10.14639/0392-100X-N1572
The 2015 ATA guidelines and 2018 Italian Consensus have produced a series of generally concordant recommendations on clinical and therapeutic management of thyroid nodules and thyroid carcinoma. Currently, the goals of treatment are to achieve the highest diseasefree survival rates through the best ratio between minimum invasiveness and cost/impact on quality of life. By analysis and comparison of the ATA Guidelines and Italian Consensus, we highlighted and commented upon the key points of differentiated thyroid cancer management. Furthermore, the aim of this work is to identify and promote uniform clinical approaches among all specialists who treat differentiated thyroid cancer and represent a starting point for a consensus drafted by the Italian Society of Otolaryngology - Head and Neck Surgery.
text/xml
1827-675X
1572
en
Nicola Palestini
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
thyroid nodule
Comparison between 2015 ATA guidelines and Italian Consensus for DTC management. A commented report
Text.Serial.Journal
https://www.actaitalica.it/
42
Thyroid
2022-03-07
2021-03-20
2022-03-07
2022-03-07
41-54
1
Nicola Palestini
2022/03/07
10.14639/0392-100X-N1572
41
Head Neck Oncology Unit, Candiolo Cancer Institute, FPO IRCCS, Italy
1827-675X
thyroid nodule
54
Comparison between 2015 ATA guidelines and Italian Consensus for DTC management. A commented report
https://www.actaitalica.it/article/download/1572/739
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:41-54; doi: 10.14639/0392-100X-N1572




Thyroid


Comparison between 2015 ATA guidelines and Italian
Consensus for DTC management. A commented
report
Confronto critico fra le linee guida ATA e il Consensus italiano sul trattamento del DTC
Giulia Arrigoni1, Erika Crosetti2, Milena Freddi2, Alessandro Piovesan3, Ruth Rossetto Giaccherino4,
Giovanni Succo5,6, Nicola Palestini2
1
  ENT Department, Chivasso Hospital, ASL TO4, Chivasso, Italy; 2 Head Neck Oncology Unit, Candiolo Cancer Institute, FPO
IRCCS, Italy; 3 Oncological Endocrinology Unit, Department of Medical Sciences, University of Turin, Città della Salute e della
Scienza, Turin, Italy; 4 Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin,
Città della Salute e della Scienza, Turin, Italy; 5 Oncology Dept. University of Turin, Italy; 6 Otolaryngology - Head and Neck Unit,
San Giovanni Bosco Hospital, Turin, Italy


SUMMARY
The 2015 ATA guidelines and 2018 Italian Consensus have produced a series of generally
concordant recommendations on clinical and therapeutic management of thyroid nodules
and thyroid carcinoma. Currently, the goals of treatment are to achieve the highest disease-
free survival rates through the best ratio between minimum invasiveness and cost/impact on
quality of life. By analysis and comparison of the ATA Guidelines and Italian Consensus,
we highlighted and commented upon the key points of differentiated thyroid cancer man-
agement. Furthermore, the aim of this work is to identify and promote uniform clinical
approaches among all specialists who treat differentiated thyroid cancer and represent a
starting point for a consensus drafted by the Italian Society of Otolaryngology - Head and
Neck Surgery.
KEY WORDS: guidelines, differentiated thyroid cancer, consensus, thyroid, thyroid nodule

RIASSUNTO                                                                                          Received: March 20, 2021
Le linee guida ATA 2015 e il Consenso Italiano 2018 hanno prodotto una serie di rac-               Accepted: November 16, 2021
comandazioni generalmente concordanti sulla gestione clinica e terapeutica dei noduli
tiroidei e del carcinoma tiroideo. Attualmente, gli obiettivi del trattamento prevedono il         Correspondence
raggiungimento di alti tassi di sopravvivenza libera da malattia, un miglior rapporto tra          Giulia Arrigoni
                                                                                                   ENT Department, Chivasso Hospital, ASL TO4,
minima invasività e costo/impatto sulla qualità della vita. Analizzando e confrontando le
                                                                                                   corso Galileo Ferraris 3, 10034 Chivasso, Italy
Linee Guida ATA e il Consenso Italiano abbiamo evidenziato e commentato i punti chiave             E-mail: giulia.arrix@gmail.com
sulla gestione differente dei tumori tiroidei. Inoltre, lo scopo di questo lavoro è identificare
e promuovere approcci clinici uniformi tra tutti gli specialisti che trattano il cancro diffe-
renziato della tiroide e, infine, rappresentare un punto di partenza per un consenso redatto         How to cite this article: Arrigoni G, Crosetti
dalla Società Italiana di Otorinolaringoiatria - Chirurgia Cervico Facciale.                         E, Freddi M, et al. Comparison between 2015
                                                                                                     ATA guidelines and Italian Consensus for DTC
PAROLE CHIAVE: linee guida, carcinoma tiroideo differenziato, consenso, tiroide, nodulo              management. A commented report. Acta Otorhi-
tiroideo                                                                                             nolaryngol Ital 2022;42:41-54. https://doi.
                                                                                                     org/10.14639/0392-100X-N1572

Introduction                                                                                       © Società Italiana di Otorinolaringoiatria
                                                                                                   e Chirurgia Cervico-Facciale
Differentiated thyroid cancer (DTC) has recently emerged as one of the most
rapidly increasing human cancers worldwide. Nowadays, a large majority of                                         OPEN ACCESS
these cancers is constituted by small non-palpable papillary thyroid tumours,                      This is an open access article distributed in accordance with
                                                                                                   the CC-BY-NC-ND (Creative Commons Attribution-Non-
whose prognosis is generally excellent. The widespread diffusion of high sensi-                    Commercial-NoDerivatives 4.0 International) license. The
tivity diagnostic tools like thyroid sonography (US) and cytology on fine needle                   article can be used by giving appropriate credit and mentio-
                                                                                                   ning the license, but only for non-commercial purposes and
aspiration (FNA) has enhanced its diagnosis. Hence, the need to review and up-                     only in the original version. For further information: https://
date diagnostic and therapeutic strategies has emerged as a fundamental priority.                  creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                             41
G. Arrigoni et al.




