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ORIGINAL ARTICLE
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Primary intracranial germ cell tumors in children 36-year experience of a single center


1 Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey
2 Department of Pediatric Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
3 Department of Radiation Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
4 Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

Correspondence Address:
Nilgun Kurucu,
Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_314_18

 > Abstract 


Purpose: Intracranial germ cell tumors (ICGCTs) comprise approximately 0.4%–3% of all brain tumors. In this study, we aim to evaluate clinical characteristics, treatment and outcomes of patients with ICGCT.
Patients and Methods: All patients with ICGCT diagnosed in Hacettepe University's Pediatric Oncology Department between January 1980 and January 2016 were evaluated, retrospectively.
Results: We identified 52 patients (male/female: 2.46) diagnosed with ICGT. Median age was 140 months. The median duration of symptoms was 3 months. Patients with endocrine symptoms were diagnosed later than others (P = 0.028). The primary site was pineal region in 20 patients, nonpineal region in 32 which included six bifocal involvements. Pineal location was more common in boys than girls (P = 0.02). Histopathological diagnosis was germinoma in 28 patients, nongerminomatous malignant germ cell tumors in 14 and immature teratoma in 4. The mean age for germinoma was higher than that of nongerminomatous tumors (P = 0.032). Patients treated with surgery and radiotherapy and chemotherapy. Median follow-up time was 52.5 months. Thirty-six patients were alive for 12–228 months. Relapsed/progressive disease was observed in 11 patients. Nongerminomatous tumors more frequently showed relapse/progression than germinoma (P = 0.06). Five-year overall and event-free survival rates for the whole group were 72.6% and 57.2%, respectively. Overall and event-free survival rates for germinoma were better than malignant nongerminomatous tumors.
Conclusion: Although the ratio of ICGCTs to central nervous system tumors in our series was similar to western countries, some clinical features such as tumor location were similar to cases from East Asian countries. Although similar protocols were used survival rates lower than developed western and eastern developed countries.

Keywords: Brain tumors, germ cell tumor, germinoma



How to cite this URL:
Kurucu N, Akyüz C, Varan A, Zorlu F, Aydin B, Söylemezoglu F, Yalcin B, Kutluk T, Büyükpamukcus M. Primary intracranial germ cell tumors in children 36-year experience of a single center. J Can Res Ther [Epub ahead of print] [cited 2019 Nov 21]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=270097




 > Introduction Top


Central nervous system (CNS) tumors are the second-most common tumors of childhood. The most common histologies in children younger than 15 years include astrocytomas and embryonal tumors, which account for 17.6% and 15% of cases, respectively. Germ cell tumors (GCTs) represent approximately 3%–5% of intracranial childhood malignancies.[1],[2]

Germ cell tumors are a rare and heterogeneous group of neoplasia originating from primordial germ cells. They account for approximately 2%–3% of all childhood malignancies. These tumors typically arise in ovaries and testis. In addition to gonads, approximately 55% of GCTs occur in extragonadal locations such as mediastinum and sacrococcygeal region. Extragonadal GCTs develop from remnants of primordial germ cells that fail to migrate during embryonic development. Although CNS is one of the extragonadal GCT sites, the management of ICGTs is different from others.[2],[3]

In this study, we evaluated clinical and demographic characteristics, the treatment and outcomes of patients with ICGCT who were treated in our department for 35 years.


 > Patients and Methods Top


All patients with GCT (n = 597) or brain tumors (n = 1467) diagnosed in Hacettepe University's Pediatric Oncology Department between January 1980 and January 2016 were evaluated in this study. Among them, patients with ICGCT were identified, and their medical data were analyzed retrospectively. Patients' age and gender, complaints and signs, the location and histopathological subtype of the tumor, radiological findings, applied treatments, and survival times were recorded.

All patients underwent a complete physical and neurological examination. The interval between symptom onset and diagnosis was noted. Alfa-fetoprotein (AFP) and β-human chorionic gonadotropin (β-HCG) levels were measured in serum in all patients. In cerebrospinal fluid, these markers could only be measured in eight patients. Computed tomography (CT) and/or magnetic resonance imaging were used to evaluate the primary tumor location, dissemination, and size. The presence of noncontiguous disease in more than one anatomic location other than bifocal tumor or tumor cells identified in CSF is described as disseminated disease. The diagnosis was confirmed histopathologically in 46 patients and by the radiological findings and tumor markers in six. Tumors were classified as pure germinoma and nongerminomatous tumors according to histopathology. The assessment of endocrinopathies and replacement treatment were carried out by an endocrinologist according to laboratory values.

