There is growing evidence indicating that tumor-associated inflammation and tumor microenvironment play a more and more important role in the cancer development, progression, metastasis , and clinical prognosis . As reported previously, MCHC and RDW were closely related to the prognosis in several types of cancers. In the present study, we also observed that high MCHC, normal RDW indicated better OS and PFS. Besides, in analyzing the correlation between factors of interest and other clinical pathological variables, MCHC was higher in patients with the lesion was located on the tail of pancreas, and rarely neurological invasion indicated better survival . Therefore, it is reasonable to combine MCHC and RDW as a simple and convenient marker to enrich the stratification of prognosis in PC patients.
MCHC means the average red blood cell hemoglobin concentration, is calculated by dividing the red blood cell specific volume (HCT) by the average red blood cell volume (MCV), and is an indicator of the average red blood cell volume . MCHC indirectly reflects the degree of anemia from a quantitative perspective. As we all know, there is increasing evidence that anemia is associated with poor survival rates for a variety of malignancies. Qu found that low MCHC (<335) was associated with unfavorable prognosis of resected lung cancer. Studies also showed that MCHC was associated with prognosis for oral and head and neck cancers. In his study, the cut-off value of MCHC was decided by ROC curve analysis based on their cohort. However, in this study, the standard value was used as the cut-off value for MCHC because we believed that it could increase the value of current results and make it universally applicable. Our findings demonstrated that preoperative MCHC was an independent predictor of OS for pancreatic cancer patients undergoing curative surgical resection. To date, only a few preliminary hypotheses explain why MCHC may affect prognosis. But the mechanism is not clear. This may be related to the following mechanism. At first, Hemoglobin is the main driving force for carrying iron, and anemia can cause excessive iron load. Iron is a trace element involved in a wide range of human metabolism. Iron deficiency and excess can lead to disease. Iron deficiency has been linked to anemia , chronic heart failure  and other conditions. Excess iron increases the risk of cancer . Even if the excess is physiological, the risk of cancer can increase. . In other words, proper iron consumption achieves a protective effect on the body. The correlation between hematological parameters and serum iron markers may be attributed to changes in iron levels that are to some extent reflected in erythrocyte morphology. Second, Iron overload often accelerates and induces oxidative stress. Oxidative stress is another factor that causes cancer to develop, and serum iron can induce and accelerate this process . Furthermore, the changes of red blood cell parameters indirectly reflect the process of oxidative stress. Third, Hemoglobin is the main driving force for carrying oxygen, and low hemoglobin can cause tissue hypoxia. Hypoxia can promote tumor progression and induce changes in the cell genome to enhance tumor growth and angiogenesis. Hypoxia induces epithelial mesenchyme transformation (EMT) , which is critical for cancer progression and metastasis. In addition, hypoxia affects angiogenesis . On the conditions of hypoxia, cancer cells exhibit adaptive metabolic changes. These include conversion of glucose to lactic acid and increased glucose uptake through promotive glucose transporters (GLUTs), a phenomenon known as the Warburg effect . Last, but not the least, Nutrition is another factor leading to the development of disease . Reduced hemoglobin means that patient's nutritional status is relatively poor. Increased incidence of complications and increased mortality in patients with nutritional risks before surgery . In clinic, accurate pretreatment staging is essential for treatment decision. Our study found that preoperative MCHC is an independent prognostic factor for pancreatic cancer, which can affect the prognosis of pancreatic cancer patients. Therefore, as novel and easily obtainable prognostic marker, preoperative MCHC can be used as a supplement to pathological stages and provide a more accurate prognosis.
