Oncogenic Determination of a Broad Spectrum of Phenotypes of Hepatocyte-Derived Mouse Liver Tumors.

Activation of the phosphoinositide 3-kinase-AKT, Yes-associated protein (YAP), and MYC pathways is involved in human liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). However, the nature of the interactions among these pathways has remained poorly understood. Herein, we demonstrate the coordination of these pathways during the formation of mouse liver tumors induced by hepatocyte-specific somatic integration of myristoylated AKT, mutant YAP, Myc, or their combinations. Although the introduction of YAP or Myc alone was inefficient in inducing tumors, these proteins accelerated tumorigenesis induced by AKT. The generated tumors demonstrated various histological features: low-grade HCC by AKT/Myc, CC by AKT/YAP, and high-grade HCC by AKT/Myc/YAP. CC induced by AKT/YAP was associated with activation of the Notch pathway. Interestingly, the combination of Myc and YAP generated tumors composed of hepatoblast/stem-like cells expressing mRNA for Afp, Dlk1, Nanog, and Sox2 and occasionally forming immature ducts. Finally, immunohistochemical analysis revealed that human HCC and CC were predominantly associated with phosphorylation of S6 and glycogen synthase kinase-3ß, respectively, and >60% of CC cases were positive for both phosphorylated glycogen synthase kinase--3ß and YAP. Our study suggests that hepatocyte-derived tumors demonstrate a wide spectrum of tumor phenotypes, including HCC, CC, and hepatoblastoma-like, through the combinatory effects of the oncogenic pathways and that the state of the phosphoinositide 3-kinase-AKT pathway is a key determinant of differentiation.

Biopsy-proven case of Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system.

A 75-year-old woman was admitted to our hospital with rapidly deteriorating consciousness disturbance. She had a 7-year history of rheumatoid arthritis (RA), which had been treated with methotrexate (MTX) and prednisolone. Brain T2-weighted MRI showed diffuse high-intensity lesions in the cerebral subcortical and deep white matter, bilateral basal ganglia and thalamus. A cerebrospinal fluid examination revealed elevated protein levels and positive Epstein-Barr virus (EBV) DNA. Human immunodeficiency virus was negative. Brain biopsy showed perivascular lymphocytic infiltration in the parenchyma and meninx with EBV-encoded small RNA (EBER). Since this case did not fulfill the criteria for chronic active EBV infection (CAEBV), she was diagnosed with Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system. High-dose methylprednisolone, acyclovir, ganciclovir and foscarnet were not effective. Although EBV is a causative agent of infectious mononucleosis (IM), lymphomas and nasopharyngeal carcinomas, vasculitic pathology of the central nervous system with EBV reactivation in the elderly is rare. Immunosuppressive drugs such as steroids and MTX are widely used to treat autoimmune disorders, but may exacerbate the reactivation of EBV. This is the first case of biopsy-proven EBV-positive/HIV-negative vasculitis during the treatment of RA with MTX and steroids. This case indicates that EBV-associated vasculitis needs to be considered as a differential diagnosis of CNS vasculitis.

Long-term outcome of amniotic membrane transplantation combined with mitomycin C for conjunctival reconstruction after ocular surface squamous neoplasia excision.

