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1494
• Rarelyparathyroidadenomaspresentasapalpablemass.
• Radiology:m Several imaging methods have been used for
localization of hyperfunctioning parathyroidtissue, including retrograde phlebotomy fordeterminationofserumparathormonelevels,CTscanning, ultrasonography, magnetic resonanceimaging (MRI), thallium subtraction scanning,andtechnetium-99msestamibiimaging.
m Technetium-99msestamibiimagingappearstobethemost useful,with localizationofmore than90% of adenomas, and has been most widelyusedinpatientswithanatomicdistortionduetoprevious surgery and in patient who are highsurgical risks;however,more routineutilizationhasgainedsupport.
m Multidimensional CT (referred to as 4D-CT)emerging technique used in detection when alesionisnotidentifiedbymoreconventionaltech-niques(e.g.,ultrasonography,sestamibiimaging)
• May be associated with hyperparathyroidism-jawtumorsyndrome(HPT-JT):m Autosomal-dominant disorder with germline
mutation in HRPT-2 gene on chromosome1q25-31
m Characterizedby:– Parathyroidadenomaorcarcinoma– Fibro-osseouslesionsofthejaw(e.g.,ossifying
fibromaofmandibleormaxilla):30%ofcases– Renal cyst, hamartoma, carcinoma: 20% of
casesm Approximately 80% of patients develop
hyperparathyroidism:– Usuallypresentslateinadolescence– Hypercalcemiatendstobesevere.
m Higher incidence of parathyroid carcinoma incomparison with patients with MEN-1 andMEN-2A
m Renallesionsmayinclude:– Renal cysts, polycystic renal disease, renal
hamartoma– Papillary renal cell carcinoma, renal cortical
adenomas,Wilmstumor• 90%ofadenomasarefoundinparathyroidglands
intheirusuallocations:m Lowerglandsaremorecommonlyinvolved.
Chapter
Neoplasms of the Parathyroid Glands
CLASSIFICATION OF NEOPLASMS OF THE PARATHYROID GLANDS (Box 33-1)
33
BOX 33-1 Neoplasms of the Parathyroid Glands
• Parathyroid adenoma• Parathyroid carcinoma• Secondary neoplasms
PARATHYROID ADENOMA (Figs. 33-1 through 33-22, Table 33-1)
Definition:Benignneoplasmoftheparathyroidparen-chymalcells,includingchiefcellsand/oroncocyticcells.
Clinical• Morecommoninfemales(F:M=3to4:1);occur
overabroadagerangebutaremostfrequentlydis-coveredinthefourthandfifthdecades.
• Represents the major cause of primaryhyperparathyroidism
• Clinical findings are essentially the same as thoseassociatedwithprimaryhyperparathyroidismduetohyperplasia(seeChapter32).
• Asinprimaryhyperparathyroidismduetohyperpla-sia, the symptomatology in patients with parathy-roid adenomas is changing as a result of routinebiochemicalscreeningandearlydetection:m Hypercalcemiamaybeincidentallydiscoveredin
asymptomaticpatients,andmanypatientscom-plainonlyoffatigue,weakness,ordepression.
m Nephrolithiasis is documented in 69% of menand in 36% of women with adenomas overall,but the incidence has been decreasing in recentyearstobetween5%and20%.
m Severe bone disease, once a common complica-tion, is now rare; however, osteopenia is oftenpresent,andjointdiseasesimilartothatfoundinpatientswithparathyroidhyperplasiaoccurs.
• Serum calcium levels are generally higher than inpatientswithprimarychiefcellhyperplasiabutnotusuallyashighasinparathyroidcarcinoma.
• Hypophosphatemia, hyperphosphaturia, and ele-vatedserumparathormonelevelsarefound.
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1495
Fig. 33-1.Classic parathyroid adenoma identified on ultrasonography.
A,Sagittalultrasonographicimageshowsahypoechoic,well-definedmass(A)justbelowtheinferiorpoleoftherightthyroidgland(*).B,TransverseultrasonographicimagewithcolorflowDopplershowstheincreasedperipheralarchofvascularityofthemassfrequentlyseenwithadenomas(A).(From Som PM, Curtin HD: Head and neck imaging, ed 5, Philadelphia, 2011, Elsevier, Fig. 41-95, p 2663.)
A
* *A
B
A
• Ectopicparathyroidadenomas:m Parathyroidadenomasmayoccurinanylocation
inwhichparathyroidtissuemaybefound,includ-ingectopicsitessuchasthemediastinum,retro-esophagealsofttissue,withinthethyroidgland,orinthymictissue
m Ectopicadenomas,especiallyintrathyroidalones,maybemissedbyclinicalevaluationand/orsurgi-calexploration:– Intrathyroidal parathyroid adenomas may be
misinterpreted by pathologic evaluation as athyroid follicular lesion or medullary thyroidcarcinoma.
m Reportsofadenomasoccurringinsupernumeraryglands include tumors arising in the vagusnerve, pericardium, or other soft tissue sites intheneck.
PathologyCytology• Occasionally enlarged parathyroid glands, either
hyperplastic or, more commonly, adenomatous,have been serendipitously subjected to fine-needleaspirationasaclinicallysuspected“solitarythyroidnodule”;reportsofultrasonicallyguidedfine-needleaspirationforlocalizationandconfirmationofpara-thyroidproliferativediseasehaveappeared.
• Anawarenessofthetypicalcytologicappearanceofparathyroidtissuecanbehelpfulduringintraopera-tiveexaminationofbiopsiesduringaneckexplora-tion for hyperparathyroidism, as examination oftouchpreparationsprovidesa rapidmeansofcon-firmingthepresenceofparathyroidtissue.
• Aspirates of parathyroid tissue typically containnumerous naked nuclei, as well as small sheets ofcells, sometimes forming acinar or follicular struc-tures;smallaggregatesofdensecolloid-likematerialmaybeseenbutarenotnumerous.
• The cells are generally small, with predominantlyround nuclei; anisonucleosis in scattered cells andoccasionallarge,atypical,nakednucleiarecommon.
• Thecytoplasmisgranularandmayexhibitscatteredlarge metachromatic granules with a May-Grünwald-Giemsa or Romanowsky stain;Papanicolaou-stainedcellshavecleartofinelygranu-larcytoplasm.
• Thenucleiaregenerallyhyperchromaticwithcoarsechromatintypicalofneuroendocrinecells.
• The distinction from follicular epithelium of thethyroidmaybedifficult,althoughthecellsareusuallysmallerthanthoseofthethyroid:m Immunohistochemical staining for PTH, parafi-
bromin,chromogranin,thyroglobulin,andTTF1maybehelpfulinthisdifferentialdiagnosis.
Gross• Adenomasarealmostalwayssolitary(seebelowfor
DoubleAdenoma).• Adenomashaveroundedborders,arefirm,brownto
tan,andarecontainedwithinadelicatecapsule;theymaybeovoidorlobulated.
• A remnant of uninvolved parathyroid tissue at theperipheryofthetumormaybevisible.
• Cystic change may be present, and when markedmaymasktheneoplasticnatureoftheproliferation;markedcysticdegeneration is frequentlyassociatedwithscarringandcalcification.
• There is significant variation in weight, with mostbetween0.3and1.0g.
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1496 SECTION 9 ParathyroidGlands
Fig. 33-2.Parathyroid adenoma.
Parathyroidadenomadetectedby201Tl/99mTc-pertechnetatesubtractionimaging(AtoC)andby99mTc-sestamibisubtractionimagingwith123I(D).A,99mTc-pertechnetateconcentratedwithinthethyroidgland.B,201Tlconcentratedwithinthyroidandparathyroidglands.C,Computertechniquesallowtechnetiumconcentratedinthethyroidglandtobesubtractedfromthalliumthataccumulateswithinthyroidandparathyroidtissue.Afterthyroidsubtraction,aparathyroidadenomaisnotedasafocusofincreasedthalliumuptake(arrows).D,99mTc-sestamibisubtractionimagingwith123Ishowsanadenomabelowtheinferiorpoleoftheleftlobeofthethyroidgland.(From Som PM, Curtin HD: Head and neck imaging, ed 5, Philadelphia, 2011, Elsevier, Fig. 41-103, p 2669.)
