沼倉 里枝

An ovarian mucinous cystic tumor where fundic glands were broadly and evenly distributed. All components were FOXA2-positive. The diagnosis is difficult between "mucinous cystadenoma with fundic gland differentiation" and "monodermal cystic teratoma composed of gastric tissue derived from endoderm".

A middle-aged woman was found to have proteinuria during a health check-up. About sixteen months later, she was diagnosed with stage IIA invasive ductal carcinoma of the right breast. Her proteinuria progressed to nephrotic syndrome with significant hematuria. Hormone therapy was initiated for her estrogen and progesterone receptor-positive breast cancer. A kidney biopsy performed 47 days after starting the therapy revealed an IgA-dominant membranoproliferative glomerulonephritis-like pattern of injury. Electron microscopy showed subendothelial-dominant electron-dense deposits (EDD), with small amounts of mesangial EDD and a single occurrence of subepithelial hump-like EDD, along with occasional mesangial interpositions. Similar pathology can be caused by IgA vasculitis with nephritis, IgA-dominant infection-associated glomerulonephritis, and liver disease-associated glomerulopathy, but all of these were ruled out. The deposited IgA was found to be galactose-deficient IgA1. Thus, IgA nephropathy with glomerular capillary IgA deposition was considered. She underwent a right partial mastectomy and sentinel lymph node biopsy in the right axilla 75 days after starting hormone therapy, followed by adjuvant radiation. Proteinuria and hematuria tended to decrease after the treatment, and this trend continued even after corticosteroid therapy for glomerulonephritis, which was administered 156 days after starting hormone therapy. Approximately 15 months after starting hormone therapy, her proteinuria had reduced to around 1.0 g/g of creatinine, and her hematuria was negative. IgA nephropathy with glomerular capillary IgA deposition is known to be resistant to corticosteroid therapy. The favorable clinical course of the rare glomerulopathy following breast cancer treatment suggested a diagnosis of paraneoplastic glomerulopathy secondary to breast cancer in our patient.

A 42-year-old woman presented with muscle weakness and hypokalemic distal renal tubular acidosis (dRTA). Investigations revealed concurrent Sjögren's syndrome (SS) and Hashimoto's thyroiditis contributing to hypokalemic dRTA. A renal biopsy revealed focal tubulointerstitial nephritis (TIN) suggestive of SS-related renal involvement, along with distinctive ischemic glomerular changes and tubular alterations consistent with hypokalemic nephropathy. Rapid improvement in tubular injury markers and hypobicarbonemia followed potassium supplementation, suggesting that hypokalemia contributed to proximal tubular injury. This case underscores the diagnostic challenge posed by the simultaneous presence of TIN and hypokalemic nephropathy, potentially masking hypokalemic nephropathy in patients with hypokalemic dRTA secondary to SS-TIN.

BACKGROUND: Inflammatory cancer-associated fibroblasts (iCAFs) was first identified by co-culture of pancreatic stellate cells and tumor organoids. The key feature of iCAFs is IL-6high/αSMAlow. We examine this phenomenon in gastric cancer using two cell lines of gastric fibroblasts (HGF and YS-1). METHODS AND RESULTS: HGF or YS-1 were co-cultured with MKN7 (a gastric adenocarcinoma cell line) in Matrigel. IL-6 protein levels in the culture supernatant were measured by ELISA. The increased production of IL-6 was not observed in any of the combinations. Instead, the supernatant of YS-1 exhibited the higher levels of IL-6. YS-1 showed IL-6high/αSMA (ACTA2)low in real-time PCR, mRNA-seq and immunohistochemistry. In mRNA-seq, iCAFs-associated genes and signaling pathways were up-regulated in YS-1. No transition to myofibroblastic phenotype was observed by monolayer culture, or the exposure to sonic hedgehog (SHH) or TGF-β. YS-1 conditioned medium induced changes of morphology and stem-ness/differentiation in NUGC-3 (a human gastric adenocarcinoma cell line) and UBE6T-15 (a human bone marrow-derived mesenchymal stem cell line). CONCLUSIONS: YS-1 is a stable cell line of gastric iCAFs. This discovery will promote further research on iCAFs for many researchers.

