Melanoma Lymph Node Metastases Research Articles

Prospective Comparison of [18F]Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography in Patients With Melanoma With Palpable Lymph Node Metastases: Diagnostic Accuracy and Impact on Treatment

Patients with melanoma with potentially resectable lymph node metastases require accurate staging to prevent unnecessary surgery. [(18)F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is attractive for this because melanoma typically is FDG avid. The aim of this prospective multicenter study was to perform a head-to-head comparison of FDG-PET and computed tomography (CT) in staging of patients with melanoma with palpable lymph node metastases in terms of diagnostic accuracy and impact on treatment. All consecutive patients with palpable, proven lymph node metastases of melanoma between mid 2003 and 2007 were prospectively included. The number/site of distant metastases detected with FDG-PET and CT were recorded. Histology/cytology or 6 months follow-up were the reference standard. Intended and performed treatment was recorded. Distant metastases were suspected by FDG-PET in 32% of the 251 patients and by CT in 29% (P = .26). Upstaging was correct in 27% by FDG-PET and in 24% by CT (P = .18). FDG-PET detected more metastatic sites (133 v 112, P = .03), detecting significantly more bone and subcutaneous metastases. Treatment changed in 19% of patients; in 79% as a result of both scans, in 17% exclusively by FDG-PET, and in 4% exclusively by CT. In 34 patients (14%), FDG-PET had an additional value over spiral CT, and in 23 patients (9%), CT had additional value over FDG-PET. As a result of FDG-PET and CT, 27% of patients were upstaged, and treatment changed in one of five patients. FDG-PET and CT are equivalent in upstaging; however, FDG-PET detected more metastatic sites, especially bone and subcutaneous. FDG-PET and/or CT are indicated in the staging of patients with melanoma with palpable lymph node metastases.

Secrets to developing Wnt‐age melanoma revealed

Secrets to developing <i>Wnt</i>‐age melanoma revealed

Surgery and radiotherapy in the treatment of cutaneous melanoma

Adequate surgical management of primary melanoma and regional lymph node metastasis, and rarely distant metastasis, is the only established curative treatment. Surgical management of primary melanomas consists of excisions with 1–2 cm margins and primary closure. The recommended method of biopsy is excisional biopsy with a 2 mm margin and a small amount of subcutaneous fat. In specific situations (very large lesions or certain anatomical areas), full-thickness incisional or punch biopsy may be acceptable. Sentinel lymph node biopsy provides accurate staging information for patients with clinically unaffected regional nodes and without distant metastases, although survival benefit has not been proved. In cases of positive sentinel node biopsy or clinically detected regional nodal metastases (palpable, positive cytology or histopathology), radical removal of lymph nodes of the involved basin is indicated. For resectable local/in-transit recurrences, excision with a clear margin is recommended. For numerous or unresectable in-transit metastases of the extremities, isolated limb perfusion or infusion with melphalan should be considered. Decisions about surgery of distant metastases should be based on individual circumstances. Radiotherapy is indicated as a treatment option in select patients with lentigo maligna melanoma and as an adjuvant in select patients with regional metastatic disease. Radiotherapy is also indicated for palliation, especially in bone and brain metastases.

Successful treatment of single lymph node metastasis of melanoma with carbon ion radiotherapy and chemotherapy

Successful treatment of single lymph node metastasis of melanoma with carbon ion radiotherapy and chemotherapy

The prognostic value of FDG-PET measured by standardized uptake value in patients with melanoma stage III evaluated in a prospective study

