Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Differentiated thyroid carcinoma: An update

Pepijn van Houten, MD, PhD candidate,
Romana T. Netea-Maier, MD, PhD, Professor, Internist-
endocrinologist *, Johannes W. Smit, MD, PhD,
Professor, Internist-endocrinologist
Department of Internal Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Center,
Nijmegen, the Netherlands

a r t i c l e i n f o
Differentiated thyroid carcinoma (DTC) is the most common
Article history: endocrine cancer. Particularly the incidence of small clinically
Available online 12 August 2022 indolent tumors has been increasing significantly during the last
decades because of increased diagnostic scrutiny, while the DTC-
Keywords: related mortality remained unchanged. In light of the increased
differentiated thyroid carcinoma awareness of the significant risk of detecting clinically indolent
papillary thyroid carcinoma tumors and the potential harm and burden associated with overly
follicular thyroid carcinoma diagnosis and the treatment, the approach towards management
diagnosis of DTC recently underwent a critical appraisal. The focus lays on
risk stratification
reducing the unnecessary burden for patients with very low risk
treatment
DTC and the correct identification of those who require treatment
that is more intensive and/or follow-up. Management of DTC in-
cludes a range of different modalities, making multidisciplinary
collaboration expedient. In this review, we elaborate on the recent
developments in diagnosis, staging and management of DTC with
specific focus on the more individualized risk assessment-based
approach.
© 2022 The Author(s). Published by Elsevier Ltd. This is an open
access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding author. Department of Internal Medicine, Division of Endocrinology, Radboud University Nijmegen Medical
Center, PO Box 9101, 6500HB Nijmegen, the Netherlands. Fax: þ31 253618809.
E-mail address: romana.netea-maier@radboudumc.nl (R.T. Netea-Maier).

https://doi.org/10.1016/j.beem.2022.101687
1521-690X/© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

Abbreviations

ACR American College of Radiology

ATA American Thyroid Association
DTC Differentiated thyroid carcinoma
EFVPTC Encapsulated follicular variant of papillary thyroid carcinoma
ESMO European Society of Medical Oncology
ETA European Thyroid Association
18
FDG-PET Fluorodeoxyglucose positron emission tomography
FNA Fine needle aspiration
FTC Follicular thyroid carcinoma
HTC Hürthle cell carcinoma
KSThR Korean Society of Thyroid Radiology
LA Laser ablation
MIT Minimally invasive techniques
MWA Microwave ablation
NIFTP Non-invasive follicular thyroid neoplasm with papillary-like nuclear features
NIS Sodium iodide symporter
PDTC Poorly differentiated thyroid carcinoma
PFS Progression free survival
PTC Papillary thyroid carcinoma
PTMC Papillary thyroid microcarcinoma
RAI Radio-active iodine
RFA Radiofrequency ablation
rhTSH Recombinant human thyrotropin
TIRADS Thyroid Imaging Reporting and Data System
TKI Tyrosine kinase inhibitor
TNM Tumor, node, metastasis
TSH Thyrotropin
US Ultrasonography

Introduction

Differentiated thyroid carcinomas (DTC) arise from the thyroid follicular cells and are the most
prevalent endocrine malignant tumors. Papillary thyroid carcinoma (PTC), follicular thyroid carcinoma
(FTC) and Hürthle cell carcinoma (HTC) are the most common variants of DTC and represent together
more than 90% of all thyroid cancers [1,2]. Risk factors strongly associated with DTC include a history of
DTC in a first-degree relative, exposure to radiation during childhood and rare genetic syndromes
[1,3,4].
The DTC incidence has increased worldwide over the last decades with a 2.5-three times higher
incidence in women than in men [2,5,6]. This increased incidence is almost entirely due to more PTC
cases, and has not been associated with an increase in DTC mortality [7]. It has been suggested that the
increase in incidence is mostly a consequence of the more widespread use of diagnostics such as neck
ultrasonography (US) and fine needle aspiration (FNA), resulting in detection of numerous clinically
indolent cases [8e11]. Increased awareness about potential over-diagnosis has led to stabilization of
DTC incidence during the most recent years [5,6,12]. It has been proposed that this is the result of
changes in clinical practice, including a less frequent use of US and more restrictive practices con-
cerning FNA, as also recommended by the most recent international guidelines [5,9,13e16].
Several recent international guidelines, including those from the American Thyroid Association
(ATA) and the European Society of Medical Oncology (ESMO), summarize recommendations for

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P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

management of patients with DTC [13,14]. To avoid redundancy, in this review we will focus only on the
updates regarding some of these recommendations and support these with the most recent evidence.

