What causes pituitary microadenomas?

Causes of Pituitary Microadenomas

Pituitary microadenomas arise from both genetic mutations (germline and somatic) and sporadic clonal expansion of genetically altered pituitary cells, with the specific etiology varying significantly by tumor type and patient age.

Genetic Causes

Germline Mutations (Hereditary)

The likelihood of identifying a genetic cause depends heavily on the tumor type and age of onset:

Prolactin-secreting microadenomas:

• MEN1 mutations occur in approximately 5% of patients with macroprolactinomas diagnosed before age 20, though microprolactinomas with MEN1 are less common 1
• AIP mutations are found in 9% of young-onset prolactinomas, but microprolactinomas with AIP mutations occur "only extremely rarely in a sporadic setting" and are primarily seen in familial cases 1
• MEN4 (CDKN1B) and MEN5 (MAX) variants are rare causes 1
• SDHx variants (3PA syndrome) are rare 1

Corticotroph microadenomas (Cushing disease):

• Germline mutations are rare overall in corticotroph adenomas 1
• MEN1 mutations identified in 2 of 55 patients under age 21 with both microadenomas and macroadenomas 1
• CABLES1 variants found in 2 of 146 pediatric patients 1
• CDKN1B variants identified in 3 of 190 pediatric patients 1
• DICER1 syndrome causes infant-onset pituitary blastoma with very low penetrance (<1%) 1

Non-functioning microadenomas:

• Identified during clinical screening in MEN1 and AIP mutation-positive patients, similar to incidentalomas 1
• Occur in 25% of patients with MEN1 syndrome 1

Somatic Mutations (Tumor-specific)

Corticotroph microadenomas:

• USP8 deubiquitinase gene mutations are implicated in over one-third of both childhood and adult-onset corticotrophinomas, most typically in female patients with corticotroph microadenomas 1
• This represents the most common somatic mutation in corticotroph microadenomas 1

Growth hormone-secreting tumors:

• Somatic GNAS mutations restricted to the pituitary are rare in children but identified in 20-40% of adult tumor samples 1

Sporadic (Non-genetic) Causes

The majority of pituitary microadenomas occur sporadically without identifiable genetic mutations 1:

• Result from clonal expansion of genetically altered cells where both pituitary and extrahypophyseal factors play a role 2
• The specific molecular mechanisms triggering this clonal expansion in sporadic cases remain incompletely understood
• Approximately 50% of all pituitary adenomas are microadenomas (<10 mm) 3, 4

Clinical Context by Tumor Type

Prolactinomas (most common functional microadenoma):

• Account for 32-66% of all pituitary adenomas 3
• In young-onset cases, 14% have genetic etiology (5% MEN1, 9% AIP) 1
• The vast majority of microprolactinomas are sporadic 1

Corticotroph microadenomas:

• Represent 98% of Cushing disease cases in children and young people 1
• Adenoma diameter frequently ≤2 mm 1
• Predominantly sporadic, with genetic causes being rare 1

Non-functioning microadenomas:

• Account for 15-54% of all adenomas 3
• Often discovered incidentally 4
• Primarily sporadic unless part of MEN1 syndrome 1

Important Clinical Pitfalls

• Do not assume all young-onset or familial microadenomas have identifiable genetic causes - even with comprehensive genetic testing, many cases remain unexplained 1
• Microprolactinomas with AIP mutations are extremely rare in sporadic settings - genetic testing is most valuable in familial cases 1
• Multiple microadenomas can coexist in the same pituitary gland, emphasizing the role of both pituitary and extrahypophyseal factors in clonal expansion 2
• Incomplete penetrance means family members with known mutations may never develop adenomas, making screening decisions complex 1