Health-related quality of life and its influencing factors in patients with primary cutaneous B-cell lymphomas: A multicentric study in 100 patients.

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.

[Cylindromas-rare but striking]. / Zylindrome ­ selten aber eindrucksvoll.

Cylindromas are rare tumors of adnexal structures in adults. They are predominantly found on the scalp and face. More impressive than incidentally diagnosed solitary cylindromas are multiple tumors in patients with familial Brooke-Spiegler syndrome. If many large cylindromas appear on the head, they are termed turban tumor. Sudden growth or ulceration should raise suspicion for malignant transformation.

[Atypical fibroxanthoma and pleomorphic dermal sarcoma]. / Atypisches Fibroxanthom und pleomorphes dermales Sarkom.

Atypical fibroxanthoma (AFX) or undifferentiated pleomorphic sarcoma (UPS) is a rare malignant neoplastic disease of the skin. At the beginning of the 1960s AFX was described as an independent entity and superficial variant of malignant fibrous histiocytoma (MFH). Since then, many controversies on the classification have arisen mainly because in many cases dedifferentiated neoplasms from other origins were falsely diagnosed as AFX. A relevant deep expansion, the invasion of nerves and vessels or the presence of tumor necrosis are described as being typical for UPS; however, in the first-line they represent risk factors for recurrence. In view of the clinical and histological features it is meaningful to consider AFX and UPS as one disease. In recent years many studies on the molecular pathological background have attempted to make a better classification of the neoplasm, without being able to so far name a certain specific histopathological or molecular pathological characteristic. The AFX/UPS is still in essence a morphological and immunohistochemical diagnosis by exclusion.

[Paraneoplastic skin diseases]. / Paraneoplastische Hauterkrankungen.

Various specific skin alterations can occur in patients with malignant diseases. If these skin diseases occur as associated symptoms of a malignant process, they are called paraneoplastic. In this overview, obligate and frequent facultative paraneoplastic skin diseases are assigned according to the triggering type of malignancy. Some of the processes predominantly show a link with malignant diseases of the digestive tract, e.g. acanthosis nigricans, florid cutaneous papillomatosis, necrolytic migratory erythema, Leser-Trélat syndrome, palmoplantar keratoderma, panniculitis and pityriasis rubra pilaris. Others are predominantly associated with a hematolymphoid malignoma, e.g. acquired ichthyosis, exfoliative erythroderma, necrobiotic xanthogranuloma, paraneoplastic pemphigus, plane xanthoma, pyoderma gangrenosum, scleromyxedema, Sweet syndrome and leukocytoclastic vasculitis. In a third group paraneoplastic skin diseases are pooled in association with other malignancies, e.g. Trousseau's syndrome, dermatomyositis, erythema gyratum repens, hypertrichosis lanuginosa acquisita and papuloerythroderma of Ofuji. In order to initiate targeted diagnostics for detection of an underlying malignant disease, it is essential that accomplished physicians recognize the skin diseases that represent obligate or potential paraneoplasms as such.

Brentuximab vedotin in CD30+ cutaneous lymphoma: How do we treat, how shall we treat? A review of the literature.

Brentuximab vedotin is an antibody-drug conjugate that brings the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. Some prior studies demonstrated good efficacy in cutaneous lymphomas. The standard therapeutic scheme is 1·8 mg kg-1 every 3 weeks. The background of this work is the fact that cutaneous lymphoma has a different pathophysiology and a dynamic other than systemic lymphomas. The objectives of this review were to get an overview of the currently used therapeutic regimen, and to check whether dose reduction or modified time intervals could be of benefit in a similar way with less toxicity. Therefore, we conducted a systematic review of the literature indexed in PubMed and the Cochrane Central Register of Controlled Trials up to April 2016. The procedure was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The review showed that the currently used therapeutic regimen is 1·8 mg kg-1 every 3 weeks. No publications of dose-finding studies in CD30+ cutaneous T-cell lymphoma (CTCL) were found. Two cases of patients, treated with a dose < 1·8 mg kg-1 , have been published. Brentuximab vedotin seems to be a powerful treatment option in refractory CD30+ CTCL, and there is a trend that dose reductions, as well as prolonged treatment intervals, work without any loss of response and with fewer side-effects.

[Aggressive primary cutaneous B-cell lymphomas and novel EBV+ entities]. / Aggressive primär kutane B-Zell-Lymphome und neue EBV-positive Entitäten.