Diagnosis

Diagnosis and staging of DTC is carried out using a combination of radiologic and pathologic mo-
dalities [13,14]. The standard diagnostic steps in patients presenting with a thyroid nodule are sche-
matically presented in Fig. 1. Given the increase in incidence of clinically indolent DTCs, the focus has
shifted lately towards better addressing the balance between the risk of over diagnosis potentially
leading to overtreatment and unnecessary burden for the patients with very low risk DTC, and the
correct identification of the patients who require treatment and/or follow-up. Moreover, among the
latter group, the diagnostic modalities are used to assess the initial staging and ongoing risk stratifi-
cation that can be used to tailor the type and intensity of treatment and follow-up.
FNA with cytological examination remains the single most important diagnostic tool to detect or
exclude DTC in patients presenting with thyroid nodules. Selection of patients who undergo FNA
should be based on the clinical features and the US nodules characteristics. Most recent international
guidelines recommend restricting FNAs to patients with nodules >1 cm, unless there is a high clinical
or US suspicion of malignancy [13,14]. This includes thyroid nodules showing focal 18Fluorodeox-
yglucose positron emission tomography (FDG-PET) uptake that have been shown to be associated with
a higher risk of malignancy [13,17]. Given the fact that most papillary thyroid microcarcinomas (PTMC)
limited to the thyroid bear a very low risk to become clinically overt, the decision to perform FNA in
nodules <1 cm should strongly consider the clinical context of the patient and critically balance the
potential risks and benefits of subsequent procedures. Therefore, active surveillance is the recom-
mended option [13].
Diagnostic neck US should be performed in all patients with a suspicion of a thyroid nodule and is
required to describe the characteristics of the thyroid nodule(s) and to assess the cervical lymph nodes.
To categorize thyroid nodules on malignancy risk and to adequately select patients who require FNA,
Kwak et al. developed the Thyroid Imaging Reporting and Data System (TIRADS) criteria in 2011 based on
the sonographic features of thyroid nodules [18]. This system is endorsed by the American College of
Radiology (ACR). Other medical societies (ATA, European Thyroid Association (ETA), and Korean Society
of Thyroid Radiology (KSThR)) have proposed different criteria for this same purpose, resulting in EU-
TIRADS and K-TIRADS, respectively [13,15,19]. The different criteria, malignancy risks and FNA size cut-
off recommendations from these classification systems are shown in Table 1. Recently, a meta-analysis of
several comparative studies on these different criteria concluded that, when compared head-to-head, the
ACR-TIRADS had a significant higher diagnostic odds ratio, defined as a better performance, than the ATA
or K-TIRADS criteria [20]. An accurate comparison with the performance of EU-TIRADS criteria could not
be performed because only a small number of studies using EU-TIRADS were included in the meta-
analysis. The meta-analysis mostly included retrospective cohort studies. More prospective studies are
needed to conclude which criteria are superior in selecting thyroid nodules requiring FNA.
The FNA result is expressed as one of the six Bethesda categories [21]. While Bethesda 2 and 6 cat-
egories can accurately identify benign and malignant nodules respectively, Bethesda 3, 4 and 5 know
large interobserver variability and cannot reliably distinguish between malignant and benign nodules
[22,23]. Therefore, many patients having nodules within these categories undergo diagnostic lobectomy
to exclude malignancy. Particularly for those patients having nodules within Bethesda 3 and 4 categories,
bearing an estimated risk of malignancy up to 30%, many of these surgeries could be unnecessary [13,24].
To reduce the number of diagnostic surgeries for nodules within the indeterminate Bethesda categories,
different diagnostic modalities have been proposed. Molecular testing, either based on DNA or RNA
technologies, limited to diagnostic mutational panels or a gene expression classifier, have been developed
to refine the diagnostic accuracy in the Bethesda 3 and 4 categories with reported sensitivity of about 90%
for most of these tests, and specificity between 49 and 92%. While the reported negative predictive value
is about 95% for most of them, making them suitable as rule-out tests, the positive predictive value varies
widely between 37 and 82% [25,26]. Furthermore, the meta-analysis and systematic review of Vriens
et al. indicate that the lack of FDG-PET uptake in nodules >15 mm with indeterminate cytology excludes
malignancy with a 100% sensitivity in those nodules [27]. Furthermore, a recent randomized controlled

