Protein induced by vitamin K absence or antagonist II-producing gastric cancer.

Protein induced by vitamin K absence or antagonist II (PIVKA-II) is a putative specific marker of hepatocellular carcinoma (HCC), but it may also be produced by a small number of gastric cancers. To date, 16 cases of PIVKA-II-producing gastric cancer have been reported, 2 of which were reported by us and all of which were identified in Japan. There are no symptoms specific to PIVKA-II-producing gastric cancer, and the representative clinical symptoms are general fatigue, appetite loss, and upper abdominal pain. Serum alpha-fetoprotein (AFP) levels are also increased in almost all cases. Liver metastasis is observed in approximately 80% of cases and portal vein tumor thrombus is observed in approximately 20% of cases. Differential diagnosis between metastatic liver tumor and HCC is often difficult. Grossly, almost all cases appear as advanced gastric cancer. Histologically, a hepatoid pattern is observed in many cases, in addition to a moderately to poorly differentiated adenocarcinoma component. The production of PIVKA-II and AFP is usually confirmed using immunohistochemical staining. Treatment and prognosis largely depends on the existence of liver metastasis, and the prognosis of patients with liver metastasis is very poor. PIVKA-II may be produced during the hepatocellularmetaplasia of the tumor cells.

Related papers:

title: Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma.
abstract: We detected des-gamma-carboxy prothrombin, an abnormal prothrombin, in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter). In contrast, levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean, 10 ng per milliliter) or metastatic carcinoma involving the liver (mean, 42 ng per milliliter), and undetectable in normal subjects. In five patients treated with vitamin K there was no reduction in abnormal prothrombin, indicating that its presence was not due to vitamin K deficiency. Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations, which later increased with recurrence of disease. Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels. Together, the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent). Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma.

title: Clinical evaluation of plasma abnormal prothrombin (des-gamma-carboxy prothrombin) in hepatobiliary malignancies and other diseases.
abstract: Des-gamma-carboxy prothrombin (DCP), a protein induced by vitamin K absence or antagonist-II (PIVKA-II) was measured in the plasma of patients with primary hepatocellular carcinoma and those with various other hepatobiliary and pancreatic diseases. DCP levels were determined by enzyme immunoassay (E-1023), using an anti-DCP monoclonal antibody. Forty-two of the 91 patients (46.2%) with hepatocellular carcinoma had abnormally elevated levels of DCP, whereas only one of the 24 patients with hepatic cirrhosis showed a slight increase. An increase was also observed in some patients with obstructive jaundice. There was no correlation between plasma levels of DCP and those of serum alpha-fetoprotein (AFP). In most patients with hepatocellular carcinoma, plasma DCP levels normalized after curative surgical resection. Plasma DCP levels were not related to the plasma concentration of vitamin K in the patients with hepatocellular carcinoma. Plasma DCP determination may be useful in the diagnosis and postoperative monitoring of the response of hepatocellular carcinoma.

title: Erythropoietin production in hepatocellular carcinoma cells associated with polycythemia: Immunohistochemical evidence
abstract: Patients with hepatocellular carcinoma sometimes have erythrocytosis and high plasma erythropoietin levels. However, previous studies have not revealed direct evidence that the carcinoma cells produce the erythropoietin. To address this question, we carried out light and electron microscopic immunohistochemical studies, using a human erythropoietin antibody to the liver in three male patients with hepatocellular carcinoma and erythrocytosis. α‐Fetoprotein localization was also examined in serial liver sections by light microscopic immunohistochemistry with an antibody to α‐fetoprotein. All three patients demonstrated high hemoglobin levels (16.7, 17.6 and 18.1 gm/dl) and high plasma erythropoietin levels (227, 266 and 280 mU/ml). In one patient the plasma erythropoietin level in the hepatic vein was significantly higher than that in the hepatic artery. The levels of plasma erythropoietin, as well as such tumor markers for hepatocellular carcinoma as serum α‐fetoprotein and plasma des‐γ‐carboxyprothrombin, were significantly reduced after treatment with an anticancer drug, cisplatin. Light microscopic immunohistochemistry showed that erythropoietin was definitely present in the cytoplasm of the hepatocellular carcinoma cells, but not in normal hepatocytes around the carcinoma lesion or in other nonparenchymal cells such as vascular endothelial cells and Kupffer cells. In electron microscopic immunohistochemistry, reaction products for erythropoietin were revealed in the cisternae of the endoplasmic reticulum in the carcinoma cells, suggesting the production of erythropoietin by these cells. Light microscopic immunohistochemistry showed that α‐fetoprotein was localized in the hepatocellular carcinoma cells that were erythropoietin positive in the serial sections. These findings indicated that hepatocellular carcinoma cells produced erythropoietin as well as α‐fetoprotein in these cases, leading to the complication of erythrocytosis. (HEPATOLOGY 1993;18:1357–1362.)

