This Article Abstract Full Text (PDF) Submit a related Letter to the Editor View responses Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Snozek, C. L. H. Articles by Grebe, S. K. G. Search for Related Content PubMed PubMed Citation Articles by Snozek, C. L. H. Articles by Grebe, S. K. G. Related Collections Thyroid Endocrine Oncology

Serum Thyroglobulin, High-Resolution Ultrasound, and Lymph Node Thyroglobulin in Diagnosis of Differentiated Thyroid Carcinoma Nodal Metastases

Departments of Laboratory Medicine and Pathology (C.L.H.S., T.J.S., R.J.S., S.K.G.G.), Medicine, Division of Endocrinology (S.K.G.G.), and Diagnostic Radiology (C.C.R.), Mayo Clinic, Rochester, Minnesota 55905; Department of Surgery, Division of Surgical Oncology and Endocrine Surgery (E.P.C.), Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232; and Jackson Thyroid and Endocrine Clinic, P.L.L.C. (J.W.S.), Jackson, Mississippi 39216

Address all correspondence and requests for reprints to: Stefan Grebe, Hilton 730, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota 55905. E-mail: grebe.stefan{at}mayo.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Clinically enlarged cervical lymph nodes in patients with a history of thyroid cancer are usually assessed by fine-needle aspiration biopsy (FNAB) followed by cytology with or without tissue core. Thyroglobulin (Tg) is frequently elevated in malignant FNAB needle-wash specimens and may possibly augment or replace cytology. Furthermore, the combination of undetectable serum Tg and an innocuous ultrasound might altogether obviate the need for biopsy.

Objectives: The objectives of the study were to: 1) determine an appropriate diagnostic cutoff for Tg levels in FNAB; 2) assess the diagnostic performance at this cutoff; and 3) compare serum Tg and FNAB needle-wash Tg levels to determine whether serum Tg levels predict positive Tg FNAB.

Design: This was a retrospective study of 122 FNAB samples in 88 athyrotic thyroid cancer patients.

Results: Fifty of 52 nonmalignant FNAB samples (96.2%) had Tg 1 ng/ml or less. All 70 malignant FNAB had Tg greater than 1 ng/ml. Of 103 specimens with diagnostic cytology, five (4.9%) had discordant Tg results; in four of these FNAB Tg was concordant with the final diagnosis. Eighteen of 19 (94.7%) FNAB with nondiagnostic (n = 16) or absent (n = 3) cytology were correctly classified by FNAB needle-wash Tg. Undetectable (<0.1 ng/ml) serum Tg was associated with a negative diagnosis in 21 of 23 biopsies (91.7%); the two cancer-positive samples were both serum Tg autoantibody positive and classified as suspicious by ultrasonography.

Conclusions: Nodal FNAB needle-wash Tg measurements complement cytology in thyroid cancer follow-up and might substitute for it. The combination of unremarkable ultrasonography and an undetectable serum Tg in Tg autoantibody-negative patients might obviate the need for FNAB.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
PERSISTENCE, RECURRENCE, or locoregional metastasis of differentiated thyroid carcinoma (DTC), most commonly involves lymph nodes in neck and is usually detected by measurement of serum thyroglobulin (Tg) concentrations, combined with physical examination, high-resolution ultrasonography, or other imaging strategies (1, 2, 3). Unfortunately, these approaches are not entirely accurate in detecting DTC (4, 5, 6, 7, 8). Consequently, most suspicious nodes undergo fine-needle aspiration biopsy (FNAB) with cytological evaluation, although inadequate cellularity or nonrepresentative sampling precludes diagnosis in up to 20% of specimens, depending on the experience and ability of the cytopathologist (9, 10).

Tg measurement in FNAB needle washes addresses many of these issues. Tg is detectable in nodes containing very small foci of metastatic DTC (11, 12, 13, 14, 15). However, there is no established diagnostic cutoff, particularly for the latest generation of highly sensitive Tg assays.

It also remains unclear whether all enlarged nodes require FNAB. Recent studies show that serum Tg levels below the functional sensitivity of highly sensitive assays typically indicate absence of significant metastatic disease in athyrotic patients (16, 17). Thus, a combination of high sensitivity serum Tg and modern ultrasound could reduce the number of patients needing FNAB.

