REVIEW URRENT C OPINION
Central nervous system germ cell tumors: an update Christelle Dufour, Le´a Guerrini-Rousseau, and Jacques Grill
Purpose of review Malignant germ cell tumors in the central nervous system are rare and not well known because they occur mainly in adolescents, an age in which patients are dispersed in adult and pediatric wards. Their biology starts to be unraveled by high-throughput genomics and their treatment is now well defined thanks to international studies, including patients from childhood through adulthood. Recent findings Chemotherapy gained definitively a role apart from radiotherapy in order to improve tumor control in secreting neoplasms, but also to decrease the volume or dose of radiation therapy in germinomas. Neurocognitive outcome remains good with some disparities because of tumor location, patients with pineal tumors being less impaired than those with supratentorial malignant germ cell tumors. Alterations in the KIT/RAS as well as in the mTOR/AKT pathways have been frequently reported and could represent interesting opportunities to introduce targeted therapies in these neoplasms. Summary Diagnosis and treatment of malignant germ cell tumor of the brain are now well established within experienced multidisciplinary teams taking care of adolescents and young adults. The prognosis of secreting tumors has not yet reached the excellent results obtained for germinomas but aggressive chemotherapy including high-dose chemotherapy with stem-cell support may contribute to improve their outcome. The role of targeted therapies has yet to be determined in view of the recently described molecular findings. Keywords alpha-fetoprotein, choriocarcinoma, germinoma, human chorionic gonadotropin, teratoma, yolk sac tumor
INTRODUCTION Intracranial central nervous system germ cell tumors (CNS GCTs) are a heterogeneous group of lesions that can be divided into germinomas, nongerminomatous GCTs (NGGCTs) and teratomas, these later lesions being often considered as a separate category. CNS GCTs are more common in children and in young adults, mainly between 10 and 19 years of age [1] and are considered the most curable primary malignant brain tumor. Recent studies [2,3] have suggested similar incidence in Japan as in the United States population. In childhood, the incidence of primary CNS GCTs remains higher in Japan than in the United States and other Western countries [4]. The majority of primary CNS GCTs arise in the pineal or suprasellar regions. The pineal gland has an unusually high incidence of primary GCTs [5,6]. At the time of diagnosis, about 5–10% of patients have both suprasellar and pineal gland involvement [5,7]. This bifocal disease occurs primarily in www.co-oncology.com
patients with germinomas [5], and it is unclear whether it represents actual spread of the tumor or synchronous development of tumors in two sites. GCTs will also arise in other midline structures of the brain, including tumors of the fourth ventricle, basal ganglia and thalamus.
CLASSIFICATION Most commonly, CNS GCTs are classified using the WHO classification system (adapted from [8]). WHO classification of intracranial GCTs is as follows: Brain Tumor Programme, Department of Pediatric and Adolescent Oncology, Gustave Roussy and University Paris-Sud, Villejuif, France Correspondence to Jacques Grill, Brain Tumor Programme, Department of Pediatric and Adolescent Oncology, Gustave Roussy and University Paris-Sud, Villejuif, France. Tel: +33 1 42 11 62 09; fax: +33 1 42 11 52 75; e-mail: [email protected] Curr Opin Oncol 2014, 26:622–626 DOI:10.1097/CCO.0000000000000140 Volume 26 Number 6 November 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Central nervous system germ cell tumors: an update Dufour et al.
KEY POINTS Presentation of GCTs can be misleading but the detection of specific biomarkers in the blood and/or the CSF (such as soluble c-kit or placental alkaline phosphatase) is an invaluable diagnostic tool that can alleviate the recourse to risky surgical procedure. Treatment strategies are defined according to the presence or absence of a significant secretion of AFP or HCG. Intensification of chemotherapy is efficient to reduce the extent of radiation or to improve the outcome of secreting GCTs. New therapeutic opportunities will comprise the targeting of druggable genetic alterations in the KIT/RAS and the mTOR pathways.
(1) (2) (3) (4) (5) (6)
1.5.0 GCTs, 2.5.1 germinomas, 3.5.2 embryonal carcinoma, 4.5.3 yolk sac tumor, 5.5.4 choriocarcinoma, 6.5.5 teratoma, (a) 5.5.1 immature, (b) 5.5.2 mature, (c) 5.5.3 teratoma with malignant transformation, (7) 7.5.6 mixed germ cell. Classifications are subjective and are also highly dependent on tumor sampling, especially when only biopsies are performed. The presence, or absence, of specific protein markers, produced and/or secreted by tumor cells, has been an extremely important adjunct in the diagnosis of GCTs [9]. These secreted markers can be measured in both serum and cerebrospinal fluid (CSF), although CSF levels are a more sensitive and reliable measure for diagnosis. The most common markers are alpha-fetoprotein (AFP) and b-human chorionic gonadotropin (b-HCG). The usual pattern of tumor marker secretion in GCTs is outlined in Table 1. AFP is a yolk cell marker and is present in endodermal sinus tumors. b-HCG is produced by normal trophoblastic tissue in the placenta, and by choriocarcinomas [10]. Germinoma may be associated with mild elevation of total HCG (< 50 IU/l in serum and CSF) indicating the presence of syncytiotrophoblastic cells. In approximately 20% of germinoma, serum levels of placental alkaline phosphatase may be elevated [11]. The relevance of this marker in diagnosing the specific type of GCT and on treatment is not yet clear. Recently, the determination of CSF placental alkaline phosphatase by the chemiluminescent
Table 1. Classification of germ cell tumors according to tumor markers Marker Tumor type
b-HCG
AFP
PLAP
c-Kit
Pure germinoma
þ/
þ
Germinoma (syncytiotrophoblastic)
þ
þ/
þ
Endodermal sinus tumor
þ
þ/
Choriocarcinoma
þ
þ/
Embryonal carcinoma
þ
Mixed GCT
þ/
þ/
þ/
þ/
Mature teratoma
Immature teratoma
þ/
þ/
þ/
b-HCG, b-human chorionic gonadotropin; AFP, alpha-fetoprotein; GCT, germ cell tumor; PLAP, placental alkaline phosphatase. Adapted from [8].
