European Journal of Haematology
REVIEW ARTICLE
Gamma-delta t-cell lymphomas s J. M. Ferreri Marco Foppoli, Andre Unit of Lymphoid Malignancies, Division of Onco-Hematological Medicine, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy
Abstract Gamma-delta T-cell lymphomas are aggressive and rare diseases originating from gamma-delta lymphocytes. These cells, which naturally play a role in the innate, non-specific immune response, develop from thymic precursor in the bone marrow, lack the major histocompatibility complex restrictions and can be divided into two subpopulations: Vdelta1, mostly represented in the intestine, and Vdelta2, prevalently located in the skin, tonsils and lymph nodes. Chronic immunosuppression such as in solid organ transplanted subjects and prolonged antigenic exposure are probably the strongest risk factors for the triggering of lymphomagenesis. Two entities are recognised by the 2008 WHO Classification: hepatosplenic gamma-delta T-cell lymphoma (HSGDTL) and primary cutaneous gamma-delta T-cell lymphoma (PCGDTL). The former is more common among young males, presenting with B symptoms, splenomegaly and thrombocytopenia, usually with the absence of nodal involvement. Natural behaviour of HSGDTL is characterised by low response rates, poor treatment tolerability, common early progression of disease and disappointing survival figures. PCGDTL accounts for miniBEAM CHOP = >HDS/ASCT
(74)
1
M/35
–
LSG15
NR
(116)
1
M/39
Crohn’s synd.
HyperC-VAD-ICE
VP16, TBI
(117)
1
F/8
–
CHOP-like
CTX, TBI
M/46 M/51 M/23 M/12 M/19
– – Rheumatoid art. – –
M/27 M/18
Crohn’s synd. Crohn’s synd.
ICE IVAC = >EPOCH ICE Pentostatin Cladribina = >CHOP/ICE IVAC = >ALE ALL = >IVAC
(76)
Intensification & conditioning
Response at transplant
PFS/OS (months)
Cause of death
CR1 CR1 CR1 CR1 CR1 PR1 CR1
32+/36+ 12+/14+ 8+/13+ 15/25 /6 /9 21+/21+
– – – HSGDTL Toxicity Toxicity –
PR
2/2
PTLD
PR2
2/2
GVHD
CR1
86+/86+
–
CR1
NR
CR1
12+/12+
–
PR
58+/58+
–
PR1
11+/11+
–
PR1
11/11
HSGDTL
PD
30+/30+
–
L-PAM, FLU, ALE TTP, CTX, TBI L-PAM, FLU, Bus TTP, CTX, TBI CTX, TBI
NR NR NR NR NR NR HLA identical brother Matched unrelated HLA-matched sibling HLA identical sister HLA-matched sibling Matched unrelated Unrelated-cord blood Matched unrelated HLA identical brother HLA-matched brother NR NR NR NR NR
CR1 PD PR1 PD PD
6/51+ 10/10 3/66+ 3/13 150+/150+
– Toxicity – HSGDTL –
TTP, CTX, TBI VP16, TBI
NR NR
CR1 CR1
5+/5+ 3+/3+
– –
TTP, CTX, TBI
Donor
Table includes case series reported after the year 2.000. N°, number of assessable patients; ALE, Alemtuzumab; asp, PEG-asparaginase; FLU, fludarabine; A, cytarabine; CTX, cyclophosphamide; TBI, total-body irradiation; TTP, thiotepa; BEAM, BCNU, etoposide, cytarabine, melphalan; ASCT, autologous stem cell transplantation; EDHAP, cisplatin, VP16, cytarabine; L-PAM, melphalan; Bus, busulfan; CR, complete remission; PFS, progression-free survival; OS, overall survival; NR, not reported; PTLD, post-transplant lymphoproliferative disorder; HSGDTL, hepatosplenic gammadelta T-cell lymphoma. HDS/ASCT, high-dose sequential chemotherapy supported by autologous stem cell transplant.
