Clinical significance of mucinous component in colorectal adenocarcinoma: A propensity score-matched study

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This study aims to investigate the clinical significance and prognostic value of mucinous component (MC) in colorectal adenocarcinoma (AC). Methods: Patients with colorectal AC and AC with MC (ACMC) (1–100%) underwent surgical resection between January 2007 and February 2018 were retrospectively reviewed.

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Nội dung Text: Clinical significance of mucinous component in colorectal adenocarcinoma: A propensity score-matched study

Yan et al. BMC Cancer (2021) 21:1286 https://doi.org/10.1186/s12885-021-09031-9 RESEARCH Open Access Clinical significance of mucinous component in colorectal adenocarcinoma: a propensity score-matched study Chuanwang Yan1†, Hui Yang2†, Lili Chen3†, Ran Liu2, Wei Shang2, Wenguang Yuan2, Fei Yang3*, Qing Sun4* and Lijian Xia3* Abstract Background: This study aims to investigate the clinical significance and prognostic value of mucinous component (MC) in colorectal adenocarcinoma (AC). Methods: Patients with colorectal AC and AC with MC (ACMC) (1–100%) underwent surgical resection between January 2007 and February 2018 were retrospectively reviewed. Propensity score matching (PSM) was performed according to a 1:1 ratio. Receiver-operating characteristic (ROC) curve was used to identify the optimal cut-off value of MC ratio for prognostic prediction. The clinicopathological features and 3-year overall survival (OS) of AC patients, mucinous adenocarcinoma (MAC) (MC > 50%) patients, and ACMC (1–50%) patients were compared before and after matching. Multivariable analysis was used for analyzing independent risk factors related to prognosis. Results: A total of 532 patients were enrolled in this study. Patients with AC, MAC, and ACMC (1–50%) exhibited dif- ferent clinicopathological features. However, their 3-year OS rates were similar (82.00% vs. 74.11% vs. 81.48%, P = 0.38). After matching, ROC curve determined 70% as the optimal cut-off value. And patients with ACMC > 70% had a much poorer 3-year OS compared with ACMC (1–70%) patients and AC patients (47.37% vs. 86.15% vs. 79.76%, P 70% was revealed as a risk factor for poor survival in univariate analysis (HR = 1.643, 95%CI = 1.025– 2.635, P = 0.039), though not an independent risk factor in multivariable analysis (HR = 1.550, 95%CI = 0.958–2.507, P = 0.074). Conclusions: MAC is usually diagnosed at an advanced stage. MAC has a similar survival with AC and ACMC (1–50%) patients before and after matching. Patients with ACMC > 70% exhibited a much poorer OS, and should be given more clinical attention. Keywords: Colorectal cancer, Adenocarcinoma, Mucinous component, Survival prognosis Introduction Colorectal cancer (CRC) ranks the world’s fourth most *Correspondence: yangf-2008@163.com; qingsw99@sdhospital.com.cn; deadly cancer with almost 900,000 deaths annually [1]. xiaalbert2758@163.com † Yan Chuanwang, Yang Hui and Chen Lili contributed equally to this work. CRC has several histological types, and mucinous adeno- 3 Department of Pathology, Jinan Central Hospital Affiliated to Shandong carcinoma (MAC) comprises about 1.6–25.4% of all CRC First Medical University, Jinan 250000, Shandong, China cases [2]. According to the World Health Organization 4 Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong (WHO) criteria, MAC is defined as “> 50% of the lesion Medicine and Health Key Laboratory of Clinical Pathology, Shandong is composed of pools of extracellular mucin that contain Lung Cancer Institute, Shandong Institute of Nephrology, Jinan, China malignant epithelium” [3]. However, 50% is more a cutoff Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Yan et al. BMC Cancer (2021) 21:1286 Page 2 of 12 Table 1 Clinicopathological parameters for patients before matching Clinicopathological parameters Adenocarcinoma Adenocarcinoma with mucinous Mucinous P component (1–50%) adenocarcinoma (> 50%) Gender 0.501 Female 174 25 18 Male 265 29 21 Age 0.150
Yan et al. BMC Cancer (2021) 21:1286 Page 3 of 12 Table 1 (continued) Clinicopathological parameters Adenocarcinoma Adenocarcinoma with mucinous Mucinous P component (1–50%) adenocarcinoma (> 50%) Right-sided 43 16 13 Left-sided 396 38 26 Defunctioning stoma 0.705 No 434 53 39 Yes 5 1 0 Postoperative complication 0.635 Absent 374 46 31 Present 65 8 8 Differentiation
