Correspondence
Preoperative BRAF(V600E) Mutation Screening Is Unlikely to Alter Initial Surgical Treatment of Patients With Indeterminate Thyroid Nodules A Prospective Case Series of 960 Patients With great interest we read the article by Kleiman et al that addressed the putative added value of preoperative BRAF(V600E) analysis to the initial surgical strategy.1 Because the basic surgical strategy for indeterminate thyroid nodules differs between many US centers and those in Europe, we propose that the data from Kleiman et al1 might lead to an opposite conclusion regarding the use of preoperative BRAF testing in the European setting. To substantiate this hypothesis, we have used data from the Netherlands Cancer Registry. As pointed out by Kleiman et al,1 the standard surgical approach to indeterminate thyroid nodules in the United States is to perform a total thyroidectomy on all patients with Bethesda category V nodules and on all nodules with “worrisome cytologic features” (eg, nuclear grooves and pseudoinclusions). Because 12 of the 13 patients with BRAF mutations had already undergone total thyroidectomy as the initial procedure based on their cytology findings, routine preoperative BRAF testing would have altered the surgery in only 1 patient. In contrast to the situation in many US centers, in the Netherlands, as well as in large parts of Europe, a diagnostic hemithyroidectomy is performed routinely on all patients with indeterminate fine-needle aspiration results. If the final histology reveals malignancy, a completion thyroidectomy is performed as second-stage surgery. In the Netherlands, 459 patients were diagnosed with differentiated thyroid cancer in 2011. In the flowchart in their study (Fig. 1), Kleiman et al did not differentiate between Bethesda category III/IV and Bethesda category V nodules. Nonetheless, we could extract this from the text and tables. In short, 36 of the indeterminate results (12%) were Bethesda category V; of those 36 results, 26 (72%) were malignant, and of those 26, 11 (31%) were BRAF positive. When we apply these results to our nationwide data, using the same distribution of relative ratios as found by Kleiman et al, we would have had 42 patients with Bethesda category V nodules. Of those 42 patients, 30 (71%) would have had a malignancy, 13 Cancer
April 1, 2014
of which (31%) would comprise a BRAF(V600E) mutation. Hence, by performing preoperative BRAF(V600E) analysis in the group of patients with Bethesda category V nodules, these 13 patients of the 42 patients examined (31%) would have benefited because their initial surgical treatment would have been changed to total thyroidectomy, and a 2-stage procedure could have been avoided. This would involve a significant benefit, including a shortened period of uncertainty for the patient, the avoidance of a second surgery, and a significant reduction in the time between diagnosis and final treatment. Of course, we realize that our analysis is not statistically flawless. For practical reasons, we have relied on the assumption that cytology scores in our country are not significantly different from those in the United States. This assumption is supported by 2 other studies describing comparable ratios of indeterminate cytology results and BRAF(V600E) positivity.2,3 Subsequently, we performed a rough estimate as to whether the BRAF(V600E) mutation analysis could be cost-effective. If only Bethesda category V nodules are tested, 42 BRAF(V600E) tests have to be performed to detect 13 BRAF(V600E) mutations. A calculation based on the costs of hemithyroidectomy and total thyroidectomy in our institution demonstrated that this would not lead to a significant increase in costs. Based on the notion that the Dutch approach is comparable to the strategy used in large parts of Europe, the introduction of preoperative BRAF testing on Bethesda category V nodules could make a difference. A considerable number of patients might be spared unnecessary 2-stage surgery without increasing the total costs of the treatment. We therefore propose that the impact of preoperative BRAF(V600E) testing of indeterminate thyroid nodules on initial surgical management is predominantly dependent on the routine initial surgical strategy that is adhered to. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Kleiman DA, Sporn MJ, Beninato T, et al. Preoperative BRAF(V600E) mutation screening is unlikely to alter initial surgical treatment of patients with indeterminate thyroid nodules: a prospective case series of 960 patients. Cancer. 2013;119:1495-1502. 2. Moses W, Weng J, Sansano I, et al. Molecular testing for somatic mutations improves the accuracy of thyroid fine-needle aspiration biopsy. World J Surg. 2010;34:2589-2594.
