Delineation of the healthy rabbit duodenum by immunohistochemistry - A short communication.

The duodenum acts as a vital organ that performs fundamental physiological functions like digestion and nutrient absorption. Situated in the lower abdomen, the duodenum is located between the stomach and the jejunum. Usually, the duodenum is divided into four anatomical portions. We here compare paraffin embedded and cryosections of the healthy rabbit duodenum for research purposes. This analysis evaluates the differential outcomes resulting from the application of these fixation methodologies in conjunction with immunohistochemical assays targeting extracellular matrix markers collagen I, collagen III, fibronectin, α-smooth muscle actin (α-SMA), and proliferation marker ki67 as well as inflammatory marker PAR-2. Subsequent recommendations are provided based on our findings. Furthermore, the advantage of an antigen retrieval step in immunohistochemical labelling of paraffin sections was demonstrated and confirmed with an isotype negative control. Basic classical histological stainings as HE, GT and elastin were also performed. Comparison of different stainings and labellings was performed in serial sections, showing that adjacent to the circular muscle of the duodenum, the connective tissue was composed of collagen I and fibronectin, while the artery and vein walls were predominantly α-SMA positive. Moreover, PAR-2 immunohistochemical staining was performed, where particularly a type of gland adjacent to Brunner's glands showed prominent PAR-2 positive areas, while the Brunner's glands themselves were PAR-2 negative. Proliferating ki67 positive cells facing the lumen were highly abundant in all kinds of glands except for the Brunner's glands. This effort serves to furnish the research community with reference imagery pertinent to scientists opting for the rabbit duodenum model. The diversity of staining techniques employed herein establishes a foundational repository of images, primed for comparative analysis against pathological conditions. Furthermore, these images hold the potential to illustrate inter-species variations. For instance, they can be juxtaposed against murine or rat intestinal tracts, or even offer insights into the human context.

Brunner gland inflammation in Crohn's disease and Celiac disease: Overlapping inflammatory patterns suggest a possible link.

Similar to celiac disease, inflammatory bowel disease frequently manifests in the duodenum. Histopathologic studies focused on mucosal alterations with little attention to submucosal Brunner glands. Recently, several studies have demonstrated overlapping features between Crohn's disease and celiac disease suggesting a putative link. However, histopathologic studies evaluating this possible link are limited, and those that are focused on Brunner glands are lacking. The present study aims to explore whether Crohn's disease and celiac disease display shared or overlapping inflammatory changes in Brunner glands. We performed a retrospective review study over 17-years retrieving duodenal biopsy specimens containing Brunner gland lobules in patients with Crohn's disease, celiac disease, and ulcerative colitis. We found 10 out of 126 duodenal biopsies (8 %) in patients with Crohn's disease and 6 out of 134 (4.5 %) duodenal biopsies in patients with celiac disease sharing inflammatory patterns in duodenal Brunner gland lobules. Both diseases showed interstitial intralobular and interlobular mixed chronic inflammation with variable fibrosis. Focally enhanced active inflammation of Brunner gland lobules was more characteristic of Crohn's disease. Intralobular epithelioid granulomas and multinucleated giant cells were specific to Crohn's disease. Ulcerative colitis patients did not show similar features. The interstitial focally enhanced chronic inflammatory pattern was significantly (p < 0.05) associated with both diseases, while the other inflammatory patterns were not (p > 0.05). This overlapping inflammatory pattern in Brunner glands in patients with Crohn's disease and celiac disease is supportive of the previously reported link between the two diseases. Pathologists should pay more attention to Brunner glands when evaluating duodenal biopsies. Further studies are warranted to validate these observations and their relevance in the pathogenesis of autoinflammatory gastrointestinal diseases.

MENIN-mediated regulation of gastrin gene expression and its role in gastrinoma development.

