Pituitary-related immune adverse events induced by programmed death Protein-1 inhibitors differ clinically from hypophysitis.

OBJECTIVE: We aimed to elucidate the clinical features of pituitary immune-related adverse events (irAEs) induced by PD-1 inhibitors in a Chinese cohort and the previous literatures. PATIENTS AND DESIGN AND MEASUREMENTS: We retrospectively analysed the clinical manifestations, laboratory examination findings, imaging features and treatments of 14 patients with pituitary irAEs caused by PD-1 inhibitors in our cohort. In addition, we searched PubMed for all English articles on pituitary irAEs induced by PD-1 inhibitors published from 1950 to 2023. A total of 47 articles were included, and the clinical characteristics of 94 patients with pituitary irAEs induced by PD-1 inhibitors in these literatures were compared to the characteristics of our cohort. RESULTS: Among the 14 patients in our cohort with pituitary irAEs induced by PD-1 inhibitors, 12 patients (85.71%, 12/14) exhibited isolated ACTH deficiency (IAD), 100.0% (14/14) of the central adrenocortical insufficiency, and 2 patients showed more than one hypothalamic-pituitary axis injury (14.29%, 2/14). Pituitary magnetic resonance imaging in all the 14 patients showed no pituitary enlargement. In previous studies we reviewed, 82.98% of the total (78/94) presented with pituitary irAEs as IAD, 100.0% (94/94) of the central adrenocortical insufficiency, and 78.33% of the patients showed no abnormality of the pituitary gland (47/60). The pituitary irAEs caused by PD-1 inhibitors did not involve typical manifestations of hypophysitis, such as pituitary enlargement, headache, visual field defects, and multiple pituitary function impairments in our cohort and the previous literatures. CONCLUSION: In our study, pituitary immune-related adverse reactions induced by PD-1 inhibitors mainly manifested isolated ACTH deficiency rather than hypophysitis.

Hypophysitis and central nervous system involvement in association with Sjögren's syndrome along with hypoparathyroidism: a case report.

BACKGROUND: Patients with autoimmune diseases can develop multiple autoimmune diseases over a long period of time, and the presence of more than one autoimmune disease in a single patient is defined as polyautoimmunity. Polyautoimmunity may be clinical evidence that autoimmune diseases share similar immunological mechanisms. CASE PRESENTATION: We report a 30-year-old woman with a unique combination of autoimmune diseases predominantly affecting the central nervous system, with hypoparathyroidism, hypophysitis, medulla involvement, and pons and temporal lobe involvement associated with primary Sjögren's syndrome (pSS), occurring independently over a long period. The patient who had a history of muscle cramps and one seizure incident, presented with vomiting and blurred vision. She was diagnosed with hypophysitis and hypoparathyroidism with calcifications in the basal ganglia and cerebellum. She recovered after four months of corticosteroid treatment for hypophysitis and was started on treatment for hypoparathyroidism. Eight months later, she developed vomiting, hiccups, vertigo, and ataxia with a focal lesion in the medulla. She recovered with immunosuppressive treatment for 2 years. Fifty-eight months after the onset of hypophysitis, she developed diplopia and dry mouth and eyes. MRI showed infiltrative lesions in the left pons and left temporal lobe. Based on positive anti-Sjögren's syndrome-related antigen A antibodies and low unstimulated whole salivary flow rate, pSS was diagnosed. She received corticosteroids and continued mycophenolate mofetil treatment with recovery of neurological symptoms. CONCLUSION: This case highlights the need for long-term follow-up to detect autoimmune disease processes involving various organs.

Hypopituitarism with secondary adrenocortical insufficiency and arginine vasopressin deficiency due to hypophysitis after COVID-19 vaccination: a case report.

