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Original Research |

A Prospective Assessment Defining the Limitations of Thyroid Nodule Pathologic Evaluation

Edmund S. Cibas, MD; Zubair W. Baloch, MD, PhD; Giovanni Fellegara, MD; Virginia A. LiVolsi, MD; Stephen S. Raab, MD; Juan Rosai, MD; James Diggans, PhD; Lyssa Friedman, RN, MPA; Giulia C. Kennedy, PhD; Richard T. Kloos, MD; Richard B. Lanman, MD; Susan J. Mandel, MD, MPH; Nicole Sindy, MBS; David L. Steward, MD; Martha A. Zeiger, MD; Bryan R. Haugen, MD; and Erik K. Alexander, MD
[+] Article and Author Information

From Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Perelman School of Medicine, University of Pennsylvania, Philadelphia; Centro Diagnostico Italiano, Milan, Italy; University of Washington School of Medicine, Seattle, Washington; Veracyte, San Francisco, California; Ohio State University, Columbus, Ohio; University of Cincinnati College of Medicine, Cincinnati, Ohio; Johns Hopkins University School of Medicine, Baltimore, Maryland; and University of Colorado School of Medicine, Aurora, Colorado.

Acknowledgment: The authors thank Dr. Ricardo Lloyd for serving as the third central histopathologist when consensus was not achieved after discussion between the first 2 central histopathologists.

Grant Support: By research grants from Veracyte to the respective institutions of the coauthors.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-0096.

Reproducible Research Statement: Study protocol, statistical code, and data set: Not available.

Requests for Single Reprints: Erik K. Alexander, MD, Brigham and Women's Hospital, 75 Francis Street, PBB-B4, Boston, MA 02115; e-mail, ekalexander@partners.org.

Current Author Addresses: Drs. Alexander and Cibas: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Drs. Baloch, LiVolsi, and Mandel: University of Pennsylvania School of Medicine, 6 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104.

Drs. Fellegara and Rosai: Centro Diagnostico Italiano, Centro Consulenze Patologica Oncologica, Via Saint Bon 20, 20147 Milan, Italy.

Dr. Stephen Raab: Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, Newfoundland A1B 3V6, Canada.

Drs. Diggans, Kennedy, Kloos, and Lanman; Ms. Friedman; and Ms. Sindy: Veracyte, 7000 Shoreline Court, Suite 250, San Francisco, CA 94080.

Dr. Steward: University of Cincinnati College of Medicine, Department of Otolaryngology–Head and Neck Surgery, Medical Sciences Building, Room 6507, ML 0528, 231 Albert Sabin Way, Cincinnati, OH 45267.

Dr. Zeiger: Johns Hopkins University School of Medicine, 600 North Wolfe Street, Blalock 606, Baltimore, MD 21287.

Dr. Haugen: University of Colorado School of Medicine, Mail Stop 8106, Aurora, CO 80045.

Author Contributions: Conception and design: E.S. Cibas, L. Friedman, G.C. Kennedy, R.B. Lanman, S.J. Mandel, M.A. Zeiger, B.R. Haugen, E.K. Alexander.

Analysis and interpretation of the data: E.S. Cibas, Z.W. Baloch, J. Rosai, J. Diggans, L. Friedman, G.C. Kennedy, R.T. Kloos, R.B. Lanman, S.J. Mandel, N. Sindy, M.A. Zeiger, B.R. Haugen, E.K. Alexander.

Drafting of the article: E.S. Cibas, Z.W. Baloch, J. Diggans, L. Friedman, G.C. Kennedy, R.T. Kloos, B.R. Haugen, E.K. Alexander.

Critical revision of the article for important intellectual content: V.A. LiVolsi, S.S. Raab, J. Rosai, L. Friedman, G.C. Kennedy, R.T. Kloos, R.B. Lanman, N. Sindy, D.L. Steward, M.A. Zeiger, B.R. Haugen, E.K. Alexander.

Final approval of the article: E.S. Cibas, Z.W. Baloch, V.A. LiVolsi, S.S. Raab, J. Rosai, L. Friedman, G.C. Kennedy, R.T. Kloos, R.B. Lanman, S.J. Mandel, D.L. Steward, M.A. Zeiger, B.R. Haugen, E.K. Alexander.

Provision of study materials or patients: S.S. Raab, G.C. Kennedy, R.T. Kloos, S.J. Mandel, M.A. Zeiger, B.R. Haugen, E.K. Alexander.

Statistical expertise: J. Diggans, G.C. Kennedy.

Administrative, technical, or logistic support: G. Fellegara, L. Friedman, R.B. Lanman, E.K. Alexander.

Collection and assembly of data: S.S. Raab, L. Friedman, G.C. Kennedy, R.T. Kloos, R.B. Lanman, N. Sindy, D.L. Steward, M.A. Zeiger, E.K. Alexander.


