|Ahead of print publication
Cytopathology-histopathology correlation and the effect of nodule diameter on diagnostic performance in patients undergoing thyroid fine-needle aspiration biopsy
Nusret Yilmaz1, Guven Baris Cansu2, Serap Toru3, Ramazan Sari1, Guzide Gokhan Ocak3, Cumhur Arici4, Hasan Ali Altunbas1, Mustafa Kemal Balci1
1 Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University, Antalya, Turkey
2 Division of Endocrinology and Metabolism, Yunusemre State Hospital, Eskisehir, Turkey
3 Department of Pathology, School of Medicine, Akdeniz University, Antalya, Turkey
4 Department of Surgery, School of Medicine, Akdeniz University, Antalya, Turkey
|Date of Submission||05-Apr-2018|
|Date of Decision||20-May-2019|
|Date of Acceptance||22-Aug-2019|
|Date of Web Publication||09-May-2020|
Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University, TR-07070, Antalya
Source of Support: None, Conflict of Interest: None
Introduction: Although thyroid fine-needle aspiration biopsy (FNAB) is established to have a good overall sensitivity and specificity, various outcomes have been reported on its performance in large nodules. The aim of the study was to evaluate the diagnostic performance of FNAB and the effect of the nodule diameter on its diagnostic performance.
Materials and Methods: The outcomes of a total of 7319 patients who underwent FNAB over the course of 5 years were analyzed retrospectively and 648 patients who had undergone post-FNAB thyroidectomy or lobectomy were included in the study. FNAB results were classified according to the Bethesda system. After evaluating the compatibility between cytology and pathology results, all-nodules and diameter-based (<4 cm and ≥4 cm) sensitivity, specificity, false positivity, false negativity, and accuracy rates of FNAB were calculated.
Results: Sensitivity of FNAB was 85.4% for all nodules, 88.3% for nodules <4 cm, and 75.8% for nodules >4 cm (P < 0.001). Specificity was 58.4% for all nodules, 49.3% for nodules <4 cm, and 75.1% for nodules >4cm (P < 0.001). While false positivity was 41.6% for all nodules, it was 50.7% for nodules smaller than 4 cm and was 24.9% for nodules larger than 4 cm (P < 0.001). False negativity was 14.6% for all nodules and was 11.7% for nodules smaller than 4 cm and 24.2% for nodules larger than 4 cm (P < 0.001). Finally, among the entire set of nodules, the accuracy was 64.4%, which was 59.2% in nodules smaller than 4 cm, and 75.2% in nodules larger than 4 cm (P < 0.001).
Conclusion: Despite a higher rate of false negativity, FNAB has higher specificity and accuracy in large nodules than those in the small nodules. Nodule diameter should not be used alone as a criterion to recommend thyroidectomy to the patient.
Keywords: Fine-needle aspiration biopsy, malignancy, nodule, thyroid
|How to cite this URL:|
Yilmaz N, Cansu GB, Toru S, Sari R, Ocak GG, Arici C, Altunbas HA, Balci MK. Cytopathology-histopathology correlation and the effect of nodule diameter on diagnostic performance in patients undergoing thyroid fine-needle aspiration biopsy. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 24]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=284075
| > Introduction|| |
Out of the thyroid nodules, roughly 5%–60% to can be detected via physical examination and imaging., Malignancy rate of thyroid nodules is approximately 5%. Thyroid fine-needle aspiration biopsy (FNAB) is widely used in addition to the obtained medical history, physical examination, and ultrasonography (USG) results for evaluating the malignancy potential of the thyroid nodules. FNAB is known to have a high sensitivity and specificity in diagnosing malignancy., FNAB is of significant help to the clinician both in the diagnosis of malignancy and in making the decision of on thyroidectomy and reduces the number of surgical interventions for benign thyroid nodules.
