S2k‐Guidelines – Cutaneous lymphomas (ICD10 C82 ‐ C86): Update 2021

Abstract

Cutaneous lymphomas (CL) are categorized as extranodal non-Hodgkin lymphomas, constituting the second most common form in this group (MALT lymphomas of the stomach are the most common extranodal form). Their incidence is estimated at one new diagnosis per 100,000 inhabitants per year in Germany [1-3]. Primary CL, by definition, present in the skin first, and at the time of diagnosis after staging is completed do not show any involvement of other organs. Secondary CL, on the other hand, are cutaneous manifestations of disseminated [4], primarily nodal lymphomas or leukemias. Primary CL comprise a large, clinically and histologically heterogeneous spectrum, with 73 % of CL categorized as cutaneous T-cell lymphomas (CTCL) and 22 % as cutaneous B-cell lymphomas (CBCL). There are other, rare forms of CL as well. Primary CL and nodal or extracutaneous lymphomas with the same cytomorphology actually differ greatly as to clinical presentation, but also prognosis and indicated treatments [5]. CL patients should therefore be treated in close collaboration between a specialized center and the primary physician. Cutaneous lymphomas are usually characterized by clonality of lymphocytes in the skin (with the exception of CD4+/CD56+ blastic plamacytoid dendritic cell neoplasia). Their cytomorphological presentation is comparable to lymphomas in other locations. Based on the specific cutaneous microenvironment, clinical and histological presentation will vary. It is essential to differentiate primary CL from skin manifestations of extracutaneous lymphomas or leukemias. Despite sometimes similar names (such as in marginal zone lymphoma and diffuse large B-cell lymphoma), cutaneous and extracutaneous/disseminated lymphomas differ as to their clinical as well as histopathological and molecular properties. One special feature in the classification of cutaneous lymphomas is the importance of clinical presentation for the final classification and prognosis. For example: A γ/δ-T-cell phenotype in itself is not sufficient for a classification as a cutaneous γ/δ-T-cell lymphoma. The classification also includes entities with unclear malignant potential (such as lymphomatoid papulosis, primary cutaneous CD4-positive small-medium T-cell lymphoproliferative disease). In analogy to systemic lymphomas, we differentiate between T-cell and B-cell neoplasias (Table 1); blastic plasmacytoid dendritic cell neoplasia is itemized as a hematological myeloic precursor neoplasia with typical primary manifestation in the skin. The new provisional WHO category of EBV-positive mucocutaneous ulcer should be mentioned as an Epstein-Barr virus (EBV)-associated skin disease, and must be differentiated from the rare EBV-positive diffuse large B-cell lymphoma. EBV-associated hydroa-vacciniforme-like lymphoproliferative disease is almost never seen in Germany. Consensus: 100 %, modified 2021 Primary cutaneous follicle center lymphoma (PCFCL) **** Primary cutaneous follicle center lymphoma: Synonymous with German term "primär kutanes Keimzentrumslymphom (PCFCL)"Primary cutaneous marginal zone B-cell lymphoma (PCMZL) Primary cutaneous diffuse large B-cell lymphoma, leg type (PCBLT) EBV-positive mucocutaneous ulcer (EBV-positive diffuse large B-cell lymphoma, not otherwise specified) ****** The EBV-positive diffuse large B-cell lymphoma is not explicitly classified as a "cutaneous lymphoma", but can present as isolated skin involvement and remains an important differential diagnosis to PCBLT and EBV-positive mucocutaneous ulceration.Primary cutaneous intravascular large B-cell lymphoma ** Entities that manifest as primary cutaneous lymphomas but are often already disseminated/systemic at the time of diagnosis.Hematological precursor neoplasms Blastic plasmacytoid dendritic cell neoplasm (BPDCN)** Entities that manifest as primary cutaneous lymphomas but are often already disseminated/systemic at the time of diagnosis. The WHO classification does not classify the cutaneous lymphomas in groups with indolent, intermediary, or aggressive growth. Diagnosis of a cutaneous lymphoma shall be performed via biopsy with histological examination of a representative lesion. Precise classification requires additional immunohistological investigations which should therefore be part of