been reported (71, 72). All these patients developed a mild to moderate, acute or chronic graft vs. host disease that were successfully controlled; furthermore, they were all alive and relapse-free at a follow-up period between 12 and 58 months. Overall results with allogeneic transplant are encouraging, even among paediatric patients (72, 73), but treatment-related mortality remains high; reduced intensity conditioning may be a good alternative (73, 74). Disease progression or relapse occur generally in the primarily involved sites and typically spare lymph nodes. Secondary dissemination to central nervous system is exceptional; consequently, ad hoc prophylaxis is not indicated as part of first-line treatment (75). Relapsing or refractory HSGDTL is usually unresponsive to conventional
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
chemotherapeutic agents. This is associated with a fast tumour growing and impairment of patients’ performance status and clinical conditions. Nevertheless, salvage treatment can be attempted using drugs that are chosen on a crossingover base from first-line treatment. In selected subjects with suitable clinical conditions and chemosensitive relapse, high-dose induction chemotherapy with allogeneic stem-cells transplantation can be indicated. Anecdotal cases of successful retreatment with allogeneic transplant in HSGDTL patients failed after upfront allogeneic transplant have been also reported (76). The poor clinical outcome of HSGDTL and the fact that they are refractory to standard chemotherapy led some investigators to treat anecdotal cases with drugs potentially useful
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in the management of TCL; some of these agents may theoretically be effective in gamma-delta TCLs as well. Some monoclonal antibodies, such as bevacizumab (antivascular endothelial growth factor A) or mogamulizumab (antichemokine receptor 4), as well as targeted therapy like bortezomib (proteasome inhibitor), vorinostat (histone deacetylase inhibitor), romidepsin, lenalidomide (immunomodulatory) or cytostatics like etoposide (topoisomerase inhibitor) and bendamustine (nitrogen mustard) have been used in single cases of advanced and/or relapsed disease (77–83), but their effectiveness should be assessed in larger series. Some recently developed specific targeted therapies may be assessed in the near future. Similarly to B-cell receptor in B-cell lymphomas, cd-TCR may be a potential therapeutic target in HSGDTL. In particular, anti-cd TCR monoclonal antibodies have been developed, but this therapy in mice led to internalisation of the receptor, not to a gamma-delta T-cell depletion (84). Another potential therapeutic target is the adhesion molecule CD44 (HCAM), which is over-expressed in HSGDTL and plays an important role in T-lymphocytes homing (65). Likewise, cytoplasmic tyrosin kinase Syk inhibitors are currently under investigation, which is of particular interest as Syk is expressed on the vast majority of PTCL cells, but not on normal T cells. There is a regulatory crosstalk between gamma-delta T cells and mesenchymal stem cells; the latter reduce the synthesis of interferon gamma and TNF and suppress proliferation of gamma-delta T cells (68); the putative therapeutic role of this interaction should be investigated further. Primary cutaneous gamma-delta t-cell lymphoma Incidence and risk factors
PCGDTL is a rare malignancy resulting from a clonal proliferation of mature and activated cytotoxic gamma-delta T cells. PCGDTL accounts for 15- and 30-cm-diameter circular area T3: Generalised skin involvement T3a: multiple lesions involving 2 non-contiguous body regions T3b: multiple lesions involving ≥3 body regions N N0: No clinical or pathologic lymph node involvement N1: Involvement of 1 peripheral lymph node region that drains an area of current or prior skin involvement N2: Involvement of 2 or more peripheral lymph node regions or involvement of any lymph node region2 that does not drain an area of current or prior skin involvement N3: Involvement of central lymph nodes M M0: No evidence of extracutaneous non-lymph node disease M1: Extracutaneous non-lymph node disease present 1 Definition of body regions: Head and neck: inferior border: superior border of clavicles, T1 spinous process. Chest: superior border: superior border of clavicles; inferior border: inferior margin of rib cage; lateral borders: mid-axillary lines, glenohumeral joints (inclusive of axillae). Abdomen/genital: superior border: inferior margin of rib cage; inferior border: inguinal folds, anterior perineum; lateral borders: midaxillary lines. Upper back: superior border: T1 spinous process; inferior border: inferior margin of rib cage; lateral borders: mid-axillary lines. Lower back/buttocks: superior border: inferior margin of rib cage; inferior border: inferior gluteal fold, anterior perineum (inclusive of perineum); lateral borders: mid-axillary lines. Each upper arm: superior borders: glenohumeral joints (exclusive of axillae); inferior borders: ulnar/radial-humeral (elbow) joint. Each lower arm/hand: superior borders: ulnar/radial-humeral (elbow) joint. Each upper leg (thigh): superior borders: inguinal folds, inferior gluteal folds; inferior borders: mid-patellae, mid-popliteal fossae. Each lower leg/foot: superior borders: mid-patellae, mid-popliteal fossae. 2 Definition of lymph node regions is consistent with the Ann Arbor system: Peripheral sites: antecubital, cervical, supraclavicular, axillary, inguinal-femoral, and popliteal. Central sites: mediastinal, pulmonary hilar, paraortic, iliac.
