[The satisfied patient in aesthetic dermatology. Consensus work on patient satisfaction in botulinum toxin A treatment]. / Der zufriedene Patient in der ästhetischen Dermatologie. Konsensusarbeit zur Patientenzufriedenheit in der Behandlung mit Botulinumtoxin A.

Patient satisfaction is an important factor for successful therapy. Many consensus reports have been published regarding correct treatment with botulinum toxin A (BTX-A). However, the focus of most of these publications has been on technical aspects and the important topic of patient satisfaction was often only one aspect among others. The Swiss Group of Esthetic Dermatology and Skincare (SGEDS) pursued these questions in a two-day consensus meeting. Patients of aesthetic dermatology are healthy and therefore place higher demands in contrast to ill patients of medical dermatology. This demands a great deal of the physician, the practice staff and the conditions in the practice to accommodate the special requirements of aesthetic clients. Informative consultation and patient education are of major importance; this also holds true for clinical performance and care before, during and after treatment with BTX-A. This publication aims at finding ways to gain greater patient satisfaction in daily practice.

Professional risk for skin cancer development in male mountain guides--a cross-sectional study.

OBJECTIVE: For reasons of their outdoor work, mountain guides (MG) are heavily exposed to ultraviolet radiation during their work. METHODS: A standardized interview and examination were performed on 283 male MG (median 41 years) from Germany, Switzerland and Austria and 309 age-matched controls. The median occupation time as MG was 17 years; 39.9% were working full-time. RESULTS: The incidence of skin cancer and precancerous lesions was obtained. Precancerous lesions as solar keratosis (SK) were significantly more frequent in MG (25.4% vs. 7.4%). There was no skin cancer [BCC, SSC, melanoma (MEL)] in the control subjects. Basal cell carcinoma (BCC) was diagnosed in 20 MG (7.1%) and SSC in four MG (1.4%). There were 10 highly suspicious melanocytic lesions; one MG had a histologically confirmed malignant MEL. Risk factors for SK in the multivariate analysis included occupation (P < 0.0001), age (P < 0.0001) and skin type (P = 0.0002). Within the MG group, age (P < 0.0001) and hair colour (P = 0.0058) were independent risk factors for SK. Severe lifetime sunburns (P = 0.0007) and skin type (P = 0.041) were the significant risk factors for BCC, within the MG group in addition to the number of guiding days (P = 0.010). The risk factor for skin cancer (BCC, SCC and MEL) was the number of heavy sunburns during lifetime (P = 0.0014). CONCLUSION: The present study demonstrates an association between high occupational ultraviolet-exposure and an increased prevalence of precancerous skin lesions and skin cancer. MG may be considered as an example for other outdoor professionals. Skin cancer of outdoor workers is likely to be an occupational disease. Primary and secondary prevention should be enforced.

Metastatic pathways and time courses in the orderly progression of cutaneous melanoma.

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.

Activity, expression, and transcription rate of the cathepsins B, D, H, and L in cutaneous malignant melanoma.

BACKGROUND: Increased activity of the protease cathepsin B has been demonstrated in many tumor cells. A correlation of cathepsin B activity and metastatic potential of melanoma has been well established. METHODS: The cathepsins B, D, H, and L were evaluated in normal skin, nevi, and melanoma samples to obtain information about their role and their regulation in melanoma. The authors localized specific proteolytic activity with histochemistry, cathepsin protein immunohistochemistry, and mRNA with in situ hybridization. RESULTS: Activities and immunoreactivities of the cathepsins B and L were found to be increased in all melanocytic lesions. However, the staining for the corresponding mRNA levels was elevated only in melanomas. Cathepsin D protein and mRNA were expressed to a higher degree only in the dysplastic nevus and in melanomas. The increase was due to tumor cells and cells of the surrounding tissue. Cathepsin H activity, immunoreactivity, and mRNA appeared to be correlated inversely with the invasive potential of the lesion. CONCLUSIONS: It may be relevant for the malignant potential of the lesion whether the increase in activity is accompanied by an increase in the mRNA level. Two different mechanisms-the existence of different mRNAs and the higher transcription rate of the cathepsin gene-have been proposed for the regulation of cathepsin B activity in tumor cells. The current data suggest that, depending on the thickness of the melanoma, cathepsin activity is regulated by different mechanisms. The up-regulation of cathepsin gene transcription appears to be characteristic for more invasive tumor cells.

