Introduction
Thyroid cancer is the second most common cancer among women as per the Saudi cancer registry in 2015.[1] Thyroid cancer incidence has been rising steadily in developed countries.[1] While thyroid cancer affects 1 in 10,000 people every year, it is the most common endocrine malignancy worldwide.[1]
Primary care practitioners commonly face thyroid nodules in family medicine clinics. A lot of the time, confusion can occur whether to keep monitoring these nodules closely or reassure patients not to worry about them. Thyroid nodules, usually found by ultrasound (US), may undergo a triaging system by fine-needle aspiration (FNA) for the cytological assessment of the nodule. FNA is the standard diagnostic procedure used to evaluate thyroid nodules before surgery.[2] The American Thyroid Association (ATA) recommends performing FNA on all thyroid nodules >1 cm.[3] Those FNAs are further categorized based on the Bethesda system.[2,3] Bethesda system is a widely accepted tool with a 95% diagnostic accuracy to stratify cancer risk.[2,3] It is divided into six categories based on the nodule cytological features. In one study based in India in 2011, the main objective was to assess the efficacy of the Bethesda System for Thyroid Cytology. They did a prospective study on 564 patients. Among these, the commonest cytological diagnosis was Hashimotos thyroiditis. Only 85 patients went for thyroidectomies, 77 of those were correlated with the cytological diagnosis. False positive were 3 cases and false negative were 5 cases.[4] Another study, done in Southwestern region of Saudi Arabia in 2012, looked at the rates of malignancy of thyroid nodules in each standard cytological diagnostic category of Bethesda system. They included 323 thyroid FNA cytology diagnoses collected as a retrospective cohort from 1998 to 2007 and have categorized them based on Bethesda system. They compared between FNAC and thyroid histopathogical results after thyroidectomy rate of malignancy on histopathologic examination. The rate of malignancy was 60% in suspicious of malignancy group and 94% in malignant group.[5] This triaging tool’s ultimate goal is to predict malignant nodules and to plan the appropriate next step.
This study aimed to determine the yield of FNA cytology of thyroid nodules within a primary care setting and to correlate factors like age, nodule size, and gender to thyroid cancer.
Methodology
This was a retrospective cohort study on all patients who underwent thyroid FNAs between January 01, 2002 and July 31, 2018 at the Family Medicine clinics linked to King Faisal Specialist Hospital and Research Center (KFSHRC). Data were collected from the electronic health records (EHR) of the included patients. Patients with a prior history of any cancer were excluded.
The structured data collection form consisted of two major sections:
- Patient demographics including age at the time of FNA, gender, body mass index (BMI) (obesity defined BMI of 30 and more), thyroid-stimulating hormone (TSH) level at the time of FNA, and reason for FNA. Patients’ ages were divided into two categories. Those younger than 45 years of age and those who were 45 years of age and older. The age 45 years old was chosen as a cutoff based on other studies due to its significance for thyroid cancer staging.[3]
- FNA results were reported based on the Bethesda System for Reporting Thyroid Cytopathology.[2,3] We have further categorized the FNA cytopathology results into three main groups: benign (including benign colloid and thyroiditis), intermediate (including atypia of undermined significance, follicular neoplasm, and suspicious for papillary thyroid carcinoma), and malignant (including papillary thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, lymphoma, and other carcinomas).
Data was exported to Statistical Package for Social Science (SPSS) after data verification, cleaning, and recoding. Variables were classified into the continuous, interval, or categorical variables. Chi-square and independent t-tests were used for comparison between groups with P values <0.05 considered statistically significant. Correlation between age and gender and FNA results was assessed using multivariate logistic regression. This research was approved by the research ethics committee (REC) and the office of research affairs (ORA) at KFSHRC.
Ethical Considerations: It is a non-interventional study and did not pose any harm to the patients. Patients’ data were dealt with in a confidential manner. Neither breach of dignity nor declaration of patient’s identity were conducted. Therefore, obtaining consent from patients was not necessary. The data were collected in a retrospective manner by reviewing electronic medical records and paper charts.
The REC at KFSHRC in Riyadh, Kingdom of Saudi Arabia (KSA) has reviewed the proposal of this project and approved it by April 16, 2019. The committee also accepted the progress report as submitted and recommended the continued approval of project number 2181-074. The form is available at the ORA, Extension 24528 or the ORA web page. REF number FMPC/699/40, received by the ORA.
Results
Out of the 263 FNAs, the majority of patients were female (81.7%) and the average age was 41.3 years (Standard deviation (SD) ± 10.1). The average BMI was 27 kg/m2 (SD ± 4.9). Eighty-seven percent had done a thyroid US and eventually underwent thyroid FNA because of goiter or compressive symptoms while 13% had an incidental finding of the thyroid nodule [Table 1].
