Commentary

2015 American Thyroid Association Management Guidelines

for Adult Patients With Thyroid Nodules and Differentiated
Thyroid Cancer: What Is New and What Has Changed?
Bryan R. Haugen, MD

Thyroid nodules are very common, and thyroid cancer is currently the fifth leading cancer diagnosis in women. The American Thyroid
Association has led the development and revision of guidelines for the management of patients with thyroid nodules and differentiat-
ed thyroid cancer (DTC). The most current revision was published in the January 2016 issue of the journal Thyroid. The current guide-
lines have 101 recommendations, with 8 figures and 17 tables that are hopefully helpful to those treating patients with thyroid nodules
and cancer. The primary goals of the American Thyroid Association Guidelines Task Force were to use the current evidence to guide
recommendations and yet be as helpful and practical as possible within the scope and strength of the evidence. The current review
focuses on new and significantly revised recommendations that may very well change clinical practice. The author notes 3 new basic
principles that have emerged in this guidelines revision: 1) the management of thyroid nodules, including the decision to perform a
fine-needle aspiration biopsy as well as follow-up decision making, will be heavily influenced by the newly developed sonographic
risk pattern; 2) the long-term management of DTC along with thyroid-stimulating hormone target goals will be heavily influenced by
the 4 categories of “response to therapy”; and 3) the management of patients with radioactive iodine-refractory DTC will be divided
into 4 basic decision-making groups: patients who should undergo monitoring, patients who should undergo directed therapies,
patients who should undergo systemic therapies, and patients who should be offered entry into clinical trials. Cancer 2017;123:372-81.
C 2016 American Cancer Society.
V

KEYWORDS: differentiated thyroid cancer, guidelines, radioactive iodine-refractory thyroid cancer, thyroid nodules, thyroid surgery.

INTRODUCTION
Guidelines Process
The primary guiding principles that were used in the development of the 2015 American Thyroid Association (ATA)
Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer were to keep the
guidelines question-based, and to base the recommendations on the highest quality of evidence possible while at the same
time trying to be helpful to clinicians treating patients with thyroid nodules and differentiated thyroid cancer (DTC).1
The striking increasing incidence in DTC and the small, stable mortality rate also had a significant influence on our delib-
erations, especially in cases in which the evidence was of lower quality. Thyroid cancer is currently the fifth most common
cancer diagnosis in women. By the year 2030, it is estimated that it will be the second leading cancer diagnosis in women
and the ninth leading cancer diagnosis in men.2
As a part of the revision process, we evaluated different recommendations and evidence grading systems, and we
adopted a revised version of the grading system from the American College of Physicians.3 We reviewed and revised some
of the original questions in the guidelines, and we generated 9 new questions. Some of these questions were generated
from feedback solicited from our membership and various stakeholders and representatives of patient groups with an in-
terest in patients with thyroid nodules and DTC.
Of all the questions that were reviewed, we generated 101 basic recommendations. Within these basic recommenda-
tions there are 191 individually assigned recommendations (eg, 8A, 8B, etc). As is shown in Figure 1, a majority of the rec-
ommendations in these guidelines were either strong recommendations based on evidence that was of moderate quality or
weak recommendations based on low-quality evidence. This is in keeping with the general principles of this grading sys-
tem.3 As also can be noted, of the 191 individual recommendations, only 11 were based on high-quality evidence, whereas
97 of these individual recommendations were based on low-quality evidence. This emphasizes the pressing need for

Corresponding author: Bryan R. Haugen, MD, Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, Anschutz
Medical Campus, Research Complex I, South Tower, Mail Stop 8106, 12801 East 17th Ave, Aurora, CO 80045; Fax: (303) 724-2930; Bryan.Haugen@ucdenver.edu

Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Cancer Center, University of Colorado School of Medicine,
Aurora, Colorado

DOI: 10.1002/cncr.30360, Received: June 22, 2016; Revised: August 30, 2016; Accepted: September 1, 2016, Published online October 14, 2016 in Wiley Online
Library (wileyonlinelibrary.com)

