CNS tumor
Sellar region tumors
Pituitary adenoma

Deputy Editor-in-Chief: Debra Zynger, M.D.
Michael Punsoni, M.D.

Topic Completed: 1 June 2018

Minor changes: 8 September 2020

Copyright: 2003-2020,, Inc.

PubMed Search: Pituitary adenoma [title] CNS tumor (free full text[sb] "last 5 years"[PDat])

Michael Punsoni, M.D.
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Cite this page: Punsoni M. Pituitary adenoma. website. Accessed September 21st, 2020.
Definition / general
  • Neuroendocrine tumor of the anterior pituitary gland composed of secretory cells with pituitary hormone production
  • Main tumor types include somatotroph, lactotroph, thyrotroph, corticotroph, gonadotroph, null cell and plurihormonal
Essential features
  • Routine assessment of histology includes determination of mitoses, pleomorphism, giant cells, inclusions, inflammatory changes, stroma, hemorrhage and vascular features
  • Evaluation of tumor proliferation potential by mitotic count and Ki67 labeling index
  • Evaluation of tumor invasion to identify clinically aggressive adenoma
  • Routine stains including ACTH, prolactin, growth hormone, TSH, LH, FSH, chromogranin, p53, and in some cases hormone receptor stains and transcription factors (Pituitary 2017;20:489)
  • Classification is based on a combination of histopathologic features, hormone content as assessed by immunohistochemistry and ultrastructural features
  • Anterior pituitary gland (adenohypophysis)
  • Pituitary adenoma
  • Atypical adenoma versus adenoma with elevated proliferative activity
  • Pituitary carcinoma
ICD coding
  • Benign neoplasm of pituitary gland D35.2
  • Malignant neoplasm of pituitary gland C75.1
  • Majority occur in sella turcica within the adenohypophysis / anterior pituitary lobe
  • Rare examples occur in extrasellar region on pituitary stalk
  • Rare prolactinomas as part of ovarian teratoma (Endocr Pathol 2014;25:321)
  • Cell differentiation driven by transcription factors lead to three main cell lineages: acidophilic, gonadotrophic and corticotrophic
  • Transcription factors:
    • PIT-1 (pituitary specific POU class homeodomain transcription factor): differentiation of somatotrophs, lactotrophs and thyrotrophs
    • SF-1 (steroidogenic factor 1): gonadotroph cell differentiation
    • T-PIT (T-box family member TBX19): proopiomelanocortin (POMC) lineage with differentiation of corticotrophs (Acta Neuropathol 2017;134:521)
  • Multistep, multicausal process including initiation and progression phases
  • Endocrine factors may induce cell proliferation: excess production of hormones (e.g. growth hormone, corticotropin, or gonadotropin)
  • Inherited syndromes:
    • MEN1 with involvement of 11q13
    • Carney complex with involvement of 2p16 and 17q
    • Familial acromegaly with involvement of 11q13 and their loci
    • McCune-Albright syndrome with involvement of 20q13.2
Clinical features
  • Most patients have clinical features of hormone excess (usually microadenoma)
  • Larger adenomas (macroadenoma defined as > 1 cm) have mass effects such as headache and visual disturbance
  • Hemorrhagic necrosis of large adenoma (pituitary apoplexy) may be a surgical emergency
  • Classified according to pituitary cell lineage:
    • Somatotroph
    • Lactotroph
    • Thyrotroph
    • Corticotroph
    • Gonadotroph
    • Null cell
  • Classification requires immunohistochemical staining for main pituitary hormones (GH, PRL, ACTH, Beta-TSH, Beta-LH, Beta-FSH and alpha-subunit of glycoproteins) and when required, pituitary transcription factors (PIT-1, SF-1, T-PIT)
  • Current classification (WHO 2017) uses likelihood of recurrence schema:
    • Low probability for recurrence: typical pituitary adenoma
    • High probability: adenoma with elevated proliferative activity
    • Malignant tumor: pituitary carcinoma
  • Use of the term "atypical adenoma" is not advocated by the 2017 WHO classification (Endocr Pathol 2017;28:228)
    • Not all so called atypical adenomas display clinically aggressive behavior
    • Some studies have shown that typical and atypical adenomas do not differ regarding recurrence and disease free survival times (Neuroendocrinology 2015;101:143)
  • Diagnosis of pituitary carcinoma is based on presence of cerebrospinal fluid or systemic metastases
    • There is no histologic distinction between typical pituitary adenoma and carcinoma
  • Serum prolactin level > 200 mcg/L in a patient with a macroadenoma greater than 10 mm in size is diagnostic of a prolactinoma
  • Oral glucose tolerance test is the definitive test for diagnosis of acromegaly
    • Serum insulin like growth factor 1 (IGF-1) level is also a good test for acromegaly
  • Serum levels of ACTH and high dose dexamethasone suppression testing are useful
  • Increased T3 and T4 levels, hyperthyroidism and goiter can be seen in patients with TSH secreting adenoma
  • Serum levels of FSH, LH and testosterone levels in men may indicate a pituitary / hypothalamic disorder affecting the gonadotropin / testosterone axis
  • CSF may be xanthochromic with crenated RBCs and high protein levels in pituitary apoplexy
Radiology description
  • Method of classification based on tumor size and degree of invasion
    • Important for planning of surgical resection
  • Microadenomas measure less than 1 cm in diameter; macroadenomas are larger than 1 cm
  • Identification of tumor extension is important: suprasellar, lateral (cavernous sinus), inferior (sphenoid sinus), posterior fossa
Radiology images

