Cutaneous t-cell lymphomasC84.8

A heterogeneous group of more than 50 different neoplasms of the lymphatic tissue is referred to as "non-Hodgkin's lymphomas" (NHL). A larger group concerns the B-cell lymphomas (about 85% of all NHL), a smaller group the T-cell lymphomas (about 10-15% of all NHL). T-cell lymphomas, with the main representatives of the"mycosis fungoides group", predominantly affect the skin.

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of cutaneous malignant lymphoid neoplasms characterized by monoclonal T-cell proliferation and originating primarily in the skin. They account for approximately 65% of all cutaneous (B- and T-cell) lymphomas. >90% of T-cell lymphomas of the skin belong to the CD4-positive group of T-helper cell lymphomas.

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). Unfortunately, the WHO lymphoma classifications in the past did not adequately address primary cutaneous non-Hodgkin lymphomas. In the 2016 updated WHO classification, the characteristics of extranodal lymphomas, including cutaneous lymphomas, were included for the first time (see Non-Hodgkin l ymphomas - classification).

In addition to the dualistic classification according to:

• Primary cutaneous B-cell lymphomas
• and
• (primary) cutaneous T-cell lymphomas (see also peripheral T-cell lymphomas)

there is now an additional distinction between:

• precursor neoplasms
• and
• peripheral (mature) lymphomas (originating from peripheral lymphoid cells)

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Within the T-cell series, cutaneous T-cell lymphomas are divided into the following groups/entities:

Progenitor T-cell lymphomas

• Progenitor T-cell lymphoblastic leukemia/lymphoma

Peripheral T-cell and NK lymphomas

• T-cell prolymphocytic leukemia
• T-cell large granular lymphocytic lymphoma (see below T-cell leukemia with large granular lymphocytes; see also Aggressive NK-cell leukemia)

Mycosis fungoides and MF variants

• Folliculotropic mycosis fungoides
• Pagetoid reticulosis
• Granulomatous slack skin

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

Adult T-cell lymphoma/leukemia (HTLV+)

Primary cutaneous CD30+ lymphoproliferative lymphomas

• Lymphomatoid papulosis
• Primary cutaneous CD30 positive anaplastic large T-cell lymphoma

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

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

Primary cutaneous peripheral T-cell lymphoma (not further specified)

• Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma
• Cutaneous gamma/delta T-cell lymphoma

• Primary cutaneous T-cell lymphoma pleomorphic small-medium-large cell

• Primary cutaneous small-medium-large cell pleomorphic T-cell lymphoproliferative disorder (provisional)
• Primary cutaneous acral CD8+T-cell lymphoma (provisional)

65% of all cutaneous malignant lymphomas (MCL) are cutaneous T-cell lymphomas (CTLC).

Incidence: 0.5-1.9/100,000 population/year.

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

Investigations of activation-induced cell death (AICD) showed that apoptosis could no longer be induced after stimulation of the T-cell receptor(TZR) (evidence of apoptosis resistance). This apoptosis resistance is possibly 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.

• CTCL of the mycosis fungoides type, with extremely low progression over years (see below parapsoriasis en plaques, large-heart inflammatory form, parakeratosis variegata; both clinical pictures are considered precursors of a cutaneous T-cell lymphoma)
• CTCL of the Sézary syndrome type, as foudroyant erythrodermic and leukemic variant.
• CTCL with single or disseminated, ulcerated or surface intact tumours (old name: Mycosis-fungoides-d'emblée).

• 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.

