肠梗阻支架置入联合新辅助化疗对完全梗阻性结直肠癌患者手术标本病理特征的影响

Effect of intestinal obstruction stent combined with neoadjuvant chemotherapy on the pathological characteristics of surgical specimens in patients with complete obstructive colorectal cancer

目的比较急诊手术、肠梗阻支架-手术、肠梗阻支架-新辅助化疗-手术这3种治疗方案对完全梗阻性结直肠癌患者手术切除标本病理特征的影响。方法采用回顾性队列研究方法,收集2012年5月至2020年8月期间,首都医科大学附属北京朝阳医院普通外科收治的完全梗阻性结直肠癌患者临床病理资料。纳入结合临床表现和影像学检查确诊为完全性结直肠梗阻、病理证实为腺癌、影像学评估可切除且无远处转移者;排除多发结直肠癌、拒绝手术和合并腹膜炎或者肠梗阻支架置入前存在肠穿孔者。研究共纳入89例完全梗阻性结直肠癌患者,根据治疗策略不同,分为急诊手术组(30例)、支架-手术组(34例)及支架-新辅助化疗-手术组(25例)。通过病理切片染色和免疫组织化学分析评估并比较3组间手术切除肿瘤标本的病理特征(包括周围神经浸润、脉管浸润、癌结节、标本内组织坏死、炎性浸润、脓肿、黏液湖形成、异物巨细胞、钙化、肿瘤细胞比例等)及生物分子标志物(包括CD34、Ki67、Bcl-2、MMP-9、HiF-α)的差异。病理学评价根据标本内有无定性评价周围神经浸润、脉管浸润和癌结节等病理特征。标本病理特征评价标准:根据标本内组织坏死、炎性浸润、脓肿、黏液湖形成、异物巨细胞、钙化以及肿瘤细胞所占视野比例进行半定量的分级评估,分为:0级:标本内未见;1级:比例为0~25%;2级:比例为25%~50%;3级:比例为50%~75%;4级:比例为75%~100%。手术切除标本免疫组织化学评价标准:根据阳性免疫细胞所占视野范围及细胞免疫强度进行评估。根据阳性细胞比例分为:0分:标本内未见;1分:比例为0~25%;2分:比例为25%~50%;3分:比例为50%~75%;4分:比例为75%~100%。将细胞免疫强度分为无(0分)、微弱(1分)、中等(2分)和强(3分)。再将两者相乘得到0~12的总分,综合评价免疫组化结果,结果定义为:阴性(0级):0分;弱阳性(1级):1~3分;中等阳性(2级):4~6分;强阳性(3级):7~9分;极强阳性(4级):10~12分。正态分布的计量资料用x±s表示,采用单因素方差分析组间差异;非正态分布的计量资料用M(Q_(1),Q_(3))表示。采用非参数检验(Kruskal-Wallis H检验)进行组间比较。结果3组间年龄、性别、肿瘤部位、美国麻醉医师协会评分、肿瘤T分期、N分期和肿瘤分化程度等基线数据比较,差异均无统计学意义(均P>0.05)。3组间切除的肿瘤标本异物巨细胞、炎性浸润和黏液湖形成等病理特征比较,差异均无统计学意义(均P>0.05)。急诊手术组、支架-手术组及支架-新辅助化疗-手术组的脉管浸润率分别为56.6%(17/30)、44.1%(15/34)和20.0%(5/25),组间比较差异有统计学意义(χ^(2)=7.142,P=0.028),支架-新辅助化疗-手术组的脉管浸润率显著低于急诊手术组(P=0.038);周围神经浸润率分别为55.3%(16/30)、41.2%(14/34)和16.0%(4/25),差异有统计学意义(χ^(2)=7.735,P=0.021),支架-新辅助化疗-手术组的周围神经浸润率显著低于急诊手术组(P=0.032);坏死分级分别为2(1,2)级、2(1,3)级和2(2,3)级,差异有统计学意义(H=10.090,P=0.006),进一步两两比较发现,与急诊手术组比较,支架-手术组和支架-新辅助化疗-手术组坏死分级更高(均P<0.05);脓肿分级分别为2(1,2)级、3(1,3)级和2(2,3)级,差异有统计学意义(H=6.584,P=0.037);进一步两两比较分析发现,急诊手术组的脓肿分级明显低于支架-手术组(P=0.037);纤维化分级分别为2(1,3)级、3(2,3)级和3(2,3)级,差异有统计学意义(H=11.078,P=0.004);进一步两两比较分析发现,支架-手术组和支架-新辅助化疗-手术组的纤维化均高于急诊手术组(均P<0.05);肿瘤细胞比例分级分别为4(3,4)级、4(3,4)级和3(2,4)级,组间比较差异有统计学意义(H=8.594,P=0.014),进一步两两比较分析发现,支架-新辅助化疗-手术组的肿瘤细胞比例显著低于急诊手术组(P=0.012);CD34分级分别为2(2,3)级、3(2,4)级和3(2,3)级,差异有统计学意义(H=9.786,P=0.007),进一步两两比较分析发现,支架组CD34高于急诊手术组(P=0.005)。结论支架置入可能增加梗阻性结直肠癌远处转移的风险。支架-新辅助化疗-手术的治疗模式促进了肿瘤细胞坏死和纤维化,减少了肿瘤细胞比例、脉管浸润和周围神经浸润,可能有助于改善支架置入后完全梗阻性结直肠癌的局部肿瘤浸润及远处转移。

Objective To compare the effects of three treatment options:emergency surgery,stent-surgery,and stent-neoadjuvant chemotherapy-surgery,on the pathological characteris-tics of surgically-resected specimens from patients with completely obstructive colorectal cancer.Methods This was a retrospective cohort study analyzing clinicopathological data of patients with complete obstructive colorectal cancer who were admitted to the General Surgery Department of Beijing Chaoyang Hospital,Capital Medical University,between May 2012 and August 2020.The inclusion criteria were diagnosed with complete colorectal obstruction,pathologically confirmed as adenocarcinoma,resectable on imaging assessment,and without distant metastasis,combined with the patients'clinical manifestations and imaging examination findings.Patients with multiple colorectal cancers,refusal to undergo