The impact of sentinel node dissection on disease-free and overall tumour-specific survival in melanoma patients: a single centre group-matched analysis of 1192 patients.

BACKGROUND: Sentinel lymph node dissection (SLND) is considered a standard staging procedure providing important prognostic information on melanoma patients. It remains a matter of debate, whether SLND and hence, removal of potential lymph node micrometastasis will alter survival outcome. OBJECTIVE: The aim of this group-matched analysis was to compare survival data of a large cohort of melanoma patients who were treated by wide local excision only (WLE) and nodal observation (WLE group) to a group of patients treated with WLE plus SLND group to investigate the potential therapeutic benefit of SLND in the treatment of patients with melanoma. METHODS AND MATERIALS: A total of 596 consecutive patients who had undergone WLE plus SLND between 1996 and 2003 were assessed. As a historical control group 596 patients treated with WLE and nodal observation but without SLND between 1986 and 1995 were selected. The groups were matched according to sex, age, Breslow tumour thickness and localization of primary tumour. The adjuvant treatment and follow-up examinations were performed according to protocols of the German Dermatologic Cooperative Oncology Group (DeCOG) and applicable study protocols that our clinic participated in; and hence, subject to change over time. RESULTS: Kaplan-Meier testing revealed significant differences in survival in favour of the SLND group. Mean overall tumour-specific survival (OS) was 102.7 months in the SLND group vs. 97.0 months in the WLE group respectively (P-value: 0.024). Disease-free survival (log-rank test: 0.003) and time to lymph node progression (P-value: <0.01) also differed significantly between the two groups. CONCLUSION: SLND is not only an important diagnostic procedure, but might also be of therapeutic benefit in terms of disease-free and overall tumour-specific survival of melanoma patients.

A multicentre pilot study investigating high-definition optical coherence tomography in the differentiation of cutaneous melanoma and melanocytic naevi.

BACKGROUND: High-definition optical coherence tomography scanners have recently been developed. OBJECTIVES: To assess the diagnostic performance of HD-OCT in the differentiation of benign melanocytic skin lesions (MSL) and cutaneous melanoma (CM). METHODS: Patients with MSL were assessed by HD-OCT. All diagnoses were histopathologically confirmed. One blinded observer evaluated both slice and en-face HD-OCT images and diagnosed MLS on the basis of an algorithm adopted from reflectance confocal microscopy, recent HD-OCT reports, and conventional OCT. RESULTS: A total of 93 MSL were studied comprising 66 benign MSL and 27 CM. The sensitivity of HD-OCT was 74.1% [95% confidence interval (CI) 53.7-88.8%)], specificity was 92.4% (95% CI 83.2-97.5%). The positive predictive value was 80%, the negative predictive value 89.7%. The performance of HD-OCT depended on tumour thickness and the presence of borderline lesions indicated by high false negative rates in very thin melanomas and high false positive rates in dysplastic naevi. CONCLUSIONS: In the distinction of MSL, HD-OCT applied in an investigator blinded fashion has a moderate diagnostic performance. The diagnostic performance of HD-OCT of MSL should be reassessed in other clinical settings.

Morphology of basal cell carcinoma in high definition optical coherence tomography: en-face and slice imaging mode, and comparison with histology.

BACKGROUND: Optical coherence tomography (OCT) allows real-time, in vivo examination of basal cell carcinoma (BCC). A new high definition OCT with high lateral and axial resolution in a horizontal (en-face) and vertical (slice) imaging mode offers additional information in the diagnosis of BCC and may potentially replace invasive diagnostic biopsies. OBJECTIVES: To define the characteristic morphologic features of BCC by using high definition optical coherence tomography (HD-OCT) compared to conventional histology. METHODS: A total of 22 BCCs were examined preoperatively by HD-OCT in the en-face and slice imaging mode and characteristic features were evaluated in comparison to the histopathological findings. RESULTS: The following features were found in the en-face mode of HD-OCT: lobulated nodules (20/22), peripheral rimming (17/22), epidermal disarray (21/22), dilated vessels (11/22) and variably refractile stroma (19/22). In the slice imaging mode the following characteristics were found: grey/dark oval structures (18/22), peripheral rimming (13/22), destruction of layering (22/22), dilated vessels (7/22) and peritumoural bright stroma (11/22). In the en-face mode the lobulated structure of the BCC was more distinct than in the slice mode compared to histology. CONCLUSION: HD-OCT with a horizontal and vertical imaging mode offers additional information in the diagnosis of BCC compared to conventional OCT imaging and enhances the feasibility of non-invasive diagnostics of BCC.

