Analysis of predictive factors for the outcome of complete lymph node dissection in melanoma patients with metastatic sentinel lymph nodes.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage patients with melanoma. However, there is no consensus concerning the practical consequences of a positive SLN, since a survival benefit of a complete lymph node dissection (CLND) has not yet been demonstrated. OBJECTIVE: We wondered whether we could identify a subgroup of patients with metastatic involvement of the SLN who could be excluded from the recommendation to undergo CLND. METHODS: At the Department of Dermatology at the University of Munich, a total of 213 patients with metastatic SLNs (24.9%) were identified among 854 patients who had undergone SLNB between 1996 and 2007. All SLN-positive patients had been advised to have CLND. Survival analyses were performed by using the Kaplan-Meier approach. RESULTS: A total of 176 (82.6%) of 213 SLN-positive patients underwent CLND. In this group, 26 patients (14.8%) showed metastatic disease in non-sentinel lymph nodes (NSLN). The 5-year overall survival (OS) was 26.1% in NSLN-positive patients and 74% in NSLN-negative patients. SLN-positive patients who refused CLND had a better prognosis than patients with CLND. Breslow tumor thickness was significantly associated with positive CLND status with higher median values in CLND-positive than CLND-negative patients (3.03 vs 2.22 mm). LIMITATIONS: The subgroup of patients with metastatic disease in CLND may have been too small to reach statistical significance for other tumor- or patient-related parameters. Mitotic indices of the primary melanomas had not been determined in this retrospective study; thus a possible correlation with lymph node status could not be tested. CONCLUSION: Among SLN-positive patients, the presence of metastatic NSLN is a highly significant poor prognostic factor. Tumor thickness is a significant prognostic parameter for positive CLND status and might be considered in the decision to perform CLND in case of metastatic SLN.

Dose-dependent development of depressive symptoms during adjuvant interferon-{alpha} treatment of patients with malignant melanoma.

BACKGROUND: Adjuvant IFN-α treatment for patients with malignant melanoma is often complicated by depression. The influence of dosage, however, is unknown. OBJECTIVE: The authors sought to elucidate this dosage effect. METHOD: Using the Zung Self-Rating Depression Scale and the German Bf-S Self-Rating (Affectivity) Scale, the authors prospectively compared the frequency and severity of IFN-α-induced depressive symptoms between a group of 29 patients receiving low-dose and 17 patients getting high-dose induction therapy for 4 weeks. RESULTS: Patients receiving high-dose induction treatment had significantly higher depression scores after 4 weeks, and significantly more patients in the high-dose group developed depression. CONCLUSION: The authors concluded that frequency and severity of IFN-α-associated depression during melanoma treatment are dose-dependent.

[A rare case of local relapsing oral melanoma]. / Ein seltener Fall eines lokal rezidivierenden oralen Melanoms.

Melanoma of the oral mucosa is an extremely rare tumor. At the time of diagnosis most melanomas are in an advanced stage because of few clinical signs. Therefore the prognosis of melanoma of the oral mucosa is often very poor. We present a 48-year-old patient with melanoma of the oral mucosa first diagnosed 22 years ago. Over 20 years several wide excisions were necessary because of multiple local relapses. Eventually, the patient died from brain metastases.

The use of high-resolution ultrasonography for preoperative detection of metastases in sentinel lymph nodes of patients with cutaneous melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) reliably assesses the status of the regional lymph node basins and provides prognostic information in patients with cutaneous melanoma, but is logistically demanding and expensive. OBJECTIVE: The aim of this study was to evaluate the ability of high resolution B-mode ultrasonography (US) for pre-operative identification and characterization of sentinel lymph nodes (SLN) in patients with cutaneous melanoma. PATIENTS AND METHODS: In a prospective trial, the use of high resolution US was assessed in 25 consecutive patients with cutaneous melanoma identified for SLNB, first, for its value in primary detection of SLN, and, second, for its value in the correct assessment of SLN after lymphoscintigraphic mapping. RESULTS: High resolution B-mode US correctly identified two of 6 positive SLN. The sensitivity, specificity, positive predictive value, and negative predictive value of US were 33.3% (95% CI 43.3-77.7), 100.0% (95% CI 88.1-100.0), 100.0% (95%CI 15.8-100.0) and 87.9% (95% CI 71.8-96.6), respectively. CONCLUSION: High resolution B-mode US cannot replace SLNB, especially in the detection of micrometastases, but it remains the most important method to assess the lymph node status for macrometastases presurgically.

