Thyroid Nodules

AACE/AME Guidelines
AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS

AND ASSOCIAZIONE MEDICI ENDOCRINOLOGI
MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE
DIAGNOSIS AND MANAGEMENT OF THYROID NODULES
AACE/AME Task Force on Thyroid Nodules
ABSTRACT symptomatic goiters may be treated surgically or with

radioiodine. Routine measurement of serum calcitonin is
Thyroid nodules are common and are frequently not recommended. Suggestions for thyroid nodule man-
benign. Current data suggest that the prevalence of palpa- agement during pregnancy are presented.
ble thyroid nodules is 3% to 7% in North America; the We believe that these guidelines will be useful to clin-
prevalence is as high as 50% based on ultrasonography ical endocrinologists, endocrine surgeons, pediatricians,
(US) or autopsy data. The introduction of sensitive and internists whose practices include management of
thyrotropin (thyroid-stimulating hormone or TSH) assays, patients with thyroid disorders. These guidelines are thor-
the widespread application of fine-needle aspiration ough and practical, and they offer reasoned and balanced
(FNA) biopsy, and the availability of high-resolution US recommendations based on the best available evidence.
have substantially improved the management of thyroid (Endocr Pract. 2006;12:63-102)
nodules.
This document was prepared as a collaborative effort
between the American Association of Clinical Abbreviations:
Endocrinologists (AACE) and the Associazione Medici AFTN = autonomously functioning thyroid nodules;
Endocrinologi (AME). Most Task Force members are CT = computed tomography; FNA = fine-needle aspi-
members of AACE. We have used the AACE protocol for ration; LOE = level of evidence; LT4 = levothyroxine;
clinical practice guidelines, with rating of available evi- LTA = laser thermal ablation; MEN2 = multiple
dence, linking the guidelines to the strength of recommen- endocrine neoplasia type 2; MeSH = Medical Subject
dations. Headings; MNG = multinodular goiter; MRI = magnet-
Key observations include the following. Although ic resonance imaging; MTC = medullary thyroid carci-
most patients with thyroid nodules are asymptomatic, noma; PEI = percutaneous ethanol injection; PTC =
occasionally patients complain of dysphagia, dysphonia, papillary thyroid carcinoma; rhTSH = recombinant
pressure, pain, or symptoms of hyperthyroidism or human TSH; T3 = triiodothyronine; T4 = thyroxine;
hypothyroidism. Absence of symptoms does not rule out a TcTUs = technetium thyroid uptake under suppression;
malignant lesion; thus, it is important to review risk fac- TPOAb = thyroid peroxidase antibody; TSH = thyroid-
tors for malignant disease. Thyroid US should not be per- stimulating hormone (thyrotropin); US = ultrasonogra-
formed as a screening test. All patients with a palpable phy; US-FNA = US-guided FNA
thyroid nodule, however, should undergo US examination.
US-guided FNA (US-FNA) is recommended for nodules
≥10 mm; US-FNA is suggested for nodules <10 mm only 1. INTRODUCTION
if clinical information or US features are suspicious.
Thyroid FNA is reliable and safe, and smears should be 1.1. Development and Use of Guidelines: Methods of
interpreted by an experienced pathologist. Patients with Bibliographic Research
benign thyroid nodules should undergo follow-up, and
malignant or suspicious nodules should be treated surgi- We searched for the primary evidence to support the
cally. A radioisotope scan of the thyroid is useful if the current guidelines by using a “clinical question” method.
TSH level is low or suppressed. Measurement of serum Each topic covered by the guidelines was translated to a
TSH is the best initial laboratory test of thyroid function related question. Each clinical question can be answered
and should be followed by measurement of free thyroxine appropriately only by certain types of clinical studies and
if the TSH value is low and of thyroid peroxidase antibody not by others. Accordingly, the bibliographic research was
if the TSH value is high. Percutaneous ethanol injection is conducted by selecting the studies able to yield a method-
useful in the treatment of cystic thyroid lesions; large, ologically reliable answer to each question.
ENDOCRINE PRACTICE Vol 12 No. 1 January/February 2006 65

66 Thyroid Nodule Guidelines, Endocr Pract. 2006;12(No. 1)
The first step was to select pertinent published ment conference, nih” [pt] OR “consensus develop-
reports. The United States National Library of Medicine ment conferences” [mh] OR “consensus development
Medical Subject Headings (MeSH) database was used as a conferences, nih” [mh] OR “guidelines” [mh] OR
terminologic filter. Appropriate MeSH terms were identi- “practice guidelines” [mh] OR (consensus [ti] AND
fied, and care was exercised to select them on a sensitive statement [ti])
rather than a specific basis. The MeSH terms and their
proper combination enabled us to retrieve the reports per- Guidelines were searched in the following databases:
tinent to a specific issue. National Guideline Clearinghouse (USA); Agency for
The second step was to select relevant published stud- Healthcare Research and Quality (USA); Canadian
ies. Beginning with the pertinent reports indexed with the Medical Association—Clinical Practice Guidelines;
appropriate MeSH terminologic filters, we applied the Canadian Task Force on Preventive Health Care; National
PubMed clinical queries methodologic filters. The clinical Institutes of Health—National Heart, Lung, and Blood
queries are grouped into 4 categories: diagnosis, etiology, Institute (USA); National Health Service Research and
prognosis, and therapy. For each clinical question, a prop- Development Health Technology Assessment Programme
er complex search string is available (1). From the combi- (UK); National Institute of Clinical Excellence (UK); New
nation of terminologic (MeSH terms) and methodologic Zealand Guidelines Group; PRODIGY Guidance—
filters (clinical queries), the relevant studies, designed to National Health Service (UK); and the Scottish
provide a reliable answer to the question, were selected. Intercollegiate Guidelines Network.
After the relevant published studies had been
retrieved, the bibliographic research continued by looking
for further evidence cited in the bibliography of each 1.2. Levels of Evidence and Grading of
report and by following the Related Articles link listed Recommendations
next to each item in MEDLINE.
Meta-analyses were searched, both in MEDLINE and The American Association of Clinical
in the Cochrane Library. Three methods were used to Endocrinologists protocol for standardized production of
search for meta-analyses in MEDLINE: clinical practice guidelines (3) was followed to rate the
available evidence and to link the guidelines to the
• Selection of “Meta-Analysis” from the “Publication strength of recommendations, on the basis of the grade
Type” menu on the “Limits” tab of the PubMed main designations described in Table 1. All references involv-
page ing clinical evidence used to support recommendation
• Application of function “Find Systematic Reviews” on grades will have denotations regarding their level of evi-
the “Clinical Queries” PubMed page dence (LOE) in the reference list.
• Use of Hunt and McKibbon’s complex string for sys-
tematic reviews (2): 1.3. Thyroid Nodules: The Scope of the Problem
AND (meta-analysis [pt] OR meta-anal* [tw] OR
metaanal* [tw] OR (quantitative* review* [tw] OR Thyroid nodules are a very common clinical finding,
quantitative* overview* [tw]) OR (systematic* with an estimated prevalence on the basis of palpation that
review* [tw] OR systematic* overview* [tw]) OR ranges from 3% to 7% (4). In a large population study (in
(methodologic* review* [tw] OR methodologic* Framingham, Massachusetts), clinically apparent thyroid
overview* [tw]) OR (review [pt] AND medline [tw])) nodules were present in 6.4% of women and 1.5% of men
(5). During the past 2 decades, the widespread use of ultra-
The Cochrane Library was browsed by entering free sonography (US) for evaluation of thyroid and nonthyroid
terms in the search window. neck disease has resulted in a dramatic increase in the
Guidelines were searched in MEDLINE and in sever- prevalence of clinically inapparent thyroid nodules, esti-
al guidelines databases. Two methods were used to search mated at 20% to 76% in the general population. Moreover,
for guidelines in MEDLINE: 20% to 48% of patients with a single palpable thyroid nod-
ule are found to have additional nodules when investigat-
• Selection of “Practice Guidelines” from the ed by US (6,7). As a consequence, we are now facing an
“Publication Type” menu on the “Limits” tab of the epidemic of thyroid nodules; the prevalence is similar to
PubMed main page that reported in autopsy data, 50%, in patients with no his-
• Use of the following GIMBE-Gruppo Italiano tory of thyroid disease (8-10).
Medicina Basata sulle Evidenze complex string for the Thyroid nodules are more common in elderly persons,
guidelines: in women, in those with iodine deficiency, and in those
“guideline” [pt] OR “practice guideline” [pt] OR with a history of radiation exposure. The estimated annu-
“health planning guidelines” [mh] OR “consensus al incidence rate of 0.1% in the United States suggests that
development conference” [pt] OR “consensus develop- 300,000 new nodules were detected in this country in 2005
Thyroid Nodule Guidelines, Endocr Pract. 2006;12(No. 1) 67
Table 1
Various Strength-of-Evidence Scales Reported in the Medical Literature
Level of Recommendation
evidence grade Description
1 Well-controlled, generalizable, randomized trial

Adequately powered
Well-controlled multicenter trial
Large meta-analysis with quality ratings
All-or-none evidence
2 Randomized controlled trial—limited body of data
Well-conducted prospective cohort study
Well-conducted meta-analysis of cohort studies
3 Methodologically flawed randomized clinical trials
Observational studies
Case series or case reports
Conflicting evidence with weight of evidence supporting the
recommendation
4 Expert consensus
Expert opinion based on experience
“Theory-driven conclusions”
“Unproven claims”
A Homogeneous evidence from multiple well-designed randomized
controlled trials with sufficient statistical power
Homogeneous evidence from multiple well-designed cohort controlled
trials with sufficient statistical power
≥1 conclusive level 1 publications demonstrating benefit >> risk
B Evidence from at least one large well-designed clinical trial, cohort or
case-controlled analytic study, or meta-analysis
No conclusive level 1 publication; ≥1 conclusive level 2 publications
demonstrating benefit >> risk
C Evidence based on clinical experience, descriptive studies, or expert
consensus opinion
No conclusive level 1 or 2 publication; ≥1 conclusive level 3
publications demonstrating benefit >> risk
No conclusive risk at all and no conclusive benefit demonstrated by
evidence
D Not rated
No conclusive level 1, 2, or 3 publication demonstrating benefit >> risk
Conclusive level 1, 2, or 3 publication demonstrating risk >> benefit
From the American Association of Clinical Endocrinologists Ad Hoc Task Force for Standardized Production of Clinical
Practice Guidelines (3).
(10). In Italy, an area with mild to moderate iodine about 5% of all thyroid nodules, independent of their size
deficiency, several thousand new nodules will be diag- (10,11). Because of the high prevalence of nodular thyroid
nosed this year. The clinical implications of these data are disease, it is neither economically feasible nor necessary
overwhelming. to submit all or even most thyroid nodules for a complete
The clinical importance of thyroid nodules, besides work-up for the assessment of their structure and function.
the infrequent cases of local compressive symptoms or Therefore, it is essential to develop and follow a reliable,
thyroid hyperfunction, is primarily the need to exclude the cost-effective strategy for diagnosis and treatment of thy-
presence of a thyroid malignant lesion, which accounts for roid nodules.
2. DIAGNOSIS occurring at a young age is 2-fold higher than in adult

patients. The risk of thyroid cancer is also higher in older
2.1. History and Physical Examination persons and in men; these patients require a more thorough
diagnostic evaluation (4,9).
2.1.1. Clinical Evaluation Symptoms such as a choking sensation, cervical ten-
Many disorders, both malignant and benign, can derness or pain, dysphagia, or hoarseness may be per-
cause thyroid nodules (Table 2) (4,9). The clinical impor- ceived as attributable to thyroid disease, but in most
tance of newly diagnosed thyroid nodules, as previously patients, these symptoms are caused by nonthyroid disor-
stated, is primarily the exclusion of thyroid malignant ders. In all symptomatic patients, evaluation should begin
lesions (4,6,11). Hence, clinical evaluation should first be by obtaining a detailed history, performing a complete
aimed at detecting symptoms or signs suggestive of malig- physical examination, and providing the information need-
nant disease. Most patients with thyroid nodules have few ed for the patient’s reassurance and for the selection of
or no symptoms, and usually no clear relationship exists appropriate clinical and laboratory investigations.
between nodule histologic features or size and the report- Sudden pain is commonly due to hemorrhage in a
ed symptoms. Thyroid nodules can grow insidiously for cystic nodule. In patients with rapid enlargement of a thy-
many years and are often discovered incidentally on phys- roid nodule, however, anaplastic carcinoma or primary
ical examination, self-palpation, or imaging studies per- lymphoma of the thyroid should always be considered.
formed for unrelated reasons. The slow onset and progression of cervical symptoms
Patients should be asked about a family history of and signs are caused by the compression of vital structures
benign or malignant thyroid disease. Familial medullary of the neck or upper thoracic cavity (trachea and esopha-
thyroid carcinoma (MTC), multiple endocrine neoplasia gus), which usually occurs only if thyroid nodules are
type 2 (MEN2), familial papillary thyroid tumors, familial embedded within large goiters. Symptoms of compression
polyposis coli, Cowden disease, and Gardner’s syndrome are infrequent and are usually noted in a minority of mid-
are rare disorders but should always be considered (12). dle-aged or elderly patients with long-standing multinodu-
Previous disease or treatments involving the neck lar goiter (MNG). The growth of the nodular goiter into
(history of head and neck irradiation during childhood), the anterior mediastinum may cause partial occlusion of
recent pregnancy, and rapidity of onset and rate of growth the thoracic inlet, occasionally leading to venous outflow
of the neck swelling should be documented. A slow but obstruction. If the patient is asked to extend the arms over
progressive growth (during weeks or months) is sugges- the head (Pemberton’s sign), the further narrowing of the
tive of malignant involvement and should prompt further thoracic inlet is followed within a few minutes by the dis-
evaluation. tention of the external jugular veins and by facial plethora
Thyroid nodules during childhood and adolescence (4).
should induce caution; the malignancy rate for nodules When observed in the absence of large goiters, the
symptoms of tracheal compression (cough and dysphonia)
suggest an underlying malignant lesion. Patients with
rapid growth of a large solid thyroid mass and vocal cord
Table 2 paresis should undergo surgical treatment even if cytolog-
Causes of Thyroid Nodules ic results are benign (13; grade C). Differentiated thyroid
carcinomas, however, rarely cause airway obstruction,
Benign vocal cord paralysis, or esophageal symptoms, and
Multinodular goiter absence of symptoms does not rule out a malignant tumor
Hashimoto’s thyroiditis (14; grade C).
Nodular thyroid disease may be associated with sub-
Simple or hemorrhagic cysts
clinical or overt hyperthyroidism. Hyperthyroidism is sug-
Follicular adenomas gestive of a benign lesion because autonomously func-
Subacute thyroiditis tioning nodules are almost always benign and need no fur-
ther cytologic evaluation. Toxic MNGs, however, may
Malignant
harbor both hyperfunctioning (benign) areas and cold
Papillary carcinoma (potentially malignant) lesions, and thyroid nodules in
Follicular carcinoma patients with Graves’ disease are reported to be malignant
Hürthle cell carcinoma in about 9% of cases (15).
Medullary carcinoma A firm or hard, solitary or dominant thyroid nodule
Anaplastic carcinoma that clearly differs from the rest of the gland suggests an
increased risk of malignant involvement and warrants
Primary thyroid lymphoma
cytologic evaluation. The risk of cancer is not significant-
Metastatic malignant lesion ly higher in solitary nodules than in MNGs, and small dif-
ferentiated thyroid cancers are frequently devoid of
alarming characteristics on clinical evaluation (16-18; • Firm or hard consistency of nodule, ill-defined nodule
grade C). margins on palpation
Despite the low predictive value of palpation and the • Cervical adenopathy
high levels of intraobserver and interobserver variations • Fixed nodule on examination
(18,19), careful inspection and palpation of the thyroid as • Dysphonia, dysphagia, and cough
well as the anterior and lateral compartments of the neck
should always be done. 2.1.3. Key Recommendations
The key recommendations regarding history and
2.1.2. Symptoms or Signs That Warrant Further physical examination in patients with a thyroid nodule are
Investigation outlined in Table 3.
The following characteristics may increase the risk of
thyroid cancer: 2.2. US and Other Diagnostic Imaging Studies
• Prior head and neck irradiation 2.2.1. When to Perform US Evaluation

