{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T18:31:17Z","timestamp":1771007477275,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T00:00:00Z","timestamp":1658275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Background: Brain metastases (BMs) in patients with extra-pulmonary neuroendocrine neoplasms (EP\u2013NENs) are rare, and limited clinical information is available. The aim of this study was to detail the clinicopathological features, management and outcomes in patients with EP\u2013NENs who developed BMs. Methods: A retrospective single-centre analysis of consecutive patients with EP\u2013NENs (August 2004\u2013February 2020) was conducted. Median overall survival (OS)\/survival from BMs diagnosis was estimated (Kaplan\u2013Meier). Results: Of 730 patients, 17 (1.9%) had BMs, median age 61 years (range 15\u201377); 8 (53%) male, unknown primary NEN site: 40%. Patients with BMs had grade 3 (G3) EP\u2013NENs 11 (73%), G2: 3 (20%), G1: 1 (7%). Eight (53%) had poorly differentiated NENs, 6 were well-differentiated and 1 was not recorded. Additionally, 2 (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. The relative risk of developing BMs was 7.48 in patients with G3 disease vs. G1 + G2 disease (p = 0.0001). Median time to the development of BMs after NEN diagnosis: 15.9 months (range 2.5\u2013139.5). Five patients had a solitary BM, 12 had multiple BMs. Treatment of BMs were surgery (n = 3); radiotherapy (n = 5); 4: whole brain radiotherapy, 1: conformal radiotherapy (orbit). Nine (53%) had best supportive care. Median OS from NEN diagnosis was 23.6 months [95% CI 15.2\u201331.3]; median time to death from BMs diagnosis was 3.0 months [95% CI 0.0\u20138.3]. Conclusion: BMs in patients with EP\u2013NENs are rare and of increased risk in G3 vs. G1 + G2 EP\u2013NENs. Survival outcomes are poor, and a greater understanding is needed to improve therapeutic outcomes.<\/jats:p>","DOI":"10.3390\/curroncol29070405","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T11:22:24Z","timestamp":1658316144000},"page":"5110-5125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Management and Outcomes of Patients with Extra-Pulmonary Neuroendocrine Neoplasms and Brain Metastases"],"prefix":"10.3390","volume":"29","author":[{"given":"Zainul-Abedin","family":"Kapacee","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Allison","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Dawod","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-8093","authenticated-orcid":false,"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Statistics Group, Digital Services, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa","family":"Frizziero","sequence":"additional","affiliation":[{"name":"Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bipasha","family":"Chakrabarty","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prakash","family":"Manoharan","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine\/Radiology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"McBain","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Was","family":"Mansoor","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Lamarca","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Hubner","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1999-0863","authenticated-orcid":false,"given":"Juan W.","family":"Valle","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"},{"name":"Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2272-3678","authenticated-orcid":false,"given":"Mair\u00e9ad G.","family":"McNamara","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK"},{"name":"Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.annonc.2020.03.304","article-title":"Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Pavel","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1097\/PAS.0b013e318159371c","article-title":"Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity?","volume":"32","author":"Shia","year":"2008","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1097\/MPA.0b013e3181ebb56f","article-title":"The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (High-Grade) extrapulmonary neuroendocrine carcinomas","volume":"39","author":"Strosberg","year":"2010","journal-title":"Pancreas"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Feola, T., Centello, R., Sesti, F., Puliani, G., Verrico, M., Di Vito, V., Di Gioia, C., Bagni, O., Lenzi, A., and Isidori, A.M. (2021). Neuroendocrine Carcinomas with Atypical Proliferation Index and Clinical Behavior: A Systematic Review. Cancers, 13.","DOI":"10.3390\/cancers13061247"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1093\/annonc\/mds276","article-title":"Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): The NORDIC NEC study","volume":"24","author":"Sorbye","year":"2013","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1007\/s12094-018-1996-z","article-title":"Urgent need for consensus: International survey of clinical practice exploring use of platinum-etoposide chemotherapy for advanced extra-pulmonary high grade neuroendocrine carcinoma (EP-G3-NEC)","volume":"21","author":"Lamarca","year":"2019","journal-title":"Clin. Transl. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1159\/000441897","article-title":"Changes in the Epidemiology of Neuroendocrine Tumours","volume":"104","author":"Huguet","year":"2016","journal-title":"Neuroendocrinology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1159\/000504256","article-title":"Identification of Areas for Improvement in the Management of Bone Metastases in Patients with Neuroendocrine Neoplasms","volume":"110","author":"Lim","year":"2020","journal-title":"Neuroendocrinology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7288","DOI":"10.1002\/cam4.2567","article-title":"Incidence and risk factors of gastrointestinal neuroendocrine neoplasm metastasis in liver, lung, bone, and brain: A population-based study","volume":"8","author":"Zheng","year":"2019","journal-title":"Cancer Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1159\/000513249","article-title":"Unique Metastatic Patterns in Neuroendocrine Neoplasms of Different Primary Origin","volume":"111","author":"Hermans","year":"2021","journal-title":"Neuroendocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Christensen, T.D., Spindler, K.G., Palshof, J.A., and Nielsen, D.L. (2016). Systematic review: Brain metastases from colorectal cancer--Incidence and patient characteristics. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2290-5"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Krug, S., Teupe, F., Michl, P., Gress, T.M., and Rinke, A. (2019). Brain metastases in patients with neuroendocrine neoplasms: Risk factors and outcome. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5559-7"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Trikalinos, N.A., Tan, B.R., Amin, M., Liu, J., Govindan, R., and Morgensztern, D. (2020). Effect of metastatic site on survival in patients with neuroendocrine neoplasms (NENs). An analysis of SEER data from 2010 to 2014. BMC Endocr. Disord., 20.","DOI":"10.1186\/s12902-020-0525-6"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0167-8140(97)00149-7","article-title":"Brain-only metastases of small cell lung cancer; efficacy of whole brain radiotherapy. An EORTC phase II study","volume":"46","author":"Postmus","year":"1998","journal-title":"Radiother. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3400","DOI":"10.1200\/JCO.2000.18.19.3400","article-title":"Treatment of brain metastases of small-cell lung cancer: Comparing teniposide and teniposide with whole-brain radiotherapy\u2014A phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group","volume":"18","author":"Postmus","year":"2000","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1016\/S0140-6736(16)30825-X","article-title":"Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): Results from a phase 3, non-inferiority, randomised trial","volume":"388","author":"Mulvenna","year":"2016","journal-title":"Lancet"},{"key":"ref_18","first-page":"52","article-title":"Whole Brain Irradiation or Stereotactic RadioSurgery for five or more brain metastases (WHOBI-STER): A prospective comparative study of neurocognitive outcomes, level of autonomy in daily activities and quality of life","volume":"32","author":"Ferini","year":"2021","journal-title":"Clin. Transl. Radiat. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/S0140-6736(04)16250-8","article-title":"Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomised trial","volume":"363","author":"Andrews","year":"2004","journal-title":"Lancet"},{"key":"ref_20","unstructured":"The Royal College of Radiologists (2019). RCR Guidance: Radiotherapy Dose Fractionation, The Royal College of Radiologists. [3rd ed.]."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/S0360-3016(00)00547-2","article-title":"Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases","volume":"47","author":"Gaspar","year":"2000","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_22","first-page":"JCO2102314","article-title":"Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline","volume":"40","author":"Vogelbaum","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6234","DOI":"10.21037\/jtd.2020.03.90","article-title":"Radiosurgery for small-cell lung cancer brain metastases: A review","volume":"12","author":"Robin","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1080\/0284186X.2018.1564841","article-title":"Management of brain metastases from large cell neuroendocrine carcinoma of the lung: Improved outcomes with radiosurgery","volume":"58","author":"Wegner","year":"2019","journal-title":"Acta Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3171\/2016.7.GKS161459","article-title":"Gamma Knife radiosurgery for brain metastases from pulmonary large cell neuroendocrine carcinoma: A Japanese multi-institutional cooperative study (JLGK1401)","volume":"125","author":"Kawabe","year":"2016","journal-title":"J. Neurosurg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1001\/jamaoncol.2020.1271","article-title":"Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study","volume":"6","author":"Rusthoven","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1056\/NEJM199908123410703","article-title":"Prophylactic Cranial Irradiation for Patients with Small-Cell Lung Cancer in Complete Remission","volume":"341","author":"Arriagada","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1056\/NEJMoa071780","article-title":"Prophylactic Cranial Irradiation in Extensive Small-Cell Lung Cancer","volume":"357","author":"Slotman","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Meert, A.P., Paesmans, M., Berghmans, T., Martin, B., Mascaux, C., Vallot, F., Verdebout, J.M., Lafitte, J.J., and Sculier, J.P. (2001). Prophylactic cranial irradiation in small cell lung cancer: A systematic review of the literature with meta-analysis. BMC Cancer, 1.","DOI":"10.1186\/1471-2407-1-5"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1007\/s00405-015-3799-y","article-title":"Should patients with laryngeal small cell neuroendocrine carcinoma receive prophylactic cranial irradiation?","volume":"273","author":"Devaney","year":"2016","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1097\/JTO.0b013e31829f6b03","article-title":"Should Patients with Extrapulmonary Small-Cell Carcinoma Receive Prophylactic Cranial Irradiation?","volume":"8","author":"Naidoo","year":"2013","journal-title":"J. Thorac. Oncol."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/29\/7\/405\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:54:15Z","timestamp":1760140455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/29\/7\/405"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,20]]},"references-count":31,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["curroncol29070405"],"URL":"https:\/\/doi.org\/10.3390\/curroncol29070405","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,20]]}}}