ORIGINAL RESEARCH
Most Thyroid Cancers Detected by
Sonography Lack Intranodular
Vascularity on Color Doppler Imaging
Review of the Literature and Sonographic-Pathologic Correlations for
698 Thyroid Neoplasms
Grace C. H. Yang, MD, Karen O. Fried, MD
Received March 12, 2016, from the Department
of Pathology and Laboratory Medicine, Weil
Cornell Medicine–New York Presbyterian
Hospital, New York, New York USA
(G.C.H.Y.); and Lenox Hill Radiology, New
York, New York USA (K.O.F.). Revised
manuscript accepted for publication April 11,
2016.
A portion of the study was presented as
platform SSC09-08 at the Radiological Society
of North America Annual Meeting; November
29, 2015; Chicago, Illinois.
Address correspondence to Grace C. H.
Yang, MD, Papanicolaou Cytology Laboratory,
Weil Cornell Medicine–New York Presbyterian
Hospital, 525 E 68th St, Suite 766, New York,
NY 10065 USA.
E-mail: gry2001@med.cornell.edu
Abbreviations
FNA, fine-needle aspiration; FTC, follicular
thyroid carcinoma; PTC, papillary thyroid
carcinoma
doi:10.7863/ultra.16.03043
C 2016 by the American Institute of Ultrasound in Medicine | J Ultrasound Med 2017; 36:89–94 | 0278-4297 | www.aium.org
V
Objectives—This study investigated the controversy of whether hypervascularity on
color Doppler sonography correlates with thyroid malignancy by reviewing the liter-
ature and sonographic-pathologic correlation.
Methods—Over a 20-year period, 698 thyroid nodules had color Doppler and his-
topathologic data. Intranodular vascularity was graded 0 to 31, and histopathologic
findings were recorded.
Results—The data were collected from 698 patients (557 women and 141 men) with
a mean age of 48 years (range, 16–87 years). Of the 698 neoplasms, 425 were malig-
nant (mean size, 1.7 cm; range, 0.4–9 cm; 150 1 cm), and 273 were benign. The car-
cinomas included 391 papillary, 12 H€urthle cell, 9 medullary, 6 follicular, 5 poorly
differentiated, and 2 anaplastic. The grading of intranodular vascularity was 0 in 63.3%,
11 in 12.9%, 21 in 6.6%, and 31 in 17.4%. Among thyroid carcinomas, follicular car-
cinoma and the encapsulated subtype of the follicular variant of papillary carcinoma
had significantly higher intranodular vascularity than the rest (P < .0001). Benign neo-
plasms included 226 follicular adenoma/adenomatoid nodules (mean size, 3.2 cm;
range, 1.2–8.0 cm), 42 H€urthle cell adenoma/adenomatoid nodules (mean size,
2.6 cm; range, 0.8–5.5 cm), and 5 hyalinizing trabecular adenomas (mean size, 2.4 cm;
range, 0.6–6.0 cm; 4 1 cm). The grading of intranodular vascularity was 0 in 6.9%,
11 in 12.1%, 21 in 2.6%, and 31 in 78.4%. Intranodular hypervascularity was associ-
ated with adenoma/adenomatoid thyroid nodules, whereas a lack of vascularity was
related to thyroid carcinomas (P < .0001).
Conclusions—Most sonographically detected thyroid cancers lack intranodular vas-
cularity, and most hypervascular thyroid nodules are adenoma/adenomatoid nod-
ules, the encapsulated subtype of the follicular variant of papillary carcinoma, or
follicular carcinomas.
