中文摘要
胃肝样腺癌的临床病理特征与预后分析研究
研究目的：
1、回顾性分析胃肝样腺癌（HAS）的临床病理特征，并与非HAS胃腺癌的临床病理特征进行对比分析，探索完善HAS患者诊断体系；2、通过对HAS预后相关因素的研究，为预后判断提供指导；3、基于对相关基因蛋白表达层面的研究分析，为后续探索HAS发病机制及靶向治疗研究提供线索。
研究方法：
1、从2013年1月至2018年3月在东南大学附属中大医院收治的1320例胃腺癌患者中，通过严格的纳入及排除标准筛选出576例入组病例，其中5例病理标本已在我院确诊为HAS。
2、将纳入的未确诊为HAS的患者病理标本交至东南大学附属中大医院病理科经2位具病理诊断资质的医师进行二次病理诊断，新发现10例患者的组织病理标本中有肝细胞癌样分化区，即共诊断15例HAS病例。另于纳入的非HAS患者中随机抽取30例普通胃腺癌患者作为对照组。
3、通过收集已有病例资料、重新检测缺少的免疫组化指标以及电话随访的方式，完善HAS组及对照组患者的信息。
4、对比分析两组患者的的临床病理特征并系统性分析15例HAS患者的治疗及预后。
成果：
1、研究纳入HAS病例15例，平均年龄65.5±7.3岁，男女比例为4:1，入院首发症状以上腹部隐痛居多。肿瘤发生部位多位于贲门部（46.7%）及胃体部（40.0%）。HAS患者分期以IV期居多（40.0%），分化程度以低分化腺癌为主（86.7%），发生淋巴结侵犯11例（73.3%），远处转移6例（40.0%）。其中11例患者记录肿瘤最大径以及神经、脉管侵犯情况，肿瘤最大径范围4-14cm，平均最大径5.4±3.2cm，侵犯神经者8例（72.7%），侵犯脉管者8例（72.7%）。对照组纳入普通胃腺癌病例30例，平均年龄61.6±10.0岁，男女比例为2:1，入院首发症状以腹痛居多。肿瘤发生部位多位于胃窦部（33.3%）及胃体部（30.0%）。对照患者分期以III期居多（43.3%），分化程度以低分化腺癌为主（73.3%），发生淋巴结侵犯22例（73.3%），远处转移4例（13.3%）。其中27例患者记录肿瘤最大径以及神经、脉管侵犯情况，肿瘤最大径范围0.6-18cm，平均最大径6.0±3.9cm，侵犯神经者19例（70.4%），侵犯脉管者16例（59.3%）。以上临床病理特征，HAS组及对照组间的差异无统计学意义（P＞0.05）。
2、与对照组相比，HAS组患者的血清AFP值明显升高；HAS组患者较普通胃腺癌更易发生肝脏转移；HAS组患者GPC3、AFP、EGFR及VEGF蛋白的表达水平更高。上述差异有统计学意义（P＜0.05）。
3、HAS组患者的中位生存时间为12月，普通胃腺癌患者的中位生存时间为42月，两组间差异有统计学意义（P＜0.05）。
4、单因素分析显示肿瘤标记物CEA水平、TNM分期、淋巴结分期、远处转移、免疫组化AFP染色强度及根治性手术是影响HAS患者预后的危险因素。多因素分析矫正后显示远处转移、免疫组化AFP染色强度为影响HAS患者预后生存的独立危险因素。
结论：
1、HAS是胃腺癌一种少见的类型，以中老年男性患者多见，临床症状与普通胃腺癌无特殊差异，HAS肝转移率高，预后差，中位生存时间显着低于普通胃腺癌；2、HAS患者血清AFP水平显着高于普通胃腺癌患者，该指标可在HAS的诊断中起到重要辅助作用，对血清检查中AFP明显升高的胃腺癌患者建议行癌组织免疫组化AFP、GPC3的检测，有助于减少误诊及漏诊几率；3、远处转移以及免疫组化AFP染色强度是影响HAS患者预后的独立危险因素；4、GPC3、AFP、VEGF、EGFR可能为HAS的潜在治疗靶点，值得进一步探索研究。
关键词： 胃肝样腺癌； 临床病理特征； 预后。
Abstract
Analysis of clinicopathological characteristics and prognosis in hepatoid adenocarcinoma of stomach。
Objective:
1、The clinical and pathological characteristics of HAS were retrospectively analyzed and compared with that of non-HAS gastric adenocarcinoma, so as to form a more completemulti-dimensional diagnosis system of HAS.
2、By studying prognostic factors of HAS, prognosis can be guided.
3、Based on the research and analysis of gene protein level, it provides clues for the follow-up research of pathogenesis and targetedtherapy in HAS.
Methods:
1、From January 2013 to March 2018, according to the strict inclusion and exclusion criteria,576 cases were enrolled onto the study from the 1320 cases of patients with gastric cancer, and 5patients have been confirmed of HAS among the enrolled patients.
