Metastatic pathways and time courses in the orderly progression of cutaneous melanoma

Meier, Friedegund; Will, Susanne; Ellwanger, Ulf; Schlagenhauff, Bettina; Schittek, Birgit; Rassner, G.; Garbe, Claus

doi:10.1046/j.1365-2133.2002.04867.x

Cited by 277 publications

(275 citation statements)

References 24 publications

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“…In contrast to this assumption, two other studies by Nowecki and Cascinelli with similar follow-up periods of 34 and 29 months, respectively, all showed a significant impact of SLN status on overall survival upon multivariate analysis (Cascinelli et al, 2000;Nowecki et al, 2003). Furthermore, Meier demonstrated that distant metastasis in patients with prior metastasis to lymph nodes already evolves after a median followup period of 25 months (Meier et al, 2002). …”

Section: Discussionmentioning

confidence: 92%

Sentinel node status in melanoma patients is not predicitive for overall survival upon multivariate analysis

et al. 2005

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Sentinel lymph node biopsy (SLNB) has become a widely accepted standard procedure in the staging of patients with cutaneous melanoma and absence of clinical lymph node metastases, although there is no final proof that SLNB influences overall survival in these patients. This study investigated the accuracy of SLNB and the clinical outcome of patients after a mean follow-up of 22 months. Between 1998 and 2003, SLNB was performed in 309 consecutive patients. Patients with one or more positive sentinel lymph nodes (SLNs) were subjected to selective lymphadenectomy (SL). Survival analyses were performed using the Kaplan -Meier approach. A Cox proportional-hazard analysis was used for univariate and multivariate analysis to explore the effect of variables on survival. Sentinel lymph nodes were identified in 299 of 309 patients (success rate: 96.8%). Of these, 69 (23%) had a positive SLN. The falsenegative rate was 9.2%. Recurrence of disease to the regional lymph node basin (3.0%) and to the locoregional skin (2.6%) was rare in SLN-negative patients in contrast to SLN-positive patients (7.2 and 17.4%, respectively). The 3-year overall survival was 93 and 83% for SLN-negative and SLN-positive patients, respectively. Upon multivariate analysis, SLN status (Po0.001), Breslow thickness (Po0.02) and ulceration (Po0.026) were all found to be independent prognostic factors with respect to disease-free survival, whereas Breslow thickness proved to be the only significant factor with respect to overall survival.

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Section: Discussionmentioning

confidence: 92%

Sentinel node status in melanoma patients is not predicitive for overall survival upon multivariate analysis

et al. 2005

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“…2 Sentinel lymph nodes are the first lymph nodes to drain a tumor bed, and represent the first expected site of metastasis of melanoma. 3,4 Sentinel lymph nodes are a site of contact between tumor-associated antigens and the adaptive immune system and represent a regional unit of metastasis and immune response. Accordingly, sentinel lymph nodes are an ideal setting for the investigations of the early immunologic (endocrine and paracrine) events that lead up to melanoma progression from a primary tumor to metastatic cancer.…”

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confidence: 99%

Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis

et al. 2011

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In order to characterize the degree of immunosuppression in regional immunity in patients with melanoma, we used immunohistochemistry to analyze markers of T-cell subtype and polarity, costimulation, dendritic cell maturation, monocytes, lymphatic vasculature, and angiogenesis. Specifically, we analyzed expression of CD4, CD8, CD14, CD40, CD86, CD123, HLA-DR, IL-10, LYVE, VEGFR3, and VEGF-C in lymph nodes. We compared sentinel lymph nodes with and without metastasis from patients with melanoma with both infection inflamed (reactive) and dormant human lymph nodes. There were no differences demonstrated between sentinel lymph nodes with or without metastasis from patients with melanoma in any of the markers that were tested. Both groups of sentinel lymph nodes had fewer CD8 þ T cells than either set of control nodes. Whereas the infection inflamed lymph nodes demonstrated Th2 polarity, the dormant lymph nodes demonstrated Th1 polarity. In conclusion, changes in regional immunity appeared to precede metastasis in melanoma. Whether there was tumor present in sentinel lymph nodes or not, these nodes demonstrated a marked decrease in cytotoxic T cells compared with both sets of controls. Furthermore, the control lymph nodes used for comparison can significantly impact interpretation, as the dormant and reactive lymph nodes markedly varied in their immune profiles. These immunologic changes may explain the successful metastasis of melanoma in the midst of the immune environment of the sentinel lymph node, and lend insights into the mechanisms of lymphatic metastases in other solid malignancies. Modern Pathology (2011) 24, 487-494; doi:10.1038/modpathol.2010.227; published online 10 December 2010Keywords: angiogenesis; cytotoxic T cells; lymph nodes; melanoma; regional immunity Lymph node metastasis is one of the most important prognostic factors in melanoma.1 Whereas patients without nodal involvement generally have excellent outcomes, those with nodal involvement more commonly experience recurrence after resection and diminished survival. Previous investigations suggest that melanoma-draining lymph nodes demonstrate immunologic alterations and are likely immunosuppressed.2 Sentinel lymph nodes are the first lymph nodes to drain a tumor bed, and represent the first expected site of metastasis of melanoma.3,4 Sentinel lymph nodes are a site of contact between tumor-associated antigens and the adaptive immune system and represent a regional unit of metastasis and immune response. Accordingly, sentinel lymph nodes are an ideal setting for the investigations of the early immunologic (endocrine and paracrine) events that lead up to melanoma progression from a primary tumor to metastatic cancer. In the past year, we have described that patients with metastatic melanoma exist in a state of systemic chronic inflammation driven by tumorderived vascular endothelial growth factor (VEGF) overproduction leading to systemic immune polarization to a state of CD4 cell Th2 bias.5 Consequently, we sought to determine if similar differen...

