17_McClure_17.indd 637 11/14/2012 3:50:15 PM CHAPTER 17 Hematology 638 von Willebrand disease von Willebrand factor (vWF) functions as the carrier protein for fac tor VIIIC, protecting it from degradation, which facilitates platelet adhesion to damaged e ndothelium. De \201 ciency in vWF leads to reduced factor VIII activity and impaired plate let function. \200 Von Wi;;ebrand disease (vWD) is an inherited bleeding disorder due to de \201 ciency or ab normal function of vWF. Incidence M = F. \200 71:5000. There are three main subtypes: \200 \200 Type Type severity. In Type IIb there is usually thrombocytopenia. Type cases. Severe. I: autosomal dominant. 70% of cases. Mild \200\223moderate severity. II: autosomal dominant or recessive. 25% of cases. Mild \200\223moderate III: autosomal recessive. Almost complete absence of vWF. <5% Presentation Presentation is very variable. Type III usually has severe mucosal bleed- ing, but when FVIII level is very low picture is similar to hemophilia A. Other types may vary from virtually asymptomatic to easy bruising with associated excessive bleeding from dental surgery, trauma, surgery, and menorrhagia (always screen for vWD in any female with menorr hagia or iron de \201 ciency s to menorrhagia). Investigations APTT is usually i (if facto r VIII activity is low); PT n; platelet count usu- ally normal except in Type IIb; PFA i; f actor VIIIC d; vWF antigen levels reduced and function d. Note: vWF is an acute phase prote in, as is FVIII, and may be raised to normal immediately after birth and following trauma, illness, or traumatic venepunc- ture (hence dif \201 cult to make a diagnosis of mild vWD in a child!). Management \200 \200 Avoid NSAIDs and IM injections. Minor bleeding may respond to local pressure or tranexamic acid (locally with mouthwash or systemically 20 \200\22325mg/kg tds for 74 \200\2235 days). More signi \201 cant bleeds or minor surgery may respond to DDAVP (avoid if type IIB as f urther reduces platelet count). Severe bleeding or severe disease requires virally-inactiva ted plasma-derived factor VIII concentrate combined with vWD factor (no recombinant product currently available). Manage as for severe hemophilia A. Complications Mainly occur in undiagnosed cases. May be profoundly anemic s to chron- ic bl ood loss and iron de \201 ciency. If receiving plasma derived products there is the risk o f viral infection or exposure to new variant Creutzfeldt \200\223Jakob disease (nvCJD). Acu te joint involvement is rare except in type III. In severe disease, complications are other wise similar to hemophilia A. 17_McClure_17.indd 638 11/14/2012 3:50:15 PM VON WILLEBRAND DISEASE 639 Prognosis Patients with type I and II disease rarely have severe bleeds and generally have normal life expectancy and quality of life, especially in men (no peri- ods). Severity seem s to improve with age, but also knowledge about how to manage bleeds improves with age. Eve n those with type III, if properly managed, should normal have life expectancy. Other congenital clotting factor de \201 ciencies \200 \200 \200 De \201 ciency of every coagulation factor exists, but most are very rare. All have autoso mal recessive inheritance. The most common defects are those of \201 brinogen (e.g. dys \201 brinogenaemia or hypo \201 brinogenaemia) and speci \201 c de \201 ciency of factor s VII, II prothrombin, V, XI, XIII, and X. Factor XII de \201 ciency results in prolonged APTT, but no bleeding tendency. In general, the severity of bleeding tendency varies from that of mild hemophilia to a fami lial bruising tendency. Most patients present with bleeding after surgery (circumcision, tr auma, or dental extraction) rather than spontaneous bleeding or haemarthrosis. Can rarely p resent as cord hemorrhage in the neonatal period \200\224usually caused by FXIII de \201 c iency. Congenital a \201 brinogenaemia is clinically the most severe, and haemor- rhagic m anifestations usually appear within the \201 rst 2yrs of life. Patients with this conditi on require weekly IV infusions of \201 brinogen. Depending on speci \201 c de \201 cient factor, PT and/or APTT will be increased (XIII de \201 ciency excepted). Generally, any boy with unexplained bleeding in infancy or as a to ddler with isolated raised APTT must be considered to have hemophilia until proven otherwis e. Unless bleeding is catastrophic, send blood for urgent factor assays and treat with appr opriate factor rather than FFP, unless in extremis. Acquired haemorrhagic disorders \200 Haemorrhagic disease of the newborn. Due to vitamin K de \201 ciency. rare early presentat ion occurs within 24hr of life with serious \200 bleeding, including intracranial hemorrh age (mothers may be completely vitamin K de \201 cient); more classical presentation occur s in \201 rst week of life in breast- fed infants with GI bleeding, widespread bruising, occasionally intracranial hemorrhage; late presentation occurs after the \201 rst week of life, again in breast- fed infants, and usually associated with a variety of diseases that compromise or reduce the availability of vitamin K, e.g. cystic \201 brosis with diarrhe a, alpha1 antitrypsin de \201 ciency, liver diseases. \200 Coagulation factor de \201 ciencies secondary to liver disease. DIC (see b p.635). 