Cutaneous Cephalic Neurocristic Hamartoma on the Head With Melanocytic, Cartilage, Blood Vessel, Neural, and Bony Tissue.

ABSTRACT: We report on a congenital tumor of the face and scalp in a male newborn, histologically proven to contain melanocytes, cartilage, and bone, vascular, and neural tissue as part of a pigmented congenital tumor. Thus, this tumor was classified as a cutaneous cephalic neurocristic hamartoma.

Vernarbende Alopezien.

Primär vernarbende Alopezien (PVA) werden nach der Klassifikation der North American Hair Research Society nach ihrem prominenten entzündlichen Infiltrat in vier Gruppen eingeteilt: PVA mit lymphozytärem, neutrophilem, gemischtzelligem oder unspezifischem Entzündungsmuster. Der Haarausfall kann subklinisch beginnen und langsam fortschreiten, so dass der genaue Erkrankungsbeginn oft schwer nachzuvollziehen ist. Die Diagnose wird häufig verzögert gestellt. Während die meisten vernarbenden Alopezien bei vollständiger Ausprägung anhand des klinischen Bildes klar zugeordnet werden können, ist die Diagnosestellung in der Frühphase oder im Endstadium häufig schwierig. Bei Erstvorstellung sollte eine ausführliche Anamnese und dermatologische Ganzkörperuntersuchung, inklusive Trichoskopie durchgeführt werden. In klinisch unklaren Fällen sollte eine Biopsie erfolgen. Aufgrund der Seltenheit der PVA gibt es bisher nur eine niedrige Evidenz über die Wirksamkeiten der Vielzahl der verschiedenen angewandten Therapien. Ziele der Therapie einer PVA sind, den Haarausfall zu stoppen oder zumindest zu verzögern, die klinischen Entzündungszeichen zu reduzieren, weitere Vernarbung zu verhindern sowie die subjektiven Symptome zu lindern. Ein Nachwachsen in bereits vernarbten Arealen sollte nicht erwartet werden. Eine antientzündliche Therapie mit topischen Kortikosteroiden der Klasse III-IV und/oder mit intrakutanen intraläsionalen Triamcinolonacetonid-Injektionen kommt bei den meisten PVA in Betracht. Die Wahl der systemischen Therapie hängt von der Art des prädominierenden entzündlichen Infiltrates ab und umfasst antimikrobielle/antibiotische oder immunmodulatorische/immunsuppressive Ansätze. Psychologische Unterstützung und Camouflage-Techniken sollten den Patienten angeboten werden.

Cicatricial alopecia.

In the classification of the North American Hair Research Society, primary cicatricial alopecias (PCA) are divided into four groups according to their prominent inflammatory infiltrate: PCAs with lymphocytic, neutrophilic, mixed or nonspecific cell inflammation pattern. The hair loss can begin subclinically and progress slowly so that the exact onset of the disease is often difficult to determine. The diagnosis is often delayed. While most forms of cicatricial alopecia can be clearly diagnosed based on clinical presentation in the acute disease stage, diagnosis can be challenging in the subacute, early or late disease stages. At first presentation, a detailed patient history and dermatological examination of the body, including trichoscopy, should be performed. In clinically unclear cases, a biopsy should be performed. Due to the scarcity of primary cicatricial alopecia, there is little evidence on the efficacy of the various therapies. The aims of treatment are to stop or at least delay hair loss and progression of the scarring process, reduce clinical inflammation signs as well as to alleviate subjective symptoms. Hair re-growth in already scarred areas should not be expected. Anti-inflammatory treatment with topical corticosteroids class III to IV and / or with intracutaneous intralesional triamcinolone acetonide injections can be considered in most of the primary cicatricial alopecias. The choice of systemic therapy depends on the type of predominant inflammatory infiltrate and includes antimicrobial, antibiotic or immunomodulating/immunosuppressive agents. Psychological support and camouflage techniques should be offered to the patients.

In vivo study for the discrimination of cancerous and normal skin using fibre probe-based Raman spectroscopy.

