Background: In recent years, remarkable advances in cancer immunotherapy have been introduced in the field of oncology. Since the discovery of immune checkpoint inhibitors (ICIs), these groups of medications have become a crucial treatment for several types of adult cancer. Summary: To date, pediatric experience with this group of medications is limited. Nevertheless, as clinicians, we have to be aware of the possible immune-related adverse events including immune-related endocrinopathies (thyroid dysfunction, diabetes mellitus, adrenal insufficiency, and pituitary insufficiency) that have been reported regarding these medications. These adverse events probably result from uncontrolled activation of the immune system. Key Message: Early diagnosis, monitoring, and treatment of immune-related endocrinopathies associated with ICIs treatment are also essential for the best supportive care and administration of ICIs in pediatric patients. This review presents the current data on the immune-related endocrinopathies associated with the ICIs treatment, with suggestions for management.

In recent decades, survival rates of patients with pediatric cancer have significantly improved, reaching over 80% for children with all types of cancer in high-income countries [1]. Unfortunately, certain tumor types remain resistant to conventional surgical, radiotherapy, and chemotherapy combinations, thus relapsing and/or refractory disease remain associated with poor outcomes. Our understanding of the molecular processes leading to cancerous cells and maintenance of tumoral ecosystems has significantly improved, with attention on the role of immunotherapies in pediatric oncology.

We present the biological rationale behind immunological therapy of pediatric neoplasms, current novel drugs targeting the immune checkpoint, and immune-related endocrinopathies associated with immune checkpoint inhibitors (ICIs) treatment. The potential endocrine adverse events in pediatric patients treated with ICIs were previously reviewed by Ihara [2]. However, additional experience with ICI treatment in pediatric cancer has accumulated in recent years, as presented in this current review. Although reviews and clinical data on endocrine adverse effects in adults treated with ICIs, together with updated local guidelines for managing endocrine immune-related adverse events, have already been published, data on reported endocrine adverse events in children are limited with no published guidelines for their management in pediatric patients. The aim was to increase awareness among clinicians and guide them in the early diagnosis and management of potential endocrine adverse effects of the major endocrine glands during the treatment of pediatric patients with ICIs.

Cancer immunotherapy attempts to amplify or reprogram the inherent capacity of immune cells and their humoral arsenal to eliminate tumor cells by ideally recognizing antigens expressed only on tumoral cells [3]. Since T lymphocytes (T cells) represent a major class in immunosurveillance and tumor eradication with long-term memory and their presence within solid tumors can impact patients’ survival, various approaches have been implemented to use T cells for controlling tumor growth or inducing tumor regression [4]. Cancer cells can change their surface antigens, evading immunosurveillance. In addition, tumor cells express ligands that bind inhibitory T-cell receptors, known as immune checkpoints, which deactivate T cells [5, 6].

Immune checkpoints are specific proteins that physiologically balance the immune destruction of foreign antigens and the development of autoimmune host organ injury [7]. A cardinal feature of T-cell deactivation is the overexpression of inhibitory receptors, including programmed death receptor-1 (PD-1, CD279), cytotoxic T-lymphocyte antigen 4 (CTLA-4, CD152), lymphocyte-activation gene-3 (LAG-3), T-cell immunoglobulin domain and mucin domain-3 (TIM-3), IL-10 receptor, and killer immunoglobulin receptors. Some of these molecules exert their immunosuppressive effects by down-regulating the normal T-cell response and increasing the number and activity of FoxP3+ regulatory T cells (Tregs) [8].

Peripheral tolerance is a physiological process aimed at suppressing potentially autoreactive naïve T cells in lymph nodes or peripheral tissues that is regulated by two different pathways: the checkpoints programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) [9, 10]. CTLA-4, type I transmembrane glycoprotein receptor (immunoglobulin superfamily), is constitutively expressed on memory T cells and Tregs, which is critical in preventing self-reactive T cells from inducing autoimmunity [10]. It is homologous to CD28 and shares the same B7 ligands, B7-1 (CD80) and B7-2 (CD86), but has a negative effect on T-cell activation. Several suppressive mechanisms for T-cell functions have been attributed to CTLA-4, with a decreased immune response to tumor-associated antigens [11].

PD-1 is a protein expressed on the surfaces of activated T cells, B and NK cells, macrophages, dendritic cells, and monocytes [12] that has a pivotal role in the immune response. Two PD-1 ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), can engage PD-1 to render T-cell dysfunctional while maintaining the exhausted T-cell phenotype [13]. PD-L2 is exclusively expressed on activated dendritic cells and macrophages, whereas PD-L1 has a broad tissue distribution including tumor cells and is rapidly induced by inflammatory mediators.

ICIs are targeted drugs (bioengineered monoclonal antibodies) that elicit an anti-tumor response by stimulating the immune system. They act by targeting inhibitory receptors and ligands expressed on T lymphocytes and tumor cells. These drugs can effectively overwhelm the cancer cell’s resistance by allowing immune cells to target and remove them.

The anti-CLTA-4 antibody (ipilimumab) prevents CD80 and CD86 on antigen-presenting cells from binding to CTLA-4 on T cells. By blocking CLTA-4 signaling, they enhance T-cell activation and proliferation of the immune response [14].

