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Department of Endocrine, Metabolic and Digestive Diseases (E.P., R.G., C.P., R.R.); Department of Diagnostic (A.B., A.C., S.T., C.M.P.), Ospedale Regina Apostolorum, Albano (Rome) 00041, Italy; and Department of Experimental Medicine (F.N.); Department of Physiopathology (V.T.), 2nd Faculty, Università La Sapienza, Rome 00161, Italy
Address all correspondence and requests for reprints to: Enrico Papini, Department of Endocrine, Metabolic and Digestive Diseases Ospedale Regina Apostolorum, Via San Francesco 50, Albano (Rome 00041), Italy. E-mail: . papinie{at}virgilio.it
Abstract
The aim of the study was to correlate the sonographic [ultrasound (US)] and color-Doppler (CFD) findings with the results of US-guided fine needle aspiration biopsy (FNA) and of pathologic staging of resected carcinomas to establish: 1) the relative importance of US features as risk factors of malignancy; and 2) a cost-effective management of nonpalpable thyroid nodules.
Four hundred ninety-four consecutive patients with nonpalpable thyroid nodules (8–15 mm) were evaluated by US, CFD, and US-FNA. Ninety-two patients with inadequate cytology were excluded from the study. All patients with suspicious or malignant cytology underwent surgery, whereas subjects with benign cytology had clinical and US control 6 months later.
Thyroid malignancies were observed in 18 of 195 (9.2%) solitary thyroid nodules and in 13 of 207 (6.3%) multinodular goiters. Cancer prevalence was similar in nodules greater or smaller than 10 mm (9.1 vs. 7.0%). Extracapsular growth (pT4) was present in 35.5%, and nodal involvement in 19.4% of neoplastic lesions, with no significant differences between tumors greater or smaller than 10 mm. At US cancers presented a solid hypoechoic appearance in 87% of cases, irregular or blurred margins in 77.4%, an intranodular vascular pattern in 74.2%, and microcalcifications in 29.0%.
Irregular margins (RR 16.83), intranodular vascular spots (RR 14.29), and microcalcifications (RR 4.97) were independent risk factors of malignancy. FNA performed on hypoechoic nodules with at least one risk factor was able to identify 87% of the cancers at the expence of cytological evaluation of 38.4% of nonpalpable lesions.
The majority of nonpalpable thyroid tumors can be identified by cytological evaluation of lesions presenting hypoechoic appearance in conjunction with one independent risk factor. Due to the nonnegligible prevalence of extracapsular growth and nodal metastasis, US-FNA should be performed on all 8–15 mm hypoechoic nodules with irregular margins, intranodular vascular spots or microcalcifications. Nonpalpable lesions of the thyroid without risk factors should be followed by means of clinical and US evaluation.
THE DISCOVERY RATE of nonpalpable thyroid nodules in the general population is increasing as a consequence of the widespread use of ultrasound (US) evaluation of the cervical region (1, 2). There is considerable controversy over whether clinically unapparent thyroid lesions should be assessed by fine needle aspiration biopsy (FNA) (3, 4). The conflicting attitudes are due to uncertainty about both the prevalence of malignancy in small thyroid lesions and the biological behavior of thyroid microcarcinomas (5, 6, 7, 8, 9, 10), usually diagnosed retrospectively in resected goiters. Hence it has been suggested that, in the absence of previous neck irradiation or other identifiable risk factors, nonpalpable thyroid nodules not exceeding 10 or 15 mm in diameter should be managed only with neck palpation follow-up (3, 11).
Few prospective studies (12, 13, 14, 15) have been addressed to the systematic evaluation of thyroid nodules incidentally discovered at sonography to correlate the dimensions and the US and color-Doppler (CFD) findings with the prevalence of cancer and its pathologic staging.
