胆囊神经内分泌癌临床特征及诊治分析：附3例报告并文献回顾

Analysis of clinical characteristics, diagnosis and treatment of neuroendocrine carcinoma of gallbladder: a report of 3 cases and literature review

摘要:

背景与目的 胆囊原发性神经内分泌癌（GB-NEC）极为罕见且预后差，由于GB-NEC病例非常少见，目前少有系统总结其临床特征的研究。因此，本研究对扬州大学附属兴化市人民医院收治的GB-NEC病例及近20年中文献报道的GB-NEC病例进行总结分析，以期提高对该病的认识。方法 回顾收治的3例GB-NEC患者资料，并收集2000年1月—2020年12月间文献报道的121例GB-NEC病例的相关资料，分析患者的基本临床特征、预后因素及治疗结局。结果 收治的3例患者均因腹痛等非特异性症状就诊，3例均行手术治疗，术后病理与免疫组化证实均为GB-NEC（1例意外胆囊癌）。3例均行术后辅助化疗，中短期随访期间2例死亡，1例存活。124例GB-NEC患者的中位年龄为58岁，其中女性占62.9%（78/124）；72.1%（44/61）为小细胞癌，32.5%（29/84）为混合型神经内分泌癌。中位生存时间在全组患者中为11个月，在不同临床分期患者中随着临床分期增加而缩短。将49例有完整资料的患者纳入分析，结果显示，年龄>80岁（HR=1.364，95% CI=1.026~1.860，P=0.049）、TNM分期（II期vs. I期：HR=10.408，95% CI=2.554~42.404，P=0.001；III期vs. I期：HR=13.167，95% CI=3.288~52.732，P<0.001；IV期vs. I期：HR=38.022，95% CI=9.738~148.459，P<0.001）、手术（非根治术vs.未手术：HR=0.122，95% CI=0.022~0.786，P=0.027；根治术vs.未手术：HR=0.088，95% CI=0.019~0.481，P=0.006）、化疗与否（HR=0.517，95% CI=0.305~0.983，P=0.042）是生存结局的独立影响因素。糖类抗原125（CA125）水平的升高与更晚的临床分期相关（r=0.727，P<0.05）。亚组分析中，术式（胆囊切除术vs.根治术：HR=2.889，95% CI=0.908~9.168，P=0.072）、化疗与否（HR=3.120，95% CI=0.768~12.676，P=0.112）对于I、II期患者的结局影响差异无统计学意义。术式（胆囊+转移灶切除术vs.根治术：HR=0.675，95% CI=0.113~4.023，P=0.667）和化疗与否（HR=2.109，95% CI=0.808~5.994，P=0.127）对III期患者结局的影响无统计学意义。IV期患者行化疗有生存优势（HR=2.785，95% CI=1.376~5.636，P=0.004），主要体现在小细胞癌患者（中位值生存时间：9个月vs. 3个月，P<0.001），而对大细胞癌患者效果不显著（中位值生存时间：5个月vs. 2个月，P=0.247）；手术不能改善IV期患者预后（根治术vs.未手术：HR=0.533，95% CI=0.232~1.233，P=0.138；非根治术vs.未手术：HR=0.932，95% CI=0.434~2.000，P=0.856）。结论 提高早期诊断率是改善GB-NEC患者预后的关键。I~III期患者可行手术切除，但胆囊癌根治术是不必要的；晚期小细胞癌患者行化疗可以帮助提高生存率以及手术切除可能。CA125可能作为GB-NEC的预后指标，但需要更多的研究证明。

Abstract:

Background and Aims Primary neuroendocrine carcinoma of the gallbladder (GB-NEC) is extremely rare and its prognosis is generally poor. There are few studies systematically summarizing its clinical characteristics now due to the scarce cases of GB-NEC. Therefore, this study was performed to summarize and analyze the GB-NEC cases treated in the Xinghua People's Hospital, Yangzhou University and the reported cases of GB-NEC in literature in recent 20 years in order to increase the awareness of this disease.Methods The clinical data of 3 patients with GB-NEC treated in the authors' hospital were reviewed, and the relevant data of 121 reported cases of GB-NEC in literature from January 2000 to December 2020 were extracted. The general clinical feature, prognostic factors and treatment outcomes of patients were analyzed.Results The 3 GB-NEC patients were all hospitalized for non-specific symptoms including abdominal pain and underwent surgical treatment. Their specimens were confirmed as GB-NEC (including one case of accidental gallbladder cancer) by postoperative pathological and immunohistochemical examinations. All the 3 patients received postoperative adjuvant chemotherapy, and 2 cases died and one case was still alive during a short- or medium-term period of follow-up. Of the total 124 patients with GB-NEC, the median age was 58 years, female cases accounted for 62.9% (78/124), 72.1% (44/61) were small cell carcinoma and 32.5% (29/84) were mixed neuroendocrine carcinoma. The median survival time was 11 months in the whole group of patients, and was decreased as the clinical stage advanced in different clinical stage groups. Analysis of the variables of 49 patients with complete data showed that age >80 years (HR=1.364, 95% CI=1.026-1.860, P=0.049), TNM stage (stage II vs. stage I: HR=10.408, 95% CI=2.554-42.404, P=0.001; stage III vs. stage I: HR=13.167, 95% CI=3.288-52.732, P<0.001; stage IV vs. stage I: HR=38.022, 95% CI=9.738-148.459, P<0.001), surgery (non-radical surgery vs. non-surgery: HR=0.122, 95% CI=0.022-0.786, P=0.027; radical surgery vs. non-surgery: HR=0.088, 95% CI=0.019-0.481, P=0.006) and receiving chemotherapy or not (HR=0.517, 95% CI=0.305-0.983, P=0.042) were independent factors affecting survival outcomes. The increase of carbohydrate antigen 125 (CA125) level was associated with higher clinical stage (r=0.727, P<0.05). In subgroup analysis, the surgical procedure (cholecystectomy vs. radical surgery: HR=2.889, 95% CI=0.908-9.168, P=0.072) and receiving chemotherapy or not (HR=3.120, 95% CI=0.768-12.676, P=0.112) exerted no significant influence on the outcomes in stage I and II patients. The surgical procedure (cholecystectomy plus metastasis resection vs. radical surgery: HR=0.675, 95% CI=0.113-4.023, P=0.667) and receiving chemotherapy or not (HR=2.109, 95% CI=0.808-5.994, P=0.127) had no significant effect on the outcome in stage III patients. Chemotherapy offered a survival advantage in stage IV patients (HR=2.785, 95% CI=1.376-5.636, P=0.004), which was mainly reflected in patients with small cell carcinoma (median survival time: 9 months vs. 3 months, P<0.001), while was not significant in patients with large cell carcinoma (median survival time: 5 months vs. 2 months, P=0.247); Surgery did not improve the prognosis of stage IV patients (radical surgery vs. non-surgery: HR=0.533, 95% CI=0.232-1.233, P=0.138; non-radical surgery vs. non-surgery: HR=0.932, 95% CI=0.434-2.000, P=0.856).Conclusion Improving the early diagnosis efficiency is important for the prognosis of patients with GB-NEC. For staged IIII patients, surgical resection can be performed, but radical cholecystectomy is unnecessary; chemotherapy can help improve the survival rate and increase the chance of surgical resection in patients with advanced small cell carcinoma. CA125 may be used as a prognostic indicator for GB-NEC, but it still needs more studies to be proven.