Xanthomatous Hypophysitis: A Case Report and Comprehensive Literature Review.

Purpose: Xanthomatous hypophysitis (XHP) is an extremely rare form of primary hypophysitis for which there is a lack of clinical experience. A comprehensive understanding of its clinical characteristics, diagnosis and treatment is needed. Methods: Here, we report a case study and conduct a systematic review of XHP. Thirty-six cases were included, and their clinical manifestations, endocrine assessment, imaging features, treatment and follow-up data were collected and analyzed. Results: The mean age at diagnosis was 39.1 years, and females were predominant (75.0%). The most common symptom was headache (68.6%), and 66.7% of female patients presented menstrual disorders. The most common pituitary dysfunction was growth hormone (GH) deficiency. More than half of patients exhibited central diabetes insipidus (CDI). The majority of patients had an imaging presentation of a cystic lesion with peripheral enhancement. Pituitary stalk thickening was observed in half of the patients. Total lesion resection was achieved in 57.1% of cases. The recurrence rate after partial resection and biopsy was significantly higher than that after total lesion resection (57.1% vs. 0.0%, P = 0.0147). The most common pituitary hormone abnormalities to resolve after surgery were hyperprolactinemia (100.0%) and GH deficiency (91.7%). The typical pathological feature was inflammatory infiltration of foamy histiocytes, which showed positivity for CD68. Conclusion: Diagnosis of XHP is difficult when relying on clinical symptoms and imaging features. Therefore, surgical histopathology is necessary. Based on the available evidence, total lesion resection is recommended for treatment. However, the long-term prognosis for this rare disease remains unclear.

Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH.

PURPOSE: Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis. METHODS: A retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis. RESULTS AND CONCLUSIONS: Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P < 0.001), TSH index (P < 0.001) and standardised TSH index (P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis.

Corticotropic insufficiency in a monocentric prospective cohort of patients with lung cancer treated with nivolumab: Prevalence and etiology.

INTRODUCTION: Cancer therapy has greatly progressed in the past few years, due to development of immune checkpoint proteins. These immunotherapies, when applied to eligible patients, have significantly reduced mortality but are prone to induce immune side-effects, including pituitary disorder and low adreno-corticotropic hormone (ACTH) and cortisol levels. We aimed to assess the prevalence and etiology of corticotropic insufficiency through a systematic screening of cortisol and ACTH levels in patients with lung cancer treated with nivolumab perfusion. MATERIAL AND METHODS: All patients from our Center with indications for nivolumab treatment for pulmonary squamous cell carcinoma or adenocarcinoma resistant to chemotherapy were successively included and underwent cortisol and ACTH assay before each nivolumab perfusion. When cortisol was below normal without ACTH elevation, we screened for pituitary metastasis, hypophysitis or corticosteroid treatment that could explain the corticotropic insufficiency. RESULTS: Data from 75 patients (80.0% men, 20.0% women) showed 10.7% asymptomatic corticotropic insufficiency, with a mean cortisol level of 2.76±1.27µg/dl. Diagnosis was made during the first 2 months of nivolumab treatment in 88% of cases. Corticosteroid treatment explained the low cortisol level in 25.0% of cases. No pituitary metastases were found. Hypophysitis was suspected in 75.0% of cases. CONCLUSION: In a 75-patient cohort with non-small cell lung cancer treated with the PD1 antibody nivolumab and systematically screened for cortisol abnormalities, 10.7% of patients showed asymptomatic corticotropic insufficiency. Excluding corticotropic insufficiency secondary to corticosteroid treatment, 8.0% of patients presented cortisol level<5µg/dl attributed to hypophysitis. Cortisol screening enables hydrocortisone replacement treatment to be prescribed if necessary, preventing risk of adrenal crisis.

Primary hypophysitis: Experience of a Single Tertiary Center.

PURPOSE: The authors review the clinical outcomes of patients with primary hypophysitis (PH). METHODS: Patients with PH who were followed up between 2007 and 2018 at our clinic were evaluated. Clinical, endocrinologic, pathologic, radiologic findings and treatment modalities were assessed. RESULTS: Seventeen patients with PH were assessed. The median follow-up was 24 (range, 6-84) months. Histologic confirmation was available in 8 patients (6 lymphocytic hypophysitis, 1 lymphocytic-granulomatous hypophysitis, 1 xanthomatous hypophysitis). None of the cases were diagnosed after pregnancy. Two patients had an autoimmune disease. The most commonly seen symptom was headache. The most common anterior pituitary deficiencies were hypocortisolemia and hypothyroidism. The radiologic findings of the patients at the time of diagnosis revealed various results including space-occupying lesion (41.2%), loss of posterior hypophysis bright spot (47.1%), pituitary stalk thickening (41.2%), uniform contrast enhancement (17.6%), partially empty sella (11.8%), optic chiasm compression (11.8%). The most frequent initial treatment modality was observation. Ten patients who were followed up conservatively had no endocrinologic deterioration; additional treatment was not needed in 8 of these 10 patients. The second most frequent initial treatment modality was pituitary surgery. Five patients received steroid treatment. We found serious adverse effects during steroid treatment in 3 of 5 (60%) patients; unilateral avascular necrosis of the femoral head (n=2), diabetes mellitus(n=1). CONCLUSION: Correctly diagnosing PH and giving appropriate treatment is challenging. It is unclear whether active treatment with steroids improves clinical outcomes. The serious adverse effects of steroids are also taken into account. Observation, surgery and/or radiotherapy can be appropriate treatment modalities for selected patients.

