ANNALS O F C LIN IC A L AND LABORATORY S C IE N C E , 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. R yw lin D epartm ent o f Pathology b-

Laboratory M edicine,
M ount Sinai Medical Center
and University o f Miami School o f M edicine,
M iami Beach, FL 33140

ABSTRACT
H istologic sections of thyroid glands resected from 12 patients w ith
H ashim oto’s thyroiditis have b een studied in w hich areas w ere present
show ing clear nuclear changes such as those seen in papillary carcinoma.
T he p atients’ ages ranged from 28 to 78 years (mean = 57.3); 11 w ere
w om en and one was a man. T he lesions p resented as focal, ill-defined areas
d isp lay in g clear n u c le a r changes of th e cells w ith in otherw ise w ell-
circum scribed adenom atous nodules, or as small clusters of cells showing
the characteristic clear n uclear features random ly adm ixed w ith the H ashi­
m oto’s elem ents. Histologically, the lesions w ere characterized by a range
of nuclear features that included optically clear nuclei, prom inent cytoplas­
mic invaginations w ith intranuclear cytoplasmic inclusions, and occasional
nuclear grooves. In two cases, focal papillary formations w ere seen that
w ere lin ed by cells w ith optically clear nuclei. In two other cases, w ell-
circum scribed nodules bearing the architectural features of trabecular
hyalinizing adenom a w ith focal clear nuclear changes w ere also present. In
three cases, small (<0.5 cm) w ell-circum scribed nodules bearing cyto-
logical features indistinguishable from those of m icroscopic papillary car­
cinom a w ere also p resent in addition to the areas of clear nuclear change.
Follow -up of 1.5 to 19 years (mean = 9 years) show ed no evidence of
recurrence or m etastases in any of our patients. O ur study appears to indi­
cate that thyroid follicular epithelium in patients w ith H ashim oto’s thy­
roiditis 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 autoim m une
process w ith possible prem alignant connotation. H ow ever, 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 M edical C enter,
4300 Alton Road, M iami Beach, F L 33140
513
0091-7370/95/1100-0513 $01.50 © Institute for Clinical Science, Inc.
514 BERHO AND SUSTER
Introduction
The follicular epithelial changes that
occur in H ashim oto’s th y roiditis (HT)
have b e e n em phasized since its original
d escription in 1912.1 T he p resen ce of
oncocytic features in the epithelial cells
lining the follicles is a classical histolog­
ical featu re of this co n d itio n th at has
been regarded together w ith the intersti­
tial ly m p h o id in filtra te s as th e m ost
im portant criteria to m ake the diagno­
sis.2,3 A num ber of events that can com­
plicate the course of the disease, such as
the developm ent of m alignant lym phom a
or papillary carcinom a have also b een
studied.4,5,6’7,8’9 A nother unusual feature
of H T w hich has b een m entioned as a
potential source of confusion for diagno­
sis is focal clear n u clear change w ith
some deg ree of overlapping sim ilar to
that o b served in papillary carcinom a.3
W ith th e c u rren t em phasis on nuclear
features for the diagnosis of papillary car­
cinom a of the thyroid, critical evaluation
of lesions bearing such features becom es
essential for adequate interpretation.
T w elve cases are reported in w hich
clear n u c le a r ch an g es re m in isc e n t of
those seen in papillary carcinom a were
p resent in thyroid lesions associated with
H ash im o to ’s th y ro id itis. T h e p o ssib le
pathogenesis and clinical significance of
these lesions are discussed.
M aterials and M ethods
All cases accessioned under the diag­
nosis of H ashim oto’s thyroiditis in the
surgical pathology files at M ount Sinai
M e d ic a l C e n t e r o f G r e a te r M ia m i
b e tw e en th e years 1974 to 1992 w ere
review ed. O f a total of 56 cases on w hich
thyroid surgery was done, H T was found
incidentally in 22 patients who u n d er­
w e n t lo b e c to m y or su b to ta l th y ro id ­
e c to m y for o th e r re a s o n s , in c lu d in g
m alignant lym phom a, carcinom a of the
papillary, follicular or oncocytic type, as
w ell as benign follicular and oncocytic
neoplasm s and m ultinodular goiter. In
the rem aining 34 cases, H T was th e pri­
mary histological finding in lobectom y
specim ens of patients presenting w ith a
thyroid nodule. In this latter group, it was
possible to identify foci of clear nuclear
changes sim ilar to those observed in pap­
illary carcinom a in 12 cases.
Histological criteria for inclusion in the
study w ere the presence of optically clear
n u clear changes in the follicular cells
e ith e r focally w ithin otherw ise b en ig n
h y perplastic nodules or adm ixed w ith
the thyroid parenchym a in areas affected
by the H ashim oto’s thyroiditis. From 6
to 13 h e m a to x y lin a n d e o s in (H & E)
s ta in e d s e c tio n s w e re a v a ila b le for
review in each case. In cases 5 and 7,
paraffin-em bedded tissue sections w ere
incubated w ith antibodies against thyro-
globulin,* calcitonint and carcinoem bry-
onic antigen (CEA)t by the avidin-biotin-
peroxidase complex (ABC) tec h n iq u e.10
N onim m une ra b b it and m ouse serum
was su b stitu te d for neg ativ e controls.
A ppropriate positive controls w ere run
concurrently for all a n tib o d ies tested .
T he data abstracted from the p a tie n ts’
records included sex, age at tim e of sur­
gery, presenting clinical signs and sym p­
toms, and m ode of treatm ent. Follow -up
information was obtained by contacting
the referring physicians.
Results
C l in ic a l F e a t u r e s
The clinical features of our patients are
shown in table I. E leven patients w ere
w om en and one was a man. T he p atients’
ages ranged from 28 to 78 years (m ean =
57.3). T he m ost common presenting sign
was a palpable neck mass that appeared
as a cold nodule on thyroid scan. Two
p a tie n ts had a d d itio n a lly a h isto ry of
* Biogenex, San Ramon, CA.
t Dako, Santa Barbara, CA.
 NUCLEAR CHANGES IN HASHIMOTO S THYROIDITIS 51 5

