1 s2.0 S014067362300020X Main

Seminar
Thyroid cancer
Debbie W Chen, Brian H H Lang, Donald S A McLeod, Kate Newbold, Megan R Haymart
The past 5–10 years have brought in a new era in the care of patients with thyroid cancer, with the introduction of Published Online
transformative diagnostic and management options. Several international ultrasound-based thyroid nodule risk April 3, 2023
https://doi.org/10.1016/
stratification systems have been developed with the goal of reducing unnecessary biopsies. Less invasive alternatives
S0140-6736(23)00020-X
to surgery for low-risk thyroid cancer, such as active surveillance and minimally invasive interventions, are being
Division of Metabolism,
explored. New systemic therapies are now available for patients with advanced thyroid cancer. However, in the setting Endocrinology, and Diabetes,
of these advances, disparities exist in the diagnosis and management of thyroid cancer. As new management options Department of Internal
are becoming available for thyroid cancer, it is essential to support population-based studies and randomised clinical Medicine, University of
Michigan, Ann Arbor, MI, USA
trials that will inform evidence-based clinical practice guidelines on the management of thyroid cancer, and to include
(D W Chen MD,
diverse patient populations in research to better understand and subsequently address existing barriers to equitable Prof M R Haymart MD);
thyroid cancer care. Department of Surgery,
The University of Hong Kong,
Introduction Diagnosis of thyroid cancer Queen Mary Hospital, Hong
Kong Special Administrative
Based on the GLOBOCAN 2020 database of cancer Clinical presentation and pathways to thyroid cancer Region, China
incidence and mortality by the WHO International diagnosis (Prof B H H Lang MBBS);
Agency for Research on Cancer, thyroid cancer has the Thyroid cancers traditionally presented with a palpable Department of Endocrinology
and Diabetes, Royal Brisbane
ninth highest cancer incidence worldwide.1,2 Although thyroid nodule. Currently, detection with palpation and Women’s Hospital,
thyroid cancer can occur in people of any gender, accounts for about 30–40% of thyroid cancer Brisbane, QLD, Australia
women account for approximately 75% of all patients diagnoses.14,16,17 Additional common pathways to diagnosis (D S A McLeod PhD); Population
with thyroid cancer.2,3 Thyroid cancer can also occur include imaging unrelated to the thyroid (eg, carotid Health Department, QIMR
Berghofer Medical Research
across a range of ages, but the median age of diagnosis ultrasounds, and cross-sectional imaging of the neck, Institute, Brisbane, QLD,
is early 50s. Thyroid cancer is the most common spine, and chest); thyroid ultrasounds in patients who Australia (D S A McLeod);
malignancy in adolescents and adults aged are hyperthyroid or hypothyroid without palpable thyroid Thyroid Unit, The Royal
16–33 years.4,5 nodules; serial ultrasounds on patients with known Marsden NHS Foundation
Trust, London, UK
Thyroid cancer is categorised into three broad thyroid nodules; and as an unexpected finding of (K Newbold MD)
histological categories: (1) differentiated thyroid cancer, occult thyroid cancer on histopathological examination
Correspondence to:
which includes papillary, follicular, and oncocytic of thyroid tissue after surgery for presumed benign Dr Megan R Haymart, Division of
thyroid carcinoma; (2) medullary thyroid cancer, which disease.16 Metabolism, Endocrinology, and
is sometimes associated with the multiple endocrine Ultrasound is the recommended initial imaging Diabetes, Department of Internal
Medicine, University of
neoplasia type 2 syndromes; and (3) anaplastic thyroid modality to assess palpable thyroid nodules or thyroid Michigan, Ann Arbor, MI 48109,
cancer, which often arises from differentiated thyroid nodules documented by other imaging techniques. USA
cancer and has a high mortality. Although distribution Ultrasound is extremely sensitive in identifying the [email protected]
by cancer type can vary by country, papillary thyroid
cancer accounts for approximately 80% of cases.6,7 In
the past 40 years, there has been a rise in thyroid cancer Search strategy and selection criteria
incidence globally, which has disproportionately We searched PubMed, Cochrane Library, and Embase for full-
affected women and has been more prominent in some text articles published between 2015 and 2022. The search
countries (eg, South Korea) than others.2,8–10 Many was not limited to English language publications.
studies have shown that this observed worldwide We searched the databases using the terms: “thyroid cancer”,
increase in thyroid cancer incidence is largely driven by “thyroid neoplasm”, “thyroid neoplasms” and “diagnostic
increased detection of small, low-risk papillary thyroid imaging”, “thyroid neoplasms” and “diagnosis”, “thyroid
cancer, which has occurred due to greater use of thyroid neoplasms” and “classification”, “thyroid neoplasms” and
ultrasonography.8–14 “molecular diagnosis”, “thyroid neoplasms” and
In the past 5 to 10 years, care of thyroid cancer has “psychology”, “thyroid neoplasms” and “thyroidectomy”,
undergone a transformation, with new management “thyroidectomy”, “thermal ablation”, “active surveillance”,
options now available. In the setting of these new “thyroid” and “clinical trials”, “thyroid cancer disparities”,
developments, there has been renewed interest in “thyroid” and “disparities”, and “disparities in cancer clinical
understanding disparities in thyroid cancer care trials”. We selected publications from the past 5 years, but we
delivery within countries. Although not all contem did not exclude commonly referenced and highly regarded
porary treatment options are available in every country,15 publications published before 2018. We also searched the
in this Seminar, we discuss the diagnosis and reference lists of articles identified by this search strategy and
management of thyroid cancer, highlighting cutting- selected those that we regarded to be relevant. Our reference
edge management options and relevant disparities in list was also modified after comments from peer reviewers.
thyroid cancer care.
www.thelancet.com Published online April 3, 2023 https://doi.org/10.1016/S0140-6736(23)00020-X 1

Seminar
number and characteristics of thyroid nodules, and high- ultrasound use should be avoided and settings in which
risk features associated with greater risk of malignancy, use of thyroid ultrasound is clinically supported are listed
such as irregular margins, punctate echogenic foci, and in figure 1.
extrathyroidal extension.18 Fine needle aspiration (FNA) is a reliable, commonly
Because overdiagnosis of thyroid cancer is a real issue, used, and well accepted method for diagnosing thyroid
with real harms (eg, unnecessary surgery with potential cancer, except in rapidly progressive neck masses for
complications, personal and societal costs of treatment,19 which core biopsy might be preferred.24 For patients with
psychological effects of a cancer diagnosis, and decreased multinodular goitre, FNA of all nodules might not be
quality of life after cancer diagnosis),20,21 clinicians should feasible and decisions about which nodules to perform
strive to avoid overdiagnosis. This balance is difficult to biopsy on should be based on the malignancy risk of
achieve because not all patients with progressive, each nodule.
metastatic thyroid cancer have palpable thyroid nodules, Several international risk stratification systems have
and not all diagnoses of the lowest-risk thyroid cancers been developed that use sonographic features of thyroid
are avoidable. For example, incidental intrathyroidal nodules to determine malignancy risk, and make
microcarcinomas that would probably never cause recommendations about which nodules to evaluate
symptoms or death, can be diagnosed histologically after further with FNA. The features of the four major systems
surgery for benign thyroid disease.16 To avoid used globally, which share common features and lexicon,
overdiagnosis, evidence-based guidelines are consistent are summarised in table 1; namely, the American
in discouraging screening for thyroid cancer in Thyroid Association, the American College of Radiology
asymptomatic individuals,22 including in people with Thyroid Imaging and Reporting And Data System (ACR
hyperthyroidism or hypothyroidism and no palpable TI-RADS), the European Thyroid Imaging and Reporting
thyroid nodules.23 Clinical scenarios in which thyroid Data System (EU-TIRADS), and the revised Korean
Scenarios and recommendations for thyroid ultrasound use Balancing potential for overdiagnosis vs underdiagnosis
Routine ultrasound strongly discouraged Considerations:
• Screening for thyroid cancer • Ultrasound unnecessary for diagnosis of primary condition
• Thyrotoxicosis • Large potential to identify clinically non-significant disease
• Hypothyroidism Recommendations:
• Euthyroid Hashimoto thyroiditis • Examine for palpable thyroid nodules
• Suspected painless thyroiditis or subacute thyroiditis • Educate on potential harms of incidental diagnosis
Ultrasound reasonable, but caution advised in interpreting incidental findings Considerations:

• Equivocal or possible thyroid nodules on examination • Ultrasound defines extent and characteristics of known nodule
• Thyroid nodules found in unrelated imaging • Large potential to identify clinically non-significant disease
Recommendations:
• Discuss potential for incidental findings
• Educate on potential harms of incidental diagnosis
Ultrasound encouraged Considerations:

• Palpable thyroid nodule • Ultrasound defines extent and characteristics of known nodule
• Potential exists to identify non-clinically significant disease
Recommendations:
• Discuss potential for incidental findings
• Educate on potential harms of incidental diagnosis
Ultrasound encouraged, potentially with additional imaging Considerations:

• Palpable thyroid nodule with background history of: • Ultrasound defines extent and characteristics of known nodule
Radiation exposure, particularly in childhood • History or clinical features predict higher risk and disease severity
Previous thyroid cancer • Lower likelihood of incidental diagnosis
Familial clinically significant thyroid cancer, medullary thyroid cancer, multiple • Additional investigations might be appropriate
endocrine neoplasia type 2 Recommendations:
• Palpable thyroid nodule or neck mass with history of: • CT neck (± chest) if invasive disease or bulky lymphadenopathy
Rapid growth of thyroid nodule or neck mass
Compressive symptoms (eg, voice change or dysphagia)
Anterior neck pain
Suspected infectious thyroiditis
• Enlarging neck mass with systemic symptoms
• Palpable thyroid nodule or neck mass with examination findings of:
Objective voice change
Hard, palpable thyroid nodule
Fixed neck mass
Lymphadenopathy
• Low serum thyrotropin concentration with functional imaging findings of:
Focal thyroid uptake (to confirm diagnosis of an autonomous nodule)
Hypofunctional area in thyroid gland (to confirm presence of nodule)
Figure 1: Recommendations for the use or avoidance of thyroid ultrasound
2 www.thelancet.com Published online April 3, 2023 https://doi.org/10.1016/S0140-6736(23)00020-X

