Submitting Author: Ondrejka, Sarah Lynn, DO
Institution: Department of Clinical Pathology, Cleveland Clinic, Cleveland, Ohio
Additional authors:Eric D. Hsi, MD
Session: Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1

A 64 year-old man with fatigue, weight loss, lymphadenopathy, and splenomegaly was diagnosed with T-LBL on lymph node (LN) biopsy. He had normocytic anemia (hemoglobin, 9.2 g/dL), thrombocytopenia (platelet count, 65 x 10^3/μL), and normal WBC count (4.82 x 10^3/μL) notable only for mild absolute eosinophilia (0.48 x 10^3/μL). A staging bone marrow biopsy was performed. Treatment had commenced with a vincristine/prednisone-based modified Larson protocol for acute lymphoblastic leukemia. Following release of the conventional cytogenetic analysis report on the lymph node specimen, imatinib was added, but it was stopped after 18 days due to refractory cytopenias and worsening peripheral edema. The patient thereafter developed inexplicable increases in the WBC count (38.3 x 10^3/μL) and absolute eosinophil count (8.69 x 10^3/μL), suggesting progression. He ultimately chose hospice care.

Left level 5 lymph node: 10% neutral buffered formalin fixed paraffin-embedded tissue

Lymph node histologic sections demonstrate a diffuse and vaguely nodular infiltrate of medium-sized atypical lymphoid cells with round to slightly irregular nuclei, dispersed chromatin, small but distinct nucleoli, and scant cytoplasm. Mitotic figures are readily noted.

Bone marrow: Core biopsy - Zinc formalin; Clot section - 10% neutral buffered formalin fixed paraffin-embedded tissue

The bone marrow biopsy is negative for a T-LBL, but displays mild hypercellularity with granulocytic and megakaryocytic hyperplasia, eosinophilia (7%, range 0-6%), and mild dysgranulopoiesis and dyserythropoiesis, suggesting a myeloid neoplasm difficult to classify in the WHO classification based on morphology alone. Focal paratrabecular aggregates of histiocytes are present.

Lymph node: Flow cytometric studies demonstrate an abnormal T-cell population positive for CD1a, CD2, CD3 (cytoplasmic, dim subset surface), CD4 (dim, subset), CD5, CD7, CD8, CD10 (dim), CD38, and TdT, but negative for CD34. Immunohistochemical stains show that CD3 and TdT are diffusely positive. CD20, CD21, and TCL-1 highlight remnants of follicles, but the atypical cells are negative. CD34 and keratin AE1/AE3 are negative. Chromogenic in situ hybridization for Epstein-Barr Virus-encoded RNA (EBER) is also negative.

Bone marrow: Flow cytometric analysis of the bone marrow aspirate is negative for involvement by leukemia. Immunostains for CD3, CD20, PAX5, CD34, and TdT show no evidence of T-lymphoblastic lymphoma. A CD68 stain highlights the histiocytes which are negative for organisms (PAS, AFB, GMS stains).

Conventional cytogenetic analysis demonstrated 46,XY,t(5;17)(q33;p13)[9]/46,XY[1] in lymph node and 46,XY,t(5;17)(q33;p13)[9]/45,X,-Y[5]/46,XY[6] in bone marrow.

FISH analysis performed on both bone marrow and lymph node specimens confirmed rearrangement of PDGFRB (CytoCell,LPH031-A). Because the breakpoints matched those of RABEP1/PDGFRB, additional FISH analysis targeted the RABEP1 locus. A single color BAC probe (RP11-457I18, BlueGnome) encompassing the RABEP1 locus and TP53 probe (Abbott) confirmed disruption of RABEP1 (17p13.2/RABEP1).

FISH was negative for translocations of PDGFRA and FGFR1.

Myeloid neoplasms with PDGFRB rearrangement are considered a specific entity in the WHO classification and included alongside myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA and FGFR1. PDGFRA and FGFR1-related disorders appear to arise from a common pluripotent (myelod/lymphoid) stem cell since the genetic abnormalities are present in both the myeloid and lymphoid components. However, the PDGRFB category is thought to arise from a myeloid stem cell. To date, a case of myeloid and lymphoid neoplasm with documented PDGFRB in both processes has not been reported. Such a case would justify inclusion of PDGFRB in the list of rearrangements seen in myeloid and lymphoid neoplasms with eosinophilia and a modification of WHO nomenclature.

Since ETV6(TEL)/PDGFRB in chronic myelomonocytic leukemia (CMML) with t(5;12)(q33;p12) was reported in 1994, over 20 PDGFRB fusion partners have emerged. Translocation with the gene encoding Rabaptin-5 was identified in a patient with CMML who responded to imatinib therapy (see references below). This RABEP1/PDGFRB fusion has not been described in lymphoid neoplasms.

References:

Magnusson MK, Meade KE, Brown KE, et al. Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. Blood. 2001;98(8):2518-2525.

Magnusson MK, Meade KE, Nakamura R, Barrett J, Dunbar CE. Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene. Blood. 2002;100(3):1088-1091.

T-lymphoblastic lymphoma and myeloid neoplasm with eosinophilia in association with the RABEP1/PDGFRB fusion oncogene

Myeloid and lymphoid neoplasm with RABEP1/PDGFRB rearrangement, presenting with T-lymphoblastic lymphoma and eosinophilia

Case 12