Normal Serum Alpha-fetoprotein Levels Research Articles

Serum Alpha-Fetoprotein as a Predictor of Liver Fibrosis in HBeAg-Positive Chronic Hepatitis B Patients.

Background and Objectives: Non-invasive methods for evaluating liver fibrosis have been a crucial focus of clinical research. The aim of the current study is to assess the accuracy of serum alpha-fetoprotein (AFP) in determining the stage of liver fibrosis in patients with chronic hepatitis B (CHB) who are positive for HBeAg. Materials and Methods: The current study included a total of 276 HBeAg-positive CHB patients who underwent liver biopsy. The levels of serum AFP were measured in these patients using electrochemiluminescence immunoassays. The correlations between serum AFP levels and other laboratory parameters were analyzed using Spearman's correlation analysis. Binary logistic regression analysis was performed to determine the independent associations between serum AFP levels and liver fibrosis. The diagnostic performance of serum AFP and other non-invasive markers was evaluated using receiver operating characteristic (ROC) curves. Results: A total of 59 (21.4%) patients were found to have elevated levels of serum AFP (>7 ng/mL). These patients displayed a significantly higher proportion of both advanced fibrosis and cirrhosis compared to those with normal serum AFP levels (0-7 ng/mL). The level of serum AFP was positively associated with levels of serum globulin (GLB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL), as well as the AST-to-platelet ratio (APRI), fibrosis-4 (FIB-4), and Scheuer's classification, and negatively correlated with platelet (PLT) counts. Furthermore, serum AFP was found to be independently associated with significant fibrosis, advanced fibrosis, and cirrhosis. The results of the ROC analysis showed that serum AFP was an effective predictor of significant fibrosis, advanced fibrosis, and cirrhosis, with an area under the receiver operating characteristic curve (AUROC) of 0.773 (95% CI: 0.721-0.821), 0.889 (95% CI: 0.847-0.923), and 0.925 (95% CI: 0.887-0.953), respectively. These values are higher than those of the APRI and FIB-4. Conclusions: Serum AFP could serve as a valuable supplemental biomarker for determining the severity of liver fibrosis in HBeAg-positive patients with chronic hepatitis B.

The outcomes and prognostic factors of patients with hepatocellular carcinoma and normal serum alpha fetoprotein levels

Alpha fetoprotein (AFP) is the most widely used tumor marker for hepatocellular carcinoma (HCC). Nevertheless, few studies have investigated the prognostic factors of HCC patients with normal serum AFP levels. We retrospectively enrolled 2198 patients with HCC and normal serum AFP levels (<20ng/mL) from 2007 to 2020. Overall survival (OS) rates were calculated by the Kaplan-Meier method, and analyses of the prognostic factors were performed using a Cox proportional hazard model. Among the enrolled patients, 1385 (63%) patients were in the low-normal AFP group (serum AFP levels ≤7ng/mL), and 813 (37%) patients were in the high-normal AFP group (serum AFP levels between 7 and 20ng/mL). The high-normal AFP group had poorer liver functional reserve, more multiple tumors, and smaller tumor size compared to those in the low-normal AFP group. After a median follow-up of 32.4 months, 942 patients died, and the 5-year OS rate was 54.4%. The 5-year OS rates were 57.4% and 49.8% in the low-normal AFP group and high-normal AFP group, respectively (p=0.001). A multivariate analysis showed the independent prognostic factors of poor OS were no anti-viral therapy, advanced albumin-bilirubin grades, the presence of vascular invasion, tumor size ≥5cm, and non-curative treatment modalities. Serum AFP levels were not associated with OS according to the multivariate analysis. Liver functional reserve, anti-viral therapy, tumor size, vascular invasion, and treatment modalities, determined the outcomes of HCC patients with normal serum AFP levels, but serum AFP levels did not.

Transcriptomic Analyses Reveal Long Non-Coding RNA in Peripheral Blood Mononuclear Cells as a Novel Biomarker for Diagnosis and Prognosis of Hepatocellular Carcinoma.

