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Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

      Incidence and epidemiology

      Primary cutaneous lymphomas (PCLs) are defined as non-Hodgkin lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. After gastrointestinal lymphomas, PCLs are the second most common group of extranodal non-Hodgkin lymphomas, with an estimated annual incidence of 1/100 000 in Western countries. PCLs must be distinguished from nodal or systemic malignant lymphomas involving the skin secondarily, which often have another clinical behaviour, have a different prognosis and require a different therapeutic approach. In recent lymphoma classifications, PCLs are therefore included as separate entities. Within the group of PCLs, distinct types of cutaneous T cell lymphoma (CTCL) and cutaneous B cell lymphoma (CBCL) can be distinguished [
      • Willemze R.
      • Jaffe E.S.
      • Burg G.
      • et al.
      WHO–EORTC classification for cutaneous lymphomas.
      ,
      WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.
      ]. In the Western world, CTCLs constitute ∼75%–80% of all PCLs [with mycosis fungoides (MF) as the most common type of CTCL] and CBCL ∼20%–25% [
      • Willemze R.
      • Jaffe E.S.
      • Burg G.
      • et al.
      WHO–EORTC classification for cutaneous lymphomas.
      ]. However, different distributions have been observed in other parts of the world. In Southeast Asian countries, CTCLs other than MF [in particular Epstein–Barr virus-associated natural killer (NK)/T cell lymphomas] are much more common than in Western countries, while CBCLs are much more uncommon [
      • Tan S.H.
      • Sim C.S.
      • Ong B.H.
      Cutaneous lymphomas other than mycosis fungoides in Singapore: a clinicopathological analysis using recent classification systems.
      ,
      • Park J.H.
      • Shin H.T.
      • Lee D.Y.
      • et al.
      World Health Organization–European Organization for research and treatment of cancer classification of cutaneous lymphoma in Korea: a retrospective study at a single tertiary institution.
      ]. PCLs are rare diseases and patients should ideally be seen by a multidisciplinary team of dermatologists, pathologists, haematologists and radiation oncologists.

      Diagnosis and pathology/molecular biology

      The diagnosis and classification of PCLs should always be based on a combination of clinical, histological, immunophenotypical and genetic data. Demonstration of clonal T cell receptor or immunoglobulin gene rearrangements in lesional skin or peripheral blood may be a valuable adjunct in selected cases. However, clinical and histopathological features are, in most cases, the most important deciding factors for therapeutic planning. PCLs should be classified according to the criteria of the revised 2017 World Health Organization (WHO) classification ( see Table 1) [
      WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.
      ].
      Table 1WHO-EORTC classification for cutaneous lymphomas
      Cutaneous T cell lymphoma
      Mycosis fungoides (MF)
      Variants of MF

      • Folliculotropic MF
      • Pagetoid reticulosis
      • Granulomatous slack skin
      Sézary syndrome
      Primary cutaneous CD30+ lymphoproliferative disorders

      • Primary cutaneous anaplastic large cell lymphoma
      • Lymphomatoid papulosis
      Subcutaneous panniculitis-like T cell lymphoma
      Extranodal NK/T cell lymphoma, nasal-type
      Primary cutaneous peripheral T cell lymphoma-not otherwise specified

      • Primary cutaneous γ/δ T cell lymphoma
      • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma
        Provisional entities.
      • Primary cutaneous acral CD8+ T cell lymphoma
        New provisional entity in the revised 2017 WHO classification [2].
      • Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder
        Provisional entities.
      Cutaneous B cell lymphoma
      Primary cutaneous marginal zone lymphoma
      Primary cutaneous follicle centre lymphoma
      Primary cutaneous diffuse large B cell lymphoma, leg type
      EORTC, European Organization of Research and Treatment of Cancer; NK, natural killer; WHO, World Health Organization.
      Adapted from [
      • Willemze R.
      • Jaffe E.S.
      • Burg G.
      • et al.
      WHO–EORTC classification for cutaneous lymphomas.
      ] with permission.
      a Provisional entities.
      b New provisional entity in the revised 2017 WHO classification [
      WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.
      ].

      Staging and risk assessment

      In all cases, adequate staging should be carried out to exclude the presence of extracutaneous disease. Recommendations for the initial staging of patients with MF/Sézary syndrome (SS) are presented in Table 2. Flow cytometry of the peripheral blood is usually recommended for all stages of MF. However, it is debatable whether this test is justified in patients who are not suspected to have SS. Computed tomography (CT) and/or fluorodeoxyglucose-positron emission tomography (FDG-PET) scans are optional in early-stage MF. Bone marrow examination is usually not indicated in patients with MF/SS.
      Table 2Recommendations for staging evaluation in patients with MF/SS [
      • Olsen E.
      • Vonderheid E.
      • Pimpinelli N.
      • et al.
      Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ]
      Complete physical examination including:

      • Determination of type(s) of skin lesions
      • Identification of any palpable lymph node, especially those ≥ 1.5 cm in largest diameter or firm, irregular, clustered or fixed
      • Identification of any organomegaly
      Skin biopsy

      • Most indurated area if only one biopsy
      • Routine histology and immunophenotyping
      • Evaluation for clonality of TCR gene rearrangement (optional)
      Blood tests

      • CBC with manual differential, liver function tests, LDH, comprehensive chemistries
      • TCR gene rearrangement and relatedness to any clone in skin (optional)
      • Analysis for abnormal lymphocytes by either Sézary cell count with determination absolute number of Sézary cells and/or flow cytometry (including CD4+/CD7 or CD4+/CD26) (optional)
      Radiological tests

      • CT scans of chest, abdomen and pelvis alone ± FDG-PET (optional in patients with early-stage MF)
      Lymph node biopsy