lymphoma, are usually long-term survivors (85). Accordingly, PCGDTL should be considered as a separate entity with an aggressive behaviour and marked primary resistance to most chemotherapeutic agents and to radiotherapy, which is independent from the TCR phenotype. Overall prognosis is poor, with a median survival of 15 months and a 5-yr overall survival (OS) of 10% (87). Patients with subcutaneous fat involvement tend to have a worse prognosis as compared with those with epidermal or dermal disease only (87). In the largest reported series (91), disease progression was associated with extensive ulcerated lesions, and deaths
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often resulted from complications of haemophagocytic syndrome and CNS involvement. Nevertheless, anecdotal cases with an indolent behaviour, suggesting some prognostic heterogeneity, have been also reported (107, 108). Treatment
To date, there is no established therapy for PCGDTL and treatment guidelines are mostly based on anecdotal reports. A relevant methodological limitation in reported series regards the inclusion of both entities, PCGDTL and subcutaneous panniculitis-like TCL with an alpha/beta phenotype, and often results have not been reported separately (109). This introduces an important interpretation bias as the latter lymphoma is associated with a significantly better prognosis than PCGDTL, with a 5-yr OS of 82% and 11%, respectively (104). Moreover, the presence of haemophagocytic syndrome is associated with poorer prognosis in patients with subcutaneous panniculitis-like TCL with an alpha/beta phenotype (5-yr OS: 46% vs. 91%; P < 0.001), whereas this complication did not significantly change prognosis in PCGDTL (104). Most reported cases have been managed with doxorubicin-based polychemotherapy (CHOP regimen or derivatives), whereas ASCT or allogeneic SCT have been mostly used in case of progressive disease. Management with prednisone, psoralen and ultraviolet A irradiation, alone or in combination with radiotherapy and chemotherapy, has been also reported. Upfront steroids are associated with a 50% overall response rate, but duration of response was shorter than 6 months for most patients (110). Half of PCGDTL patients treated with first-line CHOP achieve an objective response, but tumour regression is often followed by early disease progression and death (111). Narrow-band ultraviolet radiation and low-dose methotrexate have been shown to be useful therapies in the patch/plaque lesions of PCGDTL, especially in elderly people (112). Bexarotene has been used alone, in combination with, or as maintenance therapy after CHOP/ CHOP-like regimen, and a single case of a patient with PCGDTL with partial remission under denileukin diftitox and complete response after its combination with bexarotene has been reported (113). Given its aggressiveness and poor responsiveness to conventional-dose treatments, some investigators have followed the example of HSGDTL and have treated selected PCGDTL patients with dose-intensive chemotherapy consolidated by autologous or allogeneic SCT (114). In a revision of 13 cases of both refractory or recurrent PCGDTL and subcutaneous panniculitis-like TCL with an alpha/beta phenotype treated with high-dose chemotherapy followed by autologous (n = 12) or allogeneic SCT, complete remission rate was 92%, and median response duration was 14 months; however, the absence of a distinction between the two lymphoma subgroups impairs the value of these results (110).
