First ever case report of co-occurrence of hobnail variant of papillary thyroid carcinoma and intrathyroid parathyroid adenoma in the same thyroid lobe

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InternationalJournalofSurgeryCaseReports70(2020)40–52

ContentslistsavailableatScienceDirect

International

Journal

of

Surgery

Case

Reports

jo u r n al ho me p a g e :w w w . c a s e r e p o r t s . c o m

First

ever

case

report

of

co-occurrence

of

hobnail

variant

of

papillary

thyroid

carcinoma

and

intrathyroid

parathyroid

adenoma

in

the

same

thyroid

lobe

Omer

Al-Yahri

a

_,

_Abdelrahman

_Abdelaal

a

_,

_Walid

_El

_Ansari

b,c,d,∗

_,

_Hanan

_Farghaly

e

_,

Khaled

Murshed

e

_,

_Mahmoud

_A.

_Zirie

f

_,

_Mohamed

_S.

_Al

_Hassan

a

a_Department_of_General_Surgery,_Hamad_General_Hospital,_Doha,_Qatar b_Department_of_Surgery,_Hamad_General_Hospital,_Doha,_Qatar c_College_of_Medicine,_Qatar_University,_Doha,_Qatar

d_School_of_Health_and_Education,_University_of_Skövde,_Skövde,_Sweden e_Department_of_Lab_Medicine_&_Pathology,_Hamad_General_Hospital,_Doha,_Qatar f_Department_of_{Endocrinology,}_Hamad_General_Hospital,_Doha,_Qatar

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Articlehistory:

Received21February2020

Receivedinrevisedform16April2020 Accepted18April2020

Availableonline5May2020 Keywords:

Hobnailpapillarythyroidcarcinoma Parathyroidadenoma

Neckmass Molecularproﬁle BRAFV600E_mutation

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INTRODUCTION:Thehobnailvariantofpapillarythyroidcancer(PTC)israre.Intrathyroidparathyroid adenoma(ITPA)isalsorare.Co-ocurrenceofPTCandITPAinthesamethyroidlobeisextremelyrare. Likewise,primaryhyperparathyroidismwithsuchnon-medullarythyroidcarcinomaisrare.Thespecific molecularprofileofhobnailPTC(HPTC)isdifferentfromtheclassic,poorlydifferentiatedandanaplastic variantsandmaycontributetoitsaggressivebehavior.HPTC’sgeneticprofileremainsunclear. PRESENTATIONOFCASE:A61-year-oldwomanpresentedtoourendocrineclinicwithgeneralizedaches, bonepain,polyuria,andrightneckswellingofafewmonths’duration.Laboratoryfindingsrevealed hypercalcemiaandhyperparathyroidism.Ultrasoundoftheneckshowed4.6cmcomplexnodulewithin therightthyroidlobe.Sestamibiscansuggestedparathyroidadenomaintherightthyroidlobe. Fine-needleaspiration(FNA)revealedatypicalfollicularlesionofundeterminedsignificance.Sheunderwent rightlobectomy,whichnormalizedtheintraoperativeintactparathyroidhormonelevels.Finalpathology withimmunohistochemicalstainsdemonstratedHPTCandIPTA(2cmeach).Next-generationsequencing investigatedthemutationspectrumofHPTCanddetectedBRAFV600Emutation.

CONCLUSIONS:Aparathyroidadenomashouldnotexcludethediagnosisofthyroidcarcinoma.Thyroid evaluationisneededforpatientswithprimaryhyperparathyroidismtopreventmissingconcurrent thy-roidcancers.CytomorphologicfeaturestodistinguishthyroidfromparathyroidcellsonFNAcytology mustbeconsidered.Immunohistochemicalstainsareimportant.BRAFV600Eisthemostcommon muta-tioninHPTC.ThisispossiblytheﬁrstreportedcaseofHPTCandITPAco-occurringwithinthesame thyroidlobe.Studiesthatdeﬁneothermolecularabnormalitiesmaybeusefulastherapeutictargets.

1. Introduction

Papillary thyroid cancer (PTC) is the most commontype of endocrinemalignancy.Itsincidencerangesfrom0.3%to2.7%,and mean ageis 57 years (range 17–87 years) [1]. Its prognosis is usuallyfavorable[2–6].ThevastmajorityofPTCvariantsare well-differentiated(WD),suchaspapillaryandfollicularvariants,with survivalratesofapproximately95%at40years[7].Despitethat,

∗ Correspondingauthorat:DepartmentofSurgery,HamadGeneralHospital,3050, Doha,Qatar.

E-mailaddress:welansari9@gmail.com(W.ElAnsari).

15–20%ofWDvariantsbecomeradioiodinerefractory(RAI-R)and noothertherapeuticoptionsareavailableatthistime[8].

Thehobnailvariantofpapillarythyroidcarcinoma(HPTC)isa rareentity[9–18],hasaprevalenceof<2%,andisusuallymore aggressivethanclassicalPTC[12,19,20].ComparedtotheWDPTC, HPTCdisplays aggressiveclinical behavior in theform of large tumorsize,lymphnodemetastasis,localrecurrence,distant metas-tasis,radioactiveiodinerefractoriness,diseaseprogression,worse outcomeandhighermortality[10,16,17,19,20].

