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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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Individualized risk estimation over time.(A) The predicted 5-y survival by DCCD, tumor thickness, and ulceration for all 1,027 patients. Dots indicate patients who were alive at the end of follow-up; circles indicate patients who died from melanoma (n = 138). The red symbols indicate patients with ulcerated melanomas. The patients left of the vertical line at DCCD + 1 = 1 (n = 502) displayed no DCCs in their sentinel nodes. Dots located on the same continuous line represent patients with the same 5-y survival, which is depicted at the right end of the lines (red lines for the patients with ulcerated melanoma). For example, for Patient 1 and Patient 5 from (B) (circled in blue), the estimated 5-y survival of Patient 1 is >99.5%, while for Patient 5 it is about 6%. The parametric survival model is based on the lognormal distribution and includes DCCD, thickness, and ulceration. (B) Time-dependent hazard rates for 14 individual patients with five different hazard rates (1–5) with their observed thickness, DCCD, and ulceration status, and their corresponding predicted 5-y survival rates and median survival times. Different combinations of thickness, DCCD, and ulceration status may indicate the same risk of death from melanoma. In contrast to the Cox model, the predicted hazard ratios vary over time. (C) A nomogram enables estimating the 5-y survival probability. The 5-y survival probability is the value at the intersection of a straight line connecting DCCD and tumor thickness with the central straight line. For illustration, the blue lines exemplify the same Patients 1 and 5 that are marked in (A) and described in (B). Patient 5 had an ulcerated melanoma, and therefore the red scale must be used, while Patient 1 had a non-ulcerated melanoma, so survival probability is given on the black scale. Note that the nomogram has not been independently validated and therefore is not yet suitable for clinical use.
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pmed-1001604-g005: Individualized risk estimation over time.(A) The predicted 5-y survival by DCCD, tumor thickness, and ulceration for all 1,027 patients. Dots indicate patients who were alive at the end of follow-up; circles indicate patients who died from melanoma (n = 138). The red symbols indicate patients with ulcerated melanomas. The patients left of the vertical line at DCCD + 1 = 1 (n = 502) displayed no DCCs in their sentinel nodes. Dots located on the same continuous line represent patients with the same 5-y survival, which is depicted at the right end of the lines (red lines for the patients with ulcerated melanoma). For example, for Patient 1 and Patient 5 from (B) (circled in blue), the estimated 5-y survival of Patient 1 is >99.5%, while for Patient 5 it is about 6%. The parametric survival model is based on the lognormal distribution and includes DCCD, thickness, and ulceration. (B) Time-dependent hazard rates for 14 individual patients with five different hazard rates (1–5) with their observed thickness, DCCD, and ulceration status, and their corresponding predicted 5-y survival rates and median survival times. Different combinations of thickness, DCCD, and ulceration status may indicate the same risk of death from melanoma. In contrast to the Cox model, the predicted hazard ratios vary over time. (C) A nomogram enables estimating the 5-y survival probability. The 5-y survival probability is the value at the intersection of a straight line connecting DCCD and tumor thickness with the central straight line. For illustration, the blue lines exemplify the same Patients 1 and 5 that are marked in (A) and described in (B). Patient 5 had an ulcerated melanoma, and therefore the red scale must be used, while Patient 1 had a non-ulcerated melanoma, so survival probability is given on the black scale. Note that the nomogram has not been independently validated and therefore is not yet suitable for clinical use.

Mentions: To fully exploit the power of our quantitative assay, we combined the three most important risk factors identified by multivariable analysis (tumor thickness, DCCD, and ulceration) for individual risk assessment at diagnosis and during follow-up. While results of Cox models represent a useful summary for the average hazard ratios, we observed that the assumption of proportional hazards was not fulfilled for tumor thickness and DCCD (Figure S3). Therefore, we employed a lognormal survival model based on tumor thickness, DCCD, and ulceration that allows the calculation of changes in individual risk over time and of the predicted 5-y survival for all 1,027 patients (Figure 5A). Figure 5A shows that patients with thin melanomas never harbored high DCC numbers in their lymph nodes and poorest outcome was seen for thick tumors and high DCCD. It should be noted that DCCD and tumor thickness are plotted on a logarithmic scale, and therefore the curves of equal 5-y survival probability appear as straight lines. On a linear scale these curves (isoboles) are convex (Figure S4), which indicates synergism [26]. Using this model, we calculated the time-dependent hazard rates for 14 individual patients with five different hazard rate curves (Figure 5B). This calculation revealed that DCC-negative and DCC-positive patients might display identical hazard rate functions (e.g., compare Patients 2a and 2b in Figure 5B) and also that the hazard rate peaks later in low-risk than in high-risk patients. Furthermore, tumor thickness, DCCD, and ulceration state can be integrated into a preliminary nomogram to determine the 5-y survival of individual patients (Figure 5C).


