Incidence and survival of cutaneous melanoma in Belgium and the Netherlands from 2004 to 2016: striking differences and similarities of two neighbouring countries.

BACKGROUND: Cutaneous melanoma (CM) is a multifactorial disease, with both environmental and genetic factors involved. The incidence of CM has risen rapidly during the last decades, making it a growing public health problem. OBJECTIVES: The purpose of this retrospective study was to compare incidence and survival data of CM between two neighbouring countries, Belgium (BE) and the Netherlands (NL). METHODS: Data were collected by the Belgian Cancer Registry (BCR) and the Netherlands Cancer Registry (NCR) from 1 January 2004 until 31 December 2016. Mucosal melanoma, in situ CM and melanoma in children from 0 to 14 years were excluded. Age-standardized incidence rates were calculated using the World Standard Population (WSR) per 100 000 persons. Five-year relative survival ratios were calculated using the Ederer II methodology. RESULTS: Total number of CM was higher in NL (63 789) compared with BE (27 679). The WSR was 1.5 times higher in NL compared with BE (27.7 vs. 18.6/100 000/year). The WSR of stage IV tumours was higher in BE than in NL (0.3 vs. 0.2/100 000/year). Five-year relative survival of stage IV tumours was higher in BE compared with NL (27.2% vs. 13.7%). CONCLUSIONS: Incidence of CM was higher in NL, indicating a higher risk of CM diagnosis. Stage IV tumours were relatively more frequent in BE for both sexes, while relative survival of stage IV tumours was higher in BE. As geographical location and latitude of both neighbouring countries are almost identical, other factors like differences in behaviour, follow-up and/or treatment may explain these differences.

Lesion-directed screening to optimize skin cancer detection in dermatology practice: an observational study.

BACKGROUND: Early detection of skin cancer is still a major challenge in dermatology practice today. While surveillance programs are offered to high-risk patients, systematic total-body examination (TBE) in the general population is not cost-effective. In the past, we demonstrated that a lesion-directed screening (LDS) in the general population delivered similar detection rates to TBE and was less time-consuming. OBJECTIVES: To study whether a lesion-directed early-access consultation can optimize skin cancer detection in dermatology practice. METHODS: In this observational study, we offered an early-access consultation in patients contacting the dermatology department concerning 1 or 2 lesions of concern meeting predefined criteria. RESULTS: 342 persons were seen at the dermatology department after triage by phone. Skin cancer detection rate was 13.2% (4.1% for melanoma). If advised/referred by a doctor skin cancer detection rate was 23.6% (9% for melanoma). With a history of skin cancer, detection rate was 24.3% (4.3% for melanoma). In patients with no referral and a negative history of skin cancer, detection rate was 7.7% (1.7% for melanoma), which is at least triple the rates reported by population-based screening programs. In patients in whom the index lesion was benign, worry of having skin cancer had decreased significantly by the end of the consultation. Additional total-body examination in these patients had low additional detection rate (0.5%) and a high number of unnecessary excisions (number needed to excise 13). CONCLUSIONS: An early-access dermatology consultation for LDS after triage by phone resulted in high overall skin cancer and melanoma detection rates. Our data indicate that performing TBE is especially useful if the index lesion is suspicious. In addition to surveillance programs in high-risk patients, LDS may be a way to optimize skin cancer detection in the general population and use available time more efficiently in daily dermatology practice.

Chemoprevention of basal cell carcinoma: reply from authors.

The review started from the question whether early detection of BCC in the general (asymptomatic) population could lead to any benefit in terms of outcome and cost. In other words, should early detection efforts for skin cancer (secondary prevention) also include BCC? Review of available literature suggests that early detection and adequate treatment of BCC of the face could increase cost-effectiveness. Although these results could also pertain to patients who have had already a history of BCC, their setting is different since they may already be in a follow-up programme (tertiary prevention). This article is protected by copyright. All rights reserved.

Is early detection of basal cell carcinoma worthwhile? Systematic review based on the WHO criteria for screening.

