In some studies, PNI has been confirmed as a new prognostic tool for cancer, and a low PNI has been shown to be significantly associated with lower survival for pancreatic cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, colorectal cancer, renal cell carcinoma, and ovarian cancer [31–37]. In other reports, the cut-off value of PNI used to predict prognosis was 42-47.8. The results of our retrospective analysis showed that low preoperative PNI and high CRP levels were prognostic factors for poorer OS and DFS in patients with oral cancer. In this study, we divided the patients into two groups based on a PNI cut-off value of 42.9 derived from the ROC curve, and we compared the clinical background factors in the two groups. The cut-off value of 42.9 that we used in this study is within the range used in previous studies; therefore, it can be argued that PNI is a practical tool to assess postoperative prognosis [38–40]. In the multivariate analysis, a low PNI, a high CRP level, and perineural invasion were significantly associated with poorer OS. Significant differences were also observed in the HR (Hazard Ratio) with respect to the surgical margin, postoperative treatment, and PNI in the multivariate analysis for DFS. Additionally, the two groups showed differences in the DFS and the 5-year OS. These results suggest that the low PNI group has a poorer preoperative nutritional status and a higher degree of inflammatory response than the high PNI group, resulting in poor prognosis. The PNI, which is estimated using the serum albumin level and the lymphocyte count, reflects the nutritional and immunological state of the patient. Previous studies have reported the PNI as a prognostic factor affecting OS for different malignancies [41–45].
Microenvironmental inflammation affects the growth of tumor cells and promotes angiogenesis and metastasis [46, 47]. The immune system recognizes cancer cells and secretes, as a response, inflammatory cytokines, leading to hypercytokinemia [46–48]. Interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) are two cancer-associated cytokines. These cytokines cause the resolution of the extracellular matrix and neovascularization. Consequently, growth, invasion, and metastasis of tumors are accelerated. However, it is difficult to easily measure these cytokines [49, 50]. Blood biochemical changes caused by these cytokines can be assessed by measuring inflammatory reaction markers based on the systemic inflammatory reaction. [46–51]. To date, numerous traditional systemic inflammation markers have been reported, including the Glasgow Prognostic Score [52, 53] based on plasma components, the neutrophil-to-lymphocyte ratio [54, 55] derived from the number of blood cells, the lymphocyte-to-monocyte ratio [56, 57], CRP-to-albumin ratio [58], and the PNI [27, 59] based on serum albumin levels and lymphocyte counts. Most of these markers are based on blood cell counts, serum protein level measurement, and the ratios derived from these parameters. Albumin is a significant component of the plasma protein content and reflects the nutritional status, whereas lymphocytes reflect the immunological state; therefore, the ratio of serum albumin level to the lymphocyte count is associated with the survival of patients with cancer [60–62].
Low PNI levels show poor prognosis for oral cancer because the inflammatory cytokines IL-6 and IL-8 increased the number of neutrophils and decreased those of lymphocytes besides enhancing proteolysis [48–51]. Thus, low PNI was considered as an indicator of high inflammatory cytokine levels. The release of cytokines by cancer cells results in a rise in the serum CRP level at the same time. Elevated CRP levels have been reported to be associated with a lower rate of DFS and OS in operable oral cancers [62]. Similarly, some reports have investigated the impact of serum albumin and CRP on the outcome of combination chemoradiotherapy in cases of unresectable head and neck cancers [63]. The association between OS and CRP has been reflected in this study.
The mechanisms underlying the associations between systemic inflammatory response and survival in patients with oral squamous cell carcinoma are not evident. However, using albumin levels and lymphocyte counts, the components used for PNI calculation, cancer cachexia associated with growth factors release, impaired cell-mediated immune response, and angiogenesis can be estimated [64–68]. These mechanisms are complex and include a combination of the factors mentioned above. Therefore, further studies involving metrics such as the PNI, along with an appropriate grading system for it, are necessary to assess its prognostic value in oral cancer. We incorporated the PNI in a prognostic model, and the prospective analysis of this model in a large group of patients was essential to assess the pretreatment risk. In the following paragraphs, we provide some hypotheses to explain why a low PNI level is associated with a poor prognosis for oral cancer.
First, the levels of serum albumin, which is a chief component of plasma proteins, can reflect the nutritional status, while lymphocytes, which can eliminate cancer cells and are important components of the immune system, can reflect the immunological state. Thus, the PNI reflects the nutritional and immunological states of the host and can indicate the prognosis in patients with cancer. Consistent with this, the results of some studies have shown that the PNI, after an adjustment for other risk factors, was an independent prognostic factor for the OS.
Second, a low PNI has been reported to be associated with poorer tumor prognosis (increased depth of tumor, lymph node metastasis, poor TNM staging), and an extensive hematic and lymphatic spread. In the multivariate analysis, a significant association was observed between perineural invasion and OS. Cytokines may promote perineural invasion; however, the relationship between such invasion and the PNI is not clear at the moment. Perineural invasion and its relation to PNI are future research themes in oral squamous cell carcinoma.
Multivariate analysis also showed a significant association of the surgical margin, postoperative treatment, and PNI with the DFS. Therefore, PNI has a role in predicting DFS. Moreover, a low PNI is associated with malnutrition and immunosuppression and may inhibit the success of chemoradiotherapy. In this context, PNI can be thought of as having a prognostic value in predicting DFS.
These results suggest that in evaluating systemic inflammatory response in oral cancer, a blood protein reflects the actual situation rather than the blood cells. This suggestion is consistent with a previously published report [27].
Using clinical background factors including the PNI, we performed single multivariate analyses, including factors that are most related to prognosis, and found that a low PNI value was related to prognosis. These results suggest that the PNI is independent of clinical background and surgical-related factors and that the relationship between the PNI and the prognosis may involve a different mechanism from that associated with tumor markers. These results suggest that PNI can predict the prognosis of oral cancer before surgery.
A limitation of this study is the retrospective analysis of data from a single facility. Additionally, the ROC, when determining the cutoff value was relatively low, affected by a treatment protocol, and the number of samples in this study was likely not sufficient (102 cases). Furthermore, since the median observation period was as short as 48.1 months, an increase in the number of cases and longer observation periods are essential. In cases involving metastasis or inflammation, inflammatory cytokines increase the production of acute-phase proteins such as CRP in the liver and reduce the production of albumin. Therefore, when examining a condition including an inflammatory response and considering the change in nutritional status using biomarkers, it should be assumed that the inflammatory response (CRP and white blood cell count) is normal and does not vary [57]. Whether low PNI is the cause or the effect of tumor progression remains unknown, and additional research is required to elucidate this problem.
The assessments of the PNI are cheaper than those involving tumor markers, and the PNI can be easily calculated using blood samples. Therefore, the PNI can be a prognostic factor for OS and may be a useful long-term marker for evaluating recurrence and metastasis before postoperative chemoradiotherapy and during follow-up. Furthermore, poor nutritional status leads to delay and abandonment of postoperative adjuvant therapy and immunological treatment. Thus, these findings may partially explain the relationship between low OS and low PNI in patients with oral cancer.