surgery,and concurrent peritonitis or intestinal perforation before stenting of the intestinal obstruction were excluded.Eighty-nine patients with completely obstructive colorectal cancer were enrolled in the study and were divided into emergency surgery group(n=30),stent-surgery group(n=34),and stent-neoadjuvant chemotherapy-surgery group(n=25)according to the treatment strategy.Differences in the pathological features(namely perineural infiltration,lymphovascular infiltration,tumor deposits,specimen intravascular necrosis,inflammatory infiltration,abscesses,mucus lake formation,foreign body giant cells,calcification,and tumor cell ratio)and biomolecular markers(namely cluster of differentiation(CD)34,Ki67,Bcl-2,matrix metalloproteinase-9,and hypoxia-inducible factor alpha)were recorded.Pathological evaluation was based on the presence or absence of qualitative evaluation of pathological features,such as peripheral nerve infiltration,vascular infiltration,and cancer nodules within the specimens.The evaluation criteria for the pathological features of the specimens were as follows:Semi-quantitative graded evaluation based on the proportion of tissue necrosis,inflammatory infiltrates,abscesses,mucus lake formation,foreign body giant cells,calcification,and tumor cells in the field of view within the specimen were classified as:grade 0:not seen within the specimen;grade 1:0–25%;grade 2:25%–50%;grade 3:50%–75%;and grade 4:75%–100%.The intensity of cellular immunity was classified as none(0 points),weak(1 point),moderate(2 points),and strong(3 points).The two evaluation scores were then multiplied to obtain a total score of 0–12.The immunohistochemical results were also evaluated comprehensively,and the results were defined as:negative(grade 0):0 points;weakly positive(grade 1):1–3 points;moderately positive(grade 2):4–6 points;strongly positive(grade 3):7–9 points;and very strong positive(grade 4):10–12 points.Normally-distributed values were expressed as mean±standard deviation,and one-way analysis of variance was used to analyze the differences between the groups.Non-normally-distributed values were expressed as median(interquartile range:Q1,Q3).A nonparametric test(Kruskal–Wallis H test)was used for comparisons between groups.Results The differences were not statistically significant when comparing the baseline data for age,gender,tumor site,American Society of Anesthesiologists score,tumor T-stage,N-stage,and degree of differentiation among the three groups(all P>0.05).The differences were not statistically significant when comparing the pathological characteristics of the resected tumor specimens,such as foreign body giant cells,inflammatory infiltration,and mucus lake formation among the three groups(all P>0.05).The rates of vascular infiltration were 56.6%(17/30),41.2%(15/34),and 20.0%(5/25)in the emergency surgery,stent-surgery,and stent-neoadjuvant chemotherapy-surgery groups,respectively,with statistically significant differences between the groups(χ^(2)=7.142,P=0.028).Additionally,the rate of vascular infiltration was