1 Department of Medicine III (Hematology, Oncology and Transfusion Medicine), 2 Department of Neuropathology, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany
Received 15 February 2002; revised 22 April 2002; accepted 22 April 2002
Abstract
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
Germ-cell tumors are primarily gonadal neoplasms but may also arise extragonadally in the midline structures of the body (retroperitoneal, mediastinal) including the central nervous system (CNS). Most pineal gland tumors are germ-cell tumors and can be subdivided into nongerminomatous germ-cell tumors and germinoma (seminoma) (Figure 1; modified from refs 13). Due to their excellent radiosensitivity, localized CNS germinomas are routinely treated with radiotherapy of the primary tumor bed with curative intention [18]. However, mental and pituitary hormonal dysfunctions are major drawbacks of radiotherapy [913]. Radiotherapy treatment is not sufficient for patients with spinal seeding, extracranial disease or disease relapse who will also require chemotherapy.
|
Case report
A 27-year-old female patient presented with vertigo, headache, emesis and progressive ataxia. The patient had a history of grand mal seizures since the age of 12; valproic acid had been successfully used as a prophylactic regimen during the previous 6 years.
A lumbar puncture showed 250.6 cells/µl with a total protein level of 1327 mg/l. Magnetic resonance imaging (MRI) localized a prominent tumor in the pineal gland with suprasellar and cerebellar metastases, edema and involvement of the petrous bone. Another MRI evaluation revealed cerebrospinal dissemination and spinal bone metastases (arch of L2, L3) (Figure 2AC). -Fetoprotein and ß-human chorionic gonadotropin in serum and spinal fluid were not elevated; serum lactate dehydrogenase (LDH) was 161 U/l (range 120240). There were no signs of impaired renal function or metabolic disturbances and liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT)] were within normal range. Cholinesterase (2653 U/l, normal range 28007400) and total serum protein (60 g/l, normal range 6687) were slightly reduced indicating impaired hepatic function possibly due to the long-term use of valproic acid.
|
|
Ten months after discontinuing therapy the patient reported a generalized seizure which had occurred at home. Magnetic resonance imaging scans showed no sign of tumor relapse and valproic acid as prophylactic anti-convulsive medication was restarted without any further convulsive episodes. Our patient, currently 22 months out of therapy, is in excellent general condition with no evidence of disease and has returned to work as an architect. She reports no cognitive deficits and shows no signs of hormone dysfunction (normal thyroid tests, regular menstrual cycle).
Discussion
Primary CNS germinomas are highly radiosensitive and localized disease is curable with involved field radiotherapy in up to 95% of cases [14, 6, 7, 19]. Synchronous involvement of the pineal and suprasellar region is seen in up to 12% of cases [20]. Cerebrospinal seeding occurs in about 4% [4], which requires craniospinal therapy. A CNS germinoma with spinal seeding and extracranial metastases is exceptionally rare [16, 2123]; peritoneal seeding due to a ventriculoperitoneal shunt may be responsible for widespread disease [24, 25]. Radiotherapy is not sufficient in the extracranially metastasized situation or for nongerminomatous germ-cell tumors of the pineal gland [3, 6]. Several studies have shown that CNS germinomas are chemosensitive [13, 1416]; chemotherapy regimens were cisplatin- or carboplatin-based, as in the treatment of primary gonadal neoplasms.
Methotrexate is a very potent chemotherapeutic drug with a tolerable and well-known toxicity profile. When higher doses are applied systemically, adequate cerebrospinal and intracranial drug levels can be achieved, making MTX suitable for various leptomeningeal cancers as well as for primary CNS lymphoma therapy [18, 26]. Methotrexate has never been used before in the treatment of CNS germinoma.
In our patient with extracranially metastasized CNS germinoma we achieved a sustained complete remission with single-agent high-dose MTX chemotherapy; toxicity was confined to a reversible increase in liver enzymes.
In a recently published study by Oka et al. [9], 91.7% of all patients treated with radiotherapy for suprasellar germinoma required hormone replacement and 50% of the patients showed remarkably low mental function after radiotherapy. Several studies have demonstrated that children especially suffer from a multitude of neurocognitive deficits when treated with brain radiotherapy which worsen over time [1012, 27]. Attempts have been made to reduce late effects by dose reduction [19] or a combination of reduced-intensity irradiation and chemotherapy [28]. A combined treatment with radiochemotherapy, however, has a higher risk of leukencephalopathic alterations [26, 29].
Successful, but less toxic, treatments with chemotherapeutic regimens, such as high-dose methotrexate, is now a new attractive therapeutic option with the potential of reducing radiotherapy use.
Footnotes
+ 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; E-mail: toffi001{at}zedat.fu-berlin.de
References
1. Calaminus G, Bamberg M, Branzelli MC et al. Intracranial germ cell tumors: a comprehensive update of the European data. Neuropediatrics 1994; 25: 2632.[ISI][Medline]
2. Schöber C, Schmoll HJ. Pinealistumoren bei Jugendlichen und Erwachsenen. In Schmoll HJ, Höffken K, Possinger K (eds): Therapiekonzepte Onkologie. Heidelberg: Springer Press 1999; 524538.
