J Clin Pthol 1986;39:483-488 Histometry of thyroids contining few nd multiple nodules M AL-MOUSSA, J SWANSON BECK From the Deprtment ofpthology, The University ofdundee, Ninewells Hospitl nd Medicl School, Dundee SUMMARY Histometric mesurements were mde on individul nodules nd the internodulr thyroid on glnds from 15 ptients without evidence of endocrine thyroid disese: some of the thyroids hd multiple nodules. Mesurements of the surviving internodulr thyroid tissue showed tht the vrious components were ech within the norml rnge for thyroids from ptients with no evidence of thyroid disese, but there were considerble devitions within few glnds in the colloid:epithelium rtio tht were ssocited with histologicl ppernces of dilted or collpsed cini. The interprettion of these ppernces presented difficulties, but it ws concluded tht the blnce of evidence fvoured the inference tht the internodulr prt of the glnd ws under physiologicl growth control t the time of study. The nodules vried in size: most contined proportiontely less epithelium nd more colloid thn the internodulr thyroid. t ws concluded tht the nodules were unlikely to be secreting utonomously in these ptients. Spordic non-toxic goitre is the commonest ctegory of disese found in the thyroid of cliniclly euthyroid ptients.' During the erlier stges in the development of this disese the thyroid is thought to hve the ppernce of colloid goitre, but, s the disese runs its nturl course the thyroid is chnged progressively into nodulr goitre.2 The etiology of this process is controversil nd still incompletely understood, but it seems to be response to low vilbility of iodine to the individul thyroid cini.3 There hs been very ctive interest in the structure nd function of the nodules in the dvnced disese, nd it is now cler tht such nodules re usully not neoplstic. The nodules re sometimes utonomously functioning-"hot"-nd sometimes metboliclly inctive-"'cold"-with respect to vidity of uptke of iodine from the blood nd responsiveness to denohypophysel control.4 By contrst, there hs been reltively little interest in the intervening compressed residul non-nodulr thyroid tissue filling the spce between the nodules. This pper reports the histometric mesurements of the internodulr portions of "norml" thyroid tissue within nodulr thyroids nd contrsts these with comprble mesurements on the individul nodules in the nodulr glnds nd the whole thyroids of "norml" controls. Accepted for publiction 11 November 1985 Mteril nd methods This study ws performed on 15 thyroids: 14 were obtined t necropsy from three men nd eleven women (ged 52-88 yers) nd one ws n opertion specimen from mn ged 58. Tble shows the detils of the ptients nd their thyroids. The glnds ll contined rounded encpsulted nodules tht were not obviously neoplstic on histologicl exmintion. Four of the glnds contined multiple nodules (1, 36, 5, nd 145, respectively), nd the others contined seven nodules (two cses), four nodules (two), three nodules (two), two nodules (one), nd single nodule (four). Six of the glnds hd volume greter thn 4 ml nd these were regrded s goitrous. Ech glnd ws weighed nd fixed: its volume ws determined immeditely fter removl from the ptient nd t intervls during processing for histologicl exmintion with the wter displcement cn nd by pplying Simpson's rule5 to mesurements of the surfce re of 1 cm slices of the glnd with methods described previously.6 The surfce of ech fixed slice ws exmined for exposed nodules nd then plpted: where hidden nodule ws suspected n incision ws mde perpendiculr to the surfce to llow inspection. When nodule ws identified the region of the glnd ws sliced t 1-2 mm intervls to expose the mximum dimeter for mesurement. The first three glnds in the series were exmined exhustively 483 J Clin Pthol: first published s 1.1136/jcp.39.5.483 on 1 My 1986. Downloded from http://jcp.bmj.com/ on 15 August 218 by guest. Protected by copyright.
