Bone marrow neoplastic
Bone marrow - neoplastic myeloid
Myeloid / lymphoid neoplasms with eosinophilia and gene rearrangement
FLT3 rearrangement
Authors: Sara Niyazi, D.O., Ling Zhang, M.D.
Editorial Board Member: Anamarija M. Perry, M.D.
Last staff update: 26 November 2024 (update in progress)
Copyright: 2023-2024, PathologyOutlines.com, Inc.
PubMed Search: Myeloid / lymphoid neoplasm with FLT3 rearrangement
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Peripheral smear description | Peripheral smear images | Positive stains | Flow cytometry description | Flow cytometry images | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Niyazi S, Zhang L. FLT3 rearrangement. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticFLT3rearr.html. Accessed December 4th, 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
Epidemiology
- More common in males; M:F = ~1.4:1.0 (Mod Pathol 2021;34:1673)
- Age range: 2 - 80 years (median, fifth decade)
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
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
- Splenomegaly and lymphadenopathy may be found in some patients (Mod Pathol 2021;34:1673)
- Lytic bone lesions may be seen on imaging (Mod Pathol 2021;34:1673)
- Soft tissue masses can be seen in certain cases (Mod Pathol 2021;34:1673)
Prognostic factors
- FLT3 mutations are typically associated with a poor prognosis and aggressive clinical course (J Natl Compr Canc Netw 2020;18:1248)
- Disease course and aggressiveness may vary based on specific fusion (Cold Spring Harb Mol Case Stud 2023;9:a006243)
Case reports
- 8 month old boy with fever, hepatosplenomegaly, lymphadenopathy and diffuse rash mimicking juvenile myelomonocytic leukemia (JMML) (Blood Adv 2021;5:1899)
- 33 year old man with pruritus and urticaria (Cold Spring Harb Mol Case Stud 2023;9:a006243)
- 47 year old man with leukocytosis and splenomegaly and 49 year old man with lymphadenopathy, leukocytosis and thrombocytopenia (Cold Spring Harb Mol Case Stud 2018;4:a003079)
- 60 year old man with painful lesion in left medial clavicle with histologic diagnosis of myeloid sarcoma (Leuk Res 2020;99:106460)
- 64 year old man with fatigue, weight loss, splenomegaly, leukocytosis and thrombocytopenia (Br J Haematol 2020;191:297)
Treatment
- Small molecule FLT3 inhibitors, such as sorafenib, midostaurin and sunitinib, have produced favorable response and may improve survival (Leukemia 2014;28:2090, Haematologica 2019;104:e398)
- Allogeneic hematopoietic stem cell transplantation may result in remission for some patients (Ann Hematol 2014;93:535)
Microscopic (histologic) description
- Histologic findings vary based on phenotype and include
- Proliferation of small to medium sized primitive cells in T lymphoblastic leukemia / lymphoma
- Panmyelosis or granulocytosis in cases of myeloproliferative neoplasms (Br J Haematol 2020;191:297)
- Eosinophilia, regardless of phenotype
- Mastocytosis in bone marrow (Cold Spring Harb Mol Case Stud 2023;9:a006243)
Microscopic (histologic) images
Contributed by Ling Zhang, M.D.
T lymphoblastic lymphoma: lymphoblasts
T lymphoblastic lymphoma: lymphoblasts and eosinophils
T lymphoblastic
leukemia / lymphoma:
hypercellular
bone marrow
Myeloid hyperplasia in bone marrow
T lymphoblastic lymphoma: CD3
T lymphoblastic lymphoma: TdT
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
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
- Disease can manifest as AML, CEL, myeloid sarcoma, MDS, MDS / MPN, T ALL / LBL or as a combination of myeloid / lymphoid neoplasms and will stain as such
Flow cytometry description
- Specific flow cytometry findings vary by phenotype
- Findings may include
- Increased blast population (Leuk Res 2020;99:106460)
- Altered antigen expression, such as atypical expression of surface cell markers (Cold Spring Harb Mol Case Stud 2023;9:a006243)
- Varying clonal abnormalities within the blast cell population (J Hematopathol 2014;7:71)
Flow cytometry images
Contributed by Ling Zhang, M.D. and Sara Niyazi, D.O.
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
t(13;14)(q12;q32) TRIP11::FLT3 fusion
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
- Peripheral blood
Differential diagnosis
- All myeloid or lymphoid neoplasms not involving FLT3 rearrangements or fusion
Additional references
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?
- Activation of tumor suppressor genes through promoter hypermethylation
- Dysregulation of DNA mismatch repair genes
- Ligand independent activation involving a receptor tyrosine kinase
- 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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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?
- CCDC88C
- ETV6
- GOLGB1
- 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
