Prognostic factors of pediatric pineal region tumors at a single institution

doi:10.21203/rs.3.rs-2244511/v1

Purpose: To identify factors of a worse prognosis among different histological types of pineal region tumors in pediatric patients treat at a single institution in a 30-year period.

Material and Methods: 151 pediatric patients (< 18 years of age) treated between 1991 and 2020 were analyzed. Kaplan-Meyer survival curves were created and the log-rank test was used to compare the main prognostic factors in the different histological types.

Results: Germinoma was found in 33.1%, with an overall 60-month survival rate of 88%; the female sex was the only factor of a worse prognosis. Non-germinomatous germ cell tumors were found in 27.1%, with an overall 60-month survival rate of 67.2%; metastasis upon diagnosis, residual tumor and the absence of radiotherapy were associated with a worse diagnosis. Pineoblastoma was found in 22.5%, with an overall 60-month survival rate of 40.7%; the male sex was the only factor of a worse prognosis; a tendency toward a worse outcome was found in patients < 3 years of age and those with metastasis upon diagnosis. Glioma was identified in 12.5%, with an overall 60-month survival rate of 72.6%; high grade gliomas were associated with a worse prognosis. Atypical teratoid rhabdoid tumors was found in 3.3% and all patients died within a 19-month period.

Conclusion: Pineal region tumors are characterized by the heterogeneity of histological types, which exert an influence on the outcome. Knowledge of the prognostic factors for each histological types is of extreme importance to the determination of guided multidisciplinary treatment.

Pineal gland

germ cell tumors

pineoblastoma

glioma

atypical teratoid rhabdoid tumor

The pineal gland – also denominated the epiphysis – is a brain structure located in the posterior incisural space bordered above by the splenium of the corpus callosum and pillars of the fornix, below by the anterosuperior portion of the cerebellum, anteriorly by the mesencephalic roof and lamina quadrigemina, laterally by the pulvinar of the thalamus and para-hippocampal gyrus bilaterally and posteriorly by the apex of the free margin of the tentorium.[35]

Pineal region tumors are rare, corresponding to 0.4 to 1% of intracranial tumors in the adult population, and are more frequent in the pediatric population, with an incidence ranging from 2.7 to11% [1, 17, 26]. These tumors are characterized by the heterogeneity of histological types, with germ cell tumors and pineal parenchymal tumors accounting for the largest portion (> 70%), followed by tumors derived from adjacent structures, such as glioma, meningioma, ependymoma, embryonal tumors (atypical rhabdoid/teratoid tumor) and metastasis. The management and treatment of these tumors include the study of tumor markers in the blood and cerebrospinal fluid (beta-HCG and alpha-fetoprotein), biopsy of the tumor, treatment of hydrocephaly by endoscopy or shunt, chemotherapy, radiotherapy and surgical resection. The outcome depends primarily on the histological type of the tumor.

The aim of the present study was to investigate the prognostic factors of each histological type of tumor in the pineal gland region in the pediatric population and long-term outcome of patients treated at a single institution in a 30-year period.

Study design and inclusion of patients

A retrospective study was conducted involving the analysis of electronic medical and physical records of patients treated at the Neurosurgery Service of the Escola Paulista de Medicina and Instituto de Oncologia Pediátrica de São Paulo (IOP/GRAACC) between 1991 and 2020. This project received approval from the ethics committee of IOP and Universidade Federal de São Paulo (certificate N°; 4.332.210).

Pediatric patients (< 18 years of age) with a diagnosis of a tumor in pineal gland region determined by magnetic resonance were included. Patients with non-neoplastic lesions, such as a pineal cyst, were excluded.

Degree of resection and outcome

The degree of resection was classified as total, subtotal (residual tumor ≤ 1.5 cm³) and open biopsy (residual tumor > 1.5 cm³). Overall survival was defined as the time in months from the date of the diagnosis (considered the date of the 1st imaging exam) to death. Progression-free survival was defined as the time in months between the date of diagnosis and the date of the recurrence or progression of the tumor in 60 months. Recurrence was considered the return of the disease after surgery, chemotherapy or radiotherapy that had eliminated the disease based on magnetic resonance of the head and/or tumor markers.

Statistical analysis

Statistical analysis was performed using Kaplan-Meyer survival curves and the Mantel-Cox log-rank test when two groups were compared or the log-rank test for trend when more than two groups were compared. Qualitative variables were analyzed using either the chi-squared test or Fisher’s exact test, depending on the sample size and distribution (normal or non-normal) for each set of samples. The Kruskal-Wallis test was used for multiple comparisons of medians of nonparametric samples. A p-value ≤ 0.05 was considered indicative of statistical significance. Data analysis and the creations of graphs were performed using GraphPad Prism 8, version 8.0.1.

