Intermediate-thickness Primary Melanoma Research Articles

Current standards of surgical management in primary melanoma.

Melanoma accounts for the majority of skin cancer-related deaths, and its incidence continues to rise worldwide. While advanced disease has historically been associated with poor long-term survival, early-stage disease has a favorable prognosis and therefore, early diagnosis is paramount. Resection of primary melanoma requires a balance of maximizing oncological outcome while minimizing morbidity. Wide excision with 1-2 cm margins, depending on depth of the tumor, is the standard of care for surgical treatment of primary, invasive melanoma. Sentinel lymph node biopsy is indicated for patients with clinically node-negative, intermediate-thickness primary melanomas but should also be considered in selected patients with thin and thick primaries. In this article, historical perspectives and key clinical trials regarding the current guidelines for the surgical management of primary melanoma are discussed.

Adjuvant Interferon in Melanoma: Is Duration of Therapy Important?

Adjuvant Interferon in Melanoma: Is Duration of Therapy Important?

Sentinel lymph node biopsy in melanoma patients

Appropriate surgical management of regional lymph nodes is critical in patients with cutaneous melanoma. The use of intraoperative lymphatic mapping and sentinel lymph node biopsy (SLNB) has increased significantly in the past decade. SLNB is performed as minimally invasive procedure that provides accurate staging of melanoma patients with no clinically detectable nodal disease. In many melanoma units across the world, it became the standard for detection of occult regional node metastasis in patients with intermediate-thickness primary melanoma. Use of SLNB in patients with thin melanomas is still under evaluation. Although SLNB has been established as staging procedure in melanoma patients, its therapeutic role is still not clear. Large-scale ongoing randomized trials should elucidate whether SLNB with complete lymphadenectomy has a survival benefit in melanoma patients with early lymph node metastases compared to 'watch-and-wait' policy (observation).

Surgery and Sentinel Lymph Node Biopsy

In patients with melanoma, surgery is pivotal not only for the primary tumor but also for regional and often distant metastases. The minimally invasive technique of sentinel node (SN) biopsy has become standard for detection of occult regional node metastasis in patients with intermediate-thickness primary melanoma; in these patients it has a central role in determining prognosis and a significant impact on survival when biopsy results are positive. Its role in thin melanoma remains under evaluation. The regional tumor-draining SN also is a useful model for studies of melanoma-induced immunosuppression. Although completion lymphadenectomy remains the standard of care for patients with SN metastasis, results of ongoing phase III trials will indicate whether SN biopsy without further lymph node surgery is adequate therapy for certain patients with minimal regional node disease.

New boundaries for lymphatic mapping-report of the Fifth International Sentinel Node Conference

The Fifth Biennial International Sentinel Node Society meeting was held in Rome from 1 to 4 November 2006. Compared with previous meetings, there was a shift in focus from aspects of the clinical technique of the procedure to aspects of basic science that indicate the biology of the disease. The authors report on conference presentations relating to melanoma, including discussion of results from the Multicentre Selective Lymphadenectomy Trial 1 in intermediate thickness primary melanoma.

Improved long-term survival in patients with intermediate thickness primary melanoma managed by sentinel node biopsy

8576 Background: Although improved disease-free survival (DFS) with sentinel node biopsy (SNB) for clinically localized melanoma was observed at the interim analysis from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) there was not yet an improvement in overall survival (OS). We hypothesize this was due to the few observed early deaths. To investigate this we simulated the MSLT-1 protocol using our institutional database. Methods: 3,800 patients undergoing wide excision with or without SNB were matched by primary stage/ulceration/site and patient demographics. Patients with positive sentinel nodes (SN) underwent immediate completion lymphadenectomy (CLND) whereas non-SNB patients managed by nodal observation underwent delayed CLND at nodal recurrence. Survival was determined by the Kaplan-Meier method. Significance was determined using log-rank and Cox regression analysis. Results: Among matched pairs of SNB and non-SNB patients with 1.2–3.5 mm primaries, projected 10-year OS was 76% with SNB versus 63% without SNB (p=0.0008). There was no corresponding statistically significant difference between all 2001 SNB patients and 1799 non-SNB patients, or within the thin primary and thicker primary groups. By multivariate analysis, only SN status (p<0.0001), Breslow thickness (p<0.0001) and ulceration (p=0.0001) were independently predictive of OS. Conclusions: Our long-term data suggest that performing SNB will improve OS in patients with intermediate thickness melanoma but not with thicker or thinner melanomas as compared to observation and delayed CLND. No significant financial relationships to disclose. [Table: see text]