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P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

Fig. 1. Flowchart schematically showing the diagnostic steps in patients presenting with a thyroid nodule. This flowchart was
designed taken into account references [13e15,18,19,21].

trial indicates that an FDG-PET/CT-based diagnostic approach towards indeterminate nodules can reduce
up to 40% of unnecessary diagnostic surgeries provided that the nodules are not Hürthle cell neoplasia
which often show increased FDG-PET uptake [28]. Used in conjunction with clinical evaluation and other
available tools, these techniques have the potential to improve preoperative diagnostic accuracy of
thyroid nodules. Future studies are warranted to establish the most clinically and cost-effective approach
algorithm to optimize the diagnostic approach.
In another effort to reduce the burden of DTC diagnosis and treatment, Nikiforov et al. introduced
the term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) to
replace the encapsulated follicular variant of PTC (EFVPTC), estimated to represent 10e20% of all DTC
diagnosed in Europe and North America [29,30]. By removing the term ‘cancer’ from this diagnosis,
their goal was to promote a more conservative treatment strategy for NIFTP, with a lesser burden to the
patient. NIFTPs show a rather indolent behavior. Several studies on clinical outcomes of patients with
NIFTP have shown total absence of lymph node or distant metastases during follow-up [30e36]. Other
studies showed low rates of microscopic (<2 mm) lymph node metastases (2e5%) [37e40]. However,
some of these tumors showed features characteristic of classic PTC and not all tumors were entirely
sampled. Therefore, the diagnostic criteria of NIFTP were updated in 2018 and now exclude tumors
with well-formed papillae [41]. Moreover, the absence of mutations typical for PTC (BRAFV600E, TERT,

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 P. Houten, R.T. Netea-Maier and J.W. Smit
Table 1
Comparison between the criteria, malignancy risks and FNA size cutoffs of the ACR-TIRADS, EU-TIRADS, K-TIRADS and ATA classification systems.

1 2 3 4 5

ACR-TIRADS [18] 0 pointsa 2 pointsa 3 pointsa 4-6 pointsa 7 or more pointsa

Malignancy risk <2% <2% 5% 5e20% >20%
FNA size cutoff No FNA No FNA 2.5 cm 1.5 cm 1 cm
EU-TIRADS [15] No nodule Pure cyst, entirely Ovoid, smooth isoechoid/ Ovoid, smooth, mildly At least 1 future of high
spongiform hyperechoic, no features of hypoechoic, no features of suspicion:
high suspicion high suspicion - Irregular shape
- Irregular margins
- Microcalcifications
- Marked hypo-echogenicity
Malignancy risk 0% 0% 2e4% 6e17% 26e87%

Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687
FNA size cutoff No FNA No FNA unless compressive >2 cm >1.5 cm >1 cm
K-TIRADS [19] No nodule Spongiform, partially cystic Partially cystic or Solid hypo-echoic nodule Solid hypoechoic nodule with
nodule with comet tail isohyperechoic nodule without any of 3 suspicious any of 3 suspicious features
artifact or pure cyst without any of 3 suspicious features or partially cystic
5

