Clinicopathological factors predict residual lymph node metastasis in locally advanced rectal cancer with ypT0-2 after neoadjuvant chemoradiotherapy

For locally advanced rectal cancer (LARC), neoadjuvant chemoradiotherapy (NCRT) combined with radical surgery based on the principle of total mesorectal excision (TME) is one of the standard treatments. NCRT could reduce the local recurrence rate compared with TME alone (van Gijn et al. 2011). Despite the relatively favorable prognosis of this treatment strategy, a permanent stoma is often required following abdominoperineal resections in patients with middle-low LARC, and a temporary ostomy is required in 70–90% of cases where middle or upper LARC patients receive low anterior resections (Roodbeen et al. 2021a; b; Snijders et al. 2013). Furthermore, a considerable proportion (about 10%) of temporary stomas were not reversed (Kim et al. 2016; Zhang et al. 2022). About 20–60% of patients also experienced genitourinary alterations, low anterior resection syndrome, sexual dysfunction, and a significantly diminished quality of life (Emmertsen and Laurberg 2012; Li et al. 2021; Marijnen et al. 2005; Wallner et al. 2008).

Therefore, the utilization of organ-preserving strategies, including local excision (LE) and watch-and-wait (W&W) strategy, has gradually gained widespread attention because it can preserve the function of the anus. In LARC patients after NCRT, if the remnant primary tumor only infiltrated the muscle layer or more superficially layer, it could be removed through the LE technique. Notably, one recent study has reported high pathological complete response rates (44.3%) and significantly reduced postoperative complications were observed in stage T2 and superficial T3 tumors treated with NCRT and subsequent LE compared to TME (Serra-Aracil et al. 2023). The W&W strategy, is an appealing approach in rectal cancer patients who achieved clinically complete response (cCR) following NCRT (Habr-Gama 2006; van der Valk et al. 2018). The OPRA study, which enrolled 324 patients, demonstrated that half of the patients achieved organ preservation through total neoadjuvant therapy (TNT) and selective W&W without apparent harm to survival (Garcia-Aguilar et al. 2022). Additionally, our center’s prior research also confirmed that the combination of NCRT plus consolidation CAPEOX with intentional W&W or LE can lead to approximately two-thirds of organ preservation in MRI-defined low-risk rectal cancer patients (Wang et al. 2023).

However, residual lymph node metastases (RLNM) in the mesorectum remained a great concern as it posed an important risk of local and distant recurrence in patients with LARC (Haak et al. 2021; Yeo et al. 2010). Even in ypT0 rectal cancer patients after NCRT, positive RLNM still significantly reduced 5-year Disease-free survival (DFS) (88.5% vs. 45.2% for ypN0 vs. ypN+, p < 0.001), as shown by the Korean Radiation Oncology Group (KROG) (Yeo et al. 2010). A series of previous studies have confirmed that the incidence of RLNM varied in TME specimens with different ypT stage rectal cancers (Bosch et al. 2016; Kim et al. 2006; Park et al. 2013; von den Grun et al. 2018). The key point of TME is to completely remove the intact mesorectum to avoid a positive resection margin and resect potentially metastatic mesorectal lymph nodes, and the quality of the surgery plane has been proven an important prognostic factor for local recurrence (Quirke 2003; Quirke et al. 2009). Though LE may achieve proper lateral and radial margins of the primary tumor, it failed to provide sufficient evidence for the absence of RLNM (Landmann et al. 2007). In the GRECCAR-2 study (Rullier et al. 2017), rectal carcinoma with good response after NCRT was considered suitable for LE. After LE, a TME was required for ypT2-3 tumors and patients with ypT0-1 had a follow-up. There is no difference in 5-year oncological outcomes between LE and TME (Rullier et al. 2017).

