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Notes: Zusammenfassung Es wird über elektronenmikroskopische, histochemische und biochemische Untersuchungen bei sog. Reticulosarkomatose der Haut (Gottron) berichtet. Die elektronenmikroskopischen Befunde zeigen, daß das Tumorgewebe ein charakteristisches feingewebliches Substrat besitzt. Es setzt sich zusammen aus vielkernigen Zellkomplexen und in diesen gelegenen einkernigen Individualzellen. Die einfach ausgebildete und schwach konturierte Membran zwischen einkernigen Einzelzellen und mehrkernigen riesenzellartigen Zellformationen spricht dafür, daß die Einzelzellen unter Verlust ihres Plasmalemms in die sie umgebenden riesenzellartigen Zellformationen aufgehen. Das weitgehende Fehlen von Kernmembranen, die hohe Zahl von freien Ribosomen und die Verminderung sowie morphologische Alteration der Mitochondrien sprechen für einen hohen Stoffwechsel der Tumorzellen, der vorwiegend auf die Produktion zelleigenen Proteins ausgerichtet ist. Histochemisch waren die Tumorzellen charakterisiert durch einen starken Reaktionsausfall auf das glykolytische Enzym Lactatdehydrogenase. Der histochemische Reaktionsausfall auf Enzyme des Citronensäurecyclus und der Atmungskette war vermindert. Die quantitativ-biochemischen Untersuchungsergebnisse zeigten relativ hohe Aktivitäten von Hauptkettenenzymen und des Pentosephosphat-Shunts bei vergleichsweise niedrigen Aktivitäten von Enzymen, die mitochondrial lokalisiert sind (NAD-spezifische Glutamatdehydrogenase) oder speziellen Stoffwechselwegen zuzuordnen sind.

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: 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: 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: Proteolytic activity was demonstrated histochemically in frozen sections of basal cell carcinomas (BCCs). After incubation of tissue sections in 0.1 m phosphate buffer with 0.25 m NaCl the tumour epithelium was almost completely destroyed. The basal and squamous cell layers of the disintegrated to varying degrees, particularly where they were directly in contact with tumour epithelium. Serine and metalloprotease inhibitors diminished this tissue destruction, lodoacetate enhanced tumour destruction, urea and potassium thiocyanate even more so. The high proteolytic activity of BCC demonstrated in this study may be an important factor in the proliferative, invasive and destructive behaviour of this tumour.

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 Tyrosinase reverse transcription–polymerase chain reaction (RT–PCR) has been shown to be highly sensitive in detecting tumour cells in melanoma patients. Objective To assess whether the detection of minimal residual disease by RT–PCR is improved by concomitant analysis of sentinel lymph nodes (SLNs), bone marrow (BM) and peripheral blood (PB) in patients with primary melanoma. Methods Thirty-five SLNs, 41 BM samples and 26 PB specimens from 26 patients with primary cutaneous melanoma (tumour thickness ≥ 0·75 mm) were examined by nested RT–PCR for tyrosinase and Melan-A. SLNs and BM samples were also analysed by histopathology. RT–PCR findings were related to tumour thickness of the primary melanoma. Results Overall, melanoma cells were detected by RT–PCR in 13 of 26 patients (50%). Seven patients had positive RT–PCR results in their SLNs (27%), including all patients (n = 4) with histologically positive SLNs, two patients had positive findings in their BM exclusively detected by RT–PCR (8%) and six patients in PB (23%). The presence of tumour cells detected by RT–PCR in SLNs was not related to the presence of melanoma cells in BM and/or PB. The incidence of RT–PCR-positive SLNs was significantly associated with greater tumour thickness (P = 0·004). Both patients with positive RT–PCR findings in their BM had a large tumour thickness (≥ 2 mm). No association between positive RT–PCR findings in PB and greater tumour thickness was observed. Conclusions RT–PCR-positive SLNs were strongly associated with greater tumour thickness, underlining the prognostic significance of SLN positivity. Similar to certain epithelial malignancies, molecular investigation of the BM might provide complementary prognostic information in the early stages of melanoma. In contrast, no association between positive RT–PCR results in PB and increasing tumour thickness was found, implying that RT–PCR findings in PB are of doubtful clinical relevance in primary melanoma.