The practice of thyroid surgery has undergone substantial changes in the past three to five years... more The practice of thyroid surgery has undergone substantial changes in the past three to five years, partially as a result of the incorporation of technology such as high-resolution endoscopy. Early adopters of endoscopic thyroid surgery will share the perspectives of their experience with this new approach to the management of a defined segment of thyroid diseases. Where possible, evidencebased discussions will be presented. Specific issues that will be considered will include (1) lessons learned during the early application of endoscopic techniques in this country, (2) the value of the enhanced visualization associated with endoscopes, (3) the cosmetic advantages conferred by minimal access surgery that is facilitated by endoscopic technology, and (4) an algorithm for the rational implementation of endoscopic thyroid techniques in a modern thyroid surgical practice.
MINISEMINARS function. The last speaker will discuss the current research on robotic assisted rec... more MINISEMINARS function. The last speaker will discuss the current research on robotic assisted reconstruction and its future advantages and challenges ahead. Educational Objectives: 1) Understand the role of transoral robotic surgery in head and neck cancer. 2) Understand the current use of robotic reconstructive surgery. 3) Understand the indications and future potential for robotic-assisted reconstructive surgery.
Objective: To develop evidence-based recommendations for safe, effective, and appropriate thyroid... more Objective: To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy. Background: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US. Methods: The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. Results: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions,
American Thyroid Association (ATA) leadership asked the ATA Thyroid Nodules and Differentiated Th... more American Thyroid Association (ATA) leadership asked the ATA Thyroid Nodules and Differentiated Thyroid Cancer Guidelines Task Force to review, comment on, and make recommendations related to the suggested new classification of encapsulated follicular variant papillary thyroid carcinoma (eFVPTC) without capsular or vascular invasion to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The task force consists of members from the 2015 guidelines task force with the recusal of three members who were authors on the paper under review. Four pathologists and one endocrinologist were added for this specific review. The manuscript proposing the new classification and related literature were assessed. It is recommended that the histopathologic nomenclature for eFVPTC without invasion be reclassified as a NIFTP, given the excellent prognosis of this neoplastic variant. This is a weak recommendation based on moderate-quality evidence. It is also noted that prospective studies are needed to validate the observed patient outcomes (and test performance in predicting thyroid cancer outcomes), as well as implications on patients' psychosocial health and economics.
ABSTRACT Background: The role of prophylactic central lymph node dissection in papillary thyroid ... more ABSTRACT Background: The role of prophylactic central lymph node dissection in papillary thyroid cancer (PTC) is controversial in patients who have no pre- or intraoperative evidence of nodal metastasis (clinically N0; cN0). The controversy relates to its unproven role in reducing recurrence rates while possibly increasing morbidity (permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injury). Methods & Results: We examined the design and feasibility of a multi-institutional prospective randomized controlled trial of prophylactic central lymph node dissection in cN0 PTC. Assuming a 7 year study with 4 years of enrollment, 5 years of average follow-up, a recurrence rate of 10 % after 7 years, a 25% relative reduction in the rate of the primary endpoint (newly identified structural disease; i.e. persistent, recurrent or distant metastatic disease) with central lymph node dissection and an annual dropout rate of 3%, a total of 5,840 patients would have to be included in the study to achieve at least 80% statistical power. Similarly, given the low rates of morbidity several thousands of patients would need to be included to identify a significant difference in rates of permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injury. Conclusion: Given the low rates of both newly identified structural disease and morbidity after surgery for cN0 PTC, prohibitively large sample sizes would be required for sufficient statistical power to demonstrate significant differences in outcomes. Thus, a prospective randomized controlled trial of prophylactic central lymph node dissection in cN0 PTC is not readily feasible.
MINISEMINARS practice guideline `Improving Voice Outcomes after Thyroid Surgery.' The guideline w... more MINISEMINARS practice guideline `Improving Voice Outcomes after Thyroid Surgery.' The guideline will focus on the excision of thyroid tissue using any method or with any surgical approach and the planned perioperative assessment of the voice. Educational Objectives: (1) Understand the guideline development group's recommendations on voice in thyroid surgery. (2) Learn about the guideline's development methodology. (3) Learn about future research needs.