Novel biomarkers are highly required for the diagnosis and predicting prognosis of hepatocellular carcinoma (HCC). In this study, we investigated the profiles of long non-coding RNAs (lncRNAs) obtained from the peripheral blood mononuclear cells (PBMCs) of patients with HCC and PBMCs from a co-culture model using transcriptomic analysis. The differentially expressed lncRNAs (DElncRNAs) were then characterized and integrated as cancer-induced lncRNAs. Among them, three up-regulating DElncRNAs including MIR4435-2HG, SNHG9 and lnc-LCP2-1 and one down-regulating, lnc-POLD3-2, were identified. The functional analysis showed that these enriched lncRNAs were mainly associated with carcinogenesis and immune responses. Following further validation in PBMCs samples (100 HBV-related HCC, 100 chronic hepatitis B and 100 healthy controls), MIR4435-2HG, lnc-POLD3-2 and their combination were revealed to be sensitive biomarkers in discriminating HCC from non-HCC (AUROC = 0.78, 0.80, and 0.87, respectively), particularly among individuals with normal serum alpha-fetoprotein levels. Additionally, high circulating SNHG9 expression was shown to be an independent prognostic factor of overall survival in patients with HCC. These results indicate that determining these lncRNAs in PBMCs could serve as novel diagnostic and prognostic biomarkers for HBV-related HCC.

Differential alternative splicing between hepatocellular carcinoma with normal and elevated serum alpha-fetoprotein

BackgroundSerum alpha-fetoprotein (AFP) is the approved serum marker for hepatocellular carcinoma (HCC) screening. However, not all HCC patients show high (≥ 20 ng/mL) serum AFP, and the molecular mechanisms of HCCs with normal (< 20 ng/mL) serum AFP remain to be elucidated. Therefore, we aimed to identify biological features of HCCs with normal serum AFP by investigating differential alternative splicing (AS) between HCCs with normal and high serum AFP.MethodsWe performed a genome-wide survey of AS events in 249 HCCs with normal (n = 131) and high (n = 118) serum AFP levels using RNA-sequencing data obtained from The Cancer Genome Atlas.ResultsIn group comparisons of RNA-seq profiles from HCCs with normal and high serum AFP levels, 161 differential AS events (125 genes; ΔPSI > 0.05, FDR < 0.05) were identified to be alternatively spliced between the two groups. Those genes were enriched in cell migration or proliferation terms such as “the cell migration and growth-cone collapse” and “regulation of insulin-like growth factor (IGF) transport and uptake by IGF binding proteins”. Most of all, two AS genes (FN1 and FAM20A) directly interact with AFP; these relate to the regulation of IGF transport and post-translational protein phosphorylation. Interestingly, 42 genes and 27 genes were associated with gender and vascular invasion (VI), respectively, but only eighteen genes were significant in survival analysis. We especially highlight that FN1 exhibited increased differential expression of AS events (ΔPSI > 0.05), in which exons 25 and 33 were more frequently skipped in HCCs with normal (low) serum AFP compared to those with high serum AFP. Moreover, these events were gender and VI dependent.ConclusionWe found that AS may influence the regulation of transcriptional differences inherent in the occurrence of HCC maintaining normal rather than elevated serum AFP levels.

A challenging case of alpha-fetoprotein-result discrepancies in a patient with chronic hepatitis B.

Alpha-fetoprotein (AFP) is the most abundant serum protein found in the human fetus, produced by the yolk sac and the liver [1]. The levels of maternal serum AFP reach a peak value at ∼28–32 weeks of gestation and decrease rapidly after birth and usually drop to the normal at 8–12 months of age. The normal serum AFP level for an adult is <20 ng/mL [2]. In contrast, liver-tumor cells usually synthesize and secrete an increased level of AFP. Abdominal ultrasound and AFP are generally recommended as the screening modality for HCC for patients at risk for development of hepatocellular carcinoma (HCC) [1]. AFP-L3, an isoform of AFP that binds Lens culinaris agglutinin, can be particularly useful in the early identification of aggressive HCC [2]. These assays, however, can generate false-positive and false-negative AFP values. Of patients with advanced HCC, ∼20% had normal AFP levels, whereas some patients with liver diseases had significant AFP elevation without liver cancer in long-term surveillance [3]. Elevated AFP levels could be associated with active liver diseases with hepatocyte regeneration [4, 5]. In that setting, the AFP level will decline with improvement of the underlying liver condition. Our case illustrated the dilemma and uncertainties as a result of persistent abnormal AFP values after extensive clinical investigations.

Usefulness of Circulating Methylated p16 as a Noninvasive Molecular Biomarker for Hepatitis C-Related Hepatocellular Carcinoma with Normal Serum Alpha-Fetoprotein Levels.