.'-..-: 484 Mouss, Beck Tble 1 Detils ofptients Code Sex Age Body Body Body Totl nterstitil thyroid tissue No of (yer) height weight surfce thyroid nodules (cm) (kg) re (m2) volume (ml) Clculted Epithelium Colloid "Lumen' Strom volume % ml % ml % ml including (ml) vessels % ml F 65 155 57 1-54 264 29-12 3-3 53 14-7 8 2-2 27 7-4 5 2 82 163 61 1-67 24-14-6 15 2-1 46 6-6 7 1-33 4-6 1 3 F 52 155 65 1-66 32-5 26-8 1 2-7 73 18 7 3-8 14 3-6 7 4 88 148 46 1 38 12-2 9-2 15 1 3 39 3-4 5-5 4 3-5 4 5 55 153 55 1-51 12-5 12 21 2-5 31 3-6 1 1-1 39 4-6 3 6 F 85 155 45 1-43 7 5 7-16 1-1 44 3 8-6 33 2-2 3 7 F 78 153 53 1-49 57 16-5 16 2-4 44 6-8 6 9 35 5-2 1 8 F 63 147 65 1-53 64-2 43-8 14 6-2 6 25-7 5 2-1 21 8-7 9 M 76 168 54 1-65 42-19-3 16 2-9 48 8-6 8 1-4 28 5-1 1 F 77 16 64 1-66 16-5 16 18 2-8 45 7-1 12 1-9 26 4 1 11 M 72 168 71 1-81 33 3-6 9 2-7 38 1-9 11 3-1 43 12-4 2 12 F 73 158 77 1-75 31 18-4 19 3 5 3 5 3 5 1-45 8 1 7 13 M 7 167 7 1-8 19. 18 8 1 1-9 45 8- S -9 4 7-1 4 14 F 82 157 42 142 15 1 8 11 1-1 4 4-3 3 3 47 5 36 15 M 58 16 78 1-78 558t 25-13 3-1 56 13-7 2 5 3 7-1 145 Retrction spce between colloid nd cinr epithelium; topxertion specimen. to ensure tht this smpling procedure did not miss 5- smll nodules. The dimeter of the individul nodules ws mesured with ruler. The volume of ech nodule ws clculted on the 1 ssumption tht it ws sphericl. Histometric mesurements were mde on sections of every nodule nd Ē on the internodulr thyroid tissue (ssessing ech ntomicl unit s if it were whole thyroid), s 5-2 described previously6: these results were then used to 4- clculte bsolute vlues for volumes of histologicl.. components, number of cini/unit volume, nd internl nd externl surfce res of the cini. We ppre- E -.- 3-. cited tht these methods would probbly result in 2- smll overestimte of the numbers of cini nd their 1.~~ surfce res in nodules, becuse the bsic ssumption tht cini re roughly sphericl is only prtly A 2 4 6 8 s ~ '1 vlid due to the occsionl occurrence of prtly fused v &W -W%f %~ :- o-% Ar2 (uorwc djcent cini. 4- Results 2 3- -f : The totl volumes of the nodulr thyroids were substntilly greter thn those of the norml glnds 2. ; 1 V; studied under similr conditions (Fig. l).6 When, i 1 1 however, the volume of the internodulr prt of ech of the nodulr glnds ws clculted it becme cler tht the vlues for this residul "norml" component.lro 2 4 6 8 1 were comprble with those of the whole volume of Age (yers) the norml glnds studied previously (Fig. lb). Fig. () Volume ofnodulr thyroids mesured before fixtion. Solid symbols indictefemle ptients nd open symbols results on mle ptients. "Htched" re includes ll observtionsfrom previous survey oflocl ptients without ny evidence of thyroid disese.6 (b) Volumes ofinterstitil portions of thyroidprenchym between nodules. Mesurements were mde fterfixtion nd slicing ofglnds, nd these were correctedfor shinkge. Most observtions lie within "norml" rnge. Accordingly, the first stge of this investigtion determined the extent to which the internodulr portions of the nodulr glnds corresponded to the whole glnds of control subjects who did not hve endocnne disese. The primry mesurements were obtined by poitt counting (Tble 1). Virtully ll of the mesurements in ech of the ctegories fell within the rnge observed in control ptients from Tyside6 of J Clin Pthol: first published s 1.1136/jcp.39.5.483 on 1 My 1986. Downloded from http://jcp.bmj.com/ on 15 August 218 by guest. Protected by copyright.
