Haematology. Barbara J. Bain
bodies (top), rare acanthocytes (top right), target cells (bottom left), giant platelets (bottom right) and thrombocytosis. An unusual feature was the presence of cells with haemoglobin condensed at the two poles of the cell and of irregularly contracted cells including hemighosts (top right and bottom left). An even more unusual feature was the presence of Plasmodium falciparum gametocytes (bottom right) and trophozoites (top). HPLC showed absent haemoglobin A, haemoglobin S 86.5% and haemoglobin F 5.1%.
Sickle cell trait protects from falciparum malaria but the converse is true of sickle cell anaemia, in which malaria can be life‐threatening. Opportunistic detection of malaria parasites in a patient in whom the diagnosis has not been suspected clinically can be life‐saving. Another warning sign in this patient is the presence of irregularly contracted cells and hemighosts. This observation correlates with the presence of hypoxia (Siow et al. 2017).
Reference
1 Siow W, Matthey F and Bain BJ (2017) The significance of irregularly contracted cells and hemighosts in sickle cell disease. Am J Hematol, 92, 966–967.
MCQ
1 Causes of worsening anaemia that would be likely in a 30‐year‐old African or Afro‐Caribbean woman with sickle cell anaemia include:Folic acid deficiencyHaemolytic crisisParvovirus B19 infectionSplenic infarctionSplenic sequestrationFor answers and discussion, see page 206.
17 Acute myeloid leukaemia with t(8;21)(q22;q22.1)
A 53‐year‐old woman was referred for investigation after presenting to her GP with a recent history of lethargy, myalgia, fever and headache. Her FBC showed Hb 100 g/l, WBC 3.4 × 109/l, neutrophils 0.5 × 109/l and platelets 39 × 109/l. The blood film showed small numbers of myeloblasts with some containing Auer rods. The bone marrow aspirate showed a prominent myeloblast population (approximately 40% of nucleated cells) with cytoplasmic granules (all images ×100 objective) with some showing Auer rods (top centre, top right, bottom left, bottom right). There was myeloid maturation to neutrophils with some cells showing hypogranularity (myelocytes, top left and neutrophils, bottom left, bottom right) but significantly, the nuclear morphology of maturing cells was also abnormal. Note the abnormal neutrophil segmentation (top centre, bottom right) and pseudo‐Pelger–Huët anomaly (bottom left) including complete failure of segmentation resulting in a round nucleus (bottom centre). This subtype of AML can often be predicted on the basis of the marked granulocyte dysplasia, particularly the abnormalities in nuclear morphology in the maturing myeloid cells.
The blast cells had a CD34+, CD117+, MPO+, CD13+, CD33+, CD15+, CD19+ immunophenotype. Cytoplasmic CD3 and CD79a were not expressed. Note the CD117/CD15 co‐expression; this indicates a myeloid maturation defect as CD15 is normally only acquired by maturing myeloid cells (neutrophil or monocyte lineage) when CD117 is lost. This feature can be useful in tracking minimal (or measurable) residual disease using flow cytometry as it is not seen in normal marrow cells. The karyotype was 46,XX,t(8;21)(q22;q22.1),del(9)(q13q22) indicating a RUNX1‐RUNX1T1 rearrangement and a favourable prognosis. Additional chromosomal changes, especially deletion of the long arm of chromosome 9, are common in this entity and this does not influence prognosis. The morphological features described here are typical of AML with this recurrent cytogenetic abnormality. The patient was treated with four cycles of chemotherapy and remains in remission 5 years later.
MCQ
1 Acute myeloid leukaemia with t(8;21)(q22;q22.1); RUNX1‐RUNX1T1:Can be diagnosed despite blast cells being less than 20% in blood and bone marrowMay have an increase in bone marrow eosinophils and precursorsOften shows trilineage dysplasiaShould be classified as mixed phenotype acute leukaemia when there is expression of CD19, CD79a and PAX5Shows an association with systemic mastocytosis with a KIT D816V mutationFor answers and discussion, see page 206.
18 Chronic neutrophilic leukaemia
A 72‐year‐old man was referred for assessment of chronic asymptomatic neutrophilia. The initial blood tests had been triggered by a clinical diagnosis of gout. He had shown a chronic unexplained persistent neutrophilia and the most recent full blood count showed Hb 130 g/l, WBC 115 × 109/l, neutrophils 92 × 109/l and platelets 132 × 109/l. The blood film showed neutrophilia with minimal dysplasia, minimal left shift and no excess of blast cells. The neutrophils showed normal or increased granulation and some were vacuolated (all images ×100 objective). A bone marrow aspirate showed myeloid hyperplasia with no excess of blasts, eosinophils or basophils. Molecular analysis did not show BCR‐ABL1. Two mutations in CSF3R were identified: T618I in exon 12 and E778X in exon 17. These findings are in keeping with a diagnosis of chronic neutrophilic leukaemia (CNL).
Chronic neutrophilic leukaemia is a rare myeloid disorder characterised by a chronic neutrophilia with mature neutrophils, often splenomegaly and the absence of a reactive trigger. Serum LDH and vitamin B12 levels are typically high and G‐CSF levels are low. The diagnosis was largely one of exclusion until a strong association with mutations in the CSF3R gene was demonstrated. This is important in that mutations in CSF3R identify this as a clonal rather than reactive disorder and this is a defining feature in the 2016 WHO classification (Bain et al. 2017). In addition, there should be peripheral blood leucocytosis ≥25 × 109/l with at least 80% being mature neutrophils or band cells and <10% being neutrophil precursors with no monocytosis. The type of CSF3R mutation appears to influence prognosis, being worse in the majority of patients who have this mutation (Szuber et al. 2018). Mutations in CSF3R are not essential for diagnosis but when absent the situation should be carefully reviewed and a leukaemoid reaction should be considered. In addition to CSF3R, mutations in ASXL1, SETBP1, SRSF2 and rarely JAK2 have been reported. Traditionally, CNL has been treated with chemotherapy, interferon or hypomethylating agents but responses have often been partial and not sustained. Without effective disease control many patients ultimately progress to blast crisis. More recently, the use of the JAK inhibitor ruxolitinib has been explored as CNL shows aberrant activation of the JAK/STAT pathway (Szuber et al. 2020).
References
1 Bain BJ, Brunning RD, Orazi A and Thiele J (2017) Chronic neutrophilic leukaemia. In Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H and Thiele J (Eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th Edn. IARC Press, Lyon, pp. 37–38.
2 Szuber N, Finke CM, Lasho TL, Elliott MA. Hanson CA, Pardanani A and Tefferi A (2018) CSF3R‐mutated chronic neutrophilic leukemia: long‐term outcome in 19 consecutive patients and risk model for survival. Blood Cancer J, 8, 21.
3 Szuber N, Elliott M and Tefferi A (2020) Chronic neutrophilic leukaemia: 2020 update on diagnosis, molecular genetics, prognosis and management. Am J Haematol, 95, 212–224.
MCQ
1 Increased neutrophil granulation (‘toxic’ granulation) is a usual feature of:Chronic myeloid leukaemia, BCR‐ABL1‐positiveChronic neutrophilic leukaemiaG‐CSF (filgrastim) therapyLeukaemoid reaction to multiple myelomaSepsisFor answers and discussion, see page 206.
19 Essential thrombocythaemia