Drug-induced mucosal alterations observed during esophagogastroduodenoscopy.

Several features of drug-induced mucosal alterations have been observed in the upper gastrointestinal tract, i.e., the esophagus, stomach, and duodenum. These include pill-induced esophagitis, desquamative esophagitis, worsening of gastroesophageal reflux, chemotherapy-induced esophagitis, proton pump inhibitor-induced gastric mucosal changes, medication-induced gastric erosions and ulcers, pseudomelanosis of the stomach, olmesartan-related gastric mucosal inflammation, lanthanum deposition in the stomach, zinc acetate hydrate tablet-induced gastric ulcer, immune-related adverse event gastritis, olmesartan-asso-ciated sprue-like enteropathy, pseudomelanosis of the duodenum, and lanthanum deposition in the duodenum. For endoscopists, acquiring accurate knowledge regarding these diverse drug-induced mucosal alterations is crucial not only for the correct diagnosis of these lesions but also for differential diag-nosis of other conditions. This minireview aims to provide essential information on drug-induced mucosal alterations observed on esophagogastroduodenoscopy, along with representative endoscopic images.

Autophagy Contributes to Homeostasis in Esophageal Epithelium Where High Autophagic Vesicle Level Marks Basal Cells With Limited Proliferation and Enhanced Self-Renewal Potential.

BACKGROUND & AIMS: Autophagy plays roles in esophageal pathologies both benign and malignant. Here, we aim to define the role of autophagy in esophageal epithelial homeostasis. METHODS: We generated tamoxifen-inducible, squamous epithelial-specific Atg7 (autophagy related 7) conditional knockout mice to evaluate effects on esophageal homeostasis and response to the carcinogen 4-nitroquinoline 1-oxide (4NQO) using histologic and biochemical analyses. We fluorescence-activated cell sorted esophageal basal cells based on fluorescence of the autophagic vesicle (AV)-identifying dye Cyto-ID and then subjected these cells to transmission electron microscopy, image flow cytometry, three-dimensional organoid assays, RNA sequencing, and cell cycle analysis. Three-dimensional organoids were subjected to passaging, single-cell RNA sequencing, cell cycle analysis, and immunostaining. RESULTS: Genetic autophagy inhibition in squamous epithelium resulted in increased proliferation of esophageal basal cells under homeostatic conditions and also was associated with significant weight loss in mice treated with 4NQO that further displayed perturbed epithelial tissue architecture. Esophageal basal cells with high AV level (Cyto-IDHigh) displayed limited organoid formation capability on initial plating but passaged more efficiently than their counterparts with low AV level (Cyto-IDLow). RNA sequencing suggested increased autophagy in Cyto-IDHigh esophageal basal cells along with decreased cell cycle progression, the latter of which was confirmed by cell cycle analysis. Single-cell RNA sequencing of three-dimensional organoids generated by Cyto-IDLow and Cyto-IDHigh cells identified expansion of 3 cell populations and enrichment of G2/M-associated genes in the Cyto-IDHigh group. Ki67 expression was also increased in organoids generated by Cyto-IDHigh cells, including in basal cells localized beyond the outermost cell layer. CONCLUSIONS: Autophagy contributes to maintenance of the esophageal proliferation-differentiation gradient. Esophageal basal cells with high AV level exhibit limited proliferation and generate three-dimensional organoids with enhanced self-renewal capacity.

Exploring the clinical relevance of "Angico Gum": an effective biopolymer for topical protection of oesophageal mucosa in gastroesophageal reflux disease patients.

OBJECTIVES: Angico gum (AG) (Anadenanthera colubrina var. Cebil [Griseb.] Altschul) is utilized by some Brazilian communities to alleviate symptoms from gastroesophageal reflux disease. Here, we aimed to investigate the "in vitro" topical protective capacity of AG on human esophageal mucosa. METHODS: Biopsies of the distal esophageal mucosa were collected from 35 patients with heartburn (24 non-erosive and 11 with erosive oesophagitis (EE)) and mounted in Üssing chambers. AG was applied topically, followed by exposure with acid solution (pH 2.0 or pH 1.0), where transepithelial electrical resistance (TER) and The transepithelial permeability for fluorescein was assessed. The incubation of the AG labeled with FITC in the esophageal mucosa was localized by fluorescence microscopy. KEY FINDINGS: Pretreatment with AG prevented the drop in TER induced by acid solution, as well as significantly decreases the fluorescein permeability in non-erosive patients. The protective effect of AG was sustained for up to 120 min both in biopsies of non-erosive and erosive esophagitis. Confocal microscope images showed mucosal luminal adherence of FITC-labeled AG. CONCLUSION: AG had a prolonged topical protective effect against acid solution in mucosal biopsies of patients with non-erosive and erosive esophagitis.