• Family history of MTC or MEN2 High-resolution US is the most sensitive test available
• Age <20 years or >70 years to detect thyroid lesions, measure their dimensions accu-
• Male sex rately, identify their structure, and evaluate diffuse
• Growing nodule changes in the thyroid gland. US can identify thyroid
Table 3
Key Recommendations
Regarding History and Physical Examination
in Patients With a Thyroid Nodule*
•Remember that the vast majority of nodules are asymptomatic, and absence of
symptoms does not rule out a malignant lesion (grade C)†
•Always obtain a biopsy specimen from solitary, firm, or hard nodules. The risk of
cancer is similar in a solitary nodule and MNG (grade B)
•Record the following information (grade C):
Family history of thyroid disease
Previous neck disease or treatment
Growth of the neck mass
Hoarseness, dysphonia, dysphagia, or dyspnea
Location, consistency, and size of the nodule
Neck tenderness or pain
Cervical adenopathy
Symptoms of hyperthyroidism or hypothyroidism
•Factors suggesting increased risk of malignant potential (grade C):
History of head and neck irradiation
Family history of MTC or MEN2
Age <20 or >70 years
Male sex
Growing nodule
Firm or hard consistency
Cervical adenopathy
Fixed nodule
Persistent hoarseness, dysphonia, dysphagia, or dyspnea
*MEN2 = multiple endocrine neoplasia type 2; MNG = multinodular goiter; MTC =

medullary thyroid carcinoma.
†See Table 1 for explanation of grades.
nodules that have been missed on physical examination, ranges from 5.4% to 7.7% and appears to be similar to that
isotope scanning, and other imaging techniques (20). This reported for palpable lesions (5.0% to 6.5%) (16,22-24;
study, however, should not be performed on an otherwise grade C). Clinical criteria for a malignant nodule are lack-
normal thyroid gland nor used as a substitute for a physi- ing in most cases of nonpalpable lesions, and only a few
cal examination. Because of the high prevalence of clini- patients with palpable thyroid nodules present with a his-
cally inapparent, small thyroid nodules and the low-grade tory or findings on physical examination suggestive of
aggressiveness of most thyroid cancers, US should not be thyroid carcinoma (14; grade C). Hence, to avoid the inap-
performed as a screening test in the general population propriate use of US-FNA in a large part of the general
unless well-known risk factors have been recognized. population, it is essential to determine, on the basis of their
US should be performed in all patients with a history US features, which thyroid lesions have a high malignant
of familial thyroid cancer, MEN2, or childhood cervical potential (see Appendix 2).
irradiation, even if palpation yields normal findings (20;
grade C). The physical finding of adenopathy suspicious 2.2.3. US Criteria for US-FNA in Impalpable Nodules
for malignant involvement in the anterior or lateral neck
compartments warrants US examination of the lymph Solitary Versus Multiple Nodules. The risk of cancer
nodes and thyroid gland because of the risk of a lymph is not significantly higher in impalpable solitary thyroid
node metastatic lesion from an otherwise unrecognized nodules than in MNGs (16); this finding confirms what
papillary microcarcinoma. has been observed in palpable lesions (17,18; grade C).
In all patients with palpable thyroid nodules or MNG, Size. Malignant involvement is not less frequent in
US should be performed to accomplish the following: nodules <10 mm in diameter; thus, an arbitrary diameter
cutoff of 10 or 15 mm for cancer risk is not justified (14).
• Help with the diagnosis in difficult cases (as in Both recent (16) and older data (25,26) suggest that some
Hashimoto’s thyroiditis) microcarcinomas can have an aggressive course; there-
• Look for coincidental thyroid nodules fore, early diagnosis and treatment of small tumors are
• Detect US features suggestive of malignant growth and clinically important (grade C).
select the lesions to be recommended for fine-needle US Features and Color Doppler Findings. Among
aspiration (FNA) biopsy (see Table 17) the diagnostic imaging techniques, high-resolution US is
• Choose the gauge and length of the biopsy needle the most accurate for predicting the presence of malignant
• Obtain an objective measure of the baseline volume cells in thyroid lesions that cannot be palpated. The report-
and characteristics of the lesions that will be assigned ed specificity for diagnosing cancer is 85.8% to 95.0% for
to follow-up or medical therapy microcalcifications (small intranodular punctate hyper-
echoic spots with scanty or no posterior acoustic shadow-
In patients with nonspecific symptoms (cervical pain, ing), 83.0% to 85.0% for irregular or microlobulated mar-
dysphagia, persistent cough, voice changes), US evalua- gins, and 80.8% for chaotic arrangement of intranodular
tion of the thyroid gland should be performed only on the vascular images (16,21; grade C). For these characteris-
basis of findings on physical examination and the results tics, the predictive value for cancer is partially blunted by
of appropriate imaging and laboratory tests. their low sensitivity (29.0% to 59.2%, 55.1% to 77.5%,
Standardized US reporting criteria should be fol- and 74.2%, respectively), and no single US sign indepen-
lowed, indicating position, shape, size, margins, content, dently is fully predictive of a malignant lesion. Never-
echogenic pattern, and, whenever possible, the vascular theless, a hypoechoic appearance of a thyroid nodule
pattern of the nodule (see Appendix 1). Nodules with (defined as a decreased echogenicity in comparison with
malignant potential should be identified, and FNA biopsy the surrounding parenchyma, similar to that of the cervical
should be suggested to the patient. strap muscles) in conjunction with one of the US patterns
associated with malignant tumors effectively indicates a
2.2.2. US as First Step for Routine Diagnosis of Thyroid subset of impalpable thyroid nodules at high risk for can-
Nodule cer (16). A rounded appearance or a “more tall (antero-
Widespread use of high-resolution US has led to the posterior) than wide (transverse)” shape of the nodule and
discovery of unsuspected small thyroid nodules of inde- a “marked hypoechogenicity” of a solid lesion (hypo-
terminate significance (6,14). Clinically inapparent thy- echoic even in comparison with the cervical muscles) are
roid lesions (14% to 24% of those with a diameter >10 additional US patterns suggestive of malignant potential
mm) are detected by US in about half (27% to 72%) of the (27; grade B).
women who undergo such assessment (6,21). Many of The presence of at least 2 suspicious sonographic cri-
these nodules are further evaluated by US-guided FNA teria reliably identifies most neoplastic lesions of the thy-
(US-FNA). roid gland (87% to 93% of cases). Thus, it is possible to
The prevalence of cancer reported in studies focused restrict the number of US-FNA procedures to about a third
on the cytologic evaluation of nonpalpable thyroid lesions of the impalpable thyroid nodules (16,27; grade B).
2.2.4. US Criteria for US-FNA in Palpable Nodules evaluation (10,30,31). The central role of the endocrinolo-
Solitary Versus Multiple Nodules. The risk of cancer gist in thyroid nodule evaluation and FNA biopsy is clear,
is not significantly higher in palpable solitary thyroid nod- and recent surveys have emphasized that almost 100% of
ules than in multinodular lesions or in nodules embedded endocrinologists use FNA biopsies for diagnosis of thy-
in diffuse goiters (17). Moreover, 50% of thyroid glands roid nodules. It is axiomatic that thyroid nodules are com-
with a “solitary” nodule based on palpation have other mon, thyroid glands frequently contain more than 1 nod-
small nodules disclosed by US (18). In multinodular thy- ule, and nodules are often benign. FNA is critical in estab-
roid glands, the cytologic sampling should be focused on lishing benignity (Fig. 1 and 2).
lesions characterized by suspicious US features rather than
on larger or clinically dominant nodules (28). 2.3.1. Procedure
US Features and Color Doppler Findings. The US Detailed reviews of aspiration biopsy of thyroid nod-
characteristics suggestive of malignant involvement in ules have been published previously (30-33). Before FNA
palpable thyroid nodules are the same as in impalpable is performed, the thyroid gland should be palpated, and the
nodules. On color Doppler examination, hypervascularity nodule or nodules to be aspirated should be carefully iden-
with chaotic arrangement of blood vessels (related to arte- tified. The procedure is explained to the patient, and the
riovenous shunts and tortuosity of vessel course) is usual- patient’s questions and concerns should be satisfactorily
ly seen, whereas hypovascular lesions, sometimes answered. The patient then is placed supine on the exam-
observed in papillary microcarcinomas (because of their ining table with the neck fully extended, supported by a
high fibrous component), are rare (29; grade C). In addi- pillow under the shoulders. Adequate lighting should be
tion, large neoplastic lesions may be characterized by available. The skin is cleansed with alcohol, and the
degenerative changes and multiple fluid areas, findings patient is asked not to swallow or talk during the needle
only exceptionally noted in microcarcinomas. placement. Local anesthesia is not required. An assistant
Extracapsular Growth. Extension of irregular hypo- or a nurse may be needed to help with the procedure,
echoic lesions beyond the thyroid capsule, invasion of preparation and labeling of slides, and application of pres-
prethyroid muscles, posterior extracapsular growth, and sure over the puncture sites.
infiltration of the recurrent laryngeal nerve are threatening Commonly, a 27- or 25-gauge 1.5-inch (3.8-cm)-long
US findings demanding immediate cytologic assessment needle attached to a 10-mL disposable plastic syringe is
(28). used. Some clinicians use a mechanical syringe holder,
Complex or Cystic Lesions. Most complex thyroid such as the Cameco syringe pistol (Precision Dynamics
nodules with a dominant fluid component are benign. US- Corporation, Burbank, CA). The needle is inserted into the
FNA, however, should always be performed because the nodule without suction, and after the tip is in the nodule,
rare papillary thyroid carcinoma (PTC) can be cystic (28). suction is applied while the needle is moved back and
Suspicious Cervical Adenopathy. The presence of forth within the nodule. This maneuver helps dislodge cel-
enlarged lymph nodes with rounded appearance, no hilum, lular material, which is then sucked into the needle; with-
cystic changes, microcalcifications, or chaotic hypervas- in a few seconds, the aspirate appears in the needle hub.
cularity is highly suspicious. Such nodes and any coexis- At that point, suction is released, the needle is with-
tent thyroid nodules, whatever their size, always warrant drawn, and smears are prepared. The syringe is removed
US-FNA (28). from the needle and filled with air by retracting the
plunger. The needle is then reattached to the syringe, and
2.2.5. Other Diagnostic Imaging with the bevel pointing down, one drop of aspirated mate-
Magnetic resonance imaging (MRI) and computed rial is placed on each of several glass slides. Smears are
tomography (CT) should not be used routinely because then prepared by using 2 glass slides, similar to those used
they are rarely diagnostic for malignant lesions in nodular to make blood smears. Prepared slides can be air-dried or
thyroid disease. MRI and CT may be of value, however, if wet-fixed by immediate submersion in 95% ethyl alcohol
assessment of size or substernal extension of a goiter is for Papanicolaou staining. Some facilities use automated
desired for clinical management. Remember that CT con- cytology systems, such as Thin Prep, wherein the speci-
trast medium usually contains iodine and reduces subse- men is placed in the solution for the system and reviewed
quent uptake of radioiodine (131I). later in the laboratory. Usually, 2 to 4 aspirations are made
from different sites in each nodule; for each aspiration, 2
2.2.6. Key Recommendations to 4 slides are prepared. In general, 8 to 12 slides are pre-
The key recommendations pertaining to performance pared per biopsy (10,32-34).
of US and other diagnostic imaging as well as US-FNA in Nonaspiration biopsy of a thyroid nodule can also be
patients with thyroid nodules are summarized in Table 4. performed. In this technique, the hub of a 25-gauge needle
is held in a pencil-grip fashion, the needle is inserted gent-
2.3. FNA Biopsy ly into the nodule, and, after aspirate flows into the hub,
the needle is withdrawn. Cellular material in the needle
Thyroid FNA biopsy is now established as reliable shaft is expelled onto glass slides, and smears are prepared
and safe and has become an integral part of thyroid nodule as described in the previous paragraph.
Table 4
Key Recommendations Regarding Ultrasonography and Other Diagnostic Imaging
in Patients With a Thyroid Nodule*
•US evaluation
Not recommended (grade C†): as a screening test in the general population; in patients with normal thyroid on
palpation and low risk for thyroid cancer
Recommended (grade C): for high-risk patients (history of familial thyroid cancer, MEN2, or external
irradiation); for all patients with palpable thyroid nodules or MNG; for those with adenopathy suggestive of a
malignant lesion
•US reporting criteria (grade C):
Describe position, shape, size, margins, content, echogenic pattern, and, whenever possible, the vascular pattern
of the nodule
Identify the nodule at risk to be malignant, and stratify the nodule with a risk score based on the US findings
Identify the nodules for FNA biopsy
•No US-FNA of nodules <10 mm unless suspicious US findings or high-risk history (grade C)
•US-FNA of nodules of any size in patients with history of neck irradiation or family history of MTC or MEN2
(grade C)
•US-FNA should be based on US features (grade B)
•US-FNA should be performed on all hypoechoic nodules ≥10 mm with irregular margins, chaotic intranodular
vascular spots, a more-tall-than-wide shape, or microcalcifications (grade B)
•US findings suggestive of extracapsular growth or metastatic cervical lymph nodes warrant an immediate
cytologic evaluation, no matter the size of the lesions (grade B)
•In complex thyroid nodules, obtain US-FNA sampling of the solid component of the lesion before fluid drainage
(grade C)
•Thyroid incidentalomas should be followed by US in 6-12 months and regularly thereafter (grade D)
•MRI and CT are not indicated in routine nodule evaluation (grade C)
*CT = computed tomography; FNA = fine-needle aspiration; MEN2 = multiple endocrine neoplasia type 2; MNG =
multinodular goiter; MRI = magnetic resonance imaging; MTC = medullary thyroid carcinoma; US = ultrasonography;
US-FNA = US-guided FNA.
Immediately after withdrawal of the needle, gentle (32). Benign cytology includes benign colloid nodule,
pressure is applied to the aspiration site (or sites) to pre- macrofollicular adenoma, lymphocytic thyroiditis, granu-
vent hematoma formation. In the absence of problems and lomatous thyroiditis, or benign cyst. The most common
if the patient is comfortable, the patient is allowed to leave benign diagnosis is “colloid nodule,” which may be found
after a few minutes of observation. in the setting of a normal thyroid, a benign nodule, an
MNG, or a macrofollicular adenoma.
2.3.2. Cytologic Diagnosis Malignant (positive) results can be identified reliably
FNA results may be diagnostic (satisfactory) or non- by the cytopathologist (33; grade C). The most frequent
diagnostic (unsatisfactory), as outlined in Table 5. The malignant lesion encountered is PTC. Aspirates of PTC
specimen is labeled “diagnostic” or “adequate” if it con- are characterized by increased cellularity; tumor cells
tains a minimum of 6 groupings of well-preserved thyroid arranged in sheets and papillary cell groups; and typical
epithelial cells, consisting of at least 10 cells per group. nuclear abnormalities, including intranuclear holes and
Specimens labeled as “nondiagnostic” or “unsatisfactory” grooves. Medullary carcinoma is characterized by hyper-
have an inadequate number of cells, which can be attribut- cellularity, tumor cells that are notably noncohesive, and
able to cystic fluid, bloody smears, or poor technique in nuclei that are hyperchromatic and located at the end of an
preparing slides (10,32). elongated cell body. Amyloid may be found in 50% to
A benign (negative) cytodiagnosis is the most com- 60% of cases, appearing as amorphous background mate-
mon finding, accounting for approximately 70% of results rial that is readily stained with Congo red. Immuno-
LT4
LT4
Fig. 1. Flowchart, indicating scheme for the diagnosis and management of palpable thyroid nodules. FNA = fine-needle aspiration;
LT4 = levothyroxine; MNG = multinodular goiter; PEI = percutaneous ethanol injection; SN = single nodule; TPOAb = thyroid perox-
idase antibody; TSH = thyroid-stimulating hormone (thyrotropin); US = ultrasonography.
LT4
LT4
Fig. 2. Flowchart, showing recommended scheme for the diagnosis and management of ultrasonography-determined thyroid inciden-
talomas. FNA = fine-needle aspiration; LT4 = levothyroxine; TPOAb = thyroid peroxidase antibody; TSH = thyroid-stimulating hor-
mone (thyrotropin); US = ultrasonography.
Large-needle thyroid biopsy does not have a higher

