Secondary Hypophysitis Research Articles

Deciphering the Presentation and Etiologies of Hypophysitis Highlights the Need for Repeated Systematical Investigation

Abstract Context Hypophysitis is defined as an inflammation of the pituitary gland and/or infundibulum. Objective Our aim was to characterize the initial course and evolution of patients with hypophysitis according to the different etiologies. Methods Retrospective observational study conducted in a university referral hospital center. Patients over 15 years of age were included if they had a diagnosis of hypophysitis between January 2014 and October 2023, with the exclusion of hypophysitis secondary to immune checkpoint inhibitors. Results Sixty-one patients (64% women; median age, 34 years) were included. Polyuria–polydipsia, headache, and asthenia were present in 64%, 48%, and 44% of cases respectively. At diagnosis, at least 1 anterior pituitary deficiency was present in 91.5% of cases and vasopressin deficiency in 56%. Magnetic resonance imaging was abnormal in 97% of cases. Secondary hypophysitis was found in 46% of cases (n = 28), including sarcoidosis in 28% (n = 17) and L (Langerhans) group histiocytoses in 13.1% (n = 8). Among patients with secondary hypophysitis, pituitary deficiency preceded systemic manifestations in 23% and occurred concomitantly in 23% of cases. Patients were treated in 36% of cases (glucocorticoids, surgery), without improvement of pituitary hormone deficits. Conclusion A systemic etiology of hypophysitis was found in almost half of the patients. Pituitary disorders preceded the systemic disease in a quarter of the cases. This emphasizes the importance of a systematic repeated workup looking for a secondary etiology of hypophysitis in these patients.

Acquired isolated ACTH deficiency co-occurrence with breast cancer irrespective of paraneoplastic syndrome: coincidence or inevitability.

A 52-year-old female patient with breast cancer presented with a history of fatigue and malaise 1 year prior. She was diagnosed with isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) on endocrinological examination. Her pituitary gland showed normal morphology. Paraneoplastic IAD associated with breast cancer was suspected; however, immunofluorescence staining revealed no ectopic ACTH or proopiomelanocortin expression in the tumor tissue. Subsequently, the patient was diagnosed with idiopathic acquired IAD concurrent with breast cancer, ruling out paraneoplastic syndrome. Although malignancy should be considered a potential cause of IAD, not all patients with concurrent IAD and malignancy necessarily develop paraneoplastic syndrome. Several adrenal insufficiency symptoms are similar to the nonspecific symptoms associated with malignancies, and therefore, the diagnosis of IAD remains challenging, especially in patients with cancer. When we encounter a case of IAD accompanied by a malignant tumor, it is important to suspect that paraneoplastic IAD, a novel clinical condition as secondary hypophysitis, may be the etiologic agent. Although malignant tumours should be considered a potential cause of IAD, not all patients with concurrent IAD and malignancy necessarily develop paraneoplastic autoimmune hypophysitis.

P-52 Our objective was to present a case with secondary hypophysitis

Abstract Clinical Case A 36-year-old male patient was admitted to an external center with weakness, sexual dysfunction, polydipsia and polyuria. The Laboratory analysis showed partial hypopituitarism (Table 1). The sella MR imaging was performed to determine the etiology. It was showed that the thickness of the pituitary gland was thinner than normal (3 mm, Partially Empty Sella). The pituitary stalk was also significantly enlarged, measuring up to 7.5 mm, and there was an increase in contrast enhancement, as shown in Figure 1. The patient was subsequently started on Prednisolone, L-thyroxine, testosterone propionate, and Desmopressin acetate to treat panhypopituitarism. The ACE level was within the normal range, and tests including quantiferon, vasculitis markers (c-ANCA, P-ANCA, ANA), AFP, Beta hCG, LDH, and beta2 microglobulin all yielded negative results. Given these findings and considering primary hypophysitis, a pulse steroid therapy of 1 gram was administered over a span of 2 days (Figure 1). In the control pituitary MRI 3 months after the treatment: Heterogeneous contrast-enhancing thickening of approximately 16×10mm in the pituitary stalk and a lesion of approximately 22×10mm in the diameter of the epiphysis with heterogeneous contrast enhancement were observed (Figure 2). During this period, the patient was considered to have hypophysitis again, and 1 gr of pulse steroid treatment was administered for 2 days. (Figure 2) Six months after the start of the treatment, the patient was admitted due to sudden onset of double vision and headache. In the pituitary MRI, he was referred to our center upon detection of a 22×13×10 mm contrast-enhancing bilobular lesion that slightly compresses the optic chiasm, and also a 15×10 mm lobulated lesion in the pineal gland (Figure 3). An emergency operation was planned for the lesion, who was compressing the optic chiasm and whose progressing mass size was, for diagnostic and therapeutic purposes. The patient underwent surgery. Preoperative b hCG was negative, and AFP was 2.6 (<13). The histopathological examination revelaed germinoma. Conclusion Hypophysitis is a rare inflammatory disease that affects the pituitary gland and infundibulum as a result of autoimmune, infiltrative, infectious, neoplastic, drug-induced or sometimes unknown pathogenic processes. Some authors recommend a biopsy if the pituitary stalk size is >6.5 mm or if new lesions develop on the stalk. Germinomas, one of the causes of secondary hypophysitis, usually present with a hypothalamic/pineal mass and isolated stalk thickening and has been reported in only a few cases. Serologically, beta human chorionic gonadotropin (β-hCG) and alpha-fetoprotein (85-90%) may be normal in brain germinomas. Therefore, normal negative results of AFP and B-hCG do not exclude germinoma. Table 1

