Abstract
Purpose
Few studies have reported the association of macroscopic classification with clinicopathological characteristics and prognosis of ulcerative colitis-associated colorectal cancer (UC-CRC), unlike sporadic CRC. In this study, we aimed to clarify the clinical significance of macroscopic classification of UC-CRC.
Methods
The cohort included 480 patients with UC-CRC with invasion beyond the muscularis propria treated at 43 Japanese institutions between 1983 and 2023. The patients were divided into six groups based on the macroscopic type (types 0–5), and clinicopathological features and prognoses were compared.
Results
Among 480 patients, 66 (13.8%), 75 (15.6%), 116 (24.2%), 63 (13.1%), 68 (14.2%), and 92 (19.2%) had type 0–5 tumors, respectively. There were significant differences in the clinicopathological characteristics with a younger age in type 4 or 5 tumors than in type 2 tumors (p < 0.01) and a higher frequency of undifferentiated carcinomas (p < 0.01) and lymph node metastasis (p < 0.01) and more advanced depth of invasion (p < 0.01) in type 4 tumors than in type 1 or 2 tumors. Type 4 and 5 were independent risk factors for 5-year recurrence-free survival (p = 0.02; type 4 [HR: 6.35], type 5 [HR: 5.25]) and type 0, 4, and 5 for overall survival (p = 0.02; type 0 [HR: 4.51], type 4 [HR: 5.70], type 5 [HR: 4.02]).
Conclusions
Type 0, 4, and 5 tumors were characteristic macroscopic types of UC-CRC and correlated with worse prognosis. Therefore, endoscopic diagnosis of the macroscopic type of UC-CRC might be helpful in determining tumor aggressiveness.
Keywords: Ulcerative colitis, Ulcerative colitis associated cancer, Macroscopic classification, Prognosis
Introduction
There is an increasing trend in the number of patients with ulcerative colitis (UC), [1, 2] and those with longstanding UC are at a higher risk of developing colorectal cancer (CRC). [3] The prevalence of CRC among patients with UC is 8% at 20 years after the initial UC diagnosis and increases to 18% at 30 years. [4] With recent advancements in UC medications, the prevalence of surgical treatment for patients refractory to medications has reduced, whereas the prevalence of surgical indications for UC-associated CRC (UC-CRC) has increased owing to the increase in the number of longstanding UC cases. [5] With the increasing incidence of UC-CRC, it is crucial to understand its clinicopathological features.
UC-CRC has clinicopathological features that are different from those of sporadic CRC. [6, 7] When adjusted for the stage at diagnosis, UC-CRC has a worse prognosis than sporadic CRC. Pathologically, the prevalence of the undifferentiated types, such as mucinous or signet ring cell carcinomas, is higher among UC-CRC cases than among sporadic CRC cases, [8] and morphologically, the proportions of superficial- and invasive-type lesions are also higher in UC-CRC cases than in sporadic CRC cases. [6] UC-CRC and sporadic CRC have different carcinogenic pathways, and these different genetic mutation backgrounds may influence the difference in their clinicopathological characteristics. [9–12].
In Japan, macroscopic classification of CRC is routinely determined by colonoscopy. According to the Japanese Society for Cancer of the Colon and Rectum (JSCCR), [13] the main macroscopic types are superficial (type 0), polypoid (type 1), ulcerated with clear margin (type 2), ulcerated with infiltration (type 3), diffusely infiltrating (type 4), and unclassified (type 5) (Fig. 1). Lesions presume to be Tis and T1 cancers by colonoscopy are classified as type 0, and tumors considered to invade beyond the muscularis propria by colonoscopy are classified as Types 1–5.
Fig. 1.
Macroscopic types defined in the Japanese Society for Cancer of the Colon and Rectum (JSCCR). The yellow arrow outlines the tumor margin
The macroscopic features of tumors are readily determined using colonoscopy and can be influenced by background genetic features. The frequency of mutations in several genes, such as Kirsten rat sarcoma viral oncogene homolog (K-Ras), tumor protein p53 (TP53), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), has been reported to vary depending on the macroscopic type of CRC. [14, 15] Therefore, macroscopic classification is considered helpful in understanding the underlying carcinogenesis of CRC, which can influence the clinicopathological features of CRC.
Additionally, macroscopic classification is reported to be an independent risk factor for recurrence of sporadic CRC and is associated with poor survival in patients; however, few studies exist on the association of macroscopic classification with clinicopathological characteristics and prognosis of UC-CRC. [16, 17] Thus, in this study, we aimed to clarify the differences in clinicopathological characteristics and oncological prognoses among the macroscopic types of UC-CRC using a large multicenter cohort.