The incidence of basal cell carcinoma (BCC) has risen three- to fourfold over the last 30 years and is expected to continue to increase with ageing of the population. Although BCC has a good prognosis, it causes significant morbidity and has an important impact on the public health budget due to direct treatment costs. Based on the existing evidence, a systematic evaluation of the World Health Organization criteria was performed to determine whether earlier detection of BCC could reduce morbidity and cost. BCC slowly increases in size, with a median increase in diameter of 0·5 mm over 10 weeks. There is an important delay in diagnosis ranging from 19 to 25 months. In several studies BCC size was the main determinant of treatment cost, surgical complexity, reconstruction technique and the specific surgical procedure performed, such as Mohs micrographic surgery or surgical excision. One study showed that size also seems to affect the cost per treatment for other nonsurgical options. The use of vismodegib, an inhibitor of the hedgehog pathway, is confined to locally advanced or metastatic BCC. Delays in diagnosis and appropriate treatment are the most important underlying causes in the occurrence of giant BCC and/or BCC with metastasis. Although the latter represent only a very small fraction of all BCCs, the majority of them are located in the facial region. The available data point to a slow increase in the size of BCCs over time. Size is one of the major determinants in choice of treatment and the associated cost, especially for facial BCC. Therefore we conclude that current data support early detection and adequate management of BCCs on the face.

Rosettes and other white shiny structures in polarized dermoscopy: histological correlate and optical explanation.

BACKGROUND: Rosettes are a specific form of a white shiny structure seen with polarized dermoscopy. The precise morphological correlate and optical explication are not known. OBJECTIVE: To estimate the frequency of rosettes in ex vivo dermoscopy and to find explication and morphologic correlate of this dermoscopic feature. METHODS: A series of 6108 consecutive skin biopsies were examined with ex vivo dermoscopy and when rosettes were present serial transverse sections with polarization were examined. RESULTS: In this series of 6108 consecutive skin biopsies, rosettes were found on ex vivo dermoscopy in 63 cases. When multiple we observed that they are always oriented at the same angle. Transverse sections with polarization of these lesions proved that smaller rosettes are mainly caused by polarizing horny material in adnexal openings, and larger rosettes by concentric perifollicular fibrosis. CONCLUSIONS: Rosettes are an optical effect of crossed polarization by concentric fibrosis or horny material and hence are not lesion-specific.

Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma.

In melanoma, both the induction of immunosuppression by tumor cells and the inflammatory antitumor response can induce an upregulation of counter-regulatory mechanisms such as indoleamine 2,3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1) and CTLA-4+ regulatory T-cells (Tregs) in the tumor microenvironment. Even though these immunosuppressive mediators are targets for immunotherapy, research investigating their expression in the peripheral blood is lacking. We therefore, performed flow cytometry on PBMCs of stage I-IV melanoma patients. IDO expression was detected in plasmacytoid dendritic cells (pDC) and monocytic myeloid-derived suppressor cells (mMDSC), and increased in advanced disease stage (p = 0.027). Tryptophan breakdown confirmed the functional activity of IDO and was linked with increased PD-L1+ cytotoxic T-cells (p = 0.009), relative lymphopenia (p = 0.036), and a higher mDC/pDC ratio (p = 0.002). High levels of circulating PD-L1+ cytotoxic T-cells were associated with increased CTLA-4 expression by Tregs (p = 0.005) and MDSC levels (p = 0.033). This illustrates that counter-regulatory immune mechanisms in melanoma should be considered as one interrelated signaling network. Moreover, both increased PD-L1+ T-cells and CTLA-4 expression in Tregs conferred a negative prognosis, indicating their in vivo relevance. Remarkably, circulating CTLA-4, IDO, and pDC levels were altered according to prior invasion of the sentinel lymph node and IDO expression in the sentinel was associated with more IDO+ PBMCs. We conclude that the expression of IDO, PD-L1, and CTLA-4 in the peripheral blood of melanoma patients is strongly interconnected, associated with advanced disease and negative outcome, independent of disease stage. Combination treatments targeting several of these markers are therefore likely to exert a synergistic response.

Peritumoral indoleamine 2,3-dioxygenase expression in melanoma: an early marker of resistance to immune control?