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Foppoli and Ferreri
Although a single case report of a patient with PCGDTL relapsed after allogeneic stem-cell transplantation who achieved a second remission through cyclosporine withdrawal suggests the possibility of a graft vs. T-cell lymphoma effect (115), selecting the best timing for allogeneic SCT remains a difficult issue in this disease. Intensified therapies are rarely accepted by both patient and practitioner as long as the symptoms do not appear life-threatening, which is often the case in PCGDTL. Early recognition of possible candidates for allogeneic SCT and individualised, toxicityreduced conditioning regimens, combined with modern concepts of immunoprophylaxis, could contribute to minimise transplant-related mortality. The standard treatment for mucosal gamma-delta TCL has not been established, but no evidence suggests that these patients should be managed diversely from those with PCGDTL.
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Disclosure 16.
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77. Advani RH, Hong F, Horning SJ, Kahl BS, Manola J, Swinnen LJ, Habermann TM, Ganjoo K. Cardiac toxicity associated with bevacizumab (Avastin) in combination with CHOP chemotherapy for peripheral T cell lymphoma in ECOG 2404 trial. Leuk Lymphoma 2012;53:718–20. 78. Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:4293–7. 79. Dueck G, Chua N, Prasad A, Finch D, Stewart D, White D, van der Jagt R, Johnston J, Belch A, Reiman T. Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma. Cancer 2010;116: 4541–8. 80. Zinzani PL, Pellegrini C, Broccoli A, et al. Lenalidomide monotherapy for relapsed/refractory peripheral T-cell lymphoma not otherwise specified. Leuk Lymphoma 2011;52:1585–8. 81. O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 2011;29:1182–9. 82. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007;12:1247–52. 83. Woo S, Gardner ER, Chen X, et al. Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res 2009;15:1496–503. 84. Le Gouill S, Milpied N, Buzyn A, et al. Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. J Clin Oncol 2008;26:2264–71. 85. Rodriguez-Pinilla SM, Ortiz-Romero PL, Monsalvez V, et al. TCR-gamma expression in primary cutaneous T-cell lymphomas. Am J Surg Pathol 2013;37:375–84. 86. Ralfkiaer E, Wollf-Sneedorff A, Thomsen K, Geisler C, Vejlsgaard GL. T-cell receptor gamma delta-positive peripheral T-cell lymphomas presenting in the skin: a clinical, histological and immunophenotypic study. Exp Dermatol 1992;1:31–6. 87. Toro JR, Liewehr DJ, Pabby N, Sorbara L, Raffeld M, Steinberg SM, Jaffe ES. Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood 2003;101:3407–12. 88. Toro JR, Beaty M, Sorbara L, Turner ML, White J, Kingma DW, Raffeld M, Jaffe ES. Gamma delta T-cell lymphoma of the skin: a clinical, microscopic, and molecular study. Arch Dermatol 2000;136:1024–32. 89. Arnulf B, Copie-Bergman C, Delfau-Larue MH, et al. Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood 1998;91:1723–31. 90. Ishida M, Iwai M, Yoshida K, Kagotani A, Okabe H. Primary cutaneous B-cell lymphoma with abundant reactive
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gamma/delta T-cells within the skin lesion and peripheral blood. Int J Clin Exp Pathol 2014;7:1193–9. 91. Guitart J, Weisenburger DD, Subtil A, et al. Cutaneous gammadelta T-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas. Am J Surg Pathol 2012;36:1656–65. 92. Yamamoto K, Matsuoka H, Yakushijin K, Funakoshi Y, Okamura A, Hayashi Y, Minami H. A novel five-way translocation, t(3;9;13;8;14)(q27;p13;q32;q24;q32), with concurrent MYC and BCL6 rearrangements in a primary bone marrow B-cell lymphoma. Cancer Genet 2011;204:501–6. 