Injectable, Drug-Eluting Nanocrystals Prevent Fibrosis and Stricture Formation In Vivo.

BACKGROUND & AIMS: Tissue fibrosis results from uncontrolled healing responses leading to excessive mesenchymal cell activation and collagen and other extracellular matrix deposition. In the gastrointestinal tract, fibrosis leads to narrowing of the lumen and stricture formation. A drug treatment to prevent fibrosis and strictures in the gastrointestinal tract would be transformational for patient care. We aimed to develop a stricture treatment with the following characteristics and components: a small molecule with strong antifibrotic effects that is delivered locally at the site of the stricture to ensure correct lesional targeting while protecting the systemic circulation, and that is formulated with sustained-release properties to act throughout the wound healing processes. METHODS: A high-throughput drug screening was performed to identify small molecules with antifibrotic properties. Next, we formulated an antifibrotic small molecule for sustained release and tested its antifibrotic potential in 3 animal models of fibrosis. RESULTS: Sulconazole, a US Food and Drug Administration-approved drug for fungal infections, was found to have strong antifibrotic properties. Sulconazole was formulated as sulconazole nanocrystals for sustained release. We found that sulconazole nanocrystals provided superior or equivalent fibrosis prevention with less frequent dosing in mouse models of skin and intestinal tissue fibrosis. In a patient-like swine model of bowel stricture, a single injection of sulconazole nanocrystals prevented stricture formation. CONCLUSIONS: The current data lay the foundation for further studies to improve the management of a range of diseases and conditions characterized by tissue fibrosis.

Cross-Sectional Imaging Characteristics of Pancreatic Intraductal Oncocytic Papillary Neoplasms.

PURPOSE: Pancreatic intraductal oncocytic papillary neoplasms (IOPN) are rare precursors to pancreatic ductal adenocarcinoma. We report cross-sectional computed tomography and magnetic resonance imaging (where available) findings of pancreatic IOPNs. MATERIALS AND METHODS: Consecutive cases of pancreatic IOPNs identified on pathology between 2008 and 2020 at University of Pittsburgh and Johns Hopkins University were included in the study. Cross-sectional imaging of all patients was reviewed by two subspecialty trained abdominal radiologists. Patient demographics, cross-sectional imaging appearances and growth characteristics were evaluated. RESULTS: In this dual-center study, 14 patients with IOPNs were included. Median age was 64 years, and 64% were male. The median size of the lesions was 5.4 cm (range, 1.4-12.3 cm). All patients had either an enhancing mural nodule (93% of patients) and/or thick internal septations (29%). Thin/imperceptible outer wall was seen in 93%. Main duct was involved in 64% of the cases. Only 14% of the cases did not demonstrate abutment of the main duct. Histologic evaluation of surgical specimen showed high-grade dysplasia without invasive carcinoma in 57% and invasive carcinoma in 43% of cases. Lesions with invasive carcinoma were larger (7.1 cm vs 4.3 cm, P = 0.05) and tended to have larger mural nodule (3.7 cm vs 1.8 cm) compared with those without invasive carcinoma. CONCLUSION: Pancreatic IOPNs are rare cystic premalignant lesions, which among resected cases, are predominantly seen in middle aged men, are often large, have enhancing mural nodules and frequently harbor invasive carcinoma.

A Novel Patient-like Swine Model of Perianal Crohn's Disease.

