4. V DedicationTo the nurses, and others,who use the information in this book,and to the children they serve,we dedicate this work.To my husband Chris and our children,Vivian, Sam and Suzanne –to the moon and back.Deborah TomlinsonTo my parents, and Michael.I am forever grateful for your love and support.Nancy E. Kline
5. VII Preface“Pediatric Oncology Nursing: Advanced Clinical etiology, symptoms and clinical signs, diagnostic andHandbook” is a joint effort between nurses in Cana- laboratory procedures, treatment, prognosis, and fol-da, the UK, and the USA. This is a ﬁrst-time collabo- low up care are included for each of the disorders.ration between pediatric hematology and oncology Part Three covers cancer treatment, includingnurses from two continents and represents a blend- chemotherapy, radiation therapy, peripheral steming of knowledge from these experts. The book is de- cell transplantation, surgery, gene therapy, and com-signed to be a comprehensive clinical handbook for plementary and alternative medicine. The principlesnurses in advanced practice working with pediatric and description of treatment, method of treatmenthematology / oncology patients. Speciﬁc issues relat- delivery, potential side effects, and special considera-ed to young children and adolescents with cancer and tions for each type of treatment are discussed.hematologic disorders are discussed. Part Four focuses on the side effects of cancer Twenty-two contributors and two editors partici- treatment in relation to metabolic processes and thepated in the writing of this text. Nurses in advanced gastrointestinal, hematologic, respiratory, urinary,practice and academic roles – nurse practitioners, cardiovascular, neurologic, musculoskeletal, integu-clinical nurse specialists, clinical instructors, lectur- mentary, and endocrine systems. The incidence, eti-ers, and educators – were involved. One of the most ology, treatment, prevention, and prognosis are in-appealing features of this text is the varied experience cluded for each side effect reviewed.represented by nurses from different countries and Part Five includes essential information regardingdifferent educational backgrounds. supportive and palliative care of pediatric cancer pa- The book is divided into ﬁve sections: pediatric can- tients. Nutrition, hydration, pain, transfusion thera-cers, hematologic disorders, treatment of childhood py, growth factors, and care of the dying child arecancer, side effects of treatment and disease, and sup- covered. The principles of treatment for these condi-portive and palliative care. Many tables and illustra- tions, method of delivery, and special considerationstions are included for quick reference in the clinical for certain conditions are included.setting. Future perspectives and opportunities for As the editors of “Pediatric Oncology Nursing: Ad-new treatment options and research are discussed. vanced Clinical Handbook” we want to recognize and Part One focuses on pediatric cancers: the leuke- thank everyone who participated in the developmentmias and solid tumors. The most common pediatric of this text. We are profoundly aware of the personaltumors, as well as some rare tumors, are discussed time and commitment that was devoted to make thiswith regard to epidemiology, etiology, molecular ge- an outstanding resource, and we are grateful. It is ournetics, symptoms and clinical signs, diagnostic and hope that nurses in advanced clinical practice willlaboratory testing, staging and classiﬁcation, treat- ﬁnd this publication useful and that it will enrichment, prognosis, and follow-up care. knowledge and improve care for young people with Part Two focuses on pediatric hematology. The cancer and hematologic disorders.anemias, bleeding disorders, neutropenia, and throm-bocytopenia are discussed in detail. Epidemiology, Deborah Tomlinson, Nancy E. Kline
6. IX ContributorsSharon Beardsmore SRN, RSCN, Dip Palliative Care Nicki Fitzmaurice RGN, RSCN, Dip N, BScPaediatric Macmillan Nurse, Paediatric Macmillan Nurse, Birmingham’sBirmingham’s Children’s Hospital NHS Trust, Children’s Hospital NHS Trust, Birmingham, UKBirmingham, UK Ali Hall RSCN, RGN, BA, M.Phil,Jane Belmore RSCN, RGN, Dip Palliative Care Ad Dip Child DevelopmentMacmillan Clinical Nurse Specialist, Schiehallion Paediatric Oncology Outreach Nurse Specialist,Day Care Unit, Royal Hospital for Sick Children, Schiehallion Day Care Unit, Yorkhill NHS Trust,Yorkhill NHS Trust, Glasgow, G3 8SJ, Scotland, UK Glasgow, G3 8SJ, Scotland, UKRosalind Bryant MN, RN, PNP Eleanor Hendershot RN, BScN, MNInstructor of Pediatrics, Clinical Nurse Specialist/Acute Care NursePediatric Nurse Practitioner, Practitioner, Hospital For Sick Children,Texas Children’s Cancer Center Division of Hematology Oncology –and Hematology Service, 6621 Fannin MC1-3320, Solid Tumor Program, 555 University Avenue,Houston, TX 77030, USA Toronto, Ontario, M5G 1X8, CanadaChristine Chordas MSN, RN, CPNP Kathleen E. Houlahan MS, RNPediatric Nurse Practitioner, Jimmy Fund Clinic, Nurse Manager, Hematology/Oncology/Dana Farber Cancer Institute, 44 Binney Street, Stem Cell Transplant, Children’s Hospital Boston,D306, Boston, MA 02115, USA 300 Longwood Avenue, Boston, MA 02115, USASandra Doyle MN, RN Elizabeth Kassner MSN, RN, CPNPClinical Nurse Specialist, Hospital For Sick Children, Instructor of Pediatrics, Pediatric NurseDivision of Hematology Oncology, Practitioner, Texas Children’s Cancer Center555 University Avenue, Toronto, Ontario M5G 1X8, and Hematology Service, 3000 Bissonnet Street,Canada #2304, Houston, TX 77005, USAAngela M. Ethier MSN, RN, CNS, CPN Mark W. Kieran MD, PhDClinical Instructor and Fellow, Director, Pediatric Medical Neuro-Oncology,UTSHC School of Nursing, 4223 University Blvd., Assistant Professor of Pediatrics,Houston, TX 77005, USA Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
7. X Contributors Nancy E. Kline PhD, RN, CPNP, FAAN Margaret Parr RGN, RSCN, ENB240 Children’s Hospital Boston, Wolbach 201, Paediatric Oncology Nurse Specialist, 300 Longwood Avenue, Boston, MA 02115, USA Children’s Services, E Floor, East Block, Queen’s Medical Centre, Derby Road, Nan D. McIntosh RSCN, RGN, BSc (Hons), Nottingham, NG7 2UH, UK NP Diploma Haematology Advanced Nurse Practitioner, Fiona Reid RSCN, RGN Schiehallion Day Care Unit, Yorkhill NHS Trust, Staff Nurse Glasgow, G3 8SJ, Scotland, UK Raigmore Hospital, Old Perth Road, Inverness, 1V2 3UJ, Scotland, UK Anne-Marie Maloney RN, BSc, MSc CNS/NP, The Hospital for Sick Children, Debbie Rembert MSN, RN, CNS 555 University Avenue, Toronto, Ontario M5G 1X8, Clinical Instructor and Fellow, Canada UTSHC School of Nursing, 4201 Ruskin, Houston, TX 77005, USA Ethel McNeill RSCN, RGN, BSc Endocrine Nurse Specialist, Department Chris M. Senter RGN, RSCN, ONC of Child Health, Yorkhill NHS Trust, Macmillan Clinical Nurse Specialist, Glasgow, G3 8SJ, Scotland, UK Royal Orthopaedic Hospital, Orthopaedic Oncology Service, Bristol Road South, Northﬁeld, Colleen Nixon RN, BSN, CPON Birmingham, B31 2AP, UK Patient Educator, Inpatient Oncology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, Nicole M. Sevier MSN, RN, CPNP MA 02115, USA Instructor of Pediatrics, Pediatric Nurse Practitioner, Texas Children’s Cancer Center Robbie Norville MSN, RN, CNS and Hematology Service, 6621 Fannin MC1-3320, Bone Marrow Transplant/Cell and Gene Therapy, Houston, TX 77030, USA Clinical Nurse Specialist, Texas Children’s Cancer Center and Hematology Service, Cara Simon MSN, RN, CPNP 6621 Fannin MC1-3320, Houston, TX 77030, USA Instructor of Pediatrics, Pediatric Nurse Practitioner, Texas Children’s Cancer Center Joan M. O’Brien RN, BSN, CPON and Hematology Service, 6621 Fannin MC1-3320, Hematology/Oncology Clinical Educator, Houston, TX 77030, USA Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA Deborah Tomlinson MN, RSCN, RGN, Dip. Cancer Nursing Jill Brace O’Neill MS, RN-CS, PNP Macmillan Lecturer/Project Leader, David B. Perini Quality of Life Clinic, School of Nursing Studies, Dana-Farber Cancer Institute, University of Edinburgh, D-321, 44 Binney Street, 31 Buccleuch Place, Edinburgh, EH8 9JT, Boston, MA 02115, USA Scotland, UK
20. Chapter 1 1 PART I Leukemia Deborah Tomlinson Contents Leukemia is the most common malignancy that af-1.1 Acute Lymphoblastic Leukemia . . . . . . . . . . . 2 fects children, accounting for approximately a third 1.1.1 Epidemiology . . . . . . . . . . . . . . . . . . 2 1.1.2 Etiology . . . . . . . . . . . . . . . . . . . . . 4 of cancer diagnoses. It may be deﬁned as a neoplastic 188.8.131.52 Genetic Factors . . . . . . . . . . . . . 4 disease that involves the blood-forming tissues of the 184.108.40.206 Environmental Factors . . . . . . . . . 4 bone marrow, lymph nodes, and spleen. 1.1.3 Molecular Genetics . . . . . . . . . . . . . . 6 1.1.4 Symptoms and Clinical Signs . . . . . . . . 7 Normal hematopoiesis occurs in these blood- 1.1.5 Diagnostics . . . . . . . . . . . . . . . . . . 8 forming tissues; the development of blood cells is 1.1.6 Staging and Classiﬁcation . . . . . . . . . . 8 shown in Fig. 1.1.A range of extracellular protein fac- 220.127.116.11 Risk Classiﬁcation . . . . . . . . . . . . 8 tors regulates the growth and differentiation of path- 18.104.22.168 Cell Morphology . . . . . . . . . . . . 10 22.214.171.124 Cytochemistry . . . . . . . . . . . . . 10 ways of developing cells. This ensures that the mature 126.96.36.199 Immunophenotyping . . . . . . . . . 10 blood cell types are produced in appropriate pro- 188.8.131.52 Cytogenetics . . . . . . . . . . . . . . 11 portions. Leukemia is a clonal disease that is due 1.1.7 Treatment . . . . . . . . . . . . . . . . . . . 12 184.108.40.206 Induction . . . . . . . . . . . . . . . . 12 to genetic mutations and transformation of a single 220.127.116.11 Intensiﬁcation/Consolidation . . . . . 13 early progenitor myeloid or lymphoid cell during 18.104.22.168 CNS-directed Therapy . . . . . . . . . 13 hematopoiesis. The type of leukemia that results is 22.214.171.124 Maintenance/Continuing Treatment 14 therefore dependent on the cell lineage that is affect- 126.96.36.199 Allogeneic Stem Cell Transplant . . . 14 1.1.8 Prognosis . . . . . . . . . . . . . . . . . . . 15 ed by the mutation. Table 1.1 shows the blood cells 1.1.9 Follow-up . . . . . . . . . . . . . . . . . . . 15 that can be affected from either stem cell lineage. In 1.1.10 Future Perspectives . . . . . . . . . . . . . . 15 leukemia, there is an overproduction of immature1.2 Acute Myeloid Leukemia . . . . . . . . . . . . . . 16 1.2.1 Epidemiology . . . . . . . . . . . . . . . . . 16 white blood cells that cannot function effectively. 1.2.2 Etiology . . . . . . . . . . . . . . . . . . . . 16 These immature white blood cells, such as the 188.8.131.52 Genetic Factors . . . . . . . . . . . . . 16 myeloblasts, lymphoblasts, and monoblasts, are com- 184.108.40.206 Environmental Factors . . . . . . . . . 16 monly called “blasts.”An abnormal population of im- 1.2.3 Molecular Genetics . . . . . . . . . . . . . . 16 1.2.4 Symptoms and Clinical Signs . . . . . . . . 17 mature white blood cells decreases the space avail- 1.2.5 Diagnostics . . . . . . . . . . . . . . . . . . 17 able for the production of other healthy blood cells 1.2.6 Staging and Classiﬁcation . . . . . . . . . . 17 produced by the bone marrow. The blast cells may 1.2.7 Treatment . . . . . . . . . . . . . . . . . . . 19 1.2.8 Prognosis . . . . . . . . . . . . . . . . . . . 19 then enter the blood and may also inﬁltrate the cen- 1.2.9 Follow-up . . . . . . . . . . . . . . . . . . . 19 tral nervous system (CNS). 1.2.10 Future Perspectives . . . . . . . . . . . . . . 20 The two broad classiﬁcations of leukemia are acute1.3 Chronic Myeloid Leukemia . . . . . . . . . . . . . 20 and chronic. The most common types of leukemia 1.3.1 Epidemiology and Etiology. . . . . . . . . . 20 1.3.2 Molecular Genetics . . . . . . . . . . . . . . 20 are 1.3.3 Symptoms and Clinical Signs . . . . . . . . 20 ▬ Acute lymphoblastic leukemia (ALL), which ac- 1.3.4 Diagnostics . . . . . . . . . . . . . . . . . . 21 counts for 75–80% of childhood leukemia 1.3.5 Treatment . . . . . . . . . . . . . . . . . . . 21 1.3.6 Prognosis . . . . . . . . . . . . . . . . . . . 21 1.3.7 Future Perspectives . . . . . . . . . . . . . . 211.4 Juvenile Myelomonocytic Leukemia . . . . . . . 211.5 Langerhans Cell Histiocytosis . . . . . . . . . . . 22References . . . . . . . . . . . . . . . . . . . . . . . . . . 23
21. 2 Chapter 1 D.Tomlinson Figure 1.1 Hemopoiesis: The lymphoid stem cell differentiates into T-lymphocytes and B-lymphocytes. Natural Killer (NK) cells are also thought to derive from the lymphocyte stem cell. Image credit: K. Lofsness, University of Minnesota ▬ Acute myeloid leukemia (AML), also known as acute nonlymphoblastic leukemia (ANLL), which 1.1 Acute Lymphoblastic Leukemia accounts for 20–25% of childhood leukemia 1.1.1 Epidemiology The most common type of chronic leukemia is ▬ Chronic myeloid (or myelocytic) leukemia (CML), ALL affects slightly more males than females (1.2:1) which accounts for less than 5% of childhood and peaks between the ages of 2 and 6 years. In in- leukemia fants there is a higher number of females affected. Globally, the highest incidence of ALL appears to be in Europe and North America, with about 5 cases in 100,000 of 0–14-year-old children. The lowest inci- dence, of about 0.9 in 100,000, is in Kuwait and Bom- bay. There may be a lack of clarity regarding some
22. Leukemia Chapter 1 3Table 1.1. Lineage and function of major types of blood cells Blood cell Lineage Function Half-life Red blood cells Myeloid stem cells Transport oxygen from lungs to tissue About 120 days (erythrocytes) Transport some carbon dioxide from tissues to lungs Platelets (thrombocytes) Myeloid stem cells Repair blood vessels and participate in 7–10 days clotting mechanism White blood cells Crucial in immunity (leucocytes) Monocytes Myeloid stem cells Can differentiate into macrophages; 1–3 days in blood phagocytosis; antigen presentation; 3 months in tissues immune regulation Granulocytes – Neutrophils Myeloid stem cells Phagocytosis, killing bacteria 6–12 hours in blood – Eosinophils Myeloid stem cells Detoxify products from allergic response; 2–3 days in tissues phagocytosis – Basophils Myeloid stem cells Involved in allergic response; source of Minutes to hours in immune inhibitors (e.g., histamine) blood, then in tissue for about 12 days – Monocytes Myeloid stem cells Contain enzymes that kill foreign bacteria Undetermined Lymphocytes Lymphoid stem cells Role in immunity Undetermined; cells can move between blood and lymphoid tissues – T lymphocytes Attack invaders directly – B lymphocytes Produce antibodies – Others: null cells, natural killer cells, lymphokine-activated killer cells, tumor- inﬁltrating lymphocytesincidence ﬁgures due to the lack of true population- Stiller et al. reported that children of Asian and Westbased registration of cancer. However, ALL generally Indian ethnic origin had patterns of ALL incidencehas a higher incidence in afﬂuent industrialized na- that were similar to those of Caucasians. Interesting-tions within white populations. The incidence tends ly, other later studies of ALL incidence in areas of theto be lower among the black populations of the same United Kingdom have reported an increased risk,nations. although not signiﬁcantly so, of ALL among South In a study in the United States, Pan et al. (2002) Asian children compared with non-Asian childrencompared the incidence of leukemia in Asian-Amer- (McKinney et al. 2003; Powell et al. 1994). However,icans and their descendents and in Caucasians. This these increases may be due to socioeconomic status,study reported a lower incidence of leukemia in which has been linked to childhood cancers.Asian-Americans irrespective of birthplace. In 1991,
23. 4 Chapter 1 D.Tomlinson Table 1.2. Syndromes with a predisposition to leukemia 220.127.116.11 Environmental Factors Genetic bone marrow failure syndromes predisposed It is accepted that ionizing radiation is a causal factor to leukemia: in leukemia. Following the atomic bombs in Japan, Fanconi’s anemia children who were exposed acquired an increased Diamond-Blackfan anemia risk of developing leukemia. Individuals exposed in Shwachman-Diamond syndrome Congenital dyskeratosis utero, however, showed no increase in incidence of Kostmann’s infantile genetic agranulocytosis leukemia. This ﬁnding is in contrast to the suggested Genetic syndromes predisposed to leukemia results of various studies that showed an increased as one of the illnesses: risk of leukemia and other cancers (by about 40%) to Chromosomal abnormality: children exposed in utero to diagnostic radiography Down’s syndrome (trisomy 21) (Doll and Wakeford 1997). There is no doubt that ion- Chromosome 8 trisomy syndrome izing radiation is a causal factor in leukemia; howev- DNA repair/tumor suppressor deﬁciency: er, there are uncertainties regarding various aspects Ataxia telangiectasia of its effect on leukemogenesis. Li-Fraumeni syndrome Neuroﬁbromatosis type 1 A signiﬁcant change in thought surrounds the Bloom syndrome clusters of reported childhood ALL around nuclear Nijmegen/Berlin breakage syndrome installations. The suspicion that background radia- Retinoblastoma: tion was the cause of these clusters has moved to- RB1 gene is important in the histiogenesis of ALL wards Kinlen’s theory (1995) that population mixing, herd immunity, and abnormal response to infection (Table compiled from Mizutani 1998) of unusually susceptible children increases the risk of ALL. This “delayed infection” or “hygiene” hypothesis 1.1.2 Etiology suggests that ALL in children is caused by a lack of exposure to infection in infancy, with an abnormal The factors involved in the cause of childhood can- response to a later common infection incurred after cers are unclear. Many different etiologies have been mixing with other children in playgroups or schools. suggested and investigated, but few are well estab- Therefore, circumstances that alter the pattern of in- lished. It would be misleading to associate the cause fections in infants may contribute to the etiology of of any childhood malignancy wholly to genetic or en- ALL. vironmental factors, but the study of various factors Table 1.3 highlights studies that have been under- can improve the understanding of events that may taken to investigate various possible factors in the lead to leukemia in children. etiology of childhood leukemia and other cancers.All theories surrounding the causes of ALL, or indeed the 18.104.22.168 Genetic Factors majority of childhood cancers, leave much unex- plained, and further studies are necessary to conﬁrm Syndromes that have a component of hereditary or or reject the conclusions of those available. genetic predisposition to leukemia have been identi- Because of the public interest that surrounds the ﬁed and are listed in Table 1.2. A study by Mellemk- majority of these potential risk factors, parents will jaer et al. in 2000 has shown that children of parents continue to form theories regarding their children’s with autoimmune disease are slightly more suscepti- illnesses (Ruccione et al. 1994). Nurses have a role in ble to leukemia. eliciting parents’ causal explanations so that the con- tent of these concerns can be related to the parents’ adjustment and management of their experience of childhood cancer.
24. Leukemia Chapter 1 5Table 1.3. Reported environmental links to childhood leukemia and current conclusions Possible environmental link Current conclusions Parental use of tobacco Paternal smoking before pregnancy may be a potential risk factor for the generality of childhood cancers. Studies do not provide signiﬁcant evidence (Pang et al. 2003; Sorahan et al. 2001) Vitamin K prophylaxis in infants Inconsistent associations reported. However, conﬁrmed beneﬁts of vitamin K outweigh the hypothetical association with any childhood cancer (Parker et al. 1998; Passmore et al. 1998; Roman et al. 2002; Ross and Davies 2000). Living near landﬁll sites No excess risk of any cancer reported (Jarup et al. 2002) Proximity to railways No association reported between risk of childhood leukemia and railway proximity (Dickinson et al. 2003). Small association with railway density assumed consequence of population mixing and proximity of railways in deprived urban areas Children born after in-vitro No increased risk of childhood cancer reported in studies published fertilization (Bergh et al. 1999; Klip et al. 2001) Prenatal ultrasound No association with childhood leukemia found (Naumburg et al. 2000) Supplementary oxygen Resuscitation with 100 % oxygen immediately postpartum is associated with childhood ALL; further studies warranted (Naumburg et al. 2002a) Breastfeeding Contradicting reports of association with a reduced risk of acute leukemia (Lancashire and Sorahan 2003; UK Childhood Cancer Study Investigators 2001; Shu et al. 1999) Pet (healthy or sick) ownership No relationship (Swensen et al. 2001) Family cancer history May be a risk factor for childhood acute leukemia (Perrillat et al. 2001) Electromagnetic ﬁelds (EMF)/ Do not support hypothesis of an association (Skinner et al. 2002; power lines Steinbuch et al. 1999) Natural radionucleotides in Results do not indicate increased risk of leukemia (Auvinen et al. 2002) drinking water, including uranium In utero exposure to metronidazole No reported increased risk (Thapa et al. 1998) Allergies or family history Reduced risk of ALL; no such pattern seen with AML (Schuz et al. 2003) of allergies Exposure to pesticides May increase risk (Ma et al. 2002); further studies needed Perinatal exposure to infection Some association reported between maternal lower genitourinary tract infection in utero and risk of childhood leukemia (Naumburg et al. 2002b).This supports hypothesis that an infectious agent is involved in etiology of ALL (Kinlen 1995) Population mixing Increased risk of ALL in children 1–6 years old in high tertile of population mixing (Alexander et al. 1999; Boutou et al. 2002). Further support for infectious agents possessing direct or indirect cause
25. 6 Chapter 1 D.Tomlinson cause changes in a surface receptor, causing it to send 1.1.3 Molecular Genetics signals as though it were being activated by a growth Clonal chromosomal abnormalities (originating in a factor. single cell) are detectable in around 90% of child- The exact number of mutations required to trans- hood ALL cases. The leukemia then evolves by the ac- form a normal cell into a malignant cell is unknown, crual of mutations within a clone. The abnormalities but research indicates that two or more mutations, or are responsible for a loss of controlled cell growth, di- “hits,” are involved. The ﬁrst hit is thought to occur in vision, and differentiation. the womb, which in ALL is likely to be a developmen- To review the biology of chromosomes: tal accident affecting a chromosome. This would then suggest that a second hit after birth is necessary be- ▬ Genes carry instructions to make proteins essen- fore ALL develops. This theory has arisen mainly tial for cell growth, division, and differentiation. from observed high concordance rates of leukemia in ▬ A deoxyribonucleic acid (DNA) molecule carries infant monozygotic twins (that is, if one twin has the genetic information in coded form. leukemia, so will the other) and the study of neonatal ▬ DNA is a nucleic acid made of chains of nu- blood spots or Guthrie cards. In twins, it is consid- cleotides. ered that the leukemogenic event arises in one twin, ▬ Nucleotides have three components – a phosphate and the cells from the abnormal clone then spread to group, a pentose sugar, and a base. the other via shared placental anastomosis. Poly- ▬ In DNA the sugar is deoxyribose, and the bases are merase chain reaction (PCR) has been used to identi- adenine, guanine, thymine, and cytosine. fy the same fusion gene sequence in neonatal blood ▬ DNA consists of two chains of nucleotides linked spots as is in patients’ leukemic cells at diagnosis. In across their bases by weak hydrogen ions. These all cases of infant leukemia, there are fusions of the two complementary strands of nucleotides are MLL gene; in many cases of childhood ALL, there are linked in a double helix formation. fusions of the TEL-AML 1 gene. These gene fusions ▬ The bases have speciﬁc afﬁnities with each other, would indicate the ﬁrst hit or mutation. Table 1.4 so that thymine pairs only with adenine, and cyto- shows the classiﬁcation of types of mutation that can sine pairs only with guanine. occur. In childhood ALL, reciprocal translocations ▬ The base sequence is the key to the control of the account for approximately 25% of the chromosomal cell and is referred to as the genetic code. abnormalities. The translocations involve exchanges ▬ The length of DNA in cells is so great that there is of tracks of DNA between chromosomes, resulting in a signiﬁcant risk of entanglement and breakage. the generation of chimeric or fusion genes. There During mitosis, proteins called histones bind to may also be changes in chromosome number DNA and wrap it into 46 compact manageable (ploidy), gene deletions, or single nucleotide base chromosomes (23 pairs). changes in genes. (The chromosome number is also ▬ The complete chromosome complement of a cell is measurable as the DNA index, in which 46 chromo- referred to as the karyotype. somes equals a DNA index of 1). Some genes are associated with the transformation of As discussed earlier, the process by which a nor- a normal cell to a malignant cell. These are known as mal cell transforms into a leukemic cell is unclear. oncogenes (or proto-oncogenes) and tumor suppres- However, improved molecular analysis techniques sor genes. Mutations in the DNA of these genes may have assisted in identifying mechanisms regulating cause them to produce an abnormal product or dis- cell growth and differentiation. These include the fol- rupt their control so that they are expressed inappro- lowing: priately, making products in excessive amounts or at the wrong time. Some oncogenes may cause extra ▬ Polymerase chain reaction (PCR) production of growth factors, which are chemicals ▬ Fluorescence in situ hybridization (FISH) that stimulate cell growth. Other oncogenes may ▬ Flow cytometry for immunophenotyping
26. Leukemia Chapter 1 7Table 1.4. Types of mutation to genetic code Mutation Description Presentations Point mutation Change in DNA sequence Mis-sense mutation, usually a Can occur in base substitution, deletion, or addition decrease in function May result in wrong amino acid being inserted into protein Chromosomal Alteration in the gross structure of chromosomes Translocation mutation Results from cell breakage and reunion of chromosomal Rearrangement material during the cell cycle Genomic mutation Change in number of chromosomes in the genome Ampliﬁcation Aneuploidy (loss or gain of single chromosome▬ Digitized karyotype imaging/multicolor spectral Initially, symptoms may ﬂuctuate daily, with the child karyotyping feeling exhausted one day and ﬁne the next. The child▬ Microarray proﬁling may have suffered from repeated ear or other infec-▬ Southern blotting tions that have been frequently resistant to treat-▬ Western blotting ment. This is often associated with a history of fre- quent visits to the family general practitioner.Molecular analysis has proved indispensable for Physical ﬁndings may include the following:identifying prognostic factors and therapeutically ▬ pallor and lethargyimportant genetic subtypes of childhood ALL. The ▬ pain at the sites of disease inﬁltration, especially inranges of subtypes are based on gene expression, long bonesantigens that delineate cell type, and chromosomal ▬ petechiaeand molecular abnormalities. There is currently a rel- ▬ bruising or unusual bleeding (including noseatively sophisticated understanding of the genetic bleeds)basis of ALL, which will be discussed further in the ▬ enlarged liver or spleen, causing the abdomen tofollowing sections. protrude ▬ enlarged lymph nodes and fever1.1.4 Symptoms and Clinical Signs In less than 10% of cases the disease has spread to theALL usually presents as an acute illness of short on- CNS at diagnosis. This may cause related symptomsset, but symptoms are occasionally slow and insidi- ofous. Symptoms relate to the inﬁltration of the bone ▬ headachemarrow and other affected organs by the prolifera- ▬ poor school performancetion of lymphoblastic cells. The presenting features ▬ weaknessoften appear like many childhood illnesses. Parents ▬ vomitingor children may describe the following: ▬ blurred vision▬ irritability ▬ seizures▬ night sweats ▬ difﬁculty maintaining balance▬ fatigue In 60–70% of children with the T-cell type of ALL,▬ bone pain, which may present as limping there is involvement of the thymus. Enlargement of▬ loss of appetite the thymus caused by an accumulation of white blood cells can give rise to an anterior mediastinal
27. 8 Chapter 1 D.Tomlinson mass that can cause pressure on the trachea, causing leukemia. A portion of the bone marrow aspirate and coughing, shortness of breath, pain, and dysphagia. the chloroma biopsy/trephine are then analyzed to In some cases the pressure may also compress the su- detect other features of the leukemic cells to help de- perior vena cava and cause swelling of the head and termine what type of leukemia is present. Other tech- arms. niques are used to extend the diagnosis. In rare circumstances acute leukemia may present A lumbar puncture is performed to determine any with extremely high blast cell counts, known as hy- CNS involvement; a sample of cerebrospinal ﬂuid perleukocytosis. This state of the disease can cause (CSF) is examined for blast cells. respiratory failure, intracranial bleeding, and severe These procedures are most often performed using metabolic abnormalities, conditions that are the sedation or anesthetic. Therefore, because of the main causes of high early mortality. The process that potential anesthetic difﬁculties that could develop, a leads to these complications has become known as chest x-ray is vital to assist in diagnosing infection or leukostasis. It had been thought that leukostasis was detecting a mediastinal mass. caused by overcrowding of leukemic blasts. However, it is now evident that leukostasis results from adhe- 1.1.6 Staging and Classiﬁcation sive interactions between blasts and the vascular en- 22.214.171.124 Risk Classiﬁcation dothelium. Damage to the endothelium is likely due to cytokines that are released. The adhesion mole- Once a diagnosis of ALL has been conﬁrmed, cell cules displayed by the blasts and their response to the morphology, cytogenetics, and immunophenotyping environment are probably more important factors in are determined to elicit more deﬁned prognostic fac- leukostasis formation than numbers of cells. Leuko- tors. Treatment can then focus on “risk-directed” pro- pheresis is routinely used to reduce the leukocyte tocols developed through well-designed clinical tri- count in the initial phase when there is hyperleuko- als. This strategy uses the child’s likelihood of relapse cytosis. It remains unclear whether this is the most or resistance to treatment to intensify or reduce the efﬁcient method of treating leukostasis. However, treatment to ensure adequate cell kill within accept- further research should indicate the most appropri- able levels of toxicity. The signiﬁcance of various re- ate use of this procedure. ported risk factors has led to some debate. Difﬁculty also arises when comparing results between different 1.1.5 Diagnostics countries and centers using locally-assigned risk cat- egories. However, over the past few decades several If ALL is suspected following the history and physical features have been determined to be more favorable examination of the child, initial investigations in- prognostic factors. In 1993, following a previous ini- clude a complete blood count, urea and electrolyte tiative in Rome, collaborative groups met to establish counts, and a chest x-ray. The blood count may point those features that would indicate “standard risk” to a diagnosis of leukemia with blast cells present or ALL. These are known as the Rome/NCI (National an elevated white blood cell count. Figure 1.2a shows Cancer Institute) criteria: a normal blood ﬁlm, and Fig. 1.2b is a blood ﬁlm ▬ WBC <50,000/mm3 from a child with ALL. However, the necessary diag- ▬ Female nostic investigation is a bone marrow examination. ▬ 1–9 years of age The bone marrow is usually taken from the iliac bone ▬ non-T/non-B at the iliac crest. Despite the new technologies avail- able, ALL is still usually diagnosed by an experienced pediatric oncologist and/or pathologist examining a Romanowsky-stained bone marrow smear with a high-powered microscope. More than a 25% blast cell count in the marrow conﬁrms a diagnosis of
28. Leukemia Chapter 1 9 Figure 1.2 a, b a Normal blood ﬁlm (¥25) b ALL blood ﬁlm (¥25). Image credit: Dr Angela Thomas, RHSC, Edinburgh a bAll other patients are “high risk.” volvement, hemoglobin level, platelet count, and Other factors are used to determine risk classiﬁca- number of blast cells in the CSF at diagnosis. Howev-tion, but the number and array of factors used to clas- er, subgroups of patients with different outcomes cansify ALL make it difﬁcult to establish any one system. be predicted by blast karyotype, molecular abnor-Consequently, there is a lack of precision within most malities, and early response to treatment, with re-risk classiﬁcation systems. Varying conclusions have sponse to treatment proving to be increasingly morebeen reported with regard to the prognostic signiﬁ- important. The persistence of lymphoblasts in bonecance of other characteristics, including the presence marrow following a week of induction therapy is as-of Down’s syndrome; liver and spleen size; the pres- sociated with a poor prognosis, with less than 30%ence of an anterior mediastinal mass; French-Amer- survival at 5 years no matter what subsequent thera-ican-British subtype; body mass index; and CNS in- py is given (Hann 2001).
29. 10 Chapter 1 D.Tomlinson Table 1.5. French-American-British Classiﬁcation of acute lymphoblastic leukemia Category Deﬁnition Features % of patients L1 Small cells with scant cytoplasm Associated with good treatment response 90 % L2 Large cells with abundant cytoplasm Indicates more refractory to therapy if 9% 10–20 % L2 cells are present L3 Large cells with prominent nucleoli Mature B-cell phenotype; frequently presents 1% as lymphoma; poor prognosis Interestingly, a study by Gajjar and colleagues in Table 1.6. Categories of acute lymphoblastic leukemia 2000 found that traumatic lumbar puncture at diag- Category of ALL Percentage (approximately) nosis of childhood ALL indicated adverse outcomes and was an indication to intensify intrathecal (IT) Common or pre-B 80 % therapy. T-cell 10 % Mature B 7% 126.96.36.199 Cell Morphology Null (early B-precursor) 3% Despite other ways of looking at cells, a morphologi- All forms other than T-cell are considered as B-precursor cell cal classiﬁcation that is still widely applied is the ALL French-American-British (FAB) system. This classiﬁ- cation is based on the morphology (appearance, 188.8.131.52 Immunophenotyping structure, and cytochemistry) and number of cells, and it deﬁnes three categories (Table 1.5). This sys- ALL is probably best classiﬁed on the basis of im- tem is limited due to very unevenly divided numbers munophenotyping. Antigens on the surface of nor- of patients in each category and to a morphological mal hematopoietic cells express changes as the cells feature that correlates with responsiveness to con- mature in the bone marrow. Technology has pro- ventional therapy – the presence of cytoplasmic vac- duced monoclonal antibodies to many of these cell uoles – not included in the FAB system. Vacuoles are cluster-of-differentiation (CD) antigen groups. These present in 25–30% of patients and are associated are each given a classiﬁcation number preﬁxed with with a lower presenting white cell count and the CD. Some CD antigen groups relate to lymphocyte “common” ALL immunophenotype. sublineage (CDs 1–8 mark various stages of T-cell lineage; CDs 19–22, 24, and 79a mark B cells) and some to myeloid lineage, whereas others mark more 184.108.40.206 Cytochemistry primitive features (CD10 and CD34). Other useful Several biochemical markers have been identiﬁed to immunologically deﬁned cell characteristics include assist in the classiﬁcation of leukemia. However, little the following: is added to the morphology of ALL, with the excep- ▬ Cytoplasmic immunoglobulins found in pre-B- tion of cell ALL ▬ Periodic-acid Schiff positivity, seen in around ▬ Surface immunoglobulins found in mature B-ALL 15% of cases correlating with common ALL ▬ Terminal deoxynucleotidyl transferase (TdT) ▬ Acid phosphatase positivity in T-ALL found in immature lymphoid cells Using these markers enables the classiﬁcation of ALL into major categories (Table 1.6).
30. Leukemia Chapter 1 11Table 1.7. Outcome prediction associated with ploidy status of acute lymphoblastic leukemia Ploidy status Number of chromosomes Percentage of childhood Predicted response per malignant cell ALL cases to treatment Hyperdiploidy >50 25–30 % Favorable Hypodiploidy <50 5–10 % Poor Near-haploidy <30 <1 % Very poor ALL cells occasionally express cell antigens more Other signiﬁcant abnormalities includeusually associated with myeloid lineage. Opinion is ▬ rearrangements of the MLL genedivided as to whether this is clinically signiﬁcant. ▬ rearrangements of the MYC gene with im- munoglobulin genes220.127.116.11 Cytogenetics ▬ rearrangements of T-cell receptor genes ▬ mutations of p16 (a tumor suppressor gene)Cytogenetic abnormalities are detectable in most ▬ mutations of p53 gene (although uncommon incases of childhood ALL. They can be categorized ei- childhood ALL, these mutations are associatedther by the number of chromosomes (ploidy) or by with relapse or refractory leukemia)the structural changes and rearrangements based ondetailed analysis of the karyotype. The assessment of The effects of these genetic alterations in leukemiaploidy status is clinically useful in predicting progno- help to explain adverse clinical outcomes. For exam-sis (Table 1.7). ple, the Philadelphia chromosome results in the pro- With regard to structural changes, the identiﬁca- duction of an active kinase enzyme that drives celltion of translocations and marker chromosomes and proliferation independently of normal requirementsthe delineation of complex chromosome aberrations for growth factor and blocks apoptosis (programmedhave been possible with multicolor spectral kary- cell death). Therefore, drug responsiveness pathwaysotyping. The most signiﬁcant chromosome (Ch’) may be blocked. Normal p53 protein is required to in-translocations identiﬁed in childhood ALL include duce cell death following anoxia or DNA damagethe following: from exposure to drugs or irradiation. Mutations in the p53, common in relapse of leukemia, may explain▬ Ch’12 and Ch’22; i.e., t(12;22), resulting in the drug resistance in more advanced disease. ETV6/AML1 fusion gene Although the risk criteria features must be consid-▬ the Philadelphia chromosome, which is transloca- ered important predictors of outcome, it would ap- tion t(9;22) and gives rise to the BCR/ABL fusion pear that they are most beneﬁcial in predicting risk gene in ALL that indicates a poor prognosis groups in B-cell lineage but not consistently in T-cell▬ t(1;19), giving rise to E2A/PBX1 which is a translo- disease (Eden et al. 2000). Overall, 30–40% of chil- cation of pre-B ALL dren with T-lineage ALL relapse within the ﬁrst 18▬ t(12;21), giving rise to TEL/AML1 (also termed months after diagnosis, and approximately 20% of ETV6/CBFA2 fusion gene), which has been com- children with “standard risk” ALL relapse. Some monly reported as indicating a good prognosis groups of patients require further intensiﬁcation of▬ t(4;11), giving rise to MLL/AF4, which is a typical therapy. Consequently, more sophisticated approach- translocation occurring in infant leukemia es to risk classiﬁcation that incorporate the molecu- lar genetic ﬁndings and minimal residual disease measurement have the potential for identifying high- er-risk children.
