In this study, EOCRC had the most tumor locations in the rectum and proximal colon while LOCRC had the most tumor locations in the distal colon. This study demonstrated significantly more clinical anemia in EOCRC patients with predominant tumor locations in the proximal colon relative to the distal colon and rectum. These findings confirm the results of several previous studies.5,16 The fecal occult blood test (FOBT) screening has been reported to have high sensitivity for detecting tumors of the colon and rectum, indicating that both colon and rectal cancers frequently bleed into the lumen. The distinction between proximal and distal colorectal cancer may be mechanically related to bleeding, but other effects such as immunological mechanisms need to be considered as well. 5,16,17
Proximal colon tumors often have distinct genetic characteristics (in particular, the BRAF V600E mutation and MMR deficiency/mismatch repair deficiency), which result from the development of serrated precursor lesions via the serrated route of colorectal carcinogenesis. 16,18 Patients with MMR-deficient tumors have a very high prevalence of anemia (72.5%), and both microcytic and normocytic anemia were more common in the MMR-deficient subgroup. However, MMR-deficient tumors were predominantly located in the proximal colon. In addition, MMR deficiency was not a significant predictor of blood hemoglobin levels in multiple linear regression. Further studies are needed to reliably analyze blood haemoglobin levels in MMR deficiency cases at different tumor sites.
Blood haemoglobin levels in colorectal cancer are inversely related to systemic inflammation. High serum IL-8, and low serum albumin, are mainly associated with normocytic anemia. IL-8 is a proinflammatory chemokine associated with the promotion of neutrophil chemotaxis and degranulation. Serum IL-8 levels are elevated in many malignancies and IL-8 is thought to be an important contributor to cancer-associated inflammation. Serum albumin levels reflect systemic inflammation since albumin synthesis decreases in response to IL-6. These findings support the notion that, in particular, normocytic anemia in colorectal cancer is associated with systemic inflammation. These associations may also have therapeutic significance, as modulation of the inflammatory response has shown some potencies of inflammatory anemia treatment.5,16,18
The patient mortality rate increased in advanced stages (stage IV, IIIA, and IIIB) in both the early-onset and late-onset CRC groups. This is in line with previous studies. The 5-year survival rate ranges from 77% in stage I colorectal cancer cases to only 2% in stage IV CRC cases. In developed countries, the five-year life expectancy is over 60%, but it is lower to < 50% in Iran. However, the 5-year survival for all cases of CRC increased from 42.7–44.6%, although not statistically significant (p = 0.76).19 Meanwhile, according to data from other centers in Indonesia, out of 142 CRC patients included in the study, 43% of patients survived during the observation period (five years). By analysis, subjects aged < 45 years showed a better 5-year survival (47.4% vs 41.3%).20 However, the study found no significant difference between age and survival. This finding differs from a study by Chao-Hsien et al which showed age to be a predictor of survival and prognosis in colorectal cancer.20 Early stages show a better prognosis whereas, in those with advanced stages, the cancer develops very progressive and aggressively so that it can reduce survival rates. 5,16−20
Based on the correlation analysis between variables, it was found that anemia, histopathological features, and tumor location significantly had a low correlation with the incidence of CRC onset. Taken together, these findings support the notion that, in particular, normocytic anemia in CRC is associated with systemic inflammation. Anemia is more common in EOCRC with the predominant tumor location in the proximal tumor area. This condition is related to genetic and molecular factors as previously described.
Based on the histopathological aspect, in theory, as many as 90% of CRC cases originate from the glandular mucosa and belong to the type of adenocarcinoma originating from the colorectal mucosal epithelial cells.5,21 Adenocarcinoma is characterized by the formation of glands. EOCRC has different pathological features compared to LOCRC. EOCRC tends not to have precursor adenomatous lesions and signet ring cell is common, whereas in late-onset there is no signet ring cell at all.22,23 This is in line with what was found in this study.
Signet ring cells show an infiltrative pattern or there is a collection of extracellular mucin and is classified as poorly differentiated.22 In other studies, EOCRC showed a feature of gland formation around 50–95% and was moderately differentiated.9,10 Left colorectal cancer is more common compared to the right and is associated with a worse pathological features and prognosis. On the other hand, the majority of cases of EOCRC are diagnosed as more advanced stages. EOCRC shows a lower survival rate compared to LOCRC patients. In this present study, adenocarcinoma was the dominant pathological feature in both groups as has been reported in other studies. 5,21,22,23 Other studies have also reported a higher prevalence of poorly differentiated histological signet ring cells in young colorectal patients presenting with aggressive tumors. However, in this study, there is no statistically significant correlation between the clinicopathological features of CRC in both onset and mortality rates.