtained for clear cell sarcoma of the kidney and MRI or CT of the brain in a malignant rhabdoid tumor. Radiographic examination of the chest is required to determine the presenceof pulmonary metastases.CT scans of the lungs are not routinely obtained, because pulmonary metastases from Wilms tumor can be identified on conventionai radiograph. Occasionally a CT scan demonstratesisolated nodules in patients with normal chest radiographs; the true nature of these nodules is uncertarn. 2142. PARTXXI I CancerandBenignTumors Most centers follow chemotherapy guidelines provided by the National ril/ilms Tumor Study Group. For stage I and II tumors with favorable histologn vincristine and actinomycin D are STAGEDESftIPTION administered. For stage III tumors with favorable histology, vinI Tum0r Stage islirnited tokidney andiscompletely,excised,Capsular intact; n0tumor rupture; surface cristine, actinomycin D, and doxorubicin are administered, and n0residual tumor apparent beyond margifts 0feKision radiation therapy also is administered to the tumor bed. For stage Stage Il Tumor extends beyond kidney butisrompietely excised, Regional extension oftumor;vesel IV tumors with favorable histologn vincristine, actinomycin D, infiltration;tumor biopsied orlocal spillage oftumor confined h theflank Noresidual lumor and doxorubicin are administered, and radiation therapy also is apparent atorbeyond margins ofexcision administered to all the sites of known disease,particularly the lll Residual Suge non-hematogenous tumor confined t0theabdomen Lymph node involvement of lungs. If tumor in the liver is present, surgical resection rather periaortic hilus, peritoneal chains, orbeyond; diffuse contamination bytumorspillage; peritoneal implants 0ftumor,tumor than radiation therapy may be considered. Resistant tumors that extends margins micrmcopically beyond surgical or ma(roscopically;tumor notcompletely removable intovital because oflocal infrltratlon fail to respond to chemotherapy and radiation therapy, or tumors Strucures that recur, may be consideredfor surgical resection and alternate, Stage lV Deposits beyond stage lll(e.g,lung, liver, bone, brain) investigational chemotherapy. Suge V Bilateral renal involvement atdiagnosis For tumors with unfavorable histology, vincristine, acrino(ommitteeWilmltumor:status lvodified fiom NationalWilmilumfi study rE0ft,190 .l1in1ncol191;9:877-887 mycin D, doxorubicin, and cyclophosphamide are administered, and radiation therapy also is administered to all the known sites of disease.Clear cell sarcoma of bone has resoonded to a combination of cisplatin, doxorubicin, and radiarion therapy. Additional therapy with cyclophosphamide or ifosfamide also may be STAGING. The staging systemmosr often used was developedby considered. the National \Wilms Tumor Study group (Table 499-41 and the Most patients tolerate treatment extremely well, although stage correlates with prognosis (Ta6le 499-5). Stage I Wilms therapy may cause both acute and chronic adverse effects. Most tumor is confined to the kidney and, by definition, is excisedcomacute adverse effects consist of nausea, vomiting, and myelosuppletely with the capsular surface intact. StageII Wilms rumor also pression with possible superimposed infection. Antiemetics is confined to the kidney, although the capsule is penetrated or usually are administered for transient nausea and vomiting. tumor is present in the perirenal soft tissue.StageIII \il/ilms tumor Actinomycin D and doxorubicin may cause mouth ulcers, which has postsurgical residual non-hematogenousextension. Spread is usualiy are mild and inconsequential.Vincristine may cause conconfined to the abdomen and may involve the perirenal bed, stipation and abdominal pain. Chronic adverse effects may draining lymph nodes, or the surrounding tissue and organs by involve the gastrointestinal, hepatic, cardiac, reproductive, and contiguity. Stage IV Wilms tumor is characterized by hematogeskeletal systems. Intestinal obstruction may result from adhenous metastases.The metastasesusually involve the lungs and sions, fibrosis, or volvulus. Rarely, radiation therapy enteritis or occasionally the liver. Stage V Wilms tumor is characterized by malabsorption may supervene.Severehepatic damage may occur bilateral renal involvemenr. with veno-occlusive disease,which usually is caused by the concomitant administration of actinomycin D with radiation therapy TREATMENT.Controversial issues in the management of Wilms to the liver. tumor include the use of preoperativechemotherapyand radiaCongestivecardiac failure may occur after treatment with doxrion therapn and also the composition of chemotherapeutic orubicin, particularly if administered in combination with radiaagents.The intent is to reduce the incidenceand nature of late tion therapy to the lungs. The cumulative dose of doxorubicin effects while providing optimum therapy. Indications for partial usually is limrted, to prevent cardiac damage, to 200-300 md^t, nephrectomy must still be defined, as must the role of surgery particularly in patients with pulmonary metastaseswho will subalone in patients with low-risk Wilms tumor. The optimal presequently receive pulmonary radiation therapy. operativeimaging approach to assessthe nature of the diseasein Radiation therapy to the chest can affect breast maruration, the presenting kidney and contralateral kidney for bilateral 'Wilms and treatment to the uterus may result in low birthweight infants. tumor also has not yet been determined. Radiation therapy to the ovaries may result in premature Surgical extirpation of the tumor should be performed. The menopause and reproductive dysfunction. Kyphoscoliosis also patency of rhe inferior vena cava should be established prior to may occur after radiation therapy if it is administered to the hemithe resection; if it is not patent, preoperative chemotherapy abdomen with only part of the vertebral column included in the should be administered. During the operation the contralateral but usuallycan be avoidedwith modern kidney should be examined to exclude bilateral Wilms tumor. The ;:.0iil!T..:.rtal, liver should be inspected for possible metasrases,although C! Recurrent tumors and pulmonary metastases may develop MRI, or ultrasonography may have identified metastasespreopwithin the frrst 2 yr after diagnosis.A variety of follow-up schederatively. The retroperitoneal lymph nodes should be examined ules have been implemented for early detection and treatment, and suspicious nodes biopsied for tumor rnvolvement. Every such as monthly follow-up with a clinical evaluation and chest attempt should be made to avoid spillage of tumor. radiograph for the first 2 years. The interval between visits over the next 3 yr is extended, and at the 5th year the visits are annual. Ultrasonography of the abdomen is performed after compietion of treatment to detect the presenceof recurrent tnmot estabiish the integrity of rhe coniralateral kidney, and is then "trd obtained annually. It also is important for long-term sursuRvrvAr vivors to have systematic follow-up with measurementsof blood HISTOTOGY/STAGE 2 Yr(%) 4 Yr(%) pressure, urine protein, serum creatinine, renal clearance, and Favorable | renal size, especially if they were treated for bilateral \(ilms 98 9l Favorable ll 96 94 tumor. Favorablell 91 88 lnoperableWilms Tumor.Chemotherapy is administered for all Favorable lV 88 82 Wilms tumors that appear inoperable. In these circumstancesthe Anapla$ic | 89 89 diagnosis usually is established by percutaneous needle biopsn Anaplastic ll-l\/ 56 54 with the selection of chemotherapy dictated by histologic criteM0diied fromNational Wilm(TumOr study [omn]ifiee:Wilm( tum0r. status reputj990 Jlin )nol 1991;9.877-BBl ria. For tumors with favorable histologn vincristine and actino- I Neoplasmsof theKidneyr 21t(l Chaptet4!19 mycin D are used for stagesI and II, with vincristine, acrinomycin D, and doxorubicin for tumors of stagesIII and IV. For tumors with unfavorable histology, treatment involves a combination of vincristine, actinomycin D, doxorubicin, and cyclophosphamide. In most instancesa reduction in tumor size is obtained. The prognosis for inoperable tumors treated with chemotherapy, surgery, and, if required, radiation therapy, usually is favorable, with survival rates of >50%. .Wilms Bilateral Wilms Tumor.Chemotherapy for bilateral tumor is identical to that employed for inoperable tumors, and is given to render the tumor amenable to surgical extirpation, which may include unilateral nephrectomy and contralateral partial nephrectomy or bilateral partial nephrectomies.These maneuvers permit ablation of viable neoDlasmand conservation of renal tissue. Surgical procedures are dictated by the extent of tumor and response to chemotherapy. Postoperativel% chemotherapy and, often, radiation therapy are administered. Occasionally, preoperative radiation also is utilized. These therapeutic strategieshave yielded survival rates of 60-85%. Salvage Chemotherapy.Patients with relapse during or following treatment with conventional therapy often respond to alternate treatment, particularly those with tumors of favorable histology. In these circumstances, combination chemotherapy with vincristine, doxorubicin, cyclophosphamide, and actinomycin D or ifosfamide, carboplatin, and etoposide may be used. High-dose chemotherapy with bone marrow rescue also has been employed. A multidisciplinary salvagestrategy with surgery, ;lrti,,l.r therapy,and chemotherapy usuallyvieldsthe best PR0GNOSIS.There is remarkable correlation among the DNA content in the cells of Wilms tumor, histologic subtype, and treatment outcome. Stem lines of both the primarv tumor and metastases are in the diploid and low ,n..rploid (tryperdiploid) range. Tumors with hyperdiploid content also are characteristic of the anaplastic (unfavorable) varieties and have enormous complex translocations. They respond poorly to chemotherapy.The prognosis is worse with a larger tumor (>500 g), advanced stage (III and IV), and an unfavorable histologic subtype. \07ilms tumor is a paradigm of successful multidisciplinary treatment, and >607o of patients with all stagesgenerally survive. StagesI through III have a cure rate of >90"/'. o OTHER 499.2 KonrvTuuoRs lrrrGnlmnerrt C0NGENITAIMES0BIASTICNEPHROMA.Congenital mesoblastic nephroma is a unique congenital neoplasm of the infant kidney that rarely metastasizes.It occurs more often in boys and has been noted to produce renin. The tumor is a massive,firm, infiltrative, solitary renal mass. Grossly and microscopically it resembles a Ieiomyoma or a low-grade leiomyosarcoma with trapped nephrons. Microscopy reveals fibroblast or myofibroblast cells. The tumor accounts for the majority of congenital renal tumors. Most casesare considered benign, and opinion is divided regarding the utility of chemotherapy. One report noted that vincristine and actinomycin administered as adjuvant therapy did not prevent metastases. In another report, metastatic disease apparently responded to vincristine, doxorubicin, and cyclophosphamide. NEPHR0GENIC RESTS.The term "nephrogenic rests," or nodular renal blastema or nephroblastomatosis, refers to the abnormal persistenceof embryonal renal tissue. The favorable survival and responserate of bilateral rifilms tumor suggestsa strong relation to the nephrogenic rests. It has been suggestedthat a brief course of relatively nontoxic chemotherapy, such as vincristine and actinomycin D, may be beneficial for nephrogenic rests by reducing the large volume of the kidneys. Persistent blastema and nephroblastic abnormalities appear to remain in the kidneys of many, if not all, treated patients, despite the reduction in renal volume. Nephrogenic nestsdetectedin one kidney should prompt a careful evaluation of the contralateral kidney. Radiographic follow-up with CT scanning also may be indicated. Whether chemotherapy reduces the subsequent development of rWilms tumor ls unKnown. Tumors of the kidney occaMULTICYSTICNEPHROBLAST0MA. sionally may contain cysts, some of which may be linked to Wilms tumor. Several diagnostic terms may be applied to such tumors, including cystic partially differentiated nephroblastoma (CPDN), polycystic nephroblastoma, and multilocular nephroma. Most casesof multicystic nephroblastoma occur in patients a benign <1 yr of age. This type of tumor biology indicates 'Wilms tumor, process. However, if there is definite evidence of treatment with chemotherapy is justified. RENAI CEtt CARCIN0MA.Renal cell carcinoma is rare in the first decadesof life, but occasionally has been reported in children and teenagers. It usually presents as an abdominal mass and/or hematuria. Complete resection may achieve cure. OccasionallS adjuvant treatment with interferon and S-fluorouracil has been recommended. CABCINOMA.This is a rare, highly aggressive RENALMEDULTARY tumor associatedwith sickle cell trait, presenting with hematuria and a flank mass. Metastasis is usually present at the time of diagnosis. The prognosis is poor. Blakely ML, Ritchey ML: Controversialissuesin the maintenanceof Wilms' ttmor. Semin Pediatr 2001 1'0:127-1'31. de Kraker J, Graf N, van Tinteren H, et al: Reduction of postoperative chemotherapyin children with stage 1 intermediate-riskand anaplastic 'Wilms' tumour (SIOP 93-01 trial): A randomized controlled trial. Lancet 2004;364:1229-1235. Dome JS, Liu T, Krasin M, et al: Improved survival for patientswith recurrent Wilms tumor: The experienceat St. Jude Children'sResearchHospital. I Pediatr Hematol Oncol 2O02;24:1'92-798. Firoozi F, Kogan BA: Follow-up and managementof recurrentWilms' tumor. Urol Clin North Am 2003;30:869-879. Fischbach BV, Trout KL, Lewis J, et al: VAGR syndrome: A clinical review of 54 cases.Pediatrics 2005;116:984-988. Fukuzawa R, BreslowNE, Morison IM, et al: Epigeneticdifferencesbetween 'Wilms' tumours in white and east-Asian children. Lancet 2004;363: 446451.. risk estimatesof Wilms Gronskov K, OlsenJH, SandA, et al: Population-bases tumor in sporadicaniridia. Hum Genet 2001;109:11-18 KalapurakalJA, Dome JS,PerlmanEJ, et al: Managementof Wilms' tumour: Current practice and future goals Lancet Oncol 2004;5:37-46. Malcolm AIJU,Jaffe N, Folkman MJ, et al: Bilateral rVilms' tumor. Int I Radidt Oncol Biol Phys 1.980;5:167-174. Patel K, Livni N, Macdonald D: Renal medullary carcinoma,a rare causeof haematuriain sickle cell trait. Br I Haeruatol 2006J32:L. Pirich LM, Chou P, \Talterhouse DO: Prolonged survival of a patient with sicklecell trait and metastaticrenal medullarycarcinorna.J PediatrHematol Oncol 1999)l:67-69. Pritchard-JonesK, Pritchard J: Successof clinical trials in childhood $films' tumour around the world. Lancet 2004;364:1'468-1'470. 