Pituitary Adenoma
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Pituitary Adenoma?
Section titled “1. What is Pituitary Adenoma?”Pituitary adenoma is a benign tumor arising from the glandular cells of the anterior pituitary. It is the most common cause of chiasmal compression in adults and the most frequent tumor in the sellar region.
It accounts for 12–15% of symptomatic intracranial tumors. Including autopsy and imaging studies, up to 25% of the population may harbor them, but most are incidental and asymptomatic, with an average prevalence of 16.7% (14.4% at autopsy, 22.5% on imaging). According to the Japan Brain Tumor Registry, they account for about 18% of primary brain tumors. Three percent of cases are associated with MEN1. Ectopic pituitary adenomas (EPA) account for approximately 0.48% of all cases 6).
Two axes of classification are clinically important: classification by size and classification by hormonal activity.
The frequency distribution in Japan is shown below.
| Type of adenoma | Proportion (approximate) |
|---|---|
| Non-functioning adenoma | About 50% (most common) |
| Prolactin-producing adenoma | About 25% |
| GH-producing adenoma | About 20% |
| Others (ACTH, TSH, LH/FSH producing) | Remainder |
In the 2017 WHO classification, a classification based on cell lineage (master transcription factors such as Pit-1, Tpit, etc.) was adopted. The term “atypical adenoma” is no longer recommended. Pituitary carcinoma is limited to those with metastasis and accounts for less than 1% of all cases.
Including autopsy and imaging studies, up to 25% of the population may have them, making them extremely common tumors. However, symptomatic cases account for only 12–15% of all intracranial tumors. Most are discovered incidentally without symptoms.
2. Main symptoms and clinical findings
Section titled “2. Main symptoms and clinical findings”Subjective symptoms
Section titled “Subjective symptoms”- Visual abnormalities: Decreased visual acuity and visual field defects are the most common subjective symptoms. In non-functioning adenomas, visual field defects are often the only initial symptom.
- Headache: Headache may occur even without extension outside the sella turcica. Physical effects on the diaphragma sellae are considered the main cause.
- Symptoms due to prolactin-producing adenoma (prolactinoma): In women, amenorrhea, galactorrhea, and infertility; in men, hypogonadism and erectile dysfunction. Symptoms in men are subtle and often lead to delayed diagnosis.
- Symptoms due to GH-producing adenoma: In children, gigantism; in adults, acromegaly (facial changes, enlargement of hands and feet, hirsutism).
- Symptoms due to ACTH-producing adenoma: Cushing’s syndrome (moon face, central obesity, hypertension, hirsutism, hyperpigmentation).
- Symptoms due to TSH-producing adenoma: Hyperthyroidism (weight loss, excessive sweating, goiter). Not associated with thyroid eye disease.
- Acute onset (pituitary apoplexy): Hemorrhage or necrosis within an existing tumor causes acute severe headache, visual field defects, and ocular motor disturbances.
Clinical Findings (Findings Confirmed by Physician Examination)
Section titled “Clinical Findings (Findings Confirmed by Physician Examination)”Visual Field Defect Patterns
Section titled “Visual Field Defect Patterns”A tumor extending superiorly selectively damages the crossing fibers (from the nasal hemiretina) of the optic chiasm from below. This typically results in bitemporal hemianopia respecting the vertical meridian.
- Early findings: Visual field defects begin in the upper temporal quadrant in both eyes.
- Asymmetry: Incomplete and asymmetric hemianopia is common.
- Junction scotoma: A characteristic finding due to damage to the anterior angle of the optic chiasm.
- Advanced cases: As compression increases, non-crossing fibers are also affected, and defects extend into the nasal visual field.
Fundus and OCT Findings
Section titled “Fundus and OCT Findings”- Band atrophy (bow-tie atrophy): Chronic compression selectively atrophies the horizontal quadrant of the optic disc. This is a specific finding for chiasmal lesions. Papilledema is rare.
- OCT (macular retinal inner layers): Selective thinning of the nasal area relative to the vertical meridian of the fovea. OCT can detect mild optic atrophy earlier than fundus examination. It is also useful for predicting visual function prognosis after treatment.
- OCT (cpRNFL): Thinning of the temporal and nasal quadrants.