BACKGROUND: Although vaccination against coronavirus disease (COVID-19) has several side effects, hypopituitarism due to hypophysitis has rarely been reported. CASE PRESENTATION: An 83-year-old healthy woman, who had received her fourth COVID-19 vaccine dose 2 days before admission, presented to the emergency department with difficulty moving. On examination, impaired consciousness (Glasgow Coma Scale: 14) and fever were observed. Computed tomography and magnetic resonance imaging of the head revealed swelling from the sella turcica to the suprasellar region. Her morning serum cortisol level was low (4.4 µg/dL) and adrenocorticotropic hormone level was normal (21.6 pg/mL). Central hypothyroidism was also suspected (thyroid stimulating hormone, 0.46 µIU/mL; free triiodothyronine, 1.86 pg/mL; free thyroxine, 0.48 ng/dL). Secondary adrenocortical insufficiency, growth hormone deficiency, delayed gonadotropin response, and elevated prolactin levels were also observed. After administration of prednisolone and levothyroxine, her consciousness recovered. On the 7th day of admission, the patient developed polyuria, and arginine vasopressin deficiency was diagnosed using a hypertonic saline test. On the 15th day, the posterior pituitary gland showed a loss of high signal intensity and the polyuria resolved spontaneously. On the 134th day, the corticotropin-releasing hormone loading test showed a normal response; however, the thyrotropin-releasing hormone stimulation test showed a low response. The patient's disease course was stable with continued thyroid and adrenal corticosteroid supplementation. CONCLUSIONS: Herein, we report a rare case of anterior hypopituitarism and arginine vasopressin deficiency secondary to hypophysitis following COVID-19 vaccination.

Pituitary hypophysitis in granulomatosis with polyangiitis (GPA): a case series.

Granulomatosis with polyangiitis (GPA) rarely involves the pituitary gland. Pituitary involvement has been reported in ~ 1% of all cases of GPA. Most commonly, pituitary swelling and inflammation results in symptoms due to pituitary mass effect and arginine vasopressin deficiency. To date, there are no pituitary-specific treatment guidelines for this rare condition. We present three patients with GPA-related hypophysitis highlighting the spectrum of pituitary involvement. All three patients were successfully treated with immunosuppressive regimens that included rituximab (RTX). Following remission induction with high-dose glucocorticoids, patients received 6 monthly RTX for remission maintenance. RTX was well tolerated without significant side effects.

A case of hypophysitis after COVID-19 vaccination with a detection of anti-pituitary antibody, with review of literature.

COVID-19 vaccines have resulted in a remarkable reduction in both the morbidity and mortality associated with COVID-19. However, there are reports of endocrine rare clinical conditions linked to COVID-19 vaccination. In this report, we present a case of hypophysitis following COVID-19 vaccination and review the literature on this condition. This case involved a 72-year-old male with type 1 diabetes who experienced symptoms such as vomiting, appetite loss, and headaches following his fifth COVID-19 vaccine dose. He was diagnosed with secondary adrenal insufficiency; subsequent assessment revealed an enlarged pituitary gland. Unlike previous cases, our patient has partial recovery from pituitary insufficiency, and his pituitary function gradually improved over time. Anti-pituitary antibodies (APAs) against corticotrophs, thyrotrophs, gonadotrophs, and folliculo stellate cells (FSCs) were detected in serum samples taken 3 months after onset. Hypophysitis after COVID-19 vaccination is a rare clinical condition, with only eight cases reported by the end of 2023, most occurring after the initial or second vaccination. Symptoms of hypophysitis after COVID-19 vaccination are similar to those of classic pituitary dysfunction. Pituitary insufficiency is persistent, with five of the above eight patients presenting posterior pituitary dysfunction and three patients presenting only anterior pituitary dysfunction. Two of those eight patients had autoimmune diseases. Our case suggests a potential link between acquired immunity, APA production, and pituitary damage. To elucidate the etiology of hypophysitis associated with COVID-19 vaccination, detailed investigation of patients with nonspecific symptoms after vaccination against COVID-19 is necessary.

A case series of adrenal insufficiency (likely due to hypophysitis) in cancer patients treated with immune checkpoint inhibitors.

