Clinicopathological factors associated with synchronous distant metastasis and prognosis of stage T1 colorectal cancer patients

Abstract

It is rare and understudied for patients with stage T1 colorectal cancer to have synchronous distant metastasis. This study was to determine the clinicopathological factors associated with distant metastasis and prognosis. T1 colorectal cancer patients diagnosed between 2010 and 2015 were obtained from the SEER database. Logistic regression was applied to determine risk factors related to distant metastasis. Cox-proportional hazard models were used to identify the prognostic factors for patients with distant metastasis. Among 21,321 patients identified, 359 (1.8%) had synchronous distant metastasis and 1807 (8.5%) had lymph node metastasis. Multivariate analysis revealed that younger age, positive serum CEA, larger tumor size, positive tumor deposit, perineural invasion, lymph node metastasis, histology of non-adenocarcinoma and poorer differentiation were significantly associated with the increased risk of synchronous distant metastasis. Older age, female, African American, positive CEA, positive lymph node metastasis, positive tumor deposit, larger tumor size, no chemotherapy, inadequate lymph node harvesting and no metastasectomy were correlated with worse survival in these patients with synchronous distant metastasis. Patients with metastasis to the liver displayed the highest rate of positive CEA. We conclude that T1 colorectal cancer patients with multiple risk factors need thorough examinations to exclude synchronous distant metastasis. Chemotherapy, adequate lymph node cleaning and metastasectomy are associated with improved survival for those patients with distant metastases. Positive serum CEA may be useful in predicting distant metastases in patients at stage T1.

Introduction

Colorectal cancer is one of the most commonly diagnosed malignancies and the third leading cause of cancer-related deaths in the United States ¹. The JACC TNM staging system divides colorectal cancer into Tis and T1-T4 stages based on tumor invasion depth. Colorectal cancer limited to the inner layer or the submucosa of the bowel, is defined as the T1 stage. Most of the colorectal cancers at this stage are cured by surgical resection or even by endoscopic dissection. Only a small portion of these patients died due to recurrence and particularly distant metastasis of this disease. Distinguishing high-risk patients from most of the other low-risk patients is essential for providing appropriate therapy, improve survival and for avoiding unnecessary treatment.

Metastatic seeding occurs early in colorectal cancer ². It has been anecdotally reported that stage T1 colorectal cancer patients developed synchronous distant metastasis. A Japanese multicenter study previously reported only 0.2% (4 of 1,806) synchronous liver metastasis in colorectal cancer patients at stage T1 ³. Another Japanese study found that 2 of 213 (0.9%) colorectal cancer patients at this stage developed synchronous liver metastasis ⁴. A Japanese case study reported the synchronous liver metastasis without lymph node metastasis in a patient with T1 stage colorectal cancer (T1N0M1) ⁵. A more recent case report identified a patient with a moderately differentiated T1 adenocarcinoma, had suspicious synchronous liver metastasis, which was not detected by preoperative imaging examination ⁶. With the advent of detection technology, it is possible more T1colorectal patients are diagnosed with synchronous distant metastases. Among all patients at the T1 stage, this group of patients is expected to have the worst prognosis even after the most aggressive treatments. However, the clinicopathological features and prognostic factors of these patients have not been well studied.

This study was performed using the SEER national database to first compare clinicopathological features between stage T1 colorectal cancer patients with and without synchronous distant metastases. Logistic regression analyses were then applied to examine the risk factors correlated with distant metastases. Cox proportional hazard models were further employed to determine the risk factors associated with prognosis in patients with synchronous distant metastases. Findings from this population based study will assist to improve the management of stage T1 colorectal cancer patients.

Results

Clinicopathological Factors Predicting Distant Metastasis

Logistic regression analysis was applied to determine the clinicopathological factors correlated with the risk of synchronous distant metastasis. Both univariate and multivariate analyses showed that younger age, positive serum CEA, larger tumor size (> 5 cm), non-adenocarcinoma, higher grade, positive tumor deposit, perineural invasion and lymph node metastasis were significantly associated with an increased risk of distant metastasis (Table 2). A receiver operating characteristic (ROC) curve was constructed to evaluate the performance of the predicting model built based on these risk factors (Fig. 2). The area under the ROC curve was 0.879 in distinguishing stage T1 colorectal cancer patients with synchronous distant metastases, from those without distant metastases.

