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Endocrine, Metabolic & Immune Disorders-Drug Targets, XXXX, XX, 1-10 1
GUIDELINES
1871-5303/XX ? XXXX Bentham Science Publishers
Italian Guidelines for the Management of Non-Functioning Benign and
Locally Symptomatic Thyroid Nodules
Enrico Papini1, Anna Crescenzi2, Annamaria D’Amore3, Maurilio Deandrea4, Anna De Benedictis5, Andrea Frasoldati6, Roberto
Garberoglio7, Rinaldo Guglielmi1, Celestino Pio Lombardi3, Giovanni Mauri8, Rosa Elisa Miceli9, Soraya Puglisi10, Teresa
Rago11, Domenico Salvatore12, Vincenzo Triggiani13, Dominique Van Doorne14, Zuzana Mitrova15, Rosella Saulle15, Simona
Vecchi15, Michele Basile16, Alessandro Scoppola17, Agostino Paoletta18, Agnese Persichetti19, Irene Samperi20, Renato Cozzi21,
Franco Grimaldi22, Marco Boniardi23, Angelo Camaioni24, Rossella Elisei11, Edoardo Guastamacchia13, Giulio Nati25, Tommaso
Novo26, Massimo Salvatori27, Stefano Spiezia28, Gianfranco Vallone29, Michele Zini6 and Roberto Attanasio30,
1Department of Endocrine and Metabolic Diseases, Ospedale Regina Apostolorum, Albano Laziale, Rome, Italy; 2Department of Endocrine
Organs and Neuromuscolar Pathology, Università Campus Bio-Medico di Roma, Rome, Italy; 3Endocrine Surgery Division, Agostino Ge-
melli School of Medicine, University Foundation Polyclinic, Rome, Italy, 4Endocrinology and Center for Thyroid Diseases, Ospedale Mau-
riziano "Umberto I", Turin, Italy; 5Quality Management - Clinical Direction, Fondazione Policlinico Universitario Campus Bio-Medico,
Rome, Italy; 6Struttura Complessa di Endocrinologia, Arcispedale S. Maria Nuova, IRCCS, Reggio Emilia, Italy; 7Freelancer at Thyroid
Multidisciplinary Center at Humanitas Cellin , Turin, Italy; 8Interventional Radiology, IRCCS European Institute of Oncology, Milan, Italy;
9Private practice, Rome, Italy; 10Department of Clinical and Biological Sciences, Internal Medicine, AOU San Luigi di Orbassano, University
of Turin, Turin, Italy; 11Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 12Department of Public Health,
University Federico II, Naples, Italy; 13Interdisciplinary Department of Medicine-Section of Internal Medicine, Geriatrics, Endocrinology
and Rare Diseases, University of Bari, Bari, Italy; 14Associazione Medici Endocrinologi, relationship with Patients’ Associations, Rome
Italy; 15Department of Epidemiology, Lazio Region Health Service, Rome, Italy; 16High School of Economy and Management of Health
Systems, Catholic University of Sacred Heart, Rome, Italy; 17Department of Endocrinology, Ospedale Santo Spirito, Rome, Italy; 18Depart-
ment of Endocrinology, ULSS6 Euganea, Padova, Italy; 19Department of Firefighters, Public Rescue and Civil Defense, Ministry of Interior,
Rome, Italy; 20Department of Endocrinology, ASL Novara, Novara, Italy; 21President of Associazione Medici Endocrinologi, Milan, Italy;
22Past-president of Associazione Medici Endocrinologi, Udine, Italy; 23General Oncologic and Mini-invasive Surgery Department, ASST
Grande Ospedale Metropolitano Niguarda, Milan, Italy; 24Otolaryngology Department, San Giovanni-Addolorata Hospital, Rome, Italy;
25ASL Roma, Rome, Italy; 26Department of Endocrinology, Santa Maria Nuova Hospital, Turin, Italy; 27Nuclear Medicine Unit, Fondazione
Policlinico Universitario A. Gemelli IRCCS and Department of Radiological and Hematological Sciences, Catholic University of Sacred
Heart, Rome Italy; 28Department of Endocrine and Ultrasound-Guided Surgery, Ospedale del Mare, Naples, Italy; 29Department of Radiol-
ogy, Federico II University Hospital, Naples Italy; 30AME Scientific Committee, Milan, Italy
Abstract: Aim: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign
thyroid nodules causing local symptoms in adults outside of pregnancy.