      • Excisional biopsy in patients with a node that is either ≥ 1.5 cm in diameter and/or is firm, irregular, clustered or fixed
      • Routine histology, immunohistochemistry and TCR gene rearrangement analysis
      CBC, complete blood count; CT, computed tomography; FDG-PET, fluorodeoxyglucose-positron emission tomography; LDH, lactate dehydrogenase; MF, mycosis fungoides; SS, Sézary syndrome; TCR, T cell receptor
      Adapted from [
      • Olsen E.
      • Vonderheid E.
      • Pimpinelli N.
      • et al.
      Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc.
      Initial work-up for patients with a PCL other than MF/SS also includes complete physical examination, representative skin biopsy, complete and differential blood cell count, routine serum biochemistry with lactate dehydrogenase (LDH) and appropriate imaging studies (CT and/or FDG-PET scans) [
      • Kim Y.H.
      • Willemze R.
      • Pimpinelli N.
      • et al.
      TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ]. In PCLs with a predominantly subcutaneous presentation, such as subcutaneous panniculitis-like T cell lymphoma (SPTCL) and primary cutaneous gamma/delta T cell lymphoma (PCGD-TCL), FDG-PET is essential to evaluate the extent of disease. In patients with typical lymphomatoid papulosis (LyP) or primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder (LPD), CT and FDG-PET scans are not required. Bone marrow biopsy and aspirate should be carried out in cutaneous lymphomas with an intermediate or aggressive clinical behaviour but is not required in cutaneous lymphomas with an indolent clinical behaviour, unless indicated by other staging assessments [
      • Kim Y.H.
      • Willemze R.
      • Pimpinelli N.
      • et al.
      TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ,
      • Olsen E.
      • Vonderheid E.
      • Pimpinelli N.
      • et al.
      Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ]. Bone marrow examination is not indicated in patients with primary cutaneous marginal zone lymphoma (PCMZL), but its significance in primary cutaneous follicle centre lymphomas (PCFCLs) is controversial [
      • Kim Y.H.
      • Willemze R.
      • Pimpinelli N.
      • et al.
      TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ,
      • Senff N.J.
      • Kluin-Nelemans H.C.
      • Willemze R.
      Results of bone marrow examination in 275 patients with histological features that suggest an indolent type of cutaneous B-cell lymphoma.
      ].
      Prognosis is extremely variable depending on the type of PCLs and the stage of disease. For clinical staging of MF and SS, the revised tumour, node, metastasis and blood (TNMB) staging system should be used (Tables 3 and 4) [
      • Olsen E.
      • Vonderheid E.
      • Pimpinelli N.
      • et al.
      Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ]. Apart from clinical stage, older age, large cell transformation and increased LDH values have been identified as independent unfavourable prognostic factors in MF [
      • Agar N.S.
      • Wedgeworth E.
      • Crichton S.
      • et al.
      Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal.
      ,
      • Scarisbrick J.J.
      • Prince H.M.
      • Vermeer M.H.
      • et al.
      Cutaneous Lymphoma International Consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model.
      ,
      • Alberti-Violetti S.
      • Talpur R.
      • Schlichte M.
      • et al.
      Advanced-stage mycosis fungoides and Sézary syndrome: survival and response to treatment.
      ]. For PCLs other than MF/SS, a separate TNM classification system has been published [
      • Kim Y.H.
      • Willemze R.
      • Pimpinelli N.
      • et al.
      TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ]. This staging system is primarily meant to document extent of disease and cannot be used as a prognostic guide.
      Table 3Revised TNMB classification of MF/SS [
      • Olsen E.
      • Vonderheid E.
      • Pimpinelli N.
      • et al.
      Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ]
      T (skin)
      T1Limited patch/plaque (involving < 10% of total skin surface)
      T2Generalised patch/plaque (involving ≥ 10% of total skin surface)
      T3Tumour(s)
      T4Erythroderma
      N (lymph node)
      N0No clinically abnormal peripheral lymph nodes
      N1Clinically abnormal peripheral lymph nodes; histologically uninvolved
      N2Clinically abnormal peripheral lymph nodes; histologically involved (nodal architecture uneffaced)
      N3Clinically abnormal peripheral lymph nodes; histologically involved [nodal architecture (partially) effaced]
      NxClinically abnormal peripheral lymph nodes; no histological confirmation
      M (viscera)
      M0No visceral involvement
      M1Visceral involvement
      B (blood)
      B0No circulating atypical (Sézary) cells (or < 5% of lymphocytes)
      B1Low blood tumour burden (≥ 5% of lymphocytes are Sézary cells, but not B2)
      B2High blood tumour burden (≥ 1000/µl Sézary cells and positive clone)
      MF, mycosis fungoides; SS, Sézary syndrome; TNMB, tumour, node, metastasis, blood.
      Reprinted from [
      • Olsen E.
      • Vonderheid E.
      • Pimpinelli N.
      • et al.
      Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc.
      Table 4Revised clinical staging system for MF/SS [
      • Olsen E.
      • Vonderheid E.
      • Pimpinelli N.
      • et al.
      Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ]
      Clinical stage
      IAT1N0M0B0-1
      IBT2N0M0B0-1
      IIAT1–2N1-2M0B0-1
      IIBT3N0–2M0B0-1
      IIIT4N0–2M0B0-1
      IVA1T1–4N0-2M0B2
      IVA2T1–4N3M0B0-2
      IVBT1–4N0–3M1B0-2
      MF, mycosis fungoides; SS, Sézary syndrome. Reprinted from [
      • Olsen E.
      • Vonderheid E.
      • Pimpinelli N.
      • et al.
      Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
      ] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc.

      Treatment

      The choice of treatment depends on the type of PCL and the stage of disease. Due to their heterogeneity and rarity, controlled clinical trials in PCLs are almost non-existent, with a few exceptions mainly concerning recently marketed drugs. Recommendations are therefore largely based on (retrospective) cohort studies and expert opinions discussed during consensus meetings of the European Organization of Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Group, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC) and the International Lymphoma Radiation Oncology Group (ILROG), including consensus recommendations for clinical end points and response criteria in MF/SS [
      • Olsen E.A.
      • Whittaker S.
      • Kim Y.H.
      • et al.
      Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer.
      ].

       Mycosis fungoides and variants

      Since early aggressive chemotherapy (ChT) is associated with considerable side effects but does not improve survival, a stage-adapted conservative therapeutic approach is recommended for MF and its variants [
      • Kaye F.J.
      • Bunn Jr, P.A.
      • Steinberg S.M.
      • et al.
      A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides.
      ,
      • Trautinger F.
      • Eder J.
      • Assaf C.
      • et al.
      European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.
      ,

      National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology; Mycosis fungoides/Sézary syndrome (Version 2.2018 – January 2, 2018). https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf (8 January 2017, date last accessed).

