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An 80-year-old woman was found to have a 40-mm depressed-type gastric cancer. Computed tomography showed multiple lymph node enlargement, including paraaortic lymph nodes. The extent of lymph node enlargement was significant compared with the depth of the primary lesion. We conducted distal gastrectomy, D2 lymph node dissection, and a paraaortic lymph node biopsy. Microscopically, the tumor was diagnosed as mucosal cancer. In the dissected lymph nodes, noncaseating granuloma was found without metastasis of adenocarcinoma. Immunohistochemical staining using Propionibacterium acnes-specific antibodies showed a large number of P. acnes-positive cells in the granulomas. Finally, the tumor was diagnosed as early-stage gastric cancer and sarcoidosis.

BACKGROUND The foci of distant metastasis from extramammary Paget’s disease (EMPD) are the lung, liver, truncal bones, vertebrae, and brain. However, skull metastases have not been reported. OBSERVATIONS The authors treated a patient with calvarial and skull base metastases from EMPD who had undergone wide local resection of EMPD 8 years before, and they report his clinical course. LESSONS Because EMPD with distant metastasis is fatal, it should be recognized that EMPD can metastasize to the skull even when it seemed to be in remission for several years.

An 80-year-old woman presented with a 30-mm protruding lesion-like submucosal tumor with a central depression located at the anterior wall of the upper gastric body. The depressed area had a well-demarcated margin, while the other area was covered by a non-neoplastic mucosa. A biopsy specimen revealed neuroendocrine carcinoma. Endoscopic ultrasonography revealed a heterogeneous mass with a clearly distinguished border in the submucosal layer. The mass had two distinct areas adjacent to each other. In addition, a hypoechoic zone was observed on the margin of the mass. Distal gastrectomy was performed. The final diagnosis was a mixed neuroendocrine-non-neuroendocrine neoplasm arising from the heterotopic gastric gland.

Introduction: This study aimed to identify the characteristics of superficial non-ampullary duodenal epithelial tumors (SNADETs) based on the mucin phenotype using magnifying narrow-band imaging with acetic acid spray (MA-NBI) and evaluate the efficacy of MA-NBI in differentiating gastric-type (G-type) from intestinal-type (I-type) lesions. Methods: We retrospectively identified 59 resected SNADETs in 59 patients who underwent MA-NBI. We evaluated surface patterns using MA-NBI to differentiate G-type from I-type lesions. Surface structures were classified into three patterns: tubular, villous, or oval structures. Lesions displaying a single pattern among the three patterns were classified as monotype, whereas those displaying multiple surface patterns were classified as mixed type. In addition, lesions with disorganized and unclear structures with irregular margins were classified as irregular surface structures. Results: In total, 32 (54%), 26 (44%), and 1 (2%) lesions were classified as Vienna category 3, 4, and 5 tumors, respectively, whereas 49 (83%) and 10 (17%) were classified as I- and G-type lesions, respectively. Oval structures were more frequently observed in G-type lesions (70%), whereas tubular structures were more frequently observed in I-type lesions (78%) (p < 0.001). Category 4 and 5 lesions had significantly higher mixed and irregular surface structure rates than category 3 lesions (41 vs. 6%, p = 0.003 and 81 vs. 3%, p < 0.001, respectively). Conclusion: MA-NBI can distinguish the mucin phenotypes of SNADETs and may facilitate histological grade diagnosis.

A 73-year-old man was initially diagnosed with a 50-mm, depressed-type early gastric cancer on the anterior wall of the angulus, and the lesion was curatively resected en bloc by endoscopic submucosal dissection. Pathology revealed a 54 mm × 43 mm differentiated-type predominant adenocarcinoma with focal undifferentiated-type component that was confined to the mucosa without ulceration. Eleven years after endoscopic submucosal dissection, lymph node metastasis along the lesser curve was incidentally detected on magnetic resonance imaging and diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy. The patient received distal gastrectomy with D2 lymph node dissection. A resected lymph node revealed a well-differentiated adenocarcinoma with a poorly differentiated component; thus, the final diagnosis was late recurrence of early gastric cancer originally treated by endoscopic submucosal dissection. This report demonstrates that metastatic recurrence may occur in curative endoscopic submucosal dissection for early gastric cancer and that gastric cancer can recur even after more than 5 years.

A 55-year-old-man presented with low-grade fever, general fatigue, appetite loss and body weight loss. An electrocardiogram (ECG) showed the presence of long QT syndrome (LQTS), and laboratory test...

A 75-year-old male patient has been followed-up for mixed-type intraductal papillary mucinous neoplasm (IPMN) in the tail of the pancreas for about 20 years. Upon close examination, he was diagnosed of high-risk stigmata due to a nodule having a contrast effect of 5mm or more in the tumor. Based on this, a distal pancreatectomy was performed. Histopathological analysis revealed concomitant IPMN (low-grade) and pancreatic neuroendocrine neoplasm (PNEN) (G1). This prompted us to report a very rare case of coexisting PNEN and IPMN with an interesting pathological finding that might suggest its pathogenic mechanism.