Management of dermatofibrosarcoma protuberans with fibrosarcomatous transformation: an evidence-based review of the literature.

Fibrosarcomatous transformation represents a rare event in dermatofibrosarcoma protuberans (DFSP) with unpredictable biological behaviour. No guidelines for the adequate treatment of patients with this rare neoplasm have been published. Herein, we present a comprehensive review of the literature comprising 157 patients with transformed DFSP focussing on surgical and adjuvant treatment modalities for this tumour. In the cohort examined, local recurrence occurred in 36% of cases and was significantly lower in patients treated by wide excision with margins ≥2 cm when compared with those treated with local excision without defined margins (P = 0.01). Consistently, negative margin status was associated with a lower recurrence rate when compared with positive or unknown margin status (P = 0.01). Distant metastases were detected in 13% of patients, which is significantly higher when compared with ordinary dermatofibrosarcoma protuberans. Systemic dissemination was preceded by local recurrence in 81% of cases, and is therefore strongly associated with tumour recurrence (P ≤ 0.001). The present data confirm that wide excision with margins ≥ 2 cm represent the gold standard in the treatment of transformed dermatofibrosarcoma protuberans, and prevents recurrence as well as metastasis. When R0-resection is not feasible, adjuvant radiation should be considered for cases with incomplete resection or unknown surgical margins. Irresectable or metastatic transformed DFSP harbouring the COL1A1-PDGFB fusion gene should be treated with imatinib in the palliative setting or as an adjunctive treatment before surgery, although responses may be short-lasting.

New reasons for histopathological nail-clipping examination in the diagnosis of onychomycosis.

BACKGROUND: Onychomycosis is a common problem. Today, the gold standard in the diagnosis of onychomycosis is the direct microscopy and fungal culture. But direct microscopy is regarded as having a low sensitivity and fungal culture takes long time. In addition, in cases of controlling the antifungal treatment course, the present gold standard is often not a reliable tool because of the inhibition of the fungal growth in the culture. OBJECTIVE: The purpose of this study was to compare the present gold standard with histological examination with periodic acid-Schiff staining (PAS) of nail clippings in the diagnosis of onychomycosis in a large cohort. MATERIALS AND METHODS: We prospectively evaluated 1146 nail samples from 851 patients with clinical signs of onychomycosis using direct microscopy and fungal culture in comparison with PAS-stain. RESULTS: A total of 631 nail samples revealed a positive result in at least one test. The most sensitive single test for the diagnosis of onychomycosis was PAS with 82%, followed by culture (53%) and direct microscopy (48%). In 64 cases, in which a prediagnostic antimycotic treatment has been initiated, PAS showed to have by far the highest sensitivity (88%) in comparison with culture (33%) or direct microscopy (50%). CONCLUSIONS: Periodic acid-Schiff staining is the single method with the highest sensitivity in terms of detection of fungal elements (hyphae) in nail specimens. Especially in cases with prior antifungal treatment, histological analysis of PAS-stained nail clippings should be considered as an appropriate diagnostic tool.

[Topical terbinafine. Reduction of duration of therapy for tinea pedis]. / Terbinafin-Topika. Ultimative Verkürzung der Therapiedauer bei Tinea pedis.

Superficial fungal infections are common and worldwide in distribution. Latest estimates suggest one- third of the population in Europe has a fungal infection of their feet, with dermatophyte infections of the skin of the feet (tinea pedis) most common. Tinea pedis interdigitalis is by far most common and can be effectively treated topically. Common agents include azoles, hydroxypyridones and allylamines, with morpholines used less frequently. While most antifungals have mainly fungistatic effects on dermatophytes, the causative agents of tinea pedis, terbinafine--an allylamine--is fungicidal. Due to this feature shorter treatment periods are possible using topical terbinafine. For effective treatment of uncomplicated tinea pedis interdigitalis, azole cream preparations are often used twice daily for four weeks whereas 1% terbinafine cream can be applied once a day for one week. Since 2006, 1% terbinafine is also available as a film-forming solution (FFS), which makes single-dose treatment possible. FFS may prove superior in daily practice with increased compliance and thus reduced recurrences.

