10.14639/0392-100X-N1903
Objectives. This study aimed to report the rate of thyroid malignancy in benign fine-needle aspirations (Bethesda II) at King Abdulaziz Medical City and evaluate the factors that affect false-negative outcomes of FNA. Methods. All patients referred for thyroidectomy from 2009 to 2019 were reviewed (n = 1968). Only patients with a benign FNA, corresponding to the Bethesda II, were included (n = 384). Information on age, gender, body mass index (BMI), serum thyroid-stimulating hormone, type of surgery and histopathological outcomes were retrieved. Results. Of the sample (n = 384) with an initial benign FNA, 63 patients had a malignancy on postoperative pathological examination, yielding an overall false-negative rate of 16.4%. The most frequently reported histopathological type was papillary thyroid microcarcinomas (n = 52). For the false-negative group, the mean age was 43.8 years (range 21-70 years) with an 84.1% female predominance. The surgical choice for 74% (n = 46) of cases was total thyroidectomy. Age, gender, thyroid function and BMI did not affect the false-negative rate of benign FNA (p &gt; 0.05). Conclusions. This study found a higher risk of malignancy compared to the literature related to benign FNA. The risk of malignancy should be considered, even with benign FNA.
text/xml
1827-675X
1903
en
Abdulaziz  Alsalem 
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
fine-needle aspiration
Risk of thyroid carcinoma in patients treated surgically with assumed benign cytology in Riyadh, Saudi Arabia
Text.Serial.Journal
https://www.actaitalica.it/
42
Thyroid
2022-06-30
2021-11-06
2022-07-26
2022-07-26
237-242
1
Abdulaziz  Alsalem 
2022/06/30
10.14639/0392-100X-N1903
237
Department of Otolaryngology, Head and Neck Surgery, King Abdulaziz Medical City, Riyadh, Saudi Arabia
1827-675X
fine-needle aspiration
en
242
Risk of thyroid carcinoma in patients treated surgically with assumed benign cytology in Riyadh, Saudi Arabia
https://www.actaitalica.it/article/download/1903/822
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:237-242; doi: 10.14639/0392-100X-N1903




Thyroid


Risk of thyroid carcinoma in patients treated surgically
with assumed benign cytology in Riyadh, Saudi Arabia
Il rischio di carcinoma tiroideo in pazienti con citologia preoperatoria di benignità
a Riyadh, Arabia Saudita
Mohammed Al Essa1, Aseel Doubi1, Lama Aldosari2,4, Abdullah Alkhaldi2,4, Manar Alzahrani2-4,
Mada Alsadi2-4, Abdulaziz Alsalem3
1
 Department of Otolaryngology, Head and Neck Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 2 College of
Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; 3 Department of Otolaryngology, Head and Neck
Surgery, King Abdulaziz Medical City, Riyadh, Saudi Arabia; 4 King Abdullah International Medical Research Center, Riyadh, Saudi Arabia




