Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade

www.expert-reviews.com ISSN 1744-6651 © 2009 Expert Reviews Ltd 10.1586/EEM.09.37 General features of autoimmune hypophysitis Autoimmune (lymphocytic) hypophysitis (AH), is a chronic inflammation of the pituitary gland caused or accompanied by pituitary autoimmunity [1,2]. It can be classified etiologically into two groups: primary and secondary hypophysitis. Primary hypophysitis is, by definition, of unknown etiology. It is diagnosed on clinical and radiological grounds or, when available, by pathological examination. Pathology classifies primary hypophysitis into three forms: lymphocytic, granulomatous and xanthomatous, although some patients have mixed lymphocytic and granulomatous or granulomatous and xanthomatous forms, so that the relationship between these entities remains to be established. Lymphocytic hypophysitis is the most common form and the topic of this review. Granulomatous hypophysitis is characterized by an infiltration of multinucleated giant cells and histiocytes, surrounded by lymphocytes, mainly T cells [3], and plasma cells. Xanthomatous hypophysitis is very rare; it was originally described in 1998 in three women [4], and in eight additional patients thereafter [3,5–8]. It features cystic-like areas of liquification, infiltrated by lipid-rich foamy histiocytes and lymphocytes. Secondary hypophysitis is caused by local or systemic processes. Local processes that arise within or around the pituitary gland and are associated with lymphocytic infiltration of the pituitary gland include germinoma [9], ruptured Rathke cleft cyst [10], pituitary adenoma [11], and craniopharyngioma [12]. Systemic processes that involve the pituitary are most commonly associated with a granulomatous reaction and include Wegener granulomatosis [13], sarcoidosis [14], Langerhans cell histiocytosis [15] and, more rarely nowadays, TB [16]. In the last 5 years a new entity has emerged in this group: hypophysitis secondary to the administration of an antibody that blocks cytotoxic T-lymphocyte antigen (CTLA)-4 [17], an entity that will be explored in detail in this review. Autoimmune hypophysitis was first reported in 1962 in a young woman who died 14 months after delivery of her second child because of severe adrenal insufficiency [18]. Only 12 additional patients, mainly post-mortem, appeared in the literature during the following 20 years. The first two ante-mortem patients diagnosed by CT scan were reported in 1980 [19,20] and the first one diagnosed by MRI in 1988 [21]. The widespread use of MRI and greater awareness of AH in the medical community have significantly increased the number of published AH patients (Figure 1). Many others are diagnosed but not published, and even more patients remain undiagnosed because of varying clinical presentations and courses. Thus, although AH has been traditionally considered a rare disease, it Angelika Gutenberg, Melissa LandekSalgado, Shey-Cherng Tzou, Isabella Lupi, Abby Geis, Hiroaki Kimura and Patrizio Caturegli† Author for correspondence Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Tel.: +1 443 287 8911 Fax: +1 410 614 3548 [email protected] Autoimmune hypophysitis is an increasingly recognized disorder that enters in the differential diagnosis of nonfunctioning pituitary masses. The differential diagnosis of these conditions is challenging because of similar clinical presentations and radiological signs. This review describes the essential features of hypophysitis and the other nonfunctioning pituitary masses. It also emphasizes a recently described feature of hypophysitis: its appearance with unexpectedly high frequency in patients receiving treatments that abrogate the function of cytotoxic T lymphocyte antigen 4.