Primary cutaneous large B­cell lymphomas (PCBLT), EBV-positive large B­cell lymphomas, not otherwise specified (EBV+ DLBCL, NOS), and primary cutaneous intravascular large B­cell lymphomas (PCIVLBL) are recognized as cutaneous lymphomas with intermediate to poor prognosis. Differentiation from indolent B­cell lymphomas or other pathologies of the skin can be complex, both clinically and histologically, but vital for the outcome of the patient. The combination of immunotherapy and polychemotherapy regimens, such as R­CHOP, has led to significant improvements in prognosis, especially in diffuse large B­cell lymphomas. Therapeutic decisions need to be individually made for each patient, ideally within an interdisciplinary tumor conference. Immunosenescence may be an important factor in the pathogenesis of EBV+ DLBCL, NOS in elderly individuals. Their prognosis is less favorable than that of patients with EBV-negative PCBLT, whereby this has been observed particularly in elderly patients. One third of patients with PCIVLBL progress to systemic disease. The occurrence of nodal manifestation is rarely observed. Symptoms may vary depending on the organ system involved. Currently there are no evidence-based therapy recommendations due to the rarity of the disease. EBV-positive mucocutaneous ulcer is a new provisional category in the current WHO classification for lymphoid neoplasms. It has been segregated from EBV+ DLBCL, NOS due to its self-limiting course and good response to conservative therapy.

[Systemic treatment of distant metastatic malignant melanoma]. / Systemische Therapie des fernmetastasierten malignen Melanoms.

CONTEXT: Systemic therapy of advanced metastatic malignant melanoma has been considerably changed by the approval of new drugs in recent years. The targeted therapy with the B-RAF inhibitors vemurafenib and dabrafenib achieves rapid tumor reduction but is often followed by the development of resistance in the further course of therapy. By immunotherapy with ipilimumab, on the other hand, a plateau effect becomes apparent in the survival curves. OBJECTIVE: The aim of this article is to discuss the treatment options for patients with advanced melanoma with special reference to new treatment options and substances for which approval is soon to be expected. METHODS: Treatment recommendations, taking into account the S3 guidelines on diagnosis, treatment and follow-up of melanoma and recent publications (Pubmed and manual search) are presented. RESULTS: In patients with B-RAF mutations, targeted therapy with the B-RAF inhibitor vemurafenib achieves response rates of 50-60 %, comparable with the B-RAF inhibitor dabrafenib, yet resistance often occurs after approximately 7 months. By immunotherapy with ipilimumab long-term survival can be achieved in approximately 20 % of patients. CONCLUSION: The treatment options for patients with metastatic melanoma have considerably improved in recent years. Several highly effective substances have recently become available and the approval of more potent substances is expected this year.

[Phlebology in German departments of dermatology. An analysis on behalf of the German Society of Phlebology]. / Phlebologie an deutschen Hautkliniken. Eine Bestandsaufnahme im Auftrag der Deutschen Gesellschaft für Phlebologie.

BACKGROUND: Phlebologic diseases have become extremely common and have major socio-economic impact. However, the percentage of dermatologists working in phlebology appears to be decreasing according to the data of the German Society of Phlebology (DGP). METHODS: To investigate the reasons for this development, we--on behalf of the DGP--sent a questionnaire to 120 German Departments of Dermatology in autumn 2012. RESULTS: In 76 returned questionnaires, the number of physicians with additional fellowship training in phlebology averaged 1.5; the average number of those who fulfill the criteria for training fellows in phlebology was 0.9. In 71.1 % of the departments there was a phlebologist. A special phlebologic outpatient clinic existed in 73.7 % of the departments. Sonography with Doppler (89.5 %) and duplex (86.8 %) was used as the most frequent diagnostic tool. For therapy, compression (94.7 %), sclerotherapy (liquid 78.9 %, foam 63.2 %, catheter 18.4 %), endoluminal thermic procedures (radio wave 28.9 %, laser 17.1 %) and surgery (especially crossectomy and stripping 67.1 %, phlebectomy of tributaries 75 %) were used. The average number of treatments was very heterogenous in the different departments. CONCLUSIONS: Phlebology definitely plays an important role in dermatology. Most departments fulfill the formal criteria for the license to conduct advanced training in phlebology. A wide spectrum of phlebological diagnostic and therapeutic procedures is available.

Expression of the T-cell regulatory marker FOXP3 in primary cutaneous large B-cell lymphoma tumour cells.

