10.14639/0392-100X-N1412
Objective. The incidence of papillary thyroid carcinoma (PTC) has increased in recent years and its treatment remains controversial. The objective of this study is to identify clinicopathological predictive factors of tumour recurrence.Methods. We retrospectively analysed 4,085 patients who underwent thyroidectomy for PTC from 1996 to 2015. Patients were stratified according to American Thyroid Association (ATA) risk categories and clinicopathological features were evaluated to identify independent factors for recurrence.Results. After a mean follow-up of 58.7 (range 3-256.5) months, tumour recurrence was diagnosed in 176 (4.3%) patients, mostly in lymph nodes. Distant metastasis occurred in 18 patients (0.4%). There were 3 (0.1%) cancer-related deaths. Multivariate analysis showed that tumour size &gt;10 mm, multifocality, extrathyroidal extension and lymph node metastasis (all, P &lt; 0.001) were independent risk factors for recurrence. Further, recurrence was identified in 1.6% of the ATA low-risk, 7.4% of the intermediate-risk and 22.7% of the high-risk patients (P &lt; 0.001). Conclusions. In PTC patients, tumour size &gt;10 mm, multifocality, extrathyroidal extension and presence of lymph node metastasis as well as the ATA recurrence staging system effectively predict recurrence.
text/xml
1827-675X
1412
en
Luiz Paulo Kowalski
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
survival
Predictive factors for recurrence of papillary thyroid carcinoma: analysis of 4,085 patients
Text.Serial.Journal
https://www.actaitalica.it/
41
Thyroid
2021-07-07
2021-01-23
2021-07-08
2021-07-08
236-242
1
Luiz Paulo Kowalski
2021/07/07
10.14639/0392-100X-N1412
236
Head and Neck Surgery and Otorhinolaryngology Department, A. C. Camargo Cancer Center, Sao Paulo, Brazil;  Head and Neck Surgery Department, University of Sao Paulo, Sao Paulo, Brazil
1827-675X
survival
242
Predictive factors for recurrence of papillary thyroid carcinoma: analysis of 4,085 patients
https://www.actaitalica.it/article/download/1412/622
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:236-242; doi: 10.14639/0392-100X-N1412




Thyroid


Predictive factors for recurrence of papillary thyroid
carcinoma: analysis of 4,085 patients
Fattori predittivi di recidiva di carcinoma papillare della tiroide: analisi di 4.085 pazienti
Andre Ywata de Carvalho1, Hugo Fontan Kohler1, Camila Couto Gomes2, Jose Guilherme Vartanian1, Luiz Paulo Kowalski1,3
1
  Head and Neck Surgery and Otorhinolaryngology Department, A.C. Camargo Cancer Center, Sao Paulo, Brazil; 2 Surgical
Oncology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil; 3 Head and Neck Surgery Department, University of Sao Paulo,
Sao Paulo, Brazil


