Keywords
Fine needle aspiration - guidelines - management - therapy - thyroid cancer - thyroid
nodule - thyroid surgery - ultrasound-guided biopsy
Introduction
Many thyroid nodules are found in autopsy and using thyroid ultrasound (US) in population
studies.[[1]] The increased use of sensitive imaging techniques such as magnetic resonance imaging
(MRI), computed tomography (CT), and the carotid US increased referrals for the evaluation
of incidentally detected thyroid nodules.[[2]],[[3]]
The majority of thyroid nodules are benign. However, an aggressive diagnostic approach
to generally benign nodules or microcarcinomas resulted in overdiagnosis and unnecessary
management of thyroid nodules.[[4]] Consequently, updated comprehensive clinical practice guidelines (CPGs) relating
to the management of thyroid nodules and differentiated thyroid cancer have been published
by endocrine societies.[[5]],[[6]]
Several clinical practice patterns were observed with great interest in the international
differences in thyroid nodule management among participants in routine laboratory
testing, special measurements, and different management approaches.[[7]],[[8]],[[9]] However, these surveys acknowledged the inclusion of a small and perhaps under-representative
group of participants from developing countries such as those from the Middle East
and Africa (MEA).[[9]] We have previously documented practice patterns in managing common endocrine conditions
by physicians from these regions using online surveys.[[10]],[[11]],[[12]],[[13]],[[14]] Thyroid nodules and thyroid cancer in the Middle East and Gulf seem to increase
interest.[[15]],[[16]],[[17]] The current survey aimed to scope the clinical practice patterns in managing thyroid
nodules by physicians in managing thyroid disease from MEA.
Materials and Methods
Study design
The study is a cross-sectional electronic questionnaire-based study conducted between
August 12, 2018, and March 31, 2019. The Survey Monkey® (SVMK Inc., San Mateo, California,
USA) was used to create, disseminate, and analyze the questionnaire. The questionnaire
was E-mailed to a convenience sample of physicians primarily practicing in the MEA
and is likely to manage thyroid disease. They were identified from databases of health-related
bodies, professional groups, and recent continuous professional development events
as previously described.[[10]],[[11]],[[12]],[[13]],[[14]] The initial invitation E-mail explained the rationale of the study. Biweekly reminders
were sent for nonresponders and partial responders. The survey service automatically
blocked repeat submissions from the same internet protocol address, the Institutional
Review Board of Sheikh Khalifa Medical City, Abu Dhabi, UAE. Respondents provided
electronic consent before they can get access to the actual questionnaire.
Survey questionnaire
The questions were adapted from a previously published survey.[[9]] The questions covered diagnostic evaluation, choice of therapy, and follow-up of
an index case of a solitary thyroid nodule [[Table 1]]. Most questions required a single best response to being selected from multiple
choices. Some questions allowed additional free-text comments. The original questionnaire
was constructed in such a manner to omit phrasing that could influence respondents'
answers, and a broad range of choices was given, arranged alphabetically, numerically,
or in random order.[[9]] Additional questions were included to define respondents' demographic and professional
profiles and their regional and international affiliations similar to our previous
studies.[[10]],[[11]],[[12]],[[13]],[[14]] A corrective single question was sent to all original respondents to follow the
original methodology. A corrective single question was sent to all original respondents
to follow the original methodology.
Table 1: Index thyroid nodule case٭
Data collection and statistical analysis
Survey responses were anonymously collected and stored electronically by the survey
service, accessible in a password-protected manner. Only responses from those who
met the inclusion criteria were analyzed (i.e., endocrinologists, internal medicine
specialists with interest and practice in endocrinology, endocrine surgeons, oncologists,
and nuclear medicine physicians) practicing in the MEA. No data were collected on
nonresponders and no qualifying responders. The survey management service online tools
were used for the examination of results and the descriptive analysis. We treated
the whole group as one cohort, and we did not attempt to conduct any subgroup analysis.
