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Objective: Hypophysitis is considered a rare inflammatory disease of the pituitary gland. For a long time, primary autoimmune hypophysitis has stood out as the most relevant type of hypophysitis. However, with the advent of immunotherapy for the treatment of malignancies and identification of hypophysitis as an immune-related adverse event, hypophysitis has garnered increasing interest and recognition. Therefore, awareness, early recognition, and appropriate management are becoming important as the indication for immunomodulatory therapies broaden., Methods: In this review, we discuss the epidemiology, diagnosis, and treatment of hypophysitis with a focus on recent data and highlight subtypes of particular interest while recognizing the gaps in knowledge that remain., Results: Regardless of cause, symptoms and signs of hypophysitis may be related to mass effect (headache and visual disturbance) and hormonal disruption that warrant prompt evaluation. In the vast majority of cases, a diagnosis of hypophysitis can be made presumptively in the appropriate clinical context with radiologic findings consistent with hypophysitis and after the exclusion of other causes., Conclusion: Although subtle differences currently exist in management and outcome expectations between primary and secondary causes of hypophysitis, universally, treatment is aimed at symptom management and hormonal replacement therapy., (Copyright © 2022 AACE. Published by Elsevier Inc. All rights reserved.)

Hypophysitis is defined as inflammation of the pituitary gland. It is a heterogeneous condition as it can originate from different parts of the pituitary gland, can be caused by different pathophysiological processes, and can be isolated or the manifestation of a underlying systemic disease. Hypophysitis usually presents with endocrine deficiencies, including diabetes insipidus, with varying patterns. A subset of patients presents with mass effects. The last decades major progress has been made in the understanding of this disease. New forms are now recognized, new diagnostics are being developed, and specific treatments are proposed. This review provides an overview of the current knowledge on hypophysitis using an aetiology-based approach and provides the clinician with a stepwise approach to the patient with (suspected) hypophysitis., (Copyright © 2021. Published by Elsevier Masson SAS.)

IgG4-related hypophysitis is a rare disease, due to a lymphoplasmocytic IgG4 positive infiltration of the pituitary. Literature data are scarce, even though the description of cases has drastically increased over the last years. The aim of this review is to better characterize the natural history, the diagnosis and the management of IgG4-related hypophysitis, based on a clinical case, an exhaustive Pubmed research, and a reappraisal of the criteria for diagnosis. We will specifically focus on the differences with other etiologies of hypophysitis, in the aim of improving the diagnostic procedures for all the physicians who could have to take care of such patients., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis of small vessels that affect the pituitary gland in less than 1% of cases being exceptionally rare. To describe the clinical, biochemical, radiological findings, treatment, and outcomes of 4 patients with GPA-related hypophysitis. A systematic review of published cases with the same diagnosis is presented as well. A cross-sectional case series of patients with hypophysitis due to GPA from 1981 to 2018 at a third level specialty center. Literature review was performed searching in seven different digital databases for terms "granulomatosis with polyangiitis" and "pituitary gland" or "hypophysitis," including in the analysis all published cases between 1950 and 2019 with a minimum follow-up of 6 months. We found 197 patients with GPA in our institution of whom 4 patients (2.0%) had pituitary involvement. Clinical characteristics and outcomes are described. We also reviewed 7 case series, and 36 case reports describing pituitary dysfunction related to GPA from 1953 to 2019, including the clinical picture of an additional 74 patients. Pituitary dysfunction due to GPA is rare. Treatment is targeted to control systemic manifestations; nevertheless, the outcome of the pituitary function is poor. Central diabetes insipidus, particularly in younger women with other systemic features, should raise suspicion of GPA.Key Points• Involvement of the pituitary gland is an uncommon manifestation in GPA patients. The presence of central diabetes insipidus in the setting of systemic symptoms should prompt its suspicion.• In patients with pituitary involvement due to GPA, affection of other endocrine glands is rare, neither concomitant nor in different times during the disease course. This may arise the hypothesis of a local or regional pathogenesis affection of the gland.• There is no consensus on the best therapy strategy for GPA hypophysitis. Although the use of glucocorticoids with CYC is the most common drug combination, no differences in the outcome of the pituitary function and GPA disease course are seen with other immunosuppressants.• Poor prognosis regarding pituitary function is expected due to possible permanent pituitary tissue damage that results in the need of permanent hormonal replacement.