Seminar
Definition Risk of malignancy Recommendations

American Thyroid Association (2016)
Benign Purely cystic nodules (no solid component) <1% No FNA
Very low suspicion Spongiform nodules or partially cystic nodules without suspicious features <3% Consider FNA if ≥20 mm
present
Low suspicion Isoechoic or hyperechoic solid nodules or partially cystic nodules with 5–10% FNA if ≥15 mm
eccentric solid areas and without higher-risk features
Intermediate suspicion Hypoechoic solid nodules without higher risk features 10–20% FNA if ≥10 mm
High suspicion Hypoechoic solid nodule or solid hypoechoic component of a partially cystic >70–90% FNA if ≥10 mm
nodule with one or more high-risk features; namely, irregular margins
(ie, infiltrative or microlobulated), microcalcifications, taller-than-wide
shape, disrupted rim calcifications with extrusive soft tissue, or
extrathyroidal extension
American College of Radiology Thyroid Imaging, Reporting and Data Systems (2017)*
TR1 0 points; benign <2% No FNA
TR2 2 points; not suspicious <2% No FNA
TR3 3 points; mildly suspicious 5% FNA if ≥25 mm
TR4 4–6 points; moderately suspicious 5–20% FNA if ≥15 mm
TR5 ≥7 points; highly suspicious ≥20% FNA if ≥10 mm
European Thyroid Imagining and Reporting Data Systems (2017)
EU-TIRADS 1 Normal; no nodule NA No FNA
EU-TIRADS 2 Benign; pure cysts or spongiform nodules 0% No FNA
EU-TIRADS 3 Low risk; ovoid isoechoic or hyperechoic nodule with smooth margin and 2–4% FNA if >20 mm
no high-risk features
EU-TIRADS 4 Intermediate risk; ovoid mildly hypoechoic nodule with smooth margin and 6–17% FNA if >15 mm
no high-risk features
EU-TIRADS 5 High risk; at least one of the following high-risk features: irregular shape, 26–87% FNA if >10 mm; FNA or
irregular margins, microcalcifications, or marked hypoechogenicity (and active surveillance if
solid) <10 mm
Revised Korean Thyroid Imagining and Data Systems (2021)
K-TIRADS 1 No nodule NA No FNA
K-TIRADS 2 Benign; isoechoic or hyperechoic spongiform, or partially cystic nodule with <3% No FNA unless continuous
intracystic echogenic foci and comet-tail artifact or pure cyst and significant growth
K-TIRADS 3 Low suspicion; partially cystic, either partially cystic nodule, or isoechoic or 3–10% FNA if >20 mm
hyperechoic nodule without any suspicious features
K-TIRADS 4 Intermediate suspicion; solid hypoechoic nodule without any suspicious 10–40% FNA if >10 to 15 mm
features, or either partially cystic or isoechoic or hyperechoic nodule with any
suspicious features, or entirely calcified nodule or extensive parenchymal
punctate echogenic foci (microcalcifications) without discrete nodules
(suspicious for diffuse sclerosing variant of papillary thyroid cancer), or
diffusely infiltrative lesions (suspicious for infiltrative malignancy such as
metastasis or lymphoma)
K-TIRADS 5 High suspicion; solid hypoechoic nodule with any suspicious features: >60% FNA if >10 mm (and select
punctate echogenic foci, nonparallel orientation (taller-than-wide shape), cases of small nodules
or irregular margins >5 mm)
FNA=fine needle aspiration. *Points in the following five feature categories are summed to determine a risk category from TR1 to TR5. Composition: 0 points (purely cystic or
spongiform), 1 point (mixed cystic and solid), or 2 points (solid or almost completely solid); echogenicity: 0 points (anechoic), 1 point (hyperechoic or isoechoic), 2 points
(hypoechoic), or 3 points (very hypoechoic); shape assessed on transverse plane: 0 points (wider than tall), or 3 points (taller than wide); margin: 0 points (smooth or
ill-defined), 2 points (lobulated or irregular), or 3 points (extrathyroidal extension); echogenic foci (choose all that apply): 0 points (none or large comet-tail artifact),
1 point (macrocalcifications), 2 points (peripheral or rim calcifications), or 3 points (punctate echogenic foci).
Table 1: Comparison of thyroid nodule risk stratification systems and recommendations for FNA
Thyroid Imaging Reporting and Data System the American and European Thyroid Associations’
(K-TIRADS).18,25–27 These risk stratification systems follow systems recommend against FNA of nodules that show
a pattern-based classification,18,25,26 with the exception of high uptake on thyroid scintigraphy, which would
ACR TI-RADS, which generates an additive points score usually be done after confirmation of a low or suppressed
for individual morphological features.27 All four risk serum thyrotropin concentration (irrespective of
stratification systems show concordance in recommen other ultrasound classification).18,25 All systems now
ding FNA for sonographically suspicious lymph nodes, recommend a default lower size limit of 10 mm for
independent of any thyroid nodule features or size. Both FNA of sonographically high-risk nodules to limit

Seminar
overdiagnosis of small, possibly indolent papillary mutation sequencing (DNA and RNA) for nucleotide
microcarcinomas. However, the K-TIRADS and EU- variations, insertions or deletions, copy number variations,
TIRADS give clinicians flexibility to recommend FNA of gene fusions, and abnormal gene expression.33 Afirma
smaller lesions (specifically mentioned in the Korean Gene Sequencing Classifier measures the transcriptome
system are nodules that could be invasive to adjacent and sequence of nuclear and mitochondrial RNAs, and
structures) and mention the management option of measures changes in genomic copy number.32 A
active surveillance for small, pathologically proven continuing issue with the assays is correct identification
cancers.25,26 of oncocytic thyroid cancer, but major improvements have
Results of FNA are reported using standardised already occurred, and future assay versions can be
frameworks. Reporting methods vary globally, although expected to address this deficiency further. Unfortunately,
they generally use similar themes to the Bethesda the high cost and logistics of ThyroSeq v3 and Afirma
system,28 which divides cytology results into six categories limit the feasibility and availability of their use in many
(figure 2). Aside from category 1, which indicates either countries where alternative testing can be used in the
cystic fluid or inadequate sampling, the other categories evaluation of thyroid nodules.34,35
indicate increasing likelihood of malignancy. Benign
cytology (category 2) has an extremely low cancer risk. Management of differentiated thyroid cancer
Given the low false-negative rate of FNA cytology, For all patients, the initial management of differentiated
follow-up (eg, surveillance ultrasound) for patients with thyroid cancer should be guided by the pretreatment risk
benign cytology should be informed by the malignancy assessment, which includes physical examination,
risk of the nodule.18,26,27,29 Category 3 and 4 lesions are ultrasound assessment, and cytological interpretation.
often referred to as indeterminate and represent difficult Unnecessary or too invasive treatment should be avoided.
diagnoses for cytology; the traditional approach to Initial management options, from least to most invasive,
recurrent category 3 or first diagnosis of category 4 include active surveillance, minimally invasive
cytology is diagnostic lobectomy. In the past decade, the interventions, and surgery. In some patients, additional
developed molecular diagnostic techniques reduced the treatment with radioactive iodine, thyroid hormone
need for diagnostic lobectomy and have substantially suppression, and systemic therapies might be
altered diagnostic algorithms in locations where these appropriate. Initial management options for papillary
techniques are available and affordable.30 Nodules in thyroid cancer, the most common thyroid cancer type,
categories 5 and 6 are very frequently confirmed to be based on tumour characteristics, are shown in figure 3.
thyroid cancers and should be managed as per the
management of thyroid cancer described later. Active surveillance
Multiple approaches to molecular diagnostic testing of To avoid surgical risks and overtreating indolent tumours,
FNA specimens have been commercialised and updated active surveillance is sometimes considered an acceptable
over the last decade, with the ThyroSeq v331 and Afirma alternative to immediate surgery in patients with small,
platforms32 prospectively validated for use in classifying low-risk papillary thyroid cancer.18,36,37 During active
indeterminate (Bethesda category 3 or 4) thyroid nodules. surveillance, patients undergo serial neck ultrasounds,
They use next-generation sequencing approaches linked including evaluation of the thyroid and cervical lymph
to proprietary diagnostic algorithms. ThyroSeq v3 uses nodes, to identify disease progression. The ideal tumour
Category 1 Category 2 Category 3 Category 4 Category 5 Category 6

(non-diagnostic or (benign) (AUS or FLUS) (FN or SFN) (suspicious for malignancy) (malignant)
unsatisfactory) Cancer risk 0–3% Cancer risk 6–18% Cancer risk 10–40% Cancer risk 45–60% Cancer risk 94–96%
Cancer risk 5–10%
After 1–3 months
If ongoing suspicion,
After 1–3 months

repeat FNA
Surveillance Surveillance Surveillance ultrasound Molecular If probable or Thyroid cancer

ultrasound ultrasound diagnostic testing proven cancer management should be
OR OR OR informed by patient
Repeat FNA Diagnostic lobectomy preference. If undergoing
Repeat FNA thyroid surgery, the extent
of surgery is determined
OR based on patient history
and physical examination,
Molecular diagnostic testing tumour characteristics, and
If probable or proven cancer
OR results of ultrasound
Diagnostic lobectomy findings, and cytology.
Figure 2: Algorithm for thyroid nodule management based on results of the thyroid nodule fine needle aspiration
AUS=atypia of undetermined significance. FLUS=follicular lesion of undetermined significance. FN=follicular neoplasm. FNA=fine needle aspiration. SFN=suspicious
for follicular neoplasm.

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Papillary thyroid carcinoma
Unifocal ≤10 mm* and: >10 mm to 40 mm and: With evidence of lymph Characterised by tumour Characterised by gross
• no extrathyroidal • no extrathyroidal node metastases size >40 mm (T3) extrathyroidal extension
extension (not clinical T3 extension (not clinical T3 (clinical N1) (clinical T4) OR distant
or T4 disease); or T4); metastases (clinical M1)
• no lymph node • no lymph node
metastases (clinical N0); metastases (clinical N0);
• no distant metastases • no distant metastases
(clinical M0); and (clinical M0);
• no cytological evidence of • no cytological evidence
aggressive disease of aggressive disease
Patient prefers Patient prefers Patient preference

non-surgical option surgery
Active surveillance† Lobectomy Total thyroidectomy§¶ Total thyroidectomy with Total thyroidectomy with
or minimally invasive therapeutic selective neck or without prophylactic
intervention‡ dissection¶ central neck dissection¶
Radioactive iodine therapy Consider radioactive

not routine iodine therapy
Consider radioactive Recommend radioactive
iodine therapy iodine therapy
for T3 disease for T4 and M1 disease
Radioactive iodine therapy
Figure 3: Initial management of papillary thyroid carcinoma