To determine optimal clinical management of nonpalpable thyroid nodules our study set out to correlate, in a prospective series, the findings of US and CFD examinations with the cytological and histological results so as to assess: 1) the prevalence of cancer; 2) the prevalence of malignancy in nodules greater or smaller than 10 mm, in solitary vs. multiple lesions and in dominant vs. nondominant lesions within multinodular goiters; 3) the relative risk of malignancy of the main US features (echogenicity, echo-structure, margins, vascular images, and microcalcifications); 4) the prevalence, on the basis of TNM stage, of aggressive behavior of the discovered thyroid cancers and the possibility of fixing a dimensional cut-off for the threat of extracapsular or metastatic growth; 5) cost-effective criteria for identifying which nonpalpable thyroid lesions should undergo FNA evaluation.
Subjects and Methods
Patients
Four hundred ninety-four consecutive patients (from 16 to 84 yr old, mean age: 47.8 ± 13.3 yr; males 64 and females 430) with nonpalpable thyroid nodules entered the prospective study between June 1995 and June 2000. Cases were selected from 3500 patients, referred to our thyroid clinic for US-guided FNA from the greater Rome metropolitan area, a low-endemic zone for goiter (16).
Entry criteria included: presence at US evaluation of a thyroid nodule that was nonpalpable or ill-defined at physical examination and either solitary or within multinodular goiter; greatest diameter of the lesion ranging from 8 to 15 mm; 99mTc thyroid scan consistent with a nonvisualized or hypofunctioning nodule; normal levels of serum TSH and free thyroid hormones (FT4 and FT3).
The study was conducted according to the principles of the Helsinki declaration. Written informed consent was obtained from all subjects.
Methods
The US and CFD examinations were performed with a commercially available real time scanner (Acuson Sequoia, Mountain View, CA), equipped with a linear transducer operating at 8.5–13 Mhz for morphological study and at 4.7 Mhz for CFD evaluation, capable of visualizing solid lesions as small as 2 mm in size.
During a US panoramic study, the US pattern of thyroid parenchyma (homogeneous, nonhomogeneous, with multiple lesions) and the volume of the nodule were assessed (17). A careful evaluation of the following parameters was carried out on all lesions with a diameter over 8 mm: echogenicity (hyper, iso- or hypoechoic), echo structure (solid, mixed, or cystic), margins (well defined, irregular, or blurred) and presence of hyperechoic spots (coarse calcifications or microcalcifications) (18, 19).
CFD examinations were performed with biplanar scanning (20, 21). The amplifer gain was individually chosen in each case to be at a level immediately under the point of appearance of random color noise. Pulse repetition frequency was established at 500–750 Hz, which is useful for slow flow evaluation. US output power and write/echo priority were maintained at constant values. Vascularity pattern was evaluated using sagittal and transverse scans performed along the maximum diameter of the nodule, and three types of vascularity (22, 23) were identified: type 0, absence of flow signals; type 1, vascular images in peripheral position; type 2, intranodular flow with multiple vascular images.
The US and CFD examinations were performed and registered by two skilled sonographers according to a standard procedure.
After the assessment of sonographic features, US-guided FNA was performed by three experienced endocrinologists, with 27- and 23-gauge needles, according to a previously described technique (24, 25, 26).
Cytological material was smeared on slides immediately after aspiration (solid lesions) or after cytocentrifugation (in the case of fluid collections) and stained by May-Grunwald-Giemsa and Papanicolaou stains. Cytological specimens were evaluated by an experienced cytopathologist and classified as benign, suspicious or malignant. Cytological smears labeled as suspicious included proliferative lesions of follicular epithelia and lesions with minor nuclear changes not clearly diagnostic for malignancy. Samples were defined as sufficient when six or more clusters of follicular cells with each group containing at least ten follicular cells were present on the slides (25, 26).
Cases with benign cytology had clinical and US control after 6 months to rule out changes in nodule volume or clinical features. In the case of nodule growth, a second US-FNA was performed to rule out overlooked malignancies (27).
All patients with suspicious or malignant cytology underwent surgery. The accuracy of intraoperative diagnosis was improved by the use of cytospray fixation of frozen intraoperative sections (28) and the comparative observation of cytological imprints. Total thyroidectomy with cervical node exploration was performed on all such patients with intraoperative diagnosis of cancer (26). Lymph node dissection in the central neck ipsilateral to the nodule was performed in patients with suspicious nodal enlargement. Removal of lateral neck nodes was performed in cases of confirmed nodal metastases at intraoperatory sampling.
