Clinical implications of the 2022 WHO classification on the multidisciplinary management of PitNETS patients.

The review explores the 2022 update to the World Health Organization (WHO) classification of pituitary adenomas, now referred to as pituitary neuroendocrine tumors (PitNETs), and his possible impact on the clinical management of PitNET patients. The review highlights the differences and the evolution from the 2017 to 2022 version, with the current classification considering the lineage of the tumor cells, cell type, hormones produced, and other auxiliary characteristics for a comprehensive histological classification. The revision in terminology reflects a broader perspective on neuroendocrine neoplasia. The new approach based on transcription factors, hormone expression and other biomarkers has allowed a major revision of the nomenclature and a more accurate classification of pituitary adenomas. Furthermore, in some cases this approach is also assuming a prognostic value, useful in clinical practice. However, despite this elaborate classification and stratification, the review points out the lack of a robust grading or staging system and suggests the need for further research and validation of diagnostic methods. Despite these limitations, the revised classification presents a significant step towards understanding and managing PitNETs patients.

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.

Pituitary Enlargement and Hypopituitarism in Patients Treated with Immune Checkpoint Inhibitors: Two Sides of the Same Coin?

BACKGROUND: Immune checkpoint inhibitor hypophysitis (IIHs) is an emerging problem in cancer patients treated with immune checkpoint inhibitors (ICIs). We aimed to describe the clinical and molecular features of a multicenter series of IIHs. METHODS: Demographic and clinical features were retrospectively collected for all cases. Anti-pituitary and anti-hypothalamus autoantibodies were also measured. RESULTS: Nine patients were included. Six patients were treated with nivolumab and three with ipilimumab. Secondary hypoadrenalism was diagnosed in all patients. Pituitary MRI showed pituitary enlargement in two cases and no abnormalities in the other seven. Anti-pituitary antibodies were positive in 57.1% of cases and anti-hypothalamus antibodies in 85.7% of cases. Multidisciplinary treatments were established by a neuroendocrinologist and oncologists: all patients were treated with hydrocortisone replacement; ICI was withdrawn in two cases. At follow-up, hypoadrenalism persisted in all cases. Pituitary enlargement on MRI spontaneously recovered in the two affected patients. We found that the typical features of hypophysitis involved more frequently females and patients treated with ipilimumab. CONCLUSIONS: Although this study did not clarify if autoimmune secondary hypoadrenalism and ICI hypophysitis on brain imaging are two sides of the same disease, our preliminary data underline the need for molecular studies of IIHs and of autoimmune ICIs-related hypopituitarism.

De-escalation treatment with pasireotide for acromegaly: a long-term experience.

INTRODUCTION: Pasireotide long-acting release (LAR) is approved for second-line treatment of acromegaly. Starting pasireotide LAR 40 mg every 4 weeks is recommended and then up-titrate to 60 mg monthly in case of IGF-I uncontrolled levels. We present three patients treated with a de-escalation approach with pasireotide LAR. CASE 1: A 61-year-old female diagnosed with resistant acromegaly was treated with pasireotide LAR 60 mg every 28 days. When IGF-I reached the lower age range, therapy was decreased to pasireotide LAR 40 mg and then to 20 mg. In 2021 and 2022, IGF-I value remained within the normal range. CASE 2: A 40-year-old female diagnosed with resistant acromegaly underwent three neurosurgeries. In 2011, she was enrolled in the PAOLA study and assigned to pasireotide LAR 60 mg. Due to IGF-I overcontrol and radiological stability, therapy was downscaled to 40 mg in 2016 and to 20 mg in 2019. The patient developed hyperglycemia, which was treated with metformin. CASE 3: A 37-year-old male diagnosed with resistant acromegaly was treated with pasireotide LAR 60 mg in 2011. In 2018, therapy was decreased to 40 mg due to IGF-I overcontrol and in 2022 to 20 mg. He developed hyperglycemia, but HbA1c values remained under 48 nmol/L for 7 years. CONCLUSION: De-escalation treatment with pasireotide LAR may allow a greater proportion of patients to achieve control of acromegaly, particularly in selected cases of clinically aggressive acromegaly potentially responsive to pasireotide (high IGF-I values, invasion of the cavernous sinuses, partial resistance to first-line somatostatin analogues and positive expression of somatostatin receptor 5). Another benefit may be IGF-I oversuppression overtime. The major risk seems to be hyperglycemia.