SUMMARY
Objective. The incidence of papillary thyroid carcinoma (PTC) has increased in recent
years and its treatment remains controversial. The objective of this study is to identify
clinicopathological predictive factors of tumour recurrence.
Methods. We retrospectively analysed 4,085 patients who underwent thyroidectomy for
PTC from 1996 to 2015. Patients were stratified according to American Thyroid Associa-
tion (ATA) risk categories and clinicopathological features were evaluated to identify inde-
pendent factors for recurrence.
Results. After a mean follow-up of 58.7 (range 3-256.5) months, tumour recurrence was
diagnosed in 176 (4.3%) patients, mostly in lymph nodes. Distant metastasis occurred in 18
patients (0.4%). There were 3 (0.1%) cancer-related deaths. Multivariate analysis showed
that tumour size >10 mm, multifocality, extrathyroidal extension and lymph node metas-
tasis (all, P < 0.001) were independent risk factors for recurrence. Further, recurrence was
                                                                                                   Received: January 23, 2021
identified in 1.6% of the ATA low-risk, 7.4% of the intermediate-risk and 22.7% of the
                                                                                                   Accepted: April 16, 2021
high-risk patients (P < 0.001).
Conclusions. In PTC patients, tumour size >10 mm, multifocality, extrathyroidal extension
                                                                                                   Correspondence
and presence of lymph node metastasis as well as the ATA recurrence staging system ef-
                                                                                                   Andre Ywata de Carvalho
fectively predict recurrence.                                                                      A.C. Camargo Cancer Center. Rua Professor Anto-
KEY WORDS: thyroid, papillary carcinoma, recurrence, survival                                      nio Prudente, 211, 01509-010, Sao Paulo, Brazil
                                                                                                   Tel. +55 11 2189-5172
                                                                                                   E-mail: andreywata@bol.com.br
RIASSUNTO
Obiettivo. L’incidenza del carcinoma papillare tiroideo (PTC) è aumentata negli ultimi             Funding
anni e il suo trattamento rimane controverso. L’obiettivo di questo studio è identificare i        None.
fattori predittivi clinicopatologici di recidiva tumorale.
Metodi. Abbiamo analizzato retrospettivamente 4.085 pazienti sottoposti a tiroidectomia            Conflict of interest
per PTC dal 1996 al 2015. I pazienti sono stati stratificati in base alle categorie di rischio     The Authors declare no conflict of interest.
dell’American Thyroid Association (ATA) e le caratteristiche clinicopatologiche sono state
valutate per identificare fattori indipendenti di recidiva.                                          How to cite this article: Ywata de Carvalho
Risultati. Dopo un follow-up medio di 58,7 (range, 3-256,5) mesi, la recidiva del tumore             A, Kohler HF, Gomes CC, et al. Predictive fac-
è stata diagnosticata in 176 pazienti (4,3%), principalmente nei linfonodi. Metastasi a di-          tors for recurrence of papillary thyroid carci-
stanza si sono verificate in 18 pazienti (0,4%). Ci sono stati 3 (0,1%) decessi correlati al         noma: analysis of 4,085 patients. Acta Otorhi-
cancro. L’analisi multivariata ha mostrato che le dimensioni del tumore > 10 mm, la multi-           nolaryngol Ital 2021;41:236-242. https://doi.
focalità, l’estensione extratiroidea e le metastasi linfonodali (tutti, P < 0,001) erano fattori     org/10.14639/0392-100X-N1412
di rischio indipendenti per la recidiva. Inoltre, la recidiva è stata identificata nell’1,6% dei
pazienti ATA a basso rischio, nel 7,4% dei pazienti a rischio intermedio e nel 22,7% dei           © Società Italiana di Otorinolaringoiatria
pazienti ad alto rischio (P < 0,001).                                                              e Chirurgia Cervico-Facciale
Conclusioni. Nei pazienti con PTC, la dimensione del tumore > 10 mm, la multifocalità,
l’estensione extratiroidea e la presenza di metastasi linfonodali, nonché il sistema di sta-                      OPEN ACCESS
diazione delle recidive ATA, predicono efficacemente la recidiva.                                  This is an open access article distributed in accordance with
                                                                                                   the CC-BY-NC-ND (Creative Commons Attribution-Non-
PAROLE CHIAVE: tiroide, carcinoma papillare, recidiva, sopravvivenza                               Commercial-NoDerivatives 4.0 International) license. The
                                                                                                   article can be used by giving appropriate credit and mentio-
                                                                                                   ning the license, but only for non-commercial purposes and
                                                                                                   only in the original version. For further information: https://
                                                                                                   creativecommons.org/licenses/by-nc-nd/4.0/deed.en




236
                                                                          Predictive factors for recurrence of papillary thyroid carcinoma




