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Itroductio

Athoid nodule is a discete lesion within the thoidgland that is palpabl o adiologicall distinct fom thesuounding thoid paenchma.1 Nodula diseases of the

thoid ae ve common, seen in about 8.5 % of the population.

2

The ae commone amongst women. Thoid cance is elativelae- the incidence is 8.7 pe 100000 people pe ea, though thisseems to have been inceasing ove the eas.3 Hence, wheneve apatient pesents with a thoid swelling, the task of the clinicianis to distinguish the benign nodule fom the malignant one. Thisis a difficult task, and no test is pefect in this egad. Howeve,a easonable amount of success can be achieved b good clinicalevaluation and appopiate investigations.

EtiologyThe etiolog of thoid nodules is divese. Benign causes

include the colloid nodule and the classical multinodula goite.Occasionall, Hashimotos thoiditis and Gaves Disease ma

pesent with nodulait. Malignant causes include thoidcance, lmphoma as well as metastasis to the thoid gland.The impotant causes ae listed in table 1. This aticle will notdiscuss nodules in association with hpo- o hpethoidismin detail, and will focus onl on the commonl encounteedpoblem of euthoid thoid nodules.

ClinicalEvaluationThe focus of clinical evaluation is to diffeentiate thoid

cances fom benign swellings. The following featues aesuspicious and should suggest a malignant thoid swelling:famil histo of thoid cance, apid nodule gowth, a vefim/ had nodule, clinical signs of fixit to suoundingstuctues, vocal cod paalsis/ hoaseness of voice, egional

lmph node enlagement o the pesence of anothe lesion(fo e.g. a lung nodule on chest x-a) that suggests a distantmetastases. While the above mentioned featues ae classicalfeatues, it must be emembeed that man patients do not comewith these tpical featues, and the pesence of the followingfactos in addition to the thoid nodule should evoke futheinvestigations: male gende, extemes of age (70 eas),histo of neck iadiation, nodule >4cm in size o the pesenceof an pessue smptoms.4

Ivestigatiosblood tests: A TSH value that is < 0.2 mU/L indicates

hpethoidism and a TSH that is >4 mU/L indicateshpothoidism, and both ae situations whee medical theap

ma be consideed.Ultrasonography(USG): The USG is a ve cost-effectiveimaging pocedue, and is highl sensitive in assessing

nodule size and numbe.5, 6 B itself; USG is not ve useful indetemining whethe a nodule is benign o malignant. Howeve,combining the USG with a Dopple can esult in a betteestimation of malignant potential: isk of malignanc is lowewhen a nodule has an exclusivel peinodula vascula patten

than when thee is a puel cental vascula patten. In addition,the following pattens suggest malignanc: iegula shape,ill-defined bodes, hpoechogenecit, solidit, heteogenousintenal echoes, micocalcifications, absence of a halo, ananteoposteio to tansvese diamete atio (A/T) geate thanone, infiltation into egional stuctues and suspicious egionallmph nodes. Of note, while multinodulait does not excludemalignanc, the absence of a tul dominant nodule in thissetting ma make cance an unlikel possibilit.

Fie eedle aspiratio iopsy (FnAb): This is unaguablthe best single test, and uses a 23-27 gauge needle to aspiatesamples fo ctological assessment. With expeience, adequatesamples can be obtained in >95% cases. USG-guided FNAB canlowe the occuence of non-diagnostic smeas.7 Degeneatingand cstic nodules ae poblematic to aspiate. In this setting, theaccuac is impoved b using ultasound-guided aspiationsfom the appopiate solid zones. Oveall all, a USG-guidedFNAB with an onsite confimation of adequate cellulait of thesmea b a tained ctopathologist is the investigation with thehighest sensitivit and specificit. In suspicious nodules, takingmultiple aspiates will help to impove the sensitivit.

