Malignancy risk for thyroid nodules larger than 4 cm and diagnostic reliability of ultrasound-guided FNAB results
Erdem Karadeniz1, Mesut Yur2, Ayetullah Temiz3, Müfide Nuran Akçay1
1Department of General Surgery, Ataturk University School of Medicine, Erzurum, Turkey
2Clinic of General Surgery, Trabzon Kanuni Training and Research Hospital, Trabzon , Turkey
3Clinic of General Surgery, Erzurum Regional Training and Research Hospital, Erzurum , Turkey
Objective: Our aim in the present study was to investigate the relation between thyroid nodule diameter and malignancy, and the diagnostic accuracy of fine needle aspiration biopsy (FNAB) for thyroid nodules larger than 4 cm.
Material and Methods: Preoperative patient demographics such as age and gender, thyroid nodule diameter, FNAB results and postoperative pathology results were recorded. The relation between age, gender, thyroid nodule size of the patients and malignancy was examined. Also, the sensitivity, specificity, false negativity, false positivity and accuracy rates of FNBA of the patients whose thyroid nodule size was lower than 4 cm and the ones whose thyroid nodule size was higher than 4 cm were analyzed.
Results: There was no significant difference between males and females in terms of malignancy rate (p= 0.15). There was no significant relation between malignancy and patient age (p= 0.92). No significant difference was found between the group with thyroid nodule diameter of > 4 cm and the group thyroid with nodule diameter of < 4 cm in terms of malignancy (p= 0.91). In the group with thyroid nodule diameter of > 4 cm, sensitivity, specificity, false negativity, false positivity, and accuracy rates of FNAB were 15%, 100%, 84%, 0%, and 70%, respectively. In the group with thyroid nodule diameter of < 4 cm, sensitivity, specificity, false negativity, false positivity, and accuracy rates of FNAB were 53%, 100%, 46%, 0% and 80%, respectively.
Conclusion: Our study put forward that thyroid nodule diameter is not the only predictor parameter whilst predicting malignancy. However, it was observed that FNAB sensitivity and false negativity were higher when the thyroid nodules with > 4 cm diameter were compared to the thyroid nodules with < 4 cm diameter.
Keywords: Thyroid nodule diameter, malignancy, fine needle aspiration biopsy, false negativity
Thyroid nodules are very common in the general population. Clinically palpable nodules are observed in 4-7% of the population (1). Prevalence rate is higher when the thyroid gland is evaluated with imaging methods. Thyroid nodules can be found in 17-67% of the adult population when evaluated with cervical ultrasonography (USG) (2). Although most thyroid nodules are benign, the prevalence of thyroid cancer has recently risen dramatically (3). Malignancy rate in thyroid nodules is about 5%-20% (4). In case a nodule is detected on physical examination, the critical question is whether it is benign or malignant. Standard thyroid nodule evaluation protocol consists of patient’s history, physical examination, serum thyroid stimulating hormone (TSH) level, cervical USG, and fine needle aspiration biopsy (FNAB). Consideration of clinical factors combined with USG findings gives a clue about the malignancy of the nodule. Particularly hypoechogenic nature of the nodule, presence of calcification, irregular or infiltrative borders, and increased vascularity of the nodule are important predictors of malignancy (5,6). As a reliable, rapid and low-cost method, FNAB is accepted as a gold standard diagnostic tool for the assessment of thyroid nodules. With a false negativity rate under 5%, FNAB is widely used by clinicians. False negativity and non-diagnostic cytology rates are reduced when FNAB is performed under USG guidance (2,7). There are studies reporting that increased nodule diameter is associated with malignancy risk and can be used as a predictor of malignancy (8,9). On the other hand, there are also studies reporting that there is no association between nodule diameter and malignancy risk (10,11). Some authors recommend thyroidectomy for nodules larger than 4 cm even when FNAB result is benign due to increased malignancy risk and increased false negativity rate (12,13). Yet, other studies show no difference between small and large nodules with regard to the false negativity of FNAB (14,15).
In many centers, the patient is referred to surgery when the nodule size is greater than 4 cm even if FNAB result is negative. Our aim in the present study was to examine the validity of this approach, to investigate the relationship between nodule diameter and malignancy, and the diagnostic accuracy of FNAB for nodules larger than 4 cm.
Material and Methods
The study included 322 patients who underwent thyroid surgery in our clinic between October 2010 and January 2015 due to the diagnosis of nodular goiter. Data were obtained retrospectively from patient files. The study was carried out in accordance with the declaration of Helsinki. Cystic and complex (solid + cystic) nodules were excluded from the study.