'Wilms' tumor: The Ritchey ML: The role of preoperative chemotherapy for NWTSG perspective. \7ilms' Tumor Study Group. Semin Urol Oncol . 1.999;17:21,-27 ShambergerRC: Pediatric renal tumors. Semin Surg Oncol 1999;16:105120. 2144r PARTXXI r CancerandBenignTumors The annual incidence of soft tissue sarcomas is 8.4 casesDer million white children <14yr of age. Rhabdomyosarcoma accounts for more than r/1of soft tissuesarcomas.The prognosis most strongly correlateswith extent of diseaseat diagnosis, primary tumor site, and type of treatment. RHABDOMYOSARCOMA EPIDEMI0L0GY The most common pediatric soft tissuesarcoma, rhabdoml'osarcoma,accounts for -3.5"/u of childhood cancers. Thesetumors may occur at virtually any anatomic site but usually are found in the head and neck (25%), genitourinary rract (22o/ol, extremities(18%); retroperironealand other sitesaccount for the remainder of primary sires.The incidenceat each anatomic site is related ro both patient age and tumor rype. Exrremity lesions are more likely to occur in older children and to have alveolar histology'.Rhabdomyosarcomaoccurs with increasedfrequency in patients with neurofibromarosisand has been associatedwith maternal breast cancer in the Li-Fraumeni syndrome, suggesring a geneticinfluence. PATH0GENESIS, Rhabdomyosarcomais thought ro arisefrom rhe same embryonic mesenchymeas striated skeletalmuscle.On rhe basisof light microscopicappearance,it belongsto the group of small round cell tumors that includes Ewing sarcoma, neuroblastoma,and non-Hodgkin lymphoma. Definitive diagnosisof a pathologic specimenmay require immunohistochemicalstudies using antibodiesto skeletalmuscle(desmin,muscle-specific acrin, Myo-D) and electron microscopy. Determination of the specifichisrologicsubtypeis important in treatment planning and assessment of prognosis.There are four recognizedhistologic subtypes.The embryonal type accountsfor about 60% of all casesand has an intermediateprognosis.The botryoid type, a variant of the embryonal form in which tumor cells and an edemaroussrroma project into a body cavity like a bunch of grapes, is found most often in the vagina, uterus, bladder, nasopharynx, and middle ear. The alveolar type accounts for about 15ol' of casesand often is characterizedby 2;13 or 1;13 chromosomal rranslocations.The tumor cells tend to srow in cores that often have cleft-like spacesresemblingalveoli. Alveolar tumors occur mosr often in the trunk and extremities and carry the poorest prognosis.The pleomorphic type (adult form) is rare in childhood and accountsfor only 1%oof cases. CLINICAL MANIFESTATI0NS. The most common presenringfeature rs a mass that may or may not be painful. Symptoms are caused by displacement or obstruction of normal structures (Table -500-1).Origin in the nasopharynx may be associatedwith nasal congestion,mouth breathing,epistaxis,and difficulty with swallowing and chewing. Regional extension into the cranium can produce cranial nerve paralysis,blindness,and signsof increased intracranial pressure with headache and vomiting. When the tumor developsin the face or cheek there may be swelling, pain, trismus, and, as extension occurs, paralysis of cranial nerves. Tumors in the neck can produce progressiveswelling with neurologic symptoms after regional extension. Orbital primary tumors usually are diagnosed early in their course becauseof associatedproptosis, periorbital edema, ptosis, change in visual acuity, and local pain. \When the tumor arises in the middle ear, the most common early signs are pain, hearing loss, chronic otorrhea, or a mass in the ear canall extensions of tumor produce cranial nerve paralysis and signs of an intracranial mass on the REGION Head andneck 0rbit Nasopharynx Paranasal sinuses Middle ear 5YMP1OM5 Asymptomatt mass, mimk enlarged lymph node may paralysis, Proptosit chemosjs, orular eyelid mas pain,dysphagia,oanial pahies local Snoring,nasal vokeepistaxit rhinorrhea, nerve (ranial pain,sinusitis,obstru(tion,epista)(is, palsies nerve Swelling, palsiet polypoid Chr0nic media,hemonhagic discharge, cranial nerve otitis extruding mas5 irritating Hoarseness, cough Larynx (usually) Irunk Asymptomatjc mass Biliary tract HepatomEaly,jaundice Retfoperitoneum mastascites,gastrointestrnal tract Painless 0rurinary cord obstruction,spinal symptoms Bladder/prostate Hematuria, urinary retention, mast abdominal c0nstipation genital Female tract Polypoid extrusion tissue,vulval vaginal ofmucosanguineous nodule genital Male trad Painful orpainless saotal mass Extremity Painless mas,may bevery small butwithsecondary lymph node involvement Metastatic Nonspecifrc symptoml assocjated withthediagnosis ofleukemia tom McDowell HP:Update onchildhood rhabdomyosa KonaArchDisChild2ffi3j88:354-i57. involved side. An unremitting croupy cough and progressive stridor can accompany rhabdomyosarcoma of the larynx. Because most of these signs and symptoms also are associated with common childhood conditions, clinicians must be alert to the possibility of tumor. Rhabdomyosarcoma of the trunk or extremities often is first noticed after trauma and initially may be regarded as a hematoma. If the swelling does not resolve or increases,malignancy should be suspected. Involvementof the genitourinarytracr can produce hematuria, obstruction of the lower urinary tract, recurrent urinary tract infections, incontinence, or a mass detectable on abdominal or rectal examination. Paratesticular tumors usually present as a painless,rapidly growing mass in the scrotum. Vaginal rhabdomyosarcoma may present as a grapelike mass of tumor tissue bulging through the vaginal orifice, known as sarcoma botryoides, and can causeurinary tract or large bowel symptoms. Vaginal bleeding or obstruction of the urethra or rectum may occur. Similar findings can be noted with uterine prlmarles. Tumors in any location may disseminateearly and present with symptoms of pain or respiratory distress associated with pulmonary metastases. Extensive bone involvement can produce symptomatic hypercalcemia. In such cases,it may be difficult to identify the primary lesion. DIAGN0SIS.Early diagnosis of rhabdomyosarcoma requires a high index of suspicion. The microscopic appearanceis of a small round blue cell tumor. Neuroblastoma, lymphoma, and Ewing sarcoma also are small round blue cell tumors. The differential diagnosis depends on the site of presentation. Definrtive diagnosis is established by biopsy, microscopic appearance, and results of immunohistochemical stains. A lesion in an extremity may be thought to be a hematoma or hemangioma, an orbital lesion resulting in proptosis may be treated as an orbital cellulitis, or bladder obstructive symptoms may be missed. Adolescents may ignore paratesticular lesions for a long time. Unfortunately, several months often elapse between the initial symptoms and biopsy. Diagnostic procedures are determined mainiy by the area of involvement. CT or MRI is necessaryfor evaluation of the primary tumor site. \fith signs and symptoms in the head and neck area, radiographs should be examined for evidence of a tumor mass and for indications of bony erosion. CT or MRI should be performed to identify intracranial extension and also may reveal bony involvement or erosion at the base of the skull. For abdominal and pelvic tumors, ultrasound, CT with contrast, or MRI can help delineatethe tumor (Fig. 500-1). A radionuclide bone scan, chest Cl and bilateral bone marrow aspirate and r 2145 I SoftTissue $6vssrn65 Chapter500 or metastatic disease to adjacent structures or regional lymph nodes should be completed, even if the procedure is limited to biopsy. Treatment is based on the primary tumor location and diseasestage, which defines the clinical group. Most patients are given preoperative chemotherapy in an attempt to reduce the extent of surgery required and to preserve vital organs, particularly of the genitourinary tract. Group I tumors are treated with complete local excision followed by chemotherapy to reduce the likelihood of subsequent metastases.Group II tumors (microscopic residual tumor) are treated with surgery followed by local irradiation and systemic chemotherapy. Group III tumors (gross residual tumor) are treated with systemicchemotherapy followed by irradiation and, if possible, surgery. Group IV rhabdomyosarcoma (metastatic) is treated principally with systemic chemotherapy and irradiation. Standard chemotherapeutic agents include vincristine, dactinomycin, and cyclophosphamide. Topotecan and irinotecan are being evaluated in therapeutic trials. PROGN0SIS.Prognostic factors include stage, histology, and primary site. Among patients with resectable tumor, 80-90% have prolonged disease-freesurvival. Unresectable tumor localized to certain favorable sites, such as the orbit, also has a high likelihood of cure. Aborx 70"/" of patients with incompletely resected tumor also achieve long-term disease-free survival. Patients with disseminated disease have a poor prognosis; only 112of these are cured. about 1/2achieve remission, and fewer than Older children have a poorer prognosis than younger children. For all patients, surveillance for late effects of cancer treatment (such as impaired bone growth secondary to radiation, sterility from cyclophosphamide, and second malignancies) is important. SARCOMAS TISSUE OTHER SOFT The non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) constitute a heterogeneousgroup of tumors that account ior 3o/" of all childhood malignancies (Table 500-2). Becausethey are relatively rare in children, much of the information about their natural history and treatment has been derived from studies of adult patients. In children, the median age at diagnosis is 12 yr, with a male:femaleratio o[ 2.3:1 . Thesetumors commonly arise in the trunk or lower extremities. The most common histologic types are synovial sarcoma (42"A1,fibrosarcoma (13%), malignant fibrous histiocytoma (I2%1, and neurogenictumors (10%). Molecular genetic studies often prove useful in diagnosis, as several of these tumors have characteristic chromosomal translocations. Surgery remains the mainstay of therapy, but a careful search for lung and bone metastasesshould be undertaken before surgical excision. Lymph node spread is rare, and routine dissection Figure500-1.A, PelvicCT of a child with a bladderrhabdomyosarcoma. is not recommended. Chemotherapy and radiation therapy B, MRI of a childwith a parameningeal rhabdomyosarcoma. should be considered for large, high-grade, and unresectable tumors. The role of chemotherapyfor non-rhabdomyosarcomatous tumors is not as well defined as for rhabdomyosarcoma. Patients with unresectable or metastatic disease are treated with multibiopsy should be performed to evaluate the patient for the presagent chemotherapy in addition to radiation and/or surgery. ence of metastatic diseaseto Dlan treatment. The most critical size, stage (clinical group), invasiveness,and histologic Tumor element of the diagnostic worklup is examination of tumor tissue, grade correlate with survival. which includes the use of soecial histochemical stains and immunostains. Cytogenetics and molecular genetics may be helpful in detecting specificchromosomal translocations of fusion proteins present in alveolar rhabdomyosarcoma. Lymph nodes Arndt CAS, Crist WM: Medical progress:Common musculoskeletaltumors N Engl J Med 7999;341':342-352 of chitdhood and adolescence. also should be sampled for presenceof diseasespread, especially Baker KS, Anderson JR, Lind MP, et al: Benefit of intensifiedtherapy for in tumors of the extremities. Patients with completely resected tumors have the TREATMENT. best prognosis. Unfortunateln most rhabdomyosarcomas are not completely resectable. At the initial surgery, tumor margins should be carefully defined and an appropriate searchfor regional parients with local or regional embryonal rhabdomyosarcoma:Results from the Intergroup Rhabdomyosarcoma Study lY. J Clin Oncol 2000;18:2427-2434. Crist rVM, AndersonJR, M ezaJL,et al: Intergrouprhabdomyosarcomastudy: IV. Results for patients with nonmetastatic disease. I Clin Oncol 2001;1,9:3091-31'02. 2146 ' PARTXXI TIssUE TYPI Adlpose Cancer andBenignTumors TUMOR Liposarcoma NATURAT HIsIORY ANDBIOIOCY AveryraretumorUsua|yaIi5esntheeXt|emitie50rIetr0perit0ne|m;aSS0(iatedWithanonrandomtrans|ocation,t(12;16)h13 rare|ymetastasrzes;wide]oca|exctsionsthetreatmento[choireThero|eofradiationtherapyandchemotherapyine eshbllshed Fibrous Frbrosarcoma Mo$commonsoftt ssue inchldren<1 yt [ongenital fibrosarcoma ncythat(0mmonlyansesntheextrem rtiesortrunkandrarely sarcoma sa low-grademaligna metastas zesSurgical excsron istreatment ofchoce;dramal( responses chemotherapy mayoccur Inchildren >4 yr,thenatural hi5t0ry issimllar t0preoperative t0 t h a t i n a d u l t s ( a 5 - y r s u r v i v a l r a t e o f 6 0 Teox )c;iw s li od ne as n ud r gpirceao p e r a t i r l e ( h e m o t h e r a p y a r e c o m m o n l y u s e d Mallgnaft frbrous hlstiocytomaM o s t c o m m o n | y a r l s e s n t h e t r U n k a n d e X t r e m l t i e 5 , d e e p i n t h e 5 U b c U t a n e 0 u 5 a y e [ H i 5 t 0 | 0 g i | l y l b d | v | d d Iheanqiomatoidtypetendstoafectyoungerpatient5andi5cUrabieWith5Urgi(a]re5ecti0na|0neWide5Urgi(a|eXci5i0nthe produred vetum0r regressi0fs 0bject Vasrllar Hemanqropeil[ytomd 0 f e n a n s e s l n t h e l o w e r e X t r e m t i e 5 0 r r e t r 0 p e r i t 0 r ] e U m ; m a y p r e s e n t W i t h h y p 0 q l y ( e m i a a n d h y p o p h o s p h a t e m i c r i c k e t 5 B 0 t h b e (omplete (q22;q11) tcns0(ati0ns t(12; l9) (q13;ql3) have andt(13;22) been described surgical excisi0n isthetreatment 0fchorce [hemotherapyand radiation therapy mayproduce responses Angosarcoma Rare inchildren; 3370 arseinskin, 25%n softt sue,and2590 inI ver; Assoriated breast, orbone withchronic lymphedema andexposure t0vinychloride inadults 5ur\rival rate lsp00r(1270 at5 yr)desprte responses s0me tochemotherapy/radiati0n therapy Hemangioendorhelioma [anoccur n softt ssue, liver, andungLoca]ized esions have afavorable outcome, lesions n lungandliver often aremultifocal andhave a poorpr0gn0srs Perpheralnerves l'leurcfrbrosarcoma A s o k n o w n a s t h e m a l i g n a n t p e r i p h e r a l n e r v e s h e a t h t u m o r . D e ' r e o p s i n u p t 0 l 6 T 0 0 f p a t i e n t s w f t hDNeFe' lt;i ao lnms o sf t 5 0 7 0 o i ( u r i n p a t i e (ommonly 11 q13 or17q11andp53m!tati0ns chr0m0s0me 22q have reported intrufkandextremities been anses andusually isloca lyinvasive [omploe surgical lsnecessary forsurvival, exrisi0n fesp0nse t0(hemotherapy issub0ptimal Synovium 5ynovial sarcoma presenting lhemost insome common NRSIS series Often inthe3rddecade,but33% 0fpatrents are<20yrTypically arises arornd theknee orthlgh andis thard(terlzed random bya non translo(ation t(X,T8)(p1i; q11) Wide l excision isnecesary surgica adiati0n thecpy isefectlve n mlcr0sc0pic r€sid ualdisease, and if0siamide-based inadvanced therapy rsa(tive drsease Unknown Alveolar softpartsarcoma Slowgrowingtumor; tendst0 re(ur 0rmeta$asize t0 ungandbrar nyeanafterdiagnosis 0ftenarisesrntheextrem itiesandheaddfd neckA myoqenic orqinhasbeen proposed Resectron p0ssrble, ofprimary afdmetastatic sites, when 6 recommended SmoothmuscleLeiomyosarcoma (q14;q2l) Often inthegastr0intestinal arises tract andmaybeassociated withat(12;14) translocation Asociated withEpstein-Bafr\/irus rnimmunodefciency ( ncluding syndromes AlD5) [0mplete surqicl excisr0n isthetreatmert 0iih0ice Ninelrchbromatcl s,i'1RlT5, norrhatdomyosarcoma sol1 trrle saroma \ l c l ) o u e l l I I l ) r l i l ) ( l . r r c o n e h l t l l r o o r l r l r . r l . r l o n r r o s r r r c o n r {. r . l 1 ) r - s( hitt l 0 ( ) l r i l S :I i + I t \ l c r e r \ \ ' H . \ P L r r t rS l : \ o f t t r : s u c \ J r c o n t J \ o i c h r l c l h o o c l( J n t ( , t T t d t R e l 1 0 0 . + il ( ) : l ( ' 9 l f i 0 S p u n t S I . l ) o r l r r r ' t t (e \ . i { L r r r ) S . e r . r l ; I ) r o g n o s t i gh c r o r s f o r c h r l c l r e nr r n d r t d o l c s c c r t r :r r i r h . u r c l e . r l l r r c s c c t e c ln o n r h r t l ) L ] o n t \ o s . l f ! ( ) n t\.