A B
C D
Histology• Wellcircumscribedanduncommonlysurroundedby
athinfibrouscapsule:m Completeencapsulationnotcommonlyseen
• Hypercellular proliferation lacking intraparenchy-mal fat cellswithdiffusegrowth;vaguenodularitymaybepresentandrarelymaybemultinodular.
• A rim of non-neoplastic parathyroid tissue foundin association with only about half of theadenomas:m Very helpful finding, if present, in making the
distinctionbetweenadenomaandhyperplasiam “Rim” generally contains abundant stromal fat
cells,incontrasttotheverycellularadenoma.
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1497
B
*
A
C
D
Fig. 33-3.4D-CT in the detection of a small adenoma.
A,UnenhancedCTscanatthelevelofthelowerpolesofthethyroidglandshowsnodiscreteadenoma.B,Immediatefirst-passimagefollowingcontrastadministrationshowsatiny,avidlyenhancingadenomaintherightparaesophagealregion(anteriorto*).C,Secondpassat60secondsshowssomewashoutofenhancement,whichisclearlylessthanontheimmediatepostcontrastscan.D,Lastpassdelayedimageat90secondsshowslittleenhancementoftheadenoma,whichisstillreadilyidentifiable.Onanotherpatient:E,CoronalreconstructedCTimagefromimmediatefirst-passenhancedCTscanshowsalargeadenomabelowtheinferiorpoleoftheleftthyroidlobe(arrow).
E
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1498 SECTION 9 ParathyroidGlands
Fig. 33-4.Parathyroid adenoma.
Parathyroidadenomaappearingasalargeencapsulatedlesionbulgingintotheoperativefield.Adenomasaretypicallyeasilydissectedfreeofadjacentstructures;difficultyinremovingaparathyroidtumorshouldraisesuspicionforaparathyroidcarcinoma.
Fig. 33-5.Parathyroid adenoma.
Cutsectionofaparathyroidadenomashowsahomogeneous,lighttanappearance;adelicateinconspicuouscapsuleispresent.Aremnantofuninvolvedparathyroidtissueisnotgrosslyvisible.
F G
**
F,Coronalmaximumintensityprojectionimageinanteriorprojectionshowstheadenoma(arrow).G,Coronalmaximumintensityprojectionimageintheposteriorprojectionshowstheadenoma(*)posteriortothecommoncarotidartery.(Cases courtesy of Dr. Lawrence Ginsberg. From Som PM, Curtin HD: Head and neck imaging, ed 5, Philadelphia, 2011, Elsevier, Fig. 41-101, p 2667.)
Fig. 33-3, cont’d
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1499
m Nuclei of residual normal or atrophic parathy-roidglandtypicallysmallerthanthenucleioftheadenoma.
• Growthpatternsincludesolid(diffuse)sheets,cords,nests,acini,follicles,andmicrocysts:m Follicle formation may contain eosinophilic
“colloid-like”material.m Distincttrabecularpatternisuncommon.
• Predominantlycomposedofchiefcells:m Nucleiroundandregularwithcentraltoslightly
basal location within the cell and have incon-spicuous nucleoli; usually lack significantpleomorphism:– Cells with hyperchromatic enlarged nuclei as
well as multinucleated cells are common andcanbe found scattered throughout the tumoror may be clustered in small foci; these scat-tered atypical nuclei are not an indicator ofmalignancy in the absence of other evidenceof a malignancy (see section on parathyroidcarcinoma).
m Cytoplasmvaries,includingslightlyeosinophilic,amphophilic,clear,oroxyphilic.
m Chiefcellsofanadenomafrequentlylargerthanthe non-neoplastic chief cells in the uninvolvedrimofparathyroidtissue,ifoneispresent
m Oncocyticcellsmaybeseeninvariablenumbers,focally admixed with chief cells or as nodularaggregates.
• Mitotic figures are identifiable in many adenomas,butusuallynumberfewerthan1per10high-powerfields;mitoticratesashighas4mitosesper10high-powerfieldshavebeendescribedinoccasionalcases.
• Delicate vascular network composed of thin fibro-vascularstroma,sinusoid-likebloodvesselsorcapil-lariestraversetheneoplasm.
Fig. 33-6.Parathyroid adenoma.
Parathyroidadenomaappearingasanodularfocuswithcysticchangeandassociatedcalcification.
Fig. 33-7.Parathyroid adenoma, fine-needle aspiration.
A,Cellularsmearwithcohesivegroupsofsmallepithelialcellsandfragmentsofpinkcolloid-likematerialmaysuggestafollicularneoplasmofthyroidorigin;thecolloid-likematerial,however,issomewhatsparse(Diff-Quickstain).B,Thecellsarefragile,yieldingsmearswithnumerousnakednuclei,someofwhicharelargeandhyperchromatic;scatteredlargeatypicalnucleiarecommoninparathyroidadenomas(Diff-Quick).C,Papanicolaou-stainedsmearshowsscatteredcompactclustersofsmallepithelialcellswithdistinctcellbordersandarimofclearcytoplasm;thenucleiaresmallandhyperchromatic.
A
B
C
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1500 SECTION 9 ParathyroidGlands
Fig. 33-8.Parathyroid adenoma.
A,Parathyroidadenomacharacterizedbyhypercellularproliferationdevoidofintraparenchymalfat,whichinthelowerportionoftheillustrationhasawell-definedcapsuleseparatingthecellularproliferationfromathinrimofcompressednormalparathyroidglandparenchyma.B,Athighermagnification,thecellsandnucleioftheadenoma(bottom)arelargerthanthoseoftheresidualnon-neoplasticparathyroidglandparenchyma(top).
A
B
Fig. 33-9.Parathyroid adenoma.
A,Diffuseproliferationofchiefcellswithscatteredadmixedoncocyticcells.B,Tumoristraversedbydelicatefibrovascularstroma.
A
B
• Intraparenchymalfatcellsabsentbutmayfocallybeseenassinglecellsorgroupsintheperipheralaspectoftheneoplasm:m Neoplasticcellsusuallyhavelessintracellularfat
thandothecellsintheuninvolved(orsuppressed)parathyroidtissue,eitherinotherglandsorinarim of non-neoplastic parathyroid tissue in anadenomatousgland.
• Cells with markedly enlarged and hyperchromaticpleomorphic or bizarre-appearing nuclei may bepresentandwhenpresent:m Appearadmixedwithbland-appearingnuclei.m Tendtobefocallyandnotdiffuselyidentified.m Occurintheabsenceofincreasedmitoticactivity
and/orotherfeaturesthatmaybeassociatedwithparathyroidcarcinoma.
• Reactiveanddegenerativechangesmaybepresent,including cyst formation, edema, fibrosis, hemor-rhage (freshor in the formofhemosiderindeposi-tion),orinfarction:m Mayoccurspontaneouslyormayoccurfollowing
a traumatic event such as prior surgery to theneckorfine-needleaspirationbiopsy
m Presence of reactive and degenerative changes,especiallyfibrosis,maycauseadherencetoadja-centstructures,suggestinginvasivegrowthandapossiblediagnosisofparathyroidcarcinoma.
m Infarctedtumormayretainantigenicityforpara-thyroidhormone.
• Rarely,anassociatedmature lymphocyticcell infil-tratemaybepresent.
• Uninvolvedparathyroidparenchymalcellsinpatientswithadenomasaretypicallysmallerandoftenhavemore stromal fat cells than the glands in patients
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1501
Fig. 33-10.Parathyroid adenoma.
Parathyroidadenomasmaybecomposedofanadmixtureof(A)chiefcells,(B)oncocyticcells,and/or(C)clearcells.Inanygiventumortwoorallofthecelltypesmaybepresent,creatingamosaicpattern.
A
B
C
Fig. 33-11.IHC staining in parathyroid adenoma.
