12-Pediatric.qxd 10.12.2003 04.28 PM Page 466 Childhood immune (idiopathic) thrombocytopenic purpura (ITP) ITP occurring in children differs from the adult form of the disease ((cid:9) p388) in two ways \200\224first, most cases are of abrupt onset and rapidly self- limiting, and secondly those that progress to chronicity have a lower mor- bidity and mortality. Epidemiology Incidence of ITP in children overall around 4 \200\2235 per 100,000 per year. 10 \200\22320% become chronic \200\224i.e. last >6 months. Pathophysiology Thrombocytopenia mediated by antibodies opsonizing platelets that are then destroyed by the reticuloendothelial system. Antibodies can be part of immune complexes non -specifically attached to platelet Fc receptors (as in typical acute childhood ITP) or true autoantibodies usually targeted at glycoproteins IIb/IIIa and Ib (as found in up to 75% of chronic childhood ITP and commonly in adults). Clinical features 2 Onset of bruising petechiae abrupt (80 \200\22390%) or insidious (10 \200\22320%). 2 May have gingival and oral mucosal bleeding or epistaxis. 2 Life threateni ng bleeding extremely rare. 2 Child otherwise perfectly well. 2 May have history of recent infection; specific (rubella, varicella) or non- specific (URTI). 466 2 Can follow vaccination. Laboratory diagnosis 2 Isolated thrombocytopenia; blood count otherwise normal. 2 Marrow sh ows abundant megakaryocytes and is otherwise normal (not necessary to investigate unless cl inical course or presenting features unusual). 2 Platelet antibody studies difficult to perform and not necessary in most cases since they do not alter management. 2 Exclude EBV infection (infectious mononucleosis). 2 Exclude multisystem autoimmune diseas e (ACL, ANA, positive DAT test) \200\224not necessary unless disease becomes chronic. 2 Exclude underlying immunodefi ciency syndrome (HIV, Wiskott \200\223Aldrich). Differential diagnosis 2 Congenital or familial thrombocytopenias. 2 Leukemia or aplastic a nemia. 2 Other rare thrombocytopenias (e.g. type IIB vWD). 2 Multisystem autoimmune disease \200\224Evans \200\231 syndrome (AIHA + immune thrombocytopenia), systemic lupus erythematosus. 2 Immune thrombocytopenia associated with immunodeficiency due to other disease \200\224HIV infection, Hodgkin \200\231s disease, Wiskott \200\223Aldrich syn- drome. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 467 Pediatric hematology Management Newly presenting Seldom require urgent therapy though this is frequently given, either poly- valent IVIg 0.8g/kg (single dose) or prednisolone 4mg/kg. Never justified in t he absence of obvious bleeding since neither therapy without risk. Simple observation for s pontaneous recovery should be preferred. Chronic No therapy is needed based on platelet count alone. Absence of symp- toms and signs is sufficient. Excessive restriction of activities is seldom jus- tified. Open access to e xpert help and advice provides reassurance to families and teachers. If therapy required to control symptoms (recurrent nosebleeds, menorrhagia) try local measures or hormonal contro l. Regular IVIg or steroids seldom effective and may produce more prob- lems than untreated disease. For the most difficult cases (very rare) splenectomy still worth considering, tho ugh post-splenectomy mortality may be > than that of untreated ITP. Newer therapies include danazol and rituximab, though experience still anecdotal and long-term risks not yet evalu ated. Life-threatening hemorrhage or other emergency Risk of life-threatening hemorrhage very sma ll (<1/1000 in first week after diagnosis) though is a function of a platelet count <10 \200\22320 109/L and the time exposed to this. Risk consequently rises in rare children with chronic unremitting severe disease for >1 \200\2232 years for whom more adven- turous therapy (splenectomy, rituximab) can be contemplated, though risk still small and those of treatment may be higher. If a large intracranial (ICH) or other catastrophic bleed occurs, this can be dealed with by simul- taneous massive platelet transfusion, IVIg, IV methylpred nisolone and (if the diagnosis is beyond doubt) emergency splenectomy. Mortality of major I CH less than 50% given active therapy. 467 Outlook Most children with ITP recover irrespective of therapy, usually within weeks or occ asionally within months. Even 75% of those whose problem persists for >6 months eventually spontaneously remit, sometimes several years later. It is very rare for children to carry I TP into adult life and beyond, and the occasional individuals who do are unlikely to much t rou- bled by it or to develop autoimmune disease of other systems. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in a dults, children and in pregnancy (2003) Br J Haematol, 120, 574 \200\223596. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 468 Haemolytic uraemic syndrome Characterized by a triad of microangiopathic haemolytic anemia (MAHA), renal failure and th rombocytopenia. More common in children than adults and of two types; the more common epide mic form and the less common sporadic form closely related to thrombotic thrombocytopenic p urpura (TTP) \200\224a disease primarily of adults that also rarely occurs in children. TTP has the same triad of signs with two others \200\224fever and neurologic disturbances ((ci d:9) p530) Pathogenesis HUS usually occurs in outbreaks and in 90% is due to Escherichia coli 0157 and other verocytotoxin-producing E coli. Food sources of the infection include uncooked/under -cooked meats, hamburgers and poor food hygiene. The verocytotoxin causes endothelial damag e, particularly of the renal endothelium, leading to the formation of fibrin-rich microthro mbi and MAHA. Clinical features 2 Young children (<4 years) are especially prone to the disease. 2 Acute onset with a history of abdominal pain and bloody diarrhea. 2 Onset of 5 urine output heral ding renal failure occurs days later. 2 In 10% onset is non-epidemic and insidious \200 \224can be associated with chemotherapy/TBI. 2 Other symptoms: anemia (may be severe), jaundice, bruising, bleeding. 2 Absence of fever and neurologic signs distinguish it from TTP. Laboratory findings 2 MAHA may be severe. 2 Movie shows fragmented RBCs/schistocytes/sphero cytes. 2 Thrombocytopenia. 2 Coagulation tests: PT/APTT \200\224usually normal; fibrinogen and F/XDPs 468 also normal. Reduced large vWF multimers. 2 Proteinuria and haematuria. 2 Biochemical evidence of renal failure. 2 Stool culture may be +ve for E coli. Differential diagnosis 2 TTP ((cid:9) p530). 2 Other causes of MAHA and renal failure. Complications 2 ARF7CRF rare but more likely in older children and those with spo- radic insidious onset HUS. 2 Microvascular thrombosis and infarction of other organs. Treatment 2 Renal failure \200\224fluid restriction, correct electrolyte imbalance. 2 If an uria persists >24h \200\224dialysis as necessary. 2 Blood transfusion for anemia. 2 Platele t transfusion rarely needed \200\224may 4 thrombotic risk. 2 Severe persistent disease may require plasmapheresis as for TTP ((cid:9) p530). 2 Specific treatment: none of proven value. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 469 Pediatric hematology Outcome Epidemic HUS has a good prognosis, patients usually recover and it rarely recurs. C RF does occur occasionally. Insidious onset HUS has a poorer prognosis. Overall mortality 5%. 469 12-Pediatric.qxd 10.12.2003 04.28 PM Page 470 Childhood cancer and malignant blood disorders Epidemiology In Europe 1 child in 600 develops cancer before the age of 15. Annual inci- de nce 1:10,000; 1200 new cases/year in UK. Pattern of childhood cancers is very different fr om that seen in adults: carcinomas are rarely seen. Overall, childhood cancer is slightly m ore common in boys than girls. 2 Leukaemias account for about 35% of the total: 80% are som e type of ALL, 15% some type of AML. 5% chronic myeloid leukaemias, (adult and juvenile typ es) or myelodysplastic syndromes. CLL does not occur in children. 2 Brain tumors are commonest solid malignancies, 25% of the total. Different tumor types fr om adults; commonest medulloblastoma in posterior fossa. 2 Embryonal tumors 15%, seen almost exclusively in children. Include neuroblastoma, nephrob lastoma (Wilms \200\231 tumor), rhabdomyosar- coma, hepatoblastoma. 2 Bone tumors 5% osteosarcoma, Ewing \200\231s sarcoma. 2 Lymphomas 9% \200\224NHL and Hodg kin \200\231s disease. NHL in children closely related biologically to ALL; low grade disease very rare. 2 Remainder of cases are mainly germ cell and primitive neuroecto- dermal tumors (PNETs), including retinoblastomas. Etiology 2 Childhood cancer generally represents aberrant growth and develop- ment rather t han defective repair and renewal from which most adult tumors arise. 470 2 Growths arising in infancy are mostly congenital and the genetic muta- tions concerned ar ise in utero. Causes of such mutations and those arising later in childhood largely unknown . 2 Although isolated cases are attributable to high dose radiation (e.g. thyroid cancer in Chernobyl survivors), there is no convincing link to levels of background radiation or electromagnetic fields. 2 Population mixing studies have suggested that patterns of exposure to infection may contr ibute to some cases of ALL in the peak years of incidence (2 \200\2236 years). 2 Childhood cancer rarely familial, but study of retinoblastoma (rare tumor that is commonly familial) has led to better understanding of tumor suppressor genes; germline mutation in one allele of RB gene in affected families only gives rise to tumors in cells where there is an acquired mutation in the other, healthy, wild type allele (the \200\230two hit \200\231 hypothesis). 