TABLE I

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 years

2 F 68 Diffuse goiter + cold nodule Lobectomy A & W at 2 years
in left lobe
3 F 29 Cold nodule in right lobe Lobectomy A & W at 18 years
4 F 77 Cold nodule in left lobe Lobectomy A & W at 3.5 years
5 F 77 Cold nodule in right lobe Subtotal Died 4 years after surgery
History of hypothyroidism thyroidectomy owing to cardiac failure;
no evidence of recurrence
or metastasis
6 F 78 Nodular goiter for several Subtotal Died 3 years after surgery
years thyroidectomy 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 years
9 F 28 Cold nodule in left lobe Lobectomy A & W at 17 years
10 F 53 Cold nodule in left lobe Lobectomy A & W at 17 years
11 F 45 Cold nodule in right lobe Lobectomy A & W at 11 years
12 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
p a tie n ts h ad a d d itio n a lly a histo ry of
hypothyroidism for several years. Surgi­
cal treatm ent consisted of lobectom y in
10 cases, and subtotal thyroidectom y in
two. No enlarged cervical lym ph nodes
w ere noted at the tim e o f surgery in any
o f th e p a tie n ts . O n fo llo w -u p , n in e
patients are alive and w ell, w ith no evi­
dence of recurrence or m etastases from 1
to 19 years after surgery (mean follow-up
= 9 years). T hree patients died of unre­
lated causes (Cases 5, 6, and 7).
P a t h o l o g ic a l F in d in g s
Gross fin d in g s: T he lobectom y speci­
m ens ranged from 2 to 8 cm in greatest
d im e n sio n . T h e e x te rn al surface was
described as smooth in six, and irregular
w ith a m ultinodular aspect in four. C ut
section rev e a le d a hom o g en eo u s pale
th y ro id p aren ch y m 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 thy­
roidectom y specim ens.
Histologic findings: T he m ost striking
finding on m icroscopic exam ination was
the presence in all cases of a range of
nuclear changes sim ilar to those seen in
papillary carcinoma, including optically
c le a r n u c le i, p ro m in e n t c y to p la s m ic
invaginations w ith nuclear pseu d o in clu ­
sions, varying degrees of overlapping of
n u c le i and n u c le a r grooves (figure 1
A-C). T he optically clear n u clei w ere
characterized by a thickened, som ew hat
irregular nuclear m em brane w ith prom i­
nent peripheral m argination of chrom atin
and absence of nucleoli. T hese nuclear
features w ere usually unevenly distrib­
uted and seen focally w ithin unencapsu­
lated and w ell-circum scribed adenom a­
tous 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, fea­