Method
Patients
This study was reported in accordance with the STROBE guidelines. The medical records of patients with UC diagnosed with CRC between 1983 and 2023 were retrospectively collected from 43 institutions, including surgery and gastroenterology departments, within the JSCCR. The data were sent to the Department of Surgical Oncology at the University of Tokyo for further analysis. Cancer stage was determined according to the Tumor-Node-Metastasis Classification of Malignant Tumors, 8th Edition, of the Union for International Cancer. [18] Among 1249 patients with UC-CRC, those with early cancer, including pTis (pathologically, the tumor is confined to the mucosa and does not invade the submucosa) or pT1 (pathologically, the tumor is confined to the SM and does not invade the muscularis propria) [13] cancer, unclear macroscopic type, or sporadic CRC were excluded. Therefore, 480 patients with UC-CRC were retrospectively analyzed (Fig. 2). Baseline information on patient characteristics, treatment details, histopathological findings, and long-term oncological outcomes was collected. The patients were divided into six groups based on macroscopic types defined in the Japanese classification [13, 19]: Types 0–5. In patients with multiple lesions, only the most advanced lesions were analyzed. Factors compared among the six groups were: sex, age at UC diagnosis, disease duration, the extent of inflammation, age at UC-CRC diagnosis, the primary site of the main tumor, depth of the main tumor, lymph node metastasis, pathological stage (pStage), lymphatic or venous invasion, histology, and concurrent dysplasia. Excluding pStage IV and non-curative resection cases, 5-year recurrence-free survival (RFS) and overall survival (OS) rates were also compared.
Fig. 2.
Flow diagram of patient inclusion
Statistical analysis
Statistical analyses were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC, USA). Categorical variables were compared using Pearson’s chi-square test, whereas continuous variables were categorized into six groups using analysis of variance. Survival analysis was performed using the Kaplan–Meier method and compared using the log-rank test. Variables with p < 0.1 in univariate analyses were subjected to multivariate Cox proportional hazards analyses to generate hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical significance was set at p < 0.05. Owing to the retrospective registration of patient data, there were missing data in the dataset. As the percentage of missing data for most variables was < 10%, we excluded missing data for each analysis in this study.
Results
Clinical characteristics
Patients’ clinicopathological features are presented in Table 1. Among the 480 patients, 13.8%, 15.6%, 24.2%, 13.1%, 14.2%, and 19.2% had type 0, 1, 2, 3, 4, and 5 tumors, respectively. Patients with type 0, 3, 4 or 5 were significantly younger than those with type 2 (type 0: p = 0.01, type 3, 4, 5: p < 0.01). Similarly, the median ages at CRC diagnosis of patients with type 0, 1, 3, 4, or 5 was also significantly younger than those with type 2 (type 0, 1: p = 0.03, type 3, 4, 5: p < 0.01). No significant differences in sex, duration of UC, extent of inflammation, and the primary site of the main tumor were observed among the tumor types.
Table 1.
Clinicopathological features of patients with UC-CRC according to the macroscopic classification of tumors
| Variable | Type 0 (n = 66) | Type 1 (n = 75) | Type 2 (n = 116) | Type 3 (n = 63) | Type 4 (n = 68) | Type 5 (n = 92) | p | |
|---|---|---|---|---|---|---|---|---|
| Age at diagnosis of UC, years | Median (IQR) | 32.9 (22–45) | 35.9 (23–48) | 40.7 (25–53) | 30.7 (20–40) | 32.2 (21–42) | 30.5 (20–38) | < 0.01 |
| Sex, n (%) | Male | 42 (64.6%) | 48 (64.0%) | 71 (61.7%) | 38 (60.3%) | 47 (69.1%) | 54 (58.7%) | 0.82 |