FRI341 Nothing Great Comes Without Its Risks; A Rare Case Of Pembrolizumab Induced Hypophysitis

Abstract Disclosure: A.K. Fernando: None. R. Cheema: None. Introduction: Immune checkpoints are proteins expressed by immune cells and are crucial for maintaining self-tolerance. Immune checkpoint inhibitors (ICIs) are antibodies that inhibit these checkpoints and enhances T-cell activation and antitumor activity. This emerged as a powerful tool in treating cancer, however its use is jeopardized by various immune related adverse events (IRAEs). Secondary hypophysitis, although rare, is associated with immunotherapy. The incidence of hypophysitis is considerably lower with PD-1 inhibitors such as pembrolizumab (0.5-1.5%) than with CTLA-4 inhibitors. We present a case of hypophysitis following initiation of pembrolizumab for NSCLC. Case: A 64-year-old Caucasian male was seen in Endocrinology for evaluation of abnormal TFTs with nonspecific symptoms of fatigue and malaise. He was recently diagnosed with poorly differentiated lung carcinoma with metastasis to brain. After completing XRT, he was started on pembrolizumab/trastuzumab. TFTs prior to initiation of treatment were unremarkable. He developed a mild rash and fatigue post treatment but otherwise treatment was well tolerated. TFTs at week 8 after starting ICIs showed TSH 0.09 uIU/mL (0.27-4.2), T4 0.8 ng/dL (0.9-1.7) and T3 2.2 pg/mL (2.5-4.3). MRI Sella showed enlargement of the pituitary gland and stalk suggestive of hypophysitis. Pembrolizumab was discontinued. Additional studies showed low total testosterone 19.5 ng/dL (193-740) and free testosterone 4.5 pg/mL (35-130) with inappropriately normal gonadotropins suggestive of central hypogonadism. Other pituitary axis were intact. Cosyntropin stimulation test confirmed intact HP Adrenal axis. He was started on levothyroxine and hydrocortisone (20 mg AM and 10 mg PM) for hypophysitis. His symptoms improved. He is closely being monitored with plan to repeat MRI Sella in 3 months and to re-evaluate his HP adrenal prior to weaning off steroids. Discussion: IRAEs from ICIs typically present within 6 to 12 weeks but can present several months to years later. The non-specific nature of symptoms in patients on PD-1 inhibitors can delay clinical recognition with dire consequences. Treatment involves hormone replacement and stopping immunotherapy. Though benefit of GC in patients with grades 1-2 hypophysitis is unclear, low dose corticosteroids have been used to mitigate pituitary inflammation. High dose GC although commonly used in patients with critical illness (grades 3-4), its use remains controversial as they have not shown to significantly alter overall survival. Some degree of pituitary function may recover 4-12 weeks following withdrawal of ICIs. Given the increase in use of ICIs and the serious nature of IRAEs, it is critical to be aware of clinical manifestations, diagnosis, and management of this entity. Presentation: Friday, June 16, 2023

Unveiling the Etiopathogenic Spectrum of Hypophysitis: A Narrative Review.

