Lymphomas Associated with FGFR1 Abnormalities



Lymphomas Associated with FGFR1 Abnormalities


Roberto N. Miranda, MD










Lymphoma associated with FGFR1 rearrangement displays a biphasic pattern with a lymphoblastic image component in the upper half and a myeloid image component in the lower half.






A) FGFR1 is a transmembrane monomer. B) FGFR1 dimerizes upon growth factor binding. C) The t(8;13) (p11;q12) leads to the formation of ZNF198-FGFR1 chimeric protein, which is constitutively activated.


TERMINOLOGY


Abbreviations



  • Fibroblast growth factor receptor 1 (FGFR1) abnormalities


  • 8p11 myeloproliferative syndrome (EMS)


Synonyms



  • Bilineal lymphoma or blastic T-cell/myeloid lymphoma


  • T-lymphoblastic leukemia/lymphoma ± eosinophilia


  • Synonyms of 8p11 myeloproliferative syndrome



    • Myeloid and lymphoid neoplasms with FGFR1 gene abnormalities



      • 2008 World Health Organization classification


    • 8p11 stem cell leukemia/lymphoma syndrome


Definitions



  • Lymphoblastic lymphoma occurring in patients with 8p11 myeloproliferative syndrome



    • T-cell, T-cell/myeloid, or rarely B-cell lineage reported in literature


  • Definition of 8p11 myeloproliferative syndrome



    • Clinically aggressive disease associated with FGFR1 gene abnormalities


    • Diagnostic features include



      • Myeloproliferative neoplasm usually associated with dysplasia and eosinophilia


      • Lymphadenopathy usually due to T-lymphoblastic leukemia/lymphoma


      • Frequent progression to acute myeloid leukemia


ETIOLOGY/PATHOGENESIS


Cell of Origin



  • Unknown but suspected to be pluripotent (lymphoid/myeloid) stem cell


CLINICAL ISSUES


Epidemiology



  • Age



    • Range: 3-84 years; median: 44 years


  • Gender



    • Slight male predominance


Presentation



  • Patients may present with fatigue, night sweats, weight loss, or fever



    • ˜ 20% of patients are asymptomatic, and disease is discovered incidentally


  • Most patients present with lymphadenopathy



    • Usually generalized but can be localized


  • Hepatomegaly, splenomegaly, and hepatosplenomegaly are common


  • Extranodal sites of disease are uncommon



    • Sites reported: Tonsil, lung, and breast


Laboratory Tests



  • Leukocytosis is common at presentation; median: 46 x 109/L



    • Neutrophilia, eosinophilia, and monocytosis are common


  • Anemia or thrombocytopenia in ˜ 50% of patients


Natural History



  • Common evolution to acute leukemia of myeloid or mixed lineage


Treatment



  • Various protocols for acute leukemia have been used and have not been effective


  • Early stem cell transplantation may lead to long-term remission


Prognosis



  • Poor despite aggressive chemotherapy



    • Most patients die of disease



MICROSCOPIC PATHOLOGY


Histologic Features



  • Lymph node



    • Diffuse or partial effacement of architecture



      • Paracortical distribution in cases with partial involvement


    • Neoplastic cells are blasts that may show single file pattern of infiltration


    • Mature eosinophils are commonly admixed within neoplasm


    • Prominent high endothelial venules are common


    • In some cases, biphasic pattern with 2 components can be observed



      • Sheets of cells that are consistent with lymphoblasts (appear darker)


      • Larger cells with moderately abundant eosinophilic cytoplasm (appear pale)


  • Bone marrow



    • Usually hypercellular, eosinophilia is common


    • Blast count usually normal or slightly increased



      • ˜ 15% of cases reported had > 20% blasts


    • Blasts are usually of myeloid or myeloid/lymphoid lineage


    • Features raise suspicion for myeloproliferative or myeloproliferative/myelodysplastic neoplasm


  • Peripheral blood smear



    • Leukocytosis with left shift in granulocyte maturation; ± blasts


    • Eosinophilia very common; ± monocytosis


ANCILLARY TESTS


Immunohistochemistry



  • Many cases of lymphoma in EMS reported as T-lymphoblastic leukemia/lymphoma



    • T-cell antigens(+), TdT(+), CD1a(+), Ig(-), B-cell antigens(-)


  • For cases of bilineal lymphoma in EMS that have 2 morphologic components



    • Myeloid cells express 1 or more myeloid-associated antigens



      • Myeloperoxidase(+/-), CD68(+/-), CD117(+/-), lysozyme(+/-), CD15(-/+)


    • Lymphoblasts: T-cell antigens(+), TdT(+), CD1a(+)


Flow Cytometry



  • Suspicion of EMS is helpful to ensure analysis of lymphoid and myeloid components


