LETTER TO THE EDITOR How Do You Calculate the Sensitivity of Preoperative Ultrasonography-guided Fine Needle Aspiration (FNA) for Axillary Staging in Breast Cancer? To the Editor: was interested to read the article by Houssami et al.1 In the article, I was surprised to find the figures quoted for the median sensitivity of ultrasonography-guided needle biopsy for axillary nodes to be as high as 79.6%. This was because when reading the sensitivity figures for 2 of the larger studies2,3 included in the systematic review I found that their figures did not at all correlate with the actual figures in their respective articles. Barauh et al2 in their study of 502 patients who underwent axillary staging with ultrasonography, found 74 with suspicious appearing nodes and performed fine-needle aspiration (FNA). Of these 74 patients, 39 were found to have positive cytology and directed straight to axillary lymph node dissection (ALND). The remainder of the 463 patients went on to have sentinel lymph node biopsy (SLNB). The total number of patients to return with positively involved sentinel lymph nodes were 137 of the 502. This means that the sensitivity of preoperative ultrasonography-guided FNA for identifying axillary lymph node metastases is 28.5% (39/137) and 39 patients benefited from avoidance of SLNB by being fast tracked directly to ALND path. However, in the analysis by Houssami et al,1 to create their forest plot they have used the figure of 74 as their denominator for the total number of patients in the study by Barauh et al.2 They have only considered the number of patients who underwent ultrasonography and FNA in their analysis and have excluded the remaining 428 who were also assessed by ultrasonography. In so doing, they are able to create a figure for the sensitivity of the study by Barauh et al2 of 73.5%, which could be misinterpreted. It gives the impression that the sensitivity of the study by Barauh et al2 is 3 times the true value as calculated by the original authors and overestimates the sensitivity of ultrasonography-
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Disclosure: The authors have no disclosures to make concerning financial and personal relationships with other people or organizations that could inappropriately influence their work. C 2015 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/15/26201-e0022 DOI: 10.1097/SLA.0000000000000414
e22 | www.annalsofsurgery.com
guided FNA/biopsy. Similarly for the study of Van Rijk et al,3 the denominator for calculations consists only of the 58 patients who underwent ultrasonography and FNA/biopsy, excluding the remaining 674 patients. This means again that in the calculation by Houssami et al,1 they find the sensitivity for Van Rijk et al3 to be 61.7%, when the study itself by the authors themselves quotes their results as 21%. The authors conclude that ultrasound biopsy of the axilla is accurate for the initial staging of the women with invasive breast cancer when their calculations only apply to the minority of these patients who required biopsy based on radiological opinion. In order to provide an accurate representation of the sensitivity it is essential to ensure that the total population which underwent ultrasonography imaging in each study is considered and the number of true positive results from the whole cohort including those undergoing ultrasonography but not undergoing FNA or biopsy are considered. Only in this way is it possible to ascertain an accurate determination of the sensitivity of ultrasonography-guided FNA/biopsy and the number of patients who are able to avoid unnecessary SLNB and go directly to ALND. Muneer Ahmed, MBBS, BSc (Hons), MA, MRCSEd Michael Douek, MD, FRCS Breast Surgery King’s College London Great Maze Pond, London, UK [email protected]
REFERENCES 1. Houssami N, Ciatto S, Turner RM, et al. Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla. Ann Surg. 2011;254:243–251. 2. Baruah BP, Goyal A, Young P, et al. Axillary node staging by ultrasonography and fine-needle aspiration cytology in patients with breast cancer. Br J Surg. 2010;97:680–683. 3. van Rijk MC, Deurloo EE, Nieweg OE, et al. Ultrasonography and fine-needle aspiration cytology can spare breast cancer patients unnecessary sentinel lymph node biopsy. Ann Surg Oncol. 2006;13:31– 35.