e20000 Background: FDG-PET is a sensitive modality to detect melanoma metastases; melanomas are typically FDG-avid and melanoma shows an unpredictable pattern of spread. Furthermore, FDG-PET is able to quantify FDG uptake and the amount of FDG uptake, measured by the standardized uptake value (SUV), might be important for the prediction of disease specific survival (DSS) or disease free survival (DFS). Therefore, aim of this study was to perform a prospective analysis to determine whether SUV is of prognostic value in the DFS and DSS of melanoma patients with palpable lymph node metastases. Methods: From July 2002 until December 2007, all consecutive patients with palpable, histology or cytology proven lymph node metastases of melanoma referred to the University Medical Centre Groningen for examination with FDG-PET were prospectively included. The SUVmean (70% isocontour) and SUVmax in the lymph node metastasis were calculated for patients who showed no distant metastases on chest X-Ray, FDG-PET and CT. Univariate and multivariate survival analysis was performed to determine whether SUV was associated with DFS and DSS (Cox Proportional Hazard analysis). Results: Overall, 70 patients were eligible. High SUV values were present in axillary metastases (p=0.118), in patients who had more than 15 nodes removed (p=0.061) and in patients with a large tumor size in the lymph node (p=0.0001). Patients with a low SUVmean had a 3-years DFS of 54.3% as compared to 28.1% for patients with a high SUVmean (HR 2.02;p=0.051). In multivariate analysis SUVmean seems to be associated with DFS (p=0.063). DSS for patients with a high SUV was decreased, however not statistically significant (HR 1.71; p=0.182). Conclusions: The SUV in the lymph node metastasis seems to be associated with disease-free survival for melanoma patients clinically stage III. No significant financial relationships to disclose.

Endothelial Nitric Oxide Synthase Mediates Lymphangiogenesis and Lymphatic Metastasis

Lymphatic metastasis is a critical determinant of cancer prognosis. Recently, several lymphangiogenic molecules such as vascular endothelial growth factor (VEGF)-C and VEGF-D were identified. However, the mechanistic understanding of lymphatic metastasis is still in infancy. Nitric oxide (NO) plays a crucial role in regulating blood vessel growth and function as well as lymphatic vessel function. NO synthase (NOS) expression correlates with lymphatic metastasis. However, causal relationship between NOS and lymphatic metastasis has not been documented. To this end, we first show that both VEGF receptor-2 and VEGF receptor-3 stimulation activate eNOS in lymphatic endothelial cells and that NO donors induce proliferation and/or survival of cultured lymphatic endothelial cells in a dose-dependent manner. We find that an NOS inhibitor, L-NMMA, blocked regeneration of lymphatic vessels. Using intravital microscopy that allows us to visualize the steps of lymphatic metastasis, we show that genetic deletion of eNOS as well as NOS blockade attenuates peritumor lymphatic hyperplasia of VEGF-C-overexpressing T241 fibrosarcomas and decreases the delivery of metastatic tumor cells to the draining lymph nodes. Genetic deletion of eNOS in the host also leads to a decrease in T241 tumor cell dissemination to the lymph nodes and macroscopic lymph node metastasis of B16F10 melanoma. These findings indicate that eNOS mediates VEGF-C-induced lymphangiogenesis and, consequently, plays a critical role in lymphatic metastasis. Our findings explain the correlation between NOS and lymphatic metastasis seen in a number of human tumors and open the door for potential therapies exploiting NO signaling to treat diseases of the lymphatic system.

Imaging of Lymph Node Micrometastases Using an Oncolytic Herpes Virus and [18F]FEAU PET

BackgroundIn patients with melanoma, knowledge of regional lymph node status provides important information on outlook. Since lymph node status can influence treatment, surgery for sentinel lymph node (SLN) biopsy became a standard staging procedure for these patients. Current imaging modalities have a limited sensitivity for detection of micrometastases in lymph nodes and, therefore, there is a need for a better technique that can accurately identify occult SLN metastases.Methodology/Principal FindingsB16-F10 murine melanoma cells were infected with replication-competent herpes simplex virus (HSV) NV1023. The presence of tumor-targeting and reporter-expressing virus was assessed by [18F]-2′-fluoro-2′-deoxy-1-β-D-β-arabinofuranosyl-5-ethyluracil ([18F]FEAU) positron emission tomography (PET) and confirmed by histochemical assays. An animal foot pad model of melanoma lymph node metastasis was established. Mice received intratumoral injections of NV1023, and 48 hours later were imaged after i.v. injection of [18F]FEAU. NV1023 successfully infected and provided high levels of lacZ transgene expression in melanoma cells. Intratumoral injection of NV1023 resulted in viral trafficking to melanoma cells that had metastasized to popliteal and inguinal lymph nodes. Presence of virus-infected tumor cells was successfully imaged with [18F]FEAU-PET, that identified 8 out of 8 tumor-positive nodes. There was no overlap between radioactivity levels (lymph node to surrounding tissue ratio) of tumor-positive and tumor-negative lymph nodes.Conclusion/SignificanceA new approach for imaging SLN metastases using NV1023 and [18F]FEAU-PET was successful in a murine model. Similar studies could be translated to the clinic and improve the staging and management of patients with melanoma.

