CD24 and PRAME Are Novel Grading and Prognostic Indicators for Pineal Parenchymal Tumors of Intermediate Differentiation.

The pineal parenchymal tumors of intermediate differentiation (PPTIDs) are extremely rare tumor entities. They exhibit low-risk (grade II) and high-risk (grade III) malignancies, which may lead to different therapies and prognosis. However, the histological grading criteria remains elusive, and novel biomarkers may be helpful to differentiate the grade of PPTIDs. Immunohistochemical staining for CD24, PRAME, POU4F2, and HOXD13, and their clinicopathologic analyses were performed in pineal parenchymal tumors and other tumors in the pineal region. CD24 and PRAME were expressed in 9/11 (81.8%) and 8/11(72.7%) cases of PPTIDs grade III, compared with 6/18 (33.3%) and 5/18(27.8%) cases of PPTIDs grade II. The levels of CD24 and PRAME were significantly higher in PPTIDs grade III than grade II. However, there were no differences of HOXD13 and POU4F2 expression levels in PPTIDs grade II and grade III. Interestingly, high expression of CD24 and PRAME were prevalently found in high-grade tumors of the central nervous system. In addition, PPTIDs patients with high expression levels of CD24 and PRAME exhibited a significant shorter survival time. The results of PPTIDs grading by CD24 and PRAME were mostly consistent with WHO criteria, except for two cases. According to the prognostic information of patients, we found that the combination of CD24 and PRAME expression for grading PPTIDs might be more valuable than WHO criteria only. CD24 and PRAME are novel markers for grading and prognostic evaluation of PPTIDs that may be helpful to determine the therapeutic decision for PPTIDs patients.

Nuclear CRX and FOXJ1 Expression Differentiates Non-Germ Cell Pineal Region Tumors and Supports the Ependymal Differentiation of Papillary Tumor of the Pineal Region.

Papillary tumor of the pineal region (PTPR) is a neuroepithelial neoplasm first described in 2003. Despite the anatomic association of PTPR with the pineal gland, the features of these tumors resemble those of the ependymal circumventricular subcommissural organ (SCO) of the posterior third ventricle. Given the presumed distinct derivation of PTPR and pineal parenchymal tumors, we hypothesized that expression of lineage-specific transcription factors could distinguish these tumors and provide additional insight into the differentiation of PTPR. A broad series of pineal region samples was reviewed, including 7 benign pineal glands, 4 pineal cysts, 13 pineocytomas, 28 pineal parenchymal tumors of intermediate differentiation, 11 pineoblastomas, and 18 PTPR. All samples were evaluated by immunohistochemistry for expression of CRX, a master transcriptional regulator of photoreceptor differentiation expressed in pineal gland and retina and/or FOXJ1, a master transcriptional regulator of ciliogenesis expressed in normal ependymal cells and ependymal neoplasms. Diffuse nuclear CRX expression is present in 100% of pineal samples. FOXJ1 is negative in all pineal samples. CRX staining is present in 53% of PTPR, though expression is nearly always limited to rare cells. Diffuse nuclear FOXJ1 expression is present in 100% of PTPR. Fetal human SCO diffusely expressed FOXJ1 but was negative for CRX. Immunohistochemistry for FOXJ1 and CRX differentiates non-germ cell pineal region tumors with high sensitivity and specificity, including pineal parenchymal tumors and PTPR. Our findings support the hypothesis that PTPR have ependymal differentiation and are phenotypically more similar to SCO than pineal gland.

Low-grade oligodendroglioma of the pineal gland: a case report and review of the literature.