Epithelial-Fibroblast Crosstalk in Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is an emerging form of food allergy that exerts a significant clinical and financial burden worldwide. EoE is clinically characterized by eosinophil-rich inflammatory infiltrates in esophageal mucosa and esophageal dysfunction. Remodeling events in esophageal epithelium and lamina propria also frequently occur in patients with EoE. Because subepithelial fibrosis is associated with esophageal stricture, the most severe consequence of EoE, there exists an urgent need for a deeper understanding of the molecular mechanisms mediating fibrosis in EoE. Here, we review emerging evidence from experimental model systems that implicates crosstalk between esophageal epithelial cells and underlying stromal cells in EoE fibrosis. We further discuss implications for epithelial-stromal interaction with regard to EoE patient care and propose future directions that may be pursued to further the understanding of epithelial-stromal crosstalk in EoE pathobiology.

Epithelial overexpression of IL-33 induces eosinophilic esophagitis dependent on IL-13.

BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE. OBJECTIVE: We hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE. METHODS: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2-/-, eosinophil-deficient, and IL-13-/- mice. Finally, EoE33 mice were treated with dexamethasone. RESULTS: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and TH2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathologic changes in vivo. EoE33 mice were responsive to steroids. CONCLUSIONS: IL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery.

Lysyl Oxidase Regulates Epithelial Differentiation and Barrier Integrity in Eosinophilic Esophagitis.

BACKGROUND & AIMS: Epithelial disruption in eosinophilic esophagitis (EoE) encompasses both impaired differentiation and diminished barrier integrity. We have shown that lysyl oxidase (LOX), a collagen cross-linking enzyme, is up-regulated in the esophageal epithelium in EoE. However, the functional roles of LOX in the esophageal epithelium remains unknown. METHODS: We investigated roles for LOX in the human esophageal epithelium using 3-dimensional organoid and air-liquid interface cultures stimulated with interleukin (IL)13 to recapitulate the EoE inflammatory milieu, followed by single-cell RNA sequencing, quantitative reverse-transcription polymerase chain reaction, Western blot, histology, and functional analyses of barrier integrity. RESULTS: Single-cell RNA sequencing analysis on patient-derived organoids revealed that LOX was induced by IL13 in differentiated cells. LOX-overexpressing organoids showed suppressed basal and up-regulated differentiation markers. In addition, LOX overexpression enhanced junctional protein genes and transepithelial electrical resistance. LOX overexpression restored the impaired differentiation and barrier function, including in the setting of IL13 stimulation. Transcriptome analyses on LOX-overexpressing organoids identified an enriched bone morphogenetic protein (BMP) signaling pathway compared with wild-type organoids. In particular, LOX overexpression increased BMP2 and decreased the BMP antagonist follistatin. Finally, we found that BMP2 treatment restored the balance of basal and differentiated cells. CONCLUSIONS: Our data support a model whereby LOX exhibits noncanonical roles as a signaling molecule important for epithelial homeostasis in the setting of inflammation via activation of the BMP pathway in the esophagus. The LOX/BMP axis may be integral in esophageal epithelial differentiation and a promising target for future therapies.

The prospective validation of a scoring system to assess mucosal cleanliness during EGD.