In 2015, the American Thyroid Association (ATA) re-               genicity, margins and shape, calcification, vascularity and
leased the revised version of the guidelines (GL) for the         elastography, to stratify the risk of malignancy and to se-
management of thyroid nodules and DTC 1. Compared to              lect nodules which should undergo FNA. The ATA GL de-
the previous revision (2009) 2, there are many novelties for      scribe 5 different US patterns, defining high, intermediate,
diagnostic work-up and treatment of DTC. The most rel-            low, very low suspicion and benign classes. The IC instead
evant concerns the selection of thyroid nodules amenable          proposes a simplified scheme with only 3 classes of risk:
to cytological evaluation by FNA, routinely recommended           low-US-risk (Class 1), intermediate-US-risk (Class 2) and
in nodules ≥ 1 cm only, even if with highly suspicious US         high-US-risk (Class 3). Both classifications are based on
pattern. Moreover, the restraint of total thyroidectomy (TT)      previously specified US characteristics (IC is based on EU-
followed by post-operative radioactive iodine (RAI) abla-         TIRADS criteria) 4. Table I compares the two GLs. Each
tion and suppressive therapy for high-risk cases of DTC           category defines a dimensional cut-off as an indication to
only, while the intermediate or low-risk cases can be man-        FNA. According to the IC, US-guided FNA is recommend-
aged more conservatively.                                         ed in Class 3 thyroid nodules > 10 mm in diameter, and in
In 2018, six scientific Italian Societies involved in cure of     Class 2 nodules > 20 mm. For Class 1 nodules, the indica-
patients affected by thyroid cancer developed the “Italian        tion is restricted to lesions > 20 mm, only if symptomatic,
Consensus on diagnosis and treatment of differentiated thy-       increasing in size, associated with high-risk factors, or be-
roid cancer: joint statements of six Italian societies” 3. They   fore surgery or percutaneous therapy. Nodes < 5 mm nodes
produced a collection of practical statements on selected         should be monitored by US even if they show high-risk US
relevant issues in the management of thyroid nodules and          features. For high-risk nodules of 5-9 mm the IC admits the
cancer, based on an adaption of ATA GL according to the           possibility to proceed both with FNA and US monitoring,
Italian scenario and expert opinion of the multidisciplinary      based on clinical characteristics and patient preference.
panel.                                                            FNA is recommended for subcapsular, posterior or para-
The aim of this paper is to analyse the two different guide-      tracheal lesions, for suspicious lymph nodes, extra-thyroid
lines, underlying the differences and similarities to iden-       spread and clinical thyroid cancer risk factors. The ATA GL
tify and promote standardised clinical approaches among           states that FNA should not be performed on nodules ≤ 1
all specialists who treat differentiated thyroid cancer. This     cm, thus making the diagnosis of papillary micro carcino-
paper could also be used as a basis for a hypothetical Ital-      mas impossible. To conclude, both GLs consider features
ian Society of Otolaryngology - Head and Neck Surgery             of US nodules to be more relevant than size in defining the
guidelines drafting.                                              risk of cancer, and to select nodules to submit to FNA. In
                                                                  general, a more invasive approach is limited to carefully
                                                                  selected cases. The main difference in GLs is the possibil-
Materials and methods                                             ity, given by the IC, to perform FNA in nodules 5-9 mm.
ATA GL 1 and IC 3 were reviewed. The 24 topics covered in
IC were taken as reference points, as are considered a sum-       FNA
mary of the most relevant diagnostic and therapeutic issues.      Cytological examination is essential in the choice of thera-
We grouped items into macro areas to produce a uniform            peutic strategy: it allows a US suspicious nodule to be clas-
publication. Differences and similarities between the two         sified into cytological categories, according to increasing
sets of recommendations, their implications in clinical           risk of malignancy. Nodules can be stratified from probably
practice, the grey areas in understanding and disseminating       benign (false negatives < 3%) to almost certainly malig-
the GL, together with the most relevant topics in areas of        nant (probability ~100%). The main pitfall of cytology is
future research, were highlighted.                                the risk stratification of follicular pattern and/or oxyphilic
                                                                  (Hürthle) cell lesions (vascular/capsular invasion is not
                                                                  evaluable on cytology), classified as indeterminate. Over-
Diagnosis                                                         all, 10-15% of FNAs provide inadequate results, while a
US                                                                diagnosis of follicular/oxyphilic lesions of indeterminate
Thyroid US usually represents the first imaging study in the      significance is made in 10-20% of FNAs 5. Although sev-
evaluation of thyroid nodules, thanks to its high predictive      eral molecular analyses have been proposed to overcome
value, ease and reproducibility of the techniques, lack of        this diagnostic pitfall, the proper clinical management of
exposition to ionising radiation, non-invasiveness, repeat-       indeterminate nodules is still debated.
ability, and low cost, even if operator dependent. US al-         The cytological reports used in the GL are different. The
lows, based on nodule size and number, structure and echo-        ATA refers to the Bethesda classification system 6, while



42
                                               Comparison between 2015 ATA guidelines and Italian Consensus for DTC management. A commented report




Table I. Comparison between ultrasound risk categories and indications to FNA.
                                    Italian Consensus                                                             ATA Guidelines
    Risk definition                               Cut-off for FNA                                  Risk definition             Cut-off for FNA
 Class 1                                             ≥ 20 mm                                 Benign                                No biopsy
 (EU-TIRADS 2-3)                                                                             Very low suspicion                    ≥ 20 mm
                                                                                             Low suspicion                         ≥ 15 mm
 Class 2                                             ≥ 20 mm                                 Intermediate suspicion                ≥ 10 mm
 (EU-TIRADS 4)
 Class 3                                            ≥ 10 mm                                  High suspicion                        ≥ 10 mm
 (EU-TIRADS 5)                5-9 mm  consider patient characteristics and preference




IC uses the classification proposed in 2014 by AIT-AME-                          aerodigestive tract invasion. Routine preoperative 18FDG-
SIE and SIAPEC-IAP 7. Bethesda classification includes                           PET scans are not recommended by the ATA and not even
6 diagnostic categories: (I) non-diagnostic/unsatisfactory;                      mentioned in the IC. Serum Tg and anti-thyroglobulin
(II) benign; (III) atypia of undetermined significance/fol-                      antibody (TgAb) determination is not recommended. Se-
licular lesion of undetermined significance (AUS/FLUS);                          rum calcitonin measurement as a screening test for medul-
(IV) follicular neoplasm/suspicious for follicular neoplasm                      lary thyroid carcinoma is recommended by the IC for all
(FN/SFN), a category that also encompasses diagnosis                             patients with thyroid nodules at diagnosis, or at least for
of Hürthle cell neoplasm/suspicious for Hürthle cell neo-                        patients undergoing surgery. The ATA currently does not
plasms; (V) suspicious for malignancy (SUSP) and (VI)                            express opinions on this issue (no recommendations, insuf-
malignant. The Italian classification also includes 6 catego-                    ficient evidence), while in previous editions it was not rec-
ries, which are: TIR 1/TIR 1C (non-diagnostic/cystic nod-                        ommended as it is not cost-effective 2,8. The comparison of
ule), TIR 2 (benign nodules), TIR 3A (low-risk indetermi-                        preoperative imaging and laboratory testing is summarised
nate lesion), TIR 3B (high-risk indeterminate lesion), TIR                       in Table III.
4 (suspicious nodule) and TIR 5 (malignant nodule).
The two systems show slight differences and there is clear                       Tumour treatment
parallelism in the respective risk classes and management
(Tab. II). In evaluation of cytologically indeterminate nod-                     DTC Surgery
ules, the ATA GL give a greater role to molecular testing,                       The long-standing debate on the best surgical strategy for
which in Italy currently has a very limited use possibly due                     these cases has been stimulated by the last edition of ATA
to its high cost. When surgical treatment is chosen, specific                    GL, which significantly differs from the previous one. The
recommendations on the extent of resection according to                          2009 edition proposed a more aggressive strategy, and to-
the clinical situation are made.                                                 tal thyroidectomy was considered the best option for (al-
                                                                                 most) every tumour > 1 cm, independently of the evidence
Other investigations                                                             of loco-regional or distant metastases 2. This approach was
US is the most sensitive imaging technique for examina-                          justified by retrospective data suggesting improved out-
tion of thyroid gland and neck lymph nodes: both the ATA                         comes (in terms of both recurrence and survival) after total
and IC recommend it for all patients undergoing thyroid-                         thyroidectomy 9-13. Furthermore, it allows performance of
ectomy for malignant or suspicious cytologic findings. In                        radioiodine remnant ablation, easing a follow-up strategy
case of US suspicious cervical lymph nodes (≥ 8-10 mm,                           based on US studies and serum Tg surveillance.
according to ATA GL), US-guided FNA for cytology and/                            The 2015 edition of ATA GL outlines a more conservative
or thyroglobulin (Tg) assessment in the needle washout is                        attitude, with surgical strategy depending on the actual risk
strongly suggested, if this could change surgical manage-                        of recurrence/death of each patient. This change has been
ment. Cross-sectional imaging studies (CT and MRI, both                          the consequence of an overwhelmingly increased diagno-
with contrast medium) of the neck, mediastinum and lung                          sis of small and early-stage tumours. Most, according to
are recommended after US in case of advanced disease                             more recent studies 14-18, are low-risk tumours characterised
clinical suspicion (invasive primary tumour and multiple or                      by similar optimal outcomes when treated with loboisth-
bulky lymph node involvement). Tracheal and/or oesopha-                          mectomy or total thyroidectomy. Moreover, the additional
geal endoscopy should be considered in case of suspected                         complications risk observed in total thyroidectomy has led