Background/Aims: The aim of the present study was to evaluate the efficacy of magnifying narrow band imaging with acetic acid spray (MA-NBI) in differentiating category 4/5 lesions from category 3 lesions of superficial non-ampullary duodenal epithelial tumors (SNADETs) as per Vienna Classification and to compare the diagnostic performances of both MA-NBI and magnifying narrow band imaging (M-NBI). Methods: We retrospectively identified 60 resected SNADETs (31 category 3 lesions and 29 category 4/5 lesions) in 60 patients who underwent M-NBI and MA-NBI preoperatively. We evaluated vascular and surface patterns using M-NBI and MA-NBI for characterizing category 3 and 4/5 lesions. The surface pattern was classified as tubular, villous, or mix structure using MA-NBI. In addition, lesions with disorganized and unclear structures with irregular margins that can be clearly recognized by MA-NBI were defined as irregular surface structures. Results: For MA-NBI, category 4/5 lesions had a significantly higher mix structure rate and higher irregular surface structure rate than category 3 lesions (62 vs. 16%, p < 0.001, and 86 vs. 19%, p < 0.001, respectively). The diagnostic accuracy of MA-NBI using mix and irregular surface structures for identifying category 4/5 lesions was as follows: sensitivity, 62/86%; specificity, 84/77%; positive predictive value, 78/78%; negative predictive value, 70/86%; and accuracy, 73/82%. The diagnostic accuracy of MA-NBI using irregular surface structure was significantly higher than that of M-NBI (p < 0.05). Conclusion: MA-NBI may be useful in differentiating between category 3 and category 4/5 lesions of SNADETs.

We herein report a unique case of type B2 thymoma-associated myasthenia gravis which was ameliorated by immunosuppressive therapy in combination with chemotherapy. However, the patient subsequently developed pure red cell aplasia and marked lymphocytosis after additional chemotherapy aimed at improvement of thymoma. While a separate immunosuppressive regimen was effective for anemia, lymphocytosis was exacerbated. The biopsied thymoma specimen contained CD4+, CD8+, and CD4+/CD8+ T cells, some of which were CD3−, suggesting immature thymocytes. In contrast, majority of the peripheral lymphocytes were polyclonal CD3+/CD8+/T cell receptor (TCR)αβ+ T cells. The CD4/CD8 ratio in the present patient might be affected by immunosuppressive agents, resulting in CD8+ T cell expansion associated with pure red cell aplasia. Although several cases of thymoma accompanied by peripheral T cell lymphocytosis were reported, marked CD8+ T cell proliferation is extremely rare.

Introduction Non-islet cell tumor hypoglycemia is a rare paraneoplastic syndrome associated with tumors. Although it mainly occurs in solid tumors of mesenchymal and epithelial origin, but rarely also in hematopoietic and neuroendocrine origin. Case presentation We describe a 65-year-old man with a muscle-invasive bladder urothelial carcinoma, which rapidly progressed against systemic chemotherapy consisting of gemcitabine and cisplatin. Notably, the patient developed hypoglycemia at the terminal stage of the disease. Pathological diagnosis was giant cell urothelial carcinoma, which was strongly positive for insulin-like growth factor-II in immunohistochemistry. We established patient-derived xenograft from insulin-like growth factor-II producing bladder urothelial carcinoma that caused non-islet cell tumor hypoglycemia. Although we evaluated the efficacy of the neutralizing antibody, there was no statistically significant inhibitory effect on tumor growth. Conclusion To the best of our knowledge, this is the first report of insulin-like growth factor-II-producing urothelial carcinoma that have been recapitulated in a patient-derived xenograft model.

Case 1 : A 65-year-old man visited withfrequent urination and dysuria. Pyuria and bacteriuria were observed and prostate specific antigen (PSA) was elevated to 5.69 ng/ml. Prostate cancer and urinary tract infection were suspected. A antibiotics were administered and prostate magnetic resonance imaging (MRI) was performed. Massive prostate cancer was strongly suspected from the MRI findings and prostate needle biopsy was performed. The pathological examination revealed nonspecific granulomatous prostatitis. Case 2 : A 69-year-old man visited withfrequent urination. Urinalysis was normal and PSA was elevated to 4.52 ng/ml. Diffuse prostate cancer was suspected from the MRI findings and prostate needle biopsy was performed. Pathological findings were similar to those in case 1. Case 3 : A 61-year-old man presented withno urinary symptoms. Urinalysis was normal and PSA was elevated to 11.64 ng/ml. Medical history was renal pelvic cancer and bladder cancer. He had undergone a transurethral resection of the bladder tumor (TURBT) and intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. Prostate cancer was suspected from the MRI findings and prostate needle biopsy was performed. Pathological findings were granulomatous prostatitis. In these three cases, the structure of these prostate capsules was preserved although extensive prostate cancer was suspected from the findings of MRI T2-weighted and diffusion weighted images. Although histopathologic examination is mandatory for differential diagnosis between granulomatous prostatitis and diffuse prostate cancer, prostate MRI may help to distinguish these diseases.

Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS (p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

Insulin-like growth factor 2 is overexpressed in various cancers, and is associated with a poor prognosis. Also, it is known that insulin-like growth factor 2 is an etiology of non-islet cell tumor hypoglycemia. In this report, we describe a case of unexpected hypoglycemia caused by a dedifferentiated liposarcoma producing insulin-like growth factor 2. A large mass in the retroperitoneum was detected in a 61-year-old man who complained of appetite loss. Despite having no history of diabetes mellitus, hypoglycemia suddenly occurred after admission, but oral glucose therapy was ineffective. After total parenteral nutrition, tumor resection was attempted, but failed as a result of rigid adhesion to the surrounding organs. The patient died of the disease 21 days after surgery. Pathological diagnosis at autopsy revealed dedifferentiated liposarcoma, and immunohistochemical staining showed that the tumor excreted insulin-like growth factor 2. The possibility of an insulin-like growth factor 2-producing tumor should be taken into consideration when we encounter a patient with spontaneous hypoglycemia resistant to glucose substitution therapy.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) has been incorporated into the recent international histological classification of renal tumors. However, to date, there are limited studies describing the clinicopathological features of fumarate hydratase (FH)-deficient RCC, including the hereditary (HLRCC) and sporadic forms. Herein, we present a clinicopathological study of seven cases with FH-deficient RCC. The age of patients ranged from 26 to 70 years with mean and median age of 51.7 and 57 years, respectively. The follow-up data of all patients were available. One patient was alive without the disease and five patients were alive with active disease. One patient died of the disease. Family history of RCC, or skin or uterine smooth muscle tumor within second degree of kinship was present in four of seven patients. Metastasis was observed in all tumors. Metastatic sites included bone, lungs, liver, peritoneum, ovaries, tonsils, or lymph nodes. Grossly, the cut surface of the tumor usually showed light brown, brown, or whitish color. Microscopically, the cytoplasm of the tumor cells was predominantly eosinophilic and all tumors displayed various architectural patterns such as papillary, tubular, solid, or microcystic patterns. Furthermore, two tumors demonstrated a tubulocystic pattern. Sarcomatoid change and rhabdoid features were seen in five tumors and two tumors, respectively. Large cytomegaloviral (CMV) inclusion-like eosinophilic nucleoli surrounded by a clear halo were identified in all tumors. All tumors showed negative immunohistochemical reaction for FH protein. False positive results of TFE3 protein were observed in three tumors. Furthermore, a germline mutation of FH gene was identified in one patient with family history of the disease. In conclusion, FH-deficient RCC includes hereditary and sporadic forms. Grossly, this tumor is solitary and occurs unilaterally. Histologically, the tumor is characterized by various patterns such as papillary, tubular, solid, tubulocystic, or microcystic, has eosinophilic cytoplasm and CMV-like high-grade nuclei. FH-deficient RCCs frequently metastasize to other anatomic sites. TFE immunoreactivity may occur in some FH-deficient RCCs, and immunohistochemistry can accurately diagnose these tumors and mutational analysis of FH gene.

Langerhans cell histiocytosis (LCH) with primary involvement of the upper gastrointestinal (GI) tract is rare. We report 2 adult cases of localized LCH in the upper-GI tract, including the second reported adult case of esophageal LCH and review 11 previously reported cases. Case 1 involved the esophagus of a 61-year-old man; histiocytosis was detected when endoscopy was performed for an examination of epigastric pain. Case 2 involved the stomach of a 56-year-old woman wherein the lesion was detected during a follow-up endoscopy after Helicobacter pylori infection. Both biopsy specimens exhibited diffuse proliferation of mononuclear cells with nuclear convolution and a background of eosinophilic infiltrate. The cells were immunohistochemically positive for CD1a and langerin, and BRAF V600E mutation was detected in Case 2. Follow-up endoscopy for both cases revealed that the lesions disappeared without any treatment. It is important to avoid misdiagnosing LCH of the upper-GI tract as a malignant neoplasm.

We herein report a unique case of type B2 thymoma-associated myasthenia gravis which was ameliorated by immunosuppressive therapy in combination with chemotherapy. However, the patient subsequently developed pure red cell aplasia and marked lymphocytosis after additional chemotherapy aimed at improvement of thymoma. While a separate immunosuppressive regimen was effective for anemia, lymphocytosis was exacerbated. The biopsied thymoma specimen contained CD4

BCOR-CCNB3 sarcoma is a recently recognized tumor morphologically and clinically simulating Ewing sarcoma. We herein retrospectively collected clinicopathologic data on BCOR-CCNB3 sarcoma in the Kyoto University Hospital over the last 10 years. Three (20%) bone sarcomas were revealed to be diffusely positive for CCNB3 immunohistochemistry among 15 pediatric cases of undifferentiated sarcoma morphologically similar to Ewing sarcoma, while the other cases showed completely negative staining. The three patients with immunohistochemically CCNB3-positive tumors were all male, aged between 11 and 17, and confirmed to have the BCOR-CCNB3 fusion transcript by RT-PCR. Radiologically, all cases had well-demarcated solid masses with bone destruction. Although the tumors were basically small round cell tumors, less monomorphic histological patterns such as short spindle cells, a myxoid matrix, and hemangiopericytoma-like pattern were also observed in both biopsy and resected specimens. Two patients achieved a complete response after chemotherapy for Ewing sarcoma and osteosarcoma, respectively. These results demonstrated that the application of CCNB3 immunostaining was useful for differentiating BCOR-CCNB3 from a group of 'Ewing-like sarcomas' and may contribute to the evaluation of treatment strategies for bone sarcomas.