372 Cancer February 1, 2017


Figure 1. Individual recommendations for thyroid nodules, the management of differentiated thyroid cancer (DTC), and the moni-
toring and management of advanced (radioactive iodine-refractory) DTC. Individual recommendations were categorized by the
strength of the recommendation (strong, weak, or no recommendation) and the quality of the evidence (high, moderate, low,
and insufficient).
continued research in this field to try and generate
moderate-quality and high-quality evidence for recommen-
dations in our evidence-based guidelines. An example of a
strong recommendation based on high-quality evidence is
recommendation 11: “if the nodule is benign on cytology,
further immediate diagnostic studies or treatments are not
required.” This is supported by many studies demonstrat-
ing that the risk of malignancy is quite low in a thyroid
nodule with benign cytology.4-8 We did have 22 individual
recommendations that were strong recommendations
based on low-quality evidence. I view these primarily as ex-
pert opinion recommendations in which we felt strongly
that a course of action should or should not be followed,
but this unfortunately was only supported by low-quality
evidence and therefore is the expert opinion consensus of
the group. One such example is recommendation 14,
which states that molecular testing should be performed in
Clinical Laboratory Improvement Amendments/College of
American Pathologists (CLIA/CAP)–certified molecular
laboratories. It was believed that the proliferation of non-
certified laboratories could put accurate molecular testing
at risk, but we did not have sufficient evidence to classify
this as moderate-quality evidence. Another example is rec-
ommendation 60, which states “there is no role for routine
adjuvant EBRT [external-beam radiotherapy] to the neck
in patients with DTC after initial complete surgical remov-
al of the tumor.” There is some evidence supporting this
recommendation, but to my knowledge large-scale studies
have not been performed to date and we believed this did
not meet moderate-quality evidence, but we felt strongly
that this should not be routinely offered to patients who
have undergone complete surgical removal of their tumor.
In the next few sections, I will go into more detail re-
garding new and significantly revised recommendations
Cancer February 1, 2017
ATA 2015 Thyroid Nodule/DTC Guidelines/Haugen
that may very well change clinical practice, but I note 3 new
basic principles that have emerged in this guidelines revi-
sion: 1) the management of thyroid nodules, including the
decision to perform a fine-needle aspiration (FNA) biopsy
as well as follow-up decision making, will be heavily influ-
enced by the newly developed sonographic risk pattern; 2)
the long-term management of patients with DTC along
with thyroid-stimulating hormone (TSH) target goals will
be heavily influenced by the 4 categories of “response to
therapy”; and 3) the management of patients with radioac-
tive iodine (RAI)-refractory DTC will be divided into 4 ba-
sic decision-making groups: patients who should undergo
monitoring, patients who should undergo directed thera-
pies, patients who should undergo systemic therapies, and
patients who should be offered entry into clinical trials.
Although there are many changes to this new guide-
lines revision, it should be noted that approximately 70%
of the recommendations have not been substantially
changed from the 2009 guidelines.9 There has either been
insufficient new evidence with which to change the rec-
ommendations or the new evidence supported the existing
recommendations. I have attempted to compare the 2009
and 2015 ATA guidelines (Table 1), highlighting some of
the changes and new recommendations as well as potential
clinical implications of the changes.
What is New or Changed for Patients With
Thyroid Nodules?
Of the 54 individual recommendations in this section, 15
(28%) are new or significantly revised. The very first rec-
ommendation is new, and states that we cannot recom-
mend for or against ultrasound screening in individuals
with a family history of DTC. It is interesting and some-
what ironic that this very first recommendation is a no rec-
ommendation based on insufficient evidence.
373
Commentary

TABLE 1. Highlighted New or Changed Recommendations in 2015 ATA Management Guidelines

