GALECTIN-3 EXPRESSION IN PAPILLARY THYROID

CARCINOMA: RELATION TO HISTOMORPHOLOGIC GROWTH

PATTERN, LYMPH NODE METASTASIS, EXTRATHYROID
INVASION, AND TUMOR SIZE
Dubravka S. Cvejic, PhD,1 Svetlana B. Savin, PhD,1 Ivana M. Petrovic, MSc,1
Ivan R. Paunovic, MD, PhD,2 Svetislav B. Tatic, MD, PhD,3 Marija J. Havelka, MD, PhD3
1
Institute for the Application of Nuclear Energy – INEP, University of Belgrade, 11080 Zemun-Belgrade,
Banatska 31b, Serbia and Montenegro. E-mail: dubravka@inep.co.yu
2
Centre for Endocrine Surgery, Institute of Endocrinology, Diabetes and Diseases of Metabolism,
Clinical Center of Serbia, Belgrade, Serbia and Montenegro
3
Institute of Pathology, Medical Faculty, University of Belgrade, Serbia and Montenegro

Accepted 16 April 2005

Published online 9 September 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20276

invasion of PTC, thus being irrelevant clinically from this aspect.

Abstract: Background. Galectin-3 has been recently recog-
Galectin-3 is an excellent marker for classical PTC but must be
nized as a promising presurgical marker of thyroid malignancy.
used with caution in diagnosing unconventional variants of PTC
Methods. Galectin-3 expression was examined immunohis-
because of the possibility of false-negative results. A 2005 Wiley
tochemically in 202 specimens of papillary thyroid carcinoma
Periodicals, Inc. Head Neck 27: 1049 – 1055, 2005
(PTC) in relation to histomorphologic subtypes and clinicopatho-
logic data. Keywords: galectin-3; thyroid; papillary carcinoma; immunohis-
Results. The sensitivity of galectin-3 immunostaining versus tochemistry; tumor marker
conventional histology was 98% (100 of 102) for classical PTC,
85.2% (46 of 54) for follicular variant, and 50% (23 of 46) for
follicular/solid variant of PTC. All cases (n = 36) involving lymph
node metastases and 42 of 45 cases with extrathyroid invasion
expressed galectin-3. However, among the galectin-3 – positive A number of different substances have been
cases (n = 169), 133 were without lymph node metastases, and evaluated as potential molecular markers in the
127 were without extrathyroid invasion. Galectin-3 expression differential diagnosis of thyroid neoplastic le-
was not related to the size of intrathyroid PTC. sions. Among them, galectin-3 seems to be one
Conclusions. Galectin-3 immunohistochemical expression
of the most promising immunohistochemical
itself is not an indicator of local metastatic spread or extrathyroid
markers of thyroid malignancy.
Galectins are a family of lectin molecules
Correspondence to: D. Cvejic
endowed with a carbohydrate recognition domain
that specifically recognizes beta-galactosides.1
Contract grant sponsor: Supported by the Ministry of Science and Envi-
ronment Protection of the Republic of Serbia, project 1504 ‘‘Glycobio- Human galectin-3 is a 31-kDa protein constitu-
logical aspects of physiological and pathophysiological processes.’’ tively expressed by immune cells and several
B 2005 Wiley Periodicals, Inc. epithelial cells. Galectin-3 localization is domi-

