Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®)–Health Professional Version

Childhood Pineoblastoma

Clinical Presentation

Pineoblastoma often results in hydrocephalus due to blockage of cerebrospinal fluid at the third ventricular level and other symptoms related to pressure on the back of the brain stem in the tectal region. Symptoms may include a constellation of abnormalities in eye movements (Parinaud syndrome) manifested by pupils that react poorly to light but better to accommodation, loss of upgaze, retraction or convergence nystagmus, and lid retraction. As they grow, these tumors may also cause hemiparesis and ataxia.[1]

Cellular and Molecular Classification

Pineoblastoma is histologically similar to medulloblastoma and shares histologic features with embryonal tumors; however, because of the World Health Organization (WHO) classification, its histogenesis is linked to the pineocyte (a type of pineal cell) and is classified separately.[2] This classification does not take into account the molecular genetic makeup of these tumors.[2]

Genomic molecular characterizations of embryonal tumors and pineoblastomas have demonstrated substantial heterogeneity among these tumors. These tumors are also molecularly different from medulloblastomas.[3,4]

Although the WHO classification system does not yet use molecular findings to classify nonmedulloblastoma embryonal tumors, future classification will most likely be based on both histological and molecular findings and, possibly, the site of origin in the nervous system.

Pineoblastoma, which was previously conventionally grouped with embryonal tumors, is now categorized by the World Health Organization (WHO) as a pineal parenchymal tumor. Given that therapies for pineoblastoma are quite similar to those utilized for embryonal tumors, the previous convention of including pineoblastoma with the central nervous system (CNS) embryonal tumors is followed here. Pineoblastoma is associated with germline mutations in both the RB1 gene and in DICER1, as described below:

Pineoblastoma is associated with germline mutations in RB1, with the term trilateral retinoblastoma used to refer to ocular retinoblastoma in combination with a histologically similar brain tumor generally arising in the pineal gland or other midline structures. Historically, intracranial tumors have been reported in 5% to 15% of children with heritable retinoblastoma.[5] Rates of pineoblastoma among children with heritable retinoblastoma who undergo current treatment programs may be lower than these historical estimates.[6-8]
Germline DICER1 mutations have also been reported in patients with pineoblastoma.[9] Among 18 patients with pineoblastoma, 3 patients with DICER1 germline mutations were identified, and an additional 3 patients known to be carriers of germline DICER1 mutations developed pineoblastoma.[9] The DICER1 mutations in patients with pineoblastoma are loss-of-function mutations that appear to be distinct from the mutations observed in DICER1 syndrome–related tumors such as pleuropulmonary blastoma.[9]

Staging Evaluation

Dissemination at the time of diagnosis occurs in 10% to 30% of patients with pineoblastoma.[10] Because of the location of the tumor, total resections are uncommon, and most patients have only a biopsy or a subtotal resection before postsurgical treatment.[10,11] Staging for children with pineoblastomas is the same as that performed for children with medulloblastoma; however, the patients are not assigned to average-risk and high-risk subgroups for treatment purposes (refer to the medulloblastoma Staging Evaluation section of this summary for more information).[10]

Treatment Option Overview for Childhood Pineoblastoma

Table 5 describes the standard treatment options for newly diagnosed and recurrent childhood pineoblastoma.

Table 5. Standard Treatment Options for Childhood Pineoblastoma

Treatment Group		Standard Treatment Options
Newly diagnosed childhood pineoblastoma	Children aged 3 years and younger	Biopsy (for diagnosis) or subtotal resection
		Adjuvant chemotherapy
		High-dose, marrow-ablative chemotherapy with autologous bone marrow rescue or peripheral stem cell rescue
	Children older than 3 years	Surgery
		Adjuvant radiation therapy
		Adjuvant chemotherapy
Recurrent childhood pineoblastoma		There are no standard treatment options. (Refer to the Treatment of Recurrent Childhood Medulloblastoma and Other CNS Embryonal Tumors section of this summary for more information.)

Treatment of Childhood Pineoblastoma

Treatment of children aged 3 years and younger

Standard treatment options for children aged 3 years and younger with pineoblastoma include the following:

Biopsy

Biopsy is usually performed to diagnose pineoblastoma.

Adjuvant chemotherapy

Children aged 3 years and younger with pineoblastoma are usually treated initially with chemotherapy in the hope of delaying, if not obviating, the need for radiation therapy.[12] Overall prognosis for this group of children remains very poor. In two sequential multicenter prospective clinical trials, all five children younger than 3 years who were treated with chemotherapy died.[13][Level of evidence: 2A] In children responding to chemotherapy, the timing and amount of radiation therapy required after chemotherapy is unclear. The addition of craniospinal irradiation to chemotherapy-based regimens may successfully treat some children but with anticipated neurodevelopmental decline.[14][Level of evidence: 2A]

High-dose, marrow-ablative chemotherapy with autologous bone marrow rescue or peripheral stem cell rescue

High-dose, marrow-ablative chemotherapy with autologous bone marrow rescue or peripheral stem cell rescue has been used with some success in young children.[15][Level of evidence: 2Di]

