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Clinical characteristics of synchronous colorectal cancers in Japan

Clinical characteristics of synchronous colorectal cancers in Japan Background: Incidence and clinical characteristics of synchronous colorectal cancer (sCRC) patients significantly vary among studies, likely due to differences in surveillance methodology. If remain undetected, sCRC can progress to more advanced stages seriously aggravating patient prognosis. We studied the incidence and clinicopathological characteristics of Japanese patients with sCRCs who underwent surgery for primary CRC and received exhaustive perioperative surveillance. Methods: We recruited 1005 patients with surgically resected CRCs between January 2007 and December 2011. The associations of clinical and pathological factors with sCRC development were assessed by univariate and multivariate logistic regression. Results: Eighty-four patients (8.4 %) developed sCRCs, 16 of them (19.0%)harboring threeormorecancers.Companion sCRCs were smaller and earlier stage than the index lesion (P < 0.0001). In multivariate analysis, advanced age (odds ratio (OR) 1.03 per year; P = 0.009) and left colon tumor location (OR 1.78; P = 0.013) are associated with higher risk of sCRCs, particularly in females. Overall survival did not differ between solitary CRC and sCRC (P =0.62). Conclusions: Our results highlight the importance of perioperative colonoscopy examination to ensure the absence of sCRCs that, being small and early staged, are more difficult to detect. The incidence of sCRC, and notably of triple or more sCRCs, was higher than previously recognized. Because they are also significantly higher than expected by merely stochastic accumulation of individual cancerous lesions, we suggest that the occurrence of many sCRC reflects a hitherto uncharacterized predisposition condition. Keywords: Colorectal cancer, Synchronous colorectal cancer, Multiple colorectal cancers, Surgical resection, Colon stenosis Background 8.1 %, with only small size studies reporting an incidence Colorectal cancer (CRC) is the second and third cause higher than 4 % [4–20]. of cancer death in male and female, respectively, in de- Well-established risk factors for sCRC development veloped countries [1]. Although CRC incidence in Japan are familial CRC syndromes, ulcerative colitis, and micro- and other Asian countries is lower than in western satellite instability (MSI) [13, 21]. A preoperative precise countries, during the last few decades, it has been rapidly diagnosis of sCRC is essential, because it may influence increasing, according to recent reports from the World clinical decision-making regarding the type and extension Health Organization [2, 3]. The incidence of synchronous of the surgical procedure as well as the use of additional CRC (sCRC) has been estimated to range between 1.1 and treatments. Furthermore, if overlooked, synchronous tu- mors may require additional surgery and might grow into more advanced stages ultimately leading to the develop- * Correspondence: [email protected] ment of distant metastases. Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan The aim of this study was to investigate the incidence Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut rate of sCRCs in a consecutive series of non-familial d’investigació en ciéncies de la salut Germans Trias I Pujol (IGTP), Campus Japanese CRC patients and determine the clinical and Can Ruti, 08916 Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 2 of 8 pathological features of patients developing sCRCs, to esti- for those exhibiting a normal distribution, or Wilcoxon- mate the relative contribution of the different risk factors. Mann–Whitney test for those that deviated from a normal distribution. Deviation from normality was determined by Methods Shapiro’s test. Differences in survival were studied using Patients Cox’s proportional hazards regression model. Differences We reviewed 1022 consecutive patients that underwent were considered statistically significant at P < 0.05. The surgery for primary CRC in Saitama Medical Center, Jichi concordance between locations of sCRCs for the same Medical University, between January 2007 and December individual was analyzed using Kappa (K) statistic. Ac- 2011. Seventeen cases were excluded from the analysis, curacy was considered poor when K waslessthan0.20, including suspected familial adenomatous polyposis syn- fair to good when K was between 0.20 and 0.40, and drome (FAP, n = 4), hereditary nonpolyposis colorectal good when K was larger than 0.40 [15]. All statistical cancer (HNPCC, n = 1), patients with history of previous analyses were performed using R (ver.3.1.2.) [26] and CRC (n = 9), and patients with ulcerative colitis (n =3). OpenEpi web server [27]. The remaining 1005 patients were included in this study. Mean patient age was 67.4 ± 11.2 years and mean follow- Results up interval was 44.3 ± 19.5 months. Clinical and pathological features of sCRCs In this study, only cancerous lesions histologically proven Among 1005 patients who underwent surgery for CRC, were considered. Multiple CRC was defined according to 84 patients (8.4 %) developed sCRCs (Table 1). Of these, the criterion of Moertel et al. [22]: a pathologically proven 16 patients (19.0 %) harbored triple or more sCRCs as adenocarcinoma and distinctly separated from the previous follows: triple sCRCs occurred in eight patients, quadruple line of anastomosis. Cancers diagnosed within 6 months in seven, and quintuple in one. In total, 193 sCRCs were before or after the initial diagnosis were considered as detected in these 84 patients. Table 1 summarizes the sCRC. In sCRCs, the most pathologically advanced cancer differences between patients with solitary CRC and pa- was designated as the index tumor. When more than one tients with sCRC. Three factors were statistically sig- tumor were diagnosed with identical pathological stage, the nificant in these univariate analyses: gender (P = 0.044), largest one was considered the index tumor and the other age (P = 0.028), and tumor location (P = 0.031). Other lesions were considered the companion tumors. clinicopathogical features such as tumor size, T stage, Colonoscopy was used as standard a preoperative sur- tumor differentiation, status of lymph node metastasis veillance of the whole colon [23]. Some patients harbored status, and frequency of extracolonic malignancies were advanced tumors which prevented the advance of the col- not different between sCRC and solitary CRC. Overall onoscope to more proximal colon, i.e., impassable stenosis. survival of sCRC patients was also similar to that of These