Elevated Serum Α-fetoprotein Level Research Articles

Viral hepatitis is associated with intrahepatic cholangiocarcinoma with cholangiolar differentiation and N-cadherin expression

Viral hepatitis-associated intrahepatic cholangiocarcinoma is thought to have common disease processes with hepatocellular carcinoma, but until now the histomorphological and genetic features of viral hepatitis-associated intrahepatic cholangiocarcinoma is still unknown. From 2000 to 2010, 170 patients with intrahepatic cholangiocarcinoma who received detailed pathological assessment and regular follow-up at the National Taiwan University Hospital were selected for this study. Of 170 patients, 69 (41%) were positive for hepatitis B and/or C virus. These patients were younger, were more frequently male, and had elevated serum α-fetoprotein levels as compared with seronegative intrahepatic cholangiocarcinoma patients. Grossly these tumors were mostly of the mass-forming type, and histologically, cholangiolar differentiation was more frequently seen. We identified N-cadherin as an immunohistochemical marker strongly associated with hepatitis virus infection. The prevalence of viral hepatitis in patients with N-cadherin-positive intrahepatic cholangiocarcinoma was 75%, and that in N-cadherin-negative patients was only 37%. N-cadherin-positive patients were younger, had elevated α-fetoprotein, and had no hepatolithiasis. All N-cadherin-positive intrahepatic cholangiocarcinomas were of the mass-forming type. N-cadherin positivity was strongly associated with cholangiolar morphology and lack of carcinoembryonic antigen and MUC2 expression, whereas K-RAS mutations were less frequent. Our results indicate that a subgroup of intrahepatic cholangiocarcinoma characterized by cholangiolar differentiation and N-cadherin expression is strongly associated with viral hepatitis.

Blood Neutrophil-to-lymphocyte Ratio Predicts Survival in Patients with Unresectable Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization

Purpose To evaluate whether the neutrophil-to-lymphocyte ratio (NLR) predicts survival in patients with unresectable hepatocellular carcinoma (HCC) before and after transarterial chemoembolization treatment. Materials and Methods Clinical and laboratory data for 145 consecutive patients undergoing transarterial chemoembolization for unresectable HCC during 2001–2004 were analyzed retrospectively. The NLR was recorded before and 3 days after treatment. Results The pretreatment mean NLR was 3.3; 59 (40.7%) patients had an elevated NLR (≥ 3.3). The median survival of patients with a high NLR was 8 months (range 1–28 months) compared with 12 months (range 2–41 months) for patients with a normal NLR; a significant difference was found in overall survival (log-rank test, P = .001). The NLR was increased in 127 (87.6%) patients after transarterial chemoembolization and was decreased in 18 patients; the increase indicated better outcomes (log-rank test, P = .006). Age (≥ 49 y), high NLR, decreased NLR after treatment, large tumor (≥ 5 cm), vascular invasion, and elevated serum α-fetoprotein (AFP) level all were predictors of poor survival. Multivariate analysis showed that a high NLR ( P = .041) and vascular invasion ( P = .040) were independent factors for predicting worse survival. Conclusions A high NLR independently predicts poor survival in patients with unresectable HCC undergoing transarterial chemoembolization treatment, and an increased NLR indicates a better outcome than a decreased NLR for patients after transarterial chemoembolization.

From the Archives of the AFIP: Pediatric Liver Masses: Radiologic-Pathologic Correlation Part 2. Malignant Tumors

Malignant primary hepatic tumors in children include lesions unique to the pediatric age group and others that are more common in adults. Important considerations when evaluating a child with a liver tumor are the age of the patient, laboratory findings, and specific imaging features. The most common primary malignant hepatic tumor in the pediatric population, hepatoblastoma occurs almost exclusively in patients younger than 5 years with no history of liver disease. Hepatoblastoma is associated with elevated serum α-fetoprotein (AFP) level and appears predominantly solid. Hepatocellular carcinoma (HCC) is the most common malignant liver tumor in older children, often with a history of liver disease. HCC is associated with elevated serum AFP level and also appears as a solid mass. Fibrolamellar carcinoma occurs in adolescents without elevated AFP level and contains a T2-hypointense fibrous scar that usually does not enhance. Undifferentiated (embryonal) sarcoma occurs in young children, contains cystic and mucoid components, and mimics a cyst at magnetic resonance imaging and computed tomography but appears solid at ultrasonography. Epithelioid hemangioendothelioma is a multifocal vascular tumor in older children with a distinctive imaging appearance of confluent peripheral nodules with adjacent capsular retraction. Angiosarcoma rarely occurs in young children and frequently shows evidence of hemorrhage. Embryonal rhabdomyosarcoma of the biliary tree is unique to children, usually under 5 years of age, and frequently demonstrates an intraductal growth pattern. Knowledge of the pathologic features of these tumors and their imaging appearances can help radiologists offer an appropriate differential diagnosis and management plan.