93. Hoefnagel JJ, Vermeer MH, Jansen PM, et al. Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases. Arch Dermatol 2005;141:1139– 45. 94. Yi L, Qun S, Wenjie Z, Wen Z, Jian L, Yan Z, Fengchun Z. The presenting manifestations of subcutaneous panniculitislike T-cell lymphoma and T-cell lymphoma and cutaneous gammadelta T-cell lymphoma may mimic those of rheumatic diseases: a report of 11 cases. Clin Rheumatol 2013; 32:1169–75. 95. Hirakawa K, Fuchigami T, Nakamura S, Daimaru Y, Ohshima K, Sakai Y, Ichimaru T. Primary gastrointestinal T-cell lymphoma resembling multiple lymphomatous polyposis. Gastroenterology 1996;111:778–82. 96. de Bruin PC, Kummer JA, van der Valk P, van Heerde P, Kluin PM, Willemze R, Ossenkoppele GJ, Radaszkiewicz T, Meijer CJ. Granzyme B-expressing peripheral T-cell lymphomas: neoplastic equivalents of activated cytotoxic T cells with preference for mucosa-associated lymphoid tissue localization. Blood 1994;84:3785–91. 97. Katoh A, Ohshima K, Kanda M, Haraoka S, Sugihara M, Suzumiya J, Kawasaki C, Shimazaki K, Ikeda S, Kikuchi M. Gastrointestinal T cell lymphoma: predominant cytotoxic phenotypes, including alpha/beta, gamma/delta T cell and natural killer cells. Leuk Lymphoma 2000;39:97–111. 98. Al Omran S, Mourad WA, Ali MA. Gamma/delta peripheral T-cell lymphoma of the breast diagnosed by fine-needle aspiration biopsyDiagn Cytopathol 2002;26:170–3. 99. Scolnik MP, Burgos RA, Paz A, et al. Nonhepatosplenic gamma delta T-cell lymphoma with initial testicular compromise. Am J Hematol 2000;65:260–2. 100. Tsujikawa T, Itoh A, Bamba M, Andoh A, Hodohara K, Inoue H, Fujiyama Y, Bamba T. Aggressive jejunal gamma deltaTcell lymphoma derived from intraepithelial lymphocytes: an autopsy case report. J Gastroenterol 1998;33:280–4. 101. Kumar S, Krenacs L, Medeiros J, Elenitoba-Johnson KS, Greiner TC, Sorbara L, Kingma DW, Raffeld M, Jaffe ES. Subcutaneous panniculitic T-cell lymphoma is a tumor of cytotoxic T lymphocytes. Hum Pathol 1998;29:397–403. 102. Willemze R, Jansen PM, Cerroni L, et al. Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases. Blood 2008;111:838–45. 103. Przybylski GK, Wu H, Macon WR, et al. Hepatosplenic and subcutaneous panniculitis-like gamma/delta T cell
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REVIEW ARTICLE
Gamma-delta t-cell lymphomas s J. M. Ferreri Marco Foppoli, Andre Unit of Lymphoid Malignancies, Division of Onco-Hematological Medicine, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy
Abstract Gamma-delta T-cell lymphomas are aggressive and rare diseases originating from gamma-delta lymphocytes. These cells, which naturally play a role in the innate, non-specific immune response, develop from thymic precursor in the bone marrow, lack the major histocompatibility complex restrictions and can be divided into two subpopulations: Vdelta1, mostly represented in the intestine, and Vdelta2, prevalently located in the skin, tonsils and lymph nodes. Chronic immunosuppression such as in solid organ transplanted subjects and prolonged antigenic exposure are probably the strongest risk factors for the triggering of lymphomagenesis. Two entities are recognised by the 2008 WHO Classification: hepatosplenic gamma-delta T-cell lymphoma (HSGDTL) and primary cutaneous gamma-delta T-cell lymphoma (PCGDTL). The former is more common among young males, presenting with B symptoms, splenomegaly and thrombocytopenia, usually with the absence of nodal involvement. Natural behaviour of HSGDTL is characterised by low response rates, poor treatment tolerability, common early progression of disease and disappointing survival figures. PCGDTL accounts for miniBEAM CHOP = >HDS/ASCT
(74)
1
M/35
–
LSG15
NR
(116)
1
M/39
Crohn’s synd.