HPTCusuallypresentswithneckswelling,pain,compressive symptoms, orcervical lymphadenopathy. Presentationssuchas tracheal invasion, acute massive hemoptysis, and intratracheal thrombosisarealsoencountered[15,21].HPTChistological hall-markisapredominanceofcellswithhobnailappearancearranged https://doi.org/10.1016/j.ijscr.2020.04.025

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O.Al-Yahrietal./InternationalJournalofSurgeryCaseReports70(2020)40–52 41

inamicropapillarypattern[16].Micropapillaearelinedby elon-gatedcellswithhighnuclear/cytoplasmicratioandapicallyplaced nucleithat producea hobnail appearance[10]. Hobnailpattern with micropapillary structures was described as a loss of cel-lular polarity/cohesiveness [22]. Diagnosis of HPTC requires ≥ 30%hobnail-micropapillarypatterninthetumor,althoughminor hobnailmicropapillaryfeatures(5–30%)aresigniﬁcant.PTCwith hobnailfeature≤ 30%isless aggressivethanHPTCwith≥30% hobnailfeaturebutstillhasapoorprognosis[10,19].

Intrathyroidparathyroidadenoma(ITPA)israre,situatedtotally withinthethyroid,surroundedbythyroidparenchyma,withan incidenceof<1%ofallhyperparathyroidismcases[23,24].Some authorscategorizeITPAintocompletetype,completelywrapped by thyroid tissue; and incomplete type, wrapped in ≥ 50% by thyroid tissue. Parathyroid adenoma (PA) that are wrapped in ≤50%,lieunderthepseudocapsuleorsheathcoveringthe thy-roidglandarenotconsideredITPA[25,26].ITPAusuallyresultsin primaryhyperparathyroidism(PHPT)and presentswith asymp-tomatic hypercalcemiaon routinescreening. However, atypical presentationsincludecalciumhomeostasisdisturbancesor normo-calcemicPHPT.TheclassicalmanifestationsofPHPT(bones,stones, abdominal moans, psychic groans) are frequently encountered indeveloping countries,and hypercalcemicsymptoms couldbe presente.g.anorexia,nausea,constipation,polydipsia,andpolyuria

[27–30].

HPTCcasesaredocumented[4,9–18],andmanyITPAcaseshave beenpublished.However,only2caseshavebeenreportedasa simultaneousco-occurrenceofPTCandITPA[31,32].Tothebestof ourknowledge,therearenopublishedreportsofthesimultaneous coexistenceofHPTCandITPAinthesamethyroidlobe.Thispaper reportsthefirstcaseofco-occurrenceofHPTCandITPAinthesame thyroidlobeandfurtherdefinestheclinical/molecular character-isticsofHPTCthatmaybeusefulforprognosticstratificationand mayprovidetherapeutictargets.Wereportthiscaseinlinewiththe updatedconsensus-basedsurgicalcasereport(SCARE)guidelines [33].

2. Patientpresentation

A 61-year-oldwoman presented tothe endocrinology clinic withgeneralizedboneache,polyuriaandrightneckmassforthe lastfewmonths.Therewasnopasthistoryofkidneystonesandshe didnotreportothersymptoms.Shehadahistoryofhypertension anddyslipidemiaontreatment;otherwise,therewereno contrib-utorychronicmedicaldiseasesorpastsurgicalintervention.There wasnofamilyhistoryofthyroidcancer.Onphysicalexamination, shewasvitallystable,goodbodybuilt,verygoodphysical perfor-mance,andneurologicalexaminationwasunremarkable.Shehada smooth,non-tenderrightneckswelling(3–4cm)thatmovedwith swallowing.

3. Investigations 3.1. Blood

Revealedhighcorrectedcalcium(2.74mmol/L),highintactPTH (111pg/mL).VitaminDwas44ng/mL,andTSHandT4wereboth normal.CBC,liverandkidneyfunctionswereunremarkable. 3.2. Ultrasoundoftheneck

Largecomplexnoduleinrightthyroidlobe(4.6×2.4cm)with cysticcomponent,focaldenseareaofcalciﬁcation,andperipheral vascularity.Leftthyroidlobeshowedfewsmallhypoechoic nod-ules,thelargestwas3.5mm.Isthmuswasunremarkable. There

weresmallnon-signiﬁcantlymphnodesalongleftupperjugular andbothuppercervicalregions.Nomasswasobservedinbilateral parathyroidregions.

3.3. Parathyroidsestamibiscan

Earlyandlateanteriorimagesofneckandmediastinumtaken at20minand2hafterIVinjectionof10mCiradiotracer.Normal earlythyroidtissueuptakeandlatephysiological washoutwere observedwithfeaturesofhighuptakeandretainedfocalactivity relatedtothelowerpoleoftherightthyroidlobe,suggestiveof rightinferiorPA.Therewasalsoabigcoldnoduleprojectingfrom thelateralborderoftherightthyroidlobe,suggestiveofthyroid nodule(Fig.1).

3.4. Cytopathology

Ultrasound-guidedfine-needleaspirationofthecomplex nod-uleinrightlobewasdone.About10mLofstraw-coloredfluidwas aspirated fromthecysticpart.Thecalcified solid partwasalso aspirated.Thesamplewasprocessedas4fixedslides(papstain) and4air-driedslides(DiffQuik).Microscopically,thereweresome Hurthlecellsclusterswithabnormalfeatures,fewfollicularcells, macrophages,minimalcolloid,andblood,consistentwithatypical follicularlesionofundeterminedsignificance(FLUS).

4. Surgicaltechnique

Thecasewasdiscussedatthethyroidmulti-disciplinary meet-inganditwasdecidedtoconductrighthemithyroidectomywith removaloftherightinferiorPA.Under generalanesthesia, con-ventional neck exploration didnot reveal the PA, and surgery proceededwithrighthemithyroidectomyasplanned,whichwas followed by a sudden drop of intraoperative rapid PTH (94.3% drop from pre-incision serum baseline, conﬁrming excision of ITPA).Surgerywasconcluded.Thepatientrecoveredsmoothlywith noperi-operation complications.Anexperiencedseniorsurgeon undertooktheprocedure.

