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, 0250-7005/2015 $2.00+.40 1635 ANTICANCER RESEARCH 35: 1635-1640 (2015) 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).