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Summary Non-IBD colitides (NIBDC) are intestinal diseases clinically and endoscopically overlapping with Inflammatory Bowel Diseases (IBD), sometimes with a similar histological picture. NIBDC include entities such as infectious colitis, ischemic colitis, pseudomembranous colitis, eosinophilic colitis, autoimmune enterocolitis, segmental colitis associated with diverticulosis, drug-induced colitis, radiation-induced colitis, diversion colitis, and microscopic colitis, this last including two entities: collagenous and lymphocytic colitis. The knowledge of the most useful histological features and the main clinical data for each entity is mandatory in daily clinical practice, for correct pathological diagnosis and clinical management.

Pathologists are often called upon to diagnose colitides that differ from the two main forms of inflammatory bowel disease (IBD). These non-IBD colitides include infectious colitis, microscopic colitis, ischemic colitis, eosinophilic colitis, autoimmune enterocolitis, segmental colitis associated with diverticulosis, drug-induced colitis, radiation colitis and diversion colitis. The diagnosis of these different disease entities relies on the histopathological examination of endoscopic biopsies of the gastrointestinal tract. This paper reviews the main histomorphological characteristics of the various Non-IBD colitides.

Autoimmune gastritis (AIG) is a gastric pathologic condition affecting the mucosa of the fundus and the body and eventually leading to hypo-achlorhydria.We report our clinical and pathological experience with AIG.Data from patients with a diagnosis of AIG seen in the period January 2002-December 2012 were retrieved. Only patients with complete sets of biopsies were analyzed.Data from 138 patients were available for analysis. Pernicious anemia was present in 25% of patients, iron deficiency anemia was found in 29.7% of patients, hypothyroidism in 23% of patients, type 1 diabetes in 7.9% of patients, and vitiligo in 2.8% of patients. Parietal cell antibodies were positive in 65% of patients, and no patient had serology positive for celiac disease. All gastric biopsies showed glandular atrophy associated with enterochromaffin-like (ECL)-cells hyperplasia, features limited to the mucosa of the fundus and body, and focal glandular intestinal metaplasia. Helicobacter pylori was negative in all cases.AIG was strongly associated with anemia; atrophy, intestinal metaplasia and ECL hyperplasia in the gastric fundus and body are hallmarks of this condition.

Diagnosis of the inflammatory bowel diseases ulcerative colitis (UC) and Crohn's disease (CD) relies mainly on the histopathological examination of endoscopic biopsies of the gastrointestinal tract. To facilitate the accurate diagnosis of these two conditions, this paper addresses key issues on the: (A) gastrointestinal biopsy procedure, (B) histomorphological characteristics of UC and CD, and (C) diagnosis of dysplasia. The 13 statements presented here represent the consensus of two groups of Italian pathologists (IG-IBD and GIPAD).

Background It is generally thought that gallbladder motility plays a more or less important role in the pathogenesis of gallstones. Some studies have shown that some abnormalities of its intrinsic innervations, but these studies were usually limited to one cell component. Aims We investigated the main cell components of gallbladder intrinsic innervation in patients with and without gallstones. Methods Archival gallbladder specimens from 39 patients, 27 with gallstones (age range 45–69 yrs) and 12 patients without gallstones (age range 39–71 yrs) were obtained. Full thickness sections were obtained from the gallbladder neck and immunohistochemistry was carried out for enteric neurons (neuron-specific enolase and calretinin), enteric glia (S100) and interstitial cells of Cajal (CD117 and CD34); tryptase staining was also done to distinguish the latter from mast cells. Results Apart from calretinin-positive neurons, patients with gallstones featured a significant decrease of neurons, enteric glial cells (EGC) and mast cells compared to those without gallstones; interstitial cells of Cajal were extremely few and only found in two patients, one for each group. Conclusions The intrinsic innervations of the gallbladder is abnormal in gallstone patients, and this may contribute to gallstone formation in these subjects.

