2018 NPA-04

This case was originally published in 2018. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 45-year-old woman presented with a three-month history of progressive headaches, panhypopituitarism, and diabetes insipidus. MRI showed a heterogeneously enhancing sellar and suprasellar lesion extending from the pituitary through the infundibulum into the hypothalamus (Image A and Image B). The radiographic differential diagnoses included inflammatory versus infectious etiology, sarcoidosis, lymphoma, and pituitary macroadenoma. The patient underwent surgical excision of this mass. There was a rapid clinical and radiological amelioration of symptoms after surgery and corticosteroid treatment. There were no other systemic manifestations.

Tissue Site
Sellar region

The whole slide image provided is an H&E stain of sellar region from a trans-sphenoidal.

Hypophysitis, a chronic inflammation of the pituitary gland, is a rare entity classified by histopathologic findings, etiology, and anatomic location. The clinical and radiographic manifestations of hypophysitis may mimic neoplasms due to enlargement and/or mass formation of the anterior and/or posterior pituitary gland (Image A and Image B), and patients are therefore sometimes subjected to surgical resection where the ultimate diagnosis relies on the pathologist.

Based on histopathologic appearance, the two most common forms of hypophysitis are lymphocytic and granulomatous, followed by four rarer variants: mixed, xanthomatous, necrotizing, and plasma cell-rich. Based on its etiology, hypophysitis can be divided into primary hypophysitis, which is the most common form and has an autoimmune basis but not a directly identifiable cause, and secondary hypophysitis that develops from an external, contiguous or systemic etiology. Examples of secondary hypophysitis include Rathke cleft cyst and craniopharyngioma, where inflammation of the pituitary is the result of a local insult, and tuberculosis, sarcoidosis, granulomatosis with polyangiitis, or administration of immunomodulatory drugs, where inflammation of the pituitary gland occurs as a result of a systemic condition. Hypophysitis may also be classified by anatomic location as adenohypophysitis, infundibulo-neurohypophysitis, or panhypophysitis.

Lymphocytic hypophysitis is the most common form of pituitary inflammation and is characterized by a diffuse infiltration of mature lymphocytes into the pituitary gland accompanied to a lesser extent by scattered eosinophils and plasma cells in the acute and subacute phases, and extensive fibrosis in late stages. Women are more commonly affected (F:M ratio 3:1) and there is a 40% association with pregnancy and the postpartum period. Granulomatous hypophysitis is also more common in women (F:M ratio 4:1); however, an association with pregnancy is not a feature. The key finding is the presence of true granulomas with associated T-cells and some plasma cells. Cases of hypophysitis represented by the xanthomatous, mixed, and necrotizing variants have rarely been reported in the literature.

Since the first case report in 2001, IgG4-related hypophysitis has become more recognized as a separate entity amongst the inflammatory conditions of the pituitary gland. However, given the sparse reports in the literature, well-defined histopathologic criteria were not consistently applied. In 2011, Leporati and collaborators proposed three criteria for the diagnosis of IgG4-related hypophysitis (Table 1). Only one of these criteria involves histological evidence of pituitary inflammation while the other criteria assess IgG-related disease in other organs and utilize specific clinical, laboratory, and imaging data. IgG4-related hypophysitis can therefore be diagnosed without histopathological confirmation.

Table 1: Diagnostic criteria for IgG4-related hypophysitis.

^{Modified from Leporati P, Landek-Salgado MA, Lupi I, Chiovato L, Caturegli P. IgG4-related hypophysitis: a new addition to the hypophysitis spectrum. J Clin Endocrinol Metab. 2011 Jul;96(7):1972.}

Microscopically, IgG4-related hypophysitis is characterized by a plasma cell-rich infiltration (Image C and Image D) with abundance of IgG4-secreting plasma cells (Image H). To a lesser extent, the inflammatory infiltrate also includes lymphocytes, occasional eosinophils, and sparse neutrophils. As the inflammation progresses, fibrous replacement of the pituitary parenchyma and atrophic acini can be observed (Image E). Storiform fibrosis (Image F) has been described as a characteristic feature in IgG4-related pancreatitis or IgG4-related disease in other organs, but it is not a required feature for hypophyseal cases. Obliterative phlebitis has been consistently absent in hypophysitis in documented cases. IHC for the detection of plasma cells such as CD138 (Image G) or IgG is key to establishing a baseline for the assessment of the IgG4:IgG ratio. IgG4 immunostaining is an essential test since it provides strong confirmatory evidence for the diagnosis. In the case presented here, the ratio of IgG4 to CD138 positive plasma cells was estimated at 40%, and greater than 10 IgG4-producing plasma cells per high-power field were identified (Image H), fulfilling the criteria for the diagnosis. It is worth mentioning that the plasmacytic inflammatory infiltrate was polyclonal, demonstrated by heterogeneous expression of kappa and lambda light chains (Image I and Image J) admixed with histiocytes (Image K).

• IgG4-related hypophysitis is a rare inflammatory process of the pituitary gland that may mimic pituitary neoplasms.
• Morphologically, IgG4-related hypophysitis is characterized by a prominent lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells with or without accompanying storiform fibrosis.
• The cutoff for the number of plasma cells per high-power field suggested by different authors to establish a IgG4-related hypophysitis diagnosis ranges from 10 to 50, with 10 as a minimum requirement. Another option is to apply the IgG4+ to total IgG+ plasma cell ratio used for the diagnosis of IgG4 pancreatitis, where an IgG4+ to total IgG+ plasma cell ratio over 40% is diagnostic.
• If no biopsies are available, a third option for diagnosis includes characteristic imaging, increased serum IgG4 levels (>140 mg/dl), and a good response to steroids, evidenced by improvement of symptoms and shrinkage of the pituitary lesion.

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