Left-sided location is a risk factor for lymph node metastasis of T1 colorectal cancer: a single-center retrospective study

Between April 2001 and December 2018, a total of 1262 T1 CRC cases were resected endoscopically or surgically at Showa University Northern Yokohama Hospital, Japan. Written informed consent was obtained from all the patients prior to endoscopy. Our ethics committee approved the study protocol (approval number: 17H107). This study was registered with the University Hospital Medical Network Clinical Trials Registry (UMIN 000032733). Patients who underwent surgery because of a synchronous invasive carcinoma (n = 45) and those who were diagnosed with Lynch syndrome (n = 3) or ulcerative colitis (n = 6) were excluded. In some cases, detailed pathological evaluation was not possible owing to the loss of or damage to the specimen, and thus these were also excluded. Furthermore, we did not include patients who received preoperative chemotherapy or radiotherapy. In total, 1142 cases were included. Of these, 776 cases were left-sided (descending colon to rectum), and 366 cases were right-sided (cecum to transverse colon). We analyzed clinicopathological features including patient age, sex, tumor size, morphology, initial treatment, depth of invasion, histological grade, vascular invasion, lymphatic invasion, tumor budding, and lymph node metastasis (LNM). We classified tumor morphology into three types according to the Paris classification and Kudo’s classification: flat type (IIa, laterally spreading tumor), protruded type (Is, Ip, Isp), and depressed type (IIc, IIa+IIc, IIc+IIa, Is+IIc, Ip+IIc). [17] Surgical specimens were used as the standard for the presence of LNM. For patients with endoscopic resection, local lymph node recurrent cases detected by CT or MRI were defined as LNM-positive, regardless of the period. In the endoscopic resection alone group, the mean follow-up period was 41.5 ± 34.7 months (Fig. 1).

All resected specimens were retrieved and immediately fixed in a 10% buffered formalin and were observed with a focus on the pit pattern using a stereomicroscope. They were then cut at the point where the deepest invasion area could be exposed on the cut end surface. The other histological specimens were cut into parallel 2- to 3-mm-thick sections and stained with hematoxylin and eosin (H&E). Tumor size was measured after formalin fixation. All specimens were diagnosed based on the World Health Organization Classification of Tumors [18] and the current JSCCR (Japanese Society for Cancer of the Colon and Rectum) guidelines [19]. Histological grade was classified in view of the World Health Organization criteria as follows: well-differentiated adenocarcinoma, moderately differentiated adenocarcinoma, poorly differentiated adenocarcinoma (Por), and mucinous carcinoma (Muc). In this study, a Por/Muc component was considered to be present if any part of the lesion contained any of these features. Vascular invasion was diagnosed by double staining with H&E and Victoria blue (Muto Pure Chemicals Co., Ltd., Tokyo, Japan) and lymphatic invasion was diagnosed by H&E staining and immunostaining with D2-40 antibody (Dako North America Inc., Carpinteria, CA, USA). Tumor budding was defined as a cancer cell nest consisting of one to five cells at the invasive margin of the carcinoma. After selecting the field where budding was the most intensive, the number of buddings was counted with a × 20 objective lens. Depending on the number of buddings, budding grade was scored as follows: BD1, 0–4; BD2, 5–9; and BD3, ≥ 10. BD 2–3 was defined as tumor budding-positive [20, 21]. The depth of submucosal invasion was assessed according to the JSCCR classification as < 1000 μm (T1a) and ≥ 1000 μm (T1b) [19].

Nominal and ordinal variables are expressed as frequencies and percentages. Continuous variables are reported as mean ± standard deviation (SD). Continuous variables were compared using Student’s t tests, whereas dichotomous variables were compared using chi-squared or Fisher exact tests, as appropriate. Multivariate logistic regression analysis regarding LNM was subsequently performed to calculate odds ratios and 95% confidence intervals (CIs). All statistical analyses were performed using JMP Pro version 14.0.0 (SAS Institute Inc., Cary, NC, USA). All P values were two sided, and P < 0.05 was considered statistically significant.

The clinicopathological characteristics of 1142 patients are shown in Table 1. Table 2 shows the clinicopathological features of left- and right-sided T1 CRC. Left-sided T1 CRC showed significantly higher rates of LNM (left-sided 12.0% vs. right-sided 5.4%, P < 0.05) and was accompanied by higher rates of lymphatic invasion (left-sided 32.7% vs. right-sided 23.2%, P < 0.05) than right-sided T1 CRC. Left-sided T1 CRC also showed higher rates of T1b cases (left-sided 78.4% vs. right-sided 68.3%, P < 0.05) and surgical resections (left-sided 67.9% vs. right-sided 59.6%, P < 0.05). In morphology, left-sided T1 CRC showed significantly lower rates of flat type morphology (left-sided 27.6% vs. right-sided 53.0%, P < 0.05). In contrast, the protruded type was significantly more frequent in left-sided T1 CRC (left-sided 51.2% vs. right-sided 20.5%, P < 0.05). For pathological features, left-sided T1 CRC showed significantly lower rates of Por/Muc (left-sided 11.6% vs. right-sided 16.1%, P < 0.05). Patients with left-sided T1 CRC were younger (left-sided 64.9 ± 11.5 years vs. right-sided 68.7 ± 11.6 years, P < 0.05) than those with right-sided T1 CRC. No significant differences were found in the other factors.

Table 3 shows the clinicopathological features of left- and right-sided T1 CRC without the JSCCR guidelines’ curative cases, which had one or more risk factors such as lymphovascular invasion, tumor budding, Por/Muc component, or T1b. Higher rates of initial endoscopic resection, lymphatic invasion, and LNM were evident in left-sided T1 CRC.

We also compared the differences in clinicopathological features by each location in Table 4. The sigmoid colon and rectum showed higher positive rates of lymphatic invasion and tumor budding than other sites. The rectum also showed the highest rate of vascular invasion (38.9%). Patients’ age was younger in sigmoid (64.9 ± 11.2) and rectum (63.9 ± 11.5) T1 CRC. Fewer cases were operated upon in the descending colon (46.9%), whereas more cases were operated upon in the sigmoid and rectum (70.3% and 66.8%, respectively). T1 CRC of the sigmoid colon and rectum showed a higher rate of LNM (12.4% and 12.1%) than other sites. The frequency of LNM with each morphology at both locations is shown in Table 5. Sigmoid lesions of the depressed type showed the highest percentage of LNM (13.2%).

Table 6 shows the relationships between clinicopathological factors and LNM identified by univariate and multivariate logistic analyses. Left-sided location was an independent risk factor for LNM (OR, 2.42; 95% CI, 1.23–4.78). Furthermore, lymphovascular invasion, histological grade, and sex were independent risk factors for LNM in T1 CRC.

Figure 2 shows images of a typical left-sided T1 CRC case, demonstrating its lymphovascular invasion-positive, tumor budding-positive, and LNM-positive features.