BACKGROUND: Gliomas are a very rare subtype of pineal region tumours, whereas oligodendrogliomas of the pineal region are exceedingly rare, since there have been only 3 cases of anaplastic oligodedrogliomas reported this far. METHODS-RESULTS: We present a case of a low-grade oligodendroglioma arising in the pineal gland of a 37 year-old woman. The patient presented with diplopia associated with a cystic pineal region mass demonstrated on MRI. Total resection was performed and histological examination showed that the cystic wall consisted of tumour cells with a central nucleus a perinuclear halo and minimal pleomorphism. Immnunohistochemical analysis showed that these cells were diffusely positive for CD57, and negative for GFAP, CD10, CD99, cytokeratins, neurofilaments and synaptophysin. FISH analysis was performed in a small number of neoplastic cells, which were not exhausted after immunohistochemistry and did not reveal deletion of 1p and 19q chromosome arms. However, the diagnosis of a low grade oligodendroglioma of the pineal gland was assigned. CONCLUSION: Although the spectrum of tumours arising in the pineal gland is broad, the reports of oligodendrogliomas confined to this location are exceedingly rare, and to the best of our knowledge there is no report of a low-grade oligodendroglioma. However, they should be added in the long list of tumours arising in the pineal gland.

Pineal germinoma with a prominent epithelioid cell granuloma component: case report.

A 20-year-old man presented with a rare case of germinoma with a large component of epithelioid cell granuloma manifesting as oscillopsia. Magnetic resonance imaging demonstrated a mass in the pineal region with homogeneous enhancement with gadolinium. Craniotomy was performed, ending in biopsy. The initial histological diagnosis was epithelioid cell granuloma, but systemic investigation detected no evidence of granulomatous disorder. A revised diagnosis of germinoma was based on positive immunohistochemical staining for placental alkaline phosphatase (PLAP) and c-kit. Histological diagnosis is sometimes incorrect if granulomatous reaction is dominant. Immunohistochemical staining for PLAP and c-kit should be performed if germinoma is clinically suspected.

Review of pineal anlage tumor with divergent histology.

Pineal anlage tumor is an extremely rare tumor that is not listed in the 2000 World Health Organization Classification of nervous system tumors. It has been defined as a primary pineal tumor with both neuroepithelial and ectomesenchymal differentiation and without endodermal differentiation. We review the literature on this tumor, including the clinical presentation, gross pathology, histopathology, immunohistochemistry, differential diagnosis, and prognosis.

Ex vivo pediatric brain tumors express Fas (CD95) and FasL (CD95L) and are resistant to apoptosis induction.

Fas (APO-1/CD95/TNFRSF6) is a member of the tumor necrosis/nerve growth factor receptor family that signals apoptotic cell death in sensitive cells. Expression of Fas and its agonistic ligand (FasL/TNFSF6) was investigated in ex vivo pediatric brain tumor specimens of various histologic types. Fas expression was identified in all of the 18 tumors analyzed by flow cytometry and immunohistochemistry. FasL expression was identified in most of the 13 tumors analyzed by both Western analysis and immunohistochemistry. Nine of these tumor specimens were treated with either the agonistic anti-Fas antibody (APO-1) in combination with protein A or FasL in short-term cytotoxicity assays. Sensitivity to apoptosis induced by the topoisomerase II inhibitor, etoposide, was also assessed. Despite the presence of Fas, all the specimens analyzed demonstrated a high degree of resistance to Fas-mediated apoptosis. These 9 specimens also showed a high degree of resistance to etoposide. Only 2 of the 9 specimens were susceptible to etoposide-induced cell death, whereas only 3 were sensitive to Fas-mediated apoptosis. One brain tumor was sensitive to both Fas ligation and etoposide treatment. This contrasted with the high degree of susceptibility to both etoposide- and Fas-induced apoptosis observed in the reference Jurkat cell line. The results suggest that Fas expression may be a general feature of tumors of the CNS and that a significant degree of resistance to Fas-mediated apoptosis may exist in ex vivo pediatric brain tumor specimens.

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.

Pineal malignant rhabdoid tumor with chondroid formation in an adult.

