In Neuroanatomy

7/27/2019 In Neuroanatomy

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In neuroanatomy, a nucleus is a brain structure consisting of a relatively compact cluster of

neurons. It is one of the two most common forms of nerve cell organization, the other being

layered structures such as the cerebral cortex or cerebellar cortex. In anatomical sections, a

nucleus shows up as a region of gray matter, often bordered by white matter. The

vertebrate brain contains hundreds of distinguishable nuclei, varying widely in shape and

size. A nucleus may itself have a complex internal structure, with multiple types of neuronsarranged in clumps (subnuclei) or layers.

The term "nucleus" is in some cases used rather loosely, to mean simply an identifiably

distinct group of neurons, even if they are spread over an extended area. The reticular

nucleus of the thalamus, for example, is a thin layer of inhibitory neurons that surrounds the

thalamus.

Some of the major anatomical components of the brain are organized as clusters of

interconnected nuclei. Notable among these are the thalamus and hypothalamus, each of

which contains several dozen distinguishable substructures. The medulla and pons also

contain numerous small nuclei with a wide variety of sensory, motor, and regulatory

functions.In the peripheral nervous system, a cluster of neurons is referred to instead as a ganglion.

Examples

Brainstem: red nucleus, vestibular nucleus, inferior olive

Cerebellum: dentate nucleus, emboliform nucleus, globose nucleus, fastigial nucleus

Basal ganglia: striatum (caudate and putamen), pallidum (globus pallidus, medial and

lateral), substantia nigra, subthalamic nucleus

Cranial nerve nuclei

Nucleus Accumbens

The nucleus accumbens (NAcc), also known as the accumbens nucleus or as the nucleus

accumbens septi (Latin for nucleus leaning against the septum) or as part of the pleasure

center, is a collection of neurons and forms the main part of the ventral striatum. It is

thought to play an important role in reward, pleasure, laughter, addiction, aggression, fear,

and the placebo effect.[1][2][3]

Each half of the brain has one nucleus accumbens. It is located where the head of the

caudate and the anterior portion of the putamen meet just lateral to the septum

pellucidum. The nucleus accumbens and the olfactory tubercle collectively form the ventral

striatum, which is part of the basal ganglia.[4]

The nucleus accumbens can be divided into two structuresthe nucleus accumbens core

and the nucleus accumbens shell. These structures have different morphology and function.

The principal neuronal cell type found in the nucleus accumbens is the medium spiny

neuron. The neurotransmitter produced by these neurons is gamma-aminobutyric acid

(GABA), one of the main inhibitory neurotransmitters of the central nervous system. These

neurons are also the main projection or output neurons of the nucleus accumbens.

While 95% of the neurons in the nucleus accumbens are medium spiny GABA-ergic

projection neurons, other neuronal types are also found such as large aspiny cholinergic

interneurons.

[edit]Output and input
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.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Thalamushttp://en.wikipedia.org/wiki/Thalamic_reticular_nucleushttp://en.wikipedia.org/wiki/Thalamic_reticular_nucleushttp://en.wikipedia.org/wiki/Vertebratehttp://en.wikipedia.org/wiki/White_matterhttp://en.wikipedia.org/wiki/Gray_matterhttp://en.wikipedia.org/wiki/Cerebellumhttp://en.wikipedia.org/wiki/Cerebral_cortexhttp://en.wikipedia.org/wiki/Neuronhttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Neuroanatomy


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[edit]

Output

The output neurons of the nucleus accumbens send axon projections to the ventral analog

of the globus pallidus, known as the ventral pallidum (VP). The VP, in turn, projects to the

medial dorsal nucleus of the dorsal thalamus, which projects to the prefrontal cortex as well

as the striatum. Other efferents from the nucleus accumbens include connections with thesubstantia nigra and the pontine reticular formation.

[edit]

Input

Major inputs to the nucleus accumbens include prefrontal association cortices, basolateral

amygdala, and dopaminergic neurons located in the ventral tegmental area (VTA), which

connect via the mesolimbic pathway. Thus the nucleus accumbens is often described as one

part of a cortico-striato-thalamo-cortical loop.

Dopaminergic input from the VTA is thought to modulate the activity of neurons within the

nucleus accumbens. These terminals are also the site of action of highly-addictive drugs such

as cocaine and amphetamine, which cause a manifold increase in dopamine levels in the

nucleus accumbens.

Another major source of input comes from the CA1 and ventral subiculum of the

hippocampus to the dorsomedial area of the Nucleus accumbens. The neurons of the

hippocampus have a noteworthy correlation to slight depolarizations of cells in the nucleus

accumbens, which makes them more positive and therefore more excitable. The correlated

cells of these excited states of the medium spiny neurons in the Nucleus accumbens are

shared equally between the subiculum and CA1. The subiculum neurons are found to

hyperpolarize (increase negativity) while the CA1 neurons "ripple" (fire > 50 Hz) in order to

accomplish this priming. [5]

Caudate nucleus

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Brain: Caudate nucleus

Transverse Cut of Brain (Horizontal Section), basal

ganglia is blue

The caudate nucleus is a nucleus located within the basal ganglia of the brains of many

animal species. The caudate nucleus is an important part of the brain's learning and memory

system.

Anatomy
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Caudate nucleus within the skull

The caudate nuclei are located near the center of the brain, sitting astride the thalamus.

There is a caudate nucleus within each hemisphere of the brain. Individually, they resemblea C-shape structure with a wider "head" (caput in Latin) at the front, tapering to a "body"

(corpus) and a "tail" (cauda). Sometimes a part of the caudate nucleus is referred to as the

"knee" (genu).[1]

Transverse view of the caudate nucleus from a structural MR image

The head and body of the caudate nucleus form part of the floor of the anterior horn of the

lateral ventricle. After the body travels briefly towards the back of the head, the tail curves

back toward the anterior, forming the roof of the inferior horn of the lateral ventricle. This

means that a coronal (on a plane parallel to the face) section that cuts through the tail will

also cross the body and head of the caudate nucleus.

The caudate nucleus is related anatomically to a number of other structures. It is separated

from the lenticular nucleus (made up of the globus pallidus and the putamen) by the

anterior limb of the internal capsule. Together the caudate and putamen form the dorsal

striatum.

[edit]
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Neurochemistry

The caudate nucleus is highly innervated by dopamine neurons. These neurons originate

mainly from the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc).

There are also additional inputs from various association cortices.

[edit]Physiology

[edit]

Learning and memory

Historically, the basal ganglia as a whole have been implicated in higher-order motor

control.[2] The caudate nucleus was initially thought to primarily be involved with control of

voluntary movement. More recently, it has been demonstrated that the caudate is highly

involved in learning and memory,[3] particularly regarding feedback processing.[4] In

general, it has been demonstrated that neural activity will be present within the caudate

while an individual is receiving feedback. People with hyperthymesia appear to have slight

increases in the sizes of the caudate nucleus as well as of the temporal lobe of the cortex.[5]

[edit]

Emotion

The caudate nucleus has been implicated in responses to visual beauty, and has been

suggested as one of the "neural correlates of romantic love".[6][7]

[edit]

Language comprehension

The left caudate in particular has been suggested to have a relationship with the thalamus

that governs the comprehension and articulation of words as they are switched between

languages.[8][9][edit]

Threshold control

The brain contains large collections of neurons reciprocally connected by excitatory

synapses, thus forming large network of elements with positive feedback. It is difficult to see

how such a system can operate without some mechanism to prevent explosive activation.

