No abstract

Isolated high-grade PanIN may present with pancreatic duct stenosis. Therefore, intensive investigations including pancreatic juice cytology will be required for patients with unexplained pancreatic duct stenosis. The abnormal expression of p53 and SMAD4 is infrequent, while GNAS may be mutated in premalignant lesions mainly affecting the main pancreatic duct, similar to KRAS.

Type 2 autoimmune pancreatitis (type 2 AIP) develops in isolation or sometimes in association with ulcerative colitis. Its diagnosis requires the histologic confirmation of granulocytic epithelial lesions (GELs) with no diagnostic biomarker currently available. This study aimed to elucidate the tissue expression of cytokines and their diagnostic value in this condition. In quantitative polymerase chain reaction for multiple cytokines using tissue-derived mRNA, the expression level of interleukin (IL)-8 was markedly higher in type 2 AIP than in type 1 AIP (P<0.001). In immunostaining, IL-8 expression was detected in the ductal/ductular epithelium (11/13; 85%) and infiltrating neutrophils or lymphocytes (12/12; 100%) in type 2 AIP, but was almost entirely negative in type 1 AIP (n=13; both, P<0.001). Although obstructive pancreatitis adjacent to pancreatic cancers (peritumoral pancreatitis) exhibited IL-8 expression in the epithelium (3/12; 25%) and inflammatory cells (10/12; 83%), expression levels were significantly lower than those in type 2 AIP (P<0.001 and 0.020, respectively). The presence of either GELs or IL-8-positive epithelium discriminated type 2 AIP from type 1 AIP or obstructive pancreatitis with 92% sensitivity and 92% to 100% specificity. Furthermore, CD3/IL-8-coexpressing lymphocytes were almost restricted to type 2 AIP. Interestingly, a similar pattern of IL-8 expression was also observed in colonic biopsies of ulcerative colitis. In conclusion, the overexpression of IL-8 may underlie the development of GELs in type 2 AIP, and IL-8 immunostaining or IL-8/CD3 double staining may become an ancillary method for its diagnosis. The similar expression pattern of IL-8 in ulcerative colitis also suggests a pathogenetic link between the 2 conditions.

The bone marrow microenvironment, known as 'hematopoietic stem cell niche,' is essential for the survival and maintenance of hematopoietic stem cells. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases, which eventually result in leukemic transformation (acute myelogenous leukemia with myelodysplasia-related changes, AML-MRC). However, the precise components and functions of the MDS niche remain unclear. Recently, CXCL12-abundant reticular cells were shown to act as a hematopoietic stem cell niche in the murine bone marrow. Using immunohistochemistry, we show here that CXCL12 þ cells were located in the cellular marrow or perivascular area, and were in contact with CD34 þ hematopoietic cells in control and MDS/AML-MRC bone marrow. MDS bone marrow exhibited higher CXCL12 þ cell density than control or AML, not otherwise specified (AML-NOS) bone marrow. Moreover, AML-MRC bone marrow also exhibited higher CXCL12 þ cell density than control bone marrow. CXCL12 þ cell density correlated positively with bone marrow blast ratio in MDS cases. CXCL12 mRNA level was also higher in MDS bone marrow than in control or AML-NOS bone marrow. In vitro coculture analysis revealed that overexpression of CXCL12 in stromal cells upregulated BCL-2 expression of leukemia cell lines. Triple immunostaining revealed that the CD34 þ hematopoietic cells of MDS bone marrow in contact with CXCL12 þ cells were BCL-2-positive and TUNEL-negative. In the bone marrow of MDS cases, CXCL12-high group showed significantly higher Bcl-2 þ /CD34 þ cell ratio and lower apoptotic cell ratio than CXCL12-low group. Moreover, CXCL12-high refractory cytopenia with multilineage dysplasia (RCMD) cases had a greater tendency to progress to refractory anemia with excess blasts (RAEBs) or AML-MRC than CXCL12-low RCMD cases. These results suggest that CXCL12 þ cells constitute the niche for CD34 þ hematopoietic cells, and may be associated with the survival/antiapoptosis of CD34 þ hematopoietic cells and disease progression in MDS. Thus, CXCL12 þ cells may represent a novel MDS therapeutic target.

The present study aimed to compare clinicopathologic features between idiopathic multicentric Castleman's disease (n=22) and IgG4-related disease (n=26). Histology was analyzed using lymph node and lung biopsies. The expression of IL-6 mRNA in tissue was also examined by in situ hybridization and real-time PCR. Patients with idiopathic multicentric Castleman's disease were significantly younger than those with IgG4-related disease (p<0.001). Splenomegaly was observed in only idiopathic multicentric Castleman's disease (p=0.002), while pancreatitis and sialo-dacryoadenitis were restricted to IgG4-related disease (both p<0.001). Serum IgG4 concentrations were commonly elevated at >135 mg/dL in both groups (p=0.270). However, the IgG4/IgG ratio in IgG4-related disease was significantly higher than that in Castleman's disease (p<0.001). Histologically, sheet-like plasmacytosis was highly characteristic of idiopathic multicentric Castleman's disease (p<0.001), while plasmacytic infiltration in IgG4-related disease was always associated with intervening lymphocytes. Similar to laboratory findings, the IgG4/IgG-positive plasma cell ratio, but not the IgG4-positive cell count, was significantly higher in IgG4-related disease (p=0.002). Amyloid-like hyalinized fibrosis was found in 6/8 lung biopsies (75%) of Castleman's disease. The over-expression of IL-6 mRNA was not confirmed in tissue samples of Castleman's disease by either in situ hybridization or quantitative real-time PCR. In conclusion, useful data for a differential diagnosis appear to be age, affected organs, the serum IgG4/IgG ratio, sheet-like plasmacytosis in biopsies, and the IgG4/IgG-positive cell ratio on immunostaining. Since IL-6 was not over-expressed in tissue of idiopathic multicentric Castleman's disease, IL-6 may be produced outside the affected organs, and circulating IL-6 may lead to lymphoplasmacytosis at nodal and extranodal sites.