Management of CNS germinoma

SUMMARY 

The following is a general overview of the management of CNS germinomas. Over the last 35 years, CNS germinomas have become one of the pediatric brain tumors with the best outcomes with a greater than 85% overall survival over 5 years. This is in part due to the fact that germinomas are very responsive to chemotherapy and radiation. Some of the major challenges going forward will be to find ways to minimize the adverse effects of our treatments particularly with regard to radiation and to improve the quality of life of patients who develop neurologic, neurocognitive and/or endocrine deficiencies.

Practice points .

• CNS germinomas comprise about 3% of all pediatric brain tumors and 90% of cases are diagnosed before 20 years of age. Signs and symptoms are largely influenced by tumor location, size and the extent of involvement and type of endocrine dysfunction.

• Germinomas can spread by direct infiltration of the surrounding brain parenchyma or remotely via cerebrospinal fluid (CSF) in the subarachnoid space or subependemally, within the ventricles.

• Germ cell tumors may secrete measurable oncoproteins such as β-human chorionic gonadotropin and α-fetoprotein in the serum or CSF. Pure germinomas, by definition, only secrete HCG. The α-fetoprotein levels in the serum and CSF are normal.

• Complete surgical removal does not play a major role in the management of these highly vascular tumors. Histological diagnosis following a craniotomy or endoscopic biopsy is recommended for the majority of patients with normal serum and CSF oncoprotein levels.

• Radiation alone used in relatively high doses and volumes usually provides a curative option for the majority of patients but the late effects of therapy have motivated cooperative clinical trial groups to explore the efficacy and safety of combining chemotherapy with lower volumes and doses of radiation therapy. The validation of this multimodality approach is therefore the major goal of most cooperative group clinical trials.

• The current proposed treatment in a current Childrenn's Oncology Group protocol for CNS germinomas consists of four cycles of chemotherapy with carboplatin and etoposide followed by lower dose whole ventricular radiation therapy with a boost to the primary tumor.

CNS germinomas are derived from totipotent germ cells and are a subcategory of the broader term, CNS germ cell tumors (GCTs). Intracranial GCTs comprise about 3% of pediatric brain tumors [1,2]. They occur more commonly in children and adolescents with a peak between 10 and 12 years of age. Ninety percent of cases are diagnosed before 20 years of age. Historically, the incidence for primary CNS GCTs has been higher in Asian countries when compared with the USA. However, a more recent survey from Japan [3] has challenged this observation and found that the incidence rate is similar to that found elsewhere, that is, 0.10 per 100,000 person-years [4].

Germinomas, comprise two-thirds of intracranial GCTs. The other third is composed of mixed malignant germ cell tumors (MMGCT) and mature teratomas. This review will focus on germinomas. Although there is a predilection of CNS germinomas, in general, in males, with a male to female ratio of 1.88:1 [5], there is much higher proportioin of males in pineal region primaries. In one series of 50 patients with pineal germinoma, the male to female ratio was 13:1 [6]. Germinomas arise predominantly in midline locations: suprasellar or infundibular (49%) and pineal (37%). When both of these sites are involved at diagnosis, the syndrome is designated as a bifocal or multifocal germinoma and comprises approximately 8% of germinoma presentations. Other possible sites of involvement are the third ventricle, basal ganglia, thalamus, lateral and fourth ventricles and on occasion, the tumor is widespread at presentation and it is difficult to determine the precise primary site. There is an association between gender and primary site. For example, 75% of females with germinomas are more likely to have a suprasellar primary and 67% of males are more likely to have a pineal region tumor [5]. Germinomas have been associated with specific hereditable syndromes. For example, there is an increased increase incidence of germinoma in Klinefelter, Noonan and Down's [7] syndromes [8,9].

