|Year : 2020 | Volume
| Issue : 7 | Page : 1664-1671
Mucinous histology as a poor prognostic factor in young patients with Stage II rectal cancer: A population-based study
Chi Wu, Jie Bai
Department of Anesthesiology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
|Date of Submission||04-May-2020|
|Date of Decision||13-Jul-2020|
|Date of Acceptance||29-Oct-2020|
|Date of Web Publication||9-Feb-2021|
1678 Dongfang Road, Shanghai 200127
Source of Support: None, Conflict of Interest: None
Background: Mucinous adenocarcinoma (MA) is a distinct histotype of rectal cancer, possibly having prognostic differences with adenocarcinoma (AD). We investigated the prognostic significance of mucinous histology in patients with Stage II rectal cancer.
Patients and Methods: Eligible patients were retrieved from the Surveillance, Epidemiology, and End Results database from 2004 to 2017, and the survival difference between AD and MA patients in the overall and subgroup populations (divided by age) was compared. Multivariate Cox proportional hazard regression analysis was performed to assess whether the mucinous histotype was an independent prognostic factor.
Results: A total of 10, 910 patients with Stage II rectal cancer were enrolled and divided into a young group (≤55 years, n = 3248) and an old group (>55 years, n = 7662). Patients with MA exhibited a lower cancer-specific survival rate than those with common AD in the overall population and the young group, but not in the old group. The analysis revealed that the mucinous histotype was an independent prognostic factor in the young group, but not in the old group. Moreover, after excluding patients with risk factors (including poorly differentiated or undifferentiated tumor grade, T4 stage, <12 lymph nodes examined, and elevated preoperative carcinoembryonic antigen level), prognosis of the mucinous histotype was poorer in the young group than that in the old group.
Conclusion: The mucinous histotype was an independent prognostic factor in young patients with Stage II rectal cancer. The presence of mucinous histology reflected poor prognosis, especially in the low-risk young population.
Keywords: Mucinous adenocarcinoma, outcome, prognostic characteristics, rectal cancer, Stage II adenocarcinoma
|How to cite this article:|
Wu C, Bai J. Mucinous histology as a poor prognostic factor in young patients with Stage II rectal cancer: A population-based study. J Can Res Ther 2020;16:1664-71
| > Introduction|| |
Colorectal cancer (CRC), one of the most common and devastating malignancies of the digestive tract, consists of colon cancer and rectal cancer, depending on the location of the tumor., Accumulative studies have demonstrated the etiological and survival difference between colon and rectal cancers., Anatomical factors, location, blood supply, drainage, and innervation are significantly different between colon and rectal cancers. Colon cancer also varies significantly from rectal cancer in genetic mutation and mutation pattern.
The histological subtypes of CRC include adenocarcinoma (AD), mucinous adenocarcinoma (MA), signet-ring carcinoma, and other rare types. Specifically, MA is a distinct histotype, accounting for approximately 5%–20% of all CRC cases, and second only to AD.,, There has been a long-standing debate over the accurate histological definition of MA. To date, MA is generally characterized by an abundant mucinous component produced by neoplastic cells, comprising >50% of the entire tumor volume., The prognosis of patients with MA is still controversial; some studies have demonstrated poorer prognosis in patients with colorectal MA,,,, while others have not revealed any prognostic difference., This variation in reported results might be due to differences in the study populations and diverse tumor stages and features. In terms of clinicopathological characteristics, colorectal MA has been more frequently found in the proximal colon than the distal colon or rectum., Moreover, it has also been reported that MA is more common in younger and female populations.
The existing studies on the prognostic effects of mucinous histology have primarily focused on advanced-stage CRC, while Stage II CRC has rarely been investigated. In addition, Park et al. reported a difference in the prognostic significance of the mucinous histotype between colon and rectal cancers in nonmetastatic CRC. Their study revealed that mucinous histology might be an independent prognostic factor in colon cancer, but not in rectal cancer. However, in another study, Hyngstrom et al. demonstrated that the mucinous subtype is associated with poorer survival outcomes in rectal cancer than in colon cancer.