The number of approved immune checkpoint inhibitors (ICIs) and their indications have significantly increased over the past decade. Immune-related adverse effects (irAEs) of ICIs vary widely in presentation and symptoms and can present diagnostic challenges to emergency department (ED) physicians. Moreover, when ICIs are combined with radiotherapy, cytotoxic chemotherapy, or targeted therapy, the attribution of signs and symptoms to an immune-related cause is even more difficult. Here, we report a series of 5 ED cases of adrenal insufficiency in ICI-treated cancer patients. All 5 patients presented with severe fatigue and nausea. Four patients definitely had and one patient possibly had central adrenal insufficiency, and 4 patients had undetectable serum cortisol levels. The majority of the patients had nonspecific symptoms that were not recognized at their first ED presentation. These cases illustrate the need for a heightened level of suspicion for adrenal insufficiency in ICI-treated cancer patients with hypotension, nausea and/or vomiting, abdominal pain, fatigue, or hypoglycemia. As ICI use increases, irAE-associated oncologic emergencies will become more prevalent. Thus, ED physicians must update their knowledge regarding the diagnosis and management of irAEs and routinely inquire about the specific antineoplastic therapies that their ED patients with cancer are receiving. A random cortisol level (results readily available in most EDs) with interpretation taking the circadian rhythm and the current level of physiological stress into consideration can inform the differential diagnosis and whether further investigation of this potential irAE is warranted.

[Clinical characteristics of programmed cell death-1 inhibitor-associated hypophysitis].

Objective: To explore the clinical features of programmed cell death-1 (PD-1) inhibitor-associated hypophysitis and improve the understanding of the disease. Methods: For the present retrospective case series study, the clinical data of patients with PD-1 inhibitor-associated hypophysitis who were treated at the Affiliated Hospital of Hebei University and the 3rd Hospital of Hebei Medical University from January 2020 to May 2023 were collected for analysis of clinical manifestations and prognosis. Results: Fifteen cases of PD-1 inhibitor-induced hypophysitis were included, with 13 males and 2 females. The mean age of onset was (62.1±7.5) years, and the median time of onset was 6.5 (4.7, 11.6) cycles of PD-1 inhibitor. At diagnosis, 14 patients complained of gastrointestinal symptoms, and 12 patients complained of fatigue. There were 12, 1, 1, 5, and 1 cases of hyponatremia, hypokalemia, hypoglycemia, hypotension, and fever, respectively. Secondary adrenocortical insufficiency occurred in all cases. Moreover, four patients had secondary hypothyroidism, and two patients had secondary hypogonadism. Posterior pituitary hypofunction was not found. Pituitary MRI showed one case each of vacuolar sella turcica, pituitary cystic lesion, pituitary stalk slightly shifted to the left, high metabolism in the sella turcica, and pituitary abnormal signal, while no abnormalities were found in 11 cases. The follow-up time was (47.66±11.93) weeks. At the last follow-up, one patient's serum levels of adrenocorticotropic hormone and cortisol returned to normal. Conclusions: Hypophysitis associated with PD-1 inhibitors occurs later, and gastrointestinal symptoms and fatigue are the most common clinical manifestations. PD-1 inhibitor-associated hypophysitis mainly manifests as adrenocortical hypofunction, and some cases manifest as hypothyroidism and hypogonadism. In addition, patients with PD-1 inhibitor-associated hypophysitis show no obvious imaging changes in the pituitary gland.

Preferential B cell differentiation by combined immune checkpoint blockade for renal cell carcinoma is associated with clinical response and autoimmune reactions.

Combined immune checkpoint blockade (ICB) is effective therapy for renal cell carcinoma (RCC). However, the dynamic changes in circulating B cells induced by combined ICB have not been clarified. The present study prospectively examined 22 patients scheduled to receive ICB for unresectable or metastatic RCC between March 2018 and August 2021. Eleven patients received combined therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), and the other 11 patients received nivolumab monotherapy. Comprehensive phenotypes of circulating immune cells obtained prior to and after ICB therapy were analyzed by flow cytometry. Although the proportion of naïve B cells among total B cells was significantly decreased, that of switched memory B cells was significantly increased after combined therapy. In responders, the proportion of B cells among peripheral blood mononuclear cells was significantly higher prior to ICB therapy, and the proportion of switched memory B cells among total B cells tended to increase after ICB therapy. Of note, the proportion of plasmablasts among total B cells was significantly increased after ICB therapy in patients who developed severe immune-related adverse events (irAEs), and the proportion of B cells among peripheral blood decreased significantly. Furthermore, in four of five patients who developed immune-related hypophysitis following combined therapy, anti-pituitary antibody was detected in the serum. These results suggested that immune-related hypophysitis was closely related to the increase in circulating plasmablasts. Collectively, this study suggests that combined ICB promotes the differentiation of B cell populations, which is associated with efficient tumor suppression and development of irAEs.