title: Des-gamma-carboxy prothrombin (PIVKA-II) and alpha-fetoprotein-producing IIc-type early gastric cancer.
abstract: We describe the case of a 56-yr-old man with primary gastric adenocarcinoma, who had an extremely high plasma level of des-gamma-carboxy prothrombin (2.45 AU/ml) and of serum alpha-fetoprotein (2810 ng/ml). Histopathologically, the gastric cancer was a IIc type of early cancer which consisted of a combination of a poorly differentiated adenocarcinoma and a well-differentiated tubular adenocarcinoma. The association of a hepatic tumor including hepatocellular carcinoma or liver metastasis was ruled out by ultrasonography, computed tomography, radiocolloid liver scan, magnetic resonance imaging, and angiography. Foci strongly resembling hepatocellular carcinoma (hepatoid differentiation) were noted in the gastric tumor. Localization of des-gamma-carboxy prothrombin and alpha-fetoprotein within the tumor cells, especially within the hepatoid differentiated foci, was demonstrated by the immunohistochemical staining of tissue obtained at biopsy and the resected specimen. This case seems to be the first case reported in which des-gamma-carboxy prothrombin was produced by the gastric cancer. This finding supports the theory of hepatoid differentiation of a gastric cancer.

title: Double cancer of the stomach, one AFP-producing tumor
abstract: In recent years, many cases of alpha-fetoprotein-producing gastric cancer (AFPGC) characterized by increased serum levels of alpha-fetoprotein (AFP) and AFP positivity of the gastric cancer have been reported. Here we present a case of AFPGC coexistent with a different histological type of gastric cancer: The AFPGC was Borrmann type 1 advanced gastric cancer with multiple liver metastasis and appeared to produce both AFP and des-γ-carboxy prothrombin (PIVKA-II). The second cancer was IIc type early gastric cancer and did not produce AFP. Despite receiving palliative chemotherapy, the patient died, due to hepatic failure, 45 days after admission.

title: Alpha-fetoprotein- and des-gamma-carboxy prothrombin-producing advanced gastric cancer
abstract: A case of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) producing gastric cancer with multiple liver metastasis is reported. The simultaneous presence of Borrmann I gastric cancer and IIa aggregating type gastric cancer was noted. Borrmann I gastric cancer was a poorly differentiated adenocarcinoma, while IIa aggregating type gastric cancer was a moderately differentiated adenocarcinoma. Plasma levels of AFP and DCP were 247 000 ng/ml and 320 000 mAU/ml, respectively. Immunohistochemical staining confirmed the production of these two proteins in Borrmann I gastric cancer.

title: Des-gamma carboxy prothrombin (PIVKA-II) and alpha-fetoprotein producing gastric cancer with multiple liver metastases.
abstract: We describe the case of an 87-year-old woman who presented to Tokyo Kousei Nenkin Hospital because of appetite loss and general fatigue. Multiple liver masses and Borrmann type 2 gastric tumor were detected. A clinical diagnosis of hepatocellular carcinoma and gastric cancer was made based on the patient's high levels of serum alpha-fetoprotein (AFP; 490 200 ng/mL) and protein induced by vitamin K absence or antagonist-II (PIVKA-II, 2284 mAU/mL). The patient's general condition worsened gradually and she died 42 days after admission. Autopsy revealed that the predominant histological structure of the gastric tumor was trabecular or sheet-like, although a tubular structure was also found. Venous invasion was prominent. Immunohistochemically, the tumor tissue was positive for AFP and a few tumor cells were positive for PIVKA-II. The histological appearance and immunohistochemical features of the hepatic tumors resembled that of the gastric tumor. This case was pathologically diagnosed as AFP- and PIVKA-II-producing gastric carcinoma with multiple liver metastases. When tumors are found in the stomach and liver and serum PIVKA-II level is abnormally high, the possibility of PIVKA-II-producing gastric cancer with liver metastasis should be considered, especially when hepatitis virus markers are negative and liver cirrhosis is not present.

