High-dose chemotherapy with autologous blood stem cell transplantation for aggressive subcutaneous panniculitis-like T-cell lymphoma

Abstract

To the Editor: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare variant of peripheral T-cell lymphoma included in the European Organization for Research and Treatment of Cancer cutaneous lymphoma classification.1Santucci M. Pimpinelli N. Massi D. Kadin M.E. Meijer C. Muller-Hermelink H.K. et al.EORTC cutaneous lymphoma task force cytotoxic/natural killer cell cutaneous lymphomas: report of EORTC cutaneous lymphoma task force workshop.Cancer. 2003; 97: 610-627Crossref PubMed Scopus (209) Google Scholar Patients show erythematous, multiple subcutaneous nodules or plaques localized to the extremities or trunk, and constitutional symptoms including fever, fatigue, and weight loss.2Gonzalez C.L. Medeiros U. Braziel Rmjaffe E.S. T-cell lymphoma involving subcutaneous tissue: a clinicopathological entity commonly associated with hemophagocytic syndrome.Am J Surg Pathol. 1991; 15: 17-27Crossref PubMed Scopus (407) Google Scholar SPTCL is characterized histologically by infiltration of the subcutaneous fatty tissue with malignant lymphocytes in a lobular panniculitis-like pattern. Most cases have shown phenotypic and immunologic features of cytotoxic T lymphocytes.3Salhany K.E. Macon W.R. Choi J.K. Elenitsas R. Lessin S.R. Felgar R.E. et al.Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes.Am J Surg Pathol. 1998; 22: 881-893Crossref PubMed Scopus (296) Google Scholar The lymphoma may behave indolently in some patients, but in most instances can run an acute, aggressive course in which the majority of patients develop a fatal hemophagocytic syndrome.4Weenig R.H. Ng C.S. Perniciaro C. Subcutaneous panniculitis-like T-cell lymphoma: an elusive case presenting as lipomembranous panniculitis and a review of 72 cases in the literature.Am J Dermatopathol. 2001; 23: 206-215Crossref PubMed Scopus (115) Google Scholar Although about half of patients with SPTCL treated with chemotherapy and/or radiotherapy achieve complete remissions, mortality has been reported to be as high as 81%.5Romero L.S. Goltz R.W. Nagi C. Shin Ssho A.D. Subcutaneous T-cell lymphoma with associated hemophagocytic syndrome and terminal leukemic transformation.J Am Acad Dermatol. 1996; 34: 904-910Abstract Full Text PDF PubMed Scopus (65) Google Scholar Autologous stem cell transplantation has been described only in a few patients with SPTCL.6Haycox C.L. Back A.L. Raugi Gjpiepkom M. Subcutaneous T-cell lymphoma treated with systemic chemotherapy, autologous stem cell support, and limb amputation.J Am Acad Dermatol. 1997; 37: 832-835Abstract Full Text Full Text PDF PubMed Google Scholar, 7Koizumi K. Sawada K. Nishio M. Katagiri E. Fukae J. Fukada Y. et al.Effective high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in a patient with the aggressive form of cytophagic histiocytic panniculitis.Bone Marrow Transplant. 1997; 20: 171-173Crossref PubMed Scopus (40) Google Scholar, 8Hashimoto H. Sawada K. Koizumi K. et al.Effective CD34+ selected autologous peripheral blood stem cell transplantation in a patient with subcutaneous panniculitic T cell lymphoma (SPTCL) trasformed into leukaemia.Bone Marrow Transplant. 1999; 24: 1369-1371Crossref PubMed Scopus (20) Google Scholar, 9Reimer P. Rudiger T. Muller J. et al.Subcutaneous panniculitis-like T-cell lymphoma during pregnancy with successful autologous stem cell transplantation.Ann Hematol. 2003; 82: 305-309PubMed Google Scholar, 10Mukai H.Y. Okoshi Y. Shimizu S. et al.Successful treatment of a patient with subcutaneous panniculitis-like T-cell lymphoma with high-dose chemotherapy and total body irradiation.Eur J Haematol. 2003; 70: 413-416Crossref PubMed Scopus (29) Google Scholar In this letter, we report a patient diagnosed with aggressive SPTCL successfully treated with autologous peripheral blood stem cell (PBSC) transplantation and review all the published cases of SPTCL treated with this therapeutic approach.A 32-year-old woman was referred to our clinic in October 2000 for some indurated, painful, erythematous areas on her legs that had been present for 8 months. She had experienced fever and excessive fatigue during the past several months. An excisional biopsy of a leg lesion was performed. Histopathologic findings of skin biopsy specimen disclosed infiltration of the subcutaneous fatty tissue by atypical small to medium lymphocytes and some large lymphoid cells with irregular nuclei, showing characteristic rimming along adipocytes (Fig 1). There was no erythrophagocytosis or angioinvasion. In