ANNALS O F CLINICAL AND LABORATORY SCIEN CE, Vol. 25, No. 6 C opyright © 1995, Institute for Clinical Science, Inc.

Clear Nuclear Changes in Hashimoto’s Thyroiditis

A Clinicopathologic Study of 12 Cases*

MARIANA BERHO, M.D. and SAUL SUSTER, M.D.

Arkadi M. Rywlin Departm ent o f Pathology b- Laboratory Medicine,

Mount Sinai Medical Center and University o f Miami School o f Medicine,

Miami Beach, FL 33140

ABSTRACT

Histologic sections of thyroid glands resected from 12 patients with Hashimoto’s thyroiditis have been studied in which areas were present showing clear nuclear changes such as those seen in papillary carcinoma. The patients’ ages ranged from 28 to 78 years (mean = 57.3); 11 were women and one was a man. The lesions presented as focal, ill-defined areas d isplaying clear nuclear changes of the cells w ith in otherw ise well- circum scribed adenomatous nodules, or as small clusters of cells showing the characteristic clear nuclear features randomly admixed with the H ashi­moto’s elem ents. Histologically, the lesions were characterized by a range of nuclear features that included optically clear nuclei, prom inent cytoplas­mic invaginations with intranuclear cytoplasmic inclusions, and occasional nuclear grooves. In two cases, focal papillary formations were seen that were lined by cells with optically clear nuclei. In two other cases, well- circum scribed nodules bearing the architectural features of trabecular hyalinizing adenoma with focal clear nuclear changes were also present. In three cases, small (<0.5 cm) well-circumscribed nodules bearing cyto- logical features indistinguishable from those of microscopic papillary car­cinoma were also present in addition to the areas of clear nuclear change. Follow-up of 1.5 to 19 years (mean = 9 years) showed no evidence of recurrence or metastases in any of our patients. Our study appears to indi­cate that thyroid follicular epithelium in patients with Hashimoto’s thy­roiditis may exhibit a range of clear nuclear changes sim ilar to those encountered in papillary carcinoma. Such changes may represent another form of response of follicular epithelium to the underlying autoimmune process with possible prem alignant connotation. However, they should be interpreted in context w ith the rest of the findings w ithin the involved gland to avoid an overdiagnosis of malignancy.

* Send reprint requests to: Saul Suster, M.D. D epartm ent of Pathology, M ount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140

5130091-7370/95/1100-0513 $01.50 © Institute for Clinical Science, Inc.

5 1 4 BERHO AND SUSTER

Introduction

The follicular epithelial changes that occur in H ashim oto’s thyroiditis (HT) have been em phasized since its original description in 1912.1 The presence of oncocytic features in the epithelial cells lining the follicles is a classical histolog­ical feature of this condition that has been regarded together w ith the intersti­tial lym pho id in filtra tes as the m ost im portant criteria to make the diagno­sis.2,3 A num ber of events that can com­plicate the course of the disease, such as the developm ent of malignant lymphoma or papillary carcinom a have also been studied.4,5,6’7,8’9 Another unusual feature of HT which has been m entioned as a potential source of confusion for diagno­sis is focal clear nuclear change w ith some degree of overlapping sim ilar to that observed in papillary carcinom a.3 W ith the curren t em phasis on nuclear features for the diagnosis of papillary car­cinoma of the thyroid, critical evaluation of lesions bearing such features becomes essential for adequate interpretation.

Tw elve cases are reported in which clear nu c lea r changes rem in iscen t of those seen in papillary carcinoma were present in thyroid lesions associated with H ashim oto’s thyro id itis. The possib le pathogenesis and clinical significance of these lesions are discussed.

