Advances in understanding pituitary tumors.

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by  Kopczak, Anna

Published:02January2014
©2014Facultyof1000Ltd
Advances in understanding pituitary tumors
Anna Kopczak*, Ulrich Renner and Günter Karl Stalla
Address:MaxPlanckInstituteofPsychiatry,ClinicalNeurendocrinologyGroup,Kraepelinstraße2-10,80804Munich,Germany
*Correspondingauthor:AnnaKopczak([email protected])
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Abstract
Pituitarytumorsarecommoninthegeneralpopulation.Sinceneuroimagingtechniqueshaveimproved,
pituitary tumors are more often diagnosed incidentally. About 16.7% of the general population show
changes in the pituitary gland. Predominantly, pituitary tumors are benign pituitary adenomas. Pituitary
carcinomasoraggressivepituitarytumorsareextremelyrare.Theymightdevelopfrombenignadenomas.
Newgeneticandepigeneticabnormalitieshelpustounderstandpituitarytumorigenesisandmightleadto
therapeuticaltargetingdrugsinthefuture.Macroadenomas(>1cm)canleadtovisualfielddisturbances,
compression of cranialnerves,hypopituitarism, and infiltrationof the cavernoussinuses. Thefunctional
statusofthepituitarytumorisimportant.Abouthalftoonethirdofallpituitarytumorsarenon-functioning
pituitary adenomas. The other pituitary tumors show a specific pattern of hormone secretion. About
25%to41%ofallpituitarytumorsareprolactinomas,acromegalywithproductionofgrowthhormone
represents10%to15%ofadenomas,Cushing’sdiseasewithproductionofadrenocorticotropichormone
accountsfor10%,andotherhormonalcharacteristicsarelesscommon.Transsphenoidalresectionand
total adenomectomy are desirable. Radiosurgery has enriched the surgical treatment options. Surgical
treatment is the intervention of choice except for prolactinomas, where pharmaceutical treatment
is recommended. Pharmaceutical treatment consists of dopamine agonists such as cabergoline and
somatostatin analogues that include octreotide and pasireotide; retinoic acid is of theoretical interest
while peroxisome proliferator-activated receptor-gamma-ligands arenotclinically useful. In acromegaly,
pegvisomant is a further treatment option. Temozolomide should be considered in aggressive pituitary
tumors.Ingeneral,pharmaceuticaloptionsdevelopedrecentlyhaveextendedtherepertoireoftreatment
possibilitiesofpituitarytumors.
Recent advances Complex (CNC), or Familial Isolated Pituitary Adenomas
Epidemiology (FIPAs).InMEN1syndrome,pituitarytumorsoccuralong-
Pituitary tumors are common in the general population. side (entero-) pancreatic tumors, parathyroid hyperplasia,
In 16.7%, changes in the pituitary gland can be detected lipomas, and angiofibromas. This autosomal-dominant
[1]. Since neuroimaging techniques have recently syndromecontributesto2.7%ofallpituitarytumors[3].
improved,pituitarytumorsaremorefrequentlydiagnosed
incidentally. In most cases, pituitary tumors are benign adenomas.
Pituitarycarcinomasareextremelyrare,andinthesecases
Usually,pituitarytumorsareassignedasprimarytumors theassumptionisthattheyareformerbenignadenomas
ofthecentralnervoussystem(CNS)andcontributeto5% that have undergone additional genetic mutations [4].
to 20% of all primary CNS tumors [2]. In 95% of cases, Thesechangesinduceaninvasivetumorprogressionand
pituitary tumors occur sporadically. Only in 5% may a thedevelopmentofmetastasis,mainlyintothebrainor
familial genetic background be assumed, e.g. as part of spinalcord.Distantmetastasiscanbefoundintheliver,
Multiple Endocrine Neoplasia (MEN) Type 1, Carney’s lung,orlymphnodes.
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In childhood, craniopharyngiomas occur with an inci- changesmightbeofinterestforthedevelopmentofnew
dence of 0.5-2/million/year. Survival rates after surgical drugs. Further investigations and studies are therefore
treatment are rather high:between 91% and 98% [5]. necessary.
Pituitaryadenomasareclassifiedpartiallydependingon Diagnosis
their size into microadenomas (<1 cm) and macroade- Since magnetic resonance imaging (MRI) techniques
nomas (>1 cm). The size of the adenoma corresponds haveimprovedandare usedmorewidelyinthegeneral
with compromising effects on the optic chiasm, cranial population, pituitary adenomas are more frequently
nerves, and cavernous sinuses, but tumor size does not diagnosed incidentally. Pituitary tumors such as NFPA
reflect its clinical importance [6]. This classification is mightnotbeidentifiedformanyyears.Incontrast,macro-
supplemented by immunochemistry and functional adenomas can cause local symptoms such as visual dis-
status. Pituitary tumors are classified as functioning or turbanceswhentheopticchiasmiscompressed.