Validation of a Nomogram to Predict the Presence of Sentinel Lymph Node Metastases in Melanoma

Lymph node involvement is a very important prognostic factor for cutaneous melanoma. In this paper we try to validate a nomogram that was created at the Memorial Sloan-Kettering Cancer Center, New York, to predict the probability of metastases in the sentinel nodes of patients with cutaneous melanoma. Values of the following variables were collected in 218 patients with cutaneous melanoma and sentinel lymph node: age, thickness, level of Clark, location of the lesion, and ulceration or not, and the nomogram was applied to assess the probability of sentinel node involvement in each patient. The discrimination of the nomogram was assessed by calculating the area under the receiver operating characteristics (ROC) curve, and to assess the accuracy of the nomogram actual probabilities were plotted against the nomogram-calculated predicted probability. The overall predictive accuracy of the nomogram was 0.869 (95% confidence interval 0.813-0.925). Mean predicted probability of sentinel node metastasis was highly correlated to the observed risk (r = 0.953; P < 0.012). The nomogram is a useful diagnostic tool that provides an adequate accurate prediction of the probability of sentinel lymph node metastases in patients with cutaneous melanoma.

Erratum to Experimental frontiers for clinical applications: Novel approaches to understanding mechanisms of lymph node metastases in melanoma

Sentinel lymph nodes are the first nodes to receive lymph from primary tumors and are the preferential site of initial metastases. Sentinel nodes show morphology changes that suggests immune modulation with reduced antigen-presenting dendritic cells, activated T lymphocytes, high endothelial venules and transvenular migration of T lymphocytes. Tumor cells generate down-regulatory molecules. We postulate that tumor-induced immune dysfunction facilitates establishment of nodal metastases. Nodal immune modulation can be reversed by granulocyte macrophage colony-stimulating factor (GMCSF), a finding with implications for future therapy to prevent or reverse these nodal metastases.

Activated Stat-3 in Melanoma

Recent studies have demonstrated that the Src-Stat pathway may play an important role in melanoma. We examined the expression of phosphorylated Stat-3 (pStat-3), activated Stat-1 (pStat-1) and interferon alpha receptor subunit 1(IFNAR-1) in human melanocytic neoplasms. Compound nevi (6), dysplastic nevi (4), congenital nevi (2), primary melanoma (14), and sentinel lymph node metastasis (40) were examined. Specimens were evaluated for phospho-Stat-1 (pStat-1), phospho-Stat-3 (pStat-3), and IFNAR-1 by immunohistochemistry. Staining was scored from 1 to 3 based on a composite score that took into account both the percentage of tumor cells staining and the intensity of stained cells. Normal melanocytes or benign nevi expressed little pStat-1, pStat-3, or IFNAR-1. In primary cutaneous melanoma, 6 of 14 skin biopsies showed activated Stat-3. However, in melanoma metastatic to regional lymph nodes, 16 of 26 had activated Stat-3 but only 6 of 23 had activated Stat-1. Melanoma tumors had high levels of either pStat-3 or pStat-1 but not both. All melanoma specimens but not benign melanocytes had cytoplasmic IFNAR-1 staining. An increase in Stat-3 activity was seen in melanoma but not in benign nevi or skin melanocytes. There appeared to be an inverse correlation between the levels of pStat-3 and pStat-1 in a given specimen. The relationship between activated Stat-3 and biological behavior of melanocytic lesions observed in this study warrants further exploration.

Change in treatment as result of FDG-PET and CT in clinically stage III melanoma patients: A prospective study in 221 patients

