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Granular lymphocytic leukemia derived from γδ T-cell expressing cytotoxic molecules
Leukemia Research 25 (2001) 259– 261 www.elsevier.com/locate/leukres
Case report
Granular lymphocytic leukemia derived from gd T-cell expressing cytotoxic molecules Takeshi Saito a, Kazuto Togitani a, Jun Murakami a, Takashi Watanabe a, Ryuji Tanosaki a, Yukio Kobayashi a, Yoshihiro Matsuno b, Kensei Tobinai a,* b
a Hematology Di6ision, National Cancer Center Hospital, 5 -1 -1, Tsukiji, Chuo-ku, Tokyo 104 -0045, Japan Clinical Laboratory Di6ision, National Cancer Center Hospital, 5 -1 -1, Tsukiji, Chuo-ku, Tokyo 104 -0045, Japan
Received 17 July 2000; accepted 17 August 2000
Abstract We here present an extremely rare case of granular lymphocytic leukemia derived from gd T-cell (gd T-GLL). The blood picture at diagnosis was as follows; white cell count 25.7 ×109/l containing 94% atypical lymphocytes with cytoplasmic granules, hemoglobin 11.8 g/dl and platelet count 124 ×109/l. The atypical lymphocytes were positive for CD2, CD3, CD5, CD7, CD56 and TCR gd, but negative for CD4, CD8, CD57, TCR ab and B-cell antigens. The cytotoxic molecules, T-cell intracellular antigen-1 (TIA-1) and granzyme B, were positive by immunocytochemical analysis. Southern blot analysis showed rearrangement of T-cell receptor Jg and Cb genes but germline configuration of the JH gene. Neither serum antibody against human T-cell leukemia virus type-I (HTLV-I) nor the integration of HTLV-I proviral DNA was detected. CT scan showed splenomegaly but no lymph node enlargement. A diagnosis of gd T-GLL was made, and she has been followed up without any therapies for more than 4 years. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Granular lymphocytic leukemia; gd T-GLL; gd T-cell; T-cell receptor; Cytotoxic molecule
1. Introduction Most T-cell malignancies express T-cell receptor (TCR) ab on their cell surfaces, and a very few cases show the TCR gd phenotype. Recently, a variety of clinico-pathologic spectrum of post-thymic gd T-cell malignancies has been recognized, including hepatosplenic, cutaneous, intestinal, thyroidal and nodal onsets [1–3], however, gd T-cell malignancy showing the clinical features compatible with granular Abbre6iations: GLL, granular lymphocytic leukemia; gd T-GLL, GLL derived from gd T-cell; TCR, T-cell receptor; HTLV-I, human T-cell leukemia virus type-I; TIA-1, T-cell intracellular antigen-1; World Health Organization, WHO; LGL, large granular lymphocyte; NK-GLL, GLL derived from natural killer cell; ab T-GLL, GLL derived from ab T-cell. * Corresponding author. Tel.: + 81-3-35422511; fax: +81-335423815. E-mail address: [email protected] (K. Tobinai).
lymphocytic leukemia (GLL) is extremely rare [4–6]. We here present a case of GLL derived from gd T-cell (gd T-GLL), that expressed cytotoxic molecules.
2. Case report A 49-year-old Japanese woman visited the National Cancer Center Hospital in October 1998 because of persistent lymphocytosis and recurrent mucositis. She had been suffering from them for three years when she consulted her physician because of general fatigue. Chest and abdominal CT scans showed splenomegaly but no lymph node enlargement. The blood picture at diagnosis was as follows; white cell count 25.7×109/l with 94% atypical lymphocytes that had granules in their cytoplasms (Fig. 1), hemoglobin 11.8 g/dl and platelet count 124× 109/l. Bone marrow aspiration showed normoplastic marrow with 14.3% granular
0145-2126/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 0 ) 0 0 1 1 5 - 6
260
T. Saito et al. / Leukemia Research 25 (2001) 259–261
Fig. 1. Leukemic cell in the peripheral blood (original magnification ×100, Wright– Giemsa staining). A mature lymphoid cell with azurophilic granules is recognized.
