Elisa Baranski Lamback

Background: Posterior pituitary tumors (PPTs) are rare sellar neoplasms arising from pituicytes. Historically classified as distinct benign entities, including pituicytoma (or classical pituicytoma), spindle cell oncocytoma (SCO), granular cell tumor (GCT) of the sellar region, and ependymal pituicytoma, recent World Health Organization updates have unified them within a single pathological spectrum. Methods: This review comprehensively synthesizes the evidence supporting the spectrum concept, integrating clinical, histopathological, genomic, epigenomic, and tumor immune microenvironmental findings of pituicytomas, SCOs and GCTs. As ependymal pituicytomas are extremely rare, we synthetize their findings separately at the end of the review. Results: Clinically, PPTs may mimic non-functioning pituitary adenomas or present as suprasellar masses, and can cause neurological and endocrine deficits due to mass effect. Surgery remains the treatment of choice, with radiotherapy considered for selected patients. Recent molecular studies have provided important insights into their biology. Chromosomal copy number variations (CNV) distinguished PPTs into three major prognostic subtypes: CNV-negative pituicytomas and SCOs associated with more favorable outcomes than the CNV-positive subtypes, and a third group composed of GCTs that have favorable outcomes. Additionally, PPTs exhibit substantial driver diversity: pituicytomas and SCOs are enriched for pathogenic variants in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways associated with downstream phosphorylated extracellular signal-regulated kinase (pERK) activation, whereas GCTs are characterized by relative genomic stability. Moreover, SCOs display an immune-active microenvironment, contrasting with the highly immunosuppressive profile observed in pituicytomas. Conclusion: These genomic and immune discoveries provide a rational for targeted therapy for refractory PPTs.

Purpose A subgroup of GATA3-positive silent corticotroph adenomas (SCA) was identified by transcriptomics. We aimed to compare clinical, radiological and surgical outcomes of SCA with and without GATA3. Methods Tumor volume calculated using Di Chiro-Nelson formula; microcystic appearance defined as small areas of marked hyperintensity on T2W. Cavernous sinus invasion was assessed with Knosp (grades 3–4 considered invasive), and sellar floor invasion by Hardy-Wilson (grade E as massive invasion). Three to six months after surgery, MRI was repeated to evaluate the extent of the surgical resection, and then annually to assess recurrence or tumor progression, and the need for reoperation or radiotherapy. Results Among 45 SCA, 11 (24.4%) were GATA3-positive. The GATA3 patients were more frequently male (72.7% vs. 29.4%, p = 0.016) and had larger tumor volume [34.8 cm³ (2.8-130.8) vs. 11.2 cm³ (3.4–89.8), p = 0.023]. Notably, 81.8% of the GATA3-positive SCA were giant adenomas compared to 24.2% in the other group (p = 0.001), with higher frequency of sphenoid invasion (60% vs. 10.3%, p = 0.004), but with no difference in cavernous sinus invasion (p = 0.299). Gross total resection was less frequent in the GATA3-positive SCA (0% vs. 32.2%, p = 0.041). No difference was seen regarding age, microcystic aspect, granulation pattern, Ki-67, mitoses and post-surgical outcome. Conclusion About one quarter of SCA displayed GATA3-positivity and was seen more frequently in men. GATA3-positive SCA are characterized by large tumor size and massive infrasellar invasion, but not aggressive features as no differences in post-surgical outcomes were detected in our cohort.

Acromegaly caused by ectopic growth hormone–releasing hormone (GHRH)-secreting neuroendocrine tumor (NET) is extremely rare, with cosecreting NETs even more seldom. We report a case of a female patient who presented with primary hyperparathyroidism (pHPT) and a GHRH- and insulin cosecreting pancreatic NET (pNET) and genetically confirmed multiple endocrine neoplasia type 1 (MEN1), within an undiagnosed family with various MEN1-related NETs. Due to the diagnosis of MEN1, screening for pituitary tumor was performed with biochemical evidence of acromegaly. Sellar magnetic resonance imaging revealed a sellar lesion, which was excised and compatible with somatotroph hyperplasia. Postoperatively, the patient developed severe hypoglycemia requiring hospitalization and the pNET was removed. Histopathology confirmed GHRH and insulin secreting pNET. Ectopic acromegaly in MEN1 is exceedingly rare. Patients with MEN1 often present with multiple pNETs, which may exhibit multihormonal secretion and frequently cosecrete GHRH and insulin in MEN1, while hypoglycemia may not be manifested possibly due to GH and insulin's counteractive effects on glucose metabolism.

Objective: Corticotroph tumors (CTs) derive from the TBX19 lineage and are functioning (FCTs) or nonfunctioning (NFCTs). In FCTs, the main pathogenic variants are found in USP8, enhancing proopiomelanocortin (POMC) transcription through epidermal growth factor receptor (EGFR) signaling, resulting in a higher secretion index compared with wild type (WT). POMC is cleaved by prohormone convertase 1/3, encoded by proprotein convertase subtilisin/kexin type 1 gene (PCSK1), into ACTH. PCSK1 is inhibited by PCSK1N, which in turn is inhibited by transcription factor paired box 6 (PAX6). We aimed to compare gene expressions involved in POMC processing among NFCTs, USP8+ FCTs, and WT FCTs. Methods: Fresh CTs were collected to quantify TBX19, POMC, EGFR, PCSK1, PCSK1N, and PAX6 by polymerase chain reaction. Sanger sequencing was performed to detect USP8 variants. ACTH levels were normalized to tumor diameter to calculate the secretion index. Results: We included 42 NFCTs, 13 WT FCTs, and 11 USP8+ FCTs. NFCTs had lower TBX19, POMC, and PAX6 compared with both FCT groups, but similar PCSK1N. TBX19 correlated positively with POMC (R = +0.460; P = 0.002) and PAX6 (R = +0.327; P = 0.030). USP8+ FCTs had a higher secretion index (P = 0.019), higher PCSK1 (P = 0.037), and also lower PCSK1N (P = 0.041), compared with WT, despite similar TBX19 and POMC. Secretion index only correlated with PCSK1N (R = −0.469; P = 0.021). Conclusions: In NFCTs, low TBX19 may contribute to their nonfunctioning phenotype. In FCTs, USP8+ and WT displayed similar POMC levels, but downstream POMC, USP8+ had a higher PCSK1 and lower PCSK1N, which may account for their comparatively increased secretory activity.