2009 Recommendation 2015 Recommendation Potential Clinical Implications

Table 3: Biopsy thyroid nodules pri-
marily based on size and individual
sonographic features
Recommendations 7-11: Use of a 4-
tiered cytology classification
Recommendation 8: General consid-
eration of the use of molecular
markers
Recommendation 22: Routine preop-
erative use of non-US imaging
(MRI, CT, PET) is not
recommended
Recommendation 26: Thyroidectomy
is recommended for all patients
with PTC measuring >1 cm
None
None
Recommendation 36: 30-100 mCi of
131
I for remnant ablation
Recommendation 37: 100-200 mCi of
131
I for adjuvant therapy
Broad recommendations for long-
term follow-up
RAI-refractory disease not specifically
defined
None
Recommendation 8, Table 6: Biopsy thyroid nodules
primarily based on sonographic pattern, followed
by size
Recommendations 9-12: Use of a 6-tiered Bethesda
cytology classification system
Recommendations 13-17: Specific recommendations
for the use of molecular markers
Recommendation 33: Preoperative use of neck CT
(with contrast) or MRI is recommended for
patients with clinical suspicion of advanced
disease
Recommendation 35B: Thyroidectomy or lobectomy
can be used in properly selected patients with
PTCs measuring 1-4 cm
Recommendations 39-42: Perioperative
management of voice issues
Recommendation 46: Guidance for an optimal
histopathology report
Recommendation 55A: 30 mCi of 131I for remnant
ablation
Recommendation 56: >30-150 mCi of 131I for
adjuvant therapy
Recommendation 49: Specific recommendations for
long-term follow-up based on response to therapy
Recommendation 91: RAI-refractory disease careful-
ly defined
Recommendations 96-98: Series of recommenda-
tions regarding the use of kinase inhibitors and
the management of toxicities
Fewer thyroid nodules will require a
biopsy
Better stratify the likelihood of malig-
nancy for patients with indetermi-
nate cytology
Reduce unnecessary surgeries
Improve directed surgical therapy for
patients with aggressive disease
Reduce surgical hypoparathyroidism,
RLN damage, and need for thyroid
hormone therapy in some patients
with low-risk DTC
Improve surgical voice outcomes
Uniform communication between
pathologists and clinicians and
better risk stratification
Reduce potential for RAI toxicity
Reduce potential for RAI toxicity
More personalized follow-up therapy
and monitoring
Fewer patients receiving large
administered activities of RAI that
will not be helpful
Use of kinase inhibitors and manage-
ment/avoidance of toxicities

Abbreviations: ATA, American Thyroid Association; CT, computed tomography; DTC, differentiated thyroid cancer; 131I, iodine-131; mCi, millicurie; MRI, mag-
netic resonance imaging; PET, positron emission tomography; PTC, papillary thyroid carcinoma; RAI, radioactive iodine; RLN, recurrent laryngeal nerve; US,
ultrasound.

Sonographic risk patterns
Recommendation 8, which has 6 individual recommen-
dations within it and is accompanied by Figure 2 as well
as a table for ease of use, focuses on the use of the sono-
graphic risk pattern to help guide which nodules should
undergo FNA biopsy and which nodules do not need bi-
opsy. This sonographic risk pattern is based on the princi-
ples that: 1) high-risk features and low-risk features each
tend to associate; 2) that a constellation or pattern of fea-
tures has a higher sensitivity and specificity then individu-
al features alone; and 3) that intraobserver correlation is
better for overall sonographic patterns than it is for indi-
vidual sonographic features. The guidelines have identi-
fied 5 basic malignancy risk patterns: 1) high suspicion, 2)
intermediate suspicion, 3) low suspicion, 4) very low sus-
picion, and 5) benign. We hope that the widespread use
of these sonographic patterns will help with communica-
tion between radiologists and clinicians, will improve pa-
tient care, and will serve as a foundation for future
research correlating these sonographic patterns with cytol-
ogy findings and molecular results. I believe that this may
be the single most important change that we have brought
to this section and possibly to the entire guidelines. An-
other seemingly small but hopefully substantial change is
recommendation 8E, which states that a diagnostic FNA
is not required for any thyroid nodule measuring
<10 mm, even those with a suspicious sonographic
pattern. This is a strong recommendation based on
moderate-quality evidence that does not focus on diagnos-
tic accuracy but primarily focuses on the outcome of
these patients regardless of whether they had a DTC mea-
suring <10 mm.10-12 This also is closely linked to recom-
mendation 12, which generally recommends surgery for a
cytology result that is diagnostic for a primary thyroid ma-
lignancy but leaves open consideration of an active surveil-
lance management approach in patients with tumors of

