Mixed echoic thyroid nodules on ultrasound: approach to management.

Abstract

To evaluate malignancy risk according to ultrasound (US) features and size change on follow-up US in mixed echoic thyroid nodules and to suggest management guidelines thereof.
Among patients who underwent US-guided fine needle aspiration biopsy, 316 mixed echoic nodules in 303 patients were included after excluding the patients with pure solid or cystic nodules or without further cytopathologic evaluation. We evaluated malignancy risk according to US features and changes in size and shape on follow-up US.
The malignancy rate was 31.6% (6 of 19) for nodules with suspicious US features and 2.7% (8 of 297) for nodules without suspicious US features (p<0.001). Among 265 nodules with no suspicious US features and initial benign cytology, 15 nodules with suspicious US change and decreased size, 25 nodules with no suspicious US change and increased size, and 225 nodules with no suspicious US change and no change in size were observed on follow-up USs. The malignancy risk thereof was 0%, 0% and 0.4%, respectively (p=1.000).
Mixed echoic nodules with no suspicious US features and benign cytology can be followed up using US, as they revealed very low malignancy rates, even if they showed growth on follow-up US.

Full text

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Yonsei Med J http://www.eymj.org Volume 53 Number 4 July 2012
812
Original Article
http://dx.doi.org/10.3349/ymj.2012.53.4.812
pISSN: 0513-5796, eISSN: 1976-2437
Yonsei Med J 53(4):812-819, 2012
Mixed Echoic Thyroid Nodules on Ultrasound:
Approach to Management
Yu-Mee Sohn,1 Jung Hyun Yoon,2 Hee Jung Moon,3 Eun-Kyung Kim,3 and Jin Young Kwak3
1Department of Radiology, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul;
2Department of Radiology, CHA Bundang Medical Center, CHA University College of Medicine, Seongnam;
3Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea.
Received: August 24, 2011
Revised: September 9, 2011
Accepted: September 21, 2011
Corresponding author: Dr. Jin Young Kwak,
Department of Radiology,
Research Institute of Radiological Science,
Yonsei University College of Medicine,
50 Yonsei-ro, Seodaemun-gu,
Seoul 120-752, Korea.
Tel: 82-2-2228-7400, Fax: 82-2-393-3035
E-mail: docjin@yuhs.ac
∙ The authors have no financial conflicts of
interest.
© Copyright:
Yonsei University College of Medicine 2012
This is an Open Access article distributed under the
terms of the Creative Commons Attribution Non-
Commercial License (http://creativecommons.org/
licenses/by-nc/3.0) which permits unrestricted non-
commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Purpose: To evaluate malignancy risk according to ultrasound (US) features and
size change on follow-up US in mixed echoic thyroid nodules and to suggest man-
agement guidelines thereof. Materials and Methods: Among patients who under-
went US-guided fine needle aspiration biopsy, 316 mixed echoic nodules in 303
patients were included after excluding the patients with pure solid or cystic nod-
ules or without further cytopathologic evaluation. We evaluated malignancy risk
according to US features and changes in size and shape on follow-up US. Results:
The malignancy rate was 31.6% (6 of 19) for nodules with suspicious US features
and 2.7% (8 of 297) for nodules without suspicious US features (p<0.001).
Among 265 nodules with no suspicious US features and initial benign cytology,
15 nodules with suspicious US change and decreased size, 25 nodules with no sus-
picious US change and increased size, and 225 nodules with no suspicious US
change and no change in size were observed on follow-up USs. The malignancy
risk thereof was 0%, 0% and 0.4%, respectively (p=1.000). Conclusion: Mixed
echoic nodules with no suspicious US features and benign cytology can be fol-
lowed up using US, as they revealed very low malignancy rates, even if they
showed growth on follow-up US.
Key Words: Mixed echoic thyroid nodules, fine needle aspiration biopsy, ultra-
sound
INTRODUCTION
Many thyroid nodules are incidentally detected in daily clinical practice, and they
are present in nearly 50% of adults, increasing in prevalence with age;1 however,
less than 5% of those nodules are malignant.2 Cystic thyroid nodules represent 15-
53.8% of all surgically excised thyroid nodules,3-7 including true or simple thyroid
cysts, with an epithelial lining, and mixed nodules with a predominantly fluid
component.2,6 Among them, cystic thyroid nodules which are thyroid nodules
characterized by the presence of both solid and cystic components and are referred
to as “mixed echoic thyroid nodules”,8 have been regarded as benign lesions that
can be managed conservatively in the past.9,10 However, the percentage of malig-

