Acta Neuropathol (2006)
DOI 10.1007/s00401-006-0033-4

O R I GI N A L P A P E R

Kazuhiko Mishima Æ Yukinari Kato Æ Mika K. Kaneko
Youya Nakazawa Æ Akiko Kunita Æ Naoya Fujita
Takashi Tsuruo Æ Ryo Nishikawa Æ Takanori Hirose
Masao Matsutani

Podoplanin expression in primary central nervous system germ celltumors: a useful histological marker for the diagnosis of germinoma
Received: 15 September 2005 / Revised: 13 December 2005 / Accepted: 14 December 2005
Ó Springer-Verlag 2006

Abstract Podoplanin, a mucin-like transmembranesialoglycoprotein, promotes platelet aggregation andmay be involved in cancer cell migration, invasion,
metastasis, and malignant progression. Podoplanin/
aggrus is highly expressed in testicular seminoma, suggesting that it may be a sensitive marker for testicularseminomas. Here we investigated the expression of podoplanin in central nervous system (CNS) germ cell tumors (GCTs) by immunohistochemical staining oftumor samples from 62 patients. In 40 of 41 (98%)
germinomas (including germinomatous components inmixed GCTs), podoplanin was diﬀusely expressed on thesurface of germinoma cells; lymphocytes, interstitialcells, and syncytiotrophoblastic giant cells were negative
for podoplanin. Except for immature teratomas (12/17;71%), podoplanin expression was absent in non-gerKazuhiko Mishima and Yukinari Kato contributed equally to thiswork.
Y. Kato (&) Æ Y. Nakazawa Æ A. Kunita Æ N. Fujita Æ T. Tsuruo
Institute of Molecular and Cellular Biosciences,
The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku,
113-0032 Tokyo, Japan
E-mail: yukinari-k@bea.hi-ho.ne.jp
Tel.: +81-3-5841-7863
Fax: +81-3-5841-8487
K. Mishima Æ R. Nishikawa Æ M. Matsutani
Department of Neurosurgery, Saitama Medical School,
38 Morohongo, Moroyama-machi, Iruma-gun,
350-0495 Saitama, Japan
M. K. Kaneko
Department of Developmental Neuroscience,
Tokyo Metropolitan Institute for Neuroscience,
2-6, Musashidai, Fuchu, 183-8526 Tokyo, Japan
T. Tsuruo
Cancer Chemotherapy Center, Japanese Foundation for Cancer
Research, 3-10-6, Ariake, Koto-Ku, 135-8550 Tokyo, Japan
T. Hirose
Department of Pathology, Saitama Medical School,
38 Morohongo, Moroyama-machi, Iruma-gun,
350-0495 Saitama, Japan

minomatous GCTs, including seven teratomas, sevenembryonal carcinomas, seven yolk sac tumors, and seven choriocarcinomas. In immature teratomas, focal
podoplanin staining was observed in fewer than 10% ofimmature squamous and columnar epithelial cells. Thus,
podoplanin expression may be a sensitive immunohistochemical marker for germinoma in CNS GCTs. As
such, it may be useful for diagnosis, for monitoring theeﬃcacy of treatment, and as a potential target for antibody-based therapy.
Keywords Podoplanin Æ Germinoma ÆGerm cell tumor Æ YM-1 Æ Tumor marker

Introduction
Germ cell tumors (GCTs) of the central nervous system(CNS) are a heterogeneous group of lesions found inchildren and young adults. They are classiﬁed into ﬁvebasic histological types—germinoma, teratoma, embryonal carcinoma, yolk sac tumor, and choriocarcinoma—and into mixed tumor types when two or morecomponents are present [14]. The prognosis of GCTs,
independent of their location in the CNS, is highly
dependent on the histological subtype. In general, germinomas are sensitive to radiotherapy and chemotherapy and have a better prognosis than nongerminomatous GCTs containing highly malignant
components (e.g., embryonal carcinoma, yolk sac tumor, or choriocarcinoma). The 5-year survival rates are
95.4 and 17.4%, respectively [11].
Tumor markers can be helpful in diagnosing GCTs
and assessing prognosis. Alpha-fetoprotein (AFP) is
produced by yolk sac tumors, a part of embryonal carcinomas and immature teratomas, and beta humanchorionic gonadotropin (HCG) is produced by syncytiotrophoblasts in choriocarcinomas. Embryonal carcinomas often have both of these components andtherefore are associated with both markers [21]. Humanplacental alkaline phosphatase (PLAP), expressed by