Raman spectroscopy has proved its capability as an objective, non-invasive tool for the detection of various melanoma and non-melanoma skin cancers (NMSC) in a number of studies. Most publications are based on a Raman microspectroscopic ex vivo approach. In this in vivo clinical evaluation, we apply Raman spectroscopy using a fibre-coupled probe that allows access to a multitude of affected body sites. The probe design is optimized for epithelial sensitivity, whereby a large part of the detected signal originates from within the epidermal layer's depth down to the basal membrane where early stages of skin cancer develop. Data analysis was performed on measurements of 104 subjects scheduled for excision of lesions suspected of being malignant melanoma (MM) (n = 36), basal cell carcinoma (BCC) (n = 39) and squamous cell carcinoma (SCC) (n = 29). NMSC were discriminated from normal skin with a balanced accuracy of 73% (BCC) and 85% (SCC) using partial least squares discriminant analysis (PLS-DA). Discriminating MM and pigmented nevi (PN) resulted in a balanced accuracy of 91%. These results lie within the range of comparable in vivo studies and the accuracies achieved by trained dermatologists using dermoscopy. Discrimination proved to be unsuccessful between cancerous lesions and suspicious lesions that had been histopathologically verified as benign by dermoscopy.

Modes of action of diclofenac 3%/hyaluronic acid 2.5% in the treatment of actinic keratosis.

BACKGROUND: The efficacy of topically applied diclofenac 3 % in combination with hyaluronic acid 2.5 % in the treatment of actinic keratoses (AKs) has been demonstrated in several clinical studies, but the exact mode of action is still unclear. This study evaluates the potential molecular and cellular main modes of action of topically applied diclofenac in the treatment of AKs. PATIENTS AND METHODS: In this prospective study 20 male patients with AKs were treated for 90 days with topically applied diclofenac 3 %/hyaluronic acid 2.5 %. Before and after treatment, skin biopsies were taken from the treatment area and were investigated histologically and immunohistochemically as well as compared to healthy skin. For this purpose, markers for inflammation (COX-2, CD3, CD8), apoptosis (p53), cell cycle arrest (p53, p21), proliferation (Ki67), and angiogenesis (CD31) were examined. RESULTS: The immunohistochemical analysis demonstrated a significant decrease in expression of COX-2, CD3 and CD8. Furthermore, there was a clear reduction of CD31 expression as a marker for angiogenetic processes. Additionally, there was a tendency toward a reduction in markers for proliferation and apoptosis. CONCLUSIONS: The efficacy of diclofenac 3 %/hyaluronic acid 2.5 % in the treatment of AKs is probably due to anti-inflammatory and anti-angiogenic effects, potentially associated with anti-proliferative and apoptosis-inducing underlying mechanisms.

Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses.

Increasing incidence rates of cutaneous malignancies, paralleling rising survival times of grafts and patients in organ transplant recipients, represents an escalating challenge for dermatologists worldwide. Especially, invasive squamous cell carcinomas (SCC) in immuno-compromised patients are characterized by significantly increased morbidity and mortality and characteristically outnumber basal cell carcinoma in this population. Effective management of actinic keratoses (AK) could help to prevent the further development of invasive SCC. Diclofenac in hyaluronic acid has previously shown to be an effective and well tolerated option for the treatment of AK in immuno-competent patients. However, its safety and efficacy in organ-transplant patients has not been evaluated in a controlled study so far. 32 organ transplant patients (kidney (+/- pancreas), liver, heart) screened at our specialized transplant dermatology outpatient clinic were found eligible and were randomized to either active treatment (24) or vehicle (8). Patients who had stable status of the transplanted graft in the 12 months prior to entering the study and >/= 3 AK lesions in a contiguous 50 cm2 area on the face, forehead, hands or balding scalp were eligible for inclusion in the study. Treatment of AK with 3% diclofenac in 2.5% hyaluronic acid or placebo twice daily was conducted over a total of 16 weeks, followed by a final evaluation 4 weeks after last application of the study drug. Biopsies were taken from the treated areas at the final visit to verify clinical clearance. Patients were assessed for safety variables that included adverse events, local skin reactions, laboratory results, dosage of immunosuppressive medication and indication of graft rejection. A 24 months follow up was conducted after the end of treatment. 87% (n = 28/32) of the patients completed the 16 week treatment phase and presented for final evaluation 4 weeks after end of treatment. In the diclofenac 3% gel treatment group, a complete clearance of AK lesions was achieved in 41% (9/22) compared to 0% (0/6) in the vehicle group. Side effects in most of the patients included a mild erythema and a mild to moderate swelling of the areas treated. No graft rejections or trends for a deterioration of graft function were detected. No meaningful trends were observed in laboratory results. In 55% of the previously cleared patients, new AK developed in the study area after an average of 9.3 months. None of these patients developed invasive SCC in the study area within 24 months of follow-up. This study demonstrated a greater lesion clearance rate of AKs in OTRs treated with diclofenac 3% gel than with vehicle. Despite recurrent AK in 55% of the previously cleared patients, the 24 month results showed no invasive SCC in this group. This study suggests that diclofenac 3% gel is not only an efficient and well tolerated treatment for multiple AKs in OTRs but also may prevent invasive SCC in these high-risk patients.

