Cutaneous t-cell lymphomas C84.8

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Hadrian Tran

All authors of this article

Last updated on: 30.11.2021

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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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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 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

In the past, the WHO classifications did insufficient justice to 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:

an additional distinction is made between:

  • Precursor neoplasms
  • and
  • peripheral (mature) lymphomas (which originate from peripheral lymphoid cells).

differentiated. Within the T-cell series, further groups/entities are distinguished):

Progenitor cell lymphomas

  • Progenitor T-cell lymphoblastic leukemia/lymphoma

Peripheral T-cell and NK lymphomas

Mycosis fungoides variants and subtypes

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

Adult T-cell lymphoma/leukemia (HTLV+)

Primary cutaneous CD30+ lymphoproliferative disorders

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)

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

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

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 atopy. Currently, the efficacy of the histone deacetylase inhibitor vorinostat is being tested in phase 2 trials with moderate success so far.

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
  7. Hanson M et al (2003) Bexarotene reverses alopecia in cutaneous T-cell lymphoma. Br J Dermatol 149: 193-196
  8. Herrmann JJ et al (1995) Treatment of mycosis fungoides with photochemotherapy (PUVA) - long-term follow-up. J Am Acad Dermatol 33: 234-242
  9. Kashani-Sabet M et al (2001) A modified staging classification for cutaneous T-cell lymphoma. J Am Acad Dermatol 45: 700-706
  10. Klemke CD et al (2006) New insights into the molecular biology and targeted therapy of cutaneous T-cell lymphomas. J Dtsch Dermatol Ges 4: 395-405
  11. Klemke CD (2012) Apoptosis resistance in cutaneous T-cell lymphoma. Act Dermatol 38: 74-77
  12. Marchi E et al (2005) Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients. Cancer 104: 2437-244
  13. Mehrany K et al (2003) Cutaneous T-cell lymphoma and atopy: is there an association? Br J Dermatol 149: 1013-1017
  14. Ponte P et al (2010) Efficacy of narrowband UVB vs. PUVA in patients with early-stage mycosis fungoides. J Eur Acad Dermatol Venereol 24:716-721
  15. Roenigk HH et al (1990) Photochemotherapy alone or combined with interferon alfa-2a in the treatment of cutaneous T-cell lymphoma. J Invest Dermatol 95: 198S?205S
  16. Sterry W et al (1995) Cutaneous malignant lymphomas. Z Hautkr 70: 781-788
  17. Suchin KR et al (2002) Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol 138: 1054-1060
  18. Willemze R et al (1997) EORTC classification for primary cutaneous lymphomas: a proposal from cutaneous lymphoma study group of the European Organization for Research and Treatment of Cancer. Blood 90: 354-371
  19. Willemze R et al (2005) WHO-EORTC classification for cutaneous lymphomas. Blood 105: 3768-3785
  20. Zackheim HS et al (1990) Topical carmustine (BCNU) or cutaneous T-cell lymphoma: a 15-year experience in 143 patients. J Am Acad Dermatol 22: 802-810

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Last updated on: 30.11.2021