Risk of thyroid carcinoma in patients treated surgically with assumed benign cytology in Riyadh, Saudi Arabia| ACTA Otorhinolaryngologica Italica

Abstract

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 > 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.

Introduction

Thyroid nodules are common with a suggested prevalence of 8-65% in autopsy data, 19-35% with ultrasound and 2-6% with palpation ¹. Thyroid cancer is the most frequent endocrine carcinoma, constituting 90% of all endocrine malignancies, and is considered to be one of the fastest-growing cancers ^2,3. The rate of thyroid cancer has increased during the last 30 years, with an average increase of 48.0% in males and 66.7% in females ⁴. The most likely explanation for this is the extensive employment of ultrasonographic and cytological techniques, which ensures early diagnosis of occult thyroid nodules ^1,5. According to the last Saudi Cancer Registry Report, thyroid cancer is the second most prevalent malignancy in females, and the ninth in males. A 26-fold increase in the incidence of thyroid cancer has been reported in Saudi Arabia, ranging from 71 new cases in 1990 to 1900 new cases in 2016 ⁶.

Fine-needle aspiration (FNA) has become the procedure of choice to differentiate benign from malignant thyroid nodules and guide surgical treatment of patients with FNA-proven carcinoma. The routine use has led to an increase in cancer detection in surgical specimens from 15% to more than 30% and a decrease in the number of surgical interventions by 25% ⁷. The Bethesda scoring system classifies the results of FNA specimens according to the cytopathologic features and estimates the risk of malignancy for each category as follows: (I) non-diagnostic or unsatisfactory, 5-10%; (II) benign, 0-3%; (III) atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS), 10-30%; (IV) follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 25-40%; (V) suspicious for malignancy (SM), 50-75%; and (VI) malignant, 97-99%.) ⁸.

Although FNA is considered the gold standard for preoperative diagnoses, it has some limitations in that false-negative and false-positive results can occur ⁹. Accurate FNA cytology diagnosis is dependent on various factors, including skills of the operator, specimen preparation, FNA techniques and cytology interpretation ¹⁰. The study aimed to report the rate of thyroid malignancy in cases of benign FNA (Bethesda category II) at King Abdulaziz Medical City (KAMC).

Materials and methods

Study design and population

This retrospective study was conducted at KAMC. All patients referred for thyroid surgery were reviewed from January 1^st, 2009, to December 31^st, 2019 (n = 1968). Only patients with benign FNA, corresponding to the Bethesda category II were included (n = 384), using a non-probability sampling technique. All the patients with benign thyroid disease, Bethesda category II with an FNA, who had thyroid surgery and a final pathology report were included. Patients with another Bethesda category or who did not have surgery and no final pathology report were excluded.

Data collection

We used a structured data collection sheet to retrieve information from the outpatient surgery clinics. Demographic information and disease characteristics were retrieved from the “BestCare” electronic health record system. The medical files and histopathology reports of patients who had thyroidectomy for benign thyroid disease were reviewed. Data including age, gender, body mass index (BMI), fine-needle aspiration cytology (FNAC), serum thyroid-stimulating hormone (thyroid function), type of thyroidectomy and final histopathologic diagnoses and features were collected. The identified thyroid cancer cases were classified based on size as microcarcinoma, defined as a papillary thyroid cancer measuring 1.0 cm or less in the largest diameter. Macrocarcinoma was defined as any thyroid cancer measuring more than 1.0 cm. The thyroid function results were classified as hypothyroid, euthyroid and hyperthyroid. Patient data were reviewed to establish an association between FNA results and histopathological outcomes.

Statistical analysis

The data were entered in Microsoft Excel 2019, and the Statistical Package for Social Sciences (SPSS) version 21 was used for data cleaning and analysis. A P-value of < 0.05 was considered statistically significant in all tests. The quantitative data were analysed with descriptive statistics. The categorical variables, such as the type of thyroid disease, are described as percentage and frequency. The continuous variables, such as body mass index, are reported as mean ± standard deviation (SD). Inferential statistics were used to describe the comparative variables using chi-square and t-test.

Results

Of the 1968 files reviewed, the sample size was 384 patients, 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 of patients who underwent surgery are illustrated in Table I.

