Aya Nawata

Overexpression of Peroxiredoxin 4 Affects Intestinal Function in a Dietary Mouse Model of Nonalcoholic Fatty Liver Disease

Background Accumulating evidence has shown that methionine- and choline-deficient high fat (MCD+HF) diet induces the development of nonalcoholic fatty liver disease (NAFLD), in which elevated reactive oxygen species play a crucial role. We have reported that peroxiredoxin 4 (PRDX4), a unique secretory member of the PRDX antioxidant family, protects against NAFLD progression. However, the detailed mechanism and potential effects on the intestinal function still remain unclear. Methods & Results Two weeks after feeding mice a MCD+HF diet, the livers of human PRDX4 transgenic (Tg) mice exhibited significant suppression in the development of NAFLD compared with wild-type (WT) mice. The serum thiobarbituric acid reactive substances levels were significantly lower in Tg mice. In contrast, the Tg small intestine with PRDX4 overexpression showed more suppressed shortening of total length and villi height, and more accumulation of lipid in the jejunum, along with lower levels of dihydroethidium binding. The enterocytes exhibited fewer apoptotic but more proliferating cells, and inflammation was reduced in the mucosa. Furthermore, the small intestine of Tg mice had significantly higher expression of cholesterol absorption-regulatory factors, including liver X receptor-α, but lower expression of microsomal triglyceride-transfer protein. Conclusion Our present data provide the first evidence of the beneficial effects of PRDX4 on intestinal function in the reduction of the severity of NAFLD, by ameliorating oxidative stress-induced local and systemic injury. We can suggest that both liver and intestine are spared, to some degree, by the antioxidant properties of PRDX4.

Correlation of T follicular helper cells and plasmablasts with the development of organ involvement in patients with IgG4-related disease

Objective To assess the role of an abnormal immune network in the pathology of IgG4-related disease (IgG4-RD). Methods Sixteen patients diagnosed with IgG4-RD at our institution were selected. Peripheral immunocompetent cells were immunophenotyped by multicolour flow cytometry to assess the association between clinical manifestation and pathological findings. Results Compared with healthy controls, IgG4-RD patients showed comparable proportions of Th1 and Th17 cells, but higher proportions of Treg and follicular helper T (Tfh) cells. Further, the proportions of class-switched memory B cells and plasmablasts were higher in patients. Among all phenotypes, in particular, the plasmablast proportion increased from 4.2% (controls) to 16.5% (patients). The serum IgG levels were found to be correlated with the proportions of plasmablasts and Tfh cells, but not with those of other T cell subsets. In patients with extraglandular symptoms, only plasmablasts, Tfh cells and memory Treg cells were increased. Histopathological examination revealed a marked Tfh (CD4+ Bcl6+) cell infiltration; the increase of Tfh cells in the peripheral blood thus reflected the degree of Tfh cell infiltration into the tissue. Although steroid therapy reduced plasmablast and Tfh cell proportions, the memory Treg cell proportion remained unchanged. Conclusion The association found between Tfh cells and plasmablasts, linked with biological plausibility, suggests that Tfh cells contribute to the pathogenesis of IgG4-RD. Our results also suggested that controlling the Tfh cell-plasmablast axis could be a novel therapeutic strategy for treating IgG4-RD.

Coincidence between malignant perivascular epithelioid cell tumor arising in the gastric serosa and lung adenocarcinoma

A 4-mo history of both epigastralgia and back pain was presented in a 39-year-old male. Computed tomography showed right lung nodule and abdominal mass attached to the gastric wall, measuring approximately 30 mm and 70 mm in diameter. Since biopsy samples from the lung and abdomen revealed poorly differentiated adenocarcinoma and malignant tumor, clinicians first interpreted the abdominal mass as metastatic carcinoma, and a right lower lobectomy with following resection of the mass was performed. Gross examination of both lesions displayed gray-whitish to yellow-whitish cut surfaces with hemorrhagic and necrotic foci, and the mass attached to the serosa of the lesser curvature on the gastric body. On microscopic examination, the lung tumor was composed of a proliferation of highly atypical epithelial cells having abundant eosinophilic cytoplasm, predominantly arranged in an acinar or solid growth pattern with vessel permeation, while the abdominal tumor consisted of sheets or nests with markedly atypical epithelioid cells having pleomorphic nuclei and abundant eosinophilic to clear cytoplasm focally in a radial perivascular or infiltrative growth pattern. Immunohistochemically, the latter cells were positive for HMB45 or α-smooth muscle actin, but the former ones not. Therefore, we finally made a diagnosis of malignant perivascular epithelioid cell tumor (PEComa) arising in the gastric serosa, combined with primary lung adenocarcinoma. Furthermore, small papillary carcinoma of the thyroid gland was identified. The current case describes the coincidence of malignant PEComa with other carcinomas, posing a challenge in distinction from metastatic tumor disease.

