1 Department of Lymphoma and Myeloma, 2 Department of Hematopathology and 3 Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Received 25 July 2001; revised 21 January 2002; accepted 11 February 2002
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Abstract |
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The aim of this study was to explore the association between extent of cutaneous involvement, presenting features and progression-free survival (PFS) in patients with primary cutaneous non-Hodgkins lymphoma (PCNHL) of aggressive histology.
Methods:
Previously untreated patients with localized or extensive PCNHL of aggressive histology, treated with combination chemotherapy, but excluding lymphoblastic lymphoma and mycosis fungoides and its variants, were reviewed retrospectively.
Results:
We identified 53 patients, of whom 52 (35 males, 17 females) were treated with doxorubicin-based regimens. Median age was 52 years (range 2581 years), and disease was localized and extensive in 37 and 16 patients, respectively. Twenty-four patients had diffuse large B-cell lymphoma, nine had grade 3 follicular lymphoma, 13 had peripheral T-cell lymphoma (PTCL; not otherwise specified) and seven had anaplastic large cell lymphoma (WHO classification). With a median follow-up of 101 months (range 2237 months) for survivors, the 10-year PFS was 65 ± 7% and overall survival was 72 ± 8%. The first failure involved the skin in 33% of B-cell and 91% of relapsing T-cell lymphomas. Univariate analysis revealed that PTCL (P = 0.005), lymphopenia (P = 0.01) and high serum levels of ß2-microglobulin (P = 0.0006) and LDH (P = 0.002), but not extent of skin involvement, were associated with inferior PFS. Multivariate analysis revealed that only PTCL and high serum lactate dehydrogenase (LDH) were independently associated with inferior PFS.
Conclusions:
PTCL and elevated serum LDH level, but not extent of cutaneous involvement are associated with inferior PFS in aggressive PCNHL treated with combination chemotherapy.
Key words: histology, lymphoma, prognosis, skin, stage
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Introduction |
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The treatment of PCNHL has varied over the years and has included radiotherapy, combination chemotherapy or combined modality regimens [5, 813]. Only one prospective study [14] has been performed on PCNHL, excluding mycosis fungoides and its variants. However, the optimal treatment of PCNHL with aggressive histology, of either B-cell or T-cell immunophenotype, has not yet been defined. Radiotherapy alone has been used for patients with localized B-cell PCNHL [4, 7, 8, 15], but relapse rates ranging from 32% to 100% have been reported [8, 1618]. However, when the absence of extracutaneous disease for 6 months was not required as a diagnostic criterion, PCNHLs with aggressive histology were not curable with radiotherapy alone [11, 18]. In contrast, after doxorubicin-based regimens and variable adjuvant radiotherapy, the 12-year progression-free survival (PFS) for Ann Arbor Stage (AAS) I PCNHL was 71% [18]. A multicenter prospective clinical trial of 49 patients with aggressive PCNHL reported event-free survival (EFS) of only 50% at 5 years after combination chemotherapy [14].
Most studies report survival, which is affected by both initial and post-relapse therapy. The latter is always variable and has changed greatly over time. Survival is also limited by the immutable natural limit of life expectancy, which is obviously shorter for older patients. Therefore, we consider PFS a more suitable end point for retrospective analysis.
The outcome of aggressive histology PCNHL with extensive cutaneous disease remains undefined. Our objective was to define the frequency, clinical and laboratory features, response to combination chemotherapy, patterns of relapse, PFS and survival of adults with histologically aggressive PCNHL. We also wished to determine any association between extent of skin involvement, presenting features and clinical outcome.
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Patients and methods |
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Pathology review
After review of all available slides, diagnoses were rendered according to the WHO classification [19]. Tumor types considered as having an aggressive histology included B-DLCL, ALCL, follicular lymphoma (FL) grade 3 (large cell) and all subtypes of PTCL.
