BACKGROUND:Hidradenitis suppurativa (HS) is a chronic inflammatory disease that is highly correlated with obesity. Haptoglobin serum levels have recently been recognized as an important biomarker linking obesity with chronic inflammation. OBJECTIVE:To compare haptoglobin with previously proposed serum biomarkers for the determination of disease severity in HS patients. For this purpose, disease severity of HS patients was determined by a panel of clinical scores as well as several risk factors, such as weight and smoking habits. METHODS:A prospective, diagnostic accuracy study was performed at the International Centre for Hidradenitis suppurativa/Acne inversa Bochum (ICH). The study included a total of 263 patients, including 131 who had a confirmed diagnosis of HS in Hurley I (n = 16), II (n = 56) and III (n = 59) HS, and 132 healthy controls. The main outcome was to identify serological inflammatory markers for HS disease severity [severe (III) vs. moderate/mild (II/I)] as assessed by Hurley classification. RESULTS:The serum levels of acute phase proteins haptoglobin and CRP, as well as the number of neutrophils in peripheral blood, number of monocytes, the systemic immune-inflammation index and the pan-immune-inflammatory value correlated with disease severity according to established clinical scores (mHSS, SAHS, Hurley, DLQI). HS patients had significantly higher haptologlobin levels compared to healthy controls. Logistic regression analysis revealed haptoglobin as the only independent marker predicting severe HS. CONCLUSION:In this prospective study, we discovered that the serum levels of the acute phase protein haptoglobin levels serve as an independent marker of disease severity in HS. While this presents the first study in the context of HS. Thus, the present data not only yield a highly promising serum marker to be further validated.

Background Microcystic adnexal carcinoma (MAC) is a rare skin neoplasm that has not been characterized on a molecular basis. Aim To assess expression profiles of Hedgehog (HH) signalling molecules in MAC and control tumours. Methods Immunohistochemistry was performed for Sonic Hedgehog (SHH), Indian Hedgehog (IHH), Patched 1 (PTCH1) and Smoothened (SMO) on patient MAC tissue (n = 26) and control tumour tissue, including syringoma (SyG; n = 11), trichoepithelioma (TE; n = 11) and basal cell carcinoma (BCC; n = 12) tissues. Results Patched 1 and SMO immunoreactivity was significantly higher in BCC than in SyG, TE or MAC (P < 0.001 and P < 0.03, respectively). The highest IHH expression was observed in BCC and TE compared with SyG and MAC (P < 0.04). Notably, the highest SHH protein expression was observed in SyG compared with MAC, TE and even BCC (P < 0.001). In patients with MAC, SMO immunoreactivity significantly (r = 0.51; P < 0.01) correlated with PTCH1 expression. Further correlation studies did not show significant associations between the HH expression markers assessed (P > 0.05). Conclusion Our results indicate that alterations of the HH signalling are unlikely to play a major role in the pathogenesis of MAC, which is in contrast to the morphologically similar BCC and TE. Our observation provides additional information to the limited molecular pathology knowledge on this rare tumour.

Hydroxyurea and ruxolitinib are frequently used to treat myeloproliferative disorders, including polycythaemia vera, and chronic treatment is associated with many cutaneous adverse effects such as the development of aggressive non-melanoma skin cancer (NMSC). We report an 85-year-old man with a history of hydroxyurea- and ruxolitinib-treated polycythaemia vera who was referred for the management of progressively growing tumours on his scalp. Histopathology of the largest scalp lesion revealed a partly desmoplastic cutaneous squamous carcinoma with perineural invasion. Initial imaging revealed metastatic disease in cervical lymph nodes, bones and lungs. The scalp lesions were successfully treated with bleomycin-based electrochemotherapy. Under initial systemic therapy using four cycles of cetuximab, metastatic disease progressed. Following the approval by the health insurance, compassionate use of pembrolizumab monotherapy was initiated. After three cycles of pembrolizumab, however, metastatic disease further progressed and the patient finally died from global respiratory insufficiency. The present case exemplifies the cutaneous adverse effects of long-term hydroxyurea and ruxolitinib therapy, frequently resulting in highly aggressive NMSCs that are usually not responsive to systemic treatments even such as immune checkpoint inhibitors.