BACKGROUND: Perianal Crohn's disease is associated with poor outcomes and high medical costs. It is notoriously difficult to treat despite therapeutic advancements for luminal disease. A large animal model that mimics human perianal disease is needed to test innovative therapies. OBJECTIVE: This study aimed to create a swine model that replicates the inflammatory component and therapeutic challenges found in patients with perianal Crohn's disease. DESIGN: This was an animal preclinical study. SETTINGS: The experiments were performed at the animal laboratory at the Johns Hopkins University. PATIENTS: Four sus scrufus female pigs were included in the study. INTERVENTIONS: Four female pigs underwent creation of 3 surgical perianal fistulas each, 1 rectovaginal and 2 perianal. Size 24 French setons were placed to maintain patency of the fistula tracts for 4 weeks. After removal of the setons, trinitrobenzene sulfonic acid was administered into the fistula tract to create and maintain local inflammation mimicking perianal Crohn's disease. MAIN OUTCOMES MEASURES: An MRI was obtained to assess the fistulas and the pigs were euthanized to review histopathology. RESULTS: Three inflammatory chronic fistula tracts were successfully created in each pig as confirmed by MRI and examination under anesthesia. This is the first report of maintaining patent fistulas in swine 2 weeks after removal of setons. For the first time, we reported that 2 pigs developed branching fistulas and small abscesses reminiscent of human perianal Crohn's disease. The corresponding histopathologic examination found significant chronic active inflammation on standard hematoxylin and eosin staining. LIMITATIONS: The fistulas were surgically induced and did not occur naturally. CONCLUSIONS: A chronic perianal fistula model in pigs that strongly resembles human perianal Crohn's disease was successfully created. This model can be used to test novel therapeutics and techniques to pave the path for human trials. See Video Abstract at http://links.lww.com/DCR/B969 . UN NUEVO MODELO PORCINO SIMILAR A UN PACIENTE DE LA ENFERMEDAD DE CROHN PERIANAL ANTECEDENTES: La enfermedad de Crohn perianal se asocia con malos resultados y altos costos médicos. Es notoriamente difícil de tratar a pesar de los avances terapéuticos para la enfermedad luminal. Se precisa de un modelo animal grande que imite la enfermedad perianal humana para probar terapias innovadoras.OBJETIVO:Nuestro objetivo de este estudio fue crear un modelo porcino que replique el componente inflamatorio y los desafíos terapéuticos que se encuentran en los pacientes con enfermedad de Crohn perianal.DISEÑO:Este fue un estudio preclínico en animales.AJUSTES:Los experimentos se realizaron en el laboratorio de animales de la Universidad Johns Hopkins.PACIENTES:Se incluyeron en el estudio cuatro cerdas sus scrofa.INTERVENCIONES:Cuatro cerdas fueron sometidas a la creación de 3 fístulas perianales quirúrgicas cada una: 1 recto vaginal y 2 perianales. Se colocaron sedales de 24 French para mantener la permeabilidad de los trayectos fistulosos durante 4 semanas. Tras el retiro de los sedales, se administró ácido trinitrobenceno sulfónico en el trayecto de la fístula para crear y mantener la inflamación local simulando la enfermedad de Crohn perianal.PRINCIPALES MEDIDAS DE RESULTADOS:Se obtuvo una resonancia magnética para evaluar las fístulas y los cerdos fueron sacrificados para revisar la histopatología.RESULTADOS:Se crearon de manera exitosa tres trayectos fistulosos inflamatorios crónicos en cada cerdo, confirmados por imágenes de resonancia magnética y examen bajo anestesia. Este es el primer informe de preservación de fístulas permeables en cerdos 2 semanas tras el retiro de los setones. Por primera vez, informamos que dos cerdos desarrollaron fístulas ramificadas y pequeños abscesos que recuerdan a la enfermedad de Crohn perianal humana. El examen histopatológico correspondiente encontró una significativa inflamación crónica activa en la tinción estándar de hematoxilina y eosina.LIMITACIONES:Las fístulas se indujeron quirúrgicamente y no se produjeron de forma natural.CONCLUSIONES:Se logro recrear con éxito un modelo de fístula perianal crónica en cerdos que se asemeja mucho a la enfermedad de Crohn perianal humana. Este modelo se puede utilizar para probar nuevas terapias y técnicas para allanar el camino para los ensayos en humanos. Consulte Video Resumen en http://links.lww.com/DCR/B969 . (Traducción-Dr Osvaldo Gauto).

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.

Perianal Paget's disease as spread from non-invasive colorectal adenomas.

AIMS: Paget's disease of the perianal skin is a rare form of extramammary Paget's disease, and may be a primary intraepithelial adnexal neoplasm or secondary due to spread from an underlying colorectal lesion, nearly always colorectal adenocarcinoma. Secondary perianal Paget's disease associated with non-invasive colorectal adenomas is exceedingly uncommon, with only a few reported cases. METHODS AND RESULTS: Herein, we present the clinical and pathological features of the largest series of secondary perianal Paget's disease arising in association with colorectal adenomas. There was gender parity and the median age was 72 years (range = 68-76 years). In all cases, perianal Paget's disease was associated with colorectal adenomas, including three (75%) conventional tubular adenomas and one (25%) tubulovillous adenoma with serrated foci. All adenomas had high-grade dysplasia and one had intramucosal adenocarcinoma (lamina propria invasion; Tis), but all lacked submucosal invasion. The intraepithelial Paget's cells showed a colorectal phenotype by immunohistochemistry in all cases. At follow-up, two patients had no evidence of disease at 6 and 87 months, one had residual perianal Paget's disease at 8 months and one developed invasive adenocarcinoma of the perianal tissue at 36 months. CONCLUSIONS: Similar to its mammary analogue, secondary perianal Paget's disease may arise in association with invasive and/or in-situ colorectal lesions. Although the latter is an uncommon presentation of a recognised rare disease, knowledge of this phenomenon is important to forestall overdiagnosis of invasion and potential overtreatment. The clinical course is variable, such that close follow-up is required.

