Clinicopathological characteristics and survival in colorectal signet ring cell carcinoma: a population-based study

We aimed to reveal clinicopathological features and explore survival-related factors of colorectal signet ring cell carcinoma (SRCC). A population-based study was carried out to investigate colorectal SRCC by using data extracted from the surveillance, epidemiology and end results (SEER) database between 2004 and 2015. In total, 3,278 patients with colorectal SRCC were identified, with a median age of 63 (12–103) years old. The lesions of most patients (60.49%) were located in the cecum–transverse colon. In addition, 81.27% patients had advanced clinical stage (stage III/IV), and 76.69% patients had high pathological grade. The 3–, 5–year cancer‐specific survival and overall survival rate was 35.76%, 29.32% and 32.32%, 25.14%. Multivariate analysis revealed that primary site in cecum–transverse colon, married, received surgery, lymph node dissections ≥ 4 regional lymph nodes were independent favorable prognostic. Meanwhile, aged ≥ 65 years, higher grade, tumor size ˃5 cm and advanced AJCC stage were associated with poor prognosis. Patient age, tumor grade, marital status, tumor size, primary tumor location, AJCC stage, surgery and number of dissected lymph node had significant correlation with prognosis of colorectal SRCC.

covariates and endpoint. We analyzed the patients' characteristics according to the following factors: year of diagnosis (2004-2007, 2008-2011, 2012-2015); insured status (uninsured/unknown, any medicaid/ insured; age(< 65, ≥ 65); marital status (unmarried, married); gender (female, male); race (black, white or others); primary site(cecum-transverse colon, descending colon-sigmoid, multiple, rectum and unknown); grade (grade I/II, grade III/IV, unknown); tumor size (≤ 5 cm, ˃5 cm,unknown); AJCC stage ( stage I, II, III, IV); surgery(no surgery, local tumor excision /partial colectomy, total colectomy), and lymph node dissection (none or biopsy, 1 to 3 regional lymph nodes removed, ≥ 4 regional lymph nodes removed, unknown).The widowed or single (never married or having a domestic partner) or divorced or separated patients were classified as unmarried. The primary tumor site was classified as cecum-transverse colon (including the cecum, appendix, ascending colon, hepatic flexure and the transverse colon), descending colon-sigmoid (including the splenic flexure and descending and sigmoid colons), multiple, rectum and unknown 18 . Year of diagnosis was equally divided into 2004-2007, 2008-2011, 2012-2015, which was referred to the previous papers 19,20 . The grouping of the age 21 and tumor size 22 also refers to the published studies. In addition, the staging of cancer is based on the 6th edition of AJCC stage system, which adapted to patients in the SEER database with a diagnosis time of 2004-2015 23 .
The endpoint of this study was cancer-specific survival (CSS) and overall survival (OS). CSS was defined as the period from diagnosis to death attributed to colorectal SRCC. OS was defined as the period from diagnosis to death from any cause. Statistical analysis. Kaplan-Meier (K-M) method was employed for univariate analysis and stratified analysis, followed by log-rank test to determine the differences of OS and CSS. Of note, if variables had P values ≤ 0.1 in univariate analysis, they were incorporated into multivariate Cox proportional hazard analysis. SPSS software version 19.0 (SPSS Inc., Chicago, USA) was adopted for statistical analysis, and GraphPad Prism 5 was adopted for plotting survival curves. A two-sided P < 0.05 was suggestive of statistical significance.

Results
patients' characteristics. Based on the inclusion and exclusion criteria, 3,278 eligible subjects were included. The flowchart of patient selection was displayed in Fig. 1.The patients' features and therapeutic regimens were listed in Table 1. Of all the included patients, the median age was 63 (12-103) years old, with the male to female ratio of nearly 1:1.The lesions were mostly located in cecum-transverse colon (60.49%), 640 cases (19.52%) were detected in rectum, 515 cases (15.71%) were observed in descending colon-sigmoid and only 50 cases (1.53%) were located in overlapping of colon. Most of colorectal SRCC were in advanced clinical stage (stage III/IV: 81.27%) and high pathological grade (grade III/IV: 76.69%). Surgical resection was performed