Histometry of thyroids contining few nd multiple nodules.} 121..:.:::::..:: :: : EE :::::::..::.-...::..:.X :......: t6- uw L 2 4 6 Age (yers) -.4 L D.-. 3.. 2 t,... 1 &._- 2 4 6 Age (yers) _4 3- u 2- t i 1 L :.:::::: ::... 2 14 6 Age (yers). so 1 so 1 w 8 1 1.2 :g.8-4............._... 485...S_ w -..-.:... -... L......-....:.....:...,...: EL..., ^,[... -2-4 -6-8 Body sur 1. 1.2 1.4 (m2) re 1.6 1.8 2. 2 4 6 Age (yers) Fig. 2 Histometric mesurements on interstitil surviving "norml" portions ofnodulr thyroids. () Volume ofepithelium relted to ge; (b) volume ofinterstitil thyroid relted to body surfce re; (c) volume ofcini relted to ge; (d) internl surfce re ofcini relted to ge; (e) totl number ofcini relted to ge.. = w --- w.......... - 8 1 comprble ge (Fig. 2) nd lso ly within the 95% confidence limits described by the men stndrd devition. The mesurements of the internodulr prts in the nodulr glnds bore similr correltion to body weight, height, nd surfce re s the whole glnds of the control ptients (Fig. 2b). Similrly, the totl volume of the cini (Fig. 2c) nd their internl surfce re (Fig. 2d), nd the totl number of cini in the internodulr glnd (Fig. 2e) were similr to the corresponding mesurement for the control glnds. Although the primry mesurements fell within the norml rnge, there ws some imblnce between them in certin specimens. n cse 3 the colloid: epithelium rtio ws bout 4: 1, corresponding to histologicl ppernce of dilted cini of the type seen in colloid goitre; the totl volume of epithelium in this glnd, however, ws 2-7 ml (not reduced), but the colloid volume ws considerbly incresed (18-7 ml, ner the higher limit of norml). Cse 8 ws generlly similr, with high epithelium content (6-2 ml) nd proportiontely more colloid (25-7 ml). By contrst, cses 5 nd 12 hd reltively more epithelium (2.5 nd 3-5 ml, respectively), compred with colloid content towrds the lower limit of norml (3-6 nd 5-3 ml, respectively), nd presented histologicl ppernce of smller reltively collpsed cini with more prominent epithelil lining. By contrst, there ws much more vribility in the mesurements on the thyroid nodules. Tble 2 summrises the findings on glnds contining fewer thn seven nodules. Figs. 3 nd b show the mesurements on two multinodulr glnds: the results of histometry on the four other multinodulr glnds were generlly similr to these exmples. J Clin Pthol: first published s 1.1136/jcp.39.5.483 on 1 My 1986. Downloded from http://jcp.bmj.com/ on 15 August 218 by guest. Protected by copyright.
486 Mouss, Beck Tble 2 Summry ofhistometric.findings on nodules in thyroids withfour orfewer nodules No ofnodules Volume (ml) Acinr volume No offollicds nternl Externl Epithelium Colloid spce Strom (ml) (x 16) surfce surfce (%) re (m2) re (m2) Cse 4 1-119 89 5 33 35 68 25 2-36 27-2 -1-11 8 68 24 3-36 -21-3 -9-11 2 39 36 4 3-3 2-58 -3-55 -59 1 7 19 Cse 5 1-34 -3-6 -8-9 13 75 9 2-34 -24-1 -8-1 21 5 22 3-53 -43-12 -13-14 1 72 13 Cse 6 1-37 -23-4 -11-13 18 41 37 2-122 -99-2 -25-26 8 74 16 3-37 -29-7 -8-9 9 7 18 Cse 3 41-5 18-4 27-8 -84 1-1 14 32 48 Cse8 212 12 18-9 -54-57 19 37 38 Cse9 24-2 13 4 11-8 -53-62 15 41 4 Ce 1-55 -48-12 -13-15 15 72 11 Cse 1-4 -27-2 -1-11 1 58 26 2 3-26 1.19 2-5 -6-7 13 24 56 Cse 13 1-118 -81-9 -4-41 9 6 25 2-118 -77-8 -35-3 11 54 28 3-55 -49-9 -13-13 7 84 7 4-28 -178-5 -5-6 11 52 29 1 5 1 5 1-5.1. 3 53 1 b 33 1. 1 4 7-o- -._-- A B C D E F G 5..5.1.~~~~~~~2 9 2. : 1. 5-14 3w2 N6.13 2.23.817.2.18 3 1 318- %8 822 1 8177 8 6 ll 12i5 :11.12 12-14. w.22. 11.17.5 3 5 12 3 84 N6.13 A B C D E F G Fig. 3 Digrm summrisingfindings in individul nodules (solid squres) nd in interstitil "norml" thyroid (solid circle with centrl open str) from () cse 2 contining 1 nodules nd (b) cse 15 contining 145 nodules. Lbelsfor columns indicte: A = totl volume (ml); B = cinr volume (ml); C = totlfolliculr number ( x 16); D = internl surfce re ofcini (m2); E = externl surfce re ofcini (m2); F = epithelil volume s % of totl volume; G = colloid spce volume s % of totl volume. J Clin Pthol: first published s 1.1136/jcp.39.5.483 on 1 My 1986. Downloded from http://jcp.bmj.com/ on 15 August 218 by guest. Protected by copyright.