BackgroundScreening of hepatocellular carcinoma (HCC) is challenged especially in patients with normal alpha-fetoprotein (AFP) levels. Aberrant p16 methylation has been implicated in HCC.Objectives and AimsThis study aimed to assess serum methylated p16 (MP16) expression levels and to evaluate MP16 diagnostic performance in HCC detection among HCV-infected Egyptian patients with normal AFP levels.MethodsMP16 levels were quantified using real-time PCR in 230 serum samples (30 healthy controls, 95 with HCV-HCC, 40 with chronic hepatitis C “CHC” and 65 with HCV cirrhosis). Diagnostic performance of MP16 for diagnosis of HCC was done using receiver operator characteristic curve analysis.ResultsSerum MP16 levels were significantly higher in HCC than CHC, cirrhosis, and healthy subjects and significantly higher in HCC with normal AFP levels than those with higher AFP. ROC curves revealed promising diagnostic performance for MP16 in discriminating HCC with normal AFP levels from non-HCC cases. This predictive ability improved by combining MP16 and AFP (AUC of 0.872 with 100% sensitivity, 76.5% specificity, 79.1% positive predictive value, 100% negative predictive value, and 87.5% accuracy).ConclusionMP16 can be a potential noninvasive molecular biomarker for HCC detection in patients with hepatic mass(es) and normal AFP levels especially in those where liver biopsy and radiological imaging cannot be done.

Small cells indifferentiated hepatoblasotma in childhood : a rare aggressive malignancy

A new born of two months years old was admitted for abdominal mass which the echography confirmed the hepatic origin. The biological analysis showed an elevated Lactic Acid Dehydrogenase (LDH) serum level, but no elevated alpha fetoprotein neither catecholamins nor other marquers. The abdominal scan confirmed hepatic mass at the expense of two segments. The fine needle scan guided biopsy was done and revealed a neoplastic proliferation of cells, histologically slightly larger than lymphocytes and measure (7-8 um) in size. They are round to oval with scant cytoplasm, relatively fine nuclear chromatin, inconspicuous nucleoli and only minimal mitotic activity. They grow in a diffuse pattern but usually form clusters either intimately inter-mixed with other epithelial cell types or forming nests in an almost ‘organoid’ pattern (A). Immunohistochemically, small cells showed positivity for pancytokeratin (B) as well as vimentin (D). They did not express alpha-fetoprotein (AFP) (C). Thus, the final diagnosis been retained : small cell undifferentiated hepatoblastomas (SCUD-HB) is associated with an aggressive biological course and poor survival. The negative prognostic impact is conferred even by small areas in an otherwise large tumor. Rarely, particularly in infants, the entire hepatoblastoma is composed of small undifferentiated cells ; such tumors account for approximately 5% of all hepatoblastomas. SCUD-HB is associated with low or normal serum AFP levels. SCUD-HB retain expression of INI1 but a small subset present morphological rhabdoid features, including loss of nuclear expression of INI1. Transition between the two types has been described.

Utility of Cytokeratin7 Immunocytochemistry in the Cytopathological Diagnosis of Fibrolamellar Hepatocellular Carcinoma.

Objective:To distinguish fibrolamellar hepatocellular carcinoma (FL-HCC) variant from the conventional hepatocellular carcinoma (HCC) by cytology, immunocytochemistry, and morphometry.Study Design:Retrospective detailed cytomorphological, immunocytochemical, and morphometric analysis was performed in 6 cases of FL-HCC reported on fine needle aspiration. Cell block immunocytochemistry (CB-ICC) for CK7 and CD68 was performed in four cases. Morphometry was carried out with Cell A software. Area of the cell, nucleus and nucleolus was measured in 50 nuclei per case in 6 cases each of FL-HCC and HCC.Results:The mean age of patients with FL-HCC was 19 years and all had normal serum alpha-fetoprotein levels. Fine needle aspiration smears showed large polygonal cells with abundant cytoplasm, vesicular nucleus and prominent nucleolus, associated with variably cellular fibrous stromal fragments. Intranuclear inclusions, cytoplasmic eosinophilic inclusions, and bile were also noted. FL-HCC showed strong membrano-cytoplasmic CK7 positivity and cytoplasmic granular and canalicular positivity for CD68. In contrast, HCC showed weak focal positivity for CK7 and only canalicular CD68 positivity. Morphometry revealed that FL-HCC cells were 2.19 times the size of HCC.Conclusion:CK7 immunocytochemistry on cell blocks is useful for confirming and distinguishing it from HCC.

