Notes: Summary Background  It is known that two-thirds of patients who develop clinical metastases following treatment of a primary cutaneous melanoma initially present with locoregional metastases and one-third initially present with distant metastases. However, few reports in the literature give detailed figures on different metastatic pathways in cutaneous melanoma. Objectives  The aim of the present study was to perform a detailed analysis of the different metastatic pathways, the time course of the development of metastases and the factors influencing them. Methods  In a series of 3001 patients with primary cutaneous melanoma at first presentation, 466 subsequently developed metastasis and were followed-up over the long term at the University of Tuebingen, Germany between 1976 and 1996. Different pathways of metastatic spread were traced. Associated risk factors for the different pathways were assessed. Differences in survival probabilities were calculated by the Kaplan–Meier method and evaluated by the log-rank test. Results  In 50·2% of the patients the first metastasis after treatment of the primary tumour developed in the regional lymph nodes. In the remaining half of the patient sample the first metastasis developed in the lymphatic drainage area in front of the regional lymph nodes, as satellite or in-transit metastases (21·7%) or as direct distant metastases (28·1%). Anatomical location, sex and tumour thickness were significant risk factors for the development of metastasis by different pathways. The most important risk factor appeared to be the location of the primary tumour. The median intervals elapsing before the first metastasis differed significantly between the different metastatic pathways. The direct distant metastases became manifest after a median period of 25 months, thus later than the direct regional lymph node metastases (median latency period, 16 months) and the direct satellite and in-transit metastases (median latency period, 17 months). In patients who developed distant metastases the period of development was independent of the metastatic route. The time at which the distant metastases developed was roughly the same (between 24 and 30 months after the detection of the primary tumour), irrespective of whether satellite or in-transit metastases, lymph node metastases or distant metastases were the first to occur. Conclusions  The time course of the development of distant metastasis was more or less the same irrespective of the metastatic pathway; this suggests that in patients with in-transit or satellite metastasis or regional lymph node metastasis, haematogenic metastatic spread had already taken place. Thus, the diagnostic value of sentinel lymph node biopsy and the therapeutic benefit of elective lymph node dissection may be limited, as satellite and in-transit metastases or direct distant metastases will not be detected and haematogenous spread may already have taken place when the intervention is performed.

Notes: Summary Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been shown to be effective in transplant patients. Some case reports and pilot studies have suggested efficacy against systemic lupus erythematosus (LE), particularly in the case of lupus nephritis. Reports on MMF treatment of skin manifestations of LE are still anecdotal. We report two cases with extensive skin lesions owing to subacute cutaneous LE (SCLE). Both patients had been treated with azathioprine and antimalarials without effect. Finally both patients were given highly dosed glucocorticosteroids, which were also ineffective but led to vertebral fractures because of long-term steroid treatment in one patient and steroid-induced psychosis in the other. MMF 2 g daily caused the skin manifestations to disappear within a few weeks in both patients. One patient was followed up for more than 24 months, and showed good toleration of MMF treatment. The skin remained stable over this period when at least 1 g MMF per day was administered. In conclusion, MMF appears to be an attractive treatment option in skin manifestations of SCLE, and seems to be beneficial for patients with steroid-refractory lesions that are also resistant to treatment with immunosuppressants or antimalarials. The observations suggest that further evaluation of this route in randomized controlled trials is warranted.