      ,
      • Whittaker S.
      • Hoppe R.
      • Prince H.M.
      How I treat mycosis fungoides and Sézary syndrome.
      ]. Patients with only patches and/or plaques covering < 10% (stage IA) or ≥ 10% of the skin surface (stage IB) should be treated with skin-directed therapies, including topical steroids, psoralens plus ultraviolet A (PUVA), narrow-band ultraviolet B (nb-UVB) and topical cytostatic agents, such as mechlorethamine (nitrogen mustard) (Figure 1). nb-UVB is recommended for patients with patches or very thin plaques but PUVA is preferred for patients with thicker plaques [III, A] [
      • Trautinger F.
      • Eder J.
      • Assaf C.
      • et al.
      European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.
      ,
      • Whittaker S.
      • Hoppe R.
      • Prince H.M.
      How I treat mycosis fungoides and Sézary syndrome.
      ]. Topical steroids can be recommended as monotherapy for stage IA disease with patches/flat plaques. In stage IB, topical steroids can be used as adjuvant therapy for selected skin lesions. Topical application of mechlorethamine, either in aqueous solution or in an ointment-based preparation, has been used successfully for decades in the treatment of early-stage MF. A commercial 0.02% gel preparation was approved by the European Medicines Agency (EMA) as an orphan drug for the treatment of early stage MF [II, B] [
      • Lessin S.R.
      • Duvic M.
      • Guitart J.
      • et al.
      Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides.
      ]. In patients developing one or few infiltrated plaques or tumours (stage IIB), additional low-dose local radiotherapy (RT) may suffice [III, A] [
      • Neelis K.J.
      • Schimmel E.C.
      • Vermeer M.H.
      • et al.
      Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas.
      ]. Local RT can be curative in patients with early localised disease, particularly in patients with unilesional MF and pagetoid reticulosis [IV, A]. In such patients, local RT is most commonly administered with electrons (energy dependent on the thickness of the lesion), with bolus to achieve full skin dose, a margin of ≥ 2 cm and a total dose of 20–24 Gy [IV, A] [
      • Specht L.
      • Dabaja B.
      • Illidge T.
      • et al.
      Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.
      ]. For patients with more extensive infiltrated plaques and tumours, or patients refractory to skin-directed therapies, systemic therapy with interferon alpha (IFNα) or retinoids (including bexarotene), commonly combined with PUVA or other skin-directed therapies, or a combination of IFNα and retinoids or total skin electron beam therapy (TSEBT), can be considered [III, B] [
      • Trautinger F.
      • Eder J.
      • Assaf C.
      • et al.
      European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.
      ,
      • Whittaker S.
      • Hoppe R.
      • Prince H.M.
      How I treat mycosis fungoides and Sézary syndrome.
      ,
      • Quaglino P.
      • Maule M.
      • Prince H.M.
      • et al.
      Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium.
      ]. TSEBT was often given to total doses of 30–36 Gy, but lower doses (10–12 Gy) have been employed with the advantages of shorter duration of the treatment period, fewer side effects and opportunity for re-treatment [III, A] [
      • Hoppe R.T.
      • Harrison C.
      • Tavallaee M.
      • et al.
      Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials.
      ,
      • Kamstrup M.R.
      • Gniadecki R.
      • Iversen L.
      • et al.
      Low-dose (10-Gy) total skin electron beam therapy for cutaneous T-cell lymphoma: an open clinical study and pooled data analysis.
      ]. In patients with advanced and refractory disease, gemcitabine or liposomal doxorubicin may be considered, but responses are generally short-lived [II, B] [
      • Marchi E.
      • Alinari L.
      • Tani M.
      • et al.
      Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients.
      ,
      • Dummer R.
      • Quaglino P.
      • Becker J.C.
      • et al.
      Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012.
      ]. Other agents like the fusion toxin denileukin diftitox and histone deacetylase (HDAC) inhibitors, such as vorinostat and romidepsin, have been approved in the United States by the Food and Drug Administration (FDA) for patients with relapsed and refractory CTCL, but have not yet been registered for CTCL in Europe [
      • Prince H.M.
      • Duvic M.
      • Martin A.
      • et al.
      Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma.
      ,
      • Olsen E.A.
      • Kim Y.H.
      • Kuzel T.M.
      • et al.
      Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma.
      ,
      • Whittaker S.J.
      • Demierre M.F.
      • Kim E.J.
      • et al.
      Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.
      ]. Multi-agent ChT is only indicated in patients with effaced lymph nodes or visceral involvement (stage IV), or in patients with widespread tumour stage MF, which cannot be controlled with skin-targeted and immunomodulating therapies or who failed single-agent ChT, but—similar to single-agent ChT—responses are generally short-lived [IV, B] [
      • Hughes C.F.M.
      • Khot A.
      • McCormack C.
      • et al.
      Lack of durable disease control with chemotherapy for mycosis fungoides and Sezary syndrome: a comparative study of systemic therapy.
      ]. Local palliation of cutaneous as well as extracutaneous lesions may be achieved with local RT to doses ≥ 8 Gy [III, A] [
      • Neelis K.J.
      • Schimmel E.C.
      • Vermeer M.H.
      • et al.
      Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas.
      ].
      Figure 1
      Figure 1Recommendations for the treatment of MF/SS. aMost commonly PUVA. AlloSCT, allogeneic stem cell transplantation; ChT, chemotherapy; ECP, extracorporeal photopheresis; IFNα, interferon alpha; MF, mycosis fungoides; MTX, methotrexate; nb-UVB, narrow-band ultraviolet B; PUVA, psoralens plus ultraviolet A; RT, radiotherapy; SS, Sézary syndrome; SDT, skin-directed therapy; TSEBT, total skin electron beam therapy.
      Recent studies report high response rates of brentuximab vedotin (BV; an anti-CD30 monoclonal antibody coupled to the anti-tubulin agent monomethyl auristatin E) in patients with advanced MF/SS expressing CD30 [II, B] [
      • Duvic M.
      • Tetzlaff M.T.
      • Gangar P.
      • et al.
      Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis.
      ,
      • Kim Y.H.
      • Tavallaee M.
      • Sundram U.
      • et al.
      Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project.
      ,
      • Prince H.M.
      • Kim Y.H.
      • Horwitz S.M.
      • et al.
      Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.
      ]. In a phase II trial including 28 patients with CD30+ relapsed or refractory MF, BV showed a 54% overall response rate (ORR) with a median time to response of 12 weeks and a median duration of response of 32 weeks in patients with MF, independent of the degree of CD30 expression [
      • Duvic M.
      • Tetzlaff M.T.
      • Gangar P.
      • et al.
      Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis.
      ]. Another phase II study reported an ORR of 70% in a group of 32 patients with relapsed or refractory MF/SS with a wide range of CD30 expression levels [
      • Kim Y.H.
      • Tavallaee M.
      • Sundram U.
      • et al.
      Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project.
      ]. Results from a recent phase III trial, which compared BV to physician’s choice of methotrexate (MTX) or bexarotene in 128 patients with relapsed or refractory CD30+ CTCL, including 97 patients with MF, showed ORR lasting at least 4 months (ORR4) and complete response (CR) rate of 50% and 10%, respectively, in MF patients treated with BV compared with 10% and 0%, respectively, in the control group [
      • Prince H.M.
      • Kim Y.H.
      • Horwitz S.M.
      • et al.
      Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.
      ]. Median progression-free survival (mPFS) was 15.9 months in the BV group compared with 3.5 months in the control group.
      In relatively young patients with refractory, progressive MF or with SS, allogeneic stem cell transplantation (alloSCT) should be considered. Durable responses have been reported, but experience is still limited and the optimal conditioning regimen and the optimal timing for an allogeneic transplant are currently unknown [V, C] [
      • Virmani P.
      • Zain J.
      • Rosen S.T.
      • et al.
      Hematopoietic stem cell transplant for mycosis fungoides and Sézary syndrome.
      ]. Recent studies suggest that patients may benefit from tumour debulking with TSEBT or BV before transplantation [
      • Duvic M.
      • Donato M.
      • Dabaja B.
      • et al.
      Total skin electron beam and non-myeloablative allogeneic hematopoietic stem-cell transplantation in advanced mycosis fungoides and Sezary syndrome.
      ,
      • Schneeweiss M.
      • Porpaczy E.
      • Koch M.
      • et al.
      Transformed mycosis fungoides: bridging to allogeneic stem cell transplantation with brentuximab vedotin.
      ]. Results with autologous stem cell transplantation (ASCT) in MF and SS have been disappointing.
      Promising new drugs are currently under evaluation in clinical trials, including mogamulizumab [
      • Ogura M.
      • Ishida T.
      • Hatake K.
      • et al.
      Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma.
      ,
      • Duvic M.
      • Pinter-Brown L.C.
      • Foss F.M.
      • et al.
      Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma.
      ,