On the other hand, anti-PD-1 and anti-PD-L1 antibodies (nivolumab, pembrolizumab) block PD-L1, inhibit interaction between PD and PD-L1, and enhance anti-tumor immune response by restoring T-cell cytotoxic function, resulting in an anti-tumor effect while facilitating the generation of memory T cells to provide long-term anti-tumor response [15]. Figure 1a, b presents the physiology of immune checkpoint and the mechanism of action of checkpoint inhibitors.

Fig. 1.

a The physiology of immune checkpoint. Antigen-presenting cells (APCs) present antigens to cytotoxic CD8+ T cells through interaction of major histocompatibility complex (MHC) molecules and T-cell receptors (TCR). T-cell activation requires costimulatory signals mediated by the interaction between B7 and CD28. Tumor cells express the immune checkpoint activator programmed cell death ligand 1 (PD-L1) and produce antigens that are captured by inhibitory signals from cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1 checkpoints. This reduces T-cell response; the tumor cells escape immune surveillance with promotion of tumor proliferation. b Mechanism of action of checkpoint inhibitors. Monoclonal antibodies targeting CTLA-4 (ipilimumab), PD-1 (nivolumab, pembrolizumab), and PD-L1 (atezolizumab, avelumab, durvalumab) block immune inhibitory checkpoints (CTLA-4, PD-1, and PD-L1, respectively), stimulate T-cell activation, and restore anti-tumor immune response, resulting in tumor cell death.

Fig. 1.

a The physiology of immune checkpoint. Antigen-presenting cells (APCs) present antigens to cytotoxic CD8+ T cells through interaction of major histocompatibility complex (MHC) molecules and T-cell receptors (TCR). T-cell activation requires costimulatory signals mediated by the interaction between B7 and CD28. Tumor cells express the immune checkpoint activator programmed cell death ligand 1 (PD-L1) and produce antigens that are captured by inhibitory signals from cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1 checkpoints. This reduces T-cell response; the tumor cells escape immune surveillance with promotion of tumor proliferation. b Mechanism of action of checkpoint inhibitors. Monoclonal antibodies targeting CTLA-4 (ipilimumab), PD-1 (nivolumab, pembrolizumab), and PD-L1 (atezolizumab, avelumab, durvalumab) block immune inhibitory checkpoints (CTLA-4, PD-1, and PD-L1, respectively), stimulate T-cell activation, and restore anti-tumor immune response, resulting in tumor cell death.

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Cancers with higher numbers of mutations have an increased chance of responding to immunotherapy because they are likely to have an increased presence of neoantigens that activate T cells. However, pediatric cancers are usually less immunogenic than adult cancers, with scarce neoantigens. Therefore, the efficacy of ICI treatment is less impressive than seen with adult cancers. Nevertheless, there are subgroups of pediatric cancers with distinct biologic features that render them exceptionally sensitive to ICI therapies. One subgroup includes tumors with mismatch repair deficiency and/or polymerase-proofreading deficiency, leading to hypermutation and expression of neoantigens that may prime a T-cell response.

A second potential subgroup includes SMARCB1 (a major regulator of chromatin compaction and gene accessibility to transcription machinery)-deficient tumors, with postulated mechanisms of splicing dysregulation and endogenous retroviral re-expression leading to neoantigen expression, together with increased tumor immune infiltration. Both hypermutated cancers and SMARCB1-deficient cancers seem to present more neoantigens and have enhanced tumoral inflammation. Indeed, occurrence of pediatric hypermutated cancers [16] and SMARCB1-deficient cancers, together with the potential prognostic role of immunosuppressive checkpoint molecules (CTLA-4, PD-L1), represent a promising rationale supporting the use of ICIs also for pediatric cancers.

Pediatric tumor types with expression of checkpoint proteins that are positive for CTLA-4 include neuroblastoma, osteosarcoma, melanoma, and embryonal rhabdomyosarcoma. Those positive for PD-1/PD-L1 include Ewing sarcoma, soft tissue sarcomas, non-Hodgkin’s lymphoma, neuroblastoma, metastatic osteosarcoma, retinoblastoma, alveolar and embryonal rhabdomyosarcoma, anaplastic Wilm's tumor, and intracranial solid tumors such as glioma, germinoma, ependymoma, and medulloblastoma [17, 18].

Unfortunately, there is limited efficacy and safety data focusing on immune checkpoint molecules in children and potential benefits in recurrent or refractory pediatric solid tumors, but evidence is accruing rapidly. To date, 22 clinical trials have been published on the use of ICIs in children and adolescents with cancer [19‒40]. The first pediatric checkpoint inhibitor study was a phase I trial of ipilimumab in 33 patients with recurrent or refractory solid tumors (melanoma [n = 12], sarcoma [n = 17], or other refractory solid tumors [n = 4]) [19].

