Performance of protein induced by vitamin K absence or antagonist-II assessed by chemiluminescence enzyme immunoassay for hepatocellular carcinoma detection: a meta-analysis

Objectives: In the setting of surveillance for hepatocellular carcinoma (HCC) detection, the use of serum biomarkers in addition to ultrasonography (US) is still a matter of debate. Hence, we performed a meta-analysis to evaluate the diagnostic accuracy of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) alone or in combination for HCC detection in patients at risk of tumor development.

Materials and methods: We performed a systematic search in PubMed and Scopus database for original articles published in English from 2011 to 2017, investigating the accuracy of PIVKA-II alone or in combination with AFP (reported as area under the curve [AUC]) for HCC detection among patients at risk of tumor development. Furthermore, we focused on studies in which serum PIVKA-II was assessed by highly sensitive chemiluminescence immunoassay (CLEIA).

Results: A total of 11 studies (873 patients with HCC and 1244 patients with advanced liver disease/cirrhosis) were included in the meta-analysis. The weighted summary AUC (sAUC) of PIVKA-II and AFP for the discrimination between patients with HCC and those without was 0.791 (0.746–0.837) and 0.767 (0.732–0.803), respectively. The combination of PIVKA-II?+?AFP results in a sAUC of 0.859 (0.837–0.882). The performance for HCC detection of PIVKA-II?+?AFP was significantly superior to each biomarker used alone (ΔsAUC?=?0.068, p?=?.032 and ΔsAUC?=?0.092, p?Conclusion: In clinical practice, the use of PIVKA-II?+?AFP in addition to US examination may improve the effectiveness of surveillance among patients at risk for HCC development.     

Postoperative changes in protein-induced vitamin K absence or antagonist II levels after hepatectomy in patients with hepatocellular carcinoma: relationship to prognosis

Background. α-Fetoprotein (AFP) has been used as a marker for hepatocellular carcinoma (HCC). However, AFP levels are often high in patients with chronic hepatitis or cirrhosis. Protein-induced vitamin K absence or antagonist II (PIVKA-II) is more sensitive for the diagnosis of HCC and prediction of patient survival. Changes in these markers after treatment may reflect treatment curability and patient outcome. Methods. We conducted a retrospective analysis of prognosis of 63 HCC patients with high preoperative levels of AFP and PIVKA-II who underwent hepatectomy and examined the relationship between postoperative changes in both markers at 1 month and patient survival. Subjects were divided into three groups according to changes in these tumour markers after hepatectomy: normalization (N) group, decreased but still above the normal level (D) group and unchanged (U) group. Results. There were no significant differences in the numbers of patients who developed tumour recurrence between changes in AFP and PIVKA-II. Survival analysis showed no significant differences in tumour-free and overall survivals between groups with respect to AFP level. The PIVKA-II-N group showed significantly better tumour-free and overall survival compared with the D and U groups (p<0.01). Multivariate analysis that included other prognostic factors identified changes in PIVKA-II level as a significant and independent prognostic factor associated with overall survival. Discussion. Although changes in AFP did not correlate with patient prognosis, normalization of PIVKA-II was significantly associated with good patient survival after hepatectomy. Normalization of PIVKA-II after hepatectomy reflected the efficacy of treatment and is a suitable predictor of prognosis in HCC patients.     

Simultaneous measurements of serum alpha-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma. South Tohoku District Study Group

OBJECTIVE: We evaluated the measurements of serum alpha-fetoprotein (AFP) and the protein induced by vitamin K absence (PIVKA-II) in 734 patients with chronic hepatitis (CH) and liver cirrhosis (LC) who had been followed-up for the development of hepatocellular carcinoma (HCC). METHODS: Serum AFP and PIVKA-II were measured every month and abdominal ultrasonography was performed every 3 months. Youden's index (sensitivity + specificity -1) was calculated. RESULTS: On an average follow-up period of 374.5 days, HCC was detected in three HBsAg-positive LC patients (10.0%/yr), four anti-HCV-positive CH patients (1.35%/yr), 21 anti-HCV-positive LC patients (7.8%/yr), and one patient with both HBsAg- and anti-HCV-positive LC (22.7%/yr). At the time of HCC detection, the size of HCC was 4.7+/-0.6 (mean +/- SD) cm in HBsAg-positive patients and 2.4+/-1.3 cm in anti-HCV-positive patents. Cut-off values of 20 ng/ml for AFP (Youden's index = 0.422) and 60 mAU/ml for PIVKA-II (Youden's index = 0.316) gave the highest index for each marker. When these two markers were combined, cut-off values of 40 ng/ml for AFP and 80 mAU/ml for PIVKA-II gave the highest index (Youden's index = 0.500, sensitivity = 65.5%, specificity = 85.5%, positive predictable value = 14.8%, negative predictable value = 98.3%). The levels of AFP or PIVKA-II increased within three months before the detection of HCC. CONCLUSIONS: Simultaneous measurements of serum AFP and PIVKA-II levels that are performed every 3 months are useful for detecting a developing HCC. The optimal cut-off values for AFP and PIVKA-II may be 40 ng/ml and 80 mAU/ml, respectively.     

