甲胎蛋白阴性肝癌早期诊断的探讨

A comparative study on 150 cases of alpha fetoprotein (AFP) nonproducing primary liver cancer (PLC) in subclinical and moderate stages and 133 cases of intrahepatic solid space-occupying lesion (SOL) other than PLC was undertaken. All were operated and proven by pathology. The results indicated that in the intrahepatic SOL patients with negative serum AFP the diagnosis of PLC could be established if any one of the following items was confirmed: (1) Definite evidence of liver cirrhosis; (2) Hypoecho or inhomogeneous echo sonodensity on ultrasonography plus positive serum HBsAg; (3) Positive 99mTc-PMT liver scan (4) No overfilling of SOL on blood pool scintiscan plus positive HBsAg; (5) No enhancement after injection of contrast medium on computed tomography plus positive HBsAg. The positive rates of the above items in PLC and non-PLC groups were: (1) 73.2% vs. 0.9%, (2) 48.1% vs. 9.6%, (3) 64.3% vs. 14.3%, (4) 27.3% vs. 3.9% and (5) 34.6% vs. 0%, respectively. Statistically, these differences were significant. In conclusion, according to the above mentioned criteria, detection rate of over 90% with over 85% specificity can be obtained for AFP negative PLC.     

ENZYMO－ROCKET ELECTROPHORETIC ASSAY AND CROSSED AFFINITY ENZYMOIMMUNOELECTROPHORESIS AND ITS APLICATION IN DIAGNOSIS OF PLIMA

ＥＮＺＹＭＯ－ＲＯＣＫＥＴＥＬＥＣＴＲＯＰＨＯＲＥＴＩＣＡＳＳＡＹＡＮＤ　ＣＲＯＳＳＥＤＡＦＦＩＮＩＴＹＥＮＺＹＭＯＩＭＭＵＮＯＥＬＥＣＴＲＯＰＨＯＲＥＳＩＳＡＮＤＩＴＳ　ＡＰＬＩＣＡＴＩＯＮＩＮＤＩＡＧＮＯＳＩＳＯＦＰＬＩＭＡＲＹ　ＬＩＶＥＲＣＡＮ...     

An autopsy case of a gastric cancer associated with elevated AFP, CEA and CA19-9

A 48-year-old male developed gastric cancer (Borrmann III) with lung and liver metastases. Laboratory examination revealed a markedly elevated AFP (24, 241 ng/ml), CEA (9739.8 ng/ml), and CA-19-9 (726U/ml). Nevertheless, he underwent a subtotal gastrectomy for the hemostasis of a bleeding malignant lesion. Histological examination showed a moderately differentiated adenocarcinoma. A PAP for an AFP and a CEA disclosed positive staining. In addition, An autopsy revealed metastases to the liver and lungs with a positive result of PAP for AFP and CEA. Further, CA19-9 also was confirmed weakly in these same tissues, histochemically. Therefore this gastric cancer was considered an AFP, CEA, and CA19-9-producing tumor. Gastric cancer with 3 elevated tumor markers in the same patient is rare and its mechanism may elucidate the origin of gastric cancer and the resulting differentiation in the foregut.     

Hepatocellular Carcinoma and its Early Detection by AFP Testing in Mongolia

Liver cancer is one of the leading causes of cancer death in Mongolia. Since 1982-1986 , when HCC became themost frequent cancer among the Mongolian population, the rate has been increasing continuously. In the period2000-2005 years 35.3%of all newly registered cancer cases were liver cancers, with an incidence rate of 51.3 per100,000 population. Compared to the previous 5 year period, the rate increased by 11%. The objective here was toanalyze hepatitis B (HBV) and C virus (HCV)-related HCC cases and to evaluate the possibility of tumor marker(AFP) testing for early detection in Mongolia. Sera from a total of 513 patients with chronic liver diseases, livercirrhosis and HCC were analyzed for liver function (ALAT, ASAT) and hepatitis virus markers (HBsAg, anti-HCV).Sera from 316 patients were also examined for alpha-fetoprotein (AFP) levels. The overall incidence of HBsAg oranti-HCV were very high ( 95.3%) among all patients. Some 33.5% (66/197) of patients with HCC were positive forHBsAg and 45.2% (89/197) for anti-HCV. Moreover, 17.3% ( 34/197) of HCC patients demonstrated co-infectionwith HBV and HCV. AFP levels were elevated in 4.6% (11/238) and 29.5% (23/78) of chronic hepatitis and cirrhosispatients, respectively. In HCC cases, 84.3% (166) of patients had increased level of AFP ranging from 32ng/ml tomore than 400 ng/ml. We conclude that HBV/HCV infection is the main factor related to development of HCC inMongolia and that testing for AFP serum levels is a useful tool for early detection and diagnosis.     

