Dynamic tuft cell expansion during gastric metaplasia and dysplasia.

Tuft cells are chemosensory cells associated with luminal homeostasis, immune response, and tumorigenesis in the gastrointestinal tract. We aimed to elucidate alterations in tuft cell populations during gastric atrophy and tumorigenesis in humans with correlative comparison to relevant mouse models. Tuft cell distribution was determined in human stomachs from organ donors and in gastric pathologies including Ménétrier's disease, Helicobacter pylori gastritis, intestinal metaplasia (IM), and gastric tumors. Tuft cell populations were examined in Lrig1-KrasG12D , Mist1-KrasG12D , and MT-TGFα mice. Tuft cells were evenly distributed throughout the entire normal human stomach, primarily concentrated in the isthmal region in the fundus. Ménétrier's disease stomach showed increased tuft cells. Similarly, Lrig1-Kras mice and mice overexpressing TGFα showed marked foveolar hyperplasia and expanded tuft cell populations. Human stomach with IM or dysplasia also showed increased tuft cell numbers. Similarly, Mist1-Kras mice had increased numbers of tuft cells during metaplasia and dysplasia development. In human gastric cancers, tuft cells were rarely observed, but showed positive associations with well-differentiated lesions. In mouse gastric cancer xenografts, tuft cells were restricted to dysplastic well-differentiated mucinous cysts and were lost in less differentiated cancers. Taken together, tuft cell populations increased in atrophic human gastric pathologies, metaplasia, and dysplasia, but were decreased in gastric cancers. Similar findings were observed in mouse models, suggesting that, while tuft cells are associated with precancerous pathologies, their loss is most associated with the progression to invasive cancer.

Curative resection with endoscopic submucosal dissection of early gastric cancer in Helicobacter pylori-negative Ménétrier's disease: A case report.

BACKGROUND: Adult-onset Ménétrier's disease is strongly associated with Helicobacter pylori (H. pylori) infection and an elevated risk of carcinogenesis. Cases of early-stage gastric cancer developed in H. pylori-negative Ménétrier's disease are extremely rare. We report a case of early gastric cancer in H. pylori-negative Ménétrier's disease that was curatively resected with endoscopic submucosal dissection (ESD). CASE SUMMARY: A 60-year-old woman was referred to our hospital after her medical examination detected anemia. Contrast-enhanced upper gastrointestinal (UGI) radiography revealed translucency of the nodule-aggregating surface with giant rugae. Blood tests showed hypoproteinemia and were negative for serum H. pylori immunoglobulin G antibodies. The 99mTc-DTPA-human serum albumin scintigraphy showed protein loss from the stomach. UGI endoscopy showed a 40-mm protruding erythematous lesion on giant rugae of the greater curvature of lower gastric body, suggesting early-stage gastric cancer due to Ménétrier's disease. En bloc resection with ESD was performed for diagnosis and treatment. Histology of ESD showed well-differentiated tubular adenocarcinoma. The cancer was confined to the mucosa, and complete curative resection was achieved. Foveolar hyperplasia and atrophy of the gastric glands were observed in non-tumor areas, histologically corresponding to Ménétrier's disease. Three years after ESD, gastric cancer had not recurred, and Ménétrier's disease remained in remission with spontaneous regression of giant gastric rugae. CONCLUSION: Complete curative resection was achieved through ESD in a patient with early-stage gastric cancer and H. pylori-negative Ménétrier's disease.

Menetrier's disease exacerbating ulcerative colitis and relieved by gastrectomy.

Ménétrier's disease (MD) is a rare gastropathy characterised by giant rugal folds which can present with nausea, vomiting, abdominal pain and protein losing gastropathy. We report a 21-year-old woman with comorbid MD and ulcerative colitis (UC). Management was complicated by limited treatment options for MD, significant symptom burden, worsening nutrition and difficulty determining which disease was the predominant cause of symptoms. Since age 18 the patient experienced recurrent UC flares characterised by diarrhoea, persistent vomiting and corticosteroid dependence. Endoscopic assessment demonstrated concurrent MD and active UC. Octreotide and cetuximab were trialled given persistent hypoalbuminaemia and suspicion for MD associated protein-losing gastropathy. UC management comprised dose-optimised infliximab and methotrexate. Repeat endoscopic assessment demonstrated improvement in UC without corresponding improvement in symptoms or hypoalbuminaemia. Nasojejunal feeding and parenteral nutrition failed to significantly improve nutritional status and accordingly the patient proceeded to radical total gastrectomy. Postoperatively, MD-associated symptoms and hypoalbuminemia resolved completely.