3. Balmaceda C, Modak S, Finlay J. Central nervous system germ cell tumors. Semin Oncol 1998; 25: 243250.[ISI][Medline]
4. Schild SE, Scheithauer BW, Haddock MG et al. Histologically confirmed pineal tumors and other germ cell tumors of the brain. Cancer 1996; 78: 25642571.[ISI][Medline]
5. Cho BK, Wang KC, Nam DH et al. Pineal tumors: experience with 48 cases over 10 years. Childs Nerv Syst 1998; 14: 5358.[ISI][Medline]
6. Huh SJ, Shin KH, Kim IH et al. Radiotherapy of intracranial germinomas. Radiother Oncol 1996; 38: 1923.[ISI][Medline]
7. Wolden SL, Wara WM, Larson DA et al. Radiation therapy for primary intracranial germ-cell tumors. Int J Radiat Oncol Biol Phys 1995; 32: 943949.[ISI][Medline]
8. Fuller BG, Kapp DS, Cox R. Radiation therapy of pineal region tumors: 25 new cases and a review of 208 previously reported cases. Int J Radiat Oncol Biol Phys 1995; 32: 943949.[ISI][Medline]
9. Oka H, Kawano N, Tanaka T et al. Long-term functional outcome of suprasellar germinomas: usefulness and limitations of radiotherapy. J Neurooncol 1998; 40: 185190.[ISI][Medline]
10. Packer RJ, Sutton LN, Atkins TE et al. A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: Two-year results. J Neurosurg 1989; 70: 707713.[ISI][Medline]
11. Radcliffe J, Packer RJ, Atkins TE et al. Three- and four-year cognitive outcome in children with noncortical brain tumors treated with whole-brain radiotherapy. Ann Neurol 1992; 32: 551554.[ISI][Medline]
12. Sands SA, Kellie SJ, Davidow AL et al. Long-term quality of life and neuropsychologic functioning for patients with CNS germ-cell tumors: from the First International CNS Germ-Cell Tumor Study. Neuro-oncol 2001; 3: 174183.[ISI][Medline]
13. Hooda BS and Finlay JL. Recent advances in the diagnosis and treatment of central nervous system germ-cell tumours. Curr Opin Neurol 1999; 12: 693696.[Medline]
14. Hupperets PSGJ, Defesche HF, de Bruijckere LM, Twijnstra A. The role of chemotherapy in intracranial germinoma: A case report. Ann Oncol 1999; 10: 723726.[Abstract]
15. Vijayaraghavan S, Brock C, Monson JP et al. Does the rapid response to cisplatin-based chemotherapy justify its use as primary treatment for intracranial germ-cell tumours? Q J Med 1993; 86: 801810.[ISI][Medline]
16. Itoyama Y, Kochi M, Yamashiro S et al. Combination chemotherapy with cisplatin and etoposide for hematogenous spinal metastasis of intracranial germinoma: case report. Neurol Med Chir (Tokyo) 1993; 33: 2831.
17. Ng HK. Cytologic diagnosis of intracranial germinoma in smear preparations. Acta Cytol 1995; 39: 693697.[ISI][Medline]
18. Glantz MJ, Cole BF, Recht L et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 1998; 16: 15611567.[Abstract]
19. Bamberg M, Kortmann RD, Calaminus G et al. Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89. J Clin Oncol 1999; 8: 25852592.
20. Glenn OA, Barkovich AJ. Intracranial germ cell tumors: a comprehensive review of proposed embryologic deriviation. Pediatr Neurosurg 1996; 24: 242251.[ISI][Medline]
21. Pelissou I, Ravon R, Moreau JJ et al. Multiple metastases during the course of pineal germinoma. Neurochirurgie 1985; 31: 537540.[ISI][Medline]
22. Nakamura T, Kato T, Hahimoto N et al. Lumbosacral metastasis of intracranial germinoma. Spine 1990; 15: 336338.[ISI][Medline]
23. Itami J, Kondo T, Niino H et al. Bone metastasis of intracranial germinoma. Acta Oncol 1999; 38: 267268.[ISI][Medline]
24. Kim K, Koo BC, Delaflor RR, Shaikh BS. Pineal germinoma with widespread extracranial metastases. Diagn Cytopathol 1985; 1: 118122.[Medline]
25. Pallini R, Bozzini V, Scerrati M et al. Bone metastasis associated with shunt-related peritoneal deposits from a pineal germinoma. Case report and review of the literature. Acta Neurochir (Wien) 1991; 109: 7883.[ISI]
26. Thiel E, Korfel A, Hinkelbein W. Primary CNS lymphoma: chemotherapy followed by radiotherapy or chemotherapy alone? A randomized multicentric study. Front Radiat Ther Oncol 1999; 33: 349353.[Medline]
27. Asai A, Matsutani M, Kohno T et al. Subacute brain atrophy after radiation therapy for malignant tumors. Cancer 1989; 63: 19621974.[ISI][Medline]
28. Oi S. Recent advances and racial differences in therapeutic strategy to the pineal region tumor. Childs Nerv Syst 1998; 14: 3335.[ISI][Medline]
29. Bleyer WA, Griffin TW. White matter necrosis, mineralizing microangiopathy and intellectual abilities in survivors of childhood leukemia: Association with central nervous system irradiation and methotrexate. In Kagan JA, Gilbert AR (eds): Radiation Damage to the Central Nervous System. New York, NY: Raven Press 1980; 155174.