In the present study, the median age at surgery for index CRC and the cumulative incidence rates of metachronous CRC were significantly lower in the rectal group than in the colon group. No significant difference in the OS was found between the two groups. In patients with genetically proven LS, no study has compared the risk and site of metachronous CRC development after index RC surgery with those after index CC surgery. Since index RC accounts for only 10.4%–18.0% of all index CRCs in patients with genetically proven LS [1, 2, 4, 5], there seems to be very little data on metachronous CRC after resection of index RC. In this study, 16.1% of all index CRC in patients with genetically proven LS were RC patients, similar to the findings reported in previous studies. It has been reported that 15%–54% of patients with genetically proven LS or hereditary nonpolyposis colorectal cancer (HNPCC; defined by the clinical criteria only) developed metachronous CRC (Table 4) [9,10,11,12].

Kalady et al. [10] proposed that TPC with IPAA should be strongly considered as an index RC in patients with HNPCC. However, only 15% of patients with HNPCC after surgery for index RC had metachronous CRC in their study. Among previous studies, only Win et al. [12] targeted genetically proven LS. In that study, metachronous CRC occurred in 21 (27%, over a median of 9 [range, 1–32] years) of 79 patients with LS who underwent anterior or abdominoperineal resection of the index RC, in which the cumulative incidence of metachronous CRC was 19%, 47%, and 69% at 10, 20, and 30 years, respectively. In their report, 76% (16 of 21 patients) of metachronous CRCs were located in the right-sided colon, and none occurred in the remnant rectum. Win et al. [12] also stated that TPC should be considered in patients with LS diagnosed with index rectal cancer. In our study, 83.3% (5 of 6 patients) of metachronous CRC cases that developed after index RC surgery were located in the right-sided colon and none in the remnant rectum, which is consistent with the results reported by Win et al. [12]. However, it has been suggested that the carcinogenic risk of LS may be affected by race, ethnicity, region [13,14,15,16,17], lifestyle, environmental factors [18,19,20,21,22], and genotype [1,2,3]. Further case series are needed to draw definitive conclusions regarding metachronous CRC after index RC.

Although an analysis of the OS was beyond the scope of the present study, the OS after surgery for CRC was comparable between the rectal and colon groups. Similarly, no significant differences were observed between the male and female patients. Regarding the OS of patients with LS, consideration of the influence of CRC as well as other LS-associated tumors is necessary. Endometrial and ovarian cancers are important LS-associated tumors, particularly in female patients. LS-associated tumors were the most common cause of death in both the groups. Gynecological tumors are the most common cause of death in the colon group. After surgery for index CRC, colonoscopic surveillance and surveillance of extracolonic LS-associated tumors are considered important. Although gynecological tumors are considered particularly important in female patients, whether they contribute to the improvement in the OS remains unclear. Regarding the cause of death, 28.6% of the patients in the colon group had CRC, whereas all deaths in the rectal group were due to extracolonic LS-associated tumors, without any deaths due to CRC. Therefore, extended surgery is unlikely to prolong the survival period of the index RC in patients with LS. Furthermore, extensive surgery, such as IPAA, cannot be recommended as a standard treatment.

In the present study, metachronous CRC occurred in 29.1% of the patients (61 of 162 patients) in the colon group, and 13.1% of the patients had RC (4.9% of all index CC cases). If all patients with index CC had undergone extensive surgery, such as TC with IRA, 62.7% (101 [93 without metachronous CC and 8 with metachronous RC] of 162 patients) would have undergone unnecessary extensive surgery. In the rectal group, metachronous CRC occurred in 19.4% (6 of 31 patients), and all occurred in the colon. If extended surgery, such as TPC with IPAA, had been performed for all index RC cases to avoid metachronous CRC (actually all with metachronous CC), the remaining 80.6% (25 of 31 patients) of index RC patients who did not develop metachronous CRC would have undergone unnecessary extended surgery. Considering the risk and location of metachronous CRC, extended surgery, such as TPC with IPAA, for index RC is less effective than extended surgery, such as TC with IRA, for index CC, from the viewpoint of metachronous CRC reduction and worsening the quality of life after IPAA.

Interestingly, the incidence of metachronous CRC was lower in the rectal group than in the colon group. To our knowledge, no other study has directly compared these cases within the same cohort. In reports from the same study group, Parry et al. [23] reported the incidence of metachronous CRC after index CC surgery, and Win et al. [12] reported the incidence of metachronous CRC after index RC surgery. Although each study was a separate report, the incidence of metachronous CRC after segmental colectomy in 332 index CC cases was 22% (74 cases; median, 9 years). In addition, the cumulative incidences of metachronous CRC were 16%, 41%, and 62% at 10, 20, and 30 years, respectively. The incidence of metachronous CRC after surgical resection (anterior or abdominoperineal resection) in 79 patients with index RC was 27% (21 cases; median, 9 years). Furthermore, the cumulative incidences of metachronous CRC were 19%, 47%, and 69% at 10, 20, and 30 years, respectively. However, the risk of metachronous CRC in patients with index CC previously reported [6, 23,24,25,26] was similar to that in the present study. Therefore, more data on metachronous CRC after index RC and the results of the comparison between the two groups must be accumulated in the future before drawing a conclusion.

Regarding the reason for the lower cumulative incidence of metachronous CRC in the rectal group than in the colon group, there were no marked differences in patient characteristics between the two groups other than the age at the onset of index CRC. We evaluated the effects of colonoscopy surveillance after surgery. However, many patients experienced index CRC onset several decades earlier. Therefore, detailed records of colonoscopy surveillance were not obtained. As colonoscopy surveillance within three years after CRC surgery has been recommended in patients with LS [27,28,29], we reviewed whether or not colonoscopy had been performed even “within three years.” There was no significant difference in the performance of endoscopy surveillance within three years after resection of the index CRC between the colon and rectal groups. Surgeons and oncologists in Japan seem to have recognized the importance of postoperative colonoscopy surveillance even before the publication of the guideline [30]. Therefore, postoperative colonoscopy surveillance was performed satisfactorily, regardless of the index CRC site, and the cumulative incidence of metachronous CRC was unaffected. The further accumulation of cases is necessary to reach a consensus on whether or not there is a biologically different background between the index CC and index RC in patients with LS.

Several limitations associated with the present study warrant mention. First, this was a retrospective study, the sample size was relatively small, and the follow-up period after index CRC surgery was too short to evaluate the lifetime risk of metachronous CRC. In particular, the frequency of index RC in patients with LS was as low as previously reported. Second, we were unable to examine the detailed interval of colonoscopy surveillance after surgery for the index CRC and the quality of colonoscopy management. In addition, no assessment was performed for any causative gene. Despite these limitations, we believe that this study holds value in its reporting of the incidence and sites of metachronous CRC in patients with LS with index RC and index CC. Thus, this report will help consider the optimal surgical treatment for index RC.

To our knowledge, there have been no other reports on index RC and metachronous CRC in patients with LS in East Asia, including Japan. In conclusion, we cannot recommend extended surgery, such as TPC with IPAA, as the standard surgical treatment for index RC in patients with LS. Careful colonoscopy surveillance for metachronous CRC and surveillance for extracolonic LS-associated tumors might be important, although further research with a larger cohort is needed to achieve definitive conclusions.