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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 5  |  Page : 134-142

Challenges and advances in the management of pediatric intracranial germ cell tumors: A case report and literature review

1 Department of Paediatric Oncology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, B4 6NH, UK
2 Department of Paediatric Oncology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, B4 6NH; Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

Date of Web Publication30-Oct-2018

Correspondence Address:
Dr. Gerard Cathal Millen
Department of Paediatric Oncology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, B4 6NH
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_36_17

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Intracranial germ cell tumors are a heterogeneous group of tumors, broadly classified into germinomatous, nongerminomatous, or teratoma subtypes. Treatment has evolved over recent decades to include multimodal therapy combining surgery, radiotherapy, and chemotherapy. Although the majority of intracranial germs cell tumors are treated successfully, management can be fraught with complexities and present significant clinical challenges. Bifocal disease is well described, but rare, and therefore its behavior is not well characterized, particularly in nongerminomatous disease. This case report presents an interesting case, with both rare and common complications, in particular, to emphasize the challenges of germ cell tumor management. With a focus on bifocal disease, we review the published cases and highlight how advanced imaging and magnetic resonance spectroscopy can be used in management. Advances in biology, targeted agents, and novel diagnostic tools are also discussed.

Keywords: Bifocal disease, functional imaging, growing teratoma syndrome, intracranial germ cell tumors, relapse

How to cite this article:
Millen GC, Manias KA, Peet AC, Adamski JK. Challenges and advances in the management of pediatric intracranial germ cell tumors: A case report and literature review. Cancer Transl Med 2018;4:134-42

How to cite this URL:
Millen GC, Manias KA, Peet AC, Adamski JK. Challenges and advances in the management of pediatric intracranial germ cell tumors: A case report and literature review. Cancer Transl Med [serial online] 2018 [cited 2019 Jun 27];4:134-42. Available from: http://www.cancertm.com/text.asp?2018/4/5/134/244520

  Introduction Top

Intracranial germ cell tumors (iGCTs) are a heterogeneous group of tumors classified by the World Health Organization into (1) germinomas, (2) embryonal carcinomas, (3) yolk sac tumors, (4) choriocarcinomas, (5) teratomas, and (6) mixed germ cell tumors.[1],[2] A more practical, treatment-based classification divides iGCTs into three groups: (1) germinomas, (2) nongerminomatous germ cell tumors (NGGCTs), and (3) teratomas. Clinical management of these rare tumors can be difficult. We present a case that highlights some of the common and rarer challenges including bifocal disease, growing teratoma syndrome (GTS) and the management of relapsed disease. We also discuss the use of novel imaging techniques and other diagnostic tools as well as the use of targeted therapies. Fully informed consent was obtained from the family.

  Case Report Top

A 10-year-old boy presented with worsening squint, intermittent, severe headaches, polydipsia, polyuria, behavioral change, and increasing lethargy. Examination revealed papilledema, a 6th cranial nerve palsy, Parinaud's syndrome, and advanced puberty. Magnetic resonance imaging (MRI) revealed two midline tumors, suprasellar and pineal [Figure 1]. Appearances were consistent with that of a germ cell tumor. Diffusion-weighted imaging (DWI) and[1] H-magnetic resonance spectroscopy (MRS) showed that the two components displayed very different profiles [Figure 2]. There were no malignant cells in the cerebrospinal fluid (CSF). Serum and CSF tumor markers showed raised α-fetoprotein (AFP) (76 and 8 kU/L, respectively) and β-human chorionic gonadotropin (β-HCG) (31 and 7 iU/L, respectively). The imaging and tumor markers were consistent with a diagnosis of an NGGCT.
Figure 1: Magnetic resonance imaging at presentation. (a) T2-weighted axial image showing suprasellar and pineal tumors. (b) T1-weighted sagittal images showing both tumors

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Figure 2: 1H-magnetic resonance spectroscopy at presentation showing marked differences between the suprasellar and pineal lesions. (a) Suprasellar lesion showing high choline and creatine peaks. (b) Pineal lesion showing predominant lipid peak

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Treatment commenced on the SIOP CNS GCT II trial (cisplatin, etoposide and ifosfamide chemotherapy [PEI], surgical resection, and focal radiotherapy). During the first cycle, the patient rapidly deteriorated with reduced consciousness. The size of the suprasellar tumor was significantly increased on imaging, however, the pineal aspect had resolved [Figure 3]. Urgent surgical debulking was undertaken and histology showed mostly mature teratomatous tissue, in keeping with GTS. Of note, focal AFP staining gave suspicion of small foci of yolk sac tumor. Modification to the chemotherapy regimen was required due to brittle diabetes insipidus (DI) and fluid shifts, altered neurological state, and renal toxicity. Despite this, a good treatment response was observed and tumor markers normalized. Resection of the suprasellar residual disease carried unacceptable morbidity; therefore, the patient received a dose of 54 Gy through proton radiotherapy, with the field encompassing the pineal and suprasellar region, while sparing the whole ventricles.
Figure 3: T2-weighted magnetic resonance images showing marked increase in the suprasellar element of the tumor. (a) Axial. (b) Sagittal

