Isolated Adrenocorticotropin Deficiency due to Nivolumab-induced Hypophysitis in a Patient with Advanced Lung Adenocarcinoma: A Case Report and Literature Review

Abstract

A 63-year-old Japanese woman with advanced lung adenocarcinoma developed isolated adrenocorticotropin deficiency caused by immune checkpoint inhibitor (ICI)-related hypophysitis following 8 months of nivolumab therapy. Prompt corticosteroid replacement therapy effectively relieved her secondary adrenal insufficiency symptoms and allowed her to pursue nivolumab therapy, which had been effective for the control of lung adenocarcinoma. Human leukocyte antigen (HLA) typing revealed the presence of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which is associated with susceptibility to autoimmune polyglandular syndrome with pituitary disorder in the Japanese population. This case suggests that genetic factors, such as HLA, contribute to the development of endocrinopathies induced by ICIs.

Keywords: human leukocyte antigen; hydrocortisone; hypophysitis; lung adenocarcinoma; nivolumab.

Figure 1.

Chest computed tomography (CT) scans. (A) Chest CT performed in March 2014 showing a 1.2-cm tumor at the apex of the right lung (white arrow). (B) Chest CT performed in April 2016 showing 1.6- and a 2.3-cm tumors on the right pleura (long white arrows) and a 1.0-cm tumor in the lower lobe of the left lung (short white arrow). (C, D) Chest CT performed in July 2016 (C) and November 2016 (D) showing marked reduction in the diameters of the lung and pleural tumors.

Figure 2.

Histopathological findings of the resected lung tissue (July 2014). (A) The gross appearance of the cut surface of the apex of the right upper lung shows a 1.5-cm tumor (black arrow). (B-E) A microscopic examination of the right lung tumor. Proliferation of moderately and poorly differentiated atypical glands was observed (B, C: Hematoxylin and Eosin staining), indicating lung adenocarcinoma. The cytoplasm of the tumor cells was immunohistochemically positive for surfactant protein A (D), and the tumor cell nuclei were positive for thyroid transcription factor-1 (E).

Figure 3.

Magnetic resonance imaging (MRI) scans. (A-C) Brain MRI scans obtained at the diagnosis of isolated adrenocorticotropin deficiency (December 2016). Sagittal T1-weighted plain MRI scans (A) showing a symmetric round-shaped pituitary gland and a slightly thickened hypophyseal stalk. A normal high-intensity signal was observed in the posterior lobe of the pituitary. Gadolinium-enhanced MRI scans (B, sagittal plane; C, coronal plane) showing homogeneous enhancement of the hypophyseal stalk and pituitary gland with a pituitary intermediate lobe cyst. The width, length, and height of the pituitary gland are 14.2, 12.4, and 5.6 mm, respectively. (D-F) Brain MRI scans obtained after corticosteroid replacement therapy (April 2017). Sagittal T1-weighted plain MRI scans (D) showing no abnormalities in the hypothalamus, hypophyseal stalk, or pituitary gland. Gadolinium-enhanced MRI scans (E, sagittal plane; F, coronal plane) showing homogeneous enhancement of the hypophysial stalk and pituitary gland, with a small pituitary intermediate lobe cyst. The width, length, and height of the pituitary gland are 11.4, 12.1, and 4.4 mm, respectively.