31. 12 Chapter 1 D.Tomlinson reduced relapse risk if it is not replaced by alternative 1.1.7 Treatment intensiﬁcation strategies (Chessells et al. 2002). Therapy for ALL has improved to such a degree that When treatment begins, the lysis of leukemic cells about 80% of childhood ALL is curable. The cytotox- causes an increase in uric acid levels in the blood. ic drugs used have been available for over 20 years, Therefore, a uricolytic agent (uric acid depletor) is but better understanding of the pharmacology of routinely prescribed. This is usually allopurinol, but these drugs has led to more effective protocols being investigations continue to seek a more effective devised that also attempt to avoid long-term adverse agent, such as nonrecombinant urate oxidase. effects. Improvements have also been made in sup- The steroid of choice is normally prednisolone, portive care to reduce morbidity and mortality. The but research continues to establish the efﬁcacy of aim of treatment for ALL is to effectively halt the pro- dexamethasone. duction of abnormal cells and eradicate the disease. L-asparaginase can be derived from several Treatment protocols for ALL are constantly attempt- sources, including ing to improve in terms of efﬁcacy and long-term ▬ Polyethylene-glycol (PEG) L-asparaginase toxicity. Protocols for ALL generally include the fol- ▬ Escherichia coli (E. coli) asparaginase lowing features: ▬ Erwinia asparaginase (derived from Erwinia caro- 1. Induction tovora or Erwinia chrysanthemi). 2. Intensiﬁcation/consolidation Each of these L-asparaginase preparations has differ- 3. CNS-directed therapy ent pharmacokinetic properties and different toxic 4. Maintenance/continuing treatment tendencies. PEG L-asparaginase has a longer half-life The drugs normally administered during the treat- than E. coli asparaginase, which in turn has a longer ment for ALL are shown in Table 1.8. (Part 3 will de- half-life than Erwinia asparaginase. Given in equiva- tail cytotoxic drugs further). Treatment for ALL con- lent doses, the one with a longer half-life should be tinues for a period of 2 or 3 years. However, in- more effective but is also more toxic. Reports com- fant ALL remains a challenge to treat. Most investiga- paring the efﬁcacy of different preparations have de- tors treat infants as a unique subgroup, giving multi- bated the clinical signiﬁcance of the results. Due to ple drugs at high doses. Intensive systemic and IT the sources of the preparations, they can all display treatments seem to provide adequate therapy for the immunogenicity and cause allergic side effects. How- CNS, even in infants with CNS involvement at diag- ever, the presence of antibodies does not necessarily nosis, thus avoiding cranial irradiation in these in- cause an allergic reaction. Other toxicities, including fants. coagulation disorders, liver toxicity, and acute pan- creatitis, are related to the inhibition of protein syn- 18.104.22.168 Induction thesis. Few studies have compared the effect of the various asparaginase preparations on the coagula- The drugs used initially to induce a remission are tion proteins. Erwinia asparaginase has been report- vincristine, steroids, and a third drug – L-asparagi- ed as having a less pronounced effect on coagulation nase or an anthracycline – given over a 4-week peri- than E. coli asparaginase does. This may be argued to od. This three-drug induction usually produces re- be dose-related rather than preparation-related. mission in about 95% of children. CNS prophylax- Fresh frozen plasma (FFP) was often transfused pri- is/treatment is also started immediately with IT or to L-asparaginase if coagulation screening showed methotrexate. In the past, protocols included a decrease in any coagulation proteins, but this is now daunorubicin during induction. This was later omit- thought to be of no clinical beneﬁt. Protocols for the ted due to treatment-related mortality and potential treatment of ALL usually specify one particular late cardiotoxicity. However, research suggests that preparation of L-asparaginase. However, allergic re- early treatment with daunorubicin could achieve a actions usually require the discontinuation of thera-
32. Leukemia Chapter 1 13Table 1.8. Drugs commonly used in the treatment of acute lymphoblastic leukemia Drugs Route of Induction Intensiﬁcation CNS prophylaxis Maintenance administration Vincristine Intravenous * * * L-asparaginase Subcutaneous/ * intramuscular Prednisolone/ Oral * * * dexamethasone Co-trimoxazole Oral * Methotrexate Oral * Methotrexate Intrathecal * * * * Methotrexate (with Intravenous * folinic acid rescue) Daunorubicin Intravenous *possibly * Etoposide or Intravenous * cyclophosphamide Cytarabine Intravenous * Thioguanine Oral * (may be replaced with mercaptopurine) Mercaptopurine Oral *py and subsequent substitution with a different 22.214.171.124 Intensiﬁcation/Consolidationpreparation. This substitution is necessary, but it isgenerally thought that the different preparations are This block of treatment is given following inductionnot therapeutically interchangeable, although there is and again about 4 months later (depending on theprobably no adverse prognostic impact of allergy to protocol). Clinical trials have also investigated the in-asparaginase. troduction of a third block, which seemed to com- Because of the risk of Pneumocystis jiroveci pneu- pensate for the omission of anthracyclines in induc-monia (PCP) in immunocompromised patients, sul- tion but with possibly little other beneﬁt.famethoxazole/trimethoprim (SMX/TMP) or co-tri-moxazole is given as effective prophylaxis. This is 126.96.36.199 CNS-directed Therapynormally administered as an oral preparation (usual-ly two or three times per week) but may be given in- Prophylactic CNS therapy is based on the premisetravenously if the patient’s condition requires it. On that the CNS provides a sanctuary site for leukemicoccasion, due to adverse reactions including pro- cells that are undetectable at diagnosis and that canlonged periods of neutropenia, a secondary alterna- be protected from systemic therapy by the blood-tive may be necessary. These alternatives include brain barrier. If preventative therapy were not givenaerosolized/nebulized pentamidine, oral dapsone, to children with ALL, over 50% would develop CNSand oral atovaquone. Pentamidine can be given intra- disease. Regular (usually every 12 weeks) lumbarvenously, but systemic toxicities may be higher with punctures are performed in order to administer ITthis method of administration. methotrexate. Additionally, high-dose methotrexate is given intravenously, usually at 4-weekly intervals between intensiﬁcation blocks. High-dose metho-
33. 14 Chapter 1 D.Tomlinson trexate infusions were introduced to protocols to re- 188.8.131.52 Allogeneic Stem Cell Transplant place cranial irradiation because of its associated ad- verse side effects, and the beneﬁts are still under in- Some high-risk leukemias may indicate the need for vestigation. Cranial radiotherapy may be reserved for transplantation from the time of diagnosis, such as children thought to be at especially high risk of CNS Philadelphia-chromosome-positive ALL. However, as involvement (T-cell with high white count at diagno- transplantation and chemotherapy are improving, sis) or for those with CNS inﬁltration at diagnosis. these patients are continually subject to review. Stem Triple IT therapy (including the addition of cytara- cell transplantation has not been shown to improve bine and hydrocortisone) is also under investigation outcomes for infant ALL or other very-high-risk ALL. in some protocols. 1.1.8 Prognosis ! Note: It is vital that the IT methotrexate NEVER be confused with the intravenous vincristine that The prognosis of ALL is one of the highest of child- is normally given on the same day. This would result hood malignancies, with a survival rate of around in fatality. 80%. Studies have investigated the inﬂuence on sur- vival of ethnicity and socioeconomic status. Increas- 184.108.40.206 Maintenance/Continuing Treatment ing levels of deprivation were associated with poorer survival from all cancers, including leukemia, but Oral methotrexate administered weekly and oral 6- only before other prognostic factors were taken into mercaptopurine administered daily are the mainstay consideration (McKinney et al. 1999). However, de- of most continuation regimens. Administering these spite continuing improved protocols, the rate of re- drugs in the evening appears to give a better clinical lapse has decreased only slightly over the last decade. outcome. This result may be mainly due to issues sur- The main improvements in survival rates have been rounding compliance; it may be easier for parents or due to improved management of relapse, especially adolescents to remember drugs at this time of day. for those relapsing off treatment. Relapse of ALL is Studies have indicated the need to give continuation most commonly treated with marrow ablative therapy to the limits of tolerance by titrating doses chemotherapy and allogeneic stem cell transplant against myelosuppression and reiterating the impor- following the achievement of a second remission. tance of compliance. This may result in periods of Late bone marrow relapse of several years may be discontinuing therapy during this phase, but this is treated by intense chemotherapy alone, leaving the thought to be a positive event if it is related to neu- possibility of transplant in third remission if neces- tropenia. Therapy is not usually discontinued if there sary. Allografts from unrelated donors are an option is an episode of elevated liver enzymes. Maintenance that has provided encouraging results when there is a therapy also includes continuing intravenous (IV) lack of suitable related donors. Transplant with um- vincristine, PCP prophylaxis, and CNS-directed ther- bilical cord blood stem cells is another option. apy every 4 weeks. The survival rate of 80% is the mean that disguis- The progression of each stage of the protocol relies es rates that range from 10–90%. The failure of im- on a degree of return of normal bone marrow func- proved rates of survival has been most notable in tion, where the blood component levels are within high-risk groups. However, the relapse that occurs in normal limits. Periods of neutropenia are associated standard risk groups must also be explained. Reasons with any ALL treatment protocol during which the may be pharmacological in cases of noncompliance child/adolescent becomes immunocompromised. or drug resistance. Drug sensitivity testing and Procedures regarding supportive care are adhered to greater vigilance may help to identify those at risk and are as important as the cytotoxic therapy with re- and allow for intervention. Other reasons for treat- gard to ensuring the best outcomes for these children ment failure may be due to intrinsically resistant dis- and adolescents. ease or to recurrence from residual disease. Testicu-
34. Leukemia Chapter 1 15lar relapse of ALL can occur, possibly because this ▬ Secondary malignancies induced by epipodophyl-area is a sanctuary site. However, this is a rare event, lotoxins (etoposide), radiation, or alkylatingaffecting approximately 1% of boys with ALL, and is agents. Exposure to epipodophyllotoxins has pro-normally treated with local radiation therapy and duced an increase in secondary acute myeloidchemotherapy. Approximately 10–13% of pediatric leukemia. There is a marked excess of brain tu-ALL cases have T-lineage phenotype, and 30–40% of mors among children who received cranial irradi-these still relapse during treatment. More sophisti- ation before the age of 5.cated approaches to risk classiﬁcation and measure- ▬ Osteonecrosis caused by glucocorticoids (pred-ment of minimal residual disease to capture patients nisolone, dexamethasone). This is most often seenwho would beneﬁt from more intense treatment may in adolescents.go some way to increase overall event-free survival ▬ Altered bone density induced by glucocorticoids,rates (survival free from relapse). which increases susceptibility to fractures. ▬ Some potential impairment of intellectual devel-1.1.9 Follow-up opment, which is measurable by a fall in IQ of 10–20 points.Following the completion of therapy for ALL, it is ▬ Psychosocial sequelae of a diagnosis of and treat-crucial to monitor these children and adolescents for ment for leukemia, which are signiﬁcant. Theretwo reasons: may be problems regarding relationships, career, insurance, and mortgage application, and emo-1. Blood counts will be carried out to ensure that tional issues such as depression, anger, and confu- signs of relapse can be detected, but with decreas- sion. Many studies have highlighted the need to in- ing frequency over a number of years. Follow-up clude excellent psychosocial care throughout the may also include bone marrow aspiration yearly disease trajectory and beyond. initially for the same reason.2. As therapy becomes more successful, late side ef- Approaches to minimize adverse effects without af- fects are of increasing concern. fecting treatment outcome have included the devel- opment of new drugs, such as the liposomal formula-Long-term effects of antileukemic treatment include tion of daunorubicin; the use of cardioprotectivethe following: agents; alternative administration schedules, such as▬ Chronic cardiotoxicity induced by anthracyclines continuous infusions/prolonged infusion times (the (daunorubicin), which can manifest as sudden on- advantages of which are debatable); and the monitor- set irreversible heart failure. The severity of car- ing of minimal residual disease, which allows for re- diac dysfunction is related to the cumulative dose duction or optimization of drug doses. of anthracycline.▬ Hypothalamic-pituitary axis and gonadal damage 1.1.10 Future Perspectives induced by radiation. Growth problems may cause short stature and obesity later in life, and girls may The lack of speciﬁcity of most prognostic factors, as undergo precocious puberty. Growth hormone previously discussed, has led to the search for more therapy may be required. It is less clear if chemo- relevant features of disease. Minimal residual disease therapy alone can impair growth. Testicular radio- (MRD) – that is, submicroscopic leukemia – can be therapy renders males sterile, and most will re- detected at deﬁned time points by identifying clone- quire androgen replacement throughout puberty. speciﬁc T-cell receptors using PCR or immunoglobu- Chemotherapy may lead to subfertility, which can lin gene rearrangements using ﬂow cytometry. This improve over time. Ovaries are less sensitive to highly sensitive and highly speciﬁc prognostic infor- chemotherapy, but if they are irradiated, estrogen mation allows for deﬁnition of new risk groups. replacement will be necessary. Alkylating agents Treatment may possibly be reduced in children and are also likely to cause gonadal damage. adolescents with fast clearance of leukemic cells. Per-
35. 16 Chapter 1 D.Tomlinson sistent disease could require treatment modiﬁcation Children with Down’s syndrome have an increased and intensiﬁcation. risk of AML, with an estimated 10–15-fold increase in Levels of MRD may be deﬁned as incidence compared with that of the general child- hood population (Hasle et al. 2000). These children’s ▬ Negative – nothing detectable with two markers risk of ALL is also increased but not to the same de- ▬ Indeterminate – no result or low positive (1¥10–5– gree. The reasons for their predisposition to leukemia 1¥10–4 nucleated bone marrow cells) are unclear. Presence of the extra chromosome 21 ▬ Positive – more than one nucleated bone marrow may disrupt the genetic balance, which in turn in- cell in 10,000 (>1¥10–4). creases susceptibility to further trauma. However, in- Bone marrow samples from diagnosis and a later de- dividuals with Down’s syndrome do not appear to ﬁned time point, such as the end of induction thera- have a higher risk of other malignancies. Hypotheses py, are compared. Treatment can then be assigned ac- for this may include an increased susceptibility for cording to the clinical trial in place. Sequential mon- apoptosis (programmed cell death) in Down’s syn- itoring of MRD can also elicit further risk assess- drome, causing cell death rather than malignant ment. For example, the persistence of MRD beyond 4 transformation after cell injuries (Hasle 2001). months is associated with an increased risk of re- lapse. 1.2.2 Etiology Remarkable advances have been made by deﬁning 220.127.116.11 Genetic Factors molecular abnormalities involved in leukemogenesis and drug resistance. This has led to the development The various conditions that have a predisposition to of promising new therapeutic strategies. Recognition AML are akin to those of any acute leukemia of inherited differences in the metabolism of an- (Table 1.2), with the addition of myelodysplastic syn- tileukemic drugs has enabled the selection of optimal drome (monosomy 7). drug dosages and scheduling. This could be useful to increase antileukemic effects and to reduce late ef- 18.104.22.168 Environmental Factors fects. Future strategies will incorporate more speciﬁc risk-directed therapy and greater international col- Similarly, the causal risk factors associated with AML laboration. Ultimately, progress made should result are the same as for ALL (see Table 3). Interestingly, al- in improved clinical management and increased cure lergy or a family history of allergy (including hay rates for childhood ALL. fever, neurodermatitis, asthma, and, to a lesser de- gree, eczema) have been associated with a decreased risk of ALL but not of AML (Schuz 2003). 1.2 Acute Myeloid Leukemia Until recently, a Vietnam-era herbicide, Agent Or- ange (dioxin), was reported to be a parental exposure 1.2.1 Epidemiology link to childhood AML. However, subsequent studies Acute myeloid leukemia (AML) is most often seen in have ruled out any increased risk (Ahmad 2002). adults over age 40, but the annual incidence of child- hood AML is approximately 4.7 per 100,000 and is 1.2.3 Molecular Genetics constant from birth to 10 years of age. Incidence peaks slightly in adolescence, and AML is the more The defect that occurs in AML appears to be an arrest common leukemia found in neonates. Boys and girls in the differentiation pathway of myeloid progenitors appear to be affected equally. It is generally reported or precursors. Fusion genes generated by transloca- that AML is equally distributed among ethnic groups, tions of chromosomes block cell differentiation. but a study by McKinney et al. (2003) indicated a sig- These genes can be detected by PCR, and clonal chro- niﬁcantly higher incidence of AML among South mosomal abnormalities of dividing bone marrow Asians in an urban English city. cells have been identiﬁed in more than 70% of chil-
36. Leukemia Chapter 1 17dren diagnosed with AML. The most common fusion less common in AML, and hepatosplenomegaly isgenes detected in AML are more marked in infants with AML. CNS involvement of AML, occurring in 5–15% of▬ AML1/ETO from t(8,21), most often seen in acute cases, can cause symptoms similar to those of CNS myeloblastic leukemia involvement in ALL:▬ MLL/AF10 from t(10,11)▬ Inversion of ch16, creating CRFB/SMMHC ▬ Headache▬ Trisomy 8 ▬ Poor school performance▬ Monosomy 7 ▬ Weakness▬ PML/RARA from t(15,17), most common in acute ▬ Vomiting promyelocytic leukemia ▬ Blurred vision ▬ SeizuresFusions of the MLL gene occur in about 50% of ▬ Difﬁculty maintaining balancecases of AML. These fusions are thought to be fetalin origin, as this fusion is often detected on the Hyperleukocytosis can be present at diagnosis ofGuthrie card or neonatal blood spot of those children childhood AML and may or may nor require leuko-who subsequently develop AML. This is possibly pheresis therapy. Approximately 15–20% of childrenthe initiating event in childhood AML that requires present with leukocyte counts >100¥109g/l, whichadditional secondary genetic alterations to cause may lead to leukostasis. Testicular inﬁltrates are un-leukemia. common in AML.1.2.4 Symptoms and Clinical Signs 1.2.5 DiagnosticsAML can have a similar presentation to that of ALL, If the history and physical examination suggestwith symptoms appearing 1–6 weeks before diagno- leukemia, examination of peripheral blood and bonesis. The presenting signs and symptoms include the marrow samples is required, as with the diagnosis offollowing: ALL. Bone marrow ﬁndings include a hypercellular trephine/biopsy sample and an aspirate sample▬ Pallor showing more than 30% blast cells. To conﬁrm a di-▬ Fatigue, weakness agnosis of AML, the same procedures as for diagnos-▬ Petechiae ing ALL are applied.▬ Fever, infection▬ Sore throat▬ Lymphadenopathy 1.2.6 Staging and Classiﬁcation▬ Skin lesions There is presently no therapeutically or prognostical-▬ Gastrointestinal symptoms, including pain, nau- ly meaningful staging system for AML. Cytochemical sea, and vomiting staining of bone marrow smears using Sudan black▬ Gingival changes or inﬁltrates stain produces a positive result in AML, and esteraseThe presenting lesions or inﬁltrates result from stains distinguish further subgroups. Immunophe-chloromas (or granulocytic sarcomas or myeloblas- notyping also assists in determining the originatingtomas), which are localized collections of leukemic cell line. Cluster-of-differentiation antigen groups re-blast cells. Presentation with bleeding can be due to lated to myeloid lineage include CD11, CD13–15, anddisseminated intravascular coagulation (DIC) and CD33.may be indicative of acute promyelocytic leukemia. If the myeloid cell line is involved and a diagnosisDIC can occur as a result of the release of procoagu- of AML is conﬁrmed, the French-American-Britishlants from abnormal promyelocytic granules (see classiﬁcation system for AML is applied. There areChapter 16). Complaints of presenting bone pain are eight different classiﬁcations or types of AML (M0 to
37. 18 Chapter 1 D.Tomlinson M7), based on appearance of the diseased cells under blast cell differentiation. This standardization began the microscope (Table 1.9). Each subtype refers to the in 1976, but with improvements in treatment out- particular myeloid lineage affected and the degree of come, this approach to classiﬁcation has limited clin- ical relevance. Approximately 80% of children less than 2 years of age have either M4 or M5 FAB sub- Table 1.9. French-American-British (FAB) classiﬁcation of acute types. M7 is most common in children under 3 years, myeloid leukemia particularly in those with Down’s syndrome. FAB Cell morphology Myelodysplastic syndrome (MDS) is a preleuk- group emic syndrome that has a relationship with some types of AML (MDS-related AML or MDR-AML). Ap- M0 Myeloid leukemia with minimal proximately half of the cases of AML follow MDS, and differentiation these patients generally have a very poor prognosis. M1 Myeloblastic leukemia The other main group consists of those cases unrelat- M2 Myeloblastic leukemia – undifferentiated ed to MDS, with a suggested name of true de novo M3 Promyelocytic leukemia with 15;17 AML (TDN-AML). This led to subclassiﬁcation of translocation AML based on its relationship with MDS. The World M4 Myelomonocytic leukemia Health Organization (WHO) attempted to reﬁne the M5 Monocytic leukemia: FAB classiﬁcation by incorporating the AML/MDS M5a – without differentiation relationship. This classiﬁcation, shown in Table 1.10, M5b – with differentiation has been a cause for debate over the past few years. M6 Erythroblastic leukemia However, the WHO classiﬁcation incorporates sub- M7 Megakaryoblastic leukemia categories of AML with recurring translocations, AML related to MDS, and subsets of treatment-relat- Table 1.10. World Health Organization classiﬁcation of acute myeloid leukemia Group Subgroups Acute myeloid leukemia with recurrent Acute myeloid leukemia with t(8;21) genetic abnormalities Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16) or t(16;16) Acute promyelocytic leukemia (AML with t(15;17) and variants Acute myeloid leukemia with MLL abnormalities Acute myeloid leukemia with Following an MDS or MDS/myeloproliferative disorder multilineage dysplasia Without antecedent myelodysplastic syndrome Acute myeloid leukemia Alkylating agent-related and MDS, therapy-related Topoisomerase type II inhibitor-related Other types Acute myeloid leukemia not Acute myeloid leukemia minimally differentiated otherwise speciﬁed Acute myeloid leukemia without maturation Acute myeloid leukemia with maturation Acute myelomonocytic leukemia Acute monoblastic and monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myeloﬁbrosis Myeloid sarcoma Adapted from Head 2002
38. Leukemia Chapter 1 19ed AML based on their relation to the ﬁrst two Down’s syndrome patients have a markedly in-groups. Therefore, this system may assist clinical de- creased responsiveness to therapy. However, thiscisions and be useful in analyzing biologic studies in causes an increased treatment-related morbidity andAML. It is of note that MDS-AML is more prominent mortality, which has meant that AML protocols havein the elderly, with only 15% of cases in children and been tailored speciﬁcally for this population of chil-young adults (Head 2002). The TDN-AML group, re- dren. Stem cell transplant is rarely indicated in theselated to a set of recurring cytogenetic translocations circumstances. Of note are cases when infants withand inversions, has a median age approximating the Down’s syndrome, usually under 2 months of age, aremedian age of the population (Head 2002). diagnosed with AML or transient leukemia and achieve complete spontaneous remission.1.2.7 Treatment 1.2.8 PrognosisThe most dramatic outcomes for children with AMLhave resulted from intensive therapy over a brief pe- Despite signiﬁcant improvements in the outcomes ofriod of time. Treatment usually includes a protocol children with AML, the cure rate is only approxi-with an induction anthracycline (usually daunoru- mately 50%. About 45% of children with AML re-bicin) and cytarabine. An important component of lapse, and there remains little information about thepost-remission therapy appears to be several courses best treatment for this group of children.of high-dose cytarabine. The addition of mitox- In 2002 (a), Rubnitz and colleagues reported thatantrone is possibly also beneﬁcial. Intensive therapy the only independent factors indicating a favorableusually induces remission in about 90% of children. prognosis wereThe challenge then is to prolong the remission. In ▬ a presenting leukocyte count of <50¥109/lover 60% of these children, an allogeneic stem cell ▬ the genetic factor of translocation t(9;11)transplant is the chosen treatment option once ﬁrstremission has been achieved. However, if cytogenet- Another favorable prognostic factor, as mentionedics are favorable, such as t(15;17), t(8;21) or inv16, in- previously, is the constitutional trisomy 21 (Down’stensive chemotherapy consolidation may be the syndrome), despite the increased risk for developingtreatment of choice even if a matched sibling donor is AML. These children also have a decreased risk of re-available (Sung et al. 2003). These patients would be lapse that is unrelated to having the favorable abnor-transplanted after relapse. There is no evidence to malities of t(15;17), inv16, or t(8;21).suggest that autologous transplant is of any beneﬁt in It is worth noting that results of another study bypediatric acute leukemia. (Part 3 will cover stem cell Rubnitz et al. (2002b) debate the favorable outcome oftransplants in detail.) The use of some form of CNS t(8;21) that was previously reported.treatment is included. Children with M4 and M5 havethe highest incidence of CNS disease. 1.2.9 Follow-up Acute promyelocytic leukemia (APM) (i.e., FABsubtype M3) can often be treated with all-trans Children and adolescents need appropriate and sen-retinoic acid and chemotherapy, which achieves a re- sitive follow-up, similar to that following ALL treat-mission and cure in most children with AML of this ment. The speciﬁc features of follow-up for AML con-type. This outcome is possible due to the transloca- cern the increased incidence of relapse and the in-tion t(15;17) involving a breakpoint that includes the creased number of children and adolescents who re-retinoid acid receptor. Fatal hemorrhagic complica- ceive transplant as a standard modality of treatment.tions can occur before or during induction in thissubtype. There is a low incidence of CNS disease inchildren with APM. A lumbar puncture is not per-formed, and IT chemotherapy is not required.
39. 20 Chapter 1 D.Tomlinson Despite this obvious relationship between radiation 1.2.10 Future Perspectives and CML, only 5–7% of adult cases of CML have doc- The progress in therapy for AML lags behind that for umented exposure to excessive radiation, and previ- ALL. Allogeneic bone marrow transplant from a ous exposure is infrequent in children with CML matched family donor appears to remain the best op- (Freedman 1994). In patients younger than 20 years tion for most patients. Drug resistance is an apparent of age, the incidence is less than 1 in 100,000, with factor in AML and is being investigated by studying 80% of these cases being over the age of 4 years. leukemic blast cells or minimal residual disease. In adult patients with AML, the expression of the 1.3.2 Molecular Genetics multidrug resistance gene (MRD1) deﬁnes a poor prognostic group. This is not a similar ﬁnding in chil- CML is normally a hematological disease of the eld- dren with AML (Steinbach et al. 2003). A study by erly, characterized by the BCR/ABL oncogene caused Steinbach et al. (2003) investigated the expression of by a translocation between the ABL gene on Ch’9 and ﬁve of the genes encoding the multidrug resistance- the BCR gene on Ch’22. The resulting chromosome associated proteins (MRP) in children with AML and 22, with a shortening of the long arm, is known as the their response to chemotherapy. Expression of MRP3 Philadelphia (Ph’) chromosome. The BCR/ABL gene was found to be involved in drug resistance, produc- fusion product is thought to be causative in CML and ing a poorer prognosis, and the expression of MRP2 has multiple effects on diverse cell functions, such as was, to a lesser extent, also associated with poor prog- growth, differentiation, adhesion, and apoptosis. nosis. Expression of high levels of both these genes indicated a particularly poor prognosis. This study 1.3.3 Symptoms and Clinical Signs suggests that these proteins, MRP3 and possibly MRP2, could provide markers for risk-adapted ther- The “chronic phase” of leukemia that results then apy and possible targets for the development of drugs evolves into a more rapidly progressive phase known that would overcome multidrug resistance in child- as the “accelerated phase” and ultimately “blast cri- hood AML. sis.” The chronic phase lasts about 3 years but can Alternative approaches to therapy may include range from a few months to 20 years. The accelerated risk-directed therapy based on different prognostic phase generally occurs over a 3–6-month period. The criteria, differentiation therapy with all-trans- ﬁnal phase is generally resistant to current treatment retinoic acid, immunotherapy with monoclonal anti- and is therefore fatal. bodies, or tumor vaccines. The signs and symptoms of CML can vary de- pending on the phase the disease has reached: ▬ The chronic phase has a nonspeciﬁc onset over 1.3 Chronic Myeloid Leukemia weeks to months, with complaints of fatigue, 1.3.1 Epidemiology and Etiology anorexia, weight loss, and excessive sweating. Physical presentation includes pallor, bruising, An increase in the incidence of adult chronic myeloid low-grade fever, sternal bone pain, and spleno- leukemia (CML) has been seen in three populations: megaly that is sometimes accompanied by he- ▬ The Japanese exposed to radiation released from patomegaly. atomic bombs in Nagasaki and Hiroshima ▬ Signs and symptoms of the accelerated phase pres- ▬ Patients with ankylosing spondylitis treated with ent over a few months and are similar to those of spine irradiation the chronic phase but with more episodes of unex- ▬ Women with uterine cervical carcinoma who re- plained fever, lymphadenopathy, and bruising and ceived radiation treatment (Freedman 1994) petechiae caused by thrombocytopenia.
40. Leukemia Chapter 1 21▬ The blastic phase presents with symptoms identi- 1.3.7 Future Perspectives cal to those of acute leukemia For children with CML, current efforts should aim to reduce transplant-related deaths. Cytogenetic studies1.3.4 Diagnostics to identify further risk factors will assist in the un-CML is characterized by the presence of large num- derstanding of the cell biology of this disease.bers of granulocytes in the blood, with mild anemiaand thrombocytosis. The numbers of basophils andeosinophils are increased.A characteristic laboratory 1.4 Juvenile Myelomonocytic Leukemiafeature is a marked reduction or absence of leukocytealkaline phosphatase (LAP) activity, which results A subgroup of CML is juvenile myelomonocyticfrom a decrease in monocytes that normally secrete a leukemia (JMML), formerly called juvenile chronicfactor that induces LAP activity (Freedman 1994). myeloid leukemia (JCML). This subgroup represents Cytogenetic analysis of the marrow cells will dis- less than 1% of cases of childhood leukemia. Contro-play the Philadelphia chromosome in over 90% of versy surrounds the classiﬁcation of this subgroup,new patients with CML. Absence of cytogenetic or and it may be termed as chronic myelomonocyticmolecular abnormalities in chromosome 22 would leukemia (CMML). Most patients are less than 2 yearsrule out a diagnosis of CML. of age, with 95% younger than 4 years (Freedman 1994).1.3.5 Treatment Children frequently present with complaints of malaise, bleeding, or fever, often with localized infec-In children with CML, allogeneic bone marrow trans- tion. Less common presentations include pulmonaryplant is normally the treatment of choice. This treat- symptoms (cough, wheezing, tachypnea), abdominalment is providing promising survival rates even in distension and discomfort, weight loss, and occasion-the event of advanced disease and histoincompatibil- ally bone pain. On examination, splenomegaly is aity with donor marrow (Sharathkumar et al. 2002). frequent feature; pallor and hepatomegaly may alsoAnother treatment that has produced encouraging be present. Skin manifestations may be seen, with anresults, reported by Millot et al. (2002), uses a combi- eczematous rash that is unresponsive to topical treat-nation of interferon and cytarabine for children with ment. Xanthoma and café-au-lait spots are often as-Philadelphia-chromosome-positive CML. This may sociated with JMML. These skins ﬁndings are alsooffer an alternative to transplantation in children and common in neuroﬁbromatosis, and an interrelation-adolescents in the chronic phase of CML. ship between neuroﬁbromatosis and JMML has been established (Freedman 1994).1.3.6 Prognosis Peripheral blood samples show an increasing number of circulating monocytes in all cases. Imma-For children with the adult form of CML, the impor- ture granulocytes, anemia, and thrombocytopeniatance of prognostic factors is difﬁcult to deﬁne due to are also frequently present. The cells in JMML do notthe low incidence of disease. Remissions can be in- contain the Philadelphia chromosome, although oth-duced, but relapse is common and long-term sur- er chromosomal abnormalities are present.vivors are rare. This disease is more progressive and less respon- sive to treatment than Ph’-chromosome-positive CML. Prognosis is poor, and a bone marrow trans- plant is required as early as possible for these chil- dren, particularly when a matched relative donor is available.
41. 22 Chapter 1 D.Tomlinson Table 1.11. Common Symptoms of Histiocytosis System Symptom Gastrointestinal Abdominal pain, vomiting, diarrhea, jaundice, weight loss, esophageal bleeding Bone Bone pain, headaches (skull lesions), limp (leg lesions) CNS (brain) Diabetes insipidus, mental deterioration, headaches, dizziness, seizures, increased intracranial pressure CNS (pituitary gland) Polydipsia, polyuria, dehydration, short stature, delayed puberty Pulmonary Feeding problems (infants), chest pain, dyspnea, cough, hemoptysis Oral Facial swelling and pain, loss of teeth, swollen and bleeding gingiva, swollen lymph nodes Skin Scaly rash Ear Inﬂammed, draining ear canal, rash behind ears studies, complete blood count and blood chemistries, 1.5 Langerhans Cell Histiocytosis and tissue or skin biopsy. Single-system (localised) LCH usually disappears Histiocytosis is not deﬁned as a malignancy, but it is on its own without any treatment. Although treated treated with cancer therapies (e. g., chemotherapy, ra- with chemotherapy there has been no speciﬁc re- diotherapy) and pediatric oncology nurses may be search trial for the use of cytotoxic therapy in LCH. involved in the care of a child with Langerhan’s cell This may occur following a biopsy. In a small number histiocytosis. of children, treatment will be needed and low-dose A histiocyte is a normal cell in the immune system radiotherapy, surgery and steroids may be used. Mul- found in the bone marrow, blood, skin, liver, lungs, ti-system (disseminated) disease is usually treated lymph glands and spleen. Histiocytosis identiﬁes a with chemotherapy and steroids. The combination group of disorders that have proliferation of cells of and duration of therapy will vary depending on the the mononuclear phagocyte and dendritic cell sys- severity of the illness. Eighty percent of children who tems. In Langerhans cell histiocytosis (LCH), the develop LCH will recover from it. histiocytes move into tissues where they are not nor- A small number of children may develop side mally found and cause damage to those tissues. The effects many years later, because of the treatment cause of LCH is unknown. Suggested hypotheses they have received. This is more likely to happen include the possibility of clonal abnormalities; cyto- when treatments have been intensive. Possible late kine or chemokine abnormality causing abnormal side effects include reduced growth, infertility, expression of Langerhan’s cells; a combination of pulmonary and cardiac abnormalities, and second oncogenesis and immune dysregulation (Egeler et al., malignancy. 2004); and lesional Langerhans cells that control the persistance and progression themselves (Annels et al., 2003). The Histiocyte Society, an international body, was formed in 1987 and has outlined morphology, immnohistiochemistry and clinial criteria required for LCH. The symptoms of LCH are dependent on the body system involved and are listed in Table 1.11. Tests to diagnose LCH may include radiographs, CT
42. Leukemia Chapter 1 23 Gajjar A, Harrison PL, Sandlund JT, Rivera GK, Ribeiro RC,References Rubnitz JE, Razzouk B, Relling MV, Evans WE, Boyett JM, Pui CH (2000) Traumatic lumbar puncture at diagnosis ad-Ahmad K (2002) Agent Orange no longer linked to childhood versely affects outcome in childhood acute lymphoblastic AML. The Lancet Oncology 3(4):199 leukemia. Blood 96(10):3381–3384Alexander FE, Boyle P, Carli PM, Coebergh JW, Ekbom A, Levi Hann I, Vora A, Harrison G, Harrison C, Eden O, Hill F, Gibson F, McKinney PA, McWhirter W, Michaelis J, Peris-Bonet R, B and Richards S (2001) Determinants of outcome after in- Petridou E, Pompe-Kirn V, Plesko I, Pukkala E, Rahu M, tensiﬁed therapy of childhood lymphoblastic leukaemia: Stiller CA, Storm H, Terracini B, Vatten L, Wray N (1999) results from Medical Research Council United Kingdom Population density and childhood leukaemia: results of the acute lymphoblastic leukaemia XI protocol. British Journal EUROCLUS Study. European Journal of Cancer 35(3):439– of Haematology 113(1):103–114 444 Hasle H (2001) Pattern of malignant disorders in individualsAnnels NE, Da Costa CE, Prins FA, Willemze A, Hogendoorn, with Down’s syndrome. The Lancet Oncology 2(7):429–436 Egeler RM (2003) Aberrant chemokine receptor expression Hasle H, Clemmensen IH, Mikelsen M (2000) Risks of and chemokine production by Langerhans cells underlies leukemia and solid tumours in individuals with Down’s the pathogenesis of Langerhans cell histiocytosis. Journal syndrome. Lancet 355(9199):165–169 of Experimental Medicine 197(10): 1385–1390. Head DR (2002) Proposed changes in the deﬁnitions of acuteAuvinen A, Kurttio P, Pekkanen J, Pukkala E, Ilus T, Salonen L myeloid leukemia and myelodysplastic syndrome: are they (2002) Uranium and other natural radionuclides in drink- helpful? Current Opinion in Oncology 14(1):19–23 ing water and risk of leukemia: a case-cohort study in Fin- Jarup L, Briggs D, de Hoogh C, Morris S, Hurt C, Lewin A, Mait- land. Cancer Causes and Control 13(9):825–829 land I, Richardson S, Wakeﬁeld J, Elliott P (2002) CancerBergh T, Ericson A, Hillensjo T, Nygren KG, Wennerholm UB risks in population living near landﬁll sites in Great Britain. (1999) Deliveries and children born after in-vitro fertilisa- British Journal of Cancer 86(11):1732–1736 tion in Sweden 1982–1995: a retrospective cohort study. Kinlen LJ (1995) Epidemiological evidence for an infective Lancet 354(9190):1579–1585 basis in childhood leukaemia. British Journal of CancerBoutou O, Guizard AV, Slama R, Pottier D, Spira A (2002) Pop- 71(1):1–5 ulation mixing and leukaemia in young people around the Klip H, Burger CW, de Kraker J, van Leeuwen FE, OMEGA-proj- la Hague nuclear waste reprocessing plant. British Journal ect group (2001) Risk of cancer in the offspring of women of Cancer 87(7):740–745 who underwent ovarian stimulation for IVF. Human Re-Chessells JM, Harrison G, Richards SM, Gibson BE, Bailey CC, production16(11):2451–2458 Hill FG, Hann IM (2002) Failure of a new protocol to im- Lancashire RJ, Sorahan T; OSCC (2003) Breastfeeding and prove treatment results in paediatric lymphoblastic childhood cancer risks: OSCC data. British Journal of Can- leukaemia: lessons from the UK Medical Research Council cer 88(7):1035–1037 trials UKALL X and UKALL XI. British Journal of Haema- Ma X, Bufﬂer PA, Gunier RB, Dahl G, Smith MT, Reinier K, tology 118(2):445–55 Reynolds P. (2002) Critical windows of exposure to house-Dickinson HO, Hammal DM, Dummer TJB, Parker L, Bithell JF hold pesticides and risk of childhood leukemia. Environ- (2003) Childhood leukaemia and non-Hodgkin’s lym- mental Health Perspective 110(9):955–960 phoma in relation to proximity to railways. British Journal McKinney PA, Feltbower RG, Parslow RC, Lewis IJ, Glaser AW, of Cancer 88(5):695–698 Kinsey SE (2003) Patterns of childhood cancer by ethnicDoll R, Wakeford R (1997) Risk of childhood cancer from fetal group in Bradford, UK 1974–1997. European Journal of Can- irradiation. The British Journal of Radiology 70: 130–139 cer 39(1):92–7Eden OB, Harrison G, Richards S, Lilleyman JS, Bailey CC, McKinney PA, Feltbower RG, Parslow RC, Lewis IJ, Picton S, Chessells JM, Hann IM, Hill FG, Gibson BE (2000) Long- Kinsey SE, Bailey CC (1999) Survival from childhood cancer term follow-up of the United Kingdom Medical Research in Yorkshire, UK: Effect of ethnicity and socio-economic Council protocols for childhood acute lymphoblastic status. European Journal of Cancer 35(13):1816–1823 leukaemia, 1980–1997. Medical Research Council Child- Mellemkjaer L, Alexander F, Olsen JH. (2000) Cancer among hood Leukaemia Working Party. Leukemia 14(12):2307– children of parents with autoimmune diseases. British Jour- 2320 nal of Cancer 82(7):1353–7Egeler RM, Annels NE, Hogendoorn PC (2004) Langherhans Millot F, Brice P, Phillipe N, Thyss A, Demeoq F, Wetterwald M, cell histiocytosis: A pathological combination of oncogen- Boccara JM, Vilque J-P, Guyotat D, Guilhot J, Guilhot F esis and immune dysregulation. Pediatric Blood Cancer (2002) a-Interferon in combination with cytarabine in 42(5): 401–403. children with Philadelphia chromosome-positive chronicFreedman MH (1994) Chronic myelocytic leukemia in infancy myeloid leukemia. Journal of Pediatric Hematology/Oncol- and childhood. In: Pochedly C (ed) Neoplastic Diseases ogy 24(1):18–22 of Childhood Volume 1. Harwood Academic Publishers, Switzerland
43. 24 Chapter 1 D.Tomlinson Naumburg E, Bellocco R, Cnattinigius S, Jonzon A, Ekbom A Schuz J, Morgan G, Bohler E, Kaatsch P, Michaelis J (2003) (2000) Prenatal ultrasound examinations and risk of child- Atopic disease and childhood acute lymphoblastic leuk- hood leukaemia: case-control study. British Medical Jour- emia. International Journal of Cancer 105(2):255–260 nal 320(7230):282–283 Sharathkumar A, Thornley I, Saunders EF, Calderwood S, Naumburg E, Bellocco R, Cnattinigius S, Jonzon A, Ekbom A Freedman MH, Doyle J (2002) Allogenic bone marrow (2002a) Supplementary oxygen and risk of childhood lym- transplantation in children with chronic myelogenous phatic leukaemia. Acta Paediatrica 91(12):1328–1333 leukemia. Journal of Pediatric Hematology/Oncology 24(3): Naumburg E, Bellocco R, Cnattinigius S, Jonzon A, Ekbom A 215–219 (2002b) Perinatal exposure to infection and risk to child- Shu XO, Linet MS, Steinbuch M,Wen WQ, Buckley JD, Neglia JP, hood leukemia. Medical and Pediatric Oncology 38(6):391– Potter JD, Reaman GH, Robison LL (1999) Breast feeding 397 and risk of childhood acute leukemia Journal of the Na- Pan JW, Cook LS, Schwartz SM, Weis NS (2002) Incidence of tional Cancer Institute 91(20): 1765–1772 leukemia in Asian migrants to the United States and their Skinner J, Mee TJ, Blackwell RP, Maslanyj MP, Simpson J, Allen descendants. Cancer Causes and Control 13(9):791–795 SG, Day NE, Cheng KK, Gilman E,Williams D, Cartwright R, Pang D, McNally R, Birch JM on behalf of the UK Childhood Craft A, Birch JM, Eden OB, McKinney PA, Deacon J, Peto J, Cancer Study Investigators (2003) Parental smoking and Beral V, Roman E, Elwood P,Alexander FE, Mott M, Chilvers childhood cancer: results from the United Kingdom Child- CE, Muir K, Doll R, Taylor CM, Greaves M, Goodhead D, Fry hood Cancer Study. British Journal of Cancer 88(3):373–381 FA, Adams G, Law G (2002) Exposure to power frequency Parker L, Cole M, Craft AW, Hey EN (1998) Neonatal vitamin K electric ﬁelds and the risk of childhood cancer in the UK. administration and childhood cancer in the north of Eng- British Journal of Cancer 87(11):1257–1266 land: retrospective case-control study. British Medical Jour- Sorahan T, McKinney PA, Mann JR, Lancashire RJ, Stiller CA, nal 316(7126):189–193 Birch JM, Dodd HE, Cartwright RA (2001) Childhood can- Passmore SJ, Draper G, Brownbill P, Kroll M (1998) Case-con- cer and parental use of tobacco: ﬁndings from the inter- trol studies of relation between childhood cancer and regional epidemiological study of childhood cancer neonatal vitamin K administration. British Medical Journal (IRESCC). British Journal of Cancer 84(1):141–146 316(7126):178–184 Steinbach D, Lengemann J, Voigt A, Hermann J, Zintl F, Sauer- Perrillat F, Clavel J, Jaussent I, Baruchel A, Leverger G, Nelkn B, brey A (2003) Response to chemotherapy and expression of Phillippe N, Schaison, Sommelet D, Vilmer E, Bonaiti-Pellie the genes encoding the multidrug resistance-associated C, Hemon D (2001) Family cancer history and risk of child- proteins MRP2, MRP3, MRP4, MRP5, and SMRP in child- hood acute leukemia (France). Cancer Causes and Control hood acute myeloid leukemia. Clinical Cancer Research 12(10):935–941 9(3):1083–1086 Powell JE, Parkes SE, Cameron AH, Mann JR (1994) Is the risk Steinbuch M, Weinberg CR, Buckley JD, Robison LL, Sandler of cancer increased in Asians living in the UK? Archives of DP (1999) Indoor residential radon exposure and risk of Disease in Childhood 71(5):398–403 childhood acute myeloid leukaemia. British Journal of Can- Roman E, Fear NT, Ansell P, Bull D, Draper G, McKinney P, cer 81(5):900–906 Michaelis J, Passmore SJ, von Kries R (2002)Vitamin K and Stiller CA, McKinney PA, Bunch KJ, Bailey CC, Lewis IJ (1991) childhood cancer: analysis of individual patient data from Childhood cancer and ethnic group in Britain: a United six case-control studies. British Journal of Cancer 86(1):63–9 Kingdom children’s Cancer Study Group (UKCCSG) study. Ross JA, Davies SM (2000) Vitamin K prophylaxis and child- British Journal of Cancer 64(3):543–548 hood cancer. Medical and Pediatric Oncology 34(6):434– Sung L, Bucktein R, Doyle JJ, Crump M, Detsky AS (2003) Treat- 437 ment options for patients with acute myeloid leukemia with Rubnitz JE, Raimondi SC, Halbert AR, Tong X, Srivastava DK, a matched sibling donor: a decision analysis. Cancer 97(3): Razzouk BI, Downing JR, Pui CH, Ribeiro RC, Behm FG 592–600 (2002b) Characteristics and outcome of t(8;21)-positive Swensen AR, Ross JA, Shu XO, Reaman GH, Steinbuch M, Robi- childhood acute myeloid leukemia: a single institution’s ex- son LL (2001) Pet ownership and childhood acute leukemia perience. Leukemia 16(10):2072–2077 (USA and Canada). Cancer Causes Control 12(4):301–303 Rubnitz JE, Raimondi SC, Tong X, Srivastava DK, Razzouk BI, Thapa PB, Whitlock JA, Brockman Worrell KG, Gideon P, Shurtleff SA, Downing JR, Pui CH, Ribeiro RC, Behm FG Mitchel EF Jr., Roberson P, Pais R, Ray WA (1998) Prenatal (2002a) Favourable impact of the t(9;11) in childhood acute exposure to metronidazole and risk of childhood cancer: a myeloid leukemia. Journal of Clinical Oncology 20(9): retrospective cohort study of children younger than 5 years. 2302–2309 Cancer 83(7):1461–1468 Ruccione KS, Waskerwitz M, Buckley J, Perin G, Hammond GD UK Childhood Cancer Study Investigators (2001) Breastfeed- (1994) What caused my child’s cancer? Parents’ responses to ing and childhood cancer. British Journal of Cancer 85(11): an epidemiology study of childhood cancer. Journal of Pe- 1685–1694 diatric Oncology Nursing 11(2):71–84
45. 26 Chapter 2 E. Hendershot 2.8.6 Staging and Classiﬁcation . . . . . . . . . 63 Solid tumors account for 30% of all pediatric malig- 2.8.7 Treatment . . . . . . . . . . . . . . . . . . 65 nancies. Pediatric tumors are most often classiﬁed by 2.8.8 Prognosis . . . . . . . . . . . . . . . . . . 66 2.8.9 Follow-up . . . . . . . . . . . . . . . . . . 66 histology rather than anatomic location, as is done in 2.8.10 Future Directions . . . . . . . . . . . . . . 66 adult tumors. The most commonly occurring pedi- 2.9 Rhabdomyosarcoma . . . . . . . . . . . . . . . . 66 atric solid neoplasms are brain tumors, neuroblas- 2.9.1 Epidemiology . . . . . . . . . . . . . . . . 66 toma, and Wilms’ tumor. Other malignancies that af- 2.9.2 Etiology . . . . . . . . . . . . . . . . . . . 66 fect the pediatric population include Hodgkin’s lym- 2.9.3 Molecular Genetics . . . . . . . . . . . . . 67 2.9.4 Symptoms and Clinical Signs . . . . . . . 67 phoma, non-Hodgkin’s lymphoma, Ewing’s sarcoma, 2.9.5 Diagnostics . . . . . . . . . . . . . . . . . 68 osteosarcoma, hepatoblastoma, retinoblastoma, and 2.9.6 Staging and Classiﬁcation . . . . . . . . . 68 rhabdomyosarcoma. These and other less commonly 2.9.7 Treatment . . . . . . . . . . . . . . . . . . 69 occurring tumors will be reviewed in this chapter. 2.9.8 Prognosis . . . . . . . . . . . . . . . . . . 70 2.9.9 Follow-up . . . . . . . . . . . . . . . . . . 70 2.9.10 Future Perspectives . . . . . . . . . . . . . 70 2.10 Non-rhabdomyosarcomatous 2.1 Hodgkin’s Disease Soft Tissue Sarcomas . . . . . . . . . . . . . . . . 71 2.11 Germ Cell Tumors . . . . . . . . . . . . . . . . . . 73 Hodgkin’s disease (HD) is a malignant disease of the 2.11.1 Epidemiology . . . . . . . . . . . . . . . . 73 reticuloendothelial and lymphatic systems. It has a 2.11.2 Etiology . . . . . . . . . . . . . . . . . . . 73 2.11.3 Molecular Genetics . . . . . . . . . . . . . 73 predictable pattern of spread through contiguous 2.11.4 Symptoms and Clinical Signs . . . . . . . 73 nodes. It does occur, although rarely, in extralym- 2.11.5 Diagnostics . . . . . . . . . . . . . . . . . 74 phatic organs. 2.11.6 Staging and Classiﬁcation . . . . . . . . . 75 2.11.7 Treatment . . . . . . . . . . . . . . . . . . 75 2.11.8 Prognosis . . . . . . . . . . . . . . . . . . 76 2.1.1 Epidemiology 2.11.9 Follow-up . . . . . . . . . . . . . . . . . . 76 2.11.10 Future Perspectives . . . . . . . . . . . . . 77 HD comprises 5% of all pediatric malignancies. The 2.12 Rare Tumors . . . . . . . . . . . . . . . . . . . . . 77 overall incidence of HD each year is approximately 2.12.1 Adrenocortical Carcinoma (ACC) . . . . . 77 6.6 per million children under the age of 15, with a 2.12.2 Melanoma . . . . . . . . . . . . . . . . . . 77 peak in incidence in 14-year-olds of 23.1 per million. 2.12.3 Nasopharyngeal Carcinoma . . . . . . . . 78 2.12.4 Thyroid Carcinoma . . . . . . . . . . . . . 78 (Gurney et al., 1999). There tends to be a male pre- References . . . . . . . . . . . . . . . . . . . . . . . . . . 79 dominance in children less than 15, at which point Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . 82 the incidence becomes more equal between males and females. There is a characteristic bimodal distri- bution of age of onset that differs geographically. In industrialized nations, there is a peak incidence around the age of 20, followed by a second peak that occurs in the 50s. In developing countries, however, the ﬁrst peak occurs earlier into childhood. HD is rare in children less than 5 years of age.
46. Solid Tumors Chapter 2 272.1.2 Etiology mediastinal mass. Other systemic symptoms include pruritus, urticaria, and fatigue. Splenic enlargementIn general, HD tends to be diagnosed most frequent- may be observed with abdominal involvement, andly in patients with abnormal immune systems. There splenic disease is present in one-third of patients.has been a strong association noted between the de- Idiopathic thrombocytopenia purpura occurs invelopment of HD and previous Epstein-Barr virus 1–2% of children with HD and is often associated(EBV) infection, especially early and prolonged expo- with autoimmune hemolytic anemia (Hudson andsure. The virus has been noted in the Reed-Sternberg Donaldson, 2002).cells in 50% of HD patients (Hudson and Donaldson, HD typically spreads via lymphatics rather than2002); HD is characterized by the presence of Reed- hematogenous routes. Extralymphatic organs such asSternberg cells (see section 2.1.5). EBV has been as- the bone and bone marrow may be involved in ad-sociated with HD to varying degrees based on eth- vanced disease. Parenchymal lung lesions are alsonicity and is found in 93% of Asians, 86% of Hispan- sometimes present.ics, 46% of whites, and 17% of African-Americanchildren who are affected (Hudson and Donaldson, 2.1.5 Diagnostics2002). The role of HHV6 in disease development is also Physical examination will demonstrate the presencebeing investigated. HD has been noted with greater of any signiﬁcant lymphadenopathy. Although afrequency in patients with a family history of HD, chest x-ray can be performed quickly to determineataxia telangiectasia, or immunodeﬁciency syn- the presence of a mediastinal mass, computerized to-dromes such as human immunodeﬁciency virus mography (CT) of the neck, chest, abdomen, and(HIV). pelvis is necessary to evaluate the extent of disease. Nuclear imaging such as a gallium scan and, more re-2.1.3 Molecular Genetics cently, positron emission tomography (PET) scan- ning provides additional information on the extent ofCytogenetic abnormalities, often characteristic in disease and the response to treatment. Gallium posi-other tumors, are not diagnostic in HD. tivity is found in 70% of patients (Chauvenet et al., 2000). Gallium is taken up by underlying pathology,2.1.4 Symptoms and Clinical Signs predominantly malignancy; however, it can be taken up by infection and thrombosis as well. Bone scanHD usually presents with painless lymphadenopathy. should be done if clinically warranted; i.e., bone pain,On physical examination the lymph node is usually elevated alkaline phosphatase, or metastatic disease.described as ﬁrm and rubbery, and it may be sensi- Bilateral bone marrow aspirate and biopsies are nec-tive or painful if it has enlarged quickly. Eighty per- essary to rule out bone marrow involvement. A stag-cent of individuals present with disease in the cervi- ing surgical laparotomy is no longer routinely per-cal area, and 60% of those affected have some degree formed in pediatric patients.of mediastinal disease. Systemic symptoms are pres- A biopsy of the affected node is required for diag-ent in 25–30% of children and include nosis. An excisional biopsy is preferred because it preserves the architecture of the node and because▬ fever >38ºC for more than 3 days the sample must be large enough to locate the pres-▬ drenching night sweats ence of Reed-Sternberg cells. HD is characterized by▬ weight loss comprising 10% of body weight over a the presence of Reed-Sternberg cells, which are giant period of 6 months (Chauvenet et al., 2000) multinucleated cells with abundant cytoplasm, theRespiratory symptoms of cough or chest pain may be nucleolus having a characteristic “owl’s eye” appear-obvious if signiﬁcant mediastinal disease is present. ance. In most cases the Reed Sternberg cells are B-Superior vena cava syndrome can also occur due to a cells, and in 10–20% of cases, T-cells (Hudson and
47. 28 Chapter 2 E. Hendershot Table 2.1. Ann Arbor staging classiﬁcation for Hodgkin’s lymphoma (adapted from Pinkerton et al., 1999) Stage Characteristics I Involvement of a single lymph node region or a single extralymphatic organ or site II Involvement of two or more lymph node regions on the same side of the diaphragm or solitary involvement of an extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm III Involvement of lymph node regions on both sides of the diaphragm, which may be accompanied by localized involvement of extralymphatic organ or site or by involvement of the spleen, or both IV Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement “B” staging includes subjective symptoms such as fever, night sweats, and weight loss (10 % of body weight in previous 6 months) Pinkerton et al., 1999 Donaldson, 2002). Malignant cells comprise less than presents as localized disease. Lymphocyte-depleted 1% of tumor cells, with the remainder being inﬂam- HD occurs very rarely in children and is more com- matory inﬁltrates. Histopathological studies carried mon in HIV infection; it frequently presents as ad- out on Hodgkin’s tumors consist of hematoxylin, vanced disease involving bone or bone marrow eosin, and special immunohistochemical staining for (Hudson and Donaldson, 2002). surface markers, including CD15, CD20, and CD30. The Ann Arbor Staging Classiﬁcation System is Immunophenotyping of RS cells indicates expression generally used to stage disease (Table 2.1). of certain activation antigens, including the IL2 re- ceptor, Ki-1, the transferrin receptor, and HLA-DR 2.1.7 Treatment (Hudson and Donaldson, 2002). Blood work should include a complete/full blood The goal of treatment for children with HD has be- count (CBC) and differential; cytopenias may be seen come increasingly focused on response-based thera- with bone marrow disease. Liver and renal function py and on minimizing late effects. Chemotherapy and tests including alkaline phosphatase, should be done. radiation therapy are the cornerstones of treatment Elevations of the erythrocyte sedimentation rate in HD. Surgery is not used in HD treatment; its only (ESR), copper, and ferritin are often seen because of role is to obtain tissue biopsy. Children are at an in- increased activity of the reticuloendothelial system. creased risk for late secondary malignancies result- ing from having both chemotherapy and radiothera- 2.1.6 Staging and Classiﬁcation py at a time when they are still growing. For this rea- son, attempts to minimize treatment for those chil- HD includes four major subtypes: nodular scleros- dren who already do well based on stage and histol- ing, mixed cellularity, lymphocyte-predominant, and ogy are being trialed. lymphocyte-depleted. Nodular sclerosing (NS) is the Chemotherapy is an important part of the treat- most common subtype, occurring in 60% of patients; ment for HD. Nitrogen mustard was one of the ﬁrst disease is often found in the lower cervical, supra- drugs to be used for treating this disease, but due to clavicular, and mediastinal lymph nodes. Mixed cel- subsequently recognized signiﬁcant toxicities, specif- lularity occurs in 30% of patients, often in children ically a relatively high incidence of secondary malig- less than 10 years of age, those with advanced disease, nancies (predominantly acute myeloid leukemia) and those with extranodal involvement. Lympho- and infertility, it is no longer commonly used. Cur- cyte-predominant HD occurs in 10–15% of patients, rently treatment is being modiﬁed and efforts made is more common in males and younger children, and to avoid the use of alkylators and other drugs with
48. Solid Tumors Chapter 2 29signiﬁcant long-term sequelae. Drugs that are pre- 5 year overall survival is 99%, event-free survival isdominantly used in the treatment of HD include 93%, and there have been no toxicity concerns.mechlorethamine (M), vincristine (O), prednisone Schwartz describes a North American Pediatric On-(P), procarbazine (P), adriamycin (A), methotrexate cology Group (POG) trial for advanced disease (POG(MT) bleomycin (B), vinblastine (V), etoposide (E), 9425) in which the early responder received threedacarbazine (D), and cyclophosphamide (C). Drug courses of ABVE-PC versus ﬁve courses for the slowcombinations that have and are currently being used responders or partial responders, followed by radia-in the treatment of HD are MOPP-ABV; ABVD, tion therapy. The results show that the overall 2 yearCOPP-ABV, ABVE-PC, VEPA, BEACOPP, and VAMP. event-free survival is 88.2%, with 90.8% for early re- Radiation therapy also plays a vital role in treating sponders, which comprised 61% of the children, andHD. Involved ﬁeld radiation therapy includes the ar- 87.7% for slow responders, which represented 38% ofeas that are clinically involved as well as the sur- the children. Progressive disease was found in 1% ofrounding lymph nodes. This approach is being used children. These results suggest that tailoring therapymore commonly now in efforts to decrease the radia- has good outcomes in both cohorts of early and latetion ﬁeld, thereby decreasing late effects. Mantle responders but, by reducing treatment, may avoid lateradiation, involving a larger ﬁeld (submandibular, effects in those who respond early.submental, cervical, supraclavicular, infraclavicular, The treatment for relapsed patients usually con-axillary, mediastinal, and pulmonary hilar nodes), sists of high-dose chemotherapy followed by autolo-was typically used in previous protocols. In some gous stem cell transplant (ASCT). If radiation thera-instances of mantle radiation, the tumor volume may py has not been used in the initial treatment of thebe enlarged to include the cardiac silhouette or lung disease, it may have a role in the treatment of the re-ﬁelds as well. When pelvic radiation is needed, surgi- lapsed tumor.cal repositioning of the ovaries to a central midlineposition is possible, enabling a midline pelvic block 2.1.8 Prognosisto protect ovaries and minimize toxicity. Tailored therapy considers and evaluates early re- The overall survival of children and adolescents withsponse to therapy for the purpose of limiting the cu- HD is 90% (Schwartz, 2003). Adverse prognostic fea-mulative chemotherapy doses while maintaining efﬁ- tures include bulky disease, as deﬁned by a masscacy. Early responders continue to have improved greater than 10 cm (6 cm in children) in size, andoutcomes compared with slow responders. Schwartz large mediastinal adenopathy. Smith et al. (2003) de-(2003) describes a protocol using VEPA (vincristine, scribe a prognostic factor analysis as reported in twoetoposide, prednisone, adriamycin) that does not in- POG studies. They found that stage IV disease andclude any alkylators, which has been shown to be ef- the male gender showed an inferior event-free sur-fective for low-stage disease without radiation thera- vival. In Children’s Cancer Group (CCG) trials, theypy. Donaldson et al. (2002) also studied low-risk chil- found that elevated ESR, liver size, and mediastinaldren and adolescents with stage I, stage IIa, and IIb bulk among stage III patients was prognostic for in-without bulky mediastinal disease or peripheral ferior EFS. They also found that advance stage, bulkynodal disease. These patients were treated with four mediastinal disease, NS histology, and systemiccycles of VAMP (vincristine, adriamycin, methotrex- symptoms were prognostic for both inferior disease-ate and prednisone) followed by low-dose involved free survival and overall survival. Anemia and leuko-ﬁeld radiation. Those who had a complete response cytosis may also predict an inferior outcomeafter two cycles of VAMP were treated with 15 Gy ofinvolved ﬁeld radiation therapy, and those who hadonly a partial response to two cycles of VAMP re-ceived 22.5 Gy of radiation therapy. The mean follow-up for these patients has been 5–10 years, and the
49. 30 Chapter 2 E. Hendershot 2.1.9 Follow-up 2.1.10 Future Perspectives The follow up for HD must be long term, due to the Future trials for HD treatment will continue to focus many late effects that have affected this cohort of pa- on tailored disease protocols in an attempt to mini- tients. Most relapses occur within the ﬁrst 3 years off mize late effects while continuing to maintain and ex- therapy; however, relapse has been documented as ceed current excellent survival data. As more ad- long as 10 years post-treatment (Hudson and Don- vances are made, immunotherapy and vaccine and aldson, 2002). Disease should be followed with chest monoclonal antibody therapy may be of use in he x-ray and CT scanning of the primary site. Gallium treating HD in the future. Rituximab is being studied scans are sometimes used to follow those who are at now to determine its effectiveness at targeting lym- high risk for recurrence. PET may play a larger role in phocyte-predominant HD (Donaldson, 2003). this regard in the future as more centers gain access to PET scanners. Scans are often carried out every 3 months for the ﬁrst year off treatment, every 4 2.2 Non-Hodgkin’s Lymphoma months for the second, and then every 6 months up until 5 years, as per POG protocols. Blood work such Non-Hodgkin’s lymphomas (NHL) are a group of as CBC and differential, ESR, TSH, T4, LH, FSH, malignancies that are derived from cells of the im- testosterone, and estradiol must all be monitored. mune system and lymphoid tissue. They are an ag- Late effects of therapy must be monitored careful- gressive form of cancer characterized by rapid cell di- ly. Thyroid dysfunction in the form of nodules, hy- vision and an often high tumor burden at diagnosis. pothyroidism, and hyperthyroidism occur more fre- quently in patients who have been treated with radi- 2.2.1 Epidemiology ation therapy as compared with the general popula- tion. The incidence of hypothyroidism is four to ﬁve Lymphomas in general account for about 12% of all times higher in patients treated with radiation thera- childhood malignancies and are the third most com- py for HD compared with the general population mon type of childhood cancer (Sandlund et al., 1996). (Sklar et al. 2000). Thyroid problems usually present NHL accounts for 60% of lymphomas; it occurs at an within the ﬁrst 5 years post-therapy but can occur incidence of approximately 8.4 per million children until 20 years post-therapy. TSH and T4 must there- under the age of 20 per year (Gurney et al. 1995). fore be monitored. Echocardiogram and pulmonary Males are affected twice as often as females, and function tests must be done to monitor for late car- whites twice as often compared with blacks in the diomyopathies and pulmonary ﬁbrosis, secondary to United States. Burkitt’s lymphoma, an NHL subtype, anthracycline and bleomycin, respectively (with or is endemic in equatorial Africa and accounts for ap- without radiation). The risks of secondary tumors at proximately 50% of all childhood cancers. In other various sites can occur in the two to three decades areas of the world, Burkitt’s lymphoma occurs spo- following treatment (Metayer et al., 2000). Patients radically and is less common. treated for HD have the highest incidence of second malignancies of all of the pediatric malignancies. In- 2.2.2 Etiology fertility and primary ovarian failure can occur fol- lowing chemotherapy and pelvic irradiation. Coun- There are different etiologies of NHL depending on seling must be done regarding lifestyle behaviors geographical location. It has become apparent that such as smoking. individuals who are immunocompromised are at a higher risk of developing NHL, including those who are HIV infected and those who have undergone bone marrow transplant. EBV has been implicated in most of these lymphomas. Those individuals who
50. Solid Tumors Chapter 2 31Table 2.2. Summary of major histological categories, immunophenotypes, common cytogenetic abnormalities, and commonsites of disease of non-Hodgkin’s lymphomas ((Magrath, 2002; Cairo and Perkins, 2000)) Histological category Immunophenotype Cytogenetic Common sites of of lymphoma abnormalities disease Burkitt’s B-cell (CD 19, CD 20, CD22, CD79, t(8;14), t(8;2) and Abdomen, head, neck CD77, CD10) t(8;22) Large B-cell B-cell (CD19, CD20, CD22, CD38, Bcl-6 or bcl-2 t(8;14) Abdomen, CD79, sometimes CD10) TdT neg in 5–10 % mediastinum Burkitt’s-like B-cell (MIB-1 positivity) t(8;14) Abdomen, head, neck Lymphoblastic Pre-T (CD77, CD7, CD5, CD2,CD1, T-cell t(11;14) Thorax CD3, CD4, CD8, TdT pos) CALLA sometimes observed t(7;14), t(8;14), Lymph nodes, bone t(10;14) marrow Pre-B (CALLA, B4, HLA-DR) B-cell t(1;19), t(4;11) Anaplastic large cell T-cell or null (CD 30) t(2;5), and variants Lymph nodes, skin, Ki-1+ soft tissue, CNS, intrathoracic Peripheral T-cell lymphoma T-cell Unknown Variablehave been previously treated for HD are also at an in- ▬ Head and neck: 30%creased risk for developing NHL due to cumulative ▬ Abdominal: 30%effects of treatment; the risk is increased further if ▬ Intrathoracic, mediastinal, or hilar adenopathy:the individual has had a splenectomy. In African 25% (Cairo and Perkins, 2000)Burkitt’s lymphoma, there is a very high correlationwith those who have been previously infected with Localized disease can present as a ﬁrm, nontenderboth EBV and malaria. In the developed world there mass in virtually any location.has been no clear etiology for the development of Advanced metastatic disease is present in 70% ofNHL. children who present with NHL (Cairo and Perkins, 2000).Table 2.3 indicates various presentations of NHL.2.2.3 Molecular Genetics 2.2.5 DiagnosticsCytogenetic abnormalities are commonly found inNHL and assist in their diagnosis. A summary of A thorough history, physical exam, radiologic imag-the major histological categories of NHL with their ing, and tumor biopsy are needed to diagnose NHL.associated cytogenetic abnormalities is shown in NHL is a rapidly growing tumor and often createsTable 2.2. major metabolic disturbances that can be life-threat- ening. Frequent blood work for biochemistry abnor-2.2.4 Symptoms and Clinical Signs malities is a necessity while monitoring for signs of tumor lysis syndrome.Like many tumors, the presenting signs and symp- The sequence of investigations usually depends ontoms of NHL vary greatly depending on tumor loca- the location of the primary tumor. Table 2.4 showstion. NHL usually presents as extranodal disease in the possible investigations that may be carried outchildren. The primary presentations are as follows: when a diagnosis of NHL is suspected.
