TDP-43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons.

Mislocalization and abnormal deposition of TDP-43 into the cytoplasm (TDP-43 proteinopathy) is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the pathogenic mechanism of the diseases linked to TDP-43 is largely unknown. We hypothesized that the failure of mRNA transport to neuronal axons by TDP-43 may contribute to neurodegeneration in ALS and FTLD, and sought to examine the function of TDP-43 by identifying its target mRNA for axonal transport. We found that mRNAs related to translational function including ribosomal proteins (RPs) were decreased by shRNA-based TDP-43 knock-down in neurites of cortical neurons. TDP-43 binds to and transports the RP mRNAs through their 5' untranslated region, which contains a common 5' terminal oligopyrimidine tract motif and a downstream GC-rich region. We showed by employing in vitro and in vivo models that the RP mRNAs were translated and incorporated into native ribosomes locally in axons to maintain functionality of axonal ribosomes, which is required for local protein synthesis in response to stimulation and stress to axons. We also found that RP mRNAs were reduced in the pyramidal tract of sporadic ALS cases harboring TDP-43 pathology. Our results elucidated a novel function of TDP-43 to control transport of RP mRNAs and local translation by ribosomes to maintain morphological integrity of neuronal axons, and proved the influence of this function of TDP-43 on neurodegeneration in ALS and FTLD associated with TDP-43 proteinopathy.

Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site.

OBJECTIVE: Amyloid-ß plaques and neurofibrillary tangles composed of tau protein are the neuropathological hallmarks of Alzheimer's disease. In recent years, marked progress has been made in Alzheimer's disease research using tau ligands for positron emission tomography (PET). However, the issue of off-target binding, that is, the binding of ligands to regions without tau pathology, remains unresolved. Tissues with melanin-containing cells (MCCs) have been suggested as binding targets for tau ligands. In the present study, we characterized the MCC-binding properties of representative tau PET ligands. METHODS: Autoradiographic studies of [18F]AV-1451 and [18F]THK5351 were conducted using postmortem human midbrain sections. Saturation-binding assays of [18F]AV-1451 and [18F]THK5351 were performed with B16F10 melanoma cells. The blocking effects of 25 compounds against [18F]THK5351 binding to B16F10 cells were used to investigate the relationship between chemical structure and MCC binding. RESULTS: Autoradiography demonstrated specific binding of the radioligands in the substantia nigra. [18F]AV-1451 and [18F]THK5351 exhibited saturable binding to melanoma cells ([18F]AV-1451: Kd = 669 ± 196 nM, Bmax = 622 ± 269 pmol/mg protein; [18F]THK5351: Kd = 441 ± 126 nM, Bmax = 559 ± 75.5 pmol/mg protein). In blocking studies with melanoma cells, compounds bearing multiple aromatic rings and an aminopyridine group, including tau ligands such as AV-1451, PBB3, and a lead compound of MK-6240, exhibited the inhibition of [18F]THK5351 binding comparable to self-blocking by THK5351 (> 70% at 10 µM). CONCLUSIONS: These studies suggest that the binding properties of [18F]AV-1451 and [18F]THK5351 are sufficient to expect highlighting of tissues with a high density of MCCs. The findings of the present study should aid the development of neuroimaging ligands that do not bind to MCC.

Changes in telomere length with aging in human neurons and glial cells revealed by quantitative fluorescence in situ hybridization analysis.

AIM: The telomere is a structure present at the ends of chromosomes, and is known to shorten with aging and successive rounds of cell division. However, very little is known about telomere attrition in post-mitotic cells, such as neurons. METHODS: Using our originally developed quantitative fluorescence in situ hybridization method, we analyzed age-dependent alterations of telomere length in three types of cells in the human cerebrum: neurons and glial cells in both the gray and white matter. RESULTS: In adults, telomeres were significantly longer in neurons than in glial cells, whereas in infants, telomere lengths did not differ among the three cell types. No aging-related telomere attrition was evident in neurons. However, the telomeres of glial cells were shorter in older individuals than in younger individuals, and attrition was more rapid in the white matter than in the gray matter. CONCLUSIONS: The present results suggest that the telomeres of neurons remain stable throughout life, whereas telomeres in white matter glial cells become significantly shorter with age. Examination of adults showed no significant correlation between telomere length and age in the three cell types. Although the present study was cross-sectional, the results suggest that telomere shortening before adolescence contributes to the significant decrease of telomere length in white matter glial cells. The present findings in normal cerebral tissues will be informative for future studies of telomere stability in the diseased brain. Geriatr Gerontol Int 2018; 18: 1507-1512.