Effective treatment for dermatophytoses of the foot: effect on restoration of depressed cell-mediated immunity.

Superficial infections caused by dermatophyte fungi are highly prevalent throughout the world. Modern antimycotic agents like the azole itraconazole or the synthetic allylamine terbinafine greatly improved treatment outcomes in comparison with former therapeutic options with griseofulvin or older azole preparations like ketoconazole or fluconazole. In randomized trials involving patients with dermotophytoses, a great effectiveness has been shown especially for terbinafine. Oral terbinafine in general is well tolerated, has a low potential for drug interactions and, therefore, may be the most often used therapeutic agent for dermatophyte onychomycosis. However, there is a group of patients suffering from chronic dermatophytoses or early reinfections after antifungal therapy. For these patients, a depression of the delayed-type hypersensitivity reactivity was postulated. Just recently, effective antimycotic treatment, in particular with terbinafine, was shown to enhance and restore cell-mediated immunity, which potentially improves the therapeutic outcome even for this group of patients.

Factors associated with a high tumour thickness in patients with melanoma.

BACKGROUND: Prognosis of patients with melanoma is strongly associated with tumour thickness at time of diagnosis. Therefore, knowledge of patient characteristics and behaviour associated with a high tumour thickness is essential for the development and improvement of melanoma prevention campaigns. OBJECTIVES: The present study aimed to identify sociodemographic, clinical and behavioural factors associated with high tumour thickness according to Breslow. METHODS: The study population consisted of 217 patients with histologically proven primary invasive cutaneous melanomas seen at the Department of Dermatology and Allergology at the Ludwig-Maximilian-University Munich, Germany, between January 1999 and January 2001. Personal interviews were conducted by two physicians to obtain information on sociodemographic characteristics and on patients' knowledge of melanoma symptoms, sun behaviour, delay in diagnosis and related factors. Multivariate linear and logistic regression analysis with stepwise variable selection was used to identify risk groups with a high tumour thickness. To assess possible effect modifications, interaction terms were included in the regression analysis. RESULTS: The median tumour thickness was 0.8 mm (interquartile range 0.5-1.6). Fifty-seven patients (26%) had tumour thickness >1.5 mm. In a multivariate linear regression analysis, patients living alone and patients with a low educational level showed a significantly greater tumour thickness. The relation of melanoma knowledge to tumour thickness was modified by the melanoma subtype: whereas lack of melanoma knowledge led to an increased tumour thickness for the subtypes superficial spreading melanoma, lentigo maligna melanoma and unspecified malignant melanoma, no significant effect was estimated for the subtypes nodular melanoma (NM) and acrolentiginous melanoma (ALM). Sex, age, self-detection of melanoma, patient delay and professional delay were not significantly associated with the tumour thickness in multivariate linear regression. Similar results were found in multivariate logistic regression. CONCLUSIONS: An increased tumour thickness was found in subjects living alone and having a low educational level. These subjects should be targeted in future prevention campaigns in a more focused way. Further efforts are necessary to improve knowledge and earlier detection of melanoma subtypes NM and ALM.

The pH of the skin surface and its impact on the barrier function.

The 'acid mantle' of the stratum corneum seems to be important for both permeability barrier formation and cutaneous antimicrobial defense. However, the origin of the acidic pH, measurable on the skin surface, remains conjectural. Passive and active influencing factors have been proposed, e.g. eccrine and sebaceous secretions as well as proton pumps. In recent years, numerous investigations have been published focusing on the changes in the pH of the deeper layers of the stratum corneum, as well as on the influence of physiological and pathological factors. The pH of the skin follows a sharp gradient across the stratum corneum, which is suspected to be important in controlling enzymatic activities and skin renewal. The skin pH is affected by a great number of endogenous factors, e.g. skin moisture, sweat, sebum, anatomic site, genetic predisposition and age. In addition, exogenous factors like detergents, application of cosmetic products, occlusive dressings as well as topical antibiotics may influence the skin pH. Changes in the pH are reported to play a role in the pathogenesis of skin diseases like irritant contact dermatitis, atopic dermatitis, ichthyosis, acne vulgaris and Candida albicans infections. Therefore, the use of skin cleansing agents, especially synthetic detergents with a pH of about 5.5, may be of relevance in the prevention and treatment of those skin diseases.

