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 × 109/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.


Figure 1. (a) Hematoxylin and eosin (H&E) stained section of initial bone marrow biopsy revealed a hypercellular marrow with eosinophilia, 500× original magnification. (b) A karyotype performed on the aspirate revealed trisomy 21 as well as a translocation between chromosomes 8 and 13, which was later classified as t(8;13)(p12;q12). (c) Cytospin prepared from lymph node tissue (Wright Giemsa stain, 1000× original magnification) revealed numerous medium-sized immature lymphoid cells with high nuclear to cytoplasmic ratios with scattered eosinophils. (d) The H&E stained section of the lymph node biopsy, 500× original magnification, revealed a sheet-like infiltrate of monotonous immature lymphoid cells. (e) Terminal deoxynucleotidyl transferase (TdT) immunohistochemical stain was diffusely positive in the neoplastic cells in a nuclear pattern confirming the diagnosis of T lymphoblastic lymphoma, 500× original magnification. (f) A repeat bone marrow aspirate revealed many atypical spindled mast cells, Wright Giemsa stain at 1000× original magnification. (g) The corresponding bone marrow biopsy revealed a perivascular infiltrate with spindled nuclei and abundant pale cytoplasm, H&E at 500× original magnification. (h) These cells were positive for tryptase by immunohistochemical stain, consistent with mast cells, 200× original magnification. (i) These atypical mast cells coexpressed CD25 by immunohistochemical stain, 200× original magnification. (j) A follow-up bone marrow aspirate showed numerous large blasts with high nuclear to cytoplasmic ratios, round nuclei with distinct nuclear membranes, prominent nucleoli, and deep blue cytoplasm, Wright Giemsa stain at 1000× original magnification. (k) The corresponding bone marrow biopsy revealed a hypercellular marrow with sheets of large blasts, H&E at 500× original magnification. (l) These blasts were diffusely positive for glycophorin, confirming that these were erythroblasts, immunohistochemical stain at 500× original magnification.

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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, BCR-ABL1 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 lymphoma, as in our patient. It is important to note that not all abnormalities of chromosome 8p11-12 involve the FGFR1 gene as translocations of 8p11-12 may involve the MYST3 gene or neither aforementioned gene [5]. Therefore, FISH studies may be required for confirmation. Secondary abnormalities may also be noted, with trisomy 21 being the most common [1], also seen in our patient.

Upon referral to our institution, a complete blood count revealed hemoglobin of 16.7 g/dL, white blood cell (WBC) count of 33.2 × 109/L with some left shift to rare blasts (<1%), platelet count of 176 × 109/L and 8% eosinophils (absolute eosinophil count of 2.7 × 109/L). A repeat bone marrow biopsy showed similar findings to the prior bone marrow with blasts enumerated at less than 5%, but also showed an abnormal immature T-cell population expressing strong CD45, CD4, partial CD8, CD2, CD5, variable CD7, cytoplasmic CD3 and TdT, but lacking surface CD3 and CD34. Furthermore, there was an increase in scattered mast cells with spindled morphology (Fig. 1). By flow cytometry and immunohistochemistry, these mast cells expressed CD25 without CD2. PCR for KIT D816V point mutation was negative and serum tryptase was 14.7 ng/mL (normal value <11.5 ng/mL).

Mastocytosis is currently defined, according to the 2008 WHO, as a clonal, neoplastic proliferation of mast cells in one or multiple organs [12, 13]. Systemic mastocytosis (SM) is diagnosed when one major criterion and one minor criterion or at least three minor criteria are present. The major diagnostic criterion for SM is fulfilled by the presence of multifocal dense mast cell infiltrates (≥15 mast cells per aggregate) detected histologically in the bone marrow or in another extracutaneous organ(s). Minor criteria include: (1) ≥25% of the mast cells in the infiltrate are spindle-shaped or show atypical morphology or ≥25% are immature or atypical on BM aspirate smears, (2) a serum tryptase level is persistently greater than 20 ng/mL (this parameter is not valid if there is an associated clonal myeloid disorder), (3) detection of the characteristic KIT D816V mutation, and (4) expression of CD2, CD25 or both in neoplastic mast cells. With only the two findings of spindled mast cells expressing CD25, the patient did not meet current diagnostic criteria for SM.

