2009, Volume 25, Number 1, Page(s) 038-044
Follicular-patterned thyroid lesions
F. Fulya KÖYBAŞIOĞLU1, Özgür İlhan ÇELİK1, Nuray Güneri TOSUNOĞLU2, Binnur ÖNAL1, Ayşegül ADABAĞ1
1TC SB Ankara Dışkapı YB Eğitim ve Araştırma Hastanesi, 1. Patoloji Bölümü Sitopatoloji Ünitesi, ANKARA, TÜRKİYE
2Gazi Üniversitesi, Ticaret ve Turizm Eğitim Fakültesi Bilgisayar Uygulamaları Eğitimi, ANKARA, TÜRKİYE
Keywords: Follicular lesion, thyroid, cytopathologic criteria, cerebriform nucleus, fine needle aspiration cytology
Our aim is to determine the minimal cytopathologic
criteria needed to make differential diagnosis in
follicular-patterned lesions of the thyroid gland.
Materials and Methods: We reviewed 56 fine needle
aspiration cytology specimens which were reported as
“suspicious for follicular-patterned lesions of thyroid”
between years 2001 and 2005 in our hospital and their
histological slides. Parameters for cytopathologic assesment
are cellularity, colloid formation, multilayered
rosette formation, follicular cell rings, monolayered
sheets, intact follicles, hyperplastic papillae, hyaline
stromal fragments, intranuclear inclusions, nuclear
grooves, angulated nuclei, nucleoli, cerebriform nuclei,
nuclear size, macrophages, flame cells and Hurthle
cells. Statistical analysis was performed using χ2 and
Fisher's-exact tests and Kolmogorov-Simirnov test.
Results: Four cytopathologic features–cerebriform
nuclei, angulated nuclei, nuclear grooves and intranuclear
inclusion- were constantly observed in the follicular
variant of papillary carcinoma (p< 0.05). Diluted
colloid, monolayered sheet, nuclear size, macrophage
and nucleoli were frequently seen in nodular hyperplasia
(p< 0.05). The nuclear size was the sole differential
cytopathologic criteria between follicular adenoma and
follicular carcinoma (p<0.05).
Conclusion: Detailed cytopathologic examination was
found to be important in differentiating follicular variant
of papillary carcinoma from nodular hyperplasia.
On the other hand, none of the cytopathologic findings
were sufficient to distinguish follicular adenoma from
follicular carcinoma. Therefore, cytopathologists should
report such lesions as “follicular neoplasms”.
Fine needle aspiration cytology (FNAC)
of thyroid nodules has been proved to be reliable primary diagnostic tool in the diagnosis of
. However, follicular
neoplasms are at grey zone4
among various follicular-patterned lesions of
the thyroid including nodular hyperplasia, follicular
variant of papillary carcinoma, follicular
adenoma, and follicular carcinoma, is the main
area of diagnostic difficulty4,5,6
. The purpose
of this study was to determine the minimal cytological
criteria needed to make differential diagnosis
in follicular-patterned lesions of the thyroid
The cytological samples for this study
were obtained by a retrospective computerized
search of all our thyroid FNAC reports. A total
of 4080 thyroid FNAC were performed in the
Cytology Unit and Radiology Department of
our hospital between April 2001 and December
2005. Among them, cytology was benign in
2711 (66.45 %), malignant in 46 (1.13 %) and
nondiagnostic in 1098 (26.91 %) patients. These
groups were excluded from our study. Two
hundred twenty five (5.51%) specimens were
evaluated as suspicious cytology (diagnosis) for
follicular-patterned lesions of the thyroid (descriptive
diagnosis). Histopathological follow-up
was available for 56 (24.8%) cases which were
operated in our hospital which also constituted
the study group. Histopathological diagnoses of
these 56 cases were nodular hyperplasia (NH)
(n=29, 51.8%), follicular adenoma (FA) (n=13,
23.2%), follicular variant of papillary carcinoma
(FVPC)(n=9, 16.1%) and follicular carcinoma
(FC) (n=5, 8.8 %).
Thyroid fine needle aspirations were
performed by (cyto)pathologists and radiologists
using 22-27 gauge needles attached to 10
ml plastic syringes. (Cyto)pathologists used
Cameco syringe holders (Cameco, Sweden) in
order to fix the syringe, and prepared both airdried
and wet-fixed (95% ethanol) smears
Radiologists smeared the aspirated materials directly on clean glass slides and let them airdry.
The air-dried smears were stained with May
–Grünwald Giemsa (MGG) and the alcoholfixed
smears with Papanicolaou (PAP) and
Hematoxylene-Eosin (HE) solutions.
The parameters for cytological assessment
included cellularity, the presence of colloid,
multilayered rosettes (a form of ring lined by
stratified follicular cells), follicular cell rings
(small follicular groups of follicular cells from 6
to 12 are arranged as a ring with or without a
small amount of central colloid ), monolayered
sheets, intact follicles (consisted of spheres of
colloid surrounded by nuclei imparting a threedimensional
appearance), hyperplastic papillae
(Hp) (papillary cellular structures containing
intact- nonintact follicles), hyaline stromal fragments,
intranuclear inclusions (INI), nuclear
groove (NG), angulated nuclei, nucleoli, cerebriform
nuclei, nuclear size, macrophages, flame
cells and Hurthle cells (Figure 1,2,3,4).