The surgical samples were cut before fixation for macroscopic examination. Evaluation was carried out performing multiple 5-mm slices of the whole thyroid gland to accurately define the dimensions of malignant lesions and their multifocality. Specimens were fixed in buffered formalin, embedded in paraffin and stained with hematoxylin and eosin for histologic study. All neoplastic lesions were staged according to tumor size, nodal involvement, and distant metastasis (TNM) classification criteria (29).
Serum levels of TSH, free thyroid hormones (FT3 and FT4) were determined with commercially available IRMA and RIA kits (Sorin Biomedica, Saluggia, Italy; and Radim, Pomezia, Italy).
Statistical analyses
Clinical, US, cytological, and pathological findings were separately registered and blind-processed for statistical evaluation (CP and VT). The frequency distribution of thyroid cancer in the different groups of nodule volume and of US and CFD features was compared by 
2 and Fisher exact tests. The relative risk of malignancy was evaluated by logistic regression analysis. The significance level was set at P less than 0.05.
Results
Reasons for investigation
Nonpalpable thyroid nodules were diagnosed by US performed for the following reasons: diffuse or multinodular goiter, cervical constriction or pain, doubtful palpation of the thyroid gland, follow-up after lobectomy due to benign thyroid nodules, hoarseness, carotid echo-Doppler evaluation, and cervical adenopathy. Only two (16.6%) of the 12 patients referred because of cervical adenopathy presented neoplastic nodal involvement.
Cytological and histological results
Ninety-two of 494 patients (18.6%) presented inadequate cytological specimens and were excluded from the study. The prevalence of inadequate sampling was greater in nodules above than in nodules below 10 mm (22.5 vs. 16.6%, P = ns) and in mixed than in solid lesions (28.0 vs.17.5%, P = ns).
Of the 402 nodules included in the study, 195 (48.5%) were solitary and 207 (51.5%) were embedded in a multinodular goiter. At cytological evaluation, 306 lesions were benign (76.3%), 73 were suspicious (18.1%), and 23 were malignant (5.7%).
The 96 nodules that were suspicious or malignant at cytological evaluation underwent surgery. Eleven cases with benign cytology were operated upon 6 months later because of a marked increase of volume or of local discomfort due to enlarging goiter.
Histological examination (107 subjects) showed carcinomas in 31 cases (28.9%), follicular adenomas in 24 cases (22.4%), and benign thyroid disease in 52 cases (48.6%).
The overall distribution of the combined cytological and histological diagnosis was as follows: malignancies 31 cases (7.7%), follicular adenoma 24 cases (5.9%) and benign thyroid disease 347 cases (86.3%). Thyroid carcinomas were papillary in 87%, follicular or Hurthle-cell in 6.5%, and medullary in 6.5% of cases. The cytological and histological results together with US features are summarized in Table 1
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Local extension with extracapsular growth (pT4 at TNM staging) was present in 11 of 31 cancers (35.5%) without significant differences between tumors smaller and greater than 10 mm (33.3 vs. 36.8%; P = ns). Nodal involvement was found in 6 of 31 (19.4%) neoplastic lesions.
Multifocal malignancies were observed in 4 of 31 cases (12.9%). Cytological diagnosis of multifocal malignancy was obtained preoperatively in 2 of 4 cases (50%). No distant metastases were observed. No correlation was observed between aggressive growth and dimensions of thyroid nodules, multinodularity, age, or sex.
Clinical and US reevaluation, performed after 6 months on patients with benign cytological samples, showed no major changes in 276 of 306 cases. A repeated US-FNA, performed on the 30 (9.8%) growing lesions, confirmed in all cases but one (papillary carcinoma) the previous benign cytological results. TNM staging of the malignant lesions is summarized in Table 2.
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Malignant lesions presented more frequently than did benign nodules a solid hypoechoic appearance (87.0 vs. 56.6%; P = 0.009), irregular or blurred margins (77.4% vs. 14.5%; P = 0.0001), and intranodular vascular pattern (74.2 vs. 19.1%; P = 0.0001). Microcalcifications were observed in 9 of 31 (29.0%) cancers and in 15 of 371 (4.0%) benign thyroid nodules (P = 0.0001).