The goals of this study were to: 1) determine a diagnostic cutoff for Tg in nodal FNAB needle washes, 2) compare performance of this cutoff to cytology and final diagnosis, and 3) evaluate whether high-sensitivity serum Tg and high-resolution ultrasonography might identify nodes that do not require FNAB.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Experimental subjects

Tg results were reviewed retrospectively for FNAB washings tested at the Mayo Clinic or Vanderbilt University Medical Center, under protocols approved by the respective institutional review boards. The study included 122 FNAB from 88 patients (70% female) from Mayo, Vanderbilt, and several other practices that send FNAB needle wash samples to the Mayo Clinic. All patients had previously undergone near-total or total thyroidectomy for DTC; at Mayo this involved central compartment neck dissection in most cases. No further distinctions were made on the basis of treatment or monitoring protocols. Although limited clinical information was available for outside patients, those seen at Mayo were evenly distributed among T1 (26%), T2 (32%), and T3 (29%; the remaining 13% had incomplete histories available). All but one of the Mayo patients had current or previous lymph node metastatic disease. At Mayo and Vanderbilt (49.1% of biopsies), decisions to biopsy were made primarily on clinical grounds without prior knowledge of serum Tg results.

Cases with histological confirmation of metastatic thyroid carcinoma, or clear imaging or clinical evidence of recurrence at more than 1 yr follow-up were designated as final diagnosis positive (DX-POS), whereas those deemed free of metastatic disease by the same criteria were classified as final diagnosis negative (DX-NEG). Biopsies of different sites from the same patient were considered independently.

Ultrasound

Ultrasound criteria for possible malignant infiltration of lymph nodes included rounded contour and short-to-long axis ratio greater than 0.3–0.7 (location dependent); heterogeneous, irregular internal echogenicity; internal punctuate calcifications or fluid components; and an abnormal color Doppler pattern of increased peripheral, spotted, or mixed disorganized flow. Criteria for benign nodes included homogeneous, uniform echogenicity and a Doppler pattern of central hilar flow with regular vessel branching (5).

FNAB, cytology, and needle wash

The methods described below are those used at Mayo and Vanderbilt. Procedures and cytopathology at other practices may differ. Ultrasound-guided FNAB is performed on a supine patient with the neck hyperextended. A 25-gauge needle is inserted obliquely within the transducer plane of view and moved back and forth through the nodule to compensate for patient movement and needle deflection. There is no suction device; cells move into the needle via capillary action. Three to six separate passes are performed, each with a new needle.

Contents of the biopsy needles are expelled onto glass slides and smeared with a second slide to spread the fluid across the surface. Slides are fixed in 95% alcohol, Papanicolaou stained to identify cellular detail, and read by cytopathologists.

After collection of the cytology samples, each FNAB needle is then washed with 0.1–0.5 ml of normal saline; the washes from all needles are pooled (final volume 0.5–1 ml) and sent to the laboratory directly (in-house patients), or frozen for transport to the laboratory (outside patients).

Thyroglobulin and Tg autoantibody (TgAb) testing

Blood-contaminated FNAB needle washes were spun and the clear supernatant removed for Tg testing; blood-free samples were tested without manipulation. At Mayo, Tg was measured on a DXI automated immunoassay-analyzer (Beckman Coulter, Fullerton, CA). The analytical sensitivity (signal to noise ratio of 3) is 0.06 ng/ml; the functional sensitivity (interassay coefficient of variation < 20%) is 0.1 ng/ml (17). At Vanderbilt, FNAB needle wash Tg was measured on an Immulite 2000 automated immunoassay-analyzer (Siemens, Tarrytown, NY), with analytical and functional sensitivities of 0.2 and 0.9 ng/ml, respectively (Siemens Tg packet insert). Quality control measures for Tg in FNAB needle washes included spike recovery in samples with Tg levels less than 1 ng/ml, to detect false-low interferences (e.g. autoantibody interference) and analysis of multiple dilutions to detect hooking, matrix effects, or heterophile interference. Recovery of exogenous Tg spiked into saline FNAB needle washes was approximately 25% higher than in serum-based matrix (range 100–140% of predicted). Because this bias was consistent, we decided not to complicate sample collection by requiring use of serum-based needle washes.