Treatment of children older than 3 years

Standard treatment options for children older than 3 years with newly diagnosed pineoblastoma include the following:

Surgery

Surgery is usually the initial treatment for patients with pineoblastoma to diagnose the tumor.[16] Total and near-total resection is infrequently obtained in patients with pineoblastoma, and the impact of the degree of resection on outcome is unknown.[10,11]

Adjuvant radiation therapy

The usual postsurgical treatment for patients with pineoblastoma begins with radiation therapy, although some trials have utilized preradiation chemotherapy. The total dose of radiation therapy to the tumor site is 54 Gy to 55.8 Gy using conventional fractionation.[10,11]

Craniospinal irradiation with doses ranging between 23.4 Gy and 36 Gy are also recommended because of the propensity of this tumor to disseminate throughout the subarachnoid space.[10,11]

Adjuvant chemotherapy

Chemotherapy is usually utilized in the same way as outlined for high-risk medulloblastomas in children with nondisseminated disease at the time of diagnosis. (Refer to the Treatment of children older than 3 years with high-risk medulloblastoma section in this summary for more information.)

The 5-year disease-free survival rate exceeds 50% in children with localized disease at diagnosis undergoing aggressive resection.[10,11,17,18][Level of evidence: 1iiA] The Children's Oncology Group (COG) COG-ACNS0332 (NCT00392327) study of 36 patients with nonmedulloblastoma embryonal tumors (which included 26 pineoblastomas) reported a 5-year overall survival (OS) of 78.5% (95% confidence interval, 62.2%–94.8%).[18][Level of evidence: 1iiA]

For patients with disseminated disease at the time of diagnosis, survival is considerably poorer.[10,11] In the COG-ACNS0332 (NCT00392327) study, there was no significant difference in event-free survival or OS according to metastatic status.

Treatment options under clinical evaluation for childhood pineoblastoma

For patients with pineoblastoma, a variety of different treatment approaches are under evaluation, including the use of higher doses of chemotherapy after radiation therapy supported by peripheral stem cell rescue and the use of chemotherapy during radiation therapy.

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG , the Pediatric Brain Tumor Consortium , or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

References

Chintagumpala MM, Paulino A, Panigrahy A, et al.: Embryonal and pineal region tumors. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2015, pp 671-99.
Louis DN, Perry A, Reifenberger G, et al.: The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131 (6): 803-20, 2016. [PUBMED Abstract]
Pomeroy SL, Tamayo P, Gaasenbeek M, et al.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415 (6870): 436-42, 2002. [PUBMED Abstract]
Sturm D, Orr BA, Toprak UH, et al.: New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 164 (5): 1060-72, 2016. [PUBMED Abstract]
de Jong MC, Kors WA, de Graaf P, et al.: Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol 15 (10): 1157-67, 2014. [PUBMED Abstract]
Ramasubramanian A, Kytasty C, Meadows AT, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (4): 825-9, 2013. [PUBMED Abstract]
Abramson DH, Dunkel IJ, Marr BP, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (6): 1319-20, 2013. [PUBMED Abstract]
Turaka K, Shields CL, Meadows AT, et al.: Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. Pediatr Blood Cancer 59 (1): 121-5, 2012. [PUBMED Abstract]
de Kock L, Sabbaghian N, Druker H, et al.: Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol 128 (4): 583-95, 2014. [PUBMED Abstract]
Jakacki RI, Zeltzer PM, Boyett JM, et al.: Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Childrens Cancer Group. J Clin Oncol 13 (6): 1377-83, 1995. [PUBMED Abstract]
Timmermann B, Kortmann RD, Kühl J, et al.: Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 20 (3): 842-9, 2002. [PUBMED Abstract]
Mason WP, Grovas A, Halpern S, et al.: Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol 16 (1): 210-21, 1998. [PUBMED Abstract]
Hinkes BG, von Hoff K, Deinlein F, et al.: Childhood pineoblastoma: experiences from the prospective multicenter trials HIT-SKK87, HIT-SKK92 and HIT91. J Neurooncol 81 (2): 217-23, 2007. [PUBMED Abstract]
Friedrich C, von Bueren AO, von Hoff K, et al.: Treatment of young children with CNS-primitive neuroectodermal tumors/pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens and radiotherapy. Neuro Oncol 15 (2): 224-34, 2013. [PUBMED Abstract]
Fangusaro J, Finlay J, Sposto R, et al.: Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience. Pediatr Blood Cancer 50 (2): 312-8, 2008. [PUBMED Abstract]
Jakacki RI, Burger PC, Kocak M, et al.: Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (5): 776-83, 2015. [PUBMED Abstract]
Gururangan S, McLaughlin C, Quinn J, et al.: High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas. J Clin Oncol 21 (11): 2187-91, 2003. [PUBMED Abstract]
Hwang EI, Kool M, Burger PC, et al.: Extensive Molecular and Clinical Heterogeneity in Patients With Histologically Diagnosed CNS-PNET Treated as a Single Entity: A Report From the Children's Oncology Group Randomized ACNS0332 Trial. J Clin Oncol : JCO2017764720, 2018. [PUBMED Abstract]