Notes: Background  Digital image analysis has been introduced into the diagnosis of skin lesions based on dermoscopic pictures.Objectives  To develop a computer algorithm for the diagnosis of melanocytic lesions and to compare its diagnostic accuracy with the results of established dermoscopic classification rules.Methods  In the Department of Dermatology, University of Tuebingen, Germany, 837 melanocytic skin lesions were prospectively imaged by a dermoscopy video system in consecutive patients. Of these lesions, 269 were excised and examined by histopathology: 84 were classified as cutaneous melanomas and 185 as benign melanocytic naevi. The remaining 568 lesions were diagnosed by dermoscopy as benign. Digital image analysis was performed in all 837 benign and malignant melanocytic lesions using 64 different analytical parameters.Results  For lesions imaged completely (diameter ≤ 12 mm), three analytical parameters were found to distinguish clearly between benign and malignant lesions, while in incompletely imaged lesions six parameters enabled differentiation. Based on the respective parameters and logistic regression analysis, a diagnostic computer algorithm for melanocytic lesions was developed. Its diagnostic accuracy was 82% for completely imaged and 84% for partially imaged lesions. All 837 melanocytic lesions were classified by established dermoscopic algorithms and the diagnostic accuracy was found to be in the same range (ABCD rule 78%, Menzies' score 83%, seven-point checklist 88%, and seven features for melanoma 81%).Conclusions  A diagnostic algorithm for digital image analysis of melanocytic lesions can achieve the same range of diagnostic accuracy as the application of dermoscopic classification rules by experts. The present diagnostic algorithm, however, still requires a medical expert who is qualified to recognize cutaneous lesions as being of melanocytic origin.

Notes: Background  The dermoscopic classification is a useful tool for handling patients with atypical naevi (Clark naevi).Objectives  To investigate if the dermoscopic classification of atypical naevi is of any value to discriminate benign from malignant melanocytic lesions.Methods  Consecutive patients (n = 205) were included with 254 suspicious melanocytic lesions, confirmed by histopathology at the Pigmented Lesions Clinic of the Department of Dermatology, University Medical Center, University of Tuebingen, Germany. In this retrospective study, dermoscopic images of benign and malignant melanocytic lesions were classified according to the dermoscopic classification of atypical naevi (reticular, globular, homogeneous or combinations of two of these) and pigmentation (uniform, central hyper- or hypopigmentation, eccentric peripheral hyper- or hypopigmentation, or multifocal hyper- or hypopigmentation). The three-structure type (reticular, globular and homogeneous) was additionally defined.Results  Reticular, homogeneous and reticular–homogeneous types were significantly more frequent in naevi than in melanomas, whereas the three-structure type was significantly more frequent in melanomas (P 〈 0·001). A sensitivity of 86·7%, specificity of 87·7% and diagnostic accuracy of 87·4% was obtained. Uniformly pigmented and centrally hyperpigmented types were significantly more frequent in naevi than in melanomas, whereas eccentric peripheral hyperpigmented and multifocal hyper- or hypopigmented types were significantly more frequent in melanomas (P 〈 0·001).Conclusions  The dermoscopic classification of atypical naevi (Clark naevi) is useful to discriminate benign from malignant melanocytic lesions. The three-structure type and eccentric peripheral hyperpigmentation were significantly more frequently found in malignant than in benign melanocytic lesions. The knowledge of these two dermoscopic types should be helpful for the management of patients presenting with multiple melanocytic lesions.

Notes: Light microscopic studies have shown that nevus cell nests and melanoma nests are surrounded by basement membrane (BM) material containing type IV collagen and laminin. This study confirms this by electron microscopy and relates it to proteins which interact with the basement membrane. Nevi except for dysplastic and Spitz nevi, malignant melanomas, and melanoma metastases were studied by immunohistopathology, routine electron microscopy (EM), and immunoelectron microscopy. The lesions were incubated with monoclonal antibody (moAb) against type IV collagen, laminin, and the integrin α6 and studied by light microscopy. In addition, melanomas were studied by immuno-EM after incubation with a moAb against matrix metalloproteinase-2 (MMP-2). Nevus cell nests and melanoma nests are surrounded by BM material containing type IV collagen and laminin by immuno-EM. The BM material various in thickness and is amorphous. Type IV collagen, laminin, and MMP-2 are synthesized by melanoma cells as well as adjacent fibroblasts. Destruction or loss of the BM is not mandatory for melanoma invasion or even metastasis. Possibly the BM material is a protective wall for melanoma cells. Interactions between melanocytes and the extracellular matrix of which the BM is a part, can be traced back to the migration of melanocytes from the neural crest.