The post-surgical histopathological examination identified 63 cases of thyroid cancer in the group with a preoperative benign FNA. The mean age of the group with thyroid cancer was 44.7 years (range 21-70 years) with a female predominance (84.1%). Of the 63 cases, 52 (82.5%) were papillary thyroid microcarcinoma, and 9 (14.3%) were papillary thyroid macrocarcinoma (diameter range, 1.1-4.1 cm). Follicular carcinoma was found in 2 (1.6%) cases, with one case having both follicular thyroid carcinoma and papillary thyroid microcarcinoma. The false-negative rate was 16.4%. If microcarcinomas were excluded, the false-negative rate was 2.9%. The histopathological outcomes of thyroid cancer cases are presented in Table II. The surgical choices for the group with thyroid cancer were a total thyroidectomy in 46 (73%) patients, hemithyroidectomy in 14 (22.2%) and 3 (4.8%) who underwent completion hemithyroidectomy. Of the 14 patients that underwent hemithyroidectomy, 5 had an initial diagnosis of papillary macrocarcinoma. Subsequently, those 5 patients needed a second surgery and malignancy was identified in only 1 case following completion hemithyroidectomy. The remaining 9 patients had an initial diagnosis of papillary microcarcinoma, but only 3 needed a completion hemithyroidectomy and all turned to be negative for malignancy. In total, 8 patients needed a completion hemithyroidectomy out of 14 patients. Table III shows the ultrasonographic and clinical features of the 11 patients who were found to have macrocarcinoma.

Discussion

The presence of malignancy in patients operated for benign thyroid disease is frequently reported the literature, which is also supported by the current observational retrospective study findings ¹¹. Fine needle aspiration (FNA) is the gold standard diagnostic test to evaluate and categorise thyroid nodules. It is an accurate, safe, rapid and minimally-invasive diagnostic tool to manage thyroid nodules. However, the American Thyroid Association guidelines recommend that FNA should be done for nodules greater than 1 cm or nodules with a suspicious ultrasound (US) pattern. Microcarcinomas, defined as malignant lesions < 1 cm in size, can be missed and found incidentally following thyroidectomy ^12,13. Since most patients with benign FNA cytology, without any other indications, do not undergo resection of the thyroid nodules, false-negative FNA cytology is problematic as it can adversely affect the patient’s outcome and delay treatment. It is imperative to explore the potential of underlying thyroid malignancy in a benign FNA ¹⁴.

In this study, 63 of 384 patients with a benign FNA had thyroid cancer in the post-surgical histopathological examination, translating to a false-negative rate of 16.4%. The literature frequently reports a false-negative rate of benign FNA lower than 16.4%. The post-surgical histological analysis of preoperative benign thyroid in a study identified thyroid cancer in 14.5% ¹⁴. Other studies reported rates of incidental thyroid cancers in a preoperative benign FNA cytology as 11, 10.4 and 10.8% ^5,11,15.

Multiple factors can be the reason for the incidence of false-negative FNA results. Studies have indicated that using a combination of experienced technologists, ultrasound-guided FNA and accurate interpretation of the final cytological results can significantly decrease false-negative results ¹⁶. The literature frequently reports papillary thyroid carcinoma (PTC) and especially micro PTC as the most prevalent types of thyroid cancer ¹⁷. Studies indicated that micro PTC accounted for 30% of all thyroid carcinoma ¹⁸. Similarly, a meta-analysis conducted in 2008 stated that micro PTC accounts for an average of 22.9% of malignant tumours ¹⁹. These studies confirm the current findings with micro PTC as the highest type of thyroid carcinoma in 52 of 63 patients treated surgically with benign FNAs, followed by 9 cases of macro PTC; however, follicular carcinoma was reported in only 2 cases, one of which had both follicular thyroid carcinoma and micro PTC.