method could provide a clinically useful tumor marker for the diagnosis and monitoring of intracranial germinoma (94% sensitivity; 97% specificity) [12 ]. Additionally, S-kit, a soluble form of the c-kit (transmembrane tyrosine kinase receptor that plays a crucial role in the development of germ cells) could be a novel tumor marker for CNS germinomas [13]. &&
CLINICAL PRESENTATION GCTs in the pineal region most commonly present with hydrocephalus associated with ophthalmologic signs, somnolence, ataxia, seizures and behavioral changes. Parinaud’s syndrome, caused by the involvement of adjacent midbrain structures, is also seen at presentation in up to 50% of pineal GCTs. Patients with suprasellar GCTs almost always present with hypothalamic/pituitary axis dysfunction at least diabetes insipidus [5]. In the presence of a thickening of the pituitary stalk during the workout of a diabetes insipidus, the association with another pituitary deficit is suggestive of a tumor [14 ] as well as its persistence over a period of 6 months; both conditions should trigger the need for a biopsy even if biomarkers remain negative in the blood and in the CSF [7]. More than half (54%) of patients may have a duration of symptoms prior to diagnostic MRI greater than 6 months [15]. No difference in terms of progression-free survival was found between patients who experienced a delay in diagnosis and those who did not. &&
DIAGNOSIS The neuroimaging characteristics of CNS GCTs alone are unable to reliably differentiate germinoma
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from NGGCTs or from other tumors. A tumor biopsy is required for diagnosis, except in cases in which characteristic serum and/or CSF tumor marker elevations exist (AFP > 25 ng/ml and/or total HCG > 50 IU/l in serum or CSF) [7]. CNS GCTs have a propensity to disseminate throughout the neuroaxis, even at early stages. All patients with a suspected CNS GCT require an extensive metastatic evaluation including an MRI of the brain and spine with gadolinium and CSF cytology after cytocentrifugation as tumor cells may be rare. Among the 169 patients of the SIOP CNS GCT 96 trial, the occurrence of relapses correlated with incompleteness of the pretherapeutic diagnostic work-up and increased from 4 to 24%.
TREATMENT The treatment of germinomas should be distinguished from that of secreting GCTs.
Germinomas Germinomas carry an excellent prognosis with 5-year PFS rates and cure in over 90% of patients. Germinomas are extremely radiosensitive and 5-year survival rates exceeding 90% have been reported with radiotherapy alone [16–20]. Historically, localized germinomas were treated with 36 Gy craniospinal irradiation with a boost to the primary tumor site for a total of 50–54 Gy. Owing to the incidence of clinically significant radiationinduced late effects, including endocrinopathies, second malignancies and neurocognitive impairment, recent studies have evaluated reducedvolume or reduced-dose radiation therapy. Reduced volumes and dose reductions are usually combined with preirradiation chemotherapy. Investigations demonstrating the low incidence of spinal relapse in patients for whom spinal irradiation was omitted suggested that radiation therapy can be limited to whole brain or whole ventricle with a boost to the primary tumor site without increasing the risk of spinal relapse [21]. The addition of neoadjuvant chemotherapy has been attempted in an effort to reduce the dose and/or volume of radiation [22]. Although multiple regimens have been shown to be effective, many experts advocate the use of carboplatin and etoposide owing to comparable efficacy and reduction in the number of complications suffered by patients with diabetes insipidus when compared with patients treated with ifosfamide and cisplatin-containing regimens. Despite the known chemosensitivity of germinomas, chemotherapy without irradiation is associated with significantly inferior outcomes and is not recommended as a treatment strategy [23]. Recently, the International 624
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Society of Pediatric Oncology published their outcomes from SIOP CNS GCT 96 comparing two treatment regimens for intracranial germinoma: chemotherapy with focal primary site irradiation of 40 Gy in patients with localized disease vs. dose-reduced craniospinal irradiation alone (24-Gy craniospinal irradiation with a 16-Gy boost to the primary tumor site) [24 ]. There was no difference in overall survival but the relapse rate was lower in patients receiving CSI (4/125 vs. 7/65, P ¼ 0.04). When combined treatment is used, the ventricular area should be included in the radiation field [25]. The current Children’s Oncology Group ACNS1123 and SIOP GCT II studies are designed to evaluate the efficacy of further reduction of the radiation therapy in patients with localized germinoma treated with chemotherapy. Historically, the standard of care for patients with disseminated germinomas was craniospinal irradiation at the dose of 36 Gy administered with a boost to the primary lesion to 50 (Gy). The Germany MAKEI 89 protocol supported the craniospinal irradiation alone with a reduced dose to 30 Gy with a boost to 45 Gy [17]. Most recently, the SIOP CNS 96 trial included 45 patients with metastatic disease of whom 28 received only craniospinal irradiation dose of 24 Gy with a boost to 40 Gy and 17 had received additional chemotherapy before craniospinal irradiation [24 ]. Overall survival at 5 years was 98% for all patients. In this setting, there was no additional benefit provided by the inclusion of chemotherapy in the treatment regimen. The prognostic impact of the extent of surgical resection, either initially or after chemotherapy for pure germinoma has also been a matter of debate. An analysis of pooled data from the first, second and third International Central Nervous System Germ Cell Tumor Study groups by Souweidane et al. [25] found better outcomes in patients who had less than 1.5 cm2 of residual disease, suggesting that more aggressive resection may provide some benefit. In the SIOP CNS GCT 96 study [24 ], event-free survival was identical in patients with and without residual disease, indicating that extensive resection at diagnosis is not necessary. Until these hypotheses are supported by future studies, gross total resection is not considered the standard of care. In relapsed germinoma patients who received reduced-dose radiation therapy for their initial disease, salvage therapy with additional irradiation may be successful with or without chemotherapy. Myeloablative chemotherapy with autologous hematopoietic cell rescue may be considered for those patients with relapsed disease in whom craniospinal radiation can not be repeated [26,27]. &&
&&
&&
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Central nervous system germ cell tumors: an update Dufour et al.