                                                                                                                                                 43
G. Arrigoni et al.




Table II. Comparison between cytological risk categories and therapeutic management. FNA Fine needle aspiration US ultrasonography.
 Italian           Risk of            Recommended management                     ATA              Risk of             Recommended management
 Consensus       malignancy                                                   Guidelines        malignancy
 TIR 1               Undefined   Solid nodules: repeat FNA (consider        I Non-diagnostic   1-4%        Repeat US-guided FNA
 TIR 1C                          core-needle biopsy).                                                      Consider surgery for nodules with
                                 Cystic nodules: clinical and US follow-                                   high suspicion sonographic pattern,
                                 up.                                                                       in the case of growth (> 20% in two
                                 Consider diagnostic surgery for                                           dimensions), or if clinical risk factors
                                 persistently non-diagnostic solid nodules                                 for malignancy are present. The best
                                 > 1 cm with suspicious clinical and                                       surgical choice for a single nodule
                                 US features, or in the case of growth                                     is lobectomy. Total thyroidectomy if
                                 (> 20% in two dimensions). The best                                       contralateral nodules, and/or specific
                                 surgical choice for a single nodule                                       risk factors, patient’s choice.
                                 is lobectomy. Total thyroidectomy if
                                 contralateral nodules, and/or specific
                                 risk factors, patient’s choice.
 TIR 2                < 3%       No treatment, unless surgery is                II Benign      0-3%        No treatment, unless surgery is
                                 indicated for clinical reasons: large-size                                indicated for clinical reasons: growing
                                 (> 4 cm) and symptomatic nodules,                                         nodules of large size (> 4 cm) causing
                                 nodules that develop suspicious                                           compressive or structural symptoms, or
                                 US changes or increase in volume,                                         clinical concern.
                                 hyperfunctioning nodules > 3 cm.                                          Nodules with high suspicion US
                                 Local treatment techniques (laser or                                      pattern: repeat US and US-guided FNA
                                 radiofrequency) may be considered.                                        within 12 months. Nodules with low
                                                                                                           to intermediate suspicion US pattern:
                                                                                                           repeat US at 12-24 months.
 TIR 3A               5-15%      Follow-up if favourable clinical and US          III          5-15%       Consider repeat FNA (or a second
                                 features; a repeat FNA is recommended;        AUS/FLUS                    opinion review of the cytopathology
                                 molecular testing can be a useful                                         slides) and molecular testing.
                                 adjunct.                                                                  If both not performed or inconclusive,
                                 Surgery in the other cases.                                               either surveillance or diagnostic surgery,
                                                                                                           depending on clinical risk factors, US
                                                                                                           pattern and patient preference
 TIR 3B              15-30%      Surgery as preferred option.                  IV FN/SFN       15-30%      Diagnostic surgery is the long-
                                 Close follow-up may be proposed to                                        established standard of care.
                                 selected patients with favourable clinical                                Molecular testing may be an alternative
                                 and US features (after discussion of                                      option, to supplement malignancy risk
                                 treatment options); molecular testing                                     assessment data (consider informed
                                 can be a useful adjunct.                                                  patient preference)
 TIR 4               60-75%      Surgery in most cases (as for TIR 5            V SUSP         60-75%      Surgery
                                 category).                                                                Molecular testing may be considered,
                                 Molecular testing for better                                              if such data would be expected to alter
                                 characterisation may be considered in                                     surgical decision making
                                 selected cases.

 TIR 5                > 98%      Surgery                                      VI Malignant     97-99%      Surgery
                                 Close follow-up may be offered to                                         Consider active surveillance in (A)
                                 patients with very low-risk papillary                                     patients with very low risk tumours
                                 microcarcinomas (see Item 5), and                                         (e.g., papillary microcarcinomas without
                                 to elderly patients with incidentally                                     evident metastases or local invasion,
                                 discovered papillary cancers, at high                                     and no cytologic evidence of aggressive
                                 surgical risk and without evidence of                                     disease), (B) patients at high surgical
                                 extra thyroid spread.                                                     risk, or (C) with a relatively short life
                                                                                                           expectancy, or (D) with concurrent
                                                                                                           medical/surgical issues that need to be
                                                                                                           addressed first.


to suggest loboisthmectomy for low-risk patients, espe-                       gery can be recommended on a case sensitive basis. The
cially in low-volume thyroid surgery centers. In low-risk                     IC has substantially endorsed the recommendations of the
non-confirmed patients, the possibility of second-step sur-                   ATA (summarised in Table IV). Both IC and ATA consider,



44
                                               Comparison between 2015 ATA guidelines and Italian Consensus for DTC management. A commented report




Table III. Comparison of preoperative staging imaging and laboratory test.
 Imaging/Laboratory                                                      Italian Consensus                              ATA Guidelines
 Neck ultrasound                                                               Yes                                              Yes
 FNA lymph nodes + Tg on needle washout                                        Yes                                              Yes
                                                                                                             (if ≥ 8-10 mm in the smallest diameter)
 CT/MRI                                                                         Yes                                             Yes
                                                                    (for advanced disease only)                     (for advanced disease only)
 Tracheoscopy and/or oesophagoscopy                                             Yes                                             Yes
                                                            (for suspected aerodigestive tract invasion)   (for suspected aerodigestive tract invasion)
 18FDG-PET                                                                      No                                              No
 Tg/TgAb determination                                                          No                                              No
 Calcitonin determination                                                       Yes                                              ?



