Branch-duct Intraductal Papillary Mucinous Neoplasm with Rapidly Developing Intracystic Xanthogranulomatous Nodules.

We herein report a case of a branch-duct intraductal papillary mucinous neoplasm (IPMN) with rapidly developing intracystic xanthogranulomatous nodules. A unilocular cystic lesion without a mural nodule was found in the pancreatic tail of a 69-year-old man. Ten months later, multiple mural nodules emerged unexpectedly within the cyst, and the patient underwent distal pancreatectomy. Based on immunohistochemical studies and a molecular analysis, we diagnosed him with branch-duct IPMN of the gastric immunophenotype. Fragility of the pancreatic duct mucosa and consequent exposure of the wall to pancreatic juice might have caused marked granulation nodule formation in the cyst lumen.

Imprint cytology of clear cell sarcoma-like tumor of the gastrointestinal tract in the small intestine: A case report.

Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is an extremely rare malignant neoplasm in the digestive tract. Its cytomorphologic features have never previously been reported. Here, we describe a case of CCSLGT, including its cytologic examination findings. A 47-year-old woman presented with a mass in the small intestine, which was resected and sent for imprint cytology. Imprint smears revealed tumor cells with light eosinophilic or clear cytoplasm in a necrotic background. Many of the tumor cells were arranged in a perivascular growth with a pseudopapillary formation, and there were some non-neoplastic osteoclast-like giant cells. Histological examination revealed solid nests and a pseudopapillary pattern of the tumor cells with clear or pale eosinophilic cytoplasm and large nuclei with small nucleoli. Immunohistochemistry showed positive for vimentin, S-100, and SOX-10, and negative for SMA, c-KIT, cytokeratin, HMB-45, and MelanA. The EWSR1 gene split signal was detected by reverse transcriptase fluorescence in situ hybridization, and EWSR1-CREB1 gene fusion was indicated by reverse transcriptase polymerase chain reaction analysis. From these findings, we diagnosed the tumor as CCSLGT. To best of our knowledge, this is the first description of the imprint cytology features of CCSLGT.

ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma.

BACKGROUND/AIM: Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignant tumours, so the identification of molecular targets for ICC is an important issue. Zinc finger E-box binding homeobox 1 (ZEB1) is a key inducer of epithelial-mesenchymal transition (EMT). The aim of the present study was to clarify the clinical significance of ZEB1 in ICC and the associations between ZEB1 expression and EMT-related proteins. METHODS: We immunohistochemically examined the expression of EMT-related proteins, namely ZEB1, vimentin and E-cadherin, in ICC specimens from 102 patients. The clinicopathological and prognostic values of these markers were evaluated. RESULTS: ZEB1 and vimentin were expressed in 46.1% and 43.1% of tumours, respectively, and E-cadherin expression was lost in 44.1% of tumours. ZEB1 expression showed a significant inverse correlation with E-cadherin expression (p=0.004) and a positive correlation with vimentin expression (p=0.022). Altered expression of ZEB1 was associated with aggressive tumour characteristics, including advanced tumour stage (p=0.037), undifferentiated-type histology (p=0.017), lymph node metastasis (p=0.024) and portal vein invasion (p=0.037). Moreover, overall survival rates were significantly lower for patients with high ZEB1 expression than for patients with low ZEB1 expression (p=0.027). Kaplan-Meier analysis also identified E-cadherin expression (p=0.041) and vimentin expression (p=0.049) as prognostic indicators for overall survival. CONCLUSIONS: ZEB1 expression is associated with tumour progression and poor prognosis in patients with ICC through positive correlations with vimentin and negative correlations with E-cadherin. ZEB1 expression is associated with a poor prognosis and might be an attractive target for the treatment of ICC.

Importance of luminal membrane mesothelin expression in intraductal papillary mucinous neoplasms.

The present study demonstrated that luminal membrane mesothelin expression is a reliable prognostic factor in gastric cancer. Intraductal papillary mucinous neoplasms (IPMNs) often exhibit a spectrum of dysplasia, ranging between adenoma and carcinoma. Therefore, an immunohistochemical analysis of mesothelin expression in IPMN was performed in the present study, focusing on the localization of mesothelin. IPMNs were classified into two groups, IPMNs associated with invasive carcinoma and low-high (L-H) grade dysplasias. The tumors were classified as mesothelin-positive or -negative and in the mesothelin-positive cases, the localization of mesothelin was evaluated as luminal membrane- or cytoplasmic-positive. Among the 37 IPMNs, mesothelin expression was observed in 21 samples (56.8%), including 46.2% (12 out of 26) of the L-H dysplasia and 81.8% (9 out of 11) of the invasive carcinoma samples (P=0.071). Luminal membrane localization was observed in 10 samples (27%), including 15.4% (4/26) of the L-H dysplasia samples and 54.5% (6 out of 11) of the invasive carcinoma samples (P=0.022). Six patients experienced post-operative recurrence, with five of the recurrent tumors exhibiting mesothelin expression and all six exhibiting luminal membrane localization. It was concluded that immunohistochemical examinations for mesothelin expression and localization are clinically useful for prognostic assessments and decision making regarding further treatment subsequent to surgical procedures in patients with IPMN.

