产AFP胃癌的临床病理及预后分析
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摘要
研究目的
产AFP胃癌是胃癌的一种少见类型,现有的文献多为个例报道,其临床病理特征不详。我们回顾性分析我院104例产AFP胃癌,阐明它的临床病理特征及影响预后的因素:进一步根据组织结构有无肝样分化区将产AFP胃癌分为肝样腺癌及非肝样腺癌,通过比较两者间的临床病理特征及预后,阐明胃肝样腺癌是一种独特的亚型。
材料与方法
第一部分
1996.01-2007.12期间,复旦大学附属肿瘤医院外科共收治胃癌4426例。大部分患者术前及随访中通过放射免疫的方法测定了血清中AFP及CEA水平,其中有173例术前血清AFP高于正常(≥10μg/L),经排除伴有慢性肝炎、原发性肝癌等影响血清中AFP水平的疾病后,共有111例血清中AFP升高且经手术治疗的胃癌患者入组,收集所有入组患者的蜡块标本,运用免疫组化Envision两步法检测AFP在胃癌原发灶、部分转移淋巴结及肝转移灶中的表达情况,其中有104例患者的原发灶标本中AFP免疫组化染色呈阳性,这部分病例被命名为产AFP胃癌。详细记录产AFP胃癌患者的临床病理资料:年龄、性别、术前血清中AFP水平、术前血清中CEA水平、手术性质、手术切除方式、淋巴结清扫范围、肿瘤部位、肿瘤大小、肿瘤的大体类型、浸润深度、组织学类型、分化程度、脉管癌栓、神经侵犯、淋巴结转移、肝转移及肿瘤分期,并对患者进行随访,分析临床病理特征及影响预后的因素。统计分析软件:SPSS 13.0软件包,对两组资料同一因素的相关性检验采用卡方检验和Fisher精确概率法,分析影响产AFP胃癌肝转移的高危因素用logistic回归,生存情况分析采用Kaplan-Meier计算生存曲线,用log-rank进行显著性检验,P＜0.05为具有统计学意义。
第二部分
调取104例产AFP胃癌患者的H.E染色切片,请病理专科医生读片,判断是否具有肝样分化区,把具有肝样分化区的病例即为胃肝样腺癌,同时对于无典型的肝样分化区的病例结合AFP、SYN及CHG免疫组化染色情况进行鉴别。其余产生AFP但H.E染色切片上不具有肝样分化区的病例作为对照组。比较两组间的临床病理特征及预后差异,包括术前血清中AFP水平、术前血清中CEA水平、肿瘤部位、肿瘤大小、肿瘤的大体类型、浸润深度、组织学类型、分化程度、脉管癌栓、神经侵犯、淋巴结转移、肝转移、肿瘤分期及预后。统计分析软件:SPSS 13.0软件包,对两组资料同一因素的相关性检验采用卡方检验和Fisher精确概率法,分析影响肝样腺癌及非肝样腺癌肝转移的高危因素用logistic回归,分析生存情况采用Kaplan-Meier计算生存曲线,用log-rank进行显著性检验。P＜0.05为具有统计学意义。
研究结果
第一部分
1.术前血清AFP升高的111例病人中,AFP免疫组化染色阳性104例,占93.7%。AFP在产AFP胃癌的原发灶、转移淋巴结及肝转移灶中可以呈现不同程度表达。
2.患者术前血清中的AFP水平最低为10μg/L,最高为3000μg/L,平均为153μg/L,中位值为41μg/L。术后患者血清AFP水平不同程度降低,根治性手术后,AFP水平都降至正常,姑息性手术后血清AFP都有不同程度的降低,但难以降至正常范围,术后发生肝转移时AFP水平再次升高。
3.术前血清中AFP水平与组织标本中AFP表达情况无相关性。
4.本组病例中男女比为2.9:1;平均年龄为60岁;肿瘤位于胃窦部53例(51%);肿瘤直径大于5 cm 65例(63%);BorrmannⅢ83例(80%);浆膜面受侵犯74例(71%);组织学类型以低分化腺癌为主,共64例(62%);分化程度多为低分化65例(63%);脉管癌栓66例(64%);淋巴结转移85例(82%);肝转移63例(60.6%),同时性肝转移7例(6.7%),异时性肝转移56例(57.7%);Ⅲ、Ⅳ期病人71例(68%)。
5.104例产AFP胃癌,共有63例发生了肝转移,发生率为60.6%。其中同时性肝转移7例(6.7%),异时性肝转移56例(57.7%)。术后发生肝转移时间最短为2月,最长为32月,平均时间为7.7个月。异时性肝转移高危因素包括:术前血清AFP高于100μg/L、术前血清CEA升高、脉管癌栓阳性、淋巴结阳性、浆膜面侵犯及Ⅲ、Ⅳ期;Logistic回归分析显示,只有术前AFP高于100μg/L及脉管癌栓阳性是影响术后肝转移的独立高危因素。