BACKGROUND/AIM: "Stromal high expression" of Nicotinamide N-methyltransferase (NNMT), previously reported as a poor prognostic factor of gastric cancer, was based on immunohistochemical H-score. However, this could simply indicate an increase in cancer-associated fibroblasts (CAFs) because NNMT is positive for fibroblasts. To verify this, the proportion and staining intensity of stromal NNMT-positive stellate/spindle cells were evaluated separately and examined for its association with related proteins (H3K4me3, H3K27me3, and LOXL2). PATIENTS AND METHODS: Immunohistochemistry for NNMT, H3K4me3, H3K27me3, and LOXL2 was performed on 521 tissue microarrays of gastric cancer. Cancer stromal stellate/spindle cells were evaluated according to morphology, proportion, and stain intensity of NNMT, loss of H3K4me3 and H3K27me3, and stain intensity of LOXL2. Their associations with clinicopathological characteristics and overall survival were examined. RESULTS: Higher staining intensity of NNMT was not related to a poorer prognosis. However, higher proportion of NNMT-positive stellate/spindle cells indirectly contributed to a poor prognosis. It was associated with CAF-like morphology and a global decrease in H3K4me3/H3K27me3, which were both associated with high LOXL2 expression. These three factors were independent poor prognostic factors. In addition, in the LOXL2-high group, prognosis significantly deteriorated with the presence of a global decrease in H3K4me3/H3K27me3. CONCLUSION: The higher proportion of NNMT-positive cancer stromal cells in gastric cancer serves as an indicator for identifying unfavorable prognostic CAFs that show a global decrease in H3K4me3/H3K27me3. This facilitates research on the nature of these cells and their characteristics.

＜文献概要＞症例のポイント ・ペムブロリズマブ投与中に生じたlichen planus pemphigoides(LPP)の1例を経験した.・LPPは紅斑や扁平苔癬様皮疹が先行し,その後に水疱を生じる症例が比較的多い.・抗BP180抗体は比較的低値である.・ステロイド内服を行わずに軽快した症例もあり,治療反応性はよい傾向である.

BACKGROUND: Currently, there is an unwavering consensus that the standard surgery for congenital biliary dilation (CBD) is extrahepatic bile duct resection and choledochojejunostomy. However, decades prior, choledochocyst-gastrointestinal anastomosis without extrahepatic bile duct resection (internal drainage surgery, IDS) was preferred for CBD because of its simplicity. Currently, there is almost no chance of a surgeon encountering a patient who has undergone old-fashioned IDS, which has been completely obsolete due to the risk of carcinogenesis from the remaining bile duct. Moreover, the pathological condition long after IDS is unclear. Herein, we report a case of life-threatening bile duct bleeding as well as carcinoma of the bile duct 62 years after IDS in a patient with CBD. CASE PRESENTATION: An 82-year-old Japanese woman with hemorrhagic shock due to gastrointestinal bleeding was transferred to our hospital. She had a medical history of unspecified surgery for CBD at the age of 20. Based on imaging findings and an understanding of the historical transition of the surgical procedure for CBD, the cause of gastrointestinal bleeding was determined to be rupture of the pseudoaneurysm of the dilated bile duct that remained after IDS. Hemostasis was successfully performed by transcatheter arterial embolization (TAE) in an emergency setting. Then, elective surgery for extrahepatic bile duct resection and choledochojejunostomy was performed to prevent rebleeding. Pathological examination revealed severely and chronically inflamed mucosa of the bile duct. Additionally, cholangiocarcinoma (Tis, N0, M0, pStage 0) was incidentally revealed. CONCLUSION: It has been indicated that not only carcinogenesis, but also a risk of life-threatening bleeding exists due to long-lasting chronic inflammation to the remnant bile duct after IDS for CBD. Additionally, both knowledge of which CBD operation was performed, and an accurate clinical history are important for the diagnosis of hemobilia.

Epithelioid hemangioma is a rare benign vascular tumor that consists of capillary-sized vessels lined by epithelioid endothelial cells. Diffuse cavernous hemangioma is a congenital benign vascular neoplasm consisting of increased dilated vessels. We report a case of epithelioid hemangioma and diffuse cavernous hemangioma that co-occurred in the rectum. To our knowledge, this is the first report in which two rare vascular lesions coexisted. Because both epithelioid hemangioma and diffuse cavernous hemangioma are often clinically confounded by malignant tumors, differentiating these benign lesions from other possible malignant tumors is significant.