      YH Kim , M.Bagot, L.Pinter-Brown et al Anti-CCR4 antibody, mogamulizumab, demonstrates significant improvement in PFS compared to vorinostat in patients with previously treated cutaneous T-cell lymphoma. Blood (ASH Annual Meeting Abstracts) 2017; 130: abstr 817.

      ]. A phase I/II open-label multicentre, randomised clinical trial demonstrated an ORR of 47% for SS patients and 29% in MF patients, with a dramatic clearance of malignant cells from the peripheral blood in 18 of 19 patients with blood involvement [
      • Duvic M.
      • Pinter-Brown L.C.
      • Foss F.M.
      • et al.
      Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma.
      ]. An open-label multicentre randomised phase III study comparing mogamulizumab with vorinostat in 372 patients with relapsed or refractory MF or SS showed a significantly better ORR (28% versus 5%) and PFS (7.7 months versus 3.1 months) in the mogamulizumab group [

      YH Kim , M.Bagot, L.Pinter-Brown et al Anti-CCR4 antibody, mogamulizumab, demonstrates significant improvement in PFS compared to vorinostat in patients with previously treated cutaneous T-cell lymphoma. Blood (ASH Annual Meeting Abstracts) 2017; 130: abstr 817.

      ].

       Sézary syndrome

      SS is defined by a triad of erythroderma, generalised lymphadenopathy and the presence of clonally related neoplastic T cells with cerebriform nuclei (Sézary cells) in skin, lymph nodes and peripheral blood [
      • Willemze R.
      • Jaffe E.S.
      • Burg G.
      • et al.
      WHO–EORTC classification for cutaneous lymphomas.
      ,
      WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.
      ]. Being a systemic disease (i.e. leukaemia) by definition, systemic treatment is required (Figure 1). Skin-directed therapies like PUVA or potent topical steroids may be used as adjuvant therapy. Extracorporeal photopheresis (ECP), either alone or in combination with other treatment modalities such as IFNα, retinoids, TSEBT and PUVA, has been suggested as the treatment of choice in SS and erythrodermic MF [IV, B] [
      • Trautinger F.
      • Eder J.
      • Assaf C.
      • et al.
      European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.
      ,

      National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology; Mycosis fungoides/Sézary syndrome (Version 2.2018 – January 2, 2018). https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf (8 January 2017, date last accessed).

      ,
      • Whittaker S.
      • Hoppe R.
      • Prince H.M.
      How I treat mycosis fungoides and Sézary syndrome.
      ]. ORRs range from 30% to 80% with CR rates ranging from 14% to 25%, depending on the ECP regimen and the type of combination used. However, the suggested superiority of ECP over the traditional low-dose ChT regimens has not yet been substantiated by controlled randomised trials [
      • Russell-Jones R.
      Extracorporeal photopheresis in cutaneous T-cell lymphoma. Inconsistent data underline the need for randomized studies.
      ]. Prolonged treatment with a combination of low-dose chlorambucil and prednisone is often effective in controlling the disease but is unlikely to yield complete responses. Low-dose alemtuzumab (10 mg subcutaneous, 3 times weekly for 12 weeks) [IV, A], single-agent ChT (gemcitabine, PEGylated liposomal doxorubicin) [V, B], multi-agent ChT [IV, B] and alloSCT [IV, C] have been recommended as second-line treatment of SS [
      • Trautinger F.
      • Eder J.
      • Assaf C.
      • et al.
      European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.
      ,
      • Whittaker S.
      • Hoppe R.
      • Prince H.M.
      How I treat mycosis fungoides and Sézary syndrome.
      ,
      • Bernengo M.G.
      • Quaglino P.
      • Comessatti A.
      • et al.
      Low-dose intermittent alemtuzumab in the treatment of Sézary syndrome: clinical and immunologic findings in 14 patients.
      ]. It should be emphasised that comparison of treatment results in the different studies is almost impossible due to differences in diagnostic criteria used for SS.