However, most experience with ICIs in pediatric cancers to date has targeted the PD-1 axis. Most of the pediatric data are based on four phase I/II studies published between 2020 and 2022: nivolumab [20], pembrolizumab [21], atezolizumab [22], and avelumab [23], when monotherapies were tested against several recurrent and refractory pediatric tumors. All studies reported that ICIs were well tolerated in children, but only 3% of patients with solid tumors experienced an objective response. Adverse events were similar to those reported in adults, with the exception of more frequent cytopenia. The most common reported immune-related adverse event was hepatic toxicity. In malignancies such as pediatric Hodgkin lymphoma, the ICIs that target PD-1/PD-L1 were the most helpful, probably due to its underlying biology having susceptibility to such therapies.

Although ICIs may not benefit all pediatric patients with cancer, emerging data have highlighted subsets of pediatric patients for whom ICIs are more promising because of their unique tumor biology that results in higher neoantigen burdens or more infiltrating immune cells, rendering them uniquely sensitive to ICI therapies. Larger and dedicated trials are ongoing to fully evaluate the efficacy of ICIs for pediatric patients with these cancer subtypes; results to date indicate that ICIs may improve outcomes in at least some subsets of pediatric cancers that otherwise prove difficult to treat [24‒31, 33, 34, 36, 38‒40].

Both CTLA-4 and PD-1 play a key role in the maintenance of immunological tolerance to self-antigens, preventing autoimmune disorders. Therefore, ICIs that control T cells to fight cancer can trigger autoimmune-like manifestations in different organ systems, generally referred to as immune-related adverse events (irAEs). In adults, severe irAEs (grades 3–4) developed in 40% of patients treated with combination ICIs (anti-PD-1 and anti-CTLA-4) [41]. Combinations of ICIs regimens are associated with increased rate and severity of irAEs as compared to PD-1/PD-L1 blockade alone, which appear to be related to dose of ipilimumab (anti-CLTA-4 antibody).

irAEs can manifest as immune-mediated destruction of multiple tissues (e.g., skin, gut, endocrine organs, lungs, heart, and nervous system), which can have a significant clinical impact including interruption of cancer treatment, permanent organ dysfunction, hospitalization, and premature death [42]. Thus, the unpredictable off-target toxicities to critical organs, besides being life-threatening, are concerning for children with immature organs who are potentially prone to life-long disabilities [43].

Immune-related endocrine events (irEEs) are considered one of the most common toxicities experienced from ICIs, affecting up to 40% of treated adult patients, depending on the drugs used [44‒47]. The exact mechanism of irEEs is not completely understood. Probably, there is an interplay between genetics and cellular and humoral autoimmunity. It is suspected that ICI-induced immune activation causes the destruction of most or all the hormone-producing cells. Studies in adult patients have showed a cross-reactivity for T cells, which acted against tumor antigens and antigens in tissues where the irEEs developed [48]. In addition, T cells are further stimulated by specific chemokines that were increased in adult patients with irEEs and who also have circulating autoantibodies against organ-specific targets [49]. Also, an association with the HLA-DR allele was documented for some irAEs [44].

The clinical course of irEEs varies among individuals. Endocrinopathies usually occur after the first weeks of treatment with ICIs, and most adverse events occur within the first months of initiating ICI therapy in both children and adults. However, some endocrinopathies can emerge more than a year after the initiation of ICI therapy [21, 50]. Patients with irEEs may present with a more indolent course or subclinical disease, which makes early recognition and diagnosis challenging. Once symptoms start manifesting, most hormone-producing cells have already been destroyed by the activated T cells. As a result, irEEs can be irreversible [51].

The risk of developing irEEs varies with specific ICI agent used, either as monotherapy or in combination. The severity of these irEEs varies widely, and diagnosis of irEEs can be challenging since subtle, non-specific symptoms at presentation may be diagnosed as the natural course of cancer progression or cancer therapy-associated side effects. Therefore, close monitoring of symptoms is important, and biochemical surveillance of hormone levels is essential for a correct diagnosis [44]. Interestingly, adult patients who developed irEEs had better clinical responses to ICI therapy and survival as compared to those without irEEs [51].

Endocrinopathies secondary to ICI use may include thyroiditis, hypophysitis, primary adrenal insufficiency, autoimmune diabetes mellitus, and calcium abnormalities. In pediatric patients treated with ICIs, occurrence of hypophysitis and primary adrenal insufficiency is very rare.

ICI-induced endocrine-related adverse events are classified by the severity of signs and symptoms from grades 1 (very mild symptoms) to 5 (death due to complications) [52]. In adult patients, with the occurrence of some of the endocrinopathies, ICIs may be withheld until hormone replacement has begun, especially in patients with more severe presentations [53]. Recommendations for pediatric patients have not been published.

Table 1 summarizes the reported irEE in studies including pediatric patients treated with ICIs.

Table 1.