Clinicopathological characteristics of distant metastases of adenocarcinoma, squamous cell carcinoma and urothelial carcinoma: An autopsy study of older Japanese patients.

AIM: We aimed to clarify the characteristics of malignancies in older adults focusing on distant metastasis in the whole body. METHODS: We retrospectively evaluated 7710 cases of autopsies (4011 men, 3699 women, median age of 80 years), and analyzed the characteristics of metastasis of adenocarcinoma, squamous cell carcinoma and urothelial carcinoma in each organ. RESULTS: The total number of cases with adenocarcinoma, squamous cell carcinoma or urothelial carcinoma was 2856, and most of them were adenocarcinomas. Among them, 1604 had metastatic lesions, and patients with metastasis were younger than those without metastasis. The major primary organs of adenocarcinoma were the stomach, colon, lung, prostate, gallbladder and pancreas, whereas those for squamous cell carcinoma were the lung, esophagus and uterus. Urothelial carcinoma cases were found in the urinary bladder, kidney and ureter. Metastatic adenocarcinomas mainly originated from the stomach, colon, lung, pancreas and gallbladder. Metastatic squamous cell carcinomas were from the lung, esophagus and uterus, whereas the kidney, bladder and ureter were the primary origins of metastatic urothelial carcinomas. Squamous cell carcinoma showed the highest incidence of metastasis, suggestive of it being of an aggressive phenotype. Furthermore, metastatic ability and the preferred metastatic sites varied among primary organs. CONCLUSIONS: We revealed an accurate incidence and the characteristics of metastatic cancer in a large-scale autopsy study of older Japanese patients from one institution. Identifying these features might prompt screening for malignancies, and consequently improve quality of life for older adults. Geriatr Gerontol Int 2018; 18: 211-215.

Pathological and immunoblot analysis of phosphorylated TDP-43 in sporadic amyotrophic lateral sclerosis with pallido-nigro-luysian degeneration.

Transactivation response DNA-binding protein 43 kDa (TDP-43) is a key protein of sporadic amyotrophic lateral sclerosis (ALS), and phosphorylated form of TDP-43 (p-TDP-43) is a major pathological protein that accumulates in sporadic ALS. p-TDP-43 is found not only in primary motor neurons, but often propagates to non-motor systems as well. However, pallido-nigro-luysian (PNL) degeneration (PNLD) is rarely associated with ALS. We describe here a 68-year-old ALS patient presenting severe PNLD. He had difficulty walking due to poor movement of his right leg, and was diagnosed as having Parkinson's disease because of akinesia. About 2 years after onset, weakness of his left hand and leg led to a diagnosis of ALS. Tube feeding and non-invasive positive-pressure ventilation were initiated. He died of respiratory failure at the age of 71. There was no family history of either neurological disorders or dementia. Neuropathological examination revealed severe loss of neurons and gliosis in the PNL system in addition to the upper and lower motor neuron system. p-TDP-43 pathology was widespread in the PNL and motor neuron systems and also in the amygdala and hippocampus where no significant gliosis or neuronal loss was detected. Synuclein pathology was not observed in the investigated areas. Immunoblot analysis of p-TDP-43 C-terminal fragments showed a type B band pattern consistent with sporadic ALS. This is the first case of ALS with PNLD, in which p-TDP-43 distribution was widespread in the hippocampal formation (Nishihira type 2 and Brettschneider stage 4), and the type B immunoblot pattern was confirmed. Our case indicated that the PNL system can be involved in the disease process in sporadic ALS cases, although rarely. We also reviewed previous autopsy cases of ALS with PNLD to clarify the clinicopathological features.

Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers.