A Simple Noninvasive Index Can Predict Hepatocellular Carcinoma in Patients with Chronic Hepatitis B

Screening for possible development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is essential for risk prediction and early therapy. This study reported a novel model comprised of routine laboratory variables for predicting HCC from CHB. A retrospective study was performed among 463 participants. alpha-fetoprotein (AFP), platelet and alanine aminotransferase (ALT) ratio (APAR) was constructed to differentiate HCC from CHB or non-cancer with area under the receiver operating characteristic curves (AUC) of 0.815 and 0.868 in the training set, 0.831 and 0.861 in the validation set, respectively. In participants with low or normal AFP (<100 ng/mL), the diagnostic efficacy of APAR measured by AUC were 0.817 and 0.809 for predicting HCC from CHB or non-cancer, and at a cutoff of 0.47, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 89%, 60%, 67% and 86%, respectively. For participants with normal AFP (<20 ng/mL), the AUC of APAR were 0.839 and 0.746 accompanied by a cutoff of 0.36 with sensitivity, specificity, PPV, and NPV of 88%, 69%, 71%, and 87%, respectively. In conclusion, APAR is an effective model for HCC screening especially in those with low even normal serum AFP levels.

Tumor del seno endodérmico extragonadal de localización vulvar: descripción de un caso y revisión de la literatura

An extragonadal location of a yolk sac tumour is rare and may display normal levels of serum alpha-fetoprotein.We report a case of a 34-year-old woman with a vulvovaginal tumour initially thought to be an undifferentiated carcinoma of the vulva. However, a new histological and immunohistochemical assessment and subsequent determination of serum AFP confirmed the diagnosis of yolk sac tumour.Vulvar yolk sac tumor is rare with only 16 cases described in the literature. However, an accurate differential diagnosis should be made in order to indicate the correct treatment.

Glypican-3 is a potential prognostic biomarker for hepatocellular carcinoma after curative resection

Glypican-3 (GPC3), an oncofetal protein, is overexpressed in hepatocellular carcinoma (HCC). The diagnostic efficacy of GPC3 for HCC has been evaluated intensively in recent years; however, the prognostic value of GPC3 for HCC has not been well clarified. The purpose of this study was to investigate the relationship between GPC3 and postoperative patient survival in a prospective database. GPC3 protein was detected by immunohistochemistry. The relationship between GPC3 expression level and patients' clinicopathologic factors was analyzed. Kaplan-Meier survival analysis was used to calculate patients' survival and was compared by using the log rank test. The Cox regression model was used to identify the risk factors associated with prognosis. GPC3 was expressed in 84% of HCC tissues. GPC3 protein expression was correlated with thenumber of tumors (P = .015), serum alpha-fetoprotein (AFP) level (P = .011), and TNM stage (P=.006). High GPC3 expression was an independent risk factor for poor postoperative disease-free survival (hazard ratio [HR] = 0.469; 95% confidence interval [CI] 0.303-0.727; P = .001); and overall survival (HR = 0.435; 95% CI, 0.257-0.736; P = .002). Stratification analysis indicated that GPC3 had a good predictive value for tumor recurrence in patients with HCC who have normal serum AFP levels. Also, GPC3 expression status could predict the outcomes of patients with stage I disease. GPC3 is a potential and reliable biomarker for predicting tumor recurrence and overall survival in HCC patients after curative resection.

Late relapse (&gt;2 years) on surveillance in stage I non-seminomatous germ cell tumours; predominant seminoma only histology

