Evaluation of the relationship between pan-immune inflammation value and prognostic factors in germ-cell testicular cancer: analysis of stage, lymph node involvement, and metastasis.

1.
Introduction
Testicular malignancies account for approximately 1% of all cancers in men [1]. Nonetheless, it represents the most common solid malignancy among males aged 20 to 35 years [2]. In developed countries, the prevalence of testicular cancer is approximately 5.7 per 100,000 and studies have shown that this rate has been increasing over time [3,4]. Germ cell tumors account for 90%–95% of all testicular neoplasms. Although the overall mortality rate of testicular tumors is low, they can cause significant socioeconomic and psychological challenges for young men. The 5 year survival rate has been reported to be approximately 97% [5,6].
Human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) are routinely used for both diagnosis and follow-up. These biomarkers are essential for diagnosis; however, they have limited sensitivity and specificity [7]. Prognosis primarily depends on factors such as stage at diagnosis and the presence of metastasis, despite the overall high survival rate in testicular cancer [2]. For these reasons, novel diagnostic and prognostic biomarkers are being explored.
Numerous studies have demonstrated that inflammation plays a significant role in cancer development and progression [8]. Lymphocytes promote apoptosis in tumor cells by mediating cytotoxic immune responses [8]. In contrast, neutrophils and monocytes constitute key components of the innate immune defense against carcinogenic stimuli [8]. A delicate balance exists among these immune cell populations; when disrupted in favor of tumor progression, neutrophils, monocytes, and platelets may contribute to tumor growth and dissemination [8]. Previous studies have shown that cancer-associated macrophages derived from monocytes, together with neutrophils and platelets, facilitate primary tumor expansion, invasion, and distant metastasis [8]. Based on this evidence, inflammatory indices such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), hemoglobin–albumin–lymphocyte–platelet (HALP) score, and systemic immune-inflammation index (SII) have been developed to predict prognosis in various malignancies, and their prognostic significance has been validated.
The pan-immune inflammation value (PIV) is a recently proposed biomarker, and studies have demonstrated its superiority over other inflammatory indices in predicting prognosis in metastatic colorectal cancer [9,10]. Studies have also indicated that PIV is effective in predicting prognosis in other urological malignancies, including bladder and prostate cancers [11,12]. However, the association between PIV and testicular tumors has not yet been investigated in the existing literature. Therefore, we aimed to evaluate the association between PIV and prognostic factors, including stage, lymph node involvement, and distant metastasis, in patients with germ cell testicular tumors.

2.
Materials and methods
The study was approved by the Institutional Ethics Review Board (approval no: 2025/010.99/12/26; approval date: 24 January 2025). Medical records of 256 patients aged 18 to 65 years who underwent radical orchiectomy for testicular tumors between January 2014 and January 2024 were evaluated. Patients who were not pathologically diagnosed with germ cell tumors (n = 48), had a history of other malignancies (n = 9), had missing data, or presented with conditions affecting inflammatory markers—such as immunosuppressive disorders, medication use, or active infections—(n = 21) were excluded. Consequently, 178 patients with testicular tumors pathologically confirmed as germ cell tumors were included in the study.
Patient age, histopathological findings, preoperative and postoperative PIV values, tumor markers, and radiological imaging results were recorded. The PIV was calculated using the following formula: (monocyte count × neutrophil count × platelet count) / lymphocyte count, expressed in 109/L. Clinical staging was performed based on contrast-enhanced abdominal and thoracic computed tomography obtained the day before surgery. Patients were classified according to the TNM classification system, tumor stage, and International Germ Cell Cancer Collaborative Group (IGCCCG) risk groups. The S stage was evaluated according to serum tumor markers measured during the second postoperative week. Postoperative follow-up was conducted according to the European Association of Urology guidelines [13]. The relationships between the PIV score and tumor stage, prognosis, lymph node involvement, and metastasis were analyzed. Written informed consent was obtained from all participants prior to study enrollment.

2.1. Statistics
Statistical analyses were performed using SPSS 21.0 (IBM Corp., Armonk, NY, USA). Skewness and kurtosis were calculated to assess the normality of the data distribution. Results were presented as medians and interquartile ranges (IQR) for nonnormally distributed data. Nonnormally distributed variables were analyzed using the Mann–Whitney U test and the Kruskal–Wallis test. Median (IQR) values were used to describe continuous variables with nonnormal distribution. Categorical variables were expressed as numbers and percentages. The prognostic performance of PIV was evaluated using receiver operating characteristic (ROC) curve analysis and the corresponding area under the curve (AUC). Statistical significance was set at a p value of <0.05.

