Thyroid nodules are increasingly found incidentally on cross-sectional imaging studies performed for nonthyroid indications. The challenge is to diagnose the minority of malignant nodules while limiting the impact on the large majority of patients with benign nodules. This article reviews the epidemiology of thyroid cancer, the role of ultrasonography in the triage of thyroid nodules for biopsy, and areas of continuing controversy that require further research.
is an Assistant Professor of Radiology, and
is an Associate Professor of Diagnostic Radiology and the
Director of Sonography, Department of Diagnostic Radiology,
University of Maryland Medical Center, Baltimore, MD.
Thyroid nodules are extremely common. In a frequently cited
postmortem series, nodules were found in 50% of the study
Thyroid nodules are more prevalent with increasing age, but the
majority of these nodules are undetectable by physical examination.
Palpable nodules occur in 4% to 7% of the population; however,
high-resolution ultrasonography (US) reveals nodules as small as 2
mm in 35% to 67% of the general population.
In addition, thyroid nodules are increasingly found incidentally on
cross-sectional studies performed for nonthyroid indications.
Fortunately, the vast majority of these nodules are benign
(adenomas and adenomatoid nodules of multinodular goiters);
approximately 2% to 12% are found to represent malignancy upon
The diagnostic challenge is to efficiently and effectively diagnose
the minority of patients with thyroid malignancy, while limiting
the medical, emotional, and financial burden placed on the
overwhelming excess of patients with benign nodules.
Ultrasonography of the thyroid gland has emerged as an important
diagnostic tool in this process. Sonographic features of malignant
and benign thyroid nodules have been established, but these have
variable specificity and sensitivity. Nodules with highly
suspicious features (to be discussed below) should undergo
diagnostic fine-needle aspiration (FNA) prior to surgery. However,
a clear distinction between potentially malignant nodules that
require FNA biopsy and benign "leave alone" nodules is not always
feasible because of considerable overlap in the US features of
benign and malignant nodular thyroid disease. This article will
review the epidemiology of thyroid cancer, the role of US in the
triage of thyroid nodules for biopsy, and areas of continuing
controversy where specific research studies may further clarify
this complex subject in the future.
Clinical context of thyroid cancer
There are 4 main types of thyroid cancer: papillary, follicular,
medullary, and anaplastic. Papillary carcinoma accounts for the
majority, 80%, and follicular is the second most common type,
comprising 10% to 20% of cases. Medullary and anaplastic subtypes
are rare, with medullary carcinoma responsible for 3% to 5% and
anaplastic for 1% to 2% of thyroid cancers.
Patients with papillary and follicular cancers tend to present with
well-differentiated cancers that often do well after treatment,
despite the presence of metastases to cervical lymph nodes in 20%
to 50% of cases.
They are slow-growing and have a good prognosis with very low
mortality and recurrence rates at 30 years. The 30-year survival
rate for papillary cancer is approximately 95%.
In fact, autopsy reports have shown a high rate of clinically
occult thyroid cancer with small, incidental, papillary tumors
found in up to 13% of the U.S. population and 35% of the population
in some European countries.
In contrast, the clinical diagnosis of thyroid cancer is
relatively rare, constituting only 1% of new cancer diagnoses each
The discrepancy between occult thyroid cancer and clinically
diagnosed disease supports the long-recognized existence of a
subclinical form of thyroid cancer.
The incidence of clinical disease has rapidly increased over the
past 3 decades from a rate of 3.6 per 100,000 in 1973 to 8.7 per
100,000 in 2002.
Interestingly, this increase is predominantly due to a dramatic
increase in the diagnosis of small papillary cancers, and the
mortality rate from thyroid cancer has been unaffected over the
same period, remaining stable at approximately 0.5 deaths per
100,000. These findings suggest that the increasing incidence more
likely reflects improved detection of subclinical disease as the
use of thyroid US has become more widespread, rather than a rise in
the true occurrence of the disease.
