Clinical Thyroidology / Original Paper

Eur Thyroid J 2018;7:319–326 Received: June 11, 2018

Accepted: August 24, 2018
DOI: 10.1159/000493261 Published online: September 28, 2018

Differentiated Thyroid Cancer:

How Do Current Practice Guidelines
Affect Management?
Patrick W. Owens a Terri P. McVeigh a, b Eoin J. Fahey a Marcia Bell c
       

Denis S. Quill a Michael J. Kerin a Aoife J. Lowery a

     

a Discipline
of Surgery, Lambe Institute for Translational Research, NUI Galway, Galway, Ireland; b Cancer Genetics
 

Unit, The Royal Marsden NHS Foundation Trust, London, UK; c Department of Endocrinology, Galway University
 

Hospital, Galway, Ireland

Keywords dedicated thyroid cancer clinic between August 2014 and

Differentiated thyroid cancer · Papillary cancer · Follicular August 2017 were included. Clinicopathological characteris-
cancer · Guidelines · Risk stratification · British Thyroid tics and management strategies were assessed. Results:
Association Ninety-four percent (n = 168/178) of patients were surgically
managed in adherence with guidelines. A minority (n = 10)
received surgery not aligned with guidelines. Ninety-seven
Abstract percent (n = 172/178) of RRA treatment decisions were in ac-
Background: International best-practice guidelines recom- cordance with guidelines. The BTA guidelines recommend-
mend completion thyroidectomy and radioiodine remnant ed a personalised decision-making approach for 18.0% (n =
ablation (RRA) for patients with differentiated thyroid cancer 32) and 44.9% (n = 80) of surgery and RRA treatment deci-
(DTC) > 4 cm or with specific risk factors. Patients with DTC sions, respectively. The more aggressive, treatment-driven
<1 cm without risk factors are recommended for lobectomy approach was typically favoured by the multidisciplinary
alone. Indications for aggressive surgery and RRA are less team, with 97% (n = 31/32) undergoing completion thyroid-
clearly defined for tumours measuring 1–4 cm. A person- ectomy and 100% (n = 80) proceeding to RRA. Conclusions:
alised approach to decision-making is recommended. Ob- Management of DTC at our institution closely adheres to
jectives: This study assesses therapeutic approaches to DTC contemporary clinical practice guidelines. The finding of
as compared to the current British Thyroid Association (BTA) more aggressive management in those requiring a person-
clinical practice guidelines. We ascertained the effect of alised decision-making approach highlights the require-
equivocal guidance in the 1–4 cm tumour cohort on contem- ment for improved risk stratification in this cohort to ratio­
porary practice patterns. Methods: Data were obtained from nalise management strategies. © 2018 European Thyroid Association
a prospectively maintained thyroid cancer database of pa- Published by S. Karger AG, Basel

