Diagnostic Capability of Cerebrospinal Fluid-Placental Alkaline Phosphatase Value in Intracranial Germ Cell Tumor.

OBJECTIVE: Most types of intracranial germ cell tumors (IGCTs) are sensitive to chemoradiation. However, biopsy specimens are usually small and thus cannot be used for obtaining an accurate pathological diagnosis. Recently, the cerebrospinal fluid (CSF) placental alkaline phosphatase (PLAP) value has been considered a new biomarker of IGCTs. The present study aimed to evaluate the discriminatory characteristics of the CSF-PLAP value upon diagnosis and at the time of recurrence in patients with IGCTs. METHODS: Between 2015 and 2019, this study included 37 patients with tumors located in the intraventricular and/or periventricular region. The CSF-PLAP level was assessed before the patients received any treatment. The PLAP level was evaluated during and after first-line chemoradiotherapy in 7 patients with IGCTs. The CSF-PLAP values were compared according to histological diagnosis, and the correlation between these values and radiographical features was assessed. The CSF-PLAP values of 6 patients with IGCTs with suspected recurrence were evaluated based on neuroimaging findings. RESULTS: The CSF-PLAP values were significantly higher in patients with IGCTs than in those with other types of brain tumor (n = 19 vs. 18; median: 359.0 vs. <8.0 pg/mL). The specificity and sensitivity were 88 and 95%, respectively, with a cutoff value of 8.0 pg/mL. In patients with IGCT, the CSF-PLAP value was higher in patients with germinoma than in those with nongerminomatous germ cell tumors (n = 12 vs. 7; median: 415.0 vs. 359.0 pg/mL). Regarding the time course, the CSF-PLAP value decreased to below the detection limit after the reception of first-line chemoradiotherapy in all 7 patients. A significant correlation was observed between the initial CSF-PLAP value and the tumor reduction volume after receiving first-line chemoradiotherapy (p < 0.0003, R2 = 0.6165, logY = 1.202logX - 1.727). Among the patients with suspected IGCT recurrence (n = 6), the CSF-PLAP value was high in patients with recurrence (n = 3; median: 259.0 pg/mL), and that in patients (n = 3) without recurrence was below the lower detection limit. CONCLUSIONS: The CSF-PLAP level is a useful biomarker during the initial diagnosis of IGCTs and at the time of recurrence. It may be associated with the volume of germinomatous components of tumors.

Intracranial germinoma causing cerebral haemiatrophy and hypopituitarism.

A young woman presented with primary amenorrhoea, progressive haemiparesis, visual disturbance, dementia and focal motor seizures. Investigations showed hypopituitarism, unilateral cerebral atrophy and inflamed cerebrospinal fluid. A trans-sphenoidal biopsy gave a unifying diagnosis of a pituitary germinoma.

Perifocal Inflammatory Reaction with Volume Fluctuation Caused by Diagnostic Radiation-Induced Regression in Germinoma Makes Histological Diagnosis Difficult despite Its Disappearance following Treatment: A Significant Pitfall and Countermeasures to It.

We present a pediatric case of neurohypophyseal germinoma with a perifocal inflammatory reaction (PIR) with volume fluctuation caused by diagnostic radiation-induced regression (DRIR). On-target biopsy failed to confirm the histology because PIR hardly contained any germinoma cells. DRIR-related fluctuation of the tumor volume disguised germinoma as inflammation. We analyzed the cerebrospinal fluid (CSF) and detected a high level of placental alkaline phosphatase (PLAP), which demonstrated the neurohypophyseal lesion to be germinoma and brought the patient from successful radiochemotherapy up to complete remission. PIR adjacent to the germinoma (PIRAG) disappeared completely following radiochemotherapy, although it contained almost no germinoma cells. Examination of the CSF-PLAP level can complement the diagnosis of germinoma and will decrease the risk of misdiagnosis. Neurosurgeons should keep in mind PIRAG, DRIR, and the diagnostic value of CSF-PLAP when germinoma is suspected.

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.

Potential role of ventricular tumor markers in CNS germ cell tumors.