Other findings
Section titled “Other findings”- Pupil: If there is asymmetry in visual field defects between the two eyes, a relative afferent pupillary defect (RAPD) will be positive.
- Ocular motility disorder: If the tumor invades the cavernous sinus, it can cause cranial nerve III, IV, and VI palsy, leading to diplopia.
- Severe complications of pituitary apoplexy: Rarely, compression of the anterior cerebral artery can lead to cerebral infarction. A systematic review reported 47 cases in the literature, with a mortality rate of 26.8% 3).
The optic chiasm is located almost directly above the pituitary gland. An adenoma growing upward compresses the crossing fibers of the optic chiasm (fibers from the nasal half of each retina) from below, resulting in temporal visual field defects in both eyes, with the vertical meridian as the boundary. In addition to compression, ischemia may also be involved.
3. Causes and risk factors
Section titled “3. Causes and risk factors”Mechanism of tumor development
Section titled “Mechanism of tumor development”Most pituitary adenomas are benign and occur sporadically. The following genetic factors are known to be involved.
- PTTG (pituitary tumor transforming gene): Overexpressed in hormone-secreting adenomas.
- AIP gene mutation: Associated with increased risk of invasive GH-producing adenomas.
- MEN1 (multiple endocrine neoplasia type 1): Associated with 3% of cases.
Risk Factors for Pituitary Apoplexy
Section titled “Risk Factors for Pituitary Apoplexy”Risk factors that trigger pituitary apoplexy (hemorrhage or infarction within the tumor) are diverse2).
| Category | Major Risk Factors |
|---|---|
| Hormonal | Pregnancy/postpartum, estrogen therapy, GnRH/TRH stimulation tests |
| Blood/Vascular | Coagulopathy/thrombocytopenia, anticoagulant therapy |
| Hemodynamic Changes | Sudden blood pressure elevation (exercise), after cardiac surgery, after spinal anesthesia |
| Other | Radiation therapy, diabetes, head trauma, dopamine agonist therapy |
Regarding pituitary apoplexy during pregnancy, a review reported 36 cases, most occurring in the second trimester. Headache was the most common initial symptom, and surgery was required in more than half of the cases1).
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”Imaging Diagnosis
Section titled “Imaging Diagnosis”- MRI (first choice): May show isointensity to brain parenchyma on both T1- and T2-weighted images; contrast-enhanced MRI should be performed. Coronal sections are particularly useful for understanding the anatomical relationship with the optic chiasm.
- CT: Performed as an adjunct. Diagnosis is often difficult for microadenomas. The low-density area of the suprasellar cistern disappears and appears as a slightly high-density area.
Visual Field and Ophthalmic Examination
Section titled “Visual Field and Ophthalmic Examination”- Visual field testing: Essential for detecting bitemporal hemianopia respecting the vertical meridian. Regular visual field testing is important for assessing disease progression and treatment efficacy.
- Optical coherence tomography (OCT): Has higher sensitivity for detecting mild optic atrophy than fundus examination and can quantitatively evaluate localized thinning of the inner retinal layers.
- Diagnosis of ectopic adenoma: PET/MRI combining 68Ga-labeled somatostatin analogs and 18F-FDG is useful for differentiating tumor localization5).
Endocrine Examination
Section titled “Endocrine Examination”Essential for evaluating functional adenomas.
- Prolactin (PRL): Normal values are <20 ng/mL in men and <25 ng/mL in women. In prolactinomas, levels rise above 200 ng/mL (sometimes >10,000). Differentiation from mild elevation due to pituitary stalk compression (stalk effect) is necessary.
Differential Diagnosis
Section titled “Differential Diagnosis”- Tuberculum sellae meningioma: While pituitary adenoma typically presents with symmetric bitemporal hemianopia, tuberculum sellae meningioma often presents with unilateral central scotoma or junctional scotoma. MRI shows a characteristic dural tail sign.
- Craniopharyngioma: Compresses the optic chiasm from above, resulting in bitemporal hemianopia starting from the lower fields.
- Lymphocytic hypophysitis: The entire pituitary gland is enlarged and shows a triangular shape convex upward. Differentiation is difficult without biopsy.
- Tilted disc / optic nerve hypoplasia: Often can be differentiated by careful visual field testing.
5. Standard Treatment
Section titled “5. Standard Treatment”Except for prolactinomas, surgery is the first-line treatment.
