Association between high-resolution MRI-detected extramural vascular invasion and tumour microcirculation estimated by dynamic contrast-enhanced MRI in rectal cancer: preliminary results

Extramural vascular invasion (EMVI), defined histologically as the presence of tumour cells within blood vessels outside the muscularis propria of the rectal wall, is associated with a higher risk of local and distant recurrence and poorer survival [1, 2]. Although dissemination of tumour cells into small vessels (< 3 mm in diameter) can be histologically confirmed, this identification is of little clinical importance [2, 3]. In addition, when involved vessels are extensively destroyed beyond recognition, they are underreported by pathologists [4]. Furthermore, the reported detection rates of EMVI vary widely due to heterogeneity in staining, the extent of histopathological evaluation or diagnostic criteria for EMVI [1, 4, 5]. High-resolution magnetic resonance imaging (MRI), generally consisting of thin sections (3 mm) with an in-plane resolution of 0.5–0.8 mm, is the primary imaging modality for preoperative local staging of rectal cancer [6]. This method has shown accuracy in identifying EMVI, especially in vessels greater than 3 mm in diameter [3, 7, 8]. In addition, several studies have suggested that MRI-detected EMVI (mrEMVI) is a strongly predictive of poor prognosis [9, 10]. Therefore, the identification of EMVI based on high-resolution MRI can be regarded as more clinically relevant than histological identification.

Tumour angiogenesis, which is regulated by numerous factors, is a fundamental process in the growth and invasion of rectal cancer [11]. Among the most critical regulator of angiogenesis is vascular endothelial growth factor (VEGF) [12]. Microvessel density (MVD), which is a measurement of the density of microvessels, has been found to be correlated with VEGF expression, and both of these immunohistochemical markers are widely used to evaluate tumour angiogenesis [13, 14]. Immunohistochemistry is invasive, time consuming and has poor measurement repeatability, whereas dynamic contrast-enhanced MRI (DCE-MRI) is a promising method to noninvasively evaluate tumour microcirculation in vivo. Kinetic parameters estimated from DCE-MRI are able to assess tumour blood flow, capillary permeability and permeability surface area, which may reflect tumour biology. The three principle parameters are the volume transfer constant between blood plasma and extravascular extracellular space (EES) (K^trans, min^− 1), the rate constant between EES and blood plasma (k_ep, min^− 1) and the volume of EES per unit volume of tissue (v_e, 0 < v_e < 1) [15].

Neovascularization usually has an immature vascular structure that can be easily infiltrated by tumour cells [16, 17]. However, the relationship between EMVI status and tumour microcirculation in patients with rectal cancer has not been studied previously. Hence, this study aims to investigate whether patients with different mrEMVI statuses show any difference in DCE-MRI parameters (K^trans, k_ep and v_e), with the ultimate aim of identifying a potential relationship between mrEMVI status and tumour microcirculation.

In the present study, we evaluated the association between mrEMVI status and tumour microcirculation in rectal adenocarcinoma. No significant difference was found in the DCE-MRI parameter K^trans between mrEMVI-negative and mrEMVI-positive patients, whereas the DCE-MRI parameters k_ep and v_e were revealed to be associated with mrEMVI status. It is interesting to note that mrEMVI-positive patients with rectal adenocarcinoma had significantly lower k_ep and higher v_e values than mrEMVI-negative patients.

It is now well established that angiogenesis is essential for tumour growth, invasion and lymphatic and haematogenous spread of tumour cells [11]. Newly formed capillaries are characterized by tortuous architecture and increased permeability compared with mature vessels; thus, they can be easily penetrated by tumour cells [16, 17]. mrEMVI, which is associated with a worse outcome, is an imaging indicator of tumour progression [10, 22]. In terms of biological explanations, we propose that tumour cells within intratumoural vessels, with further development, may extend into vessels outside the rectal wall to form EMVI [10, 23]. Thus, it can be presumed that the invasive degree of neovascularization is significantly different between mrEMVI-negative and mrEMVI-positive patients and that this alteration induces differences in the microcirculatory environment in tumour tissues. Quantitative perfusion parameters from DCE-MRI, a functional imaging method, provide information regarding related pathophysiological properties in vivo. Notably, mrEMVI-positive patients had significantly lower k_ep values. The k_ep value equals the flux rate of contrast agent from the EES to plasma, which depends largely on capillary permeability and the permeability surface area [15]. Based on the above hypothesis, the presence of a considerable number of tumour cells within the tumour vessels decreases the permeability surface area and thereby decreases the k_ep value in mrEMVI-positive patients. Clearly, a cluster of invasive tumour cells might cause decreased blood supply in the corresponding area due to a reduced permeability surface area, leading to an increased degree of tissue hypoxia and microscopic necrosis and, thus, an enlarged EES. The v_e value represents the fractional volume of the EES, which is affected by the integrated effects of cell proliferation and necrosis [24]. Thus, it was not unexpected that the v_e value was significantly higher in mrEMVI-positive patients. Yeo et al. [25] also demonstrated that microscopic internal necrotic areas showed a decreased k_ep value. In addition, it has been shown that the loss of function of cell-cell adhesion molecules, a pivotal step in tumour progression, leads to a larger interstitial space, which is reflected by a higher v_e value [26, 27].

