Prediction of recurrence of hepatocellular carcinoma after curative hepatectomy using preoperative Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein

Aim: Lens culinaris agglutinin A‐reactive fraction of α‐fetoprotein (AFP‐L3) status has been reported to be an independent prognostic factor in patients with hepatocellular carcinoma (HCC). In this study, we evaluated the clinical usefulness of measuring preoperative AFP‐L3 to predict the recurrence and prognosis of HCC after curative hepatectomy. Methods: One hundred and forty‐two HCC patients who underwent curative hepatectomy were examined for the correlation between preoperative tumor marker, including AFP, des‐γ‐carboxy prothrombin (DCP) and AFP‐L3, and clinicopathological variables. The prognostic factors of disease‐free survival rates and overall survival rates were also determined using clinicopathological variables including these three tumor markers. Results: There were similar tendencies in the relationship between these three markers and malignant behaviors including lower grade tumor differentiation or vascular invasion. In multivariate analysis, increased AFP‐L3 value (P = 0.019) was found to be an independent prognostic factor of disease‐free survival after curative hepatectomy. In addition, elevated DCP (P = 0.013) and AFP‐L3 values (P = 0.012) were found to be independent prognostic factors. Furthermore, the preoperative AFP‐L3 value in the patients with early recurrence (within 1 year after hepatectomy) was significantly higher than that in those without early recurrence (26.9 ± 19.5 % vs 14.2 ± 19.8 %, P = 0.047). Conclusion: Preoperative AFP‐L3 value was strongly correlated to disease‐free and overall survival rate and the timing of recurrence, so it appears that it would be useful to predict the recurrence and prognosis of HCC after curative hepatectomy.     

Relationship between Lens culinaris agglutinin-reactive alpha-fetoprotein and pathologic features of hepatocellular carcinoma.

AIM: We investigated pathological features of Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3)-positive hepatocellular carcinoma (HCC) in order to seek a pathological basis of poor prognosis of HCC patients with elevated AFP-L3. METHODS: A total of 111 patients with HCC < or =5 cm in diameter who underwent hepatic resection were studied. Serum AFP-L3 concentration was measured within a month prior to surgery by lectin-affinity electrophoresis coupled with antibody-affinity blotting, and expressed as AFP-L3 percentage of total AFP. AFP-L3 of 10% or higher was judged to be positive. Pathologic features of resected HCC specimens were evaluated and classified concerning growth pattern (expansive or infiltrative growth), capsule formation, capsule infiltration, septal formation, portal vein invasion, hepatic vein invasion, bile duct invasion, and intrahepatic metastasis. These macroscopic and microscopic findings were compared between AFP-L3-positive and negative HCC specimens. RESULTS: Thirty-three (29.7%) were positive for AFP-L3. The prevalence of HCC with infiltrative growth, with capsule infiltration, with septum formation, with portal vein invasion, and with hepatic vein invasion was significantly higher in AFP-L3-positive group (P=0.0121, 0.0290, 0.0442, 0.0314, and 0.0433, respectively). These pathologic features reportedly indicate the progression of the tumor. CONCLUSIONS: AFP-L3-positive HCC had several pathologic features of progressed state of HCC, which accounted for the AFP-L3 as an indicator of poor prognosis of HCC.     

Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to the percentage of Lens culinaris agglutinin-reactive alpha-fetoprotein

BACKGROUND AND AIM: The Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) has been reported to be a highly useful marker for hepatocellular carcinoma (HCC) compared with a conventional serum AFP concentration, which allows earlier detection of HCC compared with using other imaging modalities and predicting prognosis after therapy. A collaborative prospective study involving nine Japanese hospitals was conducted to analyze the relationships between the tumor characteristics of a HCC patient and the percentage of AFP-L3/AFP total at the initial detection. METHODS: Between 1 October 1996 and 30 September 1997, a total of 388 patients with newly diagnosed HCC were registered. RESULTS: The cut-off level of the percentage of AFP-L3 was altered from 15 to 10%. The AFP-L3-positive HCC patients demonstrated the characteristics of having an advanced tumor, such as the number of tumors, maximum diameter, tumor spread, portal vein invasion, tumor stage, and tumor classification. With the conventional cut-off level of 15% of the percentage of AFP-L3, the malignant characteristics were more definite than that of 10%. However, no significant differences of serum AFP concentration were observed for malignant characteristics such as maximum diameter and histopathological grading. CONCLUSION: Serum AFP concentration does not reveal a malignancy of HCC, however, the AFP-L3-positive HCC has biologically malignant characteristics, especially portal vein invasion and lower tumor classification, and is an advanced tumor regardless of small tumor size and lower serum AFP concentration. As AFP-L3 shows the tumor characteristics, its presence should be an important factor in the determination of therapy and prognosis of patients.     

