Over the past two decades, the specific clinical significance of KRAS mutation for patients’ individual medical management has been studied and applied to patient management [14]. There is a consensus that anti-EGFR antibody therapy is an effective choice for some metastatic rectal carcinoma patients without KRAS mutation [15]. Reasons for patients who cannot benefit from anti-EGFR therapy may be explained by the heterogeneity of tumor. However, medical imaging methods may disclose certain features associated with KRAS mutation. The feasibility of combining medical imaging parameters to predict KRAS mutation has been proven in some previous studies [16, 17, 18]. In the study of Pierre Lovinfosse et al. (19), rectal cancers with KRAS or NRAS mutations display a significantly higher glucose metabolism than wild-type cancers with 18F-FDG PET/CT imaging. Kenji Kawada et al. [10, 20], found 18F-FDG accumulation into metastatic CRC assessed by SUVmax (the maximum standardized uptake value for the primary tumor) was associated with KRAS status. As for MRI, Yanyan Xu et al. [21], found that lower mean-ADC (apparent diffusion coefficient) and higher D* (pseudodiffusion coefficient) value on MRI with KRAS mutation in rectal carcinoma. And the study of YU RI SHIN et al. [5], showed that KRAS mutation was associated with N stage, gross tumor pattern, axial length of the tumor, and the ratio of the axial to the longitudinal dimensions of the tumor on MRI. So far as we know, there is no study focuses on the correlation between CT image features and KRAS status of rectal cancer.
Our study took in both observed CT features and anatomical based measurement on preoperative CT images and found that the diameter of SRV was significantly increased in positive KRAS mutation patients. However, no significant difference was found between KRAS mutation group and KRAS wild type group in the diameter of IMV. This can be explained by the anatomical characteristics that SRV is the direct vein for rectum. The key point that SRV only receives the blood flow from rectum making SRV particularly sensitive to any factors influencing the biological process of rectum. However, IMV receives blood from both SRV and sigmoid vein, there is decreased accuracy of IMV to predict hemodynamics changes of rectum.
It is well known that the obstruction of proximal vein and increased distal blood flow are two major mechanisms for venous dilatation. Our study excluded patients with other neoplastic, infectious, or vascular diseases to ensure the specificity of SRV predicting a blood flow change of rectum. Earlier researches have reported the close relationship between tumor evasiveness of colorectal cancer and its drainage vein diameters. Chih-Chun Wu et al. [13] found that rectal cancer patients with positive lymphovascular invasion showed a significantly increased mean superior haemorrhoidal vein diameter. The study of Aman N. Khan further supported this finding where patients with right hemicolon cancer showed a significantly increased mean SMV (superior mesenteric vein) diameter at presentation [22]. Therefore, drainage vein diameters may become an effective predictor for evaluation of colorectal cancer. In our study, we further investigated the possibility of SRV diameter for predicting KRAS mutation of rectal cancer.
Pathologically, increased venous blood flow and emerging collateral vessels in rectal cancer are two leading reasons for the increased diameter of the SRV. Destruction of microcirculation in the tumor increases the venous blood in the vein, and demand for increased blood supply promotes the development of collateral vessels. VEGF is found to be the strongest mitogen of endothelial cells, which is a key regulator of tumor angiogenesis, vascular remodeling and vascular sprouting. Vega-Avila E et al. [23] found that VEGF helped vascular proliferation during cancer development, leading to increased blood supply to the tumor. Previous research has proved that KRAS mutation supports the production of VEGF and decline of angiogenesis inhibitors thrombospondin [24, 25, 26]. According to the research by Dong-MyungYeo [12], the microvessel density (MVD) evaluated on DCE-MRI correlates with the expression level of VEGF, which is consistent with the KRAS mutation [24]. And the study carried out by Milena Krajnovi´ c et al. [27] found that the simultaneous presence of KRAS mutations and high VEGF expression were related to worse response to chemoradiotherapy (CRT), frequent appearance of local recurrences, distant metastasis and shorter overall survival in rectal cancer.
In our study, LNE was also more likely to occur in rectal cancer patients with KRAS mutation. This could be explained by two mechanisms. One is that at the same time of increased blood flow of rectum, lymphatic system homeostasis was maintained by lymphangiogenesis, offering more chances for tumor cells to spread. The other explanation is lymph node metastases. However, according to the pathological results, there was no significant difference in lymph node metastases between KRAS mutation and wild-type groups. This suggest that hemodynamic factors might have an earlier influence on the enlargement of lymph node.
In our pathological findings, there was no significant difference between KRAS mutation group and KRAS wild type group in the presence or absence of lymphovascular emboli, signet ring cell, histological type. This should be interpreted with caution due to the small number of patients with evidence of lymphovascular emboli, signet ring cell, which were three, one, and five patients respectively. In the part of differentiation extent (p = 0.03), considering the case number of high and low differentiation group, further research still needed. In our study, there was no significant difference between KRAS mutation group and KRAS wild type group in the presence and absence of peripheral fat interval infiltration. This might be explained by that local tumor aggressiveness was driven by multiple oncogenes and among which KRAS was not the only determining factor [28]. It was suggested in a study conducted by Weihua Li [29] that poor tumor cellularity, tumor heterogeneity, and adjuvant therapy may confound the molecular diagnosis of CRC and should be highlighted in prospective assessment. In the process of diagnosis, imaging characteristics could show focus besides the rectum and provide complementary information to gene testing. There are still many unanswered questions about the association between the mutation at gene level and medical imaging parameters that we can measure. Future studies are still required to explore these possibilities. In medical imaging aspects, MSCT, MRI, and 18F-FDG-PET/CT are all important examinations for us to have further insight into the role of KRAS mutation in rectal carcinoma. Positive results have already been seen on MRI [5, 12, 21] and 18F-FDG-PET/CT [11, 19] for predicting KRAS mutation in colorectal carcinoma. However, CT predictors of KRAS mutation in rectal carcinoma had not been described previously. In this study, increased diameter of SRV and LNE were found in KRAS mutation group.
However, there are some limitations for this study. First, LOT was measured on a single plane, unavoidable factor including the corrugation and crooked distribution of the rectal wall. Due to the relatively small sample size of 89 patients, statistical bias cannot be excluded in this retrospective study and no test was set to verify our result. Thus, further studies are still required to explore other potential imaging predictors and apply to larger population to provide stronger clinical evidence.
In conclusion, this study has demonstrated feasibility in using the diameter of SRV to predict KRAS mutation in rectal cancer patients, and LNE on preoperative CT images can also be one of the important indicators.