Pituitary Adenoma

Epidemiology and Etiology:

• Most common cause of hyperpituitarism is an adenoma
• Incidence of up to 25% in routine autopsies
• Adults (peak 30s-50s)
• Prolactinomas (lactotroph adenomas) are most frequent type (30%)
• Growth hormone (somatotroph cell) adenomas are second most frequent
• ACTH-producing (corticotroph adenoma) (10-15%)
• 30-40y peak
• F:M = 8:1
• Rare in childhood
• 25% are non-functioning (but most are actually clinically silent gonadotroph adenomas)

Common sites:

•  Sella turcica
• may encroach on optic chiasm in suprasellar region
• extension into cavernous and sphenoid sinuses

Gross features:

•  microadenoma < 1cm
• corticotroph adenomas are usually small at diagnosis (4-6mm)
• red, soft
• macroadenoma > 1cm
• erosion of sella turcica maybe
• encapsulated or not (30% are not encapsulated)
• infiltration of local bone, dura, and (rarely) brain is ok (invasive adenoma)
• hemorrhage and necrosis are ok (larger adenomas)

Histologic features:

• relatively uniform population (cellular monomorphism distinguishes adenoma from non-neoplastic pituitary parenchyma)
• polygonal cells in sheets or cords
• sparse connective tissue
• absence of a significant reticulin network (distinction from non-neoplastic pituitary parenchyma)
• nuclei uniform or pleomorphic
• mitotic activiy modest usually
• histologic appearance cannot reliably predict functional status
• prolactinoma:
• weakly acidophilic or chromophobic cells (overwhelming majority)
• calcifications – psammoma bodies or extensive calcification
• GH-secreting adenomas:
• Densely granulated subtype:
• Monomorphic, acidophilic cells
• Sparsely granulated subtype:
• Chromophobe cells
• Considerable nulear and cytologic pleomorphism
• Corticotroph adenomas:
• Characteristic sinusoidal pattern around capillaries
• Monomorphic round cells
• Basophilic (densely granulated) or amphophilic usually
• Chromophobic (sparsely granulated) occasionally
• Mitoses extremely rare
• Non-neoplastic corticotrophs:
• Crooke hyaline change often
• No histologic criteria for malignancy
• Malignancy is based on presence of metastases.

Immunophenotype:

Marker:	Sensitivity:	Specificity:
Pit-1
Prolactin (prolactinoma) (mammosomatotroph adenomas)
GH (strong in densely granulated, weak and focal in sparsely granulated) (also mammosomatotroph adenomas)
LMWK (perinuclear in a densely granulated GH adenoma) (diffuse cytoplasmic often in corticotroph)
PAS (corticotroph)	Chromophobic corticotroph adenomas tend to be weakly PAS positive only
POMC (corticotroph)
ACTH (corticotroph)
Beta-endorphin (corticotroph)
Beta-LPH (corticotroph)

Molecular features:

• monoclonal (even plurihormonal adenomas)
• G-protein mutations
• Gs-alpha mutations (stimulatory G-protein, subunit alpha) (GNAS1 gene) (40% of somatotroph cell adenomas) (minority of corticotroph adenomas) (not found in thyrotroph, lactotroph, and gonadotroph adenomas)
• Mutation involving the GTPase activity (self-limiting functional part) (forming the gsp oncogene)
• Constitutive activation of Gs-alpha -> persistent generation of cAMP -> unchecked proliferation
• Activating RAS mutations (aggressive / advanced pituitary adenomas)
• Overexpression of MYC (aggressive / advanced pituitary adenomas)
• Familial:
• MEN 1
• Majority of corticotroph adenomas are sporadic
• Multiple chromosomal imbalances on CGH (50-80%)
• Corticotroph adenoma:
• LOH glucocorticoid receptor (30%)

Other features:

•  Note that mildly elevated prolactin can occur with any pituitary or suprapituitary mass (stalk effect)
• Cushing disease caused by corticotroph adenomas
• Nelson syndrome – large destructive corticotroph adenomas after bilateral adrenal gland removal
• EM:
• Corticotroph:
• Bundles of 7nm intermediate filaments
• Numerous secretory granules often under cell membrane
• Recurrence rate after surgery:
• Corticotroph adenoma:
• 15-20% at 5-6y

References:

•  Robbins & Cotran Pathologic Basis of Disease (2005)