Reported immune-related endocrine events of ICIs treatment in studies including pediatric patients

Indication of treatmentType of ICIPatients, nPatient age, years, median (range)Rate of reported immune-related adverse events (%)Ref. No.
Relapsed or refractory solid tumors or lymphoma Nivolumab (anti-PD-1 antibody) 85 14 (1–27) Hypothyroidism (14) 20 
Hyperthyroidism (9) 
Advanced melanoma or PD-L1-positive, advanced, relapsed/refractory solid tumor or lymphoma Pembrolizumab (anti-PD-L1 antibody) 154 13 (8–15) Hypothyroidism (8) 21 
Hyperthyroidism (4) 
Thyroiditis (1) 
Adrenal insufficiency (1) 
Previously treated solid tumors, non-Hodgkin lymphoma, Hodgkin lymphoma Atezolizumab (anti-PD-L1 antibody) 90 14 (10–17) Hypothyroidism (7) 22 
Hyperthyroidism (1) 
T1D with DKA (1) 
Refractory or relapsed solid tumors Avelumab (anti-PD-L1 antibody) 21 12 (13–17) Hypothyroidism (7) 23 
Unresectable stage III or IV malignant melanoma Ipilimumab (anti-CLTA-4 antibody) 12 15 (12–16) Hyperglycemia (12) 24 
Recurrent or refractory pediatric brain tumors Nivolumab (anti-PD-1 antibody) 10 12.5 (2–17) Hyperglycemia (10) 26 
Recurrent/refractory CNS tumors Ipilimumab (anti-CLTA-4 antibody), nivolumab (anti-PD-1 antibody) and/or pembrolizumab (anti-PD-L1 antibody) 11 13.9 (4–20.7) T1D (9) 27 
Hypothyroidism (9) 
Recurrent and refractory classical Hodgkin lymphoma Nivolumab (anti-PD-1 antibody) plus brentuximab vedotin +/− bendamustine 10 13 (9–16) Hypothyroidism (10) 28 
Lymphoma, bone and soft tissue tumors, CNS tumors, other solid tumors Anti-PD-1 antibody 109 12 (1–18) Hypothyroidism (14.7) 29 
T1D with DKA (0.92) 
Relapsed or refractory cancer Anti-PD-1 antibody or anti-PD-L1 antibody 22 7.7 (1–15) Hypothyroidism (4.5) 30 
Hyperthyroidism (9.1) 
Relapsed or refractory solid tumors Nivolumab (anti-PD-1 antibody) 13 15 (5.5–19.4) Hyperglycemia (7.7) 31 
Advanced osteosarcoma Camrelizumab (anti-PD-1 antibody) and apatinib (TKI) 43 (21 pediatric patients) 19 (11–43) Hypothyroidism* (81.4) 32 
Relapsed or refractory Hodgkin lymphoma Camrelizumab (anti-PD-1 antiboy) 19 27 (12–66) Hypothyroidism (16) 33 
Relapsed or refractory solid tumors Nivolumab (anti-PD-1 antibody) and ipilimumab (anti-CLTA-4 antibody) 55 15 (4–28) Hyperglycemia (1.8) 34 
Hypothyroidism (1.8) 
Hyperthyroidism (1.8) 
Relapsed or refractory Hodgkin lymphoma Nivolumab (anti-PD-1 antibody) and brentuximab vedotin (anti CD-30) 31 16 Hypothyroidism (3) 36 
High-grade CNS malignancies Nivolumab (anti-PD-1 antibody) with/without ipilimumab (anti-CLTA-4 antibody) 166 10 (1–21) Not reported 37 
Advanced alveolar soft part sarcoma Atezolizumab (anti-PD-L1 antibody) 52 (3 pediatric patients) 2–17 Hyperthyroidism (13.5) 38 
Hypothyroidism (13.5) 
(not specified if seen in pediatric patients) 
Advanced/recurrent malignancies Sintilimab (anti-PD-1) 29 1–18 Hypothyroidism (17.2) 39 
Hyperthyroidism (13.8) 
Indication of treatmentType of ICIPatients, nPatient age, years, median (range)Rate of reported immune-related adverse events (%)Ref. No.
Relapsed or refractory solid tumors or lymphoma Nivolumab (anti-PD-1 antibody) 85 14 (1–27) Hypothyroidism (14) 20 
Hyperthyroidism (9) 
Advanced melanoma or PD-L1-positive, advanced, relapsed/refractory solid tumor or lymphoma Pembrolizumab (anti-PD-L1 antibody) 154 13 (8–15) Hypothyroidism (8) 21 
Hyperthyroidism (4) 
Thyroiditis (1) 
Adrenal insufficiency (1) 
Previously treated solid tumors, non-Hodgkin lymphoma, Hodgkin lymphoma Atezolizumab (anti-PD-L1 antibody) 90 14 (10–17) Hypothyroidism (7) 22 
Hyperthyroidism (1) 
T1D with DKA (1) 
Refractory or relapsed solid tumors Avelumab (anti-PD-L1 antibody) 21 12 (13–17) Hypothyroidism (7) 23 
Unresectable stage III or IV malignant melanoma Ipilimumab (anti-CLTA-4 antibody) 12 15 (12–16) Hyperglycemia (12) 24 
Recurrent or refractory pediatric brain tumors Nivolumab (anti-PD-1 antibody) 10 12.5 (2–17) Hyperglycemia (10) 26 
Recurrent/refractory CNS tumors Ipilimumab (anti-CLTA-4 antibody), nivolumab (anti-PD-1 antibody) and/or pembrolizumab (anti-PD-L1 antibody) 11 13.9 (4–20.7) T1D (9) 27 
Hypothyroidism (9) 
Recurrent and refractory classical Hodgkin lymphoma Nivolumab (anti-PD-1 antibody) plus brentuximab vedotin +/− bendamustine 10 13 (9–16) Hypothyroidism (10) 28 
Lymphoma, bone and soft tissue tumors, CNS tumors, other solid tumors Anti-PD-1 antibody 109 12 (1–18) Hypothyroidism (14.7) 29 
T1D with DKA (0.92) 
Relapsed or refractory cancer Anti-PD-1 antibody or anti-PD-L1 antibody 22 7.7 (1–15) Hypothyroidism (4.5) 30 
Hyperthyroidism (9.1) 
Relapsed or refractory solid tumors Nivolumab (anti-PD-1 antibody) 13 15 (5.5–19.4) Hyperglycemia (7.7) 31 
Advanced osteosarcoma Camrelizumab (anti-PD-1 antibody) and apatinib (TKI) 43 (21 pediatric patients) 19 (11–43) Hypothyroidism* (81.4) 32 
Relapsed or refractory Hodgkin lymphoma Camrelizumab (anti-PD-1 antiboy) 19 27 (12–66) Hypothyroidism (16) 33 
Relapsed or refractory solid tumors Nivolumab (anti-PD-1 antibody) and ipilimumab (anti-CLTA-4 antibody) 55 15 (4–28) Hyperglycemia (1.8) 34 
Hypothyroidism (1.8) 
Hyperthyroidism (1.8) 
Relapsed or refractory Hodgkin lymphoma Nivolumab (anti-PD-1 antibody) and brentuximab vedotin (anti CD-30) 31 16 Hypothyroidism (3) 36 
High-grade CNS malignancies Nivolumab (anti-PD-1 antibody) with/without ipilimumab (anti-CLTA-4 antibody) 166 10 (1–21) Not reported 37 
Advanced alveolar soft part sarcoma Atezolizumab (anti-PD-L1 antibody) 52 (3 pediatric patients) 2–17 Hyperthyroidism (13.5) 38 
Hypothyroidism (13.5) 
(not specified if seen in pediatric patients) 
Advanced/recurrent malignancies Sintilimab (anti-PD-1) 29 1–18 Hypothyroidism (17.2) 39 
Hyperthyroidism (13.8) 

