Background
Pituitary tumors are common neoplasms that constitute approximately 15% of all intracranial tumors. [1] Among sellar neoplasms, pituitary adenomas are the most common, accounting for up to 90% of the tumors diagnosed in this region. [2]
The history of pituitary tumor biology is rich. Analysis of DNA extracted from the teeth of an Irish giant (7'7" tall) who lived from 1761 to 1783 revealed a mutation in the AIP gene – the same mutation found in four Northern Irish families with pituitary tumors. This suggests a shared genetic link dating back centuries. Interestingly, the giant's skull, examined in 1909 by renowned physicians Harvey Cushing and Sir Arthur Keith, showed an enlarged pituitary fossa, further supporting the diagnosis. [3] Subsequent technological advances in genetics have expanded our knowledge of pituitary adenoma pathogenesis.
The clinical presentation of pituitary adenomas is broad. Some adenomas, called "functioning adenomas," secrete hormones that disrupt the body's endocrine system, leading to various conditions. Others, known as "nonfunctioning adenomas," do not produce hormones but can still cause symptoms by pressing on surrounding brain structures. Early diagnosis and treatment are crucial for managing these tumors and achieving optimal outcomes for patients. [1]
Pathophysiology
Around 95% of pituitary adenomas are sporadic. [4] The molecular basis underlying pituitary adenoma pathogenesis encompasses several mechanisms: activating mutations, receptor signaling defects, chromosomal instability and DNA damage, as well as senescence. [4]
Multiple oncogene abnormalities have be involved in pituitary tumorigenesis, such as G-protein abnormalities, RAS gene mutations, or p53 gene deletions, mutations, and rearrangements. [4] Nonfunctioning adenomas have been associated with hypermethylation of p16. [4] Galectin-3 (Gal-3), a gene involved in cell growth and apoptosis, has been described in prolactinomas and corticotrophin adenomas. [5] Additionally, familial pituitary adenomas, such as familial gigantism and acromegaly, have been associated with mutations in the aryl hydrocarbon-interacting protein gene (AIP). [4] Hereditary pituitary adenomas have also been linked to multiple endocrine neoplasia (MEN) syndromes, such as MEN types 1 and 4. [6]
Although pituitary tumorigenesis is heterogeneous and recurrent cell-specific oncogenic mutations are uncommon, recurrent oncogene mutations have been reported in GNAS (somatotrophin adenomas), USP8 (corticotrophin adenomas), and rarely in NR3C1. [4]
Most of these tumors are benign, but certain factors involved in tumorigenesis may determine their aggressiveness. For instance, the presence of p53 correlates with more aggressive tumor behavior. Furthermore, mutations in AIP, MEN1, and GPR101 have been found to be more frequently invasive. [7] Likewise, the pituitary tumor transforming gene-1 (PTTG-1) is an oncogene that has also been implicated in pituitary tumors as a marker of invasiveness and recurrence. [4, 8]
Classification of pituitary tumors
Pituitary tumors are classified according to size as microadenomas (< 1 cm diameter) or macroadenomas (≥ 1 cm diameter). They are also classified based on staining characteristics as chromophobic or chromophilic tumors. The latter can be further subdivided using hematoxylin and eosin stains into eosinophilic or basophilic. [9]
Advances in electron microscopy and immunohistochemistry have enabled hormone identification in many adenomas previously classified as chromophobic. These techniques have also allowed for the characterization of specific hormone production in eosinophilic tumors and revealed that many tumors exhibit multihormonal production.
The 2022 WHO classification of endocrine and neuroendocrine tumors classifies sellar tumors based on cell lineage determined by transcription factors, hormones, and other biomarkers. [10] Notably, "pituitary adenoma" is replaced with "pituitary neuroendocrine tumor" (PitNET).
PitNETs are categorized by the following cell lineages:
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PIT1 lineage: This includes somatotroph, lactotroph, mammosomatotroph, thyrotroph, mixed somatotroph and lactotroph, mature plurihormonal PIT1-lineage, immature PIT1-lineage, and acidophil stem cell tumors.