title: PIVKA-II-producing advanced gastric cancer
abstract: We describe the case of a 68-year-old man with primary advanced adenocarcinoma of the stomach, who displayed extremely high plasma levels of protein induced by vitamin K antagonist (PIVKA)-II (15 600 mAU/ml) and normal levels of alphafetoprotein (AFP) (4 ng/ml). Ultrasonography and dynamic computed tomography ruled out hepatocellular carcinoma (HCC) or liver metastasis. After preoperative chemotherapy, pancreatico-spleno total gastrectomy with D2 lymphadenectomy was performed. Postoperatively, plasma levels of PIVKA-II returned to within the normal range (29 mAU/ml). Microscopic examination revealed stomach adenocarcinoma showing various histological types, such as moderately to poorly differentiated mucinous adenocarcinoma, but hepatoid differentiation of gastric adenocarcinoma was not detected. Localization of PIVKA-II and AFP within tumor cells was demonstrated by immunohistochemical staining using monoclonal antibodies. These results indicate that tumor cells from gastric cancer may produce PIVKA-II. Some cases of PIVKA-II- and AFP-producing advanced gastric cancer with liver metastasis have been reported, but this is the first report of gastric cancer without liver metastasis producing PIVKA-II alone.

title: Alpha-fetoprotein (AFP)- and des-gamma-carboxy prothrombin (DCP)-producing adenocarcinoma of the stomach with liver metastasis in a patient with chronic hepatitis C.
abstract: A 45-year-old man was admitted to our hospital because of chronic hepatitis C and a large liver tumor accompanied by increased serum levels of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), the tumor markers for hepatocellular carcinoma. Endoscopic examination revealed advanced gastric cancer. Biopsy specimens of the stomach and liver showed gastric adenocarcinoma and its metastasis to the liver. Immunohistochemical studies demonstrated that adenocarcinoma cells both of the stomach and liver, were positive for the antibodies against AFP as well as DCP. Expression of AFP mRNA was shown in the cancer cells of the stomach. Accordingly, we diagnosed this patient with AFP- and DCP-producing adenocarcinoma of the stomach together with liver metastasis.

title: Des-gamma carboxy prothrombin (PIVKA-II)- and alpha-fetoprotein (AFP)-producing gastric cancer
abstract: Since Liebman et al.1 reported, in 1984, that protein induced by vitamin K absence or antagonist-II (PIVKA-II) was increased in the plasma of hepatocellular carcinoma (HCC) patients, PIVKA-II has been regarded as a new tumor marker of HCC. Although case reports of α-fetoprotein (AFP)-producing gastric cancer have been gradually increasing, PIVKA-IIproducing gastric cancer is very rare. In this report, we describe a case of PIVKA-IIand AFP-producing gastric cancer. A 61-year-old man was hospitalized with the chief complaint of appetite loss. Barium study and upper digestive tract endoscopy revealed a 10-cm-sized Borrmann type-3 gastric cancer. Hepatic masses up to 8 8 6-cm in size were also detected by abdominal computed tomography and ultrasonography. AFP and PIVKA-II values in the serum were abnormally high (AFP, 495.2 ng/ml [L2 subfraction, 21.4%; L3 subfraction, 75.6%]; normal value, 20 ng/ml; PIVKA-II, 635 mAU/ml; normal value, 40 mAU/ml). Thus, total gastrectomy and liver biopsy were performed. In the resected specimen, an 8.0 7.0/9.5 8.5-cm-sized Borrmann type-3 gastric cancer occupied mainly the posterior wall from the upper gastric body to the pyloric antrum . Histologically, tumor cells proliferated to form tubular, papillary, trabecular, and solid structures. Immunohistochemically, AFPpositive tumor cells and PIVKA-II-positive tumor cells were found; the AFP-positive tumor cells were distributed mainly in the trabecular or solid structure and the PIVKA-II-positive tumor cells were distributed mainly in the tubular structure . The tumor in the liver showed a structure similar to that of the gastric tumor; however, immunohistochemical staining for AFP and PIVKA-II was negative. Adjuvant chemotherapy was performed; however, the residual hepatic tumor enlarged and the patient died 6 months after the diagnosis. We made a pathological diagnosis of PIVKA-IIand AFPproducing gastric carcinoma with liver metastasis for this patient. Although AFP and PIVKA-II production in the liver tumor was not confirmed immunohistochemically, the following findings suggested that it was a metastatic tumor: (1) the histological structures of the gastric and hepatic tumors were similar, (2) hepatitis virus markers were all negative, (3) there was no remarkable change in the nontumorous liver tissue pathologically. The cause of the negative staining for AFP and PIVKA-II in the liver tumor was probably sampling limitations. In recent years, the mechanism of AFP production in most cases of AFP-producing gastric carcinoma has been assumed to be retrodifferentiation to yolk sac tumor or fetal gastrointestinal tract, as determined by the investigation of AFP-lectin combination. However, the AFP subfraction pattern in the present patient resembled that of HCC; so, hepatoid metaplasia may have been the cause of the AFP production in this particular patient. The mechanism by which gastric cancer acquires the ability to produce PIVKA-II is unknown. Some researchers have suggested that the mechanism of hepatocellular metaplasia is involved. However,  An 8.0 7.0/9.5 8.5-cmsized Borrmann type-3 cancer occupies mainly the posterior wall from the upper gastric body to the pyloric antrum

