hematology interest group cnl myeloproliferative neoplasm
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Hematology Interest Group Myeloproliferative Neoplasm October 20, 2017 Chronic Neutrophilic Leukemia Clinical History A 65-year-old male presents for further evaluation of diffuse bone pain, abdominal discomfort, and progressive fatigue for the last several months. Examination reveals splenomegaly. Laboratory evaluation reveals a leukocyte count of 76,900/uL (76.9 x 109/L), hemoglobin 11.8 g/dL (118 g/L), and platelet count of 91,000/uL (91 x 109/L). Bone marrow aspiration and biopsy revealed hypercellular bone marrow, less than 5% blasts, and no evidence of dysplasia. Testing for BCR-ABL rearrangement and JAK2 V617F mutation was negative. 1 Laboratory Results Hemogram Patient’s Results Reference Range Hemoglobin (HgB) 11.8 g/dL (118 g/L) 12-16 g/ dL (120 160 g/L) RDW 17.2 % 37-47% Mean Corpuscular Volume (MCV) 91 fl 80-100 fl Platelets 91 x 109/L 140-440 x 109/L White Blood Cell Count (WBC) 76.9 x109/L 4.8-10.8 x109/L Peripheral Blood Smear Three peripheral blood static images are shown: 2 Peripheral Blood The peripheral blood film shows marked leukocytosis, a mild anemia, and a decreased platelet count. Marked leukocytosis consisting mostly of increased numbers of mature neutrophils and bands with a slight left-shift. There is no eosinophilia or basophilia. Toxic granulation of the neutrophils and occasional granulocyte precursor containing Dohle Bodies are seen. No circulating myeloblasts or neutrophil dysplasia seen. 3 Differential Differential Patient’s Results Reference Range Neutrophils 47.3 x109/L 2.0-7.0 x 109/L Bands 22.3 x109/L Lymphocytes 4.23 x109/L 1.0-3.0 x 109/L Monocytes 0.38 x109/L 0.2-1.0x 109/L Eosinophils 0.00 x109/L 0.02-0.5x 109/L Basophils 0.00 x109/L 0.02-0.1x 109/L Metamyelocytes 1.92 x109/L 0.00-0.00x 109/L Myelocytes 0.77 x109/L 0.00-0.00x 109/L Reticulocyte Count 158 x 109/L 10 - 90 x 109/L Bone Marrow 4 5 This bone marrow core biopsy shows the classic granulocytic predominance and hypercellularity. Megakaryocyte morphology is normal. 6 Bone Marrow Biopsy and Aspirate Both biopsy and aspirate are of good quality. Cellularity is 90 %. ME ratio is increased (M/E ratio= 10:1). Granulopoiesis is hyperplastic, shows healthy granulation and left-shift. . There is no increase in blast cells. No eosinophilia or basophilia. Erythropoiesis is reduced but appears normoblastic. Megakaryocytes are present but there is no crowding. The biopsy does not show any streaming pattern. The trabecular bone is unremarkable. The lymphoplasmacytic complement is unremarkable. Bone Marrow Differential (500 Cells Counted) Neutrophils 15% Late normoblasts 5% Plasma cells 0% Bands 32% Intermediate normoblasts 1% Lymphocytes 3% Metamyelocytes 23% Early normoblasts 0% Monocytes 0% Myelocytes 20% Proerythroblasts 0% Eosinophils 0% Promyelocytes 1 % Basophils 0% Blasts 0% Cytogenetics Normal Male Karyotype Chromosome Abnormalities CSF3R mutation by PCR-based DNA Sanger sequencing for exons 14 and 17 was performed on the bone marrow aspirate. The following mutation was detected and translates into the following predicted protein change: p.T618I. Diagnosis Chronic Neutrophilic Leukemia 7 Discussion Clinical findings: Chronic neutrophilic leukemia (CNL) is a BCR/ABL-negative myeloproliferative neoplasm characterized by a high number of mature neutrophils in the peripheral blood and a hyperplastic bone marrow. CNL is primarily a disease of adults and is generally diagnosed in the 6th decade of life with a slight predominance of males over females. Symptoms include weight loss, easy bruising, bone pain, night sweats, mucosal bleeding, and hepatosplenomegaly. At diagnosis the majority of patients have a mild normochromic normocytic anemia (median hemoglobin 11 g/dl), the platelet count is variable. Peripheral blood shows a leukocytosis with an average WBC of 39×109/L (WBC WHO criteria >25×109 /L) that primarily consists of mature granulocytes. Segmented and bands account for > 80% of the total WBC and frequently show toxic