Systemic diseases affecting the GI tract: A review of clinical and histopathologic manifestations.

A variety of systemic diseases may affect the gastrointestinal (GI) tract. Since the GI tract responds to injury in limited ways, identifying these processes may be challenging, especially on small endoscopic biopsies. This article reviews the clinicopathologic features of commonly encountered systemic diseases affecting the tubular GI tract: sarcoidosis, graft vs. host disease, mast cell disorders, systemic sclerosis, and IgG-4 related disease. In addition, we offer guidance in differentiating them from their mimics.

Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, P < .001), noncolorectal GI site involvement (50%, P = .02), multifocal GI lesions (43%, P = .005), nonpolypoid lesions (71%, P < .001), infiltrative histologic growth pattern (78%, P = .04), and persistent disease (57%, P < .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.

Lobular capillary hemangioma (pyogenic granuloma) of the gastrointestinal tract: Clinicopathologic analysis of 34 cases.

OBJECTIVES: Lobular capillary hemangioma (LCH) rarely involves the gastrointestinal (GI) tract. This study describes clinicopathologic features of LCH in a cohort of GI cases. METHODS: We defined lobular capillary hemangioma as "a proliferation of capillary-sized blood vessels arranged at least focally in a lobular configuration," searched departmental archives for cases, and recorded clinicopathologic findings. RESULTS: We identified 34 GI tract LCHs from 16 men and 10 women; 4 patients had multiple lesions. Mean age was 64 years. Cases arose in the esophagus (n = 7), stomach (n = 3), small bowel (n = 7), and colorectum (n = 17). Twelve patients had anemia or rectal bleeding. No patients had a known genetic syndrome. The lesions manifested as mucosal polyps, with median size of 1.3 cm. Microscopically, 20 lesions were ulcerated, and most involved the mucosa, with 9 extending into the submucosa. Vessel dilation was present in 27 patients, endothelial hobnailing in 13, hemorrhage in 13, and focal reactive stromal atypia in 2. Follow-up information was available for 10 patients, none of whom developed same-site recurrence. Six of the 26 cases (23%) were extradepartmental consultations, including 2 of the multifocal cases. CONCLUSIONS: Gastrointestinal tract LCHs often arise as colorectal polyps. They are typically small but can reach a few centimeters in size and can be multifocal.

B3 thymoma mimicking poorly differentiated thyroid carcinoma: Diagnostic pitfalls of anterior mediastinal mass fine needle aspiration.

B3 thymoma is a rare malignant type of thymic epithelial neoplasm found in the anterior mediastinum. Diagnosis of thymoma from fine needle aspiration (FNA) can be challenging due to the infrequency of sampling and its morphologic overlap with other entities such as squamous cell carcinoma, lymphoma or thyroid carcinoma. We report a case of B3 thymoma mimicking poorly differentiated thyroid carcinoma. We present its diagnostic pitfalls on cytology specimens, especially where it concerns identifying the correct location of the lesion, discuss the differential diagnosis, and correlation with the corresponding surgical resection specimen. A neck computed tomography angiogram (CTA) revealed a partially calcified 2.1 cm mass inferior to the left thyroid lobe in a 51 yr old woman being evaluated for stroke/TIA symptoms. She was referred for evaluation of the lesion. On the initial FNA and core needle biopsy, the lesion showed high-grade epithelioid cells with abundant lymphocytic infiltration and occasional necrosis, and was diagnosed as a high-grade carcinoma, favored to represent a poorly differentiated thyroid carcinoma considering the location on imaging. The patient subsequently underwent total thyroidectomy, central neck dissection, and thymectomy. Final surgical pathologic diagnosis indicated a type B3 thymoma. Due to the infrequency of sampling, thymoma poses a diagnostic challenge on preoperative FNA or core needle biopsy. Herein, we present a case of B3 thymoma with a preoperative cytologic specimen that consisted of hyperchromatic sheets of epithelioid tumor cells with a background of lymphocytes without definitive follicular cells or colloid. The core needle biopsy and cell block material showed abundant necrosis, intermixed lymphocytes and neoplastic epithelial cells with strong positive staining for pan-keratin and p40. The cytology and core needle biopsy material were interpreted as representing a probable thyroid neoplasm and raised a broad differential including anaplastic thyroid carcinoma, poorly differentiated thyroid carcinoma with squamous features, metastatic squamous carcinoma, and metastatic carcinoma to a lymph node. The final surgical resection specimen showed a B3 type-thymoma.

Overexpression of programmed death ligand 1 in refractory inflammatory bowel disease.