features (microcalcification, or isohyperechoic nodule

nonparallel orientation, with any of 3 suspicious
spiculated or features
microlobulated margin)
Malignancy risk 0% <3% 3e15% 15e50% >60%
FNA size cutoff No FNA No FNA 1.5 cm 1 cm 1 cm
ATA classification e Benign e Purely Very low suspicion e Low suspicion e Isoechoic Hypoechoic solid nodule Solid hypoechoic nodule or
categories are not cystic nodules Spongiform or partially or hyperechoic solid or with smooth margins solid hypoechoic component of
numbered like the cystic nodules without any partially cystic nodule with without microcalcifications, a partially cystic nodule with
TIRADS classifications but sonographic features eccentric solid areas extrathyroidal extension or irregular margins,
instead are named [13] described in low, without microcalcification, taller than wide shape microcalcifications, taller than
intermediate or high irregular margin or wide shape, rim calcifications
suspicion extrathyroidal extension, or with small extrusive soft tissue
taller than wide shape component and/or
extrathyroidal extension
Malignancy risk <1% <3% 5e10% 10e20% >70e90%
FNA size cutoff No FNA Consider at 2 cm Recommend at 1.5 cm Recommend at 1.5 cm Recommend at 1 cm
a
Composite score based on composition, echogenicity, shape, margin and echogenic foci.
P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

and TP53) was added as a secondary criterion and examination of the entire tumor became mandatory.
Genetic events that are more commonly detected in FTC such as RAS mutations or PAX8/PPARg rear-
rangements cannot distinguish between follicular carcinoma and adenoma, including Hürthle cell
variants, and have not been included in the diagnostic criteria.

Initial and ongoing staging

In DTC, different staging systems can be used. The tumor, node, metastasis (TNM) classification
system is optimized to predict mortality from DTC [42]. Moreover, the risk stratification proposed by
the ATA and ESMO guidelines predicts recurrence, which is a relevant outcome measure in DTC [13,14].
These staging systems can be used as guidance for initial treatment strategies. In addition, risk strat-
ification should be continued during follow-up. This ongoing stratification system was first described
by Tuttle et al. and later modified by Vaisman et al. [43,44]. It is based on response to therapy, on which
patients should be stratified during their follow-up as: excellent response, biochemical incomplete
response, structural incomplete response or indeterminate response. This stratification system can
predict both recurrence as mortality, has been validated by several studies and can guide the intensity
of follow-up [45e47]. Tumors bearing pathologic BRAF mutations, particularly in combination with
TERT mutations have been associated with unfavorable outcome. However, although molecular testing
is expected to contribute in the future to prognostic assessment, at the moment the way it can be
practically used for this purpose has not yet robustly been established.

Treatment

Treatment strategy of DTC patients mostly consists of a combination of surgery, radio-active iodine
(RAI) administration and thyrotropin (TSH) suppression therapy [13]. The extent of the different
treatment modalities depends on initial and ongoing risk stratification. The recommended manage-
ment of patients with DTC is schematically presented in Fig. 2. Recent developments have questioned
some of the traditional treatment strategies, particularly with respect to low-risk DTC, while other
treatment modalities have been introduced.

A less extensive surgical approach for low-risk DTC

Total thyroidectomy is the standard surgical procedure for the management of DTC [13,14]. For
patients with intermediate- and high-risk DTC, total thyroidectomy with the addition of neck lymph
node dissection in case of clinical or US evidence of lymph node metastases, remains the recommended
initial surgical approach. However, several large retrospective studies have shown that in low-risk
PTMC and in carefully selected low-risk DTC patients, unilateral lobectomy can be an alternative
without reducing survival rates or increasing risk of recurrence [48e54]. As unilateral lobectomy is
associated with lower complication rates and lower costs, large multicenter prospective randomized
controlled studies to validate these findings would be very interesting [55]. Nonetheless, given high
long-term survival and low prevalence of recurrences associated with these tumors, a well-powered
prospective randomized study requires very large patient groups and a lengthy follow-up, which are
likely only feasible based on non-inferiority endpoints. Moreover, uniform protocols need to be
established for the intensity and duration of follow-up in patients with low-risk DTC who undergo
lobectomy as primary treatment. For patients with low-risk PTMC, defined as unifocal tumors limited
to the thyroid, without extra thyroidal extension, clinical or US evidence of lymph node or distant
metastases and/or other risk factors such as worrisome pathological (e.g. tall cell, insular or columnar
cell variants) or molecular features (e.g. combination of pathological BRAF and TERT mutations) uni-
lateral lobectomy is the recommended treatment [13,14]. Moreover, several studies summarized in
recent systematic reviews and meta-analyses, indicate that patients with low-risk PTMC are eligible for
image-guided minimally invasive techniques (MIT), particularly thermal ablation (e.g. laser ablation
(LA), radiofrequency ablation (RFA) and microwave ablation (MWA)); with comparable results with
respect to local disease control and low complication rates [56e61]. Therefore, in centers where
expertise is available, MIT can be offered as an alternative to surgery in patients with incidentally

