Programmed death receptor-1 (PD-1) is expressed on the surface of activated T cells. T cells become inactivated if programmed death-ligand 1 (PD-L1), made by cancer cells, binds to PD-1. Nivolumab is an anti-PD-1 monoclonal antibody that blocks PD-L1 from binding to PD-1, allowing the T cells to function.

Cytotoxic T lymphocyte antigen 4 (CTLA4) is a protein receptor that serves as an immune checkpoint and down regulates T-cell activation and proliferation against cancer cells. Ipilimumab, an anti-CTLA4 monoclonal antibody, blocks CTLA4 which leads to enhanced T-cell activation and antitumor effects.

Nivolumab and ipilimumab are ICPis which have improved survival in patients with advanced melanoma but are commonly associated with immune-related adverse events (irAE), including endocrinopathies, colitis, dermatitis and hepatitis. ⁽¹⁾ Autoimmune hypophysitis, also known as lymphocytic hypophysitis, is a rare condition which has now emerged as a relatively common irAE of ICPis, with many case reports describing this phenomenon. ^(2-5) A recent multi-centre retrospective review conducted by Faje et al reported 13.6% and 0.5% of patients treated with ipilimumab and anti-PD-1 (nivolumab or pembrolizumab) respectively to have developed hypophysitis. ⁽⁶⁾

Hypophysitis can affect only the anterior pituitary (adenohypophysitis), infundibulum and posterior pituitary (infundibulo-neurohypophysitis), or the entire pituitary gland (panhypophysitis). The anterior pituitary gland produces and releases ACTH, FSH, LH, Growth hormone, prolactin and TSH, while the posterior pituitary gland is connected to the hypothalamus through the infundibulum, releasing oxytocin and vasopressin produced in the hypothalamus.

Patients with hypophysitis commonly present with symptoms including headache, fatigue, nausea, dizziness, altered mental status, myalgia, and low blood pressure. The diagnosis of ICPi induced hypophysitis is established by the presence of low levels of pituitary hormones mentioned above, following treatment with ICPis, with or without radiographic pituitary enlargement. ⁽⁶⁾ It is important to note that primary adrenal insufficiency may also be an irAE of ICPi. The differentiation between primary and secondary adrenal insufficiency relies on the ACTH level in the setting of low cortisol level. A high ACTH level suggests primary adrenal insufficiency while a low ACTH level suggests secondary adrenal insufficiency. Our patient’s ACTH level was low, which is compatible with a diagnosis of secondary adrenal insufficiency due to hypophysitis.

Here we have reported a case of adenohypophysitis following treatment of metastatic melanoma with ICPis. Our patient was initially treated with nivolumab monotherapy. Before symptom onset, he was already found to have abnormal TFTs suggestive of secondary hypothyroidism 2 months after starting nivolumab. The morning cortisol level was 160nmol/L at the time. The patient was started on thyroxine replacement and no further pituitary hormone tests were carried out.

It was speculated that the attending clinician was falsely reassured by a morning cortisol of 160nmol/L, which was within the reference interval (133-537nmol/L). Cheung et al suggested that for outpatients who were ambulatory and not under stress, a morning cortisol of ≤124 nmol/L indicated adrenal insufficiency, and a value of ≥428 nmol/L signaled adequate adrenal reserve. ⁽⁷⁾ In other words, when the morning cortisol level falls between the gray area of >124nmol/L and <428nmol/L, proceeding to confirmatory tests such as LDSST to diagnose adrenal insufficiency is recommended if the clinical suspicion is high.

Our patient subsequently received 4 cycles of ipilimumab/nivolumab due to disease progression of metastatic melanoma. After the fourth cycle, he developed symptoms of hypophysitis and blood tests revealed low TSH, IFG-1 and ACTH. Prolactin, LH, FSH and testosterone levels were either normal or raised. ICPi induced hypophysitis does not necessarily affect all pituitary axes. Faje et al reported that Anti-PD-1 monotherapy patients often only had isolated central adrenal insufficiency while deficiencies in other pituitary axes were observed more often in the ipilimumab monotherapy and combination therapy groups. ⁽⁶⁾ ICPi induced hypophysitis commonly affects anterior pituitary gland and rarely affects the infundibulum and posterior pituitary causing DI. ⁽⁸⁾ Faje et al did not report cranial diabetes insipidus in any patient in a cohort study of 106 ipilimumab or anti-PD-1 induced hypophysitis cases. ⁽⁶⁾ 

MRI of our patient showed normal pituitary gland enhancement with no focal mass lesion or suprasellar extension. Faje et al reported pituitary gland enlargement in 98% of patients with ipilimumab induced hypophysitis. In contrast, only 28% of patients treated with Anti-PD-1 monotherapy were reported to have pituitary enlargement. Optic chiasm compression was not found in any patient with ipilimumab or nivolumab induced hypophysitis. ⁽⁶⁾ 

The American Society of Clinical Oncology (ASCO) guideline suggests ICPi induced hypophysitis to be graded 1-4 according to their severity. Hypophysitis with none or mild symptoms are grade 1; moderate symptoms with the ability to perform activities of daily living (ADL) are grade 2; and severe symptoms with medically significant or life-threatening consequences plus loss of ability to perform ADL are grade 3-4. ⁽⁹⁾

Holding ICPi for grade 1-2 hypophysitis can be considered, and secondary adrenal insufficiency should be replaced by physiological maintenance dose hydrocortisone (15-20mg daily in divided dose). Our patient had severe symptoms affecting his ADL, therefore his hypophysitis was graded 3-4 according to the ASCO guideline, which suggests these patients to receive stress dose IV hydrocortisone (50-100mg every 6-8 hours) and taper it down to physiological maintenance dose hydrocortisone over 5-7 days and hold ICPi until the patient is stabilised on hormonal replacement. For those with significant pituitary swelling on MRI, severe headache, optic chiasm changes or visual changes, a pulse dose treatment of oral prednisolone 1-2mg/kg daily (or equivalent) tapered over at least 1-2 weeks to physiological maintenance dose is suggested ⁽⁹⁾

In most patients with ICPi induced hypophysitis, long term hormonal supplement is usually required as anterior pituitary function recovery is uncommon. Discontinuing ICPi in mild hypophysitis is not necessary and one study found the incidence of hypophysitis may positively predict survival in melanoma patients treated with Ipilimumab. ⁽¹⁰⁾ Our patient inappropriately received medium dose glucocorticoid for more than 3 months. According to clinical notes, his low spot morning cortisol level was falsely interpreted as an indication to continue medium dose glucocorticoid.

In conclusion, autoimmune hypophysitis is increasingly recognised as an irAE of ICPis. Clinicians should suspect, diagnose, and treat this condition promptly as the resulting adrenal insufficiency can be life-threatening. Morning cortisol levels should be interpreted carefully, with consideration of confirmatory tests when its result is >124nmol/L and <428nmol/L. Anterior pituitary hormone production is usually affected, and recovery is uncommon, therefore patients usually require long term hormonal supplement. A low morning cortisol level while on physiological maintenance dose hydrocortisone is not an indicator to increase glucocorticoid dose. Pituitary gland enlargement on imaging may or may not be present with hypophysitis. The management of ICPi induced hypophysitis should be guided by its severity grading according to the ASCO guideline. ⁽⁹⁾