BACKGROUND:In patients with cutaneous melanoma (CM), the time span between resection of the primary tumour and sentinel lymph node biopsy (SLNB) as well as the subsequent interval between SLNB and complete lymph node dissection (CLND) varies greatly.AIM:To determine whether very early timing of SLNB after resection of the primary tumour, or timing of CLND after SLNB affect the clinical outcome of patients with CM, compared with longer time intervals.METHODS:We compared the time spans between complete resection of the primary tumour and SLNB, and the interval between SLNB and CLND in a cohort of 896 patients with melanoma who had undergone SLNB. An interval between primary resection and SLNB or between SLNB and CLND of up to 7 days was classified as very early (VE-SLNB and VE-CLND, respectively). This time span was compared with intervals of > 7 days. Univariate and multivariate statistics were performed.RESULTS:VE-SLNB was significantly associated with the presence of micrometastases. However, this was probably due to tumour thickness being significantly higher in patients with VE-SLNB compared with patients with later SLNB. Importantly, VE-SLNB was not significantly associated with disease relapse and VE-CLND was not associated with melanoma-specific death.CONCLUSIONS:VE-SLNB and VE-CLND neither improved nor worsened the clinical outcome of patients. Thus, timing of SLNB and CLND has no influence on the overall clinical outcome of patients with melanoma. Our findings support the rational planning of lymph node surgery after resection of the primary tumour and provide help for effective patient counselling.

Background The role of T regulatory lymphocytes (Tregs) and their immunosuppressive mechanisms in the context of programmed death (PD)-1 blockade is not completely understood. Objectives To assess the impact of PD-1-blocking antibody treatment on Treg subpopulations in the blood. Methods We studied circulating Treg subpopulations in patients with melanoma under nivolumab or pembrolizumab treatment using flow cytometry and correlated these findings with clinical outcomes. Results These analyses revealed that the frequency of CD4(+) CD25(++) CD127(-) PD-1(+) lymphocytes (PD-1(+) Tregs) significantly decreased after the first cycle of immunotherapy (23% vs. 8 center dot 6%, P = 0 center dot 043). Compared with patients who did not show a significant decline of PD-1(+) Tregs after the first treatment, those who did had better clinical outcomes with respect to progression-free survival (PFS, P = 0 center dot 022) and melanoma-specific death (MSD, P = 0 center dot 0038). Multivariate analysis confirmed that a significant decline of PD-1(+) Tregs in peripheral blood after the first treatment cycle is a significant predictor of more favourable PFS and MSD (P = 0 center dot 04 and 0 center dot 017, respectively). Interestingly, the occurrence of immune-related adverse events was also an independent predictor for decreased risk of MSD (P = 0 center dot 047; odds ratio 0 center dot 064, 95% confidence interval 0 center dot 0042-0 center dot 97). Conclusions We provide preliminary evidence that circulating PD-1(+) Tregs rapidly decline after the initiation of treatment with PD-1-blocking antibodies, which is associated with reduced risk of melanoma progression and MSD. Patients showing no decrease of these PD-1(+) Tregs in peripheral blood are characterized by an impaired response to immune checkpoint blockade and worse outcome. What's already known about this topic? Programmed death (PD)-1-blocking antibodies are highly effective in melanoma treatment. However, more than half of patients do not benefit from this therapy and to date it is difficult to predict which patients will respond to it. What does this study add? PD-1-blocking antibody therapy rapidly results in a decline of circulating PD-1(+) T regulatory cells (Tregs). What is the translational message? Patients showing a decrease of PD-1(+) Tregs appear to have better clinical outcome under PD-1 treatment.

For many decades and until recently, medical approach to dermatologic diseases has been based on the physician's ability to recognize and treat symptoms. Nowadays, advances in the understanding of the biology of diseases and in technologies for intervening against them have allowed physicians to diagnose and treat underlying disease processes rather than simply addressing the symptoms. This means that rather than addressing 'the disease in humans', physicians can now address the particular pathologic (biologic, molecular) disturbance as it presents in the individual patient, i.e., physicians now can practice something much closer to 'personalized medicine', leading to greater benefits for the patients and the health of society in general. The deeper understanding of ultraviolet radiation, the importance of photoprotection and increased knowledge about signalling pathways of melanoma and carcinoma have led to more complete care for the dermatologic patient. The current popularity for excessive exposure to the sun, without adequate application of the appropriate photoprotection remedies, is the origin of melanoma, but also for the weakening of the structure and functions of the skin. Indeed, fragility of the skin can affect humans around the world. In the senior population, this skin fragility is accompanied by pruritus, whereas atopic dermatitis is an inflammatory disease with highest prevalence in children and adolescents. Acne, the number one reason for dermatologic consultations worldwide, increases its prevalence in adolescents and in females. Senescent alopecia affects humans after menopause and andropause. The articles in this publication present an overview of the current advanced understanding of the diagnosis and therapeutic approaches in 6 fields of dermatology - dermatopaediatry and gerontodermatology, oncodermatology, hair loss, atopic dermatitis, photoprotection and acne - and thereby serve as a useful compendium of updated information and references for all healthcare professionals who see patients with presentations of the symptoms of these diseases.

