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Myeloid and lymphoid Neoplasms with FGFR1 abnormalities: diagnostic and therapeutic challenges

The patient is a 46-year-old Chinese-American man who came to medical attention in China 4 months prior with a viral-like syndrome and painful enlargement of a submandibular lymph node. His white blood cell count was elevated (20 3 10/L). The patient was treated symptomatically by his physicians in China. The patient subsequently developed progressive cervical lymphadenopathy and was referred to an oncologist. A bone marrow biopsy was performed and demonstrated a hypercellular marrow (90%) with left-shifted myeloid hyperplasia and eosinophilia (Fig. 1). Given these findings, there was a concern for a myeloproliferative neoplasm. Testing of the peripheral blood for the Janus Kinase 2 (JAK2) V617F mutation and polymerase chain reaction analysis for BCR-ABL1 were both negative. However, bone marrow chromosome analysis revealed the translocation t(8;13)(p12;q12) (Fig. 1). In addition, trisomy 21 was detected. The patient then underwent excisional biopsy of an enlarged, painful inguinal lymph node which revealed T lymphoblastic lymphoma (Fig. 1). He was referred to our institution for further management. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA (platelet derived growth factor receptor alpha), PDGFRB (platelet derived growth factor receptor beta) or FGFR1 (fibroblast growth factor receptor-1) are a set of entities which are now included in their own separate major category in the current WHO classification of tumors of hematopoietic and lymphoid tissues [1]. This group represents three separate entities which all result from the formation of an abnormal fusion gene that encodes an aberrant tyrosine kinase. Eosinophilia is characteristic in all three entities. Myeloid and lymphoid neoplasms with PDGFRA rearrangement most commonly present with chronic eosinophilia, but also can present as acute myeloid leukemia (AML), T lymphoblastic leukemia or both. This syndrome is rare and more common in men than women (male (M):female (F) of 17:1) with a median age of diagnosis in the late 5th decade. The bone marrow and peripheral blood are always involved and tissue infiltration by eosinophils is typical. The most common cytogenetic abnormality reveals a FIP1L1-PDGFRA fusion gene from a cryptic del(4)(q12). Due to the cryptic nature of the deletion found in the majority of cases, molecular studies [polymerase chain reaction (PCR)] or FISH (fluorescence in situ hybridization) may be necessary for diagnosis. Myeloid neoplasms with PDGFRB rearrangement have many similar features to myeloid and lymphoid neoplasms with PDGFRA rearrangement; however, prominent differences exist. Patients typically present with features of chronic myelomonocytic leukemia with eosinophilia; however, some cases present as atypical chronic myeloid leukemia, BCRABL1 negative with eosinophilia, chronic eosinophilia or myeloproliferative neoplasm (MPN) with eosinophilia. This entity is also more common in men but not to the degree as cases associated with PDGFRA rearrangement (M:F of 2:1). Cytogenetic analysis typically reveals t(5;12)(q31 33;p12) resulting in the formation of an ETV6-PDGFRB fusion gene. Myeloid and lymphoid neoplasms with FGFR1 abnormalities were described in 1977 by Manthorpe et al. [2] and the term 8p11 myeloproliferative syndrome was suggested in 1995 by Macdonald et al. [3]. This entity is more heterogeneous in nature as the presentation may be as a MPN (typically with eosinophilia), AML, T or B lymphoblastic lymphoma/leukemia or a mixed phenotype acute leukemia [1,4]. This neoplasm also occurs across a wide age range but the median age of diagnosis is slightly younger than that of the other two entities (44 years of age) [4]. Furthermore, the male predominance is not as marked (M:F of 1.17:1). Bone marrow and peripheral blood are almost always involved (a reported 90% of cases show eosinophilia), with a minority of patients presenting with only lymph node involvement secondary to lymphoblastic lymphoma or myeloid sarcoma [4]. A recent review identified four patients at one center with FGFR1 rearrangements detected by FISH, and of these four patients, only two had eosinophilia [5]; this highlights the broad clinical spectrum of this entity. Cytogenetic studies reveal a translocation, or rarely an insertion, involving the 8p11-12 breakpoint resulting in a variety of fusion genes involving a portion of the FGFR1 gene. The most common translocation is t(8;13)(p11;q12) resulting in a ZNF198-FGFR1 fusion gene [6]. A recent review described the currently known cytogenetic abnormalities, which included 10 additional translocations and one insertion [4]. Since this review, at least three additional abnormalities have been described, t(3;8;9)(p25;p21;q34), t(1;8)(q25;p11.2) and t(7;8)(q22;p11) [7–9]. Depending on the partner gene, different manifestations may be apparent. Specifically, patients with t(8;22)(p11;q11) often show peripheral blood basophilia and may be confused with chronic myelogenous leukemia [10]. Whereas cases with t(6;8)(q27;p12) often present with polycythemia [11]. If tonsillar involvement is noted, t(8;9)(p11;q34) is the most likely finding and monocytosis may be prominent [4]. Lastly, patients with t(8;13)(p11;q12) more often present with or develop lymphadenopathy secondary to T lymphoblastic