Prolonged survival after repeat resection of pulmonary metastasis from hepatocellular carcinoma

We report a patient in whom two pulmonary resections were performed for lung metastasis after hepatic resection of hepatocellular carcinoma (HCC). A 56‐year‐old Japanese man with an 8‐year history of chronic liver disease was admitted with elevated serum alpha‐fetoprotein (AFP) and a liver tumor that had been detected by ultrasonography. Computed tomography showed a 6‐cm tumor in the medial segment of the liver, and partial resection of the medial segment was performed. Thirty‐six months after the first operation, pulmonary resection was performed for a solitary metastasis in the left lung. Fifty‐one months after the second operation, a solitary metastatic tumor was detected in the right lung, without any evidence of recurrence or other metastatic foci, and thoracoscopic partial resection of the right lung was performed as the third operation. The patient is alive 36 months after the second pulmonary resection, has a normal AFP value, and shows no signs of recurrent or metastatic foci. Repeat pulmonary resection for metastasis from HCC resulted in long‐term survival in this patient.     

Plasma abnormal prothrombin (PIVKA-π): A new and reliable marker for the detection of hepatocellular carcinoma

We evaluated the clinical usefulness of a protein induced by vitamin K absence, antagonist-prothrombin (PIVKA-II), in detecting hepatocellular carcinoma (HCC) specifically in patients with liver cirrhosis, and the possible correlation between levels of PIVKA-II and pathological features of HCC. Plasma levels of PIVKA-II and alpha-fetoprotein (AFP) were measured in 628 patients with various diseases, including 253 with liver cirrhosis and 116 with HCC. PIVKA-II was detected (greater than or equal to 0.1 arbitrary unit/mL) in 54.3% of HCC and the concentration showed a positive correlation with the tumour size. As a screening test for the detection of HCC, PIVKA-II produced values comparable with those of AFP with a sensitivity, specificity and validity of 52.8, 98.8 and 51.6% respectively. Sixteen of 45 patients (37%) with HCC who had low AFP (less than 100 ng/mL) levels were positive for PIVKA-II. No apparent relationship, however, could be found between the levels of PIVKA-II and the aetiology or pathological findings of HCC. These results suggest that PIVKA-II can be a reliable marker for detecting HCC in patients with liver cirrhosis.     

Serological markers of liver cancer

Serological markers for hepatocellular carcinoma (HCC) are important for early diagnosis, as well as monitoring of tumour aggressiveness, treatment responsiveness, recurrence and survival. The three most common markers are total alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3) and protein induced by vitamin K absence or antagonist-II (PIVKA-II). Total AFP has the sensitivity of 60% and specificity of 90% for the detection of HCC. Increase in the percentage of AFP-L3 over the total AFP (>10%) is very specific for small HCC. PIVKA-II is also more specific than total AFP in detecting HCC. AFP-L3 and PIVKA-II levels correlate with tumour aggressiveness and prognosis. All three markers are useful for monitoring treatment responsiveness and tumour recurrence. Since the levels of the three markers are independent of each other, combination of measurement of two or three markers will increase the sensitivity and diagnostic accuracy. Some novel markers including glypican-3 are being extensively studied.     