RDW, as one of the classical evaluation indexes which can effectively reflect the heterogeneity of erythrocyte volume, and is usually used for evaluation of blood diseases, cardiovascular diseases as well as infectious diseases . In recent years, it has been found that its value is related to the malignant tumor, as a new molecular marker for prognosis and recurrence. Studies have found that an increase in RDW will bring a poor prognosis, which has been confirmed in gastric cancer, colon cancer, liver cancer and other malignant tumor. In this study, we found that Elevated RDW was closely associated with poor prognosis in patients with pancreatic cancer after surgery. In short, preoperative RDW can predict the survival of such patients. The underlying mechanism of cancer development caused by high RDW is generally interpreted as the following. At first, RDW elevation is strongly associated with increase of interleukin-6 and tumor necrosis factor-α, both of which can affect the tumor cell biological behaviors . Pro-inflammatory cytokines are considered to affect iron metabolism and erythropoietin production, shorten the lifespan of red blood cells and induce the release . And then, RDW has been reported as a biomarker in response to inflammation and oxidative stress . Inflammation and oxidative damage foster the progression of cancer, including sustaining proliferative signaling, evading growth suppressors, and activating invasion and metastasis, thus impacting patient survival. Moreover, a higher tumor stage can result in a greater extent of systemic inflammation by the secretion of cytokines and release of tumor-degradation products , which then decreases lifetime of red blood cells and increases RDW level. Last, patients with cancer might change their dietary habits or eat less due to insufficient energy intake, which might lead to malnutrition.
To our surprise, we also found that preoperative MCHC and RDW had an effect on the recurrence of patients with pancreatic cancer after surgery. RDW has been proven to be a marker of tumor recurrence in oral cancer . To date, there are no studies regarding the relationship between MCHC and cancer recurrence. According to the literature, few inflammatory markers can achieve a monitoring effect on tumor recurrence. And in this article, compared with the relationship between MCHC and prognosis, the relationship between MCHC and recurrence is more meaningful. In short, for preoperative MCHC levels of less than 354, we can take interventions to prolong the relapse time of the disease and prolong the survival of patients. But the mechanism by which MCHC affects relapses is also unclear and has never been reported. Possible mechanism may be due to inflammation related to malnutrition, immune dysfunction, platelet activation, angiogenesis and cytokine activation . Therefore, preoperative MCHC has a certain predictive effect on the recurrence of pancreatic cancer after surgery. Compared with other monitoring methods, it has the advantages of economy, non-invasiveness and convenience.
The study also revealed some associations between the MCHC and RDW and clinical pathologic features previously shown to be predictive of worse outcomes. Such as, patients with high MCHC often suffer from tumors in pancreatic body and tail. It is well known that patients with pancreatic body and tail have a better prognosis than the head. Then, patients with high MCHC are less prone to nerve invasion. Pain is a common clinical symptom of pancreatic cancer, neuropathy is a characteristic of pancreatic cancer, as is well-known that this neuropathy is significantly related to prognosis . In addition, MCHC is associated with HCT, MCV, because they are all indicators of anemia. Although there was no correlation between RDW and clinical pathological parameters, it was significantly correlated with tumor markers. As we all know, tumor markers represent the activity of tumor to some extent, and indirectly reflect the severity and changes of the diseases . RDW combined with CEA and CA19-9 can better predict the prognosis and relapse of patients. Although MCHC and RDW was associated with a number of variables, the relationship between them and OS was not modified by any other clinical pathological factors, which suggested that both MCHC and RDW were stable predictors of prognosis in patients with pancreatic cancer.
This study also had some flaws. At first, this study was a retrospective study. Although we had excluded factors such as blood system diseases and inflammatory diseases that might cause MCHC changes before the study, there were still many unavoidable interference factors which could affect the results of this experiment. Then, this study was single-centered with small sample, leading to biases in sample selection and results analysis. More medical institutions and samples are still needed to further verify this result. Finally, Due to grouping according to the normal range, there was a certain deviation in the two groups of samples, which might have some impacts on our experimental results. In summary, although this study had certain shortcomings, MCHC and RDW had good predictive values for prognosis and recurrence of patients with pancreatic cancer after surgery. At the same time, these indexes achieved the advantages of cheap, convenient, non-invasive, as well as certain research values.