Zusammenfassung
Primäre kutane T-Zell Lymphome (CTCL) sind gekennzeichnet durch einen Tropismus maligner T-Zellen in das Hautorgan und besonders die Epidermis. Die klassischen und häufigsten Formen des CTCL stellen die Mycosis fungoides (MF) und das Sézary-Syndrom (SS). Der Verlauf der Erkrankung ist zu Beginn über viele Jahre indolent, jedoch ist insgesamt eine Progression der Erkrankung mit sukzessivem Befall der Lymphknoten, des Blutes oder der viszeralen Organe zu erwarten. Bei Patienten in den frühen Stadien IA, IB (T1, T2) liegt die 10-Jahres-Überlebensrate zwischen 100 und 67,4 % [1]
[2]. Entwickelt sich jedoch eine Transformation des Tumors von einer kleinzelligen in eine großzellige Variante, sinkt die mittlere Lebenserwartung auf 19,4 Monate; sind die Rezirkulationsorgane Lymphknoten (mittlere Lebenserwartung = 4,2 Jahre), Blut oder viszerale Organe (2-Jahres-Überlebensrate = 66 %) befallen, ist die Lebenserwartung deutlich erniedrigt. Häufig führen initial eingeleitete Standardtherapiemaßnahmen zu Remissionen, jedoch kommt es in der Regel zu Rezidiven. Die Therapie bleibt somit palliativ. Im Folgenden wird das Standardvorgehen bei der Behandlung von kutanen T-Zell-Lymphomen dargelegt, das z. B. die Photochemotherapie, Interferone und Retinoide umfasst; darüber hinaus werden neue Therapieoptionen diskutiert.
Abstract
Primary cutaneous T-cell lymphomas (CTCL) are characterized by homing of malignant T-cells into the skin and especially into the epidermis. The classical and most common forms of CTCL are mycosis fungoides (MF) and Sézary syndrome (SS). The course of the disease is usually indolent for several years; progression of the disease, however, occurs slowly in every patient and involves the recirculation compartments, i. e. lymph nodes and peripheral blood, and finally spreads to the visceral organs. Early stage MF patients (stage IA/IB) have a 10-year survival rate of about 100 %/67 % [1]. Patients, however, who undergo transformation to large-cell lymphoma have a poor prognosis (medium time of survival: 19.4 months). Once lymph nodes (medium time of survival: 4.2 years) or blood and visceral organs (2-year survival rate: 66 %) are involved the survival rate also drops consideraly. Although there is an initial response to standard therapy, all patients relapse and therefore treatment for CTCL continues to be palliative. In this review, we present the current therapeutic concepts for treatment of CTCL including photochemotherapy, interferons, and retinoids and discuss novel treatment options.
Literatur
-
1
Kim Y H, Chow S, Varghese A, Hoppe R T.
Clinical characteristics and long-term outcome of patients with generalized patch and/or plaque (T2) mycosis fungoides.
Arch Dermatol.
1999;
135
26-32
-
2
Kim Y H, Jensen R A, Watanabe G L, Varghese A, Hoppe R T.
Clinical stage IA (limited patch and plaque) mycosis fungoides. A long-term outcome analysis.
Arch Dermatol.
1996;
132
1309-1313
-
3
Dippel E, Assaf C, Hummel M. et al .
Clonal T-cell receptor gamma-chain gene rearrangement by PCR-based GeneScan analysis in advanced cutaneous T-cell lymphoma: a critical evaluation.
J Pathol.
1999;
188
146-154
-
4
Klemke C D, Dippel E, Dembinski A, Poenitz N, Assaf C, Hummel M, Stein H, Orfanos C E, Goerdt S.
Clonal T-cell receptor gamma-chain gene rearrangement by PCR-based GeneScan analysis in the skin and the blood of patients with parapsoriasis and early stage mycosis fungoides.
J Pathol.
2002;
in press
-
5
Assaf C, Hummel M, Dippel E, Goerdt S, Müller H H, Anagnostopoulos I, Orfanos C E, Stein H.
High detection rate of T cell receptor-beta chain rearrangements in T-cell lymphoproliverations by family specific polymerase chain reaction in combination with GeneScan technique and DNA sequencing.
Blood .
2000;
96
640-646
-
6
Willemze R, Kerl H, Sterry W. et al .
EORTC classification for primary cutaneous lymphomas: a proposal from the cutaneous lymphomas study group of the European organisation for research and treatment of cancer.
Blood.
1997;
90
354-371
-
7
Lamberg S I, Green S B, Byar D P. et al .
Clinical staging for cutaneous T-cell lymphoma.
Ann Intern Med.
1984;
100
187-192
-
8
Dippel E, Goerdt S, Assaf C, Stein H, Orfanos C E.
Cutaneous T-cell lymphoma severity index and T-cell gene rearrangement.
Lancet.
1997;
350
1776-1777
-
9
Dippel E, Schrag H, Goerdt S, Orfanos C E.
Extracorporeal photopheresis and interferon-alpha in advanced cutaneous T-cell lymphoma.
Lancet.
1997;
350
32-33
-
10
Dummer R, Willers J, Dobbeling U, Burg G.