Nongerminomatous germ cell tumors
NEUROCOGNITIVE OUTCOME
NGGCTs have a poorer prognosis, with reported survival rates ranging from 40 to 70% [7]. NGGCTs are less radiosensitive. Treatment regimens using irradiation without chemotherapy have resulted in 5-year overall survival rates of only 20–40% [5,28]. Radiation therapy remains an important component of treatment strategies for NGGCTs, as patients treated with chemotherapy alone experience recurrent disease in approximately 50% of cases [29,30]. The addition of neoadjuvant chemotherapy to radiation therapy has significantly improved survival in patients with NGGCT to the range of 60–70%, and is currently considered part of the standard of care. The most active chemotherapeutic agents include: cisplatin, carboplatin, oxaliplatin, etoposide, bleomycin, ifosfamide, gemcitabine, taxanes and vinblastine [7]. The use of neoadjuvant chemotherapy with radiation therapy results in a very high rate of response and permits use of decreased doses of radiation therapy with acceptable toxicity and excellent long-term tumor-related outcomes for NGGCTs. For NGGCTs, significantly improved survival rate was associated with extent of tumor resection [31]. Radical removal is preferred to biopsy or subtotal removal not only for precise histological characterization, but also to give the maximal chance of survival [32]. The presence of a residual mass after chemotherapy and radiation therapy has been associated with disease recurrence in several studies, and some groups advocate second-look surgery intended to remove residual tumor that did not respond to other therapeutic modalities; there is indeed a possibility that this would represent previously undetected teratoma requiring surgical excision [25]. Malignant recurrent or refractory NGGCTs after treatment combining surgery and chemotherapy are rare and large series evaluating the long-term outcome, and the impact of the treatment regimens on the postrelapse survival in children are lacking. The complete surgical removal of the tumor appears essential although not sufficient by itself [33]. Further studies are needed to improve the prognosis of these patients. High-dose chemotherapy with stem-cell rescue may be considered if tumor burden can be minimized by conventional chemotherapy [27]. The AFP level in serum and/or CSF correlates with the risk of relapse; AFP levels higher than 1000 ng/ml are associated with a significantly worse outcome [34,35]. In the current SIOP GCT II trial, these patients with AFP more than 1000 ng/ml will be considered high risk and will receive intensified chemotherapy.
General cognitive abilities appear stable and intact after treatment for most children with CNS GCT, but a significant decline in working memory, processing speed and visual memory becomes evident over time [36]. Cognitive outcome depends on tumor site and irradiation field. Perceptual reasoning for patients with pineal tumors was poor and significantly lower than patients with bifocal tumors. Furthermore, patients with pineal tumors displayed early and stable deficits in working memory, information processing speed and visual memory [37]. Patients with tumors in the basal ganglia region had lower full-scale Intellectual Quotient than those with tumors in the pineal or suprasellar regions [38]. Similarly, patients with basal ganglia tumors had significantly lower performances in working memory, verbal comprehension and perceptual reasoning. In terms of adaptive functioning and quality of life, patients with basal ganglia tumors had measures of selfdirecting, selfcare skills, leisure, communication and functional academics that were again significantly worse than in the pineal and suprasellar patient groups, along with significantly lower measurements of psychosocial health, such as behavior and selfesteem [37]. In this same study, patients who received whole-ventricle irradiation had higher full-scale IQ measurements compared to those who received whole-brain irradiation.