tients treated for DTC in a tertiary referral centre at the Uni-

versity Hospital Galway. Consecutive patients attending a

© 2018 European Thyroid Association Patrick W. Owens

Published by S. Karger AG, Basel Lambe Institute for Translational Research, NUI Galway
Costello Road
E-Mail karger@karger.com
Galway H91 V4AY (Ireland)
www.karger.com/etj E-Mail patrickowens1 @ gmail.com
 Introduction distant metastases. Patients with tumours ≤1 cm without
risk factors do not benefit from RRA. Personalised deci-
Thyroid cancer (TC) is the most common endocrine sion-making is advised for those with tumours measuring
malignancy, accounting for 1% of all cancers, with an in- 1–4 cm without risk factors [9].
cidence of 162 cases per year in Ireland [1]. The National We aimed to describe the patterns of DTC presenta-
Cancer Registry Ireland reports increasing incidence of tion and treatment strategies and to assess the degree of
TC from 60 per year during the mid 1990s to 160 per year adherence to clinical practice guidelines (BTA 2014) in
during the late 2000s [1]. Similar trends are reported patients treated for DTC at our institution. We further
worldwide, including the United Kingdom, the United examined those patients where a personalised decision-
States, and South Korea [2–4]. This observed increased making approach was recommended and how this subset
incidence primarily comprises differentiated TC (DTC), was managed in the context of equivocal guidelines.
without a concomitant increase in mortality, suggesting
potential overdiagnosis of indolent pathology [4–7]. In
Ireland, the 5-year TC survival rate has improved from Materials and Methods
71% (1994–1998) to 91.8% (2010–2014), while the 5-year
Data were prospectively recorded from consecutive patients at-
DTC-specific survival is 98% [1]. Data from 51,061 DTC
tending a specialist TC clinic in a tertiary referral centre (Univer-
patients from the US Surveillance, Epidemiology, and sity Hospital Galway) over 3 years (August 2014–2017). Data col-
End Results database report an overall 5-year survival of lection was undertaken at the time of blood and sputum sample
96.5% [8]. The mainstay of TC treatment involves surgi- collection for inclusion in the University Hospital Galway TC Bio-
cal resection with or without adjuvant radioiodine rem- Bank. Patient demographics, tumour histology, and staging pa-
rameters were recorded, in addition to surgical and RRA man­
nant ablation (RRA); it follows that overdiagnosis of DTC
agement strategies. All patients were discussed in an endocrine
results in potentially avoidable morbidity arising from surgery multidisciplinary team. TC staging and FNAC were desig-
surgical or RRA therapies. nated as per the AJCC Cancer Staging Manual (7th edition) and
The key recommendations of the British Thyroid As- the UK Royal College of Pathologists thyroid cytology guidelines,
sociation (BTA) 2014 guidelines for the management of respectively [10, 11]. The BTA guidelines for the management of
thyroid cancer were accepted as best-practice guidelines [9]. Data
thyroid cancer include diagnostic lobectomy for those
recording and statistical analysis were performed using Microsoft
with Thy3 or Thy4 fine-needle aspiration cytology Excel and IBM SPSS v22. Pearson’s χ2 test was used to compare
(FNAC). Total thyroidectomy (TT) is advised for patients categorical variables, while one-way ANOVA with Tukey post hoc
with Thy5 FNAC or with confirmed DTC following diag- analyses was utilised for comparing three or more categorical, in-
nostic lobectomy where tumour size exceeds 4 cm or dependent samples.
measures any size with risk factors including multifocal,
bilateral, extrathyroidal, or familial disease, and those
with clinically or radiologically involved nodes or distant Results
metastases. Lobectomy alone is deemed sufficient for pa-
tients with unifocal papillary thyroid microcarcinoma Data were collected from 178 consecutive patients. Of
(microPTC, < 1 cm) without risk factors; these include these, 130 patients (73%) were female. The median age at
multifocality, larger size (6–10 mm), extrathyroidal ex- diagnosis was 43.5 years (range 15–83 years). One hun-
tension, poor differentiation, and desmoplastic fibrosis dred and fifty-two patients (85%) had papillary TC while
or an infiltrative growth pattern. There is a paucity of 26 (15%) had follicular TC. The median tumour size was
peer-reviewed randomised or prospective studies to sup- 26 mm (range 1–110 mm). Multifocal disease was present
port an advantage of TT over lobectomy in patients with in 36% of patients (n = 64). Lymphovascular invasion and
unifocal tumours measuring 1–4 cm without risk factors. extracapsular extension were evident in 33% (n = 58) and
In these cases, the BTA guidelines recommend a person- 31% (n = 55) of tumours, respectively. Forty-eight per-
alised decision-making approach, which advocates a cent (n = 86) had lymph nodes excised, with a mean har-
shared doctor-patient decision-making process in con- vest of 7.6 ± 8.5 nodes. Thirty-four patients had con-
junction with multidisciplinary team input, with due firmed lymph node metastases, representing 40% of those
consideration for recurrence risk, patient comorbidities, with nodes excised and 19% of all patients. The average
and personal circumstances and values [9]. number of positive nodes retrieved was 4.7 ± 4.4.
The BTA recommends RRA for all patients with DTC FNAC results were available for 77% of patients (n =
>4 cm or any size with gross extrathyroidal extension or 118) (Fig. 1). All 13 patients with Thy5 FNAC underwent

320 Eur Thyroid J 2018;7:319–326 Owens/McVeigh/Fahey/Bell/Quill/Kerin/

DOI: 10.1159/000493261 Lowery
 Color version available online
80
Primary total thyroidectomy
70
Completion thyroidectomy
60 Lobectomy alone

Number of patients
50

40

30

20

10

0
No FNAC Thy1 Thy2 Thy3 Thy4 Thy5
Royal College of Pathologists Thy category
Fig. 1. Surgical management per Royal Col-
lege of Pathologists Thy category.