Immune checkpoint (IC) therapy provides substantial benefits to cancer patients but can also cause distinctive toxicities termed immune-related adverse events (irAEs). Biomarkers to predict toxicities will be necessary to improve management of patients receiving IC therapy. We relied on serological analysis of recombinant cDNA expression libraries to evaluate plasma samples from patients treated with IC therapy and identified autoantibodies, both in pretreatment and on-treatment samples prior to the development of irAEs, which correlate with the development of immune-related hypophysitis (anti-GNAL and anti-ITM2B autoantibodies) and pneumonitis (anti-CD74 autoantibody). We developed an enzyme-linked immunosorbent assay and tested additional patient samples to confirm our initial findings. Collectively, our data suggest that autoantibodies may correlate with irAEs related to IC therapy, and specific autoantibodies may be detected early for the management of irAEs., Competing Interests: Competing interest statement: J.P.A. has ownership in Jounce, Neon, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Hummingbird, Dragonfly, Lytix, and Tvardi Therapeutics and serves as a consultant for Jounce, Kite Pharma, Neon, Amgen, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Tvardi Therapeutics, Lytix, Hummingbird, and Dragonfly. P.S. has ownership in Jounce, Neon, Constellation, Oncolytics, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Lytix, Hummingbird, and Dragonfly and serves as a consultant for Constellation, Jounce, Kite Pharma, Neon, BioAtla, Pieris Pharmaceuticals, Oncolytics Biotech, Merck, BioMx, Forty-Seven, Polaris, Apricity, Marker Therapeutics, Codiak, ImaginAb, Hummingbird, Lytix, and Dragonfly. J.G. serves as a consultant for ARMO Biosciences, AstraZeneca, CRISPR Therapeutics, Jounce, Nektar, Polaris, Pfizer, and Symphogen. C.G.D. and J.P.A. are coauthors on a 2016 workshop report.

Purpose: New-onset pituitary gland lesions are observed in up to 18% of cancer patients undergoing treatment with immune checkpoint blockers (ICB). We aimed to develop and validate an imaging-based decision-making algorithm for use by the clinician that helps differentiate pituitary metastasis (PM) from ICB-induced autoimmune hypophysitis (HP)., Materials and Methods: A systematic search was performed in the MEDLINE and EMBASE databases up to October 2018 to identify studies concerning PM and HP in patients treated with cytotoxic T-lymphocyte-associated protein 4 and programmed cell death (ligand) 1. The reference standard for diagnosis was confirmation by histology or response on follow-up imaging. Patients from included studies were randomly assigned to the training set or the validation set. Using machine learning (random forest tree algorithm) with the most-described six imaging and three clinical features, a multivariable prediction model (the signature) was developed and validated for diagnosing PM. Signature performance was evaluated using area under a receiver operating characteristic curves (AUCs)., Results: Out of 3174 screened articles, 65 were included totalising 122 patients (HP: 60 pts, PM: 62 pts). Complete radiological data were available in 82 pts (Training: 62 pts, Validation: 20 pts). The signature reached an AUC = 0.91 (0.82, 1.00), P < 10 -8 in the training set and AUC = 0.94 (0.80, 1.00), P = 0.001 in the validation set. The signature predicted PM in lesions either ≥ 2 cm in size or < 2 cm if associated with heterogeneous contrast enhancement and cavernous extension., Conclusion: An image-based signature was developed with machine learning and validated for differentiating PM from HP. This tool could be used by clinicians for enhanced decision-making in cancer patients undergoing ICB treatment with new-onset, concerning lesions of the pituitary gland., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose of Review: IgG4-related disease (IgG4-RD) is increasingly recognized as a fibroinflammatory disease with a plethora of organ-specific manifestations but a particular predilection for head and neck tissues, including the nervous system. This review discusses general features and organ-specific presentations of IgG4-RD as well as treatment considerations, particularly emphasizing features of neuro-ophthalmic interest., Recent Findings: IgG4-RD is emerging as a common cause of several fibroinflammatory disorders in the head and neck that were previously considered idiopathic, such as sclerosing orbital pseudotumor, orbital myositis, hypophysitis, and hypertrophic pachymeningitis. New and unusual presentations continue to be described, including a number of vascular manifestations. Substantial progress has been made in elucidating the cell types involved in IgG4-RD, and new pathogenic models are being proposed. Although clinicopathologic correlation remains the cornerstone of diagnosis, ancillary tests such as flow cytometry for circulating plasmablasts and PET-computed tomography have high sensitivity, and certain radiologic features are recognized to be particularly suggestive, such as infraorbital nerve enlargement in IgG4-RD orbitopathy. IgG4-RD often responds to steroids but incomplete responses and relapses are common. Rituximab is emerging as a promising new therapy., Summary: The current review summarizes manifestations of IgG4RD that are of particular relevance to neuro-ophthalmic practice.

