Case Report: Ipilimumab-Induced Panhypophysitis: An Infrequent Occurrence and Literature Review

Abstract

BackgroundImmune checkpoint inhibitors (ICIs), by unleashing the anticancer response of the immune system, can improve survival of patients affected by several malignancies, but may trigger a broad spectrum of adverse events, including autoimmune hypophysitis. ICI-related hypophysitis mainly manifests with anterior hypopituitarism, while the simultaneous involvement of both anterior and posterior pituitary (i.e., panhypophysitis) has rarely been described.Case PresentationIn June 2015, a 64-year-old man affected by liver metastases of a uveal melanoma was referred to us due to polyuria and polydipsia. Two months prior, he had started ipilimumab therapy (3 mg/kg iv every 21 days). The treatment was well-tolerated (only mild asthenia and diarrhea were reported). A few days before the fourth cycle, the patient complained of intense headaches, profound fatigue, nocturia, polyuria (up to 10 L urine/daily), and polydipsia. Laboratory tests were consistent with adrenal insufficiency, hypothyroidism, and transient central diabetes insipidus. The pituitary MRI showed an enlarged gland with microinfarcts, while the hypophyseal stalk was normal, and the neurohypophyseal ‘bright signal’ in T1 sequences was not detected. The treatment included dexamethasone (then cortisone acetate at replacement dose), desmopressin, and levothyroxine. Within the next five days, the symptoms resolved, and blood pressure, electrolytes, glucose, and urinalysis were stable within the normal ranges; desmopressin was discontinued while cortisone acetate and levothyroxine were maintained. The fourth ipilimumab dose was entirely administered in the absence of further side effects.ConclusionAs ICIs are increasingly used as anticancer agents, the damage to anterior and/or posterior pituitary can be progressively encountered by oncologists and endocrinologists in their clinical practice. Patients on ICIs and their caregivers should be informed about that risk and be empowered to alert the referring specialists early, at the onset of panhypopituitarism symptoms, including polyuria/polydipsia.

Endocrine Toxicities of Antineoplastic Therapy: The Adrenal Topic

“…irAEs are inherently related to immunological mechanisms of action of ICIs and may potentially affect all organs, with the skin, gastrointestinal apparatus, and endocrine systems being mainly affected [36]. Hypophysitis, thyroid dysfunction, type 1 diabetes mellitus (T1DM), central diabetes insipidus, and PAI are ICI-induced endocrine irAEs [37,38]. Causative and risk factors eliciting the endocrine system's involvement (and other organs) in ICI-related toxicity are currently unknown.…”

Immune Checkpoint Inhibitors as a Threat to the Hypothalamus–Pituitary Axis: A Completed Puzzle

“…However, other endocrine glands may be more rarely affected (adrenals, parathyroids, pancreas), and metabolic abnormalities have also been described [ 7 , 8 ]. Recently, central diabetes insipidus (CDI) has been reported as an irAE deriving from the dysfunction of posterior pituitary/hypothalamus in patients who are receiving treatment with ICI [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Herein, we briefly summarize the current evidence regarding ICI-induced injury to the hypothalamus–pituitary axis.…”

Endocrine Toxicities of Antineoplastic Therapy

“…Thyroid dysfunctions are the most common side effects of immunotherapy, affecting 30% of treated patients. Hypothyroidism is more common in patients treated with PD-1 inhibitors and in combination therapies [ 20 ], and although adverse events are usually immune-mediated, it is caused by autoimmune thyroiditis in only 45% of cases [ 21 ]. PD-1 inhibitors are also associated with an increased risk of hyperthyroidism, which is usually transient and followed by hypothyroidism, although cases of Graves’ disease and thyroid eye disease have also been described [ 21 ].…”

“…Contrary to thyroid changes, hypophysitis is more associated with CTLA-4 inhibitors, but again, combination therapy increases the risk [ 22 ]. Patients may have both a bulking effect, due to increased pituitary tissue, and hormonal insufficiency: isolated adrenocorticotropic hormone (ACTH) deficiency is more common in patients treated with PD-1 and PD-L1, while CTLA-4 inhibitors usually cause multiple anterior pituitary insufficiency [ 21 ]. The concomitant development of diabetes insipidus and anterior pituitary deficiency due to CTLA-4 inhibitors has been rarely described.…”

“…More rarely, immunotherapy has been associated with primary adrenal insufficiency (0.7% of patients) [ 20 ]. While rare, it is important to consider this potential side effect, as it could present with an adrenal crisis [ 21 ]. Finally, new onset or worsening of hyperglycemia has been described in up to 2% of patients, rarely associated with diabetic ketoacidosis requiring immediate treatment [ 21 ].…”