There is some indirect evidence[10] that the caudate may perform this regulatory role by

measuring the general activity ofcerebral cortex and controlling the threshold potential.

[edit]

Role in obsessive compulsive disorder

It has been theorized that the caudate nucleus may be dysfunctional in persons with

obsessive compulsive disorder (OCD), in that it may perhaps be unable to properly regulate

the transmission of information regarding worrying events or ideas between the thalamus

and the orbitofrontal cortex.

A neuroimaging study with positron emission tomography found that the right caudate

nucleus had the largest change in glucose metabolism after patients had been treated with

paroxetine.[11] Recent SDM meta-analyses ofvoxel-based morphometry studies comparing

people with OCD and healthy controls have found people with OCD to have increased grey

matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei, while

decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate

gyri.[12][13] These findings contrast with those in people with other anxiety disorders, whoevince decreased (rather than increased) grey matter volumes in bilateral lenticular /
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caudate nuclei, while also decreased grey matter volumes in bilateral dorsal medial

frontal/anterior cingulate gyri.[13]

Hypophyseal portal system

Vein: Hypophyseal portal system

Latin venae portales hypophysiales

The hypophyseal portal system is the system of blood vessels that link the hypothalamus

and the anterior pituitary in the brain.

It allows endocrine communication between the two structures : the hypothalamus secretes

releasing and inhibitory hormones in the portal system such as corticotropin-releasing

hormone or thyrotropin-releasing hormone, and they are received by the anterior pituitary.

Using these, the anterior pituitary is able to fulfill its function of regulating the other

endocrine glands.

Hypophysiotropic peptides released near the median eminence are transported to the

anterior pituitary, where they exert their physiologic effects. Branches from the internal

carotid artery provide the blood supply to the pituitary. The superior hypophyseal arteries

form the primary capillary plexus that supplies blood to the median eminence. From this

capillary network, the blood is drained in long hypophyseal portal veins into the secondaryplexus. The hypophysiotropic peptides released at the median eminence enter the primary

plexus capillaries. From there, they are transported to the anterior pituitary via the long

hypophyseal portal veins to the secondary plexus. The secondary plexus is a network of

fenestrated sinusoid capillaries that provides the blood supply to the anterior pituitary. The

cells of the anterior pituitary express specific G protein-coupled receptors that bind the

neuropeptides, activating intracellular second-messenger cascades that produce the release

of anterior pituitary hormones. [1]

It is one of the portal systems of circulation of the human body; that is, it involves two

capillary beds connected in series by venules. One other such system is the hepatic portal

system.[2]

[edit]

Hormone transport

Mechanism for hormone transport via hypothalamoportal vessels:

cells regulated by different nuclei in the hypothalamus, i.e., neurons that release

neurotransmitters as hormones in the connective link between the pituitary and the

brain. Hypothalamic hormones stimulate the release of the respective hormone

from the anterior pituitary gland.

ligands (in this case, hormones released by the hypothalamus to activate hormone release

from the anterior pituitary) are picked up by blood vessels, then taken to the

anterior pituitary where they are broken down and released back into blood vessels
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hypothalamoportal vessels act as a local route for blood flow directly from the

hypothalamus to the anterior pituitary.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Dopamine agonists

Class Summary

These agents directly stimulate postsynaptic dopamine receptors. Dopaminergic neurons in

tuberoinfundibular processes modulate the secretion of prolactin from the anterior pituitary

by secreting a prolactin inhibitory factor, believed to be dopamine

Bromocriptine (Parlodel)

Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist; partialdopamine D1-receptor agonist. Inhibits prolactin secretion with no effect on other pituitary

hormones. May be given with food to minimize possibility of GI irritation.

Hyperprolactinemia (Parlodel)

Initial: 1.25-2.5 mg PO qDay

May increase by 2.5 mg/day q2-7Days

Usual therapeutic dosage 5-7.5 mg/day, ranges from 2.5-15 mg/day

Up to 30 mg/day has been used in some patients with amenorrhea &/or galactorrhea

Parkinson Disease (Parlodel)

1.25 mg PO q12hr

May increase dose by 2.5 mg/day q2-4Weeks

Safety >100 mg/day not established

Acromegaly (Parlodel)

1.25-2.5 mg PO qHS for 3 days

May increase by 1.25-2.5 mg/day at q3-7Days

Not to exceed 100 mg/day

Diabetes (Cycloset)

Quick release formulation (Cycloset) is the only bromocriptine product indicated for

diabetes mellitus type 2 as adjunct to diet and exercise to improve glycemic control

Initial dose: 1 tablet (0.8 mg) PO qDay increased weekly by 1 tablet until maximal tolerated

daily dose of 1.6-4.8 mg is achieved
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Take within 2 hours after waking in the morning with food

Note: Cycloset is not indicated for hyperprolactinemia, Parkinson disease, or acromegaly

Neuroleptic Malignant Syndrome (Off-label)

2.5-5 mg PO 2-3 times/day; not to exceed 45 mg/day

Administration: take with food

Hepatic Impairment

Dose adjustment may be necessary; there are no guidelines

Mechanism of Action

Semisynthetic ergot alkaloid, dopamine receptor agonist, inhibits prolactin secretion, and

lowers blood levels of growth hormone in acromegaly

Quick-release formulation of bromocriptine (Cycloset) is thought to act on circadian

neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic

drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and

postprandial states in patients with insulin-resistant

Pharmacokinetics

Half-life elimination: 4-4.5 hr (initial phase); 8-20 hr (terminal phase)

Excretion: 85% feces (via biliary elimination); urine (2.5-5.5%)

Protein bound: 90-96% (to albumin)

Peak plasma time: 1-3 hr

Vd: 61L

Absorption: 28% from GI tract

Bioavailability: 28% (parlodel); 65-95% (cycloset)

Metabolism: Completely in liver, principally by hydrolysis of the amide bond to produce

lysergic acid and a peptide fragment

Cabergoline (Dostinex)

Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist with low

affinity for D1 receptors.

Hyperprolactinemic Disorders of Either Idiopathic or Pituitary Adenoma Origin

Initital:0.25 mg 2 times per week PO

May increase by 0.25 mg q4Weeks (or longer) up to 1 mg 2 times per week

Pharmacology
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Half-life:63-69 hr

Distribution

High levels in pituitary (100x of plasma)

Peak Plasma: 30-70 pg/mL following single oral doses of 0.5-1.5 mg

Excretion

Urine: 22%

Feces: 60%

Other Information

Protein Bound: 40-42%

Metabolism: extensively hydrolyzed

Renal Clearance: 0.08 L/min

Mechanism of Action

Dopamine receptor agonist with high affinity for D2 receptors, thereby inhibiting prolactin

release

Quinagolide (Norprolac)

Pituitary selective dopamine-2 receptor agonist used in cases of bromocriptine resistance or

intolerance. Used in the UK, not available in US.


