Lymphomas Associated with FGFR1 Abnormalities

Roberto N. Miranda, MD

Key Facts

Terminology

Lymphoblastic lymphoma occurring in patients with 8p11 myeloproliferative syndrome
EMS is aggressive disease associated with FGFR1 gene abnormalities; diagnostic features include
- Myeloproliferative neoplasm usually associated with dysplasia and eosinophilia
- Lymphadenopathy usually due to T-LBL or bilineal T-cell/myeloid lymphoma
- Frequent progression to acute myeloid leukemia
Synonym of 8p11 myeloproliferative syndrome
- Myeloid and lymphoid neoplasms with FGFR1 abnormalities (WHO, 2008)

Clinical Issues

Lymphadenopathy is common
- Cases associated with t(8;13)(p11;q12)
Leukocytosis is common at presentation
Poor prognosis despite aggressive chemotherapy
Stem cell transplantation may lead to long-term remission

Microscopic Pathology

Diffuse or partial effacement of architecture by blasts
Mature eosinophils are commonly admixed within neoplasm
In some cases, biphasic pattern can be observed
- Sheets of lymphoblasts
- Larger cells, often perivascular, with moderate eosinophilic cytoplasm

Ancillary Tests

Chromosome 8p11/FGFR1 gene abnormalities

Lymphoma associated with FGFR1 rearrangement displays a biphasic pattern with a lymphoblastic

component in the upper half and a myeloid

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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