Table 5 diagnostic accuracy than FNA, is cumbersome, and is
Fine-Needle Aspiration associated with pain and, occasionally, severe bleeding.
Cytologic Diagnosis Currently, the use of large-needle biopsy in the routine
management of thyroid nodules is not advised.
Diagnostic (satisfactory specimen)
Benign (negative) 2.3.3. FNA Results
Malignant (positive) As already noted, about 70% of FNA specimens are
Suspicious (indeterminate) classified as benign; in addition, 5% are malignant, 10%
are suspicious, and 10% to 20% are nondiagnostic or
Nondiagnostic (unsatisfactory specimen)
unsatisfactory (30,33,37-39). The result of FNA is impor-
Foam cells
tant in deciding whether to manage the patient medically
Cyst fluid or surgically. Some reviews and reports have indicated
Blood that the selection of patients for surgical treatment on the
basis of FNA results has increased the yield of cancer from
15% to 50% (37,40; grade C). The sensitivity and speci-
staining with calcitonin can sometimes be helpful in diffi- ficity of FNA performed by experienced personnel are
cult cases. Other malignant lesions include primary excellent, as shown in Table 6.
anaplastic carcinoma and high-grade metastatic cancers A major concern is the possibility of a false-negative
(33). FNA result—that is, a missed diagnosis of malignant dis-
Suspicious (indeterminate) results include specimens ease (37,38,41; grade C). The false-negative rate is 1% to
for which a definite cytologic diagnosis cannot be made 11% (mean, 5%). Some methods for minimizing false-
(33-35). Often these include follicular neoplasms, Hürthle negative results are itemized in Table 7. Another concern
cell neoplasms, papillary cancer, or lymphoma. Follicular is the false-positive FNA rate, defined as the percentage of
neoplasms appear as hypercellular specimens with monot- patients with positive FNA results but negative histologic
ony of cells, microfollicular arrangement, and diminished findings for cancer. This rate varies from less than 1% to
or absent colloid. Hürthle cell neoplasm is diagnosed in an 7%, as indicated in Table 6 (37,38; grade C).
aspirate that is almost entirely Hürthle cells, usually with
absent or scanty colloid that lacks a lymphoid cell popula- 2.3.4. Adverse Effects and Conclusions
tion, as found in Hashimoto’s thyroiditis. FNA biopsy of a thyroid nodule often causes slight
Nondiagnostic (unsatisfactory) aspirates are those temporary pain and is occasionally associated with a
with too few epithelial cells, accounting for 10% to 20% minor hematoma. No serious adverse effects and no seed-
of specimens (30,36). The criteria for judging aspirates as ing of tumor cells in the needle track have been reported
inadequate or nondiagnostic are arbitrary and vary some- (32,33; grade C). FNA is now considered safe, useful, and
what among laboratories. Commonly, inadequate smears cost-effective. The accuracy of FNA is 95%.
are collected from cystic lesions that are leaking fluid and
degenerative foam cells. Other causes of inadequate 2.3.5. Key Recommendations
smears include too much blood, excessive air-drawing, The key recommendations regarding FNA biopsy
and insufficient experience with FNA techniques. procedures and pitfalls are presented in Table 8.
Table 6
Summary Characteristics for Thyroid Fine-Needle Aspiration: Results of Literature Survey
Mean Range
Feature (%) (%) Definition
Sensitivity 83 65-98 Likelihood that patient with disease has positive test results
Specificity 92 72-100 Likelihood that patient without disease has negative test results
Positive predictive value 75 50-96 Fraction of patients with positive test results who have disease
False-negative rate 5 1-11 Fine-needle aspiration negative; histology positive for cancer
False-positive rate 5 0-7 Fine-needle aspiration positive; histology negative for cancer
Data from Gharib (10), Castro and Gharib (30), Gharib and Goellner (33), and Jeffrey and Miller (39).
functioning (“cold”). Hot nodules almost never represent

Table 7 clinically significant malignant lesions, whereas cold nod-
Ways to Minimize False-Negative Results ules have a reported malignant risk of about 5% to 8%.
on Fine-Needle Aspiration Because the vast majority (77% to 94%) of thyroid lesions
of Thyroid Nodules are cold and only a small minority of these are malignant,
the predictive value of hypofunctioning nodules for the
Follow-up cytologically benign nodules presence of malignant involvement is low. The diagnostic
Aspirate multiple nodule sites specificity is further reduced in small lesions (<1 cm),
Aspirate multiple nodules in multinodular goiter which may not be identified by scintigraphy (42,43).
The role of scintigraphy in the diagnostic work-up of
Submit cyst fluid for examination
thyroid nodules is limited, especially in countries with
Review slides with experienced cytopathologist iodine-rich diets, in which serum thyrotropin (thyroid-
stimulating hormone or TSH) measurement and thyroid
US can correctly diagnose autonomous nodules in most
patients (42,43), and FNA facilitates accurate diagnosis of
2.4. Radionuclide Scanning
a malignant lesion (40). Moreover, because the resolution
2.4.1. Diagnostic Accuracy of US is considerably greater than that of scintigraphy,
Thyroid scintigraphy is the only technique that allows radionuclide scanning has little place in the topographic
for assessment of thyroid regional function and detection assessment of nodular goiter and no place in the measure-
of areas of autonomously functioning thyroid tissue. On ment of thyroid nodules.
the basis of the pattern of radionuclide uptake, nodules On the basis of these considerations, scintigraphy is
may be classified as hyperfunctioning (“hot”) or hypo- generally not useful as a first-step diagnostic study in the
Table 8
Key Recommendations Relating to Thyroid
Fine-Needle Aspiration Biopsy Procedures and Pitfalls*
•Thyroid FNA biopsy has been established as reliable and safe and has become an
integral part of thyroid nodule evaluation
•Clinical management of thyroid nodules should be guided by the results of
ultrasonographic evaluation and FNA biopsy
•Thyroid smears should be reviewed by a cytopathologist with a special interest in
thyroid disease
•Diagnostic pitfalls:
False-negative results are usually due to inadequate sampling
False-positive results are usually due to “suspicious” findings
Gray zones in cytologic reports are follicular neoplasms, Hürthle cell neoplasms,
and cytologic findings suggestive of but not diagnostic for papillary carcinoma
•Standardization of terminology will improve patient care. Cytologic diagnoses should
be organized into 4 categories—inadequate material, benign, suspicious, and
malignant tumors (see Table 5)
Inadequate, unsatisfactory, or nondiagnostic: smears with few or no follicular cells
Benign or negative: group including colloid nodule, Hashimoto’s thyroiditis, cyst,
thyroiditis
Suspicious or indeterminate: cytologic results that suggest a malignant lesion but
do not completely fulfill the criteria for a definitive diagnosis, including follicular
neoplasms, Hürthle cell tumors, and atypical papillary tumors
Malignant or positive: group consisting of primary (thyroid) or secondary
(metastatic) cancers
*FNA = fine-needle aspiration.

evaluation of thyroid nodules. In geographic regions with tures can be misleading; poor image quality when
iodine deficiency, however, thyroid scintigraphy is still uptake is low
used as part of the evaluation of patients with thyroid nod- 123I advantages:
ules (44) because it provides useful information on the •Better visualization of retrosternal thyroid tissue;
functional characterization of thyroid nodules. In patients better images when thyroid uptake is low
in these regions, the serum TSH may remain unsuppressed 123I disadvantages:
even if autonomy is present because of the low synthesis •Higher cost; less comfortable for the patient (delayed
rate of thyroid hormones by iodine-depleted thyroid imaging at 24 hours is often used)
glands (45). Moreover, in the early phases of autonomy, •Less readily available; imaging times usually longer
the bulk of autonomous tissue may be insufficient to sup-
press the TSH level (46,47), and the early recognition of 2.4.2. Indications for Thyroid Scintigraphy
autonomous nodules, before they induce the suppression Thyroid scintigraphy is indicated in the following
of TSH, may be useful for planning the subsequent diag- settings:
nostic and therapeutic management.
Quantitative pertechnetate scintigraphy (that is, calcu- • Single thyroid nodule or MNG and suppressed TSH
lation of technetium thyroid uptake under suppression level; FNA not necessary
[TcTUs]) is used primarily in Germany (48). TcTUs is a • Large MNG, especially with substernal extension
sensitive and specific technique for the diagnosis and • In search of ectopic thyroid tissue (for example, stru-
quantitation of thyroid autonomy and is a reliable predic- ma ovarii or sublingual thyroid)
tor of hyperthyroidism in the setting of euthyroid autono- • In subclinical hyperthyroidism to identify occult
my. A few reports suggest that patients with thyroid auton- hyperfunctioning tissue
omy and TcTUs of 3% or more should be treated even if • Some investigators suggest evaluation of follicular
the serum TSH level is normal. Those patients with TcTUs neoplasms with a scintiscan to identify a functioning
between 2% and 3% should be considered for treatment if cellular adenoma that may be benign; however, most
they have a high risk of developing overt hyperthyroidism. such nodules are cold on a scintiscan
In patients with TcTUs less than 2%, there is no indication
for radioiodine treatment (48). 2.4.3. Key Recommendations
Thyroid scintigraphy can be performed with The key recommendations for performance of thyroid
99mTcO - or 123I. The advantages and disadvantages of scintigraphy are summarized in Table 9.
4
each of these imaging agents are as follows:
2.5. Laboratory Evaluation
99mTcO - advantages:
4
•Less expensive; more readily available; more rapid 2.5.1. Assessment of Thyroid Function
examination Measurement of the serum TSH concentration is the
99mTcO - disadvantages: single most useful laboratory test in the initial evaluation
4
•Tc is trapped but not organified (risk of false-posi- of thyroid nodules because of the high sensitivity of the
tive images); activity in esophagus or vascular struc- TSH assay in detecting even subtle thyroid dysfunction
Table 9
Key Recommendations for Performance
of Thyroid Scintigraphy*
•Perform thyroid scintigraphy for a thyroid nodule or MNG if the

TSH level is below the lower limit of the normal range or if ectopic
thyroid tissue or a retrosternal goiter is suspected (grade B)†
•In iodine-deficient areas, perform thyroid scintigraphy for a thyroid
nodule or MNG even if the TSH level is in the low-normal range
(grade C)
•Use 123I or 99mTcO - for thyroid scintigraphy (grade B)
4
*MNG = multinodular goiter; TSH = thyroid-stimulating hormone

