{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:21:22Z","timestamp":1790724082234,"version":"4.1.0"},"reference-count":27,"publisher":"Harborside Press, LLC","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,24]]},"abstract":"\n Background:<\/jats:bold>\n Hypophysitis is a serious adverse event stemming from immune checkpoint inhibitor (ICI) therapy for malignancy. This study aimed to characterize ICI-induced hypophysitis, identify diagnostic challenges, and evaluate an association with survival in a large cancer cohort.\n Methods:<\/jats:bold>\n We performed a retrospective cohort study of adult patients with cancer who received ICIs between December 1, 2012, and December 31, 2019. We identified 839 patients who received CTLA-4, PD-1, or PD-L1 inhibitors or a combination thereof who were followed for a median of 19.4 months. Hypophysitis was defined as MRI evidence of pituitary gland and\/or stalk enlargement or biochemical evidence of hypopituitarism if not explained by another etiology.\n Results:<\/jats:bold>\n A total of 16 (1.9%) patients developed hypophysitis a median of 7 months after ICI initiation, with most patients having melanoma (9\/16; 56.2%) or renal cell carcinoma (4\/16; 25%). Two patients also had exogenous glucocorticoid exposure but exhibited secondary hypothyroidism and secondary adrenal insufficiency (AI). Median age at the start of ICI was 61.3 years and 57% were men. Patients who developed hypophysitis were younger compared with those who did not develop hypophysitis (median age, 57 vs 65 years;\n P<\/jats:italic>\n =.011). Hypophysitis occurred most frequently after combination therapy (13.7%) compared with CTLA-4 monotherapy (1.9%), PD-1 monotherapy (1.2%), and PD-L1 monotherapy (0.8%) (\n P<\/jats:italic>\n <.0001). Pituitary gland enlargement on MRI occurred more frequently after CTLA-4 inhibitor monotherapy or combination therapy (5\/7; 71.4%) compared with PD-1\/PD-L1 inhibitor monotherapy (1\/6; 16.7%). The survival benefit of hypophysitis was not apparent after addressing immortal time bias and adjusting for other variables affecting patient outcomes.\n Conclusions:<\/jats:bold>\n Secondary AI occurred in all patients, and secondary hypothyroidism occurred in half. Classic pituitary gland enlargement is usually absent in PD-1\/PD-L1 inhibitor\u2013induced hypophysitis. Further pituitary evaluation must be conducted to differentiate secondary AI resulting from exogenous glucocorticoids and hypophysitis in patients with cancer receiving ICIs. The link between hypophysitis and ICI efficacy needs further investigation.\n <\/jats:p>","DOI":"10.6004\/jnccn.2022.7098","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T12:47:07Z","timestamp":1677242827000},"page":"281-287","source":"Crossref","is-referenced-by-count":47,"title":["Hypophysitis and Secondary Adrenal Insufficiency From Immune Checkpoint Inhibitors: Diagnostic Challenges and Link With Survival"],"prefix":"10.6004","volume":"21","author":[{"given":"Jake","family":"Johnson","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitney","family":"Goldner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duaa","family":"Abdallah","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apar Kishor","family":"Ganti","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupam","family":"Kotwal","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4047","reference":[{"key":"B1","series-title":"Curr Opin Endocrinol Diabetes Obes","first-page":"427","article-title":"Hypophysitis from immune checkpoint inhibitors: challenges in diagnosis and management","volume":"28","author":"Kotwal A","year":"2021","unstructured":"Kotwal A. Hypophysitis from immune checkpoint inhibitors: challenges in diagnosis and management. Curr Opin Endocrinol Diabetes Obes 2021;28:427\u2013434."},{"key":"B2","series-title":"Expert Rev Endocrinol Metab","first-page":"381","article-title":"Hypophysitis induced by immune checkpoint inhibitors: a 10-year assessment","volume":"14","author":"Di Dalmazi G","year":"2019","unstructured":"Di Dalmazi G, Ippolito S, Lupi I, Hypophysitis induced by immune checkpoint inhibitors: a 10-year assessment. Expert Rev Endocrinol Metab 2019;14:381\u2013398."