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P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

Fig. 2. Flowchart showing the recommended management of patients with DTC. This flowchart was designed taking into account
references [13,14,43,44].

discovered low-risk PTMC who are not eligible or decline surgery [62]. The ETA and the Cardiovascular
and Interventional Radiological Society of Europe have recently published a guideline on application of
MIT in thyroid carcinoma [62]. This document describes the techniques that are suitable for different
indications and details the characteristics of patients that could be eligible for MIT. Moreover, accu-
mulating evidence indicates that active surveillance can provide a safe option in selected patients with
low-risk PTMC who are not eligible or decline surgery [63]. Currently no studies are available providing
head-to-head comparison of these treatment modalities for PTMC and there is still limited long-term
data available on the outcome of the patients treated by MIT or undergoing active surveillance,
particularly in populations of European descent. Nonetheless, as these approaches are being increas-
ingly used in Europe and the USA, it is to be expected that more studies will accumulate knowledge on
the safety and long-term outcome of these procedures and their potential to improve long-term quality
of life for patients with DTC. Moreover, broader implementation of shared-decision making should
enable a better participation of patients in decisions about their management, can help improving the
communication with their physicians, provide better empowerment and satisfaction about the de-
cisions which better match their preferences and expectations [64].

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P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

RAI-treatment in DTC

Given the evidence of improved prognosis of patients with DTC after introduction of RAI-treatment
following surgery, RAI-treatment has been recommended for many years for the large majority of DTC
patients. In the past decade however, the place of RAI in the treatment armamentarium for DTC was
reappraised, considering the more individualized risk assessment-based approach.
In patients with DTC, RAI can be administered for several indications:

- To destroy normal thyroid tissue remnant (remnant ablation), which renders follow-up of thyro-
globulin levels sensitive to DTC recurrence.
- In adjuvant setting, to destroy presumed foci of DTC, thus reducing recurrence risk.
- Treatment of persistent or recurrent disease.

The additive value of post-surgical RAI-treatment should be based on individual prognostic factors
regarding risk of cancer related death or disease recurrence [65]. For this, the aforementioned risk
stratification is paramount [13,42]. While it is widely agreed on that post-surgical RAI-treatment is
indicated in high-risk DTC patients, there is less consensus regarding the indications in intermediate-
and low-risk patients.
In intermediate-risk patients, individual risk factors should be considered when estimating the
benefits of RAI-treatment. A systematic review by Sacks et al. concluded that survival was improved in
DTC patients >45 years with TNM stage III who received RAI-treatment compared to patients who did not
[66]. The benefit in patients aged <45 years was unclear. The recent ETA consensus statement indicates
that advanced age, aggressive histology, large volume of nodal disease and extra nodal extension, mul-
tiple N1 and/or lymph node metastases outside the central neck have been associated with the greatest
benefit of adjuvant RAI-treatment [65]. More prospective studies are needed to further elucidate the
individual factors associated with benefit from RAI-treatment in intermediate-risk DTC patients.
The benefit of post-surgical RAI-treatment in low-risk patients is, in light of emerging evidence,
highly debated. As shown by a systematic review by Verburg et al. including 11 retrospective cohort
studies, results are not consistent [67]. Recently, a randomized controlled trial by Leboulleux et al.
showed that in patients with low-risk DTC undergoing thyroidectomy, a follow-up strategy without
RAI-remnant ablation was non-inferior to a follow-up strategy including RAI-remnant ablation [68].
The primary endpoint was the percentage of patients without an event during 3 years after
randomization. This event was a composite endpoint of functional, structural and biologic criteria.
More studies are needed to validate these findings and particularly to assess long-term outcomes. Until
then, the indication of RAI-treatment in low-risk DTC patients should be based on individual prog-
nostic risk factors. Regarding RAI-activity required in low-risk DTC patients, two large randomized
controlled trials have been reported in which high-dose post-operative RAI-ablation (3.7 GBq) was
compared to low-dose (1.1 GBq). The ESTIMABL1 trial, conducted in 24 centers in France between 2007
and 2010, included 752 low risk DTC patients, randomized between four treatment strategies: low or
high dose RAI-ablation combined with TSH-stimulation using either recombinant human TSH (rhTSH)
or thyroid hormone withdrawal [69]. After a median follow-up of 5.4 years, no differences in recur-
rence rates were found between the different treatment strategies. The HiLo trial took place in 29
centers in the United Kingdom, also between 2007 and 2010 [70]. In this study, 438 patients were
randomized between the same treatment strategies as the ESTIMABL1 trial. The results showed no
significant differences in recurrence rates between the treatment strategies after a median follow-up of
6.5 years. Based on the data it is currently recommended that, if post-surgical remnant ablation is
prescribed in low-risk patients, this can take place using 1.1 GBq 131I preceded by rhTSH to reduce the
amount of radioactivity administered and the discomfort caused by thyroid hormone withdrawal.