Galectin-3 in Papillary Thyroid Carcinoma HEAD & NECK December 2005 1049
nantly cytoplasmic but also can be nuclear,
membranous, or extracellular, depending on the
cell type and physiologic conditions, which sug-
gests multifunctionality for this molecule.1 – 3
Because of its interactions with carbohydrate
and noncarbohydrate ligands, galectin-3 may
play a role in a wide spectrum of biologic and
pathologic processes, such as differentiation, cell
growth and apoptosis,4,5 cell adhesion,6 immune
response,7 mRNA splicing,8 neoplastic transfor-
mation,9,10 and metastatic processes.11
Altered expression of galectin-3 in human tu-
mors compared with their normal tissue coun-
terparts has been documented for many tumor
types (reviewed by Danguy et al9 and van den
Brule et al10). Thus, galectin-3 has been exten-
sively studied in thyroid tissue during the past
few years.12 – 31 These studies demonstrated im-
munohistochemical overexpression of galectin-3
in thyroid carcinomas, in both histologic sec-
tions 12 – 14,17,18,21 – 25,30,31 and cytologic speci-
mens,15,16,19,20,26,28 whereas its expression in
nonmalignant thyroid cells was absent or weak.
Therefore, galectin-3 was identified as a po-
tential presurgical immunohistochemical marker
for distinguishing benign from malignant thy-
roid tumors.
According to the dedifferentiation state, thy-
roid carcinomas originating from the epithelial
follicular cells are in general classified as fol-
lows: well-differentiated carcinomas (papillary
and follicular carcinomas) and poorly differenti-
ated carcinomas and undifferentiated (anaplastic)
thyroid carcinomas. All authors investigating
galectin-3 expression in thyroid tumors have
found the highest level of expression in well-
differentiated thyroid carcinomas and subse-
quent downregulation from poorly differentiated
toward undifferentiated carcinomas. Further-
more, different patterns of galectin-3 expression
were identified for each subhistotype of follicular
carcinoma, starting with a high level in the well-
differentiated subtype and ending with a low level
in the poorly differentiated follicular carcinoma
subtype.15,20 Interestingly, the highest level of
galectin-3 expression in the spectrum of malig-
nant thyroid tumors was found to be associated
with papillary tissue architecture (ie, with the
classical [papilliform] variant of papillary thy-
roid carcinoma [PTC]). However, PTC also oc-
curs in different histomorphologic variants.32 – 37
Whether galectin-3 expression varies in associa-
tion with the histologic growth pattern of PTC has
not been pointed out in previous studies.
1050 Galectin-3 in Papillary Thyroid Carcinoma
In this study, we addressed this issue by exam-
ining immunohistochemically galectin-3 expres-
sion in a series of 202 cases of paraffin-embedded
tissues of PTC in relation to the histomorphologic
growth pattern. In addition, because clinical data
were available for this relatively large series of
PTC, immunostaining results were also correlated
with the occurrence of lymph node metastases,
extrathyroid invasion, and tumor size.
MATERIALS AND METHODS
Patients and Tissue Specimens. Formalin-fixed,
paraffin-embedded tissues from 202 surgically
removed PTCs were used for this immunohisto-
chemical analysis. Tumors were selected from the
archival material of the Institute of Endocrinol-
ogy, Diabetes and Metabolism, Clinical Center
of Serbia, Belgrade. Histologic slides from the
thyroid tumor tissue stained by hematoxylin-
eosin were reevaluated by two pathologists (S.
T. and M. H.) to confirm the diagnosis, according
to widely accepted histologic criteria32 – 35 and to
subclassify the variants of papillary carcinomas.
Nuclear features (ground glass nuclei, grooved
nuclei, and nuclear pseudoinclusions, at least two
of them), regardless of the growth pattern, were
taken as the ‘‘gold standard’’ for confirming the
diagnosis of papillary carcinoma. Selected papil-
lary carcinoma cases included different histologic
variants, and we divided them into three main
categories according to the histologic growth
pattern: (1) classical PTC with papillary archi-
tecture (CL-PTC, 102 cases), (2) follicular variant
of PTC (FV-PTC, 54 cases), and (3) follicular
variant of PTC including areas with a solid
growth pattern (FV/SOLID-PTC, 46 cases).
Information concerning age, sex, lymph node
metastases involvement, extrathyroid invasion,
and tumor size was retrieved by reviewing the
pathology reports. The patients included 169 fe-
males and 33 males (ratio, 5:1), ranging from 10
to 72 years old, with an average age of 46 years.
The tumor size ranged from 2 mm to 10 cm. With
regard to tumor size, the cases were divided into
groups (T1– T4) according to the TNM classifi-
cation of thyroid tumors38: T1, <10 mm; T2,
10 – 40 mm; T3, >40 mm (T1 –T3 = intrathyroid);
and T4, extension outside the thyroid capsule (ie,
extrathyroid invasion). In 36 cases, lymph node
metastases (LNM) were present at the time of
surgery, and extrathyroid invasion (EI) was pres-
