Bone marrow neoplastic

• Primary myelofibrosis is an uncommon myeloproliferative neoplasm characterized by a proliferation of predominantly abnormal megakaryocytes and granulocytes in the bone marrow, which in fully developed disease is associated with reactive deposition of fibrous connective tissue and extramedullary hematopoiesis

Diagnostic criteria for prefibrotic primary myelofibrosis	Diagnostic criteria for primary myelofibrosis, fibrotic stage
Diagnosis of prefibrotic primary myelofibrosis requires that all 3 major criteria and at least 1 minor criterion are met	Diagnosis of overt primary myelofibrosis requires that all 3 major criteria and at least 1 minor criterion are met
Major criteria
Megakaryocytic proliferation and atypia, without reticulin fibrosis grade > 1a, accompanied by increased age adjusted bone marrow cellularity, granulocytic proliferation and (often) decreased erythropoiesis WHO criteria for BCR::ABL1 positive chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myelodysplastic syndromes or other myeloid neoplasms are not met JAK2, CALR or MPL mutation Or presence of another clonal marker Or absence of minor reactive bone marrow reticulin fibrosis	Megakaryocytic proliferation and atypia, accompanied by reticulin or collagen fibrosis grades 2 or 3a WHO criteria for essential thrombocythemia, polycythemia vera, BCR::ABL1 positive chronic myeloid leukemia, myelodysplastic syndrome or other myeloid neoplasms are not met JAK2, CALR or MPL mutation Or presence of another clonal marker Or absence of reactive myelofibrosis
Minor criteria
Presence of at least 1 of the following, confirmed in 2 consecutive determinations Anemia not attributed to a comorbid condition Leukocytosis ≥ 11 x 109/L Splenomegaly detected clinically or by imaging Lactate dehydrogenase level above the upper limit of the institutional reference range Leukoerythroblastosis	Presence of at least 1 of the following, confirmed in 2 consecutive determinations Anemia not attributed to a comorbid condition Leukocytosis ≥ 11 x 109/L Splenomegaly detected clinically or by imaging Lactate dehydrogenase level above the upper limit of the institutional reference range Leukoerythroblastosis

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H. and AFIP

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.

• Some cases show low side scattering, aberrant CD56 expression in granulocytes and monocytes and an abnormal CD13 / CD16 maturation pattern (Am J Clin Pathol 2010;133:314)

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.

• No specific genetic marker
• No BCR::ABL fusion gene (or classify as chronic myeloid leukemia); presence of del(13)(q12-22) or der(6)t(1;6)(q21-23;p21.3) is strongly suggestive of primary myelofibrosis
• Shows karyotypic abnormalities in up to 50% of cases
  • Frequent abnormalities include del(20q), del(13q), +8, +9 and abnormalities of 1q
• Unfavorable karyotype (complex karyotype; > 3 abnormalities) (Virchows Arch 2023;482:53)
  • Isolated +8, isolated -7/7q-, i(17q), -5/5q-, 12p-, 11q23 rearrangement or inv(3) and an abnormal karyotype with abnormalities of chromosomes 5, 7, 17 or 12p-
• Mutations (Am J Hematol 2023;98:801)
  • Driver mutations
    • JAK2 V617F mutation (50 - 60%)
    • CALR mutations (25 - 30%)
    • MPL mutations (5 - 10%)
    • Triple negative for mutations in JAK2, CALR and MPL (8 - 12%)
  • Other mutations
    • Include ASXL1, EZH2, TET2, IDH1 / IDH2, SRSF2 or SR3B1
• Driver mutational profile is associated with overall survival
  • CALR mutated cases have better survival compared to others
  • Triple negative cases have the shortest survival compared to others

• Other causes of leukoerythroblastosis or dry taps:
  • Granulomatous marrow disease, metastases to marrow (desmoplasia but no increased reticulin) or lymphoma
• Other myeloid disorders:
  • Myeloproliferative neoplasms:
    • Chronic myelogenous leukemia:
      • Positive BCR::ABL translocation
    • Polycythemia vera:
      • Dispersed less atypical megakaryocytes and prominent erythroid element
    • Essential thrombocythemia:
      • Uniformly enlarged megakaryocytes with deeply lobulated (staghorn) nuclei, in loose clusters; normal myeloid:erythroid ratio
  • Myelodysplastic / myeloproliferative neoplasms:
    • Show hybrid myelodysplastic and myeloproliferative features manifested by at least 1 cytopenia and at least 1 cytosis in blood
    • Myeloid maturation is intact and usually mature cells predominate
    • Exact subtype should be diagnosed based on the specific criteria of the entity
  • Myelodysplastic syndromes are a heterogeneous group of entities that demonstrate:
    • Variable degrees of ineffective hematopoiesis
    • < 20% blasts in marrow
    • Peripheral blood with unexplained and persistent cytopenia(s), < 20% blasts, < 1.0 x 10⁹/L monocytes and dysplasia in 1 or more myeloid lineages
  • Mastocytosis:
    • Shows focal, compact aggregates of mast cells in bone marrow core biopsy
    • Cells can show the following patterns of infiltration: paratrabecular, perivascular or parafollicular
    • Presence of atypical mast cell supports the diagnosis
    • Most cases will harbor a KIT D816V mutation
• Reactive thrombocythemia:
  • Causes include exercise, allergic reaction, reaction to medications, inflammatory disorders, asplenism, infection, connective tissue disorders, metastatic cancer, lymphoproliferative disorders and iron deficiency
• Acute myelofibrosis:
  • Subtype of acute myeloid leukemia that shows > 20% blasts in peripheral blood or bone marrow
  • Patients also present with bone marrow fibrosis, fever and pancytopenia
• Autoimmune myelofibrosis:
  • Generally shows diffuse reticulin fibrosis and an associated autoimmune disease such as rheumatoid arthritis
• Primary hyperparathyroidism:
  • Rarely causes myelofibrosis and pancytopenia (Int J Lab Hematol 2007;29:464)

A 57 year old man presented with fatigue, splenomegaly and hepatomegaly. A complete blood count demonstrated anemia and thrombocytosis. A bone marrow aspirate and biopsy were ordered (shown above). What statement about this disease is correct?

1. CALR mutation is the most common mutation encountered
2. Complex karyotype is common
3. MPL mutation is the most common mutation encountered
4. Some cases can be triple negative for mutations in JAK2, CALR and MPL

D. Some cases can be triple negative for mutations in JAK2, CALR and MPL. Primary myelofibrosis cases harbor a phenotypic driver mutation in JAK2 V617F mutation (50 - 60%), CALR mutations (25 - 30%) and MPL mutations (5 - 10%) and are triple negative for mutations in JAK2, CALR and MPL (8 - 12%). Answer B is incorrect because complex karyotype is uncommon. Answers A and C are incorrect because CALR and MPL are less common than JAK2 mutations.

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Reference: Primary myelofibrosis

What is the most common genetic mutation in primary myelofibrosis?

1. ABL
2. CALR
3. JAK2
4. MPL

C. JAK2. Primary myelofibrosis cases harbor a phenotypic driver mutation in JAK2 V617F mutation (50 - 60%), CALR mutations (25 - 30%) and MPL mutations (5 - 10%) and are triple negative for mutations in JAK2, CALR and MPL (8 - 12%). Answers B and D are incorrect because CALR and MPL are less common than JAK2 mutations. Answer A is incorrect because ABL mutations have not been described in primary myelofibrosis.

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Reference: Primary myelofibrosis