Hence, in rectal cancer patients with ypT0-2 after NCRT, predicting RLNM and carefully selecting suitable individuals for organ-preserving strategies is especially significant. Tumor remnants in the bowel wall may provide histopathological risk factors for RLNM. Advanced ypT-stage, high-grade histopathology and residual tumor diameter ≥ 10 mm have been proven to be prognostic factors for RLNM in ypT0-2 tumors after NCRT in previous studies (Bosch et al. 2016; von den Grun et al. 2018). High-resolution magnetic resonance imaging (MRI) also played a crucial role in assessing primary tumor staging and response to treatment, and some parameters of MRI, such as mesorectal fascia (MRF) status and extramural venous invasion (EMVI) status have been proven to be correlated with prognosis in LARC patients after NCRT (Bates et al. 2022; Horvat et al. 2019). However, standard T2-weighted MRI with diffusion-weighted imaging (DWI) was still unable to accurately evaluate RLNM after NCRT (Al-Sukhni et al. 2012).

To further investigate the possible MRI parameters and other clinicopathologic factors that predict positive RLNM, thereby providing evidence in the real world for selecting patients suitable for organ-preserving strategies, we conducted this retrospective study.

In this study, we intended to identify MRI parameters and other clinicopathological factors correlated with RLNM in a cohort of 417 LARC patients with ypT0-2 after chemoradiotherapy. By multivariable analysis, we developed a novel nomogram for predicting RLNM, and the nomogram was constructed by four variables, including baseline MRI-defined positive MRF status, high-grade histopathology at biopsy, advanced ypT stage and presence of PNI. The nomogram had good discrimination and calibration efficacy and showed good clinical usefulness. This tool will make it easier to predict RLNM in clinical practice and assist physicians in determining the most appropriate strategy for their patients.

In recent years, the feasibility of organ preservation strategies has been substantiated by various prospective randomized controlled studies (Garcia-Aguilar et al. 2022; Rullier et al. 2017; Serra-Aracil et al. 2023; Wang et al. 2023). The GRECCAR-2 phase 3 trial proved in carefully selected patients with ypT0-1, the local recurrence rate of LE was not significantly different from that of TME (Rullier et al. 2017). However, the lack of precise evaluation in lymph nodes in the mesorectum in LE or W&W was a major limitation. The incidence of RLNM was variable after TME in different ypT stages (ypT0: 2.2–17.4%; ypT1: 7.7–20.8%; ypT2: 16.9–25.8%, ypT3-T4: 43.9–49.0%) (Bosch et al. 2016; Kim et al. 2006; Park et al. 2013; von den Grun et al. 2018). It has been demonstrated that RLNM displayed a highly aggressive tumor phenotype that was resistant to NCRT (Fokas et al. 2020) and was highly correlated with poor prognosis and adverse outcomes (Huebner et al. 2012). The risk of RLNM, therefore, has hindered the further implementation of intentional organ preservation strategies.

To our best knowledge, few studies have studied the relationship between MRI parameters and RLNM. MRI has become an integral part of the baseline staging and treatment planning in rectal cancer. However, the accuracy of MRF in identifying lymph nodes was still unsatisfactory, particularly in restaging N after NCRT (Al-Sukhni et al. 2012; Bates et al. 2022; Taylor et al. 2014). A meta-analysis has demonstrated that the sensitivity and specificity of MRI in identifying metastatic lymph nodes were 0.690–0.840 and 0.590–0.810, respectively (Al-Sukhni et al. 2012). Therefore, the predicted value of other risk features in MRI for RLNM may be considered, such as MRF status. MRF involvement implies that tumor cells have extended beyond the rectal wall and invaded the mesorectal fascia, thereby increasing the likelihood of spreading to lymph nodes. In the MERCURY study, patients who were MRF positive had a higher rate of RLNM than those who were MRF negative (67.9% vs. 37.7%) (Taylor et al. 2014). It is noteworthy that 57.8% of patients in the MERCURY study were accepted with primary surgery without NCRT. In our study, the rate of RLNM was 8.3% and 17.2% for MRF-negative and MRF-positive, respectively (p = 0.006), indicating the relative reliability of baseline MRF in predicting RLNM after NCRT. Furthermore, cT3 and MRF-positive were also classified as advanced (Ugly) in the risk stratification of rectal cancer recommended by ESMO (Glynne-Jones et al. 2018).