Papillary microcarcinomas have been described as being less aggressive than the well-differentiated thyroid cancers, with a shallow frequency of distant metastases and a favourable prognosis. Although papillary thyroid microcarcinomas have an excellent prognosis, they are associated with a 1% disease-related mortality rate, a 2.5% distant metastasis rate and a 5% lymph node recurrence rate ²⁰. In a Chinese study investigating incidental thyroid carcinoma (mostly micro PTC’s), 28.75% were multifocal, 18.5% had thyroid capsular invasion, with 6.2% associated with vascular invasion ²⁰. Similarly, in the current study, multifocality was found in 8 (15.4%) cases of microcarcinoma, extrathyroidal extension in 6 (11.5%), extracapsular invasion in 1 (1.9%), lymph vascular invasion in 1 (1.9%) and a positive surgical margin in 3 (5.8%) cases.

Due to the increasing prevalence of incidental thyroid cancer, the optimal surgical procedure for benign thyroid disease remains debatable. Some authors support total thyroidectomy for benign thyroid disease as the most appropriate procedure, considering the risks associated with cancer multifocality and second surgery ^2,21,22. In the current study, total thyroidectomy was the surgical choice for 46 (73%) cases, and hemithyroidectomy and completion hemithyroidectomy were performed in 14 (22.2%) and 3 (4.8%) cases, respectively. Of the 14 patients who had a hemithyroidectomy, 8 had completion thyroidectomy.

Knowing the risk of malignancy is critical for decision-making and for patient counselling regarding the most appropriate management. The possibility of having a malignancy despite a benign FNA result should be discussed with the patient when a non-surgical intervention is chosen. The patient should be aware of the need for regular follow-up. A higher rate of false-negative FNA results was reported in this study, stressing the importance of an appropriate sampling technique when performing the FNA and improved ultrasonography methods for detecting thyroid carcinomas ²⁵. Different characteristics of thyroid malignancy on ultrasound have been reported in the literature, such as ill-defined margin, presence of calcification, irregular shape, invasion to adjacent organs, hypoechogenicity and heterogeneity. In this study, we reported some ultrasonographic feature of the 11 cases that were found to have macrocarcinoma. Two of 11 patients were found to have microcalcification, 6 had hypoechoic nodules and 2 had heterogenous nodules. Other clinical factors should be taken into consideration when assessing the risk of malignancy, including but not limited to age, gender, nodule size and surrounding lymphadenopathy ^1,24.

The main limitation of this study is its retrospective design. Also, the fact that it was conducted in a single centre limited the sample size. We encourage more multicentric studies with a larger sample size to evaluate more data to be able to approach patients appropriately. In the current study, only patients who had surgery were included, which may have resulted in selection bias as it is likely that the patients who were selected for surgery were deemed clinically suspicious by their treating physicians compared to non-surgical candidates.

Conclusions

A higher risk of thyroid malignancy in a patient with a benign FNA was reported in the current study compared to the literature. The overall false-negative rate of benign FNA was 16.4%; most of the identified cancer cases had papillary thyroid microcarcinoma accounted for 82.5%. The risk of malignancy should be considered and discussed with the patient, even with a benign FNA. The patient’s presentation, as well as their individual risk factors, should not be ignored.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions

MAlessa: concepts, design, definition of intellectual content, manuscript review, guarantor. AD: concepts, design, definition of intellectual content, literature search, manuscript editing, manuscript review. LA: concepts, design, definition of intellectual content, literature search, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, manuscript review. AAlkhaldi and MMA: concepts, design, definition of intellectual content, literature search, data acquisition, manuscript preparation, manuscript editing, manuscript review. MAlsadi: literature search, data acquisition, manuscript preparation, manuscript editing, manuscript review. AAlsalem: concepts, design, definition of intellectual content, manuscript editing, manuscript review.

Ethical consideration

Because it is a chart review, informed consent was not needed. However, the patient’s privacy and confidentiality would be insured. The data would be saved on password-protected computers.