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“…There are >10 million new cases of MM diagnosed every year (1). In total, ~21% of MM patients present with focal skin metastasis and 50% with regional lymph node metastasis (1). MM patients with distant metastasis (stage IV) usually have poor prognoses, with a median survival time of 5-8 months, and the ≥5-year survival rate is <2% (2).…”

Section: Introductionmentioning

confidence: 99%

“…There are >10 million new cases of MM diagnosed every year (1). In total, ~21% of MM patients present with focal skin metastasis and 50% with regional lymph node metastasis (1).…”

Section: Introductionmentioning

confidence: 99%

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Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma: A clinical study

Chen

Zhao

et al. 2016

Oncology Letters

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Abstract. The present study aimed to evaluate the efficacy and safety of in situ immunotherapy with dinitrophenyl (DNP) hapten in combination with laser therapy for patients with malignant melanoma (MM). Between February 2008 and March 2012, 72 patients with stage III or IV MM were enrolled. Patients received in situ DNP alone (n=32) or in combination with laser therapy (n=32), and each group received dacarbazine chemotherapy. The levels of peripheral cluster of differentiation (CD)4 + CD25 + regulatory T cells (Tregs), interleukin (IL)-10 and tumor growth factor (TGF)-β were detected by ELISA. The association between delayed-type hypersensitivity (DTH) and survival time was evaluated. Although peripheral Treg levels significantly decreased over time in the two groups (P<0.001), there was no significant difference between the treatment groups (P= 0.098). Patients receiving the combination treatment exhibited significantly higher interferon-γ production by CD8 + and CD4 + T cells (both P<0.001), as well as significantly reduced levels of IL-10, TGF-β1 and TGF-β2. In addition, patients in the combination treatment group experienced significantly longer overall survival (OS; P=0.024) and disease-free survival (DFS; P=0.007) times; a DTH response of ≥15 mm was also associated with increased OS time and DFS time (P≤0.001). Finally, no severe adverse events were observed in either treatment group. Overall, in situ immunization with DNP in combination with laser immunotherapy may activate focal T cells, producing a regional antitumor immune response that increases cell-mediated immunity and improves survival in MM patients. Thus, this may represent a novel therapeutic strategy for patients with unresectable, advanced MM. IntroductionDerived from neural crest cells, malignant melanoma (MM) accounts for ~1.5% of all tumors and is the cutaneous malignancy with the highest mortality rate (1). There are >10 million new cases of MM diagnosed every year (1). In total, ~21% of MM patients present with focal skin metastasis and 50% with regional lymph node metastasis (1). MM patients with distant metastasis (stage IV) usually have poor prognoses, with a median survival time of 5-8 months, and the ≥5-year survival rate is <2% (2). With social and economic development, the incidence of MM is increasing each year (3).The poor prognosis of MM patients is reflective of the lack of an effective therapy. Systemic chemotherapy, including mono-and poly-chemotherapies, immunomodulatory therapies and vaccination therapy with dendritic cells (DCs) or genetically modified tumor cells, remains controversial (2). Although there is evidence showing that the combined use of interleukin (IL)-2, interferon (IFN) and chemotherapeutics may achieve a response rate as high as 64% (4,5), the efficacy of systemic therapy remains disappointing; systemic monotherapy usually achieves a clinical response rate of <15% (6-10). However, prospective, randomized clinical trials have shown no evidence that other drugs are superior to dacarbazine (DTIC) for MM pa...

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Metastatic pathways and time courses in the orderly progression of cutaneous melanoma

Cited by 277 publications

References 24 publications

Sentinel node status in melanoma patients is not predicitive for overall survival upon multivariate analysis

Sentinel node status in melanoma patients is not predicitive for overall survival upon multivariate analysis

Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis

Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma: A clinical study

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