Management should be informed by patient preference and results of the preoperative evaluation, which should include results from the physical examination, imaging (ie, neck ultrasound),
and cytology. *Many clinical guidelines do not recommend fine needle aspiration in nodules <10 mm with low-risk features. If followed, then management options for unifocal papillary thyroid
carcinoma ≤10 mm might not apply. †Active surveillance is not practised in all countries. Transition from active surveillance to surgery should be considered in patients with low-risk papillary thyroid
cancer when there is evidence of tumour enlargement, extrathyroidal extension, tumour invasion into the recurrent laryngeal nerve, trachea, or oesophagus, new lymph nodes that are biopsy-proven
thyroid cancer, or new distant metastasis. ‡Minimally invasive interventions for thyroid cancer are not widely used in all countries. Patients who are interested in minimally invasive interventions for
treatment of thyroid cancer should be treated at high-volume centres. §Near-total or total thyroidectomy is necessary if the overall strategy is to include radioactive iodine therapy postoperatively.
¶Some variation in management of papillary thyroid carcinoma exists in countries based on availability of resources. For example, in countries where radioactive iodine therapy is not widely available,
the type of thyroid surgery is not based on indications for postoperative radioactive iodine therapy. In countries where calcium monitoring and replacement are not readily available, a thyroid
lobectomy might be considered for unilateral papillary thyroid cancer to decrease risk of postoperative hypoparathyroidism and hypocalcemia.
characteristic for active surveillance is suggested to be a reasonable alternative for patients with low-risk papillary
unifocal papillary thyroid cancer measuring up to 10 mm, thyroid microcarcinomas who prefer, and are able to
which is situated away from the recurrent laryngeal nerve adhere to, this management strategy and have high
and oesophagus, and is without evidence of extrathyroidal surgical or anaesthetic risks, shortened life expectancy, or
extension, metastases, or aggressive cytology. In a case comorbid diseases that need to be addressed before
series,38 patients undergoing active surveillance were surgery.18,36
transitioned to surgical treatment when the tumour size Despite the promising data from published case series,
increased substantially or cancer spread to regional lymph the general adoption of active surveillance into clinical
nodes. Since the initial active surveillance studies in Japan practice in many countries has been slow due to patient,
in the 1990s,38,39 active surveillance for low-risk papillary physician, and systems barriers, such as limitations of
thyroid cancer has been studied in diverse, but mostly the health-care system infrastructure in some countries
small patient cohorts (ie, studies with an n ranging to allow for long-term follow-up of patients with serial
from 57 to 1235, recruited from Colombia, Italy, Japan, neck ultrasounds, while minimising the potential for
South Korea, and the USA) with promising results.40–43 A patients to be lost to follow-up.45–47 In countries where a
2019 meta-analysis reported that only 5·3% of the papillary restrictive thyroid nodule evaluation protocol (such as
thyroid microcarcinomas grew and 1·6% developed refraining from taking a biopsy of thyroid nodules
lymph node metastases over the 5-year surveillance measuring <10 mm in size) is practised, active
period.44 Even when the tumour grew or developed nodal surveillance of cancer measuring 10 mm or smaller is
metastases, delayed surgery after a period of active less relevant.48 Although the use of active surveillance for
surveillance did not worsen the overall survival of patients larger tumour sizes is now being evaluated,40,41,47,49
when compared with patients who underwent immediate additional work is needed to establish whether it is a
surgery.38,39,41,42 Therefore, active surveillance might be a practical option for large tumours worldwide.

Seminar
Minimally invasive interventions wound complications, and need for thyroid hormone
When interventional treatment for the lowest-risk disease replacement.65 In the past, total thyroidectomy was the
is desired, minimally invasive interventions, such as preferred treatment for any differentiated thyroid cancer
ultrasound-guided radiofrequency ablation, microwave measuring greater than 10 mm.64,66 However, a 2014 study
ablation, and laser ablation, offer a promising alternative to by Adam and colleagues suggests that for papillary
surgery. Although these three thermal ablation modalities thyroid cancers measuring greater than 10 mm but less
have slightly different mechanisms of actions, they share than 40 mm without clinical high-risk features
similar tumour selection criteria, method of tumour (ie, extrathyroidal extension, metastases, or aggressive
response, and types of post-procedural complications.50–52 cytology), the survival and recurrence risks do not
Currently, most physicians agree that the ideal tumour statistically differ significantly between patients who
characteristics for minimally invasive interventions are underwent lobectomy and total thyroidectomy.67 As a
intrathyroidal papillary thyroid cancers measuring less result, the 2015 American Thyroid Association and 2019
than 10 mm and located more than 5 mm from heat- European Society for Medical Oncology clinical practice
sensitive structures such as the trachea, oesophagus, and management guidelines for thyroid cancer have
recurrent laryngeal nerve. Inadvertent heat injury to the considered lobectomy as an equivalent option to total
nearby recurrent laryngeal nerve resulting in temporary thyroidectomy in larger (>10 mm to <40 mm) low-risk
voice hoarseness remains the most common complication papillary thyroid cancers.18,36 Benefits of lobectomy
after treatment.50 To minimise harm to surrounding compared with total thyroidectomy include fewer
structures, safety margins beyond the target lesion are complications, shorter operating time, and less reliance
recommended.50–52 on thyroid hormone replacement.18,65 Some patients and
Multiple studies have shown the efficacy and safety of physicians might still choose total thyroidectomy over
minimally invasive interventions in treating papillary lobectomy to enable the use of radioactive iodine ablation
thyroid microcarcinoma.53–58 Although the use of minimally or to improve ease of long-term surveillance.68 Shared
invasive interventions has yielded promising results for decision making should occur and the potential risks and
treatment of low-risk papillary thyroid cancer, most studies benefits of the two surgical approaches, and the
have been retrospective and predominantly based in China, subsequent treatment plan, should be thoroughly
Italy, and South Korea.51,54–57 There has also been no direct discussed with the patient before surgery.
comparisons between the use of minimally invasive
interventions and active surveillance. Therefore, Postoperative management of differentiated thyroid
ultrasound-guided thermal ablation should only be cancer
considered in patients with low-risk thyroid cancer who are After total thyroidectomy, radioactive iodine therapy and
not surgical candidates or who prefer this treatment option, thyrotropin suppression can be considered for patients
and who have access to high-volume centres (figure 3).50–52 with differentiated thyroid cancer. Radioactive iodine can
In the future, for patients with clinically significant be used to destroy normal residual thyroid tissue (remnant
thyroid cancers, minimally invasive interventions might ablation) and presumed (adjuvant therapy) or known
be an alternative treatment option with fewer complication (targeted therapy) residual or metastatic disease.18 The
risks than surgery. Since 2021, the use of thermal ablation effectiveness of radioactive iodine in patients with high-
in thyroid cancer measuring up to 38 mm (T1b–T2) and risk disease is well established; however, the benefits of
with high-risk features has been examined.59–62 However, radioactive iodine in patients with intermediate-risk
these retrospective studies included small patient cohorts disease and some low-risk disease remain controversial
(n ranging from 12 to 172) and had short follow-up (figure 3).18,69,70 In a retrospective study spanning nearly five
duration (mean 19·8–25·0 months; range decades, Hay and colleagues showed that radioactive
6–60 months).59–62 Thus, more research is needed to iodine remnant ablation did not reduce cause-specific
understand the role of thermal ablation in the treatment mortality or tumour recurrence rates in a cohort of patients
of patients with clinically significant thyroid cancers. with stage I papillary thyroid cancer.71 In 2022, Leboulleux
and colleagues published a prospective, randomised,
Surgery phase 3 trial of 730 patients with low-risk differentiated
Surgery remains the mainstay of treatment for patients thyroid cancer (TNM stage T1a–T1b, N0 or Nx, or M0)
with a suspected or cytologically confirmed differentiated undergoing thyroidectomy, which confirmed non-
thyroid cancer (figure 3). Historically there has been inferiority when evaluating occurrence of a functional,
controversy over the most appropriate extent of thyroid structural, or biologic event in the short term, for a follow-
resection (lobectomy, which is removal of half the thyroid up strategy that did not involve use of radioactive iodine.72
gland versus total thyroidectomy, which is removal of the These results are consistent with many observational
entire thyroid gland).63,64 Surgical risks are greater in studies. An ongoing trial of no radioiodine versus
patients who undergo total thyroidectomy as compared radioiodine in patients with low-risk differentiated thyroid
with lobectomy. The risks of thyroid surgery include cancer (TNM stage T1a–T3, N0–N1a or Nx, or M0) has yet
recurrent laryngeal nerve injury, hypoparathyroidism, to report outcomes (NCT01398085).

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Thyrotropin suppression using supraphysiological FDA-approved for treatment of advanced differen

doses of levothyroxine is commonly used to decrease risk tiated thyroid cancer and subsequently became the
of thyroid cancer recurrence in patients with predominant first-line treatment.76
differentiated thyroid cancer. This treatment is based on As second-line therapy for patients with radioiodine-
the rationale that, in patients with differentiated thyroid refractory differentiated thyroid cancer, the FDA and
cancer, higher thyrotropin might stimulate thyroid EMA have approved cabozantinib, a multitargeted
cancer cell proliferation and thyroglobulin production.18 tyrosine kinase inhibitor, on the basis of the results of the
However, the risks and benefits of thyrotropin phase 3 COSMIC-311 trial.77 The COSMIC-311 trial
suppression should be balanced. For example, the benefit enrolled patients who had received previous treatment
is low in patients with low-risk thyroid cancer, and with sorafenib or lenvatinib, and up to two previous
similarly for patients with an excellent response to VEGFR tyrosine kinase inhibitors. After a median
treatment or with comorbidities such as cardiovascular follow-up of 6·2 months, the primary analysis showed a
disease or osteoporosis, the risks might exceed the median progression-free survival benefit of cabozantinib
benefits.18 compared with placebo (median not reached in the
cabozantinib group vs 1·9 months in the placebo group;
Systemic therapies for advanced differentiated thyroid HR 0·22, 96% CI 0·13–0·36; p<0·0001). At the extended
cancer follow-up analysis, cabozantinib showed a sustained
The past decade has seen a major change in the improvement in median progression-free survival
management of advanced thyroid cancer (appendix p 1). (11·0 months vs 1·9 months; HR 0·22, 96% CI 0·15–0·32; See Online for appendix
Historically, once differentiated thyroid cancer no longer p<0·0001) and an overall survival benefit compared with
responded to radioiodine therapy, there were no active placebo (median 19·4 months vs non-evaluable; HR 0·76,
treatment options. Patients would commonly be offered 95% CI 0·45–1·3).78
supportive care to ameliorate symptoms, but there were For patients with RET fusion-positive radioiodine-
no available options to alter the natural history of the refractory thyroid cancer, selpercatinib and pralsetinib
disease. Currently, eight systemic therapies are approved have been approved by the FDA with selpercatinib also
by the US Food and Drug Administration (FDA) for use approved by the EMA as second-line treatment after
in patients with advanced thyroid cancer (table 2). disease progression on sorafenib, lenvatinib, or both.
For patients with radioiodine-refractory locally advanced The phase 1/2 LIBRETTO-001 trial evaluated
or metastatic differentiated thyroid cancer, two oral selpercatinib in patients who had previously received a
multitargeted tyrosine kinase inhibitors, sorafenib tosilate multitargeted kinase inhibitor such as sorafenib,
and lenvatinib, have been approved by the FDA and the lenvatinib, or both, or other systemic agent.79 The
European Medicines Agency (EMA) as first-line therapy. overall response rate was 79% (95% CI 54–94) and
The phase 3 DECISION trial73 reported a 5-month 87% of responding patients had responses lasting
improvement in median progression-free survival for 6 months or longer.80 Similarly, in the phase 1/2
patients treated with sorafenib tosilate compared with ARROW trial, which evaluated pralsetinib in patients
placebo (10·8 months vs 5·8 months; hazard ratio with previously treated RET fusion-positive thyroid
[HR] 0·59, 95% CI 0·45–0·76; p<0·0001). Patients who cancer, the overall response rate was 89% (95% CI
had received previous targeted therapy or chemotherapy 52–100) and all the responding patients had responses
for thyroid cancer were excluded from the trial. Similarly, lasting 6 months or more.81, 82
the phase 3 SELECT trial74 reported a median progression-
free survival of 18·3 months in the lenvatinib group Medullary thyroid cancer
compared with 3·6 months in the placebo group (HR 0·21, For patients with medullary thyroid cancer, preoperative
99% CI 0·14–0·31; p<0·001). In the SELECT trial, patients evaluation includes measurement of calcitonin and
could have received up to one previous treatment with a carcinoembryonic antigen concentrations, genetic
tyrosine kinase inhibitor. testing for presence of germline RET proto-oncogene
In a multicentre retrospective cohort study of South mutation, and cross-sectional imaging. Depending on
Korean patients with radioiodine-refractory advanced the specific RET mutation, patients need evaluation for
differentiated thyroid cancer or poorly differentiated pheochromocytoma and possibly hyperparathyroidism.
thyroid cancer, first-line treatment with lenvatinib was Surgery remains the initial treatment for cure in
associated with a longer progression-free survival patients with early-stage medullary thyroid cancer.
compared with sorafenib tosilate (35·3 months vs Although total thyroidectomy with bilateral central
13·3 months; p=0·001).75 In the USA, a retrospective compartment dissection is considered standard therapy,
2010–16 observational study examining real-world the extent of lymph node dissection in the lateral
prescribing patterns among patients with advanced compartment remains controversial.83,84 Since 2018,
thyroid cancer found that sorafenib tosilate was the several studies have found that in patients without
most common therapy used in the first-line and second- preoperatively diagnosed lateral neck disease, elective
line setting until 2015—the year that lenvatinib was lateral neck dissection showed no statistically significant

