Features such as tumor infiltration depth, lymph node metastasis, and EMVI are significantly associated with poor prognosis among colon cancer patients. The overall survival rate of patients with T4 stage colon cancer without lymph node metastasis is significantly lower than that of patients with T1–2 stage with lymph node metastasis [19, 20, 21]. Patients with T3/T4 stage are more likely to experience local regional recurrence or distant metastasis [22]. Some studies have revealed that patients at high risk for recurrence require more aggressive treatments, including more extensive lymph node dissection and hyperthermia and intraperitoneal chemotherapy (HIPEC) [23]. Therefore, identification of patients at high risk for recurrence who will benefit from individualized treatment is essential for improving colon cancer patient prognosis and survival rates. However, in this study, the consistency between preoperative radiological and postoperative pathological staging was poor (κ = 0.232, P < 0.001). The accuracy of T3 stage diagnosis was 60.9% (64/105), while that of T4a staging was 68.6% (72/105), which were consistent with the results of other studies [3, 4, 7]. Moreover, the accuracy of staging of the ascending colon and the descending colon tumors was poorer than that of tumors located in other colon sites. Furthermore, an excessive assessment phenomenon was present in ascending colon and descending colon tumors. Therefore, preoperative radiological staging may be insufficient for correctly identifying patients at high risk for recurrence [22]. On the one hand, due to the special anatomical structure of the colon, tumor staging by radiology is challenging, in particular in the peritoneal mesothelial organs (ascending and descending colon). The posterior walls of the ascending and descending colons are not covered with peritoneum, and the T stages at these sites were only T3 or T4b. On the other hand, when the colon wall is surrounded by a large amount of fat, it is difficult to distinguish fibroinflammatory reaction, connective tissue proliferation and tumor invasion in radiology [7], substantially impacting staging by preoperative radiology. Some studies have shown that MRI (magnetic resonance imaging) has higher diagnostic consistency than CT scan in locally advanced colon cancer, which can better identify serosal invasion [22, 24, 25]. Therefore, it is possible to combine CT and MRI preoperatively to improve the consistent rate of staging diagnosis and better identify patients with high recurrence risk.
Pathologically, it is difficult to determine whether tumor cells have invaded the peritoneum [26]. In previous studies, the diagnostic approaches for evaluating colon cancer with serosal invasion were varied and consistent [27]. On the one hand, mesenteric serosa surrounded by fat is difficult to identify. Furthermore, suspected sites of peritoneal invasion usually include peritoneal fracture and retroperitoneal structures, which makes it difficult for the pathologist to obtain samples and accurately determine the location of the peritoneum [12]. On the other hand, invasive tumors that approach the peritoneum often cause inflammation [28], including recruitment of inflammatory cells, such as CD68 and CD204 macrophages, to the vicinity of the serosa [12]. It is difficult to diagnose peritoneal invasion by H&E staining. Evaluating elastic lamina invasion performs better in terms of determining overall survival rates than evaluating tumor infiltration depth [12]; thus, elastic lamina staining is expected to become a new anatomical hallmark replacing traditional serosa invasion diagnostics. In this study, we not only found a higher risk for recurrence among T3 ELI (+) patients than for T3ELI (−) patients (P = 0.000) but also a higher risk for recurrence among T3ELI (+) patients than for pT4a patients (P = 0.013). T3ELI (+) (HR, 8.444 [95% CI, 1.736–41.067]; P = 0.008) was an independent risk factor for postoperative recurrence of stage III colon cancer. This may be related to the microenvironment of tumor metastases [29, 30]. Some studies have shown that the sites where tumors invade the elastic lamina usually show a greater extent of fibrosis and tumor budding [12, 13, 31]. Therefore, when the invasive tumor approaches the serosa, the tissue fibrosis and tumor buds increase rapidly. This process can form a tumor microenvironment that promotes the development of the tumor [13].
