PLR and PSA showed a favorable connection in this study. According to our knowledge, this study is the first to examine and discover this link among American men without a history of cancer using the NHANES database. The association between PLR and PSA has only been studied once so far, and due to the small sample size and the missing data in some samples, the relationship between PLR and PSA still needs to be clarified [21]. 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. Our study population was selected from NHANES (2001–2010), excluding 45,548 ineligible participants. The study's results showed that for everyone increase in 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 4.0 ng/mL. The results have been confirmed by sensitivity analysis and are robust.
Platelet and lymphocyte counts are routinely measured as parameters based on blood. PLR represents a marker of inflammation. High PLR reflects elevated platelet-dependent pro-tumor responses and reduced lymphocyte-mediated anti-tumor immune responses, which may contribute to cancer progression and poor prognosis. Platelets have been shown to promote cancer cell growth and metastasis through direct and indirect actions [24–25]. In 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[26]; On the other hand, platelet-derived microparticles promote the invasiveness of PCa cells through upregulation of MMP-2 production [27]. Currently, a considerable amount of evidence indicates that lymphocytes are the cellular basis of cancer immunosurveillance and can inhibit tumor cell proliferation and metastasis [28]. Huang SH et al. [29] showed that the high circulating lymphocytes before treatment could better predict relapse-free survival and slightly better overall survival in patients with HPVorphyngeal cancer. Sznurkowski JJ et al. [30] concluded that the increased number of tumor-infiltrating lymphocytes (TIL) is associated with a better 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 [31, 32]. It is well-established that a systemic inflammatory response strongly correlates with the development and prognosis of tumors [31–35]. As a commonly used marker of systemic inflammation, the prognostic value of NLR has also been powerfully demonstrated in PCa [23, 36, 37]. However, the prognostic significance of PLR in PCa is still in conflict [17, 18, 23].
A study shows evidence that PLR is an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in PCa patients [38]. Similarly, Yuksel OH et al. [17] reported that PLR could differentiate BPH from PCa to support its diagnostic value. However, Lee JW et al. [18] concluded that the PLR before the biopsy did not significantly predict CSPCa to negate its diagnostic value. Similar results were reported by Sun Z and Shuo Wang et al. Their studies showed that after comparing the predictive role of several inflammatory markers in PCa, the association between PLR and PCa or PSA was insignificant and lacked diagnostic and prognostic value[16, 23]. Because most studies involve comparatively low-risk Asian male populations, studies are still needed to assess the relationship between PLR and PSA levels. Therefore, we hypothesized that PLR may affect PSA concentrations and may lead to testing bias, which could lead to conflicting interpretations. In addition, we need to conduct further cohort trials to understand the function of PLR as a protective or risk factor in the progression of PCa.
Our findings support a positive correlation between PLR and PSA. We observed that lower values of PLR populations are associated with lower PSA(Figure 2). Therefore, the probability of detecting asymptomatic PCa may be lower in a low PLR population, meaning that the specificity of PCa detection is improved. In the meantime, if PCa is already present, people with a higher PLR are more likely to be diagnosed at an earlier stage by PSA testing. Accordingly, our results suggest that the detection bias due to the positive correlation between PLR and PSA does not explain the positive association between PLR and late-stage PCa.
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 over-diagnosis of asymptomatic PCa. Therefore, if PLR can elevate the PSA produced by prostate tumors or alter the ability of tumor-derived PSA to enter the serum, it is necessary to adjust the PSA threshold for further examination of various platelet cell lymphocytes. Other studies are needed to explore the mechanisms of how the PLR affects PSA concentration and its impact on PCa screening. In addition, prospective cohort studies are still required to confirm the causal relationship, and Serum platelets and lymphocytes are involved in both PCa genesis and development, which also needs to be verified by in vitro and in vivo experiments.
Compared to previously published articles, this study has a couple of strengths. Firstly, it is the first large sample cross-sectional study to find a negative association between PLR and PSA in US men with a non-tumor history. Secondly, the present study sample was a multilayer random sample with high reliability and standardized data, which represents the general US population. Then, we performed a sensitivity analysis and constructed a smoothing curve based on a fully adjusted model to investigate the possible linear relationship between PLR and PSA concentration. However, our study also has some limitations in interpreting the results. Primarily, it is challenging to distinguish causality in our study due to the inherent limitations of the NHANES database as a cross-sectional survey. Therefore, prospective cohort studies are still needed to confirm the cause. In addition, we excluded participants diagnosed with PCa, with factors affecting PSA concentrations and missing data. As such, our results cannot explain the above population. And lastly, our survey is based on the NHANES database, which is limited to the American people. As a result, generalizability is geographically limited. All of the points mentioned above require further evaluation and investigation in the future.