Table 1. Clinicopathological parameters based on surgical outcome

Primary TT Lobectomy alone Lobectomy followed by

completion thyroidectomy

Number of patients 67 (38%) 6 (3%) 105 (60%)

Female 51 (76%) 2 (33%) 77 (73%)
Age, years 46±16 50±23 46±16
Preoperative FNAC Thy1 3 (5%) 0 (0%) 7 (7%)
Preoperative FNAC Thy2 6 (9%) 0 (0%) 13 (12%)
Preoperative FNAC Thy3 12 (18%) 5 (83%) 57 (54%)
Preoperative FNAC Thy4 15 (22%) 1 (17%) 5 (5%)
Preoperative FNAC Thy5 13 (19%) 0 (0%) 0 (0%)
No preoperative FNAC 18 (27%) 0 (0%) 23 (22%)
Papillary (final histology) 61 (91%) 5 (83%) 86 (82%)
Follicular (final histology) 6 (9%) 1 (17%) 19 (18%)
Size, mm 22 (2–110) 5.25 (2–65) 30 (1–110)
Multifocal 26 (39%) 0 (0%) 38 (36%)
Nodal disease 25 (37%) 0 (0%) 9 (9%)
Lymphovascular invasion 29 (43%) 1 (17%) 28 (27%)
Extracapsular extension 23 (34%) 1 (17%) 31 (30%)

Values are presented as n (%), mean ± SD, or median (range). FNAC, fine-needle aspiration cytology; TT, total thyroidectomy.

primary TT. Primary TT was also performed for 3, 6, 12, Surgery

and 15 patients with Thy1–4 FNACs, respectively. Of Thirty-eight percent of patients (n = 67) underwent
these 36 patients, 24 had features identified on preopera- primary TT. Sixty-two percent (n = 111) had thyroid lo-
tive imaging indicating TT (size >4 cm, lymphadenopa- bectomy, with 95% of those (n = 105/111) proceeding to
thy, extracapsular or bilateral disease). TT was performed completion thyroidectomy (Table 1). Six patients (3%)
for benign indications (e.g., multinodular goitre, Graves’ had lobectomy alone; these were more likely to be male
disease) in 9 patients, while 3 patients had no definitive (68%, n = 4/6) compared to those who proceeded to com-
indication for upfront TT. pletion thyroidectomy (27%, n = 28/105) (p = 0.031). Tu-
mour size >4 cm, multifocality, and extracapsular exten-

DTC: How Current Guidelines Affect Eur Thyroid J 2018;7:319–326 321

Management DOI: 10.1159/000493261
 Table 2. Surgical management compliance with the BTA 2014 guidelines

Patients Compliant with

BTA guidelines

All patients 178 (100%) 168 (94%)

<1 cm 27 (15%) 18 (67%)
1–4 cm 113 (63%) 113 (100%)
>4 cm 38 (21%) 37 (97%)
Multifocal 64 (36%) 64 (100%)
Lymphovascular invasion 58 (33%) 57 (98%)
Extracapsular extension 55 (31%) 54 (98%)
Age >45 years 86 (48%) 79 (92%)

Values are presented as n (%). BTA, British Thyroid Association.

Table 3. Clinicopathological details for patients where the BTA recommended a personalised decision-making
approach (n = 178)

PDM recommended for PDM recommended for

surgical management (n = 32) RRA management (n = 80)

Had thyroidectomy/RRA 31 (97%) 66 (83%)

Female 25 (78%) 66 (83%)
Age, years 37±10 43±15
Papillary cancer 28 (88%) 70 (88%)
Follicular cancer 4 (13%) 10 (12%)
Size, mm 21 (2–40) 22 (10–40)
<1 cm 8 (25%) 1 (1%)
1–4 cm 24 (75%) 79 (99%)
>4 cm 0 (0%) 0 (0%)
Multifocal disease 4 (all microPTC) 30 (38%)