Logistic regression analysis demonstrated that independent risk factors of malignancy at US examination of nonpalpable thyroid nodules are: irregular or blurred nodular margins (OR 16.8, P = 0.001), an intranodular vascular pattern (OR 14.3, P = 0.0011) and microcalcifications (OR 4.9, P = 0.05). A nonsignificant increase in the relative risk was presented by a hypoechoic appearance (OR: 1.9) and by the presence of solitary lesions (OR: 1.4). Dimensions greater than 10 mm showed no increase in relative risk (OR: 0.99).
Specificity, sensitivity, and predictive value for malignancy of the different sonographic features are summarized in Tables 3 and 4.
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Cost effectiveness of US-guided FNA
The number of diagnostic procedures performed, the percentage of nonpalpable cancers discovered and the pT4 stages detected according to different selection criteria (US-guided FNA performed on all nonpalpable nodules, on nodules greater than 10 mm, on all hypoechoic nodules or on hypoechoic nodules with at least one independent US risk factor) are summarized in Table 5.
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The use of US in the assessment of thyroid disease has greatly increased the detection of small thyroid nodules unrecognized at clinical examination (1, 2). As thyroid nodules are shown by US to be present in 30–50% of the population and fewer than 5.0–6.5% of these are malignant (12), US-guided FNA has become increasingly popular (25). The question of whether clinically unapparent thyroid lesions should be assessed by FNA biopsy is still unresolved (12). It seems not to be cost effective to perform a US-guided cytological evaluation of all incidentally discovered thyroid nodules (3, 11), and opinions still vary about the clinical significance of thyroid microcarcinomas. Most reports have shown that incidentally discovered papillary carcinomas of thyroid gland follow an indolent course (7, 30, 31, 32), but a few series have demonstrated a not insignificant number of microcarcinomas associated with extracapsular growth and nodal or distant metastases (5, 6, 8, 9, 10, 33, 34, 35, 36). The discordant results of these studies are probably due to the heterogeneous criteria used for enrollment (most surveys were retrospective surgical series including lesions with dimensions as small as 3 mm) and to the frequently ill-defined clinicopathologic staging of thyroid carcinomas.
The aim of our study was to evaluate prospectively a controlled series of incidental thyroid nodules to correlate the US and CFD findings with the cytological results of US-FNA as well as with the pathologic staging of those microcarcinomas that underwent surgery.
The definition of the relative importance of US and CD features as risk factors for malignancy and the assessment of the actual prevalence of aggressive microcarcinomas in thyroid incidentalomas should help determine the optimal management of nonpalpable thyroid nodules.
Adequacy of cytological specimens
The prevalence of US-FNA samples that were inadequate for diagnosis (18.6%) was similar to that previously reported in nonpalpable lesions (18.5–18.8%) (13, 15). In our series, inadequate specimens were more frequently linked to the presence of fluid areas than to the dimension of the lesions smaller than 10 mm (28.0 vs. 22.5%). Although the adequacy of cytological specimens was greater in nodules above than in nodules below 10 mm, the difference was so small (83.4 vs. 77.5%, P = ns) that the diagnostic effectiveness of US-FNA appears not to be blunted in lesions under 10 mm.
In our series, 8 of 31 detected malignancies were classified as suspicious nodules at preliminary cytological evaluation. We did not classify these cases as false negatives.
The prevalence of histologic diagnoses of benign nodule in the group of cytologically suspicious nodules (defined as proliferative lesions of follicular epithelia and lesions with minor nuclear changes not clearly diagnostic for malignancy) was higher than usually reported. This is partially due to the effort to minimize the risk of overlooking malignancies in the course of the present study. Indeed, at histologic examination many of these benign lesions were hyperplastic and adenomatous nodules characterized by a microfollicular pattern but devoid of a perinodular capsula. On this basis, they were not classified as adenomas.