Introduction                                                    lymph node dissection was performed if clinical involve-
                                                                ment was confirmed based on sonographic findings and
The incidence of thyroid cancer is increasing worldwide,
                                                                intraoperative exploration of the neck compartments. Elec-
mainly due to the greater number of papillary thyroid carci-
                                                                tive central neck dissection was performed in the presence
nomas (PTC) incidentally discovered after the widespread
                                                                of extrathyroidal extension. For patients who were patho-
use of ultrasound-guided fine needle aspiration biopsy in
                                                                logically confirmed to have high risk findings mainly ex-
patients with suspected thyroid diseases 1. Excellent out-
                                                                trathyroidal extension and cervical lymph node metastasis,
comes following therapy of PTC have been demonstrated,
                                                                routine 131I treatment was administered after withdrawal of
with 10-year survival rates of 93% 2. However, despite the
                                                                hormone therapy for at least 4 weeks. Some patients re-
favourable long-term prognosis, locoregional recurrences
                                                                ceived radioiodine (RAI) ablation with the purpose of facil-
have been described in up to 28% of patients 3.
                                                                itate follow-up or destroy foci of micrometastatic disease.
There is no consensus regarding the natural history of PTC
                                                                Diagnostic scintigraphy was performed before 131I admin-
and treatment options range from observation to total thy-
                                                                istration and 2-5 days later. Levels of thyroglobulin (tg),
roidectomy and neck lymph node dissection followed by
                                                                and anti-tg antibodies were measured postoperatively just
radioactive iodine (RAI) ablation 4.
                                                                before RAI. Most PTC patients received oral therapy with
The risk of recurrence in PTC can be estimated based
                                                                levothyroxine postoperatively, in attempt to prevent hy-
upon selected clinicopathologic features such as the pres-
                                                                pothyroidism or to suppress thyroid-stimulating hormone
ence of extrathyroidal extension, aggressive histologies,
                                                                (TSH) based on risk assessment.
vascular invasion, regional metastases, or high levels of
postoperative serum thyroglobulin suggestive of distant
                                                                Follow-up
metastases. The 2009 ATA guidelines for the manage-
                                                                Patients were assessed every 3 months for the first year,
ment of thyroid cancer proposed a system to estimate the
                                                                every 6 months between the second and fifth years, and
risk of relapse of differentiated thyroid cancer based upon
these clinicopathologic findings 5. Additional prognostic       every 12 months thereafter at the discretion of the attend-
variables as extent of lymph node involvement and BRAF          ing physician based on the risk of the individual patient.
mutation profile were included in an updated version of         The follow-up visits included palpation of the neck, dos-
the 2015 ATA risk stratification system 6 (Tab. I). How-        age of serum TSH, tg and anti-tg antibody levels, and ul-
ever, these additional variables have not been rigourously      trasound examination of the cervical lymph nodes. Disease
assessed.                                                       recurrence was defined as the first clinical reappearance of
The aim of this study was to review the characteristics of      tumour. It included all clinical events reported (local re-
PTC at diagnosis in a single cancer centre retrospective co-    lapses, lymph node metastases, and distant metastases) and
hort and to identify the clinical and pathological features     confirmed by imaging modalities, biopsy or surgery.
associated with tumour recurrence. We also evaluated the
2009 ATA risk stratification system for prediction of cancer    Prognostic parameters
recurrence.                                                     Patient characteristics, surgery data, pathological features
                                                                and postoperative clinical outcomes were retrieved from
                                                                the medical charts. Pathological characteristics of thyroid-
Materials and methods                                           ectomy specimens included: tumour size, minor extrathy-
                                                                roidal extension (invasion of perithyroidal soft tissues or
Study population and treatment                                  strap muscles) and gross extrathyroidal extension (invasion
After obtaining institutional review board approval, we         of subcutaneous soft tissues, recurrent laryngeal nerve, es-
retrospectively reviewed the medical records of 4,104 con-      ophagus, trachea, larynx, carotid artery or mediastinal ves-
secutive patients treated for papillary thyroid cancer (PTC)    sels), multifocality, aggressive histology (e.g.: tall cells,
between January 1996 and December 2015. Only patients           diffuse sclerosing and solid), pathologically confirmed
with a postoperative pathologic diagnosis of PTC were in-       neck lymph node metastasis, lympho-vascular invasion
cluded and 19 patients were excluded due to concurrent          and chronic lymphocytic thyroiditis. Patients were clas-
thyroidal malignancies. Most patients had an initial total      sified according to 2009 ATA risk stratification system as
or subsequent completion thyroidectomy, based on patient        low, intermediate or high risk for recurrence 5.
preference and clinical criteria such as previous neck irra-
diation, hypothyroidism, familial predisposition or bilateral   Statistical methods
nodularity. Many physicians and patients chose bilateral        The primary end point of the study was disease-free sur-
thyroidectomies aiming to simplify follow-up. Therapeutic       vival (DFS). Categorical variables were described by the



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A. Ywata de Carvalho et al.