Central diabetes insipidus related to anti-programmed cell-death 1 protein active immunotherapy.

Cancer immunotherapy is a breakthrough strategy entwined with toxicity. Immune-related hypophysitis is conventionally considered distinctive of cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. Immune-related central diabetes insipidus (CDI) is exceptional. CDI rarely manifests as hypernatremia, which is almost always euvolemic. We report a 71-years-old male patient with advanced lung cancer who experienced severe chronic hypernatremia presented as alterations in mental status five months after initiation of treatment with the anti-PD-1 checkpoint inhibitor nivolumab. Combination of persistenthypernatremia, polyuria, high plasma osmolality and hyposthenuria raised suspicion of diabetes insipidus, prompting measurement of serum concentration of arginine vasopressin(AVP). The inappropriately undetectable serum levels of AVP confirmed central diabetes insipidus (CDI). Nivolumab-related hypophysitis was recognized as possible cause of CDI. Further hormonal assessment excluded any endocrinopathy indicating disorder of posterior pituitary. Pituitary MRI was normal with persistence of hyperintensity of posterior pituitary on T1-weighted images (bright spot). The patient was scheduled to receive 1-deamino-8-D-arginine vasopressin (DDAVP), but he died suddenly due to cardiac arrest before initiation of treatment. Our report describes the first case of nivolumab related CDI, building on existing literature through: (I) underscoring hypovolemic hypernatremia as CDI manifestation; (ii) bringing into spotlight the rare anti-PD-1 treatment related hypophysitis; (iii) enriching the limited evidence on immune-related CDI. Increased awareness of nivolumab related CDI will enable prompt recognition and therapeutic intervention.

MANAGEMENT OF ENDOCRINE DISEASE: Immune check point inhibitors-induced hypophysitis.

In recent years, the development of immunotherapy has constituted a revolution in the therapy for many cancers, with a specific toxicity profile including endocrine immune-related adverse events. Immune check point inhibitors (ICI)-induced hypophysitis is a common endocrine side effect, particularly with CTLA-4 antibodies and combination therapy, with frequent hormonal deficiencies at diagnosis. It can be difficult to evoke such diagnosis as the initial clinical symptoms are not specific (headache, asthenia…); thus, patients receiving such immunomodulatory therapies should be closely monitored by systematic hormone measurements, especially in the first weeks of treatment. Usually, hormonal deficiencies improve, except for corticotroph function. Despite a lack of large prospective studies on ICI-induced hypophysitis, some detailed longitudinal cohort studies have focused on such cases of hypophysitis and allow for optimal monitoring, follow-up and management of patients with this immune-related adverse event. In the case of ICI-induced hypophysitis, patients need long-term multidisciplinary follow-up, with specific education for those patients with corticotropin deficiency to allow them to be autonomous with their treatment. In this review, based on a clinical case, we detail the most relevant and novel aspects related to the incidence, diagnosis, treatment, evolution and management of hypophysitis induced by immunotherapy, with a focus on possible mechanisms and current recommendations and guidelines. Lastly, we emphasize several key points, such as the absence of indication to systematically treat with high-dose glucocorticoid and the pursuit of immunotherapy in such hypophysitis. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

Clinical and hormonal characteristics of patients with different types of hypophysitis: a single-center experience.