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Drug targets Median progression-free Response rates (%) Main adverse effects*
survival
Radioiodine-refractory locally advanced or metastatic differentiated thyroid cancer †
Sorafenib (for first-line therapy)‡; clinical VEGFR1, VEGFR2, VEGFR3, RET, 10·8 vs 5·8 months (HR 0·59, CR: 0% vs 0%; PR: Hand-foot skin reaction, diarrhoea,
trial: DECISION (n=417 patients, phase 3 BRAF, and PDGFR 95% CI 0·45–0·76; p<0·0001) 12·2% vs 0·5%; SD: alopecia, fatigue, rash or desquamation,
RCT vs placebo with 1:1 allocation and 41·8% vs 33·2% weight loss, hypertension, increased serum
crossover allowed) thyrotropin concentration, pruritus,
anorexia, oral mucositis, and nausea
Lenvatinib (for first-line therapy)‡; clinical VEGFR1, VEGFR2, VEGFR3, RET, 18·3 vs 3·6 months (HR 0·21, CR: 1·5% vs 0%; PR: Hypertension, diarrhoea, fatigue,
trial: SELECT (n=392 patients, phase 3 RCT PDGFR, FGFR1, FGFR2, FGFR3, 99% CI 0·14–0·31; p<0·001) 63·2% vs 1·5%; SD: anorexia, weight loss, nausea, stomatitis,
vs placebo with 2:1 allocation and crossover and FGFR4 23% vs 54·2% hand-foot skin reaction, proteinuria,
allowed) vomiting, headache, and dysphonia
Cabozantinib (for second-line therapy); VEGFR2, RET, and MET Median PFS not reached (96% CI CR: 0% vs 0%; PR: 9% vs 0%; Diarrhoea, hand-foot skin reaction,
clinical trial: COSMIC-311 (n=187 patients, 5·7-NE) vs 1·9 months (1·8–3·6; SD: 61% vs 34% anorexia, alanine aminotransferase rise,
phase 3 RCT vs placebo with 2:1 allocation HR 0·22, 96% CI 0·13–0·36; aspartate aminotransferase rise, nausea
and crossover allowed) p<0·0001)
RET fusion-positive radioiodine-refractory thyroid cancer§
Selpercatinib; clinical trial: LIBRETTO-001 Selective inhibitor of RET and 20·1 months (95% CI 9·4–NE)¶ ORR: 79% (95% CI 54–94)¶ Dry mouth, diarrhoea, fatigue, nausea,
(n=19 previously treated patients, phase 1/2 oncogenic RET mutants constipation, and increased aspartate
open-label, multi-cohort study) aminotransferase concentration
Pralsetinib; clinical trial: ARROW Selective inhibitor of RET and Not reached at time of publication ORR: 89% (95% CI 52–100) Increased aspartate aminotransferase,
(n=9 previously treated patients, phase 1/2 oncogenic RET mutants increased alaninine aminotransferase
open-label, multi-cohort study) concentration, constipation, decreased
white blood cells, neutropenia, aesthenia,
and hyperphosphataemia
Locally advanced or metastatic medullary thyroid cancer
Vandetanib; clinical trial: ZETA VEGFR2, RET, and EGFR 30·5|| vs 19·3 months (HR 0·46, CR: 0 vs 0; PR: 45 vs 13; SD: NA Diarrhoea, rash, nausea, hypertension,
(n=331 patients, phase 3 RCT vs placebo 95% CI 0·31–0·69; p<0·001) fatigue, headache, anorexia, and acne
with 2:1 allocation)
Cabozantinib; clinical trial: EXAM VEGFR2, RET, and MET 11·2 vs 4·0 months (HR 0·28, CR: 0% vs 0%; PR: 28% vs 0%; Hand-foot syndrome, weight loss,
(n=330 patients, phase 3 RCT vs placebo 95% CI 0·19–0·40; p<0·001) SD: 48·1% vs 50% anorexia, nausea, fatigue, dysgeusia, hair
with 2:1 allocation) colour change, hypertension, stomatitis,
constipation, haemorrhage, vomiting,
mucosal inflammation, and dysphonia
RET-mutant advanced or metastatic medullary thyroid cancer
Selpercatinib; clinical trial: LIBRETTO-001 Selective inhibitor of RET and 1-year PFS: 82% (95% CI 69–90%) ORR in previously treated Dry mouth, diarrhoea, fatigue, nausea,
(n=143 patients [n=55 treated previously, oncogenic RET mutants in previously treated cohort vs cohort: 69% (95% CI 55–81); constipation, and increased aspartate
n=88 treatment naive], phase 1/2 open- 92% (95% CI 82–97%) in ORR in treatment naive aminotransferase concentration
label, multi-cohort study) treatment naive cohort¶ cohort: 73% (95% CI 62–82)
Pralsetinib; clinical trial: ARROW Selective inhibitor of RET and Not reached at time of publication ORR in previously treated Decreased white blood cells, neutropenia,
(n=76 patients [n=55 treated previously, oncogenic RET mutants cohort: 60% (95% CI 46–73); increased aspartate aminotransferase
n=23 treatment naive], phase 1/2 open- ORR in treatment naive concentration, increased alaninine
label, multi-cohort study) cohort: 66% (95% CI 46–82) aminotransferase concentration,
aesthenia, hyperphosphataemia, and
constipation
BRAF V600E-mutant anaplastic thyroid cancer
Dabrafenib and Trametinib; clinical trial: Dabrafenib: BRAF inhibitor; 6·7 months (95% CI 4·7–13·8)** ORR: 56% (95% CI Fatigue, pyrexia, nausea, chills, vomiting,
ROAR (n=36 patients, phase 2 open-label, Trametinib: MEK inhibitor 38·1–72·1);** headache, diarrhoea, anaemia, rash,
non-randomised basket study) CR: 8;** PR: 47;** SD: 31** constipation, and hyperglycaemia
PFS=progression-free survival. RCT=randomised controlled trial. HR=hazard ratio. CR=complete response. PR=partial response. SD=stable disease. NE=not estimable. ORR=overall response rate. *Adverse events
that are reported to have occurred in at least 20% of the study cohort. †These US Food and Drug Administration-approved systemic therapies are not available in all countries for the treatment of advanced
differentiated thyroid cancer. In some countries, commercially available small-molecule tyrosine kinase inhibitors, such as axitinib, pazopanib, and sunitinib, can be considered if clinical trials are not available or
appropriate. ‡For progressive or symptomatic locally advanced, or distant metastatic differentiated thyroid cancer, the National Comprehensive Cancer Network recommends lenvatinib (preferred) or sorafenib
as first-line therapy. §For patients with disease progression on selpercatinib and pralsetinib, there are no data on the efficacy of subsequent treatment with multitargeted tyrosine kinase inhibitors, such as
sorafenib, lenvatinib, or cabozantinib. ¶Independent review. ||Predicted median progression-free survival. ** Investigator assessment.
Table 2: Systemic therapies for management of advanced thyroid cancer
difference in biochemical cure, disease recurrence, or and cabozantinib, have been approved by the FDA and
survival.85,86 EMA for treatment of locally advanced or metastatic
For patients with inoperable and progressive medullary medullary thyroid cancer. The phase 3 ZETA trial87 showed
thyroid cancer, cytotoxic chemotherapy has historically a significant improvement in median progression-free
yielded disappointing results. However, since 2011, survival in patients randomised to receive vandetanib
two multitargeted tyrosine kinase inhibitors, vandetanib compared with placebo (30·5 months predicted vs