Click Here to Zoom
|Figure 1: Hyaline stromal fragment attached to epithelial cells
(May Grünwald Giemsa x100).
The presence of these cytomorphological
features was scored ranging from 0 to 2.
[(for colloid: 0, none; 1, watery; 2, globularropy)
(for the nuclear size-comparison to a red
blood cell- 1, 2; 2, >x2) (for the other cytomorphological
features: 0, absent; 1(mild),
<50% of that case; 2 (High), >50% of that
case)]. Hypocellular slides were excluded in this
study, as they were ‘nondiagnostic'. Other available
data such as patients' age, gender and
nodule size were also considered.
The statistical methods used included χ2
analysis and Fisher's exact test and Kolmogorov-
Simirnov Test (α=0.05).
Age of the patients ranged from 19 to
66 years with median of 42 years, and 18%
(n=10) of the cases were male and 82% (n=46)
of them were female. The cytological features,
which were found to be statistically significant,
are shown in Table 1.
Click Here to Zoom
|Table 1: Histopathological diagnosis according to criteria
which were found statistically significant.
The cytological findings, which were
found to be statistically significant, in defining
nodular hyperplasia, are absence of angulated
(n=28, 68.3%) and cerebriform (n=29, 58%)
nuclei, small nuclear size (nuclear size 2, 3 and
4). The presence of a follicular cell ring, flame
cells, Hurthle cells, hyperplastic papillae, hyaline
stromal fragments and intact follicules did
not appear to have any importance in cytological
diagnosis of NH.
Click Here to Zoom
|Table 2: Results of Fisher's Exact Test for follicular-patterned
Cerebriform nuclei (n=6, 100%) and
angulated nuclei (n=9, 60%) (p<0.05) were the
most important diagnostic cytological features
for FVPC cases as well as the presence of INI
(n=4, 66.7%) and nuclear grooves (n=6, 37.5%)
(p<0.05) (Table 2 and 4). Cellularity, nuclear
size, the presence of follicular cell rings, colloid,
flame cells, Hurthle cells, hyperplastic papillae,
hyaline stromal fragments, intact follicules,
macrophages, monolayered sheets, multilayered
rosettes and nucleoli were not found to be diagnostic
for FVPC (p>0.05).
In FA cases, the only significant cytological
feature was the nuclear size (>x2 of a red
blood cell, n=9, 37.5%) (p<0.05) (Table 2). The
presence of follicular cell ring, colloid, flame
cells, Hurthle cells, hyperplastic papillae, hyaline
stromal fragments, INI, intact follicules,
macrophages, monolayered sheets, multilayered
rosettes, nuclear grooves or nucleoli was not statistically significant (p>0.05).
In case of FC, we could not define any
statistically significant cytological diagnostic
criteria for, but nodule size, which is a clinical
parameter, was found more significant than the
Fine needle aspiration cytology of the
thyroid has been a standard procedure in the
preoperative examination of patients for many
years. This procedure is recommended by most
of the guidelines1,2,3,6,7,8
. Fine needle aspiration
should be the first test to be ordered in an
euthyroid patient with a palpable thyroid nodule9,10
. Most cytopathologists follow a “cytological
classification” which is usually divided
into 4 categories: inadequate cytology, benign
lesion, suspicious lesion for malignancy, and
malignant lesion. Sometimes “a doubtful (suspicious)
lesion” or “follicular neoplasm favouring
benign or malignant” can be added as a fifth
. Thyroid FNAC is indeterminate in
5-42% patients who later has established diagnoses
of atypical, follicular lesion, follicular
neoplasm, or suspicious for malignancy6,11
Indeterminate diagnoses can lead to repeat aspiration
or surgical excision12
. One important
limitation is its inability to differentiate certain
percentage of follicular lesions6,12,13,14,15
Deshpande et al. have used the term
follicular neoplasm in FNAC of the thyroid for
hyperplastic nodules, follicular adenomas and
follicular carcinomas due to difficulty in differentiating
these three lesions by FNAC16.
The accuracy rate of a definitely malignant
diagnosis with thyroid FNAC has been
shown to range between 90 and 100%; however,
only the up to 20% of the cases diagnosed as
“follicular neoplasms” were reported as malignant
on the examination of the surgical excision
materials12,14. The goal of thyroid FNAC is
to identify the nodules that require surgery and
to decrease the number of unnecessary thyroidectomies
for patients with benign disease15,17.
Among 4080 FNAC samples, 225
(5.51%) of them were diagnosed as “suspicious
cytology for follicular patterned lesions”. Fifty
six of two hundred and twenty five cases
(24.88%) underwent surgical excision.
