ABCC2 brush-border expression predicts outcome in papillary renal cell carcinoma: a multi-institutional study of 254 cases.

AIMS: Papillary renal cell carcinoma (PRCC) histologic subtyping is no longer recommended in the 2022 WHO classification. Currently, WHO/ISUP nucleolar grade is the only accepted prognostic histologic parameter for PRCC. ABCC2, a renal drug transporter, has been shown to significantly predict outcomes in PRCC. In this study we evaluated the prognostic significance of ABCC2 IHC staining patterns in a large, multi-institutional PRCC cohort and assessed the association of these patterns with ABCC2 mRNA expression. METHODS AND RESULTS: We assessed 254 PRCCs for ABCC2 IHC reactivity patterns that were stratified into negative, cytoplasmic, brush-border <50%, and brush-border ≥50%. RNA in situ hybridization (ISH) was used to determine the transcript level of each group. Survival analysis was performed with SPSS and GraphPad software. RNA-ISH showed that the ABCC2 group with any brush-border staining was associated with a significant increase in the transcript level, when compared to the negative/cytoplasmic group (P = 0.034). Both ABCC2 groups with brush-border <50% (P = 0.024) and brush-border ≥50% (P < 0.001) were also associated with worse disease-free survival (DFS) in univariate analysis. Multivariate analysis showed that only ABCC2 IHC brush-border (<50% and ≥50%) reactivity groups (P = 0.037 and P = 0.003, respectively), and high-stage disease (P < 0.001) had a DFS of prognostic significance. In addition, ABCC2 brush-border showed significantly worse DFS in pT1a (P = 0.014), pT1 (P = 0.013), ≤4 cm tumour (P = 0.041) and high stage (P = 0.014) groups, while a similar analysis with high WHO/ISUP grade in these groups was not significant. CONCLUSION: ABCC2 IHC brush-border expression in PRCC correlates with significantly higher gene expression and also independently predicts survival outcomes.

ATG16L1 protects from interferon-γ-induced cell death in the small intestinal crypt.

The breakdown of the intestinal mucosal barrier is thought to underlie the progression to Crohn disease (CD), whereby numerous risk factors contribute. For example, a genetic polymorphism of the autophagy gene ATG16L1, associated with an increased risk of developing CD, contributes to the perturbation of the intestinal epithelium. We examined the role of Atg16l1 in protecting the murine small intestinal epithelium from T-cell-mediated damage using the anti-CD3 model of enteropathy. Our work showed that mice specifically deleted for Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1ΔIEC) had exacerbated intestinal damage, characterized by crypt epithelial cell death, heightened inflammation, and decreased survival. Moreover, Atg16l1 deficiency delayed the recovery of the intestinal epithelium, and Atg16l1-deficient IECs were impaired in their proliferative response. Pathology was largely driven by interferon (IFN)-γ signaling in Atg16l1ΔIEC mice. Mechanistically, although survival was rescued by blocking tumor necrosis factor or IFN-γ independently, only anti-IFN-γ treatment abrogated IEC death in Atg16l1ΔIEC mice, thereby decoupling IEC death and survival. In summary, our findings suggest differential roles for IFN-γ and tumor necrosis factor in acute enteropathy and IEC death in the context of autophagy deficiency and suggest that IFN-γ-targeted therapy may be appropriate for patients with CD with variants in ATG16L1.

Predictors of recurrence of dysplasia or cancer in patients with dysplastic Barrett's esophagus following complete eradication of dysplasia: a single-center retrospective cohort study.

BACKGROUND AND AIMS: Endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) for Barrett's esophagus (BE)-related high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) are considered effective treatments for eradication of BE. Little is known about the impact of achieving complete eradication of intestinal metaplasia (CE-IM) following the complete eradication of neoplasia (CE-N), specifically if CE-IM reduces the risk of recurrent dysplasia. METHODS: Retrospective cohort study of consecutive patients with BE and HGD or intramucosal cancer (IMC)-treated endoscopically at a tertiary referral center between 2001 and 2019. Association between CE-IM and recurrent dysplasia after CE-N was evaluated. RESULTS: A total of 433 patients treated with EMR and/or RFA were included. Of these, 381 (88%) achieved CE-N, of which 345 (80%) had adequate follow-up for inclusion in the analysis. A total of 266 (77%) patients achieved CE-IM; with a median follow-up since initial treatment for HGD/IMC of 45.9 months (IQR 25.9, 93.1); 20 patients (5.8%) had recurrent dysplasia after achieving CE-N. Kaplan Meier survival curves revealed that time free of recurrence in those who achieved CE-IM was significantly higher (p = 0.002). In the multivariable analysis, CE-IM was associated with a significant lower hazard of recurrence (HR 0.2, 95% CI 0.1, 0.6), whereas the number of endoscopic treatments to achieve CE-N was associated with a significant higher hazard of recurrence (HR 1.1, 95% CI 1.0, 1.2). CONCLUSION: Achieving CE-IM following CE-N reduces the risk of recurrent dysplasia and should be considered a treatment target among patients with BE undergoing endoscopic therapies for HGD or EAC.