Treatment of locally advanced, metastatic and RAI-refractory DTC

Most DTC patients have an excellent prognosis with a 10-years survival around 90% [1,71,72].
Nonetheless, a minority develops recurrent or metastatic disease and of these, approximately 40%
become resistant to conventional treatment [14]. The overall survival for patients with advanced or

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P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

metastatic DTC resistant to RAI-therapy is poor, with 5- and 10-years survival rates of 50% and 10%
respectively [73,74]. Treatment modalities for these patients are limited and rarely result in cure of the
disease. Nevertheless, during the last decades new treatment modalities have been introduced that
have improved progression-free survival (PFS). They include both local and systemic treatments.

Local treatment

In case of recurrent disease, surgical removal of metastases and/or RAI-treatment (as long as the
tumor has not become refractory) are the preferred treatment modalities. For patients with RAI-
refractory DTC that are not amenable to surgery such as patients with a poor condition, patients
declining surgery or patients with unresectable disease, other local treatment options are available,
such as external beam radiotherapy and more recently introduced image-guided MIT. In unresectable
DTC, MIT may be used for symptomatic tumor volume reduction [62]. Two case series of unresectable
local recurrent DTC treated with RFA showed volume reduction rates of 51% and 81% [75,76]. MIT can
also be used for reduction of symptoms caused by distant metastases. DTC most commonly metas-
tasizes to lung and bones [73,77]. A recent retrospective multicenter study investigated the efficacy and
safety of MIT (RFA, MWA, cryoablation) in pulmonary DTC metastases [78]. After a median follow-up of
5.2 years, local tumor progression was observed in four of 34 DTC patients. No major complications
occurred. Two prospective multicenter trials studied the efficacy of RFA and cryoablation in 55 and 61
patients respectively with symptomatic bone metastases, including DTC patients [79,80]. Pain severity
decreased significantly after follow-up periods of three and six months. Both studies, however,
included patients with different primary malignancies and the specific results for patients with DTC
were not mentioned. Multidisciplinary teams with expertise on both traditional treatment of DTC and
MIT should carry out the selection of patients amenable for specific local therapies.

RAI redifferentiation therapy

Patients with RAI-refractory DTC have a worse prognosis than patients with RAI-sensitive DTC, and
additional treatment options are limited [73]. RAI-refractory disease is often the result of dedifferen-
tiation, defined as loss of expression of thyroid specific genes involved in thyroid metabolism and
functioning, including genes involved in iodide uptake and organification such as sodium iodide
symporters (NIS) [81]. Dedifferentiation is associated with somatic mutations that constitutively
activate MAPK-pathways and are drivers of carcinogenesis and tumor progression [81]. Therefore,
therapies that counter the dedifferentiation mechanisms, so-called redifferentiation therapy, have
recently been explored. Redifferentiation of RAI-refractory DTC has gained interest, because it can
result in patients being able again to receive RAI-treatment. Reinduction of RAI-uptake has been
described in different small cohorts of 10 and 12 RAI-refractory DTC patients treated with BRAF-
inhibitors dabrafenib or vemurafenib [82,83]. Another study showed increased RAI-uptake in RAI-
refractory PTC patients treated with selumetinib, which is an inhibitor of MEK1 and MEK2 [84]. In
the latter study, 8 out of 20 treated patients had sufficient uptake of iodide to undergo RAI-treatment.
Five showed partial responses, and the other three showed stable disease after six months follow-up.
Several other studies have been described using different pharmacological approaches [85]. Although
these results are promising, more studies in larger cohorts are needed for validation.