BACKGROUND AND AIMS: Cleanliness of the mucosa of the upper GI (UGI) tract is critical for performing a high-quality EGD. The aim of this study was to validate a recently developed UGI cleanliness scale (the Polprep: Effective Assessment of Cleanliness in Esophagogastroduodenoscopy [PEACE] system) in the detection of clinically significant lesions (CSLs) in the UGI tract. METHODS: Patients who underwent a complete diagnostic EGD were prospectively enrolled from August 2021 to October 2022. The UGI tract (esophagus, stomach, and duodenum) cleanliness was scored from 0 to 3 for each segment. The primary outcomes were the detection of CSLs and PEACE scores. RESULTS: Of 995 patients enrolled from 5 centers, adequate cleanliness (AQ; all scores ≥2) was found in 929 patients. In multivariate regression analysis, AQ was associated with the number of diagnosed CSLs (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.06-3.01; P = .03). Other factors related to CSL detection were duration of EGD (OR, 1.29, 95% CI, 1.23-1.35, P < .001), male sex (OR, 1.33, 95% CI, 1.04-1.71; P = .025), and EGD indication (dyspepsia, alarm symptoms, gastritis surveillance, other indications vs GERD) (OR, 0.43 [95% CI, 0.31-0.6, P < .001], OR, 0.44 [95% CI, 0.28-0.67, P < .001], OR, 0.44 [95% CI, 0.25-0.76; P = .004], and OR, 0.44 [95% CI, 0.31-0.62; P < .001], respectively). Twenty-seven patients were diagnosed with UGI neoplasia, all in patients with adequate cleanliness of the UGI tract. CONCLUSIONS: Adequate cleanliness of the UGI tract as assessed with the PEACE system was associated with a significantly higher detection rate of CSLs during EGD. The relationship of this scale with UGI neoplasia detection warrants further investigation.

The utility of balloon-based and standard impedance technology to diagnose esophageal mucosal diseases in children.

BACKGROUND: Standard impedance catheters and balloon-based mucosal impedance catheters (BBMI) have been used to assess mucosal integrity and diagnose mucosal diseases. The goal of this study was to determine the age-related technical issues associated with mucosal balloon inflation, validate the BBMI measurement against a standard impedance probe, and compare software-generated diagnoses to histologic diagnoses. METHODS: We prospectively recruited patients undergoing endoscopy, during which patients underwent standard mucosal impedance catheters and BBMI measurements. Measurements were compared to each other, to the histologic diagnoses, and to the number of eosinophils per high power field. We then compared the patients' diagnosis to that assigned by the BBMI software. KEY RESULTS: Sixty-two patients (mean age: 62 ± 62 months) were recruited, including non-GERD (N = 40), GERD (N = 15), and EoE (N = 7) patients. There were significant differences between the impedance values measured by the two technologies at each esophageal height (p < 0.003). There were significant correlations between the mean impedance values taken by the two catheters in the distal (r2 = 0.272, p = 0.04), mid (r2 = 0.371, p < 0.001), and proximal (r2 = 0.259, p = 0.05) esophagus. There were significant differences in BBMI impedance values across diagnoses in the mid and proximal esophagus (p = 0.024 and 0.025, respectively). While not statistically significant (p = 0.061-0.073), the standard catheter showed similar trends by diagnosis. Using the BBMI diagnostic prediction software, 33%-72% of patients were misclassified. CONCLUSION AND INFERENCES: While there was significant variability in impedance values between technologies within patients, regional measurements were consistent across catheters. Automated analyses lacked the sensitivity to diagnose inflammatory disorders.

Benign esophageal stricture model construction and mechanism exploration.

Esophageal stricture is a debilitating condition that negatively impacts patients' quality of life after undergoing endoscopic mucosal resection (EMR). Despite its significance, this disease remains underexplored due to the lack of a stable animal model. Under direct visualization with choledochoscopy, we retrogradely damaged the esophageal mucosal layer through the gastrostomy to create a rat model of esophageal stricture. The development of histological defects in the mucosal layer was assessed over a 2-week period after model induction. Then the models were evaluated using X-ray barium radiography, Hematoxylin-Eosin, Masson's trichrome, Sirius red, and Victoria blue staining, multiphoton microscopic imaging. Additionally, the molecular mechanisms of esophageal stricture were explored by conducting RNA transcriptome sequencing, PCR, immunohistochemistry, and immunofluorescence staining. We successfully established fifteen rat models of esophageal stricture by injuring the mucosal layer. In the model group, the mucosal defect initially occurs and subsequently repaired. The epithelium was absent and was plastically remodeled by collagen during the acute inflammatory phase (Day 1), proliferation phase (Day 7), anaphase of proliferation (Day 10), and plastic remodeling phase (Day 14). We observed increased expression of COL1A1, acta2, FGF, IL-1, and TGF-ß1 pathway in the model group. We established a highly repeatable rat model of esophageal stricture, and our results suggest that the mucosal defect of the esophagus is a critical factor in esophageal stricture development, rather than damage to the muscularis layer. We identified Atp4b, cyp1a2, and gstk1 as potential targets for treating esophageal stricture, while the TGF-ß pathway was found to play an important role in its development.

