ANTICANCER RESEARCH 35: 1635-1640 (2015)

The Impact of Thyroid Nodule Size on the Risk of Malignancy in Follicular Neoplasms

YASIN IBRAHIM1, SALAH ELDIN H. MOHAMED1, AHMED DENIWAR1, ZAID H. AL-QURAYSHI1, AMNA N. KHAN2, KRZYSZTOF MOROZ3, PAUL FRIEDLANDER4 and EMAD KANDIL1

1Division of Endocrine and Oncological Surgery, Department of Surgery, 2Division of Endocrine, Department of Medicine, 3Department of Pathology, and 4Department of Otolaryngology, Tulane University School of Medicine, New Orleans, LA, U.S.A.

Abstract. Background/Aim: Studies have shown that the risk Thyroid nodules are present in 4-7% of the general of malignancy in follicular neoplasms is as high as 30%. population, of which about 5% are diagnosed as malignant Often, surgery is recommended for such lesions, not for (1-5). Fine-needle aspiration (FNA) is the most cost- therapeutic purposes but as a diagnostic method, leading to effective and accurate evaluation of thyroid nodules. It is increased hospital costs and related morbidities. Recent recommended for nodules measuring 1 cm, more as this studies have suggested that tumor size predicts malignant cutoff has been shown to have high sensitivity and potential of these follicular neoplasms. Our aim was to specificity (6). However, there is controversy about the identify the impact of nodule size on the risk of malignancy accuracy of FNA cytology for nodules larger than 4 cm for such lesions. Patients and Methods: A retrospective due to a high (up to 20%) false-negative rate (7, 8). FNA medical chart review was undertaken for patients who cytological findings help physicians decide whether to underwent thyroid surgery at a single academic North monitor these thyroid nodules or to refer the patients for American Institution. A total of 120 follicular lesions, surgery (9). Since FNA was introduced into clinical follicular neoplasms (Bethesda category IV) or follicular practice 50 years ago, the number of patients referred for lesions of undetermined significance (Bethesda category III) thyroidectomy has decreased by 25% (10). in 110 patients undergoing thyroid surgery were evaluated. One serious limitation is the inability to differentiate Nodule size as measured by ultrasound, fine-needle aspiration follicular adenoma from follicular carcinoma. Capsular cytological results, and final histopathology reports were invasion with or without additional vascular invasion is reviewed. Analysis was performed by classification according necessary to confirm the diagnosis of carcinoma (11). Such to nodule size: <3 cm, ≥3 cm, <4 cm and ≥4 cm. Results: Out indeterminate cytology (including follicular neoplasm) of the 120 nodules, 48 (40%) were reported to be malignant represents 22-42% of FNA cytology (12). on final pathological examination. The malignancy rate in Several studies have shown that approximately 27-52% of nodules <3 cm and ≥ 3cm was 41% and 37.8%, respectively lesions diagnosed as follicular neoplasm via FNA cytology (p=0.84). When 4 cm was used as the cut-off, the rate in often revealed via histopathology to be malignant lesions. nodules <4 cm and ≥4 cm was 40.6% and 37.5%, respectively The most common malignancy was found to be papillary (p=0.82). Conclusion: Increased thyroid nodule size does not thyroid carcinoma followed by follicular carcinoma (9, 13). increase the malignancy rate for follicular neoplasms. Hence, The majority (48-73%) of such nodules are benign, which we recommend against routine total thyroidectomy for means that many patients are unnecessarily exposed to patients with follicular neoplasms based on the size criteria. surgery for diagnostic purposes. Thyroid surgeries can be associated with serious compli - cations, including thyroid hormone imbalance, hypo parathy - roidism, recurrent laryngeal nerve injury, bleeding, and Correspondence to: Emad Kandil, MD, FACS, Associate Professor infection, in addition to incurring increased costs of hospi - of Surgery, Edward G. Schlieder Chair in Surgical Oncology, Chief, talization (8). Endocrine Surgery Section, Tulane University School of Medicine, Improving the ability to predict the risk of malignancy of 1430 Tulane Avenue, New Orleans, LA 70112, U.S.A. Tel: +1 follicular lesions would help clinicians to make the best 5049887407, e-mail: [email protected] decision regarding which patients should be referred to Key Words: Nodule size, follicular neoplasms, follicular lesion of surgery, and the extent of surgery when indicated (11). Hemi- undetermined significance, thyroid malignancy, thyroid cancer. thyroidectomy, which might be considered for benign lesions,