The aim of the study is to evaluate the long-term clinical results of amniotic membrane transplantation (AMT) combined with mitomycin C (MMC) for reconstruction of conjunctival defects created during the excision of ocular surface squamous neoplasia (OSSN). Eight consecutive eyes of seven patients (five males and two females; mean age, 64 ± 19 years) treated by one surgeon (KH) were included in this study. AMT was performed after excision of a mass region, along with 0.04 % MMC treatment for the exposed sclera. The tumor size, histopathological retrieval, AM graft size after tumor excision, recurrence, and postoperative complications were recorded. During a mean postoperative follow-up period of 60.9 ± 14.6 months (range 36-78 months), the ocular surfaces completely re-epithelialized in all cases. The median size of the tumor was 44.4 ± 21.2 mm2 (range 13-67 mm2). The histopathological diagnoses were five cases of squamous cell carcinoma in situ (SCC in situ) and three cases of dysplasia. The median size of the AM graft after tumor excision was 100.8 ± 32.7 mm2 (range 49-151 mm2). A case of recurrent SCC in situ with a preoperative history of using MMC eye drops developed further corneal limbal deficiency and was treated with therapeutic soft contact lenses. A case of dysplasia with a history of large pterygial excision developed symblepharon postoperatively was treated with AMT 6 months after tumor excision. The tumors recurred in two eyes with SCC in situ and were successfully treated with continuous AMT and MMC. No severe complications, such as infections, corneal or scleral thinning, or ulceration developed in all cases. The combination of AMT and MMC is effective for safe reconstruction over the long-term after the excision of OSSN with postoperative careful observation and treatment. In recurrent tumor excision cases, AMT is a suitable technique for repeated ocular surface reconstruction.

[Intrapulmonary Thymoma Suspected of Malignancy].

A 68-year-old woman was found a nodule of the right lower lobe. Malignancy was suspected by positive positron emission tomography-computed tomography finding. Wedge resection was performed to establish the diagnosis, and the pathological diagnosis was a type AB thymoma. At 13 months after operation, no recurrence was observed.

A case of pathology-proven neuromyelitis optica spectrum disorder with Sjögren syndrome manifesting aphasia and apraxia due to a localized cerebral white matter lesion.

A woman with Sjögren syndrome manifesting as aphasia with a left deep cerebral white matter lesion tested positive for anti-aquaporin 4 (AQP4) antibody. Open biopsy of the lesion revealed active demyelination with edematous changes and the preservation of most axons, indicating a non-necrotic demyelinating lesion. Immunostaining for AQP4 was diffusely lost, whereas the loss of glial fibrillary acidic protein immunostaining was limited but with highly degenerated astrocytic foot processes in perivascular areas. These results suggested neuromyelitis optica spectrum disorder (NMOSD) pathology rather than Sjögren-related vasculitis. Only cerebral cortical symptoms with a cerebral white matter lesion could be observed in NMOSDs.

Validity and reproducibility of Ki-67 assessment in gastrointestinal stromal tumors and leiomyosarcomas.

With the aim of standardizing Ki-67 immunohistochemistry, we assessed interobserver and interlaboratory variability of the Ki-67 labeling index and Ki-67 score among eight general pathologists for 24 gastrointestinal stromal tumors (GISTs) and 12 leiomyosarcomas, which were predominantly of the gastrointestinal (GI) tract, mesentery and retroperitoneum, based on a review of a tissue microarrays subjected to immunohistochemistry with antibodies for Ki-67. For Ki-67 immunostaining of mesenchymal tumors of the GI tract, including GISTs, differences were seen in the scores given by regional hospitals. Conversely, for two categories of the Ki-67 labeling index, namely <10% and ≥10%, concordance of the Ki-67 score between microscopic observation and image analysis, and between the observers, was good, but it was not good for the other four categories of the index for <5%, 5-9%, 10-29%, and ≥30%. The concordance of the Ki-67 scores between the observers in two categories was higher using the Ki-67 pre-stained tissue microarrays (TMAs) within each participating institute than that using the Ki-67 stained TMAs between the participating institutes. The reproducibility of a 10% cut-off value for the Ki-67 labeling index to predict the prognosis of GISTs was relatively high, but there is an urgent need to standardize the staining technique.

Combined large cell neuroendocrine carcinoma with giant cell carcinoma of the lungs: a case report.

Combined large cell neuroendocrine carcinoma of the lungs (combined LCNEC) with giant cell carcinoma is extremely rare. A 65-year-old man was found to have an abnormal shadow in his left lung field. Computed tomography revealed a solid, round mass measuring 2.8 × 2.2 cm that was located in the left S9. The patient underwent left lower lobectomy and mediastinal lymph node dissection. Histopathological examination revealed an LCNEC, combined with giant cell carcinoma. The patient received by S-1 (TS-1, an oral fluoropyrimidine) chemotherapy, and he has been disease-free for over 8 months. Combined LCNEC with giant cell carcinoma is an extremely rare tumor with high malignant potential, and thus, multidisciplinary therapy and close follow-up are advised.

