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Quantitative measurement of melanoma spread in sentinel lymph nodes and survival.

Ulmer A, Dietz K, Hodak I, Polzer B, Scheitler S, Yildiz M, Czyz Z, Lehnert P, Fehm T, Hafner C, Schanz S, Röcken M, Garbe C, Breuninger H, Fierlbeck G, Klein CA - PLoS Med. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Tübingen, Tübingen, Germany.

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.

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The prognostic impact of disseminated cancer cells in sentinel nodes.(A) The figure shows the Kaplan-Meier survival estimates for 502 patients with DCCD = 0 (blue line) and for 249 patients with 0< DCCD ≤3 (red line). Even patients with low numbers of DCCs had a significantly reduced survival in comparison to patients without DCCs (86% 5-y survival versus 92% 5-y survival; hazard ratio 1.63, 95% CI: 1.02–2.58). (B) Hazard ratios (in black) for the three DCCD categories of Table 2 together with their 95% confidence intervals as a function of their median DCCD values on a log scale. The red line provides the hazard ratios for the linear model where log(DCCD + 1) is entered as a continuous variable. The predicted curve is within the confidence intervals. The unit risk ratio 1.81 is the hazard ratio corresponding to a 10-fold increase of DCCD + 1. (C) Relation of Breslow's thickness and risk of death from melanoma. Hazard ratios (in black) are given for the three groups of Table 2 (melanomas with 2 mm ≤ tumor thickness ≤4 mm; 4< tumor thickness ≤8 mm; tumor thickness >8 mm) together with their 95% confidence intervals as a function of their median thickness values on a log scale. The red line shows the predicted hazard ratios for the model where log(thickness) enters as a continuous variable. We show only the values ≥1.3 mm, i.e., the median value of the reference group in Table 2. The predicted line is within the confidence intervals. The unit hazard ratio 18.6 corresponds to a 10-fold increase of thickness.
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pmed-1001604-g004: The prognostic impact of disseminated cancer cells in sentinel nodes.(A) The figure shows the Kaplan-Meier survival estimates for 502 patients with DCCD = 0 (blue line) and for 249 patients with 0< DCCD ≤3 (red line). Even patients with low numbers of DCCs had a significantly reduced survival in comparison to patients without DCCs (86% 5-y survival versus 92% 5-y survival; hazard ratio 1.63, 95% CI: 1.02–2.58). (B) Hazard ratios (in black) for the three DCCD categories of Table 2 together with their 95% confidence intervals as a function of their median DCCD values on a log scale. The red line provides the hazard ratios for the linear model where log(DCCD + 1) is entered as a continuous variable. The predicted curve is within the confidence intervals. The unit risk ratio 1.81 is the hazard ratio corresponding to a 10-fold increase of DCCD + 1. (C) Relation of Breslow's thickness and risk of death from melanoma. Hazard ratios (in black) are given for the three groups of Table 2 (melanomas with 2 mm ≤ tumor thickness ≤4 mm; 4< tumor thickness ≤8 mm; tumor thickness >8 mm) together with their 95% confidence intervals as a function of their median thickness values on a log scale. The red line shows the predicted hazard ratios for the model where log(thickness) enters as a continuous variable. We show only the values ≥1.3 mm, i.e., the median value of the reference group in Table 2. The predicted line is within the confidence intervals. The unit hazard ratio 18.6 corresponds to a 10-fold increase of thickness.

Mentions: We evaluated DCCD as biomarker according to the REMARK criteria [25]. Of the standard prognostic factors, sentinel node histopathology (p<0.001), age (p<0.001), thickness (p<0.001), ulceration (p<0.001), and localization of the primary melanoma (p = 0.04) were associated with poor outcome in the univariable Cox regression analyses (see Table 2 and Figure S2 for Kaplan-Meier estimates). Increasing DCCD values were negatively associated with the time to death from melanoma in the univariable Cox regression analyses (p<0.001). We assessed the prognostic impact of DCCD after categorizing the values into four groups (Table 2). We found that even the detection of low DCCD values (0<DCCD ≤3) conferred a significant risk of death (hazard ratio 1.63, 95% CI 1.02–2.58, p = 0.04; Table 2 and Figure 4A) compared to patients without DCCs. Increasing hazard ratios were obtained for categories with higher DCCD values (Table 2). The relationship of increasing DCCD values and the hazard ratio is plotted in Figure 4B on the logarithmic scale. The unit risk ratio (corresponding to a 10-fold increase of DCCD + 1, e.g., from a DCCD of zero to a DCCD of nine) was 1.81 (95% CI 1.61–2.01), and a linear relation (on log scale) between DCCD and hazard ratio was identified (Figure 4B). A similar log-linear relationship was seen between tumor thickness and hazard ratio (Figure 4C).