17_McClure_17.indd 639 11/14/2012 3:50:15 PM CHAPTER 17 Hematology 640 Platelet function disorders Congenital causes All are rare and autosomal recessive. They ar e due to the following: \200 Defective platelet membrane speci \201 c glycoproteins, which cause defective adhesion to \201 brinogen, e.g. Glanzmann disease (thromboasthenia), Bernard-Soulier syndrome (BSS), vWD (usually AD) (see b p.638). Defective or de \201 cient platelet granules (normal relea se induces coagulation cascade, vasoconstriction, platelet aggregation), e.g. TAR syndrome, Chediak \200\223Higashi syndrome. Acquired causes May be s to drugs, e.g. NSAIDs, corticosteroids, antihistamines, renal dise ase, liver disease, and diets rich in garlic, ginger, and Indian spices. Presentation \200 \200 \200 \200 Easy bruising and purpura. Mucocutaneous bleeding. Menorrhagia. Positive family history is common (although in most AR syndromes both parents are unaffected). Investigations \200 Usually normal platelet count (except in BSS which usually has mild thrombocytopenia). i \200 \200 \200 Platelet size, e.g. giant platelets in BSS. Prolonged PFA. If congenital platelet functional disorder suspected, perform PFA followed b y formal platelet aggregation studies using ristocetin, collagen, adenosine 5-diphosphate ( ADP), arachidonic acid, and adrenaline; and platelet nucelotide ratios. Interpretation is c omplex, so seek hematologist help. Treatment \200 \200 \200 Control bleeding, e.g. apply pressure in mild cases. Correct underlying abnormality or stop responsible drug. Give tranexamic acid for minor bleeding, e.g. mouth washes or systemical ly 20 \200\22325mg/kg tds for < 5 days. Give platelet transfusion if bleeding severe or to cover for surgery. Note: Need to give HLA matched platelets to avoid HLA speci \201 c anti -platelet antibody formation, if child likely to need frequent transfusions. Avoid drugs th at inhibit platelet function, e.g. NSAIDs and IM injections. Consider oral contraceptives i n teenage girls to control menorrhagia. Prognosis Prognosis is generally good with normal life expectancy. Serious bleeding is rare , but can be dif \201 cult to manage, particularly in children with multiple anti-platelet or anti-HLA antibodies. 17_McClure_17.indd 640 11/14/2012 3:50:15 PM THROMBOCYTOSIS 641 Thrombocytosis Normal platelet count <450 \227 109/L; platelet counts >1000 \227 109/L ma y cause thrombosis or bleeding when platelets are dysfunctional. Causes Almost always, thrombocytosis in infants and children is reactive. Increased production occurs with \200 Acute or chronic infection. \200 Acute or chronic hemorrhage. \200 Trauma or surgery. \200 Kawasaki \200\231s disease. \200 Iron de \201 ciency anemia. \200 Certain malignancies, e.g. Wilm \200\231s tumor. \200 Any in \202 ammatory disease, e.g. ulcerative colitis. \200 Primary myeloproliferative disorder, e.g. essential thrombocytheaemia (ET) or in association with chronic myeloid leukemia (CML ). Decreased destruction Post-splenectomy. On examination look for signs of iron de \201 cien cy anemia, bruising or bleeding, splenomegaly, signs of Kawasaki \200\231s disease (see b p .716) and general ill health. The most common scenario is for the child to be totally well having recovered from an acute infection and a follow-up FBC shows a raised platelet count. Investigations \200 \200 \200 e.g. WCC i in infection or signs of iron de \201 ciency anemia. FBC: CRP/ESR: Bone marrow aspirate only ever indicated if primary myeloproliferative disord er (MPD) such as essential thrombocytheaemia is suspected (which is very rare). i in in \202 ammatory/malignant conditions. Management \200 \200 \200 Treat underlying cause. Watch and wait in reactive cases, as requires no treatment. Give as pirin in Kawasaki \200\231s disease (one of the few indications for aspirin in children). Prognosis Reactive thrombocytosis generally has an excellent prognosis. Primary causes are very rare and have a variable prognosis. They are best managed by a pediatric hematologist. 