Ultrasound in the evaluation of palpable and incidentally
found thyroid nodules
A thyroid nodule is a discrete lesion within the thyroid gland
that is sonographically distinguishable from the remaining
parenchyma. Thyroid nodules may present as a palpable finding on
physical examination; however, they are increasingly being
discovered as incidental findings on unrelated imaging studies,
such as neck or chest computed tomography (CT), cervical magnetic
resonance imaging (MRI), or carotid or parathyroid US (Figure 1).
In most instances, patients with incidentally found thyroid nodules
undergo US as the next step in their evaluation. Palpable nodules
have traditionally been evaluated clinically by the determination
of risk factors for thyroid cancer, such as neck irradiation and
family history, followed by thyroid function tests. If the nodule
is not hyperfunctioning, cytologic diagnosis is made by
endocrinologist-performed FNA biopsy, usually without imaging
guidance. However, as US has been shown to be more sensitive than
physical examination, patients with palpable nodules are now more
commonly also evaluated by US as a first step.
Ultrasound evaluation has the advantages of being able to
characterize the presenting nodule, evaluate the rest of the
thyroid for other nonpalpable nodules (often multiple) (Figure 2),
and can be used to guide percutaneous biopsies (Figure 3).
As a consequence of the increasing use of diagnostic imaging-US in
particular-we are in the midst of an epidemic of thyroid
The sonographic detection of thyroid nodules, and therefore
thyroid cancer, at a smaller size and a presumed earlier stage
raises the question of the clinical relevance of small thyroid
cancers and any decrease in morbidity and mortality afforded to the
patient. There have been no studies that have shown a clinical or
therapeutic advantage to finding thyroid cancer at a smaller size.
Are we truly helping patients when we diagnose small thyroid
cancers that in many cases might have remained clinically occult?
The answer to this question is difficult to determine because of
the ethical considerations and impracticality of performing a study
with nonoperative management of nodules with positive cytology.
Conversely, it is impractical to biopsy every incidentally found
thyroid nodule and all of the additional nonpalpable nodules found
by US in almost half of the patients with a palpable nodule.
In addition to the economic cost of thyroid US and FNA biopsies of
these hundreds of millions of nodules, the diagnosis of thyroid
cancer would increase dramatically, with additional economic costs
and morbidity associated with surgery, its complications, and any
potential adjuvant therapy. These issues highlight the need for a
practical, cost-effective and safe approach for the management of
thyroid nodules. Currently, US is the most effective imaging
modality used for evaluating nodules prior to FNA or surgery.
Which nodules should be biopsied?
The overall incidence of malignancy in patients with thyroid
nodules selected for FNA is between 9% and 13%, regardless of the
number of nodules present and regardless of whether the nodule is a
palpable or a nonpalpable incidental finding.
Ultrasound evaluation plays an important role in selecting which
nodules need to be biopsied. Many studies have sought to define US
features that may distinguish benign from malignant nodules. This,
however, has proved to be an elusive goal. While there are definite
US features that have been shown to be associated with thyroid
malignancy, several of these features are variably seen, and others
show a great deal of overlap with the US features of benign
nodules. Selecting which nodules to biopsy involves incorporating
an understanding of these US features, the classic patterns that
are seen in specific conditions, and the general recommendations
put forth by the Society of Radiologists in Ultrasound addressing
the issue of when to perform a biopsy. Additionally, the importance
of clinical context should not be underestimated.
When present, fine, nonshadowing echogenic foci representing
microcalcifications are highly indicative of papillary thyroid
cancer, with a specificity of 95% (Figures 4 and 5).
However, this finding has a low sensitivity (29% to 59%), since
microcalcification is often not present in malignant nodules.
Additionally, thyroid cancer may show a variety of other types of
calcification, including irregular coarse calcification (Figure 6)
and, rarely, peripheral "egg-shell" calcification (Figure
7)-calcification types that are more commonly seen in benign
nodules (Figure 8).
Microcalcification must be distinguished from the inspissated
colloid that may also appear as tiny echogenic foci. In
contradistinction to microcalcification, the presence of colloid is
a reliable indicator of benignity.
