Quantitative measurement of melanoma spread in sentinel lymph nodes and survival

PLoS Med. 2014 Feb 18;11(2):e1001604. doi: 10.1371/journal.pmed.1001604. eCollection 2014 Feb.

Abstract

Background: Sentinel lymph node spread is a crucial factor in melanoma outcome. We aimed to define the impact of minimal cancer spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival.

Methods and findings: We analyzed 1,834 sentinel nodes from 1,027 patients with ultrasound node-negative melanoma who underwent sentinel node biopsy between February 8, 2000, and June 19, 2008, by histopathology including immunohistochemistry and quantitative immunocytology. For immunocytology we recorded the number of disseminated cancer cells (DCCs) per million lymph node cells (DCC density [DCCD]) after disaggregation and immunostaining for the melanocytic marker gp100. None of the control lymph nodes from non-melanoma patients (n = 52) harbored gp100-positive cells. We analyzed gp100-positive cells from melanoma patients by comparative genomic hybridization and found, in 45 of 46 patients tested, gp100-positive cells displaying genomic alterations. At a median follow-up of 49 mo (range 3-123 mo), 138 patients (13.4%) had died from melanoma. Increased DCCD was associated with increased risk for death due to melanoma (univariable analysis; p<0.001; hazard ratio 1.81, 95% CI 1.61-2.01, for a 10-fold increase in DCCD + 1). Even patients with a positive DCCD ≤3 had an increased risk of dying from melanoma compared to patients with DCCD = 0 (p = 0.04; hazard ratio 1.63, 95% CI 1.02-2.58). Upon multivariable testing DCCD was a stronger predictor of death than histopathology. The final model included thickness, DCCD, and ulceration (all p<0.001) as the most relevant prognostic factors, was internally validated by bootstrapping, and provided superior survival prediction compared to the current American Joint Committee on Cancer staging categories.

Conclusions: Cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death. A model based on the combined quantitative effects of DCCD, tumor thickness, and ulceration predicted outcome best, particularly at longer follow-up. If these results are validated in an independent study, establishing quantitative immunocytology in histopathological laboratories may be useful clinically.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics
  • Chi-Square Distribution
  • Child
  • Comparative Genomic Hybridization
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Lymph Nodes / pathology*
  • Lymphatic Metastasis
  • Male
  • Melanoma / chemistry
  • Melanoma / genetics
  • Melanoma / mortality*
  • Melanoma / secondary*
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Staging
  • Predictive Value of Tests
  • Proportional Hazards Models
  • Risk Assessment
  • Risk Factors
  • Sentinel Lymph Node Biopsy*
  • Skin Neoplasms / chemistry
  • Skin Neoplasms / genetics
  • Skin Neoplasms / mortality*
  • Skin Neoplasms / pathology*
  • Time Factors
  • Young Adult

Substances

  • Biomarkers, Tumor

Grant support

This work was supported by grants from the University of Tübingen (IZKF-1686-0-0, to AU) and the Ludwig-Hiermaier Stiftung (to AU) and by grants from the Wilhelm-Sander Stiftung (2003.005), the Deutsche Krebshilfe (108008), and the Bavarian State Ministry of Sciences, Research and the Arts (to CAK). No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.