Reported sensitivity, specificity, and accuracy rates for FNAB exhibit a varying fashion both interstudies and intersites.,,,,, Contradictory results have been accumulated on the diagnostic performance of FNAB in large nodules., While FNAB has a good overall diagnostic performance in thyroid malignancies, there are studies that suggest a role to nodule diameter in FNAB accuracy, thus recommend lobectomy in large nodules regardless of the FNAB result due to high false negativity and high malignancy prevalence in large nodules. However, there are also other studies that report good diagnostic performance in large nodules, advocating in favor of a similar management to that of the small nodules.
In this study, data over a course of 5 years in our center were evaluated retrospectively and cytology results of FNAB, their pathological correlation and diagnostic performance of FNAB were evaluated. In addition, FNAB's diagnostic performance in nodules smaller than 4 cm and larger than 4 cm was compared.
| > Materials and Methods|| |
Records of patients older than 18 years, diagnosed with nodular or multinodular goiter, who underwent thyroid FNAB followed by total/subtotal thyroidectomy or lobectomy in Akdeniz University Hospital of School of Medicine, Department of Adult Endocrinology, between 2009 and 2014 were retrospectively analyzed. Only the patients whose FNAB results were reported according to the Bethesda system were included in the study.
Age, gender, thyroid function tests, thyroid autoantibodies, nodule size, FNAB results, thyroidectomy indications, and postthyroidectomy pathology results of the patients were examined. Nodules were classified according to their sizes in groups of <4 cm and ≥4 cm, which is the longest diameter as measured by USG. All FNABs were performed by experienced endocrinologists, guided by USG, in our endocrinology clinic. In case of patients with multiple nodules, FNAB was performed in all nodules larger than 1 cm if they show different USG findings. In the presence of multiple nodules with similar USG characteristics, FNAB was performed in the largest nodule. In cases with nodules not exceeding 1 cm, FNAB was performed in the presence of clinical risk factors or suspicious USG findings. Biopsy results were classified according to the Bethesda system into categories of nondiagnostic, benign, atypia of undetermined significance/follicular lesion of US (AUS/FLUS), follicular neoplasia/suspected follicular neoplasia (FN/SFN), suspected malignancy (SM), and malignant. FNAB results of patients who underwent biopsy in more than one nodule or multiple biopsies from one nodule at different times were classified in the category with a higher risk of malignancy.
Surgical indications of patients were recorded based on the most suitable cause among the causes including malignancy, indeterminate FNAB result (AUS/FLUS significance, FN/SFN, SM), pressure symptoms, patient's request due to cosmetic reasons, hyperthyroidism, and thyroidectomy performed during parathyroidectomy. After thyroidectomy, whether the final pathology results were benign or malignant, and subtypes if malignant, were evaluated. Based on the pathology results of the thyroidectomy material, patients who had nodules other than the nodules in which biopsy was performed, or incidental thyroid malignancy in nodules, were not included in the study.
To calculate the sensitivity and specificity of FNAB, after excluding the patients with nondiagnostic FNAB results, FNAB results were classified as true positive (TP) for patients with indeterminate or malignant FNAB results whose pathology results were reported as malignant, false negative (FN) for patients with benign FNAB result whose pathology results were reported as malignant, true negative (TN) for patients whose both FNAB and pathology results were reported as benign, and false positive (FP) for patients with indeterminate or malignant FNAB results whose pathology results were benign. Patients with FN/SFN FNAB result and follicular adenoma as the pathology result were considered FP. Then, sensitivity (TP/[TP + FN]), false negativity rate (1-sensitivity), specificity (TN/[TN + FP]), false positivity rate (1-specificity), positive predictive value (PPV) (TP/[TP + FP]), negative predictive value (NPV) (TN/[TN + FN]), and accuracy ([TP + TN]/[TP + TN + FP + FN]) were calculated. Comparisons regarding the diagnostic performance of FNAB based on nodule diameter (sensitivity rates, specificity rates, etc.) were calculated using Z-test for the difference between two proportions.
