European Society of Endocrine Surgeons (ESES)

consensus statement on advanced thyroid cancer:

definitions and management

Marco Raffaelli1,2,

* , Nikolaos Voloudakis1,3

, Marcin Barczynski4 , Katrin Brauckhoff5 , Cosimo Durante6 ,

Joaquin Gomez-Ramirez7 , Ioannis Koutelidakis3

, Kerstin Lorenz8 , Ozer Makay9 , Gabriele Materazzi10, Rumen Pandev11,

Gregory W. Randolph12, Neil Tolley13, Menno Vriens14 and Thomas Musholt15

1

UOC Chirurgia Endocrina e Metabolica, Centro Dipartimentale di Chirurgia Endocrina e dell’Obesità, Fondazione Policlinico Universitario Agostino Gemelli

IRCCS, Rome, Italy

2

Centro di Ricerca in Chirurgia delle Ghiandole Endocrine e dell’Obesità (CREO), Università Cattolica del Sacro Cuore, Rome, Italy

3

Second Surgical Department, Aristotle University of Thessaloniki, G. Gennimatas Hospital, Thessaloniki, Greece

4

Department of Endocrine Surgery, Jagiellonian University Medical College, Krakow, Poland

5

Department of Breast and Endocrine Surgery, Haukeland University Hospital, Bergen, Norway

6

Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy

7

Endocrine Surgery Unit, General Surgery Department, Hospital Universitario La Paz, IdiPaz Madrid, Madrid, Spain

8

Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

9

Centre for Endocrine Surgery, Ozel Saglik Hospital, Izmir, Turkey

10Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy

11Department of General Surgery, University Hospital St Marina, Medical University Pleven, Pleven, Bulgaria

12Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, USA

13Endocrine Surgery Service, Imperial College NHS Healthcare Trust, London, UK

14Department of Surgical Oncology and Endocrine Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands

15Section of Endocrine Surgery, Department of General, Visceral and Transplantation Surgery, University Medicine Mainz, Mainz, Germany

*Correspondence to: Marco Raffaelli, UOC Chirurgia Endocrina e Metabolica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168

Rome, Italy (e-mail: marco.raffaelli@unicatt.it)

Received: April 21, 2024. Revised: June 16, 2024. Accepted: July 15, 2024

© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/

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Introduction

Thyroid cancer is the most common endocrine malignancy and

consists of a diverse group of histological entities1

. Although

ranging from indolent and well differentiated to aggressive and

rapidly developing carcinomas, advanced disease may present in

each histological subtype. Even though the characteristics of

advanced thyroid cancer are recognized intuitively by

experienced surgeons in the field, a common definition among

scientific societies is yet to be reached2

. General definitions of

advanced disease are included in the broader management

guidelines for each cancer subtype, such as the American

Thyroid Association (ATA) guidelines for differentiated thyroid

cancer (DTC)3

, medullary thyroid cancer (MTC)4

, and anaplastic

thyroid cancer (ATC)5

. In the European setting, the 2019 European

Society of Medical Oncology (ESMO) guideline6 on thyroid cancer

includes a subsection on the management of advanced disease

for each thyroid cancer type. Given the recent progress and new

developments in targeted therapy, depending on the genetic

alterations of the tumour, new interest has emerged in better

defining advanced thyroid disease and selecting candidates for

tailored therapy, either in an adjuvant systemic or neoadjuvant

setting. This is reflected in the most recent published position

statement by the American Head and Neck Society (AHNS) and

International Thyroid Oncology Group7

, as well as the clinical

practice guidelines update by ESMO for the use of systemic

therapy in advanced thyroid cancer8

. Nevertheless, existing

efforts to define advanced thyroid cancer and to produce

management guidelines have been burdened by a common

denominator, the lack of high-quality evidence, especially

regarding definitions and surgical management.

In May 2023, the European Society of Endocrine Surgeons

(ESES) organized the 10th biennial conference with the topic

‘Consensus meeting on advanced endocrine malignancies’, in

Mainz (Germany). One working group was tasked to evaluate the

current evidence on advanced thyroid carcinoma, and to

produce a position statement to be discussed and voted for by

the ESES assembly at the Mainz conference. The members of

this working group are the authors of the present manuscript.

Methods

Working group composition, original draft, and

statements production

The working group consisted of 14 surgeons with expertise in the

management of thyroid malignancies and an endocrinologist

(C.D.) with extensive involvement in similar projects6,8

. The

working group was tasked with carrying out an extensive

up-to-date literature review, constructing the initial draft, and

BJS, 2024, znae199

https://doi.org/10.1093/bjs/znae199

Guideline

proposing subsequent relevant statements. This process was

undertaken via web-based meetings and supplemented with

additional regular electronic communications. Performing a

systematic review of the literature with the aims set for this

position statement was deemed non-feasible and

counterintuitive for several reasons. First, the term ‘advanced

thyroid cancer’ is not clearly defined, which would result in the

omission of a multitude of publications, whereas, in contrast, a

significant number of publications include this term without

referring to the specific criteria used. Hence, the literature search

was performed extensively by subgroups of three or four working

group members for each section, whereas the remaining working

group members were invited to review the data and supplement

the results with relevant, high-quality references. In addition,

several statements were the products of expert opinion because

no relevant supporting data had been published at the time. The

initial draft and relevant statements were then circulated among

the working group members for revisions before commencing the

modified Delphi process.

Panel composition and modified Delphi process

The modified Delphi method is a well established process used to

achieve consensus systematically, and has been recently applied

in several publications on thyroid cancer7,9,10. To reflect the

diversity of clinical practice in Europe, while maintaining high

expertise among contributing voters, the working group invited

members of the Executive Council of ESES, the examiners of the

Division of Endocrine Surgery, and the national delegates from

each country represented in the ESES, to participate in a

two-round modified Delphi process. The latter, along with the

working group members, formed a panel of 41 participants (full

list in Acknowledgements) who voted on a dedicated invite-only

electronic interface, powered by Qualtrics© (Qualtrics, Provo,

UT, USA) thus providing coded data for analysis. Panellists voted

on their level of agreement according to a Likert scale ranging

from 1 (strongly disagree) to 9 (strongly agree). The survey also

allowed panellists to provide feedback and free-text comments

on the statements during the first phase. Panellists with missing

answers or with difficulties interpreting the statements were

contacted individually through subsequent mailings to provide

definite answers. Appropriate revisions of the initial statements

were made by the methodology leadership (M.R., N.V.) according

to the first survey feedback.

The statements were considered to meet consensus if there was

a mean score of at least 7.0 (agree), and either four or fewer outlier

responses, or six or fewer outlier responses with fewer than three

responses below 5 (disagreement). Near-consensus was assigned

to statements with a mean of 6.50 or greater and, in addition,

eight or fewer negative outliers. Non-consensus was the default if

the above conditions were not met. Outliers were defined by any

value at least 2 Likert points away from the mean. Negative

outliers refer to outliers where the response was that of

disagreement (below 5). The quality of evidence for each

statement was stratified as high, moderate, low, or expert

opinion, depending on the type of publication that data were

extracted from. Data stemming from RCTs were considered to

represent high-quality evidence, whereas those from

non-randomized prospective trials were of moderate quality, and

data from retrospective analyses or case series were deemed to

be of low quality. Where no supportive data were available, the

term expert opinion was used.

Finalization of position statement and

organizational approval

During the 10th ESES biennial conference in Mainz, Germany, the

results of the survey were discussed in a dedicated General

Assembly (GA) meeting. For statements that reached

near-consensus, a GA vote was undertaken, both to classify the

statements as accepted or not, and to honour the ESES tradition

of active participation of all members in position statement

production11,12. Voting options were limited to agree—neutral—

disagree. An agreement level of equal to or more than 80% of

total voters with less than 10% negative votes was set as a

threshold for reaching consensus. The entirety of the consensus

statement was finally approved by the GA, and thereby has full

organizational support as an ESES statement. A summary of the

statements is presented in Tables S1–S6.

Results

Definitions and incidence

Concerning extent, invasiveness, and distant spread, advanced

thyroid cancer has been associated with the presence of one, or

a combination, of three main features: local, regional, and

distant advanced disease. Evaluating all 25 262 thyroid cancer

cases registered between 1 January 2015 and 31 December

2021 in the Eurocrine® registry, 3917 were considered to be

characterized as advanced disease. Distant metastases were

present in 525 patients (2.1%), extended regional (nodal) disease

in 3008 (11.9%), and locally advanced disease in 1147 (4.5%)

(unpublished data - M.R., N.V., T.M.).

Most of these features are well defined in existing classification

systems, such as the eighth edition of the AJCC Staging Manual13.

The focus, however, of such classifications is oncological

parameters, such as mortality, and they were not created to

portray with accuracy a complex issue such as advanced thyroid

disease. To better capture this concept, disease-specific

morbidity, as well as the surgical and non-surgical challenges of

managing these patients, should also be considered. That said,

the TNM classification is globally the most widely recognized and

used system and, in that sense, any major deviations from its

application when defining advanced disease might render any

new definition impractical for everyday clinical and research use.

Locally advanced disease

Locally advanced disease in thyroid cancer has been associated

repeatedly with worse prognosis and increased mortality both

for DTC14–17 and MTC18–22. Morbid sequelae of local invasion,

such as airway obstruction and haemorrhage, are commonly

involved in disease-specific causes of death from DTC15,16. This

is also depicted in the eighth edition of the AJCC classification,

in which the presence of T4 tumours upstages patients from II

to III (for age 55 years and over) in DTC, from III to IVa for MTC,

and from IVa to IVb in anaplastic cancer13. Concerning the point

of infiltration among T4 tumours, the most frequent site

reported is the recurrent laryngeal nerve (RLN) in up to 69% of

patients, followed by the trachea/larynx in up to 42%, and the

oesophagus/pharynx in 21%23–27. Fortunately, intraluminal

tracheal and oesophageal infiltration, which carry a worse

prognosis, are less common25,26. T3b tumours, although

infiltrative, mainly concern the strap muscles. En bloc removal of

the strap muscles can be performed quite easily in most centres,

without the need for reconstruction or accompanied by

2 | BJS, 2024, Vol. 111, No. 8

increased complication rates for the patient9

. In addition, gross

extrathyroidal extension (ETE) involving only the strap muscles

does not affect disease-specific survival according to recent

publications14,28,29. As such, T3b tumours could be omitted from

the definition of locally advanced cancer. Another controversial

point in defining locally advanced tumours is infiltration of the

RLN alone, regarding which there are discrepancies in the

literature. In the landmark study by McCaffrey et al.23, which

analysed 262 patients with invasive papillary cancer, no

significant independent impact on survival was shown with

muscle, laryngeal, and RLN invasion. When only the RLN was

involved, favourable outcomes were also reported by Ito et al.30

concerning relapse-free survival, whereas other research groups

reported no difference in disease-specific survival14. Regardless

of oncological outcomes, management of RLN infiltration

demands a high level of surgical expertise in balancing

preoperative and intraoperative options with local disease

control and patient expectations, because voice complications

and impaired swallowing function can be permanent and

debilitating31–33.

Statement 1: All thyroid primary malignancies classified as pT4

according to the AJCC 8th edition have to be considered locally

advanced tumours.

Consensus: Yes (8.05)

Outliers: 2

Evidence level: Low

Except for invasion of subcutaneous soft tissue

Consensus: No (4.72)

Outliers: 32

Evidence level: Low

Except for RLN invasion.

Consensus: No (3.92)

Outliers: 33

Evidence level: Low

Regional advanced disease

Regional lymph node metastases are commonly observed both in

patients with DTC and those with MTC. Metastases to the regional

lymph nodes occur in approximately 30–80% of patients with

papillary thyroid carcinoma (PTC)34,35 and 34–81% of those with

MTC36–40. The impact of nodal involvement in DTC has been

verified in large studies of the Surveillance, Epidemiology, and

End Results database. Podnos et al.41 reported that the overall

survival rate at 14 years was 82% for patients with

node-negative and 79% for those with node-positive disease (P <

0.050), whereas others42 observed that cervical lymph node

metastases conferred an independent risk of death in all

patients with follicular carcinoma, and in patients with PTC

aged at least 45 years, but did not affect survival in patients

with PTC younger than 45 years. Although not portrayed in the

AJCC eighth edition stratification, individual publications have

consistently reported a worse prognosis in terms of

disease-specific survival and recurrence in patients with N1b

compared with N1a disease, especially in older age groups43–47.