3.
Results
The study included a total of 178 male patients. The mean age of the patients was 32.34 ± 9.62 years, with a median of 31 (range: 17–61). Histopathological evaluation revealed 90 seminomas (50.6%), five embryonal carcinomas (2.8%), 74 mixed germ cell tumors (41.6%), one yolk sac tumor (0.6%), seven teratomas (3.8%), and one choriocarcinoma (0.6%). According to the TNM classification, the cohort consisted of 52 (29.2%) pT1, 108 (60.7%) pT2, and 18 (10.2%) pT3 patients. Table 1 summarizes the histological subtypes of tumors and their corresponding stages following orchiectomy.
No significant difference in PIV scores was observed when comparing tumor histological types and laterality. Analysis of the relationship between PIV and TNM stage revealed a statistically significant increase in PIV scores with higher tumor T stages (p = 0.01) (Table 1). The mean PIV scores were significantly higher in patients with lymph node involvement and metastasis compared with those without (p = 0.01 and p = 0.04, respectively). The association between a history of retroperitoneal lymph node dissection (RPLND) and PIV was not statistically significant (p = 0.574). Analysis of the relationship between PIV scores and IGCCCG risk groups revealed a statistically significant increase in PIV values among higher risk categories (p = 0.01) (Table 2).
The optimal cut-off value of the PIV score for predicting lymph node positivity was 555.5, with 75.5% sensitivity and 77.5% specificity as shown as Figure 1 (AUC = 0.802; 95% CI, 0.729–0.875; p < 0.001). The corresponding cut-off for predicting metastasis was 565.32, with 78.9% sensitivity and 76.1% specificity (AUC = 0.795; 95% CI, 0.676–0.915; p < 0.001) as shown as Figure 2 (Table 3).

4.
Discussion
The present study investigated the relationship between PIV and the clinicopathological characteristics of testicular cancer. This particular aspect has not been previously researched. Our findings revealed that PIV can predict the stage, lymph node involvement and distant in germ cell testicular tumors. Pan-immune inflammation value is a new biomarker that reflects systemic inflammation status by combining four parameters with a high predictive rate [14].
A healthy immune system has a significant role in detecting and eliminating cancer cells. However, cancer cells have a favorable condition to evade apoptosis under immunosuppressive status. Besides that, some kind of tumoral cells might manipulate the immune system to their advantage to create an immunosuppressive microenvironment that facilitate their growth and spread [15]. With all these information, many studies have reported on the relationship between inflammation and cancer prognosis [2,3,10,16]. Based on this studies, PIV -a novel indicator combining four different hematological parameters- has been defined.
There are numerous studies that suggest PIV predicts prognosis in solid tumors. The increase in neutrophils and platelets, along with a decrease in lymphocytes, has previously been reported to be associated with poorer prognosis in cancer patients [17–19]. Therefore, PIV has been defined with combining more than one immune factors. PIV provides information about both tumoral microenvironment and the immune status [15].
The association between PIV and urological malignancies has been investigated in previous studies. Kayar et al. evaluated the relation between PIV and non-metastatic muscle invasive bladder cancer in 119 patients. They reported that high PIV value was associated with poorer overall survival (OS) and disease free survival (DFS). Additionally, it was stated that PIV is superior to systemic immune inflammation index (SII) and platelet-lymphocyte ratio in predicting DFS [11]. In another study about patients who underwent radical cystectomy, PIV and other inflammation biomarkers (SII, NLR) were compared. It was stated that high PIV value has a relationship with poor relapse free Survival and OS [20]. Zhu et al. investigated the success of systemic inflammation markers in predicting prostate cancer in patients with PSA levels between 4 and 20. They reported that higher PIV has highly effective in predicting prostate cancer (p = 0.001) [21].
The relationship between testicular cancer and inflammation markers has been previously investigated. Ekici et al. indicated that decreased hemoglobin, albumin, platelet, and lymphocyte scores (HALP) correlate with advanced disease and worse prognosis in individuals with testicular cancer [2]. Ilktac et al. investigated the association between NLR and testicular cancer. They reported that NLR is successful in predicting localized and non-localized disease [16]. In a review, it was reported that high SII values were associated with worse PFS and OS in patients with testicular cancer [22]. However, there are no prior studies investigating the relationship between PIV and testicular cancer.
Our findings reveal a statistically significant association between higher PIV scores and advanced tumor stage, presence of metastasis, presence of lymph node involvement in patients with testicular cancer. We found that PIV value higher than 555.5 was predictive for lymph node involvement. Additionally, we identified that when the PIV score exceeds 562.32 at the time of diagnosis, the likelihood of the patient being metastatic statistically increases.
We would like to emphasize that our study is the first of its kind. We think it is better to compare PIV with other immune markers such as NLR, PLR, SII in testicular cancer prognosis with subgroup analysis.
Our study has some limitations. First of all, our study was designed with a retrospective nature. Secondly, the study is based on data from a single tertiary center. A significant portion of the follow-up data of the patients were lacked after second postoperative year. Therefore, we are unable to provide cancer-spesific Survival or OS rates. We acknowledge that confounding factors cannot be entirely eliminated, as all indicators were obtained from peripheral blood samples of patients. Moreover, although our study did not reveal a significant difference between PIV and germ cell tumors, the absence of a subgroup analysis represents a limitation. We believe that the success of PIV might be better understood with multicentric, prospective studies.

5.
Conclusion
This study is the first study that demonstrated a significant association between higher PIV scores and more advanced testicular tumors, presence of metastases. The PIV score, with its low cost-effectiveness, could serve as a prognostic tool for testicular tumor patients with high life expectancy. In this way, it can assist in stratifying risk and providing information about treatment management strategies at the time of diagnosis.