Methods: This GL has been developed following the methods described in the Manual of the National Guideline Sys-
tem. For each question, the panel appointed by Associazione Medici Endocrinology (AME) identified potentially rele-
vant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as “critical”
and “important” were considered in the systematic review of evidence and only those classified as “critical” were
considered in the formulation of recommendations.
Results: The present GL contains recommendations about the respective roles of surgery and minimally invasive treat-
ments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy
as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thy-
roid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral
thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a sympto-
matic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary
care or when referred to specialists.
Conclusion: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hos-
pitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the
implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign
thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions
and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term re-
placement therapy and the management of surgical complications may also be speculated.
A R T I C L E H I S T O R Y
Received: January 06, 2023
Revised: January 06, 2023
Accepted: January 11, 2023
DOI:
10.2174/1871530323666230201104112
Keywords: Thyroid nodule, thyroidectomy, hemi-thyroidectomy, ablation, thermo-ablation, radiofrequency, laser, microwave,
HIFU, ultrasound, ethanol injection.
Address correspondence to this author at the AME Scientific Committee, Milan, Italy; E-mail: roberto.serena@libero.it
This is an Open Access article published
under CC BY 4.0
https://creativecommons.org/licenses/
by/4.0/legalcode
2 Endocrine, Metabolic & Immune Disorders-Drug Targets, XXXX, Vol. XX, No. XX Papini et al.
1. INTRODUCTION
Thyroid nodules are detected in 5-7% of the adult popula-
tion at physical examination [1] and in up to 60% of adult fe-
males as an incidental finding during imaging procedures [2,
3]. Most nodules are benign, but 5-15% may be malignant,
with a risk level depending on sex, age, and medical history
[2, 3]. Fine needle aspiration (FNA) is a reliable procedure to
stratify the risk of malignancy [2, 3] and no therapy is required
for cytologically benign, non-hyperfunctioning thyroid nod-
ules if they are asymptomatic [4]. However, a low but not neg-
ligible fraction of these nodules progressively grows until lo-
cal pressure symptoms develop [4].
The diagnostic workup and the therapeutic management of
this frequent clinical problem drains considerable health re-
sources, while patients’ quality of life (QoL) may be nega-
tively affected by aggressive treatment modalities. Data from
the USA demonstrate a progressive increase in thyroid sur-
gery (+39% from 1996 to 2006) [5] and in total thyroidecto-
mies for benign disease (from 17.6% during 1993-1997 to
39.4% during 2003-2007) [6]. European data are aligned: 60%
of thyroid surgeries are performed in France for benign nodu-
lar thyroid disease [7] and only 30% of thyroid surgeries for
benign diseases in Germany are due to hyperthyroidism or lo-
cal pressure symptoms [8].
An appropriate work-up for nodular thyroid disease,
aimed at decreasing unwarranted surgery, should follow the
sequential steps listed below [1-3, 9-12].
1. History: pay attention to family history of thyroid sur-
gery, thyroid tumors, genetic syndromes associated with
thyroid neoplasms, and personal history of external radi-
ation or nuclear fall-out.
2. Physical examination: pay attention to the anterior and
lateral neck for lymphadenopathy.
3. Laboratory: first assay thyrotropin [TSH) to rule out al-
terations of thyroid function. If they are present, free thy-
roid hormone levels should be determined. If TSH is low,
perform a thyroid scintiscan to disclose regional hyper-
function. Hot nodules are generally benign and do not re-
quire cytologic examination. If TSH is high, anti-thyroid
antibodies should be evaluated. Normal serum calcitonin
reliably rules out medullary thyroid carcinoma.
4. Neck ultrasound (US): examination should be performed
by a skilled operator with a high-frequency linear probe.
Malignancy risk classification should be applied to the
nodule according to EU-TIRADS system [1-3, 9, 10, 13].
