New Perspectives on Diagnostics, Prognosis, and Therapy in Aggressive Endocrine Tumours

114 Pages·2012·7.26 MB·English

Journal of Oncology
New Perspectives on
Diagnostics, Prognosis,
and Therapy in Aggressive
Endocrine Tumours
Guest Editors: Marialuisa Appetecchia, Bruce H. R. Wolffenbuttel,
and Saadi Al Jadir
New Perspectives on Diagnostics, Prognosis,
and Therapy in Aggressive Endocrine Tumours
Journal of Oncology
New Perspectives on Diagnostics, Prognosis,
and Therapy in Aggressive Endocrine Tumours
Guest Editors: Marialuisa Appetecchia,
ff
Bruce H. R. Wol enbuttel, and Saadi Al Jadir
Copyright©2012HindawiPublishingCorporation.Allrightsreserved.
Thisisaspecialissuepublishedin“JournalofOncology.”AllarticlesareopenaccessarticlesdistributedundertheCreativeCommons
AttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisprop-
erlycited.
Editorial Board
ThomasE.Adrian,UAE ToshiyukiIshiwata,Japan DirkRades,Germany
MassimoAglietta,Italy AndreasH.Jacobs,Germany ZviRam,Israel
BruceBaguley,NewZealand IsmailJatoi,USA DirkReinhardt,Germany
DavidBall,Australia G.Kaspers,TheNetherlands PaulG.Richardson,USA
A.J.M.Balm,TheNetherlands MichaelJ.Kerin,Ireland MichelRigaud,France
FredericG.Barr,USA Tu¨rkerKilic¸,Turkey Jo¨rgRitter,Germany
SørenM.Bentzen,USA TimothyJ.Kinsella,USA MackRoach,USA
RolfBjerkvig,Norway Jo¨rgKleeff,Germany BerndF.M.Romeike,Germany
PeterMcLarenBlack,USA GeorgeO.Klein,Sweden VolkerRudat,Germany
SusanaM.Campos,USA MarkJ.Krasna,USA ThomasJ.Rutherford,USA
MichaelA.Carducci,USA MasatoshiKudo,Japan SihamSabri,Canada
StefanoCascinu,Italy RobertLangley,USA AysegulaA.Sahin,USA
SoonmeeCha,USA AllanLipton,USA GiovanniScambia,Italy
SusanChang,USA JayS.Loeffler,USA P.MagnusSchneider,Switzerland
ThomasR.Chauncey,USA DarioMarchetti,USA PeterE.Schwartz,USA
DennisS.Chi,USA ShahlaMasood,USA JalidSehouli,Germany
EdwardA.Copelan,USA KeisukeMasuyama,Japan EdgarSelzer,Austria
RichardCrevenna,Austria IanE.McCutcheon,USA FrancisSeow-Choen,Singapore
MassimoCristofanilli,USA MineshMehta,USA DongM.Shin,USA
ChristosDervenis,Greece SofiaD.Merajver,USA JeanF.Simpson,USA
AndreasDietz,Germany BradleyJ.Monk,USA KeshavK.Singh,USA
FrederickE.Domann,USA YoshihiroMoriya,Japan JudithA.Smith,USA
AvrahamEisbruch,USA SatoruMotoyama,Japan LawrenceJ.Solin,USA
JoannG.Elmore,USA JamesL.Mulshine,USA LuisSouhami,Canada
ThomasJ.Fahey,USA AryaNabavi,Germany AlphonseG.Taghian,USA
DominicFan,USA PatrickNeven,Belgium HiromitsuTakeyama,Japan
PhillipG.Febbo,USA ChristopheNicot,USA NelsonTeng,USA
DouglasL.Fraker,USA FelixNiggli,Switzerland C.H.J.Terhaard,TheNetherlands
HenryS.Friedman,USA PatriziaOlmi,Italy DouglasS.Tyler,USA
HaniGabra,UK JanI.Olofsson,Norway RaulA.Urrutia,USA
CicekGercel-Taylor,USA Fre´de´riqueP.-Llorca,France VincenzoValentini,Italy
WilliamJ.Gradishar,USA RichardT.Penson,USA DanielVallbo¨hmer,Germany
AkiraHara,Japan MichaelC.Perry,USA M.vandenBrekel,TheNetherlands
RobertM.Hermann,Germany JosephM.Piepmeier,USA JohnR.vanNagell,USA
MarioHermsen,Spain M.StevenPiver,USA BrunoVincenzi,Italy