6.产AFP胃癌患者的1年、3年、5年生存率分别为53%、35%、28%,中位生存时间14.06个月。其中根治性手术后的1年、3年、5年生存率分别为60%、42%、37%,姑息性手术后的1年、3年、5年生存率分别为27%、9%、0%。影响产AFP胃癌患者预后的因素包括:术前血清CEA水平、肝转移、手术性质、脉管癌栓、浆膜面侵犯、淋巴结转移及术后病理分期;影响产AFP胃癌患者预后的独立因素包括:术前血清CEA水平、肝转移及术后病理分期。
第二部分
1.胃肝样腺癌HE特点:大部分肿瘤由非肝样腺癌区及肝癌样分化区构成,少部分肿瘤仅可见肝癌样分化区,在两种肿瘤组织明显不同的区域有移行过渡区。非肝样腺癌区可见异形的腺癌呈管状或乳头状;更具有特征的区域为肝癌样分化区,瘤细胞排列成条索状、腺泡状、管状或实体状,间质为血窦或富含毛细血管的结缔组织。瘤细胞胞浆丰富、呈嗜酸性,胞浆中偶见嗜伊红颗粒,部分瘤细胞胞浆透亮,少数瘤细胞呈脂肪变性改变,胞浆内未见胆色素。核大而明显、不规则,位于细胞中央,可见1～2个明显的核仁,核染色质粗细不一,核分裂相在分化低的区域易见,并可见巨核或畸形核。
2.胃肝样腺癌免疫组化特点:因本组中的肝样腺癌都来自于产AFP胃癌病例,所以45例胃肝样腺癌的AFP免疫组化染色全部阳性。AFP阳性主要分布在肝样分化区的肿瘤细胞胞浆内,部分肝样腺癌病例的腺癌区亦见有局灶性AFP阳性细胞。部分肝样腺癌同时伴有SYN,CHG免疫组化染色阳性。
3.胃肝样腺癌电镜特点:肿瘤细胞排列成片,细胞呈多边形,类圆形;核大,卵圆形;核仁大而明显;胞质丰富,内质网发达呈层状,核糖丰富,有的细胞胞质内含多数密电子圆形颗粒;细胞间可见桥粒。
4.胃肝样腺癌的脉管癌栓率为75.6%明显高于非肝样腺癌的54.2%(P=0.025),前者异时性肝转移发生率为66.7%,高于后者的44.1%(P=0.022)。两者在年龄、性别分布、肿瘤部位、肿瘤大小、大体类型、浆膜面侵犯、组织学类型、分化程度、淋巴结转移、术后病理分期、术前血清AFP、术前血清CEA及异时性肝转移发生时间方面相似。
5.胃肝样腺癌患者发生异时性肝转移率为73.2%,高于对照组46.4%(P=0.022)。前者异时性肝转移发生时间为6.1±2.7月,短于后者的9.5±7.9月,但是差异无统计学意义。胃肝样腺癌异时性肝转移的高危因素包括:脉管癌栓阳性、淋巴结阳性、术后病理分期,其中独立危险因素为术后病理分期;而没有发现与非肝样腺癌异时性肝转移明显相关的高危因素。
6.胃肝样腺癌患者的1年、3年、5年生存率分别为37%、13%、9%,中位生存时间9.54个月;非肝样腺癌患者的1年、3年、5年生存率分别为64%、52%、42%,中位生存期39.04个月。影响胃肝样腺癌患者预后的因素包括:术前血清CEA、肝转移、手术性质、脉管癌栓、浆膜面侵犯、淋巴结转移及术后病理分期,其中影响胃肝样腺癌预后的独立危险因素为肝转移。
结论
1.产AFP胃癌生物学行为差,常发生脉管癌栓、淋巴结转移及肝转移。
2.检测患者血清中AFP值对于术前诊断及术后随访产AFP胃癌有重要意义。
3.术前血清CEA水平、病理分期及肝转移是影响产AFP胃癌预后的独立因子。
4.除手术治疗外,可能还需结合化疗、放疗或介入治疗。
5.胃肝样腺癌生物学行为较非肝样腺癌差,是产AFP胃癌中的一种特殊类型。
6.肝转移是影响胃肝样腺癌预后的唯一因素。
OBJECTIVE
α-Fetoprotein-producing gastric cancer is reported as a way of case reports,and clinicopathologic features still are not clarified as a result of a rare type of gastric cancer.To clarify the clinicopathologic characteristics and prognostic factors ofα-Fetoprotein-producing gastric cancer,we retrospectively analysed the data of 104 cases.On the basis of hepatoid differentiation area in lesion,α-Fetoprotein-producing gastric cancer was classified into two subgroups:hepatoid adenocarcinoma of the stomach and non-hepatoid adenocarcinoma of stomach,then carried out a control research.