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Medication Summary

Treatment for diabetes insipidus (DI) varies with the form of the disorder. In central DI and

most cases of gestational DI, the primary problem is a deficiency of antidiuretic hormone

(ADH)also known as arginine vasopressin (AVP)and therefore, physiologic replacement

with desmopressin is usually effective. A nonhormonal drug can be used if response is

incomplete or desmopressin is too expensive.

Desmopressin has no role in the treatment of nephrogenic DI or primary polydipsia.

Nonhormonal drugs usually are more effective in treating nephrogenic DI.

Vasopressin-Related Hormones

Class Summary

In patients with central DI, replacement of endogenous ADH with exogenous hormones

prevents complications of DI and reduces morbidity.

View full drug information

Desmopressin (DDAVP, Stimate)

Desmopressin is a synthetic analogue of ADH with potent antidiuretic activity but no

vasopressor activity.


Vasopressin (Pitressin)

Vasopressin has vasopressor and ADH activity. It increases water resorption at collecting

ducts (ADH effect). At high doses, it also promotes smooth muscle contraction throughoutthe vascular bed of renal tubular epithelium (vasopressor effects). However,

vasoconstriction is also increased in splanchnic, portal, coronary, cerebral, peripheral,

pulmonary, and intrahepatic vessels.

Antidiabetics, Sulfonylureas

Class Summary

The hypoglycemic agent chlorpropamide helps to relieve diuresis in patients with DI.


Chlorpropamide

Chlorpropamide promotes renal response to ADH.

Anticonvulsants

Class Summary

Certain antiepileptic drugs, such as carbamazepine, have proven helpful in DI.


Carbamazepine (Tegretol, Carbatrol, Equetro)
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Carbamazepine possibly ameliorates DI by promoting the release of ADH. It is not useful in

nephrogenic DI and generally is not a first-line drug.

Diuretics, ThiazideClass Summary

Diuretics may reduce flow to the ADH-sensitive distal nephron.


Hydrochlorothiazide (Microzide)

Hydrochlorothiazide is a thiazide diuretic that decreases urinary volume in the absence of

ADH. It may induce mild volume depletion and cause proximal salt and water retention,

thereby reducing flow to the ADH-sensitive distal nephron. Its effects are additive to those

of other agents.

Nonsteroidal Anti-inflammatory Agents (NSAIDs)

Class Summary

The mechanism of action of NSAIDs is not known, but these agents may act by inhibiting

prostaglandin synthesis.


Indomethacin (Indocin)

Inhibition of prostaglandin synthesis reduces the delivery of solute to distal tubules,

reducing urine volume and increasing urine osmolality. Indomethacin is usually used in

nephrogenic DI.


Ibuprofen (Caldolor, Advil, Motrin)


reducing urine volume and increasing urine osmolality. Ibuprofen is usually used in

nephrogenic DI.


Naproxen (Naprosyn, Naprelan, Aleve, Anaprox)


Diclofenac (Voltaren, Cataflam XR, Zipsor, Cambia)

View full drug informationKetoprofen
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reducing urine volume and increasing urine osmolality.

Diuretics, Potassium-SparingClass Summary

Diuretics may reduce flow to the ADH-sensitive distal nephron.


Amiloride

Amiloride is a potassium-sparing diuretic. Thus, the risk of hypokalemia is decreased when

amiloride is used in combination with hydrochlorothiazide. In addition, the 2 agents are

synergistic with respect to antidiuresis.
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Desmopressin (trade names: DDAVP, DesmoMelt, Stimate, Minirin) is a synthetic

replacement for vasopressin, the hormone that reduces urine production. It may be taken

nasally, intravenously, or as an oral or sublingual tablet. Doctors prescribe desmopressin

most frequently for treatment ofdiabetes insipidus, bedwetting, or nocturia.

Chemistry

Desmopressin (1-desamino-8-D-arginine vasopressin) is a modified form of the normal

human hormone arginine vasopressin, a peptide containing nine amino acids.

Compared to vasopressin, desmopressin's first amino acid has been deaminated, and the

arginine at the eighth position is in the dextro rather than the levo form (see

stereochemistry).

[edit]

Mode of action

Desmopressin works by limiting the amount of water that is eliminated in the urine.

Desmopressin binds to V2 receptors in renal collecting ducts, increasing water reabsorption.It also stimulates release ofvon Willebrand factor from endothelial cells by acting on the V2

receptor.

Desmopressin is degraded more slowly than recombinant vasopressin, and requires less

frequent administration. In addition, it has little effect on blood pressure, while vasopressin

may cause arterial hypertension.

[edit]

Clinical uses

[edit]

Nocturnal EnuresisDoctors prescribe desmopressin frequently for treatment. It is usually in the form of

desmopressin acetate, DDAVP. Patients taking DDAVP are 4.5 times more likely to sleep

without disruption than with placebo. [1] [2] Examples of these situations are overnight

camp and sleepovers.

US drug regulators banned treating bedwetting with desmopressin nasal sprays after two

patients died and 59 other patients suffered seizures. The patients were using desmopressin

when they developed hyponatremia, an imbalance of the body's sodium levels. [3]

FDA regulators said that desmopressin tablets could still be considered safe for nocturnal

enuresis treatment, as long as the patient was otherwise healthy. Patients must stop taking

desmopressin if they become sick and have severe vomiting and diarrhea, fever, the flu, orsevere cold. They should also be very cautious during hot weather or following strenuous

exercise that may make them thirsty.

A healthy body needs to maintain a balance of water and salt (sodium). If sodium levels

become too low (hyponatremia) either as a result of increased water take-up or reduced

salt levels a person may have seizures and, in extreme cases, may die. [4]

[edit]

Coagulation disorders

Desmopressin can be used to promote the release ofvon Willebrand factor (with

subsequent increase in factor VIII survival secondary to vWF complexing) in patients with

coagulation disorders such as von Willebrand disease, mild hemophilia A (factor VIIIdeficiency), and thrombocytopenia. It can be used with uremic induced platelet dysfunction.
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It is not effective in the treatment of hemophilia B (factor IX deficiency), severe hemophilia

A, or von Willebrand 2B.

[edit]

Diabetes insipidus

Desmopressin is used in the treatment of central diabetes insipidus (DI), to replaceendogenous ADH that is missing in the central nervous system type of this disorder

(decreased production of ADH from the posterior pituitary). It is also used in the diagnostic

workup for diabetes insipidus, in order to distinguish central from nephrogenic DI.