Descriptive data are presented as mean or median (range) values or n (%), as appropriate. For comparison of numerical variables, Mann–Whitney U test was used. Categorical variables were compared with Chi-square or Fisher's tests. Survival analyses were done by using Kaplan–Meier method and curves were compared using the log-rank test.


 > Results Top


We identified 52 patients who were diagnosed with ICGCTs within the 35-year period. There were 37 boys and 15 girls with a median age of 140 (13–210) months. The male/female ratio was 37/15 (2,46). Two patients (3.8%) were aged <36 months, 14 (26.9%) were aged 36–120 months, 28 (53.8%) were aged 121–180 months, and 8 (15.4%) were >180 months of age.

The most common complaints were headache (n = 26, 50%), nausea and vomiting (n = 23, 44.2%), symptoms related to vision (n = 23, 44.2%), and polydipsia/polyuria (n = 19, 36.5%) [Table 1]. Five patients were admitted to the hospital with confusion and three with seizure. None of the patients had another preexisting condition except one case who had Down syndrome.
Table 1: Features of patients according to tumor location

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The median interval between symptoms onset and diagnosis was 3 (1–24) months. In 14 patients (26.9%), time to the diagnosis was 6 months or longer. Of the 32 patients, who had neurological and/or visual symptoms, 27 (84.4%) patients were referred to the hospital earlier than 6 months (median 1 month), while this ratio was 55% in patients with endocrine symptoms (median 4.5 months) (P = 0.028). Mean prediagnosis symptom duration in suprasellar tumors was longer than pineal tumors (7.8 ± 8.9 vs. 3.4 ± 4.0, P = 0.05). Age, sex, and histopathology of tumor were not related with the lag time.

The most common physical examination signs were lateral or medial gaze palsy (n = 14, 26.9%), components of parinaud syndrome (n = 8, 15.3%), changes in visual acuity/field (n = 12, 23%), motor deficit (n = 7, 13.4%), and fascial paralysis (n = 3, 5.6%) [Table 1]. Papilledema was identified in eight patients. Endocrinological investigation revealed combined/multiple pituitary hormone deficiency in 18 patients, diabetes insipidus in four, precocious puberty in four, diencephalic syndrome in one [Table 1].

Tumors were located in the pineal region in 20 patients (38.5%), suprasellar region in 20 (38.5%) and were bifocal in 6 (11.5%). In 11.5% of total patients, the tumors were found in rare locations: basal ganglia (n = 4), cerebellopontine (n = 1), and temporoparietal regions (n = 1). The median maximum diameter of tumors was 26 (8–90) mm. Tumor size did not vary according to tumor location. In 51.4% of boys, the tumors were located in the pineal region while this ratio was only 6.7% in girls (P = 0.02). There were no differences in age distribution according to tumor localization. About 95% of suprasellar tumors had endocrinological disturbance, while this ratio was 10% in pineal tumors (<0.00001).

Intracranial and/or spinal seeding was observed in nine patients. Hydrocephalus was diagnosed in 24 patients, and half of them required replacement of ventriculoperitoneal shunt. In 83.3% of patients with hydrocephalus, the tumors were located in pineal region or were bifocal. One patient who was diagnosed with radiological findings and high β-HCG (248490 IU/ml) had bilateral multiple pulmonary metastasis. This patient was evaluated with thorax and abdominal CTs and scrotal ultrasonography and no other tumoral mass was found. Serum AFP level was high in six, β-HCG in seven and both markers in four patients. Among eight patients in whom cerebrospinal markers were measured, AFP was found to be high in three, β-HCG in one and both in one. The β-HCG levels were high in five histopathologically proven germinoma, and the values changed between 12 and 180 (median 20.9). Histopathological diagnosis was performed in 46 patients. Of this diagnosis was germinoma in 28 (60.8%), mixed GCT in 9 (19.6%), yolk sac tumor in 2 (4.4%), immature teratoma in 4 (8.7%), and malignant teratoma in 3 (6.5%) of patients. The components of mixed GCT were germinoma and teratoma in two, germinoma and yolk sac tumor in one, germinoma and embryonal carcinoma in one, germinoma and choriocarcinoma in one, yolk sac tumor and embryonal carcinoma in two, and yolk sac tumor and immature teratoma in two. Mean age for germinoma and nongerminomatous tumors was 143.60 ± 47.12 and 124.66 ± 31.81, respectively (P = 0.032). About 52% of pineal tumors were germinoma, while in suprasellar region this ratio was 81.6% (P = 0.07). Histopathological subtypes of four tumors located in basal ganglia were germinoma in two, immature teratoma in one and mixed germ cell tumors in another.