Fig. 2. Immunocytochemical staining of the peripheral blood clot sections (original magnification × 100, immunoperoxidase staining). Cytotoxic molecule, TIA-1 was strongly positive.
lymphocytes and 19.5% erythroid cells. Cytogenetic analysis on bone marrow cells revealed the abnormal karyotype; 46, XX, add (9) (q34) in 2/20 metaphases. Serological examinations for human T-cell leukemia virus type-I (HTLV-I) and human immunodeficiency virus were negative. HTLV-I provirus was not detected in the extracted DNA from peripheral blood mononuclear cells by Southern blot hybridization. Flow cytometric analysis disclosed that her peripheral blood lymphoid cells were positive for CD2 (99.9%), CD3 (99.4%), CD5 (99.3%), CD7 (99.2%) and CD56 (97.9%), but negative for CD4 (0.6%), CD8 (4.1%), CD57 (16.8%) and B-cell markers such as CD19 (0.4%) and CD20 (0.4%). These cells did not react with a monoclonal antibody against TCR ab (WT31) (3.3%), but reacted with a monoclonal antibody against TCR gd (TCRd1) (98.5%). Immunocytochemical analysis disclosed that cytotoxic molecules, granzyme-B and T-cell intracellular antigen-1 (TIA-1), were strongly positive in the granular lymphocytes of the peripheral blood clot sections (Fig. 2). Southern blot hybridization of the extracted DNA from the peripheral blood mononuclear cells showed rearrangements of TCR Jg and TCR Cb1 genes, but germline configuration of JH gene. From these findings, a diagnosis of GLL derived from gd T-cell (gd T-GLL) was made. She has been followed up without any therapies for more than four years, and disease progression has not been observed.
showing gd T-cell phenotype were not described. In these classifications, large granular lymphocyte (LGL) leukemia of T-cell type or T-cell granular lymphocytic leukemia (T-GLL) was described as a distinct mature T-cell chronic lymphoproliferative disorder. Most cases of LGL leukemia of T-cell type or T-GLL show the CD3 + , CD4-, CD8 + , TCR ab + phenotype [7]. The immunophenotype of the present case; CD3+ , CD4 −, CD8 − , TCR ab− , TCR gd+ ; indicates that she is a very rare case of T-GLL derived from gd T-cell, similarly to a few cases reported previously [4–6]. It is known that cytotoxic lymphocytes such as NK cells and cytotoxic T-cells contain unique protein within their azurophilic granules including T-cell intracellular antigen-1 (TIA-1) and granzyme-B. Their expression has been studied in a large series of non-Hodgkin’s lymphomas, and it was reported that TIA-1 and granzyme-B cytoplasmic granules were detected in 70% of anaplastic large cell lymphomas and 23% of peripheral T-cell lymphomas [9]. However, the expression of these cytotoxic molecules in LGL leukemia or GLL has not been extensively analyzed yet. The positive findings for the cytotoxic molecules in the granular lymphocytes of the present case indicate that the leukemic cells are derived from activated cytotoxic T lymphocytes. In the case of GLL derived from ab T-cell (ab T-GLL) or GLL derived from natural killer cell (NKGLL), the course is usually indolent; however, occasional patients with both types show a more aggressive course [7,10]. In particular, such cases of NK-cell type are categorized as aggressive NK-cell leukemia in the WHO Classification [8]. In contrast, the natural history of gd T-GLL remains unknown, because only a very few cases have been reported. One 80-year-old male patient remained asymptomatic for 22 months without therapy [5], another 17-year-old female patient died of disease progression 18 months after splenectomy [6],
3. Discussion In the Revised European – American Lymphoma Classification [7] and the World Health Organization (WHO) Classification [8], only hepatosplenic gd T-cell lymphoma [1] was listed up as a distinct entity derived from gd T-cell, and other mature T-cell neoplasms
T. Saito et al. / Leukemia Research 25 (2001) 259–261
and the present patient has been followed up without any therapies for more than 4 years. Further studies are needed to elucidate the natural history of gd T-GLL. Here, we report an extremely rare case of gd T-GLL expressing cytotoxic molecules. The present case study would provide useful information for further elucidation of the diverse clinicopathologic spectrum of postthymic gd T-cell malignancy.