We report a case of lethal hepatorenal insufficiency in a 52-year-old man who received successful simultaneous hepatorenal transplantation from a deceased donor. The patient had undergone live-donor liver transplantation for type-C hepatitis and liver cirrhosis 11 years before he developed graft liver dysfunction due to recurrent viral hepatitis and cirrhosis. At that instance, he also developed end-stage renal dysfunction due to calcineurin inhibitor nephropathy and hepatorenal syndrome. Although he needed three open hemostases and abundant blood transfusion, he was withdrawn from continuous hemodiafiltration on the 55th day and discharged from the hospital on the 272nd day postoperatively. Simultaneous hepatorenal transplantation was reported to be associated with more favorable outcomes of graft function, lower rejection rates, but higher perioperative complication rates compared with liver transplantation alone in patients on hemodialysis. Particularly, close attention should be paid for hemostasis since patients have a hemorrhagic tendency until the recovery of graft liver function.

Pilomyxoid astrocytoma (PMA) is a recently identified type of pilocytic astrocytoma (PA) with shorter progression-free and overall survival, higher rate of recurrence, and higher risk of leptomeningeal spread compared to pilocytic tumors (WHO grade 2 designation). A case is presented here in which intraoperative imprint smears of a pineal region tumor in a 14-year-old girl revealed cytologic monomorphism, elongated cells with bland nuclei embedded in a myxoid background. The tumor cells possessed uniformly round nuclei with a smooth nuclear outline, fine granular chromatin, and small nucleoli. Slender cytoplasmic fibrillary processes and angiocentric arrangement were observed but Rosenthal fibers or eosinophilic granular bodies were absent. A cytologic diagnosis of PMA of the pineal region was suggested by intraoperative smear preparation. Histology and immunohistochemical results confirmed the final diagnosis. This report shows that smear preparation can be trustworthy for the intraoperative diagnosis of PMA, helping to determine the appropriate neurosurgical procedure and therapeutic implications.

Chronic expanding hematoma is defined as a structure with central mass of blood and granulation tissue encapsulated with dense fibrous membrane that slowly grows over a month. We report a case of a 67-year-old man with left adrenal chronic expanding hematoma who underwent surgical resection after 7-year surveillance, presenting natural history of an adrenal chronic expanding hematoma.

Myxopapillary ependymoma (MPE) is a rare variant of conventional ependymoma found predominantly in the sacrococcygeal region in young adults and characterized by its distinct epithelial and stromal components (WHO grade I designation). MPE with extensive osteolysis is extremely uncommon and only up to 40 cases have been documented. A case is presented here in which imprint smears of a sacral tumor in an 18-year-old man revealed complex papillary structures, small loose clusters, or cord-like structures of bland tumor cells embedded in a myxoid or mucinous background. The tumor cells possessed uniformly round nuclei with a smooth nuclear outline, fine granular chromatin, and small nucleoli. Slender cytoplasmic fibrillary processes and occasional intracytoplasmic vacuoles were observed. A cytologic diagnosis of a MPE was suggested and histochemical and immunohistochemical studies were conducted on formalin-fixed, paraffin-embedded material. Immunohistochemically, the tumor cells showed diffuse and strong membranous and cytoplasmic staining for cytokeratin AE1/AE3, glial fibrillary protein, and S-100 protein, but negative for epithelial membrane antigen, pan-neuroendocrine markers (i.e., NSE, chromogranin A, synaptophysin), or brachyury. The proliferative index with MIB-1 was around 10%. The diagnosis of osteolytic MPE was confirmed based on cytopathologic, histopathological, immunohistochemical results, radiologic findings, and the location of the tumor. We demonstrated here the cytopathological features of osteolytic MPE with emphasis on differential diagnostic considerations.

Purpose To assess the incidence of difficulty in complete dissection between the right adrenal gland and the liver at the time of laparoscopic surgery for adrenal tumor and to elucidate its cause histopathologically. Patients and methods Thirty-six patients underwent laparoscopic right adrenalectomy between 2004 and 2011 at our institution. Two reviewers independently assessed difficulty in dissection for the 36 nonedited video records of laparoscopic right adrenalectomy in blinded fashion. Twenty-seven records were evaluable for the judgment of difficulty in dissection between the lower surface of the liver and the right adrenal gland. On the other hand, the gross and microscopic relationship between the right adrenal gland and the surface of the liver was investigated in 32 cadavers. Results Incomplete resection of the adrenal gland was found in 11 of 27 (40.7%) patients. Difficulties in dissection because of adhesions between the liver and the adrenal gland were apparently recognized in 5 of 27 (18.5%) patients. Pathologic assessment for cadavers revealed that capsules between these two organs are partially fused in 10 of 32 (31.3%) cases. Histopathologically, intermingling of parenchymal cells (infiltration through the fibrous capsules) was observed in nine (28.1%) cases. Conclusions The tight adhesion between the lower surface of the liver and the adrenal gland because of intermingling of parenchymal cells of both organs is a major cause of incomplete resection of right adrenalectomy. Surgeons have to keep this fact in mind during right adrenalectomy to avoid unnecessary adverse events.

We report a 40-year-old man with end-stage renal disease due to IgA nephropathy who underwent deceased donor kidney transplantation. The donor was diagnosed to be brain-dead due to cerebral hemorrhage after her second liver transplantation for non-viral liver cirrhosis. Intraoperative 1-hour biopsy of the graft kidney revealed moderate global glomerular sclerosis (22%) and interstitial fibrosis (40%) consistent with underlying nephrosclerosis or calcineurin inhibitor nephrotoxicity. Although hemodialysis was needed until the graft began functioning several days after the kidney transplantation, the postoperative clinical course thereafter was uneventful and the graft functioned well with stable serum creatinine levels around 2.4 mg/dl at 6 monthspos toperatively.

