Mucin occasionally accumulates intracellularly in colorectal mucinous adenocarcinomas, resulting in signetring cell morphology. In the current practice of pathology, there is no definitive rule on how to report a minor component of signet-ring cells in colorectal mucinous adenocarcinomas. We hypothesized that the absence of signet-ring cell component might have a favorable effect on survival of mucinous adenocarcinoma patients. To assess the biological characteristics of colorectal mucinous adenocarcinoma, we analyzed its clinicopathological features, microsatellite instability status, and survival outcomes and compared them with those of colorectal signet-ring cell carcinoma. A total of 266 consecutive colorectal mucinous adenocarcinoma patients and 65 signet-ring cell carcinoma patients were included. Mucinous adenocarcinomas, by comparison with signet-ring cell carcinomas, were characterized by development at an older age, less frequent vascular invasion and lymph node metastasis, and lower TNM stage at presentation. A total of 21 (22%) of 95 mucinous adenocarcinomas and 12 (19%) of 63 signet-ring cell carcinomas were high-frequency microsatellite instability. Patients with mucinous adenocarcinoma had significantly better survival than those with signet-ring cell carcinoma (Po0.0001) or than those with signet-ring cell carcinoma showing 450% extracellular mucin by volume (Po0.0001). In univariate analysis, absence of signet-ring cell component (P ¼ 0.0197), absence of vascular invasion, decreased invasion depth, no lymph node metastasis, and lower TNM stage had a favorable effect on survival of mucinous adenocarcinoma patients. Absence of vascular invasion, no lymph node metastasis, and lower TNM stage had a favorable effect on survival of signet-ring cell carcinoma patients. Multivariate analysis showed that higher TNM stage and T stage 4 were independent predictors of poor outcome in patients with mucinous adenocarcinoma. Our observations strongly suggest that pathologists should report the percentage of signet-ring cell component in colorectal mucinous adenocarcinomas and mucinous adenocarcinoma has different biologic behavior compared with signet-ring cell carcinoma. Modern Pathology (2008Pathology ( ) 21, 1533Pathology ( -1541 doi:10.1038/modpathol.2008 published online 10 October 2008 Keywords: colorectal mucinous adenocarcinoma; signet-ring cell; survival Although colorectal adenocarcinoma has a relatively better prognosis than other gastrointestinal malignancies with the same stage, specific histological types of colorectal carcinoma such as mucinous adenocarcinoma and signet-ring cell carcinoma have a poor prognosis. 1-3 Colorectal mucinous adenocarcinoma and signet-ring cell carcinoma are adenocarcinomas in which the cancer cells produce excess mucin. A unique pathologic feature of signet-ring cell carcinoma is the presence of signetring cells, which are single tumor cells with intracytoplasmic mucin that displaces their nuclei. The infiltrating cells spread diffusely throughout the bowel wall. I...