       Primary cutaneous CD30+ lymphoproliferative disorders

      The group of primary cutaneous CD30+ LPDs includes primary cutaneous anaplastic large cell lymphoma (C-ALCL) and LyP, which form a spectrum of disease. Both C-ALCL and LyP have an excellent prognosis, with a 10-year survival of 90% and almost 100%, respectively [
      • Bekkenk M.W.
      • Geelen F.A.
      • van Voorst Vader P.C.
      • et al.
      Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.
      ]. LyP is clinically characterised by recurrent, self-healing papulonecrotic or papulonodular skin lesions. Since a curative therapy is not available and none of the available treatment modalities affects the natural course of the disease, in patients with relatively few non-scarring lesions, an expectant policy can be followed (Figure 2). In the case of cosmetically disturbing lesions (e.g. scarring or many papulonodules), low-dose oral MTX (5–20 mg/week) and PUVA are the most effective therapies for reducing the number of skin lesions [IV, A] [
      • Bekkenk M.W.
      • Geelen F.A.
      • van Voorst Vader P.C.
      • et al.
      Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.
      ,
      • Kempf W.
      • Pfaltz K.
      • Vermeer M.H.
      • et al.
      EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma.
      ,
      • Bruijn M.S.
      • Horváth B.
      • van Voorst Vader P.C.
      • et al.
      Recommendations for treatment of lymphomatoid papulosis with methotrexate: a report from the Dutch Cutaneous Lymphoma Group.
      ]. Relapses after withdrawal of treatment are common and maintenance treatment is often required for adequate disease control. Patients with C-ALCL generally present with solitary or localised (ulcerating) tumours or nodules and should be treated with RT or surgical excision (Figure 2). In case of complete spontaneous remission, no further therapy is required [
      • Bekkenk M.W.
      • Geelen F.A.
      • van Voorst Vader P.C.
      • et al.
      Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.
      ]. Patients presenting with multifocal skin lesions can best be treated with low-dose MTX, as in LyP [IV, A], or with RT [IV, A] in the case of only a few lesions [
      • Bekkenk M.W.
      • Geelen F.A.
      • van Voorst Vader P.C.
      • et al.
      Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.
      ,
      • Kempf W.
      • Pfaltz K.
      • Vermeer M.H.
      • et al.
      EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma.
      ,
      • Melchers R.C.
      • Willemze R.
      • Bekkenk M.W.
      • et al.
      Evaluation of treatment results in multifocal primary cutaneous anaplastic large cell lymphoma: report of the Dutch Cutaneous Lymphoma Group.
      ]. The ILROG suggests radiation with electrons, with bolus, a margin of ≥ 2 cm and a total dose of 24–30 Gy [
      • Specht L.
      • Dabaja B.
      • Illidge T.
      • et al.
      Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.
      ,
      • Million L.
      • Yi E.J.
      • Wu F.
      • et al.
      Radiation therapy for primary cutaneous anaplastic large cell lymphoma: an International Lymphoma Radiation Oncology Group multi-institutional experience.
      ]. In a recent study in 63 patients with C-ALCL, a total dose of 20 Gy in 8–10 fractions was found to be effective and well-tolerated in patients presenting with solitary or localised skin lesions. For patients with multifocal or relapsing skin lesions, a radiation dose of 8 Gy (2 × 4 Gy) was suggested [
      • Melchers R.C.
      • Willemze R.
      • Daniëls L.A.
      • et al.
      Recommendations for the optimal radiation dose in patients with primary cutaneous anaplastic large cell lymphoma: a report of the Dutch Cutaneous Lymphoma Group.
      ].
      Figure 2
      Figure 2Recommendations for the initial management of primary cutaneous CD30+ LPDs. C-ALCL, cutaneous anaplastic large cell lymphoma; LPD, lymphoproliferative disorder; LyP, lymphomatoid papulosis; MTX, methotrexate; PUVA, psoralens plus ultraviolet A; RT, radiotherapy.
      Recent studies report high response rates of BV in patients with primary cutaneous CD30+ lymphoproliferations [
      • Duvic M.
      • Tetzlaff M.T.
      • Gangar P.
      • et al.
      Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis.
      ,
      • Kim Y.H.
      • Tavallaee M.
      • Sundram U.
      • et al.
      Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project.
      ,
      • Prince H.M.
      • Kim Y.H.
      • Horwitz S.M.
      • et al.
      Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.
      ]. In the phase III trial, which compared BV to physician’s choice of MTX or bexarotene, BV showed an ORR4 and CR rate of 75% and 31%, respectively, in C-ALCL patients treated with BV compared with 20% and 7%, respectively, in the control group [
      • Prince H.M.
      • Kim Y.H.
      • Horwitz S.M.
      • et al.
      Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.
      ]. BV should be considered in cases with multifocal skin lesions refractory to conventional therapies and in patients developing extracutaneous disease [II, B] [
      • Melchers R.C.
      • Willemze R.
      • Bekkenk M.W.
      • et al.
      Evaluation of treatment results in multifocal primary cutaneous anaplastic large cell lymphoma: report of the Dutch Cutaneous Lymphoma Group.
      ]. Multi-agent ChT is only indicated in patients presenting with or developing extracutaneous disease and in rare patients with rapidly progressive skin disease [
      • Bekkenk M.W.
      • Geelen F.A.
      • van Voorst Vader P.C.
      • et al.
      Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.
      ,
      • Kempf W.
      • Pfaltz K.
      • Vermeer M.H.
      • et al.
      EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma.
      ].

       Subcutaneous panniculitis-like T cell lymphomas

      The term SPTCL is only used for cases with an α/β T cell phenotype, which have a favourable prognosis, particularly if not associated with a haemophagocytic syndrome (HPS), which is frequently an extremely aggressive clinical syndrome requiring immediate intervention. One study reported 5-year overall survival (OS) rates of 91% and 46% in SPTCL patients without and with an HPS, respectively [
      • Willemze R.
      • Jansen P.M.
      • Cerroni L.
      • et al.
      Subcutaneous panniculitis-like T-cell lymphoma: definition, classification and prognostic factors: an EORTC Cutaneous Lymphoma Group study of 83 cases.
      ]. In SPTCL without associated HPS, systemic steroids or other immunosuppressive agents (ciclosporin, MTX) should be considered first; in cases of solitary skin lesions, RT with electrons is advised [IV, A]. Little information on radiation dose is available, but a dose of 40 Gy has been used. Bexarotene may be also effective in SPTCL [
      • Mehta N.
      • Wayne A.S.
      • Kim Y.H.
      • et al.
      Bexarotene is active against subcutaneous panniculitis-like T-cell lymphoma in adult and pediatric populations.
      ]. Multi-agent ChT is required only in cases with progressive disease not responding to immunosuppressive therapy and in cases with HPS.