Acute kidney injury (AKI) is a common clinical condition defined as a rapid decline in kidney function. AKI is a global health burden, estimated to cause 2 million deaths annually worldwide. Unlike AKI in the young, which is reversible, AKI in the elderly often leads to end-stage renal disease, and the mechanism that prevents kidney repair in the elderly is unclear. Here we demonstrate that aged but not young mice developed multiple tertiary lymphoid tissues (TLTs) in the kidney after AKI. TLT size was associated with impaired renal function and increased expression of proinflammatory cytokines and homeostatic chemokines, indicating a possible contribution of TLTs to sustained inflammation after injury. Notably, resident fibroblasts from a single lineage diversified into p75 neurotrophin receptor[+] (p75NTR[+]) fibroblasts and homeostatic chemokine–producing fibroblasts inside TLTs, and retinoic acid–producing fibroblasts around TLTs. Deletion of CD4[+] cells as well as late administration of dexamethasone abolished TLTs and improved renal outcomes. Importantly, aged but not young human kidneys also formed TLTs that had cellular and molecular components similar to those of mouse TLTs. Therefore, the inhibition of TLT formation may offer a novel therapeutic strategy for AKI in the elderly., 高齢者腎臓病の新たな病態メカニズムの発見・新規治療戦略の可能性を拓く. 京都大学プレスリリース. 2016-07-22.

Primary hepatic neuroendocrine carcinoma (NEC) is rare, and its origin, clinical features, diagnosis and treatment have not been clarified. Primary mixed NEC and hepatocellular carcinoma (HCC) is even rarer and is divided into either combined type or collision type. We report a patient with the combined type of mixed NEC and HCC. A 72-year-old male was diagnosed with HCC and underwent hepatectomy because of the presence of two tumors in his liver. Histological examination demonstrated that one of the tumors had both NEC and HCC components. The transitional zone was noted in the immunohistological examination, and the tumor was determined to be the combined type of primary mixed NEC and HCC. This was the first description of an HCC component being found in an NEC-dominant area in a primary mixed NEC and HCC tumor. Three weeks after hepatectomy, an abdominal computed tomography scan showed extensive regional and para-aortic lymphadenopathy, and early relapse was suspected in the patient. The patient died 3 months after the operation despite treatment with combination chemotherapy. This report describes an unfavorable case and summarizes all the primary mixed NEC and HCC tumor cases that have been previously reported.

We previously reported that the pVHL‐atypical PKC‐JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C‐C motif) ligand‐2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786‐O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC.

Primary clear cell carcinoma (CLCC) of the lung is an extremely rare disease and is a subtype of large cell carcinoma, according to the World Health Organization (WHO) classification. A case is presented here in which intraoperative squash smears in a 53-year-old man revealed sheet and small clusters or tumor cells with prominent nucleoli and fine granular chromatin. Abundant translucent cytoplasm with occasional cytoplasmic vacuoles and intracytoplasmic eosinophilic inclusions was also identified. A cytopathologic diagnosis of a CLCC was suggested. Further evaluation and immunohistochemical studies were conducted on formalin-fixed, paraffin-embedded material. Nests of slightly acidophilic clear tumor cells with a prominent cellular membrane and an alveolar growth pattern were identified on H&E sections. Immunohistochemically, the tumor cells showed diffuse and strong membranous staining for CK(AE1/AE3), CK7, and CA19-9 but were negative for Napsin A, CK20, CDX2, TTF-1, alpha-fetoprotein, chromogranin A, synaptophysin, CD10, and CD56. The diagnosis of primary CLCC of the lung was confirmed based on cytopathologic, histopathologic, immunohistochemical results, and a detailed systemic examination to exclude a possible extrapulmonary origin. We report here the cytopathological features of CLCC of the lung with an emphasis on differential diagnostic considerations. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.

Primary lymphoepithelioma-like carcinoma (LELC) of the lung is an extremely rare disease that occurs more commonly in Asians, and is composed of undifferentiated carcinoma with prominent lymphoid stroma. LELC is reported to be closely associated with Epstein-Barr virus (EBV) infection. A case is presented here in which bronchial brushing smears in a 70-year-old man, revealed large clusters of neoplastic cells with scant cytoplasm. The nuclei were large, hyperchromatic, of irregular contour and with prominent nucleoli. Also identified were prominent intratumoral lymphoid infiltration and brisk mitotic figures. We detected EBV-coded small RNA in situ hybridization in smears. A cytologic diagnosis of a LELC was suggested. Further evaluation and immunohistochemical studies were conducted on formalin-fixed, paraffin-embedded material. Cords or nests of large neoplastic cells with enlarged nuclei and prominent nucleoli with marked lymphoid infiltration and lymphoid stroma were identified on H&E sections. Immunohistochemically, the tumor cells showed diffuse and strong membranous staining for CK(AE1/AE3), CK5/6, CK34βE12, Napsin A and Bcl-2 but were negative for CK7, CK14, CK20, EMA, TTF-1, chromogranin A, synaptophysin and CD56. The proliferative index with MIB-1 was around 60%, and the p53 positive cells around 20%. The diagnosis of primary LELC of the lung was confirmed based on cytopathologic, histopathologic, immunohistochemical and EBER results, and a detailed systemic examination to exclude possible extrapulmonary (nasopharyngeal) origin. We report the cytopathological features of LELC of the lung and demonstrate here for the first time the positivity of the EBER with RNA-ISH method in smears with emphasis on differential diagnostic considerations.