BACKGROUND: There is increasing reliance on oncoprotein assays such as the ß-subunit of human chorionic gonadotropin (ß-hCG) and alpha-fetoprotein (AFP) for diagnosis or confirmation of histology of central nervous system (CNS) germ cell tumors (GCT), but the relative diagnostic sensitivity and reliability of assays from serum (S), lumbar (L), and ventricular (V) cerebrospinal fluid (CSF) are uncertain. PROCEDURE: A total of 86 patients with CNS GCT were identified from our database. Fourteen patients had contemporaneous ß-hCG and/or AFP measurements from serum, ventricular, and lumbar CSF at diagnosis (n = 13) or relapse (n = 1), constituting the subjects for this report. Their primary tumor sites were: pineal (n = 8), suprasellar (n = 1), or both (n = 5). Their mean age at diagnosis was 16.0 years (range 9.1-25.9). The male:female sex ratio was 13:1. RESULTS: For the germinoma-treated patients (n = 8), the median (range) ß-hCG values (S, V, L) were 0 (0-6.9), 7.0 (0-57.4), 8.3 (0-34.0) mIU/ml. For patients managed as mixed malignant GCT (MMGCT) (n = 6), the median (range) ß-hCG values (S, V, L) were 3.9 (0-58.0), 3.6 (0-147.0), 61.8 (0-358.0) mIU/ml. The median (range) AFP values were 7.5 (0-27,400.0), 2.0 (0-2,981.0), 3.0 (0-14,015.0) ng/ml. Lumbar CSF ß-hCG values were equal or greater than those in ventricular CSF or serum in 12 of 13 cases (92.3%). All patients with MMGCT had lumbar AFP equal or greater than the ventricular CSF values, while serum AFP values remained highest. CONCLUSIONS: Ventricular CSF values cannot be considered a replacement for lumbar CSF. Lumbar CSF is the most reliable source of tumor markers to establish baseline and follow-up diagnostic endpoints.

A multimodal approach including craniospinal irradiation improves the treatment outcome of high-risk intracranial nongerminomatous germ cell tumors.

PURPOSE: To evaluate whether a multimodal approach including craniospinal irradiation (CSI) improves treatment outcome in nongerminomatous germ cell tumor (NGGCT) patients. METHODS AND MATERIALS: We reviewed the records of 32 patients with NGGCTs. Fourteen patients belonged to the intermediate prognosis group (immature teratoma, teratoma with malignant transformation, and mixed tumors mainly composed of germinoma or teratoma), and 18 patients belonged to the poor prognosis group (other highly malignant tumors). Patients with pure germinoma or mature teratoma were excluded from this study. Nineteen patients were treated with a combination of surgery, chemotherapy, and radiotherapy (RT); 9 patients received chemotherapy plus RT; 3 patients received surgery plus RT; and 1 patient received RT alone. Twenty-seven patients received CSI with a median of 36 Gy (range, 20-41 Gy) plus focal boost of 18-30.6 Gy, and 5 patients received whole-brain RT (WBRT) (20-36 Gy) or focal RT (50.4-54 Gy). The rate of total and subtotal resection was 71.9%. The median follow-up for surviving patients was 121 months. RESULTS: Treatment failed in 7 patients. Three of the 5 patients who received focal RT or WBRT had local failure. Four cerebrospinal fluid (CSF) failures occurred after CSI. No failure occurred in the intermediate prognosis group. Ten-year recurrence-free survival (RFS) and overall survival (OS) for all patients were 77.6% and 74.6%, respectively. Ten-year RFS for the intermediate and poor prognosis groups were 100% and 61.1%, respectively (p = 0.012). OS for the two groups were 85.1% and 66.7%, respectively (p = 0.215). Tumor histology and CSI were significant prognostic factors for RFS, and CSI was significantly associated with OS. CONCLUSIONS: A multimodal approach was effective for treating NGGCTs. CSI should be considered for patients with poor prognostic histology.

Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma.