MATERIALS AND METHODS
PARTⅠ
During January 1996 and December 2007,4426 patients with histologically confirmed primary gastric adenocarcinoma underwent were admitted to the Department of Abdominal Surgery in Affiliated Cancer Hospital of Fudan University. Serum AFP and CEA were estimated in most cases before operation and during the follow-up period by the radioimmunoassay methods.Among these cases,173 had an abnormal level of serum AFP(≥10μg/L).The patients who had not received operation and those who had chronic hepatitis,hepatocellular carcinoma were excluded.At last,111 patients who received gastrectomy and had abnormal elevation of serum AFP were included.AFP staining of the all primary gastric cancer lesions,a part of metastatic lymph nodes and hepatic metastatic lesions were performed by the EnVision method with formalin-fixed,paraffin-embedded materials. Immunohistochemical results showed that the specimens of 104 patients were stained with AFP positively.Therefore,these cases were defined asα-Fetoprotein-producing gastric cancer.The clinicopathologic parameters were recorded accurately:age and sex of patients,preoperative serum level of AFP and CEA,quality of operation,type of operation,type of lymph node dissection,tumor location,tumor size,tumor gross type,invasion depth,histologic type,tumor grade,vascular invasion,nervous invasion,lymph node metastasis,live metastasis and tumor stage.All these patients were followed up regularly after operation.The prognostic factors and correlation between other clinicopathologic characteristics were investigated.The association of clinicopathological factors was evaluated by Chi-square test and Fisher-exact test.The logistic analysis was used to evaluate the influential factor of liver metastasis.The survival rate was calculated by Kaplan-Meier method,and differences between survival curves were examined with log-rank test.The level of significance was P＜0.05.Statistical analyses and graphics were performed using the SPSS 13.0 statistical package(SPSS,Inc.,Chicago,IL).
PARTⅡ
The HE staining slices ofα-Fetoprotein-producing gastric cancer were reviewed by pathologist.The cases revealing hepatoid differentiation were termed as hepatoid adenocarcinoma of the stomach.The others without hepatoid differentiation were defined as control group.The biological behaviour and prognosis were compared between two groups as follows:preoperative serum level of AFP and CEA,tumor location,tumor size,tumor gross type,invasion depth,histologic type,tumor grade, vascular invasion,nervous invasion,lymph node metastasis,live metastasis and tumor stage.The association of clinicopathological factors was evaluated by Chi-square test and Fisher-exact test.The logistic analysis was used to evaluate the influential factor of liver metastasis.The survival rate was calculated by Kaplan-Meier method,and differences between survival curves were examined with log-rank test.The level of significance was P＜0.05.Statistical analyses and graphics were performed using the SPSS 13.0 statistical package(SPSS,Inc.,Chicago,IL).
RESULTS
PARTⅠ
1.One hundred and eleven had an abnormal elevation of serum AFP(≥10μg/L).Imumuohistochemical staining demonstrated that AFP was produced in the primary lesions of 104 cases(93.7%).Immunohistochemical staining demonstrated that AFP was not only produced in the gastric primary lesions,but also in the metastatic lymph nodes and metastatic lesion of liver.
2.Preoperative serum AFP ranged from 10μg/L to 3000μg/L,with a mean value of 153μg/L and median value of 41μg/L.Serum level of AFP radically operated cases dropped to a normal level,but serum AFP level of those with palliative operation showed an incomplete fall,an abnormal elevation after operation always indicated a recurrence or liver metastasis.
3.Preoperative serum level of AFP was not correlated with the expression of AFP in gastric cancer lesions.
4.Sex ratio was 2.9:1,with a mean age of 60 yr.The patients were characterized by tumor location in the gastric antrum(53/104,51%),tumor size larger than 5 cm(65/104,63%),BorrmannⅢtype(83/104,80%),serosal invasion(74/104, 71%),poorly differentiated adenocarcinoma(64/104,62%),poorly differentiated (65/104,63%),vascular permeation(66/104,64%),lymph node metastasis(85/104, 82%),liver metastasis(63/104,60.6%),synchronous liver metastasis(7/104,6.7%), metachronous liver metastasis(56/97,57.7%),and stageⅢorⅣdisease(71/104, 68%).
5.Of 104 AFP-producing gastric cancer,there were 63 liver metastases.The overall incidence of liver metastasis was 60.6%(63/104) in our series.There were 7 (7/104,6.7%) synchronous and 56(56/97,57.7%) metachronous liver metastases. Metachronous liver metastasis occurred from 2 to 32 months,with an average of 7.7 months after gastrectomy.Metachronous liver metastasis were significantly correlated with preoperatively elevated serum level of AFP(≥100μg/l),preoperatively elevated serum level of CEA(≥10μg/l),vascular permeation,lymph node metastasis,serosal invasion,and stageⅢorⅣ.Logistic regression analysis showed that only preoperative AFP(≥100μg/l) and vascular permeation were independently influential factors of metachronous liver metastases.
