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.



  • Fibroblast growth factor receptor 1 (FGFR1) abnormalities

  • 8p11 myeloproliferative syndrome (EMS)


  • 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


  • 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


Cell of Origin

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



  • Age

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

  • Gender

    • Slight male predominance


  • 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


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

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


  • Poor despite aggressive chemotherapy

    • Most patients die of disease


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



  • 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


  • 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


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


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


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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