Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy.

Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.

Papillary tumor of the pineal region: ultrastructural study of a case.

Papillary tumor of the pineal region (PTPR) is a recently classified neuroepithelial tumor for which there has been little comprehensive ultrastructural study. Here, we describe the radiographic, intraoperative, histologic, immunohistochemical, and in-depth ultrastructural findings in a case of PTPR. This study corroborates that PTPR has concomitant ependymal, neuroendocrine, and secretory features, and details novel ultrastructural as well as immunohistochemical features that further this argument. Discrepancies with prior descriptions of PTPR are described, as these differences may reflect phenotypic variability in this rare tumor, and the ultrastructural features that relate to the putative ependymal origin of the entity are emphasized.

Pineal parenchymal tumor with marked retinoblastic differentiation: case report.

A 53-year-old woman was found to have a tumor in the pineal region. Histologically, Homer-Wright rosettes were sporadically distributed in a diffuse proliferation of round tumor cells that were immunoreactive for synaptophysin and chromogranin. A few perivascular pseudorosettes were also present, and the perivascular tumor cells were immunoreactive for glial fibrillary acidic protein and vimentin. By electron microscopy, well-developed junctions and pronounced interdigitation of abutting plasma membranes were noted in many tumor cells, as well as abundant intracytoplasmic microtubules. These findings indicated that the tumor was a pineal parenchymal tumor accompanied by an extraordinary epithelial-like differentiation, suggesting retinoblastic photoreceptor cell differentiation.

Cytogenetic and ultrastructural study of a pineocytoma case report.

The authors report a case of pineocytoma in a 44-year-old woman suffering from headache, vomiting and Parinaud syndrome. At histopathological examination the neoplasm showed a ill-defined lobulate pattern with some small pineocytomatous rosettes. The electron-microscopy revealed cells of moderate size and oval nuclei with smooth nuclear envelopes; well-developed organelles were found in the, abundant cytoplasm. The chromosome analysis revealed this kariotype: 58-59, XXX, -4, -5, -13, - 14, -15, + 19. This is the first report of a pineocytoma with ultrastructural and cytogenetic study; it confirms the literature findings of the electron-microscopy, whereas there is partial accordance with the previous cytogenetic studies.

Spontaneous pinealoma in a male Crj:CD (SD) IGS rat.

A pinealoma (benign) was found in a 61-week-old male Crj:CD (SD) IGS rat. The neoplasm was located between the cerebral hemispheres and the cerebellum. Histologically, the tumor cells consisted of two cell types: large, pale-staining cells and small dark-staining cells. A fibrovascular stroma divided the tumor cells into incomplete lobules or nest structures. Relatively numerous mitoses were noted in the tumor cells. Ultrastructurally, the tumor cells contained dense-cored vesicles, approximately 120 nm in diameter.

Immunohistochemical, ultrastructural, biochemical and in vitro studies of a pineocytoma.

Using both tumor specimen and cultured tumor cells, we have studied the differentiation of a pineocytoma by light and electron microscopy (EM) and immunohistochemical demonstration of glial, neuronal and neuroendocrine markers. Only interstitial cells were labeled with anti-glial fibrillary acidic protein and anti-S100 protein antibodies. Synaptophysin, neurofilaments and tau labeling was found in cells forming the pineocytomatous rosettes. Some cells also bound the anti-tryptophan hydroxylase antibody (TPOH), but no staining was seen after application of anti-chromogranin A or S-antigen antibodies. EM provided evidence for neurosensory differentiation demonstrating the presence of vesicle-crowned rodlets, cilia (9+0) and fibrous filaments. In culture, tumor cells proliferated slowly and showed positive immunolabeling for vimentin and TPOH. Expression of mRNA coding for TPOH, serotonin N-acetyltransferase, hydroxyindole-O-methyl-transferase and c-myc was found in the tumor using reverse transcriptase-polymerase chain reaction. These results demonstrate neuronal differentiation of this pineocytoma and suggest that the neoplastic pineal cells are capable of synthesizing serotonin and melatonin.

Clinicopathological study on pineocytoma.