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

• The therapy of CTCL experiences an increasing standardization and should refer to the "EORTC consensus recommendations" developed in 2006, especially with regard to mycosis fungoides and Sézary syndrome. The prognosis of low-malignant CTCL varies greatly from patient to patient. However, clinical experience undoubtedly proves that many patients remain in clinical stage Ia (see also below parapsoriasis en plaques, large inflammatory form and parakeratosis variegata) of their disease for years or even decades. Aggressive forms of therapy in CTCL have so far not been able to prolong the relapse-free time in clinical stage Ia and Ib of the disease. There is rather the impression that this increases the progression and acute nature of the lymphoma. Therefore, the therapy regimens have to be adapted to the respective disease stages.
• Concomitant therapy independent of stage: No drying detergents. Bland local therapy with oily topical preparations and oil baths. Externally, initially moderately to strongly 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 tablets/day or levocetirizine (e.g. Xusal) 1-2 tablets/day, also antihistamines with a sedative component such as dimetindene (e.g. Fenistil).
• Stage-dependent basic therapy:
  • UVB therapy: Is suitable as basic therapy in increasing dosage in case of predominance of stage Ia spots. Under this restriction, complete remission is achieved in 54% of patients. Narrow spectrum UVB is equivalent to PUVA therapy in this stadium.
  • Systemic PUVA therapy or PUVA bath therapy with and without retinoids or α-interferons (stages I-III). In all stages (I-III), PUVA therapy is to be used as basic therapy. The PUVA bath therapy, which has fewer side effects, is preferable in stages I and II (except for plaques in the facial area!). Therapy duration over several months, in case of remissions minimal maintenance therapy as well as therapy breaks are to be aimed at. Complete remissions in stage Ia are reported with 80-100%, stage Ib with 60-90% and in stage IIa with 30-50%, with a remission duration of 1-5 years. In case of insufficient response of PUVA monotherapy, combinations of PUVA with interferons and retinoids are recommended.
    • Interferon alfa (e.g. Roferon, Intron A) initially 3 times/week 3 million IU s.c., increase to 9 million IU if possible.
    • Retinoids such as 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 discontinuation of interferon alfa or acitretin, as well as reduction of the irradiation frequency, e.g. 1 time/week or once/every 2 weeks, discontinuation.
  • Extracorporeal photopheresis as monotherapy and combination therapy (stage Ib and II): From stage Ib onwards, suitable as basic therapy for all stages. "First-line" therapy for patients with Sézary syndrome. Particularly suitable for therapy are patients who are still largely immunocompetent, with a low proportion of circulating Sézary cells in the peripheral blood (10-30%) and without visceral organ infiltrations. Therapy cycles with initially 14-day later 4-week intervals. As monotherapy, the procedure is predominantly insufficient. The following combinations are recommended:
    • Interferon alfa-2a (e.g. Roferon A, Intron A) initially 3 times/week 3 million IU s.c., increase to 9 million IU if possible.
    • Retinoids such as 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 (Neotigason) 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 (1-25 months), so that monotherapy cannot be recommended.
  • Bexarotene as monotherapy (stage IIb-IVb): Indicated when a patient has failed to respond to at least one systemic therapy. Initial: 1 time/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 participants in phase II trials with 32 subjects. 53% had a partial response to treatment, while 25% had 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 sequentially inhibits protein synthesis by IL-2 overexpressing cells, can favorably influence the clinical course. Prior administration of corticosteroids reduces the incidence of side effects.
• Radiotherapy (stage IIb and III): Domain in stage IIb and III. Radiotherapy treatment of early forms of CTCL (stage Ia) is not justified in our opinion. In the presence of skin tumors, complete remissions are regularly observed under radiotherapy.
  • Isolated tumors: fractionated soft X-ray therapy (2 times/week, GD 25-30 Gy, ED 2-5 Gy, 30-60 kV; equipment: Dermopan Siemens or R.T. 100 Müller).
  • Generalized tumors or erythroderma: whole body irradiation with fast electrons (GD: 30 Gy, ED 2 Gy).
• Stage-dependent chemotherapy (stage I and II): Local chemotherapy is primarily practiced in 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. A therapy-limiting side effect of melphalan is the extremely high sensitization rate of 40%. BCNU seems to be evaluated more favourably with approximately comparable results with regard to the side effect profile (see below Common Toxicity Criteria).
  • Palliative therapeutic approach: In progressive disease. Here, too, treatment with a less aggressive regimen (e.g. Knospe regimen) should be attempted first, before more aggressive combinations are used. The following regimens are used: bud regimen, CHOP regimen, COPBLAM regimen. Handling, side effects and laboratory controls see below. Cytostatic drugs.
  • Vorinostat 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 drug shows significant antitumor activity in cutaneous T-cell lymphoma.
• Regarding supportive therapy measures see below. Cytostatic agents, supportive therapy.

TNM staging of cutaneous T-cell lymphomas (CTCL)

Phase 2 trials are currently testing the efficacy of the histone deacetylase inhibitor vorinostat, with moderate success to date.

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