Preoperative patient demographics such as age and gender, nodule diameter, FNAB results and postoperative pathology results were recorded. FNAB was performed under USG guidance by radiologists in a radiology clinic. For solitary nodules, FNAB was performed on that nodule, whereas for multinodular cases, FNAB was performed on the nodule showing malignant characteristics in ultrasonographic assessment, or on the largest (dominant) nodule. Nodule diameters were recorded from USG reports in the unit of cm. FNAB results were categorized according to Bethesda classification as non-diagnostic (category 1), benign (category 2), atypia of undetermined significance (AUS)/ follicular lesion of undetermined significance (FLUS) (category 3), follicular neoplasm/suspicious for a follicular neoplasm (category 4), suspicious for malignancy (category 5), and malignancy (category 6) groups. Surgical indications for patients with benign and non-diagnostic FNAB results in Bethesda categories 1 and 2 were cosmetic problems and compression findings for nodules larger than 4 cm, whereas for nodules smaller than 4 cm, surgical indications were presence of clinical symptoms (being dysphagia or disphonia, nodule’s fast growth) and the existence of nodule malignancy chance radiologically (nodule being hypoechoic, having micro qualifications, nodule having irregular sidelines, increase in vascularity in Doppler). Thyroidectomy was performed by surgeons experienced in the field of endocrine surgery. For evaluation of sensitivity, specificity, false negativity, false positivity and accuracy of FNAB, Bethesda category 2 was accepted as a negative result, while category 6 was accepted as a positive result. Inadequate and suspicious categories were not included in the analysis.
The relation between age, gender, nodule size of the patients and malignancy was examined. Also, the sensitivity, specificity, false negativity, false positivity, and accuracy rates of FNBA of the patients whose nodule size was lower than 4 cm and the ones whose nodule size was higher than 4 cm were analyzed.
Chi-square and independent t-tests were used in statistical analysis. Normality assessment was made with Kolmogorov-Smirnov test. p< 0.05 was considered significant.
Of the 322 patients included, 54 (16.8%) were males and 268 (83.2%) were females. Mean age was 48.4 ± 13.9 years with a range of 13-91 years. 222 (68.9%) patients had multiple nodules, whereas 100 (31.1%) patients had solitary nodules. 257 (79.8%) patients had nodules with a diameter of < 4 cm, while 65 (20.2%) patients had nodules with a diameter of > 4 cm. Preoperative FNAB results were nondiagnostic in 39 (12.1%) patients; benign in 131 (40.7%) patients; AUS/FLUS in 14 (4.3%) patients; follicular neoplasm/suspicious for follicular neoplasm in 107 (33.2%) patients; and suspicious for malignancy in 5 (1.6%), Malign cytology was observed in 26 (8.1%) patients. Mean nodule diameter was 2.8 ±-1.3 cm (0.5-9.5 cm). Types of surgery were total thyroidectomy in 266 (82.6%) patients, lobectomy in 53 (16.4%) patients and complementary thyroid surgery in 3 (0.9%) patients. Postoperative final pathology results were benign in 195 (60.6%) patients and malignant in 127 (39.4%) patients. Among patients with malignant results, detected histopathological types were papillary carcinoma in 106 patients, Hurthle cell carcinoma in 9 patients, follicular carcinoma in 6 patients, medullary carcinoma in 2 patients, poorly differentiated carcinoma in 2 patients, and anaplastic carcinoma in 1 patient. Malignancy was seen in 101 (37.6%) of the female patients and 26 (48.1%) of the male patients (Table 1). There was no significant difference between males and females in terms of malignancy rate (p= 0.15). Mean age of the patients in the malignant group was 48.7 (22-85) years, and that of the patients in the benign group was 49.3 (13-91) years. There was no significant relationship between malignancy and patient age (p= 0.92). Malignancy was seen in 26 (40%) of the 65 patients with a nodule diameter of > 4 cm and in 101 (39.2%) of 257 patients with a nodule diameter of < 4 cm. No significant difference was found between the group with a nodule diameter of > 4 cm and the group with a nodule diameter of < 4 cm in terms of malignancy (p= 0.91). In the group with a nodule diameter of > 4 cm, malignancy was observed in 3 of 10 patients in non-diagnostic FNAB category, 11 of 35 patients in benign category, none of the patients in AUS/FLUS category, 10 of 16 patients in follicular neoplasm/suspicious for follicular neoplasm category, and both of the 2 patients with malignant FNAB results while in the group with a nodule diameter of < 4 cm, malignancy was observed in 3 of 29 patients in non-diagnostic category, 21 of 96 patients in benign category, 3 of 12 patients in AUS/FLUS category, 47 of 91 patients in follicular neoplasm/suspicious for follicular neoplasm category, 3 of 5 patients in suspicious for malignancy category, and in all of the 24 patients in the malignancy category (Tables 2,3). In general, the sensitivity, specificity, false negativity, false positivity, and accuracy rates of FNAB were 44%, 100%, 55%, 0%, and 70%, respectively. In the group with a nodule diameter of > 4 cm, sensitivity, specificity, false negativity, false positivity and accuracy rates of FNAB were 15%, 100%, 84%, 0% and 70%, respectively. In the group with a nodule diameter of < 4 cm, sensitivity, specificity, false negativity, false positivity and accuracy rates of FNAB were 53%, 100%, 46%, 0% and 80%, respectively (Table 4).