HyperC-VAD-ICE
VP16, TBI
(117)
1
F/8
–
CHOP-like
CTX, TBI
M/46 M/51 M/23 M/12 M/19
– – Rheumatoid art. – –
M/27 M/18
Crohn’s synd. Crohn’s synd.
ICE IVAC = >EPOCH ICE Pentostatin Cladribina = >CHOP/ICE IVAC = >ALE ALL = >IVAC
(76)
Intensification & conditioning
Response at transplant
PFS/OS (months)
Cause of death
CR1 CR1 CR1 CR1 CR1 PR1 CR1
32+/36+ 12+/14+ 8+/13+ 15/25 /6 /9 21+/21+
– – – HSGDTL Toxicity Toxicity –
PR
2/2
PTLD
PR2
2/2
GVHD
CR1
86+/86+
–
CR1
NR
CR1
12+/12+
–
PR
58+/58+
–
PR1
11+/11+
–
PR1
11/11
HSGDTL
PD
30+/30+
–
L-PAM, FLU, ALE TTP, CTX, TBI L-PAM, FLU, Bus TTP, CTX, TBI CTX, TBI
NR NR NR NR NR NR HLA identical brother Matched unrelated HLA-matched sibling HLA identical sister HLA-matched sibling Matched unrelated Unrelated-cord blood Matched unrelated HLA identical brother HLA-matched brother NR NR NR NR NR
CR1 PD PR1 PD PD
6/51+ 10/10 3/66+ 3/13 150+/150+
– Toxicity – HSGDTL –
TTP, CTX, TBI VP16, TBI
NR NR
CR1 CR1
5+/5+ 3+/3+
– –
TTP, CTX, TBI
Donor
Table includes case series reported after the year 2.000. N°, number of assessable patients; ALE, Alemtuzumab; asp, PEG-asparaginase; FLU, fludarabine; A, cytarabine; CTX, cyclophosphamide; TBI, total-body irradiation; TTP, thiotepa; BEAM, BCNU, etoposide, cytarabine, melphalan; ASCT, autologous stem cell transplantation; EDHAP, cisplatin, VP16, cytarabine; L-PAM, melphalan; Bus, busulfan; CR, complete remission; PFS, progression-free survival; OS, overall survival; NR, not reported; PTLD, post-transplant lymphoproliferative disorder; HSGDTL, hepatosplenic gammadelta T-cell lymphoma. HDS/ASCT, high-dose sequential chemotherapy supported by autologous stem cell transplant.