Table I. Initial American Thyroid Association risk of recurrence classification.
 Low risk                   No local or distant metastases
 (all the following)        All macroscopic tumour has been resected
                            No invasion of locoregional tissues
                            Tumour does not have aggressive histology (e.g.: tall cell, insular, columnar cell carcinoma, Hurthle cell carcinoma, follicular thyroid
                            cancer)
                            No vascular invasion
                            No 131I uptake outside the thyroid bed on the post-treatment scan, if done
                            Clinical N0 or ≤ 5 pathologic N1 micrometastases (< 0.2 cm)*
                            Intrathyroidal, encapsulated follicular variant of papillary thyroid cancer*
                            Intrathyroidal, well differentiated follicular thyroid cancer with capsular invasion and no or minimal (< 4 foci) vascular invasion*
                            Intrathyroidal, papillary microcarcinoma, unifocal or multifocal, including BRAFV600E mutated (if known)*
 Intermediate risk          Microscopic invasion into the perithyroidal soft tissues
 (any of the following)     Cervical lymph node metastases or 131I uptake outside the thyroid bed on the post-treatment scan done after thyroid remnant
                            ablation
                            Tumour with aggressive histology or vascular invasion
                            Papillary thyroid cancer with vascular invasion*
                            Clinical N1 or > 5 pathologic N1 with all involved lymph nodes < 3 cm*
                            Multifocal papillary microcarcinoma with extrathyroidal extension (ETE) and BRAFV600E mutated (if known)*
 High risk                  Macroscopic (gross ETE) invasion of tumour into the perithyroidal tissues
 (any of the following)     Incomplete tumour resection
                            Distant metastases
                            Postoperative serum thyroglobulin suggestive of distant metastases*
                            Pathologic N1 with any metastatic lymph node ≥ 3 cm*
                            Follicular thyroid cancer with extensive vascular invasion (> 4 foci of vascular invasion)*
*
    Additional prognostic variables included in the 2015 ATA risk stratification system.



frequency and number of each unique category. For con-
tinuous variables, results were reported as range, mean and
standard deviation (SD). Patients were followed-up until
death, recurrence or the last date the patient was known to
be alive. Disease-free survival probabilities were estimated
by the Kaplan-Meier technique including the log-rank test
to compare recurrence. P-values < 0.05 were considered
significant. Univariate analyses were performed separately
for each of the variables using the Cox regression model.
All parameters in univariate analysis were included in the
multivariate survival model. The backward selection tech-
nique was conducted with a P-value of < 0.10 used to select
variables to the final model. Next, potential independent
prognostic factors of recurrence were defined. The Sch-
oenfeld and scaled Schoenfeld residuals verified whether                                   Figure 1. Temporal evolution of papillary thyroid carcinomas and proportion
the proportional assumption of risks was valid for the final                               of microcarcinomas.
Cox multivariate regression model. All statistical analyses
were performed using computer software Stata: version 16
(StataCorp LP, College Station, Texas).                                                    of 963) in 2006-2010, and 63% (1,651 of 2,622) in 2011-
                                                                                           2015 (Fig. 1).
                                                                                           Clinicopathological features and risk stratification of the
Results                                                                                    4,085 patients included in this retrospective study are pre-
From January 1996 to December 2015, both the number                                        sented in Table II. Most patients (4,031-98.7%) underwent
of patients treated for papillary thyroid carcinoma (PTC)                                  initial total thyroidectomy or completion thyroidectomy.
and the proportion of papillary thyroid microcarcinomas                                    Central lymph node dissection (level VI) was performed in
(PTMCs) increased over time: 42% (29 of 69 patients) in                                    725 patients (17.7%), of whom 184 (4.5%) underwent con-
1996-2000, 60.8% (262 of 431) in 2001-2005, 61.9% (596                                     comitant lateral dissection (levels IIa, III, IV, Vb). Radioio-



238
                                                                                           Predictive factors for recurrence of papillary thyroid carcinoma