patients received an alternative surveillance modality, solitary CRC patients (P = 0.62) (Fig. 1). Multivariate lo- e.g., 3DCT, barium enema study, colonoscopy after self- gistic regression analysis using gender, age, and tumor expanding metallic stent (SEMS) placement across the location as explanatory variables confirmed that these obstructing lesion, or intraoperative colonoscopy. three factors independently associated with sCRCs risk Tumor stage was defined according to the tumor, lymph (Table 2). When patients were stratified according to nodes, and metastasis (TNM) classification of the American gender, both age and tumor location retained statistical Joint Committee on Cancer (6th edition) [24]. Tumor lo- significance in women but not in men (Table 2). cation was classified into three groups as follows: right colon (appendix, cecum, ascending, hepatic flexure, and Incidence of sCRCs is not explained by stochastic transverse colon), left colon (splenic flexure, descending, accumulation of lesions sigmoid, and rectosigmoid junction), and rectum. The incidence of sCRC among patients (84 in 1005) was more than twofold higher than predicted by purely sto- Ethics approval and consent to participate chastic accumulation of cancerous lesions considering the In this retrospective study, anonymized clinical informa- reported CRC incidence in the Japanese population [28], tion from patients from the Saitama Medical Center, after adjusting by age and gender (standardized incidence Jichi Medical University, was employed. The study was ratio (SIR) = 2.2; confidence interval (CI) = 1.75–2.69; P = −10 approved by the Research Ethics Committee at Saitama 2.1 × 10 ). Moreover, among the 84 sCRC patients, 16 Medical Center, Jichi Medical University, complying with had 3 or more sCRC, an incidence 2.3-fold higher than the ethical guidelines of the Declaration of Helsinki [25]. expected under the assumption that sCRC lesions would occur independently with the probability of 0.084 per Statistical analysis cancer (expected = 7; CI = 2–13; binomial distribution; −4 Categorical variables were compared using Fisher’s exact P =9.4 ×10 ). A more refined analysis adjusting by age test. Continuous variables were compared using t test (in 10-year bins) and gender confirmed a 2.2-fold higher Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 3 of 8 Table 1 Clinical and pathological characteristics of patients with Incidence of sCRC in older vs. younger patients solitary vs. synchronous CRC Familial CRC has been associated with a higher incidence Solitary CRC Synchronous CRC P value* of sCRC [13]. Self-reported familial cases were excluded from our analyses (see the “Methods” section). However, (921 cases; (84 cases; 8.4 %) 93.6 %) the proportion of HNPCC cases among the initially re- Gender (male/female), no. 575/346 62/22 0.044 cruited 1022 patients was very low (n = 1, 0.1 %), even for the Japanese population [8]. In the self-reported 1005 Mean age, years ± SD 67.1 ± 11.3 70.3 ± 9.5 0.028† non-familial cases included in the analysis, there were 73 Follow-up months ± SD 44.6 ± 19.5 41.6 ± 18.7 0.097† patients (7.3 %) younger than 50 years (Additional file 1: Location of solitary 0.031‡ Figure S1), a few of which could correspond to unreported Right side 308 (33.4 %) 26 (31.0 %) cases with family history of cancer. To assess whether the Left side 282 (30.6 %) 37 (44.0 %) inclusion of these patients might be associated with the Rectum 331 (35.9 %) 21 (25.0 %) high incidence of sCRC found in our study, we compared the sCRC incidence in patients older vs. younger than Average size; mm ± SD 44.4 ± 25.6 43.8 ± 19.0 0.55† 50 years. Notably, sCRC incidence was higher in older T factor 0.26† (83/932, 8.9 %) than in younger (1/73, 1.4 %) patients Tis 32 (3.5 %) 0 (odds ratio (OR) = 7.03; CI = 1.2–284.9, P = 0.02). Similar T1 94 (10.2 %) 7 (8.3 %) results were obtained when cutting at a higher age thresh- T2 136 (14.8 %) 12 (14.3 %) old of 60 years: 75/786 (9.5 %) in older vs. 9/219 (4.1 %) in T3 443 (48.1 %) 49 (58.3 %) younger patients (OR = 2.46; CI = 1.2–5.7; P =0.008). T4 213 (23.1 %) 16 (19 %) Diagnosis and treatments of patients with sCRCs No residual/uncertain§ 3 (0.3 %) 0 The vast majority of the sCRCs were diagnosed preopera- Differentiation 0.25 tively (n = 185, 95.9 %), either by standard preoperative pap + wel + mod 883 (95.9 %) 83 (98.8 %) colonoscopy (n = 179, including the 84 index lesions and poor + muc + sig 38 (4.1 %) 1 (1.2 %) 94 synchronous lesions), by barium enema (three tumors Lymph node metastasis 0.81 in two patients), 3DCT (two tumors in two patients), or by intraoperative colonoscopy (one tumor in one patient). N0 573 (62.2 %) 51 (60.7 %) SEMS were placed in six stenotic patients, but none of N1/2/3/4 348 (37.8 %) 33 (39.3 %) them were found to harbor sCRCs. Only eight sCRCs Stage, no. 0.45 (4.1 %) were incidentally identified by postoperative 0 32 (3.2 %) 0 pathological analysis in four patients (Table 3). I 185 (18.4) 15 (17.9 %) Secondary, tertiary, or quaternary sCRCs were signifi- II 322 (35.0 %) 31 (36.9 %) cantly smaller and less advanced than the index tumor (Table 3). sCRCs tended to occur in the same surgical seg- III 270 (29.3 %) 26 (31.0 %) ment, with a fair to good association (K =0.30, P = 0.0001) IV 112 (12.2 %) 12 (14.3 %) (Table 4). However, 43 patients (51.2 %) developed sCRCs Survival ratio 0.62|| in different surgical segments. 3 years 83.1 % 81.0 % sCRCs were treated by endoscopy (36 tumors in 24 5 years 75.7 % 74.5 % patients), by standard surgery (125 in 69 patients) or by Extracolonic malignancies 0.85 extended surgery (32 tumors in 15 patients). All patients in which endoscopical resection of the companion sCRCs No 828 (89.9 %) 75 (89.3 %) was performed subsequently underwent standard surgery Yes 93 (10.1 %) 9 (10.7 %) for the resection of the index lesion (Table 3). We found Values in parentheses are percentages unless indicated otherwise no difference in survival between patients who underwent Italicized data, P values <0.05 *Fisher’s exact test extended surgery compared to patients with standard Mann–Whitney test || surgery (P = 0.91). Log-rank test Significance between the rectum and left side Numbers of no residual/uncertain were not included in the calculation Examination and treatment of patients with impassable stenosis In this series, 139 patients harbored locally advanced risk of additional companion carcinomas in patients that tumors in the left colon or rectum narrowing the lumen already harbored one index sCRC (SIR = 2.16; CI = 1.43– and preventing the passage of the colonoscope (impass- −4 3.14; P =6×10 ). able stenosis), thus hampering the detection of