[Refractory esophageal stricture of esophageal mucous membrane pemphigoid after allogeneic hematopoietic stem cell transplantation].

Haploidentical allogeneic hematopoietic stem cell transplantation from her brother was performed on a 41-year-old lady with no prior history of pemphigoid to treat recurrent AML. On day 59 following transplantation, she experienced esophageal stenosis. During immunosuppressive therapy for graft vs. host disease, this condition was controlled with periodic esophageal dilatation (GVHD). Her esophageal stricture, which required periodic dilatation, grew worse after she stopped immunosuppressive therapy because of recurrent AML. The esophageal mucosa was easily hemorrhagic and desquamative. Histologic analysis revealed that the squamous cell layers had been divided. Indirect immunofluorescence was negative for IgG and positive for IgA on the epidermal layers, while direct immunofluorescence showed a linear deposition of IgG on the basement membrane zone. It was determined through immunoblotting utilizing recombinant protein of BP180 C-terminal domain that both IgG and IgA antibodies were present, supporting the diagnosis of mucous membrane pemphigoid with anti-BP180. After allogeneic transplantation, basal epidermal cell destruction by GVHD may result in autoimmune blistering disorders, which expose basement membrane proteins and antigen presentation. A similar mechanism could apply to our situation. For rare GVHD cases, a thorough histological diagnosis is required.

Challenges in Inter-rater Agreement on Lamina Propria Fibrosis in Esophageal Biopsies.

BACKGROUND: Mucosal biopsies in eosinophilic esophagitis (EoE) can exhibit lamina propria (LP) fibrosis, which may portend stenotic complications; however, the histologic diagnosis of LP fibrosis is subjective. We sought to assess and improve the consistency of LP fibrosis diagnosis among our pathologist group. METHODS: At a large pediatric hospital, 25 esophageal biopsy slides from 19 patients (16 with EoE) exhibiting a wide spectrum of LP area, artifacts, and fibrosis severity were scanned into whole-slide images. Staff pediatric pathologists (n = 8) separate from the authors classified each biopsy by LP adequacy and fibrosis severity 1 month before and after completion of an educational tutorial. Consensus was defined as >70% agreement. RESULTS: At baseline, 16/25 (64%) cases reached consensus for no fibrosis (n = 3), fibrosis (n = 7), or inadequate LP (n = 6); agreement was fair (α = 0.34). Post-tutorial, 13/25 (52%) cases reached consensus for no fibrosis (n = 2), fibrosis (n = 7), or inadequate LP (n = 4); agreement was again fair (α = 0.33). There was moderate agreement in grading of fibrosis severity (α = 0.54). CONCLUSION: We document only fair-to-moderate agreement in the diagnosis of esophageal LP fibrosis and adequacy in a large pediatric pathologist group despite targeted education, highlighting a challenge in incorporating this feature into EoE research and clinical decision-making.

Extracellular distribution of galectin-10 in the esophageal mucosa of patients with eosinophilic esophagitis.

Eosinophilic esophagitis is a T-cell-driven allergic condition hallmarked by eosinophil infiltration of the esophagus. Eosinophils exposed to proliferating T cells release galectin-10 and have T-cell suppressive function in vitro. The aims of this study were to evaluate if eosinophils co-localize with T cells and release galectin-10 in the esophagus of patients with eosinophilic esophagitis. Esophageal biopsies from 20 patients with eosinophilic esophagitis were stained for major basic protein, galectin-10, CD4, CD8, CD16, and CD81 and analyzed by immunofluorescence confocal microscopy before and after topical corticosteroid treatment. CD4+ T-cell numbers decreased in the esophageal mucosa of responders to treatment but not in the non-responders. Suppressive (CD16+) eosinophils were present in the esophageal mucosa of patients with active disease and decreased after successful treatment. Unexpectedly, eosinophils and T cells were not in direct contact with each other. Instead, the esophageal eosinophils released large amounts of galectin-10-containing extracellular vesicles and featured cytoplasmic projections that contained galectin-10, both of which disappeared from the esophagus of the responders but remained in the non-responders. To conclude, the presence of CD16+ eosinophils together with the massive release of galectin-10-containing extracellular vesicles in the esophageal mucosa might indicate that eosinophils exert T-cell suppression in eosinophilic esophagitis.

