Life-threatening hemorrhage or other emergency Risk of life-threatening hemorrhage very sma ll (<1/1000 in 1st week after diagnosis) though is a function of a platelet count <10 \200 \22320 x 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 adventurous therapy (splenectomy, rituximab) can be contemplated, though risk still small and those of treatme nt may be higher. If a large intracranial (ICH) or other catastrophic bleed occurs, this ca n be dealed with by simultanous massive platelet transfusion, IVIg, IV methylpred- nisolone and (if the diagnosis is beyond doubt) emergency splenectomy. Mortality of major ICH <50% given active therapy. 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, some- times several years later. It is very rare for children to carry ITP into adult life and beyond, and the occasional individuals who do are unlikely to be m uch troubled by it or to develop autoimmune disease of other systems. Further reading Guidelines for the investigation and management of idiopathic thrombocytope nic purpura in adults, children and in pregnancy (2003). Br J Haematol, 120, 574 \200\22396 . 606 CHAPTER 12 Pediatric hematology Haemolytic uraemic syndrome Characterized by a triad of microangiopathic haemolytic anemia (MAHA), renal failure, and thrombocytopenia. More common in children than adults and of 2 t ypes; the more common epidemic form and the less common sporadic form closely related to th rombotic thrombocytopenic purpura (TTP) \200\224a disease primarily of adults that also rar ely occurs in children. TTP has the same triad of signs with two others \200\224fever and n eurological disturbances (E Thrombotic thrombocytopenic purpura, p.538) 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/unde rcooked meats, hamburgers, and poor food hygiene. The verocytotoxin causes endothelial dama ge, particularly of the renal endothelium, leading to the formation of fi brin-rich micro- thrombi and MAHA. Familial haemolytic uraemic syndrome (5 \200\22310% of cases) have a defi ciency or dysfunction of complement factor H, which results in excessive C3 activation. Clinical features \200 Young children (<4 years) are especially prone to the disease. \200 Acute onset with a history of abdominal pain and bloody diarrhea. \200 Onset of d u rine output heralding renal failure occurs days later. \200 In 710% onset is non-epidemic and insidious \200\224can be associated with chemotherapy/TBI. Other symptoms: anemia (may be severe), jaundice, bruising, bleeding. \200 Absence of fev er and neurologic signs distinguish it from TTP. Laboratory \201 ndings \200 MAHA may be severe. \200 Movie shows fragmented RBCs/schi stocytes/spherocytes. \200 Thrombocytopenia. \200 Coagulation tests: PT/APTT \200\224us ually n; Fgn and F/XDPs also n; reduced large vWF multimers. Proteinuria and haematuria. \200 Biochemical evidence of renal failure. \200 Stool cult ure may be +ve for E. coli. Diff erential diagnosis \200 TTP (E Thrombotic thrombocytopenic purpura, p.538). \200 O ther causes of MAHA and renal failure. Complications \200 ARF l CRF rare but more likely in older children and those with sporadic insidious onset HUS. Microvascular thrombosis and infarction of other organs. Treatment \200 Renal failure \200\224fl uid restriction, correct electrolyte imbalance. \200 If anuria persists >24h \200\224dialysis as necessary. \200 Blood transfusion for a nemia. 607 HAEMOLYTIC URAEMIC SYNDROME Platelet transfusion rarely needed \200\224may i thrombotic risk. \200 Severe persistent disease may require plasmapheresis as for TTP (E Thrombotic thrombocytopenic purpura, p.538). Specifi c treatment: none of proven value. In familial form replacement of factor H with FFP may be helpful. 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 7 5%. 608 CHAPTER 12 Pediatric hematology Childhood cancer and malignant blood disorders Epidemiology In Europe 1 child in 600 develops cancer before the age of 15. Annual incidenc e 1:10,000; 71200 new cases/year in UK. Pattern of child- hood cancers is very diff erent f rom that seen in adults: carcinomas are rarely seen. Overall, childhood cancer is slightly more common in boys than girls. \200 Leukaemias account for about 35% of the total: 80% a re some type of ALL, 15% some type of AML. 5% CMLs, (adult and juvenile types) or myelodysp lastic syndromes. CLL does not occur in children. Brain tumors are commonest solid malignancies, 25% of the total. Diff erent tumor types from adults; commonest medulloblastoma in posterior