374 Cancer February 1, 2017

 ATA 2015 Thyroid Nodule/DTC Guidelines/Haugen

Figure 2. American Thyroid Association (ATA) sonographic risk patterns for thyroid nodules and risk of malignancy. Reprinted
with permission from Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for
Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: the American Thyroid Association Guidelines Task Force
on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:1-133.

very low risk, including papillary microcarcinomas with-
out clinically evident metastases or local invasion noted at
the time of careful ultrasound examination. The previous
guidelines in 2009 had a cutoff measurement of 5 mm,
and we know that many of the thyroid nodules identified
by imaging for another reason measure between 5 to
10 mm.13-15 These strong revised recommendations will
hopefully reduce the many unnecessary FNA biopsies
with the attendant subsequent testing and therapy. More
studies in different populations are needed to either solidi-
fy or refute this recommendation.
Indeterminate cytology
There is a large new section that includes recommenda-
tions 13 through 20 regarding the approach to patients
with indeterminate cytology that is significantly changed
from the 2009 guidelines. This section incorporates a
large discussion on molecular testing, but does not en-
dorse any single test because it was believed that the evi-
dence did not support any single molecular test for all
patients with indeterminate cytology, and that the land-
scape of molecular testing is rapidly changing. Therefore,
we focused on the basic principles of molecular testing
and not on the endorsement of specific tests. For patients
with atypia of undetermined significance/follicular lesion
of undetermined significance (AUS/FLUS) cytology, rec-
ommendation 15 states that either repeat FNA biopsy or
molecular testing are viable approaches to these patients.
This recommendation also clearly states that any worri-
some clinical features and suspicious sonographic fea-
tures should be taken into account when deciding on
surveillance, repeat FNA biopsy, molecular testing, or di-
agnostic surgery. As is clearly stated in all of these recom-
mendations for patients with indeterminate cytology,
informed patient preference and feasibility should be
considered in clinical decision making. For patients with
cytology that is consistent with follicular neoplasm, rec-
ommendation 16 does first note that diagnostic surgical