nodule it is -3. Nodules of 3-4 mm dimeter, however, were redily detected by plption, nd so the overll probbility tht nodules of 3 mm dimeter, or greter, would be detected in this study must pproch 1-. We considered tht the error introduced into this study by filing to detect smller nodules would be insignificnt in reltion to either the totl thyroid volume (rnge 7-5-558 ml) or the clcu- Histometry of thyroids contining few nd multiple nodules 487 The individul nodules were mostly smller thn lted intemodulr thyroid volume (rnge 7--43-8 the internodulr portion of the glnd: in two of the ml), s 3 mm dimeter sphericl nodule hs volume of only -1 ml. We concluded tht the clcu- nine glnds with few nodules, however, nd in three of the six multinodulr glnds nodule ws lrger lted volume nd histometric indices for the internodulr thyroid tissue would not be unduly bised by thn the internodulr thyroid tissue, but the nodule usully hd proportiontely fewer more distended the mnner of detection nd mesurement of the nodules. cini. Most nodules, whether lrge or smll, hd proportiontely (v/v) more colloid nd less epithelium The cses selected for this study were delibertely thn the interstitil thyroid glnd. These mesurements correspond to the generlly mcrogestive of metbolic effects of thyroid disese, nd it chosen becuse the ptients hd not hd evidence sugfolliculr histologicl ppernce seen in 228 (82.8%) would be resonble to ssume tht they hd been of the 275 nodules: most of the nodules hd cini euthyroid. The interprettion of the histometric lined by flttened epithelium, but mny showed scttered smll res in which prt of the lining of individ- results for the internodulr thyroid presents certin ul cini ws composed of tller epithelium. There were few colloid cysts. Discussion n the pst clinicl nd pthologicl interest in nodulr thyroids hs concentrted on the nture of the nodules, in prticulr, distinguishing them from neoplsms nd determining whether individul nodules re utonomous in reltion to the pthogenesis of thyrotoxicosis. These spects of nodulr thyroids hve been emphsised in the most recent review': there re no published reports of histometric mesurement. Two min methods were used to identify nodules in the thyroids exmined in this study. The primry method ws inspection of the cut surfce of the 1- cm slices, nd this hs the clssicl disdvntges of the "cherry cke" problem-nmely, tht nodule with dimeter less thn the thickness of the slice hs certin probbility of escping detection. Due to the rndom selection of the plne of sectioning there is n equl likelihood tht the centre of the nodule will lie t ny point on n imginry line pssing directly through the slice, nd nodule will be visible on the cut surfce when its centre lies t distnce less thn its rdius from the cut surfce: consequently, the probbility tht nodule of given size will be visible is 2r/t, where r = rdius nd t = slice thickness. Thus ll nodules with dimeter greter thn 1- cm will be exposed t the surfce: the probbility tht smll nodule will be exposed is linerly relted to its dimeter, nd, with cm slices, the probbility tht n 8 mm nodule will be exposed is -8 nd for 3 mm difficulties. On the one hnd, the vrious mesurements for the internodulr prts of the glnds ll ly within the "norml" rnge. On the other hnd, the colloid:epithelium rtios for the internodulr prts of some glnds were pprently bnorml due to devi-- tion of the component vlues in opposite directions while still within the norml rnge. Thus glnd cn dopt histologicl ppernce suggestive of colloid goitre while still retining the norml content of epithelium. When ptient with Grves' disese is treted preopertively with inorgnic iodide the