5. Pathology

5.1. Finalhistopathologyofrightthyroidlobe

H&E sectionsrevealedthe coexistenceof encapsulated non-invasive HPTCmeasuring 2cm with all marginsuninvolved by carcinoma.Nolymphovascular,perineuralinvasionor extrathy-roidalextensionwereseen.AJCCstagingwaspT1b(Fig.2AandB). Also,anITPAmeasuring2cmcompletelysurroundedbythyroid tissuewasidentiﬁed(Fig.3).

5.2. Immunohistochemicalstains

IntheHPTC,thecarcinomademonstrateddecreased staining withthyroglobulinandpositivestainingwithHBME-1,galectin-3, andCK19(controlschecked).IntheITPA,TTF-1,thyroglobulinand chromograninimmunostainswereperformed(controlschecked). Theparathyroidadenomawaspositiveforchromograninbut nega-tiveforTTF-1andthyroglobulin,whichhighlightedonlythethyroid tissue(Fig.4A,B).

SangersequencingwasperformedontheampliﬁedtargetDNA. ItrevealedanucleotidechangefromThymine(T)toAdenine(A)in codonnumber600inexon15oftheBRAFV 600E_gene._This_change_in nucleotideresultsinaminoacidchangefromValine(V)toGlutamic acid(E).ThisconﬁrmedtheBRAFV 600E_mutation_in_our_case₍_Fig.₅_).

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Fig.1.Earlyandlate99mTcMIBIParathyroidScanimagesofneckandmediastinumanteriorlyat20minand2h.

Fig.5.MutationinBRAFV 600E_gene_demonstrates_result_due_to_a_nucleotide_change_from_Thymine_(T)_to_Adenine_(A)_in_codon_number₆₀₀_in_exon₁₅_of_the_BRAF_gene._This

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Fig.2.A.photomicrographdepictingpapillarystructureswithhyalinizedstalks

linedbyepithelialcellsexhibitinghobnailingintocysticspaces.Apsammomatous

calciﬁcationisalsopresent(hematoxylinandeosinstain,×100).B.high-powerview

showsthehobnailgrowthpatternoftheepithelialcellswhichhavethenuclear

fea-turesofpapillarythyroidcarcinomaintheformofnuclearenlargement,overlapping

ofthenuclei,irregularnuclearmembraneswithoccasionalnucleargrooves.Thecells

haveabundanteosinophiliccytoplasmwithoncocyte-likeappearance(hematoxylin

andeosinstain,×400).

Fig.3. Histologicalsectionshowsawell-circumscribedparathyroidadenomawith

athincapsulesurroundedbythyroidtissue(hematoxylinandeosinstain,×40).

Fig.4. A.TTF1immunohistochemicalstaindemonstratesnegativestaininginthe

parathyroidadenoma(left)andpositivenuclearstainingintheadjacentthyroid

tissue(right).B.Thyroglobulinimmunostainisalsonegativeintheparathyroid

adenomaanddemonstratespositivestainingintheadjacentthyroidtissue.

6. Followup

Thepatienthadnoperioperativecomplicationsandwas dis-chargedafter2days.Thecasewasagaindiscussedatthethyroid multi-disciplinarymeeting,whichdecidedthatthepatient’srisk stratiﬁcationcategorywaslowrisk(althoughthecasedisplayed oneintermediateriskfeature,i.e.aggressivetumorhistology hob-nail variant) [8]. Henceit wasdecided thatthe patientwill be underclosefollowupwithultrasoundevery6months.Neck ultra-soundat6monthsrevealedthattheleftlobewasheterogeneous withmultiple smallhypoechoicnodules, thelargest measuring 2.4×1.7mm,andnosuspiciouslymphnodes.FNACrevealed col-loid nodule with cystic degeneration. At 12 months she was completelyasymptomatic,withnobonepain,normalcalciumand PTH levels, and neck ultrasound and CT scan neck and thorax revealednometastaticdiseaseormass,lymphadenopathyorlung metastasis.Thepatientwassatisﬁed.

7. Discussion

HPTCisa recentlydescribed aggressivevariantofPTC, com-prising 0.3%–2.7% of PTCs [2,4,10]. IPTA is documented,but its co-occurrencewithPTCisextremelyrare[31,32].HPTCcaseshave beenreportedintheliterature[4,9–18],andapproximately160 ITPAcaseshavebeenreported(2007–2018,Tables1and2). How-ever,onlytwocaseswereasimultaneousco-occurrenceofPTCand

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44 O. Al-Yahri et al. / International Journal of Surgery Case Reports 70 (2020) 40–52 Table1

ReviewofliteratureofIntrathyroidParathyroidAdenoma(2007–2012).

Study* N Gender Age,y Side Presentation Ca

(mg/dl)/PTH (pg/mL)

Radiology FNAC Treatment Typeof ectopic parathy-roid pathol-ogy** Pathology Postoperative Complica-tions Outcome Abboud 2007 Lebanon [42] 6a ₄_F, 2M 54 2in superiorPT 4ininferior PT H,not speciﬁed HighCa andPTH U/Sableto predict4 casesof ITPAfrom6 cases — Exploration, 3/6p subtotalT loboisth mectomy 3/6ptotal enucleation ofPA

ITPAb ₃_true_type

ITPA 3partial typeITPA 12to96m followupc Complete symptoms resolution, NofCaand PTH Cheng 2009 USA[36] 1 F 73 LTlobe Asymptomatic HCandT swelling 11.6/199 99mTc suggestT adenoma, parathy-roidlesion couldnot beruled out FNAC: Hurthel cells+ lym-phocytes consistent with Hashimoto thyroiditis