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an emerging immunomodulating factor in cancer. IDO expression in tumour-negative sentinel lymph nodes (SLNs) of patients with melanoma has a negative prognostic value. OBJECTIVES: To analyse the expression pattern of IDO and associated immunological changes in corresponding primary melanomas (PMs), SLNs and metastases. METHODS: In 120 patients with melanoma, PMs with corresponding SLNs (n = 85) and metastases (n = 18) were analysed by immunohistochemical staining for IDO and FoxP3. Tumour-infiltrating lymphocytes (TILs) were scored. IDO expression in stimulated peripheral blood mononuclear cells (PBMCs) was analysed in 27 patients. RESULTS: IDO expression in the sentinel node strongly correlated with endothelial IDO expression in the peritumoral stroma of the corresponding primary (P < 0·001) and metastatic melanoma (P < 0·05). Sentinel IDO positivity was inversely correlated with CD8+ lymphocytes (P = 0·01) and TILs (P = 0·05) in PM. Both IDO expression in the sentinel (P < 0·01) and the PM (P = 0·04) had a negative prognostic effect on overall survival, independent of Breslow thickness, sex, age, ulceration and sentinel invasion. IDO expression by PBMCs after stimulation with cytotoxic T-lymphocyte antigen 4 was not correlated with sentinel IDO expression but tended to correlate with disease stage (P = 0·04). CONCLUSIONS: Endothelial IDO expression is highly consistent in primary, sentinel and metastatic tissues of patients with melanoma, indicating that immune suppression in melanoma is determined very early in the disease course. This supports that IDO expression in melanoma is a marker of antitumour immune response with an independent prognostic value.

A cross-sectional study on the prevalence of metabolic syndrome in psoriasis compared to psoriatic arthritis.

BACKGROUND: Increasing epidemiological evidence suggests associations between psoriasis, psoriatic arthritis (PsA) and metabolic disease. Elucidating the complex relationship between these comorbidities may have important management implications. OBJECTIVE: The aim of this study was to examine the difference in prevalence of metabolic disease burden between patients with psoriasis who lack arthritic manifestations (PsO) and PsA patients. METHODS: We performed a cross-sectional study in 123 patients with PsO and PsA. Metabolic syndrome was defined using the new criteria developed by the International Diabetes Foundation (IDF) in 2004. Therefore, clinical examination and standard survey were performed and fasting blood samples were collected. RESULTS: One hundred and four patients were analysed, of which 49 were PsO and 55 were PsA patients. We found that prevalence of the metabolic syndrome according to the IDF criteria was significantly higher in the PsO (44.9%) compared with the PsA group (25.5%) (P = 0.037). Looking closer at the individual components of the metabolic syndrome, this difference can mainly be attributed to the significantly higher prevalence of abdominal obesity in PsO (83.7%) vs. PsA (65.5%) (P = 0.034). For other individual components of the metabolic syndrome such as triglycerides, high-density lipoproteins, hypertension and plasma glucose, we could not show statistically significant differences between the groups. CONCLUSION: Metabolic syndrome is more prevalent in patients with PsO than in PsA patients, mainly determined by the higher prevalence of abdominal obesity in PsO compared with PsA group.

Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression.

Deregulation of signaling pathways that control differentiation, expansion and migration of neural crest-derived melanoblasts during normal development contributes also to melanoma progression and metastasis. Although several epithelial-to-mesenchymal (EMT) transcription factors, such as zinc finger E-box binding protein 1 (ZEB1) and ZEB2, have been implicated in neural crest cell biology, little is known about their role in melanocyte homeostasis and melanoma. Here we show that mice lacking Zeb2 in the melanocyte lineage exhibit a melanoblast migration defect and, unexpectedly, a severe melanocyte differentiation defect. Loss of Zeb2 in the melanocyte lineage results in a downregulation of the Microphthalmia-associated transcription factor (Mitf) and melanocyte differentiation markers concomitant with an upregulation of Zeb1. We identify a transcriptional signaling network in which the EMT transcription factor ZEB2 regulates MITF levels to control melanocyte differentiation. Moreover, our data are also relevant for human melanomagenesis as loss of ZEB2 expression is associated with reduced patient survival.

Clinical profile of generalized vitiligo patients with associated autoimmune/autoinflammatory diseases.

