Clinicopathological Analysis of Densely and Sparsely Granulated Somatotroph Tumors of Pituitary.

OBJECTIVE: Somatotroph tumors are the second most common type of pituitary neuroendocrine tumors, which can be further classified into 2 subtypes-densely granulated somatotroph tumors (DGSTs) and sparsely granulated somatotroph tumors (SGSTs). The aim of this study was to investigate the clinical significance of the 2 subtypes in a retrospective analysis. METHODS: From the database of the Ningbo Clinical Pathology Diagnosis Center, we collected patients diagnosed with pituitary somatotroph tumors. We then compiled pertinent clinical and radiological data and proceeded with histopathological examination involving hematoxylin-eosin staining and immunohistochemical staining. Subsequent analysis compared the 2 subtypes using either χ2 test or Fisher exact test. RESULTS: We analyzed 40 cases of somatotroph tumors, 18 cases DGSTs and 22 SGSTs. Male-to-female ratio was 5:4 for DGSTs and 4:7 for SGSTs. Mean age was 52.83 years for DGSTs and 47.18 years for SGSTs. Statistically significant differences were observed between the DGST and SGST groups in invasiveness (P = 0.0267) and postoperative remission (P = 0.007). Cells of both DGSTs and SGSTs exhibited coexpression of PIT1, growth hormone, and CAM5.2, although the patterns of CAM5.2 expression differed between the 2 subtypes. CONCLUSIONS: The efficacy of CAM5.2 staining in distinguishing between DGSTs and SGSTs was demonstrated. SGSTs, with their increased invasiveness and lower remission rate, are a high-risk subtype. The histological subtype of somatotroph tumors plays a crucial role in guiding treatment decisions and prognostic evaluation in affected patients.

Three-dimensional chromatin landscapes in somatotroph tumour.

BACKGROUND: The three-dimensional (3D) genome architecture plays a critical role inregulating gene expression. However, the specific alterations in thisarchitecture within somatotroph tumors and their implications for gene expression remain largely unexplored. METHODS: We employed Hi-C and RNA-seq analyses to compare the 3D genomic structures of somatotroph tumors with normal pituitary tissue. This comprehensive approachenabled the characterization of A/B compartments, topologically associateddomains (TADs), and chromatin loops, integrating these with gene expression patterns. RESULTS: We observed a decrease in both the frequency of chromosomal interactions andthe size of TADs in tumor tissue compared to normal tissue. Conversely, the number of TADs and chromatin loops was found to be increased in tumors. Integrated analysis of Hi-C and RNA-seq data demonstrated that changes inhigher-order chromat in structure were associated with alterations in gene expression. Specifically, genes in A compartments showed higher density and increased expression relative to those in B compartments. Moreover, the weakand enhanced insulation boundaries were identified, and the associated genes were enriched in the Wnt/ß-Catenin signaling pathway. We identified the gainedand lost loops in tumor and integrated these differences with transcriptional changes to examine the functional relevance of the identified loops. Notably, we observed an enhanced insulation boundary and a greater number of loops in the TCF7L2 gene region within tumors, which was accompanied by an upregulation of TCF7L2 expression. Subsequently, TCF7L2 expression was confirmed through qRT-PCR, and upregulated TCF7L2 prompted cell proliferation and growth hormone (GH) secretion in vitro. CONCLUSION: Our results provide comprehensive 3D chromatin architecture maps of somatotroph tumors and offer a valuable resource for furthering the understanding of the underlying biology and mechanisms of gene expression regulation.

KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

IMPORTANCE: A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. OBJECTIVE: We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. SETTINGS: We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. RESULTS: One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. CONCLUSIONS AND RELEVANCE: Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.