Melanoma Lymph Node Metastases Research Articles

Epidermal Growth Factor Facilitates Melanoma Lymph Node Metastasis by Influencing Tumor Lymphangiogenesis

Alterations in epidermal growth factor (EGF) expression are known to be of prognostic relevance in human melanoma, but EGF-mediated effects on melanoma have not been extensively studied. As lymph node metastasis usually represents the first major step in melanoma progression, we were trying to identify a potential role of primary tumor-derived EGF in the mediation of melanoma lymph node metastases. Stable EGF knockdown (EGFkd) in EGF-high (M24met) and EGF-low (A375) expressing melanoma cells was generated. Only in EGF-high melanoma cells, EGFkd led to a significant reduction of lymph node metastasis and primary tumor lymphangiogenesis in vivo, as well as impairment of tumor cell migration in vitro. Moreover, EGF-induced sprouting of lymphatic but not of blood endothelial cells was abolished using supernatants of M24met EGFkd cells. In addition, M24met EGFkd tumors showed reduced vascular endothelial growth factor-C (VEGF-C) expression levels. Similarly, in human primary melanomas, a direct correlation between EGF/VEGF-C and EGF/Prox-1 expression levels was found. Finally, melanoma patients with lymph node micrometastases undergoing sentinel node biopsy were found to have significantly elevated EGF serum levels as compared with sentinel lymph node-negative patients. Our data indicate that tumor-derived EGF is important in mediating melanoma lymph node metastasis.

Intron A inhibits lymph node metastasis in melanoma via inhibition of lymphangiogenesis by downregulating Prox1 protein expression

Intron A is the most commonly used biologically active cytokine in the treatment for high risk patients with melanoma, but the mechanism of molecular basis of intron A in melanoma are not fully understood yet. Lymph node metastasis is an independent and reliable prognostic factor for melanoma and tumor-induced lymphangiogenesis is known to play an important and active role in the promotion of cancer metastasis to lymph nodes in melanoma. The purpose of this study is to investigate the effect and mechanism of Intron A on lymphangiogensis.

Epigenetic disruption of cadherin‐11 in human cancer metastasis

Little is known about the molecular events occurring in the metastases of human tumours. Epigenetic alterations are dynamic lesions that change over the natural course of the disease, and so they might play a role in the biology of cancer cells that have departed from the primary tumour. Herein, we have adopted an epigenomic approach to identify some of these changes. Using a DNA methylation microarray platform to compare paired primary tumour and lymph node metastatic cell lines from the same patient, we observed cadherin-11 promoter CpG island hypermethylation as a likely target of the process. We found that CDH11 DNA methylation-associated transcriptional silencing occurred in the corresponding lymph node metastases of melanoma and head and neck cancer cells but not in the primary tumours. Using in vitro and in vivo cellular and mouse models for depleted or enhanced CDH11 activity, we also demonstrated that CDH11 acts as an inhibitor of tumour growth, motility and dissemination. Most importantly, the study of CDH11 5′-CpG island hypermethylation in primary tumours and lymph node metastases of cancer patients showed this epigenetic alteration to be significantly confined to the disseminated cells. Overall, these results indicate the existence of metastasis-specific epigenetic events that might contribute to the progression of the disease. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Prognostic value of the standardized uptake value for 18F-fluorodeoxyglucose in patients with stage IIIB melanoma