Evidence and interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma.

The primary treatment of a melanoma is surgical excision. An excisional biopsy is preferred, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for higher tumor thickness should be applied either at primary excision or in a two-step procedure. When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm and this operation should be performed in centers where both the operative and nuclear medicine teams are experienced. In clinically identified lymph node metastases, radical lymph node dissection is considered standard therapy. If distant metastases involve just one internal organ and operative removal is feasible, then surgery should be seen as therapy of choice. Radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable. In regional lymph nodes, radiation therapy is usually recommended when excision is not complete (R1 resection) or if the nodes are inoperable. In distant metastases, radiation therapy is particularly indicated in bone metastases, brain metastases and soft tissue metastases.

Evidence-based and interdisciplinary consensus-based German guidelines: systemic medical treatment of melanoma in the adjuvant and palliative setting.

Systemic medical treatment of melanoma is administered in the adjuvant and palliative setting. Adjuvant therapy may be considered in patients with primary melanoma with more than 1.5 mm tumor thickness and with regional node metastasis. Presently no indication for systemic adjuvant chemotherapy or for adjuvant therapy with nonspecific immune-stimulatory agents outside controlled studies is seen. Interferon-alpha is the first substance in the adjuvant therapy of melanoma, which has shown to present a significant advantage to the patients in some prospective randomized studies. Good arguments for using adjuvant interferon-alpha therapy in high-risk melanoma patients exist. Both high-dose and low-dose interferon-alpha show promise. The major indications for systemic chemotherapy and chemoimmunotherapy are inoperable recurrent tumors, inoperable regional metastases and distant metastases (stage IV). As treatment in such situations is primarily palliative, the effect of any regimen on the quality of life must be carefully weighed. As a first line treatment, single agent therapy is recommended, as polychemotherapy or biochemotherapy did not show significant advantages for prolongation of survival; hence they are more toxic. An urgent need for development of new treatment modalities is necessary and general principles of experimental immunotherapy are outlined.

Variations in the peroxisome proliferator-activated receptor-gamma gene and melanoma risk.

There is strong evidence to suggest that the peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear receptor family of transcriptional regulators, mediates tumor suppressive activities in a variety of human cancers. Recently, PPARgamma agonists were found to inhibit growth of melanoma cell lines. Here, we tested the possibility that variations in the gene encoding PPARgamma (PPARG) influence melanoma risk. Two variations of PPARG (P12A[rs1801282] and C161T [rs3856806]) were investigated in two independent case-control studies with a total of 832 melanoma patients and 790 control individuals. In the first study, homozygous carriers of the rare *T allele of the C161T polymorphism in exon 6 of PPARG were significantly more common among patients with melanoma than among healthy subjects (6.0 vs. 2.0%; P=0.0096) and this association was independent of clinical risk factors such as skin type and nevus count (odds ratio 5.18; 95% confidence interval 1.68-15.96; P=0.0041). This finding, however, could not be replicated in the second case-control study. We therefore conclude that the investigated PPARG polymorphisms are not likely to constitute a significant risk factor for the development of melanoma among German Caucasians.

Evidence and interdisciplinary consense-based German guidelines: diagnosis and surveillance of melanoma.