},{"key":"B3","series-title":"Endocr Rev","first-page":"17","article-title":"Endocrine toxicity of cancer immunotherapy targeting immune checkpoints","volume":"40","author":"Chang LS","year":"2019","unstructured":"Chang LS, Barroso-Sousa R, Tolaney SM, Endocrine toxicity of cancer immunotherapy targeting immune checkpoints. Endocr Rev 2019;40:17\u201365."},{"key":"B4","series-title":"JAMA Oncol","first-page":"173","article-title":"Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis","volume":"4","author":"Barroso-Sousa R","year":"2018","unstructured":"Barroso-Sousa R, Barry WT, Garrido-Castro AC, Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 2018;4:173\u2013182."},{"key":"B5","series-title":"Nat Rev Endocrinol","first-page":"389","article-title":"Endocrine toxicities of immune checkpoint inhibitors","volume":"17","author":"Wright JJ","year":"2021","unstructured":"Wright JJ, Powers AC, Johnson DB. Endocrine toxicities of immune checkpoint inhibitors. Nat Rev Endocrinol 2021;17:389\u2013399."},{"key":"B6","series-title":"J Clin Endocrinol Metab","first-page":"4078","article-title":"Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma","volume":"99","author":"Faje AT","year":"2014","unstructured":"Faje AT, Sullivan R, Lawrence D, Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 2014;99:4078\u20134085."},{"key":"B7","series-title":"Endocr Relat Cancer","first-page":"371","article-title":"Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution","volume":"21","author":"Ryder M","year":"2014","unstructured":"Ryder M, Callahan M, Postow MA, Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer 2014;21:371\u2013381."},{"key":"B8","series-title":"Eur J Endocrinol","first-page":"211","article-title":"Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab- associated hypophysitis","volume":"181","author":"Faje A","year":"2019","unstructured":"Faje A, Reynolds K, Zubiri L, Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab- associated hypophysitis. Eur J Endocrinol 2019;181:211\u2013219."},{"key":"B9","series-title":"JNCI Cancer Spectr","first-page":"pky021","article-title":"The current understanding of the endocrine effects from immune checkpoint inhibitors and recommendations for management","volume":"2","author":"Girotra M","year":"2018","unstructured":"Girotra M, Hansen A, Farooki A, The current understanding of the endocrine effects from immune checkpoint inhibitors and recommendations for management. JNCI Cancer Spectr 2018;2:pky021."},{"key":"B10","series-title":"Endocr Relat Cancer","first-page":"G1","article-title":"French Endocrine Society guidance on endocrine side effects of immunotherapy","volume":"26","author":"Castinetti F","year":"2019","unstructured":"Castinetti F, Albarel F, Archambeaud F, French Endocrine Society guidance on endocrine side effects of immunotherapy. Endocr Relat Cancer 2019;26:G1\u201318."},{"key":"B11","series-title":"J Clin Oncol","first-page":"4073","article-title":"Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update","volume":"39","author":"Schneider BJ","year":"2021","unstructured":"Schneider BJ, Naidoo J, Santomasso BD, Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021;39:4073\u20134126."},{"key":"B12","article-title":"NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities","author":"Thompson JA","unstructured":"Thompson JA, Schneider BJ, Brahmer J, NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities. Version 1.2022. Accessed October 1, 2022. To view the most recent version, visit https:\/\/www.nccn.org"},{"key":"B13","series-title":"Annu Rev Med","first-page":"313","article-title":"Autoimmune endocrinopathies: an emerging complication of immune checkpoint inhibitors","volume":"72","author":"Quandt Z","year":"2021","unstructured":"Quandt Z, Young A, Perdigoto AL, Autoimmune endocrinopathies: an emerging complication of immune checkpoint inhibitors. Annu Rev Med 2021;72:313\u2013330."},{"key":"B14","series-title":"Eur J Endocrinol","first-page":"R107","article-title":"Management of endocrine disease: immune check point inhibitors-induced hypophysitis","volume":"181","author":"Albarel F","year":"2019","unstructured":"Albarel F, Castinetti F, Brue T. Management of endocrine disease: immune check point inhibitors-induced hypophysitis. Eur J Endocrinol 2019;181:R107\u2013118."