All sera were tested for TgAbs on the DXI (Beckman Coulter). The upper reference limit is 2.3 IU/ml. FNAB needle-wash samples were not assayed for TgAb, both because spike recovery assays were performed and because it has been shown that FNAB Tg measurement is unaffected by serum TgAbs (18, 19).

Data analysis

Statistics were calculated using PEPI (version 4.04; Sagebrush Press, Las Vegas, NV). P values were generated by ² and Fisher exact analyses.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Of 122 FNAB (52 DX-NEG, 70 DX-POS), 119 (97.5%) were assessed for cytology; of these, 103 were adequate for cytological diagnosis (Table 1). The remaining 16 FNAB were nondiagnostic: three were from acellular, cystic nodules, 11 were hypocellular or contained only blood cells, and two had epithelial cells that were too degenerated or poorly preserved for diagnosis.

Establishment of an FNAB Tg diagnostic cutoff

Tg concentrations in DX-NEG and DX-POS needle washes are shown (Fig. 1A). Fifty of 52 DX-NEG FNAB (96.2%) had needle-wash Tg 1 ng/ml or less; the other two DX-NEG samples had needle-wash Tg of 2.0 and 6.7 ng/ml. All 70 DX-POS FNAB had needle-wash Tg greater than 1 ng/ml; the lowest needle-wash Tg in a DX-POS sample was 2.5 ng/ml. A 1 ng/ml cutoff for FNAB needle-wash Tg provides 100% sensitivity, 96.2% specificity, 100% negative predictive value for Tg 1 ng/ml or less, and 97.2% positive predictive value for Tg greater than 1 ng/ml (Fig. 1, A and B).

View larger version (11K): [in this window] [in a new window]   FIG. 1. A, Tg concentrations in fine-needle biopsies. The distribution of Tg concentrations in biopsy samples (FNAB Tg, ordinate) is shown according to the final diagnosis of each of 122 specimens (abscissa). B, Receiver operator characteristics curve for FNAB Tg measurements in this study. The area under the curve is 0.999 (95% confidence intervals 0.997–1.000). C, Relationship of serum Tg to final diagnosis. The distribution of Tg concentrations in 73 sera (serum Tg, ordinate) is shown according to the final diagnosis of the biopsy associated with each serum sample (abscissa). Forty-four are DX-POS, and 29 are DX-NEG.

Sixteen of 119 FNAB had nondiagnostic cytology; in contrast, Tg was successfully measured in all specimens for a significantly higher diagnosis rate (P < 0.0002). For 19 FNAB without definitive cytology (16 nondiagnostic, three not performed), final diagnosis was established by surgical pathology (five samples), repeat FNAB and cytology (1 sample), more than 1 yr disease-free follow-up (10 samples), or empirical ablation based on clinical suspicion and imaging results (three samples). Needle-wash Tg correctly classified 10 of 11 DX-NEG (90.9%) and all eight DX-POS FNAB in these 19 samples; the lone false-positive FNAB had a needle-wash Tg concentration of 2.0 ng/ml. Thus, needle-wash Tg showed 94.7% agreement ( = 0.89) with ultimate patient diagnoses when FNAB cytology was uninformative.

Comparison of needle-wash and serum Tg

Serum Tg ranged from less than 0.1–25 ng/ml in DX-NEG patients and less than 0.1–1212 ng/ml in DX-POS patients (Fig. 1C). Although there was no correlation between needle-wash Tg and serum Tg concentrations, nearly all DX-NEG had needle-wash Tg levels below the corresponding serum Tg (not shown). All but two DX-POS FNAB had more Tg in needle washes than serum, often with many orders of magnitude difference.

