Etiology

The etiology of most pituitary adenomas remains unknown.[20] Studies done using molecular biology have suggested potential mechanisms.

Pituitary adenomas are monoclonal in origin, suggesting intrinsic genetic alterations as initiating events.[21]​ Hypothalamic hormones and other local growth factors may have an important role in promoting the growth of already transformed pituitary cell clones and also the expansion of small adenomas into large or invasive tumors.[20]​[22]​​​ Abnormal cell proliferation, differentiation, and hormone secretion may result from "gain of function" (i.e, activating mutations of oncogenes) or "loss of function" (i.e., inactivating mutations of tumor suppressor genes).

Most pituitary adenomas are sporadic but some arise as components of familial tumor syndromes, such as multiple endocrine neoplasia type 1, familial isolated pituitary adenomas, and Carney complex.[20][21]

Pathophysiology

Nonfunctional pituitary adenomas are associated with hypermethylation of the p16 locus, cyclin dependent kinase inhibitor 2A (CDKN2A) gene, on chromosome 9p21.3. The CDKN2A gene is a tumor suppressor gene, and its product, CDKN2A protein, is important in the control of G to S phase transition in the cell cycle via inhibition of CDK4-mediated retinoblastoma protein 1 (RB1) phosphorylation. Hypermethylation of this gene inactivates the gene with no CDKN2A protein synthesis, leading to unregulated cell growth.[23][24]

Pituitary adenoma cells, particularly from clinically nonfunctional pituitary adenomas (CNFPAs), express PPAR-gamma in vitro. Rosiglitazone, a PPAR-gamma ligand, has been shown to reduce tumor cell proliferation and pituitary tumor growth in animal models. Rosiglitazone induces a G0 to G1 cell cycle arrest, decreasing the number of cells entering into the S phase.[25][26][27] However, although rosiglitazone is licensed for treatment of patients with type 2 diabetes, the use of the drug has been severely restricted in the US by the FDA due to the increased risk of cardiovascular problems.[28] Rosiglitazone is not indicated for treatment of pituitary tumors.

Pituitary tumor transforming gene (PTTG) overexpression has been implicated in pituitary tumorigenesis. PTTG mRNA is elevated in nonfunctional tumors and growth hormone- and prolactin-producing tumors. PTTG protein is involved in intracellular signaling.[29] PTTG induces fibroblast growth factor 2 (FGF-2) expression, which mediates cell growth and angiogenesis.[30]

Classification

2021 World Health Organization classification of tumors of the central nervous system, fifth edition[2]

Tumors of the sellar region:

  • Adamantinomatous craniopharyngioma

  • Papillary craniopharyngioma

  • Pituicytoma, granular cell tumor of the sellar region, and spindle cell oncocytoma

  • Pituitary adenoma/pituitary neuroendocrine tumor (PitNET)

  • Pituitary blastoma

Pathologic classification of pituitary adenomas/PitNET

The 2021 WHO classification continues to follow the 2017 (4th edition) WHO categories for pituitary adenomas according to their pituitary cell lineage rather than the hormone produced.[2][3][4][5]

  • Lactotroph adenomas

  • Somatotroph adenomas

  • Thyrotroph adenomas

  • Corticotroph Adenomas

  • Gonadotroph adenoma

  • Null cell adenoma

  • Plurihormonal adenomas.

Immunohistochemistry is applied for the main pituitary hormones. If a tumor is still not classifiable by the pituitary hormone expression according to a cell lineage, immunostaining for transcription factors and other factors is used.[5]

​Nonfunctional versus functional[6]

  • Nonfunctional: no hypersecretion of hormone. May be completely asymptomatic and detected incidentally on imaging for other reasons (incidentalomas) or cause significant hypothalamic or pituitary dysfunction and visual or other symptoms due to their large size. Knowledge of the histopathological subtype is relevant because certain clinically nonfunctional pituitary adenomas (CNFPAs) have a more aggressive clinical course.[7] Other rare tumors, such as spindle cell oncocytomas of the adenohypophysis, may be clinically indistinguishable from CNFPAs.​

  • Functional: hypersecretion of hormone. Some of these tumors may present as CNFPAs with mass effect, due to subtly defective or inefficient hormone hypersecretion. Such examples include silent adrenocorticotropic hormone (ACTH) and growth hormone (GH) adenomas, with the former having a more aggressive natural history in some cases with higher risk of tumor invasion and recurrence. The majority of gonadotroph adenomas present as CNFPAs with mass effect because they may only secrete the alpha or beta subunits, or be inefficient in hormone hypersecretion.[5]​​

Tumor size​[6]​​

Microadenoma: tumor size <1 cm.

Macroadenoma: tumor size ≥1 cm.

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