5. US-guided FNA: thyroid sampling should be performed
according to an algorithm integrating clinical suspicion,
nodule size, and US risk classification [9, 10, 13]. Use a
validated classification for cytology reporting [14],
mainly the 2014 Italian Consensus for the Classification
and Reporting of Thyroid Cytology [15]. In several major
series, malignancy risk is lower than 3% for the TIR2 cat-
egory.
The standard treatment for nodular thyroid disease that
causes clinical symptoms is surgery [2]. Selective resection of
the nodule is no more employed, due to the high rate of peri-
and post-operative complications and recurrence. The resec-
tion of the affected lobe and isthmus is currently suggested for
benign monolateral nodules and also for differentiated thyroid
carcinomas (DTC) staged as clinically pT1 and pT2 [2, 11].
This approach prevents the need for complete replacement
therapy [16]. Conversely, total thyroidectomy remains the
first choice for bilateral multinodular goiter, Graves’ disease,
and advanced DTC. Importantly, high-volume thyroid sur-
geons achieve better outcomes with a lower rate of complica-
tions [17-19]. A suggested cut-off is 50 thyroidectomies
yearly per surgeon or 100 thyroidectomies per center [20].
In the last decades, image-guided non-surgical procedures
(MIT) have become available for the management of benign
thyroid nodules, aiming to relieve of local pressure symptoms
[21]. MIT includes chemical ablation with ethanol injection
[PEI] [22, 23] and thermal ablation with laser [LTA] [24], ra-
diofrequency [RFA] [25-27], microwaves [MWA] [28, 29], or
high intensity focused ultrasounds (HIFU) [30]. The long-term
follow-up of these procedures is still limited (up to 5 years in
most series) and in 10-15% of the cases, a partial regrowth of
the nodule occurs, warranting further treatment [21].
TSH-suppressive treatment with levo-thyroxine (LT4)
[31-33] and radioiodine ablation [34] are no more employed
in this setting due to low efficacy and potential side effects.
Due to the high prevalence of benign nodular disease, the
management algorithm should be based on the risk-benefit
and cost-efficacy ratios of the different procedures as well as
on their accessibility. Physicians should advice patients about
the therapeutic options, and inform them about the risks and
benefits of the available procedures and of their impact on
QoL to allow a shared decision with patients.
The aim of this guideline (GL) is to answer the question:
What is the efficacy of hemithyroidectomy plus thyroid isth-
mus resection vs. total thyroidectomy vs. ablative procedures,
vs. other non-invasive treatments, vs. no treatment for patients
with benign symptomatic thyroid nodules?
2. METHODS
This GL was developed according to the Methodological
manual for the production of clinical practice GLs developed
by the National Center for the Clinical Excellence, Quality
and Safety of Care of the Italian National Institute of Health
(http://www.snlg-iss.it). Appendix 1 details the names and
roles of all the people involved in the GL development team.
2.1. Clinical Questions
The recommendations are the answers to a clinical ques-
tion, formulated by the panel using the Population-Interven-
tion-Comparison-Outcome (PICO) framework (Appendix 2).
2.2. Selection of Outcomes
For each question, the panel identified potentially relevant
outcomes, which were then rated for their impact on therapeu-
tic choices using a 9-point scale, namely:
? 1–3 points: outcomes of limited relevance
? 4–6 points: important, but not critical outcomes
? 7–9 points: critical outcomes.
Italian Guidelines for Management of Thyroid Nodule Endocrine, Metabolic & Immune Disorders-Drug Targets, XXXX, Vol. XX, No. XX 3
Only outcomes classified as “critical” and “important”
were considered in the systematic review of evidence and only
those classified as “critical” were considered in the formula-
tion of recommendations [35].
2.3. Literature Review and Assessment of the Quality of
Evidence
A systematic search for each question was performed on
the following databases: Cochrane Library, MEDLINE, Em-
base, Web of Science, and CINAHL (from inception to Octo-
ber 2020).
Specific search strategies were used for each database, as
specified in each section of Appendix 3. No time or language
limits were imposed for all the searches. References of re-
trieved items were searched for further studies meeting inclu-
sion criteria.