fossa. Embryonal tumors 15%, seen almost exclusively in children. Include neuroblastoma, nephrobla stoma (Wilms tumor), rhabdomyosarcoma, hepatoblastoma. Bone tumors 5% osteosarcoma, Ewing sarcoma. \200 Lymphomas 9% \200\224NHL and Hodgkin dis ease. NHL in children closely related biologically to ALL; low-grade disease very rare. Remainder of cases are mainly germ cell and primitive neuroectodermal tumors (PNETs), including retinoblastomas. Etiology \200 Childhood cancer generally represents aberrant growth and development. Defective repair and renewal may also be important in some cancers. Growths arising in infancy are mostly congenital and the genetic mutations concerned arise in utero. Causes of such mutations and those arising later in chi ldhood largely unknown. Although isolated cases are attributable to high-dose radiation (e.g. thyroid cancer in Chernobyl survivors), there is no convincing link to levels of back ground radiation or electromagnetic fi elds. Population mixing studies have suggested that patterns of exposure to infection may contribute to some cases of ALL in the peak years of incidence (2 \200\223 6 years). 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 1 allele of RB gene in aff ected 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). Cancer arising in older children may still be due to intrauterine event as concordance stud ies in identical twins with ALL have shown identical genetic mutations in malignant cells s ome years after birth. This suggests twin l twin transfer of potentially malignant clone th rough shared circulation. 609 CHILDHOOD CANCER AND MALIGNANT BLOOD DISORDERS Hematological eff ects of non-haemic tumors (for leukaemias, lymphomas, and MDS see appropr iate sections) \200 Marrow infi ltration may be evident at the time of presentation (most commonly neuroblastoma, less commonly Ewing sarcoma, rhabdomyosarcoma). Associated with anemia, occasionally other cytopenias. Blood count hardly ever n if marrow involved. Peripheral blood may show leucoerythroblastic picture, but not as commonly in adult cancers metastasizing to BM. Non-haemic tumors appear on cytomorphology as poorly diff erentiated fragile blast cells, o ften in sheets or clumps (unlike leukaemic blasts). Marrow infi ltration may arise as a late event in terminally progressive disease in other t umors, including CNS malignancies, PNETS, and germ cell tumors. Investigations in suspected childhood cancer Hematology \200 FBC and fi lm. Leukemia usua lly refl ected in the blood count: i or d WBC, thrombocytopenia and anemia. Blasts often present. In a small percentage, blood count entirely n. With other malignancies there may be signs of marrow infi ltration, anemia, or no abnormalities at all. BM aspirate and trephine if blood count abnormal. In children generally done under GA. Bilateral samples needed in the staging of neuroblastoma. Biochemistry \200 Full biochemical profi le. \200 Urinary catecholamines for neuroblast oma (easy test to do in unexplained bone pain). Tumor markers: -FP, HCG, in hepatoblastoma or germ cell tumors. Radiology \200 CXR for mediastinal mass (mandatory pre-anesthetic). \200 Abdominal USS. \200 CT/MRI scan of 1 lesion. CT chest/abdomen may be required for staging. In young children sedation/general anesthetic usually needed for CT/MRI scans. Histology Solid tumors need adequate biopsy material for diagnosis taken under general anes thetic. Genetics Fresh tumor material from all childhood cancers should be sent for cytogenetic and molecular genetic studies. Information from these is increasingly being used in risk-strat ifying therapy and in predicting outcome. 610 CHAPTER 12 Pediatric hematology 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 pro- tocol. This is co-ordinated b y the United Kingdom Children \200\231s Cancer Study Group and similar groups in other coun tries, and the success of such trials and studies is one of the reasons for the improved ou tlook for childhood cancer. Overall long-term survival is 760%. Late eff ects 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 eff ects from drugs (e.g. cardiotoxicity), and psychological well- being. There is an i risk of further malignancy developing which varies according to both the 1 diagnosis and treatment used. 611 CHILDHOOD CANCER AND MALIGNANT BLOOD DISORDERS 612 CHAPTER 12 Pediatric hematology Childhood lymphoblastic leukemia Lymphoblastic leukemia ( \200\230acute \200\231 is superfl uous, but disease widely known as ALL) is a