Neuroglial heterotopias (NGH) are rare congenital head and neck lesions composed of differentiated neuroectodermal tissue and representing developmental heterotopias rather than true neoplasms. The case of a male neonate with respiratory distress and early feeding problems depicting a retropharyngeal space mass which in the intraoperative squash smears revealed glial cells with multiple cytoplasmic processes is reported here. Small clusters of cuboidal epithelial cells with rosette-like ependymal structures and cuboidal cells arranged in sheets or branching folds suggestive of choroid plexus cells were also identified. Through this cytological approach a cytologic diagnosis of a NGH or low-grade astrocytoma was suggested. Further evaluation and immunohistochemical studies were conducted on formalin-fixed, paraffin-embedded material. Glial cells, ependymal structures and choroid plexus were identified on H&E sections. Immunohistochemically, the glial cells showed diffuse and strong cytoplasmic staining for glial fibrillary acidic protein (GFAP) and S-100 protein and focal immunoreactivity for synaptophysin and neurofilament. The proliferative index with MIB-1 was around 4%. The diagnosis of NGH of the retropharyngeal space was confirmed based on the clinical, cytopathologic, histopathology, immunohistochemical results, and the location of the tumor. We demonstrated here for the first time the cytopathological features of NGH of the retropharyngeal space with emphasis on differential diagnostic considerations. Diagn. Cytopathol. 2011. © 2010 Wiley-Liss, Inc.

Warty (condylomatous) carcinoma (WC) is a rare specific variant of invasive squamous cell carcinoma that shows hybrid features of condyloma with invasive cell carcinoma. As compared with conventional squamous cell carcinoma, WC tends to run a less aggressive clinical course. A case is presented here in which squash smears of a penile foreskin tumor in a 65-year-old male revealed small cohesive clusters and sheets of tumor cells in papillary configurations. The neoplastic cells were polygonal to elongated and contained oval nuclei, coarse chromatin pattern, and distinct nucleoli. Nuclear pleomorphism and loss of nuclear polarity were observed. Characteristically, there were also many koilocytes demonstrating mild to moderate nuclear atypia and perinuclear cytoplasmic halos. A cytologic diagnosis of a verruciform penile tumor was suggested. Histologic examination of the tumor showed a hyper-parakeratotic arborizing papillomatous growth with thin fibrovascular cores and the tips were variably rounded or tapered. Obvious koilocytic cytopathic change, nuclear pleomorphism, and focal stromal invasion were observed. Immunohistochemically, the tumor cells showed diffuse and strong membranous staining for cytokeratin (AE1/AE3) while the MIB-1 and p53 immunoreactive cells were confined to the basal areas of the papillae. No lymphovascular invasion was detected in D2-40 or elastic Van-Gieson stains. On the basis of the overall features, we confirmed a final diagnosis of penile WC. We demonstrated here for the first time the cytopathological features of penile WC with emphasis on differential diagnostic considerations. Diagn. Cytopathol. 2010;38:841–845. © 2010 Wiley-Liss, Inc.

The development of an epidermoid cyst in an intrapancreatic accessory spleen is an extremely rare lesion, with only 17 cases being reported in the English literature. All such cases were located in the pancreatic tail, some of which showed carbohydrate antigen 19-9 (CA19-9) immunoreactivity in the lining of the epithelium. A few of them indicated an elevation of the serum CA19-9 level. Here we report three cases of an epidermoid cyst in an intrapancreatic accessory spleen. Cases 1 and 2 were 57-year-old and 70-year-old women, while case 3 was a 37-year-old man. All three cases were asymptomatic. Serum CA19-9 levels showed within normal limits (case 1), slightly elevated (case 2), and clearly elevated (case 3). They underwent a distal pancreatectomy with splenectomy (cases 1 and 2) and without splenectomy (case 3). Grossly, the surgical specimen was a well-demarcated, multiple (case 1) or solitary (cases 2 and 3) cystic mass in the pancreatic tail. A high level of fluid CA 19-9 was detected in case 1. Microscopically, the cystic walls were lined with squamous and cuboidal epithelium, which were surrounded by normal splenic tissue and hyalinized fibrous tissue. The lining squamous epithelium was revealed as nonkeratinizing (Cases 1 and 2) or keratinizing (Case 3). Immunohistochemically, CA19-9 was positive in the monolayer and surface layer of the cuboidal epithelium, but negative for the keratinizing squamous epithelium. As for the histogenesis, it is suggested that the cystic lining of the epithelium may derive from the pancreatic duct which protrudes into the accessory spleen.

BCOR-CCNB3 sarcoma is a recently recognized tumor morphologically and clinically simulating Ewing sarcoma. We herein retrospectively collected clinicopathologic data on BCOR-CCNB3 sarcoma in the Kyoto University Hospital over the last 10 years. Three (20%) bone sarcomas were revealed to be diffusely positive for CCNB3 immunohistochemistry among 15 pediatric cases of undifferentiated sarcoma morphologically similar to Ewing sarcoma, while the other cases showed completely negative staining. The three patients with immunohistochemically CCNB3-positive tumors were all male, aged between 11 and 17, and confirmed to have the BCOR-CCNB3 fusion transcript by RT-PCR. Radiologically, all cases had well-demarcated solid masses with bone destruction. Although the tumors were basically small round cell tumors, less monomorphic histological patterns such as short spindle cells, a myxoid matrix, and hemangiopericytoma-like pattern were also observed in both biopsy and resected specimens. Two patients achieved a complete response after chemotherapy for Ewing sarcoma and osteosarcoma, respectively. These results demonstrated that the application of CCNB3 immunostaining was useful for differentiating BCOR-CCNB3 from a group of 'Ewing-like sarcomas' and may contribute to the evaluation of treatment strategies for bone sarcomas.