Six cases of pineocytoma, which had developed in the parenchyma of the adult pineal body, were examined immunohistochemically and under an electron microscope, after the malignancy of each case had been determined using our classification. One case was rated as grade 1 showing a lobular structure and resembling the normal pineal body. Two cases were rated as grade 2 without a lobular structure but with pineocytomatous rosettes (P-rosettes). Two cases were rated as grade 3 without P-rosettes but with few mitotic figures. One case was rated as grade 4 with marked cellular pleomorphism, numerous mitotic figures and necrotic foci. When examined immunohistochemically, neuron-specific enolase was positive but glial fibrillary acidic protein was negative in all cases. Under an electron microscope, all cases showed abortive synapses, and clear or dense core vesicles. These findings allow us to make two conclusions. First, pineocytoma is always a tumor of neuronal lineage, regardless of their grade of malignancy. Second, the grade 4 pineocytoma should be distinguished from the type of tumor classically called "pineoblastoma." That is, the former seems to be a biologically dedifferentiated tumor, while the latter seems to be biologically undifferentiated tumor.

Structural and ultrastructural characteristics of human pineal gland, and pineal parenchymal tumors.

We have studied 20 pineal parenchymal tumors (PPT) and 4 normal or cystic pineal glands both by light and electron microscopy and immunohistochemistry with antibodies against glial markers [glial fibrillary acidic protein (GFAP) and protein S-100] or neural/neuroendocrine markers [neurofilaments (NF), synaptophysin and chromogranin A]. Light microscopy revealed the cellular organization of pinealocytes in the normal gland and in different morphological types of pineal tumors (typical pineocytomas, PPT with intermediate differentiation, mixed PPT exhibiting elements of both pineocytoma and pineoblastoma and pineoblastomas). Immunohistochemistry showed the presence of GFAP and protein S-100 in interstitial cells in non-neoplastic pineal gland. Cell processes were labeled with anti-synaptophysin and anti-NF antibodies. No immunoreactivity was found for chromogranin A in non-neoplastic pineal gland. In pineocytomas, GFAP and protein S-100 were observed in interstitial cells. Synaptophysin and NF were present in the large rosettes of pineocytomas. Synaptophysin, NF and chromogranin A were present in pineocytomas with a lobular arrangement of cells. Anti-chromogranin A immunoreactivity was also seen in lobular areas of some PPT with intermediate differentiation. Analysis of normal human pineal gland by electron microscopy showed the presence of vesicle-crowned rodlets (VCR or synaptic ribbons), fibrous filaments (F), paired twisted filaments but few dense-core vesicles (DCV) in normal pinealocytes. Tumoral pineal cells appeared to differentiate either towards a neurosensory pathway characterized by the presence of sensory cells elements (VCR and F), or towards a neuroendocrine pathway, with the occurrence of many DCV. Immunogold labeling demonstrated the presence of chromogranin A in neurosecretory granules.

Differential expression of retinal proteins in a pineal parenchymal tumor.

The pineal gland and retina share histogenetic features that reflect a similar neurosensory/photosensory ontogeny. Pineal parenchymal tumors demonstrate a highly variable and incomplete photosensory differentiation evidenced by specific cytoarchitectural features and the expression of photosensory retinal S-Antigen (S-Ag). Despite these neuro-ontogenetic parallels, pineal parenchymal tumors have not been well studied for the neuroretinal phenotypes that accompany normal neuroretinal development. The investigation of photoreceptor gene expression may provide an important insight into the histogenesis of pineal parenchymal neoplasms. In this study, a pineal parenchymal tumor of the "mixed pineoblastoma/pineocytoma" type was examined for the expression of several photoreceptor, glial and neuronal proteins including: interphotoreceptor retinoid-binding protein (IRBP), rod opsin, cone opsin, S-Ag and cellular retinaldehyde-binding protein (CRA1BP). The detection of IRBP and its mRNA, the earliest photoreceptor-associated protein expressed during retinal development, corroborated the rudimentary photosensory differentiation of this tumor which had limited cytoarchitectural evidence for pineal differentiation. The analysis of IRBP expression may facilitate the diagnostic recognition of primitive pineal neoplasms and further define the neuroretinal differentiation which occurs in pineal parenchymal tumors.

[A case of an cerebello-pontine angle pineoblastoma].

