Clinical significance and pitfalls of human chorionic gonadotropin-related tumor markers for intracranial germinomas.

PURPOSE: Measuring serum and cerebrospinal fluid human chorionic gonadotropin (hCG) is essential for the diagnosis of intracranial germ cell tumors. There are three types of hCG-related markers in clinical use: hCGß, intact hCG, and total hCG. The best marker for the diagnosis of intracranial germ cell tumors, especially germinoma, is currently unknown. This study aimed to evaluate the usefulness of these hCG-related markers. METHODS: We investigated 19 serum samples obtained from 6 patients with histologically diagnosed germinoma treated in our institute. Serum hCGß, intact hCG, and total hCG values were measured before, during, and after treatment. Samples with hCG values above the lower limits were considered positive. RESULTS: The positivity rates of serum hCGß, intact hCG, and total hCG were 6% (1/17), 47% (7/15), and 42% (8/19), respectively, with the latter two having significantly higher positivity rates than hCGß (p = 0.041). Both intact and total hCGs showed similar values. The median values of hCGß, intact hCG, and total hCG before treatment were 0.1 ng/mL, 4.6 mIU/mL, and 4.5 mIU/mL, respectively. CONCLUSION: Serum intact and total hCGs have higher detection rates than hCGß in patients with germinoma using available commercial measurement tools.

Human chorionic gonadotropin detection in cerebrospinal fluid of patients with a germinoma and its prognostic significance: assessment by using a highly sensitive enzyme immunoassay.

OBJECTIVE Human chorionic gonadotropin (HCG) can be detected in a certain population of patients with a germinoma, but the frequency of germinoma HCG secretion and the prognostic value of HCG in the CSF are unknown. METHODS The authors measured HCG levels in sera and CSF in patients with a histologically confirmed germinoma by using a highly sensitive assay known as an immune complex transfer enzyme immunoassay (EIA), which is more than 100 times as sensitive as the conventional method, and they analyzed the correlation between HCG levels and the prognoses of patients with a germinoma. RESULTS HCG levels in sera and CSF of 35 patients with a germinoma were examined with the immune complex transfer EIA. The median CSF HCG levels in patients with a germinoma during the pretreatment and posttreatment evaluations were 192.5 pg/ml (range 1.2-13,116.5 pg/ml) and 18.7 pg/ml (1.2-283.9 pg/ml), respectively. Before treatment, the CSF HCG level was greater than the cutoff value in 85.7% of the patients with a germinoma. The authors compared survival rates among the patients by using a CSF HCG cutoff level of 1000 pg/ml, and the difference was statistically significant between the groups (p = 0.029, log-rank test). CONCLUSIONS Results of this study demonstrate that most germinomas secrete HCG. Patients with a germinoma that secretes higher amounts of HCG in their CSF experienced recurrence more frequently than those with lower CSF HCG levels.

A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours.

BACKGROUND: The current biomarkers alpha-fetoprotein and human chorionic gonadotropin have limited sensitivity and specificity for diagnosing malignant germ-cell tumours (GCTs). MicroRNAs (miRNAs) from the miR-371-373 and miR-302/367 clusters are overexpressed in all malignant GCTs, and some of these miRNAs show elevated serum levels at diagnosis. Here, we developed a robust technical pipeline to quantify these miRNAs in the serum and cerebrospinal fluid (CSF). The pipeline was used in samples from a cohort of exclusively paediatric patients with gonadal and extragonadal malignant GCTs, compared with appropriate tumour and non-tumour control groups. METHODS: We developed a method for miRNA quantification that enabled sample adequacy assessment and reliable data normalisation. We performed qRT-PCR profiling for miR-371-373 and miR-302/367 cluster miRNAs in a total of 45 serum and CSF samples, obtained from 25 paediatric patients. RESULTS: The exogenous non-human spike-in cel-miR-39-3p and the endogenous housekeeper miR-30b-5p were optimal for obtaining robust serum and CSF qRT-PCR quantification. A four-serum miRNA panel (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p): (i) showed high sensitivity/specificity for diagnosing paediatric extracranial malignant GCT; (ii) allowed early detection of relapse of a testicular mixed malignant GCT; and (iii) distinguished intracranial malignant GCT from intracranial non-GCT tumours at diagnosis, using CSF and serum samples. CONCLUSIONS: The pipeline we have developed is robust, scalable and transferable. It potentially promises to improve clinical management of paediatric (and adult) malignant GCTs.

