The role of extranodal extension (ENE) in penile cancer is controversial and has not been well studied. The aim of this study was to investigate the importance of ENE in predicting prognosis and presence of pelvic lymph node metastasis (PLNM) in penile cancer patients.
Zhang et al BMC Cancer (2015) 15:815 DOI 10.1186/s12885-015-1834-4 RESEARCH ARTICLE Open Access The importance of extranodal extension in penile cancer: a meta-analysis Zhi-Ling Zhang1,2†, Chun-Ping Yu1,2,3†, Zhuo-Wei Liu1,2, Liliya Velet4, Yong-Hong Li1,2, Li-Juan Jiang1,2 and Fang-Jian Zhou1,2* Abstract Background: The role of extranodal extension (ENE) in penile cancer is controversial and has not been well studied The aim of this study was to investigate the importance of ENE in predicting prognosis and presence of pelvic lymph node metastasis (PLNM) in penile cancer patients Methods: We searched related studies in Medline, Embase, Cochrane Library, and Scopus database Hazard ratio (HR) and odds ratio (OR) were directly extracted or indirectly estimated from the included studies Results: A total of ten studies with 1,142 patients were included in this meta-analysis Patients with ENE showed a worse cancer-specific survival (CSS) (HR = 1.90, 95 % confidence interval [CI] = 1.35–2.67, P = 0.0002) and overall survival (HR = 4.04, 95 % CI = 1.02–16.1, P = 0.05) than those without ENE Further subgroup analysis revealed that the predictive value of ENE for CSS in penile cancer patients was significant regardless of the study’s country of origin, but not in the subgroup with shorter follow-up time ( 100 cases) No significant publication bias was observed, as suggested by Begg’s and Egger’s tests Conclusions: ENE is associated with worse prognosis and high risk of PLNM in penile cancer patients Due to the limited number of studies included in this meta-analysis, a large-scale, well-designed study will be required to verify our results Keywords: Extranodal extension, Penile cancer, Prognosis, Meta-analysis, Pelvic lymph node metastasis Background Penile cancer is an uncommon malignancy, with an incidence of less than 1/100,000 in Western countries [1, 2] The prevalence of penile cancer is higher in developing regions, yet the overall tendency is showing a decrease in morbidity [3–5] It is imperative to identify prognostic factors of this disease, however due to its rarity this task is difficult Generally, the most widely accepted prognostic factor of penile cancer is the status of the regional lymph nodes [6–8] The 7th American Joint Committee on Cancer (AJCC) cancer staging manual [9] categorizes * Correspondence: zhoufj@sysucc.org.cn † Equal contributors Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P R China State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P R China Full list of author information is available at the end of the article patients with a single positive inguinal lymph node as pN1, and multiple as pN2 Penile cancer with inguinal lymph node metastasis (LNM) shows a poorer prognosis than those without inguinal LNM In addition, the prognosis of patients with pelvic lymph nodes metastasis (PLNM) is even worse [10–12] Extranodal extension (ENE) is defined as extension of tumor through the lymph node capsule into the perinodal fibrous-adipose tissue Along with the number and location of LNM, ENE is also considered a negative prognostic factor in penile cancer patients In the latest AJCC TNM staging [9], both ENE and PLNM are staged as pN3, suggesting that ENE is an extremely terrible pathologic finding However, the role of ENE in penile cancer is still controversial Certain studies have indicated that penile cancer patients with ENE had a lower 5-year survival rate compared with those without ENE © 2015 Zhang et al Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Zhang et al BMC Cancer (2015) 15:815 [13–16] Several other reports, however, find that ENE is not an independent prognostic factor [17, 18] As for PLNM, the European Association of Urology (EAU) guideline recommends considering ENE in inguinal lymph nodes as a risk factor for PLNM [19], even though some studies have failed to find a significant predictive role of ENE for PLNM [16, 20, 21] The above-mentioned contradictory results contribute to the uncertainty of the role of ENE in penile cancer These controversial results regarding ENE may be attributed to the rarity of penile cancer Both the number of patients and statistical power in each individual study is limited In the current study, we performed a metaanalysis that pooled together all the related studies focusing on the role of ENE in penile cancer We aimed to better illuminate the importance of ENE in predicting survival and the risk of PLNM in penile cancer patients Methods This meta-analysis was preformed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria [22] Literature search strategy We