Hypophysitis and Secondary Adrenal Insufficiency From Immune Checkpoint Inhibitors: Diagnostic Challenges and Link With Survival.

BACKGROUND: Hypophysitis is a serious adverse event stemming from immune checkpoint inhibitor (ICI) therapy for malignancy. This study aimed to characterize ICI-induced hypophysitis, identify diagnostic challenges, and evaluate an association with survival in a large cancer cohort. METHODS: We performed a retrospective cohort study of adult patients with cancer who received ICIs between December 1, 2012, and December 31, 2019. We identified 839 patients who received CTLA-4, PD-1, or PD-L1 inhibitors or a combination thereof who were followed for a median of 19.4 months. Hypophysitis was defined as MRI evidence of pituitary gland and/or stalk enlargement or biochemical evidence of hypopituitarism if not explained by another etiology. RESULTS: A total of 16 (1.9%) patients developed hypophysitis a median of 7 months after ICI initiation, with most patients having melanoma (9/16; 56.2%) or renal cell carcinoma (4/16; 25%). Two patients also had exogenous glucocorticoid exposure but exhibited secondary hypothyroidism and secondary adrenal insufficiency (AI). Median age at the start of ICI was 61.3 years and 57% were men. Patients who developed hypophysitis were younger compared with those who did not develop hypophysitis (median age, 57 vs 65 years; P=.011). Hypophysitis occurred most frequently after combination therapy (13.7%) compared with CTLA-4 monotherapy (1.9%), PD-1 monotherapy (1.2%), and PD-L1 monotherapy (0.8%) (P<.0001). Pituitary gland enlargement on MRI occurred more frequently after CTLA-4 inhibitor monotherapy or combination therapy (5/7; 71.4%) compared with PD-1/PD-L1 inhibitor monotherapy (1/6; 16.7%). The survival benefit of hypophysitis was not apparent after addressing immortal time bias and adjusting for other variables affecting patient outcomes. CONCLUSIONS: Secondary AI occurred in all patients, and secondary hypothyroidism occurred in half. Classic pituitary gland enlargement is usually absent in PD-1/PD-L1 inhibitor-induced hypophysitis. Further pituitary evaluation must be conducted to differentiate secondary AI resulting from exogenous glucocorticoids and hypophysitis in patients with cancer receiving ICIs. The link between hypophysitis and ICI efficacy needs further investigation.

A case of pituitary gland abscess associated with granulomatous hypophysitis.

BACKGROUND: Granulomatous hypophysitis is a rare disease that presents with chronic inflammation of the pituitary gland. In this study, we reported a case of granulomatous hypophysitis associated with a pituitary abscess. CASE PRESENTATION: A 39-year-old woman presented with a 2-year history of infertility. For the past six months, she has suffered from amenorrhea, decreased libido, headaches, and vertigo. She was referred to our hospital with a suspected diagnosis of nonfunctioning pituitary adenoma based on her presentation and brain MRI findings. She underwent trans-sphenoidal surgery (TSS). Direct observation during surgery revealed drainage of malodor pus and pituitary gland abscess. The histopathological evaluation also showed granulomatous hypophysitis and neutrophilic microabscess formation. The patient was initially treated with high doses of ceftriaxone (2 g twice daily) and metronidazole (500 mg (mg) four times per day). Also, the patient received cortisol replacement therapy after the operation. After obtaining the antibiogram and culture results, the treatment regimen was continued for 4 weeks postoperatively, followed by amoxicillin-clavulanate (500/125 mg three times daily) for a total duration of 12 weeks. CONCLUSION: The patient recovered uneventfully and the postoperative MRI was normal without any remnant lesions.

Concurrent IgG4-related hypophysitis and clinically nonfunctioning gonadotroph pituitary neuroendocrine tumor.