PurposeFDG PET/CT is an excellent tool to detect melanoma metastases and also allows quantification of FDG uptake using standardized uptake value (SUV). The aim of this study was to prospectively investigate the potential prognostic value of SUV for disease-free survival (DFS) and disease-specific survival (DSS) for patients with stage IIIB melanoma.MethodsFrom November 2003 to March 2008, all consecutive patients were included in the present study. Inclusion criteria were: palpable, histology- or cytology-proven lymph node metastases of melanoma, and referred to the University Medical Centre Groningen for FDG PET and CT examination. Patients without distant metastases were evaluated. Multivariable survival analysis was performed to determine whether SUV was associated with DFS and DSS (Cox proportional hazard analysis).ResultsIn 80 patients (without distant metastases, 65 %) SUV could be measured. Overall 5-year DFS was 41 % (95% CI 26–56 %) and 24 % (95% CI 12–38 %) in patients with a low and high SUVmean (p = 0.02), respectively. Overall 5-year DSS was 48 % (95% CI 31–62 %) and 30 % (95% CI 17–45 %) in patients with a low and high SUVmean (p = 0.04), respectively. In the multivariable analysis, SUVmean was associated with DFS (hazard ratio 1.7; p = 0.048), but was not associated with DSS (hazard ratio 1.6; p = 0.1). The number of positive nodes, extranodal growth and gender were also associated with survival.ConclusionFDG uptake in clinically overt nodal melanoma metastases is inversely associated with DFS. Univariate analysis showed an association with DSS. However, after adjustment for potential confounders this association was no longer significant. If these findings are confirmed in larger studies, SUVmean could potentially be used (in addition to the number of positive nodes, tumour size and extranodal growth) as a factor in deciding on adjuvant systemic treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-012-2182-0) contains supplementary material, which is available to authorized users.

Epigenetics of regional lymph node metastasis in solid tumors

Regional nodal status remains one of the most important prognostic factors in several solid tumors including melanoma, breast cancer, and gastrointestinal malignancies. However, despite the accuracy of lymph node (LN) staging, patients who are LN negative are still at risk for development of recurrence and distant metastasis. As such, numerous molecular studies have focused on genetic and transcriptome changes in primary and metastatic tumors to discover molecular determinants that can predict aggressive metastatic disease and/or correlated to clinical outcomes. More recently, epigenetic aberrations have been investigated in solid cancers and are associated with tumorigenesis and disease progression. These epigenetic alterations have demonstrated potential utility as diagnostic and prognostic biomarkers and are being developed into novel targeted treatment strategies, as epigenetic changes can be reversed by appropriate drugs. If patients who are at increased risk of developing metastases or recurrence can be accurately identified, this will help stratify patients into more appropriate treatment and follow-up. This review discusses some of the recent studies on regional LN metastases in melanoma, breast cancer, and colorectal cancer, focusing on the potential clinicopathological utility of epigenetic aberrations in the management of cancer patients.

原発不明悪性黒色腫リンパ節転移の3例

原発不明悪性黒色腫リンパ節転移の3例

Comparison of the influence of photodynamic reaction on the Me45 and MEWO cell lines in vitro

Aim of the studyPhotodynamic therapy (PDT) is an approved, minimally invasive and highly selective therapeutic approach to a variety of tumors. It is based on specific photosensitizer accumulation in the tumor tissue, followed by irradiation with visible light. The photochemical interactions of the photosensitizer, light and molecular oxygen produce singlet oxygen and other reactive oxygen forms. The imbalance between ROS generation and antioxidant capacity of the body gives rise to oxidative stress in the cell, which initiates cell death in PDT. The aim of this study was to investigate the effect of photodynamic reactions in human melanoma cell lines.Material and methodsPhotofrin® (Ph) was used for the photodynamic reaction in vitro as a photosensitizer. The primary cell line was MEWO cell line (granular fibroblasts), derived from a human melanoma. As a recurrent cell line we used Me45 cell line, derived from a lymph node metastasis of skin melanoma. We compared cell viability (MTT assay) to determine the effectiveness of applied therapy. The intracellular distribution of photosensitizer (Photofrin) and localization of mitochondria (Mito-Tracker Green) were detected by confocal microscopy.ResultsWe observed that Me45 and MEWO cell viability was dependent on the time of incubation after irradiation. In the recurrent cell line Ph accumulated mainly in the mitochondrial membranes and in MEWO cells also in the cytoplasm. The primary melanoma cell line exhibited significantly reduced cellular proliferation (below 50%) after photodynamic reaction with Ph.ConclusionsThe applied photodynamic reaction was more effective in primary melanoma cells. Additionally, mitochondrial localization of Ph can lead to disturbances of mitochondrial transmembrane potential and finally to release of apoptotic proteins.