2、The histopathological specimens of the enrolled cases were diagnosed for the second time by 2 physicians qualified for pathological diagnosis in the southeast universiry affiliated zhongda hospital and histopathological specimens from 10 newly discovered cases showed areas of hepatoid differentiation. Thus, a total of 15 HAS cases were found. In addition, 30 cases of common gastric adenocarcinoma patients were randomly selected as the control group.
3、The information of patients in the HAS group and the control group were improved by collecting the existing case data, detecting the missing pathological indicators again and telephone follow-up.
4、The clinicopathological features of the two groups were compared and the treatment and prognosis of 15 HAS patients were analyzed.
Resaults:
1、15 HAS patients were enrolled in this study, the average age was 65.5±7.3 years old, and the ratio of male to female was 4:1. The most common first diagnosis was Abdominal pain, and the most of the tumor sites were located in the cardia (46.7%) and the corpus (40.0%). The HAS patients were mostly stage IV (40.0%), the differentiation was mainly poorly differentiated adenocarcinoma (86.7%), the lymph node involvement occurred in 11 cases (73.3%), and the distant metastasis occured in 6 cases (40.0%). 11 HAS patients were recorded the largest diameter of the tumor, neurological and vascular invasion, in which the largest diameter of the tumor ranging from 4 to 14 cm, with an average maximum diameter of 5.4±3.2 cm, 8 patients (72.7%) invaded the nerve, and 8 patients (72.7%) invaded the vascular. In the control group, 30 cases of common gastric adenocarcinoma were included, with an average age of 61.6±10.0 years old, and the ratio of male to female was 2:1. The most common first diagnosis was Abdominal pain, and the most of the tumor sites were located in the antrum (33.3%) and the corpus (30.0%). The control patients were mostly stage III (43.3%), and the differentiation was mainly poorly differentiated adenocarcinoma (73.3%). lymph node involvement occurred in 22 cases (73.3%), and distant metastasis in 4 cases (13.3%). Among them, 27 patients were recorded the largest diameter of the tumor, neurological and vascular invasion, in which the largest diameter of the tumor ranging from 0.6 to 18 cm, with an average maximum diameter of 6.0±3.9 cm, 19 patients (70.4%) invaded the nerve, and 16 patients (59.3%) invaded the vascular. The above clinicopathological features showed no significant difference between the HAS group and the control group (P>0.05).
2、Compared with the control group, the serum AFP value of the HAS group was significantly higher, the HAS group was more prone to liver metastasis than the common gastric adenocarcinoma,and the HAS group had higher expression of GPC3, AFP, EGFR and VEGF protein. The above differences were statistically significant (P<0.05).
3、The median survival time of patients in the HAS group was 12 months, and the median survival time of patients with common gastric adenocarcinoma was 42 months. The differencebetween the two groups was statistically significant （P＜0.05）.
4、Univariate analysis showed that tumor markers CEA, TNM staging, lymph node staging,AFP immunohistochemical staining and radical surgery were risk factors for prognosis. Aftermultivariate analysis of the results, it was found that distant metastasis and immunohistochemical AFP expression levels were independent risk factors for prognosis.
Conclusions:
1、HAS is a rare type of gastric adenocarcinoma which is more common in middle-aged and elderly men, and there is no special difference of clinical symptoms between HAS and common gastric adenocarcinoma. HAS has higher liver metastasis rate, more poor prognosis, and shorter median survival time than that of common gastric adenocarcinoma；2、The AFP level in peripheral blood of HAS patients is significantly higher than that of patients with common gastric adenocarcinoma which can play an important auxiliary role in the diagnosis of HAS. It is suggeted that detecting the immunohistochemical AFP and GPC3 in gastric adenocarcinoma patients with a marked increase in AFP in serum tests can help to reduce the chance of misdiagnosis and missed diagnosis;3、Distant metastasis and immunohistochemical AFP staining intensity are independent risk factors affecting the prognosis of HAS patients;4、AFP, GPC3, VEGF and EGFR may be potential therapeutic targets of HAS, which is worth further exploration.