BACKGROUND: Primary cutaneous B-cell lymphomas (PCBCL) are subdivided into the aggressive form, primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT) and two subtypes of indolent behaviour (primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone B-cell lymphoma). The difference in clinical behaviour can be explained by the tumour cell itself, or the lymphoma microenvironment including the antitumour immune response. OBJECTIVES: To investigate the presence of regulatory T cells (Treg), CD4+CD25+FOXP3+, in the microenvironment of PCBCL in correlation with clinical outcome. METHODS: Tumour specimens of 55 consecutive cases of PCBCL were blinded and analysed for FOXP3, CD4 and CD25 expression by immunohistochemistry. Confocal images were taken with a Leica SP5. Statistical analyses were performed to determine significance. The test was considered significant when P<0.05. RESULTS: The CD4 and FOXP3 expression as well as the CD4/FOXP3 ratio were significantly increased in PCBCL of indolent behaviour in contrast to PCLBCL, LT (P=0.0002 for CD4, P<0.0001 for FOXP3 and P=0.0345 for FOXP3/CD4 ratio). CD25 expression did not differ in the three groups (P=0.9414). Within the group of patients with PCLBCL, LT we identified a subgroup with FOXP3+ tumour cells as demonstrated by CD20/FOXP3 double stainings. Patients with FOXP3+ PCLBCL, LT tumour cells showed a better prognosis on Kaplan-Meier analysis. CONCLUSION: High numbers of Treg in the lymphoma microenvironment correlate with a better prognosis in PCBCL. In PCLBCL, LT the presence of FOXP3+ tumour cells is beneficial for prognosis suggesting that FOXP3 expression of PCLBCL, LT tumour cells might serve as a tumour suppressor.

Prospective evaluation of follow-up in melanoma patients in Germany - results of a multicentre and longitudinal study.

BACKGROUND: Patient numbers requiring long-term melanoma surveillance are constantly rising. Surveillance is costly and guideline recommendations vary substantially. METHODS: In this German nationwide study, information on surveillance and treatment of patients diagnosed with melanoma and melanoma in situ (MMis) between April and June 2008 was prospectively collected over four years. Additionally, patient self-report questionnaires were evaluated to assess anxiety, depression, health-related quality of life, socio-demographic information and use of disease specific health information sources at year 4 after primary diagnosis. RESULTS: Complete data was available for 668 patients from 67 centres, of whom 96.0% were in regular melanoma surveillance. In year 3-4 of surveillance, only 55.6% of locoregionary metastases were detected during surveillance visits. Only 33.3% were self-detected by the patient even though 69.4% were documented as being clinically visible or palpable. Costs of 4year surveillance of 550 patients without tumour recurrence (stage I-IIC and MMis) accumulated to 228,155.75 €. Guideline-adherence for follow-up frequency, lymph node ultrasound, S100 serum level tests and diagnostic imaging recommendations was approximately 60% in year 3-4 of surveillance. Multivariate regression analysis showed that certain patient/tumour characteristics and regional differences were significantly associated with guideline deviations. The percentage of patients who exceeded published cut-off scores indicating clinically relevant symptoms of anxiety and depression were significantly increased. Patients frequently reported lack of psychosocial support and education but ascribed great importance to these. CONCLUSIONS: We recommend further reduction of melanoma follow-up in low-risk melanoma patients and improvement of psycho-social support and patient education for all melanoma patients.

Distribution of constitutive nitric oxide synthase immunoreactivity and NADPH-diaphorase activity in murine telogen and anagen skin.

The freely diffusible radical nitric oxide is generated by nitric oxide synthase, and is a pleiotropic, bioregulatory molecule that regulates, e.g., the vascular tone, functions as a major neurotransmitter, and is involved in macrophage-mediated cytotoxicity and platelet aggregation. Constitutive nitric oxide synthase exhibits NADPH-diaphorase activity that can be demonstrated histochemically. To study whether this enzyme is present in mammalian skin during distinct phases of the murine hair cycle, we have examined cryosections of C 57 BL-6 mouse skin in telogen and depilation-induced anagen VI. Histochemical analysis of NADPH-diaphorase activity was complemented by immunohistology, using two specific rabbit antisera against constitutive neuronal nitric oxide synthase. Epidermis and the outer root sheath showed both immunoreactivity for the enzyme and NADPH-diaphorase activity, whereas dermal papilla and sebaceous glands displayed only strong NADPH-diaphorase activity, suggesting that this enzyme histochemical test measures additional enzymes besides nitric oxide synthase. Intrinsic nitric oxide synthase immunoreactivity was also detected by immunoblot in mouse skin homogenates, staining proteins of an apparent 160-kDa molecular weight. Compared to telogen skin, these immunoreactive proteins were quantitatively increased in anagen VI skin. Thus, our study suggests that defined epithelial compartments of normal murine skin are capable of synthesizing nitric oxide and that the molecule may be involved in skin physiology, growth, and remodeling.