Serum alpha-fetoprotein and lens culinaris agglutinin-reactive fraction of alpha-fetoprotein in patients with hepatocellular carcinoma

ABSTRACT— A fraction of serum α-fetoprotein (AFP) reactive with lens culinaris agglutinin (LCA) was measured by affinity chromatography in serum samples from 102 patients with hepatocellular carcinoma (HCC) and 48 patients with chronic liver diseases without HCC. Its usefulness as a marker of HCC was evaluated. The mean ± SD percentage of this fraction in total AFP was 3.10 ± 3.17% in 48 patients with chronic liver diseases without HCC. When the cut-off level was set at 12.6% (mean + 3 SD), the sensitivity was 36.3%, the specificity was 100%, and the accuracy was 56.7% in the 102 patients with HCC. This lentil lectin-reactive AFP was positive in 7 of 25 patients (28%) who had single small liver cancer (Ψ < 20 mm), suggesting its clinical usefulness as a tumor marker. The lentil lectin-reactive AFP showed no correlation with the serum concentration of AFP or des-γ-carboxy prothrombin (DCP). In patients with HCC showing an AFP level of 20 ng/ml or above, the lentil lectin-reactive fraction is a highly specific tumor marker. We consider it to be useful as an adjunct in the diagnosis of HCC.     

Surgical treatment of recurrent hepatocellular carcinoma based on the mode of recurrence: repeat hepatic resection or ablation are good choices for patients with recurrent multicentric cancer

Hepatocellular carcinomas (HCC) often recur after curvative resection. Recurrence in the remnant liver originates from intrahepatic metastasis (IM) from the primary resected tumor, and/or from multicentric (MC) occurrence. In order to achieve better survival after intrahepatic recurrence in HCC patients, we have surgically treated patients according to the recurrence pattern. In this study, we investigated the advantage of repeat surgery for MC recurrent HCC. The subjects were 176 patients who had undergone primary macroscopically complete tumor removal for HCC at our department from 1984 to 1999. Differential diagnosis of IM and MC recurrence was done by pathological analysis. Twenty‐nine of the 149 patients with recurrence (19.5%) underwent a total of 31 second and third operations. Of the 29 patients, 18 had MC (14 received repeat hepatectomy and 4, microwave tissue coagulation [MTC]), 7 had IM (4 had repeat hepatectomy and 3, MTC), and, in 4 patients, pathological investigation failed to determine the mode of recurrence. The 1‐, 3‐, and 5‐year survival rates for MC patients after the repeat operations were 100%, 69.7%, and 58.1%, respectively, and the 1‐, 3‐, and 5‐year survival rates for the IM patients were 57.1%, 14.3%, and 14.3%, respectively. Survival after the repeat operation was significantly better in the MC group than in the IM group (P = 0.0016). Moreover, there was no significant difference between survival in the MC group after a repeat operation and survival in control patients after an initial hepatectomy (P = 0.9282). These results indicated that patients with resectable or ablative recurrent MC HCC have almost the same survival benefit after repeat operations as patients who undergo initial curative resection of HCC.     

Recent topics on α‐fetoprotein

Zinc‐fingers and homeoboxes 2 (ZHX2) and zinc‐finger and BTB domain containing 20 (ZBTB20) repress the postnatal expression of α‐fetoprotein (AFP) by interacting with the AFP gene promoter regions. ZHX2 inhibits the expression of AFP and cyclins A and E. ZBTB20 is negatively regulated by CUX1, which promotes cell‐cycle progression, suggesting that AFP reactivation is closely linked to hepatocyte proliferation. A slight elevation in the serum AFP level often occurs in patients with chronic hepatitis C in the absence of hepatocellular carcinoma (HCC) and is an independent risk factor for HCC development to complement the fibrosis stage. In addition, the sustained elevation of AFP after interferon therapy is a risk factor of HCC development. AFP levels are clinically useful in predicting the outcomes of liver transplantation and sorafenib therapy for HCC patients. A low preoperative AFP level is a predictor of long‐term survival and is associated with a low recurrence rate of HCC after liver transplantation. AFP response (≥20% decrease in AFP during 6–8 weeks of treatment) rather than radiological outcomes is a significant prognostic factor for survival in sorafenib‐treated HCC patients. Highly sensitive Lens culinaris agglutinin‐reactive AFP (AFP‐L3) is 5–10 times more sensitive than conventional AFP‐L3, and useful for early detection of HCC in patients with total AFP below 20 ng/mL.     