Lesionalcellsofparathyroidadenomasareimmunoreactivefor(A)parathyroidhormoneand(B)parafibromin(diffusenuclearstaining).
A
B
Fig. 33-12.Parathyroid adenoma.
Parathyroidadenomashowingcord-likeortrabeculargrowthcomposedofcellswithclear-appearingcytoplasm.
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1502 SECTION 9 ParathyroidGlands
A
B
C
Fig. 33-13.Parathyroid adenoma.
A,Parathyroidadenomashowingafollicularpatternofgrowth(so-calledfollicularvariant)thatmaycauseconfusionwiththyroidfollicularneoplasms;immunoreactivityfor(B)parathyroidhormoneand(C)parafibromin(nuclear),coupledtotheabsenceofthyroglobulinandTTF1(notshown)allowfordifferentiatingparathyroidadenomafromathyroidfollicularlesion.
Fig. 33-14.
A,Parathyroidadenomacomposedofuniformandbland-appearingnucleiinlowerportionofimageaswellasnumerouslargecellswithhyperchromaticnuclei;intralesionalfibrosisisalsopresent.B,Bizarre-appearingpleomorphicandhyperchromaticnucleiadmixedwithbland-appearingnuclei.Suchfindingsintheabsenceofincreasedmitoticactivityand/orotherfeaturesassociatedwithparathyroidcarcinomacanbeseeninparathyroidadenomas.
A
B
without hyperparathyroidism; they also have morecytoplasmicfat,oftenfoundaslargedroplets,thannormallyfunctioningparathyroidglands.
• Histochemicalstains:m Colloid-like material in follicular structures are
PASpositive.m Considerablevariationintheliteratureregarding
theutilityof fat stains in thediagnosisofpara-thyroidproliferativediseases
m Generally, hyperfunctioning cells have a signifi-cantly decreased amount of intracellular fat(usingSudanblackoroilredO)comparedwith
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1503
normalorsuppressedparenchymalcells;thereis,however,variabilityinthisfinding.
m Fat stains, when used with adequate clinicalinformation, intraoperative findings, and histo-logicexamination,areuseful if their limitationsarekeptinmind.
• Immunohistochemistry:m Positiveforparathyroidhormoneandparafibro-
min(nuclearstaining):– Majority of parathyroid adenomas express
parafibromin– Loss of parafibromin expression may be
seeninpatientswithhyperparathyroidism-jawtumorsyndromeindicativeofgeneinactivationthroughmutationoftheHRPT-2gene.
m Cytokeratin,chromograninApositivem Calcitonin and synaptophysin typicallynegative
but in smallpercentageof casesmaybe focallypositive
m PAX8 (nuclear) reactivity present in approxi-mately40%ofadenomasandhyperplasia
m Galectin3rarelypositive(<5%).m Ki67(MIB1)proliferativeindexislow:
– Anindexgreaterthan5%shouldraisesuspi-cionforcarcinoma,butthediagnosisofcarci-noma requires confirmatory diagnosticfindings.
– Proliferativeindicesindifferentiatingadenomafrom carcinoma are of limited utility givenoverlappingfindingsintheselesions.
Fig. 33-15.Parathyroid adenoma.
Parathyroidadenomawithassociatedreactiveanddegenerativechanges,includingfibrosisandhemorrhagemayresultinadherencetosurroundingstructures,clinicallysuggestingapossiblediagnosisofparathyroidcarcinoma.Suchchangesmayoccurspontaneouslyormayoccurfollowingatraumaticeventsuchaspriorsurgerytotheneckorfine-needleaspirationbiopsy.
Fig. 33-16.Parathyroid adenoma.
A,Parathyroidadenomawithinfarctionbutretentionofghostoutlinesoftheneoplasm.Notetheresidualnoninfarctedandnon-neoplasticparathyroidparenchyma,includingmaturefat(upper right).B,Parathyroidhormoneimmunoreactivityispresentintheinfarctedtumorandintheresidualnon-neoplasticparathyroidparenchyma(upper right).
A
B
m CyclinD1stainingin39%ofcasesm NegativeforthyroglobulinandTTF-1
• Electronmicroscopy:m Adenomas associated with very high serum
calciumlevelsmayhavealargenumberofmicro-villi,whicharethoughttoreflectahigherlevelofendocrineactivity
m Adenomas often have more abundant roughendoplasmic reticulum and more prominentGolgiapparatusthannon-neoplasticcells.
m Annulatelamellaemaybeseen.• Cytogeneticandmolecularfindings:
m Approximately5%showpericentricinversionofchromosome11,causing translocationofcyclin
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1504 SECTION 9 ParathyroidGlands
m Distinction between hyperplasia and adenomamay be extremely difficult and requires thepathologic examination of more than a singlegland.
• Diagnosticcriteriafordoubleadenomasinclude:m 2enlarged,hypercellularparathyroidglandsm Intraoperativeconfirmationthatremainingpara-
thyroidglandsarenormaland/orbiopsyprovenhistologicallynormalparathyroidglands
m Absence of family history of MEN or familialhyperparathyroidism
m Permanentcureofhypercalcemiafollowingexci-sionofenlargedglands:– Arguablythemostdefinitivecriterion– Requires years of follow-up to include moni-
toring of serum calcium and parathyroidhormonelevels
D1 (CCND-1/PRAD-1) gene with parathyroidhormone gene, resulting in overexpression ofcyclinD1.
m Somatic mutation in MEN-1 gene at 11q13 in40%ofcases
m AbsenceofRETmutationm 5% have somatic mutation in CDKN1B gene
(p27Kip1)
Double Parathyroid Adenomas• Most“multipleadenomas”representcasesofasym-
metricornodularhyperplasia:
Fig. 33-17.Intrathyroidal parathyroid adenoma.
A,Intrathyroidalparathyroidadenoma(lower)predomi-nantlycomposedofchiefcellsaswellasoncocyticcells(arrow)andclearcells(arrowhead)surroundedbythyroidfollicularepithelialcellsandanadenomatoidnodule(upper right).B,Histologically,theintrathyroidalparathyroidadenomashowstypicalmorphologicfindingspredominantlycomposedofchiefcellsandsharplyseparatedfromthecolloid-filledthyroidfollicles(left side).
A
BFig. 33-18.Oncocytic parathyroid adenoma.
A,Thetumorisencapsulatedand(B)exclusivelycomposedofcellswithgranulareosinophilic-appearingcytoplasm.
A
B
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1505
Fig. 33-19.Parathyroid lipoadenoma.
Lipoadenomasformcords,islands,andfolliclesadmixedwithstromalfatcellswithmatureadipocytes,thelattermakingupfrom20%to90%oftheneoplasm.Lipoadenomasareencapsulatedandmaybeassociatedwitharimof“normal”gland(notshown)andcanbedifficulttodistinguishfromnormalparathyroidglandinsmallbiopsies.
Fig. 33-20.Parathyroid adenoma associated with osteitis fibrosa cystica.
Left panel,Theadenomaistypicalwithadistinctcapsuleandarimofnormalparathyroidparenchymaincludingmaturefat(lower);right panel,thetumoriscomposedofchiefcells.Thepatienthadapathologicfractureofthehumerusaswellasgeneralizedosteopeniawithmultiplelyticskeletallesions.Atthetimeofpresentationhehadhypercalcemia.Theinitialclinicalimpressionwasmetastaticcarcinomawithsecondaryhypercalcemia.
Fig. 33-21.Brown tumor of hyperparathyroidism.
ThehumerallesionfromthepatientinFig.33-20.Left panel,Dissectingosteitis,withresorptionoftrabecularboneandreplacementbyfibroustissue;thepresenceofhemosiderinindicateshemorrhagesecondarytomicrofracturesintheweakenedbone.Right panel,Browntumorofhyperparathyroidismdevelopsafterrepeatedcyclesofboneresorption,microfractures,andhemorrhage,leadingtolargeareasofcysticdegenerationwithaggregatesofosteoclastsandforeignbodygiantcellsinafibroblasticstromacontaininghemosiderin.