turing: (A) thickened nuclear m em branes with opti­
cally clear nuclei (case 1) (H&E, x400); (B) occa­
sional nuclear pseudoinclusions (arrows) (case 3)
(H&E, X400); and (C) cells with prom inent infold­
ings of the nuclear m em brane resulting in the for­
mation of nuclear grooves (case 11) (1I&E, x4()0).
 NUCLEAR CHANGES IN HASHIMOTO’S THYROIDITIS 517

papillary carcinoma. In two other cases

(cases 5 and 7), well circum scribed tum or
nodules were found composed of follicu­
lar cells with focally clear nuclei that
w ere arranged in trabeculae separated by
fibrocollagenous stroma displaying the
histologic architecture of hyalinizing tra­
becular adenom a (figure 4). Because of
the prom inent hyaline stroma and som e­
w hat carcinoidal appearance im parted by
the trabecular growth pattern, immuno-
histochem ical stains for calcitonin, CEA
and th y ro globulin w ere p erform ed in
th ese two cases; calcito n in and CEA
stains were uniformly negative in both,
and thyroglobulin was focally positive in
one. In three cases (cases 1, 2, and 11),

FIGURE 2. A large adenom atoid nodule com­

posed o f tightly packed follicles lin ed by cells
show ing clear nuclear changes is present in this
gland (case 6) (H&E, x40).

clusters of cells showing the characteris­

tic c le a r n u c le a r fe a tu re s ran d o m ly
adm ixed w ith the H ashim oto’s elem ents
(figure 3). Psammoma bodies could not
be identified. The thyroid parenchym a
s u rro u n d in g th e le sio n s in all cases
show ed the characteristic features of HT,
including dense lymphocytic interstitial
infiltration w ith formation of lym phoid
n o d u le s w ith g e rm in a l c e n te rs , and
prom inent oncocytic changes of follicular
cells.
In two of these cases, the previously
described nuclear features were noted in
F ig u r e 3. C lear nuclear changes are focally
cells lin in g larger, d iste n d e d follicles present (lower right) w ithin thyroid parenchym a in
sim ulating the m acrofollicular variant of this example of HT (case 10) (H&E, x40).
518 BERHO AND SUSTER

small (<0.5 cm), discrete unencapsulated

n o d u le s c o n ta in in g sm a ll f o llic le s
entirely com posed of cells bearing clear
nuclear features w ere also identified. In
one of them , the clear nuclear changes
w ere also present in cells lining small,
thin, w ell-developed papillae (figure 5).
None of these lesions displayed a stellate
low -pow er configuration or the prom i­
n e n t strom al d e sm o p la sia fre q u e n tly
associated with m icropapillary carcinoma
of the thyroid; however, the cytological
and architectural features observed in
them w ere indistinguishable from those
of microscopic papillary carcinoma.

F i g u r e 5. A s m 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 s c o p ic p a p illa r y c a r c in o m a s h o w in g s le n d e r
p a p illa e lin e d b y c e l l s w it h c le a r n u c le a r fe a tu r e s is
s e e n (c a s e 2 ) (H & E , x 2 0 0 ) .