6.The 1-,3-,5-yr survival rates of the AFP-producing gastric cancer were 53%, 35%,and 28%for all the patients,that of radical and palliative operation were 60%, 42%,37%,and 27%,9%,0%,respectively.The significant prognostic factors included:preoperative serum CEA,liver metastasis,operative curability,vascular permeation,serosal invasion,lymph node metastasis,and pathological stage.The independent prognostic factors included:preoperative serum CEA,liver metastasis, and pathological stage.
PARTⅡ
1.Microscopic features:tumor lesions were composed of adenocarcinoma and hepatoid differentiation,and there were transition areas between them.Some portions of adenocarcinoma displayed tubular or papillary type.Distinct area was composed of hepatoid differentiation,the tumor cells tended to be arranged in a trabecular fashion or solid nests separated by a narrow fibrous stroma composed of sinusoid-like capillaries.The tumor cells were cuboidal with abundant eosinophilic granular cytoplasa and occasionally displayed hyaline globules,fatty degeneration in cytoplasa. Nuclei were big and irregular centrally situated in cell.Some cells had one or more obvious nucleolus.Nuclear chromatin was uneven.Mitotic figure was commonly found in poorly differentiated area.Meganucleus or bizarre nucleus could also be found.
2.All cases of HAS were stained positively for AFP.Positive staining for AFP was not only found in cytoplasm of hepatoid differentiated area but also in cytoplasm of focal adnocarcinomous area.A part of cases were stained positively for SYN and CHG.
3.In the adenocarcinomous portion,microvilli were found both on the luminal surface and in the intracytoplasmic lumina,most of which had central core filaments. In the hepatoid differentiated protion,the cytoplasm of tumor cells was filled with numerous mitochondria,and juctional apparatus was well-formed between tumor cells. Occassionally,intercellular lumina with microvilli resembling bile canaliculi were found.
4.Hepatoid adenocarcinoma of stomach(HAS) had a significantly higher rates of vascular permeation than non-hepatoid adenocarcinoma of stomach(non-HAS) (75.6%vs 54.2%,P=0.025).Metachronous liver metastasis was significantly more predominant in the HAS than non-HAS(73.2%vs 46.4%,P=0.022).There were no significant differences in age,sex ratio,tumor location,tumor size,gross type,serosal invasion,pathology,histological type,lymph node metastasis,pathologic stage, preoperative serum AFP,preoperative serum CEA,and liver metastasis-free interval between HAS and non-HAS.
5.The incidence of metachronous liver metastasis in HAS was significantly higher than that of non-HAS(73.2%vs 46.4%,P=0.022).The former had a shorter liver metastasis-free interval than the non-HAS(average 6.1±2.7 vs 9.5±7.9,P =0.276).The metachronous liver metastasis of HAS were significantly associated with vascular permeation,lymph node metastasis,pathologic stage,and logistic analysis showed that the pathologic stage was only independent influential factor of liver metastasis.Such correlation was not found in non-HAS.
6.The 1-,3-,5-yr survival rates of the HAS were 37%,13%,and 9%for all the patients,that of non-HAS were 64%,52%,and 42%,respectively.The significant prognostic factors included:preoperative serum CEA,liver metastasis,operative curability,vascular permeation,serosal invasion,lymph node metastasis,and pathological stage.The independent prognostic factor was liver metastasis.
CONCLUSIONS
1.AFP-producing gastric cancer had very invasive biological behaviour,and usually manifested with venous invasion,lymph node metastasis,and liver metastasis.
2.Evaluation of AFP level in preoperative serum played an important role in preoperative diagnosis and postoperative follow-up.
3.Independent prognostic factors for AFP-producing gastric caner included preoperative serum AFP,pathologic stage,and liver metastasis.
4.In addition to surgery,other therapy such as chemotherapy,radiotherapy or interventional therapy should be considered.
5.Gastric hepatoid adenocarcinoma should be distinguished from the AFP-producing gastric cancer that lack hepatoid features.
6.Liver metastasis was one and only independent prognostic factor of gastric hepatoid adenocarcinoma.