Significance of serum protein S100 levels in screening for melanoma metastasis: does protein S100 enable early detection of melanoma recurrence?

A number of recent reports suggest serum protein S100 as a prognostic parameter in patients with metastatic melanoma. In the present study, serum protein S100 was investigated as a tumour marker for screening for melanoma metastasis in patients attending regular follow-up examinations. During the period from September 1997 to December 1998, serum protein S100 levels were measured by an immunoluminometric assay in 411 consecutive high risk melanoma patients (666 samples) and in 120 control subjects. Melanoma patients with resected primary tumours with a tumour thickness of 1.5 mm or more with resected metastasis were included in the study. Overall, 41 of the 411 patients developed metastasis during the period of observation. According to the distribution of protein S100 levels, the following different cut-off values were examined: 0.08 microg/l (95 percentile of the control group) and 0.13 microg/l (95 percentile of the group of melanoma patients without metastasis). The test efficiency for protein S100 as a diagnostic test for the detection of metastasis was highest for the cut-off value of 0.13 microg/l. In eight of the 41 patients (19.5%), elevation of protein S100 was the first sign of recurrence. Of the 41 patients with metastatic disease, 13 had elevated protein S100, giving a sensitivity of 0.32. The specificity for the detection of metastasis was 0.96. In eight of the 14 patients (57%) who developed distant metastasis, elevated S100 values were the first sign of tumour progression. In conclusion, determination of serum protein S100 levels enables earlier detection of distant metastasis in patients at high risk for metastasis. The impact on survival time needs to be investigated in follow-up studies.

High prevalence of seborrhoeic dermatitis on the face and scalp in mountain guides.

BACKGROUND: High incidence rates of seborrhoeic dermatitis (SD) have been reported in HIV-infected individuals, indicating immunosuppression to be involved in the pathogenesis. OBJECTIVE: To establish the prevalence of SD in mountain guides who have a high occupational exposure to solar UV radiation. PATIENTS AND METHODS: In November 1999, 283 mountain guides were physically examined on the face and scalp for symptoms of SD in Austria (n = 75), Switzerland (n = 123) and Germany (n = 85); they were 21.3-93.1 years of age (median age 41.4 years). RESULTS: Forty-six of 283 (16. 3%) mountain guides when examined clinically were found to have SD. The median age of mountain guides with SD was 41.2 years. There were similar incidence rates in all three countries. CONCLUSION: SD affects mountain guides in a clearly higher percentage as the general population. We suggest UV-induced immunosuppression due to occupational sun exposure as a pathogenetic factor.

Ultrasound examination of regional lymph nodes significantly improves early detection of locoregional metastases during the follow-up of patients with cutaneous melanoma: results of a prospective study of 1288 patients.

BACKGROUND: In regional lymph node metastasis of cutaneous melanoma, the number and volume of involved lymph nodes are the most important prognostic factors. Several studies have revealed that palpation of the lymphatic drainage area(s) and regional lymph nodes has a high rate of false-negative results during follow-up. The aim of the current study was to assess the sensitivity and specificity of ultrasound versus clinical diagnosis in the detection of subcutaneous and regional metastases. METHODS: During a period of 42 months, a total of 6328 lymphatic drainage areas were examined clinically and by ultrasound (7.5-10 MHz) in 1288 melanoma patients at 4435 follow-up consultations. When an ultrasound finding was suggestive of metastasis, surgery and histopathologic evaluation were performed. The results of clinical examination, ultrasound examination, and histopathologic findings were compared. RESULTS: In 504 ultrasound examinations performed on 235 patients, metastatic disease was diagnosed in 263 examinations following surgery (179 patients). Due to advanced disease or rejection, an additional 56 patients did not undergo surgery. In 239 of the 263 positive findings (90.9%), metastases from melanoma were histopathologically confirmed. In 8 cases (3%) a second malignancy and in 16 cases (6. 1%) benign lymphadenopathy was histopathologically diagnosed. Palpation of subcutaneous lymph nodes and lymph nodes gave false-negative results in 68 of the 238 cases of histopathologically proven metastases (28.6%). Clinical examination was least sensitive in the supraclavicular, axillary, and infraclavicular regions. The sensitivity and specificity for ultrasound examination were 89.2% and 99.7%, respectively, and 71.4% and 99.7% for clinical examination, respectively. CONCLUSIONS: For early diagnosis of in-transit and regional lymph node metastases in cutaneous melanoma, ultrasound scanning is distinctly superior to clinical examination. Controlled follow-up studies are proposed to examine the possible beneficial effects on survival time resulting from the ultrasound examinations of the lymphatic drainage area(s) and regional lymph nodes.