The role of melanoma tumor‐derived nitric oxide in the tumor inflammatory microenvironment: Its impact on the chemokine expression profile, including suppression of CXCL10

Melanoma appears to be heterogeneous in terms of its molecular biology, etiology and epidemiology. We previously reported that the expression of inducible nitric-oxide synthase (iNOS) in melanoma tumor cells is strongly correlated with poor patient survival. Therefore, we hypothesized that nitric oxide (NO) produced by iNOS promotes the melanoma inflammatory tumor microenvironment associated with poor outcome. To understand the role of NO and iNOS in the melanoma inflammatory tumor microenvironment, polymerase chain reaction arrays of inflammatory and autoimmunity genes were performed on a series of stage III melanoma lymph node metastasis samples to compare the gene expression profiles of iNOS-expressing and nonexpressing tumor samples. The results indicate that expression of CXC chemokine ligand 10 (CXCL10) was inversely correlated with iNOS expression, and the high CXCL10-expressing cases had more favorable prognoses than the low CXCL10-expressing cases. Functional studies revealed that treating iNOS-negative/CXCL10-positive melanoma cell lines with a NO donor suppressed the expression of CXCL10. Furthermore, scavenging NO from iNOS-expressing cell lines significantly affected the chemokine expression profile. Culture supernatants from NO scavenger-treated melanoma cells promoted the migration of plasmacytoid dendritic cells, which was diminished when the cells were treated with a CXCL10-neutralizing antibody. CXCL10 has been reported to be an antitumorigenic chemokine. Our study suggests that the production of NO by iNOS inhibits the expression of CXCL10 in melanoma cells and leads to a protumorigenic tumor microenvironment. Inhibiting NO induces an antitumorigenic environment, and thus, iNOS should be considered to be an important therapeutic target in melanoma.

Melanoma lymph node metastasis occurring simultaneously with multifocal sarcoidosis affecting lymph nodes and the lung: a diagnostic pitfall

ejd.2011.1457 Auteur(s) : Benjamin Chaigne1 benjamin.chaigne@hotmail.fr, Adeline Perrinaud1, Alexandre Penaud2,6, Marie-Christine Machet3,6, Yann Venel4, Sylvain Marchand-Adam5,6, Laurent Machet1,6 1 Department of Dermatology 2 Department of Plastic Surgery 3 Department of Pathology 4 Department of Nuclear Medicine 5 Department of Pneumology, University Hospital, 37044 Tours, France 6 University Francois-Rabelais, Tours, France Antigenic stimulation (including the development of cancer) and adjuvant [...]

Neoadjuvant therapy for high‐risk bulky regional melanoma

Clinically detectable regional lymph node melanoma metastasis (AJCC stage IIIB-C) carries a risk of relapse and death that approaches 70% at 5 years. Surgical management is the cornerstone of therapy, with postoperative adjuvant therapy utilizing high-dose interferon alfa-2b (HDI). Neoadjuvant chemotherapy or immunotherapy in addition to surgery has been demonstrated to improve outcome in the management of patients with a variety of solid tumors. In patients with melanoma, the characteristics of the host immune response differ between patients with earlier stage and those with more advanced stages of disease (and particularly between those with measurable active disease and those without measurable gross disease) providing rationale for neoadjuvant approaches with immunotherapy. Host immune tolerance is now understood to impede the results of therapy for advanced disease, but appears to be less an issue for patients with microscopic high-risk operable disease, where the host may be more susceptible to immunologic interventions. Phase II studies have shown that neoadjuvant biochemotherapy has limited activity in melanoma patients with local-regional metastases, where chemotherapy may potentially alter the effects of immunotherapeutic agents. Studies of neoadjuvant HDI therapy for high-risk melanoma patients with bulky regional stage IIIB-C lymphadenopathy have shown unexpectedly high clinical and pathologic response rates, without increased morbidity. Through the design of neoadjuvant trials utilizing promising emerging melanoma therapeutics in which it is possible to obtain biopsy samples before and after therapy, a greater understanding of the dynamic interaction between tumors and the immune system is possible. This should lead to the identification of new targets for the treatment of melanoma and aid the development of new immunotherapy that may have greater specificity and less toxicity. This will simplify the evaluation of promising new combinations of agents with HDI to build on the clinical, immunologic, and molecular effect of this therapy for patients with melanoma.