title: Solitary AFP- and PIVKA-II-producing hepatoid gastric cancer with giant lymph node metastasis.
abstract: A 61-year-old man was admitted to our hospital because of abdominal pain and an abdominal mass. The patient had anemia and elevated serum alpha-fetoprotein (AFP) (9630ng/mL) and PIVKA-II (91mAU/mL) levels. Roentgenographic examination revealed an extra-gastric tumor in the upper abdomen, and gastroscopy revealed Bormann type 2 gastric cancer in the lower portion of the stomach. The preoperative diagnosis was synchronous gastric cancer and hepatocellular carcinoma (HCC), and surgery was performed. The extra-gastric tumor appeared to be an extra-hepatically growing HCC because the tumor was fed by vessels ramifying from the umbilical portion of the liver. Distal gastrectomy with resection of the extra-gastric tumor was performed, and histological examination of the resected specimen revealed that the gastric cancer was an AFP-producing hepatoid gastric adenocarcinoma and that the extra-gastric tumor was a lymph node metastasis. AFP-producing hepatoid gastric adenocarcinoma tends to metastasize to the regional lymph nodes and form a giant tumor. A giant tumor in the upper abdomen associated with gastric cancer may therefore be a clinical manifestation of AFP-producing hepatoid gastric adenocarcinoma.

title: [A case of AFP and PIVKA-II producing gastric carcinoma].
abstract: A 71-year-old man was admitted to our hospital with edema of the ambilateral crura and liver dysfunction. Serum levels of AFP and PIVKA-II were both abnormally high. An abdominal CT revealed many low density masses in both lobes of the liver. Endoscopic examination and gastric radiography showed a Type 1 tumor in the fornix of the stomach. Biopsy specimen showed poorly differentiated adenocarcinoma. Immunohistochemical stains demonstrated the presence of AFP and PIVKA-II in tumor cells. A diagnosis of AFP and PIVKA-II producing gastric carcinoma with liver metastasis was made and the internal use of S-1 was started. The result of treatment was determined to be partial response. However, the condition of his entire body gradually worsened and he died of hepatic insufficiency.

title: Three different types of alpha-fetoprotein in the diagnosis of malignant solid tumors: use of a sensitive lectin-affinity immunoelectrophoresis.
abstract: A sensitive new technique for lectin-affinity immunoelectrophoresis was applied to samples from 28 infants and children in order to distinguish the origin of elevated alpha-fetoprotein (AFP) in sera. This new immunoelectrophoresis was successfully performed within 24 hours in sera with AFP as small as 910 ng/mL. With combined use of concanavalin A (Con A) and lentil agglutinin (LCH) binding tests, AFPs were classified into three subtypes: benign hepatic condition type (six patients), hepatocellular carcinoma type (nine patients) and yolk sac type (12 patients). AFP was of hepatocellular carcinoma type in all seven patients with hepatoblastoma, and of benign hepatic condition type in six of seven patients with elevated AFP due to conditions such as hepatitis, biliary atresia, and normal newborn. The question as to whether AFP produced in "hepatoblastoma" is of benign hepatic condition type or hepatocellular carcinoma type was first answered by the information in this present report. The differentiation between yolk sac and general hepatic AFPs was completed with the Con A binding test.