Prognostic factors for stage T1 colorectal patients with synchronous distant metastasis

Cox-proportional hazard regression models were applied to analyze risk factors associated with survival in patients with distant metastases. Both univariate and multivariate results showed that age, gender, race, CEA status, tumor size, histology, grade, tumor deposit, number of lymph node harvested, lymph node metastasis, metastatic sites, chemotherapy and metastasectomy were significantly associated with cancer specific survival (Table 3). The survival curves of the risk factors are presented in Fig. 3A-F and Supplemental Fig. S2A-2F).

Univariate and multivariate survival analysis revealed that age, race, histology, tumor grade, tumor deposit, harvested lymph node number, lymph node metastases, metastatic sites, chemotherapy and metastasectomy were associated with overall survival in stage T1 colorectal patients with synchronous distant metastasis (Table 3).

Tumor Histology And Survival

It was surprising that mucinous adenocarcinoma was associated with improved cancer specific survival and overall survival in stage T1 colorectal cancer patients with synchronous distant metastases (Table 3 and Fig. 2D). We therefore analyzed the correlation between tumor histology and survival in all stage T1 patients and patients without synchronous distant metastases. The results indicated that adenocarcinoma was associated with better cancer specific and overall survival in all stage T1 patients or patients without synchronous distant metastases (Supplemental data Fig. S3A-S3D).

Serum CEA Status And Metastatic Sites

Stage T1 colorectal cancer patients without distant metastases had a relatively low rate (5.7%) of positive serum CEA. The rate of positive serum CEA was significantly increased to approximately 30% in patients with synchronous non-liver distant metastases, and further significantly increased to 60% in patients with synchronous distant metastases to liver (Table 4).

Discussion

T1 colorectal cancer patients with synchronous distant metastases have a poor prognosis even after the most aggressive treatment. Due to the very low incidence, their clinicopathological characteristics have not been well characterized. Using the SEER database, this population-based study identified multiple clinicopathological factors associated with the increased risk of synchronous distant metastases: diagnosis at a younger age, positive serum CEA, larger tumor size, positive tumor deposit, perineural invasion and lymph node metastasis, histology of non-adenocarcinoma and poorer differentiation. The predicting model using these risk factors had an area under the ROC of 0.879 in distinguishing patients with distant metastasis from those without distant metastasis. Most described risk factors have been associated with increased risk of recurrence due to heightened aggressive metastases in advanced staged colorectal cancer; however, very few have been previously reported to be risk factors related to lymph node metastases and recurrence in T1 colorectal cancer patients ^5,7−9.

This study indicated that patients with T1 colorectal cancer who have all or most of the risk factors are very likely to have distant metastases. Through combination with molecular markers and advanced screening technology, these risk factors may be useful to distinguish T1 colorectal cancer patients with high risk of distant metastasis, from those with low-risk of distant metastases.

CEA is a valuable serum biomarker in differential diagnosis, disease monitoring and evaluation of therapeutic efficacy in colorectal cancer. This study showed that patients with positive CEA had a significantly worse survival and a higher risk of distant metastasis. Moreover, T1 colorectal cancer patients without metastasis had a low percentage of had positive serum CEA, which was significantly increased in patients with non-liver distant metastases, and further significantly increased in patients with liver metastases. These results suggest that serum CEA is particularly useful to screen synchronous liver metastasis in patients with T1 colorectal cancer. A previous study reported that CEA was as effective as computed tomography (CT) imaging in assessing the response of chemotherapy in colorectal cancer patients with liver metastases ¹⁰. CEA has been shown to play a direct role in assisting metastasis of colorectal cancer cells to the liver and therefore it is a potential target in the treatment of liver metastasis ¹¹.