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19·3 months; HR 0·46, 95% CI 0·31–0·69; p<0·001). The role of this combination drug therapy in the
Similarly, the phase 3 EXAM trial88 reported that neoadjuvant setting to enable surgical resection has been
cabozantinib significantly prolonged median progression- reported89 and is currently being investigated in clinical
free survival compared with placebo (11·2 months vs trials (NCT04675710). Furthermore, a single-institution
4·0 months; HR 0·28, 95% CI 0·19–0·40; p<0·001). retrospective cohort study of 135 patients with anaplastic
In 2020, selpercatinib and pralsetinib were approved thyroid cancer treated with immunotherapy plus
by the FDA for treatment of patients with advanced or dabrafenib and trametinib combination therapy has
metastatic RET-mutant medullary thyroid cancer, with yielded promising results.89 Genomic profiling should
selpercatinib also approved by the EMA as second-line also look for other drug targets such as RET (eg,
therapy after disease progression on vandetanib, selpercatinib or pralsetinib), ALK (eg, crizotinib), or
cabozantinib, or both. The phase 1/2 LIBRETTO-001 trial NTRK (eg, entrectinib or larotrectinib) fusions.
showed that in a cohort of previously treated patients, Unfortunately, in patients with no targetable genomic
selpercatinib yielded an overall response rate of 69% alterations, and in places where therapy is not easily
(95% CI 55–81), with 76% of the responding patients available or affordable, treatment options remain scarce.
having responses lasting at least 6 months.79,80 In the However, the phase 2 ATLEP trial92–94 has reported
cohort of treatment-naive patients, the overall response encouraging results for patients treated with lenvatinib
rate was 73% (95% CI 62–82), with 61% of responding and pembrolizumab combination therapy at the interim
patients having responses lasting at least 6 months.79,80 analysis point. In a cohort of 35 patients with stage 4
Similarly, the phase 1/2 ARROW study showed that in a anaplastic thyroid cancer (n=27) or poorly differentiated
cohort of formerly treated patients, pralsetinib yielded an thyroid cancer (n=8), the overall response rate at 3
overall response rate of 60% (95% CI 46–73), with 79% of months was 34·3% partial response (12 of 35) for all
responding patients having responses lasting at least patients. Within 2 years of treatment, the best overall
6 months.82,83 In the cohort of treatment-naive patients, response for anaplastic thyroid cancer was 51·9% partial
overall response rate was 66% (95% CI 46–82), with response (14 of 27) and 44·4% stable disease (12 of 27).
84% of responding patients having responses lasting at Among the patients with anaplastic thyroid cancer, the
least 6 months.81 median progression-free survival was 9·5 months,
overall survival was 10·25 months, and seven (25·9%)
Anaplastic thyroid cancer patients survived more than 2 years. Grade 3/4 toxicities
There is a continuum of thyroid cancer histology—from included haemorrhage, fistula development, auto
well differentiated, to poorly differentiated, to anaplastic. immune hepatitis, and pulmonary embolism.94
Anaplastic thyroid cancer, an aggressive solid tumour For patients with anaplastic thyroid cancer, living in
with a disease-specific mortality approaching 100%, often areas of high poverty is associated with lower overall and
presents in patients as a rapidly growing and invasive disease-specific survival.95 Therefore, as these new,
neck mass.89 Therefore, prompt evaluation and rapid promising treatment options are now available, equitable
implementation of a treatment plan by a multidisciplinary access to them is increasingly important.
team at a centre with experience in treating anaplastic
thyroid cancer is recommended. Advanced care planning Challenges to equitable thyroid cancer care
with a multidisciplinary team, including palliative care Disparities in the diagnosis of thyroid cancer
when available, is also recommended to discuss realistic Although an increase in thyroid cancer incidence has
treatment options and patients’ end-of-life goals. been observed worldwide, irrespective of country income
The initial approach to patients with anaplastic thyroid level, there exists large geographical heterogeneity in the
cancer depends on whether the primary tumour is rate of this increase,2 which suggests that some countries
resectable, if targeted therapy is available and affordable, might be more affected by ultrasonography-driven
and the BRAF status of the tumour. Most patients will be overdiagnosis of thyroid cancer than others. Globally,
considered for systemic therapy given the advanced stage thyroid cancer incidence rates are five times greater in
of most anaplastic thyroid cancers at time of diagnosis. high and very high Human Development Index countries
For patients with a BRAF V600E mutation, which is than in low and medium Human Development Index
present in up to 45% of anaplastic thyroid cancers,90 countries, with mortality rates similar.² However, beyond
dabrafenib, a BRAF inhibitor, and trametinib, a mitogen- comparing incidence and mortality rates, there has not
activated protein kinase inhibitor, should be considered. been an in-depth analysis of between-country disparities
The phase 2 ROAR study91 cohort included 36 patients in thyroid care.
with BRAF V600E-mutated unresectable or metastatic In many countries, thyroid cancer care delivery and
anaplastic thyroid cancer treated with dabrafenib and outcomes are suggested to be influenced by social
trametinib. After a median follow-up of 11·1 months determinants of health, which is defined by WHO as “the
(range 0·9–76·6), the overall response rate was 56% conditions in which people are born, grow, work, live,
(95% CI 38·1–72·1), median progression-free survival and age, and the wider set of forces and systems shaping
was 6·7 months, and overall survival was 14·5 months. the conditions of daily life”.96 Studies in individual

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countries have identified economic status, the the survivorship period. Hispanic and Asian patients with
neighbourhood and physical environment, and education thyroid cancer reported greater cancer-related worry, and
access and quality as major contributors to disparities low-acculturated Hispanic women reported greater
along the thyroid cancer care continuum,97 which starts unmet information needs and more vulnerability to
before the diagnosis and treatment of cancer (appendix thyroid cancer-related financial hardship in the USA
p 2). compared with high-acculturated Hispanic women with
In the USA low socioeconomic status and no insurance thyroid cancer.123–126
or Medicaid insurance is associated with more advanced In addition to disparities in care based on race or
papillary thyroid cancer at presentation, when compared ethnicity, studies have found differences based on
with private insurance.98,99 Similar disparities in thyroid education. Patients without a higher education degree
cancer presentation have also been observed in countries are less likely to receive guideline-appropriate thyroid
with universal health coverage, such as Canada and cancer care, and more likely to report thyroid cancer-
Saudi Arabia.100,101 A potential contributing factor might related worry and to overestimate their risk of thyroid
be the non-medical costs related to accessing medical cancer recurrence and mortality.109,123,127
care (ie, travel costs to tertiary centres). More research is Differential access to high-volume physicians and to
needed to understand the causes of such disparities in clinical trials is a major contributor to the observed
countries with universal health care. disparities in thyroid cancer care. In the USA, Cai and
Racial and ethnic disparities are also consistently colleagues128 found racial and ethnic disparities in rates
shown to exist in thyroid cancer care. Among patients of outpatient visits for most medical and surgical
with thyroid cancer in the USA, being Hispanic, Asian, specialties, including endocrinology and otolaryngology.
or Black has been reported to be associated with Radhakrishnan and colleagues129 found that patient-
diagnosis of more advanced disease.99,100,102,103 Racial and reported involvement of endocrinologists, primary care
ethnic disparities in thyroid cancer care have also been physicians, and surgeons in thyroid cancer diagnosis and
shown outside of the USA, with Melanesian men and treatment varies by race and ethnicity, with patients from
women of New Caledonia, a French territory in the south minority racial and ethnic groups being less likely to report
Pacific, found to have thyroid cancer incidence rates involvement of their surgeons in thyroid cancer diagnosis
several times higher than any other ethnic group.104 and treatment decision making, compared with non-
Unfortunately, additional data on racial and ethnic Hispanic white patients. Regarding thyroid surgery, the
disparities in other countries are not readily available importance of individual surgeon experience for optimal
due to the absence of routine data collection on race and patient outcomes has been well documented. In 1998, Sosa
ethnicity in more than 20 countries, including France, and colleagues130 reported that surgeons performing the
Germany, Italy, Japan, Portugal, South Korea, Spain, and highest volume of thyroid surgeries led to shorter length of
Sweden.105–108 Without robust statistics on the identities hospital stay and the lowest complication rates for patients.
of its citizens, research opportunities to use national Similar findings have been replicated in multiple studies
administrative databases to identify and address thyroid over the subsequent two decades.114,131–134 Differential access
cancer disparities that might exist are suboptimal. to high-volume surgeons and hospitals continues to be an
issue, which results in worse outcomes for vulnerable
Inequities due to differential access to quality thyroid patient populations. In the USA, Black and Hispanic
cancer care patients are more likely to have thyroid surgery performed
Studies of diverse patient populations, including those by low-volume surgeons compared with white patients
from Canada, New Zealand, South Korea, and the USA, with thyroid cancer. Also, patients with low income are
have identified inequities in thyroid cancer management, more likely to have the surgery performed by low-volume
with patients from minority racial and ethnic groups, and surgeons than patients from high-income groups.114,131–134 In
patients from lower socioeconomic status experiencing Germany, there are also disparities in referral patterns for
a disproportionate burden of disease and surgical treatment of papillary and medullary thyroid
mortality.98,99,102–104,109–122 In the USA, higher rates of cancer. Machens and colleagues35 reported that as the travel
postoperative complications, such as voice abnormalities, distance from a German specialist centre for thyroid
greater health-care costs, and worse survival, are observed cancer increased, there was a selective referral of younger
among patients with thyroid cancer from minority racial patients (with increased distance mean age goes down
or ethnic groups.95,98,103,113–116 In a diverse region of New from 53 to 35 years for papillary thyroid cancer, from 65 to
Zealand with free public health care, operation waiting 49 years for non-carriers with medullary thyroid cancer,
times for thyroid surgery were statistically significantly and from 40 to 23 years for RET carriers with medullary
longer for Māori and Pacific Islanders compared with thyroid cancer; all p</=0·001).
Europeans. Also, Polynesian patients had statistically
significantly higher postoperative haemorrhage rates Differential access to clinical research participation
compared with non-Polynesian patients.121,122 Race and Disparities exist in access to and enrolment in clinical
ethnicity also impact the experience of patients during trials, which offer novel cancer therapeutics with the