Summary statistics were prepared for responses to each question. Because not every
participant answered all questions, the percentage of respondents providing a given
answer was calculated individually for each question, using the number of respondents
to that question as the denominator.
Results
Respondents' demographic and professional profiles
A total of 3579 were invited, 2029 (56.7%) opened the E-mail invitation, 59 (1.6%)
messages bounced, 104 (2.9%) opted out, 528 (14.8%) clicked through. Of those 438
respondents who attempted to participate, 364 provided complete answers, and 74 only
provided partial responses. Eventually, 212 respondents (of whom 197 answered all
the questions) were deemed valid and analyzed. The majority used the English version
for their responses (92.0%). Respondents' demographic and professional profiles are
summarized in [[Table 2]]. Adult endocrinologists and pediatric endocrinologists were the leading two groups
representing 79.3% of the respondents. Three-quarters were career physicians (consultant/attending),
and the remainder were middle-grade physicians such as specialists and fellows. In
total, nearly half (45%) were in clinical practice for over 20 years. Over half of
the respondents (50.3%) were members of the American Association of Clinical Endocrinologists,
and 42.5% were members of regional societies of endocrinology and thyroid disease
(excluding mainly diabetic groups), membership of other societies were also reported
[[Table 2]]. Access to the resources such as thyroid hormones, drugs, and imaging measurements
was almost universal. However, access to competent surgeons, nuclear medicine facilities,
and molecular testing were less readily available [[Table 2]].
Table 2: The demographic and professional characteristics of survey respondents, available
resources for care of thyroid patients, and the respondentsʼ professional affiliations
Diagnostic evaluation of the index case
Laboratory testing
The proportions of respondents ordering the listed laboratory testing for most of
their patients, similar to the index case, are shown in [[Figure 1]]a. In addition to 97.2% of respondents requested thyroid-stimulating hormone (TSH)
testing, 52.8% would obtain a free T4 level, and 23.6% would also order thyroid peroxidase
antibodies. Factors prompting respondents to measure serum calcitonin included a family
history of medullary thyroid cancer (87.2%), a patient history of phaeochromocytoma
(62.6%) or hyperparathyroidism (49.3%), a family member with an unknown type of thyroid
cancer (47.9%), and the presence of coarse calcifications on thyroid US (23.7%).
Figure 1: Diagnostic evaluation of the index case thyroid nodule. Number of respondents as
a percentage who would request various testing modalities in the index case, including
(a) routine laboratory tests and (b) imaging requested. Respondents were allowed to
select multiple items concurrently. ٭Other denotes either neck computed tomography,
neck magnetic resonance imaging, or 8 luoro-2-deoxy-D-glucose positron emission tomography-computed
tomography
Imaging
Thyroid US would be obtained at baseline in the index case by 98.1% of respondents,
with the study performed by radiology alone in 80.2%, in the respondent's clinic 25.9%
[[Figure 1]]b. An assessment of cervical lymph nodes is reportedly performed routinely at the
thyroid US by 89.6% of respondents. A radionuclide thyroid scan would be obtained
by 23.1% of respondents. Additional studies such as MRI, CT of the neck, or 2-fluoro-2-deoxy-D-glucose
positron emission tomography (18FDG-PET) would be requested by a minority of respondents
(3.8%, 3.3%, 1.9%, respectively).
Fine needle aspiration techniques
US guidance is routinely utilized for thyroid fine needle aspirations (FNAs) according
to 74.9% of respondents and used selectively according to 15% of respondents. Respondents
reported that US-guided FNAs are most commonly performed by a single person operating
the US while sampling the nodule (30.9%) or with an assistant operating the US. In
comparison, another performs the FNA according to others (15.5%). US-guided FNA procedures
are documented using digital or printed images taken during the procedure in 14.5%.
Nearly half (47.1%) of respondents stated that thyroid FNAs are performed by radiologists.