Radiation Treatment and Radiosurgery

If surgery is unable to remove the entire tumor, then radiation treatment may be necessary

to control the tumor and prevent it from growing. Radiation may also be an option for

patients who are medically unsuitable for surgery or do not want to have surgery.

Conventional radiation treatment directs a small number of radiation beams toward the

entire region around the sella turcica and pituitary gland. This technique results in a

significant area of normal tissue being included in the treatment field. To compensate for

this, conventional radiation treatment is given in daily doses over several weeks. Such

therapy is generally very effective in preventing the tumor from growing. For hormone-

producing tumors, it is also effective in gradually lowering the hormone levels over many

years. Despite the fact that with conventional radiotherapy the optic chiasm receives as

much radiation as does the tumor, the risks of visual complications are very low. However,

the same cannot be said about normal hormonal function. Since both the pituitary and the

hypothalamus (another important hormone control center) receive radiation during

treatment, nearly half the patients treated with conventional radiation will eventually

develop abnormally low hormone levels (hypopituitarism).

Radiosurgery is a new option for treating pituitary adenoma. By focusing the radiation on

only the tumor, this form of treatment minimizes the anatomical spread of radiation to

normal brain. Emerging data indicates that radiosurgery may be more effective than

conventional radiation in lowering abnormal hormone production, and does so over a

shorter time interval.

Most radiosurgery techniques, like surgery itself, require treatment to be delivered as a one-

time procedure. However, some of the unwanted side-ffects of radiation, including the most

feared, visual loss, may be accentuated by delivering the radiation all in one day rather than

over several sessions; this risk of radiation injury is greatest in those patients where the

pituitary is close to or involves the optic chiasm or hypothalamus. In higher risk patients, the

risk of injury to critical brain structures may be reduced by staging the radiosurgical ablation.
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Overview

Tumors of the pituitary gland and sellar region represent approximately 10-15% of all brain

tumors,[1] of which the great majority in this region are pituitary adenomas. Pituitary

adenomas predominantly affect females between the third and sixth decades of life;

however, no age group is spared.[2] Pituitary adenomas are uncommon in the pediatric

population, but most tumors of childhood are clinically functioning adenomas and arethought to be more aggressive.[3]

Rates for pituitary tumors in the United States are slightly higher among black persons (2.92

per 100,000 person-years) than among white persons (1.82 per 100,000 person-years).[1]

Incidental adenomas can be found in nearly 10% of autopsied patients.[4, 5]

Comparatively, primary tumors of the neurohypophysis are rare, and in general, they are

similar to primary tumors of the central nervous system (CNS). The neurohypophysis,

however, is a common site for metastases.[6]

The following are histologic examples of the normal pituitary gland and a pituitary adenomafor comparison.

Histology of a normal anterior pituitary gland. The gland is formed by multiple cell types,

including basophilic, eosinophilic, and chromophobic cells (hematoxylin-eosin stain).

Normal pituitary versus pituitary adenoma. Note the delicate acinar pattern of a normal

pituitary gland (left), in contrast with disruption of the normal reticulin network in adenoma

(right) (Wilder's reticulin stain).

Classification

Numerous types of tumors may involve the pituitary gland and sellar region, reflecting the

complex anatomy of this area. These may be classified as shown in Table 1, below).

Table 1. Tumors and Tumorlike Lesions of the Pituitary Gland and Sellar Region (Open Table

in a new window)

Tumors of anterior pituitary Pituitary adenoma

Atypical adenoma
http://refimgshow%282%29/http://refimgshow%281%29/


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Pituitary carcinoma

Spindle cell oncocytoma

Tumors of posterior pituitary Pituicytoma

Granular cell tumor

Gangliocytoma

Tumors of nonpituitary origin Craniopharyngioma

Meningioma

Chordoma

Langerhans cell histiocytosis

Metastases

Cystic lesions Rathkes cleft cyst

Arachnoid cyst

Epidermoid/dermoid cyst


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Inflammatory lesions Lymphocytic hypophysitis

Granulomatous hypophysitis

Sarcoidosis

As noted earlier, the most common tumors, by far, are the pituitary adenomas. In addition

to tumors, a variety of nonneoplastic lesions may affect the pituitary gland, bringing a

number of processes into the differential diagnosis of the tumors involving this region.

The more common lesion types are defined as follows:

Pituitary adenomas are benign epithelial tumors derived from intrinsic cells of the

adenohypophysis

Pituitary carcinomas are characterized by the presence of either craniospinal

dissemination or systemic metastases[7]

Spindle cell oncocytoma of the adenohypophysis is a rare primary tumor that may be

derived from the follicle-stellate cells of the anterior pituitary gland[8]

Pituicytomas are a subtype of low-grade astrocytoma that originates in the posterior

pituitary or infundibulum; in the past, these tumors were designated as posterior

pituitary astrocytomas or infundibulomas[9] ; pituicytomas are believed to originate

from pituicytes, the intrinsic glial cells of the posterior pituitary gland

Granular cell tumors are glial tumors that arise either in the pituitary stalk or posterior

pituitarythey are usually incidental tumors found in adults at autopsies and only

rarely present as symptomatic masses (there are about 60 reported cases in the

literature[10] ); granular cell tumors of the sella are also known as choristoma of the

neurohypophysis, granular cell pituicytoma, granular cell myoblastoma, and granular

cell tumorette

Craniopharyngiomas represent 12% of all intracranial neoplasms and about 10% of the

tumors of the sellar region[11] ; they are histogenetically related to Rathkes cleft

and derive from the pituitary anlagen; although the majority of craniopharyngiomas

differ markedly from Rathkes cleft cysts, rare tumors demonstrating features of

both have been described[12]

Inflammatory hypophysitis is a rare disorder of the pituitary gland characterized by focal

or diffuse inflammatory infiltration and ultimate destruction of the gland.

See also Pituitary Tumors, Pituitary Macroadenomas, Pituitary Microadenomas, Pituitary

Apoplexy, and Pituitary Disease and Pregnancy.

Anterior Pituitary Gland Tumors Pituitary Adenomas

In this section the general characteristics of pituitary adenomas are discussed, followed by

separate sections on subtypes of pituitary adenomas, atypical adenomas, pituitary

carcinomas, and spindle cell oncocytomas.

General characteristics of pituitary adenomas
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Pituitary adenomas are classified clinically into 2 groups--clinically functioning adenomas

and clinically nonfunctioning adenomas--according to whether an endocrine syndrome is

present or absent. Most adenomas are functioning tumors; these include prolactin (PRL)

producing, growth hormone (GH)producing, adrenocorticotropic hormone (ACTH)

producing, and thyroid-stimulating hormone (TSH)producing adenomas (see Table 2,

below).[13]

Table 2. Surgical Frequency of Pituitary Adenoma Types at University of Virginia, 1992-2006*

(Open Table in a new window)

Pituitary Adenoma Type Frequency, %

ACTH-secreting adenomas

23

PRL-secreting adenomas 22

Null cell adenomas 19

Gonadotropin-secreting adenomas 18

GH-secreting adenomas 14

GH- and PRL-secreting adenomas 3TSH-secreting adenomas 1*

N = approximately 2600.

