MAC is relatively infrequent subtype of neoplasm that accounts for 10–20% of all primary CRC [1, 5, 13]. For this reason, this entity is typically underrepresented in CRC research, and a lot of its biology remains poorly understood. Incidence in our department, MAC comprised about 12% (50/400) of surgical resected cases. This study demonstrated that a high frequency of KRAS mutation, but low BRAF and MMR deficiency rates. Among these,the KRAS mutation rate was equal to 38.5%, which was close to most of the previous reports either about Chinese or other ethnicities in CRC patients [2,14.15]. BRAF mutation rates are significantly different in previous studies of Chinese population [16]. Like in other studies, these two gene (KRAS and BRAF) mutations were mutually exclusive [17, 18]. Similar to Xiaodong Li’s study [16], we found that both BRAF or KRAS mutations has no correlation with amount of mucinous component in the tumours.
In the present study, the prevalence of MSI was lower than that reported in the literature [19–21]. Our findings, together with Kepil et al reports, suggest that this finding might have arisen from a geographical/ ethnic difference [22]. Besides, our results did not demonstrate a significant relationship between PFS outcome and MMR deficiency. Also, contrary to previous reports [23], we found that P53 negative expression patients were more prone to metastatic relapse, although no significant association was found. This may be partially because the number of MMR deficiency or P53 negative expression case is limited in our study.
The mucinous component of CRC has been drawing attention in recent years. Most currently studies comparing CRC with MAC use this criterion, nevertheless, their impact on patients’ prognosis has remained controversial. The present results do not agree with some previous reports [3, 10] but support those of a recent study by Gonzalez et al [5] and Chen et al [2], in which they state that the proportion of mucinous component of MAC has no significant influence on patient prognosis. While mucinous features should still be mentioned, utilizing criteria such as a 50% cut off is not supported by our data. However, we found the bigger the tumor size, the higher the number of mucinous.
In addition to investigating the prognostic significance of the percentage of tumour glands producing mucin, we also evaluated the morphology of the different tumour cells types in mucin pools. MAC tumour cells exhibit highly diverse morphological features, such as layers, acinar or cribriform structures, or individual signet ring cells. SRC is defined by the presence of ≥ 50% of tumour cells with intracytoplasmic mucin. It has been reported that compared with MAC, patients with SRC were more frequently associated with metastatic disease, metastases at multiple sites, and had a poorer survival than MAC patients [24, 25]. Interestingly, during the follow-up period of 32 months, one SRCC patient did not experience any tumor recurrence. The morphology of SRCC case is shown in (Figure. 1c). This patient showed high TIL counts. Our findings suggest that, to the contrary, no correlation was found between the different morphological types and PFS for the SRC or MAC. Additionallly, while one study did find that PDCs grade had the highest accuracy in predicting RFS in CRC patients, no significant results were found for MAC patients. Taken together, we found histologic characteristics of MAC, including percentage of tumor volume comprised of mucus, were not predictive of outcome.
Lymphocytic infiltration is a major immunological defense against tumor cells in solid tumors and is a potential predictor of CRC[26, 27]. Williams et al8found TIL status to be a strong independent predictor of PFS in mucinous component tumors, and a superior predictor of prognosis compared with histological grade. The more TIL infiltrates in the tumor microenvironment, the better the prognosis may be. Likewise, we also demonstrated that TIL status was a strong independent predictor of PFS in MAC. Although the histologic subtype of SRCC was once thought to convey additional risk of mortality, our study demonstrates that, SRCC patients with high TIL levels also showed better PFS prognosis. Furthermore, our study found more male patients diagnosed with TIL-low tumors than female patients. The results of our study suggest that using the grade of TIL status instead of WHO grade of the entire tumor can help identify patients with a high risk of recurrence more accurately.
This study still had certain limitations. Firstly, this study was a retrospective analysis, and these patients’ long-term survival could not be obtained at present. Secondly, limitations of our study include its small patient sample, as well as the low number of adverse events (recurrences), both factors likely contributed to the lack of statistical significance of TIL status in multivariate analysis. A larger sample size may be needed to adequately detect these issues in the future.
In summary, TIL status showed statistically significant association with PFS. In contrast, other parameters, including KRAS or BRAF mutational status、MMR deficiency、percent of glands producing mucin and the morphology of the different tumor cell types in mucin pools showed no significant correlation. Consequently, TIL assessment should be considered for introduction into clinical practice and included in the pathology report of MAC. The result also revealed that the current cut off of 50% mucin component to define MAC might be challengeable. To confirm these findings, further studies with larger sample size are needed.