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potential to improve patient outcomes and establish inform clinical practice guidelines on the treatment of
standards of care for advanced thyroid cancer.136,137 Since thyroid cancer. Clinical trials and population-based
2011, the FDA has approved eight novel therapeutics for studies examining the optimal extent of thyroid surgery
patients with advanced thyroid cancer. Although the and use of radioactive iodine therapy in diverse cohorts
clinical trials that led to FDA approval of these drugs of patients with low-risk and intermediate-risk disease,
recruited patients from up to 164 centres in 25 countries, who represent most patients with thyroid cancer, are
the final patient cohort, which was enrolled from needed to inform evidence-based clinical practice. In
predominantly European and North American sites, addition, investment in building long-term research
included an average of only 24% non-White participants infrastructure and strengthening research capacity in
(range 5–50), including 3–44% Asian patients, 0–3% low-income and middle-income countries is needed to
Black patients, and 0–1% reported as Hispanic patients increase the globalisation of clinical research.14,138–140 High-
in each of the clinical trials.73,74,77,79,82,87,88,91 This absence of quality population-based studies and large randomised
diversity and representation from minority racial and clinical trials on effective thyroid cancer management
ethnic groups and from low-income and middle-income strategies tailored to disease severity and involving
countries in clinical trials contributes to thyroid cancer patients from low-income, middle-income, and high-
care disparities by limiting access to high-quality care for income countries would yield greater concordance in
vulnerable patient populations and compromising the thyroid cancer clinical practice guidelines between
generalisability of trial results. countries and be more applicable to an international
population.
Summary and future directions Contributors
Increased access to thyroid ultrasound has DWC, BHHL, DSAM, KN, and MRH drafted, revised, and approved this
contributed to thyroid cancer overdiagnosis with a Seminar.
worldwide rise in thyroid cancer incidence and stable Declaration of interests
mortality rates.1,2,5,6,8–14,16,17 To address the overdiagnosis of We declare no competing interests.
thyroid cancer and subsequent overtreatment of patients Editorial note: The Lancet Group takes a neutral position with respect to
with low-risk thyroid cancer, several international territorial claims in published maps and institutional affiliations.
ultrasound-based thyroid nodule risk stratification References
systems have been developed that recommend against 1 Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020:
GLOBOCAN estimates of incidence and mortality worldwide for
biopsy of thyroid nodules of less than 1 cm. Furthermore, 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209–49.
non-surgical treatment options, such as active surveillance 2 Pizzato M, Li M, Vignat J, et al. The epidemiological landscape of
and minimally invasive interventions, are being explored thyroid cancer worldwide: GLOBOCAN estimates for incidence
and mortality rates in 2020. Lancet Diabetes Endocrinol 2022;
and have shown promising results in some patient 10: 264–72.
populations. The management of patients with advanced 3 LeClair K, Bell KJL, Furuya-Kanamori L, Doi SA, Francis DO,
thyroid cancer who would, historically, have been offered Davies L. Evaluation of gender inequity in thyroid cancer diagnosis:
differences by sex in US thyroid cancer incidence compared with a
supportive care has also changed drastically over the past meta-analysis of subclinical thyroid cancer rates at autopsy.
decade, with the development of new molecular-based JAMA Intern Med 2021; 181: 1351–58.
personalised systemic therapies. As these cutting-edge, 4 Araque DVP, Bleyer A, Brito JP. Thyroid cancer in adolescents and
young adults. Future Oncol 2017; 13: 1253–61.
novel manage ment options are increasingly becoming
5 National Cancer Institute. Cancer stat facts: thyroid cancer.
available for patients with thyroid cancer, it is essential https://seer.cancer.gov/statfacts/html/thyro.html. (accessed
that equity and inclusion are considered. Every individual Dec 10, 2022).
who is diagnosed with thyroid cancer should have the 6 Aschebrook-Kilfoy B, Ward MH, Sabra MM, Devesa SS. Thyroid
cancer incidence patterns in the United States by histologic type,
same opportunity to receive high-quality cancer care, 1992–2006. Thyroid 2011; 21: 125–34.
regardless of race or ethnicity, proficiency in the country’s 7 American Cancer Society. What is thyroid cancer? 2019. https://
official language, and socioeconomic status. www.cancer.org/cancer/thyroid-cancer/about/what-is-thyroid-
cancer.html. (accessed Dec 10, 2022).
To attain health equity in thyroid cancer care, more 8 Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M,
research, and more funding for thyroid cancer research, Dal Maso L. Worldwide thyroid-cancer epidemic? The increasing
is needed to tailor treatment to disease severity and to impact of overdiagnosis. N Engl J Med 2016; 375: 614–17.
better understand and address the factors that contribute 9 Ahn HS, Kim HJ, Welch HG. Korea’s thyroid-cancer “epidemic”–
screening and overdiagnosis. N Engl J Med 2014; 371: 1765–67.
to disparities in the quality and delivery of thyroid cancer 10 Davies L, Welch HG. Increasing incidence of thyroid cancer in the
care (appendix p 3). As the molecular characterisation of United States, 1973–2002. JAMA 2006; 295: 2164–67.
thyroid cancer and development of novel targeted 11 Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in
thyroid cancer incidence and mortality in the United States,
therapies continue to revolutionise thyroid cancer care, 1974–2013. JAMA 2017; 317: 1338–48.
we need to consider not only the cost of these new 12 Haymart MR, Reyes-Gastelum D, Caoili E, Norton EC, Banerjee M.
management options, but also the accessibility to The relationship between imaging and thyroid cancer diagnosis and
survival. Oncologist 2020; 25: 765–71.
molecular testing and novel therapies for patients in
13 Haymart MR, Banerjee M, Reyes-Gastelum D, Caoili E, Norton EC.
low-income and middle-income countries. It is important Thyroid ultrasound and the increase in diagnosis of low-risk thyroid
to design and implement randomised clinical trials to cancer. J Clin Endocrinol Metab 2019; 104: 785–92.

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14 Sajisevi M, Caulley L, Eskander A, et al. Evaluating the rising 36 Filetti S, Durante C, Hartl D, et al. Thyroid cancer: ESMO clinical
incidence of thyroid cancer and thyroid nodule detection modes: practice guidelines for diagnosis, treatment and follow-up.
a multinational, multi-institutional analysis. Ann Oncol 2019; 30: 1856–83.
JAMA Otolaryngol Head Neck Surg 2022; 148: 811–18. 37 Chou R, Dana T, Haymart M, et al. Active surveillance versus
15 Zafereo M, Yu J, Onakoya PA, et al. African head and neck society thyroid surgery for differentiated thyroid cancer: a systematic
clinical practice guidelines for thyroid nodules and cancer in review. Thyroid 2022; 32: 351–67.
developing countries and limited resource settings. Head Neck 38 Ito Y, Uruno T, Nakano K, et al. An observation trial without
2020; 42: 1746–56. surgical treatment in patients with papillary microcarcinoma of the
16 Rahman ST, McLeod DSA, Pandeya N, et al. Understanding thyroid. Thyroid 2003; 13: 381–87.
pathways to the diagnosis of thyroid cancer: are there ways we can 39 Sakai T, Sugitani I, Ebina A, et al. Active surveillance for T1bN0M0
reduce over-diagnosis? Thyroid 2019; 29: 341–48. papillary thyroid carcinoma. Thyroid 2019; 29: 59–63.
17 Kahn C, Simonella L, Sywak M, Boyages S, Ung O, O’Connell D. 40 Sanabria A. Active surveillance in thyroid microcarcinoma in a
Pathways to the diagnosis of thyroid cancer in New South Wales: Latin-American cohort. JAMA Otolaryngol Head Neck Surg 2018;
a population-based cross-sectional study. Cancer Causes Control 144: 947–48.
2012; 23: 35–44. 41 Tuttle RM, Fagin JA, Minkowitz G, et al. Natural history and
18 Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid tumor volume kinetics of papillary thyroid cancers during active
Association management guidelines for adult patients with thyroid surveillance. JAMA Otolaryngol Head Neck Surg 2017;
nodules and differentiated thyroid cancer: the American Thyroid 143: 1015–20.
Association guidelines task force on thyroid nodules and 42 Oh HS, Ha J, Kim HI, et al. Active surveillance of low-risk papillary
differentiated thyroid cancer. Thyroid 2016; 26: 1–133. thyroid microcarcinoma: a multi-center cohort study in Korea.
19 Barrows CE, Belle JM, Fleishman A, Lubitz CC, James BC. Thyroid 2018; 28: 1587–94.
Financial burden of thyroid cancer in the United States: an estimate 43 Molinaro E, Campopiano MC, Pieruzzi L, et al. Active surveillance
of economic and psychological hardship among thyroid cancer in papillary thyroid microcarcinomas is feasible and safe:
survivors. Surgery 2020; 167: 378–84. experience at a single Italian center. J Clin Endocrinol Metab 2020;
20 Nickel B, Tan T, Cvejic E, et al. Health-related quality of life after 105: e172–80.
diagnosis and treatment of differentiated thyroid cancer and 44 Cho SJ, Suh CH, Baek JH, et al. Active surveillance for small
association with type of surgical treatment. papillary thyroid cancer: a systematic review and meta-analysis.
JAMA Otolaryngol Head Neck Surg 2019; 145: 231–38. Thyroid 2019; 29: 1399–408.
21 Jensen CB, Pitt SC. Patient perception of receiving a thyroid cancer 45 Pitt SC, Yang N, Saucke MC, et al. Adoption of active surveillance
diagnosis. Curr Opin Endocrinol Diabetes Obes 2021; 28: 533–39. for very low-risk differentiated thyroid cancer in the United
22 Lin JS, Bowles EJA, Williams SB, Morrison CC. Screening for States: a national survey. J Clin Endocrinol Metab 2021;
thyroid cancer: updated evidence report and systematic review for 106: e1728–37.
the US Preventive Services Task Force. JAMA 2017; 317: 1888–903. 46 Hughes DT, Reyes-Gastelum D, Ward KC, Hamilton AS,
23 The Endocrine Society. Choosing wisely: five things physicians and Haymart MR. Barriers to the use of active surveillance for thyroid
patients should question. 2018. https://www.choosingwisely.org/ cancer results of a physician survey. Ann Surg 2022; 276: e40–47.
societies/endocrine-society/ (accessed Dec 10, 2022). 47 Ghai S, O’Brien C, Goldstein DP, et al. Ultrasound in active
24 Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid surveillance for low-risk papillary thyroid cancer: imaging
Association guidelines for management of patients with anaplastic considerations in case selection and disease surveillance.
thyroid cancer. Thyroid 2021; 31: 337–86. Insights Imaging 2021; 12: 130.
25 Russ G, Bonnema SJ, Erdogan MF, Durante C, Ngu R, Leenhardt L. 48 Lončar I, van Dijk SPJ, Metman MJH, et al. Active surveillance for
European Thyroid Association Guidelines for ultrasound papillary thyroid microcarcinoma in a population with restrictive
malignancy risk stratification of thyroid nodules in adults: the diagnostic workup strategies. Thyroid 2021; 31: 1219–25.
EU-TIRADS. Eur Thyroid J 2017; 6: 225–37. 49 Ho AS, Kim S, Zalt C, et al. Expanded parameters in active
26 Ha EJ, Chung SR, Na DG, et al. 2021 Korean thyroid imaging surveillance for low-risk papillary thyroid carcinoma:
reporting and data system and imaging-based management of thyroid a nonrandomized controlled trial. JAMA Oncol 2022;
nodules: Korean Society of Thyroid Radiology consensus statement published online Sep 15. doi: 10.1001/jamaoncol.2022.3875.
and recommendations. Korean J Radiol 2021; 22: 2094–123. 50 Kim JH, Baek JH, Lim HK, et al. 2017 Thyroid radiofrequency
27 Tessler FN, Middleton WD, Grant EG, et al. ACR thyroid imaging, ablation guideline: Korean Society of Thyroid Radiology.
reporting and data system (TI-RADS): white paper of the ACR Korean J Radiol 2018; 19: 632–55.
TI-RADS Committee. J Am Coll Radiol 2017; 14: 587–95. 51 Mauri G, Hegedüs L, Bandula S, et al. European Thyroid
28 Cibas ES, Ali SZ. The 2017 Bethesda system for reporting thyroid Association and Cardiovascular and Interventional Radiological
cytopathology. Thyroid 2017; 27: 1341–46. Society of Europe 2021 clinical practice guideline for the use of
29 Durante C, Costante G, Lucisano G, et al. The natural history of minimally invasive treatments in malignant thyroid lesions.
benign thyroid nodules. JAMA 2015; 313: 926–35. Eur Thyroid J 2021; 10: 185–97.
30 Kobaly K, Kim CS, Mandel SJ. Contemporary management of 52 Jasim S, Patel KN, Randolph G, et al. American Association of
thyroid nodules. Annu Rev Med 2022; 73: 517–28. Clinical Endocrinology disease state clinical review: the clinical
31 Steward DL, Carty SE, Sippel RS, et al. Performance of a multigene utility of minimally invasive interventional procedures in the
genomic classifier in thyroid nodules with indeterminate cytology: management of benign and malignant thyroid lesions. Endocr Pract
a prospective blinded multicenter study. JAMA Oncol 2019; 5: 204–12. 2022; 28: 433–48.
32 Patel KN, Angell TE, Babiarz J, et al. Performance of a genomic 53 Cao XJ, Wang SR, Che Y, et al. Efficacy and safety of thermal ablation
sequencing classifier for the preoperative diagnosis of cytologically for treatment of solitary T1N0M0 papillary thyroid carcinoma:
indeterminate thyroid nodules. JAMA Surg 2018; 153: 817–24. a multicenter retrospective study. Radiology 2021; 300: 209–16.
33 Nikiforova MN, Mercurio S, Wald AI, et al. Analytical performance 54 Kim HJ, Chung SM, Kim H, et al. Long-term efficacy of
of the ThyroSeq v3 genomic classifier for cancer diagnosis in ultrasound-guided laser ablation for papillary thyroid
thyroid nodules. Cancer 2018; 124: 1682–90. microcarcinoma: results of a 10-year retrospective study. Thyroid
34 Zafereo M, McIver B, Vargas-Salas S, et al. A thyroid genetic 2021; 31: 1723–29.
classifier correctly predicts benign nodules with indeterminate 55 Cho SJ, Baek SM, Lim HK, Lee KD, Son JM, Baek JH. Long-term
cytology: two independent, multicenter, prospective validation trials. follow-up results of ultrasound-guided radiofrequency ablation for
Thyroid 2020; 30: 704–12. low-risk papillary thyroid microcarcinoma: more than 5-year
35 Santos MTD, Buzolin AL, Gama RR, et al. Molecular classification follow-up for 84 tumors. Thyroid 2020; 30: 1745–51.
of thyroid nodules with indeterminate cytology: development and 56 Zhang M, Tufano RP, Russell JO, et al. Ultrasound-guided
validation of a highly sensitive and specific new miRNA-based radiofrequency ablation versus surgery for low-risk papillary thyroid
classifier test using fine-needle aspiration smear slides. Thyroid microcarcinoma: results of over 5 years’ follow-up. Thyroid 2020;
2018; 28: 1618–26. 30: 408–17.