Includes silent corticotroph adenomas.

ACTH = adrenocorticotropic hormone; GH = growth hormone; PRL = prolactin; TSH = thyroid-

stimulating hormone.

Nonfunctioning adenomas

About one third of all pituitary adenomas are unassociated with either clinical or

biochemical evidence of hormone excess.[14] In this group are included adenomas that

produce both follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the less

differentiated null cell adenomas, and silent adenomas. These clinically nonfunctioning

adenomas commonly present with signs and symptoms related to local mass effect, such as

headaches, neurologic deficits of the cranial nerves (including visual field disturbances), and

mild hyperprolactinemia due to pituitary stalk compression ("stalk effect").

Classifications based on size, anatomic features, histologic patterns, and hormone content

On the basis of size and anatomic features, adenomas are divided into microadenomas

(tumors < 1 cm in diameter) and macroadenomas (tumors >1 cm in diameter). Giant

adenomas (tumors > 4 cm) may occur but are rare. Macroadenomas show an increased

tendency toward suprasellar extension, gross invasion, and recurrence (see the following

image). A radiologic classification proposed by Hardy[15] is the one most often used in

clinical practice.


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Neuroimaging of pituitary adenoma. T1-weighted magnetic resonance image (MRI) without

(left) and with (right) contrast shows macroadenoma compressing optic chiasma.

Grossly, pituitary adenomas are soft lesions with a tan-brown discoloration.

Morphologically, they may show a variety of histologic patterns, including diffuse, papillary,

and trabecular arrangements similar to those of other neuroendocrine tumors. Cytologically,

tumor cells may be acidophilic, basophilic, or chromophobic; however, these tinctorial

characteristics do not identify specific adenoma types (see the images below).

Histology of a normal anterior pituitary gland. The gland is formed by multiple cell types,

including basophilic, eosinophilic, and chromophobic cells (hematoxylin-eosin stain).

Normal pituitary versus pituitary adenoma. Note the delicate acinar pattern of a normal

pituitary gland (left), in contrast with disruption of the normal reticulin network in adenoma

(right) (Wilder's reticulin stain).

Histology of pituitary adenoma. Pituitary adenomas may display several typical

neuroendocrine patterns and have different tinctorial features of tumor cells, including

basophilic, eosinophilic and chromophobic appearances. These cytologic and architectural

qualities, however, are not diagnostic of specific subtypes of adenoma.

Pituitary adenomas are also classified according to the hormone content of the tumor cells

as determined by immunohistochemistry (IHC). This classification provides significant

information for clinical practice.[16] In a few tumors, however, analysis of the adenoma's

ultrastructural aspects is necessary.[17] In this article, we follow the guidelines andclassification scheme for pituitary gland tumors that was released by the World Health
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Organization (WHO) in 2004 (see Table 3, below).[18]

Table 3. Morphofunctional Classification of Pituitary Adenomas (Open Table in a new

window)

Clinical Presentation Pituitary Adenoma TypeACTH-secreting adenomas Corticotroph adenoma

PRL-secreting adenomas Sparsely granulated lactotroph adenoma

Densely granulated lactotroph adenoma

GH-secreting adenomas Densely granulated somatotroph adenoma

Sparsely granulated somatotroph adenoma

GH- and PRL-secreting adenomas Mixed GH- and PRL-cell adenoma

Mammosomatotroph-cell adenoma

Acidophilic stem-cell adenoma 3

TSH-secreting adenomas Thyrotroph adenoma

Gonadotropin-secreting adenomas Gonadotroph adenoma

Nonfunctioning adenomas Null-cell adenoma

Oncocytoma

Silent adenomas Silent corticotroph adenoma (subtypes I and II)

Silent adenoma subtype III


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ACTH = adrenocorticotropic hormone; GH = growth hormone; PRL = prolactin; TSH = thyroid-

stimulating hormone.

Tumorigenesis

The mechanisms involved in human pituitary tumorigenesis and tumor progression are stillnot well understood. Pituitary adenomas appear to develop through a multistep and

multicausal process to which endocrine factors, hereditary genetic disposition, and specific

somatic mutations may all contribute. An extended review of the mechanisms of pituitary

tumorigenesis is beyond the scope of this article.

Pituitary adenomas arise mostly in a sporadic manner, and only a minority occur as part of

hereditary or familial syndromes.[19] The large majority of adenomas are monoclonal

expansions, as demonstrated by X-chromosomal inactivation analysis.[20] Hereditary

conditions associated with development of pituitary adenomas include the following:

Multiple endocrine neoplasia type 1 (MEN-1), linked to somatic mutations of the MEN-1

gene

Carney complex, linked to mutations of the tumor suppressor gene PRKAR1A

McCune-Albright syndrome, linked to activating mutation of the gsp oncogene (discussed

below)

A few other rare familial syndromes are also associated with pituitary adenomas:

Pituitary adenoma predisposition (PAP), associated with a germline mutation of the AIP

(aryl hydrocarbon receptor-interacting protein) gene

Isolated familial somatotrophinoma (IFS), associated with a loss of heterozygosity at the

11q13 locus but not with the MEN-1 gene

Familial isolated pituitary adenoma (FIPA), for which a single genetic alteration has not

been characterized, although mutations of the AIP gene have been reported to

occur in about 15% of families[21]

In the majority of sporadic adenomas, however, the primary genetic defect remains

unknown. A number of oncogenes and tumor suppressor genes have been recognized as

potential participants in the tumorigenesis of pituitary adenomas.

The most commonly found genetic alteration in sporadic tumors is an activating mutation of

the gsp gene, an oncogene mostly identified in GH-cell adenomas.[22, 23, 24] The gsp

mutation has been identified in about 40% of GH-secreting adenomas,[23, 24, 25] but it is

rare in other pituitary tumor subtypes, occurring in only 10% of clinically nonfunctioning

pituitary adenomas and 5% of corticotroph adenomas.[25]

Other oncogenes and tumor suppressor genes that have been shown to be linked to

pituitary tumorigenesis include the oncogene PTTG (pituitary tumor-transforming gene), the

proto-oncogene H-ras, and the tumor suppressor genes RB and TP53. However, it seems

that these genes are not directly associated with pituitary adenoma tumorigenesis but may

play a role during the progression and malignant transformation of these tumors.[26] For

details, readers may consult any of several outstanding reviews on the subject.

Pituitary Adenoma Subtypes

This section will discuss subtypes of pituitary adenomassuch as prolactin (PRL)secreting,

growth hormone (GH)secreting, mixed GH- and PRL-secreting, adrenocorticotropic

hormone (ACTH)secreting, thyroid-stimulating hormone (TSH)secreting, gonadotropin-

secreting adenomas, and null cell adenomas and oncocytomas, silent adenomas, and
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plurihormonal adenomas.

