- Email: [email protected]
T-cell large granular lymphocytosis associated with malignant thymoma
Leukemia Research 36 (2012) e187–e189
Contents lists available at SciVerse ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor T-cell large granular lymphocytosis associated with malignant thymoma
1. Introduction T-cell large granular lymphocytosis (T-LGL) is a proliferative disorder of CD3+ CD8+ T lymphocytes characterized by the clonal rearrangement of the T-cell receptor (TCR) and is consequently often termed a “leukemia” [1]. While this rare disorder has a typically indolent course and is classically associated with cytopenias, a variety of other autoimmune disorders, Sjogrens syndrome and rheumatoid arthritis have been commonly associated with T-LGL. The clonal nature of the disorder has created controversy, with conflicting claims for describing the disorder as a leukemia versus immune dysregulation. Although the etiology has not been conclusively elucidated, chronic activation of T-cells by an auto-reactive or viral antigen [2] and defects in apoptosis [3] have been implicated in the pathogenesis. Thymomas are typically slow-growing primary mediastinal tumors, both benign and malignant, that arise from thymic
epithelial cells. Malignant thymomas are a rare neoplasm, with an incidence of 0.15 cases per 100,000 [4]. While thymomas are known to be associated with numerous autoimmune conditions including myasthenia gravis and hematological paraneoplastic syndromes such as pure red cell aplasia (PRCA), malignant thymomas have not been associated with T-LGL. We present a previously unreported observation of T-LGL in the setting of malignant thymoma along with a review of the literature. The simultaneous occurrence of these two rare diseases – both affecting T-cell function and associated with autoimmune conditions supports immune dysregulation as the etiology for T-LGL. 2. Case report A 71-year-old Caucasian male was referred for evaluation of pancytopenia. He had a history of borderline epithelial type thymoma (WHO B2/B3) diagnosed 3 years previously (Fig. 1A–C). The tumor extended to the lung with extensive involvement of the diaphragmatic pleura and pericardium (Masaoka stage T4, N0, M0/stage IVa). The thymoma was treated surgically with a mass
Fig. 1. (A) Histopathology slide showing thymoma type B2 involving lung parenchyma (arrow indicates bronchial mucosa) (hematoxylin and eosin, 10×). (B) Histopathology slide of thymoma showing scattered isolated ovoid epithelioid cells with vesicular chromatin and conspicuous nucleoli in relatively heavy lymphocytic background (hematoxylin and eosin, 40×). (C) Axial contrast-enhanced CT image of the upper chest showing two right pleural masses (arrows) from the patient’s resected thymic primary and surgical clips in the anterior mediastinum. (D and E) Wright stained peripheral blood smear showing plentiful large granular lymphocytes at low power (D) and at high power (E). 0145-2126/$ – see front matter. Published by Elsevier Ltd. doi:10.1016/j.leukres.2012.03.008
Letter to the Editor / Leukemia Research 36 (2012) e187–e189
wedge resection of the right upper lobe and resection of some diaphragmatic masses followed by chemotherapy. He received cisplatin and docetaxel 4× cycles, then cyclophosphamide, doxorubicin and vincristine 4× cycles, 6 cycles of weekly paclitaxel 2× consecutive weeks with 1 week off and carboplatin and paclitaxel every 3 weeks 5×. After the fifth cycle of the carboplatin and paclitaxel, the chemotherapy was put on hold because the patient developed pancytopenia. In the work up for the pancytopenia, the patient’s CBC revealed a leukocyte count of 2.86 × 103 /L, an absolute neutrophil count of 0.85 × 103 /L, hemoglobin 12 g/dL, and a platelet count of 120 × 103 /L. He eventually became dependent on weekly platelet transfusions. The pancytopenia was initially attributed to slow recovery from chemotherapy. A bone marrow was performed after the CBC did not improve with conservative management for 4 months. Of note, the lowest blood counts obtained included a leukocyte count of 2.32 × 103 /L, an absolute neutrophil count of 0.61 × 103 /L, hemoglobin 7.3 g/dL, and a platelet count of 30 × 103 /L. The bone marrow aspirate and biopsy revealed a hypoplastic marrow with an average cellularity of 10%, 1.5% blasts, the absence