• Iftheabovecriteriaarefulfilled,thenadiagnosisofdoubleadenomascanbeconfirmed.
• Truedoubleparathyroidadenomasarerare:m Majority(greaterthan70%)arebilateralm Predilectstosuperiorglands
Histologic Variants of Parathyroid Adenoma• Oncocytic(oxyphilic)adenoma(seeFig.33-18):
m Exclusively composed of oncocytic cells withprominenteosinophilicgranularcytoplasm
m Demographicfeaturesaresimilartothoseofthemorecommonadenomascomposedofchiefcells
m Thoughttobenonfunctional;usuallyassociatedwith lesser degree of hypercalcemia; however,several reports document an association withprimaryhyperparathyroidism
m Composed of large cells with abundant eosino-philic granular cytoplasm and hyperchromaticnuclei:– Scattered large atypical nuclei or multinucle-
atedcellsmaybeseen.– Cytoplasm is stuffed with mitochondria on
electronmicroscopy.m Animportantdifferentialconsiderationisthefre-
quentpresenceofnodularoncocyticcellchangeseeninnormalglandswithincreasingage.
m Intrathyroidallocalizationmaysuggestadiagno-sis of an oncocytic thyroid follicular (so-calledHürthlecell)neoplasm:– Parathyroid oncocytic adenomas have more
distinctcellmembranes.
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1506 SECTION 9 ParathyroidGlands
m Circumscriptionand/orencapsulationaswellaslarge size (1 to 15cm) support adenomatousnature:– May be associated with a compressed rim of
“normal”glandm May be difficult to recognize as “abnormal”
parathyroid tissue in small biopsies, when theyareeasilymistakenfornormalparathyroidtissuebecauseoftheabundanceofstromalfat
m Stromal fat often contains areas of fibrosis ormyxoidalteration.
m Mostareassociatedwithhyperparathyroidism.• Otherrarevariantsofparathyroidadenomainclude:
m Papillary variant characterized by prominentpapillaryarchitecture:– May not be a “true” variant but papillary
architecture, especially in association withfibrosis and hemorrhage (recent and remote),likelyisareactive/degenerativephenomenon
m Follicular variant characterized by prominentfollicular(acinar)architecture
m Water-clearvariantcharacterizedbypresenceofpolygonalcellswithclearcytoplasmanddistinctcellmembranes.
• Atypicalparathyroidadenoma:m Definition: parathyroid tumor showing features
worrisomeforparathyroidcarcinomabutlackingabsolute diagnostic features for parathyroidcarcinoma
m Synonymsincludeatypicalparathyroidneoplasm,parathyroidneoplasmof uncertain biologic sig-nificance, or parathyroid neoplasm inconclusiveformalignancy
m Atypicalhistologicfeaturessuggestingcarcinomabutfallingshortforthisdiagnosismayinclude:– Capsular irregularities or invasion without
infiltrationintoadjacentsofttissues– Increased mitotic activity (>5 per 10 high-
powerfields)– Intralesional fibrosis characterized by broad
fibrousbandscoursingthroughthelesion– Coagulativenecrosis– Diffusecellularatypia– Diffuse sheet-like growth of monotonous
cells with increased nuclear-to-cytoplasmicratio
– Macronucleoliinmanycellsm Atypical parathyroid adenomas lack conclusive
featuresdiagnosticforcarcinomaincluding:– Invasionofsurroundingsofttissues– Invasion of surrounding structures including
thyroidgland,larynx,trachea,pharynx,esoph-agus,carotidartery,recurrentlaryngealnerves
– Angioinvasion– Perineuralinvasion– Metastasis
– Presence of thyroglobulin and TTF1 supportlesionofthyroidorigin.
• Lipoadenoma(seeFig.33-19)m Alsoreferredtoasparathyroidhamartomam Rarebenignneoplasmcharacterizedbyprolifera-
tion of chief and oxyphilic cells forming cords,islands, and follicles admixed with matureadipocytes:– Matureadipocytesmakeupfrom20%to90%
oftheneoplasm.
Fig. 33-22.Brown tumor of hyperparathyroidism.
Browntumorofhyperparathyroidismcharacterizedby(A)proliferationofnumerousmultinucleatedgiantcellsandmononuclearcells,aswellasfociofhemorrhage;thegiantcellstendtobeclusteredratherthandiffuselydistributed.B,Thenucleiofthemultinucleatedgiantcellsareratherblandandaresimilartothoseofthesurroundingmononuclearcells.Amitoticfigure(arrow)ispresent.Thebrowntumorofhyperparathyroidismishistologicallysimilartogiantcell(reparative)granuloma,therebyrequiringclinicalandlaboratorycorrelationtodifferentiatetheselesions.
A
B
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1507
TABLE 33-1 Comparative Features of Parathyroid Proliferative Diseases
Hyperplasia Adenoma Carcinoma
Gender; age Slight female predilection; most common in 5th-6th decades
More common in women; most common in 4th decade
Equal gender predilection; wide age range
Clinical Asymptomatic or complaints of lethargy, weakness, polyuria, polydipsia, arthralgia, constipation, and depression
Similar to hyperplasia Similar to hyperparathyroidism of benign cause but more severe due to the higher serum calcium levels; higher proportion of renal disease (nephrolithiasis) and bone disease; peptic ulcer disease; palpable neck mass more common than in adenoma
Serum calcium 11.7 mg/dl (average) 12.5-13.5 mg/dl Often >14 mg/dl
Intraoperative findings
2 or more glands enlarged, easily dissected; enlargement may be very asymmetric
1 gland enlarged; easily dissected; more frequent in lower glands or ectopic sites
1 gland enlarged; often adherent to surrounding tissues
Weight Total gland weight usually <1 g, but may be up to 5 g
0.3-1.0 g commonly, but may weigh several grams in patients with bone disease
>1.5 g (often much larger)
Capsule Circumscribed by capsule of parathyroid gland, may be incomplete. No compressed rim of atrophic or normal parathyroid tissue
Thin tumor capsule, often surrounded by rim of uninvolved parathyroid, which may appear atrophic
Thickened capsule; rim of normal parathyroid rarely seen
Gross appearance Gray-brown, soft. Cut surface may be homogeneous or nodular. Lacks fibrous bands
Red-brown, firm. Usually homogeneous, lacks fibrous bands
Gray-white, firm, often lobulated or irregular. Fibrous bands often produce coarse nodularity
Histologic pattern Diffuse or nodular, sometimes pseudofollicular or acinar
Diffuse or nodular, frequently pseudofollicular or acinar
Diffuse, nodular, pseudofollicular, or acinar; often trabecular pattern with distinctive nuclear palisading predominates
Cytologic features Chief cells predominate; transitional and oncocytic cells often present
Chief cells predominate, but mixture of chief, transitional, and oncocytic cells may be seen; rarely, purely oncocytic
Cells usually resemble chief cells, but variable cytoplasmic oncocytic change may be seen; cell borders often indistinct
Intracytoplasmic lipid
Decreased Decreased in tumor; abundant in atrophic rim of parathyroid
Usually absent
Stromal fat cells Scanty to absent Usually absent in tumor; present rim of atrophic parathyroid
Absent
Nuclear morphology Normal to slightly increased N-to-C ratio; usually without nuclear pleomorphism
Nuclei enlarged, with variability in size; scattered groups of large pleomorphic, hyperchromatic nuclei, or multinucleated cells
Increased N-to-C ratio; enlarged atypical nuclei; often with monotonous (bland appearing) nuclei
Nucleoli Inconspicuous to small Inconspicuous to small Frequently prominent and enlarged
Mitoses Common (60% of cases; most with <1 mitotic figure/10 HPF)
Common (70% of cases; most with <1 mitotic figure/10 HPF)
Common (80% of cases), may include atypical mitoses; may be numerous
Continued
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1508 SECTION 9 ParathyroidGlands
Hyperplasia Adenoma Carcinoma
Capsular and vascular invasion
Absent Absent; entrapment of tumor cells may occur in capsule if degenerative changes present
Capsular invasion present in two thirds; may involve only capsule or extend into adjacent tissues
Vascular invasion present in up to 15%; usually in capsular vessels
Remainder of gland Entire gland is abnormal Normal or atrophic Normal
Degenerative changes
May be seen in very large glands
Includes hemorrhage, areas of fibrosis, and cystic change
Common, especially in larger adenomas; includes hemorrhage, fibrosis, and cystic change, sometimes calcification
Tumor cell necrosis; calcification and cystic changes may be present
Treatment Subtotal parathyroidectomy with surgical removal of three glands, leaving a remnant of the 4th or total parathyroidectomy* with autotransplantation of parathyroid tissue in forearm
Surgical removal of the enlarged gland
En bloc resection, including ipsilateral thyroid lobe and adjacent soft tissues
Prognosis Excellent Excellent Up to 50% of patients are cured by en bloc resection; considered an indolent malignancy even in presence of recurrence or metastasis with long survival even after recognition of tumor recurrence; morbidity and mortality correlate to complications of severe hypercalcemia
Recurrence and metastasis
Recurrence in approximately 16% of cases due to inadequate neck exploration and may not be evident for years
Absent Recurrence in two thirds of patients usually within 3 years of the first surgery; metastasis is 35%, is a late event usually preceded by local recurrence; most commonly to lung, cervical lymph nodes, and liver
Familial and/or MEN association
Yes, in approximately 20% of cases
Uncommon Rare
TABLE 33-1 Comparative Features of Parathyroid Proliferative Diseases—cont’d
g, Grams; HPF, high power fields; MEN, multiple endocrine neoplasia syndrome; N-to-C, nuclear-to-cytoplasmic.*Particularly in cases of familial hyperparathyroidism.