Reply: ur meta-analysis of the accuracy and utility of axillary node needle biopsy focused on ultrasound-guided fine needle biopsy or core needle biopsy (collectively re1 ferred to as UNB). The answer to the question title raised by the letter from Ahmed2 is conditional to the defined index test one proposes
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Disclosure: The authors declare no conflicts of interest. 10.1097/SLA.0000000000000415
to evaluate. We explicitly defined UNB as the index test in the Methods section of our metaanalysis, hence to determine test accuracy we modeled data on subjects who underwent the index test. We did not model ultrasound data and UNB data as a combination testing strategy, because this addresses a slightly different question to that investigated in our accuracy models for UNB, a question which is nonetheless clinically relevant and is being addressed through a related meta-analysis (in progress) from our team. We are delighted that study-specific data from our meta-analysis were scrutinized by others2 and point out that our forest plots displayed all extracted data for subjects who had UNB (numbers that were true or false positive, and true or 1 false negative, Figure 1) to ensure complete transparency about the data included in the analysis. Despite the clarity on our part, our analyses appear to have been misinterpreted.2 Ahmed’s letter incorrectly states that we reported a median sensitivity for UNB. Again, we refer to the Methods of our meta-analysis; we modeled data to estimate pooled sensitivity (and also pooled specificity), which differs analytically to descriptive study-level statistics such as the median sensitivity. To model and pool data across studies using various definitions, metaanalysis necessitates consistent definitions for the numerator and denominator (put simply, this avoids mixing apples and oranges). To model sensitivity and specificity of UNB, we defined data in terms of the number of women who underwent the index test and hence the 1 true or false positives (or negatives) for UNB. Here it should be noted that studies of axillary node needle biopsy were heterogeneous with regard to whether they defined subjects in terms of all breast cancer patients, or those who had undergone ultrasonography, or those who had UNB. Because of this heterogeneity, we additionally presented the total number of subjects as well as the number of patients 1 who had UNB (Table 1) to inform readers about the number of women selected to UNB from the total number of breast cancer patients. Furthermore, because ultrasound sensitivity substantially affects UNB accuracy (shown in our models of covariates, Table 2) and given the variability across studies as to whether or not ultrasound-specific data were provided, we presented modeled estimates of UNB accuracy stratified by ultrasound sensi1 tivity (Figure 3). The information displayed in Figure 3 allows readers to understand the accuracy of UNB in the context of the variability in ultrasound sensitivity. To avoid fragmented consideration of our meta-analysis’ results, leading to potential misinterpretation, we strongly encourage readers to peruse our findings on UNB accuracy jointly with those we reported on UNB
Annals of Surgery r Volume 262, Number 1, July 2015
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 262, Number 1, July 2015
1
clinical utility (Table 1). We reported the proportion of all patients triaged directly to axillary surgery on the basis of UNB result (19.8%), and the proportion of all patients with metastatic axillary nodes potentially triaged directly to axillary surgery on the basis of UNB (55.2%) to help clinicians judge its utility as a triage test to axillary surgery. These results mean that although UNB has moderate to good sensitivity in patients who 1 had undergone the test (Table 1) only an approximate half of breast cancer patients harboring metastatic axillary nodes can be identified preoperatively and potentially triaged to axillary surgery using UNB, translating to a modest proportion (
I
Disclosure: The authors have no disclosures to make concerning financial and personal relationships with other people or organizations that could inappropriately influence their work. C 2015 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/15/26201-e0022 DOI: 10.1097/SLA.0000000000000414
e22 | www.annalsofsurgery.com
guided FNA/biopsy. Similarly for the study of Van Rijk et al,3 the denominator for calculations consists only of the 58 patients who underwent ultrasonography and FNA/biopsy, excluding the remaining 674 patients. This means again that in the calculation by Houssami et al,1 they find the sensitivity for Van Rijk et al3 to be 61.7%, when the study itself by the authors themselves quotes their results as 21%. The authors conclude that ultrasound biopsy of the axilla is accurate for the initial staging of the women with invasive breast cancer when their calculations only apply to the minority of these patients who required biopsy based on radiological opinion. In order to provide an accurate representation of the sensitivity it is essential to ensure that the total population which underwent ultrasonography imaging in each study is considered and the number of true positive results from the whole cohort including those undergoing ultrasonography but not undergoing FNA or biopsy are considered. Only in this way is it possible to ascertain an accurate determination of the sensitivity of ultrasonography-guided FNA/biopsy and the number of patients who are able to avoid unnecessary SLNB and go directly to ALND. Muneer Ahmed, MBBS, BSc (Hons), MA, MRCSEd Michael Douek, MD, FRCS Breast Surgery King’s College London Great Maze Pond, London, UK [email protected]
REFERENCES 1. Houssami N, Ciatto S, Turner RM, et al. Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla. Ann Surg. 2011;254:243–251. 2. Baruah BP, Goyal A, Young P, et al. Axillary node staging by ultrasonography and fine-needle aspiration cytology in patients with breast cancer. Br J Surg. 2010;97:680–683. 3. van Rijk MC, Deurloo EE, Nieweg OE, et al. Ultrasonography and fine-needle aspiration cytology can spare breast cancer patients unnecessary sentinel lymph node biopsy. Ann Surg Oncol. 2006;13:31– 35.
