Ipilimumab-Induced Hypophysitis: MR Imaging Findings

Abstract

SUMMARY:Ipilimumab is a promising new immunotherapeutic antineoplastic agent with clinical activity in the treatment of metastatic melanoma and renal cell carcinoma. With advances in immunotherapy, however, a host of new side effects related to the mechanism of action of these drugs has appeared. At our institution, 3 patients presented with hypophysitis, which was attributed to an autoimmune process based on the documented relationship of the drug to other autoimmune phenomena and significant and rapid improvement with discontinuation of the drug and addition of steroids. We present the imaging findings in 3 patients with presumed ipilimumab-induced hypophysitis. Ipilimumab, also known as MDX-010, is a human monoclonal antibody that has been shown to overcome the suppressive effects of cytotoxic T-lymphocyte antigen 4 expression, thereby enhancing the immune response against tumors. 1 This drug has been shown in trials to have clinical activity against metastatic melanoma.2 Side effects are related to its mechanism of action, including development of immune-related adverse events such as hypophysitis, colitis, uveitis, dermatitis, and arthritis, among others. 3 We describe 3 cases in which patients treated with ipilimumab developed both MR imaging and clinical findings characteristic of hypophysitis. We will describe these findings and provide a brief discussion of the causes and imaging characteristics of hypophysitis. Case Reports Case 1Patient 1 was a 70-year-old man originally diagnosed with a Clark level IV melanoma of the right shoulder, and later found to have cervical nodal metastasis. He was enrolled in an ipilimumab study and received 3 doses of antibody at 10 mg/kg for 6 weeks. Shortly after his third dose, he presented with complaints of visual hallucinations, lack of energy, dizziness on erect position, and anorexia. MR imaging revealed no evidence of metastatic disease but instead showed enlargement of the pituitary gland from the original baseline (from 5 mm craniocaudally to 12 mm). Laboratory studies disclosed the following values: a total T4 of 3.6 g/dL (normal, 5.5-11.0 g/dL) and a drop in adrenocorticotropic hormone (ACTH) from 21 to 9 pg/mL, thyroidstimulating hormone (TSH) from 1.99 to 0.005 L, and cortisol from 9.04 to 2.31 g/dL compared with laboratory values obtained before initiation of therapy. He also had a total testosterone level Ͻ20 ng/dL with a decrease in luteinizing hormone and follicle-stimulating hormone (FSH). He received tapering doses of prednisone starting at 60 mg daily as well as levothyroxine (Synthroid) 50 mcg daily. Follow-up laboratory values and imaging showed improvement for several weeks following discontinuation of ipilimumab, along with corresponding improvement in symptoms on replacement therapy (Fig 1). Case 2Patient 2 was a 44-year-old man with stage IV desmoplastic neurotropic melanoma found in the lower lip. He initially underwent excision and radiation therapy but was later found to have neurotropic spread along the maxillary division of the trigeminal ne...

Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports

“…The incidence of hypophysitis due to ipilimumab has been reported to range from 0 to 17 % in clinical trials for melanoma and for renal cell carcinoma. Anatomic evaluation of the pituitary gland with MRI in conjunction with serial biochemical evaluations may be helpful in monitoring therapy-induced hypophysitis and preventing life-threatening side effects [19,20]. It may also be helpful in the differential diagnosis of melanoma to consider both brain metastasis and hypophysitis as autoimmune reaction.…”

ENDOCRINE SIDE-EFFECTS OF ANTI-CANCER DRUGS: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses

“…Contrast enhancement of the pituitary may or may not be homogeneous (58). However, MRI changes appear to be of lesser magnitude compared with those seen in classic LyH (54) and in some cases, the gland may show normal radiologic features (54,58).…”

Ipilimumab-Induced Autoimmune Hypophysitis: Diagnostic and Management Challenges Illustrated by a Clinical Case

“…The height of pituitary may increase modestly, from 3.4 mm -6.0 mm to 7.7 mm -11.8 mm. 1,[11][12][13] Pituitary enlargement is a highly sensitive indicator of ipilimumab-induced AH and may cause compression of optic chiasm and visual defects, although this situation is rarely seen. 2,6,7 A metastatic lesion must be considered in patients with malignant melanoma with evidence of pituitary enlargement (with or without hypopituitarism).…”

“…2 Pituitary MRI may also be normal in some cases of ipilimumab-induced AH. [11][12][13] The management of ipilimumab-induced AH is controversial. Ipilimumab-induced AH has been managed with initial high-dose of glucocorticoids, but some authors have questioned this approach.…”