An autopsy case of myocardial infarction due to idiopathic thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by systemic platelet-von Willebrand factor aggregation, organ ischemia and profound thrombocytopenia. In this report, we describe an autopsy case of a 77-year-old Japanese man diagnosed with idiopathic TTP. He had no history of cardiovascular disease symptoms, such as chest pain, ST segment elevation, and elevation of cardiac enzyme levels, except arrhythmia. The patient suddenly died despite receiving many treatments. On autopsy, macroscopically and microscopically, acute and chronic myocardial infarction manifested as petechiae and fibrotic foci and covered a wide area in the myocardium, including the area near the atrioventricular node. The microthrombi in the small arterioles and capillaries were platelet thrombi, which showed positive results for periodic acid-Schiff stain and factor VIII on immunohistochemical staining. The cause of the sudden death was suspected to be myocardial infarction, including a cardiac conduction system disorder due to multiple platelet microthrombi. Asymptomatic myocardial infarction is an important cause of death in TTP. Therefore, the heart tissue, including the sinus-atrial node and the atrioventricular node, should be microscopically examined more closely in autopsy cases of patients with TTP who experienced sudden death of TTP. This report is a critical teaching case considering that its cause of sudden death may be arrhythmia due to a myocardial infarction including cardiac conduction system disorder by platelet microthrombi.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2113354005156739

Post-mastectomy benign lymphangioendothelioma of the skin following chronic lymphedema for breast carcinoma: a teaching case mimicking low-grade angiosarcoma and masquerading as Stewart-Treves syndrome

Benign lymphangioendothelioma (BL) represents a very rare lymphatic vascular proliferation. Our aim is to be aware that owing to its characteristic features, pathologists can easily misinterpret it as cutaneous low-grade angiosarcoma when examining only small specimens. In the present case, multiple small and yellowish to reddish soft nodules were noticed in the edematous left arm of a 54-year-old Japanese female 4 years after the radical mastectomy with axillary lymph nodes dissection and following radiotherapy to the chest for the left breast carcinoma. The biopsy specimen showed an ill-defined lesion composed of a proliferation of irregular and sometimes anastomosing vascular structures in the dermis, lined by endothelial cells having mildly hyperchromatic and pleomorphic nuclei, but no mitotic figures. As the lesion grew within deeper dermis, these proliferating vessels dissected dermal collagenous bands, occasionally arranged in low-papillary projections and/or characteristic hobnail cytomorphology. We first interpreted it as low-grade angiosarcoma following chronic lymphedema due to the operation, i.e., the so-called Stewart-Treves syndrome. Although additional treatments were performed for 7 years, she had neither local invasion nor metastases of these tumors, respectively, and was alive and well. Retrospective immunohistochemical findings demonstrated that these mildly atypical endothelial cells were strongly positive for lymphatic vessel endothelial hyaluronan receptor (LYVE)-1 as well, and MIB-1 labeling index was less than 1%. Therefore, we finally made a diagnosis of BL of the skin. MIB-1 labeling index might be useful and adjunctive aids for reaching the correct diagnosis of cutaneous BL, especially in case of small or inadequate specimens.Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_197

Basal Cell Adenocarcinoma of the Sublingual Gland: A Case of an Inadequate FNA Cytology Specimen Rendering Conclusive Diagnosis Difficult

A history of a gradual increase in swelling mass was presented in the sublingual gland of a 72-year-old female. The inadequate cytologic specimens retrospectively contained some clusters of three-dimensional monomorphic and round basaloid cells having hyperchromatic small nuclei and scant cytoplasm, along with a small amount of spherical globules of amorphous material and myxoid stroma, adjacent to few squamous metaplastic tumor nests. We first interpreted it as a pleomorphic adenoma, basal cell adenoma (BCA), or adenoid cystic carcinoma (ACC). A tumor extirpation was performed, and gross examination revealed a non-capsulated and ill-defined tumor lesion, looking grayish to yellowish-white, focally associated with fat invasion. On microscopic examination, the tumor was predominantly composed of a proliferation of small to medium-sized mildly atypical epithelial cells having very rare mitoses, often arranged in a cribriform or alveolar growth pattern with peripheral nuclear palisading and scattered squamous differentiation, embedded in a prominent eosinophilic hyaline material. Therefore, we finally made a diagnosis of invasive basal cell adenocarcinoma (BCAC), defined as the malignant counterpart of benign BCA. We should be aware that owing to its characteristic features, cytopathologists might be able to determine correct diagnosis, based on multiple and adequate samplings.