Staging
All available records were reviewed to verify presentation, staging, treatment and outcome. Staging evaluation included physical examination, bone marrow aspirates and biopsies, and chest radiographs. Computerized axial tomography of chest, abdomen and pelvis was performed in 49 patients. In four patients presenting before the introduction of computerized axial tomography, the radiographic exclusion of thoracic and abdominal involvement was based on tomograms and lymphangiograms, and was confirmed by negative exploratory laparotomy in three of them. Radioimmunoassay was used to determine serum levels of ß2-microglobulin, whose upper normal limit was 2.0 mg/dl. However, for analysis of PFS, ß2-microglobulin levels were considered high if >3.0 mg/dl, as previously defined in the tumor score model [21].
The AAS [22] was determined after review of all clinical, laboratory, pathological and radiographic data in a multidisciplinary planning conference attended by hematologists, medical oncologists, radiation oncologists, hematopathologists and diagnostic radiologists. We determined the AAS to be I in 37 patients with one or more lesions, which were localized to a restricted single anatomic area. These included a single upper extremity in six patients, a single lower extremity in five patients, the head in 11 patients, and either anterior or posterior trunk in 15 patients. By contrast, the AAS was determined to be IV in 16 patients who had multiple skin lesions involving more than one anatomic area. The assignment of AAS IV was based on the involvement of anterior and posterior trunk in six patients, of upper and lower extremities in two patients, of trunk and either upper or lower extremities in four patients, of trunk and scalp in one patient, of scalp and lower extremities in one patient, and of both lower extremities in two patients.
Treatment
Treatment according to standard or investigational regimens was based on risk assessment according to histological diagnosis and previously published prognostic criteria [21], and was decided in a multidisciplinary planning clinical conference attended by hematologists, medical oncologists, radiation oncologists, hematopathologists, and diagnostic radiologists. Therapy was administered either at the University of Texas M.D. Anderson Cancer Center, or by collaborating community physicians. However, all response determinations were performed at the M.D. Anderson Cancer Center. Signed informed consent was obtained before all procedures and investigational therapy, as required by the Investigational Review Board. Treatment of localized aggressive lymphomas changed after 1980 from radiation therapy alone to combination chemotherapy, almost always including doxorubicin and often followed by adjuvant radiotherapy. Combination chemotherapy regimens were assigned partly according to the pathological diagnosis, which was in turn rendered according to the Working Formulation [23] before 1994, and thereafter according to the Revised European American Lymphoma (REAL) classification [24], and is currently determined according to the WHO classification [19]. Treatment regimens included: cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) [25] in 13 patients; CHOP with bleomycin (CHOP-B) [26] in 21 patients; CHOP alternating with etoposide, mitoxantrone, vincristine and prednisone (OPEN) [27] in 10 patients; cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) [28] in one patient; CHOP-B alternating with cisplatin, high-dose cytarabine and dexamethasone (DHAP) [29] in one patient; CHOP alternating with cyclophosphamide, methotrexate, etoposide and dexamethazone (C-MED) [30] in three patients; hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethazone and high-dose cytarabine and methotrexate (Hyper-CVAD) [31] in one patient; and alternating triple therapy consisting of doxorubicin, cisplatin, cytarabine and methylprednisolone (ASHAP), alternating with methotrexate, leucovorin, doxorubicin, vincristine, bleomycin, cyclophosphamide and methylprednisolone (M-BACOS), and with ifosfamide, mesna, mitoxantrone and etoposide (MINE) in two patients [32]. One patient with subcutaneous panniculitis-like PTCL was originally thought to have mycosis fungoides and was initially treated with C-MED and interferon, however, the diagnosis was subsequently revised following pathology review. For the purpose of this analysis, CNOP was considered a doxorubicin-equivalent regimen. Radiotherapy was administered at the end of chemotherapy to 31 patients according to specific investigational protocols or at the discretion of the treating physicians. Median dose was 40 Gy (range 3050 Gy).