51. 32 Chapter 2 E. Hendershot Table 2.3. Presentations of non-Hodgkin’s lymphoma Features Signs and symptoms Indication Meningoencephalitis Headache CNS disease found commonly in Burkitt’s Cranial nerve palsies lymphoma Altered level of consciousness Waldeyer’s ring involvement Tonsillar hypertrophy Burkitt’s lymphoma Jaw lesion Swelling Endemic Burkitt’s Pain Systemic features Fever Anaplastic large cell lymphoma Weight loss Night sweats Anorexia Malaise Mediastinal mass Persistent nonproductive cough Intrathoracic disease, common in T-cell Dysphagia lymphoblastic lymphoma Dyspnea Chest pain Superior vena cava syndrome Swelling of the upper extremities Intrathoracic lesion Distended neck veins Common in T-cell lymphoblastic lymphoma Decreased breath sounds Dyspnea or stridor due to mass pressing on internal structures, pericardial effusion Acute abdomen Abdominal distension Abdominal lymphoma Pain B-cell Rebound tenderness (Intussusception is not an uncommon Shifting dullness presentation for abdominal Burkitt’s lymphoma) Nausea Vomiting GI bleeding Change in bowel habits Intussusception Bone pain Local pain Bony disease, can occur in large cell lymphomas, Swelling lymphoblastic lymphomas, and Burkitt’s Skin involvement Painful lesions Particularly anaplastic large-cell lymphoma Testicular involvement Pain Localized anaplastic large-cell lymphoma or Swelling lymphoblastic lymphoma. Pancytopenia Infection Metastatic disease – bone marrow Fatigue Lymphoblastic lymphoma or Burkitt’s Bleeding lymphoma common
52. Solid Tumors Chapter 2 33Table 2.4. Possible investigations in the diagnosis of non-Hodgkin’s lymphoma Investigation Rationale Chest x-ray To detect mediastinal mass and pulmonary lesions CT of the neck, chest, For staging and evaluating all sites of potential disease (tracheal compression would also be abdomen, pelvis noted on the CT and is critical to recognize before administering general anesthetics) CT of the head To detect CNS involvement Ultrasound of the abdomen To determine if there are abdominal masses and to ensure patency of the urinary tract system before beginning chemotherapy Bone scan and skeletal To detect bone metastases survey Gallium scan Often lymphomas show avidity for gallium, and scanning after it is administered outlines tumor throughout the body Also used to assess response to treatment PET scan As PET scans become more accessible, they will likely be used in the diagnostic workup and monitoring of patients with NHL Endoscopy Indicated if gastrointestinal bleeding is a presenting symptom Complete/full blood If cytopenias are present, bone marrow involvement is likely count and differential Renal function tests Abnormalities may suggest tumor lysis Liver function studies Baseline prior to treatment Lactate dehydrogenase Nonspeciﬁc but can be elevated in NHL, possibly indicating a high tumor burden (LDH) Blood cultures If fever present Coagulation studies such To evaluate possible disseminated intravascular coagulation as PTT, INR, ﬁbrinogen, d-dimers Viral studies for EBV, CMV, To look for evidence of causation (HIV testing should be considered in a patient with a HSV, hepatitis A, B, and C primary CNS lymphoma because of the high incidence of CNS lymphomas in the HIV population) B- and T-cell function tests If an underlying immunodeﬁciency is being considered Bilateral bone marrow If the bone marrow has greater than 25 % blasts, the lymphoma would be treated as a aspirates and biopsies leukemia based on the cellular phenotype of either B or T lineage (Pinkerton et al., 1999) Lumbar puncture To examine the cerebrospinal ﬂuid for malignant cells A biopsy of the node or mass is necessary to make of leukocyte common antigen CD45 will conﬁrma deﬁnitive diagnosis. NHLs are in the class of blue lymphoid cell proliferation as it is not present in non-round cell tumors. They are differentiated from other hematologic malignancies (Magrath, 2002). Seeblue round cell tumors based on immunophenotyp- Table 2.2 to view a summary of immunophenotypinging, karyotyping, southern blotting, polymerase and cytogenetic differences in the various subtypeschain reaction (PCR), and microarray. The presence of NHL.
53. 34 Chapter 2 E. Hendershot Table 2.5. St Jude staging systems for childhood non-Hodgkin’s lymphoma (adapted from Pinkerton et al., 1999) Stage I Single tumor (extranodal) or single anatomic area (nodal) with the exclusion of mediastinum or abdomen Stage II Single tumor (extranodal) with regional lymph nodes Two or more nodal areas on the same side of diaphragm Two single tumors (extranodal) with or without regional lymph node A resectable primary GI tumor with or without involvement of mesenteric nodes only Stage III Two single tumors (extranodal) above and below the diaphragm Two or more nodal areas above and below the diaphragm All primary intrathoracic tumors All extensive primary intra-abdominal disease All paraspinal or epidural tumors Stage IV Any of the above with the initial involvement of either the central nervous system and/or the bone marrow (<25 %) Pinkerton et al., 1999 Table 2.6. Non-Hodgkin’s lymphoma incidence according to subtype and cell of origin (adapted from Pinkerton et al., 1999) Cell type Subgroup Proportion of NHL (%) B-Cell I. Precursor B neoplasm B lymphoblastic 5% II. Peripheral B neoplasm Follicular 0.4 % Diffuse large B cell 3% Primary mediastinal 0.4 % Burkitt’s 42 % High-grade Burkitt’s and Burkitt’s-like 4% T-Cell I. Precursor T neoplasm T lymphoblastic 20 % II. Peripheral T-cell PTL unspeciﬁed 1% Anaplastic large cell 15 % Nonspeciﬁc/intermediate 9.2 % Pinkerton et al., 1999 2.2.6 Staging and Classiﬁcation Staging normally follows the St Jude Children’s Re- search Hospital schema, which was based on the Ann The classiﬁcations of childhood NHL are divided into Arbor Hodgkin’s classiﬁcation (see Table 2.5). This three main categories: staging and classiﬁcation system is used for all histo- logic subtypes of NHL. Incidence can also be deﬁned ▬ Lymphoblastic (30%) by the B-cell or T-cell lineage of the tumor (Table 2.6). ▬ Large cell (20%) The National Cancer Institute has provided break- ▬ Small noncleaved cell, Burkitt’s or Burkitt’s like downs of the incidence in which the various forms of (40%). lymphoma can present (Table 2.6).
54. Solid Tumors Chapter 2 352.2.7 Treatment chemotherapeutic agents are used throughout the treatment course (see Table 2.7).Treatment for NHL depends on the histologic sub- Small noncleaved cell lymphomas are B-cell lym-type and stage of disease. Most protocols now assign phomas and have much shorter treatments. Treat-patients to risk groups in order to determine intensi- ment consists of two to six cycles of intense chemo-ty of treatment. Surgery is primarily used for diagno- therapy with no maintenance therapy. Large B-cellsis and staging of NHL, with the exception of abdom- lymphomas are generally treated as per the smallinal tumors. Radiation therapy is not generally used noncleaved cell lymphomas protocols as well. (Seein treating these tumors except in emergency situa- Table 2.7.)tions. NHL is primarily treated with chemotherapy. Anaplastic large-cell lymphomas have been treat-Emergent complications arise quite often in the treat- ed by a variety of approaches. Some of the best resultsment of NHL based on the tumor’s location and size, have been from the German BFM group, who haveand therefore must be anticipated, diagnosed, and used B-cell lymphoma protocols without local radia-treated rapidly. tion therapy. (See Table 2.7.) Debulking surgery has demonstrated no beneﬁt to CNS prophylaxis is a necessary part of NHL treat-effective chemotherapy (Patte, 1997). Most abdomi- ment for most patients. Patients who have complete-nal lymphomas are the B-cell immunophenotype, ly resected abdominal primaries, or stage I diseaseand presentation often mimics an acute abdomen. that is not in close proximity to the CNS, normally doBowel obstruction or intussusception can also occur. not require CNS prophylaxis. Generally, all others areIn these cases, gross total excision of the primary is treated with varying degrees of CNS prophylaxis thatwarranted, followed by adjuvant chemotherapy (Pat- consists of intrathecal methotrexate and/or intrathe-te,1997). cal cytarabine (Magrath, 2002). Radiation therapy is not generally a part of NHL Autologous stem cell transplant is often used forprotocols. It is used in the urgent treatment of supe- only partial response to therapy in B-cell lym-rior vena cava obstruction and for central nervous phomas. Allogeneic transplant is indicated for T-cellsystem (CNS) involvement causing nerve palsies. relapses after response to salvage therapies has beenProphylactic radiation has generally been shown to determined. In anaplastic large-cell lymphoma, re-have no advantage in active CNS or limited-stage dis- lapse therapy using retinoic acid and interferon hasease and is not used in multiagent chemotherapy reg- been used with some effect at maintaining long re-imens (Cairo and Perkins, 2000). missions (Magrath, 2002). Chemotherapy regimens are based on the im- Treatment and tumor complications can occurmunophenotype of the lymphoma (B- versus T-cell). emergently and must be anticipated. Tumor lysis syn-In general, T-cell lymphomas receive longer and less drome is seen frequently in NHL and speciﬁcally inintense treatments, and B-cell lymphomas are treated Burkitt’s and Burkitt’s-like lymphoma because offor shorter periods but with higher doses of alkylat- their rapid doubling times. Other complications in-ing agents and antimetabolites. NHLs are sensitive to clude respiratory distress, abdominal emergencies,a variety of chemotherapeutic agents, probably due superior vena cava syndrome, esophageal compres-to the aggressive nature of the disease with its rapid sion, cardiac tamponade, paraplegia, increased in-doubling time and high growth fractions. tracranial pressure, obstructive jaundice, pancreati- Lymphoblastic lymphomas are most often treated tis, renal failure, and infection. The treatment of theseon protocols similar to leukemia protocols. Treat- complications is discussed further in other sections.ment involves three phases, induction, consolidation,and maintenance, and generally lasts 2–3 years. Pa-tients are usually not divided into risk groups be-cause most patients have advanced disease. Multiple
55. 36 Chapter 2 E. Hendershot Table 2.7. Treatment summaries for non-Hodgkin’s lymphoma (from Cairo and Perkins, 2000; reprinted with permission) Stage and histology Chemotherapy Cooperative Length of % Survival regimen group therapy (3–5 years) Stages I and II (St Jude) COPADA SFOP 6 weeks 95 or Group A (FAB) B large or SNCCL COMP CCG 6 months 85 Lymphoblastic CHOP BFM 8 weeks 90 COMP BFM-NHL Stages III and IV or Group B and C SNCCL LMB-89 SFOP 6 months 80–90 Orange CCG 8 months 70–80 NCI-89-C-41 NCI 6 months 70–80 Total-B POG 4 months 60–70 BFM-NHL BFM 4 months 60–80 Lymphoblastic (AD)COMP CCG 18–24 months 70 LSA-L2 CCG/POG 18–24 months 70 BFM-NHL BFM 18–24 months 90 Large Cell COMP (D) CCG 18–24 months 60–70 B cell APO(+) POG 18 months 60–70 LMB-89 SFOP 4–6 months 90 ORANGE CCG 4–6 months 90 BFM-NHL BFM 4–6 months 70–80 NCI-89-C-41 NCI 4–6 months 80–90 Anaplastic CHOP/MACOOP-B ST JUDE’S 6 months 75 BFM-NHL-B BFM 6 months 80 HM 89–91 SFOP 6–8 months 60–70 2.2.8 Prognosis 2.2.9 Follow-up The event-free survival for all stages of NHL ranges Follow-up for children treated for NHL needs to con- widely. The overall survival following the treatment sider surveillance for disease recurrence and late ef- of Burkitt’s, Burkitt’s-like, and large B-cell lym- fects of treatment. Most relapses of Burkitt’s lym- phoma, including advanced stage disease, is 90% phoma occur with 12 months. If children with lym- (Magrath, 2002). For lymphoblastic lymphoma and phoblastic lymphoma has not relapsed 30 months anaplastic large cell lymphoma, the overall survival is from the start of treatment, they have a very high 80–90%. Children treated for T-cell acute lym- probability of cure (Magrath, 2002). phoblastic leukemia as per the BFM Rez protocol Surveillance scans of the primary tumor can be have displayed an event-free survival of 92% (Ma- done using CT or ultrasound, depending on the tu- grath, 2002). mor’s location. These should be carried out every 3 months for the ﬁrst year off treatment and then with decreasing frequency over several years. Gallium or PET scans are very helpful in the surveillance for NHL recurrence and can be done on a similar sched-
56. Solid Tumors Chapter 2 37ule to primary tumor imaging. CBCs are necessary,especially in lymphoblastic lymphomas, to look for 2.3 Ewing’s Sarcoma Family of Tumorsrecurrence of bone marrow disease, which is charac-terized by blasts in the peripheral smear. Ewing’s sarcoma family of tumors (ESFT) comprises Late effects of chemotherapy for NHL include a a group of neoplasms that can arise in bone and softvariety of potential problems because so many differ- tissue and that share similar histologic and molecu-ent chemotherapeutic agents are used. Cardiotoxicity lar features. These tumors include Ewing’s sarcoma,from anthracycline therapy is a potential; follow-up extraosseous Ewing’s sarcoma, peripheral primitiveechocardiograms should be routinely done at least neuroectodermal tumor (PPNET), and Askin tumorevery 2–4 years in the absence of problems. Appro- (a chest wall tumor). Ewing’s sarcoma is the morepriate attention needs to be paid to growth and de- undifferentiated form of the tumor, whereas PPNETvelopment; for unknown reasons a signiﬁcant group is more differentiated. ESFTs are thought to deriveof children treated for NHL go on to become obese. from neural crest cells.Children who have been treated with signiﬁcantamounts of intrathecal chemotherapy may be at 2.3.1 Epidemiologymore risk for learning problems. Neuropsychologicaltesting may be appropriate so that speciﬁc help can ESFT is the second most frequently seen primary ma-be given to these children. Secondary malignancies lignant bone tumor in childhood and represents 3%are always a concern following treatment with VP16 of all pediatric malignancies (Venkateswaran et al.,and alkylating agents, so surveillance is paramount. 2001). The incidence is approximately 2.8 per millionSkeletal sequelae are a potential following the use of annually in individuals less than 20 years of age. ESFThigh-dose steroids. Osteoporosis is a concern, as is occurs most often in the second decade of life, withavascular necrosis; no speciﬁc follow-up is required the highest age-speciﬁc rates occurring at 13 years offor this, but awareness is crucial. Infertility and go- age (Gurney et al., 1995). ESFT is extremely rare in in-nadal dysfunction may be a problem following treat- dividuals over the age of 30 and in Chinese and blackment with alkylating agents. children. There is a slight male dominance in the in- cidence of this tumor.2.2.10 Future Perspectives 2.3.2 EtiologyNewer techniques such as microarray analysis mightbe useful in determining the exact rate of response to The cause for ESFT is not known. There does not ap-therapy. Examining gene expression patterns and pear to be strong associations with congenital syn-proteomic analysis may help to determine therapy dromes or familial cancer syndromes.response rate so that the appropriate intensity oftherapy can be given for each histological subtype of 2.3.3 Molecular Geneticslymphoma. Targeting viral proteins in Burkitt’s lym-phoma is one area of research; it is hoped that a mod- ESFTs are in the group of small blue round cell tu-iﬁed Myc gene may be able to induce tumor lysis of mors. Molecular genetics is invaluable in helping tothese cells. There are thoughts also that the antisense distinguish ESFT from other small blue round cellcould cause cell death in DNA sequences involving tumors. Fluorescence in situ hybridization (FISH)the (8;14) translocation if targeted appropriately. and reverse transcriptase polymerase chain reaction (RTPCR) are used to detect cytogenetic changes in the tumor for diagnostic purposes. Immunocyto- chemical staining also helps in this differentiation.
57. 38 Chapter 2 E. Hendershot ESFTs display a characteristic t(11;22) (q24;q12) cough, dyspnea, unequal breath sounds, and rales, that fuses the EWS and the FLI1 gene; this genetic may indicate large pulmonary metastases. translocation is found in most tumors (Pinkerton et al. 1999). A second chromosomal translocation con- 2.3.5 Diagnostics sists of a t(21;22)(q22;q12), which fuses the EWS and the ERG gene (Ginsberg et al., 2002). Less frequently A plain ﬁlm of the affected area is usually the ﬁrst di- observed changes involve trisomy 8 and 2 and dele- agnostic test ordered. On x-ray, ESFT will show up as tions of chromosome 22, 16q, and 1p36 (Ginsberg et a destructive lesion of the diaphysis of the bone that al., 2002). These aberrations are though to cause dys- is poorly marginated. It may also have an onion peel function in tumor suppressor genes, and their pres- characteristic, which is indicative of a periosteal re- ence might be prognostic of poor outcome. action. CT or magnetic resonance imaging (MRI) of the primary should be performed to achieve better 2.3.4 Symptoms and Clinical Signs delineation of the soft tissue component of the tumor as well as examine its blood supply and tumor exten- ESFT can occur in both long and ﬂat bones. The inci- sion. Chest x-ray should be done to look for lung dence anatomically is split almost in half, with tu- metastases; however, a CT of the chest is needed to mors arising in extremities (53%) and the central look for smaller pulmonary nodules. Fig. 2.1 shows axis (47%). the CT of a patient with Askin tumor (chest wall In the central axis mass). A bone scan is indicated to look for bony metastases. Fig. 2.2 shows a metastatic PNET on bone ▬ 45% occur in the pelvis scan. Bilateral bone marrow aspirates and biopsies ▬ 34% occur in the chest wall are necessary to rule out bone marrow disease. ▬ 12% in the spine A biopsy is indicated to determine deﬁnitive diag- ▬ 9% in the head and neck. nosis. Tumor histology may be undifferentiated or In the extremities: differentiated showing Homer-Wright rosettes. The tumor specimen should be evaluated with routine ▬ 52% of tumors are found in distal bones staining and immunohistochemistry. Adrenergic, ▬ 48% in proximal bones muscle, and lymphoid markers should be negative, (Ginsberg et al., 2002) and the tumor should stain positive for CD99 and vi- Children typically present with symptoms caused by mentin (Ginsberg et al. 2002). Cytogenetic studies the primary tumor. Pain and swelling are often pres- and RTPCR should be ordered to look for the charac- ent. A palpable mass is frequently seen, and fractures teristic t(11;22). are evident in 5% of cases (Jurgens et al., 1997). It is There are no deﬁnitive blood tumor markers for not uncommon for a child to present after a pro- the ESFT; however, an elevated lactate dehydrogenase longed history of increasing pain or mass or after a (LDH) may indicate a large tumor burden or rapid traumatic injury that does not heal. Neurological im- tumor growth. Elevated LDH has also been associat- pairments or weakness may accompany spinal le- ed with a less favorable outcome. An elevated white sions. Urinary and bowel incontinence may accom- blood cell count or ESR can also be seen at times with pany large pelvic tumors. advanced disease. Twenty percent of patients have metastatic disease at diagnosis (Ginsberg et al. 2002). Metastases usual- 2.3.6 Staging and Classiﬁcation ly follow a hematogenous route, spreading to lungs, bone, and bone marrow. Fever may indicate systemic There is not an elaborate staging system for the ESFT. or advanced disease. Infections, bleeding, and lethar- The tumor is described in terms of the presence or gy may reﬂect pancytopenia suggesting bone mar- absence of metastases. row involvement. Respiratory symptoms, such as
58. Solid Tumors Chapter 2 39Figure 2.1CT of a patient with Askin tumor(chest wall mass) 2.3.7 Treatment The goals of treatment for the ESFT are threefold: ▬ Cure the disease ▬ Preserve useful function in affected area ▬ Minimize the long-term sequelae Chemotherapy, radiation therapy, and surgery may all be used in treating this malignancy. Chemo- therapy is delivered initially in order to shrink the tu- mor. Surgery or radiation therapy is then used to es- tablish local control. This is then followed by a main- tenance period of chemotherapy. Treatment for ESFT generally lasts up to a year. Chemotherapy is initially used for cytoreduction in the treatment of the ESFT. After local control has been established, chemotherapy is given to treat mi- crometastatic disease that may have occurred at the time of surgery or local control. Common chemo- therapeutic agents are vincristine, actinomycin, or doxorubicin and cyclophosphamide, alternating with VP16 and ifosfamide. Growth factors such as granu-Figure 2.2 locyte colony-stimulating factor (GCSF) are oftenMetastatic PNET on bone scan used following chemotherapy to hasten white blood cell recovery.
59. 40 Chapter 2 E. Hendershot Surgery is the preferred method of establishing lo- the feasibility of surgical resection. Tumors of the cal control. It is used most often in local control for pelvis are often associated with poor response. Five- tumors of the extremities The entire bony or soft tis- year disease-free survival rates range from 70–75% sue lesion needs to be excised using initial imaging (Rodriguez-Galindo et al., 2002a). If metastases are studies ensuring a disease-free margin of approxi- present at diagnosis, the 2-year disease-free survival mately 3 cm. Margins of 2 cm are generally acceptable is less than 30% (Hawkins et al., 2002). Prognosis fol- if is near a joint articulation (Ginsberg et al., 2002). lowing relapse is poor, with long-term survival less Gross or microscopic disease postoperatively is treat- than 25% (Rodriguez-Galindo et al., 2002a). Some ed with radiation therapy. children do better with late or local recurrence. Lung Local control following the use of radiation thera- metastases tend to respond to treatment more than py along with systemic chemotherapy delivers a cure metastatic disease elsewhere in the body. rate of 75–90%. Radiation therapy is often the only The tumor volume, LDH result, and the amount of option that is available for tumors of the central axis, tumor necrosis at the time of surgery are thought to in which radical surgery in not feasible. A total tumor be of prognostic signiﬁcance; however, current treat- dose of 55–60 Gy is delivered to the whole bony lesion ment decisions are not usually based on these crite- with a 3 cm margin (a smaller margin is used if it ria. The subtype of fusion gene is also prognostic, avoids radiating an epiphysis); the original imaging with EWS-FLI1 favoring a better outcome than other studies are used to make this determination (Gins- genetic abnormalities. A retrospective study carried berg et al., 2002). out by Jenkin and colleagues (2002) that looked to de- Metastases are treated with surgery and/or radia- termine prognostic factors in localized Ewing’s sar- tion therapy, depending on the location of the tu- coma and PNET of bone found that age less than or mors. In the lungs, both surgical resection and radia- equal to 14, with the primary in a distal extremity or tion therapy can be effectively used, depending on the skull, and tumor volume <200 ml were associated tumor location. Dose intensiﬁcation regimens for with a favorable prognosis. The amount of neural dif- metastatic disease using standard chemotherapy ferentiation did not appear to have a prognostic sig- with VACIME (vincristine, adriamycin, cyclophos- niﬁcance. phamide, ifosfamide, mesna, etoposide) plus periph- eral blood stem cell support and GCSF have been at- 2.3.9 Follow-up tempted with no real increase to disease-free survival (Hawkins et al., 2002). Future Children’s Oncology Follow-up requires focus on both recurrent disease Group (COG) protocols are currently considering the and late effects of treatment. Recurrent disease is at use of antiangiogenic therapies with vinblastine and greatest risk in the ﬁrst 5 years following treatment Celebrex in conjunction with standard chemothera- for ESFT. Protocols usually request imaging studies py therapy for metastatic disease at diagnosis.Angio- including CT or MRI of the primary, CT of the chest, genesis is a process by which tumors form new blood and sometimes bone scan to be done every 3 months vessels; the purpose of antiangiogenic therapies is to following therapy for the ﬁrst year and then with de- target the factors that contribute to the development creasing frequency over the next several years. of new blood vessels, inhibiting or antagonizing them Late effects of therapy must also be considered in in order to arrest or prevent tumor growth. the follow-up of these patients. Children are at risk of developing a secondary neoplasm such as a myeloid 2.3.8 Prognosis leukemia (related to the administration of alkylating agents) or a solid tumor in a previously irradiated Prognosis for the ESFT depends largely on the loca- site. The incidence of secondary malignancies in this tion of the tumor and the presence of metastases at group has been reported between 5% and 20% fol- diagnosis. Cutaneous, subcutaneous, distal bone, and lowing a period of observation of 20 years (Jurgens et rib tumors tend to have higher cure rates because of al., 1997). Cardiomyopathy or congestive heart failure
60. Solid Tumors Chapter 2 41can occur following anthracycline therapy; therefore, spurt in adolescence. There are several associationscardiac function should be monitored with echocar- between osteosarcoma and other pathologies. It isdiograms. Toxicities to the liver, kidney, nervous sys- known that osteosarcomas can be caused by ionizingtem, and endocrine system must be considered and radiation, and this is implicated in 3% of osteosarco-any symptoms investigated accordingly. mas (Link et al., 2002). It has also been found that os- teosarcoma can arise in patients with hereditary mul-2.3.10 Future Perspectives tiple exostoses, Paget’s disease, ﬁbrous dysplasia, chronic osteomyelitis, multiple osteochondroma, andFuture therapies may involve targeting cytostatic sites of bone infarcts. A genetic predisposition hasagents or be immunologically targeted therapies. been found between hereditary retinoblastoma (Rb)Monoclonal antibody therapies are also currently be- and osteosarcoma. The Rb gene is a tumor-suppres-ing researched. The French group is advocating that sor gene and important in apoptosis. It has been esti-future studies be tailored to account for prognostic mated that between 8% and 90% of carriers of thefeatures such as histological response to chemother- Rb1 mutation will acquire a secondary malignancy,apy (percent of tumor necrosis) and tumor volume including osteosarcoma by the age of 30 (Link et al.,(Oberlin et al., 2001). Topotecan plus cyclophos- 2002). The Rb1 mutation has also been implicated inphamide shows promise in 35% of recurrent ESFTs the pathogenesis of sporadic osteosarcoma. Muta-and may continue to play a role in the future (Saylors tions of p53 have also been found in osteosarcoma,et al., 1999). suggesting that inactivation of p53, which is a tumor- suppressor gene, plays a key role in the development of osteosarcoma. There is a higher incidence of os-2.4 Osteosarcoma teosarcoma in Li-Fraumeni syndrome.Osteosarcoma is a primary bone tumor that is 2.4.3 Molecular Geneticsthought to arise from mesenchymal bone-formingcells. It is characterized by the production of osteoid. The diagnosis of osteosarcoma is primarily based on tumor histology. Although there is not a speciﬁc cy-2.4.1 Epidemiology togenetic or molecular maker for osteosarcoma, there is a great deal of research in the area of geneticsOsteosarcoma is the third most common solid tumor that is focusing on better understanding of the dis-of children and adolescents and the most frequently ease and determining prognostic criteria.occurring primary bone tumor in this population It is well known that a relationship exists between(Wittig et al., 2002). The peak incidence of osteosar- osteosarcoma and the Rb1 gene mutation as well ascoma is in the second decade of life, a period charac- p53 mutations. Loss of heterozygosity at the Rb geneterized by rapid bone growth. It occurs at an annual occurs in 70% of sporadic osteosarcomas, and loss ofrate of approximately 3 per million children less than heterozygosity at the Rb locus is thought to be a poor15 years of age (Gurney et al., 1995). The incidence is prognostic factor (Ragland et al., 2002). Many otherslightly higher in African-Americans than whites and genetic abnormalities continue to be examined to de-in males than females. termine their role in the disease. C-Myc is expressed more often in those with osteosarcoma who develop2.4.2 Etiology metastatic disease. HER2/neu (human epidermal growth factor receptor 2) is expressed in approxi-The etiology of osteosarcoma is largely unknown. mately 40% of patients who develop early pulmonaryThere appears to be an association between rapid metastases. Important discoveries are starting to bebone growth and the development of osteosarcoma, made in identifying the signiﬁcance of these abnor-as evidenced by its high incidence during the growth malities.
61. 42 Chapter 2 E. Hendershot 2.4.4 Signs and Symptoms Osteosarcoma commonly affects the metaphyseal growth plates of long bones. Although osteosarcoma can occur in any bone, the anatomic sites most com- monly affected are the distal femur, the proximal tib- ia, and the proximal humerus. Osteosarcoma metas- tasizes most frequently to the lung, followed by bone. Gross metastatic disease is present at diagnosis in less than 20% of cases (Kager et al., 2003). Osteosarcoma typically presents with pain and/or soft tissue swelling in the affected area. The mass it- self may be warm, and vascularity over the mass may be found. There is often decreased range of motion in the affected limb. The duration of symptoms prior to diagnosis may range up to 6 months. Respiratory symptoms at diagnosis would only be present in very advanced pulmonary disease and are rare. Systemic symptoms of disease, such as fever and night sweats, are uncommon. Lymphadenopathy in proximal lymph nodes is also very rare. 2.4.5 Diagnostics The workup up of a patient who presents with pain and/or swelling should start with a thorough health history paying special attention to any pain and the duration of the symptoms. Diagnostic imaging, blood tests and tumor biopsy are all needed. Figure 2.3 Plain ﬁlms of the affected area may reveal a lytic Plain ﬁlm of patient with osteosarcoma lesion with indistinct margins or ossiﬁcation in soft tissue with a sunburst pattern that is characteristic of osteosarcoma (see Fig. 2.3). Reactive new bone for- mation can also be seen frequently under the perios- teum forming a “Codman’s angle” or “Codman’s tri- There are no speciﬁc blood tumor markers for os- angle” (Ragland et al., 2002). An MRI of the affected teosarcoma. Elevations of LDH are seen in up to 30% area would further examine the tumor boundaries, of patients at diagnosis (Link et al., 2002). However, the soft tissue component, and the relationship to LDH is an acute phase reactant and is not tumor-spe- joints, blood vessels, and neurovascular bundle. A ciﬁc. Elevations of alkaline phosphatase are present chest x-ray determines the presence of pulmonary in over half of patients, but again do not correlate re- metastases, but CT is more sensitive for smaller pul- liably with disease. Abnormalities cannot necessarily monary nodules. A bone scan should also be per- be distinguished between bone and liver etiologies, formed to pick up areas of skeletal metastases. Bony but experience has shown that they may have a poor metastases occur in 10% of patients with osteosarco- prognostic signiﬁcance. ma at diagnosis (Link et al., 2002).
62. Solid Tumors Chapter 2 43Table 2.8. Enneking system for staging osteosarcomas cally. Chemotherapy agents that are sensitive to os- teosarcoma are doxorubicin, cisplatin, and high-dose Grade 1 Low-grade osteosarcoma methotrexate. Agents such as cyclophosphamide, Grade 2 High-grade osteosarcoma ifosfamide, and VP16 have also shown to be useful. Typically, chemotherapy is given for 2–3 months pri- Grade 3 Osteosarcoma with distant metastases or to local surgical control. Dose intensiﬁcation regi- A Intracompartmental mens have become possible with the use of GCSF B Extracompartmental post-myelosuppressive chemotherapy cycles. Local control consists of three options: 1. Amputation: Amputation is usually reserved for A biopsy is necessary for obtaining deﬁnitive diag- tumors that cannot be removed with adequate sur-nosis. Open biopsy is preferred so that contamination gical margins. It is also frequently used in large tu-of skin and surrounding structures is minimized. mors that do not respond well to chemotherapyHistologically, osteosarcoma is characterized by the and to tumors that have produced skip lesions.presence of spindle cells and the production of tumorosteoid (Jurgens et al., 1997). 2. Limb salvage: Limb salvage procedures can be done for 90–95% of tumors today (Wittig et al.,2.4.6 Staging and Classiﬁcation 2002). They are appropriate when the tumors can be removed effectively with negative margins,There are varied histological patterns of osteosarco- meaning that the tumor is removed with a rim ofma with osteoblastic being the most common, with healthy tissue around the tumor. In order to re-an incidence of 78%, followed, in descending order of construct the limb and/or joint, an endoprosthe-frequency, by chondroblastic, ﬁbroblastic, malignant sis, allograft, arthrodesis, intercalary allograft, orﬁbrous histiocytoma-like, giant cell-rich, telang- metallic prosthesis can be used.iectatic, low-grade intraosseous, small cell, and juxta- 3. Rotationplasty: Rotationplasty is another proce-cortical (Pinkerton et al., 1999). dure that is used when there is a large tumor Staging in osteosarcoma is generally quite straight- around the knee joint. The leg is amputated at theforward and considers intra- and extracompartmen- distal femur, and the ankle joint is preserved, ro-tal factors (whether tumor extends through cortex to tated 180 degrees, and reattached. This producesbone), as well tumor grade and presence of metas- an artiﬁcial knee joint from which the prosthesistases. Table 2.8 shows the Enneking staging system can be effectively secured for a greater range offor osteosarcoma. The tumors are divided into low motion (see chapter 21).and high-grade variants depending on the number ofmitoses, anaplasia, cellularity, and pleomorphism. Metastatic disease at diagnosis predicts a poor out-Stage IIB is the most common presentation of con- come. Treatment aims should be the same: neoadju-ventional osteosarcoma. vant chemotherapy and surgical resection of disease. Radiation therapy has been used but is not terribly2.4.7 Treatment useful. Bone marrow transplant does not currently have a role in osteosarcoma.Treatment of osteosarcoma consists of surgical resec- Relapse still occurs in 30–40% of patients despitetion of the primary and neo-adjuvant chemotherapy. aggressive chemotherapy and surgical resection inHistorically treatment for osteosarcoma consisted nonmetastatic osteosarcoma of the extremities. Theonly of amputation of the primary. The outcome was post-relapse survival in this group is poor. The ma-poor with long-term survival at 10% (Ferrari et al., jority of relapses occur in the lung. Accepted strate-2003). Currently, with use of adjuvant and neoadju- gies for treatment include surgical resection, evenvant chemotherapy, survival has increased dramati- when this requires multiple thoracotomies. In a
63. 44 Chapter 2 E. Hendershot retrospective analysis by Ferrari et al.. (2003), they 2.4.9 Follow-up found that systemic chemotherapy using ifosfamide showed some utility in relapsed osteosarcoma; how- Patients need to be followed for both recurrent and ever, it had little use in pulmonary metastases except metastatic disease as well as for late effects of the in a subset of patients with three or more pulmonary treatment itself. Imaging scans of the primary and nodules. They also found that relapsed patients with the chest are done normally every 3 months for the one or two pulmonary nodules did better (5-year event- ﬁrst year and then at increasing intervals for at least free survival 24%) than those who had bony metas- the next several years before ﬁnally being done annu- tases or more than two pulmonary nodules. Bony ally. metastases have a poor outcome, but every attempt Late effects of chemotherapy include cardiomy- should be made for complete surgical resection. opathies related to anthracycline use and hearing im- pairments related to cisplatin chemotherapy. Neuro- 2.4.8 Prognosis logical, hormonal, and psychological late effects should also be considered when assessing patients. The overall survival of patients with nonmetastatic Infertility and secondary malignancies may result disease at diagnosis, with the tumor located in an ex- from the use of high-dose alkylating agents. tremity, is 60–70%, whereas the survival of patients with metastases at diagnosis remains poor, at 2.4.10 Future Perspectives 15–20% (Bacci et al. 2002a,b). Prognosis of osteosar- coma depends largely on the extent of disease at di- New chemotherapeutic agents have not shown to be agnosis. Parosteal and intraosseous well-differentiat- effective in phase I and II trials. Dose intensiﬁcation ed osteosarcomas tend to have a favorable prognosis. regimens with current chemotherapeutic agents us- There appears to be no relationship between histo- ing cardioprotective agents are being reviewed. There logical subtypes and overall survival. However, is interest in immunomodulation vaccine therapy telangiectatic osteosarcomas (which produce lytic le- and antiangiogenic agents.Antiangiogenic agents are sions) have a poor prognosis (Link et al., 2002). The used to target and impede the tumor’s ability to site of the tumor plays a role in prognosis, with axial form new blood vessels, thereby inhibiting tumor tumors faring worse than skeletal, most likely related growth. Liposomal muramyl tripeptide-phosphati- to the difﬁculty in surgical resection of axial tumors. dylethanolamine (MTPPE) was trialed by the Pedi- The tumor size also has a prognostic signiﬁcance, atric Oncology Group (POG) and Children’s Cancer with tumors less than 5 cm having better outcomes. Group (CCG) and showed some promise when used Prognosis in children under 10 years old at diagnosis with conventional chemotherapy. There are current tends to be poorer. Elevations of LDH may have ad- plans for a Phase II trial using inhaled GMCSF to verse prognosis. Loss of heterozygosity at the Rb gene stimulate macrophage activity for lung metastases. may indicate that the tumors are more likely to There are also research studies in progress attempt- metastasize. HER 2/erbB-2 over expression may be ing to use monoclonal antibodies to target HER2 re- associated with inferior outcome. The response to ceptors (Link et al., 2002). Administration of a bone- preoperative chemotherapy is prognostic in that seeking radioisotope, samarium, is being tested with those tumors with greater than 98% necrosis or less autologous stem cell transplant for metastatic bony than 2% viable tumor at the time of local control disease. have a better outcome. The multidrug-resistance phenotype encodes p-glycoprotein, which if overex- pressed may indicate an unfavorable outcome be- cause p-glycoprotein has a propensity to actively pump chemotherapy from tumor cells (Link et al., 2002).
64. Solid Tumors Chapter 2 45 Hepatitis B infection has been shown to be patho-2.5 Liver Tumors genic in HCC. HCC also develops in the presence of cirrhosis and underlying liver disease. There is someApproximately two-thirds of all liver tumors are suggestion that parenteral nutrition in infancy is as-malignant. The most commonly occurring malignant sociated with HCC in childhood. Maternal exposureliver tumor is hepatoblastoma followed by hepatocel- to oral contraceptive pills, fetal alcohol syndrome,lular carcinoma. and gestational exposures to gonadotropins are envi- ronmental factors implicated as possibly leading to2.5.1 Epidemiology HCC. The following genetic syndromes that are asso- ciated with a higher incidence of HCC include glyco-Malignant liver tumors occur at an annual incidence gen storage disease, hereditary tyrosinemia, Alagilleof approximately 1.5 cases per million children under syndrome, other familial cholestatic syndromes, neu-the age of 15, and they comprise 1.1% of all child- roﬁbromatosis, and ataxia-telangiectasia (Tomlinsonhood cancers (Tomlinson and Finegold, 2002). Hepa- and Finegold, 2002).toblastoma (HB) is the most common malignant liv-er tumor affecting children and represents two- 2.5.3 Molecular Geneticsthirds of all liver tumors in this population. In infan-cy, the incidence is 11.2 per million, and this steadily Several chromosomal abnormalities occur in HB, butdecreases throughout childhood. Ninety percent of very few have been linked to HCC.HBs occur during the ﬁrst 5 years of life, 68% present In HB the most common chromosomal abnormal-within the ﬁrst 2 years, and 4% are present at birth ities involve trisomy 2 and 20, and a translocation be-(Stocker, 2001). The mean age of diagnosis was found tween (1;4)(q12;q34), all of which are of unknownto be 19 months in a POG trial. There is a male pre- signiﬁcance (Stocker, 2002). Loss of heterozygosity atdominance ranging from 1.4:1–2.0:1, (Tomlinson and 11p15, which is a known tumor suppressor gene, hasFinegold, 2002), and Caucasians are affected up to also been shown in HB and BWS. In a German study,ﬁve times more often than African-Americans. There 48% of HBs had a mutation at the B-catenin gene; theis an increased incidence of HB in the Far East. signiﬁcance of this requires further exploration Hepatocellular carcinoma (HCC) accounts for (Tomlinson and Finegold, 2002).23% of all childhood liver tumors. It accounts for less Mutations in the tumor suppressor gene (p53)than 0.5% of all pediatric malignancies, with an an- have been reported in HCC and are associated with anual incidence of 0.5–1 case per million children shorter survival (Tomlinson and Finegold, 2002).(Czauderna et al., 2002). There is a higher male pre-dominance affected by this tumor, and it most often 2.5.4 Symptoms and Clinical Signsoccurs after the age of 10. The presentations of HB and HCC are often quite2.5.2 Etiology similar to those of other abdominal tumors. Symp- toms depend on the size of the tumor and can ariseSome researchers have suggested in recent years that from the mass effect of space-occupying lesions.prematurity is linked to HB development. The cause Children most often present with an asympto-of this is unknown. In Japan’s registry for pediatric matic abdominal mass. On physical examination, amalignancy the risk for HB is inversely correlated ﬁrm, irregular mass may be palpated in the right up-with birth weight (Tomlinson and Finegold, 2002). per quadrant of the abdomen with extension acrossThere is an association with HB and certain condi- the midline or down to the pelvis. Pain, weight loss,tions such as Beckwith-Wiedemann syndrome (BWS), anorexia, nausea, and vomiting may occur in ad-familial adenomatous polyposis (FAP), Li-Fraumeni vanced disease. Jaundice is quite uncommon, occur-syndrome, trisomy 18, and glycogen storage disease. ring only 5% of the time (Stocker, 2001). Infants can
65. 46 Chapter 2 E. Hendershot Figure 2.4 CT scan of patient with hepato- blastoma present with failure to thrive. Severe osteopenia is of- trasound is useful in identifying a mass with in- ten seen at diagnosis and is usually picked up inci- creased echogenicity, which is suggestive of malig- dentally on imaging; however, pathologic fractures nancy; Doppler will give information about the tu- occur infrequently. An acute abdomen is present in mors vascularity. CT or MRI is needed to assess the the case of tumor rupture. Seventy percent of chil- extent of disease and the presence of local lymph dren are anemic at diagnosis, and 35% have throm- nodes. Fig. 2.4 shows Hb as picked up on CT scan. Tu- bocytosis (Stocker, 2001). Precocious puberty may be mors often show patchy disease on post-contrast CT, apparent in children whose tumors secrete beta hu- and 50% of tumors show speckled or amorphous cal- man chorionic gonadotropin (BHCG). Hypertension ciﬁcations (Tomlinson and Finegold, 2002). CT of the can rarely occur in this population due to abnormal chest is necessary to rule out lung metastases. Bone rennin secretion. Clinical signs of BWS should be scan is sometimes ordered to rule out bony metas- considered, including macroglossia and hemihyper- tases, as is MRI of the brain to rule out intracranial trophy, because of the increased incidence of HB in spread; however, these are not standard practice. children with BWS. Patients at risk for developing HB A biopsy is necessary for deﬁnitive diagnosis, and including those with BWS or FAP, are often placed on tumor resection at diagnosis is preferred if surgically a surveillance schedule to look for disease. feasible. HB has two distinct classes based on histol- Metastases tend to spread to lung, bone, and brain. ogy. The ﬁrst class shows epithelial histology with further variants that include a fetal pattern, a mixed 2.5.5 Diagnostics embryonal and fetal pattern, macrotrabecular pat- tern, and undifferentiated small cell pattern. The sec- The diagnosis of either HB or HCC depends on im- ond class involves mixed epithelial and mesenchymal aging, blood, physical exam, and ultimately biopsy to histology. Further variants of the mixed histology in- determine tumor histology. clude variants with teratoid features and those con- x-ray of the abdomen is often one of the ﬁrst diag- taining mesenchymal elements such as osteoid and nostic tests ordered. A right upper quadrant mass is cartilage (Stocker, 2001). seen, and sometimes calciﬁcation is present. An ul-
66. Solid Tumors Chapter 2 47Table 2.9. Children’s Oncology Group staging of hepatoblastoma (adapted from Tomlinson and Finegold, 2002) Stage I Tumors are those that are completely resected and have a typical histology of a purely fetal (favorable histology) histologic pattern with a low mitotic index (<2 per 10 high-power ﬁelds Stage I Tumors that are completely resected with a histological picture other than purely fetal with low (other histology) mitotic index Stage II Tumors are grossly resected with evidence of microscopic residual disease. Such tumors are rare, and patients with this stage have not fared differently from those with stage I tumors. Resected tumors with preoperative or intraoperative spill are classiﬁed as stage II Stage III (Unresectable) Tumors are those that are considered by the surgeon to be not resectable without undue risk to the patient.This includes partially resected tumors with measurable tumor left behind. Lymph node involvement is considered to constitute stage III disease and may require evaluation with a second laparotomy after the initial four courses of chemotherapy Stage IV Tumors that present with measurable metastatic disease to lungs or other organsHCC has four main histologic types: widely available. The AFP is an important tumor marker in liver tumors and is useful in evaluating re-▬ Trabecular pattern is almost always seen in some sponse to treatment and recurrent disease. After part of HCC complete tumor resection, the AFP should return to▬ Compact and pseudoglandular variants normal within 6 weeks.▬ Scirrhous is a rare type▬ Fibrolamellar carcinoma is another rare variant of HCC that is not associated with cirrhosis; it shows 2.5.6 Staging and Classiﬁcation an increased alfa-fetoprotein (AFP) and has a male Staging of liver tumors has been done by two differ- predilection and a more favorable prognosis ent methods by two distinct groups. The North (Suriawinata and Thung, 2002) American Children’s Oncology Group (COG) stagesA CBC should be ordered as well as liver and renal hepatoblastoma by the standard postsurgical tumorfunction blood tests. Liver enzymes and bilirubin status (Table 2.9). The International Society of Pedi-may be elevated. Coagulation studies should be car- atric Oncology (SIOP) uses a pretreatment classiﬁca-ried out before any surgical procedure to ensure that tion schema called PRETEXT, which helps determineliver disease has not interfered with the coagulation feasibility of tumor resection based on the number ofpathway. BHCG is sometimes elevated in liver tumors liver segments involved using preoperative imagingand should be checked; elevations usually correlate scans (Tomlinson and Finegold, 2002).with features of precocious puberty. AFP is a protein HCC is staged much the same way as HB; however,that is produced by the fetal liver and is elevated in it is graded differently based on histological differen-the blood of infants during the ﬁrst 6–9 months of life tiation. Stage I HCC resembles normal hepatocytes,(Shafford and Pritchard, 1997). This protein is in- stage II and III cells show moderate differentiation,creased in 90% of HBs and 60% of HCCs (Pinkerton and stage IV tumor cells are very poorly differentiat-et al., 1999). In infants being worked up for a liver ed and often metastatic (Suriawinata and Thung,mass, it may be difﬁcult to distinguish between nor- 2002).mal AFP and malignant AFP. It is possible to frac-tionate the malignant and nonmalignant AFP by im-munoelectropheresis; however, this lab service in not
67. 48 Chapter 2 E. Hendershot 2.5.7 Treatment only be biopsied if suspicious for disease. In a COG study, surgery alone is the only treatment for stage I For both HB and HCC, surgical resection is crucial tumors with pure fetal histology, which are complete- for cure and is the single most important factor pre- ly resected at diagnosis (Rowland et al., 2002). Biopsy dicting survival. Chemotherapy often plays a large of any suspicious pulmonary lesions should occur at role postoperatively and sometimes preoperatively if diagnosis, and residual lesions should be surgically the tumor is unresectable at diagnosis. More recently, removed at the completion of therapy. liver transplantation is playing a role in unresectable Chemotherapy agents that have shown utility in tumors. The use of radiation with these liver tumors the treatment of HB include cisplatin, doxorubicin, is controversial. ifosfamide, vincristine, and 5 ﬂuorouracil. Irinotecan Surgery resection is the most important part of has showed some activity in phase II trials and recur- curative therapy for children with HB. Forty to 60% rent disease. Sequential use of carboplatin, carbo- of HB tumors are inoperable at diagnosis and 10 to platin-vincristine-5FU, and high-dose cisplatin- 20% have pulmonary metastases (Stocker, 2001). etoposide in a POG phase II study showed response Surgery is often not possible at diagnosis if both liv- in metastatic HB and in patients with unresectable er lobes are affected, if there is tumor in the porta he- disease at diagnosis, similar to other regimens but patis, or if bulky lymphadenopathy exists. Presurgi- perhaps with less toxicity (Katzenstein et al., 2002a,b). cal chemotherapy for unresectable lesions renders Table 2.10 shows the most recent chemotherapy regi- them resectable 85% of the time (Stocker, 2001). Sur- mens for HB. gical resection may include a lobectomy or triseg- HCC has traditionally treated with the same mentectomy based on the extent of disease. Lymph chemotherapy agents used in the treatment of HB but nodes and the porta hepatis should be sampled dur- with less success. The results of a Pediatric Oncology ing surgery; the celiac and paraaortic nodes need Group and Children’s Cancer Group intergroup study Table 2.10. Chemotherapy regimens for hepatoblastoma (adapted from Tomlinson and Finegold, 2002) Study group Schema Overall survival Number of Reference (length of follow-up) patients Children’s Cisplatin 67a (2 years) 26 Ortega et al. Cancer Group (1991) Doxorubicin day 1–4 Plan: 4 courses Pediatric Cisplatin course 1 and then cisplatin, 67 %a (4 years) 60 Douglass et al. Oncology Group vincristine, 5 FU courses 2–5 (1993) International Cisplatin 24-hour infusion and 75 %b (5 years) 154 Pritchard et al. Society of doxorubicin 48-hour infusion (2000) Pediatric Oncology Plan: 4 courses-surgery-2 courses German Society of Ifosfamide 75 %b 72 Von Schweinitz Pediatric Oncology Cisplatin (median 64 months) et al. (2000) and Hematology Doxorubicin Plan: 2 or 4 courses-surgery-2 courses a Includes only patients with unresectable disease at presentation b Includes patients with all stages at presentation Refer to references to obtain full schema
68. Solid Tumors Chapter 2 49using a prospective trial using a uniform treatment The survival rates for patients with HCC remain veryapproach to HCC were published by Katzenstein and poor. In all reported HCC series, the therapeutic re-colleagues (2002). The treatment involved cisplatin, sponse to chemotherapy is poor and overall survivalvincristine and ﬂuorouracil (5-FU), or cisplatin and is less than 30% (Czauderna et al. 2002).continuous infusion doxorubicin as determined byrandomization. Neither regimen was effective in con- 2.5.9 Follow-uptrolling residual or metastatic disease in childrenwith HCC. For lack of better treatment, most often Follow-up should be similar for both HB and HCC,patients with HCC are usually treated using the same and must consist of physical examination, abdominalprotocols that are used for HB with poor results. ultrasound for tumor recurrence, and chest x-ray forSurgery is vital in these patients, but unfortunately, evidence of pulmonary metastases. CT scan may be aonly 10–20% of these tumors are resectable. more sensitive way to monitor for recurrence and Radiation therapy is sometimes used if there is metastases once off treatment, but this should be de-minimal or gross residual disease, but its utility is cided based on individual patient needs. Surveillancecontroversial and not widely accepted. There are should be done every 3 months for at least the ﬁrst 2high rates of side effects from tumor irradiation as years and then with decreasing frequency. Monitor-well. ing of the AFP is essential and is often the ﬁrst indi- Liver transplantation is now done in the United cation that the tumor has recurred.States, and malignancies account for 2% of liver Monitoring for late effects of the treatment is alsotransplants in children. Transplant is often consid- necessary. Audiograms should be done periodicallyered but not limited to instances where tumors are to look for hearing loss resulting from cisplatin ther-unresectable and show chemosensitivity. A recent apy. Echocardiograms should be done following an-study showed that children who had initially unre- thracycline therapy because the potential for cardiacsectable liver tumors and were treated initially with sequelae from treatment exists. Infertility problemschemotherapy followed by hepatectomy and liver may be an issue once children are older. If the patienttransplant had post-transplant survival rates at 5 has undergone liver transplantation, secondary lym-years of 83% for HB and 68% for HCC (Tomlinson phoproliferative disorders may occur. Psychological,and Finegold, 2002). endocrine, and hormonal issues may need to be ad- dressed as well.2.5.8 Prognosis 2.5.10 Future PerspectivesThe most important prognostic factor in HB is com-plete surgical resection. Pure fetal histology and low Clearly there needs to be better treatment availablemitotic count impart an excellent outcome. Small-cell for HCC. Studies have proven that HCC does not re-undifferentiated tumors are associated with poor spond to chemotherapy as HB does. Novel agentsprognosis independent of any other variable. The cure need to be examined for their potential role in treat-rate for a patient with HB and lung metastases is 70%. ing both these liver tumors. The overall survival for children with HB is Effort needs to be placed on developing standard-65–70%. The overall survival rates for the various ized surveillance programs for those who carry astages of disease are genetic predisposition to developing a liver tumor, as early intervention would hopefully improve out-Stage I: 100% comes for this group of patients.Stage II: 75–80%Stage III: 65–68%Stage IV: 0–27% (Stocker, 2001)
69. 50 Chapter 2 E. Hendershot high-risk treatment protocols. Gene ampliﬁcation, al- 2.6 Neuroblastoma terations in gene expression, and tumor suppressor gene inactivation are some of the major factors that Neuroblastoma (NBL) is a tumor that arises from inﬂuence risk determination. neural crest cells that make up the sympathetic or pe- N-Myc ampliﬁcation occurs in approximately 25% ripheral nervous system and can grow in the sympa- of all NBLs (Matthay and Yamashiro, 2000). N-Myc is thetic ganglia, adrenal medulla, and other sites. NBL an oncogene found on chromosome 2 band q24, and is an undifferentiated and highly malignant tumor, its ampliﬁcation is associated with aggressive and ad- ganglioneuroblastoma is a more differentiated tu- vanced disease. It is a powerful predictor of outcome mor, and ganglioneuroma is a fully differentiated tu- regardless of stage and age. Loss of heterozygosity at mor without malignant potential. chromosome 1p36 has also been shown to have an unfavorable outcome and is a very common chromo- 2.6.1 Epidemiology somal abnormality. 1p is thought to harbor a yet-to- be-identiﬁed tumor suppressor gene, and deletion of NBL is the most common pediatric extracranial ma- this may cause tumors to grow uncontrollably. There lignancy and the most frequently occurring cancer in appears to be an association between a chromosome infancy. Although it accounts for approximately 10% 1p deletion and N-Myc ampliﬁcation (Matthay and of all childhood malignancies, it accounts for 15% of Yamashiro, 2000). Chromosomal gains of 17q are also all cancer deaths (Alexander, 2000). The incidence is a frequent genetic event and often correlate with 1p about 9.7 cases per one million children (Gurney et deletions, therefore pointing to an unfavorable prog- al. 1995). It affects boys at a slightly higher rate than nosis (Tomioka et al. 2003). Deletions on chromo- girls, 1.2:1.0, and is slightly more predominant in some 11 and 14 have also been found in some tumors white children compared with black. The median age and again the thought is that they may encode tumor at diagnosis is 17.3 months (Brodeur and Maris, 2002). suppressor genes. Ploidy, the number of chromo- somes pairs, is another important determination. In- 2.6.2 Etiology fants with NBL who have a DNA index (DI) of >1 (more than 46 chromosome pairs) respond well to The cause of NBL is unknown. According to current standard chemotherapy.A DI equal to1 would predict evidence, environment does not appear to play a role. a poorer response to standard therapy and often re- Correlation with intrauterine exposure to several quires more aggressive treatment. Ploidy does not agents such as alcohol, medications, and maternal use appear to be as signiﬁcant in children older than 1 of hair-coloring products has been proposed, but none year (Brodeur, 2003). Neurotrophin receptor expres- of these hypotheses have not been conﬁrmed. Al- sion is widely correlated with genetic and biologic though most cases of NBL are sporadic, there seems to features. TrkA, TrkB, and TrkC are tyrosine kinases be a small group, approximately 1–2%, that are famil- that code for receptors of the nerve growth factor ial (Brodeur and Maris, 2002). NBL has been identiﬁed (NGF) family. High TrkA often corresponds with a in other disorders of neural crest cells, such as neuroﬁ- lack of N-Myc ampliﬁcation, and therefore a favor- bromatosis, Hirschsprung’s disease, Beckwith-Wiede- able outcome. TrkB, however, is expressed in higher- mann syndrome (BWS), and DiGeorge syndrome. stage tumors that show N-Myc ampliﬁcation and have an unfavorable prognosis. The risk classiﬁcation 2.6.3 Molecular Genetics table takes into account both clinical features such as stage and age as well as biological risk factors to de- Neuroblastoma is a disease in which enormous ad- termine an appropriate treatment intensity protocol. vances have been made regarding the molecular and See Table 2.11 for proposed NBL risk groups based on genetic aspects. More recently these results have been clinical and biologic tumor features for Children’s used to stratify children into low, intermediate and Oncology Group protocols.