Table II. Patients and tumour characteristics.
 Characteristics                                               No. patients
 Gender                           Female           80.7%          3,297
                                   Male            19.3%           788
 Age (years):                    Mean (SD)       43.7 (13.1)      4,085
                                  Median             43
                                  Range             7-88
                                   < 55            78.8%          3,218
                                   ≥ 55            21.2%           867
 Tumour size (mm):               Mean (SD)       11.2 (9.9)       4,085
                                  Median              9
                                  Range           0.2-140
                                 ≤ 10 mm           62.1%          2,538       Figure 2. Pattern of recurrence of papillary thyroid carcinoma.
                                 > 10 mm           37.9%          1,547
 Aggressive histology                                4%            164
 Multifocality                                     33.5%          1,370       independently associated with tumour size > 10 mm [Haz-
 Bilaterality                                      22.7%           928        ard Ratio (HR) 1.68; 95% Confidence Interval (CI) 1.21-
 Extrathyroidal extension           Minor          15.7%           641        2.33; P = 0.002], multifocality (HR 1.48; CI 95% 1.1-2.01;
                                    Gross           5.1%           209
                                                                              P = 0.01), extrathyroidal extension (HR 1.57; CI 95% 1.14-
 Lympho-vascular invasion                            2%             80
                                                                              2.16; P = 0.006) and lymph node metastasis (HR 4.74; 95%
                                                                              CI 3.41-6.61; P < 0.001) (Tab. III).
 Lymph node metastasis              cN1             10%            406
                                                                              According to the 2009 ATA risk stratification system, pa-
                                    pN1            17.2%           703
                                                                              tients were classified as low (66.7%), intermediate (28.1%)
 Chronic lymphocytic                               33.2%          1,356
 thyroiditis                                                                  or high-risk (5.2%). Recurrence was observed in 43 (1.6%)
 ATA risk stratification          Low-risk         66.7%          2,727       of 2,727 low-risk patients, 85 (7.4%) of 1,147 intermediate-
 category                                                                     risk patients and in 48 (22.7%) of 211 high-risk patients.
                                Intermediate       28.1%          1,147       Five years disease-free survival probability was significant-
                                    High           5.2%            211        ly lower in high-risk (73.1%) than in intermediate (90.8%)
                                                                              and low-risk (94.8%) patients (Fig. 3).

dine administration (I131) was performed post-surgically                      Discussion
in 2,569 patients (62.9%). Dose of iodine ranged from 22
                                                                              The incidence of papillary thyroid carcinoma (PTC) is rap-
to 463 mCi (mean: 137.5 mCi; SD: 42.2 mCi).
                                                                              idly rising, mostly due to increased presurgical diagnosis
After a mean follow-up of 58.7 months (range 3-256.5
                                                                              of incidental tumours 7. The prevalence of occult PTC in
months), tumour recurrence was diagnosed in 176 patients
(4.3%), mostly in neck lymph nodes (see Fig. 2). Me-
dian time to recurrence was 56.8 months (range, 3-256.5
months; SD 40.2). There were 3 (0.1%) cancer-related
deaths, all associated with progression of lung metastases.
Forty-two patients (1%) died from other causes.
Cox regression univariate analysis showed that male gen-
der (P = 0.001), age < 55 years (P = 0.018), tumour size
> 10 mm (P < 0.001), multifocality (P < 0.001), bilaterality
(P < 0.001), extrathyroidal extension (P < 0.001), aggres-
sive histologic variant (P = 0.004), lympho-vascular inva-
sion (P < 0.001) and lymph node metastasis (P < 0.001)
were significantly associated with tumour recurrence. In
contrast, chronic lymphocytic thyroiditis did not affect
disease-free survival rate (P = 0.287). Multivariate Cox
regression analyses revealed that cancer recurrence was                       Figure 3. Kaplan-Meier recurrence estimates based on ATA risk categories.



                                                                                                                                                     239
A. Ywata de Carvalho et al.




Table III. Univariate and multivariate cancer-recurrence logistic regression analyses of PTC patients.
                                                                                   Univariate analysis                 Multivariate analysis
                                                                             HR (95% CI)                 P-value    HR (95% CI)            P-value
 Male gender                                                               1.79 (1.29-2.48)           0.001
 Age < 55 years                                                            1.65 (1.09-2.51)           0.018
 Tumour size > 10 mm                                                       2.91 (2.13-3.95)          < 0.001       1.68 (1.21-2.33)            0.002
 Multifocality                                                             2.04 (1.51-2.74)          < 0.001       1.48 (1.10-2.01)             0.01
 Bilaterality                                                              1.77 (1.30-2.42)          < 0.001
 Extrathyroidal extension
    Yes                                                                    3.16 (2.35-4.26)          < 0.001       1.57 (1.14-2.16)            0.006
    Minor                                                                  1.71 (1.15-2.55)           0.008
    Gross                                                                  7.65 (5.39-10.86)         < 0.001
 Aggressive histology                                                      2.17 (1.28-3.69)           0.004
 Lympho-vascular invasion                                                  3.07 (1.71-5.54)          < 0.001
 Lymph node metastasis                                                     6.87 (5.09-9.26)          < 0.001       4.74 (3.41-6.61)       < 0.001
 Chronic thyroiditis                                                       0.84 (0.61-1.16)           0.287
HR and 95% CI estimated by COX regression models.