Patients with Stage II rectal cancer generally have good outcomes; however, a significant number eventually suffer from local recurrence and even distant metastasis. In consideration of the distinct differences between colon cancer and rectal cancer, and the controversy over the prognostic value of mucinous histology in Stage II CRC, the present study was designed to identify the prognostic value of the mucinous histotype in Stage II rectal cancer by retrieving eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database. Moreover, mucinous histology is more commonly detected in young patients., Thus, patients were divided into young (≤55 years) and old (>55 years) groups based on the results of a previous study that reported the mean age of rectal MA occurrence to be 54.2 ± 16.25 years. We aimed to examine whether there was a prognostic difference of mucinous histology in different age groups.
| > Patients and Methods|| |
The National Cancer Institute's SEER program, initiated in 1973 and updated annually, recovers approximately 28% of the total US population cancer incidence and patient survival by collecting and recording data from 18 population-based cancer registries.
SEER*Stat is an online access tool provided by the SEER program to extract patient data. We, therefore, collected patient data from the SEER dataset through 2004–2017 using the SEER*Stat v 8.3.5 tool according to the SEER program codes, and data specific to the type of tumor as “CS” codes.
Eligible patients were retrieved from the SEER database. The patient inclusion criteria were as follows: (1) patients were 18 years old or older; (2) patients were pathologically confirmed with Stage II rectal cancer; and (3) only AD and MA were included. The exclusion criteria were as follows: (1) patients were burdened with other primary malignancies unless rectal cancer was the first diagnosed malignancy (to obtain accurate cancer-specific survival [CSS]); (2) patients with <1-month survival or were lost to follow-up; and (3) patients whose relevant clinicopathological data were inaccessible from the SEER database. Because the SEER database is publicly available, local ethical approval was waived.
The following data were collected from the SEER database: age at diagnosis; race; sex; tumor grade, size, stage, and histology; the number of examined lymph nodes; preoperative carcinoembryonic antigen (CEA) level; survival (months); and cause of death. In our study, the primary end point was CSS, which was defined as the time interval from tumor diagnosis to the latest follow-up or date of death due to rectal cancer that was determined by specific codes provided by SEER.
Patients were divided into a young group and an old group according to age at diagnosis. As appropriate, Pearson's Chi-square test or Fisher's exact test was utilized to compare baseline clinicopathological characteristics. Subsequently, Kaplan–Meier survival curves were plotted, followed by log-rank tests to compare survival differences between groups. To further assess the potential correlation between various clinicopathological parameters and patient survival, multivariate Cox proportional hazard regression analysis was performed to simultaneously relate the considered risk factors to survival time in the different age groups. The hazard ratio (HR) and 95% confidence interval were calculated to identify independent prognostic factors in patients with Stage II rectal cancer. Patients with one or more of the following risk factors were excluded from the subgroup analysis: poorly differentiated or undifferentiated tumors, T4 tumor stage, inadequately sampled lymph nodes (<12), and elevated preoperative CEA level. In these low-risk patients, we further confirmed whether there was a survival difference between the AD and MA groups. SPSS software (SPSS Inc., Chicago, IL, USA, v 22) and R software for Mac v 3.6.1 (The R Foundation for Statistical Computing, Vienna, Austria) were employed for statistical analysis. A two-sided P < 0.05 was considered statistically significant.
