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Concomitant Essential Thrombocythemia and Mature B -Lymphoproliferative Disorder in a Patient

A-64-year old male presented with cough, weight loss, and maculopapular rash for 15-20 days. On examination, he was found to have cervical lymphadenopathy and splenomegaly. His leukocyte count was 62.1x109/L, platelets were 1169x109/L and LDH was 816 IU/L. Peripheral blood film showed a leukoerythroblastic picture with thrombocytosis. He was started on hydroxyurea and allopurinol. Subsequently, bone marrow evaluation was done which depicted increased lymphoid cells with an M:E ratio of 4:1. Cellular areas exhibited an increase in myeloid precursors along with prominent lymphoid cells and abundant megakaryocytes. Immunohistochemistry showed an increase in B-lymphocytes. Grade MF-2 reticulin fibrosis was noted. Overall findings suggested essential thrombocythemia (ET). On flow cytometry, CD45-positive lymphoid cells population was 31% and showed reactivity to Pan-B-markers with lambda light chain restriction. Janus Kinase 2 (JAK 2) mutation was detected while BCR-ABL1 translocation was negative. A diagnosis of ET progressing to myelofibrosis and mature B-lymphoproliferative disorder was made. Hydroxyurea and allopurinol were stopped while ruxolitinib was introduced and 2.5 years later he remains stable on this treatment.


INTRODUCTION
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) characterized by sustained thrombocytosis and increased number of large, mature megakaryocytes in the bone marrow. It can manifest with episodes of thrombosis or hemorrhage. Up to 40-50% of patients with ET harbor the Janus Kinase 2 V617F mutation. Janus Kinase 2 617F positive ET and B-lymphoproliferative disorders are considered 2 distinct, clonal hematologic entities 1 . Their coexistence in a single individual is exceedingly rare 1, 2 . Development of MPNs as a ramification of therapy in patients with various neoplasms has been well described in literature 3,4 . However, occurrence of MPN in treatment-naïve B-lymphoproliferative disorders in patients with MPN has been much less frequently reported. Here we describe the initial presentation, work up and management of an elderly gentleman who was diagnosed with both ET and Blymphoproliferative disorder.

Case presentation
A 64-year-old male was admitted to our center with complaints of cough, weight loss and maculopapular rash on body. The rash was present on his face and trunk for 15-20 days and he had non-productive cough for the past two weeks. He denied any constitutional ''B" symptoms apart from weight loss. His past medical history was significant for hypertension and benign prostatic hyperplasia. On examination, he was found to have cervical  and Pan-B (CD20) marker by immunohistochemistry was applied on bone trephine biopsy specimen, which was interpreted as increase in B-lymphocytes. Reticulin stain showed grade MF-2 reticulin fibrosis. Overall findings were suggestive of essential thrombocythemia. In view of increased CD20 positive cells, immunophenotyping by flow cytometry was recommended. CD45 positive lymphoid cells population was 31%. This population showed reactivity to Pan-B-markers i.e. CD19 (26%), CD20 (27%), CD22 (26%), CD23 (11%) and cCD79a (30%) along with HLA-DR (12%) and CD45 (35%). Double bright positivity of CD19 and CD5 typical of chronic lymphocytic leukemia (CLL) was absent. This population also showed positivity to lambda light chains restriction (kappa 0%, lambda 13%). Results were consistent with mature-B-lymphoproliferative disorder (B-LPD). JAK2 mutation was detected by PCR while BCR-ABL1 translocation was not detected by fluorescence in situ hybridization (FISH). Since double bright positivity for CD19 and CD5 was absent along with absence of FMC7, a diagnosis of mature-B-lymphoproliferative disorder was made. Cyclin D1 was applied on bone trephine, which was negative, and the infiltration did not reveal a follicular pattern. Ki67 was approximately 30%. A diagnosis of essential thrombocythemia (ET) progressing to myelofibrosis and Blymphoproliferative disorder was made. Patient was discharged in a stable condition and followed up on an outpatient basis. Ruxolitinib therapy at a dose of 5mg twice daily was initiated while hydroxyurea was reduced to 500 mg daily and then later stopped. A wait and watch approach was adopted for the B-lymphoproliferative disorder. Ruxolitinib was later increased to 10mg twice daily. The platelet count decreased to 341x10 9 /L, WBC to 33x10 9 /L and hemoglobin to 9.7 g/dl. After a few months, ruxolitinib was switched to 15 mg daily with the counts remaining stable. The patient remains stable and asymptomatic two and half years after initial presentation. The most recent blood counts show hemoglobin at 10.9 g/dl, WBC 31.1x10 9 /L, and platelets 445x10 9 /L. The patient is followed up regularly on an outpatient basis.

DISCUSSION
In this report we have described the case of a 64year-old gentleman with dual pathologies of essential thrombocythemia and mature B LPD. Janus Kinase 2 V617F positive ET and Blymphoproliferative disorders e.g. B-CLL are two distinct, clonal hematologic malignancies with their concomitant existence in a single individual being exceedingly rare. The prevalence of CLL in the United States is 40 per 100,000 persons and that of MPN is 115 per 100,000 citizens, and the expected prevalence of the occurrence of both diseases in a single individual is 4.6 × 10⁻⁸ 5-7 . The pathophysiology in play behind concomitant development of a myeloproliferative disorder (MPD) and a lymphoid neoplasm remains unclear. One explanation is a "trigger hit" occurs in an early progenitor cell, which can differentiate into both lymphoid and myeloid cells. This can be followed by additional molecular events that cause genomic instability during lymphoid and myeloid neoplastic differentiation leading to two diseases that have the same origin but arise from different cellular lines [8][9] . If the JAK2 mutation occurs in pluripotent stem cells, both myeloid and lymphoid cells may harbor the mutation. However, only myeloid cells will possess the mutation if it succeeds lineage differentiation. Another postulate is that the lymphoid neoplasm and MPD may develop from different progenitor cells purely by chance. In this scenario, the JAK 2 mutation may be absent in lymphoid cells 10 . Another theory reasons that a MPN could lead to variations in cytokines that can be fibrogenic, osteogenic, angiogenic and leukemogenic. This results in a change in bone marrow environment caused by the MPN 1 . The possibility of clonal involvement of both  17 . In our patient, although it is unlikely that the myelofibrosis could be a repercussion of such an indolent lymphoproliferative disorder, it could possibly have accelerated the natural course of the ET, because it is known that ET is rarely leads to fibrosis. Cases of rare, unrelated concomitant hematologic malignancies provide a diagnostic challenge. Myeloid proliferation in MPNs usually presents with leukocytosis and it is easy to miss a concurrent lymphocytosis due to B-lymphoproliferative disorders. LPD accompanied with MPD is usually indolent and mainly requires wait and watch approach.
International Journal of Hematology Oncology and Stem Cell Research ijhoscr.tums.ac.ir

CONCLUSION
We report a rare case of ET with concomitant B-LPD. The patient is stable on Ruxolitinib and maintaining platelet counts while he is on wait and watch approach for B-LPD.