In this study, we found significantly better DFS and OS for dMMR subtype patients compared with pMMR subtype patients, although both were classified clinically as HNPCC. Furthermore, similar to LS and FCCTX have different phenotypic features, we found significant differences existing between dMMR and pMMR subtype patients, as summarized in Table 5, a review of the literature (6, 13-16), including age at time of CRC diagnosis, tumor location, rate of metachronous CRC and rate of extra-colonic secondary tumors. As shown in table 1, the age at time of CRC diagnosis was 6.3 years older for pMMR. There was a right colon predominance (61.7% vs. 27.3%) for dMMR patients compared to a rectal tumor predominance (41.8% vs. 11.7%) for pMMR patients. Furthermore, significantly higher frequencies of secondary-site primary tumors (16.7% vs. 1.8%) and metachronous CRC (20.57 person-year vs. 6.18 person-year) were found in dMMR patients compared to pMMR patients. Moreover, we found significantly more N0 tumors in dMMR (70.8%) compared with pMMR (50.9%) (p = 0.049), as shown in table 1.
In addition to noting different phenotypes between dMMR and pMMR subtype patients, this retrospective study determined that extended colectomy was performed more often for dMMR than pMMR patients (35.8% vs. 14.6%, p = 0.004). Most studies recommend extended resection, such as subtotal or total colectomy rather than segmental resection or hemicolectomy, for the surgical treatment of dMMR or LS patients because of the high risk of metachronous CRC (13, 17-19). However, no prospective or randomized study has demonstrated that extended resection confers a survival benefit compared with segmental resection for HNPCC patients. Furthermore, little is known about the ideal operation type may be tailored according to MMR status. In this study, we determined that the risk of metachronous colorectal cancer in pMMR subtype was significantly lower than that of dMMR subtype and comparable to that of sporadic CRC. Furthermore, in pMMR subtype patients, the tumor was more frequently located in the rectum, and extended colectomy, which was only performed in 14.6% of these patients, was not the preferred surgical treatment. However, segmental colectomy itself for pMMR patients did not significantly affect surgical outcomes and was not an independent factor for OS and DFS. Clinically, these two disease subtypes are both classified as HNPCC; the inherent difficulty lies in distinguishing the two because preoperative genetic testing such as microsatellite instability or dMMR status are not always available in daily clinical practice and may affect surgical decision making. However, surgeons have some clues that suggest pMMR subtype patients, such as older age (average age 54.3 years in this study), less right colon involvement (27.3% in this study), and a higher rate of rectal involved (41.8% in this study)(14, 15). Thus, extended colectomy might be recommended for HNPCC patients without rectal tumor involvement and age younger than 50 years because of the higher rate of dMMR subtype with these features. In contrast, segmental resection might be recommended for HNPCC patients who present with rectal cancer and older age due to the high rate of pMMR with these features.
However, for all HNPCC patients, post-operation MMR status should be routinely checked. Post-operative colonoscopy and extra-colonic surveillance were thus individualized based on MMR data(17-19). Post-operation frequent colonoscopy surveillance of dMMR subtype patients who undergo segmental or hemicolectomy is recommended because the risk of metachronous CRC becomes an important issue, as shown in this study (6.18 for pMMR patients and 20.57 person-years for dMMR patients, p <0.001). In this study, pMMR patients had a low rate of metachronous colorectal cancer, and 85% of these cases underwent segmental colectomy; this highlights the idea that that as respect to pMMR patients might benefit from a follow-up program similar to that of sporadic CRC, because of the low incidence of secondary-site tumors. In addition, because of the low rate of secondary-site cancer in pMMR, the post-operative surveillance of these patients might target the CRC only, with a longer interval (such as 3-5 years)(16, 18). However, for dMMR patients, postoperative surveillance of secondary-site cancers (15.0% vs. 5.3%) should be emphasized. Clinically, routine determination of post-operative tumor MMR status is strongly recommended to tailor surveillance programs and improve outcomes.
This analysis benefits from the use of a cohort of patients with standardized computerized data collection, providing the opportunity to compare dMMR and pMMR subtypes for detailed analysis of clinicopathologic variables. However, the major limitation of this study is its retrospective nature. This study did not involve universal screening of mismatch repair proteins using immunohistochemical staining. Instead, screening was performed for cases whose family history fulfilled the A-II criteria. Therefore, few cases were missed in this cohort.