Table IV. Recommendations for total thyroidectomy or lobo-isthmectomy (equal for ATA and IC).
 Total thyroidectomy (at least one of the following)                        Thyroid cancer > 4 cm
                                                                            Extrathyroidal macroscopic extension (ETE) (cT4)
                                                                            Clinically apparent lymph node metastases (cN1)
                                                                            Distant metastases (cM1)
 Lobo‑isthmectomy                                                           Thyroid cancer ≤ 1 cm
                                                                            No ETE
                                                                            No clinical evidence of lymph node metastases (cN0)
                                                                            No distant metastases cM0
 Lobo‑isthmectomy or total thyroidectomy                                    Thyroid cancer 1 to 4 cm
                                                                            No ETE
                                                                            No clinical evidence of lymph node metastases (cN0)
                                                                            No distant metastases cM0



among several risk factors, previous head and neck expo-                       For PTMC ATA recommends loboisthmectomy if there are
sure to ionising radiation to be of particular relevance in                    no other indications for total thyroidectomy, but admits the
the choice of total thyroidectomy, i.e. mandatory if post-                     possibility to consider active surveillance as an alterna-
surgical radioiodine treatment is expected. The ATA also                       tive in selected patients with very low-risk tumours (e.g.,
emphasises that patient referral to high-volume thyroid sur-                   PTMC without clinical evidence of metastases or local in-
geons is associated with superior outcomes, and this should                    vasion, and no cytologic evidence of aggressive disease),
be considered in cases with more extensive disease.                            high surgical risk because of comorbid conditions, rela-
                                                                               tively short life expectancy (e.g., serious cardiopulmonary
Papillary microcarcinoma treatment                                             disease, other malignancies, very advanced age), or con-
A particular category of DTC is papillary thyroid microcar-                    current medical or surgical issues requiring priority care.
cinoma (PTMC), defined as a papillary carcinoma ≤ 1 cm                         However, a clinical conundrum can be envisioned in the
in size. Most of these tumours have an indolent behaviour,                     advice by the ATA against performing FNA in nodules ≤ 10
as shown by prospective studies in Japan on many patients                      mm, thus preventing the possibility of diagnosis of PTMC.
with biopsy-proven PTMCs not submitted to surgery and                          The IC instead admits FNA also in high-US-risk nodules
followed for 15 years according to an active surveillance                      between 5 mm and 9 mm in size.
protocol 19-22. Unfortunately, neither clinical aspects nor                    In IC, active surveillance may be considered for very low-
cytology can reliably differentiate the minority of PTMCs                      risk PTMC in particular situations: high risk surgical pa-
that will significantly progress from the majority of indo-                    tients; patients who refuse surgical treatment; patients
lent PTMCs. Likewise, isolated molecular biology (BRAF                         potentially eligible to controlled clinical trials. The deci-
mutation) is not able to identify microcarcinomas with a                       sion requires a thorough discussion with the patient, and
more aggressive attitude, but the concomitance of BRAF                         a careful clinical and cytological risk stratification. Active
with other oncogenic mutations (PIK3CA, AKT1, TERT                             surveillance is not recommended in case of neck irradiation
promoter, or TP53) may be a specific marker of a less fa-                      history, US extra-thyroid extension, subcapsular or poste-
vourable outcome of PTC 23-26.                                                 rior localisation, multifocal or bilateral tumour, coexistence



                                                                                                                                                          45
G. Arrigoni et al.




of Graves’ disease, suspicious lymph node involvement,            The risk of subclinical nodal metastases in DTCs cN0
aggressive cytological features and BRAF mutation. If a           raises the question of prophylactic lymph node dissection.
conservative approach of watchful waiting is selected, neck       Today there is general agreement that prophylactic lateral
US examination every 6 months in the first two years and          neck dissection is not an option: the ATA does not even ad-
once a year thereafter is recommended.                            dress the topic, while the IC states that it is only advisable
                                                                  in cN1 patients. On the contrary, the role of prophylactic
Completion thyroidectomy                                          central neck (level VI) dissection (pCND) for cN0 disease
Both the ATA and IC state that a completion thyroidectomy         remains controversial. Several lines of clinical evidence
must be offered to those patients to whom a total thyroid-        led to consider pCND appropriate, as in this area lymph
ectomy would have been chosen if the diagnosis of thyroid         node metastases are frequent and often not evident on pre-
cancer had been available before the initial surgery. The IC      operative imaging 29 or at the time of surgery. Furthermore,
specifies that completion thyroidectomy is mandatory for          the procedure allows more precise staging of the disease,
DTCs > 4 cm, or with ETE and/or lymph node metasta-               and reoperation in the central neck for nodal recurrence is
ses, or in case of aggressive variants. This latter indication,   challenging and carries a non-negligible risk of compli-
not considered by the ATA, must be kept in mind for thor-         cations. On the other hand, in several studies pCND has
ough patient information: in some cases suitable for limited      shown little or no improvement in long-term outcomes,
surgery, the indication for total thyroidectomy can emerge        while increasing the chances of temporary and permanent
from histological examination. It is worth noting that re-        morbidity (especially hypoparathyroidism) 30,31. The ATA
cent publications have reported that up to 43.5% of patients      proposes a cautious attitude and a careful assessment of
who meet ATA preoperative criteria for lobectomy would            the risk-benefit ratio. The 2009 edition stated that pCND
require a second operation due to high-risk features on fi-       may be performed in clinically uninvolved central neck
nal pathology 27,28. The ATA GLs also state that in selected      lymph node PTC patients, and that near total or total thy-
cases radioiodine ablation of the remaining lobe can be           roidectomy without pCND may be appropriate for small
considered as an alternative to completion thyroidectomy.         (T1/T2), non-invasive, clinically node-negative PTCs and
However, data regarding long-term outcomes are limited            most follicular cancers. The decision of whether to perform
and suggest a slightly higher proportion of patients with         a pCND is then made considering available surgical exper-
persistent detectable Tg. This approach never caught on in        tise, and a simple near-total thyroidectomy may be safer in
European countries, and therefore the IC does not take it in-     less experienced surgical hands 2. The 2015 edition takes
to consideration. Both the ATA and IC agree on the equal-         an even more cautious attitude, stating that pCND (ipsi-
ity of surgical risks between a two-stage thyroidectomy           lateral or bilateral) should be considered in patients with
and primary total thyroidectomy. The IC, however, points          advanced primary tumours (T3/T4) or cN1b, or if lymph
out that this is true in specialised centers, and stresses the    node involvement extent could be useful for planning fur-
importance of avoiding any contralateral dissection in the        ther therapeutical steps, and that a thyroidectomy without
first surgery. Finally, the ATA advises against prophylactic      pCND can be considered appropriate for small (T1/T2),
lymph node dissection for cN0 disease, while the topic is         non-invasive, cN0 PTCs and for most follicular cancers.
not appraised in the IC.                                          The IC endorses the ATA GL recommendations (Tab. V),
                                                                  but also suggests considering an ipsilateral pCND with im-
Lymph node treatment                                              mediate frozen section examination in selected patients.
                                                                  It can be argued that ipsilateral pCND may represent the
A large proportion of patients with papillary carcinoma           best compromise between the conflicting need to minimise
have regional lymph node metastases at the time of diagno-        the risk of complications, and to guarantee maximum local
sis, mainly in the central neck compartment. Lymph node           radicality and accurate staging.
metastases significantly increase the risk of locoregional
recurrence, especially if multiple and bulky, and/or with
extracapsular nodal extension, but the impact on overall
                                                                  Pathological report
survival is little if any.                                        The ATA staging system follows the AJCC 7th edition/TNM
The role of therapeutic lymph node dissection is well es-         Classification System for DTC 32 while the more recent
tablished whenever metastatic nodal disease is discovered         IC follows the 8th edition 33. A complete pathology report
at preoperative investigations (cN1) or intraoperatively. In      should indicate, besides the basic tumour features for his-
these cases, both the ATA and IC confirm the indication of        tological classification and staging (according to the TNM
therapeutic lymph node dissection.                                classification of AJCC/UICC), status of resection margins