Clinical presentation, diagnosis & staging of CNS germinoma

Signs and symptoms are largely influenced by tumor location, size and the extent of involvement and type of endocrine dysfunction. The initial symptom in patients with suprasellar primaries is usually related to endocrine deficiencies and the prodrome may evolve over months even years. Most patients primary tumors in the suprasellar region present with a protracted history of polyuria and polydipsia related to diabetes insipidus followed by other endocrine deficiencies such as growth failure, hypocortisolism, precocious puberty and hypothyroidism. Fatigue, altered sleep patterns and difficulty with scholastic achievement are prominent symptoms [10,11]. Thus, any pediatric patient with acquired diabetes insipidus should be highly suspected of having a CNS suprasellar germinoma. As the tumor extends dorsally, it may compress the optic chiasm causing impaired visual acuity and constricted visual fields. Patients sometimes do not recognize these symptoms until later in the evolution of the disease. Further tumor progression will result in obstructive hydrocephalus and possible symptoms related to metastatic or multifocal dissemination.

Patients with involvement in the pineal or posterior third ventricular region as a solitary or multifocal primary usually have a shorter prodrome and present with symptoms of raised intracranial pressure, diplopia and signs of Parinaud's syndrome, that is, vertical gaze limitation, light/near dissociation of pupillary response and convergence nystagmus. With progressive growth of the tumor, the midbrain becomes compressed causing aqueductal compression and obstructive hydrocephalus and dysfunction of the dorsal midbrain.

The initial evaluation of a CNS GCT suspect should include head CT to rule out calcifications in patients with suprasellar tumors (i.e., craniopharyngioma) followed by MRI with contrast of the brain and spine. The appearance of a pineal region germinoma on MRI may include a heterogenous, contrast-enhancing mass variably shaped with occasional intratumoral cysts and calcifications. There may also be peritumoral edema in the adjacent thalamus and midbrain, obstructive hydrocephalus and subependymal metastases in a periventricular distribution (see Figure 1). Tumors of the suprasellar region initially expand the infundibulum and as they enlarge, it will displace the chiasm, fill the third ventricular space and when very large, cause hydrocephalus. Germinomas can spread by direct infiltration of the surrounding brain parenchyma such as in the basal ganglia or disseminated to other locations either by subependymal spread throughout the ventricles or remotely via cerebrospinal fluid (CSF) in the subarachnoid space or within the ventricles.

Figure 1. . Typical MRI findings.

Axial (A) and saggital (B) T-1 post contrast study reveals a contrast-enhancing solid and cystic mass in the pineal region. The ventricles are decompressed following an endoscopic third ventriculostomy.

GCTs may secrete measurable oncoproteins such as β human chorionic gonadotropin (BHCG) and α-fetoprotein (AFP) into the serum or CSF. Tumor markers from the serum and CSF may be useful surrogate biomarkers and can spare some patients the need for a biospy. Serum tumor markers for AFP and HCG are often very informative in patients with mixed malignant GCTs (MMGCT), but not always in germinomas. Pure germinomas should always have normal AFP levels in the serum and lumbar CSF but may have a low level of HCG. Assays of lumbar CSF is imperative for an accurate diagnosis and staging since oncoprotein levels are often much higher than in the serum [12]. Lumbar CSF assays are a more reliable source than ventricular CSF for repeated accessibility and published norms [13].

In the absence of oncoprotein elevations, the standard of care is surgical confirmation of the tumor histology. Perhaps the single exception is in patients with bifocal or multifocal primaries where there is a high association with germinoma, as long as the serum and CSF AFP are normal. Thus, in patients with bifocal germinoma, the presence of normal lumbar and serum BHCG and normal levels of AFP supports the clinical impression of a germinoma and histologic confirmation is not usually obtained. The specific quantitative criteria for using serum or lumbar CSF, HCG values to distinguish between germinoma vs. MMGCT is on ongoing debate. Previously, a level of 50 IU/l in either serum or CSF was used as a upper limit, but current investigational clinical trials in North America, Europe and Asia have raised this value to 100 IU/l. AFP levels are normal in pure germinoma including in the CSF. AFP is normally synthesized in the fetus. The serum values peak at 15 weeks of gestation with a serum half-life of 5–7 days and these values progressively decline until they normalize at 8 months of age. Therefore, when evaluating an infant suspected of a CNS GCT, it is important to carefully compare the serum levels to publish normative values according to months after birth [14].