(thyrotropin).
(48,49; grade C). The measurement of serum free thyroid 2.5.6. Calcitonin Assay
hormones and thyroid peroxidase antibody (TPOAb) lev- Calcitonin is a useful serum marker of MTC and cor-
els should be the second diagnostic step, which is neces- relates well with tumor burden (57). Although routine
sary for confirmation and definition of thyroid dysfunction measurement of calcitonin in patients with thyroid nodules
if TSH levels are outside the normal range. has been recommended (58), this practice remains contro-
versial (59-61). MTC is reported to be present in less than
2.5.2. TSH Assay 0.5% of the population with thyroid nodules, and large-
First- and second-generation TSH assays did not have scale studies of nodular thyroid disease have reported a
adequate sensitivity to detect minor thyroid dysfunction prevalence of MTC ranging from 0.4% to 1.4% of patients
(50). Third-generation TSH chemiluminometric assays, (54,62,63). In addition, the risk of false-positive results
with detection limits of about 0.01 μΙU/mL, should be should be considered; high levels of serum calcitonin can
used in current clinical practice. They detect TSH levels be present in patients with conditions such as impaired
even in cases of mild hyperthyroidism and make possible renal function or gastroenteric diseases treated with proton
a reliable diagnosis of subclinical thyroid hyperfunction pump inhibitors (64,65).
(51,52). Calcitonin testing is imperative in those patients with
a history of familial MTC or MEN2, but routine testing of
2.5.3. Serum Free Thyroxine and Free Triiodothyronine serum calcitonin in all patients with unselected thyroid
If the serum TSH level is within the normal range, the nodules does not seem to be cost-effective. A baseline
measurement of free thyroid hormones adds no further rel- serum calcitonin value of 10 to 100 pg/mL is abnormal
evant information. If TSH levels are low, however, mea- (normal baseline, <10 pg/mL) and should be followed by
surement of free thyroxine (T4) and free triiodothyronine further investigations; values that exceed 100 pg/mL are
(T3) levels is necessary to confirm the presence of hyper- highly suggestive of MTC.
thyroidism or consider central hypothyroidism, in which The pentagastrin-stimulated calcitonin assay is used
both TSH and free T4 levels may be low. in Europe to screen family members of patients with
In order to limit unnecessary laboratory testing, the MTC. In the United States, pentagastrin is no longer avail-
following strategy should be followed for most patients able, and calcium is used to stimulate calcitonin, although
with thyroid nodules (52,53; grade C): family screening should be done by genetic testing. A
blood test for germline mutations of the RET proto-onco-
• Serum TSH level within normal limits: no further test- gene should be done for diagnosis or screening of at-risk
ing family members (66,67).
• High serum TSH: test free T4 and TPOAb to evaluate
for hypothyroidism 2.5.7. Key Recommendations
• Low serum TSH: test free T4 and T3 to evaluate for The key recommendations for laboratory evaluation
hyperthyroidism of patients with thyroid nodules are shown in Table 10.
2.5.4. Antibody Assays 3. MANAGEMENT AND THERAPY

TPOAb should be measured in patients with high lev-
els of serum TSH (54). High levels of serum TPOAb and Clinical management of thyroid nodules should be
a firm, diffusely enlarged thyroid are very suggestive of guided by the results of US evaluation and FNA biopsy
autoimmune or Hashimoto’s thyroiditis (54,55). (Fig. 1 and 2; see Appendix 3).
Occasionally, a nodular goiter may represent Hashimoto’s
thyroiditis. 3.1. FNA-Positive Thyroid Nodule
The utility of the antithyroglobulin antibody assay is
controversial. Thyroglobulin antibody testing should be 3.1.1. Interventional Strategies
reserved for the few patients with US and clinical findings If cytologic results are positive (consistent with a pri-
suggestive of chronic lymphocytic thyroiditis in conjunc- mary thyroid malignant lesion), surgical intervention is
tion with normal serum TPOAb levels (54). almost always necessary (59,68). If cancer is due to
metastatic disease, efforts should be directed toward find-
2.5.5. Thyroglobulin Assay ing the primary lesion, which often precludes a thyroid
Serum thyroglobulin correlates with the iodine status surgical procedure. The extent of thyroidectomy is a mat-
and the size of the thyroid gland rather than with the nature ter of controversy. Currently (in 2006), if preoperative
of a thyroid nodule and adds no further information to the FNA suggests PTC, near-total or total thyroidectomy is
aforementioned tests. Routine assessment of serum the preferred approach (59,68-71). The surgical procedure
thyroglobulin in the diagnosis of thyroid nodules is not should be performed by an experienced thyroid surgeon,
recommended (56; grade C). and lymph nodes within the central compartment of the
Table 10
Key Recommendations for Laboratory Evaluation
of Thyroid Nodules*
•Serum TSH should be tested first, with a third-generation assay

(grade B)†
•If TSH level is low (<0.5 μIU/mL), measure free T4 and T3; if
TSH level is high (>5.0 μIU/mL), measure free T4 and TPOAb
(grade C)
•Routine assessment of serum thyroglobulin is not recommended
for the diagnosis of thyroid nodules or nodular goiter (grade C)
•Serum calcitonin should be measured if FNA or family history
suggests MTC (grade B)
*FNA = fine-needle aspiration; MTC = medullary thyroid

carcinoma; T3 = triiodothyronine; T4 = thyroxine; TPOAb = thyroid
peroxidase antibody; TSH = thyroid-stimulating hormone
(thyrotropin).
neck (level 6) should be removed (68,71). Cervical lymph should be managed more aggressively. The therapeutic
nodes in levels 2, 3, and 4 should be evaluated preopera- decisions for such lesions should be formulated by a
tively by palpation and US. Suspicious lymph nodes multidisciplinary team (69).
identified preoperatively by US or discovered intra-
operatively should be removed and sent for frozen section. 3.1.2. Key Recommendations
Histologic confirmation of metastatic disease should be The key recommendations for management of FNA-
followed by selective (modified) ipsilateral neck positive thyroid nodules are outlined in Table 11.
dissection (59,68-71).
Patients with a diagnosis of PTC by FNA or con- 3.2. FNA-Negative Thyroid Nodule
firmed at surgical intervention, with a nodule <1 cm in
diameter and no evidence of lymph node involvement, 3.2.1. Levothyroxine Suppressive Therapy
may be treated by lobectomy plus isthmectomy alone Efficacy. Suppression of serum TSH (<0.1 μIU/mL)
(59,69-71). Therefore, we recommend that all patients with levothyroxine (LT4), a controversial therapeutic prac-
undergoing thyroid surgical treatment be evaluated by US tice, is aimed at shrinking palpable thyroid nodules and
preoperatively. preventing the appearance of new nodules or the growth of
Advanced, poorly differentiated follicular carcino- the smaller ones coexistent with a dominant mass
mas, Hürthle cell tumors, and medullary carcinomas (60,61,72).
Table 11
Key Recommendations for Management of Thyroid Nodules
That Are Positive by Fine-Needle Aspiration*
•For a thyroid nodule with positive (malignant) FNA results, surgical treatment is recommended (grade B)†
•Review US and cytologic results with the patient and family; discuss treatment options; answer all
questions and concerns; recommend surgical excision and discuss potential complications; obtain surgical
consultation, preferably with a surgeon experienced in endocrine surgical procedures (grade D)
•For most patients, especially those with differentiated cancers >1 cm, familial disease, and clinical or US
evidence of multifocal disease, capsular invasion, or involved nodules, total or near-total thyroidectomy is
indicated. Lymph nodes within the central compartment of the neck (level 6) should be removed, especially
if the surgeon has specific training for and experience with thyroid surgical techniques (grade C)
*FNA = fine-needle aspiration; US = ultrasonography.

Several reports have shown that shrinkage of thyroid • LT4 treatment should never be fully suppressive
nodules occurs more frequently in patients with long-term because of the adverse effects associated with pro-
TSH suppression than in untreated patients (73-76; grade longed subclinical hyperthyroidism (grade A)
A). A clinically significant (>50%) decrease in nodule vol- • If a thyroid nodule does not shrink or grows while the
ume, however, is obtained with LT4 therapy in only a patient is receiving LT4 therapy, reaspiration is indicat-
minority of patients—20% of those with palpable thyroid ed (grade C)
nodules (77,78; grade A). The growth of many thyroid • LT4 suppressive therapy is not useful for prevention of
nodules seems to be minimally dependent on TSH levels; goiter recurrence after lobectomy (grade B)
part of the observed beneficial effect of LT4 therapy on
pressure symptoms or cosmetic complaints is probably Key Recommendations. The key recommendations
because of the decrease in volume of the still-TSH-depen- regarding LT4 therapy in patients with FNA-negative thy-
dent perinodular thyroid tissue. Reduction of nodule vol- roid nodules are presented in Table 12.
ume seems to be more effective in small, recently diag-
nosed thyroid nodules, in lesions with colloid features at 3.2.2. Surgical Treatment
FNA evaluation, and in geographic regions with border- Surgical Indications. The following situations are
line iodine deficiency (79). indications for surgical treatment in a patient with a thy-
Further nodule growth and appearance of new nod- roid nodule.
ules, however, may be impeded by LT4 suppressive thera-
py. A 5-year prospective randomized study and a few Symptoms. Patients may report dysphagia, a choking
meta-analyses have suggested that nodule growth, new sensation, shortness of breath (especially when supine),
nodule appearance, and the growth of the thyroid gland as dyspnea on exertion, hoarseness, neck pressure, or pain.
a whole may be decreased in patients treated with LT4 in These symptoms often occur if a thyroid nodule is large or
comparison with a control group (80,81; grade A). has a substernal component. It is important to verify that
Adverse Effects. LT4 treatment should not be targeted the symptoms are associated with the nodule or goiter and
toward complete TSH suppression. Indeed, sustained sub- not with other disease processes, such as pulmonary or
clinical hyperthyroidism is associated with a significant cardiac disease, esophageal disorders, or other head and
decrease in bone density in postmenopausal women, neck tumors (grade C).
although no available evidence has indicated an increase Associated Hyperthyroidism. A large toxic uninodular
in the rate of bone fractures (72,82,83; grade A). goiter or MNG may be treated surgically or with radioio-
Moreover, in elderly patients with suppressed levels of dine. A patient with a toxic nodule can be treated with thy-
serum TSH, a 3-fold increase in atrial fibrillation and roid lobectomy only, whereas a patient with multinodular
increased mortality attributable to cardiovascular diseases hyperthyroidism should undergo near-total thyroidectomy
have been reported (72,84,85; grade B). (grade C).
Candidates for LT4 Treatment. Currently, routine Nodular Growth. Should a thyroid nodule increase in
LT4 treatment in patients with nodular thyroid disease is size despite benign findings on FNA, surgical resection
not recommended (72). LT4 therapy may be considered in should be considered. The risk of malignant involvement
patients from iodine-deficient geographic areas, in young in this situation, however, is quite low.
patients with small thyroid nodules and colloid features at Suspicious or Malignant FNA Results. Patients with
cytologic sampling, and in those who have nodular goiters suspicious thyroid nodules can be treated with thyroid
with no evidence of functional autonomy. The use of LT4 lobectomy and isthmectomy or total thyroidectomy,
should be avoided in patients with large thyroid nodules or depending on whether the patient already has hypothy-
long-standing goiters, if the TSH level is <1 μIU/mL, in roidism, a history of irradiation, or multiple thyroid nod-
postmenopausal women or in men older than 60 years, and ules or has a treatment preference. At the time of the sur-
in patients with osteoporosis, cardiovascular disease, or gical procedure, frozen section should be performed to
systemic illnesses. help guide the surgical decision making; often, however, it
The physician and the patient should be aware of the is not useful in distinguishing benign from malignant nod-
following: ules (86). In the future, molecular markers may be helpful
as an adjunct to FNA in the distinction of these lesions
• LT4 treatment induces a clinically significant reduction (see section 4.4) (87).
of thyroid nodule volume in only a minority of patients; Most patients with a substantiated well-differentiated
the variables of response are not known (grade A) thyroid malignant lesion on FNA are treated with total or
• Long-term TSH suppression may prevent an increase in near-total thyroidectomy followed by radioiodine therapy.
size of a thyroid nodule and of the thyroid itself, but Patients with MTC should also undergo, at a minimum,
nodule regrowth occurs after cessation of therapy; thus, concomitant central lymph node dissection and, in some
commitment to long-term therapy seems inevitable cases, either ipsilateral or bilateral modified radical neck
(grade A) dissection (88).
Table 12
Key Recommendations Regarding Levothyroxine Therapy for
Thyroid Nodules That Are Negative by Fine-Needle Aspiration*
•Use of LT4 therapy may be considered in the following (grade C†):

Patients from geographic areas with iodine deficiency
Young patients with small thyroid nodules
Nodular goiters with no evidence of functional autonomy
•Use of LT4 therapy should be avoided in most cases and especially in the following
(grade C):
Large thyroid nodules and goiters, particularly in the presence of symptoms or signs
of functional autonomy
Clinically suspicious lesions or lesions with an inadequate cytologic sample
Postmenopausal women and men older than 60 years
Patients with osteoporosis or systemic illnesses
Patients with cardiovascular disease
•Facts to remember:
LT4 treatment induces a clinically significant reduction of thyroid nodule volume in
only a minority of patients (grade B)
Long-term TSH suppression may be associated with bone loss and arrhythmia in
elderly patients and menopausal women (grade B)
LT4 treatment should never be fully suppressive (TSH <0.1 μIU/mL) (grade C)
Nodule regrowth is usually observed after cessation of LT4 therapy (grade C)
If nodule size decreases, LT4 therapy should be continued long term (grade D)
If thyroid nodule grows during LT4 treatment, reaspiration and possibly surgical
treatment should be considered (grade D)
*LT4 = levothyroxine; TSH = thyroid-stimulating hormone (thyrotropin).