},{"key":"B15","series-title":"Cancer","first-page":"3706","article-title":"High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma","volume":"124","author":"Faje AT","year":"2018","unstructured":"Faje AT, Lawrence D, Flaherty K, High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer 2018;124:3706\u20133714."},{"key":"B16","series-title":"J Immunother Cancer","first-page":"e000779","article-title":"Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study","volume":"8","author":"Kobayashi T","year":"2020","unstructured":"Kobayashi T, Iwama S, Yasuda Y, Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study. J Immunother Cancer 2020;8:e000779."},{"key":"B17","series-title":"Pituitary","first-page":"488","article-title":"Ipilimumab-induced hypophysitis, a single academic center experience","volume":"22","author":"Snyders T","year":"2019","unstructured":"Snyders T, Chakos D, Swami U, Ipilimumab-induced hypophysitis, a single academic center experience. Pituitary 2019;22:488\u2013496."},{"key":"B18","series-title":"J Investig Med","first-page":"939","article-title":"Immune checkpoint inhibitor- induced hypophysitis: lessons learnt from a large cancer cohort","volume":"70","author":"Kotwal A","year":"2022","unstructured":"Kotwal A, Rouleau SG, Dasari S, Immune checkpoint inhibitor- induced hypophysitis: lessons learnt from a large cancer cohort. J Investig Med 2022;70:939\u2013946."},{"key":"B19","series-title":"Pituitary","first-page":"82","article-title":"Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights","volume":"19","author":"Faje A","year":"2016","unstructured":"Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. 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Clin Cancer Res 2015;21:749\u2013755."},{"key":"B24","series-title":"Intern Med J","first-page":"1066","article-title":"Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series","volume":"45","author":"Lam T","year":"2015","unstructured":"Lam T, Chan MM, Sweeting AN, Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. Intern Med J 2015;45:1066\u20131073."},{"key":"B25","series-title":"Curr Opin Endocrinol Diabetes Obes","first-page":"517","article-title":"Survival benefit of endocrine dysfunction following immune checkpoint inhibitors for nonthyroidal cancers","volume":"28","author":"Kotwal A","year":"2021","unstructured":"Kotwal A, Ryder M. Survival benefit of endocrine dysfunction following immune checkpoint inhibitors for nonthyroidal cancers. Curr Opin Endocrinol Diabetes Obes 2021;28:517\u2013524."},{"key":"B26","series-title":"Cancer Immunol Immunother","first-page":"1795","article-title":"Associations between immune-related thyroid dysfunction and efficacy of immune checkpoint inhibitors: a systematic review and meta-analysis","volume":"71","author":"Cheung YM","year":"2022","unstructured":"Cheung YM, Wang W, McGregor B, Associations between immune-related thyroid dysfunction and efficacy of immune checkpoint inhibitors: a systematic review and meta-analysis. Cancer Immunol Immunother 2022;71:1795\u20131812."},{"key":"B27","series-title":"Cancer Res","article-title":"Autoimmune hypophysitis is a marker of favorable outcome during treatment of melanoma with ipilimumab","volume":"75","author":"Eatrides JM","year":"2015","unstructured":"Eatrides JM, Weber J, Egan K. Autoimmune hypophysitis is a marker of favorable outcome during treatment of melanoma with ipilimumab. Cancer Res 2015;75(Suppl):Abstract B23."}],"container-title":["Journal of the National Comprehensive Cancer Network"],"original-title":[],"link":[{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/21\/3\/article-p281.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/jnccn.org\/downloadpdf\/journals\/jnccn\/21\/3\/article-p281.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/jnccn.org\/downloadpdf\/journals\/jnccn\/21\/3\/article-p281.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T15:35:44Z","timestamp":1678462544000},"score":1,"resource":{"primary":{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/21\/3\/article-p281.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,24]]},"references-count":27,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.6004\/jnccn.2022.7098","relation":{},"ISSN":["1540-1405","1540-1413"],"issn-type":[{"value":"1540-1405","type":"print"},{"value":"1540-1413","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,24]]}}}