Multivariate Analysis of Prognostic Factors Among 2,313 Patients With Stage III Melanoma: Comparison of Nodal Micrometastases Versus Macrometastases

Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands
Journal of Clinical Oncology (Impact Factor: 18.43). 04/2010; 28(14):2452-9. DOI: 10.1200/JCO.2009.27.1627
Source: PubMed


To determine the survival rates and independent predictors of survival using a contemporary international cohort of patients with stage III melanoma.
Complete clinicopathologic and follow-up data were available for 2,313 patients with stage III disease in an updated and expanded American Joint Committee on Cancer (AJCC) melanoma staging database. Kaplan-Meier and Cox multivariate survival analyses were performed.
Among all 2,313 patients with stage III disease, 81% had micrometastases, and 19% had clinically detectable macrometastases. The 5-year overall survival was 63%; it was 67% for patients with nodal micrometastases, and it was 43% for those with nodal macrometastases (P < .001). Tremendous heterogeneity in survival was observed, particularly in the microscopically detected nodal metastasis subset (from 23% to 87% for 5-year survival). Multivariate analysis demonstrated that in patients with nodal micrometastases, number of tumor-containing lymph nodes, primary tumor thickness, patient age, ulceration, and anatomic site of the primary independently predicted survival (all P < .01). When added to the model, primary tumor mitotic rate was the second-most powerful predictor of survival after the number of tumor-containing nodes. In contrast, for patients with nodal macrometastases, the number of tumor-containing nodes, primary ulceration, and patient age independently predicted survival (P < .01).
In this multi-institutional analysis, we demonstrated remarkable heterogeneity of prognosis among patients with stage III melanoma, especially among those with nodal micrometastases. These results should be incorporated into the design and interpretation of future clinical trials involving patients with stage III melanoma.

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Available from: Alexander Maximiliaan Eggermont,
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    • "Previous studies have described prognostic factors of stage III progression. In their study of 441 patients with macrometastases, Balch et al. reported that number of nodes and age were independent predictors of survival and that primary tumour attributes did not influence survival [5]. "
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    ABSTRACT: Background Current staging algorithms in melanoma patients undergoing therapeutic lymph node dissection (LND) fail to accurately distinguish long-term survivors from those at risk of rapid relapse. Our goal was to establish and validate nomograms for predicting both recurrence and survival after LND. Methods A prospective cohort of stage IIIB and IIIC melanoma patients was ascertained from a tertiary hospital in Brisbane, Australia. Failure-time multivariate analysis identified key factors that, in adjusted combinations, generated nomograms to predict 2-year recurrence and 5-year melanoma-specific survival. The predictive value of these nomograms was further validated in a patient cohort from Rotterdam, The Netherlands. Results In 494 Australian patients, number of positive lymph nodes, extra-capsular extension and nodular histopathological subtype were the main independent predictors of 2-year recurrence while age, number of positive nodes and extra-capsular extension were the independent predictors of survival. Predictive value was confirmed in The Netherlands cohort of 331 patients. The nomograms were able to classify patients according to their 2-year recurrence and 5-year survival rates even within each stage III sub-class. Conclusions Models that include extra-capsular extension predict outcomes in patients with clinically involved lymph nodes. This tool may help tailor treatment and monitoring of this group of patients.
    European journal of cancer (Oxford, England: 1990) 05/2014; 50(7). DOI:10.1016/j.ejca.2014.02.010 · 5.42 Impact Factor
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    • "Stage III disease, however, is highly heterogeneous. Five-year survival ranges from 87% for stage III patients with one nodal micro-metastasis and a primary lesion less than 2 mm down to 36% for stage III patients with four or more involved nodes (Balch et al., 2010). Patients with stage IIC disease (negative sentinel node but primary lesion 4 mm or greater or 2 mm with ulceration) have a 5-year survival of only 48% (Balch et al., 2009). "
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    ABSTRACT: Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin fixed and paraffin embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53 immune gene panel predictive of non-progression (AUC=0.920) defined. The signature predicted disease specific survival (DSS P<0.001) and relapse free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a co-expression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001) and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger dataset annotated based on prospectively gathered data.Journal of Investigative Dermatology accepted article preview online, 12 February 2014; doi:10.1038/jid.2014.85.
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    • "Ocular melanoma differs from the cutaneous variant not only in the mode of presentation but in the pattern of metastatic spread. While cutaneous melanoma commonly metastasizes to regional and distant lymph node basins [3], their ocular counterparts, as a rule, spread to the liver and, rarely, to other organs, such as lung, bone, skin, and central nervous system [4]. "
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    ABSTRACT: . Visceral metastatic spread of ocular melanoma most commonly occurs via hematogenous route to the liver. Lymphatic spread of ocular melanoma into abdominal lymph nodes has not been reported previously. Case Presentation . A 47-year-old man with a history of ocular melanoma presented with a soft tissue mass on CT scan. The mass encased the portal structures of the hepaticoduodenal ligament. Image-guided biopsy revealed it to be a metastatic melanoma to lymph nodes. The patient underwent surgery with the intent to prolong disease-free survival. On final pathological examination, two lymph nodes were found harboring metastatic melanoma. Conclusion . Extrahepatic lymphatic intra-abdominal spread of ocular melanoma is not impossible. Since this mode of spread is rare, the oncologic significance of surgical resection of isolated intra-abdominal nodal with metastatic ocular melanoma is difficult to determine at the present time.
    05/2013; 2013(2):534730. DOI:10.1155/2013/534730
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