Abstract：
BACKGROUND: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are rare malignancies. Here we presented two cases and reviewed the related literature.
METHODS: Our two patients were postoperatively diagnosed with gallbladder MiNENs, which pathologically consisted of a large cell neuroendocrine carcinoma and papillary adenocarcinoma. After cholecystectomy, one patient had a survival time of 30 months, while the other remained alive through 12 months of follow-up. In the literature, a total of 72 cases of gallbladder MiNENs were identified, and with our two patients included, we calculated a male-to-female ratio of 0.22 and a mean age of 64.5 years for the 74 reported cases. About one-half of these patients were found to have gallstones and presented with abdominal pain or discomfort in a relatively early stage. The preoperative diagnosis of these 74 cases mainly relied on abdominal ultrasound, contrast-enhanced computed tomography (CT) scanning, and magnetic resonance imaging or positron emission tomography/CT. However, the final diagnosis was established based upon the pathological evidence and expression of synaptophysin (Syn) and/or chromogranin A identified by immunohistochemical staining or neurosecretory granules detected by electron microscopy. Fifty-eight patients (78.4%) underwent various operations including simple cholecystectomy (n = 14), en bloc cholecystectomy (n = 9), standard or non-standard radical cholecystectomy (n = 25), or extended radical cholecystectomy (n = 6). The mean size of the resected gallbladder masses was 50.8 ± 36.1 mm (n = 63) with regional lymph node metastasis in 37 patients (52.1%), liver invasion or staging greater than T3 in 33 patients (45.8%), and hepatic metastasis in 26 patients (35.1%). The postoperative median survival time was 36 ± 11.42 months (95% confidence interval, 13.62 to 58.38 months). The log-rank analysis did not find that postoperative adjuvant chemotherapy contributed to a longer survival time relative to that among the patients who did not receive chemotherapy (numbers of patients, 15 versus 43; survival times, 36 months versus 30 months, p > 0.05).
CONCLUSIONS: Our two cases and the cases in the literature suggest that MiNENs of the gallbladder predominantly occur in women; are associated with early lymph node metastasis, local hepatic invasion, and hepatic metastasis; and can be managed by various surgeries as well as chemotherapy combined with somatostatin analogs.
METHODS: Our two patients were postoperatively diagnosed with gallbladder MiNENs, which pathologically consisted of a large cell neuroendocrine carcinoma and papillary adenocarcinoma. After cholecystectomy, one patient had a survival time of 30 months, while the other remained alive through 12 months of follow-up. In the literature, a total of 72 cases of gallbladder MiNENs were identified, and with our two patients included, we calculated a male-to-female ratio of 0.22 and a mean age of 64.5 years for the 74 reported cases. About one-half of these patients were found to have gallstones and presented with abdominal pain or discomfort in a relatively early stage. The preoperative diagnosis of these 74 cases mainly relied on abdominal ultrasound, contrast-enhanced computed tomography (CT) scanning, and magnetic resonance imaging or positron emission tomography/CT. However, the final diagnosis was established based upon the pathological evidence and expression of synaptophysin (Syn) and/or chromogranin A identified by immunohistochemical staining or neurosecretory granules detected by electron microscopy. Fifty-eight patients (78.4%) underwent various operations including simple cholecystectomy (n = 14), en bloc cholecystectomy (n = 9), standard or non-standard radical cholecystectomy (n = 25), or extended radical cholecystectomy (n = 6). The mean size of the resected gallbladder masses was 50.8 ± 36.1 mm (n = 63) with regional lymph node metastasis in 37 patients (52.1%), liver invasion or staging greater than T3 in 33 patients (45.8%), and hepatic metastasis in 26 patients (35.1%). The postoperative median survival time was 36 ± 11.42 months (95% confidence interval, 13.62 to 58.38 months). The log-rank analysis did not find that postoperative adjuvant chemotherapy contributed to a longer survival time relative to that among the patients who did not receive chemotherapy (numbers of patients, 15 versus 43; survival times, 36 months versus 30 months, p > 0.05).