Histopathological diagnoses of these 56 cases
were malignant in 14 (25%) and benign in 42
(75%) cases. Among the benign lesions, 29
(1.8%) were nodular hyperplasia, and 13 (23.2%)
were follicular adenomas. These findings were
similar to those of Baloch et al. where 9 nodules
(69%) were benign, and 4 nodules (31%) were
malignant18. Greaves et al. reported an excision
rate of 41%, with 67 benign lesions (70%)
and 29 malignancies (30%)6.
Baloch et al. reported that nodules of 3
cm or greater were commonly associated with
malignancy12. In our study, the size of the FC
nodules was greater than all other follicularpatterned
lesions, but the size of the nodules in
FAs was greater than the nodules of FVPC
We found that that the most significant
distinguishing features of nodular hyperplasia
different from other follicular-patterned lesions
were diluted colloid (73,3%), monolayered sheets
(76.0%), smaller nuclear size (
For the (cyto)pathologist, diagnosis of a
benign lesion is based on the following criteria
(that may be applied to a solitary nodule as well
as a multinodular thyroid gland): an average
number of cells, abundant colloid, the lack of
follicular architecture or a very discrete microfollicular
architecture, the absence of anisokaryosis
and marked hyperchromatism, the lack of
nucleolar hypertrophy, and sometimes a few
fibroblasts and a variable number of histiocytes8.
Hag et al. reported that NH was histologically
characterized by the presence of hyperplastic
papillae. Hyperplastic papillae were easily
recognised in cell blocks and less readily in
smears1. But Kung et al. reported their presence
in only 8% of the smears from the cases
of NH19. In our materials, hyperplastic papillae
were detected in 66,7% of smears of NH, but
this was not statistically significant (p>0,05).
The occurrence rate of Hp in FVPC was found
out to be 25%. This value was similar to that
found by Hag et al. They reported the incidences
of hyperplastic papillae and colloid in FVPC as
25% and 75%, respectively1. But Hp should
not be accepted as a definitive sign of benignity.
Overlapping nature of these features made the
differentiation of FVPC from NH rather difficult.
Other features frequently encountered in
NH were follicular cell rings, flame cells,
Hurthle cells, hyaline stromal fragments, intact
follicules and less frequently INI, NG and angulated
nuclei (Table 1).
The FVPC is the most common cause
for false-negative FNA results. The presence of
abundant colloid, monolayer sheets, and paucity
of nuclear features of papillary carcinoma caused
Cytological findings such as colloid,
multilayered rosettes, follicular cell rings, monolayered
sheets, hyperplastic papillae, hyaline
stromal fragments, nuclear groove- even present
focally- are important clues to identify FVPC11. The diagnosis of FVPC is solely dependent
on the nuclear features (oval, enlarged, overlapped nuclei with optically clear or ground-glass
appearance and frequent grooves and pseudoinclusions)20. The characteristics of optically
clear nuclei of papillary carcinoma may be caused
by the alteration of chromatin associated
with RET/PTC oncogene, enhanced by formalin
fixation artefact and are not seen in cytological
specimens, except when processed with Ultrafast
In our study, the presence of cerebriform
nuclei, angulated nuclei, nuclear grooves,
intranuclear inclusions was statistically highly
significant (p<0,05) in differentiation of papillary
carcinoma folliculary variant from follicular
neoplasm. Additionally, we found out that
the presence of cerebriform cells in FVPC (100
%) is very important, as they have been described
a little in this neoplasm previously in the
Wu et al. reported that the cytological
diagnosis of FVPC could be difficult because of
the paucity of nuclear changes of papillary carcinoma
and overlapping features of both benign
and malignant follicular lesions20. In some
cases, cytological interpretation of FVPC may
also be difficult owing to the paucity of nuclear
features of papillary carcinoma, and can be mistaken
as hyperplastic nodules. Baloch et al.
diagnosed such lesions as suggestive of papillary
carcinoma and recommended intraoperative
frozen section and touch preparation for definitive
In FNA of FVPC, the most consistent
low-power architectural finding is the presence
of flat syncytial sheets. Flat syncytial sheets in
FVPC often branch with nuclear crowding and
are different from flat sheets of colloid nodule,
which usually form a honeycomb pattern20.
In our study, monolayered sheets were present
in12% of FVPC.
In our study, the only significant cytological
feature was the nuclear size (>x2 of a red
blood cell) for FA. Other cytological criteria
were not statistically significant. El Hag et al.
reported that FA showed none of the aforementioned features. They were always moderately
cellular, usually devoid of colloid and demonstrated
rings and round to ovoid crowded clusters
of follicular cells1. Similar results were also
reported by Das et al.12.
The assessment of detailed cytological
findings of follicular-patterned thyroid lesions
was helpful in differential diagnosis between
follicular variant of papillary carcinoma and
nodular hyperplasia. We think that the presence
of cerebriform nucleus in FVPC is very important.
Differentiation among various follicularpatterned
lesions of thyroid will decrease the
number of unnecessary surgeries. Additionally,
cytological findings are not sufficient enough to
distinguish follicular adenoma from follicular
carcinoma. Therefore, (cyto)pathologists should
continue to indicate these lesions as “follicular
neoplasms” in fine-needle aspiration cytology
reports of the thyroid.
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