An extremely rare case of a left cerebello-pontine angle (CP angle) pineoblastoma has been reported. The patient was a 32-year-old male whose initial manifestations were those of increased intracranial pressure. CT scan showed a large enhancing mass located at the left CP angle, associated with a moderate occlusive hydrocephalus. Left suboccipital craniectomy was performed. The mass was an extramedullary tumor which had compressed the left cerebellar hemisphere, and was easily separable from the adjacent tissue. The tumor was totally resected, and the patient had a temporary release from the symptoms. Recurrence and spinal dissemination were found within the ensuing few months. The tumor had invaded deeply through the left CP angle into the cerebellar parenchyme, and showed no anatomical connection with the pineal body. The tumor dissemination was also observed widely in the spinal subarachnoid space. No abnormalities at the pineal region were able to be confirmed using CT and MRI studies. Irradiation to the whole brain, to the localized left CP angle and to the spinal cord with additional chemotherapy was given. The patient died half a year after the first operation. Autopsy was not performed. Histopathologically, the tumor was delineated into lobular structures by reticulin fibrils and vimentin-positive interstitial tissue. Tumor cells were small in size, and had irregularly shaped hyperchromatic nuclei with increased mitotic figures, and formed various types of rosettes; pineocytomatous, Flexner-Wintersteiner, Homer-Wright and perivascular. Fine argyrophilic cell processes with club-shaped expansions were demonstrated inside the pineocytomatous rosettes.(ABSTRACT TRUNCATED AT 250 WORDS)

Pineal germinomas and testicular seminoma: a comparative ultrastructural study with special references to early carcinomatous transformation.

We have investigated the ultrastructural characteristics of 16 cases of pineal germinomas and compared them with those of 18 cases of testicular seminomas. Glandular differentiation of tumor cells was found in both though it was more consistently noted in pineal germinomas than in testicular seminomas. This feature was interpreted to represent early carcinomatous transformation of germinoma cells. It not only explains the difficulties occasionally encountered in distinguishing germinoma and its anaplastic variant from embryonal carcinoma, but also has implications for our understanding of germ cell neoplasia, particularly the place of germinoma/seminoma in the nosology of such tumors.

Pineocytoma with neuronal differentiation--case report.

The authors describe a case of pineocytoma studied by light and electron microscopy and the immunoperoxidase method. The tumor consisted of two types of cells bearing either chromatin-rich or pale nuclei. These cells were arranged in rosettes and contained pale, eosinophilic material at the center, or in lobular patterns with thin connective tissue and a few blood vessels. Bodian silver staining disclosed a delicate tangle of argyrophilic fibers and processes with small, club-like terminations. These findings are characteristic of pineocytoma. On ultrastructural examination, the tumor cells were found to be closely packed, in clumps separated by numerous fine or expanded, interlacing processes, some of which contained microtubules. A few dense core vesicles and clusters of clear vesicles similar to synaptic vesicles were seen, the latter being aggregated around desmosome-like thickenings in the cellular membrane, suggestive of a synaptic complex. Some tumor cells were positive for neuron-specific enolase and S-100 protein. Only a few cells positive for glial fibrillary acidic protein were distributed in the tumor tissue, but it was not ascertained if they were tumor cells or normal, pre-existing astrocytes. The tumor was diagnosed as a pineocytoma with neuronal differentiation.

Pineoblastoma in a cockatiel.

Pineoblastoma, a primitive neoplasm of pineal gland origin, was diagnosed in a cockatiel based on gross, histopathological, and electron-microscopic findings.

Pineocytoma. Observation of an autopsy case by electron microscopy and cell markers.

An autopsy case of a 69-year-old female with pineocytoma was reported. The tumor showed neuronal differentiations, which were confirmed not only by light microscopy and electron microscopy, but also by a cell marker of neuron-specific enolase. In addition, existence of astrocytes in the tumor which distributed sparsely was ascertained by electron microscopy and cell markers such as S-100 protein and glial fibrillary acidic protein.

Spontaneous pineal body tumours (pinealomas) in Wistar rats; a histological and ultrastructural study.

The pathology of 5 cases of pinealomas in Wistar rats used in long-term toxicological studies is described both grossly, microscopically and ultrastructurally, together with a review of the related literature.

Endothelial tubuloreticular structures in intracranial germinomas.

In studying three human intracranial germinomas tubuloreticular structures were observed within the cisterns of granular endoplasmic reticulum (RER), as well as occasionally within dilated perinuclear spaces of capillary endothelial cells. These tubuloreticular structures seen as a network of branching, convoluted, tubular profiles appear to originate from amorphous material. The development of these structures could be classified into three stages. In Stage I, the precursor substance appears as dense amorphous material within the cisterns of RER. Stage II is marked by the transformation of the amorphous material to coarse particulate material which aggregates to form tubular units. During the first and second stages, the distended RER that participates in the formation of these structures is accompanied by numerous attached ribosomes and is closely associated with mitochondria. In Stage III, the tubular units fuse with one another to form the tubuloreticular structure. In this third stage both ribosomes and mitochondria are almost absent. As a result of the almost complete disappearance of these organelles at this time, both the attached ribosomes and mitochondria may play an important role in the synthesis of the precursor substance as well as in its transformation to the tubuloreticular structure.