Cancer February 1, 2017 375

Commentary
excision is the long-established standard of care for the
management of these individuals, but after consideration
of clinical and sonographic features, molecular testing may
be used to supplement malignancy risk and clinical deci-
sion making. The guidelines do go into detailed and refer-
enced discussion of different molecular tests but primarily
focus on the principles of ideal testing having a high sensi-
tivity and specificity along with high negative and positive
predictive values. Furthermore, a robust test to rule out
malignancy needs a high sensitivity and negative predictive
value whereas a robust test to rule in malignancy requires a
high specificity and positive predictive value. There have
been additional molecular tests brought into clinical use
and new publications since these guidelines were accepted
that support our approach to discussing more basic princi-
ples of molecular testing rather than recommending any
one specific test.16,17
Active Surveillance
It is worth noting that recommendation 12, which focuses
on patients with malignant FNA cytology, states that sur-
gery is “generally” recommended for these patients. This
is a subtle but significant change from recommendation 7
in the 2009 guidelines that simply states “surgery is rec-
ommended.” The guidelines discuss potential active sur-
veillance for patients with small tumors of very low risk,
those patients with a high surgical risk, patients with a
short life expectancy, and patients with medical or surgical
issues that may need to be addressed before surgery. Active
surveillance of patients with malignant cytology from
nodules measuring <10 mm remains controversial and is
primarily supported by active surveillance studies con-
ducted among carefully selected Japanese patients.10,12 It
is important to note that in section D3, under directions
for future research in the guidelines, there is a substantial
discussion recommending more research in the area of ac-
tive surveillance of patients with low-risk primary DTC.
Monitoring strategies for benign cytology
I believe that recommendation 23, which discusses moni-
toring strategies for patients with benign FNA cytology, is
worth noting because this recommendation again bases
monitoring on the sonographic risk pattern of the nodule.
For example, patients with a high-suspicion ultrasound
pattern should undergo a repeat ultrasound and
ultrasound-guided FNA biopsy within 12 months, where-
as patients with an ultrasound pattern with low to inter-
mediate suspicion can wait 12 to 24 months before
undergoing repeat ultrasound. Furthermore, patients who
have nodules with an ultrasound pattern with very low
376
suspicion may not need any follow-up ultrasound after a
benign FNA biopsy, but if it is considered it should be
done after >24 months. This approach will hopefully re-
duce unnecessary frequent imaging and excess repeat
FNA biopsy for patients who are unlikely to benefit.
Finally, we added a new recommendation, number
24, that hopefully helps to provide guidance for monitor-
ing those patients who do not meet FNA criteria. As noted
in the paragraph above for patients with benign FNA cy-
tology, those patients who do not meet FNA criteria
should have follow-up ultrasound based on the sono-
graphic risk pattern.
What Is New or Changed for Patients With DTC?
This section, which includes the initial management, re-
sponse to therapy, and long-term follow-up of patients
with DTC is to the best of my knowledge the largest sec-
tion, with 81 individual recommendations, 18 of which
(22%) are new or have been significantly changed.
Preoperative neck imaging
A preoperative complete neck ultrasound is still recom-
mended for all patients undergoing surgery for malignant
or suspicious cytology (recommendation 32), but these
revised guidelines are now making a strong recommenda-
tion for the preoperative use of cross-sectional imaging,
which includes contrast-enhanced computed tomogra-
phy (CT) of the neck as an adjunct ultrasound for
patients with a clinical suspicion of advanced disease
(recommendation 33). The 2009 guidelines recom-
mended against the routine use of these imaging modali-
ties in patients with DTC, which is not necessarily
different from recommendation 33 in the new guide-
lines; we basically are placing a different emphasis on im-
aging in this important subgroup of patients. There is
emerging evidence that this cross-sectional imaging can
complement ultrasound as a preoperative test, and that
intravenous contrast for a CT of the neck is generally
cleared within 4 to 6 weeks and should not have a signifi-
cantly negative impact on subsequent RAI testing or
therapy.18-21 There appears to be a persistent concern
that intravenous contrast should not be used at these ear-
ly stages of therapy for patients with DTC, but this con-
cern does not appear to be supported by the evidence
and the use of cross-sectional imaging can be very helpful
in patients with clinical suspicion of advanced disease.
Consideration of lobectomy for DTC
Recommendation 35B may be the most controversial and
misunderstood recommendation in these revised
Cancer February 1, 2017