Response definitions, outcome end points and statistical analysis
Complete remission (CR) was defined as absence of disease for at least 1 month, as determined by physical examination, appropriate laboratory and imaging studies, and skin biopsy, if indicated. Partial response (PR) was defined as >50% reduction of tumor area measurable in two dimensions. Progressive disease (PD) was defined as enlargement (>25%) of an existing site of disease, or the development of disease in a previously uninvolved site. All other responses were considered as stable disease (SD). Primary treatment failure was defined as failure to achieve either CR or PR during initial therapy. Relapse was defined as disease progression occuring at least 1 month after the achievement of CR or PR. PFS was measured from the beginning of treatment to the time of primary treatment failure, relapse or last follow-up. All other events, including toxic deaths, deaths from unrelated causes or the development of non-lymphoid neoplasms, were censored. Survival was measured from start of treatment to last follow-up or to death from any cause. The actuarial probability of PFS and overall survival was determined by the method of KaplanMeier [33]. The statistical significance of differences between groups was determined with the log-rank test, and the statistical relationship between variables with Coxs proportional hazards model [34].
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Results |
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Response to treatment
Overall, 50 of the 53 patients (94%) who received combination chemotherapy achieved a complete remission. Progressive disease during the initial therapy was observed only in three patients, all of whom had PTCL; two with AAS I and one with AAS IV. One patient died from progressive lymphoma, while the other two underwent salvage therapy followed by autologous bone marrow transplantation, and are alive and free of disease after 38 and 70 months, respectively. All seven patients with primary cutaneous ALCL received doxorubicin-based therapy, which was followed by adjuvant radiotherapy in four. Four of them are still in complete remission, and one died free of disease 18 years after treatment. Two patients relapsed, and one was salvaged with MINE [32] and is now in remission 6 years later. The other patient presented with a single lesion on his lower extremity, but died of progressive lymphoma in spite of all salvage therapy. The two patients with ALCL of null-cell phenotype achieved complete remission and did not relapse.
PFS, survival and prognostic features
After a median follow-up of 101 months (range 2237 months) for survivors, 20 patients remain in complete remission, 20 have progressed and 13 have died. Ten of these deaths were due to progressive lymphoma, but none were due to treatment-related toxicity. The estimated 10-year PFS (actuarial ± standard error) was 65% ± 7% (Figure 1A), and survival was 72% ± 8% (Figure 1B).
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Time to relapse was shorter for the T-cell immunophenotype: 75% of their relapses occurred within the first year (range 144 months; Figure 2). In contrast, only 30% of the recurrences of B-cell tumors occurred within the first year (range 6197 months) and a more protracted pattern of relapse was evident (Figure 2).
The site of the first failure was exclusively cutaneous, without evidence of dissemination to lymph nodes or viscera, in eight of 20 (40%) relapsing patients. Relapses were exclusively extracutaneous in seven patients (35%), and three involved the central nervous system. Five patients had simultaneous cutaneous and extracutaneous relapse (25%). Thus, among all 20 relapsing patients, the skin was involved during the first relapse in 13 (65%). No significant difference was found in terms of patterns of relapse between patients who presented with either AAS I or IV disease (data not shown). Failures involving the skin occurred sooner after the beginning of treatment (10 out of 13 within 1 year, range 134 months) than exclusively extracutaneous failures (range 8166 months). This difference probably reflects the fact that 91% of relapsing lymphomas with a T-cell immunophenotype did so with cutaneous involvement compared with 33% for relapsing lymphomas with a B-cell immunophenotype. Therefore, T-cell immunophenotype is not only characterized by a more frequent and earlier relapse than its B-cell counterpart, but also by a strikingly more frequent cutaneous tropism. The location of the cutaneous relapse in relation to the radiotherapy ports could be determined in nine patients; it was within the radiotherapy port in four patients, at its margin in one and at distant cutaneous sites in four.
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Discussion |
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This conclusion is based on a retrospective analysis of patients with localized or disseminated PCNHL of aggressive histology, excluding lymphoblastic lymphoma and mycosis fungoides and its variants. These patients were identified from a database including all untreated patients with lymphoma presenting to our institution, without requiring that disease remained localized to skin for 6 months after the initial diagnosis. This criterion eliminates possible selection bias by excluding from the study patients with an aggressive clinical course, and allows for treatment decisions at the time of the initial patient presentation. According to departmental policy, all these patients were treated with combination chemotherapy regimens suitable for aggressive lymphomas. These regimens almost always contained doxorubicin, and were followed by adjuvant radiotherapy in 58% of them. Thus, there is little chance of selection bias by only treating with chemotherapy patients with perceived adverse presentations.
