Preoperative platelet-to-lymphocyte ratio as a predictor of inguinal lymph node metastasis in penile cancer

Background: Penile cancer (PC) is a rare malignancy with poor prognosis. To date, reliable preoperative biomarkers for lymph node status and prognosis are still lacking. This study aims to explore the potential role of preoperative platelet-to-lymphocyte ratio (PLR) as a predictor of inguinal lymph node invasion in PC patients.
Methods: Retrospective analysis was conducted on anamnestic, clinical, and laboratory data of PC patients who underwent surgical treatment between January 2016 and October 2023. Inguinal lymphadenectomy was performed as per EAU guidelines. PLR, calculated as the ratio between platelet-to-lymphocyte values obtained from preoperative blood analyses, was assessed within 30 days before surgery. Patients were categorized into pN- (no lymph node metastasis) and pN+ (lymph node metastasis confirmed pathologically). Statistical analyses included Kruskal-Wallis and Mann-Whitney U tests, univariate logistic regression, and ROC curve analysis with Youden index, assuming p<0.05 as statistically significant.
Results: Overall, 60 PC patients were retrospectively involved in the study. A total of 36 (60%) patients reported ILN metastases, confirmed by inguinal lymphadenectomy (pN+), while no ILN metastases (pN-) were reported in 24 (40%) patients. The AUC for predicting ILN metastasis by preoperative PLR was 0.71 (p=0.014). According to the ROC curve analysis and the Youden Index, a cut-off for PLR was set at 122.4. On Univariable logistic regression analysis, the presence of T stage ≥ 2 (OR = 3.21; 95% CI: 1.43-7.47, p=0.011), lymphovascular invasion (OR = 3.78; 95% CI: 1.56-5.90, p=0.003), clinical node-positive disease (OR = 19.86; 95% CI: 5.91-41.03, p<0.001) and PLR ratio > 122.4 (OR = 7.22; 95% CI: 1.41-22.71, p=0.0148) were independent predictors of pN+ disease.
Conclusions: The current study confirms the relationship between cancer and inflammation. When elevated preoperatively, PLR may be associated with inguinal lymph node invasion in PC patients.

Thomas A, Necchi A, Muneer A, et al. Penile cancer. Nat Rev Dis Primers. 2021; 7:11. DOI: https://doi.org/10.1038/s41572-021-00246-5

Morrison BF. Risk factors and prevalence of penile cancer. West Indian Med J. 2014; 63:559-60.

Fankhauser CD, de Vries HM, Roussel E, et al. Lymphovascular and perineural invasion are risk factors for inguinal lymph node metastases in men with T1G2 penile cancer. J Cancer Res Clin Oncol. 2022; 148:2231-2234. DOI: https://doi.org/10.1007/s00432-022-04012-2

Cilio S, Tufano A, Pezone G, et al. Sexual outcomes after conservative management for patients with localized penile cancer. Curr Oncol. 2023; 30:10501-10508. DOI: https://doi.org/10.3390/curroncol30120765

Babbar P, Yerram N, Crane A, et al. Penile-sparing modalities in the management of low-stage penile cancer. Urol Ann. 2018; 10:1-6. DOI: https://doi.org/10.4103/UA.UA_93_17

Manjunath A, Brenton T, Wylie S, et al. Topical therapy for noninvasive penile cancer (Tis)-updated results and toxicity. Transl Androl Urol. 2017; 6:803-808. DOI: https://doi.org/10.21037/tau.2017.06.24

Shabbir M, Muneer A, Kalsi J, et al. Glans resurfacing for the treatment of carcinoma in situ of the penis: surgical technique and outcomes. Eur Urol. 2011; 59:142-7. DOI: https://doi.org/10.1016/j.eururo.2010.09.039

EAU-ASCO Penile Cancer Guidelines. Edn. presented at the EAU annual congress Milan 2023.

Teh J, Duncan C, Qu L, et al. Inguinal lymph node dissection for penile cancer: A contemporary review. Transl. Androl. Urol. 2020;9:3210-3218. DOI: https://doi.org/10.21037/tau.2019.08.37

Hakenberg OW, Compérat EM, Minhas S, et al. EAU guidelines on penile cancer: 2014 Update. Eur. Urol. 2015; 67:142-150. DOI: https://doi.org/10.1016/j.eururo.2014.10.017

Flammia RS, Tufano A, Antonelli L, et al. Diagnostic performance of magnetic resonance imaging for preoperative local staging of penile cancer: a systematic review and meta-analysis. Appl. Sci. 2021;11:7090. DOI: https://doi.org/10.3390/app11157090

Hu C, Bai Y, Li J, et al. Prognostic value of systemic inflammatory factors NLR, LMR, PLR and LDH in penile cancer. BMC Urol. 2020; 20:57. DOI: https://doi.org/10.1186/s12894-020-00628-z

Liu S, Fang J, Jiao D, Liu Z. The predictive value of inflammatory markers for pathological response of ipsilateral supraclavicular lymph nodes and for prognosis in breast cancer after neoadjuvant chemotherapy. Gland Surg. 2020; 9:1354-1362. DOI: https://doi.org/10.21037/gs-20-341

Azizi M, Peyton CC, Boulware DC, et al. Prognostic value of neutrophil-to-lymphocyte ratio in penile squamous cell carcinoma patients undergoing inguinal lymph node dissection. Eur. Urol. Focus 2019; 5:1085-1090. DOI: https://doi.org/10.1016/j.euf.2018.06.008