       Primary cutaneous extranodal NK/T cell lymphoma, nasal type

      Primary cutaneous extranodal NK/T cell lymphoma, nasal type is an Epstein–Barr virus-associated type of lymphoma with an aggressive clinical behaviour, which is very rare in Western countries, but more common in Asia and Central and South America [
      WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.
      ]. The skin is the second most common site of involvement after the nasal cavity/nasopharynx and, in some patients, skin lesions may be the only manifestation of disease [
      • Ahn H.K.
      • Suh C.
      • Chuang S.S.
      • et al.
      Extranodal natural killer/T-cell lymphoma from skin or soft tissue: suggestion of treatment from multinational retrospective analysis.
      ,
      • Wu C.C.
      • Takahashi E.
      • Asano N.
      • et al.
      Primary cutaneous NK/T-cell lymphoma of nasal type: an age-related lymphoproliferative disease?.
      ,
      • Chang S.
      • Yoon G.
      • Huh J.
      • et al.
      Comparison of primary and secondary cutaneous CD56+ NK/T cell lymphomas.
      ]. Patients presenting with only localised skin lesions (stage IE) have a somewhat better prognosis than localised lesions in non-cutaneous sites [
      • Wu C.C.
      • Takahashi E.
      • Asano N.
      • et al.
      Primary cutaneous NK/T-cell lymphoma of nasal type: an age-related lymphoproliferative disease?.
      ,
      • Chang S.
      • Yoon G.
      • Huh J.
      • et al.
      Comparison of primary and secondary cutaneous CD56+ NK/T cell lymphomas.
      ]. In rare cases with small, solitary lesions, RT alone can be considered, as long-term disease control has been achieved with this approach in some reported cases [V, C] [
      • Zheng Y.
      • Jia J.
      • Li W.
      • et al.
      Extranodal natural killer/T-cell lymphoma, nasal type, involving the skin, misdiagnosed as nasosinusitis and fungal infection: a case report and literature review.
      ,
      • Liaw T.
      • Hu S.C.
      Nasal-type extranodal natural killer/T-cell lymphoma presenting as a solitary non-healing lower leg ulcer.
      ,
      • Watabe D.
      • Kanno H.
      • Inoue-Narita T.
      • et al.
      A case of primary cutaneous natural killer/T-cell lymphoma, nasal type, with indolent clinical course: monoclonal expansion of Epstein-Barr virus genome correlating with the terminal aggressive behaviour.
      ]. This is also the option for older or frail patients who cannot tolerate intensive ChT. In general, however, combined modality treatment with L-asparaginase containing ChT, such as SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide) is the preferred mode of treatment, combined with RT, for localised disease, as it is for nasal NK/T cell lymphomas, although there is still a paucity of data on the outcome of this treatment in primary cutaneous NK/T cell lymphoma [V, B] [
      • d'Amore F.
      • Gaulard P.
      • Trümper L.
      • et al.
      Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ]. Recommended radiation doses are higher than for other lymphomas, with 50 Gy to the initial lesion and a boost of 5–10 Gy to residual disease [IV, A] [
      • Specht L.
      • Dabaja B.
      • Illidge T.
      • et al.
      Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.
      ]. In patients presenting with generalised skin lesions, the disease shows an aggressive clinical behaviour and should be treated as other patients with stage II–IV disease [
      • d'Amore F.
      • Gaulard P.
      • Trümper L.
      • et al.
      Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ].

       Primary cutaneous peripheral T cell lymphoma-not otherwise specified

      Within the group of primary cutaneous peripheral T cell lymphoma-not otherwise specified (PTCL-NOS), four somewhat better-defined subgroups have been included as (provisional) entities (see Table 1) [
      • Willemze R.
      • Jaffe E.S.
      • Burg G.
      • et al.
      WHO–EORTC classification for cutaneous lymphomas.
      ,
      WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.
      ]. These include PCGD-TCL, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell lymphoma (CD8+ AECTCL), primary cutaneous CD4+ small/medium T cell LPD and primary cutaneous acral CD8+ T cell lymphoma. For cases that do not fit into one of the well-defined types of CTCL, including these rare subtypes, the term primary cutaneous PTCL-NOS is maintained. Both PCGD-TCL and CD8+ AECTCL have in common a generally aggressive clinical course and poor prognosis, and should therefore be managed according to the ESMO guidelines for PTCL-NOS [
      • d'Amore F.
      • Gaulard P.
      • Trümper L.
      • et al.
      Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ]. Patients with primary cutaneous CD4+ small-medium T cell LPD and patients with a primary cutaneous acral CD8+ T cell lymphoma have an indolent clinical behaviour and excellent prognosis. Patients usually present with a solitary skin lesion, which should be treated with local RT or surgical excision [IV, A].

       Cutaneous B cell lymphoma

      In the WHO-EORTC classification, three main types of CBCL are distinguished: PCMZL, PCFCL and primary cutaneous diffuse large B cell lymphoma, leg type (PCLBCL-LT). PCMZL and PCFCL are indolent types of CBCL with a disease-related 10-year-survival exceeding 90%, while PCLBCL-LT has a more unfavourable prognosis (disease-related 5-year survival, approximately 50%). EORTC/ISCL consensus recommendations for the management of these three types of CBCL have been formulated and are, with minor modifications, presented in Figures 3 and 4 [
      • Senff N.J.
      • Noordijk E.M.
      • Kim Y.H.
      • et al.
      European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas.
      ]. Recommended radiation doses for localised PCMZL and PCFCL are 24–30 Gy [IV, A], whereas for palliative treatment of multifocal disease, low-dose RT (4 Gy) is often sufficient [III, A] [
      • Neelis K.J.
      • Schimmel E.C.
      • Vermeer M.H.
      • et al.
      Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas.
      ,
      • Specht L.
      • Dabaja B.
      • Illidge T.
      • et al.
      Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.
      ]. For the more aggressive PCLBCL-LT, systemic treatment with rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) is recommended if the patient can tolerate multi-agent ChT [IV, A]. For localised disease, the systemic treatment is combined with RT, and a radiation dose of 36–40 Gy is recommended; if no systemic treatment is given, a dose of 40 Gy is recommended [IV, B] [
      • Specht L.
      • Dabaja B.
      • Illidge T.
      • et al.
      Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.
      ]. These patients are often elderly, and for disseminated or recurrent disease, rituximab as a single drug may achieve remissions. PCLBCL-LT has the phenotype and gene expression profile of ABC-type diffuse large B cell lymphoma (DLBCL) and shows a high frequency of MYD88 and CD79B mutations, which results in constitutive activation of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signalling [
      • Pham-Ledard A.
      • Prochazkova-Carlotti M.
      • Andrique L.
      • et al.
      Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma.
      ]. Recent studies suggest that PCLBCL-LT patients may benefit from treatment with Bruton's tyrosine kinase (BTK) inhibitors, which block the NF-κB pathway [
      • Gupta E.
      • Accurso J.
      • Sluzevich J.
      • et al.
      Excellent outcome of immunomodulation or Bruton's tyrosine kinase inhibition in highly refractory primary cutaneous diffuse large B-cell lymphoma, leg type.
      ].
      Figure 3
      Figure 3Recommendations for the initial management of PCMZL and PCFCL. aIn the case of evidence for Borrelia burgdorferi infection. bSingle or combination chemotherapy appropriate for low-grade malignant B cell lymphomas. ChT, chemotherapy; i.l., intralesional; i.v., intravenous; PCFCL, primary cutaneous follicle centre lymphoma; PCMZL, primary cutaneous marginal zone lymphoma; RT, radiotherapy.
      Figure 4
      Figure 4Recommendations for the initial management of PCLBCL-LT. IFRT, involved-field radiotherapy; i.v., intravenous; PCLBCL-LT, primary cutaneous large B cell lymphoma, leg type; R-CHOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; RT, radiotherapy.