possible Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 4 of 8 Fig. 1 Overall survival of CRC patients with solitary (in black) or synchronous CRCs (in red)(P = 0.62, log-rank test) sCRCs developing at more proximal locations. Of these, series [4–20] and significantly higher than expected by 54 patients received 3DCT analysis and one synchronous stochastic accumulation of cancerous lesions considering tumor was detected, 53 patients underwent barium enema the incidence of CRC in the general population of Japan −10 study and two synchronous tumors were found, four (SIR = 2.2; CI = 1.75–2.69; P =2.1 ×10 ). In this regard, underwent colonoscopy after SEMS placement across the our data is consistent with the long-standing but still obstructing lesion and no synchronous tumors were found, unresolved observation that cancer patients are at higher and five underwent intraoperative colonoscopy and one risk of developing second independent malignancies that synchronous tumor was found. The other 23 patients could cancer-naïve individuals [29]. Moreover, the incidence of not receive any additional analysis of the proximal colon. In triple or more sCRC patients in our study (16 in 1005, these patients, three synchronous tumors were incidentally 1.6 %) was significantly higher than previously reported −4 found by pathological reports after surgery. In total, only (0.1–0.7 %, P =9.6 × 10 ) [9, 10, 13–15, 18] and 2.2-fold four of the 139 (2.9 %) distal-stenotic CRC patients devel- higher than expected by stochastic accumulation of in- oped sCRCs in the proximal colon. dependent cancers. Thus, patients who developed one sCRC were at increased risk of developing additional Discussion synchronous malignancies. The higher propensity to de- The incidence of sCRC (8.4 %) in our group of 1005 CRC velop independent cancers in cancer patients compared patients is higher than that found in most of previous with the general population, and within them the exist- ence of patients with even higher propensity to multiple Table 2 Multivariate logistic regression analysis of risk factors CRCs, further supports that genetic and environmental for the development of synchronous CRC risk factors, and not only stochastic molecular mecha- Group Factor Odds ratio (95 % CI) P value nisms, underlie cancer susceptibility [30]. All patients (n = 1005) Gender (male) 1.67 (1.02–2.84) 0.047 Age at diagnosis was an independent risk factor for the occurrence of sCRC when considering men and women Age 1.03 (1.01–1.05) 0.009 together (Table 2). This observation is also in agreement Location (left) 1.78 (1.12–2.81) 0.013 with most previous reports [15, 17, 19, 20]; however, some Men (n = 637) Age 1.02 (0.99–1.05) 0.16 reports did not find an association, or even found a reverse Location (left) 1.60 (0.93–2.72) 0.08 association, between age and synchronous CRC develop- Women (n = 368) Age 1.06 (1.02–1.11) 0.010 ment [9, 11]. Notably, when stratifying the patients accord- Location (left) 2.62 (1.05–6.41) 0.035 ing to gender, we found that age was a stronger risk factor In italics, P values <0.05 in womenthaninmen (Table 2).Tothe best of our Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 5 of 8 Table 3 Pathological findings, surveillance, and treatment methods of synchronous CRC patients Index S2 S3 S4 S5 Number of patients 84 84 16 8 1 Location of tumor Right side 26 31.0 %) 31 (36.9 %) 3 (18.8 %) 1 (12.5 %) 1 Left-side 37 (44.0 %) 37 (44.0 %) 10 (62.5 %) 7 (87.5 %) 0 Rectum 21 (25.0 %) 16 (19.0 %) 3 (18.8 %) 0 0 P value 0.58 0.47 0.081 Average size, mm ± SD 43.8 ± 19.0 23.9 ± 15.1 18.0 ± 8.3 14.9 ± 1.5 15 P value* <0.001 <0.001 <0.001 N.A. T stage Tis 0 (0 %) 39 (46.4 %) 11 (68.8 %) 6 (75 %) 1 T1 7 (8.3 %) 23 (27.4 %) 4 (25 %) 1 (12.5 %) 0 T2 12 (14.3 %) 8 (9.5 %) 1 (6.25 %) 0 0 T3 49 (58.3 %) 10 (11.9 %) 0 0 0 T4 16 (19 %) 1 (1.2 %) 0 0 0 No residual/uncertain 0 3 (3.6 %) 0 1 (12.5 %) 0 P value <0.001 <0.001 <0.001 N.A. Histological type pap + well + mod 83 (98.8 %) 81 (96.4 %) 14 (87.5 %) 6 (75 %) 0 poor + muc + sig 1 (1.2 %) 0 0 0 0 Others/no residual/uncertain† 0 3 (3.6 %) 2 (12.5 %) 2 (25 %) 1 P value 1 1 1 N.A. Diagnosis methods Endoscopy (pre-op) 84 (100 %) 75 (89.3 %) 12 (75 %) 7 (87.5 %) 1 3DCT 0 2 (2.4 %) 0 0 0 Barium enema study 0 2 (2.4 %) 1 (6.25 %) 0 0 Endoscopy (intra-op) 0 1 (1.2 %) 0 0 0 Post-op pathologically 0 4 (4.8 %) 3 (18.8 %) 1 (12.5 %) 0 Treatment methods Endoscopic resection 0 24 (28.6 %) 6 (37.5 %) 5 (62.5 %) 1 Normal surgery 69 (82.1 %) 45 (53.6 %) 9 (56.3 %) 2 (25 %) 0 Extended surgery 15 (17.9 %) 15 (17.9 %) 1 (6.25 %) 1 (12.5 %) 0 Values in parentheses are percentages unless otherwise indicated P values were calculated comparing to index tumor using Fisher’s exact test except for *Mann–Whitney test In italics, P values <0.05 Numbers of others/no residual/uncertain were not included in the calculation knowledge, no previous report mentioned this gender dis- parity in the association between age and sCRC risk. CRC patients with family history of cancer have a higher predisposition to develop sCRC [13]. In our study, all pa- tients with self-reported or diagnosed familial syndromes Table 4 Location of index and companion synchronous CRCs were excluded (FAP or HNPCC, see the “Methods” sec- Companion synchronous tumor location tion). However, the information regarding family history Index tumor location Right colon Left colon Rectum K was essentially based on self-reported, possibly inaccurate, Right colon (n = 26) 17 11 2 testimonials from the patients. Due to the retrospective Left colon (n = 37) 10 35 8 design, we could not obtain more detailed and accurate Rectum (n = 21) 8 9 9 0.30 information. The incidence of confirmed HNPCC in our Unweighted Cohen’s kappa: P = 0.0001 series was 0.1 %, which is low even when considering that Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 6 of 8 the incidence of HNPCC has been reported to be as low Among 1005 cases, total colonoscopy could not be per- as 0.4 % in Japan [8], certainly much lower than in North formed in 227 patients (22.6 %) due to impassable stenosis. American or European populations (1–3 %) [8, 31, 32]. This was not a serious concern when occurring in the It is therefore possible that a few individuals classified right side colon (n = 88), because the whole proximal as non-familial cases were actually undiagnosed HNPCC colon would be resected during the standard surgical patients. right hemicolectomy. When the advanced lesion was We then analyzed the incidence of sCRC in patients located in left colon or rectum (n = 139), however, the older vs. younger than 50 years, taking into account that patients underwent other modality of surveillance to most HNPCC