Abstract 1446: Dissecting the role of PTEN/Akts in metastatic melanoma

Abstract Melanoma is an aggressive human cancer whose incidence is increasing more rapidly than any other cancer in the United States. It is characterized by an extremely high potential to develop metastases and poor response to current therapy. Although the genetic studies indicated that melanoma genesis related with molecular lesions in c-MET, INK4a, Ras/Raf, p53 and PTEN pathways, the molecular mechanism inciting metastatic melanoma are poorly understood. PTEN is a major tumor suppressor in humans. To study the role of PTEN in progression of human melanoma, we first used tissue microarrays to examine PTEN expression in 30 lymph node melanoma metastases, 30 primary melanomas, and 9 normal skin tissues. Our results showed that PTEN loss was significantly correlated with progression to the metastatic state. Moreover, analysis of various human melanoma cell lines demonstrated that PTEN expression was related to metastatic behavior, supporting the notion that PTEN is involved in the metastatic regulation of melanoma. PTEN has phosphatase activity that can act upon both polypeptide and phosphoinositide substrates. The PTEN lipid phosphatase is a ubiquitous regulator of PI3K signaling pathway. The loss of expression or mutational inactivation of PTEN protein enhances the phosphorylation of PKB/AKT and thus influences cell survival signaling. Interestingly, a PTEN mutant, which loses lipid but not protein phosphatase activity, lacks the ability to induce either G1 arrest or apoptosis, but nonetheless retains the ability to inhibit cell spreading and motility, suggesting that PTEN protein phosphatase activity is important for these behaviors. To further dissect the role of this PTEN activity in metastasis, we have established a model system containing exploiting mutant PTEN proteins with various phosphatase activities. We found that wild type PTEN can inhibit cell motility and invasiveness, while PTEN mutants cannot. Notably, wild type PTEN was able to reduce the metastatic potential of melanoma cells, whereas phosphatase deficient PTEN could promote the melanoma cell metastatic behavior. We found that PTEN mediates metastatic activity through the AKT pathway. We further determined that Akt 3 was key mediators of metastatic potential in melanoma cells in vivo. Akt3 could also rescue PTEN-mediated inhibition of metastasis. PTEN loss and Akt3 overexpression functioned synergistically to promote metastasis. Our data demonstrate that metastatic behavior in melanoma cells is dependent on the status of PTEN protein phosphatase activity and downstream Akt3, and suggest that AKT/PTEN signaling should be considered as a therapeutic target in metastatic melanoma Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1446. doi:10.1158/1538-7445.AM2011-1446

Abstract 401: Inducible nitric oxide synthase suppresses the expression of CXCL10 and hence leads to the poor outcome of Stage III malignant melanoma

Abstract Melanoma is the deadliest form of skin cancer and exhibits extremely aggressive growth characteristics. Accumulating evidence suggests that melanoma is heterogeneous in response to therapies as well as etiology, survival with advanced disease, and tumor mutational status. Our previous studies showed that the expression of inducible nitric-oxide synthase (iNOS) in melanoma tumor cells strongly correlate with poor patient survival. We are hypothesizing that iNOS is a key molecule in melanoma signature comprising an inflammatory microenviroment of poor outcome. To gain further insight into the nature of the melanoma inflammatory microenvironment, PCR array related to inflammatory and autoimmunity gene was done on a series of Stage 3 melanoma lymph node metastases samples to compare the gene expression level directly between iNOS-positive and -negative tumor samples. As a result, we found the significant correlation between iNOS expression and suppression of CXC Chemokine ligand 10 (CXCL10) in mRNA and protein levels. In the set of 16 cases of Stage3 melanoma samples, high CXCL10 expressing group showed the favorable prognosis compared to low CXCL10 expressing group. In the further in vitro analysis, we found that nitric oxide (NO) provided by S-nitroso-N-acetyl-l,l-penicillamine suppresses the expression of CXCL10 in iNOS negative and CXCL10 positive melanoma cell. Quenching the NO with NO scavenger, 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide in iNOS positive and CXCL10 negative cell lines induces the expression of CXCL10. CXCL10 is reported to play the role in the recruitment of cytotoxic immune cells such as CD8+ T cells, and NK cells into the tumor microenvironment. CXCL10 also has a function of antagonizing the activities of angiogenic factors such as bFGF and IL-8 and it is considered as an anti-tumorigenic protein. Our study suggests that production of NO by iNOS inhibits the expression of CXCL10 in melanoma and comprises the pro-tumorigenic tumor microenvironment. Inhibition of NO may have a possibility to render the tumor microenvironment to anti-tumorigenic status. Therefore, iNOS will be a good target in the treatment of melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 401. doi:10.1158/1538-7445.AM2011-401