Yan et al. BMC Cancer (2021) 21:1286 Page 4 of 12 Hospital of Shandong First Medical University & Shan- clinic. Physical examination, serum tumor markers, dong Provincial Qianfoshan Hospital were reviewed. including CEA, and abdominal/chest/pelvic imaging Final diagnosis was confirmed by pathology. Patients with using a CT scan were used for surveillance. Colonos- a history of cancer, two or more cancers, synchronous copy was performed at the 1st and 2nd year after surgery. distant metastasis, local excision, palliative surgery, and Overall survival (OS) was defined as the period from the no complete clinicopathological or follow-up data were surgery to death from any cause. excluded. We collected the following data of each patient from clinical records: gender, age, history of smoking Pathological evaluation and alcoholism, the American Society of Anesthesiolo- For each case, the number of paraffin block for pathologi- gists (ASA) class, comorbidities (hypertension, diabetes cal evaluation was determined based on the tumor size (1 mellitus, coronary artery disease (CAD), and hepatitis), block per cm). Tumor sections from paraffin blocks were preoperative carcinoembryonic antigen (CEA), carbohy- stained with hematoxylin-eosin. The ratio of MC area drate antigen 19–9 (CA19–9), albumin, and hemoglobin was separately evaluated by two pathologists, and the (HGB) levels, occult blood status, operative factors (oper- mean value was adopted. If the difference in estimated ation time, perioperative blood transfusion, defunction- values was 10% or greater, the two pathologists reas- ing stoma, and postoperative complications), and tumor sessed the specimens to determine the consensus. Finally, factors (tumor location, differentiation, signet-ring cell tumors, with MC proportion ranging from 1 to 100%, component, perineural invasion (PNI), lymphovascular were classified into 10 groups evenly with 10% ingredi- invasion (LVI), T stage, N stage, M stage and TNM stage). ent per group. Classical gland-forming adenocarcino- Written informed consent was signed by each patient. mas with variable size and configuration of the glandular This study was approved by the First Affiliated Hospital structures were classified as AC. ACMC was defined as of Shandong First Medical University & Shandong Pro- tumors with 1–100% of the lesion being composed of vincial Qianfoshan Hospital Institutional Review Board. mucin, typically characterized by pools of extracellular mucin that contain malignant epithelium as acinar struc- Follow‑up method tures, strips of cells, or single cells. And those with more Patients were followed up postoperatively every 6 months than 50% mucin in tumor were labelled as MAC. Signet for 2 years, and then annually for 3–5 years at outpatient ring cell component was defined as AC with signet ring Fig. 1 Survival of patients in the AC group, the MAC group and the ACMC (1–50%) group before matching. A. All involved patients. B. TNM stage I patients. C. TNM stage II patients. D. TNM stage III patients
Yan et al. BMC Cancer (2021) 21:1286 Page 5 of 12 cells, regardless of extent, which typically show displace- CEA, CA19–9, albumin, and HGB levels, occult blood ment and molding of the nucleus. status, operative factors and tumor factors. Receiver- operating characteristic (ROC) curve was used to iden- Statistical analysis tify the optimal cut-off value of MC ratio for prognostic The data are presented as the mean and SD or as the prediction. At each ratio, the sensitivity and specificity median and range. For differences in categorical vari- for survival were determined and plotted, thereby gener- ables, chi-square analysis, Fisher exact test or Kruskal- ating a ROC curve. According to the (0, 1) criterion, the Wallis ANOVA test was performed where appropriate. point on of the curve with the shortest distance to the Survival was depicted with Kaplan-Meier curves and coordinate (0, 1) was chosen as the cut-off value. Two- compared using log-rank tests. Univariable and multivar- sided P ≤ 0.050 was considered statistically significant. iable survival analyses using Cox regression models were All statistical analyses were performed using the SPSS performed to identify prognostic factors. Hazard ratios software program (version 22.0 for Windows, IBM SPSS (HRs) were presented with 95% confidence intervals Statistics, IBM Corporation, Armonk, NY). (95%CI). Propensity-score