OBJECTIVE: The inflammation of the pituitary gland is known as hypophysitis. It is a rare disease accounting for approximately 0.24%-0.88% of all pituitary diseases. The natural course of hypophysitis is variable. Main forms are histologically classified as lymphocytic, granulomatous, IgG4 related and xanthomatous. We aim to present our patients with hypophysitis and compare clinical, laboratory and radiological features. SUBJECTS AND METHODS: We retrospectively reviewed our database of 1.293 patients diagnosed with pituitary diseases between 2010 and 2017. Twelve patients with hypophysitis were identified. Demographical data, clinical features, endocrinological dysfunction, imaging findings, treatment courses and follow-up periods were evaluated. RESULTS: The frequency of hypophysitis was found 0.93% in all cases of the pituitary disease. Twelve patients (nine females and three males), ages between 17-61 years, were evaluated. The characteristic features of our patients tended to be predominantly female and young. Diagnosis of hypophysitis was made after pituitary biopsy in four patients, and in eight patients after pituitary operation due to adenoma. Headache (67%) and visual problems (33%) were the most frequent nonendocrine symptoms. Anterior pituitary hormone deficiencies (63.7%) and/or diabetes insipidus (17%) were seen among patients. According to histopathological forms, four had lymphocytic, seven had granulomatous and one had xanthogranulomatous types. Contrast enhancement heterogeneous and thickened pituitary stalk were the most common radiological alterations. CONCLUSION: Hypophysitis should be considered in the differential diagnosis of sellar masses. It can mimic pituitary adenomas in radiological and endocrinological aspects. The different patterns of pituitary hormone deficiencies may be seen in the course of the disease.

Clinical and hormonal characteristics of patients with different types of hypophysitis: a single-center experience

ABSTRACT Objective: The inflammation of the pituitary gland is known as hypophysitis. It is a rare disease accounting for approximately 0.24%-0.88% of all pituitary diseases. The natural course of hypophysitis is variable. Main forms are histologically classified as lymphocytic, granulomatous, IgG4 related and xanthomatous. We aim to present our patients with hypophysitis and compare clinical, laboratory and radiological features. Subjects and methods: We retrospectively reviewed our database of 1.293 patients diagnosed with pituitary diseases between 2010 and 2017. Twelve patients with hypophysitis were identified. Demographical data, clinical features, endocrinological dysfunction, imaging findings, treatment courses and follow-up periods were evaluated. Results: The frequency of hypophysitis was found 0.93% in all cases of the pituitary disease. Twelve patients (nine females and three males), ages between 17-61 years, were evaluated. The characteristic features of our patients tended to be predominantly female and young. Diagnosis of hypophysitis was made after pituitary biopsy in four patients, and in eight patients after pituitary operation due to adenoma. Headache (67%) and visual problems (33%) were the most frequent nonendocrine symptoms. Anterior pituitary hormone deficiencies (63.7%) and/or diabetes insipidus (17%) were seen among patients. According to histopathological forms, four had lymphocytic, seven had granulomatous and one had xanthogranulomatous types. Contrast enhancement heterogeneous and thickened pituitary stalk were the most common radiological alterations. Conclusion: Hypophysitis should be considered in the differential diagnosis of sellar masses. It can mimic pituitary adenomas in radiological and endocrinological aspects. The different patterns of pituitary hormone deficiencies may be seen in the course of the disease.

Fall in thyroid stimulating hormone (TSH) may be an early marker of ipilimumab-induced hypophysitis.

PURPOSE: Hypophysitis develops in up to 19% of melanoma patients treated with ipilimumab, a cytotoxic T-lymphocyte antigen-4 antibody. Early detection may avert life-threatening hypopituitarism. We aimed to assess the incidence of ipilimumab-induced hypophysitis (IH) at a quaternary melanoma referral centre, and to determine whether cortisol or thyroid stimulating hormone (TSH) monitoring could predict IH onset. METHODS: We performed a retrospective cohort study of ipilimumab-treated patients at a quaternary melanoma referral centre in Australia. The inclusion criteria were patients with metastatic or unresectable melanoma treated with ipilimumab monotherapy, and cortisol and TSH measurements prior to ≥ 2 infusions. The main outcomes were IH incidence and TSH and cortisol patterns in patients who did and did not develop IH. RESULTS: Of 78 ipilimumab-treated patients, 46 met the study criteria and 9/46 (20%) developed IH at a median duration of 13.0 weeks (range 7.7-18.1) following ipilimumab initiation. All patients whose TSH fell ≥ 80% compared to baseline developed IH, and, in 5/9 patients with IH, TSH fell prior to cortisol fall and IH diagnosis. Pre-cycle-4 TSH was significantly lower in those who developed IH (0.31 vs. 1.73 mIU/L, P = 0.006). TSH fall was detected at a median time of 9.2 (range 7.7-16.4) weeks after commencing ipilimumab, and a median of 3.6 (range of - 1.4 to 9.7) weeks before IH diagnosis. There was no difference in TSH between the groups before cycles 1-3 or in cortisol before cycles 1-4. CONCLUSIONS: TSH fall ≥ 80% may be an early marker of IH. Serial TSH measurement during ipilimumab therapy may be an inexpensive tool to expedite IH diagnosis.