FredH.Hochberg,USA AlfredoQ.-Hinojosa,USA JochenA.Werner,Germany
WilliamJ.Hoskins,USA JanetS.Rader,USA
Contents
NewPerspectivesonDiagnostics,Prognosis,andTherapyinAggressiveEndocrineTumours,
MarialuisaAppetecchia,BruceH.R.Wolffenbuttel,andSaadiAlJadir
Volume2012,ArticleID820938,2pages
GeneticandClinicalFeaturesofMultipleEndocrineNeoplasiaTypes1and2,C.Romei,E.Pardi,
F.Cetani,andR.Elisei
Volume2012,ArticleID705036,15pages
NewTreatmentinAdvancedThyroidCancer,DarioGiuffrida,AngelaPrestifilippo,AlessiaScarfia,
DanielaMartino,andStefaniaMarchisotta
Volume2012,ArticleID391629,10pages
AdrenocorticalCarcinoma:CurrentTherapeuticState-of-the-Art,AmirH.Lebastchi,JohnW.Kunstman,
andTobiasCarling
Volume2012,ArticleID234726,11pages
MerkelCellCarcinoma:ARetrospectiveStudyon48CasesandReviewofLiterature,FernandoCirillo,
MarcoVismarra,InesCafaro,andMarioMartinotti
Volume2012,ArticleID749030,9pages
CurrentandEmergingTherapeuticOptionsinAdrenocorticalCancerTreatment,AntonioStigliano,
LidiaCerquetti,CamillaSampaoli,BarbaraBucci,andVincenzoToscano
Volume2012,ArticleID408131,13pages
ManagementStrategiesforAggressiveCushing’sSyndrome:FromMacroadenomastoEctopics,
CarlottaPozza,ChiaraGraziadio,ElisaGiannetta,AndreaLenzi,andAndreaM.Isidori
Volume2012,ArticleID685213,9pages
RadiolabeledSomatostatinAnaloguesTherapyinAdvancedNeuroendocrineTumors:ASingleCentre
Experience,A.Filice,A.Fraternali,A.Frasoldati,M.Asti,E.Grassi,L.Massi,M.Sollini,A.Froio,P.A.Erba,
andA.Versari
Volume2012,ArticleID320198,10pages
TheInsulinandIGF-IPathwayinEndocrineGlandsCarcinogenesis,RobertaMalaguarnera,
AlaideMorcavallo,andAntoninoBelfiore
Volume2012,ArticleID635614,19pages
UpdatedandNewPerspectivesonDiagnosis,Prognosis,andTherapyofMalignant
Pheochromocytoma/Paraganglioma,GabrieleParenti,BenedettaZampetti,ElenaRapizzi,
ToninoErcolino,ValentinoGiache´ andMassimoMannelli
Volume2012,ArticleID872713,10pages
HindawiPublishingCorporation
JournalofOncology
Volume2012,ArticleID820938,2pages
doi:10.1155/2012/820938
Editorial
New Perspectives on Diagnostics, Prognosis, and Therapy in
Aggressive Endocrine Tumours
MarialuisaAppetecchia,1BruceH.R.Wolffenbuttel,2andSaadiAlJadir3
1EndocrinologyUnit,ReginaElenaNationalCancerInstitute,53ElioChianesiStreet,00144Rome,Italy
2DepartmentofEndocrinology,UniversityMedicalCenterGroningen,Groningen,TheNetherlands
3Endocrinology&DiabetesUnit,DepartmentofInternalMedicine,FujairahHospital,Fujairah,UAE
CorrespondenceshouldbeaddressedtoMarialuisaAppetecchia,[email protected]
Received6November2012;Accepted6November2012
Copyright©2012MarialuisaAppetecchiaetal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttribution
License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly
cited.
The research process is not entirely complete and sounds Most of these tumors appear as sporadic on one hand,
until the results are validated and transmitted to an appro- andonothertheymightbeclustersorfamilialpartofgenetic
priatetargetaudiencethroughmodernpublication. syndromelikeMEN1,MEN2,orothermoreraredisorders.