Esophageal schwannoma: a case report.

Most tumorous lesions of the esophagus are esophageal cancers. Benign primary tumors of the esophagus are uncommon, and account for approximately 2% of all esophageal tumors. More than 80% of benign esophageal tumors are leiomyomas, with schwannomas being rare. A 55-year-old woman visited our internal medicine department with complaints of palpitations and discomfort during swallowing. A chest computed tomography scan showed a lobulated tumor (75 × 57 × 80 mm) in the upper to middle mediastinum, with homogenous inner opacity, compressing the esophagus. Upper gastrointestinal endoscopy revealed a smooth-surfaced elevated lesion covered with normal mucosa, and a schwannoma was diagnosed based on the biopsy result. The tumor was large. It was thus considered to be difficult to repair the esophagus by direct anastomosis after tumor resection. Therefore, subtotal esophagectomy and esophagogastrostomy in the right thorax were performed. Histopathological examination revealed spindle-shaped cells in a fasciculated and disarrayed architecture and nuclei in a palisading pattern. Immunohistochemical studies revealed S100 protein positivity and the absence of staining for α smooth muscle actin (αSMA), CD34 and CD117, thereby establishing the diagnosis of benign schwannoma. Her postoperative course was uneventful and there has been no evidence of recurrence to date.

[Fungal dacryocystitis with cacosmia after penetrating keratoplasty--taxonomy and identification of pathogenic fungi based on DNA sequence analysis].

CASE: A 76-year-old woman with a history of penetrating keratoplasty had cacosmia associated with dacryocystitis. Two species of yeast-like fungi were isolated from the contents of her lacrimal sac. Each cultured fungus had a unique, distinctive odor. Althogh treated with an oral antifungal agent and washing of the nasolacrimal duct, the cacosmia was not improved. The continuous dacryocystitis with cacosmia was treated by dacryocystectomy. Two yeast-like fungi were again isolated from the contents of the lacrimal sac. Pathological examination confirmed a diagnosis of fungal dacryocystitis based on the fungal hyphae observed on the excised lacrimal sac wall. The cacosmia promptly disappeared. The fungi isolated from the contents of lacrimal sac were identified by DNA sequencing as Wickerhamomyces anamalus (Pichia anomala-Candida pelliculosa) and Galactomyces geotrichum (Geotrichum candidum). CONCLUSION: The cause of cacosmia in the present case was fungal dacryocystitis. Antibiotic eye drops and steroid eye drops for the treatment of penetrating keratoplasty can cause atypical fungal presentation in the inconsistently treated lacrimal system and can induce dacryocystitis. Careful usage and consideration is necessary in the long-term use of antibiotics and steroids following corneal transplantation.

Ectopic thymoma presenting as a giant intrathoracic tumor: a case report.

Ectopic thymoma rarely presents as an intrathoracic tumor. We report a case of ectopic thymoma presenting as a giant right intrathoracic tumor that was treated with resection. The patient was a 50-year-old Japanese woman who presented with the chief complaint of chest pain. Detailed examination revealed a solid tumor measuring 15 × 10 × 8 cm in diameter, with a clear border. The Imaging findings suggested a solitary fibrous tumor, and surgery was performed. At surgery, the tumor was found to be adherent to the diaphragm, mediastinal pleura, and lower lobe of the lung, although it could be dissected with relative ease and was removed. Pathological diagnosis indicated a type B1 tumor with no capsular invasion according to the World Health Organization classification, and a diagnosis of Masaoka stage I thymoma was made. No continuity with the normal thymus tissue was seen, and the thymoma was considered to be derived from ectopic thymic tissue in the pleura.

Role of treatment for solitary pulmonary nodule in breast cancer patients.