SUMMARY
Objectives. This study aimed to report the rate of thyroid malignancy in benign fine-needle
aspirations (Bethesda II) at King Abdulaziz Medical City and evaluate the factors that affect
false-negative outcomes of FNA.
Methods. All patients referred for thyroidectomy from 2009 to 2019 were reviewed
(n = 1968). Only patients with a benign FNA, corresponding to the Bethesda II, were in-
cluded (n = 384). Information on age, gender, body mass index (BMI), serum thyroid-
stimulating hormone, type of surgery and histopathological outcomes were retrieved.
Results. Of the sample (n = 384) with an initial benign FNA, 63 patients had a malignancy
on postoperative pathological examination, yielding an overall false-negative rate of 16.4%.
The most frequently reported histopathological type was papillary thyroid microcarcino-
mas (n = 52). For the false-negative group, the mean age was 43.8 years (range 21-70 years)
with an 84.1% female predominance. The surgical choice for 74% (n = 46) of cases was
total thyroidectomy. Age, gender, thyroid function and BMI did not affect the false-negative
rate of benign FNA (p > 0.05).                                                                   Received: November 6, 2021
Conclusions. This study found a higher risk of malignancy compared to the literature re-         Accepted: March 14, 2022
lated to benign FNA. The risk of malignancy should be considered, even with benign FNA.
                                                                                                 Correspondence
KEY WORDS: thyroid carcinoma, benign cytology, malignancy, fine-needle aspiration                Manar Alzahrani
                                                                                                 College of Medicine, King Saud bin Abdulaziz
RIASSUNTO                                                                                        University for Health Sciences, Riyadh 11426,
Obiettivi. Questo studio analizza il rischio di cancro della tiroide in pazienti con citologia   Saudi Arabia
                                                                                                 E-mail: manaralkhatam@gmail.com
preoperatoria di benignità (Bethesda II) sottoposti a chirurgia presso la King Abdulaziz
Medical City, valutando i fattori che determinano i risultati falsi negativi agli agoaspirati
preoperatori (FNA).                                                                                How to cite this article: Al Essa M, Doubi A,
Metodi. Sono stati revisionati i dati di tutti i pazienti sottoposti a tiroidectomia dal 2009      Aldosari L, et al. Risk of thyroid carcinoma in
al 2019 (n = 1968). Sono stati inclusi solo i pazienti con un FNA benigno, corrispondente          patients treated surgically with assumed benign
al Bethesda II (n = 384). Sono state recuperate informazioni su età, sesso, indice di massa        cytology in Riyadh, Saudi Arabia. Acta Otorhi-
corporea (BMI), TSH sierico, tipo di intervento chirurgico ed esiti istopatologici.                nolaryngol Ital 2022;42:237-242. https://doi.
                                                                                                   org/10.14639/0392-100X-N1903
Risultati. Del campione (n = 384) con FNA benigno iniziale, 63 pazienti presentavano un
tumore maligno all’esame patologico postoperatorio, ottenendo un tasso complessivo di
                                                                                                 © Società Italiana di Otorinolaringoiatria
falsi negativi del 16,4%. Il tipo istopatologico più frequentemente riportato è stato il mi-     e Chirurgia Cervico-Facciale
crocarcinoma papillare della tiroide (n = 52). Per il gruppo dei falsi negativi, l’età media
era di 43,8 anni (range 21-70 anni) con una predominanza femminile dell’84,1%. La scelta                        OPEN ACCESS
chirurgica per il 74% (n = 46) dei casi è stata la tiroidectomia totale. Età, sesso, funzione
tiroidea e BMI non hanno influenzato il tasso di falsi negativi di FNA benigno (p > 0,05).       This is an open access article distributed in accordance with
                                                                                                 the CC-BY-NC-ND (Creative Commons Attribution-Non-
Conclusioni. Questo studio ha indicato un rischio più elevato di malignità rispetto alla         Commercial-NoDerivatives 4.0 International) license. The
letteratura relativa all’FNA benigno. Il rischio di malignità dovrebbe essere considerato,       article can be used by giving appropriate credit and mentio-
anche con FNA benigno.                                                                           ning the license, but only for non-commercial purposes and
                                                                                                 only in the original version. For further information: https://
PAROLE CHIAVE: carcinoma tiroideo, citologia benigna, malignità, aspirazione con ago sottile     creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                         237
M. Al Essa et al.