LHT ITPA — Noneover

19mfollow up Remained asymp-tomatic,N ofCa Silaghi 2011 Romania [45] 1 F 48 RTlobe H,HC symptoms, bonepain, weight loss,with 3cmMsin inferiorR poleofT 13.7/1200 U/S 42×27×36mm, inhomoge-neous lesion,inR T.99mTc intense tracer uptake; X-ray osteolytic lesions — RHT ITPA — Hungry bone syndrome, tetany requiring lengthy calcium+ VitDTx& bisphos-phonates Complete symptoms resolution, NofCa+ PTHafter1 year Herden 2011 Switzerland [41] 4 — — — H,not speciﬁed —d _U/S detected ITPAinone patient; 99mTc donefor3 p,failedto identify anyITPA — Startedby neck explo-ration, failedto detect diseased gland, proceeded toHT ITPA — — — Goodman 2011USA [24] 72e _— _— _90%_lower lateralT,7% posteriorof middle part, 3%upper pole — — — — — — — — —

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O. Al-Yahri et al. / International Journal of Surgery Case Reports 70 (2020) 40–52 45 Table1(Continued)

(mg/dl)/PTH (pg/mL)

Radiology FNAC Treatment Typeof ectopic parathy-roid pathol-ogy** Pathology Postoperative Complica-tions Outcome Mazeh 2012 USA[23] 49f _77%_F23%M g 54+/−2g ₄₈_p_clear location identiﬁed, 75% inferior, 25% superiorg_. 40%bone pain28% asymp-tomatic26% fatigue22% Kstones Familyand radiation history presentin 10%and4% ofpg 11.1/192+/−35g_99mTc donefor 95%ofp and diagnosed ITPAin 70%;U/S donefor 35%ofp, diagnosed ITPAin61% g FNACdone for5p. correctly and localizedit in4/5of them Bilateral exploration in28(53%) p,MIPin25 (47%)p, and proceeded withTLin 32%ofp and enucle-ation/partial TLin68%of p ITPAsingle (44p) ITPA Double adenoma (5p) — Complications (12p);5 transient Hc;2 permanent Hc;2p hoarseness transient; othersmild dysphagia, urine retentiong Complete symptoms resolution, Ca&PTHN Tanaka 2012 Japan[35] 1 F 58 MiddleofR Tlobe Asymptomatic HC 11.4/114 U/S:13mm RTlesion suggesting Ttumor; 99mTc radiotracer accumula-tion suggest ITPA — RT lobectomy +removal ofRupper PTwhich wasnormal ITPA 9×6×5mm ITPA None Remained asymp-tomatic,N ofCa&PTH Heller 2012 USA[40] 50, 13were trueIPTAh — — — H,not speciﬁed — U/S diagnosed partialITPA in25/37 (68%)ofp, and complete ITPAin 12/13 (93%)ofp — Parathyroidectomy (typeof procedure not mentioned) ITPAh _— _— _— Dutta 2013 India[39] 1 F 24 LowerL lobe H,bone pain, general weakness, O/E 2×2cm palpable Ndinlower LTlobe 12.1/1283 99mTc poor uptakein lowerLT; U/S 22×18mm Clesion, suggest simpleTC + 6×10mm lesion, posteriorto T, suggested PA FNA-iPTH from adenoma waslower thanserum level, FNA-iPTH from suspecting TCshows 3480pg/mL. LHT+L inferior parathy-roidectomy i ITPA Clesion linedby chiefcell variantPT cells, surrounded bynormal Tfollicular cells, suggest ITCPA Tetany Complete symptoms resolution, Ca&PTHN

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46 O. Al-Yahri et al. / International Journal of Surgery Case Reports 70 (2020) 40–52 Table1(Continued)

(mg/dl)/PTH (pg/mL)

Radiology FNAC Treatment Typeof ectopic parathy-roid pathol-ogy** Pathology Postoperative Complica-tions Outcome Díaz-Expósitoa 2014 Spain[38] 1 F 56 UpperRT lobe Normocalcemic H,not speciﬁed 10.3/105 U/S:single Nd 14×11×16 mm, mid-upper RT ColloidNd RHTj _ITPA _— _— _N_of_PTH Rodrigo 2014 Spain[37] 2 — — OneinR side (supernu-merary), Thesecond not mentioned H,butnot speciﬁed — — — RHTk _ITPA, supernu-merary — — Complete symptoms resolution, Ca&PTHN Mirhosaini 2016 Iran[44] 1 F 29 Inferior poleofLT lobe Neck swelling suspicious ofTNd Notdone before surgery U/S:solid HPMs, 25×20mm ininferiorL T Follicular neoplasia LHT ITPA3cm — Transient Hc Remained asymp-tomatic,N ofCa Shi 2016 China[43] 2 F 59,45 PTAinR lowerTin1 p,and medialpart ofLTlobe inotherp Firstp: neck swelling, Secondp: twitching ofarmsand legs,O/E neck swelling Onepnot known Secondp: 10.7/182 FirstpU/S: HPNd 1.4×0.9cm inRlower T.Secondp, U/S: 1.8×1.1cm LTMs Firstp suspected PTC; Secondp suspected PA

Surgeryl _ITPA _— _— _CA_&_PTH_N

Payá Llorente 2016 Spain[34] 1 F 49 Inferior poleofthe RTlobe Asymptomatic HCon routine labs, Bipolar disorder andon lithiumTx for20y 11.7/140 U/S:Rretro T1cmNd,L TNd<1cm. 99mTc: radiotracer accumula-tioninR lobe (non-ectopic solitary PA?) — TTm _ITPA _L_T_Nd_was nodular hyperplasia Noneover 6m No symptoms appeared, NCa&PTH Kageyama 2017 Japan[48] 1 F 66 LTlobe Recurrent pancreati-tis(beer drinker), HC; incidental Kstones 12.3/253 Contrast CT:28mm LTNd, increased 99mTc uptake