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Table I. Demographics of 110 patients with 120 follicular neoplasms on Table II. Clinical and FNA cytology features of malignant and benign FNA cytology. nodules.

No. of patients (%) No. of patients (%)

Variable (n) Malignant Benign p-Value* Variable (n) Malignant Benign p-Value*

Mean age (SD), years 46.8 (13.6) 53.5 (12.4) 0.008 Size Age category <3 cm 34 (41%) 49 (59%) 0.84 ≤45 years 19 (52.8%) 17 (47.2%) 0.06 ≥3 cm 14 (37.8%) 23 (62.2%) >45 years 24 (32.4%) 50 (66.6%) <4 cm 39 (40.6%) 57 (59.4%) 0.82 Sex ≥4 cm 9 (37.5%) 15 (62.7%) Male (n=23) 9 (39.1%) 14 (60.9%) 1 FNAC Female (n=87) 34 (39.1%) 53 (60.9%) FN 13 (65%) 7 (35%) 0.023 Race FLUS 35 (35%) 65 (65%) White (n=50) 21 (42%) 29 (58%) 0.78 Echogenicity African-American (n=56) 21 (37.5%) 35 (62.5%) Hypoechogenic 9 (31%) 20 (69%) 0.34 Other (n=4) 1 (25%) 3 (75%) Hyper/isoechogenic 8 (53.3%) 7 (46.7%) Clacification *Two-sided Fisher's exact test for the categorical variables, and two- No 17 (32.1%) 36 (67.9%) 0.24 sided Student's t-test for the continuous variables. Yes 8 (50%) 8 (50%) Internal vascularity No 6 (33.3%) 15 (66.7%) 0.77 Yes 11 (42.9%) 20 (57.1%) is safer than total thyroidectomy due to the associated lower FNAC: Fine needle aspiration cytology; FN: follicular neoplasm; FLUS: follicular lesion of undetermined significance. *Calculated by t-test, risk of nerve injury and overall complications (14, 15). Chi-square test, or Fisher's exact test, when appropriate. Many clinical factors, including age, sex, presence of microcalcifications, hypoechoiety, and internal vascularity have been examined to determine their utility in predicting the risk of malignancy in follicular lesions. However, results Data analysis. Age, gender, and race were reported. Using different size criteria (<3 cm, ≥3 cm, <4 cm, ≥4 cm), preoperative FNA have been contradictory (16). biopsy and surgical histopathological results of all follicular lesions Debate exists regarding the usefulness of clinical features, were reviewed and documented. Follicular lesions included folli- including nodule size, in predicting malignancy. The risk of cular neoplasms (Bethesda category IV) and follicular lesions of follicular cancer increases with nodule size, as compared to undetermined significance (FLUS) (Bethesda category III). Ultraso - reduced risk of papillary thyroid cancer in larger nodules (i.e. nographic features of these lesions, including size, calcifications, more than 2 cm) (16). echogenicity, and internal vascularity, were also documented. Recent studies suggest that tumor size predicts Statistical analysis. The pathological features of follicular lesions malignant potential in follicular neoplasms of the thyroid of different size categories (<3 cm vs. ≥3 cm, and <4 cm vs. ≥4 cm) (17). This is consistent with the American Thyroid Asso - were documented. The p-value for the significance of differences ciation guidelines which recommend total thyroidectomy was calculated by two-sided Student’s t-test for the continuous for follicular lesions larger than 4 cm due to increased risk variables and by two-sided Fisher’s exact test for the categorical of malignancy (18). variables. Logistic regression analysis was used to test the Our objective was to identify the impact of size on the risk association between size and different pathological categories. The of malignancy of such lesions with indeterminate diagnosis. p-values were considered statistically significant if less than 0.05. This could provide vital information for surgeons in counseling patients regarding the extent of surgery needed. Results