matched (PSM) analysis was conducted to minimize bias. The 1:1 matching process Results was performed by using the nearest neighbor matching Patient characteristics before matching method, with a maximum caliper width of 0.03 times the A total of 532 CRC patients were enrolled in this study. standard deviation of the logit (propensity score). Vari- The clinicopathological features of these patients ables adjusted included gender, age, history of smoking are shown in Table 1. Mean age of the patients was and alcoholism, ASA class, comorbidities, preoperative (64.51 ± 12.09) years, including 315 males and 217 Table 2 Univariable and multivariable analysis for patients before matching Parameters Univariable analysis Multivariable analysis HR 95% CI P value HR 95% CI P value Gender Female vs. Male 1.156 0.770–1.737 0.485 Age
Yan et al. BMC Cancer (2021) 21:1286 Page 6 of 12 Table 3 Clinicopathological parameters for patients after matching Clinicopathological parameters Adenocarcinoma vs. P Adenocarcinoma vs. P Adenocarcinoma vs. P Mucinous component Mucinous component Mucinous adenocarcinoma (1–100%) (1–50%) (> 50%) Gender 0.537 0.418 0.051 Female 42/38 19/23 23/15 Male 42/46 31/27 11/19 Age 0.606 1.000 0.318
Yan et al. BMC Cancer (2021) 21:1286 Page 7 of 12 Table 3 (continued) Clinicopathological parameters Adenocarcinoma vs. P Adenocarcinoma vs. P Adenocarcinoma vs. P Mucinous component Mucinous component Mucinous adenocarcinoma (1–100%) (1–50%) (> 50%) Tumor location 0.717 1.000 0.380 Right-sided 19/21 12/12 6/9 Left-sided 65/63 38/38 28/25 Defunctioning stoma 1.000 1.000 1.000 No 83/83 49/49 34/34 Yes 1/1 1/1 0/0 Postoperative complication 1.000 0.790 0.770 Absent 68/68 41/42 27/26 Present 16/16 9/8 7/8 Differentiation 0.872 0.509 0.625 Well+Moderate 54/55 34/37 20/18 Poor 30/29 16/13 14/16 Signet-ring cell component 1.000 1.000 1.000 Absent 83/83 49/50 34/33 Present 1/1 1/0 0/1 PNI 1.000 1.000 1.000 No 80/80 47/47 33/33 Yes 4/4 3/3 1/1 LVI 0.223 1.000 0.105 No 77/72 44/44 33/28 Yes 7/12 6/6 1/6 T stage 0.816 0.779 1.000 1/2 11/10 8/7 3/3 3/4 73/74 42/43 31/31 N stage 0.757 0.230 0.324 0 38/40 22/28 16/12 1/2 46/44 28/22 18/22 TNM stage 0.757 0.230 0.324 I-II 38/40 22/28 16/12 III 46/44 28/22 18/22 ASA American Society of Anesthesiologists, CAD coronary artery disease, CEA carcinoembryonic antigen, CA19–9 carbohydrate antigen 19–9, HGB hemoglobin, TNM tumor-lymph node-metastasis, LVI lymphovascular invasion, PNI perineural invasion females. Postoperative complication rate was 15.2% the patients with all TNM stages, TNM stage I, II, and III (81/532). As indicated in Table 1, MAC patients have were similar among the AC group (82.00, 91.51, 90.68, a higher rate of CA19–9 ≥ 37 U/ml (P = 0.006), albu- and 72.56%), ACMC (1–50%) group (81.48, 100, 83.33, min
Yan et al. BMC Cancer (2021) 21:1286 Page 8 of 12 P = 0.001), postoperative complication (HR = 2.312, (HR = 2.389, 95%CI = 1.314–4.344, P = 0.004), advanced 95%CI = 1.485–3.599, P
Yan et al. BMC Cancer (2021) 21:1286 Page 9 of 12 similar (Table 3). The rate of patients receiving adjuvant MC > 70% (HR = 1.643, 95%CI = 1.025–2.635, P = 0.039), chemotherapy was 58.33% (98/168 cases), including 49 in PNI (HR = 2.969, 95%CI = 1.049–8.400, P = 0.040), LVI the AC group, 27 in the MAC group, and 22 in the ACMC (HR = 2.675, 95%CI = 1.218–5.878, P = 0.014), advanced (1–50%) group. The 3-year OS rates of the patients with N stage (HR = 2.555, 95%CI = 1.231–5.300, P = 0.012), all TNM stages, TNM stage I, II, and III were similar in and advanced TNM stage (HR = 2.555, 95%CI = 1.231– the AC group (79.76, 100, 90.63, and 69.57%), ACMC 5.300, P = 0.012) were identified to be risk factors for poor (1–50%) group (84.00, 100, 86.36, and 77.27%) and the OS (Table 4). Multivariable analysis found that advanced MAC group (67.65, 100, 63.64, and 68.18%) (P > 0.05) N stage (HR = 2.210, 95%CI = 1.035–4.719, P = 0.041) and (Fig. 2A-D). To further to define the prognostic value of TNM stage (HR = 2.210, 95%CI = 1.035–4.719, P = 0.041) MC in CRC patients, ROC curve was adopted and 65% were independent risk factors for poor OS (Table 4). of mucinous area was determined as the optimal cut-off score (area under the curve = 0.677) (Fig. 2E). To increase specificity, 70% was used for the following analysis. As a Discussion result, patients with ACMC > 70% showed a much poorer MAC has different clinicopathological features