CONCLUSIONS: Our two cases and the cases in the literature suggest that MiNENs of the gallbladder predominantly occur in women; are associated with early lymph node metastasis, local hepatic invasion, and hepatic metastasis; and can be managed by various surgeries as well as chemotherapy combined with somatostatin analogs.
摘要：
背景：胆囊的混合性神经内分泌-非神经内分泌肿瘤（MINENs）是罕见的恶性肿瘤。在这里，我们提出了两个案例，并回顾了相关文献。
方法：我们的两名患者在术后诊断为胆囊MiNENs，病理上包括大细胞神经内分泌癌和乳头状腺癌。胆囊切除术后,一名患者的生存时间为30个月，而另一个在12个月的随访中仍然存活。在文学中,共发现72例胆囊MINENs，包括我们的两个病人,我们计算出74例报告病例的男女比例为0.22,平均年龄为64.5岁.这些患者中约有一半被发现患有胆结石，并在相对较早的阶段出现腹痛或不适。这74例患者的术前诊断主要依靠腹部超声,对比增强计算机断层扫描（CT）扫描，和磁共振成像或正电子发射断层扫描/CT。然而,最终诊断是基于病理学证据和通过免疫组织化学染色或电子显微镜检测到的神经分泌颗粒鉴定的突触素(Syn)和/或嗜铬粒蛋白A的表达。58例患者（78.4%）接受了各种手术，包括单纯胆囊切除术（n=14），整块胆囊切除术（n=9），标准或非标准根治性胆囊切除术（n=25），或扩大的根治性胆囊切除术（n=6）。切除的胆囊肿块的平均大小为50.8±36.1mm（n=63），其中37例（52.1％）有区域淋巴结转移，33例（45.8％）的肝侵犯或分期大于T3，肝转移26例(35.1%)。术后中位生存时间为36±11.42个月(95%可信区间,13.62至58.38个月）。log-rank分析未发现术后辅助化疗相对于未接受化疗的患者的生存时间更长（患者数量，15对43；生存时间，36个月与30个月相比，p>0.05)。
结论：我们的两个病例和文献中的病例表明，胆囊的MiNENs主要发生在女性中；与早期淋巴结转移有关，局部肝浸润，和肝转移；并且可以通过各种手术以及与生长抑素类似物相结合的化学疗法来管理。
方法：我们的两名患者在术后诊断为胆囊MiNENs，病理上包括大细胞神经内分泌癌和乳头状腺癌。胆囊切除术后,一名患者的生存时间为30个月，而另一个在12个月的随访中仍然存活。在文学中,共发现72例胆囊MINENs，包括我们的两个病人,我们计算出74例报告病例的男女比例为0.22,平均年龄为64.5岁.这些患者中约有一半被发现患有胆结石，并在相对较早的阶段出现腹痛或不适。这74例患者的术前诊断主要依靠腹部超声,对比增强计算机断层扫描（CT）扫描，和磁共振成像或正电子发射断层扫描/CT。然而,最终诊断是基于病理学证据和通过免疫组织化学染色或电子显微镜检测到的神经分泌颗粒鉴定的突触素(Syn)和/或嗜铬粒蛋白A的表达。58例患者（78.4%）接受了各种手术，包括单纯胆囊切除术（n=14），整块胆囊切除术（n=9），标准或非标准根治性胆囊切除术（n=25），或扩大的根治性胆囊切除术（n=6）。切除的胆囊肿块的平均大小为50.8±36.1mm（n=63），其中37例（52.1％）有区域淋巴结转移，33例（45.8％）的肝侵犯或分期大于T3，肝转移26例(35.1%)。术后中位生存时间为36±11.42个月(95%可信区间,13.62至58.38个月）。log-rank分析未发现术后辅助化疗相对于未接受化疗的患者的生存时间更长（患者数量，15对43；生存时间，36个月与30个月相比，p>0.05)。
结论：我们的两个病例和文献中的病例表明，胆囊的MiNENs主要发生在女性中；与早期淋巴结转移有关，局部肝浸润，和肝转移；并且可以通过各种手术以及与生长抑素类似物相结合的化学疗法来管理。