Twenty-one of 29 DX-NEG FNAB were associated with undetectable (<0.1 ng/ml) serum Tg. Only two DX-POS had undetectable serum Tg (Fig. 1C); the corresponding needle-wash Tg levels were 21 and 8050 ng/ml. Both DX-POS patients with undetectable serum Tg were TgAb positive, indicating that the undetectable serum Tg was likely due to TgAb interference; in agreement with this, both nodes were highly suspicious by ultrasonography. Ten additional DX-POS samples had low serum Tg (1 ng/ml) without TgAb. Thus, even low (but detectable) serum Tg concentrations may suggest malignancy. By contrast, 100% of patients with undetectable serum Tg and no TgAb (10 cases) were DX-NEG, with nonmalignant FNAB cytology and undetectable needle-wash Tg. Thus, patients with serum Tg less than 0.1 ng/ml, no TgAb, and benign-appearing ultrasonography are unlikely to have persistent or recurrent disease, and may not require FNAB.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study adds to the evidence that measuring Tg concentrations in FNAB needle washes improves the evaluation of suspicious lymph nodes in DTC patients. It is, however, important to note that this was a retrospective analysis and may be subject to selection bias because, for example, ultrasonographically innocuous nodes might be less frequently biopsied.

A 1 ng/ml cutoff for FNAB needle-wash Tg provided 100% sensitivity, 96.2% specificity, and 97.2% positive predictive value. This cutoff is well within the range of modern Tg immunoassays with functional sensitivity 0.1–1 ng/ml. The Tg concentration in FNAB needle washes might not correspond exactly to the level of Tg in the nodule because rinsing the needle dilutes the analyte; a small quantity of normal saline should therefore be used, 0.5–1 ml in total, which is sufficient for adequate elution, testing, and quality control.

Fifty of 52 (96.2%) DX-NEG FNAB had needle-wash Tg level 1 ng/ml or less, whereas no DX-POS FNAB had Tg below the cutoff. The 1 ng/ml cutoff was chosen conservatively for two reasons: first, the number of samples in the 1–10 ng/ml range was small (Fig. 1A), and second, the risks associated with false-negative results were deemed unacceptable. The absence of false negatives in our study likely results in part from improved assay performance but mainly from the deliberate choice of a cutoff designed to avoid false-negative results. Cutoffs used in previous studies have varied widely, but notably, previous studies using low needle-wash Tg cutoffs also reported excellent performance with few false negatives or false positives (18, 20), supporting the use of a conservative needle-wash Tg cutoff. In this study, only two DX-NEG nodules had needle-wash Tg above the cutoff, whereas malignant nodules were associated with needle-wash Tg as low as 2.5 ng/ml, suggesting that any elevation above 1 ng/ml is highly indicative of disease. In our retrospective, largely tertiary care patient population, this resulted in very few false positives, a promising finding that needs to be corroborated in prospective studies using the same cutoff.

The diagnostic performance of needle-wash Tg at the 1 ng/ml cutoff compared favorably with cytology (95.1% overall agreement) and allowed accurate diagnosis in 18 of the 19 cases in whom cytology was nondiagnostic or not performed. In four of the five cases in whom cytology and FNAB needle-wash Tg measurement disagreed, Tg analysis was more accurate than cytology as a monitoring tool.

Finally, undetectable serum Tg in the absence of TgAb was 100% predictive of needle-wash Tg 1 ng/ml or less, negative cytology, and DX-NEG. Only two DX-POS FNABs were from patients with undetectable serum Tg; both had TgAb and highly suspicious ultrasonographic findings, supporting the role of noninvasive imaging as a diagnostic guide. These results therefore suggest that TgAb-negative patients with nonsuspicious neck ultrasound and undetectable serum Tg may not require FNAB, unless there is strong clinical suspicion of recurrence. This is an exciting finding that may reduce the need for biopsies. However, it must be supported by larger, prospective studies before a shift in clinical practice can be recommended.

Regardless of the algorithm to select patients for FNAB, the diagnostic strategy for FNAB should include high-sensitivity needle-wash Tg measurement. This study suggests that a needle-wash Tg cutoff of 1 ng/ml compares favorably with cytopathology for detection of DTC in cervical lymph nodes. Compared with cytology, Tg analysis is less operator dependent; provides diagnosis of samples with poor cellularity (e.g. cystic lesions); and, with appropriate logistics, might reduce costs and turnaround time. By contrast, cytology allows diagnosis of non-DTC neoplasia and nonmalignant disorders that cause abnormal neck lymph nodes. The decision to proceed with FNAB Tg analysis, cytology, or both, depends on access to FNAB Tg testing, the skill and experience of the cytopathologist, and the nature of the nodule itself.