paraffin sections, the atypical lymphocytes stained positively by immunohistochemistry for CD3 (Fig 2), CD8, TIA1, CD45RO, CD38, CD43, and partially for CD5, whereas staining for CD4, CD30, CD20, CD79, CD56, CD68, and Epstein-Barr virus was negative. Clonal T-cell receptor gamma chain gene rearrangement was detected by polymerase chain reaction. A bone-marrow biopsy specimen and aspirate showed no evidence of infiltration by lymphoma cells or hemophagocytes. All these findings led to the diagnosis of SPTCL.Fig 2Immunohistochemical staining showing reactivity for CD3. (Original magnification: ×40.)View Large Image Figure ViewerDownload (PPT)Although there was a lack of laboratory and instrumental evidence of systemic involvement or hemophagocytosis, we decided to treat the patient with combination chemotherapy because of the presence of new cutaneous lesions and the partial compromise of her general state. Therefore, chemotherapy with etoposide, doxorubucin, cyclophosphamide, prednisone, and bleomycin (VACOP-B) regimen was started in October 2000, but 1 month after the end of the first chemotherapic regimen, a total body positron emission tomogram showed a possible residual disease at two limited areas of the left leg and at one limited area of the right leg. After a confirmatory biopsy, new chemotherapy with vinorelbine was started on March 17, 2001, but after the fourth dose the disease progressed. Therefore, we considered the therapeutic option of the high-dose chemotherapy followed by autologous PBSC transplantation. We started a dexamethasone, high-dose cytarabine, and cisplatin (DHAP) regimen on June 10, 2001, which was continued for 3 cycles every 3 weeks with clinical complete remission and good tolerance. Therefore, we proceeded with the procedures for mobilization and collection of autologous PBSCs. On August 27, 2001, mobilization protocol was started. Subsequently, the conditioning regimen with thiotepa (7.5 mg/kg × 2) the first day and melphalan (70 mg/m2) the second day was started on November 16, 2001, and PBSCs were reinfused on November 20, 2001. She was discharged from the hospital on December 5, 2001, in good condition. No maintenance chemotherapy has been required.Autologous PBSC transplantation has been described only in a few cases of SPTCL (Table I). The positive results obtained in our case and in 5 other cases indicate that for patients with aggressive SPTCL, the use of dose-intensive therapy, including high-dose chemotherapy with stem cell support, should be evaluated as a potential primary therapy. However, it is difficult to assess the necessity of this therapeutic approach for patients with SPTCL as cases with a benign clinical course have been described. In a recent study, it has been suggested that it is possible to predict which patients with SPTCL require aggressive treatment and to identify those patients in whom the disease will pursue a more indolent course.11Hoque S.R. Child F.J. Whittaker S.J. et al.Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients.Br J Dermatol. 2003; 148: 516-525Crossref PubMed Scopus (129) Google Scholar According to this study, CD56+ cases showing expression of the T-cell receptor are more likely to develop hemophagocytic syndrome. However, diagnostic emphasis should be placed also on cellular atypia and the cumulative clinical course.Table IPreviously published cases concerning autologous blood stem cell transplantation for aggressive subcutaneous panniculitis-like T-cell lymphomaCaseAge (y)/SexPrevious therapyOutcome1. Romero et al5Romero L.S. Goltz R.W. Nagi C. Shin Ssho A.D. Subcutaneous T-cell lymphoma with associated hemophagocytic syndrome and terminal leukemic transformation.J Am Acad Dermatol. 1996; 34: 904-910Abstract Full Text PDF PubMed Scopus (65) Google Scholar23/FSteroids, CHOP, mini-BEAMDied 6 wk post-tx2. Haycox et al6Haycox C.L. Back A.L. Raugi Gjpiepkom M. Subcutaneous T-cell lymphoma treated with systemic chemotherapy, autologous stem cell support, and limb amputation.J Am Acad Dermatol. 1997; 37: 832-835Abstract Full Text Full Text PDF PubMed Google Scholar39/MCHOP, DHAP+RT, ICECR/16 mo+3. Koizumi et al7Koizumi K. Sawada K. Nishio M. Katagiri E. Fukae J. Fukada Y. et al.Effective high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in a patient with the aggressive form of cytophagic histiocytic panniculitis.Bone Marrow Transplant. 1997; 20: 171-173Crossref PubMed Scopus (40) Google Scholar20/MCHOP-ECR/12 mo+4. Hashimoto et al8Hashimoto H. Sawada K. Koizumi K. et al.Effective CD34+ selected autologous peripheral blood stem cell transplantation in a patient with subcutaneous panniculitic T cell lymphoma (SPTCL) trasformed into leukaemia.Bone Marrow Transplant. 