Hypophysitis, a rare inflammatory disorder of the pituitary gland, has seen an uptick in reported cases in recent years. Our objective is to summarize the most recent research on the etiopathogenesis, molecular mechanisms, and genetics of both primary and secondary hypophysitis. Primary autoimmune hypophysitis (PAH): During the acute phase of the disease, the pituitary gland in enlarged due to the infiltration of T and B lymphocytes. The chronic phase is characterized by progressive and irreversible pituitary atrophy. APA may play a role in the management, diagnosis, and prognosis of PAH. Specific autoantibodies such as anti-GH, anti-PIT-1, and anti-T-PIT have been found in patients with hypophysitis and hypopituitarism. A recent study suggested that a mechanism of escaping clonal deletion and mounting an immune response against self antigens can explain the unusual nature of the immune response observed in PAH patients. A cytokine array shows the presence of gamma-interferon and interleukin-17. Patients carrying mutations in the PIT1 or PROP1 genes may present PAH. Individuals carrying the HLA DQ8 haplotype are four times more likely to develop PAH. Immune checkpoint inhibitors induce hypophysitis (IIHs): IIHs is an increasingly frequent toxicity of in patients on treatment with inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1). ICIs inhibit the CTLA-4 pathway, leading to overactivation of T lymphocytes. The binding of PD-1/PD-L1 suppresses the activity of T cells, promotes the conversion of T-helpers into T-regulatory cells, and activates pro-survival signaling pathways in cancer cells. Cytokines play a crucial role in IIHs. B-cell infiltration has been observed in IIHs, suggesting that antibody-mediated pituitary injury may contribute. Genetic polymorphisms of CTLA-4 and PD-1 genes can increase the risk of IIHs. HLA alleles may also be involved in the onset of IIHs; this HLA association presents a possible alternative mechanistic hypothesis. IIHs may also be linked to a paraneoplastic syndrome triggered by ectopic expression of pituitary specific antigens. SARS-CoV-2-related hypophysitis: Recently, the literature has reported occurrences of hypophysitis associated with the SARS-CoV-2 virus; long COVID-19 may also present as infundibulo-neuro-hypophysitis. The virus enters the central nervous system because of its distinct interaction with angiotensin-converting enzyme receptors via spike proteins binding the capillary endothelium, and it directly damages the pituitary cells. The effect of SARS-CoV-2 can occur indirectly through inflammation and the release of cytokines. The exact mechanism remains ambiguous. The available data on endocrine complications associated with the SARS-CoV-2 vaccine are scant. Nonetheless, isolated cases of hypophysitis have been documented. Treatment of hypophysitis: Glucocorticoids are the cornerstone in managing primary hypophysitis, given their targeted action on inflammation. A better understanding of the etiopathogenesis and molecular mechanism of hypophysitis can lead to more effective and personalized treatment strategies.

Xanthomatous sypophysitis secondary to a ruptured Rathke's cleft cyst

Abstract Introduction Hypophysitis (HP) is a rare disease which develops secondary to chronic or acute inflammation of the pituitary gland and may cause symptoms related to pituitary dysfunction and mass compression. HP can be classified based on the anatomical location of pituitary involvement (adenohypophysitis, infundibulo-neurohypophysitis, or panhypophysitis), the etiology (primary or secondary), and the histopathology (lymphocytic, granulomatous, xanthomatous, IgG4, necrotizing, or mixed forms). Lymphocytic HP is the most common subtype of primary HP, while xanthomatous HP (XHP) is considered the rarest form, with 35 reported cases, to date. In our report, we describe a case with panhypopituitarism due to XHP secondary to the rupture of an Rathke's cleft cyst (RCC). Clinical Case A 35-year-old woman was initially admitted to a Gynecology clinic with a 2-year history of amenorrhea and headache. She was started on cabergoline 0.5 mg twice a week for macroprolactinoma. Due to persistent amenorrhea with low gonadotropins, she was referred to our Endocrinology clinic. Her pituitary function profile revealed panhypopituitarism (Table 1) and a 13×11×12 mm sized sellar mass with diffuse enhancement which sustained toward the infundibulum and dura was observed on the gadolinium-enhanced pituitary MRI. The patient underwent an endoscopic endonasal transsphenoidal approach for tumor resection and thick yellowish fluid draining from the lesion was observed (Figure 1). The histopathological diagnosis was reported as a rupture of an Rathke's cleft cyst and a xanthomatous hypophysitis. The surgery did not improve the symptoms/pituitary functions, however, headache recovered immediately after the first dose of high dose methylprednisolone treatment. Conclusion The exact mechanism by which XHP occurs still remains unclear. The development of the characteristic histopathological lesion which consists of lipid-laden “foamy” histiocytes and CD68 positive macrophages has been previously attributed to the extension of an autoimmune/lymphocytic spectrum. On the other hand, various recent case presentations have reported to consider the inflammatory process of XHP related to the rupture of a RCC. XHP is an uncommon inflammatory process of the pituitary gland which should be included in the differential diagnoses, if a patient presents with headache, panhypopituitarism and if yellowish fluid is drained from a cystic lesion intraoperatively. In agreement with the recent reports, our case presentation may also indicate a recommendation to classify XHP as secondary hypophysitis which could be caused by a ruptured cystic lesion. Here, we present a patient with XHP which developed as an inflammatory response to a ruptured RCC and the transsphenoidal surgery did not improve the symptoms/pituitary functions, while headache recovered immediately after the first dose of high dose methylprednisolone treatment.