Background: Lymphocytic hypophysitis is a rare inflammatory lesion in the sellar region. Lymphocytic hypophysitis secondary to ruptured Rathke cleft cyst (RCC) is even more rarely seen. Clinical characteristics, treatment strategies, and prognosis remain elusive., Case Description: A 58-year-old Chinese woman with a 3-year history of intermittent headache and new development of polydipsia, polyuria, and binocular visual acuity decline over the past 4 months was admitted to our hospital. On admission, endocrine results were normal. Ophthalmic testing showed bitemporal visual field deficits and decreased visual acuity of both eyes. Pituitary dynamic magnetic resonance imaging showed a cystic sellar lesion measuring 5.6 × 5.2 × 6.2 mm with tumor shrinkage compared with initial neuroimaging. Transsphenoidal surgery was performed for tumor resection. An additional biopsy of the anterior pituitary lobe was performed because of intraoperative abnormal appearances of the pituitary gland. Pathology examinations revealed the specimen of the cystic lesion to be RCC and exhibited infiltration of massive lymphocytes, diffused plasmocytes, and eosinophils that were diagnostic of lymphocytic hypophysitis in the anterior pituitary lobe. During follow-up, the lesion of lymphocytic hypophysitis showed spontaneous shrinkage in the absence of steroid treatment after RCC resection. Final diagnosis was lymphocytic hypophysitis secondary to ruptured RCC., Conclusions: We present a rare case of lymphocytic hypophysitis secondary to ruptured RCC and provide clinical data of such lesions in the literature. Full understanding of the clinical features plays an important role in diagnosis and treatment of lymphocytic hypophysitis secondary to ruptured RCC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Recently developed immunotherapeutic agents, like anti-cytotoxic T lymphocyte antigen 4 antibody (CTLA4), anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1), have demonstrated substantial potential for the treatment of a variety of malignancies. Autoimmune side effects from these agents are diverse and can include multiple endocrinopathies like immunotherapy induced hypophysitis (IH). These toxicities appear to be more frequent in patients receiving anti-CTLA4 antibody compared to PD1/PDL1 agents. The diagnosis of IH is generally based on the presence of new hypopituitarism without an alternative etiology and radiographic pituitary enlargement or not while on treatment with Immunotherapy. Patients with IH frequently present non-specifics symptoms like headache, fatigue or weakness. ACTH and TSH deficiencies are more frequent. TSH and gonadotrophin deficiencies may be reversible but ACTH deficiency appears permanent. Glucocorticoid and thyroid hormone replacement should be instituted early after the diagnosis of IH, androgen replacement can be deferred initially and discussed by the patient. High-dose glucocorticoid does not improve the outcome of IH and should be reserved for patients with persistent severe headache, severe hyponatremia or visual defects. Patient education, early identification by measuring TSH, free thyroxine, morning ACTH and cortisol levels before each treatment cycle and proper treatment are the core of IH management., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objective: A wide range of treatment-related side effects result in specific neurologic symptoms and signs and neuroimaging features. Even to the most seasoned neuroradiologist, elucidating therapy-related side effects from other common mimics can be challenging. We provide a pictorial survey of some common and uncommon medication-induced and therapy-related neuroimaging manifestations, discuss pathophysiology and common pitfalls in imaging and diagnosis., Methods: A case-based review is utilized to depict scenarios on a routine basis in a general radiology or neuroradiology practice such as medication-induced posterior reversible encephalopathy syndrome to the more challenging cases of pseudoprogression and pseudoregression in temozolmide and bevacizumab therapy in gliobastoma treatment protocols., Conclusion: Knowledge of the treatment-induced imaging abnormalities is essential in the accurate interpretation and diagnosis from the most routine to most challenging of clinical situations. We provide a pictorial review for the radiologist to employ in order to be an invaluable provider to our clinical colleagues and patients.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a membrane glycoprotein expressed by activated effector T cells (Teffs) and participates in the repression of T cell proliferation, cell cycle progression and cytokine production. Currently, antibodies targeting CTLA-4, ipilimumab and tremelimumab are widely used as a therapeutic approach in a variety of human malignancies. However, their detailed mechanism remains unclear. Therefore, in this review, we focused specifically on recent findings concerning the role of CTLA-4 in immune response and also discussed clinical studies of targeting CTLA-4, alone or in combination with other therapies for the treatment of cancers. CTLA-4 blockade is used as a therapeutic approach for the treatment of cancer through competing with CD28-positive costimulation for binding to their shared B7 ligands or exhibiting direct inhibitory effect on signaling molecules in the cytoplasmic tail. At present, antibodies for targeting CTLA-4 or in combination with other therapies significantly reinforced the anti-tumor effect and improved the prognosis of malignant disease. In addition, severe adverse events of targeting CTLA-4 therapy could be a challenge for the development of this therapeutic strategy. This review may provide some new insights for clinical studies of targeting CTLA-4., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