An unexpected complication of prophylactic esophageal stenting: esophageal stent impaction after thread dislocation.

A 47-year-old woman was referred to our department with opportunistic endoscopic findings of two submucosal esophageal bulges, approximately half the circumference of the esophagus, both nearly 2.0 cm in size, and 24-27 cm from the incisors. Ultrasound endoscopy diagnosed smooth muscle tumors originating from the muscularis propria layer and she next underwent submucosal tunneling endoscopic resection. Intraoperatively, part of the tumor could not be separated from the muscularis propria layer and a U-shaped tumor was finally resected. A fully covered self-expanding esophageal nitinol stent was then inserted, covering the full circumference esophageal mucosa. The stent was fixed by ears with knotted thread and proton pump inhibitors were given for 1 week.

Decreased Expression of NRF2 Target Genes after Alcohol Exposure in the Background Esophageal Mucosa of Patients with Esophageal Squamous Cell Carcinoma.

Patients with esophageal squamous cell carcinoma (ESCC) might have a specific mechanism for the carcinogenesis by alcohol consumption in the background esophageal mucosa, and nuclear factor erythroid 2-related factor 2 (NRF2), which plays a protective role against esophageal carcinogenesis, and barrier dysfunction might be associated with this phenomenon. This study aimed to confirm this hypothesis. Twenty patients with superficial ESCCs (ESCC patients) and 20 age- and sex-matched patients without ESCC (non-ESCC patients) were enrolled. Biopsy samples were obtained from non-neoplastic esophageal mucosa: one for histological evaluation, one for quantitative real-time polymerase chain reaction (PCR), and two for the mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) and, thereafter, for PCR. The TEER after acetaldehyde or both acetaldehyde and ethanol exposure did not differ significantly between ESCC and non-ESCC patients. Unlike non-ESCC patients, mRNA levels of NRF2 target genes and claudin4 in ESCC patients tended to decrease after the exposure, with a significant difference between no exposure and both acetaldehyde and ethanol exposure in NRF2 target genes (p < 0.05). Furthermore, in ESCC patients, the decreased tendency of mRNA levels of NRF2 target genes after the exposure was more pronounced in high-risk states, such as aldehyde dehydrogenase 2 (ALDH2) Lys alleles (Glu/Lys + Lys/Lys), Lugol-voiding lesion grade C, and drinking history. In conclusion, the protective role of NRF2 against carcinogenesis from alcohol exposure might be disrupted in the background esophageal mucosa of ESCC patients, which might lead to a high incidence of metachronous ESCC.

Comparison of tumor-associated and nontumor-associated esophageal mucosa microbiota in patients with esophageal squamous cell carcinoma.

Esophageal microbiota plays important roles in esophageal squamous cell carcinoma (ESCC). The aims of this study were to clarify the changes in the bacterial community during ESCC development and identify latent pathogenic bacteria which may contribute to esophageal carcinogenesis and progression. Fresh tumor and nontumor esophageal mucosal samples were collected from 31 men with ESCC. High-throughput 16s rRNA sequencing was performed, and the operational taxonomic unit data and bacterial classification annotation were obtained and analyzed. The Ace, Chao, Shannon, Simpson indexes, and operational taxonomic unit numbers were higher in nontumor tissues than in tumor tissues, although without statistical significance. There were 4 phyla and 28 genera found to show significant differences between tumor and nontumor samples. The general probiotic Lactobacillus was 1.98-fold higher in nontumor tissues, while the general pathogenic genera Fusobacterium was 4.35-fold higher in tumor tissues. For tumor tissue samples, the genera Treponema and Brevibacillus were significantly higher in N1 and N2 stages, respectively, and Acinetobacter was significantly higher in T3 stage. For nontumor tissues, the genus Fusicatenibacter was significantly higher in T2 stage, and Corynebacterium, Aggregatibacter, Saccharimonadaceae-TM7x, and Cupriavidus were significantly higher in T4 stage. Additionally, bacteria related to nitrotoluene degradation were enriched in nontumor tissues, while bacteria related to base excision repair were enriched in tumor tissues. The relative abundance of several phyla and genera are different between tumor and nontumor tissue samples. The altered bacterial microbiota is correlated with different tumor stages and some microbes may take part in the carcinogenesis and development of ESCC.