the diagnostic process. If involvement of the blood is suspected, FACS analysis/flow cytometry is recommended, see Table 2. Molecular biological clonality analysis should be performed. Consensus: 100 %, modified 2021 Imaging procedures, lymph node/bone marrow biopsy, and laboratory invest igations to exclude extracutaneous involvement or secondary cutaneous lymphoma should be performed depending on the histological subtype of the lymphoma and the tumor stage according to Tables 2 and 3. Consensus: 100 %, modified 2021 CRP, differential blood count, liver enzymes, creatinine, LDH, electrolytes. Immune electrophoresis if indicated ** The recommendations apply for first-time staging. Staging examinations adapted to the individual patient situation should be performed after therapy, in case of disease progression, and for aggressive types of lymphoma.Borrelia serology in B-cell lymphoma if indicated ** The recommendations apply for first-time staging. Staging examinations adapted to the individual patient situation should be performed after therapy, in case of disease progression, and for aggressive types of lymphoma.Special hematological investigations if indicated ** The recommendations apply for first-time staging. Staging examinations adapted to the individual patient situation should be performed after therapy, in case of disease progression, and for aggressive types of lymphoma.Further laboratory investigations depending on planned treatments Full-body CT scan°° Full-body CT scans: neck, thorax, abdomen, pelvis using intravenous contrast agents, lymph node sonography, PET CT scan if indicated°°°° Retrospective examinations with small number of cases predominantly showed a significant superiority of 18F-FDG PET/CT scans compared to conventional imaging methods, especially in the detection of lymph node and organ manifestations [14-17]. Nevertheless, larger prospective studies with sufficient evidence are currently lacking. In general, the costs for PET-CT-examinations for this indication are not covered by the statutory health insurances. Chest X-ray, lymph node sonography In the majority of skin lymphomas, clinical examination will already offer a provisional diagnosis, yet histological immunohistological, and molecular biological investigations are essential for confirmation. Apart from inspection of the whole skin, clinical examination of all lymph node stations is part of the primary examination. Staging of CL should be performed according to the TNM classification proposed by the ISCL-EORTC/EORTC CL update B (blood) classification. Consensus: 100 %, modified 2021 Staging of CTCL is performed using the TNM classification which also offers a certain prognostic factor. Especially in mycosis fungoides (MF), early stages (IA–IIA) usually have a very good prognosis with mean survival times of about 10 to 20 years. This T classification is not suitable for other types of lymphoma. The N category is also not the optimal solution in a clinical sense (for example N1/N2: clinically normal lymph nodes are usually not biopsied). For these reasons, the TNM classification for MF and Sézary syndrome (SS) has been revised and is now available as an updated TNMB classification, including changes regarding B staging (Tables 4, 5) [18, 19]. Future investigations and studies should utilize the revised classification. Macules Plaques ± macules Macules Plaques ± macules clone negative clone positive clone negative clone positive The International Society of Cutaneous Lymphomas (ISCL) and the EORTC have proposed a dedicated classification of stages for CTCL, excluding MF and Sézary syndrome [20], which should find application in the future (Table 6). solitary lesion, diameter < 5 cm solitary lesion, diameter > 5 cm Involvement diameter between 15 and 30 cm Involvement diameter > 30 cm multiple skin lesions distributed over two non-adjacent body regions multiple skin lesions > 3 body regions It should be noted that, as opposed to the staging of MF/SS [18], the current "Non-MF/SS staging" does not offer any prognostic significance but at this point in time only reflects anatomical spreading. The position of clonality analysis in removed lymph nodes has been introduced for the first time [21, 22]. Treatment of MF shall be performed according to the recommendations in Table 7. Consensus: 100 %, modified 2021 Treatment