features here support a diagnosis of a myeloproliferative neoplasm and molecular studies showed a pathogenic intragenic CALR deletion. In the circumstances it is difficult to accurately classify this myeloproliferative neoplasm but the diagnosis is likely to be primary myelofibrosis. This patient has two unrelated disorders which had caused understandable diagnostic difficulty. It is important to link any new development to a known disorder but it is also advisable that the clinician keeps an open mind, and considers all potential options when patients show an unexpected clinical evolution.
MCQ
1 Unstable haemoglobins:Affect only the α or β globin chainCan be associated with the presence of two variant haemoglobins as well as haemoglobin ACan be detected by instability on heating or exposure to isopropanolHave normal oxygen affinityWhen clinically manifest, usually indicate homozygosityFor answers and discussion, see page 206.
16 Sickle cell anaemia in crisis
A 33‐year‐old woman with known sickle cell anaemia, newly arrived in the United Kingdom, presented to Accident and Emergency with a painful crisis. She was breathless, febrile and faintly jaundiced. Her FBC showed Hb 51 g/l, RBC 1.72 × 1012/l, Hct 0.165, MCV 95.8 fl, MCH 29.8 pg, MCHC 311 g/l, WBC 13.8 × 109/l and platelet count 445 × 109/l. Bilirubin was increased to 141 μmol/l and ALT was mildly increased to 55 u/l. CRP was markedly increased to 137 mg/l. Examination of the blood film (all images ×100 objective) showed boat‐shaped cells (top) but surprisingly infrequent sickle cells. There were some nucleated red blood cells and polychromasia was present. The changes of hyposplenism were present, specifically Howell–Jolly 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.