group of clonal malignancies all arising in de vel- oping lymphocytes. There is more overlap with lymphomas than in adults. Commonest mali gnant disease in childhood (35% of all cancers). Incidence 4 \200\2235/100,000 children per year with a peak incidence between 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 \200\2236 years, and may be abnormal respo nse to infection where exposure to pathogens delayed or precipitated by population mixing. Evidence implicating back- ground ionizing or electromagnetic radiation now discredited. Ca use of T-ALL unknown. Pathophysiology \200 780% childhood ALLs arise in developing B lymphocytes; 720% in devel oping T cells. Acquired genetic mutations found in the various subtypes are growing in numb er as the molecular biology of leukemia unravels. In early B cells commonest mutation is a fusion between the TEL gene at 12p13 and the AML1 gene at 21q22 \200\224arises in 20% overall; other common mutati ons are t(1;19)(q23;p13.3) \200\2248% overall, t(9;22) (q34;q11.2) BCR-ABL (Ph chromosome); 5% overall. 730% have \200\230high hyperdiploidy \200\231 (>50 chromosomes per cell) with or without translocations; 7% show hypodiploidy. Infants (<18 months) frequently have a mutation of the MLL gene on chromosome 11 involving a range of fusion partners; most commonly AF4 on chromosome 4. These changes mark biologically diff erent types of precursor B-derived ALL in terms of clinical features and response to treatment. 1 \200\2232% of ALLs have features of mature B cells and a mutation where the MYC gene is t ranslocated adjacent to the Ig heavy chain locus \200\224 t(8;14). Also called Burkitt-type as the cell biology is similar to that of Burkitt lymphoma. T-ALL shows greater genetic diversity than B-derived disease but 12 recurring cytogenetic abnormalities now defi ned and under study. Clinical importance ye t to be defi ned. ALL also classifi ed by immunophenotyping using antibody cell markers for various diff erentiation antigens designated clusters of diff erentiation (CD), numbere d according to their order of discovery. Immunophenotypes so defi ned include early pre-B ( 60%), pre-B (20%), transitional pre-B (1%), B-ALL (1%) and T-ALL (18%). Clinical features \200 Commonly presents insidiously in 3 ways, separately or combined. \200 Signs of marrow failure \200\224often anemia predominates, with extreme pallor and listlessness (60%); also bruising/petechiae (40%). 613 CHILDHOOD LYMPHOBLASTIC leukemia Hepatosplenomegaly and lymphadenopathy ( \200\230lymphomatous \200\231 features) 10 \200\22320%. Bone pain mimicking irritable hip(s) or juvenile rheumatoid 10 \200\22320%. Laboratory features \200 Usually pancytopenia with circulating blast cells indicates diag nosis. \200 Confi rmed by BM examination and classifi ed by immunophenotyping and cytogen etic/molecular genetic analysis. Classifi cation based on expression profi ling might becom e available in the future. In sick children with very high blast cell counts classifi cation studies can be carried out on peripheral blood, but marrow always preferred. Peripheral blood count may show cytopenias without obvious blasts (aleukaemic picture) when diff erential diagnosis is aplastic anemia. \200 Kidney/liver function usually normal, b ut ALLs with high blast counts and rapid cell turnover may have tumor-lysis organ dysfuncti on before therapy (urate nephropathy with i urea, creatinine, and d urine output). Treatment of newly diagnosed disease \200 All modern protocols have common elements of re mission induction (RI), consolidation/intensifi cation (C/I), CNS directed treatment, and c ontinuing (maintenance) therapy with or without delayed intensifi cation (DI). RI drugs include dexamethasone, vincristine, and asparaginase. \200 C/I and DI drugs incl ude anthracyclines, cytarabine, cyclophosphamide asparaginase, and thioguanine. CNS therapy is intrathecal cytarabine and MTX (radiotherapy now reserved for those with active CNS infi ltration only). Maintenance therapy is a 2 \200\2233 year schedule of daily thiopurine (6-mercaptopurine) and weekly oral methotrexate. ALL is the only human malignancy that requires such a drawn-out chemotherapy module, immunosuppressive rather than antineoplastic. B-ALL is an exception; it does not respond to conventional ALL therapy, does not need maint enance and is treated on a 6 month intensive lymphoma schedule (E Childhood lymphomas, p.61 6). \200 Treatment is usually risk-directed based on biological features of the disease with more intensive schedules reserved for those with adverse prognostic factor s (E see Prognostic factors, p.614). BMT rarely used as 1st-line therapy. Outlook 98% overall will remit on modern therapy, 75 \200\22380% overall will become long-t erm disease-free survivors \200\224fi gures vary according to prognostic factors (E see Pro gnostic factors, p.614). >95% long-term survivors in low-risk disease. Treatment of relapse \200 Some 20 \200\22325% of children will relapse; either on treatme nt or after its completion. Outlook depends on length of 1st remission; very bleak if relapse on treatment. 