of SS shall be performed according to the recommendations in Table 8. Consensus: 100 %, modified 2021 Treatment of CD30+-lymphoproliferative skin diseases shall be performed according to the recommendations in Table 9. Consensus: 100 %, modified 2021 Treatment of cutaneous B-cell lymphomas shall be performed according to the recommendations in Table 10a, 10b. Consensus: 100 %, modified 2021 Extracorporeal photopheresis (ECP), if indicated combined with PUVA, IFNα, and/or bexarotene PUVA combined with IFNα and/or bexarotene Since the CL represent a heterogeneous group of diseases, treatment strategies must be based on a precise diagnosis (entity-appropriate), prognosis, previous treatments, and tumor staging (stage-appropriate). There are only a handful of controlled studies that contain this essential information. Treatment of CTCL must always be differentiated from treatment of CBCL. For the more common CTCL types, a stage-appropriate and basically restrictive treatment approach is recommended. In the early stages, topical treatments such as topical steroids, phototherapy, topical chemotherapy with cBCNU/chlormethine, topical bexarotene gel, or topical immunotherapy with imiquimod are preferred. In stages IA, IB, and IIA, phototherapy with narrow-band UVB (UVB 311 nm) or PUVA (psoralen plus UVA, e.g. oral PUVA, bath-, creme- or shower PUVA) may be performed. PUVA should be utilized primarily for patients with thick plaques or folliculotropic MF. Both PUVA and UVB 311 nm are appropriate for treating erythrodermic MF [23]. For localized CTCL, radiotherapy with a total dose of typically ≥ 30 Gy in single doses of 2 Gy will lead to sustained local disease control in 90–100 % of cases [24]. Low-dose palliative radiotherapy (4–8 Gy) for cutaneous B-cell and T-cell lymphoma is an alternative approach [25]. New studies show that radiotherapy with 4 Gy can adequately control the lesions of indolent cutaneous BCL [26]. For CTCL, use of 8 Gy in one or two fractions led to complete remission in ≥ 92 % of patients [27]. In stage IIB, this approach can be combined interferon-PUVA or bexarotene-PUVA or bexarotene alone, to achieve sustained disease control in the early stages. Other multimodal therapeutic combinations are feasible as well. In cases of low tumor burden, a combination of topical or systemic treatment with low dose radiation has proven successful, especially due to the reassuring side-effect profile. In general, total skin electron beam treatment at conventional doses (30–36 Gy) is a feasible option in patients with cutaneous T-cell lymphoma; however, this is associated with higher-grade skin toxicity [28, 29]. Newer studies show that low-dose total skin electron beam treatment at 10–12 Gy over a period of 2–3 weeks can be considered a reliable and safe treatment option to achieve short-term success with a lower toxicity profile [28, 30, 31]. Subsequently, adjuvant topical or systemic treatment should be considered to maintain remission (maintenance therapy) [32, 33]. Systemic treatments, such as a combination of PUVA with retinoids or recombinant interferon-alpha, are the obvious choice for advanced stages (Table 7) [34-36]. Bexarotene, another systemic medication, can also be recommended [37-40]. Use of interferon-alpha is, however, limited by the fact that the approved preparation Roferon has been withdrawn and is no longer available for treating patients with cutaneous lymphomas. There are no generic alternatives. There are some case reports in the literature of patients successfully treated with pegylated interferons (PEG-IFN) off label. Two larger studies on PEG-IFN have been published. PEG-IFNα-2a was used in CTCL patients (n = 13) at doses of 180 μg/week and 270 or 360 μg/week, respectively. The medication was effective and well tolerated, with no significant differences in the efficacy of lower or higher doses [41]. In a total of 17 patients, PEG-IFNα-2b (1.5 μg/kg body weight [BW]/weeks) plus PUVA (n = 9) was compared with the former standard treatment of IFNα-2a (9 MIU 3 x/week) plus PUVA (n = 8). This study showed excellent efficacy for PEG-IFNα-2b, although side effects such as liver toxicity and myelosuppression were observed more frequently in comparison, highlighting the need for special attention in such cases and the need of starting with a moderate dose e.g. 180 ug of PEG-IFNa-2b [42]. The antibody conjugate brentuximab vedotin is another treatment option for advanced CD-30-positive MF (tumor stage). In 2019, the monoclonal anti-CCR4 antibody mogamulizumab was approved as a systemic second-line treatment for treatment-refractive and advanced MF and SS. It is especially effective for blood involvement [43]. Alternatively, there are two histone deacetylase inhibitors: vorinostat [44] (approved in the USA in 2006) and romidepsin [45] (approved 2011, USA), as well as the antimetabolite pralatrexate [46] (approved 2011, USA). The fusion toxin denileukin diftitox is currently no longer available [47]. Monochemotherapies, for example with gemcitabine which may be used in low-dose [48, 49] or doxorubicin [50], are preferred over polychemotherapies due to a more favorable side effect profile. The latter can induce massive immunosuppression without any improvement in survival [51]. The stage-adapted treatment recommendations are still based on the TNM classification published by the MF Cooperative Group in 1979. In the future, treatment recommendations will be based on the revised TNM classification [18]. Extracorporeal photopheresis is effective for SS, with few side effects. This can also be combined with interferon-alpha, PUVA, topical corticosteroids, or bexarotene (Table 8) [63]. In late stages, palliative chemotherapy is also an option (Table 8). It should be noted, however, that this has no proven effect on survival and may result in further immunosuppression with more frequent infectious complications. Second-choice treatments include bexarotene (preferably in combination with PUVA and ECP), low-dose methotrexate (MTX; preferably in combination with PUVA and ECP), or total skin electron beam treatment. Doxorubicin or gemcitabine can be considered for debulking in advanced staged of Sézary syndrome. Alemtuzumab should be preferably used at low doses since high doses are associated with a high rate of infection. Allogenic stem cell transplants may be indicated for selected patients. If the tumor cells show CD30 expression, brentuximab vedotin may be used as an alternative [56]. Since 2019, the monoclonal anti-CCR4 antibody mogamulizumab has been available as a systemic second-line treatment for SS (after at least one previous systemic treatment), and is generally well tolerated [43]. Several HDAC inhibitors (vorinostat, romidepsin) are approved for treating SS outside Europe. CBCL without further manifestations offer a much better prognosis than nodal B-cell lymphomas. Thus, in many cases topical treatment is sufficient. Surgical removal or radiotherapy are feasible options. In individual cases, interferon treatment may result in complete remission. Polychemotherapy is only indicated for extracutaneous manifestations. For most rare CL, there are no large studies and thus no evidence-based treatment recommendations or approved therapeutic options. For the treatment of indolent CTCL, acral CD8+ T-cell lymphoproliferation, and CD4+ small-/medium size T-cell lymphoproliferative disease, excision or topical treatment are sufficient. For blastic plasmacytoid dendritic cell neoplasia (BPDCN) in a CR1 situation (complete remission directly after the first chemotherapy course), the primary recommendation is an allogenic or autologous bone cell transplant [69, 70]. Hematooncologists must therefore be consulted early for optimal treatment planning. Tagraxofusp was approved in November 2020 as a first-line monotherapy for adult patients with BPDCN. This compound consists of a shortened diphtheria toxin (DT) fusion protein linked with recombinant human interleukin-3 (IL-3) to target CD123-expressing cells. Tagraxofusp irreversibly inhibits protein synthesis of target cells by inactivating elongation factor 2 (EF2). This induces apoptosis (cell death) [71]. For subcutaneous panniculitis-like T-cell lymphomas without evidence of hemophagocytic syndrome (HPS), prednisolone monotherapy is recommended [72], if indicated also in combination with ciclosporin or MTX [73-75]. Due to the limited number of newly approved therapies, treatment of primary cutaneous lymphomas with innovative forms of therapy should preferably be performed in the context of clinical trials (www.clinicaltrials.gov). In the course of improved decoding of the molecular bases and differentiated immune phenotyping, individualized