Introduction                                                     disease, Bethesda category II with an FNA, who had thy-
                                                                 roid surgery and a final pathology report were included. Pa-
Thyroid nodules are common with a suggested prevalence
                                                                 tients with another Bethesda category or who did not have
of 8-65% in autopsy data, 19-35% with ultrasound and
                                                                 surgery and no final pathology report were excluded.
2-6% with palpation 1. Thyroid cancer is the most frequent
endocrine carcinoma, constituting 90% of all endocrine ma-
                                                                 Data collection
lignancies, and is considered to be one of the fastest-grow-
                                                                 We used a structured data collection sheet to retrieve infor-
ing cancers 2,3. The rate of thyroid cancer has increased dur-
                                                                 mation from the outpatient surgery clinics. Demographic
ing the last 30 years, with an average increase of 48.0% in
                                                                 information and disease characteristics were retrieved from
males and 66.7% in females 4. The most likely explanation
                                                                 the “BestCare” electronic health record system. The medi-
for this is the extensive employment of ultrasonographic
                                                                 cal files and histopathology reports of patients who had
and cytological techniques, which ensures early diagnosis
                                                                 thyroidectomy for benign thyroid disease were reviewed.
of occult thyroid nodules 1,5. According to the last Saudi
                                                                 Data including age, gender, body mass index (BMI), fine-
Cancer Registry Report, thyroid cancer is the second most
                                                                 needle aspiration cytology (FNAC), serum thyroid-stimu-
prevalent malignancy in females, and the ninth in males.
                                                                 lating hormone (thyroid function), type of thyroidectomy
A 26-fold increase in the incidence of thyroid cancer has
been reported in Saudi Arabia, ranging from 71 new cases         and final histopathologic diagnoses and features were col-
in 1990 to 1900 new cases in 2016 6.                             lected. The identified thyroid cancer cases were classified
Fine-needle aspiration (FNA) has become the procedure of         based on size as microcarcinoma, defined as a papillary
choice to differentiate benign from malignant thyroid nod-       thyroid cancer measuring 1.0 cm or less in the largest di-
ules and guide surgical treatment of patients with FNA-prov-     ameter. Macrocarcinoma was defined as any thyroid cancer
en carcinoma. The routine use has led to an increase in can-     measuring more than 1.0 cm. The thyroid function results
cer detection in surgical specimens from 15% to more than        were classified as hypothyroid, euthyroid and hyperthy-
30% and a decrease in the number of surgical interventions       roid. Patient data were reviewed to establish an association
by 25% 7. The Bethesda scoring system classifies the results     between FNA results and histopathological outcomes.
of FNA specimens according to the cytopathologic features
and estimates the risk of malignancy for each category as        Statistical analysis
follows: (I) non-diagnostic or unsatisfactory, 5-10%; (II)       The data were entered in Microsoft Excel 2019, and the Sta-
benign, 0-3%; (III) atypia of undetermined significance/fol-     tistical Package for Social Sciences (SPSS) version 21 was
licular lesions of undetermined significance (AUS/FLUS),         used for data cleaning and analysis. A P-value of < 0.05 was
10-30%; (IV) follicular neoplasm/suspicious for follicular       considered statistically significant in all tests. The quantitative
neoplasm (FN/SFN), 25-40%; (V) suspicious for malignan-          data were analysed with descriptive statistics. The categorical
cy (SM), 50-75%; and (VI) malignant, 97-99%.) 8.                 variables, such as the type of thyroid disease, are described as
Although FNA is considered the gold standard for pre-            percentage and frequency. The continuous variables, such as
operative diagnoses, it has some limitations in that false-      body mass index, are reported as mean ± standard deviation
negative and false-positive results can occur 9. Accurate        (SD). Inferential statistics were used to describe the compara-
FNA cytology diagnosis is dependent on various factors,          tive variables using chi-square and t-test.
including skills of the operator, specimen preparation, FNA
techniques and cytology interpretation 10. The study aimed       Results
to report the rate of thyroid malignancy in cases of benign
FNA (Bethesda category II) at King Abdulaziz Medical             Of the 1968 files reviewed, the sample size was 384 pa-
City (KAMC).                                                     tients, with Bethesda category II thyroid FNA results.
                                                                 The majority (81%) were female, and the mean age was
                                                                 44.3 ± 18.85 years. The demographic and clinical variables
Materials and methods                                            of patients who underwent surgery are illustrated in Table I.
Study design and population                                      The post-surgical histopathological examination identified
This retrospective study was conducted at KAMC. All              63 cases of thyroid cancer in the group with a preoperative
patients referred for thyroid surgery were reviewed from         benign FNA. The mean age of the group with thyroid cancer
January 1st, 2009, to December 31st, 2019 (n = 1968). Only       was 44.7 years (range 21-70 years) with a female predomi-
patients with benign FNA, corresponding to the Bethesda          nance (84.1%). Of the 63 cases, 52 (82.5%) were papillary
category II were included (n = 384), using a non-probabili-      thyroid microcarcinoma, and 9 (14.3%) were papillary thy-
ty sampling technique. All the patients with benign thyroid      roid macrocarcinoma (diameter range, 1.1-4.1 cm). Folli-



238
                                                                                                                         Thyroid carcinoma in benign cytology