m Mostatypicalparathyroidadenomasprovetobebenigninlong-termfollow-up,butowingtotheuncertainty in their malignant potential, theyhavebeentermedatypical.
m Treatment is similar to a typical parathyroidadenoma, but patients should be followed forpotential recurrent hyperparathyroidism, localrecurrence of tumor, and/or evidence of aggres-sivebehavior(e.g.,metastasis).
Differential Diagnosis• Primarychiefcellhyperplasia(seeTable33-1)• Parathyroidcarcinoma(seeTable33-1)• Follicularneoplasmofthyroidgland
Treatment and Prognosis• Mostwidelyacceptedtherapyisexcisionoftheade-
nomatous gland with biopsy of at least one addi-tionalglandthatis“normal”insize
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1509
• Some favor a full bilateral neck exploration withsubtotal parathyroidectomy and have reported alower incidence of recurrent hypercalcemia thatrequiredreoperation:m There isanincreasedincidenceofpostoperative
hypoparathyroidismwiththisprocedure.• Recurrence rates vary significantly and may reflect
problems in classification, particularly in cases ofhyperplasiawithnodules,whichmayerroneouslybedesignatedasadenomas.
• Although generalized osteopenia is now morecommon, osteitis fibrosa cystica, also known asbrowntumorofhyperparathyroidismisoccasionallyseen(seeFigs.33-20to33-22):m Mayoccurinhyperparathyroidismofanycause
but is related to degree and duration of serumcalciumelevation
m Lesionsarecharacterizedbyresorptionofbone,whichisreplacedbyfibroustissue,probablyasareparativeresponsetomicrofractures
m Hemorrhagewithinthefibroustissueleadstotheaccumulationofhemosiderinandaproliferationof multinucleated giant cells in addition to theosteoclasts
m With timedegenerative changes lead to the for-mationofcysticspaces
m Osteitis fibrosa cystica cannot be distinguishedhistologically from the giant cell (reparative)granuloma of the jaw; clinical information isessential.
• Recurrent hyperparathyroidism following surgeryfor an adenoma may also result from incompleteexcision,ruptureofthetumorcapsulewithspillageinto the operative field, or from hyperfunction ofautografted parathyroid tissue following subtotalparathyroidectomy.
PARATHYROID CARCINOMA (Figs. 33-23 through 33-38, see Table 33-1)
Definition:Malignantneoplasmofparathyroidparen-chymalcells.
Clinical• Rare neoplasm; responsible for approximately 2%
ofcasesofhyperparathyroidism• Nogenderpredilection;most common infifthand
sixthdecades:m Affectpatientsapproximatelyadecadeyounger
thanthosewithadenomasm Rarecasesreportedinchildren
• Clinicalfindings associatedwithparathyroid carci-nomaarelistedinBox33-2.
• Most patients have severe hypercalcemia andhypophosphatemia:m Mean serum calcium 14.0mg/dl, in contrast to
mean serum calcium of 12.0mg/dl in benignhyperparathyroidism
• Occasionalnormocalcemicpatientsmayoccur.• Symptomsareduetoexcessiveparathyroidhormone
secretion and are similar to those in patients withhyperparathyroidismofbenigncausebuttendtobemoresevereduetothehigherserumcalciumlevels:m Presenting symptoms include polyuria, polydip-
sia,fatigueandweakness,depression,bonepainand fracture (high incidence in earlier series),renalcolicandnephrolithiasis(uptotwothirdsofpatientsinearlierstudies,butprobablydecreas-ingwithroutinebiochemicalscreeningandearlierdetection), peptic ulcer disease, and recurrentpancreatitis.
• Palpableneckmassesmorecommonthaninhyper-plasiaoradenoma.
• Etiologyisunknown:m Mostcasesaresporadic.m Lossoftheretinoblastoma(Rb)tumor-suppressor
genemayplayanimportantroleinthedevelop-mentofparathyroidcarcinoma,and itsabsencemay be helpful in distinguishing parathyroidadenomafromcarcinoma.
m Some cases occur in hyperparathyroidism-jawtumor syndrome, MEN, or familial isolatedhyperparathyroidism.
m Externalbeamirradiationtotheneckmaybeapossibleriskfactor.
m Rare cases occur in patients with secondaryhyperparathyroidism,possiblylinkingthedevel-opmentofparathyroidcarcinomafromparathy-roidadenomaorhyperplasia.
• May be associated with hyperparathyroidism-jawtumorsyndrome(HPT-JT):m Autosomal-dominant disorder with germline
mutation in HRPT-2 gene on chromosome1q25-31
m Characterizedby:– Parathyroidadenomaorcarcinoma– Fibro-osseouslesionsofthejaw(e.g.,ossifying
fibromaofmandibleormaxilla):30%ofcases
BOX 33-2 Clinical Features Associated with Malignancy in Parathyroid Neoplasms
• Serum calcium level >14 mg/dl• Serum parathormone levels 2 to 3 times normal• Severe metabolic manifestations: nephrolithiasis, bone
disease, etc.• Palpable neck mass• Difficulty in surgical dissection owing to adherence to
surrounding structures
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1510 SECTION 9 ParathyroidGlands
Fig. 33-23.Parathyroid carcinoma in a patient with severe hyperparathyroidism.
A,AxialT2-weightedMRimageshowsademarcated2.5-cmmediastinalmass(*)thatrepresentsaparathyroidcarcinoma.B,AxialT2-weightedMRimageofanotherpatientwithhypercalcemiashowsanonhomogeneousmassintherighttracheoesophagealgroove.Themarginsareslightlyunsharp.Thisisaparathyroidcarcinoma.C,AxialT2-weightedMRimageshowsalargemassintherighttracheoesophagealgrooveinthispatientwithseverehypercalcemia.Atsurgery,thiswasaparathyroidcarcinoma.(From Som PM, Curtin HD: Head and neck imaging, ed 5, Philadelphia, 2011, Elsevier, Fig. 41-110, p 2674.)
A
*
B
C
– Renal cyst, hamartoma, carcinoma: 20% ofcases
– Approximately 80% of patients develophyperparathyroidism.
– Usuallypresentslateinadolescence– Hypercalcemiatendstobesevere.
m Higher incidence of parathyroid carcinoma incomparison with patients with MEN-1 andMEN-2A
m Renallesionsmayinclude:– Renal cysts, polycystic renal disease, renal
hamartoma– Papillary renal cell carcinoma, renal cortical
adenomas,Wilmstumor
Radiology• Imagingproceduresareofsimilarutilityasinpara-
thyroidadenomas.