NEW MOLECULAR FINDINGS AND THERAPEUTIC OPPORTUNITIES Owing to the scarcity of tumor specimens available for research, until recently little was known about these rare diseases. Intracranial GCTs share some of the biological characteristics of the extra-CNS ones. KIT point mutations are the single most frequent alteration reported in germinomas [38,39]. The KIT/ RAS signaling pathway is frequently mutated in more than 50% of the tumors [40 ] in which KIT and RAS mutations are mutually exclusive and associated with chromosomal instability [41]. Somatic alterations are also described in the AKT/ mTOR pathway that could represent another therapeutic target apart from c-kit inhibition [40 ]. &&
&&
CONCLUSION After significant improvement in survival using conventional anticancer therapies, the management of intracranial GCTs is becoming more sophisticated with stratification of treatment according to risk factors with the aim of minimizing treatmentrelated side-effects. Some situations remain difficult
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to solve and warrant the development of new therapeutics targeting the specific alterations now identified in intracranial GCTs. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 200-2009. Neuro Oncol 2012; 14 (Suppl 5):V1–V49. 2. Nakamura H, Makino K, Yano S, et al. Kumamoto Brain Tumor Research Group. Epidemiological study of primary intracranial tumors: a regional survey in Kumamoto prefecture in southern Japan–20-year study. Int J Clin Oncol 2011; 16:314–321. 3. Davis FG, Dolecek TA, McCarthy BJ, Villano JL. Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data. Neuro Oncol 2012; 14:1171–1177. 4. Makino K, Nakamura H, Yano S, Kuratsu J. Incidence of primary central nervous system germ cell tumors in childhood: a regional survey in Kumamoto prefecture in southern Japan. Pediatr Neurosurg 2014; 49:155–158. 5. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985; 63:155–167. 6. Villano JL, Propp JM, Porter KR, et al. Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro Oncol 2008; 10:121– 130. 7. Echevarria ME, Fangusaro J, Goldman S. Pediatric central nervous system germ cell tumors: a review. Oncologist 2008; 13:690–699. 8. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114:97– 109. 9. Allen J, Nisselbaum J, Epstein F, et al. Alphafetoprotein and human chorionic gonadotropin determination in cerebrospinal fluid. An aid to the diagnosis and management of intracranial germ-cell tumors. J Neurosurg 1979; 51:368– 374. 10. Haase J, Borgaard-Pedersen B. alpha-feto-protein (AFP) and human chorionic gonadotropin (HCG) as biochemical markers of intracranial germ-cell tumours. Acta Neurochir (Wien) 1979; 50:67–69. 11. Shinoda J, Yamada H, Sakai N, et al. Placental alkaline phosphatase as a tumor marker for primary intracranial germinoma. J Neurosurg 1988; 68:710– 720. 12. Watanabe S, Aihara Y, Kikuno A, et al. A highly sensitive and specific && chemiluminescent enzyme immunoassay for placental alkaline phosphatase in the cerebrospinal fluid of patients with intracranial germinomas. Pediatr Neurosurg 2012; 48:141–145. This article describes a new assay that could be used for noninvasive diagnosis of germinomas by measuring the placental alkaline phosphatase which is a promising biomarker for nonsecreting GCTs. 13. Takeshima H, Kuratsu J. A review of soluble c-kit (s-kit) as a novel tumor marker and possible molecular target for the treatment of CNS germinoma. Surg Neurol 2003; 60:324–325. 14. Robison NJ, Prabhu SP, Sun P, et al. Predictors of neoplastic disease in && children with isolated pituitary stalk thickening. Pediatr Blood Cancer 2013; 60:1630–1635. This interesting study tackles the recurrent diagnostic dilemma in front of an enlarged pituitary stalk. It shows that the presence of an anterior pituitary hormonal deficit is a good predictor of the presence of a tumor in patients with associated diabetes insipidus. Conversely, the absence of any hormonal deficit excludes a priori the possibility of a tumor. 15. Sethi RV, Marino R, Niemierko A, et al. Delayed diagnosis in children with intracranial germ cell tumors. J Pediatr 2013; 163:1448–1453. 16. Haddock MG, Schild SE, Scheithauer BW, Schomberg PJ. Radiation therapy for histologically confirmed primary central nervous system germinoma. Int J Radiat Oncol Biol Phys 1997; 38:915–923. 17. 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; 17:2585–2592.
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18. Ogawa K, Shikama N, Toita T, et al. Long-term results of radiotherapy for intracranial germinoma: a multiinstitutional retrospective review of 126 patients. Int J Radiat Oncol Biol Phys 2004; 58:705–713. 19. Maity A, Shu HK, Janss A, et al. Craniospinal radiation in the treatment of biopsy-proven intracranial germinomas: twenty-five years’ experience in a single center. Int J Radiat Oncol Biol Phys 2004; 58:1165–1170. 20. Merchant TE, Sherwood SH, Mulhern RK, et al. CNS germinoma: disease control and long-term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 2000; 46:1171–1176. 21. Alapetite C, Brisse H, Patte C, et al. Pattern of relapse and outcome of nonmetastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience. Neuro Oncol 2010; 12:1318–1325. 22. Bouffet E, Baranzelli MC, Patte C, et al. Combined treatment modality for intracranial germinomas: results of a multicentre SFOP experience. Socie´te´ Franc¸aise d’Oncologie Pe´diatrique. Br J Cancer 1999; 79:1199–1204. 23. Da Silva NS, Cappellano AM, Diez B, et al. Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study. Pediatr Blood Cancer 2010; 54:377–383. 24. Calaminus G, Kortmann R, Worch J, et al. SIOP CNS GCT final report of && outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 2013; 15:788–796. This article reports the largest trial performed to date in children with germinomas. It shows that craniospinal irradiation offers a slightly better chance of progressionfree survival than combined therapy with local irradiation and chemotherapy in nonmetastatic germinomas. The comparison of the two approaches in terms of neuropsychological sequelae and growth is still to be analyzed. 