Introduction

Penile cancer (PC) is an aggressive malignancy in which the most important prognostic factor for cancer specific survival (CSS) is the involvement of regional lymph nodes (LNs). Lymph node density (LND) could become a superior prognostic tool for CSS, by accounting for both extent of dissection and nodal disease burden. We aim to validate LND as a prognostic factor for CSS in a contemporary series of patients with PC treated and followed at a single high-volume center, treating more than 25 PC patients per year, over a 13-year period.

Methods

Clinical charts of all patients with PC who underwent surgical treatment between 2007 and 2020 were reviewed. Clinicopathological data was collected and analyzed retrospectively. We only included patients with ≥ 8 LNs removed in a unilateral ILND or ≥16 LNs when a bilateral approach was used. We attempted to find an optimal threshold for LND, capable of maximizing effect difference in terms of CSS and RFS between dichotomized groups. To determine this threshold, we used the chi-squared and the Mann–Whitney tests, and it was required to fulfill the proportional hazards assumption. We assessed different thresholds previously reported in the literature. In our study the optimal threshold for LND was determined to be ≤ 20%

Descriptive statistics were used to summarize patient characteristics, CSS and RFS were graphically represented by Kaplan-Meier estimates. Harrell's C index for CSS and RFS were calculated for LND and pN stage, to determine which variable has a superior predictive capacity

Results

We identified 110 patients with PC who underwent ILND at our institution, of these, 87 were node-positive and were included in the final analysis. Overall estimates of CSS showed a 3-year CSS of 43% (95% CI: 32-54), the estimated 3-year CSS for the patients with a LND ≤ 20% was 69% (95% CI: 50-82) and 26% (95% CI: 14-39) in the group with a LND >20% (Log-rank P = 0.001). The estimated 3-year RFS for the patients with LND ≤ 20% was 61% (95% CI: 42-76) and 30% (95% CI: 16-44) in the group with a LND >20% (Log-rank P = 0.009). The results of univariate analysis indicate that in patients with a LND >20% the risk for cancer specific mortality was increased (HR 2.68; 95% CI: 1.45-4.98, P = 0.002) compared with LND ≤ 20%. In the and Cox multivariate analysis after Adjusting for age and pN stage the association increased (HR 2.73; 95%, CI 1.38-5.40, P = 0.004). Harrell´s C index for CSS was 0.63 for LND vs. 0.54 for pN stage, suggesting a 9% higher concordance for LND and CSS.

Conclusions

Lymph node density stands as a promising tool for risk-stratifying patients with node-positive PC after ILND. In this retrospective study, LND was a significant predictor of CSS and RFS when using a LND >20% threshold, and also showed a superior predictive ability than pN stage. These results support the use of the LND parameter in clinical practice with a final goal to improve risk stratification, and individualized adjuvant treatment decision-making to patients with high-risk of cancer specific mortality.

中文翻译：

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腹股沟淋巴结密度作为淋巴结阳性阴茎癌患者癌症特异性生存的有力预测因子

介绍

阴茎癌 (PC) 是一种侵袭性恶性肿瘤，其中癌症特异性生存 (CSS) 最重要的预后因素是区域淋巴结 (LN) 的受累。通过考虑解剖范围和淋巴结疾病负担，淋巴结密度 (LND) 可以成为 CSS 的一种优越的预后工具。我们的目标是验证 LND 作为 CSS 的预后因素在当代一系列 PC 患者中的治疗和随访在单个大容量中心，在 13 年期间每年治疗超过 25 名 PC 患者。

方法

回顾了 2007 年至 2020 年间接受手术治疗的所有 PC 患者的临床图表。收集临床病理资料并进行回顾性分析。我们仅纳入在单侧 ILND 中切除 ≥ 8 个 LN 或在使用双侧方法时切除 ≥ 16 个 LN 的患者。我们试图找到 LND 的最佳阈值，能够最大化二分组之间在 CSS 和 RFS 方面的效果差异。为了确定这个阈值，我们使用了卡方检验和 Mann-Whitney 检验，并且需要满足比例风险假设。我们评估了文献中先前报道的不同阈值。在我们的研究中，LND 的最佳阈值被确定为 ≤ 20%

描述性统计用于总结患者特征，CSS和RFS由Kaplan-Meier估计图形表示。针对 LND 和 pN 阶段计算 CSS 和 RFS 的 Harrell C 指数，以确定哪个变量具有优越的预测能力

结果

我们确定了 110 名在我们机构接受 ILND 的 PC 患者，其中 87 名淋巴结阳性，并被纳入最终分析。CSS 的总体估计显示 3 年 CSS 为 43%（95% CI：32-54），LND ≤ 20% 患者的 3 年 CSS 估计为 69%（95% CI：50-82） LND > 20%（对数秩P  = 0.001）的组中有 26%（95% CI：14-39）。LND ≤ 20% 患者的估计 3 年 RFS 分别为 61% (95% CI: 42-76) 和 LND >20% (Log-秩P  = 0.009）。单变量分析的结果表明，在 LND >20% 的患者中，癌症特异性死亡率的风险增加（HR 2.68；95% CI：1.45-4.98，P = 0.002) 与 LND ≤ 20% 相比。在调整年龄和 pN 阶段后的和 Cox 多变量分析中，关联增加（HR 2.73；95%，CI 1.38-5.40，P  = 0.004）。LND 的 Harrell's C 指数为 0.63，而 pN 阶段为 0.54，表明 LND 和 CSS 的一致性高 9%。

结论

淋巴结密度是对 ILND 后淋巴结阳性 PC 患者进行风险分层的有前途的工具。在这项回顾性研究中，当使用 LND > 20% 的阈值时，LND 是 CSS 和 RFS 的重要预测因子，并且还显示出比 pN 阶段更好的预测能力。这些结果支持在临床实践中使用 LND 参数，最终目标是改善风险分层，并为癌症特异性死亡率高风险患者制定个性化的辅助治疗决策。