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Five months later, the patient presented with increased vomiting, headache, and hypernatremia. Serum tumor markers were raised (AFP 117 ikU/mL and β-HCG 28 iU/L) and imaging confirmed relapse with two new foci of disease in the posterior fossa obex and right parietal shunt tract (both outside the radiation field) [Figure 4]. Reinduction chemotherapy with GemPOX (gemcitabine, paclitaxel, and oxaliplatin) was prescribed.[3] Both metastatic lesions decreased in size before stabilizing. The residual at the obex was excised and histology showed mature teratoma with no evidence of malignant disease. Treatment was consolidated with high-dose thiotepa and etoposide with stem cell rescue, followed by 36 Gy delivered through craniospinal irradiation (CSI). At the time of completion, tumor markers remained negative and residual abnormalities stable.
Figure 4: T2-weighted magnetic resonance imaging at relapse showing two new foci of disease at the obex (a) and the right parietal shunt tract (b)

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Four months following the salvage treatment, although prognosis remains poor, the patient is conceivably cured. He has pan-hypopituitarism, hypothalamic damage, and little functional vision. His neurocognition is markedly affected and his memory and processing skills are poor. The prospect of an independent life is slight.

  Discussion Top

Intracranial germ cell tumors

iGCTs comprise 3% of pediatric brain tumors in the West and up to 15% in Asia.[4],[5],[6],[7] Germinomas occur twice as often as NGGCTs.[4],[6],[8],[9] In general, iGCTs are predominantly midline tumors arising in the pineal and suprasellar regions but also occur in the basal ganglia, third ventricle, thalamus, and cerebral hemispheres.[8],[10] While presentation may occur at any age, the incidence is highest in the first two decades of life, with the median reported age ranging from 13 to 14.[5],[10],[11] A strong male preponderance of 2–7:1 is seen in all iGCTs, but particularly in pineal tumors (11.5:1).[4],[6],[12] Presentation typically depends on tumor location. Pineal lesions commonly have raised intracranial pressure (ICP), hydrocephalus, and Parinaud's syndrome caused by dorsal midbrain compression.[13],[14] Suprasellar lesions can present insidiously and rarely exhibit raised ICP. Endocrinological abnormalities are common, particularly DI. This can be present before radiologically detectable disease.[15] Growth hormone deficiency, precocious puberty, delayed sexual development, and menstrual irregularities can also occur. Despite treatment, endocrinopathies, especially DI, usually persist and cause considerable morbidity.[15],[16],[17] Diagnosis may be significantly delayed following the onset of symptoms.[18] Loss of vision is caused by direct compression of the visual pathways, hydrocephalus-related optic atrophy, or as a side effect of surgery.[19] Behavioral or psychiatric disturbances are common secondary to protracted endocrine deficiencies or direct tumor infiltration of the basal ganglia or hypothalamus.[20]

Imaging plays a central role in the diagnosis and management of iGCT. Although conventional imaging is rarely sufficient for diagnosis, characteristic features facilitate differentiation from other central tumors and between histological subtypes.[21] Germinomas usually demonstrate homogeneous enhancement, whereas NGGCTs enhance heterogeneously. Advances in imaging herald the development of several techniques that provide additional information about tissue characteristics, including DWI MRI and[1] H-MRS, which begin to be used to improve noninvasive diagnoses. DWI provides information about tissue cellularity through measuring the microscopic rate of water diffusion in tissue.[21],[22],[23],[24] As germinomas are highly cellular, most demonstrate significantly restricted diffusion compared to NGGCTs.[25],[26] MRS provides information about tissue metabolites, such as choline (membrane synthesis), N-acetylaspartate (neuronal marker), and mobile lipids (apoptosis and necrosis).[27] This is presented as a graphical spectrum characteristic of tumor type [Figure 5]. In general, iGCTs have significantly higher lipid and macromolecule concentrations relative to other tumors. Germinomas are characterized by very high lipid and total choline levels and the presence of taurine.[28] Teratomas have significantly lower total choline and creatine levels than germinomas, with high lipids reflecting intratumoral fat.[28],[29]
Figure 5: Example of1H-magnetic resonance spectroscopy with different markers labeled