BACKGROUND: Some patients develop immunoglobulin G4 (IgG4)-related hypophysitis associated with systemic diseases. More than 30 cases of IgG4-related hypophysitis have been reported. However, biopsy has rarely been performed in these patients, and none have had an associated pituitary neuroendocrine tumor (PitNET). We present a case of concurrent IgG4-related hypophysitis and PitNET. CASE PRESENTATION: A 56-year-old Japanese man arrived at the hospital with visual impairment, bitemporal hemianopia, and right abducens nerve palsy. Magnetic resonance imaging revealed pituitary body and stalk swelling as well as a small poorly enhanced right anterior lobe mass. Laboratory and loading test results suggested hypopituitarism. Because IgG4 level was elevated, a systemic examination was performed; multiple nodules were found in both lung fields. The diagnosis was based on an endoscopic transnasal biopsy of the pituitary gland. A histopathological examination revealed a marked infiltration of plasma cells into the pituitary gland, which was strongly positive for IgG4. The histological features of the resected tumor were consistent with those of gonadotroph PitNET, which was immunohistochemically positive for follicle-stimulating hormone-ß and steroidogenic factor-1, and no plasma cell infiltration was observed. Based on the histopathological examination results, steroid therapy was initiated, which reduced pituitary gland size and serum IgG4 levels. DISCUSSION AND CONCLUSIONS: This is the first reported case of IgG4-related hypophysitis with PitNET. Although no pathological findings indicating a relationship between the two conditions were found, we were able to preoperatively differentiate multiple lesions via detailed diagnostic imaging.

Central diabetes insipidus: a late sequela of BNT162b2 SARS-CoV-2 mRNA vaccine?

BACKGROUND: The development of an effective vaccine is a powerful tool to contain the global spread of coronavirus disease 2019 (COVID-19). Still, it raises potential safety concerns about the subsequent enhancement of associated immunopathology. Increasing evidence shows that the endocrine system, including the hypophysis, may be involved in COVID-19. Moreover, occasional but increasing reports of endocrine disorders involving the thyroid have been reported after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Among them, a few cases encompass the pituitary. Here we report a rare case of central diabetes insipidus following SARS-CoV-2 vaccination. CASE PRESENTATION: We report a 59-year-old female patient with a 25-year history of Crohn's disease in long-term remission, who presented with sudden onset of polyuria eight weeks after administration of an mRNA SARS-CoV-2 vaccination. Laboratory evaluation was consistent with isolated central diabetes insipidus. Magnetic resonance imaging displayed involvement of the infundibulum and the posterior hypophysis. Eighteen months after the vaccination, she is still under desmopressin treatment and had stable pituitary stalk thickening on magnetic resonance imaging. Although Crohn's disease-associated hypophysitis has been reported, it is scarce. In the absence of other recognizable causes of hypophysitis, we believe the involvement of the hypophysis in our patient may have been triggered by the SARS-CoV-2 vaccine. CONCLUSIONS: We report a rare case of central diabetes insipidus potentially associated with SARS-CoV-2 mRNA vaccination. Further studies are needed to understand better the mechanisms underlying autoimmune endocrinopathies development in the context of COVID-19 infection and SARS-CoV-2 vaccination.

Paraneoplastic autoimmune hypophysitis: a novel form of paraneoplastic endocrine syndrome.

Paraneoplastic syndromes are defined by symptoms or signs resulting from damage to organs or tissues that are remote from the site of malignant neoplasms or its metastasis. They are due to tumor secretion of functional hormones or peptides or are related to immune cross-reactivity with the host tissue. In particular, paraneoplastic endocrine syndromes are mainly caused by ectopic hormone production by the tumor such as PTHrP in humoral hypercalcemia in malignancy and ACTH in ectopic ACTH syndrome. Recently, it has been reported that a specific form of hypophysitis is caused as an immune-mediated paraneoplastic syndrome; paraneoplastic autoimmune hypophysitis, in which an ectopic pituitary antigen expression in the tumor evoked autoimmunity against pituitary-specific antigens, resulting in hypophysitis and exhibiting the injury of specific anterior pituitary cells by cytotoxic T cells. This novel clinical entity, paraneoplastic autoimmune hypophysitis consists of several conditions such as anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and immune checkpoint inhibitor-related hypophysitis with common mechanisms. These conditions can explain at least in part, the underlying mechanisms of acquired specific pituitary hormone deficiencies. In addition, it is important to apply a comprehensive discipline of onco-immuno-endocrinology to understand the pathophysiology and this approach; the expansion and application of immune-mediated paraneoplastic syndrome to endocrine diseases may give a new clue to understand pathophysiology of the autoimmunity against endocrine organs.