Prevalence of cancer
The prevalence of cancer in our series (7.7%) was similar to that previously assessed by means of cytological and histological evaluation in nonpalpable thyroid lesions (15). The prevalence of cancer reported by Leenhardt was 5.4%, but the actual prevalence would probably have been higher if all the nodules suspicious or malignant at cytological evaluation had been submitted to surgery (13). The prevalence of cancer in nonpalpable thyroid nodules was slightly higher than that reported in palpable lesions (5.0–6.5%) (26). The higher malignancy rate is probably due to the careful selection of the lesions to submit to FNA in the case of incidentally discovered nodules. Moreover, the systematic US-FNA evaluation of thyroid nodules could have detected a few microcarcinomas devoid of aggressive behavior and destined not to grow into palpable lesions.
In our study, the prevalence of papillary carcinomas was higher than in the major surgical series of thyroid cancer (37, 38). However, it is noteworthy that 6.5% of carcinomas were follicular or Hurthle-cell cancers and 6.5% were medullary cancers, i.e. tumors that clearly indicate surgical resection irrespective of their size.
Risk of malignancy
Clinical criteria (solitary vs. multiple nodules, nodules greater vs. smaller than 10 mm) were of no use in determining the risk of malignancy. Solitary nodules presented a higher but not significantly increased risk of cancer as opposed to lesions embedded in multinodular goiters, confirming what observed in palpable nodules (39). The prevalence of malignancy was not significantly higher in nodules greater than in nodules smaller than 10 mm, and a dimensional cut-off of 10 (or 15) mm seemed unhelpful. Moreover, as no patient with malignant lesions presented clinical risk factors for malignancy such as external head and neck irradiation, previous surgery for thyroid neoplasms or a positive family history, the diagnosis of thyroid cancer could not have been made without US-guided FNA.
Aggressive behavior
The clinical significance of thyroid cancer in nonpalpable lesions is controversial (32). However, in our series TNM staging demonstrated extracapsular growth in 35.5% and nodal involvement in 19.4% of not incidentally resected thyroid cancers. The nonnegligible prevalence of extrathyroidal spread is in accordance with previous series that have shown a rate of invasive growth of occult thyroid carcinomas ranging from 15.9–63.8% of cases (5, 6, 7, 8).
The prevalence of extracapsular or metastatic growth was similar in nodules over and under 10 mm, and multifocal cancers were associated with both over and under 10-mm lesions. Therefore, as observed in a previous surgical report (6), it is impossible to fix an effective dimensional cut-off for the risk of extracapsular or metastatic growth.
Value of US and CFD findings as predictors of malignancy
US findings are important in predicting malignancy in nonpalpable lesions. Although previous reports (15) have denied that US findings have a predictive role, in our series logistic regression analysis confirmed that irregular or blurred nodular margins, an intranodular vascular pattern and microcalcifications were closely linked to neoplastic lesions (19). On the other hand, a hypoechoic appearance or the presence of solitary lesions were not independent risk factors for malignancy in nonpalpable thyroid nodules.
The presence of microcalcifications presented a higher specificity for malignancy (95%) than the findings of irregular margins (85%) or intranodular vascular images (80.8%), but the predictive value of microcalcifications was blunted by their low sensitivity (29.0% vs. 77.5% and 74.2%, respectively).
In incidentally discovered thyroid lesions, as has been reported in earlier papers on palpable nodules (22), no single US and CFD pattern taken by itself is highly predictive for malignancy. In our series as well, limiting FNA to nonpalpable nodules with these US features means that a few small thyroid cancers (13%) are lost. Nonetheless, the combination of hypoechoic appearance with the US and CFD patterns associated with malignancy succeeds in pointing out the relatively narrow subset of nonpalpable thyroid nodules (about 25% of the whole series) at high risk of malignancy.
Cost-effectiveness criteria for FNA evaluation
The present epidemic of small thyroid cancers was not clinically assessable until the advent of high resolution ultrasonography. This would seem to confirm that a number of these microcarcinomas are devoid of clinical significance and that a dimensional cut-off point should be fixed to avoid large scale treatment with thyroidectomy (1–2% of female population could be involved in unnecessary surgical procedures). For this reason, we established a minimum diameter of 8 mm (well within the limits of pT1 at TNM staging) for nonpalpable nodules to be subjected to cytologic evaluation while recommending US follow-up of smaller lesions.