In case of detection of a thyroid nodule, determination of its malignancy probability is of key importance for the clinician. Numerous studies have been conducted to investigate many parameters to be used in the prediction of the malignancy-risk of thyroid nodules. Studies examining the relationship between age and malignancy risk of nodules have shown contradicting results. Pinchot et al. have reported a higher prevalence of thyroid cancer among the elderly population in comparison to the young adults (16). Godazaneh; however, has found a higher prevalence of thyroid cancer among young adults compared to the elderly (17). On the other hand, in their studies, Rosario et al. and Rapari et al. have reported that there is no significant association between age and malignancy (8,18). In our study, mean patient age was similar in benign and malignant groups (48.7 and 49.3 years, respectively), and no significant association was found between age and malignancy (p= 0.92> 0.05). Raparia et al. have studied patients with FNAB results as suspicious for follicular carcinoma or Hurthle cell neoplasm or suspicious for malignancy, and they have found a higher prevalence of malignancy among males in comparison to females (8). Kim et al. have studied patients with thyroid nodules larger than > 4 cm, and they have reported that there is no significant difference between males and females with regard to malignancy (p= 0.78) (12). In our study, a significant difference was not found between male and female groups in terms of malignancy (p= 0.15).
Many studies have examined the association between thyroid nodule size and malignancy risk and reported contradicting results. In their study including patients with FNAB results as suspicious for follicular carcinoma or Hurthle cell neoplasm or suspicious for malignancy, Rapari et al. have reported a higher frequency of malignancy among patients with nodules larger than 2 cm (p< 0.001) (8). McCoy et al. have reported a higher prevalence of malignancy for nodules ≥ 4 cm (9). In a meta-analysis, Hammad et al. have examined the relationship between nodule size and malignancy and categorized nodules in three groups based on their diameter as < 3 cm, 3-5.9 cm, and ≥ 6 cm. In a comparison of 3-5.9 cm group with < 3 cm group, they have found higher malignancy risk in the group with nodule size between 3-5.9 cm (p= 0.02) (< 3 cm). In a comparison of ≥ 6 cm group with < 3 cm group, they have found that malignancy risk is lower in ≥ 6 cm group (p< 0.001) (19). In another study, McHenry et al. have reported that the mean diameter of malignant nodules is lower than that of benign nodules (p< 0.001), and therefore, the nodule diameter could not be a predictor of malignancy (10). In their study including patients with nodule size > 4 cm, Kim et al. have not found an association between nodule diameter and malignancy (p= 0.13) (12). Godazandeh et al. have not determined a significant difference between patients with nodule size > 4 cm and < 4 cm in terms of malignancy rate (p= 0.29) (17). Megwalu et al. have studied nodules ≥ 4 cm and have not detected an association between nodule size and malignancy (p= 0.7) (20). In our study, there was no significant difference between the > 4 cm group and the < 4 cm group in terms of malignancy (p= 0.91). Conflicting results from various studies suggest that nodule size on its own is not a reliable parameter for predicting malignancy. Deciding on medical follow-up or surgery, based on the nodule diameter alone, would not be a correct approach.
