Cutaneous t-cell lymphomas (overview) C84.8

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Hadrian Tran

All authors of this article

Last updated on: 29.10.2020

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Synonym(s)

CTCL; Cutaneous T-cell lymphoma; Cutaneous T cell lymphomas; Cutaneous T-cell lymphomas; KTZL; T-cell lymphomas of the skin; T Cell lymphomas of the skin

Definition
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Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of cutaneous malignant lymphoid neoplasias characterized by monoclonal T-cell proliferation and primarily originate from the skin. They account for about 65% of all cutaneous lymphomas. >90% of T-cell lymphomas of the skin belong to the CD4-positive group of T-helper cell lymphomas.

Classification
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The classification of cutaneous T-cell lymphomas (CTCL) is based on clinical, histological/immunohistological and molecular biological criteria (WHO-EORTC classification; see also S2k guideline Cutaneous Lymphomas).

WHO-EORTC classification of cutaneous T-cell lymphomas

Mycosis fungoides and its variants and subtypes

Sézary syndrome (about 2.5% of all T-cell lymphomas)

Adult T-cell lymphoma/leukemia (HTLV+)

Primary cutaneous CD30+ lymphoproliferative diseases

Subcutaneous panniculitis-like CTCL (< 1% of all T-cell lymphomas)

Extranodal NK/T cell lymphoma nasal type (older names: Granuloma gangraenescens nasi)

Primary cutaneous T-cell lymphomas not further specified (NOS)

Occurrence/Epidemiology
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  • 65% of all malignant cutaneous lymphomas (MCL) are cutaneous T-cell lymphomas (CTLC).
  • Incidence: 0.5-1.9/100,000 inhabitants/year.

Etiopathogenesis
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Unknown. Discussed are HTLV-1 and EBV viruses, high-grade type I sensitization and permanent immunosuppression (HIV, drugs). Only for adult T-cell lymphoma (ATLL), the human T-lymphotropic virus, HTLV -1 or - 2 could be detected as the triggering oncogenic virus.

Investigations of activation-induced cell death (AICD) showed that after stimulation of the T-cell receptor (TZR) no apoptosis could be induced (proof of apoptosis resistance). This may be due to an overexpression of c-FLIP, an inhibitor of the apoptosis process. Furthermore, it could be shown that CTCL tumor cells exhibit a "constitutive activation" of the transcription factor NF-.kappaB. This may lead to new therapeutic approaches.

Manifestation
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Men and women in late adulthood are affected.

Localization
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Very different clinical manifestations (for clinical stage classification see Table 1), which are determined by the type of lymphoma. Clinically clearly distinguishable:In addition, there are some less frequently encountered, classifiable and currently still unclassifiable entities.

Clinical features
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Patchy, plaque-like, erythrodermic (type Mycosis fungoides or Sézary syndrome) or nodular skin lesions (type small to medium-sized pleomorphic lymphomas or CD30-positive or CD30-negative large-cell cutaneous T-cell lymphomas) Lymph node enlargements are often detectable in advanced tumor stages, but always in the erythrodermal forms. Systemic involvement with circulation of atypical lymphocytes is possible, especially in the case of extensive, especially erythrodermic infestation.

Laboratory
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Systemic involvement with circulation of atypical lymphocytes (reduction of maturation markers in flow cytometry), especially in cases of extensive, especially erythrodermal, infestation is possible. Frequently, an increase in the IgE level is also detectable. Up to 1/3 of patients show LDH increases and blood eosinophilia.

Histology
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Different, lymphatic tumor cell infiltrates. See below the respective clinical pictures. Characteristic for T-cell lymphomas is the tropism of the lymphoma cells, which refers to both the surface epithelium and the deep epithelium (adnexa).

Diagnosis
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The diagnosis is made clinically. In addition to routine laboratory and organ analysis, the diagnosis is confirmed by histological, immunohistological, molecular biological, radiological and sonographic imaging.
  • Immunophenotyping: This allows differentiation between T and B cell series; also detection of T cell subpopulations using CD4, CD8 and CD30 antibodies
  • T-cell receptor gene rearrangement: Diagnostically important (although not conclusive); detection of monoclonality of T-cell infiltrates is possible with this method (see also pseudolymphomas of the skin).
  • FACS-analysis: Diagnostically important for leukaemic forms (always in Sézary syndrome). In addition to the absolute numbers of CD4-positive and CD8-positive cells, their maturation can be analysed by determining the CD7 and CD26 markers (maturity markers).
  • Lymph node diagnostics: Sonographic examination of skin-near lymph nodes; if necessary, lymph node biopsy and fine tissue diagnostics.
  • Bone marrow biopsy: Since bone marrow involvement is rare in the early forms of CTCL (T1-3, N0-1, M0), this diagnostic procedure is generally unnecessary.