Tyrosine kinase inhibitors

During the last decades, tyrosine kinase inhibitors (TKIs) have established an important position in the
treatment of many malignancies. Table 2 presents an overview of targeted therapies associated with
improved progression free survival in phase 1e3 trials in patients with DTC. Two TKIs are currently
approved for the treatment of RAI-refractory progressive DTC: lenvatinib and sorafenib. This is based on two
phase three, randomized, double blind, placebo controlled multicenter trials, the SELECT trial and the
DECISION trial, showing a prolonged PFS in patients with RAI-refractory locally advanced or metastatic DTC
with disease progression, versus placebo [86,87]. However, none of these studies was able to show a benefit
in terms of overall survival between groups, which is partially explained by the crossover design of the

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P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

Table 2
Overview of targeted therapies associated with improved progression free survival in phase 1e3 trials in patients with DTC.

Group of agents Drug name Mechanism of action Trial

Multikinase Lenvatinib Inhibitor of VEGFR 1e3, PDGFR, FGFR 1e4, KIT SELECT e phase 3 [87]
inhibitors and RET
Sorafenib Inhibitor of VEGFR 1e3, PDGFR, FGFR, KIT and DECISION e phase 3 [86]
RET
Vandetanib Inhibitor of EGFR, VEGFR 2e3 and RET NCT00537095 - phase 2 [100]
Cabozantinib Inhibitor of c-MET, RET and VEGFR 2 NCT02041260 e phase 2 [101]
Motesanib Inhibitor of VEGFR 1e3, PDGFR and KIT NCT00121628 e phase 2 [102]
Nindetanib Inhibitor of VEGFR 103, FGFR 1e3 and PDGFR NCT01788982 e phase 2 [103]
Pazopanib Inhibitor of VEGFR 1e3, PDGFR and KIT NCT00625846 e phase 2 [104]
Sunitinib Inhibitor of VEGFR 1e3, PDGFR, KIT, FLT3, CSF- Phase 2 [105]
1R and RET
BRAF inhibitors Vemurafenib Selective inhibitor of BRAF kinase NCT01286753 e phase 2 [106]
Dabrafenib Selective inhibitor of BRAF kinase NCT01723202 e phase 1/2
[107]
RET inhibitors Selpercatinib Selective inhibitor of RET kinase LIBRETTO-001 e phase 2 [94]
Pralsetinib Selective inhibitor of RET kinase ARROW e phase 2 [108]
TRK inhibitors Larotrectinib Selective inhibitor of TRK kinase NCT02122913 e phase 1 [109]
Entrectinib Selective inhibitor of TRK kinase ALKA-372-001 - phase 1,
STARTRK-1 e phase 1, &
STARTRK-2 - phase 2 [110]
mTOR inhibitors Everolimus Inhibitor targeting PI3K/AKT/mTOR pathway NCT01164176 e phase 2 [111]
VEGFR inhibitor Axitinib Inhibitor of VEGFR 1-3 NCT00389441 e phase 2 [112]

studies. Besides the registration trials, subsequent ‘real-world’ studies have confirmed the sustained clinical
efficacy of both sorafenib and lenvatinib [88e90]. Prospective comparative studies between these TKIs for
treatment of DTC are not available. Recommendations for treatment and follow-up of patients with
advanced RAI-refractory DTC have recently been summarized in a comprehensive ETA guideline [91].

