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PA18.1-2 | Benign Leukocytosis & Leukemias — PBL Case

CLINICAL SETTING

Arjun is a 7-year-old boy from a semi-urban town in Maharashtra, brought to the district hospital by his mother after three weeks of refusing to walk due to knee and leg pain, progressive pallor, and high-grade fever unresponsive to paracetamol. She notes that he has been unusually quiet — he stopped playing cricket with friends two weeks ago, complaining that his legs hurt when he ran. He has been eating poorly and has lost 2 kg over the past month. One week ago, he developed swollen glands in the neck that the local doctor treated as bacterial tonsillitis with amoxicillin, but the swellings did not reduce. On examination: pale +++ (conjunctival pallor, pale palms), temperature 39.1°C, pulse 124/min. Bilateral non-tender cervical and axillary lymph nodes (2–3 cm each). Liver 4 cm below the right costal margin; spleen 5 cm below the left costal margin. Sternum tender on direct pressure. No petechiae on the skin today. CBC: Hb 6.8 g/dL (normocytic normochromic), WBC 68,000/µL (blasts 72%, neutrophils 14%, lymphocytes 12%, monocytes 2%), platelets 28,000/µL. Peripheral smear: numerous large blast cells with scant cytoplasm, round to convoluted nuclei, and fine chromatin; no Auer rods visualised. A chest X-ray ordered by the receiving doctor reveals a superior mediastinal widening.

Trigger 1: Initial Presentation

The paediatric registrar reviews Arjun: a 7-year-old with three weeks of bone pain, pallor, fever, generalised lymphadenopathy, and hepatosplenomegaly. CBC shows pancytopenia dominated by a blast count of 72% on the peripheral smear (WBC 68,000/µL). Peripheral smear blasts are large with scant cytoplasm, no Auer rods. A chest X-ray shows superior mediastinal widening. The registrar recognises that this constellation requires urgent attention.

DISCUSSION POINTS

  • Arjun has blasts on the peripheral smear and more than 20% blasts — what is the diagnostic significance of the ≥20% blast threshold, and how does this establish 'acute' versus 'chronic' leukaemia?
  • The clinical triad in acute leukaemia arises from marrow failure — explain how pancytopenia (anaemia, neutropenia, thrombocytopenia) produces Arjun's specific symptoms of pallor, fever, and absence of petechiae today despite low platelets.
  • Sternal tenderness on direct pressure — what is the pathophysiological basis of this sign in acute leukaemia, and why is it diagnostically valuable in a child presenting with pallor and bone pain?
  • The mediastinal widening on chest X-ray in a child with acute leukaemia — which leukaemia subtype is most strongly associated with a mediastinal mass, and what cell lineage does this implicate?
Click to reveal Trigger 2: Investigations (discuss previous trigger first!)

Trigger 2: Investigations

A bone marrow aspirate and trephine biopsy are performed. The marrow is hypercellular with 82% lymphoblasts replacing normal haematopoiesis. Cytochemistry: Myeloperoxidase (MPO) negative; Sudan black B negative; TdT (terminal deoxynucleotidyl transferase) positive. Flow cytometry immunophenotyping: CD2+, CD3+, CD5+, CD7+, CD34+; CD19−, CD10−, CD20−. Cytogenetics: hyperdiploidy not detected; no t(12;21); no Philadelphia chromosome; no t(4;11). The morphology, cytochemistry, and immunophenotype are reviewed: the blasts are MPO-negative (ruling out AML), TdT-positive (confirming immaturity), and the T-cell markers (CD3, CD7) confirm T-ALL. The mediastinal mass on CT represents a thymic/mediastinal T-cell lymphoblastic mass with peripheral blood spill.

DISCUSSION POINTS

  • Explain why MPO negativity and TdT positivity together are used to distinguish ALL from AML — what do each of these markers indicate about the blast cell's lineage and maturation stage?
  • Compare B-ALL and T-ALL: which is more common in childhood, which is more common in adolescents/adults, and what is the significance of the mediastinal mass in Arjun's case for the T-cell lineage origin?
  • Cytogenetics significantly affects prognosis in ALL — the t(12;21) ETV6-RUNX1 translocation confers a favourable prognosis in B-ALL, while the Philadelphia chromosome [t(9;22)] in ALL (Ph+ ALL) is high risk. How does knowing Arjun has T-ALL without these changes affect prognostic categorisation?
  • A WBC of 68,000/µL with 72% blasts puts Arjun at risk for tumour lysis syndrome — what metabolic derangements constitute TLS, why does it occur, and what targeted intervention is started before chemotherapy to prevent it?
Click to reveal Trigger 3: Diagnosis & Management (discuss previous trigger first!)