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenic for familial Parkinson's disease. However, it is unknown whether levels of LRRK2 protein in the brain are altered in patients with LRRK2-associated Parkinson's disease. Because LRRK2 mutations are relatively rare, accounting for approximately 1% of all Parkinson's disease, we accessioned cases from five international brain banks to investigate levels of the LRRK2 protein, and other genetically associated Parkinson's disease proteins. Brain tissue was obtained from 17 LRRK2 mutation carriers (12 with the G2019S mutation and five with the I2020T mutation) and assayed by immunoblot. Compared to matched controls and idiopathic Parkinson's disease cases, we found levels of LRRK2 protein were reduced in the LRRK2 mutation cases. We also measured a decrease in two other proteins genetically implicated in Parkinson's disease, the core retromer component, vacuolar protein sorting associated protein 35 (VPS35), and the lysosomal hydrolase, glucocerebrosidase (GBA). Moreover, the classical retromer cargo protein, cation-independent mannose-6-phosphate receptor (MPR300, encoded by IGF2R), was also reduced in the LRRK2 mutation cohort and protein levels of the receptor were correlated to levels of LRRK2. These results provide new data on LRRK2 protein expression in brain tissue from LRRK2 mutation carriers and support a relationship between LRRK2 and retromer dysfunction in LRRK2-associated Parkinson's disease brain.

Distinct deposition of amyloid-ß species in brains with Alzheimer's disease pathology visualized with MALDI imaging mass spectrometry.

Amyloid ß (Aß) deposition in the brain is an early and invariable feature of Alzheimer's disease (AD). The Aß peptides are composed of about 40 amino acids and are generated from amyloid precursor proteins (APP), by ß- and γ-secretases. The distribution of individual Aß peptides in the brains of aged people, and those suffering from AD and cerebral amyloid angiopathy (CAA), is not fully characterized. We employed the matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) to illustrate the spatial distribution of a broad range of Aß species in human autopsied brains. With technical advancements such as formic acid pretreatment of frozen autopsied brain samples, we have: i) demonstrated that Aß1-42 and Aß1-43 were selectively deposited in senile plaques while full-length Aß peptides such as Aß1-36, 1-37, 1-38, 1-39, 1-40, and Aß1-41 were deposited in leptomeningeal blood vessels. ii) Visualized distinct depositions of N-terminal truncated Aß40 and Aß42, including pyroglutamate modified at Glu-3 (N3pE), only with IMS for the first time. iii) Demonstrated that one single amino acid alteration at the C-terminus between Aß1-42 and Aß1-41 results in profound changes in their distribution pattern. In vitro, this can be attributed to the difference in the self-aggregation ability amongst Aß1-40, Aß1-41, and Aß1-42. These observations were further confirmed with immunohistochemistry (IHC), using the newly developed anti-Aß1-41 antibody. Here, distinct depositions of truncated and/or modified C- and N-terminal fragments of Aßs in AD and CAA brains with MALDI-IMS were visualized in a spacio-temporal specific manner. Specifically, Aß1-41 was detected both with MALDI-IMS and IHC suggesting that a single amino acid alteration at the C-terminus of Aß results in drastic distribution changes. These results suggest that MALDI-IMS could be used as a standard approach in combination with clinical, genetic, and pathological observations in understanding the pathology of AD and CAA.

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid ß (Aß) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aß. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aß burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

Carbohydrate Antigen 19-9-Positive Gastric Adenocarcinoma: Autopsy Findings and Review of the Literature.

Carbohydrate antigen 19-9 (CA19-9) is a well-known tumor marker for pancreatobiliary cancer, and several studies have shown that an elevated serum CA19-9 level is associated with more aggressive biological behavior in gastric cancer (GC). However, the clinicopathological characteristics of CA19-9-positive GC remain unclear. We herein report an autopsy case of CA19-9-positive GC in an 84-year-old man who was admitted to our hospital because of paralysis and anemia. Autopsy revealed an ulcerative-invasive tumor measuring 72 × 60 mm in the anterior wall of the gastric body. The tumor had invaded beyond the muscularis propria, and metastasized to the lung, liver, and regional lymph nodes. Histologically, the tumor cell had oval nuclei with abundant clear cytoplasm, and tubular and/or papillary features with prominent lymphovascular permeation and perineural invasion, mimicking pancreatobiliary carcinoma. Immunohistochemically, the tumor cells showed diffuse immunopositivity for CA19-9 and carcinoembryonic antigen. According to a review of cases reported in the literature, CA19-9-positive GCs show clinicopathological characteristics such as antral location, ulcerative-infiltrating gross feature, differentiated histology, prominent lymphatic and venous invasion, higher proportion of metastasis, and higher clinical stage. These results suggest that CA19-9-positive GC is pathologically a distinctive type of tumor with aggressive biological behavior.

