Advertisement

Multimodality imaging of endocrine immune related adverse events: a primer for radiologists

      Highlights

      • Immune checkpoint inhibitors are commonly associated with endocrine adverse events.
      • Organ involved, timing and severity of event depends on type of drug.
      • Hypophysitis and thyroid disorders are common and occur early during treatment.
      • Adrenalitis, endocrine pancreatic and gonadal toxicity occur rarely.
      • Immune related endocrine toxicities often occur with multi-organ involvement.

      Abstract

      Immune-related endocrine adverse events occur in up to one third of patients treated with immune checkpoint inhibitors. The purpose of this article is to provide a comprehensive review of the multimodality imaging features of the different immune-related endocrine adverse events. In this article, we will introduce the different types of immune checkpoint inhibitors used in clinical practice, and for each endocrine organ affected we will describe the clinical presentation, the multimodality imaging features at presentation and after treatment, and the possible differential diagnosis.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Imaging
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • U.S. Food and Drug Administration
        Yervoy approval letter.
        (Available via)
        • Hodi F.S.
        • O'Day S.J.
        • McDermott D.F.
        • et al.
        Improved survival with ipilimumab in patients with metastatic melanoma.
        N Engl J Med. 2010; 363: 711-723
        • Motzer R.J.
        • Escudier B.
        • McDermott D.F.
        • et al.
        Nivolumab versus everolimus in advanced renal cell carcinoma.
        N Engl J Med. 2015; 373: 1803-1813
        • Reck M.
        • Rodríguez-Abreu D.
        • Robinson A.G.
        • et al.
        Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
        N Engl J Med. 2016; 375: 1823-1833
        • Kudo M.
        Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials.
        Oncology. 2017; 92: 50-62
        • Marrone K.A.
        • Ying W.
        • Naidoo J.
        Immune-related adverse events from immune checkpoint inhibitors.
        Clin Pharmacol Ther. 2016; 100: 242-251
        • González-Rodríguez E.
        • Rodríguez-Abreu D.
        • Spanish Group for Cancer Immuno-Biotherapy (GETICA)
        Immune checkpoint inhibitors: review and management of endocrine adverse events.
        Oncologist. 2016; 21: 804-816
        • Byun D.J.
        • Wolchok J.D.
        • Rosenberg L.M.
        • Girotra M.
        Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies.
        Nat Rev Endocrinol. 2017; 13: 195-207
        • Michot J.M.
        • Bigenwald C.
        • Champiat S.
        • et al.
        Immune-related adverse events with immune checkpoint blockade: a comprehensive review.
        Eur J Cancer. 2016; 54: 139-148
        • Puzanov I.
        • Diab A.
        • Abdallah K.
        • et al.
        Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
        J Immunother Cancer. 2017; 5: 95
        • National Cancer Institute
        Common Terminology Criteria for Adverse Events (CTCAE) v.4 2010.
        • Larkin J.
        • Chiarion-Sileni V.
        • Gonzalez R.
        • et al.
        Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
        N Engl J Med. 2015; 373: 23-34
        • Dillard T.
        • Yedinak C.G.
        • Alumkal J.
        • Fleseriu M.
        Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes.
        Pituitary. 2010; 1: 29-38
        • Torino F.
        • Corsello S.M.
        • Salvatori R.
        Endocrinological side-effects of immune checkpoint inhibitors.
        Curr Opin Oncol. 2016; 28: 278-287
        • D'Angelo S.P.
        • Larkin J.
        • Sosman J.A.
        • et al.
        Efficacy and safety of nivolumab alone or in combination with Ipilimumab in patients with mucosal melanoma: a pooled analysis.
        J Clin Oncol. 2017; 35: 226-235
        • Kwak J.J.
        • Tirumani S.H.
        • Van den Abbeele A.D.
        • Koo P.J.
        • Jacene H.A.
        Cancer immunotherapy: imaging assessment of novel treatment response patterns and immune-related adverse events.
        Radiographics. 2015; 35: 424-437
        • Weber J.S.
        • Postow M.
        • Lao C.D.
        • Schadendorf D.
        Management of Adverse Events Following Treatment With Anti-Programmed Death-1 Agents.