Surveillance is a standard management approach following orchidectomy for stage I non-seminomatous and mixed germ cell tumours. Patients who relapse following this approach are treated with cisplatin-based chemotherapy, with retroperitoneal lymph node dissection considered for patients with post-chemotherapy residual masses. We reviewed the clinicopathological data for all patients who relapse greater than 24 months after commencing our surveillance programme. Between 1989 and 2008, 453 patients with a median age of 30 years were entered into our surveillance program for stage I non-seminomatous germ cell tumours (NSGCTs) after orchidectomy alone. All primary tumour specimens contained NSGCT, with seminomatous elements identified in 168 cases (37%). One-hundred patients (22%) relapsed and the majority of relapses occurred within the first 2 years (76 ≤ 12 months, 15 ≥ 12 months ≤ 2 years). Nine patients relapsed after more than 2 years of surveillance. We found a high incidence of pure seminoma (56%) at sites of metastatic disease in this group. All late-relapsing patients were alive and disease free at a median follow up of 45 months from relapse. We recommend that late-relapsing patients with normal serum alpha fetoprotein levels undergo biopsy to define histologically the nature of recurrent disease. In those with pure seminoma retroperitoneal lymph node dissection for post chemotherapy residual masses can be avoided.

Abstract 4578: Comparative subcellular proteomics study of hepatocellular carcinoma cell lines differentially expressed alpha fetoprotein: Annexin A2 could serve as a potential histological and serological biomarker

Abstract Hepatocellular carcinoma (HCC) is a common tumor worldwide with an extremely poor prognosis. Alpha-fetoprotein (AFP) is the only available HCC serological biomarker and has limited effect at early stages. Previous work has proven that AFP-producing and -nonproducing HCC cells have different gene/protein expression profiles. To identify additional candidates that might aid in HCC diagnosis, in addition to giving a better understanding of the mechanisms underlying hepatocarcinogenesis, subcellular fraction proteins from multiple liver cancer (HepG2, Hep3B and SK-HEP-1) and normal cells (HL-7702) were separated and identified using a 2-DE/MALDI-TOF-TOF approach. In total, 50 differentially-expressed proteins between liver cancer and normal liver cells were identified from different fractions including the cytosol, membrane/organelles and nuclear proteins. Among them, the tumor-related protein Annexin A2, was verified to be significantly upregulated in HCC tissues (63.5%, 80/126) especially in AFP-normal cases based on large-scale clinical specimens. Serum levels of Annexin A2 measured by an established ELISA assay were found to be significantly elevated in HCC patients compared with healthy individuals. The serum concentration was also correlated with histological grade. Combined use of AFP and Annexin A2 could increase the diagnostic performance of HCC. These data suggest that Annexin A2 may serve as a novel serological/histological candidate involved in HCC, especially among individuals with normal levels of serum AFP. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4578.

Quantitative Proteomic Signature of Liver Cancer Cells: Tissue Transglutaminase 2 Could Be a Novel Protein Candidate of Human Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common diseases worldwide, with extremely poor prognosis due to failure in diagnosing it early. Alpha-fetoprotein (AFP) is the only available biomarker for HCC diagnosis; however, its use in the early detection of HCC is limited, especially because about one-third of patients afflicted with HCC have normal levels of serum AFP. Thus, identifying additional biomarkers that may be used in combination with AFP to improve early detection of HCC is greatly needed. A quantitative proteomic analysis approach using stable isotope labeling with amino acids in cell culture (SILAC) combined with LTQ-FT-MS/MS identification was used to explore differentially expressed protein profiles between normal (HL-7702) and cancer (HepG2 and SK-HEP-1) cells. A total of 116 proteins were recognized as potential markers that could distinguish between HCC and normal liver cells. Certain proteins, such as AFP, intercellular adhesion molecule-1 (ICAM-1), IQ motif containing GTPase activating protein 2 (IQGAP2), claudin-1 (CLDN1) and tissue transglutaminase 2 (TGM2), were validated both in multiple cell lines and in 61 specimens of clinical HCC cases. TGM2 was overexpressed in some of the AFP-deficient HCC cells (SK-HEP-1 and Bel-7402) and in about half of the tumor tissues with low levels of serum AFP (17/32, AFP-negative HCC). Trace amounts of TGM2 were found to be expressed in the samples with high serum AFP (26/29, AFP-positive HCC). Moreover, TGM2 expression in liver tissues showed an inverse correlation with the level of serum AFP in HCC patients. Notably, TGM2 existed in the supernatant of the AFP-deficient SK-HEP-1, SMMC-7721 and HLE cells, and it was found to be induced in AFP-producing cells (HepG2) by specific siRNA silence assay. Serum TGM2 levels of 109 HCC patients and 42 healthy controls were further measured by an established ELISA assay; the levels were significantly higher in HCC patients, and they correlated with the histological grade and tumor size. These data suggest that TGM2 may serve as a novel histological/serologic candidate involved in HCC, especially for the individuals with normal serum AFP. These novel findings may provide important clues to identify new biomarkers of HCC and indirectly improve early detection of the disease.

