Spleen
Hematogenous neoplasms
Myelofibrosis

Author: Jaleh Mansouri, M.D. (see Authors page)

Revised: 7 March 2018, last major update September 2013

Copyright: (c) 2003-2018, PathologyOutlines.com, Inc.

PubMed Search: Myelofibrosis[TI] spleen[TIAB] free full text[sb]

See also: Chronic myeloid neoplasms chapter
Cite this page: Mansouri, J. Myelofibrosis. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/spleenmyelofibrosis.html. Accessed May 21st, 2018.
Definition / general
  • Clonal myeloproliferative neoplastic process characterized by abnormal proliferation of megakaryocytes and granulocytes in bone marrow, marrow fibrosis, extramedullary hematopoiesis (EMH)
Terminology
  • Also called agnogenic (idiopathic) myeloid metaplasia, chronic idiopathic myelofibrosis, myelofibrosis / sclerosis with myeloid metaplasia, idiopathic myelofibrosis
Epidemiology
  • Often occurs in sixth and seventh decades
  • No gender preference
Sites
  • Blood and bone marrow
  • Spleen, in cases with EMH
  • Other less common sites include liver, kidney, gastrointestinal tract
Pathophysiology
  • Postulated defect in hematopoietic stem cell with abnormal cellular proliferation of megakaryocytes and granulocytes, increasing reticulin fibrosis progressing to collagen fibrosis and osteosclerosis
  • May transform to acute leukemia
  • Characterized by prefibrotic (cellular) and fibrotic stages
Etiology
  • Exposure to chemicals such as benzene, ionizing radiation
  • Familial / inherited forms exist
Clinical features
  • May be asymptomatic in early stages
  • Often presents with hepatosplenomegaly and nonspecific symptoms, such as fatigue, weight loss, night sweats, increased infection, thrombosis, bleeding episodes
  • Late stages associated with portal hypertension, congestive heart failure and acute leukemia
Diagnosis
  • Need 3 major and 2 minor criteria for diagnosis of primary myelofibrosis (PMF)
  • Major criteria:
    1. Megakaryocyte proliferation and atypia, often with reticulin or collagen fibrosis OR in absence of fibrosis
      • Megakaryocyte changes seen with increased bone marrow cellularity and granulocytic proliferation
    2. Demonstration of JAK2 V617F or other clonal marker (MPL W515K / L)
    3. Must not meet WHO criteria for polycythemia vera, chronic myelogenous leukemia (BCR-ABL1+), myelodysplastic syndrome, other myeloid neoplasms
      • OR in absence of clonal marker, bone marrow fibrosis or other changes not secondary to infection, autoimmune / inflammatory conditions, toxicity, hairy cell leukemia, lymphoid neoplasms or other malignancy
  • Minor criteria:
    1. Leukoerythroblastosis
    2. Increased serum LDH (lactate dehydrogenase)
    3. Anemia
    4. Splenomegaly
Laboratory
  • Anemia, leukocytosis, thrombocytosis, increased LDH
Prognostic factors
  • Histologic stage at diagnosis (prefibrotic versus fibrotic)
  • Adverse factors include age > 70 years, anemia (Hb < 10 g/dL), thrombocytopenia (< 100,000), abnormal karyotype
Case reports
Treatment
  • Splenectomy (only produces modest results)
  • JAK inhibitors such as ruxolitinib show encouraging results (Ther Adv Hematol 2013;4:15)
Gross description
  • Massively enlarged spleen, averaging 2 kg
  • Diffusely dark red and moderately firm with multiple areas of hemorrhage
Microscopic (histologic) description
  • Extramedullary hematopoiesis in red pulp
  • Megakaryocytes may have atypical features and resemble Reed-Sternberg cells
  • Also congestion, hemosiderosis, reduction in lymphoid follicles
Microscopic (histologic) images

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Bone marrow: prominent fibrosis and osteosclerosis

Peripheral smear description
  • Leukoerythroblastosis, megakaryocytic nuclei, thrombocytosis with abnormal platelet forms
  • Anisopoikilocytosis with tear drop red blood cells (dacrocytes)
  • Blasts (if transforming to acute leukemia)
Peripheral smear images

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Peripheral blood: megakaryoblasts and platelets

Positive stains
  • Granulocytes: Leder chloroacetate esterase
  • Megakaryocytes: PAS+ cytoplasm, factor VIII related antigen
  • WHO Classification, 2008, marrow fibrosis (MF) scoring system uses reticulin stain:
    • MF 0 Scattered linear reticulin with no intersections of fibers (normal marrow)
    • MF 1: Loose reticulin network with many intersections of fibers, especially in perivascular areas
    • MF 2: Increased reticulin fibrosis with extensive fiber intersections, occasionally with focal collagen deposition or osteosclerosis
    • MF 3: Diffuse and dense increase in reticulin fibrosis with extensive fiber intersections and coarse collagen bundles, often with osteosclerosis
Negative stains
Flow cytometry description
  • Generally noncontributory, except to rule out preleukemia / leukemia or associated lymphoid neoplasm
Molecular / cytogenetics description
  • Molecular:
    • JAK2 V617F mutations in up to 50% of patients with primary myelofibrosis, not specific for myelofibrosis since also seen in other chronic myeloproliferative processes such as essential thrombocytopenia and polycythemia vera
    • Endothelial cells in spleen may demonstrate JAK2 V617F mutations (Blood 2013;121:360)
    • MPL W515K / L mutations in up to 5% of patients with primary myelofibrosis
  • Cytogenetics: karyotypic abnormalities include del(13)(q12-22), der(6)t(1;6)(q21-23;p21.3), del(20q), partial trisomy 1q but are not diagnostic
Differential diagnosis