The aim of this study was to develop evidence-based recommendations for safe, effective and appro... more The aim of this study was to develop evidence-based recommendations for safe, effective and appropriate thyroidectomy. Background: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the United States. Methods: The medical literature from January 1, 1985 to November 9, 2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. Results: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions,
This is the author manuscript accepted for publication and has undergone full peer review but has... more This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as
Archives of Otolaryngology-head & Neck Surgery, 2008
To report the results of a multiinstitutional experience with the minimally invasive videoassiste... more To report the results of a multiinstitutional experience with the minimally invasive videoassisted thyroidectomy, which was conceived in Europe and Asia and has only recently been embraced in the United States.
OBJECTIVE To determine the association between pathologic features and molecular classes (BRAF-li... more OBJECTIVE To determine the association between pathologic features and molecular classes (BRAF-like, RAS-like, and non-BRAF-like non-RAS-like [NBNR]). METHODS Retrospective review of a merged database containing 676 patients, 84% (571/676) were assigned to a molecular class from publicly accessible sequenced data of thyroid neoplasms. RESULTS The merged cohort included 571 neoplasms: 353 (62%) BRAF-like, 172 (30%) RAS-like, and 46 (8.1%) NBNR. Lymph node metastasis (any N1 disease) was present in 166/337 (49%) of BRAF-like, 23/164 (14%) of RAS-like, and 0/46 (0%) of NBNR and are significantly different (P < .001). Gross extra-thyroidal extension was observed in 27 patients, including 24/331 (7%) of BRAF-like, 2/160 (1%) of RAS-like, and 1/46 (2%) of NBNR (P = .01). N1B lymph node metastases or T4 disease was present in 74/333 (22%) of BRAF-like, 10/160 (6%) of RAS-like, and 1/46 (2%) of NBNR (P < .0001). Distant metastasis was present in 4/151 (2.6%) of BRAF-like, 2/50 (4%) of RAS-like and 0/46 for NBNR (P = .627). Angioinvasion was present in 0/81 (0%) of BRAF-like, 3/53 (6%) of RAS-like, and 3/46 (7%) of NBNR (P = .08); and multifocality was present in 27/81 (33%) of BRAF-like, 9/53 (17%) of RAS-like, and 1/46 (2%) for NBNR (P = .0001). CONCLUSION Pathological features of metastasis, gross extra-thyroidal extension, and multifocality were more prevalent in BRAF-like samples compared to RAS-like and NBNR. A trend towards increased frequency of angioinvasion in RAS-like and NBNR cancers compared to BRAF-like samples was observed. Further studies are needed to evaluate if preoperative knowledge of molecular mutations in thyroid tumors aids in decision-making regarding extent of surgery.
Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodul... more Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further inform the risk of thyroid cancer in nodules predicted to be positive or negative by MT remains unknown. Aim: To test if clinical parameters, including patient age, gender, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] vs American College of Radiology TI-RADS systems), radiation exposure, or family history of thyroid cancer can modify the probability of thyroid cancer or NIFTP predicted by MT. Methods: We studied 257 thyroid nodules in 232 patients from 10 study centers with indeterminate fine needle aspiration cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression were used for data analysis. Results: The presence of cancer/NIFTP was associated with positive TSv3 results (OR 61.39, P<0.0001). On univariate regression, patient gender, age, and Bethesda category were associated with cancer/NIFTP probability (P<0.05 for each). Although ATA (P=0.1211) and TI-RADS (P=0.1359) US categories demonstrated positive trends, neither were significantly associated with cancer/NIFTP probability. A multivariate regression model incorporating the four most informative non-MT covariates (gender, age, Bethesda category, and ATA US pattern) (Model #1) yielded a C index of 0.653; R2=0.108. When TSv3 was added to Model #1, the C index increased to 0.888; R2=0.572. However, age (P=0.341), Bethesda category (P=0.272), and ATA US pattern (P=0.264) were nonsignificant, and other than TSv3 (P<0.0001), male gender was the only non-MT parameter that potentially contributed to cancer/NIFTP risk (P=0.095). The simplest and most efficient clinical model (#3) incorporated TSv3 and gender (C index=0.889; R2=0.588). Conclusions: In this multicenter study of thyroid nodules with indeterminate cytology and molecular testing, neither the ATA nor TI-RADS US scoring systems further informed the risk of cancer/NIFTP beyond that predicted by TSv3. Although age and Bethesda category were associated with cancer/NIFTP probability on univariate analysis, in sequential nomograms they provided limited incremental value above the high predictive ability of TSv3. Patient gender may contribute to cancer/NIFTP risk in thyroid nodules with indeterminate cytology.