A systematic review was performed through the following
steps:
1. Selection of the eligible studies obtained with the initial
search, based on title and abstract, for retrieval as full text.
2. Identification among retrieved full-text items of relevant
studies, based on a priori inclusion and exclusion criteria.
3. Assessment of potential bias using validated instruments
(Cochrane criteria for RCT – [36] - and checklist New-
castle-Ottawa Scale for observational studies – [37]).
4. Extraction of main characteristics of the selected studies
(enrolled population, considered outcomes, results), sum-
marized in tables.
5. Quantitative synthesis for each outcome, calculating odds
ratio (OR) for categorical outcomes and weighted mean
difference (WMD) for continuous variables with 95%
confidence intervals (CI). Quantitative meta-analysis was
performed with RevMan 5.4 using fixed effects models.
6. Assessment of heterogeneity (I2) by the I2 statistic stating
the percentage of variability in effects esteem due to het-
erogeneity rather than to chance.
7. The overall quality and strength of available evidence for
outcomes selected by the panel were rated using the
GRADE criteria.
8. Synthesis of results, using the GRADEPro Guideline De-
velopment tool (https://gradepro.org), with the frame-
works EtD, which summarize results of systematic re-
views for problem priority, desired and undesired effects
of treatments, the strength of available evidence, values
and preferences of stakeholders, economic resources
needed, equity, acceptability, and feasibility of interven-
tions.
2.4. Pharmacoeconomic Studies
The economic evaluation was performed by a pharmaco-
economist with specific expertise (MB).
Since official data about costs of surgery and thermoabla-
tion for thyroid nodules were not always available, we per-
formed a survey among panel members from different disci-
plines and regions that were representative of the Italian health
system setting, looking for specific drivers that contribute to
the total cost of each procedure (either surgery or thermoabla-
tion). Specifically for each procedure, we investigated the du-
ration, type, and dosage of employed drugs, type and quanti-
ties of disposable materials, number and time of involvement
of each operator, and percentage of patients requiring a care-
giver during and after the procedure (indirect costs).
We calculated the mean value for each parameter to allow
their use in the different regional settings under Italian Na-
tional Health Service (NHS).
The Activity based costing (ABC) analysis is a useful tool
to calculate resource employment and evaluation of the gross
cost of procedures. ABC follows three steps:
1. Resource identification using a specific survey among the
interdisciplinary panelists. The resources required to pro-
vide the investigated procedures were detailed to quantify
each component (time of operators’ activities, materials,
drug dosage, technical resources, etc.).
2. Cost determination by consultation with scientific litera-
ture and specific databases (such as price lists) [38-43].
3. Valorization of results: the data obtained during the pre-
vious steps were combined to define the aggregate value
of each action and the whole process [44].
The economic analysis evaluated the four large resource
categories employed in the procedure under investigation:
? The direct cost paid by NHS for drugs.
? The direct cost paid by NHS for disposable materi-
als.
? The direct cost paid by NHS for the working time of
operators and the use of structures.
? Indirect costs sustained by patients and caregivers.
To assess the costs driven by potential complications, we
evaluated the rate of occurrence for each complication of the
various procedures and we expressed the relative cost as the
corresponding fraction. Namely, if the cost of a specific com-
plication was € 5000, including all the drivers (employed
drugs, hospital stay, and loss of productivity), and if the com-
plication is reported to occur in 1% of patients, the sum of €
50 was added to the total cost of the procedure.
2.5. Development of Recommendations
The GL panel examined and discussed each clinical ques-
tion: the EtD frameworks, the tables of evidence, and the sum-
maries of results (forest plots of meta-analyses). The GL panel
formulated recommendations (which were rated as strong or
weak) based on the priority of the problems, benefits, and
harms of the options, strengths of evidence, values and pref-
erences, use of resources, feasibility, acceptability, and equity
of the procedure.
Disagreements were settled through collective discussion.
If evidence was not available or it was inappropriate for a
formal rating of the quality of evidence, the GL panel devel-
oped indications for good clinical practice, which should be
considered complementary to recommendations.