The AJCC edition 7-TNM staging defines tumor deposits as a macroscopic or microscopic tumor nest or nodule in adjacent adipose tissue, without lymph node structure ¹². However, tumor deposits are often overlooked in TNM staging, particularly when they coexist with lymph node metastasis. Many clinicians are confused about the actual prognostic impact of tumor deposits. This study indicated that less than 1% of T1 colorectal cancer patients had tumor deposits. Multivariate Cox proportional hazard analysis showed that tumor deposits were significantly associated with an increased risk of distant metastasis, and adverse survival outcomes. Multiple studies and reviews have reported that tumor deposits are associated with increased local recurrence and distant metastasis rates, and overall survival in colorectal cancer patients ^13–15. Due to the limit of the database, it is not possible to determine other characteristics of tumor deposits (such as their location, diameter, and shape) and their correlation with prognosis.

Primary colorectal mucinous adenocarcinoma and signet-ring cell are two rare subtypes of colorectal cancer with a poorer prognosis than typical adenocarcinoma ^16,17. Mucinous carcinoma may respond poorly to chemotherapy than adenocarcinoma as mucins may be an obstacle to drug delivery. This study revealed that mucinous adenocarcinoma was associated with worse survival in all T1 patients or patients without synchronous distant metastases. However, it was associated with improved cancer survival in T1 colorectal cancer patients with synchronous distant metastases. The association between mucinous adenocarcinoma and prognosis is still inconsistent in colorectal cancer patients ^16,18−22.

Perineural invasion is a pathological process in which the tumor infiltrates the nerve structure and spreads along the nerve sheath ²³. The perineural invasion has been served as an important risk factor related to recurrence and a low survival rate in colorectal cancers and other cancers ^24–26. Perineural invasion is also being used as a novel target to block tumor progression and improve survival ²³. This study found a very low rate (0.9%) of perineural invasion in T1 colorectal cancer patients. It was significantly correlated with the increased risk of synchronous distant metastases, but not associated with the survival in these T1 colorectal cancer patients with synchronous distant metastases.

National Comprehensive Cancer Network (NCCN) guidelines recommend sampling at least 12 lymph nodes for adequate staging of colorectal cancer ²⁷. Adequate lymph node cleaning has been associated with better prognosis in colorectal cancer patients at other stages ^28,29, but not in others^30,31. This study revealed that harvesting over 12 lymph nodes was associated with increased survival in stage T1 colorectal cancer patients with distant metastasis, which supports harvesting an adequate number of lymph nodes to improve the survival in these high-risk stage T1 patients.

Stage T1 colorectal cancer patients with synchronous distant metastasis are treated the same as patients with distant metastasis at other stages ³². In the past decade, the efficacy of systematic chemotherapy, particularly with the recently developed personalized target therapy, has dramatically improved in the treatment of patients with metastatic colorectal cancer. However, the benefit of chemotherapy has not been previously studied in T1 patients with synchronous distant metastasis. In this study, 70.3% of patients with synchronous distant metastasis received chemotherapy, whereas only 7.3% of patients without distant metastasis received chemotherapy. Chemotherapy was associated with a significantly improved survival in stage T1 colorectal cancer patients with distant metastasis. Similar to this finding, a previous study using the National Cancer Database reported that adjuvant chemotherapy significantly improved survival in stage T1 colorectal patients with lymph node metastasis ³³. The survival benefit of chemotherapy supports its use for these high-risk T1 colorectal cancer patients.

Distant metastases are the main cause of death in colorectal cancer patients. Both metastatic burden and its involvement of vital organs are important prognostic factors for metastatic colorectal cancer ³⁴. This study indicated that patients with metastases to multiple-sites, or bone, or brain had significantly worst survival compared to those with liver or lung metastasis alone. Among all patients with synchronous distant metastasis, 56 (14.8%) patients received metastasectomy. Multivariate survival analyses using Cox proportional hazards models revealed that metastasectomy was significantly associated with increased survival in stage T1 colorectal cancer patients with synchronous distant metastasis. The metastasectomy in metastatic colorectal cancer demonstrated the survival beneficial in previous studies ^34–37. Simultaneous colorectal and minor hepatic resections are considered to be safe for most patients with synchronous liver metastases ³⁸.