Only through well-designed publication of results in Thesetumorsordinarilysecretehormonesoftheglands
established peer-reviewed journals or scientific congresses thathavearisenfrom,andsometimestheyarenonsecretors,
can new ideas and research findings be disseminated and majorityarebenignandothersaremalignant;someofthese
effectivelyincorporatedintoclinicalpracticeandeventually neoplasmstendtohaveindolentcourse,othersareshortand
improvementinphysician’sperformanceandpatient’shealth aggressive, as their clinical presentation and management
outcome. vary accordingly. It is not surprising to find these tumors
in unusual or ectopic sites that eventually rendered their
We had ensured that all published reports of research
topographyandpresentationdifficult.
have been reviewed by suitably qualified reviewers (e.g.,
Last decades had shown a great development and
includingstatisticalreviewwhereappropriatelyneeded).
tremendoussuccessesineruptionofvarietyofbiochemical;
Therefore, we are intended in our journal to achieve
immunochemical; imaging techniques and most of these
successful medical writing in order to serve as the optimal
tumors showed their biological activity before their size
pathway to advance medical knowledge, promote critical
could be detected by the conventional diagnostic testing.
thinking, incite scientific debate by involving a lot of
Currently,mostofendocrineneoplasmscanbesuccessfully
expertiseinourpublications,andmaintainthehighdegree
localized and subsequently have made their managements
ofscientificandprofessionalqualitybesidesconsideringthe
feasible.
continuingprogressindifferentfields,modernmedicine.
In this special issue, we had tried to incorporate many
Endocrinetumorsareamixedgroupofdiseasesinwhich aspects in studying these tumors including genetics behav-
neoplasticcellsarefoundintissuesoftheendocrinesystem, iors,diagnosis,clinicalcourse,newmodalitiesindiagnosis,
which includes the thyroid, adrenal, pancreas, parathyroid, management,andsurgicalapproachesaswellaschemother-
andpituitaryglands. apyandspecificpalliativeproceduresinmetastaticdisease.
Endocrine-related neoplasm has been enlarged to the Clinical studies and review articles in this special issue
domain of endocrine system to neural tissue as the havedemonstratedthemostrecentupdatesindiagnosisand
embryonic development is closely interrelated; therefore, new treatment strategies, besides the enormous improve-
neuroendocrine tumors will be literally included in our ment in molecular biology of some relatively uncommon
researches, neuroendocrine tumors (Merkel cell, islet cell, tumors that certainly will be of utmost importance to the
MCT,pheochromocytoma,carcinoidsetc.). practicingpractitioners.
2 JournalofOncology
Thyroid cancer is the most common endocrine tumor. MTCpatients,especiallyinMENs2Band2A,arenotcured
Besidesstandardtreatmentfordifferentiatedthyroidcancer, by surgery. Recently, developed molecular therapeutics that
the research for new therapies in advanced nonmedullary targettheRETpathwayhaveshownverypromisingactivity
andmedullarythyroidcarcinomas,withtheadventoftyro- inclinicaltrialsofpatientswithadvancedMTC.
sine kinase inhibitors as well as antiangiogenic inhibitors, There is growing evidence of the role of IGF system
those patients could have an advantage with new target dysregulation in endocrine neoplasms, and we will discuss
therapy. thepossibleimplicationsofthesefindingsfortumorpreven-
Inadrenocorticalcarcinomaradicalsurgeryisconsidered tionandtreatment,withamajorfocusoncancersfromthe
the therapy of choice in the first stages of ACC. Mitotane, thyroid, adrenal, and ovary, which are the most extensively
an adrenolytic drug with significant toxicity and unpre- studied. However, multiple molecular abnormalities of the
dictable therapeutic response, is used in the treatment of IGF system frequently occur in endocrine neoplasms and
ACC. Although, treatment for this aggressive cancer is still may have a role in tumorigenesis as well as in tumor
ineffective.Overthepastyears,thegrowinginterestinACC progressionandresistancetotherapies.
hascontributedtothedevelopmentoftherapeuticstrategies
MarialuisaAppetecchia
inordertocontrasttheneoplasticspread.
The efficacy of radiolabeled somatostatin analogues in BruceH.R.Wolffenbuttel
SaadiAlJadir
patients with advanced neuroendocrine tumors had been
illustrated in one article and clearly had exhibited that
overalltumorresponseratewasappreciable,andPRRTisa
promisingperspectiveforpatientswithadvancedNETs.
