Abstract
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. 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. 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.
Highlights
For melanoma staging, sentinel node biopsy has been established to assess melanoma cell dissemination and has become the most widely used procedure to determine the regional lymph node status in patients with cutaneous melanoma [1,2]
A model based on the combined quantitative effects of disseminated cancer cells (DCCs) density (DCCD), tumor thickness, and ulceration predicted outcome best, at longer follow-up
Severe concerns about the immunocytological assay may be raised by (1) the loss of architectural information, which helps to differentiate between intra-lymphatic nevi and colonies of melanoma cells, (2) the difficulty to identify melanoma colonies by morphological criteria, and (3) the fact that the gp100 antigen for melanoma detection may be down-regulated. We addressed these concerns by careful evaluation of lymph node preparations from melanoma and non-melanoma patients using a second melanomaassociated antibody directed against Melan-A and by genetic analysis of the gp100-positive cells
Summary
Sentinel node biopsy has been established to assess melanoma cell dissemination and has become the most widely used procedure to determine the regional lymph node status in patients with cutaneous melanoma [1,2]. The chance of detecting rare tumor cells by histopathology depends on the number of sections screened [8], and extensive histopathological protocols [7,9,10,11] can achieve a detection rate of 30% but require the analysis of 24 to 36 slides per node [7] Since this translates into 42 h of examination time for about ten melanoma patients a week [12], it is obviously impracticable for many institutions. Signs of melanoma are a change in the appearance of a mole (a pigmented skin blemish) or the development of a new and unusual pigmented lesion If these signs are noticed and the melanoma is diagnosed before it has spread from the skin into nearby lymph nodes and other tissues, surgery often provides a cure. The outlook is generally poor, novel therapies may prolong a patient’s life
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