Discussion
According to the WHO definition, colorectal SRCC is a special type of CRC with prominent intracytoplasmic mucin in over 50% of tumor cells 24 , featured by unique clinical manifestation as well as distinct outcome. Colorectal SRCC has been validated to have poorer prognosis compared with other common CRC 4 . Colorectal SRCC, a rare subtype of CRC, consists of 0.1% to 2.6% of all CRC cases 25,26 . Previous research found similar incidence of SRCC between female and male 6,27 and most SRCC cases are located in the right colon, with rectal SRCC of approximately 20% 28 . Additionally, the initial diagnosis of SRCC is generally at advanced stage, compared with  www.nature.com/scientificreports/ www.nature.com/scientificreports/ colorectal non-SRCC 4 . For instance, according to a large cohort study in the USA, 80% of colorectal SRCC were initially diagnosed with stage III and IV, which were only 50% in non-SRCC (P < 0.01) 28 . These findings are consistent with our study. Moreover, we found that the median age was 63 years old in patients with colorectal SRCC, and 1537 (46.89%) patients were old patients. Our results should be more reliable in this large population-based study while most previous researches on colorectal SRCC were only based on single institution. Colorectal SRCC is independently related to increased mortality risks 18,20 . Ramya et al. have revealed that the median OS was 18.6 months by involving 206 subjects with colonic SRCC 7 . In addition, the stage-specific 5-year survival rate was declined with advanced stage. The above results are basically consistent with our results, while the median survival time of our study is shorter (16.0 months).
Multiple studies have evaluated the stage-associated in colorectal SRCC, with consistent outcomes indicating better survival in early-stage SRCC 7 . Tumor location may be another independent prognostic indicator 29 . These two prognostic factors are both found in our study. In addition, we found that pathological grade and tumor size were independent prognostic factors of colorectal SRCC.
In terms of the optimal therapeutic regimens, the multidisciplinary management is required for colorectal SRCC. To be specific, surgical intervention is vitally involved in treating localized tumors 12 . Additionally, a large population-based study has evaluated the significance of adjuvant chemotherapy by extracting relevant data from nationwide population-based Netherlands Cancer Registry, which enrolled 1972 subjects with colorectal SRCC from 1989 to 2010. In this study, better survival outcome was detected in stage III colon SRCC patients receiving adjuvant chemotherapy than those without 6 . Tao Shi et al. also found an association between chemotherapy and better survival outcomes in colorectal SRCC patients suffering from distant metastasis 21 . In contrast, the role of radiotherapy in colorectal SRCC is less studied which has not been evaluated alone or combined with chemotherapy in SRCC histology to date. Nevertheless, neoadjuvant chemoradiotherapy could give rise to good therapeutic response in rectal SRCC population 30 . This study further emphasized the importance of operation in colorectal SRCC, including the number of dissected lymph node, and regional lymph node dissection ≥ 4 significantly improved the prognosis of patients.
To our knowledge, the current research is the largest population-based study to explore prognostic indicators in colorectal SRCC in the past decade. In total, 3,278 colorectal SRCC patients were analyzed after retrieving from SEER database. SEER database renders the assessment of a large cross-section of cancer patients and provides long-term follow-up information without inherent institutional biases. Meanwhile, there are certain limitations in our research. Firstly, as a retrospective research based on SEER database, the intrinsic selection biases exists in this study 15,17 . Furthermore, not all data are available from the SEER database, such as molecular-genetic profiles. Thirdly, as the radiotherapy and chemotherapy variables have a relatively low sensitivity, we didn't include the data of radiotherapy and chemotherapy to avoid reporting misleading results. Finally, we could not determine the therapeutic response or recurrence rate according to the data extracted from SEER. Thus, further investigations are warranted in the future.

conclusion
In conclusion, we analyzed clinicopathological features as well as survival of colorectal SRCC patients using a population-based approach. Consequently, patient age, tumor grade, marital status, tumor size, primary tumor location, AJCC stage, surgery and dissected lymph node had significant correlation with prognosis of colorectal SRCC. Our study is the largest population-based research to investigate clinicopathological features and survival of patients with colorectal SRCC. Hopefully, our findings are of great significance for the management and future prospective studies for colorectal SRCC.