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TPIT lineage: This lineage consists of corticotrophin tumors.
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SF1 lineage: This lineage includes gonadotrophin tumors.
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PitNETs with no distinct cell lineage: This category includes plurihormonal tumors and null cell tumors.
This classification identifies subtypes with more aggressive behaviors and replaces "pituitary carcinoma" with "metastatic PitNETs." [10] However, because this classification relies on histopathology requiring resection, the clinical PANOMEN 3 classification was developed to guide prognosis and therapy for both resected and unresected tumors. PANOMEN 3 utilizes an evidence-based score incorporating risk factors, including age, sex, phenotype, secretory status, hypopituitarism, size, mass effect, invasion, residual tumor, histopathology, and genetic syndromes. [11]
Clinical presentation pathogenesis
Clinical manifestations are due to the local effect of the mass and distant endocrine manifestations that can affect a variety of organ systems. These effects are due to lack or excess of a given stimulating hormone on the target organ. [1]
Endocrine manifestations can be diverse. For example, even nonfunctioning adenomas can be associated with elevated prolactin blood levels. In this situation, hyperprolactinemia is secondary to stalk effect, which is the consequence of compression of the pituitary stalk by the sellar mass that interrupts the dopamine inhibitory signal from the hypothalamus to the prolactin-secreting cells of the adenohypophysis. [1]
Pituitary macroadenomas can also cause distinct visual field defects. Bitemporal hemianopia, a typical pattern in these cases, arises from compression of the optic chiasm. A study using cadaveric specimens measured the comparative pressure gradients between nasal crossing and temporal uncrossed fibers. Two 30-gauge needles connected to pressure transducers and a digital pressure monitor introduced into the chiasm of donated cadaveric specimens acted as sensors. A pediatric Foley catheter was placed into the pituitary fossa and gradually inflated to simulate the effect of a pituitary mass. Results show that pressure was consistently higher in the central aspect of the chiasm than in the lateral chiasm. [12] New engineering models of chiasmal compression (finite element modeling) may provide the possibility of measuring the degree of chiasmal compression in each patient based on MRI anatomic findings. [13]
Hormonal deficiencies - Clinical effects
Growth hormone deficiency [1]
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Adults - Increased rate of cardiovascular disease, obesity, reduced muscle strength and exercise capacity, and increased cholesterol
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Infants - Hypoglycemia
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Children - Decreased height and growth rate
Gonadotrophin deficiency [1]
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Men - Diminished libido and impotence; testes shrink in size, but spermatogenesis generally preserved
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Women - Diminished libido and dyspareunia; breast atrophy in chronic deficiency
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Children - Delayed or frank absence of puberty
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Adolescent girls - Present similarly to adult women
Thyrotropin deficiency - Malaise, weight gain, lack of energy, cold intolerance, and constipation [1]
Corticotrophin deficiency [1]
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Unlike primary adrenal insufficiency, mineralocorticoid function (which is dependent on the angiotensin-renin axis) is not affected; deficiency is limited to glucocorticoids and adrenal androgens
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Initially, symptoms are nonspecific (eg, weight loss, lack of energy, malaise); severe adrenal insufficiency may present as a medical emergency
