Cerebrospinal Fluid Alpha-fetoprotein Research Articles

Cerebrospinal Fluid Levels of AFP and hCG: Validation of the Analytical Method and Application in the Diagnosis of Central Nervous System Germ Cell Tumors.

The determination of Human Chorionic Gonadotropin (hCG) and Alpha Fetoprotein (AFP) levels on serum and amniotic fluid plays a fundamental role in the diagnosis and follow-up of specific physiological or pathological conditions (e.g., pregnancy, threat of abortion or germ cell tumors). Recently, the quantification of hCG and AFP in other biological fluids has gained great attention to support the diagnosis, prognosis and follow-up of neoplastic diseases deriving from trophoblastic cells, such as germinomas. Most of the commercial kits for hCG and AFP assays are developed to be used on biological fluids such as serum/plasma and/or urine by manufacturing companies. The aim of this work was to evaluate the suitability of the analytical method certified for the use on serum, and/or amniotic fluid for the quantification of hCG and AFP in cerebrospinal fluid, carrying out an internal validation protocol. The data reported here show that the automated immunochemical method is fit for quantification of hCG and AFP in cerebrospinal fluid (CSF), allowing selective and specific diagnosis of secreting germ cell tumors. This is confirmed by the positive correlation between elevated levels of hCG or AFP and the diagnosis of brain tumors.

Clinical utility of circulating miR-371a-3p for the management of patients with intracranial malignant germ cell tumors.

BackgroundThe current biomarkers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) have limited sensitivity/specificity for diagnosing malignant germ cell tumors (GCTs) and “marker-negative” patients require histological confirmation for diagnosis. However, GCTs at intracranial sites are surgically relatively inaccessible and biopsy carries risks. MicroRNAs from the miR-371~373 and miR-302/367 clusters are over-expressed in all malignant GCTs and, in particular, miR-371a-3p shows elevated serum levels at diagnosis for testicular disease.MethodsUsing our robust preamplified qRT-PCR methodology, we quantified miR-371a-3p levels in serum and cerebrospinal fluid (CSF) in a series of 4 representative clinical cases, 3 with intracranial malignant GCT and 1 with Langerhans cell histiocytosis (LCH), compared with appropriate control cases.ResultsSerum and/or CSF miR-371a-3p levels distinguished those with intracranial malignant GCTs from LCH and, if known in real time, could have helped clinical management. The benefits would have included (1) the only confirmatory evidence of an intracranial malignant GCT in 1 case, supporting clinical decision making; (2) early detection of intracranial malignant GCT in another, where an elevated CSF miR-371a-3p level preceded the histologically confirmed diagnosis by 2 years; and (3) confirmation of an intracranial malignant GCT relapse with an elevated serum miR-371a-3p level, where serum and CSF AFP and HCG levels were below thresholds for such a diagnosis.ConclusionsThis series highlights the potential for microRNA quantification to assist the noninvasive diagnosis, prognostication, and management for patients with intracranial malignant GCTs. Serum and CSF should be collected routinely as part of future studies to facilitate the extension of these findings to larger patient cohorts.

Human chorionic gonadotropin elevation is not an intracranial germ cell tumor signature