4 Endocrine, Metabolic & Immune Disorders-Drug Targets, XXXX, Vol. XX, No. XX Papini et al.
2.6. External Review
The panel appointed a board of external reviewers with
specific expertise in thyroid disease management. External re-
viewers received a draft version of the GL and submitted their
comments to the panel, which included, after a dedicated dis-
cussion, the amendments to the GL document.
2.7. Value of Recommendations
Quality of evidence was rated as:
? High: highly reliable data whose confidence in es-
timated effects is very unlikely to be modified by
further studies.
? Moderate: moderately reliable data whose confi-
dence in estimated effects could be modified by fur-
ther studies.
? Low: still limited and uncertain results which need
further research for a reliable assessment of the pos-
itive and negative effects of the intervention.
? Very low: available data are not reliable and the es-
timates of effects should be considered with cau-
tion.
The strength of recommendations was rated as strong or
weak.
A strong recommendation implies:
? For clinicians: the majority of patients should re-
ceive the recommended intervention.
? For patients: almost all properly informed patients
should follow the recommendation whereas only a
small fraction of them may choose different op-
tions.
? For the policy makers: the recommendation can be
employed for planning the use of the available re-
sources.
A weak recommendation implies:
? For clinicians: the final choice should include care-
ful consideration of patients’ values and prefer-
ences.
? For patients: the majority of properly informed pa-
tients will follow the recommendation, but a minor-
ity of them may choose different options.
? For the policy makers: a discussion involving the
stakeholders should be performed on the issue.
3. RESULTS
The PRISMA flow diagram for the selection of the stud-
ies is illustrated in Appendix 4. Two randomized controlled
trials (RCT) [45, 46] and 12 observational studies (nine ret-
rospective – [47-55] and three prospective – [56-58]) met all
the inclusion criteria. The methodological quality evaluation
of selected studies is detailed in Appendix 4 and Appendix
5, respectively.
No studies that compared thyroidectomy with TSH-sup-
pressive or semi-suppressive treatment with LT4, iodine sup-
plements, food integrators, radioiodine treatment, or clinical
observation were retrieved.
3.1. Comparison between Hemithyroidectomy and Thy-
roidectomy
One RCT [45] and eight observational studies evaluated
this topic [56, 58].
Major peri-procedural complications were addressed in
two studies [48, 52] but no quantitative synthesis could be per-
formed.
Minor peri-procedure complications were addressed in an
RCT with 90 participants [45] and in five observational stud-
ies with 1390 patients [46, 48, 52, 56, 58]. Both studies re-
ported a much lower incidence of hypocalcemia after he-
mithyroidectomy (relative risk - RR -, 0.12; 95% confidence
interval - CI -, 0.06-0.25).
No study addressed the outcome of the cure for local signs
and symptoms.
3.2. Comparison between Hemithyroidectomy and Ther-
moablation
This topic was addressed in one RCT with the use of
MWA [46, 53] and four observational studies with the use of
RFA [53], HIFU [54, 56], and MWA [55].
QoL was evaluated in two studies [45, 52] but no quanti-
tative synthesis could be performed. The RCT [46] employed
the questionnaire SF-36 and after a 6-month follow-up re-
ported an improvement in general health, vitality, and mental
health in the MWA group (N = 28) compared to the surgical
group (N = 24). QoL scores were lower in the surgical group
and superimposable in the MWA group when compared to the
general population. In an observational study employing the
HRQoL scale [53], the group treated with RFA achieved after
6 months a significantly higher improvement in general
health, vitality, and mental health as compared to the surgical
group (N = 108 for both groups).
The same RCT [46] did not observe any difference be-
tween the two groups for persistent local pain, acute hy-
pocalcemia, and wound infection. An observational study of
101 patients [55] reported an increased risk of acute hy-
pocalcemia in the surgical group as compared to MWA (RR,
13.61; 95% CI, 0.80-232.14). Three observational studies
with 401 participants [54, 55, 57] showed an increased risk of
wound infection or skin burn in the surgical group (RR, 4.54;
95% CI, 0.22-92.2).
3.3. Economic Evaluation
The mean cost per patient of the procedures under evalua-
tion is € 4211,92 for hemithyroidectomy, € 5185,36 for total
thyroidectomy, and € 1560,06 for thermoablation (Table 1).