(l ) f t t r s s L l c \ r t r c o l t t r l \r r t , l r . t l r s i , o f l l l I r r r i t n r s l u , 1 r ( r l , l t \ r l L L r l tt h i l t l r c n ' sR e s e r r e h I I o : l . i r , r l| ( . l i t t l ) t t , r , l 1 9 9 9 il - : 1 6 9 - - l - ( ) t S t c rt n s \ l ( ( , r I | ( J n r e n f f o r e h r l t l l r o o r rl h . i b t l o n r ro s r r r c o n r l :I l r c c o s r o l c L r r r I tttLtl ()ttt,,l l()t)i:(.:-- S-1 growth and malignant transformation. Parienrswith osteosar\ ' ( ' n r JJ r c t . r l l c rt h : r nr h c i r p e e r so f s i m i l r r . r g t ' . PATll0GINtSlS.Although the causeof osteosarcomais unknown, r t r t ; i n g t ' n t ' t i co r l c q u i r e J e , r r r J i t i t r r p r sr e d i s p o r ef J t i e n t \ t ( ) clevelopment of osteosarcoma. Patients with hereditarv rctinoblastomahave a signiticantlyincreasedrisk of developing ostcosarcoma.Thc sites of osteosarcomain thesepatlentsinitially $'ere thoLlllht to be located only in previousl.uirradiated areas, but more recentlvthey have been shown to arise in sitesf:rr fronr the racliation field. Predispositionto dcvelopment of osteosarcoma in these patients may be relared to loss of heterozygosity of the RII gcne. Osteosarcomaalso occurs in the Li-Fraumeni Chapter 501r Neoplasms of Bone . Mai-lcruarur 501.1 TurrnoRs 0FB0NE T h e a n u r - r r irrl r c i c l e n coci r n r r J i g n e nl r. o n e r u n ' r o r si n r h e L I S A i s r p p r o r r r l : r t c l \ r i l s c sp c r n r i l l i o r tn ' h i t c c h i l c l r c n< 1 4 r ' r 'o f a g c . n i t h r r s l i g h r l r l o u er i n c i c l c n c er n A f r i c a n - A n r e r i c r rcnh i l d r c n . O s t c t l s r r r c t l t l lilst t h e r I , r s t e() n t n t '(n I r i n t . r r r r n a l i g n a n tb c l n e tutttor ir.rclrilclren rrntl rrrlolcsccnts. follon'eclLrr F-*ing s:lrconril il;lll:,,i li'"1 ;,f':,,,],.] 1"1,,, ill,:l]li ::i:,;,\:';.,:ll ilff;,iJill: i l r c n r o s t l i k c l r t o o c c u r i n t l r c s c c o n ccl l e c a c locf l i i c . OSTEOSARCOMA f Pl*FllllliLt]ilt I.hc ennual inciclcnceof osteosarcomarn the USA r s . 5 . 6c r s c s p e r r n r l l i o nc h i l c l r c n< 1 . 51 ' r o f a g e . T h e h i g h e s tr i s k pcriocl for clevclopn'rent of osteosarcor-na is during the adolescent growth spurf ! suggcsting rrn :rssocrrtiotrbetwecn rapid bonc FEAiURE OSTEOSARCOMA Aqe Race 5ex(M; F) tell 5econd decade AI la(es 15:l 5pind ecell-producinq osreoid TAMITY OFTUMORs fl4,iN6 Second decade Primariy whltes 15:1 Undifferentlated smalround cel,probaby of neural origin Predrsposition Retnoblastoma, LiJraumenr syndrome, None known Paget radiothempy disease, 5ite Metaphyses oflongbones Diaphyses of ongbones,flat bones Presentation pain pain Loca andswellinq;often, history of Local andswelling;fever nJury Radiographk 5deroti(destructi0n(lesscommonly Primarily penosteal lytic, multi aminar ('0ni0n ytic);sunbust pdttern frndinqs reaition skinning") Diffe'ential Ewrngsarcoma,osteomyelitis 0$eomyelitis, granuloma, eOsin0philic dragnos6 lymphoma, neuroblastoma, rna000my05atcoma l\4etastasisLungs,bones Lung, bones Treatment Chemotherapy Ihemotherapy Ablative surgery ofprimary tumor Radiotherapy and/or surgery ofprimary IUMOT 0ut(0me With0utmeiastases:70%cured;with Wlthout metastases: 60%cured; with <20%survival melastases meta$ases atdragn0sis, atdiagn0sis, 20-3070 survival of Bone r 2147 Ghapter 501r Neoplasms Osteosarcoma 30 EwingSarcoma -A E c) 1F ---:/ Males 949 Females 700 Total 1649 c o o o 6 t12 74 248 22- -508 . L:I J6 -3 33- A -3 24 45 Age in decades 21 1 Males 303 Females209 Total 512 1 12 9 6 B 3 1111- Aoe in decades Figurc 501-1. A, Age and skeletaldistribution of 1,649 casesof osteosarcomain the Mayo Clinic files. B, Age and skeletaldistribution ol 5'12casesof Ewing sarcomain the Mayo Clinic files. (From Unni KK [editor]: Dahlin's Bone Tumors: GeneralAspectsand Data on 11,087 Cases,5th ed. Philadelphia,LippincottRaven, 1996. Reprinted by permissionof the Mayo Foundation.) syndrome, which is a familial cancer syndrome associatedwith germline mutations of the p53 gene. Kindreds with Li-Fraumeni syndrome have a spectrum of malignanciesin 1st-degreerelatives, including carcinoma of the breast, soft tissue sarcomas, brain tumors, leukemia, adrenal cortical carcinoma, and other malignancies.Rothmund-Thomson syndrome is a rare syndrome associated with short stature, skin telangiectasia, small hands and feet, hypoplastic or absent thumbs, and a high risk of osteosarcoma. Osteosarcoma also can be induced by irradiation for Ewing sarcoma, craniospinal irradiation for brain tumors, or high-dose irradiation for other malignancies. Other benign conditions that can be associatedwith malignant transformation to osteosarcoma include Paget disease,enchondromatosis, multiple hereditary exostoses,and fibrous dysplasia. The pathologic diagnosis of osteosarcomais made by demonstration of a highly malignant, pleomorphic, spindle cell neoplasm associated with the formation of malignant osteoid and bone. There are four pathologic subtypes of conventional highgrade osteosarcoma: osteoblastic, fibroblastic, chondroblastic, and telangiectatic.No significant differencesin outcome are associated with the various subtypes, although the chondroblastic component of that subtype may not respond as well to chemotherapy. The role in prognosis of various genes such as drug resistance-relatedgenes,tumor suppressorgenes,and genes related to apoptosis is being evaluated. Telangiectatic osteosarcomamay be confused with aneurysmal bone cyst becauseof its lytic appearanceradiographically. Highgrade osteosarcoma typically arises in the diaphyseal region of long bones and invades the medullary cavity. It also may be associated with a soft tissue mass. Two variants of osteosarcoma, parosteal and periosteal osteosarcoma, should be distinguished from conventional osteosarcoma because of their characteristic clinical features. Parosteal osteosarcoma is a low-grade, welldifferentiated tumor that does not invade the medullary cavity and most commonly is found in the posterior aspect of the distal femur. Surgical resection alone often is curative in this lesion, which has a low propensity for metastatic spread. Periosteal osteosarcoma is a rare variant that arises on the surface of the bone but has a higher rate of metastatic spread than the parosteal type and an inrermediateprognosis. CtINICAI MANIFESTATI0NS. Pain, limp, and swelling are the most common presenting manifestations of osteosarcoma. Because these tumors occur most often in active adolescents,initial complaints may be attributed to a sports injury or sprain; any bone or joint pain not responding to conservattvetherapy within a reasonable amount of time should be investigated thoroughly. Additional clinical findings may include limitation of motion, ioint effusion, tenderness,and warmth. Results of routine laboratory tests, such as a complete blood cell count and chemistry panel, usually are normal, although alkaline phosphataseor lactic dehydrogenaselevels may be elevated. DIAGN0SIS.Bone tumor should be suspected in a patient who presents with deep bone pain, often causing nighttime awakening, a palpable mass, and a radiograph demonstrating a lesion. The lesion may be mixed lytic and blastic in appearance, but new bone formation usually is visible. The classic radiographic appearanceof osteosarcomais the sunburst pattern (Fig. 501-2). When osteosarcoma is suspected,the patient should be referred to a center with experiencein managing bone tumors. The biopsy and the surgery should be performed by the same surgeon so that the incisional biopsy site can be placed in a manner that will not compromise the ultimate limb salvage procedure. Tissue usually is obtained for molecular and biologic studies at the time of the initial biopsy. Before biopsy, MRI of the primary lesion and the entire bone should be performed to evaluate the tumor for its proximity to nerves and blood vessels, soft tissue and ioint extension, and skip lesions. The metastatic work-up should be performed before biopsy and includes CT of the chest and radionuclide bone scan to evaluate for lung and bone metastases, respectively. The differential diagnosis of a lytic bone lesion includes histiocytosis, Ewing sarcoma, lymphoma, and bone cyst. 'S(ith chemotherapy and surgery, the 5-yr diseaseTBEATMENT. free survival rate of patients with nonmetastatic extremity osteosarcoma rs 65-75"/". Complete surgical resection of the tumor is important for cure. The current approach is to treat patients with preoperative chemotherapy in an attempt to facilitate limb salvageoperations and to treat micrometastatic disease immediately. Up to 80% of patients are able to undergo limb salvage operations after initial chemotherapy. Some institutions use intra-arterial chemotherapy to infuse chemotherapy directly into an artery feeding the tumor, although this has not been shown to be better than conventional intravenous chemotherapy. It is important to resume chemotherapy as soon as possible after surgery. Lung metastasespresent at diagnosis should be resected by thoracotomies at some time during the course of treatment. Active agents currently in use in multidrug chemotherapy regi- 2148I PARTXXI I GancerandBenignTumors EWING SABCOMA EPIDEMI0L0GY. The incidence of Ewing sarcoma in the USA is 2.1 cases per million children. It is extremely rare among AfricanAmerican children. Ewing sarcoma, an undifferentiated sarcoma of bone, also may arise from soft tissue. The term Ewing sarcoma family of tumors refers to a group of small, round cell, undifferentiated tumors thought to be of neural crest origin that generally carry the same chromosomal translocation. This family of tumors includes Ewing sarcoma of bone and soft tissue and peripheral primitive neuroectodermal tumor. Treatment protocols for these tumors are the same whether the tumors arise in bone or soft tissue. Anatomic sites of primary tumors arising in bone are distributed evenly between the extremities and the central axis (pelvis, spine, and chest wall). Primary tumors arising in the chest wall are often referred to as Askin tumors. Figure501-2.Radiograph of anosteosarcoma of thefemurwith typical"sunburst"appearance of boneformation. mens for conventional osteosarcoma include doxorubicin, cisplatin, methotrexate, and ifosfamide. One of the most important prognostic factors in osteosarcoma is the histologic response to chemotherapy. An international cooperative group is evaluating a randomized trial of the postoperative addition of high-dose ifosfamide with eroposide to standard three-drug therapy with cisplatin, doxorubicin, and methotrexate to improve the outcome of patients with a poor histologic response.Good histologic responderswill be randomized to the addition of PEGylated interferon a,2b. After limb salvage surgery, intensive rehabilitation and physical therapy is necessary to ensure maximal functional outcome. For patients who require amputation, early prosthetic fitting and gait training is essential to enable rhem to resume acriviries as normally as possible. Before definitive surgery, patients with tumors on weight-bearing bones should be instructed to use crutches to avoid srressing the weakened bone and causing a pathologic fracture. The role of chemotherapy in parosteal and periosteal osteosarcoma is not well defined. PR0GN0SIS.Surgical resection alone is curative only for patients with parosteal osteosarcoma. Conventional osteosarcoma requires multiagent chemotherapy. Up to 7 5"/" of patients with nonmetastatic extremity osteosarcoma are cured with current multiagent treatment protocols. The prognosis is not as favorable for patients with pelvic tumors as for those with primary rumors in an extremity. From 20-30% of patients who have limited numbers of pulmonary metastasesalso can be cured with aggressive chemotherapy and resection of lung nodules. Patients with bone metastasesand those with widespread lung metastaseshave an extremely poor prognosis. Long-term follow-up of patients with osteosarcoma is important to monitor for late effects of chemotherapy such as cardiotoxicity from anthracycline, Patients who develop late, isolated lung metastasesmay be cured with surqical resection alone. PATHOGENESIS. Immunohistochemical staining assistsin the diagnosis of Ewing sarcoma to differentiate it from small round blue cell tumors such as lymphoma, rhabdomyosarcoma, and neuroblastoma. Histochemical stains may react positively with certain neural markers on tumor cells (neuron-specific enolase and 5-100), especially in peripheral primitive neuroectodermal tumor. Reactivity with muscle markers (e.g., desmin, actin) is absent. Additionally, the cell surface glycoprotein MIC-2 usually is positive. A specific chromosomal translocation, t(71;22), or a variant thereof is found in most of the Ewing sarcoma family of tumors. Analysis for the translocation by routine cytogeneticsor