Dear editor, For many years, in case of suspicion of a germ cell tumor (GCT), human chorionic gonadotropin (HCG), its beta subunit and alpha-fetoprotein (AFP) have been used as specific markers in the blood and/or cerebrospinal fluid (CSF) for clinical decision-making [4]. A positive test is an indication for treatment, without requiring histological confirmation [5]. We report a first description of CSF HCG elevation in a non-cystic suprasellar craniopharyngioma, contradicting this dogma. A 52-year-old male with a history of arterial hypertension and tinnitus complained of a decrease in left-side visual acuity over a few weeks, associated with polyuro-polydipsia syndrome. MRI examination revealed a suprasellar lesion of 16×18×16 mm, with a moderate hyper-T2 signal and an iso-T1 signal with homogeneous gadolinium enhancement. The lesion did not have a cystic component (see Fig. 1). Spinal MRI was negative, and the cerebral CT scan did not show any calcification of the tumor. Hormone analysis revealed a pituitary deficiency. Biological analysis of the CSF performed as part of the etiological assessment revealed an elevation of HCG to 10.8 IU/l (normal levels <5 IU/l) and of free beta-HCG to 1.1 ng/ml (normal levels <0.1 IU/l). Elevation of AFP was not detected in the blood or CSF. No abnormal cells were found in the CSF. No elevation of these markers was found in the blood. Given the many atypical features in our patient, we decided to perform a robot-assisted stereotaxic biopsy. The final diagnosis was papillary craniopharyngioma and excluded germinoma. Due to the high risk of surgical treatment, and after a multidisciplinary discussion, the tumor was treated by radiotherapy. Six months after that, the patient recovered his visual field loss, but the hypopituitarism remained. The MRI showed a volumetric reduction of the tumor and a decrease in contrast enhancement. This report points out two issues: First, some authors [2, 3, 6] have suggested that many cystic pineal, sellar or suprasellar lesions, including cystic craniopharyngioma, are able to produce theses markers through their wall (descriptions of HCG in benign pineal cyst contents and walls). This observation of a solid craniopharyngioma demonstrates for the first time that the tumor itself is able to secrete low levels of HCG and β-HCG that may be detectable in the CSF. CSF AFP elevation was also detected in two cases of craniopharyngiomas, one of which was proven to be a malignant form [2]. So far, no blood elevation of these markers has been reported in craniopharyngiomas. Second, therefore, physicians involved in brain management need to be aware that HCG or AFP CSF positivity in a patient with a suprasellar tumor is not a specific GCT signature and is not enough information for making therapeutic decisions. Our clinical case underlines the importance of multidisciplinary discussions and the necessity to perform a biopsy in patients showing isolated suprasellar lesions (bipolar pineal and suprasellar locations remain suggestive of germinoma), positive for CSF markers but with atypical P. Bourdillon (*) : E. Jouanneau Department of neurosurgery A, Hopital Neurologique et Neurochirurgical Pierre Wertheimer, Hospices Civils de Lyon, 59 bd Pinel, 69500 Bron, France e-mail: pierre.bourdillon@neurochirurgie.fr

CSF and serum AFP in patients without gestational or neoplastic AFP-secretion

Background. The measurement of alpha-fetoprotein (AFP) in cerebrospinal fluid (CSF) is important for the diagnosis of intracranial or intraspinal trophoblastic tumors. The current study was performed to establish reference values for AFP in CSF and to explore the relationship of CSF AFP and serum AFP in patients. Material and methods. CSF samples were obtained from 351 inpatients admitted because of various neurological diseases, excluding those who were pregnant, had active liver disease, or who had trophoblastic or other malignant tumors. In 256 of the 351 patients, paired samples of CSF and serum were obtained. Both CSF AFP and serum AFP were measured. The 97.5th percentile and maximum value of CSF AFP were obtained. The CSF AFP and serum AFP concentrations in each of the 256 paired samples were compared. Results. The 97.5th percentile and maximum value of CSF AFP concentration for overall participants were 1.042 and 1.950 g/L, respectively. The CSF AFP concentration was found to be higher than the simultaneous serum AFP concentration only in 1.6% (4/256) of participants. Conclusions. The reference value determined in this study for CSF AFP is significantly lower than that usually used in clinical practice. A CSF AFP concentration higher than the simultaneous serum AFP concentration but lower than the upper reference limit does not necessarily suggest abnormal intrathecal AFP-secretion.

Diagnostic utility and correlation of tumor markers in the serum and cerebrospinal fluid of children with intracranial germ cell tumors

In order to predict whether tumor markers assist in the histopathologic diagnosis of germ cell tumors (GCTs), we analyzed the correlation of beta human chorionic gonadotropin (βhCG) and alpha-fetoprotein (AFP) in serum and cerebrospinal fluid (CSF) samples at baseline and subsequent follow-up examinations. A retrospective study of patients diagnosed with intracranial GCTs between July 1985 and February 2011 at our institution was conducted to review clinical, surgical, radiological, laboratory, and histopathologic data. Of the 67 patients eligible for the study, 42 had germinomas and 25 non-germinomatous GCTs. At baseline, serum and CSF AFP agreed in 97.9 % of patients (Cohen's Kappa 0.93). Baseline βhCG samples agreed in only 72.5 % of patients (Cohen's Kappa 0.46). In most cases, values were higher in serum for AFP and in CSF for βhCG. ROC curves estimated from logistic regression model indicated that CSF and serum samples had almost equal diagnostic utility, and the DeLong test showed that the difference in area under curves was not statistically significant. During follow-up (185 paired CSF and serum values from 43 patients), 90.3 % of AFP values correlated between CSF and serum (Cohen's Kappa 0.22, showing fair agreement). For βhCG, 96.2 % of values agreed in serum and CSF (Cohen's Kappa 0.61). In some patients, intracranial GCTs can be diagnosed based solely upon positive serum AFP values. In addition, marker values from serum only may be sufficient to predict tumor relapse at interval follow-up examinations.