Trigger 3: Diagnosis & Management

Arjun is diagnosed with T-cell Acute Lymphoblastic Leukaemia (T-ALL) with mediastinal involvement. He is transferred to a regional paediatric oncology centre. The oncology team explains the diagnosis to the family, obtains consent for multi-agent induction chemotherapy (VPDL protocol: vincristine, prednisolone, daunorubicin, L-asparaginase), and initiates allopurinol, aggressive IV hydration, and urine alkalinisation before the first dose. Prophylactic intrathecal methotrexate is planned for CNS sanctuary disease prevention. Daily CBC monitoring reveals WBC falling from 68,000 to 3,200/µL over 7 days — consistent with response. Remission is defined as <5% blasts in the bone marrow on day 28 assessment.

DISCUSSION POINTS

  • Distinguish the clinical and haematologic features of acute leukaemia from a reactive leucocytosis and from a leukaemoid reaction — what specific CBC and smear findings distinguish these in Arjun's context?
  • Compare the presenting features, immunophenotype, and cytogenetics of ALL versus AML in a tabulated format — at what ages does each predominate, and what is the significance of the presence of Auer rods specifically?
  • The pathogenesis of acute leukaemia involves a 'two-hit' model — explain how a Type I mutation (e.g., FLT3-ITD causing proliferation) and a Type II mutation (e.g., TEL-AML1 blocking differentiation) cooperate in leukaemogenesis, and how this model informs targeted therapy.
  • Arjun's mother asks the doctor if the infection her son had last month 'caused' the leukaemia — how would you counsel her about the established aetiological factors (radiation, chemicals, chromosomal syndromes, viruses) and the concept of a somatic mutation origin?

Group Task Assignments

Group 1: Reactive leucocytosis vs leukaemia — a classification exercise

  • Build a structured table comparing neutrophilia, lymphocytosis, leukaemoid reaction, and leukoerythroblastic reaction: define each, list two common causes, and state one key peripheral smear feature that distinguishes each.
  • Apply the LAP (leukocyte alkaline phosphatase) score concept: explain why a leukaemoid reaction has a high LAP score but CML has a low LAP score, and how this test helps distinguish the two.

Competencies: PA18.1

Group 2: Acute leukaemia — AML vs ALL

  • Draw a comparison table for AML vs ALL covering: cell of origin, peak age, key cytogenetic/molecular markers, specific morphological hallmark (Auer rods), cytochemistry (MPO, TdT, Sudan black), immunophenotype markers, and one bad-prognosis and one good-prognosis genetic subtype.
  • Describe the peripheral blood and bone marrow findings in acute leukaemia: what does the smear look like, what is the blast threshold, and what does a hypercellular marrow full of blasts indicate?

Competencies: PA18.2

Group 3: Chronic leukaemias — CML and CLL

  • Create a side-by-side comparison of CML and CLL: molecular driver (BCR-ABL1 vs no single mutation), age group, blood film appearance (full myeloid spectrum + basophilia vs mature small lymphocytes + smudge cells), organomegaly pattern, and targeted treatment principle.
  • Explain the Philadelphia chromosome t(9;22): what genes fuse, what protein is produced, and why imatinib (a tyrosine kinase inhibitor) is a rational treatment that targets this specific molecular abnormality.

Competencies: PA18.2

Group 4: Leukaemia aetiology and pathogenesis

  • Enumerate the established aetiological risk factors for leukaemia (ionising radiation, benzene, alkylating agents, chromosomal instability syndromes like Down syndrome and Fanconi anaemia, HTLV-1) with one clinical example for each.
  • Explain the concept of maturation arrest in acute leukaemia pathogenesis: how does a somatic mutation that blocks differentiation while maintaining proliferative capacity lead to marrow failure and circulating blasts?

Competencies: PA18.2

Group 5: Clinical integration — leukaemia diagnostic algorithm

  • Construct a stepwise diagnostic algorithm for a child presenting with pancytopenia and blasts on the peripheral smear: starting from 'suspected acute leukaemia', progressing through bone marrow examination, cytochemistry (MPO vs TdT), immunophenotyping (CD markers), and cytogenetics to reach a specific diagnosis and risk category.
  • Apply your algorithm to three brief vignettes: (a) a 5-year-old with t(12;21), B-ALL markers, no mediastinal mass; (b) a 15-year-old with a mediastinal mass and T-cell markers; (c) a 65-year-old with Auer rods and MPO-positive blasts.

Competencies: PA18.1, PA18.2

Learning Issues

Research these questions and bring your findings to the discussion.

  1. [PA18.1] What are the causes of neutrophilia, neutropenia, lymphocytosis, eosinophilia, and monocytosis, what is a leukaemoid reaction and how is it distinguished from CML using the LAP score, and what are the peripheral smear features of infectious mononucleosis including the nature and significance of atypical lymphocytes?
  2. [PA18.2] What is the etiology, pathogenesis (maturation arrest, two-hit model, chromosomal translocations), classification (AML vs ALL, CML vs CLL), clinical features (marrow failure triad, organ infiltration), and haematologic features (blast threshold, Auer rods, cytochemistry markers, immunophenotype, cytogenetics) of acute and chronic leukaemias?