Clinical evaluation of plasma des-γ-carboxy prothrombin as a marker protein of hepatocellular carcinoma in patients with tumors of various sizes

We measured des--carboxyprothrombin (DCP) (prothrombin induced by vitamin K absence or antagonist-II, abbreviated as PIVKA-II) by a newly developed enzyme immunoassay using an anti-DCP monoclonal antibody in 665 human subjects, of which 112 were patients with hepatocellular carcinoma (HCC). PIVKA-II was elevated to more than 0.1 AU/ml in 54 of the 112 patients (48.2%) with HCC, while it was positive only in 7.1% of those with liver cirrhosis and 3.1% of those with chronic hepatitis. Three patients with elevated PIVKA-II greater than 0.1 AU/ml who had been diagnosed as having liver cirrhosis by ultrasonography and computed tomography at the start of this study developed a diffuse type of HCC three or six months later, which was detected by angiography. No obvious correlation was observed between plasma PIVKA-II concentration and serum -fetoprotein (AFP) level in HCC patients. Of the 112 HCC patients, 40.2% showed an increase in AFP to above 200 ng/ml. In the remaining patients, 32.8% had a PIVKA-II concentration greater than 0.1 AU/ml. In these patients with a negative or low serum AFP concentration, PIVKA-II proved to be a valuable tumor marker for laboratory diagnosis of HCC. Among them, 59.8% tested positive for PIVKA-II and/or AFP. Thus, combination assay with PIVKA-II and AFP seems useful for increasing the accuracy of laboratory diagnosis of HCC. None of patients with a solitary tumor smaller than 2 cm had elevated PIVKA-II. In patients with larger-sized and multiple HCC, positive results of elevated PIVKA-II were more frequent than those of increased AFP. Thus, the determination of PIVKA-II may be more useful than AFP assay in patients with larger-sized and multiple tumors. The levels of plasma PIVKA-II concentration were higher in patients with larger-sized and multiple tumors than in those with smaller ones. In 20 patients, PIVKA-II decreased significantly after transcatheter arterial embolization (TAE) therapy, and in eight of these 20 patients it normalized after TAE. In conclusion, plasma PIVKA-II might be used as a valuable marker for the diagnosis and screening of HCC, especially in patients with negative or low AFP and in those with larger-sized and multiple tumors. However, its usefulness for mass screening of small HCC is limited.     

Assessment of the benefits and risks of percutaneous biopsy before surgical resection of hepatocellular carcinoma

BACKGROUND/AIMS: Because of a potential risk of needle tract seeding, the use of ultrasound (US)-guided biopsy for the diagnosis of hepatocellular carcinoma (HCC) is controversial. This study was aimed at determining the usefulness, accuracy and safety of this technique as well as the incidence of needle tract seeding. METHODS: From 1986 to 1996, 137 patients who underwent resection or transplantation for suspected HCC had US-guided biopsy before surgery. The analysis of the resected liver was compared to the results of biopsy. Patients were assessed with a mean follow up of 38 months. RESULTS: The diagnosis of HCC was established by biopsy in 122 patients (89%). Thirteen of the 15 patients with negative biopsy were shown to have HCC after surgery. The remaining two patients had non-malignant nodules. Sensitivity and accuracy of US-guided biopsy were 90 and 91%, respectively. Accuracy was significantly influenced by the location of the nodule but not by its size. Needle tract seeding occurred in two patients (1.6%). CONCLUSIONS: In this series, the incidence of needle tract seeding was less than 2% and no recurrence was observed after local excision. This risk should be balanced with the risk of deciding an aggressive treatment in a patient without malignancy. Patients with negative biopsy should undergo a second biopsy and/or repeated investigations by imaging techniques.     

Hepatocellular carcinoma and synchronous liver metastases from colorectal cancer in cirrhosis: A case report

A 68-year-old Caucasian man with hepatitis C virus-related cirrhosis was admitted to our Unit in February 2010 for a diagnostic evaluation of three centimetric hypoechoic focal liver lesions detected by regular surveillance ultrasound. The subsequent computer tomography (CT) led to a diagnosis of unifocal hepatocellular carcinoma (HCC) in VI hepatic segment, defined the other two nodules in the VI and VII segment as suspected metastases, and showed a luminal narrowing with marked segmental circumferential thickening of the hepatic flexure of the colon. Colonoscopy detected an ulcerated, bleeding and stricturing lesion at the hepatic flexure, which was subsequently defined as adenocarcinoma with a moderate degree of differentiation at histological examination. Finally, ultrasound-guided liver biopsy of the three focal liver lesions confirmed the diagnosis of HCC for the nodule in the VI segment, and characterized the other two lesions as metastases from colorectal cancer. The patient underwent laparotomic right hemicolectomy with removal of thirty-nine regional lymph nodes (three of them tested positive for metastasis at histological examination), and simultaneous laparotomic radio-frequency ablation of both nodule of HCC and metastases. The option of adjuvant chemotherapy was excluded because of the post-surgical onset of ascites. Abdomen CT and positron emission tomography/CT scans performed after 1, 6 and 12 mo highlighted a complete response to treatments without any radiotracer accumulation. After 18 mo, the patient died due to progressive liver failure. Our experience emphasizes the potential coexistence of two different neoplasms in a cirrhotic liver and the complexity in the proper diagnosis and management of the two tumours.     