614 CHAPTER 12 Pediatric hematology Salvage therapy more successful if relapse >2 years off therapy. \200 Relapsed T-ALL more diffi cult to treat successfully than other types. \200 Treatment includes intensive che motherapy with the addition of podophyllins, anthracycline analogs, and fl udarabine. BMT reserved for those who show slow-to-clear residual disease by PCR amplifi cation of uni que disease-specifi c Ig or TCR gene rearrangements, those who relapse on treatment and tho se with relapsed T-ALL. Prognostic factors \200 Several features of ALL predict response to current standard therapies and are used to stratify treatment. Infants <1 year have a poor outlook, and olde r children >10 years do less well than those 1 \200\22310 years. High presenting WBC (>100 \227 109/L) in boys marks high risk, as do some genetic features (MLL gene rearrangements, BCR-ABL fusion genes, hypodiploidy). All children with T-ALL, and all with slow disease clearance during the 1st few days of the rapy, are excluded from being classifi ed as low risk. \200 Low risk B-precursor ALL is t hat which shows none of these features. \200 Minimal residual disease (MRD) monitoring by molecular methods is being incorporated into clinical trials to assist prognostic stratifi cation. Late eff ects of therapy With i long survivors, late eff ects of therapy are becoming more impor- tant. Most morbidity seen after TBI given for BMT. Problems include: \200 Growth failure due to CNS damage from radiation. \200 Intellectu al defi cit due to CNS damage from radiation. \200 Precocious puberty (girls>boys) after cranial radiation. \200 Infertility (boys >girls) not dependent on radiation. \200 Obes ity (girls >boys) not dependent on radiation. \200 7 \200\22310-fold i risk of brain tumo rs not dependent on radiation. 615 CHILDHOOD LYMPHOBLASTIC leukemia 616 CHAPTER 12 Pediatric hematology Childhood lymphomas Lymphomas account for around 8 \200\22310% of all childhood cancers (th is equates to around 1 per 100,000 children per year). Around 30 \200\22335% are Hodgkin di sease, the rest NHL. Hodgkin disease Clinical features Uncommon <5 years; incidence increases during the early t eenage years. The disease is biologically the same as that of adults and the histological c lassifi cation is identical (E see Hodgkin lymphoma ((HL, Hodgkin disease), p.214 for more details), though mixed cellularity disease may be more common in the young. Staging is also similar to adults (E Table 5.9, p.217), but overall children and adolescents have a greate r proportion of low-stage disease (I and II). Stage IV accounts for <10% of childhood cases . Treatment and outcome Treatment is so successful that most eff orts are currently directe d at reducing toxicity and late eff ects. Radiotherapy for stage I disease is being attenua ted, and some therapists have abandoned it as 1st-line treatment and rely on chemotherapy a lone. Chemotherapy regimens in turn are evolving (to avoid or minimize alkylating agents an d their eff ect on fertility and anthracyclines with their potential for cardiotoxicity), b ut at present the traditional drugs are still being used with or without involved fi eld ra diotherapy, 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 fi eld radiotherapy, and >80% should achieve long-term EFS. NHL Childhood NHL are a heterogeneous group of tumors quite diff erent from those seen in a dults. Virtually all are disseminated, high-grade diff use malignancies of immature B or T lymphocytes, and many are closely related to subtypes of ALL that occur in this age group. Classifi cation of NHL has always been confusing, but the Revised European American Lymphom a system is currently preferred. This maps disease in children into 6 categories: 1. Burkitt lymphoma, Burkitt-like lymphoma, high-grade B-cell disease Diff erent manifestat ions of biologically very closely related diseases and pathologically indistinguishable fro m B-ALL. 745% of the total. Characteristic \200\230starry sky \200\231 histological patter n and deeply basophilic blasts on Romanowsky stains with prominent vacuoles (FAB L3 fea- tu res). Associated with chromosomal translocation involving MYC locus on chromosome 8 and Ig heavy chain gene on 14 (or less commonly with a or light chain gene on 2 or 22) with resultant dysregulation of MYC gene transcription; the MYC product functions as a transcrip tion factor. 