Testicular Rosai-Dorfman disease clonally related to CMML - Case report and literature review.

BACKGROUND: Rosai-Dorfman disease (RDD), a rare form of non-Langerhans cell histiocytosis with heterogenous clinical features, arises from precursor cells that give rise to cells of the histiocytic and monocytic lineages. An association with hematological neoplasms has been reported. Testicular RDD is rarely described, with only 9 reported cases in the literature. Genetic data to assess clonal relationships between RDD and other hematological neoplasms remain scarce. We describe an instance of testicular RDD against a background of chronic myelomonocytic leukemia (CMML), with genetic studies in both neoplasms. CASE PRESENTATION: A 72-year-old patient with a history of CMML sought evaluation of growing bilateral testicular nodules. Solitary testicular lymphoma was suspected; orchidectomy was performed. The diagnosis of testicular RDD was established morphologically and confirmed immunohistochemically. Molecular analysis of testicular lesions and of archived patient bone marrow revealed the KRAS variant c 0.35 G>A / p.G12D in both, suggesting a clonal relationship. CONCLUSION: These observations support classifying RDD as a neoplasm that can be clonally related to myeloid neoplasms.

Clinicopathologic Features and Prognostic Impact of Lymph Node Involvement in Patients With Breast Implant-associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare T-cell lymphoma that arises around breast implants. Most patients manifest with periprosthetic effusion, whereas a subset of patients develops a tumor mass or lymph node involvement (LNI). The aim of this study is to describe the pathologic features of lymph nodes from patients with BI-ALCL and assess the prognostic impact of LNI. Clinical findings and histopathologic features of lymph nodes were assessed in 70 patients with BI-ALCL. LNI was defined by the histologic demonstration of ALCL in lymph nodes. Fourteen (20%) patients with BI-ALCL had LNI, all lymph nodes involved were regional, the most frequent were axillary (93%). The pattern of involvement was sinusoidal in 13 (92.9%) cases, often associated with perifollicular, interfollicular, and diffuse patterns. Two cases had Hodgkin-like patterns. The 5-year overall survival was 75% for patients with LNI and 97.9% for patients without LNI at presentation (P=0.003). Six of 49 (12.2%) of patients with tumor confined by the capsule had LNI, compared with LNI in 8/21 (38%) patients with tumor beyond the capsule. Most patients with LNI achieved complete remission after various therapeutic approaches. Two of 14 (14.3%) patients with LNI died of disease compared with 0/56 (0%) patients without LNI. Twenty percent of patients with BI-ALCL had LNI by lymphoma, most often in a sinusoidal pattern. We conclude that BI-ALCL beyond capsule is associated with a higher risk of LNI. Involvement of lymph nodes was associated with decreased overall survival. Misdiagnosis as Hodgkin lymphoma is a pitfall.

Holes in gastric mucosa in upper gastrointestinal endoscopy.

Gastritis cystica profunda (GCP) is a rare disease that shows multiple cystic gastric glands dispersed within the submucosa of the stomach. GCP occurs most commonly in patients who have undergone previous gastric surgery and presents as subepithelial tumor or a polypoid lesion. Here, we report the case of GCP in a 79-year-old patient who had undergone Billroth II gastric resection. During upper gastrointestinal endoscopy multiple lesions like tiny holes in the mucosa were observed. Endoscopic ultrasound showed cystic structures in the gastric submucosa. Biopsies finally proved the dispersed mucosal glands in the submucosa, which are pathognomonic for GCP. So far, in all published cases, GCP presented as polypoid lesions with no mucosal damage in upper gastrointestinal endoscopy. It is for the first time that GCP has been diagnosed with cystic lesions connected to the gastric lumen with a porus in each of the cysts.

Type I interferon signalling in the intestinal epithelium affects Paneth cells, microbial ecology and epithelial regeneration.