The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues. Gastrinomas are neuroendocrine neoplasms that overproduce the hormone gastrin and can arise sporadically or as part of the MEN1 syndrome, in which mutations in the MEN1 gene lead to loss or inactivation of MENIN protein. Gastrin is a peptide hormone that is primarily synthesized in the gastric antrum and stimulates the secretion of histamine from enterochromaffin-like (ECL) cells and subsequently acid from parietal cells in the gastric corpus. In addition, gastrin exerts a mitogenic function primarily on ECL cells and progenitor cells in the gastric isthmus. Current studies seek to understand how MEN1 mutations generate a mutant MENIN protein that abrogates its tumor suppressor function. Mutations in the MEN1 gene are broadly distributed throughout its nine protein-coding exons, making it difficult to correlate protein structure with its function. Although disruption of the Men1 locus in mice causes functional neuroendocrine tumors in the pituitary and pancreas, gastrinomas do not develop in these transgenic animal models. Prior studies of human gastrinomas suggest that tissue-specific microenvironmental cues in the submucosal foregut may contribute to tumorigenesis by reprogramming of epithelial cells toward the neuroendocrine phenotype. Accordingly, recent studies suggest that neural crest-derived cells are also sensitive to reprogramming when MEN1 is deleted or mutated. Thus, the goal of this report is to review our current understanding of how MENIN modulates gastrin gene expression while highlighting its role in the prevention/suppression of neuroendocrine cell transformation.

In vitro cell cultures of Brunner's glands from male mouse to study GLP-1 receptor function.

Exocrine glands in the submucosa of the proximal duodenum secrete alkaline fluid containing mucus to protect the intestinal mucosa from acidic stomach contents. These glands, known as Brunner's glands, express high glucagon-like peptide 1 receptor (GLP-1R) levels. Previous studies have suggested that activation of the GLP-1R induces expression of barrier protective genes in Brunner's glands. Still, the lack of a viable in vitro culture of Brunner's glands has hampered additional studies of the functional consequences of GLP-1R activation. In this study, we established a procedure to isolate and culture cells derived from murine Brunner's glands. The isolated glandular cells retained functional GLP-1R expression in culture, making this in vitro system suitable for the study of GLP-1R activation. We found that cells derived from the Brunner's glands of mice pretreated with semaglutide contained significantly more mucus compared with Brunner's glands from vehicle-treated mice. Our data suggest a protective intestinal response upon semaglutide treatment, but further studies are required to leverage the full potential of cultured Brunner's gland cells.

Functional human gastrointestinal organoids can be engineered from three primary germ layers derived separately from pluripotent stem cells.

Human organoid model systems lack important cell types that, in the embryo, are incorporated into organ tissues during development. We developed an organoid assembly approach starting with cells from the three primary germ layers-enteric neuroglial, mesenchymal, and epithelial precursors-that were derived separately from human pluripotent stem cells (PSCs). From these three cell types, we generated human antral and fundic gastric tissue containing differentiated glands surrounded by layers of smooth muscle containing functional enteric neurons that controlled contractions of the engineered antral tissue. Using this experimental system, we show that human enteric neural crest cells (ENCCs) promote mesenchyme development and glandular morphogenesis of antral stomach organoids. Moreover, ENCCs can act directly on the foregut to promote a posterior fate, resulting in organoids with a Brunner's gland phenotype. Thus, germ layer components that are derived separately from PSCs can be used for tissue engineering to generate complex human organoids.

Effect of Pomegranate Peels Aqueous Extract on the Histological Structure of Small Intestine of Local Male Rabbits (Oryctolagus cuniculus).

Most feed materials are predominantly complex and in insoluble forms as animals use them. The aim of digestion processes, therefore, is to sequentially modify the feed substances into simple and soluble forms that are appropriate for absorption and ingestion. This study aimed to investigate the possible effect of pomegranate peel aqueous extract on the histological structure of the small intestine of local male rabbits (Oryctolagus cuniculus). Twelve healthy adult male rabbits acquired from a local market in Iraq- Baghdad was used in this study. The animals were divided into two main groups, six animals in the control group, while the other six were considered as treated groups with pomegranate peel extract. The pomegranate extract was prepared by the maceration method. The experiment lasted for two months, from 1/10/2020 to 1/12/2020. The results showed that the tunica mucosa of the duodenum of the experimental group has huge overcrowded intestinal villi associated with hypertrophy of mucosal villi, in addition to a marked increase in the population of goblet cells and their secretory activities. The tunica submucosa was occupied by a thick layer of Brunner's glands, which were compound tubular mucous alveolar type and had clear cytoplasm. The jejunum of the experimental group showed that the mucosal layer was characterized by a marked increase of intestinal plica circularis, which is associated with the projection of pyramidal-shaped intestinal mucosa. The epithelial mucosa was (pseudostratified columnar epithelium) covered by a thick brush border of microvilli. The histological arrangement of various layers of the ileum was nearly analogous to that of the jejunum except for some distinctive differences. An evident aggregated lymphocytes forming Payers patches occupied the tunica submucosa in both the control and treated groups. The most historical parameters in all segments of the small intestine revealed a significant increase in experimental animals compared to control animals. In conclusion, the aqueous extract of pomegranate peels have apparent positive effects on the histological structure of the small intestine of rabbits improving, positively the digestive efficiency of animals and enhancing the efficiency of the immune system in the animal through an apparent increase in the numbers of goblet cell that plays importance for immunity of the body.