Evaluation of Absolute Serum α-Fetoprotein Levels in Liver Transplant for Hepatocellular Cancer

An elevated serum α-fetoprotein (AFP) level before orthotopic liver transplant (OLT) is predictive of mortality after OLT for hepatocellular carcinoma (HCC). Retrospective analysis of a population-based cohort. United Network for Organ Sharing registry (2003-2008). We identified 2253 patients who underwent OLT for HCC with available pre-OLT serum AFP values. Patients were stratified by AFP levels into low (<20 ng/mL), medium (20-399 ng/mL), or high (≥400 ng/mL) groups. Clinical and pathological characteristics were compared among groups. Survival curves were constructed by the Kaplan-Meier method, and univariate and multivariate Cox-regression analysis was performed. Of the 2253 patients, 1210 (53.7%), 805 (35.7%), and 238 (10.6%) were in the low, medium, and high AFP groups, respectively. On univariate analysis, the low AFP group demonstrated the best 4-year survival (76%) compared with the medium (65%; P = .001) and high (57%; P < .001) AFP groups. When AFP levels in patients with only stage II HCC underwent assessment, improved survival in the low AFP group was still observed (P < .001). On multivariate analysis, the medium and high AFP groups were associated with higher mortality (hazard ratios, 1.50 [95% confidence interval, 1.19-1.89; P = .001] and 2.11 [1.55-2.88; P < .001], respectively). Serum AFP level is an independent prognostic predictor of outcome after OLT for HCC. The association between serum AFP value and post-OLT survival warrants further investigation to potentially better allocate donor allografts for HCC.

RASSF2A promoter methylation in hepatitis B virus-related hepatocellular carcinogenesis and its correlation with elevated serum α-fetoprotein level

Loss of the RASSF2A expression induced by methylation-mediated silencing has been reported in several human cancers, but the methylation status of RASSF2A in hepatocellular carcinoma (HCC) is rarely studied so far. In this study, we investigated the RASSF2A expression and its methylation status in a cohort of 45 hepatitis B virus-associated HCC tissues and their adjacent non-carcinoma tissues by using RT-PCR and MS-PCR. Promoter methylation of RASSF2A was found in 31 (68.9%) out of 45 HCC tissues and 12 (40%) out of 30 adjacent normal tissues, respectively (P<0.05). The methylation status of PASSF2A was closely associated with the loss of RASSF2A expression and elevated serum alpha-fetoprotein level, but not significantly with clinical stage, hepatic fibrosis and K-ras mutation. It was concluded that aberrant methylation of the RASSF2A gene with the subsequent loss of RASSF2A expression plays an important role in the pathogenesis of HCC.

STROMAL-PREDOMINANT MESENCHYMAL HAMARTOMA OF THE LIVER WITH ELEVATED SERUM ALPHA-FETOPROTEIN LEVEL

Mesenchymal hamartoma of the liver (MHL) is an uncommon, benign, tumor-like lesion and is usually diagnosed in the first 2 years of life. Its pathogenesis remains unclear. Treatment of choice is radical excision. The authors report a case of solid stromal predominant MHL in a 12-month-old male infant who also had an elevated serum α-fetoprotein level. He also had hypospadias, which might represent a spectrum of developmental anomalies. It usually presents as an asymptomatic mass, however, as in the reported case, it may cause several complications due to the compression of surrounding structures. He was successfully treated with total excision of the pedunculated large tumor without any complication.

