Background
Pierre Marie, a French neurologist (Salpetriere Hospital, Paris) was the first to describe a disease that involved the pituitary gland. In 1886, he studied 2 patients with clinical findings of what he termed acromegaly and postulated that the pituitary gland was involved in the pathogenesis.
Pituitary tumors are common neoplasms, and recognition of their presentation is critical since a favorable therapeutic outcome is dependent on early identification of the lesion.
The history of pituitary tumor biology is rich. A recent DNA examination from the teeth of an Irish patient with gigantism (7 ft, 7 in in height), who lived from 1761 to 1783 and was housed at the Hunterian Museum in London, revealed the same mutation in the AIP gene (c.910 C- T mutation) present in 4 families with pituitary tumors from Northern Ireland. This patient shared common haplotypes with the recent families studied. The skull of the index patient was actually examined by Harvey Cushing and Sir Arthur Keith in 1909 and found to have an enlarged pituitary fossa. Current technologic advances in genetics, as demonstrated by Chahal et al, permit a fascinating insight into the causes of human diseases spanning probably over 57 generations. [1]
Pituitary tumors are common neoplasms, and recognition of their presentation is critical since a favorable therapeutic outcome is dependent on early identification of the lesion.
Villwock et al noted that pituitary tumors constitute 10-15% of all diagnosed intracranial tumors, 90% of which are adenomas. In a study of pituitary tumor diagnoses and procedures from 1993 to 2011, they found that pituitary tumor diagnoses and resections have grown significantly over the past 20 years and that transsphenoidal surgical resection has increased, while transfrontal resections have decreased. [2]
Pathophysiology
Multiple oncogene abnormalities may be involved in pituitary tumorigenesis. G-protein abnormalities, ras gene mutations, p53 gene deletions, mutations, and rearrangements, and the association of pituitary tumors with the syndrome of multiple endocrine neoplasia have been described and are involved in the development of adenomas in the pituitary gland. The pituitary tumor transforming gene-1 (PTTG-1) is a newly discovered oncogene that serves as a marker of malignancy grades in several endocrine malignancies; this gene is known to regulate the cellular mitosis process and forced expression of this gene induces tumor formation in nude mice. PTTG-1 is overexpressed in pituitary tumors. [3]
Recent work suggests that pituitary tumorigenesis is more heterogenous than formerly thought. [4] Nonfunctioning adenomas are associated with hypermethylation of p16 prolactinomas, and corticotropin-secreting tumors express galectin-3 (Gal-3), a gene involved in cell growth and apoptosis. Inhibition of Gal-3 may serve as a molecular therapeutic target. Mutations of the aryl hydrocarbon-interacting protein gene (AIP) may be present in some cases of familial gigantism and acromegaly, as well as other pituitary tumor types. [5, 6]
Most of these tumors are benign, but certain factors involved in the genesis of the tumor may determine its rate of growth and aggressiveness. For instance, the presence of p53 correlates with more aggressive tumor behavior.
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. Pituitary adenomas, with a few exceptions, are not under the control of hypothalamic releasing factors.
An explanation for the development of bitemporal visual-field defects in association with pituitary tumors has been a subject of renewed interest. In a recent study, comparative pressure gradients were measured between nasal crossing and temporal uncrossed fibers. Two 30-gauge needles connected to separate pressure transducers and a digital pressure monitor were introduced into the chiasm of donated cadaveric specimens. A pediatric Foley catheter was placed into the pituitary fossa and gradually inflated to simulate the effect of a pituitary mass. Pressure was consistently higher in the central aspect of the chiasm than in lateral chiasm. [7] New engineering models of chiasmal compression (finite element modeling) may be developed in the future, taking into account the geometry of the nasal crossing fibers and the increased mechanical pressure; theoretically, this could provide the possibility of measuring the degree of chiasmal compression in each patient based on MRI anatomic findings. [8]
Classification of pituitary tumors
Based on size, pituitary tumors can be divided into microadenomas (< 1 cm diameter) and macroadenomas (>1 cm diameter). They also can be classified on the basis of staining characteristics, as chromophobic and chromophilic tumors. The latter can be further subdivided using hematoxylin and eosin stains (ie, eosinophilic or basophilic). [9]
However, this classification has proven to be of no clinical value and now has been replaced by a more functional classification that involves electromicroscopy and immunohistochemistry. These techniques have identified hormonal production in many chromophobe adenomas, enabling pathologists to identify hormones that are produced by eosinophilic tumors. They also have demonstrated that many tumors produce more than one hormone. The mutated form of p53, a tumor suppressor, also can be determined histologically. The presence of this mutated gene suggests a tumor with rapid growth.
The endocrinologic morbidity that is associated with pituitary tumors is dependent on the specific underproduction or overproduction of a hormone or hormones associated with the tumor.
Hormonal deficiencies - Clinical effects
Growth hormone deficiency
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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
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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
Corticotrophin deficiency
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Unlike primary adrenal insufficiency, mineralocorticoid function (which is dependent on the angiotensin-renin axis) not affected; deficiency limited to glucocorticoids and adrenal androgens
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Initially, symptoms 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)
Hormonal overproduction - Clinical effects
Prolactin
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Hypogonadism, if hyperprolactinemia sustained
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Women - Amenorrhea, galactorrhea, and infertility
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Men - Decreased libido, impotence, and rarely galactorrhea
Growth hormone
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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, confirm the diagnosis.
Acromegaly frequently results in glucose intolerance, with 20% of patients progressing to diabetes mellitus.
Respiratory difficulty and sleep apnea are fairly common.
Cardiac complications result from acromegalic cardiomyopathy.
Although patients have a bulky appearance, they are generally weak as a result of associated myopathy.
Carpal tunnel syndrome is seen frequently.
Lumbar canal stenosis can present with a syndrome resembling amyotrophic lateral sclerosis.
Acromegaly may be associated with colonic polyps, although an increased colon cancer incidence has not been shown definitively.
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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
United States
Pituitary tumors represent anywhere between 10% and 15% of all intracranial tumors.
Incidental pituitary tumors are found in approximately 10% of autopsies.
The incidence of acromegaly is approximately 3 per million. Acromegaly has no sex predilection.
International
The incidence of pituitary tumors is probably the same worldwide.
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.
Pituitary apoplexy can be a lethal complication.
Morbidity associated with macroadenomas may include permanent visual loss, ophthalmoplegia, and other neurological complications.
Tumor recurrence is also a possibility.
CNS metastases and, rarely, distant metastases occur with pituitary tumors.
Endocrine abnormalities are amenable to correction. However, damage in many organ systems as a result of long-standing uncorrected deficiencies may be irreversible.
Sex
Symptomatic prolactinomas are found more frequently in women. Cushing disease also is more frequent in women (female-to-male ratio 3:1).
Age
Most pituitary tumors occur in young adults, but they may be seen in adolescents and elderly persons. Acromegaly usually is seen in the fourth and fifth decades of life.
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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.