The surgical intervention was performed in 46 patients at diagnosis. Gross total resection was performed in 12 (23.1%) patients, subtotal resection in 22 (42.3%), and biopsy in 12 (23.1%). Surgical resection was performed in 85.7% of nongerminomatous GCT and half of these were gross total resection while 67.9% of germinoma cases underwent surgical excision. The extent of surgery did not have any effect on survival rates. Only one patient with immature teratoma underwent second look surgery. These patients received adjuvant therapy after biopsy, however disease progression was observed following the treatment. Gross total excision of the mass was performed, and pathological examination revealed mature teratoma. She was diagnosed as growing teratoma syndrome and followed up 11 years without disease.

Forty-three patients received BEP (cisplatin100 mg/m 2/dose first day, bleomycin 15 mg/m 2/dose second day, etoposide 100–120 mg/m 2/dose 1–3 days), one received CVB (carboplatin 450 mg/m 2/dose first day, vinblastine 6 mg/m 2/dose first day, bleomycin 15 mg/m 2/dose second day) and one received CEB (carboplatin 450 mg/m 2/dose first day, bleomycin 15 mg/m 2/dose second day, etoposide 100–120 mg/m 2/dose 1–3 days) protocols every three weeks. The median number of chemotherapy courses was six.[1],[2],[3],[4],[5],[6],[7],[8],[9] Most of the patients (67.6%) received 2–4 courses chemotherapy before radiotherapy. However, we did not observe any difference in survival rates between patients who initially received radiotherapy and those who received radiotherapy after a number of courses of chemotherapy. Radiotherapy was administered to 44 patients and doses varied between 40–55 Gy (median 46 Gy). The median dose in germinoma was 46.0 Gy while it was 50.40 Gy for nongerminomatous tumors other than immature teratomas. There was a significant difference between the mean radiotherapy dose in these two diagnostic groups (46.14 ± 34.9 Gy vs. 49.64 ± 35.4 Gy; P = 0.014). Four patients who died following surgery, one patient who had received chemotherapy before radiotherapy but died after the first course due to infection, one patient who abandoned treatment after chemotherapy and two patients who abandoned treatment after surgery did not receive radiotherapy. Radiotherapy was administered to the focal tumor region in 10 (22.7%), the whole ventricular system in 10 (22.7%), the whole cranium in 14 (31.9%) patients and craniospinal in 10 (22.7%), each with a boost to the primary tumor. Nine patients who had craniospinal seeding metastasis and one patient with mixed germ cell tumor containing a choriocarcinoma component received craniospinal irradiation. All nongerminomatous tumors received cranial or craniospinal radiotherapy while 60% of germinomas received focal or ventricular radiotherapy. We did not find any negative effect of reduction in radiotherapy dose or volume on survival in germinomas.

The median follow-up time was 52.5 months. Thirty-six patients were alive for 12–228 months. Relapsed/progressive disease was observed in 11 patients within median 8 (3–46) months. About 46% of nongerminomatous tumors had relapse/progression while this ratio was 16.7% for germinoma (P = 0.06). The relapse locations were primary site in two patients, spinal leptomeningeal in one, primary site and leptomeningeal in one, intracranial region other than primary site in five and distant site in two (one pulmonary, one hepatic, and pulmonary). Four patients died due to progressive disease, four due to complications after surgery, and three due to febrile neutropenia. Three patients who were noncompliant to endocrine treatment died at home. Two patients, one with germinoma and one with teratoma, were lost to follow-up after surgery. Five-year overall survival (OS) and event-free survival (EFS) rates for the whole group were 72.6% and 57.2%, respectively. Overall and EFS rates for germinoma were better than other subtypes except immature teratoma (80% vs. 53.9%, P = 0.07 and 65.6% vs. 39.3%, P = 0.03) [Figure 1] and [Figure 2]. Sex, age, tumor location, interval between symptom onset and diagnosis, chemotherapy, radiotherapy, and extent of surgery did not have any effect on overall and EFS rates.
Figure 1: Overall survival according to histopathology

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Figure 2: Event-free survival according to histopathology

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 > Discussion Top


Intracranial germ cell tumors (ICGCTs) are a rare heterogeneous group of tumors whose age-standardized incidence rate (ASR) for 0–19 years of age varies by country between 0.1/1.000.000 and 3.8/1.000.000.[4] The incidence rate in East Asian countries is higher than in the United States and other Western countries.[4],[5],[6],[7] For example, ASR was 1.7 in a million in the USA, while it was 3.8 in Japan. The ASR in Turkey (0.7/1.000.000) was lower than Japan and even some western countries but similar to other Middle Eastern countries such as Jordan and Israel.[4] There is also considerable variation in the ratio of ICGCTs to CNS tumors, ranging from 3% to 5% in the United States to 14% in Japan.[4],[5],[6] In our 35-year case series, similar to western countries, ICGCT constituted 3.5% of 1467 brain tumors. The peak incidence for ICGCTs is 10–14 years of age.[2],[4],[7] Most of our cases (51.9%) were between 10 and 14 years of age with a median of 11.5 years.