patients develop CRC before that age decide the most appropriate surgical treatment. Among [31, 33]. Notably, the incidence of sCRC was higher in these patients, sCRCs were detected in the proximal older patients (OR = 7.03; CI = 1.2–284.9, P =0.02). In colon of five patients: in two cases by using 3DCT, one addition, HNPCC tumors preferentially develop in the by barium study, one by intraoperative colonoscopy, right side colon, but in our study, most of the sCRCs and one was incidentally detected in the post-surgery (68.4 %) developed in the left colon or rectum. Taking pathological analysis. Since there are some difference of these observations together, it seems unlikely that the detection rate among 3DCT, barium enema, and colon- high sCRC incidence found in our series was due to inad- oscopy [38], we confess the possibility that some sCRC vertently inclusion of familial CRC patients in the study. might have been missed among the patients with im- Previous studies reported that sCRC develops in the passable stenosis. right colon more frequently than solitary CRC, although The prognosis of patients with sCRC, compared with this association has not been confirmed in other studies patients with solitary CRC, is unclear. It has been docu- [7, 12]. In our series, we found no difference in the fre- mented to be better, the same, or worse, depending on the quency of solitary vs. synchronous CRCs developing in study [15, 39]. This variation is likely caused by differences the right colon. However, we found a higher incidence of in sample size, length of follow-up, and other factors such sCRCs in the left colon (comprising descending and sig- as different proportion of advanced vs. early tumors and, moid colon) and a lower incidence in the rectum (Table 1). therefore, needs to be interpreted with caution. In our In our series, sCRCs often developed closely to each other, study, we found no difference in tumor size, stage, differ- facilitating in some cases clinical and pathological detec- entiation, or in survival rates between solitary and sCRC tion (Table 4). However, 43 patients (51 %) harbored patients (Table 1). The most important complications sCRCs in separate surgical segments, a proportion that is associated with sCRC in comparison with solitary CRC in line with previous findings (43 to 78 %) [6, 34]. In 28 of derive mainly from the higher propensity of these pa- these patients, sCRCs could be resected by endoscopy tients to develop metachronous tumors [40] as well as combined with standard surgery. In the remaining 15 the possibility of overlooking small or difficult to access patients, however, extended surgery was performed to synchronous lesions that might later develop into more resect all the lesions. advanced cancers. We found no significant differences in size or stage between the sCRC index lesions (the larger and more Conclusions advanced among the sCRCs) and solitary cases (Table 1). We show that the sCRC incidence is higher than that of On the other hand, the companion sCRCs were smaller most previous reports. Triple or more sCRCs were also and less advanced than both the index lesions (Table 3) detected more frequently than in previous studies. We and the solitary tumors, in agreement with previous re- studied a relatively large consecutive series of CRC pa- ports [5, 9, 16, 34]. Small or early CRCs are more likely to tients that, in contrast with other reports, underwent be overlooked in the preoperative surveillance [35, 36]. throughout perioperative examination by several comple- Some of the tumors found during the postoperative mentary methodologies to minimize the accidental over- follow-up (metachronous) might be in fact overlooked looking of sCRC lesions. Since false positives are absent in sCRCs, although it is difficult to distinguish metachro- our study, as all identified lesions were histologically nous and sCRC with precision [37]. proven, it seems more likely that the lower frequency re- A common reason why synchronous lesions may be ported is due to the presence of false negatives in some missed is impassable stenosis due to large tumors in the previous studies. Ethnic factors may also influence the distal side of colon, preventing the lesions in the prox- actual incidence differences, and a further examination of imal colon from being examined [7]. If a patient cannot this issue is warranted. undergo complete examination of the large bowel before Our results strengthen the importance of a thorough, the surgery, colonoscopy analysis is required during, or extensive examination to avoid overlooking small or early- as soon as possible after surgery: otherwise, the overlooked staged synchronous lesions. When the locally advanced tumors might advance and reach an unresectable status. tumor narrows the lumen and prevents the passage of the Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 7 of 8 colonoscope, it is recommended to analyze the prox- Institució Catalana de Recerca i Estudis Avançats (ICREA), Catalan Institution for Research and Advanced Studies, Pg. Lluís Companys 23, 08010 Barcelona, imal colon by other methodologies in order to decide Spain. the most appropriate surgical procedure. Patients that cannot undergo complete colon surveillance need to be Received: 4 May 2016 Accepted: 18 October 2016 studied as soon as possible after surgery to rule out the existence of sCRCs. References Our results are also valuable at a more fundamental 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer level, showing that the sCRC incidence cannot be explained statistics. CA Cancer J Clin. 2011;61:69–90. just by the stochastic accumulation of individual cancerous 2. Sung JJ, Lau JY, Goh KL, Leung WK, Asia Pacific Working Group on Colorectal C. Increasing incidence of colorectal cancer in Asia: implications lesions and consequently of the underlying somatic cancer- for screening. Lancet Oncol. 2005;6:871–6. driving genomic alterations. We conclude that this can 3. 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A prospective cohort study shows unique epigenetic, genetic, and prognostic features of synchronous colorectal cancers. Gastroenterology. 2009;137:1609–20. e1-3. Submit your next manuscript to BioMed Central 40. Kato T, Alonso S, Muto Y, Perucho M, Rikiyama T. Tumor size is an and we will help you at every step: independent risk predictor for metachronous colorectal cancer. Oncotarget. 2016;7:17896–904. • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png World Journal of Surgical Oncology Springer Journals

Clinical characteristics of synchronous colorectal cancers in Japan

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2016 The Author(s).