9069 Background: An important part in the treatment planning for metastatic melanoma is an evaluation of the presence or absence of distant melanoma metastases. However, melanoma has the well-known feature to spread to unusual sites and the presence of multiple metastases is usually a contraindication for surgery. The aim of this study was to assess how treatment changed as result of the FDG-PET and spiral CT in patients clinically stage III melanoma. Methods: All consecutive patients older than 18 years with palpable, histology/cytology proven lymph node metastases of melanoma referred to the five participating hospitals between July 2003 and July 2007 for examination with FDG-PET and CT were prospectively included in this study. All patients were considered candidates for further surgical intervention in the form of a regional lymph node dissection. Performed treatment was recorded to define a change in treatment plan. Results: Overall, 221 patients were included in the five hospitals. More than half the patients were male, median age was 57.9 (range 23.2–93.1) years. The primary melanoma was mostly located on the lower extremities (35.6%) or trunk (35.6%). PET and CT were comparable in detecting liver and abdominal metastases, CT detected more lung metastases and PET detected more bone and skin metastases. Treatment changed in 41 patients (18.6%), mostly as result of both scans (n=34), or PET alone (n=5) or CT alone (n=2). In 28 patients treatment changed to chemotherapy, 6 patients received a superficial lymph node dissection for local control while 3 patients received two lymph node dissections as result of other lymph node metastases that were detected. Conclusions: In conclusion, treatment changed in 19% of the melanoma patients with palpable lymph node metastases, mostly as result of both scans. The identification of metastatic disease did not always change the clinical management of the patients. The PET scan, with the CT scan as a good alternative are indicated in staging of melanoma patients with palpable lymph node metastases. No significant financial relationships to disclose.

Prognostic factors of cutaneous melanoma in relation to metastasis at the sentinel lymph node: A case-controlled study

Background The selection of patients who will undergo sentinel lymph node biopsy is primarily based on the histopathologic features of cutaneous melanoma. The purpose of this study is to identify prognostic factors that predict the sentinel lymph node metastasis in melanoma. Methods Sixty-nine melanoma patients underwent sentinel lymph node biopsy at Padova Plastic Surgery Institute. Univariate chi-square and multivariate logistic regression analyses were conducted to identify the relationship between prognostic factors and positive sentinel lymph node. A Receiver Operating Characteristics (ROC) Curve was performed to identify the ideal Breslow thickness cutpoint at which to perform sentinel node biopsy. Results Eleven of the 69 patients (16%) had sentinel lymph node metastases. By univariate analyses Breslow's thickness ( p = 0.001), ulceration ( p = 0.001), and lymphovascular invasion ( p < 0.0001) were found to be significant prognostic factors for the prediction of sentinel node micrometastases. The ROC Curve identified a Breslow thickness of 1.19 mm to be the most suitable cutpoint for sentinel lymph node positivity ( p = 0.003, sensibility 80%, specificity 69.6%). Conclusions Patients with Breslow thickness ≥1.19 mm, ulceration, and lymphovascular invasion are at higher risk for occult lymph node metastases. In addition it is important to use multiple selection criteria when performing sentinel lymph node biopsy especially in patients with thin melanomas.

Pelvic Wall Metastasis From Malignant Melanoma Mimicing Subserous Myoma Uteri

A 67-year-old woman presented with a solid adnexial mass (as a subseruos myomas) which was detected during her routine control. Her past medical history revealed that her left leg's fifth finger was amputated for nodular type malignant melanoma two years ago. During her following up, the solid mass size measured bigger. Because of suspecting leimyosarcoma, we performed explorotive laparotomy. The mass was seen on the left arterio-venous iliac region and resected succesfully. Histopathological examination revealed neoplastic cell proliferation in iliac lymph node (metastasis of malign melanoma).

Osteopontin as a molecular prognostic marker for melanoma

Osteopontin has been suggested as a marker of disease progression in patients with melanoma because of its overexpression in recent microarray analyses. However, its prognostic role in melanoma has not been fully defined. Osteopontin expression status was examined using immunohistochemical analysis of a tissue microarray that contained primary cutaneous melanomas from 345 patients. The correlation between osteopontin expression and several histologic markers for melanoma was assessed by using the Chi-square test and the Le directional test. The impact of osteopontin expression on recurrence-free survival (RFS) and disease-specific survival (DSS) of patients with melanoma was examined using Cox regression and Kaplan-Meier analyses. The impact of increasing osteopontin expression on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis. High osteopontin expression was associated with increased tumor thickness (P = .037), Clark level (P = .035), and mitotic index (P = .046). Kaplan-Meier analysis demonstrated an association between osteopontin expression and reduced RFS (P < .03) and DSS (P = .05). Multivariate Cox regression analysis demonstrated that high osteopontin immunostaining had an independent impact on the DSS of this melanoma cohort (P = .049). In addition, osteopontin expression was significantly predictive of SLN metastasis (P = .009) and SLN burden, as assessed by the mean number of SLN metastases (P = .0025). Multivariate logistic regression analysis demonstrated an independent role for osteopontin expression in predicting SLN status (P = .0062). The current results validated the role of osteopontin as an independent prognostic marker for melanoma and provided new evidence for its predictive role in melanoma lymph node metastasis.

