Aya Ishii

Fatty acid binding protein 7 as a marker of glioma stem cells.

Glioblastomas are the most aggressive brain tumors. Glioblastoma stem cells (GSCs) are thought to be responsible for the recurrence, chemoresistance, and poor prognosis of glioblastoma. Fatty acid binding protein 7 (FABP7), which is a cellular chaperone for a variety of omega‐3 fatty acids, is a known marker for neural stem cells. In this study, using a newly developed anti‐FABP7 antibody and patient‐derived GSC lines, we evaluated the expression of FABP7 in GSCs. Using immunocytochemistry, Western blotting, and qPCR analyses, FABP7 was found to be highly enriched in GSCs and its localization was found in cytosol and nuclei. FABP7 expression was significantly downregulated in differentiated GSCs induced by the addition of serum. In the glioma surgical specimens, FABP7 was highly expressed in the majority of glioblastoma. Double immunostaining for FABP7 and Sox2 showed that FABP7+Sox2+ tumor cells were significantly increased in glioblastoma (grade IV) compared with diffuse astrocytoma (grade II) and anaplastic astrocytoma (grade III). Our data introduces FABP7 as a marker for GSCs and further highlights its possible significance for glioma diagnosis and treatment.

Increased cytoplasmic S100A6 expression is associated with pulmonary adenocarcinoma progression

S100A6 is a calcium‐binding protein implicated in many cellular processes and frequently upregulated in cancer. Recently it was reported that S100A6 is one of the genes having higher expression in adenocarcinoma mixed subtype with a bronchioloalveolar carcinoma (BAC) component than in pure BAC. To clarify the association of S100A6 expression with stepwise progression of lung adenocarcinoma, S100A6 protein expression was examined on immunohistochemistry in 92 formalin‐fixed and paraffin‐embedded lung adenocarcinomas. Both the nucleus and cytoplasm of the tumor cells were stained, and the nuclear and cytoplasmic expression of S100A6 was assessed individually. In addition, six frozen surgical specimens were selected, and the expression of S100A6 was confirmed on western blotting. As a result, although it was not possible to detect any significant correlation between nuclear S100A6 immunoreactivity and tumor progression, advanced adenocarcinoma had significantly higher cytoplasmic S100A6 expression than non‐invasive lesions or normal lung tissue (P < 0.05). Moreover, the BAC component tended to have weaker staining than any of the other components. These findings indicate that S100A6 may be associated with the stepwise progression and/or invasion of lung adenocarcinoma, especially BAC‐type adenocarcinoma. The present results suggest the utility of S100A6 immunohistochemistry as a marker for estimation of malignancy in adenocarcinoma with a BAC component.

Histological Characterization of the Tumorigenic "Peri-Necrotic Niche" Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma.

Background Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically. Methods Multi-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α+) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II–IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay. Results A small subpopulation of HIF-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α+ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity. Conclusions These data suggest that the “peri-necrotic niche” harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas.

Pathological features of highly invasive glioma stem cells in a mouse xenograft model

Glioma stem cells (GSCs) may be a source of tumor progression and recurrence after multimodal therapy, because of their high invasive potential. The purpose of this study was to compare the invasive and migratory properties of GSCs and non-GSCs and examine the distribution of these cells in a mouse xenograft model. Three GSC lines, G144, Y02, and Y10, cultured from human glioblastoma, were used in the study. Matrigel-invasion assays of infiltration and time-lapse studies of migration were performed for comparison of the GSCs with the corresponding differentiated non-GSC lines. Cells were also transplanted into mouse brain and the different distribution of GSCs and non-GSCs was examined in the tumor xenograft model. All 3 GSC lines had greater invasion and migration ability than the corresponding non-GSCs. In vivo, GSCs infiltrated more widely than non-GSCs and reached the contralateral hemisphere via the corpus callosum in the early stage of tumorigenesis. GSCs also primarily penetrated the subventricular zone (SVZ). GSCs have high invasive potential and tend to be present in the outer tumor bulk and infiltrate the contralateral hemisphere via the corpus callosum, in addition to penetrating the SVZ.

Sarcoidosis with pulmonary hypertension exacerbated by Takayasu-like large vessel vasculitis.

A 72‐year‐old male visited the hospital with a complaint of dyspnea. Under the diagnosis of pulmonary hypertension (PH) due to chronic thrombotic and/or embolic disease, this patient received anti‐coagulant therapy. Unfortunately, the respiratory state deteriorated and died 34 days after admission. At autopsy, noncaseating granulomas, which were diagnostic of sarcoidosis, were found in bilateral enlarged hilar lymph nodes, lungs, heart, liver, spleen, testis and epididymis. In pulmonary vasculature, the following three kinds of lesions were observed; (i) sarcoid granulomatous vasculitis at the peripheral arteries and veins, (ii) intimal fibrous lesions ubiquitously found in proximal and peripheral arteries which were thought to be organized thromboemboli, (iii) Takayasu‐like large vessel vasculitis with a huge fresh mural thrombus narrowing the lumen of most proximal portion of right pulmonary artery. Autopsy findings indicate that chronic sustained PH state in this patient was attributable to thrombotic and/or thromboembolic disease, and Takayasu‐like vasculitis with thrombus played a role in the final deterioration of respiratory state through exacerbation of PH. In sarcoidosis patients, vasculitic lesions which can be formed in both small and large pulmonary arteries must be raised as the differential diagnosis for the initial cause of PH as well as the accelerating factor of PH.