Programmed death ligand 1 (PD-L1) dysregulation has been implicated in chronic inflammatory diseases, but its role in regulating intestinal mucosa inflammation is still unclear. The aim of this study was to assess PD-L1 expression in the intestinal mucosa of patients with refractory inflammatory bowel disease (IBD) compared to controls. We evaluated PD-L1 expression by immunohistochemistry in colectomy specimens of patients with ulcerative colitis (UC) and Crohn disease (CD) compared to controls. PD-L1 expression was assessed in colonic epithelium and inflammatory cells, along with the location of the inflammatory cells expressing PD-L1. All cases were stained with CD3, CD4, CD8, FOXP3, CD20, CD68, and CD90 immunostains to determine the types of cells expressing PD-L1. The UC group showed significantly higher PD-L1 expression in the colonic epithelium than both CD and control groups (both P < 0.001), and CD was also significantly higher than the control group (P = 0.004). Both UC and CD groups showed similar PD-L1 expression in the inflammatory infiltrate but significantly higher than the control group (both P < 0.001). Among both IBD groups, higher IBD activity was associated with higher levels of PD-L1 expression in the colonic epithelium (P < 0.05) and inflammatory infiltrate (P < 0.001). When comparing PD-L1 expression to lineage-specific markers, CD3+, CD4+ T cells, CD68+ macrophages, and CD90+ colonic stromal cells appeared to be expressing PD-L1. These findings implicate a role for PD-L1 in the dysregulation of the immune response in refractory IBD. Further studies are warranted to better understand the role of the immune regulatory pathways in intestinal mucosa.

Hepatic Secondary Syphilis Can Cause a Variety of Histologic Patterns and May Be Negative for Treponeme Immunohistochemistry.

The rate of syphilis in the United States has been increasing steadily in the past decade, but it remains an uncommon diagnosis in tissue biopsies. Most of the pathology literature on hepatic syphilis consists of older series or case reports. This study aimed to systematically characterize the histologic spectrum of hepatic syphilis in a contemporary cohort. Clinicopathologic features of 14 hepatic syphilis cases between 2012 and 2018 were analyzed to characterize the broad spectrum of histologic changes. Thirteen patients were men (age range: 19 to 59 y); 6 had known human immunodeficiency virus, 7 were men known to have sex with men, and no patient had known prior syphilis. Hepatic syphilis was the primary clinical suspicion in only 1 patient. Common symptoms included jaundice, rash, and abdominal pain. Thirteen had elevated transaminases, and 12 had elevated alkaline phosphatase. Pathologic changes were grouped into 5 histologic patterns: biliary-pattern injury (n=5), acute hepatitis (n=4), autoimmune hepatitis-like (n=1), fibroinflammatory mass-forming lesion (n=2), and no particular pattern (n=2). Nearly all showed portal and lobular lymphocytes and plasma cells; 12 had prominent histiocytes/Kupffer cells, 9 had ductular reaction, and 7 had duct inflammation. Occasional focal findings included dropout (n=7), phlebitis (n=7), and loose granulomata (n=5). Treponeme immunohistochemistry was positive in 10 and negative in 4, though treatment was given before biopsy in 3 of those 4. Thirteen patients had rapid plasma reagin testing either before or after biopsy, with 1:64 or higher titer. All patients who received treatment recovered. Hepatic syphilis is rare but likely underrecognized. It exhibits a variety of histologic appearances and therefore should be considered in several hepatic differential diagnoses, especially in men who have sex with men. Kupffer cells, granulomata, and phlebitis may suggest the diagnosis regardless of predominant histologic pattern. Negative treponeme immunohistochemical staining does not exclude the diagnosis, including in untreated patients.

Liver Pathology and SARS-CoV-2 Detection in Formalin-Fixed Tissue of Patients With COVID-19.

OBJECTIVES: The novel coronavirus, severe acute respiratory syndrome coronavirus 2, causing coronavirus disease 2019 (COVID-19) remains a global health threat and a significant source of human morbidity and mortality. While the virus primarily induces lung injury, it also has been reported to cause hepatic sequelae. METHODS: We aimed to detect the virus in formalin-fixed tissue blocks and document the liver injury patterns in patients with COVID-19 compared with a control group. RESULTS: We were able to detect viral RNA in the bronchioalveolar cell blocks (12/12, 100%) and formalin-fixed, paraffin-embedded tissue of the lung (8/8, 100%) and liver (4/9, 44%) of patients with COVID-19. Although the peak values of the main liver enzymes and bilirubin were higher in the patients with COVID-19 compared with the control group, the differences were not significant. The main histologic findings were minimal to focal mild portal tract chronic inflammation (7/8, 88%, P < .05) and mild focal lobular activity (6/8, 75%, P = .06). CONCLUSIONS: We found that most patients who died of COVID-19 had evidence of mild focal hepatitis clinically and histologically; however, the virus was detected in less than half of the cases.

Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett's Esophagus to Invasive Esophageal Adenocarcinoma.

OBJECTIVE: The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett's Esophagus (BE) to esophageal adenocarcinoma. BACKGROUND: The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC. METHODS: The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett's Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry. RESULTS: BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively. CONCLUSION: Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium.

Histopathology of SPINK-1 Hereditary Pancreatitis.

Hereditary pancreatitis is a rare form of recurrent acute pancreatitis that typically has an onset in early adulthood. We report a rare case of hereditary pancreatitis in an individual with a serine protease inhibitor Kazal type 1 (SPINK1) mutation. Histologically the pancreas showed features of chronic pancreatitis with variable fibrosis, acinar destruction, and prominent inspissated secretions within the pancreatic ducts. Additionally, focal areas of low-grade pancreatic intraepithelial neoplasia (PanIN) were present. Although the histopathology of common gene mutations resulting in hereditary pancreatitis have been well described, the histopathology of pancreatitis secondary to SPINK1 mutation has been described in only one previous study.

Wirelessly controlled, bioresorbable drug delivery device with active valves that exploit electrochemically triggered crevice corrosion.

Implantable drug release platforms that offer wirelessly programmable control over pharmacokinetics have potential in advanced treatment protocols for hormone imbalances, malignant cancers, diabetic conditions, and others. We present a system with this type of functionality in which the constituent materials undergo complete bioresorption to eliminate device load from the patient after completing the final stage of the release process. Here, bioresorbable polyanhydride reservoirs store drugs in defined reservoirs without leakage until wirelessly triggered valve structures open to allow release. These valves operate through an electrochemical mechanism of geometrically accelerated corrosion induced by passage of electrical current from a wireless, bioresorbable power-harvesting unit. Evaluations in cell cultures demonstrate the efficacy of this technology for the treatment of cancerous tissues by release of the drug doxorubicin. Complete in vivo studies of platforms with multiple, independently controlled release events in live-animal models illustrate capabilities for control of blood glucose levels by timed delivery of insulin.

Gastrointestinal Malakoplakia: Clinicopathologic Analysis of 26 Cases.

Malakoplakia is an inflammatory process related to defective macrophage response to bacterial infection. To further characterize the clinicopathologic manifestations of gastrointestinal malakoplakia, 26 cases were identified from 6 institutions. Hematoxylin and eosin-stained slides and available stains were reviewed, and pertinent clinicopathologic features analyzed. Sixteen patients were women (62%). Mean patient age was 64 (range: 24 to 83). Sites included the colorectum (n=23), appendix (n=1), and stomach (n=2). Clinical indications for tissue procurement included screening (n=14), tumor resection (n=5), diarrhea (n=1), adenoma surveillance (n=1), ulcerative colitis flare (n=1), abdominal pain (n=1), and appendicitis (1). All cases featured histiocytes with abundant, pale, eosinophilic cytoplasm focally containing Michaelis-Gutmann bodies. The process frequently involved the mucosa (n=19), with architectural distortion in 13 cases. Lymphoid aggregates were present in 18 cases, which were prominent or obscuring in 11 (all colon biopsies) and provoked concern for lymphoma in 2. Associated findings included adenocarcinoma (n=5), adenoma (n=2), gastric hyperplastic polyps (n=1), chemical gastritis (n=1), collagenous colitis (n=1), and active chronic colitis (n=2). In cases with available stains, Michaelis-Gutman bodies were highlighted by Periodic Acid-Schiff with diastase, Von Kossa, and iron stains. Although 2 cases were positive for Tropheryma whipplei antibody, no T. whipplei transcripts were detected on real-time polymerase chain reaction. All patients with available follow-up are alive and well with no additional instances of malakoplakia. Malakoplakia of the gastrointestinal tract is a benign, incidental finding. Although histologic features in the stomach and colon resections are similar to those at other sites, exuberant lymphocytic response in colon biopsies and immunoreactivity with T. whippleii antibody may provoke initial confusion and lead to unnecessary time and resource investment.

Characterization of Novel Injectable Lifting Agents Used in Colonic Polyp Removal: An Emerging Amyloid Mimic.