Expression Profile of the GLP-1 Receptor in the Gastrointestinal Tract and Pancreas in Adult Female Mice.

Therapies based on glucagon-like peptide-1 receptor (GLP-1R) agonism are highly effective in treating type 2 diabetes and obesity, but the localization of GLP-1Rs mediating the antidiabetic and other possible actions of GLP-1 is still debated. The purpose with this study was to identify sites of GLP-1R mRNA and protein expression in the mouse gastrointestinal system by means of GLP-1R antibody immunohistochemistry, Glp1r mRNA fluorescence in situ hybridization, and 125I-exendin (9-39) autoradiography. As expected, GLP-1R staining was observed in almost all ß-cells in the pancreatic islets, but more rarely in α- and δ-cells. In the stomach, GLP-1R staining was found exclusively in the gastric corpus mucous neck cells, known to protect the stomach mucosa. The Brunner glands were strongly stained for GLP-1R, and pretreatment with GLP-1 agonist exendin-4 caused internalization of the receptor and mucin secretion, while pretreatment with phosphate-buffered saline or antagonist exendin (9-39) did not. In the intestinal mucosa, GLP-1R staining was observed in intraepithelial lymphocytes, lamina propria lymphocytes, and enteroendocrine cells containing secretin, peptide YY, and somatostatin, but not cholecystokinin. GLP-1R staining was seen in nerve fibers within the choline acetyl transferase- and nitric oxide-positive myenteric plexuses from the gastric corpus to the distal large intestine being strongest in the mid- and hindgut area. Finally, intraperitoneal administration of radiolabeled exendin (9-39) strongly labeled myenteric fibers. In conclusion, this study expands our knowledge of GLP-1R localization and suggests that GLP-1 may serve an important role in modulating gastrointestinal health and mucosal protection.

Histopathologic Manifestations of Crohn Disease in Duodenal Endoscopy Biopsy: The Value of Different Patterns of Involvement of Brunner Glands.

Crohn disease (CD) not uncommonly involves the upper gastrointestinal tract, usually gastric antrum and proximal duodenum. The most consistent histopathologic manifestations of CD in duodenal biopsies are mucosal erosion, focal active inflammation, and granulomas. Since CD is a transmural inflammation and since duodenal biopsy may include submucosal Brunner glands, we aimed to find if CD has any specific histopathologic manifestations in Brunner gland lobules and their ducts compared to other duodenal inflammatory lesions. We carried out a retrospective review study over 6 years retrieving duodenal biopsy specimens in CD patients. We compared duodenal specimens involved by CD with other inflammatory lesions, for example, ulcerative colitis (UC), Helicobacter pylori-associated gastritis, non-Helicobacter gastritis, Celiac sprue, infections, and drugs. We found focal active duodenitis and erosion in CD cases and non-CD cases. Granulomas were found in CD cases. Five cases of CD showed inflammatory and degenerative changes of Brunner glands. Focal patchy active inflammation of only portion of submucosal Brunner gland lobule, mucosal Brunner glands, and their ducts was solely found in CD cases. This focally enhanced inflammation of Brunner glands was not found in other lesions. Whether this phenomenon of focal active "lobulitis" and "ductitis" is a specific sign of duodenal CD compared to UC and other inflammatory lesions warrants verification. We encourage endoscopists to include submucosal Brunner lobules in their duodenal biopsy samples and pathologists to look for these patterns of involvement particularly in patients suspected of CD.

Brunner's Gland Adenocarcinoma in an Aged Western Gorilla (Gorilla gorilla).

