Frequency distribution of histologic subtypes in CRC
71,810 CRC patients were included in this study from SEER registers during 2010 – 2012. According to the ICD-O-3 codes and description, 49,131 (68.4%) cases were classified as adenocarcinoma NOS, not otherwise specified. All the rest 22,679 (31.6%) patients were analyzed for the frequency distribution of histologic subtypes in CRC (Supplementary Table 1). Except for adenocarcinoma with neuroendocrine differentiation (Code 8574), which is a distinct subtype but accounts for very small population, all the others (n = 22,636, 99.8%) were included in this study and categorized into four histologic subtypes: CA, MAC, SRRC, and AM. The commonest subtype was CA, with 15, 812 cases accounting for 69.9%. The numbers and frequencies of MAC, SRCC and AM were 5,689 (25.1%), 814 (3.6%), and 321 (1.4%), respectively (Table 1). Both SRCC and AM are relatively rare with a frequency of less than 5%.
Comparisons of clinicopathologic differences between histologic subtypes
MAC was more common in female (P< 0.001) and older patients (P< 0.001) compared with CA. There was no significant difference in the distribution of gender and sex between CA and SRCC or AM. Compared with CA, all the other three subtypes were found to be less common in rectal cancer (all P< 0.001). In addition, all of MAC, SRCC, and AM, were significantly associated with some features of more aggressive tumors, including poor tumor differentiation, large size of primary tumors, high level of carcinoembryonic antigen (CEA), advanced T stage and N stage, distant metastasis, high positive rates of circumferential resection margin (CRM) involvement and perineural invasion, as well as requent presence of tumor deposits (all P< 0.001, Table 2).
We further compared the clinicopathologic differences between AM and the other two relatively more aggressive histologic subtypes: MAC and SRCC. Compared with MAC, AM was found more frequently in males (P= 0.05). AM was also associated with aggressive tumor characteristics including poor differentiation (P < 0.001), more advanced T and N stage (P < 0.001), distant metastasis (P= 0.002), higher positive rates of CRM (P< 0.001), perineural invasion (P< 0.001), and frequent presence of tumor deposits (P< 0.001). As for the comparison between AM and SRCC, AM was associated with better differentiation (P< 0.001), distant metastasis (P< 0.001), and perineural invasion (P= 0.003). No differences were found in other clinicopathologic characteristics between AM and SRCC. Detailed information was shown in Table 2.
The prognostic value of histologic subtypes
We compared the 3-year CRC specific OS rates between histologic subtypes (Table 3) in the general population and subgroups stratified by TNM stage (0+Ⅰ/Ⅱ/Ⅲ/Ⅳ), tumor location (Colon / Rectum), sex (Male / Female) and age(≤ 66 / > 66).The 3-year OS rates was 90.3 ± 0.004%, 71.6 ± 0.01%, 38.0 ± 0.06% and 49.8 ± 0.06% for CA, MAC, SRCC, and AM, respectively. MAC, SRCC, and AM showed significantly poor survival rates compared with CA. And this difference sustained in most of the subgroups, except for certain TNM stage subgroups. Specifically, in stage IV patients MAC didn’t show significant different in 3-year OS rate compared with CA, while SRCC and AM in stage 0+Ⅰand stage Ⅱ, respectively. Compared with AM, MAC showed significantly better 3-year OS in the general population as well as in most subgroups, while no prognostic differences were found between AM and SRCC (Table 3). The CRC-specific OS of the four subtypes estimated using the Kaplan-Meier method was shown in Figure 1.
We then conducted univariate and multivariate analysis for the prognostic differences in CRC specific OS between histologic subtypes. By univariate analysis, besides histologic subtypes (P< 0.001), other significant prognostic factors included age (≤ 66 / > 66, P< 0.001), tumor location (Colon / Rectum, P< 0.001), grade (Well differentiated / Moderately differentiated / Poorly differentiated or undifferentiated, P< 0.001), TNM stage (0+Ⅰ/Ⅱ/Ⅲ/Ⅳ, P< 0.001), race (American Indian/Alaska Native / Asian or Pacific Islander / Black / White, P< 0.001), insurance status (Insured / Others, P< 0.001), marital status (Married / Widowed / Others, P< 0.001), CEA level (Normal / Borderline / Elevated, P< 0.001), CRM (Negative / Positive, P< 0.001), perineural invasion (Negative / Positive, P< 0.001) and tumor deposits (Absent / Present, P< 0.001). All the significant prognostic factors identified by univariate analysis were included for multivariate Cox regression analysis. Factors remained as independent prognostic factor included age (P< 0.001), grade (0.001), TNM stage (P< 0.001), marital status (0.003), CEA (P< 0.001), CRM (P< 0.001), tumor deposits (P< 0.001) and histologic subtype (P< 0.001). After adjusting for confounding factors, compared with CA, MAC didn’t have a significantly different prognosis (P = 0.20, hazard ratio (HR) and 95% confidence interval (95% CI): 1.14 (0.93 – 1.39)), while the inferior prognosis of SRCC and AM remained significant (P< 0.001 and P = 0.003, HR and 95% CI: 1.88 (1.37 – 2.58) and 1.89 (1.25 – 2.85), respectively) (Table 4). In addition, compared with AM, MAC had a significantly better prognosis (P = 0.01, HR and 95% CI: 0.60 (0.40 – 0.90)), while no survival difference was found between AM and SRCC (P = 0.98, HR and 95% CI: 0.99 (0.65 – 1.53)) (Table 4).