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1511
Pathology• Pathologicfindingspotentiallyassociatedwithpara-
thyroidcarcinomaarelistedinTable33-2.
Gross• Average size is larger than parathyroid adenomas:
mean weight 6.7g (range 1.5 to 27g), althoughsmaller tumors are being identified more often inrecentyears.
• Maybeencapsulatedorinfiltrative
Fig. 33-24.Parathyroid carcinoma.
Parathyroidcarcinomaappearingasalargetumorwithareasofcysticdegenerationassociatedwithlargenodulesofviabletumor;thecapsuleisgrosslythickened.
Fig. 33-25.Parathyroid carcinoma.
Parathyroidcarcinomaappearingasanirregular,infiltrative,indurated,whiteneoplasmadherenttotheadjacentthyroidlobe(on the left).Difficultiesindissectionaparathyroidlesionfromadjacentstructuresissuggestive,althoughnotdefinitivelydiagnostic,forcarcinoma.Histologicconfirmationisalwaysrequiredforadiagnosisofparathyroidcarcinoma.
Fig. 33-26.Parathyroid carcinoma.
Someparathyroidcarcinomaslikethisonearemoreadvancedatpresentationwithextensiveinvasionofsurroundingtissues.Casessuchasthisoneareraretodayasaresultofroutinebiochemicalscreeningofmostpopulationsindevelopedcountries.
Fig. 33-27.Parathyroid carcinoma.
Parathyroidcarcinomacharacterizedbyathickenedcapsule,andfibrousbandsdissectingthroughthetumordividingthetumorintoseparatenodules;thetumorwasadherenttoandinvadedintothethyroidgland(right).
• Browntogray-white,carcinomasmayhaveasmooth,firmcutsurfaceindistinguishablefromanadenomaormaybedistinctlyindurated
• Difficulty indissectionofthetumorandadherenceto the thyroid gland are common intraoperativeobservations.
Histology• Histologic criteria in diagnosing parathyroid carci-
nomaaredetailedinTable33-2.• Manyparathyroidcarcinomasareencapsulated,and
usually the capsule of a carcinoma is thicker thanthatseeninmostadenomas:m Some adenomas with reactive and degenerative
changeshavethickandunevencapsules.
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1512 SECTION 9 ParathyroidGlands
Fig. 33-28.Parathyroid carcinoma.
Parathyroidcarcinomawithacellularfibrousbandscoursingthroughtheneoplasmdividingthetumorintomultiplenodules.
Fig. 33-29.Parathyroid carcinoma.
Parathyroidcarcinomashowingvascularinvasionwithinanendothelial-linedbloodvessel.
Fig. 33-30.Parathyroid carcinoma.
Parathyroidcarcinoma(P)withperineuralinvasion(arrows).Theneoplasticproliferationincludesratherbland-appearinganduniformnuclei,butthepresenceofneurotropismrepresentsinvasivegrowthdiagnosticforcarcinoma.
P
Fig. 33-31.Parathyroid carcinoma.
Parathyroidcarcinomacharacterizedbyhypercellularityandtrabeculargrowth.
TABLE 33-2 Pathologic Features Associated with Malignancy in Parathyroid Neoplasms
Features Definitively Diagnostic for MalignancyFeatures Worrisome for But Not Definitively Diagnostic for Malignancy
• Invasive growth including into:Surrounding soft tissuesSurrounding viscera or vital structures (thyroid gland,
larynx, trachea, esophagus, pharynx, carotid artery, recurrent laryngeal nerve)
• Vascular invasion• Perineural invasion• Metastatic disease:
Regional lymph nodesDistant sites
• Large size (mean weight 6.7 g)• Adherence to surrounding structures (e.g., thyroid tissue, others)• Irregular contour; lack of distinct encapsulation• Thick capsule• Intralesional fibrous bands• Mitotic activity (especially >5 per 10 HPF)• Coagulative tumor necrosis• Diffuse cellular atypia• Diffuse sheet-like monotonous small cells with increased N : C• Macronucleoli in many tumor cells• Trabecular growth• Spindling of tumor cells
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1513
evenfocally,shouldraisesuspicionforthediag-nosisofcarcinoma.
m Nuclearpalisadingmaybeprominentintrabecu-larareas.
m Spindlingofcellsisalsoafeaturemoreoftenseenincarcinomasthaninbenignproliferations.
m Trabecular pattern and spindle-shaped cells,although worrisome for a possible diagnosis ofcarcinoma,arenotdefinitivediagnostic featuresforcarcinoma.
• Growthpatternsalsovaryandincludesolidsheets,acinarformation,cords,rosettes,and,ofparticulardifferential diagnostic significance, trabecularpattern:m Trabecularpatternisafindingmoreoftenidenti-
fied in association with parathyroid carcinomathaninadenomaorhyperplasia,anditspresence,
Fig. 33-33.Parathyroid carcinoma.
Acomparisonofthenucleiinparathyroidcarcinoma(left)withparathyroidadenoma(right)showsthecellsofthecarcinomatohaveahighernuclear-to-cytoplasmicratiothanthoseoftheadenoma.Suchafeatureisworrisomebutintheabsenceofotherfindingsisnotdiagnosticforcarcinoma.
Fig. 33-34.Parathyroid carcinoma.
Parathyroidcarcinomawithspindle-shapedtumorcells.
Fig. 33-35.Parathyroid carcinoma with mitotic figure (arrow).
Mitosesarenot,bythemselves,accuratepredictorsofmalignancy,becausetheymaybeseeninparathyroidhyperplasiaandadenomas.
Fig. 33-32.Parathyroid carcinoma.
Highermagnificationofthepreviousillustrationshowsthetrabecularpatternofgrowthcomposedoffairlyuniform,monotonous-appearingnuclei,althoughscatteredenlarged(pleomorphic)nucleiarepresent.Suchenlargedatypicalnucleicanbeseeninadenomas,andbyitselfisnotadefinitivediagnosticfeatureforcarcinoma.Suchenlargedatypicalnucleiareconsideredtobeanuncommonfeatureinparathyroidhyperplasia.
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1514 SECTION 9 ParathyroidGlands
• Nuclearpleomorphismislesscommonthaninade-nomas, which often contain scattered foci withenlargedatypicalnuclei:m Monotonyofnuclearsizeandshapeisfrequently
presentincarcinomas.m Pleomorphism, when present, is usually more
diffusethaninadenomas.• Mitotic activity is identified in most, but not all,
parathyroidcarcinomas:m Presenceofatypicalmitosesisvirtuallydiagnostic
ofmalignancym Althoughahighmitoticrateisahelpfulfeature,
the presence of mitotic activity exceeding 1 per10high-powerfieldsinaminorityofparathyroidadenomasandinparathyroidhyperplasiamaybeseen.
m Overlap inmitoticactivitybetweenallparathy-roidproliferativediseases (i.e.,adenoma,hyper-plasia, and carcinoma) makes mitotic activity ausefulfindingonlywhencoupledwithotherfea-turesofmalignancy.
• Capsularinvasionmaybeobviousinsomecases,ormay be represented only by irregular tongues orislands of parathyroid tissue protruding into thecapsule;invasionbeyondthecapsuleisindicativeofmalignancy:m Entrapped islands of parathyroid parenchymal
cells in benign disease should be distinguishedfrom these invasive foci by their rounded con-toursandlackofdesmoplasticreaction.
• Follicularpatternofgrowthnotoftenifeverseeninparathyroidcarcinomas
• Tumorcellsmayhavevariablemorphology:m Someareasmayshowsimilarfeaturesasbenign
chief cells with slightly eosinophilic to clearcytoplasm.
m Otherareasmaycontainenlargedcellswithmoredistinctly eosinophilic cytoplasm, large nucleiwithprominentnucleoli.
m Rareoncocyticcellvariantidentified.
Fig. 33-36.Parathyroid carcinoma with necrosis.