A 50-year-old male western gorilla (Gorilla gorilla) presented with severe bradypragia, anorexia and vomiting. Despite continuous administration of antiphlogistic analgesic drugs and supportive care, the animal died and was submitted for post-mortem examination. Macroscopically, a large mass was located in the duodenum. The mucosal surface of the duodenum was irregular and thickened, and the lumen narrowed. The duodenal lesion was identified as a tubular adenocarcinoma and the neoplastic cells were strongly positive for cytokeratin AE1/AE3, cytokeratin 7, cytokeratin 19 and mucin-6 protein. Ultrastructurally, the apical cytoplasm of neoplastic cells had electron dense granules and apical microvilli. This is the first reported case of Brunner's gland adenocarcinoma in a gorilla.

Brunner's gland hyperplasia in a geriatric chimpanzee (Pan troglodytes), an infrequently reported lesion.

Benign duodenal tumours have very rarely been reported in captive non-human primates and are also rare in human beings. Brunner's gland hyperplasia has not been fully described in a non-human primate. Here, we report Brunner's gland hyperplasia in a geriatric chimpanzee, which was an incidental finding during post-mortem examination.

Large Brunner's gland adenoma of the duodenum for almost 10 years.

BACKGROUND: Brunner's gland adenoma is a rare benign tumor arising from Brunner's glands. It is mostly small in size, and patients with this tumor are asymptomatic. CASE PRESENTATION: We report the case of a 63-year-old woman with upper gastrointestinal obstruction for almost 10 years, who was pathologically diagnosed with large Brunner's gland adenoma of the duodenum. Postoperatively, no sign of recurrence has been noted until now. CONCLUSION: This study may help clinicians to understand and provide a more accurate diagnosis of Brunner's gland adenoma.

Brunners gland cyst: rare differential diagnosis of dyspeptic symptoms / Cisto da glândula de Brunner: diagnóstico diferencial raro de sintomas dispépticos

abstract A 60-year-old woman was under investigation of dyspeptic symptoms. The upper gastrointestinal endoscopy showed a cystic subepithelial lesion in the second portion of the duodenum, measuring 8 mm in its longest diameter. The biopsy showed dilated Brunner's gland lobular ducts with scattered stromal elements, what characterized a Brunner's gland cyst. Brunner's gland cyst should be included in the differential diagnosis of gastrointestinal bleeding, dyspepsia, gastroesophageal reflux disease (GERD), malabsorption syndrome, anemia, among others. The correct nomenclature is important to facilitate research for articles specifically related to each duodenal cystic lesions and better understanding of these diseases, as some may have malignant potential.

resumen Paciente femenina, de 60 años de edad, tenía quejas dispépticas. La endoscopía digestiva reveló lesión subepitelial ubicada en la segunda porción del duodeno con aspecto quístico (signo de la tienda de campaña), de 8 mm en su mayor diámetro. Se realizó biopsia de la lesión. El análisis histopatológico mostró dilatación de los ductos lobulares de las glándulas de Brunner, acompañada por elementos estromales dispersos, identificando un quiste de las glándulas duodenales. Es un diagnóstico diferencial de sangrado intestinal, dispepsia, enfermedad por reflujo gastroesofágico (ERGE), malabsorción y anemia. La nomenclatura es importante tanto para buscar artículos específicos de cada lesión quística en el duodeno como para mejor caracterizar esas lesiones, puesto que algunas pueden tener potencial maligno.

resumo Paciente do sexo feminino, 60 anos, com queixas dispépticas. A endoscopia digestiva revelou lesão subepitelial localizada na segunda porção do duodeno com aspecto cístico (sinal da tenda positivo), de 8 mm no seu maior diâmetro. Biópsia da lesão foi realizada. A análise histopatológica mostrou dilatação dos ductos lobulares das glândulas de Brunner, acompanhada por elementos estromais dispersos, caracterizando um cisto da glândula de Brunner. É um diagnóstico diferencial de sangramento intestinal, dispepsia, doença do refluxo gastroesofágico (DRGE), má absorção e anemia. A nomenclatura é importante tanto para a pesquisa de artigos específicos de cada lesão cística no duodeno quanto para melhor caracterização dessas lesões, uma vez que algumas podem apresentar potencial maligno.