granulation and dohle bodies. There is no increase in monocytes, eosinophils, basophils, myelocytes, metamyelocytes, or myeloblasts. No granulocytic dysplasia is evident. CNL diagnosis had remained primarily one of exclusion until the discovery of oncogenic mutations in the colony-stimulating factor 3 receptor gene (CSF3R). Mutations in CSF3R activate the receptor, leading to the proliferation and differentiation of granulocytic precursors into mature segmented neutrophils,the hallmark feature of CNL. This breakthrough discovery, which was made recently in 2013, provided a molecular pathogenesis and phenotypic characterization facilitating an accurate and specific diagnosis of CNL. In 2016 the World Health Organization diagnostic guidelines for CNL were updated to include the various CSF3R mutations. Additional clinicopathologic characteristics of CNL include: ● Hyperuricemia - A reflection of high bone marrow cellular turnover. ● Elevated lactate dehydrogenase—LDH is an enzyme found in all normal and abnormal cells. It is released from cells into the blood and is associated with energy production. ● Elevated vitamin B12–binding protein - Synthesized by the granulocytes, reflecting the degree of leukocytosis. ● Mild anemia - Hemoglobin level about 11g/dl (110 g/L) ● Elevated leukocyte alkaline phosphatase (LAP) levels— Enzyme found in white blood cells. 8 World Health Organization (WHO), as of 2016, the diagnostic criteria for CNL are the following: 1. PB WBC ≥25 × 109/L Segmented neutrophils plus band forms ≥80% of WBCs Neutrophil precursors (promyelocytes, myelocytes, and metamyelocytes) <10% of WBC Myeloblasts rarely observed Monocyte count <1 × 109/L No dysgranulopoiesis 2. Hypercellular BM Neutrophil granulocytes increased in percentage and number Neutrophil maturation appears normal Myeloblasts <5% of nucleated cells 3. Not meeting WHO criteria for BCR-ABL1+ CML, PV, ET, or PMF 4. No rearrangement of PDGFRA, PDGFRB, or FGFR1, or PCM1-JAK2 5. Presence of CSF3R T618I or other activating CSF3R mutation or In the absence of a CSFR3R mutation, persistent neutrophilia (at least 3 mo), splenomegaly and no identifiable cause of reactive neutrophilia including absence of a plasma cell neoplasm or, if present, demonstration of clonality of myeloid cells by cytogenetic or molecular studies. Differential Diagnosis: Prior to reaching a diagnosis of CNL one must exclude processes capable of causing a reactive neutrophilia or a leukemoid reaction. Granulocytic dysplasia or evidence of monocytosis would suggest an alternate diagnosis such as atypical CML (aCML) or chronic myelomonocytic leukemia (CMML). Cytogenetic and molecular analysis were done and were negative for BCR/ABL1 excluding the diagnosis of CML. Similarly, there was no evidence of other classic BCR/ABL1-negative MPNs such as polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Further molecular testing was completed and were negative for rearrangements of JAKV617F, PDGFRA, PDGFRB, and FGRF1. Peripheral blood smears revealed a leukocytosis (>25 x109/L.) with a increased numbers of mature-appearing neutrophils (>80%). The bone marrow was hypercellular at 90 %,with a increased M/E ratio >10%, no increase in myeloblasts, no dysplasia was noted and the pathologist referred to the lymphoplasmacytic complement as being “unremarkable”. 9 References 1. Am. J. Hematol. 91:342–349, 2016. 2015 Wiley Periodicals, Inc 2. https://www.researchgate.net/publication/269718702_Molecular_genetics_of_chronic_neutrophi lic_leukemia_chronic_myelomonocytic_leukemia_and_atypical_chronic_myeloid_leukemia [accessed Oct 23, 2017] 3. Maxson, Julia E., and Jeffrey W. Tyner. "Genomics of chronic neutrophilic leukemia." Blood 129.6 (2017): 715-722. Web. 23 Oct. 2017. http://www.bloodjournal.org/content/129/6/715.abstract 4. Uppal G, Gong J Chronic neutrophilic leukaemia. Journal of Clinical Pathology Published Online First: 16 June 2015. Doi: 10.1136/jclinpath-2015-203060 Read more on our website Samantha Dewey, MLS(ASCP)SH © Hematology Interest Group 10
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