| Female | 23 (35.4%) | 27 (36.0%) | 44 (38.3%) | 25 (39.7%) | 21 (30.9%) | 38 (41.3%) | ||
| Duration of UC, years | Median (IQR) | 19.3 (13–23) | 16.2 (8–21) | 16.8 (10–25) | 19.9 (13–26) | 16.7 (11–23) | 18.4 (12–25) | 0.22 |
| Extent of inflammation, n (%) | Total colitis | 54 (87.1%) | 56 (75.7%) | 86 (74.8%) | 51 (82.3%) | 54 (81.8%) | 75 (84.3%) | 0.29 |
| Left-sided colitis | 8 (12.9%) | 18 (24.3%) | 29 (25.2%) | 11 (17.7%) | 12 (18.2%) | 14 (15.7%) | ||
| Age at diagnosis of CRC, years | Median (IQR) | 51.6 (42–61) | 51.8 (44–61) | 57.6 (48–68) | 50.0 (38–59) | 48.8 (37–59) | 48.9 (41–58) | < 0.01 |
| Primary site of the main tumor, n (%) | right-side colon | 15 (22.7%) | 14 (18.7%) | 31 (26.7%) | 11 (17.5%) | 8 (11.8%) | 16 (17.8%) | 0.20 |
| left-side colon | 51 (77.3%) | 61 (81.3%) | 85 (73.3%) | 52 (82.5%) | 60 (88.2%) | 74 (82.2%) | ||
| Depth of the main tumor, n (%) | pT2 | 37 (56.1%) | 35 (46.7%) | 19 (16.4%) | 3(4.8%) | 4 (5.9%) | 20 (21.7%) | < 0.01 |
| pT3 | 27 (40.9%) | 36 (48.0%) | 78 (67.2%) | 33 (52.4%) | 29 (42.7%) | 46 (50.0%) | ||
| pT4a/T4b | 2 (3.0%) | 4 (5.3%) | 19 (16.4%) | 27 (42.9%) | 35 (51.5%) | 26 (28.3%) | ||
| Lymph node metastasis, n (%) | Absent | 53 (84.1%) | 55 (73.3%) | 63 (55.3%) | 27 (43.6%) | 22 (33.3%) | 47 (52.8%) | < 0.01 |
| Present | 10 (15.9%) | 20 (26.7%) | 51 (44.7%) | 35 (45.4%) | 44 (66.7%) | 42 (47.2%) | ||
| pStage of the main tumor, n (%) | pStageI | 31 (49.2%) | 30 (40.0%) | 16 (13.9%) | 3 (4.8%) | 4 (5.9%) | 13 (14.4%) | < 0.01 |
| pStageII | 22 (34.9%) | 25 (33.3%) | 46 (40.0%) | 23 (37.1%) | 16 (23.5%) | 31 (34.4%) | ||
| pStageIII | 10 (15.9%) | 20 (26.7%) | 46 (40.0%) | 27 (43.6%) | 27 (39.7%) | 38 (42.2%) | ||
| pStageIV | 0 (0%) | 0 (0%) | 7 (6.1%) | 9 (14.5%) | 21 (30.9%) | 8 (8.9%) | ||
| Histology, n (%) | Differentiated | 51 (81.0%) | 58 (79.5%) | 86 (76.1%) | 38 (62.3%) | 36 (53.7%) | 57 (65.5%) | < 0.01 |
| Undifferentiated | 12 (19.0%) | 15 (20.5%) | 27 (23.9%) | 23 (37.7%) | 31 (46.3%) | 30 (34.5%) | ||
| Lymphatic invasion, n (%) | Absent | 36 (54.6%) | 36 (48.0%) | 46 (39.7%) | 16 (25.4%) | 13 (19.2%) | 30 (32.6%) | < 0.01 |
| Present | 30 (45.4%) | 38 (50.7%) | 69 (59.5%) | 45 (71.4%) | 51 (75.0%) | 58 (63.0%) | ||
| Venous invasion, n (%) | Absent | 43 (65.2%) | 38 (50.7%) | 53 (45.7%) | 16 (25.4%) | 16 (23.5%) | 35 (38.0%) | < 0.01 |
| Present | 22 (33.3%) | 35 (46.7%) | 62 (53.5%) | 45 (71.4%) | 48 (70.6%) | 53 (57.6%) | ||
| Concurrent dysplasia, n (%) | Absent | 19 (29.2%) | 31 (41.9%) | 52 (46.0%) | 27 (45.8%) | 26 (39.4%) | 35 (38.9%) | 0.23 |
| Present | 42 (64.6%) | 36 (48.7%) | 49 (43.4%) | 23 (39.0%) | 30 (45.5%) | 47 (52.2%) |
Abbreviations: UC, ulcerative colitis; IQR, interquartile range; CRC, colorectal cancer
Pathological characteristics
As shown in Table 1, the pathological factors significantly differed among the macroscopic types. The depth of tumor invasion was more advanced in type 3 tumors than in type 0, 1, 2, in type 4 tumors compared to type 0, 1, 2, or 5 tumors, and in type 5 tumors compared to type 0 or 1 tumors (p < 0.01). In addition, the frequency of lymph node metastases was higher in patients with type 2 or 5 tumors than in those with type 0 (p < 0.01), in patients with type 3 tumors than in those with type 0 or 1 tumors (p < 0.01), and in patients with type 4 tumors than in those with type 0, 1 (p < 0.01) or 2 tumors (p = 0.03). As a result, the prevalence of pStage significantly differed among the groups (p < 0.01). A higher proportion of undifferentiated carcinomas was observed in patients with type 4 tumors than in those with type 0, 1, or 2 tumors. In addition, the rates of lymphatic and venous invasion were higher in patients with type 3 tumors than in those with type 0 and in patients with type 4 tumors than in those with type 0 or 1 (p < 0.01).