617 CHILDHOOD LYMPHOMAS 2. Precursor B-lymphoblastic lymphoma Indistinguishable pathologically from common ALL. 75% of the total. Commonly presents as a solitary SC swelling, typically on the scalp. 3. Precursor T-lymphoblastic lymphoma Indistinguishable pathologically from T-ALL. 720% of the total. 66% have mediastinal involvement. Marrow involvement common in advanced disease; so may be classifi ed as T-ALL rather than stage IV NHL. 4. Diff use large B-cell lymphoma Including 1 sclerosing mediastinal form; no leukaemic c ounterpart, accounts for 73 \200\2234% of the total. Chiefl y abdominal. Occasionally medi- astinal. Has some features of Burkitt but no MYC gene mutation. 5. Peripheral T-cell lymphoma unspeci \201 ed No leukaemic counterpart. Skin involvement. Retrospective review shows most so classifi ed to be type 6 (large cell anaplastic, see cat egory 6). Poorly defi ned 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. 715% of the total. Used to be diagnosed as peripheral T-cell lymphomas or \200\230malig- nant histioc ytosis \200\231. Biological hallmarks are Ki-1 (CD30)+, also t(2;5). Around 9% childhood NHLs defy classifi cation and <1% adult type fol- licular 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 (Table 12.9), though therapy is increasingly being directed more by the biology of the disease rather than its anatomical distribution or extent. Staging aff ects prognosis only within given tumor type. Table 12.9 St Jude staging system for childhood NHL Single tumor (extranodal or single nodal anatomic area), excluding mediastinum or abdomen Stage I Single extranodal tumor with regional node involvement = 2 nodal areas on the same side of the diaphragm Stage II 2 single extranodal tumors regional node involvement on same side of the diaphragm 1 GIT tumor, usually ileocaecal, involvement of associated mesenteric nodes 2 extranodal tumors on opposite sides of the diaphragm = 2 nodal areas above and below the diaphragm Stage III Presence of 1 intrathoracic tumor (mediastinal, pleural or thymic) Presence of extensive 1 intra-abdominal disease Presence of paraspinal or epidural tumors, regardless of other sites Any of the above with initial CNS and/or BM involvement Stage IV 618 CHAPTER 12 Pediatric hematology Treatment \200 Burkitt lymphoma/B-ALL: short 6-month course of pulsed intensive high-dose therapy (vincristine, steroids, MTX, cyclophosphamide, anthracyclines, and etoposide) incl uding CNS treatment. No maintenance treatment needed. B-precursor lymphoblastic: if isolated to one site, 6-month program of ALL-type therapy may suffi ce, else treat as common ALL with extended maintenanc e (E Lymphoblastic leukemia, p.612). T-precursor lymphoblastic: treated as T-ALL (E see Treatment of newly diagnosed disease, p.613). Diff use large B-cell lymphoma: treated as Burkitt lymphoma (E p.206). Large cell anaplastic Ki-1+: skin, CNS and mediastinal involvement and splenomegaly are adv erse features. Best therapy undefi ned but usually treated with short, intensive Burkitt-li ke regimens. EFS is around 775% (high-risk cases 760%). General points on therapy/outlook \200 Surgery usually indicated for the complete resecti on of a localized abdominal 1 tumor when possible. Low-dose involved fi eld radiotherapy indicated for airway or spinal cord compression. Mediastinal irradiation for persistent local disease. Given best current therapy, the outlook for most patients is good with around 80% EFS for childhood lymphomas overall. 