Fig. 33-37.Parathyroid carcinoma.
Parathyroidcarcinomashowingmarkedlyenlargedandhyperchromaticnuclei;althoughsimilarnuclearatypiacanbeseeninadenomas,thefactthatthesechangeswerediffuselypresentratherthanfocallypresent(assingleatypicalnucleiand/orinsmallclusterswithinthetumor)supportsadiagnosisofparathyroidcarcinomaandnotparathyroidadenomaorhyperplasia.Amonotonousnuclearpatternis,surprisingly,moreoftenseenincarcinomasthaninadenomas.
Fig. 33-38.Parathyroid carcinoma.
Parathyroidcarcinomacharacterizedbyamonotonousbutcrowdedproliferationofcellswithlargenucleiandverylargeeosinophilicnucleoli(macronucleoli);thesefindingsseeninsomeparathyroidcarcinomasarenottypicallypresentinbenignparathyroidlesions(i.e.,adenoma,hyperplasia);mitoticfigurescanbeseen(middle upper, upper right).
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1515
• Fibrous bands extending from a thickened capsulefrequentlydividethetumorintoirregularcompart-mentsand/ornodules.
• Angioinvasion is diagnostic of carcinoma but ispresentinaminorityofcases:m Usually foundwithinvessels in the thick tumor
capsulem Artifactually displaced clumpsof tumor cells in
vascularspacesshouldbedistinguishedfromtrueinvasionbytheirfrequentlydegeneratedappear-ance and by their lack of attachment to thevesselwall.
• Perineuralinvasion,althoughrarelyseen,isalsovir-tuallydiagnosticofmalignancy.
• Immunohistochemistry:m Positive for cytokeratins, chromogranin as well
asforparathyroidhormonem Loss of (nuclear) parafibromin staining is com-
monlybutnotinvariablyidentified:– Onlyabout50%ofcarcinomaslackparafibro-
minstaining– Somecarcinomasmayshowpositiveparafibro-
minstaining– Lossofparafibrominreportedinsporadicade-
nomas(unassociatedwithhyperparathyroidism-jawtumorsyndrome)
m HighfrequencyofcyclinD1expression(reportedinmorethan90%ofcases):– May result from loss of parafibromin ex-
pression– Mayreflectincreasedcellularproliferation– Highlevelsofexpressionalsopresentinhyper-
plasia (approximately 61%) and adenomas(approximately39%)sonotuniquely seen incarcinoma.
m Galectin-3reactivityfrequentlyseen:– Morethan90%ofcasesreportedpositive– Seen in less than 5% of parathyroid ade-
nomasm Diffusestrongstainingforproteingeneproduct
9.5(PGP9.5)frequentlyfoundm Ki67(MIB1)proliferativeindexmaybeincreased:
– Anindexgreaterthan5%shouldraisesuspi-cionforcarcinomabutthediagnosisofcarci-nomarequiresconfirmatorydiagnosticfindings.
– Proliferativeindicesindifferentiatingadenomafrom carcinoma are of limited utility givenoverlappingfindingsintheselesions.
m Loss of immunoreactivity for retinoblastoma(Rb)protein
m NegativeforthyroglobulinandTTF-1• Cytogeneticandmolecularbiology:
m Mutations of tumor suppressor gene HRPT-2maybeimportantinthepathogenesisofparathy-roidcarcinoma:
– InactivationofgermlinemutationsinHRPT-2believedtoplayasignificantroleinthedevel-opmentofparathyroidcarcinoma■ Locatedon1q25■ Encodesparafibrominknowntofunctionin
thesuppressionofcyclinD1■ Implicated in the hyperparathyroidism-jaw
tumorsyndrome■ Identifiedintwothirdsofcasesofsporadic
occurringparathyroidcarcinoma■ Practically never found in parathyroid
adenomasm Allelic loss of the retinoblastoma (Rb) tumor-
suppressorgeneiscommon:– Mayplayanimportantroleinthedevelopment
ofparathyroidcarcinoma– Loss of immunoreactivity for Rb protein
reported in 20% to 100% of parathyroidcarcinomas
– Absencemaybehelpfulindistinguishingpara-thyroid adenomas from carcinomas but notconsidered sufficiently reliable in differentiat-ingadenomafromcarcinoma
m SomaticmutationinMEN-1gene:– Foundin13%ofcarcinomas– Suggests a role in the development of
carcinomam Alleliclossofthep53m Reduced expression of cyclin-dependent kinase
inhibitorproteinp27commonlyidentified:– In contrast, adenomas show higher labeling
index.
Differential Diagnosis• Parathyroidadenoma(seeTable33-1)• Parathyroidhyperplasia(seeTable33-1)• Parathyromatosis:
m Represents microscopic foci of hyperplasticparathyroid tissue in the soft tissues of theneck in association with primary chief cellhyperplasia
m May be the cause of recurrent disease after anapparently complete resection of the grosslyevidenthyperplasticglands
m Should not be mistaken for invasion as seen inparathyroid carcinoma; differentiating featuresmayinclude:– Absence of associated fibroblastic reaction or
infiltrativecontour– Absence of an intravascular location of these
nests– Absence of other histologic features of carci-
nomashouldhelpexcludemalignancy.• Metastaticcarcinomafromanothersite
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1516 SECTION 9 ParathyroidGlands
m StageI:invasionofsurroundingsofttissues;90%disease-freesurvival
m Stage II: vascular invasion; 46% disease-freesurvival
m Stage III: invasion of vital organs or regionallymphnodemetastasis;50%disease-freesurvival
m Stage IV: distant metastases; no disease-freesurvival
SECONDARY NEOPLASMS (Fig. 33-39)
Definition: Contiguous involvement from tumors inadjacentstructuresormetastaticneoplasmsfromdistantsitesinvolvingtheparathyroidgland.
Clinical• Usually asymptomatic; may present with a neck
mass;othersymptomsmayincludehoarseness,dys-phagia,andneckpain;rarecaseshavebeenassoci-atedwithclinicalhypoparathyroidismduetomassivereplacementofmultipleglands
• May result from direct extension, especially fromthyroid or laryngeal tumors, or from metastaticspread
• Metastasis to parathyroid glands is rare; amongthe more common primary malignancies that maymetastasizetotheparathyroidglandsinclude:m Breastcarcinoma(mostcommon)m Hematologicmalignancies
Treatment and Prognosis• Surgeryistheprimarytreatmentmodalitywithrec-
ommendedtreatmentincludingenblocresection,toinclude the ipsilateral thyroid lobe, strap muscles,recurrent laryngeal nerve, trachea, or esophagus ifinvolved:m Offersthebestchanceforcurem Up to 50% of patients are cured by en bloc
resection.• Prophylactic lymphadenectomy not recommended
duetothelowrateofnodaldisease(reportedtobe6%):m Neckdissectionwarrantedifthereisclinicalevi-
denceofneck(nodal)disease• Adjuvant radiotherapy may improve local control
andlimit theoccurrenceof localrelapse,especiallywhen the carcinoma is incompletely excised withinvolvementofresectionmargins.
• Efficacyofchemotherapynotproven• In general, parathyroid carcinomas are generally
indolentbehaving:m 5-yearsurvivalfrom60%to85%m 10-yearsurvivalfrom40%to79%
• Recurrencesgenerallymanifestwithin3yearsofthefirstsurgerywithlocallyrecurrentdisease:m Recurrenceratesrangefromapproximately33%
to50%m Lowerratesofrecurrencereported(8%)withen
blocresectionm Higher recurrence rates reported (51%) when
treatedbyparathyroidglandexcision• Metastaticdiseaseoccursratherlateinthecourseof
disease:m Foundinapproximatelyonethirdofpatientsm Usually occurs several years after primary
diagnosism Sitesofmetastasesincluderegionallymphnodes,
mediastinum,lungs,liver,andbones.• Surgical resectionofmetastaticor locallyrecurrent
diseaseisfrequentlyhelpfulduetotheratherindo-lentnatureofparathyroidcarcinoma:m Patients usually survive for several years after
recognitionoftumorrecurrence.• Recurrenceand/ormetastaticdiseaseoftenmanifest
withrecurrenthypercalcemia:m Lifelong monitoring for recurrent and/or meta-
staticdiseasemosteffectivelyaccomplishedwithserumcalciumlevels.
