Ann Hematol DOI 10.1007/s00277-013-2004-x
LETTER TO THE EDITOR
IgG-lymphoplasmacytic lymphoma following polycythemia vera: JAK2 V617F and MYD88 L265P mutations separated in the same house Luisa Anelli & Antonella Zagaria & Angela Minervini & Paola Casieri & Nicoletta Coccaro & Giuseppina Tota & Crescenzio Francesco Minervini & Claudia Brunetti & Luciana Impera & Alessandra Ricco & Angelo Cellamare & Giorgina Specchia & Francesco Albano
Received: 5 November 2013 / Accepted: 26 December 2013 # Springer-Verlag Berlin Heidelberg 2014
An association of a myeloproliferative (MPN) and lymphoproliferative neoplasm (LPN) has occasionally been reported. The risk of developing LPN has been demonstrated to be significantly increased in MPN patients as compared to the general population [1]. Sporadic cases of polycythemia vera (PV) associated with LPN have been described, mainly with B-chronic lymphocytic leukemia (B-CLL) [2]. We report, for the first time, on a case of IgG-lymphoplasmacytic lymphoma (LPL) MYD88 L256P following PV JAK2 V617F. PV bearing the JAK2 gene mutation V617F in heterozygosity was diagnosed in a 69-year-old man. His disease was controlled by hydroxyurea therapy. Four years later, a diagnosis of IgGk monoclonal gammopathy of undetermined significance (MGUS) was made. The course of the PV and MGUS remained stable for the following 3 years, after which the patient presented anemia despite an interruption of the hydroxyurea treatment. In addition, total body computed tomography (CT) revealed the presence of swollen nodes in the abdomen, and the splenomegaly was not changed from the time of PV diagnosis. Bone marrow (BM) biopsy showed an intertrabecular and paratrabecular small lymphocytic interstitial infiltrate in the context of a trilineage proliferation of erythropoiesis, pleomorphic L. Anelli : A. Zagaria : A. Minervini : P. Casieri : N. Coccaro : G. Tota : C. F. Minervini : C. Brunetti : L. Impera : A. Ricco : A. Cellamare : G. Specchia : F. Albano (*) Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, P.zza G. Cesare, 70124 Bari, Italy e-mail:
[email protected]
megakaryopoiesis, and granulopoiesis suggestive of PV; no fibrosis was observed (Fig. 1a). BM immunophenotypic analysis showed the expression of the following markers: CD19+, CD20+, CD11c−, CD25+, CD103−, and FMC7+. Conventional cytogenetic analysis of G-banded BM metaphases showed a normal 46,XY karyotype. The diagnostic criteria for marginal zone NHL were not fulfilled [3], and therefore, a diagnosis of IgG-LPL was made in a patient previously affected by PV. The patient was treated with three doses of rituximab associated with three cycles of cyclophosphamide, vincristine, and prednisone (CVP). After treatment, total body CT showed progression of the lymphadenopathy, therefore the patient received six doses of rituximab associated with six cycles of cyclophosphamide, doxorubicin liposomal, vincristine, and prednisone (COMP). The patient now has stable disease (absence of LPL progression and no clinical and laboratory signs of PV) and is treated with supportive therapy only since he refused any further chemotherapy. After treatment for LPL, the anemia persisted, and the patient required periodic red blood cells transfusion. The detection of MYD88 L265P was retrospectively performed on a BM sample at the appearance of IgG-LPL by an allele-specific polymerase chain reaction (AS-PCR) assay, followed by Sanger sequencing, and by high-resolution melting (HRM) analysis, as previously reported [4, 5]; both molecular approaches revealed the MYD88 mutation (Fig. 1b–d). Moreover, molecular analysis confirmed the presence of the MYD88 L256P also in the BM sample at the appearance of MGUS. To assess the clonal independence of the PV and the IgG-LPL, we performed the AS-PCR and HRM analysis specific for MYD88 L265P on genomic DNA isolated from the peripheral blood
