Letter to the Editor

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Blood Res 2013; 48(3):

Published online September 25, 2013

https://doi.org/10.5045/br.2013.48.3.228

© The Korean Society of Hematology

Concomitant transformation of monoclonal gammopathy of undetermined significance to multiple myeloma and of essential thrombocythemia to acute biphenotypic leukemia 37 years after initial diagnosis

Pasquale Niscola1*, Gianfranco Catalano1, Stefano Fratoni2, Laura Scaramucci1, Paolo de Fabritiis1, and Tommaso Caravita1

1Hematology Unit, S. Eugenio Hospital, Rome, Italy.

2Pathology Department, S. Eugenio Hospital, Rome, Italy.

Correspondence to : Pasquale Niscola. Hematology Unit, S. Eugenio Hospital, Piazzale dell'Umanesimo 10, 00144, Rome, Italy. pniscola@gmail.com

Received: May 22, 2013; Accepted: July 1, 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

TO THE EDITOR: The occurrence of monoclonal gammopathy of undetermined significance (MGUS) and essential thrombocytopenia (ET) in the same patient is quite rare. With an anecdotal purpose, we herein report the long-term clinical history of a patient who presented with simultaneous evolution to multiple myeloma (MM) and to acute biphenotypic leukemia from MGUS and ET, respectively, with the latter conditions simultaneously diagnosed 37 years prior to this case.

The occurrence of monoclonal gammopathy of undetermined significance (MGUS) and essential thrombocytopenia (ET) in the same patient is quite rare [1-3], usually manifesting as an incidental finding. In addition, the coexistence of multiple myeloma (MM) with ET has also been rarely reported [4-8]. Moreover, the evolution of MGUS to MM simultaneously with blastic transformation of ET in the form of acute biphenotypic leukemia, as observed in this report, represents an exceptionally rare occurrence. With an anecdotal purpose, we herein report the long-term clinical history of a patient who presented with concomitant evolution of MGUS to MM and from ET to acute biphenotypic leukemia, with the original diagnosis of MGUS and ET occurring 37 years prior.

In 2010, a 77-year-old man presented to our center with increasing thrombocytosis and monoclonal paraproteinemia (IgG lambda). In 1975, at another center, he was diagnosed with MGUS associated with ET. The patient was managed according to the prevalent clinical guidelines and received low-dose acetylsalicylic acid (LD-ASA). Upon presentation to our clinic (35 years after original diagnosis and treatment), he reported that for several years he had not been followed up by periodic laboratory evaluations and hematologic examinations. Therefore, a comprehensive work-up, including a bone marrow (BM) aspirate and trephine biopsy, was performed. Megakaryocytic hyperplasia and clustering consistent with ET, along with an infiltration of IgG kappa clonally mature plasma cells (PC) consistent with MGUS, was noted. Janus kinase 2 (JAK 2) V617F, P190, and P210 mutation analyses revealed no abnormalities. In addition, no defining features potentially associated with POEMS syndrome [9], which may be suspected on the basis of the coexistence of a JAK 2-negative thrombocytosis with a monoclonal component, were found by comprehensive work-up; in particular, no organomegalies, skin changes, peripheral nerve abnormalities, or endocrinopathy were present. The radiological evaluation of his skeleton ruled out both lytic and sclerotic bone changes. Human immunodeficiency virus, hepatitis C virus, and hepatitis B virus infections were ruled out by serological evaluations. Therefore, the patient was diagnosed with IgG lambda MGUS concomitant with JAK 2-negative ET. Given the remarkable thrombocytosis (platelet count, >1,000×109/L), hydroxyurea was added to LD-ASA. Thereafter, the patient was regularly followed up until 2 years later when his hemogram showed pancytopenia concomitant with an increase in monoclonal protein concentration higher than 4 g/dL. At that time, examination of a BM aspirate revealed a 30% proportion of clonal IgG kappa PC along with 20% blasts; the latter cells, showed coexpression of lymphoid and myeloid markers, being positive for CD34, CD13, CD33, HLA-DR, CD19, and CD22. BM trephine biopsy (Fig. 1) confirmed BM infiltration by PC and blasts. Conventional cytogenetic and fluorescence in situ hybridization revealed a normal karyotype; negative JAK 2 V617F, P190, and P210 mutation analyses were confirmed. Unfortunately, no other molecular studies were performed. Physical examination revealed no remarkable findings; in particular, neither upper abdominal organomegalies nor superficial adenomegalies was palpable. Laboratory and radiologic evaluations revealed moderate Bence Jones proteinuria (lambda type) and mild pancytopenia but no other abnormalities were found. In particular, serum calcium and comprehensive metabolic, renal, hepatic, and coagulative panel results were normal. In addition, skeletal survey showed neither lytic nor sclerotic lesions throughout the axial and appendicular skeleton. The diagnosis of MM coexisting with secondary acute biphenotypic phenotype was made. The patient was evaluated as a possible candidate for treatment with hypomethylating agents, but his condition suddenly deteriorated and he died of pneumonia.