In this study, we investigated the expression of podoplanin in primary GCTs of the CNS to evaluate its
potential as a diagnostic marker for CNS germinomas.

primodial germ cells, has been widely used for immunochemical diagnosis of germinomas. However, it lacks
speciﬁcity and its low secretion titer makes detection
diﬃcult [21]. Immunohistochemical staining after tumor
resection is often important for diagnosis, and the differentiation between germinoma and non-germinomatous GCTs is essential for determining the appropriate
treatment of CNS GCTs.
Mouse podoplanin (aggrus), a 44-kDa sialoglycoprotein with platelet aggregation-inducing ability, isexpressed on the surface of mouse colon adenocarcinoma cells [22]. Antibody against podoplanin inhibitedlung metastasis of NL-17 colon carcinoma cells in vivo.
[20]. Cloning of cDNA revealed that human podoplanin
is identical to T1a, a separately isolated protein that canalso induce mouse and human platelet aggregation [5].
Therefore, podoplanin could be involved in platelet
aggregation induced by tumor cells and metastasis. Podoplanin expression was found in lymphatic endothelium and in tumor-associated lymphangiogenesis, andpodoplanin deﬁciency resulted in congenital lymphedema and impaired lymphatic vascular patterning [16].
Furthermore, podoplanin expression has been shown to
be upregulated in squamous cell carcinomas, testicularseminomas, and several sarcomas [2, 6, 7, 17].
Recently, Schacht et al. [17] showed that antibody
D2-40, originally produced against a glycoprotein
named oncofetal M2A antigen, speciﬁcally recognizes
human podoplanin. They also demonstrated strong
expression of podoplanin by ovarian dysgerminomas.
D2-40 reacts with fetal gonocytes, testicular seminoma,
and dysgerminoma [9]. Roy et al. [15] reported that D240 is a useful marker to distinguish hemangioblastoma
from metastatic renal cell carcinoma in the brain. In theadult non-neoplastic CNS, D2-40 staining was seen in
the subependymal areas, the leptomeninges and Purkinjecells.

Materials and methods
Tissue samples
Tumors specimens were obtained at surgery from 62
patients with GCTs of the CNS, ten patients with CNS
lymphomas, three patients with central neurocytoma,
three patients with pineocytoma, three patients withpineoblastoma, three patients with schwannoma, four
patients with meningioma, seven patients with metastatic brain tumors from lung cancer, three from breast
cancer, one from colorectal cancer, and two from renal
cell carcinoma. There were 27 germinomas, two germinomas with syncytiotrophoblastic giant cells (STGCs),
three embryonal carcinomas, three yolk sac tumors, twochoriocarcinomas, nine immature teratomas, four teratomas, and 12 mixed tumors (Table 1). Hematoxylinand eosin-stained slides from these cases were reevaluated to conﬁrm the diagnosis, and the tumors werecategorized according to World Health Organization
criteria [14]. Informed consent was obtained from all
patients.
Antibodies
Anti-human podoplanin (aggrus) monoclonal antibody(YM-1: Medical Biological Laboratories, Nagoya, Japan) was obtained by immunizing rats with the synthetic
peptide CEGGVAMPGAEDDVV, corresponding toamino acids 38–51 of human podoplanin plus the
N-terminal cysteine [4].