Prolactin-secreting adenomas

PRL-secreting adenomas, or prolactinomas, account for nearly 80% of functioning adenomas

and about 4050% of all pituitary adenomas.[27, 28] However, most patients with

prolactinomas are treated clinically with dopamine agonists. Therefore, the frequency ofprolactinomas in surgical series tends to be smaller.

In women, the majority of prolactinomas are microadenomas and occur during the

reproductive age period, presenting with oligomenorrhea or amenorrhea, galactorrhea, and

infertility.[27, 28] In contrast, in men and elderly women, prolactinomas are usually

macroadenomas and are most commonly associated with symptoms of tumoral mass,

including headaches, neurologic defects, and visual loss.[28] Impotence and decreased libido

are also common symptoms of hyperprolactinemia in males. The diagnosis of a prolactinoma

is confirmed by sustained hyperprolactinemia and neuroradiologic evidence of a pituitary

tumor.[2, 27]

Histologically, prolactinomas are composed of medium-sized cells with chromophobic or

slightly acidophilic cytoplasm and a central, oval nucleus (see the image below); small

nucleoli can be present. Approximately 10-20% of cases show microcalcifications.

Calcifications and amyloid bodies, although frequently seen in prolactinomas, are not

pathognomonic of this type of adenoma.[29]

Prolactin (PRL)-secreting adenoma. Left: The cells show chromophobic cytoplasm and

central nuclei (hematoxylin-eosin stain). Right: Immunochemistry (IHC) shows reactivity for

PRL in a characteristic dotlike staining pattern located near the nucleus (PRL-IHC stain).

Immunohistochemistry (IHC) shows reactivity for PRL in a very characteristic pattern of

staining, with localization near the nucleus in a dotlike pattern, also known as a Golgi

pattern.[29] On ultrastructural analysis, prolactinomas may be divided into densely and

sparsely granulated variants, although the clinical significance of this distinction is

questionable.[13, 29]

Sparsely granulated PRL cell adenomas are the most common tumors, and their cells

resemble actively secreting lactotrophs of the normal pituitary gland. The adenoma cells are

characterized by a prominent rough endoplasmic reticulum (RER) network, conspicuous

Golgi complexes, and a sparse number of small (150-300 nm) secretory granules. Misplaced

exocytosis (ie, granule extrusions on the lateral cell surfaces) is typical of these tumors.

As noted above, most patients with prolactinomas are treated to some degree with

dopamine agonists. These drugs act directly on the tumor cells, inducing atrophy of

lactotrophs and resultant tumor shrinkage.[27, 28] Histologically, tumors from patients

previously treated with such drugs are composed of smaller tumor cells, with shrinkage of

the cytoplasm and hyperchromasia of the nuclei, in addition to various degrees of

perivascular and interstitial tumoral fibrosis.[30, 31]

Growth hormonesecreting adenomas
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GH-secreting adenomas account for about 20% of pituitary adenomas. Patients present with

signs and symptoms ofacromegaly, gigantism, or both, as well as high serum GH and

insulinlike growth factor I (IGF-I) levels.[2] Acromegaly affects both sexes with similar

incidence, and the mean age at diagnosis is 4045 years.[32]

Symptoms of acromegaly are usually slowly progressive, with an average delay ofapproximately 10 years before diagnosis.[32] Less commonly, adenomas arise in children

and adolescents before the epiphyseal closure of the long bones, resulting in gigantism.

Most acromegalic patients have macroadenomas when first diagnosed; many of these

lesions show suprasellar expansion and parasellar invasion.[33] Consequently, symptoms

secondary to an expanding tumor mass, including headaches and visual field defects, may

also be present.

In about 30-50% of patients, co-secretion of PRL with GH by the tumor results in signs and

symptoms of hyperprolactinemia.[32, 33] Mixed GH- and PRL-secreting tumors are discussed

below.

Densely vs sparsely granulated GH cell adenomas

Histologically, GH-secreting adenomas are either eosinophilic or chromophobic on

hematoxylin and eosin (H&E) staining. These histologic attributes reflect the amount of

secretory granules present in the cell cytoplasm and characterize the 2 types of GH cell

adenomas--namely, densely granulated and sparsely granulated.

Densely granulated adenomas are characterized by eosinophilic tumor cells, with the

cytoplasm showing considerable granularity and reflecting great numbers of secretory

granules seen at the ultrastructural level. The nucleus tends to be central and oval, with

prominent nucleoli (see the image below).

Growth hormone (GH)-secreting adenoma. Top left: Densely granulated GH-secreting

adenomas show large cells with an eosinophilic, granular cytoplasm and a central nucleus

with prominent nucleoli (hematoxylin-eosin stain). Top right: The tumor shows intense and

diffuse immunostain for GH (GH-immunohistochemistry [IHC] stain). Bottom left: The

ultrastructure exhibits well-developed organelles and abundant large secretory granules.

Bottom right: A strong immunostain for transcription factor Pit-1 is typically seen in these

adenomas (Pit-1-IHC stain).

Sparsely granulated GH cell adenomas are composed of smaller tumor cells, with

chromophobic cytoplasm and an eccentric nucleus. In the cytoplasm, paranuclear

eosinophilic structures (fibrous bodies) are seen.[34] These structures represent

accumulations of intermediate filaments and tubular formations at the ultrastructural level

and are strongly immunoreactive for cytokeratin (see the following image).
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Growth hormone (GH)-secreting adenoma. Top left: Sparsely granulated GH-cell adenomas

are characteristically more chromophobic than densely granulated ones (hematoxylin-eosin

stain). Top right: The immunostain for GH is heterogeneous and less prominent than with

densely granulated adenomas (GH-immunohistochemistry [IHC] stain). Bottom left:

Cytokeratin immunostaining highlights fibrous bodies (FBs) typically seen in these sparsely

granulated tumors (cytokeratin-IHC stain). Bottom right: The ultrastructure of sparselygranulated GH cells displays sparse neurosecretory granules and typical FBs.

IHC staining shows a variable degree of GH immunoreactivity (see the image above). In

densely granulated adenomas, GH immunostain diffusely occupies the entire cytoplasm of

the tumor cells and tends to be dispersed diffusely within the entire tumor. By contrast, in

sparsely granulated adenomas, GH immunostain is focal within the tumor and tends to be

localized in a paranuclear distribution, similar to the Golgi pattern seen in

prolactinomas.[34]

A number of GH-secreting adenomas show secondary reactivity for other pituitary

hormones.[33, 35] Immunopositivity for PRL can be seen focally, even in patients without

clinical or biochemical evidence of hyperprolactinemia. Similarly, the presence ofimmunoreactivity for the glycoprotein hormones follicle-stimulating hormone (FSH),

luteinizing hormone (LH), and -TSH can be demonstrated in a number of GH-secreting

adenomas.[33]

Apart from the well-characterized mixed GH-/PRL-secreting adenomas (see below),

plurihormonal differentiation is not clinically symptomatic in the majority of cases.[36]

The 2 subtypes of GH cell adenomas--densely and sparsely granulated--are well

characterized by ultrastructural analysis.[13] Densely granulated adenomas are composed of

adenomatous cells that resemble the normal somatotrophs of the pituitary gland and are

characterized by a well-developed rough endoplasmic reticulum (RER) network, prominent

Golgi complexes, and numerous large (300-600 nm) secretory granules.