In the present series, had the previously proposed dimensional criteria (FNA-US restricted to nodules greater than 10 mm) been followed (3, 11), the cytological evaluation would have missed 12 of 31 thyroid carcinomas (38.7% of the actually diagnosed malignancies) and 4 of 11 cases (36.4%) of locally spreading malignancies. On the other hand, FNA-US performed on nodules of any dimension but characterized by a hypoechoic appearance in conjunction with at least one of the three identified independent risk factors (intranodular vascular images, blurred margins and microcalcifications), would have missed only 4 of 31 cases (13%) of thyroid carcinomas and 1 of 11 cases (9%) of tumors with local invasion.
The 325 of 494 cases (65.7% of the total) that would have been assigned to diagnostic procedures had a dimensional cut-off been used would have produced a ratio between the number of detected malignancies and the number of diagnostic procedures performed of 19/325 (5.8%), as opposed to a ratio of 27/125 (21.7%) when diagnostic procedures were performed on the basis of US risk factors (125/494, i.e. 25.7% of cases).
A negative rate for malignancy of 8 of 10 FNA procedures seems not to blunt the advantage of early referral for less aggressive treatment of those patients who have nonpalpable lesions which harbor small and probably still intraglandular thyroid cancer (40, 41).
Conclusions
Cytological evaluation of nonpalpable nodules presenting hypoechoic appearance in conjunction with at least one independent US risk factor succeeds in identifying the vast majority of nonpalpable thyroid tumors. Due to the nonnegligible prevalence of extracapsular growth and nodal metastasis, US-guided FNA should be performed on all 8–15 mm hypoechoic nodules with irregular margins, intranodular vascular spots or microcalcifications. Nonpalpable lesions of the thyroid without sonographic features at risk for malignancy should be followed-up repeating clinical and US evaluation after 6–12 months.
Acknowledgments
We thank John Osborne for his statistical advice and Karen Christenfeld for her help in writing the English version of this work.
Footnotes
Abbreviations: CFD, Color-Doppler; FNA, fine needle aspiration biopsy; pT4, extracapsular growth; TNM, tumor size, nodal involvement and distant metastasis classification; US, ultrasound.
Received August 14, 2001.
Accepted December 31, 2001.
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J. H. Shin, B.-K. Han, E. Y. Ko, and S. S. Kang Sonographic Findings in the Surgical Bed After Thyroidectomy: Comparison of Recurrent Tumors and Nonrecurrent Lesions J. Ultrasound Med., October 1, 2007; 26(10): 1359 - 1366. [Abstract] [Full Text] [PDF]
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D. C. Howlett and A. Speirs The Thyroid Incidentaloma Ignore or Investigate? J. Ultrasound Med., October 1, 2007; 26(10): 1367 - 1371. [Abstract] [Full Text] [PDF]
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T. Rago, F. Santini, M. Scutari, A. Pinchera, and P. Vitti Elastography: New Developments in Ultrasound for Predicting Malignancy in Thyroid Nodules J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2917 - 2922. [Abstract] [Full Text] [PDF]
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A. Lyshchik, R. Moses, S. L. Barnes, T. Higashi, R. Asato, M. I. Miga, J. C. Gore, and A. C. Fleischer Quantitative Analysis of Tumor Vascularity in Benign and Malignant Solid Thyroid Nodules J. Ultrasound Med., June 1, 2007; 26(6): 837 - 846. [Abstract] [Full Text] [PDF]
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J. K. Hoang, W. K. Lee, M. Lee, D. Johnson, and S. Farrell US Features of Thyroid Malignancy: Pearls and Pitfalls RadioGraphics, May 1, 2007; 27(3): 847 - 860. [Abstract] [Full Text] [PDF]
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J. E. Langer, J. K. Hoang, W. K. Lee, and S. Farrell Invited Commentary * Authors' Response RadioGraphics, May 1, 2007; 27(3): 861 - 865. [Full Text] [PDF]