Predictors of Malignancy in Patients With Indeterminate Biliary Strictures and Atypical Biliary Cytology: Results From Retrospective Cohort Study.

BACKGROUND: Atypical cellular features are commonly encountered in patients with indeterminate biliary strictures, which are nondiagnostic of malignancy yet cannot rule it out. This study aims to identify clinical features that could discriminate patients with indeterminate biliary strictures and atypical biliary cytology who may harbor underlying malignancy. METHODS: All patients with an indeterminate biliary stricture and an atypical brush cytology obtained during endoscopic brushings were identified in a large tertiary-care center. Demographical information, clinical data and the final pathological diagnosis were collected. The study cohort was divided based on the final diagnosis into benign and malignant groups. Descriptive and multivariable analyses were performed. RESULTS: A total of 151 patients were included in the analysis. Of these, 62.9% were males with mean age of 61.7 ± 16.4 years. Overall, there was an almost equal distribution of patients in the benign and malignant groups. Older age (≥65 years), jaundice, weight loss, intrahepatic biliary and pancreatic duct dilation, double-duct sign and presence of a mass were associated with malignancy in the univariate analysis. However, only older age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00 to 1.03), jaundice (OR 3.33, 95% CI 1.11 to 9.98) and presence of a mass (OR 12.10, 95% CI 4.94 to 29.67) were significantly associated with malignancy in the multivariate analysis. High CA19-9 was associated with malignancy only in patients with primary sclerosing cholangitis. CONCLUSION: In patients with indeterminate biliary stricture and atypical brush cytology, older age, jaundice and presence of a mass are significant predictors of malignancy. Patients with such characteristics need prompt evaluation to rule out underlying malignancy.

Autophagic Heterogeneity in Gastric Adenocarcinoma.

BACKGROUND AND AIM: Gastric/gastroesophageal junction (GEJ) adenocarcinoma is a heterogeneous disease, with various etiologies and with tumors encompassing a spectrum of histologic and molecular subtypes. "Autophagy" includes two related but distinct homeostatic processes that promote cell survival under adverse conditions, namely macro- and chaperone-mediated autophagy. There is increasing evidence of the roles autophagy may play in tumorigenesis. METHODS: Autophagic pathways were examined in the context of the heterogeneity intrinsic to gastric/GEJ adenocarcinoma, utilizing immunohistochemistry targeting specific proteins within the pathways (p62, LAMP2A, LC3B). We examined whole sections of normal and dysplastic gastric mucosa, as well as a tissue microarray of adenocarcinomas. RESULTS: Dysplastic gastric epithelium was marked by frequent nuclear p62 and aberrant LAMP2A expression compared to normal. Examining the pattern of LC3B/cytoplasmic p62 immuno-reactivity in gastric adenocarcinoma demonstrated a predominant pattern of LC3BHigh/p62High staining (56/86, 65.1%), which has been previously associated with active, but impaired macroautophagy. There were no statistically significant associations seen between LC3B/cytoplasmic p62 staining patterns with tumor grade, histotype, or approximated TCGA molecular subtype. LAMP2A and nuclear p62 and staining patterns were also heterogeneous across the cohort, but with no statistically significant associations seen. The prognostic significance of the three proteins was limited, however high nuclear p62 levels were associated with worse overall survival (log-rank p-value = 0.0396). CONCLUSION: Our data demonstrate the dynamic nature of autophagic proteins in the gastric epithelium, and we expand the biological heterogeneity observed in gastric/GEJ adenocarcinoma to include autophagy.

Nod1 promotes colorectal carcinogenesis by regulating the immunosuppressive functions of tumor-infiltrating myeloid cells.