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cords. However, informed consent for US-FNAB was ob-
tained from all patients before conducting the procedure.
From March 2006 to February 2007, 953 thyroid nodules in
868 consecutive patients underwent US-FNAB at our institu-
tion (a referral center) in Seoul, Korea. Among them, 580
nodules were excluded because they were either pure solid
(n=576) or cystic nodules (n=4). Patients who met the fol-
lowing criteria upon review of their medical records, includ-
ing cytologic and histopathologic results, were included in
this study: 1) underwent thyroid surgery, 2) at least two be-
nign cytologic results, and 3) benign results on initial cyto-
logic results with no interval change or decrease in size at
follow-up US after at least 12 months. Forty nodules were
excluded owing to increase in size on follow-up US without
further cytopathologic evaluation after demonstrating benign
results on initial cytology. Seventeen nodules were also ex-
cluded because of lack of subsequent surgery after either
papillary thyroid carcinoma (PTC) (n=2), suspicion of PTC
(n=1), and indeterminate (n=1) or lack of subsequent surgery
or follow-up FNAB after demonstrating inadequate results
(n=13) on initial cytology. In total, this study included 316
mixed echoic nodules in 303 patients (Fig. 1). The mean age
of the patients as a whole was 49.1 years (range, 16-80
years); the mean age of the male patients was 51.6 years
(range, 21-72 years), and the mean age of the female patients
was 49 years (range, 16-80 years). The mean size of the thy-
roid nodules was 20 mm (range, 4-76 mm).
nancy among these mixed echoic nodules has been report-
ed from 2% to 18%,2,4,6-8,11 however, these nodules often
show non-diagnostic or inadequate cytologic result due to
scant or no follicular cells, owing to the cystic portion,2,12
which is a challenge in managing these nodules with fine
needle aspiration biopsy (FNAB).13
Repeated FNAB or surgery is advised for nodules that in-
crease in size during follow-up.14-18 However, these mixed
echoic nodules can increase in size upon follow-up ultra-
sound (US) by cystic degeneration,3,4 or sometimes they are
decreased in size and demonstrate newly suspicious US fea-
tures after FNAB by reduction of cystic portion.19 Until
now, the management of mixed echoic thyroid nodules has
not been firmly established, nor has a concrete study thereon
been reported, to the best of our knowledge. The aim of this
study was to evaluate the risk of malignancy, according to
initial US features, US changes, or changes in size on fol-
low-up US, in mixed echoic nodules and to suggest guide-
lines for managing these nodules.
MATERIALS AND METHODS
　　　
Study population
Our institutional review board approved this retrospective
observational study, and required neither patient approval,
nor informed consent for review of patient images and re-
Fig. 1. Diagram of the study population. non-op, without operation; Op, with operation; FNA, fine needle aspiration.
Non-op
(n=2)
Malignant
(n=6)
Op
(n=4)
Non-op
(n=1)
Suspicious
(n=9)
Op
(n=8)
Non-op
(n=1)
Indeterminate
(n=1)
Mixed echoic nodules
(n=373)
Selected nodules
(n=953)
Mixed echoic nodules
(n=316)
Malignant
(n=14)
F/U US
(n=152)
FNA
(n=123)
Benign
(n=338)
Benign
(n=302)
Op
(n=23)
Without
F/U (n=40)
FNA
(n=4)
Inadequate
(n=19)
Excluded nodules with pure solid or cystic
composition (n=580)
Op
(n=2)

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814
ule. Also, we defined newly developed suspicious US fea-
tures as a transition from being probably benign on initial US
to suspiciously malignant on follow-up US after FNAB.