Lymphocytic focus score is positively related to airway and interstitial lung diseases in primary Sjögren's syndrome

OBJECTIVE Although high-resolution computed tomography (HRCT) is useful for the characterization of minute morphological changes in the lungs, no study has investigated risk factors for lung involvement detected by HRCT in patients with Sjögrens syndrome with or without respiratory symptoms. The aim of the current study was to investigate risk factors for lung involvement in patients with primary Sjögrens syndrome detected by HRCT, with a particular focus on airway and interstitial lung diseases. METHODS We performed a retrospective cohort study of patients with primary Sjögrens syndrome and investigated risk factors for lung involvement detected by HRCT. A total of 101 patients with primary Sjögrens syndrome with initial HRCT examinations were enrolled. RESULTS Higher age, dry mouth, and higher labial gland biopsy focus scores (≥4) were risk factors for airway diseases (odds ratio [OR] 1.064 confidence interval [CI] 1.026-1.102, OR 8.795 CI 2.317-33.378 and OR 3.261 CI 1.100-9.675, respectively) in the multivariable analysis. Higher age, male sex, and higher labial gland biopsy focus scores (≥4) were risk factors for interstitial lung diseases (OR 1.078 CI 1.032-1.127, OR 12.178 CI 1.121-132.307 and OR 3.954 CI 1.423-10.987, respectively) in the multivariable analysis. The presence of anti-T-lymphotropic virus type 1 antibodies was significantly more common in patients with airway diseases. CONCLUSIONS This study showed significant associations of labial gland biopsy focus scores and dry mouth with pulmonary manifestations in patients with primary Sjögrens syndrome. Focus scores as well as dry mouth may reflect lymphoproliferative activity in the lungs in patients with primary Sjögrens syndrome.

Podocyte and endothelial cell injury lead to nephrotic syndrome in proliferative lupus nephritis

Nephrotic syndrome (NS) is a major manifestation of lupus nephritis (LN). The dysregulation of podocytes, the glomerular basement membrane (GBM) and endothelial cells (ECs) results in proteinuria in glomerular diseases. The aim of our study was to clarify whether the dysregulation of these barriers is associated with NS in proliferative LN and membranous LN.

The occurrence of hypertrophic pachymeningitis with infiltration of IgG4-positive plasma cells and with different aetiology: report of three cases

Abstract We examined three patients with hypertrophic pachymeningitis (HP). The first patient was a 67-year-old man who underwent biopsy after being diagnosed with HP by magnetic resonance imaging (MRI) for loss of vision in the left eye. The patient’s serum IgG4 level was 22.1 mg/dL and IgG4/IgG ratio in histopathological examination was approximately 30%, ruling out IgG4-related disease (IgG4-RD). The patient was subsequently diagnosed with Rosai–Dorfman disease after infiltration of S-100 protein-positive histiocytes was observed. The second patient was a 45-year-old man who underwent biopsy after being diagnosed with HP by MRI for eyelid swelling and double vision. The patient’s serum IgG4 level was 42.8 mg/dL and IgG4/IgG ratio was approximately 25%, which ruled out IgG4-RD. The patient was subsequently diagnosed with idiopathic HP and idiopathic orbital pseudo-tumor. The third patient was a 66-year-old man who underwent biopsy after being diagnosed with HP by MRI for headache. The patient had an elevated serum IgG4 level of 771 mg/dL and a histopathologically determined IgG4/IgG ratio of 70% and was thus diagnosed with IgG4-RD. All the patients were treated with a glucocorticoid (prednisolone 0.6 mg/kg/day), and they responded well to the treatment. Although the clinical courses were very similar, HP was diagnosed differently in each patient. We report these three cases because we thought they are thought-provoking about the prediction of the treatment responsiveness and the potential need for a new disease classification system in HP, which is an intractable disease that is sometimes refractory to glucocorticoid therapy.

High-Grade Chondrosarcoma Associated with Spindle Cell Components of the Cricoid Cartilage

A history of recent frequency in cough and sputum was presented in a 73-year-old male. A neck CT scan revealed a heterogeneously enhanced and poorly-demarcated mass, measuring approximately 35 × 35 mm, arising from the right cricoid cartilage and projecting into the airway. The inadequate cytologic specimen contained few individual cells or small clusters of tumor cells having pleomorphic and sometimes spindle- or multi-nuclei, and abundant clear or vacuolated cytoplasm, along with an amount of metachromatic chondroid stroma. We first interpreted it merely as carcinoma. A total laryngectomy was performed, and gross examination showed a multilobulated and firm mass with a grayish to whitish, fleshy and glistening appearance, involving the cricoid cartilage and cricothyroid muscle. However, the overlying surface tracheal mucosa was smooth. Microscopically, the tumor was predominantly composed of a solid proliferation of atypical chondrocyte-like cells having hyperchromatic bi- or multi-nuclei in a lobular fashion, embedded in an abundant chondroid matrix, associated with cellular spindled cell foci. Therefore, we finally made a diagnosis of grade 2 chondrosarcoma with spindle cell components. We should be aware that owing to its characteristic features, cytopathologists might be able to determine correct diagnosis, based on multiple and adequate cytology samplings.