Precise detection of the germinomatous component of intracranial germ cell tumors of the basal ganglia and thalamus using placental alkaline phosphatase in cerebrospinal fluid.

PURPOSE: The disadvantages of biopsy for lesions in the basal ganglia and thalamus include a risk of various complications, difficulty in selecting the target tissue in some cases due to indistinct neuroimaging findings and limited availability of sample tissue. Placental alkaline phosphatase (PLAP) plays a decisive role in the diagnosis and management of intracranial germ cell tumors (IGCTs) in the basal ganglia and thalamus. The present study aimed to demonstrate the ability, specificity, and optimal use of PLAP values obtained from cerebrospinal fluid (CSF). METHODS: Twenty patients with lesions in the basal ganglia and thalamus were enrolled in this study: 11 had IGCTs and 9 had non-IGCTs. The values of PLAP and other established tumor markers in the CSF were measured in all patients before treatment. RESULTS: The mean follow-up period was 76.0 months (range, 3-168) for all lesions. PLAP was elevated in all 11 patients with IGCTs in the basal ganglia or thalamus, whereas none of the patients with non-IGCT exhibited elevated PLAP. Thus, the sensitivity and specificity of PLAP were both 100%. CONCLUSION: Our data demonstrated that the PLAP value can specifically identify the germinomatous component even in cases of IGCTs in the basal ganglia or thalamus with high sensitivity and specificity. PLAP is undoubtedly beneficial for the safe and timely detection of the germinomatous component of IGCTs in the basal ganglia and thalamus, because reliance on PLAP measurement enables us to avoid invasive surgical procedures and facilitates the prompt initiation of chemoradiation therapy.

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.

Cerebrospinal fluid ctDNA and metabolites are informative biomarkers for the evaluation of CNS germ cell tumors.

Serum and cerebrospinal fluid (CSF) levels of α-fetoprotein and ß-subunit of human chorionic gonadotropin are used as biomarkers for the management of central nervous system (CNS) germ cell tumors (GCTs). However, additional discriminating biomarkers are required. Especially, biomarkers to differentiate non-germinomatous germ cell tumors (NGGCTs) from germinomas are critical, as these have a distinct prognosis. We investigated CSF samples from 12 patients with CNS-GCT patients (8 germinomas and 4 NGGCTs). We analyzed circulating tumor DNA (ctDNA) in CSF to detect mutated genes. We also used liquid chromatography-mass spectrometry to characterize metabolites in CSF. We detected KIT and/or NRAS mutation, known as frequently mutated genes in GCTs, in 3/12 (25%) patients. We also found significant differences in the abundance of 15 metabolites between control and GCT, with unsupervised hierarchical clustering analysis. Metabolites related to the TCA cycle were increased in GCTs. Urea, ornithine, and short-chain acylcarnitines were decreased in GCTs. Moreover, we also detected several metabolites (e.g., betaine, guanidine acetic acid, and 2-aminoheptanoic acid) that displayed significant differences in abundance in patients with germinomas and NGGCTs. Our results suggest that ctDNA and metabolites in CSF can serve as novel biomarkers for CNS-GCTs and can be useful to differentiate germinomas from NGGCTs.

Targeted radioimmunotherapy for embryonal tumor with multilayered rosettes.

PURPOSE: We explored the use of intraventricular 131I-Omburtamab targeting B7-H3 in patients with ETMR. METHODS: Patients were enrolled in an IRB approved, phase 1, 3 + 3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3 were eligible. We report on a cohort of three patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi 131I-Omburtamab as a tracer followed by one or two therapeutic 131I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after 131I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 months after therapy (2 years after diagnosis). CONCLUSIONS: 131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.

Optimal radiotherapy target volumes in intracranial nongerminomatous germ cell tumors: Long-term institutional experience with chemotherapy, surgery, and dose- and field-adapted radiotherapy.

