Influence of Topical, Systemic and Combined Application of Antioxidants on the Barrier Properties of the Human Skin.

BACKGROUND: The formation of free radicals in human skin by solar ultraviolet radiation is considered to be the main reason for extrinsic skin aging. The antioxidants in human tissue represent an efficient protection system against the destructive action of these reactive free radicals. In this study, the parameters of the skin, epidermal thickness, stratum corneum moisture, elasticity and wrinkle volume, were determined before and after the treatment with antioxidant- or placebo-containing tablets and creams. METHODS: The study included 5 groups of 15 volunteers each, who were treated for 2 months with antioxidant-containing or placebo tablets, creams or a combination of antioxidant-containing tablets and cream. The skin parameters were measured at time point 0 and at week 8 utilizing ultrasound for the determination of epidermal thickness, a corneometer for stratum corneum moisture measurements, skin profilometry for quantifying the wrinkle volume and a cutometer for determining the elasticity. RESULTS: The verum cream had a positive influence on epidermal thickness, elasticity and skin moisture, but the verum tablets improved the epidermal thickness only. The combined application of verum tablets and creams led to a significant improvement of all investigated skin parameters, whereas the application of placebo tablets or cream did not influence any parameters. CONCLUSION: The topical and oral supplementation of antioxidants can be an instrument to improve several skin parameters and potentially counteract or decelerate the process of extrinsic skin aging.

Sonographic diagnostics in dermatology.

Ultrasonography non-invasively visualizes changes within the skin, skin appendages, subcutaneous tissue, subcutaneous (regional) lymph nodes and peripheral vessels. Thus it is an established diagnostic tool in dermatology. Compared to X-ray, MRI and PET, ultrasonography has some advantages; however, it is more dependent on the individual experience of the investigator. Therefore a structured education and continuous training are necessary. This review describes the physical and technical basics, the administrative requirements and the main indications in dermatology.

Hazard rates for recurrent and secondary cutaneous melanoma: an analysis of 33,384 patients in the German Central Malignant Melanoma Registry.

BACKGROUND: Knowledge about the risk for recurrence and secondary cutaneous melanoma (CM) is an important basis for patient counseling and planning of follow-up examinations. OBJECTIVES: This study aimed to analyze stage- and time-dependent hazard rates (HR) and discusses current surveillance recommendations. METHODS: Follow-up data of 33,384 patients with incident CM in stages I to III (American Joint Committee on Cancer 2002) were recorded by the German Central Malignant Melanoma Registry in 1976 through 2007. Survival was based on Kaplan-Meier estimates and HRs were calculated. RESULTS: Recurrences were recorded in 4999 patients (stage I, 7.1%; stage II, 32.8%; and stage III, 51.0%). Ten-year recurrence-free survival was 78.9% (95% confidence interval 73.1-90.5); in stage I, 89.0%; stage II, 56.9%; and stage III, 36.0%. Whereas HR for recurrent CM showed a constantly low level less than or equal to 1:125 per year for stage IA, clearly higher HRs of greater than or equal to 1:40 were recorded in stage IB for the first 3 years and generally in stages II to III. Of all patients 2.3% developed secondary melanomas, with a consistently low HR of less than 1:220 per year. LIMITATIONS: As German recommendations discontinued regular follow-up examinations after 10 years, no information can be given beyond this time point. Follow-up data of longer than 5 years were available in 41.4% of patients. CONCLUSION: For patients at stage IA with thin melanoma and low HR for recurrent CM the need for surveillance remains questionable. For patients with higher HR greater than 1:40 per year, intensified surveillance strategies should be taken into account.

Clinically misinterpreted melanoma metastases can correctly be diagnosed by ultrasound-guided fine needle aspiration cytology.