Critical Analysis of the Ultrasonographic Criteria for Diagnosing Lymph Node Metastasis in Patients With Cutaneous Melanoma

The purpose of this systematic review of the literature was to evaluate the use of ultrasonography (US) in the assessment of lymph node metastasis in patients with cutaneous melanoma. A multimodal strategy was used, which was mainly based on a PubMed database search. Among the 201 cumulative articles collected (years 1989-2009), 31 were found to match all of the inclusion criteria and to provide a description of the use of US scanning in lymph node melanoma metastasis. Data extracted included the author's name and country, journal and year of publication, prospective or retrospective nature of the study, single-center or multicenter nature of the study, period when US studies were performed, US transducers used, gray scale and color Doppler criteria used for diagnosis, and data on US accuracy. The diagnostic criteria used in the 31 selected articles were critically reviewed, illustrating to the reader the discrepancies and unclear aspects identified. On the basis of this review, the need to establish definitive, clearly defined, and univocal diagnostic criteria to be applied in daily clinical practice as well as to be used in articles to be published is emphasized.

Improved Detection of Regional Melanoma Metastasis Using 18F-6-Fluoro-N-[2-(Diethylamino)Ethyl] Pyridine-3-Carboxamide, a Melanin-Specific PET Probe, by Perilesional Administration

The efficacy of differing routes of administration of 18F-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide (18F-MEL050), a new benzamide-based PET radiotracer for imaging regional lymph node metastasis in melanoma, was assessed. B16-Black/6 metastatic melanoma cells harboring an mCherry transgene were implanted into the left-upper-foot surface of 49 C57 Black/6 mice as a model of popliteal lymph node (PLN) metastasis. Ultrasound scanning of the left PLN was performed at baseline and in combination with 18F-MEL050 PET on days 5, 9, and 14. Mice were divided into 2 groups to compare the results of tracer administration either subcutaneously at the tumor site (local) or in the lateral tail vein (systemic). After PET on each imaging day, 5 mice per group-including any with evidence of metastasis-were sacrificed for ex vivo validation studies including assessment of retained radioactivity and presence of the mCherry transgene as a surrogate of nodal tumor burden. Nine mice were judged as positive for PLN metastasis by ultrasound at day 5, and 8 PLNs were positive on 18F-MEL050 PET, 3 after systemic and 5 after local administration. Ex vivo analysis showed that ultrasound correctly identified 90% of positive PLNs, with 1 false-positive. 18F-MEL050 PET correctly identified 60% of positive PLNs after systemic administration and 100% after local administration with no false-positive results by either route. The average node-to-background ratio for positive PLNs was 6.8 in the systemic-administration group and correlated with disease burden. In the local-administration group, the mean uptake ratio was 48, without clear relation to metastatic burden. Additional sites of metastatic disease were also correctly identified by 18F-MEL050 PET. In addition to its potential for systemic staging, perilesional administration of 18F-MEL050 may allow sensitive and specific, noninvasive identification of regional lymph node metastasis in pigmented malignant melanomas.