        Oncologist. 2016; 21: 1230-1240
        • Quirk S.K.
        • Shure A.K.
        • Agrawal D.K.
        Immune mediated adverse events of anticytotoxic T lymphocyte associated antigen 4 antibody therapy in metastatic melanoma.
        Transl Res. 2015; 166: 412-424
        • Iwama S.
        • De Remigis A.
        • Callahan M.K.
        • Slovin S.F.
        • Wolchok J.D.
        • Caturegli P.
        Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody.
        Sci Transl Med. 2014; 6: 230ra45
        • Wang C.
        • Thudium K.B.
        • Han M.
        • et al.
        In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates.
        Cancer Immunol Res. 2014; 2: 846-856
        • Abdel-Rahman O.
        • ElHalawani H.
        • Fouad M.
        Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis.
        Future Oncol. 2016; 12: 413-425
        • Barroso-Sousa R.
        • Barry W.T.
        • Garrido-Castro A.C.
        • et al.
        Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis.
        JAMA Oncol. 2017; https://doi.org/10.1001/jamaoncol.2017.3064
        • Topalian S.L.
        • Sznol M.
        • McDermott D.F.
        • et al.
        Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.
        J Clin Oncol. 2014; 32: 1020-1030
        • Robert C.
        • Ribas A.
        • Wolchok J.D.
        • et al.
        Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.
        Lancet. 2014; 384: 1109-1117
        • Attia P.
        • Phan G.Q.
        • Maker A.V.
        • et al.
        Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.
        J Clin Oncol. 2005; 23: 6043-6053
        • Maker A.V.
        • Yang J.C.
        • Sherry R.M.
        • et al.
        Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma.
        J Immunother (Hagerstown, Md: 1997). 2006; 29: 455-463
        • Ryder M.
        • Callahan M.
        • Postow M.A.
        • Wolchok J.
        • Fagin J.A.
        Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution.
        Endocr Relat Cancer. 2014; 21: 371-381
        • Faje A.T.
        • Sullivan R.
        • Lawrence D.
        • et al.
        Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma.
        J Clin Endocrinol Metab. 2014; 99: 4078-4085
        • Carpenter K.J.
        • Murtagh R.D.
        • Lilienfeld H.
        • Weber J.
        • Murtagh F.R.
        Ipilimumab-induced hypophysitis: MR imaging findings.
        AJNR Am J Neuroradiol. 2009; 30: 1751-1753
        • Braschi-Amirfarzan M.
        • Tirumani S.H.
        • Hodi F.S.
        • Nishino M.
        Immune-checkpoint inhibitors in the era of precision medicine: what radiologists should know.
        Korean J Radiol. 2017; 18: 42-53
        • Vaz N.
        • Vas D.
        • Berenguer J.
        • et al.
        Hypophysitis associated with immunomodulatory therapies.
        2016 (ECR 2016/C-0895 (poster))
        • Comstock D.E.
        • Nishino M.
        • Giardino A.A.
        Headache in the setting of immunotherapy treatment for metastatic melanoma.
        JAMA Oncol. 2017; 3: 703-704
        • Bronstein Y.
        • Ng C.S.
        • Hwu P.
        • Hwu W.J.
        Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy.
        AJR Am J Roentgenol. 2011; 197: W992-W1000
        • Tirumani S.H.
        • Ramaiya N.H.
        • Keraliya A.
        • et al.
        Radiographic profiling of immune-related adverse events in advanced melanoma patients treated with Ipilimumab.
        Cancer Immunol Res. 2015; 3: 1185-1192
        • Min L.
        • Hodi F.S.
        • Giobbie-Hurder A.
        • et al.
        Systemic high dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study.
        Clin Cancer Res. 2015; 21: 749-755
        • Voskens C.J.
        • Goldinger S.M.
        • Loquai C.
        • et al.
        The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.
        PLoS ONE. 2013; 8 (Soyer HP, ed.)e53745
        • Lammert A.
        • Schneider H.J.
        • Bergmann T.
        • et al.
        Hypophysitis caused by ipilimumab in cancer patients: hormone replacement or immunosuppressive therapy.