of dysplasia, predominant lymphocytes and sparse granulopoiesis. The peripheral smear showed increased circulating large granular lymphocytes (Fig. 1D and E). Metaphase marrow cytogenetics were unremarkable (46, XY {4} 45, X, −Y {16}), with the isolated loss of the Y chromosome deemed a normal age-related phenomenon. HLA DRB1 typing was homozygous for *0701. Flow cytometry revealed granulocytopenia and B-cell paucity; increased frequency of early myeloid progenitor cells with left shift and a high frequency of cells with homogenous expression of T cell markers including CD3 and CD57. It also showed the heterogeneous expression of CD8 and CD16. On molecular studies, the peripheral blood T-cell receptor-gamma gene rearrangement was found to be clonal. This combination of an increased frequency of clonal T lymphocytes with a granulocytopenia confirmed the diagnosis of T-LGL. Cyclosporine was then initiated at a dose of 200 mg every 12 h to achieve stable level of 200–400 ng/mL for management of T-LGL along with prophylactic sulfamethoxazole–trimethoprim doublestrength, fluconazole and acyclovir. The patient responded well to cyclosporine with almost complete resolution of his circulating blood counts (Fig. 2).
Response to Cyclosporine
Cyclosporine started
Hemoglobin (g/dL)
15
10
500
400
300
200 5 100
0 0
50
100
150
200
250
Reticulocyte count (%)
e188
0 300
Time in days
Cyclosporine started
Absolute Neutrophil Count (10 3/µL)
8
6
300
200
4 100 2
0 0
50
100
150
200
250
Time in days Fig. 2. Graphs showing cell count response to cyclosporine.
0 300
Platelet Count (10 3/µL)
Response to Cyclosporine
10
Letter to the Editor / Leukemia Research 36 (2012) e187–e189
3. Discussion To the best of our knowledge, this is the first published case report of T-LGL occurring in the context of a malignant thymoma. On review of the literature, several observations support an association between benign thymic disorders and LGL leukemia. These two disorders share several clinical manifestations such as neutropenia and pure red cell aplasia [5]. Simultaneous diagnosis of LGL leukemia and thymic hyperplasia has also been reported in a patient presenting with neutropenia [6]. In our case, the patient presented with pancytopenia in the setting of persistent malignant thymoma and was found to have T-LGL. There were no other autoimmune conditions. Even though he was negative for HLA-DR4, he had an excellent response to oral cyclosporine [7]. The thymus is primarily involved in the processing, maturation and education of T-lymphocytes involving a complex interdependence between thymocytes and thymic epithelial cells. There have been reports of clonal proliferation of intra-tumor T-cells with polyclonal large granular lymphocytosis in peripheral blood [8]. It has also been postulated that PRCA with thymoma may involve a T-cell clonal disorder similar to patients with LGL leukemia [5]. Our observation is unique in that the thymoma was clearly malignant with advanced stage at presentation, and the diagnosis of T-LGL was confirmed by flow cytometry and PCR. T-LGL leukemia is known to be associated with many autoimmune diseases such as rheumatoid arthritis and PRCA, hematological disorders such as monoclonal gammopathy of unknown significance (MGUS), B-cell chronic lymphocytic leukemia (BCLL), follicular lymphoma, hairy cell leukemia, Hodgkin disease as well as malignancies of the thyroid, lung, liver, colon, prostate, testes and skin. However, associations with thymic malignancy have not been described. In addition, thymomas are associated with numerous autoimmune conditions like myasthenia gravis and PRCA. Others have found that immune-mediated suppression of erythropoiesis leads to PRCA [8,9]. Furthermore, while surgical resection of the thymoma does not reliably lead to remission of anemia, immunosuppressive medication is a therapeutic option [10]. Similarly, our patient was responsive to treatment with immunosuppressive agents. With this in mind, we suggest that the etiology of this patient’s T-LGL was a result of an autoimmune event produced by the malignant thymoma. This case documents a previously unreported association of T-LGL and malignant thymoma in the same patient. It assists in demonstrating an intimate connection between thymic dysfunction and the occurrence of the auto-reactive T cell clone. Based on this occurrence, we propose a model for the autoimmune etiology of T-LGL: deranged thymopoiesis contributing to the formation of an abnormal autoimmune T-cell clone, which fails to involute and evolves into T-LGL. Conflict of interest statement All authors have no conflicts of interest to report. Acknowledgments None. No funding to declare. This case report conforms to the requirements of the Institutional Review Board at Roswell Park Cancer Institute, Buffalo, NY.