Comparative cytokine release from human monocytes, monocyte-derived immature mast cells, and a human mast cell line (HMC-1).

To obtain further information regarding the role of cytokines during mast cell differentiation, we have investigated changes of cytokine secretion in mast cells developing from the human peripheral blood monocytic cell fraction during culture with fibroblast-derived conditioned media. The influence of stem cell factor and an antibody to the respective receptor in our culture system was studied as well. Interleukin (IL)-1 alpha, IL-1 beta, IL-6, and tumor necrosis factor (TNF)alpha were spontaneously secreted by cultured cells at day 1 and decreased markedly by day 14. Similar changes occurred also during culture with stem cell factor and were partially abrogated by an anti-receptor antibody. IL-8 was secreted at a high level throughout the culture, whereas no spontaneous secretion of IL-2, IL-3, IL-4, and IL-7 was measured at all. Upon stimulation with phorbol myristate acetate and A23187, cultured cells showed substantially more release of IL-3 and TNF-alpha after 14 d of culture, compared to peripheral blood monocytic cells. Preformed TNF-alpha was found in one of three monocytic cell preparations from peripheral blood, but not in monocytic cell-derived mast cells. During mast cell differentiation, cytokines from monocytic cells are therefore downregulated while the cells assume a pattern typically found in mast cells.

Receptor-independent G protein activation may account for the stimulatory effects of first-generation H1-receptor antagonists in HL-60 cells, basophils, and mast cells.

The first-generation histamine H1-receptor antagonists, chlorpheniramine (CPHE) and diphenhydramine (DPH), may activate histamine release from basophils and mast cells. Because CPHE and DPH are cationic-amphiphilic and because several substances with such physicochemical properties activate heterotrimeric regulatory guanine nucleotide-binding proteins (G-proteins) in a receptor-independent manner, we asked the question of whether or not H1-receptor antagonists could be G-protein activators as well. In dibutyryl cAMP-differentiated HL-60 cells, CPHE and DPH increased cytosolic Ca2+ concentration and azurophilic granule release in pertussis toxin (PTX)-sensitive manners. In HL-60 membranes, PTX-sensitive stimulations of GTPase [E.C. 3.6.1.] and binding of guanosine 5'-[gamma-thio]triphosphate by H1 receptor antagonists were observed. CPHE and DPH also increased GTP hydrolysis by the purified PTX-sensitive G-protein, transducin. In all-trans-retinoic acid-differentiated HL-60 cells and rat basophilic leukemia cells (RBL 2H3 cells), H1-receptor antagonists induced, unlike in dibutyryl cAMP-differentiated HL-60 cells, Ca2+ influx without Ca2+ mobilization from intracellular stores. CPHE and DPH also induced serotonin release from RBL 2H3 cells. Our data indicate that first-generation H1-receptor antagonists are receptor-independent G-protein activators and that such a mechanism of action accounts for their stimulatory effects in HL-60 cells, basophils, and mast cells.

Retinoic Acid receptor-gamma-selective retinoids exert antiproliferative effects on human-melanoma cell-growth in-vitro.

Malignant melanoma is a cancer with dramatically increasing incidence and mortality. Alternative approaches for therapy of disseminated malignant melanoma are urgently needed. In order to develop new alternatives for therapy of metastatic melanoma, we tested the biological activity of eight synthetic retinoids with high affinity and/or selectivity for the retinoic acid receptors (RAR) alpha, beta and gamma in comparison to all-trans retinoic acid, arotinoid acid and CD 367 in four human melanoma cell lines. The melanoma cell growth was not affected by most retinoids tested, however, two of the synthetic substances with high RAR-gamma selectivity (CD 437 and CD 2325) showed a dose-dependent antiproliferative effect on all melanoma cell lines tested with IC50 values between 10(-6) and 10(-7) M. A structurally closely related compound, CD 2398, lacking the carboxyl-terminal group and therefore exhibited no RAR-binding did not change melanoma cell growth behaviour. We demonstrate the expression of RAR-alpha, RAR-beta and RAR-gamma, in four human melanoma cell lines by polymerase chain reaction. Taken together, these results suggest that binding and stimulation of the RAR-gamma receptor might be a major factor in growth inhibition of human melanoma cell by retinoids in vitro. Although several of the compounds altered the cell surface expression of defined melanocytic differentiation markers, the correlation to changes in melanin content was poor. Furthermore, five out of eight retinoids modulated HLA-DR expression on human melanoma cells. The potent growth inhibitory effect of the RAR-gamma selective retinoids as well as their immunomodulating capacities opens an interesting alternative for new antiproliferative and immunomodulatory strategies in the therapy of metastatic melanoma.

