The difficulty with measuring the largest melanoma tumour diameter in sentinel lymph nodes.

Identification of sentinel node (SN) metastases can set the adjuvant systemic therapy indication for stage III melanoma patients. For stage IIIA patients, a 1.0 mm threshold for the largest SN tumour diameter is used. Therefore, uniform reproducible measurement of its size is crucial. At present, the number of deposits or their microanatomical sites are not part of the inclusion criteria for adjuvant treatment. The goal of the current study was to show examples of the difficulty of measuring SN melanoma tumour diameter and teach how it should be measured. Histopathological slides of SN-positive melanoma patients were retrieved using the Dutch Pathology Registry (PALGA). Fourteen samples with the largest SN metastasis around 1.0 mm were uploaded via tele-pathology and digitally measured by 12 pathologists to reflect current practice of measurements in challenging cases. Recommendations as educational examples were provided. Microanatomical location of melanoma metastases was 1 subcapsular, 2 parenchymal and 11 combined. The smallest and largest difference in measurements were 0.24 mm and 4.81 mm, respectively. 11/14 cases (78.6%) showed no agreement regarding the 1.0 mm cut-off. The median discrepancy for cases ≤5 deposits was 0.5 mm (range 0.24-0.60, n=3) and 2.51 mm (range 0.71-4.81, n=11) for cases with ≥6 deposits. Disconcordance in measuring SN tumour burden is correlated with the number of deposits. Awareness of this discordance in challenging cases, for example, cases with multiple small deposits, is important for clinical management. Illustrating cases to reduce differences in size measurement are provided.

Cumulative incidence and timing of subsequent cutaneous squamous cell carcinomas stratified for patients with organ transplantation and hematologic malignancies: A nationwide cohort study.

BACKGROUND: There is lack of nationwide data on the cumulative incidence and timing of subsequent cutaneous squamous cell carcinomas (cSCCs) among patients with a first cSCC. OBJECTIVE: To investigate the cumulative incidence and timing of subsequent cSCCs. METHODS: Patients with a first cSCC in 2007/2008 from the Netherlands Cancer Registry were linked to the Netherlands Pathology Registry for subsequent cSCCs and the Netherlands Organ Transplant Registry. Cumulative incidence function curves were calculated for subsequent cSCCs and stratified for immune status. RESULTS: Among the 12,345 patients, second to sixth cSCC occurred in 4325, 2010, 1138, 739, and 501 patients, with median time intervals of 1.4, 1.2, 0.9, 0.6, and 0.5 years after the previous cSCC, respectively. The cumulative incidence of a subsequent cSCC at 5 years increased from 28% to 67% for the second to sixth cSCC. For solid organ transplant recipients, the cumulative incidences increased from 74% to 92% and from 41% to 64% for patients with hematologic malignancy. LIMITATIONS: Only histopathologically confirmed cSCCs were included. CONCLUSION: The risk of a subsequent cSCC steeply rises with the number of prior cSCCs and immune status, while the time interval decreases. This can support more informed decisions about follow-up management.

Genetic Concordance in Primary Cutaneous Melanoma and Matched Metastasis: A Systematic Review and Meta-Analysis.

Studying primary melanoma and its corresponding metastasis has twofold benefits. Firstly, to better understand tumor biology, and secondly, to determine which sample should be examined in assessing drug targets. This study systematically analyzed all the literature on primary melanoma and its matched metastasis. Following PRISMA guidelines, we searched multiple medical databases for relevant publications from January 2000 to December 2022, assessed the quality of the primary-level studies using the QUIPS tool, and summarized the concordance rate of the most reported genes using the random-effects model. Finally, we evaluated the inter-study heterogeneity using the subgroup analysis. Thirty-one studies investigated the concordance of BRAF and NRAS in 1220 and 629 patients, respectively. The pooled concordance rate was 89.4% [95% CI: 84.5; 93.5] for BRAF and 97.8% [95% CI: 95.8; 99.4] for NRAS. When high-quality studies were considered, only BRAF mutation status consistency increased. Five studies reported the concordance status of c-KIT (93%, 44 patients) and TERT promoter (64%, 53 patients). Lastly, three studies analyzed the concordance of cancer genes involved in the signaling pathways, apoptosis, and proliferation, such as CDKN2A (25%, four patients), TP53 (44%, nine patients), and PIK3CA (20%, five patients). Our study found that the concordance of known drug targets (mainly BRAF) during melanoma progression is higher than in previous meta-analyses, likely due to advances in molecular techniques. Furthermore, significant heterogeneity exists in the genes involved in the melanoma genetic makeup; although our results are based on small patient samples, more research is necessary for validation.