LBODP071 Early Detection Of Immune-mediated Hypophysitis With Use Of Checkpoint Inhibitor Immunotherapy

Abstract Hypophysitis is an inflammatory infiltration of the pituitary gland. Association with cytotoxic T-lymphocyte antigen 4 (CTLA-4) targeting was described with a recommendation of discontinuing the treatment in such conditions . Hypophysitis has become more prevalent with increased use of immune checkpoint inhibitors with late detection being associated with a high morbidity and mortality. Symptomatic presentation, along with hemodynamic and serum abnormalities warrant urgent intervention as early measures prevent progression. This case is about a 60-year-old female with metastatic renal clear cell carcinoma status post right radical nephrectomy on combined nivolumab and ipilimumab (NIVO/IPI) and history notable for persistent atrial fibrillation on warfarin presented to the hospital after a fall. Eight days after her second cycle on NIVO/IPI, the patient developed hot flashes, vomiting, weakness, and vertiginous symptoms. Her exam was notable for atrial fibrillation with rapid ventricular rate and hypotension. Serology was notable for a sodium of 119 mEq/mL, prompting admission to the hospital. Due to high clinical suspicion for hypophysitis based on serological findings, the patient was given a dose of methylprednisolone then daily hydrocortisone to reverse the pituitary inflammation. Fludrocortisone was started for adrenal insufficiency. MRI of the brain with IV contrast was notable for abnormal enhancement and thickening of the pituitary stalk concerning for hypophysitis. The patient clinically improved with resolution of her dizziness, hot flashes, and vomiting. Her serum sodium improving to 132 mEq/mL. She was discharged home with immunotherapy held. Hypophysitis is a rare inflammatory disease affecting 1 in 7 million. Typical symptoms include headache, vision changes, fatigue, and hypopituitary deficiencies. Reported immunotherapies with incidences of secondary hypophysitis include CTLA-4 and PD-1 therapeutics. Immunotherapy associated hypophysitis occurs in <7% of patients. Hypophysitis is diagnosed by laboratory findings and imaging which can identify this acute process via enhancement and swelling of the pituitary gland . Management modalities include surgery, anti-inflammatory therapy, and conservative therapy. Medical management is mainly directed at the correction of pituitary hormone deficiencies and reduction of pituitary inflammation using glucocorticoid therapy . Presentation: No date and time listed

Differences between immunotherapy-induced and primary hypophysitis\u2014a multicenter retrospective study

ObjectiveImmune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH)DesignRetrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH.MethodsAll patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected.ResultsMedian time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 % of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002).ConclusionsClinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.

Th17 Cells Contribute to the Pathology of Autoimmune Hypophysitis.

Autoimmune hypophysitis is classified as primary if its origin is idiopathic and secondary if it develops as a consequence of treatment with immune checkpoint inhibitors. Expanding use of immunotherapy has been paralleled by the increasing hypophysitis prevalence. However, understanding of the immune responses driving the disease remains limited. Using a mouse model of primary hypophysitis, we have identified CD4+ T lymphocytes to be the main pituitary-infiltrating immune cell population. Functional analysis showed that they display a Th17 and Th1/Th17 phenotype. To examine involvement of proinflammatory Th1, Th17, and Th1/17 subsets in hypophysitis, we have isolated RNA from the formalin-fixed paraffin-embedded pituitary specimens from 16 hypophysitis patients (three of whom had hypophysitis secondary to immune checkpoint inhibitors), 10 patients with adenoma, and 23 normal pituitaries obtained at autopsy. Transcript levels of IFN-γ, IL-17A, IL-4, IL-10, TGF-β, CD4, CD8α, and class II MHC transactivator were analyzed by the reverse transcription-quantitative PCR (RT-qPCR). Pituitary glands of patients with hypophysitis showed significantly higher IL-17A, CD4, and class II MHC transactivator mRNA levels compared with adenoma and normal pituitaries. All three secondary hypophysitis patients showed detectable IL-17A levels, but other cytokines were not detected in their pituitaries. Levels of IFN-γ, IL-4, IL-10, and TGF-β did not differ between the groups. TGF-β transcript was found in significantly fewer hypophysitis pituitaries (2 out of 16) compared with adenoma (7 out of 10) and normal pituitaries (11 out of 23). Presence of TGF-β in two hypophysitis patients was associated with significantly lower IL-17A mRNA levels compared with hypophysitis patients with no detectable TGF-β (p = 0.03).