The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors

To determine the impact of diagnostic serum and/or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (b-HCG) elevations on survival in newly diagnosed patients with central nervous system germ cell tumors (CNS GCT) treated with chemotherapy with the intent to avoid irradiation. Seventy-five patients with newly diagnosed CNS GCT enrolled in two sequential internationally conducted clinical trials with serum and CSF AFP and b-HCG levels available from initial diagnosis were retrospectively analyzed. Subjects received platinum based chemotherapy and were followed with serial imaging and tumor marker evaluations. The 5-year overall survival (OS) and event free survival (EFS) for patients with normal tumor markers compared with those with elevated markers at diagnosis was 78% (95% CI 51-91%) versus 60% (95% CI 46-72%) (P = 0.08) and 22% (95% CI 7-43%) versus 28% (95% CI 16-40%) (P = 0.68). The hazard ratio of death for patients with elevated markers was 1.9 times as high as that for those with normal markers (95% CI 0.58-6.5) after adjusting for other baseline characteristics. There was no observed difference in survival among patients with histologically confirmed germinomas, irrespective of level of b-HCG. Patients with elevated tumor markers appear to have poorer OS independent of tumor histology, although these differences do not reach statistical significance (P < or = 0.05). No differences were observed in EFS between groups likely due to the poor response of chemotherapy only approach to patients with normal markers. b-HCG elevations in biopsy proven germinomas do not seem to alter a patient's prognosis.

Interpretation of alpha-fetoprotein concentrations in cerebrospinal fluid of infants

There are no published reference intervals for concentrations of alpha-fetoprotein (AFP) in the cerebrospinal fluid (CSF) of normal infants. The presence of abnormal concentrations of AFP in plasma or CSF may indicate the presence of a teratoma or a germ cell tumour with yolk sac elements. We measured CSF AFP in infants who did not have malignancy in order to determine its reference intervals. AFP was measured in the CSF and/or plasma in 128 infants. Of these, 91 infants had CSF AFP measurements, 94 infants had plasma AFP measurements and in 60 infants AFP concentrations were determined in paired CSF and plasma samples. The patients ranged in age from 1 to 110 days. Both CSF and plasma AFP concentrations were measured by a microparticle enzyme immunoassay using an AxSYM analyser. Using ages corrected for prematurity, the median CSF AFP concentration for babies -69 to 31 days old was 61 kIU/L (5th-95th centile: 2-889 kIU/L), while the median CSF AFP concentration for infants 32 to 110 days was 1.2 kIU/L (5th-95th centile: 0.1-12.5 kIU/L). By age 6 weeks, the concentrations were close to those found in adult plasma and all CSF AFP concentrations from infants with a corrected age over 2 months were <3 kIU/L. We have defined reference intervals for CSF AFP concentrations in infants. These results may assist in the diagnosis of CNS tumours, particularly congenital CNS tumours containing yolk sac elements.

Serum and cerebrospinal fluid human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) in intracranial germ cell tumors.

We report a retrospective study on serum and cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (betahCG) determination in a series of 30 patients bearing intracranial germ cell tumors. At diagnosis five patients had high serum and CSF AFP levels. No patient had positive serum AFP and negative CSF AFP or vice versa. Twelve of 30 patients had serum betahCG levels above 5 mlU/mL, eight had high betahCG only in CSF, and ten were completely negative. During treatment and follow-up both markers were accurate indicators of the response to therapy, decreasing rapidly and often becoming normal already after the first phase of treatment. We conclude that these two markers, and mostly betahCG, may be useful in the diagnosis and monitoring of the response to therapy of patients with intracranial germ cell tumors.

Central Nervous System Germ Cell Tumors.

Germ cells tumors most commonly affect children and adolescents, and occasionally arise in the central nervous system. Except for mature teratomas, they are all malignant. Pure germinomas are exquisitely sensitive to treatment and are highly curable with craniospinal radiation therapy. Surgery plays no role other than to establish the histologic diagnosis. Diagnostic confirmation includes normal levels of serum and cerebrospinal fluid alpha-fetoprotein and at most only minor elevations in beta human chorionic gonadotrophin (beta-hCG). Although it has become quite common to use chemotherapy to reduce the dose and field of radiation in the treatment of germinomas, longer follow-up in these patients is revealing a significant number of subarachnoid and ventricular recurrences. A recent follow-up study in patients treated for intracranial germinomas showed no significant difference in the psychosocial functioning of those treated with chemotherapy and radiation compared with those treated with chemotherapy alone, which raises further questions about the rationale for modifying a proven successful treatment. Malignant non-germinomatous germ cell tumors are much more resistant to treatment and difficult to cure. Surgical resection appears to have prognostic significance, although the predilection for midline structures makes complete resection difficult if not impossible at times. The best results have been obtained with platinum-based chemotherapy and full-dose craniospinal radiation therapy. Pure teratomas are not typically responsive to chemotherapy or radiation therapy and surgery is the only proven treatment modality.