| > Results|| |
The data of a total of 7319 patients who underwent FNAB over the course of the study were examined. Once this examination is accomplished, a total of 648 patients who meet the previously determined criteria and had undergone post-FNAB thyroidectomy were included in the study, and their records were analyzed. Key characteristics of the patients included in the study are given in [Table 1]. In [Table 2], FNAB results of patients and malignancy rates according to the final pathology results are given. The most common cause of thyroidectomy was indeterminate FNAB result, with a percentage of 41.9 [Table 3]. Malignant result in FNAB was the thyroidectomy indication only in 4.3% of the patients. In [Table 3], breakdown of the thyroidectomy indications of patients is shown. Postoperation malignancy was shown in pathology results of 22.1% of all patients, and accordingly, they predominantly had papillary carcinoma (88.1%) or inflicted by follicular carcinoma (5.6%) [Table 4]. In [Table 4], final pathology results after thyroidectomy are given. Malignancy rate was 24.8% in nodules smaller than 4 cm, whereas it was 16.3% in nodules larger than 4 cm.
|Table 2: Malignancy rates based on fine-needle aspiration biopsy results and pathology results|
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[Table 5] presents total as well as nodule diameter-based sensitivity, false negativity rate, specificity, false positivity rate, PPV, and NPV of 601 patients, that is, remaining patients after patient results with nondiagnostic FNAB were removed. Sensitivity and specificity rates of FNAB were 85.4% and 58.4%, respectively. When FNAB's performance in nodules larger than 4 cm and nodules smaller than 4 cm were compared, significantly higher specificity and accuracy rates were detected in nodules larger than 4 cm (P < 0.001 and <0.001, respectively), but FNAB also had a significantly lower sensitivity in this size group (P < 0.001). Moreover, in nodules larger than 4 cm, FNAB had significantly lower false positivity rate and higher false negativity rate (P < 0.001 and <0.001, respectively).
|Table 5: Fine-needle aspiration biopsy's performance based on pathology results|
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In 166 (25.6%) of 648 patients, a second FNAB was performed due to increased size and malignant nodule characteristics detected in USG, although their first FNAB results were benign. Of these patients, 31 (18.6%) underwent thyroidectomy as the second FNAB results were FN/SFN, SM, or malignant, which resulted in a malignant pathology in 12 patients (7.2%). Overall, the second FNAB changed the clinical approach in 4.7% of all patients.
| > Discussion|| |
The main motivation behind the evaluation of thyroid nodules is to determine whether the nodules are benign or malignant. FNAB is a reliable and fast method with high accuracy, which is acknowledged as the golden standard in the evaluation of thyroid nodules. With the Bethesda system (The Bethesda System for reporting thyroid cytopathology), established in 2007, the terminology being used in thyroid cytopathology was standardized which suggest cytopathology results shall be reported according to the six subgroups defined in this system. In this study, we investigated the correlation between FNAB results reported according to the Bethesda system with the histopathology results obtained subsequent to the surgery in order to explore the diagnostic performance of FNAB and any effects of nodule size on FNAB performance.
According to the Bethesda system, expected malignancy rates by the cytopathological diagnostic subgroups are reported as 1%–4%, 0%–3%, 5%–15%, 15%–30%, 60%–75%, and 90%–97% for nondiagnostic, benign, AUS/FLUS, FN/SFN, SM, and malignant cytopathology subgroups, respectively, in clinical practice; however, actual malignancy rates in diagnostic subgroups vary., The actual malignancy rates previously reported for the nondiagnostic, benign, AUS/FLUS, FN/SFN, SM, and malignant cytopathological subgroups in Bethesda system range between 9%–32%, 1%–10%, 6%–48%, 14%–34%, 53%–97%, and 94%–100%., These differences among the reported malignancy rates can be due to the differences in study designs, in patients groups included in the study and in the cytopathological evaluations of cytopathologists. The malignancy rates in nondiagnostic, benign, and AUS/FLUS subgroups in our study were higher than the expected but were comparable to the previously reported actual malignancy rates. Malignancy rate in FN/SFN subgroup was matching with the expected and the previously reported real malignancy rates. In our study, malignancy rates in SM and malignant cytopathology subgroups were 44.9% and 89.7%, respectively, and were lower than the expected and the previously reported results.