Serum alpha-fetoprotein (AFP) levels in breastfed infants with prolonged indirect hyperbilirubinemia

The aim of this prospective study was to verify normal serum AFP (alpha-fetoprotein) levels in jaundiced breastfed infants with indirect hyperbilirubinemia. Methods The study was conducted in clinically jaundiced breastfed infants, 20, or more, days old, referred to our outpatient ambulatory. Inclusion criteria were: birth at term after a physiologic pregnancy, with an Apgar score > 7 at 1 and 5 min, no evidence of congenital anomalies or diseases, direct bilirubin < 1 mg/dl, normal values of α-1-antitrypsin, glucose-6-phosphate dehydrogenase, thyroid stimulating hormone, triiodothyronine, tyroxine, and normal growth. 30 non-jaundiced breastfed infants age–weight-matched, were used as control group. Results 98 jaundiced breastfed infants satisfied inclusion criteria. Their mean serum concentration of AFP was significantly higher than control infants (3548 vs 1095 ng/ml, p < 0.001). Serum AFP levels of jaundiced infants were directly associated with serum indirect bilirubin and γ-glutamyltranspeptidase concentrations. Conclusions The most probable explanation of elevated AFP in jaundiced breastfed infants may be the presence in human milk of one or more factors which affect hepatocyte growth and/or function. Based on our finding we demonstrated that in jaundiced breastfed infants normal range of serum AFP levels are higher than previously published data for healthy infants. Our data can be useful for a right interpretation of AFP levels in breastfed infants with prolonged jaundiced and may be used to avoid unnecessary investigations.

Hepatocyte proliferation in chronic hepatitis C: correlation with degree of liver disease and serum alpha-fetoprotein.

Hepatocyte proliferation (HP) is an adaptive response to liver injury. The relationships between HP and necroinflammation, fibrosis, and serum alpha-fetoprotein (AFP) levels in chronic hepatitis C virus (HCV) infection, however, are not well understood. Proliferative hepatocytes (Ki-67+) were identified using immunohistochemical staining in formalin-fixed, paraffin-embedded liver tissue from 156 HCV RNA-positive patients with different degrees of liver histopathology. Twenty high-power fields (HPFs) in lobular areas were counted in each specimen. HP increased by 1.22 +/- 0.25 cells/HPF per increase in necroinflammation from grade 0 (median: 0.13; range: [0.1-0.5] cells/HPF) through grade 3 (median: 1.80; range: [0.0-25.2] cells/HPF; P=0.002). HP increased by 0.81 +/- 0.20 cells/HPF per increase in fibrosis from stage 0 (median: 0.33; range: [0.0-1.3] cells/HPF) through stage 3 (median: 1.70; range: [0.0-25.2] cells/HPF) and then decreased in stage 4 (to median: 0.90; range: [0.0-5.3] cells/HPF). HP also increased with advancing age (P=0.03). Among patients with advanced liver disease, HP was no higher in patients with elevated serum AFP levels (median: 1.68; range: [0.1-5.3] cells/HPF) than in those with normal serum AFP levels (median: 1.70; range: [0.0-25.2] cells/HPF; P=0.26). In patients with chronic HCV infection, HP increases with histologic progression of liver disease, but is impaired in cirrhosis. HP was not increased in patients with elevated serum AFP levels.

Role of Serum Alpha-Fetoprotein Monitoring in Detection of Recurrent Hepatocellular Carcinoma after Curative Hepatectomy