2 Cancer arising in older children may still be due to intrauterine event as concordance st udies in identical twins with ALL have shown iden- tical genetic mutations in malignant cel ls some years after birth. This suggests twin7twin transfer of potentially malignant clone through shared circulation. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 471 Pediatric hematology Hematological effects of non-haemic tumors (for leukaemias, lymphomas and MDS see following sections) 2 Marrow infiltration may be evident at the time of presentation (most commonly neuroblastoma, less commonly Ewing \200\231s sarcoma, rhab- domyosarcoma). 2 Associated with anemia, occasionally other cytopenias. Blood count hardly ever normal if marrow involved. 2 Peripheral blood may show leucoerythroblastic picture, but not as commonly in adult cancers metastasising to bone marrow. 2 Non-haemic tumors appear on cytomorphology as poorly differenti- ated fragile blast cells , often in sheets or clumps (unlike leukaemic blasts). 2 Marrow infiltration may arise as a late event in terminally progressive disease in other tumors, including CNS malignancies, PNETS and germ cell tumors. Investigations in suspected childhood cancer Hematology 2 FBC and movie. Leukemia usually reflected in the blood count: 4 or 5 WBC, t hrombocytopenia and anemia. Blasts often present. In a small percentage, blood count entire ly normal. With other malignan- cies there may be signs of marrow infiltration (see above), anemia or no abnormalities at all. 471 2 BM aspirate and trephine if blood count abnormal. In children generally done under GA. Bi lateral samples needed in the staging of neuroblas- toma. Biochemistry 2 Full biochemical profile. 2 Urinary catecholamines for neuroblastoma (easy t est to do in unex- plained bone pain). 2 Tumor markers: a-FP, bHCG in hepatoblastoma or germ cell tumors. Radiology 2 CXR for mediastinal mass (mandatory pre-anesthetic). 2 Abdominal USS. 2 CT/MRI scan of primary lesion. CT chest/abdomen may be required for staging. In young children sed ation/general anesthetic usually needed for CT/MRI scans. Histology 2 Solid tumors need adequate biopsy material for diagnosis taken under general anesthetic. Genetics 2 Fresh tumor material from all childhood cancers should be sent for cytogenetic a nd molecular genetic studies. Information from these is increasingly being used in risk-str atifying therapy and in predicting outcome. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 472 Specialist centers for treatment and investigation Children with suspected malignancy shoul d be referred to a specialist center for investigation and initial treatment. Thereafter, s hared care may be carried out nearer to home at a local hospital. Most children across the country receive treatment as part of a national trial or protocol. This is co-ordinated by the United Kingdom Children \200\231s Cancer Study Group and similar groups in other countr ies, and the success of such trials and studies is one of the reasons for the improved outl ook for childhood cancer. Overall long-term survival is 60%. Late effects It is estimated that soon 1:1000 adults will be survivors of childhood cancer. Long term follow-up clinics are needed to monitor growth, fer- tility, side effects from d rugs (e.g. cardiotoxicity) and psychological well- being. There is an increased risk of fur ther malignancy developing which varies according to both the primary diagnosis and treatme nt used. 472 12-Pediatric.qxd 10.12.2003 04.28 PM Page 473 Pediatric hematology 473 12-Pediatric.qxd 10.12.2003 04.28 PM Page 474 Childhood lymphoblastic leukemia Lymphoblastic leukemia ( \200\230acute \200\231 is superfluous, but disease widely known as ALL) is a group of clonal malignancies all arising in developing lympho- cytes. There is m ore overlap with lymphomas than in adults. Commonest malignant disease in childhood (35% of all cancers). Incidence 4 \200\2235/100,000 chil- dren per year with a peak incidence betw een 2 \200\2236 years of age. Etiology Many cases thought to be due to antenatal mutations in developing B-cell clones; M ajority of cases B-cell derived, occur between 2 and 6 years, and may be abnormal response to infection where exposure to pathogens delayed or precipitated by population mixing. Evid ence implicating back- ground ionizing or electromagnetic radiation now discredited. Cause of T- ALL unknown. Pathophysiology 2 80% childhood ALLs arise in developing B lymphocytes; 20% in developing T cells. Acquired genetic mutations found in the various sub-types are growing i n number as the molecular biology of leukemia unravels. 2 In early B cells commonest mutation is a fusion between the TEL gene at 12p13 and the AML 1 gene at 21q22 \200\224arises in 20% overall; other common mutations are t(1;19)(q23;p13.3 ) \200\2248% overall, t(9;22)(q34;q11.2) BCR-ABL (Philadelphia chromosome); 5% overall. 2 30% have \200\230high hyperdiploidy \200\231 (>50 chromosomes per cell) with or without translocations; 7% show hypodiploidy. 