title: SALL4 Represents Fetal Gut Differentiation of Gastric Cancer, and is Diagnostically Useful in Distinguishing Hepatoid Gastric Carcinoma From Hepatocellular Carcinoma
abstract: The novel stem cell marker SALL4 has been identified as a diagnostic marker of germ cell tumors, especially yolk sac tumors, in gonadal organs. To clarify the significance of SALL4 as an oncofetal protein, we investigated SALL4 expression by immunohistochemistry in non-neoplastic stomach and gastric carcinoma with particular emphasis on á-fetoprotein (AFP)-producing gastric carcinoma, as AFP-producing gastric carcinoma shares expression of AFP and glypican 3 (GPC3) with yolk sac tumors and hepatic neoplasms. A total of 338 gastric carcinomas, 60 hepatocellular carcinomas, and 48 cholangiocellular carcinomas were studied by immunohistochemistry on tissue microarrays. In addition, more detailed whole tissue section immunohistochemistry was performed on non-neoplastic gastric tissue from 5 adult and 8 fetal specimens, 6 hepatoblastomas, and 31 cases of AFP-producing gastric carcinomas. SALL4 expression was observed in the neofetal stomach in gestational week 9 and disappeared thereafter. It was also identified by tissue microarray study in a fraction of gastric carcinomas (51 of 338, 15%), associated with older age (P=0.0001), male sex (P=0.0033), intestinal-type histology (P=0.0001), and synchronous liver metastasis (P=0.0047). AFP and GPC3 were closely associated with SALL4 expression in gastric carcinoma (both, P<0.0001), and a full-section study indicated that SALL4 was positive in all 31 cases of AFP-producing gastric carcinoma with diffuse staining in 24 cases (78%). Diffuse SALL4 expression was observed in the histologic patterns of hepatoid (89%), glandular (57%), and clear cell (39%) AFP-producing gastric carcinoma. In addition, SALL4 expression was completely negative in hepatoblastoma (n=6) and hepatocellular carcinoma (n=60). SALL4 is an oncofetal protein similar to AFP and GPC3, but it represents fetal gut differentiation in gastric carcinoma. SALL4 is a sensitive marker for AFP-producing gastric carcinoma and is especially useful to distinguish hepatoid gastric carcinoma from hepatocellular carcinoma.

title: [A case of advanced gastric cancer producing alpha fetoprotein with multiple liver metastases responding to TS-1 after TAE].
abstract: We report a case of advanced gastric cancer producing Alpha Fetoprotein (AFP) with multiple liver metastases in which TS-1 is effective. Prognosis of gastric cancer producing AFP is well known to poor. A 74-year-old female was admitted complaining of anemia. She was diagnosed as having advanced gastric cancer with multiple liver metastases producing AFP by endoscopy, computed tomography and angiography. Her serum AFP level was 17,666 ng/ml and her serum CEA level was 5-2 ng/ml. After transarterial embolization (TAE), her family rejected her operation because it would not be curative. So, she was treated with TS-1, 40 mg, administered orally every day, followed by 14 days rest, as the first course. The next was TS-1, 80 mg orally administered for 6 courses. Her serum AFP level was down from 17,666 ng/ml to 94 ng/ml after 6 courses of TS-1. CT revealed that liver metastases did not change and endoscopy showed the primary lesion has diminished. Our report is the first to demonstrate that TS-1 is effective for patients with advanced gastric cancer producing AFP with multiple liver metastases.

title: [A patient with advanced gastric cancer in the gastric tube whose QOL was improved by TS-1].
abstract: We present the case of a 72-year-old man with gastric tube cancer accompanied by multiple liver metastases, after esophagectomy for esophageal cancer, whose quality of life (QOL) was improved with a small dosage of TS-1. The patient's high serum AFP level suggested alpha-fetoprotein-producing gastric cancer. He was treated with half the standard dose of TS-1, because the patient's poor general condition necessitated chemotherapy with low toxicity and high efficacy. The daily dose was 40 mg for the first three courses and 50 mg for the last two. Each treatment course consisted of a four-week administration followed by two drug-free weeks. The patient received five courses of chemotherapy at our outpatient clinic before his death from re-progression of liver metastasis. No serious side effect except temporary stomatitis was observed. A decrease in tumor markers, alpha-fetoprotein and carcinoembryonic antigen, was obtained after 4 weeks. After 2 cycles, computed tomography and endoscopy examinations showed regression of the primary tumor and liver metastases, and tumor markers were decreased remarkably. The patient's QOL improved gradually after the treatment. His performance status before the chemotherapy was 3, and improved to 1 after two cycles. The small dosage of TS-1 was effective without any adverse effects, and improved the patient's QOL, for 6 months.

title: Mechanism of the abnormal vitamin k‐dependent γ‐carboxylation process in human hepatocellular carcinomas
abstract: An important marker for hepatocellular carcinoma is the presence of des‐γ‐carboxy (abnormal) prothrombin. However, the molecular basis for the reduced carboxylation of prothrombin is unknown.

title: Genetic evolution of alpha fetoprotein producing gastric cancer.
abstract: Alpha fetoprotein (AFP) producing gastric cancer is an unusual form of aggressive adenocarcinoma with a complex histological picture, including enteroblastic and hepatoid differentiation.