The prevalence of pineal region tumors was 7.32% among all tumors of the central nervous system (151/2061) in the period from 1991 to 2020. The distribution of the histological types was as follows: pure germinoma (33.1%; n = 50); non-germinomatous germ cell tumors (27.1%; n = 41), including choriocarcinoma, endodermal sinus tumor, mature and immature teratoma and mixed tumors; pineoblastoma (22.5%; n = 34); glioma (12.5%; n = 19); embryonal tumor – atypical rhabdoid teratoid (3.3%; n = 5); and miscellaneous (1.32%; n = 2) - one patient with cavernous hemangioma and one with pineal tumor of intermediary cells). Table 1 displays the main clinical-epidemiological characteristics of the different histological types.

Table 1

Main clinical-epidemiological characteristics of histological types of Pineal region tumors
		Germinoma	NGGCT	Pineoblastoma	Glioma	AT/RT	P Value
Gender	Male Female	47 3	38 3	13 21	11 8	2 3	-
Age	Median (years)	13	9	5,5	11	0,25	< 0,0001
Time to diagnosis	Median (months)	2	0	0	0	0	0,0054
Size of the lesion	Median (cm)	3	3,8	4,3	3,2	5,5	0,0052
VPS	With Without	26 24	21 20	30 4	10 9	4 1	0,0017
ETV	Success Fail	19 8	16 5	14 12	10 3	-	0,31
Surgery ressection	Total Subtotal	13 (68,4%) 6 (31,6%)	23 (71,8%) 9 (27,2%)	17 (58,6%) 12 (41,4%)	4 (30,7%) 9 (69,3%)	3 (60%) 2 (40%)	0,02
Overall Survival	12 months 24 months 60 months	93,7% 93,7% 88%	89,4% 80,8% 67,2%	89,4% 80,8% 67,2%	89,4% 78,2% 72,6%	40% 20% 0%	< 0,0001

Germ cell tumors

Isolated germinomas were the most prevalent among the tumors of the pineal gland region, accounting for 33.1% (50/151). The male population predominated in this group, accounting for 96% of cases (47/50).

Median age upon diagnosis was 13 years (range: 6 to 25 years). Median time between the onset of symptoms and the diagnosis was two months (range: 0 to 47 months), which was the longest time among the different histological types. The median of the largest diameter of the tumor upon diagnosis was 3 cm (range: 1.4 to 5 cm).

In this group, 19 patients were submitted to surgery (38%), 13 of whom (68.4%) were submitted to total resection, three were submitted to subtotal resection and three were submitted only to biopsy of the tumor, from whom fragments of the suprasellar tumor were obtained.

The only factor related to a worse prognosis in the group of germinomas was the female sex. Positivity for the beta-HCG marker in the cerebrospinal fluid which was found in 20% of pure germinomas, was not associated with a worse prognosis (Fig. 1)

Non-germinomatous germ cell tumors (NGGCT) accounted for 27% of all tumors of the pineal gland region (41/151). Median age at diagnosis was nine years (range: 0 to 16 years) and median time between the onset of symptoms and the diagnosis was less than one month (range: 0 to 66 meses). Median size of the largest diameter of the tumor upon diagnosis was 3.8 cm (range: 0.9 to 11.8 cm).

The factors associated with a worse diagnosis in the group of non-germinomatous germ cell tumors were metastasis at diagnosis (p = 0.009), residual tumor after the conclusion of treatment, including primary surgery or second-look surgery, chemotherapy and radiotherapy (p = 0.0015) and the non-performance of radiotherapy (p = 0.04). Alpha-fetoprotein level (> or < 1000 ng/ml) was not associated with the prognosis (p = 0.41) (Fig. 2).

Pineoblastoma

Pineoblastoma constituted the third most prevalent group in our series, accounting for 22.5% (34/151) of tumors of the pineal gland region. Median age at diagnosis was 5.5 years (range: 0 to 17 years). Median time from the onset of symptoms to diagnosis was less than one month (range: 0 to 10 months). Median size of the largest diameter of the tumor at diagnosis was 4.3 cm (range: 2.8 to 7 cm). This group has the highest rate of dependence on ventricle-peritoneal shunt (88.2%; 30/34) (p = 0.0002). Twenty-nine patients were submitted to surgical resection and total resection was possible in 17 (58,6%). The general mortality rate was 52.9% (18/34) and five-year survival was 38.9%. This was the group with the second highest mortality rate, following the few cases of embryonal tumor (atypical rhabdoid/teratoid tumor).

The male sex was the only statistically significant factor associated with a worse prognosis (p = 0.03). Age less than three years and metastasis had a tendency toward a worse prognosis (p = 0.09 and 0.07, respectively). Radiotherapy, tumor size and degree of resection were not associated with the prognosis in our series (Fig. 3).