25. Souweidane M, Krieger M, Weiner HL, Finlay JL. Surgical management of primary central nervous system germ cell tumors: proceedings from the Second International Symposium on Central Nervous System Germ Cell Tumors. J Neurosurg Pediatr 2010; 6:125–130. 26. Bouffet E. The role of myeloablative chemotherapy with autologous hematopoietic cell rescue in central nervous system germ cell tumors. Pediatr Blood Cancer 2010; 54:644–646. 27. Modak S, Gardner S, Dunkel IJ, et al. Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors. J Clin Oncol 2004; 22:1934–1943. 28. Hoffman HJ, Otsubo H, Hendrick EB, et al. Intracranial germ-cell tumors in children. J Neurosurg 1991; 74:545–551. 29. Balmaceda C, Heller G, Rosenblum M, et al. Chemotherapy without irradiation: a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol 1996; 14:2908–2915. 30. Baranzelli MC, Patte C, Bouffet E, et al. An attempt to treat pediatric intracranial alphaFP and betaHCG secreting germ cell tumors with chemotherapy alone. SFOP experience with 18 cases. Societe Francaise d’Oncologie Pediatrique. J Neurooncol 1998; 37:229–239. 31. Schild SE, Scheithauer BW, Haddock MG, et al. Histologically confirmed pineal tumors and other germ cell tumors of the brain. Cancer 1996; 78:2564–2571. 32. Nam D, Cho BK, Shin HJ, et al. Treatment of intracranial nongerminomatous malignant germ cell tumor in children: the role of each treatment modality. Childs Nerv Syst 1999; 15:185–191. 33. Faure-Conter C, Orbach D, Cropet C, et al. Salvage therapy for refractory or recurrent pediatric germ cell tumors: the French SFCE experience. Pediatr Blood Cancer 2014; 61:253–259. 34. Matsutani M, Sano K, Takakura K, et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 1997; 86:446–455. 35. Kim A, Ji L, Balmaceda C, et al. The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors. Pediatr Blood Cancer 2008; 51:768–773. 36. Mabbott DJ, Monsalves E, Spiegler BJ, et al. Longitudinal evaluation of neurocognitive function after treatment for central nervous system germ cell tumors in childhood. Cancer 2011; 117:5402–5411. 37. Liang S-Y, Yang T-F, Chen Y-W, et al. Neuropsychological functions and quality of life in survived patients with intracranial germ cell tumors after treatment. Neuro Oncol 2013; 15:1543–1551. 38. Kamakura Y, Hasegawa M, Minamoto T, et al. C-kit gene mutation: common and widely distributed in intracranial germinomas. J Neurosurg 2006; 104:173–180. 39. Sakuma Y, Sakurai S, Oguni S, et al. C-kit gene mutations in intracranial germinomas. Cancer Sci 2004; 95:716–720. 40. Wang L, Yamaguchi S, Burstein MD, et al. Novel somatic and germline && mutations in intracranial germ cell tumours. Nature 2014; 511:241–245. This very recent study describes the first genomic analysis of GCTs with nextgeneration sequencing. In addition to new potential targets, it describes recurrent germline variants in a histone demethylase, JMJD1C. 41. Fukushima S, Otsuka A, Suzuki T, et al. Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas. Acta Neuropathol 2014; 127:911–925.
Volume 26 Number 6 November 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Central nervous system germ cell tumors: an update Christelle Dufour, Le´a Guerrini-Rousseau, and Jacques Grill
Purpose of review Malignant germ cell tumors in the central nervous system are rare and not well known because they occur mainly in adolescents, an age in which patients are dispersed in adult and pediatric wards. Their biology starts to be unraveled by high-throughput genomics and their treatment is now well defined thanks to international studies, including patients from childhood through adulthood. Recent findings Chemotherapy gained definitively a role apart from radiotherapy in order to improve tumor control in secreting neoplasms, but also to decrease the volume or dose of radiation therapy in germinomas. Neurocognitive outcome remains good with some disparities because of tumor location, patients with pineal tumors being less impaired than those with supratentorial malignant germ cell tumors. Alterations in the KIT/RAS as well as in the mTOR/AKT pathways have been frequently reported and could represent interesting opportunities to introduce targeted therapies in these neoplasms. Summary Diagnosis and treatment of malignant germ cell tumor of the brain are now well established within experienced multidisciplinary teams taking care of adolescents and young adults. The prognosis of secreting tumors has not yet reached the excellent results obtained for germinomas but aggressive chemotherapy including high-dose chemotherapy with stem-cell support may contribute to improve their outcome. The role of targeted therapies has yet to be determined in view of the recently described molecular findings. Keywords alpha-fetoprotein, choriocarcinoma, germinoma, human chorionic gonadotropin, teratoma, yolk sac tumor
INTRODUCTION Intracranial central nervous system germ cell tumors (CNS GCTs) are a heterogeneous group of lesions that can be divided into germinomas, nongerminomatous GCTs (NGGCTs) and teratomas, these later lesions being often considered as a separate category. CNS GCTs are more common in children and in young adults, mainly between 10 and 19 years of age [1] and are considered the most curable primary malignant brain tumor. Recent studies [2,3] have suggested similar incidence in Japan as in the United States population. In childhood, the incidence of primary CNS GCTs remains higher in Japan than in the United States and other Western countries [4]. The majority of primary CNS GCTs arise in the pineal or suprasellar regions. The pineal gland has an unusually high incidence of primary GCTs [5,6]. At the time of diagnosis, about 5–10% of patients have both suprasellar and pineal gland involvement [5,7]. This bifocal disease occurs primarily in www.co-oncology.com
patients with germinomas [5], and it is unclear whether it represents actual spread of the tumor or synchronous development of tumors in two sites. GCTs will also arise in other midline structures of the brain, including tumors of the fourth ventricle, basal ganglia and thalamus.