17_McClure_17.indd 641 11/14/2012 3:50:15 PM CHAPTER 17 Hematology 642 Thrombocytopenia See also b p.193. De \201 ned as <150 \227 109/L: as platelet count decr eases risk of bleeding and bruising increases. Risk of bleeding is moderately high <20 \227 109/L and likely if <10 \227 109/L. Causes Decreased platelet production \200 Selective more substantial bacterial infection, drugs, and poisons. Marrow severe maternal pre-eclampsia, neonatal sepsis. Marrow Marrow Hereditary: boys present with early thrombocy topenia, eczema, and immunocompromise due to immunoglobulin abnormalities), BSS, TAR syndro me. Nutritional megakaryocyte depression: viral (HIV, parvovirus, EBV) or failure: aplastic anemia, Fanconi \200\231s syndrome, severe IUGR, \200 \200 in \201 ltration: leukemia, neuroblastoma, osteopetrosis. depression: radiotherapy, cytoto xic drugs, drug reaction. Wiskott \200\223Aldrich syndrome (X-linked recessive: de \201 ciency: vitamin B12 or folate de \201 ciency. Increased destruction \200 Immune: alloimmune thrombocytopenia (NAIT), SLE, drug-induced (penicillin or heparin-induce d thrombocytopenia (HIT)), infection (e.g. malaria or HIV). Non-immune: HUS, cardiac diseas e (prosthetic valves or cardiopulmonary bypass). Hypersplenism cause \200\224effect is dilu tional, rather than destructive. ITP (most commonly in child, rarely in mother), neonatal DIC, giant haemangioma (Kasabach \200\223Merritt syndrome), : platelets pool in enlarged spleen from whatever Investigations \200 History: \200 Examination: concurrent infection. FBC and blood \201 lm. Serology: autoimmune antibodies in those with chronic ITP, viral serology (CMV, EB V along with monospot if infectious mononucelosis suspected, or HIV if unusual unexplained thrombocytopenia). Bone unexplained thrombocytopenia. Cranial drug history, family history, preceding viral illness. signs of bleeding, lymphadenopathy, hepatosplenomegaly, \200 anti-platelet antibodies (e.g. anti-HPA1) if NAIT suspected, marrow aspirate and trephine: very rarely required in cases of CT scan: if any evidence of possible intracerebral hemorrhage. Treatment \200 \200 Treat underlying cause if possible. Platelet transfusion if very low platelet count (prophy lactically, and guided by hematologists, except for ITP) or life-threatening bleeding. Sple nectomy, e.g chronic ITP, hypersplenism. Bone marrow transplant may be helpful in some inhe rited bone marrow failure syndromes. \200 17_McClure_17.indd 642 11/14/2012 3:50:15 PM ACUTE IMMUNE THROMBOCYTOPENIA 643 Acute immune thrombocytopenia ITP is caused by IgG autoimmune antibody to platelet cell mem brane anti- gens leading to platelet destruction in the spleen and liver. Presentation \200 \200 Most present between ages of 2 and 5yrs, but can occur at any age. 60% have preceding viral infection, e.g. upper respiratory tract infection (URTI). Bruising, purpura, petechiae, mu cosal bleeding, menorrhagia. Intracranial bleeds very rare (< 0.5%); often associated with trauma. Physical examination otherwise usually normal, e.g. no splenomegaly. \200 \200 Investigation \200 platelet count dd, commonly platelet size i due to compensatory FBC: megakaryocytosis. Otherwise FBC is usually normal. Testing for platelet antibodies is not clinically useful. Bone marrow in ITP normal, but striking increase in megakaryocytes. \200 Generally, bone marrow aspirate not indicated if the child is otherwise well, unless concur rent pancytopenia, hepatosplenomegaly, lymphaden- opathy, or abnormally-increased blasts on FBC suggesting alternative diag- nosis, e.g. aplastic anemia, acute leukemia, SLE (adolesc ent girls) or bone marrow failure syndrome. Management \200 Do not treat the platelet count, treat the patient! The aim of treatment is to stop the ble eding not \200\230cure \200\231 the disorder, which resolves in its own time. Increases in platelet count will usually be transient, but are usually suf \201 cient to control curre nt bleeding. Moderate bleeding can be controlled with tranexamic acid 20 \200\22325mg/kg td s for <5 days, provided haematuria is not present. Active treatment is required if patient experiencing mucosal hemorrhage, or haematuria, as all are associated with increased risk o f internal bleeding. First line therapy: Second line therapy: IV IgG 1g/kg over 2 days if s teroids not effective, alternatively can use anti-D antibody (if patient Rh+). If bleeding life-threatening or intracranial, give 15 \200\22320mL start prednisolone and IV IgG and co nsider emergency splenectomy. Splenectomy for chronic ITP is indicated if disease is not st eroid responsive and child over 5yrs. For chronic severe ITP, rituximab has been used succe ssfully in young children. Exclude other underlying immunedysregulatory or lymphoproliferat ive disorders such as X-linked lymphoproliferative (XLP). Educate parents regarding ITP, in cluding signs and symptoms that should prompt immediate return to hospital. Child can carry on with normal activities, but should avoid contact sports and NSAIDs when platelet count is low. signi \201 cant bleeding, \200 4mg/kg prednisolone for 4 days and then stop. /kg of platelets, Prognosis: acute ITP in childhood is a self-limiting disorder and >80% spon- taneously remi t within 6 \200\2238wks. Presentation after 10yrs of age or female sex increases chance of chronic disease. 