— LHT ITPA — Noneover

1y

No pancre-atitisafter 1y,Ca& PTHN

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O. Al-Yahri et al. / International Journal of Surgery Case Reports 70 (2020) 40–52 47 Table1(Continued)

(mg/dl)/PTH (pg/mL)

Radiology FNAC Treatment Typeof ectopic parathy-roid pathol-ogy** Pathology Postoperative Complica-tions Outcome Ye 2018 China[25] 12n _11:4o _46.2o _7/12_R_T 5/12LT 6/12 inferiorT 4/12 middleT 2/12 superiorT Hp _Ca_high_in 11/12 PTHhighin 15/15 U/S detected 9/12p; 99mTc detected 10/12. Combina-tionofboth modalities detected 11/12p — Parathyroidectomy, not speciﬁed how ITPA — — —

*Duetospaceconsiderations,onlyﬁrstauthoriscited;**aftersurgery;–:notreported,cannotbeinferred;99mTc(-MIBI):Technetium-99m-methoxyisobutylisonitrilescintigraphy;C:cyst/cystic;Ca:Calcium;F:female;FNA-iPTH: FineNeedleAspirationintactparathyroidhormone;FNAC:FineNeedleAspirateCytology;H:hyperparathyroidism;HC:hypercalcemia;Hc:hypocalcemia;HP:hypoechoic;HT:Hemithyroidectomy;ITCPA:intrathyroidcystic parathyroidadenoma;ITPA:intrathyroidparathyroidadenoma;L:left;M:male;m:months;Ms:mass;mg/dl:milligram/deciliter;N:normalization/normalized;Nd:nodule;O/E:onexamination;p:patients;PA:Parathyroid adenoma;pg/mL:picogram/milliliter;PT:parathyroid;PTC:Papillarythyroidcarcinoma;K:kidney;MIP:minimallyinvasiveparathyroidectomy;PTH:parathormone;R:right;SPECT:single-photonemission;T:Thyroid;TL: Thyroidlobectomy;TT:totalthyroidectomy;Tx:treatment;U/S:ultrasound;y:year.

a₃_were_complete_type_(true_type)_and₃_were_partial_type.

b _{Intrathyroidal}_parathyroid_deﬁned_as_parathyroid_adenoma_that_is_{partially/entirely}_surrounded_by_thyroid_tissue.

c _There_was_transient_hypocalcemia_in₂_of₁₇₈_patients_with_PA_{(intrathyroid}_and_{extrathyroid).}_Not_clear_if_any_of_ITPAs_were_of_these_two_or_otherwise. d _Median_values_mentioned_for_all_ITPA_and_extra_thyroid_PA₍₁₁₅_patients),_Ca_11.2_mg/dl,_PTH₁₂₉_pg/mL.

e_These₇₂_were_true_ITPA;_in_another₁₂₀_cases,_adenoma_was_partially_{intrathyroid.}

f ₁₀₁_cases_of_intrathyroid_parathyroid_gland_disease,_include_true_ITPA,_Partial_ITPA,_and_intrathyroid_parathyroid_hyperplasia,_then_selected₅₃_patients_with_true_intrathyroid_parathyroid_gland,₄₉_were_ITPA_and₄_were intrathyroidparathyroidhyperplasia.Analysiswasmadefor53casestogether.

g_These_values_are_applicable_to₅₃_patients₍₄₉_patients_with_ITPA₊₄_with_intrathyroid_parathyroid_{hyperplasia).}

h ₁₄₄_cases_of_abnormal_intrathyroid_parathyroid_gland,_then_selected₅₃_and_categorized_to_partial_ITPA₍₃₇_cases),_complete_ITPA₍₁₃_cases),_and_intrathyroid_parathyroid_carcinoma_(3)._The_current_study_deals_with_only completeITPAwhichiswell-establishedterm.

i _Surgery_started_by_left_{hemithyroidectomy}_and_there_was_drop_of_iPTH_just_before_and_after_{hemithyroidectomy}₍₁₀₅₄_to_29.4_pg/mL),_after_{conﬁrmation}_of_removal_of_{hyperparathyroidism}_source,_then_left_inferior parathyroidectomywasperformedinsameoperation.

j _started_with_minimally_invasive_surgery_and_{intraoperative}_{scintigraphy,}_parathyroid_adenoma_discovered_{(intrathyroid),}_surgery_proceeded_to_right_{hemithyroidectomy.}

k_Patient_1:_surgery_started_by_minimally_invasive_{video-assisted}_{parathyroidectomy,}_failed_to_ﬁnd_PA._Surgery_converted_to_conventional_neck_exploration_and_proceeded_with_{hemithyroidectomy.}_Patient_2:_ﬁrst_operation failed(MinimallyInvasiveVideo-assistedParathyroidectomy),patientdidnotimprove,imaginglocalizationperformedbeforesecondoperation,thenintrathyroidandhemithyroidectomyperformedbyconventionaltechnique.

l _Removed_by_surgical_{intervention,}_but_author_did_not_mention_type_of_procedures_performed.

m _Plan_was_for_right_inferior_{parathyroidectomy}_but_patient_asked_for_total_{thyroidectomy}_at_same_time._Authors_did_not_explain_why_patient_asked_for_that.

n _The_article_mixes_ITPA₍₁₂₎_with₂_cases_of_intrathyroid_parathyroid_carcinoma_and₁_case_of_intrathyroid_parathyroid_hyperplasia_and_classiﬁes_them_as_true_ITPA_12/15_&_partial_ITPA_3/15. o_ohese_values_are_for₁₅_patients_mentioned_in_the_study,₁₂_were_ITPA,₂_intrathyroid_parathyroid_carcinomsa,_and₁_intrathyroid_parathyroid_hyperplasia.

p _Article_mixes_clinical_{manifestation}_of_ITPA₍₁₂₎_with₂_cases_of_intrathyroid_parathyroid_carcinoma_and₁_case_of_intrathyroid_parathyroid_hyperplasia._Among₁₅_patients,₄_presented_with_cervical_mass,₁_with_{prolactinoma,} 2withparathyroidmass,8presentedwithosteoporosis,hypercalcemia,bone-arthrosispain,urinarycalculiandthirstcomplaints.