ent in 45 cases. No patient had distant metastatic
disease at the time of original diagnosis.
HEAD & NECK December 2005
Immunohistochemistry. A rat monoclonal anti-
body (M3/38) against galectin-3, produced by
ATCC TIB-166 (American Type Culture Collec-
tion, Rockville, MD) was kindly provided by
Dr. M. E. Huflejt, La Jolla Institute for Allergy
and Immunology, San Diego, CA. The same anti-
body was used in our previous reports on galectin-
3 expression in thyroid tissue.14,18,27
Immunostaining was performed on 4- to 6-Am
thick sections using the avidin-biotin-peroxidase
complex (ABC) technique with reagents supplied
by Vector Laboratories (Burlingame, CA).
After deparaffinizing and rehydrating, endog-
enous peroxidase activity was blocked with 0.3%
H2O2/methanol followed by nonimmune horse se-
rum for 20 minutes to block nonspecific binding.
The sections were then incubated with pri-
mary antibody against galectin-3 at 4jC over-
night at a dilution of 1:200. This was followed by
incubation with biotinylated horse anti-mouse
immunoglobulin G (IgG) (which also cross-reacts
with the primary rat antibody) for 30 minutes and
thereafter with the ABC reagents for 30 minutes.
Between each step, sections were washed three
times in phosphate-buffered saline (PBS). The re-
action was visualized using 3, 3V-diaminobenzidine
tetrahydrochloride (DAB) solution.
After counterstaining with hematoxylin, slides
were dehydrated, cover-slipped, and examined
using a Reichart – Jung microscope supplied with
a Photostar automatic camera system (Cam-
bridge Instruments, Buffalo, NY). Controls were
incubated with PBS in place of the primary
antibody, and no positive staining was observed.
The internal positive control was represented
by histiocytes.
Scoring of Staining and Statistical Data. Staining
was scored as follows: (
), no staining, (+), weak
or focal staining, and (++), moderate to strong
staining in most epithelial thyroid cells.
The sensitivity of galectin-3 immunohisto-
chemistry in confirming the diagnosis of PTC
versus classical histologic analysis (taken as the
‘‘gold standard’’) was calculated as follows: true
positive/true positive + false negative.
The efficiency of galectin-3 immunodetection
in distinguishing LNM-positive versus LNM-
negative cases and EI-positive versus EI-negative
cases, respectively, was evaluated by calculating
the sensitivity, specificity, and diagnostic accu-
racy. Specificity was defined as (true negative/
true negative + false positive), and diagnostic
accuracy was defined as (true positive + true
Galectin-3 in Papillary Thyroid Carcinoma
negative)/(true positive + false positive + true
negative + false negative).
Statistical comparisons of data were per-
formed with Student’s t test. A value of p < .05
was considered to be statistically significant.
RESULTS
When present, normal or hyperplastic thyroid
epithelial cells adjacent to malignant tissue of
papillary carcinoma showed no immunoreactivity
for galectin-3.
The results of galectin-3 immunohistochemical
staining of PTC tissue are given in Tables 1 – 3,
and some representative photographs are shown
in Figure 1.
As shown in Table 1, positive immunohisto-
chemical staining for galectin-3 was found in 169
(83.7%) cases of PTC of the 202 cases analyzed
in this study. Intensity of staining varied from
moderate/strong to weak or focal. Galectin-3 lo-
calization was dominantly cytoplasmic but also
membranous or nuclear in some cells. Galectin-
3 could not be detected immunohistochemically
in 33 cases, which means that we obtained 33
false-negative results. Thus, the sensitivity of
galectin-3 immunohistochemistry versus conven-
tional histology was 83.7% for the overall series of
PTC cases analyzed.
However, apparent differences in galectin-3
immunostaining results were found in relation to
the histologic growth pattern. The highest level of
galectin-3 expression was associated with the
group of classical papilliform PTC cases (CL-
PTC), in which 100 of 102 cases (98.0%) showed
positive galectin-3 immunostaining (moderate
to strong or weak/focal, as detailed in Table 1),
whereas only two cases were negative (2.0%),
giving 98.0% sensitivity for galectin-3 immuno-
staining. In the FV-PTC group, 46 of 54 cases
showed galectin-3 positive immunostaining, and
eight cases were galectin-3 negative (sensitivity,
85.2%). Furthermore, in the FV/SOLID-PTC
group, galectin-3 was not detected in 23 (50%)
cases, giving a sensitivity of galectin-3 immuno-
staining of only 50%. Statistically significant
differences in the sensitivity of galectin-3 immu-
nohistochemistry were found between the FV/
SOLID-group and the FV and CLV groups of PTC
cases ( p < .05).
In addition, galectin-3 immunostaining of PTC
cases was correlated with available clinical data.
Galectin-3 expression in relation to LNM and EI
is shown in Table 2. All 36 cases involving LNM
HEAD & NECK December 2005 1051
 Table 1. Galectin-3 immunostaining in PTC in relation to Table 3. Galectin-3 immunostaining* in PTC in relation to
histologic growth pattern. tumor size (Ty).