Prognosis
The 5-year RFS and OS rates were calculated for curatively treated non-metastatic cases, excluding pStage IV and non-curative resection cases (Fig. 2). The baseline characteristics of the 415 patients included in this cohort are presented in Table 2.
Table 2.
Baseline characteristics of patients with UC-associated colorectal cancer excluding pStageⅣ and non-curative resection cases
| Variable | Patients (n = 415) | |
|---|---|---|
| Age at diagnosis of UC, n (%) | < 59 years | 375 (90.4%) |
| ≥ 60 years | 36 (8.7%) | |
| Sex, n (%) | Male | 260 (63.0%) |
| Female | 153 (37.0%) | |
| Duration of UC, n (%) | < 10 years | 80 (19.3%) |
| ≥ 10 years | 333 (80.2%) | |
| Extent of inflammation, n (%) | Total colitis | 326 (78.6%) |
| Left-sided colitis | 78 (18.8%) | |
| Age at diagnosis for CRC, n (%) | < 59 years | 283 (68.2%) |
| ≥ 60 years | 132 (31.8%) | |
| Primary site of the main tumor, n (%) | right-side colon | 86 (20.7%) |
| left-side colon | 327 (78.8%) | |
| Macroscopic classification, n (%) | Type 0 | 64 (15.4%) |
| Type 1 | 71 (17.1%) | |
| Type 2 | 107 (25.8%) | |
| Type 3 | 49 (11.8%) | |
| Type 4 | 45 (10.8%) | |
| Type 5 | 79 (19.0%) | |
| pT Stage of the main tumor, n (%) | pT2/3 | 343 (82.7%) |
| pT4a/T4b | 72 (17.3%) | |
| Lymphatic or vascular invasion | Absent | 122 (29.4%) |
| Present | 285 (68.7%) | |
| Lymph node metastasis, n (%) | Absent | 252 (60.7%) |
| Present | 158 (38.1%) | |
| Histology, n (%) | Differentiated | 302 (72.8%) |
| Undifferentiated | 99 (23.9%) | |
| Concurrent dysplasia, n (%) | Absent | 165 (40.8%) |
| Present | 204 (50.5%) |
Abbreviation: UC, ulcerative colitis; CRC, colorectal cancer
The 5-year RFS and OS rates significantly differed among the macroscopic types (Fig. 3A and B). The 5-year RFS rates for patients with type 0, 1, 2, 3, 4, and 5 tumors were 83.2%, 93.7%, 78.4%, 74.6%, 49.7%, and 66.6%, respectively. The 5-year OS rates for patients with type 0, 1, 2, 3, 4, and 5 tumors were 92.0%, 93.4%, 82.2%, 73.7%, 57.5%, and 78.0%, respectively.
Fig. 3.
Recurrence-free survival and overall survival according to macroscopic type. Recurrence-free survival (A) and overall survival (B). Red, type 0; light green, type 1; blue, type 2; brown, type 3; green, type 4; purple, type 5
When stratified by pathological stage, in pStage I/II cancers, 5-year RFS rates for patients with type 0, 1, 2, 3, 4, and 5 were 89.8%, 93.8%, 91.2%, 82.5%, 79.0%, and 77.3%, respectively, which was not significantly different among the groups (Fig. 4A). Likewise, the 5-year OS rates were 94.5%, 93.8%, 89.2%, 79.9%, 84.9%, and 88.6%, respectively, and were not significantly different among the groups (Fig. 4B). In pStage III cancers, the 5-year RFS rates (Fig. 4C) for patients with type 0, 1, 2, 3, 4, and 5 were 29.6%, 93.3%, 65.9%, 59.5%, 32.3%, and 55.6%, respectively and 5-year OS rates (Fig. 4D) were 70.0%, 92.3%, 75.3%, 69.0%, 33.2%, and 62.8%, respectively, which were significantly different among the groups (p < 0.01).
Fig. 4.