While the malignancy rate expected in general in FN/SFN subgroup is higher than that in the AUS/FLUS subgroup, in some studies, alike our study, higher malignancy rates were reported in AUS/FLUS subgroup than in the FN/SFN subgroup., In the study by Theoharis et al., likewise, malignancy rate in AUS/FLUS cytopathology subgroup was higher (48.1%) than that in the FN/SFN subgroup (34.3%). In the study by Park et al., malignancy rate in AUS/FLUS subgroup (69%) was similarly found to be higher than that in the FN/SFN group (50%). In the previous studies, malignancy rates among the cytological subgroups in Bethesda system were shown to vary in a center- and the cytopathologist-dependent manner even within the same center, implying that the experience and education levels of the cytopathologists may affect FNAB results. AUS/FLUS subgroup is a subjective and heterogenous category usually yielding different interpretations among cytopathologists, and the causes listed above may have contributed to the high malignancy rate in AUS/FLUS category. Pathologists' avoidance from FP results may also have contributed to the high malignancy rate in FLUS/AUS subgroup in our study. Our results suggest that, depending on different factors, malignancy rates may be higher than the expected in AUS/FLUS subgroup, and each center should calculate their own malignancy rates, particularly for FLUS/AUS and FN/SFN subgroups and should take this fact into account during patient management.
Reported frequencies of the subtypes of thyroid malignancies are 80%–84% for papillary carcinoma, 6%–10% for follicular carcinoma, and 3%–5% for medullary carcinoma, and our results are in concordance with these results from the literature.,
FNAB features quite wide ranges of reported rates, between 67%–96.7% for sensitivity, 52%–98.7% for specificity, 39%–96.1% for PPV, 79.1%–98.2% for NPV, 7%–23.4% for false negativity, and 60%–96.3% for accuracy.,,,,,,,, Diagnostic performance attributed to FNAB in the literature varies depending on the subgroups classified as TP or FP, especially in AUS/FLUS and FN/SFN. Moreover, FNAB's diagnostic performance varies depending on the potential differences between study designs, patient groups included in the study, and cytopathological evaluations by different cytopathologists. In the meta-analysis by Bongiovanni et al., in line with our study, AUS/FLUS, FN/SFN, SM, and malignant subgroups were considered TP, stating sensitivity was 97.2%, specificity was 50.7%, PPV was 46.9%, and accuracy was 60.2%. In our study, compared to the mentioned meta-analysis, the rates of sensitivity (85.4%) and PPV (36.7%) were lower, but the rates of specificity (58.4%) and accuracy (64.4%) were higher.
Total malignancy rates in nodules larger than 4 cm happen to be at the level of 11%–50%.,,,, In contrary to the studies that report a higher malignancy rate in nodules larger than 4 cm, there also exist other studies that report a lower malignancy rate., While some studies have demonstrated higher malignancy rates in nodules larger than 4 cm suggesting surgery for patients with large nodules, in our study, the malignancy rate in nodules larger than 4 cm was found to be lower than the nodules smaller than 4 cm, and this finding indeed suggest that nodule diameter alone should not be used as a malignancy indicator.