Human chorionic gonadotropin and α-fetoprotein in cerebral spinal fluid: method validation and retrospective review.

OBJECTIVE: Measurement of human chorionic gonadotropin (hCG) and α-fetoprotein (AFP) in cerebrospinal fluid (CSF) can aid in the diagnosis of germ cell tumors (GCTs). Matrix effects can influence test results when alternative sample types are used, therefore, alternative sample types should always be validated before clinical use. Here we have validated the Advia® Centaur total hCG and AFP methods for use with CSF. We also performed a retrospective review of 5years of CSF hCG and AFP measurements sent out from our institution. DESIGN AND METHODS: Both hCG and AFP concentrations were measured using the ADVIA Centaur® total hCG or AFP assay. RESULTS: The Centaur hCG and AFP assays, performed on CSF, had intra- and inter-assay imprecisions <10.2% CV. The assays were linear over a dynamic range of 10-1000IU/L for hCG and 10-1000µg/L for AFP. Retrospective chart review confirmed that GCTs have a male predominance and are diagnosed most frequently in the second decade of life. The data also illustrate the importance of measuring both serum and CSF concentrations as CSF can be elevated in the absence of serum elevations. CONCLUSIONS: The Centaur total hCG and AFP methods accurately quantify hCG and AFP in CSF.

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

PURPOSE: 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 (ßhCG) and alpha-fetoprotein (AFP) in serum and cerebrospinal fluid (CSF) samples at baseline and subsequent follow-up examinations. METHOD: 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. RESULTS: 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 ßhCG 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 ßhCG. 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 ßhCG, 96.2 % of values agreed in serum and CSF (Cohen's Kappa 0.61). CONCLUSIONS: 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.

Validation of the human chorionic gonadotropin immunoassay in cerebrospinal fluid for the diagnostic work-up of neurohypophyseal germinomas.

BACKGROUND: The measurement of human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) is useful for the differential diagnosis of suprasellar lesions. However, the concentrations that prove diagnostic for neurohypophyseal germinoma have not been well defined. In addition, the immunoassays used for such measurements are the same as those applied in serum, and few studies have been performed regarding the validation of such techniques in CSF. The present study aims to apply the Elecsys(®) hCG + ß immunoassay from Roche Diagnostics to measure hCG in CSF, as a useful tool in the diagnosis of neurohypophyseal germinomas in children and young adults. METHODS: Validation of the immunoassay involved calculation of the functional sensitivity and reference values for hCG in CSF in 35 controls in the absence of pregnancy, trophoblastic disease or tumour pathology. For the clinical application study, three patients diagnosed with neurohypophyseal germinoma have been reviewed. RESULTS: The functional sensitivity obtained was 0.4 IU/L. The reference values for hCG in CSF ranged from undetectable values to 0.7 IU/L. The hCG concentrations in CSF in the three studied patients, with confirmed diagnosis of neurohypophyseal germinoma, were 21.1, 32.6 and 23 IU/L, respectively. CONCLUSIONS: The Elecsys® hCG + ß immunoassay from Roche Diagnostics can be used to detect hCG in CSF with high precision. According to our results, CSF-hCG concentrations that exceed the established reference interval (undetectable values to 0.7 IU/L) in the presence of suprasellar lesions and hypophyseal stalk thickening must be considered pathological, establishing the need to exclude the presence of germinoma.

Intracranial germ cell tumors: efficacy of neoadjuvant chemo-radiotherapy without surgical biopsy.

In this report, we review 41 patients with intracranial germ cell tumors (GCTs) treated at the Department of Neurosurgery, Keio University School of Medicine, in the 25-year period between January 1982 and July 2006. The main aim of the present study was to compare the effectiveness of our current intracranial GCT management protocol, comprising neoadjuvant chemo-radiotherapy without surgical biopsy of tumors as far as possible, to that of historical controls. In all patients, charts were reviewed and tumor and patient characteristics, including age, sex, type of tumor marker secreted, treatment protocol, and clinical outcomes, were compared. The relationship between these variables was analyzed by means of the Cox proportional hazards model. Thus far, four patients treated by approaches other than the current protocol have died of their tumor. The overall 5-, 10-, and 15-year survival rates of all the patients calculated by the Kaplan-Meier method were 91.9%, 88.6%, and 88.6%, respectively. According to the results of the Cox proportional hazards model, patients with secreting GCTs show statistically poorer prognoses than those with non-secreting GCTs (P = 0.0073), and although not statistically significant, patients treated with our current protocol tend to show better prognoses than historical controls (P = 0.0543). All five patients with secreting GCT treated using our current protocol are still alive after an average follow-up period exceeding 7 years, and only one of these has shown tumor recurrence. With our current treatment protocol comprising neoadjuvant chemo-radiotherapy without surgical biopsy, prognoses of patients with GCTs have improved compared to historical controls at our institution.