Ultrasound-guided fine needle aspiration cytology (US-guided FNAC) of regional nodal basins is increasingly incorporated into the national follow-up schemes of high risk melanoma patients. In this paper we describe an additional added value of US-guided FNAC in the detection and verification of subcutaneous/in-transit metastases. A patient presented with a long lasting, smooth, movable node, close to the scar of the primary melanoma, mimicking a lipoma in every clinical follow-up. Ultrasound at once suspected a metastasis. FNAC was performed within one day of sampling in an outpatient setting, without side effects. A hypothesis of an auto-vaccination in this case could not be proven by examining the T-cell response. Despite the clinically benign aspect of this metastasis, US-guided FNAC can provide diagnosis within 1 day. FNAC is a rapid, cost-effective method, free of complications, of great value in the diagnosis of putative metastases.

Previously reported sonographic appearances of regional melanoma metastases are not likely due to necrosis.

OBJECTIVES: Sonography has proven to be a reliable tool in early detection of lymph node and in-transit cutaneous-subcutaneous metastases. Those metastases normally appear as hypoechoic or even anechoic lesions on sonography. It has been assumed that this appearance is due to necrosis of the lesions, but so far, that assumption has never been proven. The purpose of this retrospective study was to evaluate whether the hypoechoic appearance of melanoma metastasis is really due to tumor necrosis. METHODS: From a radiographic database, we retrieved 212 melanoma cases imaged with sonography over a 2-year period for disease staging or follow-up. We selected 37 positive cases with 84 nodal and extranodal (satellite and in-transit) metastatic lesions and reviewed the sonograms and pathologic slides (slides available for 40 of 84 lesions). We retrospectively assessed the vascularization pattern (color Doppler images available for 78 of 84 lesions), categorizing it as poor, intermediate, or consistent. We also looked for necrosis on the histopathologic material, categorizing it into scores of 0, 1, 2, and 3 for absence of necrosis, less than 20% necrosis, 20% to 40% necrosis, and greater than 40% necrosis, respectively. RESULTS: Despite their gray scale appearance, most melanoma lesions were vascularized on color Doppler imaging and showed limited necrosis at histopathologic analysis. Consistent vascularization on Doppler imaging, excluding substantial necrosis, was found in 44 of 78 lesions (56.4%). Poor vascularization on Doppler imaging, suggesting necrosis, was present in only 14% of the lesions. Substantial necrosis (scores of 2 and 3) was found pathologically in only 10% of the lesions. CONCLUSIONS: Necrosis seems to be an uncommon event in melanoma metastasis and is probably not the basis for its low-level echo pattern on sonography. The hypoechoic appearance is very typical of melanoma metastasis and is likely due to massive melanomatous infiltration (with the poor echo reflectivity of melanin). However, confirmation in larger pathologically proven series is required.

New developments in sentinel node staging in melanoma: controversies and alternatives.

PURPOSE OF REVIEW: Melanoma incidence is increasing worldwide. Elective lymph node dissections (ELNDs) could not improve survival. The sentinel node is a targeted approach to occult lymph node metastases. There are controversies regarding the sentinel node procedure for melanoma, with regard to false-negative rates, therapeutic benefit and alternatives, such as ultrasound. The clinical relevance of minimal sentinel node tumor burden is unclear. This review analyzes these issues. RECENT FINDINGS: Through the pathological work-up of the sentinel node, the sentinel node has become an independent prognostic factor for survival in melanoma. False-negative rates of the sentinel node procedure are generally an underestimation, due to incorrect calculations. A subgroup analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT)-1 seemed to demonstrate a survival benefit, but is criticized for a number of reasons. Potentially, a subgroup of sentinel node-positive patients is prognostically false-positive, with dormant metastases, which might not become viable disease. SUMMARY: Sentinel node tumor burden is an extra dimension to predict prognosis, although we have not yet identified the correct group to undergo a completion lymph node dissection. The MSLT-2 and MINITUB studies are analyzing this issue. The EORTC recommends the Rotterdam criteria as the most reproducible and accurate measure of sentinel node tumor burden. Ultrasound-guided fine needle aspiration cytology is emerging as a potential cost-effective alternative.

Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes.