guidelines. This recommendation states that either thy-
roidectomy or lobectomy is a reasonable surgical approach
for patients with DTC measuring 1 to 4 cm without evi-
dence of extrathyroidal extension or clinically apparent
lymph node disease on preoperative examination or imag-
ing. This is a strong recommendation with moderate-
quality evidence from large database studies. A majority of
the studies have demonstrated that overall survival and
disease-free survival are not negatively impacted by lobec-
tomy compared with thyroidectomy,22-28 although a mi-
nority of studies indicated that patients treated with
thyroidectomy had a better outcome.29,30 Despite the pre-
ponderance of moderate-quality evidence in support of a
lobectomy for these patients, the task force chose a bit
more conservative path, recommending either a thyroidec-
tomy or lobectomy, leaving the thyroidectomy option in
place to enable RAI therapy or to enhance follow-up
based on disease features and/or patient preferences. It
also is recommended that these patients undergo a careful
US of the neck to assess for other thyroid nodules, extra-
thyroidal extension, and any abnormal lymph nodes. The
feedback that I have received to date suggests that many
individuals believe that we have demonstrated a strong
preference for lobectomy in patients with DTCs measur-
ing 1 to 4 cm, but although the literature may support
this approach, we did leave open the option for a lobecto-
my or thyroidectomy for these patients. It is interesting to
note that this is a strong recommendation that would be
defined as “most clinicians should offer this course of
action,” but the recommended course of action is either a
lobectomy or thyroidectomy, and neither approach is sup-
ported over the other. We left this as a strong recommen-
dation to alert clinicians to give serious consideration to a
lobectomy because this is a significant departure from pre-
vious guideline recommendations. It is interesting to note
that this is somewhat “back to the future,” because lobec-
tomy was a recommended approach for these patients dec-
ades ago. I believe that if and when this specific
recommendation is more widely adopted, surgical out-
comes and quality of life will be improved for many of
these low-risk patients.
Section B10 focuses on perioperative approaches to
voice and parathyroid issues, and includes 10 new individ-
ual recommendations to help with these important man-
agement issues.
Communication
Recommendation 39, which focuses on the importance of
perioperative communication with the patient and care
team, is a very important recommendation but has not re-
Cancer February 1, 2017
ATA 2015 Thyroid Nodule/DTC Guidelines/Haugen
Figure 3. Multidisciplinary team caring for the patient with
thyroid cancer. This team and good communication are im-
portant for the optimal care of patients with thyroid cancer,
especially those with advanced and radioactive iodine-
refractory disease. Nuc Med indicates nuclear medicine.
ceived much attention in these revised guidelines. Good
communication within the multidisciplinary care team,
which often includes clinicians, pathologists, radiologists,
surgeons, and members of other important specialties, is
critical, especially in light of some of the suggested
changes in these guidelines. Good communication will
help to optimize care for important issues, including
patients with sonographically suspicious nodules, the op-
timal use and choice of molecular testing, the timing of
contrast CT scans, lobectomy versus thyroidectomy,
issues surrounding completion thyroidectomy, decision
making regarding lymph node biopsy in follow-up care,
and optimizing care for patients with advanced RAI-
refractory DTC. Figure 3 shows the potential complexity
in the management of patients with DTC, especially those
with advanced disease. This figure also highlights the criti-
cal importance of good communication within the team. I
put the patient, together with the thyroid cancer specialist,
at the center of this multidisciplinary team interaction.
The thyroid cancer specialist is the point person for the
patient and can be from one of the many specialties (endo-
crinology, surgery, medical oncology, nuclear medicine,
etc). Recommendation 41 is notable as a new recommen-
dation that can identify those patients who should under-
go a preoperative laryngeal examination, which can help
to guide surgery and manage expectations after thyroid
surgery.
Optimal surgical pathology report
Section B15 and recommendation 46 are new and careful-
ly outline the optimal components in a surgical pathology
report. These include standard components in the
377
Commentary
TABLE 2. Important Features in a Surgical Histopa-
thology Report
 Histopathologic tumor type
 Histopathologic variants with favorable or unfavorable outcomes
 Tumor size
 Multifocality
 Extrathyroidal invasion
 Surgical margins (positive or negative)
 No. of lymph nodes examined