Surgical Therapy
Section titled “Surgical Therapy”- Hardy surgery (transsphenoidal approach): The pituitary tumor is reached through the nose and sphenoid sinus, aiming for total resection. Recently, endoscopic transsphenoidal surgery is also widely performed.
- Relief of optic chiasm compression can lead to improvement in visual acuity and visual field. However, if obvious optic atrophy has already occurred, the visual prognosis is poor.
Medical Therapy
Section titled “Medical Therapy”- Prolactinoma: Oral dopamine agonists such as bromocriptine and cabergoline are the mainstay of treatment. Tumor shrinkage and hormone normalization can be achieved in 80–90% of prolactinomas 4).
Radiation Therapy
Section titled “Radiation Therapy”- Performed as adjuvant therapy after surgery. Stereotactic radiosurgery (e.g., Gamma Knife) is also an option.
Acute Management of Pituitary Apoplexy
Section titled “Acute Management of Pituitary Apoplexy”Pituitary apoplexy is an emergency condition requiring prompt management.
- Corticosteroid replacement: If hemodynamics are unstable or signs of cortisol deficiency are present, administer hydrocortisone 100–200 mg as an intravenous bolus, followed by continuous intravenous infusion at 2–4 mg/hour or intramuscular injection of 50–100 mg every 6 hours 2).
- Surgical indications: Transsphenoidal surgery is considered in cases with severe visual loss, persistent or worsening visual field defects, or decreased level of consciousness 2). Surgical treatment in the acute phase can be expected to improve visual field deficits in most cases.
Prolactinoma is the only exception; oral dopamine agonists (bromocriptine, cabergoline) are the mainstay of treatment. Tumor shrinkage and hormone normalization can be achieved in 80–90% of cases 4). For other adenomas, surgery is the first choice.
6. Pathophysiology and Detailed Mechanisms
Section titled “6. Pathophysiology and Detailed Mechanisms”Tumor Extension Patterns and Mechanisms of Chiasmal Compression
Section titled “Tumor Extension Patterns and Mechanisms of Chiasmal Compression”Pituitary adenomas arise as soft, well-defined lesions within the sella turcica. As they grow, they extend upward and compress the optic chiasm. They may also erode the anterior clinoid process and sellar floor, or extend into the cavernous sinus and sphenoid sinus.
The optic chiasm is located almost directly above the pituitary gland. Adenomas that grow upward selectively damage the crossing fibers (from the nasal retina), causing bitemporal visual field defects respecting the vertical meridian. In addition to compression, ischemia may also play a role. Pituitary adenomas receive blood supply from the dural branches of the internal carotid artery and are strongly influenced by the systemic circulation.
Histological Features
Section titled “Histological Features”- They show a monomorphic appearance and are arranged in sheets or cords.
- The reticulin fiber network is sparse, which helps distinguish them from non-neoplastic pituitary tissue.
- Immunohistochemical staining identifies the type of secreted hormone.
- Low molecular weight keratin (LMWK) immunostaining distinguishes densely granulated from sparsely granulated types.
Mechanism of pituitary apoplexy and special conditions
Section titled “Mechanism of pituitary apoplexy and special conditions”Pituitary apoplexy is a condition in which hemorrhage or infarction occurs within a tumor, causing the lesion to rapidly swell. The unique blood supply of pituitary adenomas contributes to intratumoral hemorrhage. Prolactin-producing tumors are considered most prone to apoplexy.
Nelson syndrome is a condition in which an ACTH-secreting adenoma rapidly enlarges after bilateral adrenalectomy for Cushing syndrome, due to loss of feedback suppression by adrenal steroids.
Progression to pituitary carcinoma
Section titled “Progression to pituitary carcinoma”Pituitary carcinoma accounts for only 0.1–0.2% of all cases, and most develop from treatment-resistant invasive adenomas. An increase in the Ki-67 labeling index over time is one indicator 4).
Ectopic pituitary adenoma
Section titled “Ectopic pituitary adenoma”Ectopic pituitary adenomas arise from remnants of embryonic pituitary cells along the migration path of Rathke’s pouch. They are rare, accounting for about 0.48% of all cases 6). The most common site is the nasopharynx (66.67%), followed by the suprasellar region (25%) 5, 6).