Cytomorphology of a solitary left chest wall mass: An unusual presentation from unknown primary hepatocellular carcinoma

Hepatocellular carcinoma (HCC) may present in various ways, but only very rarely with symptoms of distant metastases or evolve from ectopic liver tissue. This report describes a case of a 62-year-old white man who was admitted for hemoptysis and a large left chest wall mass that was growing for about a year. The patient underwent Fine-needle aspiration (FNA) of the mass that revealed poorly differentiated large-cell carcinoma. A lung primary was suspected initially; however, further workup of this patient showed an elevated serum alpha-fetoprotein (AFP) level of 16,425 ng/ml. A computerized tomography (CT) scan of the abdomen showed cirrhotic liver, evidence of esophageal varices, but no evidence of a liver mass. The FNA findings were reviewed and ancillary studies were performed, including pan cytokeratin (AE1/3), Hepatocyte Paraffin 1 (HepPar-1), AFP, CD10, CD34, and polyclonal CEA. The results confirmed the diagnoses of HCC probably from occult primary or from ectopic liver tissue. The former was suggested, since serum AFP was dropped to 6,640 ng/ml following resection of the tumor. We concluded that HCC should be considered in the list of differential diagnosis of chest wall mass. HCC may present as metastatic disease from a clinically and radiologically unrecognized liver mass. FNA, coupled with ancillary studies, provides a rapid and accurate diagnostic tool in challenging cases.

CpG Island Methylator Phenotype Association with Elevated Serum α-Fetoprotein Level in Hepatocellular Carcinoma

CpG island methylator phenotype (CIMP) involves hypermethylation targeted toward the promoters of multiple genes. To gain insight into the role of epigenetic aberration of tumor-related genes in hepatocarcinogenesis, we determined a hypermethylation profile in hepatocellular carcinoma (HCC). We examined the promoter methylation status of nine genes in 50 HCCs, 50 paired nontumor tissues, and 6 normal liver tissues by methylation-specific PCR. CIMP+ was defined as having five genes that are concordantly methylated. The frequency of promoter methylation of nine genes in 50 HCCs varied from 10% in P53 to 94% in c-Myc. The methylation status of P14, P15, P16, ER, RASSF1A, WT1, and c-Myc was significantly correlated with HCC and nontumor tissues (P<0.05). Hypermethylation of one or more genes was found in 96% of HCC. CIMP was more frequent in HCC than in nontumor tissues (70% and 12%, P<0.001). There is a significant association between CIMP and methylation of P14, P15, P16, ER, RSAAF1A, and WT1 (P<0.05) and serum alpha-fetoprotein (AFP) level (P=0.017). CIMP+ was more frequent in HCC with AFP>or=30 microg/L than those with AFP<30 microg/L (P=0.005). In addition, the promoter hypermethylation of P15 and P16 was associated with elevated serum AFP levels in 35 HCC samples with CIMP+ (P<0.05). Positive correlation of CIMP and AFP levels in HCC suggests that CIMP can serve as a molecular marker of late-stage HCC development.

False-Negative Rate of Abdominal Sonography for Detecting Hepatocellular Carcinoma in Patients with Hepatitis B and Elevated Serum α-Fetoprotein Levels

Routine screening for hepatocellular carcinoma among chronic carriers of hepatitis B virus using a combination of abdominal sonography and serum alpha-fetoprotein levels is widely practiced. Negative results on an abdominal sonogram generally indicate the absence of hepatocellular carcinoma despite the elevation of alpha-fetoprotein levels, but the false-negative rate of abdominal sonography has not been established prospectively. In our screening program, we routinely investigated patients with Lipiodol (iodized oil) CT when they presented with alpha-fetoprotein levels above 20 ng/mL or a focal lesion as depicted on abdominal sonography. Lipiodol CT comprised a hepatic angiogram with injection of Lipiodol selectively in the hepatic arteries, followed by an unenhanced CT scan 10 days later. Positive findings on Lipiodol CT were confirmed histologically by biopsy or surgical resection. We defined false-negative as histologic diagnosis of hepatocellular carcinoma within 3 months of normal findings on screening abdominal sonography. One hundred three patients with elevated alpha-fetoprotein levels were investigated with Lipiodol CT within 2 months of abdominal sonography. Of these, three of 70 patients with negative abdominal sonography had histologically confirmed hepatocellular carcinoma. Thus, abdominal sonography has a false-negative rate of 4.3%. Lipiodol CT is associated with a significant false-positive rate of 43.7%. The sensitivity, specificity, and positive predictive value of abdominal sonography for early detection of hepatocellular carcinoma among hepatitis B virus carriers with elevated alpha-fetoprotein levels was 85.7%, 81.7%, and 54.5%, respectively. Negative results on a screening abdominal sonogram among hepatitis B virus carriers with elevated alpha-fetoprotein levels does not rule out the presence of small hepatocellular carcinoma. Routine use of Lipiodol CT as a supplementary screening tool is not recommended.