Current pathogenetic aspects of SÅzary syndrome and mycosis fungoides.
Hautarzt.
2001;
52
189-192
-
11
Rook A H, Heald P.
The immunopathogenesis of cutaneous T-cell lymphoma.
Hematol Oncol Clin North Am.
1995;
9
997-1010
-
12
Heald P, Edelson R.
Immunology of cutaneous T-cell lymphoma.
J Natl Cancer Inst.
1991;
83
400-404
-
13
Dummer R, Michie S A, Kell D. et al .
Expression of bcl-2 protein and Ki-67 nuclear proliferation antigen in benign and malignant cutaneous T-cell infiltrates.
J Cutan Pathol.
1995;
22
11-17
-
14
Sala A, Casella I, Grasso L. et al .
Apoptotic response to oncogenic stimuli: cooperative and antagonistic interactions between c-myb and the growth suppressor p53.
Cancer Res.
1996;
56
1991-1996
-
15
Brugnoni D, Airo P, Tosoni C. et al .
CD3-CD4+ cells with a Th2-like pattern of cytokine production in the peripheral blood of a patient with cutaneous T cell lymphoma.
Leukemia.
1997;
11
1983-1985
-
16
Buhl L, Sogaard H.
Immunohistochemical expression of IL-10 in mycosis fungoides.
Exp Dermatol.
1997;
6
195-198
-
17
Dummer R, Heald P W, Nestle F O. et al .
SÅzary syndrome T-cell clones display T-helper 2 cytokines and express the accessory factor-1 (interferon-gamma receptor beta-chain).
Blood.
1996;
88
1383-1389
-
18
Siegel R S, Pandolfino T, Guitart J, Rosen S, Kuzel T M.
Primary cutaneous T-cell lymphoma: review and current concepts.
J Clin Oncol.
2000;
18
2908-2925
-
19
Nisce L Z, Safai B, Kim J H.
Effectiveness of once-weekly total skin electron irradiation in the treatment of mycosis fungoides.
Cancer.
1981;
47
870-876
-
20
Wilson L D, Quiros P A, Kolenik S A. et al .
Additional courses of total skin electron beam therapy in the treatment of patients with recurrent cutaneous T-cell lymphoma.
J Am Acad Dermatol.
1996;
35
69-73
-
21
Bisaccia E, Gonzalez J, Palangio M, Schwartz J, Klainer A S.
Extracorporeal photochemotherapy alone or with adjuvant therapy in the treatment of cutaneous T-cell lymphoma: a 9-year retrospective study at a single institution.
J Am Acad Dermatol.
2000;
43
263-271
-
22
Bryson H M, Sorkin E M.
Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies.
Drugs.
1993;
46
872-894
-
23
Brogden R N, Sorkin E M.
Pentostatin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in lymphoproliferative disorders.
Drugs.
1993;
46
652-677
-
24
Case D C.
Combination chemotherapy for mycosis fungoides with cyclophosphamide, vincristine, methotrexate, and prednisolone.
Am J Clin Oncol.
1984;
4
453-461
-
25
Detmar M, Kreuser E D, Gollnick H. et al .
Primary cutaneous Ki-1/CD30-positive anaplastic large cell lymphoma: complete remission after COP-BLAM regimen with GM-CSF.
Eur J Dermatol.
1992;
35-38
-
26
Orfanos C E, Garbe C.
Pseudolymphome, Praelymphome und Lymphome der Haut. In: Therapie der Hautkrankheiten. Orfanos CE (ed.)
Springer-Verlag Berlin, Heidelberg,.
1995;
987-1020
-
27
Wilson L D, Licata A L, Braverman I M. et al .
Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy.
Int J Radiat Oncol Biol Phys.
1995;
32
987-995
-
28
Winkelmann R K, Diaz-Perez J L, Buechner S A.
The treatment of Sézary syndrome.
J Am Acad Dermatol.
1984;
10
1000-1008
-
29
Briffa D V, Warin A P, Harrington C I, Bleehen S S.
Photochemotherapy in mycosis fungoides.
Lancet.
1980;
2
49-53
-
30
Dippel E, Orfanos C E.
Indikationen und therapeutischer Nutzen der extrakorporalen Photopherese.
Z Hautkr.
1996;
71
723-725
-
31
Kerscher M, Lehmann P, Plewig G.
PUVA bath therapy. Indications and practical implementation.
Hautarzt.
1994;
45
526-528
-
32
Plettenberg H, Stege H, Megahed M. et al .
Ultraviolet A1 (340 - 400 nm) phototherapy for cutaneous T-cell lymphoma.
J Am Acad Dermatol.
1999;
41
47-50
-
33
Edelson R, Berger C, Gasparro F. et al .
Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results.
N Engl J Med.
1987;
316
297-303
-
34
Owsianowski M, Garbe C, Ramaker J, Orfanos C E, Gollnick H.
Therapeutic experiences with extracorporeal photopheresis. Technical procedure, follow-up and clinical outcome in 31 skin diseases.
Hautarzt.
1996;
47
114-123
-
35
Asadullah K, Docke W D, Haeussler A, Sterry W, Volk H D.