17_McClure_17.indd 643 11/14/2012 3:50:15 PM CHAPTER 17 Hematology 644 Thrombophilia These haemostatic disorders predispose to venous or arterial thrombo- sis. \200 \200 May be inherited or acquired. Most inherited thrombophilias are asymptomatic or present in adult life. In children, most present in the newborn period or following thrombogenic event s (trauma, surgery or pregnancy). Newborns requiring intensive support often have multiple thrombotic risk factors including sepsis, dehydration, polycythaemia, and central vascular lines. Inherited thrombophilia should be considered when there is an unexplained arterial o r venous thrombosis, neonatal venous thrombosis, or positive family history. Inherited causes Activated protein C resistance or factor V Leiden de \201 ciency Commones t inherited form of venous thrombophilia. Activated protein C (APC) is an anticoagulant for med in the vascular epithelium and limits haemostasis with cofactor protein S. Over 90% of APC resistance is due to factor V Leiden (FVL) de \201 ciency (a polymorphism present in 2 \200\2235% of pop- ulation). Adults heterozygotes for FVL de \201 ciency have 5 \200\2231 0 \227 increased risk of venous thrombosis, and homozygotes \22730. Whilst homozygous FVL de \201 ciency will often present in children, heterozygous children are unlikely to expe rience a signi \201 cant risk unless an additional prothrombotic risk factor is also prese nt. Prothrombin G20210A mutation Similar incidence to FVL de \201 ciency. It results in a high er average prothrombin level. Heterozygotes have a two- fold risk of thrombosis in adults. Protein C de \201 ciency Thromboembolism is rare in childhood, but severe de \201 ciency can cause life-threatening massive thrombosis in newborns, resulting in skin bruises that m ay become necrotic (purpura fulminans). Protein S de \201 ciency Autosomal dominant. This condition is clinically similar to prote in C de \201 ciency; less likely to cause thromboembolism in children. Antithrombin (III) de \201 ciency Very rare. Autosomal dominant. Associated with high thro mbotic risk, generally venous. Hyperhomocysteinanemia May be s to a genetic defect or vitam in B12 or folate de \201 ciency. Congenital homocystinuria is associated with thromboem- b olism, e.g. stroke, mental retardation, and, in later life, arteriosclerosis. Hyperlipidaemia Familial homozygous hypercholestrolemia can result in myocardial infarction in childhood, causing adult like atherosclerosis. 17_McClure_17.indd 644 11/14/2012 3:50:15 PM THROMBOPHILIA 645 Acquired causes Acquired thrombophilia is most commonly associated with: \200 \200 \200 \200 \200 \200 \200 s \200 Septicaemia; Use of central lines; Takayasu \200\231s arteritis; Kawasaki disease; PNH; Pol ycythaemia; SLE, anti-phopholipid antibody; to development of anti-protein S antibodies post-Varicella zoster virus (VZV) infection; can cause (as with congential de \201 ciency) necrotic skin bruises . Newborns, especially if preterm, are most at risk. In the newborn arterial or aortic thromb osis s to a UAC may lead to bowel infarction, NEC, buttock or leg infarction, renal arteria l thrombosis. Most common venous thrombosis involves the renal vein. Investigation of thrombophilia \200 \200 \200 FBC (polycythaemia or infection). ESR/CRP (infection or in \202 ammation). LFTs (protein C and S, and prothrombin are vitamin K-dependent factors). Standard coagulation screen. Thro mbophilia \200\230screen \200\231. Under guidance by your local laboratory, this usually i ncludes APC resistance, with FVL, prothrombin G20210A variant testing, as well as protein C , protein S, antithrombin III, and homocystine levels. \200 Treatment \200 Acute (LMW) heparin (or sometimes IV unfractionated heparin) and then warf arin, if prolonged anticoagulation required. In neonatal purpura fulminans secondary to hom ozygous protein C or S de \201 ciency, treat with FFP or protein C concentrate for 6 \200 \2238wks until skin lesions have healed. Recurrent thrombosis: treatment depends on severit y, presentation, coagulation defect, and risk factors. Long-term anticoagulation with warfa rin may be appropriate (aim for INR of 3 \200\2234). Major vessel or catheter-related throm bosis: can be treated with \201 brinolytic agents, e.g. tissue plasminogen activator (TPA ), urokinase. Prophylaxis: give SC heparin during surgery or trauma in patients with establ ished prothrombotic defects and a positive personal history. Alternatively, antithrombin II I or protein C concentrate may be given if relevant. venousthrombosis: anticoagulate with SC low molecular weight 17_McClure_17.indd 645 11/14/2012 3:50:15 PM CHAPTER 17 Hematology 646 Blood transfusion Red blood