Leukaemia and lymphoma in children

Overview

Cancer is uncommon in children, but leukaemia is the commonest childhood cancer, followed by brain tumours and then lymphomas. Acute lymphoblastic leukaemia (ALL) is now one of the great success stories of medicine: most children are cured with modern risk-directed chemotherapy. Every doctor must recognise the presentation early, because the first signs (pallor, fever, bruising, limp) are easy to dismiss.

Leukaemia: types and epidemiology

Pathogenesis

• Leukaemia is a clonal (monoclonal) proliferation of malignant blast cells that have lost the ability to mature.
• Blasts fill the marrow and suppress normal production (anaemia, neutropenia, thrombocytopenia) and infiltrate other organs.
• Chromosomal translocations create new fusion genes; for example t(9;22) joins BCR and ABL in CML and some ALL.
• ALL arises in a partly differentiated lymphoid cell; in AML the hit may be in a very early or a more committed myeloid cell.

Risk factors

• Newborns with Down syndrome may have transient myeloproliferative disorder (high white count with blasts) that settles on its own, but about 30% later develop true leukaemia.

Clinical features of acute leukaemia

From marrow failure

• Anaemia: pallor, fatigue, listlessness.
• Neutropenia: fever and infections.
• Thrombocytopenia: petechiae, bruising, epistaxis, gum bleeding.

From infiltration

• Bone and joint pain, often severe and waking the child at night; a limp or refusal to walk. It can mimic juvenile arthritis.
• Lymphadenopathy and hepatosplenomegaly.
• Testes: painless enlargement of one or both.
• CNS: headache, vomiting, seizures, cranial nerve palsies, papilloedema.
• Anterior mediastinal mass (thymus or nodes), typical of T-cell ALL in adolescent boys with a high white count: cough, breathlessness, stridor and superior vena cava obstruction.
• AML extras: gum infiltration (monocytic types), skin nodules ("blueberry muffin" lesions in infants), chloromas (granulocytic sarcomas), and DIC (especially acute promyelocytic leukaemia).
• General: anorexia, weight loss, low-grade fever, malaise.

Investigations

Blood count and film

• Anaemia in most (only about a quarter have Hb below 6 g/dL).
• Thrombocytopenia in most (but about a quarter have platelets above 100,000/mm³).
• White count may be low, normal or high: about half under 10,000/mm³ and roughly 15-20% above 50,000/mm³.
• Blasts on the peripheral film suggest the diagnosis.

Bone marrow (confirms the diagnosis)

• Aspiration (and trephine biopsy if the aspirate is dry): marrow is usually packed with blasts.
• Normal marrow has under 5% blasts; ALL is diagnosed with more than 25% lymphoblasts (Akbar).
• Flow cytometry (immunophenotype): B-precursor or T-cell ALL; myeloperoxidase positivity shows myeloid origin.
• Cytogenetics and molecular tests (FISH, PCR) for prognostic translocations.

Other essential tests

• Lumbar puncture at diagnosis: CNS leukaemia = CSF white cells above 5/µL with blasts.
• Chest X-ray: mediastinal mass or tracheal compression.
• Urea, creatinine, electrolytes, calcium, phosphate, uric acid, LDH (LDH is often raised).
• Liver function, blood group, infection screen.

Differential diagnosis

• Infectious mononucleosis (EBV): the commonest mimic (fever, nodes, spleen, atypical lymphocytes); also CMV, pertussis and TB (leukaemoid reactions).
• Aplastic anaemia: pancytopenia without organomegaly; hypocellular marrow without blasts.
• ITP: isolated low platelets, well child, no organomegaly.
• Juvenile idiopathic arthritis: bone pain and fever (leukaemic bone pain is often out of proportion, with low counts).
• Other small round cell tumours infiltrating marrow: neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, retinoblastoma.

Management of ALL

Treatment is risk-directed: children with higher-risk features receive more intensive therapy.

• Remission = under 5% marrow blasts with recovering neutrophils and platelets; achieved in over 95% of children with ALL.
• CNS therapy matters because the CNS is a sanctuary site that systemic drugs reach poorly; it cuts CNS relapse to under 5%.
• Relapse: commonest in the marrow (most serious, especially during or soon after treatment), also CNS and testis (painless swelling). Marrow relapse needs intensive chemotherapy and allogeneic stem cell transplant.

Management of AML

• Vincristine, steroids and asparaginase do not work; AML needs several cycles of very intensive myelosuppressive chemotherapy (cytarabine, daunorubicin, etoposide).
• Stem cell transplant in first remission if there is a matched sibling (except in favourable types and Down syndrome).
• Acute promyelocytic leukaemia (t(15;17)) often presents with DIC.

Supportive care

• Packed red cells and platelets as needed.
• Fever with neutropenia (neutrophils under 500/mm³) is an emergency: cultures and immediate broad-spectrum IV antibiotics.
• Co-trimoxazole prophylaxis against Pneumocystis jirovecii pneumonia.
• No live vaccines during treatment; avoid contact with measles and chickenpox; hepatitis B vaccine may be given.
• Nutrition, pain relief and psychological support for the child and family.