Abstract.Identification of critical genes which play pivotal roles in controlling tumor growth and survival will establish the basis for developing therapeutic targets. With the aim of establishing personalized medicine for treatment of solid tumors, we focused on MET amplification in gastric cancer patients, given the extreme sensitivity to c-Met inhibitor in MET amplified gastric cancer cell lines. We tested MET amplification and activation of c-Met in various gastric cancer cell lines and tissue samples from 482 gastric cancer patients who underwent curative surgery. Gastric cancer cell lines with MET amplification by quantitative real-time PCR (qPCR) and FISH predicted sensitivity to PHA-665,752, a selective c-Met kinase inhibitor. Of the 472 patients who had DNA sample available for qPCR analysis, 100 patients (21.2%) had a MET copy number greater than 4.0 copies and demonstrated poorer survival following curative surgery with statistical significance (5-year OS; 50.0 vs. 59.1%; MET amplification (+) vs. MET amplification (-); P=0.0134). These results suggest that the increased MET copy number measured by qPCR plays an important role in determining prognosis in gastric cancer patients. However, the predictive role of MET amplification for treatment response should be further explored in upcoming clinical trials. IntroductionGastric cancer is the leading cause of cancer death worldwide with the incidence of 18.9/100,000 per year (1). The incidence of gastric cancer was estimated to be 934,000 cases, with 56% of the new cases occurring in East Asia (2). Gastric cancer accounts for 20.8% of all cancers in Korea according to the Central Tumor Registry data for 2002 (3). Although overall survival of gastric cancer has been enhanced owing to the application of national fiberoptic esophagogastroduodenoscopy (EGD) screening program in adults aged over 40 years in Korea, a large proportion of patients are still diagnosed at metastatic stage. The median survival time following cytotoxic chemotherapy is still less than 1 year and thus, metastatic gastric cancer remains a therapeutic challenge for medical oncologists. The role of molecularly targeted therapy has not been adequately explored in gastric cancer when compared to other common solid tumors such as non-small cell lung cancer, breast or colorectal cancer.The MET oncogene encodes the receptor tyrosine kinase (RTK) for hepatocyte growth factor (HGF) and controls genetic programs leading to cell growth, invasion and protection from apoptosis (4). Although the definitive role of MET oncogene is yet to be determined in carcinogenesis of gastric cancer, overexpression and amplification of c-Met has been demonstrated in gastric cancer cell lines (5-9). In addition, approximately 10-20% of gastric cancer tissues and up to 40% of the scirrhous histological subtype were shown to harbor increased MET gene copy numbers (6,10,11). Importantly, PHA-665,752, a selective c-Met kinase inhibitor showed significant reduction of established tumor mass in mouse xenografts with GTL...

The great majority of primary central nervous system lymphoma (PCNSL) is known to be of B-lineage, with T-cell PCNSL (T-PCNSL) accounting for <5%. We report an unusually high incidence of T-cell lymphoma among the PCNSLs originated in a large general-care hospital in the metropolitan Seoul area. PCNSLs (n = 42) accrued from April 1995 through June 2001 were reviewed for histologic and clinical features, and immunohistochemical staining was done for CD3, CD20, CD4, CD8, Bcl-6, and CD10. Clonal rearrangements of the TCR-gamma and IgH genes were studied with semi-nested PCR in all seven cases of T-PCNSL and seven of 35 B-cell PCNSL (B-PCNSL). Formalin-fixed, paraffin-embedded specimens were used in all these studies. By immunohistochemical staining and molecular studies, seven cases (16.7%) were diagnosed as T-PCNSL, each displaying clonal rearrangement of the TCR-gamma gene, and 35 (83.3%) as B-PCNSL. Radiologically, T-PCNSL was significantly correlated with the superficial and subcortical lobar location (p<0.001), solitary mass formation (p = 0.001), presence of rim enhancement (p <0.001), and peritumoral edema (p = 0.029). Involvement of cerebrospinal fluid was observed only in B-PCNSL (n = 17) but not in T-PCNSL (p = 0.010). Histologically, T-PCNSL was characterized by a population of mixed predominantly small- and occasionally medium-sized cells (p <0.001), which were loosely scattered without forming a solid mass (p = 0.024), and perivascular infiltration was frequent (p = 0.007), in contrast to predominantly large cells of B-PCNSL, i.e., diffuse large B-cell lymphoma (DLBCL), in which the cells tended to aggregate to form monomorphous sheets (p = 0.024). In T-PCNSL, staining for CD8 was positive in five, including one with coexpression of CD4, and two were negative for CD4 and CD8. Of 24 DLBCLs tested, the pattern of Bcl-6+ tumor cells was diffusely dense, similar to that of the germinal center in nine cases (37.5%), with coexpression of CD10 in three of the nine cases. T-PCNSL accounted for 16.7% of the PCNSLs; thus, in Korea it may not be as rare as previously known. The T-PCNSL presented with certain clinical and pathologic features that were distinct from B-PCNSL and displayed preponderance of CD8 expression. DLBCL of the germinal center B-cell derivation defined by bcl-6 expression comprised 37.5% of DLBCL of the brain.