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)

Individualized risk estimation over time.(A) The predicted 5-y survival by DCCD, tumor thickness, and ulceration for all 1,027 patients. Dots indicate patients who were alive at the end of follow-up; circles indicate patients who died from melanoma (n = 138). The red symbols indicate patients with ulcerated melanomas. The patients left of the vertical line at DCCD + 1 = 1 (n = 502) displayed no DCCs in their sentinel nodes. Dots located on the same continuous line represent patients with the same 5-y survival, which is depicted at the right end of the lines (red lines for the patients with ulcerated melanoma). For example, for Patient 1 and Patient 5 from (B) (circled in blue), the estimated 5-y survival of Patient 1 is >99.5%, while for Patient 5 it is about 6%. The parametric survival model is based on the lognormal distribution and includes DCCD, thickness, and ulceration. (B) Time-dependent hazard rates for 14 individual patients with five different hazard rates (1–5) with their observed thickness, DCCD, and ulceration status, and their corresponding predicted 5-y survival rates and median survival times. Different combinations of thickness, DCCD, and ulceration status may indicate the same risk of death from melanoma. In contrast to the Cox model, the predicted hazard ratios vary over time. (C) A nomogram enables estimating the 5-y survival probability. The 5-y survival probability is the value at the intersection of a straight line connecting DCCD and tumor thickness with the central straight line. For illustration, the blue lines exemplify the same Patients 1 and 5 that are marked in (A) and described in (B). Patient 5 had an ulcerated melanoma, and therefore the red scale must be used, while Patient 1 had a non-ulcerated melanoma, so survival probability is given on the black scale. Note that the nomogram has not been independently validated and therefore is not yet suitable for clinical use.
© Copyright Policy
Related In: Results  -  Collection

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

pmed-1001604-g005: Individualized risk estimation over time.(A) The predicted 5-y survival by DCCD, tumor thickness, and ulceration for all 1,027 patients. Dots indicate patients who were alive at the end of follow-up; circles indicate patients who died from melanoma (n = 138). The red symbols indicate patients with ulcerated melanomas. The patients left of the vertical line at DCCD + 1 = 1 (n = 502) displayed no DCCs in their sentinel nodes. Dots located on the same continuous line represent patients with the same 5-y survival, which is depicted at the right end of the lines (red lines for the patients with ulcerated melanoma). For example, for Patient 1 and Patient 5 from (B) (circled in blue), the estimated 5-y survival of Patient 1 is >99.5%, while for Patient 5 it is about 6%. The parametric survival model is based on the lognormal distribution and includes DCCD, thickness, and ulceration. (B) Time-dependent hazard rates for 14 individual patients with five different hazard rates (1–5) with their observed thickness, DCCD, and ulceration status, and their corresponding predicted 5-y survival rates and median survival times. Different combinations of thickness, DCCD, and ulceration status may indicate the same risk of death from melanoma. In contrast to the Cox model, the predicted hazard ratios vary over time. (C) A nomogram enables estimating the 5-y survival probability. The 5-y survival probability is the value at the intersection of a straight line connecting DCCD and tumor thickness with the central straight line. For illustration, the blue lines exemplify the same Patients 1 and 5 that are marked in (A) and described in (B). Patient 5 had an ulcerated melanoma, and therefore the red scale must be used, while Patient 1 had a non-ulcerated melanoma, so survival probability is given on the black scale. Note that the nomogram has not been independently validated and therefore is not yet suitable for clinical use.
Mentions: To fully exploit the power of our quantitative assay, we combined the three most important risk factors identified by multivariable analysis (tumor thickness, DCCD, and ulceration) for individual risk assessment at diagnosis and during follow-up. While results of Cox models represent a useful summary for the average hazard ratios, we observed that the assumption of proportional hazards was not fulfilled for tumor thickness and DCCD (Figure S3). Therefore, we employed a lognormal survival model based on tumor thickness, DCCD, and ulceration that allows the calculation of changes in individual risk over time and of the predicted 5-y survival for all 1,027 patients (Figure 5A). Figure 5A shows that patients with thin melanomas never harbored high DCC numbers in their lymph nodes and poorest outcome was seen for thick tumors and high DCCD. It should be noted that DCCD and tumor thickness are plotted on a logarithmic scale, and therefore the curves of equal 5-y survival probability appear as straight lines. On a linear scale these curves (isoboles) are convex (Figure S4), which indicates synergism [26]. Using this model, we calculated the time-dependent hazard rates for 14 individual patients with five different hazard rate curves (Figure 5B). This calculation revealed that DCC-negative and DCC-positive patients might display identical hazard rate functions (e.g., compare Patients 2a and 2b in Figure 5B) and also that the hazard rate peaks later in low-risk than in high-risk patients. Furthermore, tumor thickness, DCCD, and ulceration state can be integrated into a preliminary nomogram to determine the 5-y survival of individual patients (Figure 5C).

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