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 R Jones, R Spendiff, S Fareedi, and P S Richards The role of ultrasound in the management of nodular thyroid disease Imaging, March 1, 2007; 19(1): 28 - 38. [Abstract] [Full Text] [PDF]
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 C. Cappelli, M. Castellano, I. Pirola, D. Cumetti, B. Agosti, E. Gandossi, and E. Agabiti Rosei The predictive value of ultrasound findings in the management of thyroid nodules QJM, January 1, 2007; 100(1): 29 - 35. [Abstract] [Full Text] [PDF]
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 H. Schoder and M. Gonen Screening for Cancer with PET and PET/CT: Potential and Limitations J. Nucl. Med., January 1, 2007; 48(1_suppl): 4S - 18S. [Abstract] [Full Text] [PDF]
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D. S. Ross Predicting thyroid malignancy. J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4253 - 4255. [Full Text] [PDF]
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S. K. Shetty, M. M. Maher, P. F. Hahn, E. F. Halpern, and S. L. Aquino Significance of incidental thyroid lesions detected on CT: correlation among CT, sonography, and pathology. Am. J. Roentgenol., November 1, 2006; 187(5): 1349 - 1356. [Abstract] [Full Text] [PDF]
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M. C. Frates, C. B. Benson, P. M. Doubilet, E. Kunreuther, M. Contreras, E. S. Cibas, J. Orcutt, F. D. Moore Jr., P. R. Larsen, E. Marqusee, et al. Prevalence and Distribution of Carcinoma in Patients with Solitary and Multiple Thyroid Nodules on Sonography J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3411 - 3417. [Abstract] [Full Text] [PDF]
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T. Wilson, Q. Chen, J. A. Zagzebski, T. Varghese, and L. VanMiddlesworth Initial clinical experience imaging scatterer size and strain in thyroid nodules. J. Ultrasound Med., August 1, 2006; 25(8): 1021 - 1029. [Abstract] [Full Text] [PDF]
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C. Cappelli, M. Castellano, I. Pirola, E. Gandossi, E. De Martino, D. Cumetti, B. Agosti, and E. A. Rosei Thyroid nodule shape suggests malignancy. Eur. J. Endocrinol., July 1, 2006; 155(1): 27 - 31. [Abstract] [Full Text] [PDF]
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 M Niedziela Pathogenesis, diagnosis and management of thyroid nodules in children. Endocr. Relat. Cancer, June 1, 2006; 13(2): 427 - 453. [Abstract] [Full Text] [PDF]
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K. D. Burman Micropapillary Thyroid Cancer: Should We Aspirate All Nodules Regardless of Size? J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2043 - 2046. [Full Text] [PDF]
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M. Torlontano, U. Crocetti, G. Augello, L. D'Aloiso, N. Bonfitto, A. Varraso, F. Dicembrino, S. Modoni, V. Frusciante, A. Di Giorgio, et al. Comparative Evaluation of Recombinant Human Thyrotropin-Stimulated Thyroglobulin Levels, 131I Whole-Body Scintigraphy, and Neck Ultrasonography in the Follow-Up of Patients with Papillary Thyroid Microcarcinoma Who Have Not Undergone Radioiodine Therapy J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 60 - 63. [Abstract] [Full Text] [PDF]
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M. C. Frates, C. B. Benson, J. W. Charboneau, E. S. Cibas, O. H. Clark, B. G. Coleman, J. J. Cronan, P. M. Doubilet, D. B. Evans, J. R. Goellner, et al. Management of Thyroid Nodules Detected at US: Society of Radiologists in Ultrasound Consensus Conference Statement Radiology, December 1, 2005; 237(3): 794 - 800. [Abstract] [Full Text] [PDF]
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S. R. Steele, M. J. Martin, P. S. Mullenix, K. S. Azarow, and C. A. Andersen The Significance of Incidental Thyroid Abnormalities Identified During Carotid Duplex Ultrasonography Arch Surg, October 1, 2005; 140(10): 981 - 985. [Abstract] [Full Text] [PDF]