Penciclovir cream--improved topical treatment for herpes simplex infections.

Human herpesviruses can be found worldwide and cause many viral infections in immunocompetent as well as in immunocompromised patients. Herpes simplex virus (HSV) diseases can be the cause of life-threatening disease, especially in neonates. After initial infection, HSV persists latently in host neurons with the risk of periodical reactivation over a lifetime. The development of acyclovir, a potent and specific nucleoside inhibitor of the herpes DNA polymerase, was a milestone in the history of antiviral drugs in the late 1970s. During the last decades a better understanding of the replication and disease-causing state of HSV types 1 and 2 has been achieved enabling the development of new and potent antiviral compounds. In the mid-1990s, for example, valacyclovir and famciclovir were launched as prodrugs of acyclovir with improved bioavailability. Despite the numerous drugs available for the systemic treatment of HSV infections, the topical application of a cream containing an antiviral agent is still the most convenient method of treating herpes simplex labialis/facialis in the general population. For some time, the topical standard treatment for recurrent HSV infections has been acyclovir cream, despite the fact that the evidence for efficacy in recurrent episodes has been equivocal. Penciclovir, a novel acyclic nucleoside analogue, has demonstrated efficacy against HSV types 1 and 2 and seems to have a pharmacological advantage due to a prolonged half-life of its active form in HSV-infected cells. This review discusses and compares the topical treatment modalities available for HSV infections. As a conclusion, different studies are available that have shown that it is possible to reduce viral replication and hasten lesion resolution with 1% penciclovir treatment beyond the prodromal phase of the HSV infection. Comparing data of topical treatment with acyclovir and penciclovir revealed a superiority for penciclovir cream showing a significant decrease in time to lesion healing, lesion area and pain. While systemic acyclovir or valacyclovir may be valid drugs especially for HSV prophylaxis, 1% penciclovir cream should be preferred as topical treatment since there are good therapeutic results independent of the phase of development of herpetic eruptions.

Disease progression in patients with thin cutaneous melanomas (tumour thickness < or = 0.75 mm): clinical and epidemiological data from the Tumour Center Munich 1977-98.

BACKGROUND: Although survival in patients with thin melanomas (tumour thickness < or = 0.75 mm) is usually excellent, thin melanomas have the potential to metastasize. OBJECTIVES: To determine risk factors for the development of disease progression in patients with thin cutaneous melanomas. METHODS: A retrospective study was performed between 1977 and 1998 to identify risk factors for the development of disease progression in 2302 patients with cutaneous melanoma with tumour thickness < or = 0.75 mm, diagnosed and treated at the Department of Dermatology and Allergology, Ludwig-Maximilians University, Munich, Germany. The Kaplan-Meier method was used to estimate the influence of different clinical characteristics for the occurrence of first progression during 10 years of follow-up. RESULTS: An analysis of the data from 6298 patients with cutaneous melanoma identified 2302 patients (37%) who presented with cutaneous melanoma with a tumour thickness < or = 0.75 mm, without clinical signs of metastasis at initial diagnosis (clinical stage Ia). A small subgroup of our patients (77 of 2302) developed metastatic disease during the follow-up period. The estimated rate of occurrence of metastasis after 10 years of follow-up was 4.7%. The mean follow-up time was 62 months (median 46). Of these 77 patients, 16 experienced progression at the primary tumour site and 32 presented with regional lymph node metastases. Twenty-eight patients primarily developed systemic metastases (seven patients with and 20 without regional lymph node metastases, one patient with regional lymph node metastases and local recurrence). In one patient the primary site of metastatic disease was not reported. Clinical characteristics included age, sex of the patient and different subtypes of cutaneous melanoma: superficial spreading melanoma, nodular melanoma, acrolentiginous melanoma (ALM) and lentigo maligna melanoma (LMM). Male patients and patients with LMM or ALM were significantly over-represented (P = 0.02 and P = 0.002). In the group of 77 patients with thin melanomas (< or = 0.75 mm), local recurrence was over-represented as compared with those with melanomas > 0.75 mm. No difference in group was found for overall survival after the occurrence of lymph node metastasis as the first manifestation of disease progression. CONCLUSIONS: Thorough follow-up and skin examination is recommended for a subgroup of patients with thin tumours, which consists of male patients with LMM or ALM located in the head and neck region.