Recurrence-free survival and overall survival according to macroscopic type adjusted for pathological stages Recurrence-free survival (A) and overall survival (B) in stage I/II UC-CRC, and recurrence-free survival (C) and overall survival (D) in stage III UC-CRC. Red, type 0; light green, type 1; blue, type 2; brown, type 3; green, type 4; purple, type 5
Subsequently, multivariate Cox proportional hazards analyses were performed for the significant factors related to RFS and OS. Regarding the RFS, differences in duration of UC (p = 0.07), extent of inflammation (p = 0.09), macroscopic features (p < 0.01), depth of the main tumor (p < 0.01), lymphatic or vascular invasion (p < 0.01), lymph node metastasis (p < 0.01), histology (p < 0.01), and concurrent dysplasia (p = 0.07) were observed in univariate analyses (Table 3). Multivariate Cox proportional hazards analyses revealed that pT4 (p = 0.02; HR: 2.22, 95% CI: 1.21–4.07]), lymph node metastasis (p < 0.01; HR: 3.65, 95% CI: 2.03–6.76), macroscopic classification (p < 0.01; type 4 HR: 6.35, 95% CI: 1.69–23.8, and type 5 HR: 5.25, 95% CI: 1.46–18.9) were independent prognostic factors for RFS (Table 3). Regarding the OS, significant differences in sex (p = 0.02), duration of UC (p = 0.02), macroscopic features (p < 0.01), depth of the main tumor (p < 0.01), lymphatic or vascular invasion (p < 0.01), lymph node metastasis (p < 0.01), and histology (p < 0.01) were observed in univariate analyses (Table 4). Multivariate Cox proportional hazards analyses revealed that lymphatic or vascular invasion (p = 0.04; HR: 2.14, 95% CI: 1.02–5.10) and lymph node metastasis (p < 0.01; HR: 2.94, 95% CI: 1.64–5.38) were independent prognostic factors for OS. Moreover, the macroscopic classifications type 0 (HR: 4.51, 95% CI: 1.20–16.9), type 4 (HR, 5.70; 95% CI, 1.81–18.0), and type 5 (HR: 4.02, 95% CI: 1.28–12.7) were independent prognostic factors for OS (p = 0.02; Table 4).
Table 3.
Univariate and multivariate analyses of risk factors for RFS
| Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|
| 5-year RFS (%) | p-Value | HR | 95% CI | p-Value | ||
| Age at diagnosis of UC | < 59 years | 76.0 | 0.20 | |||
| ≥ 60 years | 84.9 | |||||
| Sex | Male | 74.5 | 0.38 | |||
| Female | 79.0 | |||||
| Duration of UC | < 10 years | 66.2 | 0.07 | 1 | 0.29 | |
| ≥ 10 years | 79.1 | 0.71 | 0.39–1.36 | |||
| Extent of inflammation | Total colitis | 77.9 | 0.09 | 1 | 0.22 | |
| Left-sided colitis | 68.7 | 1.55 | 0.76–2.91 | |||
| Age at diagnosis of CRC | < 59 years | 73.7 | 0.11 | |||
| ≥ 60 years | 81.8 | |||||
| Primary site of the main tumor | right-side colon | 80.7 | 0.22 | |||
| left-side colon | 75.0 | |||||
| Macroscopic classification | < 0.01 | 0.02 | ||||
| Type 0 | 83.2 | 4.24 | 0.96–18.8 | |||
| Type 1 | 93.7 | 1 | ||||
| Type 2 | 79.3 | 2.76 | 0.78–9.81 | |||
| Type 3 | 70.1 | 2.28 | 0.54–9.59 | |||
| Type 4 | 52.0 | 6.35 | 1.69–23.8 | |||
| Type 5 | 66.6 | 5.25 | 1.46–18.9 | |||
| pT Stage of the main tumor | pT2/3 | 82.2 | < 0.01 | 1 | 0.02 | |
| pT4a/T4b | 48.6 | 2.22 | 1.21–4.07 | |||
| Lymphatic or vascular invasion | Absent | 88.2 | < 0.01 | 1 | 0.12 | |
| Present | 71.2 | 1.81 | 0.86–4.29 | |||
| Lymph node metastasis, n (%) | Absent | 87.2 | < 0.01 | 1 | < 0.01 | |
| Present | 58.5 | 3.65 | 2.03–6.76 | |||
| Histology, n (%) | Differentiated | 81.0 | < 0.01 | 1 | 0.61 | |
| Undifferentiated | 64.9 | 1.16 | 0.64–2.06 | |||
| Concurrent dysplasia, n (%) | Absent | 73.5 | 0.07 | 1 | 0.18 | |
| Present | 81.6 | 1.21 | 0.42–1.19 | |||
Abbreviations: UC, ulcerative colitis; CRC, colorectal cancer; RFS, recurrence-free survival; CI, confidence interval; HR, hazard ratio
Table 4.