e189
Contributions. AH, PP, PS and MB wrote the paper. PW provided flow cytometry, TK provided pathology slides and PL provided CT images. All authors reviewed and edited the manuscript. References [1] Lamy T, Loughran Jr TP. Clinical features of large granular lymphocyte leukemia. Semin Hematol 2003;40(3):185–95. [2] Zambello R, Loughran Jr TP, Trentin L, Pontisso P, Battistella L, Raimondi R, et al. Serologic and molecular evidence for a possible pathogenetic role of viral infection in CD3-negative natural killer-type lymphoproliferative disease of granular lymphocytes. Leukemia 1995;9(7):1207–11. [3] Yang J, Epling-Burnette PK, Painter JS, Zou J, Bai F, Wei S, et al. Antigen activation and impaired Fas-induced death-inducing signaling complex formation in Tlarge-granular lymphocyte leukemia. Blood 2008;111(3):1610–6. [4] Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003;105(4):546–51. [5] Masuda M, Arai Y, Okamura T, Mizoguchi H. Pure red cell aplasia with thymona: evidence of T-cell clonal disorder. Am J Hematol 1997;54(4):324–8. [6] Rossi D, Franceschetti S, Capello D, Conconi A, Casadio C, Valente G, et al. Simultaneous diagnosis of CD3+ T-cell large granular lymphocyte leukaemia and true thymic hyperplasia. Leuk Res 2007;31(7):1019–21. [7] Battiwalla M, Melenhorst J, Saunthararajah Y, Nakamura R, Molldrem J, Young NS, et al. HLA-DR4 predicts haematological response to cyclosporine in T-large granular lymphocyte lymphoproliferative disorders. Br J Haematol 2003;123(3):449–53. [8] Handa SI, Schofield KP, Sivakumaran M, Short M, Pumphrey RS. Pure red cell aplasia associated with malignant thymoma: myasthenia gravis, polyclonal large granular lymphocytosis and clonal thymic T cell expansion. J Clin Pathol 1994;47(7):676–9. [9] Murakawa T, Nakajima J, Sato H, Tanaka M, Takamoto S, Fukayama M. Thymoma associated with pure red-cell aplasia: clinical features and prognosis. Asian Cardiovasc Thorac Ann 2002;10(2):150–4. [10] Thompson CA, Steensma DP. Pure red cell aplasia associated with thymoma: clinical insights from a 50-year single-institution experience. Br J Haematol 2006;135(3):405–7.