619 CHILDHOOD LYMPHOMAS 620 CHAPTER 12 Pediatric hematology Childhood acute myeloid leukemia AML in children accounts for 715% of all malignant blood d isorders, with around 80 \200\22390 new cases arising in the UK each year. Unlike ALL, the disease is classifi ed on morphological grounds using the FAB clas- sifi cation (Table 12.1 0), as is AML in adults (E see Table 4.1, p.127). The frequency of the diff erent subtypes diff ers in children, however. M6 AML is very rare whereas M7 (megakaryocyte derived AML) i s more common \200\224especially in children with Down syndrome. Table 12.10 Proportion of children with de novo AML by FAB type M0 M1 M2 M3 M4 M5 M6 M7 % of total 2 18 29 8 16 17 2 8 Pathophysiology AML is a clonal neoplasm arising from developing blood cells aff ecting all haemopoietic cell lines, most commonly granulocyte or monocyte precursors but also occasio nally involving immature erythroblasts or megakaryocytes. Apart from 1 , de novo disease f or which no cause can be identifi ed, some cases of AML are due to chemotherapy given for o ther diseases (2 AML), and some arise in children with predisposing syndromes where the r isk is greatly i and where specifi c subtypes of AML may develop. \200 2 AML caused by topoisomerase II inhibitors (e.g. etoposide) has a latency of 1 \200\2233 years and is of F AB type M4/M5 with a characteristic MLL gene mutation. 2 AML caused by alkylating agents (e.g. cyclophosphamide) has a latency of 4 \200\2236 years, a myelodysplastic phase, and loss or deletions of chromosomes 5, 7, or both. Down syndrome children are 20 \227 more likely to develop leukemia than normal children; i nfants are more likely to develop M7 AML, older Down children develop ALL. Other conditions predisposing to AML in children are Fanconi anemia and Bloom syndrome (E F anconi anemia, p.594), dyskeratosis congenita, Kostmann syndrome and Shwachman \200\223 Dia mond syndrome (E Rare congenital marrow failure syndromes, p.596), Diamond \200\223Blackfan anemia (E Congenital red cell aplasia, p.590), and neurofi bromatosis. Apart from the specifi c changes in 2 AMLs, clonal chromosome abnor- malities are found i n blasts from 790% of those with de novo disease. 2/3 of these are non-random, and many are associated with characteristic clinical and biological features. 621 CHILDHOOD ACUTE MYELOID leukemia Table 12.11 Commonest genetic mutations in childhood AML Abnormality Involved FAB type Frequency Clinical features genes t(8;21) M2 10 \200\22315% Extramedullary chloromas Good outlook ETO; AML1 t(15;17) M3 5 \200\22310% Coagulopathy Responds to retinoids PML; RARA Inv16(p13q32) MYH11; CBFB M4eo 7 \200\22310% Extramedullary deposits Good outlook t(9;11) M4/M5 7 \200\22310% Infants, CNS disease Poor outlook AF9; MLL t(1;22) M7 2 \200\2233% 2 myelofi brosis Down syndrome N/K Laboratory features \200 Peripheral blood shows a variety of abnormalities \200\224usuall y pancytopenia with circulating blasts. WBC seldom >50 \227 109/L though can occasionally be very high with symptoms of leucostasi s \200\224deafness, confusion, and impaired consciousness. BM usually shows heavy overgrowth of blasts with diff erent morphology depending on FAB type. Auer rods (abnormal elongated 1 granules seen on Romano wsky stains in cytoplasm of malignant 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 M 3. Cytochemistry may help; non-specifi c esterase +ve in M4/M5 AML, not other types and myelop eroxidase positivity can help distinguish between poorly diff erentiated AML and ALL. M7 AM L may develop extensive marrow fi brosis making aspiration diffi cult; trephine histology n eeded. Genetic abnormalities common in blast cells (see Table 12.11). \200 Immunophenotyping les s important than in ALL, though essential for immediate diagnosis of M7 AML which has no di stinguishing morphological or cytochemical features. CD antigens expressed vary according t o FAB type; CD33 strongly +ve in all, CD13 in M2/3; CD4 in M4/M5 and CD41/61 in M7. M6 dise ase expresses glycophorin A. 622 CHAPTER 12 Pediatric hematology Clinical features Children with advanced AML are commonly sicker than those with ALL. They can present with bleeding, haemostatic failure, and/or septi- caemia as manifestations of m arrow failure and profound neutropenia. Extramedullary chloromas (solid deposits of maligna nt cells) arise in around 10% of cases. They may precede marrow failure (or even detect- ab le marrow infi ltration). They can arise internally around the spine or spinal cord, causin g pressure symptoms and mimicking non-haemic solid tumors. They are more common in AML with t(8;21). Peri-orbital chlo- romas 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 diff erent drug combinations 4 or 5 times, giving a total treatment time of around 6 months. Results using this approach have improved for children in the best risk groups to the point where allogen eic BMT is no longer considered the consolidation treatment of choice even if a matched don or is available. \200 Drugs used in remission induction include daunorubicin, etoposide, cytarabine, and mitoxantrone (mitozantrone). Drugs used in post induction and consolidation treatment include amsacrine, high-dose cytar abine, L-asparaginase, etoposide, and mitoxantrone (mitozantrone). 