Background The lack of anti-fibrotic agents targeting intestinal fibrosis is a large unmet need in inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis. Previous studies have found that perinatal tissue (umbilical cord, UC; placenta, PL)-derived mesenchymal stem cells (MSCs) reduce fibrosis in several organs. However, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of MSCs derived from UC and PL (UC/PL-MSCs) on human primary intestinal myofibroblasts (HIMFs). Methods The HIMFs were treated with TGF-β1 and co-cultured with UC/PL-MSCs. We used a small molecular inhibitor CCG-100602 to examine whether serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) are involved in TGF-β1-induced fibrogenic activation in HIMFs. The anti-fibrogenic mechanism of UC/PL-MSCs on HIMFs was analyzed by detecting the expression of RhoA, MRTF-A, and SRF in HIMFs. Results UC/PL-MSCs reduced TGF-β1-induced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs. This anti-fibrogenic effect was more apparent in the UC-MSCs. TGF-β1 stimulation increased the expressions of RhoA, MRTF-A, and SRF in the HIMFs. TGF-β1 induced the synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a MRTF-A/SRF-dependent mechanism. Co-culture with the UC/PL-MSCs downregulated fibrogenesis by inhibition of RhoA, MRTF-A, and SRF expression. Conclusions UC/PL-MSCs suppress TGF-β1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and could be considered as a novel candidate for stem cell-based therapy of intestinal fibrosis.

Although germline mutations of met proto-oncogene on human chromosome 7q31-34 have been known as useful molecular markers of hereditary papillary renal cell carcinoma (RCC), the expression of MET, a product of met proto-oncogene, has not been fully studied in sporadic RCC, along with its clinical significance. We investigated the expression of MET by immunohistochemistry in 182 cases of renal neoplasm encompassing 145 RCC, 25 urothelial carcinomas of renal pelvis, and 12 oncocytomas. MET was diffusely and strongly expressed in 90% of papillary RCC, all collecting duct carcinomas, and 92% of urothelial carcinomas of renal pelvis. On the contrary, clear cell RCC, chromophobe RCC, and oncocytomas were negative or focally positive for MET expression. In clear cell RCC, MET expression was positively correlated with high nuclear grade, presence of infiltrative growth, tumoral necrosis, papillary architecture, sarcomatoid component, tumoral involvement of the renal pelvis or ureter, involvement of the calyx, and lymphatic invasion. In conclusion, diffuse and strong expression of MET in papillary RCC and collecting duct carcinoma might be helpful in discriminating from the other subtypes of RCC with tubular or papillary growth. In case of MET expression observed in clear cell RCC, it might correlate with those clinicopathological parameters implying aggressive behavior.

ObjectiveTo assess the relationship between apparent diffusion coefficient (ADC) values on diffusion-weighted magnetic resonance (MR) imaging and pathologic measures of a tumor using a prostate cancer xenograft model.Materials and MethodsEighteen athymic nude mice with 36 PC-3-induced tumors were sacrificed to obtain specimens immediately after MR imaging in order to compare the findings on MR images with those seen on pathological specimens. Using a high-field small-animal MR scanner, T1- and T2-weighted imaging and DW MR imaging was performed. Tumors were then processed for Hematoxylin and Eosin staining to evaluate tumor cellularity, intratumoral necrosis and immunostaining using antibodies directed against CD31 and vascular endothelial growth factor (VEGF) to determine the levels of microvessel density (MVD). Mean ADC values that were measured on the solid portion within each tumor were compared with tumor volume, cellularity, degree of necrosis, VEGF expression, and MVD in the corresponding section of the pathological specimen.ResultsMean ADC values of the solid portion within the PC-3-induced high-grade tumors were significantly correlated with the degree of intratumoral necrosis (r = 0.63, p < 0.0001) and MVD (r = -0.44, p = 0.008) on pathologic slides. The ADC values were not significantly correlated with tumor cellularity, VEGF expression, or tumor volume in high-grade prostate cancer tissues.ConclusionIn the xenografted prostate cancer model, the ADC values of the solid portion of the tumors are significantly correlated with tumor necrosis and MVD of the pathologic specimens. The ADC values may be utilized as surrogate markers for the noninvasive assessment of tumor necrosis and MVD in high-grade prostate cancer.