Values are presented as n (%), mean ± SD, or median (range). BTA, British Thyroid Association; microPTC,
papillary thyroid microcarcinoma; PDM, personalised decision-making; RRA, radioiodine remnant ablation.

sion were associated with an increased rate of completion diological lymphadenopathy and a recent history of me­
thyroidectomy compared to lobectomy alone (p = 0.044, tachronous laryngeal cancer. The remaining 2 patients
p = 0.027, and p = 0.044, respectively). No significant as- proceeded to completion thyroidectomy based on prefer-
sociation was observed between histological subtype or ence alone, with age >45 years being their only relative
age and surgical procedure. risk factor for recurrence. The rate of surgical manage-
Ninety-four percent of patients (n = 168/178) were ment in agreement with the guidelines was not signifi-
surgically managed in strict adherence with the BTA cantly affected by sex (p = 0.824), age > 45 years (p =
guidelines (Table 2). Of those not aligned with the guide- 0.158), or histological subtype (p = 0.671).
lines (n = 10), 1 had a tumour >4 cm at lobectomy, but Personalised decision-making was recommended fol-
declined completion thyroidectomy. Nine patients had lowing thyroid lobectomy in 32 patients (Table 3); 24 pa-
tumours <1 cm without risk factors, of whom 4 had pri- tients had intermediate size tumours (1–4 cm) without
mary TT for multinodular goitre causing mass effect. Five risk factors, 4 had microPTC measuring 6–10 mm, while
patients had interval completion thyroidectomy follow- 4 with microPTC <6 mm exhibited multifocal disease. A
ing lobectomy where not indicated by guidelines, and 2 more aggressive, treatment-driven approach was typical-
due to personal preference on a background of thyroid ly favoured by patients and the multidisciplinary team,
tumour family history; another patient had interval ra- with 97% (n = 31/32) proceeding to completion thyroid-