BACKGROUND: Marked elevations of AFP and bHCG in serum or CSF may serve as surrogate diagnostic markers in lieu of histology for primary CNS mixed, malignant germ cell tumors. There is less information on the diagnostic sensitivity of bHCG assays in germinoma. PROCEDURE: We report baseline serum and lumbar CSF bHCG values in 58 newly diagnosed, histologically confirmed germinoma patients gathered from two prospective clinical trials which required that patients have a normal AFP and bHCG ≤50 mIU/ml in serum and lumbar CSF. RESULTS: The location of the primary tumors was: suprasellar(23); pineal(20); suprasellar/pineal(9); and other sites(6). The mean age of the study population was 13.5 (4.3-25.9) years. A total of 23(40%) patients had elevations of bHCG in either serum or CSF, 20(34.5%) of whom had only bHCG elevations in CSF. The patients' bHCG profiles were divided into four categories: I (normal serum and lumbar CSF bHCG), 35(60%); II (normal serum and elevated CSF bHCG), 20(34.5%); III (elevated serum and CSF bHCG), 2(3.5%); and IV (elevated serum and normal CSF bHCG), 1(2%). The median CSF bHCG level was 7.7(2.5-16) in the 22 patients with abnormal CSF values and the lumbar value was higher than the serum value in 20 of 23(87%) patients with bHCG elevations. CONCLUSIONS: Lumbar CSF was a more informative screen for bHCG than serum but the majority of patients (60%) had normal bHCG values at diagnosis. Until a more sensitive tumor marker for germinoma is devised, histologic confirmation remains the standard of care. Pediatr Blood Cancer 2012; 59: 1180-1182. © 2012 Wiley Periodicals, Inc.

Bifocal intracranial germinoma: a retrospective analysis of treatment outcomes in 20 patients and review of the literature.

PURPOSE: Bifocal germinoma (BFG) is a rare intracranial neoplasm for which the choice of radiation therapy (RT) field is controversial. Some believe that BFG represents disseminated disease requiring craniospinal irradiation (CSI), whereas others believe that BFG represents localized disease and advocate for more limited fields. METHODS AND MATERIALS: We analyzed 20 BFG patients at our institutions with classic bifocal lesions (pineal gland and suprasellar region). In addition, we identified 60 BFG patients from the literature. The RT fields, use of chemotherapy and extent of disease were recorded and analyzed for each patient. RESULTS: There were 55 patients with bifocal lesions only (Group I), and 25 with bifocal lesions plus ventricular and/or CSF positive disease (Group II). The 5-year progression-free survival was 95% for Group I and 80% for Group II. In Group I, there were no failures in patients receiving CSI (n = 11), two spinal failures in those treated with more limited RT fields without chemotherapy (n = 17), and one spinal failure with chemotherapy (n = 23). In Group II, there were no failures in patients receiving CSI (n = 11), but four spinal failures were observed in patients receiving more limited RT fields with chemotherapy (n = 13); 1 patient who received whole-brain RT without chemotherapy experienced failure in the spine and brain. CONCLUSIONS: CSI is associated with excellent PFS in BFG. In Group I BFG patients, omission of spinal irradiation appears to be a reasonable approach, especially when chemotherapy is used. Patients with Group II BFG are best treated with CSI.

A highly sensitive and specific chemiluminescent enzyme immunoassay for placental alkaline phosphatase in the cerebrospinal fluid of patients with intracranial germinomas.

BACKGROUND: Placental alkaline phosphatase (PLAP) in cerebrospinal fluid (CSF) has been proposed as a tumor marker for intracranial germinomas. The purpose of the present study was to develop a sensitive assay for measuring CSF PLAP and to evaluate the clinical significance of PLAP in patients with germinomas. METHODS: A chemiluminescent enzyme assay for PLAP was developed using an anti-human-PLAP monoclonal antibody. PLAP concentrations were determined in 37 controls, 36 germinomas, 3 nongerminomatous germ cell tumors, 21 gliomas and 12 other brain tumors. RESULTS: The assay detection limit was 5 pg/ml. The median PLAP concentration in the control group was below the detection limit. Significantly higher PLAP levels were detected in all 36 germinoma patients, with values ranging from 16 to 3,700 pg/ml. The high PLAP concentrations of 17 germinoma patients decreased to below the detection limit after complete remission had been achieved with radiochemotherapy. The sensitivity and specificity of PLAP for germinomas were 94 and 97%, respectively, with a cutoff value of 30 pg/ml. CONCLUSIONS: The results of this study suggest that the determination of CSF PLAP by the chemiluminescent method described here provides a clinically useful tumor marker for the diagnosis and monitoring of intracranial germinomas.

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.

Late spinal metastases from an isolated pineal region germinoma mimicking a schwannoma.