Plasma Abnormal Prothrombin Levels in Patients with Small Hepatocellular Carcinoma

The diagnostic value of plasma abnormal prothrombin (PIVKA-II) measurements in detecting relatively small hepatocellular carcinomas (HCC), less than 5 cm in diameter, was compared with that of serum α-feto-protein (AFP) determinations. Among 18 patients with relatively small hepatocellular carcinoma (HCC), abnormal PIVKA-II values were found in only three (16.6%). Highly elevated serum AFP levels (>200 ng/ ml) relatively specific for HCC were seen also in three patients. However, nonspecific elevation of PIVKA-II in patients with liver cirrhosis not accompanied by HCC was much less than that of AFP. Although complementary, both tests appear to be of limited value in early detection of HCC, indicating that searches for other markers are necessary, to allow early detection of small HCC.     

The diagnostic approach to hepatocellular carcinoma

Risk factors and symptoms of hepatocellular carcinoma (HCC): The main risk factors of HCC include infection with hepatitis B or C virus, as well as alcohol consumption. There are no specific symptoms of HCC, making early diagnosis and detection of the disease difficult. When HCC presents with specific clinical symptoms, the tumour is typically very far advanced. Surveillance in liver cirrhosis: The most common serological marker used in HCC diagnosis is alpha-fetoprotein (AFP), but other tumour markers such as the des-gamma-carboxyprothrombin (DGCP) or fractions of AFP (AFP-L3) exist and there use is discussed in this context. Surveillance should be done by sonography at 6 (to 12) months intervals. The single nodule in the cirrhotic liver: Ultrasound is the most commonly used imaging modality for detecting HCC tumour nodules with a large range of reported sensitivities. HCC may appear as a hypoechoic, isoechoic, or hyperechoic round or oval lesion with intratumoural flow signals on Doppler or power Doppler sonography. The differentiation of smaller malignant lesions in cirrhotic livers can be improved by contrast-enhanced ultrasound (CEUS). Spiral computed tomography (CT) and magnetic resonance imaging (MRI) with and without contrast enhancement play an important role in the diagnosis and staging of HCC. If the vascular pattern on imaging is not typical, biopsy becomes necessary. The patient with known HCC: Different tumour markers are used in the evaluation of tumour progression, prediction of patient outcome and treatment efficacy. Among the various staging systems used in the context of HCC, the Barcelona-Clinic-Liver-Cancer (BCLC) staging system is currently the only staging system that takes into account tumour stage, liver function, physical status and cancer-related symptoms. Beside surgical resection, non-surgical treatments such as percutaneous ethanol injection (PEI), radiofrequency thermoablation (RFTA) and trans-arterial chemoembolisation (TACE) are used. Successful tumour "bridging" with ablative therapy methods can be achieved in carefully selected patients on the waiting list for orthotopic liver transplantation. Contrast-enhanced sonography is able to control the ablation treatment of HCC.     

A long-term survivor of ruptured hepatocellular carcinoma after hepatic resection

Abstract We treated a patient who had previously undergone a hepatic resection for ruptured hepatocellular carcinoma (HCC) but developed a solitary peritoneal recurrence at the site of the incision 8 years and 9 months later. Since no other recurrence was evident, we resected the tumour. The primary tumour was 2.5 cm in size and histological examination revealed HCC without any histological risk factors for intrahepatic recurrence. The peritoneal tumour consisted of less differentiated cancer cells than those found in the primary tumour. The positive rates of Ki-67 were 10% in the primary tumour and 23.3% in the peritoneal recurrence. The DNA indexes in both tumours were considered to be identical.
The comparison between the primary and peritoneal tumours suggested that the histological differentiation and proliferation activity can change after recurrence, in spite of consistent DNA ploidy contents. Clinically, a patient who undergoes a hepatic resection for ruptured HCC can survive for a long time, such as 10 years, if they have good liver function and small HCC without any histological risk factors for intrahepatic recurrence. However, since late recurrence is possible, a follow up for as long as 10 years is recommended.     