        Exp Clin Endocrinol Diabetes. 2013; 121: 581-587
        • Albarel F.
        • Gaudy C.
        • Castinetti F.
        • et al.
        Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma.
        Eur J Endocrinol. 2015; 172: 195-204
        • Ahmadi J.
        • Meyers G.S.
        • Segall H.D.
        • et al.
        Lymphocytic adenohypophysitis: contrast-enhanced MR imaging in five cases.
        Radiology. 1995; 195: 30-34
        • Joshi M.N.
        • Whitelaw B.C.
        • Palomar M.T.
        • Wu Y.
        • Carroll P.V.
        Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review.
        Clin Endocrinol (Oxf). 2016; 85: 331-339
        • Lee H.
        • Hodi F.S.
        • Giobbie-Hurder A.
        • et al.
        Characterization of thyroid disorders in patients receiving immune checkpoint inhibition therapy.
        Cancer Immunol Res. 2017; 5: 1133-1140
        • Brown R.L.
        Tyrosine kinase inhibitor-induced hypothyroidism: incidence, etiology, and management.
        Target Oncol. 2011; 6: 217-226
        • Sanderson K.
        • Scotland R.
        • Lee P.
        • et al.
        Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma.
        J Clin Oncol. 2005; 3: 741-750
        • Orlov S.
        • Salari F.
        • Kashat L.
        • Walfish P.G.
        Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies.
        J Clin Endocrinol Metab. 2015; 100: 1738-1741
        • Fecher L.A.
        • Agarwala S.S.
        • Hodi F.S.
        • Weber J.S.
        Ipilimumab and its toxicities: a multidisciplinary approach.
        Oncologist. 2013; 18: 733-743
        • De Filette J.
        • Jansen Y.
        • Schreuer M.
        • et al.
        Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab.
        J Clin Endocrinol Metab. 2016; 101: 4431-4439
        • Doi T.
        • Piha-Paul S.A.
        • Jalal S.I.
        • et al.
        Pembrolizumab (MK-3475) for patients (pts) with advanced esophageal carcinoma: preliminary results from KEYNOTE-028.
        J Clin Oncol. 2015; 33: 4010a
        • Ribas A.
        • Puzanov I.
        • Dummer R.
        • et al.
        Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
        Lancet Oncol. 2015; 16: 908-918
        • Weber J.S.
        • Gibney G.T.
        • Yu B.
        • et al.
        Survival, biomarker, and toxicity analysis of nivolumab (NIVO) in patients that progressed on ipilimumab (IPI).
        J Clin Oncol. 2015; 33: 9055a
        • Rossi E.
        • Sgambato A.
        • De Chiara G.
        • et al.
        Endocrinopathies induced by immune-checkpoint inhibitors in advanced non-small cell lung cancer.
        Expert Rev Clin Pharmacol. 2016; 9: 419-428
        • Corsello S.M.
        • Barnabei A.
        • Marchetti P.
        • De Vecchis L.
        • Salvatori R.
        • Torino F.
        Endocrine side effects induced by immune checkpoint inhibitors.
        J Clin Endocrinol Metab. 2013; 98: 1361-1375
        • Delivanis D.A.
        • Gustafson M.P.
        • Bornschlegl S.
        • et al.
        Pembrolizumab-induced thyroiditis. Comprehensive clinical review and insights into underlying involved mechanisms.
        Clin Endocrinol Metab. 2017; https://doi.org/10.1210/jc.2017-00448
        • Narita T.
        • Oiso N.
        • Taketomo Y.
        • et al.
        Serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab.
        J Dermatol. 2016; 43: 210-214
        • Verma I.
        • Modi A.
        • Tripathi H.
        • Agrawal A.
        Nivolumab causing painless thyroiditis in a patient with adenocarcinoma of the lung.
        BMJ Case Rep. 2016; https://doi.org/10.1136/bcr-2015-213692
        • Min L.
        • Vaidya A.
        • Becker C.
        Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy.
        Eur J Endocrinol. 2011; 164: 303-307
        • Anderson L.
        • Middleton W.D.
        • Teefey S.A.
        • et al.
        Hashimoto thyroiditis: part 1, sonographic analysis of the nodular form of Hashimoto thyroiditis.
