How are pituitary adenomas classified?

Classification of Pituitary Adenomas

Pituitary adenomas are classified based on multiple complementary systems: hormonal functionality, size, histopathological characteristics with immunostaining patterns, and molecular markers including Ki-67 proliferation index. 1, 2

Primary Classification Systems

By Hormonal Function

Pituitary adenomas are fundamentally categorized by their secretory characteristics:

• Functioning adenomas (70% of cases) produce excess hormones and include:

  • Prolactinomas (53% of all adenomas) - secrete prolactin, causing hypogonadism, infertility, and galactorrhea 2
  • Somatotropinomas (12% of cases) - secrete growth hormone, causing acromegaly in adults and gigantism in children 2
  • Corticotropinomas (4% of cases) - secrete ACTH, resulting in Cushing disease 2
  • Thyrotropinomas (rare) - secrete TSH, causing hyperthyroidism 1, 3
  • Functioning gonadotroph adenomas (exceptionally rare) 1

• Non-functioning pituitary adenomas (NFPAs) (30% of cases) do not produce hormones but may cause mass effect symptoms 2

By Size

• Microadenomas: <1 cm in diameter 1, 2
• Macroadenomas: ≥1 cm in diameter (48% of tumors) 1, 3, 2
• Giant adenomas: >4 cm in size 1, 4

Histopathological Classification

Immunohistochemical Profiling

All operated pituitary adenoma tissue should undergo histopathological assessment including immunostaining for pituitary hormones and Ki-67, with additional immuno-profiling when relevant. 1

The European Pituitary Pathology Group recommends a multilevel approach:

• Basic immunostaining panel: pituitary hormones, cytokeratin, and Ki-67 1
• Additional markers when indicated:
  • Transcription factors (if immunonegative, scanty hormonal staining, or plurihormonal patterns) 1
  • Chromogranin, somatostatin receptor, and p53 in selected cases 1
  • O6-methylguanine-DNA methyltransferase for aggressive tumors being considered for temozolomide therapy 1

Granulation Pattern

Functioning adenomas are further subclassified by granulation pattern (via electron microscopy or cytokeratin staining):

• Densely granulated - typically more responsive to medical therapy 5
• Sparsely granulated - particularly important for GH-secreting adenomas, as this subtype shows less responsiveness to somatostatin analog treatment 5

Prognostic Classification

Ki-67 Proliferation Index

Ki-67 staining should be accurately quantified (positive staining per 500-1,000 neoplastic cells in two hotspots) to help predict clinical outcomes. 1

• Ki-67 ≥3% combined with local invasion on imaging predicts a 25% recurrence rate after surgery in pediatric patients 1
• In pediatric series, 55% of patients had Ki-67 ≥3% 1

Aggressive Adenomas

Identification requires assessment of:

• Ki-67 labeling index (most important adverse prognostic factor) 5
• Number of mitoses 5
• Nuclear expression of p53 5
• Invasive character on imaging 5

Genetic Classification

Genetic assessment should be offered to all children and young people with pituitary adenomas, with particular emphasis on those with GH and prolactin excess due to high prevalence of genetic abnormalities. 1

Genetic syndromes associated with pituitary adenomas include:

• Familial isolated pituitary adenoma 1
• Multiple endocrine neoplasia type 1 (MEN1) 1
• MEN1-like syndrome 1
• Phaeochromocytoma-paraganglioma-related pituitary disease 1
• AIP mutations 1

Clinical Pitfalls

The traditional classification into eosinophilic, basophilic, and chromophobe types is no longer sufficient and should not be used, as it fails to correlate with modern clinical syndromes and treatment responses 6. The current WHO 2022 classification emphasizes functional and molecular characteristics over outdated morphological categories 1, 5.