1999; 24: 1369-1371Crossref PubMed Scopus (20) Google Scholar21/MCHOP+RT, VIP-ECR/14 mo+5. Reimer et al9Reimer P. Rudiger T. Muller J. et al.Subcutaneous panniculitis-like T-cell lymphoma during pregnancy with successful autologous stem cell transplantation.Ann Hematol. 2003; 82: 305-309PubMed Google Scholar35/FCHOPCR/5 mo+6. Mukai et al10Mukai H.Y. Okoshi Y. Shimizu S. et al.Successful treatment of a patient with subcutaneous panniculitis-like T-cell lymphoma with high-dose chemotherapy and total body irradiation.Eur J Haematol. 2003; 70: 413-416Crossref PubMed Scopus (29) Google Scholar24/MCHOPCR/24 mo+7. Current case32/FVACOP-B, vinorelbine, DHAPCR/24 mo+CHOP, Cyclophosphamide, adryamicin, vincristine, and prednisone; CHOP-E, cyclophosphamide, adryamicin, vincristine, prednisone, and etoposide; F, female; M, male; mini-BEAM, carmustine, etoposide, cytarabine, and melphalan; RT, radiotherapy; tx, treatment; VACOP-B, etoposide, doxorubucin, cyclophosphamide, prednisone, and bleomycin; VIP-E, etoposide, ifosfamide, cisplatin, and epirubicin. Open table in a new tab To the Editor: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare variant of peripheral T-cell lymphoma included in the European Organization for Research and Treatment of Cancer cutaneous lymphoma classification.1Santucci M. Pimpinelli N. Massi D. Kadin M.E. Meijer C. Muller-Hermelink H.K. et al.EORTC cutaneous lymphoma task force cytotoxic/natural killer cell cutaneous lymphomas: report of EORTC cutaneous lymphoma task force workshop.Cancer. 2003; 97: 610-627Crossref PubMed Scopus (209) Google Scholar Patients show erythematous, multiple subcutaneous nodules or plaques localized to the extremities or trunk, and constitutional symptoms including fever, fatigue, and weight loss.2Gonzalez C.L. Medeiros U. Braziel Rmjaffe E.S. T-cell lymphoma involving subcutaneous tissue: a clinicopathological entity commonly associated with hemophagocytic syndrome.Am J Surg Pathol. 1991; 15: 17-27Crossref PubMed Scopus (407) Google Scholar SPTCL is characterized histologically by infiltration of the subcutaneous fatty tissue with malignant lymphocytes in a lobular panniculitis-like pattern. Most cases have shown phenotypic and immunologic features of cytotoxic T lymphocytes.3Salhany K.E. Macon W.R. Choi J.K. Elenitsas R. Lessin S.R. Felgar R.E. et al.Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes.Am J Surg Pathol. 1998; 22: 881-893Crossref PubMed Scopus (296) Google Scholar The lymphoma may behave indolently in some patients, but in most instances can run an acute, aggressive course in which the majority of patients develop a fatal hemophagocytic syndrome.4Weenig R.H. Ng C.S. Perniciaro C. Subcutaneous panniculitis-like T-cell lymphoma: an elusive case presenting as lipomembranous panniculitis and a review of 72 cases in the literature.Am J Dermatopathol. 2001; 23: 206-215Crossref PubMed Scopus (115) Google Scholar Although about half of patients with SPTCL treated with chemotherapy and/or radiotherapy achieve complete remissions, mortality has been reported to be as high as 81%.5Romero L.S. Goltz R.W. Nagi C. Shin Ssho A.D. Subcutaneous T-cell lymphoma with associated hemophagocytic syndrome and terminal leukemic transformation.J Am Acad Dermatol. 1996; 34: 904-910Abstract Full Text PDF PubMed Scopus (65) Google Scholar Autologous stem cell transplantation has been described only in a few patients with SPTCL.6Haycox C.L. Back A.L. Raugi Gjpiepkom M. Subcutaneous T-cell lymphoma treated with systemic chemotherapy, autologous stem cell support, and limb amputation.J Am Acad Dermatol. 1997; 37: 832-835Abstract Full Text Full Text PDF PubMed Google Scholar, 7Koizumi K. Sawada K. Nishio M. Katagiri E. Fukae J. Fukada Y. et al.Effective high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in a patient with the aggressive form of cytophagic histiocytic panniculitis.Bone Marrow Transplant. 1997; 20: 171-173Crossref PubMed Scopus (40) Google Scholar, 8Hashimoto H. Sawada K. Koizumi K. et al.Effective CD34+ selected autologous peripheral blood stem cell transplantation in a patient with subcutaneous panniculitic T cell lymphoma (SPTCL) trasformed into leukaemia.Bone Marrow Transplant. 1999; 24: 1369-1371Crossref PubMed Scopus (20) Google Scholar, 9Reimer P. Rudiger T. Muller J. et al.Subcutaneous panniculitis-like T-cell lymphoma during pregnancy with successful autologous stem cell transplantation.Ann Hematol. 