Background: Melanoma of unknown primary (MUP) is an uncommon clinical subtype of melanoma of known primary (MKP).Objectives: We aimed to compare treatment outcomes of MUP and MKP patients who had undergone therapy with immune checkpoint inhibitors (ICPI).Methods: We studied 41 metastatic melanoma patients (32 with MKP and 9 with MUP) with an indication for ICPI.Results: Clinical characteristics such as age, gender, stage of disease, etc., did not significantly differ (P < .05) between MUP and MKP patients. 20/32 (62.5%) melanoma-specific deaths (MSD) were observed in the MKP group, whereas 2/9 (22.2%) were detected in the MUP group (P = .035). On logistic regression, the MUP status proved to be an independent predictor for a more favorable outcome under immunotherapy when compared to MKP (P = .030).Conclusion: Our preliminary results indicate that MUP patients show better clinical outcome under ICPI when compared to MKP.

Background Mutations in kinetochore gene KNSTRN accelerate the development of cutaneous squamous cell carcinoma (SCC) and may correlate with different histological classifications of actinic keratosis (AKs). Objective To determine KNSTRN gene mutation frequency in healthy skin (HS), actinically damaged skin (ADS), in AKs with different histomorphological gradings and invasive SCCs. Methods All samples were histologically evaluated. AK lesions were additionally classified according to their upwards (AK I-III) and downwards (PRO I-III) directed growth pattern. Mutation analyses of all samples were performed using the Sanger method. Results With one exception, all detected mutations in KNSTRN gene showed an alanine-to-glutamate substitution at codon 40 (p.Ala40Glu). p.Ala40Glu mutation was found in 6.9% (2/29) of HS, in 16.1% (5/31) of ADS, in 18.3% (20/109) of AKs and in 30.0% (9/30) of invasive SCCs. Further stratification of AKs using the common AK classification of Rowert-Huber revealed the p.Ala40Glu mutation in 14.7% (5/43), 13.3% (4/30) and 24.4% (11/45) (AK I, II and III). In contrast, the new PRO classification showed a distribution of 3.6% (1/28) in PRO I, 21.7% (13/60) in PRO II and 28.6% (6/21) in PRO III. Mutation frequency in HS showed significant differences compared to AKs classified as PRO III and invasive SCCs (P < 0.05). In contrast, there were no statistically significant differences between HS and AKs when classified according to Rowert-Huber. Conclusions Recurrent somatic mutation p.Ala40Glu in KNSTRN gene is associated with basal proliferating AKs in accordance with invasive SCCs. This supports the impact of basal proliferative pattern in terms of progression.

Journal of the European Academy of Dermatology and VenereologyVolume 33, Issue 12 p. e446-e447 Letter to the Editor Expression of indolamine-2,3-dioxygenase and cyclooxygenase-2 in different disease stages of cutaneous squamous cell carcinoma T. Gambichler, Corresponding Author T. Gambichler t.gambichler@klinikum-bochum.de orcid.org/0000-0001-7862-3695 Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanyCorrespondence: T. Gambichler. E-mail: t.gambichler@klinikum-bochum.deSearch for more papers by this authorL. Selke, L. Selke Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this authorI. Rüddel, I. Rüddel Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this authorM. Dreißigacker, M. Dreißigacker Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this authorE. Stockfleth, E. Stockfleth Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this authorL. Schmitz, L. Schmitz orcid.org/0000-0002-9627-2179 Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this author T. Gambichler, Corresponding Author T. Gambichler t.gambichler@klinikum-bochum.de orcid.org/0000-0001-7862-3695 Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanyCorrespondence: T. Gambichler. E-mail: t.gambichler@klinikum-bochum.deSearch for more papers by this authorL. Selke, L. Selke Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this authorI. Rüddel, I. Rüddel Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this authorM. Dreißigacker, M. Dreißigacker Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this authorE. Stockfleth, E. Stockfleth Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this authorL. Schmitz, L. Schmitz orcid.org/0000-0002-9627-2179 Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, GermanySearch for more papers by this author First published: 28 June 2019 https://doi.org/10.1111/jdv.15763Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume33, Issue12December 2019Pages e446-e447 RelatedInformation