A pineal tumour in a 27-year-old male is presented with the characteristic histological features of a pineal malignant rhabdoid tumor (MRT) with chondroid formation. Occasionally, tumor cells contained a single well-demarcated hyaline globular inclusion within the cytoplasm adjacent to the nucleus. The stroma of these tumors tends to be densely hyalinized and become chondroid. Immunohistochemical staining was positive for vimentin, epithelial membrane antigen, chromogranin A, synaptophysin, neuron-specific enolase, S-100 protein, and muscle actin. Despite surgery and radiochemotherapy, the tumor recurred in the pineal region and metastasized to the lower lobe of right lung. The patient died 2 years after the initial diagnosis. This is the second published case of central nervous system-MRT appearing in an adult. The clinical and pathological features of pineal MRT in this patient are presented.

Pure yolk sac tumors in genital and extragenital sites: study on three pedriatic cases, with cytological findings on two.

Cytopathological findings on three pedriatic gonadic-extragonadic pure yolk sac tumor are reported: the highly variable histological patterns (reticular, solid, festooning or pseudopapillary, polyvesicular vitelline), reflecting differentiation towards extraembryonic yolk sac structures, are not appreciated in cytologic samples. Since the tumor's cytologic spectrum is very broad, the most diagnostic differential difficulty with yolk sac tumor is adenocarcinoma. The presence of intracellular and extracellular hyaline globules, that are periodic acid-Schiff stain (PAS) positive and diastase resistant and correspond to alpha-fetoprotein production, alpha-fetoprotein positivity of the neoplastic cells; showing nuclear pleomorphism and vacuolated "bubbly" cytoplasm are the most consistent cytologic hallmarks of this neoplasm, which diagnosis would be confirmed by histologic, immunocytochemical and clinical findings.

Clinicopathological study of pineal parenchymal tumors: correlation between histopathological features, proliferative potential, and prognosis.

This study describes the clinicopathologic features of 13 cases with pineal parenchymal tumors. Based on the histopathologic findings, especially the extent of atypia and pineocytic differentiation as determined by Bodian's staining, we classified these tumors into pineocytomas (4), pineocytomas with anaplasia (4) and pineoblastomas (5). All the cases with pineocytoma and pineocytoma with anaplasia were adults, and all the cases with pineoblastoma were younger children. One patient with pineocytoma died of other disease 7 months after initial treatment. One patient with pineocytoma with anaplasia died 168 months after initial treatment. The other patients with pineocytoma and pineocytoma with anaplasia survived between 9 and 179 months after surgery. However, all of the five pineoblastoma patients died within 14 months after initial treatment. The mean MIB-1 index in pineoblastomas was significantly higher than that in other types of pineal parenchymal tumors, but there were no differences between pineocytomas and pineocytomas with anaplasia with respect to the MIB-1 index. The mean MIB-1 index in neurofilament protein-immunopositive cases was significantly lower than that in immunonegative cases. With regard to the malignant potential, we emphasize that a clear distinction should be made between pineoblastomas in children and other types of pineal parenchymal tumors in adults.

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.

In vitro karyotypic and immunophenotypic characterisation of primitive neuroectodermal tumours: similarities to malignant gliomas.

Monoclonal antibody (Mab) mediated immunotherapy of brain tumours requires the identification of tumour-restricted cell surface antigens. We have characterised four primitive neuroectodermal tumours, which included pineoblastoma, medulloblastoma and ependymoblastoma cultures, that demonstrated in vitro evidence of malignant behaviour (anchorage-independent growth and nu/nu xenograft tumour formation). The cytogenetic findings ranged from normal G-banded and Q-banded karyotypes through mixed near-diploid/hyperdiploid. These cultures resembled the cell surface immunophenotypic spectrum of malignant gliomas. They were distinguished from normal glia in vitro by the expression of restricted fetal mesenchymal, neuronal, myoblastic, melanocytic, epidermal, chondrocytic, lymphoid and epithelial antigens. Certain antigens appeared sufficiently represented among central nervous system (CNS) neoplasms to afford potential targets for Mab-mediated immunotherapy.