产AFP胃癌是胃癌的一种少见类型,现有的文献多为个例报道,其临床病理特征不详。我们回顾性分析我院104例产AFP胃癌,阐明它的临床病理特征及影响预后的因素:进一步根据组织结构有无肝样分化区将产AFP胃癌分为肝样腺癌及非肝样腺癌,通过比较两者间的临床病理特征及预后,阐明胃肝样腺癌是一种独特的亚型。
材料与方法
第一部分
1996.01-2007.12期间,复旦大学附属肿瘤医院外科共收治胃癌4426例。大部分患者术前及随访中通过放射免疫的方法测定了血清中AFP及CEA水平,其中有173例术前血清AFP高于正常(≥10μg/L),经排除伴有慢性肝炎、原发性肝癌等影响血清中AFP水平的疾病后,共有111例血清中AFP升高且经手术治疗的胃癌患者入组,收集所有入组患者的蜡块标本,运用免疫组化Envision两步法检测AFP在胃癌原发灶、部分转移淋巴结及肝转移灶中的表达情况,其中有104例患者的原发灶标本中AFP免疫组化染色呈阳性,这部分病例被命名为产AFP胃癌。详细记录产AFP胃癌患者的临床病理资料:年龄、性别、术前血清中AFP水平、术前血清中CEA水平、手术性质、手术切除方式、淋巴结清扫范围、肿瘤部位、肿瘤大小、肿瘤的大体类型、浸润深度、组织学类型、分化程度、脉管癌栓、神经侵犯、淋巴结转移、肝转移及肿瘤分期,并对患者进行随访,分析临床病理特征及影响预后的因素。统计分析软件:SPSS 13.0软件包,对两组资料同一因素的相关性检验采用卡方检验和Fisher精确概率法,分析影响产AFP胃癌肝转移的高危因素用logistic回归,生存情况分析采用Kaplan-Meier计算生存曲线,用log-rank进行显著性检验,P＜0.05为具有统计学意义。
第二部分
调取104例产AFP胃癌患者的H.E染色切片,请病理专科医生读片,判断是否具有肝样分化区,把具有肝样分化区的病例即为胃肝样腺癌,同时对于无典型的肝样分化区的病例结合AFP、SYN及CHG免疫组化染色情况进行鉴别。其余产生AFP但H.E染色切片上不具有肝样分化区的病例作为对照组。比较两组间的临床病理特征及预后差异,包括术前血清中AFP水平、术前血清中CEA水平、肿瘤部位、肿瘤大小、肿瘤的大体类型、浸润深度、组织学类型、分化程度、脉管癌栓、神经侵犯、淋巴结转移、肝转移、肿瘤分期及预后。统计分析软件:SPSS 13.0软件包,对两组资料同一因素的相关性检验采用卡方检验和Fisher精确概率法,分析影响肝样腺癌及非肝样腺癌肝转移的高危因素用logistic回归,分析生存情况采用Kaplan-Meier计算生存曲线,用log-rank进行显著性检验。P＜0.05为具有统计学意义。
研究结果
第一部分
1.术前血清AFP升高的111例病人中,AFP免疫组化染色阳性104例,占93.7%。AFP在产AFP胃癌的原发灶、转移淋巴结及肝转移灶中可以呈现不同程度表达。
2.患者术前血清中的AFP水平最低为10μg/L,最高为3000μg/L,平均为153μg/L,中位值为41μg/L。术后患者血清AFP水平不同程度降低,根治性手术后,AFP水平都降至正常,姑息性手术后血清AFP都有不同程度的降低,但难以降至正常范围,术后发生肝转移时AFP水平再次升高。
3.术前血清中AFP水平与组织标本中AFP表达情况无相关性。
4.本组病例中男女比为2.9:1;平均年龄为60岁;肿瘤位于胃窦部53例(51%);肿瘤直径大于5 cm 65例(63%);BorrmannⅢ83例(80%);浆膜面受侵犯74例(71%);组织学类型以低分化腺癌为主,共64例(62%);分化程度多为低分化65例(63%);脉管癌栓66例(64%);淋巴结转移85例(82%);肝转移63例(60.6%),同时性肝转移7例(6.7%),异时性肝转移56例(57.7%);Ⅲ、Ⅳ期病人71例(68%)。
5.104例产AFP胃癌,共有63例发生了肝转移,发生率为60.6%。其中同时性肝转移7例(6.7%),异时性肝转移56例(57.7%)。术后发生肝转移时间最短为2月,最长为32月,平均时间为7.7个月。异时性肝转移高危因素包括:术前血清AFP高于100μg/L、术前血清CEA升高、脉管癌栓阳性、淋巴结阳性、浆膜面侵犯及Ⅲ、Ⅳ期;Logistic回归分析显示,只有术前AFP高于100μg/L及脉管癌栓阳性是影响术后肝转移的独立高危因素。