autopsy specimens is as high as 35.6% 8 and a similar high                       recurrence because of removal of all potential foci in both
frequency of incidental PTC is seen in 7.2% of thyroid                           lobes 14. However, salvage resection is quite effective in the
glands surgically resected for benign diseases 9. In our se-                     few patients that recur and the surgical risks of two-stage
ries, PTC increased significantly over the years, most been                      procedure (lobectomy followed by completion thyroidec-
nonpalpable tumours incidentally diagnosed during neck                           tomy) are similar to those following bilateral thyroidec-
radiologic procedures, such as ultrasonography or comput-                        tomy 6.
ed tomography performed during follow-up due to other                            Due to a high incidence of multifocality and lymph node
cancers.                                                                         metastasis in the level VI, some authors recommend a total
Studies analyzing PTC of all sizes described recurrence                          thyroidectomy and concomitant central lymph node dis-
rates ranging from 6.6 to 28% 3,10. In our series, we found                      section (CLND) in patients with clinically node negative
a low recurrence rate (4.3%), which is probably influenced                       (cN0) PTC to avoid reoperation or reduce locoregional
by a high percentage (62.1%) of papillary thyroid micro-                         recurrence 15. However, routine elective CLND might in-
carcinomas (PTMC) which are defined as carcinomas ≤ 1                            crease the risk of postoperative complications, especially
cm. Recurrence was more frequently identified following                          permanent hypocalcaemia 16. In fact, microscopic nodal
thyroidectomy in patients with tumours >1 cm compared                            disease is rarely of clinical importance since it often re-
with PTMC (7.3% versus 2.5%). In a meta-analysis includ-                         mains quiescent or subsequent RAI administration ablates
ing 6,839 PTMC patients, Yi et al. found a recurrence rate                       these occult foci. Based on 2015 ATA guidelines, prophy-
of 2.8% 11, very similar to ours. As we know, PTMCs are                          lactic CLND must be indicated only in cN0 patients who
less aggressive 12 and most thyroid nodules < 1 cm should                        have advanced primary tumours (T3 or T4) 6.
not undergo fine-needle aspiration (FNA). Furthermore,                           Most authors 17, but not all 18, agree that post thyroidec-
most of our patients (83.9%) had asymptomatic or inciden-                        tomy RAI is not beneficial in reducing cancer recurrence
tal PTC which demonstrate a much lower recurrence rate                           or mortality in low-risk and some intermediate-risk PTC
than symptomatic or nonincidental tumours 13.                                    patients. Since no long-term randomised trials were identi-
Another possible reason for the low recurrence rate ob-                          fied, conclusions are limited to observational studies. Most
served in this series is that most patients were submitted                       of our patients received RAI, with the purpose of destroy-
to total thyroidectomy, based on patient preference and                          ing foci of micrometastatic disease in intermediate-high
clinical criteria such as previous neck irradiation, hypo-                       risk tumours or making follow-up easier by improving the
thyroidism, familial predisposition, bilateral nodularity                        sensitivity of thyroglobulin.
or as a strategy to simplify follow-up. Some investigators                       As expected, the majority of our PTC patients had recur-
favour total thyroidectomy, as an appropriate initial treat-                     rence in lymph nodes: 30.1% exclusively in level VI; 42%
ment for PTC, with the advantage of providing lower local                        in lateral neck levels; and 17.6% in both, central and lat-



240
                                                                           Predictive factors for recurrence of papillary thyroid carcinoma




