Research Article: BRAF immunohistochemistry predicts sentinel lymph node involvement in intermediate thickness melanomas

Date Published: April 30, 2019

Publisher: Public Library of Science

Author(s): Atte A. Manninen, Maria Gardberg, Susanna Juteau, Suvi Ilmonen, Joonas Jukonen, Noora Andersson, Olli Carpén, Nikolas K. Haass.


Sentinel node biopsy (SNB) is an important step in melanoma staging and prognostication. It is commonly performed for patients with intermediate thickness melanomas, based on clinicopathological features. However, only 20–25% of patients eventually demonstrate nodal involvement. The aim of this study was to evaluate whether tissue biomarkers with links to melanoma biology, together with clinicopathological parameters, could aid in the prediction of sentinel node involvement and improve selection of patients for SNB. In addition, we examined the role of these clinical or biological markers in disease outcome.

We collected a case-control cohort of 140 intermediate thickness (Breslow 0,9–4,0mm) melanoma patients with or without SNB involvement matched for age, gender, Breslow thickness and location. From this cohort, we tested the predictive value of common clinicopathological parameters (ulceration, mitotic count and tumor regression) and FMNL-2, ezrin and BRAF V600E immunoreactivity, for sentinel node involvement and survival. We further analyzed the correlations in the superficial spreading melanoma subtype.

Based on our case control analysis, of the markers, BRAF V600E status (p = 0.010) and mitotic count (p = 0.036) correlated with SNB involvement. SNB status was a strong independent prognosticator for recurrence free survival (RFS p<0.001), melanoma specific survival (MSS p = 0.000) and overall survival (OS p = 0.029). In the superficially spreading melanoma subgroup, BRAF V600E positivity indicated poorer RFS (p = 0.039) and OS (p = 0.012). By combining the Breslow thickness, mitotic count and BRAF immunohistochemistry, we identified a group of superficially spreading melanomas with an excellent survival probability independent of SNB status. These results demonstrate that BRAF immunohistochemistry could serve as a useful addition to a marker panel for selecting intermediate thickness melanoma patients for SNB.

Partial Text

Cutaneous melanoma is a common malignant neoplasia with over 230 000 cases and 55 000 cancer deaths annually [1]. While death rates are projected to remain stable, melanoma incidence and treatment costs are estimated to rise significantly through 2030 [2].

The median age was 57.9 y (range 31–83 y). Of the 140 patients 72 were female and 68 were male. Location of the melanoma was most often trunk area (N = 64), followed by lower limb (N = 36), upper limb (N = 20) and head and neck (N = 20). The most common melanoma subtype was superficially spreading melanoma (N = 71), followed by nodular (N = 50) and acral (N = 6). Thirteen cases could not be categorized. In the entire cohort, ulceration was present in 32 (22.9%) primary melanomas (Table 1). We performed further division of the cohort in to smaller subgroups according to melanoma location and pathological characteristics. The only subgroup that remained sufficiently large for statistical analyses was the superficially spreading melanoma group (N = 71).

Sentinel node biopsy provides important information for melanoma staging and for adjuvant treatment decisions. However, the current practice for selecting individuals for SNB is far from optimal, since only 20–25% of biopsied patients actually demonstrate lymph node involvement. In this study we wanted to test whether clinicopathological parameters or novel biomarkers, either alone or in combination, could indicate the probability of sentinel node involvement and thereby improve the selection of patients for SNB. In a matched case–control setting we demonstrate that mitotic count and BRAF V600E immunohistochemistry significantly correlate with SNB positivity in cutaneous melanomas of intermediate thickness. Our study also shows that in this matched cohort, SNB involvement is a strong independent predictor of RFS, MSS and OS. Finally, we show preliminary evidence that a combination of Breslow thickness, mitotic count and BRAF immunohistochemistry may identify a group within superficial spreading melanomas with an improved survival probability independent of SNB analysis.




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