Collision tumor of hepatocellular carcinoma and neuroendocrine carcinoma involving the liver: Case report and review of the literature

Primary hepatic neuroendocrine carcinoma(NEC) with concurrent occurrence of hepatocellular carcinoma(HCC) of the liver is very rare. Only 8 cases have been reported in the literature. Concurrent occurrence of HCC and NEC in the liver is classified as combined type or collision type by histological distributional patterns; only 2 cases have been reported. Herein, we report a case of collision type concurrent occurrence of HCC and NEC, in which primary hepatic NEC was in only a small portion of the nodule, which is different from the 2 previously reported cases. A 72-year-old male with chronic hepatitis C was admitted to our hospital for a hepatic mass detected by liver computed tomography(CT) at another clinic. Because the nodule was in hepatic segment 3 and had proper radiologic findings for diagnosis of HCC, including enhancement in the arterial phase and wash-out in the portal and delay phases, the patient was treated with laparoscopic left lateral sectionectomy. The pathology demonstrated that the nodule was 2.5 cm and was moderately differentiated HCC. However, a 3 mm-sized focal neuroendocrine carcinoma was also detected on the capsule of the nodule. The tumor was concluded to be a collision type with HCC and primary hepatic NEC. After the surgery, for follow-up, the patient underwent a liver CT every 3 mo. Five multiple nodules were found in the right hepatic lobe on the follow-up liver CT 6 mo post-operatively. As the features of the nodules in the liver CT and MRI were different from that of HCC, a liver biopsy was performed. Intrahepatic recurrent NEC was proven after the liver biopsy, which showed the same pathologic features with the specimen obtained 6 mo ago. Palliative chemotherapy with a combination of etoposide and cisplatin has been administered for 4 months, showing partial response.     

Diagnostic value of AFP-L3 and PIVKA-Ⅱin hepatocellular carcinoma according to total-AFP

AIM:To evaluate diagnostic value ofα-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence-Ⅱ(PIVKA-Ⅱ)in hepatocellular carcinoma(HCC). METHODS:One hundred and sixty-eight patients during routine HCC surveillance were included in this study.Of the 168 patients,90(53.6%)had HCC including newly developed HCC(n=82)or recurrent HCC after treatment(n=8).Sera were obtained during their first evaluation for HCC development and at the time of HCC diagnosis before commencing HCC treatment.HCC was diagnosed by histological examination,appropriate imaging characteristics-computed tomography or magnetic resonance imaging.Control sera were collected from 78 patients with benign liver disease(BLD),which were obtained during routine surveillance with a suspicion of HCC.AFP,AFP-L3 and PIVKA-Ⅱwere measured in the same serum by microchip capillary electrophoresis and liquid-phase binding assay on a micro-total analysis system Wako i30 auto analyzer.The performance characteristics of three tests and combined tests for the diagnosis of HCC were obtained using receiver operating characteristic curves in all populations and subgroups with AFP<20 ng/mL. RESULTS:Of 90 HCC patients,38(42.2%)patients had AFP<20 ng/mL,20(22.2%)patients had AFP 20-200 ng/mL and 32(35.6%)patients had AFP>200 ng/mL.Of the 78 BLD patients,74(94.9%)patients had AFP<20 ng/mL.After adjustment for age and HBV infection status,AFP-L3 levels were higher in HCC than in BLD among patients with low AFP levels(<20 ng/mL)(P<0.001).In a total of 168 patients,areas under the curve(AUC)for HCC were 0.879,0.887,0.801 and 0.939 for AFP,AFP-L3,PIVKA-Ⅱand the combined markers,respectively.The combined AUC for three markers showed higher value than the AUCs of individual marker(P<0.05).AFP-L3 had higher AUC value than PIVKA-Ⅱfor HCC detection in entire patients(P =0.043).With combination of AFP-L3(cut-off>5%) and PIVKA-Ⅱ(cut-off>40 AU/L),the sensitivity were 94.4%and specificity were 75.6%in all patients.In 112 patients with lo     

Real impact of tumor marker AFP and PIVKA-II in detecting very small hepatocellular carcinoma (≤ 2 cm,Barcelona stage 0) - assessment with large number of cases