Univariate and multivariate analyses of risk factors for OS
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| 5-year OS (%) | p-Value | HR | 95% CI | p-Value | |||
| Age at diagnosis of UC | < 59 years | 77.5 | 0.89 | ||||
| ≥ 60 years | 82.2 | ||||||
| Sex | Male | 77.4 | 0.02 | 1 | 0.03 | ||
| Female | 88.4 | 0.54 | 0.28–0.96 | ||||
| Duration of UC | < 10 years | 69.9 | 0.02 | 1 | 0.08 | ||
| ≥ 10 years | 84.6 | 0.56 | 0.31–1.08 | ||||
| Extent of inflammation | Total colitis | 82.4 | 0.35 | ||||
| Left-sided colitis | 76.3 | ||||||
| Age at diagnosis of CRC | < 59 years | 78.9 | 0.41 | ||||
| ≥ 60 years | 87.0 | ||||||
| Primary site of the main tumor | right-side colon | 90.0 | 0.13 | ||||
| left-side colon | 79.0 | ||||||
| Macroscopic classification | <0.01 | 0.02 | |||||
| Type 0 | 92.0 | 4.51 | 1.20–16.9 | ||||
| Type 1 | 93.4 | 1 | |||||
| Type 2 | 82.2 | 2.23 | 0.72–6.87 | ||||
| Type 3 | 73.7 | 2.56 | 0.72–9.06 | ||||
| Type 4 | 57.5 | 5.70 | 1.81–18.0 | ||||
| Type 5 | 78.0 | 4.02 | 1.28–12.7 | ||||
| pT Stage of the main tumor | pT2/3 | 85.4 | <0.01 | 1 | 0.13 | ||
| pT4a/T4b | 62.4 | 1.63 | 0.86–3.00 | ||||
| Lymphatic or vascular invasion | Absent | 93.7 | <0.01 | 1 | 0.04 | ||
| Present | 75.7 | 2.14 | 1.02–5.10 | ||||
| Lymph node metastasis, n (%) | Absent | 90.2 | <0.01 | 1 | <0.01 | ||
| Present | 67.0 | 2.94 | 1.64–5.38 | ||||
| Histology, n (%) | Differentiated | 86.6 | <0.01 | 1 | 0.27 | ||
| Undifferentiated | 69.5 | 1.38 | 0.77–2.41 | ||||
| Concurrent dysplasia, n (%) | Absent | 81.6 | 0.74 | ||||
| Present | 81.5 | ||||||
Abbreviations: UC, ulcerative colitis; CRC, colorectal cancer; OS, overall survival; CI, confidence interval; HR, hazard ratio
Discussion
In the present study, there was a close association between the clinicopathological characteristics and macroscopic classification of UC-CRC. Moreover, we found that macroscopic features correlated with oncological outcomes, such as RFS and OS.
First, we evaluated the distribution of the macroscopic patterns of UC-CRC. In a previous report, among sporadic CRC cases invading deeper than the submucosa, type 2 tumors were dominant and accounted for 68% of CRC cases, followed by type 3 (12%), type 1 (10%), and type 0 (8%) tumors, whereas type 4 and 5 tumors were scarce (both 1%). [6] In the present study, 13.8%, 15.6%, 24.2%, 13.1%, 14.2%, and 19.2% of patients with UC-CRC had type 0, 1, 2, 3, 4, and 5 tumors, respectively. As previously reported, UC-CRC is characterized by a lower proportion of localized ulcerative type and a higher proportion of infiltration with an ill-defined edge tumor (type 4) and non-classifiable type (type 5) than sporadic CRC. [6] Furthermore, considering that our study included only tumors developing deeper than muscularis propria and that ordinally lesions presumed to be pTis and pT1 cancers are classified as superficial (type 0), the high proportion of type 0 tumors with invasion beyond the muscularis propria is also considered to be characteristic of UC-CRC. [18] Noguchi T reported that even with annual surveillance endoscopy, 27% of patients with UC-CRC were diagnosed as having cancer with invasion beyond the muscularis propria. This is probably associated with the high prevalence of type 0 tumors with invasion beyond the muscularis propria in UC-CRC, which is difficult to detect in the early stage by surveillance endoscopy. [20]
Macroscopic features are reported to be influenced by genetic mutation patterns. The mutation frequency of K-Ras is significantly lower in flat adenomas compared to polypoid adenomas or CRC. [13] Other mutations of genes, such as TP53 and PIK3CA, and epigenetic mutations, such as LINE-1 hypomethylation, also influence the macroscopic morphology. [14] Therefore, the morphological difference between UC-CRC and sporadic CRC may be due to the different carcinogenic pathways. Sporadic CRC arises from the accumulation of genetic mutations, known as the adenocarcinoma sequence, whereas UC-CRC arises from genetic mutations induced by chronic inflammation, known as the inflammation-dysplasia–carcinoma sequence. [9–12] This difference in carcinogenesis results in different genetic mutation patterns, [21] which can lead to different macroscopic patterns in UC-CRC and sporadic CRC.
