Colon cancer is closely associated with inflammation which has been unraveled as a crucial hallmark in all the steps of colon tumorigenesis, including initiation, invasion, progression, and metastasis. Recent work has elucidated that cancer-associated inflammatory markers are increasingly used in the early diagnosis and prognosis of malignant tumors and closely related with the progression of diseases[29, 30]. Therefore, this study assessed the diagnostic efficacy of the common inflammatory indexes (LMR, AGR, and MPV) and detected whether they could be used as surrogate markers in the progression of colon cancer.
In this retrospective analysis, we discovered that the healthy controls had significantly higher MPV compared to the benign colon disease patients and colon cancer patients, which was consistent with the result of Lalosevic et al., but contrary to the findings of Li et al. and Kilincalp et al.. The differences may be due to health groups included criteria and population selection. We found that the MPV values in the first two articles (Lalosevic and Li) were 9.06 and 10.7, which were similar to the results of this study (9.32), but the wide gulf was obtained from the article of Kilincalp in the MPV values (7.82). Moreover, previous research illustrated that MPV was connected with obesity, smoking and so on, which may also differ among the studies population, resulting in the inconsistent outcomes. Although no association was demonstrated between clinical stage and MPV in our current finding, the results revealed that the MPV levels in patients with stage III–IV were higher than that in cases with stage with I–II, which was similar to Li’s study. And the present study is the first research revealing the correlation between MPV and the tumor size.
In concordance with previous results, the colon cancer patients had a lower LMR level than the benign colon disease patients and healthy controls did. For example, Evrim et al. observed that the level of monocyte-to-lymphocyte ratio (MLR) was higher in the gastric cancer group than it was in the intestinal metaplasia and healthy control groups. A study by Luo et al. found that MLR was significantly elevated in patients carrying urothelial carcinoma of the bladder relative to healthy controls. Moreover, our study disclosed that the level of LMR was significantly correlated with the features of colon cancer, such as lymph node metastasis, tumor size, and clinical stage. Indeed, Ozawa et al. demonstrated that cancer-specific survival was significantly worse in patients with low LMR levels than in high-LMR patients, and LMR may be an independent prognostic marker for stage III and IV colon cancer patients. Peng et al. assessed the prognosis of patients harboring colorectal liver-only metastases and elucidated that elevated LMR predicted a favorable outcome in both 5-year recurrence-free survival and overall survival of patients with lymph node metastases and liver tumor up to a diameter of less than 5 cm. Furthermore, several meta-analyses have demonstrated that malignant patients with high preoperative LMR have better predicted clinical outcomes compared with patients with low LMR in populations comprising Asians, digestive system carcinomas, non-metastatic diseases and early disease stages[40, 41], which confirmed our findings.
Emerging evidence suggests that AGR is mainly used as a clinical indicator for several kinds of cancers. Growing tumors induce hypoalbuminemia via secreting inflammatory cytokines, which may inhibit albumin synthesis and promote albumin loss, resulting in weak systemic response. Rasouli et al. reported that patients with malignant tumors had a decreased concentration of albumin, which were measured by colorimetric methods, compared with healthy controls, which was accordant with the present study results. Globulin, as a reflector for most proinflammation protein, was increased by the accumulation of acute-phase proteins and immunoglobulins. The AGR, which is compatible with hypoalbuminemia and hyperglobulinemia, may be able to more accurately reflect the nutritional and inflammatory state, and thus, is associated with the progression of neoplasia. The electrophoretic data of serum proteins showed that the AGR was significantly decreased in 85 patients harboring cancer relative to controls. Cheng et al. confirmed that the globulin-to-albumin ratio (GAR), was significantly higher in the subjects with liver disease compared with individuals with no evidence of liver disease. Quite a few studies revealed that patients with lower pretreatment AGR were related to worse survival than higher AGR subjects in colorectal cancer, gastric cancer, pancreatic cancer, nasopharyngeal carcinoma, and esophageal cancer. Moreover, a significant correlation based on the above-mentioned researches was observed between clinical characteristics and the level of AGR, such as lymph node metastasis, tumor size, distant metastasis, and tumor stage. In agreement with previous studies, this study found that the value of AGR in the colon cancer patients was lower than that in the benign colon diseases and healthy individuals; furthermore, it showed that the AGR was associated with lymph node metastasis, distant metastasis, tumor size, and clinical stage.
CEA is a serum glycoprotein that is mainly secreted by cells of the large intestine, and it has been widely applied as a tumor marker for the malignant characteristics of colorectal cancer. Unfortunately, high levels of CEA are not present in about 15% of large intestine cancers, and elevated CEA is commonly revealed in severe malignant tumors. In clinical practice, increased circulating levels of CEA are observed not only in cancer patients but also in some benign intestinal lesions. Therefore, the sensitivity and effectiveness of CEA are not sufficient for clinical diagnosis and treatment, but CEA has a high specificity in colorectal cancer[51, 52], as well as in differentiating colorectal cancer patients from those with benign colorectal diseases.
Consistent with previous studies, the sensitivity and diagnostic value of CEA were not noticeable in identifying colon cancer from benign colon diseases (43.43%, 0.686), while the specificity was up to 87.72%. Whereas we found that CEA combined with LMR or AGR generated a significantly better diagnostic sensitivity and AUC than CEA used alone in discriminating colon cancer patients and benign colon diseases cases. Similar to this pilot study, a previous report displayed that LMR possessed a moderate ability (AUC = 0.71) and could contribute to distinguishing patients carrying gastric cancer from those with intestinal metaplasia, the diagnostic efficiency was similar to that of our study in colon cancer. Meanwhile, the AUC value of MPV combined with CEA had a good diagnostic ability and sensitivity for distinguishing controls from colon cancer patients (AUC = 0.950 and 91.24%) and patients with benign colon diseases (AUC = 0.886 and 84.49%), was superior compared with individual indicators and related reporter. For example, Milica et al. revealed that ROC curve analysis showed high diagnostic efficacy of NLR, PLR and MPV in CRC patients compared with individual markers (AUC = 0.904). In many malignancies, AGR exhibited good diagnostic efficacy (AUC = 0.81) in differentiating cancer patients from healthy controls, which squared with our results. All these findings suggest that the combination of CEA with LMR, AGR or MPV could not only be used as a colon cancer diagnostic biomarker but may also improve the diagnostic efficiency of detecting the progression of patients harboring colon cancer.
There are certain potential limitations in the current research. On the one hand, this is a retrospective analysis of a relatively small sample size from a single center, so selection bias and statistical validity should be noted, which may affect the final results about the associations between the LMR or AGR and colon cancer. We failed to stratify benign colon diseases due to the relatively small sample size. On the other, confounding factors, including dietary habits and family histories, cannot be completely ruled out, which may prevent us from drawing any firm conclusions. Therefore, a large-scale, prospective study with multiple centers is still needed to validate these results.