Galectin-3 immunostaining* Staining intensity

PTC histologic Positive Negative
growth pattern ++ +
Sensitivity ++ + (++/+), totalz (
), total
CL-PTC 92 8 2 98.0%y T1 (n = 60) 33 (55.0%) 14 (23.3%) 47 (78.3%) 13 (21.7%)
(classical (90.2%) (7.8%) (2.0%) T2 (n = 83) 57 (68.7%) 13 (15.7%) 70 (84.3%) 13 (15.7%)
papilliform) T3 (n = 14) 8 (57.1%) 2 (14.3%) 10 (71.4%) 4 (28.6%)
(n = 102)
*Staining was scored as follows: (
) no staining, (+) weak or focal
FV-PTC 35 11 8 85.2%z staining, and (++) moderate to strong staining in the majority of thyroid
(follicular (64.8%) (20.4%) (14.8%) epithelial cells.
variant) yAccording to Hermanek and Sobin.38 Details in ‘‘Material and Methods.’’
(n = 54) zDifferences not statistically significant (p > .05) for T1 vs T2, T2 vs T3 and
T1 vs T3.
FV/SOLID-PTC 12 11 23 50.0%§
(follicular (26.1%) (23.9%) (50.0%)
variant with
solid areas) (n = 36) LNM involvement. The diagnostic ac-
(n = 46) curacy of galectin-3 immunodetection in distin-
Total (n = 202) 139 30 33
guishing LNM-positive from LNM-negative cases
(68.8%) (14.9%) (16.3%)
Positive: 169 Negative: 33 83.7% was only 34.2%.
(83.7%) (16.3%) Galectin-3 immunostaining in PTC in relation
Abbreviations: PTC, papillary thyroid carcinoma; CL-PTC, classical
to EI of PTC is also shown in Table 2. Galectin-3
papillary thyroid carcinoma with papillary architecture; FV-PTC, follicular was immunohistochemically detected in 42 of
variant of papillary carcinoma; FV/SOLID-PTC, follicular variant of 45 cases (93.3%) with EI (sensitivity, 93.3%) and
papillary carcinoma including areas with a solid growth pattern.
*Staining was scored as follows: (
) no staining, (+) weak or focal in 127 of 157 cases (80.9%) without EI (specificity,
staining, and (++) moderate to strong staining in the majority of thyroid 19.1%). Thus, in a similar way to LNM involve-
epithelial cells.
Note. p < .05 for § vs y and vs z.
ment, galectin-3 expression itself did not indicate
the presence of EI. The diagnostic accuracy of
galectin-3 immunodetection in distinguishing
were galectin-3 positive (sensitivity, 100%). In the PTC cases with and without EI was only 35.6%.
group of PTC cases without LNM, there were 133 Galectin-3 immunoexpression was also corre-
(80.1%) cases showing galectin-3 positivity and 33 lated with the tumor size of PTC. The cases were
(19.9%) cases negative for galectin-3 immunos- divided into four groups (T1– T4), as detailed in
taining (specificity, 19.9%). Although it seemed ‘‘Material and Methods.’’ Group T4 (extension
that higher levels of galectin-3 expression were beyond the gland), consisting of the cases with EI,
associated with primary tumors involving LNM, was analyzed in Table 2. Table 3 shows galectin-3
galectin-3 expression itself did not indicate local expression in relation to the size of intrathy-
metastatic spread of PTC, because among the roid PTC (groups T1 – T3). There were no signifi-
total of 169 cases expressing galectin-3 there cant differences in galectin-3 expression among
were more cases without (n = 133) than with groups T1, T2, and T3, which indicates that
galectin-3 is not associated with the size of intra-
thyroid PTC.
Table 2. Galectin-3 immunostaining* in PTC in relation to lymph
node metastases and extrathyroid invasion.
DISCUSSION
LNM (+) LNM (
) EI (+) EI (
)
(n = 36) (n = 166) (n = 45) (n = 157) During the past few years, galectin-3 has been
widely investigated as a potential immunohisto-
Galectin-3 positive 36 133 42 127
(+/++), number
chemical marker of thyroid malignancy.12 – 31
Galectin-3 negative 0 33 3 30 Because of its high expression in thyroid carcino-
(
), number mas and the absence or weak expression in
Sensitivity, % 100.0 93.3 normal and benign thyroid tissue, the findings
Specificity, % 19.9 19.1 indicate the diagnostic value of galectin-3 immu-
Diagnostic accuracy, % 34.2 35.6
nohistochemistry in distinguishing benign from
Abbreviations: PTC, papillary thyroid carcinoma; LNM, lymph node malignant thyroid tumors.
metastases; EI, extrathyroid invasive.
*Positive staining: strong to moderate (++) and weak/focal (+); negative
The highest levels of galectin-3 immunohisto-
staining: absence of staining. chemical expression are associated with papillary