Key Words—color Doppler; fine-needle aspiration; head and neck ultrasound;
intranodular vascularity; thyroid neoplasm; thyroid sonography
n 2004, Foschini et al1 demonstrated a network of blood vessels
I that formed the core of papillae in 8 papillary thyroid carcinomas
(PTCs; mean size, 4.5 cm) in a 3-dimensional reconstruction
study from surgical specimens. In 2000, Gritzmann et al2 stated that
thyroid carcinomas are centrally vascularized lesions, and cystic PTC
contained a hypervascular mural nodule. However, in a study of 17
Yang and Fried—Most Thyroid Cancers Lack Intranodular Vascularity on Color Doppler
cases of cystic PTC with grayscale sonographic and
Doppler correlation, most of the mural nodules had
minimal or no vascularity.3
There has been controversy4 over whether thyroid
cancers have increased intranodular vascularity on color
Doppler imaging: more vascularity in 10 studies5–14
(comprising a sum of 186 cancers, 547 adenomas, and
705 goiters); no difference in 6 studies15–20 (comprising
a sum of 421 cancers, 393 adenomas, and 100 goiters);
and less vascularity in 2 studies,21,22 plus this study
(comprising a sum of 719 cancers, 402 adenomas, and
774 goiters). In 2010, Moon et al22 reported that most
of the 269 thyroid cancers (comprising 99.25% PTCs
with a mean size of 1 cm and 24% microcarcinomas)
were avascular. In the same year, on the basis of a meta-
analysis of 457 follicular neoplasms from 4 stud-
ies,6,9,10,12 Iared et al23 concluded that predominant
internal flow on color Doppler sonography is associated
with malignancy in follicular neoplasms, and the absence
of internal flow or predominately peripheral flow indi-
cates a low probability of malignancy in follicular neo-
plasms. Similarly, in another meta-analysis of 284
malignant nodules with 13% follicular thyroid carcino-
mas (FTCs) from 31 studies, Brito et al24 reported that
increased internal vascularity was more predictive of
malignancy in follicular neoplasms. The American Thy-
roid Association guidelines attributed this controversy
over the correlation of intranodular hypervascularity
with thyroid malignancy to the percentages of FTCs in
different studies.25 Follicular carcinomas accounted for
less than 1% in the study that showed no such correla-
tion22 and 10% to 22% in the studies6,9,10,12 and meta-
analysis that showed a correlation.23 In contrast to PTC,
a tumor rich in lymphatic vessels with lymph node
metastasis, FTC is rich in blood vessels with hematoge-
nous metastasis.26
In an analysis of literature with data specific to intra-
nodular vascularity, the percentages of FTCs and the
number and size of malignant nodules were noted. The
size of malignant nodules ranged from a mean of 1.0 cm
from the study by Moon et al22 to 3.5 cm from the study
by Miyakawa et al.11 The composition of malignant nod-
ules in different studies was variable. The percentages of
FTCs ranged from 0.75% in the study by Moon et al22
to 100% in 3 studies.9–11 The composition of benign
nodules was also variable. Some studies included only
adenomas, whereas other studies also included goi-
ters.6,7,13–16,22 Adenomas typically are vascular, whereas
90
goiters typically are avascular. The purpose of this study
was to investigate this controversy by reviewing color
Doppler studies in the literature as well as cases collected
over the past 20 years during on-site assessments by the
first author.
Materials and Methods
Patients
This study was a retrospective interpretation of prospec-
tively acquired data. Ultrasound-guided fine needle aspi-
rations (FNAs) were done by an on-site cytopathologist
in 2 private radiology offices in Manhattan, with patients
referred by endocrinologists, thyroid surgeons, and gen-
eral practitioners. Patients’ consent for follow-up was
obtained before FNA, and they were informed of the
preliminary results immediately. Thyroidectomies were
performed in different hospitals in New York City. All
data were deidentified before the study and thus exempt
from the Internal Review Board.
Ultrasound-Guided FNA
From 1995 to 2006, the radiologists in office A used a
27-gauge needle attached to a 10-mL syringe with 3 mL
of suction, guided by a 10–5-MHz compact linear array
probe on an HDI 3000 ultrasound system (Philips
Healthcare, Bothell, WA). From 2006 to the present,
the radiologists in office B sampled with a 27-gauge nee-
dle without suction, guided by a 15–7-MHz linear array
probe with a small footprint on an iU22 ultrasound sys-
tem (Philips Healthcare, Andover, MA). The needle tip
was echogenic and could be followed while watching the
monitor; thus, a large nodule with different echogenic
appearances could be sampled by the radiologist thor-
oughly, and a mural nodule within a cyst likewise could
be sampled. The FNA team consists of 3 members: a
radiologist, a registered medical diagnostic sonographer,
and a cytopathologist.27
Color Doppler Studies
Color Doppler examinations were performed by using
the standard equipment settings for thyroid glands.
