Response to Letter to the Editor From Asa and Mete: "Hypophysitis, the Growing Spectrum of a Rare Pituitary Disease".

Dear Editor,

We thank Asa and Mete for their interest in our article “Mini-review: Hypophysitis, the Growing Spectrum of a Rare Pituitary Disease” (1), in which we discuss diagnosis and management of hypophysitis (Hy), address common clinical questions, and describe a variety of underlying etiologies and conditions associated with Hy. The authors (2) point to an omission of xanthomatous Hy often associated with rupture of a Rathke cleft cyst. However, we detail that xanthomatous Hy is often linked to rupture of a Rathke cleft cyst or other cystic pituitary masses and could be an important unrecognized clinical problem. This is highlighted in case 2 (1) (a patient with xanthomatous Hy and craniopharyngioma) and in Figure 1 (1). Furthermore, additional literature on this topic is referenced in the article (1).

The authors (2) also raise an important fact regarding the evolving nomenclature of Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). Recent discovery of activating mutations in proto-oncogene B rapidly accelerated fibrosarcoma (BRAF) V600E and other genes involved in MAPK pathways in many patients with LCH and ECD, have shed new light on these entities, pointing to a neoplastic process and new treatment options for some, but not all, patients. In the article (1), we referenced several recent reports (3-6) that describe these genetic pathways and note available treatments in the text and figures, including use of targeted BRAF and MEK inhibitor therapies (1).

Disease pathogenesis of LCH and ECD is characterized by histiocytic infiltration and inflammation in multiple organs (3, 7) and, as such, these disorders were grouped for differential diagnosis and treatment as infiltrative disorders/multisystemic disease. Interestingly, Goyal et al (8) and Gulati et al (3), as cited by the authors (2), although focusing on a new proposed ECD/LCH nomenclature, also describe hypothalamic/pituitary involvement as infiltrative. As highlighted (1), we concur that it is important to raise awareness of the origin of ECD and LCH as both diagnosis and treatment are complex and require specific imaging, tissue biopsy, chemotherapy, targeted therapy (eg, BRAF and MEK inhibitors), glucocorticoids, radiation, or a combination of all. Furthermore, management pathways for ECD and LCH vs those for malignancy with mass effect are different, as shown in Figure 5 (1).

As we wrote (1), knowledge of both primary and secondary Hy types and nomenclature of infiltrative and inflammatory conditions have been evolving. We look forward to diagnosis and treatment improvements for patients with these complex disorders.