Lactotroph PitNET/adenoma associated to granulomatous hypophysitis in a patient with Crohn's disease: A case report.

Granulomatous hypophysitis is a rare and poorly understood condition. Although certain cases are treated as primary pituitary autoimmune disorders, rare cases may be associated with pituitary neuroendocrine tumours (PitNETs) and systemic inflammatory diseases. Here, we report a case of a 47-year-old man that underwent endoscopic trans-sphenoidal excision of a pituitary mass diagnosed as PitNET. On histologic evaluation, the neoplasm showed an admixture of granulomas with extensive inflammatory infiltrate and lactotroph PitNET/adenoma. Careful anamnestic examination revealed a diagnosis of Crohn's disease 20 years prior. Although rarely done, both PitNET and Crohn's disease may be associated with granulomatous hypophysitis, and our patient had both conditions. During the 6-year follow-up, PitNETs and hypophysitis did not recur, while Crohn's disease was only partially controlled by medical therapy. To our knowledge, this is the first description of association of granulomatous hypophysitis, PitNET and Crohn's disease.

Hypophysitis: Defining Histopathologic Variants and a Review of Emerging Clinical Causative Entities.

Inflammatory disease of the pituitary gland is known as hypophysitis. There are multiple histological subtypes, the most common being lymphocytic, and the pathogenesis is variable and diverse. Hypophysitis can be primary and idiopathic or autoimmune related, or secondary to local lesions, systemic disease, medications, and more. Although hypophysitis was previously accepted as an exceedingly rare diagnosis, a greater understanding of the disease process and new insights into possible etiologic sources have contributed to an increased frequency of recognition. This review provides an overview of hypophysitis, its causes, and detection strategies and management.

Hypophysitis secondary to pembrolizumab: a case report and review of the literature.

Pembrolizumab is a mAb against the programmed cell death protein-1 (PD-1). It has been approved for the treatment of advanced melanoma (unresectable or metastatic) in adults. Side effects associated with the use of anti-PD-1 are usually considered well tolerated; nevertheless, there are immune-related adverse events that may require treatment discontinuation. A 79-year-old man diagnosed with stage IV right scapular melanoma experienced unspecific symptoms and alterations of the hypothalamus-hypophysis axis after six cycles with pembrolizumab. The case was compatible with immune-related hypophysitis. Autoimmune thyroiditis and primary hypophysitis were excluded and toxicity due to pembrolizumab was considered the cause of hypophysitis. Pembrolizumab was discontinued and toxicity was managed with corticosteroids and hormonal replacement therapy (HRT). After 7 months of follow-up, symptoms were controlled with HRT but thyrotropin and corticotropin hormones had not recovered. It was decided not to reintroduce immunotherapy. Although endocrine disorders are common with the use of anti-PD-1, hypophysitis is very rare. However, clinical signs and symptoms can be nonspecific, therefore, it has probably been underdiagnosed. Monitoring hormones before and during the treatment is important for an early diagnosis and also to replace the alterations with HRT to control the symptoms. Hormonal function does not always recover, but it does not mean immunotherapy cannot be restarted and it should be evaluated in every case.

Differences between immunotherapy-induced and primary hypophysitis-a multicenter retrospective study.

OBJECTIVE: Immune 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) DESIGN: Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH. METHODS: All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected. RESULTS: Median 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). CONCLUSIONS: Clinically, 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.

Preoperative differentiation of hypophysitis and pituitary adenomas using a novel clinicoradiologic scoring system.