高カルシウム血症を伴った犬の肝芽腫の1例

hypercalcemia, and radiography revealed an abdominal mass. Experimentallaparotomy showed a large, solid mass originating from the liver. Because the mass was big and tended to bleedwhen manipulated, we abandoned complete excision and collected samples for histophathology. The patientdied 2 days after the operation. The mass was diagnosed as hepatoblastoma. Elevated parathyroidhormone-related protein (PTH-rP) and serum α-feto protein levels suggested that the PTH-rP secreted by hepatoblastomacells led to hypercalcemia in the patient.

Elevated maternal serum midtrimester α-fetoprotein levels are associated with fetoplacental ischemia

Objective: Elevation of maternal serum α-fetoprotein in the second trimester is associated with poor pregnancy outcome, including fetal death, preterm delivery, and fetal growth restriction. We hypothesized that placental ischemia may be the common underlying pathogenesis of these outcomes. Thus we tested angiogenin, a potent inducer of neovascularization, in midtrimester amniotic fluid of patients with elevated maternal serum α-fetoprotein values to determine whether α-fetoprotein elevation is due to ischemia with subsequent stimulation of angiogenesis. Study Design: In this case-control study, patients with elevated maternal serum α-fetoprotein levels (≥2.0 multiples of the median, n = 9) at triple screen were matched with two controls ( n = 18) on the basis of year of amniocentesis and maternal age, race, and parity. The median elevation of maternal serum α-fetoprotein in the study population was 4.01 multiples of the median (range 2.65 to 7.24 multiples of the median). Inclusion criteria were (1) singleton gestation, (2) no evidence of fetal structural or chromosomal anomalies, and (3) genetic amniocentesis. Amniotic fluid was immunoassayed for angiogenin (Quantikine, R&D Systems; sensitivity 0.026 ng/ml, interassay and intraassay coefficients of variation 4.6% and 2.9%, respectively). Statistical analysis included one-way analysis of variance and regression with p < 0.05 significant. Angiogenin and maternal serum α-fetoprotein values were normalized with use of natural log transformation for statistical analysis. Results: Angiogenin values were significantly elevated in patients with high maternal serum α-fetoprotein levels (median 31.1 [range 9.2 to 54.6] vs 17.1 [range 9.0 to 29.2] ng/ml, p = 0.02). Mean gestational age at sampling, maternal age, and year of amniocentesis were not significantly different between the study and control groups (each p > 0.05). As anticipated, there was a significant increase in preterm deliveries and small-for-gestational-age neonates in the patients with elevated maternal serum α-fetoprotein levels (each p < 0.01). Conclusions: Midtrimester amniotic fluid angiogenin levels are significantly elevated in patients with elevated midtrimester maternal serum α-fetoprotein levels. Because angiogenin is a known marker of tissue ischemia, resulting in neovascularization, we hypothesize that elevation of maternal serum α-fetoprotein levels at triple screen is due to placental ischemia.

Multiple Hepatoblastomas Associated with Trisomy 18 in a 3-Year-Old Girl

A very rare case of full trisomy 18 associated with multiple hepatoblastomas is reported. The patient also had ventricular septal defect and patent ductus arteriosus, which were repaired at 6 months of age. After the cardiac surgery, she was noted to have an abdominal mass and an elevated serum α-fetoprotein level. A partial hepatic lobectomy was performed at 7 months of age, and the resected tumor was diagnosed as a fetal-type hepatoblastoma. At 2 years and 4 months of age, a chest radiograph disclosed an elevated left diaphragm, and abdominal ultrasonography demonstrated a tumor in the left hepatic lobe. The resected tumor was also diagnosed as a fetal-type hepatoblastoma. Chromosomal analysis demonstrated that the karyotypes of peripheral blood and hepatic tumor cells obtained on two occasions were both 47,XX, +18. She has no evidence of recurrence at 3 years of age without specific therapy.

The effect of fetomaternal bleeding on the risk of adverse pregnancy outcome in patients with elevated second-trimester maternal serum α-fetoprotein levels