BACKGROUND: Metastatic pulmonary tumors secondary to breast cancer detected either before or after surgery are predominantly multiple and bilateral. However, in cases detected to have a solitary pulmonary nodule (SPN), determining whether the lesion represents a primary cancer, metastasis, or a benign pulmonary lesion can be difficult. MATERIALS AND METHODS: Between January 2000 and December 2009, we performed breast cancer surgery on 1,226 patients, of which 49 cases (3.9%) were detected to have pulmonary lesions before or after the surgery. In 14 of these patients, video-assisted thoracoscopic surgery was performed to remove a SPN. RESULT: Pathological examination of the resected specimens in these 14 cases revealed metastatic pulmonary tumor in 8 cases, primary lung cancer in 3 cases, and benign disease in 3 cases. While lobectomy was performed in one of these patients with metastatic pulmonary tumor, the remaining 7 underwent partial resection of the lung. The primary lung cancer was an adenocarcinoma in all 3 patients, and lobectomy plus mediastinal lymph node dissection was performed in these patients. The tumor grading based on pathological diagnosis was T1N0M0, p-Stage 1A in all 3 patients. The prognosis was good in the breast cancer patients in whom the metastatic lung tumor was a SPN. CONCLUSION: Evaluating the immunohistochemical cytokeratin profile and levels of the TTF-1 and GCDFP-15 of the lesion was useful when distinguishing between pulmonary cancer and metastatic pulmonary tumor. In addition, some patients exhibited changes in the biological properties of the metastatic tumor, and delete tumor resection by video-assisted thoracoscopic surgery can be useful for deciding the drug treatment strategy in some cases.

Surgical treatment of intracystic carcinoma of the breast.

BACKGROUND: Intracystic carcinoma of the breast is a type of breast cancer with favorable prognosis where cancer arises from the cystic wall. However, it is a relatively rare disease, and no general consensus has been reached on its definition, including pathogenesis, extramural invasion, and lymph node metastasis. METHODS: Six patients who underwent surgery at the Department of Surgery at Asahikawa Medical University are presented. In each patient, background factors, diagnosis, surgery, pathological diagnosis, and prognosis were investigated. RESULTS: Fine needle aspiration showed class V disease in three patients and class III disease in the other three, and lumpectomy was performed for class III patients. Three patients underwent breast-conserving surgery While extramural invasion was seen in three patients, lymph node metastasis was absent in all patients. CONCLUSION: When it is difficult to diagnose intracystic carcinoma of the breast by fine needle aspiration, active lumpectomy is necessary. Because extramural invasion and lymph node metastasis have been reported, it is necessary to carefully determine the range of excision and rationally perform lymph node dissection, such as sentinel node biopsy.

Alpha-fetoprotein-producing primary lung carcinoma: a case report.

Alpha-fetoprotein (AFP)-producing lung adenocarcinoma is a rare type of lung cancer, with its characteristics not yet fully clarified. We recently encountered a case of this type of lung cancer. The patient was a 69-year-old man who consulted an internist with the chief complaint of epigastric pain. Chest X-ray and CT revealed a lobulated mass measuring 70 mm in diameter in the right lower lung field and a metastasis in the right hilar lymph nodes. Of the tumor markers, the serum AFP was elevated (4620 ng/ml), and the serum carcinoembryonic antigen and carbohydrate antigen 19-9 were also slightly elevated. Transbronchial lung biopsy revealed the diagnosis of lung cancer. Under thoracoscopic assistance, right lower lobectomy + mediastinal lymph node dissection was carried out. Immunostaining showed the tumor cells to be AFP-positive. The tumor was thus diagnosed as an AFP-producing lung adenocarcinoma. The patient followed an uneventful clinical course after the surgery, with serum AFP decreasing to the normal range by about 2 weeks after the surgery. As of this writing, no sign of tumor recurrence has been noted. This case is presented here with a review of the literature.

Use of tissue microarrays and immunohistochemistry to standardize the diagnosis of gastrointestinal stromal tumors.

