2020 NPB-09

This case was originally published in 2020. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

The patient is a 17-year-old woman who presented with three weeks of morning headaches that spontaneously resolved after rising. New-onset diplopia prompted a visit to her physician who noted papilledema. She underwent an emergent MRI scan (Image A and Image B) which revealed hydrocephalus and a third ventricular mass. She was admitted to the hospital and the next day underwent third ventriculostomy, shunt placement, and a biopsy/resection of the lesion.

Tissue Site
Posterior third ventricle

The whole slide image provided is an H&E-stained section of the third ventricular mass.

Brain MRI (Image A and Image B) shows an enhancing lobulated mass in the posterior third ventricle with obstruction of the aqueduct. No other lesions are identified in the CNS. The resected lesion demonstrates a small round blue cell tumor characterized by diffuse sheets of hyperchromatic cells with high nuclear:cytoplasmic ratios (Image C, Image D, and Image E). Homer Wright and Flexner-Wintersteiner rosettes and fleurettes may be seen in some cases. Mitoses are easily found (Image D and Image E), and there is a high Ki-67 labelling index (Image F). The tumor cells express neuronal markers including synaptophysin (Image G), neuron specific enolase (Image H), and neurofilament (Image I). Very rare cytoplasmic granules positive for chromogranin A are seen (Image J). Staining for GFAP reveals only scattered positive entrapped glial cells (Image K). There is virtually no collagen in the mass (not shown) and only minimal vessel-associated reticulin deposition (Image L). These radiological, histological, and IHC features are diagnostic of pineoblastoma.

Pineoblastomas are rare CNS neoplasms that occur predominantly in children and young adults. They represent about one third of primary pineal parenchymal neoplasms. Given the characteristic location and microscopic appearance of pineoblastoma, it does not usually present a major diagnostic challenge. Differentiation from pineocytoma rests on that tumor’s features of relatively uniform cell morphology, pineocytomatous rosettes, and very low mitotic rate. Pineal parenchymal tumor of intermediate differentiation (PPTID) may also be considered in the differential but tends to have more cell uniformity, open salt-and-pepper chromatin, more abundant cytoplasm, and generally fewer mitotic figures than pineoblastoma. The pineal parenchymal tumors all show similar IHC staining profiles, although the Ki-67 proliferative indices are usually quite disparate: <1% in pineocytoma, 3.5% to 16.1% in PPTID, and 23.5% to 50.1% in pineoblastoma. Like pineoblastoma, central neurocytoma also expresses synaptophysin but is usually negative for neurofilament, demonstrates a low mitotic rate, and is comprised of monomorphic tumor cells, often with an oligodendroglial appearance. Diffuse midline glioma may show focal synaptophysin immunoreactivity but is fundamentally a glial tumor with S100, OLIG2, and variable GFAP positivity. While the pineal region is a common location for germinomas, they are histologically distinct from pineoblastoma, composed of large pleomorphic cells with irregular nuclei and prominent nucleoli admixed with clusters of small reactive lymphocytes. Germinomas do not stain for neuronal markers.

The molecular characteristics of pineoblastoma are still being elucidated. It is well documented that alterations in the retinoblastoma gene (RB1) predispose to this neoplasm and are associated with the familial retinoblastoma syndrome. This is not unexpected given the association between the ontogeny of the pineal gland and the eyes. More recently, abnormalities in the DICER1, DROSHA, and DGCR8 genes have been identified in some cases of pineoblastoma. These proteins are all involved in microRNA processing.

The recognition that DICER1 abnormalities are associated with numerous neoplasms occurring in multiple sites has given rise to the concept of “DICER1 syndrome” in which individuals, especially children, exhibit a range of benign and malignant seemingly-unrelated tumors in many organs. Pleuropulmonary blastoma is the hallmark of this syndrome, but an array of CNS tumors may also be seen, including pituitary blastoma, intraocular medulloepithelioma, and pineoblastoma. While DICER1 syndrome is a rare condition, it should be considered in patients with pineoblastoma, especially in those with a history of other tumors. A mutation in DICER1, typically germline, is associated with loss of heterozygosity of the wild-type allele; the inactivation of the nonmutated allele leads to absence of the DICER1 protein and loss of its regulatory functions in the cell.

Pineoblastomas are the most aggressive of the primary pineal neoplasms and are particularly so in the setting of RB1 mutations. Increased patient survival is associated with complete resection of the lesion and the absence of spread via CSF to other sites. While the overall survival rates vary widely between studies, they have been increasing over time.

• Pineoblastomas are the most aggressive primary pineal neoplasm (WHO grade IV) and are composed of primitive cells that label with many neuronal markers and have a high mitotic index.
• Pineocytomas, PPTID, and pineoblastomas show similar IHC profiles, although the Ki-67 proliferative indices differ.
• Abnormalities in RB1, DICER1, DROSHA, and DGCR8 genes are associated with pineoblastoma, and pineoblastomas are one of many primitive neoplasms associated with DICER1 syndrome.
• Pineoblastomas commonly spread via CSF to other sites, a feature associated with a worse prognosis.

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