Table 1 Results of podoplanin immunostaining in 62 patients with GCTs
Tumor type

Pure GCTs
Germinoma
Germinoma with STGCs
Non-germinomatous GCTs
Embryonal carcinoma
Yolk sac tumor
Choriocarcinoma
Immature teratoma
Teratoma
Mixed GCTs
Germinoma and teratoma
Germinoma and choriocarcinoma
Immature teratoma, yolk sac tumor,
embryonal carcinoma, choriocarcinoma,
and germinoma
Immature teratoma and germinoma

No. of cases

Podoplanin immunostaining

Positive cells

+++

++

+

–

27
2

25
2

0
0

1
0

1
0

3
3
2
9

0
0
0
0

0
0
0
0

0
0
0
4

3
3
2
5

4

0

0

0

4

3
1
4

3
1
0

0
0
0

0
0
4

0
0
0

Germinoma component
Germinoma component
Germinoma and immature
teratoma

4

0

0

4

0

Germinoma and immature
teratoma

Germinoma cells
Germinoma cells

Squamous and columnar
epithelial cells

Western blot analysis
The tissues were solubilized with lysis buﬀer [25 mM
Tris (pH 7.4), 50 mM NaCl, 0.5% Na deoxycholate, 2%Nonidet P-40, 0.2% SDS, 1 mM phenylmethylsulfonyl
ﬂuoride, and 50 mg/ml aprotinin] and electrophoresed
under reducing conditions on 10–20% polyacrylamidegels (DRC, Tokyo, Japan). The separated proteins weretransferred to a nitrocellulose membrane. After blocking
with 4% skim milk in PBS, the membrane was incubatedﬁrst with YM-1 or anti-b-actin antibody (Sigma, St.
Louis, MO, USA), and then with peroxidase-conjugatedsecondary antibodies (Amersham, Buckinghamshire,UK) and developed for 3 min with ECL reagents(Amersham) using Kodak X-Omat AR ﬁlm.
Immunohistochemistry
For immunohistochemical analysis, specimens weredeparaﬃnized, rehydrated, and incubated ﬁrst with YM1 (1:20 dilution of concentrated culture supernatantfrom Medical Biological Laboratories) at room temperature for 1 h, then with biotin-conjugated secondaryanti-rat IgG antibody (DakoCytomation, Glostrup,
Denmark) for 1 h, and ﬁnally with peroxidase-conjugated avidin-streptavidin complex (Vectastain ABC Kit,
Vector Laboratories, Peterborough, UK) for 1 h. Color
was developed with 3, 3-diaminobenzidine tetrahydrochloride tablet sets (DakoCytomation) for 3 min.
Immunohistochemical staining for tumor markers
including beta-HCG, AFP, and PLAP was also used to
conﬁrm the classiﬁcation. Podoplanin expression wassemi-quantitatively assessed from the percentage of tumor cells with cytoplasmic/membrane staining: 0, no
staining; +, <10%; ++, 10–50%; and +++, >50%.

Results
Immunohistochemical analysis of podoplanin in CNS
GCTs
The immunohistochemical ﬁndings are summarized inTable 1. Podoplanin immunoreactivity was detected in
26 of 27 (96%) pure germinomas; the staining was graded as +++ in 25 cases and as + in one. One germinoma was negative for podoplanin. Including
germinomatous components in mixed GCTs, 40 of 41(98%) germinomas were stained by YM-1.
Immunostaining for podoplanin showed a diﬀuse
cell-surface pattern in germinoma cells (Fig. 1a). Immunostaining revealed germinoma cells inﬁltrating into
brain parenchyma (Fig. 1b) and in the germinomatouscomponents of mixed tumors (Fig. 1c). Nontumor
components such as inﬁltrated lymphocytes and stromalcells were negative for podoplanin, as were STGCs.
Among the non-germinomatous GCTs and mixed
GCTs, 12 of 17 immature teratomas were positive forFig. 1 Immunohistochemical detection of podoplanin in CNS
germinomas. a The surface of germinoma cells is strongly positive(brownish color). Lymphocytes and interstitial cells are negative.
Germinoma cells inﬁltrating into brain parenchyma (b) andgerminomatous components in mixed GCTs (c) are also positive.
Bar 10 lm