CLASSIFICATION Most commonly, CNS GCTs are classified using the WHO classification system (adapted from [8]). WHO classification of intracranial GCTs is as follows: Brain Tumor Programme, Department of Pediatric and Adolescent Oncology, Gustave Roussy and University Paris-Sud, Villejuif, France Correspondence to Jacques Grill, Brain Tumor Programme, Department of Pediatric and Adolescent Oncology, Gustave Roussy and University Paris-Sud, Villejuif, France. Tel: +33 1 42 11 62 09; fax: +33 1 42 11 52 75; e-mail: [email protected] Curr Opin Oncol 2014, 26:622–626 DOI:10.1097/CCO.0000000000000140 Volume 26 Number 6 November 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Central nervous system germ cell tumors: an update Dufour et al.
KEY POINTS Presentation of GCTs can be misleading but the detection of specific biomarkers in the blood and/or the CSF (such as soluble c-kit or placental alkaline phosphatase) is an invaluable diagnostic tool that can alleviate the recourse to risky surgical procedure. Treatment strategies are defined according to the presence or absence of a significant secretion of AFP or HCG. Intensification of chemotherapy is efficient to reduce the extent of radiation or to improve the outcome of secreting GCTs. New therapeutic opportunities will comprise the targeting of druggable genetic alterations in the KIT/RAS and the mTOR pathways.
(1) (2) (3) (4) (5) (6)
1.5.0 GCTs, 2.5.1 germinomas, 3.5.2 embryonal carcinoma, 4.5.3 yolk sac tumor, 5.5.4 choriocarcinoma, 6.5.5 teratoma, (a) 5.5.1 immature, (b) 5.5.2 mature, (c) 5.5.3 teratoma with malignant transformation, (7) 7.5.6 mixed germ cell. Classifications are subjective and are also highly dependent on tumor sampling, especially when only biopsies are performed. The presence, or absence, of specific protein markers, produced and/or secreted by tumor cells, has been an extremely important adjunct in the diagnosis of GCTs [9]. These secreted markers can be measured in both serum and cerebrospinal fluid (CSF), although CSF levels are a more sensitive and reliable measure for diagnosis. The most common markers are alpha-fetoprotein (AFP) and b-human chorionic gonadotropin (b-HCG). The usual pattern of tumor marker secretion in GCTs is outlined in Table 1. AFP is a yolk cell marker and is present in endodermal sinus tumors. b-HCG is produced by normal trophoblastic tissue in the placenta, and by choriocarcinomas [10]. Germinoma may be associated with mild elevation of total HCG (< 50 IU/l in serum and CSF) indicating the presence of syncytiotrophoblastic cells. In approximately 20% of germinoma, serum levels of placental alkaline phosphatase may be elevated [11]. The relevance of this marker in diagnosing the specific type of GCT and on treatment is not yet clear. Recently, the determination of CSF placental alkaline phosphatase by the chemiluminescent
Table 1. Classification of germ cell tumors according to tumor markers Marker Tumor type
b-HCG
AFP
PLAP
c-Kit
Pure germinoma
þ/
þ
Germinoma (syncytiotrophoblastic)
þ
þ/
þ
Endodermal sinus tumor
þ
þ/
Choriocarcinoma
þ
þ/
Embryonal carcinoma
þ
Mixed GCT
þ/
þ/
þ/
þ/
Mature teratoma
Immature teratoma
þ/
þ/
þ/
b-HCG, b-human chorionic gonadotropin; AFP, alpha-fetoprotein; GCT, germ cell tumor; PLAP, placental alkaline phosphatase. Adapted from [8].
method could provide a clinically useful tumor marker for the diagnosis and monitoring of intracranial germinoma (94% sensitivity; 97% specificity) [12 ]. Additionally, S-kit, a soluble form of the c-kit (transmembrane tyrosine kinase receptor that plays a crucial role in the development of germ cells) could be a novel tumor marker for CNS germinomas [13]. &&
CLINICAL PRESENTATION GCTs in the pineal region most commonly present with hydrocephalus associated with ophthalmologic signs, somnolence, ataxia, seizures and behavioral changes. Parinaud’s syndrome, caused by the involvement of adjacent midbrain structures, is also seen at presentation in up to 50% of pineal GCTs. Patients with suprasellar GCTs almost always present with hypothalamic/pituitary axis dysfunction at least diabetes insipidus [5]. In the presence of a thickening of the pituitary stalk during the workout of a diabetes insipidus, the association with another pituitary deficit is suggestive of a tumor [14 ] as well as its persistence over a period of 6 months; both conditions should trigger the need for a biopsy even if biomarkers remain negative in the blood and in the CSF [7]. More than half (54%) of patients may have a duration of symptoms prior to diagnostic MRI greater than 6 months [15]. No difference in terms of progression-free survival was found between patients who experienced a delay in diagnosis and those who did not. &&
DIAGNOSIS The neuroimaging characteristics of CNS GCTs alone are unable to reliably differentiate germinoma
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from NGGCTs or from other tumors. A tumor biopsy is required for diagnosis, except in cases in which characteristic serum and/or CSF tumor marker elevations exist (AFP > 25 ng/ml and/or total HCG > 50 IU/l in serum or CSF) [7]. CNS GCTs have a propensity to disseminate throughout the neuroaxis, even at early stages. All patients with a suspected CNS GCT require an extensive metastatic evaluation including an MRI of the brain and spine with gadolinium and CSF cytology after cytocentrifugation as tumor cells may be rare. Among the 169 patients of the SIOP CNS GCT 96 trial, the occurrence of relapses correlated with incompleteness of the pretherapeutic diagnostic work-up and increased from 4 to 24%.