polymerase chain reaction analysis for the chimeric fusion gene products E!fS/ILI1 or EuflS/ERG can be helpful in confirming the diagnosis in extremely undifferentiated tumors. CLINICALMANIFESTATI0NS.Symptoms of Ewing sarcoma are similar to those of osteosarcoma. Pain, swelling, limitation of motion, and tendernessover the involved bone or soft tissue are common presenting symptoms. In the case of huge chest wall primary tumors, patients may present with respiratory distress. Patientswith paraspinal or vertebral primary tumors may present with symptoms of cord compression. Ewing sarcoma often is associated with systemic manifestations such as fever or weight loss; patients may have undergone treatment for a presumptive diagnosis of osteomyelitis. Patients also may have a delay in diagnosis when their pain or swelling is attributed to a sports injury. DIAGN0SIS.The diagnosis of Ewing sarcoma should be suspected in a patient who presentswith pain and swelling, with or without systemic symptoms, and with a radiographic appearance of a primarily lytic bone lesion with periosteal reaction, the characteristic onion-skinning (Fig. 501-3). A large associatedsoft tissuemass often is visualized on MRI or CT (Fig. 501-4). The differential diagnosis includes osteosarcoma,osteomyelitis, Langerhans' cell histiocytosis, primary lymphoma of bone, metastatic neuroblastoma, or rhabdomyosarcoma in the case of a pure soft tissue lesion. Patients should be referred to a center wiih experiencein managing bone tumors for evaluation and biopsy. Thorough evaluation for metastatic diseaseincludes CT of the chest. radionuclide bone scan, and bone marrow aspirate and biopsy specimens from at least two sites. MRI of the tumor and the entire length of involved bone should be oerformed to determine the exact extension of the soft tissue and bony mass and the proximity of tumor to neurovascular structures. To avoid compromising an ultimate potential for limb salvage by a poorly planned biopsy incision, the same surgeon should perform the biopsy and the surgical procedure. CT:guided biopsy of the lesion often provides diagnostic tissue. It is important to obtain adequate tissue for special stains, cytogenetics,and molecular studies. TREATMENT.Tumors of the Ewing sarcoma family are best managed with a comprehensive multidisciplinary approach Chaptet501r Neoplasms of BoneI 2149 such as very intensive chemotherapy with peripheral blood stem cell rescue,are being investigated in these patients. Long-term follow-up of patients with Ewing sarcoma is important becauseof the potential for late effects of treatment such as anthracycline cardiotoxicity; second malignancies, especially in the radiation field; and late relapses,even as long as t0 yr alter initial diagnosis. o BrucruTuuons AND TUMoR-uKE 501.2 PRocrssrs oFBoNE Figure501-3.Radiograph of tibial Ewingsarcoma showingperiosteal elevation or "onion-skinning." Benign bone lesions in children are common in comparison with the relatively rare malignant neoplasmsof bone and present diagnostic challenges. Some, although histologically benign, can be life-threatening. No single element in the history or diagnostic test is sufficient to rule out malignancies or suggestnonneoplastic conditions. A broad range of diagnostic possibilities must be considered when confronted with an unknown bone lesion. Benign lesions may be painless or painful, especially if a pathologic fracture is impending. Night pain that awakens a child is suggestive of malignancy; relief of such pain with aspirin is common with benign lesions such as osteoid osteomas. Rapidly enlarging lesions usually are associated with malignancy, but several benign lesions, such as aneurysmal bone cysts, may enlarge faster than most malignancies. Several conditions, such as osteomyelitis,may simulatethe appearanceof benign bone tumors. Many benign bone tumors are diagnosed incidentally or after pathologic fracture. Management of these fractures is similar to that of nonpathologic fractures in the same location. It is unusual incorporating the surgeon, chemotherapisr, and radiation oncologist in planning therapy. Multiagent chemotherapy is important becauseit can shrink the tumor rapidly and usually is given before local control is attempted. The addition of ifosfamide and etoposide to the conventional agents of vincristine, doxorubicin, and cyclophosphamide improves the outcome of nonmetastatic Ewing sarcoma. Chemotherapy usually causes dramatic shrinkage of the soft tissue mass and rapid, significanr pain relief. Current randomized studies of chemotherapy in Ewing sarcoma are evaluating the role of dose intensity for both metastatic and nonmetastatic Ewing sarcoma. An international cooperative group trial is evaluating whether myeloablative chemotherapy and stem cell rescue is superior to chemotherapy with lung irradiation for patients with pulmonary metastases.Myeloablative chemotherapy for patients with extremely high risk disease(bone and marrow metastases)also is being studied, as are approaches using angiogenesisinhibitors on a standard chemotherapy backbone. Ewing sarcoma is considered a radiosensitive tumor, and local control may be achieved with radiation or surgery. Radiation therapy is associatedwith a risk of radiation-induced second malignancies, especially osteosarcoma,as well as failure of bone growth in skeletally immature patients. Many centers prefer surgical resection, if possible, to achieve local control. It is important to provide patients with crutches if the tumor is in a weight-bearing bone to avoid a pathologic fracture before definitive local control. Chemotherapy should be resumed as soon as possible after surgery. PR0GN0SIS.Patients with small, nonmetastatic, distally located extremity tumors have the best prognosis, with a cure rate of up to 757". The type of chromosomal translocation may be related to prognosis. Patients with pelvic tumors have, until recently, had a much worse outcome. Patients with metastatic diseaseat diagnosis, especially bone or bone marrow metastases,have a poor prognosis, with <30% surviving long term. New approaches, Figure 501-4. MRI of tibial Ewing sarcoma showing a large associatedsoft nssuemass. 2150r PARTXXI I CancerandBenignTumors for benign bone tumors to interfere with fracture healing. Likewise, the fractures rarely result in changes or healing of these tumors, which usually are treated after the fracture has healed. Radiographs of any suspected bone lesion should always be obtained in two planes. Additional studies may be necessaryto help arrive at the correct diagnosis and to guide treatment. Although these lesions are benign, many do require intervention. Osteochondroma (exostosis) is one of the most common benign bone tumors in children. Because many are completely asymptomatic and unrecognized, the true incidence of this lesion is unknown. Most osteochondromas develop in childhood, arising from the metaphysis of a long bone, particularly the distal femur, proximal humerus, and proximal tibia. The lesion enlarges with the child until skeletal maturity. Most are discovered from 5-15 yr of age when the child or parent notices a bony, nonpainful mass. Some are discovered becausethey are irritated by pressure during athletic or other activities. Osteochondromas appear radiographically as stalks or broad-based projections from the surface of the bone. usually in a direction away from rhe adiacent ioint. Invariably. the lesion is radiographically smaller than suggestedby palpation becausethe cartilage "cap" covering the lesion is not seen. This cartilage cap may be up to 1 cm thick. Both the cortex of the bone and the marrow sDaceof the involved bone are continuous with the lesion. Malignant degeneration to a chondrosarcoma is rare in children but may occur in as many as l7o of adults. Routine removal is not performed unless the lesion is large enough to cause symptoms or if rapid lesion growth occurs. Multiple hereditary exostoses is a related but rare condition characterized by the presence of multiple osteochondromas. Severely involved children may have short stature, limb-length inequality, premature partial physeal arrests, and deformity of both the upper and lower extremities. These individuals must be monitored carefully during growth. Enchondroma is a benign lesion of hyaline cartilage that occurs centrally in the bone. Most of theselesions are asymptomatic and occur in the hands. Most are discovered incidentally, although pathologic fractures often lead to the diagnosis.Radiographically, the lesions occupy the medullary canal, are radiolucent, and are sharply marginated. Punctate or stippled calcification may be presentwithin the lesion, but this is much more common in adults than in children. Almost all enchondromas are solitary. Most can simply be observed,with curettage and bone grafting reservedfor those lesionsthat are symptomatic or large enough to weaken the bone structurally. Multifocal involvement is referred to as Ollier disease and may result in bony dysplasia, short stature, limblength inequality, and joint deformity. Surgery may be necessary 'When to correct or prevent such deformities. multiple enchondromas are associated with angiomas of the soft tissue, the condition is referred to as Maffucci syndrome. A high rate of malignant transformation has been reported in both of thesemultifocal conditions. Chondroblastoma is a rare lesion usually found in the epiphysis of long bones. Most patients present in the second decade with complaints of mild to moderate pain in the adjacent joint. Common sites include the hip, shoulder, and knee. Muscle atrophy and local tendernessmay be the only clinical findings. The lesion appearsradiographically as a sharply marginated radiolucency within the epiphysis or apophysis, occasionally with metaphyseal extension across the physis. Proximity to the joint may cause deformity of the subchondral bone, an effusion, or erosion into the joint. Recognition is important because most lesions can be cured with curettage and bone grafting before joint destruction occurs. Chondromyxoid fibroma is an uncommon benign bone tumor in children. This metaphyseal lesion usually causes pain and local tenderness.The lesion occasionallv mav be asvmotomatic. Chondromyxoid fibroma appears radiograpLicallyas eccentric, lobular, metaphysealradiolucency with sharp, sclerotic, and scal- loped margins. The lower extremity is involved most often. Treatment usually consists of curettage and bone grafting or en bloc resection. Osteoid osteoma is a small benign bone tumor. Most of these tumors are diagnosed between 5-20 yr of age. The clinical pattern is characteristic, consisting of unremitting and gradually increasing pain that often is worst at night and is relieved by aspirin. Males are affected more often than females. Any bone .rn b. involved, but the most common srtes are the proximal femur and tibia. Vertebral lesions may cause scoliosis or symptoms that mimic a neurologic disorder. Examination may reveal a limp, atrophy, and weakness when the lower extremity is involved. Palpation and range of motion do not alter the discomfort. Radiographs are distinctive, showing a round or oval metaphyseal or diaphyseal lucency (0.5-1.0 cm diameter) surrounded by sclerotic bone. The central lucency, or nidus, shows intense uptake on bone scan. About 25% of osteoid osteomasare not visualized on plain radiographs but can be identified with CT. Becauseof the small size of the lesion and its location adiacent to thick cortical bone, MRI is poor at detecting osteoid osteomas. Treatment is directed at removing the lesion. This may involve en bloc excision, curettage, or percutaneous CT:guided ablation of the nidus. Patientswith mild pain may be treated with salicylates. Some lesions resolve spontaneously after skeletal maturlly. Osteoblastoma is a locally destructive, progressively growing lesion of bone with a predilection for the vertebrae, although almost any bone may be involved. Most patients note the insidious onset of dull aching pain, which may be present for months before they seek medical attention. Spinal lesions may cause neurologic symptoms or deficits. The radiographic appearance is variable and less distinctive than that of other benign bone tumors. A6out 25o/" show features suggesting a malignant neoplasm, making biopsy necessaryin many cases.Expansile spinal lesions often involve the posterior elements. Treatment involves curettage and bone grafting or en bloc excision, taking care to preserve nerve roots when treating spinal lesions. Surgical stabilization of the spine may be necessary. Fibromas (nonossifying fibroma, fibrous cortical defect, metaphyseal fibrous defect) are fibrous lesions of bone that occur in 40'/' of children >2yr of age. They most likely represent a defect in ossification rather than a neoplasm and usually are asymptomatic. Most are discovered incidentally when radiogr"phr are taken for other reasons, usually to rule out a fracture after trauma. Occasional pathologic fractures can occur through rare large lesions. Physical examination usually is unrevealing. Radiographs show a sharply marginated eccentric lucency in the metaphyseal cortex. Lesions may be multilocular and expansile,with extension from the cortex into the medullary bone. The long axis of the lesion runs parallel to that of the bone. Approximately 50% are bilateral or multiple. Because of the characteristic radiographic appearance, most lesions do not require biopsy or treatment. Spontaneous regression can be expected after skeletal maturity. Curettage and bone grafting may be recommended for lesions occupying more than 50% of the bone diameter becauseof the risk of a pathologic fracture. Unicameral bone cysts can occur at any age in childhood but are tate in children <3 yr of age and after skeletal maturity. The cause of these fluid-filled lesions is unknown. Some resolve soontaneously after skeletal maturity is reached. Most are asymptomatic until diagnosis,which usually follows a pathologic fracture. Such fractures may occur with relatively minor trauma, such as with throwing or catching a ball. Unicameral bone cysts appear radiographically as solitary, centrally located lesions within the medullary portion of the bone. These cysts are most common in the proximal humerus or femur. They often extend to (but not through) the physis and are sharply marginated. Thinning and expansion of the cortex occurs but does not exceed the width of the adjacent physis. Treatment involves allowing the pathologic r Retinoblastoma .2151 Ghapter502 fracture