BACKGROUND: Pulmonary NUT carcinoma is rare, but lethal, thus, must not be overlooked. The definitive diagnosis is made by a NUT monoclonal antibody or gene analysis, but these are not always routinely available. Therefore, the diagnosis depends on this rare disease being suspected from the clinical and pathological findings. Generally, NUT carcinoma of the lung occurs near the hilum in younger adults with severe subjective symptoms. Histologically, it is characterized by the monomorphic growth of small cells which showed positivity of p63 immunohistochemistry. CASE PRESENTATION: An 82-year-old man was referred for an incidental finding of an abnormal shadow at the peripheral apex of the right lung on computed tomography for a regular follow-up examination of renal cancer. Microscopically, small cell carcinoma was initially suspected; however, immunohistochemistry was not typical. NUT carcinoma with BRD4-NUT fusion was ultimately diagnosed using a NUT monoclonal antibody, fluorescence in situ hybridization, and RNA-seq. p63 and p40 protein expression was not detected. CONCLUSIONS: This is the first case of pulmonary NUT carcinoma to show negativity for p63 and is the oldest among previously reported cases. The present case suggests that NUT carcinoma should be suspected when the morphology of monomorphic growth of small cells without lineage-specific differentiation, regardless of age, clinical symptoms, the tumor location, or p63 expression.

Cancer stem cells (CSCs) play a decisive role in the development and progression of cancer. To investigate CSCs in Epstein-Barr virus (EBV)-associated carcinoma (EBVaGC), we screened previously reported stem cell markers of gastric cancer in EBV-infected gastric cancer cell lines (TMK1 and NUGC3) and identified CD44v6v9 double positive cells as candidate CSCs. CD44v6/v9+/+ cells were sorted from EBVaGC cell line (SNU719) cells and EBV-infected TMK1 cells and these cell populations showed high spheroid-forming ability and tumor formation in SCID mice compared with the respective CD44v6/v9-/- cells. Sphere-forming ability was dependent on the nuclear factor-κB (NF-κB) signaling pathway, which was confirmed by decrease of sphere formation ability under BAY 11-7082. Small interfering RNA knockdown of latent membrane protein 2A (LMP2A), one of the latent gene products of EBV infection, decreased spheroid formation in SNU719 cells. Transfection of the LMP2A gene increased the sphere-forming ability of TMK1 cells, which was mediated through NF-κB signaling. Together, these results indicate that CD44v6v9+/+ cells are CSCs in EBVaGC that are maintained through the LMP2A/NF-κB pathway. Future studies should investigate CD44v6/v9+/+ cells in normal and neoplastic gastric epithelium to prevent and treat this specific subtype of gastric cancer infected with EBV.

BACKGROUND: Pre-resection pleural lavage cytology is useful to predict tumor recurrence and the prognosis of lung cancer patients. Recently, extracellular vesicles (EVs) isolated from effusion specimens have come under the spotlight, and several studies showed that microRNA in EVs is associated with prognosis. MicroRNA-21 (miR-21) is a representative onco-microRNA, and miR-21 in EVs (EV-miR-21) promotes cancer dissemination by inducing mesothelial to mesenchymal transition (MMT) in the peritoneal cavity. In this study, we isolated EVs from pleural lavage fluid and focused on EV-miR-21 as a diagnostic factor with a relationship to pleural dissemination. METHODS: The Cancer Genome Atlas dataset comprising of 448 cases of lung adenocarcinoma, tissue microarray of 144 cases of lung adenocarcinoma, and pleural lavage fluid of 41 cases was used to examine miR-21 expression levels. The function of EV-miR-21 was investigated in vitro. RESULTS: The miR-21 expression level in primary sites was associated with a poor prognosis and correlated with pleural invasion of adenocarcinoma. EV-miR-21 levels in pleural lavage fluid were associated with positive cytology and pleural invasion in the primary sites, even in cytology-negative cases. In vitro studies demonstrated that EV-miR-21 induces the MMT. Mesothelial cells in the MMT showed functions similar to cancer-associated fibroblasts, which are an important stromal component in primary sites and disseminated pleural lesions. CONCLUSIONS: EV-miR-21 in pleural lavage fluid is important as a diagnostic and prognostic factor. Moreover, EV-miR-21 induces the MMT, which can form premetastatic niches of dissemination in the pleural cavity.