CNS, central nervous system; DKA, diabetic ketoacidosis; ICI, immune checkpoint inhibitor; PD-1, programmed death receptor-1; T1D, type 1 diabetes; TKI, thyrosin kinase inhibitor.

*May be also related to TKI treatment.

Table 2.

Comparison of endocrine immune-related adverse events in pediatric and adult patients treated with immune checkpoint inhibition

Pediatric patientsAdult patients
Thyroid dysfunction 
 Association with pre-existing thyroid autoimmunity Unknown Possible positive association 
 Association between ICIs-induced thyroid dysfunction and overall survival outcome Unknown Possible positive association 
Hypothyroidism 
 Time range of onset after initiation of ICIs treatment 2–48 weeks 2–6 weeks 
 Severity of symptoms grading 1–2 1–2 
Hyperthyroidism 
 Time range of onset after initiation of ICIs treatment 3–16 weeks 4–6 weeks 
 Severity of symptoms grading 1–2 1–2 
Hypophysitis 
 Time range of onset after initiation of ICIs treatment Unknown 9–19 months 
 Severity of symptoms grading Unknown 1–4 
 Association between ICIs-induced pituitary dysfunction and overall survival outcome Unknown Possible positive association 
Primary adrenal insufficiency 
 Time range of onset after initiation of ICIs treatment 2 weeks 10 weeks 
 Severity of symptoms grading 3–4 3–4 
 Association between ICIs-induced pituitary dysfunction and overall survival outcome Unknown Unknown 
Type 1 diabetes 
 Time range of onset after initiation of ICIs treatment 5–6 months 1–12 months 
 Severity of symptoms grading 3–4 3–4 
 Association between ICIs-induced pituitary dysfunction and overall survival outcome Unknown Unknown 
Pediatric patientsAdult patients
Thyroid dysfunction 
 Association with pre-existing thyroid autoimmunity Unknown Possible positive association 
 Association between ICIs-induced thyroid dysfunction and overall survival outcome Unknown Possible positive association 
Hypothyroidism 
 Time range of onset after initiation of ICIs treatment 2–48 weeks 2–6 weeks 
 Severity of symptoms grading 1–2 1–2 
Hyperthyroidism 
 Time range of onset after initiation of ICIs treatment 3–16 weeks 4–6 weeks 
 Severity of symptoms grading 1–2 1–2 
Hypophysitis 
 Time range of onset after initiation of ICIs treatment Unknown 9–19 months 
 Severity of symptoms grading Unknown 1–4 
 Association between ICIs-induced pituitary dysfunction and overall survival outcome Unknown Possible positive association 
Primary adrenal insufficiency 
 Time range of onset after initiation of ICIs treatment 2 weeks 10 weeks 
 Severity of symptoms grading 3–4 3–4 
 Association between ICIs-induced pituitary dysfunction and overall survival outcome Unknown Unknown 
Type 1 diabetes 
 Time range of onset after initiation of ICIs treatment 5–6 months 1–12 months 
 Severity of symptoms grading 3–4 3–4 
 Association between ICIs-induced pituitary dysfunction and overall survival outcome Unknown Unknown 

Thyroid Dysfunction

Thyroid dysfunction is the most commonly occurring endocrine irAE with a combined incidence of approximately 15% in adult patients (Table 2). Similarly, in pediatric patients treated with ICIs, thyroid dysfunction is the most reported endocrinopathy, with hypothyroidism reported in 4–17% [18, 20‒23, 25, 27‒30, 33, 34, 36, 38, 39] and hyperthyroidism in 1–14% of patients [20‒22, 30, 34, 38, 39].