Glioma

Glioma accounted for 12.5% (19/151) of tumors of the pineal gland region, with a mortality rate of 26.3% (5/19). Median age at diagnosis was 11 years (range: 0 to 22 years) and median time between the onset of symptoms and diagnosis was less than one month (range: 0 to 6 meses). The median size of the largest diameter of the tumor at diagnosis was 3.2 cm (range: 0.9 to 6.1 cm).

Fifteen patients in this group were classified with low grade glioma (Grades I and II, according to the World Health Organization [WHO]) and four were classified with high grade glioma (Grades III and IV, according to the WHO), all of whom died. Mean survival was 16.5 months (5 to 31 meses). Six patients underwent endoscopic biopsy and one underwent stereotactic biopsy, all of which (100%) contributed to the histopathological diagnosis.

A total of 68.4% (13/19) were submitted to surgical resection, only four of whom received total resection (30.7%). Compared to the other histological types, this group was the poorest with regards to the degree of resection.

High grade gliomas (III and IV) had a worse prognosis compared to low grade gliomas (I and II). The degree of resection and need for a ventriculoperitoneal shunt were not associated with the prognosis in our series (Fig. 4).

Overall survival in this group was 89.4%, 78.2% and 72.6% at 12, 24 and 60 months, respectively. Five-year disease-free survival was 72.6%.

Embryonal tumor – atypical teratoid rhabdoid tumor

Five patients had a histopathological diagnosis of atypical teratoid rhabdoid tumor in the region of the pineal gland, all of whom were diagnosed at one year of age or younger. All were submitted to surgery (three total resections and two subtotal resections). Median size of the largest diameter of the tumor was 5.5 cm (range: 4.4 to 6.1 cm). Median survival was 11 months and all patients died within 24 months, excepted 1 that lost follow up (Table 2).

Table 2

Clinical-epidemiological results of patients with embryonal tumor (atypical teratoid rhabdoid tumor). IS = Infratentorial supracerebelar, T = Transcortical, OT = Occipital transtentorial
	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Gender	Female	Male	Female	Female	Male
Age (months)	12	7	3	2	1
Size of the lesion (cm)	4,4	5,5	6,1	4,7	5,3
Surgery	Yes	Yes	Yes	Yes	Yes
Approach	IS	IS	T	IS	OT
Ressection	Total	Total	Subtotal	Subtotal	Total
Relapse	No	No	Yes	No	Yes
Chemotherapy	Yes	Yes	Yes	Yes	Yes
Radioterapy	No	Yes	No	No	No
VPS	Yes	Yes	No	Yes	Yes
Outcome	Death	Death	Lost follow up	Death	Death
Overall Survival (months)	2	2	21	11	19

Pineal region tumors are rare, accounting for 0.4 to 1% of intracranial tumors in the adult population at large European and American centers [2, 18]. A higher incidence was reported in a Japanese series (3.2 to 4%) [19]. According to Herrada-Pineda, the incidence is between 3 and 8% [16]. Raimondi and Tomita reported an incidence of 9%, which is one of the highest in the literature [33]. Oi and Cheng reported that the epidemiological characteristics of the Japanese population are completely different from those of Caucasians and even other Asian countries, such as China, with the frequency of tumors up to fivefold greater in the Japanese population compared to Western populations [7, 8, 29]. In 2012, however, McCarthy et al. refuted this hypothesis by demonstrating in an epidemiological study the lack of a significant difference in the incidence of germ cell tumors in the pineal region between the American and Japanese populations [25]. In agreement with this statement, we found an incidence of 7.3% for tumors of the pineal region, which is higher than the figure found in most Western series.

Analyzing the incidence of these tumors in terms of sex, Ali-Hussain et al. found a male to female ratio of 3:1 [1, 20], which is the same ratio found in the present series. Considering the distribution per sex within histological groups, the difference was greater for germ cell tumor. Germinomas were more prevalent in the male sex compared to the female sex and this difference was accentuated when considering the pineal region, with the ratio ranging from 5:1 to 22:1 and a median of 14:1 [11], which is close to the ratio found in the present series (15:1). The most widely accepted theory for the difference between sexes was proposed by Sano and regards that the fact that closure of the neuropore occurs later in females than males; thus, the migration of embryonal cells reaches deeper portions of the nervous system in the formation of membranes, reaching the neuro-hypophysis more commonly, whereas this migration reaches more superficial portions of the neural tube in males, such as the pineal region. This theory explains the greater prevalence of germ cell tumors in the pineal region in males and the greater prevalence of germ cell tumors in the sellar region over the pineal region in females [36]. Genetic and hormonal factors may also play a role. Jennings et al. found an association between germ cell tumors and an increase in the secretion of gonadotrophins in patients with cryptorchidism, testicular feminization and gonadal dysgenesis [18].