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Abstract

Background: Incidence and clinical characteristics of synchronous colorectal cancer (sCRC) patients significantly vary among studies, likely due to differences in surveillance methodology. If remain undetected, sCRC can progress to more advanced stages seriously aggravating patient prognosis. We studied the incidence and clinicopathological characteristics of Japanese patients with sCRCs who underwent surgery for primary CRC and received exhaustive perioperative surveillance. Methods: We recruited 1005 patients with surgically resected CRCs between January 2007 and December 2011. The associations of clinical and pathological factors with sCRC development were assessed by univariate and multivariate logistic regression. Results: Eighty-four patients (8.4 %) developed sCRCs, 16 of them (19.0%)harboring threeormorecancers.Companion sCRCs were smaller and earlier stage than the index lesion (P < 0.0001). In multivariate analysis, advanced age (odds ratio (OR) 1.03 per year; P = 0.009) and left colon tumor location (OR 1.78; P = 0.013) are associated with higher risk of sCRCs, particularly in females. Overall survival did not differ between solitary CRC and sCRC (P =0.62). Conclusions: Our results highlight the importance of perioperative colonoscopy examination to ensure the absence of sCRCs that, being small and early staged, are more difficult to detect. The incidence of sCRC, and notably of triple or more sCRCs, was higher than previously recognized. Because they are also significantly higher than expected by merely stochastic accumulation of individual cancerous lesions, we suggest that the occurrence of many sCRC reflects a hitherto uncharacterized predisposition condition. Keywords: Colorectal cancer, Synchronous colorectal cancer, Multiple colorectal cancers, Surgical resection, Colon stenosis Background 8.1 %, with only small size studies reporting an incidence Colorectal cancer (CRC) is the second and third cause higher than 4 % [4–20]. of cancer death in male and female, respectively, in de- Well-established risk factors for sCRC development veloped countries [1]. Although CRC incidence in Japan are familial CRC syndromes, ulcerative colitis, and micro- and other Asian countries is lower than in western satellite instability (MSI) [13, 21]. A preoperative precise countries, during the last few decades, it has been rapidly diagnosis of sCRC is essential, because it may influence increasing, according to recent reports from the World clinical decision-making regarding the type and extension Health Organization [2, 3]. The incidence of synchronous of the surgical procedure as well as the use of additional CRC (sCRC) has been estimated to range between 1.1 and treatments. Furthermore, if overlooked, synchronous tu- mors may require additional surgery and might grow into more advanced stages ultimately leading to the develop- * Correspondence: [email protected] ment of distant metastases. Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan The aim of this study was to investigate the incidence Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut rate of sCRCs in a consecutive series of non-familial d’investigació en ciéncies de la salut Germans Trias I Pujol (IGTP), Campus Japanese CRC patients and determine the clinical and Can Ruti, 08916 Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 2 of 8 pathological features of patients developing sCRCs, to esti- for those exhibiting a normal distribution, or Wilcoxon- mate the relative contribution of the different risk factors. Mann–Whitney test for those that deviated from a normal distribution. Deviation from normality was determined by Methods Shapiro’s test. Differences in survival were studied using Patients Cox’s proportional hazards regression model. Differences We reviewed 1022 consecutive patients that underwent were considered statistically significant at P < 0.05. The surgery for primary CRC in Saitama Medical Center, Jichi concordance between locations of sCRCs for the same Medical University, between January 2007 and December individual was analyzed using Kappa (K) statistic. Ac- 2011. Seventeen cases were excluded from the analysis, curacy was considered poor when K waslessthan0.20, including suspected familial adenomatous polyposis syn- fair to good when K was between 0.20 and 0.40, and drome (FAP, n = 4), hereditary nonpolyposis colorectal good when K was larger than 0.40 [15]. All statistical cancer (HNPCC, n = 1), patients with history of previous analyses were performed using R (ver.3.1.2.) [26] and CRC (n = 9), and patients with ulcerative colitis (n =3). OpenEpi web server [27]. The remaining 1005 patients were included in this study. Mean patient age was 67.4 ± 11.2 years and mean follow- Results up interval was 44.3 ± 19.5 months. Clinical and pathological features of sCRCs In this study, only cancerous lesions histologically proven Among 1005 patients who underwent surgery for CRC, were considered. Multiple CRC was defined according to 84 patients (8.4 %) developed sCRCs (Table 1). Of these, the criterion of Moertel et al. [22]: a pathologically proven 16 patients (19.0 %) harbored triple or more sCRCs as adenocarcinoma and distinctly separated from the previous follows: triple sCRCs occurred in eight patients, quadruple line of anastomosis. Cancers diagnosed within 6 months in seven, and quintuple in one. In total, 193 sCRCs were before or after the initial diagnosis were considered as detected in these 84 patients. Table 1 summarizes the sCRC. In sCRCs, the most pathologically advanced cancer differences between patients with solitary CRC and pa- was designated as the index tumor. When more than one tients with sCRC. Three factors were statistically sig- tumor were diagnosed with identical pathological stage, the nificant in these univariate analyses: gender (P = 0.044), largest one was considered the index tumor and the other age (P = 0.028), and tumor location (P = 0.031). Other lesions were considered the companion tumors. clinicopathogical features such as tumor size, T stage, Colonoscopy was used as standard a preoperative sur- tumor differentiation, status of lymph node metastasis veillance of the whole colon [23]. Some patients harbored status, and frequency of extracolonic malignancies were advanced tumors which prevented the advance of the col- not different between sCRC and solitary