The most important finding of the present study was determining the clinicopathological features of UC-CRC based on macroscopic features. UC-CRC has an earlier occurrence, worse outcome, and a higher rate of aggressive histological features, such as mucinous or signet ring cell type, than sporadic CRC. [6, 22] This difference may be due to differences in the genetic mutation backgrounds of UC-CRC and sporadic CRC. However, it is difficult to clearly divide CRC into UC-CRC and sporadic CRC groups based on genetic mutation signatures. This indicates that even in UC-CRC cases, there should be a tumor with carcinogenesis and genetic characteristics similar to those of sporadic CRC. In the present study, we found that patients with type 0, 1, 3, 4, and 5 tumors were younger than those with type 2 tumors. A higher proportion of undifferentiated carcinomas was also observed in patients with type 4 tumors than in those with type 0, 1, or 2 tumors. The depth of tumor invasion was more advanced in type 3 tumors than in type 0, 1, or 2 tumors, in type 4 tumors than in type 0, 1, 2, or 5 tumors, and in type 5 tumors than in type 0 or 1 tumors. In addition, the frequency of lymph node metastases was higher in patients with type 3 tumors than in those with type 0 or 1 tumors and in patients with type 4 tumors than in those with type 0, 1, or 2 tumors. As mentioned above, the tumor presumed to be early cancer endoscopically was classified as type 0 tumor, and the tumor presumed to be cancer with invasion beyond the muscularis propria was classified as type 1–5. For this reason, clinicopathological features of type 0 tumors could not be equally compared with that of the other types of tumors. Considering that localized and ulcerative types, such as type 1 and 2 tumors, are typical morphologies in sporadic CRC cases and that infiltration with an ill-defined edge tumor, particularly type 4 tumors, and non-classifiable types are characteristic morphologies in UC-CRC cases, our results indicate that, based on macroscopic classification, UC-CRC may be divided into a group with more prominent characteristics of UC-CRC and a group with similar characteristics to sporadic CRC.
Notably, our findings also revealed that macroscopic classification significantly influenced the RFS and OS of patients with UC-CRC. Several studies have revealed prognostic factors for UC-CRC, such as pStage, sex, and duration of UC. [22] In the present study, we found that 5-year RFS and OS were also significantly different among the macroscopic types. As there was a high proportion of fewer tumors with invasion beyond the muscularis propria in the type 0 tumor group, the 5-year RFS and OS were examined in a stage-matched situation. Both the 5-year RFS and OS were significantly different among macroscopic types in Stage III cases, and type 0, 4, and 5 tumors, which are characteristic macroscopic features of UC-CRC, showed poor prognosis. Multivariate Cox proportional hazards analyses revealed that, in addition to sex, duration of UC, depth of tumor invasion, lymphatic or vascular invasion, lymph node metastasis, and histology, macroscopic classification was a prognostic factor for 5-year RFS and OS in univariate analyses. In multivariate Cox proportional hazards analyses, macroscopic classification was an independent risk factor for 5-year RFS, in addition to the depth of the main tumor and lymph node metastasis, and for 5-year OS, in addition to sex, lymphatic and vascular invasion, and lymph node metastasis. Furthermore, among the macroscopic classification, type 4 and 5 tumors were significant independent risk factors for 5-year RFS and type 0, 4, and 5 for 5-year OS. Considering that patients with UC-CRC have worse survival than those with sporadic CRC, as previously reported, [6, 23, 24] these findings suggest that biological malignancy and macroscopic types might be closely associated and that type 0, 4, and 5 tumors have more prominent characteristics of UC-CRC.
This study has some limitations. First is its retrospective design, and some cases may be missing from the database of each institution, resulting in selection bias. However, collecting a large number of UC-CRC cases from a single institution is difficult, and this large-scale multicenter study of UC-CRC is a strength of our study. Second, the diagnosis of UC-CRC and sporadic CRC was established in each institution and was not centralized. These diagnoses are sometimes difficult; therefore, some sporadic CRC cases may be included as UC-CRC cases, and some UC-CRC cases may be included as sporadic CRC cases. Third, to clarify the relationship between the macroscopic type and biological malignancy, it is important to compare UC-CRC and sporadic CRC in macroscopic classification-matched situations. However, there is a large discrepancy in disease prevalence between UC-CRC and sporadic CRC; therefore, comparing these two groups in macroscopic classification-matched situations is difficult. Finally, we did not examine the differences in gene mutations among the macroscopic types of UC-CRC, which should be assessed in future studies.
In conclusion, our findings revealed that the clinicopathological features and oncological outcomes significantly differed among the macroscopic types of UC-CRC. A high proportion of type 0, 4, and 5 tumors was a significant feature of UC-CRC. Among the six macroscopic types, type 4 and type 5 tumors had clinicopathological features such as earlier occurrence and a higher rate of aggressive and histological features. Additionally, in multivariate Cox proportional hazards analyses that included factors such as sex, duration of UC, depth of tumor invasion, lymphatic or vascular invasion, lymph node metastasis and histology, type 0, 4, and 5 tumors also had worse outcomes, which had been reported to be the characteristics of UC-CRC itself. Therefore, an endoscopic diagnosis of the macroscopic classification of UC-CRC might be helpful in assessing tumor aggressiveness.