cell transfusion Whole blood is not usually available, but is u seful when severe hypovolae- mia s to acute blood loss occurs. Otherwise, packed RBC are pr eferred. Small volume QUAD or Octapus packs are preferred for newborns as multiple aliquots can be dispensed as required from a single unit to reduce donor exposure (within a 28-day period). Formula for calculation of transfusion volume: Packed cells volume (mL) = desired rise in H b (g/dL) \227 weight (kg) \227 4 Platelet transfusion \200 Indicated for bleeding due to signi \201 cant thrombocytopenia or as prophylaxis in patien ts receiving myelosuppressive chemotherapy or with bone marrow failure when platelet count <10 \227 109/L. Platelet concentrate volume: \211 15kg, single apheresis unit/standard \200\230pool \200\231 of 4U. if child \200\231s weight <15kg give 10 \200\22320mL/kg; if Albumin \200 \200 Rarely used in modern pediatrics; 0.9% saline is usually now preferred. 20% albumin is indi cated to correct signi \201 cant hypoproteinaemia. Fresh frozen plasma Indications \200 \200 \200 DIC or acute blood loss. Emergency therapy of non-speci \201 c coagulation failure. To cor rect coagulation de \201 ciencies where no speci \201 c concentrate available. Volume = 10 \200\22320mL/kg (as guided by coagulation results) Cryoprecipitate \200 Rich in clotting factors VIII, XIII, \201 brinogen, and vWF. The main indication is to co rrect clotting defects induced by massive transfusion or DIC, especially if \201 brinogen <1.0g/L. Volume is: 1U/10kg (= 5mL/kg), or if child weighs 15 \200\22330kg give 5U (1U = 1 bag), over 30kg give 10U. Intravenous immunoglobulin Normal immunoglobulin is predominantly IgG and is obtained from the pooled serum of >1000 blood donations. Indications include: \200 \200 Hypogammaglobinaemia, e.g. X-linked hypogammaglobinaemia; Rarely, prophylaxis following inf ectious contact in immunocompromised, e.g. CMV, hepatitis A, measles, chicken pox; Immunomo dulation, e.g. ITP, neonatal alloimmune thrombocytopenia; Speci \201 c IgGs also available , e.g. ZIG for prevention of potentially life-threatening chickenpox in immunocompromised c hildren with no immunity. \200 17_McClure_17.indd 646 11/14/2012 3:50:15 PM BLOOD TRANSFUSION 647 Special requirements CMV negative blood components These are required for: \200 \200 \200 Intrauterine transfusion. Neonates and infants up to 1yr. CMV seronegative recipients of al logeneic BMT ( introduction of universal leucocyte depletion of red cell products this is p robably now unnecessary!). (cid:1) since the Irradiated blood products (inactivates T lymphocytes) These are required in: \200 \200 Intrauterine and neonatal exchange transfusions. Patients undergoing stem cell harvest for autografts (a week before until 3 \200\2236mths afterwards). Patients undergoing allogenic haemopoietic stem cell transplant (a week before and inde \201 nitely thereafter). Patient s with suspected and con \201 rmed Hodgkin lymphoma. Patients receiving purine analogs suc h as \202 udarabine, clofaribine, etc., inde \201 nitely. DiGeorge syndrome and other co ngenital T cell immunode \201 ciencies. Granulocyte transfusion. New indications are for p atients being treated for aplastic anemia with ALG and cyclosporine. \200 17_McClure_17.indd 647 11/14/2012 3:50:15 PM CHAPTER 17 Hematology 648 Blood transfusion reactions Major blood incompatibability An example is group A blood being transfused to a child with blood group O. Signs and symptoms of intravascular haemolysis m ay appear after only 5 \200\22310mL blood infusion with: \200 Pain at venepuncture site. \200 Agitation, \202 ushing, chest/abdominal/ \202 ank pain. \200 Fever, hypotension , haemoglobinaemia, haemoglobinuria, renal failure. Treatment \200 \200 \200 \200 \200 Stop transfusion immediately. Keep IV line open with saline. Monitor vital signs and urine output. Recheck patient and blood unit ID number. Give supportive care. Watch for hypotensi on, respiratory and renal failure. Inform the blood bank. Minor incompatibilities (i.e. group O+ blood given to an O- child) will not cause intravasc ular haemolysis but will cause sensitization and problems for future transfusions, in parti cular in females during later pregnancies. Bacterial infected blood products Most serious reactions are seen with platelets (kept at r oom temperature where bacteria can multiply and produce toxins). At its most severe there i s sudden hypotension, fever, rigors, systemic collapse, and DIC. Treatment Give IV broad-spectrum antibiotics (unlikely to help as the reaction is toxin med iated but will stop the development of further sepsis), inotropic support, and intensive ca re support as required. Delayed reaction after a platelet transfusion, i.e. not immediate, but within a few hours, must raise the suspicion of an infected product, requiring immediat