Doppler amplification was set at a level at which normal
thyroid tissue displayed no noise and just under the level
at which random noise appeared.
On-site Cytopathologic Assessments
Aspirated material was expelled onto a glass slide, and an
oval smear was made and dried under a heating lamp.
J Ultrasound Med 2017; 36:89–94
 Yang and Fried—Most Thyroid Cancers Lack Intranodular Vascularity on Color Doppler

The first air-dried smear was stained with Diff-Quik Statistical Analyses
(Dade Behring, Newark, DE) for assessment of the The Fisher exact test and Pearson v2 text were used to
background and cellularity. If the first smear had abun- analyze the categorical variables. P < .05 was considered
dant colloid and few cells, then the second smear was statistically significant. Stata/IC version 14.1 software
also stained with Diff-Quik. If the first smear was bloody, (StataCorp, College Station, TX) was used to perform
atypical, suspicious, or cellular, the second air-dried statistical analyses.
smear was rehydrated and hemolyzed in saline and
stained with the ultrafast Papanicolaou (UFP) stain28 for Results
assessment of nuclear and architectural features. Since
most thyroid nodules are filled with colloid, the ultrafast We observed 698 thyroid nodules from 698 patients
Papanicolaou stain was performed only in a minority of (557 women and 141 men) with a mean age of 48 years
cases. The ultrafast Papanicolaou stain was performed (range, 16–87 years). As shown in Table 1, there were
on-site before 2006 and in the cytology laboratory after 273 benign neoplastic nodules, including 226 follicular
2006. adenoma/adenomatoid nodules (mean size, 3.2 cm;
range, 1.2–8.0 cm), 42 H€urthle cell adenoma/adenoma-
Data Collection toid nodules (mean size, 2.6 cm; range, 0.8–5.5 cm),
The sonographic findings, including the size of the nod- and 5 hyalinizing trabecular adenomas (mean size,
ule and detailed grayscale and color Doppler data, were 1.8 cm; range, 0.6–3.2 cm). The 425 malignant nodules
documented at the time of the FNA procedure in a File- measured 0.4 to 9.0 cm (mean, 1.7 cm), and 150
Maker Pro database (FileMaker, Inc, Santa Clara, CA) (35.3%) were microcarcinomas (1 cm). The
on a laptop computer and incorporated into FNA
reports. Histologic follow-ups were obtained from differ- Table 1. Comparison of the Intranodular Vascularity of 698
Thyroid Neoplasms on Color Doppler Sonography
ent hospitals by the cytopathologist.
Intranodular Vascularity, n (%)
Inclusion Criteria Type 0 (288) 11 (88) 21 (35) 31 (287) P
The study included cytologic reports for follicular neo- Benign (273) 19 (6.9) 33 (12.1) 7 (2.6) 214 (78.4) <.0001
plasms, H€urthle cell neoplasms, neoplasms that were Malignant 269 (63.3) 55 (12.9) 28 (6.6) 73 (17.2) <.0001
suspicious for the follicular variant of PTC, PTC, medul- (425)
lary carcinoma, and anaplastic carcinoma (ie, Bethesda Pearson v2(6) 5 263.5834; P <.0001; Fisher exact test P <.0001.