Materials and M ethods

All cases accessioned under the diag­nosis of Hashim oto’s thyroiditis in the surgical pathology files at M ount Sinai M e d ic a l C e n te r o f G re a te r M iam i betw een the years 1974 to 1992 were reviewed. O f a total of 56 cases on which thyroid surgery was done, HT was found incidentally in 22 patients who under­w en t lobectom y or sub to ta l th y ro id ­ectom y for o th e r reaso n s, in c lu d in g m alignant lymphoma, carcinoma of the papillary, follicular or oncocytic type, as well as benign follicular and oncocytic

neoplasm s and m ultinodular goiter. In the rem aining 34 cases, HT was the pri­mary histological finding in lobectomy specimens of patients presenting with a thyroid nodule. In this latter group, it was possible to identify foci of clear nuclear changes similar to those observed in pap­illary carcinoma in 12 cases.

Histological criteria for inclusion in the study were the presence of optically clear nuclear changes in the follicular cells e ither focally w ithin otherw ise benign hyperplastic nodules or adm ixed w ith the thyroid parenchyma in areas affected by the Hashimoto’s thyroiditis. From 6 to 13 hem atoxy lin and eosin (H& E) s ta in e d sec tio n s w ere a v a ila b le for review in each case. In cases 5 and 7, paraffin-em bedded tissue sections were incubated with antibodies against thyro- globulin,* calcitonint and carcinoembry- onic antigen (CEA)t by the avidin-biotin- peroxidase complex (ABC) technique.10 N onim m une rabb it and m ouse serum was substitu ted for negative controls. Appropriate positive controls w ere run concurrently for all antibodies tested . The data abstracted from the patien ts’ records included sex, age at tim e of sur­gery, presenting clinical signs and symp­toms, and mode of treatm ent. Follow-up information was obtained by contacting the referring physicians.

Results

C l i n i c a l F e a t u r e s

The clinical features of our patients are shown in table I. E leven patients were women and one was a man. The patients’ ages ranged from 28 to 78 years (mean = 57.3). The most common presenting sign was a palpable neck mass that appeared as a cold nodule on thyroid scan. Two patien ts had additionally a h istory of

* Biogenex, San Ramon, CA. t Dako, Santa Barbara, CA.

TABLE I

NUCLEAR CHANGES IN HASHIMOTO S THYROIDITIS 515

Clinical and Pathologic Features in Patients with Clear Nuclear Changes in Hashimoto's Thyroiditis

Case Sex/Age Presentation Treatment Follow-up

1 F 64 Cold nodule in left lobe Lobectomy A & W at 1.5 years2 F 68 Diffuse goiter + cold nodule

in left lobeLobectomy A & W at 2 years

3 F 29 Cold nodule in right lobe Lobectomy A & W at 18 years4 F 77 Cold nodule in left lobe Lobectomy A & W at 3.5 years5 F 77 Cold nodule in right lobe

History of hypothyroidismSubtotalthyroidectomy

Died 4 years after surgery owing to cardiac failure; no evidence of recurrence or metastasis

6 F 78 Nodular goiter for several years

Subtotalthyroidectomy

Died 3 years after surgery owing to diabetic coma

7 M 76 Cold nodule in left lobe Lobectomy Died 3 years after surgery; no evidence of recurrence or metastasis

8 F 57 Cold nodule in left lobe Lobectomy A & W at 19 years9 F 28 Cold nodule in left lobe Lobectomy A & W at 17 years10 F 53 Cold nodule in left lobe Lobectomy A & W at 17 years11 F 45 Cold nodule in right lobe Lobectomy A & W at 11 years12 F 49 Cold nodule in left lobe Lobectomy A & W at 11 years

A & W = alive and well.

as a cold nodule on thyroid scan. Two patien ts had additionally a history of hypothyroidism for several years. Surgi­cal treatm ent consisted of lobectomy in 10 cases, and subtotal thyroidectomy in two. No enlarged cervical lymph nodes were noted at the time of surgery in any of th e p a tie n ts . O n fo llow -up , n in e patients are alive and well, with no evi­dence of recurrence or m etastases from 1 to 19 years after surgery (mean follow-up = 9 years). Three patients died of unre­lated causes (Cases 5, 6, and 7).

