Prostate cancer (PCa) was the second-most common cause of cancer-related fatalities in humans in 2020 and the most common cancer in men (1). The most recognized biomarker for the early identification of PCa is serum prostate-specific antigen (PSA). PSA is highly specific for PCa. The widespread use of PSA testing has increased the detection rate of asymptomatic PCa, defined as highly differentiated PCa (2). Although there are more alternatives for the early diagnosis of PCa thanks to the development of new biomarkers including SelectMDx, ConfirmMDx, Pca3, MIPS, ExoDX and mpMRI, PSA testing remains the most widely used screening tool due to its favorable affordability and applicability (3). Most recently, the United States Preventive Services Task Force recently updated their guidelines, which upgraded the PSA recommendation level from a D as a screening-based level to a C as an advocate for personal screening (4,5). However, several studies have demonstrated that PSA concentrations may be influenced by additional factors that may help to cause bias in identifying PCa (6-8). Overdiagnosis or under-diagnosis affected by numerous factors, may result in inappropriate and unnecessary therapy (9). Therefore, screening PCa based on PSA concentration still has certain problems to be solved (10).

Inflammation is one of the most significant and well-known variables influencing cancer development (11). Hematological indicators that can indicate the state of the immune-inflammatory response in patients with cancer have recently received increasing attention (12,13). Systemic immune inflammatory index (SII), C-reactive protein (CRP) levels, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are some of these measures. Because NLR and PLR are readily available and inexpensive, they have been extensively examined in several malignancies (14-16). PLR is a systemic parameter based on inflammation. Previous research has explored the diagnostic function of PLR in patients with PCa; however, findings remain inconclusive. Yuksel et al (17) found that PLR may distinguish between benign prostatic hyperplasia and PCa, ultimately serving as a diagnostic tool for PCa. Conversely, Lee et al (18) determined that pre-biopsy PLR is not predictive of clinically significant PCa (CSPCa), and thus, does not provide diagnostic value for PLR. Indeed, there may be some correlation between PLR and PSA metabolism, which may lead to detection bias in PCa diagnosis. Furthermore, to the best of the authors' knowledge, it was found that this phenomenon has never been reported before.

Consequently, a secondary data analysis was performed on the National Health and Nutrition Examination Survey (NHANES) data. After controlling for a large number of influencing factors, it was sought to clarify the relationship between PLR and PSA concentration in men without PCa in the USA.

PLR and PSA exhibited a favorable connection in the present study. To the best of the authors' knowledge, the present study is the first to examine and discover this link among men from USA without a history of cancer using the NHANES database. Although PLR and PSA have been studied previously, an association between them has not been discovered, and previous studies have suffered from small sample sizes and missing data (21). Accordingly, the connection between PLR and PSA necessitates additional research to clarify their relationship. Therefore, it is essential to further comprehend the individual variability in PSA concentrations that may emerge from PLR to prevent the bias of PSA testing during the diagnosis of prostate-related disorders. The present study population was drawn from NHANES (2001-2010), excluding 45,548 ineligible participants. The results of the present study revealed that with every increment of PLR, the PSA concentration increased by 0.004 ng/ml, which means that if the PLR increased by 100, the PSA concentration would increase by 0.4 ng/ml. Sensitivity analysis confirmed the results, which are robust.

Platelet and lymphocyte counts are routinely measured as parameters based on blood tests. PLR represents a marker of inflammation. High PLR reflects elevated platelet-dependent pro-tumor responses and reduced lymphocyte-mediated anti-tumor immune responses, which could potentially lead to cancer progression and a poor prognosis. Platelets have been shown to promote cancer cell growth and metastasis through direct and indirect actions (22,23). On PCa, on the one hand, platelets adhere to tumor cells with the help of fibrinogen; at the same time, they promote more fibrinogen aggregation around tumor cells by forming thrombin, thus protecting them from the cytotoxicity of natural killer cells (24); on the other hand, platelet-derived microparticles promote the invasiveness of PCa cells through upregulation of MMP-2 production (25). Currently, a considerable amount of evidence indicates that lymphocytes are the cellular basis of cancer immunosurveillance and can inhibit tumor cell proliferation and metastasis (26). Huang et al (27) revealed that high pre-treatment levels of circulating lymphocytes are associated with longer relapse-free survival and slightly improved overall survival (OS) in patients with oropharyngeal cancer. Sznurkowski et al (28) concluded that the increased number of tumor-infiltrating lymphocytes is associated with an improved prognosis in various cancers, including breast and colorectal. As a parameter combining platelet count and lymphocyte count, PLR can provide relatively accurate prognostic information about cancer patients (29,30). It is widely accepted that there is a strong correlation between the development and prognosis of tumors and a systemic inflammatory response (31-33). As a commonly used marker of systemic inflammation, the prognostic value of NLR has also been powerfully demonstrated in PCa (34-36). However, the significance of PLR in PCa prognosis remains conflicting (17,18).