Background: In search of novel biomarkers of response to bevacizumab in metastatic colorectal cancer (mCRC), we analyzed the expression and prognostic role of several proteins related to angiogenesis. Methods: A retrospective, multicenter study on 80 surgical samples from mCRC patients treated in first line with bevacizumab plus chemotherapy was accomplished. The following proteins were analyzed by immunohistochemistry: hERG1 potassium channel, β1-integrin, pAKT, NFkB, HIF-1α, HIF-2α, p53, VEGF-A, GLUT-1, and CA-IX. Data were analyzed in conjunction with the clinicopathological characteristics of the patients, KRAS status, response to bevacizumab, and follow-up. Results: (1) All the proteins were expressed in the samples, with statistically significant associations between HIF-1α and gender, HIF-2α and left colon, hERG1 and VEGF-A, β1-integrin and HIF-2α, GLUT-1 and both HIF-1α and HIF-2α, and CA-IX and VEGF-A. (2) At the univariate analysis, positivity for hERG1, VEGF-A, and the active form of HIF-2α (aHIF-2α), and the G3 histological grade showed a positive impact on progression-free survival (PFS). (3) hERG1 and aHIF-2α maintained their positive impact on PFS at the multivariate analysis. (4) hERG1 behaved as a protective factor for PFS independently on KRAS status. Conclusions: hERG1 and aHIF-2α might help to identify patients who would benefit from bevacizumab treatment.

7-Hydroxymatairesinol (7-HMR) is a plant lignan abundant in various concentrations in plant foods. The objective of this study was to test HMRLignan™, a purified form of 7-HMR, and the correspondingPicea abiesextract (total extractP. abies; TEP) as dietary supplements on a background of a high-fat diet (HFD)-induced metabolic syndrome in mice and in the 3T3-L1 adipogenesis model. Mice, 3 weeks old, were fed a HFD for 60 d. Subgroups were treated with 3 mg/kg body weight 7-HMR (HMRLignan™) or 10 mg/kg body weight TEP by oral administration. 7-HMR and TEP limited the increase in body weight (−11 and −13 %) and fat mass (−11 and −18 %) in the HFD-fed mice. Epididymal adipocytes were 19 and −12 % smaller and the liver was less steatotic (−62 and −65 %). Serum lipids decreased in TEP-treated mice (−11 % cholesterol, −23 % LDL and −15 % TAG) and sugar metabolism was ameliorated by both lignan preparations, as shown by a more than 70 % decrease in insulin secretion and insulin resistance. The expression of several metabolic genes was modulated by the HFD with an effect that was reversed by lignan. In 3T3-L1 cells, the 7-HMR metabolites enterolactone (ENL) and enterodiol (END) showed a 40 % inhibition of cell differentiation accompanied by the inhibited expression of the adipogenic genesPPARγ,C/EBPαandaP2. Furthermore, END and ENL caused a 10 % reduction in TAG uptake in HEPA 1–6 hepatoma cells. In conclusion, 7-HMR and TEP reduce metabolic imbalances typical of the metabolic syndrome and obesity in male mice, whereas their metabolites inhibit adipogenesis and lipid uptakein vitro.

Although glucocorticosteroids (GS) and mesalazine are effective and widely employed to treat moderate-to-severe ulcerative colitis (UC), information regarding the factors responsible for response to such therapy is still scarce. One of these factors is thought to be an increased number of mucosal eosinophils. The aim of our study was to determine whether the presence of hypereosinophilia in colonic mucosa of UC patients might influence the short-term response to l treatment with GS and mesasalazine. Clinical, endoscopic, and pathologic data from patients with a recent diagnosis of moderate UC, who had not undergone treatment, were obtained, and the short-term outcome after 1 month of conventional first-line treatment (mesalazine plus GS) was evaluated. There were 53 patients with a median age of 37 years (95% CI 30–47).Overall, at the end of treatment period 16 (30%) patients responded, whereas a response was not observed in the other 37 (70%) patients. Interestingly, all patients of this latter group had colonic mucosal hypereosinophilia. No significant differences were found between the two groups concerning sex and age at diagnosis, but hypereosinophilia was inversely correlated with the duration of the disease (p = 0.054), and significantly correlated to the localization of UC (p = 0.0023). In addition, The Mayo score was significantly higher in patients with hypereosinophilia (median 8; 95% CI 8–9;) when compared to patients without hypereosinophilia (median 7; 95% CI 7–7, p