| > Results|| |
Demographic features and clinicopathological characteristics
In the present study, 10,910 patients with Stage II rectal cancer were selected from the SEER database (2004–2017) according to the inclusion and exclusion criteria [Supplementary Figure 1]. Patients were divided into a young group and an old group using 55 years old as a cutoff value. We further analyzed the clinicopathological characteristics between AD and MA. As shown in [Table 1], there were 190 cases (5.85%) of MA in the young population, and 443 cases (5.78%) of MA in the old population. In both the young and old populations, the MA patients were more likely to harbor an more advanced tumor grade (both P < 0.001); a larger tumor size (P = 0.010 and P < 0.001 in the young and old groups, respectively); an more advanced pathological T stage (P = 0.010 and P < 0.001 in the young and old groups, respectively); and a higher preoperative CEA level (P = 0.001 in both groups). There were no statistically significant differences in race, gender, or the number of lymph nodes sampled (all P > 0.05 in both groups).
|Table 1: Clinicopathological features of patients with Stage II rectal cancer|
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Kaplan–Meier survival curves were plotted to analyze and compare the association between the different histological subtypes. During the follow-up period for the young group, 475 of the 3058 AD patients died due to cancer-related causes (15.5%) compared to 50 of the 190 MA patients (26.3%). For the old population, 1827 of the 7219 AD patients (25.3%) and 135 of the 443 MA patients (30.5%) died due to cancer-related causes. Of the overall population, a significantly lower survival rate was observed in MA patients than that in AD patients [Figure 1]a. As shown in [Figure 1]b, the 5-year CSS of MA patients (73.8%) was statistically significantly lower than that of AD patients (84.8%) in the young population (P < 0.001). However, there was no statistically significant difference in the 5-year CSS between MA patients (67.7%) and AD patients (73.2%) (P = 0.058) [Figure 1]c.
|Figure 1: Kaplan–Meier survival curves for comparison of cancer-specific survival between Stage II rectal AD and MA. (a) overall population, (b) young group, and (c) old group. AD = adenocarcinoma, MA = mucinous adenocarcinoma|
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Prognostic factors of Stage II rectal cancer
The multivariate Cox proportional hazards model was utilized to identify the prognostic factors for Stage II rectal cancer. As shown in [Table 2], MA was indeed an independent prognostic factor in the young population (HR = 1.361, P = 0.043), however MA was not an independent prognostic indicator for the old population (HR = 1.051, P = 0.580). Moreover, in the young group, Black population (HR = 1.322, P = 0.034), being female (HR = 0.786, P = 0.010), poor tumor differentiation (HR = 1.672, P = 0.014), larger tumor size (>5 cm) (HR = 1.438, P = 0.001), advanced pathological T stage (HR = 2.301, P < 0.001), number of sampled lymph nodes < 12 (HR = 2.149, P < 0.001), and elevated preoperative CEA level (HR = 1.960, P < 0.001) were all independent prognostic factors in patients with Stage II rectal cancer. While in the old population, poor tumor differentiation (HR = 1.471, P < 0.001), larger tumor size (>5 cm) (HR = 1.443, P < 0.001), T4 stage (HR = 2.064, P < 0.001), inadequately sampled lymph nodes (HR = 2.191, P < 0.001), and positive preoperative CEA level (HR = 1.595, P < 0.001) were independent prognostic factors in patients with Stage II rectal cancer.
The T stage is a well-defined risk factor for the prognosis of CRC. Stratified by T stage, MA exerted a significantly negative effect on the prognosis of T3 patients in the young population, but not in the old group [Figure 2]a and [Figure 2]b. However, there was no significant survival difference between AD and MA patients at the T4 stage in either group [Figure 2]c and [Figure 2]d. Similarly, in patients stratified by preoperative CEA level, MA was significantly correlated with poorer prognosis in patients with a normal preoperative CEA level in both young and old groups [Figure 3]a and [Figure 3]b. However, no significant association was found between histological subtype and prognosis in patients with elevated preoperative CEA levels [Figure 3]c and [Figure 3]d. In addition, a stratified analysis of the 5-year CSS rate between MA and AD patients was performed based on demographic features and clinicopathological characteristics [Table 3]. To exclude the confounding effects of well-featured risk factors on patient prognosis, patients with the following risk factors were eliminated: poorly differentiated or undifferentiated tumor grade, T4 tumor grade, <12 lymph nodes examined, and elevated preoperative CEA levels. For the remaining low-risk patients, Kaplan–Meier curves showed significantly superior survival in AD patients than in MA patients in the young population [Figure 4]a. In contrast, the survival difference between AD and MA was barely detectable in the old population [Figure 4]b.