Hemorragia digestiva en paciente con hiperplasia de glándulas de Brunner / Digestive tract hemorrhaging in a patient with Brunner's gland hyperplasia

Resumen Objetivo: analizar las características epidemiológicas, bases etiopatogénicas y presentación clínica, así como el diagnóstico y el tratamiento de la hiperplasia de glándulas de Brunner (HGB). Métodos: describir un caso de HGB diagnosticado de forma incidental durante una endoscopia electiva y realizar una revisión de la literatura disponible hasta el momento. Resultados: esta neoformación consiste en una proliferación glandular localizada preferentemente en el duodeno proximal. Su diagnóstico, normalmente realizado mediante biopsia endoscópica, puede asociarse con complicaciones que, aunque infrecuentes, no deben ser subestimadas. Conclusiones: las neoplasias duodenales representan un porcentaje pequeño dentro del total de las que afectan al tracto gastrointestinal. Debido a que el diagnóstico de estas lesiones suele realizarse de forma casual durante una endoscopia programada, el tratamiento deberá basarse en la sintomatología, así como el tamaño de las mismas, de acuerdo con los estándares de tratamiento de cada centro.

Abstract Objective: This study analyzes the epidemiological characteristics, etiological and pathogenic bases, clinical presentation, diagnosis and treatment of Brunner's gland hyperplasia. Methods: We describe a case of Brunner's gland hyperplasia that was diagnosed incidentally during elective endoscopy and review the available literature. Results: This neoplasm consists of glandular proliferation preferentially located in the proximal duodenum. Its diagnosis, normally made by endoscopic biopsy, can be associated with complications that, although infrequent, should not be underestimated. Conclusions: Duodenal neoplasms are a small percentage of those that affect the gastrointestinal tract. Because diagnosis is usually made by chance during a scheduled endoscopy, treatment should be based on the symptoms and size of the lesion according to the treatment standards of each medical center.

Endosonographic Appearances of a Rare Duodenal Tumour, Brunner's Gland Hamartoma.

Brunner's gland hamartoma (BGH) is a rare sub-epithelial tumour of the duodenum, which may cause haemorrhagic or obstructive gastrointestinal symptoms. Their accurate histological diagnosis often remains elusive before resection. Although endoscopic ultrasonography (EUS) is considered an excellent modality to study lesions within the gastrointestinal wall, only a few reports have described endosonographic characteristics of BGHs. A reliable pre-resection diagnosis with EUS may not only allay fear of malignancy but may as well avert a major surgery for the patients. In this report, we present a rare case of a large BGH in a young female who presented with acute gastrointestinal bleeding. Here, the endosonographic features assuaged the concern for malignancy while aiding in complete and uneventful surgical resection of the tumour via a submucosal plane.

Brunneroma: reporte de un caso / Brunneroma: a case report

RESUMEN Fundamento: las glándulas de Brunner son estructuras túbulo-acinares ubicadas en la submucosa del duodeno. Su crecimiento excesivo por lo regular no da síntomas o estos son mínimos, lo cual es conocido como adenoma de glándulas de Brunner, hamartoma o brunneroma. Su localización más frecuente es en la primera porción del duodeno y muy raro por debajo de la ampolla de Váter. Objetivo: presentar el caso clínico de un paciente con el diagnóstico de Brunneroma. Caso Clínico: paciente femenina, blanca de 72 años de edad con antecedentes de padecer de úlcera duodenal hace 20 años que ingresa con dolor difuso en abdomen superior acompañado de deposiciones abundantes como borra de café, sudoraciones profusas y pérdida ligera de peso en el último mes. Conclusiones: el Brunneroma es una lesión benigna poco frecuente del duodeno; puede descubrirse de forma accidental y en algunas ocasiones pueden causar hemorragia digestiva.

ABSTRACT Background: The Brunner's glands are tubular structures located in the submucosa of the duodenum. Their excessive growth does not usually give symptoms or at least they are minimum. This is known as Brunner's gland adenoma, Hamartoma or Brunneroma. Its most frequent localization is in the first portion of the duodenum, but it is extremely strange below the ampulla of Vater. Objective: to present the clinical case of a patient with the diagnosis of Brunneroma. Clinical case: white-skinned, 72 years-old, female patient with antecedents of a 20-years duodenal ulcer who is hospitalize with diffuse pain in superior abdomen accompanied by abundant depositions like coffee powder, profuse sweating and slight loss of weight in the last month. Conclusions: Brunneroma is a not very frequent benign lesion of the duodenum; it can be discovered accidentally and in some occasions it may cause digestive hemorrhage.