BACKGROUNDIn hepatocellular carcinoma (HCC), detection and treatment prior to growth beyond 2 cm are relevant as a larger tumor size is more frequently associated with microvascular invasion and/or satellites.AIMTo examine the impact of the tumor marker alpha-fetoprotein (AFP) or PIVKA-II in detecting very small HCC nodules (≤ 2 cm in maximum diameter, Barcelona stage 0) in the large number of very small HCC. The difference in the behavior of these tumor markers in HCC development was also examined.METHODSA total of 933 patients with single-nodule HCC were examined. They were subdivided into 394 patients with HCC nodules ≤ 2 cm in maximum diameter and 539 patients whose nodules were > 2 cm. The rates of patients whose AFP and PIVKA-II showed normal values were examined.RESULTSThe positive ratio of the marker PIVKA-II was significantly different (P < 0.0001) between patients with nodules ≤ 2 cm in diameter and those with nodules > 2 cm, but there was no significant difference in AFP (P = 0.4254). In the patients whose tumor was ≤ 2 cm, 50.5% showed normal levels in AFP and 68.8% showed normal levels in PIVKA-II. In 36.4% of those patients, both AFP and PIVKA-II showed normal levels. The PIVKA-II-positive ratio was markedly increased with an increase in the tumor size. In contrast, the positivity in AFP was increased gradually and slowly.CONCLUSIONIn the surveillance of very small HCC nodules (≤ 2 cm in diameter, Barcelona clinical stage 0) the tumor markers AFP and PIVKA-II are not so useful.     

Role of serum prothrombin induced by vitamin K absence or antagonist-II in the early detection of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Objective. The role of serum prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) in the early detection of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection has not yet been clearly identified. The purpose of the study was to evaluate the sensitivity and specificity of PIVKA-II, alone or in combination with alpha-fetoprotein (AFP), for the detection of HCC during surveillance, and to determine whether PIVKA-II was a significant risk factor for patient survival. Material and methods. During surveillance, 106 HCC cases and 100 non-HCC cases of chronic HBV infection were included. Sensitivity and specificity of AFP and PIVKA-II were obtained through cut-off values of 20 ng/ml and 40 mAU/ml, respectively. The Cox proportional hazards model was used to determine whether PIVKA-II would be a significant risk factor for patient survival. Results. The sensitivity rates of AFP and PIVKA-II were 57.5% (61/106) and 51.9% (55/106), respectively. Of 45 patients negative for AFP, 22 were positive for PIVKA-II. A combination of AFP and PIVKA-II increased the sensitivity to 78.3% (83/106). The specificities of AFP and PIVKA-II were 88.0% and 97.0%, respectively. PIVKA-II was not a significant risk factor for patient survival after multivariate analysis. Conclusions. PIVKA-II can be used as a tumor marker for the early detection of HCC in patients with chronic HBV infection, especially in combination with AFP.     

Clinical evaluation of plasma abnormal prothrombin (PIVKA-II) in patients with hepatocellular carcinoma

The clinical usefulness of plasma abnormal prothrombin, defined as a protein induced by vitamin K absence or antagonist-II: PIVKA-II, as a tumor marker for hepatocellular carcinoma (HCC), was evaluated. Plasma PIVKA-II concentration was determined by an enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody specific for PIVKA-II. Forty-one (65%) out of 63 patients with HCC had an abnormal PIVKA-II level above 0.13 arbitrary units (AU)/ml; the level was above 0.3 AU/ml in 33 patients (52%) and above 0.5 AU/ml in 27 patients (43%). On the other hand, most of the 282 patients with various liver diseases other than HCC had normal or slightly elevated levels of PIVKA-II. Their values were all below 0.5 AU/ml, with the exception of 2 patients with decompensated liver cirrhosis. The patients with PIVKA-II values above 0.5 AU/ml were strongly suspected of having HCC. Plasma PIVKA-II levels were not related to serum alpha-fetoprotein (AFP) levels, but were above 0.5 AU/ml in 14 (44%) out of the 32 patients whose serum AFP levels were below 400 ng/ml. In some patients with HCC, PIVKA-II was increased throughout the course of the disease, and in others it normalized after surgical resection of the tumor. We conclude that the plasma PIVKA-II assay by the ELISA method using a monoclonal antibody is a useful diagnostic tool for monitoring HCC, particularly in HCC patients with low AFP levels.     

Immunohistologic study on the expressions of alpha-fetoprotein and protein induced by vitamin K absence or antagonist II in surgically resected small hepatocellular carcinoma.

