{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:12:13Z","timestamp":1760721133433,"version":"build-2065373602"},"reference-count":27,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Veterinary Clinical Sciences CORP"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Veterinary Sciences"],"abstract":"<jats:p>Efforts by the World Health Organization (WHO) have clarified the descriptive nomenclature and histologic grading of neuroendocrine neoplasms (NENs) in human medicine. Employing a standardized stratification scheme in conjunction with specific immunohistochemical markers, such as gastrin, enhances prognostic accuracy and guides treatment recommendations. Yet, this classification system has yet to be applied consistently in veterinary pathology. Histopathologic features and gastrin expression were analyzed in a group of canine gallbladder (GB) NENs. Based on the human WHO histologic system, which stratifies grade based on proliferative indices (mitotic count and Ki67%), all gradable GB NENs were classified as neuroendocrine tumors (NETs) rather than neuroendocrine carcinomas (NECs). Only one GB NET was positive for gastrin using immunohistochemical staining. Collectively, our data suggest that canine GB NENs have a lower grade than most human GB NENs and rarely express gastrin. The use of proliferative indices in the histologic characterization of canine GB NENs is likely to improve prognostic information. Given the limited expression of gastrin in these neoplasms in dogs, this marker is unlikely to be widely applicable as a druggable target.<\/jats:p>","DOI":"10.3390\/vetsci12100989","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T16:13:03Z","timestamp":1760717583000},"page":"989","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proliferation-Based WHO Grading and Heterogeneous Gastrin Expression in Canine Gallbladder Neuroendocrine Tumors"],"prefix":"10.3390","volume":"12","author":[{"given":"Yen-Tse","family":"Wu","sequence":"first","affiliation":[{"name":"Emergency & Critical Care, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA"},{"name":"Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7366-4391","authenticated-orcid":false,"given":"Ingeborg M.","family":"Langohr","sequence":"additional","affiliation":[{"name":"Global Discovery Pathology & Multimodal Imaging, Translation Models Research Platform, Sanofi, Cambridge, MA 02141, USA"},{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Set","family":"Sokol","sequence":"additional","affiliation":[{"name":"Antech Diagnostics, Mars Petcare Science & Diagnostics, Loveland, CO 80538, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jodie","family":"Gerdin","sequence":"additional","affiliation":[{"name":"Antech Diagnostics, Mars Petcare Science & Diagnostics, Loveland, CO 80538, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0723-8313","authenticated-orcid":false,"given":"Chin-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Office of Research and Graduate Education, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyler J.","family":"Butsch","sequence":"additional","affiliation":[{"name":"Departments of Pathobiology & Diagnostic Investigation and Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1082-1155","authenticated-orcid":false,"given":"Andrea N.","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"},{"name":"Departments of Pathobiology & Diagnostic Investigation and Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kelly, N., Wu, Y.-T., and Johnston, A.N. (2024). Gallbladder Neuroendocrine Neoplasms in Dogs and Humans. Vet. Sci., 11.","DOI":"10.3390\/vetsci11080371"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1177\/1040638720978172","article-title":"Clinical, Histopathologic, and Immunohistochemical Features of 13 Cases of Canine Gallbladder Neuroendocrine Carcinoma","volume":"33","author":"Bankoff","year":"2021","journal-title":"J. Vet. Diagn. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Liu, Y.-G., Jiang, S.-T., Zhou, Y., Zhang, J.-W., Sang, X.-T., Zhang, L., Lu, X., and Xu, Y.-Y. (2023). Primary Gastrinoma of the Gallbladder: A Case Report and Review of the Literature. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1279766"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"zqab062","DOI":"10.1093\/function\/zqab062","article-title":"Gastrin: From Physiology to Gastrointestinal Malignancies","volume":"3","author":"Duan","year":"2021","journal-title":"Function"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/bcp.13146","article-title":"Netazepide, a Gastrin\/Cholecystokinin-2 Receptor Antagonist, Can Eradicate Gastric Neuroendocrine Tumours in Patients with Autoimmune Chronic Atrophic Gastritis","volume":"83","author":"Boyce","year":"2017","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"G1481","DOI":"10.1152\/ajpgi.1997.272.6.G1481","article-title":"Somatostatin Inhibits Gastrin Release and Acid Secretion by Activating Sst2 in Dogs","volume":"272","author":"Lloyd","year":"1997","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"407","DOI":"10.5326\/JAAHA-MS-6270","article-title":"Treatment of Gastrin-Secreting Tumor with Sustained-Release Octreotide Acetate in a Dog","volume":"51","author":"Kim","year":"2015","journal-title":"J. Am. Anim. Hosp. Assoc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1177\/104063879700900122","article-title":"Gastrin-Secreting Pancreatic Endocrine Tumor in a Dog (Putative Zollinger-Ellison Syndrome)","volume":"9","author":"Hayden","year":"1997","journal-title":"J. Vet. Diagn. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1111\/j.1748-5827.1997.tb03466.x","article-title":"Evaluation of Somatostatin Analogues for the Detection and Treatment of Gastrinoma in a Dog","volume":"38","author":"Altschul","year":"1997","journal-title":"J. Small Anim. Pract."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1158\/1940-6207.CAPR-21-0050","article-title":"Randomized Controlled Trial of the Gastrin\/CCK2 Receptor Antagonist Netazepide in Patients with Barrett\u2019s Esophagus","volume":"14","author":"Abrams","year":"2021","journal-title":"Cancer Prev. Res."},{"key":"ref_11","first-page":"4971","article-title":"Somatostatin Receptor Immunohistochemistry in Neuroendocrine Tumors: Comparison Between Manual and Automated Evaluation","volume":"7","author":"Kaemmerer","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.bpg.2005.02.010","article-title":"Epidemiology, Tumour Biology and Histopathological Classification of Neuroendocrine Tumours of the Gastrointestinal Tract","volume":"19","author":"Anlauf","year":"2005","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"437","DOI":"10.7150\/thno.3645","article-title":"THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET\/CT to Personalized Radionuclide Therapy\u2014The Bad Berka Experience","volume":"2","author":"Baum","year":"2012","journal-title":"Theranostics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1038\/s41379-018-0110-y","article-title":"A Common Classification Framework for Neuroendocrine Neoplasms: An International Agency for Research on Cancer (IARC) and World Health Organization (WHO) Expert Consensus Proposal","volume":"31","author":"Rindi","year":"2018","journal-title":"Mod. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocr. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Batts, T.L., Sasaki, E., Miller, M., Sparago, J., Bauer, R.W., Paulsen, D., Boudreaux, B., Liu, C.-C., Byrum, S.D., and Johnston, A.N. (2023). Neoplastic Signatures: Comparative Proteomics of Canine Hepatobiliary Neuroendocrine Tumors to Normal Niche Tissue. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0280928"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lessels, N., Woolford, L., and Hayward, D. (Aust. Vet. J., 2025). Gastric Gastrinoma in a Dog: A Case Report, Application of Current WHO Criteria for Prognostication and Validation of a Local Gastrin Immunohistochemistry Assay, Aust. Vet. J., early view.","DOI":"10.1111\/avj.13469"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/j.1939-165X.2010.00243.x","article-title":"CASE REPORT: Metastatic Pancreatic Polypeptide-Secreting Islet Cell Tumor in a Dog: Pancreatic Polypeptidoma in a Dog","volume":"39","author":"Wamsley","year":"2010","journal-title":"Vet. Clin. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1354\/vp.09-VP-0019-K-FL","article-title":"Gastric Neuroendocrine Carcinomas in Bearded Dragons (Pogona vitticeps)","volume":"46","author":"Ritter","year":"2009","journal-title":"Vet. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1177\/1040638718779638","article-title":"Gastrinoma and Zollinger-Ellison Syndrome in Canids: A Literature Review and a Case in a Mexican Gray Wolf","volume":"30","author":"Struthers","year":"2018","journal-title":"J. Vet. Diagn. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jcpa.2018.02.005","article-title":"Small Intestinal Lymphatic Hypoplasia in Three Dogs with Clinical Signs of Protein-Losing Enteropathy","volume":"160","author":"Malatos","year":"2018","journal-title":"J. Comp. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1177\/03009858251324652","article-title":"Immunohistochemical and Histomorphologic Characterization of Canine Neoplasms of the Disseminated Neuroendocrine System","volume":"62","author":"Champion","year":"2025","journal-title":"Vet. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1177\/030098588101800404","article-title":"Canine Hepatic Carcinoids","volume":"18","author":"Patnaik","year":"1981","journal-title":"Vet. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1136\/gut.50.1.52","article-title":"Identification of Somatostatin Receptor Subtypes 1, 2A, 3, and 5 in Neuroendocrine Tumours with Subtype Specific Antibodies","volume":"50","author":"Kulaksiz","year":"2002","journal-title":"Gut"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1159\/000330616","article-title":"Monoclonal Antibodies Against the Human Somatostatin Receptor Subtypes 1\u20135: Development and Immunohistochemical Application in Neuroendocrine Tumors","volume":"95","author":"Schmid","year":"2012","journal-title":"Neuroendocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"340","DOI":"10.2967\/jnumed.123.265706","article-title":"Sequencing of Somatostatin-Receptor\u2013Based Therapies in Neuroendocrine Tumor Patients","volume":"65","author":"Strosberg","year":"2024","journal-title":"J. Nucl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/jvim.16966","article-title":"Use of Octreotide for the Treatment of Protein-Losing Enteropathy in Dogs: Retrospective Study of 18 Cases","volume":"38","author":"Jablonski","year":"2024","journal-title":"J. Vet. Intern. Med."}],"container-title":["Veterinary Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-7381\/12\/10\/989\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T16:50:52Z","timestamp":1760719852000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-7381\/12\/10\/989"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,14]]},"references-count":27,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["vetsci12100989"],"URL":"https:\/\/doi.org\/10.3390\/vetsci12100989","relation":{},"ISSN":["2306-7381"],"issn-type":[{"value":"2306-7381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,14]]}}}