IMPORTANCE Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indetermina... more IMPORTANCE Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery. OBJECTIVE To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules. DESIGN, SETTING, AND PARTICIPANTS Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules. INTERVENTIONS A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3). MAIN OUTCOMES AND MEASURES The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules. RESULTS Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%. CONCLUSIONS AND RELEVANCE In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.
The Journal of the American Osteopathic Association, 2018
Thyroid nodules are increasingly common. Although guidelines have been published, it is unclear w... more Thyroid nodules are increasingly common. Although guidelines have been published, it is unclear whether recommendations for the use of fine-needle aspiration (FNA) and ultrasonography are followed. To evaluate the impact of a quality improvement initiative regarding utilization of FNA and ultrasonography before resection of malignant thyroid neoplasms at a community-based hospital. A retrospective medical record review of patients who received thyroidectomy with histologically proven malignant thyroid neoplasms at a community-based teaching center in the Midwest in 2014 revealed inconsistent use of FNA and ultrasonography per national guidelines. Thus, a quality improvement initiative was conducted using the PDSA (Plan, Do, Study, Act) method and included both an intradepartmental outreach effort and an interdisciplinary hospital cancer committee presentation. To determine the success of the initiative, medical records were reviewed from January 1, 2015, through July 1, 2016 (after ...
BACKGROUND Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiratio... more BACKGROUND Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment. METHODS We performed a 19-month, prospective, multicenter validation study involving 49 clinical sites, 3789 patients, and 4812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. We obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules in this analysis, and its performance was assessed. RESULTS Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for "atypia (or follicular lesion) of undetermined clinical significance," "follicular neoplasm or lesion suspicious for follicular neoplasm," or "suspicious cytologic findings" were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule. CONCLUSIONS These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results. (Funded by Veracyte.
The Journal of Clinical Endocrinology & Metabolism, 2014
Background: Increasingly, patients with thyroid nodule cytology labeled atypical (or follicular l... more Background: Increasingly, patients with thyroid nodule cytology labeled atypical (or follicular lesion) of undetermined significance (AUS/FLUS) or follicular neoplasm (FN) undergo diagnostic analysis with the Afirma gene expression classifier (GEC). No long-term, multisite analysis of Afirma GEC performance has yet been performed. Methods: We analyzed all patients who had received Afirma GEC testing at five academic medical centers between 2010 and 2013. Nodule and patient characteristics, fine needle aspiration cytology, Afirma GEC results, and subsequent clinical or surgical follow-up were obtained for 339 patients. Results were analyzed for pooled test performance, impact on clinical care, and site-tosite variation. Results: Three hundred thirty-nine patients underwent Afirma GEC testing of cytologically indeterminate nodules (165 AUS/FLUS; 161 FN; 13 suspicious for malignancy) and 174 of 339 (51%) indeterminate nodules were GEC benign, whereas 148 GEC were suspicious (44%). GEC results significantly altered care recommendations, as 4 of 175 GEC benign were recommended for surgery in comparison to 141 of 149 GEC suspicious (P Ͻ .01). Of 121 Cyto Indeterminate/GEC Suspicious nodules surgically removed, 53 (44%) were malignant. Variability in site-to-site GEC performance was confirmed, as the proportion of GEC benign varied up to 29% (P ϭ .58), whereas the malignancy rate in nodules cytologically indeterminate/GEC suspicious varied up to 47% (P ϭ .11). Seventy-one of 174 GEC benign nodules had documented clinical follow-up for an average of 8.5 months, in which 1 of 71 nodules proved cancerous. Conclusions: These multicenter, clinical experience data confirm originally published Afirma GEC test performance and demonstrate its substantial impact on clinical care recommendations. Although nonsignificant site-to-site variation exists, such differences should be anticipated by the practicing clinician. Follow-up of GEC benign nodules thus far confirm the clinical utility of this diagnostic test.