performed a search in the Medline, Embase, Cochrane Library and Scopus databases to identify relevant studies for this meta-analysis Our search duration lasted until November 18, 2014 We utilized the following terms and combinations for searching: “penile cancer or carcinoma of penis or penis cancer or penile neoplasms” and “extranodal or extra capsular or capsular penentration or perinodal” Furthermore, references of retrieved articles and reviews were manually screened for additional studies Inclusion and exclusion criteria Studies were considered eligible if they met both of the following criteria: (1) published in English and (2) reported the association between ENE and prognosis and/ or the risk of PLNM of penile cancer Studies were excluded based on the following criteria: (1) letters, case reports, reviews, and conference abstracts; (2) studies which did not provide sufficient information to estimate hazard ratio (HR) or odds ratio (OR) and 95 % confidence interval (CI); and (3) studies with duplicated data or a repeated analysis When the same group reported duplicated data in papers, we only included the most informative one Data extraction and quality assessment We extracted the useful data from eligible studies by using a standard information collection survey including the following items: first author’s name, publication year, recruitment period, country of origin, follow-up time, Page of 10 number of patients, number of patients with ENE, and HR/OR with 95 % CI The quality of the included studies was assessed by the Newcastle-Ottawa Scale (NOS) [23] Studies with seven or more stars were defined as high quality studies Two authors (Zhi-Ling Zhang and Chun-Ping Yu) independently reviewed the above data, and all disparities were resolved by discussions between the authors Statistical analysis In order to analyze the impact of ENE on the survival of penile cancer patients, we synthesized survival data from the included studies using the reported HR and its 95 % CI When the survival data was not directly reported, we used a mathematical estimation to calculate the necessary data with the methods reported by Tierney et al [24] By convention, an observed HR > implied worse survival for patients with ENE The association between ENE and PLNM was evaluated by OR All numbers needed for calculating OR and their 95 % CIs were directly extracted from the multivariable logistic regression or univariate analysis If a study provided both, the results of multivariable and univariate analysis, we used the former We used Higgins I2statistic to quantify the heterogeneity of the pooled results If it was I2 < 50 %, indicating the absence of heterogeneity, then a fixedeffects model was used to estimate the pooled HRs/ORs Otherwise, the random-effects model was used Subgroup analysis was used to detect the potential heterogeneity among studies Begg’s funnel plot and Egger’s linear regression test were conducted to examine publication bias in the literature [25, 26] A sensitivity analysis was conducted to confirm the robustness of the pooled results, during which data from each individual study was sequentially removed All P values were two-tailed and the P values of implied ENE was significantly associated with worse prognosis CSS, cancer specific survival; OS, overall survival; ENE, extranodal extension; CI, confidence interval For OS, patients with ENE showed a lower OS rate compared with those without ENE (HR = 4.04, 95 % CI: 1.02–16.1, P = 0.05) (Fig 2b) Only two studies were included in this analysis, therefore a stratified analysis was not performed Association between ENE and PLNM in penile cancer patients Four studies investigated the relationship between ENE in inguinal lymph nodes and the presence of PLNM Our meta-analysis revealed that patients with ENE had a higher risk of presenting with PLNM (Fig 3, OR = 4.95, 95 % CI: 2.58–9.49, P < 0.001) and significant heterogeneity was not found (I2 = %, P = 0.508) Subgroup analysis revealed that the predictive role of ENE for PLNM was only observed in studies with a sample size larger than 100 (OR = 5.54, 95 % CI: 2.63–11.68, P < 0.001) We also took into consideration what each study identified as its study object For example, some studies identified the patient as the object, whereas others used the individual Zhang et al BMC Cancer (2015) 15:815 Page of 10 Table Stratified analysis of pooled hazard ratios for penile cancer patients with ENE Analysis No of studies (No of patients) HR/OR (95 % CI) P Value Model Heterogeneity I2 (%) Whole group CSS 4(581) 1.90(1.35,2.67) 0.0002 Fixed 29 Phet 0.24 Subgroup1: Location European 2(381) 1.54 (1.01, 2.36) 0.05 Fixed 0% 0.40 North American 2(200) 2.79 (1.58, 4.92) 0.0004 Fixed 0% 0.36 < 36 months 2(126) 1.37 (0.68, 2.76) 0.38 Fixed 0% 0.45 ≥ 36 months 2(455) 2.26 (1.18, 4.34) 0.01 Random 60 % 0.11 4(353) 4.95 (2.58, 9.49)