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Currently, the diagnosis of iGCT is approached by surgery or the assessment of tumor markers. A tissue diagnosis, through biopsy or a more aggressive surgical approach, is the accepted method of diagnosis in germinomas. Surgery, however, risks significant morbidity.[30] Scrutiny of tumor markers allows diagnosis without surgery in some patients, specifically NGGCTs. Up to 85% of NGGCTs secrete one or more of the three main tumor markers: AFP, β-HCG, and placental alkaline phosphatase.[31],[32] Pure germinomas do not secrete any tumor markers, although some germinomas contain syncytiotrophoblastic cells, which secrete low levels of β-HCG. As tumor markers are raised in CSF and serum, both of them are assessed.[2],[33],[34] Most experts consider an AFP level of >10 ng/mL diagnostic of NGGCT.[35],[36],[37] β-HCG is more controversial. In the West, β-HCG higher than 50 mIU/mL is currently diagnostic of NGGCT without a biopsy.[11] In Japan, a more liberal β-HCG cutoff is applied up to 200 mIU/mL if the histology is in keeping with a germinoma. No difference in outcome has been reported for patients treated in this fashion.[34],[38],[39]

Prognosis of iGCT is based mainly on histology. Clear evidence supports a worse prognosis for NGGCTs than germinomas (5-year overall survival [OS] 50%–56% vs. 84%–100%, respectively).[37],[40],[41] Treatment combines surgery, chemotherapy, and radiotherapy. The chosen approach depends on the histology and geographical location. For example, in the East, up-front surgery is performed, whereas in the West, limited surgery for diagnostic purposes is favored.[11],[30],[42] Achieving a complete response (CR), either by initial total resection or by the removal of residual tumor after neoadjuvant therapy, is directly related to outcome.[5],[43],[44] The exception is intracranial teratomas, where the preferred treatment is surgical excision, as adjuvant or neoadjuvant therapy has no proven efficacy.[2],[45]

For many decades, radiotherapy has been the backbone of treatment for iGCTs. Germinomas are exquisitely radiosensitive, with a 5-year OS of over 90% with craniospinal radiotherapy alone.[10],[38],[46] Although cure rates are excellent, long-term morbidity and mortality have led to attempts to omit or reduce radiation fields raising several clear points. CSI has a role but can be limited to metastatic or relapsed disease.[10],[38],[46] Radiotherapy is an essential component in treatment and the elimination of radiotherapy altogether has been shown to result in high relapse rates (up to 50%).[37],[41] In germinoma, tumor bed radiotherapy leads to unacceptable rates of ventricular relapses, therefore, the recommended field for germinomas is whole ventricular radiotherapy (WVI).[10],[11],[47] NGGCTs are less radiosensitive and a higher dose (54 Gy) is often prescribed.[48] The optimal field is disputed. In Europe, focal tumor bed radiation is given, based on the relatively few distant relapses. In Japan, NGGCTs stratify as high risk and therefore receive CSI, whereas WVI is used in the current ANCS1123 trial. CSI is recommended for metastatic lesions.[33],[49],[50],[51]

The OS in patients with germinoma is excellent with or without chemotherapy. Adjuvant chemotherapy is, therefore, used to reduce the radiation dose or field and the associated morbidity while maintaining the excellent OS.[52] Regarding NGGCTs, chemotherapy is fundamental to improved survival.[37],[41],[49] Commonly used agents include carboplatin, cisplatin, etoposide, bleomycin, cyclophosphamide, and ifosfamide.[10],[36],[41],[43] Data show that the dose and field of radiotherapy can be safely reduced in both germinomas and NGGCTs treated with concurrent chemotherapy. High-dose chemotherapy with autologous stem cell rescue (HDC + AuSCR) has shown promise, albeit mainly in the context of relapsed disease, and is being investigated in Europe and North America in high risk, poorly responsive disease.[40],[53],[54],[55]

Bifocal or metastatic disease?

Bifocal iGCTs are described as simultaneously occurring tumors in the suprasellar and pineal region and are well-recognized phenomenon. First described in 1974 as “double midline intracranial atypical teratomas,” the main controversy in management is whether they represent localized metasynchronous tumors or metastatic disease, thus dictating the most appropriate management.[56]

The typical appearance of bifocal disease on an MRI scan is considered so archetypical that, in the absence of tumor markers, a diagnosis of germinoma is accepted without biopsy.[57],[58] Bifocal NGGCT is diagnosed if tumor markers are raised. However, other tumors are reported, including histologically confirmed NGGCT with negative markers and metastatic malignant embryonal tumors.[57],[59]