Idiopathic Hypophysitis

Introduction: Hypophysitis is a heterogeneous condition that leads to inflammation of the sella / suprasellar region, potentially resulting in hormonal deficiencies or mass effects. Prevalence of hypophysitis ranges from 0.2% to 0.88%. Annual incidence of hypophysitis is 1 case per 9 million individuals. We present an interesting case of idiopathic hypophysitis. Clinical Case: A 52-year-old female was evaluated for secondary hypothyroidism. Patient complained of excess fatigue, weight gain, headaches, polyuria with nocturia and vision changes. She was seen by ophthalmology for formal visual field testing revealing right superior quadrantanopia. Labs significant for TSH 4 uIU/mL (ref range 0.27-4.2uIU/mL), FT4 0.72ng/dL (ref range 0.93-1.7 ng/dL), Anti TPO ab negative, AM cortisol 8.9UG/dL, ACTH 18pg/mL, IGF1 127ng/mL, prolactin 7ng/mL, FSH 102MIU/mL, LH 41 MIU/mL. MRI sella revealed homogenous enhancement of the pituitary with convex superior margin - 0.8*1*0.9cm concerning for hyperplasia. Due to the concern for hypophysitis, an extensive inflammatory workup was pursued which was negative. She was started on thyroid hormone replacement and DDAVP. An empiric trial of high dose steroids failed to provide any relief. During workup, patient complained of transient right sided face and arm tingling, diagnosed with TIA and started on aspirin. Due to worsening headaches, a pituitary biopsy was pursued. Pathology significant for glandular tissue ruling out inflammatory, neoplastic, and infectious etiologies. Neurology diagnosed the patient with hemicrania continua. Patient is currently maintained on thyroid hormone replacement and DDAVP with close follow-up. Discussion: The incidence of hypophysitis has recently increased due to increased awareness and also due to the use of medications like ICI. Primary hypophysitis is mostly due to autoimmune etiology. Secondary hypophysitis could result from infections, neoplastic conditions or an adverse effect of medications. Clinical presentations ranges from being asymptomatic to having features of hypopituitarism. Usually presents with mass effect, visual symptoms due to the upward expansion of the pituitary gland impinging the dura mater and optic chiasm. This is followed by symptoms of hormone deficiency, central DI and hyperprolactinemia. Central AI has been reported in 20%-75%, central hypogonadism in 15%-60%, central hypothyroidism in 25%-58%, GH deficiency in 5%-41%, and prolactin deficiency in 13%-25%. Typical MRI findings include, homogeneous pituitary contrast enhancement, pituitary stalk thickening and loss of posterior pituitary bright spot, ‘figure of 8’ appearance, ‘dural tail’. Treatment consists of surgery, anti-inflammatory medications, and radiotherapy. Glucocorticoid treatment is the cornerstone for medical management; however, the overall recurrence rate is high.

Primary pituitary granulomatosis with polyangiitis and the role of pituitary biopsy, case report and literature review

