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Background: Primary cutaneous B-cell lymphomas (CBCL) are a group of rare malignant skin diseases that represent approximately 20%-30% of all primary cutaneous lymphomas (PCL). Previous studies revealed impaired health-related quality of life (HRQoL) in patients diagnosed with primary cutaneous T-cell lymphoma (CTCL). Currently, only small-sized studies investigated HRQoL in CBCL patients and lacked detailed analysis of respective subtypes., Objectives: This study aims to investigate HRQoL in CBCL patients to identify independent factors of HRQoL impairment in CBCL patients., Methods: One hundred CBCL patients were recruited from eight German PCL centres in this multicentric, cross-sectional study from 2021 to 2022. The patients completed the dermatologic HRQoL questionnaire Skindex-29 and an investigator-designed 'CBCL-Questionnaire' with additional questions on HRQoL and clinical characteristics., Results: The Skindex-29 revealed that HRQoL in CBCL patients is impaired on a mild to moderate level. The multiple regression analysis identified parameters like worries about dying, feeling prejudiced/discriminated and impairment of daily activities to be independently associated with impairment of HRQoL. Highest scores for HRQoL impairment were found in patients with primary cutaneous follicle centre lymphoma while on rituximab treatment and in patients with primary cutaneous marginal zone lymphoma while on watchful waiting., Conclusions: HRQoL is impaired in CBCL patients, even though, in the face of indolent disease course and favourable prognosis in the majority of cases. Of note, our investigator-designed tool identified worries about dying, feeling prejudiced/discriminated, and the type of treatment to have a negative impact on patients' HRQoL. Our study highlights the importance of a thorough patient-doctor communication to capture overall disease burden because generic HRQoL tools might lack of disease-specific items., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Cutaneous lymphomas comprise different subgroups with distinct biological behavior. Mycosis fungoides, the most common cutaneous lymphoma, presents with patches, plaques, tumors and erythroderma. Therapeutic options depend on stage and comprise local skin-directed treatment in early stages, while later stages and Sézary syndrome require systemic therapies including bexarotene, interferon or brentuximab vedotin. While the rare CD4-positive lymphoproliferation and acral CD8-positive lymphoma present with an invariably indolent course, cutaneous peripheral T‑cell lymphomas exhibit an aggressive clinical behavior. Among the subgroup of cutaneous B‑cell lymphomas, primary cutaneous marginal zone lymphoma and follicle center cell lymphoma belong to indolent entities with almost unrestricted overall survival, whereas cutaneous large B‑cell lymphoma presents with a significant risk of systemic dissemination and is associated with high lethality.

Cutaneous lymphomas comprise different subgroups with distinct biological behavior. Mycosis fungoides, the most common cutaneous lymphoma, presents with patches, plaques, tumors and erythroderma. Therapeutic options depend on stage and comprise local skin-directed treatment in early stages, while later stages and Sézary syndrome require systemic therapies including bexarotene, interferon or brentuximab vedotin. While the rare CD4-positive lymphoproliferation and acral CD8-positive lymphoma present with an invariably indolent course, cutaneous peripheral T‑cell lymphomas exhibit an aggressive clinical behavior. Among the subgroup of cutaneous B‑cell lymphomas, primary cutaneous marginal zone lymphoma and follicle center cell lymphoma belong to indolent entities with almost unrestricted overall survival, whereas cutaneous large B‑cell lymphoma presents with a significant risk of systemic dissemination and is associated with high lethality.

Primary cutaneous B‑cell lymphomas are rarely encountered and represent 25% of all cutaneous lymphomas. Follicular B‑cell lymphoma and marginal zone lymphoma belong to indolent subtypes which as a rule have no systemic dissemination and, thus, a mostly unchanged life expectancy. Therefore, skin-directed treatment options such as excision or radiotherapy are usually sufficient to control the disease. In contrast, cutaneous diffuse large B‑cell lymphoma and EBV-associated B‑cell lymphomas of the skin belong to more aggressive entities which demand a systemic first-line upfront therapy with R‑CHOP. Nevertheless, mortality is still high and comparable to that of systemic/nodal large B‑cell lymphomas so that the identification of pathogenetic driver mutations or novel therapeutic targets may pave the way to better target-oriented therapies.