Images hosted on other servers:
Missing Image

Sellar masses

Prognostic factors
  • Invasive, aggressive adenomas often recur over several years and may evolve into pituitary carcinoma
  • Most pituitary carcinomas are hormonally active (most commonly lactotroph adenomas with hyperprolactinemia, followed by corticotroph adenomas with Cushing disease)
  • Crooke cell adenomas are aggressive adenomas with prominent Crooke hyaline change (described below) (Endocr Pathol 2017;28:228)
Case reports
  • Surgical approaches
    • Commonly via transsphenoidal route (minimally invasive)
    • Transfrontal approach for larger adenoma
    • Partial versus gross total resection
  • Dopamine agonists can reduce prolactin levels and size of prolactin adenoma
  • Somatostatin analogs can reduce hormone (GH and TSH) secretion but may cause little reduction in tumor size
  • Clinically non functioning tumors may show little response to medical therapy
  • Radiation therapy for tumors resistant to medical therapy or for surgical remnant from subtotal resections
    • Therapy may include LINAC radiotherapy, stereotactic radiotherapy or radio surgery
    • Single fraction or fractionated radiosurgery are options (Pituitary 2017;20:489)
  • Small studies have shown tumor response to temozolomide therapy in aggressive prolactin and ACTH producing adenomas (Eur J Clin Invest 2011;41:1133)
Gross description
  • Tumors less than 1 cm are microadenomas; larger tumors are macroadenomas
  • Giant adenomas are rare tumors greater than 5 cm
Frozen section images

Contributed by Michael Punsoni, M.D.
Frozen section Frozen section

Frozen section

Microscopic (histologic) description
  • Most adenomas show moderately abundant cytoplasm with a uniform nuclear morphology, stippled chromatin and inconspicuous nucleoli
  • Cells may be classified as acidophilic, basophilic or chromophobic based on tinctorial differences
  • Cytoplasmic appearance usually correlates with content of hormone containing secretory cells (i.e. densely versus sparsely granulated)
  • Crush artifact is common and is often present during intraoperative consultation
  • Crooke's hyaline change is characterized by large chromophobic or eosinophilic cells with a glassy hyaline appearance (due to accumulation of keratin filaments)
    • Seen in neoplastic and nonneoplastic corticotrophs
    • If prominent, called Crooke hyaline adenoma; the WHO terminology is “Crooke cell adenoma”
  • Null cell adenomas are composed of adenohypophysial cells that do not exhibit any cell type specific differentiation, including pituitary transcription factors (Brain Pathol 2012;22:443)
Microscopic (histologic) images