Preliminary evaluation of benign vascular lesions using in vivo reflectance confocal microscopy.

BACKGROUND: Reflectance confocal microscopy (RCM) is a novel noninvasive imaging technique for in vivo evaluation of cutaneous lesions at near-histologic resolution. The applicability of RCM for various neoplastic and inflammatory skin diseases has been shown, but a descriptive evaluation of different vascular lesions has not yet been performed. OBJECTIVES: To define specific RCM criteria for congenital and acquired vascular lesions and to determine whether these criteria may assist in their differential diagnosis. MATERIALS AND METHODS: Seven patients with a clinical diagnosis of vascular lesion, including spider angioma, venous lake, cherry angioma, pyogenic granuloma, port wine stain, angiokeratoma, and lymphangioma, participated in this study. Skin sites were systematically analyzed using RCM, and biopsy was obtained for clinically indeterminate lesions. RESULTS: For each entity, characteristic RCM criteria could be identified and selected parameters correlated well to established histopathologic findings. The most relevant criteria included the diameter of the vessels and degree of vascular tortuosity or dilation. Additional findings such as flow velocity, inflammation, and disruption of the epidermal architecture could be documented. CONCLUSION: The findings of this preliminary evaluation indicate that RCM may aid in the noninvasive characterization of inflammatory, proliferative, and ectatic vascular malformations in vivo.

Treatment of multiple, multiform actinic keratoses on the head with imiquimod 5% cream.

The objective of this non-controlled interventional clinical study was to evaluate the efficacy of imiquimod in the treatment of fields with multiple, multiform AK. 180 office-based dermatological practices in Germany participated. Patients with clinically typical, visible AK lesions on the head were treated with 5% imiquimod cream 3 times per week for 4 weeks followed by a 4 week treatment pause. If lesions were still present, a second treatment course of treatment (COT) was given. Complete clearance rate, i.e. no clinically visible AK lesions in the treatment area, was the main outcome measure. 829 patients were enrolled. The complete clearance rate was 40.5% after the first COT and 68.9% overall. Altogether, 85.4% of the 7,427 baseline lesions were cleared. Patients with hyperkeratotic/hypertrophic lesions showed comparable responses. Local skin reactions were the most commonly reported adverse effects, causing discontinuation in only 4 patients. Severity of the local skin reactions was a strong predictor of the outcome. Patients with multiple multiform AK on the head can be successfully and safely treated with topical imiquimod in daily practice. Assurance of patient understanding that treatment success is closely correlated to proper drug administration is important.

Clinical applicability of in vivo reflectance confocal microscopy for the diagnosis of actinic keratoses.