categories 4–6). Nodules with nondiagnostic, benign,
and atypical cytologic findings (ie, Bethesda categories
1–3) or cytologic findings without histologic follow-ups Table 2. Comparison of the Intranodular Vascularity and
were excluded from the study. Deep-seated thyroid nod- Histopathologic Subtypes of 425 Malignant Thyroid Nodules on
ules were also excluded because of inaccessibility by Color Doppler Sonography
color Doppler imaging. Only the index nodule that led Intranodular Vascularity
to surgery was included; thus, a single nodule was Histopathologic
Subtype 0 (269) 11 (54) 21 (29) 31 (73)
included for each patient. Hospital cases that the first
author reported during the study period were excluded, Anaplastic carcinoma (2) 2 0 0 0
Poorly differentiated 2 2 0 1
including 271 thyroid carcinomas and 97 adenoma/
carcinoma (5)
adenomatoid nodules. FTC (6) 0 1 1 4
Medullary carcinoma (9) 7 1 1 0
Color Doppler Grading €rthle cell carcinoma (12)
Hu 2 3 2 5
The grading was focused on the intensity of color within Encapsulated PTC, 7 4 6 34
follicular variant (51)a
the nodule. Peripheral vascularity and vascularity pat- Remaining PTC (340) 249 43 19 29
terns were excluded from the study. Intranodular vascu- 2
Pearson v (21) 5 163.9191; P <.0001; Fisher exact test P <.0001.
larity was graded as follows: 0, avascular or minimally a
Encapsulated carcinoma had significantly higher intranodular
vascular; 11, mildly vascular; 21, moderately vascular; vascularity than the remaining papillary carcinomas (Pearson
and 31, highly vascular. v2(6) 5 263.5834; P <.0001).

J Ultrasound Med 2017; 36:89–94 91

Yang and Fried—Most Thyroid Cancers Lack Intranodular Vascularity on Color Doppler

intranodular vascularity was significantly higher in carcinomas; 12 were H€urthle cell carcinomas; 51 were
benign neoplastic nodules than malignant nodules. As the encapsulated follicular variant of PTC; and 340 were
shown in Table 2, among the 425 malignant thyroid the remaining PTCs, including the infiltrative follicular
nodules, 2 were anaplastic carcinomas; 5 were poorly dif- variant, classic variant, cystic variant, tall cell variant, hob-
ferentiated carcinomas; 6 were FTCs; 9 were medullary nail variant, solid variant, diffuse sclerosing variant,
cribriform-morular variant, and Warthin-like variant.
Table 3. Comparison of the Intranodular Vascularity of Papillary Of the malignant nodules, 31 intranodular vascu-
Microcarcinomas and Larger Carcinomas, Excluding the larity was present in 4 of 6 (66.7%) FTCs and 34 of 51
Encapsulated Subtype of the Follicular Variant (66.7%) encapsulated follicular variants of PTC. In con-
Intranodular Vascularity, n (%) trast, 249 of 340 (73.2%) of the remaining PTCs had
Size (340) 0 (249) 11 (43) 21 (19) 31 (29) P grade 0 vascularity. The encapsulated follicular variant of
1 cm (150) 131 (87.3) 10 (6.7) 2 (1.3) 7 (4.7) <.0001
PTC had significantly higher intranodular vascularity
>1 cm (190) 118 (62.1) 33 (17.4) 17 (8.9) 22 (11.6) <.0001 than the remaining PTCs. As shown in Table 3, signifi-
cantly less intranodular vascularity was found in papillary
Pearson v2(3) 5 28.2671; P <.0001; Fisher exact test P <.0001.
microcarcinomas than larger PTCs only after the

Figure 1. Intranodular vascularity grading on color Doppler and representative tumors. Grade 0: PC, circumscribed FV (1.6 cm); PC, hobnail v
(1.4 cm); PC, subcapsular sclerosing FV (1 cm); and PC, infiltrative FV (0.5 cm). Grade 1: PC, solid variant (0.9 cm); PC, cribriform morular v
(3.1 cm); and FC, minimally invasive (3 cm). Grade 2: PC, encapsulated FV (1.3 cm); Hu €rthle cell carcinoma (4.6 cm); and FC, angioinvasive
(3.3 cm). Grade 3: follicular adenoma (2.5 cm); hyalinizing trabecular adenoma (2.2 cm); and FC, widely invasive (3.2 cm). FC indicates follicular
carcinoma; FV, follicular variant; PC, papillary carcinoma; and v, variant.