CSF and serum hCG in patients without gestational and neoplastic hCG-secretion.

BACKGROUND: The measurement of human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) is important for the diagnosis of intracranial or intraspinal trophoblastic tumours. The current study was performed to establish reference values for hCG in CSF and to explore the relationship of CSF hCG and serum hCG in patients who are not pregnant or do not have trophoblastic tumours. MATERIAL AND METHODS: CSF samples were obtained from 369 inpatients admitted because of various neurological diseases, excluding pregnancy, trophoblastic tumours and other malignant tumours. In 271 of the 369 patients, paired samples of CSF and serum were obtained. Both CSF hCG and serum hCG were measured. The 97.5th percentile and maximum value of CSF hCG were obtained. The CSF hCG and serum hCG concentrations in each of the 271 paired samples were compared. RESULTS: The 97.5th percentile and maximum value of CSF hCG concentration for overall participants were 1.00 and 5.00 IU/L, respectively. The CSF hCG concentration was found to be higher than the simultaneous serum hCG concentration in 81.9% (222/271) of the participants. CONCLUSIONS: The reference value determined in this study of CSF hCG in men is significantly lower than that usually used in clinical practice. A CSF hCG concentration higher than the simultaneous serum hCG concentration but lower than the upper reference limit does not necessarily suggest abnormal intrathecal hCG-secretion.

Re-evaluation of the significance of cerebrospinal fluid human chorionic gonadotropin in detecting intracranial ectopic germinomas.

This study was conducted to establish a reference value for cerebrospinal fluid (CSF) human chorionic gonadotropin (hCG) levels. We also evaluated the sensitivity of CSF hCG as a biomarker to detect intracranial ectopic germinomas that arise in rare sites other than the pineal and suprasellar regions. CSF hCG was measured in 201 male patients who had various types of neurological disease (not tumours of germ cell origin or other malignant tumours). A reference value of 1.009 U/L was established, and the CSF hCG level among different age groups was not significantly different. CSF and serum hCG were measured before and after radiotherapy in 14 consecutive patients with intracranial ectopic germinomas. The CSF hCG levels were all above 1.009 U/L before radiotherapy. In male patients, a CSF hCG value above 1.009 U/L suggests abnormal intrathecal hCG secretion. These results demonstrate that the CSF hCG assay is a sensitive method for diagnosing intracranial ectopic germinoma.

[The role of human chorionic gonadotropin in cerebrospinal fluid in the diagnosis and treatment of intracranial germinoma].

OBJECTIVE: To study the cerebrospinal fluid (CSF) and serum level of human chorionic gonadotropin (HCG) in patients with intracranial germinoma and to evaluate its diagnostic and therapeutic value. METHODS: Thirty-one patients with intracranial germinoma receiving estimation of HCG in CSF and serum in our hospital were retrospectively analyzed in terms of HCG level, its influencing factors and the relationship of HCG with clinical features. RESULTS: HCG levels in CSF of the 31 cases ranged from 0.17 IU/L to 5316.98 IU/L with a median value of 3.44 IU/L. The sensitivity of diagnosis increased from 80.6% to 90.3%, when the cut point of HCG in CSF changed from 0.60 IU/L to 0.50 IU/L. The sensitivity increased from 83.9% to 93.5% when the cut point of the ratio of CSF/serum HCG decreased from 1.8 to 1.7. HCG level of germinoma located in pineal region was higher than that in basal ganglia region, while it is lowest in sellar region. The ratio of CSF/serum HCG in different parts showed no difference. Multiple risk factors analysis revealed that serum HCG (r = 0.886, P = 0.0001) and tumor size (r = 0.748, P = 0.0211) were positively correlated with the HCG level in CSF, while course of the disease, age and gender were not correlated. After radiation therapy, HCG in CSF and serum decreased dramatically as compared with those before radiation. CONCLUSIONS: The HCG level and its dynamic change were sensitive marker of intracranial germinomas. Based on our analysis, HCG in CSF over 0.50 IU/L and the its ratio in CSF/serum over 1.7 were highly indicative of the possibility of intracranial germinomas.