For patients with MTC, the HR for disease-specific survival in

patients with regional lymphadenopathy was 9.44 (1.62 to 56 -

CI 95%)48. Neck dissections have been described as one of the

most complicated operations of the human body, requiring

expert knowledge of regional anatomy and expertise49. Surgical

excision of bulky or extensive central and lateral neck disease

has been associated with an increased risk of complications,

including RLN injury, hypoparathyroidism, and, especially for

the lateral neck, injury to various critical neurovascular

structures and lymphatic leak50–53. Concerning mediastinal

nodes in PTC, in an insightful publication by Moritani54, patients

requiring sternotomy for nodal disease excision had significantly

worse disease-free survival than those who underwent

cervicotomy alone. In patients with MTC mediastinal nodal

disease at presentation, Machens et al.55 showed this to have

prognostic significance equivalent to the presence of distant

metastatic disease. Two more features can be associated with

advanced cancer: bulky nodal disease and extranodal extension

(ENE). According to the 2015 ATA guidelines3

, patients with PTC

are classified into high-risk groups for recurrence if any

metastatic lymph node is 3 cm or larger. Lymph node

metastasis size is, however, not included in the AJCC staging

system13, despite several publications supporting the notion

that larger lymph node metastases are associated with worse

prognosis46,56–58. Concerning ENE, although definitions and

populations vary between studies, there is an overwhelming

number of publications supporting its detrimental impact on

disease-free and disease-specific survival, and it has been

incorporated as a significant risk factor for recurrence in the

ATA 2015 guidelines3,58–60.

Statement 2: Thyroid malignancies have to be considered

regionally advanced when one or more of the following

features are present:

Bulky (at least 3 cm) metastatic nodes or ENE, independently

of neck compartment involved (central and/or lateral).

Consensus: Yes (7.49)

Outliers: 4

Evidence level: Low

ENE, independently of neck compartment involved (central

and/or lateral).

Consensus: Yes (7.43)

Outliers: 5

Evidence level: Low

Lateral neck nodal disease.

Consensus: No (6.17)

Outliers: 20

Evidence level: Low

Mediastinal nodal disease (below innominate artery level).

Consensus: Yes (7.68)

Outliers: 6

Evidence level: Low

Metastatic disease

Metastatic disease is one of the main characteristics of advanced

thyroid cancer, and its presence significantly alters patient

management3–6,8

. In DTC, although patients may achieve

favourable long-term outcomes61, metastatic disease significantly

influences disease-specific and overall survival13,47. Especially for

patients with MTC, the presence of distant metastasis

detrimentally lowers 10-year survival rates to 40%, compared

with rates in patients with regional (75%) or local (96%) disease

only21,22,62. Surgical resection of locoregional disease in

metastatic thyroid cancer is generally recommended in DTC,

when appropriate and feasible, to both prevent complications of

local progression and facilitate adjuvant treatment with

radioactive iodine (RAI)3

. In MTC, more conservative surgical

options have been suggested, balancing surgical morbidity in

terms of speech, swallowing, and parathyroid function with the

potential oncological benefits of locoregional control4

.

Raffaelli et al. | 3

Statement 3: In the presence of distant metastasis, thyroid

tumours are considered advanced, independently of local and

regional status.

Consensus: Yes (8.49)

Outliers: 1

Evidence level: Low

Special considerations- Anaplastic thyroid cancer

ATC is one of the most aggressive and lethal malignancies in

humans. Although accounting for only 1–2% of all thyroid

cancers63,64, it is responsible for up to 50% of thyroid cancer

deaths63. The median life expectancy of patients with ATC is 4–5

months, 1-year survival rates are lower than 20%, and its

disease-specific mortality rate reaches 100%65,66. In addition, the

majority of patients present with distant metastases and

locoregional extension, requiring a tailored multidisciplinary

approach5,67.

Statement 4: All anaplastic thyroid carcinomas should be

considered as advanced thyroid cancer.

Consensus: Yes (8.31)

Outliers: 4

Evidence level: High

Exceptions to this might apply for small (less than 2 cm)

intrathyroidal tumours without distant metastasis.

Consensus: No (5.73)

Outliers: 26

Evidence level: Low

Special considerations - Poorly differentiated thyroid

cancer and aggressive histological variants of papillary

thyroid carcinoma

Poorly differentiated thyroid carcinoma (PDTC) has been reported

as the main cause of death from non-anaplastic follicular

cell-derived thyroid cancer68,69. Because of its distinct

morphological and behavioural characteristics, it holds an

intermediate position between differentiated and fully

dedifferentiated ATCs70. Clinical studies of PDTC are limited

because of the relative rarity of the disease, but the aggressive

nature and poor prognosis of this entity have been

demonstrated repeatedly71–73, and current staging might

underestimate its potential detrimental prognosis especially for

stage I and II disease69. Aggressive histological tumour variants,

that is columnar cell variant, hobnail variant, tall cell variant of

PTC, and features such as tumour necrosis, and high mitotic

activity and Ki-67 labelling index, have been related to increased

risk of recurrence and/or worsening of disease-free survival and,

as such, could potentially be considered as advanced disease74–77.

Statement 5: PDTCs should be considered as advanced thyroid

cancer.

Near-consensus: (6.98) Rejected

Outliers: 19

Evidence level: Low

GA voting: Agree 65.8%, Disagree 23.00%, Neutral 11.2%

Aggressive histological variants of PTC and tumours with

aggressive histological components should be considered as

advanced thyroid cancer.

Consensus: No (5.3)

Outliers: 23

Evidence level: Low

Special considerations - Indications for resection of

inoperable tumours

Inoperability and resectability of thyroid tumours are subjective

issues. Only experienced, appropriately trained and high-volume

endocrine surgeons should judge a thyroid tumour as inoperable.

Where locoregional disease control requires extensive

interventions such as tracheal resection, laryngectomy or

oesophagectomy, the oncological benefits of such an intervention

and patient preferences and wishes should be weighed against

surgical morbidity2,9

. Finally, a multidisciplinary team (MDT)

should manage patients in all phases of care, including

neoadjuvant treatment if appropriate8,78.

Statement 6: Indications for resection in locoregionally

advanced thyroid carcinomas have to be evaluated in a

multidisciplinary setting, balancing oncological benefits,

potential surgical morbidity, patient life expectations, quality

of life after resections, and patient willingness for treatment.

Consensus: Yes (8.71)

Outliers: 0

Evidence level: Expert opinion

Considering recent advancements in neoadjuvant and new

targeted systemic therapies, resectability status is a dynamic

process, which must be re-evaluated based on systemic

treatment response.

Consensus: Yes (8.41)

Outliers: 0

Evidence level: Low

Special considerations - Recurrence

Management of recurrent or persistent disease can be challenging

and such patients should be treated in high-volume referral

centres. The decision to reoperate should be made by a MDT, as

patients with regional disease are at high risk of disease

persistence and new recurrence79. The presence of scar tissue and

alterations in the thyroid bed anatomy pose an additional risk of

complications such as RLN injury and hypoparathyroidism80,81,

although in experienced centres reoperations seem to be safe and

feasible82,83.

Statement 7: Recurrent thyroid disease is not a sufficient

condition by itself to characterize a thyroid carcinoma as

advanced.

Consensus: Yes (7.44)

Outliers: 4

Evidence level: Low

Persistent thyroid disease is not a sufficient condition by

itself to characterize a thyroid carcinoma as advanced

Consensus: Yes (7.49)

Outliers: 4

Evidence level: Low

Preoperative management and work-up

Imaging

In patients with advanced thyroid cancer, in addition to the

ultrasound imaging, neck axial CT or neck MRI is

recommended84. Neck CT and/or MRI is used to evaluate the

invasion of surrounding structures, including large vessels, and

in deciding whether to perform a tracheobronchoscopy to assess

the extent of invasion of the airway lumen. CT is considered

superior to ultrasonography and more reproducible for precise

4 | BJS, 2024, Vol. 111, No. 8

three-dimensional assessment of airway invasion9

, with a mean

sensitivity, specificity, and accuracy in detecting tracheal

invasion of around 60, 90, and 83% respectively85.

Superficial infiltration of the pharyngolaryngotracheal system

is particularly difficult to determine. The extent of tracheal

infiltration has long been stratified by Shin et al., as well as other

teams86–89. In stage I, infiltration includes perichondral invasion

with adherence to the trachea, but no airway resection is

required; in stage II, the cartilage is invaded, but not the

mucosa; and in stage III or IV, the mucosa is invaded or the

spread extends into the lumen respectively. CT should be

performed with contrast, to give the most precise information

and to distinguish superficial (Shin I–II) versus deeper (Shin

III–IV) infiltration with a diagnostic accuracy potentially

reaching more than 90%. MRI seems to have lower diagnostic

accuracy than ultrasound imaging and CT, with a tendency to

overestimate the actual depth of airway invasion90. In

summary, cross-sectional neck CT with contrast is

recommended in patients with thyroid carcinomas with evident

or high clinical suspicion of locoregional advanced disease, as

described previously, as well as large primary tumours (4 cm or

larger), and in MTC where there is extensive neck disease,

evidence of distant metastases or a calcitonin level above

500 pg/ml. It is also imperative in ATC to obtain adequate

pretreatment local staging2

.

MRI may be useful if there is suspicion of oesophageal invasion.

MRI has a sensitivity of 80% and specificity of 94% for detecting

oesophageal invasion, although the effectiveness of MRI in deep

layers is slightly reduced91.

The role of metabolic imaging with PET using [

18F]

fluorodeoxyglucose (FDG) seems to be a valuable diagnostic tool

in patients with non-iodine-avid thyroid tumours, particularly

where there are gradual increases in serum thyroglobulin levels

or high suspicion based on other imaging tests. FDG PET has

also been very useful in patients with PDTC or ATC, which are

known to have increased glucose metabolism and limited or no

radioiodine uptake. FDG PET can provide prognostic information

and therefore may be useful in identifying patients at higher

risk of recurrent and metastatic disease92.

Endoscopic evaluation

Laryngoscopy is mandatory before any thyroid procedure. This is

particularly true in the presence of suspected or proven advanced

thyroid carcinoma9,93. Indeed, up to 30% of cases of laryngeal

nerve invasion are asymptomatic94. In fact, finding a unilateral

RLN palsy should prompt the request for more targeted

investigations as mentioned above (cross-sectional imaging

studies) to determine and precisely evaluate potential airway

involvement, both quantifying its radial (depth) and axial

extent. Laryngotracheoscopy allows appreciation of airway

invasion when the airway submucosa is reached (Shin III–IV) but

misses Shin I–II tracheal invasion in up to 10% of the series of

patients evaluated with endoscopy and imaging95.

Endobronchial ultrasonography (EBUS) is the last imaging

technique used for assessment of the presence and degree of

airway invasion by thyroid cancer, with a sensitivity and

specificity of 92 and 83% respectively96. EBUS is still, however,

used relatively infrequently owing to its high cost and limited

utility in evaluating tumours infiltrating at the level of the upper

thyroid poles85. Oesophagoscopy should be performed

selectively when endoluminal penetration of a tumour is

suspected, based on cross-sectional imaging or, rarely, based on

symptoms97.

Statement 8: Assessment of the aerodigestive tract by means of

sectional imaging, laryngoscopy, and digestive endoscopy is

mandatory in all patients with advanced thyroid cancer and

suspected aerodigestive tract involvement.