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Table 1: Patients demographics
FNA showed the following results: 5.3% of patients had a non-diagnostic FNA result, 74.9% had benign FNA results which include benign colloid and thyroiditis, 12.2% had intermediate FNA results (including atypia of undermined significance, follicular neoplasm, and suspicious for papillary thyroid carcinoma), and 7.6% had malignancy, which included papillary thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, and lymphoma [Figure 1].
Figure 1: Yield of thyroid nodule FNAs
The differences between the yield of thyroid FNA and age and gender are shown in Tables 2 and 3, respectively. (Excluding the non-diagnostic FNAs from the analysis).
Table 2: FNA diagnoses by age
Table 3: FNA diagnoses within both genders
Out of those who had benign thyroid FNA results, 3.5% were determined to be malignant on thyroid pathology reports after surgery. Moreover, among those who had intermediate thyroid FNA results, 50% turned out to be malignant on final thyroid pathology reports. Furthermore, of those who had malignant thyroid upon FNA, 100% had malignant thyroid pathology results. Also, in patients who had non-diagnostic FNAs, eventually, 14% of them were found to have thyroid cancer after thyroidectomy [Figures 2–5].
Figure 2: Rate of thyroid malignancy on pathology reports among benign nodules on FNA
Figure 3: Rate of thyroid malignancy on pathology reports among intermediate nodules on FNA
Figure 4: Rate of thyroid malignancy on pathology reports among malignant nodules on FNA
Figure 5: Rate of thyroid malignancy on pathology reports among non-diagnostic nodules
A total of 46 patients (17.5%) had thyroid cancer on pathology reports out of the 263 thyroid FNAs. The incidence of papillary thyroid cancer was 78.3%, 19.6% had follicular thyroid cancer, and 2.2% had medullary thyroid cancer [Figure 6].
Figure 6: Subtypes of thyroid cancer
The age-standardized incidence rate (ASIR) of thyroid cancer among our population from January 01, 2002 to July 31, 2018 was 6.48 per 100,000 [Figure 7]. Table 4 shows the characteristics of those who developed thyroid cancer in our population vs. those who had benign thyroid histopathology reports. A total of 61.9% were younger than 45 years old, 76.2% of them were females, and 85.7% of patients who developed thyroid cancer were not obese based on BMI. It also shows that 90.5% had a TSH level below 4.2 and 95.2% had a nodule size of 1 cm or more.
Figure 7: Comparison of ASIR for thyroid cancer between our population, Saudi cancer registry, and in other countries
Table 4: The characteristics of patients who had confirmed thyroid cancer on pathology reports vs. whom pathology reports confirmed they did not have cancer (n=80)
Discussion
Our study showed that females are more likely to get thyroid nodules with the majority (81.7%) of our population being women. FNA results showed that the incidence of benign FNA was 74.9%.[6] 12.2% had intermediate FNA results which are more than 7.2% that was presented in another study.[6] Finally, 7.6% had malignant FNA diagnoses compared to 5.3% in the other research.[6] Non-diagnostic thyroid FNA results, which were 5.3% in our study, were lower than that reported in other studies which can go up to 15–20% of non-diagnostic FNAs.[7] It may be due to the diagnostic accuracy of US-guided FNA that limits the findings of non-diagnostic FNAs.
Though women were more likely to get thyroid nodules, no significant differences between gender and malignant nodules on FNA were observed between men and women (10.8% vs. 7.3%, respectively, P = 0.89).[6,7] Although other studies showed that men had more chance for the nodule to be malignant on FNA than women (6.65% vs. 4.83%, P = 0.034),[6] whereas in our study men to women ratio had an insignificant P value. This finding is inconsistent with other studies that looked at the relationship between gender and thyroid malignancy. Our study did not confirm that men are more at risk of a thyroid nodule being malignant when evaluated by FNA.[7] This may be attributed to the small number of male samples, or it could be due to a selection bias in the study. If it was of statistical significance, it might be worthwhile to keep in mind while seeing patients in our Saudi community that gender differences do not play a big role in whether the nodule would be benign or malignant.
Patients under the age of 45 were more women than men (84.7% vs. 15.3%, respectively). Again, we noted that the ratios of nodules being benign, intermediate, and malignant were similar between those aged 45 and more and those aged less than 45. There was no significant correlation between age and FNA results, although literature considered age as a risk factor to developing abnormal FNA results. Some studies found a relation between FNA diagnosis and age, but they often only examine age as a continuous variable. We looked at age categorically for all FNA biopsies, and we found that malignant FNAs were as frequent in patients aged 45 years and younger when compared to older patients (7.3% vs. 9%). We looked at age continuously as well and it was not significant either. This finding opposes the results of the study done by Rago et al.,[7] which when examining age as a continuous variable found that patients diagnosed with papillary thyroid carcinoma were younger at most.