FNAB is currently considered a gold standard diagnostic tool for the evaluation of thyroid nodules. Diagnostic accuracy is particularly higher when it is performed under USG guidance and in experienced hands. Nonetheless, diagnostic accuracy of FNAB is controversial, especially for large nodules. In their study including patients with nodules of > 4 cm, Kim et al. have found general false negativity rate as 11.9%, and because of such a high rate, they have recommended consideration of surgery in case of suspicious USG findings for nodules of > 4 cm, even if FNAB is negative (12). In another study, Wharry et al. have studied patients with nodules of ≥ 4 cm and found false negativity rate of FNAB as 10.4%. They have reported that lack of suspicious USG findings would not rule out malignancy and that therefore, at least lobectomy should be considered for nodules ≥ 4 cm (13). In their study, Godazandeh et al. have found that sensitivity of FNAB is lower and false negativity rate is higher when nodule size is < 4 cm (17). Giles et al. have compared patients with a nodule size of < 3 cm and ≥ 3 cm, and they have reported that false negativity rate is higher when nodule size is ≥ 3 cm. They have stated that thyroidectomy can be considered in patients with a ≥ 3 cm nodule even if FNAB is reported as benign (21). In their study, Koo et al. have categorized thyroid nodules as ≤ 0.5, > 0.5-1, > 1-2, > 2-4, and > 4 cm. They have found high false negativity rate (50%) in the > 4 cm group and recommended frequent FNAB for patients with a > 4 cm nodule even though FNAB is reported as benign (22). Beştepe et al. have reported that false negativity rates of ≥ 4 cm nodules is two times higher than the nodules between the sizes of 1-3.9 cm (23). By contrast to these studies, Shrestha et al. have categorized thyroid nodules in three groups as 0.5-0.9 cm, 1-3.9 cm, and ≥ 4 cm. They have found higher false negativity rate in the 0.5-0.9 cm group and stated that greater nodule diameter should not automatically direct physicians towards thyroidectomy (14). Albuja-Cruz et al. have examined patients with < 4 cm and ≥ 4 cm nodules and reported that diagnostic reliability of FNAB is not influenced by the nodule size. They have recommended not to use nodule size as a single independent factor while making the decision on thyroidectomy for ≥ 4 cm nodules (15). Megwalu et al. have found false negativity rate of FNAB as 0% in their study with ≥ 4 cm nodules, and they have recommended not to perform thyroidectomy automatically in every patient with ≥ 4 cm nodule and a benign FNAB result (20). Kuru et al. have found that false negative rates are 1.3% and 4.3% when they have compared < 4 cm nodules and ≥ 4 cm nodules, respectively. They have stated that FNAB’s false negativity rates are lower in < 4 cm nodules and ≥ 4 cm nodules upon comparing ≥ 4 cm nodules with nodules between the sizes of 1-3.9 cm (24). In the present study, when > 4 cm and < 4 cm nodules were compared, it was found that FNAB had lower sensitivity and higher false negativity rate for nodules > 4 cm. In comparison to the literature data, lower sensitivity and higher false negativity rates were found in the present study. Accuracy of FNAB results may vary depending on several factors such as adequacy of sample volume, sampling from correct site, and accurate interpretation of the results. Therefore, the validity of the results of FNAB are significantly dependent on the experience of the pathologist that is in charge of the process of examination of the cytology samples and the radiologist who performs the procedure. Different findings in our series regarding FNAB results may be attributed to such factors.
Major limitation of the present study was its retrospective and single-centered design.
Our study put forward that nodule diameter was not the only predictor parameter whilst predicting the malignancy. However, it was observed that FNAB sensitivity and false negatively were higher when the nodules with a > 4 cm diameter were compared to the nodules with a < 4 cm diameter.
Ethics committee approval was not obtained because the study was a retrospective file screening study.
As the study was a retrospective file screening study, informed consent was not obtained.
Concept – E.K., M.N.A.; Design – M.N.A.; Supervision – E.K.; Materials – M.Y.; Data Collection and/or Processing – A.T.; Analysis and/or Interpretation – E.K., M.N.A.; Literature Search – E.K.; Writing Manuscript – E.K., M.Y.; Critical Reviews – M.N.A.
The authors have no conflicts of interest to declare.
The authors declared that this study has received no financial support.
- Hegedus L. The thyroid nodule. N Engl J Med 2004; 351: 1764-71.
- Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006; 40: 223-38.
- Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10-29.
- Brito JP, Yarur AJ, Prokop LJ, McIver B, Murad MH, Montori VM. Prevalence of thyroid cancer in multinodular goiter versus single nodule: a systematic review and meta-analysis. Thyroid 2013; 23: 449-55.
- Mittendorf EA, McHenry CR. Follow-up evaluation and clinical course of patients with benign nodular thyroid disease. Am Surg 1999; 65: 653-8.