Consensus: Yes (7.85)

Outliers: 2

Evidence level: Low

Fine-needle aspiration and core biopsy

Fine-needle aspiration (FNA) is generally the first type of biopsy

undertaken, but the cytological diagnosis of aggressive types of

thyroid cancer may not be easy for the pathologist, and is often

associated with interobserver variability. When the cellular yield

is insufficient, core biopsy may be diagnostic and often permits

a broader range of molecular testing98. If the FNA results are

limited or non-diagnostic, core biopsy should be performed to

confirm the diagnosis99. Some cases of advanced thyroid cancer/

ATC are, however, diagnosed only after surgical/open biopsy

despite the patients undergoing FNA and/or core biopsy.

Molecular testing

Advances in understanding of the molecular biology of thyroid

tumours have led to the development and approval of several

targeted therapies for patients with advanced thyroid cancer.

This allows the delivery of a coordinated, evidenced-based, and

individualized treatment plan to the patient, and there may be

benefit from referral to a tertiary-care setting where additional

resources are available.

BRAF V600E mutational status should be evaluated in patients

with advanced DTC/PDTC to search for additional therapeutic

options, and especially in patients with ATC, as this information

can be used for targeted BRAF inhibition5

. Somatic mutational

testing for RET, NTRK1, NTRK3, and ALK gene fusions should be

undertaken for patients with advanced DTC testing negative for

BRAF V600E. This can be achieved optimally using next-generation

sequencing of tumour RNA or DNA where available, or other

validated approaches including fluorescence hybridization7

.

Patients with locally advanced MTC may be offered somatic

RET mutational testing if the patient is to be considered for

neoadjuvant systemic therapy or as part of a clinical trial5

.

In recent years, the tumour mutational burden has emerged as

a promising response factor to immunotherapy. It should be

analysed before initiation of immunotherapy as it may inform

on response to antiprogrammed cell death 1 therapy. Although

it is true that experience in advanced thyroid carcinoma is

limited, studies of solid tumours, including thyroid cancers,

have demonstrated that high tumour mutational burden is

associated with response to pembrolizumab100.

Statement 9: Depending on local availability, somatic

mutational testing should be offered to patients with advanced

thyroid disease.

Consensus: Yes (8)

Outliers: 2

Evidence level: Low

Optimally, a multiplexed next-generation sequencing panel

should be used.

Consensus: Yes (7.67)

Raffaelli et al. | 5

Outliers: 5

Evidence level: High

Alternatively, a step-up approach could be followed, based

on individual patient and tumour characteristics.

Near-consensus: (7.28) Approved

Outliers: 7

Evidence level: Low

GA voting: Agree: 83.06%, Disagree: 7.65%, Neutral: 9.29%

In regions where availability is limited, surgery should not be

postponed.

Near-consensus: (7.29) Approved

Outliers: 7

Evidence level: Expert opinion

GA voting: Agree: 83.06%, Disagree: 7.65%, Neutral: 9.29%

Patient information, consent, and preferences

Advanced thyroid cancer is a foreboding disease, characterized by

locoregional infiltration of vital structures of the aerodigestive

tract and/or distant metastases, and thus accompanied with

high rates of morbidity, worsening of quality of life, and high

risk of recurrence and death2

.

After completing the preoperative evaluation, diagnostic

procedures and MDT assessment, patients should be fully

informed about expectations regarding possible complications,

postoperative outcomes, and chances of disease-free survival

and death. In general, patient information should include type

and extent of operation, use of neuromonitoring and

autofluorescence, duration of hospital stay, rate of

complications, and risk of recurrence or reoperation101,102.

As advanced thyroid cancer may affect voice, breathing, and

swallowing functions, the complications should be presented in

detail, and the morbidity depending on operation extent should

be clarified thoroughly9

. It is also of paramount importance to

present the patient with the imminent risks of selecting a more

conservative or neoadjuvant treatment, delaying surgery, or

opting for no intervention at all103,104.

The feasibility of achieving complete locoregional clearance of

disease, and how it will be proven after operation, should also be

included during the patient consent process. Treatment of

advanced thyroid cancer may involve a long-term intertwined

multidisciplinary process, and thus the potential postoperative

types of treatment, depending on thyroid cancer histology, and

their possible complications, should also be mentioned.

Explaining the total rates of survival, quality of life after

operation, and the need for adherence to follow-up is also

essential. It is important to have direct and detailed

conversations with patients before operation to enable them to

understand their options and the potential sequelae of

treatment. Some patients may prefer less aggressive surgical

resection in favour of preserving voice and/or swallowing

functions, whereas others may opt for a more aggressive surgical

approach to maximize the chances of disease control or avoid the

future need for active surveillance.

During preoperative communication with patients,

intraoperative decision-making should be discussed, especially

as it relates to management of the RLN and airway. It is

imperative to review the impact of various surgical decisions on

both functional and oncological outcomes so that patient choice

is appropriately and adequately informed.

Statement 10: Informed consent should be obtained after

carefully elucidating to the patient the benefits and possible

morbidity deriving from each treatment choice, as well as

highlighting the oncological sequelae in case of patient denial

or delay to intervention. Surgical extent and intraoperative

concerns that might arise should also be discussed beforehand

and patient preferences respected.

Consensus: Yes (8.76)

Outliers: 0

Evidence level: Expert opinion

Patient health status

Patient health status should be taken into consideration, and all

co-morbidities must be accounted for and addressed if

possible3,105. Cardiovascular and respiratory disorders should be

under control and anticoagulants replaced with low molecular

weight heparin.

Patients with advanced thyroid cancer, especially when the

aerodigestive tract is involved, present with increased morbidity

and may have anorexia, cachexia, and malnutrition, which

deteriorate after operation, leading to compromised nutritional

status106. Patient nutritional status should be assessed before

surgery and during follow-up. This is becoming more critical as

multikinase inhibitors (MKIs) are gaining ground8 in the

treatment of select patients with advanced thyroid cancer. MKIs

may have reduced toxicity compared with conventional

chemotherapy, but present different challenges in patient

management106. As MKIs may cause weight loss, nausea,

anorexia, stomatitis, and diarrhoea, leading to further

deterioration in health, ensuring and maintaining adequate

nutrition during preoperative and postoperative care is critical.

Head and neck malignancies can be associated with

malnutrition owing to cancer-specific symptoms, such as

dysphagia, anorexia, and malabsorption. In locally advanced

thyroid cancer and anaplastic cancer, for which the use of MKI

systemic therapy might be proposed as adjuvant, as well as

neoadjuvant, treatment, maintaining good nutrition status is

critical7,8

.

Especially in patients with suspicion of oesophageal

involvement or distant metastasis, and/or candidates for MKI

treatment, nutritional screening should be carried out before

surgical treatment and initiation of MKI treatment by evaluation

of BMI, weight loss, food intake, and measurement of caloric

intake by several validated tools approved by the European

Society for Clinical Nutrition and Metabolism106. Nutritional

therapy should start even in patients who are not yet

malnourished, with oral intake first; enteral and parenteral

fluids should be considered in the event of more severe

malnutrition.

Statement 11: The health and nutritional status of selected

patients with advanced thyroid cancer should be evaluated and

ideally optimized before operations for advanced thyroid

cancer, also taking into account the potential urgency of the

operation.

Consensus: Yes (7.46)

Outliers: 5

Evidence level: Low

Multidisciplinary team

Optimal advanced thyroid cancer treatment goes way beyond the

selection of an optimal surgical operation, leading to a

disease-free neck, but also encompasses adjuvant therapy

6 | BJS, 2024, Vol. 111, No. 8

options after operation, and neoadjuvant treatment in some

patients2,6,8

. As new therapeutic modalities for advanced thyroid

cancer are constantly emerging, the need for evidence-based

and competence-based decisions requires the assembly of a

MDT to offer an individualized approach for each patient7

.

A MDT should consist of endocrinologists, endocrine/head and

neck surgeons, nuclear medicine physicians, oncologists,

radiotherapists, pathologists, and radiologists. For selected

patients, thoracic, vascular, and/or other specialists should be

invited to participate in the discussion. The MDT should be

approved by the hospital and local authorities, and convene on

a regular basis107,108.

Tumour board representatives should follow the patient in the

preoperative setting, evaluating all the diagnostic and molecular

tests, make proposals on optimal treatment strategies, and plan

follow-up and adjuvant therapy based on surgical findings,

histology results, and patient preferences.

It is proposed that patients with advanced thyroid cancer are

referred to tertiary institutions, holding multidisciplinary

tumour boards, to be evaluated before any intervention is

scheduled.

Statement 12: Patients with advanced thyroid cancer must be

evaluated before and after surgery by a MDT, optimally

consisting of an endocrinologist, endocrine/head and neck

surgeon, nuclear medicine physician, oncologist,

radiotherapist, pathologist, and radiologist.

Consensus: Yes (8.12)

Outliers: 3

Evidence level: Low

Oncologists should participate only in selected cases.

Consensus: No (5.36)

Outliers: 24

Evidence level: Low

General treatment principles

As mentioned above, advanced thyroid cancer is optimally

managed in a high-volume tertiary referral centre led by a MDT.

Half of the disease-specific mortality from DTC is due to

progressive invasion of the aerodigestive tract109, with

incomplete resection increasing the risk of local recurrence. In

advanced cancer owing to an anaplastic tumour, neoadjuvant

treatment strategies should form part of the initial

management. A favourable therapeutic response may make the

patient a candidate for later surgery and thus provide a new

baseline for surgical decision-making.

Complete tumour clearance as part of the primary index

procedure or in treatment of local recurrence is paramount, and

improves the prognosis even in the presence of distant

metastases. Five-year survival rates of up to of 90% have been

described after full-wall tracheal resection. The management of

tumours with infiltration of the trachea and/or oesophagus

places the highest demands on the expertise of a MDT to

develop and successfully implement a personalized therapeutic

strategy. Preoperative assessment is vital to allow the execution

of successful surgery. In resectable disease, the therapeutic aim

is curative or achieving locoregional control as a minimum110.

Several factors need to be considered before making a decision

regarding a surgical approach: existing co-morbidities, the extent

and depth of the infiltration of muscles, trachea and/or

oesophagus, existing lymph node metastasis, and

reconstruction options.

Statement 13: Surgery for advanced thyroid cancer should be

performed only by high-volume surgeons, optimally in tertiary

referral centres.

Consensus: Yes (8.51)

Outliers: 1

Evidence level: Low

Surgery for advanced thyroid cancer should be performed

only by high-volume surgeons in tertiary referral centres when

multiple surgical specialties are required.

Consensus: No (7.1)

Outliers: 9

Evidence level: Low

Invasion of aerodigestive tract

Apart from the Shin classification89 mentioned previously, the

stages of laryngotracheal invasion have been further described

by Dralle et al.87 and Brauckhoff88. Several European centres

prefer the latter classification88, and so it will be described here

in short. A distinction is made between four stages of infiltration

depth. In stage I, the tumour adheres only to the perichondrium

of the trachea or larynx. In stage II, there is superficial but no

transmural infiltration. In contrast, in stage III, the tumour

reaches the lamina propria of the tracheal mucosa but does not

penetrate the epithelium. Finally, the stage 4 tumour presents

with endoluminal infiltration of the tracheal mucosa. Depending

on the site and depth of invasion, preservation of the recurrent

nerve may be impossible; however, resection of both nerves will

significantly add to morbidity, and adjunctive procedures will be

required at a later stage to facilitate decannulation of the patient.

Masuoka and Miyauchi33 described strategies to be employed in

recurrent nerve involvement. Voice and swallowing symptoms at

presentation are common in advanced thyroid cancer involving

infiltration of the trachea, oesophagus, and RLN. Oesophageal

muscle is commonly infiltrated, but intraluminal invasion

through the mucosa is exceedingly rare. Oesophageal muscle can

be resected easily down to the mucosa, requiring no further repair.