Duodenal Adenocarcinoma of Brunner Gland Origin: A Case Report.

We report a case of adenocarcinoma originating from the duodenal Brunner glands in a 47-year-old female patient. The lesion was 0.8 cm in extent and located at the posterior wall of the first part of the duodenum. Histologically, the tumor showed transition from non-neoplastic Brunner glands through dysplastic epithelium into adenocarcinoma. The carcinoma cells were strongly positive for MUC6 protein, which is an epithelial marker for the Brunner glands. Tumor protein p53 was overexpressed in the carcinoma cells, but not in the non-neoplastic or dysplastic epithelium. Dystrophic calcification was predominant. This is the first case report of duodenal adenocarcinoma of Brunner gland origin in Korea.

Duodenal Adenocarcinoma of Brunner Gland Origin: A Case Report

We report a case of adenocarcinoma originating from the duodenal Brunner glands in a 47-year-old female patient. The lesion was 0.8 cm in extent and located at the posterior wall of the first part of the duodenum. Histologically, the tumor showed transition from non-neoplastic Brunner glands through dysplastic epithelium into adenocarcinoma. The carcinoma cells were strongly positive for MUC6 protein, which is an epithelial marker for the Brunner glands. Tumor protein p53 was overexpressed in the carcinoma cells, but not in the non-neoplastic or dysplastic epithelium. Dystrophic calcification was predominant. This is the first case report of duodenal adenocarcinoma of Brunner gland origin in Korea.

A primary hepatic gastrinoma accompanied by hyperplasia of multi-nodular Brunner's glands.

BACKGROUND: Primary hepatic gastrinoma causing severe ulcerogenic syndrome is extremely rare. Herein, we report a case of primary hepatic gastrinoma accompanied by hyperplasia of multi-nodular Brunner's glands in a patient who instead, preoperatively, was suspected of having multiple duodenal gastrinomas and hepatic metastasis. CASE PRESENTATION: A 57-year-old woman consulted a clinic complaining of melena, intermittent abdominal pain, diarrhea, and vomiting which had persisted for about 3 years. Six months before her presentation, she underwent segmental resection of the jejunum for acute peritonitis due to the spontaneous jejunal perforation. A blood test revealed that her serum immunoreactive gastrin (IRG) level was 12,037 pg/mL. Subsequently, she was transferred to our hospital. On computed tomography (CT), a hypervascular tumor of 23 mm in the segment 5 (S5) region of the liver was visualized. A selective arterial secretagogue injection test (SASI test) was performed twice. The first SASI test revealed that the hepatic tumor was a gastrinoma, and there was no gastrinoma in the duodeno-pancreatic region. Additionally, somatostatin receptor scintigraphy only visualized the tumor in the liver. However, the second SASI test, which was performed during the administration of a proton pump inhibitor and a somatostatin analog (octreotide acetate), revealed that there may have been gastrinomas existing not only in the liver but also in the upper part of the duodenum or the head of the pancreas. Duodenal endoscopy revealed multiple submucosal tumors in the first and the second portion of the duodenum, although a pathological examination of biopsied specimens obtained from the duodenal lesions was negative for malignant cells. Multiple endocrine neoplasia type 1 (MEN1) was excluded from her family history, and serum levels of both intact parathyroid hormone (iPTH) and calcium were within normal ranges. An anterior segmentectomy of the liver and pancreas-preserving total duodenectomy were performed on September 9, 2013. Postoperatively, her serum immunoreactive gastrin level decreased to less than 50 pg/mL. Pathological study of the resected specimens revealed a gastrinoma in the liver, but no gastrinoma in the duodenum. Interestingly, the duodenal submucosal tumor-like lesions were hyperplastic Brunner's glands. Postoperatively, she has been well without recurrence of hypergastrinemia for 4 years. CONCLUSION: We report a case of primary hepatic gastrinoma in a patient who has been cured for 4 years postoperatively. The diagnosis was somewhat difficult due to the coexisting, multiple hyperplastic Brunner's glands of the duodenum mimicking the submucosal neuroendocrine tumors, which might have developed due to long-term hypergastrinemia.