title: Hypophysitis Secondary to Cytotoxic T-Lymphocyte-Associated Protein 4 Blockade: Insights into Pathogenesis from an Autopsy Series.
abstract: Hypophysitis that develops in cancer patients treated with monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4; an inhibitory molecule classically expressed on T cells) is now reported at an incidence of approximately 10%. Its pathogenesis is unknown, in part because no pathologic examination of the pituitary gland has been reported to date. We analyzed at autopsy the pituitary glands of six cancer patients treated with CTLA-4 blockade, one with clinical and pathologic evidence of hypophysitis, one with mild lymphocytic infiltration in the pituitary gland but no clinical signs of hypophysitis, and four with normal pituitary structure and function. CTLA-4 antigen was expressed by pituitary endocrine cells in all patients but at different levels. The highest levels were found in the patient who had clinical and pathologic evidence of severe hypophysitis. This high pituitary CTLA-4 expression was associated with T-cell infiltration and IgG-dependent complement fixation and phagocytosis, immune reactions that induced an extensive destruction of the adenohypophyseal architecture. Pituitary CTLA-4 expression was confirmed in a validation group of 37 surgical pituitary adenomas and 11 normal pituitary glands. The study suggests that administration of CTLA-4 blocking antibodies to patients who express high levels of CTLA-4 antigen in the pituitary can cause an aggressive (necrotizing) form of hypophysitis through type IV (T-cell dependent) and type II (IgG dependent) immune mechanisms.
authors.affiliation: Division of Immunology, Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland. Electronic address: pcat@jhmi.edu.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Caturegli
authors.affiliation: Division of Immunology, Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland; Department of Medicine, G. D'Annunzio University of Chieti, Chieti, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Di Dalmazi
authors.affiliation: Endocrinology Unit, Saints Anthony and Biagio, and Cesare Arrigo Hospital, Alessandria, Italy; Oncology Center, Saints Anthony and Biagio, and Cesare Arrigo Hospital, Alessandria, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Lombardi
authors.affiliation: Oncology Center, Saints Anthony and Biagio, and Cesare Arrigo Hospital, Alessandria, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Grosso
authors.affiliation: Division of Immunology, Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: H Benjamin
authors.initials: HB
authors.lastname: Larman
authors.affiliation: Division of Immunology, Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Tatianna
authors.initials: T
authors.lastname: Larman
authors.affiliation: Department of Radiology, Mesothelioma Unit, Saint Spirit Hospital, Casale Monferrato, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Taverna
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Mirco
authors.initials: M
authors.lastname: Cosottini
authors.affiliation: Department of Endocrinology, University of Pisa, Pisa, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Lupi
mesh_terms: D000328:Adult; D000368:Aged; D019138:Antibodies, Blocking / Q000008:administration & dosage* / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D001344:Autopsy; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D000072659:Hypophysitis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000276:immunology; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human