1083
Correspondence 3. Musholt TJ, Fottner C, Weber MM, et al. Detection of papillary thyroid carcinoma by analysis of BRAF and RET/PTC1 mutations in fine-needle aspiration biopsies of thyroid nodules. World J Surg. 2010;34:2595-2603.
Lutske Lodewijk, MD Jakob W. Kist, MD Gerlof D. Valk, MD, PhD Menno R. Vriens, MD, PhD Inne H.M. Borel Rinkes, MD, PhD Department of Surgery University Medical Center Utrecht Utrecht, the Netherlands DOI: 10.1002/cncr.28526, Published online December 18, 2013 in Wiley Online Library (wileyonlinelibrary.com)
Reply to Preoperative BRAF(V600E) Mutation Screening Is Unlikely to Alter Initial Surgical Treatment of Patients With Indeterminate Thyroid Nodules
2 BRAF(V600E) mutations. Although we have not formally performed the calculations, we doubt that most centers would find this to be a cost-effective strategy given such a low pretest probability of identifying a mutation. Ultimately, we believe that the most effective use of preoperative BRAF(V600E) screening is for patients who have worrisome thyroid nodules and are resistant to commit to a total thyroidectomy because of the 20% to 30% chance that the nodule is benign, meaning that they have unnecessarily committed to lifelong thyroid hormone replacement therapy. Selectively offering those patients preoperative BRAF(V600E) screening may result in preoperative confirmation of malignancy and thereby avoid a 2-stage procedure. Although the management of Bethesda category V nodules may differ between centers, the management of Bethesda III and IV nodules is less variable. Therefore, the main conclusion of our study1 that preoperative BRAF(V600E) should not routinely be performed on all patients with Bethesda category III and IV nodules due to the very low likelihood of identifying a mutation among this subgroup is likely to apply to most centers within the United States and abroad. FUNDING SUPPORT
A Prospective Case Series of 960 Patients We greatly appreciate the thoughtful comments provided by our colleagues from University Medical Center Utrecht regarding our article.1 The authors made a valid point that the implications of our study are largely dependent on institutional practice patterns. As noted, it is the practice at our institution to recommend a total thyroidectomy as the initial surgical procedure for patients with Bethesda category V nodules and Bethesda category III nodules with particularly worrisome atypical features. However, this is not the case at all centers worldwide, and there is even discrepancy among centers within the United States. Therefore, any surgeon who always recommends a hemithyroidectomy for any nodule that is not determined to be clearly malignant on preoperative fine-needle aspiration may come to an opposite conclusion to the one that we have proposed. We generally agree with Lodewijik et al that if preoperative BRAF(V600E) screening is to be offered, it is likely to be most beneficial to patients with Bethesda category V nodules as opposed to those with Bethesda III and IV nodules. As reported in our study,1 the sensitivity of BRAF screening for detecting malignancy among patients with Bethesda III and IV nodules was only 3% compared with 42% among patients with Bethesda V nodules. To follow on the argument proposed by Lodewijik et al, 272 Bethesda III or IV nodules had to be tested to detect 1084
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Kleiman DA, Sporn MJ, Beninato T, et al. Preoperative BRAF(V600E) mutation screening is unlikely to alter initial surgical treatment of patients with indeterminate thyroid nodules: a prospective case series of 960 patients. Cancer. 2013;119:1495-1502.