1052 Galectin-3 in Papillary Thyroid Carcinoma HEAD & NECK December 2005
FIGURE 1. Immunohistochemical expression of galectin-3 in papillary thyroid carcinoma (PTC) in relation to histologic growth pattern
(indirect immunoperoxidase, hematoxylin-diaminobenzidine). Strong cytoplasmic immunostaining for galectin-3 in a classical variant of
PTC (A and B). Strong positivity for galectin-3 in a follicular variant of PTC (C). Moderate positivity for galectin-3 (D) and negative
immunostaining for galectin-3 (E) in follicular/solid variants of PTC. Original magnifications: A, 10; B and C, 20; D and E, 40. [Color
figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

architecture of thyroid carcinoma. PTC is defined of galectin-3 immunohistochemistry versus con-

from the histologic features (essentially papillary
growth pattern intermingling with a follicular
growth pattern to various degrees), cytologic
features (ground glass nuclei, grooved nuclei,
and intranuclear inclusions), and biologic behav-
ior (slow growth and propensity to metastasize to
lymph nodes).32 – 37 The follicular variant is the
most common subhistotype of PTC. In addition,
some PTCs also contain focal areas of a more
cellular, solid growth pattern. According to widely
accepted histologic criteria,32 – 35 PTC is solely
defined by its characteristic nuclear features
regardless of its growth pattern. However, some-
times PTC shows a multifocal rather than a
diffuse distribution of nuclear features and can
mimic hyperplastic nodule or follicular adenoma
of the thyroid.
In previous studies on galectin-3 expression in
thyroid tumors, galectin-3 was found to be ex-
pressed in all or almost all PTCs. The sensitivity
ventional histology was reported to be in the
range of 92% to 100%, with the exception of one
study21 in which galectin-3 sensitivity for PTC
was found to be 82%. However, this type of thyroid
malignancy was mainly analyzed as part of a
spectrum of thyroid tumors, with the consequence
that in most studies a small number of PTC cases
were involved. Furthermore, it is not clear
whether the PTC cases analyzed included differ-
ent histomorphologic subtypes of PTC, because
that was not mentioned in these reports. Only the
group of LiVolsi23 noticed weaker galectin-3 ex-
pression in five of 15 cases of the follicular variant
of PTC versus classical PTC, whereas Weber
et al30 recently reported 100% sensitivity for
typical PTC, but the sensitivity for a follicular
variant of PTC was found to be 83%.
This is the first study focused on galectin-3
immunohistochemical expression in PTC in rela-
tion to different histologic growth patterns. Thus,