- Papini E, Guglielmi R, Bianchini A, Crescenzi A, Taccogna S, Nardi F, et al. Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features. J Clin Endocrinol Metab 2002; 87: 1941-6.
- Danese D, Sciacchitano S, Farsetti A, Andreoli M, Pontecorvi A. Diagnostic accuracy of conventional versus sonography-guided fine-needle aspiration biopsy of thyroid nodules. Thyroid 1998; 8: 15-21.
- Raparia K, Min SK, Mody DR, Anton R, Amrikachi M. Clinical outcomes for “suspicious” category in thyroid fine-needle aspiration biopsy: Patient’s sex and nodule size are possible predictors of malignancy. Arch Pathol Lab Med 2009; 133: 787-90.
- McCoy KL, Jabbour N, Ogilvie JB, Ohori NP, Carty SE, Yim JH. The incidence of cancer and rate of false-negative cytology in thyroid nodules greater than or equal to 4 cm in size. Surgery 2007; 142: 837-44.
- McHenry CR, Huh ES, Machekano RN. Is nodule size an independent predictor of thyroid malignancy? Surgery 2008; 144: 1062-9.
- Shi H, Bobanga I, McHenry CR. Are large thyroid nodules classified as benign on fine needle aspiration more likely to harborc cancer? Am J Surg 2017; 213: 464-6.
- Kim JH, Kim NK, Oh YL, Kim HJ, Kim SY, Chung JH, et al. The validity of ultrasonography-guided fine needle aspiration biopsy in thyroid nodules 4 cm or larger depends on ultrasonography characteristics. Endocrinol Metab 2014; 29: 545-52.
- Wharry LI, McCoy KL, Stang MT, Armstrong MJ, LeBeau SO, Tublin ME, et al. Thyroid nodules (≥ 4 cm): can ultrasound and cytology reliably exclude cancer? World J Surg 2014; 38: 614-21.
- Shrestha M, Crothers BA, Burch HB. The impact of thyroid nodule size on the risk of malignancy and accuracy of fine-needle aspiration: a 10-year study from a single institution. Thyroid 2012; 22: 1251-6.
- Albuja-Cruz MB, Goldfarb M, Gondek SS, Allan BJ, Lew JI. Reliability of fine-needle aspiration for thyroid nodules greater than or equal to 4 cm. J Surg Res 2013; 181: 6-10.
- Pinchot SN, Al-Wagih H, Schaefer S, Sippel R, Chen H. Accuracy of fine-needle aspiration biopsy for predicting neoplasm or carcinoma in thyroid nodules 4 cm or larger. Arch Surg 2009; 144: 649-55.
- Godazandeh G, Kashi Z, Zargarnataj S, Fazli M, Ebadi R, Kerdabadi EH. Evaluation the Relationship Between Thyroid Nodule Size with Malignancy and Accuracy of Fine Needle Aspiration Biopsy (FNAB). Acta Inform Med 2016; 24: 347-50.
- Rosario P, Penna G, Calsolari M. Predictive factors of malignancy in thyroid nodules with repeatedly nondiagnostic cytology (Bethesda category I): value of ultrasonography. Horm Metab Res 2014; 46: 294-8.
- Hammad AY, Noureldine SI, Hu T, Ibrahim Y, Masoodi HM, Kandil E. A meta-analysis examining the independent association betwen thyroid nodule size and malignancy. Gland Surg 2016; 5: 312-7.
- Megwalu UC. Risk of malignancy in thyroid nodules 4 cm or larger. Endocrinol Metab 2017; 32: 77-82.
- Giles WH, Maclellan RA, Gawande AA, Ruan DT, Alexander EK, Moore FD Jr, et al. False negative cytology in large thyroid nodules. Ann Surg Oncol 2015; 22: 152-7.
- Koo DH, Song K, Kwon H, Bae DS, Kim JH, Min HS, et al. Does Tumor Size Influence the Diagnostic Accuracy of Ultrasound-Guided Fine-Needle Aspiration Cytology for Thyroid Nodules? Int J Endocrinol 2016; 2016: 6.
- Bestepe N, Ozdemir D, Tam AA, Dellal FD, Kilicarslan A, Parlak O, et al. Malignancy risk and false-negative rate of fine needle aspiration cytology in thyroid nodules ≥ 4.0 cm. Surgery 2016; 160: 405-12.
- Kuru B, Gulcelik NE, Gulcelik MA, Dincer H. The false-negative rate of fine-needle aspiration cytology for diagnosing thyroid carcinoma in thyroid nodules. Langenbecks Arch Surg 2010; 395: 127-32.