Most cases are asymptomatic or mild (grade 1 or 2), both in pediatric and adult patients [20, 22, 27, 29, 34, 39, 45, 46]. Thyroid dysfunction is usually observed few weeks after ICI administration. PD-1 inhibitors are associated with higher rates of thyroid dysfunction relative to CTLA-4 inhibitors, with the highest risk for combined treatment in both pediatric and adult patients [20‒23, 28‒30, 54].

The underlying pathophysiology of thyroid irAEs is considered to be immune-mediated thyroiditis followed by destruction of the thyroid gland. The high expression of PD-L1/PD-L2 on thyrocytes could explain the high susceptibility. A previous report demonstrated the infiltration of cytotoxic T cells (CD8+) into the thyroid gland of a patient who developed thyroid dysfunction induced by the anti-PD-1 antibody nivolumab [55]. Given that the incidence of thyroid dysfunction is higher in adult patients with anti-thyroid antibody positivity, as compared with negativity at baseline [56], pre-existing autoimmunity in the thyroid may be involved in the pathogenesis of thyroid dysfunction induced by ICIs [57].

Thyroid dysfunction induced by ICIs can be classified into thyrotoxicosis and hypothyroidism. The main cause of thyrotoxicosis is destructive thyroiditis, which consists of transient thyrotoxicosis followed by hypothyroidism [58]. However, onset of thyroid dysfunction is highly variable both in children and adults, and not all patients develop the classic thyroiditis-like presentation of transient thyrotoxicosis followed by a hypothyroid phase. In adults, thyrotoxicosis has a rapid onset, typically 4–6 weeks post-ICIs initiation, and lasts approximately 6 weeks. The time to onset of thyrotoxicosis is shorter in cases of ICI combination treatment. Isolated thyrotoxicosis and hypothyroidism have both been reported, as well as subclinical disease, often short-lived and transient [54]. Recovery from hypothyroidism was only rarely reported. The development of Graves’ disease after ICIs treatment is rare.

Several studies in adults observed an association between ICI-induced thyroid dysfunction and overall survival, suggesting that the occurrence of thyroid dysfunction could represent a surrogate marker for anti-tumor response [59]. In most patients with ICI-induced thyroid dysfunction with severity grading 1–2, treatment with ICI can be continued. Of note, thyroid tests can be influenced by different factors such as drugs, non-thyroidal illness, and iodine-based contrast agents.

Pituitary Dysfunction

The overall incidence of hypophysitis is up to 17% in adult patients treated with ICIs, with male predominance [60]. The reported rate of hypophysitis and subsequent panhypopituitarism in pediatric patients is rare ∼3% [18].

Most of the data regarding ICI-related pituitary dysfunction is based on adult patients who show that pituitary dysfunction is induced by all ICI types, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies. Pituitary dysfunction induced by ICIs can be classified into two clinical types: isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) not associated with pituitary enlargement, and hypophysitis associated with deficiencies in multiple anterior pituitary hormones accompanied by pituitary enlargement [60] that can improve in a few months. Treatment with anti-CTLA-4 antibodies causes both IAD and hypophysitis, whereas treatment with anti-PD-1 or PD-L1 antibodies only causes IAD [60]. The pathophysiology of hypophysitis appears to be lymphocytic infiltration, predominantly affecting the anterior pituitary. In adult patients, central diabetes insipidus due to impaired neurohypophysial function was also reported with ICIs treatment [61].

Most adult patients treated with an anti-CTLA-4 antibody (ipilimumab) developed pituitary dysfunction within several months after treatment initiation. In contrast, with anti-PD-1 or anti-PD-L1 antibody treatment, pituitary dysfunction can develop several months to over a year after treatment initiation [60].

Most symptoms seen in adult patients with pituitary dysfunction induced by ICIs are caused by secondary adrenal insufficiency. Such symptoms include tiredness, weakness, anorexia, weight loss, digestive symptoms, decreased blood pressure, psychiatric disturbance, fever, hypoglycemic symptoms, joint pain, headache, and visual field disturbance. However, patients with IAD can also be “asymptomatic,” while symptoms are often non-specific, and thus the hormonal diagnosis of IAD can be difficult, while a.m. cortisol is not sensitive and specific enough to identify all cases. Therefore, the presence of laboratory findings of hyponatremia (due to vasopressin increase) and hypoglycemia should raise suspicion for hypocortisolism.