The heterogeneity of histological types is justified by the variety of cell types found in the region, such as germ cells, parenchymal cells of the pineal gland, glia and neuroepithelial cells. According to the American research group Surveillance Epidemiology and End Results (SEER), germ cell tumors and pineal parenchymal tumors account for 89% of tumors in this region [1]. Mottolese reports the following distribution: 27% germ cell tumors, 27% pineal parenchymal tumors and 17% glioma [26]. According to Wong, the difference is accentuated, with germ cell tumors corresponding to 50–80%, pineal parenchymal tumors 3.6–21.8% and glioma 2.4–8.1% [44]. However, these data refer to the general population. In the present sample of only pediatric patients, we had the following distribution: 60.2% germ cell tumors, 22.5% pineal parenchymal tumors and 12.5 glioma. Germ cell tumors can also be subdivided into two large groups: germinomas, accounting for 50 and 75%, and non-germinomas, which are represented by choriocarcinomas, embryonal carcinomas, endodermal sinus tumors, mixed tumors (with components of more than one histological type) as well as pure, mature or immature teratomas. This proportionality of histological types was maintained in the present sample, with germ cell tumors and pineal parenchymal tumors accounting for more than 80% of the total. Considering only germ cell tumors, germinomas corresponded to 55%.

Germ cell tumors

Currently, the gold standard for the treatment of non-metastatic pure germinomas is chemotherapy followed by radiotherapy of the entire ventricular system and a boost at the tumor site. The boost can be omitted in cases of a complete response to chemotherapy. Metastatic tumors require radiotherapy of the entire neuroaxis as well as a boost in the primary tumor and metastatic tumors, without additional chemotherapy, although there is evidence of radiotherapeutic treatment without boost when chemotherapy is performed prior to radiotherapy [14]. Bifocal tumors in the region of the pineal gland and sellar region are not considered metastatic tumors and should therefore be treated with the same protocol as localized germinomas [14]. According to Mallucci and Van Battum, in the presence of bifocal tumors with negative tumor markers and brain MRI characteristics (but not pathognomonic) of germinoma, such as hypo- or iso-intensity at T1 and iso-intensity at T2 with homogeneous capture by contrast without the continuity of both tumors, it is possible to exclude non-germinomatous germ cell tumors, making germinoma the only possible diagnosis [2, 42]. In the present series, seven patients with non-germinomatous germ cell tumors met the criteria for bifocal tumors, but all were positive for some tumor marker, lending strength to the theory of both authors. However, Cuccia reported a case of pineoblastoma with a bifocal tumor and negative markers with an image similar to germinomas, thereby considering biopsy indispensable in the case of bifocal tumors with negative markers [10].

Tumor markers are essential during the follow-up of these tumors to evaluate the response to clinical treatment and should be used together with imaging exams. Cases of the recurrence of the tumor and negative (previously positive) markers could be what is known as “growing teratoma syndrome”, which is a rare condition first described in patients with extracranial germ cell tumors that consists of an increase in the tumor following the complete normalization of previously high tumor markers and whose component is exclusively a mature teratoma [24, 27]. It is postulated that chemotherapy induces immature germ cells to differentiate into the mature teratoma phenotype. Some studies also suggest the participation of radiotherapy or even irradiation secondary to multiple sessions of computed tomography as the trigger for this differentiation and growth of the component of the mature teratoma [21, 27, 31]. Other suggest that treatment of the malignant components of germ cell tumors “enable” the uninhibited growth of the mature teratoma component [31]. Treatment consists of radical surgery, for which the prognosis is good [34]. We had two cases of germ cell tumors, both of which were submitted to total resection and had a good outcome.

B-HCG level as a prognostic factor in pure germinomas is an issue of debate in the literature. Recent studies have found no evidence of this association [28], whereas previous studies reported a better prognosis for non-B-HCG-secreting germinomas [38]. In the present sample, we found no evidence of an association between B-HCG-secreting germinomas and a worse outcome.

The risk factors associated with a worse prognosis in cases of non-germinomatous germ cell tumors are high alpha-protein levels (> 1000 ng/ml) and residual tumor after all lines of treatment instituted (primary or second-look surgery, chemotherapy and radiotherapy) [6]. The first factor was not associated with mortality in our series, but the second factor was associated, which lends strength to the current recommendation to be aggressive with residual non-germinomatous germ cell tumors. We also found that the presence of metastasis and the absence of radiotherapy were factors associated with a worse prognosis.

The overall 60-month survival rate for germinomas at our service was close to 90%, which is an excellent rate and similar to that found at other large centers specialized in childhood tumors [4, 25].

Pineoblastoma

Pineoblastomas are rare malignance embryonal tumors, the prevalence of which is higher in children and adolescents, accounting for < 1% of all pediatric tumors in childhood [32]. These tumors have an aggressive behavior, with a high frequency of metastasis to the neuroaxis (around 15% identified at diagnosis) and a high mortality rate [43].