Germinomas are potentially malignant in behavior and both infiltrate normal brain tissue as well as spread throughout the CNS. Thus, every patient should have standard staging procedures at diagnosis to include a post-op brain and spine MRI, lumbar CSF cytology and lumbar CSF tumor markers. The standard staging criteria are used where M0 signifies no evidence of metastatic disease; M1 describes only a positive cytology; M2 is indicative of intracranial metastases and M3 refers to the presence of spinal metastases.

Pathology (WHO)

Germinomas usually consist of large, epithelioid cells with cytoplasm abundantly positive for PAS. There is frequent lymphocytic infiltration. Immunohistochemistry is often helpful for confirming the diagnosis. Germinomas are highly positive for placental alkaline phosphatase. Germinomas express the cell membrane label, c-kit (CD117) and have nuclear reactivity for OCT 4 (see Figures 2 & 3). There may be intermixed synciotrophoblastic cells and positive staining for BHCG but AFP staining should be negative.

Figure 2. . Permanent sections.

The tissue consists of abundant lymphocytes, macrophages and large, round cells with pale eosinophilic cytoplasm with occasional vacuoles, distinct cytoplasmic borders and round nuclei with prominent round nucleoli.

Figure provided courtesy of [15].

Figure 3. . Immunohistochemical stains.

(A & B) Neoplastic cells are positive for placental alkaline phosphatase.

Figure provided courtesy of [15].

Management considerations & prognosis

The outcome for patients with germinoma is highly favorable, and various studies report greater than 85%, 5 years overall survival (OS). However, germinoma patients can develop recurrences late so this favorable statistic may be lower after 10–15 years of follow-up. The late effects of treatment and the presence of multiple endocrine and hypothalamic deficiencies may cause long-term impairment in quality of life. Given the rarity of CNS germinoma, there are very few prospective randomized trials exploring major treatment interventions. Rather, progress has occurred with exploratory phase II trials in patients at diagnosis differing radiation volumes (craniospinal [CSI] vs whole brain [WB] vs whole ventricular [WV]) or chemotherapy alone or neoadjuvant (pre-RT) chemotherapy and some form of modified adjuvant radiation therapy. New combinations of chemotherapy can be explored in patients with recurrent disease.

• Radiation-only experience

The German Cooperative enrolled 60 patients into radiotherapy-only prospective clinical trials MAKEI 83/86/89 between 1983 and 1993. Radiation to the craniospinal axis on the 83/86 study was 36 Gy followed by a local boost to 50 Gy and on their later 89 study CSI was reduced to 30 Gy with a 15 Gy boost. In the 83/86 study, no patient relapse was observed, and only one patient relapse in 49 patients occurred in the 89 study [16]. A 93.7% OS rate was achieved (median follow-up of 61 months). Rogers et al. challenged the consensus that CSI radiotherapy was the best treatment for localized germinomas. Their meta analysis compared recurrence rates using WB or WV radiation plus boost compared with CSI and found that a reduced-volume radiation was justifiable because there was no notable increased risk of isolated spinal relapse (2.9 vs 1.2%), respectively [17]. Radiation-therapy-only can provide a potential for cure for our patients. However, a radiation-only approach requires higher doses and larger fields, which increases the risk of long-term sequelae.

• Chemotherapy only experience in newly diagnosed patients

The First International CNS GCT Study trial was one of the largest chemotherapy-only studies in CNS germinomas (n = 45, four cycles of carboplatin 500 mg/m²/day for the first two days, etoposide 150 mg/m²/day on days 1 and 3; bleomycin 15 mg/m²/day on day 3) [18]. They found only a third of patients remained free of relapse in spite of therapy intensification and excellent initial complete responses. The majority of patients were able to be retrieved with additional chemotherapy and large volume, high-dose radiation therapy. The Second International CNS GCT (1995–1997) of chemotherapy alone used an intensified induction by substituting carboplatin with cisplatin and added high-dose cyclophosphamide. Patients received two courses of cisplatin, etoposide, cyclophosphamide and bleomycin in those with complete remission (CR) then received two courses of carboplatin, etoposide and bleomycin [19]. The 5-year OS and event-free survival were 75% (95% CI: 0.56–0.94) and 36% (95% CI: 0.13–0.59). Patients were also salvaged with radiation. Subsequent trials by this study group have concluded that even with more intensive chemotherapy regimens, chemotherapy-only regimens are significantly less effective than radiation-containing regimens.

