A Case of Langerhans Cell Histiocytosis With Multifocal, Single-System GI Tract Involvement and Literature Review.

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder, characterized by the pathologic clonal proliferation and accumulation of immature Langerhans cells within organs. Multiple organ systems can be affected, resulting in a spectrum of clinical manifestations. Isolated gastrointestinal involvement in LCH is rare and usually presents in childhood as a multisystem disease and usually has poor outcomes. We describe a 20-year-old Hispanic female with multifocal, single-system gastrointestinal LCH. Initially diagnosed from a CD1a, S100, and CD207 (Langerin) positive appendix tissue after an appendectomy and confirmed multifocal with an endoscopy. She had a full clinical and endoscopic resolution of disease with cytarabine therapy.

Do mast cells play a pathogenetic role in neurofibromatosis type 1 and ulcerative colitis?

Concurrent association of neurofibromatosis type I and ulcerative colitis has been reported in one clinical case (Tavakkoli et al., 2009). Although this association may represent a casual finding, a common pathophysiology is postulated. Mast cells have been implicated in the pathogenesis of both neurofibromatosis type 1 and ulcerative colitis (He, 2004; Yoshida et al., 2010). Mast cells are typically present in neurofibromas microenvironment where they appear to contribute to tumor initiation, progression and angiogenesis (Staser et al., 2010, 2013). Moreover, interaction of mast cells with nerves throughout the gastrointestinal tract has been correlated with progression and maintenance of ulcerative colitis (Stoyanova and Gulubova, 2002). We describe a 14 year-old male with history of neurofibromatosis type 1 and new onset of ulcerative colitis diagnosed on clinical and histological findings. On gross examination the entire colonic mucosa appeared edematous showing a peculiar granular pattern, with focal erythema, shallow ulcers and multiple sessile polyps. Hematoxylin and eosin stained tissue biopsies from the colonic mucosa showed chronic inflammatory bowel disease, severe activity, consistent with chronic ulcerative colitis. Immunohistochemistry stain of the intestinal lesions revealed high expression of Neuron Specific Enolase (NSE) and S100 highlighting the presence of a Schwann cell component. In addition, c-kit/CD117 positive stain indicated a marked increase of mast cells in the lamina propria. This pattern of cellularity in the lamina propria showing increased mast cells and augmented Schwann cell component was absent in the colonic mucosa of a normal control or a patient with ulcerative colitis alone. Our observation supports the evidence of a pathogenetic role of the mast cell in ulcerative colitis associated with neurofibromatosis type 1. Further investigations are warranted to confirm the significance of this correlation as it may impact therapeutic approaches of these pathologies.

Mutant neurogenin-3 in congenital malabsorptive diarrhea.

BACKGROUND: Neurogenin-3 (NEUROG3) is expressed in endocrine progenitor cells and is required for endocrine-cell development in the pancreas and intestine. The NEUROG3 gene (NEUROG3) is therefore a candidate for the cause of a newly discovered autosomal recessive disorder characterized by generalized malabsorption and a paucity of enteroendocrine cells. METHODS: We screened genomic DNA from three unrelated patients with sparse enteroendocrine cells for mutations of NEUROG3. We then tested the ability of the observed mutations to alter NEUROG3 function, using in vitro and in vivo assays. RESULTS: The patients had few intestinal enteroendocrine cells positive for chromogranin A, but they had normal numbers of Paneth's, goblet, and absorptive cells. We identified two homozygous mutations in NEUROG3, both of which rendered the NEUROG3 protein unable to activate NEUROD1, a downstream target of NEUROG3, and compromised the ability of NEUROG3 to bind to an E-box element in the NEUROD1 promoter. The injection of wild-type but not mutant NEUROG3 messenger RNA into xenopus embryos induced NEUROD1 expression. CONCLUSIONS: A newly discovered disorder characterized by malabsorptive diarrhea and a lack of intestinal enteroendocrine cells is caused by loss-of-function mutations in NEUROG3.

Role of macrophages and stellate cells in the pathogenesis of veno-occlusive disease: an electron microscopic case study.

Veno-occlusive disease (VOD) is an entity described as a triad of pathologic findings including ascites, tender hepatomegaly, and elevated liver enzymes. The prognosis of patients suffering from VOD is highly variable, ranging from slow resolution to the need for liver transplant. The histopathology of VOD has been described by light and electron microscopy. However, the pathogenesis of VOD is still largely unclear. In the present case study, we report the significant findings in a case of pediatric VOD following chemotherapy. We studied the liver biopsy by light and electron microscopes. In addition to previous reported findings of occlusion of the central vein with endothelial cell damage, proliferation and activation of stellate cells, and collagen deposition in the central vein wall, there were prominent activated macrophages within the lumen and wall of central veins. The following mechanism of VOD was proposed: Tissue damage activates monocytes through monocyte chemoattractant protein-1. The secretory macrophages release TGF-beta, which promotes proliferation of stellate cells to cause collagenous thickening of the central vein. The activated stellate cells produce collagen. The normal drainage of the Space of Disse and sinusoids draining into the central vein are blocked by the fibrosis. This leads to extravasated RBCs trapped within the thickened central vein wall and impaction of RBCs in the sinusoids.