A case of advanced gastric cancer producing alpha fetoprotein with multiple liver metastases responding to TS-1 after TAE]

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.     

血清r—谷氨酰转肽酶同工酶对AFP阴性肝癌的诊断价值

本文收集1984年9月至1988年6月在我院手术的AFP阴性肝癌及非肝癌肝占位性病变59例。术前用4～30％聚丙烯酰胺梯度凝胶电泳法测定其血清r—谷氨酰转肽酶同工酶。此同工酶的Ⅰ＇、Ⅱ、Ⅱ＇带为原发性肝癌特异性区带。AFP阴性肝癌出现特异性区带者占66.7％(22/33),转移性肝癌占10％(1/10)肝血管瘤等不出现特异性区带。结果表明r—谷氨酰转肽酶同工酶对AFP阴性肝癌的诊断有较大意义。     

Serum alphafetoprotein in hepatocellular carcinoma.

The serum alphafetoprotein level (AFP) was studies in 125 histologically verified cases of hepatocellular carcinoma, 66 other malignancies, 74 cases of cirrhosis of the liver, 60 of chronic aggressive hepatitis, 12 of chronic persistent hepatitis, 16 of subacute hepatitis, 36 of acute viral hepatitis, and 13 healthy hepatitis B-surface antigen (HBsAg) carriers. Double immunodiffusion and radioimmunoassay (RIA) were used in all cases. AFP greater than 10 ng-ml appeared in 90% of the cases, and was above 400 ng/ml in 69%. In 80% of those above 400 ng/ml, AFP could also be demonstrated by immunodiffusion. The AFP level in hepatocellular carcinoma was discovered to decline as the age increased. It also appeared to be related to the tumor cell type; the relatively immature cell type was more frequently associated with a higher AFP level. The presence of HBsAg did not influence the AFP level. Although the AFP in other malignancies and liver diseases ranged abnormally from 14 to 69%, the level did not exceed 400 ng/ml as in our cases of hepatocellular carcinoma (except in one case). Thus, this figure provides a diagnostic serum level of AFP for the identification of hepatocellular carcinoma.     

A case of an alpha-fetoprotein-producing intrahepatic cholangiocarcinoma suggests probable cancer stem cell origin

Recent evidence suggests that some cancers may originate from cancer stem cells, which may derive from carcinogenesis of normal stem cells. A hepatic progenitor cell population, which gives rise to hepatocytes and cholangiocytes, has been suggested in humans, though whether these cells can give rise to malignant tumors has not been confirmed. We report here a case of an alpha-fetoprotein (AFP)-producing intrahepatic cholangiocarcinoma (ICC) in an 81-year-old woman with chronic hepatitis C viral infection, suggesting malignant transformation of hepatic stem cells as a mechanism for hepatic neoplasia. Abdominal computed tomography revealed a low-density mass with surrounding enhancement measuring 5 cm x 5 cm in segments IV and VIII of the liver. The preoperative serum levels of tumor markers were 1.7 ng/ml of carcinoembryonic antigen, 22 mAU/ml of protein induced by vitamin K absence or antagonist II, 43.4 U/ml of carbohydrate antigen 19-9, and 1,560 ng/ml of AFP. Following central bisegmentectomy of the liver, serum AFP levels decreased dramatically. Histologically, the tumor cells showed indistinct glandular structures with abundant fibrous stroma. Immunohistochemical analysis demonstrated that the neoplastic cells reacted strongly to antibodies against AFP and cytokeratin (CK) 7. In addition, cancer cells showed partially positive reaction to anti-CK14, a liver stem cell marker, and to anticluster designation (CD) 133, a hematopoietic stem cell marker, and negative reaction to antihepatocyte paraffin (HepPar) 1. These data may indicate that the tumor was derived from a normal liver stem cell that underwent oncogenic transformation.     