Distinctive histopathologic findings of pancreatic hamartomas suggesting their "hamartomatous" nature: a study of 9 cases.

Pancreatic hamartoma is a rare tumor, and its characteristic histopathologic features have not yet been fully evaluated. In this study, we collected 9 cases of pancreatic hamartoma to elucidate distinctive histopathologic features that can serve to establish this tumor as a clear disease entity and thus formulate useful histopathologic criteria for this tumor. The cases comprised 4 men and 5 women with a mean age of 62.7 years. The average tumor diameter was 3.3 cm. All patients underwent surgical treatment, and none showed any recurrence postoperatively. Macroscopically, pancreatic hamartomas were well-demarcated tumors with a solid or solid and cystic appearance. Microscopically, these tumors comprised mature acini and small-sized to medium-sized ducts showing a distorted architecture with various amounts of fibrous stroma. Strikingly, the tumors consistently lacked concentric elastic fibers in their duct walls, peripheral nerves, and well-formed islets of Langerhans, all of which exist in both the normal and atrophic pancreas. Immunohistochemically, scattered chromogranin A-positive neuroendocrine cells were observed in the acinar and ductal components. Ductal components were positive for S-100 protein. Spindle-shaped stromal cells expressed CD34 and/or c-kit. These histopathologic features were distinct from those of 5 cases of pancreatic ductal adenocarcinoma, 3 cases of type 1 autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis), 3 cases of alcoholic chronic pancreatitis, and 5 cases of normal pancreas. In conclusion, pancreatic hamartomas share some distinctive histopathologic features and clinical outcomes (neither recurrence nor metastasis) that allow them to be interpreted as malformative lesions. The term "hamartoma" is appropriate for these unique lesions.

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.

Co-expression of mesothelin and CA125 correlates with unfavorable patient outcome in pancreatic ductal adenocarcinoma.

OBJECTIVES: Recent studies have shown that the high affinity of mesothelin-CA125 interaction might cause intracavitary tumor metastasis. We examined the clinicopathologic significance and prognostic implication of mesothelin and CA125 expression in pancreatic ductal adenocarcinoma. METHODS: Tissue samples from 66 pancreatic ductal adenocarcinomas were immunohistochemically examined. Proportion and intensity of constituent tumor cells with mesothelin and CA125 expression were analyzed and classified as high-level expression, defined as expression by more than 50% of tumor cells and/or moderate to strong staining, or low-level expression otherwise. RESULTS: A high level of mesothelin was correlated with a higher histological grade (P = 0.049) and the level of blood vessel permeation (P = 0.0006), whereas a high level of CA125 expression was correlated with a higher recurrence rate (P = 0.015). The expression of mesothelin was strongly correlated with that of CA125 (P = 0.0041). Co-expression of mesothelin and CA125 were associated with an unfavorable patient outcome (P = 0.0062). CONCLUSIONS: This is the first report showing that co-expression of mesothelin and CA125 were in pancreatic ductal adenocarcinoma, and such co-expression is associated with a poor prognosis. Our finding suggests that co-expression of these two factors plays a significant role in the acquisition of aggressive clinical behavior.

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.

Inferior mesenteric venous thrombosis that required operations: report of two cases.

Inferior mesenteric venous thrombosis (IMVT) is a very rare disease of colon ischemia. We experienced two cases of IMVT that required operations. The first patient was a 74-year-old male, who was admitted to our hospital because of melena and diarrhea. He was diagnosed with IMVT by angiography. As no improvement was seen after the conservative therapy for a month, left colectomy and transverse colostomy were performed. There was a small ulcer in the resected colon mucosa. The findings of histopathological examination revealed that mild and repeated ischemia of the colon had been caused. The second patient was a 70-year-old male, who was admitted to our hospital with the chief complaint of constipation, lower abdominal pain and nausea. He was diagnosed as IMVT by angiography. As no improvement was seen after the conservative therapy for a month, an operation was performed. The operative findings confirmed severe swelling of mesenteric fatty tissue and vascular ectasia of mesocolon. Left colectomy and transverse colostomy were performed. Histopathological examination of surgical specimens disclosed the multiple thrombi and almost complete occlusion of the inferior mesenteric vein, the invasion of lipid-filled macrophages as mesenteric panniculitis, and ischemic change in the sigmoid colon mucosa.