To investigate the genetic events underlying the phenotypic diversity in AFP producing gastric cancer and the ability of these tumours to produce AFP ectopically.



Multiple foci from 19 AFP producing gastric adenocarcinomas were microdissected and loss of heterozygosity (LOH) analysis was performed with a panel of microsatellite markers on nine chromosomal arms.



For informative cases, LOH was most frequently detected on 17p (100%), followed by 13q (88%), 3p (87%), 5q and 9p (80%), 11q (70%), 18q (58%), 16q (53%), and 8p (50%). The average fractional allelic loss was 0.72. LOH was detected either homogeneously throughout the microdissected foci, or only in some parts of the neoplastic foci for each case. Heterogeneous patterns of LOH indicated genetic progression and/or divergence in clonal evolution. Furthermore, in six cases with heterogeneous LOH of 13q, 13q LOH was restricted to immunohistochemically AFP positive neoplastic foci.



AFP-GC arises as an aggressive clone with extensive LOH and high fractional allelic loss. The presence of heterogeneous patterns of LOH suggested that the AFP producing carcinoma foci might evolve through genetic progression and/or genetic divergence. Silencing of the crucial gene on 13q may be involved in the acquisition of the AFP producing phenotype.

title: Comparison between the clinicopathologic features of AFP-positive and AFP-negative gastric cancers.
abstract: We compared 27 cases of alpha-fetoprotein (AFP)-positive gastric cancer with 478 cases of AFP-negative gastric cancer in our department. The incidences of AFP-positive gastric cancer were 5.4% (27/505), 7.2% (23/218), and 2.1% (4/187) for overall, advanced, and early cases of gastric cancer, respectively. Sex, age distribution, pathologic type, and serum carcinoembryonic antigen levels were similar between these two groups. Borrmann III type cancer, lymph node metastasis, lymphatic and venous microinvasion of the gastric wall, and incidence of synchronous and metachronous liver metastasis occurred more often in the AFP-positive group. It was suspected that the character of early venous invasion contributed to the high incidence of liver metastasis. Liver metastasis occurred in 72% of AFP-positive patients, all of whom died within 2 yr. Long-term survival of the AFP-positive group was worse than that of the negative group. The 1-, 3-, 5-, and 7-yr survival rates of both groups were 38.7%, 11.6%, 11.6%, 11.6%, and 71.3%, 57.8%, 52.8%, 49.6%, respectively (p less than 0.001).

title: Clinicopathologic Features of Gastric Cancers Producing Alpha-Fetoprotein
abstract: Patients with gastric cancers producing alpha-fetoprotein (AFP) were reported to have a poor prognosis with high rates of liver metastasis. The purpose of the present study was to clarify the clinicopathological features of AFP-producing gastric cancers, in particular characteristics of liver metastasis, and to evaluate treatment of these cancers.  In 27 of the 29 cases with elevated preoperative serum AFP levels among a total of 974 primary gastric cancers, AFP production was confirmed in gastric cancer cells by immunohistochemistry. These cases were included in the AFP-positive gastric cancer group (AFP(+), 2.7%). The remaining 945 cases with normal serum AFP levels were designated the AFP-negative gastric cancer group (AFP(–)).  There was a higher incidence of lymph node metastasis, a deeper invasion of the gastric wall, a higher frequency of advanced stage, a more marked lymphatic invasion and a higher rate of liver metastasis in the AFP(+) group than in the AFP(–) group. The patients received curative resection in AFP(+) group had a significantly worse survival rates in comparison to that in AFP(–) group. With respect to liver metastasis (n = 17) in AFP(+) group, of 3 cases who received curative hepatic resection, 1 patient survived more than 3 years, while the remaining 2 died in less than 3 years due to multiple liver recurrence. The patients (n = 5) who received palliative resection for liver metastasis followed by transarterial continuous infusion chemotherapy all died in less than 1 year.  AFP-producing gastric cancers had aggressive behavior and their clinical or biological features were quite different from the common AFP-negative gastric cancers. Surgical resection of liver metastasis from AFP-producing gastric cancers was unsatisfactory. The development of a novel multimodal therapy against AFP-producing gastric cancers is needed.