Our results for PFS are comparable to those of Brice et al. [14], whose prospective treatment of 49 patients with aggressive PCNHL with combination chemotherapy resulted in a 5-year event-free survival of 50%. However, they also included 22 patients with lymph node involvement at presentation, and who thus did not fulfill the criteria of PCNHL. Like us, they found T-cell PCNHL to have significantly worse 5-year PFS (35%) than diffuse large B-cell lymphoma (80%). There were only seven patients with primary cutaneous ALCL in our series, and even though this small number does not allow firm conclusions, their outcome appears favorable and is comparable with previous reports of nodal ALCL [14, 35]. The inferior outcome of PTCL compared with B-DLCL has also been observed in systemic NHLs by both the GELA group [36] and by us [37]. The similarity of outcomes between nodal and primary cutaneous NHL suggests that a separate classification scheme for PCNHL [6] is probably not needed. However, prospective investigations of the molecular and cytogenetic characteristics should determine whether the molecular pathogenesis of PCNHL is different from that of nodal NHLs.
In our series, T-cell PCNHL exhibited a remarkable predilection for cutaneous involvement during the first relapse or progression, with recurrent involvement of the skin in 91% of T-cell PCNHLs, which was exclusively cutaneous in 45% of patients. However, only 33% of B-cell PCNHL recurred in the skin at the time of first relapse. This persistent cutaneous tropism of T-cell lymphomas has previously been reported [7, 8, 14, 38, 39], but its molecular basis remains undefined. A possible explanation is that subpopulations of normal T-lymphocytes, and presumably their neoplastic counterparts, preferentially home to the skin, the site where they presumably encountered antigen for the first time. The cutaneous tropism of T-lymphocytes is most characteristic of mycosis fungoides, where multiple cutaneous relapses usually precede visceral dissemination [40]. However, other cutaneous T-cells and tumors can also express skin-homing receptors [9, 41, 42], including cutaneous lymphocyte-associated antigen, a skin-homing receptor that is expressed on normal memory T-lymphocytes and in cutaneous T-cell lymphomas [43, 44], but not in their B-cell counterparts [45]. The recirculation of lymphocytes between skin and the intravascular compartment is accomplished by complex interactions involving adhesion molecules expressed on lymphocytes, endothelial cells and parenchymal cells, and chemokines secreted by non-lymphoid cells [46, 47]. Interferon-inducible protein-10 (IP-10), which is chemotactic for T-lymphocytes, probably contributes to the epidermotropism of cutaneous T-cell lymphomas [4850]. This is consistent with the preferential detection of its cognate receptor in epidermotropic T-cell lymphomas [51]. Many chemokines, including IP-10, can protect subsets of hemopoietic progenitor cells from cytotoxic chemotherapy in vitro [52]. It is therefore possible that IP-10, or other unidentified chemokines, may contribute both to cutaneous tropism and to the chemoresistance of T-cell PCNHL.
Univariate analysis revealed that PTCL type, high serum LDH, high serum ß2-microglobulin and lymphopenia, but not AAS, were associated with significantly lower PFS. We classified as AAS IV patients with widespread cutaneous lesions at presentation, which were not limited to a single anatomic area as described in the section above entitled Staging. Even though patients with localized disease seemed to have a higher PFS than those with extensive disease, this was largely due to the preferential presentation of B-cell PCNHL with localized disease. When PFS was analyzed separately for patients with T-cell compared with B-cell immunophenotype, extensive cutaneous involvement was not associated with a statistically inferior PFS. Our data are clear for B-cell histologies, but additional patients should be analyzed to confirm this for T-cell histologies where the number of patients was small. Thus, for staging purposes, it appears that skin involvement, irrespective of its extent, might be considered AAS I. This independence of PFS from extent of cutaneous involvement was also demonstrated by multivariate analysis and is consistent with previously published results [13, 53]. The AAS system, as initially designed [22], was based on the contiguous dissemination in Hodgkins disease from one nodal area to the next, and was prognostic for radiotherapy-treated patients with this disease. The weak predictive power of AAS in PCNHL probably reflects the differences in biology between Hodgkins disease and PCNHL, some of which have been discussed previously.