PURPOSE: Hypophysitis can clinically and radiologically mimic other nonfunctioning masses of the sella turcica, complicating preoperative diagnosis. While sellar masses may be treated surgically, hypophysitis is often treated medically, so differentiating between them facilitates optimal management. The objective of our study was to develop a scoring system for the preoperative diagnosis of hypophysitis. METHODS: A thorough literature review identified published hypophysitis cases, which were compared to a retrospective group of non-functioning pituitary adenomas (NFA) from our institution. A preoperative hypophysitis scoring system was developed and internally validated. RESULTS: Fifty-six pathologically confirmed hypophysitis cases were identified in the literature. After excluding individual cases with missing values, 18 hypophysitis cases were compared to an age- and sex-matched control group of 56 NFAs. Diabetes insipidus (DI) (p < 0.001), infundibular thickening (p < 0.001), absence of cavernous sinus invasion (CSI) (p < 0.001), relation to pregnancy (p = 0.002), and absence of visual symptoms (p = 0.007) were significantly associated with hypophysitis. Stepwise logistic regression identified DI and infundibular thickening as positive predictors of hypophysitis. CSI and visual symptoms were negative predictors. A 6-point hypophysitis-risk scoring system was derived: + 2 for DI, + 2 for absence of CSI, + 1 for infundibular thickening, + 1 for absence of visual symptoms. Scores ≥ 3 supported a diagnosis of hypophysitis (AUC 0.96, sensitivity 100%, specificity 75%). The scoring system identified 100% of hypophysitis cases at our institution with an estimated 24.7% false-positive rate. CONCLUSIONS: The proposed scoring system may aid preoperative diagnosis of hypophysitis, preventing unnecessary surgery in these patients.

Discrimination between non-functioning pituitary adenomas and hypophysitis using machine learning methods based on magnetic resonance imaging­derived texture features.

PURPOSE: Hypophysitis is a heterogeneous condition that includes inflammation of the pituitary gland and infundibulum, and it can cause symptoms related to mass effects and hormonal deficiencies. We aimed to evaluate the potential role of machine learning methods in differentiating hypophysitis from non-functioning pituitary adenomas. METHODS: The radiomic parameters obtained from T1A-C images were used. Among the radiomic parameters, parameters capable of distinguishing between hypophysitis and non-functioning pituitary adenomas were selected. In order to avoid the effects of confounding factors and to improve the performance of the classifiers, parameters with high correlation with each other were eliminated. Machine learning algorithms were performed with the combination of gray-level run-length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray-level co-occurrence entropy. RESULTS: A total of 34 patients were included, 17 of whom had hypophysitis and 17 had non-functioning pituitary adenomas. Among the 38 radiomics parameters obtained from post-contrast T1-weighted images, 10 tissue features that could differentiate the lesions were selected. Machine learning algorithms were performed using three selected parameters; gray level run length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray level co-occurrence entropy. Error matrices were calculated by using the machine learning algorithm and it was seen that support vector machines showed the best performance in distinguishing the two lesion types. CONCLUSIONS: Our analysis reported that support vector machines showed the best performance in distinguishing hypophysitis from non-functioning pituitary adenomas, emphasizing the importance of machine learning in differentiating the two lesions.

Generating novel pituitary datasets from open-source imaging data and deep volumetric segmentation.

PURPOSE: The estimated incidence of pituitary adenomas in the general population is 10-30%, yet radiographic diagnosis remains a challenge. Diagnosis is complicated by the heterogeneity of radiographic features in both normal (e.g. complex anatomy, pregnancy) and pathologic states (e.g. primary endocrinopathy, hypophysitis). Clinical symptoms and laboratory testing are often equivocal, which can result in misdiagnosis or unnecessary specialist referrals. Computer vision models can aid in pituitary adenoma diagnosis; however, a major challenge to model development is the lack of dedicated pituitary imaging datasets. We hypothesized that deep volumetric segmentation models trained to extract the sellar and parasellar region from existing whole-brain MRI scans could be used to generate a novel dataset of pituitary imaging. METHODS: Six open-source whole-brain MRI datasets, created for research purposes, were included for model development. Deep learning-based volumetric segmentation models were trained using 318 manually annotated MRI scans from a single open-source MRI dataset. Out-of-distribution volumetric segmentation performance was then tested on 418 MRIs from five held-out research datasets. RESULTS: On our annotated images, agreement between manual and model volumetric segmentations was high. Dice scores (a measure of overlap) ranged 0.76-0.82 for both in-distribution and out-of-distribution model testing. In total, 6,755 MRIs from six data sources were included in the final generated pituitary dataset. CONCLUSIONS: We present the first and largest dataset of pituitary imaging constructed using existing MRI data and deep volumetric segmentation models trained to identify sellar and parasellar anatomy. The model generalizes well across patient populations and MRI scanner types. We hope our pituitary dataset will be an integral part of future machine learning research on pituitary pathologies.