treatment with targeted drugs may also become possible off-label, outside of clinical trials. For a better understanding of individual responses, data should also be collected in registries (such as ADOReg, PROCLIPI). Consensus: 100 %, modified 2021 In cutaneous T-cell lymphomas, activating phospholipase Cγ mutations with constitutive activation of the T-cell receptor-dependent NFAT pathway represent the rationale for using topical calcineurin inhibitors for MF [77]. Analogously, inhibition of deregulated toll-like receptor signaling is observed in MF [78]. Immunomodulators such as imiquimod and resiquimod could induce local remission and may thus offer a potential corticoid-free alternative in the future [52, 53]. To date, however, use of these topical treatments has only been studied in individual case reports/case series, and in the case of resiquimod in one small monocentric clinical trial (NCT01676831). Another innovative therapeutic option is intralesional application of a CD47 antibody which regulates innate immunity for tumor control. Numerous new, promising systemic therapies for CL have become available in clinical studies or off-label for systemic hematological B-cell and T-cell neoplasias. An innovative antibody targeting the surface molecule KIR3DL2 has shown promising preliminary clinical data. Drugs that interfere with epigenetic mechanisms, such as histone deacetylase inhibitors (vorinostat, romidepsin, belinostat, and panobinostat, all currently approved in the USA), or immunomodulatory compounds such as lenalidomide, constitute alternative or additive therapeutic options for MF, SS, and peripheral T-cell lymphomas [79-81]. HDAC inhibitors are not currently available in Germany outside of clinical studies (resminostat, NCT02953301). Proteasome inhibitors such as bortezomib, which interfere with the aberrantly activated NFκB pathway, may show clinical effects in MF or peripheral T-cell lymphomas in combination with conventional therapeutic options in the absence of other alternatives [82, 83]. In view of activating mutations, inhibition of the JAK/STAT pathway may also constitute an innovative therapeutic option in the future for MF and peripheral T-cell lymphomas, in analogy to its use in systemic peripheral T-cell lymphomas [84, 85]. Innovative compounds for primary CBCL include, on the one hand, more effective and/or better tolerated CD20 antibodies such as obinutuzumab or ofatumumab, which have already been approved for treating systemic B-cell lymphomas [86, 87], or (additive) immunoregulatory compounds such as lenalidomide [88, 89]. Pixantrone, an alkylating substance with reduced cardiotoxicity compared with doxorubicin, appears especially attractive for elderly patients with primary cutaneous large B-cell lymphoma in view of commonly found (cardiac) comorbidities [90, 91]. For cutaneous B-cell lymphomas as well, future decoding of deregulated pathways will facilitate the use of targeted medications such as Bruton's kinase inhibitors (ibrutinib) or phosphoinositide 3-kinase (PI3K) inhibitors (idelalisib). Some of these have already been approved for systemic B-cell non-Hodgkin lymphoma and are thus available off-label also for cutaneous B-cell lymphomas, especially treatment-refractive large B-cell lymphoma, leg type (PCBLT) [92-94]. Another promising candidate for this indication is the fusion protein polatuzumab, which has already been approved for systemic diffuse large B-cell lymphoma in combination with rituximab and bendamustine [95]. Data from clinical studies on maintenance therapy in CL are insufficient. Verified 2021 Once complete remission or an earlier stage has been achieved in advanced lymphomas, non-cytotoxic treatment recommendations in this guideline should be employed [96]. Pruritus, a common and distressing symptom in CL, impairs patients' quality of life at any stage of the disease [97]. It is frequently permanent and worsens toward the end of the day and with warmer temperatures, sometimes also upon contact with water. Sleep is often disturbed. Basic treatment, topical steroids, and oral antihistamines can only rarely achieve improvement [98]. Apart from specific treatment of the cutaneous lymphoma, symptomatic treatment of pruritus therefore deserves high priority in the therapeutic concept. 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