A case of AFP-producing gastric cancer accompanied with testicular tumor

A case of an AFP-producing gastric cancer accompanied with non-epithelial tumor is reported. A 63-year-old man, complaining of an epigastric hunger pain, was admitted to our hospital. Testing revealed that he had an extremely high level serum AFP (12,400 ng/ml) with no abnormality of liver function. A barium ingestion and a subsequent endoscopic examination determined the existence of a Borrmann III type advanced gastric cancer on the lesser curvature, extending from middle corpus to the antrum. Diagnostic imaging did not reveal any metastatic lesion in liver. After a total gastrectomy, the patient's serum AFP level rapidly decreased, followed by a recurrence he developed of a carcinomatous pleuritis and death. On autopsy, an enlargement of the right testis was noticed for the first time. Histologically, it was found to be a malignant, non-epithelial tumor, which proved negative for anti-AFP staining by the ABC method and positive for anti *L-26. On the other hand, the gastric cancer was a poorly differentiated adenocarcinoma with a hepatoid differentiation which was positive for anti-AFP staining and negative for anti-L-26 so it thus was diagnosed as an AFP-producing gastric cancer.     

Significance of AFP in gastric cancer

Serum alpha-fetoprotein (AFP) was positive in as few as 5.7-13.5% of gastric cancer patients prior to surgery, and most of the positive cases had cancer of stage IV or higher. Thus, the parameter did not seem to be very useful in diagnosis. It was positive in as many as 45% of terminal cancer patients, while many cases with AFP of more than 1000 ng/ml had metastases to the liver. Thus, AFP was proved to be useful for follow-up of the postoperative course. AFP staining was conducted in 29 dissected stomachs and five of them were positive for AFP staining.     

血清甲胎蛋白阳性胃癌患者的临床病理学特征及预后分析

背景与目的：血清甲胎蛋白（alpha-fetoprotein,AFP）阳性胃癌是一种临床上比较罕见的胃恶性肿瘤,具有与普通胃癌明显不同的生物学特点,探讨血清AFP阳性胃癌患者的临床病理学特征及影响预后的危险因素。方法：采用回顾性队列研究,分析河北医科大学第四医院外三科2012年1月1日—2015年1月1日行根治性手术治疗的2 386例胃癌患者,筛选出术前血清AFP阳性的患者,分析临床病理学特征及影响预后的因素。结果：2 386例胃癌患者中术前血清AFP阳性者245例（AFP≥20 ng/mL,10.27%）,其余2 141例术前血清AFP均为正常（AFP＜20 ng/mL,89.73%）。与血清AFP阴性组相比,血清AFP阳性组患者的同时性肝转移率、异时性肝转移率、淋巴结转移率、脉管浸润发生率更高（P均＜0.05）。2 386例胃癌患者中共有2 273例（95.26%）获得完整随访资料,全组患者5年总生存率（overall survival,OS）为49.32%,5年无病生存率（disease-free survival,DFS）为44.61%。其中血清AFP阳性者5年OS和DFS分别为37.50%和34.17%,而血清AFP阴性者5年OS和DFS分别为50.90%和45.84%,两组患者的5年OS和DFS差异均有统计学意义（P均＜0.001）。单因素分析显示,术前血清AFP的水平、年龄、病灶部位、肿瘤直径、组织学类型、Borrmann分型、肿瘤浸润深度pT分期、淋巴结转移pN分期、肿瘤pTNM分期、Lauren分型、脉管瘤栓有无、Ki-67阳性比例、术后是否化疗、术后有无肝转移是影响血清AFP阳性胃癌患者预后的危险因素（P均＜0.05）。多因素分析发现,血清AFP水平（P=0.001）、肿瘤组织学类型（P=0.002）、肿瘤浸润深度pT分期（P=0.006）、淋巴结转移pN分期（P=0.014）、肿瘤pTNM分期（P=0.001）、脉管瘤栓有无（P=0.024）和术后有无肝转移（P=0.008）是影响其预后的独立危险因素,而术后辅助化疗（P=0.031）是患者预后的保护性因素。结论：AFP阳性胃癌具有易发生肝转移、淋巴结转移且预后差的特点,血清AFP水平是影响其预后的独立危险因素,随着AFP水平的升高,其预后变差。     