• Multimodality therapy in newly diagnosed patients

The French group led by Baranzelli and Bouffet et al. enrolled 29 patients with nonmetastatic biopsy proven germinoma between 1990 and 1994. Patients received two cycles of carboplatin 600 mg/m² on day 1, etoposide 150 mg/m² on Days 1–3, ifosfamide 1.8 g/m² on days 22–26 and etoposide 150 on days 22–24, followed by radiation to the initial tumor volume at 40 Gy. Overall 4-year survival was 100% [20]. In a follow-up study by the same group, these same study results were duplicated within a larger cohort of patients (n = 57) [21]. In 1992–1996, the Japanese were able to achieve excellent results by reducing the amount of radiation. They enrolled 17 patients which were divided into two serum tumor marker groups, six were pure germinomas treated with three to four cycles of cisplatin and etoposide followed by 24 Gy local radiation therapy. The other nonpure germinomatous group received four to five cycles of ifosfamide, cisplatin and etoposide followed by 24 Gy local radiation. Their overall 2-year survival was 100% [22].

The Japanese GCT Study Group conducted a study from 1995 to 2003 for nonmetastatic germinoma (n = 228) treating with three cycles of carboplatin (450 mg/m² on day 1) and etoposide (450 mg/m² on days 1–3) and focal radiation (24 Gy) with a median follow-up of 6.3 years. The 5-year OS was 98% for germinoma (n = 123), however, 16 (13%) recurred. Several cooperative groups in France and Japan have observed a similar pattern of relapse in 10–15% of patients. Therefore, WV radiation field is currently considered the best practice for cases of nonmetastatic germinoma [11]. A multimodality approach may be the most compelling approach since it allows for reduced radiation therapy doses and volumes (see section ‘Current management’). The neoadjuvant chemotherapy may also reduced late relapses in parts of the CNS such as the spine that are not treated with radiation therapy.

• Retrieval therapy in patients with recurrent disease

One of the first GCT chemotherapy clinical trials was in 1985 [23], which demonstrated that chemotherapy agents such as cyclophosphamide, cisplatin, carboplatin and etoposide are active agents in patients with newly diagnosed and recurrent CNS GCT. These Phase II studies confirmed the activity of single and multiagent chemotherapy in patients with recurrent tumor and supported the safety of neoadjuvant design in patients with newly diagnosed germinoma. Additionally, the GemPOx regimen that is mentioned in the section ‘Conclusion & future perspective’, is useful in patients with recurrent CNS GCTs.

Current management

The initial management in patients suffering from symptoms of raised intracranial pressure due to a pineal region mass and a noncommunicating hydrocephalus is either an external ventricular drain or preferably an endoscopic third ventriculostomy hopefully accompanied by an endoscopic biopsy. Complete surgical removal does not play a major role in the management of these highly vascular tumors. Histological diagnosis following a craniotomy or endoscopic biopsy is critical for patients with normal serum and CSF oncoprotein determinations. Following complete staging with MRI brain and spine imaging and serum and lumbar CSF analysis for cytology and oncoproteins, patients are usually grouped into localized (M0) or regional (bifocal) versus disseminated disease (M+). Radiation alone used in relatively high doses and volumes usually provides a curative option for the majority of patients but the late effects of therapy have motivated cooperative clinical trial groups to explore the efficacy and safety of combining chemotherapy with lower volumes and doses of radiation therapy.

The current Children's Oncology Group ACNS 1123 has a separate protocol for localized intracranial germinoma. The overall goal is to investigate whether pre-irradiation therapy yields a high progression free survival while reducing the risk of cognitive deficits and maintaining a good quality of life. All patients with germinoma receive four cycles of a regimen consisting of carboplatin on day 1 at 600 mg/m²/day and etoposide at 150 mg/m²/day on days 1–3. If a complete response is observed with normal tumor markers, 18 Gy WV with a 12 Gy boost to the primary site will be administered. A second look surgery will be considered in patients with a partial response to chemotherapy, stable disease with more than 1.5 cm residual and progressive disease with normalization of HCG. If histology confirms mature teratoma or nonviable tumor, 18 Gy WV with a 12 Gy boost to the tumor bed will be given. Patients with more than 0.5 cm suprasellar or more than 1 cm pineal but less than or equal to 1.5 cm residual who do not undergo second-look surgery and receive 24 Gy WV and 12 Gy local boost. The safety of eliminating WV RT in patients with M0 disease who experience a CR to neoadjuvant chemotherapy is under study but remains controversial and currently the standard of care for this group of patients is chemotherapy followed by lower dose WV RT with a boost to the primary tumor.