70. Solid Tumors Chapter 2 51Table 2.11. Neuroblastoma risk groups based on clinical and biologic tumor features (Children’s Oncology Group Protocols[ANBL0032)]; reprinted with permission) INSS stage Age MYCN status Shimada histology DNA ploidy Risk group 1 0–21 Any Any Any Low 2A/2B <365 d Any Any Any Low >365–21 y Non-Amp Any – Low >365–21 y Amp Fav – Low >365–21 y Amp Unfav – High-risk 3 <365 d Any Any Any Intermediate <365 d Any Any Any High-risk >365 d-21y Fav Fav – Intermediate >365 d-21y Unfav Unfav – High-risk >354 d-21y Any Any – High-risk 4 <365 d Non-Amp Any Any Intermediate <365 d Amp Any Any High-risk >365 d-21y Any Any – High-risk 4S <365 d Non-Amp Fav >1 Low <365 d Non-Amp Any =1 Intermediate <365 d Non-Amp Unfav Any Intermediate <365 d Amp Any Any High-risk2.6.4 Symptoms and Clinical Signs Extensive involvement of the liver, skin, and/or bone marrow (<10%) in infants reﬂects stage 4S disease.Neuroblastoma can occur anywhere along the pe- This clinicopathological staging is reserved for in-ripheral nervous system, so the presentations of the fants who, along with favorable tumor biology, can bedisease vary along with the location of the primary considered low risk even with advanced disease.tumor or metastases. Neuroblastoma occurs in vari- Clinical signs of NBL vary according to the tu-ous anatomic sites as follows: mor’s location. Various presenting signs of neuro- blastoma and the possible causes are listed in▬ 28.4% in the abdomen Table 2.12.▬ 32% in the adrenals Skin lesions commonly referred to as “blueberry▬ 15% in the thorax mufﬁn” can occur in infants.▬ 5.6% in the pelvis Paraneoplastic syndromes may sometimes be▬ 2% in the neck present at diagnosis. One such syndrome is opsomy-▬ 16.9% occur elsewhere oclonus. This involves random eye movements, my- (Ninane and Pearson, 2002) oclonic jerking movements, and cerebellar ataxiaInfants tend to have more thoracic and cervical (Bataller et al., 2003). The phenomenon is though tospinal tumors than older children. Most children do arise because of the production of antineural anti-present before the age of 5 years. Rarely NBL can oc- bodies that cross-react with neural cells in cerebel-cur into adulthood. lum or elsewhere in the brain (Brodeur and Maris, NBL generally spreads via hematogenous and 2002). Children presenting with opsomyoclonus tendlymphatic routes and occasionally by regional lymph to do quite well from the tumor perspective; howev-node invasion. Bone and bone marrow are common er, long-term neurological and developmentalareas for metastases, as well as liver and skin in deﬁcits can be a large problem. Intractable diarrheainfants. Very rarely, spread to brain and lung occurs. can be a rare presentation caused by tumor secretion
71. 52 Chapter 2 E. Hendershot Table 2.12. Various presentation signs of neuroblastoma and their possible causes Clinical sign or symptom Possible cause Abdominal pain, abdominal distension, nausea, Abdominal tumor vomiting, constipation Anorexia, weight loss Mass effect of midline tumors Horner’s syndrome (ipsilateral ptosis, miosis, High thoracic and cervical tumors resulting in compromise of and anhidrosis) descending sympathetic tracks Proptosis, periorbital ecchymosis Periorbital tumor Anemia, thrombocytopenia, frequent infections Bone marrow involvement Hypertension Renal vascular compression Limp or leg pain Metastatic bone disease Decreased motion in legs, muscle weakness, Spinal or paraspinal disease bowel or bladder disturbances Weakness or paraplegia Compression of spinal cord caused by dumbbell tumors of vasoactive intestinal polypeptide (VIP); this often Neuroblastoma tumors produce several sub- has a favorable prognosis. stances that can be measured in the blood. Blood should be sent for LDH and ferritin. Neuron-speciﬁc 2.6.5 Diagnostics enolase (NSE), GD2 (a cell membrane ganglioside), and chromogranin A are produced by NBL tumors, Several screening tests are useful in diagnosing NBL. and although not routinely done at most centers, Blood and urine testing are done, in addition to tu- serum levels of these markers can be measured. mor biopsy as part of the workup. Diagnostic imag- Highly elevated ferritin levels may be associated with ing is used to evaluate the extent of tumor invasion a worse prognosis. Similarly, elevations of LDH and and any tumor dissemination. The information ob- chromogranin A are associated with unfavorable out- tained from imaging and biopsy results is used to de- comes. GD2 can be found on the surface of NBL; gan- termine risk stratiﬁcation based on both clinical and gliosides shed from the tumor might be important in biological factors. accelerating tumor progression (Brodeur, 2003). NSE Initially, imaging studies of the affected area may is a protein associated with neural cells; although consist of plain ﬁlms or ultrasound depending on the nonspeciﬁc, overall survival is worse in patients with presenting symptoms. Fig. 2.5 shows a radiograph of elevations of NSE and advanced disease (Matthay a posterior mediastinal mass found in a patient with and Yamashiro, 2000). Other blood tests such as a NBL. Following this, CT of the chest, abdomen, and CBC should also be done; any cytopenias that are pelvis should determine the extent of the disease and present may be the result of bone marrow disease. Re- the presence of metastases. On imaging the tumors nal and liver function tests should also be evaluated often show calciﬁcation. In the case of spinal tumors, to ensure normal functioning and to obtain baseline an MRI should be ordered. Bone scan should deter- levels prior to chemotherapy. mine the presence of skeletal metastases. Meta- Urinary catecholamine metabolites are elevated in iodobenzylguanidine (MIBG) scan, using a dye that is NBL in 90–95% of patients (Brodeur and Maris, taken up by catecholaminergic cells, is extremely use- 2002). Urinary vanillylmandelic acid (VMA), formed ful in identifying NBL metastases but is not available from norepinephrine, and homovanillic acid (HVA), at all centers. formed from dopamine, are considered elevated
72. Solid Tumors Chapter 2 53 Figure 2.5 Radiograph of a posterior medi- astinal mass found in a patient with neuroblastomawhen they are greater than three standard deviations totic karyorrhectic index (MKI), patient age, the de-above the upper limit of normal (Brodeur, 2002). gree of differentiation, and whether the tumor is Tumor biopsy and/or tumor resection are done schwannian stroma poor. Table 2.13 indicates thedepending on the stage of the tumor. Tissue samples pathology classiﬁcation for NBL.are sent for molecular and histopathological testing.Stage I and II tumors are usually resected at diagno- 2.6.6 Staging and Classiﬁcationsis, whereas Stage III and IV tumors are only biop-sied. Chemoreductive therapy is given in order to fa- Several staging systems exist for NBL. The interna-cilitate easier removal of higher staged tumors. Bilat- tional NBL staging system (INSS) is based on post-eral bone marrow aspirates and biopsies are needed surgical interventions for low-grade tumors accord-to determine the presence of bone marrow disease. It ing to location and respectability of the tumor; theis generally accepted that if tumor is found in the Pediatric Oncology Group’s staging is similar. Thebone marrow studies and the child has an elevated Children’s Cancer Group’s staging is based on tumorVMA/HVA, it is not necessary to biopsy the primary location on imaging. Table 2.14 outlines the varioustumor. However, valuable information gained via bi- staging systems. Most centers, in North America atological markers would not be obtained for risk strat- least, are using the INSS.iﬁcation, which may impact patient care. Histology is an important determinant in risk 2.6.7 Treatmentstratiﬁcation for these tumors. NBL is a small blueround cell tumor, and Homer-Wright pseudorosettes Surgery, chemotherapy, radiation therapy and autol-are often found in the tumor. It can be distinguished ogous stem cell transplant, and more recently im-from other small blue round cell tumors because of munotherapy and other biological therapies are allits distinctive monoclonal antibody staining pat- used in the treatment of NBL. Treatment intensity de-terns. NBL stains positively for NSE, neuroﬁlament pends on risk stratiﬁcation (Table 2.11). Essentially,proteins and synaptophysin. Shimada and colleagues the goals of treatment in those children with ad-(1984) originally developed a pathology staging sys- vanced disease are totem; some changes have been made to this earlier sys- ▬ Chemotherapy to decrease the size of both the pri-tem in order to make it internationally useful. The mary tumor and metastaseshistological determination takes into account the mi- ▬ Surgical resection of the tumor
73. 54 Chapter 2 E. Hendershot Table 2.13. Prognostic evaluation of neuroblastic tumors according to the International Neuroblastoma Pathology Classiﬁca- tion/Shimada system (taken from Shimada et al., 1999 with permission; MKI mitosis-karyorrhexis index) International Original Shimada Prognostic Neuroblastoma Pathology classiﬁcation group Classiﬁcation Neuroblastoma (Schwannian stoma-poor) Stroma-poor Favorable Favorable Favorable <1.5 yr Poorly differentiated or differentiating and low or intermediate MKI tumor 1.5–5.0 yr Differentiating and low MKI tumor Unfavorable Unfavorable Unfavorable <1.5 yr Undifferentiated tumor High MKI tumor 1.5–5.0 yr Undifferentiated or poorly differen- tiated tumor Intermediate or high MKI tumor 5 yr All tumors Ganglioneuroblastoma, (Schwannian stroma-rich) Stroma-rich intermixed Favorable intermixed (favorable) Ganglioneuroblastoma, (Composite Schwannian Stroma-rich nodular Unfavorable nodular stroma-rich/stroma-dominate (unfavorable) ganglioneuroma and stroma-poor) Maturing (Schwannian stroma-dominant) Well differentiated (favorable) Favorable Mature Ganglioneuroma ▬ Myeloablative chemotherapy followed by autolo- podophyllotoxins (Alexander, 2000; Brodeur and gous stem cell transplantation (ASCT) Maris, 2002). In metastatic disease and poor-risk ▬ Radiation therapy to areas of residual disease stage III disease, myeloablative therapy is used fol- lowed by single or double peripheral stem cell rescue. Surgery is a vital aspect of care for children with NBL. Melphalan is often an integral part of the ASCT con- For patients with low-risk disease, often stage I and ditioning regimen. II, surgical resection may be all that is required for NBL is a radiosensitive tumor. In instances where treatment. For intermediate and high-risk disease, the primary tumor cannot be fully resected, when including stage III and IV tumors, surgery is done af- there are local lymph nodes, and with microscopic ter several courses of chemotherapy have decreased residual disease, radiation therapy plays a vital the tumor size. role. Radiation is often also used for palliative pain Chemotherapy is used primarily in tumors that control and for bony tumors or spinal cord compres- are intermediate to high-risk; i.e., in metastatic dis- sion that cause distressing symptoms.Accepted treat- ease and locally-spread disease. The most common ment doses of ionizing radiation range to 30 Gy, drug combinations known to be effective are some depending on the tumor size, and fractioned doses combination of the following: cisplatin, doxorubicin, range between 150 and 400 cGy (Brodeur and Maris, cyclophosphamide, carboplatin, ifosfamide, and epi- 2002).
74. Solid Tumors Chapter 2 55 Following myeloablative therapy, maintenance 2.6.9 Follow-uptherapy often includes treatment with retinoids.Retinoic acid is used to evoke cellular differentiation Close observation for recurrent disease is imperativeof NBL in the cases of minimal residual disease; most for these children. Most relapse occurs during thechildren receive 6 months of therapy (Matthay and ﬁrst 2 years following the completion of therapy. Di-Yamashiro, 2000). Currently, several groups including agnostic imaging of the primary using CT or ultra-the North American study group, COG, are trialing sound depending on location of the tumor is indicat-targeted therapies using anti-GD2 antibody, Inter- ed. MIBG scanning is also useful for monitoring forleukin II (IL2), and granulocyte macrophage colony recurrent disease in high-risk patients. Imaging andstimulating factor (GMCSF) after autologous stem physical exam should be done every 3 months for thecell transplant to target potential minimal residual ﬁrst few years after completing therapy and then withdisease. decreasing frequency over several years, or as clini- Relapsed disease is very difﬁcult to treat following cally indicated. Urinary catecholamines should alsohigh-risk disease treatment. Chemotherapy agents be measured with the same frequency as radiologicalthat have shown response include topotecan, cy- imaging. Blood tests such as LDH and ferritin can beclophosphamide, Taxol, and VP16 (Brodeur and monitored easily, and although nonspeciﬁc, can beMaris, 2002). Targeted therapy using MIBG radioiso- used for screening along with imaging and physicaltope to deliver radiation therapy is being used at exam. Those children who remain disease-free for 5some centers and has shown some response to re- years following treatment of NBL are generally con-fractory disease. sidered cured, although with increased intensity of therapy, late recurrences may be possible.2.6.8 Prognosis Follow-up must also consider treatment-related toxicity and late effects. Ototoxicity is usually signiﬁ-The prognosis in NBL varies widely depending on cant following cisplatin therapy, and hearing aids arethe child’s age and the tumor’s stage, location, and often necessary. Growth and development may bebiology. impacted, especially if radiation therapy has been de- livered to the spinal area; this should be monitored▬ Survival rates are as high as 95% in patients with carefully. Organ toxicity is a potential following Stage I disease when the tumor has been com- chemotherapy and should be monitored through pletely excised (Alexander, 2000) blood testing where possible. Echocardiograms▬ Children with stage II disease who are older than should be done to screen for cardiomyopathies from 1 year have an 85% disease-free survival with sur- anthracycline therapies. If radiation therapy was re- gery only ceived, follow-up with a radiation oncologist is im-▬ Children older than 1 year of age with stage III dis- perative. Second malignancies must be considered a ease treated with surgery and chemotherapy have risk for long-term survivors of metastatic disease due a 50% disease-free survival; however, if radiation to the intensive multimodality therapy including ra- is added to treatment the survival may be in- diation these children would have received. Not a lot creased to 70% (Alexander, 2000). of data are available on this cohort because they are▬ High-risk patients with metastatic stage IV disease such a small group. continue to do poorly and the long term survival rate is less than 15% (Brodeur and Maris, 2002)▬ Infants, however, with stage IVS disease and good biological features have survival rates approach- ing 90%
75. 56 Chapter 2 E. Hendershot Table 2.14. Staging systems for neuroblastoma (adapted from Matthay and Yamashiro (2000) International Neuroblastoma Children’s Cancer Study Pediatric Oncology Staging System Group System Group System Stage 1 Stage I Stage A Localized tumor with complete gross Tumor conﬁned to the organ or Complete gross resection of the excision and/or microscopic residual structure of origin primary tumor and/or microscopic disease residual disease Ipsilateral lymph nodes negative Intracavitary lymph nodes not ad for tumor (nodes attached to the hered to the primary tumor, which primary tumor may be positive are histologically free of tumor for tumor) (nodes adhered to the surface of the primary tumor may be positive for tumor) Stage 2A Stage II Stage B Localized tumor with incomplete Tumor extending in continuity Grossly unresected primary tumor gross resection beyond the organ or structure of origin but not crossing the midline Representative ipsilateral nonadherent Possible regional lymph node Nodes and nodules the same as in lymph nodes negative for tumor involvement on the ipsilateral side Stage A microscopically Stage 2B Localized tumor and/or complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor Enlarged contralateral lymph nodes, which are negative for tumor microscopically Stage 3 Stage III Stage C Unresectable unilateral tumor Tumor extending in continuity Complete or incomplete resection of inﬁltrating across the midline and/ beyond the midline primary tumor or regional lymph node involvement Alternately, localized unilateral tumor Possible regional lymph node Intracavitary nodes not adhered to with contralateral regional lymph involvement bilaterally primary tumor, which are positive for node involvement tumor histologically Liver as in Stage A Stage 4 Stage IV Stage D Any primary tumor with dissemination Remote disease involving the Dissemination of disease beyond to distant lymph nodes, bone, bone skeleton, bone marrow, soft tissue, intracavitary nodes (e.g., extracavi- marrow, liver, skin, and/or other organs and distant lymph node groups tary nodes, liver, skin, bone marrow, (except as deﬁned for stage 4S) (see stage IV-S) bone) Stage 4S Stage IV-S Stage DS Localized primary tumor (as deﬁned As deﬁned in stage I or II, except for Infants <1 year with stage 1 or 2, for stages 1, 2A, or 2B) with dissemina- the presence of metastatic disease except for the presence of remote tion limited to skin, liver, and/or bone conﬁned to the liver, skin, or marrow disease conﬁned to the liver, skin, or marrow (<10 % involvement) (<10 % involvement) marrow (<10 % involvement) No bone metastases No bone metastases
76. Solid Tumors Chapter 2 572.6.10 Future Perspectives and 0.6:1 for bilateral tumors (Grundy et al., 2000). The incidence is slightly higher in African-AmericanResearchers and clinicians hope to continuously im- children and lower in Asian children compared withprove risk stratiﬁcation tools for children with NBL Caucasians. Peak age of diagnosis is between 2 and 3so that treatment intensity may correspond to disease years.characteristics as more discoveries are made. Gene Multiple other tumors arise from the kidney; theyexpression proﬁling, targeting abnormal transduc- are extremely rare and include renal cell carcinomation pathways, and the use of biologic agents are all (RCC), clear cell sarcoma of the kidney (CCSK), andareas that are being researched to treat NBL, both in rhabdoid tumor of the kidney (RTK). RCC is a tumorrelapsed and primary disease. MIBG therapy is being that is distinct from Wilms but also occurs in the kid-used at few centers as treatment for refractory dis- ney at an incidence of 0.1–0.3% of all malignancies,ease. Fenretidine, which is thought to induce apopto- representing 1.8–6.3% of malignant kidney tumorssis in tumors that may have been resistant to retinoic (Indolfe et al.. 2003). CCSK, distinct from Wilms’acid therapy, is being investigated in phase I trials tumor, was shown to have an incidence of 4% in a(Brodeur and Maris, 2002). Topotecan has shown ac- National Wilms’ Tumor Study (NWTS) (Beckwith,tivity in relapsed patients and may have a role in ﬁrst- 1998). RTK represents 2% of renal tumors registeredline therapy. Anti-angiogenic agents, which are used with NWTS (Broecker, 2000).to target and interfere with the tumor’s ability to cre-ate its own blood supply, are also being researched for 2.7.2 Etiologya potential role in this disease. Tyrosine kinase in-hibitor therapy is being researched to target TRK A, Wilms’ tumors occur sporadically in 95% of these pa-B, and C expression. The intension of current re- tients. There is, however, a familial form, comprisingsearch is to determine agents that are affective 1–2% of all Wilms’ tumors, in which tumors tend toagainst NBL and incorporate these ﬁndings into con- occur bilaterally and earlier, suggesting a germ lineventional therapy. mutation and a loss of a tumor suppressor gene. The familial form is characterized by an autosomal dom- inant trait with variable penetrance (Grundy et al.2.7 Renal Tumors 2002). The disease often occurs in the presence of ge- netic anomalies or as part of a familial predispositionThe most frequently observed malignant tumor aris- syndrome. Syndromes often associated with Wilms’ing from the kidney is Wilms’ tumor. Other less fre- are the following:quently occurring renal tumors include renal cell car- ▬ Beckwith Wiedemann (BWS) (an overgrowth syn-cinoma, clear cell sarcoma of the kidney, and rhab- drome)doid tumor of the kidney. ▬ Denys-Drash (involving genitourinary abnormali- ties)2.7.1 Epidemiology ▬ WAGR (Wilms, aniridia, genitourinary anomalies and mental retardation) (Pritchard-Jones andWilms’ tumor is the second most commonly occur- Mitchell, 1997)ring extracranial malignancy in children. It repre-sents about 6% of all childhood cancers (Blakely and Wilms’ tumor has also been described in Bloom syn-Ritchey, 2001). Wilms’ tumors can occur bilaterally or drome, incontinentia pigmenti, Li-Fraumeni, and ge-unilaterally; bilateral tumors occur either synchro- netic instability syndromes, yet no deﬁnite link existsnously or at different times. The incidence of Wilms’ (Grundy et al., 2000).tumor, or nephroblastoma, in children less than 15years of age is approximately 7.6 per million. Themale to female ratio is 0.92:1 for unilateral tumors
77. 58 Chapter 2 E. Hendershot 2.7.3 Molecular Genetics veins over abdomen. Very rarely, a child may present with metastatic disease and may show signs of respi- Several genes are described in the development of ratory difﬁculty in the presence of advanced pul- Wilms’ tumor. The ﬁrst Wilms’ tumor suppressor monary metastases. Lung, liver, bone, and brain are gene, WT1, is located at chromosome (Ch’) 11p13. It the major locations of metastases. was cloned in 1990 and is found in patients with WAGR syndrome and involves the PAX 6 gene and 2.7.5 Diagnostics WT1 allele (Grundy et al. 2002). Mutations of WT1 have been found also in some sporadic Wilms’ cases. An abdominal ultrasound is usually the ﬁrst investi- WT1 is important in normal kidney development. A gation ordered, which will reveal a mass arising from second Wilms’ tumor putative gene is identiﬁed at within the kidney. Doppler ultrasound should also be Ch’11p15, WT2. Children with BWS are predisposed used to assess patency of the renal vein and inferior to Wilms’ tumor and have mutations at Ch’11p15, the vena cava, as thrombosis can occur. CT of the ab- WT2 gene (Neville and Ritchey, 2000). The familial domen should be ordered to further assess the extent form of the disease has a locus identiﬁed at Ch’17q la- of the mass and assess for smaller lesions in the con- beled FWT1, and FWT2 is located on chromosome tralateral kidney. The liver should be thoroughly ex- 19q. These genes all appear to have a role in tumor amined because it is a common site for metastases. A development. Chromosome arms 16q, 1p, 7p, and CT of the chest should be ordered to rule out pul- 17p, the location of p53, have also been associated monary metastases. Fig. 2.6 is a chest x-ray demon- with Wilms’ tumor, but may be linked more to treat- strating pulmonary metastases in Wilms’ tumor. ment outcome than to tumorigenesis (Grundy et al., There is some debate as to whether chest x-ray is suf- 2002). There has been an association also noted be- ﬁcient to look for metastases, as smaller nodules are tween p53 mutations and anaplastic histology in 86% often not picked up. of cases, which may suggest that mutations underlie A CT or MRI of the brain should be done after a the anaplastic phenotype (Grundy et al., 2000). diagnosis of CSSK or RTK is made because metas- RCC have characteristic translocations involving tases to the brain can occur. Bone scan and skeletal breakpoint at Xp11.2. survey are also indicated in these tumors; bone scan does not always pick up lytic bone lesions, so skeletal 2.7.4 Symptoms and Clinical Signs survey is also indicated. Biopsy versus tumor resection at diagnosis re- Parents are often the ﬁrst to notice an abdominal mains controversial. There are two major Wilms’ tu- mass or abdominal distension in their child. Children mor study groups: the North American National are usually asymptomatic. Pain, gross hematuria, Wilms Tumor (NWTS) study group and the Interna- fever, and hypertension occur in approximately 25% tional Society of Pediatric Oncology (SIOP) in Eu- of children (Grundy et al., 2002). Hypertension is rope. The NWTS recommends resecting the entire usually attributed to increases in rennin activity. tumor and sampling local lymph nodes at diagnosis. Anemia, fever, and rapid abdominal distension can SIOP however, discourages biopsies and recom- occur if there has been hemorrhage into the tumor, mends chemotherapy with vincristine and actino- but this occurs rarely. Syndromes such as BWS and mycin to shrink the tumor to make surgical resection WAGR are linked to Wilms’ tumor, so features associ- easier, followed by removal and staging. If pulmonary ated with these syndromes should be noted (e.g., lesions are noted on CT scan, they should be biopsied aniridia, GU anomalies, hemihypertrophy). Rarely, at diagnosis prior to treatment. extrarenal Wilms’ tumors arise; they present as a Histologically, Wilms’ tumor can be comprised of retroperitoneal mass usually adjacent to the kidney. blastemal, epithelial, and stromal components, a tu- Symptoms of thrombosis should also be considered mor typically consists of all three components, but and note made of any leg swelling and/or prominent one component could predominate. If greater than
78. Solid Tumors Chapter 2 59 Figure 2.6 Chest x-ray demonstrating pul- monary metastases in Wilms’ tu- mortwo-thirds of the tumor composition is of one com- mation prior to treating tumors, especially with sur-ponent, the histological type is assigned to the tumor, gery, because if the contralateral kidney has theseas they can behave quite differently (Neville and nephrogenic rests, a Wilms’ tumor may develop in theRitchey, 2000). Monophasic blastemal is a highly future.invasive type of Wilms’ tumor. Cystic or partially Histologically, RCC in children tends to have adifferentiated cystic nephroma do extremely well papillary architecture (Broecker, 2000). CCSK have aand are often cured with surgery alone. Diffuse or distinct histological appearance, but several variantfocal anaplasia is associated with unfavorable histol- patterns such as epithelioid, myxoid, cystic, and spin-ogy and is seen is approximately 5% of tumors dling exist. Additionally, CCSK can show anaplastic(Neville and Ritchey, 2000). Anaplasia is character- features. This tumor is often misdiagnosed. RTK isized by large nuclei that are three times the size of thought to be neurogenic in origin. Cells have anuclei of other cells, hyperchromasia of enlarged prominent acidophilic cytoplasm, resembling rhab-cells, and the presence of polyploid mitotic features. domyoblasts. They are, however, negative for makersDiffuse anaplasia is characterized by more than one of skeletal muscle (Grundy et al., 2000).area of anaplasia in tumor sample or in regional There are no speciﬁc tumor markers for Wilms’ tu-nodes or metastases (Neville and Ritchey, 2000). mor. For the workup of a patient; however, bloodNephrogenic rests are precursor lesions to Wilms’ should be sent for CBC, liver function tests, renaltumor and are comprised of abnormally persistent function tests, and coagulation screen. It has beenembryonal nephroblastic tissue with small clusters noted that acquired Von Willebrand’s disease occursof blastemal, epithelial, or stromal cells. They are seen in 8% of Wilms’ tumor patients at diagnosis, andin kidneys of 35% of unilateral Wilms’ tumors treatment with DDAVP may be necessary to correctand nearly 100% of bilateral. The term nephroblas- coagulation prior to surgical intervention (Grundy ettomatosis describe a clinical situation in which there al., 2002).are multiple nephrogenic rests. Although they arenot malignant, it is important to know this infor-
79. 60 Chapter 2 E. Hendershot Table 2.15. Staging system for renal tumors developed by the National Wilms’Tumor Study Group Stage Description I Tumor conﬁned to the kidney and completely resected. No penetration of the renal capsule. No involvement of renal sinus vessels II Tumor extends beyond the kidney but is completely resected (negative margins and lymph nodes). At least one of the following has occurred: (i) penetration of the renal capsule (ii)invasion of the renal sinus vessels (iii) biopsy of tumor before removal (iv) spillage of tumor locally during removal III Postoperatively, gross or microscopic residual tumor remains, including inoperable tumor positive surgical margins tumor spillage involving peritoneal surfaces regional lymph node metastases, or transacted tumor thrombus IV Hematogenous metastases or lymph node metastases outside the abdomen (lung, liver, bone or brain) V Bilateral disease at diagnosis (with attempts made to stage each side at diagnosis) 2.7.6 Staging and Classiﬁcation mycin-D, and doxorubicin, then reevaluated at week 5 and resected as per the NWTS group. Bilateral tu- The NWTS developed a staging system for Wilms’ mors should be biopsied and staged separately.All ef- tumor. It is based on surgical resectability and the forts should be made to leave any healthy functioning presence of bilateral and metastatic disease (see kidney in place by performing a partial nephrectomy Table 2.15). and wedge resection; however, this should not be at- tempted if clear margins are not possible. These pa- 2.7.7 Treatment tients end up having difﬁculties with renal dysfunc- tion, and renal failure occurs in 15% of patients 15 The treatment for Wilms’ tumors always involves sur- years post-treatment, depending on remaining gery and chemotherapy and sometimes radiothera- amount of functioning kidney and/or damage related py. As previously stated, controversy surrounds the to chemotherapy drugs and radiotherapy (Neville treatment of Wilms’ tumor. SIOP asserts that if pre- and Ritchey 2000). operative chemotherapy is given, the tumor is easier Patients with RCC are treated primarily with sur- to remove and fewer complications arise. Diagnosis is gery. There is no standard treatment for advanced therefore made on clinical and diagnostic imaging stage disease. The tumors are not responsive to ra- only. The wrong diagnosis is made in 5% of cases diotherapy, and there is no current chemotherapy (Grundy et al., 2002). The approach of the NWTS–V that is effective. MacArthur et al. (1994), however, did is outlined in Table 2.16. Tumors are completely re- report complete response to interleukin-2 in one sected at diagnosis, and nodes are sampled. child with metastatic RCC. A transperitoneal surgical approach is recom- mended for surgical resection so that the contralater- 2.7.8 Prognosis al kidney can be examined intraoperatively and local lymph nodes sampled. Spillage during surgical resec- The long-term survival is approaching 90% in pa- tion results in a six-fold increase in local abdominal tients with localized Wilms’ tumors and 70% in pa- recurrence; these patients are therefore upstaged tients with metastatic disease (Pritchard-Jones, (Grundy et al. 2002). If a tumor is inoperable at diag- 2002). The results of the NWTS-IV as described by nosis due to size or thrombosis, after biopsy the tu- Neville and Ritchey (2000) show 4-year overall sur- mor is treated as a Stage III with vincristine, actino- vival to be
80. Solid Tumors Chapter 2 61Table 2.16. Protocol for National Wilms’Tumor Study-V (adapted from Neville and Ritchey, 2000) Stage of disease Surgery Radiotherapya Chemotherapy Stage I and II, favorable Nephrectomy None Pulse intensive dactinomycin, histology (no anaplasia) vincristine (18 weeks) Stage I with focal or diffuse anaplasia Stage III and IV, favorable Nephrectomy Yes Pulse intensive dactinomycin, histology vincristine, doxorubicin (24 weeks) Stage II-IV, focal anaplasia Stage II-IV, diffuse anaplasia Nephrectomy Yes Dactinomycin, vincristine, Stage I-IV, CCSK doxorubicin, cyclophosphamide, and etoposide (24 weeks) Stage I-IV, RTK Nephrectomy Yes Carboplatin, etoposide, and cyclophosphamide (24 weeksa Radiotherapy doses are approximately 1,080 cGy for the abdomen and 1,200 cGy for the lung. Only patients with stage IV lung metastases receive whole lung radiotherapy▬ 96% in stage I with favorable histology failure; cardiac sequelae might be exacerbated in▬ 91% for stage II with favorable histology those patients who also received lung radiation. Pa-▬ 91% for stage III with favorable histology tients who have been treated with VP16 need to be▬ 80% for stage IV with favorable histology screened for second myeloid leukemias, and second-▬ Stages II-IV with diffuse anaplasia was 82% ary malignancies are a risk in the radiation ﬁeld. Ovarian failure is a possible late effect resulting fromRTK in the NWTS III series had an overall 4-year sur- some of the chemotherapeutic agents.vival of 25% and CCSK stages II-IV was 75%. For pa-tients with stage I RCC, the survival is 90%; however, 2.7.10 Future Perspectiveswith stage IV disease the survival is about 0%(Broecker, 2000). The outcomes for children with Wilms’ tumor are rel- atively favorable. Future efforts will focus on tailoring2.7.9 Follow-up therapy by decreasing chemotherapy and radiation therapy when possible in order to minimize treat-Follow-up for Wilms’ tumor involves regular physical ment-related toxicity, based on risk stratiﬁcation.exams and surveillance scanning, usually with at There is also interest in learning about predisposingleast abdominal ultrasound and chest x-ray. This is factors to Wilms’ tumor and whether the use of an-usually done every 3 months for the ﬁrst 2 years, fol- tiangiogenic agents will have a future role. Topotecanlowed by every 6 months for 2 years and then with de- is being currently used in relapsed Wilms’ tumorscreasing frequency or as clinically appropriate. Renal with some effect; it may have a continued role in thefunction does need to be monitored in the remaining future.kidney quite carefully, especially if bilateral disease New therapies distinct from the protocols forexisted and radiation therapy was received. Wilms’ tumor need to be developed for RCC and RTK. Late effects of radiation therapy and speciﬁcchemotherapeutic agents should be assessed. Pa-tients who received anthracycline therapy should bemonitored for cardiomyopathy or congestive heart
81. 62 Chapter 2 E. Hendershot ed parent, and the second hit occurs after conception. 2.8 Retinoblastoma The second hit affects a somatic retinal cell. It can be a mutation in form of a deletion, chromosomal Retinoblastoma (Rb) arises from fetal retinoblasts loss by nondysjunction, or somatic recombination that normally differentiate into post-mitotic retinal (Knudson, 2001). The ﬁrst hit can either be constitu- photoreceptor cells and neurons. The tumor tends to tional (heritable bilateral or multifocal) or somatic outgrow its blood supply, which results in necrosis (nonheritable unilateral), but the second hit is always and calciﬁcation. somatic. Errors in transcription occur more often in the paternal allele, suggesting that germ line muta- 2.8.1 Epidemiology tions occur more often in spermatogenesis than oo- genesis. Predisposition to Rb is imparted by germline Rb is the most frequently diagnosed intraocular ma- mutation in 40% of cases (Hurwitz et al. 2002). It is lignancy of childhood. It represents 3% of all pedi- transmitted as an autosomal dominant trait; pene- atric malignancies, with an incidence of approxi- trance may be as high as 90%, but it is not 100%. mately 1 in 18,000 live births. Eighty percent of cases There is 50% chance that a child of an affected parent are diagnosed before the age of 3 or 4 years. Sixty per- will inherit the disease. A patient’s sibling’s can pres- cent of cases are nonheritable and unilateral. Forty ent with the disease even if the parents appear to be percent of cases are heritable (bilateral or multifo- unaffected, either because of a low penetrance allele cal), of which 5% are familial and the rest are spo- or a germline mosaicism (Hurwitz et al. 2002). The radic. Metastases can occur in up to 10–15% of pa- heritable form of the disease, characterized by the er- tients (Rodriguez and Pappo, 2003). rors in the Rb1 gene, predisposes children to a small risk for sporadic secondary malignancies and a much 2.8.2 Etiology higher risk for radiation-induced secondary malig- nancies. Rb can occur in one or both eyes. Bilateral Rb is gen- erally picked up earlier than unilateral cases. There 2.8.3 Molecular Genetics has been an association between Rb and congenital abnormalities in the 13q- syndrome (Yunis and Ram- Molecular analysis has become increasingly sensitive say, 1978), and with other abnormalities including at picking up chromosomal aberrations, although cardiovascular defects, cleft palate, infantile cortical testing is not routinely done at all centers. The Rb1 hyperostosis, dentinogenesis imperfecta, familial gene is located at chromosome 13q14. The Rb1 gene cataracts, Bloch-Sulzberger syndrome, and mental is a tumor suppressor gene and is important in apop- retardation (Hurwitz et al., 2002). The incidence of tosis. It is a key regulator of the cell cycle and there- Rb has been reported to be higher after in vitro fer- fore governs the proliferation of tumor cells. In Rb, tilization procedures. deregulation of cell proliferation occurs as a result of The heritable form of Rb is associated with errors the inactivated or absent Rb1 protein, and constraint in transcription, translocations, or deletions of ge- that is normally exerted over the cell cycle is lost (Ro- netic information on chromosome 13q14. Bilateral driguez-Galindo and Pappo, 2003). Rb can occur at different times, so conservative man- agement should be used in young infants who present 2.8.4 Signs and Symptoms with disease in one eye only, as there is potential for tumors to develop in the second eye. The most common signs of retinoblastoma are Knudson’s two-hit theory of cancer can be used to ▬ Leukocoria (cat’s eye reﬂex) – caused by the tumor, explain the etiology of Rb. One abnormal chromo- which is white and occludes the normal red retina some is commonly inherited at conception from an unaffected parent, or rarely inherited from an affect-
82. Solid Tumors Chapter 2 63▬ Strabismus – the tumor’s placement over the mac- under anesthesia. The pupils should be well dilated to ula causes loss of central vision and disruption of allow for complete visualization of the fundus. CT of the fusional reﬂex, causing the affected eye to drift the brain and orbits is needed to detect distal spread▬ Glaucoma – increased intraocular pressure due to of tumor and identify areas of calciﬁcation. MRI of the tumor the brain has been shown to be an excellent method▬ Decreased vision in one eye – caused by the tumor of localizing intraocular extent of disease as well as covering the macula or retinal detachment visualizing tumor extension into the optic nerve and orbital area. A bone marrow aspirate is often done toSome other presenting signs include esotropia, detect metastatic disease if there is an apparent riskpainful eyes, and erythematous conjunctivae. Hete- for hematogenous spread (i.e. choroidal involve-rochromia (discoloration of the iris) warrants imme- ment). A lumbar puncture may be done to determinediate enucleation because it is a sign of advanced dis- if there is metastatic extension to the cerebrospinalease. Seventeen percent of patients with Rb and 50% ﬂuid; this is especially necessary when there is opticof children with advanced Rb requiring enucleation, nerve involvement. Ultrasound is a common test thatpresent with rubeosis iridis, which is neovasculariza- is performed on eyes affected by Rb and shows the tu-tion of the surface of the iris (Hurwitz et al., 2002). mor in reference to anatomical structures (Servo-Hyphema, blood in the anterior chamber of the eye, didio et al., 1991). Fundoscopic pictures are also tak-can occur secondary to rubeosis iridis, so its presence en during the exam under anesthesia.in the absence of trauma warrants an immediate oc- Retinoblastoma can present as trilateral disease.ular examination. Glaucoma and closed angle glau- This is rare, with an incidence of 3%; 6–10% of thosecoma are also presenting symptoms that usually in- affected have a genetic predisposition to the disease.dicated advanced disease. Endophytic tumors or dif- In addition to bilateral ocular tumors, a tumor is alsofuse inﬁltrating tumors may produce pseudohypopy- seen on the pineal gland in trilateral retinoblastoma.on (cells in anterior chamber). It is typically associated with an extremely poor Metastatic spread of Rb occurs through several prognosis and usually occurs in children ages 4 andmechanisms. Tumor can spread posteriorly through younger (Hurwitz et al., 2002). Trilateral disease canthe optic nerve to the brain and cerebrospinal ﬂuid. even be seen years after successfully treated ocularThe second method of extraocular spread occurs disease and is a major cause of mortality for thesethrough lymphatic dissemination; this can occur an- children in the ﬁrst 5 years after diagnosis of bilater-teriorly through the iris and ciliary body. Direct ex- al Rb.tension can occur through sclera into the orbit. The diagnosis of Rb is made by ophthalmoscopic,Through the choroid, Rb can spread hematogenously radiologic, and ultrasonographic appearance of theto other sites in the body such as bone, bone marrow, tumor; pathological conﬁrmation is unnecessary. Rblung, and brain. is a small blue round cell tumor consisting of dense- ly packed cells. It is mitotically active, and when the2.8.5 Diagnostics eye is enucleated, there are Flexner-Winterstein rosettes, which are highly characteristic of Rb. SeeThe diagnostic workup for Rb begins with a thor- Fig. 2.7 for metastatic Rb in the bone marrow.ough history, paying particular attention to the dura-tion of symptoms and changes in the eye’s appear- 2.8.6 Staging and Classiﬁcationance. Special attention should be given to familial his-tory and incidence of Rb. There are several common growth patterns of Rb tu- Physical examination should assess visual acuity mors. With an endophytic pattern, tumor arises from(cranial nerve II), tracking (cranial nerves III, IV, and retina and grows into the vitreal cavity. These tumorsVI), strabismus, esotropia, and leukocoria. Direct and usually ﬁll the cavity and ﬂoat in the vitreous and areindirect fundoscopic examination should be done known as vitreal seeds. Exophytic tumors grow from
83. 64 Chapter 2 E. Hendershot Figure 2.7 Metastatic retinoblastoma in the bone marrow Table 2.17. The Reese-Ellsworth classiﬁcation system for retinoblastoma Group I A: Single tumor, smaller than 4 disk diametersa at or behind the equator Very favorable B: Multiple tumors, none larger than 4 disk diameters, all at or behind the equator Group II A: Solitary tumor, 4–10 disk diameters in size, at or behind the equator Favorable B: Multiple tumors, 4–10 disk diameters in size, behind the equator Group III A: Any lesion anterior to the equator Doubtful B: Solitary tumors larger than 10 disk diameters behind the equator Group IV A: Multiple tumors, some larger than 10 disk diameters Unfavorable B: Any lesion extending anteriorly to the ora serrata Group V A: Tumors involving more than half the retina Very unfavorable B: Vitreous a Disc diameter = 1.5–1.75 mm the retina into the subretinal space and cause serious The Reese-Ellsworth classiﬁcation system is cur- detachments of the retina. From the retina they can rently the most frequently used tool (Table 2.17). proceed to invade the choroid or the blood supply. A Murphree has developed a simpler staging system, mixed presentation of endophytic and exophytic pat- but this has not been adopted widely into practice at terns is the most common occurrence (Hurwitz et al., this time 2002). Diffuse inﬁltrating Rb is the least common presentation; it usually occurs in older children and is a diagnostic challenge.