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 1 course of chemothera py (65% overall), and poor risk are those without good genetics who have residual disease a t the start of course 2 of treatment (around 10% of the total). 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%. Allogeneic BMT as consolidation therapy of 1st 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. The role of autologous stem cell rescue following myeloablative conditioning in children with AML has not been established. The need for skilled supportive therapy confi nes AML therapy to specialist units. 623 CHILDHOOD ACUTE MYELOID leukemia 624 CHAPTER 12 Pediatric hematology Childhood myelodysplastic syndromes and chronic leukaemias Myelodysplastic syndromes of chi ldhood present a diff erent spectrum of disease from that seen in adults. All are rare. The FAB classifi cation of adult MDS (E p.230) has been translated to pediatric disease, but s its uncomfortably and is of limited use clinically or in understanding the complex biology of this diverse group of clonal disorders of marrow function. The proportion that map to th e various adult categories is shown in Table 12.12. \200 Many children with MDS have a mo nocytosis which results in their being classifi ed as CMML, also the clinical features and outlook for childhood CMML are quite diff erent. \200 RARS is virtually never seen in chi ldren. Table 12.12 Pediatric modifi cation of WHO classifi cation of myelodysplastic disorders Category Diseases Myelodysplastic/ myeloproliferative disease Juvenile myelomonocytic leukemia ( JMML) Down syndrome disease Transient abnormal myelopoiesis Myeloid leukemia of DS Myelodysplastic syndrome Refractory cytopenia (blood blasts <2%, marrow blasts <5%) Refractory anemia with excess blasts (blood blasts <19%, marrow blasts 5 \200\22319%) Refractory anemia with excess blasts in transformation (blood or marrow blasts 20 \200\2232 9%) 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 m arker 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, neurofi bromatosis type 1, Fanconi anemia, dyskeratosi s congenita, Kostmann syndrome, Diamond \200\223Blackfan anemia, and Shwachman \200\223Diam ond syndrome (E see Childhood acute myeloid leukemia, p.620). All these diseases pre- dispo se to leukemia, and RAEB is merely part of the evolution of AML. A substantial proportion o f childhood MDS in the RA or RAEB category is also induced by previous chemotherapy as a pr odrome to 2 AML. In 625 CHILDHOOD MYELODYSPLASTIC SYNDROMES other words all pediatric cases of RAEB/RAEB-t are best regarded as AML and treated as such if the diagnosis is not in any doubt. \200 Down syndrome children have a particular pred isposition to develop M7 (megakaryoblastic) AML in the fi rst few years of life. This is commonly preceded by a R AEB prodrome where the marrow is hard to aspirate through 2 sclerosis. The decision when to start therapy is diffi cult, but the overall outlook is potentially good with EFS >50%. 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 t he peripheral blood. It is completely self-limiting within days or weeks and is not associa ted with marrow failure, arising alongside normal haemopoiesis. It is important that chemot herapy is withheld in what is regarded as a temporary stem cell instability. Rarely the pro blem can arise in non-Down children, where trisomy 21 is found in the BM only. TAM and M7 i n Down syndrome patients has been recently shown to be associated with acquired mutations i n GATA-1. Juvenile chronic myelomonocytic leukemia (JCMML) Originally called juvenile chronic myeloid leukemia to distinguish it from adult type chronic myeloid leukemia (E CML, p.148), this p ernicious disease still has a high mortality. It is now recognized to be a clonal disorder, with all marrow cell lines involved. It has several distinctive clinical and hematological features. \200 Stigmata of fetal erythropoiesis; high HbF, i red cell i antigen expression and carbonic anhydrase activity, i MCV. Modest i WBC; average 30 \200\22340 \227 109/L, with evident monocytosis, blasts 5 \200\22310%, and occasionally a basophilia. Marrow appearances unremarkable; modest i blasts. \200 Thrombocytopenia; sometimes profou nd. \200 Skin