Discussion

Hashim oto’s thyroiditis is a non-neo­

plastic, autoim m une-m ediated condition
thought to arise from an organ-specific de­
fect in suppressor T-lym phocytes.11,12,13
D e sp ite its b e n ig n clin ical course, a
close association has b e e n established
b etw een H T and the d ev elo p m en t of
m alignancy, including m alignant lym ­
phom a and thyroid carcinom a, particu­
larly of the papillary type.4,5,6,7,8,9 There
appears to be circumstantial evidence to
F i g u r e 4 . A s m a ll, w e ll- c ir c u m s c r ib e d n o d u le support the notion that such tumors may
is s e e n c o m p o s e d o f c o r d s o f c e l l s w it h o p t ic a lly arise from neoplastic transform ation of
c le a r n u c l e i a r r a n g e d in tr a b e c u la e s e p a r a t e d b y the lym phoid or follicular hyperplastic
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 l o s e l y r e s e m ­
b l i n g h y a l i n i z i n g t r a b e c u la r a d e n o m a ( c a s e 5 ) elem ents w ithin affected glands.3,5 In
(H & E , x 4 0 ) . addition to the developm ent of m alignant
 NUCLEAR CHANGES IN HASHIMOTO’S THYROIDITIS
changes, a range of other hyperplastic
a n d m e ta p la s tic p ro c e s s e s m ay tak e
place in association w ith HT. Squamous
m etaplasia, e ith e r focal or diffuse, has
be e n observed as an incidental finding
in H T .14,15,16,17,18,19 In som e instances,
th e squam ous m etap lasia has b e e n of
such m agnitude as to sim ulate squamous
cell carcinom a.14,18
T here also appears to be an increased
incidence of em bryonal rests in HT, the
so-called solid cell nests of Yamaoka,
b e lie v e d to r e p re s e n t v estiges of the
u ltim o b ra n c h ia l b o d y .19,20 O th e r less
fre q u e n t changes o b serv ed in thyroid
glands affected by H T include squamous
cysts19,21 and the developm ent of m ulti­
p le branchial cleft-like cysts, presum ably
related to the em bryologic origin of the
thyroid from the base of the tongue.22 Lit­
tle attention, how ever, has b e e n directed
to th e n u c le a r changes th a t m ay take
place in HT. N uclear enlargem ent and
hyperchrom asia as w ell as optically clear
a p p e a ra n c e w ith o v e rla p p in g q u a lity
rem iniscent of papillary carcinom a has
b e e n observed by Rosai,3 and m entioned
as a possible source of diagnostic con­
fusion. W ith th e c u rre n t em phasis on
nuclear features for the diagnosis of pap­
illary carcinom a of the thyroid, the id en ­
tification of such features in specim ens of
H T becom es of clinical relevance.
T w elve cases of H T have b e e n studied
in w hich clear n u c le a r changes rem i­
niscent of those seen in papillary carci­
nom a of the thyroid w ere observed. All
cases w ere characterized by the presence
of cells w ith p ro m in e n t cle a r n u clear
changes bearing the features of so-called
“O rphan A nnie” nuclei. T he lesions pre­
sented as focal, ill-defined areas display­
in g c ells w ith c le a r n u c le a r featu res
w ith in o th e rw is e w e ll-c irc u m s c rib e d
adenom atous nodules, or as small clus­
ters of cells show ing the characteristic
clear nuclear changes random ly adm ixed
w ith th e H a sh im o to ’s e le m e n ts . T h e
nuclei in all cases w ere characterized by
51 9
their prom inent m argination of chrom a­
tin against the nuclear m em brane im part­
ing them w ith an optically clear appear­
ance. A dditional features suggestive of
papillary carcinom a that w ere also seen
in these areas included nuclear grooves,
pseudonuclear inclusions, focal overlap­
ping of nuclei, and in two cases, small
papillary formations lined by cells w ith
prom inent clear nuclear features.
Interestingly, two of our cases show ed
focal areas com posed of large, d istended
follicles lin e d by fo llicular cells w ith
optically clear nuclei rem iniscent of the
m acrofollicular variant of papillary carci­
noma,23 further highlighting the resem ­
blance of these lesions w ith papillary car­
cinoma. A nother in teresting finding in
our study was the presence of w ell-cir­
cum scribed nodules com posed of follicu­
lar cells w ith clear nuclei in trabecular
arrangem ent separated by fibrocollage-
no u s stro m a th a t c lo s e ly r e s e m b le d
hyalinizing trab ecu lar adenom a.24 T he