Current topics in melanoma

New approaches to melanoma are emerging. This review summarizes developments over the past 12 months. Surgical, chemotherapeutic, immunologic and targeted therapies for melanoma are evolving. Sentinel lymph node sampling is now accepted as the standard of care for patients with intermediate thickness primary melanomas. Temozolomide continues to be widely used as part of combination therapy, and recent evidence suggests that a combination of temozolomide and interferon-alpha may be superior to temozolomide alone. Meanwhile, temozolomide and thalidomide carries unacceptable thrombosis risk. In the area of immunotherapy, anti-CTLA-4 continues to show promise, but special attention must be paid to gastrointestinal toxicity. Interferon-alpha, in addition, has shown efficacy in the neoadjuvant setting with inflammatory infiltrates demonstrated in tumors. A better understanding of the complex genetic regulation of melanoma cell growth is emerging and this is expected to lead to the development of novel targeted therapies. Research is producing a more complete understanding of melanoma genetics and immune regulation. These are beginning to produce therapeutics that are impacting clinical practice.

Sentinel-Node Biopsy or Nodal Observation in Melanoma

We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma. Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy. Among 1269 patients with an intermediate-thickness primary melanoma, the mean (+/-SE) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6% in the biopsy group and 73.1+/-2.1% in the observation group (hazard ratio for recurrence[corrected], 0.74; 95% confidence interval [CI], 0.59 to 0.93; P=0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1+/-1.3% and 86.6+/-1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3+/-4.6% among patients with tumor-positive sentinel nodes and 90.2+/-1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54 to 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group (P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3+/-4.6% vs. 52.4+/-5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P=0.004). The staging of intermediate-thickness (1.2 to 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. (ClinicalTrials.gov number, NCT00275496 [ClinicalTrials.gov].).

Ki-67, Bcl-2 and p53 expression in primary and metastatic melanoma

The aim of this study was to clarify the roles of the tumour proliferation marker Ki-67, the anti-apoptotic protein Bcl-2 and the cell cycle regulator p53 in primary cutaneous and metastatic melanoma. One hundred and seventeen primary melanomas and 18 metastatic tissue samples were analysed for immunohistochemical expression of Ki-67, Bcl-2 and p53. The staining results were correlated with disease progression and clinical outcome. The patient population comprised patients diagnosed with melanoma between 1988 and 1991. The clinical follow-up period for disease recurrence was 4.6 years (median; range, 0.2-7.5 years) and the follow-up period for overall survival was 10.0 years (median; range, 8.6-15.6 years). Ki-67 expression was not a prognostic factor in primary melanoma. High Bcl-2 expression was associated with such adverse prognostic factors as male gender, old age of the patient and tumour ulceration. High Bcl-2 expression was also associated with an adverse prognosis in intermediate-thickness (1.01-4.0 mm) melanomas (n=52) for disease-free (P=0.09) and overall (P=0.08) survival. In multivariate analysis, tumour thickness was the strongest prognostic factor for disease-free survival (P<0.01). High p53 expression indicated a poorer prognosis (P=0.05). In metastatic melanoma, the expression levels of Bcl-2 and p53 were lower than those in their primary counterparts (P=0.08 for each). Ki-67 expression showed no remarkable changes. It can be concluded that high p53 expression in tumour cells is associated with a poorer prognosis in primary melanoma, and high Bcl-2 expression in tumour cells is an adverse prognostic marker in intermediate-thickness primary melanoma.

Use of Oncogene Expression as an Independent Prognostic Marker for Primary Melanoma

For 25 years, the Breslow depth of primary tumors has remained the most accurate prognostic test of survival for primary melanoma. However a number of studies have indicated that outcome for intermediate-thickness melanomas (0.75-2.49 mm) is often at variance with that predicted by the Breslow depth. This study investigated c-myc oncogene expression in 92 primary tumors of intermediate thickness using flow cytometry. Oncoprotein expression was detected in 87 tumors (95%) with a median positivity of 48% (range, 0%-96%). Survival analysis performed using the Kaplan-Meier method revealed a significant association between oncoprotein positivity and clinical outcome (p < 0.01, log-rank test). Multifactorial analysis of survival using Cox's proportional hazards model revealed c-myc oncoprotein to be an independent prognostic marker more accurate than all other clinicopathological parameters including the Breslow depth (chi(2) = 9.68, p< 0.01). Estimation of c-myc oncoprotein is therefore recommended as a powerful prognostic marker for intermediate-thickness primary melanoma.

Molecular prognostic markers in intermediate-thickness cutaneous malignant melanoma.