Melanoma is a malignant tumor that arises from melanocytic cells and primarily involves the skin. The most important exogenous etiological factor is exposure to ultraviolet irradiation. Diagnosis of melanoma is based primarily on its clinical features, and the A-B-C-D rule is useful in identifying pigmented lesions, which are suspicious for melanoma (Asymmetry, Border irregular, Color inhomogeneous and Diameter more than 5 mm). Dermoscopy is very helpful in clarifying the differential diagnosis of pigmented lesions. About 90% of melanomas are diagnosed as primary tumors without any evidence for metastasis. The tumor-specific 10-year survival for all such tumors is about 75-85%. The most important prognostic factors for primary melanoma without metastases are vertical tumor thickness (Breslow depth) as measured on the histological specimen, presence of histopathologically recognized ulceration, invasion level (Clark level) and identification of micrometastases in the regional lymph nodes via sentinel lymph node biopsy. The current tumor node metastasis classification for the staging of primary melanoma is based on these factors. Melanomas can metastasize either by the lymphatic or by the hematogenous route. About two-thirds of metastases are originally confined to the drainage area of regional lymph nodes. A regional metastasis can appear as satellite metastases up to 2 cm from the primary tumor, as intransit metastases in the skin between the site of the primary tumor and the first lymph node and as regional lymph node metastases. In the stage of regional metastasis, the differentiation between micrometastasis and macrometastasis and the number of lymph nodes involved are crucial. As soon as distant metastasis develops, prognosis depends on the site of the metastasis and on the lactate dehydrogenase levels in the blood. The frequency and extent of follow-up examinations is based on the initial tumor parameters. In thin primary melanomas up to 1-mm tumor thickness, clinical examinations at 6-month intervals are sufficient and in thicker primary melanomas, at 3-month intervals. Lymph node sonography as well as determination of the tumor marker protein S100beta are recommended. Additionally, in the stage of regional metastasis, whole body imaging should be performed every 6 months; in the stage of distant metastasis, surveillance has to be scheduled individually.

Variations of the melanocortin-1 receptor and the glutathione-S transferase T1 and M1 genes in cutaneous malignant melanoma.

Variations in the melanocortin-1 receptor (MC1R) and in the glutathione-S transferase genes mu1 (GSTM1) and theta 1 (GSTT1) have been reported to influence UV sensitivity and melanoma risk. MC1R is one of the major genes that determine skin pigmentation because the melanocortin-1 receptor regulates eumelanin synthesis. GSTT1 and GSTM1 are enzymes expressed in the skin that detoxify products of oxidative stress reactions caused by UV irradiation. In this study variations in the MC1R, GSTM1 and T1 genes were analyzed in 347 healthy subjects and 322 patients with cutaneous malignant melanoma by direct cycle sequencing, RFLP and multiplex PCR. Important phenotypic characteristics of the study participants were obtained to assess whether genetic associations occurred independently of phenotypic risk factors for melanoma. We found an association of the MC1R D84E and R151C polymorphisms with melanoma (odds ratios for carriage of the rare allele 4.96, 95% CI [1.06-23.13], P = 0.032, and 1.69, 95% CI [1.12-2.55], P = 0.013, respectively). Melanoma risk increased with the number of variant MC1R alleles carried by an individual (P = 0.003). In a multivariate model, however, only the D84E polymorphism influenced melanoma risk independently of the risk factors fair skin type, high nevus count and high age (P = 0.047). There was no effect of homozygous GST M1 or T1 deletions on melanoma risk. In contrast to previous data, there was no evidence that GSTM1 deficiency influences melanoma risk in the subgroup of individuals with red or blond hair.

No association between three xeroderma pigmentosum group C and one group G gene polymorphisms and risk of cutaneous melanoma.

Xeroderma pigmentosum (XP) patients exhibit a 1000-fold increased risk for developing skin cancers including malignant melanoma. We investigated the role of three variant alleles of the DNA repair gene XPC and one variant allele of the XPG gene in a hospital-based case-control study of 294 Caucasian patients from Germany with malignant melanoma and 375 healthy control individuals from the same area matched by sex. The polymorphisms G1580A (XPC exon 8; Arg492His), T1601C (XPC exon 8; Val499Ala), G2166A (XPC exon 10; Arg687Arg), and C3507G (XPG exon 15; Asp1104His) were not in linkage disequilibrium. The allele frequencies (cases: controls) were for 1580A 6.29%: 5.63%, for 1601C 79.08%: 78.28%, for 2166A 26.19%: 28.13%, and for 3507G 79.86%: 78.61%. We found no association of the homozygous 1580A, 1601C, 2166A, and 3507G genotypes with increased risks of melanoma: OR 1.254 (95% CI: 0.486-3.217), OR 1.108 (95% CI: 0.629-1.960), OR 0.817 (95% CI: 0.490-1.358), and OR 1.168 (95% CI: 0.670-2.044), respectively. Exploratory analyses of subgroups of melanoma patients compared to all controls indicated no association of these genotypes with increased risks for development of multiple primary melanomas (n = 28), a negative family history for melanoma (n = 277), melanomas in individuals with a low number of nevi (n = 273), melanomas in individuals older than 55 years (n = 142), and melanomas thicker than 1 mm (n = 126).