Table 2 Details the summary of evidence for the different
domains evaluated by the panel.
Italian Guidelines for Management of Thyroid Nodule Endocrine, Metabolic & Immune Disorders-Drug Targets, XXXX, Vol. XX, No. XX 5
Table 1. Comparison of the costs of the procedures.
Procedure Hemithyroidectomy Total Thyroidectomy Thermoablation
Before Treatment
- € 281.80 € 281.80 € 369.25
Periprocedural
Drugs € 12.08 € 11.49 € 1.94
Materials € 149.97 € 199.54 € 661.98
Operators € 184.65 € 232.47 € 40.64
Operating room € 1356.98 € 1685.28 -
Hospital stay € 1348.00 € 1617.60 € 193.78
Sub-total € 3051.77 € 3746.39 € 898.34
Follow-up
Standard course € 105.34 € 133.03 € 91.11
Course with acute complications € 7.98 € 9.06 € 7.93
Course with chronic complications° € 9.07 € 10.40 € 9.66
Sub-total € 49.79 € 152.50 € 108.70
Loss of Patient’s Productivity
§ € 755.97 € 1004.68 € 183.77
Gross total € 4211.92 € 5185.36 € 1560.06
Note: Acute complications were estimated to involve 3.5% of patients.
°Chronic complications were estimated to involve 3.5% of patients.
§Caregivers were estimated to be involved in the assistance of 2.5% of patients undergoing hemithyroidectomy, 5% of patients undergoing total thyroidectomy,
and 10% of patients undergoing thermoablation. Days required for recovery after the procedure were estimated, as a mean, 8.50, 11.22, and 1.82, respectively.
Table 2. Summary of evidence.
- Hemithyroidectomy vs. Thyroidectomy Hemithyroidectomy vs. Thermoablation
Desirable effects Large Moderate
Undesirable effects Small Moderate
Quality of evidence Very low Very low
Values Probably large uncertainty or variability Probably large uncertainty or variability
Balance of effects Favours hemithyroidectomy Probably favours thermoablation
Required resources Moderate savings Moderately higher costs
Quality of evidence for required resources Moderate Moderate
Cost-efficacy ratio Probably favours hemithyroidectomy Unknown
Equity Unknown Unknown
Acceptability Probably yes Probably no
Feasibility Probably yes Probably yes
6 Endocrine, Metabolic & Immune Disorders-Drug Targets, XXXX, Vol. XX, No. XX Papini et al.
3.4. Recommendations
Based on the reported analyses, the panel issued the fol-
lowing recommendations.
Question 1. What is the efficacy of hemithyroidectomy
plus isthmectomy compared to total thyroidectomy for pa-
tients with a symptomatic benign thyroid nodule?
Recommendation 1: we suggest hemithyroidectomy plus
isthmectomy, provided that clinically significant disease is not
present in the contralateral thyroid lobe (weak recommenda-
tion, very low quality of evidence).
Recommendation 2: we suggest considering total thy-
roidectomy for patients with clinically significant disease in
the contralateral thyroid lobe (weak recommendation, very
low quality of evidence).
Question 2. What is the efficacy of hemithyroidectomy
plus isthmectomy compared to ultrasound-guided ablative
treatments for patients with a symptomatic benign thyroid
nodule?
Recommendation 3: we suggest considering MIT as an
alternative option to surgery for patients with a symptomatic,
solid, benign, single, or dominant thyroid nodule (weak rec-
ommendation, very low quality of evidence).
3.5. Indications for Good Clinical Practice
The following statements reflect the opinions of the panel
members about issues not addressed by studies directly com-
paring the different therapeutic options. These statements are
complementary to the formal recommendations, are based on
clinical experience, and are unanimously agreed upon by the
panel. Thus, they are provided as an aid for good clinical prac-
tice.
1. The treatment choice for symptomatic benign thyroid
nodules is based on neck US examination and FNA cy-
tology report.
2. TSH-suppressing treatment with LT4 is not a routine op-
tion in euthyroid patients due to poor efficacy and poten-
tial side effects.