6.产AFP胃癌患者的1年、3年、5年生存率分别为53%、35%、28%,中位生存时间14.06个月。其中根治性手术后的1年、3年、5年生存率分别为60%、42%、37%,姑息性手术后的1年、3年、5年生存率分别为27%、9%、0%。影响产AFP胃癌患者预后的因素包括:术前血清CEA水平、肝转移、手术性质、脉管癌栓、浆膜面侵犯、淋巴结转移及术后病理分期;影响产AFP胃癌患者预后的独立因素包括:术前血清CEA水平、肝转移及术后病理分期。
第二部分
1.胃肝样腺癌HE特点:大部分肿瘤由非肝样腺癌区及肝癌样分化区构成,少部分肿瘤仅可见肝癌样分化区,在两种肿瘤组织明显不同的区域有移行过渡区。非肝样腺癌区可见异形的腺癌呈管状或乳头状;更具有特征的区域为肝癌样分化区,瘤细胞排列成条索状、腺泡状、管状或实体状,间质为血窦或富含毛细血管的结缔组织。瘤细胞胞浆丰富、呈嗜酸性,胞浆中偶见嗜伊红颗粒,部分瘤细胞胞浆透亮,少数瘤细胞呈脂肪变性改变,胞浆内未见胆色素。核大而明显、不规则,位于细胞中央,可见1～2个明显的核仁,核染色质粗细不一,核分裂相在分化低的区域易见,并可见巨核或畸形核。
2.胃肝样腺癌免疫组化特点:因本组中的肝样腺癌都来自于产AFP胃癌病例,所以45例胃肝样腺癌的AFP免疫组化染色全部阳性。AFP阳性主要分布在肝样分化区的肿瘤细胞胞浆内,部分肝样腺癌病例的腺癌区亦见有局灶性AFP阳性细胞。部分肝样腺癌同时伴有SYN,CHG免疫组化染色阳性。
3.胃肝样腺癌电镜特点:肿瘤细胞排列成片,细胞呈多边形,类圆形;核大,卵圆形;核仁大而明显;胞质丰富,内质网发达呈层状,核糖丰富,有的细胞胞质内含多数密电子圆形颗粒;细胞间可见桥粒。
4.胃肝样腺癌的脉管癌栓率为75.6%明显高于非肝样腺癌的54.2%(P=0.025),前者异时性肝转移发生率为66.7%,高于后者的44.1%(P=0.022)。两者在年龄、性别分布、肿瘤部位、肿瘤大小、大体类型、浆膜面侵犯、组织学类型、分化程度、淋巴结转移、术后病理分期、术前血清AFP、术前血清CEA及异时性肝转移发生时间方面相似。
5.胃肝样腺癌患者发生异时性肝转移率为73.2%,高于对照组46.4%(P=0.022)。前者异时性肝转移发生时间为6.1±2.7月,短于后者的9.5±7.9月,但是差异无统计学意义。胃肝样腺癌异时性肝转移的高危因素包括:脉管癌栓阳性、淋巴结阳性、术后病理分期,其中独立危险因素为术后病理分期;而没有发现与非肝样腺癌异时性肝转移明显相关的高危因素。
6.胃肝样腺癌患者的1年、3年、5年生存率分别为37%、13%、9%,中位生存时间9.54个月;非肝样腺癌患者的1年、3年、5年生存率分别为64%、52%、42%,中位生存期39.04个月。影响胃肝样腺癌患者预后的因素包括:术前血清CEA、肝转移、手术性质、脉管癌栓、浆膜面侵犯、淋巴结转移及术后病理分期,其中影响胃肝样腺癌预后的独立危险因素为肝转移。
结论
1.产AFP胃癌生物学行为差,常发生脉管癌栓、淋巴结转移及肝转移。
2.检测患者血清中AFP值对于术前诊断及术后随访产AFP胃癌有重要意义。
3.术前血清CEA水平、病理分期及肝转移是影响产AFP胃癌预后的独立因子。
4.除手术治疗外,可能还需结合化疗、放疗或介入治疗。
5.胃肝样腺癌生物学行为较非肝样腺癌差,是产AFP胃癌中的一种特殊类型。
6.肝转移是影响胃肝样腺癌预后的唯一因素。
OBJECTIVE
α-Fetoprotein-producing gastric cancer is reported as a way of case reports,and clinicopathologic features still are not clarified as a result of a rare type of gastric cancer.To clarify the clinicopathologic characteristics and prognostic factors ofα-Fetoprotein-producing gastric cancer,we retrospectively analysed the data of 104 cases.On the basis of hepatoid differentiation area in lesion,α-Fetoprotein-producing gastric cancer was classified into two subgroups:hepatoid adenocarcinoma of the stomach and non-hepatoid adenocarcinoma of stomach,then carried out a control research.