podoplanin; in all cases, the staining was focal (+) andlimited to basal layers of immature squamous epithelium
and immature columnar epithelium (Fig. 2a, b). Sevenembryonal carcinomas, seven choriocarcinomas, andseven yolk sac tumors were not stained with YM-1
(Fig. 2c–e, Table 1).
In pineal region, GCTs need to be distinguished fromother tumors (e.g., metastatic brain tumors, pineocytomas, and pineoblastomas). Therefore, we examined theexpression of podoplanin in other CNS tumors to assess
the speciﬁcity of podoplanin in distinguishing germinomas from certain metastatic brain tumors and someprimary brain tumors in pineal region. The immunohistochemical ﬁndings are summarized in Table 2. Podoplanin immunoreactivity was detected in one of three(33%) metastatic squamous carcinomas of the lung; thestaining was graded as +, although none of the adenocarcinomas of the lung were positive for podoplanin(n=4). Other metastatic tumors from colorectal cancer(n=1), renal cell carcinomas (n=2) and breast cancer(n=3) did not express podoplanin. Primary brain tumors in pineal region such as CNS lymphoma (n=10),
pineocytoma (n=3), pineoblastoma (n=3), and meningioma (n=4) were negative for podoplanin. Other
Fig. 2 Photomicrographs
showing immunohistochemical
detection of podoplanin in nongerminomatous GCTs. In
immature teratomas, positive
staining for podoplanin(brownish color) is limited tobasal layers of immaturesquamous epithelium (a) andimmature columnar epithelial
cells (b). Embryonal carcinoma(c), yolk sac tumor (d), andchoriocarcinoma (e) arenegative for podoplanin. Bar
10 lm

primary brain tumors such as central neurocytoma(n=3) and schwannoma (n=3) were also negative.
To conﬁrm the immunohistochemical ﬁndings fromCNS GCTs, lysates of frozen tumor specimens fromseven patients were analyzed by western-blot analysis(Fig. 3). Podoplanin protein was overexpressed in germinoma, but not in choriocarcinoma, yolk sac tumor or
normal brain tissue. Podoplanin was also detected in
two immature teratomas and one mixed tumor containing immature teratoma, germinoma, and embryonalcarcinoma.

Discussion
In this study of 62 primary GCTs of the CNS, immunostaining with monoclonal antibody YM-1 demonstrated podoplanin immunoreactivity in 98% (40/41) ofpure or mixed germinomas and a limited number of
immature teratomas, but not in embryonal carcinoma,
yolk sac tumor, choriocarcinoma, or teratoma. In mixed

Table 2 Results of podoplanin immunostaining in patients withmetastatic brain tumors and primary brain tumors
Tumor typeNo. of cases

Matastatic brain tumors
Lung
Adenocarcinoma
Sqamous cell carcinoma
BreastRenal cell
Colorectal
Primary brain tumors
Lymphoma
Pineocytoma
Pineoblastoma
Meningioma
Central neurocytoma
Schwannoma

(kDa)

1

2

3

4

Podoplanin
immunostaining
+++

++

+

4
3
3
2
1

0
0
0
0
0

0
0
0
0
0

0
1
0
0
0

4
2
3
2
1

10
3
3
4
3
3

0
0
0
0
0
0

0
0
0
0
0
0

0
0
0
0
0
0

10
3
3
4
3
3

5

6

7

8

40
Podoplanin40β-actinFig. 3 Western-blot analysis of podoplanin expression in CNS
GCTs. Tumor tissues from a germinoma (lanes 1 and 2), a mixed
tumor (mainly embryonal carcinoma with immature teratoma/
germinoma) (lane 3), an embryonal carcinoma (lane 4), a yolk sactumor (lane 5), an immature teratoma (lanes 6 and 7), and normal
brain (lane 8) were solubilized and immunoblotted with anti-human
podoplanin monoclonal antibody YM-1 (upper panel) or anti-bactin antibody (lower panel)

GCTs, staining for podoplanin was restricted to germinomatous and immature teratoma components andhighlighted germinoma cells. These ﬁndings suggest that
podoplanin may be a sensitive immunohistochemicalmarker of CNS germinoma.
Distinguishing germinoma from non-germinomatous
GCTs is of paramount importance in patient management. Neuroradiologic ﬁndings are not particularly
helpful for diﬀerentiating between histological subtypesof GCTs [12]. Unlike testicular GCTs, diagnosis of CNS
GCTs often requires immunohistochemical analysis because of the small size of the biopsy samples by recent
less invasive surgery and the morbidity associated with
irradiation of the brain. In addition, a granulomatous
inﬂammatory reaction sometimes overwhelms the tumor
cell parenchyma, causing a diagnostic failure at biopsy[8]. Therefore, a speciﬁc immunohistochemical marker
would be extremely useful for identifying tumor cells inbiopsy samples submitted for diagnosis.
Antibodies to PLAP, a cell-surface glycoprotein
elaborated by syncytiotrophoblasts and produced byprimordial germ cells, have been widely used for immu-