46
                                                 Comparison between 2015 ATA guidelines and Italian Consensus for DTC management. A commented report




Table V. Comparison of indications for neck dissection.
                                             Central compartment dissection                                       Lateral compartment dissection
                                Prophylactic                                 Therapeutic                       Prophylactic             Therapeutic
ATA             cN1b  recommended                                      cN1a  recommended                          No            cN1b  recommended
Guidelines      cT3-cT4, or if useful for planning further
                steps in therapy  allowed
Italian         cN1b  recommended                                      cN1a  recommended                          No            cN1b  recommended
Consensus       cN0  ipsilateral + immediate frozen
                section examination allowed in selected
                patients



(involved/uninvolved) and additional information that is                      risk of death from thyroid cancer, but it does not adequately
useful for risk assessment. The latter includes: presence of                  predict the risk of recurrence. In 2009, the ATA GL pro-
vascular invasion and number of invaded vessels (< 4/≥ 4),                    posed an Initial Risk Stratification System to predict the
number of lymph nodes examined/involved by tumour, size                       risk of recurrence and/or persistence of disease after surgi-
of the largest metastatic focus and presence/absence of ex-                   cal treatment 2. This system classified patients as having
tra nodal extension.                                                          low/intermediate/high-risk of recurrence and helped to ad-
The histopathologic evaluation should also identify and                       equately plan disease surveillance and therapeutic strate-
report variants of thyroid carcinoma: more unfavourable                       gies. The 2015 edition has re-proposed this classification
outcomes (tall cell, columnar cell, and hobnail variants of                   (Tab. VI), with some updates (including specific DTC his-
PTC; widely invasive follicular thyroid carcinoma; poorly                     tology, multifocality, extent of vascular invasion or extent
differentiated carcinoma), or those that may show a more                      of metastatic lymph node involvement, extrathyroidal ex-
aggressive behaviour (solid and diffuse sclerosing variants                   tension, and completeness of surgical resection). This risk
of PTC); more favourable outcomes (encapsulated fol-                          stratification plays a key role in therapeutic management
licular variant of PTC without invasion, renamed in 2016                      decisions, and particularly regarding the indications for
“non-invasive follicular thyroid neoplasm with papillary-                     RAI treatment after surgery.
like nuclear features” NIFTP 34; minimally invasive fol-                      Following the ATA GLs, the goal of postoperative RAI
licular carcinoma); associated with familial syndromes                        administration includes remnant ablation to facilitate de-
(cribriform-morular variant of PTC often associated with                      tection of recurrent disease and initial staging; adjuvant
familial adenomatous polyposis [FAP], follicular or papil-                    therapy to improve disease-free survival by theoretically
lary carcinoma associated with PTEN-hamartoma tumour                          destroying possible, but unproven foci of residual disease;
syndrome). Following the TNM 8th edition, the histological                    therapy to improve disease-specific and disease-free sur-
report should describe the predominant histotype and, if                      vival by treating persistent disease in higher risk patients.
present, a minor component of either an aggressive variant                    The indication for RAI administration after thyroidectomy
or a less differentiated tumour type (poorly differentiated                   depends on the stage of disease and risk stratification. In
or anaplastic); if metastatic deposits are detected in lymph                  the ATA GLs, RAI remnant ablation is not routinely rec-
nodes, histology should specify whether they are microme-                     ommended for low-risk patients, it should be considered in
tastases (< 2 mm in size); immunohistochemical and mo-                        ATA intermediate-risk cases and is routinely recommended
lecular analyses, when performed, should be reported or
there should be a reference to any additional report.
The IC also reports the indications on the requirements of                    Table VI. ATA risk classification system for structural disease recurrence ap-
the cytological report. It must specify the technique used                    proved by IC. DTC Differentiated thyroid cancer, LN lymph node.
to obtain the sample and include essential clinical informa-                   High risk                         Gross extrathyroidal extension
                                                                                                                 Incomplete tumour resection
tion, such as functional status, location, number, and size of                                                   Distant metastases
lesions analysed, their structure and US pattern.                                                                Lymph node > 3 cm
                                                                               Intermediate risk                 Aggressive histology
Post-surgical treatment                                                                                          Minor extrathyroidal extension
                                                                                                                 Vascular invasion
When?                                                                                                            > 5 involved lymph nodes (0.2-3 cm)
The postoperative AJCC/UICC TNM (both 7th and 8th edi-                         Low risk                          Intrathyroidal DTC
tion) staging system provides reliable information on the                                                        ≤ 5 LN micrometastases (< 0.2 cm)




                                                                                                                                                        47
G. Arrigoni et al.




for patients in a high-risk category. The IC, in agreement         Finally, rhTSH preparation should be considered in patients
with the last ATA GL, considers that the indication for post-      with DTC of any risk level who cannot tolerate hypothyroid-
surgical RAI ablation should be established based on the           ism due to concomitance of severe comorbidities (including
AJCC/UICC TNM staging (8th edition) and the Initial Risk           psychiatric conditions), or who are unable to obtain TSH
Stratification System, also considering serum Tg levels (on        elevation by THW (for these cases the Italian Medicines
thyroid hormone therapy or after TSH stimulation) and              Agency (AIFA), according to law 648/96, approved the use
neck US. For ATA low-risk patients (T1a-b, N0-X, M0-X)             of rhTSH) (Tab. VII). Both GLs recommend cautious use of
RAI remnant ablation can be avoided, especially when ba-           RAI therapy in patients with brain or proximity to the spinal
sal serum Tg or TSH-stimulated Tg are undetectable or < 5          cord or superior vena cava metastases. In these cases, the
ng/ml, and neck US is negative. For patients with interme-         onset of an acute swelling of metastatic tissue can cause neu-
diate or low-to-intermediate risk (T1-2, N1a-N1b, M0-X)            rological damage or superior vena cava syndrome. To limit
RAI ablation should be considered (advanced age, larger            the risk, the institution of temporary high-dose corticosteroid
tumours, macroscopic or clinically evident lymph node              therapy is recommended.
metastases, extra nodal extension or vascular invasion, ag-        A low iodine diet (LID) is suggested for 1-2 weeks (but
gressive histology). Finally, in high risk or intermediate-to-     for IC a restriction on the use of iodised salt is not neces-
high risk patients (T3-4, any N, any M) RAI administration         sary); avoiding iodine-containing drugs and iodinated con-
is routinely recommended.                                          trast medium is emphasised. A possible previous high-dose
A post-therapy whole-body scan (WBS), with or without              iodine exposure should also be considered when planning
SPECT/CT, is recommended by the ATA to inform disease              the treatment schedule. Measurement of urinary iodide ex-
staging and document RAI avidity of any structural dis-            cretion is recommended only in case of suspected iodine
ease. The IC does not dwell on this point, probably because        contamination.
in Italy post-therapy WBS is routinely performed.                  The IC points out the following recommendations not spe-
                                                                   cifically addressed by ATA: RAI treatment must be per-
How?                                                               formed in protected hospitalisation with collection of the
Since DCT cells retain NIS (sodium/iodide symporter) ex-           patient excreta (the obligation derives from the Italian law
pression, although reduced in comparison to normal thyroid         187/2000, transposition of the European directive 97/43
cells, high TSH levels are necessary to promote RAI uptake.        MED); at discharge, the patient and his family must be
Preparation for thyroid ablation can be performed through          provided with written information and instructions on daily
two approaches: thyroid hormone withdrawal (THW) and               behaviour, to respect the dose limits for the population and
recombinant human TSH (rhTSH) administration. If THW is            the dose constraints for family members or caregivers; in
planned, both ATA GL and IC agree that LT4 should be with-         case of travel across international borders or via airport, a
drawn for 3-4 weeks. Liothyronine (LT3) can replace LT4 in         form (including the date of treatment, the radionuclide, the
the initial weeks, but it must be withdrawn in the last 2 weeks.   administered activity and the treating facility) must be pro-
Serum TSH levels will confirm the appropriate stimuli, and         vided, since radiation detection systems can be triggered.
a level > 30 mU/L is generally recommended. Compared to            Pregnancy is an absolute contraindication to 131I therapy,
THW, the use of rhTSH is associated with similar rates of          and the ATA recommends women of childbearing age to
successful ablation and superior quality of life around the        have a negative screening test for pregnancy prior to RAI
time of RAI administration, since hypothyroidism is avoided.       administration. Thereafter, according to both GLs, preg-
However, long-term outcome data are still limited, and this        nancy should be avoided for 6-12 months. In breastfeeding
has led to some restrictions on the indications of rhTSH use       women RAI therapy should be deferred until breastfeed-
when the risk of recurrence or death is high. Indeed, rhTSH        ing or pumping has been stopped for at least 6 weeks (3
is currently approved by many international authorities for        months for ATA), as the mammary gland intensely concen-
use in preparation for RAI remnant ablation in patients who        trates iodide during lactation. In men, conception should be
do not have evidence of distant metastases. Both the ATA           avoided for 4 months (3 months for ATA); sperm banking
and IC state that rhTSH can be an alternative to THW in            could be considered in young patients with distant metasta-
patients with ATA low and intermediate-risk DTC without            ses likely requiring high cumulative activities.
extensive lymph node involvement. Conversely, in patients
with ATA high-risk DTC, loco-regional or distant metastases        Which dose?
and higher risk of disease-related mortality and morbidity,        Selection of the most appropriate activity to be adminis-
additional controlled data from long-term outcome studies is       tered is important: for remnant ablation in patients with
needed to recommend rhTSH preparation for RAI treatment.           low/intermediate-risk, both ATA and IC suggest a low ac-



