Distinguishing Autoimmune Myelofibrosis from Primary Myelofibrosis
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Distinguishing Autoimmune Myelofibrosis from Primary Myelofibrosis Bridget Marcellino, MD, PhD, Siraj M. El Jamal, MD, and John O. Mascarenhas, MD The authors are affiliated with the Abstract: Bone marrow fibrosis (BMF) is a histologic finding in Icahn School of Medicine at Mount a wide range of diseases, including malignancies, endocrine Sinai in New York, New York. Dr disorders, autoimmune diseases, and infections. Autoimmune Marcellino is a hematology/oncology myelofibrosis (AIMF) is an uncommon etiology of BMF; it can be fellow at the Tisch Cancer Institute, Dr Mascarenhas is the leader of the secondary to a defined autoimmune disease, or it can be primary Myeloproliferative Disorders Clinical in the absence of a clinically diagnosed autoimmune disease but Research Program at the Tisch Cancer the presence of serologic evidence of autoantibodies. Distinguish- Institute, and Dr El Jamal is a patholo- ing between primary myelofibrosis (PMF) and non-neoplastic AIMF gist in the Department of Pathology. is of the utmost importance because the prognosis and therapeutic options are different. This distinction, however, can be complicat- Corresponding author: ed by overlapping findings in the 2 disease entities. Here, using the John Mascarenhas, MD case of a patient with BMF in the setting of idiopathic thrombocy- Associate Professor of Medicine topenic purpura and autoimmune hemolytic anemia, we present Icahn School of Medicine at a systematic approach to distinguishing between PMF and AIMF. Mount Sinai One Gustave L. Levy Place, Box 1079 New York, NY 10029 Tel: (212) 241-3417 Introduction Fax: (212) 876-5276 E-mail: [email protected] Bone marrow fibrosis (BMF) can arise from a wide span of condi- tions, ranging from malignancies to non-neoplastic entities such as infections, endocrine disorders, and autoimmune disease (Table 1).1 BMF is commonly seen in the setting of hematologic malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS), mast cell diseases, and rarely in lymphopro- liferative disorders. The most common cause of BMF is primary myelofibrosis (PMF).2,3 It is important to note, however, that BMF has also been reported to be associated with the clinical use of thrombopoietin-receptor agonists.4 Autoimmune myelofibrosis (AIMF) is an uncommon etiology of BMF and is most often accompanied by other autoimmune dis- eases, such as systemic lupus erythematosus and rheumatoid arthritis. When BMF is associated with a defined autoimmune disease, it is termed secondary AIMF.5 However, in the absence of a primary auto- immune disease driving BMF, but the presence of serologic evidence of autoimmunity, it is termed primary AIMF. Primary AIMF is often associated with benign hematologic conditions, such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), and 6 Keywords Evans syndrome. Studies have shown that up to 40% of patients Autoimmune myelofibrosis, bone marrow fibrosis, with ITP have BMF, with the majority demonstrating minimal primary myelofibrosis reticulin fibrosis.7,8 Clinical Advances in Hematology & Oncology Volume 16, Issue 9 September 2018 619 MARCELLINO ET AL It is imperative to differentiate AIMF from PMF Table 1. Disorders Associated With Myelofibrosis because the clinical course, prognostic implication, and treatment options are vastly different. The ability to Infectious diseases distinguish between the 2 disease entities is often com- - Tuberculosis plicated by overlapping pathologic features and the fact Endocrine disorders that autoimmune abnormalities, such as the presence of - Hyperparathyroidism (primary or secondary) autoimmune serologies, can be identified in both enti- - Vitamin D deficiency (nutritional or rickets) ties.9 Cytokine-dependent mechanisms drive BMF in - Osteomalacia both AIMF and PMF; however, the predominant source Autoimmune disorders of cytokines—including transforming growth factor beta - Systemic lupus erythematosus (TGF-β), interferon gamma (IFN-γ), interleukin 8 (IL- - Sjögren syndrome 8), IL-2, IL-17, and lipocalin-2 (LCN2)—likely differs, - Systemic sclerosis with cytokines derived from lymphoid aggregates driving - Primary autoimmune myelofibrosis AIMF and those derived from megakaryocytes and plate- - Connective tissue disease lets mediating fibrosis in PMF.1,10-12 Ultimately, clonality Hematologic malignancies is a defining feature of PMF, and a driver mutation (JAK2, - Myeloproliferative neoplasms (primary myelofibrosis, MPL, or CALR) is found in 90% of cases.13,14 polycythemia vera, essential thrombocythemia) The morphologic criteria that favor AIMF rather - Myelodysplastic syndrome than PMF, as proposed by Vergara-Lluri and colleagues, - Chronic myelogenous leukemia - Hodgkin lymphoma are the following: - Non-Hodgkin lymphoma - Acute myeloid leukemia (particularly acute megakaryo- 1. Rarity or absence of a leukoerythroblastic reaction in blastic leukemia) the peripheral blood, including absence of teardrop - Acute lymphoblastic leukemia cells, nucleated red blood cells (RBCs), and blasts; - Adult T-cell leukemia/lymphoma 2. Absence of peripheral eosinophilia or basophilia; - Multiple myeloma 3. Mild degree of BMF (usually MF1); - Systemic mastocytosis 4. Absence of osteosclerosis and bone changes; Other hematologic conditions 5. Presence of hypercellular marrow characterized by ery- - Paroxysmal nocturnal hemoglobinuria throid and megakaryocytic hyperplasia (vs granulocytic - Gray platelet syndrome hyperplasia in PMF); Drug-associated conditions 5. Presence of lymphoid aggregates; and - Thrombopoietin receptor agonist toxicity 6. Absence of dysplastic features in any of the lineages, Other 15 especially the megakaryocytes. - Primary hypertrophic osteoarthropathy - Paget disease These criteria distinguish AIMF from PMF; how- - Metastatic solid malignancies ever, the distinction can remain nebulous when not all of the criteria are met. In these scenarios, it is crucial to consider the whole clinical picture in context, including the clinical presentation, time line of the disease course, without any bleeding complications. After 10 years, hypo- results of assessment for autoantibodies, bone marrow thyroidism was diagnosed and levothyroxine initiated. He pathologic findings, and results of chromosomal/genetic was still thrombocytopenic at this time and was given studies. Here, we present a case of presumed AIMF with a diagnosis of ITP; no treatment was initiated. Several associated autoimmune-mediated hemolytic anemia and months ago, he presented to his local hematologist with ITP to exemplify the process of distinguishing between complaints of dyspnea, dizziness, lightheadedness, ankle PMF and AIMF. swelling, and easy bruising. No constitutional symptoms were reported. He was found to have a hemoglobin level Case of 6.8 g/dL and a platelet count of 1000/µL, with a nor- mal white blood cell count and differential. He received a Clinical Presentation transfusion of packed red blood cells and platelets, which A 57-year-old man presented to our clinic for consultation led to the resolution of his presenting symptoms. regarding chronic thrombocytopenia. He had been found to have a platelet count of 10,000/µL 15 years prior but Laboratory Assessment did not pursue an evaluation. He was lost to follow-up, The patient was assessed for evidence of hematologic 620 Clinical Advances in Hematology & Oncology Volume 16, Issue 9 September 2018 DISTINGUISHING AUTOIMMUNE MYELOFIBROSIS FROM PRIMARY MYELOFIBROSIS Table 2. Results of Our Patient’s Laboratory Assessment agglutination, rouleaux, or polychromasia. A bone mar- row aspiration procedure produced a dry tap result. The White blood cell count, 11.5 biopsy specimen showed hypercellular marrow (90%) 103/µL with trilineage hematopoiesis and full maturation; also Hemoglobin, g/dL 6.8 noted was a disproportionate increase in atypical mega- Platelet count, 103/µL 1000 karyocytes seen singly and in clusters, with pleomorphism characterized by hypolobated and focally hyperlobated Iron, µg/dL 23 nuclei. Several small lymphocytic aggregates contained TIBC, µg/dL 359 CD3+ T lymphocytes and CD20+ B lymphocytes. Transferrin saturation, % 6 There was no evidence of dysplasia or excess plasma cells. Ferritin, ng/mL 49 Reticulin staining showed moderate to marked reticulin fibrosis (MF2-3/3), and trichrome staining was negative Folate, ng/mL 17.05 for collagen fibrosis. Vitamin B12, pg/mL 570 Erythropoietin, mIU/mL 56.6 Evaluation for Primary Myelofibrosis Coombs test Positive: The workup for a myeloproliferative neoplasm was 2+ positive DAT polyspecific largely unremarkable. Spleen size was normal by axial 2+ positive DAT IgG computed tomography. Peripheral blood cytogenetics 2+ positive DAT C3 showed a normal karyotype. Next-generation sequencing Platelet antibodies Positive of 44 myeloid-relevant genes in his peripheral blood cells ESR, mm/h 86 revealed a GATA2 mutation of unknown significance with a variant allele frequency of 49%, suggesting germ- CRP, mg/L 2.3 line origin. JAK2, MPL, and CALR were wild-type. ANA Positive (>1:80) Rheumatoid factor, IU/mL Negative (<15) Clinical Course Rheumatologic antibody Negative The patient was put on a trial of prednisone at 20 mg daily panel (anti–smooth muscle for presumed AIMF. After 1 month of treatment, the ane- Ab, anti–mitochondrial mic and thrombocytopenic cell counts had returned to Ab, anti–PR3/MPO Abs, nearly normal values. The prednisone was tapered, and anti-SSA and anti-SSB Abs, the patient will be followed to ensure the durability