A 39-year-old man presented with chief complaints of epistaxis and pain on the right cheek that lasted for approximately 2 months. A very hard calcified black mass with a foreign body was found in the right inferior nasal meatus. The patient underwent endoscopic endonasal surgery and antimicrobial therapy, which included intravenous injection of Penicillin G 4 million units 6 times/day for 1 week and oral amoxicillin 1500 mg/day for 6 months. Actinomyces species was identified from the calcified foreign body that measured 5 mm in size. There was no recurrence for 1 year after the surgery. Surgical removal and long-term high-dose penicillin for 6 months or longer are necessary because death caused by poor compliance with antibiotics have been reported in previous studies.

BACKGROUND/AIM: CD10 function in urothelial carcinoma (UC) remains controversial. We previously reported that miR-21 in UC may be a prognostic marker for cancer progression. The aim of this study was to examine the clinicopathological significance of CD10 expression in UC and its relationship with miR-21 expression. MATERIALS AND METHODS: Immunohistochemistry for CD10 was performed on 232 UCs. CD10 expression in TCs and stroma was evaluated respectively, and its association with carcinogenesis and survival was analyzed. RESULTS: High tumorous CD10 was significantly associated with higher tumor stage, histological grade and vessel infiltration, and poorer prognosis, whereas stromal CD10 was significantly associated with younger age, higher tumor stage, and vessel infiltration. On multivariable analysis, CD10 expression in TCs, miR-21 expression in TCs and TS, and tumor stage were independent prognostic factors. CONCLUSION: Tumorous CD10 is more strongly related to progression of UC than stromal CD10 and is an independent factor for UC prognosis.

BACKGROUND/AIM: Spindle-shaped stromal cells of tumors are derived from various cellular origins, including mesenchymal stem cells (MSCs). MSCs express CD73, CD90 and CD105 antigens. Herein, the aim was to investigate the association between the expression of specific MSC markers in gastric cancer stromal cells and the clinicopathological features of the disease. MATERIALS AND METHODS: The expression of CD73, CD90 and CD105 in spindle-shaped cancer stromal cells was studied by immunohistochemistry in tissue arrays containing 546 gastric cancer cases. Univariate and multivariate analyses were performed to evaluate the association of MSC marker expression with clinicopathological variables. RESULTS: Spindle-shaped cancer stromal cells expressing the MSC markers CD73, CD90 or CD105 were associated with larger tumor size, advanced cancer, venous infiltration, lymphatic infiltration, and lymph node metastasis. Statistical analysis demonstrated that the presence of CD105-positive spindle cells was an independent prognostic factor of advanced cancer, lymph node metastasis and EBV infection in multivariate analysis. CONCLUSION: Spindle-shaped gastric cancer stromal cells expressing CD73, CD90 or CD105 are involved in disease progression, and among them, CD105-positive cells are strongly associated with poor prognosis.

Destructive infiltration of invasive fungal sinusitis can easily occur into the central nervous system (CNS). Cerebral aneurysms associated with fungal infection are highly vulnerable to rupture, and can frequently and rapidly take a serious clinical course. We experienced a patient who twice developed cerebral aneurysm followed by rupture due to invasive fugal sinusitis. This 77-year-old man was admitted for progressive bilateral visual disturbance, which was initially treated as idiopathic hypertrophic pachymeningitis. The patient subsequently suffered subarachnoid hemorrhage (SAH) twice in only 12 days. Both SAH originated from different newly formed cerebral aneurysms. Trapping was performed for both ruptured aneurysms. Pathological examination of the resected aneurysms indicated the presence of fungi determined to be Aspergillus. This Aspergillus infection was also discovered inside the frontal sinus by endoscopic biopsy, so a regimen of antifungal agents was instituted. Prolonged antifungal therapy caused renal impairment, which ultimately led to the patient's death. Autopsy detected no mycotic infiltration of the major cerebral arteries, except for the 2 ruptured cerebral aneurysms. However, prolonged mycosis of the CNS, such as in the deep part in the falx cerebri and in the small veins proximal to the tentorium cerebelli, was observed, indicating that mycosis invading the cranium is refractory even to long-term administration of antifungal agents. The present case strongly suggests that urgent and proactive definitive diagnosis is essential to successfully treat invasive paranasal sinus aspergillosis. If infiltration of the CNS is suspected, early surgical resection and antifungal therapy must be initiated immediately.