Galectin-3 in Papillary Thyroid Carcinoma HEAD & NECK December 2005 1053
we observed that galectin-3 expression varies in
relation to this parameter. In fact, our results
clearly show that galectin-3 is immunohistochem-
ically expressed at the highest levels in classi-
cal PTC with a papillary architecture, whereas
its expression is slightly decreased in the fol-
licular variant of PTC and further decreased
in the follicular variant of PTC including solid
growth pattern areas. Thus, although the sensi-
tivity of galectin-3 immunostaining for the clas-
sical and the pure follicular variant of PTC was
mainly similar to the values reported in previous
studies, the number of false-negative results in
FV/SOLID PTC variants included in this study
pointed to unsatisfactory sensitivity of galectin-3
immunostaining in confirming the conventional
diagnosis of PTC.
In this study, because the relatively large
series of PTC cases was collected together with
the clinical data, we also examined the associa-
tion of galectin-3 expression with LNM, EI, and
tumor growth. Although all the PTC cases
involving LNM and most cases presented with
EI (91.4%) were galectin-3 positive in this study,
we concluded that galectin-3 immunohistochem-
ical expression itself is not an indicator of local
metastatic spread or EI of PTC, because galectin-
3 immunopositivity was found in a larger propor-
tion of cases without LNM or EI involvement.
Thus, from the results of this study, we can-
not completely confirm the finding of Kawachi
et al,17 who reported that primary PTC tumors
involving LNM contained significantly higher
concentrations of galectin-3 than tumors without
metastases. In certain types of human tumors,
such as head and neck, gastric, and colon cancers,
the level of galectin-3 expression has been
positively correlated with tumor progression and
acquisition of metastatic capabilities, whereas in
contrast, in some tumors, such as breast, ovarian,
and prostate cancer, the expression of galectin-3
is inversely correlated with metastatic potential
(reviewed by Takenaka et al11). From the results
of this study, it could be suggested that galectin-3
immunohistochemical expression is not related to
aggressiveness (local metastatic spread or EI)
of PTC.
The suggestion for a possible role of galectin-3
in metastatic processes is based on its participa-
tion in cell adhesion,5,6,11 which requires galectin-
3 to be expressed on the cell surface. However, as
shown in this and previous studies, galectin-3
localization in thyroid tumor cells is dominantly
cytoplasmic, and only occasionally membranous
1054 Galectin-3 in Papillary Thyroid Carcinoma
or nuclear, suggesting other roles for galectin-3 in
thyroid tumor biology, such as proapoptotic
activity or regulation of the cell cycle (prolifer-
ative activity). In this work, galectin-3 expression
was not found to be related to the growth of
intrathyroid PTC, indicating that this protein
probably does not contribute to the proliferative
capacity of PTC. Further efforts using methods of
cell biology are required to explain the exact
function of galectin-3 in malignantly transformed
thyroid cells.
In summary, from the aspect of clinical prac-
tice, our results could be of importance, because
they indicate that galectin-3 immunohistochem-
istry is an excellent marker for the classical
papilliform variant of PTC, but not for the uncon-
ventional cases of PTC, which are a diagnostic
problem. In our opinion, galectin-3 immunohisto-
chemistry need not be used for easily diagnosed
cases of thyroid tumors (such as classical PTC
with papillary architecture, which is easily diag-
nosed by routine histopathologic analysis) but
primarily for doubtful cases as an aid to conven-
tional histologic diagnostics.
Acknowledgments. The authors are grateful
to Dr. M. E. Huflejt, La Jolla Institute for Allergy
and Immunology, San Diego, CA, for providing
the monoclonal antibody against galectin-3 and
to Dr. K. Krgovic, Center for Endocrine Surgery,
Institute of Endocrinology, Diabetes and Dis-
eases of Metabolism, Clinical Center of Serbia,
Belgrade, Serbia and Montenegro, for reviewing
the pathologic files.
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