|Figure 2: Kaplan–Meier survival curves for comparison of cancer-specific survival between Stage II rectal AD and MA. (a) young patients at T3 stage, (b) old patients at T3 stage, (c) young patients at T4 stage, and (d) old patients at T4 stage. AD = adenocarcinoma, MA = mucinous adenocarcinoma|
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|Figure 3: Kaplan–Meier survival curves for comparison of cancer-specific survival between Stage II rectal AD and MA. (a) Young patients with negative preoperative carcinoembryonic antigen level, (b) old patients with negative preoperative carcinoembryonic antigen level, (c) young patients with positive preoperative carcinoembryonic antigen level, and (d) old patients with positive preoperative carcinoembryonic antigen level. AD = adenocarcinoma, MA = mucinous adenocarcinoma|
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|Figure 4: Subgroup analysis in low-risk patients. (a) Young patients and (b) old patients. Patients with poorly differentiated or undifferentiated grade, T4 grade, <12 lymph nodes examined, and elevated preoperative carcinoembryonic antigen levels were excluded. Kaplan–Meier survival curves were plotted to compare cancer-specific survival between stage II rectal AD and MA. AD = adenocarcinoma, MA = mucinous adenocarcinoma|
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|Table 3: Stratified analysis of 5 -year cancer-specific survival rate in Stage II rectal cancer|
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| > Discussion|| |
MA is a rare and distinct histological type of CRC, comprising 5%–20% of all CRCs., In general, the proportion of rectal MA is lower than that of colonic MA., Owing to limited studies on the effects of mucinous histology in rectal cancer, herein, we evaluated the prognostic significance of the mucinous histotype among patients with Stage II rectal cancer in different age groups by retrieving eligible patients from the SEER database. Our results revealed that mucinous histology is an independent prognostic factor in young patients (≤55 years) with Stage II rectal cancer, but not in older patients (>55 years).
In this study, the proportion of mucinous histotype was 5.80% (633 out of 10, 910 patients) with Stage II rectal cancer, which was also comparable between the young group (5.85%, 190 of 3248 patients) and the old group (5.78%, 443 out of 7662 patients). In terms of the effects of mucinous histology on survival, Kaplan–Meier curves demonstrated a poorer 5-year CSS for MA than AD in the overall population (76.7% vs. 69.6%, P = 0.001). A poorer survival was similarly observed in MA patients in the young group (5-year CSS: 84.8% vs. 73.8%, P < 0.001), but not in the old group (5-year CSS: 73.2% vs. 67.7%, P = 0.058). Young age has been reported to be an independent predictor for better survival in CRC. Indeed, after controlling for disease and therapy, the prognosis of young patients is more favorable than their older counterparts, despite the relatively more advanced disease stage in the young population. Consistently, Li et al. have reported that in Stages II and III CRC, a significantly higher CSS rate is detected in young patients than the older population. Despite the unfavorable biological behavior and advanced-stage disease, a better overall condition, faster postoperative recovery, and better performance status for subsequent adjuvant (radio) chemotherapy could compensate for the unfavorable disease features.,
To further assess the prognostic significance of the mucinous histotype, we performed multivariate Cox proportional hazard regression analysis for patients with Stage II rectal cancer and found that mucinous histology was an independent prognostic factor in the young population (HR = 1.361, P = 0.043), but not in the old group (HR = 1.051, P = 0.580). Previous studies have demonstrated that the mucinous histotype exerts no obvious negative effects on the prognosis of patients with lymph node-negative rectal cancer; this is similar to our findings in the overall population. However, the negative prognostic role of the mucinous histotype becomes clear in the young population.