Germinoma with syncytiotrophoblastic giant cells arising in the corpus callosum.

A previously healthy 31-year-old Japanese man presented with a very rare germinoma of the corpus callosum without other intracranial lesions manifesting as transitory speech disturbance. Magnetic resonance (MR) imaging revealed a heterogeneously enhanced mass in the corpus callosum extending into the cavity of the septum pellucidum. A tumor specimen obtained by stereotactic biopsy revealed a two-cell pattern germinoma containing human chorionic gonadotropin (HCG)-beta-positive giant cells. The cerebrospinal fluid and serum levels of HCG and HCG-beta subunit were measurable. The diagnosis was germinoma with syncytiotrophoblastic giant cells. Three cycles of chemotherapy consisting of ifosfamide, cisplatin, and etoposide, followed by radiation therapy achieved complete remission, and 5 cycles of chemotherapy with carboplatin and etoposide were added. MR imaging performed 40 months after the diagnosis showed a cicatricial cyst in the body of the corpus callosum, the original tumor site. All 11 previously reported cases of germinoma in the corpus callosum were associated with synchronous or metachronous intracranial lesions. These patients tended to be older than patients with general intracranial germinoma. Germinoma should be included in the differential diagnosis of corpus callosum tumors, especially in young adult males.

Open labeled, uncontrolled pharmacokinetic study of a single intramuscular hCG dose in healthy male volunteers.

The current study was designed to compare blood and cerebrospinal fluid (CSF) pharmacokinetic characteristics of two forms of human chorionic gonadotropin (hCG): Pregnyl(R), derived from human urine, and Ovitrelle(R) a recombinant form. Two separate groups, each with six older male human subjects, were dosed with either form of the drug at 10,000 IU intramuscularly (IM), and followed over a 36-hour period. No significant difference in the serum level of hCG was observed for either preparation of hCG (Peak serum conc.: 316 +/- 53 vs. 270 +/- 60 at 12 hours, 311 +/- 38 vs. 321 +/- 60 IU/l at 24 hours; AUC: 10,053 +/- 1,268 vs. 8,793 +/- 1,768, Pregnyl and Ovitrelle, mean +/- SD, respectively). Additionally, both forms of circulating hCG distributed to the central nervous system (CNS) as manifest by an increased number of subjects whose CSF samples showed detectable levels of hCG in their CSF over a 36-hour period. Similarly, there was no significant difference between the two forms when distribution to the CSF was compared at 36 hours (2.0 and 1.2 IU/l; range 1.9 - 2.1 and 1 - 1.4 IU/l for Pregnyl and Ovitrelle, resp.). This preliminary study in normal human volunteers suggests that the two forms of hCG tested, Ovitrelle(R) and Pregnyl(R), when administered IM, distribute in a similar fashion into the circulation and CSF. Consequently, we conclude that these two drugs demonstrate no statistical significant difference with respect to the CSF.

Is biopsy needed to guide management for all patients with presumed intracranial ectopic germinomas.

Intracranial germinomas may arise in sites besides pineal and suprasellar regions, which we call intracranial ectopic germinomas (IEGs). In this article we evaluated the rationality of radiotherapy in IEGs when histopathological evidence could not be obtained. Criteria for initiating experimental radiotherapy in patients with clinically presumed IEGs was established according to the reports published in this field and the experience gained from our five histopathologically verified IEG patients. When patients suspected to have IEGs met the criteria, radiotherapy following standard protocol was performed. Strict criteria was also employed to evaluate the effectiveness of radiotherapy after completion of initial experimental dose of radiation and to determine whether total dose of radiation should be delivered. Seven patients clinically suspected to have IEGs met the criteria for radiotherapy. Radiotherapy was evaluated as effective in six patients immediately after completion of initial experimental dose of radiation and the remaining dose was delivered. However, effectiveness of initial experimental radiotherapy was not testified until 2 months later in the other one patient. Total dose of radiation was completed and satisfactory results achieved in all seven patients. In conclusion, the histopathological verification is not mandatory for radiotherapy in patients with IEGs when histopathological evidence can not be obtained. Strict criteria should be followed to enroll patients to undergo experimental radiotherapy.

Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the Children's Oncology Group.

BACKGROUND: This Phase II study was designed to determine response to chemotherapy and survival after response-based radiation (RT) in children with CNS germ cell tumors. PROCEDURE: Children with germinomas and normal markers received cisplatin 100 mg/m(2) + etoposide, alternating with vincristine + cyclophosphamide (CPM) 2 g/m(2)/d, for four cycles. Children with nongerminomatous tumors or with abnormal markers received doubled doses of cisplatin and CPM. For germinoma patients in complete response (CR), RT was decreased from 50.4 to 30.6 Gy. High-risk patients received neuraxis RT: 50.4 Gy local + 30.6 Gy neuraxis in CR; 54 Gy local + 36 Gy if less than CR. RESULTS: Of 12 germinoma patients, 4 had cerebrospinal fluid (CSF) human chorionic gonadotropin (HCG) 6.9-21 mIU/ml. Of 14 nongerminomatous patients, HCG in serum or CSF was >50 mIU/ml in 9, alpha-fetoprotein (AFP) abnormal in 9. Four germinoma patients attained CR, six PR, one SD, one not evaluable after resection. Two nongerminomatous patients had CR, three PR, three SD, one PD, four not evaluable after resection; one inadequately treated patient had progressive disease (PD). Both PD patients died; one SD patient died during a seizure. Eleven germinoma patients are PF at median 66 months; one patient in CR refused RT, had PD at 10 months, received RT, and was PF at 56 months. Eleven of 14 nongerminomatous patients were PF at median 58 months. CONCLUSION: Response (germinoma, 91%; nongerminomatous, 55%) and survival are encouraging after this regimen plus response-based RT.

[Precocious puberty caused by hCG-producing germinoma involving the bilateral basal ganglia and cerebral white matter without 1ypical radiologic findings: case report].

An 8-year-old boy presented with a rare case of germinoma involving the bilateral basal ganglia and cerebral white matter manifesting as precocious puberty. Magnetic resonance (MR) imaging at the initial presentation demonstrated mild hyperintense areas in the bilateral basal ganglia and corpus callosum on T1-weighted images, and a small hyperintense spot in the right internal capsule on T2-weighted images. Human chorionic gonadotropin (hCG) level was elevated in the cerebrospinal fluid (CSF), so we strongly suspected that threre was a hCG-producing germinoma originating in the bilateral basal ganglia. Stereotactic biopsy was performed. Histological examination revealed two-cell pattern germinoma. After three cycles of combination chemotherapy consisting of ifosfamide, cisplatin, and etoposide, followed by whole brain irradiation with a total dose of 24 Gy, the CSF hCG level fell below the detection limit, but MR imaging demonstrated no significant change. Intracranial hCG-producing germinoma should be suspected in patients presenting with precocious puberty and elevated CSF hCG level. Moreover, slight intensity change on MR imaging is important to identify germinoma arising from the basal ganglia in the early stage.

[Cerebral metastasis in choriocarcinoma a case report]. / Zerebrale Metastasen beim Chorionkarzinom: ein Fallbericht.

Choriocarcinoma are malignant neoplastic tumors from the trophoblastic tissue with a tendency to early metastases. Beside pulmonary metastases there are often cerebral metastases, leading to intracerebral hemorrhage often responsible for the first clinical symptoms. In young women, symptoms like vaginal or pulmonary bleeding or neurologic disturbances shortly after a hydatiform mole or a normal pregnancy, accompanied by high levels of HCG in serum and CSF, choriocarcinoma should be considered. Choriocarcinoma are very sensitive to chemotherapy, which consists--depending on the stage of the disease--of a mono- or polychemotherapy. Cure rates are high, even in extended stages with cerebral metastases--as in the case described. Brain metastases with or without oncotic aneurysms can be rapidly controlled by immediate whole brain irradiation. Surgical interventions may be necessary in the case of life threatening bleedings. Levels of HCG in serum and cerebrospinal fluid are good markers to control the effect of therapy. But--as shown in this patient--levels of HCG in CSF may decrease protracted without affecting prognosis. Oncotic aneurysms are rarely reported and mostly detected post mortem. The presented case leads to a more optimistic attitude and demonstrates efficacy of immediately started radio- and chemotherapy.