P a t h o l o g i c a l F i n d i n g s

Gross findings: The lobectomy speci­mens ranged from 2 to 8 cm in greatest d im ension . T he ex ternal surface was described as smooth in six, and irregular with a m ultinodular aspect in four. Cut section revealed a hom ogeneous pale thyroid parenchym a in six cases, and

m ultiple small colloid nodules in four cases. Diffuse enlargem ent of the gland was observed in both of the subtotal thy­roidectomy specimens.

Histologic findings: The most striking finding on microscopic examination was the presence in all cases of a range of nuclear changes similar to those seen in papillary carcinoma, including optically c lear n u c le i, p ro m in e n t cy top lasm ic invaginations with nuclear pseudoinclu­sions, varying degrees of overlapping of nucle i and nuclear grooves (figure 1 A-C). The optically clear nuclei w ere characterized by a thickened, somewhat irregular nuclear m em brane w ith prom i­nent peripheral margination of chromatin and absence of nucleoli. These nuclear features were usually unevenly distrib­uted and seen focally w ithin unencapsu­lated and well-circumscribed adenom a­tous nodules in seven cases (cases 3, 4, 6, 8, 9, 10, and 12) (figure 2), or as small

516 BERHO AND SUSTER

FIGURE 1. Clear nuclear changes are seen, fea­turing: (A) thickened nuclear membranes with opti­cally clear nuclei (case 1) (H&E, x400); (B) occa­sional nuclear pseudoinclusions (arrows) (case 3) (H&E, X400); and (C) cells with prom inent infold­ings of the nuclear membrane resulting in the for­mation of nuclear grooves (case 11) (1I&E, x4()0).

NUCLEAR CHANGES IN HASHIMOTO’S THYROIDITIS 517

FIGURE 2. A large adenom atoid nodule com­posed of tightly packed follicles lined by cells showing clear nuclear changes is present in this gland (case 6) (H&E, x40).

clusters of cells showing the characteris­tic c le a r n u c le a r fea tu re s random ly admixed with the Hashimoto’s elements (figure 3). Psammoma bodies could not be identified. The thyroid parenchyma su rro u n d in g the lesions in all cases showed the characteristic features of HT, including dense lymphocytic interstitial infiltration with formation of lymphoid n o d u les w ith germ inal cen te rs , and prom inent oncocytic changes of follicular cells.

In two of these cases, the previously described nuclear features were noted in cells lin ing larger, d istended follicles simulating the macrofollicular variant of

papillary carcinoma. In two other cases (cases 5 and 7), well circumscribed tumor nodules were found composed of follicu­lar cells with focally clear nuclei that were arranged in trabeculae separated by fibrocollagenous stroma displaying the histologic architecture of hyalinizing tra­becular adenoma (figure 4). Because of the prominent hyaline stroma and some­what carcinoidal appearance im parted by the trabecular growth pattern, immuno- histochemical stains for calcitonin, CEA and thyroglobulin were perform ed in these two cases; calcitonin and CEA stains were uniformly negative in both, and thyroglobulin was focally positive in one. In three cases (cases 1, 2, and 11),

F igure 3. C lear nuclear changes are focally present (lower right) within thyroid parenchym a in this example of HT (case 10) (H&E, x40).

F ig u r e 5. A sm a ll, w e ll-c ir c u m s c r ib e d fo c u s o f m ic r o sc o p ic p a p illa ry c a rc in o m a s h o w in g s le n d e r p a p illa e l in e d b y c e l l s w ith c le a r n u c le a r fea tu res is s e e n (ca se 2 ) (H & E , x 2 0 0 ) .

518 BERHO AND SUSTER

small (<0.5 cm), discrete unencapsulated n o d u le s c o n ta in in g sm all fo llic le s entirely composed of cells bearing clear nuclear features were also identified. In one of them, the clear nuclear changes w ere also present in cells lining small, thin, well-developed papillae (figure 5). None of these lesions displayed a stellate low-power configuration or the prom i­n e n t strom al desm oplasia frequen tly associated with micropapillary carcinoma of the thyroid; however, the cytological and architectural features observed in them were indistinguishable from those of microscopic papillary carcinoma.