Other patient characteristics like BMI, TSH level, and nodule size were also examined to assess any risk of thyroid nodule malignancy on FNA. We were not able to find a significant correlation between any of the characteristics and FNA findings. We reason this fact to many explanations. One may be our small sample size. Other reasons might be the fact that our population was mainly primary care patients, while in other studies their subjects are usually from tertiary institutions. Some of those studies also only included patients that went through thyroidectomy, which produces a bias, especially with regard to the risk of malignancy. Also, the number of thyroid nodules in our institution has risen in recent years because of easy accessibility to imaging or FNA procedures. This growth in technology may contribute to the fact that there was no association between patients’ characteristics and FNA results.
We also were able to assess the false positive and false negative accuracy of FNA in our population by examining the pathology reports of those who underwent thyroidectomy. The overall rate of thyroid cancer (diagnosed by surgical pathology) in our patients was 17.5% among those who underwent thyroid FNAs, which is higher than the 4% malignancy rate which is reported in the literature.[8] Of patients who initially had benign FNA results, 3.5% were malignant on thyroid pathology reports. These patients with benign thyroid FNA cytology underwent thyroidectomy due to reasons like compressive symptoms of their goiter or for cosmetic purposes. Also, 50% turned out to have malignancy on thyroid pathology reports although they had intermediate FNA results. The intermediate results included atypia of undermined significance, follicular neoplasm, and suspicion for papillary thyroid carcinoma. Furthermore, 100% had malignant thyroid pathology results among those who had malignant thyroid FNA. Finally, patients who had non-diagnostic FNAs, eventually, 14% of them were diagnosed with thyroid cancer upon thyroidectomy.
A total of 80 patients (30.4%) underwent thyroidectomies, 42 of them had confirmed thyroid cancer on histopathology reports. Among patients younger than 45 years old, almost 62% had thyroid cancer versus 73% had benign thyroid histopathology (P = 1.00). Most of the patients that underwent thyroidectomies were females. A total of 76.2% of females had malignant findings on thyroid histopathology and 81.6% of females had benign findings (P = 0.29). The majority of patients who had thyroidectomies had a normal TSH whether they were confirmed to have thyroid cancer (90.5%) or they were not (89%), which showed that TSH level does not predict thyroid cancer (P = 1.00). The nodules that were 1 cm or larger in size were in 95.2% out of those who had thyroid cancer, and in 97.4% out of those who did not have thyroid cancer (P = 0.27) [Table 4] indicates the nodule size. Hence, the larger the nodule, the more it is to be thyroid cancer. In a recently done study, they did find that large nodule size is significantly related to a more aggressive thyroid cancer indicating unfavorable events.[9]
The incidence of the subtypes of thyroid cancer is shown in Figure 6. It shows that the most common type of thyroid cancer is papillary thyroid carcinoma versus the least common type is medullary thyroid carcinoma, and these results match with the international most common types of thyroid cancer.[7]
The ASIR of thyroid cancer among our population from January 2001 to July 2018 was 6.48 per 100,000, which is lower than the thyroid cancer ASIR that was reported in the Saudi Cancer Registry which was 10.3 in 2014. The ASIR of thyroid cancer reported in our study was matching the ASIR of thyroid cancer of the United Kingdom (6.4) per 100,000. It was lower than reported by other countries, such as United Arab Emirates (19.4), Kuwait (12.1), Australia (11.6), and the United States (26.4) per 100,000. But higher than China (5.7), and Bahrain (6) per 100.000 [Figure 7].
Conclusion
Predicting who is more likely to develop thyroid cancer based on FNA results is crucial to the primary care physician. Thorough investigations, including FNA, should be considered for patients presenting with a suspicious thyroid nodule, regardless of its size or the patient’s gender or age. Easy access to such investigations and referrals to specialists should be available for primary care physicians.
This study is very important to show that most of the thyroid nodules that primary care physicians face need to be investigated. Whether it was a suspicious thyroid nodule on US or not. Or whether these nodules get FNA or not, close monitoring of the clinical status of the patient, regular examinations, and USs are recommended. As we have seen in the results above, the yield of the FNA for these thyroid nodules does have an incidence of false negatives. It is the duty of the primary care physician to know that FNA is not 100% correct and follow up these nodules even if the FNA histopathology was benign. These findings contribute to correctly assessing the patients presenting with thyroid nodules.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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