High-frequency US will demonstrate comet-tail or ring-down artifact
(Figures 9 and 10) with colloid, which is not seen with
Several other US features have been evaluated for their ability
to predict malignancy. A hypoechoic or anechoic rim encircling a
nodule, known as the halo sign (Figure 11), suggests benignity;
however, this sign may be absent in >50% of benign nodules and
present in up to 20% of malignant nodules.
Marked hypoechogenicity, an irregular margin, a shape that is
taller than wide, a solid composition, the absence of a halo, and
intranodular vascularity (Figures 1, 6, and 12) have been
identified as characteristics that are suggestive of malignancy.
Because of variable sensitivities and specificities, these criteria
have limited diagnostic utility, and no one feature has been shown
to have both a high sensitivity and a high predictive value for
Purely cystic lesions (Figure 9) without solid components or
internal flow are generally considered to be benign, although they
are not void of a malignancy risk. There is a 14% cancer risk,
especially if the cyst recurs after aspiration.
It is important to note that nodule size and multiplicity have not
been shown to affect the likelihood of malignancy.
While the rate of cancer per nodule decreases, this reduction is
proportional to the number of nodules present, so the overall risk
of malignancy per patient remains unchanged in patients with
An awareness of several classic patterns of specific benign and
malignant entities should help to guide management decisions. Based
on their extensive experience at the Mayo clinic, Reading et al
have proposed a pattern-oriented practical approach to the US
evaluation of nodular thyroid disease, describing 8 typical
appearances of commonly encountered benign and malignant nodules.
This approach can triage >50% of thyroid nodules into
observation or FNA categories and is not dependent on whether the
nodule is palpable or single.
Four classic patterns have been described for nodules that need
to be biopsied. The most specific pattern is a hypoechoic nodule
with micro-calcifications, which has a positive predictive value of
70% for papillary carcinoma (Figures 4, 5, and 7).
Secondly, coarse calcifications in a hypoechoic nodule (Figures 6
and 13) also indicate the need for cytologic evaluation, as these
nodules may represent either papillary or medullary carcinoma.
While coarse calcification can be found in both benign and
malignant nodules, a central location (Figures 6 and 13) is more
suspicious and warrants FNA. Thirdly, well-marginated, ovoid, solid
nodules with a thin hypoechoic halo (Figures 14 through 16) are
likely to be follicular lesions and warrant FNA. These may have a
central vascularity. Pathologically, these follicular lesions
consist of follicular adenomas, carcinomas, and cellular
adenomatoid nodules. As these cannot be reliably distinguished by
cytologic evaluation, surgical excision is required to make the
distinction between these entities. The fourth classic pattern is
that of a solid mass with refractive shadowing from the edges,
which is believed to occur as a result of fibrosis. Internal
microcalcifications may be present.
Equally helpful are the 4 classic patterns of nodules that do
not require biopsy. Small (<1 cm) cystic nodules are benign
colloid-filled cysts and are usually multiple (Figure 2). Internal
echogenic foci with comet-tail artifacts represent colloid
crystals. It is important to visualize the ring-down artifact with
high-resolution transducers. A "honeycomb" appearance to a nodule
that consists of internal cystic spaces with thin echogenic walls
is indicative of a hyperplastic benign nodule (Figures 10 and 17).
Foci of colloid with ring-down artifacts support this diagnosis.
Thirdly, a large, predominantly cystic nodule is likely benign
(Figure 9). However, one should pay close attention to the solid
components to look for microcalcification, papillary excrescences,
and a calcified nodule within a cyst (Figures 18 and 19). Mixed
solid and cystic nodules are the most common finding in thyroid US
and are often hyperplastic benign nodules with degeneration and
internal debris as well as fibrosis (Figures 10, 17, and 20).
Recent reports indicate that 40% to 53% of all benign nodules
contained cystic components.
The relative amount of solid versus cystic components is often
quoted in the literature, but this can be subjective. In general,
the more solid a nodule, the more likely it is to be neoplastic and
to need sampling. If a mixed solid and cystic nodule is selected
for biopsy, aspiration should be targeted to the solid components
or the areas with microcalcification. Finally, a pattern of
diffuse, multiple small hypoechoic nodules with intervening
echogenic bands (Figure 21) is indicative of Hashimoto's
thyroiditis and does not require biopsy unless there is also a
focal solid mass.