Clinical evaluation of the clinicopathologic and gene expression profile (CP-GEP) in patients with melanoma eligible for sentinel lymph node biopsy: A multicenter prospective Dutch study.

Sentinel lymph node biopsy (SLNB) is recommended for patients with >pT1b cutaneous melanoma, and should be considered and discussed with patients diagnosed with pT1b cutaneous melanoma for the purpose of staging, prognostication and determining eligibility for adjuvant therapy. Previously, the clinicopathologic and gene expression profile (CP-GEP, Merlin Assay®) model was developed to identify patients who can forgo SLNB because of a low risk for sentinel node metastasis. The aim of this study was to evaluate the clinical use and implementation of the CP-GEP model in a prospective multicenter study in the Netherlands. Both test performance and feasibility for clinical implementation were assessed in 260 patients with T1-T4 melanoma. The CP-GEP model demonstrated an overall negative predictive value of 96.7% and positive predictive value of 23.7%, with a potential SLNB reduction rate of 42.2% in patients with T1-T3 melanoma. With a median time of 16 days from initiation to return of test results, there was sufficient time left before the SLNB was performed. Based on these outcomes, the model may support clinical decision-making to identify patients who can forgo SLNB in clinical practice.

Personalised decision making to predict absolute metastatic risk in cutaneous squamous cell carcinoma: development and validation of a clinico-pathological model.

Background: Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer, affecting more than 2 million people worldwide yearly and metastasising in 2-5% of patients. However, current clinical staging systems do not provide estimates of absolute metastatic risk, hence missing the opportunity for more personalised treatment advice. We aimed to develop a clinico-pathological model that predicts the probability of metastasis in patients with cSCC. Methods: Nationwide cohorts from (1) all patients with a first primary cSCC in The Netherlands in 2007-2008 and (2) all patients with a cSCC in 2013-2015 in England were used to derive nested case-control cohorts. Pathology records of primary cSCCs that originated a loco-regional or distant metastasis were identified, and these cSCCs were matched to primary cSCCs of controls without metastasis (1:1 ratio). The model was developed on the Dutch cohort (n = 390) using a weighted Cox regression model with backward selection and validated on the English cohort (n = 696). Model performance was assessed using weighted versions of the C-index, calibration metrics, and decision curve analysis; and compared to the Brigham and Women's Hospital (BWH) and the American Joint Committee on Cancer (AJCC) staging systems. Members of the multidisciplinary Skin Cancer Outcomes (SCOUT) consortium were surveyed to interpret metastatic risk cutoffs in a clinical context. Findings: Eight out of eleven clinico-pathological variables were selected. The model showed good discriminative ability, with an optimism-corrected C-index of 0.80 (95% Confidence interval (CI) 0.75-0.85) in the development cohort and a C-index of 0.84 (95% CI 0.81-0.87) in the validation cohort. Model predictions were well-calibrated: the calibration slope was 0.96 (95% CI 0.76-1.16) in the validation cohort. Decision curve analysis showed improved net benefit compared to current staging systems, particularly for thresholds relevant for decisions on follow-up and adjuvant treatment. The model is available as an online web-based calculator (https://emc-dermatology.shinyapps.io/cscc-abs-met-risk/). Interpretation: This validated model assigns personalised metastatic risk predictions to patients with cSCC, using routinely reported histological and patient-specific risk factors. The model can empower clinicians and healthcare systems in identifying patients with high-risk cSCC and offering personalised care/treatment and follow-up. Use of the model for clinical decision-making in different patient populations must be further investigated. Funding: PPP Allowance made available by Health-Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships.