Under clinical suspicion of CAI, basal measurement of cortisol levels is recommended. In these cases, basal cortisol ≥415 nmol/L (15 μg/dL) excludes CAI, although others recommend a morning or random serum cortisol level of >450 nmol/L (16.3 μg/dL) to exclude hypocortisolism [62]. When the measurement of basal cortisol is insufficient, a pituitary stimulation test is necessary [63]. Either low-dose (1 μg) or standard-dose (250 μg) synacthen stimulation test is recommended for patients with suspected CAI. Usually, a cortisol level >497 nmol/L (18 μg/dL) at 30 or 60 min indicates a normal ACTH response and excludes CAI [63]. Clinicians need to be aware of different cortisol cutoff values that are assay-specific. When using the older immunoassays that are based on polyclonal antibodies, the classic threshold of cortisol cutoff >497 nmol/L (18 μg/dL) should be used, and when using the newer highly specific cortisol assays based on monoclonal antibodies or liquid chromatography-tandem mass spectrometry (LC-MS/MS), the cortisol cutoff values can be lowered to 415 nmol/L (15 μg/dL) [64].

Of note, in patients with recent onset CAI, the 250 μg synacthen stimulation test may produce a normal cortisol response because the test exposes the adrenal glands to an overwhelming amount of ACTH, and the adrenal reserve may still be adequate to produce a normal cortisol response to exogenous ACTH, but there is no endogenous ACTH release in response to stress. Thus, the 1 μg synacthen stimulation test is more sensitive in detecting recent-onset CAI and should be considered.

Some studies in adult patients have shown a positive association between the development of pituitary dysfunction and ICIs treatment outcomes [60]. For adult patients with mild (grade 1) hypophysitis, a continuation of immunotherapy and close observation are recommended [62]. For patients with grade ≥2 toxicities, the guidelines for adults recommend withholding ICI therapy (e.g., ipilimumab) until adverse events resolve to grade ≤1. Alternatively, continuation of immunotherapy alongside hormonal therapy may be considered. In most cases of severe hypophysitis (grade 3/4), patients are treated with high-dose systemic steroids, with a gradual transition to physiological replacement doses of hydrocortisone or prednisolone. Regardless of the severity of the toxicities, ICI therapy can resume once the patient’s condition improves with steroid treatment, taking into consideration patient risks and benefits.

Primary Adrenal Insufficiency

Primary adrenal insufficiency is considered a rare complication of ICIs in adult patients [65], and only few cases have been reported in pediatric patients treated with ICIs [21]. Adrenal insufficiency appears to have a stronger association when anti-PD-1 antibodies are used as compared to CTLA-4 inhibitors. The pathophysiology of ICIs-primary adrenal insufficiency remains unclear as cases have been associated with adrenal antibodies, adrenal atrophy, and adrenalitis. Although 21-hydroxylase autoantibody positivity was reported in a patient who developed adrenal dysfunction induced by the anti-PD-L1 antibody atezolizumab [66], its utility as a biomarker of primary adrenal insufficiency induced by ICIs is unknown.

Primary adrenal insufficiency induced by ICIs is defined as decreased levels of serum cortisol, increased levels of plasma ACTH, and increased levels of plasma renin activity, resulting in the development of hyponatremia, hyperkalemia, and hypoglycemia as well as decreased response of cortisol secretion in the synacthen stimulation test.

Once the general conditions stabilize after appropriate treatments, ICI therapy can resume for patients with primary adrenal insufficiency. There are no reports of associations between the development of primary adrenal insufficiency and ICI treatment outcomes.

Type 1 Diabetes Mellitus

The overall incidence of ICIs-induced diabetes mellitus (DM) in adults is 0.9–2% [67], which can present as acute-onset or fulminant type 1 diabetes mellitus (T1DM) [68]. Pediatric patients may be at increased risk for ICIs-T1DM as compared to adult patients, given the increased incidence of spontaneous T1DM in children.

Studies of pediatric patients reported the occurrence of hyperglycemia in 2–12% of patients [24, 26, 31, 34] and cases of T1DM induced by ICIs in 1–9% of treated patients [22, 27, 29, 69]. Most reported cases of T1DM, both in pediatric and adult patients, are associated with anti-PD-1 or anti-PD-L1 antibody treatment [29, 70]. ICIs-induced DM develops often with the presence of autoantibodies and HLA genotypes associated with T1DM. Indeed, in most cases, an immune-mediated destruction of the pancreatic islets takes place. Findings suggest the involvement of cytotoxic T cells in the development of ICI-induced T1DM [71]. Median duration from the initiation of ICIs treatment to the development of T1DM is ∼5–6 months.

In a case series of adult patients, analyzing autoantibodies associated with T1DM in those who developed ICIs-induced T1DM (n = 27), the prevalence of anti-glutamic acid decarboxylase (GAD), anti-islet antigen 2 (IA2), anti-zinc transporter 8, and islet cell antibodies were 36%, 21%, 10%, and 11%, respectively [72]. Positivity for anti-GAD, anti-IA2, and anti-zinc transporter 8 autoantibodies before the initiation of ICI treatment may be a biomarker of T1DM development in a subset of patients. Also, prevalence of HLA-DR4 was higher in patients with ICIs-induced T1DM [73]. No studies have evaluated the association between T1DM development and ICI treatment outcomes.