SUMMARY BACKGROUND DATA: The more intensive sentinel node (SN) pathologic workup, the higher the SN-positivity rate. This is characterized by an increased detection of cases with minimal tumor burden (SUB-micrometastasis <0.1 mm), which represents different biology. METHODS: The slides of positive SN from 3 major centers within the European Organization of Research and Treatment of Cancer (EORTC) Melanoma Group were reviewed and classified according to the Rotterdam Classification of SN Tumor Burden (<0.1 mm; 0.1-1 mm; >1 mm) maximum diameter of the largest metastasis. The predictive value for additional nodal metastases in the completion lymph node dissection (CLND) and disease outcome as disease-free survival (DFS) and overall survival (OS) was calculated. RESULTS: In 388 SN positive patients, with primary melanoma, median Breslow thickness was 4.00 mm; ulceration was present in 56%. Forty patients (10%) had metastases <0.1 mm. Additional nodal positivity was found in only 1 of 40 patients (3%). At a mean follow-up of 41 months, estimated OS at 5 years was 91% for metastasis <0.1 mm, 61% for 0.1 to 1.0 mm, and 51% for >1.0 mm (P < 0.001). SN tumor burden increased significantly with tumor thickness. When the cut-off value for SUB-micrometastases was taken at <0.2 mm (such as in breast cancer), the survival was 89%, and 10% had additional non-SN nodal positivity. CONCLUSION: This large multicenter dataset establishes that patients with SUB-micrometastases <0.1 mm have the same prognosis as SN negative patients and can be spared a CLND. A <0.2 mm cut-off for SUB-micrometastases does not seem correct for melanoma, as 10% additional nodal positivity is found.

Management of primary and metastasized melanoma in Germany in the time period 1976-2005: an analysis of the Central Malignant Melanoma Registry of the German Dermatological Society.

This study analysed the changes of excision margins in correlation with tumour thickness as recorded over the last three decades in Germany. The study also evaluated surgical management in different geographical regions and treatment options for metastasized melanoma. A total of 42 625 patients with invasive primary cutaneous melanoma, recorded by the German Central Malignant Melanoma Registry between 1976 and 2005 were included. Multiple linear regression analysis was used to investigate time trends of excision margins adjusted for tumour thickness. Excision margins of 5.0 cm were widely used in the late 1970s but since then have been replaced by smaller margins that are dependent on tumour thickness. In the case of primary melanoma, one-step surgery dominated until 1985 and was mostly replaced by two-step excisions since the early 1990s. In eastern Germany, one-step management remained common until the late 1990s. During the last three decades loco-regional metastases were predominantly treated by surgery (up to 80%), whereas systemic therapy decreased. The primary treatment of distant metastases has consistently been systemic chemotherapy. This descriptive retrospective study revealed a significant decrease in excision margins to a maximum of 2.00 cm. A significant trend towards two-step excisions in primary cutaneous melanoma was observed throughout Germany. Management of metastasized melanoma showed a tendency towards surgical procedures in limited disease and an ongoing trend to systemic treatment in advanced disease.

Management of melanoma: a European perspective.

Clinical management of melanoma requires insight into the utility of adjuvant surgical and systemic therapy options. This article discusses the evidence from randomized, controlled trials of adjuvant surgical therapy, sentinel node biopsy, and surveillance of regional lymph node basins by ultrasound. Ultrasound also can be used to identify metastasis in the sentinel node to avoid unnecessary sentinel node biopsies. It describes the experience with chemotherapy, immunostimulants, and vaccines, which have failed as adjuvants in stage II-III disease. Interferon has a consistent effect on relapse-free survival, although it does not have a significant benefit for overall survival.

Molecular staging in stage II and III melanoma patients and its effect on long-term survival.

PURPOSE: To assess the prognostic value of serial reverse transcriptase polymerase chain reaction (RT-PCR) -based measurements of tyrosinase mRNA in peripheral blood of stage II and III melanoma patients. PATIENTS AND METHODS: During routine follow-up of American Joint Committee on Cancer stage II and III melanoma patients, serial testing for tyrosinase transcripts in peripheral blood was performed by RT-PCR. The PCR results were compared with the clinical data collected during the follow-up. RESULTS: Over a period of 3 years, 111 patients (78 stage II and 33 stage III patients) were enrolled, and tyrosinase determinations were carried out. The 6-year disease-specific survival probability was 97% for patients always showing negative RT-PCR results and 67% for patients who tested positive at least once. In a Cox proportional hazards model, the prognostic value of sex, age, site of primary tumor, histologic subtype, stage, Breslow's tumor thickness, Clark level, and the time-dependent variable PCR result was assessed. Patients with a positive RT-PCR test had a distinctly higher risk of dying from melanoma, with a hazard ratio of 12.6 (95% CI, 3.4 to 46.3; P < .001). CONCLUSION: Our study shows a strong association between PCR and disease-specific survival time. Detection of tyrosinase mRNA in peripheral blood may be of similar importance for the clinical course of melanoma as the detection of micrometastatic disease in the sentinel lymph node. Whether a combination of these two factors leads to a better definition of the prognosis of melanoma patients is under investigation in current studies.