From 1993 to 2012, 4480 GCTs were reported in SEER 18 registry of which 714 (15.9%) were ICGCT. Five hundred and thirty-six of these were in males and 178 in females with a male to female ratio of 3. For males, these constituted 18.9% of all GCTs and for females 10.7% of all GCTs registered in SEER. In Japanese registries, the male to female ratio was 2.6.[4] In our department, intracranial GCTs constituted 8.7% of 597 GCTs diagnosed, and the male/female ratio was 2.5.

It is reported that in the United States, about 60%–80% of all ICGCT were located in pineal region while this ratio was 40%–44% in Japanese registries. The majority of non-pineal tumors are located in the suprasellar region.[5],[6],[7] Pineal tumors constituted 38.5% of our 52 cases, similar to East Asian countries. In our series, pineal tumors comprised the majority of tumors in males, while non-pineal gland tumors constituted the majority of tumors in females. Simultaneous involvement of both pineal and suprasellar regions, also called bifocal ICGCT, has been reported in different studies within a range of 6%–40%.[2],[5],[6],[7],[8] In our case series similar to Japanese registries, bifocal tumors were identified in 11.5% of patients. The frequency of ICGCTs arising from atypical regions, referred to as ectopic ICGCTs, varied from 2% to 18%. It is more frequent in the Asian population.[2],[6],[9] The tumor in an atypical location such as basal ganglia was high in (11.5%) our series similar to East Asian countries.

ICGCTs can be divided into germinomas and nongerminomas, similar to gonadal GCTs. Germinomas reported as the most common histopathologic subtype.[2],[3],[5],[6] In our study, approximately two-thirds of cases were germinomas which is followed by mixed GCTs in 19.5% and immature teratoma in 8.7%. We observed that as compared to nongerminomatous tumors, germinomas were more commonly seen in older children. Germinomas are reported as the most common GCTs of the pineal region.[2],[5] In our series, however, germinomas and nongerminomatous tumors were seen with approximately equal frequency in pineal region. As compared to pineal region, the histopathology of suprasellar tumors was more commonly germinomas, although the difference was not statistically significant.

Histopathologic diagnosis was teratoma in six (4 immature and 3 malignant) of our 52 (13.4%) ICGCT patients. It constitutes 0.41% of 1467 brain tumors diagnosed in 35 years. This ratio is the same as the Japanese brain tumor registry.[2],[6],[10] The distribution of age, sex, and location of teratomas was not different from other histopathological subtypes.

Although the association between gonadal dysgenesis and gonadal GCTs as well as the association between Klinefelter syndrome and mediastinal GCTs are well established,[3] whether ICGCTs arise from an inherited predisposition is not known. One of our patients had the diagnosis of Down syndrome. Patients with Down syndrome are known as having a higher risk of leukemia. Higher incidence of testicular cancer in Down syndrome is also reported.[11] There are only 19 cases of ICGCT in children with Down syndrome in the literature. Interestingly, most of these cases were from East Asia and the tumors were mostly located in basal ganglia and cerebellum.[12] Our patient had a suprasellar teratoma.