Table I. Demographic and clinical variables associated with the presence or absence of thyroid cancer post-thyroidectomy (n = 384).
                                          Overall (n = 384)           Benign (n = 321)            Thyroid cancer (n = 63)                  P-value
 Mean age, years                              44.3 ± 12.9                   44.4 ± 0.7                     43.7 ± 1.4                       0.71
 Gender, n (%)
   Female                                      311 (81%)                   258 (80.4%)                     53 (84.1%)                       0.48
   Male                                         73 (19%)                   63 (19.6%)                      10 (15.9%)
 Mean BMI (kg/m2)                              30.9 ± 6.4                  30.6 ± 0.36                     32.3 ± 0.81                      0.057
 Thyroid function status, n (%)
   Hypothyroidism                              43 (11.2%)                   31 (9.7%)                       12 (19%)                        0.08
   Euthyroid                                  301 (78.4%)                  255 (79.4%)                      46 (73%)
   Hyperthyroidism                             40 (10.4%)                  35 (10.9%)                       5 (7.9%)



cular carcinoma was found in 2 (1.6%) cases, with one case                        is also supported by the current observational retrospective
having both follicular thyroid carcinoma and papillary thy-                       study findings 11. Fine needle aspiration (FNA) is the gold
roid microcarcinoma. The false-negative rate was 16.4%.                           standard diagnostic test to evaluate and categorise thyroid
If microcarcinomas were excluded, the false-negative rate                         nodules. It is an accurate, safe, rapid and minimally-inva-
was 2.9%. The histopathological outcomes of thyroid can-                          sive diagnostic tool to manage thyroid nodules. However,
cer cases are presented in Table II. The surgical choices for                     the American Thyroid Association guidelines recommend
the group with thyroid cancer were a total thyroidectomy in                       that FNA should be done for nodules greater than 1 cm or
46 (73%) patients, hemithyroidectomy in 14 (22.2%) and                            nodules with a suspicious ultrasound (US) pattern. Micro-
3 (4.8%) who underwent completion hemithyroidectomy.                              carcinomas, defined as malignant lesions < 1 cm in size,
Of the 14 patients that underwent hemithyroidectomy, 5                            can be missed and found incidentally following thyroidec-
had an initial diagnosis of papillary macrocarcinoma. Sub-                        tomy 12,13. Since most patients with benign FNA cytology,
sequently, those 5 patients needed a second surgery and                           without any other indications, do not undergo resection of
malignancy was identified in only 1 case following com-                           the thyroid nodules, false-negative FNA cytology is prob-
pletion hemithyroidectomy. The remaining 9 patients had                           lematic as it can adversely affect the patient’s outcome and
an initial diagnosis of papillary microcarcinoma, but only                        delay treatment. It is imperative to explore the potential of
3 needed a completion hemithyroidectomy and all turned                            underlying thyroid malignancy in a benign FNA 14.
to be negative for malignancy. In total, 8 patients needed a                      In this study, 63 of 384 patients with a benign FNA had
completion hemithyroidectomy out of 14 patients. Table III                        thyroid cancer in the post-surgical histopathological ex-
shows the ultrasonographic and clinical features of the 11                        amination, translating to a false-negative rate of 16.4%.
patients who were found to have macrocarcinoma.                                   The literature frequently reports a false-negative rate of be-
                                                                                  nign FNA lower than 16.4%. The post-surgical histological
                                                                                  analysis of preoperative benign thyroid in a study identified
Discussion                                                                        thyroid cancer in 14.5% 14. Other studies reported rates of
The presence of malignancy in patients operated for benign                        incidental thyroid cancers in a preoperative benign FNA
thyroid disease is frequently reported the literature, which                      cytology as 11, 10.4 and 10.8% 5,11,15.


Table II. Postoperative histopathological outcomes of the identified thyroid cancer in patients with a benign FNA (N = 63).
 Histopathological outcomes                             Total                               Microcarcinoma                       Macrocarcinoma
                                                      (N = 63)                                   (N = 52)                           (N = 11)
                                                        n (%)                                      n (%)                              n (%)
 Multifocal                                           10 (15.9)                                8 (15.4)                               2 (18.2)
 Lymphovascular invasion                                2 (3.2)                                 1 (1.9)                                1 (9.1)
 Positive margin                                        5 (7.9)                                 3 (5.8)                               2 (18.2)
 Extracapsular extension                                2 (3.2)                                 1 (1.9)                                1 (9.1)
 Extrathyroidal extension                             11 (17.5)                                6 (11.5)                               5 (45.5)
 Diameter (cm), mean ± SD                            0.72 ± 0.84                             0.41 ± 0.22                            2.16 ± 1.17