Colon polypectomy can require an injection of a submucosal lifting agent to fully visualize and completely remove the polyp. To the best of our knowledge, this is the largest morphologic series on the novel lifting agents Eleview and Orise. The study consisted of 1 polypectomy and 8 colon resections from 9 patients: 6 women, 3 men (mean age=64 y); Orise=6, Eleview=3; the median time interval between injection and resection=16 weeks. Pathologic diagnoses of the polyps included tubular adenoma (n=4), tubulovillous adenoma (n=4), and sessile serrated adenoma/polyp (n=1). We report that a histologically processed Orise aliquot from the manufacturer showed similar histology to that seen in the specimens from patients with confirmed Orise injection. The morphology of the agents in the patient specimens changed with time status postinjection: immediate resection of the lifting agent showed basophilic, amorphous, and bubbly-extracellular material with prominent hemorrhage, and resection ∼3 months after lifting agent injection showed prominent hyalinized, pink-amorphous ribbons and globules with a foreign body giant cell reaction and fibrosis. The epicenter of the lifting agents was in the submucosa, and the agents were neither refractile nor polarizable. Because of the morphologic overlap with amyloid, 5 cases were stained with Congo Red, and all cases were negative. In conclusion, awareness of the morphology of these new lifting agents is important for accurate diagnosis and to avoid the diagnostic pitfall of amyloid. These lesions can be definitively distinguished from amyloid by their nonreactivity on a Congo Red and familiarity with their characteristic clinicopathologic presentation.

Bioresorbable photonic devices for the spectroscopic characterization of physiological status and neural activity.

Capabilities in real-time monitoring of internal physiological processes could inform pharmacological drug-delivery schedules, surgical intervention procedures and the management of recovery and rehabilitation. Current methods rely on external imaging techniques or implantable sensors, without the ability to provide continuous information over clinically relevant timescales, and/or with requirements in surgical procedures with associated costs and risks. Here, we describe injectable classes of photonic devices, made entirely of materials that naturally resorb and undergo clearance from the body after a controlled operational lifetime, for the spectroscopic characterization of targeted tissues and biofluids. As an example application, we show that the devices can be used for the continuous monitoring of cerebral temperature, oxygenation and neural activity in freely moving mice. These types of devices should prove useful in fundamental studies of disease pathology, in neuroscience research, in surgical procedures and in monitoring of recovery from injury or illness.

Bioresorbable optical sensor systems for monitoring of intracranial pressure and temperature.

Continuous measurements of pressure and temperature within the intracranial, intraocular, and intravascular spaces provide essential diagnostic information for the treatment of traumatic brain injury, glaucoma, and cardiovascular diseases, respectively. Optical sensors are attractive because of their inherent compatibility with magnetic resonance imaging (MRI). Existing implantable optical components use permanent, nonresorbable materials that must be surgically extracted after use. Bioresorbable alternatives, introduced here, bypass this requirement, thereby eliminating the costs and risks of surgeries. Here, millimeter-scale bioresorbable Fabry-Perot interferometers and two dimensional photonic crystal structures enable precise, continuous measurements of pressure and temperature. Combined mechanical and optical simulations reveal the fundamental sensing mechanisms. In vitro studies and histopathological evaluations quantify the measurement accuracies, operational lifetimes, and biocompatibility of these systems. In vivo demonstrations establish clinically relevant performance attributes. The materials, device designs, and fabrication approaches outlined here establish broad foundational capabilities for diverse classes of bioresorbable optical sensors.

Bioresorbable pressure sensors protected with thermally grown silicon dioxide for the monitoring of chronic diseases and healing processes.

Pressures in the intracranial, intraocular and intravascular spaces are clinically useful for the diagnosis and management of traumatic brain injury, glaucoma and hypertension, respectively. Conventional devices for measuring these pressures require surgical extraction after a relevant operational time frame. Bioresorbable sensors, by contrast, eliminate this requirement, thereby minimizing the risk of infection, decreasing the costs of care and reducing distress and pain for the patient. However, the operational lifetimes of bioresorbable pressure sensors available at present fall short of many clinical needs. Here, we present materials, device structures and fabrication procedures for bioresorbable pressure sensors with lifetimes exceeding those of previous reports by at least tenfold. We demonstrate measurement accuracies that compare favourably to those of the most sophisticated clinical standards for non-resorbable devices by monitoring intracranial pressures in rats for 25 days. Assessments of the biodistribution of the constituent materials, complete blood counts, blood chemistry and magnetic resonance imaging compatibility confirm the biodegradability and clinical utility of the device. Our findings establish routes for the design and fabrication of bioresorbable pressure monitors that meet requirements for clinical use.