Quantitative measurement of melanoma spread in sentinel lymph nodes and survival.

Ulmer A, Dietz K, Hodak I, Polzer B, Scheitler S, Yildiz M, Czyz Z, Lehnert P, Fehm T, Hafner C, Schanz S, Röcken M, Garbe C, Breuninger H, Fierlbeck G, Klein CA - PLoS Med. (2014)

The prognostic impact of disseminated cancer cells in sentinel nodes.(A) The figure shows the Kaplan-Meier survival estimates for 502 patients with DCCD = 0 (blue line) and for 249 patients with 0< DCCD ≤3 (red line). Even patients with low numbers of DCCs had a significantly reduced survival in comparison to patients without DCCs (86% 5-y survival versus 92% 5-y survival; hazard ratio 1.63, 95% CI: 1.02–2.58). (B) Hazard ratios (in black) for the three DCCD categories of Table 2 together with their 95% confidence intervals as a function of their median DCCD values on a log scale. The red line provides the hazard ratios for the linear model where log(DCCD + 1) is entered as a continuous variable. The predicted curve is within the confidence intervals. The unit risk ratio 1.81 is the hazard ratio corresponding to a 10-fold increase of DCCD + 1. (C) Relation of Breslow's thickness and risk of death from melanoma. Hazard ratios (in black) are given for the three groups of Table 2 (melanomas with 2 mm ≤ tumor thickness ≤4 mm; 4< tumor thickness ≤8 mm; tumor thickness >8 mm) together with their 95% confidence intervals as a function of their median thickness values on a log scale. The red line shows the predicted hazard ratios for the model where log(thickness) enters as a continuous variable. We show only the values ≥1.3 mm, i.e., the median value of the reference group in Table 2. The predicted line is within the confidence intervals. The unit hazard ratio 18.6 corresponds to a 10-fold increase of thickness.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928050&req=5

pmed-1001604-g004: The prognostic impact of disseminated cancer cells in sentinel nodes.(A) The figure shows the Kaplan-Meier survival estimates for 502 patients with DCCD = 0 (blue line) and for 249 patients with 0< DCCD ≤3 (red line). Even patients with low numbers of DCCs had a significantly reduced survival in comparison to patients without DCCs (86% 5-y survival versus 92% 5-y survival; hazard ratio 1.63, 95% CI: 1.02–2.58). (B) Hazard ratios (in black) for the three DCCD categories of Table 2 together with their 95% confidence intervals as a function of their median DCCD values on a log scale. The red line provides the hazard ratios for the linear model where log(DCCD + 1) is entered as a continuous variable. The predicted curve is within the confidence intervals. The unit risk ratio 1.81 is the hazard ratio corresponding to a 10-fold increase of DCCD + 1. (C) Relation of Breslow's thickness and risk of death from melanoma. Hazard ratios (in black) are given for the three groups of Table 2 (melanomas with 2 mm ≤ tumor thickness ≤4 mm; 4< tumor thickness ≤8 mm; tumor thickness >8 mm) together with their 95% confidence intervals as a function of their median thickness values on a log scale. The red line shows the predicted hazard ratios for the model where log(thickness) enters as a continuous variable. We show only the values ≥1.3 mm, i.e., the median value of the reference group in Table 2. The predicted line is within the confidence intervals. The unit hazard ratio 18.6 corresponds to a 10-fold increase of thickness.
Mentions: We evaluated DCCD as biomarker according to the REMARK criteria [25]. Of the standard prognostic factors, sentinel node histopathology (p<0.001), age (p<0.001), thickness (p<0.001), ulceration (p<0.001), and localization of the primary melanoma (p = 0.04) were associated with poor outcome in the univariable Cox regression analyses (see Table 2 and Figure S2 for Kaplan-Meier estimates). Increasing DCCD values were negatively associated with the time to death from melanoma in the univariable Cox regression analyses (p<0.001). We assessed the prognostic impact of DCCD after categorizing the values into four groups (Table 2). We found that even the detection of low DCCD values (0<DCCD ≤3) conferred a significant risk of death (hazard ratio 1.63, 95% CI 1.02–2.58, p = 0.04; Table 2 and Figure 4A) compared to patients without DCCs. Increasing hazard ratios were obtained for categories with higher DCCD values (Table 2). The relationship of increasing DCCD values and the hazard ratio is plotted in Figure 4B on the logarithmic scale. The unit risk ratio (corresponding to a 10-fold increase of DCCD + 1, e.g., from a DCCD of zero to a DCCD of nine) was 1.81 (95% CI 1.61–2.01), and a linear relation (on log scale) between DCCD and hazard ratio was identified (Figure 4B). A similar log-linear relationship was seen between tumor thickness and hazard ratio (Figure 4C).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Tübingen, Tübingen, Germany.

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.

Show MeSH
Related in: MedlinePlus