	Acknowledgments

 
The authors gratefully acknowledge the time and insight shared by the many clinicians whose patients comprised the cohort for this study.

	Footnotes

 
This work was supported by National Institutes of Health Grant CA80117 (to S.K.G.G., coprincipal investigator), Mayo School of Graduate Medical Education (to C.L.H.S.), and Mayo Clinic Department of Laboratory Medicine and Pathology funds.

Disclosure Statement: J.W.S. received payment for lectures from Abbott. S.K.G.G. consults for Diagnostic Hybrids, Inc. All other authors have nothing to disclose.

First Published Online August 7, 2007

Abbreviations: DTC, Differentiated thyroid carcinoma; DX-NEG, diagnosis negative; DX-POS, diagnosis positive; FNAB, fine-needle aspiration biopsy; Tg, thyroglobulin; TgAb, Tg autoantibody.

Received May 14, 2007.

Accepted August 1, 2007.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Ringel MD, Ladenson PW 2004 Controversies in the follow-up and management of well-differentiated thyroid cancer. Endocr Relat Cancer 11:97–116[Abstract]
2. Weber T, Schilling T, Buchler MW 2006 Thyroid carcinoma. Curr Opin Oncol 18:30–35[Medline]
3. Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L, Haugen BR, Sherman SI, Cooper DS, Braunstein GD, Lee S, Davies TF, Arafah BM, Ladenson PW, Pinchera A 2003 A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 88:1433–1441[Abstract/Free Full Text]
4. Harish K 2006 Thyroglobulin: current status in differentiated thyroid carcinoma. Endocr Regul 40:53–67[Medline]
5. Schlumberger M, Berg G, Cohen O, Duntas L, Jamar F, Jarzab B, Limbert E, Lind P, Pacini F, Reiners C, Sanchez Franco F, Toft A, Wiersinga WM 2004 Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective. Eur J Endocrinol 150:105–112[Abstract]
6. Izquierdo R, Arekat MR, Knudson PE, Kartun KF, Khurana K, Kort K, Numann PJ 2006 Comparison of palpation-guided versus ultrasound-guided fine-needle aspiration biopsies of thyroid nodules in an outpatient endocrinology practice. Endocr Pract 12:609–614[Medline]
7. Kouvaraki MA, Shapiro SE, Fornage BD, Edeiken-Monro BS, Sherman SI, Vassilopoulou-Sellin R, Lee JE, Evans DB 2003 Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery 134:946–954; discussion 954–955[CrossRef][Medline]
8. Stulak JM, Grant CS, Farley DR, Thompson GB, van Heerden JA, Hay ID, Reading CC, Charboneau JW 2006 Value of preoperative ultrasonography in the surgical management of initial and reoperative papillary thyroid cancer. Arch Surg 141:489–494; discussion 494–496[Abstract/Free Full Text]
9. Orija IB, Hamrahian AH, Reddy SS 2004 Management of nondiagnostic thyroid fine-needle aspiration biopsy: survey of endocrinologists. Endocr Pract 10:317–323[Medline]
10. Florentine BD, Staymates B, Rabadi M, Barstis J, Black A 2006 The reliability of fine-needle aspiration biopsy as the initial diagnostic procedure for palpable masses: a 4-year experience of 730 patients from a community hospital-based outpatient aspiration biopsy clinic. Cancer 107:406–416[CrossRef][Medline]
11. Pacini F, Fugazzola L, Lippi F, Ceccarelli C, Centoni R, Miccoli P, Elisei R, Pinchera A 1992 Detection of thyroglobulin in fine needle aspirates of nonthyroidal neck masses: a clue to the diagnosis of metastatic differentiated thyroid cancer. J Clin Endocrinol Metab 74:1401–1404[Abstract]
12. Frasoldati A, Toschi E, Zini M, Flora M, Caroggio A, Dotti C, Valcavi R 1999 Role of thyroglobulin measurement in fine-needle aspiration biopsies of cervical lymph nodes in patients with differentiated thyroid cancer. Thyroid 9:105–111[Medline]