Comparison of clinicopathological features of patients with hepatocellular carcinoma seropositive for alpha-fetoprotein alone and those seropositive for des-gamma-carboxy prothrombin alone

BACKGROUND: There has been no comparative study of the clinicopathological features of HCC patients who are seropositive for alpha-fetoprotein (AFP) alone and those who are seropositive for des-gamma-carboxy prothrombin (DCP) alone. The authors, thus, performed this comparative study. METHODS: The clinicopathological features of patients with solitary hepatocellular carcinoma (HCC), who underwent a hepatectomy were compared among the four below groups according to the seropositivity of AFP and DCP: group A, seronegative for both AFP below 20 ng/mL and DCP below 40 mAU/mL; group B, seropositive for AFP above 100 ng/mL and seronegative for DCP; group C, seronegative for AFP and seropositive for DCP above 100 mAU/mL; and group D, seropositive for both AFP and DCP. RESULTS: Group B patients showed a higher incidence of HCC with an indistinct margin, and a somewhat higher incidence of small HCC less than 2 cm in greatest dimension compared with group C patients. By contrast, group C patients had a higher frequency of HCC with a distinct margin compared with that of an indistinct margin, large tumors more than 3 cm compared with that of small tumors less than 2 cm, and a somewhat higher frequency of moderately to poorly differentiated HCC compared with that of well-differentiated HCC. Our HCC cases showed advanced clinicopathological features in the order of group C, group B and group A. Groups C and D patients showed similar characteristics. CONCLUSIONS: Hepatocellular carcinoma patients who were seropositive for AFP alone demonstrated clinicopathological features of less advanced HCC compared with those who were seropositive for DCP alone.     

Favorable α‐fetoprotein decrease as a prognostic surrogate in patients with hepatocellular carcinoma after radiofrequency ablation

Background and Aim: To assess the significance of adequate α‐fetoprotein decrease in monitoring the treatment effects of radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC) patients. Methods: A total of 72 RFA treatments in 54 HCC patients were analyzed. The favorable α‐fetoprotein decrease was defined as the α‐fetoprotein half‐life of less than 7 days. The efficacy of the ablation response is assessed by standard imaging modality, a computed tomography scan 1 month after RFA. We assessed the correlation between different α‐fetoprotein decreases and treatment outcomes by standard imaging modality. Results: Of the 72 therapies, 15 (21%) were favorable α‐fetoprotein decreases. Fifty‐one (71%) therapies showed concordant results through standard image modality and α‐fetoprotein decrease, including 14 (27%) therapies with a complete radiological response and favorable α‐fetoprotein decrease, and the remaining 37 (73%) therapies with an incomplete radiological response and unfavorable α‐fetoprotein decrease. The accuracy was 70.8% by using α‐fetoprotein decrease in the detection treatment response based on a complete radiological response. Among the 34 therapies with a complete radiological response, 14 therapies with a favorable α‐fetoprotein decrease had a better disease‐free survival curve than 20 therapies with an unfavorable α‐fetoprotein decrease (P = 0.003). Only one case had a favorable α‐fetoprotein decrease, but incomplete radiological response, with massive necrosis, with the exception of a small residual tumor. Conclusions: A favorable α‐fetoprotein decrease has better predictive power for disease‐free survival than for an unfavorable α‐fetoprotein decrease. HCC patients after RFA with an unfavorable α‐fetoprotein decrease should be considered to have undergone incomplete treatment, despite the complete response by standard image modality post‐RFA.     

Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival.

