Body ImagingMultimodality imaging of endocrine immune related adverse events: a primer for radiologists
Introduction
The Food and Drug Administration (FDA) approval of ipilimumab for metastatic melanoma in 2011 has cleared the way for the advent of immunotherapy in clinical practice [1,2]. Since then, different molecules targeting the immune checkpoint pathways, termed immune checkpoint inhibitors (ICI), augmenting the immunologic reaction against tumor cells have shown survival improvement in several cancer types [[3], [4], [5]]. Thus, to date, FDA approved indications for the use of ICI include melanoma, non-small cell lung cancer, metastatic urothelial carcinoma, Hodgkin's lymphoma, renal cell and Merkel cell carcinoma [6]. Currently, two types of ICIs are used in clinical practice: the anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, such as ipilimumab, and the programmed cell death-1 receptor/programmed cell death-1 ligand (PD/PD-L1) inhibitors, such as pembrolizumab, atezolizumab and nivolumab. The first blocks the inhibitory activity of CTLA-4 and its ligand B7-1/2 signal present on T-cell surface, with consequent T cell activation, while PD/PD-L1 is a protein expressed on tumor cells or T-cells which blocks the tumor cell detection and consequent T-cell activation. Blocking PD1/PD-L1, the T-cell can detect tumor cell and to unleash T-cell mediated immune response [7,8].
The shift from conventional chemotherapy to immunotherapy in cancer treatment has modified and widened the possible drug associated toxicities, and oncologists and radiologists together suddenly had to face and manage new and unknown pattern of drug related adverse events. Immune checkpoint inhibitors are associated with specific adverse events, the immune related adverse events (IrAEs), which can occur frequently, in up to 90% of patients treated with CTLA-4 inhibitors and in 70% of patients treated with PD-1/PD-L1 antibodies [9].
Immune related adverse events can range from mild skin rash to lethal pneumonitis and potentially involve any organ system [9]. These adverse events are related to the widespread activation of immune system leading to impaired modulation of immune response in various organs, with autoimmune-like toxicities [10]. Immune related adverse events are graded according to The Common Terminology Criteria for Adverse Events (CTCAE) which represents a framework for reporting and guiding management of the different possible IrAEs [11]. The CTCAE grading reflects the severity of the AE and includes: grade 1 (mild), asymptomatic or with mild symptoms, managed with observations and not requiring intervention; grade 2 (moderate), requiring minimal or noninvasive intervention; grade 3 (severe), requiring hospitalization, grade 4 (life-threatening) requiring urgent intervention; grade 5 (death), referring to fatal AE [11].
The endocrine system is one of the most common systems affected by IrAE, with reported percentages of endocrine related toxicity of any grade reaching 30% in case of combination therapy, of grade 3/4 toxicity in up to 2.9% of cases [6,12]. Endocrine organs affected by ICI toxicity are hypophysis, thyroid, adrenals and rarely, the endocrine pancreas. Multi-organ involvement may occur, complicating diagnosis and management. They commonly occur early during ICI therapy, with cases of hypophysitis reported after only two cycles of CTLA-4 inhibitors [13]. The patterns of endocrine-related adverse events differ according to the type of ICIs, with hypophysitis more common in patients undergoing therapy with CTLA-4 inhibitors and thyroid dysfunction more common with PD/PD-L1 inhibitors [14]. The use of ICI combination therapy increases the incidence of endocrine adverse events, further complicating the management of these toxicities [15].
Endocrine IrAE may present in different clinical settings: as incidental findings on imaging follow-up, or in the emergency setting in case of new symptoms, or at the time of oncologic clinical follow-up evaluation. Symptoms of endocrine IrAE range from subtle and nonspecific symptoms, such as fatigue, to signs of specific organ involvement, such as diplopia in hypophysitis or hoarseness due to laryngeal nerve impingement in thyroiditis. In addition, life threatening conditions, including adrenal crisis from primary or secondary adrenal insufficiency, have been reported [9,16].
In these different clinical settings, imaging has a pivotal role in recognizing adverse events in both asymptomatic and symptomatic patient, and to exclude possible mimickers [17].
In this article we will present the various endocrine IrAEs, and for each entity we will describe the clinical presentation, the multimodality imaging features at presentation and after treatment, and the possible differential diagnosis.
Section snippets
Hypophysis
Immune checkpoint inhibitor associated hypophysitis is a common event in patients treated with CTLA-4 inhibitors, and ranges from asymptomatic hypophysitis to life threatening acute panhypopituitarism [14]. Awareness of possible hypophysitis is crucial, as hormonal replacement therapy should be promptly started in severe cases [8].
The mechanism of ICI associated hypophysitis is unknown, and an antibody mediated type II hypersensitivity reaction to ectopic CTLA-4 protein expressed on pituitary
Thyroid
Immune checkpoint inhibitor associated thyroid toxicity can present with hypothyroidism or thyrotoxicosis [5,41]. The term hyperthyroidism, used in prior reports to define ICI associated thyroid toxicity, should be discontinued as it refers to the overproduction of thyroid hormone by the thyroid gland occurring in Grave's disease or TSH-driven hyperthyroidism, whereas thyrotoxicosis is defined as any cause of thyroid hormone excess [41].
Since presentation can be subtle, careful inspection of
Adrenal glands
Immune checkpoint inhibitor associated adrenal gland toxicity generally presents with adrenalitis and subsequent adrenal insufficiency [8]. Immune-related adrenal insufficiency may be primary or secondary, related to hypopituitarism, with reduced levels of ACTH and possible involvement of multiple pituitary axes [14]. In both cases, presentation may range from mild fatigue to life threatening adrenal crisis [8]. Imaging presentation can be subtle, and careful inspection of adrenal glands should
Endocrine pancreas
Immune checkpoint inhibitor toxicity of the endocrine pancreas may present with various degrees of hyperglycemia and diabetes [8,51]. Immune checkpoint inhibitor hyperglycemia may lead to treatment resistant diabetic ketoacidosis.
The mechanism underlying the onset of ICI associated diabetes mellitus in not completely understood. It has been postulated that the underlying mechanism is autoimmune, since GAD65 autoantibodies, commonly present in patients with autoimmune type 1 diabetes, have been
Gonads
Gonadal toxicity associated with ICI has been reported as secondary hypogonadism due to hypophysitis, while primary gonadal toxicity is exceedingly rare [7,68]. The mechanism of ICI associated hypogonadism might be related to autoimmune damage of FSH- and LH-secreting hypophyseal cells, since autoantibodies directed towards these cells have been observed in patients with CTLA-4 related hypophysitis [19].
A retrospective meta-analysis of clinical trials of patients treated with ipilimumab
Conclusions
Endocrine related IrAE represents a diagnostic dilemma in oncology, as it may present with variable manifestations and varying degrees of severity and often with nonspecific clinical symptoms, from subtle asymptomatic hyperglycemia or subclinical hypothyroidism to diabetic ketoacidosis or adrenal crisis. The radiologist who is knowledgeable about the IrAE affecting the endocrine system, and who is familiar with the imaging manifestations, plays a pivotal role in recognizing adverse events,
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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