Since there were only 20 failures in this study, the maximal number of independent factors that could be optimally included in a Coxs proportional hazards model was two. We present here a prognostic model including PTCL histology and high serum LDH levels. However, since the number of patients is small, it is probably prudent to consider this model as hypothesis-generating for future investigations in larger retrospective and prospective series.
We conclude that PTCL type and elevated serum LDH levels, but not extent of cutaneous involvement, are independently associated with inferior PFS among patients with PCNHL of aggressive histology treated with combination chemotherapy. A model based on these features identifies groups of patients with unfavorable PFS who may be suitable candidates for investigational therapy.
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Acknowledgements |
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Footnotes |
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
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2. Esche BA, Fitzpatrick PJ. Cutaneous malignant lymphoma. Int J Radiat Oncol Biol Phys 1986; 12: 21112115.[ISI][Medline]
3. Willemze R, Meijer CJ. EORTC classification for primary cutaneous lymphomas: a comparison with the REAL classification and the proposed WHO classification. Ann Oncol 2000; 11: 1115.[Abstract]
4. Burg G, Kaudewitz P, Klepzig K et al. Cutaneous B-cell lymphoma. Dermatol Clin 1985; 3: 689704.[ISI][Medline]
5. Pandolfino TL, Siegel RS, Kuzel TM et al. Primary cutaneous B-cell lymphoma: review and current concepts. J Clin Oncol 2000; 18: 21522168.
6. Willemze R, Kerl H, Sterry W et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 1997; 90: 354371.
7. Kerl H, Cerroni L. Primary B-cell lymphomas of the skin. Ann Oncol 1997; 8: 2932.[ISI][Medline]
8. Santucci M, Pimpinelli N, Arganini L. Primary cutaneous B-cell lymphoma: a unique type of low-grade lymphoma. Clinicopathologic and immunologic study of 83 cases. Cancer 1991; 67: 23112326.[ISI][Medline]
9. Siegel RS, Pandolfino T, Guitart J et al. Primary cutaneous T-cell lymphoma: review and current concepts. J Clin Oncol 2000; 18: 29082925.
10. Rijlaarsdam JU, Toonstra J, Meijer OW et al. Treatment of primary cutaneous B-cell lymphomas of follicle center cell origin: a clinical follow-up study of 55 patients treated with radiotherapy or polychemotherapy. J Clin Oncol 1996; 14: 549555.[Abstract]
11. Joly P, Charlotte F, Leibowitch M et al. Cutaneous lymphomas other than mycosis fungoides: follow-up study of 52 patients. J Clin Oncol 1991; 9: 19942001.[Abstract]
12. Bunn PA, Fischmann AB, Schechter GP et al. Combined modality therapy with electron-beam irradiation and systemic chemotherapy for cutaneous T-cell lymphomas. Cancer Treat Rep 1979; 63: 713717.[ISI][Medline]
13. Bekkenk MW, Vermeer MH, Geerts ML et al. Treatment of multifocal primary cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients. J Clin Oncol 1999; 17: 24712478.