David A. Kleiman, MD Rasa Zarnegar, MD Thomas J. Fahey III, MD Department of Surgery New York Presbyterian Hospital-Weill Cornell Medical College New York, New York DOI: 10.1002/cncr.28529, Published online December 18, 2013 in Wiley Online Library (wileyonlinelibrary.com)
Risk of Recurrence of Ductal Carcinoma In Situ by Oncotype Dx Technology: Some Concerns Predicting which patients with ductal carcinoma in situ (DCIS) will develop local disease recurrence: we have Cancer
April 1, 2014
Preoperative BRAF(V600E) Mutation Screening Is Unlikely to Alter Initial Surgical Treatment of Patients With Indeterminate Thyroid Nodules A Prospective Case Series of 960 Patients With great interest we read the article by Kleiman et al that addressed the putative added value of preoperative BRAF(V600E) analysis to the initial surgical strategy.1 Because the basic surgical strategy for indeterminate thyroid nodules differs between many US centers and those in Europe, we propose that the data from Kleiman et al1 might lead to an opposite conclusion regarding the use of preoperative BRAF testing in the European setting. To substantiate this hypothesis, we have used data from the Netherlands Cancer Registry. As pointed out by Kleiman et al,1 the standard surgical approach to indeterminate thyroid nodules in the United States is to perform a total thyroidectomy on all patients with Bethesda category V nodules and on all nodules with “worrisome cytologic features” (eg, nuclear grooves and pseudoinclusions). Because 12 of the 13 patients with BRAF mutations had already undergone total thyroidectomy as the initial procedure based on their cytology findings, routine preoperative BRAF testing would have altered the surgery in only 1 patient. In contrast to the situation in many US centers, in the Netherlands, as well as in large parts of Europe, a diagnostic hemithyroidectomy is performed routinely on all patients with indeterminate fine-needle aspiration results. If the final histology reveals malignancy, a completion thyroidectomy is performed as second-stage surgery. In the Netherlands, 459 patients were diagnosed with differentiated thyroid cancer in 2011. In the flowchart in their study (Fig. 1), Kleiman et al did not differentiate between Bethesda category III/IV and Bethesda category V nodules. Nonetheless, we could extract this from the text and tables. In short, 36 of the indeterminate results (12%) were Bethesda category V; of those 36 results, 26 (72%) were malignant, and of those 26, 11 (31%) were BRAF positive. When we apply these results to our nationwide data, using the same distribution of relative ratios as found by Kleiman et al, we would have had 42 patients with Bethesda category V nodules. Of those 42 patients, 30 (71%) would have had a malignancy, 13 Cancer
April 1, 2014
of which (31%) would comprise a BRAF(V600E) mutation. Hence, by performing preoperative BRAF(V600E) analysis in the group of patients with Bethesda category V nodules, these 13 patients of the 42 patients examined (31%) would have benefited because their initial surgical treatment would have been changed to total thyroidectomy, and a 2-stage procedure could have been avoided. This would involve a significant benefit, including a shortened period of uncertainty for the patient, the avoidance of a second surgery, and a significant reduction in the time between diagnosis and final treatment. Of course, we realize that our analysis is not statistically flawless. For practical reasons, we have relied on the assumption that cytology scores in our country are not significantly different from those in the United States. This assumption is supported by 2 other studies describing comparable ratios of indeterminate cytology results and BRAF(V600E) positivity.2,3 Subsequently, we performed a rough estimate as to whether the BRAF(V600E) mutation analysis could be cost-effective. If only Bethesda category V nodules are tested, 42 BRAF(V600E) tests have to be performed to detect 13 BRAF(V600E) mutations. A calculation based on the costs of hemithyroidectomy and total thyroidectomy in our institution demonstrated that this would not lead to a significant increase in costs. Based on the notion that the Dutch approach is comparable to the strategy used in large parts of Europe, the introduction of preoperative BRAF testing on Bethesda category V nodules could make a difference. A considerable number of patients might be spared unnecessary 2-stage surgery without increasing the total costs of the treatment. We therefore propose that the impact of preoperative BRAF(V600E) testing of indeterminate thyroid nodules on initial surgical management is predominantly dependent on the routine initial surgical strategy that is adhered to. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Kleiman DA, Sporn MJ, Beninato T, et al. Preoperative BRAF(V600E) mutation screening is unlikely to alter initial surgical treatment of patients with indeterminate thyroid nodules: a prospective case series of 960 patients. Cancer. 2013;119:1495-1502. 2. Moses W, Weng J, Sansano I, et al. Molecular testing for somatic mutations improves the accuracy of thyroid fine-needle aspiration biopsy. World J Surg. 2010;34:2589-2594.