Preoperative Management. Preoperatively, in addi- A thyroid gland that extends substernally can almost
tion to standard evaluation by the anesthesia department, always be resected through a cervical approach. In this
patients with documented thyroid cancer should have an setting, only rarely is a median sternotomy necessary to
US examination of the neck, vocal cord assessment, and accomplish thyroid lobectomy or total thyroidectomy.
chest radiography to ensure that they do not have evidence The surgical procedure is usually performed with the
of pulmonary metastatic disease, although such lesions are patient under general anesthesia, although a few surgeons
rare. operate with use of local anesthesia only (89). Some
Surgical Approach. Thyroid lobectomy includes total surgeons perform this operation by using a video-assisted
or near-total lobectomy, with or without isthmectomy. technique; thus, the length of the neck incision can be
Should the patient require a completion thyroidectomy, it shortened (90).
is usually technically easier to perform if the isthmus has Postoperative Complications. As is the case with all
previously been resected; this setting would lessen the operations, bleeding or infection can occur, but these com-
need for dissection along the anterior aspect of the trachea. plications are rare. Permanent hypoparathyroidism or
Total thyroidectomy differs from near-total thyroidec- injury to the recurrent laryngeal nerve should occur in less
tomy in that a small rim of thyroid tissue is left along the than 1% of the cases when the surgical procedure is per-
cricopharyngeal muscle, where insertion of the recurrent formed by experienced surgeons.
laryngeal nerve occurs. During the surgical procedure, Key Recommendations. In Table 13, the key recom-
meticulous care must be exercised by the surgeon to iden- mendations for surgical treatment of thyroid nodules are
tify and preserve all 4 parathyroid glands and to avoid summarized.
injury to the recurrent laryngeal nerve.
Table 13
Key Recommendations Regarding Surgical Treatment
of Patients With Thyroid Nodules*
•Surgical indications in a patient with a thyroid nodule include

the following:
Associated local symptoms
Hyperthyroidism from a large toxic nodule, or hyperthyroidism
and concomitant MNG
Growth of the nodule
Suspicious or malignant FNA results
•Thyroid lobectomy includes total or near-total lobectomy, with
or without isthmectomy. Should the patient require completion
thyroidectomy, it is technically easier to perform if the isthmus
has previously been resected
•For a solitary benign nodule, lobectomy plus isthmectomy is
sufficient; for bilateral nodules, a near-total thyroidectomy is
appropriate
•The surgical procedure is usually performed with use of general
anesthesia; however, some surgeons operate with use of local
anesthesia only
•A thyroid gland that extends substernally can almost always be
resected through a cervical approach. Only rarely is median
sternotomy necessary to accomplish thyroid lobectomy or total
thyroidectomy
•With experienced surgeons, associated complications are rare
*FNA = fine-needle aspiration; MNG = multinodular goiter.
3.2.3. US-Guided Percutaneous Ethanol Injection 80.0% of patients treated with PEI but in only 24.4% and
Percutaneous ethanol injection (PEI) is a US-guided, 37.4% of patients treated with simple drainage (94-
mini-invasive therapeutic procedure for the nonsurgical 97,99,100). In large or multilocular thyroid cysts, several
management of thyroid nodules (91,92). injections may be necessary (95).
Efficacy. In the management of thyroid cysts, PEI is For autonomously functioning thyroid nodules
highly effective in the treatment of complex nodules with (AFTN), the reported short-term rate of therapeutic
a dominant fluid component. Aspiration may cure thyroid response in toxic cases ranges from 64% to more than 95%
cysts; however, recurrences are common, and surgical (101-104; grade C), but 5 years after PEI, serum TSH is
resection is often the final treatment of large relapsing detectable in only 35.3% of the treated cases (95). PEI is
lesions. Prospective randomized trials showed that PEI is reported to induce a volume decrease of 60% to 75%, but
significantly superior to aspiration alone in inducing a small residual amount of tissue persists and accounts for
reduction of nodule volume (93-95; grade C). A reduction the high relapse rate (95). Hence, PEI is not indicated for
of >50% of the baseline volume is obtained in almost 90% the treatment of toxic AFTN or hyperfunctioning nodular
of the treated cases (95-100; grade A). goiters with multiple foci of functional autonomy because
The recurrence rate of cystic lesions of the thyroid is of a high recurrence rate and the availability of alternative
very low. In a 6-month survey, fluid refilling was reported effective treatment options.
in 5% of the treated nodules, and in a 12-month prospec- A clinically significant decrease in nodule size after
tive study, only 1 of 38 complex (predominantly cystic) PEI has been reported in patients with solitary solid,
thyroid nodules recurred (95; grade A). In other published benign thyroid nodules that were cold on scintigraphy
series, volume reduction was followed by the disappear- (105,106; grade B). In comparison with LT4 treatment,
ance of compressive and cosmetic symptoms in 74.8% and PEI is more effective in inducing the reduction of nodule
volume and alleviating local symptoms (107; grade A). Key Recommendations. The key recommendations
The response, however, is much less impressive than in for use and avoidance of PEI in patients with thyroid nod-
cysts, and adverse effects are more frequent (95). ules are outlined in Table 14.
Indications. PEI should be the first line of treatment
for recurrent cystic nodules of the thyroid gland after FNA 3.2.4. Radioiodine
has ruled out a malignant lesion (13,21,23). PEI may be Radioiodine is indicated for the treatment of hyper-
considered only in AFTN with a large fluid component for thyroidism attributable to hyperfunctioning adenoma or to
a preliminary debulking before radioiodine treatment and toxic nodular goiter. The aims of radioiodine treatment are
in small AFTN with incomplete inhibition of the sur- the ablation of the autonomously functioning areas and the
rounding parenchyma, especially if a fluid component is achievement of euthyroidism (109,110). Autonomous thy-
present (108). The absence of associated scarring, expo- roid nodules are usually more radioresistant than are toxic
sure to irradiation, and late hypothyroidism may make this diffuse goiters, and higher radiation doses may be needed
procedure appealing to young patients. PEI is not indicat- for successful treatment (111).
ed in cold thyroid nodules because it necessitates repeated Efficacy and Adverse Effects. Radioiodine therapy is
treatments, induces unpleasant adverse effects (transient successful in 85% to 100% of patients with hyperfunc-
cervical pain), can be complicated by dysphonia attribut- tioning thyroid nodules or toxic MNGs (111; grade C).
able to recurrent laryngeal nerve damage, and carries the After treatment with ablative doses, the thyroid volume
risk of overlooking thyroid neoplasms. may decrease substantially (median decrease, 35% at 3
Table 14
Key Recommendations Regarding Performance of
Percutaneous Ethanol Injection in Patients With Thyroid Nodules*
•PEI should be performed:

Only by personnel familiar with US-FNA (grade D)†
On cystic thyroid lesions. PEI is highly effective in the treatment of thyroid cysts and complex
nodules with a large fluid component (grade B). Because the only alternative to PEI for recurrent
and enlarging cysts is surgical resection, PEI is the first-line nonsurgical treatment for recurrent
cystic nodules if US-FNA has ruled out a malignant lesion
•PEI should not be performed:
On solid, cold nodules, unless surgical treatment is contraindicated (grade D)
On large or toxic AFTN (nodule volume >5 mL)—the rate of cure is too low and relapse is
frequent (grade B)
On toxic MNGs (grade B)
•PEI may be considered:
In some small AFTN (nodule volume <5 mL), with a relevant fluid component and not yet
completely suppressing the surrounding thyroid parenchyma, if patients are concerned about late
hypothyroidism (grade C)
•What to do before PEI:
If the nodule is considered suitable for PEI, malignant involvement should be ruled out by US-
FNA. Multiple cytologic examinations of the cystic wall should be performed (grade C)
A thorough US examination should evaluate the position, shape, size, margins, and vascular
pattern of the nodule (grade C)
•What to do during PEI (grade D):
Continuously monitor the position of the needle tip in the nodule and of ethanol diffusion within
the nodule
Stop the procedure immediately if the patient reports severe pain, begins to cough, or has a change
in voice
*AFTN = autonomously functioning thyroid nodules; MNGs = multinodular goiters; PEI = percutaneous
ethanol injection; US = ultrasonography; US-FNA = US-guided fine-needle aspiration.
months and 45% at 24 months) (112). Radioiodine treat- tively superior to the other. Radioiodine therapy is usually
ment is effective and safe. Although investigators have defined as successful when the TSH value exceeds 0.5
indicated that high doses of radioiodine may induce thy- μIU/mL. TcTUs can also be used to evaluate the success
roid cancer, other solid tumors, or leukemia, large epi- of radioiodine treatment. If thyrotoxicosis is not defini-
demiologic studies have not shown a clinically significant tively cured, radioiodine treatment can be repeated after 3
effect (113,114; grade C). to 6 months.
After ablation of the autonomous tissue, 80% to 90% Indications. Radioiodine treatment is indicated for
of patients have euthyroidism because of residual normal small goiters (volume <100 mL) without suspected thy-
thyroid function. Nevertheless, hypothyroidism may fol- roid malignant involvement or in patients previously treat-
low radioiodine treatment if the mass of normal thyroid ed surgically or at risk for surgical intervention.
tissue is too small or if its function is decreased from coex- Radioiodine therapy, however, is not the first-line treat-
istent autoimmune thyroiditis (115) or from damage con- ment if compressive symptoms are present, if the patient
sequent to contiguity cross-irradiation from hot nodules. has large nodules that require high amounts of radioiodine
In less than 1% of patients, immunogenic hyperthyroidism and may be resistant to treatment, or if an immediate res-
may result from radioiodine treatment of toxic nodular olution of thyrotoxicosis is desired (109,110). The only
goiter because of induction of TSH receptor autoantibod- absolute contraindications to radioiodine treatment are
ies (116). pregnancy and lactation, which should be excluded by per-
Ingestion of high-iodine-content drugs (such as amio- formance of a pregnancy test (117).
darone or a saturated solution of potassium iodide) should Key Recommendations. In Table 15, the key recom-
be avoided before administration of radioiodine, so as not mendations pertaining to radioiodine therapy in patients
to impair thyroid radioiodine uptake. If possible, antithy- with thyroid nodules are presented.
roid drugs should be withdrawn at least 3 weeks before
treatment, in an effort to prevent radioiodine uptake by 3.3. Suspicious (Indeterminate) Thyroid Nodule by
normal thyroid tissue, and they should not be administered FNA
for 3 to 5 days after treatment, to avoid decreasing the
effectiveness of therapy. 3.3.1. Contributing Factors
The amount of radioiodine to be administered can be Indeterminate FNA results are due to poorly defined
fixed (300 to 1,800 MBq), without any dose calculation or morphologic criteria to distinguish benign from malignant
adjustment on the basis of clinical and goiter size and lesions. Currently, no clear-cut cytologic criteria are avail-
uptake. This approach is simple, minimizes costs, and able to help the clinician in decision making. If the cyto-
yields good results. logic appearance is equivocal, the specimen is labeled
Alternatively, an individual computation of the “suspicious for malignancy” or “indeterminate.” At surgi-
desired concentration of radioiodine (2.96 to 7.4 MBq/g) cal intervention, about 20% of such indeterminate speci-
or of radiation absorbed dose (300 to 400 Gy) at the target mens are found to be malignant lesions (30,35,118; grade
(that is, autonomous tissue) can be performed (111). For C). Repeated biopsy of these nodules is not recommended
absorbed dose estimation, Marinelli’s formula can be because it creates confusion and does not provide addi-
used: tional useful information for management. Some studies
have suggested that clinical criteria such as nodule size
DT m
A0 = 5,829 (>4 cm), fixation, and age of the patient may be associat-
U max T1 / 2eff ed with increased risk for malignant potential (119),
whereas others have not confirmed these observations
in which A0 = administered activity of 131I (MBq); DT = (118).
prescribed absorbed dose (cGy); m = autonomous tissue Results indicating a suspicious cytodiagnosis include
mass (g); Umax = maximal thyroid uptake (%); and T1/2eff follicular neoplasms, Hürthle cell tumors, and specimens
= 131I effective half-life in target tissue (h). Maximal thy- that show atypical but not classic features of PTC (34). In
roid uptake and effective half-life are measured as tracer a large series at the Mayo Clinic, 15% of follicular neo-
activity after administration of 131I, and the target volume plasms, 14% of Hürthle cell tumors, and 65% of atypical
can be estimated by US or thyroid scan. In cases of multi- lesions had histologic confirmation of malignant involve-
focal autonomy, the thyroid gland as a whole can be used ment (30). It is generally agreed that cytologically suspi-
as the target volume, and the desired absorbed dose is cious lesions should be treated surgically.
decreased to 150 to 200 Gy.
Individualized approaches can decrease ineffective 3.3.2. Key Recommendations
treatments or help to avoid administration of too much The key recommendations regarding indeterminate
radioiodine, but individualizing therapy is more complex FNA results of thyroid nodule biopsy are shown in Table
and expensive. Neither approach has been proved defini- 16.
Table 15
Key Recommendations Regarding Radioiodine Therapy
in Patients With Thyroid Nodules*
•Consider radioiodine treatment for small goiters (volume <100 mL), in those without suspected
malignant potential, in patients with a history of previous thyroidectomy, and in those at risk for
surgical intervention (grade B)†
•Radioiodine treatment is not the first-line therapy if compressive symptoms are present, if patients have
large nodules that require high amounts of radioiodine and may be resistant to treatment, or if
immediate resolution of thyrotoxicosis is desired (grade C)
•Radioiodine treatment is effective and safe. Large epidemiologic studies have shown no associated
clinically significant increase in the risk of cancers or leukemia (grade B)
•Give radioiodine therapy cautiously in elderly patients, especially those with heart disease (grade C)
•Radioiodine is contraindicated in pregnant or lactating women; always perform a pregnancy test before
administration of radioiodine in women of childbearing age (grade A)
•Avoid use of iodine contrast agents or iodinated drugs before administration of radioiodine; withdraw
antithyroid drugs at least 3 weeks before treatment and resume such regimens 3 to 5 days after
radioiodine therapy (grade C)
•Follow-up of patients should include monitoring of serum levels of TSH, free T4, and free T3; consider
repeating treatment in 3 to 6 months if TSH is still <0.1 μIU/mL (grade C)
*T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone (thyrotropin).