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 M. R. Castro and H. Gharib Continuing Controversies in the Management of Thyroid Nodules Ann Intern Med, June 7, 2005; 142(11): 926 - 931. [Abstract] [Full Text] [PDF]
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E Saggiorato, R De Pompa, M Volante, S Cappia, F Arecco, A P Dei Tos, F Orlandi, and M Papotti Characterization of thyroid 'follicular neoplasms' in fine-needle aspiration cytological specimens using a panel of immunohistochemical markers: a proposal for clinical application Endocr. Relat. Cancer, June 1, 2005; 12(2): 305 - 317. [Abstract] [Full Text] [PDF]
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 K. Krohn, D. Fuhrer, Y. Bayer, M. Eszlinger, V. Brauer, S. Neumann, and R. Paschke Molecular Pathogenesis of Euthyroid and Toxic Multinodular Goiter Endocr. Rev., June 1, 2005; 26(4): 504 - 524. [Abstract] [Full Text] [PDF]
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A. Liebeskind, A. G. Sikora, A. Komisar, D. Slavit, and K. Fried Rates of Malignancy in Incidentally Discovered Thyroid Nodules Evaluated With Sonography and Fine-Needle Aspiration J. Ultrasound Med., May 1, 2005; 24(5): 629 - 634. [Abstract] [Full Text] [PDF]
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A. Lyshchik, V. Drozd, Y. Demidchik, and C. Reiners Diagnosis of Thyroid Cancer in Children: Value of Gray-Scale and Power Doppler US Radiology, May 1, 2005; 235(2): 604 - 613. [Abstract] [Full Text] [PDF]
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 H. R. Sajjadieh, V. Sajjadieh, A. Aminorroaya, M. Amini, S. Oveisgharan, M. Reisifar, A. Adibi, M. Siavash, M. Nazem, and M. Peyman Value of Sonography in Determining the Nature of Thyroid Nodules: Evaluation of the Sonographic Characteristics Journal of Diagnostic Medical Sonography, January 1, 2005; 21(1): 38 - 44. [Abstract] [PDF]
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 S. J. Mandel A 64-Year-Old Woman With a Thyroid Nodule JAMA, December 1, 2004; 292(21): 2632 - 2642. [Full Text] [PDF]
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J. D. Iannuccilli, J. J. Cronan, and J. M. Monchik Risk for Malignancy of Thyroid Nodules as Assessed by Sonographic Criteria: The Need for Biopsy J. Ultrasound Med., November 1, 2004; 23(11): 1455 - 1464. [Abstract] [Full Text] [PDF]
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 L. Hegedus The Thyroid Nodule N. Engl. J. Med., October 21, 2004; 351(17): 1764 - 1771. [Full Text] [PDF]
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G. Pellegriti, C. Scollo, G. Lumera, C. Regalbuto, R. Vigneri, and A. Belfiore Clinical Behavior and Outcome of Papillary Thyroid Cancers Smaller than 1.5 cm in Diameter: Study of 299 Cases J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3713 - 3720. [Abstract] [Full Text] [PDF]
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J. R. Wienke, W. K. Chong, J. R. Fielding, K. H. Zou, and C. A. Mittelstaedt Sonographic Features of Benign Thyroid Nodules: Interobserver Reliability and Overlap With Malignancy J. Ultrasound Med., October 1, 2003; 22(10): 1027 - 1031. [Abstract] [Full Text] [PDF]
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B. K. Chan, T. S. Desser, I. R. McDougall, R. J. Weigel, and R. B. Jeffrey Jr Common and Uncommon Sonographic Features of Papillary Thyroid Carcinoma J. Ultrasound Med., October 1, 2003; 22(10): 1083 - 1090. [Abstract] [Full Text] [PDF]
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L. Hegedus, S. J. Bonnema, and F. N. Bennedbaek Management of Simple Nodular Goiter: Current Status and Future Perspectives Endocr. Rev., February 1, 2003; 24(1): 102 - 132. [Abstract] [Full Text] [PDF]
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D. S. Ross Nonpalpable Thyroid Nodules--Managing an Epidemic J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1938 - 1940. [Full Text] [PDF]
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