Objective: To evaluate the usefulness of serum alpha-fetoprotein (AFP) in detecting the recurrence of hepatocellular carcinoma (HCC) after curative hepatectomy. Methods: From January 1995 to February 2000, 283 patients who underwent curative resection of HCC had their post-operative serum AFP levels serially monitored, and the AFP levels at the time of diagnosis of recurrence were analyzed for those patients who developed recurrence. The patients were divided into those with normal (i.e. < 20 ng/ml, n=115) and those with elevated preoperative serum AFP levels (n=168). Results: Of the 283 patients, 151 (53.4%) developed HCC recurrence. In patients with normal preoperative serum AFP levels, the sensitivities of the postoperative serum AFP level in detecting HCC recurrence were 36.7%, 8.3% and 1.7%, respectively, using AFP cut-off levels of 20 ng/ml, 100 ng/ml and 400 ng/ml. The corresponding specificities were 86.3%, 96.1%, and 98.0%, respectively, using the three cut-off levels. In patients who had a raised preoperative serum AFP level ≥ 20 ng/ml, the sensitivities of the AFP tests were 83.1%, 55.1% and 32.6%, respectively, while the specificities were 73.4%, 86.1% and 92.7%, respectively, in detecting recurrence using the three cut-off levels. Conclusions: Serum AFP monitoring, in conjunction with imaging studies, is useful in monitoring recurrent HCC after hepatectomy. For patients with a raised preoperative serum AFP level, a postoperative serum AFP of over 20 ng/ml appears to be the best cut-off level for the detection of HCC recurrence with both satisfactory sensitivity and specificity. For patients with normal preoperative serum AFP levels, the sensitivity of postoperative serum AFP monitoring in the detection of recurrence is low, and hence the role of serum AFP monitoring is limited. Imaging studies are important for this group of patients in surveillance for recurrent HCC.

Clinicopathologic Features of Gastric Cancers Producing Alpha-Fetoprotein

Background: 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. Methods: 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(–)). Results: 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. Conclusion: 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.

High prevalence of multinodular hepatocellular carcinoma in patients with cirrhosis attributable to multiple risk factors.

To see whether or not there is an association between the cause of cirrhosis and the number of hepatocellular carcinoma (HCC) nodules, we analyzed 178 consecutive patients in whom HCC was detected during a prospective screening by abdominal ultrasound (US). The relevant information was obtained from the database of the screening programs operating at four hospitals in the Milan area. One hundred twenty-nine (72%) patients had a single tumor nodule detected by US and 49 (28%) patients had multinodular disease. Ninety-eight (55%) patients had normal serum values of alpha-fetoprotein (AFP). Tumor staging with biphasic computed tomography (CT) scan or hepatic arteriography with lipiodol revealed that 101 (57%) patients had single tumor nodules and 77 (43%) patients had more than one HCC nodule. After staging, multinodular HCC was more common in patients with multiple risk factors than in the hepatitis C virus (HCV) carriers (56% vs. 38%, P =.05). Interestingly, single tumors were as common in the 126 patients undergoing 6-month interval screening as in the 52 patients who were studied at yearly intervals. The former patients, however, had more small tumors than the latter ones (91% vs. 74%, P =.04). The 22 patients who were alcohol abusers had normal levels of serum AFP more often than the hepatitis B virus (HBV) or HCV carriers or those with multiple risk factors (86% vs. 57%, P <.04; vs. 47%, P <.002; vs. 52%, P <.006, respectively). We concluded that multinodular HCC was underdetected by real time US; it prevailed among patients with multiple risk factors. In these patients, screening with US exams every 6 months may be inadequate for early detection of liver cancer.

Hepatocellular carcinoma in children.

Hepatocellular carcinoma (HCC) occurs more frequently in subsaharan Africa and the Orient than in other geographical regions, but remains an uncommon tumour of childhood. We review six children with HCC (mean age 13 years) treated by the paediatric oncology unit at Tygerberg Hospital in Cape Town over an 8-year period (1983 - 1990). Patients presented with epigastric and right upper quadrant discomfort and hepatomegaly. The hepatitis B serum antigen (HbsAg) was positive in three patients; serum alpha-fetoprotein (AFP) levels were markedly elevated in three (range 100 - 453,000 microg/l). Age and sex did not differ significantly and all patients initially had irresectable advanced-stage tumours. Morphologically, three were highly malignant adult-type pleomorphic HCCs, two were differentiated tumours, and one a fibrolamellar subtype. The mean 2-year survival was 33% and the 5-year survival 16.6%. The biological behaviour and response to treatment of the tumours varied. Whereas three patients had a poor response to therapy, two with poorly-differentiated tumours, negative HbsAg, and normal serum AFP levels responded to doxorubicin/cisplatinum chemotherapy. This facilitated radical surgical excision. One patient of this group has survived for more than 75 months following surgical resection and remains well. HCC remains an uncommon tumour of childhood with a high mortality. Aggressive chemotherapeutic regimes in combination with surgical resection may lead to improved survival in some cases. Prevention of hepatitis B remains a priority.