nochemical diagnosis of germinomas and seminomas.
About 75–100% of germinomas and 33–86% of nongerminomatous GCTs such as embryonal carcinomas are
positive for PLAP [21]. Unfortunately, it lacks speciﬁcity
and its low secretion titer makes detection diﬃcult.
On the other hand, our ﬁndings suggest that podoplanin is highly expressed in germinomas and focallyin immature teratomas but not in embryonal carcinomas, choriocarcinomas, and yolk sac tumors and any ofthese components in mixed GCTs. Indeed, the subtypesof nongerminomatous GCTs (e.g., embryonal carcinoma, yolk sac tumor, and choriocarcinoma) occur
rarely as a pure form and are mostly seen as a part of amixed germ cell tumor in CNS GCTs, therefore thenumber of non-germinomatous GCTs examined in thisstudy might be small to conclude the speciﬁcity of podoplanin expression for germinoma.
The most common site of origin for pineal region
metastasis is the lung, followed by the breast. In ourstudy, metastatic brain tumors from lung squamous
carcinomas occasionally expressed podoplanin, as theprimary lung squamous cell carcinoma expressed podoplanin/aggrus [7]. However, adenocarcinomas fromlung and other metastatic brain tumors from colorectal
cancer, renal cell carcinoma and breast cancer did not
express podoplanin. Other primary brain tumors such as
CNS lymphoma, pineocytoma, pineoblastoma, meningioma, central neurocytoma, and schwannoma were also
negative for podoplanin. Recently, podoplanin was reported to be expressed in hemangioblastoma in the brain[15]. Thus, podoplanin is not a speciﬁc marker of germinoma in brain tumors, but could be a useful diagnostic marker for germinomas in CNS GCTs. We
suggest that the combination of several markers, such as
podoplanin detected by D2-40 or YM-1, PLAP, betaHCG, and AFP, provides more precise diagnostic
information. Establishing the clinical eﬃcacy of podoplanin as a marker for GSTs will require further
investigation.
The biological function of podoplanin is largely unknown. In mice, deﬁciency in T1a/podoplanin causes
defects attributed to disruption of epithelial-mesenchymal signaling [13] and to impairments in cell to substratum adhesion and cell migration [16]. In vascularendothelial cells, overexpression of T1a/podoplanin induces elongated cell extensions and signiﬁcantly increases cell adhesion, migration, and tube formation bypromoting rearrangement of the actin cytoskeleton [16].
PA2.26 antigen/podoplanin was identiﬁed as a cell-surface protein induced in epidermal carcinogenesis andskin remodeling. Expression of PA2.26 antigen/podoplanin in pre-malignant keratinocytes induces fullytransformed and metastatic phenotype [18, 19]. Human
PA2.26 antigen/podoplanin has been found in theinvasive front of oral squamous cell carcinomas, consistent with a role in tumor cell migration and invasion[10]. Although germinomas rarely metastasize outside
the CNS, they have a predilection for disseminating
within the subarachnoid space and for invading sur-rounding brain tissue [1, 3, 23]. These ﬁndings, together
with the upregulated expression of podoplanin we observed in CNS germinomas, suggest a potential role ofpodoplanin in the progression, invasion, and dissemination of CNS germinoma; however, its direct biological
function in germinomas remains to be established. We
are currently investigating whether enhanced podoplanin expression contributes to the invasive spread ofexperimental tumors.
In conclusion, podoplanin appears to be a sensitivemarker of germinoma and thus may be useful for diagnosis and for monitoring the eﬀects of treatment. Because of its oncogenic potential, high-level expression ingerminomas, and localization on the cell surface, podoplanin is a potential target for antibody-based therapy.
Acknowledgements This study was supported by Kanae Foundation for Life and Socio-medical science (to Y. K.). We thank Drs.
S. Takano (University of Tsukuba), J. Takahashi (University of
Kyoto), and M. Nagane (Kyorin University) for providing GCTs
samples.

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