Oncological Outcome After Lymph Node Dissection for Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Although cutaneous squamous cell carcinoma (cSCC) is common, lymph node metastases are relatively rare and are usually treated with lymph node dissection (LND). The aim of this study was to describe the clinical course and prognosis after LND for cSCC at all anatomical locations. METHODS: A retrospective search at three centres was performed to identify patients with lymph node metastases of cSCC who were treated with LND. Prognostic factors were identified by uni- and multivariable analysis. RESULTS: A total of 268 patients were identified with a median age of 74. All lymph node metastases were treated with LND, and 65% of the patients received adjuvant radiotherapy. After LND, 35% developed recurrent disease both locoregionally and distantly. Patients with more than one positive lymph node had an increased risk for recurrent disease. 165 (62%) patients died during follow-up of whom 77 (29%) due to cSCC. The 5-year OS- and DSS rate were 36% and 52%, respectively. Disease-specific survival was significantly worse in immunosuppressed patients, patients with primary tumors >2cm and patients with more than one positive lymph node. CONCLUSIONS: This study shows that LND for patients with lymph node metastases of cSCC leads to a 5-year DSS of 52%. After LND, approximately one-third of the patients develop recurrent disease (locoregional and/or distant), which underscores the need for better systemic treatment options for locally advanced cSCC. The size of the primary tumor, more than one positive lymph node, and immunosuppression are independent predictors for risk of recurrence and disease-specific survival after LND for cSCC.

Hedgehog pathway mutations are involved in the pathogenesis of plaque-type "trichoblastoma": A report of two cases.

We present two cases of plaque-type trichoblastoma with atypical foci. A rare variant of trichoblastoma is the plaque variant, which is characterized by poor circumscription and locally infiltrative growth pattern. These lesions mostly require multiple stages of Mohs micrographic surgery. Debate still exists whether this variant should be considered as a benign entity or as "low-grade" malignant counterpart of trichoblastoma. In this report we describe two cases of plaque-type trichoblastoma with atypical foci, which harbored somatic mutations in the Hedgehog pathway, thus should be acknowledged as intermediate malignancies. In addition, extensive molecular workup of both the trichoblastic and atypical component in sequential lesions in the same patient was performed.

Ambiguous melanocytic lesions: A retrospective cohort study of incidence and outcome of melanocytic tumor of uncertain malignant potential (MELTUMP) and superficial atypical melanocytic proliferation of uncertain significance (SAMPUS) in the Netherlands.

BACKGROUND: Melanocytic tumor of uncertain malignant potential (MELTUMP) and superficial atypical melanocytic proliferation of uncertain significance (SAMPUS) are descriptive and provisional terms for melanocytic tumors with ambiguous histopathological features that are not easily classified as either benign or malignant. OBJECTIVE: To investigate the incidence and clinical outcome of MELTUMP and SAMPUS in the Netherlands. METHODS: In this retrospective cohort study, we reviewed all diagnoses of MELTUMP and SAMPUS from the Dutch Nationwide Pathology Databank from 1991 to October 1, 2021. Clinical outcome was studied for cases diagnosed until October 1, 2018. RESULTS: A total of 1685 MELTUMP and 1957 SAMPUS were identified with an annual incidence of 150 to 300 cases. Metastatic behavior was seen in 0.7% of all initially diagnosed MELTUMP. All SAMPUS remained free of metastases. LIMITATIONS: Reassessment of pathology slides and confirmation of clonality between primary and metastatic lesions remained outside the scope of this study. CONCLUSION: Despite the 'uncertainty' in the nomenclature, our results demonstrate a low malignant potential for MELTUMP and no malignant potential for SAMPUS. We emphasize the importance of consultation for ambiguous melanocytic lesions and to limit the MELTUMP/SAMPUS terminology to legitimately uncertain or unclassifiable cases.

Development and Validation of an Algorithm to Identify Patients with Advanced Cutaneous Squamous Cell Carcinoma from Pathology Reports.

To facilitate nationwide epidemiological research on advanced cutaneous squamous cell carcinoma (cSCC), that is, locally advanced, recurrent, or metastatic cSCC, we sought to develop and validate a rule-based algorithm that identifies advanced cSCC from pathology reports. The algorithm was based on both hierarchical histopathological codes and free text from pathology reports recorded in the National Pathology Registry. Medical files from the Erasmus Medical Center of 186 patients with stage III/IV/recurrent cSCC and 184 patients with stage I/II cSCC were selected and served as the gold standard to assess the performance of the algorithm. The rule-based algorithm showed a sensitivity of 91.9% (95% confidence interval = 88.0‒95.9), a specificity of 96.7% (95% confidence interval = 94‒2-99.3), and a positive predictive value of 78.5% (95% confidence interval = 74.2‒82.8) for all advanced cSCC combined. The sensitivity was lower per subgroup: locally advanced (52.3‒86.2%), recurrent cSCC (23.3%), and metastatic cSCC (70.0%). The specificity per subgroup was above 97%, and the positive predictive value was above 78%, with the exception of metastatic cSCC, which had a positive predictive value of 62%. This algorithm can be used to identify advanced patients with cSCC from pathology reports and will facilitate large-scale epidemiological studies of advanced cSCC in the Netherlands and internationally after external validation.