Lin et al. investigated prognostic factors associated with pineoblastoma in the pediatric population using the SEER databank with 132 patients. Age > 5 years, radiotherapy and radical resection were associated with a higher survival rate, whereas tumors with a diameter > 30 mm were associated with a worse outcome [13].

Parikh et al., Biswas et al. and Tate et al [5, 32, 41] also found an association between age and prognosis, reporting a worse outcome among children less than 5 years of age. The faster progression time in these children and higher response rates to chemotherapy in older children are some of the justifications for the worse outcome in younger children. These researchers also associated the occurrence of metastasis with lower survival rates, similarly to those seen in medulloblastomas. We also identified a tendency toward a worse prognosis in patients with metastasis at diagnosis (p = 0.07). This association was not found in the SEER databank [13].

In the most recent consensus on pineal parenchymal tumors, in which a genomic study was conducted, five molecular subtypes were identified with distinct clinical-epidemiological characteristics [23]. The MYC/FOXR2 and RB1 subgroups are more prevalent in the population less than 3 years of age (73 and 76%, respectively) and have a much worse outcome compared to other subtypes, with overall five-year survival rates of 20.6 and 26.8%, respectively [23]. One of the justifications raised for these low survival rates is the non-use of craniospinal irradiation radiotherapy in very young children due to the number harmful effects on neuropsychomotor development [23]. In the present study, we also found a worse outcome in this population, with an overall survival rate of 25 to 45% among patients less than three years of age.

Cuccia analyzed 12 patients with pineoblastoma (median age: 7 years) and found an overall one-year and five-year survival rate of 66.6% and 50%, respectively [12]. These figures were respectively 88% and 58% in the study by SchilD [39] and 85% and 60.5% in the study by Lin [13]. In the present sample, the median age of which was five years, we found an overall one-year and five-year survival rate of 84,.5% and 40.7%, respectively. This poorer outcome may be attributed to the younger median age in the present sample compared to that of the other studies, underscoring the considerable impact of age upon presentation for this type of tumor.

Glioma

The present results show a slight predominance of the male sex (57.8%) and a median age of 11 years. The literature also describes a predominance of the male sex and age of presentation between five and 20 years [40]. Regarding the size of the tumor at diagnosis, the median of the largest diameter was 3.2 cm in the present study, which is also comparable to the size reported in previous series, likely due to the small space in which the tumor is confined and the proximity to structures that hinder tumor expansion or infiltration. Thus, small tumors are sufficient to produce symptoms [9].

Regarding surgical aspects, the low rate of total resection (30%) may be explained by the intrinsic and infiltrative characteristics of this type of tumor. This rate is comparable to that found for this histological type in all other surgical series [3]. Endoscopic biopsy had 100% sensitivity in detecting this histological type with no adverse effects, making it highly recommendable in the management of these tumors. The most widely used access was the infratentorial supracerebellar approach in the sitting position due to the greater experience of the surgeon and the fact that it enables ample access to the pineal region, permitting the dissection of the venous complex, which is ideal for small tumors centered on the midline without extension above the tentorium. The use of a ventriculoperitoneal shunt was not associated with the prognosis in the present series and was also not more effective than endoscopic third ventriculostomy. In contrast, previous studies reported benefits of the use of the device for the treatment of hydrocephaly compared to endoscopic third ventriculostomy [3, 15].

The present data are in agreement with data reported in the literature demonstrating a poorer outcome with high grade compared to low grade gliomas [22]. All patients with high grade tumors died within 31 months. However, the 12-month survival was very satisfactory in this series (89.4%) compared to the overall rate described in the literature for the general population (60%) [9]. Five-year disease-free survival was > 70%. This result is justified by the higher rate of patients with low grade tumors in the present investigation compared to that reported in previous studies, with rates of high grade tumors surpassing 65% [9, 30].

Embryonal tumors – AT/RT

Atypical teratoid rhabdoid tumors (Grade IV according to the WHO) are rare, malignant and more commonly affect children less than 3 years of age, with a very poor prognosis. The main histopathological characteristic that enables its differentiation is the absence of the INI1 marker in the immunohistochemical analysis. The main location within the central nervous system is supratentorial. Such tumors in the pineal region are rare, with few cases described in the literature, most of which are case reports or small series [37]. The present sample included five cases of embryonal tumors – AT/RT, with a median age 3 months (range: 1 to 12 months).

Patients benefit from radical surgery, when possible, as well as early, aggressive chemotherapeutic and radiotherapeutic treatment, but overall survival is low, ranging from one to 46 months [45]. In the present series, all five patients were submitted to radical surgical resection, 60% of whom (3/5) were achieved total resection. All were submitted to aggressive chemotherapy and overall survival ranged from 2 to 19 months.

