Pineoblastoma

Pineoblastoma is a grade 4 embryonal tumor of the pineal gland. It makes up under 1% of brain tumors and 25 to 45% of pineal parenchymal tumors, and is most frequent in children under 5 years, with a smaller adult group. Heritable retinoblastoma (RB1 mutation) predisposes to "trilateral retinoblastoma", in which pineoblastoma accompanies bilateral retinoblastoma, and DICER1 mutations are also associated.

Molecular groups include microRNA processing altered tumors (DICER1, DROSHA, DGCR8), MYC and FOXR2 activated tumors, and RB1 altered tumors. Cerebrospinal fluid dissemination is present in 10 to 40% at diagnosis (up to half in infants). Survival is 60 to 75% in children aged 3 or over treated with craniospinal radiotherapy, and 15 to 30% in children under 3. Complications: hydrocephalus, Parinaud syndrome, leptomeningeal spread, and late neurocognitive and endocrine effects.

• Short history of headache and vomiting from obstructive hydrocephalus (about 90%)
• Parinaud syndrome: upgaze palsy, pupillary light-near dissociation and eyelid retraction
• Ataxia and diplopia
• Infants: macrocephaly, irritability and a bulging fontanelle
• Red flags: falling consciousness, bradycardia and back pain from spinal metastases

1. MRI brain and whole spine with gadolinium: a 3 to 4 cm heterogeneous pineal mass invading adjacent structures, with restricted diffusion, avid enhancement and peripheral "exploded" calcification.
2. Serum and CSF AFP and β-hCG (normal), to exclude a germ cell tumor.
3. Biopsy or resection with histology (small round blue cells, Homer Wright and Flexner-Wintersteiner rosettes) and molecular profiling.
4. CSF cytology at least 10 days after surgery when safe.
5. Germline testing for RB1 and DICER1, and an ophthalmic examination for retinoblastoma.

Differentials: pineocytoma, pineal parenchymal tumor of intermediate differentiation, germ cell tumor, atypical teratoid rhabdoid tumor, glioma and papillary tumor of the pineal region.

• Hydrocephalus: endoscopic third ventriculostomy with biopsy.
• Surgery: maximal safe resection through a supracerebellar infratentorial or occipital transtentorial approach. Complications: Parinaud syndrome, hemorrhage and venous infarction.
• Radiotherapy (age 3 or over): craniospinal 23.4 Gy for non-metastatic disease with complete resection, 36 Gy for metastatic or residual disease, then a boost to a total of 54 to 55.8 Gy at the primary site.
• Chemotherapy: vincristine 1.5 mg/m2 IV weekly (maximum 2 mg) during radiotherapy, then cisplatin 75 mg/m2 IV day 1, lomustine 75 mg/m2 orally day 1 and vincristine 1.0 to 1.5 mg/m2 IV on days 1, 8 and 15, every 6 weeks for 8 cycles. Give sodium thiosulfate 20 g/m2 IV 6 hours after cisplatin in localized disease. Check audiology, creatinine, magnesium and blood count before each cycle.
• Children under 3 years: avoid craniospinal irradiation. Use intensive induction (vincristine 1.5 mg/m2 IV, cisplatin 75 mg/m2 IV, cyclophosphamide 1.5 g/m2 IV on 2 days with mesna 60% of the dose IV in divided doses, and etoposide 100 mg/m2 IV on 3 days) followed by high-dose thiotepa 300 mg/m2 IV daily for 3 days with autologous stem cell rescue.
• Prophylaxis during treatment: trimethoprim-sulfamethoxazole (trimethoprim 150 mg/m2 a day in 2 divided doses on 3 days each week) and ondansetron 0.15 mg/kg IV (maximum 8 mg) before chemotherapy.
• Relapse: poor outcome. Options include re-irradiation, temozolomide 150 mg/m2 orally days 1 to 5 every 28 days, and trial enrolment.

Follow-up: MRI brain and spine every 3 months for 2 years, then every 6 months to year 5. Surveillance for retinoblastoma in RB1 carriers, and for pleuropulmonary blastoma and other tumors in DICER1 carriers. Offer genetic counseling and sperm banking.