As defined by the WHO, papillary tumor of the pineal region is “a neuroepithelial tumor localized in the pineal region and characterized by a combination of papillary and solid areas with epithelial-like cells and immunoreactivity for cytokeratins” [2]. It is frequently localized in the third ventricle and extends above the quadrigeminal cistern, causing triventricular hydrocephalus.
As surmised by its name, papillary tumor of the pineal region does not arise from the pineal gland, but rather, is thought to originate from specialized secretory ependymocytes of the subcommissural organ [3]. Located in the posterior region of the third ventricle, the subcommissural organ is a circumventricular organ of the brain with a glandular structure [4]. The theory that papillary tumor of the pineal region arises from this region is confirmed by Shibahara and colleagues who showed expression of proteins presumed to be secreted by cells of the human subcommissural organ [5]. The papillary architecture of this tumor mimics subcommissural organ morphology. In addition, the ependymal cells from this region in infants are typically immunoreactive for cytokeratin, EMA, and S100 protein. In adults, these cells may remain vestigial in the subcommissural organ and have been proposed to have a role in the histogenesis of this neoplasm [6].
Papillary tumor of the pineal region shows distinct chromosomal alterations and DNA methylation and expression profiles. Losses of chromosomes 10, 3, and 22q have been described. In addition, gains in chromosomes 8p and 12 have also been identified [7]. Recently, Goschzik and colleagues, have described phosphatase and tensin homolog (PTEN) mutation and activation of PI3K/Akt/Mtor pathway in the pathogenesis [8].
While papillary tumor of the pineal region may share common features with other primary and metastatic tumors involving the central nervous system, distinct morphological, immunohistochemical, and molecular features may assist with the diagnosis of this entity. Papillary tumors of the pineal region are immunoreactive against cytokeratins, S100 protein, neuron-specific enolase (NSE), and vimentin. There is variable staining for EMA, with Jouvet and colleagues reporting weak positivity in tumor cells and focal cell surface staining especially on the pole facing the vessel or lumen of rosettes or tubes. GFAP is negative in tumor cells. However, weak expression may be noted in the perivascular region, at the periphery of the tumor or by entrapped reactive astrocytes [6]. Microtubule-associated protein 2 (MAP-2) staining has also been reported [9].
A frequent differential when considering the diagnosis of a papillary tumor of the pineal region is a papillary ependymoma. Jouvet and colleagues noted that the papillary structure of papillary tumor of the pineal region have more of an epithelial character and lack a fibrillary background when compared with an ependymoma. In contrast to papillary tumor of the pineal region, ependymomas express GFAP and only broad spectrum cytokeratin (AE1/AE3). As compared with ependymal tumors, papillary tumors of the pineal region overexpress SAM pointed domain containing ETS transcription factor (SPDEF) [7].
Immunohistochemical staining in a papillary tumor of the pineal region may be comparable with tumors of the choroid plexus. Morphologically however, the appearance of papillary tumor of the pineal region is less papillary than in a choroid plexus papilloma and more differentiated than a choroid plexus carcinoma. Although both choroid plexus papilloma and papillary tumor of the pineal region have broad fibrovascular cores, the columnar cells of papillary tumor of the pineal region are surrounded by a diffuse cellular proliferation. If available, immunohistochemical staining for transthyretin is typically strong in tumors of the choroid plexus but weak or negative in papillary tumor of the pineal region. In addition, papillary tumor of the pineal region shows negative membranous Kir7.1 staining and negative cytoplasmic stanniocalcin-1 staining, which both are frequently encountered in choroid plexus tumors [9].
Electron microscopy may assist with the diagnosis of papillary tumor of the pineal region by identifying features proposing its ependymal and secretory nature. Ependymal differentiation is suggested by identification of microvilli and zipper-like junctions. Rough endoplasmic reticulum and dilated cisternae with granular material suggest a secretory function. The dense core vesicle, indented and lobulated nucleus and numerous mitochondria help differentiate papillary tumor of the pineal region from tumors of the choroid plexus.
Little information exists regarding the biologic behavior, natural course, and optimal treatment for these patients. It is believed that these tumors behave in a similar way to ependymomas and tumors of the choroid plexus with potential for local recurrence. Santoro and colleagues provided some information regarding the natural history of papillary tumor of the pineal region. In their case report, neuro-radiological follow-up for a period of four years showed an average growth rate of 3.4 mm per year [10]. Fèvre-Montange and colleagues followed 29 of 31 patients for a mean follow-up period of 4.2 years. In their study, 21 patients experienced disease progression and 8 patients died. There was one patient who had early CSF dissemination [11]. Sato and colleagues similarly reported a case with early CSF dissemination [12]. Although there is currently no clear consensus, early aggressive multifaceted treatment with a combination of surgical resection, stereotactic radiosurgery, and chemotherapy may be advocated for tumor control.
The patient presented in this case report demised before follow-up and a post mortem examination was not performed to clarify a cause of death. Further accumulation of case reports will assist with defining this entity and may provide further insight into management of such patients.