been reported (71, 72). All these patients developed a mild to moderate, acute or chronic graft vs. host disease that were successfully controlled; furthermore, they were all alive and relapse-free at a follow-up period between 12 and 58 months. Overall results with allogeneic transplant are encouraging, even among paediatric patients (72, 73), but treatment-related mortality remains high; reduced intensity conditioning may be a good alternative (73, 74). Disease progression or relapse occur generally in the primarily involved sites and typically spare lymph nodes. Secondary dissemination to central nervous system is exceptional; consequently, ad hoc prophylaxis is not indicated as part of first-line treatment (75). Relapsing or refractory HSGDTL is usually unresponsive to conventional
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
chemotherapeutic agents. This is associated with a fast tumour growing and impairment of patients’ performance status and clinical conditions. Nevertheless, salvage treatment can be attempted using drugs that are chosen on a crossingover base from first-line treatment. In selected subjects with suitable clinical conditions and chemosensitive relapse, high-dose induction chemotherapy with allogeneic stem-cells transplantation can be indicated. Anecdotal cases of successful retreatment with allogeneic transplant in HSGDTL patients failed after upfront allogeneic transplant have been also reported (76). The poor clinical outcome of HSGDTL and the fact that they are refractory to standard chemotherapy led some investigators to treat anecdotal cases with drugs potentially useful
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cd T-cell lymphomas
in the management of TCL; some of these agents may theoretically be effective in gamma-delta TCLs as well. Some monoclonal antibodies, such as bevacizumab (antivascular endothelial growth factor A) or mogamulizumab (antichemokine receptor 4), as well as targeted therapy like bortezomib (proteasome inhibitor), vorinostat (histone deacetylase inhibitor), romidepsin, lenalidomide (immunomodulatory) or cytostatics like etoposide (topoisomerase inhibitor) and bendamustine (nitrogen mustard) have been used in single cases of advanced and/or relapsed disease (77–83), but their effectiveness should be assessed in larger series. Some recently developed specific targeted therapies may be assessed in the near future. Similarly to B-cell receptor in B-cell lymphomas, cd-TCR may be a potential therapeutic target in HSGDTL. In particular, anti-cd TCR monoclonal antibodies have been developed, but this therapy in mice led to internalisation of the receptor, not to a gamma-delta T-cell depletion (84). Another potential therapeutic target is the adhesion molecule CD44 (HCAM), which is over-expressed in HSGDTL and plays an important role in T-lymphocytes homing (65). Likewise, cytoplasmic tyrosin kinase Syk inhibitors are currently under investigation, which is of particular interest as Syk is expressed on the vast majority of PTCL cells, but not on normal T cells. There is a regulatory crosstalk between gamma-delta T cells and mesenchymal stem cells; the latter reduce the synthesis of interferon gamma and TNF and suppress proliferation of gamma-delta T cells (68); the putative therapeutic role of this interaction should be investigated further. Primary cutaneous gamma-delta t-cell lymphoma Incidence and risk factors
PCGDTL is a rare malignancy resulting from a clonal proliferation of mature and activated cytotoxic gamma-delta T cells. PCGDTL accounts for 15- and 30-cm-diameter circular area T3: Generalised skin involvement T3a: multiple lesions involving 2 non-contiguous body regions T3b: multiple lesions involving ≥3 body regions N N0: No clinical or pathologic lymph node involvement N1: Involvement of 1 peripheral lymph node region that drains an area of current or prior skin involvement N2: Involvement of 2 or more peripheral lymph node regions or involvement of any lymph node region2 that does not drain an area of current or prior skin involvement N3: Involvement of central lymph nodes M M0: No evidence of extracutaneous non-lymph node disease M1: Extracutaneous non-lymph node disease present 1 Definition of body regions: Head and neck: inferior border: superior border of clavicles, T1 spinous process. Chest: superior border: superior border of clavicles; inferior border: inferior margin of rib cage; lateral borders: mid-axillary lines, glenohumeral joints (inclusive of axillae). Abdomen/genital: superior border: inferior margin of rib cage; inferior border: inguinal folds, anterior perineum; lateral borders: midaxillary lines. Upper back: superior border: T1 spinous process; inferior border: inferior margin of rib cage; lateral borders: mid-axillary lines. Lower back/buttocks: superior border: inferior margin of rib cage; inferior border: inferior gluteal fold, anterior perineum (inclusive of perineum); lateral borders: mid-axillary lines. Each upper arm: superior borders: glenohumeral joints (exclusive of axillae); inferior borders: ulnar/radial-humeral (elbow) joint. Each lower arm/hand: superior borders: ulnar/radial-humeral (elbow) joint. Each upper leg (thigh): superior borders: inguinal folds, inferior gluteal folds; inferior borders: mid-patellae, mid-popliteal fossae. Each lower leg/foot: superior borders: mid-patellae, mid-popliteal fossae. 2 Definition of lymph node regions is consistent with the Ann Arbor system: Peripheral sites: antecubital, cervical, supraclavicular, axillary, inguinal-femoral, and popliteal. Central sites: mediastinal, pulmonary hilar, paraortic, iliac.