In the setting of a pre-existing recurrent nerve palsy or in the

presence of gross infiltration, resection of the nerve can be

followed by non-selective reinnervation using a branch of ansa

cervicalis. This is quite easy to do, requiring no more than two

8/0 Prolene® (Ethicon, Edinburgh, UK) sutures placed through

the epineurium. This should be performed at the end of the

procedure and after haemostasis before wound closure, and can

be carried out with × 2.5–3.5 loupes or even the naked eye.

Selective reinnervation using a branch of the phrenic nerve is

for a specialist laryngologist. Optimal functionality does not

occur, but reinnervation helps reduce intrinsic laryngeal muscle

atrophy. Additional postoperative procedures, such as vocal

cord augmentation, for example by injection of materials or

implants in the paraglottic space, may improve voice outcomes.

Dralle et al.87 and later Brauckhoff88 described different

scenarios for full-wall resections of the trachea. They

distinguished resection involving disease at the laryngotracheal

junction, in which preservation of the recurrent nerve on the

infiltrated side is usually not possible or it is paralyzed at

presentation, from more distal tracheal resection. Cervical and

intrathoracic resections need to be distinguished, although

many of these patients require a manubrial split as advanced

Raffaelli et al. | 7

disease is usually seen in the elderly with a short spondylitic neck.

Furthermore, access to the distal trachea is important to facilitate

mobilization of the tracheal ends to achieve a tension-free

anastomosis. It is important to avoid excessive mobilization as

the blood supply to the trachea is poor and arises

predominantly from horizontal paraoesophageal blood vessels.

Up to 50% of the trachea can be resected with an end-to-end

anastomosis in the young, but much less of the calcified and

relatively inelastic elderly trachea. Pericardial release through a

right thoracotomy can provide an extra 1–2 cm of mobilization.

In anastomotic tension, laryngeal release by suprahyoid or

infrahyoid techniques can be used, although swallowing

rehabilitation and aspiration in these patients is invariably a

postoperative challenge. Previous radiotherapy to the trachea

has such a high complication rate for tracheal resection that it

should be considered as a contraindication to surgery. The

anastomosis invariably breaks down and salvage laryngectomy

is the most likely result.

In disease involving the cricoid and larynx, the cricothyroid and

constrictor muscles can be resected down to the hypopharyngeal

mucosa with minimal morbidity. A cricoid shave can be

performed but full cricoid cartilage should not be resected as

this will destabilize the larynx. The lamina of the thyroid

cartilage can be resected down to the perichondrium, but the

anterior commissure should be preserved as this will affect the

vocal cords at Broyles’ ligament.

It is important to preserve, where possible, the internal branch

of the superior laryngeal nerve as this will influence swallowing by

affecting the afferent part of pharyngo-oesophageal phase

swallowing.

Measures to reconstruct and secure an anastomosis have been

described in detail by Musholt111. A significant risk comes from

dehiscence of the tracheal anastomosis. As a result of radical

tumour resection, the common carotid artery and the

brachiocephalic trunk are in close proximity to the anastomosis.

Air leaks with the spread of infection into the surgical area can

subsequently lead to erosion of the vessel wall and fatal bleeding.

To avoid this often lethal complication, it is recommended to

reinforce the anastomotic site with remaining strap muscles,

which at the same time can also strengthen the anastomosis.

Statement 14: In patients with invasion of the aerodigestive

tract, where local disease control requires full-thickness

excision, the decision on resection and eventual reconstruction

must be tailored to patient and tumour characteristics in

high-volume referral centres based on MDT discussion and

willingness for treatment.

Consensus: Yes (8.51)

Outliers: 0

Evidence level: Low

Statement 15: In patients with oesophageal involvement that

does not extend into the lumen, only the involved musculature

should be resected.

Consensus: Yes (8.00)

Outliers: 3

Evidence level: Low

Resection in major vessel involvement

Where invasion of major vascular structures is suspected,

preoperative planning must be thorough. Appropriate imaging

must be performed, securing the patency of the Willis’ circle

when major arteries are involved9,112. Consultation and

participation of vascular surgeons must be considered according

to surgeon expertise and local protocols. The internal jugular

vein (IJV) is the most commonly affected structure, mostly from

bulky nodal disease112. For major vein involvement, if one IJV is

affected, it can be excised without anticipating serious

complications9

. In patients with bilateral IJV involvement,

reconstruction of one side with an autologous graft can be

considered to avoid serious venous congestion of the head and

neck112,113. Arterial (common carotid artery) involvement is less

frequent and usually it is possible to preserve arterial integrity. If

there is overt invasion, requiring arterial resection for complete

tumour removal, management should be individualized and

possibly planned at the MDT level before operation.

Statement 16: In unilateral IJV involvement, the vein may be

excised without reconstruction if contralateral venous patency

is adequate.

Consensus: Yes (8.49)

Outliers: 0

Evidence level: Low

Statement 17: At least unilateral reconstruction of the IJV

should be performed in bilateral involvement, after vascular

surgeon consultation and/or participation.

Near-consensus: (7.41) Rejected

Outliers: 8

Evidence level: Low

GA voting: Agree: 74.30%, Disagree: 12.85%, Neutral: 12.85%

Lymph node involvement with extent of IIa–Vb and/or

VI–VII compartments

In the presence of lateral compartment nodal disease, levels IIa,

III, IV, and Vb are dissected routinely. Preservation of the spinal

accessory nerve, with rare exceptions, should occur as shoulder

morbidity can have a significant and negative impact on quality

of life. In addition, attention to preserving the cervical plexus

nerves is important, when feasible, to reduce neuropathic pain.

In level IV, particular attention should be made to dissecting

involved nodes from Chassaignac’s triangle, a common site of

nodal involvement. Meticulous caution is very important to

avoid injury to the lymphatic duct, phrenic nerve, and

sympathetic trunk during dissection. Lateral compartment

dissection is invariably accompanied by dissection of level VI

and occasionally VII central neck compartments. Prophylactic

lateral and central neck surgery is not recommended in general,

as this has not been shown to either improve survival or

decrease locoregional recurrence. These strategies are discussed

further in dedicated sections below.

Metastatic disease and systemic therapy

Patients with thyroid cancer who have locally advanced disease

and/or distant metastases, and are not amenable to surgery,

minimally invasive locoregional treatments or RAI, may warrant

systemic therapy. The choice of whether and when to treat

should be individual to each patient, and informed by a range of

factors, including patient performance status, clinical

manifestations of disease (because side-effects of medicinal

therapy may significantly affect daily activities in an otherwise

asymptomatic patient), tumour burden and site (with lesions

likely to cause signs and symptoms of disease being referred for

8 | BJS, 2024, Vol. 111, No. 8

treatment), documented and significant structural disease

progression114 (as a significant proportion of patients may have

spontaneous and prolonged stability of disease115), and risk of

disease progression based on tumour aggressiveness (poorly

differentiated or undifferentiated malignancies).

Thus, the risks and benefits of systemic therapy should be

weighed carefully after MDT assessment. The treatment

landscape for advanced thyroid cancer has changed

significantly in the past decade8

. A number of MKIs have

entered clinical practice for the treatment of DTC (lenvatinib

and sorafenib as first-line therapies; cabozantinib as second-line

therapy) and MTC (cabozantinib and vandetanib). More recently,

the therapeutic options for DTC, PDTC, ATC, and MTC have

been further enriched with new drugs, including selective

targeted therapies for tumours harbouring driver, actionable

mutations (for example mutations in BRAF, NTRK, and RET) and

immunotherapy. Currently, the optimal treatment sequence

and decision-making algorithm is based on regulatory

constraints, expected treatment response, and drug safety

profile8

. It is worth noting that the potential of novel therapies

to reduce tumour volume is also paving the way for the use of

these drugs in a neoadjuvant setting. Evidence for specific

subtypes is discussed in the following sections.

Facilitating adjuvant treatment

The use of external beam radiation therapy (EBRT) after surgery

for ATC is usually recommended5

. Concerning DTC, although

most studies of the role of EBRT are retrospective, with

heterogeneity in terms of patient selection, tumour features,

and methodology, it is a viable option for locoregional disease

control in patients with R1 or R2 resection116,117. Indeed, the

AHNS118 has published a relevant statement on indications for

EBRT that includes patients with gross residual or unresectable

locoregional disease after complete resection (except for those

aged less than 45 years with limited gross disease that is

RAI-avid), and in selected patients aged over 45 years with a

high likelihood of microscopic residual disease and low

likelihood of responding to RAI.

Statement 18: In cases of anticipated R1 or R2 resection, liberal

use of titanium clips to delineate the dissection bed, to

facilitate the targeting of potential EBRT, has to be considered.

Near-consensus: (7.22) Approved

Outliers: 8

Evidence level: Low

GA voting: Agree 83.33%, Disagree 8.62%, Neutral 8.05%

Follicular cell-derived non-anaplastic thyroid

cancer

Surgery remains the cornerstone for achieving control of

locoregional advanced disease in non-anaplastic follicular

cell-derived thyroid cancer, while facilitating management and

treatment of distant metastasis3

. Among 23 703 DTCs (93.8% of all

thyroid carcinomas registered in the surgical Eurocrine®

database), 3261 (13.7%) were advanced thyroid cancers. In 893

patients (27.4%), DTCs were locally advanced (T3b/T4), 2542

(77.9%) presented with regional disease (pN1b), and (10.8%) with

distant metastases (M1) (unpublished data - M.R., N.V., T.M.).

With new developments in systemic and adjuvant treatments,

more conservative options are available that may reduce surgical

morbidity and improve patient quality of life6,8,119–122. In primary

DTC, incomplete surgical excision has been associated with

higher mortality rates27,123. The aim of this section is to discuss

and make suggestions depending on the point of disease invasion.

Management of local disease

If total thyroidectomy, when feasible, is the mainstay treatment

option for locally advanced non-anaplastic follicular cell-derived

thyroid cancer, en bloc resection of invaded adjacent structures

should be balanced against the operative risk of morbidity and

oncological expectations. Invasion of local structures most

frequently involves the strap muscles, RLN, and trachea, whereas

spread to the larynx, oesophagus, and major vessels is rarer9

. In

the Eurocrine® database, between 2015 and 2021, among 161

patients with T4 DTC or poorly DTC in whom the site of

infiltration was clearly reported, it involved the RLN in 65.59%,

the trachea in 13.04%, the oesophagus and major vessels in

8.69%, and the larynx in 3.1% (unpublished data - M.R., N.V., T.M.).

Infiltrated laryngeal nerves

RLN invasion is the most common infiltration site among T4

tumours. The invasion may be directly from the tumour or

from paratracheal metastatic lymph nodes, and the degree

may vary from simple adherence to complete encasement, and

from superficial epineural to deep endoneural invasion9,124.

The management of patients with an involved RLN requires a

high degree of expertise, and implementation of preoperative

and intraoperative protocols for optimal tailored results.

Preoperative3,125,126 and postoperative110,127 laryngeal examination

is recommended in all patients with locally advanced thyroid

cancer and preoperative glottic function should be assessed.