The limitations of morphologic criteria alone in determining the prognosis for a patient with a particular intermediate-thickness primary melanoma have prompted efforts to identify other markers. In this study, the authors analyzed expression of p53, beta1 integrin, and beta3 integrin in primary tumors from 111 patients with intermediate-thickness malignant melanoma. Eighty-nine (80%) had detectable p53 protein, 58 (52%) expressed beta1 integrin, and 71 (64%) expressed beta3 integrin. Patients with beta3 positive melanomas were more likely to die of their disease (32 of 71 patients, 45%) than those with beta3 negative tumors (3 of 40 patients, 8%) (P < 0.0001). The number of involved lymph nodes, Clark's level, beta1 integrin expression, thickness, and mitotic rate also had prognostic significance. beta3 integrin was associated with subsequent lung metastases and beta1 integrin with lymph node involvement. Integrin expression, along with histopathologic criteria, is a prognostic marker for intermediate-thickness malignant melanoma and may indicate the site of subsequent metastasis. These observations may have clinical utility and suggest areas for future investigation.

Molecular oncogene markers and their significance in cutaneous malignant melanoma.

Oncogenes and other molecular tumor markers that predict tumor aggressiveness may allow individualization and optimization of surgical therapy of intermediate-thickness malignant melanoma. We examined the expression of selected markers, including the HLA-DR antigen, the heat shock protein-70 (HSP-70), and the c-myc oncogene in primary melanoma and regional nodes and related these findings to metastatic potential and survival. Forty patients with primary melanoma (1.5-4.0 mm) were studied, all of whom had prophylactic lymph node dissection and were followed for 18 months to 7 years. The primary tissue and nodes were examined using immunohistochemical techniques for the presence of HLA-DR antigen and HSP-70 protein and the expression of the c-myc oncogene. Of 40 patients, there were 23 with lesions 1 to 2.9 mm thick and 17 with lesions 3 to 4 mm thick. Nodal metastases were present in 25 of the 40 patients who had elective node dissection. HLA-DR antibody stained the primary tumor in 10 patients (25%), but there was no correlation with survival in this group. HLA-DR antibody stained the stroma and cellular infiltrates surrounding the primary tumor in 28 of 40 patients; in this group there was a correlation of HLA-DR staining of the peritumoral stroma with improved survival overall. HLA-DR staining of the peritumoral stroma also influenced survival when patients were stratified by tumor thickness groups 1 to 2.9 mm and 3 to 4 mm and presence of nodal metastases. HSP-70 was demonstrated in the primary tumor in 25% of patients, who were also shown to have significantly improved survival when compared with those whose primary tumor did not stain with HSP-70. C-myc was expressed in the primary tumor in 25%, but showed no correlation with survival. None of these proteins correlated with or predicted the presence of nodal metastases. We conclude that the use of specific molecular-oncogene markers in intermediate-thickness primary melanoma may identify patients at high risk for conventional treatment failure and reduced survival who may profit from more aggressive surgery, adjuvant therapy, or both.

Efficacy of elective lymph node dissection in patients with intermediate thickness primary melanoma

Efficacy of elective lymph node dissection in patients with intermediate thickness primary melanoma

Efficacy of elective lymph node dissection in patients with intermediate thickness primary melanoma.

One of the most controversial areas in the management of malignant melanoma concerns the efficacy of prophylactic lymph node dissection. During a retrospective computer-aided data review of over 3000 melanoma patients referred to the Duke University Cancer Center, 613 patients with complete staging along with surgical and pathologic data, having trunk and extremity melanoma, were identified with Breslow thickness in the range of 0.76 to 4.0 mm. One hundred eighty-seven of these clinically node-negative patients received an elective lymph node dissection (WLE/ND). The remaining patients were treated only with an initial wide local excision (WLE) at the time of diagnosis of their melanomas. There was no difference in age at diagnosis or male-female ratio between the treatment groups. A higher percentage of the WLE/ND group (36% vs. 31%) showed ulceration of their primary lesions and a greater mean tumor thickness (1.81 +/- 0.80 mm vs. 1.60 +/- 0.73 mm) than the WLE patients. Despite the force of these two adverse prognostic factors in the WLE/ND group, only ten deaths (5%) have occurred in the elective lymph node group compared to 51 (12%) in the control group. Using a multifactorial analysis to control for the prognostic contribution of the two most informative variables in stage I melanoma, Breslow thickness and ulceration, WLE/ND had an independent favorable effect on survival (p = 0.01). There was no apparent additional benefit to lymph node dissection in patients whose primary lesion measured less than 0.76 mm or greater than 4.0 mm in thickness. The surgeon may use survival estimates with and without elective node dissection based on a prognostic equation ("prognostigram") as a quantitative aid to treatment planning.