BACKGROUND: In vivo reflectance confocal microscopy (RCM) has been used for evaluation of the morphologic features of nonmelanoma skin cancer. The application of RCM for diagnosis of basal cell carcinoma has been reported; however, the evaluation of actinic keratoses (AKs) has only been the subject of preliminary studies. STUDY GOAL: The goal of this study was to evaluate the applicability of RCM in the diagnosis of AK in correlation with routine histology. MATERIALS AND METHODS: Forty-four Caucasians with a minimum of one AK participated in this study. Evaluation consisted of clinical examination, RCM, and routine histology, including a total of 46 AKs in the final analysis. Ten normal skin sites served as controls. RCM features of AK included parakeratosis, architectural disarray, and keratinocyte pleomorphism. Following blinded evaluations, sensitivity/specificity, kappa analysis, and Spearman's correlation were performed on all parameters. RESULTS: Sensitivity/specificity values of RCM features ranged from 80% to 98.6%. The presence of architectural disarray and cellular pleomorphism appeared to be the best predictor of AK. CONCLUSION: In summary, RCM may be a promising technology for the noninvasive detection of AK and as adjunct tool to clinical diagnosis and monitoring. However, the preliminary nature of this study warrants further investigations.

Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and usually progresses from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain partially understood. Here, we use Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status in healthy, AK and cSCC epidermis samples. Importantly, we show that AK methylation patterns already display classical features of cancer methylomes and are highly similar to cSCC profiles. Further analysis identifies typical features of stem cell methylomes, such as reduced DNA methylation age, non-CpG methylation, and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature is detected only in half of the samples, while the other half shows patterns more closely related to healthy epidermis. These findings suggest the existence of two subclasses of AK and cSCC emerging from distinct keratinocyte differentiation stages.

Genomic characterization of a novel human papillomavirus (HPV-117) with a high viral load in a persisting wart.

Warts from immunosuppressed organ transplant recipients (OTR) persist over years and may progress into non-melanoma skin cancer. Human papillomaviruses (HPV) are considered the causal agents for the development of such warts. We isolated the novel type HPV-117 from a persisting wart by rolling circle amplification. One hundred eighteen warts from immunocompetent patients (IC) and 49 warts from OTR were analyzed by HPV-117 E6 type-specific PCR. As inferred from a phylogenetic analysis, the new type HPV-117 belonged to alpha-PV species 2, including the most similar types HPV-10 and HPV-94. The general prevalence of HPV-117 in warts was 2% in IC (2/118), and 12% in OTR (6/49). The high viral load in dysplastic cells of a Verruca vulgaris was shown by in situ hybridization. Our results suggest an active role of the novel type in the development of cutaneous warts of OTR.

Impact of molecular staging methods in primary melanoma: reverse-transcriptase polymerase chain reaction (RT-PCR) of ultrasound-guided aspirate of the sentinel node does not improve diagnostic accuracy, but RT-PCR of peripheral blood does predict survival.

PURPOSE: This study analyzes (1) the value of tyrosinase reverse-transcriptase polymerase chain reaction (RT-PCR) of aspirates obtained by ultrasound-guided fine-needle aspiration cytology (US-FNAC) of sentinel nodes (SNs) in patients with melanoma before sentinel lymph node biopsy (SLNB) and (2) the value of RT-PCR of blood samples of all SLNB patients. PATIENTS AND METHODS: Between 2001 and 2003, 127 patients with melanoma (median Breslow depth, 2.1 mm) underwent SLNB. FNAC was performed in all SNs of all patients pre- and post-SLNB. The aspirates were partly shock-frozen for RT-PCR and were partly used for standard cytology. Peripheral blood was collected at the time of SLNB and at every outpatient visit thereafter. RESULTS: Thirty-four (23%) of 120 SNs were positive for melanoma. SN involvement was predicted by US-FNAC with a sensitivity of 82% and a specificity of 72%. Additional tyrosinase RT-PCR revealed the same sensitivity of 82% and a specificity of 72%. At a median follow-up time of 40 months from first blood sample, peripheral-blood RT-PCR was a significant independent predictor of disease-free survival (DFS) and overall survival (OS; P < .001). CONCLUSION: US-FNAC is highly accurate and eliminates the need for SLNB in 16% of all SLNB patients. RT-PCR of the aspirate or excised SN does not improve sensitivity or specificity. RT-PCR of blood samples predicts DFS and OS.