The clinical manifestation of ICGCT varies depending on tumor location.[2],[3],[13] Pineal tumors presented with symptoms of hydrocephalus, while suprasellar tumors caused symptoms related with endocrinopathy. One patient with signs of anorexia, emaciation, vomiting, and decreased visual field was diagnosed with diencephalic syndrome. She had a suprasellar tumor infiltrating the hypothalamus and diagnosed as germinoma after pathological examination of biopsy. This syndrome commonly occurs in association with hypothalamic and chiasmatic gliomas. We could find only two cases with ICGCT which presented with diencephalic syndrome in the literature.[14],[15] Ophthalmic symptoms were observed in all regions but the nature of these symptoms differed by location. Pineal region tumors caused diplopia and components of parinaud syndrome (impaired upward gaze, convergence nystagmus, and impaired papillary response), while patients with suprasellar tumors developed declining visual acuity and/or visual field limitations owing to encroachment on the optic nerve and optic chiasm.[2],[13] Patients with bifocal tumors exhibited various combinations of these findings.[2],[8],[13] The initial symptoms were hemiparesis, headache, and vomiting in tumors located in basal ganglia.[2],[9],[13] Common symptoms including headache, nausea, and vomiting were observed in approximately 50% of patients. In our cases, the median duration of symptoms before diagnosis was 3 months. About 27% of patients had a delayed diagnosis (≥6 months). It was reported that the median duration of symptoms until diagnosis was 7 weeks for pediatric brain tumors in general.[1] We noticed that patients with endocrinological symptoms tend to have a longer time to diagnosis compared with children with neurologic and/or ophthalmic symptoms. Sethi et al.[16] reported that 54% of patients with ICGCTs had interval of ≥6 months from onset of symptoms to diagnostic imaging, although most of them were evaluated by a pediatrician or pediatric subspecialist. They emphasized that patients with delayed diagnosis were more likely to have disseminated disease, although survival rates were not affected. We did not find any difference in either dissemination or survival rates according to time from onset of symptoms to diagnosis.

The treatment of intracranial GCTs needs a multidisciplinary approach. Aggressive resection leading to morbidity is not the goal of surgical intervention since these tumors are highly sensitive to chemotherapy and radiotherapy. If tumor markers are elevated even diagnostic biopsy may not be necessary.[13],[17] In our case series, the diagnosis was based on clinical and radiological findings in six patients. Gross total resection has been performed in only 26.2% of patients and similar to MAKEI 89 trial [18] extent of surgery had no significant impact on survival. Radiotherapy is an essential treatment for germ cell tumors. It was shown that chemotherapy alone had high recurrence rates.[19] Controversy exists over the optimal dose and volume of radiation. It was reported that with craniospinal radiotherapy alone, overall survival rates reach up to 95% for pure germinomas.[20] To minimize late side effects, reduction in radiotherapy dose and field with the use of adjuvant or neoadjuvant chemotherapy has been recommended recently, especially for germinomas.[20],[21] However, it was reported that periventricular relapse increased when focal field radiation was used.[20],[21] Therefore, whole ventricular radiation with boost to the involved field together with neoadjuvant chemotherapy is recommended now.[13],[17] Similarly, in our retrospective analysis, in germinomas, limited field radiotherapy did not have any negative effect on survival. Reduction in radiotherapy dose in germinomas also has not any effect on survival rates. There was no relationship between the disease outcome and timing of radiotherapy or the number of chemotherapy courses. Patients with nongerminomatous malignant germ cell tumors need more aggressive treatment including high dose and extensive volume radiotherapy in conjunction with chemotherapy.[13],[17]

During or after adjuvant therapy for GCTs, paradoxical growth of mature teratoma element of tumor despite the resolution of immature/malignant elements has been described and named as growing teratoma syndrome. Although there is a considerable number of cases of extracranial germ cell tumor with this syndrome few cases of ICGCT has been reported.[22] We observed growing teratoma syndrome in one patient with immature teratoma.

We found that only histopathologic subtypes affected the survival rates. Intracranial germinomas are sensitive to both radiotherapy and platinum-based chemotherapy and have a good prognosis. In various series from Japan, Europe, and the USA, the overall and disease-free survival rates in germinomas range between 80%–98% and 85%–75% at 5 years.[20],[21],[23],[24] Although the overall survival rates of our patients (80%) are not as high as those in the literature, in four of the six germinoma patients who died, the cause of death was not related to disease progression. The prognosis of nongerminomatous tumors is worse than germinomas, and 5-year OS rates were reported as between 55%–75% in different centers in developed and developing countries.[20],[21],[23],[24],[25] In our case series, survival rates of nongerminomatous tumors were similar to those reported in developing countries.

There were some limitations in our study. The retrospective analyses with a long time frame make it difficult to interpret the results. The diagnostic methods, treatment modalities, surgical techniques, and supportive therapies differ by the time. Moreover, we did not evaluate the late side effects of the treatment.


 > Conclusion Top


Although the ratio of ICGCTs to CNS tumors in our case series was similar to western countries, some clinical features such as tumor location were similar to cases from East Asian countries. Although similar protocols were used survival rates lower than western and eastern developed countries. The management of ICGCTs is complex because of the heterogeneity of their clinical presentation, location, and histopathological composition. Therefore, multidisciplinary approach is important not only for cure but also improvement of endocrinological and neurological outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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