PURPOSE: To evaluate patterns of failure after multimodality treatment of nongerminomatous germ cell tumors (NGGCTs). MATERIALS AND METHODS: We retrospectively reviewed records of 34 patients diagnosed with primary intracranial NGGCT between 1988 and 2014. RESULTS: Thirty-four patients received induction chemotherapy followed by radiation with or without surgery. Median follow-up was 11.1 years (0.8-23.3). Outcomes were significantly improved in these 34 patients (5-year overall survival [OS]: 88% versus 50%, P = 0.0092), so analysis is restricted to that subset. Disease-free survival (DFS) was 67, 60, and 54% at 5, 10, and 15 years, respectively. Elevated cerebrospinal fluid-α-fetoprotein (CSF-AFP) at diagnosis was associated with poorer DFS (37 vs. 89% at 10 years; P = 0.01). There was no statistically significant difference in OS, or DFS, or patterns of failure for limited radiotherapy volumes versus larger volumes; however, patients receiving initial local radiotherapy had 32% distant central nervous system (CNS) recurrence at 10 years compared to 0% for those receiving initial larger field irradiation (P = 0.09). Fifteen patients recurred. All four patients who relapsed in the spine had received local radiotherapy and had elevated serum and CSF-AFP at baseline. All three patients with ventricular relapse received local radiation therapy. CONCLUSIONS: NGGCT patients continue to relapse beyond 5 years. Late ventricular relapse occurred even in patients without clear evidence of germinoma component. Elevated CSF-AFP at diagnosis is associated with poor DFS and risk for distant CNS relapse. Patients with residual radiographic disease after chemotherapy or residual malignant histologies after second-look surgery have inferior outcomes. Our data support consideration of treatment intensification for these patients.

An update on the clinical diagnostic value of ß-hCG and αFP for intracranial germ cell tumors.

BACKGROUND: Pathological examination combined with tumor markers has become a standard for the diagnosis of intracranial germ cell tumors (ICGCTs), but the current concept of 'secreting germ cell tumors' and three empirically highly specific diagnostic criteria (ß-hCG ≥ 50 IU/L or αFP ≥ 10 ng/mL; ß-hCG ≥ 100 IU/L or αFP ≥ 50 ng/mL; ß-hCG > 50 IU/L or αFP > 25 ng/mL) are not based upon pathology examination or CSF cytology. Further investigation is needed to re-evaluate their value. METHODS: A multidisciplinary diagnostic team was created. Valid ß-hCG/αFP data were collected from cases of ICGCTs confirmed by pathology and CSF cytology (n = 58) between 1991 and 2012, and from suspected ICGCTs cases (n = 17) between 2011 and 2012 as controls [Langerhans cell histiocytosis (LCH), n = 12; and other intracranial tumor (ICT), n = 5]. The cut-off points for ß-hCG and αFP were calculated using receiver operating characteristic (ROC) curves. RESULTS: This study clarifies the relative rationality of one criteria (ß-hCG > 50 IU/L and αFP > 25 ng/mL); confirms new ß-hCG diagnostic cut-off points: CSF ß-hCG ≥ 8.2 IU/L and serum ß-hCG ≥ 2.5 IU/L (sensitivity of 47 and 34%, respectively, specificity of 100%, both; P < 0.05); and empirically adjusts the criteria for αFP to ≥ 3.8 ng/mL in CSF and to ≥ 25 ng/mL in serum. The total diagnostic sensitivity for ICGCTs finally increased from 34.6 to 65.4% (P < 0.05, diagnostic value of CSF ß-hCG exceeds 90%). Subtype diagnosis improved with αFP in 16.7% of non-geminomatous germ cell tumor cases. CONCLUSION: New evidence-based criteria of ß-hCG and αFP can help improving early and formal diagnosis of ICGCTs, and is of great clinical significance.

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.

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.

Liposomal cytarabine for central nervous system embryonal tumors in children and young adults.