Bifocal disease occurs in approximately 20% of iGCTs, the majority of which are germinomas [Table 1]. Most studies only state the occurrence, rather than describe the behavior of individual cases, and therefore specific demographics are not well known. When described, there are typically no discernable differences in comparison to iGCT in other sites.[60]
Table 1: Cases of bifocal intracranial germ cell tumors

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The concept of synchronous primaries is established and current treatment strategies are based on this. However, it is difficult to be definite that bifocal disease represents synchronous primaries rather than metastatic spread in all cases. A diagnosis of synchronous tumors is supported by their behavior, as data shows the equivalent outcome in bifocal compared to localized germinoma and successful treatment with WVI if there is no other metastasis.[58],[61],[62] A treatment regimen similar to that of localized disease is therefore standard practice. However, it is feasible that some of these patients present with metastatic disease, from suprasellar to pineal or visa versa, given the route of metastasis of iGCT is mostly ventricular. The true disease evolution is unknown, and reports have demonstrated cases of initially localized tumors that subsequently develop a “bifocal” component.[60] Bifocal disease also often presents with endocrine deficiencies, suggesting a primary role for the suprasellar element.[57] The higher rate of metastasis (30%–50% in bifocal disease compared to 15%–20% in nonbifocal disease) and radiologically detectable ventricular deposits in bifocal disease also supports the spread of disease.[60],[62] Some may question whether outcomes of bifocal disease are equivalent and one study of bifocal germinoma found an inferior survival rate (70% of 5-year OS in bifocal germinoma vs. 91%–93% in germinoma in other sites).[60] The authors hypothesized this difference was due to a failure to identify and adequately treat metastatic disease. Alternatively, this could represent different biology in bifocal disease, requiring more aggressive treatment. It could also represent a failure to identify NGGCT elements resulting from either a lack of biopsy or sampling error.

Bifocal NGGCT is rarely described and therefore the outcome is more uncertain. Few reports have provided separate data on germinomatous and NGGCT disease and treatment protocols vary with small numbers and treatment details missing [Table 2]. Most published cases received CSI.[63] However, the recently published SIOP CNS GCT 96 trials showed bifocal NCCGT can be treated as localized disease with focal radiation, resulting in equivalent outcomes. Full details on the bifocal patients in this study are not available.[49] Interestingly in this data, subsequent relapse was localized.
Table 2: Survival and treatment of bifocal intracranial germ cell tumors

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In this case, imaging distinguishes two different iGCT subtypes, supporting true synchronous bifocal disease. MRI showed a heterogeneous suprasellar component, suggestive of an NGGCT, whereas the homogeneous pineal component had characteristics typical of germinoma [Figure 1]. MRS demonstrated two distinct metabolic profiles [Figure 2]. The clinical response to treatment supported the differentiation between the two tumors. The pineal tumor showed a rapid complete response to chemotherapy in keeping with a germinomatous lesion. Conventional teaching dictates treatment is directed at the most malignant GCT element which, in terms of prognosis, is the NGGCT. Whether the different tumor elements act independently or whether each is a different manifestation of the same malignant multipotent cells is not currently known. Despite confidence in the diagnosis of localized disease, relapse occurred. The relapse occurred outside of the radiation field, questioning whether a wider radiation field would have prevented recurrence.[71] Serum markers were raised, implying that relapse was an NGGCT component.

With the increased resolution of imaging techniques, it is likely that bifocal disease will be more readily detected. Actively excluding metastasis on imaging and in CSF will be vital to guide treatments. Some experts even consider contiguity between tumors or ependymal seeding as evidence of dissemination and advocate surgical endoscopy for a more accurate assessment.[63],[72] MRS and functional imaging can be useful in differentiating tumor types to aid diagnosis, particularly if mixed components are suspected, or in guiding surgeons to biopsy the most malignant element.

The challenge of common and rare complications

Rapid teratomatous growth of a germ cell tumor is known as GTS. This rare but well-recognized manifestation affects <10% of patients and is characterized by rapid tumor growth during or after adjuvant therapy. It is commonly seen 3–56 months following the onset of adjuvant therapy.[73] Occurrence during the first cycle of therapy, to the best of our knowledge, has not previously been reported. GTS is more common in NGGCT and in males (ratio 4:1). MRIs have classically shown a multi-cystic, honeycombed appearance, leading to some suggesting a pathogenesis related to cystic expansion within existing teratomatous tissue, rather than tumor proliferation.[74] The only proven effective treatment is radical excision. A high index of suspicion and prompt diagnosis may facilitate this by allowing earlier surgical intervention.[75] Recently, more targeted approaches have been considered for GTS. Most expressed the retinoblastoma protein and sustained response to the CDK inhibitor palbociclib has been seen.[77],[78]

Delivery of treatment to iGCT patients presents a considerable clinical challenge. Patients often have multiple comorbidities which complicate chemotherapy administration and complications are common. Hydration fluids are problematic because of DI. Prolonged hospitilization is frequently required and treatment-related mortality high. This is often unrelated to DI.[64] Chemotherapy often requires modification due to toxicity, questioning whether, as in this case, adequate drug doses are delivered at sufficient intensity.[79] Data are lacking, both in describing whether outcome relates to treatment modification and in defining the morbidity-related complications.