The management of relapse is largely dependent on the initial treatment modality. For example, patients who received chemotherapy only can be salvaged with combinations of chemotherapy and RT. Chemotherapy regimens may include such agents as cisplatin–etoposide–ifosfamide, cisplatin–etoposide and etoposide–carboplatin. High-dose chemotherapy with autologous stem cell rescue conditioned with carboplatin and etoposide or etoposide and thiotepa can be used in patients who relapsed followed by RT [24]. Time to relapse can vary. Sawamura reported a median time to relapse of 37 months. A recent study by Alapetite and colleagues reviewed a pattern of relapse from their prospective SFOP trial for nonmetastatic germinoma treated with chemotherapy and limited field radiation. Ten of 60 patients relapsed and nine had local or locoregional relapse in the periventricular area, suggestive that a prophylactic whole ventricular field of radiation may reduce regional the incidence of regional relapse. The median time to relapse was 32 months (range: 10–121 months) [25]. Modak et al. found dose escalation thiotepa-based chemotherapy and autologous stem cell rescue to be highly effective in relapsed germinoma with a 78% (seven of nine patients) remaining in continuous remissions after 48 months [26].

Late effects

Patients who developed endocrine deficiencies due to suprasellar disease usually do not recover completely and are dependent on hormone replacement therapy for the rest of their lives. Surgery or radiation therapy may increase the severity of these endocrine and hypothalamic deficiencies. Late effects from chemotherapy are drug dependent. Each chemotherapeutic agent has its own characteristic long-term side effects and we recommend referring to the Children's Oncology Group's long-term follow-up guidelines prepared for survivors of childhood, adolescent and young adult cancer: long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers [27].

Long-term follow-up

Following initial therapy, patients should undergo regular surveillance with clinical exams, MRI scans and assessment of oncoproteins. MRI's are usually performed 2–3-times in the first 3 years followed by annual assesments thereafter. MRI's of the spine may be included annually to exclude subclincal relapse in the spine. Radiation therapy can also cause visual field impairments, endocrinopathies, cognitive decline and learning disabilities [28–30]. In one study, 17% of patients had low postoperative Karnofsky performance associated with impaired neurocognitive function. On subsequent follow-up, ten of 46 patients (21%) had even lower Karnofsky performance [28]. Strojan et al. published a review of the long-term survival and late effects in patients with CNS GCT treated with radiotherapy alone [31]. Patients who receive radiation therapy remain at increasing risk of developing cavernomas and secondary malignancies such as meningiomas and gliomas. They also should have continual follow-up with an endocrinologist and a late effects specialist if available in their area.

Conclusion & future perspective

Molecular targeted therapy is on the rise in the entire field of neuro-oncology. Exome sequencing of CNS GCT reveals that KIT and KRAS pathways are frequently mutated [32]. Dasatinib is a promising medication given its theoretical penetrance of the blood–brain barrier and its known KIT-inhibition. A recent feasibility pilot reviewed the use of Dasatinib in patients with newly diagnosed and recurrent germinoma [33–36]. No toxicities greater than grade 1 or 2 were reported other than in a patient with grade 3 anemia/neurtropenia in a patient with prior CSI. GemPOx is a prospective feasibility pilot from Children's Hospital Los Angeles using gemcitabine, oxaliplatin and paclitaxel for patients with refractory or recurrent CNS GCT that is currently accruing patients [37]. Lastly, there is an ongoing debate between the uses of photon versus proton beam radiation therapy but there seems to be a consensus that protons produce less unwanted radiation in patients requiring CSI. Refer to the National Association for Proton Therapy website for additional information and center locations [38].