Improved differentiation of benign and malignant lymphadenopathy in patients with cutaneous melanoma by contrast-enhanced color Doppler sonography.

OBJECTIVE: To evaluate whether administration of a D-galactose-based signal enhancer is useful in color Doppler sonography (CDS) for better detection of vascularity patterns, which may help to differentiate malignant from benign lymph nodes in patients with cutaneous melanomas. DESIGN: Comparison of B-mode sonography, native CDS, and signal-enhanced CDS. SETTING: Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany. PATIENTS: Twenty examinations in 19 patients (median age, 60 years; 10 men) who presented with echo-poor structures suggestive of lymphadenopathy in B-mode sonography during follow-up for cutaneous melanomas. INTERVENTIONS: Histopathologic and follow-up examinations; documentation by color prints. MAIN OUTCOME MEASURES: Frequency of detection and description of different lymph node vascularity patterns in signal-enhanced CDS. RESULTS: Signal-enhanced CDS revealed additional information about vascularization of lymph node metastases, reactive lymph nodes, hematomas, and seromas, which was helpful for the differential diagnosis in 15 of 20 examinations. For lymph node metastases, signal enhancement facilitated the detection of accessory peripheral vessels in most investigations. Concerning reactive lymph nodes, hilar vessels in part with branching to the lymph node periphery could be identified only after application of the contrast enhancer in most patients. Quantitative variables could not be measured in all cases and did not help to differentiate between malignant and reactive lymph nodes. CONCLUSIONS: Administration of a D-galactose-based signal enhancer for CDS in patients with cutaneous melanomas can help to differentiate malignant from reactive lymph nodes, hematomas, or seromas. However, these promising results require confirmation in a prospective multicenter study.

Value of ultrasonography compared with physical examination for the detection of locoregional metastases in patients with cutaneous melanoma.

In several studies the early detection of locoregional metastases in patients with cutaneous melanomas has been shown to be of prognostic value. Physical examination alone often fails to detect locoregional metastases or cannot unambiguously classify palpable lymph nodes. This study aimed to evaluate the usefulness of high resolution ultrasonography for the early detection of locoregional metastases and to compare the sensitivity and specificity of ultrasound and physical examination. A prospective study was performed between January 1997 and June 1999 in 1395 patients (721 men and 674 women) with invasive cutaneous melanoma, treated and followed up at the Department of Dermatology and Allergology, Ludwig-Maximilian-University, Munich, Germany. A total of 2650 physical and ultrasound examinations of lymphatic drainage areas were performed, and lesions suspicious for metastases were excised and diagnosed by histopathology. The results of physical and ultrasound examinations were compared. Of the 2650 ultrasound examinations, metastases were suspected in 153, whereas 290 of the 2650 physical examinations were suspicious for metastatic disease. A total of 168 patients with suspicious lesions underwent surgery; histopathological examination revealed 112 melanoma metastases and 56 other diagnoses, including one second malignancy, one neurinoma, one haemangioma and 54 reactive lymph nodes. Ultrasonographic diagnosis of melanoma metastases had a sensitivity of 92.2% and a specificity of 98.2%, whereas diagnosis by physical examination had a sensitivity of only 51.3% and a specificity of 90.9%. Thus ultrasound examination was found to be highly effective and superior to physical examination for the early detection of locoregional melanoma metastases.

Quality of life and comorbidity in localized malignant melanoma: results of a German population-based cohort study.