Disease relapse

As relapsed iGCT patients are few and not well studied, there is no consistent approach to treatment. In general, treatment is individually tailored based on previous therapy and all feasible modalities are used: attempted resection, reinduction chemotherapy, consolidation with HDC or AuSCR, and radiotherapy. Induction regimens use the first-line agents as well as more novel combinations.[40],[80] Favorable response to gemcitabine, paclitaxel, and oxaliplatin is reported in phase II trials.[3],[80],[81] Radiation at relapse, if possible, is considered a fundamental part of treatment. This proves complex as radiation fields from up-front therapy overlap. With modern techniques and experience, the ability to safely re-irradiate patients is feasible, although the survival benefit is not yet known.[80] Five-year survival of relapsed germinoma using CSI and conventional chemotherapy is reported as 55%–78%.[40],[54] Relapsed NGGCT is more challenging, and the outcome is substantially worse, though some are still salvageable. Data suggests the highest chance of cure with HDC + AuSCR. Salvage rates of 33% have been reported with thiotepa-based regimens.[54] This compares favorably to a larger cohort from the SIOP GCT 96 study where only 9% of patients with relapsed NGGCT were salvaged.[40] All survivors received HDC + AuSCR. In this cohort, there were no survivors with an elevated AFP at the time of relapse.[40],[54]

A success story? The consequences of treatment

As in all brain tumor patients, there is a fine line between treatment success and life-shattering morbidity. Most iGCT patients survive, however, the burden of a central tumor location, endocrine deficits, and treatment can be huge. Little is known of the life quality of these patients. Poor performance scores at the end of treatment, primarily related to surgical morbidity, are associated with poor quality of life.[82] Long-term mortality is ten times higher than peers, with the main causes of death being radiation-related stroke and secondary malignancies.[83]

A brighter future

As in all pediatric malignancies, an increasing emphasis is placed on tumor biology, genetics, and genomics. It has been shown that 53% of iGCTs have an identified somatic or germline mutation, many of which are targetable, including KIT/RAS and AKT/mTOR.[84],[85],[86] New targeted agents promise success without conventional late-effects. However, tumor tissue is needed to advance this work, and this is limited by the current approach of marker-based diagnosis. The question lies in whether mandating tissue collection in clinical trials for the hope of new targeted treatments justifies the risk of morbidity from surgery.

Almost paradoxically, others have concentrated efforts into developing new ways to diagnose or risk-stratify patients without the need for surgery. As discussed, functional imaging techniques may aid noninvasive diagnoses. Better assessment of disease may initiate earlier therapy. Positron emission tomography can quantify metabolic activity and may identify viable tumor to guide and tailor further therapy.[87],[88],[89] Short, noncoding areas of RNA, known as micro-RNAs, have been found circulating in the blood or CSF of all germ cell patients. The four identified micro-RNAs can be used to aid diagnosis, although they cannot yet differentiate between germinoma and NGGCT. Their largest impact may come in monitoring patients. MicroRNA presence is a sensitive indicator of disease and detection may signify relapse or refractory disease much earlier than conventional tumor markers, allowing for earlier intervention.

In the future, patients may have a diagnosis of germinoma, or NGGCT made without a biopsy, due to a combination of conventional imaging, functional imaging, tumor markers, and microRNAs.[57],[89] New classifications may emerge combining this information with histology and tumor molecular markers. An improved understanding of tumor biology may allow fine-tuning of stratification and new targeted agents may ease the burden of therapy. More astute monitoring may detect relapsed disease earlier, improving salvage, and reducing therapy. More work, however, is needed. International collaboration and shared experience must continue in order to resolve optimal treatment approaches. A more complete characterization of bifocal or mixed tumors may help better stratify these patients. More emphasis must be placed on the quality as well as quantity of life and a better description of the complications faced may help to directly manage these.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the parent/legal guardian has given their consent for images and other clinical information to be reported in the journal. The parent/guardian understands that name and initial will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

AP and KM are funded by a National Institute for Health Research Professorship (AP) grant code number 13-0053.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]


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