Cell polarity (the 'four lines') distinguishes gastric dysplasia from epithelial changes in reactive gastropathy.

AIMS: Gastric dysplasia is a risk factor for synchronous and subsequent gastric carcinoma. Distinguishing gastric dysplasia from reactive changes is subject to interobserver disagreement and is a frequent reason for expert consultation. We previously used assessment of surface cell polarity (the 'four lines') as a key feature to decrease equivocal diagnoses in Barrett oesophagus. In the current study, we examined for the presence or absence of the four lines in gastric dysplasia and reactive gastropathy. MATERIALS AND METHODS: The study includes all (n = 91) in-house biopsies with at least gastric dysplasia from the surgical pathology archives of two academic institutions during a 5-year period from 2008 to 2012. A reactive gastropathy group (n = 60) was created for comparison. RESULTS: The dysplasia/neoplasia group was comprised of 14 biopsies of gastric foveolar-type dysplasia, 59 of intestinal-type dysplasia, 14 with dysplasia in fundic gland polyps, three pyloric gland adenomas and one oxyntic gland adenoma. Loss of surface cell polarity was seen in all 88 dysplasia cases with evaluable surface epithelium. All 57 reactive gastropathy cases with evaluable surface epithelium showed intact surface cell polarity except in focal areas directly adjacent to erosions in 17 cases, where the thin wisp of residual surface mucin could not be appreciated on haematoxylin and eosin. CONCLUSION: Surface cell polarity (the four lines) was lost in all gastric dysplasia biopsies with evaluable surface epithelium and maintained in all biopsies of reactive gastropathy. Caution should be taken in using this feature adjacent to erosions in reactive gastropathy.

Pathology of intraductal papillary mucinous neoplasms.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) represent a unique opportunity to treat and prevent a curable neoplasm before it has the chance to progress to incurable cancer. This prospect, however, has to be balanced with the real risk of over treating patients with lesions that would, in fact, never progress during the life of the patient. PURPOSE: Informed clinical decisions in the treatment of IPMNs are first and foremost based on a deep understanding of the pathology of these lesions. CONCLUSIONS: Here we review the pathology of IPMNs, with an emphasis on the clinical relevance of the important features that characterize these lesions.

Some observations on Barrett esophagus and associated dysplasia.

Biopsy samples from esophageal columnar metaplasia and dysplasia are commonly encountered in Western pathology practice and knowing a few pitfalls can save both pathologists and patients a great deal of anxiety. Herein we discuss criteria for Barrett esophagus, evaluation of dysplasia, and some pitfalls in reviewing endoscopic mucosal resections. Also included is a summary of suggested follow-up for patients with Barrett esophagus.

Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.

Cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAFV600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program concurrently is tumor suppressive, and Cdx2 loss sufficiently creates permissive state for BRAFV600E-driven transformation. Human proximal colon cancers with CDX2 downregulation showed similar transcriptional program as in mouse proximal organoids with Cdx2 loss. Developmental transcription factors, such as CDX2, are thus critical in maintaining tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor development.

Aberrant p53 Expression in Gastric Biopsies and Resection Specimens Following Neoadjuvant Chemoradiation: A Diagnostic Pitfall.

Gastric mucosal biopsies and resections from patients treated with neoadjuvant radiation and/or chemotherapy are frequently encountered. These samples may show histologic features related to therapy including inflammation, ulceration, and epithelial atypia. In some cases, epithelial atypia may be marked, prompting the use of adjunct p53 immunohistochemistry. We examined p53 expression by immunohistochemistry in gastric mucosa following therapy.We evaluated the histology and p53 immunohistochemical expression in gastric mucosa from 57 resections and 3 mucosal biopsies, from 60 patients treated with radiation and/or chemotherapy for gastroesophageal carcinoma (n = 33) or pancreatic carcinoma (n = 27).We identified histomorphologic features of therapy-related epithelial changes in 50 of 60 cases (83%). Abnormal p53 expression was present at least focally in nearly half the cases (27 of 60 cases; 45%), all of which showed morphologic evidence of therapy-related epithelial changes. Neuroendocrine cell micronests were present in 37 of 60 cases (62%). Next-generation sequencing (NGS) of foci with therapy-related epithelial changes showing abnormal p53 expression and carcinoma from the same patient was attempted and yielded results in 1 patient. Interestingly, differing TP53 alterations in the patient's adenocarcinoma and in a histologically benign esophageal submucosal gland with therapy-related epithelial changes and abnormal p53 expression were identified.Our results demonstrate that abnormal p53 expression is relatively common in gastric mucosal samples following radiation and/or chemotherapy and suggest that p53 expression should be avoided when distinguishing therapy-related changes from dysplasia or carcinoma. Furthermore, our NGS results raise interesting biological questions, which may warrant further investigation.