322 Eur Thyroid J 2018;7:319–326 Owens/McVeigh/Fahey/Bell/Quill/Kerin/

DOI: 10.1159/000493261 Lowery
ectomy; 1 patient with a unifocal 15-mm papillary TC resulting in lower recurrence rates and improved surviv-
without risk factors opted for lobectomy alone. al for all patients with DTC >1 cm [12, 13]. More recent-
ly, recognition of relevant prognosticators has improved
Radioiodine Remnant Ablation risk stratification such that low-risk patients with tu-
Eighty-two percent of patients (n = 146/178) under- mours >1 cm may be treated with more selective and in-
went adjuvant RRA. RRA was more likely to be utilised in dividualised approaches while maintaining improved
patients with node positivity (p = 0.002), lymphovascular outcomes [14–17]. This is evidenced by incremental
invasion (p < 0.001), or extracapsular disease (p = 0.001). guideline amendments towards more conservative ap-
RRA utilisation was not affected by sex (p = 0.547), age proaches; the 2009 American Thyroid Association (ATA)
> 45 years (p = 0.203), histological subtype type (p = and the 2006 European Thyroid Cancer Consensus guide-
0.139), or multifocality (p = 0.067). lines both previously recommended TT for DTC >1 cm,
In relation to the BTA guidelines, 43% of patients (n = while the more recent 2014 BTA and 2015 ATA guide-
77) had definitive indications for RRA, while 12% (n = 21) lines now suggest lobectomy alone as an option for those
had definitive recommendations against RRA. A person- with tumours 1–4 cm without risk factors. Emerging evi-
alised decision-making approach was recommended for dence also advocates active surveillance for microPTC,
45% of patients (n = 80), with 66 of those (83%) progress- with interval growth over 5 years observed in < 15% of
ing to RRA (Table 3). Ninety-seven percent (n = 172/178) patients [18, 19]. Improved identification and classifica-
of RRA treatment decisions satisfied the 2014 BTA guide- tion of indolent subtypes further improves risk stratifica-
lines; 1 patient recommended for RRA due to extrathy- tion; the encapsulated follicular variant of papillary TC
roidal extension declined, while the remaining 6 patients has recently been re-designated as non-invasive follicular
received RRA outside of the BTA recommendations. thyroid neoplasm with papillary-like nuclear features, ef-
None of these 6 patients had definitive RRA indications; fectively reclassifying it as non-cancerous [20].
however, 2 had weaker risk factors for recurrence, one Almost half of our cohort was subject to the equivocal
with unilateral multifocal microPTC, the other being >45 BTA guidelines, whereby a personalised decision-making
years old. Agreement with the BTA recommendations approach was suggested. These patients typically had in-
was not significantly affected by sex (p = 0.721), age >45 termediate-sized tumours without specific recurrence risk
years (p = 0.115), or histological subtype (p = 0.884). Pa- factors. Despite large retrospective cohort studies, the in-
tients with tumours measuring <1 cm were more likely to frequency of mortality and disease recurrence events seen
undergo RRA management differing from the BTA rec- in this cohort poses a challenge for the development of
ommendations (i.e., proceeding to RRA) when compared definitive evidence-based guidelines. In the absence of
to patients in the 1–4 cm or >4 cm subgroups (p < 0.001). specific recommendations, the personalised decision-
making approach encourages consideration of factors
such as patient preference, age, comorbidity, performance
Discussion status, ability to engage with contralateral lobe follow-up,
and the potential impact of surgical complications. Clini-
This study assessed the DTC management patterns in cian preference, surgeon complication rates, and tumour
an Irish tertiary referral centre, with a focus on patients parameters tending towards guideline cut-offs (e.g., size
with intermediate-size, low-risk tumours, where a pau- approaching 1 or 4 cm) should also be considered. Almost
city of evidence prevents guidelines from supporting a all patients in our cohort who were recommended for a
definitive therapeutic approach. DTC treatment strate- personalised decision-making approach proceeded to the
gies were largely in agreement with best-practice recom- more aggressive options of completion surgery and RRA.
mendations, with concordance demonstrated in 94% of The absence of sufficient evidence to support a definitive
surgical and 97% of RRA therapeutic decisions. Where treatment course in these patients despite multiple large
discordance with guidelines was demonstrated, there was retrospective studies suggests that any benefit gained by
a tendency towards overtreatment, with 9 out of 10 surgi- this strategy is likely to be small [21]. Furthermore, the
cal and 5 out of 6 RRA treatment decisions resulting in a improved efficacy of treatments for recurrent DTC is such
more aggressive treatment (TT and RRA) where lobec- that the lower risk of recurrence for patients in the person-
tomy and no RRA was recommended. Early studies ex- alised decision-making cohort may be acceptable, given
amining the appropriate surgical management of DTC the benefit of avoiding a second surgery and exposure to
initially suggested a one size fits all approach with TT, RRA. Benefits gained by the more aggressive options may