[3]
[4]
[5]
Acknowledgements [6]
This study was supported by the Grants-in-Aid for Cancer Research (11-8) from the Ministry of Health and Welfare of Japan. T. Saito provided the concept, design, collected the data and analyzed it, drafted the article and gave final approval. K. Togitani and J. Murakami provided study materials, gave critical reviews and final approval for the paper. T. Watanabe, R. Tanosaki and Y. Kobayashi assisted with the interpretation of data, provided critical review and gave final approval. Y. Matsuno collected and analyzed data, provided study material, gave critical input to the revision and gave final approval. K. Tobinai contributed to all aspects of the study as well as providing necessary funding.
[7]
[8]
[9]
References [1] Farcet JP, Gualard P, Marolleau J-P, Le Coeudic J-P, Henni T, Gourdin M-F, Divine M, Haiouin C, Zafrani S, Goosens M, Hercend T, Reyes F. Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gd. Blood 1990;75:2213–9. [2] Ichinohasama R, Miura I, Takahashi T, Yaginuma Y, Myers J, DeCoteau JF, Yee C, Kadin ME, Mori S, Sawai T. Peripheral
.
[10]
261
CD4+ CD8− gd T cell lymphoma: a case report with multiparameter analyses. Hum Pathol 1996;27:1370– 7. Yamaguchi M, Ohno T, Nakamine H, Oka K, Matsuzaka F, Miwa H, Shiku H, Kimura N, Nanba K, Kita K. gd T-cell lymphoma: a clinicopathologic study of 6 cases including extrahepatosplenic type. Int J Hematol 1999;69:186– 95. Vie H, Chevalier S, Garand R, Moisan J-P, Praloran V, Devilder M-C, Moreau J-F, Soulillou J-P. Clonal expansion of lymphocytes bearing the gd T-cell receptor in a patient with large granular lymphocyte disorder. Blood 1989;74:285– 90. Sun T, Cohen NS, Marino J, Koduru P, Cuomo J, Henshall J. CD3+ , CD4− , CD8− large granular T-cell lymphoproliferative disorder. Am J Hematol 1991;37:173– 8. Falcao RP, Voltarelli JC, Simoes BP, Pestana DNR, Zago MA, Figueiredo MS. Malignant Tg/d lymphoproliferative disease with natural killer lytic activity. Am J Hematol 1992;41:128–31. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, Delsol G, Wolf-Peeters DW, Falini B, Gatter KC, Grogan TM, Isaacson P, Knowles DM, Mason DY, Muller-Hermelink H-K, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA. A revised European– American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361– 92. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink H-K, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting — Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835– 49. Kagami Y, Suzuki R, Taji H, Yatabe Y, Takeuchi T, Maeda S, Kondo E, Kojima M, Motoori T, Mizoguchi Y, Okamoto M, Ohnishi K, Yamabe H, Seto M, Ogura M, Koshikawa T, Takahashi T, Kurita S, Morishima Y, Suchi T, Nakamura S. Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients. Am J Surg Pathol 1999;23:1184– 200. Oshimi K, Yamada O, Kaneko T, Nishinarita S, Iizuka Y, Urabe A, Inamori T, Asano S, Takahashi S, Hattori M, Naohara T, Ohira Y, Togawa A, Masuda Y, Okubo Y, Furusawa S, Sakamoto S, Omine M, Mori M, Tatsumi E, Mizoguchi H. Laboratory findings and clinical course of 33 patients with granular lymphocyte-proliferative disorders. Leukemia 1993;7: 782– 8.