Intraoperative neuromonitoring is an indispensable tool for

making the optimal decisions on nerve management, especially

in the event of infiltration93,128. If the intraoperative findings

suggest RLN infiltration, this should be confirmed optimally

with a frozen-section examination9

. Before deciding on the

management approach, the surgical team should always

consider the following: disease characteristics, metastatic

status, patient age and occupation, patient preference and

wishes, adjuvant therapy options in the event of microscopic/

macroscopic remnant disease, possible disease progression if

the nerve remains unresected, preoperative vocal fold function,

preoperative and intraoperative status of the contralateral RLN,

and electromyographic (EMG) signals from the affected nerve

(normal along the whole course of the nerve or normal only

distal to the infiltrated site)2,124. If preoperative laryngeal function

is normal, and EMG nerve signals and signals proximal to the

infiltration site are normal, every effort should be made to retain

the structural integrity of the RLN93,94,129. In the above scenarios,

and especially in superficial invasion, shave or partial nerve

sheath excision may achieve macroscopic disease clearance and

retain RLN functionality, without a negative impact on

survival24,130–132. More conservative approaches that preserve

structural nerve integrity are considered an acceptable choice in

DTC, even when a small disease remnant might remain, as there

are no adequate data to support the survival benefits of complete

resection over shave resection and adjuvant therapy9,133. It has,

however, been reported that, in certain debulking scenarios,

patients required extensive further resection, including

laryngectomy and sternotomy, signifying that the location of

nerve infiltration (for example close proximity to laryngeal

entrance) should be taken into account133. On the other hand, in

patients with non-functioning nerves, with evidence from

preoperative laryngoscopy, and verified during surgery by the

Raffaelli et al. | 9

absence of an EMG signal along the whole course of the RLN,

especially when RLN infiltration is extensive, the RLN should be

excised9

. Complete resection can also be considered in special

circumstances, such as aggressive subtypes, recurrence, and

previous EBRT, where adjuvant treatment has or is expected to fail,

when justified by projected survival or disease-free benefits31. To

reduce the risk of bilateral vocal fold paralysis, the International

Neural Monitoring Study Group (INMSG)93 has proposed detailed

algorithms to facilitate surgeon decision-making. Among other

recommendations, the INMSG proposes to start, or switch, the

dissection on the contralateral side of the non-functioning invaded

nerve93. Similar decisions should be individualized based on

patient and tumour characteristics. Indeed, if there is preoperative

lack of function on the affected side, primary tumours should be

removed as comprehensively as possible, and dissection on the

contralateral side should be weighed against the extent of the

disease and the expected oncological benefits. Finally, recent data

suggest that, in certain patients with ATC and advanced PTC, the

function of invaded nerves may recover before surgery during

neoadjuvant therapy134. Although these data stem from a limited

case series, it is a promising concept for future management of

patients with nerve invasion.

Statement 19: For invaded RLNs with normal preoperative

laryngoscopy:

When it is possible surgically to achieve macroscopic

disease clearance, they should be managed conservatively to

maintain structural and, ideally, functional nerve integrity.

Consensus: Yes (7.98)

Outliers: 3

Evidence level: Low

When conservative management cannot achieve

macroscopic disease clearance, the decision regarding

resection should be individualized based on patient and

tumour characteristics.

Consensus: Yes (8.20)

Outliers: 2

Evidence level: Low

The above scenarios should be discussed beforehand, and

patient preferences considered.

Consensus: Yes (8.10)

Outliers: 2

Evidence level: Expert opinion

Statement 20: In unilateral vocal fold paralysis, with complete

lack of EMG signal along the course of the RLN, and inability to

maintain structural nerve integrity with conservative

techniques, while achieving local disease control:

Nerve resection should be applied, to obtain adequate

oncological clearance on the affected side. Contralateral

dissection should be weighed against extension of the disease

and the expected oncological benefits.

Consensus: Yes (8.27)

Outliers: 1

Evidence level: Expert opinion

Dissection should start on the non-affected side, and

decisions about proceeding with, and management of, the

affected side should be individualized based on patient

preferences and tumour characteristics.

Consensus: No (3.70)

Outliers: 21

Evidence level: Expert opinion

The above scenarios should be discussed beforehand, and

patient preferences considered.

Consensus: Yes (7.80)

Outliers: 4

Evidence level: Expert opinion

Statement 21: In the event of ipsilateral vocal fold paralysis,

but positive EMG signals proximal to the infiltration site of the

RLN:

When it is possible surgically to achieve macroscopic

disease clearance, such patients should be managed

conservatively to maintain structural nerve integrity.

Consensus: Yes (7.49)

Outliers: 4

Evidence level: Low

When conservative management cannot achieve

macroscopic disease clearance, the decision regarding

resection should be individualized based on patient and

tumour characteristics.

Consensus: Yes (7.60)

Outliers: 5

Evidence level: Low

The above scenarios should be discussed beforehand, and

patient preferences considered.

Consensus: Yes (7.93)

Outliers: 3

Evidence level: Expert opinion

Infiltrated viscera and/or major vessels

Management of these patients should always be aligned with

therapeutic goals, and surgery-related morbidities should be

weighed against the sequelae of non-treatment/conservative

surgery for the patient. As already discussed, preoperative

evaluation and involvement of a MDT is essential. The surgeon

should keep in mind that, especially in DTC, adjuvant therapy

including RAI or EBRT is usually indispensable to completely

control the disease locoregionally2,9

. In addition, recent

developments in systemic therapy, depending on genetic

alterations in non-anaplastic follicular cell-derived thyroid

cancer, may afford less extensive and morbidity-burdened

operations in favour of systemic and even neoadjuvant

treatment options6–8

.

Tracheal invasion

The three main techniques for disease control have traditionally

been shave or window resection, and sleeve resection with

end-to-end anastomosis9,120. For stages I and limited stage II

involvement, according to the Shin classification89, shave

resection is considered appropriate and adequate. For more

extensive infiltration, including the mucosa and lumen, sleeve

resection must be considered, but detrimental complications

might occur2,9,120. Formal segmental tracheal resection of the

involved rings may offer, if feasible, the best results in terms of

long-term oncological outcome9

. As such, considering the risk of

complication, the decision should be carefully weighed against

patient and disease characteristics as well as patient wishes. In

any event, management must be undertaken by a team with

advanced skills and complemented by other surgical specialties

according to endocrine surgeon expertise, and local protocols

and legislature.

Statement 22: In patients with limited (stage I or limited stage II

according to the Shin classification) tracheal involvement,

tracheal shaving should be performed.

Consensus: Yes (7.95)

Outliers: 3

Evidence level: Low

10 | BJS, 2024, Vol. 111, No. 8

Statement 23: In patients with extensive (stage III or IV)

tracheal involvement, tracheal resection should be considered

according to MDT goals of care and patient preferences.

Consensus: Yes (7.76)

Outliers: 2

Evidence level: Low

Laryngeal invasion

Extended invasion of the larynx reaching intraluminally is quite

rare in DTC, but results in significant morbidity and sometimes

death135. In the most common cases of extraluminal infiltration, a

partial-thickness or shave excision, usually of the cricoid or

thyroid cartilage, is preferable for local disease control9,136.

Current data are conflicting and not clearly in favour of composite

resection and reconstructions over conservative treatment and

adjuvant therapy in terms of oncological results. Therefore, even

in more extended invasion, local control should be achieved with

surgical options carrying lowest morbidity9,121,136. If a more

aggressive resection is required, it can be decided in a MDT

setting, also considering patient preferences and expectations.

Statement 24: In patients with DTC and laryngeal involvement,

local disease control should be achieved with shave or

partial-thickness excision when feasible.

Consensus: Yes (7.73)

Outliers: 3

Evidence level: Low

Statement 25: In patients with extensive (stage III or IV)

laryngeal involvement, resection should be considered

according to MDT goals of care and patient preferences.

Consensus: Yes (7.95)

Outliers: 2

Evidence level: Low

Statement 26: Aggressive laryngeal resections should not be

performed as index primary operations, but only in the event of

failure of disease control after more conservative surgical

treatment and adjuvant therapy, except where the tumour

presents an overarching burden at presentation.

Near-consensus: (7.07) Approved

Outliers: 9 (3 negative)

Evidence level: Low

GA voting: Agree: 82.56%, Disagree: 5.81%, Neutral: 11.63%

Oesophageal invasion

Oesophageal invasion is predominantly limited to the muscularis

in invasive DTC23, and usually derives from the primary

tumour137. Extension into the lumen is rare, but requires

composite reconstruction when the defect following

full-thickness resection is large and primary tension-free closure

cannot be achieved safely9

. As such, resection of the infiltrated

layers is usually sufficient to achieve local control.

Full-thickness resection and reconstruction should be

performed only when there is definitive mucosal involvement,

after discussion in a MDT setting9

. The statements listed in the

general treatment section above also apply to DTC.

Management of regional nodal disease

The adequacy of lymph node clearance in thyroid cancer, and

especially in advanced disease, is critical to avoid recurrent and/

or persistent disease138,139. It has been documented that

approximately 60–75% of all neck recurrences occur in cervical

lymph nodes3,140. In neck dissections, two principles should guide

surgical extent. The first is the comprehension that cervical

lymph nodes are without exception contained in the spaces

defined by the muscular fascias and vascular aponeuroses.

Consequently, in the absence of direct invasion, muscular,

vascular, and neural vital structures should be preserved,

whereas the fascia covering the fibrofatty tissue and nodes should

be removed en bloc139. Second, it is important to understand the

pattern of dissemination of lymphatic disease, and to balance

disease-free and disease-specific survival depending on the

compartments dissected139. To this end, the Surgical Affairs

Committee Statement of the ATA141 recommends that lateral

neck dissection for macroscopic DTC metastases should comprise

selective neck dissection of levels IIa, III, IV, and Vb. This was

further reconfirmed in the American Association of Endocrine

Surgeons (AAES) guidelines142 in 2020. More extended dissection,

including levels IIb, Va, and, exceptionally, I, should be

undertaken only if there is evident involvement. For central neck

dissection (CND), the levels involved are VI and VII. CND is

indicated for all patients with clinically involved nodes, either

determined before or during surgery, and is encouraged in

patients with larger and locally more advanced tumours (T3 and

T4)3,110,142,143. As an alternative to prophylactic bilateral CND, an

ipsilateral approach with frozen-section examination of the

ipsilateral central neck compartment could guide the extent of

neck dissection and reduce patient morbidity while avoiding

reoperations53,144. Concerning patients with DTC, lateral neck

dissection should be performed only with therapeutic intent for

known disease and not for prophylactic purposes and

accompanied by bilateral CND3,140–142,145.

Statement 27: When neck dissection for disease clearance has

been decided:

Lateral neck dissection of levels IIa, III, IV, and Vb should be

performed only with therapeutic intent for evident lateral neck

spread. Levels I, IIb, and Va should be dissected only in the

event of clinical involvement.

Consensus: Yes (8.15)

Outliers: 2

Evidence level: Low

Levels IIb and Va must be included.

Consensus: No (4.39)

Outliers: 18

Evidence level: Low

Statement 28: When lateral neck dissection for disease

clearance has been decided, it should always be accompanied

by CND, even in the absence of overt central neck involvement.

Near-consensus: (7.15) Rejected

Outliers: 7

Evidence level: Low

GA voting: Agree: 73.33%, Disagree: 19.44%, Neutral: 7.22%

In the absence of central neck involvement, and depending

on tumour characteristics, unilateral CND could be performed,

extended to the contralateral side if frozen-section

examination is positive.

Consensus: No (6.33)

Outliers: 18

Evidence level: Low

Neoadjuvant and new systemic therapy options

Evidence for the value of neoadjuvant therapy in patients with

DTC and PDTC can be found in a few case reports describing

treatment with the MKIs lenvatinib and sorafenib146. These

Raffaelli et al. | 11

reports include patients with a wide age range (20–81 years),

receiving MKI compounds for preoperative treatment of

advanced primary tumours or recurrent locally invasive

cancers, with or without concomitant EBRT. None of the

patients had gross ETE staged as T4b according to the TNM/

AJCC eighth edition. All patients experienced significant tumour

shrinkage, regardless of whether they had received EBRT,

allowing limited surgical approaches in a subset of individuals,

without extensive resections such as laryngectomy,

oesophagectomy or resection of the great vessels. Notably, all

patients undergoing MKI neoadjuvant therapy should be

informed of, and assessed for, risk of fistula before initiation of

treatment. Fistula has been reported in patients undergoing

antiangiogenic MKI treatment and harbouring locally advanced

thyroid cancers encasing the trachea, carotid artery, and/or

mediastinal vessels147. Such an extent of disease is far from rare

in patients in whom neoadjuvant therapy is considered. The use

of selective targeted therapies, without significant antiangiogenic

activity, is expected to reduce this risk. Larger studies that can

explore the long-term benefit and risk of neoadjuvant therapy at

a population level are warranted. These studies should also

address specific questions, such as the therapeutic schedule

(dosing and duration) and the profile of patients expected to

benefit from such treatments.

