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[21, 22]. Therefore, this study assessed the diagnostic efficacy of two common inflammatory indexes (LMR and AGR) and detected whether they could be used as surrogate markers for distinguishing colon cancer from benign colon diseases.
In this retrospective analysis, we found that the colon cancer patients had a lower LMR level than the benign colon disease patients and healthy controls did, and this was consistent with previous findings. 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. Luo et al. found that MLR was significantly elevated in patients carrying urothelial carcinoma of the bladder relative to healthy controls. A study by 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. Moreover, our study disclosed that the level of LMR was significantly correlated with lymph node metastasis, tumor size, and clinical stage. Indeed, 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[27, 28], 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[38, 39], 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%, 0.69), while the specificity was up to 87.72%. In addition, we found that CEA combined with LMR or AGR generated a significantly higher diagnostic sensitivity than CEA used alone did. LMR or AGR combined with CEA possessed a better AUC than LMR, AGR, or 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. In many malignancies, AGR exhibited good diagnostic efficacy (AUC = 0.81) in differentiating cancer patients from healthy controls. All these findings suggest that the combination of CEA with LMR or AGR could not only be used as a colon cancer diagnostic biomarker but may also improve the diagnostic efficiency of detecting patients harboring colon cancer from those with benign colon diseases.
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.