Intraductal papillary neoplasm of the bile duct with metachronous development in the downstream bile duct after radical resection.

We report a case of intraductal papillary neoplasms of the bile duct (IPNB) that metachronously developed twice in the downstream bile duct after radical resection. The first lesion was located in the left intrahepatic bile duct, the second lesion in the perihilar bile duct, and the third lesion in the distal bile duct. All lesions were IPNBs with associated invasive carcinoma (pancreatobiliary type). The depth of invasion was to the Glisson's capsule in the first lesion, to the subserosa in the second lesion, and to the fibromuscular layer in the third lesion, without lympho-vascular/perineural invasion and lymph-node metastasis. These were resected radically and had no biliary intraepithelial neoplasia and hyperplasia in the surrounding mucosa. In immunohistochemical examination, each lesion showed a different pattern. Although the downstream occurrence suggests intrabiliary dissemination, the mechanism of these metachronous developments may be multicentric. A literature review revealed that most metachronous cholangiocarcinomas have a grossly papillary appearance and tend to arise downstream. Our findings suggest that IPNB may develop metachronously in the residual bile duct after radical surgery, which may assist in early detection.

Type B2 vessels and infiltrative growth patterns b and c are associated with lymphatic invasion in pT1a-lamina propria mucosa esophageal squamous cell carcinoma.

BACKGROUND: Tumor growth pattern correlates with outcomes in patients with esophageal squamous cell carcinoma (ESCC), however, the clinical significance of the tumor growth pattern in pT1a-lamina propria mucosa (LPM) type of ESCC was unclear. This study was conducted to clarify clinicopathological features of tumor growth patterns in pT1a-LPM type ESCC and the relationship between tumor growth patterns and magnifying endoscopic findings. METHODS: Eighty-seven lesions diagnosed as pT1a-LPM ESCC were included. Clinicopathological findings including tumor growth pattern and narrow band imaging with magnifying endoscopy (NBI-ME) in the LPM area were investigated. RESULTS: Eighty-seven lesions were classified as infiltrative growth pattern-a (INF-a): expansive growth (n = 81), INF-b: intermediate growth (n = 4) and INF-c: infiltrative growth pattern (n = 2). Lymphatic invasion was shown in one INF-b and one INF-c lesion. NBI-ME and histopathological images were matched for 30 lesions. The microvascular pattern was classified into types B1 (n = 23) and B2 (n = 7) using the JES classification. All 23 type B1 lesions were classified as INF-a without lymphatic invasion. Type B2 lesions were classified as INF-a (n = 2), INF-b (n = 4) and INF-c (n = 1), and lymphatic invasion was present in two lesions (INF-b and INF-c). The rate of lymphatic invasion was significantly higher in type B2 than type B1 (p = 0.048). CONCLUSIONS: The tumor growth pattern of pT1a-LPM ESCC was mostly INF-a in type B1 patterns. Type B2 patterns are rarely present in pT1a-LPM ESCC, however lymphatic invasion with INF-b or INF-c was frequently observed. Careful observation before endoscopic resection with NBI-ME is important to identify B2 patterns to predict histopathology.

Distinct Clinicopathologic Features and Possible Pathogenesis of Localized ALK-positive Histiocytosis of the Breast.

Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare emerging entity characterized by systemic or localized proliferation of histiocytes harboring ALK rearrangements. Breasts are reportedly affected by ALK-positive histiocytosis. Here, we evaluated 2 localized cases of breast ALK-positive histiocytosis through a comprehensive clinicopathologic, molecular, and genomic analysis to further delineate this entity and better understand its pathogenesis. The cases involved 2 undiagnosed ALK-positive spindle-cell breast lesions. Both cases were Asian women aged 30s to 40s who underwent excisions for asymptomatic breast masses. Macroscopically, both lesions were well-circumscribed, solid masses. Microscopically, both lesions were predominantly composed of fascicles with uniform, bland spindle cells, admixed with epithelioid histiocyte-like cells and lymphoid aggregates. Immunohistochemically, the spindle and epithelioid cells coexpressed ALK and histiocytic markers (eg, CD68, CD163). Genetically, both lesions harbored KIF5B-ALK, confirmed by fluorescence in situ hybridization and polymerase chain reaction-direct sequencing analyses. Combining these results, both cases were successfully diagnosed as ALK-positive histiocytosis. Furthermore, no common or previously annotated somatic alterations were identified by whole-exome sequencing. One case harbored clonal immunoglobulin gene rearrangements according to the polymerase chain reaction-based BIOMED-2 protocol. Therefore, ALK-positive histiocytosis can be accurately diagnosed through a combination of morphologic, immunohistochemical, and molecular analyses. In this entity, breast cases may have distinct clinicopathologic features: Asian women aged 30s to 40s, asymptomatic masses, and predominant spindled morphology. For pathogenesis, ALK rearrangements could be the driver alteration, and a subset of ALK-positive histiocytosis may harbor a lymphoid lineage. These findings can be utilized to improve the diagnosis of ALK-positive histiocytosis and better understand its pathogenesis.

