Bone marrow neoplastic

Bone marrow - neoplastic myeloid

Myeloid / lymphoid neoplasms with eosinophilia and gene rearrangement

FLT3 rearrangement



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PubMed Search: Myeloid / lymphoid neoplasm with FLT3 rearrangement

Sara Niyazi, D.O.
Ling Zhang, M.D.
Page views in 2024 to date: 79
Cite this page: Niyazi S, Zhang L. FLT3 rearrangement. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticFLT3rearr.html. Accessed July 13th, 2024.
Definition / general
  • Myeloid / lymphoid neoplasms with FLT3 rearrangements are a cluster of hematopoietic stem cell neoplasms with heterogenous clinical presentations
  • Typical manifestation is a myeloid neoplasm with or without associated T lymphoblastic lymphoma / leukemia, which is derived from gene rearrangements and the formation of fusion genes involving Fms related receptor tyrosine kinase 3 (FLT3)
Essential features
  • Myeloid or lymphoid neoplasms with FLT3 gene rearrangement are rare hematologic diseases that typically have a poor clinical outcome
  • Partner fusion genes can be variable; the most common is ETV6
  • Clinical phenotype varies and the disease can manifest as acute myeloid leukemia (AML), chronic eosinophilic leukemia (CEL), myeloid sarcoma, myelodysplastic syndrome (MDS), myelodysplastic syndrome / myeloproliferative neoplasm (MDS / MPN), T lymphoblastic leukemia / lymphoma (T ALL / LBL) or as a combination or a concurrent myeloid / lymphoid neoplasm
  • FLT3 gene rearrangements are often associated with eosinophilia; however, it may be absent
ICD coding
  • ICD-O: 9969/3 - myeloid / lymphoid neoplasm with FLT3 rearrangement
  • ICD-11: 2A22 - other and unspecified myeloproliferative neoplasms
Epidemiology
Sites
  • Bone marrow, peripheral blood and lymphatic organs are typically involved
Pathophysiology
  • Formation of FLT3 fusion gene leads to constitutive phosphorylation and activation of growth factor / ligand independent proliferation (Exp Hematol 2007;35:1723)
  • Most common fusion partner gene is ETV6 / 12p13 (Cold Spring Harb Mol Case Stud 2018;4:a003079)
  • Other partner genes have been reported, including BCR / 22q11, ZMYM2 / 13q12, TRIP11 / 14q32, SPTBN1 / 2p16, GOLGB1 / 3q13, CCDC88C / 14q32, ZBTB44 / 11q24 and MYO18A / 17q12
  • Cases of acquired FLT3 fusion genes during course of disease have been reported in a subset of myeloid neoplasms
  • Phenotypic presentation is variable but fusions usually produce a myeloproliferative neoplasm or T cell lymphoblastic leukemia / lymphoma with or without associated eosinophilia (Mod Pathol 2021;34:1673)
Etiology
  • Unknown at this time
Diagrams / tables

Images hosted on other servers:
Summary of reported cases

Summary of reported cases

Clinical features
  • Patients typically present with findings related to underlying hematopoietic abnormalities, such as fatigue, frequent infections, bruising and bleeding
  • Extramedullary involvement has been reported (Mod Pathol 2021;34:1673)
  • Lymphadenopathy and splenomegaly may be present
Diagnosis
  • Essential criteria, according to the 5th edition of WHO classification, include the presence of a myeloid or lymphoid neoplasm with chromosomal rearrangements leading to the formation of a FLT3 fusion gene, with or without associated eosinophilia
Laboratory
  • Complete blood count (CBC) may show leukocytosis, anemia and thrombocytopenia (Mod Pathol 2021;34:1673)
  • Eosinophilia is common but not seen in all cases
  • Monocytosis can be seen in a subset of patients
Radiology description
Prognostic factors
Case reports
Treatment
Microscopic (histologic) description
  • Histologic findings vary based on phenotype and include
Microscopic (histologic) images