Pilomyxoid astrocytoma (PMA) is a recently identified type of pilocytic astrocytoma (PA) with shorter progression-free and overall survival, higher rate of recurrence, and higher risk of leptomeningeal spread compared to pilocytic tumors (WHO grade 2 designation). A case is presented here in which intraoperative imprint smears of a pineal region tumor in a 14-year-old girl revealed cytologic monomorphism, elongated cells with bland nuclei embedded in a myxoid background. The tumor cells possessed uniformly round nuclei with a smooth nuclear outline, fine granular chromatin, and small nucleoli. Slender cytoplasmic fibrillary processes and angiocentric arrangement were observed but Rosenthal fibers or eosinophilic granular bodies were absent. A cytologic diagnosis of PMA of the pineal region was suggested by intraoperative smear preparation. Histology and immunohistochemical results confirmed the final diagnosis. This report shows that smear preparation can be trustworthy for the intraoperative diagnosis of PMA, helping to determine the appropriate neurosurgical procedure and therapeutic implications.

The orphan GPR87 has recently been matched with its ligand LPA, which is a lipid mediator with multiple physiological functions, including cancer cell proliferation. This study aimed to clarify the role of GPR87 in urothelial carcinoma of the bladder. GPR87 expression was assessed in seven human bladder cancer cell lines. A replication-deficient recombinant adenoviral vector expressing shRNA targeting GPR87 (Ad-shGPR87), was constructed. Gene silencing was carried out using Ad-shGPR87. Immunohistochemical analysis was performed for transurethral resection of bladder tumor samples from 71 patients with non-muscle-invasive bladder cancer. We observed GPR87 expression in five of the seven cell lines, and silencing GPR87 gene expression significantly reduced cell viability. GPR87 expression was positive in 38 (54%) of 71 tumors. Ki-67 index was associated with positive GPR87 staining status (p &lt, 0.0001). Patients with GPR87-positive tumors had shorter intravesical recurrence-free survival than those with GPR87-negative tumors (p = 0.010). Multivariate analysis revealed that GPR87 staining status was an independent prognostic parameter for intravesical recurrence (p = 0.041). Progression from non-muscle-invasive to muscle-invasive tumor was more frequently observed in patients with GPR87-positive tumors, although this trend did not reach statistical significance (p = 0.056). These results warrant further prospective studies to clarify the role of GPR87 expression in intravesical recurrence and progression in bladder cancer.

Objective To evaluate the effect of phytotherapeutic agent, Eviprostat, administered after the establishment of nonbacterial prostatitis (NBP) on the stroma-to-epithelium ratio (S/E ratio), inflammatory scores, tissue macrophage infiltration, and cytokines and chemokines levels in prostate tissue and urine. Materials and Methods Ten-month-old male Wistar rats were castrated and exposed to 17-beta-isomer of estradiol for 30 days to induce NBP. Twenty-five NBP rats were divided into 5 groups: (1) NBP (0) rats sacrificed immediately after the establishment of NBP; (2,3) NBP (30)/control (CTL) and NBP (30)/Eviprostat (EVI) rats fed without or with 0.1% Eviprostat under estradiol-free for 30 days, respectively; and (4,5) NBP (60)/CTL and NBP (60)/EVI rats fed without or with 0.1% Eviprostat under estradiol-free for 60 days, respectively. The S/E ratio, inflammatory scores, and the number of macrophage infiltration in the prostate were assessed. Concentrations of cytokines and chemokines in prostatic tissue and urine were measured by enzyme-linked immunosorbent assay. Results The S/E ratio was significantly increased with time until 60 days under estradiol-free condition (P

Purpose: To assess the incidence of difficulty in complete dissection between the right adrenal gland and the liver at the time of laparoscopic surgery for adrenal tumor and to elucidate its cause histopathologically. Patients and Methods: Thirty-six patients underwent laparoscopic right adrenalectomy between 2004 and 2011 at our institution. Two reviewers independently assessed difficulty in dissection for the 36 nonedited video records of laparoscopic right adrenalectomy in blinded fashion. Twenty-seven records were evaluable for the judgment of difficulty in dissection between the lower surface of the liver and the right adrenal gland. On the other hand, the gross and microscopic relationship between the right adrenal gland and the surface of the liver was investigated in 32 cadavers. Results: Incomplete resection of the adrenal gland was found in 11 of 27 (40.7%) patients. Difficulties in dissection because of adhesions between the liver and the adrenal gland were apparently recognized in 5 o...