title: AFP-Producing Gastric Carcinoma: Multivariate Analysis of Prognostic Factors in 270 Patients
abstract: Serum α-fetoprotein (AFP) is sometimes high in patients with primary gastric carcinoma, and there is no comprehensive study on the clinicopathologic characteristics and prognostic factors of AFP-producing gastric carcinoma (AGC). To clarify the variables associated with the survival after gastrectomy for AGC, we reviewed the data of patients with AGC and examined the independent prognostic factors. We studied 270 cases of AGC reported in the Japanese literature from June 1982 to March 2001, together with 1 patient of our own experience. The clinicopathologic findings, including serum AFP level, operative curability, and stage of the disease were examined, and factors associated with survival were determined by multivariate analysis. There were 15 stage I tumors (6%), 50 stage II tumors (19%), 51 stage III tumors (20%), and 145 stage IV tumors (55%). The tumors were characterized by frequent serosal invasion (75%), lymph node metastasis (83%), liver metastasis (33%), stage III or IV disease (75%), and noncurative operation (48%). The survival was influenced by the serum AFP level, tumor size, serosal invasion, lymph node metastasis, and liver metastasis, but the independent prognostic factors were operative curability (curative vs. noncurative) and stage of the disease (I, II vs. III, IV). Although the 5-year survival rate and median survival period in all patients were 22% and 14 months, respectively, those in patients with curative gastrectomy were 42% and 29 months, respectively. The results indicate that operative curability and stage of the disease are factors associated with the survival of patients with AGC. Although tumors are often advanced and complicated with liver metastases, long-term survival can be achieved when patients with stage I or II tumor undergo curative gastrectomy.

title: Hepatoid adenocarcinoma of the stomach. A clinicopathologic and immunohistochemical analysis
abstract: The clinicopathologic and immunohistochemical features of the primary gastric hepatoid adenocarcinomas still remain unclear.

title: Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma.
abstract: Des-gamma-carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma (HCC). In the present study, we demonstrate that DCP has a mitogenic effect on HCC cell lines. Purified DCP stimulated DNA synthesis of Hep3B and SK-Hep-1 cells in a dose-dependent manner. DCP was found to bind with cell surface receptor Met causing Met autophosphorylation and also to activate STAT3 signaling pathway through Janus kinase 1. Luciferase gene reporter analysis showed that DCP induced STAT3-related transcription. Small interfering RNAs against both STAT3 and Met abrogated DCP-induced cell proliferation. DCP did not affect the mitogen-activated protein kinase pathway, Myc signaling pathway, or phosphoinositide 3-kinase/Akt pathway. Based on these results, we believe that DCP acts as an autologous mitogen for HCC cell lines. The Met-Janus kinase 1-STAT3 signaling pathway may be a major signaling pathway for DCP-induced cell proliferation.

title: Immunolocalisation of PIVKA-II in paraffin-embedded specimens of hepatocellular carcinoma.
abstract: Although serum PIVKA-II has been widely used as a tumor marker for hepatocellular carcinoma (HCC), little information is available concerning tissue PIVKA-II, and detection of tissue PIVKA-II in paraffin-embedded tissue specimens of HCC is also considered difficult.



Paraffin-embedded HCC tissues obtained at autopsy from 22 patients were subjected to immunohistochemical staining using the antibody MU-3 (Eisai Co., Ltd.) after microwave antigen retrieval.



PIVKA-II was mainly detected in the cytoplasm of HCC cells. The intensity of tissue PIVKA-II staining was not correlated with serum PIVKA-II levels or with the histotogical differentiation of HCC. However PIVKA-II staining tended to be more intense in tissue from patients with portal tumor thrombus, distant metastases, or a longer duration of HCC.