• Majordifficultyinmanagementofrecurrentdiseaseisseverehypercalcemiaanditscomplications.
• Death is related to excessive hormonal productionwithsubsequenthypercalcemiarather thandirectlytotumorburden.
• Prognosis has been shown to be related to tumorstage:
Fig. 33-39.Metastatic breast carcinoma.
Metastaticbreastcarcinomatotheparathyroidgland.Residualparathyroidparenchymaispresentinthecenteroftheimagesurroundedbyamalignantglandularlesion.Thepatienthadaknownhistoryofbreastcarcinomathatwaswidelymetastatic,includingtheparathyroidgland.Immunohistochemicalstaining(notshown)includedreactivityformammaglobin,BRST-2,andGATA-3.
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1517
– Malignantmelanoma:S100protein,HMB45,melanA,tyrosinase,MITF1,Sox10,vimentin
– Lungcarcinoma:NapsinA,TTF1– Renal cell carcinoma: RCC antibody, CD10,
PAX2,PAX8,CAIX– Prostatecarcinoma:PSA,PAP,prostein
Differential Diagnosis• Parathyroidcarcinoma:
m Reactivity for parathyroid hormone, chromo-granin
Treatment and Prognosis• Treatmentbasedonprimarysiteoforigin• Prognosispoor,relatedtodisseminationofprimary
disease
FURTHER READING
ReferencesmaybeaccessedonlineatExpertConsult.
m Malignantmelanomam Lungcarcinomam Renalcellcarcinomam Sarcomas
Pathology• Foundin11.9%ofcancerpatientsinautopsystudies• Mayinvolveoneormultipleglands• Immunohistochemistry:
m Avarietyoforgan-specificmarkersmaybehelpfulin the diagnosis of a metastatic tumor to theparathyroidgland
m Presence of specific immunomarkers helpful indistinguishing between primary and secondaryneoplasms:– Breast carcinoma: mammaglobin, BRST2,
GATA-3– Hematologic malignancies: CD45 (leukocyte
commonantigen),B-cell(CD20,others),T-cell(CD3,others)
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CHAPTER 33 NeoplasmsoftheParathyroidGlands 1517.e1
FURTHER READING
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BedettiCD,DekkerA,WatsonCG:Functioningoxyphilcelladenomaoftheparathyroidgland.Aclinicopathologicstudyoftenpatientswithhyperparathyroidism,Hum Pathol15:1121–1126,1984.
BettsG,BeckettE,NonakaD:GATA3showsdifferential immuno-histochemicalexpressionacross thyroidandparathyroid lesions,Histopathology2014.
BleiweissIJ,HarpazN,StrauchenJA,etal:Functioninglipoadenomaof theparathyroid: case report and literature review,Mt Sinai J Med56(2):114–117,Review,1989.
BombiJA,NadalA,MunozJ,CardesaA:Ultrastructuralpathologyof parathyroid glands in hyperparathyroidism: a report of 69cases,Ultrastruct Pathol17:567–582,1993.
BondesonA-G,BondesonL,LjungbergO,etal:Fatstaininginpara-thyroiddisease—diagnosticvalueandimpactonsurgicalstrategy,Hum Pathol16:1255–1263,1985.
BricaireL,OdouMF,Cardot-BautersC,etal;GTEGroup:FrequentlargegermlineHRPT2deletions in aFrenchNational cohortofpatients with primary hyperparathyroidism, J Clin Endocrinol Metab98(2):E403–E408,2013.
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Carpten JD, Robbins CM, Villablanca A, etal: HRPT2, encodingparafibromin,ismutatedinhyperparathyroidism-jawtumorsyn-drome,Nat Genet32(4):676–680,2002.
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ChowLS,EricksonLA,Abu-LebdehHS,WermersRA:Parathyroidlipoadenomas: a rare cause of primary hyperparathyroidism,Endocr Pract12(2):131–136,2006.
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DeLellisRA:Parathyroidtumorsandrelateddisorders,Mod Pathol24(Suppl2):S78–S93,2011.
DeLellisRA,MazzagliaP,MangrayS:Primaryhyperparathyroidism:a currentperspective,Arch Pathol Lab Med 132(8):1251–1262,2008.
DewandaNK,ChumberS,TandonN,KarakAK:Functioningoxyphiladenomaofparathyroid,J Postgrad Med46(3):215–216,2000.
Ducatman BS, Wilkerson SY, Brown JA: Functioning parathyroidlipoadenoma.Reportofacasediagnosedbyintraoperativetouchpreparations,Arch Pathol Lab Med110:645–647,1986.
EzzatT,MacleanGM,ParameswaranR,etal:Primaryhyperparathy-roidismwithwater clear cell content: the impact of histologicaldiagnosisonclinicalmanagementandoutcome,Ann R Coll Surg Engl95(3):e60–e62,2013.
Fleischer J, Becker C, Hamele-Bena D, etal: Oxyphil parathyroidadenoma: a malignant presentation of a benign disease, J Clin Endocrinol Metab89(12):5948–5951,2004.
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Ghandur-Mnaymneh L, Kimura N: The parathyroid adenoma. Ahistopathologic definition with a study of 172 cases of primaryhyperparathyroidism,Am J Pathol115:70–83,1984.
Gill AJ, Clarkson A, Gimm O, etal: Loss of nuclear expressionof parafibromin distinguishes parathyroid carcinomas andhyperparathyroidism-jawtumor (HPT-JT)syndrome-relatedade-nomasfromsporadicparathyroidadenomasandhyperplasias,Am J Surg Pathol30(9):1140–1149,2006.
GiorgadzeT,StrattonB,BalochZW,LivolsiVA:Oncocyticparathy-roid adenoma: problem in cytological diagnosis, Diagn Cytopa-thol31(4):276–280,2004.
GrimeliusL,DeLellisRA,BondesonL,etal:Parathyroidadenoma.InDeLellisRA,LloydRV,HeitzPU,EngC,editors:World Health Organization classification of tumours. Pathology and genetics: tumours of the endocrine organs, Lyon, 2004, IARC Press, pp128–132.
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KhanA,TischlerAS,PatwardhanNA,DeLellisRA:Calcitoninimmu-noreactivityinneoplasticandhyperplasticparathyroidglands:animmunohistochemicalstudy,Endocr Pathol14:249–255,2003.
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Obara T, Fujimoto Y, Ito Y, etal: Functioning parathyroidlipoadenoma–reportof fourcases: clinicopathologicalandultra-sonographicfeatures,Endocrinol Jpn36:135–145,1989.
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ISBN:978-1-4557-3382-8;PII:B978-1-4557-3382-8.00034-7;Author:Wenig;00034ISBN:978-1-4557-3382-8;PII:B978-1-4557-3382-8.00034-7;Author:Wenig;00034
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ISBN:978-1-4557-3382-8;PII:B978-1-4557-3382-8.00034-7;Author:Wenig;00034ISBN:978-1-4557-3382-8;PII:B978-1-4557-3382-8.00034-7;Author:Wenig;00034
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C
CHAPTER 33 NeoplasmsoftheParathyroidGlands 1517.e3
Secondary NeoplasmsDeLellisRA:Secondarytumours.InDeLellisRA,LloydRV,HeitzPU,
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Rosai J, DeLellis RA, Carcangui ML, etal: Secondary tumors. InSilverberg SG, editor: Tumors of the thyroid and parathyroid glands.Fourthseries,Fascicle21,Washington,DC,2014,ArmedForcesInstituteofPathology,pp585–587.
ISBN:978-1-4557-3382-8;PII:B978-1-4557-3382-8.00034-7;Author:Wenig;00034ISBN:978-1-4557-3382-8;PII:B978-1-4557-3382-8.00034-7;Author:Wenig;00034
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