      Personalised medicine

      Personalised approaches in the treatment of PCL are still limited. BV is used for the treatment of advanced stage refractory or relapsed CD30+ CTCL, including both patients with C-ALCL and patients with MF/SS, also with the purpose of bridging eligible patients to an alloSCT [
      • Duvic M.
      • Tetzlaff M.T.
      • Gangar P.
      • et al.
      Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis.
      ,
      • Kim Y.H.
      • Tavallaee M.
      • Sundram U.
      • et al.
      Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project.
      ,
      • Prince H.M.
      • Kim Y.H.
      • Horwitz S.M.
      • et al.
      Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.
      ,
      • Schneeweiss M.
      • Porpaczy E.
      • Koch M.
      • et al.
      Transformed mycosis fungoides: bridging to allogeneic stem cell transplantation with brentuximab vedotin.
      ]. Mogamulizumab is a humanised monoclonal antibody targeting the CC chemokine receptor 4 (CCR4), which is overexpressed on the malignant T cells in MF/SS. Mogamulizumab has shown significant clinical efficacy in MF/SS, particularly in patients with blood involvement [
      • Ogura M.
      • Ishida T.
      • Hatake K.
      • et al.
      Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma.
      ,
      • Duvic M.
      • Pinter-Brown L.C.
      • Foss F.M.
      • et al.
      Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma.
      ,

      YH Kim , M.Bagot, L.Pinter-Brown et al Anti-CCR4 antibody, mogamulizumab, demonstrates significant improvement in PFS compared to vorinostat in patients with previously treated cutaneous T-cell lymphoma. Blood (ASH Annual Meeting Abstracts) 2017; 130: abstr 817.

      ]. PCLBCL-LT frequently shows MYD88 and CD79B mutations, resulting in constitutive NF-κB activation [
      • Pham-Ledard A.
      • Prochazkova-Carlotti M.
      • Andrique L.
      • et al.
      Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma.
      ]. The efficacy of BTK inhibitors that target this pathway is currently under investigation but reports on their efficacy in CBCL are still scarce [
      • Gupta E.
      • Accurso J.
      • Sluzevich J.
      • et al.
      Excellent outcome of immunomodulation or Bruton's tyrosine kinase inhibition in highly refractory primary cutaneous diffuse large B-cell lymphoma, leg type.
      ].

      Follow-up, long-term implications and survivorship

      Follow-up recommendations should be individualised depending on the clinical situation. The frequency of follow-up visits depends on the type of PCL and the stage of disease. It may vary from every 6 or 12 months in patients with indolent types of PCL and stable disease or patients in complete remission to every 4–6 weeks in patients with active or progressive disease. Follow-up visits should focus on history and physical examination, and additional testing (histology, blood examination, imaging, etc.) should only be carried out if required. Routine imaging after treatment is not required, since tumour responses are visible to the naked eye and in most instances, recurrences are also localised in the skin. Survivorship issues are poorly studied in PCLs and are probably similar to those of patients with more common lymphomas with the same prognosis treated similarly. A long-term implication specifically found in PCL patients is the increased risk for developing skin cancers, in particular squamous cell carcinomas, following long-term treatment with PUVA.

      Methodology

      These Clinical Practice Guidelines were developed in accordance with the ESMO standard operating procedures for Clinical Practice Guidelines development, http://http://www.esmo.org/Guidelines/ESMO-Guidelines-Methodology. The relevant literature has been selected by the expert authors. A summary of recommendations is shown in Table 5. Levels of evidence and grades of recommendation have been applied using the system shown in Table 6. Statements without grading were considered justified standard clinical practice by the experts and the ESMO Faculty. This manuscript has been subjected to an anonymous peer review process.
      Table 5Summary of recommendations
      Incidence and epidemiology

      • PCLs must be distinguished from nodal or systemic malignant lymphomas involving the skin secondarily. In recent lymphoma classifications, PCLs are included as separate entities
      Diagnosis and pathology/molecular biology

      • The diagnosis and classification of PCLs should be based on a combination of clinical, histological, immunophenotypical and genetic data
      Staging and risk assessment

      • Adequate staging should be carried out to exclude the presence of extracutaneous disease
      • Initial work-up for patients with a PCL includes complete physical examination, representative skin biopsy, complete and differential blood cell count, routine serum biochemistry with LDH and appropriate imaging studies
      • In PCLs with a predominantly subcutaneous presentation (such as SPTCL and PCGD-TCL), FDG-PET is essential to evaluate the extent of disease
      Treatment

      • The choice of treatment depends on the type of PCL and the stage of disease. Due to their heterogeneity and rarity, controlled clinical trials in PCLs are almost non-existent, with a few exceptions mainly concerning recently marketed drugs
      • Recommendations are largely based on (retrospective) cohort studies and expert opinions
      Mycosis fungoides and variants

      • In MF and its variants, a stage-adapted conservative therapeutic approach is recommended
      • Patients with early-stage MF (stage IA–IIA) should be treated with skin-directed therapies including topical steroids, PUVA, nb-UVB or mechlorethamine
      • nb-UVB can be used in patients with patches or very thin plaques. In patients with thicker plaques, PUVA therapy is preferred [III, A]
      • In patients developing one or few infiltrated plaques or tumours (stage IIB), additional low-dose local RT may suffice [III, A]


      • Local RT can be curative in patients with unilesional MF and pagetoid reticulosis [IV, A]. Recommended dose is 20–24 Gy [IV, A]
      • For patients with more extensive infiltrated plaques and tumours or patients refractory to skin-directed therapies, a combination of PUVA and IFNα or PUVA and retinoids (including bexarotene), a combination of IFNα and retinoids or TSEBT can be considered [III, B]
      • TSEBT has been given to total doses of 30–36 Gy, but recently lower doses (10–12 Gy) have been employed with the advantages of shorter duration of the treatment period, fewer side effects and opportunity for re-treatment [III, A]
      • In patients with advanced and refractory disease, gemcitabine or liposomal doxorubicin may be considered, but responses are generally short-lived [II, B]
      • Multi-agent ChT is only indicated in MF patients with effaced lymph nodes or visceral involvement (stage IV), or in patients with widespread tumour stage MF, which cannot be controlled with skin-targeted and immunomodulating therapies or who failed single-agent ChT
      • Local palliation of cutaneous and as well as extracutaneous lesions may be achieved with local RT to doses ≥ 8 Gy [III, A]
      • In relatively young patients with refractory, progressive MF alloSCT should be considered. The optimal conditioning regimen and timing for an allogeneic transplant are currently unknown [IV, C]
      Sézary syndrome

      • Systemic treatment is required in combination with skin-directed therapies like PUVA or potent topical steroids used as adjuvant therapy
      • ECP, either alone or in combination with other treatment modalities such as IFNα, retinoids, TSEBT and PUVA, has been suggested as the treatment of choice in SS and erythrodermic MF [IV, B]
      • Mogulizumab has shown significant clinical efficacy in MF/SS, particularly in patients with blood involvement
      • In relatively young patients with refractory, progressive SS, alloSCT should be considered. The optimal conditioning regimen and timing for an allogeneic transplant are currently unknown [IV, C]
      • Low-dose alemtuzumab (10 mg subcutaneous, 3 times weekly for 12 weeks) [IV, A], single-agent ChT (gemcitabine, PEGylated liposomal doxorubicin) [V, B], multi-agent ChT [IV. B] and alloSCT [IV. C] are recommended as second-line treatment of SS.
      Primary cutaneous CD30+ lymphoproliferative disorders (C-ALCL and LyP)