BACKGROUND: The benefit of surveillance of hepatocellular carcinoma (HCC) for patients with hepatitis C virus (HCV) infection, in terms of long-term survival, has not yet been established. METHODS: A total of 384 consecutive anti-HCV-positive HCC patients admitted to our hospital between January 1991 and October 2003 were enrolled. Patients were categorized into two groups, a surveillance group (182 patients) and a non-surveillance group (202 patients), according to tumor detection in a surveillance program based on periodical examination via ultrasound sonography and alpha fetoprotein determination at 6-month intervals, and their survival rates were compared. RESULTS: Although there were no significant differences in age and Child-Pugh classes between the two groups, the surveillance group exhibited a smaller tumor size (19 vs. 35 mm) and a higher incidence of single HCC (67% vs. 46%), compared with the non-surveillance group (each, P < 0.001). The cumulative survival rate in the surveillance group was higher than that in the non-surveillance group (5 years survival, 46% vs. 32%, P < 0.001). When the survival after correction of the lead-time bias in the surveillance group was analyzed according to the Child-Pugh classification, the surveillance program was found to have had a favorable outcome in Child-Pugh class A patients, but not in Child-Pugh class B/C patients. CONCLUSIONS: HCC surveillance for patients with HCV infection can lead to discovery of tumors at an early stage, especially in Child-Pugh class A, resulting in a favorable outcome.     

Predictive factors of advanced recurrence after curative resection of small hepatocellular carcinoma

Background: The tumour recurrence rate after resection is still high even in patients with small hepatocellular carcinoma (HCC). The advanced patterns of recurrence occasionally occur after resection. In this study, we analysed the clinical and histological characteristics of small HCC and evaluated the predictive factors of advanced tumour recurrence. Methods: One hundred and sixty‐five patients underwent resection of small HCC measuring 3 cm or less in greatest dimension. Patterns of tumour recurrences were classified into advanced recurrence and minor recurrence based on size, number, vascular invasion and extrahepatic metastasis of recurrent tumour. We created a simple index to closely evaluate the malignant potential of small HCC, named α‐foetoprotein–size ratio index (ASRI). Results: Overall tumour recurrence was significantly associated with tumour multiplicity (P<0.001) and ASRI (P=0.001). Tumour multiplicity, ASRI and tumour differentiation were independent and significant predictive factors of advanced recurrences. The overall survival rates were lower in the advanced recurrence group than the minor recurrence or the no recurrence group. Conclusions: Patients with advanced recurrences have a poor prognosis, although they have undergone curative resection of small HCC. On the other hand, patients with minor recurrences have a relatively good prognosis. ASRI was a useful index to predict advanced recurrence after curative resection of small HCC. The therapeutic management to prevent advanced recurrences is needed.     

Community-based screening for hepatocellular carcinoma in elderly residents in a hepatitis B- and C-endemic area

Background and Aim: The aim of the present study was to elucidate a reasonable model and the efficacy of hepatocellular carcinoma (HCC) screening on an elderly population. Methods: Two‐stage HCC screening was conducted in a hepatitis C virus (HCV)‐endemic area. First, participants underwent blood tests for hepatitis B surface antigen (HBsAg), anti‐HCV antibody, serum α‐fetoprotein (AFP), aspartate aminotransferase, alanine aminotransferase, and platelet count. Patients who were abnormal for any of the six markers were enrolled for second‐stage ultrasonography. Suspected cases were referred for confirmation. HCC cases were followed for 4 years. All patients were linked to national mortality and cancer register databases to identify newly‐developed HCC, 30 months after screening. Results: A total of 461 males and 541 females were screened for HCC, with 15.1% testing positive for HBsAg and 44.3% positive for anti‐HCV. Among them, 619 (61.8%) met the criteria of ultrasonographic screening; 527 (85.1%) responded, and 16 confirmed HCC (male/female = 8/8, 68.8 ± 8 years) cases were detected. All tumor diameters were less than 5 cm, and six were less than 2 cm. AFP and thrombocytopenia were two independent predictive factors of HCC. The overall survival rates of detected cases were 93.8% and 56.3% was 1 and 4 years, respectively. The only good prognostic predictor was “underwent curative treatment”. Another seven non‐HCC residents developed HCC after screening, and five of these were with either thrombocytopenia or AFP elevation. Conclusion: Under economical consideration, AFP and platelet count should be feasible screening markers of risk identification. Early detection and prompt treatment results in good prognosis in an aged population.     

Early α‐fetoprotein response as a predictor for clinical outcome after localized concurrent chemoradiotherapy for advanced hepatocellular carcinoma

