Bone marrow neoplastic

• Up to 10% of acute myeloid leukemia (AML) cases with mutated RUNX1 at diagnosis have the RUNX1 mutation confirmed as germline change (Blood 2021;137:1428, Blood Adv 2018;2:146)
• Carriers of familial RUNX1 variants are at a ~30 - 40% lifetime risk of having a myeloid neoplasm (Leukemia 2020;34:2519)
• Incidence of development of T cell or B cell lymphoid neoplasm is unknown but recognized (see Case reports) (Pediatr Blood Cancer 2023;70:e30184, Blood Adv 2021;5:3199)

• 10 year old boy with history of thrombocytopenia, germline RUNX1 variant and new diagnosis of T cell lymphoblastic lymphoma (Pediatr Blood Cancer 2023;70:e30184)
• 12 year old girl with revertant mosaicism for the familial RUNX1 mutation (Haematologica 2020;105:e535)
• 16 year old girl and 16 year old boy (unrelated patients) with history of mild thrombocytopenia, germline RUNX1 variants and new diagnosis of B cell acute lymphoblastic leukemia (Blood Adv 2021;5:3199)

Contributed by Barina Aqil, M.D.

Contributed by Madina Sukhanova, Ph.D.


Images hosted on other servers:

• Peripheral blood, bone marrow aspirate and bone marrow core biopsy:
  • Myelodysplastic syndrome involving a variably cellular bone marrow (see comment)
  • Comment: There is dysplasia in the granulocyte, erythroid and megakaryocyte lineages. Immunochemical stain for CD34 highlights 3 - 4% blasts. No ring sideroblasts are identified. Myeloid NGS detected DNMT3A (Q656*, VAF 47%) and TET2 (Q1828*, VAF 46%) mutations. The overall findings are consistent with myelodysplastic syndrome with low blasts (MDS LB) per the WHO, 5th edition, 2022 and myelodysplastic syndrome, not otherwise specified (MDS, NOS), with multilineage dysplasia per ICC (Blood 2023;141:437).
  • Peripheral blood smear
    • Peripheral blood smear shows mild normocytic anemia
    • Red blood cells show anisopoikilocytosis including occasional teardrop forms, ovalocytes and acanthocytes
    • Absolute neutropenia with shift to immaturity
    • Thrombocytopenia with unremarkable morphology
  • Bone marrow aspirate smear / touch preparation
    • Bone marrow aspirate smear slides show several cellular spicules for evaluation
    • Myeloid precursors show shift to immaturity with many hypolobated / monolobated neutrophils
    • Erythroid precursors show progressive maturations with megaloblastic changes and occasional nuclear budding and irregular nuclear contour
    • Megakaryocytes are decreased but occasional small monolobated megakaryocytes are present
    • Touch preparations are cellular with similar findings to the bone marrow aspirates
    • Small hypolobated / monolobated megakaryocytes are present
  • Bone marrow core biopsy / particle clot
    • Bone marrow core biopsy is fragmented and has variable cellularity, overall normocellular
      • Myeloid precursors show progressive maturation with unremarkable morphology
      • Small megakaryocytes are present
    • Particle clot sections show many bone marrow particles for evaluation
      • Marrow is hypercellular for age (~80% cellular)
      • Myeloid precursors show progressive maturation with many hypolobated / monolobated neutrophils
      • Erythroid precursors are relatively decreased and show progressive maturation with unremarkable morphology
      • Megakaryocytes are present with small hypolobated / monolobated forms
  • Addendum: This addendum is being issued to report the results of additional germline genetic testing. Molecular testing of patient’s skin fibroblasts identified germline pathogenic intragenic deletion of RUNX1 (exons 5-6). This finding in conjunction with lifelong history of thrombocytopenia is consistent with myelodysplastic syndrome with germline predisposition (familial platelet disorder).

Which of the following is a characteristic phenotype of megakaryocytes in bone marrow biopsy of an asymptomatic individual with familial RUNX1 mutation (shown in the image above)?

1. Atypical megakaryocytes with separated nuclear lobes
2. Dysplastic megakaryocytes with nonlobated or bilobed nuclei
3. Numerous micromegakaryocytes
4. Small hypolobated / monolobated megakaryocytes

D. Small hypolobated / monolobated megakaryocytes is a characteristic finding during bone marrow examination of individuals with germline RUNX1 pathogenic or likely pathogenic (P / LP) variant. It should be noted that megakaryocytes are atypical but not dysplastic (Pediatr Dev Pathol 2019;22:315, Haematologica 2017;102:1661); thus, answer B is incorrect because nonlobated or bilobed megakaryocytes are common in acute myeloid leukemia (AML) with MECOM rearrangements. Answer A is incorrect because megakaryocytes with separated nuclear lobes are typical for GATA2 deficiency syndrome. Answer C is incorrect because the presence of numerous micromegakaryocytes in the bone marrow is frequently observed in myelodysplastic syndrome (MDS) with isolated del(5q) syndrome.

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Reference: Myeloid or lymphoid neoplasms with germline RUNX1 mutation

A 48 year old patient with a history of lifelong thrombocytopenia and family history of thrombocytopenia and myeloid malignancies in their mother and maternal uncle was found to have pancytopenia during routine monitoring. Bone marrow examination revealed 3 - 4% blasts, erythroid precursors with unremarkable morphology and megakaryocytes with small monolobated forms. Conventional cytogenetic analysis did not reveal any chromosomal aberrations. Single nucleotide polymorphism (SNP) array analysis detected intragenic deletion of RUNX1 and next generation sequencing (NGS) revealed pathogenic mutations in TET2, DNMT3A and ASXL1. Which of the following detected genetic abnormalities is most likely a germline one?

1. ASXL1 mutation
2. DNMT3A mutation
3. RUNX1 intragenic deletion
4. TET2 mutation

C. RUNX1 intragenic deletion. The patient's personal history and family history as well as small monolobated megakaryocytes are concerning for RUNX1 pathogenic or likely pathogenic (P / LP) variant, in this case intragenic deletion, which should be confirmed in cultured skin fibroblasts (Pediatr Dev Pathol 2019;22:315, Haematologica 2017;102:1661). Answers A, B and D are incorrect because mutations in TET2, DNMT3A and ASXL1 are common during oncogenic progression and are somatic events.

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Reference: Myeloid or lymphoid neoplasms with germline RUNX1 mutation