Cytologic evaluation
FNAB was performed by a single radiologist after US evalu-
ations of thyroid glands for either thyroid nodules with suspi-
cious US features or the largest nodule present if no suspi-
cious malignant US features were detected. FNAB was
conducted with the patient in the supine position with the
neck extended using a 23-gauge needle (Korea Vaccine,
Seoul, Korea) attached to a 20 mL disposable plastic syringe
(Kovax-Syringe, Korea Vaccine) and an aspirator under US
guidance with a free hand technique. Each lesion was aspi-
rated at least twice. All cystic fluid was aspirated as much as
possible from the cystic portion of the nodules and then
FNAB was performed on the solid portion of the nodules. If
complete aspiration was not possible in the thick cystic con-
tents of thyroid nodules, FNAB was directly conducted on
the solid portion of the mixed echoic nodules. Materials ob-
tained from FNAB were smeared on glass slides, which were
immediately placed in 95% alcohol for Papanicolau staining,
and the remaining material in the syringe was rinsed in saline
for processing as a cell block. A cytologist was not on site
during the biopsy. Cytology samples were sent to the pathol-
ogy department and the results were reported by 1 of 5 cyto-
pathologists in an official report form. Additional special
staining was performed on a case-by-case basis following the
discretion of the cytopathologist. Cytological results were
classified as into one of the following two categories: “ade-
quate” or “inadequate” for interpretation. A specimen was
considered as “adequate” if there was a minimum of six
groupings of well-preserved thyroid cells consisting of at
least ten cells per group.23 The “adequate” group was divided
into four subgroups: “benign”, “indeterminate”, “suspicious
for PTC”, and “PTC”. “Benign” cytology included colloid
nodules, nodular hyperplasia, lymphocytic thyroiditis, Graves’
disease, and postpartum thyroiditis. “Indeterminate” cytology
included follicular and Hürthle cell neoplasm. “Suspicious for
PTC” cytologic results were defined when the specimen ex-
hibited cytological atypia, but showed insufficient cellularity
for definite diagnosis of PTC. Cytologic results were desig-
nated as “PTC” when specimen revealed abundant cells with
definite cytological features of malignancy.24
Reference standards
Malignant nodules were confirmed by surgery or FNAB,
Imaging and image analysis
US was performed with an 8- to 15-MHz linear array trans-
ducer (Acuson Sequoia; Siemens Medical Solutions, Moun-
tain View, CA, USA), a 7- to 15-MHz linear array transducer
(HDI 5000; Philips Medical Systems, Bothell, WA, USA), or
a 5- to 12-MHz linear array transducer (iU22; Philips Medi-
cal Systems). Compound imaging was obtained in all images
with HDI 5000 or iU22 machines. Real-time US imaging
was performed by one of three radiologists with 11, 9, and 7
years of experiences in thyroid imaging who were aware of
the patients’ clinical background. US images were indepen-
dently reviewed by each of two radiologists dedicated to thy-
roid imaging (K.J.Y. and S.Y.M. with 9 and 3 years of expe-
rience). Each thyroid nodule was described according to US
features as devised in a previous report.20 We defined the cys-
tic nodules, as designated in previous studies,2-6,13,21,22 as
mixed echoic nodules comprising solid and cystic compo-
nents.8 These mixed echoic nodules were evaluated based on
their internal solid components. Echogenicity of the solid
portion was categorized as hyperechoic (for nodules showing
hyperechogenicity compared to the normal thyroid), isoecho-
ic (for nodules showing isoechogenicity compared to the
normal thyroid), hypoechoic (for nodules showing hy-
poechogenicity compared to the normal thyroid), or marked-
ly hypoechoic (for nodules showing hypoechogenicity com-
pared to the adjacent strap muscle). Margins of the nodules
were classified as either well-circumscribed, microlobulated,
or irregular. The degree of calcification was categorized as
microcalcification (punctate echogenic foci of 1 mm or less),
macrocalcification (punctate echogenic foci larger than 1 mm
in size or eggshell calcification), mixed calcification (micro-
calcification combined with eggshell or macrocalcification)
or negative (no calcification). Nodule shape was categorized
as wider than tall or taller than wide. US groupings of thyroid
nodules were classified as probably benign or suspiciously
malignant in these nodules, using the sonographic criteria
suggested by Kim, et al.20 Malignant sonographic character-
istics were defined as microcalcification, irregular or microl-
obulated margins, markedly hypoechogenicity, and taller
than wide shape. A suspiciously malignant nodule was de-
fined as a nodule showing one or more of the suspicious
findings presented above. If a nodule showed no suspicious
features, it was classified as probably benign. We evaluated
the changes in size and shape of the thyroid nodules on fol-
low-up US in this study. We categorized nodules as being in-
creased in size when its maximum diameter increased by
more than 3 mm,21 irrespective of the initial size of the nod-

