Isolated adrenocorticotropic hormone deficiency and sialadenitis associated with nivolumab: a case report

Abstract

Background: Immune checkpoint inhibition with anti-PD(L)1 and anti-CTLA4 antibodies has significantly changed cancer treatment during the last 10 years. Nevertheless, boosting the immune system with immune checkpoint inhibition can result in immune-related adverse events, affecting different organ systems, among which the endocrine system is the most affected. However, there are few descriptions of the association of immune-related adverse events, and the pathophysiology of some is still lacking. Here, we report a 70-year-old Caucasian patient treated with nivolumab (anti-PD1 monoclonal antibody) after resection of a unique relapse of melanoma in the neck region who presented with sicca syndrome, extreme fatigue, and weight loss 6 months after the start of anti-PD1 therapy. Blood tests revealed hypoglycemia and secondary hypocortisolism due to isolated adrenocorticotrophic hormone deficiency. Interestingly, brain methionine positron emission tomography/magnetic resonance revealed physiological metabolism of the pituitary gland, which was not increased in size, and no hypophyseal metastasis was detected. The sicca syndrome investigation revealed the absence of anti-SSA/SSB antibodies, while the labial salivary gland biopsy showed lymphoplasmatocytic infiltrates with a focus score of 1. To provide new insights into the physiopathology of the anti-PD1-related sialadenitis, we investigated the distribution of aquaporins 5 by immunostaining on the labial salivary gland acini, and compared this distribution with the one expressed in the primary Sjögren's syndrome. Contrary to patients with primary Sjögren's syndrome (in whom aquaporins 5 is mainly expressed at the basolateral side), but similar to the patients with no sialadenitis, we observed expression of aquaporins 5 at the apical pole. This new finding deserves to be confirmed in other patients with anti-PD1-related sialadenitis. Owing to these immune-related adverse events, anti-PD1 was stopped; nevertheless, the patient developed a new relapse 1 year later (March 2020) in the neck region, which was treated by radiotherapy. Since then, no relapse of melanoma was seen (1.5 years after radiotherapy), but the patient still requires hypophyseal replacement therapy. The sialoadenitis resolved partially.

Conclusion: We report a combination of sialoadenitis and hypophysitis explaining extreme fatigue in a patient who was treated in the adjuvant setting with anti-PD1 for a melanoma relapse.

Keywords: Aquaporins; Brain methionine PET/MR; Case report; Hypophysitis; Isolated adrenal insufficiency (IAD); Sialadenitis.

Fig. 1

Methionine PET/MR showing no pituitary gland mass nor enlargement. Physiological metabolism of the pituitary gland

Fig. 2

Hematoxylin–eosin staining of LSG showing lymphocytes infiltration and destruction of the gland (A ×2.5, B ×5, C ×10, D ×20)

Fig. 3

Immunostaining (×40) of AQP1 (A for the patient and Aʹ for healthy control), AQP3 (B for the patient and Bʹ for healthy control), and AQP5 (C for the patient and Cʹ for healthy control) showing no difference in the expression of these AQPs in the patient and control