Case report
Granular lymphocytic leukemia derived from gd T-cell expressing cytotoxic molecules Takeshi Saito a, Kazuto Togitani a, Jun Murakami a, Takashi Watanabe a, Ryuji Tanosaki a, Yukio Kobayashi a, Yoshihiro Matsuno b, Kensei Tobinai a,* b
a Hematology Di6ision, National Cancer Center Hospital, 5 -1 -1, Tsukiji, Chuo-ku, Tokyo 104 -0045, Japan Clinical Laboratory Di6ision, National Cancer Center Hospital, 5 -1 -1, Tsukiji, Chuo-ku, Tokyo 104 -0045, Japan
Received 17 July 2000; accepted 17 August 2000
Abstract We here present an extremely rare case of granular lymphocytic leukemia derived from gd T-cell (gd T-GLL). The blood picture at diagnosis was as follows; white cell count 25.7 ×109/l containing 94% atypical lymphocytes with cytoplasmic granules, hemoglobin 11.8 g/dl and platelet count 124 ×109/l. The atypical lymphocytes were positive for CD2, CD3, CD5, CD7, CD56 and TCR gd, but negative for CD4, CD8, CD57, TCR ab and B-cell antigens. The cytotoxic molecules, T-cell intracellular antigen-1 (TIA-1) and granzyme B, were positive by immunocytochemical analysis. Southern blot analysis showed rearrangement of T-cell receptor Jg and Cb genes but germline configuration of the JH gene. Neither serum antibody against human T-cell leukemia virus type-I (HTLV-I) nor the integration of HTLV-I proviral DNA was detected. CT scan showed splenomegaly but no lymph node enlargement. A diagnosis of gd T-GLL was made, and she has been followed up without any therapies for more than 4 years. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Granular lymphocytic leukemia; gd T-GLL; gd T-cell; T-cell receptor; Cytotoxic molecule
1. Introduction Most T-cell malignancies express T-cell receptor (TCR) ab on their cell surfaces, and a very few cases show the TCR gd phenotype. Recently, a variety of clinico-pathologic spectrum of post-thymic gd T-cell malignancies has been recognized, including hepatosplenic, cutaneous, intestinal, thyroidal and nodal onsets [1–3], however, gd T-cell malignancy showing the clinical features compatible with granular Abbre6iations: GLL, granular lymphocytic leukemia; gd T-GLL, GLL derived from gd T-cell; TCR, T-cell receptor; HTLV-I, human T-cell leukemia virus type-I; TIA-1, T-cell intracellular antigen-1; World Health Organization, WHO; LGL, large granular lymphocyte; NK-GLL, GLL derived from natural killer cell; ab T-GLL, GLL derived from ab T-cell. * Corresponding author. Tel.: + 81-3-35422511; fax: +81-335423815. E-mail address: [email protected] (K. Tobinai).
lymphocytic leukemia (GLL) is extremely rare [4–6]. We here present a case of GLL derived from gd T-cell (gd T-GLL), that expressed cytotoxic molecules.
2. Case report A 49-year-old Japanese woman visited the National Cancer Center Hospital in October 1998 because of persistent lymphocytosis and recurrent mucositis. She had been suffering from them for three years when she consulted her physician because of general fatigue. Chest and abdominal CT scans showed splenomegaly but no lymph node enlargement. The blood picture at diagnosis was as follows; white cell count 25.7×109/l with 94% atypical lymphocytes that had granules in their cytoplasms (Fig. 1), hemoglobin 11.8 g/dl and platelet count 124× 109/l. Bone marrow aspiration showed normoplastic marrow with 14.3% granular
0145-2126/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 0 ) 0 0 1 1 5 - 6
260
T. Saito et al. / Leukemia Research 25 (2001) 259–261
Fig. 1. Leukemic cell in the peripheral blood (original magnification ×100, Wright– Giemsa staining). A mature lymphoid cell with azurophilic granules is recognized.
