The aim of the present study was to explore the utility of MY as a predictor of postoperative relapse and survival in patients with stage II colon cancer. In this study, patients with MY had more frequent postoperative relapse than those without MY. Furthermore, Kaplan-Meier analyses showed that patients with MY had significantly worse RFS and OS than those without MY, and multivariate analysis demonstrated that MY was an independent predictor of postoperative relapse in patients with stage II colon cancer. These results suggest a close relationship between MY and cancer cell metastatic behavior.
DR classified by the type of fibrotic stroma is simply detected by routine H&E staining. This inexpensive pathological feature has been reported as a useful predictor for metastasis and survival in several solid cancers, including cutaneous cancer, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer [19–24]. In colorectal cancer, although the amount of fibrosis was evaluated as an index of the stromal reaction first, Ueno et al. more recently have proposed categorizing it into three types by the fibrotic responses of cancer stroma, and they reported that their classification was useful for predicting the prognosis of patients with colorectal cancer [23, 25, 26]. In the present study, since there was no association between the DR classification, except for MY (data not shown), and postoperative outcomes, DR divided into the MY group and the NMY group was explored.
Recent approaches using molecular and genetic methods may offer predictive information for relapse and survival in patients with stage II colon cancer in addition to the routine pathological examination. Microsatellite instability (MSI) due to mutation or modification of mismatch repair (MMR) is mainly detected in Lynch syndrome, which is an autosomal dominant cancer syndrome associated with an increased risk of colorectal cancer and other extracolonic malignancies, including endometrial cancer, stomach, small bowel, and ovarian cancers [27, 28]. The QUASAR trial and several studies showed that patients who were MMR-deficient (dMMR) had a higher relapse risk than those who were MMR-proficient (pMMR), but other studies showed the ineffectiveness of 5-FU chemotherapy in dMMR patients compared with in pMMR patients [29–31]. MSI is currently known to be associated with a good prognosis and not to benefit from 5-FU chemotherapy. MSI or the MMR test is therefore recommended in the NCCN guideline [6]. However, these tests need immunohistochemistry or expensive gene analyses, even though clinical evidence supporting their use is still insufficient.
Among cells of the stromal component, fibroblasts have been termed cancer-associated fibroblasts (CAFs) and are important promotors of tumor progression and metastasis [32]. CAFs can induce dedifferentiation by extracellular matrix (ECM) remodeling [29, 30] and desmoplasia by increasing the deposition of ECM [33–36]. In several reports, single or small clusters of cancer cells (TB) have been frequently observed at MY areas [19, 24], and TB was associated with DR in the present study. These results suggest that CAFs may have a critical role in regulating DR and TB. Recently, Ueno et al. reported that a tumor grading system based on DR and TB provides more precise prediction of individual patients than the conventional staging [37]. In the present study, compared with patients with either one of MY or TB, those with both MY and TB developed postoperative relapse much more frequently. The presence of both MY and TB might have a synergistic effect rather than an additive effect for postoperative relapse.
Metastasis-associated fibroblasts at the metastatic site promote the proliferation of cancer cells. [38–40]. Circulating CAFs (cCAFs) have recently been identified in the circulation as single CAFs, or a part of circulating tumor cell clusters or CAF clusters [37]. Cornil et al. reported that fibroblasts affected the proliferation of melanoma cells, and that only metastasized melanoma cells were influenced by fibroblasts [41]. Since MY has been closely associated with metastasis in previous reports, specific stimuli released by MY may move cCAFs to metastatic sites. In fact, 65% of patients with MY developed tumor relapse, whereas only 12% of patients without MY did. We therefore recommend the evaluation of DR at metastatic sites for patients who undergo surgical resection of metastatic lesions.
The present study has several limitations, such as its retrospective design and small sample size. A difference in the relapse rate between patients with mature stroma and those with intermediate stroma might have been found if the sample size had been larger. In the present study, multivariate analysis did not show that MY was an independent risk factor for OS in patients with stage II colon cancer. This might have been due to the short follow-up and the effects of AC and treatment for relapse, such as surgical intervention and intensive chemotherapy. In addition, neither MSI nor MMR, which are considered to be predictive in the NCCN guideline, was examined, and the effect of AC according to the NCCN guideline was not examined.
In conclusion, the present results suggest that MY is a useful predictive feature for postoperative relapse in patients with stage II colon cancer. Furthermore, if both MY and TB are identified in the lesion, the risk of tumor relapse is so high that AC should be considered. Since MY can be detected during the routine pathological examination using H&E staining, it can be an inexpensive and valuable marker identifying high-risk patients among patients with stage II colon cancer and for deciding whether to add AC.