PML Nuclear Bodies Are Altered in Adult-Onset Neuronal Intranuclear Hyaline Inclusion Disease.

Neuronal intranuclear hyaline inclusion disease (NIHID) is a neurodegenerative disorder characterized by the presence of eosinophilic nuclear inclusions (NIs) in diverse cell lines in systemic organs. Adult-onset NIHID typically manifests with dementia associated with leukoencephalopathy. The detection of NIs in skin biopsies is useful for an antemortem diagnosis. A previous analysis suggested that NIs in NIHID originated from nuclear bodies (NBs), an important nuclear domain related to the ubiquitin-p62-mediated protein degradation system. In this study, we analyzed skin samples from 5 NIHID and 5 control cases immunohistochemically and electron microscopically. In the control cases, small but significant amounts of ubiquitin- and p62-positive intranuclear structures were found. These structures were consistently colocalized with promyelocytic leukemia protein (PML), an essential component of NBs, in particular when activated. The p62- and PML-positive structures were more frequently found in NIHID cases. Activated NBs, having a core and a shell, were observed by electron microscopy in control but not in NIHID cases. Instead, immature and mature filamentous NIs were found only in the NIHID cases. Our results indicate that NBs could not be normally activated in the NIHID, and an abnormal alteration of NBs might be related to the pathogenesis of NIHID.

Technical feasibility of visualizing myenteric plexus using confocal laser endomicroscopy.

BACKGROUND AND AIM: In preceding studies, we identified that the myenteric plexus (MP) could be visualized with confocal laser endomicroscopy (CLE) by applying neural fluorescent probes lacking clinical safety profiling data from the submucosal side. In this study, we evaluated the technical feasibility of MP visualization using probe-based CLE (pCLE) from the serosal side with cresyl violet (CV), which has been used clinically for chromoendoscopy. METHODS: The dye affinity of CV for MP was first explored in an in vivo transgenic mouse model using neural crest derivatives labeled with green fluorescent protein. We also tested the feasibility of CV-assisted visualization of MP in human surgical specimens, wherein the tissue dying and pCLE observation were performed from the serosal side. In the human study, rate of MP visualization by pCLE was evaluated as the primary outcome. We also evaluated the sensitivity and specificity of MP visualization by pCLE, using pathological presence/absence of MP as the gold standard. RESULTS: We confirmed the dye affinity of CV to MP in all tested models. The MP appeared as brightly stained ladder-like structures with pCLE, and in the human study, MP was visualized in 12/14 (85.7%) samples, with 92.3% sensitivity and 100% specificity. In positive cases showing the ladder-like structure of MP by pCLE, the mean maximum and minimum widths of nerve strands were 54.3 (± 23.6) and 19.7 (± 6.0) µm, respectively. A ganglion was detected by pCLE in 10 cases (10/12, 83.3%). CONCLUSIONS: This study demonstrated the technical feasibility of visualizing the MP in real time by CV-assisted pCLE (UMIN-CTR number, UMIN000015056).

LRRK2 levels and phosphorylation in Parkinson's disease brain and cases with restricted Lewy bodies.

BACKGROUND: Leucine rich repeat kinase 2 (LRRK2) is a promising target for the treatment of Parkinson's disease; however, little is known about the expression of LRRK2 in human brain and if/how LRRK2 protein levels are altered in Parkinson's disease. OBJECTIVES: We measured the protein levels of LRRK2 as well as its phosphorylation on serines 910, 935, and 973 in the postmortem brain tissue of Parkinson's disease patients and aged controls with and without Lewy bodies. METHODS: LRRK2 and its phosphorylation were measured by immunoblot in brain regions differentially affected in Parkinson's disease (n = 30) as well as subjects with Lewy bodies restricted to the periphery and lower brain stem (n = 25) and matched controls without pathology (n = 25). RESULTS: LRRK2 levels were increased in cases with restricted Lewy bodies, with a 30% increase measured in the substantia nigra. In clinical Parkinson's disease, levels of LRRK2 negatively correlated to disease duration and were comparable with controls. LRRK2 phosphorylation, however, particularly at serine 935, was reduced with clinical Parkinson's disease with a 36% reduction measured in the substantia nigra. CONCLUSIONS: Our data show that LRRK2 phosphorylation is reduced with clinical PD, whereas LRRK2 expression is increased in early potential prodromal stages. These results contribute to a better understanding of the role of LRRK2 in idiopathic Parkinson's disease and may aid efforts aimed at therapeutically targeting the LRRK2 protein. © 2016 International Parkinson and Movement Disorder Society.