Ménétrier's disease in a patient with refractory ulcerative colitis: a clinical challenge and review of the literature.

Ménétrier's disease (MD) is a rare disease of the stomach, characterised by hypertrophic gastric folds leading to protein loss. The association with ulcerative colitis (UC) is rare but has been reported in the literature. We report a case of a 29-year-old male affected by UC with an additional diagnosis of MD 3 years after UC diagnosis. UC was refractory to several treatment lines (thiopurines, infliximab, vedolizumab and ustekinumab), and the patient underwent colectomy. Octreotide was administered for MD normalising blood biochemistry, but it was not effective in inducing endoscopic remission of the stomach. Treatment options in patients with MD and UC are discussed.

Abnormal Levels of Pepsinogen I and Gastrin 17 in a case of Ménétrier Disease.

BACKGROUND AND AIM: We describe a case of Ménétrier disease, occurred in female patient. METHODS: We decide to assess by non-invasive way (serum pepsinogens and gastrin 17) the secretory status of gastric mucosa, to confirm previous data of the literature, claiming high levels of both acid secretion and hypergastrinemia in this rare pathological condition. RESULTS AND CONCLUSION: We find in the subject the highest values of pepsinogen 1 - a marker of acid secretion - never described in the literature to our knowledge: 1940 mcg/L, being normal values ranging from 30-160 mcg/L. Similarly, gastrin 17, produced 90% in the antrum and responsible for negative acid feedback, was very high: 139 pg/L, ranging normal values between 1-10 pg/L. (www.actabiomedica.it).

Menetrier's disease. A diagnostic and therapeutic challenge.

We present a rare case of hypertrophic gastropathy associated with protein loss. A 35-year-old man was hospitalized for bowel habit changes, abdominal pain, generalized edema and symptomatic anemia. Pertinent laboratory findings included iron deficiency anemia (Hb 6.7g/dl, ferritin 5 ng/ml) and marked hypoalbuminemia (albumin 2.5 g/dl). Endoscopic biopsy samples of giant gastric folds observed along the greater gastric curvature revealed foveolar hyperplasia and significant parietal cell loss. Endoscopic ultrasonography showed gastric parietal thickening with preserved architecture and normal gastric wall layers. Menetrier disease was diagnosed and the patient treated with cetuximab, a monoclonal antibody that inhibits ligand binding of transforming growth factor alpha (TGFa), preventing gastric mucosa cell proliferation. After twelve months of treatment, the patient referred symptoms improvement, and gastric biopsy levels of the proliferation marker protein Ki-67 had decreased.

Presentamos un caso infrecuente de gastropatía hipertrófica asociada a pérdida de proteínas. Un hombre de 35 años fue hospitalizado por cambios en los hábitos intestinales, dolor abdominal, edema generalizado y anemia sintomática. Los hallazgos de laboratorio pertinentes incluyeron anemia ferropénica (Hb 6.7 g/dl, ferritina 5 ng/ml) e hipoalbuminemia marcada (albúmina 2.5 g/dl). Las muestras de biopsia endoscópica de pliegues gástricos gigantes observados a lo largo de la curvatura mayor gástrica revelaron hiperplasia foveolar y pérdida significativa de células parietales. La ecografía endoscópica mostró engrosamiento parietal gástrico con arquitectura conservada y capas de pared gástrica normales. Se diagnosticó enfermedad de Menetrier y se trató al paciente con cetuximab, un anticuerpo monoclonal que inhibe la unión del ligando del factor de crecimiento transformante alfa (TGFa), evitando la proliferación de células de la mucosa gástrica. Después de doce meses de tratamiento, el paciente refirió mejoría de los síntomas y los niveles de la proteína marcadora de proliferación Ki-67 en biopsia gástrica habían disminuido.

Ménétrier-like disease in a Pointer with concurrent granulomatous gastritis, helicobacteriosis and leishmaniosis: a case report.