histologicl ppernce of the thyroid chnges from the extreme hyperplsi typicl of the untreted disese into much more norml looking structure, with cuboidl epithelium lining cini distended with colloid. This chnge hs been described s "involution". t hs been shown by histometric mesurement tht the chnge induced by iodide is ssocited with n increse in colloid content without ny modifiction in the epithelium content,8 nd it ws suggested tht the lowering of the epithelium is consequence of distension of the cini nd stretching of the epithelium over much lrger surfce re. This experience suggests tht epithelil volume my be more useful indictor of hyperplsi, hypoplsi, or normlity in the thyroid thn the histologicl ppernce. We therefore suggest tht the internodulr tissue in nodulr thyroids ws in stte of norml growth control t the time of our exmintion. This conclusion cnnot, however, be extrpolted to n erlier stge of the ptient's life. t is quite possible tht the thyroid hd been exposed to excessive thyroid stimulting hormone or TSH stimultion for shorter or longer period nd tht this induced the focl overgrowth which culminted in nodule formtion. t is clerly not possible to differentite between the vrious mechnisms tht hve been suggested for the pthogenesis of the nodulr thyroid from the ppernce of the glnd in middle or old ge. t is unlikely tht ny of the nodules in the glnds studied here were "hot". t is relevnt, therefore, tht none of the nodules showed histopthologicl or his- J Clin Pthol: first published s 1.1136/jcp.39.5.483 on 1 My 1986. Downloded from http://jcp.bmj.com/ on 15 August 218 by guest. Protected by copyright.
488 tometric evidence of hyperplsi. f nodule hd been utonomous it is likely tht there would hve been suppression of TSH secretion, nd so the interstitil glnd would hve undergone trophy through loss of trophic influence: whether this will prove to be the cse will soon be determined by direct mesurement. MAM ws supported on trining fellowship from the government of the Republic of Syri. Some of the costs were supported by grnt to JSB from the Scottish Hospitl Endowments Reserch Trust (HERT 423). We re grteful to Mr RS Fwkes nd Mr R Kiddie for the preprtion of the digrms, to the medicl lbortory scientific officers of the deprtment of pthology, Ninewells Hospitl nd Medicl School, for excellent technicl help in producing the numerous histologicl sections nd to Mrs R Mitchell for secretril help. References 1 Tylor S. Spordic nontoxic goitre. n: Werner SC, ngbr SH, eds. Mouss, Beck The thyroid: fundmentl nd clinicl text. New York: Hrper nd Row, 1978:55-12. 2Tylor S. The evolution of nodulr goitre. J Clin Endocrinol Metb 1953;13:1232-47. 'Beckers C. Non toxic goitre. n: de Vissuher M, ed. The thyroid glnd. New York: Rven Press, 198:231-55. 'Studer H, Rick MM, Greer MA. Multinodulr goitre. n: Groot J, Chill GF, Odell WD, et l, eds. Endocrinology. Vol 1. New York: Grune nd Strtton 1979:489-99. 'Adms JH, Dniel PM, Prichrd MML, Venbles PJ. A method for mesuring the volume of the pituitry glnd. J Physiol 1963;166:37-9P. 6Brown RA, Al Mouss M, Beck JS. Histometry of the norml humn thyroid. J Clin Pthol 1986;39:475-82. 7Rojeski MT, Ghrib M. Nodulr thyroid disese: evlution nd mngement. New Engl J Med 1985;313:428-36. 8Wilkin TJ, Beck JS, Michie W. Does preopertive iodide tretment for thyrotoxicosis bring bout involution? J Clin Pthol 1977;3:99-12. Requests for reprints to: Professor J Swnson Beck, Deprtment of Pthology, Ninewells Hospitl nd Medicl School, PO Box 12, Dundee DD 9SY, Scotlnd. J Clin Pthol: first published s 1.1136/jcp.39.5.483 on 1 My 1986. Downloded from http://jcp.bmj.com/ on 15 August 218 by guest. Protected by copyright.