Patients and Methods Clinical demographics. A total of 944 patients were screened, out of these 110 were found to have follicular lesions upon Clinical patients. This retrospective study was approved by the FNA cytological examination. Patients’ demographics and Tulane University Medical Center Institutional Review Board pathology subsets are summarized in Table I. Patients (140492-1). The medical records of a total of 944 patients who diagnosed with benign histopathology tended to be older, with underwent thyroid surgery at Tulane University hospital between a mean age of 53.5±12.4 (SD) (N=67) years than those with 2006 and 2012 were retrospectively reviewed. One hundred and ten patients were found to have 120 follicular lesions on FNA cyto- malignant histopathology (mean age of 46.78±13.6; N=43; logical examination carried out at our Institution. All nodules p=0.008). The malignancy rate for patients ≤45 years vs. those included were ≥1 cm in size. older than 45 years was 52.8% vs. 32.4% (p=0.06).

1636 Ibrahim et al: Thyroid Nodule Size in Follicular Neoplasms

Table III. Association between follicular neoplasm size and malignancy. Discussion

Author, Country Sample Size Rate of p-Value This analysis of 110 patients with 120 clinically-relevant year (Ref) size category cancer (cm) (%) thyroid nodules suggests that follicular lesions of larger size are not associated with a higher risk of malignancy. The Kamran et al., USA 913 1-1.9 6 <0.01 malignancy rate in nodules <3 cm and those ≥3 cm was 2013 (16) ≥2 10.7 40.9% and 37.8%, respectively (p=0.84), while in those Parikh et al., USA 84 <4 31.5 0.14 <4 cm compared to those ≥4 cm, the rate of malignancy was 2013 (19) ≥4 54.5 Turanli et al., USA 49 <2 33.3 0.29 40.6% and 37.5%, respectively (p=0.82). 2011 (32) ≥2 57.8 Due to the significant complications associated with Lubitz et al., USA 144 <4 8.6 0.09 thyroid surgeries, researchers are seeking preoperative 2010 (33) ≥4 21.4 findings that can be helpful in predicting malignancy of Choi et al., Korea 114 ≤4 19.7 0.37 nodules diagnosed as follicular lesions, especially given the 2009 (24) >4 27 William et al., USA 297 ≤3 11 0.56 fact that up to 80% of follicular lesions eventually turn out to 2009 (20) >3 13.4 be benign (13, 17). Several recent studies have shown the Raparia et al., USA 145 <2 18.8 <0.001 ability of immunohistological markers such as galectin-3, 2009 (28) ≥2 47.2 HBME1, and cytokeratin-19 to improve the preoperative Mendez et al., USA 168 <4 52.6 0.19 sensitivity/specificity in differentiating benign from malignant 2008 (34) >4 37.8 Zhang et al., USA 50 ≤4 9.7 0.84 cases in such indeterminate nodules. However, they have not 2008 (35) >4 44.4 been widely accepted in clinical practice for several reasons, Gulcelik et al., Turkey 98 <4 21.5 0.039 including their operator-dependent nature, differences in 2008 (9) ≥4 47.3 analytical methods, and the overlap between follicular Yang et al., USA 397 ≤2.1 12.6 0.028 adenomas and differentiated thyroid carcinomas (19, 20). 