Figures and tables

References

1. Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab. 2008; 22:901-911. DOI
2. Askitis D, Efremidou EI, Karanikas M. Incidental thyroid carcinoma diagnosed after total thyroidectomy for benign thyroid diseases: incidence and association with thyroid disease type and laboratory markers. Int J Endocrinol. 2013; 2013:451959. DOI
3. Ferlay J, Soerjomataram I, Dikshit R. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136:E359-E386. DOI
4. Kilfoy BA, Zheng T, Holford TR. International patterns and trends in thyroid cancer incidence, 1973-2002. Cancer Causes Control. 2009; 20:525-531. DOI
5. Pezzolla A, Marzaioli R, Lattarulo S. Incidental carcinoma of the thyroid. Int J Surg. 2014; 12:S98-S102. DOI
6. Althubiti MA, Nour Eldein MM. Trends in the incidence and mortality of cancer in Saudi Arabia. Saudi Med J. 2018; 39:1259-1262. DOI
7. Mittendorf EA, Khiyami A, McHenry CR. When fine-needle aspiration biopsy cannot exclude papillary thyroid cancer: a therapeutic dilemma. Arch Surg. 2006; 141:961-966. DOI
8. Cibas ES, Ali SZ. The 2017 Bethesda system for reporting thyroid cytopathology. Thyroid. 2017; 27:1341-1346. DOI
9. Canberk Ş, Firat P, Schmitt F. Pitfalls in the cytological assessment of thyroid nodules. Turk Patoloji Derg. 2015; 31:18-33. DOI
10. Tandon S, Shahab R, Benton JI. Fine-needle aspiration cytology in a regional head and neck cancer center: comparison with a systematic review and meta-analysis. Head Neck. 2008; 30:1246-1252. DOI
11. Miccoli P, Minuto MN, Galleri D. Incidental thyroid carcinoma in a large series of consecutive patients operated on for benign thyroid disease. ANZ J Surg. 2006; 76:123-126. DOI
12. Mistry SG, Mani N, Murthy P. Investigating the value of fine needle aspiration cytology in thyroid cancer. J Cytol. 2011; 28:185-190. DOI
13. Sinna EA, Ezzat N. Diagnostic accuracy of fine needle aspiration cytology in thyroid lesions. J Egypt Natl Canc Inst. 2012; 24:63-70. DOI
14. Danese D, Sciacchitano S, Farsetti A. Diagnostic accuracy of conventional versus sonography-guided fine-needle aspiration biopsy of thyroid nodules. Thyroid. 1998; 8:15-21. DOI
15. Liu CL, Cheng SP, Lin HW. Risk of thyroid cancer in patients with thyroiditis: a population-based cohort study. Ann Surg Oncol. 2014; 21:843-849. DOI
16. Ogawa Y, Kato Y, Ikeda K. The value of ultrasound-guided fine-needle aspiration cytology for thyroid nodules: an assessment of its diagnostic potential and pitfalls. Surg Today. 2001; 31:97-101. DOI
17. Burgess JR, Tucker P. Incidence trends for papillary thyroid carcinoma and their correlation with thyroid surgery and thyroid fine-needle aspirate cytology. Thyroid. 2006; 16:47-53. DOI
18. Palo S, Mishra D. Prevalence of malignancy in multinodular goiter and solitary thyroid nodule: a histopathological audit. Int J Res Med Sci. 2016; 4:2319-2323. DOI
19. Roti E, Uberti EC, Bondanelli M. Thyroid papillary microcarcinoma: a descriptive and meta-analysis study. Eur J Endocrinol. 2008; 159:659-673. DOI
20. Chow SM, Law SCK, Chan JKC. Papillary microcarcinoma of the thyroid - prognostic significance of lymph node metastasis and multifocality. Cancer. 2003; 98:31-40. DOI
21. Peluso G, Masone S, Campanile S. Incidental thyroid papillary microcarcinoma on 1777 surgically treated patients for benign thyroid disease: a monoinstitutional experience and literature review. Memo - Mag Eur Med Oncol. 2020; 13:126-133. DOI
22. Lin Y-S, Wu H-Y, Yu M-C. Patient outcomes following surgical management of multinodular goiter. Medicine (Baltimore). 2016; 95:e4194. DOI
23. Evranos B, Polat SB, Cuhaci FN. A cancer of undetermined significance: Incidental thyroid carcinoma. Diagn Cytopathol. 2019; 47:412-416. DOI
24. Rago T, Fiore E, Scutari M. Male sex, single nodularity, and young age are associated with the risk of finding a papillary thyroid cancer on fine-needle aspiration cytology in a large series of patients with nodular thyroid disease. Eur J Endocrinol. 2010; 162:763-770. DOI