This method of immunohistochemical staining is easy and simple to use and may be helpful for detecting tissue PIVKA-II in paraffin-embedded HCC specimens.

title: Hepatoid carcinoma of the lung with production of alpha-fetoprotein and abnormal prothrombin: an autopsy case report.
abstract: Alpha-fetoprotein (AFP) is a useful tumor marker for the diagnosis of hepatic and testicular tumors. Several cases of AFP-producing lung cancer have been reported. We present here a patient with AFP-producing primary lung carcinoma, which showed high values of serum AFP (100,000 ng/mL). The concanavalin A nonbinding fraction rate of AFP was 15%. Gross and microscopic features of the lung carcinoma bore a striking resemblance to those of hepatocellular carcinoma. According to the histologic classification of lung tumor, this case was large cell carcinoma with prominent hepatoid differentiation. Immunohistochemically, we detected AFP in the cytoplasm of the neoplastic cells. We also detected another useful tumor marker for the diagnosis of hepatocellular carcinoma, i.e., des-gamma-carboxy prothrombin (protein induced by vitamin K absence or the absence of antagonist-II [PIVKA-II]), in serum using an enzyme immunoassay and in tumor cells by immunohistochemical analysis.

title: A resected case of metachronous liver metastasis from lung cancer producing alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II).
abstract: A resected case of huge liver metastasis of hepatoid adenocarcinoma of the lung is described. A 77-year-old man who presented a solitary huge liver tumor was admitted to our hospital. He had undergone right lower lobectomy of the lung for lung cancer one year before. The view of imaging studies was not a typical one of hepatocellular carcinoma. Serum levels of AFP and PIVKA-II were 334,500ng/mL and 3,890mAU/mL, respectively, and the proportion of AFP L3 was 97.9%. It was thought that they were strongly diagnostic for hepatocellular carcinoma. Extended right lobectomy of the liver was performed. Microscopically, it was poorly differentiated adenocarcinoma and diagnosed as liver metastasis from the formerly resected lung cancer. The tumor was composed of cells with both sheet-like growth and tubule formation. The neoplastic cells, in the sheet-like growth resembled hepatocellular carcinoma cells. By immunohistochemical staining with anti-AFP and anti-PIVKA-II antibodies, cancer cells of both the primary and metastatic lesions were positive. The patient eventually died of multiple liver and bone metastasis 6 months after the operation.

title: An autopsy case of hepatoid carcinoma of the ovary with PIVKA‐II production: Immunohistochemical study and literature review
abstract: A case of hepatoid carcinoma of the ovary in a 61‐year‐old Japanese woman, who showed high serum levels of α‐fetoprotein and CA125, is reported. Grossly, the left ovarian tumor, which measured 12 × 9 cm, was solid and multinodular. Histologically, the tumor resembled hepatocellular carcinoma by its architectural and cytological features. Liver cell differentiation was indicated functionally by the immunohistochemical detection of α‐fetoprotein and protein induced by vitamin K absence or antagonist II (PIVKA‐II) and by positive bile production, and the hepatocellular differentiation was structurally in accord with keratin 7, 8 and 18 expression. CA125 expression, commonly present in ovarian surface epithelial carcinomas, suggested that this neoplasm originated from ovarian common epithelial cells. There are only nine such cases in the literature. A review of these cases reveals that hepatoid carcinoma of the ovary occurs exclusively in postmenopausal women (mean age, 62.7 years) and that the prognosis is poor.

title: Hepatoid carcinoma of the pancreas producing protein induced by vitamin K absence or antagonist II (PIVKA-II) and α-fetoprotein (AFP)
abstract: We describe a rare case of hepatoid carcinoma of the pancreas with production of protein induced by vitamin K absence or antagonist II (PIVKA-II) and α-fetoprotein (AFP). The patient was a 49-year-old woman admitted because of high serum levels of PIVKA-II (1.63 AU/ml) and AFP (623 ng/ml) and abnormal ultrasonographic findings of the pancreas, found incidentally at medical checkup. Both ultrasonography and computed tomography showed swelling of the pancreas with small areas of low density, but no hepatic lesions. The serum levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were not increased. A PIVKA-II and AFP-producing pancreatic cancer was strongly suspected, and total pancreatectomy was performed. Pathological examination showed that the tumor cells were arranged in trabecular and solid patterns with bile production, and were immunohistochemically positive for PIVKA-II and AFP, resembling hepatocellular carcinoma cells. The tumor was diagnosed as hepatoid carcinoma of the pancreas, and the patient has survived 48 months after initial diagnosis. It is important that hepatoid carcinoma be considered as a possible malignant tumor of the pancreas, and simultaneous measurement of the serum levels of AFP and PIVKA-II will enable earlier diagnosis. This is the first report describing hepatoid carcinoma of the pancreas producing PIVKA-II.