BACKGROUND: Ménétrier-like disease is a rare hypertrophic canine gastropathy, reported in only seven dogs. Clinical signs are vomiting, anorexia and weight loss. Macroscopically, giant cerebriform gastric mucosal folds are typically seen in the corpus and fundus of the stomach. Histopathologically, fundic mucous cell hyperplasia and loss of parietal and chief cells are typical. CASE PRESENTATION: A nine-year-old spayed female Pointer had a history of intermittent vomiting, marked weight loss and hypoalbuminaemia. A gastroduodenoscopy was performed three times within three months with macroscopic changes remaining the same. The gastric mucosa of the corpus, fundus and proximal antrum was markedly irregular, with cerebriform mucosal folds. In the first gastric biopsies, histopathology revealed a moderate granulomatous gastritis, with a severe manifestation of Helicobacter-like organisms. Treatment for Helicobacter spp. decreased the vomiting slightly. The dog was diagnosed with concurrent leishmaniosis; the conventional anti-Leishmania treatment decreased the vomiting moderately, the hypoalbuminaemia resolved and the dog gained weight back to a normal body condition. Granulomatous gastritis was not present in the gastric biopsies after these treatments. The dog increased vomiting when palliative treatment (maropitant citrate, ondansetron and esomeprazole) was discontinued, and thus, full-thickness biopsies of the stomach were taken and Ménétrier-like disease was diagnosed. The affected area was too large to be surgically removed; thus, palliative treatment was reinstated. The dog remained clinically well 39 months after the first clinical presentation. CONCLUSIONS: This is the first report of Ménétrier-like disease in a dog with a simultaneous manifestation of granulomatous gastritis, helicobacteriosis and leishmaniosis. The clinical signs decreased after treatment of helicobacteriosis and leishmaniosis, but vomiting remained probably as a sign of Ménétrier-like disease. Treatment options for dogs are surgical removal of the abnormal area or palliative treatment. In humans, promising results for a cure have been shown with cetuximab treatment, a human monoclonal antibody, but no canine antibody is commercially available yet. The dog here was doing well 39 months after first presentation, which is the longest reported survival time for Ménétrier-like disease with only palliative treatment in dogs. Full-thickness biopsies are preferred in macroscopic hypertrophic lesions of the stomach for better assessment of Ménétrier-like disease.

Survival Times of Patients With Menetrier's Disease and Risk of Gastric Cancer.

BACKGROUND & AIMS: Menetrier's disease is a rare acquired disorder associated with giant gastric folds along with protein-losing enteropathy, low stomach acid, or achlorhydria, and histologic features of massive foveolar hyperplasia. Little is known about the etiology, clinical features, or epidemiology of this disorder, including risk of gastric cancer. We investigated the outcomes and characteristics of patients with Menetrier's disease, including development of gastric cancer and survival times. METHODS: We performed a case-control study of all Menetrier's disease cases (n = 76; mean age, 56 ± 45 y; 59% male; mean body mass index, 24) diagnosed at Mayo Clinic, Rochester, MN, from January 1975 through 2005. Diagnosis of Menetrier's disease was based on a combination of clinical, endoscopic, radiologic, and histologic features. Patients with dyspepsia who underwent gastric biopsy analysis were included as controls. We obtained demographic, clinical history, laboratory, imaging, histopathology, and follow-up data from medical records. Clinical characteristics of Menetrier's disease were analyzed using descriptive statistics. The Kaplan-Meier method was used to estimate overall survival in cases. RESULTS: Clinical features found in a significantly higher proportion of patients with Menetrier's disease than controls included vomiting, abdominal pain, postprandial fullness, and weight loss of 10 lb or more. Smoking was associated with Menetrier's disease (P = .002 vs controls), but not alcohol use. Infection with Helicobacter pylori was not associated with Menetrier's disease (2.6% of patients vs 4.0% of controls; P = 1.00). There was no significant difference between patients with Menetrier's disease vs controls in proportions with inflammatory bowel disease. Gastric cancer developed in 8.9% of patients with Menetrier's disease by 10 years after the Menetrier's disease diagnosis vs 3.7% of controls over the same time period (P = .09). Of patients with Menetrier's disease, 72.7% and 65.0% survived for 5 and 10 years, respectively, compared with 100% of controls (P < .0001 for both time periods). CONCLUSIONS: In a case-control study of 76 patients with Menetrier's disease, we found this rare disorder to be associated with increased mortality. Patients with Menetrier's disease therefore should be followed up with surveillance endoscopy.

Menetrier disease and Cytomegalovirus infection in paediatric age: report of three cases and a review of the literature.

