Isolated adrenocorticotropic hormone deficiency and thyroiditis associated with nivolumab therapy in a patient with advanced lung adenocarcinoma: a case report and review of the literature

Abstract

Introduction: Immune checkpoint inhibitors are a promising class of anticancer drugs. The clinical benefits afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events that affect multiple organs, and endocrine immune-related adverse events include thyroiditis and hypophysitis. Hypophysitis is less frequent and has a less severe clinical presentation in patients treated with other immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, than in those treated with ipilimumab. However, studies have described isolated adrenocorticotropic hormone deficiency cases associated with nivolumab, pembrolizumab, and atezolizumab therapy, most of which occurred during the course of immune checkpoint inhibitor therapy. We report a rare case of patient with isolated adrenocorticotropic hormone deficiency that occurred after nivolumab therapy.

Case presentation: A 69-year-old Japanese woman with advanced lung adenocarcinoma developed painless thyroiditis with transient elevations of serum thyroid hormones during 3 months of cancer treatment with nivolumab and began thyroid hormone replacement therapy for subsequent primary hypothyroidism. Four months after nivolumab therapy was discontinued, she developed isolated adrenocorticotropic hormone deficiency; corticosteroid replacement therapy relieved her secondary adrenal insufficiency symptoms, such as anorexia and fatigue. Human leukocyte antigen typing revealed the presence of DRB1*04:05-DQB1*04:01-DQA1*03:03 and DRB1*09:01-DQB1*03:03-DQA1*03:02 haplotypes, which increase susceptibility to autoimmune polyendocrine syndrome associated with thyroid and pituitary disorders in the Japanese population.

Conclusions: Our patient developed thyroiditis during cancer treatment with nivolumab and subsequently exhibited isolated adrenocorticotropic hormone deficiency 4 months after discontinuing the drug. Administration of nivolumab in combination with a genetic predisposition to polyglandular autoimmunity probably caused both the thyroiditis and hypophysitis, resulting in primary hypothyroidism and isolated adrenocorticotropic hormone deficiency, respectively, in our patient. The present case highlights the need for physicians to be aware that endocrine immune-related adverse events, including hypophysitis, can occur more than several months after discontinuing a drug.

Keywords: Human leukocyte antigen; Hydrocortisone; Isolated adrenocorticotropic hormone deficiency; Lung adenocarcinoma; Nivolumab; Thyroiditis.

Fig. 1

Radiological findings (July 2016). a Chest computed tomographic scan showing a tumor (3.1 cm) in the upper lobe of the right lung (arrow). b T1-weighted transverse magnetic resonance imaging of the brain showing a tumor in the left temporal lobe (arrow) and a tumor in the right cerebellar hemisphere (short arrow)

Fig. 2

Histopathological findings of biopsy specimen from the left lung tumor (July 2016). a, b Microscopic examination showing bronchial mucosal infiltration by poorly differentiated lung adenocarcinoma (a), and vascular invasion is seen (arrows) (b) (H&E staining). c, d The cytoplasm of the tumor cells was immunohistochemically positive for surfactant protein A (c), and the tumor cell nuclei were positive for thyroid transcription factor 1 (d). Ly Lymph duct, V Vein

Fig. 3

Clinical course of the patient before the onset of isolated adrenocorticotropic hormone deficiency. Bmab Bevacizumab, CDDP Cisplatin, DTX Docetaxel, FT₄ Free thyroxine, IAD Isolated adrenocorticotropic hormone deficiency, PEM Pemetrexed, Rmab Ramucirumab, TSH Thyroid-stimulating hormone

Fig. 4

Thyroid gland imaging findings (July 2017). a, b Ultrasonography of the thyroid gland showing rough and mildly low echogenicity in a slightly enlarged thyroid gland without a tumor (a). Color Doppler images revealed no increased blood flow in the thyroid gland (b). c Technetium-99m pertechnetate thyroid scintigraphy showing a low thyroid uptake (0.1%, reference range 0.5–4%) in the entire thyroid gland without a hot spot

Fig. 5

Magnetic resonance imaging of the pituitary gland (January 2018). a Sagittal T1-weighted plain magnetic resonance imaging (MRI) study showing normal high-intensity signals in the posterior lobe of the pituitary. b, c Gadolinium-enhanced MRI scans (b, sagittal plane; c, coronal plane) showing homogeneous enhancement of the normal hypophyseal stalk and mild atrophy of the anterior lobe of the pituitary gland. The width, length, and height of the pituitary gland are 16.2, 9.8, and 2.2 mm, respectively