IgG4-related disease is an immune-mediated disease with manifestations in most organ systems among them the pituitary gland. To date, few cases of histologically confirmed cases of IgG-related hypophysitis have been reported. The aim of this study was to retrospectively determine the prevalence of IgG4-related hypophysitis among cases previously diagnosed as primary hypophysitis (lymphocytic hypophysitis, granulomatous hypophysitis and hypophysitis not otherwise specified). Histological and immunohistochemical analysis revealed that 12 of 29 cases (41.4%) previously diagnosed as primary hypophysitis fulfilled the criteria for IgG4-related disease and, thus, IgG4-related hypophysitis should always be considered in the differential diagnosis of primary hypophysitis. All cases of IgG4-related hypophysitis showed a dense lymphoplasmacytic infiltrate with more than 10 IgG4-positive cells per high power field and a ratio of IgG4/IgG-positive cells of more than 40%, whereas storiform fibrosis was an inconsistent histological feature and was also seen in few cases of non-IgG-related hypophysitis, thus lacking sensitivity and specificity. Obliterative phlebitis was not seen in any case. Thus, histological criteria defined for IgG4-related disease in other organs should be modified for IgG4-related hypophysitis, accordingly., (© 2016 International Society of Neuropathology.)

The number of cases of lymphocytic hypophysitis is small, although the condition is not rare. For optimal therapy, the correct diagnosis from imaging, immunological studies, and pathological findings from a pituitary biopsy is important. Recently, anti-Rabphilin antibody has been proposed to be a biomarker for lymphocytic infundibulo-neurohypophysitis. Immunological disorders such as anti-Pit-1 antibody syndrome are similar to the pathogenesis of lymphocytic hypophysitis. Moreover, recent immune checkpoint blockade such ipilimumab has been shown to induce anti-CTLA-4-related hypophysitis. In the future, elucidating the immunological mechanism and establishing a suitable therapy will be necessary for accurate long-term prognosis.