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48 O. Al-Yahri et al. / International Journal of Surgery Case Reports 70 (2020) 40–52 Table2

ReviewofliteratureofcoexistenceofPapillarythyroidcarcinomaandIntrathyroidparathyroidadenoma.

Study* Gender Age Presentation Pre-operativeradiology Treatment Pathology Size(cm) LNMet Met

G ¨urel 2005 Turkey[32] F 76 Hyperparathyroidism symptoms(lower extremitiesbone pain) Radionuclidescana_:

Hyperactivenodule,right thyroid

Hypoactivenodule,left thyroid,suggestITPA

Lefttotalandrightsubtotal thyroidectomy,excisionoftwo parathyroidglands Rightside:MPTC Leftside: ITPA+0.1cmMPTC focus 0.8 — No Qasaimeh2009 Jordan[31] F 53 Hyperparathyroid symptoms (arthralgia,bone pain) U/SNeck=2.1×2.3×1.3cm noduleinposteriorinferior partofrightthyroidlobe, suggestITPA Right Hemithyroidec-tomy+isthemectomy ITPA PTC 1×1×0.9 1×0.9×0.8 Yes No

–:notreported,cannotbeinferred;F:Female;PTC:Papillarythyroidcarcinoma;MPTC:MicroPapillarythyroidcarcinoma;ITPA:IntrathyroidParathyroidAdenoma;LN:lymphnode;Met:Metastasis. *_Due_to_space_{considerations,}_only_ﬁrst_author_is_cited.

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O. Al-Yahri et al. / International Journal of Surgery Case Reports 70 (2020) 40–52 49 Table3

ReviewofrecentliteratureofHobnailVariantofPapillaryThyroidCarcinoma*. Studya _N _F/M ratio Age,y M (range) Surgical Tx Radioactive Iodine Tumor size, mm M (range) Hobnail fea-tures M (range) Lymphova-scular invasion Multifocal tumors (%) Nodal metas-tasis (%) AJCC stage Metastasis Follow-up M (range) Outcome Cameselle-Teijeiro 2017 Spain/Portugal [16] 2 1:1 53–62 T thyroidec-tomy+ CLND

Yes 16–65 ≥50% Yes — 50 T3 100% 6–11y One

died after6y with metas- ta-sis+local recur-rence; Second died after 11y with metastasis Watutantrige-Fernando 2018 Italy [17] 25 3:2 48 (24–73) T thyroidec-tomy+ CLND Yes 30 (7–80) >64%of patients had >30% hobnail feature 36% had 10%–29% 96%of patients 64 68 20%=T1 12%=T2 60%=T3 8%=T4 12% 39m (13−67 m) (only for19 patients) 68% had excel-lent response 32%(6 patients) had disease, (5P/S, 1P/B disease) Song 2018 China [30] 8 — — Thyroidectomy b_,c — 22 (8–46) — — — — — — — — Song 2018 Korea [18]d 2 — — T thyroidec-tomy c — — — — — — — — — — Janovitz 2018 USA [49]e 0 — — — — — — — — — — — — — Nath 2018 USA [50]f 0 — — — — — — — — — — — — —

*Tableoutlinesclinicalandpathologicalcharacteristicsbutnotmolecularproﬁleofthetumor;—:notreported/cannotbeinferred;AJCC:AmericanJointCommitteeonCancer2010(7thed.);CLND:Cervicallymphnodedissection; F/MRatio:FemaletoMaleratio;M:Mean;m:months;N:numberofcases;P/B:PersistentBiochemical;P/S:persistentstructural;PTC:PapillarythyroidCancer;T:Total;Tx:treatment;Y:years.

a_Due_to_space_{considerations,}_only_the_ﬁrst_author_is_cited. b _oes_not_detail_whether_{thyroidectomy}_was_total_or_otherwise. c _no_mention_of_cervical_{lymphadenoctomy.}

d _Authors_did_not_directly_report_values_of_individual_cases,_article_examined_disease-free_survival_and_dynamic_risk_{stratiﬁcation}_of₇₆₃_patients_with_classical_PTC_(cPTC)_and₁₄₄_with_AV-PTC,_including_TCV,_columnar_cell variantandhobnailvariants.

e_Authors_did_not_directly_report_values_of_individual_cases,_article_reviewed_aggressive_variants_of_papillary_thyroid_carcinoma,_prognostic_{signiﬁcance}_of_vascular_invasion_in_follicular_thyroid_carcinoma,_and_Hürthle_cell carcinoma.

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thyroidlobehasneverbeenreported.Thispaperreportstheﬁrst case.

Intermsofthepresentation,Table1showsthatITPApresents predominantlyinfemaleswithmeanageof52.3years.Ourcase wasa female(61years)withclassicalPHPTpresentation(bone pain,polyuria)butnokidneystones.Onexamination,aright thy-roidlobeswellingwasdiscovered,withnocompressivesymptoms, cervicallymphadenopathy,ordistancemetastasis.Our patient’s PHPTsymptomsagreewithTable1,wheremorethan50patients presentedwithclassichyperparathyroidismsymptoms.However,

Table1shows that somecaseswere asymptomatic[23,34–36].