  • Blasts are usually positive for T-lineage markers, TdT, and CD1a


Cytogenetics



  • All cases of EMS carry abnormality involving FGFR1 gene at chromosome 8p11



    • 10 translocations and 1 insertion have been identified


    • t(8;13)(p11;q12) is most common


  • Translocations are usually detected by conventional cytogenetic analysis; rarely are there cryptic translocations


  • Additional cytogenetic abnormalities are associated with progression to acute leukemia



    • Trisomy 21, in particular, is linked to progression


Molecular Genetics



  • As consequence of 8p11 abnormalities, FGFR1 gene is disrupted



    • Results in creation of novel fusion genes and chimeric proteins


  • Chimeric proteins include portions of N-terminal partner gene and C-terminal portion of FGFR1



    • Partner genes and proteins foster dimerization and constitutional activation of FGFR1 tyrosine kinase domain


  • FISH and RT-PCR can be used to detect these translocations/gene rearrangements



    • Because of rarity of disease, these tests are not routinely available


  • Most cases of lymphoma carry monoclonal T-cell receptor (TCR) gene rearrangements



    • Subset of cases lack TCR gene rearrangements




      • Suggests that neoplastic transformation occurs at stem cell stage, before gene rearrangements occur


  • Patients with EMS have clinicopathological manifestations that correlate with specific molecular abnormalities



    • ZNF198-FGFR1: Lymphoma


    • FOP-FGFR1: Polycythemia, eosinophilia, older patient age


    • CEP110-FGFR1: Monocytosis, tonsillar involvement


    • BCR-FGFR1: Chronic myelogenous leukemia-like syndrome


DIFFERENTIAL DIAGNOSIS


Myeloid Sarcoma (MS)



  • Usually, underlying myeloproliferative neoplasm (MPN) or acute leukemia (AL)



    • Less frequently, myelodysplastic syndrome (MDS) or MDS/MPN


    • Association with characteristic cytogenetic or molecular abnormalities of underlying disease


  • Approximately 5% of AML cases can present as MS



    • MS can be nodal or extranodal



      • Nodal involvement is localized rather than generalized


  • Histologically there is diffuse infiltrate of intermediate to large myeloblasts or immature myelomonocytes


  • Immunophenotype: Lysozyme(+), CD68(+), myeloperoxidase(+), CD117(+)



    • Frequently CD13(+) and CD33(+)


    • CD34(+/-), CD99(+/-)


  • Cytochemistry on touch imprints is useful to define myeloid vs. monocytic lineage


Lymphoblastic Leukemia/Lymphoma (LBL)



  • Nodal or extranodal involvement is common at presentation



    • T-LBL may present with mediastinal mass


    • B-LBL is more frequently extranodal


  • Histologically there is diffuse and uniform infiltrate of small to intermediate-sized lymphoblasts


  • Immunophenotype of immature lymphoid cells; of B-cell more frequently than of T-cell lineage


  • Cytogenetic abnormalities are common and define subtypes


Chronic Myelogenous Leukemia, Blast Phase (CML-BP)



  • Nodal or extranodal myeloid blast proliferation occurs in ˜ 15% of cases of CML



    • Usually associated with blast phase in bone marrow or peripheral blood


  • Karyotype and FISH are required to establish



    • t(9;22)(q34;q11.2)


    • Complex cytogenetic abnormalities associated with blast phase


    • BCR-ABL fusion gene


  • RT-PCR can show BCR-ABL and quantify levels


  • Patients with t(8;22)(p11;q11) may present with leukocytosis and basophilia, simulating CML


Myeloproliferative Neoplasm (MPN) or Myelodysplastic/MPN (MDS/MPN)



  • MPN or MDS/MPN may be associated with lymphadenopathy


  • Lymph node involvement may be similar to lymphomas associated with FGFR1 abnormalities


  • Myeloid infiltrates may contain variable amounts of lymphoblasts, usually of T-cell lineage


  • Negative for cytogenetic or molecular features that define other diseases, e.g., BCR-ABL, JAK2, FIP1L1-PDGFRα


  • Further studies are required to define these processes


DIAGNOSTIC CHECKLIST


Clinically Relevant Pathologic Features



  • Lymphadenopathy associated with leukocytosis and eosinophilia should raise suspicion of this disease


Pathologic Interpretation Pearls



  • Lymphadenopathy with diffuse effacement due to lymphoblasts and myeloblasts


  • Bone marrow with features of MPN or MPN/MDS and eosinophilia


  • Peripheral blood may show leukocytosis and CML-like features



SELECTED REFERENCES

1. Jackson CC et al: 8p11 myeloproliferative syndrome: a review. Hum Pathol. 41(4):461-76, 2010

2. Tefferi A et al: Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc. 85(2):158-64, 2010

3. Vega F et al: t(8;13)-positive bilineal lymphomas: report of 6 cases. Am J Surg Pathol. 32(1):14-20, 2008

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lymphomas Associated with FGFR1 Abnormalities

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