3.4. Nondiagnostic Cytologic Specimen by FNA 3.4.2. Key Recommendations

The key recommendations regarding nondiagnostic
3.4.1. Contributing Factors and Suggested Approach FNA cytologic specimens from thyroid nodules are sum-
US-FNA is indicated if the thyroid nodule is smaller marized in Table 18.
than 1 cm or impalpable by examination or if the initial
palpation-guided FNA was nondiagnostic (Table 17) 3.5. Repeated Biopsy
(14,19). Additionally, for PEI or laser ablative treatment,
US guidance is essential. Indications for reaspiration of a thyroid nodule are
An unsatisfactory (nondiagnostic) specimen usually listed in Table 19. Whether routine rebiopsy is necessary
results from a cystic nodule that yields few or no follicu- is unclear. For physicians or clinics beginning to perform
lar cells (120-122). Reaspiration yields satisfactory results FNA, reaspiration provides reassurance with the proce-
in 50% of cases (33). Despite good initial technique, dure and may decrease false-negative rates. We recom-
repeated biopsy, and US-FNA, approximately 5% of nod- mend reaspiration if a nodule enlarges, a cyst reappears, a
ules still remain nondiagnostic. Such thyroid nodules nodule is larger than 4 to 5 cm, or no shrinkage of the nod-
should be surgically excised (grade D). ule occurs after LT4 therapy (Table 19).
Several recent reports indicated that the application of
US-FNA improves results. For example, 2 European stud- 4. OTHER ISSUES AND FUTURE PERSPECTIVES
ies showed that nondiagnostic rates of 8.7% and 16% were
decreased to 3.5% and 7%, respectively, with the applica- 4.1. Thyroid Nodule During Pregnancy
tion of US-FNA (123,124; grade C). Additionally, the sur-
gical yield of cancer increased by 20% in both series with Most cases of thyroid nodules during pregnancy are in
use of US-FNA. Similar data have been reported by other patients with preexisting nodules who then become preg-
medical centers. Clearly, the application of US-FNA, with nant; occasionally, however, a thyroid nodule is detected
indications as outlined in Table 17, improves results. for the first time during pregnancy. A thyroid nodule in a
Table 16
Key Recommendations Regarding Suspicious (Indeterminate)
Fine-Needle Aspiration Biopsy of Thyroid Nodules*
•Indeterminate FNA results are due to poorly defined morphologic criteria for
distinguishing benign from malignant lesions. No clear-cut cytologic criteria are
available to aid in decision making. At surgical intervention, about 20% of
indeterminate FNA specimens are malignant lesions
•Repeated biopsy of these nodules is not recommended because it creates confusion and
does not provide additional useful information for management
•Because large-needle thyroid biopsy is not more accurate than FNA, is more
cumbersome, and is associated with pain and occasional severe bleeding, it is
currently not recommended in the management of thyroid nodules
•Clinical criteria such as nodule size (>4 cm), fixation, and age of the patient may
suggest increasing risk for malignant potential
•Currently, we recommend surgical excision of all indeterminate thyroid nodules
*FNA = fine-needle aspiration.
pregnant woman should be managed in the same way as in that LT4 is effective in reducing the size or arresting the
nonpregnant women, except for the avoidance of use of growth of thyroid nodules during pregnancy. Hence, LT4
radioactive agents for both diagnostic and therapeutic pur- therapy for thyroid nodules is not advisable during preg-
poses. Thyroid nodule diagnosis during pregnancy neces- nancy (grade C).
sitates FNA, regardless of the gestational age of the fetus.
Sharing of findings on the patient assessment among 4.1.3. FNA-Malignant Thyroid Nodule
endocrinologist, obstetrician, thyroid surgeon, pathologist, Thyroid cancer is rarely diagnosed during pregnancy.
and anesthesiologist is recommended. Furthermore, the If cancer is diagnosed during the first or second trimester,
patient’s preferences should also be appropriately consid- the patient should undergo surgical treatment during the
ered. second trimester, when anesthesia risks are minimal. If the
cytologic diagnosis is made during the third trimester, the
4.1.1. Effects of Pregnancy on Nodular Thyroid Disease surgical procedure can be postponed until the immediate
In a recently published series, thyroid nodules were postpartum period (grade C).
diagnosed in 34 of 221 pregnant patients, and they under-
went follow-up for 3 months after delivery (125). The 4.1.4. FNA-Suspicious Thyroid Nodule
mean volume of the single or dominant thyroid nodule Suspicious cytologic findings pose a difficult problem
increased from 60 mm3 at the beginning of pregnancy to during pregnancy. Although pregnancy may cause a mis-
65 mm3 at the third trimester and to 103 mm3 at 6 weeks leading diagnosis of follicular neoplasm because of a
after delivery. At the 3-month postpartum follow-up, the physiologic increase in follicular epithelium, the malig-
volume was still increased (73 mm3). New thyroid nodules
developed in 11.3% of women during pregnancy; this cir-
cumstance led to an increase in the incidence of thyroid Table 17
nodular disease from 15.3% at baseline to 24.4% 3 months Indications for Ultrasonography-Guided
after delivery. No ultrasonographically discovered new Fine-Needle Aspiration of Thyroid Nodule*
thyroid nodules were palpable. These data indicate that
pregnancy is associated with an increase in the size of pre- Nondiagnostic palpation-guided FNA
existing nodules and with the appearance of newly devel- Impalpable nodule
oped thyroid nodules, possibly because of the negative
Thyroid nodule <1 cm
iodine balance that frequently occurs during pregnancy
(126; grade C). Neck node
Ablative therapy
4.1.2. LT4 Suppressive Therapy
Although pregnancy is a risk factor for progression of *FNA = fine-needle aspiration.
nodular thyroid disease, no available evidence indicates
Table 18
Key Recommendations Regarding Nondiagnostic
Fine-Needle Aspiration Cytologic Specimens From Thyroid Nodules*
•An unsatisfactory (nondiagnostic) FNA specimen usually results from a cystic nodule
that yields few or no follicular cells
•US-FNA directed at the peripheral portion of the lesion is indicated if initial
palpation-guided FNA was nondiagnostic
•Reaspiration yields satisfactory results in 50% of cases
•Despite good initial technique, rebiopsy, and US-FNA, approximately 5% of thyroid
nodules remain nondiagnostic. Such nodules should be surgically excised (grade D)†
*FNA = fine-needle aspiration; US-FNA = ultrasonography-guided FNA.

nancy rate of follicular neoplasm in pregnant women is rhTSH. Patients are prescribed a β-adrenergic blocking
similar to that in nonpregnant women—about 14%. agent or calcium channel blocker at the time of therapy to
Therefore, deferring surgical treatment to the postpartum avoid any potential thyroid hormone-mediated adverse
period seems reasonable (grade C). effects. The standard dose (30 mCi) of 131I is given orally
72 hours after the rhTSH, and typically no substantial
4.1.5. Key Recommendations radioiodine-induced sequelae occur in the immediate post-
The key recommendations pertaining to thyroid nod- treatment period. Rarely, immunogenic hyperthyroidism
ules during pregnancy are outlined in Table 20. attributable to induction of TSH receptor antibodies has
been reported to occur several months after treatment.
4.2. Radioiodine Treatment of Nodular Goiter Patients should undergo US-FNA to rule out the pres-
ence of a malignant lesion before treatment. Currently,
As discussed earlier, the use of radioiodine for the rhTSH is approved only for scanning and thyroglobulin
treatment of toxic nodular goiter is well established. Its stimulation in patients with postoperative thyroid cancer,
use in nontoxic nodular goiter has been reported in numer- and its use to augment radioiodine treatment is considered
ous studies from geographic areas with relatively low “off-label.” Clinical trials are now under way, however, to
dietary intake of iodine (127-131). In these reports, obtain United States Food and Drug Administration
patients with MNG had elevated or high-normal 24-hour approval for its use. In elderly patients or patients with
radioiodine uptake in comparison with that in similar comorbid conditions that preclude anesthesia or surgical
patients with MNG in the United States. In geographic treatment, rhTSH-augmented radioiodine treatment has
areas of high dietary intake of iodine, patients with MNG proved to be effective for MNG (131).
usually have low radioiodine uptake accompanied by low-
normal or suppressed levels of TSH in the circulation. 4.2.2. Key Recommendations
In Table 21, the key recommendations for radioiodine
4.2.1. Use of Recombinant Human TSH treatment of nodular goiter are presented.
When patients with low-uptake MNG are given small
doses (0.1 mg) of recombinant human TSH (rhTSH), their
radioiodine uptake increases more than 4-fold within 72 Table 19
hours—the time it takes to activate the sodium-iodine Indications for Repeated Biopsy
symporter (132-134). This scenario allows delivery of suf- of Thyroid Nodule
ficient radiation therapy to the thyroid to cause a decrease
in size and amelioration of compressive symptoms within Follow-up of benign nodule
2 months. As in patients with high-uptake MNG, the aver- Enlarging nodule
age decrease in goiter size is 40% during the first year and
Recurrent cyst
60% by the end of the second year. In patients with a sup-
pressed TSH level, the TSH returns to normal or increases Thyroid nodule >4 cm
within 3 to 6 months. Initial fine-needle aspiration biopsy nondiagnostic
Free T4 and total T3 levels increase approximately No shrinkage of nodule after levothyroxine therapy
50% over baseline within 72 hours after injection of the
Table 20
Key Recommendations Relative to
Thyroid Nodules During Pregnancy*
•No evidence indicates that administration of LT4 is effective in reducing the size or
arresting the growth of thyroid nodules during pregnancy; thus, LT4 therapy during
pregnancy is not advisable (grade C)†
•For a growing thyroid nodule during pregnancy, follow-up studies should include
FNA and US (grade C)
•With a cytologic diagnosis of thyroid cancer during the first or second trimester in
a pregnant woman, surgical intervention should be undertaken during the second
trimester, when anesthesia risks are minimal. If this cytologic diagnosis is made
during the third trimester, postpone surgical treatment until the immediate
postpartum period (grade C)
•Pregnancy may cause a misleading diagnosis of follicular neoplasm. The
malignancy rate of follicular neoplasm during pregnancy is about 14%. Therefore,
defer surgical treatment to the postpartum period (grade C)
*FNA = fine-needle aspiration; LT4 = levothyroxine; US = ultrasonography.

Table 21
Key Recommendations Regarding
Radioiodine Treatment of Nodular Goiter*
•In patients with low-uptake MNG given small doses of rhTSH, radioiodine uptake
increases >4-fold within 72 hours. Sufficient radiation therapy is delivered to the
thyroid to decrease the size and to ameliorate compressive symptoms rapidly
•Average decrease in goiter size is 40% during the first year and 60% by the end of the
second year. In patients with suppressed TSH levels, the TSH value returns to
normal or increases within 3 to 6 months
•Free T4 and total T3 levels increase approximately 50% over baseline within 72 hours
after injection of rhTSH. β-Adrenergic or calcium channel blockers are given to avoid
thyroid hormone-mediated adverse effects
•131I (30 mCi) is given orally 72 hours after rhTSH. No significant radioiodine-induced
sequelae occur immediately. Rarely, immunogenic hyperthyroidism occurs
several months after treatment
•Before treatment, US-FNA should be performed to rule out a malignant lesion
•Currently, use of rhTSH to augment radioiodine treatment is considered “off-label.” In
elderly patients or patients with comorbid disorders that preclude anesthesia or
surgical intervention, however, rhTSH-augmented radioiodine treatment is effective in
management of MNG
*MNG = multinodular goiter; rhTSH = recombinant human TSH; T3 = triiodothyronine; T4 =

thyroxine; TSH = thyroid-stimulating hormone (thyrotropin); US-FNA = ultrasonography-
guided fine-needle aspiration.
Table 22
Key Recommendations Regarding Laser Thermal Ablation
in Patients With Thyroid Nodules*
•LTA is a low-cost, rapid, and effective mini-invasive technique for the treatment of
benign thyroid nodules causing pressure symptoms or cosmetic complaints
•The procedure should be performed only in carefully selected cases (high-surgical-
risk patients). In most patients, 1 to 3 sessions of LTA or a single treatment with
multiple fibers induces a nearly 50% decrease in nodule volume and the
amelioration of local symptoms (grade C)†
•LTA should be restricted to specialized centers, in light of the need for skilled
operators to avoid the risk of major complications (grade D)
*LTA = laser thermal ablation.

4.3. Laser Thermal Ablation 4.3.2. Key Recommendations

The key recommendations relative to the use of LTA
4.3.1. Technique and Outcome in patients with thyroid nodules are summarized in Table
Laser thermal ablation (LTA) is a mini-invasive pro- 22.
cedure proposed as an alternative to surgical ablation of
benign thyroid lesions causing compressive symptoms or 4.4. Histochemical Markers
cosmetic complaints (135,136; grade C). Under US guid-
Several laboratories are now developing molecular
ance, a 21-gauge needle is inserted into the thyroid lesion,
assays aimed at clarifying suspicious (indeterminate) FNA
and a thin (300-μm) optical fiber is advanced into the nee-
results. For example, HBME-1 (human bone marrow
dle sheath. With US monitoring, the needle and fiber tips
endothelial cell) is a monoclonal antibody that stains pos-
are visualized as hyperechoic spots, and during laser irra-
itively for papillary cancer but not for benign follicular
diation, the site under treatment shows an echogenic area
tumors (118,139). In addition, one of the galectins (a cal-
enlarging over time. The echogenic zone does not reflect
cium-independent class of lectins), galectin-3, which acts
the actual extent of thermal necrosis, and US and color
as a cell-death suppressor, has been reported to distinguish
Doppler evaluations provide a precise delineation of the
benign from malignant thyroid follicular tumors
laser-induced damage only after the conclusion of the
(118,140). Other markers being investigated, including
procedure (136).
thyroid peroxidase, telomerase, and others, have been used
LTA induces a burning cervical pain, which rapidly
with variable success (141). Most studies show, however,
decreases when the energy is turned off. In the few
that the markers have high sensitivity or specificity, but
patients treated by this technique to date, no permanent
not both, in diagnosing thyroid cancer. Therefore, at this
dysphonia, cutaneous burning, or damage to the vital
time, no specific tumor marker is available that will regu-
structures of the neck have been reported (137,138).
larly and reliably distinguish benign from malignant thy-
The treatment is performed on an outpatient basis, is
roid cellular tumors.
inexpensive, and is not a time-consuming procedure (30
minutes). After LTA, the patients may return home; 4.5. Ultrasonographic Media
the persistence of cervical pain can be controlled by a
2-day course of orally administered analgesics or cortico- First- and second-generation contrast agents seem to
steroids. provide only ancillary data for the diagnosis of malignant
In most patients with large thyroid nodules, 1 to 3 ses- thyroid nodules. The variation of time-intensity curves
sions of LTA or a single treatment with multiple fibers has during the transit times of the injected microbubbles offers
been reported to induce an almost 50% decrease in nodule a modest improvement over the information obtainable
volume and the amelioration of local symptoms (137,138). with traditional color Doppler or power Doppler examina-
Because of the risk of major complications and the lack of tions (142). New specifically designed microbubbles and
large prospective trials and long-term follow-up, LTA new models of US equipment with specific software are
should be restricted to specialized centers and should still needed to improve the predictive value of contrast-
be considered an experimental procedure. enhanced US for small-parts applications.
APPENDIX 1: PRACTICAL TIPS
The following are suggestions for care of patients with nodular thyroid disease, based on Task Force consensus and
other expert opinions (grade D).
Minimal Requirements for US Equipment
Overall
Advances in electronics and US technology have decreased the cost of US equipment and made it possible to have
dedicated instruments for thyroid evaluation. Phased-array transducers have made mechanical transducers obsolete. The
type of equipment required depends on its use.
Thyroid US and US-FNA