IgG4‐related disease manifesting the gastric wall thickening

IgG4‐related disease (IgG4‐RD) is a recently designated disease entity and its full picture has not yet been elucidated. Here, we report an unusual case of a patient with gastric wall thickening secondary to IgG4‐RD. A 68‐year‐old male visited our hospital with itchy skin lesions and an episode of organizing pneumonia. On the suspicion of malignancy‐associated skin lesions, computed tomography (CT) was performed. The CT revealed prominent thickening of the gastric wall. Due to the possibility of malignancy, the patient underwent distal gastrectomy. Histopathological examination showed fibrosis of the submucosa and prominent thickening of the muscularis propria. Most of infiltrating cells were IgG4‐positive plasma cells. Post‐operative blood test revealed significantly high serum levels of total IgG and IgG4. Based on these histological features, the patient was given a definitive diagnosis of IgG4‐RD. Further accumulation of cases like the present case that develop IgG4‐RD with rare manifestations would lead to the elucidation of pathogenesis.

Osteoclast-rich undifferentiated carcinoma of the urinary bladder: An immunohistochemical study

Osteoclast-rich undifferentiated carcinoma of the urinary tract is a rare tumor which histologically mimicks giant cell tumor of bone. The histogenesis of this tumor has not been clarified yet although its urothelial origin is proposed on the basis of positive reactions of an epithelial marker on mononuclear undifferentiated tumor cells and the existence of foci of a urothelial carcinoma component in some cases. We experienced a case of urinary bladder tumor diagnosed as osteoclastic-rich undifferentiated carcinoma, and performed an immunohistochemical study on the expression of various markers, including stem cell markers to further characterize the tumor properties. Immunohistochemically, CD56, nestin, and Sox2 were expressed in diffusely proliferating mononuclear tumor cells of undifferentiated features, suggesting the stemness properties of these cells. These findings might provide the clue as to the clarification of the pathogenesis of this rare tumor.

Atypical extraventricular neurocytoma in a 3-year-old girl: case report with radiological-pathological correlation

BackgroundExtraventricular neurocytoma (EVN) is a rare neuronal tumor histologically similar to central neurocytoma but arising in the brain parenchyma outside the ventricles. The minority of EVNs show atypical features including increased proliferative index, microvascular proliferation, or necrosis, and are called atypical EVN. Most of atypical EVNs occur in adults, and the tumors in children are extremely rare. A radiological-pathological correlation and radiological clue to atypical EVNs have not been clarified.Case reportWe report a case of atypical EVN in a 3-year-old girl. Magnetic resonance imaging (MRI) revealed an extraventricular intraparenchymal tumor in the left frontal lobe, which was composed of homogeneous well-demarcated cystic component and peripheral ill-delineated solid component with enhancement. Angiography demonstrated vascular proliferation and arteriovenous shunting in the tumor. Histologically, the resected tumor was diagnosed as atypical EVN. Types of the tumor borders (well-circumscribed or infiltrative) and MRI findings correlated closely. Morphology of the tumor vasculature was remarkable for microvascular proliferation and dilated, thickened veins, which corresponded to the angiographic features.ConclusionAlthough rare, atypical EVN should be included in the differential diagnosis of a cystic mass in the cerebral hemispheres in children. Radiological evaluation of tumor borders and angiographic characteristics might be useful for predicting atypicality of the tumor.

Unexpectedly long intravenous and intracardiac extension of a small-sized pulmonary pleomorphic carcinoma

Pleomorphic carcinoma of the lung is one of the uncommon histological types of lung cancers, which shows an aggressive behavior. Intravenous extension (not metastasis or direct invasion) of the tumor into the heart is a rare complication of lung cancers. We present a case of a 64-year-old man, who was admitted to hospital due to severe dyspnea. Chest CT scan revealed a 2-cm nodule in the upper lobe of the right lung. Echocardiography demonstrated a giant mass in the left atrium. Because of a considerable distance between the lung nodule and heart, the relation of these two lesions was unclear. He died four days after the admission. At autopsy, the lung nodule was pleomorphic carcinoma composed of spindle and giant cells, which invaded the pulmonary vein and extended intravenously to the left atrium. The intravenous component of the tumor measured approximately ten cm in length. At the tip of the extension, an 8 cm × 5 cm × 3 cm mass was formed in the left atrium, which obstructed the mitral valve. This case highlights a possibility that even a small-sized, peripherally located pleomorphic carcinoma of the lung could extend for an unexpectedly long distance to the heart, causing cardiac complications.

Non‐sebaceous lymphadenoma of the salivary gland with serous acinic cell differentiation, a first case report in the literature

We report an atypical case of non‐sebaceous lymphadenoma (NSL) of the parotid gland showing serous acinic cell differentiation. NSL is a rare benign salivary gland tumor with intermingled lymphoid and epithelial tissues without sebaceous differentiation. Since the first description of a case designated by Auclair et al. as ‘non‐sebaceous lymphadenoma’ in 1991, to our best knowledge, only 37 cases have been reported, and no differentiation of tumor cells into serous acinic cell lineage has been described so far. In this paper, we present a case of NSL with serous acinic cell differentiation. The patient was a 78‐year‐old female with the complaint of a painless mass in the left parotid gland. The surgically resected tumor was encapsulated and measured 13 × 9 × 9 mm. Histologically, the tumor had the features of NSL, and an unusual finding of this case was the presence of epithelial cells with serous acinic cell differentiation. Dense cytoplasm packed with basophilic granules in those cells was positive in periodic acid Schiff reaction after diastase digestion (D‐PAS), which was compatible with the feature of serous acinic cell differentiation. Possible differentiation of the epithelial component into serous acinic cell in this rare entity is warranted to avoid confusion in the diagnosis.