Contributed by Ling Zhang, M.D.
T lymphoblastic lymphoma: lymphoblasts

T lymphoblastic lymphoma: lymphoblasts

T lymphoblastic lymphoma: lymphoblasts and eosinophils

T lymphoblastic lymphoma: lymphoblasts and eosinophils

T lymphoblastic leukemia / lymphoma: hypercellular bone marrow

T lymphoblastic
leukemia / lymphoma:
hypercellular
bone marrow

Myeloid hyperplasia in bone marrow

Myeloid hyperplasia in bone marrow


T lymphoblastic lymphoma: CD3

T lymphoblastic lymphoma: CD3

T lymphoblastic lymphoma: TdT

T lymphoblastic lymphoma: TdT

T lymphoblastic lymphoma: Ki67

T lymphoblastic lymphoma: Ki67

Peripheral smear description
  • Peripheral smear findings will vary based on the specific type of myeloid / lymphoid neoplasm
  • Anemia, granulocytosis, eosinophilia and monocytosis may be present (Mod Pathol 2021;34:1673)
  • Blasts may be seen in cases of acute leukemia
Peripheral smear images

Contributed by Ling Zhang, M.D.
Circulating blasts

Circulating blasts

Positive stains
  • Staining patterns vary based on disease phenotype; positive staining will follow typical patterns for the specific phenotype
  • FLT3 rearrangement does not appear to impact staining patterns
Flow cytometry description
Flow cytometry images

Contributed by Ling Zhang, M.D. and Sara Niyazi, D.O.
T ALL with FLT3 rearrangement

T ALL with FLT3 rearrangement

Molecular / cytogenetics description
  • Chromosomal rearrangements of 13q12 involving FLT3 are typically found on karyotyping studies
  • FLT3 fusions can be detected with RT PCR, RNA sequencing or break apart FISH probes for FLT3
Molecular / cytogenetics images

Images hosted on other servers:
ETV6::FLT3 fusion RT PCR

ETV6::FLT3 fusion RT PCR

t(13;14)(q12;q32) TRIP11::FLT3 fusion

t(13;14)(q12;q32) TRIP11::FLT3 fusion

Chromosomal translocations / FISH analysis

Chromosomal translocations / FISH analysis

Sample pathology report
  • Bone marrow, right posterior iliac crest, aspirate, clot and core biopsy:
    • T lymphoblastic leukemia / lymphoma and myeloid / lymphoid neoplasm with TRIP11::FLT3 rearrangement and eosinophilia (see comment)
    • Markedly hypercellular bone marrow (~100%) with trilineage hematopoiesis, marked myeloid hyperplasia, increased eosinophils and small population (~5% of the cellularity) of CD1a+ and CD4 / CD8 double + atypical T cells
    • Mild diffuse reticulin fibrosis (1/3)
    • Adequate storage iron
    • Comment: The bone marrow biopsy is markedly hypercellular with myeloid hyperplasia and increased eosinophils. Immunostain for CD1a and flow cytometry reveal approximately 5% CD1a+ and CD4 / CD8 double positive abnormal T lymphocytes, indicating involvement by T lymphoblastic leukemia / lymphoma. T cell gene rearrangement is positive for T cell gamma gene rearrangement. FISH for BCR::ABL1 and MDS are negative. Karyotyping showed 46,XY,t(13;14)(q12;q32)[9] / 46,XY[11]. t(13;14)(q12;q32) is typically associated with a TRIP11::FLT3 fusion and could occur in patients with a myeloid / lymphoid neoplasm with eosinophilia.
    • Microscopic examination
      • Peripheral blood
        • Mild normocytic anemia
        • Granulocytosis and left shift
        • Monocytosis and increased MO1 monocytes by flow cytometry
      • Peripheral smear
        • Moderate anisopoikilocytosis
        • Mild left shifted granulocyte maturation with unremarkable morphology and no obvious blasts
      • Bone marrow aspirate smear
        • Adequacy: spicular, cellular
        • Megakaryocytes: adequate with unremarkable morphology
        • Myeloid lineage: progressive maturation with no obvious increase in blasts
        • Erythroid lineage: complete maturation with unremarkable morphology
        • Myeloid:erythroid (M:E) ratio: 7:1
        • Bone marrow differential count: blasts: 1.0 %, promyelocytes: 0.5%, myelocytes: 6.0%, metamyelocytes: 6.0%, band neutrophils: 13.0%, segmented neutrophils: 28.0%, eosinophils: 17%, basophils: 7.0%, monocytes: 3.0%, lymphocytes: 7.0%, early normoblasts: 1.0%, late normoblasts: 10.5%
      • Bone marrow clot section and core biopsy
        • Bony trabeculae: unremarkable
        • Cellularity: markedly hypercellular (~100%)
        • Megakaryocytes: increased with rare small, hypolobated forms
        • Myeloid lineage: increased with progressive maturation and no increase in blasts
        • Erythroid lineage: adequate with complete maturation
        • Estimated M:E ratio: 7:1
        • Iron stores: adequate
        • Reticulin fibrosis: mild, diffuse fibrosis (1/3)
        • Ringed sideroblasts: none seen
        • Significant findings: hypercellular bone marrow with panmyelosis and mildly prominent sinusoids
      • The following immunohistochemical studies were performed with adequate controls on the core biopsy
        • CD34: no increase in blasts
        • TdT: slight focal increase with loose clusters of positive cells (~1% of total cellularity)
        • CD3: increased T cells, involving approximately 20% of marrow cellularity
        • CD1a: scattered positive cells, approximately 5% of the cellularity
        • CD61: adequate megakaryocytes
Differential diagnosis
  • All myeloid or lymphoid neoplasms not involving FLT3 rearrangements or fusion
Board review style question #1