Sixty-eight cases of single hepatocellular carcinoma (HCC) with less than 3 cm of diameter were immunohistochemically examined for the expressions of alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II). In cancerous tissues, the expression rate was significantly higher for PIVKA-II (34 cases [50%]) than AFP (21 cases [31%]) (P <.05), suggesting a higher specificity of PIVKA-II to small HCC. Sixteen of the 68 cases (24%) were positive to both AFP and PIVKA-II, and in 8 of the 16 cases, AFP and PIVKA-II expressing areas within a nodule were clearly divided by a fibrous septum. According to histologic grades, PIVKA-II expression was confirmed in 2 of the 15 well-differentiated HCCs, and in the well-differentiated component of 6 of the 12 "nodule-in-nodule"-type well-differentiated HCCs. AFP expression was not found in well-differentiated HCCs, but found in 16 of the 40 moderately differentiated HCCs (40%) and in the moderately differentiated component of 3 of the 12 "nodule-in-nodule"-type well-differentiated HCCs. The positive rate in the tissues was correlated to the serum levels for both AFP and PIVKA-II. In addition, frequency of tissue-PIVKA-II expression was higher than tissue-AFP expression in the cases whose serum protein level was within the normal range. This indicates that AFP and PIVKA-II have different patterns of tissue expression and of secretion to the blood. In comparison with tissue-AFP-negative cases, tissue-AFP-positive HCCs had a larger tumor size, higher frequencies of portal vein invasion and intrahepatic metastasis, a high Ki-67 labeling index, and a lower rate of recurrence-free survival. Thus, tissue-AFP-positive HCCs are suggested to be biologically more malignant than those HCCs that are AFP-negative and PIVKA-II-positive.     

Hypercholesterolaemia in patients with hepatocellular carcinoma

Ninety-one (11.4%) subjects with hypercholesterolaemia (serum cholesterol level more than 250 mg/dL) of 792 Chinese patients with hepatocellular carcinoma (HCC) were studied in Taiwan. All 91 patients had large tumours greater than 7 cm in diameter and a tumour volume greater than 50%; 56 (61%) of these patients manifested tumour involvement in both lobes of the liver. The HCC patients with hypercholesterolaemia had significantly higher mean serum levels of albumin, triglyceride and alpha-fetoprotein (AFP) compared with age-sex-tumour volume matched HCC patients without hypercholesterolaemia. The associated incidence of hypoglycaemia in hypercholesterolaemic HCC patients was significantly higher than in HCC patients without hypercholesterolaemia (15/90 vs 4/90; P = 0.01). There was no significant difference in the survival analysis between HCC patients with and without hypercholesterolaemia. Eight and 11 of hypercholesterolaemic HCC patients had their tumours surgically resected and received transcatheter hepatic arterial chemoembolization (TAE), respectively. Serum cholesterol levels fell to the normal range after treatment and rose to abnormal levels again when tumours recurred after surgery or progressively enlarged after TAE. The change in pattern of serum cholesterol was parallel to the change in serum AFP. Serum cholesterol levels may serve as another marker in identifying tumour recurrence and the presence of a viable tumour mass in hypercholesterolaemic HCC patients who have received surgical resection or TAE.     

Cutoff values of protein induced by vitamin K absence or antagonist II for diagnosing hepatocellular carcinoma

Protein induced by vitamin K absence or antagonist II (PIVKA-II) is a promising serum marker for hepatocellular carcinoma (HCC). There are limited data on its cutoff value in HCC for Taiwanese cirrhosis patients. This study aimed to investigate the diagnostic value of PIVKA-II levels in patients with suspected HCC. In total, 88 patients with chronic hepatitis and suspected HCC by ultrasound, elevated α-fetoprotein (AFP) or PIVKA-II levels were consecutively enrolled. Their baseline characteristics and findings on dynamic phases of computed tomography (CT) or magnetic resonance imaging (MRI) were examined. Sixty participants had cirrhosis and 34 had HCC. The median levels of PIVKA-II in non-cirrhosis and cirrhosis patients without or with HCC were 28.0, 48.0, and 847.0 mAU/mL, respectively. The optimal cutoff value of PIVKA-II in predicting HCC was 78.0 mAU/mL. Combining AFP with PIVKAII mildly increased its diagnostic performance for HCC, yielding higher specificity and positive predictive value. Significant factors predicting HCC in multivariate regression analysis were PIVKA >78.0 mAU/mL and fatty liver. Monitoring PIVKA-II level is suitable for noninvasively assessing HCC in patients with chronic hepatitis, particularly with AFP.