e blood cultures, broad spectrum antibiotics. Alert the blood bank immediately. Transfusion-related acute lung injury (TRALI) Rapid onset cough and shortness of breath occ ur (may mimic \202 uid over- load). TRALI is caused by donor antibodies to recipient leuc ocytes. There is an ARDS-like picture, with bilateral in \201 ltrates on CXR. Respiratory sup- port is required. Febrile, non-haemolytic reactions These are due to recipient anti-HLA or granulocyte antibo dies, or cytokines in infused blood product. Reactions are secondary to red cell al- loimmu nization. Less frequent since the universal leucodepletion of blood products started in the UK in 1999. Fever and rigors occur within few hours of starting or completing the transfus ion. To treat, slow transfusion rate and give paracetamol and antihistamines. 17_McClure_17.indd 648 11/14/2012 3:50:15 PM BLOOD TRANSFUSION REACTIONS 649 Circulatory overload Results in pulmonary oedema, dyspnoea, headache, venous distension, si gns of cardiac failure. To treat slow transfusion rate and give IV fruse- mide. Transfusion-associated graft vs host disease (TaGVHD) This occurs in patients with impaired cellular immunity. Lymphocytes in donor unit \200 \230engraft \200\231 leading to rash, diarrhea, liver impairment, and bone marrow failure. There is no effective treatment. Prevention is by prior irra- diation of blood products (se e b p.647 for patients requiring irradiated blood products). Mortality is >90%. Transfusion safety UK rates of infection from blood products per transfused component: \200 \200 \200 \200 \200 Hepatitis B: Hepatitis C: HIV: Malaria: Bacterial infection: (up to 1 in 2000). Variant Cre utzfeldt-Jakob disease (CJD): UK up to 2010 in patients receiving non-leucocyte-depleted bl ood between 1996 \200\2231999). 1 in 1.5 million. 1 in 100 million. 1 in 5 million. 0.5 in 1 million (US data only). 2 in 1 million for RBC, higher for platelet transfusion unknown (4 cases reported in 17_McClure_17.indd 649 11/14/2012 3:50:15 PM This page intentionally left blank 651 Chapter 18 Oncology Epidemiology of childhood cancer 652 Clinical assessment: history 653 Clinical examination 654 Key investigations 655 Acute lymphoblastic leukemia 656 Acute myeloid leukemia 658 Chro nic myeloid leukemia (adult type) 659 Juvenile myelomonocytic leukemia 659 Lymphoma 660 Cen tral nervous system tumors (1) 662 Central nervous system tumors (2) 664 Neuroblastoma 666 Wilms \200\231 tumor (nephroblastoma) 668 Other renal tumors in childhood 669 Bone tumors 6 70 Rhabdomyosarcoma 672 Germ cell tumors 673 Primary liver tumors 674 Other rare tumors 675 Langerhans cell histiocytosis 676 Haemophagocytic lymphohistiocytosis 677 Chemotherapy 678 Stem cell transplant 680 Radiotherapy 681 Surgery 681 Acute care 682 Acute care: biochemis try 684 Acute care: other 685 Urgent care 687 Principles of follow-up 688 Palliative care 6 90 18_McClure_18.indd 651 11/14/2012 3:51:01 PM CHAPTER 18 Oncology 652 Epidemiology of childhood cancer \200 \200 Childhood cancer (age <16yrs) accounts for around 0.5% of all cancer. Approximately 1400 ne w cases of childhood cancer occur in the UK every year. Childhood cancer is the commonest c ause of death in children aged 5 \200\2239yrs and 2nd only to accidents in teenagers aged 1 0 \200\22319yrs. The annual incidence in children under 15yrs of age is 1 in 10,000. One in 600 children will have cancer at some time during childhood. \200 Causes of cancer in childhood Environmental factors do not appear to be clearly linked with childhood cancer. An inherited predisposition applies to a minority of tumors. The proportion of cases by diagnostic group (ages 0 \200\22314, UK, 1989 \200\22398) \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Leukaemias, 32%. Lymphoma, 10%. CNS tumors, 24%. Neuroblastoma, 7%. Wilms \200\231 tumor, 6 %. Bone tumors, 4%. Soft tissue sarcoma, 7%. Germ bell tumors, 3%. Retinoblastoma, 3%. Live r tumors, 1%. Others, 3%. 18_McClure_18.indd 652 11/14/2012 3:51:01 PM CLINICAL ASSESSMENT: HISTORY 653 Clinical assessment: history Include speci \201 c questions about: \200 Fevers, night sweats, anorexia, weight-loss, pallor, bruising and abnormal bleeding. Family history, including malignancy and inherited conditions. Also be aware that childhood malignancy may present with a variety of clinical features and so special attention should be paid to the following. Respiratory symptoms New episode of wheeze (usually monophonic and \201 xed) may be cause d by intrathoracic mass. Treatment with oral steroids, based on a presump- tive diagnosis o f asthma, may lead to partial response in symptoms and therefore delay the diagnosis of leu kemia or lymphoma involving medias- tinal lymphadenopathy compressing the airways. Bone and joint pain/swelling Persistent back pain should not be dismissed as innocent in