CRC. Overall onoscope to more proximal colon, i.e., impassable stenosis. survival of sCRC patients was also similar to that of These patients received an alternative surveillance modality, solitary CRC patients (P = 0.62) (Fig. 1). Multivariate lo- e.g., 3DCT, barium enema study, colonoscopy after self- gistic regression analysis using gender, age, and tumor expanding metallic stent (SEMS) placement across the location as explanatory variables confirmed that these obstructing lesion, or intraoperative colonoscopy. three factors independently associated with sCRCs risk Tumor stage was defined according to the tumor, lymph (Table 2). When patients were stratified according to nodes, and metastasis (TNM) classification of the American gender, both age and tumor location retained statistical Joint Committee on Cancer (6th edition) [24]. Tumor lo- significance in women but not in men (Table 2). cation was classified into three groups as follows: right colon (appendix, cecum, ascending, hepatic flexure, and Incidence of sCRCs is not explained by stochastic transverse colon), left colon (splenic flexure, descending, accumulation of lesions sigmoid, and rectosigmoid junction), and rectum. The incidence of sCRC among patients (84 in 1005) was more than twofold higher than predicted by purely sto- Ethics approval and consent to participate chastic accumulation of cancerous lesions considering the In this retrospective study, anonymized clinical informa- reported CRC incidence in the Japanese population [28], tion from patients from the Saitama Medical Center, after adjusting by age and gender (standardized incidence Jichi Medical University, was employed. The study was ratio (SIR) = 2.2; confidence interval (CI) = 1.75–2.69; P = −10 approved by the Research Ethics Committee at Saitama 2.1 × 10 ). Moreover, among the 84 sCRC patients, 16 Medical Center, Jichi Medical University, complying with had 3 or more sCRC, an incidence 2.3-fold higher than the ethical guidelines of the Declaration of Helsinki [25]. expected under the assumption that sCRC lesions would occur independently with the probability of 0.084 per Statistical analysis cancer (expected = 7; CI = 2–13; binomial distribution; −4 Categorical variables were compared using Fisher’s exact P =9.4 ×10 ). A more refined analysis adjusting by age test. Continuous variables were compared using t test (in 10-year bins) and gender confirmed a 2.2-fold higher Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 3 of 8 Table 1 Clinical and pathological characteristics of patients with Incidence of sCRC in older vs. younger patients solitary vs. synchronous CRC Familial CRC has been associated with a higher incidence Solitary CRC Synchronous CRC P value* of sCRC [13]. Self-reported familial cases were excluded from our analyses (see the “Methods” section). However, (921 cases; (84 cases; 8.4 %) 93.6 %) the proportion of HNPCC cases among the initially re- Gender (male/female), no. 575/346 62/22 0.044 cruited 1022 patients was very low (n = 1, 0.1 %), even for the Japanese population [8]. In the self-reported 1005 Mean age, years ± SD 67.1 ± 11.3 70.3 ± 9.5 0.028† non-familial cases included in the analysis, there were 73 Follow-up months ± SD 44.6 ± 19.5 41.6 ± 18.7 0.097† patients (7.3 %) younger than 50 years (Additional file 1: Location of solitary 0.031‡ Figure S1), a few of which could correspond to unreported Right side 308 (33.4 %) 26 (31.0 %) cases with family history of cancer. To assess whether the Left side 282 (30.6 %) 37 (44.0 %) inclusion of these patients might be associated with the Rectum 331 (35.9 %) 21 (25.0 %) high incidence of sCRC found in our study, we compared the sCRC incidence in patients older vs. younger than Average size; mm ± SD 44.4 ± 25.6 43.8 ± 19.0 0.55† 50 years. Notably, sCRC incidence was higher in older T factor 0.26† (83/932, 8.9 %) than in younger (1/73, 1.4 %) patients Tis 32 (3.5 %) 0 (odds ratio (OR) = 7.03; CI = 1.2–284.9, P = 0.02). Similar T1 94 (10.2 %) 7 (8.3 %) results were obtained when cutting at a higher age thresh- T2 136 (14.8 %) 12 (14.3 %) old of 60 years: 75/786 (9.5 %) in older vs. 9/219 (4.1 %) in T3 443 (48.1 %) 49 (58.3 %) younger patients (OR = 2.46; CI = 1.2–5.7; P =0.008). T4 213 (23.1 %) 16 (19 %) Diagnosis and treatments of patients with sCRCs No residual/uncertain§ 3 (0.3 %) 0 The vast majority of the sCRCs were diagnosed preopera- Differentiation 0.25 tively (n = 185, 95.9 %), either by standard preoperative pap + wel + mod 883 (95.9 %) 83 (98.8 %) colonoscopy (n = 179, including the 84 index lesions and poor + muc + sig 38 (4.1 %) 1 (1.2 %) 94 synchronous lesions), by barium enema (three tumors Lymph node metastasis 0.81 in two patients), 3DCT (two tumors in two patients), or by intraoperative colonoscopy (one tumor in one patient). N0 573 (62.2 %) 51 (60.7 %) SEMS were placed in six stenotic patients, but none of N1/2/3/4 348 (37.8 %) 33 (39.3 %) them were found to harbor sCRCs. Only eight sCRCs Stage, no. 0.45 (4.1 %) were incidentally identified by postoperative 0 32 (3.2 %) 0 pathological analysis in four patients (Table 3). I 185 (18.4) 15 (17.9 %) Secondary, tertiary, or quaternary sCRCs were signifi- II 322 (35.0 %) 31 (36.9 %) cantly smaller and less advanced than the index tumor (Table 3). sCRCs tended to occur in the same surgical seg- III 270 (29.3 %) 26 (31.0 %) ment, with a fair to good association (K =0.30, P = 0.0001) IV 112 (12.2 %) 12 (14.3 %) (Table 4). However, 43 patients (51.2 %) developed sCRCs Survival ratio 0.62|| in different surgical segments. 