There is no evidence for the use of MKIs or selective targeted

therapies alone in patients with advanced thyroid cancer in an

adjuvant setting. Selumetinib, a selective mitogen-activated

protein kinase kinase 1 and 2 (MEK 1/2) inhibitor, has been

investigated in combination with adjuvant RAI to evaluate its

benefit in improving complete remission rates in patients with

DTC at high risk of primary treatment failure. Eligible patients

had a large primary tumour (over 4 cm), gross ETE, and

significant neck lymph node involvement (at least 1 metastatic

lymph node(s) of 1 cm or larger, or at least 5 lymph nodes of any

size). The combination therapy was compared with RAI alone in

a placebo-controlled, double-blind RCT148. The addition of

selumetinib to RAI failed to improve the primary outcome of

complete response rate, while exposing patients to a higher rate

of treatment-related adverse events of at least grade 3.

Statement 29: Neoadjuvant MKI therapy may be an option in

properly selected patients with DTC to reduce primary tumour

burden and facilitate subsequent surgical resection for local

disease control.

Consensus: Yes (7.37)

Outliers: 4

Evidence level: Low

Medullary thyroid cancer

Advanced MTC comprises four clinical scenarios: local, regional,

systemic, and combined locoregional and systemic advanced

MTC. In advanced MTC, clinical outcomes do not differ between

sporadic and hereditary disease, and so they will be addressed

as one. A markedly raised calcitonin and/or carcinoembryonic

antigen (CEA) level without evidence of structural disease is not

considered advanced MTC. Lymph node involvement of the

central and/or lateral compartment without infiltration of

neighbouring structures owing to ENE does not represent advanced

MTC, based on oncological outcomes. As mentioned above, N1b

might, however, represent advanced disease as it is associated with

a higher morbidity rate, requiring treatment in high-volume

referral centres, as well as being linked to worse prognosis in

individual studies149. In the Eurocrine® database, between 2015 and

2021, among 1242 MTCs (4.9% of all registered thyroid carcinomas),

363 (29.2%) were advanced MTCs, sporadic in 89% of the patients.

Sixty-three (17.35%) were locally advanced (T3b/T4), 340 (95.8%)

presented with regional disease (pN1b), and 64 (17.6%) with distant

metastases (M1) (unpublished data - M.R., N.V., T.M.).

Locally advanced medullary thyroid cancer

ETE in MTC is associated with systemic disease and poorer

prognosis, and therefore is considered advanced MTC18,149–151.

ETE starts with breach of the thyroid capsule and advances to

various degrees of direct infiltration into neighbouring

structures, namely the RLN, strap muscles, soft tissue, trachea,

oesophagus, larynx, jugular vein, and common carotid artery. It

should be noted that, in MTC, there is not enough evidence in

the literature on the impact of the specific point of ETE (such as

strap muscles only or RLN) on oncological outcomes.

Regionally advanced medullary thyroid cancer

Cervical lymph node metastases with ENE are considered regional

advanced MTC independently of extension of the primary

tumour152. Often ENE in lymph node metastases is present

synchronously with locally advanced MTC.

Systemic medullary thyroid cancer

Evidence of distant metastases in one or more regions, such as

mediastinal lymph node, pulmonary, liver, bone, brain, or skin

metastases, indicates systemic advanced MTC. Combined local,

regional, and/or systemic advanced MTC is represented by any

combination of the above.

Specific considerations in pretreatment medullary thyroid

cancer diagnostics

Measurement of basal calcitonin and CEA levels must be done

before treatment as a baseline evaluation and to direct the

diagnostic algorithm. Moreover, calcitonin and, less so, CEA

levels are important factors used to assess disease burden and

response to neoadjuvant or definitive treatment during

follow-up. Cervical ultrasound imaging, clinical evaluation, and

symptoms may provide early evidence of advanced MTC,

whereas whole-body 18F-6-fluoro-L-dihydroxyphenylalanine

(F-DOPA) PET–CT is the most sensitive investigation for

assessing disease burden and prioritizing adequate treatment.

Complementary cross-sectional imaging (contrast-media CT,

MRI), and endoscopy of the trachea, bronchi, and/or

oesophagus, should be performed accordingly whenever

resection of locoregional advanced MTC is planned to direct the

surgical strategy153. In MTC, FNA or core-needle biopsy does not

serve to confirm the diagnosis, but may be used for molecular

pathology investigation with the aim of evaluating neoadjuvant

or palliative treatment modalities.

Statement 30: In advanced MTC, the following must be

determined before treatment:

Both basal calcitonin and CEA levels.

Consensus: Yes (8.07)

Outliers: 6

Evidence level: Low

Only basal calcitonin levels.

Consensus: No (7.60)

Outliers: 19

Evidence level: Low

12 | BJS, 2024, Vol. 111, No. 8

Statement 31: Before surgery for advanced MTC, whole-body

F-DOPA or 68Ga-labelled DOTATATE PET–CT should be

preferred, when available, to assess the tumour burden and

align surgical measures.

Near-consensus: (6.83) Rejected

Outliers: 14

Evidence level: Low

GA voting: Agree: 74.71%, Disagree: 10.34%, Neutral: 14.94%

Treatment

Locally advanced disease

Locally advanced MTC without evidence of distant disease in

primary surgery aims at margin-free oncological resection,

ideally followed by biochemical cure. The extent of resection

must be adapted to patient general health performance status

(Eastern Cooperative Oncology Group and ASA), co-morbidities,

and specific risk factors (for example pre-existing neural

dysfunction, such as laryngeal nerve palsy), age, and patient

preferences. Following MDT recommendation with the

anticipated risk–benefit evaluation, patient counselling is

mandatory before surgical intervention. In primary surgery and

where free resection margins are expected with optional

biochemical cure, total thyroidectomy with bilateral

compartment-oriented CND is necessary in most patients. In the

rare exception of a small primary tumour with distant

metastases (for example pulmonary) and without evidence of

lymph node metastasis, lobectomy with or without ipsilateral

central node dissection can be considered154,155. Surgical

resection of ETE in advanced MTC, without transluminal

resection of the trachea and/or oesophagus, is carried out

according to the structures involved. The infiltrated strap

muscles and central neck compartment are resected en bloc with

the thyroid and primary tumour. Where the strap muscles are

uninvolved or only partially involved, full- or outer-layer

preservation enables their use for fortification or closure of

tracheal and/or oesophageal transluminal resections. In

superficial tracheal invasion (Shin I–II), shaving is performed89.

In extramucosal oesophageal infiltration, wall resection with

preservation of mucosal integrity is undertaken. In both

procedures, intraoperative frozen-section confirmation of

tumour-free margins will direct the resection strategy.

Intraoperative evidence of unilateral RLN infiltration with

bilateral intact preoperative vocal cord function requires

functional preservation of the contralateral RLN to be confirmed

before oncological RLN resection. In the event of unilateral RLN

infiltration with preoperative vocal cord palsy and oncological

RLN resection, the indication for surgery on the contralateral

side must be evaluated carefully. Intraoperative evidence of

bilateral RLN infiltration with intact vocal cord function requires

tailored decision-making regarding which resection procedure is

most likely to preserve quality of life and have prognostic

benefit. Options are unilateral oncological RLN resection with

contralateral RLN preservation, bilateral RLN resection and

tracheostomy, or intended palliative resection with preservation

of the infiltrated RLN. A specifically demanding area of RLN

infiltration is the laryngeal–tracheal groove, where tumour

infiltration is rarely restricted to the RLN but involves the

trachea, larynx, and oesophagus simultaneously. Whenever

possible, margin-free tumour resection of the infiltrated RLN

entering the larynx, encompassing necessary tracheal shaving,

extramucosal oesophagus, and partial resection of infiltrated

areas of the larynx, should be performed. Fortification or plastic

reconstruction is not required unless relevant vascular

compromise with secondary necrosis is anticipated, and the

tracheal or oesophageal lumen are opened. Transluminal types

of tracheal resection (window, sleeve or segmental) are

performed according to the longitudinal and circumferential

extension of tumour invasion, as are transmural resections of

the oesophagus that are restricted in extent owing to limited

options for vascular preservation. Multidirectional tumour

infiltration involving the RLN, larynx, trachea, and oesophagus

may require multivisceral resection with laryngectomy, tracheal

and oesophageal resection, a free jejunal transplant

reconstruction of the digestive tract, and terminal tracheostomy

for airway management. These complex procedures are

associated with considerable complication rates; however,

selected patients benefit from these salvage manoeuvres. For

such multivisceral infiltrative scenarios, neoadjuvant treatment

is introduced, and is discussed below. Data on the outcome and

prognosis of extended resections involving the trachea, larynx,

and oesophagus in MTC are scarce, and show dismal results

compared with those for patients with DTC. Therefore, the

indication for extended and multivisceral procedures in MTC

must be weighed carefully156,157.

Statement 32: The main goal of surgery in advanced MTC is

local control and optimization of adjunctive treatment

modalities. Therefore, resection of the RLN, trachea,

oesophagus, larynx, and lymph node dissection are

recommended when local control can be achieved. The

diagnosis of advanced MTC should not preclude surgical

evaluation of resectability.

Consensus: Yes (7.39)

Outliers: 3

Evidence level: Low

Regionally advanced and metastatic disease

In MTC, lymph node metastases are strongly associated with

desmoplasia and breach of the thyroid capsule. Both features

are expected in advanced MTC, and can be assessed by

frozen-section analysis. This allows alignment with preoperative

and intraoperative evidence of lymph node metastases, and

direction of the extent of lymph node dissection at the time of

primary tumour resection158. To achieve cancer-free resection

margins and local control, bilateral central compartment lymph

node dissection is generally necessary. In the event of unilateral

RLN dysfunction or oncological RLN resection, the indication for

contralateral central compartment lymph node dissection needs

to be carefully weighed and should be performed only with

therapeutic intent. Any type of prophylactic lymph node

dissection to the central, and even more so, the lateral

compartments is discouraged. In the rare scenario of a locally

advanced MTC for which radical (R0) resection and biochemical

cure can be expected with therapeutic lymph node dissection,

the central and lateral compartments can be dissected accordingly.

Mediastinal tumour manifestation for direct tumor diffusion or

lymph node metastasis should be resected whenever technically

possible as secondary complications frequently occur159.

Tracheal, bronchial, and oesophageal resections in the

mediastinum are prone to complication and associated with

very poor outcomes. These should, therefore, be discouraged in

Raffaelli et al. | 13

favour of neoadjuvant treatment or palliative measures involving

stenting and multimodal treatment modalities4,156.

In the event of persistent and recurrent advanced MTC, full

measured tumour staging must precede evaluation of surgical

options, and the surgical principles outlined above for primary

surgery apply to resection of persistent and recurrent disease.

In MTC, distant metastases infrequently represent systemic

disease. Resection of the primary tumour can be undertaken in

such patients without extended neck resection and thus benefit

local disease control in the neck160. The role of surgery in

systemic advanced MTC, as well as in combined local, regional,

and systemic disease, is directed at local tumour control, to

alleviate symptoms or prevent complications.

Recently, neoadjuvant treatment for MTC has been introduced,

and may also reshape the role of surgery in systemic MTC, as

surgery can be extended according to treatment response161,162.

Palliative surgery is indicated whenever structural tumour growth

presents with symptoms that can be alleviated and/or to prevent

expected complications when progressive local infiltration cannot

be stalled in a timely manner by other means. Surgery in these

scenarios is directed at the local or regional problem at hand.

MTC in general is a rare entity, and advanced MTC even more

so. The diagnosis of advanced MTC should not preclude

evaluation by an experienced specialized surgeon. Patients with

advanced MTC are at increased risk of surgical morbidity, and

surgery should therefore be carried out by high-volume

surgeons in centres with extensive experience. The oncological

results of thyroid cancer surgery are significantly better when

performed by high-volume surgeons163. A recent study164

showed that surgeon volume was a significant factor for disease

recurrence (HR 2.28; P = 0.004).