90Y-TheraSpheres: The New Look of Yttrium-90.

Selective internal radiation therapy with Y-TheraSphere or Y-SIRSphere is used in the treatment of unresectable hepatic malignancies. To the best of our knowledge, this is the first Y-TheraSpheres series. BTG International Canada Inc. provided nonradiated microspheres from the Nordion manufacturer. The histologic processed microspheres were colorless, refractile, polarizable, 20 to 30 µm in diameter, and an occasional internal bulls'-eye seen with the condenser out and an internal cross seen with polarized light. Identical microspheres were identified in 15 hepatectomy specimens from four centers between February 2016 and March 2018. The patients were usually male (male=10, female=5) with a mean age of 59 years. All patients had a prior diagnosis of hepatocellular carcinoma (HCC) and documented Y-TheraSphere (mean duration from last deployment=32 wk). All surgical pathology specimens in these 15 patients were reviewed, but the microspheres were only identified in the hepatectomy specimens. During manuscript preparation, one case of Y-TheraSpheres gastritis was prospectively identified from a separate patient with a history of HCC and Y-TheraSpheres. In conclusion, recognition of Y-TheraSpheres is important so that one may consider the possibility of a nearby malignancy and or establish the cause of the background inflammatory or radiation-related injury. These structures can be easy to miss because the subtle morphology is distinct from previously reported Y-SIRSphere. Clues to the diagnosis include a history of HCC and background radiation change. We report the characteristic morphology as microspheres that overlap in size with Y-SIRSphere, but can be differentiated based on Y-TheraSpheres' colorless appearance with occasional internal bulls'-eyes with the condenser out and an internal cross with polarized light.

Lactosylceramide synthase ß-1,4-GalT-V: A novel target for the diagnosis and therapy of human colorectal cancer.

Little is known about an oncogenic signal transducer ß-1,4-galactosyltransferase-V (ß-1,4-GalT-V), in human colorectal cancer. Using quantitative RT-PCR, immunohistochemical staining and ELISA assays, we determined that ß-1,4-GalT-V gene/protein expression is specifically increased in human colorectal cancer (CRC) tumors, compared to visibly normal tissue. Furthermore, we observed a marked increase in its enzymatic activity, and its product lactosylceramide. Moreover, we found increased dihydrosphingolipid metabolites, in particular dihydrosphingomyelin in cancer tissue compared to normal. Further, inhibition of glycosphingolipid synthesis by the synthetic ceramide analog, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), concurrently inhibited colorectal cancer cell (HCT-116) proliferation, as well as ß-1,4-GalT-V mass and several glycosphingolipid levels. We conclude that ß-1,4-GalT-V may serve as a diagnostic and therapeutic biomarker for the progression of human colorectal cancer, and consequently, inhibition of GSL synthesis may be a novel approach for the treatment of this life-threatening disease.

Refractory inflammatory bowel disease: is there a role for Epstein-Barr virus? A case-controlled study using highly sensitive Epstein-Barr virus-encoded small RNA1 in situ hybridization.

A potential role for viral infections has been implicated in inflammatory bowel disease (IBD) unresponsive to medical treatment. It is well known that Epstein-Barr virus (EBV) infection can elicit a brisk mononuclear response in the gastrointestinal tract. The aim of this study was to further evaluate the role of EBV in patients with refractory IBD and compare them with nonrefractory IBD cases. Surgically resected colonic specimens from 67 patients with refractory IBD (62 with ulcerative colitis, 3 patients with Crohn disease, and 2 patients with indeterminate colitis) were retrieved. Twelve colectomy specimens from patients with ulcerative colitis who had undergone resections for dysplasia or endometriosis were included as controls. Highly sensitive EBV-encoded small RNA1 (EBER-1) in situ hybridization was performed on a representative block from each specimen. EBER-1 reactivity was graded as absent, focal, or diffuse. EBV was detected in 60% (40/67) of patients with refractory IBD compared with 25% (3/12) of the control group (P < .05). Focal EBER-1 positivity was present in 45% of cases of refractory IBD compared with 25% of controls. Diffuse EBER-1 reactivity was seen in 15% of cases of refractory IBD (10/67); none of the samples from the control group contained diffuse EBER-1 positivity. There was a positive correlation between EBER positivity and depth of inflammation and mucosal ulceration in patients with refractory IBD. Our findings suggest a potential role for EBV infection in patients with refractory IBD.