Clinicopathologic Features And Prognostic Analysis Of α-Fetoprotein-Producing Gastric Cancer

OBJECTIVEα-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 METHODSPARTⅠDuring 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).PARTⅡThe 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).RESULTSPARTⅠ1.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.PARTⅡ1.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.CONCLUSIONS1.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.