Hepatic metastases from alpha-fetoprotein producing colorectal cancer that responded remarkably to transcatheter arterial chemo-embolization

Although alpha-fetoprotein (AFP)-producing colorectal cancer is extremely rare, its potential for liver metastasis is high and the prognosis of the patient is very poor. We report a case of metastatic liver tumor from an AFP producing sigmoid colon cancer that was successfully treated with transcatheter arterial chemo-embolization (TACE). A 48-year-old female was admitted to our hospital complaining of anal bleeding, and was diagnosed as harboring a type 2 advanced tumor with two metastatic lesions in the lateral segment of the liver. Serum AFP measured 948.2 ng/ml before surgery. We performed sigmoidectomy and lateral segmentectomy of the liver. Pathological examination revealed moderately differentiated adenocarcinoma both in the primary and the metastatic lesions, and AFP-stain positive nests were seen on immunohistochemical staining. The serum AFP value returned to normal soon after the surgery. Five months later, a recurrent lesion was discovered in the right lobe of liver, and it was surgically removed. Another 4 months later, multiple liver metastases were recognized and the patient's serum AFP level was found to be 593.3 ng/ml. For the re-recurrent hepatic lesions of 5.5 cm in diameter, she underwent two courses of TACE using Lipiodol and epirubicin hydrochloride. Following the treatment, the tumor shrank rapidly and almost disappeared. The patient has been in good health for 24 months since the last TACE, and the serum AFP level has been within the normal range.     

α-fetoprotein-producing rectal cancer: Calculated tumor marker doubling time

α-fetoprotein (AFP) production by rectal cancer is very rare. In the English literature there are only a few reported cases in which serum AFP level was >1,000 ng/ml. A 43-year-old Japanese man with rectal cancer and liver metastases had a high serum AFP level (941 ng/ml) when first evaluated. Three weeks later, the serum AFP level was extremely elevated (7,060 ng/ml). He underwent abdominoperineal excision of the rectum and biopsy of liver metastases. The placement of an intrahepatic-arterial infusion catheter into the proper hepatic artery via the right gastroepiploic artery was also performed. Immunohistochemically, AFP-positive cells were identified in both the rectal and liver tumors. Nine days postoperatively, the serum AFP level was 2,000 ng/ml. In spite of intensive chemoimmunotherapy, serum AFP level was increased and 14 weeks after surgery was extremely elevated (267,300 ng/ml). The patient succumbed to cancer 3 months after surgery. To our knowledge, this is the first case of an AFP-producing rectal cancer in which AFP doubling time could be calculated as 12.8 days. © Wiley-Liss, Inc.     

A new tumor-associated antigen useful for serodiagnosis of hepatocellular carcinoma, defined by monoclonal antibody KM-2.