Upcoming systemic treatments

Mutation of the RET proto-oncogene are mostly associated with medullary thyroid carcinoma [92].
However, in a small proportion of DTC, also alterations (fusions) of RET are found [93]. This renders
them potential candidates for treatment with selective inhibitors of RET kinase such as selpercatinib
and pralsetinib. Selpercatinib was studied in 19 patients with RET fusion-positive non-medullary
thyroid carcinoma in a phase 1e2 trial [94]. An objective (complete or partial) response was seen in 79%
of the patients. Other studies with RET kinase inhibitors are ongoing.
While immune checkpoint inhibitor therapy is currently used in many cancers, its usability in DTC is
questioned [95]. A phase Ib study using the PD-1 antibody pembrolizumab in 22 patients with
metastasized DTC (15 PTC & 7 FTC) showed a partial response in only two patients [96]. In another
phase II study combined PD-1 and CTLA-4 inhibition with nivolumab and ipilimumab was used in 32
patients with different subtypes of thyroid carcinoma (17 PTC, four FTC, seven HTC and four poorly
differentiated thyroid carcinoma (PDTC)). Only two patients with HTC and one with PDTC showed a
partial response [97]. An explanation for this could be the relatively low amount of mutations in DTC
tumors, resulting in reduced immunogenicity [98]. Patients with anaplastic thyroid carcinoma could be
better candidates for these therapies.
As the advances in systemic treatment offer more alternatives for the treatment of patients with
RAI-refractory advanced DTC, one should keep in mind that these treatment modalities rarely result in
remission while still being associated with significant side effects. Therefore, maintaining a good
quality of life is paramount in these patients. For this, the effectivity but also the potential toxicity of
these treatments should be critically weight and the patients should be encouraged to contribute to the
decision-making by sharing their needs, values and preferences that should be considered [91].
Moreover, it is likely that the identification of actionable molecular alterations and the availability of
drugs that target specific alterations will pave the way towards application of molecular testing for
precision medicine in the future [99].

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P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

Summary

Management of DTC patients should be individualized according to the initial and ongoing risk
stratification and should be tailored according to individual needs and preferences. Although
prospective trials on which current recommendations are based are scarce, recent publications
have provided stronger evidence for matters such as the indications and application of RAI-
remnant ablation in patients with low-risk DTC, and efficacy of TKIs in advanced DTC. In addi-
tion, there is emerging evidence supporting the implementation of less extensive treatment in
patients with low-risk DTC and PTMC without affecting long-term outcomes. To improve
personalization of management strategies, unanswered questions remain, such as establishing
appropriate and cost-effective diagnostic algorithms in patients with thyroid nodules with inde-
terminate FNA results, selection and follow-up strategies for patients eligible for unilateral lo-
bectomy and the role of RAI-remnant ablation in intermediate-risk patients. Moreover, future
research should assess how molecular diagnostic tools can be used to assess a personalized, data-
driven risk profiling to guide diagnosis and treatment in all risk categories and to enable imple-
mentation of precision medicine in DTC. For patients with RAI-refractory DTC, expanding the
knowledge about tumor pathophysiology and clinical studies should establish the place of already
available therapies and develop new treatment modalities to improve patients' outcome and
quality of life. Finally yet importantly, further research is needed to determine patients' and
physicians’ needs and preferences but also potential barriers and facilitators for wide imple-
mentation of shared-decision making in daily practice.

Practice points

 Thorough risk stratification at diagnosis and during follow-up enables a more personalized
approach in DTC patients.
 Avoid performing FNA in thyroid nodules <1 cm, particularly in the absence of highly sus-
picious clinical or sonographic features.
 Low-risk PTMC should prompt a less aggressive primary treatment by lobectomy or MIT in
selected patients. Active surveillance could be an alternative provided that rigorous follow-up
is ensured.
 Low-risk DTC >1 cm can be amenable for lobectomy alone as an alternative to the total
thyroidectomy followed by RAI treatment.
 Total thyroidectomy followed by RAI treatment remains the mainstream treatment for the
large majority of patients with high and intermediate-risk DTC.
 Lenvatinib and sorafenib prolong PFS in patients with advanced progressive RAI refractory
DTC.

Research agenda

 To define the most accurate and cost-effective algorithm for assessing thyroid nodules.
 To define the group of intermediate risk DTC patients benefiting from postoperative RAI-
treatment.
 To define the clinical features of low-risk DTC patients for which unilateral lobectomy is a safe
alternative to total thyroidectomy and the most appropriate postsurgical follow-up strategy.
 To assess how molecular profiling can be used for precision medicine in DTC.
 To develop and assess tools to improve shared-decision making for patients with DTC.

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P. Houten, R.T. Netea-Maier and J.W. Smit Best Practice & Research Clinical Endocrinology & Metabolism 37 (2023) 101687

Declaration of competing interest

The authors declare no conflict of interest.

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