Progression of mycosis fungoides is associated with increasing cutaneous expression of interleukin-10 mRNA.
J Invest Dermatol.
1996;
107
833-837
-
36
Asadullah K, Friedrich M, Haeubetaler A, Sterry W, Docke W D, Volk H D.
Granzyme A mRNA expression in mycosis fungoides progression.
Blood.
1997;
90
3810-3811
-
37
Asadullah K, Friedrich M, Docke W D, Jahn S, Volk H D, Sterry W.
Enhanced expression of T-cell activation and natural killer cell antigens indicates systemic anti-tumor response in early primary cutaneous T-cell lymphoma.
J Invest Dermatol.
1997;
108
743-747
-
38
Bunn P AJ, Norris D A.
The therapeutic role of interferons and monoclonal antibodies in cutaneous T-cell lymphomas.
J Invest Dermatol.
1990;
95
209S-212S
-
39
Bunn P A, Foon K A, Ihde D C. et al .
Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphoma.
Ann Intern Med.
1984;
101
484-487
-
40
Stadler R, Ruszczak Z.
Interferons. New additions and indications for use.
Dermatol Clin.
1993;
11
187-199
-
41
Stadler R.
Interferons in dermatology.
Present-day standard.
Dermatol Clin.
1998;
16
377-398
-
42
Stadler R.
, Mayer da-Silva A, Bratzke B, Garbe C, Orfanos CE. Interferons in Dermatology.
J Am Acad Dermatol.
1989;
20
650-656
-
43
Stadler R, Otte H G.
Combination therapy of cutaneous T cell lymphoma with interferon alpha- 2a and photochemotherapy.
Recent Results Cancer Res.
1995;
139
391-401
-
44
Dippel E, Zouboulis C C, Tebbe B, Orfanos C E.
Myopathic syndrome associated with long-term recombinant interferon-alpha treatment in 4 patients with skin disorders.
Arch Dermatol.
1998;
134
880-881
-
45
Kuzel T M, Gilyon K, Springer E. et al .
Interferon alfa-2a combined with phototherapy in the treatment of cutaneous T-cell lymphoma.
J Natl Cancer Inst.
1990;
82
203-207
-
46
Otte H G, Herges A, Stadler R.
Combination therapy with interferon alfa 2a and PUVA in cutaneous T-cell lymphoma.
Hautarzt.
1992;
43
695-699
-
47
Roenigk H H, Kuzel T, Rosen S.
Interferons for cutaneous T-cell lymphoma monotherapy or combination with PUVA.
Australas J Dermatol.
1993;
34
13-15
-
48
Orfanos C E, Zouboulis C C, Almond-Roesler B, Geilen C C.
Current use and future potential role of retinoids in dermatology.
Drugs.
1997;
53
358-388
-
49
Thomson K, Hammar S P, Molin L, Volden G.
Retinoids plus PUVA (RePUVA) and PUVA in mycosis fungoides, plaque stage.
Acta Derm Venereol.
1989;
69
536-540
-
50
Rook A H, Prystowsky M B, Cassin M, Boufal M, Lessin S R.
Combined therapy for SÅzary syndrome with extracorporeal photochemotherapy and low-dose interferon alfa therapy. Clinical, molecular, and immunologic observations.
Arch Dermatol.
1991;
127
1535-1540
-
51
DiRenzo A, Rubegni P, De Aloe G. et al .
Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T-cell lymphoma.
Immunology.
1997;
92
99-103
-
52
Stadler R, Otte H G, Luger T, Henz B M, Kuhl P, Zwingers T, Sterry W.
Prospective randomized multicenter clinical trial on the use of interferon-2a plus acitretin versus interferon-2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II.
Blood.
1998;
92
3578-3581
-
53
Duvic M, Hymes K, Heald P. et al .
Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II - III trial results.
J Clin Oncol.
2001;
19
2456-2471
-
54
Duvic M, Cather J, Maize J, Frankel A E.
DAB389IL2 diphtheria fusion toxin produces clinical responses in tumor stage cutaneous T-cell lymphoma.
Am J Hematol.
1998;
58
87-90
-
55
Lundin J, Osterborg A, Brittinger G. et al .
CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin's lymphomas: a phase II multicenter study. European Study Group of CAMPATH-1H Treatment in Low-Grade Non-Hodgkin's Lymphoma.
J Clin Oncol.
1998;
16
3257-3263
-
56
Bigler R D, Crilley P, Micaily B. et al .
Autologous bone marrow transplantation for advanced stage mycosis fungoides.
Bone Marrow Transplant.
1991;
7
133-137
-
57
Olavarria E, Child F J, Woolford A. et al .
T-cell depletion and autologous stem cell transplantation in the management of tumor stage mycosis fungoides with peripheral blood involvement.
Br J Haematol.
2001;
114
624-631
PD Dr. E. Dippel
Klinik für Dermatologie, Venerologie und Allergologie · Universitätsklinikum Mannheim
Theodor-Kutzer-Ufer 1-3 · 68135 Mannheim
Email: edgar.dippel@haut.ma.uni-heidelberg.de
