Pathogenesis, clinical features, and treatment of plurihormonal pituitary adenoma

Abstract

Plurihormonal pituitary adenoma (PPA) is a type of pituitary tumor capable of producing two or more hormones and usually presents as an aggressive, large adenoma. As yet, its pathogenesis remains unclear. This is the first study to systematically summarize the underlying pathogenesis of PPA. The pathogenesis is related to plurihormonal primordial stem cells, co-transcription factors, hormone co-expression, differential gene expression, and cell transdifferentiation. We conducted a literature review of PPA and analyzed its clinical characteristics. We found that the average age of patients with PPA was approximately 40 years, and most showed only one clinical symptom. The most common manifestation was acromegaly. Currently, PPA is treated with surgical resection. However, recent studies suggest that immunotherapy may be a potentially effective treatment.

Keywords: immunohistochemistry; pathogenesis; pituitary adenoma; plurihormonal; stem cell.

Figure 1

The pituitary gland consists of the anterior lobe (AL), intermediate lobe (IL), and posterior lobe (PL). Plurihormonal primordial stem cells (PSC) are thought to reside in the intermediate lobe (IL) and the dorsal anterior lobe (AL), and are dispersed throughout the AL parenchyma. PSCs proliferate into adenomas under conditions that activate oncogenes, inactive tumor suppressor genes, dysregulate cell cycles, or cause mutations. Under the regulation of different transcription factors, the PSCs differentiate into different cells and secrete a variety of hormones.

Figure 2

These are the key signaling pathways of pituitary adenomas that may be involved in the initiation and progression of adult pituitary stem cell tumors. The pathways include WNT, TGFβ, NOTCH, HIPPO and SHH. The WNT, TGFβ, and NOTCH pathways may further participate in epithelium-mesenchymal transition (EMT), and promote tumor growth and spread. The WNT pathway: The WNT protein binds to the FZD receptor on the cell membrane, leading to the stabilization and accumulation of β-catenin protein, which enters the nucleus and binds to the transcription factor PROP-1, TGF7L2, regulating the expression of the target gene. The TGFβ pathway: TGFβ binds to the receptor complex, phosphorylates to SMAD2/3, and binds to SMAD4 to form a complex that enters the nucleus and binds to transcription factors to regulate the expression of target genes. The NOTCH pathway: After the NOTCH receptor binds to ligand DLL1/JAG1, NICD is released, which enters the nucleus and binds to transcription factor RBP-J to regulate gene expression. The HIPPO pathway: The protein encoded by the Hippo gene interacts with MST to activate the LATS protein, so that YAP and TAZ are phosphorylated and fixed in the nucleus, unable to enter the nucleus to regulate gene expression. When the signaling pathway is suppressed, YAP and TAZ enter the nucleus, bind to the transcription factor TEAD, and regulate gene expression. SHH pathway: In the absence of SHH, the PTCH receptor inhibits the activity of the protein SMO, and when SHH binds to PTCH, PTCH no longer inhibits SMO, thus SMO is activated and GLI protein is regulated. These proteins enter the nucleus to regulate the expression of target genes. EMT: Three families of transcription factors, ZEB, SNAIL, and TWIST, play a central role in EMT. For pituitary stem cell tumors, WNT, TGFβ, and NOTCH pathways may be involved in the regulation of EMT.