A Scoping Review and Population Study Regarding Prevalence and Histopathology of Juvenile Vulvar Melanocytic Lesions. A Recommendation.

Cases of vulvar melanocytic lesions in juveniles are rarely reported. We analyze the evidence regarding vulvar melanocytic lesions in juveniles with or without vulvar lichen sclerosus to help decision making by clinicians and pathologists. A scoping review on vulvar melanocytic lesions with or without vulvar lichen sclerosus, including malignant vulvar melanomas, in females up to age 18 years was performed. In addition, the histopathology records of the cohort of all such lesions in The Netherlands from 1991 through 2020 were investigated, and a structured analysis of tissue samples of the subset of cases with lichen sclerosus was performed. The literature study performed confirms that vulvar melanomas in juveniles are extremely rare and that published case reports are often disputed. In The Netherlands, there are no cases of malignant vulvar melanomas up to age 18 years recorded from 1991 through 2020. Atypical histopathological features are often found in biopsies of vulvar nevi in juveniles, especially with concomitant lichen sclerosus, confirming earlier case studies in the literature. We conclude that even with atypical findings, vulvar melanocytic lesions in juveniles have a benign course. To avoid unnecessary and possibly mutilating procedures, we advise referral to an expert center and adaption of existing guidelines for vulvar melanocytic lesions in juveniles.

Using a Clinicopathologic and Gene Expression (CP-GEP) Model to Identify Stage I-II Melanoma Patients at Risk of Disease Relapse.

Background: The current standard of care for patients without sentinel node (SN) metastasis (i.e., stage I−II melanoma) is watchful waiting, while >40% of patients with stage IB−IIC will eventually present with disease recurrence or die as a result of melanoma. With the prospect of adjuvant therapeutic options for patients with a negative SN, we assessed the performance of a clinicopathologic and gene expression (CP-GEP) model, a model originally developed to predict SN metastasis, to identify patients with stage I−II melanoma at risk of disease relapse. Methods: This study included patients with cutaneous melanoma ≥18 years of age with a negative SN between October 2006 and December 2017 at the Sahlgrenska University Hospital (Sweden) and Erasmus MC Cancer Institute (The Netherlands). According to the CP-GEP model, which can be applied to the primary melanoma tissue, the patients were stratified into high or low risk of recurrence. The primary aim was to assess the 5-year recurrence-free survival (RFS) of low- and high-risk CP-GEP. A secondary aim was to compare the CP-GEP model with the EORTC nomogram, a model based on clinicopathological variables only. Results: In total, 535 patients (stage I−II) were included. CP-GEP stratification among these patients resulted in a 5-year RFS of 92.9% (95% confidence interval (CI): 86.4−96.4) in CP-GEP low-risk patients (n = 122) versus 80.7% (95%CI: 76.3−84.3) in CP-GEP high-risk patients (n = 413; hazard ratio 2.93 (95%CI: 1.41−6.09), p < 0.004). According to the EORTC nomogram, 25% of the patients were classified as having a 'low risk' of recurrence (96.8% 5-year RFS (95%CI 91.6−98.8), n = 130), 49% as 'intermediate risk' (88.4% 5-year RFS (95%CI 83.6−91.8), n = 261), and 26% as 'high risk' (61.1% 5-year RFS (95%CI 51.9−69.1), n = 137). Conclusion: In these two independent European cohorts, the CP-GEP model was able to stratify patients with stage I−II melanoma into two groups differentiated by RFS.

Histopathological characteristics are instrumental to distinguish monomorphic from polymorphic maculopapular cutaneous mastocytosis in children.