2003 (21) >2.1 20.6 Baloch et al., USA 122 <3 23.1 <0.0001 Debate also persists on the usefulness of size in predicting 2002 (22) ≥3 55.5 the risk of malignancy of thyroid nodules. Many studies Ibrahim et al., USA 120 <3 40.9 0.84 reported a higher risk of malignancy in nodules >2 cm (16, 2014 (36) ≥3 37.8 21), >3 cm (22), and >4 cm (9, 23). However, this was negated by other studies, which reported no association between size and malignancy risk in follicular lesions (19, 24) (Table III). Regarding indeterminate nodules, the American Thyroid As expected, the majority of patients were female Association (ATA) recommends total thyroidectomy for (79.1%). There was no significant difference in gender or lesions larger than 4 cm, when the biopsy is suspicious for race distribution between those with benign vs. those with papillary carcinoma or shows marked atypia, in patients with malignant lesions (Table I). Among all follicular lesions, 48 family history of thyroid carcinoma, and in patients with a (40%) were found to be malignant on histopathology. Out of history of radiation exposure (recommendation rating: A). the 48 carcinomas, 23 (47.9%) were papillary carcinoma, 17 For all other nodules, the ATA recommends thyroid lobec - (35.4%) were follicular variant of papillary carcinoma, and tomy (recommendation rating: C) (18). eight (16.7%) were follicular carcinoma. It has been documented that the incidence of papillary thyroid cancer decreases, and that of follicular cancer Size of lesion. The malignancy rate in nodules <3 cm and increases as nodule size increases (16). Nodules larger than ≥3 cm was 40.9% (34/83) and 37.8% (14/37), respectively 4 cm have been documented to have a higher rate of false- (p=0.84). When 4 cm was used as the cutoff, the malignancy negative FNA cytology, which supports the recommendation rate in lesions <4 cm and ≥4 cm was 40.6% (39/96) and for surgical resection (16). 37.5% (9/24) respectively (p=0.82) (Table II). In addition, The Bethesda System for Reporting Thyroid Cytopathology our results showed that there was no significant difference in subclassifies indeterminate FNA cytology into FLUS and the final benign pathology rates of indeterminate FNA follicular neoplasm. Follicular neoplasm is differentiated from cytology between nodules <4 (59.4%) cm and ≥4 cm FLUS by nuclear atypia, trabecular pattern, loss of colloid or (62.5%) in size. mitosis (20). The estimated rates of malignancy are 5-15% and 15-30% for FLUS and follicular neoplasm, respectively (25). Sonographic features. Additional analysis showed that there Williams et al. reported similar rates of malignancy with 7.0% was no significant difference between malignant and benign (14/199) of the FLUS and 21.4% (21/98) of the follicular lesions with regard to ultrasonographic features, neoplasms being malignant (p=0.0005) (20). Our results echogenicity, calcification, or internal vascularity (Table II). showed a higher malignancy rate of 65% (13/20) for follicular