14. Brice P, Cazals D, Mounier N et al. Primary cutaneous large-cell lymphoma: analysis of 49 patients included in the LNH87 prospective trial of polychemotherapy for high-grade lymphomas. Groupe dEtude des Lymphomes de lAdulte. Leukemia 1998; 12: 213219.[ISI][Medline]
15. Kirova YM, Piedbois Y, Le Bourgeois JP. Radiotherapy in the management of cutaneous B-cell lymphoma. Our experience in 25 cases. Radiother Oncol 1999; 52: 1518.[ISI][Medline]
16. Piccinno R, Caccialanza M, Berti E, Baldini L. Radiotherapy of cutaneous B-cell lymphomas. Int J Radiat Oncol Biol Phys 1993; 27: 385389.[ISI][Medline]
17. Berti E, Alessi E, Caputo R et al. Reticulohistiocytoma of the dorsum. J Am Acad Dermatol 1988; 19: 259272.[ISI][Medline]
18. Sarris AH, Braunschweig I, Medeiros LJ et al. Primary cutaneous non-Hodgkins lymphoma of Ann Arbor Stage I: preferential cutaneous relapses but high cure rate with doxorubicin-based therapy. J Clin Oncol 2001; 19: 398405.
19. Harris NL, Jaffe ES, Diebold J et al. 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: 38353849.
20. Cabanillas F, Armitage J, Pugh WC et al. Lymphomatoid papulosis: a T-cell dyscrasia with a propensity to transform into malignant lymphoma. Ann Intern Med 1995; 122: 210217.
21. Rodriguez J, Cabanillas F, McLaughlin P et al. A proposal for a simple staging system for intermediate grade lymphoma and immunoblastic lymphoma based on the tumor score. Ann Oncol 1992; 3: 711717.[Abstract]
22. Carbone PP, Kaplan HS, Musshoff K et al. Report of the Committee on Hodgkins Disease Staging Classification. Cancer Res 1971; 31: 18601861.[ISI][Medline]
23. Non-Hodgkins Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classifications of non-Hodgkins lymphomas: summary and description of a working formulation for clinical usage. Cancer 1982; 49: 21122135.[ISI][Medline]
24. Harris NL, Jaffe ES, Stein H et al. A revised EuropeanAmerican classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 13611392.
25. McKelvey EM, Gottlieb JA, Wilson HE et al. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 1976; 38: 14841493.[ISI][Medline]
26. Lee R, Cabanillas F, Bodey GP et al. A 10-year update of CHOP-Bleo in the treatment of diffuse large-cell lymphoma. J Clin Oncol 1986; 4: 14551461.[Abstract]
27. Swan F Jr, Velasquez WS, Fuller LM. Successful outcome of patients with good risk large cell lymphoma (LCL) with a shortened schedule of treatment (RX). Proc Am Soc Clin Oncol 1991; 10: 273a.
28. Sonneveld P, de Ridder M, van der Lelie H et al. Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkins lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 1995; 13: 25302539.[Abstract]
29. Velasquez WS, Cabanillas F, Salvador P et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood 1988; 71: 117122.[Abstract]
30. Velasquez WS, McLaughlin P, Fuller LM et al. Intermediate-grade lymphomas treated with cyclophosphamidedoxorubicinvincristineprednisonebleomycin alternated with cyclophosphamidemethotrexateetoposidedexamethasone. Application of prognostic models to data analysis. Cancer 1994; 73: 24082416.[ISI][Medline]
31. Khouri IF, Romaguera J, Kantarjian H et al. Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 1998; 16: 38033809.[Abstract]
32. Cabanillas F, Rodriguez-Diaz Pavon J, Hagemeister FB et al. Alternating triple therapy for the treatment of intermediate grade and immunoblastic lymphoma. Ann Oncol 1998; 9: 511518.[Abstract]
33. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457481.[ISI]
34. Cox DR. Regression models and life tables (with Discussion). J R Stat Soc B 1972; 34: 187220.[ISI]
35. Beljaards RC, Kaudewitz P, Berti E et al. Primary cutaneous CD30-positive large cell lymphoma: definition of a new type of cutaneous lymphoma with a favorable prognosis. A European Multicenter Study of 47 patients. Cancer 1993; 71: 20972104.[ISI][Medline]
36. Coiffier B, Brousse N, Peuchmaur M et al. Peripheral T-cell lymphomas have a worse prognosis than B-cell lymphomas: a prospective study of 361 immunophenotyped patients treated with the LNH-84 regimen. The GELA (Groupe dEtude des Lymphomes Agressives). Ann Oncol 1990; 1: 4550.[ISI][Medline]
37. Melnyk A, Rodriguez A, Pugh WC et al. Evaluation of the Revised European-American Lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkins lymphoma. Blood 1997; 89: 45144520.