Serum and cerebrospinal fluid human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) in intracranial germ cell tumors

We report a retrospective study on serum and cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (betahCG) determination in a series of 30 patients bearing intracranial germ cell tumors. At diagnosis five patients had high serum and CSF AFP levels. No patient had positive serum AFP and negative CSF AFP or vice versa. Twelve of 30 patients had serum betahCG levels above 5 mlU/mL, eight had high betahCG only in CSF, and ten were completely negative. During treatment and follow-up both markers were accurate indicators of the response to therapy, decreasing rapidly and often becoming normal already after the first phase of treatment. We conclude that these two markers, and mostly betahCG, may be useful in the diagnosis and monitoring of the response to therapy of patients with intracranial germ cell tumors.

Developmental profile of plasma proteins in human fetal cerebrospinal fluid and blood

Total protein, alphafetoprotein, albumin, prealbumin, alpha-1-antitrypsin, transferrin and ceruloplasmin levels were measured in samples of human fetal and neonatal cerebrospinal fluid (CSF) (97 cases), obtained between 12 and 41 weeks of gestation. In 39 of these cases (13 to 40 weeks gestation) plasma was also available for comparative analysis. CSF was collected from lateral ventricles in the first half of gestation and from the lumbar region in the second. Since these CSF samples were obtained from different sites, the protein levels in the lateral ventricle (early) samples could not be compared directly with those in the lumbar (later) samples. However, the mean protein levels in the lumbar samples were lower than those in the ventricular samples, which is in accord with the decline in CSF protein levels described in maturing animal fetuses. Despite a wide scatter of results, particularly in the first half of gestation, significant decline in the level of CSF alphafetoprotein was demonstrated during both first and second halves of gestation, and of albumin and prealbumin in the second half. No sex differences were found except for ceruloplasmin in lumbar CSF later in gestation, when males had higher levels than females. In fetal plasma, protein levels increased with increasing gestation apart from alphafetoprotein and prealbumin which both declined progressively. CSF/plasma ratios were dissimilar for different proteins, and changed with increasing gestation. These findings support the concept that the human fetal blood brain barrier matures early.

The value of surveillance testing in childhood brain tumors.

Follow-up procedures in children with brain tumors are designed to confirm tumor response to initial therapy, identify recurrence or progression at the time of potential secondary treatment, and establish the patterns of failure. Serial use of neurologic examinations and computerized tomography scans are outlined for all tumor types. Tumors capable of subarachnoid metastasis (medulloblastoma, ependymomas, pineal/suprasellar germ cell tumors, and pineoblastoma) require periodic assessment of the neuraxis by cerebrospinal fluid (CSF) cytology and myelography to establish the frequency of subclinical meningeal seeding in study settings. Serial analysis of specific biochemical markers for medulloblastoma (CSF polyamines) and germ cell tumors (serum and CSF alpha-fetoprotein and beta-human chorionic gonadotropin) are suggested. Serial evoked potentials in brain stem gliomas are recommended.

Elevated amniotic fluid alpha fetoprotein in fetal hydrocephaly

This report associates fetal hydrocephaly with high-for-dates alpha fetoprotein (AFP) values in amniotic fluid (AF) in 4 cases. All 4 hydrocephalic pregnancies showed abnormally high AF AFP concentrations (440 1800 7300 and 4750 vs. normal range of 15-340 ng/ml). Cerebrospinal fluid (CSF) was obtained from 3 fetuses. 2 contained a high AFP concentration (6400 and 148000 ng/ml); in both cases AF AFP was greatly elevated (7300 and 1800 ng/ml). In the 3rd case the moderately elevated AF AFP (440) was associated with a similar level (345 ng/ml) in fetal CSF. The total protein concentration was abnormally high in all CSF samples but no correlation existed between the total protein and AFP in either CSF or AF. AFP in maternal and fetal sera were within normal pregnancy range. The AFP level of newborn urine (23 ng/ml) was similar to previously measured normal infant urine values. The significance of high AFP on the prognosis of these infants cannot be indicated by these results because all infants died at or shortly after delivery. Prospective studies aimed at early antenatal detection of hydrocephaly by AF AFP are warranted.