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or patient request (n=71), growth at follow-up US (n=26),
suspicious US features (n=25) and newly developed suspi-
cious features with decreased size at follow-up US (n=5).
The mean interval between initial and follow-up FNAB was
23.3 months (range, 3-51 months). Follow-up US was per-
formed in 152 nodules and the mean interval between initial
and follow-up US was 30.9 months (range, 10-58 months).

Correlations of risk of malignancy according to US
features and size change on follow-up US
Of the 316 nodules, there were 19 (6%) nodules with suspi-
cious US features and 297 (94%) nodules with no suspicious
US features. The rate of malignancy was 31.6% (6 of 19) for
thyroid nodules with suspicious US features and 2.7% (8 of
297 nodules) for those with no suspicious US features. There
was significant difference between US grouping of thyroid
nodules and the rate of malignancy (p<0.001).
Among thyroid nodules with initially benign cytology
(n=298), the malignancy rate of thyroid nodules assessed as
having suspicious US features was 7.7% (1/13) while those
with no suspicious US features was 1.1% (3/285) (p=0.164).
Of thyroid nodules (n=275) with initial benign cytology that
underwent follow-up US or FNAB, there were 26 nodules
of increased size with a mean size of 5.8 mm (from range
of 8-76 mm to the range of 12-81 mm), 156 nodules with
no change in size and 93 nodules with decreased size. There
were no thyroid nodules observed with suspicious change
and growth. Of these nodules (n=275) with initial benign
cytology that underwent follow-up US or FNAB, 265 thy-
roid nodules had no suspicious US features, while 10 had
suspicious US features. Among the 265 thyroid nodules with
no suspicious US features and benign results on initial cy-
tology, there were 15 nodules with suspicious US change
and decreased size (Fig. 2), 25 with no suspicious US change
and increased size (Fig. 3) and 225 with no suspicious US
change as well as no change or decrease in size on follow-
up US. The likelihood of a nodule being benign based on
standard reference was 100% (15 of 15) in the group of nod-
ules with suspicious US change and decreased size, 100%
(25 of 25) in the group with no change in shape and increased
size, and 99.6% in the group with no change in shape and
size or decreased size (224 of 225), respectively. Therefore,
the risk of malignancy was 0%, 0% and 0.4%, respectively,
showing no statistical difference among the three groups
(p=1.000).
Of six thyroid nodules with inadequate cytology (two con-
firmed by surgery and four by repeat FNAB), there was no
while benign nodules were confirmed as benign if they were
classified as benign at both initial and follow-up FNAB,
upon surgery, or if the nodules either decreased or showed
no interval change at follow-up US at least 12 months (mean,
30.7 months; range, 12-58 months) after being classified as
benign on FNAB.
Statistical analysis
We used a χ2-test to determine differences between malignant
and benign nodules according to categorical variables. We
also evaluated the differences between malignant and benign
nodules with continuous variables using an independent two
sample t-test. Statistical significance was assumed when the
p-value was less than 0.05. All reported p-values were two-
sided. Statistical analyses were performed by using SAS soft-
ware version 9.1 (SAS Institute Inc., Cary, NC, USA).

