{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:05:17Z","timestamp":1760058317190,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"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>Ectopic adrenocorticotropic hormone syndrome (EAS) occurs when a tumor develops neuroendocrine differentiation with the secretion of ACTH resulting in hypercortisolism and possibly Cushing\u2019s syndrome (CS). Only 5\u201310% of CS cases are attributed to EAS; of these, breast tumors comprise less than 1%. Two known variants of breast neuroendocrine tumors include neuroendocrine-differentiated carcinoma and ductal carcinoma with neuroendocrine features. Currently, guidelines for treatment are limited and EAS is associated with significant morbidity and mortality. A 39-year-old female presented with a rapidly enlarging breast mass. Biopsy demonstrated invasive poorly differentiated breast carcinoma with high-grade neuroendocrine features and necrosis. Staging at diagnosis confirmed metastatic disease of the liver and bone. First-line chemotherapy (Cisplatin\/Etoposide\/Durvalumab) was initiated with evidence of disease progression after four cycles. Given a poor response to therapy, a simple mastectomy was performed for local control and complete pathologic analysis, demonstrating high-grade neuroendocrine carcinoma with large-cell features. Second-line therapy (Adriamycin\/Cyclophosphamide) was initiated for three cycles after which the patient required admission for severe and refractory hypokalemia. Workup confirmed elevated ACTH consistent with paraneoplastic EAS and further evidence of disease progression. Third-line therapy (Nab-Paclitaxel) was initiated, and genetic testing was completed, confirming the PIK3 mutation, for which access to Alpelisib therapy was requested. Given symptoms of progressive severe CS with significant liver disease limiting medical therapies, the patient underwent urgent bilateral laparoscopic adrenalectomy after which she was able to be discharged home while awaiting additional systemic therapy. EAS resulting in CS secondary to breast neuroendocrine carcinoma is a rare and challenging diagnosis. Further research is needed to inform treatment guidelines to improve outcomes. While patient survival is dependent upon the underlying disease process, laparoscopic bilateral adrenalectomy is an accepted, definitive treatment option.<\/jats:p>","DOI":"10.3390\/curroncol32040205","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T05:10:07Z","timestamp":1743397807000},"page":"205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuroendocrine Breast Cancer-Associated Ectopic Adrenocorticotropic Hormone Syndrome Requiring Bilateral Adrenalectomy"],"prefix":"10.3390","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5485-8454","authenticated-orcid":false,"given":"Kala","family":"Hickey","sequence":"first","affiliation":[{"name":"Department of General Surgery, Faculty of Medicine, Memorial University, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Yaremko","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Memorial University, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Orr","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, Memorial University, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6641-8002","authenticated-orcid":false,"given":"David","family":"Pace","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Faculty of Medicine, Memorial University, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/S0140-6736(14)61375-1","article-title":"Cushing\u2019s Syndrome","volume":"386","author":"Lacroix","year":"2015","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3162","DOI":"10.1210\/clinem\/dgac492","article-title":"Approach to the Patient: Diagnosis of Cushing Syndrome","volume":"107","author":"Savas","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1136\/jclinpath-2016-203933","article-title":"Cushing\u2019s Syndrome: A Practical Approach to Diagnosis and Differential Diagnoses","volume":"70","author":"Pappachan","year":"2017","journal-title":"J. Clin. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1007\/s11102-022-01258-4","article-title":"Cardiovascular Health and Mortality in Cushing\u2019s Disease","volume":"25","author":"Coulden","year":"2022","journal-title":"Pituitary"},{"key":"ref_5","first-page":"281","article-title":"Cushing\u2019s Syndrome: Epidemiology and Developments in Disease Management","volume":"7","author":"Sharma","year":"2015","journal-title":"Clin. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1590\/S0004-27302007000800007","article-title":"Ectopic ACTH Syndrome","volume":"51","author":"Isidori","year":"2007","journal-title":"Arq. Bras. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4955","DOI":"10.1210\/jc.2004-2527","article-title":"Cushing\u2019s Syndrome Due to Ectopic Corticotropin Secretion: Twenty Years\u2019 Experience at the National Institutes of Health","volume":"90","author":"Ilias","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.ecl.2018.01.005","article-title":"The Ectopic Adrenocorticotropic Hormone Syndrome: Rarely Easy, Always Challenging","volume":"47","author":"Hayes","year":"2018","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1677\/joe.1.05963","article-title":"Hypomethylation in the Promoter Region of POMC Gene Correlates with Ectopic Overexpression in Thymic Carcinoids","volume":"185","author":"Ye","year":"2005","journal-title":"J. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/0960-0760(95)00044-Z","article-title":"Ectopic ACTH Syndrome","volume":"53","author":"Wajchenberg","year":"1995","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.radcr.2023.10.047","article-title":"Neuroendocrine Breast Carcinoma: The Importance of the Correlation between Histological and Radiological Findings","volume":"19","author":"Amsiguine","year":"2023","journal-title":"Radiol. Case Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sultana, Q., Kar, J., Verma, A., Sanghvi, S., Kaka, N., Patel, N., Sethi, Y., Chopra, H., Kamal, M.A., and Greig, N.H. (2023). A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management. J. Clin. Med., 12.","DOI":"10.3390\/jcm12155138"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1634\/theoncologist.2015-0309","article-title":"Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives","volume":"21","author":"Inno","year":"2016","journal-title":"Oncologist"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/his.14091","article-title":"The 2019 World Health Organization Classification of Tumours of the Breast","volume":"77","author":"Tan","year":"2020","journal-title":"Histopathology"},{"key":"ref_15","first-page":"71","article-title":"ACTH-Producing Breast Cancer: A Patient Report","volume":"53","author":"Uchida","year":"2010","journal-title":"Yonago Acta Med."},{"key":"ref_16","first-page":"e6488","article-title":"Adrenocorticotropic Hormone-Producing Extrapulmonary Small Cell Carcinoma of the Breast","volume":"11","author":"Mansour","year":"2019","journal-title":"Cureus"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1210\/jc.2005-1542","article-title":"The Ectopic Adrenocorticotropin Syndrome: Clinical Features, Diagnosis, Management, and Long-Term Follow-Up","volume":"91","author":"Isidori","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_18","unstructured":"(2025, February 18). Foundation Medicine Expands Indication for FoundationOne\u00aeCDx as a Companion Diagnostic for Piqray\u00ae (alpelisib) | Foundation Medicine. Available online: https:\/\/www.foundationmedicine.com\/press-releases\/foundation-medicine-expands-indication-for-foundationone%C2%AEcdx-as-a-companion-diagnostic-for-piqray%C2%AE-%28alpelisib%29."},{"key":"ref_19","unstructured":"(2025, February 18). FDA Approves New FoundationOne\u00aeLiquid CDx Companion Diagnostic Indications for Three Targeted Therapies That Treat Advanced Ovarian, Breast and Non-Small Cell Lung Cancer | Foundation Medicine. Available online: https:\/\/www.foundationmedicine.com\/press-releases\/fda-approves-new-foundationone%C2%AEliquid-cdx-companion-diagnostic-indications-for-three-targeted-therapies-that-treat-advanced-ovarian%2C-breast-and-non-small-cell-lung-cancer."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gallo, M., Campione, S., Di Vito, V., Fortunati, N., Lo Calzo, F., Messina, E., Ruggeri, R.M., Faggiano, A., and Colao, A.A.L. (2021). Primary Neuroendocrine Neoplasms of the Breast: Still Open Issues. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.610230"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6339","DOI":"10.1245\/s10434-022-12123-w","article-title":"Primary Breast Neuroendocrine Tumors: An Analysis of the National Cancer Database","volume":"29","author":"Martinez","year":"2022","journal-title":"Ann. Surg. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1002\/1097-0142(197805)41:5<2002::AID-CNCR2820410547>3.0.CO;2-2","article-title":"Norepinephrine-Producing Tumors of Bilateral Breasts: A Case Report","volume":"41","author":"Kaneko","year":"1978","journal-title":"Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1136\/bmj.4.5990.197","article-title":"Secretion of Immunoreactive Calcitonin by Human Breast Carcinomas","volume":"4","author":"Coombes","year":"1975","journal-title":"Br. Med. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e402","DOI":"10.4158\/ACCR-2018-0069","article-title":"Metastatic Adrenocorticotropic Hormone-Secreting Breast Cancer Treated with Bilateral Adrenalectomy","volume":"4","author":"Zheng","year":"2018","journal-title":"AACE Clin. Case Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1318","DOI":"10.1634\/theoncologist.2020-0081","article-title":"The Clinical Significance of Neuroendocrine Features in Invasive Breast Carcinomas","volume":"25","author":"Lai","year":"2020","journal-title":"Oncologist"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4463","DOI":"10.1002\/cncr.25352","article-title":"Invasive Neuroendocrine Carcinoma of the Breast","volume":"116","author":"Wei","year":"2010","journal-title":"Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, J., Wei, B., Albarracin, C.T., Hu, J., Abraham, S.C., and Wu, Y. (2014). Invasive Neuroendocrine Carcinoma of the Breast: A Population-Based Study from the Surveillance, Epidemiology and End Results (SEER) Database. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-147"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"\u00d6zdirik, B., Kayser, A., Ullrich, A., Savic, L.J., Reiss, M., Tacke, F., Wiedenmann, B., Jann, H., and Roderburg, C. (2020). Primary Neuroendocrine Neoplasms of the Breast: Case Series and Literature Review. Cancers, 12.","DOI":"10.3390\/cancers12030733"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.5858\/arpa.2016-0364-RS","article-title":"Neuroendocrine Tumors of the Breast","volume":"141","author":"Rosen","year":"2017","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Das, S., Al-Toubah, T., and Strosberg, J. (2021). Chemotherapy in Neuroendocrine Tumors. Cancers, 13.","DOI":"10.3390\/cancers13194872"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1210\/jc.2015-1818","article-title":"Treatment of Cushing\u2019s Syndrome: An Endocrine Society Clinical Practice Guideline","volume":"100","author":"Nieman","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1530\/EJE-19-0877","article-title":"MANAGEMENT OF ENDOCRINE DISEASE: Cushing\u2019s Syndrome Due to Ectopic ACTH Secretion: An Expert Operational Opinion","volume":"182","author":"Young","year":"2020","journal-title":"Eur. J. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1023\/A:1022308429992","article-title":"Medical Therapy of Cushing\u2019s Disease","volume":"5","author":"Nieman","year":"2002","journal-title":"Pituitary"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e85","DOI":"10.4158\/EP11315.CR","article-title":"Bilateral Adrenalectomy: Lifesaving Procedure in Severe Cushing Syndrome","volume":"18","author":"Han","year":"2012","journal-title":"Endocr. Pract."},{"key":"ref_35","unstructured":"Hickey, K., Yaremko, H., Orr, C., and Pace, D. (2024, January 25\u201328). Neuroendocrine Breast Cancer-Associated Ectopic Adrenocorticotropic Hormone Syndrome Requiring Bilateral Adrenalectomy. Proceedings of the Canadian Association of General Surgeons\u2014Canadian Surgery Forum Conference, Winnipeg, MB, Canada."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/32\/4\/205\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:06:23Z","timestamp":1760029583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/32\/4\/205"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,31]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["curroncol32040205"],"URL":"https:\/\/doi.org\/10.3390\/curroncol32040205","relation":{},"ISSN":["1718-7729"],"issn-type":[{"type":"electronic","value":"1718-7729"}],"subject":[],"published":{"date-parts":[[2025,3,31]]}}}