Primary (idiopathic) hypophysitis is traditionally classified into lymphocytic, granulomatous, necrotizing, or IgG4-related disease types. Secondary hypophysitis occurs in patients with systemic conditions, which if known, often obviate the need for biopsy. Primary idiopathic hypophysitis, in contrast, often mimics tumors and mandates histological confirmation of inflammation. We detail four primary hypophysitis cases, discussing challenges in histological classification. Four women, ages 32 to 76 years, presented with weakness, visual changes, fatigue, weight loss, and/or headache. Preoperatively, pituitary macroadenoma/pituitary neuroendocrine tumor was suspected. Biopsies revealed lymphocytic hypophysitis without (Case 1) and with (Case 2) IgG4+ cells (modest numbers) and granulomatous hypophysitis with necrosis, large numbers of IgG4+ cells (Cases 3 and 4), with multinucleated giant cells (Case 4). Steroid therapy, in one case with rituximab, was administered irrespective of histological classification. Lymphocytic hypophysitis comes to biopsy primarily in patients without known risk factors, eg pregnancy or drug usage. Granulomatous or necrotizing types are less common, less histologically uniform, and may contain large numbers of IgG4+ cells, a feature found both in IgG4-related disease and autoimmune disorders, especially granulomatosis with polyangiitis. In certain cases, the use of steroids, followed by rituximab for all types of hypophysitis based on clinical criteria may obviate the need for precise histological distinction.

Hypophysitis is defined by inflammation of the pituitary gland and/or infundibulum. It can cause headaches and symptoms due to hypopituitarism. Diagnosis is based on a combination of hormonal and imaging parameters but can, in individuals with an uncertain diagnosis, require a transsphenoidal biopsy. While the risk of immune checkpoint inhibitor-induced hypophysitis is well known, several aetiologies of secondary hypophysitis have been identified and hypophysitis can also occur in relation to pregnancy. Primary hypophysitis is defined by the absence of a secondary cause of hypophysitis. Although each subtype can present with distinct clinical, endocrine and radiological features, extensive overlap makes the aetiological diagnosis difficult. Management of hypophysitis is another challenging task. Whereas some studies have suggested that high-dose glucocorticoids can improve pituitary function and alleviate symptoms, others have found limited benefit. Immunosuppressive agents have also been used as targeted therapy for the underlying condition or in individuals with aggressive hypophysitis, potentially improving both clinical presentation and hormonal function. These therapeutic approaches, used alone or in combination, can be considered in selected patients with primary, pregnancy-related or secondary hypophysitis. The aim of this comprehensive Review is to critically analyse the positive and aetiological diagnostic steps and the management of all subtypes of hypophysitis.

Inflammation of the pituitary gland can be primary (without another underlying cause) or secondary (associated with a systemic inflammatory condition). Primary hypophysitis is very rare, among which xanthomatous hypophysitis as a histological type is extremely unusual. A woman in her late 50s presented with recurrent pituitary lesions over 20 years. Her general practitioner had diagnosed panhypopituitarism in her 30s; a decade later, she had presented to ophthalmology with visual loss and restricted visual fields, and a pituitary lesion was found. This recurred several times requiring multiple resections. Histopathology showed atypical inflammation in keeping with xanthomatous hypophysitis; this responded well to corticosteroid therapy. Xanthomatous hypophysitis is a rare form of steroid-responsive primary pituitary inflammation, to consider in the differential diagnosis of recurring pituitary lesions.