The practice of thyroid surgery has undergone substantial changes in the past three to five years... more The practice of thyroid surgery has undergone substantial changes in the past three to five years, partially as a result of the incorporation of technology such as high-resolution endoscopy. Early adopters of endoscopic thyroid surgery will share the perspectives of their experience with this new approach to the management of a defined segment of thyroid diseases. Where possible, evidencebased discussions will be presented. Specific issues that will be considered will include (1) lessons learned during the early application of endoscopic techniques in this country, (2) the value of the enhanced visualization associated with endoscopes, (3) the cosmetic advantages conferred by minimal access surgery that is facilitated by endoscopic technology, and (4) an algorithm for the rational implementation of endoscopic thyroid techniques in a modern thyroid surgical practice.
MINISEMINARS function. The last speaker will discuss the current research on robotic assisted rec... more MINISEMINARS function. The last speaker will discuss the current research on robotic assisted reconstruction and its future advantages and challenges ahead. Educational Objectives: 1) Understand the role of transoral robotic surgery in head and neck cancer. 2) Understand the current use of robotic reconstructive surgery. 3) Understand the indications and future potential for robotic-assisted reconstructive surgery.
Objective: To develop evidence-based recommendations for safe, effective, and appropriate thyroid... more Objective: To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy. Background: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US. Methods: The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. Results: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions,
American Thyroid Association (ATA) leadership asked the ATA Thyroid Nodules and Differentiated Th... more American Thyroid Association (ATA) leadership asked the ATA Thyroid Nodules and Differentiated Thyroid Cancer Guidelines Task Force to review, comment on, and make recommendations related to the suggested new classification of encapsulated follicular variant papillary thyroid carcinoma (eFVPTC) without capsular or vascular invasion to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The task force consists of members from the 2015 guidelines task force with the recusal of three members who were authors on the paper under review. Four pathologists and one endocrinologist were added for this specific review. The manuscript proposing the new classification and related literature were assessed. It is recommended that the histopathologic nomenclature for eFVPTC without invasion be reclassified as a NIFTP, given the excellent prognosis of this neoplastic variant. This is a weak recommendation based on moderate-quality evidence. It is also noted that prospective studies are needed to validate the observed patient outcomes (and test performance in predicting thyroid cancer outcomes), as well as implications on patients' psychosocial health and economics.
ABSTRACT Background: The role of prophylactic central lymph node dissection in papillary thyroid ... more ABSTRACT Background: The role of prophylactic central lymph node dissection in papillary thyroid cancer (PTC) is controversial in patients who have no pre- or intraoperative evidence of nodal metastasis (clinically N0; cN0). The controversy relates to its unproven role in reducing recurrence rates while possibly increasing morbidity (permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injury). Methods & Results: We examined the design and feasibility of a multi-institutional prospective randomized controlled trial of prophylactic central lymph node dissection in cN0 PTC. Assuming a 7 year study with 4 years of enrollment, 5 years of average follow-up, a recurrence rate of 10 % after 7 years, a 25% relative reduction in the rate of the primary endpoint (newly identified structural disease; i.e. persistent, recurrent or distant metastatic disease) with central lymph node dissection and an annual dropout rate of 3%, a total of 5,840 patients would have to be included in the study to achieve at least 80% statistical power. Similarly, given the low rates of morbidity several thousands of patients would need to be included to identify a significant difference in rates of permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injury. Conclusion: Given the low rates of both newly identified structural disease and morbidity after surgery for cN0 PTC, prohibitively large sample sizes would be required for sufficient statistical power to demonstrate significant differences in outcomes. Thus, a prospective randomized controlled trial of prophylactic central lymph node dissection in cN0 PTC is not readily feasible.
MINISEMINARS practice guideline `Improving Voice Outcomes after Thyroid Surgery.' The guideline w... more MINISEMINARS practice guideline `Improving Voice Outcomes after Thyroid Surgery.' The guideline will focus on the excision of thyroid tissue using any method or with any surgical approach and the planned perioperative assessment of the voice. Educational Objectives: (1) Understand the guideline development group's recommendations on voice in thyroid surgery. (2) Learn about the guideline's development methodology. (3) Learn about future research needs.