Ann Intern Med. 2013;159(5):325-332. doi:10.7326/0003-4819-159-5-201309030-00006
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Chinese translation

Background: Clinical management of thyroid neoplasms is based on light microscopic diagnosis, but its accuracy and precision are poorly defined.

Objective: To assess inter- and intraobserver variability of preoperative cytopathologic and postoperative histopathologic thyroid diagnoses.

Design: Samples were collected in a prospective, multicenter trial validating a gene expression classifier between June 2009 and December 2010.

Setting: 14 academic and 35 community clinical sites.

Patients: 653 patients with 776 surgically resected thyroid nodules of 1 cm or greater.

Measurements: Intraobserver concordance among 2 or more central histopathologists who independently read histopathology slides was calculated. Interobserver concordance between the diagnoses made by the central histopathologists and those made by local pathologists were calculated. Intra- and interobserver concordance for cytopathology was similarly calculated by comparing diagnoses made by local pathologists with those made by a central panel of 3 cytopathologists.

Results: Concordance on the histopathologic distinction between benign and malignant diagnoses was 91% comparing local with central histopathologists and 90% comparing 2 central histopathologists. Using the 6-category Bethesda System, 64.0% of diagnoses made by local and central cytopathologists and 74.7% of intraobserver diagnoses were concordant. Central cytopathologists made fewer indeterminate diagnoses than local pathologists (41.2% vs. 55.0%).

Limitations: Many local pathologists did not use the Bethesda System, so their reports were translated to allow comparison. The study required histopathology, and the study population and specimens did not encompass all newly evaluated patients with a thyroid nodule.

Conclusion: Substantial inter- and intraobserver variability exists in the cytopathologic and histopathologic evaluation of thyroid nodules, confirming an inherent limitation of visual microscopic diagnosis.

Primary Funding Source: Veracyte.

Figures

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Figure 1.

Analysis of disagreements in categorical benign versus malignant diagnoses made by expert histopathologists, as a function of specific cancer subtypes.

The y-axis represents all patients where at least 1 of the experts diagnosed the patient as having cancer. The x-axis represents the proportion of nodules diagnosed as benign by at least 1 expert for each cancer subtype (y-axis). Categorization in both axes was done while the expert was unaware of the other expert's diagnosis and the local pathologist's diagnosis. The averages of the 2 experts and 95% CIs are shown. Follicular and Hürthle cell carcinomas with capsular invasion resulted in the highest percentage of disagreement before the next step of conferral between the central histopathologists. FC-c/HCC-c = follicular/Hürthle cell carcinoma with capsular invasion; FC-v/HCC-v = follicular/Hürthle cell carcinoma with vascular invasion; FVPTC = follicular variant of papillary thyroid carcinoma; MTC = medullary thyroid carcinoma; PTC = papillary thyroid carcinoma; PTC-TCV = papillary thyroid carcinoma, tall cell variant; WDC-NOS = well-differentiated carcinoma, not otherwise specified.

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Figure 2.

Interobserver concordance of thyroid FNA cytopathologic diagnoses.

Concordance (95% CI) of diagnoses between local pathologists and central CP members (interobserver) are shown. AUS/FLUS = atypia of undetermined significance/follicular lesion of undetermined significance; CP = cytopathology panel; FN/SFN = follicular neoplasm/suspicious for follicular neoplasm; FNA = fine-needle aspiration. Top. Overall concordance for the 6-category system is lower than that for the 4-category system. Bottom. CP vs. local cytopathology diagnostic concordance is highest for benign nodules and cancer diagnoses and lowest for AUS/FLUS diagnoses and nodules suspicious for malignancy.

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Figure 3.

Frequency distribution of central panel versus local cytopathologic diagnoses and risk for malignant thyroid nodule by cytology category, stratified by CP versus local pathologist.

This figure and Table 3 depict results for local cytopathology and CP. AUS/FLUS = atypia of undetermined significance/follicular lesion of undetermined significance; CP = cytopathology panel; FN/SFN = follicular neoplasm/suspicious for follicular neoplasm. Top. Point estimates and 95% CIs are shown for the frequency of each cytopathologic diagnosis. Bottom. Risk for cancer was determined postoperatively for each cytopathologic diagnosis. For findings, see Table 3. Definitive cytopathologic diagnoses of benign nodules or cancer are made more often by the CP members, but those of AUS/FLUS and nodules suspicious for malignancy are made less often. Fewer cytologically indeterminate calls are made by the CP without a change in the risk for cancer for any given diagnostic category (e.g., the CP made more benign diagnoses, but the risk for cancer was not changed significantly from the local pathologists’ benign diagnoses).

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Figure 4.

Intraobserver concordance of thyroid FNA cytopathologic diagnoses.

Concordance (95% CI) are shown for each of 3 CP members who diagnosed the identical sample on 2 occasions more than 30 d apart. Average intraobserver concordance for the 3 CP members using the Bethesda System was 74.7%. CP = cytopathology panel; FNA = fine-needle aspiration.

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