Prognostic impact of the type of anaesthesia used during the excision of primary cutaneous melanoma.

The prognostic value of the type of anaesthesia used for the excision of malignant tumours has been a subject of controversy. Cell-mediated as well as humoral immune responses can be compromised after general anaesthesia, and recurrences may therefore occur more frequently. On the other hand, excision of primary tumours under local anaesthesia might also influence the prognosis unfavourably. The aim of the present study was to determine the prognostic impact of general and local anaesthesia for the primary excision of cutaneous melanoma. Follow-up data of 4329 patients on the Central Melanoma Registry of the German Dermatological Society were analysed. Cox proportional hazards analysis was performed to evaluate the independent significance of the prognostic factors, and survival probabilities were calculated for matched pairs using Kaplan-Meier estimates. Statistical analysis revealed an independent significant effect on survival for tumour thickness, ulceration, level of invasion, anatomical site and gender. General anaesthesia for primary excision of melanoma was associated with a decrease in the survival rate (relative risk 1.46, P<0.0001). This study revealed a slight but significantly increased risk of death for patients treated with general anaesthesia for the primary excision of melanoma. Therefore local anaesthesia should be preferred for the treatment of primary melanoma.

Awareness and early detection of cutaneous melanoma: an analysis of factors related to delay in treatment.

Factors associated with the detection of cutaneous melanomas and reasons for delay in diagnosis were investigated in 429 patients with histologically proven melanoma operated on between January 1993 and June 1996. Patients were interviewed using a standardized questionnaire. In 25% of patients, treatment was delayed for more than 1 year from the time they first noticed a suspicious pigmented lesion. Melanoma was detected by the patients themselves in 67% of women and 45% of men. The three predominant clinical symptoms of melanoma were change in colour (darker), increase in size and increase in elevation of a pigmented lesion. The role of sun exposure and of naevi as risk factors for melanoma, as well as the potential benefit of early treatment, were known by 87%, 66% and 82% of the patients, respectively. However, melanoma awareness had no impact on the time period between first observation of skin changes and treatment. Among the factors associated with delay in melanoma diagnosis, an initial incorrect diagnosis as a benign lesion by the physician first visited (in 18% of all cases) had the highest significance. Patients detecting their lesions themselves were treated significantly later than patients in whom others had remarked on changes in a naevus. Furthermore, melanomas of the head and neck were treated later than melanomas at other body sites. Further efforts to educate both the public and the medical profession are essential to ensure earlier treatment for cutaneous melanomas.

Patterns of local horizontal spread of melanomas: consequences for surgery and histopathologic investigation.

Understanding local spreading patterns of melanomas is a precondition for the localized surgical treatment and histopathologic investigation. We used hematoxylin and eosin-stained paraffin sections for a two-phase, cellular and microscopic study of patterns of lateral spread in superficial spreading melanomas (SSMs), nodular melanomas (NMs), lentigo maligna melanomas (LMMs), and acral lentiginous melanomas (ALMs). Complete histologic examination of vertical excisional margins was carried out with paraffin sections 5 mm beyond the clinical tumor border of 1395 SSMs, 376 NMs, 179 LMMs, 46 ALMs, and 37 acrally located SSMs or NMs. Further sections of embedded material were analyzed when tumor-positive margins were found. In case of continuous tumor spread, reoperations were continued until the tissue was free of tumor cells. In case of noncontinuity, a final excision was made to a minimum safety margin of 10 to 20 mm. Concentrically consecutive, 5-microm thick hematoxylin and eosin-stained sections were taken from the outside of a 10-mm safety margin inward to the clinical borders of 34 SSMs, five NMs, 10 LMMs, and five ALMs. Noncontinuous subclinical spread was found in all SSMs and NMs in the form of few isolated cell nests at the epidermis-dermis junction. Ninety-two percent of these were located within 6 mm of the central tumor. All LMMs and ALMs showed a clearly demonstrable, uninterrupted spread into the periphery at the epidermis-dermis junction, too, usually in groups of outgrowths. The probability of finding these outgrowths 5 mm beyond the clinical tumor border was 54% in LMM and ALM. Complete histologic examination of vertical excisional margins (micrographic surgery) is therefore the therapy of choice only for LMM and ALM and is inefficient for SSM and NM.