3. Radioiodine treatment, with or without rhTSH priming,
is not an appropriate option due to modest volume reduc-
tion, slow symptom decrease, potential side effects, and
risk of late hypothyroidism.
4. PEI should be considered as the first-line option for
symptomatic benign, single or dominant, nodules which
are completely or nearly completely cystic.
5. In patients with comorbidities, increased surgical risk, or
refusal of surgery, US-guided TA procedures are the ap-
propriate approach to symptomatic, benign thyroid nod-
ules.
6. US-guided ablative procedures (PEI or TA, performed
with different techniques) are safely performed in a day-
hospital setting, unless patients’ clinical conditions war-
rant hospitalization.
3.6. Guideline Update
This systematic review will be updated with the use of
the same search strings, three years from the date of the GL
final approval. The ERT and the GL panel will assess the
availability of new clinical data that could modify the overall
quality of evidence and the risk/benefit ratio and, conse-
quently, the formulation of the recommendations and their
strength.
The GL panel will also consider updating, adding, or re-
moving clinical questions or outcomes of interest and their
relative relevance. In case of changes in clinical questions
and/or critical outcomes, the process of evidence review and
development of the recommendation will be performed again.
4. DISCUSSION
Hemithyroidectomy is a well-known and standardized
procedure, while TA for thyroid nodules was introduced re-
cently. TA is a less standardized treatment modality, is per-
formed with different devices and techniques, and requires a
specific operator’s training.
The key problem in the cost determination of MIT is the
unavailability of consistent data about the various methodol-
ogies used for TA and the value of NHS reimbursement in the
different Italian regions. Thus, a preliminary survey on this
issue was performed on clinicians with specific expertise in
MIT who are routinely involved in the management of thyroid
nodular disease.
The direct cost of the surgical procedure results in the main
expense for both hemithyroidectomy (72.45% of total) and to-
tal thyroidectomy (72.24%), while is only 57.58% for TA. It
is worth noting that the cost item for health operators should
be interpreted as a “cost-opportunity”. Italian NHS operators,
indeed, are paid regardless of their specific activities.
The implementation of this GL [59] should not increase
the costs generated by the management of thyroid nodules,
though a conclusive assessment needs the evaluation of real
practice data.
Only a quarter of thyroidectomies are now performed be-
cause of malignancy, as demonstrated by two large series in
France [7] and Germany [8]. The average yearly number of
thyroidectomies (summing up the total and partial operations)
performed in Italy in the last 20 years was 40,000, but only a
quarter of them was due to malignancy [60]. These data were
retrieved from the hospital discharge forms, information that
could be biased by a few drawbacks:
? Inconstant accuracy in the compilation.
? Occasional lack of histology report.
? Missing information about laboratory data, number
and size of the nodules, US, and scintigraphic char-
acteristics of the lesion.
? Procedures performed in private structures are not
reported.
Based on their own clinical experience, panel members
esteem that at least 30% of patients operated on for benign
thyroid disease are affected by uni- or multi-nodular goiter
Italian Guidelines for Management of Thyroid Nodule Endocrine, Metabolic & Immune Disorders-Drug Targets, XXXX, Vol. XX, No. XX 7
with a dominant nodule that causes local pressure symptoms.
Accordingly, a range of 8,000-10,000 patients per year could
be suitable for TA. During the next three years, after the pub-
lication of this GL, the number of ablative treatments will
not reach this potential estimate due to the insufficient avail-
ability of centers with skilled operators in our country. Thus,
TA treatments will range from 3000 up to 9000/year, as a
consequence of increased treatment accessibility.
According to cost estimates reported in this GL, the mean
saving for each TA treatment performed in lieu of hemithy-
roidectomy could be € 2651 per patient (that is, € 4211 for
hemithyroidectomy minus € 1560 for ablation). Conse-
quently, the estimated yearly saving for NHS might range
from an initial amount of 7,953,000 to a maximum of €
23,859,000, if the NHS accessibility to TA procedures will be
adequate to satisfy all the requests.