We assessed the concordance among seven general pathologists with respect to histologic diagnosis and interpretation of c-kit proto-oncogene (KIT) and platelet-derived growth factor receptor alpha (PDGFRA) immunostaining of 36 cases of primary spindle-cell tumor, predominantly of the gastrointestinal tract, mesentery, and retroperitoneum, based on review of a tissue microarray (TMA) subjected to immunohistochemistry with antibodies to KIT/CD117, PDGFRA, vimentin, desmin, smooth muscle action, CD34, and S-100 protein. Tumors included 20 molecularly analyzed gastrointestinal stromal tumors (GISTs), 4 leiomyosarcomas, 4 schwannomas, 4 desmoid-type fibromatoses, and 4 solitary fibrous tumors. The mean overall concordance with original diagnosis for each histologic type was 91.1%, with a mean kappa value of 0.91. With respect to PDGFRA immunostaining, the four GISTs with PDGFRA mutation were interpreted as cytoplasm positive, but the 16 GISTs with c-kit mutation were interpreted as weak or positive. These results indicate that the overall concordance with original diagnosis in mesenchymal tumors with the use of immunohistochemical panels is high, despite the use of TMAs. To some extent, PDGFRA immunophenotyping may be useful in GISTs with PDGFRA mutation, but it was not highly reproducible or specific. Therefore, in KIT-negative or weakly positive GISTs, mutation analysis will be required.

Adenoid cystic carcinoma of the peripheral lung: a case report.

Adenoid cystic carcinoma of the peripheral lung is a rare entity. We recently encountered a patient with adenoid cystic carcinoma. A 75-year-old woman showed a nodular lesion with 10 mm in diameter in the right upper lung field on chest radiography. The diagnosis was unclear, but lung cancer could not be ruled out. Thoracoscopic biopsy was performed, and intraoperative pathological diagnosis revealed the carcinoma of the lung. We enforced upper lobectomy and mediastinal lymph node dissection to the patient. Histopathological examination revealed adenoid cystic carcinoma with a characteristic cribriform structure. Immunohistochemical examination revealed that the tumor cells were positive for thyroid transcription factor 1 (TTF-1), this tumor was diagnosed primary ACC of the lung.

Serological monitoring of progression of alveolar echinococcosis with multiorgan involvement by use of recombinant Em18.

Two cases of alveolar echinococcosis (AE) with multiple-organ involvement (the liver, lungs, and bone) were monitored by imaging and serology for 20 years. Resection of the bone lesion was complete in one case but incomplete in the other case. Albendazole treatment was markedly to moderately effective against hepatic and pulmonary AE lesions in both cases, whereas it had almost no effect against the bone lesion in one case. The results of the serological tests with recombinant Em18 antigen coincided with the clinical findings in each case. An enzyme-linked immunosorbent assay for the detection of immunoglobulin G (IgG) responses, especially IgG4 responses, is expected to be a real-time indicator of the dynamics of active AE.

High incidence of chromosomal abnormalities at 1p36 and 9p21 in early-stage central type squamous cell carcinoma and squamous dysplasia of bronchus detected by autofluorescence bronchoscopy.

Heavy smokers with central type squamous cell carcinoma (SCC) frequently have multiple cancerous lesions in the bronchus. Autofluorescence bronchoscopy (AFB) is useful in the detection of early bronchogenic cancer and dysplastic lesions. We investigated the loss of heterozygosity (LOH) and microsatellite instability (MSI) and expression of four proteins in 13 early stage SCC (early SCC) and 9 squamous dysplasia detected by AFB and 19 cases of surgically resected invasive SCC (invasive SCC). In early SCC and squamous dysplasia, LOH/MSI of chromosome 1p36 was found in 62 and 33%, respectively, and of 9p21 in 54 and 63%, respectively. TAp73 expression of early SCC and squamous dysplasia was lower than that of normal bronchial epithelium, and p16 expression was not detectable in these lesions. These results suggested that the genetic abnormalities had already developed in the early stage of carcinogenesis of SCC, including squamous dysplasia. The AFB system was able to reveal abnormal autofluorescence in these precancerous lesions, including squamous dysplasia.