Pineal region tumors are diverse in terms of histological type. The present study sought to identify the main risk factors associated with each type. The female sex was the only factor related to a worse diagnosis among germinomas. Residual tumor, the absence of radiotherapy and metastasis were independently associated with a worse prognosis in cases of non-germinomatous germ cell tumors. The male sex was the only significant factor associated with a worse prognosis in cases of pineoblastoma, although age less than 3 years and metastasis at diagnosis demonstrated a tendency toward a worse outcome. High grade glioma was associated with a worse outcome and was the histological type with the lowest rate of total resection; the use of a shunt was not associated with the prognosis in such cases. Atypical teratoid rhabdoid tumors are rare and it was not possible to identify significant risk factors of a worse prognosis, although the findings are in agreement with reports in the literature that such tumors affect younger children (< 1 year of age) and have a poor prognosis regardless of the treatment instituted.

The authors declare no conflicts of interest directly or indirectly related to the present study.

Ethics approval and consente to participate: Ethical approval was waived by the local Ethics Committee of Universidade Federal de São Paulo (certificate N°; 4.332.210) and Istituto de Oncologia Pediátrica (certificate IOP – 016/2020) in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.

Availability of data and material: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors have no competing interests to declare that are relevant to the content of this article.

Funding: No funds, grants, or other support was received.

Authors’ contributions: Linoel Curado Valsechi, Fernando Suzuki and Adriana Lima Leite performed the data collection. Linoel Curado Valsechi, Marcos Costa Devanir and Sergio Cavalheiro performed the analysis, prepared the figures and tables, and wrote the first draft of the manuscript. Patricia Alessandra Dastoli and Jardel Mendonça Nicácio revised the manuscriptes. All authors read and approved the final manuscript.

Acknowledgements: The authors would like to thanks the clinical staff of the Instituto de Oncologia Pediátrica – IOP, mainly Dr.Najla Saba da Silva and Dr.Andrea Capellano, for contributing to the care and study of all involved patients.