Purpose: This publication reviews the accepted knowledges and the findings still discussed on several features of autoimmune hypophysitis, including the most recently described forms, such as IgG4 and cancer immunotherapy- related hypophysitis., Methods: The most characteristic findings and the pending controversies were derived from a literature review and previous personal experiences. A single paragraph focused on some atypical examples of the disease presenting under confounding pretences., Results: Headache, visual field alterations and impaired pituitary secretion are the most frequent clinical findings of the disease. Pituitary biopsy, still considered the gold diagnostic standard, does not always receive consent from the patients. The role of magnetic resonance imaging is limited, as this disease may generate images similar to those of other diseases. The role of antipituitary and antihypothalamus antibodies is still discussed owing to methodological difficulties and also because the findings on the true pituitary antigen(s) are still debated. However, the low sensitivity and specificity of immunofluorescence, one of the more widely employed methods to detect these antibodies, may be improved, considering a predetermined cut-off titre and a particular kind of immunostaining., Conclusion: Autoimmune hypophysitis is a multifaceted disease, which may certainly be diagnosed by pituitary biopsy. However, the possible different clinical, laboratory and imaging features must be considered by the physician to avoid a misdiagnosis when examining a possibly affected patient. Therapeutic choice has to be made taking into account the clinical conditions and the degree of hypothalamic-pituitary involvement, but also considering that spontaneous remissions can occur.

Lymphocytic infundibulo-neurohypophysitis is an uncommon inflammatory disorder postulated to be autoimmune in origin. Because of the location of inflammation, it selectively affects the posterior lobe of the pituitary (neurohypophysis) and pituitary stalk (infundibulum). The most common presentation is central diabetes insipidus. Although the definitive diagnosis is established histologically by a pituitary biopsy, radiological imaging can be valuable in diagnosing this condition. In this paper, we provide an overview of the pathophysiology, investigations, management, and outcomes of lymphocytic infundibulo-neurohypophysitis.

Hypophysitis is a rare pathology. As clinical symptoms and radiologic signs are non-specific, the diagnostic is difficult. Hypophysitis's pathogenesis remains obscure but new histological and etiological variants have recently been reported. Primary hypophysitis is the main form. For the first time, hypophysitis in ANCA-associated vasculitides has been reported. An entity of immunoglobulin G4 related plasmatic hypophysitis has been described and well-defined diagnostic criteria are proven. Monoclonal antibodies directed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4), investigated in metastatic cancer, can induce hypophysitis. Hypophysitis's pathogenesis remains obscure but several candidate pituitary autoantigens have been described in the last decade, although none has proven useful as a diagnostic tool., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The major symptoms that are caused by Rathke's cleft cysts (RCCs) are visual disturbances, headaches, and endocrine insufficiencies. Among these symptoms, the endocrine insufficiencies are thought to result from the spreading of inflammation that is induced by the cyst contents onto the pituitary gland or the compression of the gland and the pituitary stalk by RCCs. Here, we present 2 rare cases with lymphocytic infundibulohypophysitis with the sudden onset of headaches and subsequent diabetes insipidus (DI). Magnetic resonance imaging revealed remarkable swelling of the pituitary gland with a small mass that was located between the anterior and the posterior lobe of the pituitary gland. Transsphenoidal surgery was performed to remove the mass, and pathological examinations of the cyst wall demonstrated that the epithelial tissue of the RCC and the posterior lobe were affected by massive lymphocytic infiltration. The clinical courses and pathological results of these patients strongly suggested that the rupture of the RCC onto the posterior lobe caused the lymphocytic hypophysitis. Postoperatively, the DI could be controlled with a smaller amount of anti-diuretic hormone replacement compared to that required preoperatively.