The concept of remission for patients with inflammatory bowel diseases has recently evolved, and should also include histological healing of the mucosa, difficult to evaluate since there is no agreement on pathological scores and those available are quite complex to use in the daily routine. We evaluated the possible usefulness of a simplified pathological score to assess histological healing of the mucosa in inflammatory bowel diseases patients compared with four commonly proposed pathological scores. Slides from 24 patients (12 Crohn’s disease, 12 ulcerative colitis, age range 24–62 years), pre- and post-treatment with biological agents and displaying endoscopic remission were assessed by two pathologists. Pre- and post-treatment results and the time employed to calculate the various scores were obtained. All scores were useful to document highly significant post-treatment decreases of histological activity. However, the simplified score needed significant less time to be calculated for each slide, had high inter-rater agreement, and avoided subjectivity from the pathologists. The simplified score is easy to calculate and seems apt to document histological healing of the mucosa, in a manner similar to the more complex scores. It remains to be established whether this score could simplify the daily routinary practice in this context.

The association between gluten related disorders and psychiatric diseases has been firmly demonstrated. Non-celiac gluten sensitivity (NCGS) is a syndrome diagnosed in patients responsive to gluten-free diet after ruling out celiac disease and wheat allergy. The pathogenesis of neuro-psychiatric disorders in NCGS is unclear. An association between gluten and schizophrenia was described for the first time in 1950 by Bender et al. In the 1950's, Dicke noted that gluten-free diet improved mood in celiac patients. In 1970, Goldberg et al., in a study of 80 celiac patients, found that 34% of them showed minor affective disorders. Bipolar disorder patients show an increase of blood anti gliadin deamidated antibodies (IgG). The effect of diet and nutrition on autistic spectrum disorders has been investigated in the last two decades, particularly focusing on the symptoms of hyperactivity and attention. Toxoplasma gondii and other neurotropic pathogens as Influenzavirus and Coronavirus may be associated with mood disorders, probably secondary to an increased intestinal permeability. Abnormalities of host-microbiota interactions or of gut-microbiota composition have been associated with central nervous system disorders, such as autism, anxiety, depression and the integrity of intestinal microbiota may be considered a potential therapeutic goal to treat these conditions.

Basal plasmacytosis is an early-onset and highly predictive feature of inflammatory bowel disease (IBD), but may have several restrictions in routine histology. Considering evidences about cooperation between eosinophils and plasma cells in IBD pathogenesis, we investigated immunostain of these two cells as a marker of disease. 343 samplings from 83 patients (52 IBD, 31 non-IBD colitis) were evaluated. The sections were stained with monoclonal antibodies against plasma cells (CD138 and MUM1), and eosinophils (CD193). Eosinophilia-associated basal plasmacytosis (EBP) was related with the histologic diagnosis of IBD (90.3% IBD and 35.4% non-IBD colitides, p < 0.005, sensitivity 90.4%). A strong relation was detected between the occurrence of EBP and (i) the achieving of a complete endoscopic mapping; (ii) the presence of other characteristic lesions of IBD in single segmental sampling, although EBP was evident in more than 40% of samples without other IBD-related lesions. EBP is a sensitive histologic feature of IBD, especially at the first endoscopic sampling, even in the absence of the other characteristic histologic lesions, and may help in formulating a more precise diagnosis in this setting.

OBJECTIVES Dilated intercellular spaces (DIS) in the esophageal epithelium can be induced by acid and reduced by proton pump inhibitors (PPI), and are thus considered a marker of gastroesophageal reflux disease (GERD). Over the years, however, DIS have also been reported in esophagitis unrelated to GERD. Because DIS have never been formally measured in eosinophilic esophagitis (EoE), we aimed at detecting and measuring DIS in EoE before and after nutritional or pharmacological therapy. METHODS In 22 children with EoE, DIS were measured by morphometry and transmission electron microscopy (TEM), before and after treatment with topical steroids (n = 16) and/or exclusion diet (n = 13). A total of 30 children undergoing upper gastrointestinal endoscopy with biopsy for nonesophageal disorders acted as controls. RESULTS In controls, the mean (± standard deviation [SD]) number of esophageal eosinophils was 0.91 (± 0.47) and the mean DIS values were 0.62 (± 0.08) μm at morphometry and 0.33 (± 0.24) μm at TEM. In patients with EoE, the mean (± SD) number of esophageal eosinophils decreased from 31.8 (± 6.96) to 6.64 (± 5.01) (P < 0.0001), and the mean DIS values decreased from 2.26 (± 0.21) to 1.23 (± 0.20) μm at morphometry (P < 0.0001), and from 2.24 (± 0.28) to 0.98 (± 0.19) μm at TEM (P < 0.0001), respectively, before and after treatment. CONCLUSIONS DIS are a prominent morphological feature of EoE, in which they can be significantly reduced by an appropriate non-PPI therapy.

