Japanese Journal of Clinical Oncology 30:291-294 (2000)
© 2000 Foundation for Promotion of Cancer Research
Levels of ß-human Chorionic Gonadotropin in Cerebrospinal Fluid of Patients with Malignant Germ Cell Tumor Can Be Used to Detect Early Recurrence and Monitor the Response to Treatment
Departments of 1Neurosurgery and 2Pediatrics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Background: Tumor marker-producing germ cell tumors of the central nervous system are malignant and require radiation and/or chemotherapy. Although serum ß-human chorionic gonadotropin (hCG) has been used to monitor the course of treatment, the levels of ß-hCG in the cerebrospinal fluid (CSF) have not been measured routinely in the clinic. To determine whether they can be used to evaluate parameters of tumor status, such as progression or response to therapy, levels of ß-hCG in the serum and CSF of patients with germ cell tumors were studied.
Methods: Fifty-four paired samples of CSF and serum were taken from seven patients with germ cell tumor and their ß-hCG levels were measured. ß-hCG was negative in both serum and CSF in 11 instances and the levels in the other 43 paired samples were analyzed for any correlation or relationship to therapy. They were also compared with the clinical courses.
Results: The mean CSF ß-hCG level was 11.5 mIU/ml, which was significantly higher than the level in serum (3.5, p = 0.002). In all the paired samples except for one time point, the level in CSF was higher than that in serum. Out of 43 instances where the ß-hCG level in CSF was elevated, the level in serum was elevated in only 16 (37.2%). Among cases of recurrent malignant germ cell tumor, there were nine instances of recurrence or progression despite therapy. In all five instances where ß-hCG CSF levels were measured, the levels were elevated prior to any increase or detectability of the serum values.
Conclusion: It seems likely that the level of ß-hCG in CSF is a good marker for monitoring tumor recurrence or evaluation of treatment results.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Although the prognosis of patients with malignant germ cell tumor has improved dramatically since the introduction of combination chemotherapy using platinum compounds, the results of treatment for mixed germ cell tumors is still unsatisfactory. Most of these tumors produce tumor markers, which can be used to detect tumor recurrence or evaluate the response to treatment. However, rapid recurrence is sometimes seen on neuroimages before or simultaneously with a rise in the levels of tumor markers in the serum. The purpose of this study was to measure levels of tumor markers in the cerebrospinal fluid (CSF) of patients with germ cell tumors and to assess whether these levels can be used to monitor parameters of tumor status such as recurrence or response to therapy.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Levels of ß-human chorionic gonadotropin (ß-hCG) in serum and CSF were measured in seven patients (Table 1). Paired samples of blood and CSF were taken on the same day or within 24 h after one of the sample pairs had been obtained. For CSF sampling, lumbar puncture was performed. In four patients with malignant germ cell tumor, these levels were measured before the treatment of recurrence. In three patients, levels of ß-hCG in CSF and/or serum were elevated and measurements were made serially during the treatment course each time after the completion of each treatment cycle. The measurements were made by enzyme immunoassay at the central laboratory of the University of Tokyo Hospital. The stability of ß-hCG during the isolation of either serum or the supernatant of CSF had been confirmed during the process of standardization in the laboratory. The treatment modalities included radiation, conventional combination chemotherapy and high-dose chemotherapy with peripheral blood stem cell transfusion or autologous bone marrow transplantation. Details of these therapies will not be discussed here. In three patients with germinoma [two germinomas and one germinoma with syncytiotrophoblastic giant cells (STGC)], the measurements were performed before initial treatment. Since the two patients with pure germinoma did not show elevated levels of ß-hCG in either the CSF or serum, their CSF ß-hCG values were not monitored. These three patients were treated according to the protocol of the Japan Pediatric Brain Tumor Study Group (1). No patient received continuous CSF drainage or CSF shunt implantation except case 4. No patient showed systemic disseminated disease.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Fifty-four paired measurements of ß-hCG in CSF and serum were made in seven patients. The level (in mIU/ml) ranged from <0.6 (undetectable and normal) to 15.0 for serum (median <0.6) and from <0.6 to 41.0 for CSF (median 1.7). Except for one time point, ß-hCG levels were always higher in CSF than in serum or both were undetectable. Fig. 1 shows the correlation between levels in CSF and those in serum. In 27 instances, the level in serum was below the detection limit (0.6 mIU/ml) and was evaluated as normal, but the levels in CSF were elevated and considered to be abnormal. In cases where the paired serum and CSF samples both showed elevated ß-hCG levels, the mean level in CSF was 11.5 (±11.0), which was significantly higher than that in serum (3.5 3.8, p = 0.002). The CSF/serum ratio was 1.3–12.0 (mean 4.3 ± 2.6) except at one time point (0.4). During the course of treatment in four recurrent cases, the ß-hCG level in CSF was elevated in three cases and repeated samplings were made. In these three patients, recurrence or resistance to therapy was observed nine times. Of these, CSF ß-hCG levels were measured on five occasions and each time the ß-hCG level was elevated prior to elevation of the serum level (Fig. 2). After elevation of the CSF level, it took between 14 and 101 (mean 64) days until the serum level became detectable. In case 1, the CSF ß-hCG level was elevated but the serum level was normal immediately after completion of the initial radiation therapy which achieved complete tumor remission on MRI. The dissemination to the fourth ventricle with local recurrence was observed 78 days later, with elevation of the serum hCG level. In other cases, repeated modified treatments prevented the neuroradiological recurrence or progression during this study period.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Although the prognosis of patients with malignant germ cell tumor has improved since the introduction of combination chemotherapy using platinum compounds, the results are still not satisfactory (1–3). Most secreting germ cell tumors which produce tumor markers are malignant germ cell tumors. This still constitutes a fatal subgroup (4), for which the treatment strategy needs to be further improved. We sometimes experience residual small lesions after radiation and/or chemotherapy, which expand rapidly to produce massive recurrence. Dissemination of malignant germ cell tumor is fairly common (2,4,5). If it were possible to detect relapse at an ultra-early stage, such recurrence would be easier to manage.