Radiouclide scaig:Nuclea scans use eithe one of theisotopes of iodine o technetium. These ae handled diffeentlb the follicula cells. Nomal follicula cells take up both, butonl adioiodine is oganified and stoed. Most benign andmalignant neoplasms concentate isotopes less avidl leadingto a cold aea on scanning. The ate of malignanc is about

10-15% in cold nodules, wheeas malignanc is ve unlikelin hot nodules. A hot nodule suggests hpethoidism- suchnodules ae usuall not malignant.

Investigationstodetectairwayobstruction:Uppe aiwasobstuction is ae in patients with goite and is indicated bsmptoms such as beathlessness and choking. Thee is a lack ofcoelation between the clinicall assessed size of the goite andthe likelihood of uppe aiwas obstuction. Plain adiogaphof the thoacic inlet and espiato flow volume loops aespecific means of identifing patients with functional tachealcompession who ma need suge.

Other tests: Antithoid peoxidase antibodies ae useful ifHashimotos thoiditis is suspected. Howeve, thoiditis cancoexist with thoid cance and theefoe a euthoid patientwith a nodule will still need evaluation despite antibodies beingpositive. The outine use of seum calcitonin measuements todetect medulla thoid cance in the evaluation of thoidnodules is contovesial.8

Combining investigationsintoapracticalapproach: Itis often impotant to use a logical and step-wise appoach inthe management of thoid nodules, and figue 1 lists such astateg.

MaagemetGeeral cosideratios

Despite the man investigative options available to theclinician, the management of the nodule essentiall depends on

the FNAB esult. The possible epots fom the ctopathologist

nodular Diseases i the ThyroidAG Unnikrishnan

Professor, Dept of Endocrinology, Amrita Institute of MedicalSciences, Cochin- 682026

Table 1: Important causes of thyroid nodules

Benign etiology

Colloid noduleHyperplastic noduleFollicular adenoma

Non-toxic/ toxic Multinodular goiterThyroiditisToxic thyroid adenoma

Malignant etiologyFollicular thyroid cancerPapillary thyroid cancerMedullary thyroid cancer

Anaplastic CancerLymphomaOther cancer/ Metastasis

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ae benign, malignant, suspicious and non-diagnostic. Thebenign epots could eithe be colloid goite, lmphocticthoiditis o a benign cst. Subjects with a benign ctolog aeconsideed tue negative if the ae followed up fo a peiod ofat least two eas this will allow identification of those withchanging smptoms fo a epeat FNAB, and tue negativit isconfimed if a diagnosis of thoid neoplasia has not been madeafte a two-ea follow-up. Suge is equied if malignant osuspicious ctolog is epoted. rapid gowth and inceasingpessue effects (beathing difficult) will signal the need fosuge. Some patients ma opt fo suge fo pessue effectslike dsphagia, o fo cosmetic easons due to the size of thegoite. It has been suggested that in subjects with a suspiciousFNAB epot, the ate of suge ma be educed futhe bsubjecting patients to adio nuclide scanning and pefomingsuge on those nodules that ae cold o wam, and simplfollowing up those with hot nodules without suge as theisk of malignanc in these nodules is ve low. About 10 - 20%of ctological specimens ma not have adequate mateial toenable an accuate intepetation and would be epoted asnon-diagnostic. A numbe of the non-diagnostic aspiates ae

due to cstic thoid lesions.A paticula poblem aises when the FNAB is epoted asfollicula neoplasm and Huthle neoplasms, as the diffeentiationbetw een adenom a and ca c inom a equ ies histol ogicaldemonstation of vascula/ capsula invasion. Suge isgeneall advised.