Only 23 respondents (11.1%) stated that FNA's were performed by the patient's endocrinologist,
whereas 17.3% stated that one or more designated endocrinologists performed all FNAs
for their practice. Pathologists and surgeons were reported to perform FNAs by 14.4%,
6.7% of respondents, respectively. However, since nonendocrinologists perform FNA,
most are unaware of the needle size, the type of anesthesia used or the number of
passes, and the method of slide preparation adopted. The reported methods of specimen
processing varied between respondents. The details on the (a) various methods of specimen
preparation, (b) who interprets the majority of thyroid FNAs performed in their practice,
(c) the elements usually considered by the pathologist while interpreting thyroid,
(d) the elements included in the majority of thyroid FNA result reports at the institution,
and (e) how long it takes after the procedure to receive final results for thyroid
FNAs performed [Supplementary Material; [Appendix 1]].[INLINE:1]
Selection of nodules for sampling by sonographic features, age, multiplicity, and
pregnancy
Six nodules with various sonographic features were listed, and respondents were asked
which nodules they would select for FNA. Responses and concordance with the American
Thyroid Association (ATA) 2015 guidelines are shown in [[Table 3]]. 94.5% would appropriately select patients with intermediate-risk nodules; 60.9%
will still do FNA for a <1 cm thyroid nodule. Furthermore, 42.1% and 31.3% of respondents
may sample a complex cystic or spongiform nodule <2 cm in size. In contrast, the majority,
i.e., 66.7% and 75.4%, will not sample an isoechoic nodule of 1.2 cm and a purely
cystic 2.5 cm nodule, respectively. However, when respondents were asked to pick a
single response to the above choices, responses split between sampling the 1.5 cm
solid hypoechoic nodule (53.4%) and a 0.7 cm hypoechoic nodule with microcalcifications
(24.3%) [[Table 3]].
Table 3: Respondentsʼ selection of thyroid nodules for fine needle aspiration sampling based
on the given ultrasound features alone٭ and the concordance with the American Thyroid
Association criteria (2015)
Furthermore, compared to the index case of a younger patient with a 1.5-cm hypoechoic
nodule, an 82-year-old woman with a similar nodule, having no suspicious clinical
or sonographic features, and a normal TSH would less likely undergo FNA by 52.9% of
respondents, equally likely by 29.4%. On the contrary, respondents are more likely
to undergo FNA by 17.6% of respondents if the patient was a 52-year-old woman with
a multinodular thyroid containing at least five solid hypoechoic nodules >1 cm in
maximal diameter. The patient had no suspicious history, physical examination, sonographic
features, and serum TSH level of 1.5 mU/L. Of 193 respondents, 29.9% would perform
sampling of 2–3 of the largest nodules, 25.9% would sample the single largest nodule,
17.8% would sample all nodules >1 cm in maximal diameter, 12.2% would not perform
FNA at all. Others (10.2%) would obtain a nuclear thyroid scan to identify “cold”
nodules for sampling. When respondents were presented with a 22-year-old woman with
a 1.5-cm thyroid nodule discovered during the 6th week of pregnancy, serum TSH was
normal, and there were no suspicious clinical or sonographic features. Out of 199
respondents, 35.2% would postpone the FNA until after delivery, 27.1% would sample
the nodule only if it grew during pregnancy, 25.6% would sample the nodule during
the first trimester, 12.1% would perform FNA during the second trimester.
Management of thyroid nodules according to various thyroid FNA results
For the Bethesda class subcategories III-VI,[[18]],[[19]] respondents were asked to select responses ranging from observation to additional
diagnostics (molecular testing or thyroid radionuclide scanning) referral for thyroid
surgery. Management of patients found to have an indeterminate or malignant result
on initial FNA shown a progressive utilization of thyroid surgery in going from Bethesda
classification system class III atypia of undetermined significance/follicular lesion
of undetermined significance (AUS/FLUS) to class VI (malignant) and a low frequency
of observation alone in this setting [[Figure 2]].