Panhypopituitarism - Refers to deficiency of several anterior pituitary hormones; may occur in a slowly progressive fashion (eg, pituitary adenomas) [1]
Hormonal overproduction - Clinical effects
Prolactin [1]
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Hypogonadism, if hyperprolactinemia is sustained
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Women - Amenorrhea, galactorrhea, and infertility
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Men - Decreased libido, impotence, and rarely galactorrhea
Growth hormone [1]
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Children and adolescents - May result in pituitary gigantism
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Adults - Acromegaly
Changes in the size of the hand and feet, coarseness of the face, frontal bossing, and prognathism result. Further changes in the voice, and hirsutism, can also occur
Acromegaly frequently results in glucose intolerance, with 20% of patients progressing to diabetes mellitus
Respiratory difficulty and sleep apnea are common
Cardiac complications result from acromegalic cardiomyopathy
Although patients have a bulky appearance, they are generally weak because of associated myopathy
Carpal tunnel syndrome is frequent
Lumbar canal stenosis can present with a syndrome resembling amyotrophic lateral sclerosis
Acromegaly may be associated with colonic polyps, although an increased colon cancer is not conclusive
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Weight gain, centripetal obesity, moon facies, violet striae, easy bruisability, proximal myopathy, and psychiatric changes
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Other possible effects - Arterial hypertension, diabetes, cataracts, glaucoma, and osteoporosis
Epidemiology
Frequency
Pituitary tumors represent 10%–15% of all intracranial tumors. [1, 15] Whereas incidental pituitary tumors are found in approximately 10% of autopsies and neuroimaging studies of healthy subjects, [15, 16, 17] clinically evident pituitary adenomas are present in 1 of 11,000 subjects in the general population. [15, 18, 19, 20, 21, 22, 23, 24] The relative frequency of clinically evident pituitary adenomas is approximately 41%–62% in prolactinomas, 15–48% in clinically nonfunctioning adenomas, 6%–14% in somatotroph adenomas, 2–6% in corticotrophin adenomas, and approximately 1% in thyrotroph adenomas. [15, 18, 19, 20, 21, 22, 23, 24]
The incidence of clinically evident pituitary adenomas has been estimated to be 40 per million individuals per year. [21, 25, 26] The annual incidence of pituitary adenomas per 1 million individuals is estimated to be in the range of 16 to 26 for prolactinomas, approximately 10 for somatotroph adenomas, and 1.6 for corticotrophin adenomas. [1, 4, 20, 27, 28] However, it is important to note that these rates can vary based on population demographics and geographic location.
Demographics
Among patients with a clinically evident pituitary adenoma, 62%–77% are women. [15, 18, 19, 20, 21, 22, 23, 24] However, sex distribution is influenced by the type of pituitary adenoma and age.
Microprolactinomas have a female to male ratio of 20:1. Likewise, annual incidence of prolactinomas is higher in women than in men: 24–37 vs 7.6–9 per million, respectively. Nevertheless, after menopause, prolactinoma incidence is similar in both sexes. [4, 22, 25, 26] Cushing disease is also more frequent in women with a female-to-male ratio of 3:1. [29] On the contrary, nonfunctioning adenoma and acromegaly have similar frequency among males and females [4, 30]
Pituitary adenoma diagnosis predominates in middle-aged and elderly adults. However, its diagnosis can occur at any age. Peak acromegaly diagnosis occurs at age 40 to 60 years, prolactinoma in women usually predominates at age 25 to 40 years, and Cushing disease disproportionally affect young women. [4]
Mortality/Morbidity
Mortality rate related to pituitary tumors is low. Advances in medical and surgical management of these lesions and the availability of hormonal replacement therapies have contributed to successful management. Nevertheless, pituitary apoplexy is a life-threatening complication.