OBJECTIVE: Intestinal epithelial cells (IECs) at the internal/external interface orchestrate the mucosal immune response. Paneth cells secrete antimicrobial peptides and inflammatory mediators, protect from pathogens and shape the commensal microbiota. Prompted by the genetic association of the locus harbouring the type I interferon (IFN) receptor (IFNAR1) with Crohn's disease, and a transcriptional signature for type I IFN signalling in Paneth cells, we studied the function of IFNAR1 in IECs. DESIGN: Type I IFN signalling was studied in mice with conditional deletion of Ifnar1 in IECs. Phenotype was characterised at baseline, and gut microbiota composition was assessed by 16S rDNA ribotyping. The role of IFNAR1 was also investigated in experimental colitis induced by dextran sodium sulfate (DSS) and colitis-associated cancer induced by DSS in conjunction with azoxymethane (AOM). RESULTS: Ifnar1(-/-(IEC)) mice displayed expansion of Paneth cell numbers and epithelial hyperproliferation compared with Ifnar1-sufficient littermates. While Ifnar1(-/-(IEC)) mice did not exhibit spontaneous inflammation or increased severity in DSS colitis compared with Ifnar1(+/+(IEC)) mice, they exhibited an increased tumour burden in the AOM/DSS model. Both hyperproliferation and tumour promotion were dependent on the microbial flora, as the differences between genotypes were marked upon separately housing mice, but disappeared when Ifnar1(-/-(IEC)) and Ifnar1(+/+(IEC)) mice were co-housed. Accordingly, ribotyping revealed marked differences between Ifnar1(-/-(IEC)) and Ifnar1(+/+(IEC)) mice that where diminished upon co-housing. CONCLUSIONS: IFNAR1 in IECs, and Paneth cells in particular, contributes to the regulation of the host-microbiota relationship, with consequences for intestinal regeneration and colitis-associated tumour formation.

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells.

Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box-binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)-mediated increase in Lgr5(+) and Olfm4(+) ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)-related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors.

Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10⁻¹6 and P = 4.1 × 10⁻8, respectively).

Response of human peritoneal mesothelial cells to inflammatory injury is regulated by interleukin-1beta and tumor necrosis factor-alpha.

Peritoneal injury is often associated with alterations of the mesothelium, resulting in peritoneal healing and adhesion formation. We analyzed the effects of pro-inflammatory cytokines on cell morphology and proliferation of human peritoneal mesothelial cells (HPMC). After 48 hours, HPMC formed a confluent layer with cell volumes of 2,662+/-111 fL. Treatment of HPMC with interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) induced mesothelial disintegration and alterations in mesothelial cell morphology, which were associated with an interleukin-1beta-triggered increase in cell volume (3,028+/-118 fL; p<0.05) and exfoliation of cells into the supernatants of cell cultures (p<0.05). Whereas TNF-alpha arrested HPMC in the G0/G1 phase (p<0.05), interleukin-1beta caused an increase of cells into the S phase of the cell cycle. In addition, interleukin-1beta and interferon-gamma exerted a proliferative effect on HPMC. These changes were independent from mesothelial Na+/H+ antiporter-1 expression. Our data indicate that the response of HPMC to inflammatory injury is regulated by interleukin-1beta and TNF-alpha reflecting their putative role in peritoneal wound healing and adhesion formation.

Neonatal type IV glycogen storage disease associated with "null" mutations in glycogen branching enzyme 1.

The fatal neonatal form of type IV glycogen storage disease (GSD IV) was diagnosed on light and electron microscopy and by analysis of GBE1 , the gene encoding glycogen branching enzyme. We report two novel truncating mutations, as well as the first genomic mutational analysis of GBE1 using denaturing high performance liquid chromatography.

Increased expression of CCL20 in human inflammatory bowel disease.

