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

Abstract

Hypophysitis is the inflammation of the pituitary gland primary or secondary to local or systemic disease. It tends to occur more with cytotoxic T-lymphocyte-associated protein 4 inhibitors (10-15% of cases), which is a different entity compared to that associated with anti-program death 1 (anti-PD1) inhibitors. We describe a case of pembrolizumab-associated hypophysitis and conduct a systematic review of the literature.A 55-year-old woman with stage pT3aN1a (TNM stadium IIIb) melanoma presented with headache, nausea and fatigue three and a half months after starting pembrolizumab. Blood analyses revealed secondary adrenal failure, thyrotropic insufficiency and defective gonadotrophin secretion. An imaging study showed an enlarged pituitary gland with a homogeneous enhancement of the gland and pituitary stalk. Interruption of anti-PD1 therapy and administration of hormonal supplementation lead to clinical, biological and radiologic improvement after eight months.We identified 17 studies (20 patients) on single-agent pembrolizumab-associated hypophysitis. Patients were treated for melanoma (n=7; 33.3%), urogenital (n=5 ; 23.8%), lung (n=4 ; 19.0%), larynx (n=1 ; 4.8%), pharynx (n=1, 4.8%), breast (n=1, 4.8%) and colon (n=1, 4.8%) neoplasia. The time to onset of pituitary insufficiency was most frequently six months (range 1.5-39.0 months) after treatment initiation. The most prevalent hormonal defect was isolated adrenocorticotropic hormone (ACTH) deficiency. Four cases were reported with multiple central hormonal defects. In those patients, an enlarged pituitary gland was also observed.Our case has distinct features, including early disease onset after single-agent pembrolizumab initiation, panhypopituitarism and increased pituitary mass. These findings are in contrast with the majority of other cases of pembrolizumab-induced hypophysitis, as most patients present an isolated ACTH deficiency. Whether or not this is a new clinical entity warrants further investigation.

Hypophysitis: Defining Histopathologic Variants and a Review of Emerging Clinical Causative Entities

“…It is often associated with inflammatory disease in the salivary glands, pancreas, or with retroperitoneal fibrosis. Infrequently, IgG4 causes isolated pituitary disease; however this only occurs in 4–5% of cases [ 9 , 27 ]. The clinical presentation of IgG4 hypophysitis is similar to that seen with immune checkpoint inhibitor-related hypophysitis [ 27 ].…”

“…Infrequently, IgG4 causes isolated pituitary disease; however this only occurs in 4–5% of cases [ 9 , 27 ]. The clinical presentation of IgG4 hypophysitis is similar to that seen with immune checkpoint inhibitor-related hypophysitis [ 27 ]. Elevated serum IgG4 is not diagnostic.…”

“…In contrast, the PD1 monoclonal antibodies camrelizumab and pembrolizumab cause hypophysitis in 0.5% of patients [ 31 ]. Hypophysitis occurs in less than 0.1% of patients treated with PDL1 inhibitors [ 4 , 27 , 30 , 32 ]. Combination therapy with CTLA4 and PD1 inhibitors causes hypophysitis in 8.8 to 10.5% of patients [ 30 ].…”

“…In anti-PD1/PDL1 ICI, hormone deficiencies are usually isolated to ACTH, and hypophysitis appears later during the course of treatment [ 30 ]. In contrast to anti-CTLA4 monoclonal antibodies, hypophysitis from anti-PD1 monoclonal antibodies appears after 6 months [ 27 ]. Patients present with fatigue, nausea, and loss of appetite [ 27 , 30 ].…”

“…In contrast to anti-CTLA4 monoclonal antibodies, hypophysitis from anti-PD1 monoclonal antibodies appears after 6 months [ 27 ]. Patients present with fatigue, nausea, and loss of appetite [ 27 , 30 ]. A rare reported presentation was seen in a patient with unexpected fatigue, nausea, hoarse voice, bucking, and difficulty in breathing [ 28 ].…”