Because of cardiometabolic and respiratory comorbidities, acromegaly standardized mortality ranges from 1.41 to 1.45. [4, 31, 32, 33] Standardized mortality ratio in patients with active Cushing disease is 4 to 16 times higher compared to the general population, secondary to stroke and coronary disease [4, 34] Prolactinomas have not reported an increase in standardized mortality ratio. [35]
Morbidity associated with macroadenomas may include permanent visual loss, ophthalmoplegia, and other neurological complications. Tumor recurrence after surgical removal may also occur. Central nerve system metastases and, rarely, distant metastases can occur with pituitary tumors. [4]
Endocrine abnormalities are amenable to correction. However, damage in many organ systems as a result of longstanding uncorrected deficiencies may be irreversible. Additionally, overtreatment with glucocorticoids or thyroid hormones in patients with hypopituitarism may lead to cardiovascular and bone comorbidities. [4]
Prognosis
Visual prognosis
Visual field improvement has been reported in 79–95% of patients undergoing pituitary adenoma resection, and visual acuity improvement in 45–86%. [36]
The pattern of visual function recovery depends on the severity of the anterior visual pathway neuronal dysfunction:
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Visual impairment due to focal conduction block: This is the first stage; patients will experience normalization of the visual field defect within a week after optic chiasm decompression. [37]
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Visual impairment secondary to demyelination or decreased axonal transport without axonal loss: This is the second stage; patients will experience a slow progressive visual function recovery between 1 to 4 months after optic chiasm decompression. [37]
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Visual impairment due to irreversible neuronal damage: Patients will have minimal visual improvement through visual pathway remodeling and remyelination. [37]
Optical coherence tomography (OCT) can be used as a tool for predicting visual function recovery after pituitary tumor treatment. Normal macular ganglion cell-inner plexiform layer (mGCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness have been associated with a better postoperative visual outcome. OCT cutoff values are difficult to determine given the variation in values depending on the machine manufacturer used. Average pRNFL thickness below 75 to 81 um, and average mGCIPL thickness below 67 um have been associated with a worse visual outcome. [38]
Tumor recurrence
A high mitotic index, a Ki67 index greater than 3%, and histological subtypes such as sparsely granulated somatotroph adenomas, silent corticotrophin adenomas, Crooke cell adenomas, plurihormonal PIT1-positive tumors, and lactotroph macroadenomas in men have been suggested as potential prognostic pathological markers for aggressiveness. [7] Additionally, an evidence-based score, PANOMEN 3, has been proposed to assess prognosis in patients with resected and unresected adenomas. [11]
Approximately 30% of resected adenomas have persistent progressive growth in the next 4 years after surgery. [1]
A meta-analysis that included 17,509 patients with pituitary adenomas treated surgically showed a 5-year postoperative recurrence rate of 4% in somatotroph adenomas, 11% in corticotroph adenomas, 12% in nonfunctioning adenomas, and 18% in prolactinomas. [39]
Pituitary carcinoma
The presence of metastasis secondary to pituitary carcinomas can occur. However, its prevalence is extremely low. Pituitary carcinomas constitute less than 0.1% of all anterior pituitary tumors. [7]
Patient Education
Successful management of pituitary adenomas requires a highly motivated and compliant patient.
Hormone-replacement therapy is demanding, and a noncompliant patient is at risk for complications due to misuse of these agents.
Interaction of a team of specialists is required to manage these lesions. One of the specialists should serve as team leader and coordinate the patient's care.
Most patients with visual field defects improved visual function after transsphenoidal surgery (TSS). [36, 40] However, the degree and rate of visual recovery varies among patients and is influenced by multiple factors. [36]
Prompt reporting of new symptoms is important in addition to routine multidisciplinary follow-up visits.
The frequency of follow-up visits depends on the presence of residual tumor, visual deficit, hormonal needs, history of radiation therapy, or other complicating circumstances.
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This is a characteristic bitemporal hemianopic visual field defect.
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This contrast-enhanced coronal MRI was obtained in a patient who complained of visual loss.
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This visual field was plotted using a Goldman perimeter (ie, kinetic perimetry). It was obtained from a patient who reported visual loss and had a normal endocrine workup. The dark areas correspond to the impaired peripheral visual field. This visual field defect is consistent with an intrasellar lesion.
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Coronal T1 precontrast MRI A (left panel), B postcontrast (middle panel) and T2 (right panel) showing a sellar mass causing obvious left and upward displacement of the optic chiasm. The mass is a histologically proven pituitary macroadenoma, which presented initially with a large cystic subfrontal extension that was successfully resected in April of 2006. This patient has been observed closely for 2.5 years and despite obvious mass effect, he has no visual complaints and the neuro-ophthalmologic evaluation is normal. Although infrequent, clinicians should be aware of this possibility. Close follow-up is required.
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Axial, sagittal, and coronal MRI of the sellae in a patient with a severe headache, normal neuro-ophthalmologic examination, and no evidence of endocrine failure. A hyperintense mass is observed in the sella with suprasellar extension. This case illustrates the clinical spectrum of pituitary apoplexy. Transsphenoidal resection confirmed the diagnosis of pituitary apoplexy.