Paediatric Menetrier disease (PMD) is a protein-losing gastropathy, presenting with generalized oedema and abdominal symptoms. PMD commonly has an acute course and may be associated with Cytomegalovirus (CMV) infection. The aim of this retrospective study is to assess the epidemiological and clinical data, diagnostic procedures, treatment and outcome of CMV-associated PMD. The medical charts of the patients with PMD and CMV infection diagnosed at our hospital have been reviewed. Then, a systematic literature's review of all the cases of PMD and a selection of those associated with CMV infection have been performed. Three previously healthy boys were admitted for vomiting and oedema. Endoscopy showed hypertrophic gastric folds and CMV infection was diagnosed. Albumin was administered in all cases, with clinical resolution within few weeks. In literature, PMD has been described in 150 children and the association between CMV and PMD was found in 89 cases. Clinical and laboratory data, radiological and histological exams, therapy and outcome were reviewed.Conclusions: Basing on the present experience and on the current knowledge, PMD has a benign course without long-term sequelae. Although PMD is rare in children, we recommend paediatricians to consider CMV-related PMD when facing children with vomiting and diffuse oedema. What is Known: • Paediatricians should consider Menetrier disease (MD) when facing oedematous child complaining of abdominal symptoms with hypoalbuminemia, without proteinuria and liver dysfunction. • Typical ultrasound features (hypertrophic gastric folds) suggest such condition which requires endoscopy and biopsy for definitive diagnosis. What is New: • A familial susceptibility to CMV gastric infection has been recently suggested; thus when suspecting MD, the family history of gastric diseases should be investigated. • Menetrier disease has been found associated with other unusual conditions either benign (such as gastric bezoar) or malign as neoplasms (acute lymphatic leukaemia and adenocarcinoma) even in children.

Ménétrier's disease in childhood: a case report from China.

BACKGROUND: Ménétrier's disease (MD) is a protein-losing gastropathy characterized by gastric hypertrophy, foveolar hyperplasia and hypoalbuminemia. MD is uncommon in childhood with nonspecific clinical symptoms, and the exact cause of pediatric MD is still unclear. CASE PRESENTATION: Here, we reported a 4 year and 10-month boy presenting with MD from China. The patient was suffered with vomiting, abdominal pain, hypoproteinemia and edema. Laboratory tests showed that the boy was infected with Clostridium difficile (CD). Gastrointestinal endoscopy revealed giant gastric folds, and histological gastric biopsies showed foveolar hyperplasia with glandular atrophy, infiltration of eosinophils in the lamina propria of the patient. Finally, the boy was recovered after supportive therapy with intravenous albumin and CD eradication. CONCLUSION: For the nonspecific clinical symptoms of MD, gastrointestinal endoscopic evaluations with gastric tissue biopsies are required to establish the diagnosis of MD in children with unexplained hypoalbuminemia.

Gastric Mucosal Hypertrophy Masquerading as Metastasis From Neuroendocrine Tumor of the Pancreas Detected on 68Ga-DOTANOC PET/CT.

A 57-year-old man, on octreotide treatment for metastatic neuroendocrine tumor pancreas, was referred for whole-body Ga-DOTANOC PET/CT scan to evaluate treatment response. PET/CT scan revealed DOTANOC-avid lesion in the head of the pancreas with multiple tracer-avid soft tissue lesions in the liver, bilateral adrenal glands, and periportal lymph nodes. In addition, diffuse intense DOTANOC-avid mural thickening with intraluminal polypoidal mass formation was noted within the stomach causing significant luminal compromise, histopathological examination of which turned out be hypertrophic hypersecretory gastropathy. This case highlights the possibility of overexpression of somatostatin receptors in gastric hypertrophy, which has been little explored in literature.

Ménétrier's disease : a case of successful treatment using long-acting octreotide.

The authors describe a 31 years old male, admitted for hematemesis, epigastric pain and lower limb edema. Laboratorial data showed haemoglobin 18.4g/dl, total proteins 2.8g/dl, albumin 1.6g/dl and hipogammaglobulinaemia. 24h urinary proteins were normal. HIV and CMV serology were negative. Upper GI endoscopy revealed markedly enlarged gastric folds covered by abundant exudative fluid. Endoscopic ultrasound showed ascites, pleural effusion and gastric wall thickening with mucosa expansion and intact submucosa. In gastric biopsies foveolar hyperplastic and regenerative mucosa were observed being suggestive of Ménétrier´s disease. Helicobacter pylori was not detected. Albumin replacement and diuretics corrected anasarca and long-acting octreotide was instituted. Nine months later, the patient was asymptomatic, serum proteins were normal (albumin 4.6g/dl and total proteins 6.5g/dl), signs of endoscopic improvement were observed with marked reduction in gastric folds and mucosal inflammation and no ultrastructural changes were detected in gastric specimens sent for electron microscopy. Ménétrier´s Disease (MD) is a rare form of hypertrophic gastropathy characterized by massive enlargement of gastric folds causing marked protein exudation. The increase in tight junction diameter is the most consistent ultraestrutural change. Octreotide is a somatostatin analogue that acts by modulating TGFαEGFR pathway, which has been associated with the pathogenic mechanisms. As well as other cases reported in literature, this case report highlights the potential of long-acting octreotide for MD treatment avoiding more expensive therapies like cetuximab and gastrectomy.