Seminar
57 Yan L, Zhang M, Song Q, Luo Y. Ultrasound-guided radiofrequency 78 Tucker N. COSMIC-311 update: cabozantinib sustains PFS benefit
ablation versus thyroid lobectomy for low-risk papillary thyroid after 10 months in RAI-DTC. 2021. https://www.targetedonc.com/
microcarcinoma: a propensity-matched cohort study of 884 patients. view/cosmic-311-update-cabozantinib-sustains-pfs-benefit-after-10-
Thyroid 2021; 31: 1662–72. months-in-rai-dtc (accessed Dec 10, 2022).
58 Dupuy DE, Monchik JM, Decrea C, Pisharodi L. Radiofrequency 79 Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in
ablation of regional recurrence from well-differentiated thyroid RET-altered thyroid cancers. N Engl J Med 2020; 383: 825–35.
malignancy. Surgery 2001; 130: 971–77. 80 US Food and Drug Administration. FDA approves selpercatinib for
59 Cao XJ, Liu J, Zhu YL, et al. Efficacy and safety of thermal ablation lung and thyroid cancers with RET gene mutations or fusions 2020.
for solitary T1bN0M0 papillary thyroid carcinoma: a multicenter https://www.fda.gov/drugs/resources-information-approved-drugs/
study. J Clin Endocrinol Metab 2021; 106: e573–81. fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-
60 Xiao J, Zhang Y, Zhang M, et al. Ultrasonography-guided mutations-or-fusions (accessed Dec 10, 2022).
radiofrequency ablation for the treatment of T2N0M0 papillary thyroid 81 US Food and Drug Administration. FDA approves pralsetinib for
carcinoma: a preliminary study. Int J Hyperthermia 2021; 38: 402–08. RET-altered thyroid cancers. 2020. https://www.fda.gov/drugs/
61 Wu J, Zhao ZL, Cao XJ, et al. A feasibility study of microwave resources-information-approved-drugs/fda-approves-pralsetinib-ret-
ablation for papillary thyroid cancer close to the thyroid capsule. altered-thyroid-cancers. (accessed Dec 10, 2022).
Int J Hyperthermia 2021; 38: 1217–24. 82 Subbiah V, Hu MI, Wirth LJ, et al. Pralsetinib for patients with
62 Yan L, Zhang M, Song Q, Xie F, Luo Y. Clinical outcomes of advanced or metastatic RET-altered thyroid cancer (ARROW):
radiofrequency ablation for multifocal papillary thyroid a multi-cohort, open-label, registrational, phase 1/2 study.
microcarcinoma versus unifocal papillary thyroid microcarcinoma: Lancet Diabetes Endocrinol 2021; 9: 491–501.
a propensity-matched cohort study. Eur Radiol 2022; 32: 1216–26. 83 Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid
63 Colombo C, De Leo S, Di Stefano M, et al. Total thyroidectomy Association guidelines for the management of medullary thyroid
versus lobectomy for thyroid cancer: single-center data and carcinoma. Thyroid 2015; 25: 567–610.
literature review. Ann Surg Oncol 2021; 28: 4334–44. 84 Perros P, Boelaert K, Colley S, et al. Guidelines for the
64 Bilimoria KY, Bentrem DJ, Ko CY, et al. Extent of surgery affects management of thyroid cancer. Clin Endocrinol 2014;
survival for papillary thyroid cancer. Ann Surg 2007; 246: 375–81. 81 (suppl 1): 1–122.
65 Patel KN, Yip L, Lubitz CC, et al. Executive summary of the 85 Pena I, Clayman GL, Grubbs EG, et al. Management of the lateral
American Association of Endocrine Surgeons guidelines for the neck compartment in patients with sporadic medullary thyroid
definitive surgical management of thyroid disease in adults. cancer. Head Neck 2018; 40: 79–85.
Ann Surg 2020; 271: 399–410. 86 Spanheimer PM, Ganly I, Chou JF, et al. Prophylacticlateral neck
66 Cooper DS, Doherty GM, Haugen BR, et al. Revised American dissection for medullary thyroid carcinoma is not associated with
Thyroid Association management guidelines for patients with thyroid improved survival. Ann Surg Oncol 2021; 28: 6572–79.
nodules and differentiated thyroid cancer. Thyroid 2009; 19: 1167–214. 87 Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with
67 Adam MA, Pura J, Gu L, et al. Extent of surgery for papillary thyroid locally advanced or metastatic medullary thyroid cancer: a randomized,
cancer is not associated with survival: an analysis of 61,775 patients. double-blind phase III trial. J Clin Oncol 2012; 30: 134–41.
Ann Surg 2014; 260: 601–05. 88 Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in
68 Menegaux F, Lifante JC. Controversy: for or against thyroid progressive medullary thyroid cancer. J Clin Oncol 2013;
lobectomy in >1cm differentiated thyroid cancer? Ann Endocrinol 31: 3639–46.
2021; 82: 78–82. 89 Maniakas A, Dadu R, Busaidy NL, et al. Evaluation of overall
69 Tuttle RM, Ahuja S, Avram AM, et al. Controversies, consensus, survival in patients with anaplastic thyroid carcinoma, 2000–2019.
and collaboration in the use of 131I therapy in differentiated thyroid JAMA Oncol 2020; 6: 1397–404.
cancer: a joint statement from the American Thyroid Association, 90 Landa I, Ibrahimpasic T, Boucai L, et al. Genomic and
the European Association of Nuclear Medicine, the Society of transcriptomic hallmarks of poorly differentiated and anaplastic
Nuclear Medicine and Molecular Imaging, and the European thyroid cancers. J Clin Invest 2016; 126: 1052–66.
Thyroid Association. Thyroid 2019; 29: 461–70. 91 Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus
70 Pacini F, Fuhrer D, Elisei R, et al. 2022 ETA consensus statement: trametinib in patients with BRAF V600E-mutant anaplastic thyroid
what are the indications for post-surgical radioiodine therapy in cancer: updated analysis from the phase II ROAR basket study.
differentiated thyroid cancer? Eur Thyroid J 2022; 11: e210046. Ann Oncol 2022; 33: 406–15.
71 Hay ID, Kaggal S, Thompson GB. Radioiodine remnant ablation in 92 Dierks C, Seufert J, Aumann K, et al. Combination of lenvatinib
stage I adult papillary thyroid carcinoma: does it improve and pembrolizumab is an effective treatment option for anaplastic
postoperative outcome? Eur Thyroid J 2022; 11: e220084. and poorly differentiated thyroid carcinoma. Thyroid 2021;
72 Leboulleux S, Bournaud C, Chougnet CN, et al. Thyroidectomy 31: 1076–85.
without radioiodine in patients with low-risk thyroid cancer. 93 Dierks C, Seufert J, Ruf J, et al. The lenvatinib/pembrolizumab
N Engl J Med 2022; 386: 923–32. combination induces long lasting and complete responses in
73 Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive patients with metastatic anaplastic or poorly differentiated thyroid
iodine-refractory, locally advanced or metastatic differentiated carcinoma: results from a retrospective study and first results from
thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet the prospective phase II ATLEP trial. Ann Oncol 2020; 31: S1085.
2014; 384: 319–28. 94 Dierks C, Ruf J, Seufert J, et al. Phase II ATLEP trial: final results for
74 Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus lenvatinib/pembrolizumab in metastasized anaplastic and poorly
placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; differentiated thyroid carcinoma. Ann Oncol 2022; 33: S750–57.
372: 621–30. 95 Roche AM, Fedewa SA, Shi LL, Chen AY. Treatment and survival
75 Kim M, Jin M, Jeon MJ, et al. Lenvatinib compared with sorafenib vary by race/ethnicity in patients with anaplastic thyroid cancer.
as a first-line treatment for radioactive iodine-refractory, Cancer 2018; 124: 1780–90.
progressive, differentiated thyroid carcinoma: real-world 96 World Health Organization. Social determinants of health. 2018.
outcomes in a multicenter retrospective cohort study. Thyroid https://www.who.int/health-topics/social-determinants-of-
2023; 391: 91–99. health#tab=tab_1 (last accessed Dec 2, 2022).
76 Dacosta Byfield SA, Adejoro O, Copher R, Chatterjee D, Joshi PR, 97 NIH National Cancer Institute. Cancer control continuum. 2020.
Worden FP. Real-world treatment patterns among patients https://cancercontrol.cancer.gov/about-dccps/about-cc/cancer-
initiating small molecule kinase inhibitor therapies for thyroid control-continuum#:~:text=The%20cancer%20control%20
cancer in the United States. Adv Ther 2019; 36: 896–915. continuum%20has,survivorship%2C%20and%20end%20of %20life
77 Brose MS, Robinson B, Sherman SI, et al. Cabozantinib for (accessed Dec 2, 2022).
radioiodine-refractory differentiated thyroid cancer (COSMIC-311): 98 Harari A, Li N, Yeh MW. Racial and socioeconomic disparities in
a randomised, double-blind, placebo-controlled, phase 3 trial. presentation and outcomes of well-differentiated thyroid cancer.
Lancet Oncol 2021; 22: 1126–38. J Clin Endocrinol Metab 2014; 99: 133–41.

