Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Myelofibrosis (MF) is a Philadelphia chromosome (BCR-ABL1)-negative myeloproliferative neoplasm (MPN) that develops from multipotent hematopoietic stem cells. MF may manifest as primary myelofibrosis (PMF) or can develop from a pre-existing disorder: polycythemia vera or essential thrombocythemia. Variable grades of cytopenia, a leuko-erythroblastic blood profile, and extramedullary hematopoiesis are characteristics of MF. These factors cause progressive splenomegaly and incapacitating disease-related constitutional symptoms that adversely affect quality of life.1
Bone marrow aspiration and biopsy samples are often obtained early in disease onset, as they are helpful for the histological diagnosis of PMF. The bone marrow sample is usually taken from the posterior iliac crest with special needles.2 Splenectomy is often reserved for patients with symptomatic splenomegaly that does not respond to medication. Indications for splenectomy include abdominal discomfort and pain, symptomatic portal hypertension, marked thrombocytopenia, and a requirement for frequent red blood cell transfusions.3,4
Bone Marrow Aspiration and Biopsy Specimen
Bone marrow testing consists of 2 steps: aspiration and biopsy. This examination is necessary to differentiate MF from other MPNs.5 Bone marrow aspiration and biopsy confirm the diagnosis of MF.6
In up to 50% of cases of PMF, the bone marrow aspirates are dry. Therefore, a bone marrow biopsy is required to confirm the diagnosis.2
Histological Features of Prefibrotic PMF
In prefibrotic PMF, the bone marrow is hypercellular. The megakaryocytes are numerous and arranged in tight clusters. Distribution adjacent to the trabeculae (“paratrabecular”) and sinuses in the bone marrow is characteristic. The megakaryocytes show a marked degree of pleomorphism and dysplastic features, including an abnormal nuclear-to-cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei. The megakaryocyte features are useful for distinguishing prefibrotic PMF from essential thrombocytopenia.1,7,8
One of the major diagnostic criteria for prefibrotic, or early-stage, PMF is megakaryocytic proliferation and atypia without a reticulin fibrosis grade higher than 1, along with increased age-adjusted bone marrow cellularity, granulocyte proliferation, and usually decreased erythropoiesis. Bone marrow fibrosis grade 1 is characterized by a loose network of reticulin with many intersections, especially in perivascular areas.8
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Histological Features of Fibrotic PMF
The bone marrow tap is dry in the fibrotic phase, which is characterized by osteosclerosis with broad and irregular bony trabeculae and significantly dilated sinuses. The bone marrow is hypocellular, with diffuse fibrosis and atypical streaming of megakaryocytes.7
In cases with bone marrow fibrosis, in addition to hematoxylin and eosin (H&E) staining, silver impregnation and trichrome staining are recommended to detect reticulin and collagen fibrosis. On silver impregnation, reticulin fibers appear black and collagen fibers appear red, so that the 2 types of fibers can be distinguished. On H&E staining, collagen fibers appear eosinophilic, and on Masson’s trichrome staining, they appear blue.8
One of the major diagnostic criteria for the fibrotic, or overt, stage of PMF is megakaryocytic proliferation and atypia, along with grade 2 or 3 reticulin and/or collagen fibrosis. Grade 2 is characterized by a diffuse and dense increase in reticulin, with extensive intersections and occasionally focal bundles of thick fibers, consistent with collagen and/or associated with focal osteosclerosis. Grade 3 is characterized by a diffuse and dense increase in reticulin with extensive intersections and course bundles of thick fibers, consistent with collagen and usually associated with osteosclerosis.8
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Splenomegaly, one of the main clinical manifestations of MF, is associated with splenic extramedullary hematopoiesis. Given the dysregulation of the bone marrow microenvironment, the development of extramedullary hematopoiesis is linked to the abnormal trafficking mechanisms of clonal hematopoietic progenitor cells and hematopoietic stem cells. It is an integral component of myelofibrosis and myeloid metaplasia (MMM) and includes 3 histological patterns of infiltration: predominant immature granulocytes, diffuse, and nodular.9
Histopathological examination of the splenic red pulp reveals extramedullary hematopoiesis in the form of megakaryocytes, granulocyte precursors, and nucleated red cells. A few of the megakaryocytes may show dysplastic features on higher magnification. Foci of extramedullary hematopoiesis forming nodules may also be noted.7,10
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- Zahr AA, Salama ME, Carreau N, et al. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies. Haematologica. 2016;101(6):660-671. doi:10.3324/haematol.2015.141283
- Lal A, Besa EC. Primary myelofibrosis workup. Medscape. Updated September 21, 2022. Accessed December 21, 2022.
- Lal A, Besa EC. Primary myelofibrosis treatment & management. Medscape. Updated September 21, 2022. Accessed December 21, 2022.
- Malato A, Rossi E, Tiribelli M, Mendicino F, Pugliese N. Splenectomy in myelofibrosis: indications, efficacy, and complications. Clin Lymphoma Myeloma Leuk. 2020;20(9):588-595. doi:10.1016/j.clml.2020.04.015
- Myelofibrosis diagnosis. Leukemia and Lymphoma Society. Accessed December 21, 2022.
- Myelofibrosis diagnosis. Mayo Clinic. Accessed December 21, 2022.
- Kaseb H, Hudnall SD. Primary myelofibrosis. PathologyOutlines.com. Accessed December 21h, 2022.
- Fujiwara H. Histological evaluation of myeloproliferative neoplasms. J Clin Exp Hematop. 2018;58(2):45-50. doi:10.3960/jslrt.18006
- Mesa RA, Li CY, Schroeder G, Tefferi A. Clinical correlates of splenic histopathology and splenic karyotype in myelofibrosis with myeloid metaplasia. Blood. 2001;97(11):3665-3667. doi:10.1182/blood.v97.11.3665
- Myelofibrosis. WebPathology. Accessed December 21, 2022.
Reviewed by Debjyoti Talukdar, MD, on 12/31/2022.