Pituitary apoplexy is an emergency condition in which hemorrhage or infarction occurs within an existing pituitary adenoma, causing the lesion to rapidly swell. It presents with sudden headache, vision loss, eye movement disorders, and impaired consciousness. Rarely, it may be complicated by cerebral infarction in the anterior cerebral artery territory, with a reported mortality rate of up to 26.8% 3).
7. Latest research and future perspectives (research-stage reports)
Section titled “7. Latest research and future perspectives (research-stage reports)”Cerebral infarction associated with pituitary apoplexy
Section titled “Cerebral infarction associated with pituitary apoplexy”Zoli et al. (2023) conducted a systematic review of cerebral infarction associated with pituitary apoplexy, collecting 47 cases from the literature. Compression at the parasellar extension of the internal carotid artery was the most common cause, and infarction in the anterior cerebral artery territory was particularly rare, with 11 cases from 10 studies. Overall mortality reached 26.8%, and they concluded that early transsphenoidal surgery to restore blood flow is important for improving outcomes 3).
Pituitary Apoplexy During Pregnancy
Section titled “Pituitary Apoplexy During Pregnancy”Gamito et al. (2023) collected 36 cases of pituitary apoplexy during pregnancy from the literature. Most occurred in the second trimester, with headache being the most frequent initial symptom. Surgery was required in more than half of the cases, and 3 preterm births and 1 maternal death were reported 1).
COVID-19 Vaccination and Pituitary Apoplexy
Section titled “COVID-19 Vaccination and Pituitary Apoplexy”Aliberti et al. (2022) reported a case of a 50-year-old man who developed severe headache, nausea, and diplopia the day after receiving the third dose of the COVID-19 mRNA vaccine (Moderna). MRI revealed hemorrhage within a giant adenoma measuring 35×27×39 mm. Immunohistochemical staining detected SARS-CoV-2 nucleoprotein in pituitary tissue for the first time, suggesting that asymptomatic infection prior to vaccination may have persisted in the pituitary vascular endothelium 2).
Treatment Strategies for Pituitary Carcinoma
Section titled “Treatment Strategies for Pituitary Carcinoma”Temozolomide (TMZ) is recommended as the first-line chemotherapy for pituitary carcinoma by the European Society of Endocrinology (ESE).
Dai et al. (2021) reported a case of progression from a treatment-resistant prolactinoma to pituitary carcinoma. The Ki-67 labeling index increased over time from 3% to 10% to 20% to 30%. The response rate to TMZ was 65.2%, with a median response duration of 30 months, but many cases acquired TMZ resistance. Molecular marker studies of Ki-67, P53, P27, telomerase, and others are ongoing 4).
Management of Ectopic TSH-Producing Microadenoma
Section titled “Management of Ectopic TSH-Producing Microadenoma”Li et al. (2021) reported a case of a suprasellar ectopic TSH-producing microadenoma in a 10-year-old girl. 68Ga-labeled somatostatin analog PET/MRI was useful for localization, and endoscopic transsphenoidal surgery achieved remission for 4 years postoperatively 5).
8. References
Section titled “8. References”- Gamito MAPO, Amaral NYB, Rodrigues CF, et al. Pituitary Apoplexy in Pregnancy: What do We Know? Rev Bras Ginecol Obstet. 2023;45(5):273-280.
- Aliberti L, Gagliardi I, Rizzo R, et al. Pituitary apoplexy and COVID-19 vaccination: a case report and literature review. Front Endocrinol. 2022;13:1035482.
- Zoli M, Guaraldi F, Rustici A, et al. Bilateral anterior circulation stroke: A rare but threatening consequence of pituitary apoplexy. Neuroradiol J. 2023;36(6):746-751.
- Dai C, Sun B, Guan S, et al. Evolution of a refractory prolactin-secreting pituitary adenoma into a pituitary carcinoma: report of a challenging case and literature review. BMC Endocr Disord. 2021;21:217.
- Li X, Zhao B, Hou B, et al. Case Report and Literature Review: Ectopic Thyrotropin-Secreting Pituitary Adenoma in the Suprasellar Region. Front Endocrinol. 2021;12:619161.
- Li Y, Zhu JG, Li QQ, et al. Ectopic invasive ACTH-secreting pituitary adenoma mimicking chordoma: a case report and literature review. BMC Neurol. 2023;23:81.