Al-Hussaini M, Sultan I, Abuirmileh N, Jaradat I, Qaddoumi I. Pineal gland tumors: experience from the SEER database. J Neurooncol. 2009 Sep;94(3):351–8. doi: 10.1007/s11060-009-9881-9.
Al-Mahfoudh R, Zakaria R, Irvine E, Pizer B, Mallucci CL. The management of bifocal intracranial germinoma in children. Childs Nerv Syst. 2014 Apr;30(4):625–30. doi: 10.1007/s00381-013-2287-1.
Alamer OB, Palmisciano P, Rowe SE, Gupta AD, Haider M, Alduhaymi M, Cohen-Gadol AA, Yu K, El-Ahmadieh TY, Haider AS. Pineal Region Gliomas: A Systematic Review of Clinical Features and Treatment Outcomes. Anticancer Res. 2022 Mar;42(3):1189–1198. doi: 10.21873/anticanres.15585
Bendel A, WJ, Ries L, et al. Epidemiology and outcome of CNS germ cell tumors in the United States, SEER (1975–2000), a disease of adolescents and young adults. Abstracts for the second international symposium on central nervous system germ cell tumors, November 18–21, 2005, Los Angeles, California. Neuro Oncol. 2005;7(4):513–33.
Biswas A, Mallick S, Purkait S, Gandhi A, Sarkar C, Singh M, Julka PK, Rath GK. Treatment outcome and patterns of failure in patients of pinealoblastoma: review of literature and clinical experience from a regional cancer centre in north India. Childs Nerv Syst. 2015 Aug;31(8):1291–304. doi: 10.1007/s00381-015-2751-1.
Calaminus G, Frappaz D, Kortmann RD, et al. Outcome of patients with intracranial non-germinomatous germ cell tumors - Lessons from the SIOP-CNS-GCT-96 trial. Neuro Oncol. 2017;19(12):1661–1672. doi:10.1093/neuonc/nox122.
Cheng MK. Brain tumours in People’s Republic of China: a statistical review. Neurosurgery 1982;10:16–21.
Committee of Brain Tumor Registry of Japan. The committee of brain tumor registry of Japan. Report of brain tumor statistic in Japan 11th ed. Neurol Med Chir (Tokio) 2003;43(Suppl.):1–11.
Choque-Velasquez J, Resendiz-Nieves J, Jahromi BR, Baluszek S, Muhammad S, Colasanti R and Hernesniemi J: Long-term survival outcomes of pineal region gliomas. J Neurooncol 148(3): 651–658, 2020. PMID: 32613272. DOI: 10.1007/s11060-020-03571-z.
Cuccia V, Alderete D (2010) Suprasellar/pineal bifocal germ cell tumors. Childs Nerv Syst 26:1043–1049.
Cuccia V, Galarza M. Pure pineal germinomas: analysis of gender incidence. Acta Neurochir (Wien). 2006 Aug;148(8):865 – 71; discussion 871. doi: 10.1007/s00701-006-0846-x.
Cuccia V, Rodríguez F, Palma F, Zuccaro G. Pinealoblastomas in children. Childs Nerv Syst. 2006 Jun;22(6):577–85. doi: 10.1007/s00381-006-0095-6.
Deng X, Yang Z, Zhang X, Lin D, Xu X, Lu X, Chen S, Lin J. Prognosis of Pediatric Patients with Pineoblastoma: A SEER Analysis 1990–2013. World Neurosurg. 2018 Oct;118:e871-e879. doi: 10.1016/j.wneu.2018.07.079.
Frappaz D, Dhall G, Murray MJ, Goldman S, Faure Conter C, Allen J, Kortmann RD, Haas-Kogen D, Morana G, Finlay J, Nicholson JC, Bartels U, Souweidane M, Schönberger S, Vasiljevic A, Robertson P, Albanese A, Alapetite C, Czech T, Lau CC, Wen P, Schiff D, Shaw D, Calaminus G, Bouffet E. EANO, SNO and Euracan consensus review on the current management and future development of intracranial germ cell tumors in adolescents and young adults. Neuro Oncol. 2022 Apr 1;24(4):516–527. doi: 10.1093/neuonc/noab252.
Gholampour S, Bahmani M and Shariati A: Comparing the efficiency of two treatment methods of hydrocephalus: Shunt implantation and endoscopic third ventriculostomy. Basic Clin Neurosci 10(3): 185–198, 2019. PMID: 31462974. DOI: 10.32598/bcn.9.10.285.
Herrada-Pineda T, Revilla-Pacheco F, Manrique-Guzman S. Endoscopic approach for the treatment of pineal region tumours. J Neurol Surg A Cent Eur Neurosurg 2013.
Hoffman H, J, Yoshida M, Becker L, E, Hendrick E, B, Humphreys R, P: Pineal Region Tumors in Childhood. Pediatr Neurosurg 1994;21:91–104. doi: 10.1159/000120821
Jennings MT, Gelman R, Hochberg F (1985) Intracranial germ-cell tumors. Natural history and pathogenesis. J Neurosurg 63: 155–167.
Jia W, MA Z, Liu IY, Zang Y, Jia G, Wan W. Transcallosal interforniceal approach to pineal region tumours in 150 children. J Neurosurg Pediatr 2011;7:98–103
Keene D, Johnston D, Strother D, et al. Epidemiological survey of central nervous system germ cell tumors in Canadian children. J Neurooncol. 2007;82:289–295.
Kuwayama K, Takai H, Nishiyama A, Hirai S, Yokosuka K, Toi H et al (2014) A mixed germ cell Ktumor that underwent dramatic size changes. No Shinkei Geka 42:859–865.
Lapointe S, Perry A and Butowski NA: Primary brain tumours in adults. Lancet 392(10145): 432–446, 2018. PMID: 30060998. DOI: 10.1016/S0140-6736(18)30990-5
Liu APY, Li BK, Pfaff E, Gudenas B, Vasiljevic A, Orr BA, Dufour C, Snuderl M, Karajannis MA, Rosenblum MK, Hwang EI, Ng HK, Hansford JR, Szathmari A, Faure-Conter C, Merchant TE, Levine M, Bouvier N, von Hoff K, Mynarek M, Rutkowski S, Sahm F, Kool M, Hawkins C, Onar-Thomas A, Robinson GW, Gajjar A, Pfister SM, Bouffet E, Northcott PA, Jones DTW, Huang A. Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study. Acta Neuropathol. 2021 May;141(5):771–785. doi: 10.1007/s00401-021-02284-5.