rashes; butterfl y distribution on face. \200 Increasing hepatosplenomega ly. \200 Associated with neurofi bromatosis type 1. May be present in >10% of cases. Poor outlook with progression associated with wasting, fever, infections, bleeding, and pulmonary infi ltrations. Monosomy 7 syndrome Conventional cytogenetic analysis of JCMML shows no abnormality in the classic syndrome, though there is a subvariety (or similar condition that may nevertheless be bio- found. Whether this logically distinct) where monosomy 7 from the diff erent is a d iff erent disorder genetics, monosomy 7 several JCMML have features in common. However, mon osomy 7 children may have: \200 A longer prodrome with RA or RAEB and no monocytosis. \200 They may respond to AML chemotherapy (JCMML responds poorly the marrow in is is not clear. Apart syndrome and and seldom remits). They may remain stable for years without therapy. \200 They respond better to BMT (JCMML achieve <40% EFS even with BMT). 626 CHAPTER 12 Pediatric hematology Adult-type chronic myeloid (granulocytic) leukemia (ATCML) ( E see Adult CML p.148.) More c ommon than JCMML, though still rare, ATCML arises in around 1 in 500,000 children per year (20 in whole of UK). Tends to aff ect older children (60% >6 years) though it has been repo rted in a 3-month-old infant. \200 Associated with Ph chromosome and t(9;22) BCR-ABL fusi on gene in all haemopoietic cells exactly as seen in adults. Natural history exactly the same as the disease in adults with chronic phase and eventual progression to accelerated acute phase. Only curative therapy is allogeneic BMT, but impressive remissions of so far unknown length are now being achieved with novel tyrosine kinase inhibitor imatin ib. For patients who lack a compatible SCT donor this is becoming 1st-line therapy in place of interferon alfa or hydroxycarbamide. 627 CHILDHOOD MYELODYSPLASTIC SYNDROMES 628 CHAPTER 12 Pediatric hematology Histiocytic syndromes Monocytes are formed in the marrow and move through the peripheral bl ood into the tissues where they become histiocytes, either in the mono- nuclear phagocytic system (MPS) or the dendritic cell system (DCS). MPS cells are antigen processing, are pred ominantly phagocytic, and include many organ-specifi c cells such as Kupff er cells and pul monary alveolar macrophages. DCS cells include tissue-based Langerhan cells (LC) which are antigen presenting. There is a variety of syndromes where histiocytes proliferate and malfu nction and some of these carry a high mortality. A few are clonal neoplasms but most are pr oduced by cytokine distur- bances. In 1991 a new classifi cation of histiocytic syndromes w as set out as shown in Table 12.13. Table 12.13 Histiocytic syndromes Disorders of dendritic cells \200 Langerhan cell histiocytosis (LCH) Class I (previously known as histiocytosis X) Disorders of macrophages \200 Haemophagocytic syndromes \200 Haemophagocytic lymphohist iocytosis (HLH): Class II 1 (genetic) \200 2 (to infection or malignant disease) Sinus histiocytosis with massive lymphadenopathy \200 Histiocytic necrotising lymphadenit is \200 Malignant histiocytic disorders: \200 Malignant histiocytosis \200 Monocytic leukaemias Class III Class I: Langerhan cell histiocytosis (LCH) Cellular destructive tissue infi ltration with LC. These are well-dif- ferentiated large cells (15 \200\22325microm) with an indented nucl eus and inconspicuous nucleolus; they are not phagocytic. Other reactive cells (granulocyte s, eosinophils, macrophages) are often present. Diagnostic criteria of LC include the prese nce of Burbeck granules on electron microscopy and immunochemical positivity for CD1A. The etiology of LCH remains unclear. Despite some evidence of clonality (not itself evi- dence of malignancy), no genetic mutations have been identifi ed and the disorder is not regarded as a form of cancer. Clinical features LCH is primarily a disease of the very young with a peak incidence of 1 \200\2233 years. It can present in a variety of ways, from a small bone lesion heavily admi xed with eosinophils (eosinophilic granuloma), through multiple lytic bone lesions, exophth almos, and diabetes insipidus (Hand \200\223 Schuller \200\223Christian disease) to multipl e tissue infi ltration involving skin, liver, lung, bone, and BM (Letterer \200\223Siwe dis ease). The eponymous terms are no longer used for what is now regarded as a common patholog y and the overarching term LCH is preferred. This is staged on 629 HISTIOCYTIC SYNDROMES