Ultrasound of the sentinel node in melanoma patients: echo-free island is a discriminatory morphologic feature for node positivity.

Unlike breast and thyroid cancer, the use of ultrasound (US)-guided fine needle aspiration cytology (FNAC) for preoperative staging is limited in melanoma. New US morphology criteria have shown that US-FNAC can correctly identify 50% of all involved sentinel nodes (SN) in melanoma patients before surgical excision. The aim of this study was to examine a new criterion: the echo-free island (EFI). A total of 1000 consecutively staged melanoma patients (Breslow thickness>1 or<1 mm, but ulcerated, Clark IV/V or regressed) scheduled for SN staging underwent preoperative US. US morphology items were assessed: peripheral perfusion, loss of central echoes, balloon shape, and EFI. FNAC was performed in case of suspicious and malignant US patterns. All patients proceeded to undergo an SN biopsy or direct completion lymph node dissection (CLND) (in the case of positive FNAC). In all, 57% of the patients were men. The mean/median Breslow thickness was 2.58/1.57 mm. The mean/median follow-up was 56/53 months. SN was positive in 21%. EFI information was available in 95.3%. EFI was seen in 40 patients (4%). EFI sensitivity was 10.8%, specificity was 97.6%, positive predictive value was 50%, and negative predictive value was 80.2%. EFI was significantly correlated to peripheral perfusion (67.5%). There was no correlation to balloon shape or loss of central echoes. Five-year melanoma-specific survival of patients with EFI was significantly worse: 80% versus 92% when absent. The EFI can be useful in the early detection of SN melanoma metastasis. It is an early sign of involvement and thus associated with a decreased survival.

Effects of time interval between primary melanoma excision and sentinel node biopsy on positivity rate and survival.

BACKGROUND: Sentinel node biopsy (SNB) is essential for adequate melanoma staging. Most melanoma guidelines advocate to perform wide local excision and SNB as soon as possible, causing time pressure. OBJECTIVE: To investigate the role of time interval between melanoma diagnosis and SNB on sentinel node (SN) positivity and survival. METHODS: This is a retrospective observational study concerning a cohort of melanoma patients from four European Organization for Research and Treatment of Cancer Melanoma Group tertiary referral centres from 1997 to 2013. A total of 4124 melanoma patients underwent SNB. Patients were selected if date of diagnosis and follow-up (FU) information were available, and SNB was performed in <180 d. A total of 3546 patients were included. Multivariable logistic regression and Cox regression analyses were performed to investigate how baseline characteristics and time interval until SNB are related to positivity rate, disease-free survival (DFS) and melanoma-specific survival (MSS). FINDINGS: Median time interval was 43 d (interquartile range [IQR] 29-60 d), and 705 (19.9%) of 3546 patients had a positive SN. Sentinel node positivity was equal for early surgery (≤43 d) versus late surgery (>43 d): 19.7% versus 20.1% (p = 0.771). Median FU was 50 months (IQR 24-84 months). Sentinel node metastasis (hazard ratio [HR] 3.17, 95% confidence interval [95% CI] 2.53-3.97), ulceration (HR 1.99, 95% CI 1.58-2.51), Breslow thickness (HR 1.06, 95% CI 1.04-1.08), and male gender (HR 1.58, 95% CI 1.26-1.98) (all p < 0.00001) were independently associated with worse MSS and DFS; time interval was not. INTERPRETATION: No effect of time interval between melanoma diagnosis and SNB on 5-year survival or SN positivity rate was found for a time interval of up to 3 months. This information can be used to counsel patients and remove strict time limits from melanoma guidelines.