In both pediatric and adult patients, the presentation of ICIs-T1DM is hyperglycemia and glucosuria with elevated levels of hemoglobin A1c. However, the increase in hemoglobin A1c may be relatively small in cases of rapid development of T1DM, while ketone bodies may be elevated in the blood and urine.

Patients with diabetic ketoacidosis should be treated with intravenous administration of insulin and saline. Once the general conditions stabilize after the appropriate treatments, the continuation of ICIs can be considered for patients with T1DM. Glucocorticoid-induced DM should also be considered in pediatric oncological patients. Polyendocrinopathy was also reported following ICI treatment and is most commonly observed as the combination of thyroid disease and another endocrinopathy: hypophysitis, T1DM, or primary adrenal insufficiency [66].

To date, several guidelines on irEEs of ICIs in adults have been published by national and international endocrine and oncologic scientific societies [62, 74‒77]. However, there are no published guidelines for managing irEEs of ICIs in pediatric patients. Suggestion of follow-up and management of irEEs in pediatric patients are based on several protocols of ICI treatment from pediatric studies [21, 34], time of onset of the ICI-related irEEs, and guidelines for general endocrine management of specific endocrinopathies in the pediatric age group.

In general, serial monitoring is indicated in children receiving ICIs, ideally at baseline before initiation of ICIs, every 2–3 weeks during the first 6 months of treatment, or preferably before each treatment cycle starts. Screening for thyroid dysfunction includes measurements of TSH, fT4, and fT3. Measurement of TSH-receptor antibody has to be considered if thyrotoxicosis is suspected. Since thyroid dysfunction can develop at a later stage and symptoms are usually non-specific, in case of cessation of ICI treatment, ongoing monitoring of TSH, fT4, fT3 is indicated for at least 2 years, or in cases of symptoms/signs of thyroid dysfunction. Replacement of levothyroxine is indicated in cases of hypothyroidism. After treatment initiation, regular monitoring of TSH and fT4 is needed in order to titrate levothyroxine dosage. In patients with low-dose replacement of levothyroxine, tapering and stopping have to be considered to assess whether thyroid function has recovered. Beta-blockers are recommended for symptomatic relief of thyrotoxicosis. Prolonged hyperthyroidism (persists >6 weeks) is usually managed with anti-thyroid medications.

Screening for adrenal and pituitary dysfunction includes measurement of morning serum cortisol, Na, K, and glucose levels prior to the initiation of ICIs with their monitoring prior to every ICI treatment cycle. In cases of low cortisol levels, ACTH measurement has to be considered. ACTH deficiency is managed by replacement therapy with physiological doses of hydrocortisone (8–10 mg/m2/day). TSH deficiency is managed by replacement therapy with levothyroxine, with dose adjustment according to the serum level of fT4. When patients simultaneously develop ACTH and TSH deficiencies, hydrocortisone must be administered first, followed by levothyroxine replacement.

In cases of suspected adrenal crisis due to primary adrenal insufficiency, treatment with high-dose glucocorticoids (50 mg/m2 hydrocortisone IV/IM followed by 50–100 mg/m2/day every 6 h) and fluid resuscitation (5% dextrose with 0.9% saline) is indicated. The presence of hyponatremia, hypotension, or salt-wasting also suggests mineralocorticoid deficiency, which is treated with fludrocortisone (0.05–0.15 mg/day) in combination with hydrocortisone. All patients should have appropriate training on stress doing and be equipped with a hydrocortisone injection kit. If glucocorticoids are considered to be stopped, assessment of the hypothalamic pituitary adrenal axis should be considered.

Screening for hyperglycemia and diabetes includes fasting glucose measurement prior to initiation of every ICI treatment cycle or occurrence of polydipsia or polyuria and at 1 month after termination of ICI treatment. In cases of documented hyperglycemia, measurements of blood pH and urine ketone are required. Measurement of C-peptide and autoantibodies against GAD, IA2, IAA, and the zinc transporter ZnT8 may be considered. Patients who develop T1DM induced by ICIs require insulin treatment. In clinical practice, both the recommendations and clinical judgment of the treating physician should be taken into account.

The novel therapeutic perspectives of ICIs will hopefully improve survival for some patients with the more aggressive and resistant forms of childhood cancers. Since it is well recognized that immune responses in children differ from those of adults, it remains unknown whether distinct irAE patterns will be seen in pediatric patients.

Managing irEEs is especially challenging and frequently requires an endocrine consultation and, often, life-long hormone supplementation. However, distinct from non-endocrine high-grade irAEs, permanent discontinuation of ICI treatment is rarely needed.

It is uncertain yet if the current guidelines for the management of irEEs in adults are appropriate for the management of pediatric patients, who may have different autoimmune risks. The frequency and type of biomarkers used for routine screening of irAEs in pediatric patients remain to be defined. Thus, further, larger clinical trials are needed to evaluate the full range of endocrine immune-related side effects of ICIs in children and adolescents.

The author wishes to thank Debby Mir for her editorial assistance.

The author is an associate editor of Hormone Research in Pediatrics.

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

S.S. is responsible for drafting the article and revising it critically for important intellectual content. The author read and approved the final manuscript.

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