Tumour lysis syndrome

• Rapid killing of a large, fast-growing tumour (ALL with high white count, Burkitt and other high-grade NHL) releases cell contents.
• Usually within 48-72 hours of starting treatment, but can occur before.

Prevention and treatment: identify high-risk patients; vigorous IV hydration (up to about 3 L/m²/day) starting before chemotherapy; allopurinol; urinary alkalinisation in some protocols; monitor electrolytes, urate and creatinine several times a day; treat hyperkalaemia (glucose and insulin, calcium gluconate); dialysis for persistent hyperkalaemia, hyperphosphataemia, fluid overload or uraemia.

Prognosis of ALL

• Overall cure of ALL is about 80% (Nelson); about 90% achieve long remission (Akbar).
• AML: cure about 50%.
• Late effects of treatment: neurocognitive problems (after cranial radiation and methotrexate), short stature, obesity, anthracycline cardiomyopathy, infertility, second cancers, psychosocial difficulties.

Lymphoma

Lymphomas are the third commonest childhood cancer, after leukaemia and brain tumours. Epstein-Barr virus is thought to play a part in both main types.

Hodgkin lymphoma

• Seen in older children and adolescents; rare under 5 years. Incidence is bimodal (young adults and over 50).
• Reed-Sternberg cells (large cells with multilobed nuclei, derived from B cells) in a background of reactive lymphocytes, plasma cells and eosinophils are the pathological hallmark.
• Presentation: painless, firm lymphadenopathy, usually cervical or supraclavicular; mediastinal nodes are common and can cause cough or breathlessness; hepatosplenomegaly is unusual; disease below the diaphragm alone is rare.
• B symptoms (prognostic): unexplained fever above 38°C, drenching night sweats, weight loss of more than 10% in 6 months.
• Histological types: nodular sclerosis (commonest, about 50-60%), mixed cellularity (about 30%), lymphocyte predominant (10-15%), lymphocyte depleted (under 5%).
• Diagnosis: excision biopsy of a node; CBC, ESR, ferritin, LDH, liver and renal tests; chest X-ray (mediastinal mass) and CT of neck, chest and abdomen; PET; bone marrow in advanced disease or with B symptoms.
• Staging (Ann Arbor): I, one node region; II, two or more regions on the same side of the diaphragm; III, regions on both sides of the diaphragm; IV, spread to extranodal organs such as marrow or liver; suffix B if B symptoms are present.
• Treatment: combination chemotherapy (ABVD- or COPP-type regimens) plus low-dose involved-field radiotherapy for selected patients.
• Prognosis: about 90% 5-year survival overall; late effects include second cancers, thyroid problems, growth problems and infertility.

Non-Hodgkin lymphoma (NHL)

• About 60% of childhood lymphomas (Akbar); commoner in boys and with immunodeficiency or after transplant.
• Childhood NHL is diffuse, high-grade and fast-growing, often extranodal, with short symptom duration; it behaves like leukaemia and spreads to marrow and CNS.

• If the marrow has 25% or more blasts, the disease is called leukaemia (B-cell or T-cell ALL).
• Diagnosis: tissue biopsy or pleural/ascitic fluid cytology; CBC, uric acid, LDH, electrolytes, calcium, phosphate, renal function; chest X-ray and CT; marrow and CSF.
• Treatment: intensive systemic chemotherapy for all, with CNS prophylaxis; radiotherapy only for life-threatening obstruction not responding to drugs; prevent tumour lysis.
• Prognosis: localised disease 90-100% survival; advanced disease about 70-95%.

Differential diagnosis of lymphadenopathy

Infectious mononucleosis, tuberculous lymphadenitis, bacterial lymphadenitis, cat-scratch disease, toxoplasmosis, leukaemia, nasopharyngeal carcinoma, rhabdomyosarcoma, branchial and thyroglossal cysts.

Quick revision

• Leukaemia is the commonest childhood cancer; ALL 75%, peak 2-5 years.
• Down, Fanconi, Bloom, ataxia-telangiectasia, NF1; radiation, benzene.
• Fever, pallor, bleeding, bone pain, nodes, liver and spleen, testes, CNS.
• Marrow: blasts above 25% (ALL); LP and chest X-ray at diagnosis.
• ALL treatment: induction, CNS therapy/consolidation, intensification, 2-3 years of maintenance.
• Tumour lysis: high urate, K, phosphate; low Ca; AKI; hydrate and give allopurinol.
• Good prognosis: age 1-10, WBC under 50,000, t(12;21), fast response; ALL cure about 80%.
• AML: gums, skin, chloroma, DIC (APL); cure about 50%.
• Hodgkin: painless cervical nodes, mediastinum, B symptoms, Reed-Sternberg cells.
• NHL: Burkitt (B cell, abdomen or jaw, t(8;14)); lymphoblastic (T cell, mediastinum).

Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).

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