 No. of lymph nodes with tumor
 Size of the largest tumor-involved lymph node
 Extranodal invasion
 Vascular invasion (no. of invaded vessels)
American Joint Committee on Cancer/TNM staging sys-
tem, as well as the number of removed and involved
lymph nodes, size of the largest involved lymph node, the
presence or absence of extranodal extension, and evidence
of vascular invasion and the number of involved blood
vessels (Table 2). It also is recommended that the patholo-
gist identify histopathologic variants associated with more
favorable and unfavorable outcomes. The consistent
reporting of these features will help the clinician to better
assess the risk of persistent or recurrent disease and per-
sonalize therapy and monitoring for each patient.
Staging, recurrence risk, and response to therapy
Recommendations 47, 48, and 49 represent another sig-
nificant evolution in our thinking and approach to
patients with DTC. These recommendations highlight
the need to assess patients by staging, risk of recurrent or
persistent disease, and response to therapy. Although dis-
ease staging is not significantly changed from previous
guidelines, this is intermittently updated by the American
Joint Committee on Cancer.31 The recurrence risk has
been expanded from the basic 3-tiered system of low risk,
intermediate risk, and high risk to a broader risk continu-
um that incorporates actual risk percentages from several
cited studies. One challenge is that many of the individual
risk criteria are cited by only one study, thereby highlight-
ing the need for further confirmatory studies in this area.
It also is important to note that patients with lymph node
metastases can now be categorized into each of the 3 risk
groups rather than simply placing all patients with lymph
node disease into the intermediate-risk category. We be-
lieve that this is an evidence-based significant advance that
will hopefully limit excess therapy and monitoring in
patients with a few, small lymph node metastases that are
now categorized in the low-risk category. Finally, recom-
mendation 49 and the subsequent text go into detail re-
garding the “response to therapy,” which is divided into 4
groups: excellent response, indeterminate response (I tell
378
patients that this is a “good” response), biochemical in-
complete response, and structural incomplete response.
These dynamic assessments need to be performed at each
visit and we believe they should have implications for the
type of monitoring, the monitoring interval, the biochem-
ical and imaging tools used, and the degree of TSH sup-
pression in these patients. This is a strong
recommendation for the use of response to therapy no-
menclature, but it is supported only by low-quality evi-
dence because this categorization has not been rigorously
tested in multiple different patient groups. Hopefully, fu-
ture studies in this area will either confirm these categories
or redefine new categories that may be more useful.
RAI Remnant Ablation, Adjuvant Therapy, and
Therapy
The recommendations for the use of RAI in patients with
DTC has not substantially changed since the 2009 itera-
tion of the guidelines, but there are 2 recommendations
worth noting. Recommendation 51 focuses on which
patients should be considered for RAI administration and
which patients may not need treatment with RAI. This is
based on the general oncologic principles of remnant abla-
tion, adjuvant therapy, and therapy. In general, patients
who are considered for remnant ablation are treated with
RAI to ablate normal thyroid tissue and improve the sen-
sitivity and specificity of monitoring tools. Patients con-
sidered for adjuvant therapy are those who have
undergone a complete resection of their disease and have
no known residual disease but are at high risk of develop-
ing recurrent disease. Patients who receive RAI therapy
are those who have known residual locoregional or meta-
static disease who need therapy in an attempt to eradicate
or control the disease. Recommendation 51 basically sug-
gests that RAI remnant ablation is not routinely recom-
mended for patients with DTC who are at low risk of
experiencing recurrent or persistent disease, that adjuvant
therapy should be considered after thyroidectomy in
patients with DTC who are at an intermediate risk of re-
current disease, and that RAI adjuvant therapy is routinely
recommended after thyroidectomy for patients with DTC
who are at high risk of developing recurrent disease. The
use of these oncologic principles and consideration of the
recurrence risk in patients with DTC will hopefully limit
the excess use of RAI in patients unlikely to benefit, while
focusing its use in that subgroup of patients who are most
likely to benefit. Recommendation 55 is complementary
to this concept, suggesting that those patients who are
considered for remnant ablation should be considered for
a lower administered activity of RAI (ie, 30 millicurie
Cancer February 1, 2017