There are conflicting reports on the diagnostic performance and reliability of FNAB in ruling out malignancy in thyroid nodules larger than 4 cm., Based on the studies which conclude a poor diagnostic performance of FNAB in large nodules, in nodules exceeding 4 cm, there is a tendency to recommend thyroidectomy, even to the patients with benign biopsy results. In studies on large thyroid nodules, FNAB's reported rates of sensitivity vary between 50% and 93%, specificity varies between 51% and 100%, PPV varies between 28.6% and 100%, NPV varies between 83.3 and 99.2%, and false negativity varies between 0.8 and 20.4%.,,,,,,,,,, In our study, in the nodules larger than 4 cm, specificity and accuracy rates of FNAB were higher than the corresponding figures above the applied threshold. Again in the larger nodule group, false negativity rate was higher, whereas false positivity rate was lower. Shrestha et al., similar to our study, have pointed out that FNAB has significantly higher specificity and accuracy rates in nodules larger than 4 cm. In the same study, no difference was detected between the large and small nodule groups in terms of sensitivity rate, false negativity rate, PPV, or NPV rates. On the other hand, Carrillo et al. have figured out a false negativity rate of 5.1% for nodules smaller than 4 cm which increases up to 20% for nodules larger than 4 cm, and thus, argued surgery should be recommended for large nodules. In our study, while the false negativity rate is higher in large nodules than that in the small nodules, specificity and accuracy rates are higher. The reason why FNAB has high false negativity rate in nodules larger than 4 cm and the benign FNAB results reported in large nodules should be carefully evaluated. Nevertheless, increased morbidity and costs due to unnecessary thyroidectomy needs to be taken into consideration. Based on the fact that, we found that FNAB has higher specificity and accuracy rates in nodules larger than 4 cm which also exhibit a lower malignancy rate compared to the nodules smaller than 4 cm, we believe that nodule diameter alone is not sufficient to recommend thyroidectomy in patients with large nodules and benign FNAB results. In this patient subset, in the presence of a medical history, physical examination, and USG imaging, in particular, findings out of which assume a malignant nature, thyroidectomy decision should be made, in our opinion, only if necessary after repeating FNAB and reevaluating all the findings.
| > Conclusion|| |
Our study is a large-scale study evaluating the diagnostic performance of FNAB in clinical practice in a region where iodine deficiency is common. We think that our study will make an important contribution to the literature in this subject. In addition, there are different opinions in the literature about whether the diagnostic performance of thyroid FNAB varies according to nodule size. Our results demonstrate that FNAB has a good diagnostic performance in large nodules as well as small nodules, except the high false negativity rate. It should be kept in mind that recommending surgical intervention to a patient despite a benign FNAB impression, which may happen as a result of the concerns regarding the poor diagnostic performance of FNAB, is a practice bringing along its additional morbidities and increased cost.
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Conflicts of interest
There are no conflicts of interest.
| > References|| |
Singer PA, Cooper DS, Daniels GH, Ladenson PW, Greenspan FS, Levy EG, et al.
Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association. Arch Intern Med 1996;156:2165-72.
Tan GH, Gharib H. Thyroid incidentalomas: Management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 1997;126:226-31.
Hegedüs L. Clinical practice. The thyroid nodule. N
Engl J Med 2004;351:1764-71.
Gharib H, Goellner JR, Johnson DA. Fine-needle aspiration cytology of the thyroid. A 12-year experience with 11,000 biopsies. Clin Lab Med 1993;13:699-709.
Wu HH, Jones JN, Osman J. Fine-needle aspiration cytology of the thyroid: Ten years experience in a community teaching hospital. Diagn Cytopathol 2006;34:93-6.
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.
Park JH, Yoon SO, Son EJ, Kim HM, Nahm JH, Hong S, et al.
Incidence and malignancy rates of diagnoses in the Bethesda system for reporting thyroid aspiration cytology: An institutional experience. Korean J Pathol 2014;48:133-9.
Yoon JH, Kwak JY, Moon HJ, Kim MJ, Kim EK. The diagnostic accuracy of ultrasound-guided fine-needle aspiration biopsy and the sonographic differences between benign and malignant thyroid nodules 3 cm or larger. Thyroid 2011;21:993-1000.
Kulstad R. Do all thyroid nodules and 4 cm need to be removed? An evaluation of thyroid fine-needle aspiration biopsy in large thyroid nodules. Endocr Pract 2016;22:791-8.
