Annals of Oncology 13: 1681–1685, 2002

Clinical case DOI: 10.1093/annonc/mdf276

Successful treatment of extracranially metastasized pineal gland

germinoma with high-dose methotrexate
T. Fietz1*, E. Thiel1, C. Baldus1, I. W. Blau1, G. Stoltenburg2 & W. U. Knauf1
1
Department of Medicine III (Hematology, Oncology and Transfusion Medicine), 2Department of Neuropathology, Universitätsklinikum Benjamin Franklin,
Freie Universität Berlin, Germany

Received 15 February 2002; revised 22 April 2002; accepted 22 April 2002

Germinoma of the pineal gland is a rare disease usually confined to the brain which responds well to
radiotherapy. Spinal seeding occurs in ∼4% of cases and distant metastases are extremely rare. We
report on a 27-year-old female with an intracranially metastasized pineal gland germinoma, meningeal
carcinomatosis and distant bone metastases. Treatment was initiated with intrathecal methotrexate
(MTX) and continued with high-dose intravenous MTX. The therapy was very well tolerated apart from
reversible hepatic toxicity requiring a dose reduction. The patient was in complete remission after three
courses followed by two consolidation cycles; the patient has now been in continuous complete
remission for more than 22 months. This is the first report to show that MTX is a potent drug in treating
pineal gland germinoma. Long-term side effects of radiotherapy such as reduced mental function or
hypopituitarism can probably be avoided. Single-agent high-dose MTX may provide high efficacy with
limited adverse effects, especially at a more advanced tumor stage with spinal seeding and extracranial
disease.
Key words: chemotherapy, intracranial germ-cell tumor, metastasis, methotrexate

Introduction vinblastine, bleomycin and ifosfamide. While some protocols

favored a combined modality treatment with the additional
Germ-cell tumors are primarily gonadal neoplasms but may
use of reduced local radiotherapy [1], others used chemo-
also arise extragonadally in the midline structures of the body
therapy alone [14, 16]. Using a new chemotherapeutic mono-
(retroperitoneal, mediastinal) including the central nervous
therapy, we report the successful treatment of a patient with
system (CNS). Most pineal gland tumors are germ-cell tumors
wide-spread primary CNS germinoma.
and can be subdivided into nongerminomatous germ-cell
tumors and germinoma (seminoma) (Figure 1; modified from
refs 1–3). Due to their excellent radiosensitivity, localized Case report
CNS germinomas are routinely treated with radiotherapy of
A 27-year-old female patient presented with vertigo, head-
the primary tumor bed with curative intention [1–8]. How-
ache, emesis and progressive ataxia. The patient had a history
ever, mental and pituitary hormonal dysfunctions are major
drawbacks of radiotherapy [9–13]. Radiotherapy treatment is
not sufficient for patients with spinal seeding, extracranial dis-
ease or disease relapse who will also require chemotherapy.
Like gonadal seminoma, CNS germinoma is a highly
chemotherapy-responsive disease and successful treatment
has been reported for both newly diagnosed and recurrent
disease [1, 3, 14–16]. The chemotherapeutic regimens were,
as in the treatment of primary gonadal neoplasms, platinum-
based with the addition of other drugs like etoposide or

*Correspondence to: Dr T. Fietz, Department of Medicine III

(Hematology, Oncology and Transfusion Medicine),
Universitätsklinikum Benjamin Franklin, Freie Universität Berlin,
Hindenburgdamm 30, D-12200 Berlin, Germany.
Tel: +49-30-84452028; Fax: +49-30-84454468; Figure 1. Pineal gland tumors (modified from Calaminus et al. [1],
E-mail: toffi001@zedat.fu-berlin.de Schöber et al. [2] and Balmaceda et al. [3]).

© 2002 European Society for Medical Oncology

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Figure 2. Magnetic resonance imaging of the brain and vertebral column at diagnosis (A, B and C) and after chemotherapy (D, E and F). Note the lesion
in the pineal region (A, white arrow) representing the primary tumor as well as lesions in the preoptic region (B, white arrow) and lumbar vertebra 2
(C, white arrow). After three cycles of high-dose methotrexate chemotherapy the lesions in the pineal (D) and preoptic (E) region can no longer be
identified. The high signal intensity in the plain T1 sequence of L3 (F) represents the fatty change after chemotherapy.