84. Solid Tumors Chapter 2 652.8.7 Treatment Focal therapies are used alone or as adjuvant treat- ment with chemotherapy. Cryotherapy can be effec-The goals of treatment for Rb are to preserve useful tively used to manage small anterior tumors.vision without compromising patient survival. The Cryotherapy entails freezing the tumor with a probe,major treatment modalities for Rb include surgical allowing the tumor to thaw, and then repeating thisenucleation, radiation, and chemotherapy, as well as process several times. It is usually performed atfocal cryotherapy and photocoagulation therapy. monthly intervals. Photocoagulation therapy is used Enucleation is used often in the management of for small posterior tumors. Laser burns are madeRb. It is used to treat large unilateral tumors with no around the tumor, which in effect cut the blood sup-visual potential. Tumors that invade the optic nerve, ply to the tumor, ultimately causing cell death.choroid, or sclera or those that extend into the orbit Until recently, chemotherapy has not played aneed to be removed. Twenty percent of children with large role in treating intraocular Rb. A study by Chanbilateral disease lose both eyes eventually (Hurwitz et et al. (1996) revealed that 30% of already enucleatedal., 2002). Enucleation is also used when extensive tumors show resistance to chemotherapy. P-glyco-seeding is evident, as with anterior invasion and sec- protein is the multidrug-resistance protein, and wasondary glaucoma. When the eye is enucleated, an or- expressed in these chemoresistant tumors (Gallie etbital implant is surgically placed and the rectus mus- al., 1996). P-glycoprotein in vitro has been shown tocles are attached to allow for some movement of the actively pump chemotherapy out of tumors. Chan eteventual prosthesis. al. (1996) found that high concentrations of cy- External beam radiation was frequently used in closporin reversed this process. A current phase IIIthe past treatment of Rb. Its disadvantages include fa- trial is ongoing to evaluate the efﬁcacy of high-dosecial hypoplasia, cataract development, retinopathy, cyclosporin in conjunction with the chemotherapyand increased risk of secondary tumors in the radia- agents vincristine, carboplatin, and etoposide. Pre-tion ﬁeld. Children who carry the germ line Rb muta- liminary data are showing good results with this ap-tion and receive radiation therapy are at a 35% in- proach, which avoids radiation therapy. Adjuvantcreased risk of developing a secondary malignancy treatment with photocoagulation and cryotherapy(Gallie et al. 1996). But because Rb cells are very ra- are used in conjunction with the chemotherapy ad-diosensitive, radiotherapy is sometimes used for the ministration. Viable tumor is often left followingtreatment of medium sized tumors. The dose, which chemotherapy, so focal therapy is imperative follow-ranges 3,500 and 4,500 cGy, is given in 20 fractions ing the cessation of chemotherapy. Other treatment(Servodidio et al., 1991). More recently stereotactic protocols continue to use similar chemotherapyradiation has been used to target some intraocular agents in conjunction with focal therapy and withouttumors, removing the need to radiate the entire orbit. the use of cyclosporin with good success for Reese-Incidence of cataracts is lessened with this approach Ellsworth eye groups 1, 2, and 3 (Friedman et al.,(Hurwitz et al. 2002). 2000). Plaque radiotherapy is another form of radiation Chemotherapy has always played a role in thetherapy. With this form of radiation treatment, cobalt treatment of metastatic disease. In advancedor iodine plaques are surgically implanted at the scle- metastatic disease high-dose chemotherapy followedral base of the tumor. The plaque remains in place for by stem cell rescue is sometimes being done where2 to 4 days and then is surgically removed. This treat- available. This is only useful if complete local controlment is used on medium-sized tumors situated away of metastatic disease has been obtained. Intrathecalfrom the optic nerve and macula (Chan et al. 1996). administration of cytarabine and topotecan has alsoPlaque radiotherapy is most often used as a second- been attempted in efforts to clear metastatic diseaseary treatment after another form has failed. in the cerebrospinal ﬂuid.
85. 66 Chapter 2 E. Hendershot 2.8.8 Prognosis diosensitizers may act to diminish the resistance of hypoxic cells to radiation, with the hope of increasing The overall 5-year survival for Rb is 90% (Hurwitz et the rate of successful radiation. al., 2002). Unfortunately, the survival in patients with metastatic disease remains poor. Optic nerve inva- sion posterior to the lamina cribrosa at time of enu- 2.9 Rhabdomyosarcoma cleation is predictive of poor prognosis. Rhabdomyosarcoma (RMS) develops from a primi- 2.8.9 Follow-up tive mesenchymal cell committed to muscle differen- tiation. They can occur anywhere in the body, even in Ongoing follow-up of children with Rb is needed well places where skeletal muscle would not be seen. after tumor control has been established. Children with hereditary disease are at risk of developing new 2.9.1 Epidemiology tumors until retinal differentiation is complete, around the age of 7. Following the treatment of Rb, Rhabdomyosarcoma is the most common soft tissue fundoscopic examinations are imperative to pick up sarcoma that occurs in children. It affects approxi- recurrent disease quickly. Eye exams are generally mately 4.5 per million children less than 15 years of done under anesthesia while the child is receiving ac- age in age (Gurney et al,. 1995). It is the third most tive therapy. Once a child is only being monitored common extracranial solid neoplasm of childhood. and is able to cooperate, eye exams can be moved to Males have a very slightly higher incidence, and the outpatient setting. whites have a 15% increased rate of occurrence com- A child treated with chemotherapy and/or radia- pared with blacks (Gurney et al., 1995). Two-thirds of tion therapy must be followed up for late effects of children presenting with RMS do so before the age of their treatment. Carboplatin can cause hearing dis- 6 (Wexler et al., 2002). Younger children tend to pres- turbances, so audiograms must be a regular part of ent with the embryonal subtype of RMS, whereas the the follow-up regimen. Secondary leukemias are a alveolar subtype occurs throughout childhood. potential following treatment with VP16. Secondary malignancies can arise in ﬁelds of prior irradiation. 2.9.2 Etiology Children with the Rb1 gene mutation are at an in- creased risk of developing secondary neoplasms. The cause of RMS is unknown. There is association Families must be taught to be conscientious in re- with other genetic syndromes including neuroﬁbro- porting any changes in their children’s health. matosis, Li-Fraumeni syndrome, and BWS (Wexler et al. 2002). Parental use of marijuana has shown a 2.8.10 Future Directions three-fold increased risk of developing RMS in some studies (Wexler et al., 2002). Other environmental Potential future directions in the treatment of Rb in- factors that are being considered as adding to the risk clude monoclonal antibody, interferon, and gene are parental use of cocaine, prior exposure to alkylat- therapy. There are also international efforts under- ing agents, intrauterine x-ray, and fetal alcohol syn- way for a clinical trial examining the use of chemo- drome. A higher incidence of RMS has also been not- therapy and focal therapy in an effort to avoid radia- ed in patients with congenital anomalies of the gas- tion therapy. The use of cyclosporine in conjunction trointestinal, genitourinary, cardiovascular and cen- with chemotherapy and focal therapy will be trialed tral nervous systems. on a larger scale to help delineate if cyclosporine re- verses multidrug resistance and results in superior outcomes compared with chemotherapy alone in treating intraocular tumors. The development of ra-
86. Solid Tumors Chapter 2 67Table 2.18. The prevalence of rhabdomyosarcoma according to primary site and the correlating clinical symptoms (Wexler etal., 2002) Site of primary tumor Prevalence Clinical symptoms Parameningeal 16 % Airway obstruction (Ear, nasal cavity, sinuses, infratem Respiratory symptoms poral fossa, pterygopalatine fossa) Nasal congestion Pain Cranial nerve palsies Orbit 9% Proptosis Periorbital swelling Other head and neck 10 % Swelling or mass Extremities 18 % Swelling or mass Genitourinary 22 % Prostate: bladder and/or bowel difﬁculties Paratesticular: scrotal swelling, pain, mass above the testes Uterus, bladder, cervix: menorrhagia, or metrorrhagia Vagina: protruding grape-like cluster (typical for botryoid) Other 25 %2.9.3 Molecular Genetics alveolar subtype. A tumor should be treated as alveo- lar even when it displays only scattered alveolar fociRMS falls into the category of small round blue-cell because alveolar imparts a worse prognosis and re-tumors. They can be differentiated from tumors with quires treatment intensiﬁcation.similar morphology based on electron microscopy, The embryonal subtypes have not revealed anyimmunocytochemistry, and cytogenetic analysis. translocations but characteristically have shown lossSixty percent of RMSs are of the embryonal subtype, of heterozygosity at 11p15.5 (Pappo et al., 1997).and 5% of those are considered the botryoid variant, The undifferentiated sarcomas tend to have a20% are the alveolar subtype, and the remaining 20% t(11;22), which are seen often in the Ewing’s sarcomaare undifferentiated (Pappo et al., 1997). A solid vari- family of tumors, and tumors are generally treatedant is referred to as a pleomorphic form revealing the similarly.presence of anaplastic cells in large sheets. Alveolar RMS has a characteristic t(2;13) seen 2.9.4 Symptoms and Clinical Signsin over one-half of patients and a second t(1;13)translocation seen less commonly (Pritchard-Jones RMS can occur anywhere in the body with the excep-and Mitchell, 1997). In the t(2;13) rearrangement, the tion of bone and is not limited to those places wherePAX3 gene is fused with the FKHR gene, whereas the skeletal muscle exists. The prevalence of the tumors(1;13) rearrangement causes fusion of PAX7-FKHR. according to primary and the correlating clinicalIt is thought that PAX3 and PAX7 are vital to muscle symptoms are listed in Table 2.18.development during embryogenesis. Patients with RMS spreads via hematogenous and lymphaticmetastatic disease and PAX7 fusion gene tend to have routes. The most common sites for metastases area more favorable prognosis than those with the PAX3 lung, lymph nodes, bone, and bone marrow.(Pappo et al., 1997). N-Myc is ampliﬁed in 10% of the
87. 68 Chapter 2 E. Hendershot Table 2.19. Clinical group staging system for rhabdomyosarcoma Clinical group Extent of disease and surgical result I A Localized tumor, conﬁned to site of origin, completely resected B Localized tumor, inﬁltrating beyond site of origin, completely resected II A Localized tumor, gross total resection but with microscopic residual disease B Locally “extensive” tumor (spread to regional lymph nodes), completely resected C “Extensive” tumor (spread to regional lymph nodes), gross total resection but with microscopic residual disease III A Localized or locally extensive tumor, gross residual disease after biopsy only B Localized or locally extensive tumor, gross residual disease after “major” resection (>50 % debulking) IV Any size primary tumor, with or without regional lymph node involvement, with distant metastases, irrespective of surgical approach to primary tumor 2.9.5 Diagnostics (Pappo et al., 1997). A bilateral bone marrow aspirate and biopsy are also done to rule out bone marrow in- Necessary diagnostic tests in the workup of a patient volvement. A lumbar puncture should be done for thought to have RMS include children with parameningeal primaries to determine whether the cerebrospinal ﬂuid is inﬁltrated with tu- ▬ imaging of the affected area mor cells. ▬ imaging of likely areas for metastases Blood work should consist of a CBC, LDH, and ▬ tumor biopsy liver function tests. Urinalysis is required. There ▬ blood work are no speciﬁc tumor markers for RMS. In planning Initial workup consists of x-ray or ultrasound of the for treatment, it is also prudent to do necessary primary, depending on location. Once a mass is iden- prechemotherapy surveillance studies such as an tiﬁed, CT or MRI scanning should be ordered to eval- echocardiogram and audiogram. uate the extent of the mass and look for evidence of bony erosion. A CT of the chest should be done to 2.9.6 Staging and Classiﬁcation look for pulmonary metastases. If the tumor is locat- ed in a paraspinal or parameningeal area, an MRI Staging normally follows two distinct systems. The should be ordered to assess the extent of disease. A ﬁrst involves the TNM (tumor, node, metastases) bone scan is ordered to rule out bony metastases. system, which takes into account not only surgical MRI of the head should be considered if the child is outcome, which may be dependent on the surgeon’s symptomatic at diagnosis or has a paraspinal pri- skill, but also site, size, local invasiveness, and pres- mary. ence of nodes and metastases, and then divides A biopsy is done to obtain a tumor specimen; this patients into distinct prognostic groups (Andrassy, can be either via core or open biopsy. The specimen 2002). (See Table 2.19.). The second grouping system, should be sent for cytogenetics with FISH (or reverse by the Intergroup Rhabdomyosarcoma Study (IRS) transcription PCR when FISH is not available). group, looks at pretreatment and operative outcome Light microscopy reveals rhabdomyoblasts or cross (Table 2.20). Both stage and group are used to deter- striations, which are both seen in skeletal muscle. mine appropriate therapy. Survival correlates with RMS cells stain positive for intermediate ﬁlaments, clinical group, while TNM staging aids in determin- desmin, vimentin, myoglobin, actin, and myoD ing risk stratiﬁcation to allow for risk-based therapy.
88. Solid Tumors Chapter 2 69Table 2.20. TNM pretreatment staging classiﬁcation for rhabdomyosarcoma (T1 conﬁned to anatomic site of origin; T2 exten-sion; NO not clinically involved; N1 clinically involved; NX clinical status unknown; MO, no distant metastases; M1 distant metas-tasis present) Stage Sites Tumor invasiveness Tumor size Regional nodes (N) Metastases 1 Orbit T1 or T2 aa or bb NO, N1, or NX MO Head and neckc Genitourinaryd 2 Bladder/prostate T1 or T2 aa NO or NX MO Extremity Cranial parameningeal Otherd 3 Bladder/prostate T1 or T2 aa N1 MO Extremity bb NO, N1, or NX MO Cranial parameningeal Othere 4 All T1 or T2 aa or bb No or N1 M1a d a <5 or =5 cm in diameter Nonbladder/nonprostateb e >5 cm in diameter Includes trunk, retroperitoneum, and so onc Excluding parameningeal Used in Intergroup Rhabdomyosarcoma Study IV2.9.7 Treatment Radiation therapy is used for microscopic tumor or residual tumor not removed during surgery. TheTreatment for RMS includes surgery, radiation thera- timing of radiotherapy is variable depending on thepy (sometimes brachytherapy), and chemotherapy. protocol used. In the IRS V protocols, radiation ther-The full treatment plan for RMS depends largely on apy begins at week 15 for patients in the high-riskthe location of the tumor. The IRS group has a strati- group, week 12 for intermediate risk, week 3 for lowﬁcation schema for tumors according to the primary risk, and immediately for some high-risk patientssite, stage, TNM and histology. The timing of each with advanced cranial tumors (Wexler et al., 2002).depends on the clinical disease group and study pro- Chemotherapy is used for cytoreduction prior totocols. In general, surgery is often followed by radia- a gross total resection and for both gross andtion therapy and chemotherapy; in cases of complete micrometastatic disease. Chemotherapeutic agentssurgical resection, chemotherapy alone is used. that are used in treating RMS are vincristine and Surgery depends largely on the site of disease and actinomycin D for low-risk tumors. Vincristine, acti-the feasibility of complete surgical resection. Surgical nomycin, and cyclophosphamide (VAC) is the goldresection also helps delineate the clinical grouping to standard for intermediate-risk RMS, although otherbe used. Surgery over the years has become more agents such as ifosfamide, etoposide, and doxo-conservative with each intergroup rhabdomyosarco- rubicin also show activity. Currently, irinotecan isma study. Treatments in a recent study have used risk being used in the IRS V protocol to determine itsstratiﬁcation based on the likelihood of disease re- activity in patients with distant metastases at diagno-currence, and divided patients into low-, intermedi- sis (Wexler et al., 2002). Chemotherapy has tradition-ate-, and high-risk groups. Risk is determined by ex- ally been given longer in RMS than in other solidamining the site and size of the tumor, nodal disease, tumors, sometimes for 12–24 months in IRS studiesand histology. (McDowell, 2003).
89. 70 Chapter 2 E. Hendershot Surgery with adequate margins is the treatment of timodal risk adapted therapy. Patients with metasta- choice for head and neck tumors where possible, al- tic disease at diagnosis (Group IV disease) continue though deforming surgery is not warranted. If com- to have a poor prognosis and a 3-year event-free sur- plete resection is not possible, then radiation therapy vival of only 25% (Breneman et al., 2003). is used. Both of these groups of patients receive chemotherapy. For RMS in the orbit, resection with- 2.9.9 Follow-up out disﬁguration is not possible, so chemotherapy and radiation therapy are the treatment of choice Follow-up protocols for children treated for RMS (Andrassy, 2002). For bladder and prostate tumors, must look for both local recurrence and late effects of surgery, with postoperative radiotherapy for both treatment. Most protocols generally require follow- gross or microscopic residual disease, and chemo- up every 3 months for the ﬁrst year, with physical therapy are used. Those children with bladder tu- exam, as well as chest x-ray or chest CT to look for mors often have dysfunction postoperatively, which lung metastases, and CT or MRI of the primary. Dur- is lessened somewhat with more conservative surgi- ing the second and third years screening may occur cal approaches and the use of radiation (Andrassy, with decreasing frequency as clinically appropriate. 2002). For paratesticular RMS, radical inguinal or- Follow-up must consider late effects of all treatments chiectomy is recommended along with ipsilateral including, site-speciﬁc radiation and surgery as well retroperitoneal lymph node dissection. Adjuvant as chemotherapy. These children generally have a chemotherapy has favorable cure rates. If nodal re- high risk for developing secondary tumors later in sections are positive, retroperitoneal radiation and life if they have been radiated and must continue to intensiﬁed chemotherapy are warranted. Vaginal, be followed (Andrassy, 2002) vulval, and uterine RMS used to be treated with radi- cal, mutilating surgery; but the IRS now recommends 2.9.10 Future Perspectives combination chemotherapy post-biopsy followed by conservative surgery and radiation therapy for in- Patients with metastatic alveolar RMS who are PAX3- completely resected disease (Andrassy, 2002). RMS of FKHR positive continue to do poorly on standard the extremities is treated when possible with limb- treatment protocols, and new targeted therapy needs sparing surgical resection. At the time of surgery, ag- to be developed. Molecular gene fusions such as the gressive lymph node sampling is warranted or, when PAX3-FKHR oncogene may be a therapeutic target in available, sentinel node biopsy, and postoperative ra- the future (Sorensen et al. 2002). Some clinicians be- diation therapy to these sites is recommended lieve that radiation therapy that is hyperfractionated, as well as conventional chemotherapy agents such as 2.9.8 Prognosis VP16 and ifosfamide, may have a role in treating ad- vanced-stage RMS (Kaefer, 2002). Others, however, The overall 5-year survival in RMS is 70% (Pappo et believe that dose escalation of chemotherapy and ra- al., 1997). A review article by Andrassy (2002) states diation therapy is futile because these are not tumor- that 90% of paratesticular tumors are cured, overall speciﬁc (Pappo et al., 1997). survival for bladder/prostate is 85%, and orbital RMS Studies testing the value of antisense, oligonu- has survival rates greater than 90%. Patients who cleotides, and ribozymes in RMS cell lines currently have limb primaries have an overall survival of 66%. exist, but their value is yet to be determined (Pappo et This is because these tumors are often disseminated al., 1997). Irinotecan and topotecan are being used in and the histology is usually of the alveolar subtype. some clinical phase II trials in patients with metasta- Patients who are high-risk, who have unresectable tu- tic disease. As with many other solid tumors current- mors in unfavorable sites, have an overall survival of ly, immunotherapy, antiangiogenic agents, and bio- 73% (McDowell, 2003). The improved prognosis and logical agents are thought to have a future role. survival in this group of patients is attributed to mul-
90. Solid Tumors Chapter 2 71Table 2.21. Prognostic factors in the NRSTS (Miser et al., 2002) Factors associated with Factors associated with Factors associated increased risk of local increased risk of distant with decreased survival relapse metastases Microscopically X X positive margins Tumor >5 cm X X X High histologic grade X X Intraabdominal X X primary tumor No radiotherapy X Invasive tumor X surgically resectable tumors treated with or without2.10 Non-rhabdomyosarcomatous radiation therapy exceeds 70% (Spunt et al., 1999).Soft Tissue Sarcomas Although the overall survival of children with completely resected tumors is generally excellent,Non-rhabdomyosarcomatous soft tissue sarcomas 20% of these children will relapse and die of their(NRSTS) are a heterogeneous group of tumors. Col- disease (Miser et al. 2002). It is important to recognizelectively they account for approximately 4% of can- those tumors with a high potential for local and dis-cers occurring in childhood (Spunt et al., 2002). tant recurrence so that appropriate adjuvant treat-NRSTS are normally staged according to the Inter- ment is utilized in their initial treatment. Prognosticgroup Rhabdomyosarcoma Study Group surgico- factors in NRSTS are described in Table 2.21.pathologic staging system. This staging reﬂects the NRSTS in general are not very chemosensitive tu-postoperative tumor status (Table 2.19). The TNM mors; however, in some instances adjuvant chemo-staging system takes into account the presurgical tu- therapy is warranted. High-grade tumors that aremor status, including size, local invasiveness, pres- surgically resected but are large (>5 cm) may beneﬁtence of nodes, and metastases. NRSTS are also grad- from adjuvant chemotherapy regardless of surgicaled, 1 through 3, and their grade is of important prog- margins. Chemotherapy has also been used as neoad-nostic signiﬁcance. Grade is based on histological juvant therapy in unresectable tumors, in those thatsubtype, amount of necrosis, number of mitoses, the have been incompletely excised, and in metastaticdegree of cellularity, and nuclear features. Collective- disease. Vincristine, actinomycin, and cyclophos-ly this information is used to determine appropriate phamide have been used with good response in inop-treatment stratiﬁcation. erable infantile ﬁbrosarcoma (Ninane 1991). Ifos- The treatment approach for NRSTS is similar re- famide and doxorubicin have been used as adjuvantgardless of tumor type. Primary treatment consists of treatment for some NRSTS (especially with synovialwide surgical excision of the tumor. A surgical mar- sarcoma), with questionable results. Metastaticgin of 1 cm is considered adequate if free of all mi- NRSTS do poorly and require new therapies.croscopic disease. Radiotherapy is sometimes used as The most commonly occurring NRSTS in childrenadjuvant treatment in the presence of microscopic will be brieﬂy discussed, with typical features uniqueresidual disease or in the presence of inadequate sur- to each tumor summarized.gical margins. The long-term survival of patients with
91. 72 Chapter 2 E. Hendershot Alveolar Soft Part Sarcoma (ASPS) This tumor is usually more aggressive and associated with metasta- found most often in late adolescence, with an inci- tic disease and poor outcome (Miser et al., 2002). This dence higher in females. It represents 0.5–1% of all tumors can metastasize to lung and bone. soft tissue sarcomas in adults and children (Pang et al., 2001). Primary sites of disease are the skeletal Leiomyosarcoma This malignant smooth muscle tu- muscles of the extremities with the deep soft tissue mor accounts for less than 2% of NRSTS in children. of the thigh and buttocks being the most common Radiation therapy may predispose a child to (Cofﬁn et al. 1997). The head and neck regions are leiomyosarcoma. Incidences of this neoplasm devel- more common in children. ASPS metastasizes to oping in the radiation ﬁeld of children previously lung, bone, and CNS. This disease has an indolent treated for retinoblastoma have been reported. EBV course, and relapses can occur very late. Imaging gen- has been linked to leiomyosarcoma in children with erally shows a large intramuscular mass with promi- HIV. A t(12;14) translocation has been noted in the nent vascularity. Chromosomal abnormalities have tumors of children with leiomyosarcoma (Miser et been identiﬁed at t(x;17)(p11.2q25) (Miser et al., al., 2002). The most common site of occurrence is the 2002). Prognosis is best for head and neck tumors but gastrointestinal (GI) tract, speciﬁcally the stomach, poor in general. but it can occur in any vascular structure or soft tis- sue. Gastric epithelioid leiomyosarcomas can occur Fibrosarcoma This spindle cell tumor has two peaks as part of Carney’s triad.When leiomyosarcoma is di- in incidence. It typically affects young infants and agnosed, regular scanning should be done to rule out children, with the second childhood peak occurring the presence or development of paraganglioma and between the ages of 10 and 15 (Carli et al., 1997). Con- pulmonary chondroma. Patients with tumors arising genital or infantile sarcomas are generally found in in the GI tract usually have a poor outcome. the distal extremities and the head and neck regions; these tumors grow rapidly but rarely metastasize. In Liposarcoma Liposarcoma most commonly affects the adult form, or in children who are older, presen- adolescents in the second decade of life, with a slight tation typically occurs in the proximal extremities, male predominance. The deep soft tissues of the ex- and the deep thoracic and pelvic regions. Adult-type tremities account for about half of pediatric cases, tumors often have cytogenetic abnormalities such a: and the second most common site of occurrence is t(x;18), t(2;5), and t(7;22) (Miser et al., 2002). These the trunk (retroperitoneum). Metastases are not tumors are more aggressive and tend to metastasize common but can occur in the lymph nodes, lung, liv- more often. The overall 5-year survival with infantile er, and brain. Liposarcomas can be of myxoid, round ﬁbrosarcoma is 84–93%, but with older children sur- cell, well-differentiated, or pleomorphic subtypes vival correlates with the adult form of the disease, (Cofﬁn et al., 1997). In the myxoid variant, which is with the 5-year overall survival being 60% (Cofﬁn et the most common, a characteristic t(12;16)(q13;p11) al., 1997; Miser et al., 2002). is often seen (Swanson and Dehner, 1991). Liposarco- mas usually have a low malignant potential, and chil- Hemangiopericytoma This neoplasm represents ap- dren generally have a low rate of recurrence (Cofﬁn et proximately 3% of all soft tissue sarcomas in children al., 1997). (Miser et al. 2002). This is a vascular tumor that often display the cytogenetic abnormalities of t(12;19) and Malignant Fibrous Histiocytoma Malignant ﬁbrous t(13;22). It is often found in the oral cavity, chest wall, histiocytoma (MFH) comprises 2–6% of all soft tis- and head and neck of infants and is termed infantile sue sarcomas in children under 20 (Cofﬁn et al., hemangiopericytoma; it is usually associated with an 1997). Males and females are affected equally. It pres- excellent outcome with complete resection. In older ents most often in the head, neck, and extremities as children and adults, the tumor is found more often in a painless mass. The lungs are a common site of the lower extremities and retroperitoneum and is metastases. Associations have been found between
92. Solid Tumors Chapter 2 73MFH and children who have received prior radiationtherapy, as well as those who have DNA repair defects 2.11 Germ Cell Tumors(Cofﬁn et al., 1997). There are four main subtypes ofthis neoplasm, with the most common being stori- Germ cell tumors (GCTs) are a heterogeneous groupform-pleomorphic; the other subtypes are giant cell, of neoplasms that arise from primordial germ cells.myxoid, and inﬂammatory. This tumor is character- They range from benign teratomas to aggressive ma-ized by p53 immunoreactivity and the ampliﬁcation lignancies. Extragonadal GCTs result from germ cellsof the MDR2 gene (Cofﬁn et al., 1997). The prognosis migrating aberrantly during fetal development. Pre-for this tumor is poor, with a relapse rate of up to 43% sumably the differences in stage of germ cell devel-and tumor death rate of 44% (Cofﬁn et al., 1997) opment at the time of tumorigenesis play a role in the malignant potential of this group of tumors.Malignant Peripheral Nerve Sheath Tumor (MPNST)MPNSTs arise from the peripheral nerve sheaths, as 2.11.1 Epidemiologytheir name suggests, and they are also referred to asneuroﬁbrosarcomas. They are among the most com- GCTs comprise 3% of all childhood neoplasms andmon of the soft tissue sarcomas occurring during occur at an annual incidence of approximately 2.4 perchildhood representing 10–20% of all NRSTS. They million children (Gurney et al., 1995). There is a bi-most commonly occur in the second decade of life, modal peak in the ages of occurrence, with the ﬁrstwith males and females being affected equally. There peak occurring in children less than 5 and the secondis a well-established association between neuroﬁbro- in adolescents 15–19. Females are affected more oftenmatosis and the development of this tumor. Muta- with benign GCTs and males are more often affectedtions of p53 on chromosome 17 have been noted. by malignant GCTs.There are, however, no characteristic genetic anom-alies in this tumor. The most common anatomic sites 2.11.2 Etiologyof presentation of MPNSTs are the extremities andtrunk. Cryptorchidism (undescended testes) and gonadal dysgenesis are known to predispose for GCTs.Synovial Sarcoma Synovial sarcoma (SS) is the mostcommonly occurring NRSTS in older children and 2.11.3 Molecular Geneticsyoung adults (Miser et al. 2002). There is a very slightmale predominance in the development of SS. It Several characteristic genetic abnormalities predom-has three histological subgroups: biphasic, which inate in GCTs, which can be divided into four groups,is the most common and represents 60% of cases, each with its distinct molecular characteristics: tu-monophasic-epithelial, and monophasic-ﬁbrous. mors of the adolescent testes, tumors of infancy, ex-SS carries a characteristic genetic alteration t(x;18) tragonadal tumors of adolescents, and tumors of the(p11;q11) (Cofﬁn et al., 1997). SS normally occurs in adolescent ovary (see Table 2.22).close proximity to a joint, tendon, or bursa. The mostcommon site of presentation is the leg near the knee 2.11.4 Symptoms and Clinical Signsor ankle joint, followed by the arm. The lung is a com-mon site for metastases; lymph nodes are less com- Clinical symptoms of disease depend on the locationmonly affected. Diagnostic imaging usually shows a of the tumor. Tumors arise either in gonadal or ex-mass with calciﬁcation. SS is one of the more tragonadal midline sites. GCTs occur in the ovarieschemosensitive NRSTSs. 25% of the time and in the testes 20% of the time. They occur in extragonadal locations more than half of the time: 25% occur in the sacrococcygeal region and 20% occur in the brain, with other sites includ-
93. 74 Chapter 2 E. Hendershot Table 2.22. Common genetic alterations associated with germ cell tumors (Cushing and Marina, 2000) GCT tumor group Ploidy Chromosomal alterations Tumors of the adolescent testes Aneuploid Isochromosome 12p Loss of 13 Gain of 8, 21,1q Tumors of infancy Teratomas Diploid Abnormalities at 1, 3, 6 Yolk sac tumor Diploid or Tetraploid Abnormalities at 1, 3, 6 Extragonadal tumors of adolescents Brain Diploid or tetraploid Loss of 13 and 8 Mediastinum Some have i(12p)a; loss of 13 and 8 Tumors of the adolescent ovary Mature teratoma 5 % show gain or loss of an entire chromosome Immature teratoma No consistent changes Malignant ovarian GCT Aneuploid i(12p)a; gains of 21 and1q a Two copies of 12p exist, both coming from the same parent ing the retroperitoneal, pelvic, and neck area (Ro- There are serum tumor markers for some of the driguez-Galindo and Pappo, 2003). GCTs metastasize GCTs. Onco-feto-proteins such as alpha feto-protein via both hematogenous and lymphatic spread. Com- (AFP) and beta human chorionic gonadotropin mon sites of metastasis are lung and liver. (BHCG) are used for screening. Elevations in AFP are Testicular tumors usually present as a mass or seen with endodermal sinus tumor (EST) and em- swelling in the scrotum and are usually not painful. bryonal carcinoma; increased BHCG is seen in chori- Ovarian tumors usually present with symptoms such ocarcinoma. Serum onco-feto-proteins should de- as pain, tenderness, and abdominal swelling. Medi- cline within a half-life following the removal of a tu- astinal disease may cause symptoms of respiratory mor, which for AFP is 7 days,- and for BHCG is 24 distress. Sacrococcygeal tumors can present with hours. Failure of these tumor markers to fall may in- symptoms of urinary retention and constipation or dicate persistent disease (Pinkerton, 1997a,b). Non- as a visible gluteal mass. CNS disease may present speciﬁc markers such as LDH are often ordered, and with headaches, visual disturbances, precocious pu- elevated levels are thought to correlate with growth of berty, hypothyroidism, and diabetes insipidus. solid tumors (Cushing and Marina, 2000). Placental alkaline phosphatase is the isoenzyme of alkaline 2.11.5 Diagnostics phosphatase and is used as a screening test at some centers; increases are seen in seminomas. Pituitary An ultrasound is usually done initially to investigate function should be evaluated before and during ther- abdominal and pelvic tumors and is helpful in differ- apy. entiating solid from cystic masses. CT of the chest, Biopsy and preferably tumor resection (but not abdomen and pelvis, is recommended to assess the mutilating surgery) are necessary for both patholog- extent of primary disease and assessing for the pres- ical diagnosis and treatment. ence of metastases. Bone scan may be indicated if bone pain is a presenting feature; however, GCTs rarely metastasize to bone.
94. Solid Tumors Chapter 2 75 Figure 2.8 Schema for differentiation path- ways for germ cell tumors (adapted from Pinkerton, 1997)2.11.6 Staging and Classiﬁcation 2.11.7 TreatmentGerm cells develop from a primordial germ cell. The treatment of both malignant and benign GCTs isThere are many different morphological subtypes, surgical resection if feasible. Mutilating surgerywhich reﬂect the pathway of differentiation to which should be avoided because GCTs are chemosensitive.the cell was dedicated prior to malignant transforma- Radiation therapy is often used for intracranial GCTstion. Fig. 2.8 shows the schema of differentiation either alone or with chemotherapy. Radiation is alsopathway for GCTs. used at times for residual disease post-chemotherapy Separate staging systems exist for ovarian and tes- or in the case of bulky mediastinal disease post-ticular tumors. However, staging of both is similar to chemotherapy.that for other solid tumors: For malignant GCTs requiring chemotherapy, platinum-containing regimens (cisplatin or carbo-▬ Stage I indicates localized disease conﬁned to pri- platin) are considered the standard of care. Other mary site, completely resected chemotherapeutic agents that have been used to treat▬ Stage II implies some degree of microscopic resid- GCTs include actinomycin, vinblastine, bleomycin, ual disease or nodal involvement (<2 cm) doxorubicin, and etoposide. Low-risk patients, those▬ Stage III is characterized by gross residual disease with stage I gonadal, are treated with surgical resec- or lymph node involvement (>2 cm) tion alone and do not require further treatment up-▬ Stage IV denotes distant metastases (Cushing et front but need to be closely followed. Similarly, ex- al., 2002) tragonadal tumors that are completely resected may not require further treatment. Those with an inter-Characteristics that are associated with the different mediate risk, including stages II–IV gonadal andhistologic subtypes of GCTs are summarized in stage II extragonadal disease are treated with stan-Table 2.23. dard chemotherapy such as PEB (cisplatin, etoposide, and bleomycin) or JEB (carboplatin, etoposide, bleomycin) for four courses. High-risk patients, those with stage III and IV extragonadal disease, usually re-
95. 76 Chapter 2 E. Hendershot Table 2.23. Germ cell tumors (GCT): subtypes, disease sites, and speciﬁc characteristics (Cushing et al., 2002) Malignant category Subtype Sites of disease Speciﬁc characteristics Benign GCT Mature teratomas Ovaries Mature elements of all three germ Sacrococcygeal area cell layers Mediastinum Benign GCT Gonadoblastoma Dysgenic gonad Mix of gonadal sex cord cells and immature germ cells GCT of intermediate Immature teratoma Ovaries Graded based on degree of behavior maturation (0–2 show benign behavior) Malignant GCT Germinoma Ovaries (dysgerminoma) Chemosensitive CNS (pineal region) Radiosensitive Testes (seminoma) Yolk sac tumor Sacrococcygeal Elevate serum AFP (endodermal sinus tumor) Testes Embryonal carcinoma Testes Major component of mixed GCT Mediastinum Ovaries Choriocarcinoma Pineal region Elevated serum bHCG Mediastinum Ovary Testes quire 6 months of chemotherapy with cisplatin, stages I through IV have an event-free survival of etoposide, and bleomycin. Intergroup studies (POG 89.6% with HDPEB (Rodriguez-Galindo and Pappo, and CCG) in the United States have shown that event- 2003). free survival can be improved in the high-risk group of GCTs if high-dose cisplatin therapy instead of the 2.11.9 Follow-up standard dosing is used in conjunction with standard dose etoposide and bleomycin (HDPEB) (Rodriguez- Close surveillance, clinical as well as regular tumor Galindo and Pappo, 2003), but the cisplatin-associat- marker assessment, should occur following the surgi- ed toxicity (ototoxicity predominantly as well as cal resection of teratomas for up to 5 years because nephrotoxicity) is severe. disease recurrence is possible. Malignant GCTs should have regular follow-up with either CT or ul- 2.11.8 Prognosis trasound of abdominal and pelvic tumors, or MRI of intracranial tumors, every 3 months for the ﬁrst year, The 5-year overall survival of those with mature and followed by a decreasing frequency of scanning inter- immature teratoma is 100% (Cushing et al,. 2002). val over the next several years. CT of the chest is rec- Results of the COG/POG randomized trials of PEB ommended at regular intervals for metastatic sur- versus HD PEB have shown that the 3-year event-free veillance. survival for those with stage II testicular tumors is Follow-up must also consider late effects of treat- 100%, and for stage I and II ovarian tumors it is ment. Cisplatin, especially high-dose cisplatin thera- 96.4% (Rodriguez-Galindo and Pappo, 2003). Those py, is associated with signiﬁcant hearing loss, and fol- with gonadal stages III and IV and extragonadal low-up audiograms are imperative so that hearing
96. Solid Tumors Chapter 2 77aids can be ordered if warranted. Nephrotoxicity can this tumor is very high in Brazil, 10–15 times that ob-also be a problem during and following cisplatin served in the United States. There is a high incidencetherapy, and renal function studies should be moni- of Li-Fraumeni syndrome in the families of the chil-tored after the completion of therapy. Pulmonary dren who acquire ACC. Germline mutations of theﬁbrosis may result from bleomycin therapy, and p53 gene are found in one-third of patients (Kockpulmonary function studies should be done regular- et al., 2002). Interestingly, in Brazil, children withly in follow-up. Secondary malignancies including ACC typically have p53 mutations but they are notmyeloid leukemias have been noted after treatment germline. Cushing syndrome, reﬂecting hormonalwith chemotherapy, especially etoposide. Those who excess, is a presenting sign of ACC in 68% of childrenhave undergone cranial radiation should receive reg- (Plowman, 1997). Evidence of the development ofular neuropsychological testing. Screening of thy- secondary sex characteristics occurs as a presentingroid, corticotropin, gonadotropin, and growth hor- sign in 95% of patients younger than 5 (Kock et al.,mone should also occur regularly following cranial 2002). Other clinical signs are abdominal pain, fever,radiation therapy. anorexia, and weight loss. In children, approximately 40% of patients secrete no active hormones, but their2.11.10 Future Perspectives inactive steroid precursors such as pregnenolone, 11- deoxycortisone, and 17-hydroxypregnenolone can beThe use of high-dose cisplatin has led to increased found in blood and urine (Kock et al., 2002). ACC cansurvival in patients with advanced malignant GCTs. present as localized disease but presents with region-Ototoxicity is a problem for these patients. Prelimi- al spread to adjacent lymph nodes or the retroperi-nary data from the recent POG study are disappoint- toneum 20% of the time. Distant metastases to lunging regarding the effectiveness of amifostine to pro- and bone can also occur. Curative treatment dependstect against signiﬁcant ototoxicity. The formal devel- on early wide total excision of the tumor while it isopment of risk groups is needed in order to stratify still encapsulated. Repeated surgeries are warrantedtreatment. The role of carboplatin, ifosfamide, and if isolated recurrences occur. For patients withouttopotecan may also be used to determine their utility surgically curable disease, mitotane therapy is oftenin relapsed GCTs. Effective treatment for high-risk initiated, which is meant to cause necrosis and dis-patients remains controversial. Future studies are ease regression while improving the endocrine sys-currently being planned that incorporate new agents tem (Plowman, 1997). Chemotherapy agents such assuch as topotecan and paclitaxel. ﬂuorouracil, etoposide, doxorubicin, and cisplatin are also sometimes used. These approaches, although they may increase length of survival, are not usually2.12 Rare Tumors curative. The prognosis is generally quite poor for ACC.There are numerous tumors that occur very infre-quently in children and adolescents. Most of the 2.12.2 Melanomararely occurring neoplasms are those that are seenmost often in the adult population. Several more Melanoma accounts for 1.3% of childhood neo-commonly occurring rare tumors will be summa- plasms; it represents the second most common carci-rized here. noma found in children (Rodriguez-Galindo and Pappo, 2003). There is a much higher incidence in2.12.1 Adrenocortical Carcinoma (ACC) whites compared with blacks and in females. Condi- tions that are associated with melanoma in childrenAdrenocortical carcinoma is a very rare and aggres- include congenital melanomas, giant congenitalsive tumor. It occurs more often in females and peaks melanocytic nevi, xeroderma pigmentosum, im-in the ﬁrst and fourth decades of life. The incidence of munosuppression, neurocutaneous melanosis, and
97. 78 Chapter 2 E. Hendershot mole phenotype (atypical moles) (Pratt and Pappo, location. Radiotherapy is the primary treatment 2002). Presenting signs may include a mole that has modality. Adjuvant chemotherapy is often used in changed in size or color, accompanied by bleeding or children, and the tumor shows response to agents itching, with a palpable subcutaneous mass or lym- such as ﬂuorouracil, cisplatin, carboplatin, metho- phadenopathy. Common sites are the trunk, head and trexate, and bleomycin. Multiple researchers have neck. Metastases generally occur via regional lymph noted survival rates to be 75% for T1 and T2 tumors, node spread prior to lung, bone, and brain. The but only 37% for T3 and T4 tumors (Pratt and Pappo, American Joint Committee on Cancer staging system 2002). Late effects of radiation such as xerostomia, of melanoma takes into account tumor thickness, ul- muscle atrophy, ﬁbrosis of the neck, and hypothy- ceration, nodal disease, and metastases (Balch et al., roidism may be some of the sequelae that affect this 2001). Children with thick melanoma >4 mm and group of children. those with lymphadenopathy should undergo imag- ing with CT and MRI to determine the presence of 2.12.4 Thyroid Carcinoma metastatic disease. Wide excision of the lesion is nec- essary for cure with adequate margins. Interoperative Thyroid carcinoma is the most commonly occurring lymphatic mapping with sentinel node biopsy has carcinoma in children (Rodriguez-Galindo and Pap- been shown to be highly sensitive at identifying po, 2003). It generally occurs more often in females, nodal disease and is usually done for lesions greater with a peak in incidence between ages 7 and 12. It is than 1 mm in thickness. Alpha interferon therapy has well established that neck irradiation is a causative been used in high risk resected melanoma (Pratt and factor in the development of thyroid carcinoma; how- Pappo, 2002). In disseminated disease, agents such as ever, it does also occur sporadically and is associated vincristine, dactinomycin, cyclophosphamide, cis- with some familial syndromes. Cervical adenopathy platin, and etoposide, and interleukin 2 have been and thyroid nodules are often the presenting clinical used with varying rates of success (Pratt and Pappo, signs; metastases generally occur in the lung and me- 2002). Prognosis depends largely on tumor stage at diastinum. Twenty percent of patients have metastat- diagnosis. ic disease at diagnosis (Kock et al., 2002). The tumor is characterized by the secretion of T3 and some- 2.12.3 Nasopharyngeal Carcinoma times T4. There are several different subtypes of thy- roid carcinoma: papillary, follicular, and anaplastic This tumor occurs in the epithelium of the nasophar- (Kock et al. 2002). Imaging is generally done with ul- ynx, generally affecting males more often than fe- trasound and thyroid scintiscan, and chest x-ray or males. There has been association of EBV infection CT is done to rule out lung metastases. A biopsy is with this tumor (Plowman, 1997). This tumor has needed to conﬁrm malignancy and histology. Com- three distinct subtypes, and children are usually af- plete surgical resection (thyroidectomy) is the treat- fected by the undifferentiated type. It arises in the ment of choice for thyroid carcinoma. Radioiodine fossa of Rosenmuller and can spread via direct exten- therapy is used postoperatively if metastatic disease sion through the oropharynx to the base of the skull is present and also to ablate any residual functioning and result in cranial nerve palsies (Pratt and Pappo, thyroid. Thyroid hormone needs to be supplemented 2002). The only clinical sign of this disease may in these patients. The prognosis for thyroid carcino- be cervical lymphadenopathy, indicating regional ma is generally quite good, with overall survival in metastases. Distant metastases are present in less some reports approaching 90%, and metastatic dis- than 5% of cases, and most common sites include ease does not necessarily impart a poor prognosis lung and bone (Plowman, 1997). The tumor is staged with the use of radioiodine therapy (Kock et al., as per the tumor, node, metastases (TNM) classiﬁca- 2002). tion system. Surgery is often not possible for na- sopharyngeal carcinoma because of its anatomical
98. Solid Tumors Chapter 2 79 Chan HSL, DeBoer F, Thiessen JJ, Budnig A, Kingston JE,References O’Brien JM, Koren G, Giesbrecht E, Haddad G, Verjee Z, Hungerford JL, Ling V, Gallie BL (1996) combining cy-Alexander F (2000) Neuroblastoma. Urologic Clinics of North closporin with chemotherapy controls intraocular retino- America 27 (3): 383–392. blastoma without requiring radiation. Clinical Cancer Re-Andrassy, RJ (2002) Advances in the surgical management of search 2: 1499–1508 sarcomas in children. American Journal of Surgery 184 (6): Chauvenet A, Schwarz CL, Weiner MA (2000) Hodgkin’s dis- 484–491. ease in children and adolescents. In Bast RC, Kufe, DW, Pol-Bacci G, Ferrari S, Lari S, Mercure M, Donati D, Longhi A, Forni lock RE, Weichselbaum RR, Holland JF, Frei E (eds), Cancer C, Bertoni F, Versari M, Pignotti E (2002a) Osteosarcoma of Medicine (5th edn.). Hamilton: B.C. Decker Inc. the limb: Amputation or limb salvage in patients treated by Cheung NK, Kushner BH, Kramer K (2001) Monoclonal anti- neoadjuvant chemotherapy. Journal of Bone and Joint body-based therapy of neuroblastoma. Hematology Clinics Surgery 84B (1): 88–92. of North America 15 (5): 853–866Bacci G, Ferrari S, Longhi A, Forni C, Zavatta M, Versari M, Cofﬁn CM, Dehner LP, O’Shea PA (1997) Pediatric Soft Tissue Smith K (2002b) High-grade osteosarcoma of the extremi- Tumors A Clinical Pathological and Therapeutic Approach ty: Differences between localized and metastatic tumors at Baltimore: Williams & Wilkins presentation. Journal of Pediatric Hematology/Oncology Cushing B, Marina N (2000). Germ cell tumors. In Bast RC, 24(1): 27–3 Kufe, DW, Pollock RE, Weichselbaum RR, Holland JF, Frei EBalch CM, Buzaid AC, Soong SJ, et al. (2001) Final version of the (eds), Cancer Medicine (5th edn.). Hamilton: B.C. Decker American joint committee on cancer staging system for cu- Inc. taneous melanoma. Journal of Clinical Oncology 16 (16): Cushing B, Perlman EJ, Marina NM, Castleberry RP (2002). 3635–3648. Germ cell tumors. In Pizzo PA and Poplack DG (eds), Prin-Bataller L, Rosenfeld MR, Graus F, Vilchez JJ, Nai-Kong V, Che- ciples and Practice of Pediatric Oncology (4th edn.). ung NV, Dalmau J (2003) Autoantigen diversity in the Philadelphia: Lippincott Williams & Wilkins. opsoclonus-myoclonus syndrome. Annals of Neurology 53: Czauderna P, Mackinlay G, Perilongo G, Brown J, Shafford E, 347–353. Aronson D, Pritchard J, Chapchap P, Keeling J, Plaschkes J,Beckwith JB (1998) Nephrogenic rests and the pathogenesis of Otte JB (2002) Hepatocellular carcinoma in children: Re- Wilms’ tumor: Developmental and clinical considerations. sults of the ﬁrst prospective study of the international soci- American Journal of Medical Genetics 79: 268–273. ety of pediatric oncology group. Journal of Clinical Oncol-Blakely ML, Ritchey ML (2001) controversies in the manage- ogy 20 (12): 2798–2804. ment of Wilms’ tumor. Seminars in Pediatric Surgery 10(3): Donaldson SS (2003) A discourse: The 2002 Wataru W. Sutow 127–31. lecture Hodgkin disease in children – perspectives andBreneman JC, Lyden E, Pappo AS, Link MP, Anderson JR, progress. Medical Pediatric Oncology 40:73–81. Parham DM, Qualman SJ, Wharam MD, Donaldson SS, Donaldson SS, Hudson MM, Lamborn KR, Link MP, Kun L, Bil- Maurer HM, Meyer WH, Baker KS, Paidas CN, Crist WM lett AL, Marcus KC, Hurwitz CA, Young JA, Tarbell NJ, We- (2003) Prognostic factors and clinical outcomes in children instein HJ (2002) VAMP and low-dose, involved ﬁeld radia- and adolescents with metastatic rhabdomyosarcoma: A re- tion for children and adolescents with favorable, early-stage port from the intergroup rhabdomyosarcoma study IV. Hodgkin’s disease: Results of a prospective clinical trial. Journal of Clinical Oncology 21(1): 78–84. Journal of Clinical Oncology 20 (14): 3081–3087.Brodeur GM (2003) Neuroblastoma: Biological Insights into a Douglass EC, Reynolds M, Finegold M, et al. (1993) Cisplatin clinical enigma. Nature Reviews Cancer 3: 203–216. vincristine and ﬂuorouracil therapy for hepatoblastoma: aBrodeur GM, Maris JM (2002) Neuroblastoma. In Pizzo PA Pediatric Oncology Group study. Journal of Clinical Oncol- and Poplack DG (eds) Principles and Practice of Pediatric ogy 11:96–99. Oncology (4th edn.). Philadelphia: Lippincott Williams & Ferrari S, Briccoli A, Mercuri M, Bertoni F, Picci P, Tienghi A, Wilkins. Brach Del Prever A, Fagioli F, Comandone A, Bacci G (2003)Broecker B (2000) Non-Wilms’ renal tumors in children. Uro- Postrelapse survival in osteosarcoma of the extremities: logic Clinics of North America 27 (3): 463–469. Prognostic factors for long-term survival. Journal of Clini-Cairo MS, Perkins S (2000) Non-Hodgkin’s lymphoma in chil- cal Oncology 21 (4): 710–715. dren. In Bast RC, Kufe, DW, Pollock RE, Weichselbaum RR, Friedman DL, Himelsein V, Shields CL, Shields JA, Needle M, Holland JF, Frei E (eds), Cancer Medicine (5th edn.). Hamil- Miller DB, Bunin GR, Meadows A (2000) Chemoreduction ton: B.C. Decker. and local ophthalmic therapy for intraocular retinoblas-Carli M, Guglielmi M, Sotti G, Cecchetto G, Ninfo V (1997) Soft toma. Journal of Clinical Oncology 18 (1): 12–17. tissue sarcomas. In Pinkerton CR, Plowman PN (eds), Pae- diatric Oncology Clinical Practice and Controversies (2nd edn.). London: Chapman and Hall.