2 Infants (<18 months) frequently have a mutation of the MLL gene on chromosome 11 involvin g a range of fusion partners; most commonly AF4 on chromosome 4. 474 2 The above changes mark biologically different types of precursor B- derived ALL in terms of clinical features and response to treatment. 2 1 \200\2232% of ALLs have features of mat ure B cells and a mutation where the MYC gene is translocated adjacent to the Ig heavy chai n locus \200\224 t(8;14). Also called Burkitt-type as the cell biology is similar to that o f Burkitt \200\231s lymphoma. 2 T-ALL shows greater genetic diversity than B-derived disease but 12 recurring cytogenetic abnormalities now defined and under study. Clinical importance yet to be defined. 2 ALL also classified by immunophenotyping using antibody cell markers for various differen tiation antigens designated clusters of differentiation (CD), numbered according to their o rder of discovery. Immunophenotypes so defined include early pre-B (60%), pre-B (20%), tran sitional pre-B (1%), B-ALL (1%) and T-ALL (18%). Clinical features 2 Commonly presents insidiously in three ways, separately or combined. 2 Signs of marrow failure \200\224often anemia predominates, with extreme pallor and listlessness (60%); also bruising/petechiae (40%). 2 Hepatosplenomegaly and lymphadenopathy ( \200\230lymphomatous \200\231 features) 10 \200\22320%. 2 Bone pain mimicking irritable hip(s) or juvenile rheumatoid 10 \200\22320%. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 475 Pediatric hematology Laboratory features 2 Usually pancytopenia with circulating blast cells indicates diagnosis . 2 Confirmed by bone marrow examination and classified by immunophe- notyping and cytogenetic/molecular genetic analysis. 2 In sick children with very high blast cell counts classification studies can be carried out on peripheral blood, but marrow always preferred. 2 Peripheral blood count m ay show cytopenias without obvious blasts (aleukaemic picture) when differential diagnosis is aplastic anemia. 2 Kidney/liver function usually normal, but ALLs with high blast counts and rapid cell turnover may have tumor-lysis organ dysfunction before therapy (urate nephr opathy with 4 urea, creatinine and 5 urine output). Treatment of newly diagnosed disease 2 All modern protocols have common elements of remissi on induction (RI), consolidation/intensification (C/I), CNS directed treatment and continui ng (maintenance) therapy with or without delayed intensifica- tion (DI). 2 RI drugs include dexamethasone, vincristine and asparaginase. 2 C/I and DI drugs include anthracyclines, cytarabine, cyclophosphamide asparaginase and thioguanine. 2 CNS therapy is intrathecal cytarabine and methotrexate (radiotherapy now reserved for those with active CNS infiltration only). 2 Maintenance therapy is a 2 \200\2233 year schedule of daily thiopurine (6-mer- 475 captopurine) and weekly oral methotrexate. 2 ALL is the only human malignancy that requires such a drawn-out chemotherapy module, immunosuppressive rather than antineoplastic. 2 B-ALL is an exception; it does not respond to conventional ALL therapy, does not need mai ntenance and is treated on a 6 month intensive lymphoma schedule ((cid:9) p478). 2 Treatment is usually risk-directed based on biological features of the disease with more intensive schedules reserved for those with adverse prognostic factors (s ee below). 2 BMT rarely used as first-line therapy. Outlook 98% overall will remit on modern therapy, 75 \200\22380% overall will become long t erm disease-free survivors \200\224figures vary according to prognostic factors (see below) . >90% long term survivors in low risk disease. Treatment of relapse 2 Some 20 \200\22325% of children will relapse; either on treatment or after its completion. 2 Outlook depends on length of first remission; very bleak if relapse on treatment. 2 Salvage therapy more successful if relapse >2 years off therapy. 2 Relapsed T-ALL more di fficult to treat successfully than other types. 2 Treatment includes intensive chemotherapy with the addition of podophyllins, anthracycline analogs and fludarabine. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 476 2 BMT reserved for those who show slow-to-clear residual disease by PCR amplification of unique disease-specific Ig or TCR gene rearrangements, those who relap se on treatment and those with relapsed T-ALL. Prognostic factors 2 Several features of ALL predict response to current standard therapies and are used to stratify treatment. Infants <1 year have a poor outlook, and older children >10 years do less well than those 1 \200\22310 years. 2 High presenting WBC (>100 109/L) in boys marks high risk, as do some genetic features (MLL gene rearrangements, BCR-ABL fusion genes, hypodiploidy). 