F ig u r e 4 . A sm a ll, w e ll-c ir c u m s c r ib e d n o d u le is s e e n c o m p o s e d o f c o rd s o f c e l l s w ith o p t ic a lly c le a r n u c le i arra n g ed in tr a b e c u la e sep a ra ted b y th in b a n d s o f f ib r o c o n n e c t iv e t is s u e c lo s e ly r e s e m ­b l i n g h y a l i n i z in g tr a b e c u la r a d e n o m a (c a s e 5) (H & E , x 4 0 ) .

Discussion

Hashimoto’s thyroiditis is a non-neo­plastic, autoimmune-mediated condition thought to arise from an organ-specific de­fect in suppressor T-lymphocytes.11,12,13 D esp ite its ben ign clin ical course, a close association has been established betw een HT and the developm ent of m alignancy, including m alignant lym­phoma and thyroid carcinoma, particu­larly of the papillary type.4,5,6,7,8,9 There appears to be circumstantial evidence to support the notion that such tumors may arise from neoplastic transformation of the lymphoid or follicular hyperplastic elem ents w ithin affected glands.3,5 In addition to the developm ent of malignant

NUCLEAR CHANGES IN HASHIMOTO’S THYROIDITIS 519

changes, a range of other hyperplastic and m e ta p la s tic p ro cesses may take place in association with HT. Squamous m etaplasia, e ither focal or diffuse, has been observed as an incidental finding in H T .14,15,16,17,18,19 In some instances, the squam ous m etaplasia has been of such m agnitude as to simulate squamous cell carcinoma.14,18

There also appears to be an increased incidence of embryonal rests in HT, the so-called solid cell nests of Yamaoka, b e liev ed to rep re sen t vestiges of the u ltim obranch ia l b o d y .19,20 O ther less frequen t changes observed in thyroid glands affected by HT include squamous cysts19,21 and the developm ent of m ulti­p le branchial cleft-like cysts, presum ably related to the embryologic origin of the thyroid from the base of the tongue.22 Lit­tle attention, however, has been directed to the nuclear changes tha t may take place in HT. Nuclear enlargem ent and hyperchromasia as well as optically clear appearance w ith o verlapp ing quality rem iniscent of papillary carcinoma has been observed by Rosai,3 and m entioned as a possible source of diagnostic con­fusion. W ith the cu rren t em phasis on nuclear features for the diagnosis of pap­illary carcinoma of the thyroid, the iden­tification of such features in specim ens of HT becomes of clinical relevance.

Twelve cases of HT have been studied in w hich clear nuclear changes rem i­niscent of those seen in papillary carci­noma of the thyroid were observed. All cases were characterized by the presence of cells w ith p rom inen t clear nuclear changes bearing the features of so-called “Orphan Annie” nuclei. The lesions pre­sented as focal, ill-defined areas display­ing cells w ith c lear n u c lea r features w ith in o therw ise w e ll-c ircum scribed adenomatous nodules, or as small clus­ters of cells showing the characteristic clear nuclear changes randomly admixed w ith the H ash im oto ’s e lem en ts . The nuclei in all cases w ere characterized by

their prom inent margination of chroma­tin against the nuclear m em brane im part­ing them with an optically clear appear­ance. Additional features suggestive of papillary carcinoma that were also seen in these areas included nuclear grooves, pseudonuclear inclusions, focal overlap­ping of nuclei, and in two cases, small papillary formations lined by cells with prom inent clear nuclear features.