BACKGROUND: The significance of associated autoimmune/autoinflammatory diseases in generalized vitiligo patients with respect to their clinical profile has not yet been completely established. OBJECTIVE: The objective of this study was to evaluate the clinical significance of associated autoimmune/autoinflammatory diseases in generalized vitiligo patients with respect to some general clinical variables, distribution pattern, disease activity and treatment response. METHODS: Seven hundred generalized vitiligo patients were included in this retrospective observational cohort study. RESULTS: Associated autoimmune/autoinflammatory diseases were present in 15.4% of the patient population and were more common in women compared with men, especially concerning thyroid disease. Only vitiligo patients with thyroid disease had clear different clinical characteristics. The percentage of total body surface area involvement was significantly (P = 0.005) higher in the presence of thyroid disease which was more pronounced in women compared with men. Patients with thyroid disease had a particular predisposition to acral and joint depigmentations. No clear differences in disease activity or response to therapy were observed in vitiligo patients with or without autoimmune/autoinflammatory disorders. CONCLUSION: The presence of associated autoimmune/autoinflammatory diseases seems to influence the clinical profile of generalized vitiligo patients. Our results support the hypothesis that in the presence of a thyroid disorder, the disease activity of vitiligo is more extensive, in particular on areas prone to friction.

The distribution pattern of segmental vitiligo: clues for somatic mosaicism.

BACKGROUND: Segmental vitiligo is characterized by a unilateral and localized distribution. So far, the underlying mechanism is still an enigma. OBJECTIVES: To get an insight into the aetiopathogenesis of segmental vitiligo by comparison with the distribution pattern of dermatoses with a possible mosaic or neurogenic background. METHODS: In this retrospective observational study the distribution pattern of 724 unilateral, linear or band-shaped control lesions was compared with 181 segmental vitiligo lesions. Clinical photographs were used to score similarities according to a defined grading system (scale ranging from 0 for no similarities to 4 for complete similarity). Control lesions were evaluated both individually and after grouping into different cell types. RESULTS: In general, only a minority of cases (36·9%), showed similarities (grade 1-4) between control lesions and segmental vitiligo. Grade 2-4 similarities were seen mainly in segmental lentiginosis (73·7%, P < 0·001). The best grade for correspondence (grade 3-4) was observed significantly more only in segmental lentiginosis (36·8% vs. 3·5%, P<0·001) and epidermal naevus verrucosus (12·5% vs. 3·7%, P=0·008) compared with the other control lesions. The distribution pattern of segmental vitiligo significantly overlapped those of other disorders originating from melanocytes. CONCLUSIONS: Our results demonstrate that the distribution pattern of segmental vitiligo is not entirely similar to any other skin disease, although some mosaic skin disorders have more overlap with segmental vitiligo than others. The remarkable clinical similarity with several cases of mosaic diseases involving melanocytes supports the hypothesis that cutaneous mosaicism may be involved in segmental vitiligo.

Clinical significance of Koebner phenomenon in vitiligo.

BACKGROUND: The clinical significance of Koebner phenomenon (KP) in vitiligo with respect to disease activity and course is still debatable. Recently, a new classification was introduced for the assessment of KP. OBJECTIVES: To evaluate the new assessment method for KP in clinical practice and to determine its clinical significance, both with respect to the clinical profile, course of vitiligo and treatment response. METHODS: Seven hundred patients with generalized vitiligo were included in this observational cohort study. KP was classified according to the new classification system into different subtypes [KP1, by history; KP2A and KP2B, by clinical examination (A, lesions on friction areas; B, linear, artefactual lesions)]. RESULTS: KP1 was positive in 34·1% of the patients, 66·3% were KP2A positive and 15·1% showed KP2B. The body surface area (BSA) was significantly (P < 0·001) higher in the presence of any KP subtype and more disease activity was found in KP1-positive and KP2B-positive patients. An earlier age at onset and elevated risk of further depigmentation despite treatment were observed in all KP-positive groups. In KP2A- and KP2B-positive patients, depigmentation of wrists/ankles was more common. In the KP2A-positive group, a significantly higher prevalence of thyroid disease was found while autoimmune diseases were less prevalent in KP2B-positive patients. CONCLUSION: The new assessment method for KP, taking into account both history and clinical examination, seems to be a useful and valuable tool for assessing KP in daily practice. Our results support the hypothesis that KP may function as a clinical parameter to assess and predict the clinical profile and course of vitiligo.