Prognostic impact of preoperative FDG-PET positive lymph nodes in lung cancer.

BACKGROUND: 2-[18F] Fluoro-D-deoxyglucose positron emission tomography (FDG-PET) is an appropriate diagnostic procedure for staging lung cancer. However, accurate evaluation of lymph node (LN) metastases by PET is controversial owing to false-positive/-negative FDG uptake results. The prognostic significance of both false-negative and false-positive LNs on FDG-PET remains to be determined. METHODS: A total of 235 patients with lung cancer were retrospectively analyzed. Maximum standardized uptake values (SUVmax) of the lymph nodes were compared with pathological LN metastases to correlate PET findings with clinicopathological variables and patients' outcomes. RESULTS: When SUVmax ≥ 4 was defined as PET-positive for LN metastasis, sensitivity, specificity, and accuracy were 46.0%, 79.5%, and 72.3%, respectively. False-negative cases and pathological n0 cases were significantly younger, had primary tumors that were smaller or lower SUVmax, and adenocarcinomas compared with false-positive and pathological n+ cases. The difference in survival time between patients with abnormal FDG uptake in the LN and those without was larger than that between pathological LN metastases and no pathological metastases in patients with adenocarcinoma. Multivariate analysis by the Cox proportional hazard model identified smoker, EGFR/ALK negative and LN positive on PET as significant adverse prognostic factors, rather than pathological n-stage. CONCLUSIONS: Abnormal FDG uptake in the LN is an important prognostic factor. Increased glucose metabolism on FDG-PET appears to be a more efficient postoperative prognostic marker than pathological n-stage in patients with lung cancer.

Clinicopathologic Significance of False-Positive Lymph Node Status on FDG-PET in Lung Cancer.

INTRODUCTION: 2-[18F] Fluoro-d-deoxyglucose (FDG) positron emission tomography (PET) is a relevant diagnostic procedure for staging lung cancer. However, accurate evaluation of lymph node metastases by PET is controversial because of false-positive FDG uptake. PATIENTS AND METHODS: A total of 245 patients with lung cancer were retrospectively analyzed. Standardized maximum uptake values (SUVmax) of the primary tumor and lymph nodes were compared to pathologic lymph node metastases to correlate PET findings with clinicopathologic variables and patient outcomes. RESULTS: The SUVmax values of metastatic lymph nodes were significantly higher than those of lymph nodes without metastases (P = .0036). When SUVmax ≥ 4 was defined as PET positive for metastasis, the sensitivity, specificity, and accuracy were 48.1%, 79.8%, and 73.1%, respectively. Multivariate logistic regression analysis showed that age > 75 years, bilateral hilar FDG uptake, and no lymph node swelling were significant factors related to false-positive lymph node metastases. Smoking status, FDG uptake in the primary tumor, and concurrent lung diseases were not significant factors. CONCLUSION: Metastatic lymph nodes show higher FDG uptake than false-positive lymph nodes, and older patient age, bilateral hilar FDG uptake, and no swollen nodes are associated with no metastases. Patients with lymph node metastases have worse survival than those with false-positive FDG-PET findings. However, abnormal FDG uptake in the lymph node is an important prognostic factor.

An unusual reversible color change in a gastric lesion during real-time endoscopy.

During endoscopy, a light purple flat lesion suddenly appeared at the antrum and the lesion disappeared subsequently. This is an unusual reversible color change that is associated with blood flow, and that must be differentiated from neoplasia.

Distribution of lanthanum carbonate in the gastric mucosa confirmed by electron microscopy with a magnified endoscopy: a case report and literature review.