For observation of tumor marker-producing (secreting) germ cell tumors, tumor markers are a good indicator of recurrence or the response to various therapies. In pure malignant germ cell tumors, such as choriocarcinoma, the levels of serum markers are very high and therefore it is not difficult to monitor them. However, in mixed germ cell tumors or in germinoma with STGC, serum tumor marker levels are not very high. Our measurement showed that in 27 out of 43 instances (63%) where the level of ß-hCG in the CSF was elevated, the level in serum was below the detection limit. These data show that tumor marker levels in the CSF of patients with marker-producing germ cell tumors are a more sensitive indicator than the corresponding values in serum. The CSF levels should be monitored in these cases before and after each treatment course if the serum level is not elevated.
Elevated levels of CSF markers have been reported by other investigators, although they did not describe the details or correlation with therapy (6,7). It is unclear why the level of ß-hCG in CSF is more elevated than that in serum. The effect of disseminated disease in the CSF is considered negligible, since among all cases there was only one instance (case 1) where distant metastasis in the central nervous system (fourth ventricle) was observed. A higher level in the CSF was always evident, regardless of the presence of disseminated disease. The volume of total body fluid is 20 times that of the CSF. The distribution, metabolism or half-life of ß-hCG in the CSF is not known in the literature, but assuming that the marker proteins produced by these tumors were to be distributed equally to serum and CSF, then the concentration in CSF would be much higher. In the treatment of three of the present cases of recurrent germ cell tumor, recurrence or resistance to therapy was observed in nine instances. Each time, elevated levels of ß-hCG were observed in the serum. In five instances, the level of this marker in the CSF was measured and each time the CSF level became elevated before the level in serum was able to indicate recurrence or resistance.
In conclusion, the level of ß-hCG in the CSF of patients with malignant germ cell tumors is higher than that in serum and can be used as a sensitive marker in the follow-up of these tumors.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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This work was partly supported by a Research Grant for Cancer from the Ministry of Health and Welfare.
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FOOTNOTES |
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+ For reprints and all correspondence: Takamitsu Fujimaki, Department of Neurosurgery, Teikyo University, 2–11–1 Kaga, Itabashi-ku, Tokyo 173-8606, Japan. E-mail: tfujimak-tky@umin.ac.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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1 Matsutani M, Ushio Y, Abe H, Yamashita J, Shibui S, Fujimaki T, et al. and the Japanese Pediatric Brain Tumor Study Group. Combined chemotherapy and radiation therapy for central nervous system germ cell tumors: preliminary results of a phase II study of the Japanese Pediatric Brain Tumor Study Group. Neurosurg Focus 1998;5(1):Article 7.
2 Itoyama Y, Kochi M, Yamamoto H, Kuratsu J, Uemura S, Ushio Y. Clinical study of intracranial nongerminomatous germ cell tumors producing alpha-fetoprotein. Neurosurgery 1990;17:454–60.
3 Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O, Funata N, et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 1997;86:446–55.[Web of Science][Medline]
4 Calaminus G, Andreussi L, Garre ML, Kortmann RD, Schober R, Gobel U. Secreting germ cell tumors of the central nervous system (CNS). First results of the cooperative German/Italian pilot study (CNS sGCT). Klin Pediatr 1997;209:222–7.
5 Hardenbergh PH, Golden J, Billet A, Scott RM, Shrieve DC, Silver B, et al. Intracranial germinoma: the case for lower dose radiation therapy. Int J Radiat Oncol Biol Phys 1997;39:419–26.[Web of Science][Medline]
6 Kurisaka M, Saitoh S, Seike M, Kamimura Y, Mori K. Gonadotropin as a tumor marker in body fluid and tumor tissues of germ cell tumors. Brain Nerve 1989;41:353–9.
7 Shibamoto Y, Takahashi M, Sasaki K. Prognosis of intracranial germinoma with syncytiotrophoblastic giant cells treated by radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:505–10.[Medline]
Received February 29, 2000; accepted April 27, 2000.
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