MATERIALS AND METHODS
PARTⅠ
During January 1996 and December 2007,4426 patients with histologically confirmed primary gastric adenocarcinoma underwent were admitted to the Department of Abdominal Surgery in Affiliated Cancer Hospital of Fudan University. Serum AFP and CEA were estimated in most cases before operation and during the follow-up period by the radioimmunoassay methods.Among these cases,173 had an abnormal level of serum AFP(≥10μg/L).The patients who had not received operation and those who had chronic hepatitis,hepatocellular carcinoma were excluded.At last,111 patients who received gastrectomy and had abnormal elevation of serum AFP were included.AFP staining of the all primary gastric cancer lesions,a part of metastatic lymph nodes and hepatic metastatic lesions were performed by the EnVision method with formalin-fixed,paraffin-embedded materials. Immunohistochemical results showed that the specimens of 104 patients were stained with AFP positively.Therefore,these cases were defined asα-Fetoprotein-producing gastric cancer.The clinicopathologic parameters were recorded accurately:age and sex of patients,preoperative serum level of AFP and CEA,quality of operation,type of operation,type of lymph node dissection,tumor location,tumor size,tumor gross type,invasion depth,histologic type,tumor grade,vascular invasion,nervous invasion,lymph node metastasis,live metastasis and tumor stage.All these patients were followed up regularly after operation.The prognostic factors and correlation between other clinicopathologic characteristics were investigated.The association of clinicopathological factors was evaluated by Chi-square test and Fisher-exact test.The logistic analysis was used to evaluate the influential factor of liver metastasis.The survival rate was calculated by Kaplan-Meier method,and differences between survival curves were examined with log-rank test.The level of significance was P＜0.05.Statistical analyses and graphics were performed using the SPSS 13.0 statistical package(SPSS,Inc.,Chicago,IL).
PARTⅡ
The HE staining slices ofα-Fetoprotein-producing gastric cancer were reviewed by pathologist.The cases revealing hepatoid differentiation were termed as hepatoid adenocarcinoma of the stomach.The others without hepatoid differentiation were defined as control group.The biological behaviour and prognosis were compared between two groups as follows:preoperative serum level of AFP and CEA,tumor location,tumor size,tumor gross type,invasion depth,histologic type,tumor grade, vascular invasion,nervous invasion,lymph node metastasis,live metastasis and tumor stage.The association of clinicopathological factors was evaluated by Chi-square test and Fisher-exact test.The logistic analysis was used to evaluate the influential factor of liver metastasis.The survival rate was calculated by Kaplan-Meier method,and differences between survival curves were examined with log-rank test.The level of significance was P＜0.05.Statistical analyses and graphics were performed using the SPSS 13.0 statistical package(SPSS,Inc.,Chicago,IL).
RESULTS
PARTⅠ
1.One hundred and eleven had an abnormal elevation of serum AFP(≥10μg/L).Imumuohistochemical staining demonstrated that AFP was produced in the primary lesions of 104 cases(93.7%).Immunohistochemical staining demonstrated that AFP was not only produced in the gastric primary lesions,but also in the metastatic lymph nodes and metastatic lesion of liver.
2.Preoperative serum AFP ranged from 10μg/L to 3000μg/L,with a mean value of 153μg/L and median value of 41μg/L.Serum level of AFP radically operated cases dropped to a normal level,but serum AFP level of those with palliative operation showed an incomplete fall,an abnormal elevation after operation always indicated a recurrence or liver metastasis.
3.Preoperative serum level of AFP was not correlated with the expression of AFP in gastric cancer lesions.
4.Sex ratio was 2.9:1,with a mean age of 60 yr.The patients were characterized by tumor location in the gastric antrum(53/104,51%),tumor size larger than 5 cm(65/104,63%),BorrmannⅢtype(83/104,80%),serosal invasion(74/104, 71%),poorly differentiated adenocarcinoma(64/104,62%),poorly differentiated (65/104,63%),vascular permeation(66/104,64%),lymph node metastasis(85/104, 82%),liver metastasis(63/104,60.6%),synchronous liver metastasis(7/104,6.7%), metachronous liver metastasis(56/97,57.7%),and stageⅢorⅣdisease(71/104, 68%).
5.Of 104 AFP-producing gastric cancer,there were 63 liver metastases.The overall incidence of liver metastasis was 60.6%(63/104) in our series.There were 7 (7/104,6.7%) synchronous and 56(56/97,57.7%) metachronous liver metastases. Metachronous liver metastasis occurred from 2 to 32 months,with an average of 7.7 months after gastrectomy.Metachronous liver metastasis were significantly correlated with preoperatively elevated serum level of AFP(≥100μg/l),preoperatively elevated serum level of CEA(≥10μg/l),vascular permeation,lymph node metastasis,serosal invasion,and stageⅢorⅣ.Logistic regression analysis showed that only preoperative AFP(≥100μg/l) and vascular permeation were independently influential factors of metachronous liver metastases.