        AJR Am J Roentgenol. 2010; 195: 208-215
        • Hegerova L.
        • Griebeler M.L.
        • Reynolds J.P.
        • et al.
        Metastasis to the thyroid gland: report of a large series from the Mayo Clinic.
        Am J Clin Oncol. 2015; 38: 338-342
        • Charmandari E.
        • Nicolaides N.C.
        • Chrousos G.P.
        Adrenal insufficiency.
        Lancet. 2014; 383: 2152-2167
        • Bacanovic S.
        • Burger I.A.
        • Stolzmann P.
        • Hafner J.
        • Huellner M.W.
        Ipilimumab induced adrenalitis: a possible pitfall in 18F-FDG-PET/CT.
        Clin Nuc Med. 2015; 40: e518-e519
        • Min L.
        • Ibrahim N.
        Ipilimumab-induced autoimmune adrenalitis.
        Lancet Diabetes Endocrinol. 2013; 1e15
        • Trainer H.
        • Hulse P.
        • Higham C.E.
        • Trainer P.
        • Lorigan P.
        Hyponatraemia secondary to nivolumab-induced primary adrenal failure.
        Endocrinol Diabetes Metab Case Rep. 2016; 16: 0108
        • Perri V.
        • Russo B.
        • Crinò A.
        • et al.
        Expression of PD-1 molecule on regulatory T lymphocytes in patients with insulin-dependent diabetes mellitus.
        Int J Mol Sci. 2015; 16: 22584-225605
        • Okamoto M.
        • Okamoto M.
        • Gotoh K.
        • et al.
        Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy.
        J Diabetes Investig. 2016; 7: 915-918
        • Mellati M.
        • Eaton K.D.
        • Brooks-Worrell B.M.
        • et al.
        Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes.
        Diabetes Care. 2015; 38: e137-8
        • U.S. Food and Drug Administration
        Keytruda prescribing information.
        (Available via)
        • U.S. Food and Drug Administration
        Opdivo prescribing information.
        (Available)
      1. Postow M, Wolchok J. Toxicities associated with checkpoint inhibitor immunotherapy. Up to date Atkins MB (Ed). Accessed 21 July 2017.

        • Hofmann L.
        • Forschner A.
        • Loquai C.
        • et al.
        Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy.
        Eur J Cancer. 2016; 60: 190-209
        • Kottschade L.
        • Brys A.
        • Peikert T.
        • et al.
        A multidisciplinary approach to toxicity management of modern immune checkpoint inhibitors in cancer therapy.
        Melanoma Res. 2016; 26: 469-480
        • Munakata W.
        • Ohashi K.
        • Yamauchi N.
        • et al.
        Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma.
        Int J Hematol. 2017; 105: 383-386
        • Miyoshi Y.
        • Ogawa O.
        • Oyama Y.
        Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes.
        Tohoku J Exp Med. 2016; 239: 155-158
        • Chae Y.K.
        • Chiec L.
        • Mohindra N.
        • Gentzler R.
        • Patel J.
        • Giles F.
        A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes.
        Cancer Immunol Immunother. 2017; 66: 25-32
        • Martin-Liberal J.
        • Furness A.J.
        • Joshi K.
        • Peggs K.S.
        • Quezada S.A.
        • Larkin J.
        Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report.
        Cancer Immunol Immunother. 2015; 64: 765-767
        • Hughes J.
        • Vudattu N.
        • Sznol M.
        • et al.
        Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy.
        Diabetes Care. 2015; 38: e55-7
        • Alessandrino F.
        • Krajewski K.M.
        • Tirumani S.H.
        • Braschi-Amirfarzan M.
        • Jagannathan J.P.
        • Ramaiya N.H.
        • et al.
        Biliary and pancreatic complications of molecular targeted therapies in cancer imaging.
        Abdom Radiol. 2017; 42: 1721-1733
        • Di Giacomo A.M.
        • Danielli R.
        • Guidoboni M.
        • et al.
        Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases.
        Cancer Immunol Immunother. 2009; 58: 1297-1306
        • Faje A.
        Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights.
        Pituitary. 2016; 19: 82-92