In malignant/ suspicious cases, total thoidectom is theteatment of choice. The onl exception could be a papillamicocacinoma (

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NewAdvancesinDiagnosisandTherapy

A majo poblem in the evaluation of thoid nodules isthe high pevalence of indeteminate ctolog cases (as highas 10-15%) on FNAB. Nuclea scintigaph has not been ableto completel ovecome this poblem. In this egad, twoimpotant modifications to the FNAB have been attempted:immunoctological studies (paticulal with galectin-3

immunostaining) and molecula ctogenetic studies. Galectin-3is not expessed in nomal thoid cells. It has been suggestedthat cells which have a tendenc to malignanc expess galectn-3.Galectin-3 has been found to be useful in diffeentiating benignfom malignant thoid lesions.16 It has been shown that ove90% of thoid cance expess galectin-3, while onl about2% of benign nodules expess galectin-3. Galectin-3 has beenshown to be useful in diagnosing small (minimall invasive)follicula cances.17 This is impotant, because an FNAB cannotdiffeentiate follicula adenoma fom a follicula cance. Acombination of molecula and ctogenetic studies afte FNABoffes an exciting pe-sugical insight into whethe a lesion isbenign o malignant. The impotant mutations studied in elationto thoid cance ae: BrAF, rAS, rET/PTC and PAX8/PPAr mutations. In cases with indeteminate ctolog, a ecentstud showed that 97% of subjects who wee mutation-positivehaboed a malignanc.18 If these esults ae cooboated, thenthe clinician will have a new tool fo deciding which nodulesshould undego thoidectom.

Finall, a ecent advancement in the management of thoidnodules has been the use of ecombinant TSH fo amplifingthe effect of I131 in shinking benign goites. recombinant TSHcan incease the uptake of iodine b thoid cells, and can thusaugment the effect of I131on nodule size. A ecent stud showedthat ecombinant TSH (TSH) injections pio to I131 theapfacilitated goite shinkage b an additional 50% as compaedto I131 alone.19 Howeve, in that stud, pain and compessivesmptoms wee moe fequent with TSH theap. In anothestud on ve lage multinodula goites, TSH-based I131theap

was shown to impove tacheal compession and impoveinspiato capacit.20 Though -TSH is now available in India;this theap is both contovesial and expeimental.

Conclusions Athyroidnoduleisadiscretelesionwithinthethyroid

gland that is palpabl o adiologicall distinct fom thesuounding thoid paenchma

Wheneverapatientpresentswithathyroidswelling,thetask of the clinician is to distinguish the benign nodule fomthe malignant

Featuressuggestiveof amalignantthyroidswellingarefamil histo of thoid cance, apid nodule gowth, a vefim/ had nodule, clinical signs of fixit to suoundingstuctues, vocal cod paalsis/ hoaseness of voice,

egional lmph node enlagement o the pesence of anothelesion (fo e.g., a lung nodule on chest x-a) that suggestsa distant metastases

Inadditiontothyroidnodule,malegender,extremesofage(70 eas), histo of neck iadiation, nodule >4cmin size o the pesence of an pessue smptoms shouldevoke futhe investigations

InvestigationsincludeTSH,Ts,T4, ultrasonography,radionuclide Scanning and FNAB

Surgeryisrequiredifmalignantorsuspiciouscytologyisepoted. rapid gowth and inceasing pessue effects(beathing difficult, dsphagia), and cosmetic easons dueto the size of the goite ae indications fo suge

Patientswitha suspiciousFNABreport are subjectedto adio nuclide scanning and suge is pefomed on

those nodules that ae cold o wam, and simpl followingup those with hot nodules without suge as the isk ofmalignanc in these nodules is ve low

Inmalignant/suspiciouscases,totalthyroidectomyistheteatment of choice

Inpatientswithabenigncytologytotalorhemi-orsubtotalthoidectom is done

Totalthyroidectomy is advocated forbilateral benignmultinodula goites

Refereces1. Coope DS, Dohet GM, Haugen Br, et al. Management guidelines

fo patients with thoid nodules and diffeentiated thoid cance:The Ameican Thoid Association Guidelines Taskfoce. Thyroid2006;16:109-42.

2. Tunbidge DCE, Hall r, Appleton D et al. The Spectum of ThoidDisease in a Communit: The Whickham Suve. In: Clin Endocrinol(Oxf); 1977:481-93.