1083
Correspondence 3. Musholt TJ, Fottner C, Weber MM, et al. Detection of papillary thyroid carcinoma by analysis of BRAF and RET/PTC1 mutations in fine-needle aspiration biopsies of thyroid nodules. World J Surg. 2010;34:2595-2603.
Lutske Lodewijk, MD Jakob W. Kist, MD Gerlof D. Valk, MD, PhD Menno R. Vriens, MD, PhD Inne H.M. Borel Rinkes, MD, PhD Department of Surgery University Medical Center Utrecht Utrecht, the Netherlands DOI: 10.1002/cncr.28526, Published online December 18, 2013 in Wiley Online Library (wileyonlinelibrary.com)
Reply to Preoperative BRAF(V600E) Mutation Screening Is Unlikely to Alter Initial Surgical Treatment of Patients With Indeterminate Thyroid Nodules
2 BRAF(V600E) mutations. Although we have not formally performed the calculations, we doubt that most centers would find this to be a cost-effective strategy given such a low pretest probability of identifying a mutation. Ultimately, we believe that the most effective use of preoperative BRAF(V600E) screening is for patients who have worrisome thyroid nodules and are resistant to commit to a total thyroidectomy because of the 20% to 30% chance that the nodule is benign, meaning that they have unnecessarily committed to lifelong thyroid hormone replacement therapy. Selectively offering those patients preoperative BRAF(V600E) screening may result in preoperative confirmation of malignancy and thereby avoid a 2-stage procedure. Although the management of Bethesda category V nodules may differ between centers, the management of Bethesda III and IV nodules is less variable. Therefore, the main conclusion of our study1 that preoperative BRAF(V600E) should not routinely be performed on all patients with Bethesda category III and IV nodules due to the very low likelihood of identifying a mutation among this subgroup is likely to apply to most centers within the United States and abroad. FUNDING SUPPORT
A Prospective Case Series of 960 Patients We greatly appreciate the thoughtful comments provided by our colleagues from University Medical Center Utrecht regarding our article.1 The authors made a valid point that the implications of our study are largely dependent on institutional practice patterns. As noted, it is the practice at our institution to recommend a total thyroidectomy as the initial surgical procedure for patients with Bethesda category V nodules and Bethesda category III nodules with particularly worrisome atypical features. However, this is not the case at all centers worldwide, and there is even discrepancy among centers within the United States. Therefore, any surgeon who always recommends a hemithyroidectomy for any nodule that is not determined to be clearly malignant on preoperative fine-needle aspiration may come to an opposite conclusion to the one that we have proposed. We generally agree with Lodewijik et al that if preoperative BRAF(V600E) screening is to be offered, it is likely to be most beneficial to patients with Bethesda category V nodules as opposed to those with Bethesda III and IV nodules. As reported in our study,1 the sensitivity of BRAF screening for detecting malignancy among patients with Bethesda III and IV nodules was only 3% compared with 42% among patients with Bethesda V nodules. To follow on the argument proposed by Lodewijik et al, 272 Bethesda III or IV nodules had to be tested to detect 1084
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Kleiman DA, Sporn MJ, Beninato T, et al. Preoperative BRAF(V600E) mutation screening is unlikely to alter initial surgical treatment of patients with indeterminate thyroid nodules: a prospective case series of 960 patients. Cancer. 2013;119:1495-1502.
David A. Kleiman, MD Rasa Zarnegar, MD Thomas J. Fahey III, MD Department of Surgery New York Presbyterian Hospital-Weill Cornell Medical College New York, New York DOI: 10.1002/cncr.28529, Published online December 18, 2013 in Wiley Online Library (wileyonlinelibrary.com)
Risk of Recurrence of Ductal Carcinoma In Situ by Oncotype Dx Technology: Some Concerns Predicting which patients with ductal carcinoma in situ (DCIS) will develop local disease recurrence: we have Cancer
April 1, 2014