This case lacks practical therapeutic implications and reliable indications for the management of this uncommon occurrence, and our report has only anecdotal value. However, the overlapping occurrence of acute biphenotypic leukemia transformed from ET and MM is extremely rare. We speculate that the synchronous evolution of ET and MGUS along with coexpression of lymphoid antigens by blastic cells could suggest a common origin of these 2 malignancies, potentially evolving from a common precursor by progressive transformation to more aggressive disorders [5]. However, this hypothesis remains to be investigated.

Fig. 1.

(A) Bone marrow (BM) biopsy shows increased immature precursors and dysmegakaryopiesis. (B) CD34 immunostain reveals 20% blasts. (C) Clusters of plasma cells (PCs) with mature-like morphology. (D) CD 138 immunostain shows strong membrane staining by sheets of PCs, representing 25/30% BM cells. (E, F) Immunostainining for light chains reveals monotypic cytoplasmic expression of lambda light chain, suggesting the neoplastic nature of PCs.


  1. Montefusco, E, Monarca, B, Tribalto, M. Coexistent idiopathic thrombocythaemia and monoclonal component: a causal association?. Scand J Haematol, 1985;35;584.
    Pubmed
  2. Kyrtsonis, MC, Kokoris, SI, Kontopidou, FN, Siakantaris, MP, Kittas, C, Pangalis, GA. Development of a myeloproliferative disorder in a patient with monoclonal gammopathy of undetermined significance secreting immunoglobulin of the M class and treated with thalidomide and anti-CD20 monoclonal antibody. Blood, 2001;97;2527-2528.
    Pubmed
  3. Tosato, F, Fossaluzza, V, Rossi, P, et al. Monoclonal gammopathy of undetermined significance in a case of primary thrombocythemia. Haematologica, 1986;71;417-418.
    Pubmed
  4. Prosper, F, Borbolla, JR, Rifon, J, et al. Coexistence of essential thrombocythemia and multiple myeloma. Ann Hematol, 1992;65;103-105.
    Pubmed
  5. Majhail, NS, Lichtin, AE. Rare coexistence of multiple myeloma with essential thrombocythemia: report of two cases. Haematologica, 2003;88;ECR09.
    Pubmed
  6. Kuroda, J, Matsumoto, Y, Tanaka, R, et al. JAK2V617F-positive essential thrombocythemia and multiple myeloma with IGH/CCND1 gene translocation coexist, but originate from separate clones. Acta Haematol, 2008;120;177-181.
    Pubmed
  7. Holtan, SG, Hoyer, JD, Buadi, FK. Multiple myeloma with concomitant JAK2-positive essential thrombocythemia post-successful autologous peripheral blood hematopoietic stem cell transplant. Bone Marrow Transplant, 2011;46;615.
    Pubmed
  8. Eskazan, AE, Ongoren, S, Ar, MC, et al. Essential thrombocythemia and multiple myeloma: two rare diseases in one patient. Clin Lymphoma Myeloma Leuk, 2011;11;442-445.
    Pubmed
  9. Dispenzieri, A. How I treat POEMS syndrome. Blood, 2012;119;5650-5658.
    Pubmed

Article

Letter to the Editor

Blood Res 2013; 48(3): 228-230

Published online September 25, 2013 https://doi.org/10.5045/br.2013.48.3.228

Copyright © The Korean Society of Hematology.