A nanofiber-hydrogel composite improves tissue repair in a rat model of Crohn's disease perianal fistulas.

Perianal fistulas (PAFs) represent a severe complication of Crohn's disease (CD). Despite the advent of biologic and small-molecule therapeutics for luminal disease, PAFs in CD (CD-PAF) are relatively resistant to treatment, with less than 50% responding to any therapy. We report an injectable, biodegradable, mechanically fragmented nanofiber-hydrogel composite (mfNHC) loaded with adipose-derived stem cells (ADSCs) for the treatment of fistulas in a rat model of CD-PAF. The ADSC-loaded mfNHC results in a higher degree of healing when compared to surgical treatment of fistulas, which is a standard treatment. The volume of fistulas treated with mfNHC is decreased sixfold compared to the surgical treatment control. Molecular studies reveal that utilization of mfNHC reduced local inflammation and improved tissue regeneration. This study demonstrates that ADSC-loaded mfNHC is a promising therapy for CD-PAF, and warrants further studies to advance mfNHC toward clinical translation.

The path(ology) from reflux oesophagitis to Barrett oesophagus to oesophageal adenocarcinoma.

This review seeks to summarise the steps in the path from reflux oesophagitis to Barrett oesophagus to oesophageal adenocarcinoma. The epidemiology, clinical presentation, definitions, pathological features, diagnostic pitfalls, and emerging concepts are reviewed for each entity. The histological features of reflux oesophagitis can be variable and are not specific. Cases of reflux oesophagitis with numerous eosinophils are difficult to distinguish from eosinophilic oesophagitis and other oesophagitides with eosinophils (Crohn's disease, medication effect, and connective tissue disorders). In reflux oesophagitis, the findings are often most pronounced in the distal oesophagus, the eosinophils are randomly distributed throughout the epithelium, and eosinophilic abscesses and degranulated eosinophils are rare. For reflux oesophagitis with prominent lymphocytes, clinical history and ancillary clinical studies are paramount to distinguish reflux oesophagitis from other causes of lymphocytic oesophagitis pattern. For Barrett oesophagus, the definition remains a hotly debated topic for which the requirement for intestinal metaplasia to make the diagnosis is not applied unanimously across the globe. Assessing for dysplasia is a challenging aspect of the histological interpretation that guides clinical management. We describe the histological features that we find useful in making this evaluation. Oesophageal adenocarcinoma has been steadily increasing in incidence and has a poor prognosis. The extent of invasion can be overdiagnosed due to a duplicated muscularis mucosae. We also describe the technical factors that can lead to challenges in distinguishing the mucosal and deep margins of endoscopic resections. Lastly, we give an overview of targeted therapies with emerging importance and the ancillary tests that can identify the cases best suited for each therapy.

Web-based pathology modules with virtual slides are effective for teaching introductory gastrointestinal pathology concepts.

Pathology interns face a steep learning curve as they transition from medical school to residency. Innovative teaching tools are needed to effectively and efficiently bridge this gap. We created four online learning modules geared toward pathology interns, for use at the beginning of the gastrointestinal pathology rotation at our institution. Our modules covered introductory esophageal, gastric, small bowel, and colonic pathology. Each module incorporated photomicrographs and annotated virtual slides, and included pre- and post-module assessment questions and a link to an anonymous survey. Twelve interns completed the modules between 9/20/2019 and 12/31/2021, including 80% of the 2020-2021 intern class. Significant improvement in performance was seen between the pre- and post-module questions for the stomach, small bowel, and colon modules (p < 0.05 for all), with a trend toward improved performance with the esophageal module. Interns rated the modules highly and indicated that they would recommend the modules to their peers. While the modules were geared toward interns, due to the coronavirus-19 pandemic we expanded access to the modules to include medical students. Medical students also found the learning modules valuable and requested more modules in the future. We conclude that online learning modules are an effective tool for teaching pathology interns and are well-received by this group. Online modules can also be seamlessly incorporated into asynchronous medical student teaching.

Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract: The Rodger C. Haggitt Memorial Lecture.

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

Gastric Mucosal Devitalization (GMD): Using the Porcine Model to Develop a Novel Endoscopic Bariatric Approach.