Unexplained maternal serum alpha-fetoprotein elevation has been associated with an increased risk of intrauterine growth retardation, preterm delivery, and intrauterine fetal death. The purpose of this study was to determine whether patients with evidence of recent fetomaternal bleeding as a cause of elevated maternal serum alpha-fetoprotein level are at a lower risk for adverse pregnancy outcome than those without such evidence. Patients with elevated maternal serum alpha-fetoprotein levels who had a singleton viable fetus without ultrasonographically detectable anomalies were offered inclusion in this study. Study participants had blood drawn for fetal cell analysis before amniocentesis. The pregnancy outcomes of patients with evidence of fetomaternal bleeding were compared with those of patients without. Of 229 patients, 109 (47.6%) had evidence of fetomaternal bleeding as a possible cause of elevated maternal serum alpha-fetoprotein. Of these, 86 (78.9%) had a normal pregnancy outcome compared with 84 of 120 (70.0%) with a negative stain for fetal cells (p not significant). There was no significant difference in the incidence of preterm delivery (14 [12.8%] vs 15 [12.5%]), intrauterine growth retardation (5 [4.6%] vs 9 [7.5%]), or intrauterine fetal death (4 [3.7%] vs 8 [6.6%]) when patients with a positive stain for fetal cells were compared with those with a negative stain. Among patients with elevated maternal serum alpha-fetoprotein levels, those with evidence of recent fetomaternal bleeding do not appear to be at decreased risk for adverse pregnancy outcome compared with those without such evidence.

Elevated serum α-fetoprotein level of nude mice bearing hepatoma cells by treatment with monoclonal antibodies to α-fetoprotein

This study was carried out to clarify the reason for elevation of serum α-fetoprotein (AFP) level of nude mice bearing hepatoma cells after treatment with monoclonal antibodies (MoAbs) to AFP. MoAbs to AFP showed no effect on the cumulative amounts of AFP secreted from human hepatoma cell line, HuH-7, in vitro. However, the treatment of nude mice bearing HuH-7N cells (HuH-7 xenograft) with MoAbs to AFP led to elevation of the serum AFP level in spite of the fact that the growth curve of HuH-7N cells was similar to that for PBS treatment. This apparent elevation of the serum AFP level is thought to be due to the slow elimination of AFP-MoAb immune complexes with little lattice structure from circulation, but not the enhancement of AFP secretion of HuH-7N cells. Thus, when using a MoAb alone or MoAb-drug conjugate, the serum AFP level should only be cautiously used as a tumor marker for evaluating the targeting immunotherapy.

Malignant benign neonatal sacrococcygeal teratoma

Thirty-six patients with benign neonatal sacrococcygeal teratoma (SCT) were treated in our medical center from 1972 to 1990. Mean gestational age was 38.6 ± 3.3 weeks with a mean birth weight of 3,484.0 ± 938.5 g. Twenty-nine patients (89%) were females. The majority of the tumors (75%) contained cystic components and 96% were Altman classification I and II. The initial surgical removal of the SCT (including the coccyx) was carried out during the first 7 days of life. Six patients (22%) developed recurrence of the tumor. Three were benign and reappeared locally after 12 ± 3 months and were reexcised. The mean serum α-fetoprotein level in this group was 13 ± 1 g/L. The malignant recurrence (all originally reported as being mature benign SCT) appeared at 20.3 ± 1.5 months and had markedly elevated serum α-fetoprotein levels (7,320 ± 4,630 μg/L). All the patients in this group had multimodal therapy including complete excision of the recurrent tumor. We conclude that SCT, although histologically benign, has an alarming potential to recur either as a benign or malignant tumor during the first 2 years of life. Close follow-up for at least 3 years (frequent examination, serum α-fetoprotein, and diagnostic imaging) is recommended for all patients who had undergone excision of SCT in the newborn period.

Hereditary persistence of alpha-fetoprotein

Persistently elevated α-fetoprotein levels were found in a 43-yr-old man in the absence of any specific pathology. Elevated serum α-fetoprotein levels were subsequently found in three first-degree relatives, two siblings, and one daughter. This represents the third documented family with hereditary persistence of α-fetoprotein. The pedigree is consistent with an autosomal dominant inheritance. Such elevated α-fetoprotein levels may be difficult to interpret in patients being screened for malignancy or in maternal serum α-fetoprotein screening programs. This rare genetic condition seems benign, with no discernable disease or functional abnormality noted in follow-up over a 6-mo period.

Raised Serum α-Fetoprotein in Sertoli-Leydig Cell Tumor (Androblastoma) of Ovary

Two cases of Sertoli-Leydig cell tumor (SLCT) of the ovary associated with elevated serum alpha-fetoprotein (AFP) levels are described. A 16-year-old girl (case 1) had a Sertoli-Leydig cell tumor containing heterologous elements in the form of mucinous epithelium; AFP was demonstrated within the Sertoli cells by immunohistochemical techniques. An 11-month-old girl (case 2) had a SLCT with a retiform pattern and heterologous elements in the form of cells resembling hepatocytes; AFP was localized in the hepatocytes by immunohistochemical techniques.