To assess the tolerability and efficacy of liposomal cytarabine (LC), an encapsulated, sustained-release, intrathecal (IT) formulation of cytosine arabinoside, in de novo and relapsed central nervous system (CNS) embryonal tumors in children and young adults. We studied retrospectively all patients less than age 30 at our institution treated consecutively with LC for medulloblastoma (MB), primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Seventeen patients received LC (2 mg/kg up to 50 mg, every 2 weeks to monthly) at diagnosis of high-risk CNS embryonal tumor (2 PNET, 3 ATRT) or relapse of MB (12 MB; 9 had leptomeningeal metastases). Sixteen patients received concurrent systemic chemotherapy. A total of 108 doses were administered (IT 82, intraventricular 26) with a mean of six (range 1-16) treatments per patient. Only three administrations were associated with adverse effects of arachnoiditis or headache. None developed malignant cerebrospinal fluid (CSF) cytology while receiving LC. All the six evaluable patients with malignant CSF cytology and treated with at least two doses cleared their CSF (mean 3 doses, range 1-5). Median overall survival in relapse patients was 9.1 months. Five patients (4 de novo and 1 relapsed) remain alive in complete remission for a median 26.8 months from first LC. Liposomal cytarabine is an easily administered, well-tolerated, and active drug in patients with high-risk embryonal neoplasms. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of LC in newly diagnosed or recurrent CNS embryonal tumors.

Challenges in management of patients with intracranial germ cell tumor and diabetes insipidus treated with cisplatin and/or ifosfamide based chemotherapy.

Patients with intracranial germ cell tumor (IGCT) often present with pituitary dysfunction, including diabetes insipidus (DI). Recent protocols have used pre-radiation chemotherapy with combinations of etoposide, carboplatin and/or cisplatin, and ifosfamide. Management of DI in these patients requires monitoring of electrolytes and fluids during chemotherapy and hyperhydration. All consecutive patients treated with chemotherapy for an IGCT during the period 1990-2007 at the Hospital for Sick Children, Toronto were reviewed. Out of 32 patients who received chemotherapy, 21 had DI. Only cycles containing cisplatin and/or ifosfamide and hyperhydration were considered. DI and non-DI patients were compared for each cycle of chemotherapy. Patients were studied for number of days in hospital per chemotherapy course, daily fluid input and output, changes in dose, schedule and route of administration of desmopressin (DDAVP) during chemotherapy, daily variations in sodium level, electrolyte monitoring requirements per day, and complications related to fluid and electrolyte disturbances. Fifty-four cycles of chemotherapy in DI patients were compared to 25 cycles in non DI patients. All 21 patients with DI required daily change in dosage and schedule of DDAVP. Marked variations in daily sodium level were observed in the DI group. Seventeen courses required prolonged admission in the DI group (one in non DI patients) and 6 patients experienced serious complications. In conclusion, DI is a risk factor for complications when cisplatin and/or ifosfamide based protocols are used. The role of these agents in the management of ICGT should be carefully evaluated and guidelines for management of DI established.

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

BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

Correlation of endoscopic biopsy with tumor marker status in primary intracranial germ cell tumors.

We retrospectively analyzed the results of eight patients who underwent endoscopic biopsy of a newly diagnosed primary intracranial germ cell tumor (GCT), and correlated tumor pathology with serum and cerebrospinal fluid (CSF) tumor markers and treatment outcome in order to determine the reliability of GCT sampling by this method. A biopsy diagnosis was made in each patient, and the tumor histology correlated with tumor marker measurements for all six patients diagnosed with germinoma and for one with a yolk sac tumor. One biopsy revealed only mature teratoma, an inconclusive result since the patient's serum and CSF tumor markers were elevated. No morbidity was experienced as a result of the operative procedure. Five of six patients diagnosed with germinoma responded completely to radiation therapy and are without evidence of disease, while one suffered a likely germinoma recurrence and was subsequently successfully retreated. We conclude that endoscopic biopsy of marker-negative germ cell tumors is a safe, reliable method of establishing a diagnosis of germinoma. However, endoscopic biopsy may fail to yield an accurate diagnosis in cases of malignant non-germinomatous tumor. We would thus conclude that when primary germ cell tumor is considered, endoscopic tumor biopsy is recommended in patients with a negative biochemical analysis, but not suggested for patients presenting with elevated tumor markers.

Pineal region tumors in children.

