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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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DCCD and standard clinical prognostic factors.For all panels, the red lines indicate the medians, and the black lines the 25th and 75th percentiles. (A) All DCCD values are plotted according to the T stage of the primary melanoma. (B) DCCD and ulceration state of the primary melanoma. (C) DCCD and status according histopathological routine analysis of the other lymph node half. (D) DCCD and localization of the primary melanoma. (E) DCCD and age category (<58 y and ≥58 y) of patient. (F) DCCD and gender of patient.
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pmed-1001604-g002: DCCD and standard clinical prognostic factors.For all panels, the red lines indicate the medians, and the black lines the 25th and 75th percentiles. (A) All DCCD values are plotted according to the T stage of the primary melanoma. (B) DCCD and ulceration state of the primary melanoma. (C) DCCD and status according histopathological routine analysis of the other lymph node half. (D) DCCD and localization of the primary melanoma. (E) DCCD and age category (<58 y and ≥58 y) of patient. (F) DCCD and gender of patient.

Mentions: On the other hand, we detected gp100-positive cells in the lymph nodes of 525 of the 1,027 melanoma patients (51%). Whenever enough cells were isolated from the lymph node half for immunocytology, we aimed to screen 2×106 lymph node cells, i.e., two slides, per patient. The median number of slides screened per node was two (range 104 to 6×106 cells). The median DCCD in patients with DCCD >0 was 4 gp100-positive cells per million isolated cells (ranging from 0.2 to 950000; Figure 1F). We evaluated the relation of DCCD with the six established prognostic factors (Figure 2). Geometric mean values of DCCD were significantly higher in thicker and ulcerated melanomas (p<0.001), in melanomas located at other sites than the extremities (p = 0.02), and in patients with a pathologically positive sentinel node (p<0.001; Figure 2).


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)

DCCD and standard clinical prognostic factors.For all panels, the red lines indicate the medians, and the black lines the 25th and 75th percentiles. (A) All DCCD values are plotted according to the T stage of the primary melanoma. (B) DCCD and ulceration state of the primary melanoma. (C) DCCD and status according histopathological routine analysis of the other lymph node half. (D) DCCD and localization of the primary melanoma. (E) DCCD and age category (<58 y and ≥58 y) of patient. (F) DCCD and gender of patient.
© Copyright Policy
Related In: Results  -  Collection

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

pmed-1001604-g002: DCCD and standard clinical prognostic factors.For all panels, the red lines indicate the medians, and the black lines the 25th and 75th percentiles. (A) All DCCD values are plotted according to the T stage of the primary melanoma. (B) DCCD and ulceration state of the primary melanoma. (C) DCCD and status according histopathological routine analysis of the other lymph node half. (D) DCCD and localization of the primary melanoma. (E) DCCD and age category (<58 y and ≥58 y) of patient. (F) DCCD and gender of patient.
Mentions: On the other hand, we detected gp100-positive cells in the lymph nodes of 525 of the 1,027 melanoma patients (51%). Whenever enough cells were isolated from the lymph node half for immunocytology, we aimed to screen 2×106 lymph node cells, i.e., two slides, per patient. The median number of slides screened per node was two (range 104 to 6×106 cells). The median DCCD in patients with DCCD >0 was 4 gp100-positive cells per million isolated cells (ranging from 0.2 to 950000; Figure 1F). We evaluated the relation of DCCD with the six established prognostic factors (Figure 2). Geometric mean values of DCCD were significantly higher in thicker and ulcerated melanomas (p<0.001), in melanomas located at other sites than the extremities (p = 0.02), and in patients with a pathologically positive sentinel node (p<0.001; Figure 2).

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