Background Pituitary dysfunction (PD) in granulomatosis with polyangiitis (GPA) is a rare manifestation of the disease with an incidence of 2% and tends to occur as the disease progresses. On very rare occasions, PD can be the initial presentation of GPA. From our literature review, only 6 such cases were documented. Case Presentation We present a rare case of GPA in a 57-year-old female who primarily presented with PD and visual disturbance without any other systemic features of GPA. Her initial ANCA screen was negative and her MRI scan showed an enlarged pituitary gland with cystic changes. A pituitary biopsy confirmed the diagnosis and she was started on immunosuppressants. After completing her immunotherapy, her diabetic insipidus subsided and her vision markedly improved. Literature Review A literature search on Pubmed, Cochrane, Open Grey, and SciELO with keywords ‘granulomatosis’, ‘polyangiitis’, and ‘pituitary’ was performed. A total of 72 articles were reviewed. 6 articles were identified where PD was the presenting complaint of GPA without other systemic involvement. Discussion Secondary hypophysitis in GPA indicates pituitary inflammation resulting from systemic disease or pituitary near-lying lesions. PD in GPA tends to occur with concomitant active disease at other sites. Headache seemed to be a common presenting feature with diabetic insipidus being the most common type of PD. Tissue biopsy is essential to confirm diagnosis. Pituitary biopsy is rarely required as other organ involvement is available for safer tissue sampling. However, in our case, pituitary biopsy had a role in confirming diagnosis and avoiding treatment delay. Conclusion PD as a primary manifestation in GPA without systemic involvement is very rare and poses a diagnostic challenge. Pituitary biopsy can aid in diagnosis, allowing prompt treatment and prevention of long-term complications of untreated GPA such as permanent pituitary dysfunction. Nevertheless, the risk and benefit of pituitary surgery in each case should be weighted.

Primary and Ipilimumab-induced Hypophysitis: A Single-center Case Series

ABSTRACT Purpose To present a case series of primary and immunotherapy-related secondary hypophysitis. Methods A single-center retrospective chart review was performed at the University of British Columbia, Vancouver, Canada. Eleven cases of primary hypophysitis and 2 cases of immunotherapy-related secondary hypophysitis were included. Of the 11 primary cases, 6 were diagnosed clinically without biopsy. Results In primary hypophysitis, headache was the most common presenting symptom (6/11; 55%) and stalk enlargement the prevailing radiologic sign (8/11; 73%). Central adrenal insufficiency (4/11; 36%), central hypothyroidism (4/11; 36%), and central diabetes insipidus (CDI) (4/11; 36%) were the most common pituitary deficiencies at presentation. Initial management included surgery (4/11; 36%), supraphysiologic steroids (2/11; 18%), or observation (6/11; 55%). Outcomes assessed included radiologic improvement (8/9; 89%), improvement in mass symptoms (4/7; 57%), anterior pituitary recovery (1/7; 14%), and CDI recovery (0/4; 0%). In immunotherapy-related hypophysitis either under observation or supraphysiologic steroid therapy, the inflammatory mass resolved and pituitary dysfunction persisted. Conclusions In primary hypophysitis, the inflammatory pituitary mass typically resolves and hypopituitarism persists. In the absence of severe or progressive neurologic deficits, a presumptive clinical diagnosis and conservative medical management should be attempted. In the absence of severe features, immunotherapy-related hypophysitis may be managed effectively without the use of supraphysiologic steroids.

Secondary hypophysitis due to immune checkpoint inhibitors – case report and literature review

Secondary hypophysitis due to immune checkpoint inhibitors – case report and literature review

Ipilimumab-Induced Secondary Hypophysitis

Ipilimumab-Induced Secondary Hypophysitis

MECHANISMS IN ENDOCRINOLOGY: Hypophysitis: diagnosis and treatment.

Hypophysitis is a rare condition characterised by inflammation of the pituitary gland, usually resulting in hypopituitarism and pituitary enlargement. Pituitary inflammation can occur as a primary hypophysitis (most commonly lymphocytic, granulomatous or xanthomatous disease) or as secondary hypophysitis (as a result of systemic diseases, immunotherapy or alternative sella-based pathologies). Hypophysitis can be classified using anatomical, histopathological and aetiological criteria. Non-invasive diagnosis of hypophysitis remains elusive, and the use of currently available serum anti-pituitary antibodies are limited by low sensitivity and specificity. Newer serum markers such as anti-rabphilin 3A are yet to show consistent diagnostic value and are not yet commercially available. Traditionally considered a very rare condition, the recent recognition of IgG4-related disease and hypophysitis as a consequence of use of immune modulatory therapy has resulted in increased understanding of the pathophysiology of hypophysitis. Modern imaging techniques, histological classification and immune profiling are improving the accuracy of the diagnosis of the patient with hypophysitis. The objective of this review is to bring readers up-to-date with current understanding of conditions presenting as hypophysitis, focussing on recent advances and areas for future development. We describe the presenting features, investigation and diagnostic approach of the patient with likely hypophysitis, including existing conventional techniques and those in the research/development arena. Hypophysitis usually results in acute and persistent pituitary hormone deficiency requiring long-term replacement. Management of hypophysitis includes control of the inflammatory pituitary mass using a variety of treatment strategies including surgery and medical therapy. Glucocorticoids remain the mainstay of medical treatment but other immunosuppressive agents (e.g. azathioprine, rituximab) show benefit in some cases, but there is a need for controlled studies to inform practice.