Pioneering studies from the early 1980s suggested that bacterial peptidoglycan-derived muramyl peptides (MPs) could exert either stimulatory or immunosuppressive functions depending, in part, on chronicity of exposure. However, this Janus-faced property of MPs remains largely unexplored. Here, we demonstrate the immunosuppressive potential of Nod1, the bacterial sensor of diaminopimelic acid (DAP)-containing MPs. Using a model of self-limiting peritonitis, we show that systemic Nod1 activation promotes an autophagy-dependent reprogramming of macrophages toward an alternative phenotype. Moreover, Nod1 stimulation induces the expansion of myeloid-derived suppressor cells (MDSCs) and maintains their immunosuppressive potential via arginase-1 activity. Supporting the role of MDSCs and tumor-associated macrophages in cancer, we demonstrate that myeloid-intrinsic Nod1 expression sustains intra-tumoral arginase-1 levels to foster an immunosuppressive and tumor-permissive microenvironment during colorectal cancer (CRC) development. Our findings support the notion that bacterial products, via Nod1 detection, modulate the immunosuppressive activity of myeloid cells and fuel tumor progression in CRC.

Tissue stress from laparoscopic grasper use and bowel injury in humans: establishing intraoperative force boundaries.

OBJECTIVES: We aim to determine what threshold of compressive stress small bowel and colon tissues display evidence of significant tissue trauma during laparoscopic surgery. DESIGN: This study included 10 small bowel and 10 colon samples from patients undergoing routine gastrointestinal surgery. Each sample was compressed with pressures ranging from 100 kPa to 600 kPa. Two pathologists who were blinded to all study conditions, performed a histological analysis of the tissues. Experimentation: November 2018-February 2019. Analysis: March 2019-May 2020. SETTING: An inner-city trauma and ambulatory hospital with a 40-bed inpatient general surgery unit with a diverse patient population. PARTICIPANTS: Patients were eligible if their surgery procured healthy tissue margins for experimentation (a convenience sample). 26 patient samples were procured; 6 samples were unusable. 10 colon and 10 small bowel samples were tested for a total of 120 experimental cases. No patients withdrew their consent. INTERVENTIONS: A novel device was created to induce compressive "grasps" to simulate those of a laparoscopic grasper. Experimentation was performed ex-vivo, in-vitro. Grasp conditions of 0-600 kPa for a duration of 10 s were used. RESULTS: Small bowel (10), M:F was 7:3, average age was 54.3 years. Colon (10), M:F was 1:1, average age was 65.2 years. All 20 patients experienced a significant difference (p<0.05) in serosal thickness post-compression at both 500 and 600 kPa for both tissue types. A logistic regression analysis with a sensitivity of 100% and a specificity of 84.6% on a test set of data predicts a safety threshold of 329-330 kPa. CONCLUSIONS: A threshold was discovered that corresponded to both significant serosal thickness change and a positive histological trauma score rating. This "force limit" could be used in novel sensorized laparoscopic tools to avoid intraoperative tissue injury.

Lgr5 and stem/progenitor gene expression in gastric/gastroesophageal junction carcinoma - significance of potentially retained stemness.

BACKGROUND: Gastric/gastroesophageal junction (GEJ) adenocarcinomas are heterogeneous, comprising four molecularly distinct subtypes, namely EBV-positive, microsatellite instability (MSI), chromosomal instability (CIN) and genomically stable (GS) subtypes, and a part of this heterogeneity may hypothesized to be different cells-of-origin. Stem/progenitor cell hierarchy in the stomach is complex, which include the Lgr5(+) gastric stem cells (GSCs). METHODS: While previous studies have focused on non-nuclear Lgr5 expression, nuclear Lgr5 expression has been reported in a subset of stem cells, and we examined nuclear Lgr5 expression in a local cohort of 95 cases of gastric/GEJ adenocarcinoma. mRNA levels for LGR5 and other stem cell marker genes were examined in the TCGA cohort. RESULTS: We observed nuclear Lgr5 expression in a 18/95 cases. Near mutual exclusivity was seen between nuclear Lgr5 and strong non-nuclear Lgr5. Both strong non-nuclear and nuclear Lgr5 expression tended to be seen more frequently with the intestinal histotype and approximated CIN molecular subtype. With respect to overall survival (OS), nuclear Lgr5 expression appears to be protective, with the worst survival being seen in the cases lacking nuclear Lgr5 and with low non-nuclear Lgr5 expression. When compared to other stem/progenitor cell markers, LGR5 mRNA expression clusters with other GSC marker genes, including VIL1. Higher expression of these GSC marker genes was associated with better OS. CONCLUSIONS: Our results show that Lgr5 expression is dynamic in gastric/GEJ adenocarcinoma and heterogeneous across the several disease attributes. We postulate that this may reflect "retained stemness" in the form of Lgr5High-GSC signature that appears to be associated with better survival.

Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer.

Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMR-deficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.

Lipocalin 2 links inflammation and ankylosis in the clinical overlap of inflammatory bowel disease (IBD) and ankylosing spondylitis (AS).

BACKGROUND: Little is known about the mechanisms underlying the clinical overlap between gut inflammation and joint ankylosis, as exemplified by the concurrence of inflammatory bowel diseases (IBD) and ankylosing spondylitis (AS). As dysbiosis may serve as a common contributor, the anti-microbial pleiotropic factor lipocalin 2 could be a potential mediator due to its roles in inflammation and bone homeostasis. METHODS: Baseline colonic pathology was conducted in the ank/ank mouse model. Serum lipocalin 2 was analyzed by ELISA, in ank/ank mutants versus C3FeB6-A/Aw-jwt/wt, in patients with concurrent AS-IBD, AS alone, IBD alone, or mechanical back pain, and in healthy controls. In the ank/ank mouse model, the expression of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) was examined by real-time PCR. Intraperitoneal injection was done with the PPARγ agonist rosiglitazone or antagonist bisphenol A diglycidyl ether for four consecutive days. Serum levels of lipocalin 2 were examined on the sixth day. RESULTS: This study showed that the ank/ank mice with fully fused spines had concurrent colonic inflammation. By first using the ank/ank mouse model with progressive ankylosis and subclinical colonic inflammation, confirmed in patients with concurrent AS and IBD, elevated circulating lipocalin 2 levels were associated with the coexisting ankylosis and gut inflammation. The intracellular pathway of lipocalin 2 was further investigated with the ank/ank mouse model involving PPARγ. Colonic expression of PPARγ was negatively associated with the degree of gut inflammation. The PPARγ agonist rosiglitazone treatment significantly upregulated the serum levels of lipocalin 2, suggesting a potential regulatory role of PPARγ in the aberrant expression of lipocalin 2. CONCLUSIONS: In summary, lipocalin 2 modulated by PPARγ could be a potential pathway involved in concurrent inflammation and ankylosis in AS and IBD.

Endoscopic Resection of Ampullary Tumours: Long-term Outcomes and Adverse Events.

BACKGROUND: The management of ampullary lesions has shifted from surgical approach to endoscopic resection. Previous reports were limited by small numbers of patients and short follow-up. The aim of this study is to describe short- and long-term outcomes in a large cohort of patients undergoing endoscopic ampullectomy. METHODS: Retrospective study of endoscopic ampullectomies performed at a tertiary center from January 1999 to October 2016. Information recorded includes patient demographics, clinical outcomes, lesion pathology, procedural events, adverse events and follow-up data. RESULTS: Overall, 103 patients underwent endoscopic resection of ampullary tumours (mean age 62.3 ± 14.3 years, 50.5% female, mean lesion size 20.9 mm; 94.9% adenomas, with a majority of lesions exhibiting low-grade dysplasia (72.7%). Complete endoscopic resection was achieved in 82.5% at initial procedure. Final complete endoscopic resection was achieved in all patients with benign pathology on follow-up procedures. Final pathology showed that 11% had previously undiagnosed invasive carcinoma. Delayed postprocedure bleeding occurred in 21.4%, all of which were managed successfully at endoscopy. Acute pancreatitis complicated 15.5% of procedures (mild in 93.8%). Perforation occurred in 5.8%, all treated conservatively except for one patient requiring surgery. Piecemeal resection was associated with significantly higher recurrence compared to en-bloc resection (54.3% versus 26.2%, respectively, P = 0.012). All recurrences were treated endoscopically. CONCLUSION: Endoscopic ampullectomy appears both safe and effective in managing patients with ampullary tumours in experienced hands. Most adverse events can be managed conservatively. Many patients develop recurrence during long-term follow-up but can be managed endoscopically. Recurrence rates may be reduced by performing initial en-bloc resection.

Pathological assessment of endoscopic resections of the gastrointestinal tract: a comprehensive clinicopathologic review.