LDL plays an important role in atherosclerotic plaque formation and macrophage differentiation. However, there is no report regarding the oxidation degree of LDL and macrophage differentiation. Our study has shown that the differentiation into M1 or M2 macrophages is related to the lipid oxidation level of LDL. Based on the level of lipid peroxidation, LDL is classified into high-oxidized LDL (hi-oxLDL) and low-oxidized LDL (low-oxLDL). The differentiation profiles of macrophages were determined by surface receptor expression and cytokine secretion profiles. Low-oxLDL induced CD86 expression and production of TNF-α and IL-12p40 in THP-1 cells, indicating an M1 macrophage phenotype. Hi-oxLDL induced mannose receptor expression and production of IL-6 and monocyte chemoattractant protein-1, which mostly match the phenotype of M2 macrophages. Further supporting evidence for an M2 polarization by hi-oxLDL was the induction of LOX-1 in THP-1 cells treated with hi-oxLDL but not with low-oxLDL. Similar results were obtained in primary human monocytes. Therefore, our results strongly suggest that the oxidation degree of LDL influences the differentiation of monocytes into M1 or M2 macrophages and determines the inflammatory fate in early stages of atherosclerosis.

BACKGROUNDGastric ‘indefinite for neoplasm/dysplasia’ (IFND) is a borderline lesion that is difficult to diagnose as either regenerative or neoplastic. There is a need for guidance in the identification of a subset of patients, who have an IFND lesion with a higher risk of malignant potential, to enable risk stratification and optimal management.AIMTo determine the clinical and pathologic factors for the accurate diagnosis of gastric IFND lesions.METHODSIn total, 461 gastric lesions diagnosed via biopsy as IFND lesions were retrospectively evaluated. Endoscopic resection (n = 134), surgery (n = 22), and follow-up endoscopic biopsy (n = 305) were performed to confirm the diagnosis. The time interval from initial biopsy to cancer diagnosis was measured, and diagnostic delays were categorized as > 2 wk, > 2 mo, > 6 mo, and > 1 year. The IFND lesions presenting as regenerating atypia (60%) or atypical epithelia (40%) at initial biopsy were adenocarcinomas in 22.6%, adenomas in 8.9%, and gastritis in 68.5% of the cases.RESULTSFour clinical factors [age ≥ 60 years (2.445, 95%CI: 1.305-4.580, P = 0.005), endoscopic size ≥ 10 mm (3.519, 95%CI: 1.891-6.548, P < 0.001), single lesion (5.702, 95%CI: 2.212-14.696, P < 0.001), and spontaneous bleeding (4.056, 95%CI: 1.792-9.180, P = 0.001)], and two pathologic factors [atypical epithelium (25.575, 95%CI: 11.537-56.695, P < 0.001], and repeated IFND diagnosis [6.022, 95%CI: 1.822-19.909, P = 0.003)] were independent risk factors for gastric cancer. With two or more clinical factors, the sensitivity and specificity for carcinoma were 91.3% and 54.9%, respectively. Ten undifferentiated carcinomas were initially diagnosed as IFND. In the subgroup analysis, fold change (5.594, 95%CI: 1.458-21.462, P = 0.012) predicted undifferentiated or invasive carcinoma in the submucosal layers or deeper. Diagnostic delays shorter than 1 year were not associated with worse prognoses. Extremely well-differentiated adenocarcinomas accounted for half of the repeated IFND cases and resulted in low diagnostic accuracy even on retrospective blinded review.CONCLUSIONMore than two clinical and pathologic factors each had significant cut-off values for gastric carcinoma diagnosis; in such cases, endoscopic resection should be considered.