com- survival compared with patients with ACMC (1–70%) pared with AC [2, 8]. Consistently with previous reports and AC patients (47.37% vs. 86.15% vs. 79.76%, P 70% in TNM stage II patients advanced T stage before matching, which indicated that (50.00% vs. 88.00% vs. 90.63%, P = 0.002) and TNM stage MAC is more advanced at diagnosis. In addition, our III patients (45.46% vs. 81.82% vs. 69.57%, P = 0.023) results showed that MAC patients have a higher rate of (Fig. 3C-D). However, the survival was similar in TNM albumin 70%) group and the ACMC (1–70%) group after matching. A. All involved patients. B. TNM stage I patients. C. TNM stage II patients. D. TNM stage III patients
Yan et al. BMC Cancer (2021) 21:1286 Page 10 of 12 Table 4 Univariable and multivariable analysis for patients after matching Parameters Univariable analysis Multivariable analysis HR 95% CI P value HR 95% CI P value Gender Female vs. Male 1.301 0.671–2.524 0.436 Age
Yan et al. BMC Cancer (2021) 21:1286 Page 11 of 12 Li et al. have detected that the combined mutation fre- Declarations quency of the two key factors of the EGFR signaling Ethics approval and consent to participate pathway, KRAS and BRAF, in the CRCs with and without This study was approved by the First Affiliated Hospital of Shandong First MC was 95.9 and 52.1%, respectively. The desregulated Medical University & Shandong Provincial Qianfoshan Hospital Institutional EGFR pathway plays a pivotal role in the development Review Board. All the experiment protocol for involving human data was in accordance with the guidelines of national in the manuscript. The study of ACMC, irrespective of the percentage [26]. Besides, obtained the written consent of all participants. low frequency of mutations in the p53 gene or overex- pression of p53 protein and loss of heterozygosity in the Consent for publication Not applicable. DCC gene have been reported [30, 31]. Genome-wide analysis found that MAC displayed 182 upregulated and Competing interests 135 downregulated genes compared with AC [29]. The Nothing to declare. most upregulated genes included those involved in cel- Author details lular differentiation and mucin metabolism, and altered 1 Department of General Surgery, Shandong Provincial Qianfoshan Hospital, biologic pathways included those associated with mucin Weifang Medical University, Key Laboratory of Metabolism and Gastrointes- tinal Tumor, the First Affiliated Hospital of Shandong First Medical University, substrate metabolism, amino acid metabolism, and the Key Laboratory of Laparoscopic Technology, the First Affiliated Hospital mitogen-activated protein kinase cascade [29]. Consist- of Shandong First Medical University, Shandong Medicine and Health Key Lab- ently, MUC2, which is one of the glycosylated proteins, oratory of General Surgery, Weifang 261000, Shandong, China. 2 Department of General Surgery, The First Affiliated Hospital of Shandong First Medical Uni- was reported to be overexpressed in MAC [32, 33]. In versity & Shandong Provincial Qianfoshan Hospital, Key Laboratory of Metabo- addition, MAC overexpresses both TYMS and GSTP1, lism and Gastrointestinal Tumor, the First Affiliated Hospital of Shandong biomarkers indicating resistance to 5-FU and oxaliplatin First Medical University, Key Laboratory of Laparoscopic Technology, the First Affiliated Hospital of Shandong First Medical University, Shandong Medicine [34]. These findings may partially illustrate the different and Health Key Laboratory of General Surgery, Jinan 250000, Shandong, China. phenotypes of MAC. 3 Department of Pathology, Jinan Central Hospital Affiliated to Shandong First In conclusion, this study detected that MAC is usu- Medical University, Jinan 250000, Shandong, China. 4 Department of Pathol- ogy, The First Affiliated Hospital of Shandong First Medical University & ally diagnosed as an advanced stage. MAC patients Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key have a similar survival with AC patients and ACMC Laboratory of Clinical Pathology, Shandong Lung Cancer Institute, Shandong (1–50%) patients before and after matching. Mucin Institute of Nephrology, Jinan, China. accounting for more than 70% in the lesion is a more Received: 16 June 2021 Accepted: 15 November 2021 valuable cut-off score of predicting poor survival. Patients with MC > 70% should be given more clinical attention. 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