2 All children with T-ALL , and all with slow disease clearance during the first few days o f therapy, are excluded from being classified as low risk. 2 Low risk B-precursor ALL is th at which shows none of these features. Late effects of therapy With 4 long survivors, late effects of therapy are becoming more im por- tant. Most morbidity seen after TBI given for BMT. Problems include 2 Growth failure due to CNS damage from radiation. 2 Intellectual deficit due to CNS damage from radiation. 2 Precocious puberty (girls> boys) after cranial radiatio n. 2 Infertility (boys > girls) not dependent on radiation. 2 Obesity (girls > boys) not de pendent on radiation. 2 7 \200\22310 fold 4 risk of brain tumors not dependent on radiation . 476 12-Pediatric.qxd 10.12.2003 04.28 PM Page 477 Pediatric hematology 477 12-Pediatric.qxd 10.12.2003 04.28 PM Page 478 Childhood lymphomas Lymphomas account for around 8 \200\22310% of all childhood cancers (this equates to around 1 per 100,000 children per year). Around 30 \200\22335% are Hodgkin \200\231s disease, the rest non-Hodgkin lymphomas. Hodgkin \200\231s disease Clinical features Uncommon <5 years; incidence increases during t he early teenage years. The disease is biologically the same as that of adults and the hist ological classification is identical (for more details (cid:9) p208), though mixed cellu- l arity disease may be more common in the young. Staging is also similar to adults ((cid:9) p 210), but overall children and adolescents have a greater pro- portion of low-stage disease (I and II). Stage IV accounts for <10% of child- hood cases. Treatment and outcome Treatment is so successful that most efforts are currently directed a t reducing toxicity and late effects. Radiotherapy for stage I disease is being attenuated, and some therapists have abandoned it as first line treatment and rely on chemotherapy alo ne. Chemotherapy regimens in turn are evolving (to avoid or minimize alkylating agents and their effect on fertility and anthracyclines with their potential for cardiotoxicity), but at present the traditional drugs are still being used with or without involved field radiot herapy, particularly in stage III or IV disease. The outlook for even stage IV disease is good, given the best current regimen of chemothera py and involved field radiotherapy, and over 80% should achieve long term EFS. 478 Non-Hodgkin \200\231s lymphoma Childhood non-Hodgkin \200\231s lymphomas are a heterogeneou s group of tumors quite different from those seen in adults. Virtually all are dissemi- nat ed, high-grade diffuse malignancies of immature B or T lymphocytes, and many are closely re lated to subtypes of ALL that occur in this age group. Classification of NHL has always been confusing, but the Revised European American Lymphoma system is currently preferred. This maps disease in children into 6 categories: 1. Burkitt \200\231s lymphoma, Burkitt-like lymphoma, high grade B-cell disease. Different manifestations of biologically very closely related diseases and pathologically indistingui shable from B-ALL. 45% of the total. Characteristic \200\230starry sky \200\231 histologi cal pattern and deeply basophilic blasts on Romanowsky stains with prominent vacuoles (FAB L3 fea- tures). Associated with chromosomal translocation involving MYC locus on chromosome 8 and Ig heavy chain gene on 14 (or less com- monly with a k or l light chain gene on 2 or 22) with resultant dysreg- ulation of MYC gene transcription; the MYC product functions as a transcription factor. 2. Precursor B lymphoblastic lymphoma. Indistinguishable pathologically from common ALL. 5 % of the total. Commonly presents as a solitary subcutaneous swelling, typically on the sca lp. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 479 Pediatric hematology 3. Precursor T lymphoblastic lymphoma. Indistinguishable pathologically from T-ALL. 20% of the total. 66% have mediastinal involvement. Marrow involvement common in advanced disease ; so may be classi- fied as T-ALL rather than stage IV NHL. 4. Diffuse large B-cell lymphoma, including primary sclerosing medi- astinal form; no leuka emic counterpart, accounts for 3 \200\2234% of the total. Chiefly abdominal. Occasionally mediastinal. Has some features of Burkitt \200\231s but no MYC gene mutation. 5. Peripheral T-cell lymphoma unspecified; no leukaemic counterpart. Skin involvement. Retr ospective review shows most so classified to be type 6 (large cell anaplastic, see below). Poorly defined entity hardly ever seen in children. 6. Large cell anaplastic, T or null cell type. No leukaemic counterpart. More frequently re cognized, and complex biological features gradually becoming better understood. 