Sparsely granulated adenomas have fewer and smaller (100-250 nm) secretory granules. The

most characteristic feature of these adenomas is the presence of fibrous bodies, which

consist of an accumulation of intermediate filaments and tubular smooth-surfaced

endoplasmic reticulum (see the previous image).

The distinction between the 2 subtypes of GH cell adenomas is important in that the

subtypes tumors appear to have different clinical behavior. Sparsely granulated GH

adenomas exhibit more aggressive biologic behavior than densely granulated tumors do.[33,

37, 38] In addition, the response of tumors to adjuvant medical treatment also differs

according to the subtype of GH cell adenoma.[39]
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As with prolactinomas, medical therapy for acromegaly with somatostatin receptor ligands,

mainly octreotide, is common practice in endocrinology.[2, 40] However, in treated GH cell

adenomas, significant reduction of tumor cell size is not commonly seen; the most common

changes are varying degrees of perivascular and interstitial fibrosis.[41, 42]

Mixed GH- and PRL-secreting adenomasAs noted in the discussion of GH-secreting adenomas above), a large percentage of these

adenomas also secrete PRL. These tumors overall constitute about 8% of pituitary

adenomas.[43] Patients with such mixed tumors present signs and symptoms of both

acromegaly and hyperprolactinemia.[33] In this group of adenomas, 3 morphologic tumor

types can be identified: (1) mixed GH cell/PRL cell adenoma, (2) mammosomatotroph cell

adenoma, and (3) acidophilic stem cell adenoma.[33, 44]

Diagnosis of these adenomas requires a more complex IHC and ultrastructural analysis of the

tissues. Moreover, their distinction is of fundamental importance in that it has clinical and

prognostic implications. Both mixed GH cell/PRL cell adenomas and mammosomatotroph

adenomas tend to grow more slowly than acidophilic stem cell adenomas do.[43, 45] In theauthors' experience, these mixed tumors behave more aggressively than any pure GH-

secreting adenomas, and the surgical cure rate is lower.[33]

Mixed GH cell/PRL cell adenomas

The predominant clinical feature of mixed GH cell/PRL cell adenomas is acromegaly. Signs

and symptoms of hyperprolactinemia are not always apparent.

Morphologically, the tumors are similar to GH-secreting adenomas, with an eosinophilic or

chromophobic appearance. Immunostains are demonstrated for both GH and PRL, with

varying degrees of staining and distribution (see the first image below). The 2 cell types may

form small groups, or they may be scattered. At the ultrastructural level, these adenomas

are bimorphous tumors, consisting of 2 separate cell populations: (1) densely or sparsely

granulated GH cells and (2) PRL cells (see the second image below).[46]

Mixed growth hormone (GH)-/prolactin (PRL)-secreting adenoma. Top left and right:

Morphologically, mixed GH-/PRL-secreting adenoma may be indistinguishable from GH

adenoma (hematoxylin-eosin stain). Bottom left and right: Immunohistochemistry (IHC)

shows intensive reaction for GH (bottom left: GH-IHC stain) and dotlike PRL immunostain

(bottom right: PRL-IHC stain).


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Mixed growth hormone (GH)-/prolactin (PRL)-secreting adenoma. The ultrastructure of

mixed GH-/PRL-secreting adenoma shows bimorphous cell population with densely

granulated GH cells and PRL cells.Mammosomatotroph cell adenomas

Mammosomatotroph cell adenoma is rare, accounting for fewer than 2% of all pituitary

adenomas and about 8% of tumors associated with acromegaly.[43, 47, 48] Like mixed GH

cell/PRL cell adenomas, these tumors are associated with elevated circulating GH levels and

acromegaly; hyperprolactinemia is less common.

Histologically, these adenomas are acidophilic on H&E staining, and IHC demonstrates the

presence of GH and PRL in the cytoplasm of the same tumor cell. These findings have been

confirmed by double-labeling studies, as well as by immunoelectron microscopy.[47]

Ultrastructural analysis demonstrates a well-differentiated adenoma composed of a

monomorphous cell population that contains features of GH and PRL cells.[47] The tumor

cells are mostly similar to densely granulated GH cells, but with irregular secretory granules

of variable sizes (2002000 nm) and containing granule extrusions and extracellular deposits

of secretory material, a feature consistent with PRL cell differentiation (see the image

below).

Mammosomatotroph cell adenoma. The ultrastructure of mixed growth hormone (GH)-

/prolactin (PRL)-secreting adenoma shows a monomorphous cell population exhibiting largesecretory granules and granular extrusion figures (arrows).
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Acidophilic stem cell adenomas

Acidophilic stem cell adenoma is very rare, representing only a small minority of GH-/PRL-

producing tumors.[33, 43] Unlike patients with the other 2 subtypes, most patients with this

tumor present with symptoms of hyperprolactinemia[45] ; acromegaly is uncommon, and

GH levels are often normal.

The majority of the tumors are rapidly growing macroadenomas with invasive features.

Because most of the patients have clinical features of hyperprolactinemia, the diagnosis is of

clinical importance in that these tumors may be mistaken for the more benign

prolactinomas.

By light microscopy, acidophilic stem cell adenomas are chromophobic, with focal oncocytic

changes of the cytoplasm. Immunoreactivity for PRL and, to a lesser extent, GH is present in

the cytoplasm of the same tumor cells.

Electron microscopy is necessary for precise identification of these adenomas.[13, 45] They

are composed of a single population of immature cells exhibiting features reminiscent of

both sparsely granulated GH cells and PRL cells. Oncocytic change, with the presence of

giant mitochondria, is characteristic of these adenomas.

Adrenocorticotropic hormonesecreting adenomas

ACTH-secreting adenomas associated with Cushing disease represent approximately 10-15%

of all adenomas.[49] Cushing disease has a peak incidence between the ages of 30 and 40

years and tends to be more frequent in females (3.5:1 female-to-male ratio).[50] In children,

Cushing disease is rare and tends to have a more aggressive clinical course and lower cure

rate.[51, 52] Cushing disease arising in prepubertal children is more common in males than

femalesthe opposite of the adult preponderance.[53] (See also Cushing Syndrome.) The

great majority of ACTH-secreting adenomas are microadenomas, and approximately 15% are

invasive at the time of surgery.[54]

On rare occasions, corticotroph cell hyperplasia may be the source of Cushing disease.

However, there is considerable controversy, from both clinical and pathologic viewpoints,

regarding this event.[55]

Histologically, ACTH-secreting adenomas are usually basophilic on H&E staining and are

often strongly positive with periodic acid-Schiff (PAS) staining (see the following image). The

cytoplasm is very granular, and the nucleus is large, with coarse chromatin and a prominent

nucleolus. Some degree of nuclear pleomorphism can be present. The cells have very

distinct cytoplasmic borders and tend to touch each other in a tilelike arrangement. Papillary

formations are very common.