significantly lower in the stent-neoadjuvant chemotherapy-surgery group than that in the emergency surgery group(P=0.038).Peripheral nerve infiltration rates were 55.3%(16/30),41.2%(14/34),and 16.0%(4/25),in the emergency surgery,stent-surgery,and stent-neoadjuvant chemotherapy-surgery groups,respectively,with statistically significant differences(χ^(2)=7.735,P=0.021).The infiltration peripheral nerve rates in the stent-neoadjuvant chemotherapy-surgery group were significantly lower than those in the emergency surgery group(P=0.032).The necrosis grade was 2(1,2),2(1,3),and 2(2,3)in the emergency surgery,stent-surgery,and stent-neoadjuvant chemotherapy-surgery groups,respectively,with statistically significant differences(H=10.090,P=0.006).Post hoc comparison revealed that the necrosis grade was higher in the stent-surgery and stent-neoadjuvant chemotherapy-surgery groups compared with the emergency surgery group(both P<0.05).The abscess grade was 2(1,2),3(1,3),and 2(2,3)in the emergency surgery,stent-surgery,and stent-neoadjuvant chemotherapy-surgery groups,respectively,with statistically significant differences(H=6.584,P=0.037).Post hoc comparison revealed that the abscess grade in the emergency surgery group was significantly lower than that in the stent-surgery group(P=0.037).The fibrosis grade was 2(1,3),3(2,3),and 3(2,3),in the emergency surgery,stent-surgery,and stent-neoadjuvant chemotherapy-surgery groups,respectively,with statistically significant differences(H=11.078,P=0.004).Post hoc analysis revealed that the fibrosis degree was higher in both the stent-surgery group and the stent-neoadjuvant chemotherapy-surgery group compared with the emergency surgery group(both,P<0.05).The tumor cell ratio grades were 4(3,4),4(3,4),and 3(2,4),in the emergency surgery,stent-surgery,and stent-neoadjuvant chemotherapy-surgery groups,respectively,with statistically significant differences(H=8.594,P=0.014).Post hoc analysis showed that the tumor cell ratio in the stent-neoadjuvant chemotherapy-surgery group was significantly lower than that in the emergency surgery group(P=0.012).The CD34 grades were 2(2,3),3(2,4),and 3(2,3)in the emergency surgery,stent-surgery,and stent-neoadjuvant chemotherapy-surgery groups,respectively,and the difference was statistically significant(H=9.786,P=0.007).Post hoc analysis showed that the CD34 grades in the emergency surgery,stent-surgery,and stent-neoadjuvant chemotherapy-surgery groups were 2(2,3),3(2,4),and 3(2,3),respectively.Post hoc analysis revealed that the CD34 concentration was higher in the stent-surgery group than that in the emergency surgery group(P=0.005).Conclusion Stenting may increase the risk of distant metastases in obstructive colorectal cancer.The stent-neoadjuvant chemotherapy-surgery treatment model promotes tumor cell necrosis and fibrosis and reduces the proportion of tumor cells,vascular infiltration,and peripheral nerve infiltration,which may help decrease local tumor infiltration and distant metastasis in completely obstructive colorectal cancer after stent placement.