Xu Z, Zhang J, Zhong Y, et al. Predictive value of the monocyteto-lymphocyte ratio in the diagnosis of prostate cancer. Medicine (Baltimore). 2021; 100:e27244. DOI: https://doi.org/10.1097/MD.0000000000027244

Tufano A, Napolitano L, Barone B, et al. Preoperative albuminto-alkaline phosphatase ratio as an independent predictor of lymph node involvement in penile cancer. Medicina 2024; 60:414. DOI: https://doi.org/10.3390/medicina60030414

Wu Y, Li C, Zhao J, et al. Neutrophil-to-lymphocyte and plateletto-lymphocyte ratios predict chemotherapy outcomes and prognosis in patients with colorectal cancer and synchronous liver metastasis. World J Surg Oncol. 2016; 14:289. DOI: https://doi.org/10.1186/s12957-016-1044-9

Wu C, Li Z, Guo S, et al. Development and validation of a nomogram for the prediction of inguinal lymph node metastasis extranodal extension in penile cancer. Front Oncol. 2021;11:675565 DOI: https://doi.org/10.3389/fonc.2021.675565

Kultravut K, Siriboonrid S. Characteristic of penile cancer and prognostic factors of inguinal and pelvic lymph node involvement. Urol Ann. 2023; 15:278-284. DOI: https://doi.org/10.4103/ua.ua_6_22

Lebentrau S, Wakileh GA, Schostak M, et al. Does the identification of a minimum number of cases correlate with better adherence to international guidelines regarding the treatment of penile cancer? Survey results of the European prospective penile cancer study (EPROPS) Front. Oncol. 2021; 11:759362. DOI: https://doi.org/10.3389/fonc.2021.759362

Kirrander P, Sherif A, Friedrich B, et al. Steering committee of the Swedish national penile cancer register. Swedish national penile cancer register: incidence, tumour characteristics, management and survival. BJU Int. 2016; 117:287-292. DOI: https://doi.org/10.1111/bju.12993

Jiang S, Liu J, Chen X, et al. Platelet-lymphocyte ratio as a potential prognostic factor in gynecologic cancers: a meta-analysis. Arch Gynecol Obstet. 2019; 300:829-839. DOI: https://doi.org/10.1007/s00404-019-05257-y

Wang J, Zhou X, He Y, et al. Prognostic role of platelet to lymphocyte ratio in prostate cancer: A meta-analysis. Medicine (Baltimore). 2018; 97:e12504. DOI: https://doi.org/10.1097/MD.0000000000012504

Herraiz-Raya L, Moreillo-Vicente L, Martínez-Ruiz J, et al. Leukocyte and platelet counts as prognostic values of testicular germ cell tumours. Actas. Urol. Esp. 2019; 43:284-292. DOI: https://doi.org/10.1016/j.acuroe.2019.02.008

Imamoglu G.I, Eren T, Baylan B, Karacın C. May high levels of systemic immune-inflammation index and hematologic inflammation markers suggest a further stage in testicular tumours? Urol. Int.2019; 103:303-310. DOI: https://doi.org/10.1159/000502658

Peksa R, Kunc M, Popeda M, et al. Combined assessment of immune checkpoint regulator VISTA on tumor-associated immune cells and platelet-to-lymphocyte ratio identifies advanced germ cell tumors with higher risk of unfavorable outcomes. Cancers 2021; 13:1750. DOI: https://doi.org/10.3390/cancers13081750

Winters BR, Mossanen M, Holt SK, et al. JL. Predictors of nodal upstaging in clinical node negative patients with penile carcinoma: a national cancer database analysis. Urology. 2016; 96:29-34. DOI: https://doi.org/10.1016/j.urology.2016.06.033

Ficarra V, Akduman B, Bouchot O, et al. Prognostic factors in penile cancer. Urology. 2010;76:S66-73. DOI: https://doi.org/10.1016/j.urology.2010.04.008

Zekan DS, Dahman A, Hajiran AJ, et al. Prognostic predictors of lymph node metastasis in penile cancer: a systematic review. Int Braz J Urol. 2021; 47:943-956 DOI: https://doi.org/10.1590/s1677-5538.ibju.2020.0959

Filippelli A, Del Gaudio C, Simonis V, et al. Scoping review on platelets and tumor angiogenesis: do we need more evidence or better analysis? Int J Mol Sci. 2022; 23:13401. DOI: https://doi.org/10.3390/ijms232113401

Tufano A, Perdonà S, Viscuso P, et al. The impact of ethnicity and age on distribution of metastases in patients with upper tract urothelial carcinoma: analysis of SEER data. Biomedicines. 2023; 11:1943. DOI: https://doi.org/10.3390/biomedicines11071943

Wojtukiewicz MZ, Sierko E, Hempel D, et al. Platelets and cancer angiogenesis nexus. Cancer metastasis Rev. 2017; 36:249-262. DOI: https://doi.org/10.1007/s10555-017-9673-1

Wakefield LM, Smith DM, Flanders KC, Sporn MB. Latent transforming growth factor-beta from human platelets. A high molecular weight complex containing precursor sequences. J Biol Chem. 1988;263:7646-54. DOI: https://doi.org/10.1016/S0021-9258(18)68547-3

Iacopino F, Pinto F, Bertaccini A, et al. Soluble E-cadherin and IL-6 serum levels in patients affected by prostate cancer before and after prostatectomy. Oncol Rep. 2012; 28:370-4.

Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer. 2011; 11:123-34. DOI: https://doi.org/10.1038/nrc3004