Previous studies involving elastic lamina staining have revealed a high rate of inability to detect the elastic lamina, partially casting doubt on whether this approach can be used to effectively evaluate the prognosis of colon cancer patients [9]. In this study, the elastic lamina was not detected in as high as 47.3% of the samples, and this effect was related to the N stage of the tumors. It has been shown that the number of negative nodes is an important independent prognostic factor for patients with stage IIIB and IIIC colon cancer [32]. Therefore, lymph node metastasis was essential for the prognosis of patients with stage III colon cancer. Our studies founded that there was no significant difference in the N stage between T3 EL (−) and T3 ELI (−) patients (P = 0.342). It might be suggested that the prognosis of T3 EL (−) was common with T3 ELI (−). Some studies have suggested similar views, they founded that there was no significant difference in the DFS (p = 0.6318) or OS (p = 0.8413) between the ELI (−) and the EL (−) [33]. With regard to the higher inability of elastic lamina detection. On the one hand, the tumor infiltrates the tissues near the serosa and produces fibroinflammatory and mesothelial reactions. This leads to the rupture and morphological distortion of the elastic lamina, which subsequently cannot be well identified. Moreover, the elastic lamina form a “ring pattern” (moving from the lower endothelial layer to the tumor, and then back to the lower endothelial layer), which further increases the difficulty of their identification [9]. On the other hand, the elastic lamina does completely cover the colon wall and its thickness varies with the anatomical location [34]. Some studies have shown that the identification rate of elastic lamina in the right side of the colon is lower than that in the left side of the colon [9, 35], and the identification rate in the rectum is lower than that in the colon [13]. Therefore, in other to avoid a high rate of elastic lamina identification failure, the pathological sampling and staining methods and diagnostic criteria need to be further developed. In clinical practice, serosal destruction by surgical resection of tumor tissue and lymph nodes is inevitable. Therefore, we advocate marking the suspected serosal invasion location on the specimen resected by surgery, allowing pathologists to carefully sample the suspected serosal invasion location. The elastic lamina may not be identified as it does not completely cover the colon wall. Therefore, the number of blocks and slices taken affects the rate of elastic lamina identification [13]. However, despite several studies, there are still no definitive guidelines regarding the number of blocks and slices needed. Furthermore, excessive sample collection and staining will cause unnecessary waste. Therefore, it may be beneficial to choose patients with T3 stage tumors with peritoneal invasion for elastic lamina staining [15]. The elastic lamina has been found to move from the nontumor area of the peritoneum to the muscularis propria when the tumor invades normal tissues [11]. It is possible to track the elastic lamina from the nontumor area to the tumor area. Therefore, rate of elastic lamina identification failure can be reduced more effectively. However, the materials used for elastic lamina staining and the criteria for diagnosis are inconsistent. We expect future prospective studies to standardize the pathological approach to diagnostics using elastic lamina staining.
For patients with stage III colon cancer and according to the NCCN guidelines, 12 cycles of FOLFOX4/mFOLFOX6 or 8 cycles of XELOX postoperative adjuvant chemotherapy have been recommended if they can tolerate intensive treatment. Patients who cannot tolerate oxaliplatin should consider capecitabine or 5-FU monotherapy. However, the disease-free survival (DFS) and overall survival (OS) rates of patients at high risk for relapse after adjuvant chemotherapy are obviously different. The results of the MOSAIC 10-year study showed that compared with that of N2 stage patients, the 5-year DFS rate of N1 stage patients increased by 16% (72.3% vs. 55.4%), and the 10-year OS rate increased by 12% (71.4% vs. 59.5%) [36]. Therefore, it is challenging to stratify recurrence risk and optimize treatment for patients with stage III colon cancer. In the 2017 IDEA study, patients with stage III colon cancer were divided into low-risk (T1, T2, T3N1) and high-risk (T4 or N2) groups. Studies have shown that the 3-month DFS rate in the high-risk group is lower the 6-month DFS rate (73.6% vs. 76.0%), while there is no difference between the 3- and 6-month DFS rates in the low-risk group. (83.1% vs. 83.3%). Additionally, different chemotherapy strategies have different prognoses. The DFS rate after 3 months of FOLFOX treatment is lower than that after 6 months of treatment, while CAPOX for 6 months in the low-risk group does not provide a treatment benefit compared with 3 months of therapy [37]. Therefore, NCCN guidelines recommend FOLFOX for 6 months or CAPOX for 3–6 months for high-risk patients with stage III colon cancer, and CAPOX for 3 months and FOLFOX for 3–6 months for low-risk patients with stage III colon cancer. However, the patient clinical features significantly related to prognosis among high-risk individuals include RAS/BRAF mutation and MMR status in addition to clinical stage. In recent years, diagnosis with circulating tumor DNA (ctDNA) has improved due to its noninvasiveness, convenience, safety, and comprehensive nature. ctDNA has application value in the diagnosis of early colorectal cancer, monitoring postoperative early recurrence, and monitoring treatment response and therapeutic resistance in patients with metastatic disease. It remains unclear whether patients with stage III colon cancer have a high risk for recurrence with postoperative adjuvant chemotherapy. Some studies have shown that ctDNA analyses can be used to assess patient risk considering postoperative adjuvant chemotherapy and guide individualized follow-up strategies [38]. The results of the phase III IDEA-France clinical trial revealed that 13.65% of patients had ctDNA-positive status before postoperative chemotherapy. In the low-risk group, the prognosis of ctDNA-positive patients after 3 months of treatment was poorer than that of ctDNA-negative patients. Therefore, further prospective clinical trials are required to define the clinicopathological features of high-risk groups.
Elastic lamina staining can not only effectively diagnose the depth of tumor infiltration but can also indicate recurrence risk in patients with stage III colon cancer after radical resection. Elastic lamina staining results can further stratify the recurrence risk of patients with stage III colon cancer, and prospective clinical trials are required to determine optimal adjuvant treatment strategies. It is expected that elastic lamina staining will be of diagnostic and treatment value for patients with colon cancer.