Moreover, in our subgroup analysis, patients with widely acknowledged risk factors were eliminated, including poorly differentiated or undifferentiated tumor grade, T4 stage, inadequately sampled lymph nodes, and elevated preoperative CEA level. It is intriguing to note that in the remaining low-risk patients, MA is significantly related to poorer prognosis in the young population, but not in the old population. Consistent with previous findings, our observation might reflect mucinous histology as a high-risk characteristic in Stage II rectal MA, after eliminating the confounding effects of other risk factors.
Several limitations should be cautiously considered in the objective interpretation of our findings. First, a lack of radiochemotherapy data might be one of the drawbacks, thus, we are unable to determine the role of radiochemotherapy on the prognosis of patients with rectal cancer. In consideration of the critical therapeutic effects of radiochemotherapy, it should be incorporated in further studies. Second, specific data on the quantity of mucus were not available, which could significantly affect the clinical outcomes of patients. Moreover, other risk factors, including obstruction, perforation, perineural, and vascular invasion, were not included in the present study, due to the unavailability of these parameters in the SEER database.
| > Conclusion|| |
In this study, we observed poorer survival rates in patients with Stage II rectal MA than with rectal AD, especially in the young population. In addition, we found that the mucinous histotype is an independent prognostic parameter in young patients with Stage II rectal MA. Subgroup analyses further revealed that the mucinous histotype presented inferior survival outcomes in young patients, but not in older patients with low-risk rectal cancer (cases with poorly differentiated or undifferentiated tumors, T4 stage, inadequately sampled lymph nodes, and elevated preoperative CEA levels were excluded).
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Conflicts of interest
There are no conflicts of interest.
| > References|| |
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al
. Colorectal cancer statistics, 2017. CA Cancer J Clin 2017;67:177-93.
van der Sijp MP, Bastiaannet E, Mesker WE, van der Geest LG, Breugom AJ, Steup WH, et al
. Differences between colon and rectal cancer in complications, short-term survival and recurrences. Int J Colorectal Dis 2016;31:1683-91.
Kalcan S, Sisik A, Basak F, Hasbahceci M, Kilic A, Kosmaz K, et al
. Evaluating factors affecting survival in colon and rectum cancer: A prospective cohort study with 161 patients. J Cancer Res Ther 2018;14:416-20.
Wei EK, Giovannucci E, Wu K, Rosner B, Fuchs CS, Willett WC, et al
. Comparison of risk factors for colon and rectal cancer. Int J Cancer 2004;108:433-42.
Wnorowski AM, Menias CO, Pickhardt PJ, Kim DH, Hara AK, Lubner MG. Mucin-containing rectal carcinomas: Overview of unique clinical and imaging features. AJR Am J Roentgenol 2019;213:1-9.
Leopoldo S, Lorena B, Cinzia A, Gabriella DC, Angela Luciana B, Renato C, et al
. Two subtypes of mucinous adenocarcinoma of the colorectum: Clinicopathological and genetic features. Ann Surg Oncol 2008;15:1429-39.
Consorti F, Lorenzotti A, Midiri G, Di Paola M. Prognostic significance of mucinous carcinoma of colon and rectum: A prospective case-control study. J Surg Oncol 2000;73:70-4.
Chand M, Yu S, Swift RI, Brown G. Mucinous carcinoma of the rectum: A distinct clinicopathological entity. Tech Coloproctol 2014;18:335-44.
Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, et al
. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020;76:182-8.
Jass JR, Sobin LH, Watanabe H. The World Health Organization's histologic classification of gastrointestinal tumors. A commentary on the second edition. Cancer 1990;66:2162-7.
Green JB, Timmcke AE, Mitchell WT, Hicks TC, Gathright JB Jr., Ray JE. Mucinous carcinoma--just another colon cancer? Dis Colon Rectum 1993;36:49-54.