3 years 83.1 % 81.0 % sCRCs were treated by endoscopy (36 tumors in 24 5 years 75.7 % 74.5 % patients), by standard surgery (125 in 69 patients) or by Extracolonic malignancies 0.85 extended surgery (32 tumors in 15 patients). All patients in which endoscopical resection of the companion sCRCs No 828 (89.9 %) 75 (89.3 %) was performed subsequently underwent standard surgery Yes 93 (10.1 %) 9 (10.7 %) for the resection of the index lesion (Table 3). We found Values in parentheses are percentages unless indicated otherwise no difference in survival between patients who underwent Italicized data, P values <0.05 *Fisher’s exact test extended surgery compared to patients with standard Mann–Whitney test || surgery (P = 0.91). Log-rank test Significance between the rectum and left side Numbers of no residual/uncertain were not included in the calculation Examination and treatment of patients with impassable stenosis In this series, 139 patients harbored locally advanced risk of additional companion carcinomas in patients that tumors in the left colon or rectum narrowing the lumen already harbored one index sCRC (SIR = 2.16; CI = 1.43– and preventing the passage of the colonoscope (impass- −4 3.14; P =6×10 ). able stenosis), thus hampering the detection of possible Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 4 of 8 Fig. 1 Overall survival of CRC patients with solitary (in black) or synchronous CRCs (in red)(P = 0.62, log-rank test) sCRCs developing at more proximal locations. Of these, series [4–20] and significantly higher than expected by 54 patients received 3DCT analysis and one synchronous stochastic accumulation of cancerous lesions considering tumor was detected, 53 patients underwent barium enema the incidence of CRC in the general population of Japan −10 study and two synchronous tumors were found, four (SIR = 2.2; CI = 1.75–2.69; P =2.1 ×10 ). In this regard, underwent colonoscopy after SEMS placement across the our data is consistent with the long-standing but still obstructing lesion and no synchronous tumors were found, unresolved observation that cancer patients are at higher and five underwent intraoperative colonoscopy and one risk of developing second independent malignancies that synchronous tumor was found. The other 23 patients could cancer-naïve individuals [29]. Moreover, the incidence of not receive any additional analysis of the proximal colon. In triple or more sCRC patients in our study (16 in 1005, these patients, three synchronous tumors were incidentally 1.6 %) was significantly higher than previously reported −4 found by pathological reports after surgery. In total, only (0.1–0.7 %, P =9.6 × 10 ) [9, 10, 13–15, 18] and 2.2-fold four of the 139 (2.9 %) distal-stenotic CRC patients devel- higher than expected by stochastic accumulation of in- oped sCRCs in the proximal colon. dependent cancers. Thus, patients who developed one sCRC were at increased risk of developing additional Discussion synchronous malignancies. The higher propensity to de- The incidence of sCRC (8.4 %) in our group of 1005 CRC velop independent cancers in cancer patients compared patients is higher than that found in most of previous with the general population, and within them the exist- ence of patients with even higher propensity to multiple Table 2 Multivariate logistic regression analysis of risk factors CRCs, further supports that genetic and environmental for the development of synchronous CRC risk factors, and not only stochastic molecular mecha- Group Factor Odds ratio (95 % CI) P value nisms, underlie cancer susceptibility [30]. All patients (n = 1005) Gender (male) 1.67 (1.02–2.84) 0.047 Age at diagnosis was an independent risk factor for the occurrence of sCRC when considering men and women Age 1.03 (1.01–1.05) 0.009 together (Table 2). This observation is also in agreement Location (left) 1.78 (1.12–2.81) 0.013 with most previous reports [15, 17, 19, 20]; however, some Men (n = 637) Age 1.02 (0.99–1.05) 0.16 reports did not find an association, or even found a reverse Location (left) 1.60 (0.93–2.72) 0.08 association, between age and synchronous CRC develop- Women (n = 368) Age 1.06 (1.02–1.11) 0.010 ment [9, 11]. Notably, when stratifying the patients accord- Location (left) 2.62 (1.05–6.41) 0.035 ing to gender, we found that age was a stronger risk factor In italics, P values <0.05 in womenthaninmen (Table 2).Tothe best of our Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 5 of 8 Table 3 Pathological findings, surveillance, and treatment methods of synchronous CRC patients Index S2 S3 S4 S5 Number of patients 84 84 16 8 1 Location of tumor Right side 26 31.0 %) 31 (36.9 %) 3 (18.8 %) 1 (12.5 %) 1 Left-side 37 (44.0 %) 37 (44.0 %) 10 (62.5 %) 7 (87.5 %) 0 Rectum 21 (25.0 %) 16 (19.0 %) 3 (18.8 %) 0 0 P value 0.58 0.47 0.081 Average size, mm ± SD 43.8 ± 19.0 23.9 ± 15.1 18.0 ± 8.3 14.9 ± 1.5 15 P value* <0.001 <0.001 <0.001 N.A. T stage Tis 0 (0 %) 39 (46.4 %) 11 (68.8 %) 6 (75 %) 1 T1 7 (8.3 %) 23 (27.4 %) 4 (25 %) 1 (12.5 %) 0 T2 12 (14.3 %) 8 (9.5 %) 1 (6.25 %) 0 0 T3 49 (58.3 %) 10 (11.9 %) 0 0 0 T4 16 (19 %) 1 (1.2 %) 0 0 0 No residual/uncertain 0 3 (3.6 %) 0 1 (12.5 %) 0 P value <0.001 <0.001 <0.001 N.A. Histological type pap + well + mod 83 (98.8 %) 81 (96.4 %) 14 (87.5 %) 6 (75 %) 0 poor + muc + sig 1 (1.2 %) 0 0 0 0 Others/no residual/uncertain† 0 3 (3.6 %) 2 (12.5 %) 2 (25 %) 1 P value 1 1 1 N.A. Diagnosis methods Endoscopy (pre-op) 84 (100 %) 75 (89.3 %) 12 (75 %) 7 (87.5 %) 1 3DCT 0 2 (2.4 %) 0 0 0 Barium enema study 0 2 (2.4 %) 1 (6.25 %) 0 0 Endoscopy (intra-op) 0 1 (1.2 %) 0 0 0 Post-op pathologically 0 4 (4.8 %) 3 (18.8 %) 1 (12.5 %) 0 Treatment methods Endoscopic resection 0 24 (28.6 %) 6 (37.5 %) 5 (62.5 %) 1 Normal surgery 69 (82.1 %) 45 (53.6 %) 9 (56.3 %) 2 (25 %) 0 Extended surgery 15 (17.9 %) 15 (17.9 %) 1 (6.25 %) 1 (12.5 %) 0 Values in parentheses are percentages unless otherwise indicated P values were calculated comparing to index tumor using Fisher’s exact test except for *Mann–Whitney test In italics, P values <0.05 Numbers of others/no residual/uncertain were not included in the calculation knowledge, no previous report mentioned this gender dis- parity in the association between age and sCRC risk. CRC patients with family history of cancer have a higher predisposition to develop sCRC [13]. In our study, all pa- tients with self-reported or diagnosed familial syndromes Table 4 Location of index and companion synchronous CRCs were excluded (FAP or HNPCC, see the “Methods” sec- Companion synchronous tumor location tion). However, the information regarding family history Index tumor location Right colon Left colon Rectum K was essentially based on self-reported, possibly inaccurate, Right colon (n = 26) 17 11 2 testimonials from the patients. Due to the retrospective Left colon (n = 37) 10 35 8 design, we could not obtain more detailed and accurate Rectum (n = 21) 8 9 9 0.30 information. The incidence of confirmed HNPCC in our Unweighted Cohen’s kappa: P = 0.0001 series was 0.1 %, which is low even when considering that Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 6 of 8 the incidence of HNPCC has been reported to be as low Among 1005 cases, total colonoscopy could not be per- as 0.4 % in Japan [8], certainly much lower than in North