Backgrounds: There are limitations in using only radiological criteria to evaluate treatment outcomes in hepatocellular carcinoma (HCC). α‐fetoprotein (AFP) is regarded as an indicator of tumour activity in HCC. Aims: We present a novel correlation between AFP response and survival outcome in patients treated with localized concurrent chemoradiotherapy (CCRT). Materials: From 2005 to 2008, 187 locally advanced HCC patients underwent localized CCRT (external beam radiotherapy at 45 Gy over 5 weeks plus a concurrent hepatic arterial infusion of 5‐fluorouracil during the first/fifth week), followed by repetitive hepatic arterial infusional chemotherapy (HAIC) with 5‐fluorouracil and cisplatin. Among them, 149 with an elevated baseline AFP level (>20 ng/ml) were finally studied. AFP response was defined as >50% decrease from baseline, 1 month after the completion of localized CCRT. Results: Patients' characteristics were as follows: median age (52 years); Child–Pugh class A/B (n=137/12 respectively); and portal vein thrombosis (n=118). AFP responders (101 patients) had better objective responses than AFP non‐responders (48 patients) after CCRT (44.5 vs. 12.5%; P<0.001) and subsequent HAIC (51.5 vs. 16.7%; P<0.001). Both median progression‐free survival (PFS, 8.1 vs. 3.9 months; P<0.001) and overall survival (OS, 13.3 vs. 5.9 months; P<0.001) were longer in AFP responders than AFP non‐responders. In multivariate analysis, AFP response and objective response were independent factors affecting PFS and OS. Furthermore, AFP non‐responders were more likely to have extrahepatic metastasis within 6 months of treatments initiation than AFP responders (59.5 vs. 25.9%; P<0.001). Conclusions: Early AFP response may be useful not only in predicting prognosis and treatment response but also in establishing optimized treatment plans for HCC.     

Noninvasive diagnostic criteria for hepatocellular carcinoma in hepatic masses >2 cm in a hepatitis B virus‐endemic area

Background: Noninvasive criteria for diagnosing hepatocellular carcinoma (HCC) suggested by the American Association for the Study of Liver Diseases (AASLD) in 2005 consisted of serum α‐fetoprotein (AFP) level >200 ng/ml or a typical enhancement pattern (arterial enhancement and portal/delayed washed out) on dynamic imaging of hepatic mass(es) >2 cm in a cirrhotic liver. Aims: To validate these criteria in a Korean population and to evaluate whether these criteria are applicable to patients without cirrhosis at a high risk of developing HCC. Methods: We prospectively investigated 206 consecutive patients with hepatic mass(es) >2 cm who underwent biopsy or surgical resection. Patients were evaluated by four‐phase dynamic computed tomography (CT) and by assays of serum AFP concentrations at baseline. Patients were classified according to the presence of risk factors or cirrhosis, and the diagnostic accuracy of each test was determined. Results: The positive predictive values (PPV) of typical CT findings or serum AFP >200 ng/ml were 97.8% in cirrhotic patients, 89.6% in high‐risk patients without cirrhosis and 82.4% in low‐risk patients. The PPVs of typical CT findings alone in these groups were 98.8, 97.6 and 87.5% respectively. In high‐risk patients without cirrhosis, the addition of serum AFP levels to typical CT findings minimally increased the diagnostic sensitivity from 81.6 to 87.8% but reduced the PPV from 97.6 to 89.6%. Conclusions: Serum AFP concentration is not a suitable diagnostic criterion for HCC. Typical CT findings can be used to diagnose HCC >2 cm both in cirrhotic patients and in high‐risk patients without cirrhosis.     

Serum α-fetoprotein level at treatment completion is a useful predictor of hepatocellular carcinoma occurrence more than one year after hepatitis C virus eradication by direct-acting antiviral treatment

Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved liver function of HCV patients. The risk of hepatocellular carcinoma (HCC) occurrence following HCV eradication has been previously reported, but HCC may have been missed following imaging diagnosis before DAA administration in previous studies. Therefore, the present study aimed to identify definite predictors of HCC occurrence ≥1 year after DAA treatment. Among 956 patients receiving DAAs for HCV infection, 567 patients who achieved sustained virologic response with no history of HCC treatment were enrolled in this study between September 2014 and July 2021. The incidence of HCC in HCV-infected patients ≥1 year following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinical characteristics and blood test results. In the present study, 25 patients developed HCC. The incidence of HCC was 1.4%, 3.2%, 4.9% and 6.8% at 2, 3, 4 and 5 years, respectively, from the end of treatment with DAAs. Multivariate logistic analysis revealed serum α-fetoprotein level at end of treatment (EOT-AFP) >3.8 ng/ml ≥1 year following treatment with DAAs (HR, 9.7; p < .0001) as an independent factor that may contribute to HCC occurrence following DAA treatment. In conclusion, serum EOT-AFP level may serve an important role in determining the risk of HCC occurrence ≥1 year after DAA treatment. Regular examinations are required even if serum EOT-AFP level is low at treatment completion.