The haptoglobin phenotype influences the risk of cutaneous squamous cell carcinoma in kidney transplant patients.

BACKGROUND: Cutaneous squamous cell carcinoma (SCC) is the most frequent skin cancer after organ transplantation. Currently, the pre-identification of transplant patients at increased risk for non-melanoma skin cancer remains difficult. OBJECTIVE: To investigate the Hp polymorphism as a marker for the identification of a subset of patients with an increased susceptibility to develop SCC/Bowen's disease. METHODS: Haptoglobin phenotyping was performed with haemoglobin-supplemented starch gel electrophoresis in 300 kidney transplant patients. High-performance gel permeation chromatography was used in case of low serum haptoglobin concentration. RESULTS: Cox regression analysis (adjusted for age, gender and Mediterranean origin) showed a significant association of the Hp 1-1 phenotype with a higher risk of SCC/Bowen's disease (P = 0.035) and multiple primary SCCs (P = 0.002). No significant difference between the Hp phenotypes was found for the development of Bowen's disease and SCCs in the first 10 years following renal transplantation. However, after a follow-up of >10 years, a significant association between the Hp 1-1 phenotype and the occurrence of Bowen's disease and SCC was reported (P = 0.002 and P = 0.001 respectively). CONCLUSIONS: This study shows an increased risk for the development of (multiple) SCCs in kidney transplant patients with the Hp 1-1 phenotype. This finding points to the role of Hp 1-1 phenotype as an important predictor in identifying a subset of patients with an increased need for preventive measures and is in agreement with the decreased anti-inflammatory capacity of this phenotype.

New insights in segmental vitiligo: case report and review of theories.

Segmental vitiligo and generalized vitiligo are in general considered to be separate entities. The aetiopathogenesis of segmental vitiligo remains unclear, although several hypotheses have been put forward including mainly neuronal mechanisms. The typical association with other autoimmune diseases, as seen in generalized vitiligo, seems to be significantly less in segmental vitiligo, although recent insights point towards a possible immune-mediated overlap between the two subtypes. In this article, we describe a case with simultaneous presence of segmental vitiligo, alopecia areata, psoriasis and a halo naevus. To our knowledge, this is the first case with this exceptional combination. This concomitant presence could support the involvement of a shared autoimmune-mediated process, and may provide new insights into the pathogenesis of segmental vitiligo and direct future research. In the light of this remarkable case, different possible aetiopathogenetic mechanisms leading to the clinical presentation of segmental vitiligo are discussed and a new three-step theory is proposed.

Halo naevi with associated vitiligo-like depigmentations: pathogenetic hypothesis.

BACKGROUND: In analogy with melanoma-associated leucoderma, halo naevi may trigger in some patients the development of additional depigmentations which are in distribution, extent and prognosis not in accordance with classic vitiligo. OBJECTIVE: The aim of this study was to support the hypothesis that in a subset of halo naevi patients vitiligo-like lesions develop directly linked to the halo phenomenon. METHODS: Forty-one patients with halo naevi were examined for the development of depigmentations not corresponding to typical vitiligo lesions. RESULTS: We identified a subset of five halo naevi patients with additional subtle depigmentations. After the occurrence of multiple halo naevi, they developed leucoderma that showed a different disease pattern than vitiligo (variable asymmetric distribution, limited extent and lack of progression). Moreover, the characteristics of these halo naevi patients with associated leucoderma were different from classic vitiligo patients (high number of halo naevi, absence of family history for vitiligo and absence of autoimmune diseases) and the timing of occurrence of the leucoderma suggested a direct relation with the halo phenomenon. CONCLUSIONS: In this article, we describe in a limited subset of patients with multiple halo naevi discrete depigmentations at distance from halo naevi which may result from a temporary autoimmune process directly linked to the halo phenomenon. This finding illustrates the collateral damage resulting from skin immunosurveillance and may have clinical consequences as the evolution pattern in this subset of patients is less progressive compared with vitiligo. We present clinical data that support this hypothesis and suggest to call it 'halo naevi-associated leucoderma'.