The aim of this study was to develop evidence-based recommendations for safe, effective and appro... more The aim of this study was to develop evidence-based recommendations for safe, effective and appropriate thyroidectomy. Background: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the United States. Methods: The medical literature from January 1, 1985 to November 9, 2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. Results: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions,
This is the author manuscript accepted for publication and has undergone full peer review but has... more This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as
Archives of Otolaryngology-head & Neck Surgery, 2008
To report the results of a multiinstitutional experience with the minimally invasive videoassiste... more To report the results of a multiinstitutional experience with the minimally invasive videoassisted thyroidectomy, which was conceived in Europe and Asia and has only recently been embraced in the United States.
OBJECTIVE To determine the association between pathologic features and molecular classes (BRAF-li... more OBJECTIVE To determine the association between pathologic features and molecular classes (BRAF-like, RAS-like, and non-BRAF-like non-RAS-like [NBNR]). METHODS Retrospective review of a merged database containing 676 patients, 84% (571/676) were assigned to a molecular class from publicly accessible sequenced data of thyroid neoplasms. RESULTS The merged cohort included 571 neoplasms: 353 (62%) BRAF-like, 172 (30%) RAS-like, and 46 (8.1%) NBNR. Lymph node metastasis (any N1 disease) was present in 166/337 (49%) of BRAF-like, 23/164 (14%) of RAS-like, and 0/46 (0%) of NBNR and are significantly different (P < .001). Gross extra-thyroidal extension was observed in 27 patients, including 24/331 (7%) of BRAF-like, 2/160 (1%) of RAS-like, and 1/46 (2%) of NBNR (P = .01). N1B lymph node metastases or T4 disease was present in 74/333 (22%) of BRAF-like, 10/160 (6%) of RAS-like, and 1/46 (2%) of NBNR (P < .0001). Distant metastasis was present in 4/151 (2.6%) of BRAF-like, 2/50 (4%) of RAS-like and 0/46 for NBNR (P = .627). Angioinvasion was present in 0/81 (0%) of BRAF-like, 3/53 (6%) of RAS-like, and 3/46 (7%) of NBNR (P = .08); and multifocality was present in 27/81 (33%) of BRAF-like, 9/53 (17%) of RAS-like, and 1/46 (2%) for NBNR (P = .0001). CONCLUSION Pathological features of metastasis, gross extra-thyroidal extension, and multifocality were more prevalent in BRAF-like samples compared to RAS-like and NBNR. A trend towards increased frequency of angioinvasion in RAS-like and NBNR cancers compared to BRAF-like samples was observed. Further studies are needed to evaluate if preoperative knowledge of molecular mutations in thyroid tumors aids in decision-making regarding extent of surgery.
Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodul... more Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further inform the risk of thyroid cancer in nodules predicted to be positive or negative by MT remains unknown. Aim: To test if clinical parameters, including patient age, gender, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] vs American College of Radiology TI-RADS systems), radiation exposure, or family history of thyroid cancer can modify the probability of thyroid cancer or NIFTP predicted by MT. Methods: We studied 257 thyroid nodules in 232 patients from 10 study centers with indeterminate fine needle aspiration cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression were used for data analysis. Results: The presence of cancer/NIFTP was associated with positive TSv3 results (OR 61.39, P<0.0001). On univariate regression, patient gender, age, and Bethesda category were associated with cancer/NIFTP probability (P<0.05 for each). Although ATA (P=0.1211) and TI-RADS (P=0.1359) US categories demonstrated positive trends, neither were significantly associated with cancer/NIFTP probability. A multivariate regression model incorporating the four most informative non-MT covariates (gender, age, Bethesda category, and ATA US pattern) (Model #1) yielded a C index of 0.653; R2=0.108. When TSv3 was added to Model #1, the C index increased to 0.888; R2=0.572. However, age (P=0.341), Bethesda category (P=0.272), and ATA US pattern (P=0.264) were nonsignificant, and other than TSv3 (P<0.0001), male gender was the only non-MT parameter that potentially contributed to cancer/NIFTP risk (P=0.095). The simplest and most efficient clinical model (#3) incorporated TSv3 and gender (C index=0.889; R2=0.588). Conclusions: In this multicenter study of thyroid nodules with indeterminate cytology and molecular testing, neither the ATA nor TI-RADS US scoring systems further informed the risk of cancer/NIFTP beyond that predicted by TSv3. Although age and Bethesda category were associated with cancer/NIFTP probability on univariate analysis, in sequential nomograms they provided limited incremental value above the high predictive ability of TSv3. Patient gender may contribute to cancer/NIFTP risk in thyroid nodules with indeterminate cytology.