The role of ultrasound in detection and management of regional disease in melanoma patients.

Melanoma follow-up programs are directed towards early detection of tumor recurrence. Because the majority of first relapses occur in the regional lymph node area, special focus is placed on this region using various techniques in addition to physical examination. During the last several years, particularly ultrasound B-scan has evolved as a technique of major importance for detection of such regional melanoma recurrences. The technique shows high sensitivity and specificity, discriminating regional or subcutaneous melanoma metastases from nonspecific nodes. Furthermore, suspicious findings can be evaluated quickly and reliably by the minimally invasive technique of ultrasound-guided fine-needle aspiration cytology (FNAC). For regional metastases located deeply or close to vulnerable structures, the new method of ultrasound-guided anchor-wire-marking facilitates subsequent surgery. In summary, ultrasound B-scan has become an essential technique in the follow-up of melanoma patients.

Ultrasound diagnosis of an atypical axillary lesion.

We report on the case of a 41-year-old man with a recently diagnosed amelanotic ulcerated melanoma, with a Breslow thickness of 3.5 mm and Clark level IV. He had a pre-existing mass in the axilla, which had grown in parallel to the developing tumor. A large regional lymph node was clinically suspected. Ultrasound (US) examination of the axilla showed a large benign lipoma but also a very atypical peripheral perfusion. At the same time, a sentinel node showed a peripheral perfusion on US. Fine-needle aspiration cytology was performed of the different lesions and showed a melanoma metastasis in the sentinel node. Thereafter, a lymph node dissection was performed. The lipoma was seen in histopathology and even the peripheral perfusion was confirmed. US and US-guided fine-needle aspiration cytology can be easily applied in the diagnosis of lymph node metastases in melanoma patients and can help determine a benign or a malignant involvement.

Ultrasound-guided fine needle aspiration cytology as an addendum to sentinel lymph node biopsy can perfect the staging strategy in melanoma patients.

BACKGROUND: Ultrasound guided fine needle aspiration cytology (US-guided FNAC) can identify microscopic involvement of lymph nodes as in breast cancer and avoid surgical sentinel node (SN). Its utility in melanoma patients is controversial and subject of this study. METHODS: Between 2001 and 2010 over 1000 stage I/II consecutive melanoma patients prospectively underwent US-FNAC prior to SN biopsy. All patients underwent lymphoscintigraphy prior to US-FNAC. The Berlin US morphology criteria: Peripheral perfusion (PP), loss of central echoes (LCE) and balloon shaped (BS) were registered. FNAC was performed in case of presence of any of these factors. SN tumour burden was measured according to the Rotterdam criteria. All patients underwent SN or lymph node dissection (LND) in case of positive FNAC. FINDINGS: Mean/median Breslow thickness was 2.58/1.57 mm. Mean/median follow-up was 56/53 months (1-132). SN positivity rate was 21%. US-FNAC Sensitivity was 71% (US only) and 51% (US-FNAC). Sensitivity of US-FNAC was highest for T4 (76%) and ulcerated melanomas (63%). PP, LCE and BS had sensitivity of 69%, 24% and 24% respectively. Sensitivity of US-FNAC increased with increasing SN tumour burden. PP was an early sign of metastasis (58% in <0.1mm metastases). Threshold size of a metastasis for FNAC was 0.3mm. Five-year survival correlated to US-FNAC status (95% in negative and 59% in positive). INTERPRETATION: Ultrasound guided FNAC (US-FNAC) according to the Berlin morphology criteria could correctly identify at least half of all tumour positive sentinel nodes, prior to the surgical SN procedure. Peripheral perfusion is an early sign of metastasis, which is very sensitive, but with lower positive predictive value (PPV). It is responsible for the sensitivity of the procedure. Balloon shape is a sign of advanced metastases, with lower sensitivity, but high PPV. US-FNAC sensitivity correlated with increasing T-stage, ulceration of the primary and increasing SN tumour burden. US-FNAC status accurately predicts survival.