Logothetis CJ, Samuels ML, Trindade A, Johnson DE (1982) The growing teratoma syndrome. Cancer 50:1629–1635).
McCarthy BJ, Shibui S, Kayama T, Miyaoka E, Narita Y, Murakami M, Matsuda A, Matsuda T, Sobue T, Palis BE, Dolecek TA, Kruchko C, Engelhard HH, Villano JL. Primary CNS germ cell tumors in Japan and the United States: an analysis of 4 tumor registries. Neuro Oncol. 2012 Sep;14(9):1194–200. doi: 10.1093/neuonc/nos155.
Mottolese C, Szathmari A, Beuriat PA. Incidence of pineal tumours. A review of the literature. Neurochirurgie. 2015 Apr-Jun;61(2–3):65–9. doi: 10.1016/j.neuchi.2014.01.005
Moiyadi A, Jalali R, Kane SV (2010) Intracranial growing teratoma syndrome following radiotherapy—an unusually fulminant course. Acta Neurochir 152:137–142.
Ogino H, Shibamoto Y, Takanaka T et al (2005) CNS germinomawith elevated serum human chorionic gonadotropin level: clinicalcharacteristics and treatment outcome. Int J Radiat Oncol BiolPhys 62(3):803–808.
Oi S, Tominaga J, Honda Y, Shinoda M, Takei F, Tsugane R, et al. Efficacy of neuroendoscopic procedures in minimally invasive preferential management of pineal region tumours: a prospective study. J Neurosurg 2000;93:245–53.
Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C and BarnholtzSloan JS: CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro Oncol 22(12 Suppl 2): iv1-iv96, 2020. PMID: 33123732. DOI: 10.1093/neuonc/noaa200.
Oya S, Saito A, Okano A, Arai E, Yanai K, Matsui T (2014) The pathogenesis of intracranial growing teratoma syndrome: proliferation of tumor cells or formation of multiple expanding cysts? Two case reports and review of the literature. Childs Nerv Syst 30:1455–1461.
Parikh KA, Venable GT, Orr BA, Choudhri AF, Boop FA, Gajjar AJ, et al. Pineoblastoma: the experience at St. Jude Children’s Research Hospital. Neurosurgery. 2017;81: 120–128.
Raimondi AJ, Tomita T. Pineal tumours in childhood. Childs Brain 1982;9:239–66
Rathod PS, Singh A, Punyashree RM, Pallavi VR, Usha A, Vijay CR, Shoba K, Rajshekar K. Growing Teratoma Syndrome a Rare Clinical Entity: Two Decades Management Experience from the Regional Cancer Institute. Indian J Surg Oncol. 2021 Mar;12(1):31–38. doi: 10.1007/s13193-020-01224-1.
Rhoton AL Jr. Tentorial incisura. Neurosurgery. 2000 Sep;47(3 Suppl):S131-53. doi: 10.1097/00006123-200009001-00015.
Sano K (1990) Pathogenesis of intracranial germ cell tumors reconsidered. J Neurosurg 90: 258–264.
Sali AP, Epari S, Nagaraj TS, Sahay A, Chinnaswamy G, Shetty P, Moiyadi A, Gupta T. Atypical Teratoid/Rhabdoid Tumor: Revisiting Histomorphology and Immunohistochemistry With Analysis of Cyclin D1 Overexpression and MYC Amplification. Int J Surg Pathol. 2021 Apr;29(2):155–164. doi: 10.1177/1066896920943289.
Sawamura Y, Ikeda J, Shirato H, Tada M, Abe H (1998) Germcell tumours of the central nervous system: treatment consider-ation based on 111 cases and their long-term clinical outcomes.Eur J Cancer 34(1):104–110
Schild SE, Scheithauer BW, Schomberg PJ, Hook CC, Kelly PJ, Frick L, Robinow JS, Buskirk SJ. Pineal parenchymal tumors. Clinical, pathologic, and therapeutic aspects. Cancer. 1993 Aug 1;72(3):870 – 80. doi: 10.1002/1097-0142(19930801)72:3<870::aid-cncr2820720336>3.0.co;2-x.
Stowe HB, Miller CR, Wu J, Randazzo DM and Ju AW: Pineal region glioblastoma, a case report and literature review. Front Oncol 7: 123, 2017. PMID: 28660172. DOI: 10.3389/fonc.2017.00123.
Tate M, Sughrue ME, Rutkowski MJ, Kane AJ, Aranda D, McClinton L, McClinton L, Barani IJ, Parsa AT. The long-term postsurgical prognosis of patients with pineoblastoma. Cancer. 2012 Jan 1;118(1):173-9. doi: 10.1002/cncr.26300. Epub 2011 Jun 29. PMID: 21717450.
Van Battum P, Huijberts MS, Heijckmann AC, Wilmink JT, Nieuwenhuijzen Kruseman AC (2007) Intracranial multiple midline germinomas: is histological verification crucial for therapy? Neth J Med 65:386–389
Villa S, Miller RC, Krengli M, Abusaris H, Baumert BG, Servagi-Vernat S, et al. Primary pineal tumors: outcome and prognostic factors. A study from the Rare Cancer Network (RCN). Clin Transl Oncol. 2012;14:827–834
Wong TT, Chen HH, Liang ML, Yen YS, Chang FC. Neuroendoscopy in the management of pineal tumours. Childs Nerv Syst 2011;27:949–59.
Yang M, Chen X, Wang N, Zhu K, Hu YZ, Zhao Y, Shu Y, Zhao ML, Gu WZ, Tang HF. Primary atypical teratoid/rhabdoid tumor of central nervous system in children: a clinicopathological analysis and review of literature in China. Int J Clin Exp Pathol. 2014 Apr 15;7(5):2411–20

No competing interests reported.

Prognostic factors of pediatric pineal region tumors at a single institution

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Material And Methods

Study design and inclusion of patients

Degree of resection and outcome

Statistical analysis

Results

Germ cell tumors

Pineoblastoma

Glioma

Embryonal tumor – atypical teratoid rhabdoid tumor

Discussion

Germ cell tumors

Pineoblastoma

Glioma

Embryonal tumors – AT/RT

Conclusion

Statements And Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1