We describe the case of a 70-year-old man with diabetic nephropathy undergoing hemodialysis. Four years following hemodialysis, he started taking lanthanum carbonate 1500 mg/day and lansoprazole 30 mg/day. Nine years following hemodialysis, he underwent screening esophagogastroduodenoscopy, which demonstrated the presence of the whitish cobblestone-like mucosa in the gastric corpus and multiple reddish depressed lesions with annular whitish mucosa in the antrum. With magnified narrow-band imaging endoscopy, a yellowish-white substance was observed in the villous structure, and subepithelial vessels were observed on the yellowish-white substance. Biopsies were taken from the whitish cobblestone-like mucosa of the upper corpus, a reddish depressed part of the antrum. Histologically, aggregates of cells containing amphophilic fine granular material were found in the mucosal interstitium. These cells stained positive for CD68 and were identified as histiocytes. Since he had been taking lanthanum carbonate for 5 years, we considered the possibility of histiocyte-mediated phagocytosis of lanthanum. Digital mapping via scanning electron microscopy with energy-dispersive X-ray spectrometry showed the presence of lanthanum and phosphorus in the interstitium and cytoplasm of histiocytes. The white, rough mucosa in the gastric body appeared 6 months following the commencement of lanthanum administration and still exists 3 years and 5 months after discontinuation of lanthanum.

A case of large cell neuroendocrine carcinoma exhibiting rhabdoid features in the esophagogastric junction.

We report a case of large cell neuroendocrine carcinoma with rhabdoid features in the esophagogastric junction. An 81-year-old man presented to Saku Central Hospital Advanced Care Center with a tumor in the esophagogastric junction. During upper gastrointestinal endoscopy, an ulcerative tumor, measuring 4 × 3 cm in diameter, was observed. Computed tomography revealed lymph node metastasis, but no metastasis to other organs was observed. A thoracoscopic subtotal esophagectomy was performed. Histopathologically, anaplastic large cells exhibited a solid growth pattern with focal and geographic necrosis. Approximately half of the tumor cells exhibited large nuclei with conspicuous nucleoli; an eosinophilic "rhabdoid" cytoplasmic inclusion; and a nucleus displaced eccentrically by the cytoplasmic inclusion body. Immunohistochemically, tumor cells, including rhabdoid cells, were focally positive for pan-cytokeratin and diffusely positive for vimentin and synaptophysin. Additionally, electron microscopy identified dense-core granules in the tumor cells. Therefore, a diagnosis of large cell neuroendocrine carcinoma with rhabdoid features was made. A few cases of esophageal neuroendocrine tumors with rhabdoid features have been reported in the lung and pancreas; however, this is the first report of large cell neuroendocrine carcinoma with rhabdoid features in the esophagogastric junction.

A case of spheroid-type localized lactoferrin amyloidosis in the bronchus.

We report a case of localized bronchial lactoferrin amyloidosis. A 47-year-old man presented with a complaint of persistent dry cough for two months. Chest computed-tomography revealed a calcification shadow of the right main bronchus; hence, a biopsy was performed, showing layered spheroid-type eosinophilic deposits in the bronchial wall. These deposits were positive for Congo red staining, exhibiting apple-green birefringence under polarized light. In addition, an electron microscopic examination demonstrated that this layered structure was formed by very thin cord-like amyloid deposits. By proteomics analysis using liquid chromatography-tandem mass spectrometry and immunohistochemistry, we confirmed that the deposited amyloid was composed of lactoferrin. While lactoferrin is known to be a precursor protein of localized corneal and seminal vesicle amyloidosis, localized lactoferrin amyloidosis of the bronchus has not been reported in the English literature. Our pathological findings suggested that localized lactoferrin amyloidosis may be caused by long-term tissue damage, and the characteristic spheroid-type appearance is thought to be associated with unique, thin cord-like amyloid deposits.

Promoter hypomethylation of SKI in autoimmune pancreatitis.

The relationship between methylation abnormality and autoimmune pancreatitis (AIP)-a representative IgG4-related disease-has not yet been elucidated. We identified SKI might have a significant methylation abnormality in AIP through methylation array analysis using the Illumina Infinium Human Methylation 450K BeadChip array, and investigated the relationship of SKI with AIP clinicopathological features. The methylation rate of SKI was assessed by quantitative SYBR green methylation-specific PCR, and the degree of SKI expression in tissue specimens was assessed by immunohistochemistry in 10 AIP cases, 14 cases of obstructive pancreatitis area in pancreatic ductal adenocarcinoma (PDA) without a history of AIP, and 9 normal pancreas (NP) cases. The SKI methylation ratio was significantly lower in AIP than in PDA and NP. Additionally, the immunohistochemical staining-index (SI) score for SKI was significantly higher in AIP than NP, although there was no significant difference between AIP and PDA. There was a strong negative correlation between SI score and SKI methylation ratio, and between the serum concentrations of IgG4 and the SKI methylation ratio. There was a moderate positive correlation between the serum concentrations of IgG4 and SI. SKI is thought to be an oncogene indicating that SKI hypomethylation and carcinogenesis might be linked to AIP. Furthermore, the correlation between serum concentrations of IgG4 and SKI methylation levels suggest SKI might be involved in the pathogenesis of AIP. However, the role of SKI has not been clearly elucidated. Further studies are needed to understand further the function of SKI.

