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.