Ann Hematol Fig. 1 Histopathology and molecular assays for detection of MYD88 L265P. a BM biopsy. Paratrabecular infiltrate of small lymphocytes and myeloid proliferation with pleomorphic megakaryocytes were observed (Giemsa, original magnification× 400). b The PCR products (223 bp) were separated on a 1.5 % agarose gel. PV sample resulted to be negative for the mutation at the diagnosis (lane 1), the mutant MYD88 L265P allele was detected in sample at the onset of MGUS (lane 2) and at the time of LPL appearance (lane 3); granulocyte population isolated from LPL sample did not bear MYD88 mutation (lane 4). Lane 5, negative control; M, marker VIII molecular weight. No further analysis of lymphocytes about JAK2 V617F mutation has been performed due to the lack of material. c The heterozygosity of MYD88 L265P in LPL sample was confirmed by Sanger sequencing. The position of MYD88 L265P locus is indicated by dark arrow. d High-resolution melting curve analysis for MYD88 gene. The differential melting properties of representative wildtype and MYD88 mutated amplicons are shown using normalized, temperature-shifted melting curves plots. WT, wild type
granulocytes fraction [6]. The analyses did not show the presence of the MYD88 gene mutation, whereas the JAK2 V617F mutation was evident. In the light of the presence of different molecular markers in PV and in IgG-LPL, these results demonstrated that the two diseases are clonally unrelated. Previously, the association between LPL and MPN, as concurrent or simultaneous diseases, has been described [2]. Moreover, two IgG-LPL cases and one IgA-LPL case have been reported to be MYD88 L265P, and this observation suggested that the MYD88 mutation may be a marker of LPL regardless of the isotype [7]. On the other hand, the lack of MYD88 L256P in a case of IgG-LPL has recently been described [8]. The occurrence of anemia during the PV treatment can be related to several factors
such as myelotoxic effect exerted by hydroxyurea, progression to post-PV myelofibrosis or other myeloid neoplasms (acute myeloid leukemia, myelodysplastic syndrome), and appearance of concomitant lymphoproliferative disorder (more often B-CLL). After excluding drug toxicity in our patient, we promptly investigated the anemia cause by BM biopsy due to the strong suspicion of disease transformation. Our experience showed that, in MPN cases associated with MGUS, hematological parameters should be monitored with shorter interval during the follow-up. In conclusion, our report shows that the onset of LPL in a PV case is sustained by a clone that is unrelated to the one bearing the JAK2 V617F mutation. Moreover, the IgG-LPL onset in PV patients could represent an unexpected cause of anemia.
Ann Hematol Acknowledgments The authors would like to thank Ms. MVC Pragnell, B.A., for language revision of the manuscript. Conflict of interest The authors declare that they have no conflict of interest. 5.
References 1. Vannucchi AM, Masala G, Antonioli E, Chiara Susini M, Guglielmelli P, Pieri L, Maggi L, Caini S, Palli D, Bogani C, Ponziani V, Pancrazzi A, Annunziato F, Bosi A (2009) Increased risk of lymphoid neoplasms in patients with Philadelphia chromosome-negative myeloproliferative neoplasms. Cancer Epidemiol Biomarkers Prev 18:2068–2073 2. Hauck G, Jonigk D, Kreipe H, Hussein K (2013) Simultaneous and sequential concurrent myeloproliferative and lymphoproliferative neoplasms. Acta Haematol 129:187–196 3. Ghobrial IM (2012) Are you sure this is Waldenstrom macroglobulinemia? Hematol Am Soc Hematol Educ Program 2012:586–594 4. Varettoni M, Arcaini L, Zibellini S, Boveri E, Rattotti S, Riboni R, Corso A, Orlandi E, Bonfichi M, Gotti M, Pascutto C, Mangiacavalli S,
6.
7.
8.
Croci G, Fiaccadori V, Morello L, Guerrera ML, Paulli M, Cazzola M (2013) Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom’s macroglobulinemia and related lymphoid neoplasms. Blood 121: 2522–2528 Wang CZ, Lin J, Qian J, Shao R, Xue D, Qian W, Xiao GF, Deng ZQ, Yang J, Li Y, Chen XX (2013) Development of high-resolution melting analysis for the detection of the MYD88 L265P mutation. Clin Biochem 46:385–387 Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352:1779– 1790 Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, Arcaini L, Pinkus GS, Rodig SJ, Sohani AR, Harris NL, Laramie JM, Skifter DA, Lincoln SE, Hunter ZR (2012) MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med 367:826–833 Manasanch EE, Braylan R, Stetler-Stevenson M, Yuan C, Gounden V, Korde N, Tageja N, Bhutani M, Calvo K, Maric I, Roschewski M, Staudt LM, Landgren O (2013) Lack of MYD88 L265P in non-IgM lymphoplasmacytic lymphoma. Leuk Lymphoma. doi: 10.3109/10428194.2013.831091