Effects of various synthetic retinoids on proliferation and immunophenotype of human melanoma cells in vitro.

Since response rates in human melanoma are low with currently available therapeutic modalities, we have reevaluated the potential usefulness of retinoids as new alternatives for therapy of metastatic melanoma. Nine synthetic retinoids with high affinity and/or selectivity for the retinoic acid receptors (RAR) alpha, beta, and gamma were studied in comparison to all-trans retinoic acid (RA) for their in vitro effects on melanoma cell proliferation and for their immunomodulating capacities using four human melanoma cell lines. Eight out of ten retinoids tested had no effect on melanoma cell growth, whereas the remaining two compounds with high RAR-gamma selectivity (CD437 and CD2325) showed a dose-dependent antiproliferative effect on all melanoma cell lines with IC50 (concentration inhibiting response by 50%) values between 10(-6) and 10(-7)M. Further analyses showed that paracrine-mediated tumor cell growth inhibition such as induction of transforming growth factor (TGF)-beta described as one mechanism of retinoid action and enzyme systems such as tyrosinase and monoamine oxidase were not involved in mediating the antiproliferative effects exerted by the two retinoids. Four of nine retinoids modulated HLA-DR expression on human melanoma cells, and expression levels of intercellular adhesion molecule 1 (ICAM-1) was increased by another subset of compounds. These effects were, however, not correlated to the receptor selectivity of the retinoids. The potent growth inhibitory effect of the RAR-gamma-selective retinoids and the immunomodulating capacities of the retinoids open an interesting alternative for new antiproliferative and immunomodulatory strategies in the treatment of metastatic melanoma.

Stem cell factor, a novel cutaneous growth factor for mast cells and melanocytes.

Mechanisms affecting mast cell and melanocyte growth and function are still poorly understood. This report summarizes the current state of knowledge on a recently described growth factor for both these cell types and for primitive haematopoietic stem cells. Stem cell factor (SCF), also named mast cell growth factor or kit-ligand, has only recently been cloned and has been shown to be encoded on human chromosome 12. It may be of specific importance in cutaneous physiology and pathology since it is produced by several cell types in the skin (e.g. fibroblasts, keratinocytes, endothelial cells) and since it affects melanocyte and mast cell growth, survival, secretion and adhesion as well as migration into tissues. Defects in the genes encoding for the SCF receptor (c-kit-protein) have been shown to be responsible for human piebaldism. A pathogenetic role in mastocytosis has recently been proposed, but remains to be proven. SCF receptor expression is decreased on cells of some malignant cell lines compared to their physiological counterparts, making it unlikely that SCF is a key factor in malignant transformation and cellular hyperproliferation. In haematopoiesis, SCF acts primarily in concert with other growth factors, and we show here that alone in serum-free culture it has no effect on mast cell growth. Furthermore, there is evidence that besides SCF, additional mast cell growth factors are secreted by fibroblasts and keratinocytes, suggesting a complex orchestration of several growth factors in the regulation of cutaneous growth and differentiation in which SCF plays only one part.

Beyond inflammation: tolerance, immunotherapy and more.

Inflammatory skin diseases such as allergic contact dermatitis, atopic dermatitis, and psoriasis are together the most frequent dermatoses and are of great medical and economic significance. Despite impressive progress in recent years, the immune pathogenesis of these diseases is not yet fully understood. In particular, it remains an open question which anti-inflammatory mechanisms can be activated to prevent development of such abnormal immune reactions in the still healthy organism, and how these anti-inflammatory processes may be enhanced and instrumentalized for treatment of these disease states.

Guess what! Eruptive vellus hair cysts.

An otherwise healthy 24-year-old woman presented with persistent asymptomatic skin-coloured papular lesions on her trunk which had appeared over 18 months, gradually increasing in number, size and the extent of the skin surface area involved. Physical examination revealed multiple flesh - to whitish - coloured papules, 2 to 5 mm in diameter, located on her neck, anterior chest wall, axillae and upper abdomen (Fig. 1). The lesions were smooth, painless on palpation and not grouped. Laboratory investigations only showed normal results. Histopathological examination of a papular lesion from the upper abdomen revealed a cystic structure in the mid-dermis lined by four to five layers of squamous epithelium with a discrete granular layer. Laminated keratinous material and multiple transversely or obliquely cut vellus hairs were present within the cyst, while sebaceous elements were lacking in the vicinity or within the cyst wall (Fig. 2a, b). Polaroscopic examination demonstrated double refractile vellus hairs in the cyst.