A 7.5- to 10.0-MHz transducer is sufficient to detect and measure thyroid nodules and to perform US-FNA. Such a
transducer allows identification of microcalcifications in real time and usually affords adequate resolution to define the
borders of nodules. A linear transducer is generally best for US-FNA. Doppler capability is necessary for determining the
vascularity of nodules and sometimes aids in defining the borders of nodules. This level of resolution will allow identifi-
cation of moderately enlarged lymph nodes (>0.5 cm) in the lateral areas of the neck but may not allow adequate evalu-
ation of lymph node characteristics (hilar line, microcalcifications, cystic necrosis).
For lymph node surveillance in the postoperative thyroid cancer patient, for parathyroid identification, and for per-
formance of PEI, a 10- to 14-MHz transducer is recommended. Power Doppler US is imperative to determine the vascu-
larity of lymph nodes and accelerates the examination by quickly identifying small vessels that may resemble lymph
nodes. It also will identify the polar artery in some parathyroid adenomas. The higher resolution allows detection of
lymph nodes ≤0.5 cm and evaluation of the aforementioned characteristics. A needle guide attachment is necessary for
PEI or LTA, to keep the needle under constant observation during the procedure.
Recommendations for US Evaluation and Reporting
The report of US examination of the thyroid is the main method of sharing information with the referring physician,
the general practitioner, and the patient. The description of the US characteristics of the thyroid should provide all the
information useful for clinical purposes. A definite diagnosis is not possible with US, but a mere descriptive report is
inappropriate if it does not include clinically useful details. Hence, an US report should enable the reader to stratify the
nodule under examination on a malignancy risk scale.
In light of the facts that US is a considerably operator-dependent imaging technique and that static images are always
unsatisfactory, we recommend paying specific attention to several aspects of the US report.
• Aims of the US report:

Describe the US elements useful for making a correct diagnosis
Describe to the patient his or her own situation; make it possible for the patient to follow the nodule over time
• Content requirements:
Position within the thyroid
Size—at least the maximal diameter, specifying whether it is longitudinal, anteroposterior, or laterolateral with
respect to the lobe anatomy
Echogenicity (anechoic, hypoechoic, isoechoic, or hyperechoic)
Presence of a fluid component (mixed nodules)
Characteristics of the borders
Presence of peripheral halo
Internal calcifications (microcalcifications or macrocalcifications)
If possible, vascular pattern
If the nodule is solitary or only a few well-separated nodules are present, each nodule should be described analyti-
cally. If multiple nodules are present, a general description of the thyroid size and structure may be advisable, pointing
out with detail the nodule (or nodules) bearing the US characteristics associated with malignant potential (see text sec-
tion 2.2), rather than describing only the largest (dominant) nodule.
The report should be typewritten and should indicate clearly the name of the operator and the clinic or hospital. It
should be stored in an archive or saved on informatic databases; it should be retrievable.
Static pictures do not provide adequate information for a typically dynamic examination, and their usefulness is lim-
ited in US. Nevertheless, inclusion of some images in the report is recommended, especially if particularly important
details are detected (suspicious nodules).
• Stylistic suggestions for writing the US report:

Be concise
Point out the pathologic aspects; avoid writing too much about normal findings. Describe normality only if a previ-
ous pathologic detail is no longer present (such as a cyst that disappeared) or if a normal report is clinically unex-
pected (for example, a thyroid nodule suspected by palpation but not shown with US)
Do not use acronyms, or cite only widely known acronyms
Use technical or easily understandable terms, avoiding words with uncertain or multiple meanings
Recommendations for US-FNA Procedure and Slide Preparation
FNA is the most important diagnostic procedure in the initial evaluation of thyroid nodules, and its accuracy influ-
ences subsequent clinical management. The use of US-FNA has increased during the past few years because its accura-
cy in diagnosing thyroid nodules exceeds that of conventional direct FNA. Proper FNA technique and smear preparation
are critical to ensure good results (see text section 2.3).
Discuss the procedure with the patients to reassure them that serious complications are unlikely. US-FNA is not
essential if the nodule is palpable, although US-FNA will be necessary if the initial report is unsatisfactory (nondiagnos-
tic). FNA is safe with use of aspirin or anticoagulants.
US-FNA should be performed by physicians with expertise and interest in thyroid disease. Requisites are experience
with palpation of thyroid nodules and with US evaluation of the thyroid, good training, and performance of several US-
guided aspirations sufficient to attain expertise.
Commercially available US devices equipped with 7.5- to 10.0-MHz transducers provide a clear and continuous visu-
alization of the thyroid gland and the needle tip on the monitor. Small transducers are especially convenient for US-FNA.
After the biopsy sites have been determined, the needle should be inserted through a steering device (US-guided FNA)
or just above the center of the transducer (US-assisted FNA). This positioning allows the needle to be inserted nearly per-
pendicular to the neck, and the tip of the needle (clearly visible as a bright spot on the screen) is observed on the moni-
tor until it reaches the biopsy target. Because of the direct visualization of the needle, accidental damage to the trachea,
carotid artery, jugular vein, or recurrent laryngeal nerve can be avoided. US-guided aspirations require a single operator
and a shorter training program than conventional direct FNA, but the flexibility of the procedure is limited by the steer-
ing device.
Large needles may produce blood contamination of the aspirated sample. A 25- or 27-gauge needle is suitable for
most palpable thyroid nodules, and its use is suggested for the first sampling of the lesion. Aspiration should be ceased
as soon as sample appears in the hub of the needle, and smears are then prepared (see text section 2.3).
With US-FNA, the operator is able to choose the biopsy site after a careful US evaluation. The recommended biopsy
sites are as follows:
• In large nodules, the peripheral part of the lesion rather than the central area, because of frequent degenerative changes
• In entirely cystic areas, the center of the lesion should be reached in order to drain the fluid content completely. Cystic
fluids should be submitted to the laboratory for evaluation. Most colloid fluids are clear yellow; clear-colorless fluid
suggests parathyroid origin, and material should be submitted for measurement of parathyroid hormone. Hemorrhagic
fluid suggests a high malignant potential
• In mixed or mostly fluid complex lesions, the needle should be addressed to the root of hubs or pedicles growing into
the cystic lumen (the inner area of the pedicle facing the lumen usually contains necrotic debris and cells with degen-
erative changes). After complete drainage of the fluid, both the solid areas and the peripheral borders of the lesion
should be sampled
A definite cytologic diagnosis should always be obtained before PEI treatment of cystic or complex lesions is
performed.
Recommendations for Cytologic Reporting
The diagnostic accuracy of FNA is increased with communication between the clinician and the cytopathologist.
Thyroid smears should be reviewed by a cytopathologist who has a special interest in thyroid disease.
• Diagnostic pitfalls:
False-positive results are usually due to “suspicious” (indeterminate) findings
Gray zones in cytologic reports are follicular neoplasms, Hürthle cell neoplasms, and cytologic findings suggestive
of but not diagnostic for papillary carcinoma
The cytologic diagnosis should be clear to help the clinician manage the condition. Thus, standardization of termi-
nology will improve patient care. Cytologic diagnoses should be organized into 4 categories—inadequate material,
benign, suspicious, and malignant tumors (see text Table 5).
• Inadequate, unsatisfactory, or nondiagnostic: smears with few or no follicular cells. Action: repeat FNA
• Benign or negative: group including colloid nodule, Hashimoto’s thyroiditis, cyst, thyroiditis. Action: observation and
follow-up. Cytologically benign but clinically suspicious lesions should be excised
• Suspicious or indeterminate: cytologic results that suggest a malignant lesion but do not completely fulfill the criteria
for a definitive diagnosis, including follicular neoplasms, Hürthle cell tumors, and atypical papillary tumors. Action:
surgical intervention for definitive diagnosis
• Malignant or positive: group consisting of primary (thyroid) or secondary (metastatic) cancers. Action: surgical con-
sultation and thyroidectomy for primary tumors; search for origin of metastatic disease
Recommendations for 131I Treatment of MNG
• Until approval by the United States Food and Drug Administration, the use of rhTSH to augment radioiodine treat-
ment of MNG is considered “off-label.” Its use should be considered in elderly patients or in those with comorbid
conditions that preclude anesthesia and surgical treatment
• Should not be used if the presence of a malignant lesion is suspected, and US-FNA should precede treatment
• Treat patient with a β-adrenergic blocking agent or calcium channel blocker during 131I treatment
• After treatment, patient should undergo follow-up for the development of hypothyroidism or hyperthyroidism
Recommendations for PEI of Cystic Lesions
Equipment and Procedure

A real-time US system with a 7.5- to 10.0-MHz probe, 95% sterile ethanol, a spinal needle, and a disposable plastic
syringe are needed. A 22-gauge, 75-mm spinal needle is used because it is a flexible needle, fitted with a mandrel and
long enough to cross the steering device and reach deep thyroid nodules. Near-complete fluid removal is performed to
facilitate clear visualization of the needle in the cavity. Without removal of the needle, a syringe containing ethanol is
then substituted for the aspirating syringe. The ethanol is slowly injected in amounts of 1 to 10 mL, depending on the vol-
ume of the aspirated fluid. It may be useful to ask the patient to talk at regular intervals during the PEI procedure to ensure
that the recurrent laryngeal nerves are intact. PEI can be performed by 1 operator, inserting the needle through a guiding
device connected to the probe, or by 2 operators, one handling the probe and the other the needle.
• PEI is performed on outpatients; the procedure is rapid (not exceeding 10 minutes); no local or general anesthesia is
needed
• There is no evidence that the serum ethanol level increases after PEI; a limited amount of ethanol is injected into the
nodule
• This procedure must be performed by experienced operators with adequate training, to avoid damage to the recurrent
laryngeal nerve or other neck structures
Avoidance of Adverse Effects

Adverse effects of PEI are generally mild and transient. Their occurrence depends on the experience of the center.
Mild local pain is common but is rapidly self-resolving or can be controlled with low doses of nonsteroidal anti-
inflammatory drugs for 1 to 2 days.
Transient dysphonia is rare after PEI treatment of cystic lesions. Special care must be taken to avoid seepage of
ethanol outside the nodule. Real-time US monitoring during PEI allows verification of the correct position of the needle
tip within the nodule and assessment of the distribution of the injected ethanol, which should be recognizable as an
expanding hyperechoic area within the cystic cavity. Ethanol seeping outside the cystic nodule is always attributable to
incorrect procedure (usually the displacement of the needle tip) and induces chemical damage to the recurrent laryngeal
nerve. After confirmation with laryngoscopy of unilateral vocal cord paresis, corticosteroid therapy (betamethasone, 1.5
mg daily) can be administered for a few days. The patients should be reassured that, in most cases, a complete recovery
from vocal cord paresis usually occurs within a few weeks.
In a few patients with severe thyrotoxicosis (rare in cystic AFTN), the procedure may be followed by transient
exacerbation of thyrotoxic symptoms. In most cases, only a slight, transient and asymptomatic increase in serum thyroid
hormone levels is observed.
Subcutaneous and intracapsular hematomas are rare and self-resolving complications, provided the patient is not
taking anticoagulants (which should be withdrawn at least 48 hours before PEI).
Serial Assessment of PEI-Treated Nodules

• Thyroid cysts: US of the neck should be performed every 6 months for 2 years and yearly thereafter
• Nontoxic AFTN: US evaluation as for thyroid cysts. Assess serum TSH and T4 every 3 months after PEI
APPENDIX 2: SUMMARY OF RECOMMENDATIONS FOR DIAGNOSIS OF THYROID NODULES
History and Physical Examination
• The vast majority of nodules are asymptomatic, and absence of symptoms does not rule out a malignant lesion (grade
C)
• Always obtain a biopsy specimen from solitary, firm, or hard nodules. The risk of cancer is similar in a solitary nod-
ule and MNG (grade B)
• Record the following information (grade C):
Family history of thyroid disease
Previous neck disease or treatment
Growth of the neck mass
Hoarseness, dysphonia, dysphagia, or dyspnea
Location, consistency, and size of the nodule
Neck tenderness or pain
Cervical adenopathy
Symptoms of hyperthyroidism or hypothyroidism
• Factors suggesting increased risk of malignant potential (grade C):
History of head and neck irradiation
Family history of MTC or MEN2
Age <20 or >70 years
Male sex
Growing nodule
Firm or hard consistency
Cervical adenopathy
Fixed nodule
Persistent hoarseness, dysphonia, dysphagia, or dyspnea
US and Other Diagnostic Imaging
• US evaluation
Not recommended (grade C): as a screening test in the general population; in patients with normal thyroid on pal-
pation and low risk for thyroid cancer
Recommended (grade C): for high-risk patients (history of familial thyroid cancer, MEN2, or external irradiation);
for all patients with palpable thyroid nodules or MNG; for those with adenopathy suggestive of a malignant lesion
• US reporting criteria (grade C):
Describe position, shape, size, margins, content, echogenic pattern, and, whenever possible, the vascular pattern of
the nodule
Identify the nodule at risk to be malignant, and stratify the nodule with a risk score based on the US findings
Identify the nodules for FNA biopsy
• No FNA of nodules <10 mm unless suspicious US findings or high-risk history (grade C)
• US-FNA of nodules of any size in patients with history of neck irradiation or family history of MTC or MEN2 (grade
C)
• US-FNA should be based on US features (grade B)
• US-FNA should be performed on all hypoechoic nodules ≥10 mm with irregular margins, chaotic intranodular vascu-
lar spots, a more-tall-than-wide shape, or microcalcifications (grade B)
• US findings suggestive of extracapsular growth or metastatic cervical lymph nodes warrant an immediate cytologic
evaluation, no matter the size of the lesions (grade B)
• In Hashimoto’s thyroiditis, the presence of hypoechoic areas due to lymphocytic infiltration should be ruled out before
performance of US-FNA on hypoechoic nodules with ill-defined margins (grade C)
• In complex thyroid nodules, obtain US-FNA sampling of the solid component of the lesion before fluid drainage
(grade C)
• Thyroid incidentalomas should be followed by US in 6 to 12 months and regularly thereafter (grade D)
• MRI and CT are not indicated in routine nodule evaluation (grade C)
FNA Biopsy
• Thyroid FNA biopsy has been established as reliable and safe and has become an integral part of thyroid nodule
evaluation
• Clinical management of thyroid nodules should be guided by the results of ultrasonographic evaluation and FNA
biopsy
• Thyroid smears should be reviewed by a cytopathologist with a special interest in thyroid disease
• Diagnostic pitfalls:
False-positive results are usually due to “suspicious” findings
Gray zones in cytologic reports are follicular neoplasms, Hürthle cell neoplasms, and cytologic findings suggestive
of but not diagnostic for papillary carcinoma
• Standardization of terminology will improve patient care. Cytologic diagnoses should be organized into 4 categories—
inadequate material, benign, suspicious, and malignant tumors
Inadequate, unsatisfactory, or nondiagnostic: smears with few or no follicular cells
Benign or negative: group including colloid nodule, Hashimoto’s thyroiditis, cyst, thyroiditis
Suspicious or indeterminate: cytologic results that suggest a malignant lesion but do not completely fulfill the crite-
ria for a definitive diagnosis, including follicular neoplasms, Hürthle cell tumors, and atypical papillary tumors
Malignant or positive: group consisting of primary (thyroid) or secondary (metastatic) cancers
Radionuclide Scanning
• Perform thyroid scintigraphy for a thyroid nodule or MNG if the TSH level is below the lower limit of the normal
range or if ectopic thyroid tissue or a retrosternal goiter is suspected (grade B)
• In iodine-deficient areas, perform thyroid scintigraphy for a thyroid nodule or MNG even if the TSH level is in the
low-normal range (grade C)
• Use 123I or 99mTcO4- for thyroid scintigraphy (grade B)
Laboratory Evaluation
• Serum TSH should be tested first, with a third-generation assay (grade B)