This population-based study has several limitations. As a retrospective study, there is an inherent bias in patient selection. Some important clinical information possibly related to prognosis is not included in the database. There is no data regarding the depth of invasion to the submucous membrane, the edge of the surgical margin. The size and number of metastases at each site are unknown. It is unclear that the patient received adjuvant or neoadjuvant chemotherapy, detailed chemotherapy regimen, dose and duration. The database lacks information on complications, the recurrence and the metachronous metastasis after the treatments as well. The strength of this study is that it is the first time to report data with a good number of T1 colorectal patients with synchronous distant metastasis.

Conclusions

Younger age, positive serum CEA, larger tumor size, positive tumor deposit, perineural invasion and lymph node metastasis, histology of non-adenocarcinoma and poorer differentiation, are associated with increased risk of distant metastasis, in T1 colorectal cancer patients. Thorough examinations to exclude distant metastasis are needed for T1 colorectal cancer patients with multiple risk factors. Chemotherapy, adequate lymph node cleaning and metastasectomy are associated with improved survival for those patients with distant metastases. Positive serum CEA may be useful in predicting distant metastases, particularly liver metastases.

Patients And Methods

The study cohort was obtained from the SEER database using SEER*Stat 8.3.6. According to the Site Recode Classifications, patients with colon (C18.0-18.9, and C26.0) and rectal (C19.9 and C20.9) cancers were identified from the SEER database. The inclusion criteria used for this study were: (a) the first primary tumor; (b) age of 18 or older; (c) diagnosed between 2010 and 2015; (d) surgery was performed with pathological confirmation; (e) pathological stage T1 according to AJCC 7th edition. The exclusion criteria were: (a) patients received preoperative radiation (downstage T stage); (b) histology other than adenocarcinoma, mucinous adenocarcinoma and signet ring cell carcinoma; (c) patients with unknown survival status or time (Fig. 1).

The following variables were gathered: age at diagnosis, gender, marital status, race, the status of serum CEA, tumor size, histologic type, differentiation, the status of lymph node metastasis, number of lymph node harvested, metastatic sites, cancer specific survival and overall survival months. The histological types were categorized using the ICD-O-3 (International Classification of Disease for Oncology, 3rd edition) coding schema: conventional adenocarcinoma (8010, 8020–8022, 8140–8141, 8144–8145, 8210–8211, 8220–8221, 8230–8231, 8260–8263), mucinous adenocarcinoma (8470, 8472–8473, 8480–8481); and signet-ring cell carcinoma (8490) ³⁹. The tumor grades were grouped as: Grade I (well differentiated); Grade II (moderately differentiated); Grade III (poorly differentiated); Grade IV (undifferentiated or anaplastic lesions). The metastasectomy was defined by ‘‘non-primary surgical procedure to a distant site’’ in the record of ‘‘surgery other regional/distant (2003+)’’ ⁴⁰. This study was based on public data from the SEER database, and it did not include interaction with human subjects or the use of personal identifying information.

Declarations

Acknowledgements

The authors thank Dr. Kristin Best for her helpful reviewing of this manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

W.C. and Q.L. designed the study. W.C., Q.L., G.W., J.L. and B.L. researched and analyzed the data. W.C and Q.L. drafted the manuscript and G.W., J.L. and B.L. attributed to critical revisions of the manuscript. All authors read and agreed on the final version of the manuscript.

Competing interests

The author(s) declare no competing interests.

Availability of data and materials

The datasets used in this manuscript are available in the Surveillance, Epidemiology, and End Results (SEER) database (http://www.seer.cancer.gov) of the National Cancer Institute.

Ethics approval and consent to participate

Not applicable. As the SEER dataset is publicly available and de-identified, therefore, the ethical approval was waived by an ethics committee.

Consent for publication

Not applicable.

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