BACKGROUND: Mastocytosis is characterized by the accumulation of mast cells (MCs) in the skin or other organs, and can manifest at any age. A significant number of paediatric mastocytosis cases persist after puberty. In particular, monomorphic maculopapular cutaneous mastocytosis (mMPCM) is often persistent and associated with systemic mastocytosis. However, clinical differentiation of MPCM from polymorphic (p)MPCM can be difficult. AIM: To identify histopathological features that can help to distinguish mMPCM from other subtypes of paediatric mastocytosis. METHODS: This was a retrospective study using skin biopsies from patients with any subtype of mastocytosis. The localization and density of the MC infiltrate, MC morphology and expression of aberrant markers were evaluated and correlated with clinical characteristics. RESULTS: In total, 33 biopsies were available for evaluation from 26 children [(10 with mMPCM, 5 with mastocytoma, 3 with diffuse cutaneous mastocytosis (DCM), 8 with pMPCM)] and 7 adults with MPCM. The MC number was increased in all patients, but was higher in children than adults (P < 0.01). The presence of mMPCM was associated with sparing of the papillary dermis from MC infiltration, whereas MC density in the papillary dermis was highest in pMPCM and DCM (P < 0.01). The positive predictive value of the presence of a reticular MC infiltrate for mMPCM was 72.7% (95% CI 51.4-87.0), and the negative predictive value was 83.3% (95% CI 42.2-97.2). There were no relevant differences in the expression of CD2, CD25 or CD30 between the different subtypes. CONCLUSION: Skin histopathology might enhance the phenotypical differentiation of mMPCM from other subtypes in children, thereby increasing the accuracy of one's prognosis.

Histopathological and immunological spectrum in response evaluation of talimogene laherparepvec treatment and correlation with durable response in patients with cutaneous melanoma.

Talimogene laherparepvec (T-VEC) is an intralesional oncolytic virotherapy for patients with irresectable stage III-IVM1a cutaneous melanoma. Although this treatment is considered to mainly act through T cell-mediated mechanisms, prominent numbers of plasma cells after T-VEC treatment have been described. The aim was to investigate how often these plasma cells were present, whether they were relevant in the response to treatment, and if these or other histopathological features were associated with durable response to treatment. Histopathological (granulomas, perineural inflammation, etc.) and immunological features [e.g. B cells/plasma cells (CD20/CD138) and T cells (CD3,CD4,CD8)] were scored and correlated with durable tumor response [i.e. complete response (CR) persisting beyond 6 months after treatment]. Plasmacellular infiltrate was examined with next-generation sequencing and immunohistochemistry (IgG, IgM, IgA, and IgD). Plasma cells were present in all T-VEC injected biopsies from 25 patients with melanoma taken at 3-5 months after starting treatment. In patients with a durable response ( n = 12), angiocentric features and granulomas were more frequently identified compared with patients without a (durable) response ( n = 13); 75% versus 29% for angiocentric features ( P = 0.015) and 58% versus 15% for granulomas ( P = 0.041). There was a class switch of IgM to IgG with skewing to certain dominant Ig heavy chain clonotypes. An angiocentric granulomatous pattern in T-VEC injected melanoma lesions was associated with a durable CR (>6 months). Plasma cells are probably a relevant feature in the mechanism of response but were not associated with durable response.

Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy.

PURPOSE: Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown. METHODS: We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population-based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk. RESULTS: sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ2 = 46.7, P < .001). CONCLUSION: Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies.

Risk factors for metastatic cutaneous squamous cell carcinoma: Refinement and replication based on 2 nationwide nested case-control studies.

BACKGROUND: Risk factors for cutaneous squamous cell carcinoma (cSCC) metastasis have been investigated only in relatively small data sets. OBJECTIVE: To analyze and replicate risk factors for metastatic cSCC. METHODS: From English and Dutch nationwide cancer registry cohorts, metastatic cases were selected and 1:1 matched to controls. The variables were extracted from pathology reports from the National Disease Registration Service in England. In the Netherlands, histopathologic slides from the Dutch Pathology Registry were revised by a dermatopathologist. Model building was performed in the English data set using backward conditional logistic regression, whereas replication was performed using the Dutch data set. RESULTS: In addition to diameter and thickness, the following variables were significant risk factors for metastatic cSCC in the English data set (n = 1774): poor differentiation (odds ratio [OR], 4.56; 95% CI, 2.99-6.94), invasion in (OR, 1.69; 95% CI, 1.05-2.71)/beyond (OR, 4.43; 95% CI, 1.98-9.90) subcutaneous fat, male sex (OR, 2.59; 95% CI, 1.70-3.96), perineural/lymphovascular invasion (OR, 2.12; 95% CI, 1.21-3.71), and facial localization (OR, 1.57; 95% CI, 1.02-2.41). Diameter and thickness showed significant nonlinear relationships with metastasis. Similar ORs were observed in the Dutch data set (n = 434 cSCCs). LIMITATIONS: Retrospective use of pathology reports in the English data set. CONCLUSION: cSCC staging systems can be improved by including differentiation, clinical characteristics such as sex and tumor location, and nonlinear relationships for diameter and thickness.