BACKGROUND: Incidences of malignant melanoma continue to increase in fair-skinned populations. At least 80% of patients are diagnosed with localized disease and can expect a 5-year relative survival rate of >90%. Given that the median age at diagnosis of malignant melanoma is 59 years, many patients already suffer chronic diseases when they are confronted with cancer. OBJECTIVES: The aim of this study was to analyze the effect of additional chronic diseases on health-related quality of life (QoL) in a population-based cohort of melanoma patients two years after presumably curative treatment. METHODS: In 2003-2004, 1085 patients with localized malignant melanoma were recruited from the population-based Munich Cancer Registry to answer validated QoL questionnaires. Information about comorbidities was also obtained. Factors predicting QoL were analyzed using multivariate logistic regression models. RESULTS: A total of 781 patients (72%) returned completed questionnaires, of which 664 (61%) could be included in the analyses. Quality of life scores and differences in subgroups (e.g., sex and age) were essentially similar to those in the general population. Age, number of comorbidities, and several chronic diseases (e.g. heart and kidney disease, diabetes, former depression) were the strongest predicting factors and influenced almost every aspect of QoL. CONCLUSIONS: Localized malignant melanoma does not worsen QoL per se, compared with QoL in the general population. Comorbidities have similar effects on QoL in malignant melanoma patients as they do in the general population. Therefore, cohorts of patients with localized malignant melanoma can represent a basis for comparisons with other cohorts of cancer patients to determine the respective impacts of cancer-related and non-cancer-related factors on QoL.

No association of vitamin D metabolism-related polymorphisms and melanoma risk as well as melanoma prognosis: a case-control study.

Melanoma is one of the most aggressive human cancers. The vitamin D system contributes to the pathogenesis and prognosis of malignancies including cutaneous melanoma. An expression of the vitamin D receptor (VDR) and an anti-proliferative effect of vitamin D in melanocytes and melanoma cells have been shown in vitro. Studies examining associations of polymorphisms in genes coding for vitamin D metabolism-related proteins (1α-hydroxylase [CYP27B1], 1,25(OH)(2)D-24hydroxylase [CYP24A1], vitamin D-binding protein [VDBP]) and cancer risk are scarce, especially with respect to melanoma. Mainly VDR polymorphisms regarding melanoma risk and prognosis were examined although other vitamin D metabolism-related genes may also be crucial. In our hospital-based case-control study including 305 melanoma patients and 370 healthy controls single nucleotide polymorphisms in the genes CYP27B1 (rs4646536), CYP24A1 (rs927650), VDBP (rs1155563, rs7041), and VDR (rs757343, rs731236, rs2107301, rs7975232) were analyzed for their association with melanoma risk and prognosis. Except VDR rs731236 and VDR rs2107301, the other six polymorphisms have not been analyzed regarding melanoma before. To further improve the prevention as well as the treatment of melanoma, it is important to identify further genetic markers for melanoma risk as well as prognosis in addition to the crude phenotypic, demographic, and environmental markers used in the clinic today. A panel of genetic risk markers could help to better identify individuals at risk for melanoma development or worse prognosis. We, however, found that none of the polymorphisms tested was associated with melanoma risk as well as prognosis in logistic and linear regression models in our study population.

Health-related quality of life before and during adjuvant interferon-α treatment for patients with malignant melanoma (DeCOG-trial).

Adjuvant treatment with interferon-α (IFN-α) for patients with malignant melanoma can improve relapse-free and overall survival, but IFN-associated side effects may reduce patient's quality of life. The aim of the study was to prospectively evaluate health-related quality of life (HRQoL) in patients with melanoma before and during Low-Dose IFN-α therapy. In a prospective multicenter trial conducted by the Dermatologic Cooperative Oncology Group, 850 patients with cutaneous stage II malignant melanoma received a standard Low-Dose of IFN-α-2a. We evaluated HRQoL using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 questionnaire at baseline and after 3, 6, and 12 months of IFN-α treatment in 282 patients. Nine of 15 subscales showed significant poorer results after 3 months of adjuvant IFN treatment. Symptoms included reduced physical functioning, reduced cognitive functioning, fatigue, nausea, pain, dyspnea, insomnia, diarrhea, and loss of appetite. We did not find a significant change over time for role, emotional, or social functioning. Only cognitive functioning and dyspnea continuously worsened through the twelfth month. At baseline women had significantly lower scores for physical and emotional functioning and for fatigue compared with men. During treatment, women scored significantly poorer on physical functioning, emotional functioning, fatigue, pain, and constipation subscales. Patients who reported having a bad or very bad QoL before treatment were 5.8 times more likely to discontinue treatment early because of psychiatric problems. We conclude that adjuvant low-dose IFN treatment is associated with significant deterioration of HRQoL. Specific psychosocial care should be offered especially for patients who report lower HRQoL and emotional problems before treatment to prevent early discontinuation.