Amanda Herko Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Priyanka Pophali Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA Paul K. Wallace Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, NY, USA Pritha Sharma Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Peter Loud Department of Diagnostic Radiology, Roswell Park Cancer Institute, Buffalo, NY, USA Thaer Khoury Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Minoo Battiwalla ∗ Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA ∗ Corresponding author at: Hematology Branch, NHLBI, National Institutes of Health, 10 Center Dr, 10-CRC, Rm 5-3581, Bethesda, MD 20892, USA. Tel.: +1 301 827 0939; fax: +1 301 827 3228. E-mail address: [email protected] (M. Battiwalla)
27 February 2012 Available online 3 April 2012
Contents lists available at SciVerse ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor T-cell large granular lymphocytosis associated with malignant thymoma
1. Introduction T-cell large granular lymphocytosis (T-LGL) is a proliferative disorder of CD3+ CD8+ T lymphocytes characterized by the clonal rearrangement of the T-cell receptor (TCR) and is consequently often termed a “leukemia” [1]. While this rare disorder has a typically indolent course and is classically associated with cytopenias, a variety of other autoimmune disorders, Sjogrens syndrome and rheumatoid arthritis have been commonly associated with T-LGL. The clonal nature of the disorder has created controversy, with conflicting claims for describing the disorder as a leukemia versus immune dysregulation. Although the etiology has not been conclusively elucidated, chronic activation of T-cells by an auto-reactive or viral antigen [2] and defects in apoptosis [3] have been implicated in the pathogenesis. Thymomas are typically slow-growing primary mediastinal tumors, both benign and malignant, that arise from thymic
epithelial cells. Malignant thymomas are a rare neoplasm, with an incidence of 0.15 cases per 100,000 [4]. While thymomas are known to be associated with numerous autoimmune conditions including myasthenia gravis and hematological paraneoplastic syndromes such as pure red cell aplasia (PRCA), malignant thymomas have not been associated with T-LGL. We present a previously unreported observation of T-LGL in the setting of malignant thymoma along with a review of the literature. The simultaneous occurrence of these two rare diseases – both affecting T-cell function and associated with autoimmune conditions supports immune dysregulation as the etiology for T-LGL. 2. Case report A 71-year-old Caucasian male was referred for evaluation of pancytopenia. He had a history of borderline epithelial type thymoma (WHO B2/B3) diagnosed 3 years previously (Fig. 1A–C). The tumor extended to the lung with extensive involvement of the diaphragmatic pleura and pericardium (Masaoka stage T4, N0, M0/stage IVa). The thymoma was treated surgically with a mass
Fig. 1. (A) Histopathology slide showing thymoma type B2 involving lung parenchyma (arrow indicates bronchial mucosa) (hematoxylin and eosin, 10×). (B) Histopathology slide of thymoma showing scattered isolated ovoid epithelioid cells with vesicular chromatin and conspicuous nucleoli in relatively heavy lymphocytic background (hematoxylin and eosin, 40×). (C) Axial contrast-enhanced CT image of the upper chest showing two right pleural masses (arrows) from the patient’s resected thymic primary and surgical clips in the anterior mediastinum. (D and E) Wright stained peripheral blood smear showing plentiful large granular lymphocytes at low power (D) and at high power (E). 0145-2126/$ – see front matter. Published by Elsevier Ltd. doi:10.1016/j.leukres.2012.03.008
Letter to the Editor / Leukemia Research 36 (2012) e187–e189
wedge resection of the right upper lobe and resection of some diaphragmatic masses followed by chemotherapy. He received cisplatin and docetaxel 4× cycles, then cyclophosphamide, doxorubicin and vincristine 4× cycles, 6 cycles of weekly paclitaxel 2× consecutive weeks with 1 week off and carboplatin and paclitaxel every 3 weeks 5×. After the fifth cycle of the carboplatin and paclitaxel, the chemotherapy was put on hold because the patient developed pancytopenia. In the work up for the pancytopenia, the patient’s CBC revealed a leukocyte count of 2.86 × 103 /L, an absolute neutrophil count of 0.85 × 103 /L, hemoglobin 12 g/dL, and a platelet count of 120 × 103 /L. He eventually became dependent on weekly platelet transfusions. The pancytopenia was initially attributed to slow recovery from chemotherapy. A bone marrow was performed after the CBC did not improve with conservative management for 4 months. Of note, the lowest blood counts obtained included a leukocyte count of 2.32 × 103 /L, an absolute neutrophil count of 0.61 × 103 /L, hemoglobin 7.3 g/dL, and a platelet count of 30 × 103 /L. The bone marrow aspirate and biopsy revealed a hypoplastic marrow with an average cellularity of 10%, 1.5% blasts, the absence