Key words: Hepatoid adenocarcinorna of the stomach, clinicopathological characteristics ,Prognosis。
第一章 前言
1.1 胃癌概述。
胃癌作为全球最常见的消化系统恶性肿瘤之一，其预后差，严重威胁了人类的健康。常见的危险因素包括幽门螺杆菌（Hp）、遗传因素、重盐少蔬菜水果的饮食习惯、饮酒及吸烟等。胃癌的发病考虑为多种因素共同作用的结果，具体发病机制目前尚未完全阐明。
据GLOBOCAN最新统计数据[1]，2018年全球胃癌新发病例数约为103.3万例，死亡病例数约为78.3万例，分别位于恶性肿瘤发病率第5位、死亡率第2位。胃癌位居女性恶性肿瘤发病率第7位，死亡率第5位；位居男性恶性肿瘤发病率第4位，死亡率第3位。由此可见，胃癌是严重威胁人类健康的癌症之一。
发展中国家每年胃癌的新发病例数所占比例超过全球新发病例数的70%，约50%的新发病例发生在亚洲东部，其中韩国发病率最高。北美、北欧及非洲等地的胃癌发病率较低。中国的胃癌新发病例数和死亡病例数分别占全球胃癌发病数和死亡数的42.6%和45.0%，位居全球183个国家中发病率第5位、死亡率第6位[1]。另据我国肿瘤登记中心最新数据统计[2]，2015年中国胃癌新发病例数约为67.9万例，其中男性病例47.8万，女性病例20.1万；死亡病例数约为49.8万例，其中男性病例33.9万，女性病例15.9万；发病人数和死亡人数均位居所有已知恶性肿瘤第2位。而在美国，2018年约有2.6万新发病例，1.08万因胃癌死亡。
发病人数和死亡人数在美国各个瘤种中均排在十名之后[3]。发病率和死亡率的不一致性提示着胃癌的早诊早治水平在发展中国家和发达国家间存在着很大区别。我国胃癌发病人数及死亡人数绝对数值均居全球之首，堪称胃癌大国，疾病负担严重，提高早诊早治水平有助于改善预后。
1.2 肝样腺癌概述。
肝样腺癌是一种发生于肝外器官的恶性肿瘤，在病理上表达与肝细胞癌（Hepatocellularcarcinoma, HCC）相似的形态学特征。肝样腺癌可起源于胃、食管、结肠、胆囊、子宫、膀胱、胰腺、卵巢等器官，其中以胃肝样腺癌（Hepatoid adenocarcinoma of stomach, HAS）最为多见，所占比率高达83.9%[4]。
1985年，Ishikura等[5]报道了一例胃癌病例，该患者在肿瘤病灶中发现了肝细胞癌样分化特点，由此首次提出HAS的概念。
HAS是原发于胃粘膜，同时病理形态上具有胃腺癌和肝细胞癌样分化特点的一种胃癌。这一类肿瘤发生率低，国外已有报道称HAS患者数占同期胃癌患者人数的0.17%[6]，中国报道HAS患者数占同期胃癌的0.37%~1.5%[7-8]。国内报道的HAS患者所占比例的地区差异较大，提示病理诊断时胃癌标本中具有肝样腺癌分化特征的区域可能被忽视或误诊。已有研究表明，HAS好发于中老年患者，男性居多[9]，易发生肝脏及淋巴结等处转移[10-12]，预后不良[13-15]。
1.3 胃肝样腺癌未来展望。
目前HAS的诊断体系尚未完善，临床医师及病理医师对此疾病的重视程度不足。仅通过寻找胃癌病理形态中的肝细胞癌样分化区域对HAS进行诊断的方式不仅增加了病理科医师的负担，且易发生漏诊及误诊情况。因此，由临床特征、血清学指标、组织及病理形态、免疫组化指标等共同形成的多方位诊断体系对HAS的诊断更具临床应用价值。相较于普通的胃癌，HAS预后更差，完整的手术切除加上后续全身化疗是治疗的关键[16-17]。但HAS病例较少，缺乏大样本数据进一步验证，因此现有研究并不具有绝对的可信度。在靶向及免疫治疗方面，有研究[8]
提出，部分HAS患者伴有表皮生长因子受体（Epidermal growth factor receptor,EGFR）、肝细胞生长因子受体（Hepatocyte growth factor receptor, HGFR）、细胞程式死亡-配体1（Programmed cell death 1 ligand 1, PD-L1）的表达阳性，提示未来EGFR受体拮抗剂如西妥昔单抗、HGFR抑制剂如克唑替尼、免疫检查点抑制剂如帕姆单抗、纳武单抗可能成为治疗HAS的潜在有效药物。
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第二章 研究对象与方法
2.1 研究对象
2.2 研究方法
第三章 研究结果
3.1、 15例HAS患者临床病理特征及治疗预后
3.2、 30例普通胃腺癌患者临床病理特征及治疗预后
3.3、 HAS与普通胃腺癌的临床病理特征比较
3.4、 HAS与普通胃腺癌的生存比较
3.5、 HAS的预后分析
第四章 讨论
第五章 总 结
1、HAS是胃腺癌一种少见的类型，以中老年男性患者多见，临床症状与普通胃腺癌无特殊差异，HAS肝转移率高，预后差，中位生存时间显着低于普通胃腺癌。
2、HAS患者血清AFP水平显着高于普通胃腺癌患者，该指标可在HAS的诊断中起到重要辅助作用，对血清检查中AFP明显升高的胃腺癌患者建议行癌组织免疫组化AFP、GPC3的检测，有助于减少误诊及漏诊几率。
3、远处转移以及免疫组化AFP染色强度是影响HAS患者预后的独立危险因素；4、GPC3、AFP、VEGF、EGFR可能为HAS的潜在治疗靶点，值得进一步探索研究。
参考文献