Fig. 2. Immunocytochemical staining of the peripheral blood clot sections (original magnification × 100, immunoperoxidase staining). Cytotoxic molecule, TIA-1 was strongly positive.
lymphocytes and 19.5% erythroid cells. Cytogenetic analysis on bone marrow cells revealed the abnormal karyotype; 46, XX, add (9) (q34) in 2/20 metaphases. Serological examinations for human T-cell leukemia virus type-I (HTLV-I) and human immunodeficiency virus were negative. HTLV-I provirus was not detected in the extracted DNA from peripheral blood mononuclear cells by Southern blot hybridization. Flow cytometric analysis disclosed that her peripheral blood lymphoid cells were positive for CD2 (99.9%), CD3 (99.4%), CD5 (99.3%), CD7 (99.2%) and CD56 (97.9%), but negative for CD4 (0.6%), CD8 (4.1%), CD57 (16.8%) and B-cell markers such as CD19 (0.4%) and CD20 (0.4%). These cells did not react with a monoclonal antibody against TCR ab (WT31) (3.3%), but reacted with a monoclonal antibody against TCR gd (TCRd1) (98.5%). Immunocytochemical analysis disclosed that cytotoxic molecules, granzyme-B and T-cell intracellular antigen-1 (TIA-1), were strongly positive in the granular lymphocytes of the peripheral blood clot sections (Fig. 2). Southern blot hybridization of the extracted DNA from the peripheral blood mononuclear cells showed rearrangements of TCR Jg and TCR Cb1 genes, but germline configuration of JH gene. From these findings, a diagnosis of GLL derived from gd T-cell (gd T-GLL) was made. She has been followed up without any therapies for more than four years, and disease progression has not been observed.
showing gd T-cell phenotype were not described. In these classifications, large granular lymphocyte (LGL) leukemia of T-cell type or T-cell granular lymphocytic leukemia (T-GLL) was described as a distinct mature T-cell chronic lymphoproliferative disorder. Most cases of LGL leukemia of T-cell type or T-GLL show the CD3 + , CD4-, CD8 + , TCR ab + phenotype [7]. The immunophenotype of the present case; CD3+ , CD4 −, CD8 − , TCR ab− , TCR gd+ ; indicates that she is a very rare case of T-GLL derived from gd T-cell, similarly to a few cases reported previously [4–6]. It is known that cytotoxic lymphocytes such as NK cells and cytotoxic T-cells contain unique protein within their azurophilic granules including T-cell intracellular antigen-1 (TIA-1) and granzyme-B. Their expression has been studied in a large series of non-Hodgkin’s lymphomas, and it was reported that TIA-1 and granzyme-B cytoplasmic granules were detected in 70% of anaplastic large cell lymphomas and 23% of peripheral T-cell lymphomas [9]. However, the expression of these cytotoxic molecules in LGL leukemia or GLL has not been extensively analyzed yet. The positive findings for the cytotoxic molecules in the granular lymphocytes of the present case indicate that the leukemic cells are derived from activated cytotoxic T lymphocytes. In the case of GLL derived from ab T-cell (ab T-GLL) or GLL derived from natural killer cell (NKGLL), the course is usually indolent; however, occasional patients with both types show a more aggressive course [7,10]. In particular, such cases of NK-cell type are categorized as aggressive NK-cell leukemia in the WHO Classification [8]. In contrast, the natural history of gd T-GLL remains unknown, because only a very few cases have been reported. One 80-year-old male patient remained asymptomatic for 22 months without therapy [5], another 17-year-old female patient died of disease progression 18 months after splenectomy [6],
3. Discussion In the Revised European – American Lymphoma Classification [7] and the World Health Organization (WHO) Classification [8], only hepatosplenic gd T-cell lymphoma [1] was listed up as a distinct entity derived from gd T-cell, and other mature T-cell neoplasms
T. Saito et al. / Leukemia Research 25 (2001) 259–261
and the present patient has been followed up without any therapies for more than 4 years. Further studies are needed to elucidate the natural history of gd T-GLL. Here, we report an extremely rare case of gd T-GLL expressing cytotoxic molecules. The present case study would provide useful information for further elucidation of the diverse clinicopathologic spectrum of postthymic gd T-cell malignancy.