Adult-onset neuronal intranuclear hyaline inclusion disease is not rare in older adults.

Neuronal intranuclear hyaline inclusion disease (NIHID) is a rare neurodegenerative disorder pathologically characterized by localized neuronal loss, and the presence of eosinophilic intranuclear inclusions in neurons and glial cells. NIHID is a heterogeneous disease entity. It is divided into three clinical subgroups: infantile, juvenile and adult forms. Recently, reports of adult-onset cases have increased. Typical adult-onset NIHID consists of cognitive dysfunction with leukoencephalopathy. This type of adult-onset NIHID can be predicted by characteristic magnetic resonance images, high intensity areas on T2-weighted/fluid-attenuated inversion recovery images and persistent high intensity at the corticomedullary junction in diffusion-weighted images. When clinically suspected, the ante-mortem diagnosis can be made by biopsy. In adult-onset NIHID, nuclear inclusions are found more frequently in glial cells, and moderate to severe white matter degeneration is often associated. Although the underlying pathological mechanisms of NIHID are largely unknown, abnormal intranuclear accumulations of proteins and/or dysfunction of protein degradation systems might be related to the pathogenesis. To further clarify the characteristics of this disease entity, biological and pathological analysis of the patients is indispensable. As this disease entity becomes better known, diagnosed cases are expected to increase. Adult-onset NIHID might not be as extremely rare as previously thought.

Imaging alterations due to squamous metaplasia in intracranial neurenteric cysts: A report of two cases.

Intracranial neurenteric cysts are rare congenital abnormalities with a broad imaging spectrum, and therefore are occasionally mistaken for other common intracranial cysts such as epidermoid and arachnoid cysts. We report two cases of neurenteric cysts in the posterior cranial fossa that were initially mistaken for other types of cysts. They exhibited signal intensity alterations in magnetic resonance imaging with significant volume expansion during their long-term observation. Both cases received surgical treatment because of clinical deterioration. Histologically, the cysts were lined by flattened or cuboidal epithelium, occasionally showing squamous metaplasia. Xanthogranulomatous inflammation and accumulation of cholesterol clefts, dry keratin and proteinaceous substance were observed in the cysts. These findings may indicate that chronic inflammation in neurenteric cysts induces squamous metaplasia, keratinization and high proteinaceous content, and causes MRI signal intensity alterations and volume expansion. We propose that MRI signal intensity alterations in neurenteric cysts may be a warning sign of their volume expansions, and thus require closer follow-up imaging and eventually surgical treatment.

BRAF V600E-mutated diffuse glioma in an adult patient: a case report and review.

Recent advances in genomic technology and genome-wide analysis have identified key molecular alterations that are relevant to the diagnosis and prognosis of brain tumors. Molecular information such as mutations in isocitrate dehydrogenase (IDH) genes or 1p/19q co-deletion status will be more actively incorporated into the histological classification of diffuse gliomas. BRAF V600E mutations are found frequently in circumscribed low-grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and extra-cerebellar pilocytic astrocytoma, or epithelioid glioblastomas (E-GBM), a rare variant of GBM. This mutation is relatively rare in other types of diffuse gliomas, especially in adult onset cases. Here, we present an adult onset case of IDH wild-type/BRAF V600E-mutated diffuse glioma, evolving from grade III to grade IV. The tumor displayed atypical exophytic growth and had unusual histological features not fully compatible with, but indicative of PXA and E-GBM. We discuss differential diagnosis of the tumor, and review previously described diffuse gliomas with the BRAF V600E mutation.

