protein induced by vitamin k antagonist - ii ( pivka - ii ) and alpha - fetoprotein ( afp ) are considered to be specific tumor markers of hepatocellular carcinoma , although pivka - ii is considered the more specific of the two . since kudo et al . first reported a case of pivka - ii- and afp - producing gastric cancer , a number of similar cases have been described . the number of reported cases of afp - producing gastric cancer has also gradually increased , with a reported prevalence of 1.31.5% of all gastric cancer cases [ 3 , 4 ] . however , reports of gastric cancer accompanied by elevated serum levels of both afp and pivka - ii are rare , and a previous review article described only 16 such cases . the prognosis of afp- and pivka - ii - producing gastric cancer has been reported to be very poor because the tumor cells were considered to have a high malignant potential and the cancer progressed rapidly . a recently developed oral derivative of 5-fluorouracil , s-1 , has been found to be effective in approximately 45% of advanced gastric cancer cases [ 6 , 7 ] , and it has also proved effect in some cases of afp - producing gastric cancer . here , we describe a case of gastric cancer producing afp and pivka - ii , which proved to be useful markers of therapeutic response . this cancer was sensitive to chemotherapy , which resulted in prolonged survival . a routine health screening using upper abdominal ultrasonography revealed hepatic tumors in an apparently healthy 65-year - old man with no known family history of gastrointestinal disorders or malignant diseases . he had no abdominal discomfort or other symptoms and no lymphadenopathy or thyroid swelling , and his abdominal findings were normal . iu / l , an alkaline phosphatase ( alp ) level of 510 iu / l , and a lactate dehydrogenase ( ldh ) level of 1,474 iu / l . tests for hepatitis c virus antibody ( hcv - ab ) and hepatitis b virus surface antigen ( hbs - ag ) were negative . as for tumor markers , serum afp and pivka - ii levels were both extremely high at 88,329 ng / ml ( afp - l3 , 75.8% ) and 296 mau / ml , respectively , whereas serum levels of carcinoembryonic antigen ( cea ) and carbohydrate antigen 19 - 9 ( ca19 - 9 ) were in the normal range . whole - body computed tomography ( ct ) revealed multiple hepatic tumors , which were less dense than normal liver tissue . the enhanced ct using contrast agent showed that the tumors had peripheral ring enhancement and a heterogeneous interior ( fig . ct also revealed a swollen lymph node surrounding the lesser curve of the stomach ( fig . 1b , arrowhead ) and a thickening of the stomach wall ( fig . 1c , arrowheads ) . the hepatic tumors had a low intensity on diffusion - weighted magnetic resonance imaging ( mri ) , and enhanced mri with contrast agent showed that the periphery of the hepatic tumors was enhanced in the arterial phase ( fig . 1d ) , but the hepatic tumors were not enhanced in the hepatobiliary phase ( fig . ct and mri findings suggested that the hepatic tumors were metastatic , and fine needle aspiration biopsy of these lesions revealed them to be poorly differentiated adenocarcinomas and thus metastases from the gastrointestinal cancer . an esophagogastroduodenoscopy ( egd ) revealed a bormann type 3 advanced tumor about 30 mm in diameter in the lower part of the stomach ( fig . 3a ) , corresponding with the specimen obtained from the fine needle aspiration biopsy of the hepatic tumors . immunohistochemical evaluation of a tumor biopsy specimen revealed that the tumor cells were positive for afp ( fig . 3c ) , as well as human epidermal growth factor receptor 2 ( her2 ; fig . 3d ) . based on the tnm classification ( international union against cancer , uicc ) , this afp- and pivka - ii - producing gastric cancer with hepatic metastasis was diagnosed as stage iv ( t2n1m1 ) . s-1 ( 80 mg / m on days 114 ) , cisplatin ( cddp ; 60 mg / m on day 1 ) , and trastuzumab ( 8 mg / kg on day 1 ) were administered every 3 weeks for 15 cycles . after 15 cycles of chemotherapy , afp and pivka - ii serum levels were greatly reduced , at 826.5 ng / ml and 51 mau / ml , respectively . egd performed 8 months after chemotherapy showed a remarkable reduction in the size of the tumor , which appeared as an excavated lesion with marginal protrusion ( fig . 2c ) . after 15 cycles of chemotherapy with s-1 , cddp , and trastuzumab , the regimen was changed due to renal dysfunction , and instead s-1 ( 60 mg / m on days 114 ) , cpt-11 ( 150 mg / m on day 1 , to replace cddp ) , and trastuzumab ( 8 mg / kg on day 1 ) were administered every 3 weeks for 15 cycles . after 30 cycles of chemotherapy , afp and pivka - ii serum levels were both lower , at 10.1 ng / ml and 41 mau / ml , respectively . egd performed 25 months after chemotherapy revealed a more remarkable reduction in the size of the tumor , which appeared as a small elevated lesion with scar ( fig . 2d ) , and ct findings at the same time showed a remarkable reduction in the size of the metastatic liver tumors defined as partial response according to the revised response evaluation criteria in solid tumors ( recist ) guideline ( version 1.1 ; fig . the patient is still alive at the time of reporting , 35 months after the initial chemotherapy , without an increase in the level of serum tumor markers , and continues to be administered chemotherapy with a combination of s-1 , cpt-11 , and trastuzumab . we describe a case of advanced gastric cancer with liver metastasis accompanied by elevated levels of serum afp and pivka - ii , in which prolonged survival was achieved due to effective combination chemotherapy . immunohistochemical examination demonstrated that the gastric cancer cells were positive for both afp and pivka - ii , thereby allowing the diagnoses of an afp- and pivka - ii - producing gastric cancer . gastric cancers rarely produce pivka - ii , and only 16 such cases were identified in a recent review . in many cases , gastric biopsy specimens appear histologically as poorly or moderately differentiated adenocarcinoma ; however , a hepatoid pattern has also been observed during the examination of surgically excised or autopsy samples . in 6 of the 9 previously reported cases of afp- and pivka - ii - producing gastric cancers , the tumor was found to be poorly differentiated adenocarcinoma , whereas 4 showed hepatoid differentiation in biopsy specimens . histologically , the tumor in this case was a poorly differentiated adenocarcinoma without hepatoid differentiation , and this type of gastric cancer actually produced afp and pivka - ii . afp - producing gastric cancers are associated with a poor prognosis , even when diagnosed at an early stage , and frequently give rise to hepatic metastases . chemotherapy for gastric cancer is the main treatment option for patients with a liver metastasis , but systemic chemotherapy with a combination of anti - cancer drugs such as cddp , 5-fluorouracil , and cpt-11 generally has poor efficacy . although s-1 , a novel oral derivative of 5-fluorouracil , has been found to be effective in several cases of afp - producing gastric cancers , long - term survival with s-1 therapy has not been reported for pivka - ii - producing gastric cancers . the prognosis in these cases largely depends on whether liver metastases are present . according to a review of 16 cases of afp- and pivka - ii - producing gastric cancers , all 3 patients without liver metastasis were still alive and free of recurrence 9 , 15 , and 17 months after surgery . twelve of the 13 patients with liver metastasis died from their disease , and the longest survival period of those patients was 6 months . the follow - up period for the only patient who was still alive with liver metastasis was just 2 months . recent studies have shown that several combination chemotherapies significantly improved the survival of patients with advanced gastric cancer . the spirits trial ( s-1 plus cddp vs. s-1 in a randomized controlled trial for the treatment of advanced gastric cancers ) showed that combined therapy with s-1 and cddp significantly prolonged survival when given as a first - line treatment for advanced gastric cancers . the overall survival ( os ) of patients treated with s-1 plus moreover , the administration of her2-targeted therapies , in particular trastuzumab combined with chemotherapy for metastatic her2-positive gastric cancers , resulted in improved response rates , time to progression , and os . trastuzumab is a molecularly targeted agent approved as a standard treatment in gastric cancers [ 14 , 15 ] . this agent induces antibody - dependent cellular cytotoxicity , inhibits her2-mediated signaling , and prevents the extracellular domain of her2 from being cleaved . the trastuzumab for gastric cancer ( toga ) study was an open - label phase iii , randomized controlled trial undertaken in 122 centers among 24 countries . it revealed that the addition of trastuzumab to conventional cytotoxic chemotherapy was clinically beneficial compared to chemotherapy alone in terms of tumor response , which suggested that combined chemotherapy with trastuzumab could be a novel , acceptable option for patients with her2-positive advanced gastric cancer . we describe here , the gastric cancer was diagnosed as stage iv , and the patient underwent chemotherapy instead of surgical treatment . the gastric cancer cells were positive for her2 on immunohistochemistry , and the patient was administered combination chemotherapy consisting of s-1 , cddp , and trastuzumab , following the practice described in previously reported cases [ 14 , 15 ] . after 15 cycles of combination chemotherapy , the patient in our case suffered renal dysfunction and was consequently administered s-1 , cpt-11 ( to replace cddp ) , and trastuzumab , but has now survived for 35 months after the initial chemotherapy and continues to have low tumor markers levels . we think that this chemotherapy regimen , and in particular the use of trastuzumab , contributed to the prolonged survival of our patient , despite the generally poor prognosis associated with gastric cancers that produce afp . to our knowledge , there was no report of afp - producing gastric cancer accompanying the expression of her2 . we described a case of gastric cancer producing afp and pivka - ii in which chemotherapy was effective and resulted in prolonged survival , and these 2 tumor markers were useful for monitoring the treatment response .
the number of reported cases of alpha - fetoprotein ( afp)-producing gastric cancer has gradually increased , with a reported prevalence of 1.31.5% of all gastric cancer cases . 
 however , reports of gastric cancer accompanied by elevated serum levels of both afp and protein induced by vitamin k antagonist - ii ( pivka - ii ) are rare . the prognosis of afp- and 
 pivka - ii - producing gastric cancer has been reported to be very poor because the tumor cells were considered to have a high malignant potential and the cancer progressed rapidly . 
 we described a case of gastric cancer producing afp and pivka - ii in which chemotherapy was effective and resulted in prolonged survival , and these two tumor markers were useful for monitoring the treatment response . 
 routine health screening using upper abdominal ultrasonography revealed hepatic tumors in an apparently healthy 65-year - old man . 
 whole - body computed tomography ( ct ) revealed multiple hepatic tumors , and an esophagogastroduodenoscopy ( egd ) revealed a bormann type 3 tumor in the lower stomach . 
 a biopsy specimen confirmed that the tumor was immunohistochemically positive for afp , pivka - ii , and human epidermal growth factor receptor 2 . 
 after chemotherapy , the gastric tumor appeared as a small elevated lesion on egd , and ct revealed a remarkable reduction in the size of the metastatic liver tumors . 
 the patient is still alive , 35 months after the initial chemotherapy .