Pituitary adenomas are common benign monoclonal neoplasms accounting for approximately 15% of intracranial tumors, while occult adenomas are discovered in as many as 25% of unselected autopsies. Pituitary tumors are usually benign, but cause significant morbidity due to their critical location, expanding size, and/or inappropriate pituitary hormone expression. True malignant behaviour with metastatic spread is very rare.

Various subtypes have been recognized on the basis of clinical presentation, as well as immunocytological and ultrastructural characteristics. About one-third of pituitary adenomas are not associated with clinical hypersecretory syndromes, but with symptoms of an intracranial mass such as headaches, hypopituitarism, or visual field disturbances, and are classified as nonfunctioning pituitary adenomas (NFPAs). Clinically non-functioning adenomas (NFPA) are actually a diverse group of tumors that include LH-, FSH- secreting adenomas, null cell adenoma and oncocytoma.

The clinical features of all other pituitary adenomas are linked to the hypersecreted hormone(s) which mark the specific cell origin, allowing the tumors to be classified as:

Prolactinomas or PRL-secreting PA, the most common of all functional pituitary adenomas. The patients usually present with amenorrhea, infertility, and galactorrhea (females), impotence or infertility (males). Tumors expressing both PRL and GH are thought to originate from a common mammosomatotroph precursor cell.

Somatotropinomas or GH-secreting PA, which cause acromegaly in adults, with bony acral changes in soft tissues and bone, and increased risk of hypertension, cardiac disease, and diabetes.

Corticotropinomas or ACTH-secreting PA, leading to Cushing disease and adrenal steroid overstimulation. Features of hypercortisolism include truncal obesity, striae, muscle wasting, hirsutism, cardiovascular complications, osteoporosis, and psychiatric disturbances.

Pure gonadotropinomas secreting intact FSH or LH are rarely encountered and may cause sexual dysfunction and hypogonadism.

Thyrotropinomas cause a mild increase in thyroxine levels with inappropriate TSH levels.

is dependent on adenoma subtype. A significantly higher frequency of multiple allelic deletions were found in invasive tumors compared to non-invasive tumors.

Usually favourable. Truly malignant metastatic behaviour is extremely rare. The unresponsiveness to pharmacological treatment is associated with more aggressive behaviour.

Technical difficulties related to the size of the samples available after surgery and the low proliferative rate of pituitary cells account for the limited cytogenetic findings. Despite these constraints a small fraction of pituitary adenomas showed an abnormal karyotype characterized by hyperdiploid or near triploid modal chromosome numbers and rare random structural abnormalities. Microsatellite and interphase FISH studies indicated that trisomy of chromosome 12 is pathogenetically important, and represents the most frequent cytogenetic alteration in human PRL. Chromosomes 5, 8 and X were also found to be preferentially overrepresented (Figure 3). Combined gains of the above chromosomes appear a non random pattern in pituitary adenoma. Comparative genomic hybridization (CGH) studies confirmed the cytogenetic and FISH evidence, but did not provide significant clues to specific subchromosomal regions.

Little is known about the genetic defects leading to pituitary tumor formation, which likely involves multiple initiating and promoting factors.

With the exception of activating mutations of GNAS1 which have been associated with 40% of somatotrophic adenomas and 10% of NFPAs, none of the candidate cell cycle, receptor, second messenger or related genes examined thus far appears to be responsible individually for more than a few percent of sporadic pituitary adenomas.

Inactivation of p27kip1 and RB1 has been associated with the development of pituitary adenomas in mice, but no similar evidence has been achieved in human.

MEN1A mutations, commonly found in patients affected by the MEN-1 syndrome, are rarely found in sporadic pituitary adenomas, despite a menin variably diminished expression has been demonstrated.

Increased expression of pituitary tumor transforming gene (PTTG) has been found in sporadic pituitary adenomas, and a role for this gene in pituitary cell proliferation is supported by development of multifocal plurihormonal focal pituitary adenomas in transgenic male mice overexpressing PTTG.

A role for HMGA2 gene in pituitary oncogenesis has been pointed out by development of PRL adenomas in HMGA2 transgenic mice and the finding of HMGA2 expression, which is switched off in the adult pituitary gland, in human prolactinomas. Amplification and/or rearrangement of the HMGA2 gene, mapping to 12q14, was observed in most of the PRLs analyzed. Increased dosage of chromosome 12 appears to be a condition predisposing to selective overrepresentation of the 12q14 region and/or rearrangement of the HMGA2 gene.
Expression of HMGA2 has been recorded also in human NFPA, which rarely harbor trisomy 12, suggesting a mechanism of activation different from that mainly operating in PRLs (Figure 2).

It remains to be determined which of the many oncogenes/growth factors and oncosuppressors reported overexpressed or underexpressed contribute to pituitary oncogenesis to identify the pathogenetic pathways which are altered in pituitary adenomas.