to heal, followed by aspiration and injection with methylprednisolone or bone marrow. Repeat injections, curettage,.and bone grafting occasionally are necessaryto treat recurrent lestons, Aneurysmal bone cyst is a reactive lesion of bone seen in or nerve root compression and associatedneurologic symptoms, including paralysis. Radiographs show eccentric lytic destruction and expansion of the metaphysis surrounded by a thin sclerotic rim of bone. Posterior elements of the spine are involved more commonly than the vertebral body. Unlike mosr other benign bone tumors, which usually are confined to a single bone, aneurysmal bone cysts may involve adjacent vertebrae. Rapid growth is characteristic and may lead to confusion with malignant neoplasms. Treatment consists of curettage and bone grafting or excision. Spinal lesions may require stabilization after excision. As with other benign tumors, attempts are made to preserve nerve roots and other vital structures. Recurrenceafter surgical treatment occurs in 20-30"/" of patients, is more common in younger than older children, and usually occurs in the first 12 yr after treatment. Fibrous dysplasia is a developmental abnormality characterized by fibrous replacement of cancellous bone. Lesions may be solitary or multifocal (polyostotic), relatively stable, or progressively more severe. Most children are asymptomatic, although those with skull involvement may have swelling or exophthalmos. Pain and limp are characteristic of proximal femoral involvemenr. Limb-length discrepancy, bowing of the tibia or femur, and pathologic fractures may be presenting complaints. The triad of usually involves observation. Surgery is indicated for patients with progressive deformitg pain, or impending pathologic fractures. Bone grafting is not as successfulin the treatment offibrous dysplasia as with other benign tumors because the lesion often recurs within the grafted bone. Reconstructive surgical techniques often are necessaryto provide stability. Osteofibrous dysplasia affects children 1-10 yr of age. This lesion usually involves the tibia. It is clinically, radiographically, and histologically distinct from fibrous dysplasia. Most children present with anterior swelling or enlargement of the leg. Progression is unlikely after 10 yr of age. Radiographs show solitary or multiple lucent, cortical, diaphyseallesions surrounded by sclerosis. Anterior bowing of the tibia often is present. The radiographic appearance closely resemblesthat of adamanrinoma, a malignant neoplasm, making biopsy more common than with other benign bone tumors. Treatment involves observation. Some lesions heal spontaneously. Excision and bone grafting should be delayed until the child is >10 yr of age because of a high recurrence rate before this age. Pathologic fractures heal with immobilization. Eosinophilic granuloma is a monosroric or polyostotic disease with no extraskeletal involvement. This latter findins distinguishes eosinophilic granuloma from the other forms oilangerhans' cell histiocytosis (Hand-Schnller-Christian or Letterer-Siwe variants), which may have a lessfavorable prognosis (seeChapter 507). Eosinophilic granuloma usually occurs during the first 3 decadesof life and is most common in boys 5-10 yr of age. The skull is most commonly affected, but any bone may be involved. Patients usually present with Iocal pain and swelling. Marked tendernessand warmth often are Dresentin the area of the involved bone. Spinal lesionsmay causepain, stiffness,and occasionalneurologic symptoms. The radiographic appearance of the skeletal lesions is similar in all forms of Langerhans' cell histiocytosis but is variable enough to mimic many other benign and malignant lesions of bone. The radiolucent lesions have well-defined or irregular margins with expansion of the involved bone and periosteal new bone formation. Spine involvement may cause uniform compression or flattening of the vertebral body. A skeletal survey is warranted becausepolyostotic involvement and the typical skull lesions strongly suggestthe diagnosis of eosinophilic granuloma. Biopsy often is necessary to confirm the diagnosis because of the broad radiographic differential diagnosis. Treatment includes curettage and bone grafting, low-dose radiation therapy, or corticosteroid injection. Observation for sympromatic lesions is reasonable becausemost osseouslesions heal soontaneously and do not recur. Children with bone lesions should be evaluated for visceral involvement becausetreatment of HandSchiiller-Christian disease and Letterer-Siwe disease is more complex and often svstemic. Arndt CAS, Crist WM: Common musculoskeletaltumors of childhood and N Engl J Med 1999;341.:342-352. adolescence. CampanacciM, CapannaR, Picci P: Unicameraland aneurysmalbone cysts. Clin Orthop Relat Res 1,986;204:25-36. CampanacciM, Laus M: Osteofibrousdysplasiaof the tibia and fibula.J Bone Joint Surg Am 1981;63:367-375. Dahlin DC, Ivins JC: Benign chondroblastoma:A study of 125 cases.Cancer 1.972;30:401413 De Alava E, Gerald lVL: Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J CIin Oncol 2000;18:204-213. FreibergAA, Loder Rl HeidelbergerKT: Aneurysmal bone cysts in young children..l Pediatr Orthop 1,994;1,4:86-91,. GinsbergJR \7oo Sl Johnson ME, et al: Ewing's sarcomafamily of tumors. In Pizzo PA, Poplack DG (editors): Principles and Practice of Pediatric Oncology,4th ed. Philadelphia,Lippincott S7illiams6c lTilkins, 2002, pp 973-1.016. Gorlick R, Anderson P, Andrulis I, et al: Biology of childhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary.Clin Cancer Res 2003;9:5442-5453. Grier H, Krailo M, Tarbell N, et al: Addition of ifosfamide and etoposideto standardchemotherapyfor Ewing'ssarcomaand primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694-701,. Grier RJ: Surgical options for children with osteosarcoma.Lancet Oncol 2005;5:85-92. Kneisl JS, Simon MA: Medical managementcompared with operativetreatment for osteoid osteoma.I Bone Joint Surg Am 1,992;74:179-1,85. Marina N, Gebhardt M, Teot L, et al: Biology and therapeuticadvancesfor pediatric osteosarcoma.Oncologist 2004;9:422-441. Rodriguez-GalindoC, Sount SL, Pappo AS: Treatment of Ewing sarcoma family of tumors: Current status and outlook for the future. Med Pediatr Oncol 2003;40:276-287. SchmaleGA, Conrad EU III, Raskind WH: The natural history of hereditary multiple exostoses.I Bone Joint Surg Am 1994;76:986-992. EPIDEMf0I0GY.Retinoblastoma occurs at a rate of 3.7 casesper million in the USA, with no racial or gender predilection. Overill, about 60o/o of casesare unilateral and nonhereditary,'l-5Y" are unilateral and hereditary, and 25o/o are bilateral and hereditary. Bilateral involvement at Dresentation is found in 42"/" of cases <1 yr of a1e,2lo/o of casesin children who are 1 yr of age, and less commonly in children presenting at older ages. 2t52 r PARTXXI I GancerandBenignTumors The hereditary form is associated with inactivation of the retinoblastoma gene (RB1), which is located on chromosome 13q14 and encodes the retinoblastoma protein (pRb), a tumor suppressor protein that controls cell-cycle phase transition and has roles in apoptosis and cell differentiation. Many types of mutations have been found, including translocations, deletions, i n s e r t i o n s .p o i n t m u t a t i o n s . a n d e p i g e n e r i cm u t a t i o n s s u c h a s hypermethylation of the promoter region. The nature of the predisposing mutation affects the penetrance and expressivity of retinoblastomadevelopment.Hereditary casesusually are multifocal and bilateral, whereas nonhereditary casestend to have unilateral, unifocal involvement. According to the "two-hit" model of oncogenesis,two mutational events are required for tumor development (see Chapter 4921.In the inherited form of retinoblastoma,the first mutation in the RB1 gene is inherited through germinal cells and a second mutation occurs subsequently in somatic retinal cells. Second mutations that lead to retinoblastoma ofren result in the loss of the normal allele and concomitant loss of heterozygosity.Many children with heritable retinoblastomahave new germinal mutations, and both parents are normal. Heterozygous carriers of oncogenic RB1 mutations demonstrate variable phenotypic expression.In the nonhereditary form of retinoblastoma, the two mutations occur in somatic retinal cells. PATH0GENESIS. Histologicalln retinoblastomaappearsas a small round blue cell tumor with rosetteformation. It may arisein any of the nucleatedlayers of the retina, exhibits various degreesof differentiation, and tends to outgrow its blood supply, resulting i n n e c r o s i sa n d c a l c i f i c a t i o n . Endophytic tumors arise from the inner surface of the retina, grow into the vitreous, and may result in vitreous seedingto other areas of the retina. Exophytic tumors grow from the outer retinal layer and may causeretinal detachment.Thesetumors can spread by direct extension to the choroid or along the optic nerve beyond the lamina cribrosa, or by hematogenousor lymphatic spreadto distant sites. CLINICAL MANIFESTATI0NS. Only about 10% of retinoblasromas are detected by routine ophthalmologic screening in the context of a positive family history. Retinoblastomaclassicallypresents with leukocoria,a white pupillary reflex (Fig. 502-1), which often is first noticed when a red reflex is not presentat routine newborn or well-child examination or in a flash photograph of the child. Strabismus often is the initial presenting complaint. Orbital inflammation,hyphema,or pupil irregularity occurswith advancing disease.Pain usually is a feature if secondaryglaucoma is present. DIAGN0SIS.The diagnosis is establishedby the characteristic ophthalmologic findrngs. Biopsy is contraindicated. Evaluation usually requires an examination under general anesthesiaby an ophthalmologist to obtain complete visualization of both eyes, which also facilitatesphotographingand mapping of the tumors. Retinal detachment or vitreous hemorrhase can complicate the e v aI u a t i o n . Orbital ultrasonographyand CT or MRI are used to evaluate the extent of intraocular diseaseand extraocular soread. Occasionally, a pineal area tumor is detected, a phenomenon known as trilateral retinoblastoma. MRI allows for better evaluation of optic nerve involvement. Bone scan, cerebrospinalfluid evaluation, and bone marrow evaluation are required only if indicated by other clinical, laboratory, or imaging findings. The differential diagnosis includes hyperplastic primary vitreous, Coats disease,cataract, visceral larva migrans, choroidal coloboma, and retinopathy of prematurity. TREATMENT. Treatment is determined by the size and location of the tumor. The primary goal is cure; the secondary goal is pre- with notedin the left eyeof a child presenting Figure.502-1.A, Leukocoria B, A largewhite tumor massnoted within the posterior retinoblastoma. eye.(FromShields chamberof the enucleated JA, ShieldsCL: CurrentmanMayo Clin Proc 7994;69:50-56.) agement of retinoblastoma. serving vision. As newer modalities for local control of intraocular tumor and more effective systemic chemotherapy have emerged, primary enucleation is being performed less often. Most unilateral diseasepresentsas a solitarn large tumor. Enucleation is oerformed if there is no potential for useful vision. With bilateial disease,chemoreduction in combination with focal therapy (laser photocoagulation or cryotherapy) has replaced the traditional approach of enucleation of the more severelyaffected eye and irradiation of the remaining eye. If feasible,small tumors can be treated with focal therapy with careful follow-up for evidence of recurrence or new tumor growth. Larger tumors often respond to multiagent chemotherapy including carboplatin, vincristine, and etoposide. If this approach fails, external-beam irradiation should be considered, although this approach may result in significant orbital deformity and increasedincidence of second malignancies in patients with germ line mutations. Brachytherapy, or episcleral plaque radiotherapS if feasible, is an alternative with less morbidity. Enucleation may be required for unresponslve or recurrent tumors. All first-degreerelatives of children with retinoblastoma should have retinal examinations to identify retinomas or retinal scars, which may suggest a predisposition to retinoblastoma even though malignant retinoblastoma did not develop. PR0GN0SIS.Approximately 95% of retinoblastomas in the USA, where extraocular extension rarely is seen, are cured. Current efforts using chemotherapy in combination with focal therapy are intended to Dreserveuseful vision and avoid irradiation or enucleation. Routine ophthalmologic examinations should continue until about 6 yr of age to detect new lesions. The prognosis for patients with metastasesis poor. Children with germ line RB1 mutations are at significant risk for development of second malignancies,especiallyosteosarcoma and also soft tissue sarcomas and malignant melanoma. The risk of cancersof the brain, nasal cavities, and eye and orbit is further increasedby the use of radiation therapy. Other radiation-related late adverse effects include cataracts, orbital growth deformities, lacrimal dysfunction, and late retinal vascular inlury. r 2153 Chapter 5ts I Gonadal andGermCellNeoplasms coccygealtumors occur predominantlyin infant girls. Testicular GCTs occur predominantly before age 4 W and after puberty. TesticularGCTsoccur much more often in whites than in blacks, whereasovarian GCTs have a slight predominancein blacks. Klinefeltersyndromeis associated with an increased risk of mediastinal GCTs; Down syndrome,undescended testes,infertility, testicularatrophy and inguinal herniasare associatedwith an increasedrisk of testicularcancer.The risk of testicularGCT is increasedin first-degree relatives,and is highestamongmonozy8OtlCrwlns. Abramson DH, ScheflerAC: Update on retinoblastoma.Retina 2004;24: 828-848. ClassonM, Harlow E: The retinoblastomatumour suppressorin development and cancer. Nat Reu Cancer 2002:2:910-917. Kleinerman R, Tucker MA, Tarone RF, et al: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma:An extendedfollow-up. J Clin Oncol 2005;23:2272-2279. Lohman DR, Gallie BL: Rerinoblastoma:Revisitingthe model prototype of inherited cancer.Am J Med Genet C (Semin Med Genet) 2004;129:23-28. Richter S, Vandezande K, Chen N, et al: Sensitive and efficient detection of RB1 gene mutations enhancescare of families with retinoblastoma,Am J Hum Genet 2003;72:253-269. Rodriguez-GalindoC, t07ilsonMW Haik BG, et al: Treatmenrof metastatic retinoblastoma. Ophthalmology 2003;1,10:7237-1240. PATH0GENESIS. The GCTsand non-GCTsarisefrom primordial germ cellsand coelomicepithelium,respectively. Testicularand sacrococcygeal GCTsarisingduring earlychildhoodcharacteristically havedeletionsat chromosomearms 1p and 5q and gains at 1q, and lack the isochromosome I2p that is highly characteristic of malignant GCTs of adults. TesticularGCT also may demonstrateloss of imprinting. BecauseGCTs may contain benignand malignantelementsin differentareasof the tumor, extensivesectioningis essentialto confirm the correctdiagnosis. The many histologicallydistinct subtypesof GCTs include teratoma (mature and immature), endodermalsinus tumor, and embryonal carcinoma (Fig. 503-1). Non-GCTs of the ovary include epithelial(serousand mucinous)and sex cord/stromal tumors;non-GCTsof the testicleincludesexcord/stromaltumors (e.g.,Leydigcell, Sertolicell). EPlDEMl0t0GY.Malignant germ cell rumors (GCTs) and gonadal tumors are rare, with an incidence of 12 casesper million persons <20 yr ol age. Most malignant tumors of the gonads in children are GCTs. The incidence varies according to age and sex. Sacro- MANIFESTATIONS ANDDIAGNOSIS. The clinical presenCLINICAL tation of germ cell neoplasmsdependson location. Ovarian Normalgerm-celldevelopment Migrationof PGCs1o genitalridge Innercellmass Blastocyst Spermatogenesis Seminiferous tubules A @ G Migration tl TGCT Seminomas Teratomas t,," / (Embryonic) ,r' ,/ / carcrnomas \ IGCNU ./ r Choriocarcinomas Combined tumors semrnomas Itr xtra-embryonic) \ B "o,n.". tumors F i g u r e 5 0 3 - 1 .A , N o r m a l g e r m c e l l d e v e l o p m e n t . E , M o d efl o r t h e o r i g i n a n d h i s t o g e n e s i s odf i f f e r e n t s u b t y p e s o f t e s t i c u l a r g e r m c e l l t u m oIrG s .C N U , i n t r a t u b u lar germ cell neoplasiaunclassified;PGC, primary germ cell; TGC! testiculargerm cell tumor(s). 