Background Dysregulation of microRNAs (miRNAs) key regulators may contribute to the pathogenesis of malignancies. miRNA machinery genes such Dicer and Drosha have been reported to be biomarkers in different cancer types. Objectives We aimed to evaluate Drosha and Dicer protein expression in cutaneous T-cell lymphoma (CTCL). Methods We performed Drosha and Dicer immunohistochemistry in 45 patients with mycosis fungoides and subtypes. Drosha and Dicer expression scores were correlated with clinical parameters including disease-specific death (DSD), stage of disease and different laboratory data. Uni- and multivariate statistics were performed. Results On univariate analysis, elevated serum LDH and low Drosha expression were significantly associated with advanced stage (P = 0.032 and 0.0062, respectively) and lymphoma-specific death (LSD; P = 0.017 and P = 0.005, respectively). Moreover, elevated circulating CD4+/CD26- lymphocytes were significantly associated with advanced stage (P = 0.032) and DSD (P = 0.0098). On multivariate analysis, low Drosha expression remained in the logistic regression model as significant independent predictor for advanced disease stages [P = 0.013; odds ratio: 5 (confidence interval) CI 1.3-19.3]. Moreover, low Drosha expression (P = 0.026) and elevated LDH (P = 0.025) remained as significant independent predictors for DSD with odds ratios of 13.5 (CI 1.3-134.4 and 8.7 CI 1.3-57.2, respectively). Conclusions Low Drosha expression is an independent predictor for advanced stage as well as LSD in CTCL patients indicating a tumour suppressor gene function of Drosha in this disorder.

Background Actinic keratoses (AKs) can histologically be classified by the extent of atypical keratinocytes throughout the epidermis or their pattern of basal proliferation. Currently, no data on the inter-rater reliability of both scores is available. Objective To evaluate the inter-rater reliability of the two classification schemes; histological grade (AK I-III) and basal proliferation (PRO I-III). Methods Histological images of 54 AKs were classified by 21 independent dermatopathologists with regard to basal proliferation (PRO I-III), histological grade (AK I-III) and assumed risk of progression into invasive carcinoma. Results Overall, of the 54 AKs 16.7% (9/54) were classified as AK I, 66.7% (36/54) as AK II, and 16.7% (9/54) as AK III. With regards to basal growth pattern, 25.9% (14/54) were classified as PRO I, 42.6% (23/54) as PRO II, and 31.5% (17/54) as PRO III. We observed a highly significant inter-rater reliability for PRO-grading (P < 0.001) which was higher than for AK-grading (Kendall's W coefficient: AK = 0.488 vs. PRO = 0.793). We found substantial agreement for assumed progression risk for AKs with worsening basal proliferation (k = 0.759) compared to moderate agreement (k = 0.563) for different AK-gradings. Conclusions Histological classification of basal growth pattern (PRO) showed higher inter-rater reliability compared to the established classification of atypical keratinocytes throughout epidermal layers. Moreover, experienced dermatopathologists considered basal proliferation to be more important in terms of progression risk than upwards directed growth patterns. It should be considered to classify AKs according to their basal proliferation pattern (PRO I-III).

BackgroundKoebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event. ObjectivesTo study molecular pathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal. MethodsWe assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long-term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs. We performed immunohistochemistry for p53, p16, Ki-67, TET-2, IDH-2, 5-hmc and 5-mc. PCR was carried out for the detection of human papilloma viruses. Mutation analysis was performed for BRAF, K-RAS and EGFR. ResultsAll lesions investigated were negative for HPV DNA. Mutations were not detected. Healthy appearing skin of both patients showed relatively high Ki-67, p16 and p53 expression which was comparable to the expression observed in primary SCCs as well as K-SCCs. Protein expression of Ki-67, p16 and mutant p53 was barely detected in the specimens of the healthy controls. A decreased protein expression of TET-2 enzyme was seen in all tumours and healthy appearing skin when compared to the skin of healthy controls. ConclusionsWe observed two patients with K-SCCs developing under DMF treatment. In healthy appearing skin of patients with K-SCCs, wound healing processes, including induction of proliferation and growth factor release, might promote the growth of preneoplastic keratinocytes and cancer formation on the basis of pre-existing altered epigenetic pathways and cell cycle dysregulation. Although fumarates can reduce TET-2 expression, the role of DMF intake in the development of K-SCCs remains unclear.