Lymphadenopathy detected by ultrasound examination as first diagnostic hint of chronic lymphocytic leukaemia in a patient with melanoma.

Recent reports indicate that patients with malignant melanoma might be at higher risk for developing a non-cutaneous unrelated second malignancy. We describe the case of a 46-year-old woman who had a malignant melanoma on her right shoulder that was treated in 1998 by surgical excision combined with axillary lymph node dissection. In 1999, ultrasound examination of peripheral lymph nodes revealed one suspicious echopoor structure in the woman's right axilla that was not palpable. Diagnostic excision and histopathological examination revealed a small B-cell lymphocytic lymphoma, and further investigations led to a diagnosis of chronic lymphocytic B-cell leukaemia (B-CLL). We would like to point out the value of high-resolution ultrasound examination in the follow-up of patients with malignant melanoma; this examination can detect early metastasis as well as other unrelated malignancies.

Delay in the diagnosis of cutaneous melanoma: an analysis of 233 patients.

Knowledge of factors associated with the detection of cutaneous malignant melanomas and reasons for delay in diagnosis are essential for the improvement of secondary prevention of cutaneous melanoma. For this reason, the extent and consequence of patient and professional delay in diagnosis and treatment was investigated in 233 patients with histologically proven primary cutaneous melanomas seen at the Department of Dermatology and Allergology at the Ludwig-Maximilians-University, Munich, Germany, between January 1999 and January 2001. Personal interviews were conducted by two physicians to obtain information on patients' knowledge of melanoma symptoms, sun behaviour, delay in seeking medical attention, professional delay and related factors. The main component of delay was patient related. Nearly one-third (29.2%) of all patients reported a delay interval of more than 12 months from the onset of an observed change in a pigmented lesion or first detection of a pigmented lesion to the first visit to a physician. The delay interval from the first visit to a physician to surgical treatment was shorter (< 1 month) in most of our patients (74.7%). The predominant symptoms of melanoma detected by patients were a change in colour and an increase in size or elevation. Most patients had obtained knowledge about cutaneous melanomas from television and magazines. A delay in diagnosis and a history of many sunburns and outdoor leisure time activities were not associated with a greater tumour thickness. However, fairer skin types, lower education levels and lack of knowledge about cutaneous melanoma were associated with a greater tumour thickness. Further efforts are necessary to improve public and medical education about early detection and prompt surgical treatment, which is known to be the most effective treatment modality for cutaneous melanomas.

Prognostic index for cutaneous melanoma: an analysis after follow-up of 2715 patients.

In 2715 of 4524 patients with cutaneous melanoma treated surgically between 1968 and 1992 prognostic parameters were analysed for their value in predicting the occurrence of first progression. All of the 2715 patients developed only one invasive cutaneous melanoma during the follow-up period. Data concerning tumour thickness and mitotic index (maximum number of mitoses per square millimetre) of the cutaneous melanomas were determined. Between the characteristics age, tumour thickness, mitotic index, prognostic index (PI), sex, site of tumour, melanoma subtype and Clark level, the value of the mitotic index, as a prognostic parameter independent of tumour thickness, and the combination of mitotic index and tumour thickness were evaluated. The development of the first metastases was documented during a mean follow-up of 7.5 years. The majority of first recurrences occurred at regional lymph nodes and attempts have been made to identify those patients at risk of developing metastatic disease. The most effective parameters proved to be tumour thickness and mitotic index. For both parameters an independent prognostic influence was shown. The prognostic index, defined as the product of tumour thickness and number of mitoses per square millimetre, was re-evaluated and confirmed. A new modified prognostic index, defined as the product of square tumour thickness and mitotic index, proved to be even more useful for defining a subgroup of patients who are at risk of developing metastases and, therefore, might benefit from adjuvant therapy.

Risk of second primary malignancies in patients with cutaneous melanoma.