• If TSH level is low (<0.5 μIU/mL), measure free T4 and T3; if TSH level is high (>5.0 μIU/mL), measure free T4 and
TPOAb (grade C)
• Routine assessment of serum thyroglobulin is not recommended for the diagnosis of thyroid nodules or nodular goiter
(grade C)
• Serum calcitonin should be measured if FNA or family history suggests MTC (grade B)
APPENDIX 3: SUMMARY OF RECOMMENDATIONS FOR MANAGEMENT AND TREATMENT

OF THYROID NODULES
Clinical management of thyroid nodules should be guided by the results of US evaluation and FNA biopsy (grade B).
FNA-Positive Thyroid Nodule
• For a thyroid nodule with positive (malignant) FNA results, surgical treatment is recommended (grade B)
• Review US and cytologic results with the patient and family; discuss treatment options; answer all questions and con-
cerns; recommend surgical excision and discuss potential complications; obtain surgical consultation, preferably with
a surgeon experienced in endocrine surgical procedures (grade D)
• For most patients, especially those with differentiated cancers >1 cm, familial disease, and clinical or US evidence of
multifocal disease, capsular invasion, or involved nodules, total or near-total thyroidectomy is indicated. Lymph nodes
within the central compartment of the neck (level 6) should be removed, especially if the surgeon has specific train-
ing for and experience with thyroid surgical techniques (grade C)
FNA-Negative Thyroid Nodule
• Use of suppressive therapy with LT4 may be considered in the following (grade C):
Patients from geographic areas with iodine deficiency
Young patients with small thyroid nodules
Nodular goiters with no evidence of functional autonomy
• Use of LT4 therapy should be avoided in most cases and especially in the following (grade C):
Large thyroid nodules and goiters, particularly in the presence of symptoms or signs of functional autonomy
Clinically suspicious lesions or lesions with an inadequate cytologic sample
Postmenopausal women and men older than 60 years
Patients with osteoporosis or systemic illnesses
Patients with cardiovascular disease
• Facts to remember:
LT4 treatment induces a clinically significant reduction of thyroid nodule volume in only a minority of patients
(grade B)
Long-term TSH suppression may be associated with bone loss and arrhythmia in elderly patients and menopausal
women (grade B)
LT4 treatment should never be fully suppressive (TSH <0.1 μIU/mL) (grade C)
Nodule regrowth is usually observed after cessation of LT4 therapy (grade C)
If nodule size decreases, LT4 therapy should be continued long term (grade D)
If thyroid nodule grows during LT4 treatment, reaspiration and possibly surgical treatment should be considered
(grade D)
Surgical Treatment
• Surgical indications in a patient with a thyroid nodule include the following:

Associated local symptoms
Hyperthyroidism from a large toxic nodule, or hyperthyroidism and concomitant MNG
Growth of the nodule
Suspicious or malignant FNA results
• Thyroid lobectomy includes total or near-total lobectomy, with or without isthmectomy. Should the patient require
completion thyroidectomy, it is technically easier to perform if the isthmus has previously been resected
• For a solitary benign nodule, lobectomy plus isthmectomy is sufficient; for bilateral nodules, a near-total thyroidecto-
my is appropriate
• The surgical procedure is usually performed with use of general anesthesia; however, some surgeons operate with use
of local anesthesia only
• A thyroid gland that extends substernally can almost always be resected through a cervical approach. Only rarely is
median sternotomy necessary to accomplish thyroid lobectomy or total thyroidectomy
• With experienced surgeons, associated complications are rare
Percutaneous Ethanol Injection
• PEI should be performed:

Only by personnel familiar with US-FNA (grade D)
On cystic thyroid lesions. PEI is highly effective in the treatment of thyroid cysts and complex nodules with a large
fluid component (grade B). Because the only alternative to PEI for recurrent and enlarging cysts is surgical resec-
tion, PEI is the first-line nonsurgical treatment for recurrent cystic nodules if US-FNA has ruled out a malignant
lesion
• PEI should not be performed:
On solid, cold nodules, unless surgical treatment is contraindicated (grade D)
On large or toxic AFTN (nodule volume >5 mL)—the rate of cure is too low and relapse is frequent (grade B)
On toxic MNGs (grade B)
• PEI may be considered:
In some small AFTN (nodule volume <5 mL), with a relevant fluid component and not yet completely suppressing
the surrounding thyroid parenchyma, if patients are concerned about late hypothyroidism (grade C)
• What to do before PEI:
If the nodule is considered suitable for PEI, malignant involvement should be ruled out by US-FNA. Multiple cyto-
logic examinations of the cystic wall should be performed (grade C)
A thorough US examination should evaluate the position, shape, size, margins, and vascular pattern of the nodule
(grade C)
• What to do during PEI (grade D):
Continuously monitor the position of the needle tip in the nodule and of ethanol diffusion within the nodule
Stop the procedure immediately if the patient reports severe pain, begins to cough, or has a change in voice
Radioiodine
• Consider radioiodine treatment for small goiters (volume <100 mL), in those without suspected malignant potential,
in patients with a history of previous thyroidectomy, and in those at risk for surgical intervention (grade B)
• Radioiodine treatment is not the first-line therapy if compressive symptoms are present, if patients have large nodules
that require high amounts of radioiodine and may be resistant to treatment, or if immediate resolution of thyrotoxico-
sis is desired (grade C)
• Radioiodine treatment is effective and safe. Large epidemiologic studies have shown no associated clinically signifi-
cant increase in the risk of thyroid cancers or leukemia (grade B)
• Give radioiodine therapy cautiously in elderly patients, especially those with heart disease (grade C)
• Radioiodine is contraindicated in pregnant or lactating women. Always perform a pregnancy test before administra-
tion of radioiodine in women of childbearing age (grade A)
• Avoid use of iodine contrast agents or iodinated drugs before administration of radioiodine; withdraw antithyroid
drugs at least 3 weeks before treatment and resume such regimens 3 to 5 days after radioiodine therapy (grade C)
• Follow-up of patients should include monitoring of serum levels of TSH, free T4, and free T3; consider repeating treat-
ment in 3 to 6 months if TSH is still <0.1 μIU/mL (grade C)
Nodules With Indeterminate FNA
• Indeterminate FNA results are due to poorly defined morphologic criteria for distinguishing benign from malignant
lesions. No clear-cut cytologic criteria are available to aid in decision making. At surgical intervention, about 20% of
indeterminate FNA specimens are malignant lesions
• Repeated biopsy of these nodules is not recommended because it creates confusion and does not provide additional
useful information for management
• Because large-needle thyroid biopsy is not more accurate than FNA, is more cumbersome, and is associated with pain
and occasional severe bleeding, it is currently not recommended in the management of thyroid nodules
• Clinical criteria such as nodule size (>4 cm), fixation, and age of the patient may suggest increasing risk for malignant
potential
• Currently, we recommend surgical excision of all indeterminate thyroid nodules
Nodules With Nondiagnostic FNA
• An unsatisfactory (nondiagnostic) FNA specimen usually results from a cystic nodule that yields few or no follicular
cells
• US-FNA directed at the peripheral portion of the lesion is indicated if initial palpation-guided FNA was nondiagnostic
• Reaspiration yields satisfactory results in 50% of cases
• Despite good initial technique, rebiopsy, and US-FNA, approximately 5% of thyroid nodules remain nondiagnostic.
Such nodules should be surgically excised (grade D)
• Whether routine rebiopsy is necessary is unclear. For physicians or clinics beginning to perform FNA, reaspiration pro-
vides reassurance with the procedure. We recommend reaspiration if a nodule enlarges, a cyst reappears, a nodule is
larger than 4 to 5 cm, or no shrinkage of the nodule occurs after LT4 therapy (see text Table 19)
Thyroid Nodule During Pregnancy
• No evidence indicates that administration of LT4 is effective in reducing the size or arresting the growth of thyroid nod-
ules during pregnancy; thus, LT4 therapy during pregnancy is not advisable (grade C)
• For a growing thyroid nodule during pregnancy, follow-up studies should include FNA and US (grade C)
• With a cytologic diagnosis of thyroid cancer during the first or second trimester in a pregnant woman, surgical inter-
vention should be undertaken during the second trimester, when anesthesia risks are minimal. If this cytologic diag-
nosis is made during the third trimester, postpone surgical treatment until the immediate postpartum period (grade C)
• Pregnancy may cause a misleading diagnosis of follicular neoplasm. The malignancy rate of follicular neoplasm dur-
ing pregnancy is about 14%. Therefore, defer surgical treatment to the postpartum period (grade C)
Radioiodine Treatment of Nodular Goiter
• In patients with low-uptake MNG given small doses of rhTSH, radioiodine uptake increases >4-fold within 72 hours.
Sufficient radiation therapy is delivered to the thyroid to decrease the size and to ameliorate compressive symptoms
rapidly
• Average decrease in goiter size is 40% during the first year and 60% by the end of the second year. In patients with
suppressed TSH levels, the TSH value returns to normal or increases within 3 to 6 months
• Free T4 and total T3 levels increase approximately 50% over baseline within 72 hours after injection of rhTSH.
β-Adrenergic or calcium channel blockers are given to avoid thyroid hormone-mediated adverse effects
• 131I (30 mCi) is given orally 72 hours after rhTSH. No significant radioiodine-induced sequelae occur immediately.
Rarely, immunogenic hyperthyroidism occurs several months after treatment
• Before treatment, US-FNA should be performed to rule out a malignant lesion
• Currently, use of rhTSH to augment radioiodine treatment is considered “off-label.” In elderly patients or patients with
comorbid disorders that preclude anesthesia or surgical intervention, however, rhTSH-augmented radioiodine treat-
ment is effective in management of MNG
Laser Thermal Ablation
• LTA is a low-cost, rapid, and effective mini-invasive technique for the treatment of benign thyroid nodules causing
pressure symptoms or cosmetic complaints
• The procedure should be performed only in carefully selected cases (high-surgical-risk patients). In most patients, 1 to
3 sessions of LTA or a single treatment with multiple fibers induces a nearly 50% decrease in nodule volume and the
amelioration of local symptoms (grade C)
• LTA should be restricted to specialized centers, in light of the need for skilled operators to avoid the risk of major com-
plications (grade D)
Histochemical Markers
• Several laboratories are developing molecular assays to clarify suspicious (indeterminate) FNA results: HBME-1,
galectin-3, thyroid peroxidase antibodies
• Most markers show either high sensitivity or high specificity, but not both, for diagnosing thyroid cancer
• No specific tumor marker is available that will regularly and reliably distinguish benign from malignant thyroid cellu-
lar tumors
Ultrasonographic Media
• First- and second-generation contrast agents provide only ancillary data for diagnosis of malignant thyroid nodules.
The variation of time-intensity curves during the transit times of the injected microbubbles offers a modest improve-
ment over the information obtainable with traditional color Doppler or power Doppler examinations (grade D)
• New specifically designed microbubbles and new models of US equipment with specific software are needed to
improve the predictive value of contrast-enhanced US for small-parts applications (grade D)

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AACE/AME Guidelines

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS

AACE/AME Task Force on Thyroid Nodules

ABSTRACT symptomatic goiters may be treated surgically or with

ENDOCRINE PRACTICE Vol 12 No. 1 January/February 2006 65

1 Well-controlled, generalizable, randomized trial

2. DIAGNOSIS occurring at a young age is 2-fold higher than in adult

• Prior head and neck irradiation 2.2.1. When to Perform US Evaluation

*MEN2 = multiple endocrine neoplasia type 2; MNG = multinodular goiter; MTC =

Large-needle thyroid biopsy does not have a higher

functioning (“cold”). Hot nodules almost never represent

*FNA = fine-needle aspiration.

•Perform thyroid scintigraphy for a thyroid nodule or MNG if the

*MNG = multinodular goiter; TSH = thyroid-stimulating hormone

2.5.4. Antibody Assays 3. MANAGEMENT AND THERAPY

•Serum TSH should be tested first, with a third-generation assay

*FNA = fine-needle aspiration; MTC = medullary thyroid

*FNA = fine-needle aspiration; US = ultrasonography.

•Use of LT4 therapy may be considered in the following (grade C†):

*LT4 = levothyroxine; TSH = thyroid-stimulating hormone (thyrotropin).

•Surgical indications in a patient with a thyroid nodule include

*FNA = fine-needle aspiration; MNG = multinodular goiter.

•PEI should be performed:

*T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone (thyrotropin).

3.4. Nondiagnostic Cytologic Specimen by FNA 3.4.2. Key Recommendations

*FNA = fine-needle aspiration.

*FNA = fine-needle aspiration; US-FNA = ultrasonography-guided FNA.

*FNA = fine-needle aspiration; LT4 = levothyroxine; US = ultrasonography.

*MNG = multinodular goiter; rhTSH = recombinant human TSH; T3 = triiodothyronine; T4 =

*LTA = laser thermal ablation.

4.3. Laser Thermal Ablation 4.3.2. Key Recommendations

APPENDIX 1: PRACTICAL TIPS

Minimal Requirements for US Equipment

Thyroid US and US-FNA

Recommendations for US Evaluation and Reporting

• Aims of the US report:

• Stylistic suggestions for writing the US report:

Recommendations for US-FNA Procedure and Slide Preparation

Recommendations for Cytologic Reporting

Recommendations for 131I Treatment of MNG

Recommendations for PEI of Cystic Lesions

Equipment and Procedure

Avoidance of Adverse Effects

Serial Assessment of PEI-Treated Nodules

APPENDIX 2: SUMMARY OF RECOMMENDATIONS FOR DIAGNOSIS OF THYROID NODULES

History and Physical Examination

US and Other Diagnostic Imaging

• Serum TSH should be tested first, with a third-generation assay (grade B)

APPENDIX 3: SUMMARY OF RECOMMENDATIONS FOR MANAGEMENT AND TREATMENT

• Surgical indications in a patient with a thyroid nodule include the following:

• PEI should be performed:

Nodules With Indeterminate FNA

Nodules With Nondiagnostic FNA

Thyroid Nodule During Pregnancy

Radioiodine Treatment of Nodular Goiter

Laser Thermal Ablation

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