                                                                                                                                                        239
M. Al Essa et al.




Table III. Ultrasonographic and clinical details for patients found to have macrocarcinoma.
 Patient no.             Sex            Age            Surgical                                Ultrasonographic features
                                                      procedure           Microcalcification     Increased vascularity       Echogenicity
 1                             F              70        TT                       -                        -                        -
 2                             F              38        HT                      Yes                      No                    Isoechoic
 3                             F              29        HT                      No                       Yes                  Hypoechoic
 4                             F              40        TT                      No                       Yes                  Hypoechoic
 5                             F              40        HT                      Yes                      Yes                  Hypoechoic
 6                             F              54        TT                      No                       Yes                   Isoechoic
 7                             F              32        TT                      No                       Yes                 Heterogenous
 8                             F              41        HT                      No                       No                   Hypoechoic
 9                             F              33        TT                      No                       No                   Hypoechoic
 10                            M              28        TT                      No                       Yes                 Heterogenous
 11                            F              29        HT                      No                       No                   Hypoechoic
TT: total thyroidectomy; HT: hemithyroidectomy.



Multiple factors can be the reason for the incidence of                           Due to the increasing prevalence of incidental thyroid
false-negative FNA results. Studies have indicated that                           cancer, the optimal surgical procedure for benign thyroid
using a combination of experienced technologists, ul-                             disease remains debatable. Some authors support total
trasound-guided FNA and accurate interpretation of the                            thyroidectomy for benign thyroid disease as the most ap-
final cytological results can significantly decrease false-                       propriate procedure, considering the risks associated with
negative results 16. The literature frequently reports papil-                     cancer multifocality and second surgery 2,21,22. In the cur-
lary thyroid carcinoma (PTC) and especially micro PTC                             rent study, total thyroidectomy was the surgical choice for
as the most prevalent types of thyroid cancer 17. Studies                         46 (73%) cases, and hemithyroidectomy and completion
indicated that micro PTC accounted for 30% of all thy-                            hemithyroidectomy were performed in 14 (22.2%) and 3
roid carcinoma 18. Similarly, a meta-analysis conducted                           (4.8%) cases, respectively. Of the 14 patients who had a
in 2008 stated that micro PTC accounts for an average                             hemithyroidectomy, 8 had completion thyroidectomy.
of 22.9% of malignant tumours 19. These studies confirm                           Knowing the risk of malignancy is critical for decision-
the current findings with micro PTC as the highest type                           making and for patient counselling regarding the most
of thyroid carcinoma in 52 of 63 patients treated surgi-                          appropriate management. The possibility of having a ma-
cally with benign FNAs, followed by 9 cases of macro                              lignancy despite a benign FNA result should be discussed
PTC; however, follicular carcinoma was reported in only                           with the patient when a non-surgical intervention is cho-
2 cases, one of which had both follicular thyroid carci-                          sen. The patient should be aware of the need for regular
noma and micro PTC.                                                               follow-up. A higher rate of false-negative FNA results was
Papillary microcarcinomas have been described as being                            reported in this study, stressing the importance of an appro-
less aggressive than the well-differentiated thyroid cancers,                     priate sampling technique when performing the FNA and
with a shallow frequency of distant metastases and a fa-                          improved ultrasonography methods for detecting thyroid
vourable prognosis. Although papillary thyroid microcar-                          carcinomas 25. Different characteristics of thyroid malig-
cinomas have an excellent prognosis, they are associated                          nancy on ultrasound have been reported in the literature,
with a 1% disease-related mortality rate, a 2.5% distant                          such as ill-defined margin, presence of calcification, ir-
metastasis rate and a 5% lymph node recurrence rate 20. In                        regular shape, invasion to adjacent organs, hypoechogenic-
a Chinese study investigating incidental thyroid carcinoma                        ity and heterogeneity. In this study, we reported some ul-
(mostly micro PTC’s), 28.75% were multifocal, 18.5% had                           trasonographic feature of the 11 cases that were found to
thyroid capsular invasion, with 6.2% associated with vas-                         have macrocarcinoma. Two of 11 patients were found to
cular invasion 20. Similarly, in the current study, multifo-                      have microcalcification, 6 had hypoechoic nodules and 2
cality was found in 8 (15.4%) cases of microcarcinoma,                            had heterogenous nodules. Other clinical factors should be
extrathyroidal extension in 6 (11.5%), extracapsular inva-                        taken into consideration when assessing the risk of malig-
sion in 1 (1.9%), lymph vascular invasion in 1 (1.9%) and a                       nancy, including but not limited to age, gender, nodule size
positive surgical margin in 3 (5.8%) cases.                                       and surrounding lymphadenopathy 1,24.



240
                                                                                                      Thyroid carcinoma in benign cytology




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