6.The 1-,3-,5-yr survival rates of the AFP-producing gastric cancer were 53%, 35%,and 28%for all the patients,that of radical and palliative operation were 60%, 42%,37%,and 27%,9%,0%,respectively.The significant prognostic factors included:preoperative serum CEA,liver metastasis,operative curability,vascular permeation,serosal invasion,lymph node metastasis,and pathological stage.The independent prognostic factors included:preoperative serum CEA,liver metastasis, and pathological stage.
PARTⅡ
1.Microscopic features:tumor lesions were composed of adenocarcinoma and hepatoid differentiation,and there were transition areas between them.Some portions of adenocarcinoma displayed tubular or papillary type.Distinct area was composed of hepatoid differentiation,the tumor cells tended to be arranged in a trabecular fashion or solid nests separated by a narrow fibrous stroma composed of sinusoid-like capillaries.The tumor cells were cuboidal with abundant eosinophilic granular cytoplasa and occasionally displayed hyaline globules,fatty degeneration in cytoplasa. Nuclei were big and irregular centrally situated in cell.Some cells had one or more obvious nucleolus.Nuclear chromatin was uneven.Mitotic figure was commonly found in poorly differentiated area.Meganucleus or bizarre nucleus could also be found.
2.All cases of HAS were stained positively for AFP.Positive staining for AFP was not only found in cytoplasm of hepatoid differentiated area but also in cytoplasm of focal adnocarcinomous area.A part of cases were stained positively for SYN and CHG.
3.In the adenocarcinomous portion,microvilli were found both on the luminal surface and in the intracytoplasmic lumina,most of which had central core filaments. In the hepatoid differentiated protion,the cytoplasm of tumor cells was filled with numerous mitochondria,and juctional apparatus was well-formed between tumor cells. Occassionally,intercellular lumina with microvilli resembling bile canaliculi were found.
4.Hepatoid adenocarcinoma of stomach(HAS) had a significantly higher rates of vascular permeation than non-hepatoid adenocarcinoma of stomach(non-HAS) (75.6%vs 54.2%,P=0.025).Metachronous liver metastasis was significantly more predominant in the HAS than non-HAS(73.2%vs 46.4%,P=0.022).There were no significant differences in age,sex ratio,tumor location,tumor size,gross type,serosal invasion,pathology,histological type,lymph node metastasis,pathologic stage, preoperative serum AFP,preoperative serum CEA,and liver metastasis-free interval between HAS and non-HAS.
5.The incidence of metachronous liver metastasis in HAS was significantly higher than that of non-HAS(73.2%vs 46.4%,P=0.022).The former had a shorter liver metastasis-free interval than the non-HAS(average 6.1±2.7 vs 9.5±7.9,P =0.276).The metachronous liver metastasis of HAS were significantly associated with vascular permeation,lymph node metastasis,pathologic stage,and logistic analysis showed that the pathologic stage was only independent influential factor of liver metastasis.Such correlation was not found in non-HAS.
6.The 1-,3-,5-yr survival rates of the HAS were 37%,13%,and 9%for all the patients,that of non-HAS were 64%,52%,and 42%,respectively.The significant prognostic factors included:preoperative serum CEA,liver metastasis,operative curability,vascular permeation,serosal invasion,lymph node metastasis,and pathological stage.The independent prognostic factor was liver metastasis.
CONCLUSIONS
1.AFP-producing gastric cancer had very invasive biological behaviour,and usually manifested with venous invasion,lymph node metastasis,and liver metastasis.
2.Evaluation of AFP level in preoperative serum played an important role in preoperative diagnosis and postoperative follow-up.
3.Independent prognostic factors for AFP-producing gastric caner included preoperative serum AFP,pathologic stage,and liver metastasis.
4.In addition to surgery,other therapy such as chemotherapy,radiotherapy or interventional therapy should be considered.
5.Gastric hepatoid adenocarcinoma should be distinguished from the AFP-producing gastric cancer that lack hepatoid features.
6.Liver metastasis was one and only independent prognostic factor of gastric hepatoid adenocarcinoma.
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[2]Ishikura H,Fukasawa Y,Ogasawarak,et al.An AFP-producing gastric carcinoma with features of hepatic differentiation:a case report[J].Cancer,1985,56(4):840-848.
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[20]Chang YC,Nagasue N,Kohono H,et al.Xenotransplantation of alpha-fetoprotein-producing gastric cancers in to nude mice:characteristics and response to chemotherapy[J].Cancer,1992,69(4):872-878.
[21]李汉贤.AFP阳性胃癌的临床特点及治疗[J].实用癌症杂志,1995,10(4):239-242.
[22]Tomiya T,Tani M,Yamada S,et al.Serum hepatocyte growth factor levels in hepatectomized and nonhepatectomized surgical patients[J].Gastroenterology,1992,103(5):1621-1624.
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