Validation of a Market-Approved Artificial Intelligence Mobile Health App for Skin Cancer Screening: A Prospective Multicenter Diagnostic Accuracy Study.

BACKGROUND: Mobile health (mHealth) consumer applications (apps) have been integrated with deep learning for skin cancer risk assessments. However, prospective validation of these apps is lacking. OBJECTIVES: To identify the diagnostic accuracy of an app integrated with a convolutional neural network for the detection of premalignant and malignant skin lesions. METHODS: We performed a prospective multicenter diagnostic accuracy study of a CE-marked mHealth app from January 1 until August 31, 2020, among adult patients with at least one suspicious skin lesion. Skin lesions were assessed by the app on an iOS or Android device after clinical diagnosis and before obtaining histopathology. The app outcome was compared to the histopathological diagnosis, or if not available, the clinical diagnosis by a dermatologist. The primary outcome was the sensitivity and specificity of the app to detect premalignant and malignant skin lesions. Subgroup analyses were conducted for different smartphone types, the lesion's origin, indication for dermatological consultation, and lesion location. RESULTS: In total, 785 lesions, including 418 suspicious and 367 benign control lesions, among 372 patients (50.8% women) with a median age of 71 years were included. The app performed at an overall 86.9% (95% CI 82.3-90.7) sensitivity and 70.4% (95% CI 66.2-74.3) specificity. The sensitivity was significantly higher on the iOS device compared to the Android device (91.0 vs. 83.0%; p = 0.02). Specificity calculated on benign control lesions was significantly higher than suspicious skin lesions (80.1 vs. 45.5%; p < 0.001). Sensitivity was higher in skin fold areas compared to smooth skin areas (92.9 vs. 84.2%; p = 0.01), while the specificity was higher for lesions in smooth skin areas (72.0 vs. 56.6%; p = 0.02). CONCLUSION: The diagnostic accuracy of the mHealth app is far from perfect, but is potentially promising to empower patients to self-assess skin lesions before consulting a health care professional. An additional prospective validation study, particularly for suspicious pigmented skin lesions, is warranted. Furthermore, studies investigating mHealth implementation in the lay population are needed to demonstrate the impact on health care systems.

Lectin and alternative complement pathway activation in cutaneous manifestations of IgA-vasculitis: A new target for therapy?

IgA-vasculitis is a systemic small-vessel leucocytoclastic vasculitis and is associated with a high morbidity. The disease can progress to IgA-vasculitis with nephritis (IgAVN) which can result in chronic renal failure. Complement activation is involved in the pathogenesis of IgA-vasculitis. A recent study has shown that cutaneous C3c deposition in IgA-vasculitis is associated with a higher risk to develop IgAVN. In the current study we investigated the different complement pathways that are activated in cutaneous IgA-vasculitis in order to reveal potential targets for intervention. In addition, we analyzed the association of complement factors with IgAVN and the clinical course of the disease. In this retrospective study, the clinicopathological features of 17 patients with IgA-vasculitis were compared with 25 non-IgA-vasculitis cases. Deposition of immunoglobulins and complement was analyzed by direct immunofluorescence for IgA, IgG, IgM, C1q, C4d, properdin, mannan-binding lectin (MBL), ficolin-2 (FCN2), MBL-associated serine protease 1/3 (MASP1/3), MASP2 and C3c. The vascular intensity and positive area was scored on a nominal scale and cumulative score was calculated by multiplying the intensity x area. Properdin was positive in 82% of IgA-vasculitis cases, reflecting alternative pathway activation. C4d was positive in 88% of IgA-vasculitis cases reflecting classical and/or lectin pathway activation, although only 12% of cases were positive for C1q. Lectin pathway activation was demonstrated by deposition of MBL (47%), MASP1/3 (53%) and MASP2 (6%) while FCN2 was found negative. Significantly more deposition of MASP1/3 was found in IgA-vasculitis versus non-IgA-vasculitis. This study demonstrates for the first time activation of lectin and alternative pathways in cutaneous manifestations of IgA-vasculitis. Hence, drugs that intervene in these complement pathways may be an interesting more targeted alternative to the current drugs, in reducing local cutaneous symptoms of the disease, with potentially less side-effects. No association was found between complement activation and IgAVN and/or response to therapy. Therefore, it is unlikely that intervention in complement activation will lead to a better clinical course of the disease.