Contributed by Michael Punsoni, M.D.
Adenoma Adenoma Adenoma


Cytology description
  • Normal pituitary has mixed cell types on smear preparation; adenomas show uniform morphology and cell type with uncommon cytologic atypia
Cytology images

Contributed by Michael Punsoni, M.D.
H&E touch prep H&E touch prep H&E touch prep

H&E touch prep

Positive stains
  • All synaptophysin positive (less frequently for chromogranin A)
  • Routine hormone stains include prolactin, ACTH, GH, TSH, LH, FSH and alpha subunit
  • Reticulin (useful in identifying normal acinar architecture versus distorted and fragmented staining pattern in adenomas)
  • CAM5.2:
    • Perinuclear pattern is a feature of densely granulated somatotroph adenomas
    • Paranuclear fibrous bodies are a conspicuous feature of sparsely granulated somatotroph adenomas
      • Occasional fibrous bodies can be seen in acidophil stem cell adenomas
    • Diffuse and strong cytoplasmic staining characteristic of corticotroph adenomas
    • Ring-like positivity characteristic of Crooke cell adenomas (Brain Pathol 2012;22:443)
  • Ki67 often used proliferative indices
  • Specific transcription factors: SF1, PIT-1 or T-PIT
Negative stains
Electron microscopy description
  • Acidophil stem cell adenomas show numerous enlarged mitochondria with loss of cristae and presence of electron dense tubular structures (Brain Pathol 2012;22:443)
Molecular / cytogenetics description
  • No specific molecular characteristics in routine clinical diagnostic workup
  • Most pituitary adenomas are sporadic tumors; minority are part of hereditary or familial syndromes
  • Somatic mutations in GNAS and USP8 genes have been found in about 40% of sporadic somatotroph adenomas and 30 - 60% of sporadic corticotroph adenomas, respectively (Cell Res 2015;25:306)
  • Syndromes associated with pituitary adenoma include: multiple endocrine neoplasia (MEN) syndromes MEN1 and MEN4, Carney complex, McCune-Albright syndrome, X-linked acrogigantism (XLAG) associated with GPR101 microduplication and hereditary pheochromocytoma and paraganglioma syndrome related to succinate dehydrogenase (SDH) genes (Acta Neuropathol 2017;134:521)
Differential diagnosis
  • Ependymoma: positive for GFAP, negative for synaptophysin
  • Metastatic carcinoma: greater degree of cytologic atypia, rarely produce hormones, clinical findings are essential, usually either CK7 or CK20 will be positive
  • Normal adenohypophysis: normal acini by reticulin staining
  • Pituitary blastoma: early childhood tumor, small blastema-like cells, true rosettes, large glandular structures, DICER1 mutation
  • Pituitary nodular hyperplasia: enlarged acini by reticulin staining
Board review style question #1
    Which of the following is true of pituitary adenoma?

  1. Most pituitary carcinomas are hormonally inactive tumors.
  2. Most pituitary adenomas are part of hereditary or familial syndromes.
  3. The diagnosis of pituitary carcinoma is based on presence of cerebrospinal fluid or systemic metastases.
  4. Diabetes insipidus is often associated with adenoma.
  5. DICER1 mutations have been described in pituitary adenoma.
Board review answer #1
C. The diagnosis of pituitary carcinoma is based on presence of cerebrospinal fluid or systemic metastases
Board review style question #2

    Which of the following is true about this entity?

  1. This immunohistochemical feature is due to accumulation of glial fibrillary acidic protein.
  2. This entity has comparable outcome to typical adenomas.
  3. This immunohistochemical feature is often seen in prolactinomas.
  4. This immunohistochemical feature is seen in response to excess steroids, such as aldosterone.
  5. The histologic change present in this entity can be seen in neoplastic and non-neoplastic corticotrophs.
Board review answer #2
E. The histologic change present in this entity can be seen in neoplastic and non-neoplastic corticotrophs.
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