IMPORTANCE Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indetermina... more IMPORTANCE Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery. OBJECTIVE To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules. DESIGN, SETTING, AND PARTICIPANTS Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules. INTERVENTIONS A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3). MAIN OUTCOMES AND MEASURES The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules. RESULTS Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%. CONCLUSIONS AND RELEVANCE In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.
The Journal of the American Osteopathic Association, 2018
Thyroid nodules are increasingly common. Although guidelines have been published, it is unclear w... more Thyroid nodules are increasingly common. Although guidelines have been published, it is unclear whether recommendations for the use of fine-needle aspiration (FNA) and ultrasonography are followed. To evaluate the impact of a quality improvement initiative regarding utilization of FNA and ultrasonography before resection of malignant thyroid neoplasms at a community-based hospital. A retrospective medical record review of patients who received thyroidectomy with histologically proven malignant thyroid neoplasms at a community-based teaching center in the Midwest in 2014 revealed inconsistent use of FNA and ultrasonography per national guidelines. Thus, a quality improvement initiative was conducted using the PDSA (Plan, Do, Study, Act) method and included both an intradepartmental outreach effort and an interdisciplinary hospital cancer committee presentation. To determine the success of the initiative, medical records were reviewed from January 1, 2015, through July 1, 2016 (after ...
BACKGROUND Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiratio... more BACKGROUND Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment. METHODS We performed a 19-month, prospective, multicenter validation study involving 49 clinical sites, 3789 patients, and 4812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. We obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules in this analysis, and its performance was assessed. RESULTS Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for "atypia (or follicular lesion) of undetermined clinical significance," "follicular neoplasm or lesion suspicious for follicular neoplasm," or "suspicious cytologic findings" were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule. CONCLUSIONS These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results. (Funded by Veracyte.
The Journal of Clinical Endocrinology & Metabolism, 2014
Background: Increasingly, patients with thyroid nodule cytology labeled atypical (or follicular l... more Background: Increasingly, patients with thyroid nodule cytology labeled atypical (or follicular lesion) of undetermined significance (AUS/FLUS) or follicular neoplasm (FN) undergo diagnostic analysis with the Afirma gene expression classifier (GEC). No long-term, multisite analysis of Afirma GEC performance has yet been performed. Methods: We analyzed all patients who had received Afirma GEC testing at five academic medical centers between 2010 and 2013. Nodule and patient characteristics, fine needle aspiration cytology, Afirma GEC results, and subsequent clinical or surgical follow-up were obtained for 339 patients. Results were analyzed for pooled test performance, impact on clinical care, and site-tosite variation. Results: Three hundred thirty-nine patients underwent Afirma GEC testing of cytologically indeterminate nodules (165 AUS/FLUS; 161 FN; 13 suspicious for malignancy) and 174 of 339 (51%) indeterminate nodules were GEC benign, whereas 148 GEC were suspicious (44%). GEC results significantly altered care recommendations, as 4 of 175 GEC benign were recommended for surgery in comparison to 141 of 149 GEC suspicious (P Ͻ .01). Of 121 Cyto Indeterminate/GEC Suspicious nodules surgically removed, 53 (44%) were malignant. Variability in site-to-site GEC performance was confirmed, as the proportion of GEC benign varied up to 29% (P ϭ .58), whereas the malignancy rate in nodules cytologically indeterminate/GEC suspicious varied up to 47% (P ϭ .11). Seventy-one of 174 GEC benign nodules had documented clinical follow-up for an average of 8.5 months, in which 1 of 71 nodules proved cancerous. Conclusions: These multicenter, clinical experience data confirm originally published Afirma GEC test performance and demonstrate its substantial impact on clinical care recommendations. Although nonsignificant site-to-site variation exists, such differences should be anticipated by the practicing clinician. Follow-up of GEC benign nodules thus far confirm the clinical utility of this diagnostic test.
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Papers by David Steward