Inflammatory bowel disease (IBD) constituting Crohn's disease (CD) and ulcerative colitis (UC) is related to a dysregulated T cell response. CCL20 attracts memory T lymphocytes and dendritic cells. We asked whether CCL20 expression is altered in IBD. Colonic biopsies were obtained from 114 subjects with IBD, non-IBD colitis, irritable bowel syndrome, and healthy controls. CCL20 and CCR6 mRNA expression was measured by Taqman-PCR, and protein secretion from colonic explant cultures (CEC) and its regulation by TNF-alpha by ELISA. CCL20, CCR6, and Langerin were identified by immunohistochemistry and immunofluorescence. CCL20 mRNA and protein were severalfold increased in involved CD and UC but not in non-IBD colitis. TNF-alpha increased and anti-TNF-alpha decreased CCL20 release in healthy control CEC but not in involved IBD colonic specimens. CCL20 localized to follicle-associated epithelium, and CCR6 to the adjacent mantle zone of lymphoid follicles. Furthermore, abundant numbers of Langerin(+) immature dendritic cells were identified in the subepithelial space of IBD specimens. CCL20 might regulate the attraction of T lymphocytes and dendritic cells in IBD.

Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis.

BACKGROUND/AIMS: Severe alcoholic hepatitis (AH) is associated with high mortality. Tumor necrosis factor-alpha (TNFalpha) has been demonstrated to play an important role in its pathophysiology. METHODS: Twelve patients with biopsy-confirmed AH and a Maddrey discriminant factor >32 were treated with a single infusion of the anti-TNF monoclonal antibody Infliximab at a dose of 5mg/kg body weight. Serial measurements were made for various cytokines using specific enzyme-linked immunoassays (ELISA). In four patients, liver biopsy samples were available pretreatment and on day+28 of therapy. RESULTS: Ten of the 12 patients are alive at a median of 15 (12-20) months. Two patients died within 30 days from septicemia. Serum bilirubin levels, Maddrey score, neutrophil count and C-reactive protein fell significantly within the first month. There was an early, though not significant, decrease in plasma levels of proinflammatory cytokines (interleukins (IL)-1beta, IL-6, IL-8, interferon-gamma), whereas plasma levels of TNFalpha remained near the sensitivity limit of the assay throughout the treatment course. While TNFalpha mRNA expression in the liver did not change, expression of IL-8, a cytokine regulated mainly by TNFalpha, was almost absent on day+28. CONCLUSIONS: Our data suggest that randomized controlled trials of anti-TNF antibody in severe AH are warranted.

Diffuse mesenterial sclerosis: a characteristic feature of chronic small-bowel allograft rejection.

Chronic rejection is the major cause of late intestinal allograft dysfunction. The aim of this study was to analyze in detail the histopathological features of chronic rejection in the ACI-to-Lewis rat model of intestinal transplantation. Chronic rejection was achieved in orthotopic small-bowel allografts (ACI-Lewis) by limited immunosuppression with cyclosporin A (CyA). Isogeneic transplants (ACI-ACI) as well as native bowels (ACI) with and without immunosuppression served as controls. Bowels were removed together with the mesenteries 90 days postoperatively and analyzed using sections stained with hematoxylin and eosin as well as Masson's trichrome. The slides were coded, randomized and analyzed by grading of histological abnormalities. The most striking alterations of the allografts were noticed in the mesenteries exhibiting an extensive infiltration by mononuclear cells accompanied by a progressive diffuse fibrosis with shrinking of the mesenteries. These changes were most pronounced in the perivascular areas of the mesenteric arteriae and venae rectae. Three of five allografts showed vasculitis with myointimal proliferation of the arteriae rectae. Focally, there was spill-over of the inflammatory cells onto the intestinal muscularis propria. The mucosa of the allografts showed mild blunting, lymphocytic infiltration of the crypt epithelium and increased crypt cell apoptoses. The submucosa was unaffected, and there were no detectable abnormalities of the enteric ganglion cells. The present data support the view that chronic rejection of intestinal allografts is characterized by a diffuse sclerosing mesenteritis which may significantly contribute to late graft dysfunction. The present model may be useful to study the pathomechanisms of this inflammatory fibrosing process.