Challenges in the diagnosis of intestinal neuronal dysplasia type B:A look beyond the number of ganglion cells

Intestinal neuronal dysplasia type B(IND-B)is a controversial condition among gastrointestinal neuromuscular disorders.Constipation is its most common clinical manifestation in patients.Despite intense scientific research,there are still knowledge gaps regarding the diagnostic criteria for IND-B in the histopathological analysis of rectal biopsies.The guidelines published in the past three decades have directed diagnostic criteria for quantifying the number of ganglion cells in the nervous plexus of the enteric nervous system.However,it is very complex to distinguish numerically what is pathological from what is normal,mainly because of the difficulty in determining a reliable control group composed of healthy children without intestinal symptoms.Thus,a series of immunohistochemical markers have been proposed to assist in the histopathological analysis of the enteric nervous system.Several of these markers facilitate the identification of other structures of the enteric nervous system,in addition to ganglion cells.These structures may be related to the etiopathogenesis of IND-B and represent new possibilities for the histopathological diagnosis of this disease,providing a view beyond the number of ganglion cells.This review critically discusses the aspects related to the disease definitions and diagnostic criteria of this organic cause of constipation.

Intestinal neuronal dysplasia type B:A still little known diagnosis for organic causes of intestinal chronic constipation

Intestinal neuronal dysplasia type B(IND-B) is a controversial entity among the gastrointestinal neuromuscular disorders. It may occur alone or associated with other neuropathies, such as Hirschsprung's disease(HD). Chronic constipation is the most common clinical manifestation of patients. IND-B primarily affects young children and mimics HD, but has its own histopathologic features characterized mainly by hyperplasia of the submucosal nerve plexus. Thus, IND-B should be included in the differential diagnoses of organic causes of constipation. In recent years, an increasing number of cases of IND-B in adults have also been described, some presenting severe constipation since childhood and others with the onset of symptoms at adulthood. Despite the intense scientific research in the last decades, there are still knowledge gaps regarding definition, pathogenesis, diagnostic criteria and therapeutic possibilities for IND-B. However, in medical practice, we continue to encounter patients with severe constipation or intestinal obstruction who undergo to diagnostic investigation for HD and their rectal biopsies present hyperganglionosis in the submucosal nerve plexus and other features, consistent with the diagnosis of IND-B. This review critically discusses aspects related to the disease definitions, pathophysiology and genetics, epidemiology distribution, clinical presentation, diagnostic criteria and therapeutic possibilities of this still little-known organic cause of intestinal chronic constipation.

Molecular genetics of gastric adenocarcinoma in clinical practice

The molecular genetics of gastric carcinoma(GC) dictates their biology and clinical behavior. The two morphologically distinct types of gastric carcinoma by Lauren classification, i.e., intestinal and diffuse cell types, have a significant difference in clinical outcome. These two types of GC have different molecular pathogenetic pathways with unique genetic alterations. In addition to environmental and other etiologies, intestinal type GC is associated with Helicobacter pylori(H. pylori) infection and involves a multistep molecular pathway driving the normal epithelium to intestinal metaplasia, dysplasia, and malignant transformation by chromosomal and/or microsatellite instability(MSI), mutation of tumor suppressor genes, and loss of heterozygosity among others. Diffuse type shows no clear causal relationship with H. pylori infection, but is commonly associated with deficiency of cell-cell adhesion due to mutation of the E-cadherin gene(CDH1), and a manifestation of the hereditary gastric cancer syndrome. Thus, detection of CDH1 mutation or loss of expression of E-cadherin may aid in early diagnosis or screening of diffuse type GC. Detection of certain genetic markers, for example, MSI and matrix metalloproteinases, mayprovide prognostic information, particularly for intestinal type. The common genetic alterations may offer therapeutic targets for treatment of GC. Polymorphisms in Thymidylate synthase to metabolize 5-fluorouracil, glutathione S-transferase for degradation of Cisplatin, and amplification/overexpression of human epidermal growth factor receptor 2 targeted by monoclonal antibody Trastuzumab, are a few examples. P13K/Akt/mT OR pathway, c-Met pathways, epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor fibroblast growth factor receptor, and micro RNAs are several potential therapeutic biomarkers for GC under investigation.