99. 80 Chapter 2 E. Hendershot Gallie BL, Budnig A, Deboer F, Thiessen JJ, Koren G, Verjee Z, Jurgens H, Winkler K, Gobel U (1997). Bone tumours. In Ling V, Chan HSL (1996) chemotherapy with focal therapy Pinkerton CR, Plowman PN (eds), Paediatric Oncology can cure intraocular retinoblastoma without radiotherapy. Clinical Practice and Controversies (2nd edn.). London: Archives of Ophthalmology 114: 13211328. Chapman and Hall Gallie BL, Dunn JM, Chan HSL, Hamel PA, Phillips RA (1991) Kaefer M, Rinck RC (2000) Genitourinary rhabdomyosarco- The genetics of retinoblastoma. Pediatric Clinics of North ma: Treatment options. Urology Clinics of North America America 28 (2): 299–313. 27(3): 471–487 Ginsberg JP, Woo SY, Johnson ME, Hicks MJ, Horowitz ME Kager L, Zoubek A, Potschger U, Kastner U, Flege S, Kempf- (2002) Ewing’s sarcoma family of tumors: Ewing’s sarcoma Bielack B, Branscheid D, Kotz R, Salzer-Kuntschik M, of bone and soft tissue and the peripheral primitive neu- Winkelmann W, Jundt G, Kabisch H, Reichardt P, Jurgens H, roectodermal tumors. In Pizzo PA and Poplack DG (eds), Gadner H, Bielack SS (2003) Primary metastatic osteosar- Principles and Practice of Pediatric Oncology (4th edn.). coma: Presentation and outcome of patients treated on Philadelphia: Lippincott Williams & Wilkins. neoadjuvant cooperative osteosarcoma study group proto- Grundy PE, Green DM, Breslow NE, Ritchey ML, Perlman EJ, cols. Journal of Clinical Oncology 21 (10): 2011–2018 Macklis RM (2002) Renal tumors. In Pizzo PA and Poplack Katzenstein HM, Krailo MD, Malogolowkin MH, Ortega JA, DG (eds), Principles and Practice of Pediatric Oncology (4th Liu-Mares W, Douglass EC, Feusner JH, Reynolds M, Quinn edn.). Philadelphia: Lippincott Williams & Wilkins. JJ, Newman K, Finegold MJ, Haas JE, Sensel MG, Castleber- Grundy PE, Green DM, Breslow NE, Ritchey ML, Thomas PRM ry RP, Bowman LC (2002a) Hepatocellular carcinoma in (2000) Renal tumors of childhood. In Bast RC, Kufe, DW, children and adolescents: Results from the pediatric oncol- Pollock RE, Weichselbaum RR, Holland JF, Frei E (eds), ogy group and the children’s cancer group intergroup Cancer Medicine (5th edn.). Hamilton: B.C. Decker Inc. study. Journal of Clinical Oncology 20 (12): 2789–2797 Gurney JG, Severson RK, Davis S, Robinson LL (1995) Inci- Katzenstein HM, London WB, Douglass EC, Reynolds M, dence of cancer in children in the United States. Cancer 75 Plaschkes J, Finegold MJ, Bowman LC (2002b) Treatment of (8): 2186–2195. unresectable and metastatic hepatoblastoma: A pediatric Gurney JG, Young JL, Roffers SD, et al. (1999) Soft tissue sarco- oncology group phase II study. Journal of Clinical Oncolo- mas. In: Gloeckler Ries LA, Smith MA, Gurney JG, et al., gy 20 (16): 3438–3444 (eds.) SEER Pediatric Monograph: Cancer incidence and Knudson AG (2001) Two genetic hits (more or less) to cancer. survival among children and adolescents, United States Nature Reviews 1: 157–170 SEER program 1975–1995. Bethesda, MD: National Cancer Kock CA, Pacak K, Chrousos GP (2002) Endocrine tumors. In Institute p. 111–124 Pizzo PA and Poplack DG (eds), Principles and Practice of Hawkins DS, Feigenhauer J, Park J, Kreissman S, Thomson B, Pediatric Oncology (4th edn.). Philadelphia: Lippincott Douglas J, Rowley SD, Gooley T, Sanders JE, Pendergrass Williams & Wilkins TW (2002) Peripheral blood stem cell support reduces the Link MP, Gebhardt MC, Meyers PA (2002) Osteosarcoma. In toxicity of intensive chemotherapy for children and adoles- Pizzo PA and Poplack DG (eds), Principles and Practice of cents with metastatic sarcomas. Cancer 95 (6): 1354–1365. Pediatric Oncology (4th edn.). Philadelphia: Lippincott Hudson MM, Donaldson SS. (2002) Hodgkin’s disease. In Pizzo Williams & Wilkins PA and Poplack DG (eds), Principles and Practice of Pedi- MacArthur CA, Issacs H, Miller JH, et al. (1994) Pediatric renal atric Oncology (4th edn.). Philadelphia: Lippincott Williams cell carcinoma: A complete response to recombinant inter- & Wilkins leukin-2 in a child with metastatic disease at diagnosis. Hurwitz Rl, Shields CL, Shields JA, Chevez-Barrios P, Hurwitz Medical and Pediatric Oncology 23: 365–371 MY, Chintagumpala MM (2002) Retinoblastoma. In Pizzo Magrath IT (2002). Malignant non-Hodgkin’s lymphoma in PA and Poplack DG (eds), Principles and Practice of Pedi- children. In Pizzo PA and Poplack DG (eds), Principles and atric Oncology (4th edn.). Philadelphia: Lippincott Williams Practice of Pediatric Oncology (4th edn.). Philadelphia: Lip- & Wilkins pincott Williams & Wilkins Indolfe P, Terenziani M, Casale F, Carli M, Bisogno G, Schiavet- Matthay KK, Yamashiro DJ (2000) Neuroblastoma. In Bast RC, ti A, Mancini A, Rondelli R, Pession A, Jenkner A, Pierani P, Kufe, DW, Pollock RE, Weichselbaum RR, Holland JF, Frei E Tamaro P, De Bernardi B, Ferrari A, Santoro N, Giuliano M, (eds), Cancer Medicine (5th edn.). Hamilton: B.C. Decker Cecchetto G, Piva L, Surico G, Di Tullio, MT (2003) Renal cell McDowell HP (2003) Update on childhood rhabdomyosarco- carcinoma in children: A clinicopathologic study. Journal of ma. Archives of Disease in Children 88 (4): 354–357 Clinical Oncology 21 (3): 530–535 Metayer C, Lynch C,F, Clarke EA, Glimelius B, Storm H, Pukkala Jenkin RD,Al-Fawaz I,Al-Shabanah M,Allam A,Ayas A, Khafa- E, Joensuu T, van Leeuwen FE, van’t Veer, MB, Curtis RE, ga Y, Rifai,S, Schultz H, Memon M, Rifai S, Schultz H,Younge Holowaty EJ, Andersson M, Wiklund T, Gospodarowicz M, D (2002) Localized Ewing sarcoma/PNET of bone – prog- Travis, LB (2000) Second cancers among long-term sur- nostic factors and international data comparison. Medical vivors of Hodgkin’s diagnoses in childhood and adoles- and Pediatric Oncology 39 (6): 586–593 cence. Journal of Clinical Oncology 18 (21): 2435–2443
100. Solid Tumors Chapter 2 81Miser JS, Pappo AS, Triche TJ, Merchant TE, Rao BN (2002) Pritchard J, Brown J, Shafford E, et al. (2000) Cisplatin, doxoru- Other Soft Tissue Sarcomas of Childhood. In Pizzo PA and bicin, and delayed surgery for childhood hepatoblastoma: a Poplack DG (eds), Principles and Practice of Pediatric On- successful approach – results of the ﬁrst prospective study cology (4th edn.). Philadelphia: Lippincott Williams & of the international society of pediatric oncology. Journal Wilkins of Clinical Oncology 18:3810–3828Neville HL, Ritchey ML (2000) Wilms’ tumor: Overview of na- Pritchard-Jones K (2002) Controversies and advances in the tional Wilms’ tumor study group results Urologic Clinics of management of Wilms’ tumour.Archives of Disease in Chil- North America 27 (3): 435–442 dren 87 (3): 241–244Ninane J (1991) Chemotherapy for infantile ﬁbrosarcoma. Pritchard-Jones K, Mitchell CD (1997) The genetic basis of chil- Medical Pediatric Oncology 19: 209 dren’s cancers. In Pinkerton CR, Plowman PN (eds), Paedi-Ninane J, Pearson ADJ (1997) Neuroblastomas. In Pinkerton atric Oncology Clinical Practice and Controversies (2nd CR, Plowman PN (eds), Paediatric Oncology Clinical Prac- edn.). London: Chapman and Hall tice and Controversies (2nd edn.). London: Chapman and Pritchard-Jones K, Mitchell CD (1997) The genetic basis of chil- Hall dren’s cancers. In Pinkerton CR, Plowman PN (eds), Paedi-Oberlin O, Deley MC, Bui BN, Gentet JC, Philip T, Terrier P, Car- atric Oncology Clinical Practices and Controversies (2nd rie C, Mechinaud F, Schmitt C, Babin-Boillettot A, Michon J edn.). London: Chapman and Hall (2001) Prognostic factors in localized Ewing’s tumours and Ragland BD, Bell WC, Lopez RR, Siegal GP (2002) Cytogenetic peripheral neuroectodermal tumours: the third study of and molecular biology of osteosarcoma. Laboratory Inves- the French Society of Paediatric Oncology (EW88 study). tigation 82(4): 365–377 British Journal of Cancer 85 (11): 1646–1654 Rodriguez-Galindo C, Pappo AS (2003) Less-frequently en-Ortega JA, Krailo MD, Haas JE, et al. (1991) Effective treatment countered tumors of childhood. In Bast RC, Pollock RE,We- of unresectable or metastatic hepatoblastoma with cis- ichselbaum RR, Gansler TS, Holland JF, Frei E (eds), Cancer platin and continuous infusion doxorubicin chemothera- Medicine (6th edn.). Hamilton: B.C. Decker py: a report from the children’s cancer study group. Journal Rodriguez-Galindo C, Billups CA, Kun LE, Rao BN, Pratt CB, of Clinical Oncology 9:2167–2176 Merchant TE, Santana VM, Pappo,AS (2002a) Survival afterPang LM, Roebuck DJ, Grifﬁth JF, Kumta SM, Metreweli C recurrence of Ewing tumors: The St. Jude Children’s re- (2001) Alveolar soft-part sarcoma: a rare soft tissue malig- search hospital experience, 1979–1999. Cancer 94 (2): nancy with distinctive clinical and radiological features. Pe- 561–569 diatric Radiology 31: 196–199 Rowland JM (2002) Hepatoblastoma: Assessment of criteriaPappo AS, Shapiro DN, Crist WM (1997) Rhabdomyosarcoma for histologic classiﬁcation. Medical and Pediatric Oncolo- biology and treatment. Pediatric Clinics of North America gy 39:478–483 44 (4): 953–972. Sandlund JT, Downing JR, Crist WM. (1996) Non-Hodgkin’sPatte C (1997). Non-Hodgkin’s lymphoma. In Pinkerton CR, lymphoma in childhood. New England Journal of Medicine Plowman PN (eds.), Paediatric Oncology Clinical Practice 334:1238–1248 and Controversies (2nd edn.). London: Chapman and Hall Saylors RL, Stine KC, Sullivan J, Bernstein M, Harris MB (1999) Medical Cyclophosphamide plus topotecan in children with recur-Pinkerton CR (1997a) Malignant germ cell tumours in child- rent or refractory solid tumors: a Pediatric Oncology Group hood. European Journal of Cancer 33 (6): 895–902 (POG) Phase II study [abstract]. Journal of Pediatric Hema-Pinkerton CR (1997b) Malignant germ cell tumours. In Pinker- tology and Oncology 21: 332 ton CR, Plowman PN (eds), Paediatric Oncology Clinical Schleiermacher G, Peter M, Oberlin O, Philip T, Rubie H, Practice and Controversies (2nd edn.). London: Chapman Mechinaud F, Sommelet-Olive S, Landman-Parker J, Bours and Hall D, Michon J, Delattre O (2003) Increased risk of systemic re-Pinkerton CR, Michalski AJ,Veys PA, (eds) (1999) Clinical chal- lapses associated with bone marrow micrometastasis and lenges in Paediatric Oncology. Oxford: ISIS Medical Media circulating tumors cells in localized Ewing tumor. JournalPlowman PN (1997) Rare tumors. In Pinkerton CR, Plowman of Clinical Oncology 21 (1): 85–91 PN (eds), Paediatric Oncology Clinical Practice and Con- Schwartz CL (2003) The management of Hodgkin’s disease in troversies (2nd edn.). London: Chapman and Hall the young child. Current Opinions In Pediatrics 15 (1): 10–16Pratt CB, Pappo AS (2002) Management of infrequent cancers Servodidio CA,Abramson DH, Romanella A (1991) Retinoblas- of childhood. In Pizzo PA and Poplack DG (eds), Principles toma. Cancer Nursing 14 (3): 117–123 and Practice of Pediatric Oncology (4th edn.). Philadelphia: Shafford EA, Pritchard-Jones, K (1997) Liver tumors. In Pinker- Lippincott Williams & Wilkins ton CR, Plowman PN (eds), Paediatric Oncology Clinical Practice and Controversies (2nd edn.). London: Chapman and Hall
101. 82 Chapter 2 E. Hendershot Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B, Tomlinson GE, Finegold MJ (2002) Tumors of the liver. In Stram DO, Gerbing RB, Lukens JN, Matthay KK, Castleber- Pizzo PA and Poplack DG (eds), Principles and Practice ry RP(1999) The International Neuroblastoma Pathology of Pediatric Oncology (4th edn.). Philadelphia: Lippincott Classiﬁcation (the Shimada system). Cancer 86(2):364–72 Williams & Wilkins Shimada H, Chatten J, Newton WA Jr, et al. (1984) Histopatho- Venkateswaran L, Rodriguez-Galindo C, Merchant TE, Po- logic prognostic factors in neuroblastic tumors: deﬁnition quette CA, Bhaskar NR, Rao BN, Pappo AS (2001) Primary of subtypes of ganglioneuroblastoma and an age-linked Ewing tumor of the vertebrae: clinical characteristics, prog- classiﬁcation of neuroblastomas. Journal of the National nostic factors, and outcome. Medical and Pediatric Oncolo- Cancer Institute 73: 405–413 gy 37: 30–35 Sklar C, Whitton J, Mertens A, Stovall M, Green D, Marina N, VonSchweinitz D, Byrd DJ, Hecker H, et al. (1997) Efﬁciency and Greffe B,Wolden S, Robinson L (2000) Abnormalities of the toxicity of ifosfamide, cisplatin and doxorubicin in the thyroid in survivors of Hodgkin’s disease: Data from the treatment of childhood hepatoblastoma. European Journal childhood cancer survivor study. Journal of Clinical En- of Cancer 33:1243–1249 docrinology and Metabolism 85 (9): 3227–3232 Wexler LH, Crist WM, Helman LJ (2002) Rhabdomyosarcoma Smith RS, Chen Q, Hudson MM, Link MP, Kun L, Weinstein H, and the undifferentiated sarcomas In Pizzo PA and Poplack Billett A, Marcus KJ, Tarbell NJ, Donaldson SS (2003) Prog- DG (eds), Principles and Practice of Pediatric Oncology (4th nostic factors for children with Hodgkin’s disease treated edn.). Philadelphia: Lippincott Williams & Wilkins with combined-modality therapy. Journal of Clinical On- Wittig JC, Bickels J, Priebat D, Jelinek J, Kellar-Graney K, cology 21 (10): 2026–2033 Shmookler B (2002) Osteosarcoma: A multidisciplinary ap- Sorensen PHB, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, proach to diagnosis and treatment.American Family Physi- Maurer HM, Bridge JA, Crist WM, Triche TJ, Barr FG (2002) cian 65 (6): 1123–1132, 1135–1136 PAX3-FKHR and PAX7-FKHR gene fusions are prognostic Yunis JJ, Ramsay N (1978) Retinoblastoma and subband dele- indicators in alveolar rhabdomyosarcoma: A report from tion of chromosome 13. American Journal of Diseases of the children’s oncology group. Journal of Clinical Oncology Children 132 (2): 161–163 20 (11): 2672–2679 Spunt SL, Hill DA, Motosue AM, Billups CA, Cain AM, Rao BN, Pratt CB, Merchant TE, Pappo, AS (2002) Clinical features and outcome of initially unresected nonmetastatic pedi- atric nonrhabdomyotous soft tissue sarcoma. Journal of Bibliography Clinical Oncology 20 (15): 3225–3235 Abramson DH, Frank CM, Susman M, Whalen MP, Dunkel IJ, Spunt SL, Poquette CA, Hurt YS, Cain AM, Rao BN, Merchant Boyd NW (1998) Presenting signs of retinoblastoma. Jour- TE, Jenkins JJ, Santana VM, Pratt CB, Pappo AS (1999) Prog- nal of Pediatrics 132 (3): 505–508. nostic factors for children and adolescents with surgically Abu-Ghosh AM, Krailo MD, Goldman SC, Slack RS, Davenport resected nonrhabdomyosarcoma soft tissue sarcoma: An V, Morris E, Laver JH, Reaman GH, Cairo MS (2002) Ifos- analysis of 121 patients treated at St Jude children’s research famide, carboplatin and etoposide in children with poor- hospital. Journal of Clinical Oncology 17 (12): 3697–3705 risk relapsed Wilms’ tumor: a children’s cancer group re- Stocker JT (2001) Liver tumors: Hepatic tumors in children. port. Annals of Oncology 13 (3): 460–469. Clinics in Liver Disease 5 (1): 259–281 Alexander J, Fizazi K, Mahe C, Culine S, Droz JP, Theodore C, Suriawinata AA, Thung SN (2002) Malignant liver tumors. Terrier-Lacombe MJ (2001) Stage I non-seminomatous Clinics in Liver Disease 6 (2): 527–554 germ-cell tumours of the testis: identiﬁcation of a subgroup Swanson PE, Dehner LP (1991) Pathology of soft tissue sarco- of patients with a very low risk of relapse. European Journal mas in children and adolescents. In Maurer HM, Ruymann of Cancer 37: 576–582. FB, Pochedly C (eds), Rhabdomyosarcoma and Related Tu- Brichard B, De Bruycker JJ, De Potter P, Neven B, Vermylen C, mors in Children and Adolescents Florida: CRC Press Cornu G. (2002) Combined chemotherapy and local treat- Tomioka N, Kobayashi H, Kageyama H, Ohira M, Nakamura Y, ment in the management of intraocular retinoblastoma. Sasaki F, Todo S, Nakagawara A, Kaneko Y (2003) Chromo- Medical and Pediatric Oncology 38: 411–415. somes that show partial loss or gain in near-diploid tumors Bussey KJ, Lawce HJ, Olson SB, Arthur DC, Kalowsed DK, Krai- coincide with chromosomes that show whole loss or gain in lo M, Giller R, Heifetz S,Womer R, Magenis RE (1999) Chro- near-triploid tumors: Evidence suggesting the involvement mosome abnormalities of eighty-one pediatric germ cell of the same genes in the tumorigenesis of high- and low- tumors: Sex-, age-, site-, and histopathologic-related differ- risk neuroblastomas. Genes, Chromosomes and Cancer 36: ences – a Children’s Cancer Group Study. Genes, Chromo- 139–150 somes and Cancer 25: 134–146.
102. Solid Tumors Chapter 2 83Carli M, Pinkerton R, Franscella E, et al. (1995) Metastatic soft- Pinkerton, CR (1999) Hepatoblastoma and hepatocellular car- tissue sarcomas in children: preliminary results of the sec- cinoma. In Pinkerton CR, Michalski AJ,Veys PA, (eds), Clin- ond European International group study (EIS). Medical Pe- ical challenges in Paediatric Oncology. Oxford: ISIS Medical diatric Oncology 25 (4): 256. Media.De Wit R, Roberts JT, Wilkinson PM, de Mulder PHM, Mead Pinkerton, CR (1999) Neuroblastoma. In Pinkerton CR, Michal- GM, Fossa SD, Cook P, de Prijck L, Stenning S, Collette L ski AJ, Veys PA, (eds), Clinical Challenges in Paediatric On- (2001) Equivalence of three or four cycles of bleomycin, cology. Oxford: ISIS Medical Media. etoposide and cisplatin chemotherapy and of 3- or 5-day Pinkerton, CR (1999) Non Hodgkin’s Lymphoma. In Pinkerton schedule in good-prognosis form cell cancer: A random- CR, Michalski AJ, Veys PA, (eds), Clinical challenges in Pae- ized study of the European organization for research and diatric Oncology. Oxford: ISIS Medical Media. treatment for cancer genitourinary tract cancer coopera- Pinkerton, CR (1999) Retinoblastoma. In Pinkerton CR, tive group and the medical research council. Journal of Michalski AJ, Veys PA, (eds), Clinical Challenges in Paedi- Clinical Oncology 19 (6): 1629–1640. atric Oncology. Oxford: ISIS Medical Media.Franzius C, Bielack S, Glege S, Sciuk J, Jurgens H, Schober O Pinkerton, CR (1999) Wilms’ Tumor. In Pinkerton CR, Michals- (2002) Prognostic signiﬁcance of 18F-FDG and 99mTc- ki AJ, Veys PA, (eds), Clinical challenges in Paediatric On- Methylene diphosphonate uptake in primary osteosarco- cology. Oxford: ISIS Medical Media. ma. Journal of Nuclear Medicine43 (8): 1012–1017. Pinkerton, CR (1999). Ewing Sarcoma/primitive neuro-ecto-Gobel U, Schneider DT, Calaminus G, Haas RJ, Schmidt P, dermal tumor. In Pinkerton CR, Michalski AJ, Veys PA, Harms D (2000) Germ-cell tumors in childhood and ado- (eds). Clinical challenges in Paediatric Oncology. Oxford: lescence. Annals of Oncology 11:263–271. ISIS Medical Media.Goorin AM, Harris MB, Bernstein M, Ferguson W, Devidas M, Pinkerton, CR (1999). Rhabdomyosarcoma. In Pinkerton CR, Siegal GP, Gebhardt MC, Schwartz, CL, Link M, Grier HE Michalski AJ, Veys PA, (eds), Clinical Challenges in Paedi- (2002) Phase II/III Trial of etoposide and high-dose ifos- atric Oncology. Oxford: ISIS Medical Media. famide in newly diagnosed metastatic osteosarcoma: A pe- Reynolds CP, Lemons RS (2001) Retinoid therapy of childhood diatric oncology group trial. Journal of Clinical Oncolo- cancer. Hematology Oncology Clinics of North America 15 gy20 (2): 426–433. (5): 867–910Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer JH, Pritchard Rodriguez-Galindo C, Daw NC, Kaste SC, Neyer WH, Dome JS, DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Pappo, AS, Rao BN, Pratt CB (2002b) Treatment of refracto- Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS ry osteosarcoma with fractionated cyclophosphamide and (2003) Addition of ifosfamide and etoposide to standard etoposide. Journal of Pediatric Hematology/Oncology 24 chemotherapy for Ewing sarcoma and primitive neuroecto- (4): 250–254 dermal tumor of bone. New England Journal of Medicine Rodriguez-Galindo, C, Wilson MW, Haik BG, Merchant TE, 348 (8): 694–701. Billups CA, Shah N, Cain A, Langston, Lipson M, Kun LE,Guillermo C, Fandino A, Casak S, Manzitti J, Raslawski E, Pratt C (2003) Treatment of intraocular retinoblastoma Schvartzman E (2003) Treatment of overt extraocular with vincristine and carboplatin. Journal of Clinical Oncol- retinoblastoma. Medical Pediatric Oncology 40:158–161. ogy 21 (10): 2019–2025Honavar SG, Singh AD, Shields CL, Meadows AT, Demici H, Rosti F, De Friorgi U, Salvioni R, Papiani F, Sebastiani L, Cater J, Shields JA (2002) Postenucleation adjuvant therapy Argnani M, Monti G, Ferrante P, Pizzocaro F, Marangolo M in high-risk retinoblastoma. Archives in Ophthalmology (2002) Salvage high-dose chemotherapy in patients with 120:923–931 germ cell tumors. Cancer 95 (2): 309–315Kullendorff CM, Soller M, Wiebe T, Mertens F (2003) Cytoge- Schleiermacher G, Peter M, Oberlin O, Philip T, Rubie H, netic ﬁndings and clinical course in consecutive series of Mechinaud F, Sommelet-Olive S, Landman-Parker J, Bours Wilms’ tumors. Cancer Genetics and Cytogenetics 140: D, Michon J, Delattre O (2003) Increased risk of systemic re- 82–87 lapses associated with bone marrow micrometastasis andMalogolowkin MH (2000) Hepatic tumors. In Bast RC, Kufe, circulating tumors cells in localized Ewing tumor. Journal DW, Pollock RE, Weichselbaum RR, Holland JF, Frei E (eds), of Clinical Oncology 21 (1): 85–91 Cancer Medicine (5th edn.). Hamilton: B.C. Decker Shankar AG, Ashley S, Craft AW, Pinkerton CR (2003) OutcomeMcLorie G (2001) Wilms’ tumor. Current Opinion in Urology 11 after relapse in an unselected cohort of children and ado- (6): 567–570 lescents with Ewing sarcoma. Medical and Pediatric Oncol-Pinkerton CR (1999) Hodgkin’s disease. In Pinkerton CR, ogy 40: 141–147 Michalski AJ,Veys PA, Clinical Challenges in Paediatric On- Shields, CL, Honavar SG, Meadows AT, Shields JA, Demirci J, cology. Oxford: ISIS Medical Media. Singh A, Friedman DL, Naduvilath TJ (2002) Chemoreduc-Pinkerton CR (1999) Osteogenic sarcoma. In Pinkerton CR, tion plus focal therapy for retinoblastoma: Factors predic- Michalski AJ, Veys PA, (eds), Clinical challenges in Paedi- tive of need for treatment with external beam radiotherapy atric Oncology. Oxford: ISIS Medical Media. or enucleation.American Journal of Ophthalmology 133 (5): 657–664
103. 84 Chapter 2 E. Hendershot Shields, CL, Honaver SG, Meadows AT, Shields JA, Demirci J, Uusitalo M, Wheeler S, O’Brien JM (1999) Ocular Oncology: Singh A, Naduvilath TJ (2002) Chemoreduction for unilat- New approaches in the clinical management of retinoblas- eral retinoblastoma. Archives of Ophthalmology 120: toma. Ophthalmology Clinics of North America 12 (2) 1653–1658 255–264 Treuner J, Jurgens H, Winkler K (1987) The treatment of 30 Zimmerman A (2002) Pediatric liver tumors and hepatic onto- children and adolescents of synovial sarcoma in accor- genesis: Common and distinctive pathways. Medical and dance with the protocol of the German Multicenter Study Pediatric Oncology 39: 492–503 for soft tissue sarcoma. Proceedings of the American Soci- ety of Clinical Oncology 6: 215
104. Chapter 3 85 Common Central Nervous System Tumors Nicki Fitzmaurice · Sharon Beardsmore Contents Primary brain tumors occur in all age groups but are3.1 Causes/Epidemiology . . . . . . . . . . . . . . . . 86 signiﬁcantly more frequent in children and adoles-3.2 Distribution/Classiﬁcation . . . . . . . . . . . . . 863.3 Staging . . . . . . . . . . . . . . . . . . . . . . . . 87 cents under 15 years old (Turini and Redaelli, 2001).3.4 Molecular Genetics of Brain Tumors . . . . . . . . 87 In the United States, central nervous system (CNS)3.5 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 87 tumors are now the most common malignancy of3.6 Specialist Referral . . . . . . . . . . . . . . . . . . 89 childhood (Copeland et al., 1999); in the United King-3.7 Hydrocephalus . . . . . . . . . . . . . . . . . . . . 89 dom (UK), however, leukaemias are still more preva-3.8 Treatment . . . . . . . . . . . . . . . . . . . . . . 89 3.8.1 Surgery . . . . . . . . . . . . . . . . . . . . 90 lent, with paediatric brain tumors continuing to be 3.8.2 Radiotherapy . . . . . . . . . . . . . . . . 90 the most common solid tumor and the most common 3.8.3 Chemotherapy. . . . . . . . . . . . . . . . 91 cause of death from childhood cancer (Bouffet, 2000).3.9 Prognosis . . . . . . . . . . . . . . . . . . . . . . . 91 They account for 25% of all children’s cancers, and3.10 Speciﬁc Tumors . . . . . . . . . . . . . . . . . . . 92 around 300 children are diagnosed each year in the 3.10.1 PNETs /Medulloblastomas . . . . . . . . . 92 3.10.2 Astrocytomas/Glial Tumors . . . . . . . . 93 UK (CancerBACUP, 2002). In comparison with most 3.10.3 Malignant Gliomas . . . . . . . . . . . . . 94 other childhood cancers, there have been only mod- 3.10.4 Other High-grade Gliomas . . . . . . . . . 95 erate improvements in survival rates for children3.11 Follow-up . . . . . . . . . . . . . . . . . . . . . . . 100 with brain tumors in the past 20 years. Mortality in3.12 The Late Effects and Rehabilitation of Survivors 100 this group of patients is high, with ﬁve-year survival3.13 Palliative Care . . . . . . . . . . . . . . . . . . . . 1003.14 Future Perspectives/New Innovations . . . . . . 100 estimated at 50% (CancerBACUP, 2002). TreatmentReferences . . . . . . . . . . . . . . . . . . . . . . . . . . 101 options typically involve a surgical approach, radio-Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . 101 therapy, and chemotherapy, applied in isolation or in various combinations or sequences. Improvements in imaging, neurosurgical tech- niques, the delivery of radiotherapy, and the inclu- sion of chemotherapy in treatment regimens have been reﬂected in improved survival for some speciﬁc histological types of tumors, i.e. cerebella medul- loblastoma (Radcliffe et al., 1994). However, there re- main major challenges unique to the paediatric are- na for those involved in planning and delivering treatment strategies. Aggressive, invasive techniques involving an often immature brain are much more likely to result in devastating late effects, with mor- bidity estimated at 50% (Macedoni-Luksic et al., 2003). In recognition of this, practitioners have now been undertaking more rigorous appraisal of treat-
105. 86 Chapter 3 N. Fitzmaurice · S. Beardsmore ment modalities and the potential risks of cognitive, Table 3.1. Incidence of most common brain tumors (Bouffet, neuroendocrine, and neuropsychological damage 2000) (Plowman and Pearson, 1997) Tumor Percentage Low-grade gliomas 25–40 % 3.1 Causes/Epidemiology High-grade gliomas 5–10 % Brain stem gliomas 8–12 % The cause of childhood brain tumors remains largely Medulloblastomas 6–20 % unknown, although there is correlation with a family history of cancer, and heredity factors have been Ependymomas 6–11 % implicated. Children with neuroﬁbromatosis, for ex- Germ cell tumors 3–15 % ample, have an increased risk of developing optic Craniopharyngiomas 6–15 % gliomas. Environmental factors such as electric and mag- netic ﬁelds, radio frequency radiation, chemicals, and mobile phones have all been suggested in the devel- Table 3.2. Classiﬁcation of paediatric brain tumors (Plowman and Pearson, 1997) opment of brain tumors. There remains, however, in- sufﬁcient evidence to support these claims. Ionising Glial tumors radiation is a known cause of brain tumors, with sec- Astrocytoma – Well differentiated ondary local malignancies being a small but signiﬁ- cystic cerebellar with mural node cant side effect of cranial radiotherapy (Kheifets, Protoplasmic/ﬁbrillary/pilocytic/ 2003). gemistocytic – Intermediate – Anaplastic Æ (glioblastoma multiforme) 3.2 Distribution/Classiﬁcation Ependymoma – Well-differentiated – Intermediate to poorly Approximately 60% of childhood brain tumors are differentiated infratentorial, including medulloblastoma, cerebellar Oligodendroglioma – Well-differentiated astrocytoma (WHO grades I–IV), brain stem glioma, – Intermediate to poorly and ependymoma (Bouffet, 2000). The remaining differentiated supratentorial tumors include low-grade astrocy- Mixed gliomas (may include areas with tomas, primitive neuroectodermal tumors, germ cell neuroectodermal features) tumors, hypothalamic and optic nerve gliomas, and Neuroectodermal tumors craniopharyngiomas. Medulloblastomas The most common tumors overall are low-grade Other CNS neuroectodermal tumors (PNETs) gliomas, with cerebellar astrocytomas being the Pineoblastoma Pineocytoma largest of this group. Amongst paediatric malignant brain tumors, medulloblastomas occur most fre- Germ cell tumors Other primary CNS germ cell tumors (other sites quently. (See Table 3.1.) usually midline third to fourth ventricles) Classiﬁcation of paediatric brain tumors (shown Craniopharyngioma in Table 3.2) can, however, be misleading, as even the Pituitary tumor most low-grade tumor may have devastating effects Choroid plexus tumors (cyst/papilloma/ because of the nature of its location. It is therefore of- undifferentiated or carcinoma) Meningioma ten unhelpful to use terms such as benign and malig- Others nant to describe speciﬁc tumors.
106. Common Central Nervous System Tumors Chapter 3 87 Table 3.3. Sites of tumors in relation to histology (adapted3.3 Staging from Plowman and Pearson, 1997) Tumor site Most common histologicalStaging remains contentious within neuro-oncology types of tumorswith little consensus regarding universal staging sys-tems. The tumor group however, that does utilise a Cerebellum Astrocytomastaging process that has prognostic implication is Ependymoma Medulloblastoma/PNETmedulloblastoma. Here the Chang operative systemis employed (Laurent et al., 1985). For other tumors,histological grade, age, site of disease, and areas of Brain Stem Astrocytomadissemination are the main prognostic factors. Hypothalmic/pineal4 Astrocytoma PNET NGGCT Teratoma3.4 Molecular Genetics of Brain Tumors Dysgerminoma Supratentorial AstrocytomaIn contrast to other childhood cancers, the molecular PNETgenetics of childhood brain tumors are poorly un- Ependymomaderstood, not only in terms of the pathophysiologybut also in terms of the characterisation of tumor-speciﬁc molecular abnormalities that predict biolog-ically favourable or unfavourable disease. The latter is the site (see Table 3.3), severity of disease, and theparticularly important in brain tumors because such child’s age and development will have an impact onknowledge may allow a more judicious use of current presenting symptoms. For example, those childrentherapies such as radiotherapy and may also identify with posterior fossa disease often have signs of in-molecular targets against which new therapies can be creased intracranial pressure (ICP):directed. Mutations of chromosome 17 have been as- ▬ Headachessociated with medulloblastoma, and mutations of ▬ Early morning vomitingchromosome 10 associated with astrocytoma. Genet- ▬ Blurred visionic abnormalities are currently used to predict biolog- ▬ Ataxiaical behaviour in neuroblastoma and rhabdomyosar- ▬ Poor concentrationcoma. Similar biologicals of tumor behaviour are ▬ Changes in vital signs (late sign)now required if we are to improve the movements ofchildhood brain tumors. Children with supratentorial tumors, however, are more likely to present with hemiparesis, hemisenso- ry loss, and/or seizures. Table 3.4 outlines the symp-3.5 Diagnosis toms and treatment of common CNS tumors in rela- tion to the primary site.Diagnosing the presence of a brain tumor may be dif- Once the child has presented to a specialist paedi-ﬁcult. Diagnosis is often complicated by a vague his- atrician, the existence of a brain lesion will generallytory of symptoms that the parents, general practi- be conﬁrmed via a thorough neurological examina-tioner, or local paediatrician may have attributed to tion that includes fundoscopy and a visual assess-common childhood illnesses. Children who have a ment, followed by magnetic resonance imaginglong insidious history of symptoms are more likely to (MRI) of the head and spine. If the presence of an in-have a lower-grade tumor. Those who present with a tracranial germ cell tumor is suspected, serum andshort history and obvious symptoms are much more cerebrospinal (CSF) levels of alpha-fetoprotein (AFP)likely to have biologically aggressive disease. Clearly and human chorionic gonadotropin (HCG) must be
107. 88 Chapter 3 N. Fitzmaurice · S. Beardsmore Table 3.4. Symptoms and treatment of CNS tumors in relation to primary site (adapted from Shiminski-Maher and Shields, 1995) Site Tumor Symptoms Treatment Supratentorial Low-grade astrocytoma Seizures With gross total resection: surgical removal and observation Visual changes Partial resection: surgical removal and either observation, radiation a or chemotherapy Endocrinopathies Hemiparesis High-grade glioma/PNET Seizures Maximal surgical resection and radiation a and/or chemotherapy Increased ICP Mental status change Hemiparesis Midline Optic nerve Visual disturbances Observation Chiasmal gliomas Endocrinopathies Surgical debulking, radiation, and /or chemotherapy Increased ICP Treatment is age-dependant and related to site of tumor Seizures Craniopharyngiomas Seizures Gross total resection: observation Visual disturbances Partial resection: observation or radiationa Increased ICP Endocrinopathies Infratentorial/ Medulloblastoma Increased ICP Maximal surgical resection and posterior fossa cranial spinal radiationa and chemotherapy Headache Morning vomiting Cranial nerve deﬁcits Ataxia Ependymoma Neck pain Maximal surgical resection and radiationa ± chemotherapy Increased ICP Cranial nerve deﬁcits Brain stem glioma Cranial nerve deﬁcits Malignant tumors diagnosed by MRI requiring radiation ± chemotherapy Increased ICP Hemiparesis Usually short history Long history/minimal Low-grade tumor, surgical debulking, symptoms/focal lesion and observation or radiation ± chemotherapy on MRI a Irradiation should be avoided when possible for children <5 years old measured. This possibility should be considered in all With some tumors that are impossible to remove, suprasellar and pineal region tumors. For those tu- it may be possible to perform stereotactic biopsy to mors with potential to seed along the CSF pathway, conﬁrm the diagnosis in order to plan treatment. CSF cytology should be undertaken at diagnosis or postoperatively.
108. Common Central Nervous System Tumors Chapter 3 89 Figure 3.1 West Midlands brain tumor re- ferrals 1978–2002 (permission to reprint given by Birmingham Children’s Hospital, UK) may be sufﬁcient to relieve the obstruction and allow3.6 Specialist Referral normal ﬂow of CSF. Other options are high-dose steroids preoperatively, external ventricular drainage,Whilst other childhood tumors have routinely been ventriculoperitoneal (VP) shunting, and ventricu-referred to specialist paediatric oncology centres lostomy.since the 1970s, many children with brain tumors For those children with VP shunts, potential com-continued to receive treatment outside of specialist plications require consideration. Shunt malforma-units. This practice resulted in less than 40% being tion, infection, and, although rare, tumor dissemina-treated within clinical trials until after 1997 (UKCC- tion should be taken into account when assessing aSG/SBNS, 1997), when a joint report recommended child who is unwell. Children may experience prob-the centralisation of care for children with brain and lems with their shunts during treatment, during peri-spinal disease. Fig. 3.1 demonstrates how the trend ods of good health, and, should they require it, duringhas changed in a local region. palliative care.3.7 Hydrocephalus 3.8 TreatmentA signiﬁcant number of children with brain tumors It is now widely accepted that the best practice forwill develop associated hydrocephalus. Noncommu- diagnosing, treating, and managing childhood CNSnicating hydrocephalus is most commonly seen in tumors is through a broad-based multidisciplinarypaediatric brain tumors and is a result of mass effect. team. Such a team includes the collaboration of pae-For some children this will present as a surgical diatric neurosurgeons, oncologists, endocrinologists,emergency around the time of diagnosis, requiring psychologists, radiotherapists, social workers, andimmediate management. The most likely symptoms play, physio-, and occupational therapists. Coordi-are headache, early morning vomiting, nausea, and nating these services should be a dedicated neuro-ataxia. The management of hydrocephalus requires oncology nurse specialist. Nursing children withthe input of a paediatric neurosurgeon with several brain tumors is considered more complex and chal-options available. Debulking or removal of the tumor lenging than generic paediatric oncology, with this
109. 90 Chapter 3 N. Fitzmaurice · S. Beardsmore patient group often being labelled as the “undesir- Conventional Radiotherapy ables”within the discipline (Ryan and Shiminski-Ma- ▬ 2 cm margin her, 1995). ▬ Parallel opposed Treatment options typically involve surgical re- ▬ Total dose 50–55 Gy moval, radiotherapy, and chemotherapy, applied in ▬ (craniospinal 25–35 Gy with boost isolation or in various combinations or sequences. to tumor bed up to a total of 50–55 Gy) Tumor type, the extent of disease, the degree of sur- gical resection, and the individual child will all have an impact on the choice of treatment modality. Despite precise planning and delivery of treatment, radiotherapy remains associated with signiﬁcant 3.8.1 Surgery long-term sequelae that may lead to signiﬁcant im- pairment of quality of life. These sequelae are partic- Primary surgery remains the mainstay of manage- ularly profound following whole brain treatment and ment for paediatric brain tumors. Depending upon irradiation of pre-school-age children. International- the site and extent of the tumor, surgical options ly, neuro-oncologists recognise the detrimental ef- range from biopsy alone to complete removal. For fects of radiotherapy on the developing brain and most malignant tumors, complete resection is an im- have advocated delaying radiation treatment in in- portant surgical goal. There is, however, a balance to fants and young children whenever possible (Plow- be struck between complete excision and the risk of man and Pearson, 1997). surgical morbidity. For some tumor types, complete An added complication for young children is their surgical excision seems to be of particular prognostic inability to remain still during the delivery of radio- importance (Sutton et al., 1990), i.e. ependymoma therapy, necessitating the use of daily anaesthetics to medulloblastoma. But in some instances, such as ensure dose accuracy. The prolonged use of anaes- optic nerve gliomas and diffuse brain stem gliomas, thetics in an already sick child is not ideal, but it is surgical excision has little role to play in tumor man- unavoidable for infants. Every effort should be made agement. via play preparation to obviate the need for anaesthe- In other germ cell tumors, chemotherapy now has sia a primary role, and the indications for surgery are Dose reductions and modiﬁed fractionations, to more circumspect (Nicholson et al., 2003). limit the toxicity of craniospinal irradiation, are fea- Increasingly, second-look surgery is an option tures of recent investigation when it is evident from imaging that excisable tumor remains. Clearly, the surgeon must measure the po- Techniques that have been used to increase the tential damage to vital structures against the beneﬁts therapeutic index (the tumor to normal tissue of removing maximum tumor. Debulking alone, dose) include however, may relieve local compression and improve the child’s symptoms while histology is sought and ▬ Stereotactic radiotherapy other treatment modalities are explored. ▬ Brachytherapy ▬ Radiosurgery 3.8.2 Radiotherapy The use of hyperfractionated radiotherapy in medulloblastoma is currently being evaluated in A signiﬁcant number of children with brain tumors Europe through the SIOP IV trial. will require radiotherapy, which aims to deliver opti- mal doses of radiation to tumor cells while sparing surrounding normal tissue.
110. Common Central Nervous System Tumors Chapter 3 91 Figure 3.2 BCH brain tumors: cumulative survival 1970–2002 (permission to reprint given by Birmingham Children’s Hospital, UK)The use of conformal radiotherapy is a subject of on- For example, chemotherapy is advantageous ingoing debate. Although this type of treatment spares treating those children under 5 years of age who, ifnormal brain tissue, an important goal, there is con- diagnosed later in life, would have radiotherapy as acern that relapse at the margin of the radiotherapy ﬁrst-line treatment. Multiagent regimens can delay orﬁeld may increase. even obviate the need for radiotherapy and its asso- ciated late effects. Likewise, stabilisation of an incom-3.8.3 Chemotherapy pletely resected tumor can be achieved by the use of chemotherapy, allowing second-look surgery.The administration of chemotherapy agents to chil- In addition to management with conventionaldren with brain tumors is a comparatively new treat- chemotherapy regimens, children with brain tumors,ment development. Until recently, chemotherapy has high-grade gliomas, and medulloblastomas are nowbeen considered of little beneﬁt due to the existence being treated with high-dose chemotherapy withof the blood-brain barrier. Recently, however, having stem cell rescue. Intensifying treatment is thought toestablished that various degrees of disruption of the improve the permeability of the blood-brain barrier,blood-brain barrier exist in brain tumors, there has and its role continues to be debated.been renewed interest in its role. Signiﬁcant prejudicedid exist regarding the role of chemotherapy and thechemosensitivity of different types of brain tumor, 3.9 Prognosisexacerbated by the existence of few randomised andpoorly designed trials evaluating the beneﬁts of drug It is prudent to be wary when discussing survival ﬁg-therapy. Chemotherapy is, however, now considered a ures. Percentage ﬁgures quoted to families can bevaluable treatment modality as part of the prospec- misleading because they are often based on the eval-tive treatment package facilitating cure. Further- uation of treatment strategies that lag behind currentmore, there is now emerging evidence suggesting practice. Fig. 3.2 demonstrates cumulative survivalthat chemotherapy is effective in paediatric brain tu- seen at Birmingham Children’s Hospital (BCH), UK.mor treatment (Taylor, 2002.)
111. 92 Chapter 3 N. Fitzmaurice · S. Beardsmore Medulloblastoma 3.10 Speciﬁc Tumors Epidemiology 3.10.1 PNETs/Medulloblastomas ▬ 25 % of paediatric brain tumors ▬ Most common between 3 and 7 years Undifferentiated neuroectodermal tumors of the and in males cerebellum have historically been referred to as ▬ Arises from primitive neuroepithelial cells medulloblastomas, while tumors of identical histol- ogy in the pineal region are diagnosed as pineoblas- Etiology tomas, and cerebral tumors are referred to as primi- ▬ Commonly arises in cerebellar vermis tive neuroectodermal tumors (PNETs). Microscopi- ▬ Invades fourth ventricle with associated cally, both medulloblastomas and PNETs consist of hydrocephalus small round cells with disproportionately large hy- ▬ Can disseminate via the CSF perchromatic nuclei. These cells are often clustered Symptoms into rosettes. ▬ Headache ▬ Morning vomiting ▬ Cranial nerve deﬁcits ▬ Ataxia Diagnostics ▬ Craniospinal imaging (Fig. 3.3) ▬ CSF analysis for free-ﬂoating tumor cells ▬ Bone scan and bone marrow aspiration to detect metastatic spread ▬ Standard risk: >5 years of age – Normal risk: >3 years of age – Posterior fossa location – Total resection or<1.5 cc of residual disease – No dissemination – Poor risk: <3 years of age – Metastatic disease – Subtotal resection (>1.5 cc of residual disease) – Non-posterior fossa location (Laurent et al., 1985) Treatment ▬ Primary surgery: gross total excision optimal ▬ Craniospinal radiotherapy + boost to the primary tumor site (optimal dose and mode of administration under investigation) ± chemotherapy ▬ Children under 5: chemotherapy Figure 3.3 ▬ National treatment strategies predominantly Craniospinal imaging of medulloblastoma seeking to reduce irradiation
112. Common Central Nervous System Tumors Chapter 3 93 Medulloblastoma (continued) Cerebellar Astrocytoma Epidemiology Prognosis ▬ Commonly occurs in the ﬁrst decade of life ▬ Nonmetastatic disease: 70–80 % overall ▬ More common in boys survival ▬ Metastatic disease: trials with craniospinal Symptoms radiotherapy, high-dose chemotherapy, ▬ Midline cerebellar signs and stem cell rescue are currently Diagnosis being evaluated ▬ History ▬ Neurological examination Supratentorial PNETs ▬ MRI commonly shows cystic tumor with mural node These are the supratentorial counterpart of medulloblastoma, having the same histological Treatment appearance ▬ Complete surgical removal of the tumor is treatment of choice ▬ Occur mainly <5 years of age ▬ Interval MRI scans to monitor for signs ▬ The majority arise in the cerebral hemi- of progression spheres/pineal region ▬ Radiotherapy ▬ Treatment considerations are similar to medulloblastoma, with survival being lower Prognosis Over 90 % of children with a fully resected pilo- Prognosis cytic astrocytoma will survive with only surgical Age-related: intervention.Those with partially resected diffuse ▬ <3 years: Very poor disease who have had radiotherapy have only a ▬ 3 years: Site-dependent 50–60 % chance of survival. Poor prognostic features include ▬ Diffuse histology3.10.2 Astrocytomas/Glial Tumors ▬ Incomplete resectionThe majority of these tumors are supratentorial ▬ Brain stem involvementand slow-growing and are referred to as low-gradeastrocytomas, pilocytic astrocytomas, oligodendro- Supratentorial Astrocytomagliomas, mixed gliomas, or gangliogliomas (Shimin-ski-Maher and Shields, 1995). Less common are ma- Epidemiologylignant gliomas of the supratentorium, i.e. anaplastic ▬ Twice as common in boysastrocytomas and glioblastoma multiforme. Treatment The Kernohan grading system incorporates grade ▬ Complete surgical removal is optimalI to grade IV, with I being favourable histology and ▬ Radiotherapy is indicated for all than thegrade IV being glioblastoma multiforme that carries lowest-grade, completely resected tumorsa fatal outcome. Anaplastic astrocytomas are histologically recog- Prognosisnisable by more frequent mitosis, cellular pleomor- ▬ Varies widelyphism, and general cellularity of the tumor. Glioblas-toma multiforme is diagnosed when areas of necrosisand peculiar cells forms are present.