2154I PARTXXI I $3nsg1andBenignTumors tumors often are quite large by the time they are diagnosed. Extragonadal GCTs occur in the midline, including the suprasellar region, pineal region, neck, mediastinum, and retroperitoneal and sacrococcygealareas.Symptoms relate to mass effect, but the intracranial GCTs often present with anterior and posterior pituitary deficits (seeChapter 497). The serum cr-fetoprotein (AFP) level is elevated with endodermal sinus tumors and may be minimally elevated with teratomas. Infants have higher levelsof AFP, which fall to normal adult levels by about 8 mo; therefore, high AFP levels must be interpreted with caution in this age group. Elevation of the B subunit of human chorionic gonadotropin (P-hCG) is seen with choriocarcinoma and germinomas. Lactate dehydrogenase (LDH), although nonspecific, may be a useful marker. If elevated, these markers provide important confirmation of the diagnosis and provide a means to monitor the patient for tumor responseand recurrence.Both serum and cerebrospinal fluid should be assayed for these markers in oatients with intracranial lesions. Diagnosis begins with physical examination and imaging studies, including plain radiographs of the chest and ultrasonography of the abdomen. CT or MRI can further delineate the primary tumor. If germ cell malignancy is strongly suggested,preoperative staging with CT of the chest and bone scan is appropriate. Primary surgical resection is indicated for tumors deemed resectable.The exception is intracranial lesions, where the diagnosis can be established with imaging and AFP or p-hCG determinations. Gonadoblastomas often occur in patients with gonadal dysgenesis and all or parts of a Y chromosome. Gonadal dysgenesisis characterizedby failure to fully masculinize the external genitalia. If this syndrome is diagnosed, imaging of the gonad with ultrasonography or CT is performed, and surgical resection of the tumor usually is curative. Prophylactic resection of dysgenetic gonads at the time of diagnosis is recommended, because gonadoblastomas, some of which contain malignant germ cell tumor elements, often develop. Gonadoblastomas may produce abnormal amounts of estrogen. Teratomas occur in many locations, presenting as masses.They are not associated with elevated markers unless malignancy is present. The sacrococcygealregion is the most common site for teratomas. Sacrococcygealteratomas occur most commonly in infants and may be diagnosed in utero or at birth, with most found in girls. The rate of malignancy in this location varies, ranging from <10% in children <2 mo of age to >50% in children >4 mo of age. Germinomas occur intracraniallv. in the mediastinum. and in the gonads. In the ovary. they are'called dysgerminomas:in the testis, seminomas. They usually are tumor marker negative despite being malignant. Endodermal sinus or yolk sac tumor and choriocarcinoma appear highly malignant by histologic criteria. Both occur at gonadal and extragonadal sites. Embryonal carcinoma most otten occurs ln tne testes. Non-germ cell gonadal tumors are very uncommon in pediatrics and occur predominantly in the ovary. Epithelial carcinomas (usually an adult tumor), Sertoli-Leydig cell tumors, and granulosa cell tumors may occur in children. Carcrnomas account Ior about r/3of ovarian tumors in females<20 yr of age; most of these occur in older teens and are of the serous or muclnous subtype. Sertoli-Leydig cell tumors and granulosa cell tumors produce hormones that can cause virilization, feminization, or precocious puberty, depending on pubertal stage and the balance between Sertoli (estrogenproduction) and Leydig cells (androgen production). Diagnostic evaluation usually focuses on the chief complaint of inappropriate sex steroid effect and includes hormone measurements,which reflect gonadotropin-independent sex steroid production. Appropriate imaging also is performed to rule out a functioning gonadal tumor. Surgery usually is curative. No effective therapy for nonresectablediseasehas been found. Complete surgical excision of the tumor usually is TREATMENT. indicated, except for patients with intracranial tumors, where the primary therapy consists of radiation therapy and chemotherapy. For testicular tumors, an inguinal approach is indicated. When complete excision cannot be accomplished, preoperative chemotherapy is indicated, with second-look surgery. For teratomas, both mature and immature, and completely resected malignant tumors, surgery alone is the treatment. Cisplatin-based chemotherapy regimens usually are curative in GCTs that cannot be completely resected, even if metastasesare present. Except for GCTs of the central nervous system, radiation therapy is limited to those tumors that are not amenable to complete excision and are refractory to chemotherapy. PR0GN0SIS.The overall cure rate for children with GCTs is >80'/". Age is the most predictive factor of survival for extragonadal GCTs. Children >12yr of age have a 4-fold higher risk of death, and a 6-fold higher risk if the tumor is thoracic. Histology has little effect on prognosis. Nonresected extragonadal GCTs have a slightly worse prognosis. Cushing B, Giller R, Cullen J]07,et al: Randomizedcomparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or with high risk malignant standard-dosecisplatinin children and adolescents germ cell tumors: A pediatric intergroupstudy-Pediatric Oncology Group 9049 a,nd Children's Cancer Group 8882. / Clin Oncol 2004;22: 2697-2700. Horwich A, Shipley J, Huddart R: Testicular germ-cell cancet. Lancet 2006;367:754-764. Marina N, London WB, Frazier L, et al: Prognosticfactors in children with extragonadalmalignant germ cell tumors: A pediatric intergroup study./ Clin Onco I 2006:24:25 44-25 48. Rogers PC, Olson TA, Cullen JV7,et al: Treatment of children and adolescents with stage I testicular and stagesI or II ovarian malignant germ cell tumors: A pediatric intergroup study-Pediatric Oncology Group 9048 and Children's Cancer Group 8891,.J Clin Oncol 2004;22:563569. SchneiderDT, SchusterAE, Fritsch MK, et al: Geneticanalysisof mediastinal nonseminomatousgerm cell tumors in children and adolescents.Gezes ChromosomesCancer 2002:3:175-1.25. Young JL, Vu XC, Roffers SD, et al: Ovarian cancer in children and young adults in the United States, 1992-1997. Cancer 2003;97:26942700. Hepatic tumors are rare in children. Primary tumors of the liver account for =Io/" of malienanciesin children. with an annual incidence of 1..6casesper mi'ilion children in the USA. From 50-60% of hepatic tumors in children are malignant, with >65"/" of these malignancies being hepatoblastomas and most of the remainder hepatocellular carcinomas. Rare hepatic malignancies include angiosarcoma,malignant germ cell tumor, rhabdomyosarcoma of the liveq and undifferentiated sarcoma. More common childhood malignancies such as neuroblastoma and lymphoma can metastasize to the liver. Benign liver tumors, which usually present in the first 6 mo of life, include hemangiomas, hamartomas, and hemangioendotheliomas. I Neoplasmsof Chapter5{14 theLiver t 2155 HEPATOBTASTOMA increased incidence of hepatoblastoma, with the risk increasing as birthweight decreases. pure elements), or the mixed type, containing mesenchymal and epithelial elements.Pure fetal histology predicts a more favorable outcome. in the diagnosis and monitoring of hepatic tumors. AFP level is elevated in almost all hepatoblastomas. Bilirubin and liver enzymes usually are normal. Anemia is common, and thrombocytosis occurs in about 1/, of patients. Hepatitis B and C serology should be obtained but usually are negative in hepatoblastoma. Diagnostic imaging should include plain radiographs and ultrasonography of the abdomen to characterize the hepatic mass. Ultrasonography can differentiate malignant hepatic massesfrom benign vascular lesions. Either CT or MRI is an accurate method of defining the extent of inrrahepatic tumor involvement and the potential for surgical resecrion. Evaluation for metastatic disease should include CT of the chest and bone scan. TREATMENT. In general, the cure of malignant hepatic rumors in children depends on complete resection of the primary rumor (Fig. 50a-1). As much as 85% of the liver can be resected,with hepatic regeneration noted within 3-4 mo after surgery.Cisplatin in combination with vincristine and S-fluorouracil or doxorubicin is effective treatment for hepatoblastoma and increasesthe chances of cure after complete iurgical resection. In low-stage tumors, survival rates >90o/" can be achieved with multimodal treatment, including surgery and adjuvant chemotherapy. !7ith tumors unresectableat diagnosis, survival rates of approximately 60oh can be obtained. Metastatic diseasefurther reducessurvival, but complete regression of disease often can be obtained with chemotherapy and surgical resection of the primary tumor and isolated pulmonary metastatic disease,resulting in survival rates of about 257". Liver transplant is a viable oprion for unresectable primary hepatic malignancies and results in good long-term survival. Pretransplant medical condition is an important predictor of outcome, and thus transplant is much more effective as the primary surgery than as salvage therapy. HEPATOCEILUIAR CARCINOMA EP|OEM|OI0GY. Hepatocellular carcinoma occursmostlyin adoIescentsand often is associatedwith hepatitis B or C infection. It is more common in East Asia and other areas where heoatitis B is endemic, and is already showing decreasedincidence following the introduction of hepatitis B vaccination. In these areas it also tends to occur in a bimodal pattern, with the younger age peak overlapping the age of hepatoblastoma presentation. It also occurs in the chronic form of hereditary tyrosinemia, galactosemia, glycogen storage disease,cx1-antitrypsindeficiencp and biliary cirrhosis. Aflatoxin B contamination of food is another risk factor. Hepatocellular carcinoma usually presents as a PATH0GENESIS. multicentric, invasive tumor consisting of large pleomorphic cells with a lack of underlying cirrhosis. The fibrolamellar variant of heoatocellular carcinoma occurs more often in adolescent and young adult patients. Although previous reports have suggested that the fibrolamellar type has a better prognosis, more recent data analysisrefutesthis. CtlNlCAt MANIFES l0NS. Hepatocellular carcinoma usually presents as a hepatic mass, abdominal distention, and symptoms of anorexia, weight loss, and abdominal pain. Hepatocellular carcinoma can present as an acute abdominal crisis with nrpture of the tumor and hemooeritoneum. The AFP level is elevated in approximately 60% of child...t with hepatocellular carcinoma. Evidence of hepatitis B and C infection usually is found in endemic areas, but not in \Testern countries or with the 6brolamellar type. Bilirubin usually is normal, but liver enzymesmay be abnormal. Diagnostic imaging should include plain radiographs and ultrasonography of the abdomen to characterize the hepatic mass. Ultrasonography can differentiate malignant hepatic massesfrom benign vascular lesions. Either CT or MRI is an accurate method of defining the extent of intrahepatic tumor involvement and the potential for surgical resection. Evaluation for metastatic disease should include CT of the chest and bone scan. Becauseof the multicentric origin of hepatocellular TREATMENT. carcinoma, complete resection of this tumor is accomplished in only 3040"/, of cases. Even with complete surgical resection, only 30%' of children are long-term survivors. Chemotherapy, including cisplatin, doxorubicin, etoposide, and S-fluorouracil, has shown some activity against this tumor, but improved longterm outcome has been difficult to achieve.Other techniouessuch as chemoembolization and liver transplantation are under srudy as therapy for hepatocellular carcinomas. Austin M! Leys CM, Feurer ID, et al: Liver transplantationfor childhood hepatic malignancy: A review of the United Network for Organ Sharing (UNOS) database.J Pediatr Surg 2006;4L:182-L86. Darbari A, Sabin KM, Shapiro CN, et al: Epidemiology of primary hepatic malignanciesin U.S. children. Hepatology 2003;38:560-566. KatzensteinHM, Krailo MD, Malogolowkin MH, et al: Hepatocellularcarcinoma in children and adolescents:Resultsfrom the Pediatric Oncology Group and Childrent Cancer Group Intergroup Study. / CLin Oncol 2002;20:2789-2797. KatzensteinHM, Krailo MD, Malogolowkin MH, et al: Fibrolamellarhepatocellular carcinoma in children and adolescents. Cancer 2003:97: 2006-201.2. Llovet JM, BurroughsA, Bruix J: Hepatocellularcarcinoma.Lancet2O03;362: 1.907-1.916. Otte JB, Pritchard J, Aronson DC, et al: Liver transplantation for hepatoblastoma: Results from the International Society of Pediatric Oncology (SIOP)study SIOPEL-I and review of the world experience.Pediatr Blood Cancer 2004;42:74-83. SchnaterJM, Kohler SE, Lamers IVH, et al: $7heredo we stand with hepatoblastoma?A review Cancer 200398:668-678. Tiao GM, Bobey N, Allen S, et al: The current managementof hepatoblastoma: A combination of chemotherapy,conventional resection,and liver transplantation.J Pediatr 2005;1,46:204-21.1. 