2003; 82: 305-309PubMed Google Scholar, 10Mukai H.Y. Okoshi Y. Shimizu S. et al.Successful treatment of a patient with subcutaneous panniculitis-like T-cell lymphoma with high-dose chemotherapy and total body irradiation.Eur J Haematol. 2003; 70: 413-416Crossref PubMed Scopus (29) Google Scholar In this letter, we report a patient diagnosed with aggressive SPTCL successfully treated with autologous peripheral blood stem cell (PBSC) transplantation and review all the published cases of SPTCL treated with this therapeutic approach. A 32-year-old woman was referred to our clinic in October 2000 for some indurated, painful, erythematous areas on her legs that had been present for 8 months. She had experienced fever and excessive fatigue during the past several months. An excisional biopsy of a leg lesion was performed. Histopathologic findings of skin biopsy specimen disclosed infiltration of the subcutaneous fatty tissue by atypical small to medium lymphocytes and some large lymphoid cells with irregular nuclei, showing characteristic rimming along adipocytes (Fig 1). There was no erythrophagocytosis or angioinvasion. In paraffin sections, the atypical lymphocytes stained positively by immunohistochemistry for CD3 (Fig 2), CD8, TIA1, CD45RO, CD38, CD43, and partially for CD5, whereas staining for CD4, CD30, CD20, CD79, CD56, CD68, and Epstein-Barr virus was negative. Clonal T-cell receptor gamma chain gene rearrangement was detected by polymerase chain reaction. A bone-marrow biopsy specimen and aspirate showed no evidence of infiltration by lymphoma cells or hemophagocytes. All these findings led to the diagnosis of SPTCL. Although there was a lack of laboratory and instrumental evidence of systemic involvement or hemophagocytosis, we decided to treat the patient with combination chemotherapy because of the presence of new cutaneous lesions and the partial compromise of her general state. Therefore, chemotherapy with etoposide, doxorubucin, cyclophosphamide, prednisone, and bleomycin (VACOP-B) regimen was started in October 2000, but 1 month after the end of the first chemotherapic regimen, a total body positron emission tomogram showed a possible residual disease at two limited areas of the left leg and at one limited area of the right leg. After a confirmatory biopsy, new chemotherapy with vinorelbine was started on March 17, 2001, but after the fourth dose the disease progressed. Therefore, we considered the therapeutic option of the high-dose chemotherapy followed by autologous PBSC transplantation. We started a dexamethasone, high-dose cytarabine, and cisplatin (DHAP) regimen on June 10, 2001, which was continued for 3 cycles every 3 weeks with clinical complete remission and good tolerance. Therefore, we proceeded with the procedures for mobilization and collection of autologous PBSCs. On August 27, 2001, mobilization protocol was started. Subsequently, the conditioning regimen with thiotepa (7.5 mg/kg × 2) the first day and melphalan (70 mg/m2) the second day was started on November 16, 2001, and PBSCs were reinfused on November 20, 2001. She was discharged from the hospital on December 5, 2001, in good condition. No maintenance chemotherapy has been required. Autologous PBSC transplantation has been described only in a few cases of SPTCL (Table I). The positive results obtained in our case and in 5 other cases indicate that for patients with aggressive SPTCL, the use of dose-intensive therapy, including high-dose chemotherapy with stem cell support, should be evaluated as a potential primary therapy. However, it is difficult to assess the necessity of this therapeutic approach for patients with SPTCL as cases with a benign clinical course have been described. In a recent study, it has been suggested that it is possible to predict which patients with SPTCL require aggressive treatment and to identify those patients in whom the disease will pursue a more indolent course.11Hoque S.R. Child F.J. Whittaker S.J. et al.Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients.Br J Dermatol. 2003; 148: 516-525Crossref PubMed Scopus (129) Google Scholar According to this study, CD56+ cases showing expression of the T-cell receptor are more likely to develop hemophagocytic syndrome. However, diagnostic emphasis should be placed also on cellular atypia and the cumulative clinical course. CHOP, Cyclophosphamide, adryamicin, vincristine, and prednisone; CHOP-E, cyclophosphamide, adryamicin, vincristine, prednisone, and etoposide; F, female; M, male; mini-BEAM, carmustine, etoposide, cytarabine, and melphalan; RT, radiotherapy; tx, treatment; VACOP-B, etoposide, doxorubucin, cyclophosphamide, prednisone, and bleomycin; VIP-E, etoposide, ifosfamide, cisplatin, and epirubicin.