Myxopapillary ependymoma (MPE) is a rare variant of conventional ependymoma found predominantly in the sacrococcygeal region in young adults and characterized by its distinct epithelial and stromal components (WHO grade I designation). MPE with extensive osteolysis is extremely uncommon and only up to 40 cases have been documented. A case is presented here in which imprint smears of a sacral tumor in an 18-year-old man revealed complex papillary structures, small loose clusters, or cord-like structures of bland tumor cells embedded in a myxoid or mucinous background. The tumor cells possessed uniformly round nuclei with a smooth nuclear outline, fine granular chromatin, and small nucleoli. Slender cytoplasmic fibrillary processes and occasional intracytoplasmic vacuoles were observed. A cytologic diagnosis of a MPE was suggested and histochemical and immunohistochemical studies were conducted on formalin-fixed, paraffin-embedded material. Immunohistochemically, the tumor cells showed diffuse and strong membranous and cytoplasmic staining for cytokeratin AE1/AE3, glial fibrillary protein, and S-100 protein, but negative for epithelial membrane antigen, pan-neuroendocrine markers (i.e., NSE, chromogranin A, synaptophysin), or brachyury. The proliferative index with MIB-1 was around 10%. The diagnosis of osteolytic MPE was confirmed based on cytopathologic, histopathological, immunohistochemical results, radiologic findings, and the location of the tumor. We demonstrated here the cytopathological features of osteolytic MPE with emphasis on differential diagnostic considerations.

e16107Background: Identification of altered metabolic pathways in metastatic renal cell carcinoma (RCC) has the potential to aid in the development of diagnosis and targeted therapies. While altera...

Pulmonary mixed squamous cell and glandular papilloma is an extremely rare neoplasm. This is the first cytological report of such a rare neoplasm. A 59-year-old Japanese man was admitted to the hospital complaining of a persistent cough and bloody sputum. A bronchial endoscopic examination revealed an endobronchial polypoid tumor. Upon bronchial brush cytology by Papanicolaou stain, squamous dysplasia showing mild atypia was suspected. The smears showed moderate cellularity with singly scattered cells or loose clusters of cells, consisting of squamous cells and a few columnar cells. Nuclei of the squamous cells showed mild atypia, but there was no nuclear atypia of the columnar cells. Upon intraoperative pathological examination by frozen section, pulmonary mixed squamous cell and glandular papilloma was suspected. Intraoperative imprint cytology by Ultrafast Papanicolaou stain showed a few differences in comparison with bronchial brush cytology, which were thought to be due to differences in obtaining cytological specimens or the steps prior to the staining. The patient underwent a segmentectomy of the left lung. Histopathological diagnosis confirmed a mixed squamous cell and glandular papilloma. The postoperative course has been uneventful for 5 years after surgery. It was thought that cytology was diagnostically inadequate on its own in the present case. However, mixed squamous cell and glandular papilloma must be considered as another type of pulmonary tumor in cytological preparations, especially in a case showing endobronchial papillary growth by bronchoscopy.

Chordoid meningioma (CM) is characterized by a striking histologic resemblance to chordoma and propensity for aggressive behavior or recurrence (WHO grade II designation). Orbital intraosseous CM is extremely uncommon and only one case report has been documented. A case is presented here in which squash smears of a left orbital tumor in a 53-year-old male revealed small clusters or cord-like structures of bland tumor cells embedded in a myxoid or mucinous background. Whorl-like structures were also identified. The tumor cells possessed uniformly round nuclei with a smooth nuclear outline, fine granular chromatin, and small nucleoli. Occasional intranuclear inclusions, coarse collageneous cytoplasmic filaments were observed. Many spindle-shaped cells with similar nuclear findings were also seen. A cytologic diagnosis of a chordoid meningioma was suggested and histochemical and immunohistochemical studies were conducted on formalin-fixed, paraffin-embedded material. Immunohistochemically, the tumor cells showed diffuse and strong membranous and cytoplasmic staining for vimentin, epithelial membrane antigen (EMA) and faintly reactive with S-100 protein but negative for pan-neuroendocrine markers (i.e., NSE, chromogranin A, synaptophysin), cytokeratin AE1/AE3, smooth muscle actin, D2-40, brachyury or class III beta-tubulin. The proliferative index with MIB-1 was less than 1%. The diagnosis of orbital intraosseous CM was confirmed based on cytopathologic, histopathological, immunohistochemical results, location of the tumor, and the lack connection to the duramater. We demonstrated here for the first time the cytopathological features of intraosseous CM with emphasis on differential diagnostic considerations. Diagn. Cytopathol. 2010; 38:818–821. © 2010 Wiley-Liss, Inc.

In this study, we examine 3CB2 expression, a marker of radial glia, after intracerebral hemorrhage (ICH). Adult male Sprague-Dawley rats received an intracaudate injection of 100 microL autologous whole blood. Animals were sacrificed, and 3CB2 expression was quantified on Western blot. Single and double labeled immunohistochemistry was used to identify which cells express 3CB2. Neurobehavioral examinations (forelimb placing test) were perfomed as an evaluation of function. By Western blot, 3CB2 was strongly expressed at day 3 and expression persisted for at least 1 month. By immunohistochemistry, 3CB2 immunoreactivity was present in large numbers of astrocytes surrounding the hematoma at day 3 after ICH. At 1 month later, 3CB2 immunoreactivity was co-localized with a neuronal marker (TUC-4). Neurobehavioral function in the 1 month after ICH group was significantly improved compared with that of 3 days after ICH. The ICH-induced 3CB2 expression in astrocytes may reflect an early response of these cells to injury, while the delayed expression in neurons might be a part of the adaptative response to injury, perhaps leading to recovery of neurobehavioral function.