1637 ANTICANCER RESEARCH 35: 1635-1640 (2015) neoplasms compared to 35% (35/100) for FLUS (p=0.023). 4 Nam-Goong IS, Kim HY, Gong G, Lee HK, Hong SJ, Kim WB In addition, Williams et al. reported that follicular neoplasm and Shong YK: Ultrasonography-guided fine-needle aspiration has a 40% rate of malignancy when larger than 4 cm (20). of thyroid incidentaloma: correlation with pathological findings. Clin Endocrinol (Oxf) 60: 21-28, 2004. Additionally, patients younger than 45 years had a higher 5 Kim DL, Song KH and Kim SK: High prevalence of carcinoma cancer rate as compared to those who were older (52.8% vs. in ultrasonography-guided fine needle aspiration cytology of 32.4%, p=0.06) in this study. This is consistent with the study thyroid nodules. Endocr J 55: 135-142, 2008. by Ozluk et al. who reported a higher cancer rate in patients 6 Silverman JF, West RL, Larkin EW, Park HK, Finley JL, <40 vs. ≥40 years (64.2% vs. 34.2%) (26). This is contrary to Swanson MS and Fore WW: The role of fine-needle aspiration prior studies that have shown that increasing age is associated biopsy in the rapid diagnosis and management of thyroid neo - with a higher cancer rate (27), and to those which docu - plasm. Cancer 57: 1164-1170, 1986. mented no association with the cancer rate at all (28). 7 Hambleton C and Kandil E: Appropriate and accurate diagnosis of thyroid nodules: a review of thyroid fine-needle aspiration. Along with other clinical factors, molecular biology is Int J Clin Exp Med 6: 413-422, 2013. playing an increasingly significant role in personalizing the 8 McCoy KL, Jabbour N, Ogilvie JB, Ohori NP, Carty SE and Yim management plan for thyroid nodules due to its ability to JH: The incidence of cancer and rate of false-negative cytology predict the patient’s tumor behavior (29). in thyroid nodules greater than or equal to 4 cm in size. Surgery Recently, a gene-expression classifier (Afirma) was found 142: 837-844; discussion 844.e831-833, 2007. to be highly beneficial in distinguishing between benign and 9 Gulcelik NE, Gulcelik MA and Kuru B: Risk of malignancy in malignant nodules in follicular lesions. This gene-expression patients with follicular neoplasm: predictive value of clinical and classifier was reported to have a sensitivity of 90% for both ultrasonographic features. Arch Otolaryngol Head Neck Surg 134: 1312-1315, 2008. FLUS and follicular neoplasm. For FLUS, the specificity 10 Amrikachi M, Ramzy I, Rubenfeld S and Wheeler TM: and negative predictive value was 53% and 95%, respecti - Accuracy of fine-needle aspiration of thyroid. Arch Pathol Lab vely. For follicular neoplasm, the respective value were 49% Med 125: 484-488, 2001. and 94% (30). 11 Lee YH, Lee NJ, Kim JH, Suh SI, Kim TK and Song JJ: In addition, a number of studies documented that BRAF Sonographically guided fine needle aspiration of thyroid nodule: mutational analysis increased the sensitivity of FNA biopsy discrepancies between cytologic and histopathologic findings. J for papillary thyroid cancer, with sensitivity of 15-84% and Clin Ultrasound 36: 6-11, 2008. 12 Seiberling KA, Dutra JC and Gunn J: Ultrasound-guided fine specificity of 97.3-100% (31). needle aspiration biopsy of thyroid nodules performed in the We acknowledge certain limitations to the present study, office. Laryngoscope 118: 228-231, 2008. some of which are: i) This study was performed 13 Jeong SH, Hong HS, Lee EH, Cha JG, Park JS and Kwak JJ: retrospectively; ii) data are from a single Institution; iii) Outcome of thyroid nodules characterized as atypia of undeter- small sample size; iv) lack of genetic testing; v) questioned mined significance or follicular lesion of undetermined significance reliability of diagnosing follicular lesion according to and correlation with Ultrasound features and BRAF(V600E) different pathologists. These findings should be investigated mutation analysis. AJR Am J Roentgenol 201: W854-860, 2013. by larger, randomized, multicenter trials. 14 Kandil E, Krishnan B, Noureldine SI, Yao L and Tufano RP: Hemithyroidectomy: a meta-analysis of postoperative need for hormone replacement and complications. ORL J Otorhino - Conclusion laryngol Relat Spec 75: 6-17, 2013. 15 Hauch, Adam: Can Surgeon Volume Mitigate Complications These data suggest that risk of malignancy of follicular neoplasms Following Total Thyroidectomy? In: Al-Qurayshi, Zaid (eds.). is not influenced by lesion size, and extent of surgery should not be Annals of surgical oncology, 2014. indicated based on size per se. 16 Kamran SC, Marqusee E, Kim MI, Frates MC, Ritner J, Peters H, Benson CB, Doubilet PM, Cibas ES, Barletta J, Cho N, Gawande A, Ruan D, Moore FD, Jr., Pou K, Larsen PR and References Alexander EK: Thyroid nodule size and prediction of cancer. J Clin Endocrinol Metab 98: 564-570, 2013. 1 Baier ND, Hahn PF, Gervais DA, Samir A, Halpern EF, Mueller 17 Ho TW, Shaheen AA, Dixon E and Harvey A: Utilization of PR and Harisinghani MG: Fine-needle aspiration biopsy of thyroidectomy for benign disease in the United States: a 15-year thyroid nodules: experience in a cohort of 944 patients. 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