Differences in tumor core distribution between palpable and nonpalpable prostate tumors in patients diagnosed using extensive transperineal ultrasound-guided template prostate biopsy.

BACKGROUND: The authors performed extensive transperineal ultrasound-guided template prostate biopsies to investigate carcinoma core distribution. METHODS: Between August 2000 and May 2004, 371 men underwent template biopsies. Three hundred twelve patients had not undergone a previous biopsy (first group) and 59 had undergone previous transrectal sextant biopsies (repeat group). Of the 312 patients in the first group, 236 had normal digital rectal examination (DRE) findings (DRE- first group) and 76 patients had an abnormal DRE (DRE+ first group). A mean of 20.1 biopsy cores (range, 9-38 cores) was taken from the entire prostate. The region > 2.0 cm from the rectal face of the prostate was defined as the anterior region and the remaining area was defined as the posterior region. RESULTS: In the DRE- first group, the carcinoma core rate (number of tumor cores/number of biopsy cores) in the anterior region (7.2%) did not differ from that of the posterior region (7.3%) (P = 0.9635). However, in the DRE+ first group, the carcinoma core rate in the posterior region (22.0%) was found to be higher than in the anterior region (13.2%) (P < 0.0001). In the repeat group, the carcinoma core rate in the posterior region (3.1%) was significantly (P = 0.0008) lower than that exhibited in the anterior region (7.2%). CONCLUSIONS: The results of the current study suggest that nonpalpable prostate carcinoma is distributed equally within the entire prostate, although palpable carcinoma is distributed mainly in the posterior region and many of the tumor foci in the anterior region may be missed by a transrectal sextant biopsy. The examination of radical prostatectomy specimens is required to prove these results.

Difference of cancer core distribution between first and repeat biopsy: In patients diagnosed by extensive transperineal ultrasound guided template prostate biopsy.

BACKGROUND: We performed extensive transperineal ultrasound guided template prostate biopsy and evaluated cancer core distribution. METHODS: From August 2000 to May 2002, 113 men with prostate specific antigen levels between 4.0 and 10.0 ng/ml underwent template biopsy. Eighty-six had no previous biopsy (first group) and 27 had previous transrectal sextant biopsies (repeat group). A mean of 18.4 biopsy cores were taken. We defined the region over 2 cm from the rectal face of the prostate as the anterior region and the other as the posterior. RESULTS: Cancer was detected in 49 of 113 (43%) men. Forty-two were in the first group and seven in the repeat group. In the first group, the cancer core rate (cancer core number/biopsy core number) in the anterior region (7.0%) had no difference from that in the posterior region (8.6%) (P = 0.7111). But in the repeat group, the cancer core rate in the anterior region (4.6%) was higher than in the posterior (1.5%) (P < 0.0001). CONCLUSIONS: These results suggest that transrectal sextant biopsies miss more cancers in the anterior region than in the posterior. We believe template technique has an advantage to be able to detect cancer equally in the anterior and posterior.

Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas.

Intraductal papillary-mucinous tumors (IPMTs) of the pancreas are characterized by dilated pancreatic ducts and ductules that are lined by tall columnar mucin-producing neoplastic epithelial cells. IPMTs have been suggested to be distinct neoplasms with a less aggressive phenotype than that of conventional ductal adenocarcinomas of the pancreas. Molecular mechanisms underlying tumorigenesis of IPMTs are beginning to be characterized. Allelic losses have frequently been detected at 9p, 17p, and 18q, suggesting that inactivation of tumor suppressor genes at these loci play a role in tumorigenesis of IPMTs. Using immunohistochemistry, we analyzed 38 IPMTs, including 9 hyperplasia, 16 adenoma, and 13 carcinoma tissues, for expression of p53, Ki-67, p16, and SMAD4. Nuclear p53 expression was observed in 5 (38%) of 13 carcinoma tissues but not in hyperplasia or adenoma tissues. Partial loss of p16 expression was observed in 9 (56%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. Partial loss of p16 expression was observed even in adenomas with mild atypia. Partial loss of SMAD4 expression was observed in 6 (38%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. The SMAD4 negative index was significantly higher in invasive carcinomas than in non-invasive carcinomas. Our results suggest that loss of p16 is an early event and p53 alteration is a late event during the progression of IPMTs. SMAD4 inactivation appears to be an early event but also involved in invasive tumor growth. Our results suggest that these alterations accumulate during the progression of IPMTs, reflecting results of analysis of allelic losses that showed a stepwise accumulation of genetic changes during progression.