The results of our retrospective analysis showed that low preoperative PNI and high CRP levels were prognostic factors for an inferior OS 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 from the ROC curve and we compared the clinical background factors in the two groups. In other previous reports, the cut-off value used to decide a prognosis of PNI was 42–46. The cut-off value of 42.9 that we indicated in this study is within this range; therefore, it is estimated that it is a postoperative prognostic practical index [28–30]. The univariate analysis showed significant differences in the survival rate in relation to smoking status, alcohol consumption, lymphatic invasion, vascular invasion, perineural infiltration, neutrophil count, CRP level, and PNI. Significant differences were also observed in the HR regarding the age, smoking status, albumin level, CRP level, and PNI. Additionally, the two groups showed differences in the 5-year OS. These results suggest that the low PNI group has a preoperatively poorer nutritional status than the high PNI group, with a higher degree of inflammatory response resulting in poor prognosis. The PNI, which is estimated by the serum albumin level and lymphocyte count, reflects the patient nutritional and immunological state. Previous studies on multiple malignant lesions have reported the PNI as a prognostic factor for the OS [31–35].
Microenvironmental inflammation affects the growth of tumor cells and promotes angiogenesis and metastasis [36, 37]. The immune system recognizes cancer cells and secretes, as a response, inflammatory cytokines, leading to hypercytokinemia [36–38]. Interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) are two cancer-associated cytokines. These cytokines cause resolution of the extracellular matrix and neovascularisation. Consequently, growth, invasion, and metastasis of tumors are accelerated. However, it is difficult to easily measure these cytokines [39, 40]. Blood biochemical changes caused by these cytokines can be assessed by the measurement of inflammatory reaction markers based on the systemic inflammatory reaction. [36–41]. To date, numerous typical systemic inflammation markers have been reported, including the Glasgow Prognostic Score [42, 43] based on plasma components, the neutrophil-to-lymphocyte ratio [44, 45] derived from the number of blood cells, lymphocyte-to-monocyte ratio [46, 47], CRP-to-albumin ratio [48], and the PNI [24, 49] 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 major component of the plasma protein content and reflects the nutritional status, whereas lymphocytes reflect the immunological state; thus, the ratio of serum albumin levels to lymphocyte count is associated with the survival of patients with cancer [50–52].
Low PNI levels showed poor prognosis for oral cancer because the inflammatory cytokines IL-6 and IL-8 increased the numbers of neutrophils and decreased those of lymphocytes besides to proteolysis enhancement [38–41]. Thus, low PNI was considered as an indicator of high inflammatory cytokine levels.
Elevated CRP levels have been reported to associate with a lower rate of disease-free survival and OS in operable oral cancers [52]. 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 [53].
The mechanisms underlying the associations between systemic inflammatory response and survival in patients with oral squamous cell carcinoma are not evident. However, considering albumin and lymphocyte counts, the components used for the PNI calculation, cancer cachexia associated with growth factors, impaired cell-mediated immune response, and angiogenesis, are expected [54–58]. These mechanisms might be complicated, and they seem to include the combination of the factors mentioned above. Thus, further studies involving biomarkers such as the PNI are necessary, along with an approved staging system 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 ingredient 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 the adjustment for other risk factors, was an independent prognostic factor for the OS.
Second, it is reported to be associated with tumor prognosis (e.g., we are old in the deeper depth of tumor, positive lymph node metastases, severer TNM stage) that low PNI is more extensive and a positive blood vessel and lymphatic invasion to the second. However, in our results, no differences were observed in the multivariable analysis although a significant difference was found in univariate analysis. This study proposes the potential prognostic utility of PNI in oral squamous cell carcinoma.
These results suggest that in the evaluation of 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 [24].
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 prognosis may involve a different mechanism from that associated with tumor markers. These results suggest that the 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, and the number of samples in this study may not be sufficient (102 cases). Furthermore, since the median observation period was as short as 48.1 months, the number of cases increases and longer observation periods are essential. In cases involving invasion 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 with biomarkers, it should be assumed that the inflammatory response (CRP and white blood cell count) is normal and does not vary [47]. 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 sample. Thus, the PNI can be a prognostic factor for OS and may be a useful long-term marker for the evaluation of 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.