Statement 33: In advanced MTC, compartment-oriented

lymph node dissection:

Should be carried out to the extent that is required

therapeutically. Any type of prophylactic lymph node

dissection should not be performed.

Consensus: No (5.85)

Outliers: 29

Evidence level: Low

Prophylactic CND should be performed routinely.

Near-consensus: (6.71) Rejected

Outliers: 18 (7 negative)

Evidence level: Low

GA voting: Agree: 78.97%, Disagree: 16.41%, Neutral: 4.62%

Statement 34: Surgery for advanced MTC should be performed

only by high-volume surgeons in high-volume centres.

Consensus: Yes (8.49)

Outliers: 0

Evidence level: Low

Neoadjuvant and new systemic treatment options

Little evidence is available on the role of systemic therapy in the

preoperative management of locally advanced MTC. Reports in the

literature do not go beyond clinical cases and case series. No

evidence at all is available on the adjuvant use of pharmacological

therapy.

The approval of selective RET kinase inhibitors (pralsetinib and

selpercatinib) by international medicine regulatory authorities,

their increasing use in clinical practice, the growing body of

evidence on their safety and efficacy profile, and the significant

proportion of patients carrying RET mutations have all favoured

therapeutic attempts in the neoadjuvant setting. In a recent

retrospective single-centre case series165, four patients were

treated with neoadjuvant selpercatinib followed by surgery.

Patients underwent 4–6 months of neoadjuvant therapy, with

drug withdrawal 3 days before surgery. All experienced tumour

shrinkage, with three of four patients achieving a partial

response according to Response Evaluation Criteria In Solid

Tumours 1.1. None of them had structural evidence of disease

after surgery (median follow-up 2 (range 0.7–3.6) years) and one

patient experienced an RLN injury. Although this approach

holds promise, larger studies are warranted. A clinical trial

exploring the value of neoadjuvant selpercatinib treatment in

patients with MTC harbouring somatic or germline RET

mutations is currently under way (NCT04759911).

Owing to the scarcity of data and experience with neodjuvant

treatment in advanced MTC, important practical aspects, such

timing of surgery, discontinuation of drugs before and after

operation, as well as treatment-free intervals are mainly based

on experience with the available substances in adjuvant and

palliative settings in MTC, and may need to be adjusted with

increasing experience. The time point of surgery in neoadjuvant

treatment planning may be chosen when the structural response

according to imaging indicates expected safe and radical tumour

resection. Systemic treatment with any type of kinase inhibitor

and/or immune checkpoint inhibitors should be discontinued at

least 5–7 days before surgery, and likewise after surgery until

successful wound healing has resumed owing to infrequent

compromise in wound healing and the risk of fistula formation.

Most of the data referring to experience with complications in

this regard are, however, not based on advanced MTC.

Statement 35: Neoadjuvant RET-targeted therapy may be an

option in selected patients with MTC to reduce the primary

tumour burden and facilitate subsequent surgical resection for

local disease control.

Consensus: Yes (7.41)

Outliers: 4

Evidence level: Low

Anaplastic thyroid cancer

Owing to its fatal prognosis, ATC is always classified as stage IV by

the AJCC TNM system13. ATC is labelled as stage IVa in the event

of a tumour confined to the thyroid gland, stage IVb if there is

tumour extension outside the thyroid but confined to the neck,

and stage IVc in the case of distant metastasis. ATC requires an

immediate multidisciplinary assessment to ensure the best

multimodal treatment. A thorough, expeditious, and complete

preoperative work-up is imperative, as discussed previously,

with emphasis on the need for efficiency and haste. Once the

status of the disease has been determined, goals of care should

be set by the MDT, in accordance with patient preferences,

following a candid, comprehensive, and meticulous discussion.

Individualized treatment options should be offered to patients,

and they should be informed about possible complications after

radical surgery, or denial of therapy. Additionally, patients

should be informed about the possibility of permanent

tracheostomy, feeding tube placement, and delay in starting

medical treatment after major surgery.

14 | BJS, 2024, Vol. 111, No. 8

Statement 36: In ATC, multidisciplinary evaluation should be

undertaken with the outmost haste and efficiency, and possible

morbidities of aggressive surgery, and the potential benefits

this surgery may provide to the patient, should be well

evaluated and balanced.

Consensus: Yes (8.46)

Outliers: 0

Evidence level: Low

Resectability

Surgery plays a critical role in the management of ATC, with the aim

of achieving potentially curative (R0) or complete macroscopic (R1)

resection of the tumour. Several studies166–170 have documented a

survival benefit in patients with ATC when complete resection

(R0/R1) is achieved. Although diagnosed rarely, patients with

stage IVa disease are candidates for total en bloc resection5,171. On

the other hand, the resectability of stage IVb tumours should be

assessed carefully based on the structures involved. The potential

benefit of mutilative surgery is questionable considering the poor

prognosis of the tumour, and the morbidity related to extensive

resections needs to be evaluated carefully. Tumour invasion of

the prevertebral fascia, and invasion or encasement of the carotid

artery and/or mediastinal vessels, are considered features

indicative of unresectability. Moreover, aggressive resections,

such as laryngectomy or pharyngo-oesophagectomy, often appear

inappropriate because of the associated morbidity172.

Nonetheless, patients with previously unresectable stage IVb ATC

may benefit from recently developed neoadjuvant treatment

modalities, which may render some cancers resectable5,7,8,78,173–175.

The role of surgical treatment in stage IVc ATC is controversial.

Optimal management must be discussed within a MDT. Individual

studies170,176 have reported that surgery of the primary tumour in

combination with multimodal therapy is associated with

improved overall survival. Moreover, surgery may play a role in

terms of preventing potentially fatal complications caused by

local tumour growth, such as airway obstruction, haemorrhage,

and vena cava superior syndrome. Besides, immunotherapeutic

and targeted therapies have been introduced for the treatment

of advanced and metastatic ATC, yielding promising results and

rendering resectability a dynamic process170,174.

Statement 37: Involvement of the aerodigestive tract and/or

major vascular structures of the neck and mediastinum,

requiring extensive resections, are factors indicating

unresectability, and surgery is generally not recommended.

Consensus: Yes (7.88)

Outliers: 2

Evidence level: Low

Palliative care versus aggressive, non-curative surgery

Palliative surgery may be undertaken to reduce airway or

oesophageal obstruction, or to reduce pain associated with

bulky tumours. Local treatments undertaken by means of

interventional bronchoscopy, in particular endotracheal stent

placement and endotracheal laser treatment, can be performed

to decrease airway obstruction or intratracheal invasion and

improve respiratory symptoms177. Nonetheless, such endoscopic

treatments do not influence the prognosis of the tumour.

Tracheostomy may be performed if there is dyspnoea or stridor.

It may also be carried out preventively in selected patients to ensure

respiratory airway patency in the event of impending airway

compromise. The decision to perform tracheostomy always

requires endoscopic tracheal examination and imaging studies to

assess the tracheal profile and displacement.

Tracheostomies in these patients may be technically challenging

because of the presence of the thyroid mass, and may require

isthmusectomy or thyroid debulking178. The decision to perform

tracheostomy must, however, be individualized, evaluated

accurately by a MDT, and discussed with the patient and their

relatives. Tracheostomy is often associated with increased

secretions, and may lead to considerable worsening of quality of

life, increased wound complications, potential tumour extension

from the stoma, and bleeding. Moreover, the tracheostomy may

be displaced owing to tumour growth and may delay appropriate

therapy178. For all these reasons, it is generally recommended to

postpone tracheostomy for as long as possible.

In patients with compromised oral feeding due to oesophageal

obstruction, enteral feeding must be ensured. Enteral feeding may

be achieved by means of a nasogastric tube, oesophageal stent or

gastrostomy. Notwithstanding, tumour invasion may lead to

oesophageal stenosis that could hinder or preclude endoscopic

gastrostomy. In such instances, surgical intervention may be

required. Gastrostomy ensures enteral feeding even when there

are side-effects from radiotherapy and allows patients to

undertake chemotherapy.

Definitive indications and definitions regarding debulking

surgery are still lacking. Overall, it is generally not

recommended because debulking may delay palliative care

options and does not prolong survival170. Debulking may be

undertaken when tumour resection is required to expose the

tracheal surface to perform tracheostomy178. Moreover, selected

patients may be candidates for debulking surgery when huge

tumour reduction can be achieved (at least 90%). Indeed, some

reports179 have documented longer survival after palliative

debulking procedures combined with radiotherapy and/or

chemotherapy compared with best supportive care.

Statement 38: Non-curative, debulking operations are

generally not recommended, although can be considered in

combination with adjuvant/systemic therapy in selected

patients in whom:

Remnant disease is anticipated to be of very low volume.

Consensus: Yes (7.12)

Outliers: 4

Evidence level: Low

It facilitates palliative treatment.

Near-consensus: (6.90) Rejected

Outliers: 14

Evidence level: Low

GA voting: Agree: 71.91%, Disagree: 11.24%, Neutral: 16.85%

Statement 39: A tracheostomy should not be placed

pre-emptively, but only when absolutely necessary for airway

management.

Consensus: Yes (8.12)

Outliers: 1

Evidence level: Low

Surgical extent and significance of R status

In recent years, it has been observed that the average survival of

patients with ATC has increased. The contribution of recent

advancements in molecular targeted therapies and radiotherapy

in this development should not be overlooked. Although

adjuvant and systemic treatment options will evolve, surgery

Raffaelli et al. | 15

remains the cornerstone of complete disease control. With that

consideration, it might be appropriate to push the limits in

selected patients.

Looking at the historical development and importance of

surgical resection, in a study by Tan et al.180, patients treated

between 1968 and 1992 had a mean overall survival of 4.5

months, whereas mean survival was 131 months among patients

in whom complete surgical resection was achieved. In another

study181, of 28 patients in total, palliative surgery was performed

in 6, and curative surgery was attempted in 12. The results

showed that surgical resection, absence of distant metastasis, and

tumour size below 6 cm indicated a survival benefit in selected

patients. In a large series182, including 121 patients from 1950 up

to 1987, average survival was 7.2 months, and the study

demonstrated that young age and absence of metastasis had a

survival benefit. Patients also survived longer if they underwent

total or subtotal thyroidectomy, and if they received radiotherapy,

chemotherapy, or both. There was, however, no statistically

significant difference between treatment types. In all three

studies, patients receiving adjuvant radiotherapy after surgery

had a favourable outcome, or a significant increase in overall

survival. Tennvall et al.

183 conducted a prospective study of 55

patients between 1984 and 1999, with the patients divided into

three groups. Different doses of hyperfractionated radiotherapy

were given to each group. Local recurrence was not observed in

any patient in the group in which the entire dose of radiotherapy

was administered before surgery.

Local control in the treatment of ATC may increase patient

quality of life and provide control of the causes of death owing to

tumour invasion of the surrounding tissues, such as asphyxia and

bleeding. In a multicentre study184 from Korea, 329 patients from

19 different centres were assessed. Curative resection and

adjuvant radiotherapy, or chemoradiotherapy, provided survival

advantages in stage IVa and IVb, but not in stage IVc disease.

Patients who actively underwent total thyroidectomy and

therapeutic neck dissection had better survival rates than those

who had no therapeutic management. A favourable trend

towards improved survival was also observed for R0 over R1

resection. Regarding surgical management of patients with stage

IVb disease, the majority of pertinent publications favoured

resection when R0/R1 was feasible. Ito et al.185 reported no

significant difference in survival between patients with stage IVa

and IVb disease when curative surgery was undertaken. In

addition, no significant difference was found between patients

with stage IVb and IVc disease in whom curative surgery could

not be performed. In line with these results, surgical intervention

was recommended by the 2021 ATA guidelines5 for patients with

resectable stage IVb disease. Prophylactic central or lateral neck

dissection was not recommended, but every attempt to remove

clinically apparent disease was, however, encouraged.