non-functioning on the basis of their ability to produce
and secrete mature hormones [1,7]. Approximately half Even small pituitary adenomas might have clinically
to one third of all pituitary tumors are non-functioning important consequences through elevated hormonal
pituitary adenomas (NFPAs) (i.e. without hormone levels and become apparent as hyperprolactinaemia,
secretion detected either by immohistochemistry or by GH,orcortisolexcess.Inthesepatients,endocrinological
elevated hormonal blood levels). The most common disturbancescanleadtosecondaryhypogonadismdueto
hormone-secreting pituitary tumor is the prolactinoma hyperprolactinaemia, acromegaly, or Cushing’s disease
(lactotrophadenoma–25%-41%),followedbysomato- (CD). Interestingly, the tumor size in prolactinomas
troph adenomas (10%-15%), corticotroph adenomas correlateswithserumprolactinlevels[14].Inmostpatients
(about 10%), thyrotroph adenomas (<1%), and gona- with prolactin levels >250µg/l, a (macro)prolactinoma
dotrophadenomas(<1%)[1,8]. mightbeassumed.Inacromegaly,patientsshowatypical
facialappearanceandacralenlargement.Thediagnosiscan
Pathophysiology and molecular genetics be confirmed by elevated basal GH levels (>0.4µg/l),
Pituitary tumors are mostly monoclonal. Therefore, elevated basal insulin-like growth factor-1 (IGF-1) levels
genetic influences in only one cell might induce tumor (depending on age-related normal values), and a lack of
transformation. In sporadic tumors, gsp oncogene is the suppression of GH in the oral glucose tolerance test with
most important one. Mutations in the alpha subunit of 75gglucoseload(GH>1µg/l)[15].InCD,typicalclinical
G protein gene — which is involved in hypothalamic symptoms such as abdominal fat distribution, red striae,
growthhormone(GH)release—mightcausecontinuous andmuscleweaknesscanleadtothesuspicionofCushing
activation of adenylyl cyclase [2]. This pattern was syndrome [16]. To verify suspected CD, 24-hour urinary
observed in 40% of GH-secreting tumors (somatotropi- cortisolleveloradexamethasonesuppressiontest(1-2mg)
nomas).UsuallythealphasubunitoftheGproteingeneis isrecommended[17].
expressed monoallelically, whereas in some cases it is
expressedbiallelicallyandthisisthroughaprocesstermed Even when neuroimaging techniques have improved,
lossofimprinting[9]. microadenomascanbedifficulttodetectinMRIandeven
later during surgery. Before surgery, coronal and sagittal
About15%ofallFIPApatientsshowmutationsinthearyl T1-weighted sections through the sella are required. MRI
hydrocarbonreceptor-interactingprotein(AIP)gene.This scans should be performed before and after contrast
chaperone might act as a tumor suppressor; mutations enhancement [18]. In order to detect small hormonal
mightinducetumorigenesis[10].Clinically,patientswith active pituitary adenomas, selective catheterization of the
FIPAareyoungerandshowbiggerpituitaryadenomasat inferiorpetrosalsinusescanbeconducted[17].
diagnosis.
The visual field and cranial nerve function have to be
The number of genes and molecular abnormalities evaluated,especiallyinmacroadenomas.MRItechniques
involved in pituitary tumorigenesis increased in the last help to identify invasion of the cavernous sinuses or
years[11].Insomecasesgeneticchangeswereassociated suprasellar tumor growth and this is important for the
with specific types of pituitary adenomas such as the surgicalapproach[19].
promotion of somatotroph pituitary tumorigenesis
through the FGFR4-G388R polymorphism [12]. In spite Surgical treatment
of genetic changes, pituitary tumors show epigenetic Surgical treatment is the first-line treatment in pituitary
changes as different histone modification and aberrant adenomas—exceptforprolactinomas,wheredopamine
DNAmethylationstatus[13].Thesegeneticandepigenetic agonistsarerecommendedastreatmentofchoice[20,21].
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Two operative techniques exist for resection of pituitary long-termtreatmentstrategy.Nevertheless,echocardiogra-
tumors.Transsphenoidal(transnasal)resectionisthemost phyisindicatedinlong-termtreatmentwithhigherdosages
common operative technique; only in extrasellar tumors ofcabergoline>2mgperweek[30].Cabergolinecanalso
is a craniotomy recommended. Intraoperative MRI scans be used in women who have indicated a wish to get
might ameliorate outcome in some patients but are not pregnant;itshouldnotbewithdrawninthesepatients[30].
generallyrecommended[22,23].Recently,stereotacticand
fractional radiosurgery such as Gamma Knife or Cyber Besidesdopamineagonists,furthertreatmentoptionsare
Knifehaveenrichedinterventionaltreatmentoptions[24]. available for corticotropinomas. In general, in CD either
the production of ACTH can be lowered or the cortisol
Selectiveadenomectomyisthetreatmentofchoiceinorder production in the adrenal gland can be reduced. New
topreservepituitaryfunction[18].InCD,surgicalcurative pharmacologicaltargetshavebeendevelopedrecentlyfor
therapy is the treatment of choice in adrenocorticotropic thetreatmentofCD.
