be distinguished from chronic lymphocytic leukaemia on the basis of CD200 expressionIs associated with a BRAF V600E mutation in the majority of patientsIs best distinguished from hairy cell leukaemia variant by expression of CD25, CD123 and CD200Requires assessment of tartrate‐resistant acid phosphatase (TRAP) activity for a firm diagnosisUsually has collagen fibrosisFor answers and discussion, see page 206.
21 Mantle cell lymphoma in leukaemic phase
A 66‐year‐old man presented with dizziness, headaches and difficulty walking. On assessment he was globally confused but had no specific neurological deficit. His full blood count showed Hb 79 g/l, WBC 602 × 109/l and platelets 70 × 109/l. He had splenomegaly but no significant lymphadenopathy. His blood film showed pleomorphic lymphoid cells varying in size from small to large, with condensed nuclear chromatin and prominent nuclear clefts and convolutions, with many of the larger cells showing cytoplasmic vacuoles (all images ×100 objective). Immunophenotyping studies identified a mature CD5−, kappa‐restricted, B‐cell lymphoproliferative disorder expressing CD19, CD20, CD79b, FMC7 and CD38. Immunohistochemistry on the marrow trephine biopsy sections showed the cells to express nuclear cyclin D1 and on karyotypic analysis a t(11;14)(q13;q32) translocation was identified with, in addition, loss of the short arm of chromosome 17 in 60% of cells. The features here are most consistent with leukaemic non‐nodal mantle cell lymphoma.
In view of the presentation, in keeping with cerebral leucostasis, he was treated by leucapheresis and emergency chemotherapy incorporating high‐dose corticosteroids, cyclophosphamide and vincristine. This was followed by six courses of high‐dose cytarabine and rituximab with an incomplete clinical response with persisting splenomegaly on CT imaging. The splenic anatomy remained abnormal with focal hypodense lesions and a splenectomy was performed. This showed extramedullary haemopoiesis but no evidence of residual lymphoma. This patient remains well and in remission 12 years later.
Mantle cell lymphoma constitutes between 3 and 10% of non‐Hodgkin lymphomas. Typically, it involves lymph nodes, but the spleen and bone marrow are also often infiltrated. The disease also has an affinity for the gastrointestinal tract but this may not necessarily be symptomatic. A subset of patients, as in the case presented here, show a leukaemic presentation with splenomegaly but without lymphadenopathy. Leukaemic non‐nodal mantle cell lymphoma is biologically different and paradoxically, despite the leukaemic manifestation, usually has a more indolent course and an appreciably better prognosis (Nadeu et al. 2020). More aggressive forms of the disease can show mutations in TP53, MYC and CDKN2A. The latter is an important tumour suppressor gene encoding proteins which in turn inhibit MDM2 (a physiological inhibitor of the TP53 pathway). Loss or mutation of either CDKN2A or TP53 leads to chemotherapy resistance and MYC mutation is typically associated with proliferative disease. Note the CD5 negativity here; approximately 5% of mantle cell lymphomas are CD5 negative so morphological assessment alongside genetic and immunohistochemical studies are still required in achieving the correct diagnosis.
Reference
1 Nadeu F, Martin‐Garcia D, Clot G, Díaz‐Navarro A, Duran‐Ferrer M, Navarro A et al. (2020) Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes. Blood, 136, 1419–1432.
MCQ
1 Mantle cell lymphoma:Can result from translocations involving CCND1, CCND2 or CCND3Is derived from marginal zone lymphocytesIs the most common pathology underlying multiple lymphomatous polyposisMay show SOX11 expression on immunohistochemistryUsually expresses CD200For answers and discussion, see page 206.
22 Infantile osteopetrosis
A 6‐month‐old boy, born to consanguineous parents, presented with failure to thrive, developmental delay and pancytopenia. He was found to have significant hearing impairment. His full blood count showed Hb 80 g/l, WBC 2 × 109/l, neutrophils 0.8 × 109/l and platelets 50 × 109/l. The blood film was leucoerythroblastic but abnormal cells were not identified. The bone marrow aspirate was markedly hypocellular. The bone marrow trephine biopsy sections were highly abnormal, showing prominent disorganised trabecular structure and whorls with a significant encroachment on, and reduction in activity of, normal haemopoietic marrow (top images ×10 objective, bottom images ×50). The normal haemopoietic marrow space appears overrun by abnormal disorganised marrow trabeculae. The clinical presentation and marrow findings are indicative of inherited infantile osteopetrosis.
Infantile osteopetrosis is a serious autosomal recessively inherited disorder of osteoclast malfunction. It presents in infancy with progressive pancytopenia and cranial nerve compromise due to uncontrolled bony overgrowth resulting from an osteoclast‐based remodelling failure. The most serious early consequences are progressive hearing and visual loss due to compression of the auditory and optical nerves, respectively. The condition needs to be recognised and treated early since, as osteoclasts are derived from bone marrow stem cells, the only effective therapy is allogeneic bone marrow transplantation.
The images above are plain X‐rays of the pelvis in a child with osteopetrosis before (left) and after (right) allogeneic stem cell transplantation.1 Note the marked improvement in bone density due to the donor‐derived stem cells and subsequent osteoclast‐related bone resorption and remodelling. The transplant also helps re‐establish the haemopoietic marrow space and thus blood count recovery.
MCQ
1 Infantile osteopetrosis can be associated with:Autosomal recessive or dominant inheritanceDecreased osteoclastsFragile bonesResponsiveness to vitamin D that renders transplantation unnecessaryIncreased osteoclastsFor answers and discussion, see page 206.
Note
1 1 Images courtesy of Professor Rob Wynn and Cambridge University Press.
23 Reactive eosinophilia
A 79‐year‐old man with a 60‐year smoking history presented with the recent onset of anorexia and weight loss with rapidly appearing skin nodules. He had no new respiratory symptoms though he had a longstanding cough attributed to chronic obstructive pulmonary disease. His full blood count showed Hb 133 g/l, WBC 58 × 109/l, eosinophils 35 × 109/l and platelets 500 × 109/l. The blood film confirmed a marked eosinophilia with a number of abnormalities of eosinophil morphology. Hypogranular eosinophils are prominent (all images ×100 objective) with some cells showing 50% loss of cytoplasmic granules (top left). There is also eosinophil cytoplasmic vacuolation (bottom left) and some basophilic granulation (top centre and bottom right). Finally, there are cells with nuclear abnormalities with some showing separation of nuclear components (top right) and even a ring nucleus (bottom centre). It might be assumed that such dramatic morphological abnormalities indicate a primary haematological