of dysplasia, predominant lymphocytes and sparse granulopoiesis. The peripheral smear showed increased circulating large granular lymphocytes (Fig. 1D and E). Metaphase marrow cytogenetics were unremarkable (46, XY {4} 45, X, −Y {16}), with the isolated loss of the Y chromosome deemed a normal age-related phenomenon. HLA DRB1 typing was homozygous for *0701. Flow cytometry revealed granulocytopenia and B-cell paucity; increased frequency of early myeloid progenitor cells with left shift and a high frequency of cells with homogenous expression of T cell markers including CD3 and CD57. It also showed the heterogeneous expression of CD8 and CD16. On molecular studies, the peripheral blood T-cell receptor-gamma gene rearrangement was found to be clonal. This combination of an increased frequency of clonal T lymphocytes with a granulocytopenia confirmed the diagnosis of T-LGL. Cyclosporine was then initiated at a dose of 200 mg every 12 h to achieve stable level of 200–400 ng/mL for management of T-LGL along with prophylactic sulfamethoxazole–trimethoprim doublestrength, fluconazole and acyclovir. The patient responded well to cyclosporine with almost complete resolution of his circulating blood counts (Fig. 2).
Response to Cyclosporine
Cyclosporine started
Hemoglobin (g/dL)
15
10
500
400
300
200 5 100
0 0
50
100
150
200
250
Reticulocyte count (%)
e188
0 300
Time in days
Cyclosporine started
Absolute Neutrophil Count (10 3/µL)
8
6
300
200
4 100 2
0 0
50
100
150
200
250
Time in days Fig. 2. Graphs showing cell count response to cyclosporine.
0 300
Platelet Count (10 3/µL)
Response to Cyclosporine
10
Letter to the Editor / Leukemia Research 36 (2012) e187–e189
3. Discussion To the best of our knowledge, this is the first published case report of T-LGL occurring in the context of a malignant thymoma. On review of the literature, several observations support an association between benign thymic disorders and LGL leukemia. These two disorders share several clinical manifestations such as neutropenia and pure red cell aplasia [5]. Simultaneous diagnosis of LGL leukemia and thymic hyperplasia has also been reported in a patient presenting with neutropenia [6]. In our case, the patient presented with pancytopenia in the setting of persistent malignant thymoma and was found to have T-LGL. There were no other autoimmune conditions. Even though he was negative for HLA-DR4, he had an excellent response to oral cyclosporine [7]. The thymus is primarily involved in the processing, maturation and education of T-lymphocytes involving a complex interdependence between thymocytes and thymic epithelial cells. There have been reports of clonal proliferation of intra-tumor T-cells with polyclonal large granular lymphocytosis in peripheral blood [8]. It has also been postulated that PRCA with thymoma may involve a T-cell clonal disorder similar to patients with LGL leukemia [5]. Our observation is unique in that the thymoma was clearly malignant with advanced stage at presentation, and the diagnosis of T-LGL was confirmed by flow cytometry and PCR. T-LGL leukemia is known to be associated with many autoimmune diseases such as rheumatoid arthritis and PRCA, hematological disorders such as monoclonal gammopathy of unknown significance (MGUS), B-cell chronic lymphocytic leukemia (BCLL), follicular lymphoma, hairy cell leukemia, Hodgkin disease as well as malignancies of the thyroid, lung, liver, colon, prostate, testes and skin. However, associations with thymic malignancy have not been described. In addition, thymomas are associated with numerous autoimmune conditions like myasthenia gravis and PRCA. Others have found that immune-mediated suppression of erythropoiesis leads to PRCA [8,9]. Furthermore, while surgical resection of the thymoma does not reliably lead to remission of anemia, immunosuppressive medication is a therapeutic option [10]. Similarly, our patient was responsive to treatment with immunosuppressive agents. With this in mind, we suggest that the etiology of this patient’s T-LGL was a result of an autoimmune event produced by the malignant thymoma. This case documents a previously unreported association of T-LGL and malignant thymoma in the same patient. It assists in demonstrating an intimate connection between thymic dysfunction and the occurrence of the auto-reactive T cell clone. Based on this occurrence, we propose a model for the autoimmune etiology of T-LGL: deranged thymopoiesis contributing to the formation of an abnormal autoimmune T-cell clone, which fails to involute and evolves into T-LGL. Conflict of interest statement All authors have no conflicts of interest to report. Acknowledgments None. No funding to declare. This case report conforms to the requirements of the Institutional Review Board at Roswell Park Cancer Institute, Buffalo, NY.