Differential diagnosis
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Therapy
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  • For the therapy of indolent cutaneous T-cell lymphomas, acral CD8+ T-cell lymphomas and CD4+ small-medium-cell T-cell lymphoproliferation, excision or local therapy measures are sufficient.

  • The therapy of CTCL is becoming increasingly standardized and should refer to the "EORTC consensus recommendations" developed in 2006, especially with regard to mycosis fungoides and Sézary syndrome. The prognosis for low malignant CTCL varies greatly from patient to patient. Clinical experience, however, shows beyond doubt that many patients remain in clinical stage Ia (see also parapsoriasis en plaques, large-heart inflammatory form and parakeratosis variegata) of their disease for years or even decades. Aggressive forms of therapy for CTCL have not yet been able to prolong the recurrence-free period in clinical stage Ia and Ib of the disease. It is rather the impression that this increases the progression and acuteity of the lymphoma. The treatment regimes should therefore be adapted to the respective stages of the disease.
  • Stage-independent concomitant therapy: No drying detergents. Blande local therapy with greasy topicals and oil baths. Initially medium to highly effective glucocorticoid ointments such as 0.25% prednicarbate (e.g. Dermatop ointment) or 0.1% mometasone furoate (e.g. Ecural ointment), later weakly effective glucocorticoids. For itching, antihistamines such as desloratadine (e.g. Aerius) 1-2 tbl/day or levocetirizine (e.g. Xusal) 1-2 tbl/day, also antihistamines with a sedative component such as dimetinden (e.g. Fenistil).
  • Stage-dependent basic therapy:
    • UVB therapy: is suitable as a basic therapy in increasing dosage in case of predominance of spots in stage Ia. With this limitation, complete remission is achieved in 54% of patients. Narrow spectrum UVB is equivalent to PUVA therapy in this stdium.
    • Systemic PUVA therapy or PUVA bath therapy with and without retinoids or α interferons (stage I-III). In all stages (I-III) PUVA therapy is to be used as the basic therapy. PUVA bath therapy with fewer side effects is preferable in stages I and II (except for plaques in the facial area!). Therapy duration over several months, in the case of remissions, minimal maintenance therapies as well as therapy breaks should be aimed for. Complete remissions in stage Ia are indicated with 80-100%, stage Ib with 60-90% and in stage IIa with 30-50%, with a remission duration of 1-5 years. If PUVA monotherapy does not respond adequately, combinations of PUVA with interferons and retinoids are recommended.
      • Interferon alfa (e.g. Roferon, Intron A) initial 3 times/week 3 million IU s.c., increase to 9 million IU if possible.
      • Retinoids like acitretin (see also RePUVA therapy) 0.5-1.0 mg/kg bw/day p.o. or in combination with interferon alfa. If therapy is successful, cautious dose reduction and outlet trial with interferon alfa or acitretin, as well as reduction of the irradiation frequency, e.g. once/week or once/every 2 weeks, outlet trial.
    • Extracorporeal photopheresis as mono- and combination therapy (stage Ib and II): Suitable as basic therapy for all stages from stage Ib onwards. "First-line" therapy for patients with Sézary syndrome. Particularly suitable for this therapy are patients who are still largely immunocompetent, with a low proportion of circulating Sézary cells in peripheral blood (10-30%) and without visceral organ infiltrations. Therapy cycles with initially 14-day and later 4-week intervals. As monotherapy, the procedure is mostly insufficient. The following combinations are possible:
      • Interferon alfa-2a (e.g. Roferon A, Intron A) initial 3 times/week 3 million IU s.c., increase to 9 million IU if possible.
      • Retinoids like Acitretin (Neotigason) 0.5-1.0 mg/day p.o.
      • "Mild" systemic chemotherapy e.g. with methotrexate 25 mg/week i.m., i.v., p.o. or chlorambucil p.o.
    • Retinoids such as acitretin (neotigasone) as monotherapy (stage Ia and IIa): In individual studies, monotherapeutic remissions were achieved in up to 30% of patients. However, the duration of remissions is too short at 1-25 months, so that monotherapy cannot be recommended.
    • Bexarotene as monotherapy (stage IIb-IVb): Indicated when a patient has not responded to at least one systemic therapy. Initial: once/day 300 mg/m2 KO p.o., later the dose can be reduced to 100-200 mg/m2 KO p.o.
    • Gemcitabine showed complete remission in 22% of the participants in Phase II trials with 32 subjects. 53% responded partially to the treatment, while 25% showed no clinical improvement.
  • Stage-dependent therapy with protein synthesis inhibitors (stage I and II): Recent phase II studies showed that denileukin Diftitox, a protein that releases Diphteria toxin and consecutively inhibits the protein synthesis of IL-2 overexpressing cells, can positively influence the clinical course. The prior administration of corticosteroids reduces the occurrence of side effects.
  • Radiation therapy (stage IIb and III): Domain in stage IIb and III. In our opinion, radiotherapy treatment of early forms of CTCL (stage Ia) is not justified. In the presence of skin tumors, complete remissions are regularly observed under radiotherapy.
    • Isolated tumours: fractionated soft X-ray therapy (2 times/week, GD 25-30 Gy, ED 2-5 Gy, 30-60 kV; devices: Dermopan Siemens or R.T. 100 Müller).
    • Generalized tumors or erythroderma: whole body irradiation with fast electrons (GD: 30 Gy, ED 2 Gy).
  • Stage I and II chemotherapy: Local chemotherapy is mainly practiced in the Anglo-American countries. Melphalan or BCNU are used. In various studies, remission rates of up to 75% are achieved in clinical stage I, and 55% in clinical stage II. The extremely high sensitization rate of 40% is to be mentioned as a therapy-limiting side effect of using Melphalan. BCNU seems to be more favourable with comparable results regarding the side effect profile (see Common Toxicity Criteria below).
    • Palliative therapy approach: For progressive disease. Here too, treatment with a less aggressive regimen (e.g. bud regimen) should be attempted before more aggressive combinations are used. Applied are the bud-scheme, CHOP-scheme, COPBLAM-scheme. Handling, side effects and laboratory controls see below cytostatic drugs.
    • Vorinostat (in the USA: ZOLINZA) is an oral histone deacetylase inhibitor that was approved by the US Food and Drug Administration (FDA) in October 2006 for the treatment of patients with refractory, advanced and refractory cutaneous T-cell lymphoma. The preparation shows clear antitumor activity in cutaneous T-cell lymphoma.
  • Regarding the supportive therapy measures see below. cytostatic drugs, supportive therapy.