ch ildren. It may re \202 ect bone pain of bone marrow expansion (leukemia or bone marrow met astases) or a spinal tumor. Abdominal mass May be: \200 \200 \200 Painless and isolated (e.g. Wilms \200\231 tumor, ovarian teratoma). Associated with genera l malaise (e.g. B-cell lymphoma, neuroblastoma). Pelvic (e.g. rhabdomyosarcoma). Raised intracranial pressure The most common presenting features of brain tumors are: \200 \200 \200 \200 \200 Headache (typically on waking). Vomiting. Ataxia. Papilloedema. Deteriorating conscious lev el. Growth and endocrine disturbances Midline CNS tumors may result in disturbance in the hypot halamic \200\223 pituitary hormone axes and present with: \200 \200 \200 \200 Poor feeding or failure to thrive (diencephalic syndrome). Polyuria and polydipsia (diabete s insipidus). Poor growth and short stature (growth hormone de \201 ciency). Hypoglycaemia (ACTH de \201 ciency). 18_McClure_18.indd 653 11/14/2012 3:51:01 PM CHAPTER 18 Oncology 654 Clinical examination Thorough general examination including: \200 \200 All lymph node stations: neck, axillae, inguinal regions. Skin: infection. Masses: measure dimensions of any mass and organomegaly. If leukemia/lymphoma suspected, assess testes for swelling and optic fundi. assess pallor, petechiae, bruising, mucosal bleeding, signs of \200 Speci \201 c diagnoses or concerns may be indicated by the following \201 ndings. Lymphadenopathy Malignancy accounts for a small proportion of cases of persistent lymphad- enopathy in children. Possible diagnoses include acute leukemia, non- Hodgkin \200\231s lym phoma, Hodgkin \200\231s disease, metastases from neuroblastoma or sarcoma. Features of enlarged lymph node that should raise concern \200 \200 \200 \200 \200 \200 Diameter >2cm Persistent or progressive enlargement Non-tender, rubbery, hard, or \201 xe d Supraclavicular or axillary position Associated with other features, e.g. pallor, letharg y Hepatosplenomegaly Unexplained mass \200\224at any site The following features should raise suspicion of malig nancy: \200 \200 \200 \200 Non-tender. Progressive enlargement. Diameter >2cm. Associated lymphadenopathy. Neurological signs The following should raise suspicion of a brain tumor: \200 \200 Cranial nerve de \201 cits from direct tumor involvement. False localizing signs: ICP). Ce rebellar signs (e.g. ataxia). Visual disturbances or abnormal eye movements: \201 eld and /or acuity defects (optic tract and suprasellar tumors); Parinaud \200\231s syndrome (paral ysis of upward gaze) suggests pineal tumor. Abnormalities of gait. Motor or sensory signs. Behavioral disturbances. Deteriorating school performance or neurodevelopmental milestones. Unexplained focal seizures. Increasing head size (infants). III and VI nerve palsies (mass effect from raised \200 \200 \200 \200 \200 \200 18_McClure_18.indd 654 11/14/2012 3:51:01 PM KEY INVESTIGATIONS 655 Key investigations The most common reason for referral to a specialist is the identi \201 cation of an abnormality on blood \201 lm. Pancytopenia Not all cell lines are equally affected, but the following problems occur as l eukemia or disseminated malignancy displaces normal bone marrow. \200 \200 \200 Pallor, lethargy (low Hb). Bruising and/or petechiae (low platelets). Unexplained fever, recurrent or persistent infection (low WBC). The following tests are used in diagnosis, staging, and assessment for prog- nosis, and as a baseline before starting treatment. Laboratory tests \200 FBC and \201 lm. \200 Coagulation studies. \200 Group and cro ss-match blood. \200 Electrolytes; renal, bone, and liver pro \201 le; urate; lactate de hydrogenase (LDH). CRP, ESR. Ferritin and neuron-speci \201 c enolase (if neuroblastoma li kely). Blood cultures. Thiopurine methyl transferase assay (in case of suspected acute lymp hoblastic leukemia (ALL)). Urine catecholamines (neuroblastoma, phaeochromocytoma). Lumbar puncture for cytospin, cell count, cytology. \200 \200 \200 \200 Imaging Sedation or general anesthetic may be needed in young children when performing thes e procedures. The choice of imaging depends on the likely diagnosis, and may include: \200 \200 \200 \200 \200 \200 CXR. CT scan chest and/or abdomen. MRI scan (better than CT for soft tissue swellings and b rain). Bone marrow aspirate and/or trephine. Technetium ( Meta-iodo-benzylguanidine (MIBG) scan (neuroblastoma, phaeochromocytoma). 