3. Davies L, Welch HG. Inceasing Incidence of Thoid Cance inthe United States, 1973-2002.JAMA 2006;295:2164-7.

4. Tuttle rM, Lema H, Buch HB. Clinical Featues Associated withan Inceased risk of Thoid Malignanc in Patients with FolliculaNeoplasia b Fine-Needle Aspiation. Thyroid 19098;8:377-83

5. Mehanna HM, Jain A, Moton rP et al. Investigating the thoidnodule. BMJ2009;338:733.

6. Koike E, Noguchi S, yamashita H, et al. UltasonogaphicChaacteistics of Thoid Nodules: Pediction of Malignanc. ArchSurg 2001;136:334-7.

7. Mogan JL, Sepell JW, Cheng MSP et al.. Fine-needle aspiationctolog of thoid nodules: how useful is it? ANZ Journal of Surgery2003;73:480.

8. Casto Mr, Ghaib H. Continuing Contovesies in the Managementof Thoid Nodules.Ann Intern Med 2005;142:926-31.

9. Delbidge L, Guinea AI, reeve TS. Total Thoidectom fo BilatealBenign Multinodula Goite: Effect of Changing Pactice.Arch Surg1999;134:1389-93.

10. Hegedus L. The thoid nodule. New Engl J Med 2004;351:1764-71.11. Zingillo M, Tolontano M, Chiaella r, et al. Pecutaneous ethanol

injection ma be a definitive teatment fo smptomatic thoidcstic nodules not teatable b suge: five-ea follow-up stud.Thyroid 1999;9:763-7.

12. Kang HW, No JH, Chung JH, et al. Pevalence, Clinical andUltasonogaphic Chaacteistics of Thoid Incidentalomas.Thyroid 2004;14:29-33.

13. McCatne Cr, Stukenbog GJ. Decision Analsis of DiscodantThoid Nodule Biops Guideline Citeia.J Clin Endocrinol Metab2008;93:3037-44.

14. Kang KW, Kim SK, Kang HS, et al. Pevalence and isk of cance offocal thoid incidentaloma identified b 18F-fluoodeoxglucosepositon emission tomogaph fo metastasis evaluation and cancesceening in health subjects.J Clin Endocrinol Metab2003;88: 4100-4.

15. Bellantone r, Lombadi CP, raffaelli M, et al. Management of Cstico Pedominantl Cstic Thoid Nodules: The role of Ultasound-Guided Fine-Needle Aspiation Biops. Thyroid 2004;14:43-7.

16. Webe KB, Shoe Kr, Heinz DE, et al. The use of a combination ofgalectin-3 and thoid peoxidase fo the diagnosis and pognosisof thoid cance.Am J Clin Path 2004;122:524-31.

17. Saggioato E, Cappia S, De Giuli P, et al. Galectin-3 as a PesugicalImmunoctodiagnostic Make of Minimall Invasive FolliculaThoid Cacinoma.J Clin Endocrinol Metab 2001;86:5152-8.

18. Nikifoov yE, Stewad DL, robinson-Smith TM, et al. MoleculaTesting fo Mutations in Impoving the Fine Needle AspiationDiagnosis of Thoid Nodules. J Clin Endocrinol Metab 2009:2009-0247.

19. Bonnema SJ, Nielsen VE, Boel-Jogensen H, et al. Impovementof Goite Volume reduction afte 0.3 mg recombinant HumanThotopin-Stimulated radioiodine Theap in Patients with aVe Lage Goite: A Double-Blinded, randomized Tial. J ClinEndocrinol Metab 2007;92:3424-8.

20. Bonnema SJ, Nielsen VE, Boel-Jogensen H, et al. recombinantHuman Thotopin-Stimulated radioiodine Theap of LageNodula Goites Facilitates Tacheal Decompession and ImpovesInspiation.J Clin Endocrinol Metab 2008;93:3981-4.