α-Synuclein aggregation in the olfactory bulb of middle-aged common marmoset.

The synaptic protein α-synuclein has been identified as a major component of Lewy bodies, a pathological hallmark of Parkinson's disease (PD). Prior to the formation of Lewy bodies, mislocalization and aggregation of the α-synuclein in brain tissue is frequently observed in various neurodegenerative diseases. Aberrant accumulation and localization of α-synuclein are also observed in the aging human brain, for which reason aging is regarded as a risk factor for neurodegenerative disease. To investigate changes in α-synuclein properties in the aging brain, we compared α-synuclein immunoreactivity in brain tissue of young (2-years-old) and middle-aged (6-years-old) common marmoset (Callithrix jacchus). Our analyses revealed marked changes in α-synuclein immunoreactivity in the olfactory bulb of common marmosets of these age cohorts. Perikaryal α-synuclein aggregations were formed in the olfactory bulb in middle-aged animals. We also observed signals of α-synuclein accumulation in hippocampus in this cohort; however, unlike in the olfactory bulb, hippocampal α-synuclein signals were localized in the synaptic terminals. We did not observe either of these features in younger marmosets, which suggest that aging may play a role in these phenomena. Our results using common marmoset brain corresponded with the observation that the α-synuclein aggregations were first occurred from olfactory bulb in human normal aged and PD brain. Therefore, common marmoset is expected as useful model for α-synuclein pathology.

Lipoma in the Corpus Callosum Presenting with Epileptic Seizures Associated with Expanding Perifocal Edema: A Case Report and Literature Review.

This report describes a rare case of a patient with lipoma presenting with epileptic seizures associated with expanding perifocal edema. The patient was a 48-year-old man who presented with loss of consciousness and convulsions. Magnetic resonance imaging (MRI) revealed a calcified mass in the corpus callosum with perifocal edema causing mass effect. An interhemispheric approach was used to biopsy the mass lesion. Histological examination revealed typical adipose cells, along with hamartomatous components. These components contained neurofilament and S-100-positive structures showing marked calcification. Fibrous cells immunoreactive for α-smooth muscle actin and epithelial membrane antigen proliferated with focal granulomatous inflammatory changes. MIB-1 index was approximately 5% in immature cells observed in granulomatous areas. We thus suspected a coexisting neoplastic component. The residual lesion persisted in a dormant state for 2 years following biopsy. Surgical resection of a lipoma is extremely difficult and potentially dangerous. However, in the present case, the lesion was accompanied by atypical, expanding, and perifocal edema. Surgical treatment was inevitable for the purpose of histological confirmation, considering differential diagnoses such as dermoid, epidermoid, and glioma. In the end, anticonvulsant therapy proved effective for controlling epileptic seizures.

TTF-1-positive oncocytic sellar tumor with follicle formation/ependymal differentiation: non-adenomatous tumor capable of two different interpretations as a pituicytoma or a spindle cell oncocytoma.

We describe herein the unique case of a 70-year-old male with a TTF-1-positive non-adenomatous sellar tumor that has unusual morphological and immunohistochemical features. MRI examination detected a 2-cm sellar mass that was enhanced heterogeneously. By histology, the tumor was composed of epithelioid and oncocytic cells arranged in a trabecular pattern with occasional luminal structures. The lesion was diffusely immunopositive for thyroid transcription factor-1 (TTF-1) and vimentin but negative for S100 protein and GFAP. Immunoreactivity for epithelial membrane antigen, low molecular weight cytokeratin (CAM 5.2), and neuronal markers was also observed in the tumor cells. By electron microscopy, the tumor cells were filled with abundant mitochondria and extended microvillous projections into small extracellular and intracellular lumens. TTF-1 is considered to be an excellent marker of pituicytes, specialized glia of the neurohypophysis. This case can be regarded as a variant of pituicytoma, showing both ependymal differentiation and oncocytic changes. However, the immunoprofile was not completely consistent with a pituicyte lineage; the epithelial features suggested a possibility of folliculostellate cell origin. TTF-1-positive sellar neoplasms might therefore have variable morphological and immunohistochemical profiles. For suitable classification of TTF-1 positive sellar neoplasms, their histological features should be carefully re-evaluated.