A previous study provided evidence that PLR is an independent prognostic factor for progression-free survival and OS in PCa patients (37). Similarly, Yuksel et al (17) reported that PLR has the potential to differentiate between benign prostatic hyperplasia and PCa. This can ultimately serve as a diagnostic tool for PCa. By contrast, Lee et al (18) concluded that pre-biopsy PLR cannot significantly predict CSPCa, rendering it inadequate for PLR diagnosis. Similar results were reported by Sun et al (16), revealing that there is no significant correlation between PLR and either PCa or PSA after comparing the predictive effects of several inflammatory markers on PCa. Therefore, the aforementioned study concluded that PLR has little diagnostic and prognostic value for PCa. Because most studies involved men from Asia at relatively low risk of developing PCa and the conclusions were not definitive, studies are still needed to assess the relationship between PLR and PSA levels. Therefore, it was hypothesized that PLR affects PSA concentrations and may create testing bias, which could result in inconsistent interpretations. Further cohort trials are necessary to further comprehend the function of PLR as either a protective or risk factor in the progression of PCa.

The findings of the present study, support a positive correlation between PLR and PSA. A positive correlation between PLR and PSA can lead to detection bias, which may have implications for PCa screening. Since PLR preferentially elevates PSA concentrations in men without PCa, PSA testing for PCa screening in men with high PLR can lead to the overdiagnosis of asymptomatic PCa. Therefore, if PLR can elevate the PSA produced by prostate tumors or enhance the ability of tumor-derived PSA to enter the serum, it is necessary to adjust the PSA threshold for further examine platelets as well as lymphocytes to ultimately rule out interference with PSA by PLR. For example, in a high PLR population, the actual PSA value should be used as the screening diagnostic criterion. Actual PSA=PSA measurement-PLR ^* 0.004. Further studies are needed to explore the mechanisms by which the PLR affects PSA concentration and its impact on PCa screening. In addition, prospective cohort studies are still needed to confirm the causal relationship and serum platelets and lymphocytes are involved in both the genesis and development of PCa, which also needs to be verified by in vitro and in vivo experiments.

Compared with prior research, the present study boasts several noteworthy findings. Firstly, it is the first large-scale cross-sectional study to find a positive association between PLR and PSA in men from USA with a non-tumor history. Secondly, the present study utilized a highly reliable, standardized, and multilayer random sample, providing a representative portrayal of the general USA population. Then, a sensitivity analysis was performed and a smoothing curve was constructed based on a fully adjusted model to investigate the possible linear relationship between PLR and PSA concentration. Nevertheless, there are certain limitations to the interpretation of the findings of the present study. Primarily, it is challenging to distinguish causality in the present study due to the inherent limitations of the NHANES database as a cross-sectional survey. Although prospective studies have demonstrated that PLR has an important predictive role in the diagnosis and prognosis of PCa (38,39), prospective cohort studies are still needed for further validation because these studies are single center with small sample sizes. To further validate the accuracy and applicability of the findings of the present study, a prospective cohort study is being designed based on a Chinese population, and the authors are working towards a multicenter study. Furthermore, participants diagnosed with PCa were excluded and those with factors impacting PSA concentrations or missing data. Consequently, the findings of the present study cannot be generalized to the aforementioned population. Lastly, the survey is based on the NHANES database, which is limited to the individuals from USA. As a result, generalizability is geographically limited. Nonetheless, in conjunction with the existing studies in China, Italy, Austria, and other regions (16,40,41), there are favorable reasons to hypothesize that the association between PLR and PSA, or PCa, is geospatially generalizable.

In conclusion, in men from USA, there is an independent and positive association between PLR and PSA, which could potentially result in overdiagnosis of asymptomatic PCa in populations with higher PLR levels.