After immunization of mice with the human hepatocellular carcinoma (HCC) cell line PLC/PRF/5, we produced monoclonal antibody KM-2, which allowed us to characterize a new HCC-associated antigen (KM-2 antigen) and to develop a sandwich-type radioimmunoassay. The KM-2 antigen was strongly expressed on the cell surface of HCC cell lines. Immunofluorescence staining of frozen sections of different tissues and tumors confirmed its specific expression on the cell surface of a group of HCC. The antigen was also detected in the bile canaliculi of normal liver. Its biochemical characterization revealed a high molecular weight (M(r) approximately 900,000) glycoprotein with an N-linked carbohydrate chain close to the peptide epitope recognized by the KM-2 monoclonal antibody. By the radioimmunoassay for the KM-2 antigen, the antigen was detected in sera of 72 (47%) of 154 patients with HCC and 3 (3%) of 102 patients with liver cirrhosis; it was not detected in 96 patients with chronic hepatitis or in 100 healthy control individuals. The positive rate of KM-2 antigen (72 of 154, 47%) was significantly (P less than 0.01) higher than that (51 of 154, 33%) of alpha-fetoprotein (AFP) when the cut-off level of AFP was taken as the widely accepted 400 ng/ml. No significant correlation was recognized between serum levels of the KM-2 antigen and AFP (r = 0.15; P greater than 0.05). In addition, among 103 patients with HCC whose AFP levels were less than 400 ng/ml, 31 (30%) were positive for the KM-2 antigen. Determination of the serum KM-2 antigen would be useful for the serodiagnosis of patients with HCC, particularly in cases with normal or low AFP levels.     

A case of hepatocellular carcinoma treated by the combined therapy of ultrasonic guided ethanol injection and transcatheter arterial embolization

Reported is the case of a 72-year-old man admitted to hospital on February, 1986, because of a liver tumor. The patients laboratory data showed the following values: HBs Ag (-), ICG (R15) 34%, AFP 2650 ng/ml. A celiac angiogram revealed hypervascular tumor in the posterior lobe (s6), and a CT showed an intra-hepatic metastasis in the left lobe (s4). The diameters of these two lesions, measured ultra sound (US) were 50 mm (s6) and 30 mm (s4). These two lesions were treated by a US-guided ethanol injection with the posterior lesion also receiving by a transcatheter arterial embolization (TAE). After this combined therapy, serum AFP level decreased to 20 ng/ml and the two lesions became reduced in size. The patient has survived for two years though he is now receiving additional ethanol injection therapy for another metastasis lesion in the s5 region.     

The fucosylation index of alpha-fetoprotein and its usefulness in the early diagnosis of hepatocellular carcinoma

The serum concentration and degree of fucosylation (fucosylation index) of alpha-fetoprotein (AFP) were determined in serum samples from 258 patients with hepatocellular carcinoma (HCC) and 114 patients with benign liver diseases. When the serum AFP concentration was below 1000 ng/ml, it could not be used as a measure to distinguish between HCC and benign liver diseases. However, the fucosylation index of AFP proved useful for such a purpose. The sensitivity of the analysis using the fucosylation index in total patients with HCC was 69%; the specificity was 96% in benign liver diseases, and the accuracy of this test was 77%. When HCC patients who were grouped according to tumor size (5 cm, 3 cm, and 2 cm in diameter) were analyzed, they all had a fucosylation index significantly higher than that in benign liver disease patients. The mean fucosylation index in 28 patients with a serum AFP concentration below 1000 ng/ml and a tumor diameter less than 3 cm was 26 +/- 30%. Corresponding values for 16 patients with an AFP concentration below 400 ng/ml and a tumor size less than 3 cm and for 8 patients with a concentration below 400 ng/ml and a tumor size less than 2 cm were 32 +/- 31% and 27 +/- 27%, respectively. These values were higher, with statistical significance, than those in patients with benign liver diseases. These data indicate that the measurement of the fucosylation index of AFP is useful for the early diagnosis of HCC.     