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.
Gul K, Ersoy R, Dirikoc A, Korukluoglu B, Ersoy PE, Aydin R, et al.
Ultrasonographic evaluation of thyroid nodules: Comparison of ultrasonographic, cytological, and histopathological findings. Endocrine 2009;36:464-72.
Carrillo JF, Frias-Mendivil M, Ochoa-Carrillo FJ, Ibarra M. Accuracy of fine-needle aspiration biopsy of the thyroid combined with an evaluation of clinical and radiologic factors. Otolaryngol Head Neck Surg 2000;122:917-21.
Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Thyroid 2009;19:1159-65.
Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda system for reporting thyroid cytopathology: A meta-analysis. Acta Cytol 2012;56:333-9.
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al.
2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-33.
Theoharis CG, Schofield KM, Hammers L, Udelsman R, Chhieng DC. The Bethesda thyroid fine-needle aspiration classification system: Year 1 at an academic institution. Thyroid 2009;19:1215-23.
Wu HH, Rose C, Elsheikh TM. The Bethesda system for reporting thyroid cytopathology: An experience of 1,382 cases in a community practice setting with the implication for risk of neoplasm and risk of malignancy. Diagn Cytopathol 2012;40:399-403.
Layfield LJ, Morton MJ, Cramer HM, Hirschowitz S. Implications of the proposed thyroid fine-needle aspiration category of “follicular lesion of undetermined significance”: A five-year multi-institutional analysis. Diagn Cytopathol 2009;37:710-4.
Paschke R, Lincke T, Müller SP, Kreissl MC, Dralle H, Fassnacht M, et al.
The treatment of well-differentiated thyroid carcinoma. Dtsch Arztebl Int 2015;112:452-8.
Ceresini G, Corcione L, Michiara M, Sgargi P, Teresi G, Gilli A, et al.
Thyroid cancer incidence by histological type and related variants in a mildly iodine-deficient area of, 1998 to 2009. Cancer 2012;118:5473-80.
Godazandeh G, Kashi Z, Zargarnataj S, Fazli M, Ebadi R, Kerdabadi EH, et al.
Evaluation the relationship between thyroid nodule size with malignancy and accuracy of fine needle aspiration biopsy (FNAB). Acta Inform Med 2016;24:347-50.
Holleman F, Hoekstra JB, Ruitenberg HM. Evaluation of fine needle aspiration (FNA) cytology in the diagnosis of thyroid nodules. Cytopathology 1995;6:168-75.
Hamming JF, Vriens MR, Goslings BM, Songun I, Fleuren GJ, van de Velde CJ, et al.
Role of fine-needle aspiration biopsy and frozen section examination in determining the extent of thyroidectomy. World J Surg 1998;22:575-9.
Meko JB, Norton JA. Large cystic/solid thyroid nodules: A potential false-negative fine-needle aspiration. Surgery 1995;118:996-1003.
McCoy KL, Jabbour N, Ogilvie JB, Ohori NP, Carty SE, Yim JH, et al.
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.
Rosario PW, Salles DS, Bessa B, Purisch S. Low false-negative rate of cytology in thyroid nodules>or=4 Arq Bras Endocrinol Metabol 2009;53:1143-5.
Mehanna R, Murphy M, McCarthy J, O'Leary G, Tuthill A, Murphy MS, et al.
False negatives in thyroid cytology: Impact of large nodule size and follicular variant of papillary carcinoma. Laryngoscope 2013;123:1305-9.
Shin JJ, Caragacianu D, Randolph GW. Impact of thyroid nodule size on prevalence and post-test probability of malignancy: A systematic review. Laryngoscope 2015;125:263-72.
Raj MD, Grodski S, Woodruff S, Yeung M, Paul E, Serpell JW, et al.
Diagnostic lobectomy is not routinely required to exclude malignancy in thyroid nodules greater than four centimetres. ANZ J Surg 2012;82:73-7.
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.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]