BACKGROUND AND AIMS: As the pig model has similar gastrointestinal anatomy and physiology to humans, we used pigs to create a gastric mucosal devitalization (GMD) model in preparation for clinical translation of this technique as an endoscopic bariatric therapy (EBT). The aims of this study were to determine the ablation parameters and technique for a successful, safe, and feasible large surface area GMD that produces weight loss. METHODS: We performed GMD using argon plasma coagulation (APC) in 3 phases. Phase 1 assessed the ablation energy required to accomplish selective mucosal ablation using ex vivo pig stomachs (n = 2). Phase 2 assessed the optimal percentage of mucosal surface area to be treated and was performed on 10 pigs. Phase 3 assessed feasibility, efficacy, and safety with 8 pigs randomized into GMD (n = 4) or sham (SH, n = 4) and survived for 1 month. Body weights (GMD, n = 4, SH, n = 4) were measured daily in phase 3 for 1 month, and relative body weights were calculated and analyzed using one-tailed Student's t-test. Percent body fat was compared between GMD and SH at baseline and 1 month post-GMD. RESULTS: Phase 1 identified the optimal ablation parameters (120 W) that were then used in phase 2. Phase 2 revealed a trend that was suggestive that the optimal percent surface area to ablate was similar to that which is removed at laparoscopic sleeve gastrectomy. In phase 3, GMD was performed over 70% surface area of the greater curvature of the stomach in four pigs. GMD pigs had significantly lower relative body weight increase compared to SH at 1 month (1.375 ± 0.085 vs 1.575 ± 0.047, p = 0.0435). MRI showed a significantly lower body fat mass at 1 month in GMD pigs (5.9 ± 0.4% vs 12.7 ± 2.3%, p = 0.026) compared to SH. CONCLUSIONS: GMD resulted in decreased weight gain in the GMD group as evidenced by a lower relative body weight at 1 month. GMD in an animal model appears to show promise as a potential weight loss therapy.

Acquired male urethral diverticulum complicated by calculi: A case report.

We present the case of a 38-year-old male with a past presumed history of traumatic genitourinary injury. Twenty-one years later, he presented with dysuria, urinary frequency, and urinary urgency and was found to have membranous stricture as well as a urethral diverticulum filled with calculi. For this rare case, we elected surgical management via urethroplasty and a urethral diverticulectomy. We present his clinical course and brief review of the diagnosis and management of male urethral diverticula.

Intra-abdominal lymphangioma: A case report.

Lymphangioma is a rare, benign congenital malformation of the lymphatic system that usually affects the neck and head in children. Intra-abdominal lymphangioma accounts for less than 5 percent of all cases of lymphangioma. The clinical presentation of intra-abdominal lymphangioma can vary from asymptomatic to nausea, vomiting, and abdominal pain. The diagnosis of intra-abdominal lymphangioma is based on imaging modalities and histopathological examination. The definitive treatment is surgical resection. Here we describe the interesting and rare case of a 29-year-old woman with lymphangioma of the retroperitoneum extending to the root of the mesentery. We focus on the diagnosis and management of this rare tumor by the application of radiological modalities and pathological analysis.

Clinicopathological study of blue nevi of the gastrointestinal (GI) tract: first case series.

AIM: Blue nevus (BN) is a benign melanocytic proliferation that is typically cutaneous. Extracutaneous BN is infrequent and is reported in the mucosa of various organs. Gastrointestinal (GI) tract BN is rare. Here, we describe the clinicopathological findings of the largest series of GI tract BNs. METHODS: A search of our Pathology Data System (1984-2019) identified six GI tract blue nevi. Clinical information, pathology reports and available H&E-stained section slides were reviewed. RESULTS: Lesions predominated in the middle-aged adults (mean 54, range 27-80) with a slight female predominance (66%). Most cases arose in the rectum and colon (83%), with one gastric lesion (17%). Four cases were identified during endoscopic examination performed either for screening or for unrelated symptoms (66%). Two patients presented with rectal bleeding (33%) unassociated with the BN. Endoscopically, most lesions appeared as superficial hyperpigmented areas (83%). One case was described as abnormal mucosa (17%). Microscopically, the mucosa was involved in all of the cases (100%). One case showed submucosal extension in addition to the mucosal component (17%). Lesions showed a proliferation of bland spindle cells with abundant granular pigment. No nuclear atypia or mitoses were identified. Immunostains showed immunoreactivity for melanocytic markers. Follow-up information available for five patients showed no recurrences to date (mean follow-up 1 year). CONCLUSIONS: BN is a benign melanocytic proliferation. It is important to be aware of the occurrence of such lesions outside of the skin and consider the possibility of BN when pigmented lesions are encountered in the GI tract.