hormone(ACTH)-producingtumors[21].Onthefirstday
post-surgery,cortisollevelsshouldbedetermined.Fasting Somatostatin analogues such as octreotide reduce ACTH
serum cortisol levels <50nmol/l (<2µg/dl) indicate a secretion. Dexamethasone and probably high levels of
remission anda low recurrencerate(10%after10 years). corticosteroids in general reduce mRNA expression of the
Iffastingserumcortisollevelsarehigherthan140nmol/l somatostatinreceptortype2(SSTR2)[31].Sinceoctreotide
(5µg/dl)inthefirstweekpost-surgery,furtherevaluationis actsviasuppressionoftheSSTR2,octreotidetreatmentisnot
necessary [21]. In case of postsurgical hypocortisolism, a alwayssuccessfulinCD.Furthermore,mostACTH-secreting
substitution therapy should be initiated [18]. In recurrent adenomas express predominantly somatostatin receptor
adenomas, irradiation or adrenalectomy should be con- type5(SSTR5)[32].Recentexperienceexistswithpasireo-
sideredasfurthertreatmentoptions[17]. tide (SOM 230), which has a high affinity for the SSTR5
receptor but also shows affinity for the SSTR1 and SSTR2
In pituitary carcinomas, it might be necessary to repeat receptors. Pasireotide may be a new effective tool in the
surgicalinterventions.Inmostcases,surgicaltreatmentwill pharmacological treatment of corticotropinomas [33-35].
be supplemented with pharmacological treatment (dopa- Acombinationofpasireotidewithadrenalblockingdrugs
mine agonists, somatostatin analogues, temozolomide). and glucorticoid receptor antagonizing drugs might be
Furthermore,radiotherapyshouldbeevaluatedinpatients necessaryintheindividualpatient[36,37].
withaggressivepituitarytumorswhensurgicalandpharma-
cologicaltreatmentoptionsfail. Furthermore, it has been shown that retinoic acid can
reduce ACTH secretion and cell proliferation. The effect
Pharmacological treatment is mediated by the nuclear retinoic acid receptor (RAR)
Hormonal active pituitary adenomas can be treated and retinoid x receptor (RXR) [38,39] and is limited to
pharmacologically.Inprolactinomas,pharmacological tumorswithACTHsecretion.Retinoicacidwasnotonly
treatment is the treatment of choice. markedly suppressing ACTH secretion in corticotroph
adenoma cells in vitro but was also effective in vivo as it
The dopamine D2 receptor subtype is the pharmacolo- stronglyreducedurinary-freecortisolinpatientswithCD,
gical target of dopamine agonists. Dopamine inhibits asshowninarecentstudy[40].Ithastobediscussedthat
prolactinproductionfromthepituitarygland[25].Since only7patientswereincludedinthisstudy.Hence,human
about 80% of all corticotropinomas also express the trialsareverylimited,andretinoicacidisnotatpresentan
dopamine D2 receptor [26], a normalization of cortisol acceptedtherapy.
levels might be achieved using dopamine agonists such
as bromocriptine or cabergoline. Dopamime agonists Peroxisome proliferator-associated receptor-gamma
arealsousedinParkinson’sdiseasewherehigherdosages (PPAR-g) ligands, such as rosiglitazone, were potent
are necessary. Since ergotamine derivatives might cause suppressors of ACTH in corticotroph cell lines in vitro or
multiple fibrosis (i.e., valvular or pulmonary fibrosis) inmousemodelsofCD[41]butwerenotclinicallyuseful
[27,28],bromocriptineorcabergolineisonlyadministered inpatientswithcorticotrophadenomas[42].
with clinical controls (i.e. echocardiography). Low-dose
cabergolinewithitslonghalf-lifeperiodof65hoursisthe Inacromegaly,dopamineagonistscanbeadministeredas
most frequently used dopamine agonist for pharmacolo- well as somatostatinreceptor ligands orthe GH receptor
gical treatment of prolactinomas and corticotropinomas. antagonist pegvisomant [43]. The aim of the pharmaco-
Clinical guidelines recommend cabergoline treatment in logical treatment in acromegaly is to normalize IGF-1
patients with hyperprolactinaemia [14]. Low-dose caber- levelsandtodecreaseGHbylessthan2.5µg/lorpossibly
golinedoesnotseemtocausecardiacfibrosis[29]evenasa lower.
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In prolactin-producing carcinomas (malignant prolacti- adenoma; SSTR2, somatostatin receptor type 2; SSTR5,
nomas), temozolomidecanbeadministeredaspharma- somatostatinreceptortype5.
cological treatment [14,44,45]. In case reports,
temozolomide reduced tumor size and prolactin levels Disclosures
in tumors that mainly did not express methylguanine- Theauthorsdeclarethattheyhavenodisclosures.
DNA methyltransferase (MGMT) [46]. Since data on
MGMTmethylationstatusandresponsetotemozolomide
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