Neurocytomas are neuronal tumors that are usually intraventricular. Rare cases can arise from extraventricular sites. To our knowledge, only 29 cases of extraventricular neurocytoma of the sellar region (EVNSR) have been reported in the literature. We describe a case of a 39-year-old woman who presented with a one-month history of refractory headache, nausea and vomiting. Magnetic resonance imaging (MRI) showed a 5.1 × 3.1 × 2.2 cm sellar and suprasellar mass, suggestive of a pituitary adenoma (PA). She had hyponatremia, obstructive hydrocephalus, and panhypopituitarism at presentation (hypogonadism, adrenal insufficiency). After glucocorticoid replacement therapy and ventriculoperitoneal shunt, the vomiting and headache resolved, but she remained with nausea and hyponatremia. She was submitted to surgery, and histopathological analysis revealed a neurocytoma with positive immunostaining for arginine vasopressin. Syndrome of inappropriate antidiuresis (SIAD) was diagnosed but did not resolve after surgery due to residual tumor, despite fluid restriction and saline replacement. SIAD later resolved with empagliflozin. In conclusion, EVNSR is extremely rare and can be misdiagnosed as PA on MRI. In the context of SIAD and extraventricular neurocytoma, a secreting arginine vasopressin tumor must be considered. SIAD can be challenging to treat, with excision of the EVNSR the treatment choice and, alternatively, empagliflozin associated with fluid restriction.

Somatic alpha thalassemia/mental retardation syndrome X-linked (ATRX) pathogenic variants have been shown to predict a malignant phenotype in neuroendocrine tumors. They were recently identified in aggressive pituitary tumors and carcinomas, mainly of corticotrophic origin. To our knowledge, these tumors are rare in a general cohort of pituitary tumors, with no cases described in null cell tumors. These variants can lead to loss of protein expression as revealed by immunohistochemistry. We describe a case of an aggressive null cell pituitary tumor with loss of ATRX expression. The patient underwent two transsphenoidal surgeries and radiotherapy and exhibited tumor growth despite conventional therapy. Analysis of the tumor samples revealed loss of ATRX expression in both surgical specimens, suggesting that ATRX may be a useful biomarker for the early identification of aggressive pituitary tumors.

Summary: Pituitary gigantism is a rare pediatric disorder caused by excess growth hormone (GH) secretion. In almost 50% of cases, a genetic cause can be identified, with pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene being the most common. We present a case of an 11-year-old boy who exhibited progressive vision loss, associated with accelerated linear growth, and weight gain. On physical examination, he had enlarged hands, right eye amaurosis, and was already above his target height. Increased GH and IGF-I concentrations confirmed the diagnosis of pituitary gigantism. Magnetic resonance imaging showed a giant sellar lesion with supra- and para-sellar extensions. He underwent two surgeries which did not achieve a cure or visual improvement. Histopathological analysis revealed a sparsely granulated tumor, negative for somatostatin receptor type 2 (SST2) and an immunoreactivity score of 6 for somatostatin receptor type 5 (SST5). Our published artificial intelligence prediction model predicted an 83% chance of not responding to first-generation somatostatin receptor ligands. Pasireotide was therefore prescribed, and afterward cabergoline was added on. IGF-I concentrations decreased but did not normalize. We discovered a novel germline single nucleotide variant in the splicing donor region of intron 2 of the AIP gene (NM_003977.4:c.279+1 G>A), classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines.

Acromegaly is a chronic systemic disease caused in the vast majority of cases by growth hormone (GH)-secreting adenoma, with surgery being the first-line treatment. When a cure is not attained with surgery, first-generation somatostatin receptor ligands (fg-SRLs) are the most common medication prescribed. Predictors of response to fg-SRLs have been studied; however, they cannot fully predict the response to fg-SRL. MicroRNAs are small RNAs, the main role of which is messenger RNA (mRNA) post-transcriptional regulation. This study aimed to identify the microRNAs involved in resistance to treatment with fg-SRLs in acromegaly. Ten patients with acromegaly undergoing treatment with fg-SRLs were selected to undergo miRNA sequencing: five controlled and five uncontrolled with treatment. Bioinformatic analysis was performed to detect differentially expressed miRNAs. Then, the same 10 samples were used for validation by qPCR and an additional 22 samples were analyzed, totaling 32 samples. e We found 59 differentially expressed miRNAs in the first analysis. miR-181a-5p and miR-181b-5p were downregulated, and miR-383-5p was upregulated in the uncontrolled group. Receiver operating characteristic (ROC) curve analysis of miR-383-5p showed an NPV of 84.3% and a PPV of 84.5%. In summary, miR-181a-5p, miR-181b-5p, and miR-383-5p are biomarkers of response to fg-SRLs, and they can be used individually or included in prediction models as tools to guide clinical decisions.