The authors believe that the preferred treatment for pineal region tumors in children requires definitive surgery with a histological diagnosis and that a conservative approach consisting of shunting and radiation therapy no longer seems to be appropriate. The results are reported of a retrospective review of the presentation, treatment, and outcome of 36 children under the age of 18 years treated between 1974 and 1986. Eleven children had germinomas (two-cell type), seven had astrocytomas, and the remaining 18 had 15 histologically different tumor types. Surgery was performed on 30 patients; there were no deaths, but a 10% rate of persistent morbidity was found. The median follow-up period was 4 years. Nine (82%) of 11 patients with germinomas are alive without evidence of recurrence; one child died from recurrent tumor in the pineal region and another is presently being treated for recurrent tumor of the spinal cord. Six (86%) of the seven patients with astrocytoma are well after biopsy and radiation therapy. Of the remaining 18 children, five (28%) died from tumor progression. The cerebrospinal fluid (CSF) tumor markers alpha-fetoprotein and beta-human chorionic gonadotropin were helpful in determining the presence of malignant germ-cell tumors, particularly those with a poor prognosis. Magnetic resonance imaging was useful for diagnosis and for planning the operative approach. Magnetic resonance images showed the presence of pineal region tumors in four children with hydrocephalus who had no evidence of tumor on computerized tomography scans. Because the great variety of tumor types found in the pineal region must be treated in different ways and because improved microsurgical and stereotaxic surgical techniques have made mortality and morbidity rates acceptably low, a biopsy diagnosis should be obtained in all patients. Preoperative assessment of CSF tumor markers and cytology is useful for the identification of patients who have a poor prognosis.

Cerebrospinal fluid polyamines: biochemical markers of malignant childhood brain tumors.

The clinical value of cerebrospinal fluid (CSF) polyamine determinations in childhood medulloblastoma has been suggested. We performed 72 CSF polyamine determinations in 35 children with primary brain tumors. Spermine values were normal and spermidine values were inconsistently elevated. CSF putrescine values, however, were consistently elevated in patients with histologically malignant brain tumors: medulloblastoma, ependymoma, pineal germ cell tumors, primitive neuroectodermal tumors, and brainstem gliomas. Children with supratentorial astrocytomas had normal CSF polyamine values. CSF putrescine values were closely correlated with clinical state, with the highest concentrations identified in patients with widely disseminated recurrent disease. We found CSF putrescine to be a sensitive indicator of active disease in childhood malignant brain tumors. Further investigation is warranted into the predictive value of CSF polyamines in determining tumor relapse before clinical or other diagnostic studies reveal recurrent disease.

Tumor markers and cytologic features of cerebrospinal fluid.

Tumor markers are useful in establishing the diagnosis of certain central nervous system tumors, especially germinal tumors of the pineal region. They are not sufficiently specific to be able to replace biopsy for exact diagnosis. They may also be useful for monitoring of therapy, as an indicator of recurrence of the tumor. Cerebrospinal fluid cytology is not generally useful in establishing a specific histologic diagnosis, especially in children, but can help to monitor therapy and predict tumor recurrence. More extensive studies are needed in both areas to define more precisely the role of markers and cytologic studies.

Alphafetoprotein and human chorionic gonadotropin determination in cerebrospinal fluid. An aid to the diagnosis and management of intracranial germ-cell tumors.

The cerebrospinal fluid (CSF) and serum of six patients with histologically verified intracranial germ-cell tumors were assayed serially for the presence of alphafetoprotein (AFP) and the beta subunit of human chorionic gonadotropin (HCG). Two patients had embryonal carcinomas, two had choriocarcinomas, and two had dysgerminomas. The marker profile for a given tumor in either CSF or serum correlated with the histological diagnosis; that is, embryonal carcinoma produced AFP and HCG, choriocarcinoma produced HCG, and dysgerminoma produced no markers. The marker levels in serum and CSF declined with therapy and rose usually prior to the development of overt clinical symptoms if the patient's tumor recurred. A CSF-to-serum gradient of the marker levels was present in three of four patients, and the serum levels were often normal when the CSF values were elevated. Ventricular marker levels were lower than the lumbar levels in two of two patients. The assay of these biological markers is a sensitive indicator of the success of therapy, and the presence of a CSF-to-serum gradient suggests that the major portion of the neoplasm rests within the central nervous system. A histological diagnosis can be inferred without the necessity of surgery in appropriate clinical contexts.