Cushing’s syndrome whenever surgery is not curative,
management of patients requires a major effort to control
excesscortisolandassociatedsymptoms.Amultidisciplinary
approach should be adopted. For aggressive ACTH depen-
dent, several drugs are able to reduce cortisol levels. Their
mechanismofactioninvolvesblockingadrenalsteroidogen-
esisandnovelchemotherapeuticagents(temozolomideand
tyrosine kinase inhibitors) which have a significant activity
againstaggressivepituitaryorectopictumors.
Recent genetic studies of malignant pheochromocy-
tomas/paragangliomas have highlighted the main pathways
involvedinpathogenesis,thussuggestingtheuseoftargeted
therapy which, nevertheless, still has to be validated. Large
collaborative studies on tissue specimens and clinical trials
in large cohorts of patients are necessary to achieve better
therapeutictoolsandimprovepatientprognosis.
Review article about insulinoma had highlighted many
aspectsonthissmallneoplasm,includingbiologicalactivity,
new emerging imaging techniques in localizing the tumor
especially in resectable ones, molecular pathogenesis of
malignant disease, and treatment modalities for aggressive
course,andputconsequenthypoglycemiaundercontrol.
Merkel cell carcinoma is a rare and aggressive neuroen-
docrine tumor of the skin. Wide surgical excision must be
associated with radiotherapy in early stages. In advanced
disease, chemotherapy is the standard option despite the
shortdurationofresponsesandpoorqualityoflife.
Multipleendocrineneoplasias(MENs)areclinicalinher-
ited syndromes affecting different endocrine glands. Three
different patterns of MEN syndromes can occur (MEN
1, MEN 2A, and MEN 2B). MEN 1 is characterized by
the neoplastic transformation of the parathyroid glands,
pancreaticislets,anteriorpituitary,andgastrointestinaltract.
Therapeuticapproachesaredifferentaccordingtothediffer-
ent endocrinopathies. In MEN 2 syndromes, the medullary
thyroid cancer is almost invariably present and can be
associated with pheochromocytoma and/or multiple ade-
nomatosisofparathyroidglandswithhyperparathyroidism.
Although surgery is the main option, nevertheless, 30% of
HindawiPublishingCorporation
JournalofOncology
Volume2012,ArticleID705036,15pages
doi:10.1155/2012/705036
Review Article
Genetic and Clinical Features of Multiple Endocrine Neoplasia
Types 1 and 2
C.Romei,E.Pardi,F.Cetani,andR.Elisei
DepartmentofEndocrinologyandMetabolism,UniversityofPisa,56124Pisa,Italy
CorrespondenceshouldbeaddressedtoR.Elisei,[email protected]
Received30July2012;Accepted16September2012
AcademicEditor:MarialuisaAppetecchia
Copyright©2012C.Romeietal. This is an open access article distributed under the Creative Commons Attribution License,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Multipleendocrineneoplasia(MEN)areclinicalinheritedsyndromesaffectingdifferentendocrineglands.Threedifferentpatterns
ofMENsyndromescanoccur(MEN1,MEN2A,andMEN2B).MENsyndromesareveryrare,affectallagesandbothsexesare
equallyaffected.MEN1ischaracterizedbytheneoplastictransformationoftheparathyroidglands,pancreaticislets,anterior
pituitary,andgastrointestinaltract.HeterozygousMEN1germlinemutationshavebeendetectedinabout70–80%ofpatients
withMEN1.Themutationsarescatteredthroughouttheentiregenomicsequenceofthegene.MEN1patientsarecharacterized
byvariableclinicalfeatures,thussuggestingthelackofagenotype-phenotypecorrelation.Therapeuticalapproachesaredifferent
according to the different endocrinopathies. The prognosis is generally good if adequate treatment is provided. In MEN 2
syndromes, the medullary thyroid cancer (MTC) is almost invariably present and can be associated with pheochromocytoma
(PHEO)and/ormultipleadenomatosisofparathyroidglandswithhyperparathyroidism(PHPT).Thedifferentcombinationof
theendocrineneoplasiagivesoriginto3syndromes:MEN2A,MEN2B,andFMTC.TheclinicalcourseofMTCvariesconsiderably
inthethreesyndromes.ItisveryaggressiveinMEN2B,almostindolentinthemajorityofpatientswithFMTCandwithvariable
degreesofaggressivenessinpatientswithMEN2A.ActivatinggermlinepointmutationsoftheRET protooncogenearepresent
in98%ofMEN2families.Astronggenotype-phenotype correlationhas beenobservedandaspecificRET mutationmaybe
responsibleforamoreorlessaggressiveclinicalcourse.ThetreatmentofchoiceforprimaryMTCistotalthyroidectomywith
centralnecklymphnodesdissection.Nevertheless,30%ofMTCpatients,especiallyinMEN2Band2A,arenotcuredbysurgery.