lymphoma, are usually long-term survivors (85). Accordingly, PCGDTL should be considered as a separate entity with an aggressive behaviour and marked primary resistance to most chemotherapeutic agents and to radiotherapy, which is independent from the TCR phenotype. Overall prognosis is poor, with a median survival of 15 months and a 5-yr overall survival (OS) of 10% (87). Patients with subcutaneous fat involvement tend to have a worse prognosis as compared with those with epidermal or dermal disease only (87). In the largest reported series (91), disease progression was associated with extensive ulcerated lesions, and deaths
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Foppoli and Ferreri
often resulted from complications of haemophagocytic syndrome and CNS involvement. Nevertheless, anecdotal cases with an indolent behaviour, suggesting some prognostic heterogeneity, have been also reported (107, 108). Treatment
To date, there is no established therapy for PCGDTL and treatment guidelines are mostly based on anecdotal reports. A relevant methodological limitation in reported series regards the inclusion of both entities, PCGDTL and subcutaneous panniculitis-like TCL with an alpha/beta phenotype, and often results have not been reported separately (109). This introduces an important interpretation bias as the latter lymphoma is associated with a significantly better prognosis than PCGDTL, with a 5-yr OS of 82% and 11%, respectively (104). Moreover, the presence of haemophagocytic syndrome is associated with poorer prognosis in patients with subcutaneous panniculitis-like TCL with an alpha/beta phenotype (5-yr OS: 46% vs. 91%; P < 0.001), whereas this complication did not significantly change prognosis in PCGDTL (104). Most reported cases have been managed with doxorubicin-based polychemotherapy (CHOP regimen or derivatives), whereas ASCT or allogeneic SCT have been mostly used in case of progressive disease. Management with prednisone, psoralen and ultraviolet A irradiation, alone or in combination with radiotherapy and chemotherapy, has been also reported. Upfront steroids are associated with a 50% overall response rate, but duration of response was shorter than 6 months for most patients (110). Half of PCGDTL patients treated with first-line CHOP achieve an objective response, but tumour regression is often followed by early disease progression and death (111). Narrow-band ultraviolet radiation and low-dose methotrexate have been shown to be useful therapies in the patch/plaque lesions of PCGDTL, especially in elderly people (112). Bexarotene has been used alone, in combination with, or as maintenance therapy after CHOP/ CHOP-like regimen, and a single case of a patient with PCGDTL with partial remission under denileukin diftitox and complete response after its combination with bexarotene has been reported (113). Given its aggressiveness and poor responsiveness to conventional-dose treatments, some investigators have followed the example of HSGDTL and have treated selected PCGDTL patients with dose-intensive chemotherapy consolidated by autologous or allogeneic SCT (114). In a revision of 13 cases of both refractory or recurrent PCGDTL and subcutaneous panniculitis-like TCL with an alpha/beta phenotype treated with high-dose chemotherapy followed by autologous (n = 12) or allogeneic SCT, complete remission rate was 92%, and median response duration was 14 months; however, the absence of a distinction between the two lymphoma subgroups impairs the value of these results (110).
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Foppoli and Ferreri
Although a single case report of a patient with PCGDTL relapsed after allogeneic stem-cell transplantation who achieved a second remission through cyclosporine withdrawal suggests the possibility of a graft vs. T-cell lymphoma effect (115), selecting the best timing for allogeneic SCT remains a difficult issue in this disease. Intensified therapies are rarely accepted by both patient and practitioner as long as the symptoms do not appear life-threatening, which is often the case in PCGDTL. Early recognition of possible candidates for allogeneic SCT and individualised, toxicityreduced conditioning regimens, combined with modern concepts of immunoprophylaxis, could contribute to minimise transplant-related mortality. The standard treatment for mucosal gamma-delta TCL has not been established, but no evidence suggests that these patients should be managed diversely from those with PCGDTL.
cd T-cell lymphomas
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Disclosure 16.
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