Endoscopic resection (ER) allows optimal staging with potential cure of early-stage luminal malignancies while maintaining organ preservation. ER and surgery are non-competing but complementary therapeutic options. In addition, histological examination of ER specimens can either confirm or refine the pre-procedure diagnosis. ER is used for the treatment of Barrett's related early carcinomas and dysplasias, early-esophageal squamous cell carcinomas and dysplasias, early gastric carcinomas and dysplasia, as well as low-risk submucosal invasive carcinomas (LR-SMIC) and, large laterally spreading adenomas of the colon. For invasive lesions, histological risk factors predict risk of lymph node metastasis and residual disease at the ER site. Important pathological risk factors predictive of lymph node metastasis are depth of tumor invasion, poor differentiation, and lymphovascular invasion. Complete resection with negative margins is critical to avoid local recurrences. For non-invasive lesions, complete resection is curative. Therefore, a systematic approach for handling and assessing ER specimens is recommended to evaluate all above key prognostic features appropriately. Correct handling starts with pinning the specimen before fixation, meticulous macroscopic assessment with orientation of appropriate margins, systematic sectioning, and microscopic assessment of the entire specimen. Microscopic examination should be thorough for accurate assessment of all pathological risk factors and margin assessment. Site-specific issues such as duplication of muscularis mucosa of the esophagus, challenges of assessing ampullectomy specimens and site-specific differences of staging of early carcinomas throughout the gastrointestinal tract (GI) tract should be given special consideration. Finally, a standard, comprehensive pathology report that allows optimal staging with potential cure of early-stage malignancies or better stratification and guidance for additional treatment should be provided.

Isolated Optic Perineuritis as the Presenting Sign of Sarcoidosis.

A 35-year-old healthy African-American woman presented with a 4-month history of gradual loss of vision in the right eye from an optic neuropathy. MRI of the orbits with gadolinium showed isolated thickening and enhancement of the right optic nerve sheath. Chest x-ray and CT-scan of the chest were performed and showed bilateral hilar and mediastinal lymphadenopathy. This was suggestive of sarcoidosis, and the diagnosis was confirmed with histopathology. The patient promptly recovered vision with high-dose corticosteroids; the thickening of the optic nerve sheath also regressed. Isolated optic nerve sheath thickening from sarcoidosis is rare and may mimic compressive optic neuropathies such as optic nerve sheath meningiomas. A systemic evaluation for systemic inflammatory etiologies should be considered in such cases.

Histo- and immunohistochemistry-based estimation of the TCGA and ACRG molecular subtypes for gastric carcinoma and their prognostic significance: A single-institution study.

Gastric cancers comprise molecularly heterogeneous diseases; four molecular subtypes were identified in the cancer genome atlas (TCGA) study, with implications in patient management. In our efforts to devise a clinically feasible means of subtyping, we devised an algorithm based on histology and five stains available in most academic pathology laboratories. This algorithm was used to subtype our cohort of 107 gastric cancer patients from a single institution (St. Michael's Hospital, Toronto, Canada), which was divided into 3 cases of EBV-positive, 23 of MSI, 27 of GS and 54 of CIN tumours. 87% of the tumours with diffuse histology were classified as GS subtype, which was notable for younger age. Examining for characteristic molecular features, aberrant p53 immunostaining was seen most frequently in the CIN subtype (43% in CIN vs. 6% in others), whereas ARID1A loss was rarely seen (6% vs. 35% in others). HER2 overexpression was seen exclusively in CIN tumours (17% of CIN tumours). PD-L1 positivity was seen predominantly in the EBV and MSI tumours. As with the TCGA study, no survival differences were seen between the subtypes. A similar strategy was employed to approximate the Asian Cancer Research Group (ACRG) molecular subtyping, with the addition of p53 IHC to the algorithm. We observed rates of ARID1A loss and HER2 overexpression that were comparable to the ACRG study. In summary, our algorithm allowed for clinically feasible means of subtyping gastric carcinoma that recapitulated the key molecular features reported in the large scale studies.

Gastrointestinal transcription factors drive lineage-specific developmental programs in organ specification and cancer.

Transcription factors (TFs) are spatially and temporally regulated during gut organ specification. Although accumulating evidence shows aberrant reactivation of developmental programs in cancer, little is known about how TFs drive lineage specification in development and cancer. We first defined gastrointestinal tissue-specific chromatin accessibility and gene expression during development, identifying the dynamic epigenetic regulation of SOX family of TFs. We revealed that Sox2 is not only essential for gastric specification, by maintaining chromatin accessibility at forestomach lineage loci, but also sufficient to promote forestomach/esophageal transformation upon Cdx2 deletion. By comparing our gastrointestinal lineage-specific transcriptome to human gastrointestinal cancer data, we found that stomach and intestinal lineage-specific programs are reactivated in Sox2high /Sox9high and Cdx2high cancers, respectively. By analyzing mice deleted for both Sox2 and Sox9, we revealed their potentially redundant roles in both gastric development and cancer, highlighting the importance of developmental lineage programs reactivated by gastrointestinal TFs in cancer.

