From Japan With Love: Another Tessera in the Hypophysitis Mosaic

Hypophysitis is a chronic inflammation of the pituitary gland that is receiving greater attention from endocrinologists and oncologists alike. It can be classified according to etiology, anatomic location, or histopathology (1, 2). Etiology distinguishes hypophysitis into primary (or idiopathic) or secondary depending on whether the cause/ mechanism of the disease is unknown or identifiable. Primary hypophysitis is rare but clinically significant because it enters in the differential diagnosis of about 30 other diseases that manifest as a non-hormone-secreting sellar mass. There are over 750 cases of primary hypophysitis published thus far, of which approximately 30% come from Japan (Figure 1A). It remains unknown whether this high prevalence reflects any true geographic or ethnic variations in risk or simply means that hypophysitis awareness is greater in Japan than elsewhere. Primary hypophysitis is more common in young adult women and usually presents with symptoms originating from compression of sellar structures or defective pituitary hormone production. Secondary hypophysitis has emerged swiftly on the medical radar due to its recent description in patients with advanced cancer receiving immunostimulatory treatments such as the CTLA-4 blocking antibody ipilimumab. These treatments were pioneered in 2003 for advanced melanoma (3) but are now used in several other types of cancer, including renal cell carcinoma (4), non-Hodgkin lymphoma (5), prostate cancer (6), pancreatic cancer (7), and non-small-cell lung cancer (8). It is a mystery why hypophysitis, traditionally considered rare, is seen with surprisingly high incidence (approximately 4%) during ipilimumab treatment. Location scholarly distinguishes adenohypophysitis, infundibuloneurohypophysitis, and panhypophysitis, depending on whether the clinical and magnetic resonance imaging (MRI) signs (and pathological findings, if available) involve the anterior lobe, the posterior lobe and the stalk, or both structures, respectively. Tissue sampling from both structures, however, is not systematically performed, so a true assessment of the extension of the involvement is seldom possible. Histopathological examination of the specimen obtained from pituitary biopsy remains the tool that establishes a diagnosis of hypophysitis with certainty. Histopathology differentiates 2 main forms of hypophysitis (Figure 1B): lymphocytic, first reported in 1962 (9); and granulomatous, described in an academic fashion by Simmonds in 1916 (10). During the past 2 decades, however, the clinicopathological spectrum of hypophysitis has expanded remarkably with the addition of 3 new forms: necrotizing in 1993 (11), xanthomatous in 1999 (12), and IgG4 plasmacytic in 2004 (13). The IgG4 plasmacytic form is the pathological counterpart of the clinical disease now called IgG4-related hypophysitis. It is characterized by the infiltration of the pituitary gland and/or stalk with numerous plasma cells. Plasma cells are also found in the lymphocytic and granulomatous forms, but are more numerous in the IgG4 plasmacytic form and predominantly produce antibodies of the IgG4 subclass. IgG4 is the least abundant of the 4 IgG subclasses in healthy people, representing about 4% of the total IgG content. It is unique in that it does not activate complement, has weakly opsonizing ability, transfers minimally across the placenta, and has very low binding affinity for Fc receptors expressed on mast cells and basophils (14). In addition, a single IgG4 molecule can display 2 different heavy/light chain pairs, thus behaving as a bispecific (functionally monovalent) antibody (14). IgG4 is physiologically pro-