The K^trans value represents the transfer rate from plasma to the EES, which has a mixed microcirculatory blood flow and permeability weighting [15, 28]. Although a mixed situation occurs most commonly, there is an overall trend of a dominating effect of flow in untreated tumours [29]. Theoretically, a cluster of tumour cells within vessels would decrease the local microcirculatory blood flow. In this study, as expected, there was a tendency towards a lower K^trans value in the mrEMVI-positive group, but the trend was nonsignificant. A possible explanation for this might be that the K^trans value is also impacted by blood perfusion, including cardiac output, hypertension and the circulatory system of an individual, which thus produces greater individual variation than other quantitative parameters. By comparison, k_ep is only influenced by the contrast concentration and fractional volumes in the tumour EES and might more accurately mirror the capillary permeability [30]. The results might also be limited by the complexity of the underlying pathophysiology.

A recent study also showed that primary rectal cancer blood flow measured by DCE-MRI was significantly lower in patients with metastatic nodes, which also represents an unfavourable prognosis [28]. However, regarding the investigation by Yu et al. [26], lymphovascular invasion was correlated with higher K^trans, k_ep and v_e values. This inconsistency may be because lymphovascular invasion may be a different entity from EMVI. In addition, quantitative perfusion parameters from DCE-MRI primarily characterize angiogenesis rather than lymphangiogenesis. Furthermore, tumour development is a complex and heterogeneous process [31]. In addition, the inconsistency of DCE-MRI protocols could also affect the results to some extent.

mrEMVI is more likely to occur with more locally advanced tumours in rectal cancer [32]. Thus, it is not surprising that larger tumour size, higher pathological tumour stage and increased metastatic regional nodes were more common in mrEMVI-positive patients. Although nodal status is vital for prognosis and treatment decision-making in rectal cancer, all kinds of imaging methods have low discriminant accuracy for nodal metastases [33]. Therefore, from a practical perspective, the presence of mrEMVI can alert radiologists to carefully scrutinize the MRI for evidence of nodal involvement. However, our study has shown that mrEMVI status was not significantly associated with synchronous distant metastasis in rectal cancer. This outcome was contrary to that of Sohn et al. [22] who found that mrEMVI was an independent significant risk factor for synchronous distant metastasis in rectal cancer. A possible explanation for this might be differences in the patient populations of the two studies. Patients who underwent curative surgery with or without neoadjuvant treatment and only underwent chemotherapy or chemoradiotherapy were enrolled in their study; however, we only enrolled patients who proceeded directly to surgery. The patients who underwent surgery only have a low likelihood of synchronous distant metastasis, potentially influencing the relationship between mrEMVI status and synchronous distant metastasis.

Our study is hindered by a few limitations. First, mrEMVI was not directly compared with histopathology results. However, the reported incidence of EMVI on histopathology is variable, impairing the prognostic predictive value of EMVI. Although tumour deposits within small vessels are still beyond the spatial resolution of current MRI techniques [8], patients with histologically confirmed EMVI involving small vessels are the same as those with no demonstrable vascular invasion, with fewer clinical implications [22, 34]. Second, not every patient in this study underwent contrast-enhanced liver MRI or FDG-PET/CT, and it is possible that some synchronous distant metastases were missed. Lastly, the relatively small sample size did not allow for substratification of outcomes based on mrEMVI scores and different histopathological types of rectal cancer.

This preliminary study suggests that the microcirculation of rectal adenocarcinoma in mrEMVI-positive patients is altered, with significantly lower k_ep and higher v_e values, enabling DCE-MRI parameters to serve as an additional tool for potentially predicting prognosis for mrEMVI-positive patients with rectal adenocarcinoma. In addition, larger tumour size, higher pathological tumour stage and metastatic regional nodes were more common in mrEMVI-positive patients.