[3]
[4]
[5]
Acknowledgements [6]
This study was supported by the Grants-in-Aid for Cancer Research (11-8) from the Ministry of Health and Welfare of Japan. T. Saito provided the concept, design, collected the data and analyzed it, drafted the article and gave final approval. K. Togitani and J. Murakami provided study materials, gave critical reviews and final approval for the paper. T. Watanabe, R. Tanosaki and Y. Kobayashi assisted with the interpretation of data, provided critical review and gave final approval. Y. Matsuno collected and analyzed data, provided study material, gave critical input to the revision and gave final approval. K. Tobinai contributed to all aspects of the study as well as providing necessary funding.
[7]
[8]
[9]
References [1] Farcet JP, Gualard P, Marolleau J-P, Le Coeudic J-P, Henni T, Gourdin M-F, Divine M, Haiouin C, Zafrani S, Goosens M, Hercend T, Reyes F. Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gd. Blood 1990;75:2213–9. [2] Ichinohasama R, Miura I, Takahashi T, Yaginuma Y, Myers J, DeCoteau JF, Yee C, Kadin ME, Mori S, Sawai T. Peripheral
.
[10]
261
CD4+ CD8− gd T cell lymphoma: a case report with multiparameter analyses. Hum Pathol 1996;27:1370– 7. Yamaguchi M, Ohno T, Nakamine H, Oka K, Matsuzaka F, Miwa H, Shiku H, Kimura N, Nanba K, Kita K. gd T-cell lymphoma: a clinicopathologic study of 6 cases including extrahepatosplenic type. Int J Hematol 1999;69:186– 95. Vie H, Chevalier S, Garand R, Moisan J-P, Praloran V, Devilder M-C, Moreau J-F, Soulillou J-P. Clonal expansion of lymphocytes bearing the gd T-cell receptor in a patient with large granular lymphocyte disorder. Blood 1989;74:285– 90. Sun T, Cohen NS, Marino J, Koduru P, Cuomo J, Henshall J. CD3+ , CD4− , CD8− large granular T-cell lymphoproliferative disorder. Am J Hematol 1991;37:173– 8. Falcao RP, Voltarelli JC, Simoes BP, Pestana DNR, Zago MA, Figueiredo MS. Malignant Tg/d lymphoproliferative disease with natural killer lytic activity. Am J Hematol 1992;41:128–31. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, Delsol G, Wolf-Peeters DW, Falini B, Gatter KC, Grogan TM, Isaacson P, Knowles DM, Mason DY, Muller-Hermelink H-K, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA. A revised European– American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361– 92. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink H-K, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting — Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835– 49. Kagami Y, Suzuki R, Taji H, Yatabe Y, Takeuchi T, Maeda S, Kondo E, Kojima M, Motoori T, Mizoguchi Y, Okamoto M, Ohnishi K, Yamabe H, Seto M, Ogura M, Koshikawa T, Takahashi T, Kurita S, Morishima Y, Suchi T, Nakamura S. Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients. Am J Surg Pathol 1999;23:1184– 200. Oshimi K, Yamada O, Kaneko T, Nishinarita S, Iizuka Y, Urabe A, Inamori T, Asano S, Takahashi S, Hattori M, Naohara T, Ohira Y, Togawa A, Masuda Y, Okubo Y, Furusawa S, Sakamoto S, Omine M, Mori M, Tatsumi E, Mizoguchi H. Laboratory findings and clinical course of 33 patients with granular lymphocyte-proliferative disorders. Leukemia 1993;7: 782– 8.