A 20-year-old male with a prior history of germinoma presented 8 years after the initial diagnosis with progressive lower back pain. The preoperative diagnosis was schwannoma based on the appearances of a tumor in the lumbosacral region on MRI; however, histologically, a germinoma "drop" metastasis was seen. This report emphasizes the need for long-term follow-up in patients with germinoma. In addition, this patient is unusual in that the preoperative assessment favored schwannoma.

Value of brain magnetic resonance imaging and tumor markers in the diagnosis and treatment of intracranial germinoma in children.

OBJECTIVE: To evaluate the role of brain magnetic resonance imaging (MRI) and tumor markers in the cerebral spinal fluid (CSF) and serum in the diagnosis and treatment of intracranial germinoma in children. METHODS: Totally 5 children (3 girls and 2 boys) who were treated in our hospital between January 2009 and December 2010 due to central diabetes insipidus. All patients received contrast-enhanced brain MRI at presentation and during each follow-up: meanwhile, their anterior pituitary hormones and tumor markers including human chorionic gonadotropin (hCG) and alpha fetoprotein (AFP) were also determined. RESULTS: Three patients presented without prior evaluation, and two patients were referred to our hospital due to exaggerated disease of unknown cause. Their ages at presentation ranged from 8 years to 12 years 1 month, and the duration of symptoms at presentation was between 1 month to 78 months. All of them had polyuria and polydipsia at presentation. Except one child, the other 4 patients had growth retardation and failure in initiation of puberty. Although the growth rate and puberty development were normal during the 2-year follow-up for the excepted child, all child experienced anterior pituitary hypofunction and an increased concentration of plasma prolactin after the lesion became enlarged. Three patients had cerebral hernia, which presented in 18, 24, and 78 months, respectively. In three patients, brain MRI at presentation showed isolated pituitary stalk thickening, which further developed into massive tumor in the hypothalamus pituitary region 18-22 months later; in the remaining two patients, large brain tumor was found via MRI at their first presentations. In all five patients, the posterior pituitary gland (bright spot) disappeared on T1-weighted MRI images. CSF hCG elevated in all five patients, and serum hCG increased in four patients; the level of hCG varied with the mass size of tumor. Serum and CSF AFP increased in only one patient. CONCLUSIONS: Patients with idiopathic central diabetes insipidus must be closely followed to identify the etiology, especially when anterior pituitary hormone deficiencies are detected. For patients with normal brain MRI results or simply isolated pituitary stalk thickening at presentation, the changes of serial contrast-enhanced brain MRI should be observed during follow-up to ensure the early detection of an evolving occult hypothalamic-stalk lesion. Determination of CSF hCG at the first presentation may be useful, because an increased CSF level of hCG precedes MRI abnormalities.

Recurrent pure CNS germinoma with markedly elevated serum and cerebrospinal fluid human chorionic gonadotropin-beta (HCGß).

Controversy continues regarding what level of serum and/or cerebrospinal fluid (CSF) human chorionic gonadotrophin-beta (HCGß) is consistent with pure germinoma of the central nervous system (CNS). We report a 10-year female with biopsy-proven pure germinoma and normal serum and CSF HCGß who experienced subsequent biopsy-proven recurrences of germinoma. At recurrence, serum and CSF HCGß levels were 560 and 3,202 mIU/ml, respectively, although final autopsy demonstrated pure germinoma. This case illustrates the need to re-evaluate the assumption that pathologically pure germinomas may be associated with high levels of HCGß which are unrelated to nongerminomatous germ cell tumor (NGGCT)/choriocarcinomatous elements.

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.

Metachronous mediastinal seminoma occurring after intracranial germinoma in an adolescent.

We report a case of a mediastinal seminoma occurring 19 months after the resolution of a pineal germinoma. A 15-year-old boy with headaches and visual changes was diagnosed with a pineal germinoma by biopsy and mildly elevated beta-human chorionic gonadatropin (beta-HCG) in serum and cerebral spinal fluid. Radiation therapy leads to the resolution of his pineal germinoma and normalization of the beta-HCG. A mediastinal seminoma (germinoma) was diagnosed nearly 2 years later because of rising serum beta-HCG. There was no evidence of recurrent central nervous system disease. The patient underwent systemic chemotherapy with the complete resolution of the mediastinal seminoma.