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Letters to the Editor |
Department of Pathology and Immunology, Division of Laboratory Medicine, Washington University School of Medicine, Saint Louis, MO
aAddress correspondence to this author at: Department of Pathology and Immunology, Division of Laboratory Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8118, Saint Louis, MO 63110, Fax 314-362-1461, E-mail gronowski{at}wustl.edu
To the Editor:
Intracranial germ cell tumors account for 0.4%–3.4% of all brain tumors (1). These tumors can be divided into 2 groups, germinomas and nongerminomatous germ cell tumors. Germinomas, which are fairly treatable, arise from primordial germ cells that fail to migrate correctly in embryogenesis. Nongerminomatous germ cell tumors (including choriocarcinomas), which are more refractory to treatment, are differentiated tumors.
Measurement of human chorionic gonadotropin (hCG)1 is an important adjunct method in the diagnosis of germ cell tumors. At high concentrations hCG can be detected in serum, but measurement of hCG concentrations in cerebral spinal fluid (CSF) is a more sensitive and reliable indicator of tumor presence (1). Pure germinomas are associated with very low concentrations of hCG in both serum and CSF. A subset of nongerminomatous germ cell tumors contains syncytiotrophoblastic giant cells. These tumors are associated with moderately increased concentrations of hCG (<1000 IU/L) in the serum, CSF, or both, and the survival rate in patients suffering these tumors is poorer than that for patients with pure germinomas (2). In contrast, choriocarcinomas, another subset of nongerminomatous germ cell tumors, are associated with very high concentrations of hCG (>1000 IU/L) in both serum and CSF. Quantification of the hCG in CSF can be important in guiding treatment and monitoring response to treatment of these tumors (2).
Currently, all quantitative hCG assays in the US have been validated for use with serum only. Because matrix effects can influence test results when alternative sample types are used, the alternative sample type should be validated for the assay before clinical use. We have validated the Advia Centaur total hCG method, developed for use with serum and internally validated for use with urine (3), for use with CSF.
We performed the study with leftover samples collected for physician-ordered testing. Institutional review board approval was obtained for this study. We created a CSF pool by combining CSF samples from 50 patients. Chart review was performed to confirm that samples were from patients with no history of blood-brain barrier breakdown or central nervous system infection. Samples were accepted if they were clear and colorless. The limit of detection was evaluated by measuring hCG in the CSF pool 15 times. The mean hCG was 3.6 IU/L (range, 3–4.1 IU/L; SD, 0.4 IU/L). The minimum detection limit, calculated as the mean + 3SD, was determined to be 4.7 IU/L with a CV of 9.7%.
Recovery studies were performed by diluting hCG-positive serum from a patient with a nongerminomatous germ cell tumor into the pooled patient CSF. Because different isoforms of hCG are produced during pregnancy, cancer, and postmenopausal states, a patient sample was used in place of commercially available hCG to ensure that the assay was validated using the correct hCG isoform. Recovery studies were performed in duplicate on 2 different days. Results from 1 experiment are shown in Table 1
. Recovery of added hCG was >100% at all concentrations in both experiments. Measurements of hCG in CSF were linear up to 400 IU/L [observed = (1.4 x expected) + 2.8; r2 = 0.989].
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The imprecision for twice-daily measurements over a 10-day period was evaluated by adding hCG-containing serum at 2 different concentrations to pooled patient CSF (total volume of serum added was <10%). Interassay imprecision (CV) was 4.6% at 153 IU/L and 2.6% at 510 IU/L.
It is important to note that most, perhaps all, hCG assays in the US are FDA approved for use as a marker for pregnancy, not as a marker for tumors. Nevertheless hCG assays are used to detect tumors. Various tumor types produce differing ratios of intact hCG to free 
-hCG and free β-hCG (4). In addition, different immunoassays preferentially recognize various forms of hCG (5). The Centaur assay does appear to preferentially recognize free β-hCG (5). This characteristic makes this particular immunoassay less than optimal for use in measuring hCG as a tumor marker and is the reason that the sample used for recovery assays was from a patient with a nongerminomatous germ cell tumor. Preferential free β-hCG recognition does not, however, account for the difference in expected vs observed concentrations that we observed, because the recovery was calculated on the basis of a nongerminomatous germ-cell tumor patient sample diluted into normal serum vs normal CSF. Therefore the difference in recovery is attributable to a matrix effect.
In conclusion, the Advia Centaur total hCG assay can be used to detect hCG in CSF with very good precision. Recovery of hCG added to CSF was >100% at all concentrations tested, indicating a moderate matrix effect. This matrix effect should be taken into account when interpreting results. Any detectable hCG in CSF is abnormal. Very high CSF concentrations (>1000 IU/L) suggest the presence of nongerminomatous germ cell tumors, which are usually refractory to treatment.
Acknowledgments
Grant/Funding Support: None declared.
Financial Disclosures: None declared.
Footnotes
1 Nonstandard abbreviations: hCG, human chorionic gonadotropin; CSF, cerebral spinal fluid. 
2 These data have been published in part in an abstract at the 2008 AACC meeting, Washington, DC.
References
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