As an important means to effectively reflect diffusion of water molecules inside and outside cells, DWI has been widely used in the differential diagnosis of benign from malignant gastrointestinal tumors, preoperative evaluation and evaluation of the effect of radiotherapy and chemotherapy (17–18). As a tumor marker with wide clinical application value, higher Ki-67 index often indicates the characteristics of active proliferation, strong infiltration and poor prognosis of tumor cells (7–8). Studies have suggested that with increase of Ki-67 level, the ADC value of tumor continues to decline (19). However, because ADC is limited by the diffusion movement of water molecules that affected by the microstructure inside and outside the cell and the influence of capillary micro perfusion, ADC cannot completely truly reflect the diffusion of water molecules inside and outside the cell. The multi b-value IVIM model proposed by Le Bihan et al can obtain the D value that reflects the real water molecule diffusion and can effectively eliminate the influence of micro perfusion.And, D* and f values can also be obtained (20) to reflect the patients’ blood perfusion. At present, the correlation between IVIM and Ki-67 index has been applied to malignant tumors such as extrahepatic cholangiocarcinoma, lung cancer, nasopharyngeal carcinoma and rectal cancer. The results show that D has better correlation with Ki-67 than that of ADC. This study found that the results are similar to above tumors and the difference of AUC value between D and ADC value was not statistically significant (Table 6). And in terms of sensitivity and specificity, the results of D is higher than that of ADC. The possible reason is that IVIM effectively eliminates the influence of capillary micro perfusion on diffusion coefficient compared with single index DWI. Based on the obvious negative correlation between ADC and D value with Ki-67, the increase of Ki-67 expression may suggest a stronger tumor cell proliferation activity, tighter cell arrangement, smaller extracellular space, higher nucleocytoplasmic ratio and more organelles, which significantly reduces the intracellular space, shows more significant restriction on the free diffusion of water molecules and therefore shows lower ADC and D (21–24).
D* and f values mainly reflect micro perfusion of new capillaries in tumor cell space, which is related to cell density, cell necrosis and bleeding. The study found that there was a negative correlation between f and Ki-67 in gastric adenocarcinoma and no significant correlation was between D* and Ki-67. By contradicting the related studies of lung cancer and nasopharyngeal carcinoma, the results of the study is consistent with the similar research in extrahepatic cholangiocarcinoma and rectal cancer. In the study on the correlation between lung cancer and nasopharyngeal carcinoma and Ki-67, there was no correlation between D* and f with the expression of Ki-67, which may be out of the histopathological differences. Histopathological differences of nasopharyngeal carcinoma is that prone to bleeding and necrosis due to their strong proliferative ability and there is obvious heterogeneity in the proportion of capillaries in the extracellular space due to the uncertainty of necrosis and bleeding. This might be one of the reasons for the above results in gastric adenocarcinoma. And, because D* and f values mainly reflect extracellular micro perfusion, there is no direct correlation with cell density, which may explain why the correlation between f with Ki-67 expression is not as good as the relationship between D and Ki-67 (25). At present, although adenocarcinoma is the main type of lung cancer, current studies are mainly on the differences between non-small cell lung cancer and small cell lung cancer. Due to many different pathological types of non-small cell lung cancer, there are great differences in vascular proliferation in intercellular space and the differences in degeneration and necrosis of lung cancer with different pathological types and degrees of differentiation. Therefore, no correlation between D* and f with the expression of Ki-67 in lung cancer (21) can be well explained. As a result of gastric adenocarcinoma, cholangiocarcinoma and rectal cancer are mainly adenocarcinoma, although the tissue structure arrangement is more loose than nasopharyngeal carcinoma, it will further squeeze the space of extracellular capillaries because it secretes more mucin, causing the proportion of microvascular perfusion in the intercellular space is not high; the cell density increases as the increase of Ki-67, resulting in the narrowing of microvascular space that accompanied by a certain degree of necrosis and bleeding, which may be the reason for the negative correlation between f and Ki-67 (26–28). In gastric adenocarcinoma, there is no significant correlation between D * and Ki-67. The possible reason is that D* is more significantly related to the diameter of blood vessels, but not directly related to the number of microvessels and cell proliferation. And the poor image quality and low signal-to-noise ratio of D* should also be considered (Fig. 1D) (29).
However, this study has some limitations. First, there is no final conclusion about the optimal number of b values and the optimal size of b values in IVIM sequence. More accurate results can be obtained by increasing the number of b values. Secondly, the effect of different parameter combinations on diagnostic efficacy was not included in the study. Therefore, further studies should be conducted.