Management of pelvic lymph nodes by sentinel node navigation surgery in the treatment of invasive cervical cancer.

OBJECTIVE: Diagnosis of lymph node metastasis is a critical issue in the treatment of cervical cancer. Many studies describing sentinel node navigation surgery (SNNS) for examination of node status have been reported in the past decade. In this study, the feasibility of node status diagnosis by SNNS, including intraoperative frozen section diagnosis, in patients with early and advanced cervical cancer was evaluated. PATIENTS AND METHODS: Fifty-eight cervical cancer patients with early and advanced stage disease were enrolled. All patients were treated with backup pelvic lymphadenectomy after SNNS. To detect sentinel lymph nodes (SLNs), radioactive material and/or blue dye were used as tracers. Lymph nodes confirmed as SLNs were immediately sent to pathologists and diagnosed by frozen section intraoperatively. RESULTS: A total of 118 and 16 SLNs were pathologically investigated in early and advanced stage cervical cancer, respectively. The detection rate of SLNs in the early and advanced stages was 94.7% and 66.7%, respectively, whereas the detection rate using 1 or 2 tracers was 62.5% and 90%, respectively. The false-negative rate and negative predictive value was 0% and 100% for all stages. Pathological diagnosis by frozen section was completed within 30 minutes in all cases. CONCLUSIONS: Our data demonstrate that SNNS in cervical cancer is a promising procedure for patients with early stage (up to Ib1) disease, especially patients with small tumor diameter (<2.0 cm). However, SNNS raises several points for discussion before it can be established as a practical clinical procedure or as part of a subsequent radical hysterectomy.

Anti-signal Recognition Particle Antibody-positive Necrotizing Myopathy with Secondary Cardiomyopathy: The First Myocardial Biopsy- and Multimodal Imaging-proven Case.

A 69-year-old Japanese woman was admitted to our hospital with progressive muscle weakness and dysphagia. She was taking pitavastatin for dyslipidemia. Her serum creatine kinase was 6,300 U/L. Pitavastatin was stopped, but her symptoms deteriorated, and cardiac congestion appeared. A muscle biopsy showed necrotizing myopathy (NM), and anti-signal recognition particle (SRP) antibody was positive. 18F-fluorodeoxyglucose-positron emission tomography showed an abnormal uptake, and magnetic resonance imaging showed abnormal gadolinium enhancement in the left ventricular wall. An endomyocardial biopsy revealed inflammatory cardiomyopathy. Steroid, tacrolimus, and intravenous immunoglobulins were effective against the symptoms. This is the first case of biopsy-proven secondary cardiomyopathy due to anti-SRP-positive NM.

HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker.

We have investigated the role of antigen-processing machinery (APM) component defects in HLA class I antigen down-regulation in laryngeal squamous cell carcinoma (SCC) lesions and assessed the clinical significance of these defects. To this end, 63 formalin-fixed, paraffin-embedded tumor lesions were examined for APM component and HLA class I antigen expression by immunohistochemistry. Calnexin, calreticulin, and ERp57 were down-regulated in approximately 25% of the lesions tested, whereas LMP2, TAP1, tapasin, and HLA class I antigens were down-regulated in at least 70% of the lesions tested. LMP2 and tapasin expression was significantly correlated with HLA class I antigen expression suggesting APM component defects as a mechanism underlying HLA class I antigen down-regulation in laryngeal SCC lesions. The expression of most APM components and HLA class I antigens was correlated with the extent of CD8+ T cell infiltration into tumor lesions. Furthermore, LMP2 and HLA class I antigen down-regulation and low CD8+ T cell infiltration were significantly associated with reduced patients' survival. Multivariate analysis identified HLA class I antigen down-regulation as an independent unfavorable prognostic marker. This association is likely to reflect the reduction in the extent of CD8+ T cell infiltration in laryngeal SCC lesions.