FC15 Combination of Dacarbazine and Dimethylfumarate efficiently reduces melanoma lymph node metastasis

Dimethylfumarate (DMF) has been shown to reduce melanoma growth and metastasis in animal models. We addressed the question of whether DMF is as effective in its antitumor activity as the US Food and Drug Administration-approved alkylating agent dacarbazine (DTIC). We also tested the possibility of an improved antitumoral effect when both therapeutics were used together. Using our severe combined immunodeficiency (SCID) mouse model, in which xenografted human melanoma cells metastasize from primary skin sites to sentinel nodes, we show that these treatments, alone or in combination, reduce tumor growth at primary sites. Our main finding was that metastasis to sentinel nodes is significantly delayed only in mice treated with a combination of DTIC and DMF. Subsequent experiments were able to show that a combination of DTIC/DMF significantly reduced lymph vessel density in primary tumors as examined by real-time PCR and immunohistochemistry. In addition, DTIC/DMF treatment significantly impaired melanoma cell migration in vitro. In vivo, DTIC/DMF therapy significantly reduced mRNA expression and protein concentration of the promigratory chemokines CXCL2 and CXCL11. In addition, our data suggest that this xenotransplantation model is suitable for preclinical testing of various combinations of antimelanoma agents.

Histomorphologic parameters and CXCR4 mRNA and protein expression in sentinel node melanoma metastasis are correlated to clinical outcome

Introduction: Sentinel lymph node (SLN) biopsy is an important independent prognostic factor for invasive cutaneuos melanoma, although its role is strongly debated. In clinical practice SLN leads to complete lymph node dissection of basin draining melanoma site. However only 7 to 30% of positive sentinel node patients present additional non SLN metastasis. Melanoma cells diffusion through SLN and extranodal spreading depends upon biological features, such as cell chemokine receptors and adhesion molecules. CXCR4 has been proposed in melanoma patients as prognostic marker. Therefore we have analyzed both histopathological parameters and CXCR4 expression in melanoma infiltrate of SLN, in order to evaluate its potential prognostic role. Materials and Methods: 47 positive lymph node metastases were collected and analysed for both histopathological parameters and CXCR4 expression. Results: micrometastases were detected in 23 cases (48.93%); metastases >2mm in 23 cases (48.93%) and isolated metastatic cells in one case (2.01%). High CXCR4 expression was observed in 21 nodal metastases. Node metastases in complete dissection were associated to >10% relative tumor area (RTA) in all lymph nodes (p=0.006). Extranodal invasion (p =0.006) and >2 mm centripetal metastasis thickness (p=0.01), while shorter Disease Free Survival (DFS) was significantly associated to high CXCR4 expression (p=0.02). Conclusion: more than 10% RTA in SLN, extranodal invasion and centripetal metastasis thickness all predict additional lymph node metastases in melanoma site draining basins. Moreover, high CXCR4 expression is correlated to shorter DFS and could be used as a prognostic marker in order to stratify melanoma patients at higher progression risk.

Constitutive Expression of the α4 Integrin Correlates with Tumorigenicity and Lymph Node Metastasis of the B16 Murine Melanoma

The lymphatic system plays a critical role in melanoma metastasis, and yet, virtually no information exists regarding the cellular and molecular mechanisms that take place between melanoma cells and the lymphatic vasculature. Here, we generated B16-F1 melanoma cells that expressed high (B16α4+) and negligible (B16α4-) levels of α4 integrin to determine how the expression of α4 integrins affects tumor cell interactions with lymphatic endothelial cells in vitro and how it impacts lymphatic metastasis in vivo. We found a direct correlation between α4 integrin expression on B16-F1 melanoma cells and their ability to form adhesive interactions with monolayers of lymphatic endothelial cells. Adhesion of B16-F1 melanoma cells to lymphatic endothelial cells was mediated by the melanoma cell α4 integrin binding to its counterreceptor, vascular cell adhesion molecule 1 (VCAM-1), that was constitutively expressed on the lymphatic endothelial cells. VCAM-1 was also expressed on the tumor-associated lymphatic vessels of B16-F1 and B16α4+ tumors growing in the subcutaneous space of C57BL/6J mice. B16-F1 tumors metastasized to lymph nodes in 30% of mice, whereas B16α4+ tumors generated lymph node metastases in 80% of mice. B16-F1 melanoma cells that were deficient in α4 integrins (B16α4-) were nontumorigenic. Collectively, these data show that the α4 integrin expressed by melanoma cells contributes to tumorigenesis and may also facilitate metastasis to regional lymph nodes by promoting stable adhesion of melanoma cells to the lymphatic vasculature.