2156I PABTXXI r Gancerand BenignTumorc Crosssectionalimagingot the abdomenandchest usingCTor MRI Serumlevelof AFP Yes I I Resecl Histologyof lesion I t Chemotherapy unlesspure fetal histology Figure 504-1. Algorithm for the management of a child who presents with a hepatoblastoma. AFP, a-fetoprotein. (From Tiao GM, Bobey N, Allen S, et al: The current management of hepatoblastoma: A combination of chemotherapy, conventional resection, and liver transplantation. J Pedian 2005:146:204-21r.1 Yes I + Resect I t CompleteChemotherapy .Consider continuation of chemotherapy livertransplantation or living-related if cadaveric livertransplant notavailable in a timelyfashion can of womenwho had chorionicvillus sampling.Hemangiomas be presentat birth but usually arise shortly after birth and grow rapidly during the first year of life, with slowing of growth in the next 5 yr and involution by 10-15 yr of age. . HeruRncronnRs 505.1 Hemangiomas,the most common benign tumors of infancS occur in about 10% of term infants (seeChapter649). The risk of hemangiomais 3-5 timeshigher in girls than boys.The risk is doubledin prematureinfantsand 10 timeshigherin offspring More thanll2of all hemangiomas CtfNfCAtMAltllFESTATl0NS. are locatedin the head and neck region. Most are solitary lesions, but the presenceof more than one cutaneouslesionincreasesthe likelihood of visceralhemangiomas.The liver is the primary site of visceralinvolvement;other involvedorgansincludethe brain, intestines,and lung. Most hemangiomasrequire no therapy,but approximately 10% of hemangiomascause significant impair- Ghapter5116. X.ts 1xP66 r 2157 ment and I"/" are life-threatening because of their location. Hemangiomas around the airway can cause airway obstruction, and those around the eyescan result in loss of vision. Ulceration is a common complication and can lead to secondary infection. Large hepatic hemangiomas or hemangioendotheliomas may result in hepatomegaly, anemia, thrombocytopenia, and highoutDut heart failure. Kasabach-Merritt syndrome is characte rized by a rapidly enlarging lesion, thrombocytopenia, microangiopathic hemolytic anemia, and coagulopathy as a result of platelet and red blood cell trapping and activation of the clotting system within the vasculature of the hemangioma. This syndrome has been shown to be associatedwith kaposiform hemangioendotheliomasor tufted nemanglomas. Cutaneous lesions usually can be diagnosed by typical appearance and rapid proliferation. Segmental hemangiomas, or those with geographic localization and some plaquelike features, recently have been shown to have a higher risk of complications and association with developmental abnormalities. A deep Iesion may require imaging studies to help differentiate it from a lymphangioma. The presenceof a midline hemangioma in the lumbosacral area indicates the need for an MRI to search for underlying asymptomatic neurologic abnormalities. Location also may dictate the need for an ophthalmologic or surgical consultation. An ultrasonographic scan or MRI of the liver should be performed if multiple cutaneous lesions are present. TREATMENT.Most hemangiomas require no specific therapy beyond reassuranceof the parents. For hemangiomas that are lifethreatening or that threaten vital functions such as eyesight,treatment is warranted. Prednisone (1-3 mg/kg/day PO) typically is the initial therapy; higher doses or intralesional corticosteroids sometimes are used. Approximately 30% of hemangiomas respond dramatically to corticosteroids and begin to regress within 1 wk; 40"/' of hemangiomas stabilize or show minimal response; and the remaining tumors do not respond. Interferon (IFN)-c (1-3 MU/m'zlday) also has been used as initial therapy and in patients who do not respond to corticosteroid therapy. Although response rates of up to 70"/" have been reported, the risk of neurologic adverse effects in 10-20% of patients necessitates caution in using IFN-c. Laser therapy has been used in some sltuailons. Treatment of patients with Kasabach-Merritt syndrome usually consists of supportive care while also beginning therapy with corticosteroids or IFN-u,. Heparin therapy is contraindicated, and platelet transfusions should be avoided in the absence of lifethreatening hemorrhage, becausethey may exacerbatethe bleeding. The use of aminocaproic acid or tranexamic acid may be beneficial. Failure to respond to therapy warrants the use of less conventional treatments. such as irradiation, embolization, or surgical resection. located in the head and neck area. Approximately 50"/" are present at birth, with most presenting by 2yr of age. There is no gender predisposition. Spontaneousregressionhas been reported of the head and neck. Brewis C, Pracy JP, Albert DM: Treatment of lymphangiomas of the head and neck in children by intralesional iniection of OK-432 (Picibanil). Clin Otolaryngol 2000;25 :130-7 34' Giguere CIvI, Bauman NM, Sato Y, et al: Treatment of lymphangiomas with Of-+:Z (Picibanil) sclerotherapy:A prospectivemulti-institutional trial' Arcb Otolaryngol Head Neck Sutg 2002;128:1137-1,144- TutvtoRs 506.1o THvRolo greatestrisk factor for thyroid cancer is prior radiation exposure' Especially following head and neck irradiation. Thyroid cancer aciounts for about 10o/" of second malignancies among cancer survivors, especially survivors of Hodgkin lymphoma, due to treatment noi only with radiation but also with alkylating.agents. Almost all are differentiated carcinomas (papillary or follicular). Bruckner AL, Frieden IJ: Hemangiomas of infancy. J Am Acad Dermatol 2003;48:477496. Chiller KG, PassaroD, FriedenIJ: Hemangiomasof infancy: Clinical characteristics,morphologic subtypes,and their relationshipto race,ethnicity,and sex. Ar ch D ermatol 2002;138 :1567-1 57 6. HYCRONANS ANDCYSTIC 505.2. LYMPHANGIOMAS Lymphatic malformations, including lymphangiomas and cystic hygromas, which arise in the embryonic lymph sac,are the second most common benign vascular tumors in children. About half are therapy. 2158r PARTXXI I GancerandBenignTumors . Patients present with a thyroid mass and/or cervical lymphadenopathy; symptoms related to abnormal hormone levels'are rare. About 20oh of thyroid nodules in young children are malignant, compared with about 10% in adolescentsand adults. Fineneedle aspiration (FNA) commonly is used ro assessthyroid nodules in adults, but the use of FNA in the pediatric population has not been firmly established, especially in preadblescent patients; surgical resection of nodules is recommended for these patients. Evaluation should include derermination of thyroid hormone levels, thyroid scan, chest radiography, and Cf'of the chest. Total thyroidectomy for diseaseconfined to one lobe has been controversial in pediatrics owing to good prognosis and the risk of complications such as hypoparathyroiaiim. However, total or near-total thyroidectomy reduces the risk of local recurrence. Routine lymph node dissectionis nor indicated, but should be done if cervical lymph nodes are involved. Treatment with iodine 131 is then usedto eradicateresidualdiseaseand treat oulmonary metastases,which occur in 5-107" of cases.pulmonary metastasesare best detected with radioiodine after resection of bulk disease. Hung w' Sarlis NJ: Currenr conrroversiesin the managementof pediatric patients with well-differentiatednonmedullary thyroid cancer: A review Thyroid 20021 2:683-702. Machens A, HolzhausenH-j, Thanh PN, et al: Malignanr progressionfrom C-cell hyperplasiaro medullary thyroid carcinoma in lG7 carriersof RET germline mutarions Surgery 203;134:425-31. ShermanSI: Thyroid carcinoma.Lancet 2003i361:501-510. SzinnaiG, Meier C, Komminoth P, er al: Review of multiple endocrineneoplasia type 2A in children: Therapeuricresultsof early thyroidectomyand prognosticvalue of codon analysis.Pediatrics 203:171.:el 32--e139. 506.2o METANoMA The incidence of melanoma in persons <20 yr oI age in the USA is 4.2 casesper million, with almost all of these casesoccurrlng in adolescents (see Chapter 650). Melanoma is more common among adolescent females than males. Incident rates of melanoma in younger age groups have remained stable in the USA, but the incidence is rapidly increasing in adults. Although sun exposure is a well-known risk factor for melanoma in adults, its role in pediatric melanoma is less clear. pediatricians Mones JM, AckermanAB: Melanomasin prepubescent children:Reviewcomprehensively, critique historically,criteria diagnostically,and coursebiologically. Am J Dermatopathol 2003)5:223-238. Pappo AS: Melanoma in children and adolescents.Eur J Cancer 2003;39: 2651,-2667 506.3o NRsopHnRyNcEAr GRRcllronaR Nasopharyngeal carcinoma is rare in the pediatric population, but is one of the most common nasopharyngeal tumors in pediatric patients. In adults, the incidence is highest in South China, but it is also high among the Inuit people and in North Africa and Northeast India. In China, it is rare in the pediatric population, but in other populations a substantial proportion of cases occur in the pediatric age group, primarily in adolescents. It occurs in males twice as often as in females and is more common in blacks. In the pediatric population the tumors are more commonly of undifferentiated histology and associatedwith EpsteinBarr virus (EBV). Nasopharyngeal carcinoma has been associated with specific HLA types. the head and neck is performed to determine the extent of locoregional disease.Chest radiographS Cl bone scan, and liver scan are used to evaluate for metastatic disease.Monitoring EBV IgA and ZEBRA (antibodies to the Epsrein-Barr virus Bam H1Z transactivator protein) protein levels also may be useful. Treatment is a combination of chemotherapv and irradiation. Cisplatin-basedchemotherapy is given before or concurrenr with irradiation. The outcome depends on the extent of disease; patients with distant metastaseshave a very poor prognosis. The use on intensity-modulated radiation therapy (IMRT) has improved local control and reduced the late adverse effects associated with radiation therapy, including hormonal dysfunction, dental caries, fibrosis, and second malignancies. Ayan I, Kaytan E, Ayan N: Childhood nasopharyngealcarcinoma: From biology to trearmenr.Lancet Oncol 2003:4:13-21. Tsao S$7,Lo KV, Huang DP: Nasopharyngealcarcinoma.In TselisA, Jenson HB (editors): Epstein-Barr Vlrzs. New York, Taylor and Francis, 2005, pp 273-295. plgmentosum. 506.4o ADENocARcINoMA 0FTHE Gor_or'r ANDRECTUM Treatment recommendations are based on adult data. The better for children than adults is unclear. Colorectal carcinoma is rare in the pediatric population. There is a.male predominance in children, as compared with a female predominance in adults. Even in parients with predisposing conditions, such as familial adenomatous polyposis and Peutz-Jeghers syndrome, cancer usually does not present until aduithood, although ge_netic.testing is available and screening should begin during childhood or adolescence. Hereditary nonpolyposis colon cancer (HNPCC), an autosomal dominant disorder, may present with early-onset colon cancer as well as a predisposition to cancersin other tissues(e.g., of Childhoodr 2159 Syndromes 507 r Histiocytosis Ghapter ovarian, brain, renal, uterine). Germline mutations in DNA mismatch repair genes (MMR) cause DNA repair errors and microsatelliteinstability. Presentingsymptoms include bloody stools or melena,abdominal pain, weight loss, and changesin bowel patterns.Signsoften are vague, often resulting in a delay in diagnosisand advanced disease.The histologic subtype differs from that seen in adults, with the majority of pediatrictumors being mucinous.Treatment consistsof surgical resectionwhen possible,with chemotherapy for unresectabletumors. Radiation therapy is useful in the treatment of rectal carcinomas. and the'Wilms tumor gene,t(1'1';221(p13;q12). Patients typically Dresentwith diffuse abdominal diseasewith no definitive primary although disease outside the abdomen is possible.. Aggressive treatmint with surgern chemotherapy, and radiation has resulted in almost universallv poor outcome' Gerald \(/L, Ladanyi M, de Alava E: Clinical, pathologic,and molecularspec: e s m o p l a s t i cs m a l l t r u m o f t u m o r s a s s o c i a t e dw i t h t ( 1 1 ; 2 2 X p 1 3 ; q 1 2 )D round-celltumor and its variants. I Clin Oncol 1998;16:3028-3036 Grady SUM: Generic testing for high-risk colon cancer patients. Gastroenterology 2003i 124:l 57 4-1 594. Marcos I, BorregoS, LlriosteM, et al: Mutations in the DNA mismatchrepair geneMLHl associatedwith early onset colon cancer./ Pedidtl 2005;1481 837-839 CARGINOMA 506.5. AoRTTOCORTIGAL Adrenocortical carcinoma is rare but is associated with the LiFraumeni and Beckwith-'Wiedemann syndromes. Due to the rarity of adrenocorticalcarcinoma in children and the association with l-i-Fraumeni syndrome, the diagnosis of adrenocortical carcinoma should prompt consultation for genetic testing. The tumor may occur at any age during childhood but is more common during the first few years of life, and more common in females. In Brazil, childhood adrenocortical carcinoma is 10 times more common than in the USA. Younger children rypically presentwith virilization, whereasadolescentspresenteither with no endocrine symptoms or with Cushing syndrome. Prognosis depends on tumor size, extent of tumor, and resectability. Although it does respond to mitotane- and cisplatin-based chemotherapn the prognosis is poor {or unresectableor metastatic disease. E, Sandrini R, FigueiredoB, et al: Clinical and outcome characteristics of children with adrenocortical tumors: A report from the International Pediatric Adrenocortical Tumor Registry J Clin Oncol Michalkiewicz 2004;5:838-845. . Drsnaopmsnc Cru-Tutuon SMAttRoutrto 506.6 Desmoplasticsmall round cell tumor (DSRCT) is a recently recognized tumor that occurs predominantly in adolescentmales. It is associatedwith a translocation between the Ewing tumor gene (1A55 ll The childhood histiocytoses constitute a diverse group of disorders, which, although individually rare, may be severein their clinical expression.These disorders are grouped together because a