formed in 227 patients (22.6 %) due to impassable stenosis. American or European populations (1–3 %) [8, 31, 32]. This was not a serious concern when occurring in the It is therefore possible that a few individuals classified right side colon (n = 88), because the whole proximal as non-familial cases were actually undiagnosed HNPCC colon would be resected during the standard surgical patients. right hemicolectomy. When the advanced lesion was We then analyzed the incidence of sCRC in patients located in left colon or rectum (n = 139), however, the older vs. younger than 50 years, taking into account that patients underwent other modality of surveillance to most HNPCC patients develop CRC before that age decide the most appropriate surgical treatment. Among [31, 33]. Notably, the incidence of sCRC was higher in these patients, sCRCs were detected in the proximal older patients (OR = 7.03; CI = 1.2–284.9, P =0.02). In colon of five patients: in two cases by using 3DCT, one addition, HNPCC tumors preferentially develop in the by barium study, one by intraoperative colonoscopy, right side colon, but in our study, most of the sCRCs and one was incidentally detected in the post-surgery (68.4 %) developed in the left colon or rectum. Taking pathological analysis. Since there are some difference of these observations together, it seems unlikely that the detection rate among 3DCT, barium enema, and colon- high sCRC incidence found in our series was due to inad- oscopy [38], we confess the possibility that some sCRC vertently inclusion of familial CRC patients in the study. might have been missed among the patients with im- Previous studies reported that sCRC develops in the passable stenosis. right colon more frequently than solitary CRC, although The prognosis of patients with sCRC, compared with this association has not been confirmed in other studies patients with solitary CRC, is unclear. It has been docu- [7, 12]. In our series, we found no difference in the fre- mented to be better, the same, or worse, depending on the quency of solitary vs. synchronous CRCs developing in study [15, 39]. This variation is likely caused by differences the right colon. However, we found a higher incidence of in sample size, length of follow-up, and other factors such sCRCs in the left colon (comprising descending and sig- as different proportion of advanced vs. early tumors and, moid colon) and a lower incidence in the rectum (Table 1). therefore, needs to be interpreted with caution. In our In our series, sCRCs often developed closely to each other, study, we found no difference in tumor size, stage, differ- facilitating in some cases clinical and pathological detec- entiation, or in survival rates between solitary and sCRC tion (Table 4). However, 43 patients (51 %) harbored patients (Table 1). The most important complications sCRCs in separate surgical segments, a proportion that is associated with sCRC in comparison with solitary CRC in line with previous findings (43 to 78 %) [6, 34]. In 28 of derive mainly from the higher propensity of these pa- these patients, sCRCs could be resected by endoscopy tients to develop metachronous tumors [40] as well as combined with standard surgery. In the remaining 15 the possibility of overlooking small or difficult to access patients, however, extended surgery was performed to synchronous lesions that might later develop into more resect all the lesions. advanced cancers. We found no significant differences in size or stage between the sCRC index lesions (the larger and more Conclusions advanced among the sCRCs) and solitary cases (Table 1). We show that the sCRC incidence is higher than that of On the other hand, the companion sCRCs were smaller most previous reports. Triple or more sCRCs were also and less advanced than both the index lesions (Table 3) detected more frequently than in previous studies. We and the solitary tumors, in agreement with previous re- studied a relatively large consecutive series of CRC pa- ports [5, 9, 16, 34]. Small or early CRCs are more likely to tients that, in contrast with other reports, underwent be overlooked in the preoperative surveillance [35, 36]. throughout perioperative examination by several comple- Some of the tumors found during the postoperative mentary methodologies to minimize the accidental over- follow-up (metachronous) might be in fact overlooked looking of sCRC lesions. Since false positives are absent in sCRCs, although it is difficult to distinguish metachro- our study, as all identified lesions were histologically nous and sCRC with precision [37]. proven, it seems more likely that the lower frequency re- A common reason why synchronous lesions may be ported is due to the presence of false negatives in some missed is impassable stenosis due to large tumors in the previous studies. Ethnic factors may also influence the distal side of colon, preventing the lesions in the prox- actual incidence differences, and a further examination of imal colon from being examined [7]. If a patient cannot this issue is warranted. undergo complete examination of the large bowel before Our results strengthen the importance of a thorough, the surgery, colonoscopy analysis is required during, or extensive examination to avoid overlooking small or early- as soon as possible after surgery: otherwise, the overlooked staged synchronous lesions. When the locally advanced tumors might advance and reach an unresectable status. tumor narrows the lumen and prevents the passage of the Kato et al. World Journal of Surgical Oncology (2016) 14:272 Page 7 of 8 colonoscope, it is recommended to analyze the prox- Institució Catalana de Recerca i Estudis Avançats (ICREA), Catalan Institution for Research and Advanced Studies, Pg. 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A prospective cohort study shows unique epigenetic, genetic, and prognostic features of synchronous colorectal cancers. Gastroenterology. 2009;137:1609–20. e1-3. Submit your next manuscript to BioMed Central 40. Kato T, Alonso S, Muto Y, Perucho M, Rikiyama T. Tumor size is an and we will help you at every step: independent risk predictor for metachronous colorectal cancer. Oncotarget. 2016;7:17896–904. • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit

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World Journal of Surgical Oncology – Springer Journals

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