Defining the Relationship Between Compressive Stress and Tissue Trauma During Laparoscopic Surgery Using Human Large Intestine.

Excessive magnitudes of compressive stress exerted on gastrointestinal tissues can lead to pathological scar tissue or adhesion formation, bleeding, inflammation or even death from bowel perforation and sepsis. It is currently unknown however, at exactly what magnitude of compressive stress that these pathologies occur. A novel simple compressive device was engineered to provide an objective means of producing discrete compressive stresses on human tissues. Samples of human large intestine (colon) were removed from consenting patients as a part of their standard surgical procedure. These samples were compressed with a range of loads normally produced by standard laparoscopic graspers in representative abdominal surgeries. After compression, specimens were processed for histological analysis and assessed. The two independent pathologists who were blinded to stress magnitudes were both able to quantify increasing tissue damage that corresponded to increasing amounts of compressive force. A threshold between 350-450 kPa was discovered that corresponded to both significant serosal thickness change and a positive histological trauma score rating. Whether the tissue injury quantified is pathologic is subject for future in-vivo longitudinal investigation but certainly based on literature, can be the basis of pathological adhesion formation or an area for hemorrhage and scar formation.

Clinical, endoscopic, and histologic characteristics of lymphocytic esophagitis: a systematic review.

OBJECTIVE: Lymphocytic esophagitis (LyE) is a novel, yet poorly described, clinicopathologic entity. The aim of this systematic review was to characterize the demographic, clinical, endoscopic, and histologic features of LyE in observational studies of adult and pediatric patients. DESIGN: We searched the Embase, MEDLINE, and SCOPUS databases for relevant studies in 2018. Two authors reviewed and extracted data from studies that met the inclusion and exclusion criteria. RESULTS: We identified 20 studies for analysis of demographic, clinical, and endoscopic features of LyE. The mean age ranged from 9 to 67 years. When pooled, there were 231 (52.7%) patients with LyE that were female. The most common presenting symptom was dysphagia reported in 191 (48.8%) patients. On endoscopy, most patients with LyE tended to have abnormal findings (69.0%), which included erosive esophagitis, multiple esophageal rings, linear furrows, and narrow-caliber esophagus. In the 31 studies used to assess the histologic definition, the cut-off number of intraepithelial lymphocytes (IELs) was reported in 16 (51.6%) studies, peripapillary IEL specification in 18 (58.1%) studies, and presence of spongiosis in 6 (19.4%) studies. CONCLUSION: We identified a spectrum of demographic, clinical, and endoscopic findings characteristic of patients with LyE. A consensus on the diagnostic criteria of LyE is required.

Efficacy of GATA3 Versus BRST2 for the Identification of Metastatic Breast Carcinoma in the Upper GI Tract: Which Performs Better?

Distinguishing primary diffuse-type gastric carcinoma (PDGC) versus gastric involvement by metastatic breast carcinoma (mBC), particularly the lobular subtype, is difficult on histology alone. Both can appear morphologically similar. GATA3, a novel transcription factor, is used in certain scenarios as an immunohistochemical marker of breast origin. Our objective was to investigate the efficacy of GATA3 in differentiating PDGC and mBC and how it compares to another breast marker, BRST2. We retrospectively stained 40 cases of PDGC and 10 control cases of mBC from upper gastrointestinal tract specimens for antibodies: GATA3, BRST2, CDX2, and estrogen receptor. Staining of tumor cells was semiquantified with a modified Allred score. GATA3 and BRST2 were positive in 17.5% and 12.5% of PDGC cases, respectively, and in 100% of mBC cases. Allred scores for GATA3 were significantly greater in mBC cases compared with PDGC (P=0.001). Allred scores were not significantly different for BRST2 due to low levels of staining in mBC cases. Although sensitivity and specificity were similar, differences in staining between PDGC and mBC were more decisive for GATA3 versus BRST2 and thus easier to interpret. In addition, 50% of PDGC cases were positive for CDX2 and none for estrogen receptor. Overall, our results show that GATA3 can reliably and correctly identify cases of mBC to the upper gastrointestinal tract. However, because a minority of PDGC were positive for GATA3, it should still be used within an antibody panel to resolve this diagnostic dilemma.