Figure 2: Management of thyroid nodules according to fine needle aspiration results. Management
of patients with an indeterminate or malignant result on initial fine needle aspiration
showed a progressive utilization of thyroid surgery in going from Bethesda classification
system class III (atypia of undetermined significance/follicular lesion of undetermined
significance) to class VI (malignant) and a low frequency of observation alone in
this setting
For nondiagnostic FNA (204), a repeat FNA for cytology is routinely performed by 82.4%.
Furthermore, an FNA specimen would be sent for molecular analysis or immunohistochemical
testing, or the patient is referred for thyroid lobectomy at this stage (by 4.9% of
respondents each). Among 204 respondents obtaining an AUS/FLUS result at initial FNA,
40.7% would repeat the FNA for cytological examination, 23.9% would refer the patient
for a diagnostic lobectomy, 13.2% would obtain molecular testing, 9.8% would recommend
a total thyroidectomy, 7.4% would observe the patient, and 5.9% would obtain a thyroid
scan. Among 202 respondents with an initial FNA showing a follicular neoplasm, the
most common response was a referral for diagnostic lobectomy (46.0%), followed by
total thyroidectomy (35.6%), repeat FNA for cytology (8.4%), molecular testing (5.4%),
thyroid scan (4.0%), and observation alone (0.5%). Among 204 respondents with an initial
FNA result interpreted as suspicious but not diagnostic for malignancy, most would
refer the patient for diagnostic surgery, including total thyroidectomy in 33.8% or
lobectomy in 32.8%. Nearly a fifth of the respondents would repeat the FNA for cytology
alone (20.1%), and only 8.8% would obtain molecular testing. A few respondents (3.9%)
would request a thyroid scan. Among 203 respondents obtaining a malignant FNA result,
81.3% would refer for total thyroidectomy; 13.8% lobectomy; and a few would pursue
the remaining options, including molecular testing, repeat FNA, or thyroid scan [[Figure 2]].
Follow-up of index case after a benign FNA
After obtaining a benign FNA result in patients such as the index case with a 1.5-cm
solitary hypoechoic solid nodule, 58.0% of respondents would follow with serial thyroid
US imaging at various intervals, whereas 18.0% would repeat the US on only one occasion,
12.0% repeat FNA to exclude false-negative results in 3–12 months, 7.5% refer back
to primary care, 4.5% monitor by palpation only. A repeat US's reported interval varied
among the 205 respondents, with 40.8% obtaining a repeat study by 6 months, 38.3%
by 12 months, and 10.7% at 3 months. However, if the index case's thyroid nodule volume
increased by more than 50%, 80.2% of the respondents would perform a repeat FNA, but
11.8% of them will send for a lobectomy (11.9%). The remaining minority would recommend
total thyroidectomy, observe the patient with a repeat US in 6–12 months (2.0%), or
give a trial of levothyroxine therapy. Follow-up for multinodular thyroid gland patients
after a benign FNA would be with the serial US by 58.0% of 200 respondents, a single
repeat the US by 18.0%, a single routine repeat FNA to exclude a false negative by
12.0%, return to primary care by 7.5%, or follow using palpation alone by 4.5% of
respondents. The concordance of respondents' choices with the latest ATA 2015 guidelines
is detailed in [[Table 4]].
Table 4: The concordance of the survey responses with the latest American Thyroid Association
clinical practice recommendations
Use of molecular testing of thyroid nodules
When asked about the type of tests used, among 199 respondents, 49.7% did not use
molecular testing in their practice, and 21.1% were not sure about the available types.
12.1% used a gene expression classifier, 4.5% used a specific mutation panel, 7.5%
used both methods simultaneously, and 5.0% used either method. The percentage of respondents
obtaining molecular testing in response to the different indeterminate or malignant
FNA results was presented above in the section. It showed a response to various thyroid
FNA results [[Figure 2]]. When respondents were directly asked which thyroid FNA interpretations currently
result in a request for molecular analysis, 48.8% reiterated that molecular analysis
is not used in their practice. The others would use it more often for AUS/FLUS (28.9%)
and follicular neoplasm/suspicious for follicular neoplasm (23.9%), for FNA suspicious
for thyroid cancer (22.4%), but less likely for FNA diagnostic of thyroid cancer (8.0%),
insufficient FNA (7.5%), and benign FNA (3.5%).