15% of the total. Used to be diagnosed as peripheral T-cell lymphomas or \200\230malignant histiocyt osis \200\231. Biological hallmarks are Ki-1 (CD30)+, also t(2;5). Around 9 % childhood NHLs defy classification and <1% adult type follic- ular lymphomas wil l occasionally arise in older children. St Jude staging system for childhood NHL A staging system for childhood NHL has been develo ped, though therapy is increasingly being directed more by the biology of the disease rathe r than its anatomical distribution or extent. Staging affects prognosis only within given t umor type. 479 St Jude staging system for childhood NHL Stage I Single tumor (extranodal or single nodal anatomic area), excluding mediastinum or abdomen Stage II Single extranodal tumor with regional node involvement = 2 nodal areas on the same side of the diaphragm 2 single extranodal tumors regional node involvement on same side of the d iaphragm Primary GIT tumor, usually ileocaecal, involvement of associated mesenteric nod es Stage III 2 extranodal tumors on opposite sides of the diaphragm = 2 nodal areas above and below the diaphragm Presence of 1 intrathoracic tumor (mediastinal, pleural or thymic) Presence of extensive primary intra-abdominal disease Presence of paraspinal or epidural tumors, regard less of other sites Stage IV Any of the above with initial CNS and/or bone marrow involvement 12-Pediatric.qxd 10.12.2003 04.28 PM Page 480 Treatment Burkitt \200\231s lymphoma/B-ALL: Short 6 month course of pulsed intensive high d ose therapy (vincristine, steroids, methotrexate, cyclophosphamide, anthracyclines and etop oside) including CNS treatment. No maintenance treatment needed. B precursor lymphoblastic: If isolated to one site, 6 month program of ALL-type therapy may suffice, else treat as common ALL with extended maintenance ((cid:9) lymphoblastic leukemi a p475). T precursor lymphoblastic: Treated as T-ALL ((cid:9) p161). Diffuse large B-cell lymphoma: Treated as Burkitt \200\231s lymphoma. Large cell anaplastic Ki-1+: Skin, CNS and mediastinal involvement and splenomegaly are adv erse features. Best therapy undefined but usually treated with short intensive Burkitt-like regimens. EFS is around 75% (high risk cases 60%). General points on therapy/outlook 2 Surgery usually indicated for the complete resection of a localized abdominal primary tumor when possible. 2 Low-dose involved field radiotherapy indicated for airway or spinal cord compression. Mediastinal irradiation for persistent local disease. 2 Given best curren t therapy, the outlook for most patients is good with around 80% EFS for childhood lymphomas overall. 480 12-Pediatric.qxd 10.12.2003 04.28 PM Page 481 Pediatric hematology 481 12-Pediatric.qxd 10.12.2003 04.28 PM Page 482 Childhood acute myeloid leukemia Acute myeloid leukemia in children accounts for 15% of all malignant blood disorders, with around 80 \200\22390 new cases arising in the UK each year. Unlike ALL, the disease is cla ssified on morphological grounds using the FAB classification, as is AML in adults ((cid:9) p150). The frequency of the different subtypes differs in children, however. M6 AML is ver y rare whereas M7 (megakaryocyte derived AML) is more common \200\224especially in children with Down syndrome. Proportion of children with de novo AML by FAB type M0 2 M1 18 M2 29 M3 8 M4 16 M5 17 M6 2 M7 8 % of total Pathophysiology AML is a clonal neoplasm arising from developing blood cells affecting all haemopoietic cell lines, most commonly granulocyte or monocyte precur- sors but also occasi onally involving immature erythroblasts or megakary- ocytes. Apart from primary, de novo di sease for which no cause can be identified, some cases of AML are due to chemotherapy given for other diseases (secondary AML), and some arise in children with predisposing syndromes where the risk is greatly increased and where specific sub- types of AML may develop. 2 Secondary AML caused by topoisomerase II inhibitors (e.g. etoposide) has a latency of 1 \200\2233 years and is of FAB type M4/M5 with a character- istic MLL gene mutation. 482 2 Secondary AML caused by alkylating agents (e.g. cyclophosphamide) has a latency of 4 \200 \2236 years, a myelodysplastic phase and loss or dele- tions of chromosomes 5, 7 or both. 2 Down syndrome children are 20 times more likely to develop leukemia than normal children; infants are more likely to develop M7 AML, older Down childr en develop ALL. 2 Other conditions predisposing to AML in children are Fanconi \200\231s anemia and Bloom \200\231s syndrome ((cid:9) p457), dyskeratosis congenita, Kostmann \200\231s syndrome and Shwachman \200\223Diamond syndrome ((cid:9) p459), Diamond \200\223 Blackfan anemia ((cid:9 ) p452), and neurofibromatosis. Apart from the specific changes in secondary AMLs (see above), clonal chromosome abnormalit ies are found in blasts from 90% of those with de novo disease. Two-thirds of these are no n-random, and many are asso- ciated with characteristic clinical and biological features. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 483 Pediatric hematology Commonest genetic mutations in childhood AML Abnormality Involved genes FAB type Frequency Clinical features ETO; AML1 t(8;21) M2 10 \200\22315% Extramedullary chloromas good outlook PML; RARA t(15;17) M3 5 \200\22310% Coagulopathy responds to retinoids Inv16(p13q32) MYH11; CBFB M4eo 7 \200\22310% Extramedullary deposits good outlook AF9; MLL t(9;11) M4/M5 7 \200\22310% Infants, CNS disease poor outlook t(1;22) N/K M7 2 \200\2233% Secondary myelofibrosis Down syndrome Laboratory features 2 Peripheral blood shows a variety of abnormalities \200\224usually pan cy- topenia with circulating blasts. 2 WBC seldom >50 109/L though can occasionally be very high with symptoms of leucostasis \200\224deafness, confusion and impaired conscious- ness. 483 2 Bone marrow usually shows heavy overgrowth of blasts with different morphology depending on FAB type. Auer rods (abnormal elongated primary granules seen on Romanowsky stains in cy toplasm of malig- nant myeloblasts) are diagnostic of AML and are not found in health. Seen in all types of AML except M6 and M7, most common in M1/2/3, particularly M3. 2 Cytochemistry may help; non-specific esterase positive in M4/M5 AML, not other types and myeloperoxidase positivity can help distinguish between poorly differentiated AML and ALL. M7 AML may develop extensive marrow fibrosis making aspiration difficult; trephine histolog y needed. 2 Genetic abnormalities common in blast cells (see above). 2 Immunophenotyping less importa nt that in ALL, though essential for immediate diagnosis of M7 AML which has no distinguish ing morpho- logical or cytochemical features. CD antigens expressed vary according to FAB t ype; CD33 strongly +ve in all, CD13 in M2/3; CD4 in M4/M5 and CD41/61 in M7. M6 disease exp resses glycophorin A. Clinical features Children with advanced AML are commonly more sick than those with ALL. Th ey can present with bleeding, haemostatic failure and/or septi- caemia as manifestations of marrow failure and profound neutropenia. Extramedullary chloromas (solid deposits of malig nant cells) arise in around 10% of cases. They may precede marrow failure (or even detectab le marrow infiltration). They can arise internally around the spine 12-Pediatric.qxd 10.12.2003 04.28 PM Page 484 or spinal cord, causing pressure symptoms and mimicking non-haemic solid tumors. They are m ore common in AML with t(8;21). Peri-orbital chloromas are also not unusual in infants with M4/M5 AML. Treatment and outlook Outcome of therapy for childhood AML has shown a dramatic improve- me nt over the last 15 years. From a dismal outlook in the 1970s through around 30% EFS in the 1980s we have now achieved >50% EFS at the turn of the 21st century. This has been due to increasingly intensive chemotherapy and parallel improvements in supportive treatment for t he secondary marrow failure it produces. The principle of treatment is to ablate marrow with chemotherapy to the point that endogeno us recovery occurs within 4 \200\2236 weeks and to repeat the process with different drug c ombinations 4 or 5 times, giving a total treatment time of around 6 months. Results using t his approach have improved for children in the best risk groups to the point where allo- ge neic BMT is no longer considered the consolidation treatment of choice even if a matched do nor is available. 2 Drugs used in remission induction include daunorubicin, etoposide, cytarabine and mitoxantrone (mitozantrone). 2 Drugs used in post induction and consolidation treatment include amsacrine, high-dose cytarabine, L-asparaginase, etoposide and mitox- antrone (mitozantrone ). 2 Good risk patients are those with t(8;21), t(15;17) and inv (16) \200\224 together accounting for around 20 \200\22325% overall; standard risk patients are those wit hout good risk genetic changes but that respond well and remit after one course of chemothe rapy (65% overall), and poor risk are those without good genetics who have residual disease at the start of course 2 of treatment (around 10% of the total). 484 2 Long term EFS for good risk children is around 75 \200\22380%, for standard risk around 60 \200\22365%, and for poor risk around 15%. 2 Allogeneic BMT as consolidation therapy of first remission is reserved for children in standard and poor risk groups. It is also used as a salvage strategy for go od risk patients who relapse. 2 The role of autologous stem cell rescue following myeloablative condi- tioning in children with AML has not been established. 2 The need for skilled supportive therapy confines AML therapy to spe- cialist units. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 485 Pediatric hematology 485 12-Pediatric.qxd 10.12.2003 04.28 PM Page 486 Childhood myelodysplastic syndromes and chronic leukaemias Myelodysplastic syndromes of childhood present a different spectrum of disease from that se en in adults. All are rare. The FAB classification of adult MDS ((cid:9) p220) has been tra nslated to pediatric disease, but sits uncomfortably and is of limited use clinically or in understanding the complex biology of this diverse group of clonal disorders of marrow func - tion. The proportion that map to the various adult categories is shown below. Adult vs. childhood MDS based on the FAB classification Category % Adults % Children Refractory anemia (RA) Refractory anemia with ring sideroblasts (RARS) Refractory anemia wi th excess blasts (RAEB) Refractory anemia with excess blasts in transformation (RAEB-t) Chr onic myelomonocytic leukemia (CMML) Unclassifiable 28 24 23 9 24 <1 16 5 16 0 50 4 2 Many children with MDS have a monocytosis which results in their being classified as CMML , also the clinical features and outlook for childhood CMML are quite different. 2 RARS is virtually never seen in children. 486 Individual disorders Refractory anemia: Children with a clonal genetic marker in the marrow who present with refractory anemia usually progress to RAEB and AML. Those without such a marker probably do not have MDS but some other cause of erythropoietic failure. RAEB and RAEB-t: Many of the RAEB syndromes in children arise in those with pre-existing di sease like Down syndrome, trisomy 8, neurofibro- matosis type 1, Fanconi \200\231s anemia, Kostmann \200\231s syndrome, Diamond \200\223 Blackfan anemia and Shwachman \200\223Diamond syndrome (see previous section). All these diseases predispose to leukemia, and RAEB is me rely part of the evolution of AML. A substantial proportion of childhood MDS in the RA or R AEB category is also induced by previous chemotherapy as a prodrome to secondary AML. In ot her words all pediatric cases of RAEB/RAEB-t are best regarded as AML and treated as such i f the diagnosis is not in any doubt. 2 Down syndrome children have a particular predisposition to develop M7 (megakaryoblastic) AML in the first few years of life. This is com- monly preceded by a RAEB prodrome where th e marrow is hard to aspirate through secondary sclerosis. The decision when to start therap y is difficult, but the overall outlook is potentially good with EFS >50%. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 487 Pediatric hematology Transient abnormal myelopoiesis (TAM): Down children also have a predisposition to develop a transient blast cell overgrowth in infancy that looks like frank leukemia with blasts in the peripheral blood. It is completely self-limiting within days or weeks and is not associ ated with marrow failure, arising alongside normal haemopoiesis. There is no genetic abnorm ality in the marrow apart from trisomy 21. It is important that chemotherapy is withheld in what is regarded as a temporary stem cell instability. Rarely the problem can arise in non -Down children, where trisomy 21 is found in the bone marrow only. JCMML (juvenile chronic myelomonocytic leukemia): Originally called juvenile chronic myeloi d leukemia to distinguish it from adult type chronic myeloid leukemia (see below), this per nicious disease still has a high mortality. It is now recognized to be a clonal disorder, w ith all marrow cell lines involved. It has several distinctive clinical and hematological f eatures. 2 Stigmata of fetal erythropoiesis; high HbF, 4 red cell i antigen expres- sion and carbonic anhydrase activity, 4 MCV. 2 Modest 4 WBC; average 30 \200\22340 109/L, with evident monocytosis, blasts 5 \200\22310%, and occasionally a basophilia. 2 Marrow appearances unremarkable; modest 4 blasts. 2 Thrombocytopenia; sometimes profound. 2 Skin rashes; butterfly distribution on face. 2 Increasing hepatosplenomegaly. 2 Associat ed with neurofibromatosis type 1. May be present in >10% of 487 cases. 2 Poor outlook with progression associated with wasting, fever, infec- tions, bleeding and pulmonary infiltrations. Monosomy 7 syndrome: Conventional cytogenetic analysis of the marrow in JCMML shows no abno rmality in the classic syndrome, though there is a subvariety (or similar condition that ma y nevertheless be biologically distinct) where monosomy 7 is found. Whether this is a diffe rent disorder is not clear. Apart from the different genetics, monosomy 7 syndrome and JCMM L have several features in common. However, monosomy 7 children may have: 2 A longer prodrome with RA or RAEB and no monocytosis. 2 They may respond to AML chemother apy (JCMML responds poorly and seldom remits). 2 They may remain stable for years without therapy. 2 They respond better to BMT (JCMML ach ieve <40% EFS even with BMT). Adult-type chronic myeloid (granulocytic) leukemia (ATCML, see Adult CML p164): More common than JCMML, though still rare, ATCML arises in around 1 in 500,000 children per year (20 i n whole of UK). Tends to 12-Pediatric.qxd 10.12.2003 04.28 PM Page 488 affect older children (60% >6 years) though it has been reported in a 3 month old infant. 2 Associated with Ph chromosome and t(9;22) BCR-ABL fusion gene in all haemopoietic cells exactly as seen in adults. 2 Natural history exactly the same as the disease in adults with benign phase and eventual progression to accelerated acute phase.