Adrenocorticotropic hormone (ACTH)-secreting adenoma. Left: Corticotroph cell adenomas

are composed of large cells with angular, slightly basophilic cytoplasm and a large nucleus

(hematoxylin-eosin stain). Right: Immunohistochemistry (IHC) for ACTH shows intenseimmunoreactivity (ACTH-IHC stain).
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Occasionally, hyaline bundles that encircle the cytoplasm, yielding a "target cell"

appearance, are observed. These represent Crookes hyaline changes, which correspond to

the accumulation of cytokeratin intermediate filaments and appear to be a direct effect of

high serum levels of cortisol on pituitary cells.[56] Crookes changes are also present in the

normal pituitary gland of Cushing disease patients (see the image below) and in patients

with other pathologic or iatrogenic hypercortisolemic states.

Crooke's changes in the anterior pituitary gland of a patient with Cushing disease. Left:

Several "target cells" consistent with corticotroph cells with hyaline bundles in the

cytoplasm can be seen (hematoxylin-eosin stain). Right: Cytokeratin immunostain highlights

Crooke's changes in corticotroph cells (cytokeratin-immunohistochemistry [IHC] stain).IHC demonstrates the presence of ACTH with various degrees of immunoreactivity. In

addition, other peptides related to the proopiomelanocortin (POMC) precursor molecule,

including -lipotropin, -endorphin, and -melanocyte-stimulating hormone, are also

expressed by tumor cells.[57] In practice, demonstration of these related peptides is less

relevant than demonstration of ACTH. Immunostaining for cytokeratin shows accumulation

in the cytoplasm, either diffuse or forming Crookes changes (see the image above).

Ultrastructurally, ACTH-secreting adenomas are characterized by well-differentiated cells

that resemble normal corticotrophs.[55] The cells contain well-developed organelles,

including RER, smooth endoplasmic reticulum (SER), conspicuous Golgi complexes, and

numerous large (250500 nm) secretory granules. The secretory granules are often of

different shapes (eg, spherical or heart-shaped) and vary in electron density. Bundles of

intermediate filaments lying adjacent to the nucleus or forming large circles (Crookes

changes) are easily identified.

Ultrastructural analysis of clinically functioning ACTH-cell adenomas is not obligatory;

histologic and immunohistochemical studies are sufficient to provide an accurate diagnosis.

Thyroid-stimulating hormonesecreting adenomas

TSH-secreting, or thyrotroph cell, adenomas are the least frequent pituitary adenomas.[58]

Clinically, they may present with inappropriately elevated TSH levels and hyperthyroidism,

but these tumors may also arise in the setting of hypothyroidism or in clinically euthyroidpatients.[59] Most TSH-secreting adenoma are invasive macroadenomas.[59]

Histologically, thyrotroph cell adenomas are frequently chromophobic by light microscopy

and are composed of elongated, angular, or irregular cells. Some degree of desmoplasia is

commonly seen within the tumors, which causes a slight firm consistency.[58]

Immunostains usually reveal variable -TSH positivity. IHC is also commonly positive for the

alpha subunit (-SU) of the glycoproteins.

At the ultrastructural level, the cells are moderately differentiated, with scant RER network

and Golgi complexes.[13] Secretory granules are small (100200 nm), spherical, and evenly

electron dense, and they are typically lined up along the cytoplasmic membrane.


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The diagnosis of TSH-secreting adenoma can be problematic if the clinical presentation and

TSH immunoreactivity are not convincing. In this situation, electron microscopy is

mandatory for appropriate diagnosis.

Gonadotropin-secreting adenomas

Gonadotropin-secreting adenomas, or gonadotroph adenomas, are adenomas that secretethe gonadotropins FSH and LH. Unlike other secreting adenomas, gonadotroph adenomas

do not usually cause a clinical syndrome related to hormone overproduction. The hormonal

production from these tumors is inefficient, and the detection of excess hormone levels is

challenging. Gonadotroph adenomas account for a large proportion of clinically

nonfunctioning adenomas and about 20% of all adenomas.[60]

Gonadotroph adenomas are most frequent in the sixth decade of age and older and have a

slight male predominance.[14] Typically, they present as clinically nonfunctioning tumors

with symptoms related to local mass effects, including visual deficits, hypopituitarism,

headaches, and cranial nerve palsies.[60, 61]

Histologically, most gonadotroph adenomas are composed of chromophobic cells with

nuclei displaying a fine chromatin pattern. The tumor cells may be arranged in a diffuse

pattern, but distinct papillary arrangements are commonly seen.[60] The papillary structures

are characterized by elongated cytoplasmic processes around blood vessels, occurring in a

pattern resembling perivascular pseudorosette formation.

Monoclonal antibodies to specific -FSH, -LH, and -SU are recommended for IHC

characterization of gonadotroph adenomas, because these lesions may demonstrate varying

degrees of reactivity for 1 or more of the gonadotropin subunits. Immunoreactive cells may

be scattered throughout the adenoma but are often clustered. Immunoreactivity for -FSH

tends to be more frequent, with a stronger and broadly distributed pattern thanimmunoreactivity for the other glycoproteins.[60]

Ultrastructurally, gonadotroph adenomas are characterized by elongated, polar cells

containing scant numbers of small (50200 nm) secretory granules. The secretory granules

are distributed unevenly within the cytoplasm or, more commonly, along the cytoplasmic

membrane. A sex-linked dichotomy between gonadotroph adenomas of male and female

patients has been described.[13, 62] In women, most of the adenomas display a typical

vacuolar transformation of the Golgi complex, giving the Golgi apparatus a honeycomb

appearance.

Characterization of gonadotroph adenomas by ultrastructural means is of scientific interest

but does not alter clinical patient management. The correlation between -FSH and -LH

immunoreactivity, degree of ultrastructural differentiation, and clinical symptoms is

relatively poor in patients with gonadotroph adenomas. At present, most patients are

treated as having a clinically nonfunctioning adenoma, and the therapeutic goals are

restoration of visual deficits, preservation of pituitary function, and prevention of

recurrence.[14]

Null cell adenomas and oncocytomas

Approximately 20% of adenomas show neither clinical nor IHC evidence of hormone

production.[14, 63] The term "null cell adenoma" is given to these tumors, based largely on

the absence of ultrastructural features providing specific differentiation.

The clinical presentation of null cell adenoma resembles that of gonadotroph adenoma;


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patients present with signs and symptoms of a mass lesion.[14, 63] Null cell adenomas most

commonly arise in postmenopausal females and elderly males, with the great majority

macroadenomas at presentation.

Histologically, null cell adenomas are chromophobic on light microscopy, and the tumor cells

may be arranged in several neuroendocrine patterns, including trabecular, papillary, anddiffuse. Oncocytic change can be seen in a number of cases, and consequently, the

designation of oncocytoma (oncocytic var

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