Diverticular disease of the colon is frequent in clinical practice, and a large number of patients each year undergo surgical procedures worldwide for their symptoms. Thus, there is a need for better knowledge of the basic pathophysiologic mechanisms of this disease entity.Because patients with colonic diverticular disease have been shown to display abnormalities of the enteric nervous system, we assessed the frequency of myenteric plexitis (i.e. the infiltration of myenteric ganglions by inflammatory cells) in patients undergoing surgery for this condition.We analyzed archival resection samples from the proximal resection margins of 165 patients undergoing left hemicolectomy (60 emergency and 105 elective surgeries) for colonic diverticulitis, by histology and immunochemistry.Overall, plexitis was present in almost 40% of patients. It was subdivided into an eosinophilic (48%) and a lymphocytic (52%) subtype. Plexitis was more frequent in younger patients; and it was more frequent in those undergoing emergency surgery (50%), compared to elective (28%) surgery (p = 0.007). All the severe cases of plexitis displayed the lymphocytic subtype.In conclusion, myenteric plexitis is frequent in patients with colonic diverticular disease needing surgery, and it might be implicated in the pathogenesis of the disease.

Purpose and background The focus was directed to the study of two of the most lignan-rich food sources: sesame and flaxseeds. Recent epidemiological and experimental evidences suggesting that these foods may improve metabolic functions underlying metabolic syndrome (MetS). Methods To characterize the effect of these oilseeds on metabolic functions, we conducted an experimental study aimed at preventing adiposity and metabolic imbalance in a mouse model of high-fat diet (HFD)-induced MetS. Statistical analysis was performed by two-way analysis of variance test followed by post hoc Bonferroni analysis. Results We studied the effect of the oilseeds sesame and flaxseed on metabolic parameters in mice on a HFD. When the HFD was integrated with 20 % of sesame or flaxseed flours, the mice showed a decrease in body fat, already at day 15, from time 0. The size of the adipocytes was smaller in epididymal fat, liver steatosis was inhibited, and insulin sensitivity was higher in mice on the supplemented diets. The supplemented diets also resulted in a significant increase in the serum levels of the lignan metabolites enterodiol and enterolactone compared with the controls. The expression of genes associated with the inflammatory response, glucose metabolism, adipose metabolism and nuclear receptor were altered by the oilseed-supplemented diets. Some of the most abundant lignans in these oilseeds were studied in 3T3-L1 preadipocyte cells and were effective in inhibiting adipocyte differentiation at the minimal dose of 1 nM. Conclusions The consumption of sesame and flaxseed may be beneficial to decrease metabolic parameters that are generally altered in MetS.

Mast cells are involved in visceral hypersensitivity and motor activity of the gastrointestinal tract. However, there is almost no information concerning mast cells in constipated patients. The purpose of this study was to investigate mast cells distribution in all colonic layers in controls and severely constipated patients with obstructed defecation. Full-thickness specimens from colons of patients undergoing surgery for obstructed defecation due to refractoriness to other therapeutic interventions (n = 11), compared to controls, were obtained and the number of mast cells (evaluated by specific monoclonal antibodies) were counted in the whole viscus and in the various colonic segments (cecum, ascending, transverse, descending, and sigmoid). Compared to controls, constipated patients had significantly higher numbers of mast cells, both as an overall number and in single colonic segments. This increase was especially evident in the mucosa and submucosa. Mast cells were homogeneously represented in the various segment of the large bowel, in both controls and patients. Degranulated mast cells were found to be close to enteric glial cells and glial filaments. Colonic mast cells are increased in obstructed defecation patients. This might represent a vicariating mechanism to the impaired colonic propulsive activity of these patients.