BACKGROUND: In several studies an increased risk for development of breast cancer, malignant lymphoma and neoplasms of the kidney as second primary cancers in patients with cutaneous melanomas was discussed. OBJECTIVES: To determine the risk for development of second primary neoplasms in patients with cutaneous melanomas. METHODS: A prospective study was performed between 1977 and 1992 to evaluate the occurrence of second primary malignancies in 4597 patients (2083 men, 2514 women) with invasive cutaneous melanomas, diagnosed and treated at the Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany. RESULTS: During a median follow-up of 7.2 years, 296 of 4597 patients (6.4%) developed one or more neoplasms at the time of or subsequent to the diagnosis of the first cutaneous melanoma. More than half of these patients developed one or more further melanomas (152, 3.3%). Cancers of the breast, prostate, colon, rectum and kidney occurred less frequently. Statistical calculations revealed a 33.8-fold increased risk for the development of a second melanoma in the entire group [relative risk 38.5 for men (95% CI, 30.4-48.1), 29.0 for women (95% CI, 22.0-37.5)]. Moreover, a significantly increased risk for the development of kidney carcinoma in men was found [relative risk 3.5 (95%, CI, 1.4-7.2)]. CONCLUSIONS: Thorough follow-up and skin examination in patients with cutaneous melanomas is recommended for early detection of other primary melanomas. Furthermore, ultrasound examinations routinely performed in melanoma patients for the detection of melanoma metastases may also be of value for early detection of kidney carcinomas in male patients.

[Metastases in malignant melanoma despite histologically negative sentinel lymph node: should the concept be changed?]. / Metastasierung beim malignen Melanom trotz histologisch negativem Sentinel Lymph Node: Muss das Konzept in Frage gestellt werden?

AIM: The Sentinel Lymph Node (SLN) is of considerable prognostic relevance, because extended lymph node dissection may not be performed in patients presenting with histologically negative SLN. The aim of the present study was to prove the prognostic value of the SLN-concept in these patients. METHODS: So far the clinical follow-up of 162 patients with histologically proven malignant melanoma and metastatically uninvolved (negative) SLN was investigated. Histological examination included standard methods (HE-Test) and special histochemical techniques (S-100, HMB-45). All patients underwent clinical examination, ultrasonic diagnosis of the regional lymph nodes, and x-ray of the chest every 3 months. RESULTS: Despite of negative SLN-findings in 8/162 patients metastases of the malignant melanoma were found after a time period of 5-27 months. Three patients presented with recurrence in the previously mapped (negative) SLN-basin. In another case the scintigraphically visualized SLN could not be identified intraoperatively by means of the hand-held gamma probe. One patient showed intransit-metastases or skin-metastases, respectively; another patient recurred in the scar area. One patient showed hematogenic dissemination (liver) which is not detectable by lymphoscintigraphy; in another patient metastases were found outside the primary lymphatic basin (cervical). CONCLUSION: In our patient group 4.9% presented with metastases despite negative SLN while published data report up to 11% (observation period 35 months), among them only 3 patients (1.9%) being real concept failures. Our results underline that there is no evidence to change this concept in patients with clinically early stage.

Late metastases of cutaneous melanoma: an analysis of 31 patients.

Analysis of data of 6298 patients with cutaneous melanoma seen at the Department of Dermatology and Allergology at the Ludwig-Maximilians University of Munich between 1977 and 1998 identified 31 patients who first experienced metastatic disease 10 or more years after surgical treatment of the primary melanoma. The mean tumor thickness in patients with late progression of disease was 1.4 mm. There was no sex predominance. Of 31 patients, 15 (48. 3%) were female and included both premenopausal and postmenopausal women at the time of initial diagnosis without any predominance. Sixteen of the 31 patients (51.6%) with late onset of progression had primary tumors located on the trunk. The prognosis after relapse was related to the site of recurrence; survival after local or regional node recurrence was often prolonged, whereas survival after distant metastases usually was limited. Survival after late recurrence did not correlate with disease-free survival. A high-risk group for late recurrence could not be identified. The data emphasize the value of continued clinical follow-up and self-examination for early detection of regional recurrences. We advocate a lifelong follow-up, also to identify other melanocytic lesions at risk (eg, dysplastic nevi, secondary or multiple melanomas).