[mCi] of iodine-131[131I]), reserving higher administered
activities for those patients receiving RAI for adjuvant
therapy or therapy. The use of these approaches should re-
duce the risk of potential side effects (eg, sialadenitis, xero-
stomia, epiphora, or secondary malignancy) in patients
with low-risk and intermediate-risk DTC.
Thyroid hormone therapy
Finally, emerging evidence has suggested that we do not
need to use complete TSH suppression with levothyrox-
ine in many patients with DTC, especially those who have
achieved an excellent or indeterminate response to thera-
py.32,33 Recommendation 70 synthesizes this evidence
into a series of individual recommendations based on re-
currence risk and response to therapy. For example, rec-
ommendation 70A suggests near-complete suppression of
TSH (<0.1 mU/L) for patients with a structural incom-
plete response to therapy. Alternatively, recommendation
70C suggests that a TSH level of 0.1 to 0.5 mU/L is ap-
propriate for high-risk patients who have had an excellent
or indeterminate response to therapy. In the most com-
mon group of patients who have low-risk or intermediate-
risk disease and a subsequent excellent or indeterminate
response to therapy, TSH does not need to be suppressed
and can be kept in the low reference range (0.5-2 mU/L).
This tailored approach to various targeted TSH levels in
long-term therapy for patients based on the recurrence
risk and response to therapy will hopefully continue to
keep the recurrence risk as low as possible while decreasing
unnecessary risk of bone loss and cardiac problems.
What Is New or Changed for Patients With
Advanced and RAI-Refractory DTC?
There have been several impressive advances in the man-
agement of patients with advanced and RAI-refractory
DTC over the past 5 to 10 years.34-38 Unfortunately, the
majority of the recommendations in this section are weak
recommendations based on low-quality evidence, a find-
ing that demonstrates the pressing need for continued re-
search in this area.
Definition of RAI-refractory DTC
Recommendation 91 attempts to define or classify RAI-
refractory, structurally evident DTC. This would appear
to be a fairly straightforward process, but our proposed
classification generated some of the most animated discus-
sions with our reviewers. We defined 4 categories of RAI-
refractory DTC: 1) locoregional or metastatic disease that
never concentrates RAI; 2) tumor tissue that loses its abili-
ty to concentrate RAI; 3) RAI is concentrated in some of
Cancer February 1, 2017
ATA 2015 Thyroid Nodule/DTC Guidelines/Haugen
the lesions but not others; and 4) metastatic disease that
progresses despite concentration of RAI. To be classified
in any of these categories, the patient needs to undergo ad-
equate preparation with a sufficiently elevated TSH and
iodine-restricted diet. In many of these cases, we docu-
mented a low urinary iodine level before classifying a pa-
tient as having RAI-refractory disease. One concern some
of the reviewers had regarding our classification was the
ongoing development of medications such as MEK inhib-
itors that may be able to transform tumors that could not
concentrate RAI into tumors that could concentrate suffi-
cient RAI for therapeutic benefit. We did consider this,
and we believe that these tumors would be reclassified as
RAI-avid tumors and the patient could be removed from
the RAI-refractory category as more of these agents dem-
onstrate potential benefit. The largest concern was the
third definition, which stated that patients with only
some tumors that concentrate RAI whereas others did not
would be classified as having RAI-refractory disease. The
intention of this classification was to ensure that patients
who had only a few lesions that concentrated RAI while a
vast majority did not would not continue to receive multi-
ple large doses of RAI, which would be unlikely to be of
benefit to the patient. The rare patient who has many
tumors that concentrate RAI but only a few that do not
overall may not have RAI-refractory disease and may ben-
efit from at least 1 additional therapeutic dose of RAI.
Approach to patients with RAI-refractory DTC
Once a patient is classified as having RAI-refractory dis-
ease, repeated treatment with RAI is not recommended.
There are 4 basic principles for managing these patients:
1) careful monitoring with active TSH suppression thera-
py; 2) directed therapy such as surgery, radiotherapy, or
thermal ablation for specific threatening or symptomatic
lesions; 3) systemic therapy, preferably with approved tar-
geted therapies; and 4) entry into clinical trials.
Recommendations 96, 97, and 98 go into detail re-
garding the use of approved and off-label kinase inhibitor
therapy for patients with progressive or symptomatic
RAI-refractory DTC. These recommendations and the
accompanying text provide detail regarding when to con-
sider kinase inhibitor therapy, management approaches to
patients when first-line therapy fails, and anticipation as
well as management of the attendant toxicities from these
therapies. The very last recommendation and discussion
concern when to consider and how to use bone-directed
therapy for patients with bone metastases.
If possible, many of these patients with RAI-
refractory DTC should be treated and managed or co-
379
Commentary
managed along with local clinicians by centers that focus
on the care of these patients with multidisciplinary teams,
access to clinical trials, and review conferences (Fig. 3).
Suggestions for Directions for Future Research
This is a somewhat overlooked section because it is at the
end of this very large document, and many readers tend to
focus on the specific recommendations. This is an impor-
tant section because we have highlighted only a few of the
many requirements for high-quality evidence for the man-
agement of patients with thyroid nodules and DTC. Dis-
cussions include the need for the continued optimization
of molecular markers for the diagnosis of DTC as well as
the prognosis for these patients and the identification of
novel therapeutic targets to help guide precision oncology
therapy. There also are discussions regarding the need for
trials of active surveillance in patients with low-risk DTC,
improving our risk stratification approaches, issues with
the measurement of serum thyroglobulin and thyroglobu-
lin antibodies, and management issues in patients with
metastatic cervical adenopathy detected on ultrasound
monitoring. We also have provided a section concerning
novel therapies for patients with RAI-refractory DTC.
Appropriately, the guidelines end with a discussion of the
importance of survivorship care and a reminder that we
need to keep our patients and their well-being at the cen-
ter of our multidisciplinary care team (Fig. 3).
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
Bryan R. Haugen has received a grant and honoraria from Genzyme
Corporation for work performed outside of the current study.
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