Gut mast cells represent an important cell population involved in intestinal homeostasis and inflammatory processes. However, their possible role has not to date been investigated in colonic diverticular disease.This study aims to evaluate colonic mast cells in patients undergoing surgery for diverticular disease.Surgical resection samples from 27 patients undergoing surgery for diverticular disease (12 emergency procedures for severe disease and 15 elective procedures) were evaluated. The number of mast cells was assessed in the various layers by means of a specific antibody (tryptase) and compared with those evaluated in ten controls. In patients with mast cells degranulation, double immunohistochemistry, also assessing nerve fibres, was carried out. In addition, the presence of myenteric plexitis was sought.Compared with controls, the number of mast cells in diverticular patients was significantly increased, both as an overall figure and in the various layers of the large bowel. In patients in whom mast cells degranulation was present, these were always closed to nerve fibres. No differences were found between the two subgroups of patients with respect to the number and distribution of mast cells; however, all patients undergoing emergency surgery (but none of those undergoing elective procedures) had myenteric plexitis, represented by lymphocytic infiltration in 67 % and eosinophilic infiltration in 33 % of cases.Patients with diverticular disease display an increase of mast cells in the large bowel. The presence of myenteric plexitis in those with complicated, severe disease, suggest that this could represent a histopathologic marker of more aggressive disease.

Background Enteric nervous system abnormalities have been described in patients with inflammatory bowel diseases. However, the mechanisms responsible for these abnormalities remain to date largely unknown. Aims We investigated the potential role of apoptotic phenomena in enteric neurons and enteroglial cells in patients with inflammatory bowel diseases. Patients and methods Full-thickness surgical specimens of 19 patients undergoing surgery for medically refractory disease (9 from the ileum of patients with Crohn's disease, 10 from the colon of patients with ulcerative colitis) were assessed for the presence of enteric neurons and enteroglial cells and for their apoptosis by two immunohistochemical methods, one also able to distinguish apoptosis from necrosis. The results were compared with those obtained in control specimens. Results Concerning Crohn's disease, the ileal segments displayed a significant increase of apoptotic enteric neurons and enteroglial cells in both the submucous and the myenteric plexus compared to controls. In patients with ulcerative colitis, compared to controls, apoptotic phenomena were significantly reduced in enteric neurons, whereas they were increased in the enteroglial cell population (submucous and myenteric plexus). Conclusions In patients with inflammatory bowel disease apoptotic phenomena involve both enteric neurons and enteroglial cells, and may play a role in the abnormalities of the enteric nervous system. The importance of these findings in the pathophysiology of these conditions remains to be determined.

HER-2/neu is a protooncogene frequently overexpressed in breast cancer. Fluorescence in situ hybridization (FISH) is a technique targeting the gene amplification, while immunohisto-chemistry detects the protein expression. Usually both are applied to paraffin-embedded tissue. The authors studied HER-2 by FISH and immunohistochemistry (HercepTest) in 81 breast carcinomas. The results showed an overall concordance (correlation coefficient 0.64). In all cases with HercepTest score 0 and 1+, nonamplification of the gene was observed. Gene amplification was found in 20% of cases with a 2+ score and in 77.78% of cases with a 3+ score. Data described in literature for 3+ carcinomas showed a 3% to 10% discrepancy between protein expression and gene amplification, while in this study this difference was up to 22.22%. As a consequence, even if it is usually considered important to analyze only 2+ cases by FISH, 3+ scores nonamplified for HER-2/neu may be a new, interesting subset. Furthermore, the authors investigated the two-variables correlation between chromosome 17 copy number, protein over-expression, gene amplification, and presence of metastatic lymph nodes. Interesting results came from the correlation between the HercepTest score and the HER-2/neu gene amplification evaluation, HercepTest and chromosome 17 aneusomy, and gene amplification and lymph nodes status. In conclusion, the FISH technique can be an important and useful diagnostic tool to integrate the results of the HercepTest and to select patients for immunotherapy.