Therearestudies(72cases)thatdidnotreporthowpatients pre-sented[24].Inthesymptomaticgroup,moststudiesdidnotspecify thefrequencyofthesymptoms[25,37–42].Anexceptionisone studywherethemostfrequentsymptomswerebonepain(40%), fatigue(26%),and kidneystones (22%)[23]. Our casehad right thyroidlobeswellingwhichsupports Table1,where6patients presentedwithneckswelling[36,39,43–45].

The investigations for a thyroid nodule with hyperparathy-roidism are pre, intra and postoperative. Preoperative ITPA diagnosiscomprises several options (Table 1). PHPT is present (with high level of serum calcium), however, normocalcemic hyperparathyroidismhasbeenreported[25,38].PreoperativePTH, althoughnot alwaysreported,ishighinall patientswhen it is performed(Table 1).Ultrasound detectedITPA in 70% of cases

[23,25,40–42]. Parathyroid Technetium (99mTc) sestamibi scan

localizedtheITPAin70%–83%[23,25].Thecombinationof ultra-sonographyandparathyroidsestamibiscanincreasesthechance ofdetectingITPA[25].

Therolepre-operativeFNAcytological(FNAC)diagnosisinHPTC andITPA aredifferent.PTC diagnosisis basedonThe Bethesda SystemforReportingThyroidCytopathologydiagnosticcategories [46].However,FNACdiagnosisofHPTCischallenging,withno con-sensusondiagnosticcriteria,althoughpre-operativediagnosisof HPTCispossible[2,21].Othershavereportedon10HPTCcases,all hadpreoperativeFNACandallhadhobnailfeature[2].Asiolietal. undertookFNACfortheir5casesandallhadhobnailfeature rang-ingbetween10%–50%[19].OthersperformedFNAC(24patients), where21 had PTC withBethesdacategory IV-V, and another3 patientswereBethesdaIII,buttheydidnotreportwhetherthe hob-nailfeaturewaspresent[17].Similarly,othersreported2caseswith pre-operativeFNACdiagnosticofPTCBethesdaVI,butagainwith nomentionofthehobnailfeature[16].Weareinpartialagreement; inourcase,preoperativeFNACshowedBethesdaIIIcytology(FLUS). Theabovefindingsmakeitdifficulttodeducetheroleof preopera-tiveFNACinthediagnosisofHPTC.Futureresearchisrequired,and adefiniteHPTCdiagnosisisusuallyconfirmedonhistopathology afterthyroidectomy.

HPTCdiagnosisbymicroscopicexaminationofthe thyroidec-tomyspecimenisalsochallenging.Atlowpower,thetumorinHPTC usually forms papillary structures that have edematous and/or ﬁbroticstalksthatcanbeassociatedwithcysticchanges[10,15], afeaturepresentinotherbenignconditionse.g.hyperplastic thy-roidnodules.Athighpower,theclassicnuclearfeaturesof PTC suchasnucleargroovingandpseudoinclusionsarelessprominent andlesscommoninHPTC[19].Moreover,cellsinHPTCcan occa-sionallyhaveeosinophiliccytoplasmreminiscentofoncocyticcells [15,19].For thesereasons,HPTCcanbeoverlookedor misdiag-nosedashyperplasticthyroidnodule.SincethisPTCvariantismore aggressive,carefulexaminationofthelesionsmustbemadewith attentiontothenuclearfeaturesofPTCsuchasnuclear enlarge-ment,nuclearoverlappingandnuclearmembraneirregularity,in additiontothefeaturescharacteristic forthisvariante.g. disco-hesivenessofcells,micropapillarypatternandapicallocationof nucleiwithinthecell withsurface bulgemakingthis “hobnail” appearance.

Likewise,theroleofpreoperativeFNACdiagnosisofITPAseems notdecisive.WhilstpreoperativeFNACdetectedITPAin4outof 5IPTApatients;FNACof2patientswithsuspicionthatonlyone ofthemhadITPA,failedtoproveITPAintheotherpatient[23,43]. However,FineNeedleAspirationintactparathyroidhormone (FNA-iPTH)froma suspectedITPAandintrathyroidcysticparathyroid adenoma(ITCPA)showedhighiPTHintheITCPA[39].Theroleof FNACinITPAisinconclusive.OurpreoperativeFNACoftheright thyroidnodulerevealedFLUS,failingtodiagnosetheITPA.

Intraoperatively,rapidPTHmonitoringisusedtoconfirmPTA removal[47].Inourcase,intraoperativerapidPTHmonitoring con-firmed ITPAexcision, dropping suddenly from228to 17pg/mL (92.5%dropat 5min)to13pg/mL(94.3%drop at10 min)after ITPAexcision.Postoperatively,histopathologyprovidesthe defini-tivediagnosiswhenthisisnotaccomplishedbeforesurgery.Inour case,histopathologyofrightthyroidlobeprovidedthediagnosisof concurrentHPTCandITPA.

Intermsofthelocation,mostITPAwerelocatedinthelower partofthethyroidgland[23,24].Table1shows10leftand13right IPTAs[25,34–39,44,45,48].Othersprovidednodocumentationof thesite/sideaffected[40–42].Weareunabletoconcludewhether thetumorbehaviorexhibitspreferencetoaparticularsideofthe thyroidgland.Incasesofco-occurrence,ourHPTCandITPAwere intherightside,inagreementwithreportswherePTCandITPA werebothintherightlobe(possiblyacoincidence),butincontrast withotherswhereeachpathologywasinadifferentlobe(Table2) [31,32].