latter entity has b e e n previously reported
in association w ith H T,25 as w ell as w ith
papillary carcinom a, leading to the sug­
gestion by some that the latter two may
be possibly related .26 Because of their
s tr ik in g tr a b e c u la r a n d r ib b o n - lik e
arrangem ent, such lesions may also sim u­
late m edullary carcinom a of the thyroid.
Im m unohistochem ical stains for calcito­
nin and CEA, how ever, w ere negative in
both of the lesions in our study.
The role of clear nuclear features in
papillary carcinom a has gained increas­
ing im portance as a major histologic cri­
terion for the diagnosis of this type of
neoplasm .26,27,28,29 A num ber of variants
of papillary carcinom a have b e e n recog­
nized in w hich the papillary architecture
is either absent or inconspicuous, yet a
firm d iag n o sis is g e n e ra lly a c h ie v e d
through the recognition of their distinc­
tive clear nuclear changes.23,26,27,28,29,30
D espite the u n d o u b ted validity of the
id e n tif ic a tio n o f th e c h a r a c te r is tic
nuclear changes for the diagnosis of pap­
520 BERHO AND SUSTER
illary carcinom a, the hazard of overread­
ing a biopsy containing such changes has
also b een underscored.
In a study by H apke and D eh n er,31
optically clear nuclei indistinguishable
from those seen in papillary carcinom a
w ere identified in a case of Graves dis­
ease and in a benign follicular adenoma.
T he authors therefore cautioned against
the use of clear nuclei as an absolute cri­
terion for the diagnosis of papillary car­
cinom a, a n d su g g ested th at w h en the
character of th e clear n u clear changes
was in question, other features such as
papillae w ith overlapping nuclei, psam-
moma bodies, and m ultifocality m ust be
sought. B ecause of the focal nature of the
changes seen in our cases as w ell as the
uneventful follow-up in our patients, it is
our b e lie f that these findings should be
separated from clinically significant pap­
illary carcinom a. It is of interest, how ­
ever, th at in three of our cases (cases 1,
2, and 11), th e areas o f clear n u clear
changes w ere also associated w ith small,
w e ll-c irc u m s c rib e d n o d u le s e n tire ly
com posed of cells w ith clear nuclear fea­
tures that w ere m orphologically indistin­
guishable from small, or m inute papillary
carcinomas. This finding raises the possi­
bility that the nuclear changes observed
in these cases may represent a preneo­
plastic stage that will eventually give rise
to the d e v e lo p m en t of papillary carci­
noma, as has b een previously suggested.3
The p rese n t study shows that thyroid
fo llicu lar e p ith e liu m in p atien ts w ith
H ash im o to ’s thy ro id itis m ay ex h ib it a
range of clear nuclear changes and other
featu res such as n u c le a r grooves and
p seudonuclear inclusions that are com­
m only associated w ith papillary carci­
noma. Such findings, w hen interpreted
out of context m ay 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 se p ara te th em from fu ll­
blow n papillary carcinom a included the
focal nature of the process, w hich was for
the m ost part seen as an incidental m icro­
scopic finding, the absence o f psam m om a
bodies, the lack of strom al scarring or
fibrosis, and the lack of infiltration into
surrounding structures in any of the cases
studied. T he etiology of this phenom e­
non rem ains unclear.
T h e u n e v e n tfu l c lin ic a 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 H ashim o­
to ’s th y roiditis does not req u ire a d d i­
tio n a l ag g ressiv e tre a tm e n t. W h e th e r
these changes represent another form of
response to the im m une injury in H T or
w h eth er they represent an early precur­
sor stage of papillary carcinom a rem ains
to b e d e te rm in e d . In any e v e n t, th e
presence of focal clear nuclear changes
against a background of H T should w ar­
ra n t a c o n se rv a tiv e a p p ro a c h by th e
pathologist. Study of additional sections
to define the extent of the process is in d i­
cated, and specific m ention of the focal
nature and the m icroscopic extent of the
findings should be relayed to the clini­
cian to avert the possibility of un n eces­
sary aggressive treatm ent.
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