{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:05:32Z","timestamp":1789538732171,"version":"build-2803163510"},"reference-count":44,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ki67 proliferation indices are used for grading well\u2010differentiated neuroendocrine tumours (NETs). Selection of tissue for staining can be challenging, especially in jejunoileal NETs (JI\u2010NETs), which can be multifocal and produce multiple metastases. This study aimed to determine parameters for selecting the most prognostically appropriate tissue for Ki67 staining in JI\u2010NETs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      We identified JI\u2010NETs with at least one nodal metastasis and\/or mesenteric tumour deposit. For each, we recorded patient age and sex; size of largest primary tumour, nodal metastasis and\/or deposit; AJCC staging; and patient outcome (recurrence and disease\u2010specific death). We stained the largest primary, node and deposit in each case for Ki67 (clone SP6, Biocare Medical CRM325, 1:50) and also assessed mitotic rates. We photographed hotspot areas on each Ki67 slide. Ki67 index was calculated for each photo using QuPath digital image analysis software after training using a random forest supervised classifier. Twenty cases underwent manual Ki67 counting to validate QuPath results. All variables were compared to patient outcomes using standard univariate and multivariate Cox proportional hazard regression (\n                      <jats:italic>\u03b1<\/jats:italic>\n                      \u2009=\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 75 JI\u2010NETs from 42 female and 33 male patients (mean age 61\u2009years), 71 had positive nodes and 47 had deposits. Mean sizes of the largest primary tumours, nodal metastases and deposits were 1.97, 1.28 and 2.0\u2009cm. Mean Ki67 was 1.82 (largest primaries), 2.24 (largest nodes) and 2.08 (largest deposits). In 51 cases (68%), the Ki67 of a node or deposit was higher than the primary tumour. Twenty\u2010one tumours (28%) recurred, with median projected time to recurrence time of 108\u2009months. Over a median overall follow\u2010up of 72\u2009months, six patients (8%) died of disease. Tumour deposit Ki67 was the only factor associated with increased risk of progression on multivariate analysis (hazard ratio [HR] 1.22 for each 1.0% increase, 95% confidence interval [CI] 1.02\u20131.46,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.032); primary and nodal Ki67 were not, nor was the highest Ki67 or the Ki67 of the largest focus within each case. No Ki67 indices were significantly relevant to overall survival on multivariate analysis, though largest tumour deposit size was (HR 1.51 for each 1.0\u2009cm increase, 95% CI 1.08\u20132.11,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.015).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Tumour deposits appear to play a key role in the outcome of patients with JI\u2010NETs. For meaningful Ki67 evaluation of JI\u2010NETs, the largest tumour deposit should be stained, if available.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/his.70279","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:44:15Z","timestamp":1789537455000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ki67 proliferation indices in advanced jejunoileal well\u2010differentiated neuroendocrine tumours are most prognostic when evaluated in mesenteric tumour deposits"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7020-9948","authenticated-orcid":false,"given":"Monika","family":"Vyas","sequence":"first","affiliation":[{"name":"Department of Pathology Beth Israel Deaconess Medical Center  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5758-5482","authenticated-orcid":false,"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5526-4220","authenticated-orcid":false,"given":"Raul S","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Emory University Hospital  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"337","volume-title":"WHO classification of tumours: endocrine and neuroendocrine Tumours","author":"Rindi G","year":"2025"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1038\/bjc.2013.156","article-title":"A comparison of Ki\u201067 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms","volume":"108","author":"Khan MS","year":"2013","journal-title":"Br. J. Cancer"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1097\/PAS.0000000000000089","article-title":"Grading of well\u2010differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate","volume":"37","author":"McCall CM","year":"2013","journal-title":"Am. J. Surg. Pathol."},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00428-017-2258-0","article-title":"Ki67 labeling index: Assessment and prognostic role in gastroenteropancreatic neuroendocrine neoplasms","volume":"472","author":"Kl\u00f6ppel G","year":"2018","journal-title":"Virchows Arch."},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1097\/00000478-200306000-00013","article-title":"Solitary versus multiple carcinoid tumors of the ileum: A clinical and pathologic review of 68 cases","volume":"27","author":"Yantiss RK","year":"2003","journal-title":"Am. J. 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Pathol."},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1007\/s00268-011-1296-z","article-title":"Long\u2010term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center","volume":"36","author":"Norl\u00e9n O","year":"2012","journal-title":"World J. Surg."},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1080\/02841860701218659","article-title":"Malignant ileocaecal serotonin\u2010producing carcinoid tumours: The presence of a solid growth pattern and\/or Ki67 index above 1% identifies patients with a poorer prognosis","volume":"46","author":"Cunningham JL","year":"2007","journal-title":"Acta Oncol."},{"key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1245\/s10434-017-5899-y","article-title":"Increased grade in neuroendocrine tumor metastases negatively impacts survival","volume":"24","author":"Keck KJ","year":"2017","journal-title":"Ann. Surg. 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Pathol."},{"key":"e_1_2_11_32_1","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1159\/000464292","article-title":"ENETS consensus guidelines for standard of Care in Neuroendocrine Tumours: surgery for small intestinal and pancreatic neuroendocrine Tumours","volume":"105","author":"Partelli S","year":"2017","journal-title":"Neuroendocrinology"},{"key":"e_1_2_11_33_1","unstructured":"National Comprehensive Cancer Network.Neuroendocrine and Adrenal Tumors Version 1.2026.https:\/\/www.nccn.org\/guidelines\/guidelines\u2010detail?category=1&id=1448."},{"key":"e_1_2_11_34_1","first-page":"13","volume-title":"WHO classification of tumours of the digestive system","author":"Rindi G","year":"2010"},{"key":"e_1_2_11_35_1","doi-asserted-by":"crossref","first-page":"e2222","DOI":"10.1210\/clinem\/dgae111","article-title":"Modified histopathological grading optimizes prediction of survival outcomes in small intestinal neuroendocrine tumors","volume":"109","author":"Daskalakis K","year":"2024","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"e_1_2_11_36_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s12022-023-09755-3","article-title":"Diagnostic, prognostic, and predictive role of Ki67 proliferative index in neuroendocrine and endocrine neoplasms: Past, present, and future","volume":"34","author":"La Rosa S","year":"2023","journal-title":"Endocr. Pathol."},{"key":"e_1_2_11_37_1","volume-title":"AJCC cancer staging system, version nine: neuroendocrine tumors of the jejunum and ileum","author":"Halfdanarson T","year":"2023"},{"key":"e_1_2_11_38_1","article-title":"Histopathologist\u2010level quantification of Ki\u201067 immunoexpression in gastroenteropancreatic neuroendocrine tumors using semiautomated method","volume":"7","author":"Saadeh H","year":"2020","journal-title":"J. Med. 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