Granulomatous mycosis fungoides: report of a case with some histopathologic features of granulomatous slack skin.

We describe a case of granulomatous mycosis fungoides, tumor stage, mimicking sarcoidosis in an 82-year-old man with a 2-year history of skin disease. The final diagnosis was established after one of seven biopsy specimens showed a nongranulomatous histologic picture of patch-stage mycosis fungoides. Monoclonality was proven for the lymphocytic population by T-cell-receptor rearrangement studies. The unusually extensive granulomatous inflammation with huge giant cells surrounded by CD1a-positive cells in the other six biopsy specimens was suggestive of the histopathology of granulomatous slack skin, another rare granulomatous cutaneous T-cell lymphoma. Because both a clinical and histologic overlap between granulomatous mycosis fungoides and granulomatous slack skin have been reported in the literature, we conclude that they may belong to the spectrum of a single disease.

[Microcirculation of cutaneous melanoma]. / Die Mikrozirkulation des kutanen Melanoms.

The microcirculation of human skin tumours can be visualized with noninvasive methods from clinical microcirculation research (capillaroscopy and laser Doppler fluxmetry (LDF). The latter can also be used to measure the blood flow in such tumours. This prospective study was designed to evaluate melanoma-associated cutaneous neoangiogenesis. We studied the microcirculation of 114 pigmented skin tumours in 103 patients (63 women, 40 men) averaging 38.8 +/- 21.1 years of age. On the basis of histological findings, we diagnosed melanocytic naevus in 86 cases and malignant melanoma in 28. The malignant melanoma was characterized by a chaotic arrangement of the capillaries, which were dilated and formed corkscrew-shaped or glomerular structures. In the transitional area between healthy and cancerous areas there was hypervascularization. The capillaries of the melanoma appeared to be more permeable towards the low-molecular-weight, water-soluble sodium fluorescein. Laser Doppler flux, a measure of cutaneous circulation in the upper 2 mm of the skin, is higher in the center of the melanoma than in either the middle of melanocytic naevus (p < 0.0005) or in neighbouring healthy skin areas (P < 0.005). In the future, antiangiogenetic therapy strategies could play a significant role in the treatment of malignant melanoma. These methods provide a reliable means of evaluating the specific antiangiogenetic efficacy of treatments for cutaneous melanoma.

Metastatic melanoma of unknown primary origin shows prognostic similarities to regional metastatic melanoma: recommendations for initial staging examinations.

BACKGROUND: Metastatic melanoma of unknown primary origin accounts for approximately 2-6% of all melanoma cases. The prognostic significance of this diagnosis is still controversial. METHODS: Of 3258 patients with malignant melanoma recorded during the period 1976-1996, 2.3% had metastases of unknown primary origin. Anatomic distribution, clinical stage, and survival probabilities were evaluated. RESULTS: Thirty patients were classified as having cutaneous or subcutaneous in-transit metastases, and they showed a 5-year survival rate of 83%. Thirty-seven patients were classified as having lymph node metastasis, and their 5-year survival rate was 50%. Disseminated disease was diagnosed in only 8 patients, who had a median survival of 6 months. Comparison of survival probabilities for patients with in-transit metastases and unknown primary tumors with the probabilities for those with cutaneous primary tumors revealed a significant advantage for the former group. No significant differences were found for patients with lymph node metastasis when those with unknown primary tumors were compared with those who had cutaneous melanomas with regional lymph node metastasis. CONCLUSIONS: The clinical disease course of patients with metastatic melanoma of unknown primary origin is similar to that of patients with primary cutaneous melanoma when the same clinical stages of the disease are compared. Based on the assumption that the majority of regional metastases develop from completely regressed primary cutaneous melanoma, recommendations for initial staging examinations in patients with unknown primary tumors are given in this article.

Prolonged survival of 2 years or longer for patients with disseminated melanoma. An analysis of related prognostic factors.

