Prognostic Significance of Systemic Inflammation Markers in Testicular and Penile Cancer: A Narrative Review of Current Literature

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TL;DR

This narrative review summarizes evidence that systemic inflammation markers—particularly the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)—are associated with disease stage, metastasis, and survival in testicular and penile cancer. NLR is the most extensively studied marker and shows consistent prognostic value in both malignancies, though data for penile cancer remain scarce. The authors conclude that these inexpensive, widely available biomarkers could complement established risk-stratification tools but require prospective validation and standardized cut-off values before routine clinical use.

Full summary

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**Background** Biomarkers play a central role in oncology for screening, diagnosis, staging, prognosis, and recurrence detection. In testicular cancer (TC), serum tumor markers (beta-hCG, AFP, LDH) have been used since the 1970s but have limitations. Penile cancer (PC) lacks well-established biomarkers entirely, relying instead on clinicopathological parameters. The link between inflammation and cancer, first proposed by Virchow in 1863, has gained renewed attention. Chronic, unresolved inflammation can drive genomic instability, suppress antitumor immunity, and promote angiogenesis and metastasis. Systemic inflammation markers derived from routine blood counts—such as NLR, PLR, SII, lymphocyte-to-monocyte ratio (LMR), and albumin-related indices—are inexpensive and accessible. This narrative review summarizes current evidence on their prognostic value in TC and PC.

**Methods** The authors searched PubMed for English-language studies published between January 2000 and November 2022, using terms including "testicular cancer," "penile cancer," "systemic inflammation," NLR, dNLR, PLR, SII, SIRI, LMR, AGR, CRP, GPS, and PNI. A secondary hand-search of reference lists supplemented the initial selection. No restriction was placed on study design. Unrelated studies, non-English articles, unavailable full texts, and conference papers were excluded.

**Key Results** *Testicular Cancer:* - **NLR:** The most extensively studied marker. Multiple retrospective and cross-sectional studies (n ranging from 36 to 164) consistently show that elevated NLR is associated with advanced disease stage, metastatic disease, and worse overall survival (OS). Cut-off values ranged from 2.685 to 4.5. In metastatic patients receiving first-line chemotherapy, NLR > 4.5 was linked with worse OS (Fankhauser et al., n=146). However, one small study (n=53) found NLR was not a reliable predictor of progression-free survival (PFS) or cancer-specific survival (CSS). - **PLR:** Findings were mixed. Some studies reported significantly higher PLR in TC patients vs. controls; others found no difference. PLR > 150 was associated with disease progression and advanced stage (Herraiz-Raya et al., n=164). In non-seminoma patients, PLR > 104 predicted advanced disease with 71% sensitivity and 88% specificity (Imamoglu et al., n=112). Peksa et al. (n=180) found that PLR > 212 was associated with worse 5-year event-free survival (89% vs. 69%, p=0.018). - **SII:** Integrating neutrophils, platelets, and lymphocytes, SII showed consistent prognostic value. Chovanec et al. (n=171) found SII > 1003 correlated with poor/intermediate IGCCCG risk, bulky retroperitoneal lymphadenopathy, and worse OS and PFS. Bumbasirevic et al. (n=88, prospective) reported median SII was significantly lower in stage I vs. stage II/III patients (533.33 vs. 824.26, p<0.001); SII > 683.21 predicted metastatic disease (sensitivity 66.10%, specificity 70.37%). Results in metastatic patients were mixed: two studies found elevated SII associated with shorter OS, while one did not. - **LMR:** Lower LMR consistently correlated with advanced stage and metastatic disease. Bumbasirevic et al. found LMR < 4.14 predicted metastasis (sensitivity 50.84%, specificity 85.18%). No significant association with OS was reported. - **CRP and albumin-related markers:** Limited data. The AMORIS study (n=202,717, 125 TC cases) found no significant association between CRP and TC risk. Low AGR (<1.47) predicted metastases and poor OS (Guner et al., n=115). GPS was a significant predictor of OS and PFS in multivariate analysis (Yoshinaga et al., n=66).

*Penile Cancer:* - **NLR:** Most studied marker in PC. Across retrospective studies (n=39 to 228), elevated NLR (cut-offs 2.8–3.0) was associated with inguinal lymph node metastases (pN+), extranodal extension (ENE), and worse OS and CSS. Azizi et al. (n=84) found NLR > 3 independently predicted OS on multivariate analysis and pN+ disease (OR=3.75, 95% CI: 1.30–10.81, p=0.014). Li et al. (n=228) reported NLR had the highest prognostic accuracy among several inflammatory biomarkers. - **PLR:** PLR > 169 correlated with CSS in univariate analysis (Li et al.). Hu et al. (n=225) found PLR was an independent predictor of pathological N stage (HR=2.478, 95% CI: 1.365–4.497, p=0.003). - **SII:** Only one study (Song et al., n=123) examined SII in PC. SII > 636.99 was associated with significantly worse median OS (10.5 months vs. 128 months, p=0.01). - **LMR:** Results were conflicting. Some studies found low LMR associated with worse CSS; others found the opposite. Lower LMR was a predictor of pN+ disease. - **CRP and albumin-related markers:** Elevated CRP (>15 mg/L) was associated with advanced stage (≥pT2) and inguinal lymphadenopathy; 5-year CSS was 38.9% vs. 84.3% (p=0.001) (Steffens et al.). Multivariate analysis confirmed CRP as an independent predictor (HR=3.34, 95% CI: 1.04–10.7, p=0.043). Low PNI and low AGR were independent predictors of worse OS (Song et al., n=123).

**Clinical Implications** Systemic inflammation markers are inexpensive, widely available, and could complement existing biomarkers and clinicopathological parameters in TC and PC. NLR is the most robust marker, with consistent prognostic value across both malignancies. SII and PLR also show promise but require further validation. The authors emphasize that significant heterogeneity in cut-off values, study designs, and endpoints prevents the establishment of universal thresholds. Prospective, multicenter studies with standardized methodology are needed before these indices can be routinely adopted. Future research should also explore biomarker utility in specific subgroups (e.g., seminoma vs. non-seminoma, recurrent TC, clinically node-negative PC) and investigate the complex interplay between systemic inflammation and the tumor microenvironment.