      • In the case of cosmetically disturbing lesions (e.g. scarring or many papulonodules), low-dose oral MTX (5–20 mg/week) and PUVA are the most effective therapies for reducing the number of skin lesions [IV, A]
      • Local RT is the first choice of treatment in patients with C-ALCL presenting with solitary or localised skin lesions. A total dose of 20 Gy is recommended
      • C-ALCL patients presenting with multifocal skin lesions can best be treated with low-dose MTX, as in LyP [IV, A], or RT [IV, A] in the case of only a few lesions
      • BV should be considered in C-ALCL patients with multifocal skin lesions refractory to conventional therapies and patients developing extracutaneous disease [II, B]
      • Multi-agent ChT is only indicated in patients presenting with or developing extracutaneous disease and in rare patients with rapidly progressive skin disease
      Subcutaneous panniculitis-like T cell lymphomas

      • In SPTCL without associated HPS, systemic steroids or other immunosuppressive agents (ciclosporin; MTX) are the first choice of treatment. In cases of solitary skin lesions, RT with electrons is advised [IV, A]
      • Multi-agent ChT is required only in cases with progressive disease not responding to immunosuppressive therapy and in cases with HPS
      Primary cutaneous extranodal NK/T cell lymphoma, nasal type

      • Primary cutaneous extranodal NK/T cell lymphoma is an aggressive lymphoma. Combined modality treatment with L-asparaginase containing ChT, such as SMILE (dexamethasone, methotrexate, ifosphamide, L-asparaginase, etoposide), combined with RT for patients with localised disease, is the preferred mode of treatment [V, B], In rare cases with small, solitary lesions, and in older or frail patients who cannot tolerate intensive ChT, RT alone can be considered [V, C]
      Primary cutaneous peripheral T cell lymphoma - not otherwise specified

      • PCGD-TCL and primary cutaneous CD8+ AECTCL are aggressive types of CTCL, which should be managed as systemic PTCL-NOS
      • Patients with a primary cutaneous CD4+ small-medium T cell LPD or a primary cutaneous acral CD8+ T cell lymphoma usually present with a solitary skin lesion, which should be treated with local RT or surgical excision [IV, A]
      Cutaneous B cell lymphoma

      • Recommended radiation doses for localised PCMZL and PCFCL are 24-30 Gy [IV, A]. For palliative treatment of multifocal disease, low-dose RT (4 Gy) is often sufficient [IV, A]
      • For the more aggressive PCLBCL-LT, systemic treatment with R-CHOP combined with RT at a radiation dose of (36–40 Gy) is recommended for localised disease if the patient can tolerate multi-agent ChT [IV, A]. If no systemic treatment is given, a dose of 40 Gy is recommended [IV, B]
      • PCLBCL-LT has the phenotype and gene expression profile of ABC-type DLBCL and should be treated as other ABC-type DLBCLs
      Personalised medicine

      • BV is used for the treatment of advanced stage refractory or relapsed CD30+ CTCL, including both patients with C-ALCL and patients with MF/SS, also with the purpose of bridging eligible patients with MF/SS to an alloSCT
      • PCLBCL-LT shows a high frequency of MYD88 and CD79B mutations
      • The efficacy of BTK inhibitors, which targets this pathway, is currently under investigation
      Follow-up, long-term implications and survivorship

      • Follow-up recommendations should be individualised depending on the clinical situation. The frequency of follow-up visits varies depending on PCL type and the stage of disease from every 6 or 12 months in patients with indolent types of PCL and stable disease or patients in complete remission to every 4–6 weeks in patients with active or progressive disease
      • Follow-up visits should focus on history and physical examination, with additional testing only if required. Routine imaging after treatment is not required, since tumour responses are visible to the naked eye and in most instances recurrences are also localised in the skin
      ABC, activated B cell; alloSCT, allogeneic stem cell transplantation; BTK, Bruton's tyrosine kinase; BV, brentuximab vedotin; C-ALCL, cutaneous anaplastic large cell lymphoma; CD8+ AECTCL, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell lymphoma; ChT, chemotherapy; CTCL, cutaneous T cell lymphoma; DLBCL, diffuse large B cell lymphoma; ECP, extracorporeal photopheresis; FDG-PET, fluorodeoxyglucose-positron emission tomography; HPS, haemophagocytic syndrome; IFNα, interferon alpha; LDH, lactate dehydrogenase; LPD, lymphoproliferative disorder; LyP, lymphomatoid papulosis; MF, mycosis fungoides; MTX, methotrexate; nb-UVB, narrow-band ultraviolet B; NK, natural killer; PCFCL, primary cutaneous follicle centre lymphoma; PCGD-TCL, primary cutaneous gamma/delta T cell lymphoma; PCL, primary cutaneous lymphoma; PCLBCL-LT, primary cutaneous diffuse large B cell lymphoma, leg type; PCMZL, primary cutaneous marginal zone lymphoma; PTCL-NOS, primary cutaneous peripheral T cell lymphoma-not otherwise specified; PUVA, psoralens plus ultraviolet A; R-CHOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; RT, radiotherapy; SPTCL, subcutaneous panniculitis-like T cell lymphoma; SS, Sézary syndrome; TSEBT, total skin electron beam therapy.
      Table 6Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service Grading System
      By permission of the Infectious Diseases Society of America [57].
      )
      Levels of evidence
      IEvidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity
      IISmall randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity
      IIIProspective cohort studies
      IVRetrospective cohort studies or case–control studies
      VStudies without control group, case reports, experts opinions
      Grades of recommendation
      AStrong evidence for efficacy with a substantial clinical benefit, strongly recommended
      BStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
      CInsufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, …) optional
      DModerate evidence against efficacy or for adverse outcome, generally not recommended
      EStrong evidence against efficacy or for adverse outcome, never recommended
      a By permission of the Infectious Diseases Society of America [
      • Dykewicz C.A.
      Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients.
      ].

      Disclosure

      RW has reported global advisory boards for Takeda and Actelion; EH has reported advisory boards for Takeda and Actelion; PLZ has reported advisory boards for Kirin Kyowa, Takeda, Verastem, Janssen, Roche, Celgene, Bristol-Myers Squibb and Merck; LS has reported advisory boards for Takeda and Merck and research agreements with Takeda and Varian; ML has reported consultancy, participation to advisory boards and research support from Abbvie, Acerta, Amgen, Archigen, Celgene, ADC Therapeutics, Gilead, Novartis, Johnson & Johnson, Roche, Roche Diagnostics, Sandoz and Takeda.

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