Cutaneous B-cell lymphomas (CBCLs) comprise a group of mature lymphoproliferative B-cell disorders that primarily affect the skin. Characterized by great biological and clinical variability among its various subtypes, CBCLs fundamentally differ from primary nodal or systemic B-cell lymphomas. Given their uncomplicated course and excellent prognosis, lymphoma classifications rank primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL) as indolent CBCLs. By contrast, diffuse large B-cell lymphoma, leg type (DLBCL-LT) in particular, represent more aggressive lymphoma variants associated with a poorer prognosis. Therapeutic decisions and diagnostic procedures are based on the exact histological and immunohistochemical classification as well as the exclusion of systemic involvement and thus differentiation from nodal and systemic lymphomas. In this context, the diagnostic workup should also include molecular biology methods. Primary therapeutic options for indolent CBCL lesions include surgery and radiation therapy, as well as systemic treatment with rituximab (anti-CD20 antibody) in case of dissemination. More aggressive CBCLs usually require a combination of rituximab and polychemotherapy, primarily the CHOP regimen or modifications thereof. Given that the pathogenesis and biology of CBCLs has not been conclusively elucidated, and given the limited therapeutic armamentarium available, there is great need for comprehensive research, especially with respect to DLBCL-LT., (© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Primary cutaneous large B-cell lymphomas, leg type (PCLBCL/LT) are primary cutaneous B-cell lymphoma (PCBCL) with an intermediate prognosis. Therefore, antracycline-based polychemotherapy combined with rituximab has been recommended as first-line treatment. Yet, despite this regimen, the 5-year survival rate remains 50-66% only. Angiogenesis, the formation of a vascular network, is essential for the pathogenesis of nodal lymphomas. So far, no study has analysed angiogenesis and its key factors in PCLBCL/LT. The present study was aimed at characterizing angiogenesis in PCLBCL/LT to identify the angiogenic molecules as potential therapeutic targets. The intra-tumoral microvessel density (MVD) was assessed by immunohistochemical studies of CD20 and CD31. The MVD was higher in PCLBCL/LT compared with indolent PCBCL. Analyses of open-source microarray data showed correlation between the angiogenic molecule angiopoietin-2 (Ang-2) and pan-endothelial cell markers. ELISA studies determined a shift between Ang-2 and Ang-1 towards Ang-2 in the peripheral blood of PCLBCL/LT patients. Immunofluorescence costainings against the Ang receptor Tie2/angiogenic integrins/CD34 revealed that the vasculature in both aggressive and indolent PCBCL tumors harbours an endothelial cell subpopulation with reduced expression of Tie2. In contrast, the alternative Ang-2 binding partners, angiogenic integrins, are strongly expressed in PCBCL. In line with these findings, downstream targets of Ang-2-integrin signalling, that is phosphorylation of focal adhesion kinase at Tyr397, and sprouting angiogenesis are enhanced in PCLBCL/LT. Our data present Ang-2 as a promising therapeutic target and anti-angiogenic therapy as a new line in treatment of PCLBCL/LT as a hitherto intractable disease., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A proangiogenic micromilieu is associated with a worse prognosis in systemic lymphoma. Hence, targeting the tumour microenvironment and its vasculature has evolved as a promising novel treatment strategy. The role of tumour neoangiogenesis in cutaneous B-cell lymphoma, however, has not yet been elucidated. Therefore, we examined the expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2, as well as microvessel density by immunohistochemistry in paraffin-embedded specimens of different subtypes of primary cutaneous B-cell lymphomas, systemic diffuse large B-cell lymphoma, and cutaneous B-cell pseudolymphoma. Primary cutaneous large B-cell lymphoma (PCLBCL) were characterized by significantly higher intratumoral expression levels of VEGF and its receptors in comparison with the indolent lymphoma subtypes. Moreover, PCLBCL exhibited significantly higher intratumoral microvessel counts. Our study provides evidence that the most aggressive subtype of cutaneous B-cell lymphoma, PCLBCL, is characterized by a proangiogenic micromilieu.

Rituximab has been established as an effective and safe therapy for cutaneous B-cell lymphoma (CBCL). Different survival pathways, that is the Raf/MEK/Erk- or the p38MAPK cascade, have been suggested as downstream mediators of rituximab and may be involved in treatment failure. Biopsies from four patients, suffering from different subtypes of CBCL, which were obtained at various time points of relapse during or after therapy with 375 mg rituximab per m2 of body surface area, were analysed for the expression of CD20, CD3, Ki-67, Raf-kinase inhibitory protein (RKIP) and bcl-2 by immunohistochemistry. No CD20-loss variants, that is the suggested main tumour escape mechanism to rituximab therapy, were observed in any specimen of relapsing CBCL. Notably, the expression of proapoptotic RKIP remained increased in these tumour samples. This was concomitated by a constant to slightly reduced proliferation status as demonstrated by Ki-67 staining. However, relapsing CBCL exhibited a strong upregulation of the antiapoptotic molecule bcl-2 in comparison to pretherapeutic levels. The immunohistochemical analyses of this case series of rituximab refractory CBCL suggest that upregulation of bcl-2 may play a major role in therapy resistance.