Inflammatory myofibroblastic tumor of the gallbladder: a case report and literature review.

A 50-year-old man had undergone chemotherapy and radiotherapy for malignant lymphoma 1 year earlier. Follow-up computed tomography revealed a gallbladder polyp. Transabdominal ultrasound demonstrated a 20-mm hypoechoic sessile polyp with basal waist in the gallbladder fundus; the surface was covered with a hyperechoic layer of non-uniform thickness. On contrast-enhanced computed tomography, the polyp showed an early uniform and sustained staining pattern. Magnetic resonance imaging revealed that the polyp had low and slightly high signal intensities on T1- and T2-weighted imaging, respectively. Gallbladder bed resection was performed with the diagnosis of special tumor. Histologically, the polyp comprised a proliferation of myofibroblast-like spindle cells with inflammatory cell infiltration, without muscularis propria or vascular invasion. Most of the polyp surface was covered with necrotic exudate, and part of the normal epithelium remained. Consequently, a diagnosis of inflammatory myofibroblastic tumor was made. The sessile shape with basal waist, epithelium shedding, and surface necrotic exudative matter may represent intraluminal expansive growth such as a subepithelial tumor. A surface with a hyperechoic layer of non-uniform thickness on gallbladder polyp can help in the diagnosis of a tumor with expansive growth directly under the epithelium with stretching/rupture of the epithelium.

A case of gastric-type adenoma with chief cell and parietal cell differentiation surrounded by complete intestinal metaplasia.

A man in his 70s received Helicobacter pylori eradication therapy after endoscopic submucosal dissection (ESD) of the stomach. A small, yellowish, protuberant lesion was later observed on the anterior wall of the lower body of the stomach on surveillance esophagogastroduodenoscopy. Narrow band imaging-magnified endoscopy showed an irregular pit and net-like vascular pattern, with the background mucosa having a light blue crest pattern. A biopsy was performed, which led to a diagnosis of adenoma with a gastric phenotype, so repeat ESD was performed. The freshly resected specimen showed a small, protuberant, flat lesion with a clear margin, and hematoxylin and eosin staining showed mild architectural and nuclear atypia. The shape of the atypical gland was similar to that of a fundic gland. MUC5AC, MUC6, pepsinogen A, and H+/K+ ATPase expressions were positive, and CD10 expression was negative, indicating that this tumor could not only differentiate to mucous neck cells but also to chief cells, parietal cells and foveolar epithelium. Therefore, this 4-mm tumor was diagnosed as a type 0-IIa tubular adenoma with fundic gland differentiation. The background mucosa showed complete intestinal metaplasia. Traditionally, gastric-type adenoma has been defined as the pyloric gland-type, but our case had a fundic gland phenotype. Therefore, a new fundic-gland adenoma subtype should be considered in this case.

Methylation of Tumor Suppressor Genes in Autoimmune Pancreatitis.

OBJECTIVES: Autoimmune pancreatitis (AIP) is a representative IgG4-related and inflammatory disease of unknown etiology. To clarify mechanisms of carcinogenesis resulting from AIP, we focused on methylation abnormalities and KRAS mutations in AIP. METHODS: Six tumor suppressor genes (NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16) that exhibited hypermethylation in pancreatic carcinoma were selected for quantitative SYBR green methylation-specific polymerase chain reaction in 10 AIP specimens, 10 pancreatic adenocarcinoma cases without history of AIP containing carcinoma areas (CAs) and noncarcinoma areas (NCAs), and 11 normal pancreas (NP) samples. KRAS mutation in codons 12, 13, and 61 were also investigated using direct sequencing. RESULTS: Hypermethylation events (≥10%) were identified in NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16 in 1, 2, 2, 0, 2, and 0 CA cases, respectively, but not in these 6 candidate genes in AIP, NCA, and NP. However, the TFPI2 methylation ratio was significantly higher in AIP than NCA and NP. Direct sequencing results for KRAS showed no single-point mutations in AIP. CONCLUSIONS: These are the first studies characterizing methylation abnormalities in AIP. AIP's inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.