Discussion
The use of imaging technology is expanding in day-to-day clinical practice.[[20]] This situation has generated increasing numbers of referrals of previously undetected
thyroid nodules and diagnosis of thyroid cancer.[[21]] Several studies reported on changes in the management of these nodules over time
in North America and Europe.[[7]],[[8]],[[9]] How well these nodules are managed according to good CPGs has not been ascertained
in many parts of the world.[[9]] The current report provides a regional survey of the patterns of clinical practices
in managing thyroid nodules. Respondents comprised a convenience sample of physicians
practicing in the MEA and involved in managing thyroid disease. This particular region
was not well represented in the recent international survey.[[9]] Thus, the study is needed to complete the global image of endocrine practice patterns
concerning thyroid nodules. The online survey methodology is well established as it
captures information in a time-and cost-effective manner. Although surveys have inherent
limitations, we have generated several reports with meaningful information from the
region covering diabetes and endocrine practice.[[10]],[[11]],[[12]],[[13]],[[14]] Ideally, a survey invites a predefined group of potential participants of homogeneous
nature.[[7]],[[8]],[[9]] However, this is not readily available in our two regions. Nonetheless, in all
our surveys, we have requested respondents to define their demographic, clinical,
and professional profile to establish their relevance to the study with our convenience
sampling.[[10]],[[11]],[[12]],[[13]],[[14]]
The key findings of the present study are (1) extensive assimilation of thyroid US
into risk assessment and sampling of thyroid nodules; (2) lower size thresholds for
FNA than those recommended in the current CPGs; (3) wide variation in technical aspects
of FNA performance and interpretation; (4) low use of molecular profiling for cytologically-indeterminate
nodules, primarily in North America; and (5) a low uptake of conservative strategy
(i.e. observation alone) in patients with cytologically indeterminate thyroid nodules.
Although diagnostic US and FNA under US guidance would be obtained at baseline by
most respondents, FNA would be performed in two-third of the cases by radiologists
and the remaining by endocrinologists. Cytology would be reported by a general cytologist
in most cases using Bethesda classification for reporting in <70% of the cases. In
most cases, the assessment of cervical lymph nodes would be obtained in line with
the latest ATA 2015 guidelines. However, surprisingly radionuclide thyroid scan would
still be opted by 23.1% of our respondents as per the 2009 ATA survey results. This
could be partly explained by a quarter of our respondents are European societies or
trained in Europe.
The recently updated ATA guidelines suggest a more restrained approach to thyroid
nodule sampling[[6]] relative to the 2009 guidelines.[[6]] A less-selective approach is being used in the current clinical practice, with
nearly two-thirds of respondents opting to sample a subcentimeter hypoechoic nodule
with microcalcifications. Almost half chose to sample a complex-cystic nodule <2 cm,
and more than a fifth selecting to sample a pure cyst for aspiration. This is peculiar
as over 50% of the respondents are members of AACE and its previous chapters and are
also actively involved in national and regional endocrine societies. The ATA 2015
guidelines recommend approaching one single or multiple thyroid nodules based on US
risk stratification. In this regard, for a single hypoechoic nodule >1 cm, most of
our respondents would appropriately select FNA. However, for multinodular goiters
with similar sonographically hypoechoic nodules, less than a quarter would similarly
address all nodules >1 cm.