Nozoe T, Anai H, Nasu S, Sugimachi K. Clinicopathological characteristics of mucinous carcinoma of the colon and rectum. J Surg Oncol 2000;75:103-7.
Kanemitsu Y, Kato T, Hirai T, Yasui K, Morimoto T, Shimizu Y, et al
. Survival after curative resection for mucinous adenocarcinoma of the colorectum. Dis Colon Rectum 2003;46:160-7.
Dai D, Zhou B, Zhong Y, Jin H, Wang X. Survival of patients with resected primary colorectal mucinous adenocarcinoma: A competing risk nomogram analysis. Oncol Lett 2019;18:6594-604.
Nitsche U, Friess H, Agha A, Angele M, Eckel R, Heitland W, et al
. Prognosis of mucinous and signet-ring cell colorectal cancer in a population-based cohort. J Cancer Res Clin Oncol 2016;142:2357-66.
Catalano V, Loupakis F, Graziano F, Bisonni R, Torresi U, Vincenzi B, et al
. Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer. Ann Oncol 2012;23:135-41.
Hugen N, Verhoeven RH, Radema SA, de Hingh IH, Pruijt JF, Nagtegaal ID, et al
. Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma. Ann Oncol 2013;24:2819-24.
Okuno M, Ikehara T, Nagayama M, Kato Y, Yui S, Umeyama K. Mucinous colorectal carcinoma: clinical pathology and prognosis. Am Surg 1988;54:681-5.
Park JS, Huh JW, Park YA, Cho YB, Yun SH, Kim HC, et al
. Prognostic comparison between mucinous and nonmucinous adenocarcinoma in colorectal cancer. Medicine (Baltimore) 2015;94:e658.
Hyngstrom JR, Hu CY, Xing Y, You YN, Feig BW, Skibber JM, et al
. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: Analysis from the National Cancer Data Base. Ann Surg Oncol 2012;19:2814-21.
Nitsche U, Maak M, Schuster T, Künzli B, Langer R, Slotta-Huspenina J, et al
. Prediction of prognosis is not improved by the seventh and latest edition of the TNM classification for colorectal cancer in a single-center collective. Ann Surg 2011;254:793-800.
Heys SD, Sherif A, Bagley JS, Brittenden J, Smart C, Eremin O. Prognostic factors and survival of patients aged less than 45 years with colorectal cancer. Br J Surg 1994;81:685-8.
Song W, Wu SJ, He YL, Cai SR, Zhang CH, Zhang XH, et al
. Clinicopathologic features and survival of patients with colorectal mucinous, signet-ring cell or non-mucinous adenocarcinoma: Experience at an institution in southern China. Chin Med J (Engl) 2009;122:1486-91.
McKay A, Donaleshen J, Helewa RM, Park J, Wirtzfeld D, Hochman D, et al
. Does young age influence the prognosis of colorectal cancer: A population-based analysis. World J Surg Oncol 2014;12:370.
Li Q, Cai G, Li D, Wang Y, Zhuo C, Cai S. Better long-term survival in young patients with non-metastatic colorectal cancer after surgery, an analysis of 69,835 patients in SEER database. PLoS One 2014;9:e93756.
Chew MH, Koh PK, Ng KH, Eu KW. Improved survival in an Asian cohort of young colorectal cancer patients: An analysis of 523 patients from a single institution. Int J Colorectal Dis 2009;24:1075-83.
Goodwin RA, Asmis TR. Overview of systemic therapy for colorectal cancer. Clin Colon Rectal Surg 2009;22:251-6.
Hu X, Li YQ, Li QG, Ma YL, Peng JJ, Cai S. Mucinous adenocarcinomas histotype can also be a high-risk factor for stage II colorectal cancer patients. Cell Physiol Biochem 2018;47:630-40.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]