Insulin-Like Growth Factor II mRNA-Binding Protein 3 Expression Correlates with Poor Prognosis in Acral Lentiginous Melanoma

<div><p>Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3) is an RNA-binding protein expressed in multiple cancers, including melanomas. However, the expression of IMP-3 has not been investigated in acral lentiginous melanoma (ALM). This study sought to elucidate its prognostic value in ALMs. IMP-3 expression was studied in 93 patients diagnosed with ALM via immunohistochemistry. Univariate and multivariate analyses for survival were performed, according to clinical and histologic parameters, using the Cox proportional hazard model. Survival curves were graphed using the Kaplan-Meier method. IMP-3 was over-expressed in 70 out of 93 tumors (75.3%). IMP-3 expression correlated with thick and high-stage tumor and predicted poorer overall, melanoma-specific, recurrence-free and distant metastasis-free survivals (<i>P</i> = 0.002, 0.006, 0.008 and 0.012, respectively). Further analysis showed that patients with tumor thickness ≤ 4.0 mm and positive IMP-3 expression had a significantly worse melanoma-specific survival than those without IMP-3 expression (<i>P</i> = 0.048). IMP-3 (hazard ratio 3.67, 95% confidence intervals 1.35–9.97, <i>P</i> = 0.011) was confirmed to be an independent prognostic factor for melanoma-specific survival in multivariate survival analysis. Positive IMP-3 expression was an important prognostic factor for ALMs.</p></div

IMP-3 was expressed in ALM and associated with its progression.

<p>(<b>A</b>) Benign melanocytic nevi such as intradermal nevus were negative for IMP-3. (<b>B</b>) Focal IMP-3 expression was found in ALM with thickness ≤ 4 mm (Breslow thickness = 1.2 mm). (<b>C</b>) Strong and diffuse cytoplasmic expression was noted in ALM with depth >4.0mm (Breslow thickness = 6 mm). <b>(D</b>) Metastatic melanoma expressed IMP-3 in most tumor cells (Bar, 100 μm).</p

Kaplan-Meier curves of survival associated with IMP-3 expression in 93 primary ALMs.

<p>IMP-3 overexpression was significantly associated with overall (<b>A</b>), melanoma-specific (<b>B</b>), recurrence-free (<b>C</b>), and distant metastasis-free survival (<b>D</b>) (<i>P</i> = 0.002, 0.006, 0.008 and 0.012, respectively; log rank test).</p

Kaplan-Meier analysis of survival in patients with or without IMP-3 expression in relation to thickness.

<p>The <i>P</i> value was obtained from comparison of four groups (log rank test). Patient with tumor thickness ≤ 4.0 mm and negative IMP-3 expression had the best overall (<b>A</b>), melanoma-specific (<b>B</b>), recurrence-free (<b>C</b>), and distant metastasis-free survival (<b>D</b>) (<i>P</i><0.001, <i>P</i><0.001, <i>P</i><0.001, and <i>P</i> = 0.001, respectively).</p

Histogram and density plot of visual analogue scale (VAS) change scores.

<p>Frequency distribution of pruritus VAS change scores in the study participants. The density of vertical axis represents the percentage of study participants. The VAS change score = VAS score at follow-up − VAS score at baseline.</p

Laboratory and clinical characteristics of participants with improved and unimproved pruritus intensity, at baseline and at follow-up.

<p>NOTE. Data are expressed as mean ± S.D for normally distributed continuous variables; as median (interquartile range) for non-normally distributed continuous variables; and as number (percentage) for categorical variables.</p><p>Abbreviations: VAS, visual analog scale.</p>*<p><i>P</i><0.05 for the statistical testing between participants with improved pruritus and those with unimproved pruritus.</p>**<p>Ca×P = Product of albumin-adjusted serum calcium (Ca) and serum phosphorus (P).</p

Identifying the appropriate threshold of baseline Kt/V by the generalized additive models (GAM) plot.

<p>(A) The GAM plot adjusted for the important covariates at baseline only (gender, Kt/V, use of high-flux dialyzer, pruritus intensity, hematocrit, creatinine, uric acid, fasting glucose, total bilirubin, and Ca×P).(B) The GAM plot adjusted for the important covariates at baseline (Kt/V, pruritus intensity, AST, and Ca×P) and the change scores of the covariates (uric acid, fasting glucose, and AST). The solid red lines show nonlinearity of multivariable-adjusted relation between baseline Kt/V and change score of pruritus (with 95% confidence intervals shown in black dotted lines). Pruritus intensity was assessed by visual analog scale scores. The little vertical bars (i.e., rugs) on the horizontal axis of the GAM plots display the distribution of individual observations. Both GAM plots identified the value around 1.5 to be the appropriate threshold of baseline Kt/V for uremic pruritus, which indicated start of the aggravation of pruritus intensity began at Kt/V <1.5.</p

Laboratory and clinical characteristics of participants at baseline and follow-up.

<p>NOTE. Data are expressed as mean ± S.D for normally distributed continuous variables; as median (interquartile range) for non-normally distributed continuous variables; and as number (percentage) for categorical variables.</p><p>Abbreviations: VAS, visual analog scale.</p>*<p><i>P</i><0.05 for the statistical testing between baseline and follow-up.</p>**<p>Ca×P = Product of albumin-adjusted serum calcium (Ca) and serum phosphorus (P).</p

Histogram and density plot of visual analogue scale (VAS) scores.

<p>(A) Frequency distribution of pruritus VAS scores at baseline in the study participants. (B) Frequency distribution of pruritus VAS scores at follow-up in the study participants. The density of vertical axis represents the percentage of study participants.</p

Demographic and clinical characteristics of participants at baseline.

<p>NOTE. Data are expressed as mean ± S.D. or number (percentage).</p