Recently,developedmoleculartherapeuticsthattargettheRET pathwayhaveshownverypromisingactivityinclinicaltrialsof
patientswithadvancedMTC.MEN2prognosisisstrictlydependentontheMTCaggressivenessandthusonthesuccessofthe
initialtreatment.
1.Introduction 2.MultipleEndocrineNeoplasiaType1
The term multiple endocrine neoplasia (MEN) defines 2.1. Definition. Multiple endocrine neoplasia type 1 syn-
clinical inherited syndromes affecting different endocrine drome(MEN1,OMIMno.131100),alsoknownasWermer’s
glands, each with its own characteristic pattern [1, 2]. In syndrome because of the description in 1954 by Dr. Paul
some cases, the tumors are malignant, in others, benign. Wermer of a pluriglandular dysfunction transmitted as a
Benign or malignant tumors of nonendocrine tissues occur dominant trait, is characterized by simultaneous neoplastic
ascomponentsofsomeofthesetumorsyndromes. transformation of multiple endocrine tissues, typically the
Three different patterns of MEN syndromes can occur parathyroid glands, pancreatic islets, and anterior pituitary.
(MEN 1, MEN 2A, and MEN 2B) with some new variants The case of an acromegalic patient with three enlarged
such as MEN 4, which is considered a variant of MEN 1 parathyroid glands and a pituitary adenoma was indeed
and the familial medullary thyroid cancer (FMTC), which firstly described in 1903 and, after small case reports,
isconsideredavariantofMEN2A[3,4].Thesesyndromes Underdahl,WoolnerandBlackin1953describedaseriesof8
arefamilialandcausedbyinheritedgeneticmutations,which patientswithvariouscombinationsofpituitary,parathyroid,
havebeendiscoveredwithinthelast20years[5]. andpancreaticisletadenomas[6].
2 JournalofOncology
Thisdisorderisstronglysuspectedeitherinpatientswith arepresentinaboutone-thirdofMEN1patients.Multiple
endocrinopathies of at least 2 of the 3 main affectedglands facial angiofibromas occur in 40–80% of MEN 1 patients.
(i.e., parathyroid, enteropancreatic, and pituitary tumors) Collagenomas are also common. These cutaneous lesions
or in patients with at least one endocrinopathy in one of may be helpful for presymptomatic diagnosis of MEN 1
theseorgansandafirst-degreerelativewhoisaffectedbyone carriers.
of these tumors (familial MEN 1). Patients with features of
MEN1syndromebutwithoutafamilyhistoryofMEN1are
2.2. Epidemiology. MEN 1 is rare, occurring in about one
affected by a sporadic form of MEN 1. MEN 1 syndrome
of 30,000 individuals, with an estimated prevalence of 2-3
presents a wide spectrum of more than 20 endocrine
per 100,000. The disorder affects all ages with a range of
and nonendocrine associated manifestations other than the
5–81yrs and both sexes equally [22]. A recent multicenter
classic endocrinopathies, including adrenocortical, gastric,
studyanalyzed734casesofMEN1andreportedadifferent
thymic or bronchial tumors, foregut carcinoids, visceral
phenotype expression of the MEN 1 disease between males
andcutaneouslipomas,meningiomas,facialangiofibromas,
and females, in particular the prevalence of pancreatic
concurring to different phenotypic presentations (Figure1)
tumors was higher in males than in females, while the
[7–9]. Thyroid tumors are also frequently associated, but
oppositehappenedforthepituitarytumors.Thymictumors
this association should be considered likely casual for the
were exclusively found in men. There was no significant
high incidence of thyroid abnormalities in the general
gender difference in the prevalence and the probability of
population. Various clinical cases report rare combinations
developingPHPT,adrenalandbronchialtumorsincontrast
of less common tumors of MEN 1 and these atypical cases
to sporadic counterparts or in the proportion of positive
arealsoknownasMEN1“phenocopyvariants.”
genetictests[23].