48
                                       Comparison between 2015 ATA guidelines and Italian Consensus for DTC management. A commented report




tivity use (approximately 30 mCi for ATA, 30-50 mCi for             cumulative doses. The most common early side effects are
IC). Higher activities (up to 150 mCi for ATA, 100 mCi or           nausea, taste disturbances and sialadenitis. Late-onset com-
more for IC) should be considered if RAI is intended for            plications include salivary and lacrimal gland damage (with
patients at high risk of persistent/recurrent disease.              xerostomia, xeropthalmia and salivary or nasolacrimal duct
Both ATA and IC mention three basic approaches to RAI               obstruction), bone marrow depression, pulmonary fibrosis,
therapy for loco-regional disease or distant metastases: ad-        gonadal disfunction, and secondary malignancies. The risk
ministration of empiric fixed activities, therapy determined        of secondary malignancies (including bone and soft tissue
by the upper limit of blood and body dosimetry [bone mar-           cancers and leukaemia) is very small and dose related; ac-
row (blood) dosimetry in the IC], and quantitative tumour or        cording to ATA it does not warrant specific screening. Both
lesion dosimetry (lesion-based dosimetry in the IC). There          GLs agree that in women RAI therapy does not increase the
are no data supporting the superiority of one approach over         risk of infertility, miscarriage and foetal malformations. In
another, so that the choice is left to the experience and re-       men, RAI therapy may be associated with temporary oli-
sources of the single institution. ATA only reports that do-        gospermia, and permanent infertility can result from cumu-
simetry methods are often reserved for patients with unusual        lative damage after multiple treatments.
situations, such as extensive lung metastases, renal failure,
children and the elderly. When an empiric activity is chosen,       RAI-refractory DTC
IC specifies that an amount of 131I ranging from 3.7 and 7.4        According to the ATA, radioiodine-refractory disease oc-
GBq (100-200 mCi) is appropriate for most patients. The             curs when (in patients with appropriate TSH stimulation
ATA agrees but recommends avoiding activities exceeding             and iodine preparation): malignant metastatic tissue does
150 mCi in patients over 70 years. Both state that the cu-          not ever concentrate RAI, tumour tissue loses the ability
mulative activity that can be administered must be assessed         to concentrate RAI, RAI is concentrated in some lesions
on an individual basis, because it depends on various factors       but not in others, or metastatic disease progresses despite
such as response to therapy, age and onset of deterministic         significant concentration of RAI. The IC adheres to the
adverse effects. Re-treatment should be performed not ear-          same criteria but by unifying the first two categories. The
lier than 6-12 months from previous treatment.                      definition of any of these possibilities depends on imaging
Both the ATA and IC agree that empirical RAI treatment              (post-therapy 131I WB scan, combined with other imaging
can be considered in selected cases with biochemical dis-           modalities). When DTC is defined as RAI refractory, there
ease, but without evidence of structural disease. The indi-         is no indication for further RAI treatment.
cations are limited to patients with high or rising serum
Tg levels, or rising TgAb levels, and negative structural or
                                                                    Systemic therapy
metabolic imaging. There is no consensus on the cut-off
value of serum Tg above which a patient should be treated,          Systemic therapy is mentioned, by both the ATA and IC,
but a relevant aspect is Tg (or TgAb) increase over time.           in RAI-refractory DTC patients with metastatic, rapidly
Another important element in selecting patients for empiric         progressive, symptomatic and/or imminently threatening
RAI therapy is the result of 18FDG-PET scanning, since              disease, not otherwise amenable to local therapies. The
18
   FDG-PET positive tumours generally do not concentrate            purpose of therapy is to reduce the growth rate and tumour
RAI. The recommended activity to be administered is 100-            burden, improve progression-free survival and control
200 mCi for ATA and 100-150 mCi (3.7-5.2 GBq) for IC.               symptoms. Kinase inhibitors (KI) are currently considered
Both GLs agree that if the post-therapy scan is negative, the       the first line of therapy, and sorafenib and lenvatinib are ap-
patient should be considered to have RAI-refractory dis-            proved for clinical use in the US and EU. These agents are
ease and no further RAI therapy should be administered.             associated with numerous adverse effects as well as serious
On the contrary, if persistent not-resectable disease is lo-        and potentially fatal risks. In view of this, both GLs always
calised, further treatment courses can be considered if evi-        recommend considering possible alternatives to their use,
dence of clinical benefits is provided. The most compelling         such as surgery or other localised approaches (including
benefit evidence from empiric RAI therapy is in the case of         radiation therapy or thermal ablation). Moreover, the ATA
pulmonary micrometastases.                                          highlights the importance of an experienced care team and
                                                                    exhaustive patient information.
RAI complications                                                   Conventional chemotherapy has historically produced dis-
The ATA and IC agree that RAI therapy is reasonably safe,           appointing results. The ATA and IC agree that today it can
but may be associated with a low risk of early and late-            be exceptionally indicated in cases where KI are ineffective
onset complications, especially after higher individual and         or cannot be used.



