TNM staging is based on the invasion depth of the primary Tumor, the presence of lymph Node metastases, and the presence of distant Metastases. The subclassification for the early (T1) tumors is described in Chap. 20.

The appearance of acellular mucinous lakes, also called colloid response, is frequently observed after neoadjuvant therapy of a rectal tumor, both in the areas of the primary tumor and in the surrounding lymph nodes (see also the paragraph on ex-positive lymph nodes). In addition, an increased number of mucinous carcinomas, where mucinous lakes contain vital tumor cells, are frequently observed after neoadjuvant therapy. However, these tumors do not cause any diagnostic problems. The discussion should be focused on acellular mucinous lakes and whether to include these in T staging. In 20–55 % [11, 12] of neoadjuvantly treated cases, acellular mucinous lakes are observed. Results on its relation with prognosis are conflicting; Shia et al. [12] did not observe a relation with recurrence-free survival, while Rullier et al. [11] demonstrated that the prognosis of patients with a colloid response (5-year DFS 64 %) is in between those for patients with downstaging (5-year DFS 80 %) and without any response (5-year DFS 54 %). In a series of patients with a pCR, acellular mucin was present in 27 % of cases. Its presence did not influence prognosis [13]. However, no studies have evaluated the difference between prognostic value of T stage including and excluding mucinous lakes, so real evidence is lacking. For practical reasons, we advise to mention the presence of mucinous lakes in the report and as it can be seen as tumor response, not to include these in the T stage.

Clinical complete response (cCR) is often a clinical end point in trials but is only well defined in a limited number of studies. The correlation with a pathological complete response is variable; a recent review [14] demonstrated that in 8 studies this correlation was described and that a cCR results in a pCR in approximately 30 % of cases. There is confusion about what exactly constitutes a pCR: Is an ypT0 resection enough or is an ypT0N0 resection required? In up to 7.1 % of ypT0 cases, lymph node metastases are still present.

Moreover, the process of determining a pCR is not standardized, and the probability of finding vital tumor cells in resections after neoadjuvant therapy is dependent on the enthusiasm of the pathologist and how many tissue blocks and section levels are investigated. In order to standardize response determination, we advised the following procedure:

Further research is needed to evaluate the usefulness of this procedure.

The presence of positive lymph nodes is the most important prognostic factor in colorectal cancer and an indication for adjuvant therapy. Downstaging due to neoadjuvant therapy can cause positive lymph nodes to become negative. It is not clear whether, in these cases, the cN is more accurate in predicting prognosis than ypN. Theoretically, one could assume that any node that was positive is an indication of early metastasis, and thus also ex-positive lymph nodes have an increased risk on metastatic disease. On the other hand, the fact that the tumor in these lymph nodes reacts so well might be an indication for a good prognosis. A problem that so far has not been solved is the adequate pretreatment imaging of lymph nodes. Although the nodes can often be seen on MRI, predicting nodal involvement remains difficult.

Numbers of ex-positive lymph nodes are not frequently reported. Prall et al. [15] described in 10 out of 24 negative lymph nodes signs of tumor regression after chemoradiotherapy (fibrosis or acellular mucin lakes); Perez et al. [16] saw mucin lakes in 6 lymph nodes (1.2 % of all negative lymph nodes). Morgan et al. [17] describe necrotic tumor in lymph nodes in 2 of their 21 patients. In an MRI study [18], regressive changes were followed radiologically. Out of 29 positive lymph nodes, 3 became mucinous on MRI, while final pathological examination confirmed negative lymph nodes with acellular mucin lakes. These series are too small to draw any conclusion about the prognostic impact of ex-positive lymph nodes.

In a study with 165 patients, Valentini et al. [19] describe three different groups: 34 cN0ypN0, 72 cN + ypN0, and 56 ypN + patients, with a distant metastases-free 5-year survival of, respectively, 87.5, 82.9, and 47.9 %, suggesting that not initial N stage but rather final pathology makes the difference. However, with the limited possibilities of reliable clinical N staging, one can question which part of the cN0ypN0 group in reality should have belonged to the cN + ypN0 group. This might have affected the prognosis in this group and thus obscure the difference between the first two groups. Moreover, more studies are needed to confirm this finding. For now it seems reasonable to describe ex-positive lymph nodes as an additional item, but staging should be done on those lymph nodes with evident tumor present.

Neoadjuvant therapy influences the number of examined lymph nodes, either by decreasing their size below the observation limit [20] or by a complete disappearance of lymphocytes. Part of lymph nodes will be replaced by fibrosis [12]. In a randomized trial with short-term radiotherapy (5 × 5 Gy), fewer lymph nodes were examined in the radiotherapy arm (7.7 versus 9.7, p < 0.001) [4]. In a large population-based study with 5647 patients [21], after radiotherapy, 7.0 lymph nodes were examined, compared to ten nodes in the surgery-only group (p < 0.0001). Bujko et al. demonstrated that the type of neoadjuvant treatment also makes a difference, with 11.4 nodes after 5 × 5 Gy compared to 7.6 nodes after radiochemotherapy (p < 0.001) [22]. Several studies demonstrated that the number of lymph nodes is not correlated with treatment response [23, 24].