Atypical mast cell proliferations have been described as a feature of myeloid and lymphoid neoplasms with PDGFRA and/or PDGFRB rearrangements [1, 13-15]. When associated with these entities, the mast cells may be scattered or present in clusters, and may show atypical morphology with spindling. Furthermore, aberrant expression of CD25 is often noted. In cases of myeloid neoplasms with PDGFRB rearrangement, CD2 may be expressed as well [16]. However, cohesive, dense aggregates are typically lacking, the KIT D816V mutation is not present and serum tryptase levels are typically less than 20 ng/mL; therefore, these cases do not meet criteria for SM [1, 13-15].

Mast cell proliferations are not well described in myeloid and lymphoid neoplasms with FGFR1 abnormalities. Two patients have been identified with this association prior to the current case [17, 18]. The first was a 29-year-old woman who originally presented with urticaria pigmentosa that progressed over a period of 3–4 years to SM [17]. Shortly afterwards, she was diagnosed with atypical chronic myeloid leukemia (BCR-ABL1 negative), in association with SM and observed to have a t(8;17) in all 20 bone marrow metaphases analyzed. The more recent case was a 31-year-old man presenting with leukocytosis and absolute eosinophilia [18]. A bone marrow biopsy showed features consistent with a MPN in blast crisis. In addition, a spindled mast cell population was detected in the bone marrow and in a cervical lymph node with CD25 coexpression noted by immunohistochemistry. KIT D816V mutation was negative and cytogenetic analysis showed a t(8;13)(p11;q12). The patient died shortly after initial diagnosis.

The patient was started on dasatinib 100 mg daily and allopurinol and immediately HLA (human leukocyte antigen) typed in preparation for a myeloablative allogeneic HLA-matched bone marrow transplant. After a month course of dasatinib, the patient's lymphadenopathy worsened and this therapy was stopped. He was then admitted for hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) therapy with rituximab. The patient initially responded, with decreased palpable and radiologic lymphadenopathy and a partial hematologic remission. After 6 cycles of hyper-CVAD, the patient was noted to have new lymphadenopathy and leukocytosis (65 × 109/L) with 7% blasts. The patient was started on second-line therapy with GCLAC (filgrastim, clofarabine, and cytarabine). However, after one cycle, he was noted to have persistent leukocytosis (66.3 × 109/L) and was started on MEC (mitoxantrone, etoposide, and cytarabine). Unfortunately, a matched bone marrow donor had still not been identified.

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA and PDGFRB are treated with imatinib with excellent response to date [19]. However, no standard therapy is known or approved for myeloid and lymphoid neoplasms with FGFR1 abnormalities. Currently, intense chemotherapeutic regimens including hyper-CVAD followed by allogeneic stem cell transplantation is recommended for patients [4, 19]. Targeted modalities are currently being investigated with some promising results. Specifically, Chen et al. reported improvement of leukocytosis, lymphadenopathy and splenomegaly over 6 months in a single case associated with ZNF198-FGFR1 by PKC412, a tyrosine kinase inhibitor [20]. The patient subsequently underwent stem cell transplant. In another patient, a partial cytogenetic response was observed after 1 year of interferon-α, allowing the patient to proceed to transplantation [21]. In a more recent report, another patient exhibited a stable hematologic and molecular remission for more than 2 years after single agent interferon-α therapy [22]. Lastly, TKI258, another tyrosine kinase inhibitor, has shown in vitro tumor growth inhibition in a case with t(7;8)(q22;p11) [9].

During his second cycle of MEC, he was admitted for Enterbacter cloacae bacteremia. A peripheral blood smear revealed 76% blasts. A bone marrow aspirate and biopsy showed a hypercellular marrow, which was predominated by immature cells (85% by aspirate differential) (Fig. 1). By flow cytometry, these cells were dim to predominantly CD45 negative and expressed CD117, glycophorin C, dim partial CD38 and dim CD4 but did not express CD34, HLA-DR, cytoplasmic CD3, CD79a, TdT or MPO (myeloperoxidase). The patient rapidly deteriorated and expired 10 days after bone marrow biopsy.

Our patient met WHO criteria for pure erythroid leukemia and FAB (French-American-British) criteria for AML-M6b. In conclusion, myeloid and lymphoid neoplasms with FGFR1 abnormalities (8p11 myeloproliferative syndrome, stem cell leukemia/lymphoma) is a rare entity typically associated with a MPN, eosinophilia, T lymphoblastic lymphoma and progression to AML, although the clinical presentation may vary from patient to patient. Cytogenetic studies will reveal a rearrangement involving 8p11-12 with various partner genes resulting in different clinical manifestations. Three cases have described an association with abnormal mast cell populations, two of which revealed CD25 coexpression on the mast cells including our case. The prognosis is poor but investigational drugs are being researched.


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