Massive Extraocular Extension and Parotid Lymph Node Metastasis of Uveal Melanoma

A 22-year-old man, diagnosed with unilateral glaucoma and treated with trabeculectomy 6 years earlier, presented with an epibulbar nodule of 6 months' duration. MRI displayed intra- and extraocular tumor, and gross invasion of the medial rectus muscle. Biopsy demonstrated uveal melanoma, and staging revealed enhancing ipsilateral parotid lymph nodes. Orbital exenteration and parotidectomy with selective neck dissection were performed. The tumor infiltrated superficial parotid nodes and extended into the parotid gland. The site of tumor origin is speculative, but a ring melanoma of the anterior chamber angle is suspected. Lymph node metastasis of uveal melanoma is rare; to our knowledge, this is the most advanced of the few reported cases.

Mélanome cutané et ganglion sentinelle : où en est-on ?

Malignant cutaneous melanoma is the cancer which has the most increased these last ten years. His prognose is linked with melanoma thickness, tumoral ulceration and lymph node metastasis. The research of these node metastasis is important for the prognosis and the treatment. The sentinel lymph node biopsy is used since 1991 and is now considered as a reliable choice for the patient staging. However, his therapeutic interest remains discussed. We discussed the used of the sentinel lymph node biopsy for malignant cutaneous melanoma with the last publications.

PO9-270 VEGFR-3 MEDIATES LYMPHANGIOGENESIS AND ALLOIMMUNE RESPONSES IN CARDIAC ALLOGRAFTS

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.

High flotillin-2 expression is associated with lymph node metastasis and Breslow depth in melanoma

High flotillin-2 expression is associated with lymph node metastasis and Breslow depth in melanoma

Acne Vulgaris: False-Positive Finding on Integrated 18F-FDG PET/CT in a Patient with Melanoma

WEB This is a Web exclusive article. alignant melanoma was diagnosed in approximately 59,580 patients in the United States in 2005. Appropriate treatment of patients with this tumor depends on accurate staging at presentation. CT has been used in the evaluation of melanoma at high risk of metastasis (i.e., thick, ulcerated primary tumors [stage IIC] or stage III disease). Because the accuracy of CT in the detection of occult metastatic lesions is limited, whole-body 18F-FDG PET has emerged as a complementary imaging technique and is being used with increasing frequency in examinations of patients with advanced melanoma [1, 2]. Although integration of PET and CT findings increases diagnostic accuracy, use of this combination in the detection of distant metastatic lesions is associated with a high falsepositive rate [3]. Awareness of potential diagnostic pitfalls is therefore needed to avoid misinterpretation of integrated PET/CT images that can lead to inaccurate staging. In particular, accurate identification of cutaneous and subcutaneous metastasis of melanoma is important because the lesions may represent new or additional regional or distant metastatic disease. Such findings may influence the overall treatment approach. We report the case of a patient with melanoma lymph node metastasis (American Joint Committee on Cancer stage III) who had 18F-FDG accumulation at the sites of acne vulgaris that might have been misinterpreted as evidence of multiple distant cutaneous or subcutaneous metastatic lesions, potentially altering the pre-PET surgical treatment plan of regional lymph node dissection.

Experimental frontiers for clinical applications: Novel approaches to understanding mechanisms of lymph Node metastases in melanoma

Sentinel lymph nodes are the first nodes to receive lymph from primary tumors and are the preferential site of initial metastases. Sentinel nodes show morphology changes that suggests immune modulation with reduced antigen-presenting dendritic cells, activated T lymphocytes, high endothelial venules and transvenular migration of T lymphocytes. Tumor cells generate down-regulatory molecules. We postulate that tumor-induced immune dysfunction facilitates establishment of nodal metastases. Nodal immune modulation can be reversed by granulocyte macrophage colony-stimulating factor (GMCSF), a finding with implications for future therapy to prevent or reverse these nodal metastases.