Notes: In embryos morphogenetically active cells transiently express the cholinergic system comprising cholinesterase activity and muscarinic acetylcholine receptors. Malignant melanomas develop from melanocytes, which are derived from the neural crest. Neural crest cells express the embryonic muscarinic system during migration. Using the monoclonal antibody M35, we now show that normal melanocytes carry no muscarinic receptors, whereas malignant melanoma cells express them again. In primary melanomas and metastatic melanomas, we identified muscarinic receptors in solid strands or groups of atypical cells. In all primary malignant melanomas studied we found inhomogeneous distributions of M35-inimunoreactivity subdividing the tumors into three different zones. In the tumor center, groups or single cells often showed only little or even no immunofluorescence. In contrast, pericentrally we detected strong immunostaining in the conglomerations of atypical melanocytes. In the peripheral infiltration zone, intensely fluorescent cells in clusters or single, were spreading into the normal tissue, leading to a more patchy staining pattern. Melanocytes of nevi also possess muscarinic receptors, showing similar distribution patterns as in the melanoma. We suggest that in malignant melanomas muscarinic receptors might play a regulative role in infiltrative growth and metastasis.

Notes: Summary Synchronous measurement of laser Doppler flux (LDF) and capillary red blood cell velocity (CBV) was performed in adjacent areas of the same nailfold during a local cold stress test in 12 healthy controls (eight women and four men) and in 22 patients (17 women and seven men) with secondary Raynaud's phenomenon before and after treatment. Two questions were addressed: Are there any differences in the signal pattern between LDF and RBV? Is it possible to detect early on in therapy, before clinical benefit becomes obvious, whether a treatment is successful or not?Despite the fact that the resulting signal patterns recorded by these two techniques are widely compatible, certain differences could be observed. In healthy controls, decrease of values during cooling time and increase after cooling were more distinct in RBV than in LDF.Compared with control values, CBV and LDF in patients with Raynaud's phenomenon were lower. After cooling CBV took an average of 3 min to reach initial value again as compared with 40s in healthy controls. During 4 min observation time, pretest values of LDF were not achieved again in patients, whereas it took 50s in healthy controls.If, after a few days of vasospasmolytic therapy, test results improved or normalized, clinical symptoms subsided gradually during the next weeks. Clinical improvement was not observed in those patients in whom cutaneous blood flow remained decreased despite therapy. CBV indicated this more clearly than LDF. Duration of flow stop at the end of cooling showed a marked improvement in patients treated successfully.Discrepancies between CBV and LDF are interpreted as being due to LDF detecting other vessels in addition to the superficial, nutritional capillaries. LDF seemed to be a poor tool for evaluating the effect of treatment. Determination of CBV and flow stop duration during local cold exposure may help in early selection of the best treatment for a patient with Raynaud's phenomenon by predicting later possible clinical benefit.

Notes: Background The aetiology of morphoea is still unknown. Borrelia burgdorferi as a causative agent of morphoea has been discussed since 1985, but the relationship remains uncertain. Objectives We aimed to find evidence for infection with B. burgdorferi by combined evaluation of different clinical and laboratory data in a group of 54 patients with morphoea. Methods In each patient, an evaluation of the case history was performed with regard to infection with B. burgdorferi, using a standardized questionnaire. Questions focused on previous tick bites and skin changes suspicious for erythema migrans (EM). The case history data of 52 patients were compared with those of 104 matched control subjects and of 25 patients with acrodermatitis chronica atrophicans (ACA). Serological examinations were performed in 53 patients with morphoea. Furthermore, lesional skin was examined for borrelial DNA in 33 patients, using nested polymerase chain reaction (PCR) for the ospA and the borrelial rRNA gene. Results Results of the questionnaire showed no differences between patients with morphoea and matched controls. In contrast, patients with ACA showed a much higher prevalence of tick bites and skin changes suspicious for EM as compared with patients with morphoea. Serological examination was positive in only one patient with morphoea alone and in two additional patients with coexistent ACA. No borrelial DNA was detected by PCR in lesional skin of 33 patients with morphoea. Conclusions No evidence was found for B. burgdorferi infection in patients with morphoea.