e189
Contributions. AH, PP, PS and MB wrote the paper. PW provided flow cytometry, TK provided pathology slides and PL provided CT images. All authors reviewed and edited the manuscript. References [1] Lamy T, Loughran Jr TP. Clinical features of large granular lymphocyte leukemia. Semin Hematol 2003;40(3):185–95. [2] Zambello R, Loughran Jr TP, Trentin L, Pontisso P, Battistella L, Raimondi R, et al. Serologic and molecular evidence for a possible pathogenetic role of viral infection in CD3-negative natural killer-type lymphoproliferative disease of granular lymphocytes. Leukemia 1995;9(7):1207–11. [3] Yang J, Epling-Burnette PK, Painter JS, Zou J, Bai F, Wei S, et al. Antigen activation and impaired Fas-induced death-inducing signaling complex formation in Tlarge-granular lymphocyte leukemia. Blood 2008;111(3):1610–6. [4] Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003;105(4):546–51. [5] Masuda M, Arai Y, Okamura T, Mizoguchi H. Pure red cell aplasia with thymona: evidence of T-cell clonal disorder. Am J Hematol 1997;54(4):324–8. [6] Rossi D, Franceschetti S, Capello D, Conconi A, Casadio C, Valente G, et al. Simultaneous diagnosis of CD3+ T-cell large granular lymphocyte leukaemia and true thymic hyperplasia. Leuk Res 2007;31(7):1019–21. [7] Battiwalla M, Melenhorst J, Saunthararajah Y, Nakamura R, Molldrem J, Young NS, et al. HLA-DR4 predicts haematological response to cyclosporine in T-large granular lymphocyte lymphoproliferative disorders. Br J Haematol 2003;123(3):449–53. [8] Handa SI, Schofield KP, Sivakumaran M, Short M, Pumphrey RS. Pure red cell aplasia associated with malignant thymoma: myasthenia gravis, polyclonal large granular lymphocytosis and clonal thymic T cell expansion. J Clin Pathol 1994;47(7):676–9. [9] Murakawa T, Nakajima J, Sato H, Tanaka M, Takamoto S, Fukayama M. Thymoma associated with pure red-cell aplasia: clinical features and prognosis. Asian Cardiovasc Thorac Ann 2002;10(2):150–4. [10] Thompson CA, Steensma DP. Pure red cell aplasia associated with thymoma: clinical insights from a 50-year single-institution experience. Br J Haematol 2006;135(3):405–7.
Amanda Herko Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Priyanka Pophali Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA Paul K. Wallace Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, NY, USA Pritha Sharma Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Peter Loud Department of Diagnostic Radiology, Roswell Park Cancer Institute, Buffalo, NY, USA Thaer Khoury Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Minoo Battiwalla ∗ Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA ∗ Corresponding author at: Hematology Branch, NHLBI, National Institutes of Health, 10 Center Dr, 10-CRC, Rm 5-3581, Bethesda, MD 20892, USA. Tel.: +1 301 827 0939; fax: +1 301 827 3228. E-mail address: [email protected] (M. Battiwalla)
27 February 2012 Available online 3 April 2012