Concomitant transformation of monoclonal gammopathy of undetermined significance to multiple myeloma and of essential thrombocythemia to acute biphenotypic leukemia 37 years after initial diagnosis

Pasquale Niscola1*, Gianfranco Catalano1, Stefano Fratoni2, Laura Scaramucci1, Paolo de Fabritiis1, and Tommaso Caravita1

1Hematology Unit, S. Eugenio Hospital, Rome, Italy.

2Pathology Department, S. Eugenio Hospital, Rome, Italy.

Correspondence to: Pasquale Niscola. Hematology Unit, S. Eugenio Hospital, Piazzale dell'Umanesimo 10, 00144, Rome, Italy. pniscola@gmail.com

Received: May 22, 2013; Accepted: July 1, 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

CASE

TO THE EDITOR: The occurrence of monoclonal gammopathy of undetermined significance (MGUS) and essential thrombocytopenia (ET) in the same patient is quite rare. With an anecdotal purpose, we herein report the long-term clinical history of a patient who presented with simultaneous evolution to multiple myeloma (MM) and to acute biphenotypic leukemia from MGUS and ET, respectively, with the latter conditions simultaneously diagnosed 37 years prior to this case.

The occurrence of monoclonal gammopathy of undetermined significance (MGUS) and essential thrombocytopenia (ET) in the same patient is quite rare [1-3], usually manifesting as an incidental finding. In addition, the coexistence of multiple myeloma (MM) with ET has also been rarely reported [4-8]. Moreover, the evolution of MGUS to MM simultaneously with blastic transformation of ET in the form of acute biphenotypic leukemia, as observed in this report, represents an exceptionally rare occurrence. With an anecdotal purpose, we herein report the long-term clinical history of a patient who presented with concomitant evolution of MGUS to MM and from ET to acute biphenotypic leukemia, with the original diagnosis of MGUS and ET occurring 37 years prior.

In 2010, a 77-year-old man presented to our center with increasing thrombocytosis and monoclonal paraproteinemia (IgG lambda). In 1975, at another center, he was diagnosed with MGUS associated with ET. The patient was managed according to the prevalent clinical guidelines and received low-dose acetylsalicylic acid (LD-ASA). Upon presentation to our clinic (35 years after original diagnosis and treatment), he reported that for several years he had not been followed up by periodic laboratory evaluations and hematologic examinations. Therefore, a comprehensive work-up, including a bone marrow (BM) aspirate and trephine biopsy, was performed. Megakaryocytic hyperplasia and clustering consistent with ET, along with an infiltration of IgG kappa clonally mature plasma cells (PC) consistent with MGUS, was noted. Janus kinase 2 (JAK 2) V617F, P190, and P210 mutation analyses revealed no abnormalities. In addition, no defining features potentially associated with POEMS syndrome [9], which may be suspected on the basis of the coexistence of a JAK 2-negative thrombocytosis with a monoclonal component, were found by comprehensive work-up; in particular, no organomegalies, skin changes, peripheral nerve abnormalities, or endocrinopathy were present. The radiological evaluation of his skeleton ruled out both lytic and sclerotic bone changes. Human immunodeficiency virus, hepatitis C virus, and hepatitis B virus infections were ruled out by serological evaluations. Therefore, the patient was diagnosed with IgG lambda MGUS concomitant with JAK 2-negative ET. Given the remarkable thrombocytosis (platelet count, >1,000×109/L), hydroxyurea was added to LD-ASA. Thereafter, the patient was regularly followed up until 2 years later when his hemogram showed pancytopenia concomitant with an increase in monoclonal protein concentration higher than 4 g/dL. At that time, examination of a BM aspirate revealed a 30% proportion of clonal IgG kappa PC along with 20% blasts; the latter cells, showed coexpression of lymphoid and myeloid markers, being positive for CD34, CD13, CD33, HLA-DR, CD19, and CD22. BM trephine biopsy (Fig. 1) confirmed BM infiltration by PC and blasts. Conventional cytogenetic and fluorescence in situ hybridization revealed a normal karyotype; negative JAK 2 V617F, P190, and P210 mutation analyses were confirmed. Unfortunately, no other molecular studies were performed. Physical examination revealed no remarkable findings; in particular, neither upper abdominal organomegalies nor superficial adenomegalies was palpable. Laboratory and radiologic evaluations revealed moderate Bence Jones proteinuria (lambda type) and mild pancytopenia but no other abnormalities were found. In particular, serum calcium and comprehensive metabolic, renal, hepatic, and coagulative panel results were normal. In addition, skeletal survey showed neither lytic nor sclerotic lesions throughout the axial and appendicular skeleton. The diagnosis of MM coexisting with secondary acute biphenotypic phenotype was made. The patient was evaluated as a possible candidate for treatment with hypomethylating agents, but his condition suddenly deteriorated and he died of pneumonia.