Proteomic analysis reveals that ACSL4 activation during reflux esophagitis contributes to ferroptosis-mediated esophageal mucosal damage.

Ferroptosis has been shown to be involved in the pathological process of many diseases. However, the function and mechanism of ferroptosis in reflux esophagitis (RE), especially in the esophageal mucosal damage, remains unknown. The purpose of this study was to screen potential therapeutic target genes that mediate RE esophageal mucosal damage and regulate ferroptosis. RE rats were established by our previous protocol and proteomic analysis of esophageal mucosa was performed. In addition, the ferroptosis-related genes were retrieved from the FerrDb database and were cross analyzed with the differential proteins of proteomics to obtain potential therapeutic target genes Acyl-CoA synthetase long-chain family 4 (ACSL4), a key enzyme for ferroptosis. In the present study, we used the ACSL4 inhibitor rosiglitazone (ROSI) and the ferroptosis inhibitor ferrostatin-1 to intervene with RE rats, and evaluate the levels of protein, histological changes, lipid peroxidation levels, iron accumulation and morphological changes in esophageal tissue by HE staining, Western blot, related kit tests, and transmission electron microscope. The results showed that both ferrostatin-1 and ROSI treatment significantly reduced the levels of iron accumulation and lipid peroxidation, and protected against ferroptosis and esophageal tissue injury in RE rats. Through Immunohistochemical staining, 16SrDNA sequencing, Enzyme linked immunosorbent assay (ELISA), Western blot and other tests on the esophagus, gut, spleen and serum of RE rats, we further found that the changes of esophageal and intestinal microbiota and the increase of peripheral blood LPS were the key factors regulating ferroptosis in esophageal epithelial tissue. On the one hand, LPS could increase the expression of ACSL4 in esophageal tissue by up-regulating special protein 1 (Sp1). On the other hand, LPS could increase the secretion of serum ferritin in spleen and the accumulation of iron in esophageal tissue by activating Capase11/GSDMD pyroptosis pathway. Collectively, this study suggests that ACSL4 and ferroptosis are potential therapeutic targets for RE esophageal mucosal damage, and esophageal and gut microecology play a critical role in this process.

Esophageal Melanocytosis: report of two cases and review of a rare and misunderstood entity.

Esophageal melanocytosis (EM) is a rare entity, which is characterized by a non-atypical melanocytic proliferation and melanin deposits in the esophageal mucosa. The confusion between the terms of melanosis and melanocytosis in the literature, the rarity of this lesion (less than 50 cases reported in the literature), its uncertain pathobiological course and the lack of experience of pathologists and gastroenterologists prompt us to draw the attention to this particular entity by reporting two cases and reviewing the literature. Magnifying endoscopy to observe intensive melanin accumulation followed by a biopsy are key for the diagnosis.

Expression of VEGF, EGF, and Their Receptors in Squamous Esophageal Mucosa, with Correlations to Histological Findings and Endoscopic Minimal Changes, in Patients with Different GERD Phenotypes.

BACKGROUND: Gastroesophageal reflux disease (GERD) may present as nonerosive reflux disease (NERD), erosive esophagitis (EE), or be complicated by Barrett's esophagus (BE). The explanation as to what determines the phenotype of GERD is awaited. Therefore, we assessed the correlation between the growth factors expression and endoscopic as histologic findings in GERD patients. METHODS: The squamous esophageal epithelium of 50 patients (20-NERD, 7-EE, 15-BE, 8 controls) was examined by: (1) magnification endoscopy with evaluation of minimal GERD changes such as: microerosions, white spots, palisade blood vessels visibility, and intrapapillary capillary loops (IPCLs) appearance, (2) histology, (3) immunohistochemistry with evaluation of the expression of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and their receptors (VEGFR and EGFR). RESULTS: The expression of VEGF, but not VEGFR, EGF, and EGFR, was significantly increased in EE patients compared to NERD patients and controls. VEGF levels correlated significantly with the presence of white spots, but not with other minimal endoscopic and histologic features. The EGFR expression correlated positively with basal cell hyperplasia and enlarged IPCLs. CONCLUSIONS: Our findings suggest a correlation between growth factors expression and findings in conventional endoscopy, formation of endoscopic minimal changes, and histologic lesions.