BACKGROUND: Once melanoma has metastasized to distant sites, the prognosis is usually poor, showing an overall median survival of 6-8 months. Long term survival is extremely rare, and there is still controversy concerning the prognostic significance of therapeutic modalities. The aim of the current study was to identify important prognostic factors associated with Stage IV melanoma. METHODS: The current study was based on data for 3258 melanoma patients, for whom clinical, pathologic, and long term follow-up information was recorded during the period 1976-1996 at the Eberhard-Karls-University in Tuebingen. Germany. The attainment of 2 years' or longer survival time by patients with disseminated melanoma was addressed, and a multivariate analysis of related prognostic factors was performed by logistic regression. RESULTS: Four hundred forty-two patients (13.6%) developed distant metastasis. The median survival time was 7 months, and the 2-year, 5-year, and 10-year survival rates were 11.9%, 6.7%, and 4.7%, respectively. Forty-five patients had prolonged survival of 2 years or longer. Significantly more females belonged to the group of long term survivors (P = 0.0186). Of the modalities of therapy given, only surgery was associated with prolonged survival (P < 0.0001). Primary metastasis to the skin (P = 0.006), the brain (P = 0.015), more than a single metastatic site (P = 0.002), and Karnofsky performance status of less than 80 (P = 0.0035) were significantly related to short term survival. In addition, subsequent development of two or more new metastatic sites was also associated with short term survival (P = 0.0025). CONCLUSIONS: In the current analysis, prolonged survival of 2 years or longer for patients with disseminated melanoma was shown to depend on gender, site of primary metastasis, number of metastatic sites, and Karnofsky performance status. Of the modalities of therapy given, only surgery significantly influenced survival. However, in a small percentage of patients, long term complete remission was achieved with chemotherapy alone or in combination with surgery, suggesting that such regimens might be curative in selected cases.

Aminopeptidase M and dipeptidyl peptidase IV activity in epithelial skin tumors: a histochemical study.

The activities of microsomal alanylaminopeptidase (APM EC 3.4.11.2) and of dipeptidyl dipeptidase IV (DPP IV EC 3.4.14.5) were histochemically studied in frozen sections of normal skin, seborrheic keratosis, basal cell carcinoma, solar keratosis, Bowen's disease and squamous cell carcinoma using amino acid- or peptide-4-methoxy-2-naphthylamides as specific chromogenic substrates. Compared to biochemical and immunohistochemical methods, the histochemical technique used in this study allows distinct localization of protease activity within the tumor tissue and the tumor-associated stroma. Strong APM activity was detectable only in the stroma of basal cell carcinoma, a result which reflects the particular tumor-stroma interaction of this semimalignant tumor. APM activity was not detectable in either healthy epidermis or the tumor parenchyma. Altered activity of DPP IV was found in the tumor cells as well as in the surrounding connective tissue: precancerous dermatoses and basal cell carcinomas had higher levels of DPP IV-activity than normal skin or benign seborrheic keratosis. Poorly differentiated malignant squamous cell carcinomas, however, showed no histochemically detectable DPP IV-activity at all. This result is in line with reports of decreased activity of this enzyme in cases of malignancy.

Demonstration of proteases in basal cell carcinomas. A histochemical study using amino acid-4-methoxy-2-naphthylamides as chromogenic substrates.

BACKGROUND: Proteases are reported to play an essential part in the proliferative, invasive, and metastasizing behavior of malignant tumors. The aim of the current study was to determine the activity and localization of proteases in basal cell carcinomas (BCC) histochemically. METHODS: Various proteases were identified histochemically in frozen sections of BCC. The following amino acid-4-methoxy-2-naphthylamides (MNA) were used as chromogenic substrates:alanine-MNA for the detection of aminopeptidase M (APM), glycyl-proline-MNA for dipeptidyl peptidase IV (DPP IV), lysyl-proline-MNA and lysyl-alanine-MNA for dipeptidyl peptidase II (DPP II), glycyl-arginine-MNA for dipeptidyl peptidase I (DPP I), and carbobenzoxy (CBZ)-arginyl-arginine-MNA for cathepsin B. RESULTS: APM activity was high in the peritumorous connective tissue, whereas the tumor epithelium and epidermis had negative results. DPP IV showed a highly positive reaction in both tumor epithelium and surrounding connective tissue. Cathepsin B and DPP I reacted strongly in the tumor epithelium but not in the peritumorous connective tissue. CONCLUSIONS: The marked activity of APM, DPP IV, DPP I, and cathepsin B may be related to the proliferation and invasive growth of BCC. The distribution of the activity of APM and DPP IV indicates dynamic interactions between the tumor epithelium and the adjacent connective tissue in the neoplastic process.

Destruction of tumour parenchyma in basal cell carcinoma by tumour-associated neutral proteases: a histochemical study.

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 epidermis disintegrated to varying degrees, particularly where they were directly in contact with tumour epithelium. Serine and metalloprotease inhibitors diminished this tissue destruction. Iodoacetate 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.