Themostcommonmutation occurringinHPTC isBRAFV 600E mutation.Thismutationisassociatedwithahigherlikelihoodof extrathyroidalextension,lymphnodemetastasis,distant metas-tasis,recurrenceandmortality[2].Molecularanalysisof10HPTC casesfoundBRAFV 600E _mutation_in₈_cases_[₂_],_and_in ₁₆_out_of 17 cases[3]. Others reportedsimilarresults[2,6,19]. BRAFV 600E mutationwasalsopresentinourcase,supportingtheassociation betweenBRAFV 600E_and_HPTC.

In terms of management, the NationalComprehensive Can-cerNetworkguidelinesindicatetotalthyroidectomyasprimary treatmentinPTCpatientswithanyof:radiationhistory,distant metastasis,bilateralnodularity,extrathyroidalextension,tumor diameter>4cm,cervicallymphnodemetastases,orpoorly differ-entiatedfeatures.However,therearenoclearcurrentguidelines forthetreatmentofHPTC[2].Table3depictsthatalmostallHPTC patientsreceivedtotalthyroidectomy[2,3,6,10,16–20].However, onepatientreceivedhemithyroidectomy[6],andourcaseisthe secondpatienttoreceivehemithyroidectomy.Thiswasbecauseour multidisciplinaryteamconcludedthattheriskstratiﬁcationofthe patientﬁttedwellinthelow-riskcategory(althoughitdisplayed afeatureofintermediaterisk,aggressivetumorhistology,hobnail variant),hencehemithyroidectomywasdecidedasappropriate.

Table3showsthatmostHPTCpatientsreceivedvariableextents

ofcervicallymphnodedissectionrangingfromcentrallymphnode dissectiontoradicalneckdissection[2,3,6,10,16,19,20]. Radioac-tiveiodineablationisalsodocumented,butitisunclearwhether suchablation was alsoundertaken by others [6,16–20]. As we undertookhemithyroidectomy,cervicallymphnodedissectionor radioactiveiodineablationwerenotrequired.Thereisagapinthe literatureregardingthemanagementofHPTC,asmanyoftheabove evidencedidnotclearlydocumenttreatmenttypeanddetailsin termsofthetype ofsurgeryandextentofcervical lymphnode dissection.Futureresearchcouldbeneﬁt froma focusonHPTC treatmentandmanagementtoprovideadvicespeciﬁcforthisPTC variantwhenco-occurringwithITPA.

In terms of prognosis of HPTC, the literature reported high mortalityrate, persistenceof disease, and highrecurrencerate

(Table 3).One study reported2 cases and both died (at6 and

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thepatientsdied[10].Likewise,astudyof19of25patients fol-lowedfor≈39monthsreportedthatnopatientsdiedofthedisease, butonethird hadpersistent disease[17]. AsforITPA(Table1), allpatientsbecameasymptomaticaftersurgerywith normaliza-tionofCaandPTHinthefollow-upperiod(range6–96months)

[23,34–39,42–45,48].However,othersreportedthatafterthyroid

surgery for ITPA,few patientshad transienthypocalcemia, and very few had permanent/prolonged hypocalcemia needing cal-ciumsupplement[23,45].Ourpatienthadexcellentoutcomes,no complications,andwasasymptomaticat12months,withnormal calciumandPTH.Herfollow-upneckultrasoundoftheremaining thyroid lobe found very small non-suspicious nodules. Subse-quently, FNAC revealed benign changes of colloid nodule with cysticdegenerationinthe remainingleftlobe, andher CT scan oftheneckand thoraxrevealednometastaticdisease,massor lymphadenopathy.

8. Conclusion

HobnailvariantPTCisextremelyrareanditscoexistencewith intrathyroidPAinthesamethyroidlobehaspossiblyneverbeen reportedbefore.TheincidentalfindingofPTCduringparathyroid surgery is rare, and requires a thorough investigation, particu-larlybyimaginginsearchforanyabnormalthyroidfindings.The presenceof PAshouldnot inanywayexcludethediagnosisof thyroidcarcinoma.The monitoringof intraoperativerapidiPTH isvitaltoconfirmthecompleteremovaloftheparathyroid ade-noma. Hemithyroidectomyisappropriate forearlystage(pT1b) HPTCcoexistingwithITPAinthesamethyroidlobe.Describingthe cytomorphologicfeaturestodistinguishthyroidfromparathyroid cellsonFNAcytologysamplesandimmunohistochemicalstains needstobeconsidered.

DeclarationofCompetingInterest

Theauthorsdeclare thatthere is noconﬂictofinterest that couldbeperceivedasprejudicingtheimpartialityoftheresearch reported.

Sourcesoffunding

Thisresearchdidnotreceiveanyspeciﬁcgrantfromanyfunding agencyinthepublic,commercialornot-for-proﬁtsector.

Ethicalapproval

TheMedicalResearchCentreatHamadMedical Corporation, Doha,Qatarapprovedthiscaseseries.

Consent

Writteninformedconsentforpublicationoftheirclinicaldetails and/orclinicalimageswasobtainedfromthepatient.

Authorcontribution

OmerAl-Yahri:Investigation,Writing-originaldraft,Writing -review&editing.

Abdelrahman Abdelaal: Investigation, Supervision, Project administration,Writing-review&editing.

WalidElAnsari:Investigation,Supervision,Project administra-tion,Writing-originaldraft,Writing-review&editing.

HananFarghaly:Investigation,Supervision,Writing-review& editing,Validation.

KhaledMurshed:Investigation,Writing-originaldraft,Writing -review&editing,Validation.

MahmoudA.Zirie:Investigation,Writing-review&editing. Mohamed S. Al Hassan: Investigation, Supervision, Project administration,Writing-review&editing.

Allauthorscriticallyreviewed,revisedandcontributedtothe ﬁnalarticle.

Registrationofresearchstudies N/A.

Guarantor

WalidElAnsari:welansari9@gmail.com. Provenanceandpeerreview

Notcommissioned,externallypeer-reviewed. References

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