Hypophysitis secondary to pembrolizumab: a case report and review of the literature

Abstract

Pembrolizumab is a mAb against the programmed cell death protein-1 (PD-1). It has been approved for the treatment of advanced melanoma (unresectable or metastatic) in adults. Side effects associated with the use of anti-PD-1 are usually considered well tolerated; nevertheless, there are immune-related adverse events that may require treatment discontinuation. A 79-year-old man diagnosed with stage IV right scapular melanoma experienced unspecific symptoms and alterations of the hypothalamus-hypophysis axis after six cycles with pembrolizumab. The case was compatible with immune-related hypophysitis. Autoimmune thyroiditis and primary hypophysitis were excluded and toxicity due to pembrolizumab was considered the cause of hypophysitis. Pembrolizumab was discontinued and toxicity was managed with corticosteroids and hormonal replacement therapy (HRT). After 7 months of follow-up, symptoms were controlled with HRT but thyrotropin and corticotropin hormones had not recovered. It was decided not to reintroduce immunotherapy. Although endocrine disorders are common with the use of anti-PD-1, hypophysitis is very rare. However, clinical signs and symptoms can be nonspecific, therefore, it has probably been underdiagnosed. Monitoring hormones before and during the treatment is important for an early diagnosis and also to replace the alterations with HRT to control the symptoms. Hormonal function does not always recover, but it does not mean immunotherapy cannot be restarted and it should be evaluated in every case.

Exploring a New Entity of Single-Agent Pembrolizumab-Associated Hypophysitis

“…In our case, we describe diffuse enlargement and homogeneous enhancement of the gland as well as moderate enlargement with the enhancement of the pituitary stalk found on magnetic resonance imaging. This is however not a widespread finding since some reported a solitary change in homogeneity or enhancement [18,22] and others normal imaging findings [9,[11][12]15,17,19,27]. As previously reported [29], the review of published cases and our case suggest that increased pituitary size is associated with multiple hormonal axis involvement [21,25,27].…”

“…In our patient, three pituitary axes were affected: the adrenocorticotropic, thyroid and gonadotrophic axes. This is a rather rare presentation reported in three other patients in the currently available literature [20][21][22]27]. The time to onset was relatively short and ranged from three to nine months and two of the patients were diagnosed with melanoma [14].…”

“…Defects of the neurohypophysis are mainly reported in the context of pituitary metastasis [4]. Ascertainment of secondary adrenal failure used different testing strategies, including morning cortisol and ACTH [9,[11][12]15,[17][18][19][20][21][22][23][24][25][26][27], short Synacthen test [12,[16][17][18]21] and corticotropin-releasing hormone (CRH) stimulation test [12,16,24]. In our patient, three pituitary axes were affected: the adrenocorticotropic, thyroid and gonadotrophic axes.…”

“…This is however not a widespread finding since some reported a solitary change in homogeneity or enhancement [18,22] and others normal imaging findings [9,[11][12]15,17,19,27]. As previously reported [29], the review of published cases and our case suggest that increased pituitary size is associated with multiple hormonal axis involvement [21,25,27]. As opposed to the enlargement and enhancement of the pituitary stalk, the same changes on the gland seem to be more specific for the diagnosis of hypophysitis using MR imaging and therefore are more accurate for follow-up purposes [30].…”

“…On the other hand, similarly to anti-CTLA-4-induced endocrine adverse events [31], except for one patient in whom de-escalation of corticosteroids and thyroid hormone supplementations were considered [27]. All patients with available data required hormonal support after a follow-up time ranging from one to 19 months.…”