Xanthomatous Hypophysitis Is Associated with Ruptured Rathke's Cleft Cyst.

Xanthomatous hypophysitis is a rare inflammatory disease of the pituitary gland that can mimic a neoplastic lesion clinically and radiologically. Its pathogenesis remains largely unknown, although recent evidence suggests that pituitary inflammation may occur as a secondary reaction to mucous content released from a ruptured cyst. In a series of 1221 pituitary specimens, we identified seven cases of xanthomatous hypophysitis. Six patients had complete radiological and biochemical workup preoperatively: a cystic-appearing pituitary mass was identified in all six patients (100%) with a mean size of 2.0cm (range 1.4-2.5cm) on imaging, and pituitary endocrine dysfunction was noted in five patients (83.3%). In all cases, the pituitary mass was resected through an endoscopic transsphenoidal approach. Pathological examination revealed the presence of foamy macrophages admixed with variable amounts of giant cells and chronic inflammatory cells, confirming the diagnosis of xanthomatous hypophysitis. Additionally, all cases presented with concurrent findings of ruptured Rathke's cleft cyst, with the exception of one patient who had previous surgery for a Rathke's cleft cyst, followed by recurrence and diagnosis of xanthomatous hypophysitis. While accurate distinction of hypophysitis from a pituitary neoplasm can be problematic in the preoperative setting, the identification of a cystic lesion in the sella turcica should raise the possibility of such an entity in the clinical and radiological differential diagnosis. The current series provides further evidence that xanthomatous hypophysitis predominantly occurs as a secondary reaction to a ruptured Rathke's cleft cyst; thus, it is best classified as a secondary (reactive) hypophysitis.

Pituitary Stalk Thickening

Abstract: MRI revealed enlargement of the pituitary stalk in two patients with different clinical presentations. A 60 y/o female had autoimmune hypothyroidism associated with blunted cortisol response to ACTH, while the other, a 30 y/o female had amenorrhea and polyuria with high plasma and low urinary osmolality. Keywords: Pituitary stalk thickening; Hypothyroidism; Adrenal insufficiency; Amenorrhea; Polyuria Case Report: As a result of the advances in imaging technologies, the finding of pituitary stalk lesions presents a diagnostic challenge to clinicians and endocrinologists. They are usually discovered incidentally on magnetic resonance imaging (MRI), or during the investigation of symptoms related to hypothalamic-pituitary dysfunction such as central diabetes insipidus or hypopituitarism. The etiology of these lesions may be congenital/developmental, inflammatory, infectious or neoplastic. Due to its particular location and function, the pituitary stalk is not often biopsied and diagnosis is based generally on clinical evaluation and images Report of two cases Enlargement of the pituitary stalk was found during the endocrine evaluation of two patients with the following clinical presentations. Patient 1: A 64 year old woman was admitted to the emergency room for vomiting and high blood pressure. Otherwise normal, she had been suffering from proximal muscle weakness, fatigue, reduced appetite, cognitive impairment and pre-tibial myxedema during the last two months. The patient denied glucocorticoid intake. Mild hyponatremia (132 mEq/l) and anemia (hct: 30%) were detected. TSH was high (13.74 µU/ml) with low FT4: 0.57ng/dl. Anti-peroxidase antibodies were positive. Serum potassium was normal (4.2 mEq/l). Serum morning cortisol was less than 1.0 µg/dl and ACTH was 6.7 pg/ml and 5.0 pg/ ml in two different occasions. An ACTH stimulating test (Synacthen 250.0 µg, i.m) showed a blunted cortisol response at 30 and 60 min after stimulus, confirming adrenal insufficiency. The remaining pituitary function was normal. MRI showed a thickened pituitary stalk (Figure 1). The patient improved on hydrocortisone and LT4. Patient 2: A 30 year old woman complained of amenorrhea and polyuria (9 L/day). She had high plasma and low urinary osmolality (311 mOsm/kg and 136 mOsm/kg, respectively). Low serum estradiol and gonadotropins were found. Thyroid and adrenal functions were normal. MRI showed a thickened pituitary stalk (Figure 2). She started on desmopressin (0.1 mg/day) which reduced daily diuresis by 60% and lowered plasma osmolality (290 mOsm/day). Additionally she began on estrogen and progestin replacement. Discussion: Pituitary stalk lesions may be found by chance or during the evaluation of endocrine disorders. In a series of 152 patients, the etiologies were attributed to neoplasia in 32%, inflammatory lesions 20%, and congenital anomalies in 9% and in 39% remained unknown [2]. Primary hypophysitis is rare, between 0.2 and 6.5% among pituitary pathologies. Three histopathological types are described in this category: lymphocytic, granulomatous and xanthomatous hypophysitis [3].These conditions are usually confined to the pituitary. In secondary hypophysitis, a systemic disease is the cause of the pituitary lesion: Sarcoidosis, Wegener granulomatosis, Langerhans cell histyocitosis and IgG4 related plasmatic histiocytosis may affect the pituitary. Monoclonal antibodies against the cytotoxic T-lymphocyte antigen-4 (CTLA-4) for treating metastatic cancer, may induce hypophysitis [4,5]. In the setting of immunosuppression, fungal infection, tuberculosis and toxoplasmosis may involve the pituitary gland [4]. Interestingly, these two patients showed different clinical presentations. After excluding secondary etiologies, primary hypophysitis was suspected in both [4]. Although histological confirmation is needed, biopsy of a pituitary stalk lesion is technically demanding, and must be performed by an experienced neurosurgeon. In order to avoid invasive procedures, the approach was based on clinical, biochemical and radiological features. A close follow-up is mandatory to detect new symptoms and to determine if the lesions progress over time.