Characterization and ontogenetic development of digestive enzymes in Pacific bluefin tuna Thunnus orientalis larvae.

The major digestive enzymes in Pacific bluefin tuna Thunnus orientalis larvae were characterized, and the physiological characteristics of the enzymes during early ontogeny were clarified using biochemical and molecular approaches. The maximum activity of trypsin (Try), chymotrypsin (Ct) and amylase (Amy) was observed at pH 6-11, 8-11 and 6-9, respectively. Maximum activity of Try, Ct and Amy occurred at 50 °C, that of lipase (Lip) was at 60 °C and that of pepsin (Pep) was at 40-50 °C. These pH and thermal profiles were similar to those for other fish species but differed from those previously reported for adult bluefin tuna. Enzyme activity for all enzymes assayed was found to decrease at high temperatures (Try, Ct, Amy and Pep: 50 °C; Lip: 40 °C), which is similar to findings for other fish species with one marked exception-increased Try activity was observed at 40 °C. Lip activity appeared to be dependent on bile salts under our assay conditions, resulting in a significant increase in activity in the presence of bile salts. Ontogenetic changes in pancreatic digestive enzymes showed similar gene expression patterns to those of other fish species, whereas marked temporal increases in enzyme activities were observed at 10-12 days post hatching (dph), coinciding with previously reported timing of the development of the pyloric caeca in bluefin tuna larvae. However, complete development of digestive function was indicated by the high pep gene expression from 19 dph, which contradicts the profile of Pep activity and previously reported development timing of the gastric gland. These findings contribute to the general knowledge of bluefin tuna larval digestive system development.

Identification and gene expression analyses of ghrelin in the stomach of Pacific bluefin tuna (Thunnus orientalis).

Full length cDNA and gene encoding ghrelin precursor and mature ghrelin peptide were identified from the stomach of Pacific bluefin tuna, Thunnus orientalis, which has unique metabolic physiology and high commercial value at fishery markets. Quantitative expression analysis was conducted for the gastric ghrelin and pepsinogen 2 genes during the early stage of somatic growth from the underyearling to yearling fish. The full length cDNA of bluefin tuna ghrelin precursor has a length of 470bp and the deduced precursor is composed of 107 amino acids. The ghrelin gene is 1.9kbp in length and has a 4 exon-3 intron structure. The major form of mature ghrelin in the stomach was an octanoylated 20-amino acid peptide with C-terminal amidation, while overall 12 different forms of ghrelin peptides, including short form of 18-amino acid peptide and seven kinds of acyl modifications were identified. The expression profiles of the gastric ghrelin and pepsinogen 2 genes showed no significant changes related to the early growth stages. The present results suggest that digestive physiology has already been functional in this growth stage of the juvenile bluefin tuna and ghrelin may have a role in the sustained digestive and metabolic activities.

Mucinous cystadenoma of the pancreas with huge mural hematoma.

A 60-year-old woman was referred for evaluation of a cystic mass in the pancreatic body that extended to the tail. Transabdominal ultrasonography demonstrated an oval cystic mass 24 cm in diameter, filled with debris. On the cyst wall there was a wide-based, smooth-surfaced, heterogeneous high-echoic protrusion that was 5 cm in diameter. On CT the protrusion showed internal enhancement. Endoscopic pancreatography showed no intraductal mucin or communication with the cyst. A distal pancreatectomy was performed under the diagnosis of mucinous cystadenocarcinoma. Grossly there was a brownish, hemispherical protrusion into the thin monolocular cyst. The cut surface of the protrusion showed a peripheral yellow-brownish area and an internal wine-colored area. Histopathologically the cyst wall consisted of tall columnar cells without atypical nuclei, ovarian-type stroma beneath the epithelium, and fibrotic tissue with abundant capillary vessels, suggestive of a mucinous cystadenoma. The protrusion was composed of peripheral organized hematoma without a covering epithelium, and internal hemorrhage and many capillary vessels, with no evidence of tumor cell necrosis. These histopathological findings appear to be similar to those of chronic expanding hematoma. The formation of a huge mural hematoma in a mucinous cystic neoplasm can occur as a repair process after the breaking of intrawall vessels.