prominent proliferation or accumulation they have ln .o--on of cells of the monocyte-macrophage system of bone marrow origin. Although these disorders sometimes are difficult to distin[uish clinicJly, accurate diagnosis is essentialneverthelessfor faiitating ptogi.tt in treatment. A systematic classification of the childhood fiistiocytoses is based on histopathologic findings (Table 507-1). A thorough, comprehensiveevaluation of a triopsy specrmen obtained at the time of diagnosis is essential. This evaluation includes studies such as electron microscopy and immunostaining that may require special sample processing' H0I0GY. Three classesof childhood hisAND CIASSIFICATI0N tiocytosis are recognized, based on histopathologic findings. The most well-known childhood histiocytosis, previously known as histiocytosis X, constitutes class I and includes the clinical entities of eosinophilic granuloma (seeChapter 501), Hand-SchiillerChristian disease, and Letterer-Siwe disease. The name Langerhans' cell histiocytosis (LCH) has been.applied to the class I histiocytoses. The normal Langerhans' cell is an antigen-presenting cell (APC) of the skin. The hallmark of LCH in all forms is the presenceof a clonal proliferation of cells of the monocyte lineagecontaining the characteristicelectron microscopic findings of a Laneerhans' cell. This is the Birbeck granule, a tennis racket-shiped bilameilar granule that, when seen in the cytoplasm of lesional cells in iCH, it diagnostic of the disease.The bitbeck granule expressesa newly characterizedantigen' langerin rcD207\. which ii involved in antigen presentation to T lymphocytes. The definitive diagnosis of LCH also can be established ty demonstrating CDla-positivity of lesional cells, which now can be done using fixed tissue' The lesions may contain various proportions of thise Langerhans' granule-containing cells, lympho.yt.t, granulocytes, monocytes' and eosinophils' TRIATMENT OFI-EsION5 CELLULAR ff ARAOERISTICS disease fordisseminated chemotherapy lsions; forisoiaed therapy Local ([D1a-p0siti\/e) granu]es withBirbeck Langerhanlcells ceLl histio(ytosls Langerhanl on transplantat manow bone alogeneic Ihemotherapy; reactivema(r0phaqeswithprominenterythr0phagocytosts Morphooqicallynorma lymph0hrstiocytoss* Familial erythrophagocytK DISEASE syndrome' Infeiti0n-ass0Liated hemophagocytic ncudinq anthtacydines chem0therapy, Antlne0plastrr or proliferation o ofmonocyteVmacrophages 0fcllswithiharacterist Neoplastic hr5tio(),tosis Malignant precu60rs their A(ute monocyti( leukemla *Also (FHL|]) lymph0hlsti0tytosis called famiialhemophaqocytic :Als0 hem0phag0(ytii lymph0hrtiotyt0sis ralled sec0ndary lll 2160r PARTXXI I CancerandBenignTumors sive. Specific genes involved with FEL include mutations of perforin, Munc 13-4, and, Syntaxin-11. The other is the infection-associated hemophagocytic syndrome (IAHS), also called secondary hemophagocytic lymphohistiocyrosis (Table 507-2i. Both diseasesare characrerized by disseminated lesions that involve many organ systems. The lesions are characterized by infiltration of the involved organ with activated phagocytic macrophages and lymphocytes, in which the lymphocyte defects are considered to be the primary abnormality. These diseasesare grouped together under the term hemophagocytic lymphohistiocytosis (HLH) [Table 507-3]. The mixed cellular lesionsof both the classI and classII histiocytoses suggest that these may be disorders of immune regulation, resulting from either an unusual and unidentified antigenic stimulation or an abnormal and somehow defective cellular rmmune response.Mutations in the perforin (PRF1) gene or the Munc 13-4 gene cause defective function of the cytotoxic lymphocyreswhose activity is inhibited in FHLH. The class III histiocytoses, in conrrasr, are unequivocal malignancres of cells of monocyte-macrophage lineage. By this definition, acute monocytic leukemia and true malignant histiocytosis are included among the classIII histiocytoses(seeChapter 495\. The existenceof neoplasmsof Langerhans'cells is controversial. Some casesof LCH demonstrare clonalitv. VIRAT Adenovirus [ytomegalovirus Dengue virus Epstein-Barr virus Herpes simplex virus Human immunodefi ciency virus Parvovirus B'19 Varkella-zo$er virus BAOERIAI, Bobesio nkroti Erucello obonus gram-nEative Enterir rods Hoemophilus influenzoe pneunontoe Mycoplosno Stophylotorcus oureus pneumoni Streptocottus oe tuirGAr. kndido olbkons (ryptocNtus neofornons (opsulot Histoplosno un MYCOBACTERIAT Myroboeu iuntube rculus RICKffTSIAt bxkllobrunetii PARASITIC Leishmonio donovoni . CussI Htsnocyrosrs 507.1 From Nathan D6,Orkin SH,Ginsburg D,etal(edit06): il, thlnlnd hki\ Heniltll\gy oflnfoncy ondhihhufl 6rhedphrlade! phia,WB saunders, 2m3,p 1381. .ln conrrast ro rhe prominence of an ApC (the Langerhans' cell) in the class I hisrioc.vtoses, the class II histiocytosesare nonmalignant proliferative disorders thar are characterized by accumulation of anrigen-processingcells (macrophages). Hemophagocytic lymphohistiocytoses (HCH) are the risult of uncontrolled hemophagocytosis and uncontrolled activation HlH,genetir Autosomal recessive Possibly associated radrographically, and may cause secondary compression of the spinal cord. In flat and long bones,osteolyriclesionswith sharp borders occur and no evidence exists of reactive new boni formation until rhe lesions begin to heal. Lesions rhat involve weight-bearing long bones may result in pathologic fracrures. Chronically draining, infected ears are commonly asiociated with destruction in the mastoid area. Bone destruction in the mandible and.maxilla may result in teeth thar, on radiographs,appear ro be free floating. With response ro rherapy, healing may be complete. About 50% of patients experienceskin involvemenr at some time during the courseof disease,usually as a hard-to-treatscaly, papular, seborrheicdermatitis of the scalp, diaper, axillary, or posterior auricular regions).The lesions may spread to involve CTLTU[AR IMMUNE TUNOION MISCEI.I-ANEOUS J cNr Perforin deficiency (PRF1 Hypertriglycerjdemia, Perforin ), Munc 13-4mutations J NKcellactNity J Monocyte killing J (MI Secondary infection-asocated Sporadic yes XLP X-linked sporadic EBV SHML L6 sporadic Sporadic ?tBV EBV J cH,rr [oagulopathy early inthe(0urse 0fthedisease NLor1 NKcellin instances associated withEBV J Anomalous EBV+elated killinq NLort NKcell NLor'l anomalous EBV-related killing Notreported J TMI SH2DIA mtation Severe, often fatalhepatitis phenomena Autoimmune Lymphoma development fromNathan DG,0rkin 5H,6tnsburg Ind ?ski\Hennt\laqy Deral(ed[06):Nlthln oflnfoncy ond(hildho04 6rhedphiladelphta,WB p j]87 Saunde6,200j, of GhildhoodI 2161 Syndromes 507 r Histiocytosis Ghapter physical examination or by these studies should be performed to establish the extent of diseasebefore initiation of treatment. The clinical courseof single-system AND PR0GN0SIS' TREATMENT disease(usually,bone, lymph node, or skin) usually.is benign, with a high chance of spontaneousremission.Therefore, treatment should be minimal and should be directed at arresting the progression of a bone lesion that could result in permanent in-"g. before it resolvesspontaneously.Curettage or, less often, low-dose local radiation therapy (5-6 Gy) may accomplish this cellhisfrom patientswith Langerhans' l;iourc i{)*' I Two skullradiographs tiocytosist,l('.t1) Left, The patientwas >2 yr of ageand had involvement (arrous).Shehada goodrecoveryRrgDr, The bonelesions limitedto rsolated (arrous),a febrile patientwas<2yr of ageand had extensive bonedisease course, anemia! severe skrn eruption, generalizedlymphadenopath,v, pulmonaryrnfiltrates, and a fataloutcomedespiteantihepatosplenomegaly, oppositeendsof the clnical Thesepatientsrepresent tumor chemotherapy. of LCH. spectrum rhe back, palms, and soles.The exanthem may be petechial or hemorrhagic, even in the absenceof thrombocytopenia.Localized or disseminatedlymphadenopathy is present in approximately 33% of patients. Hepatosplenomegaly occurs in approximately 20"h of patients. Various degreesof hepatic malfuncrion may occu! including jaundice and ascites. Exophthalmos, when present,often is bilateral and is caused by retro-orbital accumulation of granulomatoustissue.Gingival mucous memDranesmay be involved with infiltrative lesionsthat appear superficiallylike candidiasis.Otitis media is present in 30-40% of patients; deafnessmay follow destructive lesions of the middle ear. In 10-157o of patients,pulmonary infiltratesare found on radiography.The lesionsmay range from diffuse fibrosis and disseminatednodular infiltratesto diffuse cystic changes. Rarely, pneumothorax may be a complication. If the lungs are severelyinvolved, tachypnea and progressiverespiratory failure mav result. Pituitary dysfunction or hypothalamic involvement may result in growth retardation. In addition, patients may have diabetes insipidus;patients suspectedof having LCH should demonstrate the ability to concentrate their urine before going to the operating room for a biopsy. Rareln panhypopituitarism may occur. Primary hypothyroidism due to thyroid gland infiltration also may occur. Patients who are affected more severely may have systemic manifestations, including {ever, weight loss, malaise, irritabrlity, and failure to thrive. Bone marrow involvement may cause anemia and rhrombocytopenia.Two uncommon but seriousand unusual manifestationsof LCH are hepatic involvement (leading to cirrhosis)and a peculiarcentral nervoussystem(CNS) involvement characterizedby ataxia, dysarthria, and other neurologic symptoms. Hepatic involvement is associatedwith multisystem diseasethat is often already presentat the time of diagnosis.In contrast, the CNS involvement, which is progressive and histopathologicallycharacterizedby gliosis, and for which no treatment is known, may be observedonly many years after the initial diagnosisof LCH, which may have consistedonly of mild bone disease.Neither of these manifestationsevidencesLangerh a n s ' c e l l so r B i r b e c kg r a n u l e s . After tissue biopsy, which is diagnostic and is easiestto perform on skin or bone lesions,a thorough clinical and laboratory evaluation should be undertaken. This should include a series of studies in all patients (completeblood cell count, liver function tests,coagulation studies,skeletalsurvey,chest radiograph, and measurementof urine osmolality). In additron, detailed evaluation of any organ systemthat has been shown to be involved by Histiocyte Society: www.histio.org/society. HrmopHReocYTlc ll HlsrtocYTosEs: 501.2.CLAss LvrupHoHtsnocYTosls See "Classification and Pathology" above. The maior forms of HLH, familial CLINICALMANIFESTATI0NS. >7days >385{ andlasting Fever >3 tm Splenomeqaly ABNORMALITiE5: HEMATOLOGI( FOtLOWlNG TWO OFTHE (>9g/dLhemoglobrn) Anemia (>100,000 tells/pLl Ihrombocytopenia nzutrophils/rrl) Neutropenia {<1000 ABNORMALIT]ES: ONE OFIHEFOTLOWING >20 nmol/L Flypertriglyreridemia <150mg/dL Hypofibrinogenemia and n0de orlymph manow, spleen, lnbone Hem0phagocytosis neoplasia ormalignant hyperplasia ofmanow Noevidence 1961;i21868-879 Pedirfrc t ocytosis 2162I PABTXXI r CancerandBenignTumors causeresolution of the hemophagocytosis.In some patients, interferon and intravenous immunoglobulin have been effective. 507.3.CrAss lll Htsnocwosrs Acute monocytic leukemia and true malignant histiocytosis are included among the class III histiocytoses (see Chapter 495), because they are unequivocal malignancies of the monocytemacrophage lineage. marroq cerebrospinal fluid hemophagocytosis. or lymph node evidence of onset of secondary HLH in the presenceof a documented infec- umented and effectively treated, the prognosis is good without any other specific treatment. When a treatable infection cannot patients with hemophagocytosis.Rarely, the same syndrome may be identified in conjunction with a rheumatologic disorder (e.g., systemic lupus erythemarosus, Kawasaki disease)or a neopla# (leukemia); in this case, trearmenr of the underlying diseasemay Arico M, DanesinoC, PendeD, et al: Pathogenesis of haernophagocyticlymphohistiocytosis . Br J Haematol 2001;1.1.4:7 61,-769. Arico M, Imashuku S, Clementi R, et al: HemophagocyticIymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative diseasegene.Blood 2001 97:1131.-1133. Broadbent V, Gadner,H: Current therapy for Langerhanscell histiocyrosis. Hematol OncoL CIin North Am 1998;12:327-328. DomachowskeJB: Infectious triggers of hemophagocyticsyndrome in child,ren.Pediatr Infect Dis J 2005;25:1067-7068. Durken M, FinckensteinFG, Janka GE: Bone marrow transplantation in hemophagocytic lymphohistiocytosis. Leuk Lymphoma 200I;41:89-9 5. FeldmannJ, CallebautI, Raposo G, et al: Munc 13-4 is essenrialfor cyrolytic granules fusion and is mutated on a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003;1 1,5 :46 147 3. Gadner H, Grois N, Arico M, et al: A randomizedtrial of treatmentfor multisystem Langerhans' cell histiocytosis. J Pediatr 2001,i1,38:728-734. Hait E, Liang M, Degar B, et al: Gastrointestinaltract involvementin Langerhans cell histiocytosis: case reporr and literature review. pediatrics 2006; 11 8 : e 1 5 9 3 - - e 1 5 9 9 Horne A, Janka G, Egeler R, et al: Hematopoietic stem cell transplantation in haernophagocyticlymphohistiocytosis.Br J Haematol 2005;1.29:622630. Kogawa K, Lee SM, VillanuevaJ, et al: Perforin expressionin cyrotoxic lymphocytesfrom patientswith hemophagocyticlymphohistiocytosisand their family members. Blood 2002;99:61-66. Lee SM, SumegiJ, VillanuevaJ, et al: Patientsof African anceslrywith hemophagocyticlymphohistiocyrosissharea common haplotype of pRFI with a 50 delt mutation. J Pediatr 2006;149:134-137. Leonidas JC, Guelfguat M, Valderrama E: Langerhans' cell histiocytosis. Lancet 2003;351:1293-7295. Montella L, Insabato L, Palmieri G: Imatinib mesylatefor cerebral Langerhans'-cellhistiocytosis.N Engl J Med 2004;351:'J.034-1035. Ouachee-ChardinM, Elie C, de Saint BasileG, et al: Hematopoieticstem cell transplantation in hemophagocyticlymphohistiocytosis:A single-center report of 48 patients.Pediatrics2006;117:e743--e750. PalazzrDL, McClain KL, Kaplan SL: Hemophagocyticsyndromein children: An important diagnostic consideration in fever of unknown oriein. CIin I nfect D is 2003;36 :306-3 12. Valladeau J, Dezutter-Dambuyant C, Saeland S: LangerinlCD2}T sheds light on formation of Birbeck granules and their possible function in Langerhans cells. lmmunol Res 2003728:93-1,07. \Triting Group of the Histiocyte Society: Histiocytosis syndromes in childho<>d.Lancet 1,987;1:208-209.

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