Reimbursement for hemithyroidectomy, as for any proce-
dure performed in public hospitals, is not derived from the plain
sum of reported expenses but is controlled by regulatory agen-
cies. In this regard the reimbursement for hemithyroidectomy
corresponds to ICD9-CM 06.2, 06.3, and 06.51 that produce the
DRG 290, corresponding to a maximum reimbursement of €
3340 for thyroidectomy without complications. TA treatments
for thyroid nodular diseases are presently not coded by NHS. In
clinical practice, most hospitals use the code ICD9-CM 06.98
for this issue which corresponds to “other surgical procedure on
the thyroid gland”. The treatment should be performed in day-
surgery and is reimbursed with € 1373. By applying the NHS
rules, the difference between the costs of the two procedures
can be estimated in € 1967. Accordingly, the yearly saving for
NHS might range from a minimum amount of 5,901,000 (for
3000 TA-treated patients) to a maximum of € 17,703,000 (if all
suitable patients would be treated).
A few limits in the calculation of the expected costs should
be considered.
First, the estimated costs may change due to the fluctua-
tion of the price of the disposable material employed during
both surgery and TA. Second, the 15% rate of recurrency after
TA that was presumed for this analysis might be higher if this
procedure will be performed in centers without specific exper-
tise. Third, cost analysis considered the same follow-up length
for surgery and TA. This might imply an underestimation of
costs associated with TA because it is presumable that the
long-term follow-up after hemithyroidectomy might be less
intensive. Fourth, the costs of possible replacement treatments
after surgery and of its monitoring might change in the future.
Finally, the cost for the operators during surgery should be
increased because the reported calculation does not consider
the loss of time between surgical procedures, such as re-set-
ting of the operating room, preparation of the operators, and
patients weaning from anesthesia.
CONCLUSION
In conclusion, the available data suggest that the imple-
mentation of this GL recommendations will result in the pro-
gressive reduction of surgical procedures for benign thyroid
nodular disease, with a decreased number of admissions to
surgical departments for non-malignant conditions and more
rapid access to patients with thyroid cancer. Importantly, a re-
duction of indirect costs due to long-term replacement therapy
and the management of surgical complications may also be
speculated.
Additionally, an improvement in the management of thy-
roid nodular disease and thyroid patients’ QoL may be
achieved based on the indications for good clinical practice
provided by the experts’ panel.
LIST OF ABBREVIATIONS
ABC = Activity Based Costing
AME = Associazione Medici Endocrinologi (Italian
Association of Clinical Endocrinologists)
CI = Confidence Interval
CINHAL = Cumulative Index to Nursing and Allied
Health Literature
DRG = Diagnosis Related Group
DTC = Differentiated Thyroid Carcinoma
EtD = Evidence to Decision
FNA = Fine-Needle Aspiration Biopsy
GL = Guideline
GRADE = Grading of Recommendations Assessment,
Development and Evaluation
HIFU = High Intensity Focused Ultrasound
HRQoL = Health Related QoL
LT4 = Levo-Thyroxine
LTA = Laser Ablation
MESH = Medical Subject Headings
MIT = Image-Guided Minimally Invasive Treat-
ments
MWA = Microwave Ablation
NHS = National Health Service
OR = Odds Ratio
PEI = Percutaneous Ethanol Injection
PICO = Population, Intervention, Comparison, Out-
come
QoL = Quality of Life
RCT = Randomized Controlled Trial
RFA = Radiofrequency Ablation
RR = Relative Risk
SF-36 = The Short Form Health Survey
TA = Thermal Ablation Procedure
TIRADS = Thyroid Imaging Reporting and Data System
TSH = Thyrotropin
US = Ultrasonography
WMD = Weighted Mean Difference
8 Endocrine, Metabolic & Immune Disorders-Drug Targets, XXXX, Vol. XX, No. XX Papini et al.
CONSENT FOR PUBLICATION
Written informed consent was obtained from all partici-
pants.
CONFLICT OF INTEREST
Dr. Vincenzo Triggiani is the associate editor of the jour-
nal Endocrine, Metabolic & Immune Disorders-Drug Targets.
FUNDING
None.
ACKNOWLEDGEMENTS
This paper is dedicated to the memory of Marco Grandi
and Massimo Torlontano.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher’s
website along with the published article.
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