The Triangular Intermuscular Space as a Site of Lymph Node Metastasis in Melanoma of the Back

The Triangular Intermuscular Space is defined by borders of the teres major, teres minor, and long head of the triceps. Through this space pass the descending circumflex scapular artery, vena comitants, and lymphatics. We report 3 patients with truncal melanoma, presenting with recurrent disease in the TIS. These cases suggest that in patients with melanoma of the back, the Triangular Intermuscular Space, as the gateway to the axilla, may be an important site of metastatic disease.

Validation of a scoring system to predict non‐sentinel lymph node metastasis in melanoma

Sentinel lymph node biopsy (SLNB) has been widely accepted as the lymph node sampling procedure of choice for melanoma patients. Current standards of practice suggest completion lymph node dissection (CLND) for patients with a positive SLNB result. The rationale for SLNB+/-CLND is for staging and prognosis as well as local control and possibly survival improvement. CLND, however, entails significant morbidity. In addition, most patients (approximately 80%) will have no further melanoma metastases in non-sentinel nodes and these patients may not benefit from the additional dissection. We had previously developed a score (based on patient age and the total size of metastasis within the SLN) that predicted which SLN-positive patients would have a positive CLND. Utilization of this scoring system would spare a significant number of melanoma patients the risks associated with CLND. The purpose of this study was to validate this score using different melanoma populations. A retrospective chart review of all patients that had undergone SLNB for melanoma at four different Canadian centers was undertaken. Data from the Calgary Foothills Medical Center, the Winnipeg Health Sciences Center, and the Toronto Sunnybrook Health Sciences Center from January 1999 to present was collected. In addition, we identified all patients from April 2007 to present at the Misericordia Hospital in Edmonton for this study. This patient information had not been utilized when we were developing this score. The collected variables included patient age, Breslow thickness, result of SLNB, total size of SLN metastasis, largest size of SLN metastasis, and results of CLND. Logistic regression was used to test the significance of a score system's correlation (based on cutoff age of 55 years and cutoff total SLN metastasis of 5 mm) with the CLND results. We also used logistic regression to test the correlation of cutoff values of total SLN metastasis with non-sentinel lymph node (NSLN) metastasis. Data were collected on 599 patients across the four centers. Breslow thickness significantly correlated with SLN metastasis. The risk score system (based on patient age and total SLN metastasis) was significantly predictive of the CLND result in SLNB-positive patients. However, the age became non-significant on multivariate analysis. Total SLN metastasis emerged as the variable that is most predictive of NSLN metastasis. Patients with total SLN metastasis less than 2 mm had a 3.6% risk of NSLN metastasis, those with SLN metastasis from 2-5 mm had a 12.5% risk of NSLN metastasis, whereas those with total SLN metastasis of 5 mm or greater had a 30% risk of NSLN metastasis. Using cutoff values of 2 and 5 mm for total SLN metastasis, prediction of NSLN metastasis can be made in melanoma patients. Patients with less than 2 mm of total SLN metastasis are unlikely (<3.67% likelihood) to harbor NSLN metastasis; these patients may not benefit from additional nodal dissection beyond SLNB.

Do we have to pay more attention to vitiligo patients? Peculiar histopathological features of primary cutaneous melanoma preceded by vitiligo

Vitiligo is an acquired depigmenting skin disease characterized by the loss of functioning epidermal melanocytes. Vitiligo can be associated with an autoimmune disorder. An unusual and important aspect of vitiligo is its relationship to melanoma. We present herein a 34-year-old man who developed regional lymph node metastases of malignant melanoma 2 years after the diagnosis of vitiligo.