of grand mal seizures since the age of 12; valproic acid had within normal range. Cholinesterase (2653 U/l, normal range
been successfully used as a prophylactic regimen during the 2800–7400) and total serum protein (60 g/l, normal range
previous 6 years. 66–87) were slightly reduced indicating impaired hepatic
A lumbar puncture showed 250.6 cells/µl with a total pro- function possibly due to the long-term use of valproic acid.
tein level of 1327 mg/l. Magnetic resonance imaging (MRI) Cytopathological analysis of the cerebrospinal fluid showed
localized a prominent tumor in the pineal gland with supra- polymorphic tumor cells with basophilic cytoplasm surrounded
sellar and cerebellar metastases, edema and involvement of by an inflammatory infiltrate of small lymphocytic cells.
the petrous bone. Another MRI evaluation revealed cerebro- Mitotic figures were easily detected and nuclei centrally
spinal dissemination and spinal bone metastases (arch of placed with one or two prominent nucleoli (Figure 3) as seen
L2, L3) (Figure 2A–C). α-Fetoprotein and β-human chorionic in cytological smear preparations of intracranial germinoma
gonadotropin in serum and spinal fluid were not elevated; [17]. The tumor cells were negative for cytokeratin (using anti-
serum lactate dehydrogenase (LDH) was 161 U/l (range body MNF 116). The pathological diagnosis was germinoma.
120–240). There were no signs of impaired renal function or In our patient with meningeal carcinomatosis and uncon-
metabolic disturbances and liver enzymes [aspartate amino- trollable emesis we started treatment immediately with oral
transferase (AST), alanine aminotransferase (ALT)] were dexamethasone and intrathecal methotrexate (MTX), an anti-
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Figure 3. Cytospin preparation (May–Giemsa–Grünwald staining). Large tumor cells with thin cytoplasmic rim, central nucleus and prominent
nucleoli are infiltrated by small lymphocytes. Mitoses are frequent (magnification: A, 200×; B, 1000×).

metabolite with broad activity in solid tumors and a variety Karnofsky index was 100%. Two consolidation cycles up to a
of hemato-oncological diseases. Methotrexate 15 mg was total of five cycles high-dose methotrexate were administered
applied by lumbar puncture on day 1, followed by intrathecal and valproic acid was discontinued. The patient is currently
administration of MTX 10 mg via a C-port on days 2, 7, 10 and being followed-up in our outpatient clinic.
13. The patient showed a rapid response with continuous Ten months after discontinuing therapy the patient reported
improvement in nausea and emesis. A spinal tap on day 13 a generalized seizure which had occurred at home. Magnetic
contained 11 cells/µl with some scattered tumor cells. Mag- resonance imaging scans showed no sign of tumor relapse and
netic resonance imaging showed a 25% reduction in the tumor valproic acid as prophylactic anti-convulsive medication was
burden. In view of the meningeal improvement and morpho- restarted without any further convulsive episodes. Our patient,
logical MRI findings, treatment was continued with high-dose currently 22 months out of therapy, is in excellent general con-
methotrexate which offers sufficient systemic efficacy as well dition with no evidence of disease and has returned to work as
as blood–brain penetration [18]. Our patient received MTX an architect. She reports no cognitive deficits and shows no
4 g/m2 as a 4-h infusion with leukovorin rescue initiated after signs of hormone dysfunction (normal thyroid tests, regular
24 h. Serum MTX levels after 24, 36 and 48 h were within the menstrual cycle).
normal range, requiring no rescue intensification. Treatment
was well tolerated without nausea, vomiting or infectious
complications. The patient was discharged and readmitted
Discussion
after 3 weeks to continue therapy. Outpatient serum controls
in the interval showed a 40-fold increase in both AST and Primary CNS germinomas are highly radiosensitive and
ALT indicating hepatic MTX toxicity. Serum AST and ALT localized disease is curable with involved field radiotherapy in
levels at readmission returned to normal, but we decided to up to 95% of cases [1–4, 6, 7, 19]. Synchronous involvement
reduce the total dose of methotrexate to 4 g; no hepatic toxicity of the pineal and suprasellar region is seen in up to 12% of
or bone marrow suppression (WHO stage >1) were observed cases [20]. Cerebrospinal seeding occurs in about 4% [4],
after any of the following cycles. After three cycles of chemo- which requires craniospinal therapy. A CNS germinoma with
therapy, a control MR scan of the brain and lumbar spine spinal seeding and extracranial metastases is exceptionally rare
showed complete tumor remission (Figure 2D, E and F); the [16, 21–23]; peritoneal seeding due to a ventriculoperitoneal
1684

shunt may be responsible for widespread disease [24, 25]. 7. Wolden SL, Wara WM, Larson DA et al. Radiation therapy for
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CNS germinomas are chemosensitive [1–3, 14–16]; chemo-
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