Progression/forecast
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Intermediate malignancy with an average survival time of 3-5 years Progressive courses often with CD4/CD8 ratio > 10 and LDH elevation. Favourable prognosis for CD30-positivity in contrast to high malignancy in CD30-negativity.

Tables
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TNM Staging of cutaneous T-cell lymphomas (CTCL)

T (skin)

T1

limited skin infestation with spots and/or plaques (< 10% KO)

T2

generalized plaques (> 10% KO)

T3

1or> cutaneous tumours (> 1cm)

T4

Erythroderma (> 80% KO)

N (lymph node)

N0

no lymph nodes palpable

N1

Lymphadenopathy, histologically unaffected (Dutch grade 1)

N2

Palpable lymph nodes, histological involvement (Dutch grade 2)

N3

Palpable lymph nodes, histological involvement (Dutch grade 3-4)

B (peripheral blood)

B0

no atypical lymphocytes in peripheral blood

B1

atypical lymphocytes in peripheral blood (< 5%)

B1

High tumor load (> 1000 secary cells/ml with positive clone)

M (Visceral organs)

M

no involvement of visceral organs

M1

visceral involvement

Stage I

Ia

limited plaques (T1 N0 M0)

Ib

generalized plaques (T2 N0 M0)

stage II

IIa

limited or generalized plaques with enlarged lymph nodes (T1-2 N1 M0)

IIb

cutaneous tumours with/without lymphadenopathy, no histological involvement (T3 N0 M0) or (T3 N1 M0)

Stage III

III

Erythroderma with/without lymphadenopathy, no histological involvement of lymph nodes or organs (T4 N0-1 M0)

Stage IV

IV a

histological involvement of lymph nodes (T1-4 N2-3 M0)

IVb

Infestation of organs (T1-4 N0-3 M1)

Note(s)
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There are no associations with atopia. The efficacy of the histone deacetylase inhibitor vorinostat is currently being tested in phase 2 studies with moderate success so far. In the USA, approval by the FDA was already granted in October 2006.

Literature
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  1. Apisarnthanarax N et al (2002) Treatment of cutaneous T cell lymphoma: current status and future directions. Am J Clin Dermatol 3: 193-215
  2. Au WY et al (2002) CD30-positive cutaneous T-cell lymphoma with concurrent solid tumour. Br J Dermatol 146: 1091-1095
  3. Bunn PA et al (1994) Systemic therapy of cutaneous T-cell-lymphomas (mycosis fungoides and the Sezary syndrome) Ann Intern Med 121: 592-602
  4. Criscione VC et al (2007) Incidence of cutaneous T-cell-lymphoma in the United States, 1973-2002 Arch Dermatol 143: 854-859
  5. Duvic M et al (2007) Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109: 31-39
  6. Foss F (2006) clinical experience with Denileukin Diftitox. Semin Oncol 33: 11-16
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Last updated on: 29.10.2020