Reply: ur meta-analysis of the accuracy and utility of axillary node needle biopsy focused on ultrasound-guided fine needle biopsy or core needle biopsy (collectively re1 ferred to as UNB). The answer to the question title raised by the letter from Ahmed2 is conditional to the defined index test one proposes
O
Disclosure: The authors declare no conflicts of interest. 10.1097/SLA.0000000000000415
to evaluate. We explicitly defined UNB as the index test in the Methods section of our metaanalysis, hence to determine test accuracy we modeled data on subjects who underwent the index test. We did not model ultrasound data and UNB data as a combination testing strategy, because this addresses a slightly different question to that investigated in our accuracy models for UNB, a question which is nonetheless clinically relevant and is being addressed through a related meta-analysis (in progress) from our team. We are delighted that study-specific data from our meta-analysis were scrutinized by others2 and point out that our forest plots displayed all extracted data for subjects who had UNB (numbers that were true or false positive, and true or 1 false negative, Figure 1) to ensure complete transparency about the data included in the analysis. Despite the clarity on our part, our analyses appear to have been misinterpreted.2 Ahmed’s letter incorrectly states that we reported a median sensitivity for UNB. Again, we refer to the Methods of our meta-analysis; we modeled data to estimate pooled sensitivity (and also pooled specificity), which differs analytically to descriptive study-level statistics such as the median sensitivity. To model and pool data across studies using various definitions, metaanalysis necessitates consistent definitions for the numerator and denominator (put simply, this avoids mixing apples and oranges). To model sensitivity and specificity of UNB, we defined data in terms of the number of women who underwent the index test and hence the 1 true or false positives (or negatives) for UNB. Here it should be noted that studies of axillary node needle biopsy were heterogeneous with regard to whether they defined subjects in terms of all breast cancer patients, or those who had undergone ultrasonography, or those who had UNB. Because of this heterogeneity, we additionally presented the total number of subjects as well as the number of patients 1 who had UNB (Table 1) to inform readers about the number of women selected to UNB from the total number of breast cancer patients. Furthermore, because ultrasound sensitivity substantially affects UNB accuracy (shown in our models of covariates, Table 2) and given the variability across studies as to whether or not ultrasound-specific data were provided, we presented modeled estimates of UNB accuracy stratified by ultrasound sensi1 tivity (Figure 3). The information displayed in Figure 3 allows readers to understand the accuracy of UNB in the context of the variability in ultrasound sensitivity. To avoid fragmented consideration of our meta-analysis’ results, leading to potential misinterpretation, we strongly encourage readers to peruse our findings on UNB accuracy jointly with those we reported on UNB
Annals of Surgery r Volume 262, Number 1, July 2015
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 262, Number 1, July 2015
1
clinical utility (Table 1). We reported the proportion of all patients triaged directly to axillary surgery on the basis of UNB result (19.8%), and the proportion of all patients with metastatic axillary nodes potentially triaged directly to axillary surgery on the basis of UNB (55.2%) to help clinicians judge its utility as a triage test to axillary surgery. These results mean that although UNB has moderate to good sensitivity in patients who 1 had undergone the test (Table 1) only an approximate half of breast cancer patients harboring metastatic axillary nodes can be identified preoperatively and potentially triaged to axillary surgery using UNB, translating to a modest proportion (