Putative Infundibular And Pituitary Involvements Of Sapho Syndrome

ABSTRACT Objective: Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare, chronic, relapsing inflammatory osteoarticular disorder with dermatologic manifestations. SAPHO syndrome can be a rare cause of atypical symptoms including neurologic defects. We report a case with SAPHO syndrome with the endocrinologic defects most likely associated with SAPHO syndrome. Methods: Case report and review of the literature. Results: A 61-year-old Japanese female with SAPHO syndrome presented with polyuria and polydipsia. Pituitary magnetic resonance imaging (MRI) with gadolinium enhancement showed an enlarged infundibulum and pituitary with ring-enhancing masses located at the posterior pituitary and upper infundibulum. Extensive diagnostic workup excluded local and systemic infection, brain metastasis, and various secondary hypophysitis as the cause of the infundibular and pituitary lesions. There were spontaneous improvements in the MRI findings taken 4 months after her initial presentation....

Hypophysitis : Types and differential diagnosis

Inflammatory findings in the pituitary glands account for approximately 1 % of operations in the sellar region. Primary inflammation (e.g. lymphocytic and idiopathic granulomatous hypophysitis) have to be differentiated from secondary types (e.g. concomittant inflammation with Rathke's cleft cysts, craniopharyngiomas and germinomas) and involvement of the pituitary in generalized inflammation (IgG4-related disease, sarcoidosis and septicopyemia). Langerhans cell histiocytosis also has to be considered for the differential diagnostics. Lymphocytic hypophysitis shows lymphocytic infiltrations of varying density, predominantly of the T‑cell type. Granulomatous hypophysitis has the features of sarcoidosis and can only be diagnosed by exclusion of generalized sarcoidosis. Secondary hypophysitis has a mixed cell infiltration, especially by histiocytic infiltration and predominantly originates from ruptures or bleeding from Rathke's cleft cysts. The frequently very sparse remnants of cyst epithelium should be confirmed by pankeratin immunostaining.

Autoimmune hypophysitis

Autoimmune hypophysitis is an inflammation of the pituitary gland resulting from autoimmune response, which can be classified as primary hypophysitis and secondary hypophysitis according to the etiology. The clinical presentation includes hypopituitarism and a pituitary mass. The diagnosis is based on clinical findings and radiology, while the pathology serves as the golden standard. The treatment is aimed at reducing the size of the pituitary mass, replacing the defective hormones and decreasing hyperprolactinemia. This review is about the epidemiology, pathogenesis, diagnosis, and treatment of lymphocytic hypophysitis, hypophysitis secondary to cytotoxic T-4 blockade, and IgG4-related hypophysitis. (Chin J Endocrinol Metab, 2015, 31: 1008-1012) Key words: Autoimmune hypophysitis; Lymphocytic hypophysitis; Hypophysitis secondary to cytotoxic T-4 blockade; IgG4-related hypophysitis