92 J Ultrasound Med 2017; 36:89–94

 Yang and Fried—Most Thyroid Cancers Lack Intranodular Vascularity on Color Doppler
encapsulated subtype of the follicular variant of PTC
had been excluded from the calculation.
Representative tumors and intranodular vascularity
are shown in Figure 1: grade 0, 4 examples of PTC;
grade 1: 2 examples of PTC and a minimally invasive
FTC; grade 2: an encapsulated follicular variant of PTC,
a H€urthle cell carcinoma, and an angioinvasive FTC;
and grade 3: a follicular adenoma, a hyalinizing trabecu-
lar adenoma, and a widely invasive FTC.
Discussion
Previous studies were from the perspective of radiolog-
ists; this study was from the viewpoint of an on-site cyto-
pathologist, who has worked closely with radiologists for
20 years and possesses the knowledge of the 2 gray
zones of thyroid pathology:
1. It has been shown that up to 70% of adenomatoid
nodules have clonal proliferation29 and can express
various markers of malignant follicular-derived thy-
roid tumors such as RAS and PPAR-g.30 Tradition-
ally, follicular adenoma is strictly defined as solitary
and completely encapsulated, If a solitary microfol-
licular thyroid nodule is incompletely encapsulated,
or there are more than 1 completely encapsulated
microfollicular nodules in the thyroidectomy speci-
men, all would be reported as “nodular goiter” by
the traditional pathologists. Adenomatoid nodules
share the same grayscale and color Doppler sono-
graphic characteristics as follicular adenomas and
are the main cause of discrepant histologic findings
in thyroid FNA specimens reported as follicular
neoplasms.31 Therefore, adenomatoid nodules were
counted as benign neoplasms in this study.
2. Papillary thyroid carcinomas have many variants and
subtypes.32 The molecular profile and biological
behavior of the encapsulated subtype of the follicular
variant of PTC are similar to those of FTC, with
hematogenous metastasis to lung and bone, whereas
those of the infiltrative subtype of the follicular vari-
ant of PTC are similar to those of classic PTC with
lymph node metastasis.33,34 Therefore, the encapsu-
lated subtype of the follicular variants of PTC was
counted as a separate entity in this study.
Intranodular hypervascularity was more frequent in
malignant thyroid nodules larger than 1 cm than in
J Ultrasound Med 2017; 36:89–94
malignant nodules of 1 cm or smaller in a study by
Hong et al.35 Similarly, in our study, the intranodular
vascularity of papillary microcarcinomas, excluding the
encapsulated subtype of the follicular variant, was signifi-
cantly less than that of larger PTCs.
Our study differed from the study by Moon et al22 in
that nodular goiters were excluded, and mean cancer size
was 1.7 cm versus 1.0 cm in their study. The previous
studies included different patterns of color flow (spotty,
short lines, branching, and tortuous) and different distri-
butions of color flow (peripheral only, peripheral and
central, and central only), whereas our study focused on
the area of the tumor covered by the color flow.
The limitation of this study was that only 1 pathologist
and 1 radiologist participated in the study. Further studies,
separating FTC and the encapsulated follicular variant of
PTC from the remaining thyroid cancers, are necessary to
verify our findings and address the issue of interobserver
variability among radiologists as well as whether the color
Doppler results apply to power Doppler imaging.
In conclusion, most sonographically detected thy-
roid cancers lack intranodular vascularity, and most
hypervascular thyroid nodules are adenoma/adenoma-
toid nodules, the encapsulated subtype of the follicular
variant of PTC, or follicular carcinomas. Color Doppler
imaging is a valuable tool for the study of thyroid nod-
ules. The absence of intranodular color flow reinforces
suspicious grayscale features, such as a hypoechoic
appearance, blurred margins, microcalcifications, and a
taller-than-wide shape. A “spoke-and-wheel like” periph-
eral and central pattern of branching color flow, which is
typical of follicular adenomas, can predict exceedingly
bloody aspirates and alert the need for a cell concentra-
tion step to avoid nondiagnostic FNAs.32
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