AAT异质体对AFP阴性肝癌的诊断价值

目的：探讨AAT异质体对AFP阴性肝癌的诊断价值。方法：采用豌豆凝集素亲和交叉免疫电泳法，检测78例原发性肝癌（21例AFP≤20μ／L）、20例慢性肝病及29例正常对照的血清AAT异质体。数据处理用配对资料t检验及x2检验。结果：肝癌组AAT-RP百分比显著高于慢性肝病组及对照组（P＜0.05）。AFP≤20μg／L与AFP＞20μg／L肝癌患者之AAT-RP的百分比差异大显著性（P＞0.05）。AAT—RP对肝癌的敏感性为66.67％、特异性为75.00／、阳性预测值高达91.23％。对AFP≤20μg／L及AFP＞20μg／L肝癌的敏感性、特异性、阳性预测值均差异无显著性（P＞0.05）。结论;无论AFP浓度是否升高，检测AAT异质体都有助于肝癌的临床诊断。     

A case of AFP-producing gastric cancer after curative operation effectively treated with chemotherapies including hepatic arterial infusion therapy

A 63-year-old woman was admitted complaining of epigastralgia. An endoscopic examination revealed a Borrmann type 2 lesion at the greater curvature of the middle third in the stomach. Abdominal computed tomography detected no liver metastasis. The preoperative serum alpha-phetoprotein (AFP) level was elevated to 242.9 ng/ml. 5-fluorouracil (5-FU) was given 200 mg/day for 26 days orally. Distal gastrectomy with D3+ No. 16b1 lymph node dissection, cholecystectomy and hepatic arterial canulation were performed, and mitomycin C 20 mg was injected intravenously during the operation. Immunohistochemical staining of the specimen for AFP by the SAB method was positive in the cancer lesion. After the operation, FP (cisplatin 100 mg on day 1, 5-FU 750 mg on days 1-3) therapy of one course and intrahepatic arterial infusion therapy using adriamycin 10-20 mg every 2 weeks for 7 months were conducted. Moreover, the patient took UFT 400 mg/day for 26 months orally on an outpatient basis as an adjuvant chemotherapy. The only toxicity was neutropenia (grade 3), but it abated without an interruption in the chemotherapy. The AFP level declined gradually, and returned to the normal range 1 month after surgery. The patient is still alive with no sign of hepatic metastasis or recurrence 7 years and 7 months after the gastrectomy.     

Serum 5'--nucleotide phosphodiesterase isozyme--V test for human liver cancer

2,131 coded sera were obtained and tested according to the new 5'-NPDase-V isozyme test. On decoding, 99/126 (79%) samples of primary hepatoma, from the United States and other countries, were positive. In the U. S. group, 51/58 (88%) were positive, 23/58 (40%) had AFP higher than 20 ng/ml. In the non-U. S. group, 48/68 (71%) were positive for 5'-NPDase-V, as compared with AFP elevation in 45/68 (66%). 236/268 (88%) cases of cancer with known liver metastases were positive for 5'-NPDase-V. Of 1,040 cancer patients without liver scan or biopsy evidence of metastasis, 316 were positive. In a follow-up of this group of 316 cases, 109 underlying liver metastases were demonstrated by repeat scan or at autopsy within 3--6 months. All 166 sera from normal healthy persons were negative for 5'-NADase-V. Based on this large panel, 5'-NPDase-V test is a sensitive and an important diagnostic aid for cancer patients, both as an early predictor for liver metastases, and a useful marker for primary hepatoma when no other primary sites are found and when there is no evidence of severe chronic liver disease such as cirrhosis.     

Alphafetoprotein levels of liver cancer patients and controls in a European population

Serum alphafetoprotein (AFP) levels were determined by radioimmunoassay for 80 patients with primary hepatocellular carcinoma (PHC), 40 with metastatic liver cancer (MLC), and 204 controls; all were Caucasians of Greek nationality. Among histologically confirmed PHC cases, 62% had more than 1000 International Units per millilitre (IU/ml) AFP. Only one case with MLC (3%) exceeded 1000 IU/ml AFP, but lower elevations were not uncommon (13%). Among controls, none exceeded 40 IU/ml. Hepatitis B surface antigen (HBsAg) was detected among 6% of 17 histologically confirmed PHC patients with AFP less than 100 IU/ml and 60% of 63 PHC patients with more than 100 IU/ml of AFP (p < 0.001). Control subjects positive for HBsAg had significantly higher AFP values compared to those negative for it (P < 0.01) and male controls had slightly higher AFP values than female controls.