Haematology. Barbara J. Bain
expressed. The bone marrow trephine biopsy sections were also abnormal, showing prominent macrophages displaying haemophagocytosis on H&E staining (below, left image) and CD68R (below, centre image, immunoperoxidase), whilst the large neoplastic cells were highlighted using CD30 (below, right, immunoperoxidase) (all images below ×50). Immunohistochemistry showed the large cells to be ALK negative. The diagnosis was now confirmed as ALK‐negative anaplastic large cell lymphoma. The patient was transferred back to his local hospital with a view to commencing CHOP chemotherapy but after one cycle of treatment he deteriorated further and sadly died.
Haemophagocytic syndrome is a rare constellation of clinicopathological features including fever, weight loss, sweats and organomegaly, together with laboratory abnormalities including cytopenias, hyperferritinaemia, hypertriglyceridaemia, coagulopathy and bone marrow haemophagocytosis. Interestingly, according to strict diagnostic criteria, and despite the name, demonstration of the latter is not absolutely essential. In adults the typical triggers for a confirmed haemophagocytic syndrome are infective or neoplastic. In adult patients a neoplastic cause is very likely and high‐grade T‐cell and NK‐cell neoplasms are the usual culprits. In paediatric practice there are a number of inherited immunodeficiency syndromes that strongly predispose to a haemophagocytic syndrome, but neoplastic and infective triggers similar to the above have also to be considered. It is absolutely essential to consider a neoplastic cause in adult patients; this focuses attention on looking for an underlying neoplasm with subsequent targeted treatment, in which case the haemophagocytic syndrome will gradually resolve.
MCQ
1 ALK‐negative anaplastic large cell lymphoma:Generally occurs at an older age than ALK‐positive casesHas a better prognosis than ALK‐positive anaplastic large cell lymphomaHas similar histological and immunophenotypic features to breast implant‐associated anaplastic large cell lymphomaIs usually associated with t(2;5)(p23.2‐23.1;q35.1)Usually presents with localised diseaseFor answers and discussion, see page 206.
2 Bone marrow AL amyloidosis
A 47‐year‐old man presented with peripheral oedema due to nephrotic syndrome and a kidney biopsy was planned. Full blood count showed Hb 154 g/l, WBC 7.8 × 109/l and platelets 355 × 109/l. Serum creatinine was 136 μmol/l, estimated glomerular filtration rate (eGFR) 49 ml/min/1.73 m2, albumin 17 g/l and urine protein 5.4 g/l. A serum IgA lambda paraprotein (9 g/l) and excess serum free lambda light chains at 103.5 mg/l (NR 5.7–26.3) were identified.
A bone marrow aspirate identified deposits of amorphous, purple‐staining material suggestive of amyloid protein (top left image) (all images ×50 objective). The trephine biopsy sections showed diffuse eosinophilic amorphous material (top right, H&E) in keeping with amyloid deposited around fat cells, around erythroid islands, in the walls of small vessels and throughout the interstitium. Immunohistochemistry for CD138 revealed 7% plasma cells with non‐specific binding to the amyloid deposits (bottom left, immunoperoxidase) the latter deposits staining also with Sirius red (bottom right). These findings are indicative of extensive bone marrow amyloid deposition due to primary AL amyloidosis. In view of these findings the renal biopsy was now not deemed necessary.
This case illustrates the striking morphological abnormalities encountered in amyloidosis; accurate recognition of these features is important in bringing together a unified clinical diagnosis.
A second patient presented with back pain and vertebral collapse. MRI suggested a marrow infiltrative disease such as myeloma. Indeed, he was shown to have raised serum free lambda light chains (367 mg/l) but no paraprotein was detected. The bone marrow aspirate, however, was hypocellular and showed low level (<1%) involvement by plasma cells so the diagnosis was questioned. The trephine biopsy sections showed heavy involvement by AL amyloidosis (all images below, H&E, left ×10, centre and right ×50) occupying well over 80% of the marrow space, with notable involvement of vessel walls. In the cellular areas well over 90% of cells were neoplastic plasma cells. Elsewhere small pockets of malignant plasma cells were identified (below centre). Extensive bone marrow amyloidosis can influence accurate assessment of plasma cell populations and can delay accurate diagnosis.
MCQ
1 Amyloid in tissue sections can be identified by positive staining with:Congo redMartius scarlet blueMethenamine silverPrussian blueSirius redFor answers and discussion, see page 206.
3 Cup‐like blast morphology in acute myeloid leukaemia
A 54‐year‐old woman attended Accident and Emergency with fever, progressive facial pain and bleeding following a tooth extraction 1 week previously. On examination she was systemically unwell and febrile with features of a deep perimandibular soft tissue/tooth socket infection. She had prominent widespread bruising. The full blood count showed Hb 106 g/l, WBC 291 × 109/l, neutrophils 0.7 × 109/l and platelets 49 × 109/l. A coagulation screen showed PT 13 s, APTT 30 s, thrombin time 12.4 s, fibrinogen 1.0 g/l and D dimer 14 059 ng/ml (NR <230). The blood film showed a large population of myeloid blasts. Many of them displayed deep nuclear invaginations (cup‐like morphology) as shown centrally (top left and centre, bottom left and centre) or indenting one side of the nucleus (top left, bottom left and centre) (all images ×100 objective). Some blasts showed small but well‐defined nucleoli (top left, top right and bottom right). There was fine cytoplasmic granulation in some cells and some had Auer rods (top centre and right) whilst a small proportion had pseudo‐Chédiak–Higashi granules (top right, bottom right). The blasts had a CD34−, HLA‐DR−, CD117+, CD13+, CD33+, CD15−, CD14−, CD64+ and MPO+ immunophenotype resembling that often seen in acute promyelocytic leukaemia (APL), but the morphological features were not consistent with this diagnosis. T‐ and B‐lineage markers were not expressed. The karyotype was normal but both NPM1 and FLT3 were mutated with FLT3 showing an internal tandem duplication (FLT3‐ITD).
The clinical presentation here of an acute myeloid leukaemia with bleeding, bruising and coagulopathy together with a CD34−, HLA‐DR−, pan‐myeloid+, CD64+ immunophenotype should lead to consideration of APL as management of this entity clearly differs from that of other AML subtypes. However, a thoughtful examination of the blood film suggests an alternative diagnosis.
MCQ
1 Acute myeloid leukaemia with mutated NPM1 is typically associated with:An abnormal karyotypeCup‐shaped nucleiCytoplasmic expression of NPM1Expression of CD34Poor prognosisFor answers and discussion, see page 206.
4 Neutrophil morphology
The neutrophil has been a focus of attention for haematologists for many decades and this remains true today for many reasons. These phagocytic and bactericidal cells are a key player in innate immunity but have many other roles in systemic inflammation, cytokine signalling and tissue remodelling and repair. Quantitative and qualitative disorders of neutrophils can have serious consequences for the patient and, importantly, recognising the nature and existence of these abnormalities can be instrumental