38. Garcia CF, Weiss LM, Warnke RA et al. Cutaneous follicular lymphoma. Am J Surg Pathol 1986; 10: 454463.[ISI][Medline]
39. Pimpinelli N, Santucci M, Bosi A et al. Primary cutaneous follicular centre-cell lymphomaa lymphoproliferative disease with favourable prognosis. Clin Exp Dermatol 1989; 14: 1219.[ISI][Medline]
40. van Doorn R, Van Haselen CW, van Voorst Vader PC et al. Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients. Arch Dermatol 2000; 136: 504510.
41. Willemze R, de Graaff-Reitsma CB, Cnossen J et al. Characterization of T-cell subpopulations in skin and peripheral blood of patients with cutaneous T-cell lymphomas and benign inflammatory dermatoses. J Invest Dermatol 1983; 80: 6066.[ISI][Medline]
42. Haynes BF, Hensley LL, Jegasothy BV. Phenotypic characterization of skin-infiltrating T cells in cutaneous T-cell lymphoma: comparison with benign cutaneous T-cell infiltrates. Blood 1982; 60: 463473.[Abstract]
43. Borowitz MJ, Weidner A, Olsen EA et al. Abnormalities of circulating T-cell subpopulations in patients with cutaneous T-cell lymphoma: cutaneous lymphocyte-associated antigen expression on T cells correlates with extent of disease. Leukemia 1993; 7: 859863.[ISI][Medline]
44. Noorduyn LA, Beljaards RC, Pals ST et al. Differential expression of the HECA-452 antigen (cutaneous lymphocyte associated antigen, CLA) in cutaneous and non-cutaneous T-cell lymphomas. Histopathology 1992; 21: 5964.[ISI][Medline]
45. Marti RM, Hausmann G, Estrach T et al. T-cell population of primary and secondary cutaneous B-cell lymphomas does not express the cutaneous lymphocyte-associated antigen (CLA). Arch Dermatol Res 1997; 289: 327330.[ISI][Medline]
46. Priest R, Bird MI, Malhotra R. Characterization of E-selectin-binding epitopes expressed by skin-homing T cells. Immunology 1998; 94: 523528.[ISI][Medline]
47. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994; 76: 301314.[ISI][Medline]
48. Sarris AH, Esgleyes-Ribot T, Crow M et al. Cytokine loops involving interferon- and IP-10, a cytokine chemotactic for CD4+ lymphocytes: an explanation for the epidermotropism of cutaneous T-cell lymphoma? Blood 1995; 86: 651658.
49. Daliani D, Ulmer RA, Jackow C et al. Tumor necrosis factor- and interferon-
, but not HTLV-I tax, are likely factors in the epidermotropism of cutaneous T-cell lymphoma via induction of interferon-inducible protein-10. Leuk Lymphoma 1998; 29: 315328.[ISI][Medline]
50. Taub DD, Longo DL, Murphy WJ. Human interferon-inducible protein-10 induces mononuclear cell infiltration in mice and promotes the migration of human T lymphocytes into the peripheral tissues and human peripheral blood lymphocytes-SCID mice. Blood 1996; 87: 14231431.
51. Lu D, Duvic M, Medeiros LJ et al. The T-cell chemokine receptor CXCR3 is expressed highly in low-grade mycosis fungoides. Am J Clin Pathol 2001; 115: 413421.[ISI][Medline]
52. Sarris AH, Talpaz M, Deisseroth AB et al. Human recombinant interferon-inducible protein-10 inhibits the proliferation of normal and acute myelogenous leukemia progenitors. Leukemia 1996; 10: 757765.[ISI][Medline]
53. Beljaards RC, Meijer CJ, Van der Putte SC et al. Primary cutaneous T-cell lymphoma: clinicopathological features and prognostic parameters of 35 cases other than mycosis fungoides and CD30-positive large cell lymphoma. J Pathol 1994; 172: 5360.[ISI][Medline]