Interestingly, two of our cases showed focal areas composed of large, d istended follicles lined by follicular cells w ith optically clear nuclei rem iniscent of the macrofollicular variant of papillary carci­noma,23 further highlighting the resem ­blance of these lesions with papillary car­cinoma. Another in teresting finding in our study was the presence of well-cir­cumscribed nodules composed of follicu­lar cells with clear nuclei in trabecular arrangem ent separated by fibrocollage- nous strom a th a t c lo se ly re se m b le d hyalinizing trabecular adenom a.24 The latter entity has been previously reported in association with HT,25 as well as with papillary carcinoma, leading to the sug­gestion by some that the latter two may be possibly related .26 Because of their s tr ik in g tra b e c u la r and r ib b o n - lik e arrangement, such lesions may also simu­late m edullary carcinoma of the thyroid. Immunohistochemical stains for calcito­nin and CEA, however, were negative in both of the lesions in our study.

The role of clear nuclear features in papillary carcinoma has gained increas­ing importance as a major histologic cri­terion for the diagnosis of this type of neoplasm.26,27,28,29 A num ber of variants of papillary carcinoma have been recog­nized in which the papillary architecture is either absent or inconspicuous, yet a firm d iagnosis is genera lly ach iev ed through the recognition of their distinc­tive clear nuclear changes.23,26,27,28,29,30 D espite the undoubted validity of the id e n tif ic a t io n o f th e c h a ra c te r is t ic nuclear changes for the diagnosis of pap­

520 BERHO AND SUSTER

illary carcinoma, the hazard of overread­ing a biopsy containing such changes has also been underscored.

In a study by Hapke and D ehner,31 optically clear nuclei indistinguishable from those seen in papillary carcinoma w ere identified in a case of Graves dis­ease and in a benign follicular adenoma. The authors therefore cautioned against the use of clear nuclei as an absolute cri­terion for the diagnosis of papillary car­cinoma, and suggested that w hen the character of the clear nuclear changes was in question, other features such as papillae w ith overlapping nuclei, psam- moma bodies, and multifocality must be sought. Because of the focal nature of the changes seen in our cases as well as the uneventful follow-up in our patients, it is our belief that these findings should be separated from clinically significant pap­illary carcinoma. It is of interest, how­ever, that in three of our cases (cases 1, 2, and 11), the areas of clear nuclear changes w ere also associated with small, w e ll-c irc u m sc rib e d n o d u les e n tire ly composed of cells with clear nuclear fea­tures that w ere morphologically indistin­guishable from small, or m inute papillary carcinomas. This finding raises the possi­bility that the nuclear changes observed in these cases may represent a preneo­plastic stage that will eventually give rise to the developm ent of papillary carci­noma, as has been previously suggested.3

The present study shows that thyroid fo llicular ep ith e liu m in patien ts w ith H ashim oto’s thyroiditis may exhibit a range of clear nuclear changes and other features such as nuclear grooves and pseudonuclear inclusions that are com­monly associated w ith papillary carci­noma. Such findings, when interpreted out of context may lead to an erroneous diagnosis of papillary carcinoma. Some of the distinctive features seen in our cases th a t h e lp e d separa te them from fu ll­blown papillary carcinoma included the focal nature of the process, which was for

the most part seen as an incidental micro­scopic finding, the absence of psammoma bodies, the lack of stromal scarring or fibrosis, and the lack of infiltration into surrounding structures in any of the cases studied. The etiology of this phenom e­non remains unclear.

T he u n e v e n tfu l c lin ica l e v o lu tio n observed in our patients suggests that the finding of focal clear nuclear changes in thyroid glands of patients w ith Hashimo­to ’s thyroiditis does not requ ire add i­tional aggressive trea tm en t. W hether these changes represent another form of response to the immune injury in HT or w hether they represent an early precur­sor stage of papillary carcinoma remains to be d e te rm in ed . In any even t, the presence of focal clear nuclear changes against a background of HT should war­ran t a conservative approach by the pathologist. Study of additional sections to define the extent of the process is ind i­cated, and specific mention of the focal nature and the microscopic extent of the findings should be relayed to the clini­cian to avert the possibility of unneces­sary aggressive treatment.

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