TREATMENT The treatment of germinomas should be distinguished from that of secreting GCTs.
Germinomas Germinomas carry an excellent prognosis with 5-year PFS rates and cure in over 90% of patients. Germinomas are extremely radiosensitive and 5-year survival rates exceeding 90% have been reported with radiotherapy alone [16–20]. Historically, localized germinomas were treated with 36 Gy craniospinal irradiation with a boost to the primary tumor site for a total of 50–54 Gy. Owing to the incidence of clinically significant radiationinduced late effects, including endocrinopathies, second malignancies and neurocognitive impairment, recent studies have evaluated reducedvolume or reduced-dose radiation therapy. Reduced volumes and dose reductions are usually combined with preirradiation chemotherapy. Investigations demonstrating the low incidence of spinal relapse in patients for whom spinal irradiation was omitted suggested that radiation therapy can be limited to whole brain or whole ventricle with a boost to the primary tumor site without increasing the risk of spinal relapse [21]. The addition of neoadjuvant chemotherapy has been attempted in an effort to reduce the dose and/or volume of radiation [22]. Although multiple regimens have been shown to be effective, many experts advocate the use of carboplatin and etoposide owing to comparable efficacy and reduction in the number of complications suffered by patients with diabetes insipidus when compared with patients treated with ifosfamide and cisplatin-containing regimens. Despite the known chemosensitivity of germinomas, chemotherapy without irradiation is associated with significantly inferior outcomes and is not recommended as a treatment strategy [23]. Recently, the International 624
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Society of Pediatric Oncology published their outcomes from SIOP CNS GCT 96 comparing two treatment regimens for intracranial germinoma: chemotherapy with focal primary site irradiation of 40 Gy in patients with localized disease vs. dose-reduced craniospinal irradiation alone (24-Gy craniospinal irradiation with a 16-Gy boost to the primary tumor site) [24 ]. There was no difference in overall survival but the relapse rate was lower in patients receiving CSI (4/125 vs. 7/65, P ¼ 0.04). When combined treatment is used, the ventricular area should be included in the radiation field [25]. The current Children’s Oncology Group ACNS1123 and SIOP GCT II studies are designed to evaluate the efficacy of further reduction of the radiation therapy in patients with localized germinoma treated with chemotherapy. Historically, the standard of care for patients with disseminated germinomas was craniospinal irradiation at the dose of 36 Gy administered with a boost to the primary lesion to 50 (Gy). The Germany MAKEI 89 protocol supported the craniospinal irradiation alone with a reduced dose to 30 Gy with a boost to 45 Gy [17]. Most recently, the SIOP CNS 96 trial included 45 patients with metastatic disease of whom 28 received only craniospinal irradiation dose of 24 Gy with a boost to 40 Gy and 17 had received additional chemotherapy before craniospinal irradiation [24 ]. Overall survival at 5 years was 98% for all patients. In this setting, there was no additional benefit provided by the inclusion of chemotherapy in the treatment regimen. The prognostic impact of the extent of surgical resection, either initially or after chemotherapy for pure germinoma has also been a matter of debate. An analysis of pooled data from the first, second and third International Central Nervous System Germ Cell Tumor Study groups by Souweidane et al. [25] found better outcomes in patients who had less than 1.5 cm2 of residual disease, suggesting that more aggressive resection may provide some benefit. In the SIOP CNS GCT 96 study [24 ], event-free survival was identical in patients with and without residual disease, indicating that extensive resection at diagnosis is not necessary. Until these hypotheses are supported by future studies, gross total resection is not considered the standard of care. In relapsed germinoma patients who received reduced-dose radiation therapy for their initial disease, salvage therapy with additional irradiation may be successful with or without chemotherapy. Myeloablative chemotherapy with autologous hematopoietic cell rescue may be considered for those patients with relapsed disease in whom craniospinal radiation can not be repeated [26,27]. &&
&&
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Central nervous system germ cell tumors: an update Dufour et al.