Seminar
99 Weeks KS, Kahl AR, Lynch CF, Charlton ME. Racial/ethnic 120 Kus LH, Shah M, Eski S, Walfish PG, Freeman JL. Thyroid cancer
differences in thyroid cancer incidence in the United States, outcomes in Filipino patients. Arch Otolaryngol Head Neck Surg
2007–2014. Cancer 2018; 124: 1483–91. 2010; 136: 138–42.
100 Siu S, McDonald JT, Rajaraman M, et al. Is lower socioeconomic 121 Kwon HJ, Morton RP. Ethnic disparities in thyroid surgery
status associated with more advanced thyroid cancer stage at outcomes in New Zealand. ANZ J Surg 2017; 87: 610–14.
presentation? A study in two Canadian centers. Thyroid 2014; 122 Wu J, Ebrahim AK. Ethnic disparities for thyroid surgery.
24: 545–51. ANZ J Surg 2020; 90: 2527–31.
101 Almubarak AA, Albkiry YA, Alsalem AA, Elkrim Saad MA. 123 Papaleontiou M, Reyes-Gastelum D, Gay BL, et al. Worry in thyroid
The association of low socioeconomic status with advanced stage cancer survivors with a favorable prognosis. Thyroid 2019; 29: 1080–88.
thyroid cancer. J Taibah Univ Med Sci 2021; 16: 482–90. 124 Jackson Levin N, Zhang A, Reyes-Gastelum D, et al. Change in
102 Nash SH, Lanier AP, Southworth MB. Occurrence of endocrine and worry over time among Hispanic women with thyroid cancer.
thyroid cancers among Alaska Native people, 1969-2013. Thyroid J Cancer Surviv 2022; 16: 844–52.
2018; 28: 481–87. 125 Chen DW, Reyes-Gastelum D, Hawley ST, Wallner LP,
103 Nnorom SO, Baig H, Akinyemi OA, et al. Persistence of disparity in Hamilton AS, Haymart MR. Unmet information needs among
thyroid cancer survival after adjustments for socioeconomic status Hispanic women with thyroid cancer. J Clin Endocrinol Metab 2021;
and access. Am Surg 2022; 88: 1484–89. 106: e2680–87.
104 Truong T, Rougier Y, Dubourdieu D, et al. Time trends and 126 Chen DW, Reyes-Gastelum D, Veenstra CM, Hamilton AS,
geographic variations for thyroid cancer in New Caledonia, a very Banerjee M, Haymart MR. Financial hardship among Hispanic
high incidence area (1985-1999). Eur J Cancer Prev 2007; 16: 62–70. women with thyroid cancer. Thyroid 2021; 31: 752–59.
105 Publications Office of the European Commission. Directorate- 127 Chen DW, Reyes-Gastelum D, Wallner LP, et al. Disparities in risk
General for Justice and Consumers, Farkas L. Analysis and perception of thyroid cancer recurrence and death. Cancer 2020;
comparative review of equality data collection practices in the 126: 1512–21.
European Union: data collection in the field of ethnicity. 2020. 128 Cai C, Gaffney A, McGregor A, et al. Racial and ethnic disparities in
https://data.europa.eu/doi/10.2838/447194 (accessed Nov 21, 2022). outpatient visit rates across 29 specialties. JAMA Intern Med 2021;
106 Institut National de la Statistique et des Études Économiques. 181: 1525–27.
Ethnic-based statistics. 2016. https://www.insee.fr/en/ 129 Radhakrishnan A, Reyes-Gastelum D, Abrahamse P, et al. Physician
information/2388586 (accessed Nov 21, 2022). specialties involved in thyroid cancer diagnosis and treatment:
107 Pukkala E, Engholm G, Højsgaard Schmidt LK, et al. Nordic cancer implications for improving health care disparities.
registries—an overview of their procedures and data comparability. J Clin Endocrinol Metab 2022; 107: e1096–105.
Acta Oncol 2018; 57: 440–55. 130 Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA,
108 Balestra C, Fleischer L. Diversity statistics in the OECD: how do Udelsman R. The importance of surgeon experience for clinical and
OECD countries collect data on ethnic, racial and indigenous economic outcomes from thyroidectomy. Ann Surg 1998;
identity? 2018. https://www.oecd.org/officialdocuments/publicdispl 228: 320–30.
aydocumentpdf/?cote=SDD/DOC(2018)9&docLanguage=En 131 Sosa JA, Mehta PJ, Wang TS, Yeo HL, Roman SA. Racial disparities
(accessed Nov 21, 2022). in clinical and economic outcomes from thyroidectomy. Ann Surg
109 Bilimoria KY, Bentrem DJ, Linn JG, et al. Utilization of total 2007; 246: 1083–91.
thyroidectomy for papillary thyroid cancer in the United States. 132 Hauch A, Al-Qurayshi Z, Friedlander P, Kandil E. Association of
Surgery 2007; 142: 906–13. socioeconomic status, race, and ethnicity with outcomes of patients
110 Moten AS, Zhao H, Intenzo CM, Willis AI. Disparity in the use of undergoing thyroid surgery. JAMA Otolaryngol Head Neck Surg
adjuvant radioactive iodine ablation among high-risk papillary 2014; 140: 1173–83.
thyroid cancer patients. Eur J Surg Oncol 2019; 45: 2090–95. 133 Al-Qurayshi Z, Randolph GW, Srivastav S, Kandil E. Outcomes in
111 Wenaas AE, Nagy CZ, Yiu Y, Xu L, Horter K, Zevallos JP. endocrine cancer surgery are affected by racial, economic, and
Demographic and socioeconomic factors predictive of compliance healthcare system demographics. Laryngoscope 2016; 126: 775–81.
with American Thyroid Association guidelines for the treatment for 134 Adam MA, Thomas S, Youngwirth L, et al. Is there a minimum
advanced papillary thyroid carcinoma. Head Neck 2015; 37: 1776–80. number of thyroidectomies a surgeon should perform to optimize
112 Jaap K, Campbell R, Dove J, et al. Disparities in the care of patient outcomes? Ann Surg 2017; 265: 402–07.
differentiated thyroid cancer in the United States: exploring the 136 Machens A, Hauptmann S, Dralle H. Referral bias in thyroid cancer
national cancer database. Am Surg 2017; 83: 739–46. surgery: direction and magnitude. Eur J Surg Oncol 2008;
113 Kovatch KJ, Reyes-Gastelum D, Hughes DT, Hamilton AS, 34: 556–62.
Ward KC, Haymart MR. Assessment of voice outcomes following 136 Murthy VH, Krumholz HM, Gross CP. Participation in cancer
surgery for thyroid cancer. JAMA Otolaryngol Head Neck Surg 2019; clinical trials: race-, sex-, and age-based disparities. JAMA 2004;
145: 823–29. 291: 2720–26.
114 Noureldine SI, Abbas A, Tufano RP, et al. The impact of surgical 137 Unger JM, Hershman DL, Till C, et al. “When Offered to
volume on racial disparity in thyroid and parathyroid surgery. Participate”: a systematic review and meta-analysis of patient
Ann Surg Oncol 2014; 21: 2733–39. agreement to participate in cancer clinical trials. J Natl Cancer Inst
115 Nguyen MT, Hu J, Hastings KG, et al. Thyroid cancer mortality is 2021; 113: 244–57.
higher in Filipinos in the United States: an analysis using national 138 Park JJH, Ford N, Xavier D, et al. Randomised trials at the level of
mortality records from 2003 through 2012. Cancer 2017; 123: 4860–67. the individual. Lancet Glob Health 2021; 9: e691–700.
116 Roche AM, Fedewa SA, Chen AY. Association of socioeconomic 139 Park JJH, Grais RF, Taljaard M, et al. Urgently seeking efficiency
status and race/ethnicity with treatment and survival in patients and sustainability of clinical trials in global health.
with medullary thyroid cancer. JAMA Otolaryngol Head Neck Surg Lancet Glob Health 2021; 9: e681–90.
2016; 142: 763–71.
140 Park JJH, Ford N, Xavier D, et al. Randomised trials at the level of
117 Zevallos JP, Xu L, Yiu Y. The impact of socioeconomic status on the the individual. Lancet Glob Health 2021; 9: e691–700.
use of adjuvant radioactive iodine for papillary thyroid cancer.
Thyroid 2014; 24: 758–63. Copyright © 2023 Elsevier Ltd. All rights reserved.
118 Ullmann TM, Gray KD, Limberg J, et al. Insurance status is
associated with extent of treatment for patients with papillary
thyroid carcinoma. Thyroid 2019; 29: 1784–91.
119 Lee HE, Kim EA, Zaitsu M, Kawachi I. Occupational disparities in
survival in Korean women with cancer: a nationwide registry
linkage study. BMJ Open 2020; 10: e039259.

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Seminar

www.thelancet.com Published online April 3, 2023 https://doi.org/10.1016/S0140-6736(23)00020-X 1

Ultrasound reasonable, but caution advised in interpreting incidental findings Considerations:

Ultrasound encouraged Considerations:

Ultrasound encouraged, potentially with additional imaging Considerations:

Figure 1: Recommendations for the use or avoidance of thyroid ultrasound

2 www.thelancet.com Published online April 3, 2023 https://doi.org/10.1016/S0140-6736(23)00020-X

Definition Risk of malignancy Recommendations

www.thelancet.com Published online April 3, 2023 https://doi.org/10.1016/S0140-6736(23)00020-X 3

Category 1 Category 2 Category 3 Category 4 Category 5 Category 6

After 1–3 months

Surveillance Surveillance Surveillance ultrasound Molecular If probable or Thyroid cancer

4 www.thelancet.com Published online April 3, 2023 https://doi.org/10.1016/S0140-6736(23)00020-X

Papillary thyroid carcinoma

Patient prefers Patient prefers Patient preference

Radioactive iodine therapy Consider radioactive

Radioactive iodine therapy

Figure 3: Initial management of papillary thyroid carcinoma

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Thyrotropin suppression using supraphysiological FDA-approved for treatment of advanced differen­

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Table 2: Systemic therapies for management of advanced thyroid cancer

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Thyrotropin suppression using supraphysiological FDA-approved for treatment of advanced differen