The most frequent MEN 1-associated endocrinopathy,
MEN1-affectedpatientsdonotbelongtoparticulargeo-
occurringinnearly100%ofpatientsbytheageof50yrs,is
graphicalarea,andtherearenoracialorethnicpreferences.
primaryhyperparathyroidism(PHPT),characterizedbythe
Noriskfactorsareknown.
synchronous or asynchronous development of multiglan-
dular parathyroid hyperplasia with a benign course, while
extremely rare is the occurrence of parathyroid carcinoma 2.3.Pathogenesis. In1988,linkageanalysisstudiesinaffected
(PC), being only six cases of PC associated with MEN 1 in families placed the MEN 1 gene within a 2 Mb interval in
the literature [10]. Tumors of the parathyroid are often the 11q13 and subsequently loss of heterozygosity [24] studies
firstmanifestationofMEN1inmorethan85%ofpatients, narrowed the location of the gene to a 600 kb interval
withatypicalageofonsetof20–25yrs[11–13]. [25]. The candidate gene, MEN 1, was finally identified by
Gastroenteropancreaticendocrine(GEP)tumours,most positional cloning in 1997 [26]. Combined LOH studies by
arising in the pancreas as nonfunctioning neuroendocrine microsatellite analysis in tumor tissues of MEN 1 patients
tumoursorinsulinomas,developinupto70–80%ofMEN and pedigree studies of large kindred supported a tumor
1patients,andgastrinomarepresents,togetherwithforegut suppressor function of the MEN 1 gene suggesting the
carcinoids, the major cause of morbidity and mortality mechanism of biallelic inactivation firstly described by
in MEN 1, because of its high rate of metastasis [17, Knudsonforthegeneofretinoblastoma[27].
18] (Figure1). The lesions range from microadenomas TheMEN1geneconsistsof10exons,thefirstofwhich
to macroadenomas, and to metastatic carcinomas. These is untranslated, spanning 7.2kb of genomic sequence and
tumors arise after the age of 40yrs. Gastrinomas account encoding a protein, menin, of 610 amino acids, that does
for more than 50% of all GEP tumors and are typically notpresenthomologiestoanyotherknownproteins.MEN1
small (<5mm), multiple, mainly located in the duodenum mRNAisexpressedatasimilarlevelinendocrineandnonen-
andrarelyinthepancreas.Inthelattercaseitisdifficultto docrineorgans,leavingunexplainedthebasisforendocrine
distinguish these lesions from concomitant nonfunctioning predominanceofneoplasia.Meninisanuclearproteinwhose
pancreatictumors(NFPTs). bindingtotheAP1transcriptionfactorJunDsuggestsarole
The prevalence of pituitary tumors in MEN 1 ranges in transcriptional regulation. The interaction with several
between 10% and 60%, being the prolactinoma the com- partners and its participation in a variety of mechanisms,
monest MEN 1-related pituitary adenoma, although other includingregulationofcellproliferationanddifferentiation,
pituitary tumors have been described so far (Figure1). apoptosis, endocrine/metabolic functions and the mainte-
Themajorityoftumorsaremicroadenomas(<10mm).The nance of genomic stability by DNA repair, have been so
mean age ± SD of onset has been reported to be 38 ± far reported [28]. The tumor suppressor nature of MEN
15yrs. Pituitary tumors are generally more invasive, symp- 1 gene is best achieved by menin-mediated inhibition of
tomatic,withahigherprevalenceofmacroadenomasanda cell proliferation through multiple mechanisms such as (a)
worseresponsetotreatmentthanthesporadiccounterparts the interaction of menin with histone-modifying enzymes
[19,20]. (MLL, EZH2, and HDACs) that affect gene transcription;
Foregut carcinoids, especially of the lung and thymus, (b)theinteractionwithvarioustranscriptionfactors,suchas
are generally aggressive tumors and associated with a very JunD,NF-κB,PPARγ,andVDR,toinduceorsuppressgene
highlethality.Adrenaltumorsfollowabenigncourseinmost transcription; (c) the inhibition of cellular proliferation via
MEN1cases,andthemajorityarebilateral,hyperplastic,and TGF-βsignalingandWnt/β-cateninsignalingpathways;(d)
nonfunctional [21]. Lipomas, both cutaneous and visceral, the repression of pro-proliferative factors (IGFBP-2, IGF2,s