13. Cignarelli M, Ambrosi A, Marino A, Lamacchia O, Campo M, Picca G, Giorgino F 2003 Diagnostic utility of thyroglobulin detection in fine-needle aspiration of cervical cystic metastatic lymph nodes from papillary thyroid cancer with negative cytology. Thyroid 13:1163–1167[CrossRef][Medline]
14. Uruno T, Miyauchi A, Shimizu K, Tomoda C, Takamura Y, Ito Y, Miya A, Kobayashi K, Matsuzuka F, Amino N, Kuma K 2005 Usefulness of thyroglobulin measurement in fine-needle aspiration biopsy specimens for diagnosing cervical lymph node metastasis in patients with papillary thyroid cancer. World J Surg 29:483–485[CrossRef][Medline]
15. Lee MJ, Ross DS, Mueller PR, Daniels GH, Dawson SL, Simeone JF 1993 Fine-needle biopsy of cervical lymph nodes in patients with thyroid cancer: a prospective comparison of cytopathologic and tissue marker analysis. Radiology 187:851–854[Abstract/Free Full Text]
16. Giovanella L, Ceriani L, Ghelfo A, Keller F, Sacchi A, Maffioli M, Spriano G 2006 Thyroglobulin assay during thyroxine treatment in low-risk differentiated thyroid cancer management: comparison with recombinant human thyrotropin-stimulated assay and imaging procedures. Clin Chem Lab Med 44:648–652[CrossRef][Medline]
17. Smallridge RC, Meek SE, Morgan MA, Gates GS, Fox TP, Grebe S, Fatourechi V 2007 Monitoring thyroglobulin in a sensitive immunoassay has comparable sensitivity to recombinant human TSH-stimulated thyroglobulin in follow-up of thyroid cancer patients. J Clin Endocrinol Metab 92:82–87[Abstract/Free Full Text]
18. Boi F, Baghino G, Atzeni F, Lai ML, Faa G, Mariotti S 2006 The diagnostic value for differentiated thyroid carcinoma metastases of thyroglobulin (Tg) measurement in washout fluid from fine-needle aspiration biopsy of neck lymph nodes is maintained in the presence of circulating anti-Tg antibodies. J Clin Endocrinol Metab 91:1364–1369[Abstract/Free Full Text]
19. Baskin HJ 2004 Detection of recurrent papillary thyroid carcinoma by thyroglobulin assessment in the needle washout after fine-needle aspiration of suspicious lymph nodes. Thyroid 14:959–963[CrossRef][Medline]
20. Mikosinski S, Pomorski L, Oszukowska L, Makarewicz J, Adamczewski Z, Sporny S, Lewinski A 2006 The diagnostic value of thyroglobulin concentration in fine-needle aspiration of the cervical lymph nodes in patients with differentiated thyroid cancer. Endokrynol Pol 57:392–395[Medline]

This article has been cited by other articles:

				P M Clark Laboratory services for thyroglobulin and implications for monitoring of differentiated thyroid cancer J. Clin. Pathol., May 1, 2009; 62(5): 402 - 406. [Abstract] [Full Text] [PDF]

				A.-L. Borel, R. Boizel, P. Faure, G. Barbe, J. Boutonnat, N. Sturm, D. Seigneurin, I. Bricault, J.-P. Caravel, P. Chaffanjon, et al. Significance of low levels of thyroglobulin in fine needle aspirates from cervical lymph nodes of patients with a history of differentiated thyroid cancer Eur. J. Endocrinol., May 1, 2008; 158(5): 691 - 698. [Abstract] [Full Text] [PDF]

eLetters:

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor View responses Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Snozek, C. L. H. Articles by Grebe, S. K. G. Search for Related Content PubMed PubMed Citation Articles by Snozek, C. L. H. Articles by Grebe, S. K. G. Related Collections Thyroid Endocrine Oncology