RESULTS

Final cytopathologic results
Of the 316 thyroid nodules, 14 (4.4%) were malignant and
302 (95.6%) were benign. The mean size of the malignant
nodules were 19.1±13.7 mm, showing no significant differ-
ences to the benign nodules (20.0±12.2 mm) (p=0.773).
The mean age (49.6±11.7 years) of the patients with benign
nodules was significantly older than that (40.5±12.5 years,
p=0.006) of the patients with malignant nodules. There were
no significant differences between benign and malignant
nodules according to gender (p=0.337).
Among total 316 nodules, there were 298 benign results:
8 suspicious for PTC, 4 PTC and 6 inadequate results ac-
cording to follow-up US or cytopathologic confirmation.
Thirty-seven nodules (11.7%) underwent surgery without
undergoing follow-up FNAB or US, for the following rea-
sons: cytologic results suspicious for PTC (n=8) and PTC
(n=4), large size nodules with inadequate (n=2) or benign
(n=14) cytology, and upon patient request (n=9). Among
those who underwent surgery, 13 were malignant and the
remaining 24 were benign.
The remaining 279 nodules underwent follow-up FNAB
or follow-up US after more than 12 months. The mean size
of the initial thyroid nodules was 19.7±11.7 mm (range, 4-76
mm) and the mean size of the nodules after follow-up US or
FNAB was 16.9±11.5 mm (range, 2-81 mm) (p<0.001) in
these 279 nodules. Follow-up FNAB was performed in 127
nodules. The grounds for follow-up FNAB were: clinician

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ular or microlobulated margins,17,20,30,34-38 hypoechogenici-
ty,17,20,29,30,34,37,38 marked hypoechogenicity,20,29 taller than wide
shape,17,20,39 microcalcification,17,20,30,36-38,40-42 solid composi-
tion17,36-38,43 and intratumoral vascularity.17,30,34,43 US findings
are also important for the discrimination of mixed echoic
thyroid nodules. The eccentric location of a solid mural
nodule,8,17,25,44 eccentric configuration with an acute angle of
the solid portion,25 its vascularity of the solid portion,40 and
the presence of microcalcification8,25,44 have been reported
as suspicious US features in mixed echoic nodules sugges-
tive of PTC.
We intended to evaluate the risk of malignancy according
to US features and US change or size change on follow-up
US in the mixed echoic nodules. The rate of malignancy was
31.6% for thyroid nodules with suspicious US features, sig-
nificantly higher in comparison to 2.7% nodules with no sus-
picious US features in this study. These results indicate the
importance of US features in differentiating benign from ma-
malignancy. Five of them showed no suspicious US fea-
tures, and one had suspicious US features. Four nodules
showed no suspicious US change with decreased size (n=2)
and no change in size (n=2). The remaining two nodules
underwent surgery without follow-up.
DISCUSSION
Mixed echoic nodules represent 15-53.8% of all surgical
excised thyroid nodules.3-7 They have been regarded as be-
nign nodules with a rare risk of malignancy and can be
managed conservatively.9,10 However, the incidence of ma-
lignancy in these mixed echoic nodules are reported as 2%
to 18%.2,4,6-8,11,25 Accordingly, the concrete assessment of the
management of these nodules is necessary. Discriminating
between benign and malignant thyroid nodules, many re-
ports17,20,26-33 described suspicious US features such as irreg-
Fig. 2. A 51-year-old woman with a thyroid nodule in the right thyroid on US. Initial FNAB revealed the nodule to be benign on cytology, and follow-up FNAB
after 1.5 year showed the same cytologic result. (A) Initial US shows a mixed echoic nodule (>50% cystic) (arrows). (B) On follow-up US, this nodule showed
decreased size and suspicious US changes including hypoechoic and microlobulated margins and taller-than wide shape (arrows). US, ultrasound; FNAB,
fine needle aspiration biopsy.
Fig. 3. A 56-year-old woman with a thyroid nodule in the right thyroid on US. Initial FNAB revealed the nodule to be benign on cytology, and follow-up FNAB
after 3 year showed the same cytologic result. (A) Initial US shows a mixed echoic nodule (< 50% cystic) (arrows). (B) On follow-up US, this nodule showed
increased size without change in shape (arrows). US, ultrasound; FNAB, fine needle aspiration biopsy.
A
A
B
B