Nongerminomatous germ cell tumors
NEUROCOGNITIVE OUTCOME
NGGCTs have a poorer prognosis, with reported survival rates ranging from 40 to 70% [7]. NGGCTs are less radiosensitive. Treatment regimens using irradiation without chemotherapy have resulted in 5-year overall survival rates of only 20–40% [5,28]. Radiation therapy remains an important component of treatment strategies for NGGCTs, as patients treated with chemotherapy alone experience recurrent disease in approximately 50% of cases [29,30]. The addition of neoadjuvant chemotherapy to radiation therapy has significantly improved survival in patients with NGGCT to the range of 60–70%, and is currently considered part of the standard of care. The most active chemotherapeutic agents include: cisplatin, carboplatin, oxaliplatin, etoposide, bleomycin, ifosfamide, gemcitabine, taxanes and vinblastine [7]. The use of neoadjuvant chemotherapy with radiation therapy results in a very high rate of response and permits use of decreased doses of radiation therapy with acceptable toxicity and excellent long-term tumor-related outcomes for NGGCTs. For NGGCTs, significantly improved survival rate was associated with extent of tumor resection [31]. Radical removal is preferred to biopsy or subtotal removal not only for precise histological characterization, but also to give the maximal chance of survival [32]. The presence of a residual mass after chemotherapy and radiation therapy has been associated with disease recurrence in several studies, and some groups advocate second-look surgery intended to remove residual tumor that did not respond to other therapeutic modalities; there is indeed a possibility that this would represent previously undetected teratoma requiring surgical excision [25]. Malignant recurrent or refractory NGGCTs after treatment combining surgery and chemotherapy are rare and large series evaluating the long-term outcome, and the impact of the treatment regimens on the postrelapse survival in children are lacking. The complete surgical removal of the tumor appears essential although not sufficient by itself [33]. Further studies are needed to improve the prognosis of these patients. High-dose chemotherapy with stem-cell rescue may be considered if tumor burden can be minimized by conventional chemotherapy [27]. The AFP level in serum and/or CSF correlates with the risk of relapse; AFP levels higher than 1000 ng/ml are associated with a significantly worse outcome [34,35]. In the current SIOP GCT II trial, these patients with AFP more than 1000 ng/ml will be considered high risk and will receive intensified chemotherapy.
General cognitive abilities appear stable and intact after treatment for most children with CNS GCT, but a significant decline in working memory, processing speed and visual memory becomes evident over time [36]. Cognitive outcome depends on tumor site and irradiation field. Perceptual reasoning for patients with pineal tumors was poor and significantly lower than patients with bifocal tumors. Furthermore, patients with pineal tumors displayed early and stable deficits in working memory, information processing speed and visual memory [37]. Patients with tumors in the basal ganglia region had lower full-scale Intellectual Quotient than those with tumors in the pineal or suprasellar regions [38]. Similarly, patients with basal ganglia tumors had significantly lower performances in working memory, verbal comprehension and perceptual reasoning. In terms of adaptive functioning and quality of life, patients with basal ganglia tumors had measures of selfdirecting, selfcare skills, leisure, communication and functional academics that were again significantly worse than in the pineal and suprasellar patient groups, along with significantly lower measurements of psychosocial health, such as behavior and selfesteem [37]. In this same study, patients who received whole-ventricle irradiation had higher full-scale IQ measurements compared to those who received whole-brain irradiation.
NEW MOLECULAR FINDINGS AND THERAPEUTIC OPPORTUNITIES Owing to the scarcity of tumor specimens available for research, until recently little was known about these rare diseases. Intracranial GCTs share some of the biological characteristics of the extra-CNS ones. KIT point mutations are the single most frequent alteration reported in germinomas [38,39]. The KIT/ RAS signaling pathway is frequently mutated in more than 50% of the tumors [40 ] in which KIT and RAS mutations are mutually exclusive and associated with chromosomal instability [41]. Somatic alterations are also described in the AKT/ mTOR pathway that could represent another therapeutic target apart from c-kit inhibition [40 ]. &&
&&
CONCLUSION After significant improvement in survival using conventional anticancer therapies, the management of intracranial GCTs is becoming more sophisticated with stratification of treatment according to risk factors with the aim of minimizing treatmentrelated side-effects. Some situations remain difficult
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to solve and warrant the development of new therapeutics targeting the specific alterations now identified in intracranial GCTs. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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It shows that craniospinal irradiation offers a slightly better chance of progressionfree survival than combined therapy with local irradiation and chemotherapy in nonmetastatic germinomas. The comparison of the two approaches in terms of neuropsychological sequelae and growth is still to be analyzed. 25. Souweidane M, Krieger M, Weiner HL, Finlay JL. Surgical management of primary central nervous system germ cell tumors: proceedings from the Second International Symposium on Central Nervous System Germ Cell Tumors. J Neurosurg Pediatr 2010; 6:125–130. 26. Bouffet E. The role of myeloablative chemotherapy with autologous hematopoietic cell rescue in central nervous system germ cell tumors. Pediatr Blood Cancer 2010; 54:644–646. 27. Modak S, Gardner S, Dunkel IJ, et al. Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors. J Clin Oncol 2004; 22:1934–1943. 28. Hoffman HJ, Otsubo H, Hendrick EB, et al. 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Faure-Conter C, Orbach D, Cropet C, et al. Salvage therapy for refractory or recurrent pediatric germ cell tumors: the French SFCE experience. Pediatr Blood Cancer 2014; 61:253–259. 34. Matsutani M, Sano K, Takakura K, et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 1997; 86:446–455. 35. Kim A, Ji L, Balmaceda C, et al. The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors. Pediatr Blood Cancer 2008; 51:768–773. 36. Mabbott DJ, Monsalves E, Spiegler BJ, et al. Longitudinal evaluation of neurocognitive function after treatment for central nervous system germ cell tumors in childhood. Cancer 2011; 117:5402–5411. 37. Liang S-Y, Yang T-F, Chen Y-W, et al. Neuropsychological functions and quality of life in survived patients with intracranial germ cell tumors after treatment. Neuro Oncol 2013; 15:1543–1551. 38. Kamakura Y, Hasegawa M, Minamoto T, et al. 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