This case lacks practical therapeutic implications and reliable indications for the management of this uncommon occurrence, and our report has only anecdotal value. However, the overlapping occurrence of acute biphenotypic leukemia transformed from ET and MM is extremely rare. We speculate that the synchronous evolution of ET and MGUS along with coexpression of lymphoid antigens by blastic cells could suggest a common origin of these 2 malignancies, potentially evolving from a common precursor by progressive transformation to more aggressive disorders [5]. However, this hypothesis remains to be investigated.

Fig 1.

Figure 1.

(A) Bone marrow (BM) biopsy shows increased immature precursors and dysmegakaryopiesis. (B) CD34 immunostain reveals 20% blasts. (C) Clusters of plasma cells (PCs) with mature-like morphology. (D) CD 138 immunostain shows strong membrane staining by sheets of PCs, representing 25/30% BM cells. (E, F) Immunostainining for light chains reveals monotypic cytoplasmic expression of lambda light chain, suggesting the neoplastic nature of PCs.

Blood Research 2013; 48: 228-230https://doi.org/10.5045/br.2013.48.3.228

References

  1. Montefusco, E, Monarca, B, Tribalto, M. Coexistent idiopathic thrombocythaemia and monoclonal component: a causal association?. Scand J Haematol, 1985;35;584.
    Pubmed
  2. Kyrtsonis, MC, Kokoris, SI, Kontopidou, FN, Siakantaris, MP, Kittas, C, Pangalis, GA. Development of a myeloproliferative disorder in a patient with monoclonal gammopathy of undetermined significance secreting immunoglobulin of the M class and treated with thalidomide and anti-CD20 monoclonal antibody. Blood, 2001;97;2527-2528.
    Pubmed
  3. Tosato, F, Fossaluzza, V, Rossi, P, et al. Monoclonal gammopathy of undetermined significance in a case of primary thrombocythemia. Haematologica, 1986;71;417-418.
    Pubmed
  4. Prosper, F, Borbolla, JR, Rifon, J, et al. Coexistence of essential thrombocythemia and multiple myeloma. Ann Hematol, 1992;65;103-105.
    Pubmed
  5. Majhail, NS, Lichtin, AE. Rare coexistence of multiple myeloma with essential thrombocythemia: report of two cases. Haematologica, 2003;88;ECR09.
    Pubmed
  6. Kuroda, J, Matsumoto, Y, Tanaka, R, et al. JAK2V617F-positive essential thrombocythemia and multiple myeloma with IGH/CCND1 gene translocation coexist, but originate from separate clones. Acta Haematol, 2008;120;177-181.
    Pubmed
  7. Holtan, SG, Hoyer, JD, Buadi, FK. Multiple myeloma with concomitant JAK2-positive essential thrombocythemia post-successful autologous peripheral blood hematopoietic stem cell transplant. Bone Marrow Transplant, 2011;46;615.
    Pubmed
  8. Eskazan, AE, Ongoren, S, Ar, MC, et al. Essential thrombocythemia and multiple myeloma: two rare diseases in one patient. Clin Lymphoma Myeloma Leuk, 2011;11;442-445.
    Pubmed
  9. Dispenzieri, A. How I treat POEMS syndrome. Blood, 2012;119;5650-5658.
    Pubmed
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