A 32 year old man presents with fatigue, fever and unexplained weight loss for the past 3 weeks. On physical examination, splenomegaly is noted. Laboratory tests reveal leukocytosis (34 x 109/L) with increased blast cells (30%) and eosinophils (5 x 109/L) in the peripheral blood. Bone marrow biopsy is performed and demonstrates myeloid hyperplasia and eosinophilia. Genetic analysis shows the presence of an FLT3::ETV6 gene fusion. Which of the following molecular mechanisms is primarily associated with the development of the FLT3::ETV6 gene fusion and its role in leukemogenesis?

  1. Activation of tumor suppressor genes through promoter hypermethylation
  2. Dysregulation of DNA mismatch repair genes
  3. Ligand independent activation involving a receptor tyrosine kinase
  4. Overexpression of SMAC / Diablo
Board review style answer #1
C. Ligand independent activation involving a receptor tyrosine kinase. FLT3 is a receptor tyrosine kinase that normally plays a crucial role in regulating the proliferation, differentiation and survival of hematopoietic stem cells and progenitor cells. Mutations in the FLT3 gene can lead to constitutive activation of the FLT3 receptor kinase, promoting uncontrolled cell growth. Answer B is incorrect because FLT3 gene fusions do not involve mismatch repair mechanisms. Answer A is incorrect because FLT3 gene fusions involve phosphorylation and not hypermethylation. Answer D is incorrect because SMAC / Diablo overexpression has been shown to oppose tumor progression and has not been associated with development of the FLT3::ETV6 gene fusion.

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Reference: Myeloid / lymphoid neoplasm with FLT3 rearrangement
Board review style question #2
A 48 year old woman presents with fatigue, fever and extreme weakness. Laboratory tests reveal eosinophila (8 x 109/L) in the peripheral blood. You suspect an eosinophilia associated myeloproliferative neoplasm. A bone marrow biopsy is performed and genetic analysis shows the presence of an FLT3 gene fusion. What is the most commonly reported FLT3 partner fusion gene?

  1. CCDC88C
  2. ETV6
  3. GOLGB1
  4. ZBTB44
Board review style answer #2
B. ETV6. The most common FLT3 partner fusion gene is ETV6. The ETV6 gene is located on chromosome 12 and encodes a transcription factor that also plays a crucial role in the normal development of blood cells. Answers A, C and D are incorrect because although they have each been reported as a partner fusion gene with FLT3, they are not the most common.

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Reference: Myeloid / lymphoid neoplasm with FLT3 rearrangement
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