Hiroki Ishigame

Intraductal carcinoma with complex fusion of tubular glands without macroscopic mucus in main pancreatic duct: Dilemma in classification

An 84‐year‐old man, who was being followed up after lobectomy for lung carcinoma, was referred for evaluation of a dilated main pancreatic duct (MPD) from the body to the tail. Endoscopic ultrasonography demonstrated a low‐echo mass occupying the MPD from the body to the tail. Endoscopic retrograde pancreatography showed an occlusion of the MPD in the body, and brush cytology indicated malignant cells. Distal pancreatectomy was performed. Grossly, a white–yellow, irregular‐shaped solid mass without macroscopic mucus filled the lumen of the MPD. Histologically, the mass consisted of a complex fusion of tubular glands with atypical nuclei, which did not have intracellular mucus and oncocytic cytoplasm. The tumor mass showed abrupt transition to the normal epithelium. Immunohistochemically the tumor cells were partially positive for mucin 1 (MUC1) and MUC6, and negative for MUC2, MUC5AC, and lipase. Unfortunately the patient died of brain metastasis from lung carcinoma 15 months later. A review of reported cases of intraductal tubular tumors of the pancreas showed that the present case involved characteristics and immunohistochemical staining pattern similar to those of intraductal tubular carcinoma, although it might not be described as a typical intraductal tubular carcinoma under the existing Japanese rules.

Small Cell Carcinoma of the Gallbladder Combined with Adenocarcinoma

A rare case of small cell carcinoma (SCC) of the gallbladder combined with adenocarcinoma is reported. The patient was a 70‐year‐old Japanese man, who died of the disease shortly after the onset of symptoms. Autopsy disclosed a small tumor (1.0 cm in longest diameter) in the fundus of the gallbladder, with widespread metastasis. Histochemically, the tumor cells showed negative reactions for argyrophilic and argentaffin stainings, a weak immunohistochemical reaction only for neuron‐specific enolase, and negative reactions for all of the other neurosecretory markers used, including neurofilament, chromogranin, somatostatin, gastrin and leu‐7. However, electron microscopic examination revealed a few typical neurosecretory granules (NSG) in the cytoplasm of some tumor cells. We suggest that: 1. The presence of NSG in the cytoplasm of tumor cells is the most reliable diagnostic criterion for SCC. 2. SCC, at least the combined type, arises from a multipotential stem cell.

Distribution of Intraductal Lesions in Small Invasive Ductal Carcinoma of the Pancreas

Aims: To investigate the distribution of intraductal lesions in small invasive ductal carcinoma (IDC) of the pancreas. Methods: In 21 cases with IDCs microscopically ≤20 mm in diameter, the intraductal lesions around a mass were studied histologically and mapped according to the pancreatic intraepithelial neoplasia (PanIN) classification. Results: PanIN-3, PanIN-2, PanIN-1B and PanIN-1A were found in 17, 10, 20 and 21 of 21 cases, respectively, and were divided into lesions in adjacent and distal areas, respectively defined as within and beyond 10 mm from the mass as follows: 100% (17/17), 100% (10/10), 95.0% (19/20) and 90.5% (19/21) in the former, while 23.5% (4/17), 50.0% (5/10), 90.0% (18/20) and 95.2% (20/21) in the latter. PanIN-3 lesions were predominantly found in the area adjacent to the mass. In some cases, significant PanIN-3 appeared to show a consecutive geographic extension around the mass via the main pancreatic duct (MPD). The distance of PanIN-3 spread was within 25 (mean 10.5) mm from the mass edge. PanIN-2 lesions were found in the area adjacent to the mass and discontinuous with the mass or PanIN-3 lesions. PanIN-1B and PanIN-1A tended mainly to exist sporadically throughout the entire pancreas. In the MPD, PanIN-3 was found in 14 (82.4%) of 17 cases and in 36 (32.1%) of 112 lesions, which was most frequent in intraductal lesions. Conclusions: PanIN-3 lesions might be an intraductal extension of the main tumor. The resection margin of 25 mm, at least longer than 11 mm, from the mass edge will be necessary.

Masking of anionic sites by deposits in lamina rara externa in immune complex nephritis in rats.

SummaryAlterations in glomerular basement membrane (GBM) anionic sites associated with immune deposits (ID) were observed using polyethyleneimine (PEI) as a cationic probe in serum sickness nephritis induced by egg albumin (EA). The anionic sites were fewer in number than in other GBM segments and were irregular in distribution in most, but not all, of the segments of the GBM with ID on the epithelial side of the lamina densa (LD). The disappearance of anionic sites was obvious in areas where the internal aspects of the lamina rara externa (LRE) of the GBM were occupied by ID, even if the ID were very small. In contrast, the disappearance of anionic sites was not evident, even though no change in anionic sites was found in some areas, where the ID had departed from the internal aspects of the LRE and a pale band was seen between the ID and the LD. Further, PEI aggregates, showing localization of anionic sites, were seen within the low density ID, but no PEI aggregates were seen within the high density ID. The results suggest that: 1) whether or not ID induce the disappearance of anionic sites is independent of the size of the ID, but is dependent on the density of and the place occupied by the ID, and 2) the ID seem to induce the disappearance of anionic sites by masking rather than destroying them.

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. AIPs inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.

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.

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.