113. 94 Chapter 3 N. Fitzmaurice · S. Beardsmore 3.10.3 Malignant Gliomas Brain Stem Glioma Epidemiology Account for 5% of new cases of childhood malignan- ▬ Gender incidence equal cy each year. ▬ Common presenting age: 5–10 years Classiﬁed primarily by anatomic location and sec- ond by histologic phenotype. For those diagnosed Etiology within the supratentorium, treatment consists of op- ▬ Arise in the medulla, pons, midbrain, timal surgical excision/radiotherapy and chemother- and cerebral peduncles apy. Despite aggressive treatment strategies, survival ▬ Diffuse pontine gliomas are rapidly inﬁltrative in this group of patients remains poor. in nature ▬ Most commonly found in the pons, with equal distribution of histological varieties ▬ Low-grade tumors constitute <10 % of brain stem tumors Symptoms ▬ High-grade disease: short history – Multiple cranial nerve palsies – Ataxia – Hemiparesis ▬ Low-grade disease: long history – Minimal or a focal cranial nerve deﬁcit – Raised ICP Diagnostics Location, radiological appearance, and clinical features are usually diagnostic (Fig. 3.4) Treatment ▬ Treat hydrocephalus ▬ High-grade disease: steroids to alleviate neurological symptoms in short pulses – Radiotherapy is palliative, producing a mean survival of 8–10 months. Chemo- therapy and hyperfractionated radio- therapy have failed to make an impact on outcome Figure 3.4 ▬ Low-grade disease: surgical debulking Diffuse pontine glioma – Observation – Radiotherapy and/or chemotherapy may be indicated Prognosis ▬ High-grade disease: median survival 8–10 months
114. Common Central Nervous System Tumors Chapter 3 953.10.4 Other High-grade Gliomas DiagnosticsThe clinical behaviour of supratentorial and cerebel- ▬ MRI (whole brain and spine) to establish ex-lar gliomas is more difﬁcult to predict on the basis of tent of diseaseradiological and clinical characteristics, with prog- ▬ CSF cytology when possiblenosis being more related to histologic phenotype and Treatmentgrade. After resection, radiotherapy is the treatment ▬ Surgeryof choice. Long-term survival remains poor, with ▬ Treat hydrocephalus40% overall survival for grade III and 10% for grade Adjuvant treatment is age-related:IV (Lashford, 2002). >5 years of age ▬ No residual disease or disseminated disease: Intracranial Ependymoma radiotherapy to the tumor bed Epidemiology ▬ Residual disease, no disseminated disease: ▬ Paraventricular lesions usually occur re-resection in the 1st decade of life – Radiotherapy (no spinal) ▬ 50 % occurring <5 years of age – Trials are ongoing to determine role ▬ Spinal ependymomas present slightly later of chemotherapy Etiology ▬ CNS disseminated disease: radiotherapy ▬ Predominantly arise from ependymal tissue to entire CNS within the ventricular system, most common- – Trials underway looking at role ly the fourth ventricle of chemotherapy ▬ Can disseminate (more frequently with in- <5 years of age fratentorial and high grade disease) ▬ Chemotherapy ▬ Hydrocephalus common at presentation ▬ Second-look surgery Are divided into the following categories: Prognosis ▬ Overall survival: 40–60 % at 5 years ▬ Subependymoma (WHO grade I) ▬ Good prognostic factors: minimal residual ▬ Ependymoma (WHO grade II); disease post surgery variants include cellular, papillary, epithelial, ▬ Poor prognostic factors: young age clear cell, and mixed – Subtotal resection ▬ Malignant/anaplastic ependymoma (WHO grade III) Symptoms Depend on site and extent of disease Typically ▬ Neck pain ▬ Increased ICP ▬ Cranial nerve deﬁcits ▬ Ataxia
115. 96 Chapter 3 N. Fitzmaurice · S. Beardsmore Craniopharyngiomas Intracranial germ cell tumors Epidemiology Germ cell tumors arising intracranially are histo- ▬ 8 % of all childhood brain tumors logically indistinguishable from the gonadal vari- ▬ Most commonly seen <18 years eties. ▬ Mean age at diagnosis 8 years Intracranial germ cell tumors can be divided into two main groups: Etiology ▬ Arise from neural ectoderm and epithelial ▬ Germinomas: 60 % of total number of germ elements in Rathke’s pouch cell tumors ▬ Can be located anywhere in the primitive ▬ Nongerminomatous germ cell tumors craniopharyngeal duct (NGGCTs; also referred to as secreting ▬ 90 % suprasellar, 10 % intrasellar germ cell tumors) ▬ Benign and slow-growing Both groups have the potential for CSF dissemi- Symptoms nation. Presenting symptoms relate to pressure on adjacent structures: Epidemiology ▬ Visual ﬁelds and acuity defects ▬ For all intracranial germ cell tumors there is a ▬ Endocrine dysfunction male prevalence ▬ Hydrocephalus is possible ▬ Intracranial germinomas primarily present in the 2nd decade of life Diagnosis ▬ NGGCTs tend to occur earlier ▬ History ▬ MRI scan Etiology ▬ Germinomas occur predominantly in the Treatment suprasellar region ▬ Presurgical neuroendocrine and ophthalmic work-up are essential ▬ NGGCTs occur mainly as pineal tumors ▬ Treatment of hydrocephalus ▬ Complete resection optimal Symptoms Pineal tumors Prognosis ▬ Raised ICP is commonly seen Although classiﬁed as benign, they can result in ▬ Headache considerable morbidity. ▬ Vomiting Problems include Suprasellar tumors ▬ Endocrine dysfunction ▬ Visual disturbances (ﬁelds/acuity) ▬ Diabetes insipidus ▬ Diabetes insipidus ▬ Hypothyroidism ▬ Hypopituitarism ▬ Growth and sex hormone deﬁcits ▬ Headache ▬ Excessive weight gain ▬ Vomiting ▬ Visual disturbances ▬ Neuropsychological dysfunction Tumors of the basal ganglia-thalamus area ▬ Psychosocial problems ▬ Hemiparesis ▬ Precocious puberty ▬ Failure of puberty ▬ Short stature
116. Common Central Nervous System Tumors Chapter 3 97Intracranial germ cell tumors (continued) SymptomsDiagnostics Symptoms relate to tumor pressure on the optic▬ Germinoma: MRI and biopsy nerve and adjacent structures and inﬁltration:▬ NGGCT: MRI (radiological features are ▬ Decreased visual acuity or ﬁelds characteristic) ▬ Squint▬ Serum and CSF levels for AFP and HCG ▬ NystagmusTreatment ▬ Precocious pubertyGerminomas Diagnostics▬ Highly chemo/radiosensitive tumors ▬ MRI▬ Surgery has a limited role in their manage- ▬ Neurological examination ment ▬ Frequent neuro-ophthalmological testingCurrent UK treatment is (see below)▬ Craniospinal irradiation with boost to Treatment the primary tumor site ▬ Treat hydrocephalus▬ Chemotherapy followed by local radiotherapy ▬ Observation if disease and symptoms are sta- ble (spontaneous regression has been report-NGGCTs ed)▬ Chemotherapy has improved rates of cure; ▬ Treatment should be considered to stabilise nevertheless, local radiotherapy is still consid- vision ered necessary to achieve cure ▬ Surgery has limited role▬ Surgery for difﬁcult residual disease ▬ <8 years of age + NF1: chemotherapyPrognosis ▬ >8 years of age: radiotherapy▬ Germinomas: 90–100 % ▬ The lack of randomised trials makes it difﬁcult▬ NGGCTs: 60–70 % to know whether chemotherapy and radio- therapy make a differenceVisual Pathway Gliomas Prognosis ▬ Isolated optic nerve tumors have a betterEpidemiology prognosis than those that extend along the▬ 75 % of isolated optic nerve gliomas occur visual pathway or involve the chiasm <10 years ▬ Children with neuroﬁbromatosis, particularly▬ Peak incidence: 2–6 years those who are asymptomatic at diagnosis,▬ Occurs in 20 % of patients with neuroﬁbro- have improved prognosis matosis (NF1)Etiology▬ Can present anywhere along optic tracts▬ May extend to the pituitary fossa, causing hypopituitarism ,or to the hypothalamus, resulting in precocious puberty▬ Hydrocephalus may be present▬ Natural history is unpredictable
117. 98 Chapter 3 N. Fitzmaurice · S. Beardsmore Neuro-ophthalmological Testing Germinoma Visual assessment is frequently used as the criti- Comprise 60 % of the total number of germ cell cal tool to determine the need for treatment, with tumors deterioration in visual ﬁelds and/or acuity indi- Epidemiology cating the need for intervention. This can be a ▬ Intracranial germinomas primarily present in particular problem with infants and young chil- the 2nd decade of life dren as it can be difﬁcult to get consistently accu- rate results (particularly regarding visual ﬁelds). Etiology Experience has shown that even in school-age ▬ Occur predominantly in the suprasellar children, results can ﬂuctuate, and it may be un- region clear whether this ﬂuctuation relates to disease Symptoms progression or to variable patient compliance. ▬ Visual disturbances (ﬁelds/acuity) ▬ Diabetes insipidus ▬ Hypopituitarism ▬ Headache ▬ Vomiting Diagnostics ▬ MRI ▬ Biopsy Treatment ▬ Highly chemo/radiosensitive tumors ▬ Surgery has a limited role Current UK Treatment ▬ Craniospinal irradiation with boost to the primary tumor site ▬ Chemotherapy followed by local radiotherapy Prognosis ▬ 90–100 %
118. Common Central Nervous System Tumors Chapter 3 99Nonsecreting Germ Cell Tumors (NSGCTs)Epidemiology▬ NGGCTs tend to occur earlierEtiology▬ NGGCTs occur mainly as pineal tumorsSymptoms▬ Raised ICP is commonly seen▬ Headache▬ VomitingDiagnostics▬ MRI (radiological features are characteristic)▬ Serum and CSF levels for AFP and HCGTreatment▬ Sensitive to a range of chemotherapy agents▬ Chemotherapy has improved rates of cure▬ Local radiotherapy is, however, still necessary to achieve cure▬ Surgery for difﬁcult residual diseasePrognosis▬ 60–70 %Spinal TumorsRare in children. Low-grade astrocytomas areusually intramedullary, requiring extensive surgi-cal removal. Radiotherapy and chemotherapymay be required. High-grade astrocytomas of thespine require radiotherapy and, like similar dis-ease in other sites, surgery has little role. Progno- Figure 3.5sis for spinal ependymoma (Fig. 3.5) is optimal Spinal ependymomawith total surgical excision. Radiotherapy is rou-tine, with residual disease necessitating chemo-therapy.
119. 100 Chapter 3 N. Fitzmaurice · S. Beardsmore 3.11 Follow-up 3.13 Palliative Care Children treated for a brain tumor will require life- Palliative care is discussed in detail in chapter 30 of long follow-up care in a specialist centre. Interval this handbook. It is, however, prudent here to refer to MRI scanning and neurological examinations will be the complexities of symptom control for children important indicators of progress in the early months with brain tumors. Problems such as steroid depend- and years following treatment. Late effects of treat- ency, spinal involvement, seizure control, reduced ment, such as cognitive deﬁcits and endocrine dys- mobility, and speech, language, and swallowing difﬁ- function, may only become apparent in subsequent culties necessitate the input of palliative care nurses years. who specialise in the care of these children. 3.12 The Late Effects and Rehabilitation 3.14 Future Perspectives/New Innovations of Survivors New innovations include the following: It is clear that children who have been treated for ▬ Boron neutron capture therapy, which is an exper- brain tumors may have signiﬁcant long-term prob- imental form of radiotherapy that injects a chem- lems relating both to the tumor itself and to treat- ical compound containing boron into the blood- ment (Mostow et al., 1991; Plowman and Pearson, stream, which then concentrates in the brain tu- 1997). Radiotherapy, prolonged exposure to raised mor tissue. Radiotherapy with neutrons is then di- ICP, and often repeated surgical procedures all incur rected at the cancer, and when the neutrons come costs. Side effects are both physical and psychological into contact with the boron, high-energy radio- (Glaser et al., 1997) and include growth problems and therapy is released with low penetrance that weight gain relating to endocrine dysfunction, lack of spares normal tissue. energy, poor body image, low self-esteem, and de- ▬ Growth factor inhibitors to prevent the effects of creased overall ﬁtness. Adolescent survivors in par- the growth factors that allow a cancer to grow. ticular describe feelings of isolation from their peer ▬ Angiogenesis inhibitors to prevent the formation group and may lack conﬁdence socially. Problems of new blood vessels that nourish the cancers. translate into functional difﬁculties, such as poor at- ▬ Immunotherapy to stimulate the body’s own im- tendance at school, attention deﬁcit, and overt eating mune system to ﬁght the cancer. disorders. Despite the recognition of how devastating ▬ Advanced MR techniques such as MR spec- brain tumor treatment can be, this cohort of cancer troscopy, diffusion MR, and dynamic contrast-en- survivors is rarely included in studies of psychologi- hanced MR to give noninvasive information on tu- cal adjustment during and after treatment (Kline, mor function, i.e. metabolism, relation to white 1996; Radcliffe et al., 1996). If the overall burden of matter, and blood ﬂow. morbidity is to be addressed for this unique patient ▬ Conformal radiotherapy that uses three-dimen- group, consideration must to be given to strategies sional planning. The volume of radiation therapy that will facilitate development in both physical and is irregular and “conforms” to the tumor. Shaped psychological well-being (Glaser et al., 1997). Recent ﬁelds of treatment are used, which minimise the work in the UK suggests that adolescent survivors of amount of normal tissue within the radiotherapy brain tumor treatment can beneﬁt psychosocially ﬁeld. This in turn results in a decrease in acute and from a rehabilitation programme targeting their late morbidity. unique needs (Fitzmaurice and Beardsmore, 2003).
120. Common Central Nervous System Tumors Chapter 3 101 Radcliffe J, Bennett D, Kazak AE, Foley G, Phillips PC (1996)References Adjustment in childhood brain tumor survival: Child, mother and teacher report. Journal of Pediatric PsychologyBouffet E (2000) Common brain tumors in children: diagnosis 21(4):529–539 and treatment. Paediatric Drugs 2(1):57–66 Ryan JA, Shiminski-Maher T (1995) Neuro oncology nurses:CancerBACUP (2002) www.cancerbacup.uk/childrens-cancer undaunted, hopeful and enthusiastic. Journal of PediatricCopeland D, deMoor C, Moore B (1999) Neurocognitive devel- Oncology Nursing 12 (4):179–180 opment of children after a cerebellar tumor in infancy. Shiminski-Maher T, Shields M (1995) Pediatric brain tumors: Journal of Clinical Oncology 17:3476–3486 diagnosis and management. Journal of Pediatric OncologyFitzmaurice N and Beardsmore S (2003) The rehabilitation of Nursing 12(4):188–198 adolescent survivors of brain tumor treatment. Cancer Sutton LN, Goldwein J, Perilongo G, Schut L, Rorke L, Pa R Nursing Practice 2(5):26–30 (1990) Prognostic factors in childhood ependymomas.Glaser AW, Abdul Rashid NF, U CL, Walker DA (1997) School Pediatric Neurosurgery 16(2):57–65 behaviours and health status after central nervous system Taylor RE, Bailey CC, Robinson K, Weston CL, Ellison D, Iron- tumors in childhood. British Journal of Cancer 76(5): side J, Lucraft H, Gilbertson R, Tait DM, Walker DA, Pizer 643–650 BL, Imeson J, Lashford LS; International Society of Paedi-Kline NE (1996) Neuro-oncology patients and nursing re- atric Oncology; United Kingdom Children’s Cancer Study search issues Journal of Pediatric Oncology Nursing 13 Group (2002) Results of a randomized study of preradia- (1):40–42 tion chemotherapy versus radiotherapy alone for non-Kheifets LI (2003) EMF and cancer: Epidemiologic evidence to metastatic medulloblastoma: The International Society of date. World Health Organization. www.who.int. Paediatric Oncology/United Kingdom Children’s CancerLashford LS, Thiesse P, Jouvet A, Jaspan T, Couanet D, Grifﬁths study group PNET-3 study. British Journal of Neurosurgery PD, Doz F, Ironside J, Robson K, Hobson R, Dugan M, Pear- 16(2):93–95 son AD, Vassal G, Frappaz D; a United Kingdom Children’s Turini M, Redaelli A (2001) Primary brain tumors: a review of Cancer Study Group and French Society for Pediatric On- research and management. International Journal of Clinical cology Intergroup Study. (2002) Journal of Clinical Oncolo- Practice 55(7):471–475 gy 20(24):4684-4691 UKCCSG/SBNS United Kingdom Children’s Cancer StudyLaurent JP, Chang CH, Cohen ME (1985) A classiﬁcation system Group and Society of British Neurological Surgeons (1997) for primitive neuroectodermal tumors (medulloblastoma) Guidance for services for children and young people of the posterior fossa. Cancer 56(7):1807–1809 with brain and spinal tumors. Report of working party ofMacedoni-Luksic M, Jereb B, Todorovski L (2003) Long term UKCCSG and the Society of British Neurological Surgeons sequelae in children treated for brain tumors: impairments, disability and handicap. Pediatric Haematology and Oncol- ogy 20(2):89–101Mostow EN, Byrne J, Connelly RR, Mulvihill JJ (1991) Quality of Bibliography life in long term survivors of CNS tumors of childhood and Mulhern RK, Kepner JL, Thomas PR, Armstrong D, Friedman adolescents. Journal of Clinical Oncology 9(4):592–599 H, Kun LE (1998) Neuropsychological functioning of sur-Nicholson JC, Punt J, Hale J, Saran F, Calaminus G; Germ Cell vivors of childhood medulloblastoma randomized to re- Tumor Working Groups of the United Kingdom Children’s ceive conventional or reduced dose craniospinal irradia- Cancer Study Group (UKCCSG) and International Society tion: a pediatric oncology group study. Journal of Clinical of Paediatric Oncology (SIOP) (2003) Neurosurgical man- Oncology 16:1723–1728 agement of paediatric germ cell tumors of the central nerv- Shiminski-Maher T, Rosenberg M (1990) Late effects associat- ous system–a multi-disciplinary team approach for the new ed with treatment of craniopharyngiomas in childhood. millennium. Journal of Clinical Oncology 21(8):1581–1591 Journal of Neuroscience Nursing 22(4):220–225Plowman PN, Pearson ADJ (1997) Tumors of the central nervous system. In Pinkerton CR, Plowman PN (eds) Paediatric oncology: Clinical practice and controversies. Chapman and Hall Medical, London
122. 104 Chapter 4 R. Bryant 4.6 Bone Marrow Failure Syndromes . . . . . . . . . 126 4.6.1 Aplastic Anemia . . . . . . . . . . . . . . . . 126 4.1 Anemia 22.214.171.124 Acquired Aplastic Anemia . . . . . 126 126.96.36.199.1 Epidemiology . . . . . . . . . . . . 127 188.8.131.52.2 Etiology . . . . . . . . . . . . . . . 127 Anemia is deﬁned as a reduction in red cell mass due 184.108.40.206.3 Molecular Genetics . . . . . . . . . 127 to decreased production, increased loss/decreased 220.127.116.11.4 Symptoms/Clinical Signs . . . . . . 127 survival, or increased destruction of red blood cells 18.104.22.168.5 Diagnostic Testing . . . . . . . . . . 127 (RBCs). Because most oxygen is transported by 22.214.171.124.6 Treatment . . . . . . . . . . . . . . 128 126.96.36.199.7 Supportive Treatment . . . . . . . . 128 the RBCs to the body tissues, a reduction in the 188.8.131.52.8 Prognosis . . . . . . . . . . . . . . 129 red cell mass causes reduced oxygen supply to body 184.108.40.206 Inherited Aplastic Anemia . . . . . 129 cells. Consequently, anemia is a sign of an underlying 220.127.116.11.1 Epidemiology . . . . . . . . . . . . 129 pathological process, which is usually discovered 18.104.22.168.2 Etiology . . . . . . . . . . . . . . . 129 during a routine health maintenance visit. The inves- 22.214.171.124.3 Molecular Genetics . . . . . . . . . 129 126.96.36.199.4 Symptoms/Clinical Signs . . . . . . 129 tigation of anemia to determine the underlying 188.8.131.52.5 Diagnostic Testing . . . . . . . . . . 129 diagnosis includes a combination of medical history, 184.108.40.206.6 Treatment . . . . . . . . . . . . . . 130 family history, physical examination, and the initial 220.127.116.11.7 Prognosis . . . . . . . . . . . . . . 130 laboratory assessment, including the evaluation of References . . . . . . . . . . . . . . . . . . . . . . . . . . 130 the full/complete blood count (FBC/CBC), RBC in- dices/morphology, reticulocyte count, and the periph- eral smear (see Table 4.1). More extensive tests may be needed to verify the diagnosis, such as an iron panel, osmotic fragility, hemoglobin (Hgb) electrophoresis, or even a bone marrow examination (see Fig. 4.1). Table 4.1. Normal red blood cell values in children (adapted from Hastings, 2002a) Hemoglobin (g/dl) MCV (ﬂ) Age Mean –2 SD Mean –2 SD Birth (cord blood) 16.5 13.5 108 98 1–3 days (capillary) 18.5 14.5 108 95 1 week 17.5 13.5 107 88 2 weeks 16.5 12.5 105 86 1 month 14.0 10.0 104 85 2 months 11.5 9.0 96 77 3–6 months 11.5 9.5 91 74 0.5–2 years 12.0 10.5 78 70 2–6 years 12.5 11.5 81 75 6–12 years 13.5 11.5 86 77 12–18 years, female 14.0 12.0 90 78 12–18 years, male 14.5 13.0 88 78 18–49 years, female 14.0 12.0 90 80 18–49 years, male 15.5 13.5 90 80
123. Anemias Chapter 4 105Figure 4.1Diagnostic approach to the child with anemia. From Wadworth Center, New York State Department of Health. Retrieved9/13/03 from http://www.wadsworth.org. *From UpToDate webpage. Retrieved 9/17/2003 from www.UpToDate.org
124. 106 Chapter 4 R. Bryant It is important to establish whether the anemia is re- stitution on the b globin gene that causes destruction lated to one cell line (i.e., RBCs, white blood cells of RBC. [WBCs], or platelets) or multiple cell lines (i.e., RBCs, Thalassemia is a type of anemia that lacks alpha or WBCs, and platelets). If multiple cells lines are affect- beta production and therefore is etiologically classi- ed, this may indicate bone marrow production prob- ﬁed as ineffective RBC production. Morphologically lem (i.e., leukemia, aplastic anemia or metastatic the thalassemic RBCs are classiﬁed as a microcytic disease). If a single cell line is affected, this usually anemia. indicates a peripheral destruction problem such as Hemolytic anemias are divided into intracorpus- autoimmune disorders (i.e., immune thrombocy- cular defects (i.e., glucose-6-phosphate dehydroge- topenic purpura or autoimmune hemolytic anemia). nase deﬁciency hereditary spherocytosis) or extra- Anemia is classiﬁed into two main categories, corpuscular defects (i.e., autoimmune hemolytic which include the morphological and etiological anemia) that cause RBC destruction. Hemolytic ane- (physiological or functional) basis for the anemia. mia is morphologically classiﬁed as normocytic, but The mean corpuscular volume (MCV) is the most if it has more than 20% reticulocytes, it is then clas- useful of the RBC indices and is the basis for the siﬁed as macrocytic. morphological category. The morphological category Lastly, aplastic anemia (AA), which is a bone mar- divides the RBC morphology or size into normocytic row failure syndrome, is divided into inherited (i.e., (normal size RBC), microcytic (smaller than normal Fanconi’s anemia, Diamond-Blackfan anemia) or ac- RBC), and macrocytic (larger than normal size RBC) quired anemia (i.e., moderate or severe) character- anemias (see Fig. 4.1). ized by reduced or absent production of RBCs,WBCs, These categories are not mutually exclusive for a and platelets. Morphologically it is classiﬁed as nor- given anemia because an anemia may present as nor- mocytic but most often as macrocytic anemia. The mocytic and then revert to macrocytic or develop a macrocytosis develops because of stress erythro- combination of RBC sizes. The etiological category is poiesis, which produces erythrocytes with fetal char- divided according to (1) decreased or ineffective pro- acteristics that tend to be more pronounced in the in- duction of RBCs, (2) destruction of RBCs, or (3) loss herited types of AA (Shimamura and Guinan, 2003). of RBCs. Generally, in the etiological category, there is one basis for the anemia but some anemias may have more than one basis. 4.2 Iron Deﬁciency Anemia Iron deﬁciency anemia may have more than one basis and more than one morphological presentation Iron deﬁciency anemia is deﬁned as a reduction in red (see Fig. 4.1). The usual etiological category for iron cell mass due to decreased production and/or loss of deﬁciency anemia is decreased production of RBCs; RBCs (see Fig. 4.1). Infants usually have adequate iron however, this anemia may also develop because of an stores at birth unless they were born prematurely or increased loss of RBCs. Iron deﬁciency is usually maternal iron stores were inadequate. The iron stores morphologically classiﬁed as a microcytic anemia, of full-term infants gradually deplete in about four yet early iron deﬁciency is classiﬁed as a normocytic months unless replenished with iron-fortiﬁed formu- anemia (Fig. 4.1). la or breast milk supplemented with iron. Sickle cell hemoglobinopathies represent a group of genetic diseases that are all related to the presence 4.2.1 Epidemiology of Hgb S. The most common type of sickle cell dis- ease (SCD) is homozygous Hgb SS, which is morpho- Anemia caused by iron deﬁciency is a major public logically classiﬁed as a normocytic anemia when health problem, affecting 46% of school children oxygenated but as a macrocytic anemia in the pres- globally (United Nations ACC/SCN, 2000). Iron deﬁ- ence of reticulocytosis (an increased number of large ciency is the most common form of nutritional deﬁ- immature RBCs). Hgb SS is deﬁned as a protein sub- ciency. Its prevalence is highest among young chil-
125. Anemias Chapter 4 107dren between the ages of 12 months and 3 years and unusual substances such as starch, clay, toilet paper,women of childbearing age (particularly adolescent and paint chips, may be detected during the historygirls and pregnant women). and is frequently associated with iron-deﬁciency anemia. Adolescents and children less than 364.2.2 Etiology months are at the highest risk for developing iron de- ﬁciency anemia. Severe iron deﬁciency anemia is as-Iron is present in all body cells. Iron balance is main- sociated with impairment of growth and intellectualtained between dietary intake (approximately 10% development and may cause decreased motor activi-elemental iron is absorbed in the duodenum and je- ty and social interaction. The lack of iron causesjunum) and iron loss (from sloughing of the skin and damaged to epithelial cells, which has been associat-mucosal cells). There is no organ that regulates iron ed with gastrointestinal blood loss and/or increaseexcretion (Andrews, 2003). The most common causes absorption of heavy metals including lead (Andrews,of iron deﬁciency are chronic blood loss and/or inad- 2003). Therefore iron deﬁciency may enhance leadequate intake of dietary iron during rapid growth pe- absorption and inadvertently cause lead toxicity.riods. Lead is toxic to the bone marrow and affects erythro- poiesis by interfering with the heme synthetic path-4.2.3 Molecular Genetics way in all cells (Andrews, 2003).The precise mechanism by which serum iron is 4.2.5 Diagnostic Testingloaded onto transferrin (the major protein trans-porter of iron) as it leaves intestinal epithelial cells or The smear diagnostic of iron deﬁciency anemiareticuloendothelial cells is unknown. Transferrin contains microcytic, hypochromic (decreased ironbinds with the iron (total iron binding capacity = content) RBCs with poikilocytosis (varying red cellTIBC) and releases the iron into the cell. Once inside shapes), anisocytosis (different red cell sizes) andthe cell, the iron conjugates with free erythrocyte target cells (which resemble a bull’s eye target; seeportoporphyrins (FEP or EP) to form heme and Fig. 4.1). The lead poisoning smear differs from ironbinds with the globin protein to form Hgb. The Hgb deﬁciency by consisting of coarse basophilic stip-attracts the oxygen and carries it to body cells for me- pling (coarse granules studding the cytoplasm;tabolism. The remaining iron is stored as ferritin see Fig. 4.1) with microcytic hypochromic RBCs. In(soluble protein) or hemosiderin (an insoluble pro- contrast, a chronic disease anemia smear consiststein complex). Both of these complexes are found in primarily of normocytic and normochromic RBCsthe liver, bone marrow, spleen, and skeletal muscles. (see Fig. 4.1) with approximately 20% of microcyticReticuloendothelial cells acquire iron primarily by cells.phagocytosis and breakdown of aging red cells. The The iron status of the body can be assessed usingiron is then extracted from the heme and returned to several laboratory tests. During mild iron deﬁciencythe circulation to bind to transferrin and repeat the (Hgb >10 gm/dl) when the stores are depleted, thecycle. Hgb may not decrease. Consequently, elevated FEP would be a better screening test for early iron deﬁ-4.2.4 Symptoms/Clinical Signs ciency than Hgb concentration (Mei et al., 2003). The FEP is also elevated in lead poisoning but usually to aIron deﬁciency produces a microcytic, hypochromic greater level than in iron deﬁciency. Moderate ironanemia that impairs tissue oxygen transport to body deﬁciency occurs with a decreased Hgb of 7–10 g/dlcells and may cause weakness, fatigue, palpitations, and decreased MCV compared with the age-matchedlightheadedness, pallor, lethargy, tachycardia, and results. Severe iron deﬁciency is associated with de-tachypnea that may be detected on physical exam and creased Hgb (<7 g/dl) and decreased MCV comparedwhile obtaining a thorough history. Pica, a craving for with age-matched results (see Table 4.1).
126. 108 Chapter 4 R. Bryant The test most commonly used regardless of ▬ The oral iron dose is 2–6 mg/day elemental whether iron deﬁciency is mild, moderate, or severe iron/kg/day divided bid for child/infant and is the Hgb/hematocrit (Hct) concentration. Although 60–120 mg/day for adolescents. Iron preparations Hgb concentration and Hct cannot be used to deter- should be given with vitamin C-fortiﬁed juice or mine the cause of anemia, if Hgb concentration or with water because vitamin C promotes iron ab- Hct increases after a course of therapeutic iron sup- sorption from the gastrointestinal tract. Iron plementation, the diagnosis of iron deﬁciency ane- should not be taken with milk, milk products, or mia can be made even with mild iron deﬁciency antacids because they interfere with iron absorp- (Segel et al., 2002a). Other laboratory tests (including tion decreased reticulocytes, increased RBC distribution ▬ Iron fortiﬁed cereal (two or more servings) should width [RDW], decreased serum iron, decreased be added daily to the diet of the exclusive breast- transferrin saturation, elevated total iron binding ca- fed full-term infant beginning about 4–6 months pacity [TIBC], positive guaiac, and Hgb electrophore- after birth sis) can be used to differentiate iron deﬁciency ane- ▬ Preterm or low birth weight infants who are exclu- mia from anemia of other causes. Serum ferritin con- sively breastfed should take iron drops 2–4 mg/ centration is an early indicator of iron store deple- kg/day beginning 2–3 months after birth until age tion, yet is also an acute-phase reactant to chronic in- 12 months fection, inﬂammation, or diseases, which may ob- ▬ The use of low-iron milk (cow, goat, or soy) should scure the results. The MCV is the most useful of the be discouraged until after age 12 months RBC indices and is the basis for the classiﬁcation of ▬ The intake of solid foods that are rich in iron the anemias (Fig. 4.1). A decreased MCV and RBC should be encouraged in children, along with a de- with increased RDW indicates iron deﬁciency ane- crease in milk consumption to <24 ounces daily mia, whereas a decreased MCV and increased or nor- ▬ Dietary counseling regarding the intake of iron- mal RBC with normal RDW indicates thalassemia rich foods (e.g., meats, bran, lentils, beans, nuts, minor (Demir et al., 2002). and some green leafy vegetables) should be rein- There are nutritional anemias that affect normal forced red cell production that must be differentiated from ▬ Iron treatment should be continued until iron iron deﬁciency (see Fig. 4.1). Megaloblastic anemia stores are replenished (approximately 4–6 months (B12 and folate deﬁciency) may be coupled with iron of oral iron therapy after Hgb normalizes). Side ef- deﬁciency anemia. Vitamin B12 deﬁciency may devel- fects of iron therapy should be explained to the op in the strict vegetarian diet or the totally breastfed child and parents; these include gastrointestinal infant. It is treated with cobalamin injections discomfort, constipation, bloating, stained teeth 30 mg/day for 5–10 days, then weaned to 100–200 mg (to prevent, give liquid iron with a straw) and dark/ monthly; for adolescents, 100 mg daily for 10–15 days black stools then weaned to 60 mg monthly with the addition of B12 dietary sources (Lee et al., 2002). The folic acid Parenteral iron replacement is dose is 50 mg/day in infants and 1 mg/day for chil- ▬ Used when the patient is unable to ingest oral iron dren/adolescents coupled with dietary counseling to or absorb iron from the gastrointestinal tract promote intake of foods containing folic acid. ▬ Available in the United States as iron dextran (ele- mental iron) and administered as intramuscular 4.2.6 Treatment (IM) using the z-track technique, or intravenously ▬ Treatment requires the identiﬁcation of the cause (IV). The preferable route is intravenous (IV) be- of iron deﬁciency anemia, whether its due to blood cause the intramuscular injection causes pain and loss from intestinal inﬂammation/malabsorption, skin discoloration surgery, or medications (e.g., chemotherapy, anti- convulsants) and/or lack of adequate iron intake
127. Anemias Chapter 4 109▬ Composed of iron dextran and contains 50 mg 4.2.9 Prognosis elemental iron per milliliter. The dose of iron (mg) is calculated by wt (kg) ¥ desired increment Once detected, iron deﬁciency and other nutritional Hgb (g/dl) ¥ 2.5 (Hastings, 2002a). A peak reticu- anemias generally respond positively to supplemen- locytosis will usually occur 10 days after parenter- tation. Follow-up Hgb that fails to show improvement al iron is given with complete correction of anemia within 4–8 weeks after supplementing with oral iron in 3–4 weeks and dietary iron, or an anemia that recurs despite ad-▬ Given as a test dose of 12.5–25 mg, with observa- equate supplementation warrant, further investiga- tion of the patient for 30–60 minutes after the dose tion (Segel et al., 2002). Further investigation may in-▬ Associated with such adverse effects as anaphylax- clude such disorders as malignancy, copper deﬁcien- is, fever, hypotension, rash, myalgias, and arthral- cy, inborn errors of iron metabolism, or other rare gias disorders.▬ Not recommended in infants less than 4 months old (Lee et al., 2002) 4.3 Sickle Cell Disease4.2.7 Transfusion Sickle cell hemoglobinopathies represent a group ofDepending on whether the child is hemodynamically genetic diseases that are all related to the presence ofstable, children with severe anemia (Hgb <5 g/dl) Hgb S. Sickle cell trait is a benign condition that in-may require red cell transfusion. Common practice is volves approximately 35–45% of Hgb S and the re-to administer the red cells slowly (2–3 ml/kg/hour) in mainder Hgb A. Although complications are rare,multiple small volumes (aliquots) with careful moni- they have been described and include an increasedtoring of vital signs and ﬂuid balance to prevent pul- incidence of hematuria and hyposthenuria. Vaso-oc-monary edema and congestive heart failure (Glader, clusive crisis has also been reported, especially under2004). hypoxic conditions such as shock, strenuous physical activity, and ﬂying in an unpressurized aircraft or at4.2.8 Erythropoietin (Epotin Alfa, Epogen) high elevations.Recombinant human erythropoietin may be used as 4.3.1 Epidemiologytreatment for mild to moderate anemia to stimulatethe proliferation and differentiation of erythroid pre- Sickle cell disease (SCD) has been recognized as acursors (Andrews, 2003). The usual subcutaneous worldwide problem. It is a common hereditary disor-dose is 150–300 IU/kg one to three times a week. Suf- der, occurring in 1 in 375 births, with 70,000 casesﬁcient erythroid precursors must be in the bone mar- among African-Americans in the United States. SCDrow with adequate iron stores and adequate protein affects a variety of nationalities, including Africans,intake for erythropoietin to be effective (Carley, Hispanics, Arabs, Italians, Native Americans, Carib-2003). Common practice is to administer 3 mg/kg/ beans, Iranians, Turks, and, infrequently, Americanday of supplemental iron concurrently. Erythropoi- Caucasians (primarily of Mediterranean descent).etin has shown efﬁcacy in the treatment of anemia ofprematurity and in renal failure and is being investi- 4.3.2 Etiologygated as a treatment for transient bone marrow sup-pression induced by chemotherapy. Sickle cell disease(SCD) is transmitted as an incom- plete autosomal-dominant trait (Karayakin, 2000). When both parents carry the sickle cell trait (het- erozygous gene or Hgb AS), there is a 25% chance with each pregnancy of producing an infant with
128. 110 Chapter 4 R. Bryant Table 4.2. Diagnostic tests used in sickle cell disease Test Interval Baseline CBC, differential, and reticulocyte count, Each visit pulse oximetry Red cell minor antigen phenotype Visit at 6 months of age Hgb electrophoresis Conﬁrmatory 2–6 months, 2 years of age, and if needed, at 5 years age Renal and hepatitis function tests, amylase, lipase, Yearly but more often if abnormal. LDH, liver function tests, urinalysis Human immunodeﬁciency virus Yearly post-transfusion Blood cultures If febrile ≥38.5 °C Transcranial cerebral ultrasonography Yearly (start at age 2 until 16 years in Hgb SS or comparable sickle hemoglobinopathy Pulmonary function tests Age 8 and every 2 years unless abnormal Electrocardiography/echocardiography Every 2 years unless abnormal Abdominal ultrasonography Age 8–10 years or if symptomatic or Audiogram Age 8–10 years or if symptomatic Plain ﬁlms, MRI of hips/shoulders Symptomatic MRI/angiography of brain as needed Symptomatic Neuropsychological testing Age 6 years and repeat as necessary SCD (homozygous gene – Hgb SS or heterozygous 4.3.4 Symptoms/Clinical Signs Hgb S variant). The incidence of the sickle cell trait is about 8% in African-Americans in the United States, The basic pathophysiology of sickle cell is directly re- whereas it has been reported to be as 40% among lated to the abnormal Hgb S that polymerizes when West Africans. deoxygenated. Most of the complications of SCD are the result of entanglement and enmeshing of the 4.3.3 Molecular Genetics sticky, rigid, sickle-shaped cells as they block the mi- crocirculation, causing partial to complete vaso-oc- The molecular defect in Hgb SS occurs due to the clusion of vessels. The resultant decreased blood ﬂow substitution of valine for glutamic acid in the sixth to the tissues causes ischemia and infarction which position of chromosome 11 of the b-globin chain. may result in further complications. A thorough his- The second most common type of SCD is Hgb SC tory, physical exam, and periodic diagnostic tests (heterozygous variant) in which the lysine is substi- tend to identify existing complications (see Table 4.2). tuted for the glutamic acid at the sixth position of the b-chain. Other Hgb S variants include a combination 4.3.5 Diagnostic Testing of Hgb S trait and b-thalassemia trait, either produc- ing Hgb SBo thalassemia (no normal b-globin pro- The following descriptions of peripheral blood duction) or Hgb SB+ thalassemia (decreased b-globin smears are correlated with the type of SCD: production). Another frequently seen variant is the combination of Hgb SS with a-thalassemia trait ▬ The typical Hgb SS smear contains mild to moder- (usually two or three functional a-globin genes). ate normochromic, normocytic to macrocytic
129. Anemias Chapter 4 111Table 4.3. Neonatal hemoglobin patterns (adapted from Hudspeth and Symons, 2002)) Screening Conﬁrmed electrophoresis Possible genotype phenotype FA Normal newborn pattern Hgb AA FAS Benign sickle cell trait Hgb AS FAC Benign Hgb C trait Hgb AC FAA2 Benign b-thalassemia trait Hgb AA2 FS Fetal and sickle Hgb S Homozygous Hgb SS or Hgb S/bo-thalassemia or Hgb S/B+ thalassemia FSC Hgb S and Hgb C Hgb SC + FSAA2 Heterozygous Hgb S/b -thalassemia Hgb S/b+ thalassemia F Fetal Hgb F or Hgb F with delayed Hgb A Homozygous b-thalassemia major or homozygous appearance hereditary persistence of fetal Hgb F FA Barts Fetal Hgb, Hgb A, and Barts Hgb b-thalassemia silent carrier (ranges 1–2 % to 30 %) b-thalassemia trait Hgb H disease AF May indicate prior blood transfusion Retest 4 months post-transfusionHemoglobin variants are reported in order of decreasing abundance;for example,FA indicates more fetal than adult Hgb.Repeatblood specimen should be done to conﬁrm original interpretation cells with sickled cells and increased anisocytosis The differential diagnoses include disorders such as and poikilocytosis (see Fig. 4.1, plate 8). The aver- hereditary spherocytosis (HS), glucose-6-phosphate age Hgb range is 5–9 g/dl, with an average reticu- dehydrogenase (G-6PD), pyruvate kinase, thalass- locytosis 5–>20% emia, leukemia, and juvenile rheumatoid arthritis,▬ The Hgb SC smear contains normochromic, nor- which can all be excluded by obtaining the Hgb elec- mocytic cells with sickle cells, target cells, and trophoresis (see Table 4.3). spherocytes (see Fig. 4.1, plate 6). The Hgb SC av- About 2,000 infants with SCD born in the United erage Hgb range is 9–12 g/dl, with an average retic- States are identiﬁed by neonatal screening (AAP, ulocyte count between normal and 10% 2002). Neonatal screening is included in state screen-▬ The Hgb S bo-thalassemia and Hgb SS a-tha- ing programs that obtain blood via heel prick to lassemia smear contains marked microcytosis, identify primarily sickle and thalassemic hemoglo- and moderate to marked sickle cells with anisocy- binopathies (see Table 4.3). tosis and poikilocytosis. The average Hgb and reticulocytosis are commensurate with Hgb SS 4.3.6 Complications of SCD▬ Hgb S b+-thalassemia smear contains moderate microcytosis, sickle-shaped cells with anisocyto- The chronic destruction of the RBCs in SCD results in sis and poikilocytosis. The average Hgb is acute and chronic complications; however, this chap- 9–12 g/dl with reticulocytosis 5–10% ter will focus on the acute complications of SCD. Complications of SCD may occur suddenly and can rapidly become severe; therefore, the medical
130. 112 Chapter 4 R. Bryant provider should consult with a hematologist. The thema and swelling, low-grade fevers, and joint and most common complication, which is usually not life- bone pain. Osteomyelitis may be excluded by clinical threatening, is vaso-occlusive crisis or episode. Other observation, blood cultures, and, occasionally, aspira- complications that will be discussed are acute se- tion of the affected area. questration, aplastic crisis, infection, acute chest syn- drome, acute abdominal pain, and acute central nerv- 18.104.22.168.2 Treatment ous system events. Hydration (oral or intravenous), opioids and NSAIDS (oral or intravenous), incentive spirometry, adjuvant 22.214.171.124 Vaso-occlusive Crisis/Episode (VOE) therapy, rest, heat and massage to painful areas, and exercises or diversional activities (school work, ▬ Deﬁnition: Vaso-occlusive episode (VOE) occurs friends, meditation, guided imagery) are useful inter- when deoxygenated sticky, rigid sickled-shaped ventions for VOE. Whether VOE is managed by pa- RBCs block microcirculation completely or par- tient-controlled analgesia (PCA) or orally, the pain tially (infarction) causing tissue ischemia or assessment treatment should be closely monitored to necrosis. achieve optimal pain management (Jacob et al., ▬ Signs and symptoms of VOE: Most children with 2003). sickle cell anemia experience some degree of acute pain and may express their pain verbally or by cry- 126.96.36.199 Acute Sequestration Crisis ing, grimacing, or maintaining a stoic expression. Most of the children are able to describe their ▬ Deﬁnition: Acute splenic sequestration is a sud- severity of pain by using self-reporting methods den, rapid enlargement of the spleen with trap- such as the faces pain scale or the numeric pain ping of a considerable portion of the red cell mass, scale (see Fig. 4.2). Other behavior indicators may leading to acute exacerbation of anemia that drops be helpful in the pain assessment of all children, the Hgb level 2 g/dl or more below baseline including infants, such as limited movement of a ▬ Signs and symptoms: Sudden weakness, dyspnea, body part, decreased appetite, or increased irri- rapidly distending abdomen (spleen or liver en- tability. The bones and joints are major pain sites, larging), abdominal pain, lethargy, irritability, pal- with tenderness, erythema, warmth and swelling lor, vomiting, headache, tachycardia, and tachyp- frequently present. The initial site of pain in young nea are manifestations of acute sequestration. Se- children and infants is usually the small bones of vere cases of splenic sequestration may lead to cir- the hands and feet, called dactylitis or hand/foot culatory collapse (shock) and death syndrome, and may be accompanied by swelling, ▬ Diagnostic tests: Hct may drop to half the patient’s erythema, and increased warmth. Severe compli- usual value. Brisk reticulocytosis with increased cations may develop after repeated hip/shoulder nucleated red cells, moderate to severe thrombo- infarctions (i.e., avascular necrosis of the ﬁbula, cytopenia, and leukopenia may be present on the femur, or humerus, known as AVN) or repeated smear skeletal vertebrae infarctions (i.e., lordosis, scolio- ▬ Treatment: Volume expansion with a ﬂuid bolus sis, or kyphosis). and oxygen supplementation are needed immedi- ately. Immediate yet slow transfusion of small 188.8.131.52.1 Diagnostic Test/Differential aliquots packed RBCs (PRBCs) to restore intravas- A complete blood count, RBC indices, WBC count cular volume and oxygen-carrying capacity may and differential, reticulocyte count, renal and liver be instituted. Prevention of further recurrences is function tests, and, if needed, bone radiographs are achieved by elective splenectomy after the ﬁrst usually obtained during severe VOE. The differential major or second minor episode of sequestration, includes VOE versus osteomyelitis, which is difﬁcult preferably in children >2 years of age to differentiate because both are associated with ery-
132. 114 Chapter 4 R. Bryant ▬ Education: Parents should be taught splenic palpa- ▬ Diagnostic tests: A CBC with differential; C-reac- tion and educated about recognizing the signs and tive protein (CRP); cultures of blood, throat, and symptoms of splenic sequestration to aid in iden- urine; chest x-ray; and oxygen saturation should tifying initial episodes of acute sequestration and be obtained. If the chest x-ray shows an inﬁltrate, a preventing recurrent life-threatening episodes sputum culture should be obtained if possible. Af- ter a blood culture is obtained, the child should be 184.108.40.206 Aplastic Crisis started on parenteral antibiotics and admitted to the hospital. If osteomyelitis is suspected, an or- ▬ Deﬁnition: Temporary cessation of bone marrow thopedics specialist should be consulted regarding activity due to suppression by viral or bacterial in- needle aspiration and culture of the suspected fection, which causes a drop in hematocrit without bone site reticulocytosis. Parvovirus B19 is the most com- ▬ Treatment: A child with SCD and fever ≥38.5 ºC mon cause of aplastic crisis (Hastings, 2002c). must be considered an emergency because of the ▬ Signs/symptoms: Increased pallor, icteric sclera, increased risk for overwhelming sepsis resulting lethargy, irritability, headache, bone pain, weak- from splenic dysfunction ness, nausea and vomiting, and dark urine are all manifestations of aplastic crisis. Children with SCD who have a low risk of sepsis (no ▬ Diagnostic tests: The hematocrit decreases as high-risk factors, see Table 4.4) and who are older much as 10–15% per day with no compensatory than 2 years of age are treated with outpatient man- reticulocytosis. agement in several comprehensive sickle cell centers ▬ Treatment: Isolation precautions with oxygen sup- in the United States with close follow-up care (i.e., re- plementation may be instituted depending on the turn clinic visits or telephone contact) (Williams et type of infection. Transfusion of PRBCs may be in- al., 1996). After blood cultures are obtained, these stituted to prevent congestive heart failure. Folic children are given long-acting parenteral antibiotics acid should be given in the recovery phase. such as ceftriaxone (50–75 mg/kg/dose, with maxi- mum dose of 2 g). If the child is allergic to ce- 220.127.116.11 Infection phalosporin, clindamycin 15 mg/kg is given with a maximum dose of 600 mg. These children are moni- ▬ Deﬁnition: The major risk factor for increased sus- tored in the clinic or emergency center for several ceptibility to infection is splenic dysfunction. The hours prior to being discharged home with close fol- ability of the spleen to clear particles from the in- low-up care (Jakubik and Thompson, 2000). travascular space and provide antibody synthesis A SCD child without high-risk factors (see is impaired in the patient with SCD. Insidious pro- Table 4.4) is discharged on oral antibiotics for 3 days gressive ﬁbrosis of the spleen (autosplenectomy) while awaiting blood culture results. The child is pre- occurs in the Hgb SS child, usually by the age of scribed cefprozil 30 mg/kg/day divided twice daily or 6 years. Children with splenic dysfunction are Pediazole 40 mg/kg/day three times daily if cephalo- 300–600 times more likely to develop overwhelm- sporin-allergic. Any positive culture obtained from a ing pneumococcal or Haemophilus inﬂuenzae sep- child being managed on an outpatient basis requires sis and meningitis than are children without immediate hospitalization and reevaluation of the splenic dysfunction. (Karayalcin, 2000). child. High-risk factors that prevent children from ▬ Signs/symptoms: Toxic-appearing children with being eligible for outpatient management are listed fever ≥38.5 °C, chills, lethargy, irritability, tachyp- in Table 4.4. nea, tachycardia, hypoxia, and history of prior sep- sis should be treated promptly with parenteral an- tibiotics after obtaining a blood culture
133. Anemias Chapter 4 115Table 4.4. Recommended hospital management for the prophylactic penicillin 125 mg twice daily startinghigh-risk sickle cell disease patient at 2 months of age and increased to 250 mg twice Clinically ill-appearing or toxic-looking daily at 3 years of age. If the child is allergic to penicillin, then erythromycin is substituted at a Signs of cardiovascular and/or pulmonary compromise dosage of 125 mg twice daily starting at 2 months Age less than 12 months and increased to 250 mg twice daily at 3 years of Temperature ≥40 °C age (AAP, 2002). Benzathinepenicillin G 300,000 White blood count <5,000/mm3 or >30,000/mm3 units intramuscularly may be given monthly to the Platelet count <100,000 SCD patient with gastrointestinal dysfunction or who is noncompliant with oral antibiotic prophy- Hemoglobin <5 g/dl or reticulocyte count <4 % laxis. Dehydration with poor oral ﬂuid intake Pulmonary inﬁltrate and/or previous history of acute chest syndrome 18.104.22.168 Acute Chest Syndrome ▬ Deﬁnition: Acute chest syndrome (ACS) is a com- Pulse oximetry <92 % or 3 % below baseline mon cause of morbidity and mortality in children Central venous catheter with SCD and is characterized by fever, chest pain, Prior splenectomy and a new inﬁltrate on chest x-ray History of previous sepsis ▬ Signs/symptoms: Clinical manifestations of ACS Evidence of acute SCD complications may include extremity pain, rib or sternal pain, ab- Prior noncompliance or evidence of inability dominal and chest pain, cough, dyspnea, fever to comply with outpatient follow-up (≥38.5 °C), back pain, tachypnea, wheezing, hy- poxia (paO2 <75 mmHg or 3 points of transcuta- neous oxygen saturation below baseline) SOB,▬ Prevention dyspnea, dullness (palpation), or normal ausculta- Morbidity and mortality rates have decreased dra- tion (Rackoff et al., 1993) matically since the advent of established newborn ▬ Diagnostic tests: Chest radiography may be clear screening programs (United States), widespread initially but should be repeated with increasing penicillin prophylaxis, timely administration of respiratory distress or hypoxia. Blood cultures, immunizations, and parental/caregiver education. CBC, differential, reticulocyte count, type and Parental/caregiver education is aimed at reducing crossmatch, and, if possible, sputum cultures and bacterial septicemia and includes such interven- arterial blood gases should be obtained. It is ex- tions as immediate medical evaluation of febrile tremely difﬁcult to differentiate between ACS and illness (≥38.5 ºC), twice-daily administration of pneumonia. The most common organism causing prophylactic antibiotic, and compliance with ACS or pneumonia is pneumococcus, followed by immunization schedules. In addition to standard Salmonella, Klebsiella, Haemophilus inﬂuenzae, immunizations, the SCD patient should also and Mycoplasma pneumoniae and viruses. Martin receives the 23-valent pneumococcal vaccine, the and Buonomo (1997) reported that pulmonary in- meningococcal vaccine at 2 years of age with ﬁltrates resolve quickly and dramatically in chil- boosters at 5 and 10 years of age, and recommend- dren with ACS not associated with infection, ed yearly inﬂuenza virus vaccines at 6 months and whereas those with infection have a prolonged ra- older. Prophylactic penicillin is started at 2 months diographic course. of age and continued until 5–6 years of age and ▬ Treatment: Patients may deteriorate rapidly, with indeﬁnitely in the child with a history of pneumo- progression to pulmonary failure and death; coccal sepsis (Jakubik and Thompson, 2000). Cur- therefore, all patients with ACS should be treated rently, the child with SCD should be placed on in the hospital. Early recognition of respiratory