With a considerable proportion of patients (32.0%) found to have RLNM, high-grade histopathology at baseline biopsy was identified as a powerful independent predictor in our multivariate analysis. Prior studies examining rectal cancer with ypT0-2 status after NCRT and surgery have similarly concluded that high tumor grade was associated with RLNM (Bosch et al. 2016; von den Grun et al. 2018). However, the two studies assessed tumor type/grade in surgical specimens only, lacking the data of tumor grade before treatment, probably due to a small amount of biopsy tissue. Meanwhile, the histological grade/type of patients with ypT0 could only be estimated based on baseline biopsy. Using the National Cancer Database, a study of 4170 rectal cancer patients with ypT0 tumors found that tumor grade at baseline biopsy was strongly correlated with RLNM (Baucom et al. 2017). Therefore, it may be tentatively concluded that patients with high tumor grade at preoperative biopsy were at relatively high risk of RLNM.

PNI was associated with an increasing risk of local recurrence in patients with rectal cancer in previous studies (Kim et al. 2022a, b; Liebig et al. 2009). In a study of 4170 rectal cancer patients with ypT0, the presence of PNI was highly correlated with RLNM, with an incidence of PNI at 0.3% and an RLNM risk of 41.7% in PNI (+) cases (Baucom et al. 2017). Another study analyzing a cohort of 1156 rectal cancer patients found that PNI occurred in 2.1% of ypT0-2 cases and 21.6% of ypT3-4 cases, and RLNM was found in 54.7% of PNI-present cases (Kim et al. 2022b). By comparison, in this analysis, the incidence of PNI was 1.7% and the RLNM risk was 42.9% in PNI-present cases. Though the occurrence of PNI is quite rare, PNI may be a histopathological independent risk factor for RLNM among patients with ypT0-2. Of course, further prospective studies are needed to confirm the value of PNI in predicting RLNM.

There is no consensus on which threshold probability of RLNM that a patient could accept organ preservation strategies. To some extent, executing TME or organ preservation strategy may depend on individual choice and risk preferences. As researchers are concerned, the results of the GRECCAR-2 study revealed LE plus completion TME would increase morbidity and side effects compared to LE only and single TME (Rullier et al. 2017), which may compromise the potential advantages of LE. However, several prospective cohort studies, including the CARTS study (Stijns et al. 2019) and the TAU-TEM study (Serra-Aracil et al. 2023), have proven LE after NCRT could preserve organ function and improve the quality of life. Therefore, our nomogram model can be used to identify patients’ risk for RLNM through commonly used clinicopathological indicators and to help clinicians make better clinical decisions on whether to perform organ preservation strategies. As the results shown in Fig. 1a and Table 4, we initially suggest organ preservation may be a safe option for patients whose predicted probability is less than 5%. In contrast, in the subgroup of the predicted risk probability is more than 15%, TME may be a mandatory option in these patients. In addition, when the risk ranges from 5 to 15%, organ preservation may be practicable under the consideration of caution and close follow-up.

We recognized this study had some limitations that should be taken into consideration. First, it was a single-center, retrospective study with selection bias and an insufficient sample size, lacking external validation. We need a prospective and multicenter study to consolidate our findings. We used modern MRI technology in our study, and more imaging modalities may be more helpful in predicting RLNM. Besides, we lack the necessary tools to match postoperative RLNM and lymph node distribution in preoperative MRI, thus it is difficult to conduct a node-to-node evaluation. Additionally, the data of the proportion and diameter of residual tumors were not available, owing to there being few records of these two data in the pathological reports of our center before 2019. Moreover, the areas under the ROC curve may be unsatisfactory, further research is still needed to enhance the predictive performance of the model. In addition, RLNM as a surrogate endpoint could not directly replace DFS and overall survival, long-term follow-up is still needed to further confirm our findings. We have recognized this limitation and will further supplement the data in future research.

In summary, we developed a nomogram model that predicted RLNM probabilities in patients with ypT0-2 tumors. Based on four parameters, our nomogram model may be a valuable complement in predicting RLNM and assist in the decision-making process regarding organ preservation strategies in patients with LARC after NCRT. Certainly, this is a retrospective study with a limited sample size, we still need external validation and further prospective and multicenter study to consolidate our findings.