                                                                                                                                      49
G. Arrigoni et al.




Follow-up                                                      18
                                                                  FDG-PET) and/or cross-sectional (CT, MRI) studies
                                                               should be considered in patients with a high risk of per-
Early follow-up identifies disease-free patients who conse-    sistent disease only, when response to therapy cannot be
quently require less aggressive management strategies, and     adequately classified with first-level tools. ATA accurately
those with residual disease who may need closer surveil-       defines the role of each imaging technique. In particular,
lance and possible additional therapies.                       18
                                                                  FDG-PET/CT can be indicated in high-risk DTC patients
For both GLs, the initial follow-up evaluation should be       with elevated serum Tg and negative WB scan after ther-
performed at 3-6 months from initial treatment by serum        apeutic doses of RAI. It may also be considered as part
Tg (on l-thyroxine therapy), serum TgAb measurement and        of initial staging in poorly differentiated thyroid cancers
neck US (thyroid bed and central and lateral nodal com-        and invasive Hürtle cell carcinomas, especially patients
partments). For both the ATA and IC, follow-up should be       with other evidence of disease on imaging or with elevated
performed every 12-24 months. The IC states that follow-       serum Tg levels, or as a prognostic tool in patients with
up should be performed periodically, according to the pa-      metastatic disease to identify those at highest risk of rapid
tient’s risk factors and Tg levels and suggests prolonging     disease progression and disease-specific mortality. In this
follow-up frequency after 5 years, but continuing lifelong.    regard, the ATA emphasises that 18FDG uptake on PET in
Serum Tg is the most specific and sensitive marker in mon-     metastatic DTC patients is a major negative predictive fac-
itoring patients with DTC 35. Even if most laboratories cur-   tor for RAI treatment response and an independent prog-
rently use immunometric, ultra-sensitive assays (sensitivity   nostic factor for survival.
≤ 0.2 ng/ml), the patient is recommended to always per-
form the assay in the same laboratory because of possible      Post-treatment risk stratification
measurement differences.                                       In the 2006 edition of the ATA GLs, the idea of re-eval-
After total thyroidectomy and radioiodine remnant abla-        uating the risk of recurrence/death after initial treatment
tion, undetectable serum Tg levels (either basal or TSH-       were considered to modulate follow-up intensity and adapt
stimulated if basal Tg is undetectable) and negative TgAb      therapeutic decisions to the clinical situation of each indi-
are predictive of a disease-free status with a negative pre-   vidual patient 8. The subsequent 2009 and 2015 editions of
dictive value close to 100%.                                   the GL updated and developed this concept, which is now
Sometimes (low-risk patients not submitted to RAI abla-        being adopted by the IC.
tion, incomplete ablation cases, suboptimal remnant) a de-     Initial risk stratification analyses the risk of recurrence and
tectable Tg does not allow precise assessment of a patient’s   disease specific mortality, and can define the type of surgery
status. Therefore, both GLs recommend monitoring the           and the indication for RAI administration (Tab. VI). Both
trend of Tg overtime, as stable or declining Tg levels are     the IC and ATA recommend dynamic use of this classifica-
reassuring, whereas a Tg increase suggests residual/recur-     tion to evaluate the response to initial therapy and consider
rent disease. Both the ATA and IC agree that TgAb should       any changes of the calculated risk during follow-up. This
be quantitatively assessed whenever serum Tg is evaluated.     allows an individualised approach to ongoing management
Following total thyroidectomy and remnant RAI ablation,        and avoids aggressive, needless treatment of patients initially
TgAb usually disappears over a median of about 3 years         classified at intermediate or high risk, who are free from dis-
in patients without evidence of residual disease. Increased    ease after initial therapy. Table VIII compares the two classi-
TgAb values over time may serve as a surrogate marker of       fications and related classification criteria. According to the
residual normal thyroid tissue or tumour, while declining      ATA, the response to treatment can be defined as follows:
TgAb levels are considered a good prognostic sign.             • excellent, in case of stable basal Tg levels, consistent
Neck US has a primary role in follow-up, especially when          with the presence of a normal thyroid lobe, and negative
serum Tg is not a reliable marker, because thyroid cancer         US;
often spreads or recurs in cervical lymph nodes or thyroid     • biochemical incomplete, when unstimulated Tg is inap-
bed. To confirm suspicious US findings, both the ATA and          propriately high and/or increases over time in the pres-
IC recommend US-guided FNA for cytology and Tg meas-              ence of similar TSH levels, with negative US;
urement in the washout fluid. However, the ATA GL states       • structural incomplete, in the presence of morphological
that suspicious lymph nodes should be biopsied only if            evidence of disease, regardless of Tg values;
greater than 8-10 mm in the smallest diameter, and a posi-     • indeterminate, in case of non-specific US findings and/
tive result would change management; otherwise, they may          or non-evaluable Tg trend.
be followed-up without biopsy.                                 IC refers only to initial therapy response and does not in-
The IC states that other functional (whole-body RAI scan,      clude the indeterminate response.



50
                                                  Comparison between 2015 ATA guidelines and Italian Consensus for DTC management. A commented report




Table VII. Indications for rhTSH in the preparation for RAI therapy of patients with metastatic DTC in Italy, according to the law 648/96.
                                 Indications                                                                         Examples
 Patients whose serum TSH cannot be raised (at least 30 mU/mL) because of         Primary or secondary hypopituitarism
 concurrent clinical conditions                                                   Functional metastasis
 Patients with underlying comorbidities making iatrogenic hypothyroidism          Previous cerebral stroke or TIA
 potentially risky                                                                Cardiomyopathy (NYHA grade III or IV)
                                                                                  Severe renal failure (stage 3 or superior)
                                                                                  Serious mental disorders (severe depression, psychosis)



Table VIII. Response-to-therapy category comparison. Tg thyreoglobulin.
                                                    Italian Consensus                                                     ATA Guidelines
 Category                                                    Definition                                                      Definition
 Excellent response                 Negative or non-specific structural or functional imaging      Negative imaging
                                    findings                                                       and either
                                    and either                                                     Suppressed Tg < 0.2 ng/mL
                                    Suppressed Tg < 0.2 ng/mL                                      or
                                    or                                                             TSH-stimulated Tg < 1 ng/mL
                                    TSH-stimulated Tg < 1 ng/mL
 Biochemical incomplete             Negative imaging                                               Negative imaging
 response                           and                                                            and
                                    Detectable basal Tg                                            Suppressed Tg ≥ 1 ng/mL
                                    or                                                             or
                                    Detectable stimulated Tg                                       Stimulated Tg ≥ 10 ng/mL
                                    or                                                             or
                                    Rising anti-Tg antibody levels                                 Rising anti-Tg antibody levels
 Structural incomplete response     Structural or functional evidence of disease                   Structural or functional evidence of disease
                                    With any Tg level                                              With any Tg level
                                    With or without anti-Tg antibodies                             With or without anti-Tg antibodies
 Indeterminate response                                                                            Nonspecific findings on imaging studies
                                                                                                   Faint uptake in thyroid bed on RAI scanning
                                                                                                   Detectable basal Tg, but <1 ng/mL
                                                                                                   Detectable Stimulated Tg, but <10 ng/mL
                                                                                                   or
                                                                                                   Anti-Tg antibodies stable or declining in the absence of
                                                                                                   structural or functional disease