134. 116 Chapter 4 R. Bryant Table 4.5. Treatment for acute chest syndrome 4–6 hours to decrease airway hyperreactivity. Transfusion of PRBCs as a simple transfusion of Administer oxygen if hypoxic 10 cc/kg may be given. However, if the child’s res- Monitor continuous pulse oximetry piratory status continues to deteriorate (worsen- Encourage incentive spirometry ing hypoxia, anemia, chest pain, and worsening in- Administer empiric antibiotics ﬁltrates on chest radiograph), then an exchange Cephalosporin (e.g., cefuroxime 150 mg/kg/day transfusion should be performed (see Table 4.5) divided every 8 h) ▬ Preventive: Risk factors related to ACS include Macrolide (e.g., azithromycin 10 mg/kg/day young age (2–4 years), lower concentration of with 5 mg/kg/day on days 2–5) Hgb F, higher steady-state Hgb concentration, and Administer maintenance intravenous ﬂuids higher steady-state WBC count should be assessed (1,500 cc/m2/day) to prevent development of ACS (Quinn and Buchanan, 1999). Strategies to prevent ACS also in- Administer analgesic for pain (see algorithm) clude aggressive pain management and the use of Administer PRBCs if hemoglobin <10 g/dl incentive spirometry to prevent hypoventilation. Simple transfusion (10 cc/kg) Transfusion is generally recommended to de- Exchange transfusion crease the concentration of Hgb S and can theoret- ically prevent ACS (Quinn and Buchanan, 1999). Hydroxyurea is an agent that is used to upregulate Hgb F and decrease viscosity and sickling of RBC, distress (cough, chest pain, hypoxia with or which decreases the development of ACS. Stem cell without fever) and aggressive treatment with oxy- transplant is a therapy only available to limited gen if hypoxic, analgesics (see Fig. 4.2), empiric number of donors but is a known cure of SCD antibiotics, maintenance intravenous hydration (Quinn and Buchanan, 1999). (1,500 cc/m2/day), bronchodilators, respiratory treatments, and simple RBC transfusion (10 cc/kg) 22.214.171.124 Acute Abdominal Pain or exchange transfusion are instituted immediate- ▬ Deﬁnition: The etiology of acute abdominal pain ly (see Table 4.5). Oxygen treatment is monitored is unknown, although mesenteric sickling and ver- closely by pulse oximetry with an ongoing respira- tebral disease with nerve root compression have tory assessment of the patient. Incentive spirome- been suggested (Dover and Platt, 2003). try is encouraged every hour while awake, with ad- ▬ Signs/symptoms: Guarding, tenderness, rebound, ministered analgesics (see Fig. 4.2) to prevent hy- distended abdomen, fever, jaundice, right upper poventilation. After a blood culture is obtained, quadrant pain, constipation are all manifestations empiric antibiotics are given, which include a of acute abdominal pain. cephalosporin such as cefuroxime 150 mg/kg/day ▬ Diagnostic tests: CBC with differential, reticulo- divided every 8 hours (maximum dose 2 g) to cyte count, liver enzymes, pancreatic enzymes, eradicate possible pathogens such as pneumococ- hepatitis panel, urinalysis, chest/abdominal ﬁlms cus. A macrolide such as azithromycin 10 mg/kg including upright views for perforated viscus, ul- on day 1 (maximum dose 500 mg) followed by trasonography, or biliary scans may be instituted 5 mg/kg/day on days 2–5 (maximum 250 mg) is to determine the etiology of the acute abdominal given to treat possible pathogens such as My- pain. Differential diagnoses may include ACS, coplasma or Chlamydia (see Table 4.5). Hydration ileus, pneumonia, constipation, surgical abdomen, at maintenance rate (1,500 cc/m2/day) is adminis- pancreatitis, urinary tract infection, intrahepatic tered to avoid overhydration (i.e., pulmonary ede- sickling, and cholecystitis. ma). Bronchodilators such as albuterol aerosols are a common treatment that is given every
135. Anemias Chapter 4 117▬ Treatment: Maintenance intravenous ﬂuids designed to suppress the production of sickle cells, (1,500 cc/m2/day), analgesics (see Fig. 4.2), laxa- thereby reducing the chance of recurrent strokes. tives if constipated, and a surgical consult to rule However, the multiple transfusions may cause out surgical abdomen (i.e., appendicitis) are insti- complications such as hemochromatosis, alloim- tuted as soon as possible. munization, and infections such as hepatitis, HIV, and West Nile virus. Hemochromatosis is unavoid- able with prolong transfusions and is treated with126.96.36.199 Acute Central Nervous System Event parenteral desferrioxamine (see section 188.8.131.52)▬ Deﬁnition: An acute central nervous system (CNS) ▬ Preventive: Transcranial Doppler (TCD) ultra- event develops from chronically injured cerebral sonography predicts increase risk of stroke in vessels in which the lumen is narrowed or com- children who have increased ﬂow velocity pletely obliterated by sickled erythrocytes, (>200 cm/sec) in major cerebral arteries that is causing acute cerebral infarction. Approximately demonstrated on two consecutive TCDs (Segel et 7–10% of SCD (primarily Hgb SS) patients devel- al. 2002; Dover and Platt, 2003). TCDs are done op acute cerebral vascular occlusion or stroke, yearly to aid in identifying children who are at most often between the ages of 2 and 10 years. high risk for developing stroke or who have Cerebral infarction may occur as an isolated event asymptomatic brain disease. Neuropsychological or in combination with such disorders as pneumo- testing identiﬁes deﬁcits in intelligence quotient nia, aplastic crisis, viral illness, painful crisis, pri- (IQ), which has been instrumental in combination apism, and dehydration with MRI in discovering SCD children with silent▬ Signs/symptoms: Sudden and persistent head- infarcts. Silent infarcts are damage to the brain as- ache, hemiparesis, hemiplegia, seizures, coma, sociated with impaired cognitive abilities second- speech defects, gait dysfunction, visual distur- ary to sickling in cerebral vessels without any bances, and altered mentation are all manifesta- physical neurological deﬁcits (Dover and Platt, tions of a cerebral infarction 2003). Recommendations for treatment of silent▬ Diagnostic test: The initial diagnostic test done is infarcts may include either hydroxyurea therapy, a computed tomography scan (CT scan) of the transfusion program, stem cell transplant or close brain without contrast to identify intracerebral observation. The best treatment option for silent hemorrhage, abscess, tumor, or any other patholo- infarcts is unknown, but the transfusion program gy that could explain the symptoms. Magnetic res- is usually recommended as the initial option onance imaging (MRI) and angiography aid in as- sessment of infarcts associated with obstruction 4.3.7 Preparation for Surgery of intracranial vessels (i.e., the anterior and/or middle cerebral vessels), and are usually ordered Most children with SCD tolerate chronic anemia well as soon as possible after CT and only require transfusions for severe complica-▬ Treatment: The standard approach to treating a tions such as splenic sequestration, CNS infarction/ patient with acute cerebral infarction is exchange ischemia/hemorrhage, aplastic crisis, severe ACS, and transfusion followed by placement on a mainte- preparation for surgery. Because sickling of RBCs is nance monthly transfusion program. The transfu- increased during hypoxic periods, it may be neces- sion program is designed to keep Hgb S <30%, sary to transfuse the patient prior to the surgical pro- which lowers reoccurrence of stroke to 10%. In cedure that requires anesthesia. If the SCD patient untreated persons, the mortality rate is approxi- has a history of major complications (i.e., ACS, CNS mately 20%, with about 70% of the patients expe- infarctions, multiple VOE), preoperative transfusion riencing a recurrence within 3 years of the initial consists of multiple transfusions every 3–4 weeks or cerebral vascular event (Dover and Platt, 2003). exchange transfusion to obtain a goal of <30% Hgb S Maintenance monthly transfusion programs are prior to surgery. Exchange transfusion is used to re-
136. 118 Chapter 4 R. Bryant move sickled cells and replace them with normal cells 4.3.9 Future Perspectives without increasing blood viscosity. However, if the ▬ Because HU therapy is a lifetime therapy, more SCD patient has not sustained any major complica- studies are needed to determine its long-term side tions, the patient is transfused to a Hgb of 10 g/dl ir- effects in the SCD patient (Steinberg et. al, 2003). respective of the percentage of Hgb S. A simple trans- Studies to determine long-term additive effects of fusion is usually performed 2–5 days prior to the sur- HU and erythropoietin on Hgb F production are gical procedure. being researched ▬ A limited number of umbilical cord blood trans- 184.108.40.206 Hydroxyurea Therapy plants have been successful; therefore, this area is ▬ Hydroxyurea (HU) is an S-phase-speciﬁc cytotox- being researched as a possible cure for SCD ▬ There are studies focused on gene manipulation to ic agent that upregulates Hgb F, which interferes with Hgb S polymerization and increases the lifes- correct the SCD defect and cure the disease pan of the sickled RBCs. HU decreases blood vis- cosity, has an increase afﬁnity for oxygen, and re- leases a byproduct known as nitrous oxide that 4.4 Thalassemia acts as a potent vasodilator. Therefore, hydrox- yurea will aid in decreasing sickling and promot- Thalassemia is a group of inherited heterogeneous ing unobstructed circulation. anemias associated with the absence or decreased ▬ Children with SCD complications such as repeated production of normal Hgb (Table 4.6). Two broad ACS, or severe VOE are offered HU therapy classiﬁcations of thalassemia are the alpha (a)- and ▬ The initial dose of HU is 15–20 mg/kg/day and beta (b)-thalassemias, which contain deﬁcits in is escalated to 35 mg/kg/day while monitoring a- and b-thal globin production, respectively. the platelet, neutrophil, and reticulocyte counts (Powars, 2001; Steinberg et. al., 2003) 4.4.1 Alpha (a)-Thalassemia ▬ Side effects of HU include neutropenia, leukope- nia, reticulocytopenia, elevated liver enzymes, 220.127.116.11 Epidemiology nausea and vomiting, hyperpigmentation, alope- cia, and a potential mutagenic and carcinogenic The majority of a-thalassemias are located in South- effect. All patients of childbearing age must agree east Asia, Malaysia, and Southern China. to a contraceptive plan prior to starting HU 18.104.22.168 Etiology 4.3.8 Prognosis The deﬁcit in a-globin production is due to deletion SCD patients without a history of major SCD compli- or mutation of one or more of the four a-globin genes cations will have lifespans 10–15 years shorter than located on chromosome 16. the individual without SCD. In an observational study, Miller and colleagues (2002) found a signiﬁ- 22.214.171.124 Molecular Genetics cant correlation between SCD course and adverse outcomes later in childhood in children who devel- More than 30 different mutations affecting a-globin oped dactylitis before age 1 year and had a steady- genes have been described (Nathan and Orkin, 2003). state of Hgb <7 g/dl and leukocytosis in the absence ▬ Silent carrier has three functional a-globin genes of infection at an early age of 1 year. (-a/aa) ▬ a-thalassemia trait has two functional a-globin genes (-a/a or aa/–)
137. Anemias Chapter 4 119Table 4.6. Classiﬁcation of thalassemias (adapted from Nathan and Orkin, 2003) Syndrome Phenotypes Clinical ﬁndings Silent carrier a: 1–2 % Hgb Barts or 1–2 % Normal or slightly microcytic RBCs; no signs (a and b-thalassemia) Hgb CS at birth only or symptoms b: Hgb Az ≥3.5 80–90 % of Hgb F / Hgb A Thalassemia trait a: 5–10 % Hgb Barts or 1–2 % Mild anemia to elevated RBCs; (a- and b-thalassemia trait) Hgb CS at birth microcytosis/hypochromic 80–90 % Hgb F / Hgb A b: Hgb Az ≥3.5 80–90 % Hgb F / Hgb A Hgb H or Hgb CS a: 5–30 % Hgb Barts or 1–2 % Microcytic/hypochromic anemia (7–10 g/dl); (constant spring) Hgb CS at birth pale, icteric, jaundiced; hepatosplenomegaly Hgb F 70–90 % Hydrops fetalis a: combination of Hgb Barts, Hgb H. Severe anemia (6.2 g/dl average Hgb); pale, Hgb Portland usually death in utero icteric, edematous due to congestive heart failure; hepatosplenomegaly Thalassemia intermedia Hgb Az 2–7 % Anemia (6–10 g/dl) microcytosis Hgb F 20–100 % hypochromic; pale, icteric, and with Hgb A 0–80 % (depends on phenotype) hepatosplenomegaly; rarely transfused Thalassemia major Hgb Az 2–7 % Anemia average 6 g/dl with Hgb F 20–100 % microcytic/hypochromia; pale, failure to Hgb A 0–80 % (depends on phenotype) thrive, frontal bossing, thalassemic facies, short stature, hepatosplenomegaly; transfusion-dependent▬ Hemoglobin H disease has one functional a-glo- 126.96.36.199 Molecular Genetics bin gene (–/-a) and a Hgb H variant = Hgb con- stant spring (–/acsa) Within the b-globin gene, 170 mutations affect the▬ Hydrops fetalis has no functional a-globin gene transcription, translation of b-globin messenger, and (–/–) stability of b-globin product (Olivieri, 1999; Nathan and Orkin, 2003). b-thalassemia includes four clinical4.4.2 Beta (b)-Thalassemia (Cooley Anemia) syndromes (see Table 4.6):188.8.131.52 Epidemiology ▬ Silent carrier, which is asymptomatic ▬ b-thalassemia trait with mild anemia ▬ Thalassemia intermedia with moderate anemiab-thalassemia mutations are found worldwide in re- and usually no transfusion requirementgions including the Mediterranean, Africa, Southeast ▬ Thalassemia major with severe anemia and trans-Asia, India, Italy, Greece, Spain, and North America, fusion-dependentbut are uncommon in Northern Europe, Korea, andJapan. 4.4.3 Diagnostic Testing184.108.40.206 Etiology Thalassemia testing can be conﬁrmed with Hgb elec-The deﬁcit in b-globin production is due to mutation trophoresis and family studies, or if necessary, DNAof the b-globin genes located on chromosome 11. analysis can be used to make a deﬁnitive diagnosis. In
138. 120 Chapter 4 R. Bryant most states of the United States, screening for hemo- meningococcal vaccines should be given. Following globinopathies is performed on newborn infants. splenectomy, prophylactic penicillin 250 mg PO bid is Anemias in children who were not screened as new- implemented until adulthood. The importance of borns but present with hypochromic, microcytic seeking medical assistance when the splenectomized anemias must be differentiated from iron deﬁciency patient is febrile is emphasized with parents and (see formulas below). child to reduce the risk of developing overwhelming Prenatal diagnosis of a-thalassemia may be done infection. Complications of ongoing transfusion by testing the amniotic ﬂuid or obtaining chorionic therapy regimens are assessed (see section 4.2.7) in- villus sampling if there is a suspicion for a-thal trait cluding hemosiderosis. or a family history of hydrops fetalis. Differentiation between thalassemia trait and iron deﬁciency can be 4.4.5 Treatment of Hemosiderosis calculated based on the following formulas: (Iron Overload) Formulas for differentiation of thalassemia trait from Hemosiderosis is the accumulation of iron in organ iron deﬁciency (adapted from Nathan and Orkin, tissues such as liver, pancreas, and joints as a result of 2003, p 881) chronic RBC transfusion therapy received by patients Thalassemia Iron with b-thalassemia, Hgb H, sickle cell (i.e., those trait deﬁciency with a history of cerebrovascular accident, ACS, re- Mentzer index (655) tractable vaso-occlusive crisis) or bone marrow fail- MCV/RBC <13 >13 ure syndromes (Olivieri, 1999; Beare, 2002). Hemo- siderosis may also develop in the frequently trans- Shine and Lal (665) fused patient receiving myelosuppressive chemo- (MCV)2 ¥ MCH <1,530 >1,530 therapy and/or radiation treatments. Chronic hemol- England and Fraser (666) ysis and increased gut absorption of iron can also (MCV–RBC– Negative Positive result in hemosiderosis. Exchange transfusion, [5 ¥ Hb])–8.4 values values phlebotomy, and chelation therapy are the only methods to manage transfusion-related iron over- 4.4.4 Treatment load at present. Supportive therapy includes supplementation with 4.4.6 Chelation Therapy folic acid, avoidance of oxidant drugs and iron salts, prompt treatment of infectious episodes, and judi- The objective of chelation therapy is to remove excess cious use of transfusions. b-thalassemia major pa- intracellular iron and bind free extracellular iron. tients require regular transfusions to sustain life. Thalassemia intermedia patients are able to maintain 220.127.116.11 Initiation of Chelation Therapy a Hgb concentration of 6–10 g/dl without transfu- sions except during periods of infection, surgery, or ▬ Liver biopsy is the most accurate measurement of other stressors. Splenectomy may be considered in iron load, so if liver iron is 7 mg/g/dry weight or Hgb H, thalassemia intermedia, and b-thalassemia higher, then chelation should be started major if hypersplenism is present with leukopenia, ▬ Ferritin level is helpful but not reliable because thrombocytopenia, worsening anemia, or the devel- it is an acute phase reactant. Ferritin levels opment of increased requirement for transfusion >1,000 mg/ml in steady state, then start chelation (>200 ml PRBCs/kg/year). Splenectomy reduces the ▬ Cumulative transfusions of 120 ml or more transfusion requirements by eliminating the organ PRBCs/kg/year promote hemosiderosis causing the trapping of the RBCs.At least 2 weeks pri- or to splenectomy, polyvalent pneumococcal and
139. Anemias Chapter 4 118.104.22.168 Chelation Regimens July 2003, a new drug application was ﬁled with the U.S. Food and Drug Administration for deferiprone.▬ Desferrioxamine is a complex hydroxylamine with It is hoped that deferiprone will be available for use a remarkable afﬁnity to iron by the year 2005.▬ Desferrioxamine enters cells, chelates iron, returns iron to serum, and excretes the iron via kidney, liv- er, and skin 4.4.8 Prognosis▬ Desferrioxamine 20–50 mg/kg/8–12 hours nightly Bone marrow transplants from HLA-identiﬁed ¥ 5–6 days weekly donors have been successfully performed worldwide▬ Desferrioxamine by the IV route accelerates the on patients with severe b-thalassemia. A marked in- rate of iron removal crease in survival to the ﬁfth decade of life in the well-▬ Supplemental oral ascorbic acid 100 mg daily PO managed b-thalassemia patient is seen in developed enhances the urinary excretion of iron, particular- countries. ly in vitamin C-deﬁcient patients 4.4.9 Follow-up22.214.171.124 Complications of Desferrioxamine▬ Local erythema at the infusion site characterized All thalassemic b major patients should have 3- by multiple subcutaneous nodules may be sup- month interval appointments with the hematologist pressed by including 5–10 mg hydrocortisone in medical provider to manage therapies and side ef- the desferrioxamine solution fects involving hemochromatosis, vision, hearing, en-▬ Ototoxicity is a complication of desferrioxamine larged organs, and dental side effects. Other tha- therefore a hearing test should be done every lassemic patients (b-intermedia, Hgb H) are usually 6–12 months seen every 6 months provided the patients have not▬ Ocular toxicity is a complication of desferrioxam- developed any severe complications. ine; therefore, the eyes should be examined every 6–12 months 4.4.10 Future Perspectives▬ Noncompliance is an ongoing problem particular- ly with adolescent patients or parents who dread Institution of bone marrow transplantation with un- doing the desferrioxamine subcutaneous injec- related phenotypically matched donors and in utero tions transplantation are being investigated. Development▬ Do not administer desferrioxamine during infec- of transduction methods and vectors to transfer tion or fever because the mobilization of iron aids genes and correct the genetic defect are being re- in bacterial growth, particularly Yersinia enteroco- searched. litica 4.5 Hemolytic Anemia4.4.7 Clinical Advances (Hemosiderosis) Hemolytic anemias comprise a group of disordersMRI of the liver is being studied to determine that cause destruction of RBCs. The reduced RBCswhether the imaging-measured iron content is com- survival may occur as result of intracorpuscular de-parable to a liver biopsy result, thereby providing a fects due to defective intracellular enzymes (i.e., glu-noninvasive means of measuring iron accumulation cose-6-phosphate dehydrogenase deﬁciency or pyru-in the body. Another recent advance is an oral chela- vate kinase deﬁciency) or abnormal membranetor known as deferiprone (L1 or 1,2-dimethyl-3-hy- structural proteins as in hereditary spherocytosisdroxy) that has been used in Europe since 1999 in (HS). The RBC survival is also affected by the extra-chelating iron in the thalassemia major patient. In corpuscular defect of autoimmune hemolytic anemia (AIHA).
140. 122 Chapter 4 R. Bryant 4.5.1 Hereditary Spherocytosis (HS) dice, and splenomegaly. Mild to marked jaundice may be present depending on the rate of hemolysis and Hereditary spherocytosis (HS) is the most common the ability of the liver to conjugate and excrete indi- congenital RBC membrane disorder. HS is character- rect hyperbilirubinemia. ized by a deﬁciency or abnormality of the RBC mem- brane protein spectrin, one of the major skeletal cell 126.96.36.199 Diagnostic Testing membrane proteins. The HS RBCs are repeatedly trapped by the splenic sinusoids, which causes dam- Spherocytes are dense, round, and hyperchromic, age and destruction to the spherocytes. and lack central pallor on peripheral blood smear (see Fig. 4.1, plate 7). The laboratory ﬁndings of HS 188.8.131.52 Epidemiology vary according to the severity and clinical classiﬁca- tion. The trait may have a normal Hgb and normal to HS is a common inherited hemolytic anemia, with slightly elevated reticulocyte count (see Fig. 4.1, plate an estimated incidence in Northern Europe of 5). Mild HS Hgb can be 11–15 g/dl, but with an ele- 1–2 in 5,000 individuals. vated reticulocyte count can be 3–8%. In moderate to moderately severe HS, the Hgb is 8–12 g/dl to 184.108.40.206 Etiology 6–8 g/dl, respectively, with elevated reticulocyte counts above 8%. Severe HS has a Hgb <6 mg/dl and Primary molecular defects in HS reside in membrane a reticulocyte count >10. The majority of children skeletal proteins and is a common inherited he- with HS are classiﬁed as mild to moderate anemia. molytic anemia.Approximately 5–10% of cases of HS Other laboratory ﬁndings include anemia (mild to are considered new mutations. severe) depending upon the HS classiﬁcation, reticu- locyte count, and increased osmotic fragility test (the 220.127.116.11 Molecular Genetics most sensitive test for diagnosing HS). The sphero- cytes have a decreased surface area to volume ratio, Microscopically, HS cells show fewer spectrin ﬁla- and when placed in the hypotonic solution, the HS ments interconnecting spectrin/actin/protein to cells lose membrane surface area more readily be- junctional complexes, but overall skeletal architec- cause their membranes are leaky and unstable, re- ture is preserved except in the most severe forms of sulting in an increase osmotic fragility test. HS (Gallagher and Lux, 2003). Typically, HS is associ- The MCV (mean corpuscular volume) is de- ated with approximately 70% dominant and 20% re- creased except during reticulocytosis. The red cell cessive inheritance. The membrane protein defects distribution width (RDW) is elevated due to the pres- cause instability of the spectrin, which results in ence of microspheres in proportion to the degree of membrane instability, loss of surface area, and abnor- hemolysis. The Coombs’ test is negative, which ex- mal permeability, with the average lifespan of the red cludes AIHA. Several other diagnostic tests used to cell being 90 days. detect HS include the acidiﬁed glycerol lysis test, hy- pertonic cryohemolysis test, and the autohemolysis 18.104.22.168 Symptoms/Clinical Signs test. HS must be differentiated from such disorders as AIHA, G-6PD, pyruvate kinase deﬁciency, elliptocy- A thorough history and physical may elicit a family tosis, and pyropoikilocytosis. history of neonatal hyperbilirubinemia, gallstones, splenomegaly or splenectomy, and intermittent jaun- 22.214.171.124 Treatment dice that typically presents in infancy but may pres- ent at any age. Anemia is the most frequent present- ▬ Because dietary intake of folic acid is inadequate ing complaint, accompanied with reticulocytosis and for the increased needs of the erythroid HS bone manifested primarily by pallor, intermittent jaun- marrow, the patient routinely receives folic acid 1 mg/day orally to prevent megaloblastic crisis
141. Anemias Chapter 4 123▬ The parents and child are instructed regarding 4.5.2 Autoimmune Hemolytic Anemia (AIHA) signs and symptoms of hemolysis and hyper- splenism, such as increased pallor, fatigue, abdom- A condition that develops from the interaction be- inal pain, enlarging spleen, jaundice, and dark tween erythrocytes and the immune system is known urine. The family and child are instructed to avoid as autoimmune hemolytic anemia (AIHA). The most trauma to the spleen area and are shown how to common types are AIHA that is composed of warm- monitor spleen size reactive autoantibody, usually immunoglobulin▬ If splenectomy becomes necessary, it is delayed (IgG), that binds with the erythrocyte antigen at until the child is 5 or 6 because the increased risk 37 °C, or cold-reactive autoantibody, usually IgM, of postsplenic sepsis is very high in infancy and that binds to erythrocytes below 37 °C (Ware, 2003). early childhood. The child should have pneumo- These autoantibodies are recognized by the macro- coccal and meningococcal vaccines at least 2 phages, which leads to intravascular destruction of weeks prior to splenectomy. Prior to splenectomy, the erythrocyte. an abdominal ultrasonography should be done to determine spleen size and the presence of any 126.96.36.199 Epidemiology accessory spleens and/or cholelithiasis▬ After splenectomy, the child should receive pro- AIHA is estimated to occur at an annual incidence of phylactic penicillin therapy 250 mg PO bid until 1 in 80,000 persons of any age, race, or nationality. adulthood 188.8.131.52 Etiology184.108.40.206 Prognosis Children tend to develop AIHA after a recent viral ill-Splenectomy laparoscopically eliminates hemolysis ness or systemic illness because of the developmentbut exposes the patient to life-long risk for lethal of autoantibodies. The autoantibodies bind to theinfections. Platelet counts tend to increase to erythrocyte surface membrane, which results in pre->1,000¥109/l immediately after splenectomy but will mature red cell destruction, primarily in the spleen.usually decrease over several weeks without any in-tervention. Penicillin-resistant strains of S. pneumo- 220.127.116.11 Molecular Geneticsniae have developed, but the use of prophylacticpenicillin supersedes this complication because of The antierythrocyte antibodies that develop in mostthe increase risk of life-threatening infections. patients with AIHA represent a polyclonal B-lym- phocyte response that is poorly understood. Case re-18.104.22.168 Follow-up ports suggest there is an association between AIHA and certain immune response genes.Yearly follow-up is needed for CBC and liver paneland to reinforce penicillin prophylaxis. The splenec- 22.214.171.124 Symptoms/Clinical Signstomized HS patient should seek medical attentionimmediately for febrile illness. Healthcare providers Many patients present with signs and symptoms ofshould reinforce with the parents and patient that al- anemia, such as pallor, weakness, fatigue and light-though the hemolysis is eradicated, the HS still exists. headedness, with a compensated cardiovascular as- pect. Occasionally, the patient develops jaundice, due126.96.36.199 Future Perspectives to accelerated erythrocyte destruction, and dark urine, reﬂecting intravascular hemolysis. A thoroughManagement of HS by subtotal splenectomy has history must be obtained, including questions re-shown beneﬁcial results in a small cohort of patients garding medications and the possibility of underly-by decreasing hemolysis and maintaining phagocyt- ing systemic illness such as any history of newbornic function of the spleen (Baden-Meunier et al., 2001). jaundice, gallstones, splenomegaly/splenectomy, or
142. 124 Chapter 4 R. Bryant episodes of dark urine or yellow sclera. The patient the Fc receptor-mediated clearance of sensitized ery- may have a palpable spleen and liver, with tachycar- throcytes and also inhibit autoantibody synthesis. dia or a systolic ﬂow murmur manifested on physical Corticosteroids, prescribed as 1–2 mg/kg of methyl- exam. prednisolone IV q.6o ¥ 24–72 hours, and then oral prednisone 2 mg/kg/day divided three times daily, 188.8.131.52 Diagnostic Testing are given until clinically stable. The prednisone is ta- pered over 1–3 months based on steroid concentra- Peripheral blood smear is very useful in establishing tion, reticulocyte count, and DAT. the diagnosis of AIHA. It contains numerous small The second line of therapy includes intravenous spherocytes, occasional teardrop shapes or schisto- immunoglobulin therapy, with a systemic beneﬁt at cytes, polychromasia (common ﬁnding), and reticu- high doses of 5 g/kg/¥ 5 days, and may be accompa- locytes (see Fig. 4.1, plates 4 and 5). Bone marrow as- nied by plasma exchange transfusion. Exchange piration is not mandatory but may be helpful to ex- transfusion is reasonable with the large IgM antibod- clude a malignant process, myelodysplasia, or bone ies, which are removed by plasmapheresis, whereas marrow failure syndrome. The bone marrow reveals the IgG autoantibodies in the extravascular spaces erythroid hyperplasia with myeloid/erythroid ratio. respond better to splenectomy. Transfusion of RBCs Elevated lactate dehydrogenase and aspirate is difﬁcult in the AIHA patient due to difﬁculty in ob- aminotransferase levels reﬂect the release of in- taining compatible erythrocytes. The transfusion traerythrocyte enzymes; in contrast, other hepatic may result in severe hemolysis, so the transfusion is enzymes should not be elevated in AIHA. The serum started at a slow rate, checking both plasma and urine haptoglobin level is typically low because it acts as a for free Hgb. Other therapeutic modalities include scavenger for free plasma Hgb, but haptoglobin is an cyclosporin A (suppresses cellular immunity), vin- acute phase reactant and is not synthesized well in in- blastine (decrease autoantibody production), dana- fants. The unconjugated bilirubin is elevated and re- zol (decreased IgG production), azathioprine, and cy- ﬂects accelerated erythrocyte destruction. The most clophosphamide (both interfere with autoantibody useful laboratory test is the direct antiglobulin test synthesis). (DAT or Coombs’ test), which identiﬁes antibodies Splenectomy may be considered late in the dis- and complement components on the surface of circu- ease; it removes the major site of autoantibody lating erythrocytes. production, with a response in about 80% of patients. The differential diagnosis includes hereditary These children should receive pneumococcal/menin- spherocytosis, which may be excluded by performing gococcal immunizations at least 2 weeks prior to the osmotic fragility test. Other rare disorders such as splenectomy. Post-splenectomy patients should seek clostridial sepsis, Wilson’s disease, hemolytic-uremic medical attention immediately if they develop fever syndrome, thrombotic thrombocytopenic purpura, >38.5 °C and should take penicillin or erythromycin transient erythroblastopenia of childhood, or ac- (if allergic to penicillin) prophylaxis due to the possi- quired aplastic anemia are excluded by performing a bility of sepsis. DAT. 184.108.40.206 Prognosis 220.127.116.11 Treatment There is a good prognosis for the majority of children If the patient has a severe anemia or a decreasing Hgb who experience the acute self-limiting disease, with a concentration, then therapy should be instituted. mortality rate less than 10%. Therapy should begin with close observation, and corticosteroid therapy with the judicial use of ery- throcyte transfusions. The corticosteroids are widely accepted ﬁrst-line therapy. Corticosteroids inhibit
143. Anemias Chapter 4 1254.5.2.8 Future Perspectives 18.104.22.168 Molecular GeneticsRituximab appears to be a promising new treatment Since cloning of the G-6PD gene, nearly all the G-6PDfor refractory AIHA. Rituximab is a humanized variants possess a single amino acid replacement,murine monoclonal antibody directed against the which is caused by a single missense point mutationhuman CD20 antigen, which is present only on B lym- (Luzzatto, 2003). After exposure to an oxidative agentphocytes (Ware, 2003). A small study treated four (see Table 4.7), the Hgb and other proteins are oxi-chronic AIHA children with Rituximab even thoughtwo had prior splenectomies and all were dependent Table 4.7. Hemolytic oxidants associated with g-6pd deﬁ-on high-dose steroids and refractory to other im- ciency (adapted from Luzzatto, 2003)munosuppressive therapy. All four patients becametransfusion-independent and were weaned com- Analgesics and antipyreticspletely off prednisone after being treated with Ritux- Acetanilide Acetylsalicylic acid (large doses)imab, with few reactions. Para-aminosalicylic acid Acetophenetidin (phenacetin)4.5.3 Glucose-6-phosphate Nitrofuransdehydrogenase deﬁciency (G-6PD) Nitrofurazone NitrofurantoinG-6PD is the most common red cell enzyme deﬁcien- Furaltadone Furazolidonecy. Because the gene for G-6PD is usually located onthe X chromosome, males are either fully deﬁcient or Antimalarials Pentaquineof normal phenotype (Perkins, 2001). However, fe- Pamaquinemales can be deﬁcient fully, heterozygous (trait), or of Primaquinenormal phenotype (Lanzkowsky, 2000). Quinocide Chloroquine Pyrimethamine22.214.171.124 Epidemiology Plasmoquine SulfonesG-6PD deﬁciency is a worldwide gender-linked red Thiazolsulfonecell enzyme deﬁciency. The highest incidence is in DiaminodiphenylsulfoneAfricans,African-Americans, Mediterraneans, Native Sulfoxone sodiumAmericans, Southeast Asians, and Sephardic Jews. Sulfonamides Sulfanilamide Sulfamethoxazole126.96.36.199 Etiology Sulfacetamide SulfapyridineG-6PD variants may be due to deletions or point mu- Sulfadiazinetations affecting transcription and processing or the Sulﬁsoxazoleprimary structure. Therefore, G-6PD deﬁciency may Sulfathiazole Sulfacetamidenot only be caused by mutations in the coding region Miscellaneousand a decrease number of normal molecules but also Naphthalene (mothballs)by changes in the primary structure by affecting the Methylene bluecatalytic function or by decreasing stability of the Chloramphenicolprotein, or both (Luzzatto H, 2003). Probenecid Quinidine Fava beans Phenylhydrazine Nalidixic acid Infections Diabetic acidosis
144. 126 Chapter 4 R. Bryant dized. The RBC destruction starts hemolyzing the 188.8.131.52 Treatment oldest RBCs with the least G-6PD, and then progress- es toward younger RBCs and the denatured Hgb pre- Treatment depends on the extent of the acute hemol- cipitates, causing irreversible damage to the mem- ysis. Supportive care during the acute event may re- brane, and the red cells lyse. quire transfusion and must deﬁnitely include coun- seling regarding prevention of future events. Health- 184.108.40.206 Symptoms/Clinical Signs care providers should reinforce to the parents and child the need to avoid the list of oxidants that can A thorough history must be obtained, including the possibly trigger a hemolysis (see Table 4.7). For those possible precipitant of the acute event. A child with individuals undergoing chronic hemolysis, dietary G-6PD deﬁciency is hematologically normal most of supplementation with folic acid (1 mg tab/day) is rec- the time until hemolysis occurs secondary to an oxi- ommended (Hastings, 2002b). dant (see Table 4.7). Within 24–48 hours after expo- sure to an oxidant, the child may develop fever 220.127.116.11 Prognosis (38 °C), nausea, abdominal pain, diarrhea, dark- colored urine, jaundice, pallor, tachycardia, spleno- The prognosis is good provided the patient avoids megaly, and possibly hepatomegaly. exposure to the oxidants. 18.104.22.168 Diagnostic Testing 4.6 Bone Marrow Failure Syndromes The peripheral smear shows moderate to severe nor- mocytic, normochromic anemia, with marked aniso- Bone marrow failure syndromes are a reduction in cytosis, poikilocytosis, and reticulocytosis with in- the effective production of mature erythrocytes, clusion bodies (Heinz bodies) (see Fig. 4.1, plates granulocytes, and platelets by the bone marrow, caus- 4 and 5). The diagnosis is conﬁrmed by quantitative ing pancytopenia. The bone marrow failure syn- enzyme assay in reticulocyte-poor red cells or by dromes encompass aplastic anemia (AA), Fanconi’s testing RBCs after reticulocytosis resolves. Other labs anemia, paroxysmal nocturnal hemoglobinuria, that support the G-6PD diagnosis include a reduced Shwachman-Diamond syndrome, dyskeratosis con- haptoglobin, elevated WBCs (predominance of gran- genita, Diamond-Blackfan syndrome and many oth- ulocytes), elevated unconjugated bilirubin with nor- er disorders. This section will focus on AA, which is mal liver enzymes. Urine is positive for blood (free divided into acquired and inherited classiﬁcations. Hgb). Studies using polymerase chain reaction (PCR) 4.6.1 Aplastic Anemia may identify the abnormal gene as well as the bio- chemical abnormality (Perkins, 2001). Direct anti- Aplastic anemia (AA), a bone marrow failure disor- globulin test will be negative in G-6PD and will ex- der may be acquired or inherited. It is characterized clude antibody-mediated red cell destruction. Other by a reduced or absent production of blood cells in disorders to exclude from the differential include the bone marrow and peripheral blood, causing a blackwater fever (malarial infection), paroxysmal decrease of two or more cell lines (i.e., RBCs, WBCs cold hemoglobinuria, paroxysmal nocturnal hemo- and platelets). globinuria and mismatched blood transfusion (ABO mismatch). 22.214.171.124 Acquired Aplastic Anemia Aplastic anemia results from an immunologically mediated, tissue-speciﬁc, organ-destructive mecha- nism.
145. Anemias Chapter 4 12126.96.36.199.1 Epidemiology 188.8.131.52.5 Diagnostic TestingAn annual incidence of AA was established in Euro- Blood counts are depressed, and blood smear dis-pean studies as 2 per million per year. The highest plays a paucity of platelets, leukocytes, and normal tomortalities were in Japan, Thailand, and Northern macrocytic red cells with decreased reticulocytes. In-Ireland, with an incidence two or three times higher creased fetal Hgb (Hgb F) and red cell I antigen maythan in European countries and the United States. be present secondary to stress hematopoiesis. Bone marrow examination must be done by obtaining an184.108.40.206.2 Etiology aspirate and biopsy, which demonstrates the conver-Causative factors of acquired AA include toxins, med- sion of red bone marrow to yellow fatty marrow.ications, insecticides, immunologic disorders, irradi- There are decreased numbers of blood and marrowation, chemotherapy, and infections (i.e., HIV, CMV, progenitor cells due to a microenvironment that failsparvovirus, hepatitis); however, most causes are un- to support hematopoiesis.known (70% idiopathic). Myelosuppressive drugs Laboratory ﬁndings include the following:such as chemotherapy, antibiotics, insecticides, ben- ▬ Normocytic, normochromic anemia with reticu-zene compounds, and other medications cause dose- locytopenia, leukopenia, and thrombocytopeniarelated marrow suppression by damaging the DNA observed on smearand decreasing numbers of progenitors. Radiation ▬ Slightly to moderately elevated fetal Hgb noted oninjures DNA in the actively replicating progenitor Hgb electrophoresiscells, which also causes AA. ▬ Bone marrow denotes marked depression or ab- sence of hematopoietic cells and replacement by220.127.116.11.3 Molecular Genetics fatty tissue containing reticulum cells, lympho-Acquired AA is divided into severe and moderate cytes, plasma cells, and usually tissue mast cells.aplastic anemia. Moderate aplastic anemia has nor- Bone marrow biopsy is done to exclude granulo-mal to increased cellular marrow with at least two of mas, myeloﬁbrosis, or leukemia, and a bone mar-the following present: granulocyte count >500/ml, row chromosomal analysis is done to exclude Fan-platelet count >20 K/ml, and reticulocyte count >1%. coni’s anemia and myelodysplastic syndromesSevere aplastic anemia has an aplastic marrow and at ▬ Diepoxybutane test (DEB) is performed on pe-least two of the following present: granulocyte count ripheral blood to exclude Fanconi’s anemia<500/ml, platelet count <20 K/ml, and reticulocyte ▬ Sugar-water test, Ham test and ﬂow cytometry arecount <1%. done to exclude paroxysmal nocturnal hemoglo- binuria (PNH)18.104.22.168.4 Symptoms/Clinical Signs ▬ Liver function chemistries are done to excludeA detailed history, including medications, infections, hepatitisradiation exposure, and any family history of aplastic ▬ Renal function chemistries are done to exclude re-anemia, should be obtained with a thorough physical nal diseaseexamination. Thrombocytopenia and hemorrhagic ▬ Viral serology testing: hepatitis A,B,C antibodymanifestations are usually the ﬁrst symptoms and are panel, Epstein-Barr virus antibody panel, par-manifested by petechiae, ecchymoses, epistaxis, or vovirus B19 IgG and IgM antibodies, varicella an-oral mucosal bleeding. Neutropenia causes oral ul- tibody titer, and cytomegalovirus antibody titercerations, bacterial infections, and fever, which are are done to determine etiologyrarely present early in AA. Erythropenia, manifested ▬ Quantitative immunoglobulins, C3, C4 and com-by pallor, fatigue, headache, and tachycardia, tends to plement and antinuclear antibody (ANA), total he-be a late sign since red cells live approximately molytic complement (CH50), and Coombs’ test are120 days compared with platelets that live only done to exclude systemic diseases10 days and neutrophils that live 6–12 hours.
146. 128 Chapter 4 R. Bryant ▬ HLA typing of the patient and nuclear family is associated with steroids are hypertension, hyper- done to determine if bone marrow transplantation glycemia, increased susceptibility to fungal infec- match is available tion, potassium wasting, and ﬂuid retention ▬ Blood group typing is performed on the patient ▬ Cyclosporine is a speciﬁc T-cell inhibitor with for possible transfusion a recommended oral dose of 15 mg/kg/day in ▬ Clotting proﬁle including prothrombin time (PT), children to maintain blood trough levels 100– activated partial thromboplastin time (APTT), 250 mg/ml. Toxic effects from cyclosporine include and ﬁbrinogen is done to determine any clotting hypertension, azotemia, hirsutism, gingival hyper- dysfunction trophy, and increased serum creatinine levels ▬ Hematopoietic growth factors (G-CSF) have shown Differential diagnosis for pancytopenia is extensive promise in increasing neutrophil counts. G-CSF and includes myelodysplastic syndromes, preleuk- are administered subcutaneously at 5–10 mg/kg/ emias, leukemias, paroxysmal nocturnal hemoglo- day; side effects include fever, chills, headache, and binuria, myeloﬁbrosis, and some lymphomas. Pan- bone pain cytopenia may occur secondary to systemic diseases ▬ Androgens (i.e., methyltestosterone, oxymeth- such as systemic lupus erythematosus, hyper- olone) no longer have a primary role in manage- splenism, vitamin B12 or folate deﬁciencies, alcohol ment of aplastic anemia unless the therapies dis- abuse, anorexia nervosa or starvation, and infections cussed above are unsuccessful. The androgens in- such as Sarcoidosis and Legionnaires’ disease. crease erythropoietin production and stimulate erythroid stem cells. The oral dose is 2–5 mg/kg/ 22.214.171.124.6 Treatment day with side effects such as masculinization (hir- Bone marrow transplant with HLA-matched sibling sutism, deepening voice, genitalia enlargement), is the treatment of choice. If no HLA-matched sibling acne, nausea, weight gain, and liver dysfunction is available and the following indicators are present: bone marrow cellularity <30% with at least two of 126.96.36.199.7 Supportive Treatment the following ﬁndings: absolute neutrophil count ▬ Blood product support should be used sparingly <500/mm3, platelet count <20 K/mm3, reticulocyte while the family is HLA-typed count <1%, then institute the following immunosup- ▬ Thrombocytopenic precautions should be imple- pressive therapy: mented: – Promptly report signs and symptoms of bleed- ▬ Antilymphocyte globulin (ALG) or antithymocyte ing (i.e., excessive bruising/petechiae, oral pur- globulin (ATG), which are similar products from pura, melena, prolonged epistaxis or gingival either horses or rabbits and mixed with human bleeding or hematuria) thoracic duct lymphocytes or thymocytes. ALG – Avoid contact sports or rough activities (i.e., and ATG preparations contain mixtures of anti- football, soccer, wrestling, bicycle riding, skat- bodies to lymphocytes and are immunosuppres- ing, diving, tree climbing, trampolines) sive and cytotoxic (T-cell depletion). The recom- – Provide a safe environment to prevent trauma mended dose is 40 mg/kg/day ¥ 4 days. The typical (use side rails, gates, helmets, and knee pads and adverse reactions to ATG are thrombocytopenia, avoid rectal manipulation, including with ther- headache, myalgia, arthralgia, chills, fever, and mometers, suppositories, and enemas). serum sickness approximately 7–10 days follow- – Avoid oral mucosa trauma (use soft toothbrush- ing ATG administration es and avoid dental ﬂoss, electric tooth brush ▬ Methylprednisolone given as IV boluses on days and sharp food items) 1–4 at 10 mg/kg/day, then changed to an oral – Add stool softeners and increase ﬁber and ﬂuids steroid such as prednisone 1 mg/kg/d until day 30 in the diet to prevent constipation in order to prevent serum sickness. The toxicities
147. Anemias Chapter 4 12188.8.131.52.8 Prognosis Classic anomalies are seen in 75% of FA patientsWith immunosuppressive therapies or bone marrow and include short stature, absent thumbs or radii, mi-transplant, the long-term survival for patients with crocephaly, café au lait spots, skin hyperpigmenta-aplastic anemia has improved to 80%. In the Euro- tion, a broad nasal base, epicanthal folds, microg-pean International Marrow Unrelated Search and nathia, hyperreﬂexia, hypogenitalism, strabismus,Transplant trial, the survival rate from an unrelated ptosis, nystagmus, abnormalities of the ears, deaf-donor was about one-half after conventional trans- ness, mental retardation, and renal and cardiacplantation, due to a high rate of graft rejection or fail- anomalies.ure. 184.108.40.206.5 Diagnostic Testing220.127.116.11 Inherited Aplastic Anemia FBC/CBC with RBC indices,WBC count and differen- tial, platelet count, and reticulocyte count should beThe most common inherited aplastic anemia is Fan- obtained. Thrombocytopenia and leukopenia devel-coni’s anemia (FA) though several others are apart of op before pancytopenia, but severe aplastic anemiathe category (including Diamond-Blackfan anemia, develops in most cases. Examination of blood smeardyskeratosis congenita, and Shwachman-Diamond shows macrocytic red cells with mild poikilocytosis,syndrome). This section will discuss Fanconi’s ane- anisocytosis, decreased platelets and leukocytes. Themia. bone marrow is a hypocellular fatty bone marrow with decreased myeloid and erythroid precursors18.104.22.168.1 Epidemiology and megakaryocytes. Prenatal diagnosis with chori-All races and ethnic groups have been reported, in- onic villus biopsy and amniotic ﬂuid cell cultures ofcluding American Caucasians, African-Americans, FA can be made early in the pregnancy. The followingAsians, and Native Americans. The heterozygote fre- labs and tests are usually obtained:quency may be 1/300 in the United States and in Eu- ▬ ANA and DNA binding titer, Coombs’ test,rope and 1/100 in South African (Alter, 2003). rheumatoid factor, liver function tests ▬ Viral serology: HIV; EBV; parvovirus; hepatitis A,22.214.171.124.2 Etiology B, C; PCR for virusThe incidence is difﬁcult to ascertain. Approximately ▬ Serum vitamin B12 and serum folate levels25% of childhood aplastic anemia occurs in the pres- ▬ Bone marrow aspirate and biopsyence of known marrow failure genes. ▬ Cytogenetic studies on blood lymphocytes (i.e., diepoxybutane (DEB) to diagnose FA)126.96.36.199.3 Molecular Genetics ▬ Cytogenetic studies on bone marrow to exclude FAFA is an autosomal recessive trait with about 10– ▬ Acid Ham test and sugar-water test to exclude20% of families having consanguineous marriages PNH(Shende, 2000). There are limited data suggesting a ▬ Skeletal x-rays, intravenous pyelogram, chest x-raydefective gene in FA stem cells. to determine congenital anomalies188.8.131.52.4 Symptoms/Clinical Signs FA may be differentiated between thrombocytopeniaA detailed history should be obtained that includes with absent radii (TAR), amegakaryocytic thrombo-toxin and radiation exposure, medications, and any cytopenic purpura, acquired aplastic anemia, andfamily history of aplastic anemia, and a physical ex- leukemia with a hypoplastic marrow by obtaining theamination done that focuses on identiﬁcation of any above diagnostic test.congenital anomalies. Hemorrhagic manifestationssuch as petechiae ecchymoses, epistaxis, and bleedingof oral mucosa are initially observed. Other signs andsymptoms such as pallor, fatigue, headache, tachycar-dia, or infection are also seen.
148. 130 Chapter 4 R. Bryant 184.108.40.206.6 Treatment Carley A (2003). Anemia: When is it not iron deﬁciency? Pedi- Supportive care includes adherence to thrombocy- atric Nursing 29:205–211 Demir A,Yarali N, Fisgin T, Duru F, Kara A (2002). Most reliable topenic precautions (see section 220.127.116.11.7). Trans- indices in differentiation between thalassemia trait and fusion of PRBCs and/or platelets, growth factors iron deﬁciency anemia. Pediatrics International 44:612–616 (G-CSF) for neutropenia, erythropoietin, and e- Dover GI and Platt OS (2003). Sickle cell anemia. In: Nathan aminocaproic acid (0.1 mg/kg/dose every 6 hours DG, Orkin SH, Ginsburg D, Look AT (eds). Nathan and orally) may be instituted. Antibiotic and antifungal Oski’s Hematology of Infancy and Childhood, pp 762–809, Philadelphia, W.B. Saunders treatment should be used when clinically indicated.A Gallagher PG, Lux SE (2003). Disorders of the erythrocyte patient without a matched sibling should be treated membrane. In: Nathan DG Orkin SH, Ginsburg D, Look AT with androgens, usually oxymetholone 2–5 mg/kg/ (eds). Nathan and Oski’s Hematology of Infancy and Child- day. The side effects of androgens are listed in sec- hood, pp 560-684, Philadelphia, W.B. Saunders tion 18.104.22.168.6. Blood counts, liver function tests, and Glader B (2004).Anemias of inadequate production: Iron-deﬁ- ciency anemia. In: Behrman RE, Kliegman RM, Jenson periodic bone marrow biopsy (to monitor for the HB (eds). Nelson Textbook of Pediatrics, pp 1614–1616, development of myelodysplastic syndrome and Philadelphia, Saunders leukemia) are needed to monitor the patient. Hastings C (2002a). Anemia. In: The Children’s Hospital Oak- land Hematology/Oncology Handbook, pp 1–10, St. Louis, 22.214.171.124.7 Prognosis Mosby Hastings C (2002b). Hemolytic anemia. In: The Children’s Hos- The prognosis is poor, with projected survival be- pital Oakland Hematology/Oncology Handbook, pp 13–14, tween 20 and 30 years unless the patient receives St. Louis, Mosby HLA-matched nonaffected sibling bone marrow, Hastings C (2002c). Sickle cell disease. In: The Children’s Hos- which offers >70% survival. Almost 6% of FA pa- pital Oakland Hematology/Oncology Handbook, pp 19–38, tients develop myelodysplastic syndrome (dys- St. Louis, Mosby Hudspeth M, Symons H. Hematology (2002). In: Gunn VL and myelopoiesis and abnormal megakaryocytes), and Nechyba C (eds). The Johns Hopkins Hospital: The Harriet almost 10% develop acute myeloid leukemia. Lane Handbook, 16th edn, Philadelphia, Mosby Jacob E, Miaskowski C, Savedra M, et al. (2003). Management of vaso-occlusive pain in children with sickle cell disease. References Journal of Pediatric Hematology/Oncology 25(4):307–311 Jakubik LD and Thompson M (2000). Care of the child with Alter BP (2003). Inherited bone marrow failure syndromes. In: sickle cell disease. Acute complications. Pediatric Nursing Nathan DG, Orkin SH, Ginsburg D, Look AT (eds). Nathan 26(4):373–379 and Oski’s Hematology of Infancy and Childhood, pp Karayalcin G (2000). Hemolytic anemia. In: Lanzkowsky P 280–365, Philadelphia, W.B. Saunders (Ed). Manual of Pediatric Hematology and Oncology, pp American Academy of Pediatrics [AAP] (2002). Health super- 1157–182, San Diego, Academic Press vision for children with sickle cell disease. Pediatrics Lanzkowsky P (2000). Hemolytic anemia. In: Lanzkowsky P 109(3):526–535 (Ed). Manual of Pediatric Hematology and Oncology, pp Andrews NC (2003). Disorders of iron metabolism and sider- 154–157, San Diego, Academic Press oblastic anemia. In: Nathan DG, Orkin SH, Ginsburg D, Lee C, Nechyba C, Gunn VL (2002). Drug doses. In: Gunn V and Look AT (eds). Nathan and Oski’s Hematology of Infancy Nechyba C (eds). The John Hopkins Hospital: The Harriet and Childhood, pp 456–497, Philadelphia, W.B. Saunders Lane Book, pp 721–742, Philadelphia, Mosby Bader-Meunier B, Gathier F, Archambaud F, et al. (2001). Long- Luzzatto L (2003). Glucose-6-phosphate dehydrogenase deﬁ- term evaluation of the beneﬁcial effect of subtotal splenec- ciency and hemolytic anemia. In: Nathan DG, Orkin SH, tomy for management of hereditary spherocytosis. Blood Ginsburg D, Look AT (eds). Nathan and Oski’s Hematology 97(2):399–403 of Infancy and Childhood, pp 704–726, Philadelphia, W.B. Beare J (2002). Hemochromatosis. Advance for Nurse Practi- Saunders tioners, pp 63–66
149. Anemias Chapter 4 131Martin L, and Buonomo C (1997). Acute chest syndrome of Segel GB, Hirsh MG, Feig SA (2002). Managing anemia in pedi- sickle cell disease: radiographic and clinical analysis of 70 atric ofﬁce practice: parts I and II. Pediatrics in Review cases. Pediatric Radiology 27:637–641 23:75–83, 111–121Mei Z, Parvanta I, Cogswell ME, Gunter EW, Grummer-Strawn Shende A (2000). Bone marrow failure. In: Lanzkowsky P (Ed). LM (2003). Erythrocyte protoporphyrin or Hgb: which is a Manual of Pediatric Hematology and Oncology, pp 93–135, better screening test for iron deﬁciency in children and San Diego, Academic Press women? American Journal of Clinical Nutrition 77:1229– Shimamura A, Guinan E (2003). Acquired aplastic anemia. In: 1233 Nathan DG, Orkin SH, Ginsburg D, Look AT (eds). NathanMiller ST, Sleeper LA, Pegelow CH, et al. (2000). Prediction of and Oski’s Hematology of Infancy and Childhood, pp adverse outcomes in children with sickle cell disease. New 256–279 Philadelphia, W.B. Saunders England Journal of Medicine 342(2):