Hypophysitis, the Growing Spectrum of a Rare Pituitary Disease

Abstract

Hypophysitis is defined as inflammation of the pituitary gland that is primary or secondary to a local or systemic process. Differential diagnosis is broad (including primary tumors, metastases, and lympho-proliferative diseases) and multifaceted. Patients with hypophysitis typically present with headaches, some degree of anterior and/or posterior pituitary dysfunction, and enlargement of pituitary gland and/or stalk, as determined by imaging. Most hypophysitis causes are autoimmune, but other etiologies include inflammation secondary to sellar tumors or cysts, systemic diseases, and infection or drug-induced causes. Novel pathologies such as immunoglobulin G4-related hypophysitis, immunotherapy-induced hypophysitis, and paraneoplastic pituitary-directed autoimmunity are also included in a growing spectrum of this rare pituitary disease. Typical magnetic resonance imaging reveals stalk thickening and homogenous enlargement of the pituitary gland; however, imaging is not always specific. Diagnosis can be challenging, and ultimately, only a pituitary biopsy can confirm hypophysitis type and rule out other etiologies. A presumptive diagnosis can be made often without biopsy. Detailed history and clinical examination are essential, notably for signs of underlying etiology with systemic manifestations. Hormone replacement and, in selected cases, careful observation is advised with imaging follow-up. High-dose glucocorticoids are initiated mainly to help reduce mass effect. A response may be observed in all auto-immune etiologies, as well as in lymphoproliferative diseases, and, as such, should not be used for differential diagnosis. Surgery may be necessary in some cases to relieve mass effect and allow a definite diagnosis. Immunosuppressive therapy and radiation are sometimes also necessary in resistant cases.

Keywords: IgG4-related hypophysitis; hypophysitis; immunotherapy-induced hypophysitis; lymphocytic hypophysitis; paraneoplastic pituitary-directed autoimmunity; stalk biopsy.

Figure 1.

Summary of hypophysitis types, features and treatment options (created with BioRender.com). Histopathology image sources: lymphocytic (author’s [MF] pathology department), granulomatous (17), xanthomatous (9), necrotizing (23), immunoglobulin G4-related (14), and immunotherapy-induced (96). Abbreviations: ACTH, adrenocorticotrophic hormone; AI, adrenal insufficiency; APS, autoimmune polyglandular syndrome; DI, diabetes insipidus; DM, diabetes mellitus; ECD, Erdheim-Chester disease; F, female; GC, glucocorticoids; GH, growth hormone; GPA, granulomatosis with polyangiitis; HPF, high power field; LCH, Langerhans cell histiocytosis; M, male; MRI, magnetic resonance imaging; NETs, neuroendocrine tumors; POMC, proopiomelanocortin; PRL, prolactin.

Figure 2.

Case 1—Granulomatous hypophysitis. Postcontrast T1 pituitary MRI; left, coronal and right, sagittal. Enlarged and heterogeneously enhancing pituitary gland with thickened pituitary stalk and mild mass effect on the optic chiasm.

Figure 3.

Case 2—Xanthogranulomatous inflammation associated with craniopharyngioma. Postcontrast T1 pituitary magnetic resonance imaging; left, coronal and right, sagittal. Progressive partially cystic suprasellar lesion, 14 × 13 × 18 mm with mass effect on the optic chiasm.

Figure 4.

Case 3—Lymphocytic hypophysitis with isolated infundibulo-neurohypophyisitis. Postcontrast T1 pituitary magnetic resonance imaging sagittal; left, baseline, stalk thickening measuring 5 mm in diameter, otherwise normal-size pituitary gland; middle, 5 years after initial presentation, spontaneous regression of stalk thickening, now approximately 2 mm in diameter; and right, 12 years after initial presentation, complete resolution of stalk thickening.

Figure 5.

Hypophysitis treatment management algorithm (created with BioRender.com). Abbreviations: ACE, angiotensin-converting enzyme; AFP, alpha-fetoprotein; ALT, alanine aminotransferase; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; beta-hCG, human chorionic gonadotropin; CBC, complete blood count; CRP, C-reactive protein; CT, computed tomography; DI, diabetes insipidus; ECD, Erdheim-Chester disease; ESR, erythrocyte sedimentation rate; FDG-PET, fluorodeoxyglucose-positron emission tomography; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; LCH, Langerhans cell histiocytosis; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; TB, tuberculosis.