Acknowledgements
We thank all the involved doctors in the following institutions: Department of Inflammatory Bowel Disease Surgery, Hyogo Medical University; Department of Surgery, Keio University School of Medicine; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University; Department of Surgery, Fukuoka University Chikushi Hospital; Department of Surgery, Division of Inflammatory Bowel Disease Surgery, Tokyo Women’s Medical University; Department of Surgery, Tohoku University Graduate School of Medicine; Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine; Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Mie University Graduate School of Medicine; Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University; Department of Coloproctology, Tokyo Yamate Medical Center; Department of Surgery, Coloproctology Center Takano Hospital; Department of Surgery, Toho University Sakura Medical Center; Department of Gastroenterological Surgery, Graduate School of Medical, Osaka University; Inflammatory Bowel Disease Center, Yokohama City University Medical Center; Department of Colorectal Surgery, Tohoku Rosai Hospital; Department of Surgery, Kyoto University Hospital; Department of Gastrointestinal Surgery, Tokyo Medical and Dental University; Digestive disease center, Showa University Northern Yokohama Hospital; Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University; Department of Surgery, Faculty of Medicine, Kindai University; Inflammatory Bowel Disease Center, Yokkaichi Hazu Medical Center; Department of Gastroenterological Surgery Tokai University School of Medicine; Department of Surgery, Nara Medical University; Department of Surgery, Fujita Health University, School of Medicine; Department of Gastroenterological Surgery, Aichi Cancer Center Hospital; Department of Surgery, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo; Center for Gastroenterology, Department of Surgery, Urasoe General Hospital; Department of Surgery, Kurume University Hospital; Department of Gastroenterological Surgery, Saitama Medical University International Medical Center; Department of Surgery, National Defense Medical College; Department of Surgery, Teikyo University School of Medicine; Inflammatory Bowel Disease Center, Sapporo-Higashi Tokushukai Hospital; Department of Surgery, Nishinomiya Municipal Central Hospital; Department of Coloproctological Surgery, Japanese Red Cross Medical Center; Department of Surgery, Kyorin University; Department of Gastroenterological Surgery, Osaka City General Hospital; Kurume Coloproctology Center; Department of Colorectal Surgery, National Cancer Center Hospital; Department of Surgery, National Center for Global Health and Medicine; Department of Gastrointestinal and Paediatric Surgery, Tokyo Medical University; Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine; Department of Gastroenterological Surgery, Yamagata Prefectural Central Hospital; Division of Gastroenterological Surgery, Saitama Cancer Center; First Department of Surgery, Faculty of Medical Sciences, University of Fukui; Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School. We also thank Keisuke Hata for his advice on the study designs and data analysis.
Author contributions
AS was the first author, contributed to the acquisition of data for the study, and drafted the manuscript. YY contributed to the data analysis and interpretation and critically revised the manuscript for important intellectual content. TN, KS, and YA contributed to the conception of the work and revised the work critically for important intellectual content. KF, KK, MU, HI, KO, SO, DH, SO, KW, MS, YO, TW, YM, KO, KY, YS, TO, HK, KT, KH, YK, FI, JO, KD, TY, SY, FK, TH, KK, DS, JA, YA, SY, HU, KM, AM, RN, SS, and ES contributed to the acquisition of the data for the work and revised the work critically for important intellectual content. SI is the chief investigator of this study group and contributed to the design of the work, the analysis, and interpretation of data for the work, and revised the manuscript critically for important intellectual content. All the authors approved the final version to be published and agreed to be accountable for all aspects of the work to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The funding source had no role in study design, data collection, data analysis and interpretation, preparation of the manuscript, or decision to publish.
Funding
Open Access funding provided by The University of Tokyo. This work was supported by the Japanese Society of Cancer of the Colon and Rectum.
Data Availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval
This study was approved by the Ethics Committee of the University of Tokyo (2019220NI-[2]), the ethics committee of each institution, if necessary, and the Ethics Committee of JSCCR, which waived the requirement for written informed consent from patients for participation in this study owing to the retrospective nature of this study.
Consent to participate
thical approval was waived by the Ethics Committee of the University of Tokyo in view of the retrospective nature of the study and the lack of identifiable personal data.
Consent to publish
The authors affirm that human research participants provided informed consent for publication of the anonymized data.
Competing interests
The authors declare no competing interests.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.