L-thyroxine therapy                                                                balance the potential benefit of TSH suppression with its
                                                                                   possible harm.
DTC express the TSH receptor on the cell membrane and
                                                                                   The ATA gives indications on TSH suppression after initial
respond to TSH stimulation by increasing rates of cell
                                                                                   therapy and in long-term follow-up based on the clinical
growth. Hence, TSH suppression using supraphysiologic
                                                                                   situation and response to treatment (Tabs. IX, X). The IC
doses of LT4 has traditionally been considered a cornerstone
in long-term management of DTC patients to decrease the                            recommends similar management of levothyroxine therapy.
risk of recurrence. This attitude is no longer strictly fol-                       In patients with excellent response to initial treatment (and
lowed for various reasons: several studies have demonstrat-                        in those with indeterminate response, according to ATA),
ed that TSH suppression may improve outcomes in high-                              levothyroxine therapy should keep TSH in the low/normal
risk patients, while its benefit is more uncertain in low-risk                     range (0.5-2 mU/L).
cases; the appropriate degree and duration of TSH suppres-                         However, high-risk patients at diagnosis with an excellent
sion in long-term follow-up is unknown, especially in high-                        (or indeterminate) response to therapy, ATA suggests main-
risk patients judged free of disease; the administration of                        taining a moderate suppression of TSH (0.1-0.5 mU/L) for
supraphysiological doses of LT4 induces a state of subclini-                       up to 5 years.
cal thyrotoxicosis, which can cause adverse effects. Thus,                         For both the ATA and IC, patients with persistent biochem-
the choice of optimal TSH for individual patients should                           ical disease should undergo Tg, TgAb determination and



                                                                                                                                                              51
G. Arrigoni et al.




Table IX. Initial TSH suppression according to ATA Guidelines. Tg thyreoglobulin.
 Clinical situation/response to treatment                                                                                    Optimal TSH values
 High-risk thyroid cancer patients                                                                                       < 0.1 mU/L
 Intermediate-risk thyroid cancer patients                                                                               0.1-0.5 mU/L
 Low-risk thyroid cancer patients who have undergone or not remnant ablation, with undetectable Tg levels                0.5-2 mU/L
 Low-risk thyroid cancer patients who have undergone or not remnant ablation, with low Tg levels                         0.1-0.5 mU/L
 Low-risk thyroid cancer patients who have undergone lobectomy                                                           0.5-2 mU/L
                                                                                                                         (even without LT4 therapy)



Table X. TSH suppression in the long-term follow-up according to ATA Guidelines.
 Clinical situation/response to treatment                                                                                   Optimal TSH values
 Patients with a structural incomplete response                                                                          < 0.1 mU/L
 Patients with a biochemical incomplete response                                                                         0.1-0.5 mU/L
 High-risk thyroid cancer patients with an excellent or indeterminate response                                           0.1-0.5 mU/L
                                                                                                                         for up to 5 years
 Patients with an excellent or indeterminate response (especially if at low-risk for recurrence)                         0.5-2 mU/L
 Patients with an excellent or indeterminate response, who not have undergone remnant ablation                           0.5-2 mU/L



neck US every 6-12 months. For these patients, both GLs                             represent the leading clinical practice recommendations re-
suggest moderate (TSH 0.1-0.5 mU/L) or complete (TSH                                garding DTC management. However, they were developed
< 0.1 mU/L) suppression, depending on the overall clinical                          predominantly by North American experts. European ex-
context. A Tg or TgAb increase (especially when the dou-                            perts sometimes have different perspectives and divergent
bling time is < 12 months, as pointed up by the IC) suggests                        viewpoints, depending on epidemiological, methodologi-
progression and requires further morphological investiga-                           cal, practical and medico-legal differences 41. These consid-
tions to identify structural disease.                                               erations explain the opportunity of the IC, which adapts the
For persistent structural disease, both the ATA and IC agree                        ATA GLs to current practice and expert opinions in Italy.
on adopting an individualised follow-up programme that                              The result has been the series of general and homogeneous
considers multiple clinical-pathological factors, including                         recommendations on the clinical and therapeutic manage-
the location, size, growth rate, ability to concentrate radi-                       ment of thyroid nodules and DTC that was reviewed.
oiodine and intensity of 18FDG-PET uptake. In these high-                           Currently, the goal of treatment is to achieve the highest
risk patients, TSH should be maintained at < 0.1 mU/L.                              disease-free survival rate, with less invasiveness and mini-
                                                                                    mal cost and impact on the patients’ quality of life. This
Legal issues                                                                        trend, which envisages a therapeutic approach decidedly
                                                                                    more conservative than in the recent past, finds justifica-
The IC state that the guidance should not replace clinical
                                                                                    tion in both the epidemiological evolution of DTC (smaller
judgement and should be used to complement informed
                                                                                    tumours, diagnosed in the early or even preclinical phase,
clinical choices. Informed consent is mandatory to reduce
                                                                                    with a generally favourable prognosis) and in the excellent
medical conflicts by discussing different clinical choices
                                                                                    results from large series of patients.
with the patient and by taking into consideration any ex-
pression of dissent. This topic is not covered by the ATA                           Clinical data emerge from both prospective and retrospec-
GLs.                                                                                tive studies.
                                                                                    In 1993, an observational clinical trial began in Kuma Hos-
                                                                                    pital (Japan) with the aim of comparing surgery with active
Discussion                                                                          surveillance (AS) in low-risk papillary microcarcinomas.
GL on diagnosis and management of thyroid nodules and                               Patients, adequately informed, were free to choose between
differentiated thyroid carcinoma have been drawn up pe-                             the two options. About two years later, Tokyo’s Cancer
riodically by various national and international scientific                         Institute Hospital also began a stackable AS programme,
societies, and the most recent were published simultane-                            and subsequently several authors from around the world
ously or even after the ATA GL 36-40. The ATA GLs arguably                          reported their experience of AS for PTMC. Therefore, the



52
                                         Comparison between 2015 ATA guidelines and Italian Consensus for DTC management. A commented report




currently available data are plentiful and represent an AS            Authors’ contributions
experience of about 25 years on thousands of patients with            GA data collection, writing and editing the manuscript, EC
low-risk papillary microcarcinomas. They confirm a low                editing the manuscript, MF editing the manuscript, AP ed-
rate of disease progression during AS and the absence of              iting the manuscript, RRG editing the manuscript, GS con-
impact on treatment efficacy or outcomes 19-22,42,43.                 ception and design of the study, editing and supervision,
The ATA GLs are based on mainly retrospective studies.                NP conception of the study, editing and supervision.
This is one critical point, as they are founded on the analy-
sis of cases treated in an outdated manner (total thyroid-            Ethical consideration
ectomy for tumors > 1 cm that eliminates the problem of               Ethical review and approval was not required for the study.
frequent neoplasm multifocality, facilitates follow-up and            Both guidelines have been drawn up following the require-
allows radiometabolic treatment).                                     ments of the World Medical Association’s Declaration of
Therefore, some prognostic variables that we consider al-             Helsinki.
most irrelevant today, such as neoplastic microfoci in the
contralateral lobe, minimal extra-thyroid invasion, or mi-            References
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                                                                           Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thy-
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By analysing and comparing the ATA and IC GLs, we high-               8
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                                                                      9
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                                                                      12
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Funding                                                                    managed at the Mayo Clinic during six decades (1940-1999): tem-
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