Society of Radiologists in Ultrasound Consensus
The Society of Radiologists in Ultrasound (SRU) convened a
consensus conference in 2005 to sort through this complex topic in
order to define general recommendations regarding how to manage
thyroid nodules detected by US. A panel composed of radiologists,
endocrinologists, surgeons, and cytopathologists reviewed the
prevailing literature in order to define the characteristics that
place one particular nodule at an increased risk for malignancy
over another. Though nodule size does not correlate with risk of
malignancy, a size cutoff was used in defining consensus
recommendations in an attempt to balance the uncertainty of whether
diagnosing small cancers conveys a mortality or morbidity advantage
and to limit the potential for an excessive number of biopsies.
Based on these considerations, the recommendations apply to nodules
>1 cm in size and are summarized in Table 1.
The recommendations are meant to provide the physician with general
guidelines and some flexibility in the selection process, and are
not meant to be absolute, inflexible criteria.
Lymph node assessment
Evaluation of cervical lymphadenopathy is an integral component
of the US evaluation of thyroid cancer. The finding of suspicious
lymph nodes may override other US features and may prompt the
biopsy of thyroid nodules. Some patients may present with enlarged
lymph nodes secondary to occult thyroid cancer. Small cervical
lymph nodes are not uncommon, and the diagnostic challenge is to
distinguish reactive from malignant lymph nodes. Most metastatic
nodes are found in the internal jugular chain. As in imaging
evaluation of other malignancies, size matters.
Using a cutoff of 7 mm for short-axis diameter at level 2 and 6 mm
at other levels, investigators reported 93% sensitivity, 83%
specificity, and 88.5% accuracy in the US determination of
metastasis from papillary thyroid carcinoma.
In addition to size, a round node is more suspicious than an
elliptical node (Figures 22 and 23).
Microcalcifications are highly suggestive of metastatic
papillary carcinoma (Figures 24 and 25) and can be found in
approximately 50% of metastatic nodes.
Increased echogenicity of the node relative to adjacent muscle
(Figure 26) and internal cystic change (Figure 27) are also
suggestive and are found in 86% and 20% of metastatic nodes,
Microcalcification and cystic change are not seen in reactive lymph
nodes and are, therefore, more specific features. Other helpful
signs are irregularity of nodal margin and loss of echogenic fatty
It is important to consider clinical context in the
decision-making process when selecting which nodules to biopsy.
Specific factors, including patient history and findings on
physical examination, may place a patient at an increased risk for
thyroid cancer, and thereby lower the threshold for biopsy. Thyroid
nodules in patients who are younger than 20 years and older than 70
years show a higher incidence of thyroid cancer, while the
proportion of nodules that are malignant is double in males
compared with females.
Patients with a history of neck irradiation, or a family or
personal history of thyroid cancer, are also at an increased risk
for malignant nodular thyroid disease.
Medullary thyroid cancer is associated with multiple endocrine
neoplasia, type II. Physical examination findings that raise
suspicion for malignant disease include a firm, hard, or fixed
nodule, rapid growth, a nodule in the setting of dysphagia or
hoarseness, and lymphadenopathy.
The decision of whether or not to biopsy a particular thyroid
nodule should be based on the features of the nodule considered in
light of the patient's individual clinical circumstances.
Areas for further investigation
The authors have attempted to define US criteria for the
evaluation of thyroid nodules and also to convey the complexity of
the clinical conundrum of how to manage thyroid nodules. This topic
remains replete with questions for future research. What is the
true clinical significance of small papillary carcinomas in terms
of improved mortality or morbidity associated with early detection?
How should clearly benign FNA results be followed? What constitutes
substantial interval growth, especially in a nodule that has been
shown to be benign by previous biopsy? In a patient with multiple
nodules, which and how many nodules should be biopsied? Answers to
these questions and the results of continued research in this area
have great potential to further clarify the process of selecting
thyroid nodules to be biopsied. Ideally, future guidelines, and
perhaps new diagnostic tests, may help us diagnose the minority of
patients with thyroid malignancy within the majority of benign