As per ATA 2015, FNA must be performed on all new thyroid nodules in pregnancy if
TSH is normal or elevated. In our survey, nearly two-thirds of respondents would not
sample a new thyroid nodule during pregnancy and either postpone FNA until after pregnancy
or only sample if the nodule grows under observation during pregnancy. This percentage
is lower than the responses in the ATA 2015 survey (<50%).[[9]] Similarly, ATA 2015 suggests active surveillance of elderly with multiple comorbid
conditions or limited life span; in this regard, our respondents, similar to those
in ATA 2015 survey, are less likely to perform FNA.
Following most North American guidelines,[[6]],[[21]] our respondents would select the measurement of serum calcitonin in over 50% of
the cases only in the presence of thyroid nodules with suspicious US features, family
history, or clinical suspicion of medullary thyroid cancer or in the setting of multiple
endocrine neoplasias 2, the overall response not reaching 10%. The use of molecular
testing is limited due to exuberant cost, unclear role due to specificity, and positive
predictive value concerns. Close to 50% of respondents never used it, and the remaining
used it occasionally in the setting of indeterminate thyroid nodules. The choice of
further imaging by FDG PET scan, MRI, and CT scanning is also low in line with most
guidelines.[[6]],[[21]]
After obtaining a benign FNA in a thyroid nodule, the likelihood of later finding
that nodule to be malignant is 1%–10% in various series,[[23]],[[24]],[[25]] particularly low false-negative rates in patients with benign features on thyroid
US.[[25]],[[26]],[[27]] Hence, CPG would consider repeating neck US or FNA in the presence of nodular volume
growth >50% or additional suspicious US features. When faced with a hypoechoic thyroid
nodule >1.5 cm and benign FNA, close to two-thirds of our respondents favor repeating
neck the US in 6–12 months and repeat FNA if there is >50% thyroid nodule volume change
or additional suspicious US features similar to the international survey (87.2%).[[9]] However, this growth is not specific for malignant thyroid nodules.[[28]]
The survey provided a baseline scoping of clinical practice status concerning the
investigation and management of thyroid nodules in these two regions. Its findings
should be considered when attempts are made to help clinicians implement essential
updates of ATA across diverse settings. In this regard, more endocrinologists should
acquire expertise in ultrasonography, and more cytologists should become experts in
thyroid cytology. This setting may avoid unnecessary FNA of thyroid nodules or total
thyroidectomy for DTC or undergo less intense postoperative surveillance.[[29]] Furthermore, a European perspective on the ATA 2015 guidelines highlighted that
commercially available tests are developed based on the North American population.
It is crucial to assess whether such tests can be used in other populations.[[30]]
Our study has both strengths and limitations. It is the first study of its nature
from the region where increasing interest and controversies exist.[[31]],[[32]] The number of respondents was reasonably large considering the number of physicians
interested in thyroid disease. It represented a diverse group of clinicians from the
two regions of interest, which were not adequately represented. A limitation of the
current study is the low response rate and the respondents' inhomogeneous nature,
though the latter was addressed by people defining their profile in detail. Another
limitation is the unequal distribution of the representatives from various countries
and the differences in resource availability between individual countries. Besides,
it is possible that respondents to management surveys are more likely to be aware
of CPGs and potentially adhere to their recommendations.
Conclusions
The present survey of physicians managing thyroid nodules in two developing regions
documented the prevalent clinical practice patterns. It demonstrates both agreements
and focal variations with recently updated CPGs. Interpretation of the findings should
be cognizant of the limited access to specific resources, individual physicians' skills,
and traditional care organizations. Reassessment of practice patterns after adequate
time for adopting the most recent guidelines is recommended to reassess any gaps.
Besides, results should inform plans for training and continuous professional development
activities.
Authors' contribution
Equal contribution to the conception, SAB adapted the survey questionnaire and manged
it on line, analysand the data. Both authors contributed substantially to drafting
and revision of the manuscript. They both approved its final version.
Compliance with ethical principles
The Institutional Review Board at Sheikh Khalifa Medical City, Abu Dhabi, UAE, approved
the study. All participants provided informed electronic consent before they can proceed
to the survey questions.