DTC: How Current Guidelines Affect Eur Thyroid J 2018;7:319–326 323

Management DOI: 10.1159/000493261
be outweighed by both physical and psychological mor- tors. Molecular markers including gene expression pro-
bidity. The impact of extended patient waiting times, from files, somatic gene alterations, and circulating biomark-
initial diagnostic imaging and FNAC to thyroid lobecto- ers provide improved indices for diagnosis and prognos-
my, subsequent completion surgery, and onward to RRA, tication [32]. Alterations in the MAPK and PI3K-AKT
is extensive, resulting in substantial psychological mor- major signalling pathways have recently been elucidated
bidity [22]. Surgical complications are also considerable as primary pathogenetic events in DTC carcinogenesis
and include transient (8%) and permanent (2%) hyper- [33]. The 2015 ATA guidelines now advocate consider-
parathyroidism, permanent (1%), transient (2%), and di- ation of BRAFV600E proto-oncogene mutation status, if
plegic (0.4%) palsies of the recurrent laryngeal nerve, su- known, in their modified risk stratification system, al-
perior thyroid nerve injury (4%), and dysphagia (1%) [23]. though testing is not routinely advocated. The guidelines
There are also financial implications; thyroid lobectomy also acknowledge other gene mutations and rearrange-
costs EUR 5,277 per patient in Europe, including presur- ments such as BRAF, TERT, TP53, RAS, or PAX8/
gical workup, follow-up, and management of complica- PPARγ, although these are not recommended for rou-
tions over 12 months [24], in addition to the lifelong cost tine testing [34]. Rather than assessing for individual
of thyroxine replacement, follow-up, and monitoring as- high-impact mutations, commercially available risk as-
sociated with TT. In New South Wales, Australia, the in- sessment tools analyse panels of mutations, each with
creased volume of DTC treatments from 2002 to 2012, for smaller odds ratios for recurrence and mortality, but
a population of 7.5 million, has cost an additional AUD with promising overall accuracy. These include the Afir-
18,600,000 in surgery-related healthcare expenditure [25]. ma Gene Expression Classifier and the ThyroSeq Next-
RRA is also associated with significant side effects. Generation Sequencing panel. These adjuncts have dem-
Twenty percent of patients experience nausea, taste and onstrated encouraging results in the risk stratification of
smell impairment, or sialadenitis. More significant com- patients with indeterminate FNAC where diagnostic lo-
plications include impairment of haematopoiesis and go- bectomy is frequently required [35, 36]. In correctly
nadal function and increased risk for second primary identifying DTC from FNAC samples, ThyroSeq v2.1 re-
malignancies, both solid and haematological. A dose of ports a sensitivity of 91% (95% CI 79–100) and a specific-
100 mCi (3.7 GBq) of radioiodine has been estimated to ity of 92% (95% CI 86–98) [36]. This application of mo-
result in an extra 56 malignancies per 10,000 patients over lecular risk stratification may help reduce the number of
10 years [24], while Rubino et al. [26] observed up to 30% diagnostic thyroid lobectomies undertaken; over one-
dose-dependent increased risk for second primary malig- third of the patients in our cohort had initial Thy3 FNAC
nancies following RRA. results, with three-quarters of these requiring comple-
While DTC has a relatively good prognosis compared tion thyroidectomy. However, while multiple studies
to other malignancies, there remains a recurrence risk of have evaluated the utility of molecular testing in patients
5–30%, and approximately 10% of patients die of this can- with indeterminate thyroid nodules, there is a paucity of
cer [8, 27–29]. Improved risk stratification is warranted research examining the use of such markers in surgical
to identify patients at risk of mortality and recurrence. and RRA management decisions after thyroid lobectomy
Multiple risk factor assessment tools exist for estimat- for DTC [32, 37].
ing DTC mortality. Prognostication systems include the
AJCC/UICC TNM system (Tumour Nodes Metastases),
AMES (Age, Metastases, Extent, Size), MACIS (Metasta- Conclusions
ses, Age, Completeness of resection, Extrathyroidal, Size),
EORTC (European Organisation for Research and Treat- DTC management in our cohort exhibited high levels
ment of Cancer methodology), and AGES (Age, Grade, of adherence to internationally recognised best-practice
Extent, Size) [30, 31]. These prognostication systems, us- guidelines. Where surgical and RRA therapeutic deci-
ing traditional demographic and staging parameters and sions did not satisfy the guidelines, more aggressive man-
focusing predominantly on mortality rather than recur- agement approaches were usually adopted.
rence risk, have largely failed to guide management in a A large proportion of patients are subject to a person-
large subset of patients, as demonstrated by the equivocal alised decision-making approach, owing to a lack of con-
BTA 2014 guidelines for low-risk intermediate-size DTC. clusive high-level evidence to guide management. A ten-
Advances in molecular medicine have improved the dency towards more aggressive surgical and RRA inter-
understanding of DTC carcinogenesis and risk indica- vention was observed in this group.

324 Eur Thyroid J 2018;7:319–326 Owens/McVeigh/Fahey/Bell/Quill/Kerin/

DOI: 10.1159/000493261 Lowery
 These findings highlight the requirement for improved Statement of Ethics
risk stratification to rationalise management strategies
All patients provided informed written consent, which was eth-
and avoid overtreatment of patients who fall into indeter- ically approved by the University Hospital Galway research ethics
minate-risk treatment groups. committee.

Acknowledgements Disclosure Statement

This work was completed as part of an MD thesis and was sup- The authors declare no conflicts of interest.
ported by Breast Cancer Research at the Lambe Institute for Trans-
lational Research, Galway, Ireland (no specific grant number).

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DOI: 10.1159/000493261 Lowery