Introduction
Multimodality neo-adjuvant chemoradiation treatment (CRT) for patients with locally advanced rectal cancer patients leads to significant changes in the number and distribution of rectal cancer lymph nodes in the mesorectum [
1‐
5]. These changes can have an impact on the accuracy of the radiological and histological nodal staging after surgery. Recent studies have reported that radiological nodal staging after CRT is more sensitive than at primary staging imaging, with negative predictive values of up to 95 % for prediction of a ypN0 status on restaging MRI [
6,
7]. Several studies have also suggested a reduction in nodal number and size after CRT as a reason for a low nodal harvest at histological examination after CRT [
8,
9]. Accurate nodal restaging is becoming clinically more important when an organ-preserving treatment, rather than a total mesorectal excision, is considered after a good response to CRT.
The aim of this study was to explore the influence of CRT on the number and size of lymph nodes, and to generate hypotheses why nodal restaging on post-CRT MRI is more accurate than at primary nodal staging MRI.
Discussion
The aim of this study was to explore the influence of CRT on the number and size of lymph nodes and to assess why nodal restaging on post-CRT MRI has a higher sensitivity and negative predictive value than in a primary staging setting. The current study shows that the majority of the nodes (84 %) become smaller (40 %) or even completely disappear (44 %) on MRI after CRT. The smaller the node, the higher the likelihood it disappears. Nodes that are not visible anymore or that substantially decrease in size at post-CRT MRI have a very low chance of harbouring metastasis. Accuracy, and mainly sensitivity, increases in the restaging setting compared to primary staging with the highest accuracy obtained at a size cutoff of 2.5 mm. This cutoff size is much lower than the generally used size of 5 mm at primary staging.
Several studies have evaluated the effect of (chemo)radiation on lymph nodes in rectal cancer. In a study by Pral et al. the biological effects of neo-adjuvant CRT on nodes in patients with rectal cancer were evaluated [
16]. The authors found that irradiated nodes often show fibrous thickening of the capsule along with fibrosis or sclerosis of the nodal medulla, with a decrease in density of CD4+ T cells and dendritic cells in the nodal paracortex. In our study, the number and size of nodes is decreased, a finding that has been confirmed by other studies [
3,
9,
17]. Koh et al. showed that nodes that were no longer visible after CRT had a more benign appearance before CRT than the remaining nodes, which is in line with our finding that the nodes that could no longer be identified at post-CRT MRI were significantly smaller than the nodes that remained visible [
3].
Generally, AUCs of 0.72–0.75 have been reported for
primary nodal staging in rectal cancer [
11,
18,
19]. These AUCs correspond mainly with high specificities in the range of 82–88 % but with lower sensitivities of 33–58 % on a per lesion basis. In our study, a cutoff of 2.5 mm led to an AUC of 0.78 with a sensitivity of 75 % and a specificity of 64 %. This higher sensitivity after CRT with T2W-MRI has been reported previously, in the range of 80–91 % on a per lesion basis [
11,
20]. The sensitivity in the current study was based on size only, while in the studies with 80–91 % sensitivity nodal staging was based on both size and morphological criteria, which is known to yield higher accuracy results [
10]. The ideal cutoff of 2.5 mm in the present study is much lower than the 5 mm that has been advised for primary staging. Using the 5 mm cutoff in restaging would result in a very low sensitivity. This lower cutoff for post-CRT nodal staging has been previously identified by Lahaye et al. who found a cutoff of 3.3 mm to be optimal [
7].
The current study has identified some possible mechanisms for a more accurate nodal staging with MRI after CRT as compared to primary staging at diagnosis. First, there is a tendency for the smaller nodes to disappear after CRT. Almost 50 % of the nodes ≤5 mm visible on pre-CRT MRI could not be retrieved after CRT. It is this category of small nodes in which morphology criteria are most difficult to apply. When many of these small nodes have disappeared after CRT, a radiologist will be highly confident in staging these nodes as benign after CRT, thereby improving his diagnostic performance. Additionally, the ability to compare the post-CRT with the pre-CRT MR images provides the possibility to identify changes due to CRT and thereby increases confidence in predicting the yN stage. When a node shows a remarkable decrease in size, it is highly likely that the node is benign and this increases the accuracy to select yN0 patients. Another contributing factor to the higher sensitivity of MR nodal staging in a post-CRT setting is that the prevalence of patients with malignant nodes dramatically decreases after CRT than initially predicted on MRI at primary staging: 36 vs. 97 %, respectively. This lower prevalence of positive nodes after CRT will result in a decrease in false-negative findings, further explaining the better performance in identifying a ypN0 on restaging MRI. In our study nodal response coincided with tumour downstaging in 80 % of the patients (data not shown), which is in line with other studies [
3,
21,
22]. This concurrent downstaging in tumour and nodes further helps a radiologist: when there is tumour response to the CRT, he can expect to find nodal response as well.
Clinical implications
Obtaining insight into the effect of radiation on lymph nodes is important in clinical practice. Assessment of nodal response can be helpful in the planning of the extent of the resection, i.e. when there are remaining involved nodes close to the resection margins. It is also becoming more important with the increasingly considered options of organ-preservation after a good response to CRT: local excision or a wait-and-see policy [
23‐
26]. In this approach, accurate selection of ypN0 patients is essential, as the nodes remain in situ. Knowledge on the effect of radiation on nodes can help a radiologist to accurately identify ypN0 patients and thus allow for an organ-preserving treatment.
Limitations
There are some limitations to this study. First, although the data were prospectively collected as part of a study on nodal staging, it can be considered as a retrospective study. Second, the number of patients is limited. The overall number of lymph nodes, however, is large enough to allow for robust results. Third, the matching of nodes on MRI with histology may not have been 100 % accurate, and despite our efforts to match all visible nodes, this was not always possible.
Conclusion
Our study shows that after CRT, the vast majority of the lymph nodes become smaller, and almost half of them are even no longer visible on MRI. The smaller the node, the higher the likelihood it disappears on MRI. The more a node decreases in size, the smaller the likelihood of tumoural involvement. These findings can explain the higher accuracy, particularly sensitivity, of nodal staging after CRT than in a primary staging setting. First, small nodes that are difficult to stage with morphologic criteria on MRI are no longer visible after CRT. Second, the prevalence of positive nodes is lower leading to a higher negative predictive value and thus more accurate selection of the node negative patients after CRT. This increased accuracy of nodal staging after CRT can be of clinical use in organ-preserving strategies after a good response to CRT.
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