eral compartment nodes. Distant metastases were seen in         tients presented an aggressive histology, most with diffuse
18 (10.2%) of recurrent patients: 12 had lung metastases        sclerosing (1.9%), solid (1.1%) or tall cell (0.7%) variants.
only, 4 had bone metastases only, and 2 had lung and bone       We found that histological variants of PTC were associated
metastases. Of note, all 3 cancer-related deaths were asso-     with a more aggressive behaviour than the classic form and
ciated to progression of lung metastases.                       we agree with other authors 24 that patients with these vari-
Several clinicopathologic factors have been described           ants should be treated intensively with total thyroidectomy
in literature to predict recurrence of PTC 19: age, gender      and postoperative RAI, regardless of status of the regional
male, tumour diameter >1 cm, aggressive histological vari-      lymph nodes.
ants, multifocality, capsular invasion or absence of tumour     The 2017 TNM (tumor, node, metastasis) staging system
capsule, extrathyroidal extension, lymph node metastases,       from American Joint Cancer Committee/Union Interna-
proportion of metastasised and removed nodes at first op-       tionale Contre le Cancer (AJCC/UICC) is adequately used
eration > 0.5, extranodal extension, vascular invasion, mu-     to predict disease-specific mortality 25. Since death is un-
tated BRAF and TERT and non-incidental diagnosis. In a          common following management of PTC patients, we also
review of 5,768 PTC patients, Ito et al. found recurrence       use the American Thyroid Association (ATA) clinicopatho-
and cancer-specific death rates of 9.6% and 1%, respective-     logic staging system to provide initial estimates of risk of
ly. Age older than 55 years, male gender, tumour size > 2       recurrence and thus improve clinical decision making. In
cm, extrathyroidal extension and clinical node metastasis       our cancer center, the relatively high proportion of low-risk
were independent predictors of recurrence 20. Additionally,     (66.7%) or intermediate-risk (28.1%) patients probably re-
in a meta-analysis including 7,048 PTMC patients, Guo et        flects the great number of PTMC incidentally discovered.
al. found that male gender, extrathyroidal extension, lymph     Recurrence was identified in 1.6% of the low-risk, 7.4% of
node metastasis, distant metastasis, tumour size greater        the intermediate-risk and 22.7% of the high-risk patients
than 2 cm and subtotal thyroidectomy were independent           (P < 0.001). Consistent with previous publications, our
risk factors for recurrence.                                    data confirm that the risk of recurrence can be effectively
Our univariate analysis showed that, except for chronic         predicted based on ATA staging system.
lymphocytic thyroiditis, all clinicopathologic factors ana-     Some limitations of this retrospective study are mainly re-
lysed were associated with a risk of cancer recurrence. On      lated to selection bias. Recommendations on treatment and
multivariate analyses tumour size > 10 mm, multifocality,       intensity and frequency of follow-up visits and tests varied
extrathyroidal extension and mainly presence of lymph           from patient to patient based on individual surgeons and pa-
node metastasis pathologically confirmed were indepen-          tient preferences and not on an institutional protocol. This
dently associated with relapse of disease. Patients with        would lead to an increased diagnose of recurrent disease in
lymph node metastases had almost 5 times greater risk of        intermediate to high-risk patients than the less rigorous test-
relapse than pN0 patients. These findings can be explained      ing paradigm often used in low-risk patients. Furthermore,
by the strong association between most of the clinical and      important prognostic variables included in the updated ver-
pathological features analysed and the development of re-       sion of the 2015 ATA risk stratification system, such as the
gional metastases. Accordingly, previous meta-analyses re-      number and dimension of lymph node metastases, were not
vealed that central lymph node metastasis in PTC patients       assessed in this study. Finally, a median follow-up period of
are associated with male gender, younger age (< 45 years),      58.7 months may be too short as some patients with a less
larger tumour size, multifocality, extrathyroidal exten-        aggressive disease may manifest clinically significant recur-
sion and lympho-vascular invasion, but not with chronic         rence many years following initial therapy.
lymphocytic thyroiditis 21. In effect, Qu et al. found that     In summary, our data confirm that some clinicopathologi-
lymphocytic thyroiditis resulted in decreased risk of lymph     cal factors such as tumour size > 10 mm, multifocality, ex-
node metastasis 22. Additionally, So et al. in a systematic     trathyroidal extension and mainly presence of lymph node
review of 18,741 patients, found that level VI lymph node       metastasis at diagnosis, as well as ATA recurrence stag-
metastases were the most important predictive factor for        ing system, effectively predicts recurrence, thus providing
involvement of lymph nodes in the lateral compartment 23.       valuable information that can help to individualise clinical
Thus, the presence of lymph node metastases at initial di-      management and follow-up for PTC patients.
agnosis is the best predictive factor for the risk of locore-
gional recurrence in PTC patients.
Many histological variants of PTC have been described
                                                                Acknowledgements
based on histological differences, mainly the characteris-      This work was supported by the A. C. Camargo Cancer
tics of tumour cell nuclei. In our series, only 164 (4%) pa-    Center, Fundação Antonio Prudente, Sao Paulo, Brazil.



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