In a retrospective cohort study170 published in 2022, surgical

resection (R0/R1) of the tumour increased the average survival

in patients with stage IVc ATC. Debulking (R2) surgery did not

show any survival advantage. In addition to surgery,

radiotherapy, chemotherapy, multimodal therapy, and being

aged under 65 years were also shown to increase average

survival170. In another report by Yamazaki et al.176, surgical

resection was performed in 36 of 54 patients with metastatic

disease. A survival advantage was shown in the resection group.

When R0/R1 was compared with R2 resection, average survival

was significantly longer for the R0/R1 group (13 versus 1.7

months). Thus, R2 resection was not recommended by the

authors, and might even have proven harmful, highlighting the

need for careful selection of candidates for surgery176. Goffredo

et al.172 reported that absence of surgery was associated with

compromised survival for patients with stage IVa (HR 2.58; P <

0.001) and stage IVc (HR 1.35; P = 0.033) disease, whereas a

negative trend was observed for stage IVb disease (HR 1.33; P =

0.063). No differences in survival were observed for patients

with disease staged IVb and IVc based on resection margin

status. A recent systematic review186 of 40 publications revealed

that approaches to unresectability and interpretations of

resection vary widely. Patients with stage IVb disease

undergoing surgery had significantly longer survival than those

managed non-surgically (6.6 versus 2.1 months).

In a Japanese study187 of the extent of resection, patients were

divided into four groups: super-radical surgery, radical surgery,

palliative surgery, and non-surgical treatment. Super-radical

surgery was defined as segmental or total laryngectomy,

tracheal resection, oesophageal resection, mediastinal surgery

with an ostomy, and major cervical artery resection. The

prognostic index (PI) was used in selecting patients with stage

IVb ATC for super-radical surgery. PI criteria included acute

symptoms, leucocytosis, tumour size greater than 5 cm, and

distant metastasis. Each criterion scored 1 point. Patients with a

PI value of 1 or less who underwent super-radical surgery had a

50% survival rate at 1 year. In the 10 patients with a PI value of 2

or higher, the 1-year survival rate was 11%. The authors

concluded that super-radical surgery may provide a survival

advantage in selected patients187. Similarly, in a study by Brown

et al.188, aggressive complete surgery, including laryngectomy

and oesophagectomy, followed by radiotherapy, showed a

survival advantage in selected patients with stage IVb disease

(without distant metastasis or invasion into the lateral aspect of

the carotid artery). In this series, 14 of 16 operated patients did

not develop local recurrence.

According to a preliminary analysis of the Eurocrine® database,

outcomes of 253 patients who had surgery between 2015 and 2021

revealed that achieving an R0 resection seemed to increase life

expectancy. Meanwhile, only 20% of operated patients received

R0 and 44% R1 resection. Mean tumour size was 52.5 mm.

Postoperative vocal cord paralysis rates were 45, 41, and 35% for

R0, R1, and R2 resections respectively. According to the Clavien–

Dindo classification, morbidity was significantly higher after R2

procedures. Metastasis rates were 33% in R0, 42% in R1, and 72%

in R2 resections. The median survival rate was 100 days. Life

expectancy was highest after R0 procedures (260 days for R0,

159 days for R1, and 78 days for R2). Regarding neoadjuvant

therapy, no significant difference was found between groups

(P = 0.56). The use of neoadjuvant therapy had no impact on

postoperative vocal cord palsy rates and morbidity (P = 0.11).

Neoadjuvant treatment tended to have a favourable effect on

survival time, but the numbers of patients were not adequate to

yield a significant result (unpublished data - M.R., N.V., T.M.).

Evaluating the past 30 years of ATC treatment has revealed an

improvement in survival in the past 10 years. Surgical treatment

still seems to be the only definitive cure option. There is consensus

in stage IVa disease, and surgical treatment of resectable disease is

recommended5,184,185. In stage IVb disease, surgical treatment is

more controversial and should be tailored. The most common

causes of death are related to local invasion, such as respiratory

failure, bleeding, malnutrition, and vena cava syndrome.

When stage IVb disease is deemed resectable, aggressive R0/R1

resection is considered advantageous with individualized,

multidisciplinary evaluation and treatment5,170,176,187,188. There

is almost complete consensus among publications that R2

16 | BJS, 2024, Vol. 111, No. 8

resection does not provide an advantage, and that it increases

patient morbidity and 30-day mortality170,172,176. There is a lack

of objective and evidence-based criteria for deciding which

patients with stage IVb disease should undergo surgical

treatment. In stage IVc and unresectable stage IVb disease,

neoadjuvant targeted therapies that have emerged in recent

years offer some hope. Neoadjuvant treatments may render

tumours resectable, and surgical treatment can subsequently be

attempted. More studies are needed to strengthen and validate

these results. Palliative surgery of the primary tumour is only

recommended for patients to avoid lethal complications. There

are, however, studies170,176 showing that local control of the

disease can reduce mortality caused by the invasion of vital

structures by the tumour.

Statement 40: For stage IVa/IVb ATC, where R0 and R1

resection is anticipated, surgical intervention is recommended,

after thorough patient counselling and MDT discussion.

Consensus: Yes (7.88)

Outliers: 2

Evidence level: Low

Statement 41: Patients with distant metastasis (stage IVc) may

be considered for surgical treatment for:

Palliative reasons or to prevent imminent complications of

local involvement.

Near-consensus: (6.85) Rejected

Outliers: 19 (7 negative)

Evidence level: Low

GA voting: Agree: 60.33%, Disagree: 31.52%, Neutral: 8.15%

Palliative reasons only.

Consensus: No (4.58)

Outliers: 15

Evidence level: Low

Preventing imminent complications of local involvement

only.

Consensus: No (5.28)

Outliers: 20

Evidence level: Low

Statement 42: In selected patients with distant metastasis

(stage IVc), if locoregional R0/R1 resection is anticipated,

decisions on possible surgical intervention should be tailored,

after thorough patient counselling and MDT discussion.

Consensus: Yes (7.56)

Outliers: 3

Evidence level: Low

Statement 43: Local control in the treatment of ATC may

improve patient quality of life, and provides control of the

causes of death owing to local invasion.

Consensus: Yes (7.61)

Outliers: 2

Evidence level: Low

Statement 44: Total thyroidectomy, with appropriate

therapeutic dissection of the central and lateral neck lymph

node compartments, is the optimal surgical treatment in

patients with resectable disease involving both lobes.

Consensus: Yes (7.66)

Outliers: 3

Evidence level: Low

Statement 45: For unilateral intrathyroidal tumours, when R0

resection can be achieved with hemithyroidectomy:

It should be preferred over total thyroidectomy.

Consensus: No (6.00)

Outliers: 21

Evidence level: Low

It should be preferred only in patients with unilateral RLN

invasion to avoid potential bilateral vocal cord paralysis.

Consensus: No (5.18)

Outliers: 22

Evidence level: Low

Neoadjuvant and new systemic therapy options

The shift from traditional chemotherapy to targeted therapy

inhibiting specific driver mutations (selective kinase inhibitors)

or immunotherapy has changed the ATC treatment pathway.

The increased efficacy of new drugs in reducing tumour burden

has paved the way for attempts at neoadjuvant therapy to

facilitate subsequent surgical resection.

In one study78, six patients with BRAF V600E-mutated ATC

underwent neoadjuvant dabrafenib and trametinib therapy

followed by surgery and adjuvant chemoradiation. Four patients

had stage IVb and two had stage IVc diseae. R0 resection was

achieved in four patients and R1 resection in two. Two of six

patients died during follow-up from disease progression at distant

sites. The remaining patients had no evidence of structural

disease at the time of last follow-up (median follow-up from start

of neoadjuvant therapy 15 months (range: 6.4–25.2). Similar

results were reported in a case series175 that including one patient

presenting with a BRAF-mutated ATC who received neoadjuvant

dabrafenib and trametinib therapy, and two patients with

wild-type BRAF who had immunotherapy (pembrolizumab in

combination with lenvatinib). Postoperative histology revealed

two R0 and one R1 resections. These experiences demonstrated

the feasibility of this approach, it being associated with complete

resections and durable locoregional control. Evidence for the

value of using neoadjuvant, targeted therapies has also emerged

from a study66 that comparing historical cohorts and treatment

strategies. Patients were divided into three groups based on the

time of diagnosis and treatment, 2000–2013, 2014–2016, and 2017–

2019. The average survival time was 0.67, 0.88, and 1.31 years

respectively. Multifactorial analysis showed that the 2017–2019

group was significantly associated with better survival. Notably,

targeted therapies were only administered to patients in the 2017–

2019 group, and 20 patients (8 of whom had stage IVc disease)

underwent surgery after neoadjuvant BRAF inhibitor therapy,

with an average 1-year survival rate of 94%.

Neck radiotherapy, systemic therapy, or the combination of

both after complete or near-complete resection (R0 or R1)

should be considered after surgery, as they have been

associated with a lower rate of locoregional recurrence or

progression, and more favourable long-term survival5,6

. No

evidence is available yet on the value of targeted therapy or

immunotherapy in an adjuvant setting.

Final approval in the dedicated general assembly meeting

After a thorough discussion of the results, a separate vote was

held to approve the above position statement in its entirety. Of

the 184 participants, 173 (93.51%) voted in favour, 8 (4.32%)

remained neutral, and 4 (2.16%) voted against the statement.

Raffaelli et al. | 17

The present position statement was thus approved by the ESES

members and could represent a guide for uniform definition,

management, and treatment of patients with advanced thyroid

carcinomas.

Funding

The authors have no funding to declare.

Acknowledgements

The authors thank all panellists who contributed insightful

comments and feedback during the Delphi process: E. Mirallié,

M. Almquist, T. Clerici, E. Nieveen van Dijkum, A. Zielke,

D. Scott-Coombes, A. Goldmann, R. Kralik, J. M. Villar del Moral,

S. Van Slycke, F. Triponez, M. Iacobone, S. Cherenko, P. Riss,

C. Martinez Santos, F. Palazzo, R. Kaderli, I.-L. Nilsson, Z. Narbuts,

S. Schmidt, N. Besic, M.-L. Matthey Giè, N. Slijepcevic, O. Gimm,

T. Zingg, R. Koeberle Wuehrer, and F. Gyory.

Author contributions

Marco Raffaelli (Conceptualization, Data curation, Formal analysis,

Methodology, Supervision, Writing—original draft, Writing—

review & editing), Nikolaos Voloudakis (Conceptualization, Data

curation, Formal analysis, Methodology, Writing—original draft,

Writing—review & editing), Marcin Barczyń

ski (Supervision,

Writing—review & editing), Katrin Brauckhoff (Writing—original

draft, Writing—review & editing), Cosimo Durante

(Conceptualization, Methodology, Writing—original draft, Writing—

review & editing), Joaquin Gomez-Ramirez (Conceptualization,

Methodology, Writing—original draft, Writing—review & editing),

Ioannis Koutelidakis (Conceptualization, Methodology, Writing—

original draft, Writing—review & editing), Kerstin Lorenz

(Conceptualization, Methodology, Writing—original draft, Writing—

review & editing), Ozer Makay (Conceptualization, Methodology,

Writing—original draft, Writing—review & editing), Gabriele

Materazzi (Methodology, Writing—original draft, Writing—review

& editing), Rumen Pandev (Methodology, Writing—original draft,

Writing—review & editing), Gregory Randolph (Supervision,

Writing—review & editing), Neil Tolley (Methodology, Writing—

original draft, Writing—review & editing), Menno Vriens

(Methodology, Writing—original draft, Writing—review & editing),

and Thomas Musholt (Conceptualization, Methodology,

Supervision, Writing—original draft, Writing—review & editing)

Disclosure

The authors declare no conflict of interest.

Supplementary material

Supplementary material is available at BJS online.

Data availability

The data that support the findings of this study are openly

available in Figshare at http://doi.org/10.6084/m9.figshare.

25060868189. Further data can be made available upon

reasonable request to the corresponding author.

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