Secondary hypophysitis (apart from immune checkpoint inhibitor [ICI] induced) is rare and is largely described in case series. We aim to describe the distinctive characteristics of the various etiologies of secondary hypophysitis from a single center. A retrospective record review of 44 patients with secondary hypophysitis (excluding ICI) presenting to our institute between January 2002 and January 2023 was performed. The data of primary hypophysitis managed medically (n = 39) was retrieved from a prior publication and compared with common etiologies of secondary hypophysitis. The most common etiologies were histiocytic disorders - Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECD) [n = 23] and tubercular hypophysitis (TH) [n = 10]. LCH/ECD were characterized by multisystem involvement, with arginine vasopressin deficiency (AVP-D) [22/23] being the predominant endocrine presentation. TH patients presented with mass effect (9/10), focal non-enhancing areas within an enhancing sellar/suprasellar mass on magnetic resonance imaging (MRI) (10/10), with evidence of tuberculosis elsewhere in 60%. Though caseating granulomas were universal on histopathology, bacteriological confirmation was negative in all pituitary specimens. When compared to primary hypophysitis, isolated infundibuloneurohypophysitis and AVP-D were more prevalent in LCH/ECD, while the presence of a sellar/suprasellar mass with focal non-enhancing areas was more frequent in TH. Furthermore, recovery of the hormonal axis upon follow-up was more common in primary hypophysitis. Secondary hypophysitis in our cohort was predominantly histiocytic or tubercular in etiology, with LCH/ECD presenting largely with AVP-D and TH presenting with mass effects, focal non-enhancing areas, and paucibacillary disease.

Primary hypophysitis is a rare disease that is usually diagnosed retrospectively after surgery for suspected tumors of the sellar region (pituitary adenomas, craniopharyngiomas, etc.). The most common variant of the primary forms is lymphocytic hypophysitis, characterized by the presence of lymphocytes in the inflammatory infiltrate. Granulomatous hypophysitis is the second most common variant of the disease, the cause of which remains unknown. To study the frequency and nature of clinical manifestations, the features of MRI of the brain, as well as the results of neurosurgical treatment of patients with a confirmed histological diagnosis of hypophysitis. A retrospective analysis of the case reports of 14 patients with histologically confirmed diagnosis of lymphocytic (13 cases) and granulomatous (1 case) hypophysitis operated at the Burdenko Neurosurgical Center. In none of the cases before the operation, according to the MRI data, the diagnosis of "hypophysitis" was made. Clinical symptoms were manifested by headaches in 12 patients, decreased acuity and/or visual field impairment in 9 patients, oculomotor impairments in 2 patients. Hypopituitarism was detected in 12 cases, and diabetes insipidus in 8 cases. After surgery, 7 patients had a regression of headache and improved vision, in 5 cases there was no dynamics, in 1 case vision deteriorated. In all 8 patients with diabetes insipidus, it persisted after surgery. There were no new cases of diabetes insipidus. Panhypopituitarism was noted in all patients. Given the difficulty of diagnosing hypophysitis without morphological verification, as well as the rarity of these cases, prospective multicenter studies are needed to study the pathognomonic signs of hypophysitis and improve their neuroimaging methods. Первичный гипофизит — редкое заболевание, обычно диагностируемое ретроспективно после операции по поводу предполагаемых опухолей хиазмально-селлярной области (аденомы гипофиза, краниофарингиомы или др.). Наиболее частым вариантом первичных форм является лимфоцитарный гипофизит, характеризующийся наличием в воспалительном инфильтрате лимфоцитов. Гранулематозный гипофизит — второй по частоте вариант заболевания, причина которого остается неизвестной. Изучить частоту и характер клинических проявлений, особенности МРТ головного мозга, а также результаты нейрохирургического лечения пациентов с подтвержденным гистологическим диагнозом гипофизита. Проведен ретроспективный анализ историй болезни 14 пациентов с гистологически подтвержденным диагнозом лимфоцитарный (13 случаев) и гранулематозный (1 случай) гипофизит, оперированных в НМИЦ нейрохирургии им. акад. Н.Н. Бурденко МЗ РФ. Ни в одном случае до операции по данным МРТ диагноз «гипофизит» поставлен не был. Клиническая симптоматика проявлялась головными болями у 12 пациентов, снижением остроты и/или нарушением полей зрения — у 9, глазодвигательными нарушениями — у 2 пациентов. В 12 случаях был выявлен гипопитуитаризм, в 8 — несахарный диабет. После операции у 7 пациентов отмечался регресс головной боли и улучшение зрения, в 5 случаях динамики не было, в 1 случае зрение ухудшилось. У всех 8 пациентов с несахарным диабетом он сохранился и после операции. Новых случаев несахарного диабета не было. У всех пациентов отмечен пангипопитуитаризм. Учитывая трудность диагностики гипофизитов без морфологической верификации, а также редкость этих образований, необходимы проспективные многоцентровые исследования для изучения патогномоничных признаков гипофизитов и усовершенствования методов их нейровизуализации.