DISCUSSION 

In this study, we compared hCG-related markers and showed a higher detection rate of serum intact and total hCGs among patients with germinoma. Clinically, hCG is used for the diagnosis of germ cell tumors, trophoblastic disease, and pregnancy13. The molecular weight of hCG is 37.5 kDa14, with half-life of 36 h in the blood.15 The α subunit of hCG (14 kDa) is a common component of LH, FSH, and TSH, whereas its β subunit (23.5 kDa)14 is structurally specific to hCG, although they are biologically and immunologically similar to LH.6 The α subunit and β subunit are linked together by hydrophobic and ionic interactions noncovalently, and the excess amounts of the free subunits are found in the blood.16英語 の翻訳です。
Three hCG-related markers (hCGβ, free hCGβ; intact hCG, hCGα + hCGβ; and total hCG, intact hCG + free hCGβ) are currently used as tumor markers for intracranial germ cell tumors. However, the nomenclatures of commercial measuring assays are not appropriately defined for hCG-related markers. For instance, “β-hCG assay” is misleadingly used to describe an assay that measures both intact hCG and hCGβ using a hCGβ detective epitope.13 Thus, the International Federation of Clinical Chemistry established a working group to improve the standardization of hCG determinations.17 The assays should be precisely defined according to what they measure, and the manufacturers should clearly indicate the hCG variant specificity of their reagent systems.18
Because germinomas demonstrate an excellent response to chemoradiotherapy, the aggressive removal of the tumors is not necessary and only biopsy is needed.19 The information provided by hCG levels can assist in the diagnosis of germinomas before surgical interventions, allowing the neurosurgeon to have options for minimally invasive surgery such as endoscopic biopsy. The pineal region is the most common site of germinomas. For a pediatric patient with a pineal region tumor without elevation of hCG-related markers, the tumor may be diagnosed as germinoma, pineoblastoma, or pineal parenchymal tumor of intermediate differentiation. Pineal parenchymal tumors need tumor removal as much as possible.20 However, histological confirmation is necessary in these cases, because it is difficult to distinguish between germinoma and pineal parenchymal tumor with imaging unless the tumor markers are elevated. Most germinomas (93.3%) express even a small amount hCG-related markers9, whereas pineal parenchymal tumors never produce hCG-related markers. Therefore, the detection rate of hCG has a crucial clinical implication for the diagnosis and treatment of germ cell tumors.
We found that intact and total hCGs showed almost the same values, with much higher positivity rates than hCGβ. Thus, intact and total hCGs are more reliable tumor markers for intracranial germinomas.
The higher detection rate of intact and total hCGs compare with that of hCGβ can be attributed to two factors. First is the low amount of production of free hCGβ by the germinoma. Our results suggest intracranial germinomas produce less hCGβ than intact hCG. A comparison with the same measuring method such as molecular weight is needed to confirm this. As for testicular cancers, positivity rates of hCGβ, intact hCG, and total hCG are reported to be 34.8%, 24.1%, and 41.1% respectively. Total hCG is the most reliable tumor marker in diagnosis and follow-up for testicular cancers.21 Second is the measurement sensitivity. Although specific details regarding the measurement methods have not been clarified by the manufactures, detection rates depend on sensitivity of the kit for hCG-related markers. It is possible that the sensitivity for intact and total hCGs is higher than that for hCGβ in this study. Fukuoka et al. reported a high sensitivity for total hCGβ measurement in CSF, with an 85.7% positive rate using a 30-pg detection limit in germinoma.22 Although this detection method (i.e., immune complex transfer enzyme immunoassay) is helpful for the early detection of germinomas, it is not commonly available for diagnosis. The high detection rate of hCG enables an early diagnosis of germinoma. However, we need to be aware of false positives.23,24The pituitary stalk produces a small amount of hCG,25,26 although it is primarily undetectable except in postmenstrual women27. Moreover, hCG-related markers can be also positive in several tumors and other diseases such as craniopharyngioma28, colorectal cancer29, biliary and pancreatic cancer13, ovarian cancers30, renal failures31, and hypogonadism.32Thus, there is a need to identify false positives to avoid unnecessary treatment24 through the vigilant inspections of brain magnetic resonance imaging and whole-body evaluation.

Conclusion

Total and intact hCG are more valuable than hCGβ as tumor markers for intracranial germinomas based on the currently available measurement methods.
Conflict of interest: The other authors have no conflicts of interest related to this study to declare.