99Tc) bone scan. Other investigations These depend on the treatment being planned and may include: \200 gl omerular \201 ltration rate (nephrotoxic chemotherapy, EDTA: nephrectomy). Audiology assessment (platinum chemotherapy, radiotherapy). Echocardiog ram (anthracycline, pulmonary radiotherapy). Lung function (bleomycin, pulmonary radiothera py). Pituitary function (suprasellar tumors, CNS surgery or radiotherapy). \200 \200 \200 18_McClure_18.indd 655 11/14/2012 3:51:01 PM CHAPTER 18 Oncology 656 Acute lymphoblastic leukemia This is the most common malignancy in childhood. It arises fro m malig- nant proliferation of \200\230pre-B \200\231 (common ALL) or T-cell lymphoid prec ursors. The cause is unknown, but in a minority it is associated with chromoso- mal aberrat ions. Possible links to patterns of childhood infection acting as a trigger have been hypot hesized. \200 \200 ALL accounts for 25% of all childhood malignancies. Commonly presents in young children age d 2 \200\2236yrs. Presentation Typically with a short history (days or weeks), and with symptoms and signs re \202 ecting pancytopenia, bone marrow expansion, and lymphadenop- athy. Includes petechia e, bruising, pallor, tiredness, bone/joint pain/swell- ing, limp, lymphadenopathy, airway o bstruction, and pleural effusion. Speci \201 c diagnostic tests \200 \200 \200 \200 Bone CSF Clinical CXR marrow: morphology; immunophenotype; cytogenetics. for cytospin (CNS rarely involved at \201 rst diagnosis). examination of testes in boys for inappropriate swelling. for mediastinal mass. Outline of \200\230standard \200\231 treatment Induction (4wks) \200 \200 \200 Steroids (dexamethasone or prednisolone) throughout induction Weekly IV vincristine IM L-as paraginase (e.g. 9 doses in 3wks or 2 doses of pegylated asparaginase) IV daunorubicin (2 \200\2234 doses, in intermediate and high risk cases) Intrathecal (IT) methotrexate (day 18 ) \200 Note Tumor lysis syndrome (b p.684) is a signi \201 cant risk Consolidation CNS-dir ected therapy \200 Low risk cases: oral mercaptopurine. Higher risk cases: CNS-radiotherapy only for CNS +ve c ases 4-weekly doses of IT methotrexate and continuous \200 add IV cyclophosphamide, cytarabine. Maintenance Continuation treatment for at least 2yrs (3yrs for boys) \200 Daily 6-mercaptopurine (6MP), weekly oral methotrexate (doses titrated according to blood c ount) 4-weekly vincristine IV bolus and 5-day pulses of oral dexamethasone 12-weekly IT met hotrexate \200 Intensive blocks of chemotherapy One or two blocks of 8wks duration, interrupting 1st year of mainte- nance. Combinations of oral steroid, vincristine, doxorubicin, cyclophos- phamid e, cytarabine, and L-asparaginase 18_McClure_18.indd 656 11/14/2012 3:51:01 PM ACUTE LYMPHOBLASTIC leukemia 657 Prognosis Overall survival is approximately 80% with current treatment. Adverse prognostic factors include: \200 \200 \200 \200 Male gender. Age <2yrs or >10yrs. High WCC at diagnosis. Unfavorable cytogenetics: gene rea rrangements (e.g. t(4;11) in infants); AML1 ampli \201 cation; Poor response to induction and failure to remit by day 28. High level of minimal residual disease (MRD) at 28 days. Philadelphia chromosome \200\224t(9;22); MLL \200 Mature B-cell ALL (Burkitt \200\231s type, L3 morphology) Once considered a high-risk group , outlook is similar to that in stand- ard risk ALL now that patients are treated with inte nsive chemotherapy according to strategy for B-cell non-Hodgkins lymphoma (see b p.660). Relapsed ALL Extramedullary relapse (mainly CNS, testes) may present without bone marrow di sease. Treatment is strati \201 ed according to risk factors, which include: \200 \200 \200 Time from \201 rst diagnosis (risk reduces with time). Extramedullary relapse (lower risk , particularly if isolated). Minimal residual disease (MRD) status after re-induction ( \200\223ve status reduces risk). Treatment \200 \200 \200 \200 Intensive re-induction and consolidation for all risk groups. Low risk: High risk: Intermed iate risk: based on minimal residual disease and/or availability of matched donor. Radiothe rapy for extramedullary disease: receiving total body irradiation (TBI) for BMT. 2yrs of continuing conventional chemotherapy. BMT allograft. the role of BMT in this group is unclear; it may be given as a boost for those Prognosis Long-term survival varies: 10 \200\22390% depending on risk (e.g. 90% in those wi th isolated extramedullary relapse more than 2yrs off treatment). 18_McClure_18.indd 657 11/14/2012 3:51:01 PM CHAPTER 18 Oncology 658 Acute myeloid leukemia Acute myeloid leukemia (AML) accounts for 75% of all childhood malig - nancies and <20% of all acute leukaemias. It is also known as acute non- lymphoblastic le ukemia (ANLL). AML results from malignant prolifera- tion of myeloid cell precursors. AML c an be subdivided morphologically using the French \200\223American \200\223British (FAB) cl assi \201 cation system: \200 \200 \200 \200 \200 \200 \200 M1: M2: M3: M4: M5: M6: M7: AML without maturation. AML with maturation. acute promyelocytic leukemia (PML). acute myel omonocytic leukemia with eosinophilia (M4Eo). acute monocytic/monoblastic leukemia. acute e rythroleukaemia. acute megakaryocytic leukemia. Presentation \200 \200 \200 \200 \200 b p.656).